WO1997024340A1 - Oxazole derivatives, their production and use - Google Patents

Oxazole derivatives, their production and use Download PDF

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Publication number
WO1997024340A1
WO1997024340A1 PCT/JP1996/003857 JP9603857W WO9724340A1 WO 1997024340 A1 WO1997024340 A1 WO 1997024340A1 JP 9603857 W JP9603857 W JP 9603857W WO 9724340 A1 WO9724340 A1 WO 9724340A1
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Prior art keywords
substituted
alkoxy
alkyl
halogen
amino
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PCT/JP1996/003857
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French (fr)
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Yoshihiro Sugihara
Naoto Uchibayashi
Koichi Matsumura
Yukimasa Nozaki
Yuzo Ichimori
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Takeda Chemical Industries, Ltd.
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Priority to AU12094/97A priority Critical patent/AU1209497A/en
Publication of WO1997024340A1 publication Critical patent/WO1997024340A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/46—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates to oxazole deriva ⁇ tives having inhibitory activity of interleukin-6 (IL- 6) activity and that of nitrogen monoxide (NO) production of NOS inducible cells, which are of value as medicines for prophylaxis and therapy of heart diseases, autoimmune diseases, inflammatory diseases and diseases accompanied by granuloma, among other morbidities, to processes for its production, and to pharmaceutical compositions comprising said derivatives.
  • IL-6 interleukin-6
  • NO nitrogen monoxide
  • Interleukin-6 (hereinafter referred to briefly as IL-6) is a glycoprotein with a molecular mass of 26kDa as initially cloned as B-cell stimulatory factor. This cytokine is produced in T- and B-lymphocytes, onocytes, fibroblasts, keratinocytes, vascular endothelial cells, renal mesangial cells, brain astrocytes and osteoblasts. Its multifunctional physiological activity encompasses the immune system, hematopoietic system, cerebroneural system, inflammatory system, endocrine system, etc.
  • IL-6 specifically functions as 1) antibody production inducing factor, 2) hybridoma/plasmacytoma/myeloma growth factor, 3) T-lymphocyte growth factor/killer T- cell differentiation factor, 4) hematopoietic stem cell growth factor, 5) megakaryocyte maturation factor/platelet proliferation factor, 6) nerve cell stimulating factor, 7) hepatocyte stimulatory factor, 8) osteoclast activating factor, 9) renal mesangial cell growth factor, and 10) ACTH production inducing factor, etc. [The Cytokine Handbook, 2nd Ed., Academic Press, USA., pp.145-168 (1994)].
  • IL-6 has been to be involved in the various diseases, namely cardiac diseases such as myocardiopathy, cardiac hypertrophy, myocardial infarc ⁇ tion, angina pectoris, etc., various autoimmune diseases such as chronic rheumatoid arthritis, systemic lupus erythematosus, systemic scleroderma, rheumatic fever, poly yositis, periarteritis nodosa, Sjogren's syndrome, Behcet's disease, Castleman's disease, autoimmune hemolytic anemia, etc., inflammatory diseases such as mesangial proliferative nephritis, IgA nephritis, lupus nephritis, osteoporosis, bronchial asthma, atopic dermatitis, psoriasis, pleurisy, ulcerative colitis, atherosclerosis, active chronic hepatitis, alcoholic cirrhosis, gout
  • IL-6 in human proliferative glomerulonephritis inclusive of IgA nephritis, the urinary IL-6 level is elevated in proportion to the degree of progression of tissue damage and, therefore, IL-6 is utilized as a clinical marker.
  • IL-6 acts as osteoclast activating factor and exhibits potent bone resorption activity.
  • osteoclasts proliferate but this proliferation is inhibited by anti-IL-6 antibody [Science, 257. 88-91 (1992)].
  • IL-6 gene-deficient mice no bone destruction took place even after ovariectomy.
  • Nitrogen monoxide is considered to play multi-faceted roles in the mammalian body, for example as a vasodilating factor in the vascular system [Pharmacol. Rev. li, 109-142 (1991)], as a factor having tumoricidal and germicidal activity in the leukocytic system [Curr. Opin. Immunol., 3., 65-70 (1991)], and as a neurotransmitter in the nervous system, among others [Neuron, £, 3-11 (1992)].
  • NO is produced from L-arginine by NO synthase (NOS).
  • NOS NO synthase
  • cNOS exists in the vascular endothelial cells and nerve cells.
  • cNOS is calcium/calmodulin-dependent and activated by various receptor stimuli to produce a small amount of NO, thus carrying out the physiological modulations mentioned above.
  • iNOS is induced by various cytokines and bacterial lipopolysaccharides (LPS) in the macrophages and neutrophils and it has been pointed out that because it produces a large amount of NO persistently, iNOS not only shows the above-mentioned physiological activities but, when produced locally, injures the cells and tissues [Immunol. Today, 13. 157-160 (1992)].
  • iNOS vascular smooth muscle cells
  • vascular endothelial cells vascular endothelial cells
  • myocardial cells mesangial cells
  • chondrocytes sinovial cells
  • pancreatic ⁇ cells and osteoclasts are known [FASEB J., £, 3051-3064 (1992), Arch Surg. , 12JB_, 396-401 (1993), J. Biol . Chem., 4_4, 27580-27588 (1994), J. Cell. Biochem., 57, 399-408 (1995)].
  • any substance that inhibits production and release of NO from cells in which iNOS has been induced is expected to be of value as a drug for prevention and therapy of various NO- associated diseases such as, for example, atherosclerosis, myocarditis, myocardiopathy, ischemic brain disorder, Alzheimer's disease, multiple sclerosis, septicemia, chronic rheumatoid arthritis, osteoarthritis, gastric ulcer, duodenal ulcer, ulcerative colitis, diabetes, glomerulonephritis, osteoporosis, pneumonia, hepatitis, graft rejection and pain.
  • various NO- associated diseases such as, for example, atherosclerosis, myocarditis, myocardiopathy, ischemic brain disorder, Alzheimer's disease, multiple sclerosis, septicemia, chronic rheumatoid arthritis, osteoarthritis, gastric ulcer, duodenal ulcer, ulcerative colitis, diabetes, glomerulonephritis, osteoporosis, pneumonia, hepatitis,
  • L-arginine analogues [Pharmacol. Rev., ⁇ , 109-142 (1991)], a ino- guanidine [Br. J. Pharmacol., 110. 963-968 (1993), and S-ethylisothiourea [J. Biol. Chem., 4_3_, 26669-26676 (1994)], among others, have been reported for use as inhibitors of iNOS. However, these compounds are either not sufficiently active or inhibit not only iNOS but also cNOS which is in charge of physiological functions.
  • oxazole derivatives having a group bonded through a sulfinyl or sulfonyl moiety at the 5-position of the oxazole ring have excellent IL-6 inhibitory activity and NO production inhibitory activity of NOS inducible cells and are effective in the prevention and therapy of heart diseases, autoimmune diseases, inflammatory diseases, and diseases accompanied by granuloma.
  • the inventors thenceforth did further research and have completed the present invention.
  • the present invention accordingly provides:
  • R represents a C ⁇ hydrocarbon group which may be substituted, a 5- to 8-membered heterocyclic group containing at least 1 atom selected from nitrogen, oxygen, and sulfur, which may be substituted, or amino which may be substituted;
  • R represents hydrogen, cyano, an organic carboxylic acid-derived acyl group, carbamoyl which may be substi ⁇ tuted, thiocarbamoyl which may be substituted, a C ⁇ ,, hydrocarbon group which may be substituted, a 5- to 8- membered heterocyclic group containing at least 1 atom selected from nitrogen, oxygen, and sulfur, which may be substituted, amino which may be substituted, or carboxyl which may be esterified;
  • R represents hydrogen, halogen, a C L _ 19 hydrocarbon group which may be substituted, a 5- to 8-membered heterocyclic group containing at least 1 atom selected from nitrogen, oxygen, and sulfur, which may be substituted, a C 19 hydrocarbon-oxy group which may be substituted, amino which may be substituted, carboxyl which may be esterified, or a group of the formula -S(0)m-R'; where R' represents a C,. 19 hydrocarbon group which may be substituted or a 5- to 8-member
  • C,. 19 alkyl which may be substituted with (i) a 5- or 6-membered sulfur-containing heterocyclic group,
  • aralkyl which may be substituted with (i) halogen, (ii) alkoxy, (iii) amino which may be substituted with (a) C 6 . arylsulfonyl which may be substituted with alkyl or (b) C j .. 12 alkylsulfonyl, or (iv) nitro,
  • a 5- or 6-membered nitrogen- or oxgen-containing heterocyclic group (8) amino which may be substituted with (i) C ⁇ _ 12 alkyl which may be substituted with (a) C,_ ⁇ 2 alkoxy-carbonyl, (b) mono- or alkylamino or (c) a 5- or 6- membered nitrogen-containing heterocyclic group, (ii) C 7 _ 19 aralkyl which may be substituted with halogen or C._ 12 alkoxy, (iii) C 4 . 12 bridged-ring hydrocarbon group, (iv) C 6 . u aryl or (v) C 3 . 10 cycloalkyl or (9) thienopyrimidylhydrazino which may be substituted with C,_ 12 alkyl;
  • C 12 alkyl which may be substituted with (i) thienyl, (ii) oxazolyl which may be substituted with Ci_ 6 alkyl or cyano, (iii) carboxy, (iv) C 6 . 12 arylcarbonyl, (v) cyano, (vi) carbamoyl which may be mono- or di-substituted with C,_ 6 alkyl, or (vii) C 6 alkoxy-carbonyl,
  • C 6 . 12 aryl which may be substituted with (i) halogen, (ii) C._ 6 alkoxy, (iii) amino which may be substituted with (a) carbamoyl which is substituted with Ci.s alkyl or C 3 _ 8 cycloalkyl, (b) C 6 . 12 arylsulfonyl which may substituted with halogen or (c) C ⁇ alkylsulfonyl, (iv) Cj.g alkyl which may be substituted with halogen (v) nitro or (vi) hydroxy,
  • a heterocyclic group selected from the group consisting of pyrimidyl, piperidino, morpholino and 1- piperazinyl,
  • carbamoyl which may be substituted with (i) C ⁇ _ 12 alkyl which may be substituted with a 5- or 6-membered nitrogen-containing heterocyclic group, (ii) C,_ 12 alkoxy or (iii) C 7 _ 19 aralkyl, (4) a 5- or 6-membered saturated nitrogen-containing heterocyclic-carbonyl, which may be substituted with C 6 - ⁇ « aryl,
  • thiocarbamoyl which may be substituted with (i) C t- 12 alkyl or (ii) C 7 . 19 aralkyl, (6) a 5- or 6-membered saturated nitrogen-containing heterocyclic-thiocarbonyl,
  • c ⁇ -i 2 alkyl which may be substituted with a group selected from the group consisting of (i) hydroxyl which may be acylated with C 6 . 1 arylcarbonyl, (ii) halogen, (iii) carboxyl, (iv) cyano, (v) amino which may be substituted with C ⁇ _ 12 alkyl which may be substituted with a 5- or 6-membered nitrogen-containing heterocyclic group or C 7 . 19 aralkyl, (vi) a 5- or 6- membered saturated heterocyclic group containing 2 nitrogen atoms, which may be substituted with C 6 . 14 aryl, (vii) phthalimido, (viii) C 6 . 14 arylsulfonyl which may be substituted with Cj. 12 alkyl, and (ix) C 6 _ 1 aryloxy which may be substituted with halogen,
  • carbamoyl which may be substituted with (i) C,. 6 alkyl which may be substituted with pyridyl, (ii) C 7 _ n aralkyl or (iii) C ⁇ alkanoyl,
  • C,_ 6 alkyl which may be substituted with (i) hydroxy which may be acylated with C 6 . 12 arylcarbonyl, (ii) halogen, (iii) carboxyl, (iv) cyano, (v) amino which may substituted with (a) C,_ 6 alkyl which may be substituted with pyridyl or (b) C 7 . 13 aralkyl, (vi) 1- piperazinyl which may be substituted with C 6 . 12 aryl, (vii) phthalimido, (viii) C 6 _ 12 arylsulfonyl which may be substituted with C, . _ 6 alkyl, or (ix) C 6 _ 12 aryloxy which may be substituted with halogen. ( 9 ) c 7 -i 3 aralkyl which may be substituted with halogen or hydroxyl,
  • C ! _ 12 alkyl which may be substituted with a group selected from the group consisting of (i) amino which may be substituted with C 7 . 19 aralkyl or C._ 12 alkyl, (ii) a 5- or 6-membered saturated heterocyclic group containing 2 nitrogen atoms which may be substituted with C 6 _i 4 aryl, (iii) phthalimido, (iv) C 6 .
  • arylsulfonyl which may substituted with C l2 alkyl, (v) hydroxyl which may be substituted with Ci_ 12 alkanoyl, (vi) a 5- or 6-membered saturated nitrogen- and/or oxygen-containing heterocyclic group, (vii) halogen, (viii) C ! _ 12 alkoxy-carbonyl, and (ix) a 5- to 6-membered unsaturated nitrogen- and/or oxgen-containing heterocyclic group, which may be substituted with C ⁇ alkyl or cyano,
  • R represents
  • Cj. 6 alkyl which may be substituted with (i) amino wwhhiicchh mmaayy be substituted with C 7 . 13 aralkyl or C ⁇ _ 6 aaall lkrvyll, .
  • M(i ' i i 1) 1 l --npii rp ⁇ perraa7zii nnvyll wwhhii rc-hh Hboe csnubsstt-i i 1t- ⁇ u ⁇ tt-oeHd wwii 1th C : 6- ⁇ 2 aryl, (iii) phthalimide, (iv) C 6 .
  • R represents (1) C 6 alkyl which may be substituted with (i) 2-thienyl or (ii) carboxyl, (2) C 6 . 12 aryl which may be substituted with (i) halogen, (ii) C,_ 6 alkoxy or (iii) C alkylcarbamoylamino, (3) C 7 . 13 aralkyl which may be substituted with nitro, (4) amino which may be substituted with (i) C ⁇ alkyl, (ii) C 6 _ 12 aryl or (iii) C 3 . 8 cycloalkyl, or (5) morpholino;
  • R represents (1) hydrogen, (2) C ⁇ g alkyl which may be substituted with amino which may have C l . ⁇ alkyl or C 7 _
  • R 1, R2, and R 3 are as defined in 4 to obtain an oxazole derivative of the formula:
  • R , R , and R are as defined above, and n is as defined in 4,
  • R 12 represents lower alkyl or phenyl
  • n is 0, 1, or 2 with a compound of the formula: wherein R is as defined above
  • M represents an alkali metal to obtain an oxazole derivative of the formula:
  • R 1 , R 2 , and R are as defined above, or (3) reacting a compound of the formula:
  • R 2 , R 3 , and n are as defined above;
  • X represents a leaving group with a compound of the formula: wherein R and R independently represent hydrogen, a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted; R 4 and R 5 may be combined with the adjacent nitrogen atom to form a heterocyclic group to obtain an oxazole derivative of the formula:
  • R , _R3, n, R , and R are as defined above;
  • R 1, R2, and R3 are as defined in 4 which comprises
  • M represents an alkali metal and a compound of the formula:
  • R represents as defined above; X represents a leaving group, or
  • R 2 and R 3 are as defined above;
  • R 12 represents lower alkyl or phenyl;
  • n is 0, 1, or 2 with a compound of the formula:
  • R , R , R and n are as defined above with a compound of the formula:
  • R'X wherein R and X are as defined above;
  • a pharmaceutical composition comprising an oxazole derivative having a group bonded through a sulfinyl or sulfonyl moiety at the 5-position of the oxazole ring;
  • R represents a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, or amino which may be substituted
  • n represents 1 or 2
  • R represents hydrogen, cyano, acyl, carbamoyl which may be substituted, thiocarbamoyl which may be substituted, a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, amino which may be substituted, or carboxyl which may be esterified
  • R represents hydrogen, halogen, a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, a hydrocarbon-oxy group which may be substituted, amino which may be substituted, carboxyl which may be esterified, or a group of the formula -S(0)m-R, where R represents a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted; m represents 0, 1, or 2;
  • composition as described in 18 or 19, which is a prophylactic or therapeutic pharmaceutical for cardiac diseases, autoimmune diseases, inflammatory diseases, or diseases accompanied by granuloma;
  • the pharmaceutical composition as described in 18 or 19, which is a prophylactic or therapeutic pharmaceutical for myocardiopathy, cardiac hypertrophy, myocardial infarction, angina pectoris, chronic rheumatoid arthritis, systemic lupus erythe atosus, systemic scleroderma, rheumatic fever, polymyositis, periarteritis nodosa, Sj ⁇ gren's syndrome, Behcet's disease, Castleman's disease, autoimmune hemolytic anemia, mesangial proliferative nephritis, IgA nephritis, lupus nephritis, osteoporosis, amyloidosis, bronchial asthma, atopic dermatitis, psoriasis, j pleurisy, ulcerative colitis, atherosclerosis, active chronic hepatitis, alcoholic cirrhosis, gout, encephalitis, multiple mye
  • composition for inhibition of interleukin-6 activity comprising an oxazole derivative having a group bonded through a sulfinyl or sulfonyl moiety at the 5-position of the oxazole ring;
  • the pharmaceutical composition as described in 18 or 19, which is a prophylactic or therapeutic pharmaceutical for atherosclerosis, myocarditis, myocardiopathy, ischemic brain disorder, Alzheimer's disease, multiple sclerosis, septicemia, chronic rheumatoid arthritis, osteoarthritis, gastric ulcer, duodenal ulcer, ulcerative colitis, diabetes, glomerulonephritis, osteoporosis, pneumonia, hepatitis, graft rejection or pain;
  • composition for inhibition of nitrogen monoxide production comprising an oxazole derivative having a group bonded through a sulfinyl or sulfonyl moiety at the 5-position of the oxazole ring; 0
  • a method for inhibiting interleukin-6 activity in human or mammal which comprises administering an effective amount of an oxazole derivative having a group bonded through a sulfinyl or sulfonyl moiety at the 5-position of the oxazole ring, to human or the mammal;
  • a method for preventing or treating interleukin-6- associated diseases which comprises administering an effective amount of an oxazole derivative having a group bonded through a sulfinyl or sulfonyl moiety at the 5-position of the oxazole ring, to human or the mammal;
  • a method for inhibiting a nitrogen monoxide production in human or mammal which comprises administering an effective amount of an oxazole derivative having a group bonded through a sulfinyl or sulfonyl moiety at the 5-position of the oxazole ring, to human or the mammal; or
  • a method for preventing or treating nitrogen monoxide-associated diseases which comprises administering an effective amount of an oxazole derivative having a group bonded through a sulfinyl or sulfonyl moiety at the 5-position of the oxazole ring, to human or the mammal.
  • the oxazole ring forming the skeletal structure of the compound of the present invention can be expressed by the following formula: /24340
  • Compound A according to the present invention is an oxazole derivative having a group bonded through a sulfinyl (-SO-) or sulfonyl (-S0 2 -) moiety at the 5- position of the oxazole ring provided that when the substituent at the 4-position is hydrogen, (1) the compound which has 4-methoxyphenyl or 4-methoxy- phenylethinyl at the 2-position and nonafluorobutyl- sulfonyl at the 5-position, (2) the compound which has phenyl at the 2-position and (2-phenyl-5- thiazolyl)sulfonyl at the 5-position, and (3) the compound which has 3-[5-(2,3-epoxy-5-hydroxy-4-methyl- hexyl)-3,4-dihydroxytetrahydropyran-2-yl]-2-methyl-l- (E)-propenyl at the 2-position and 4-methyl- phenylsulfonyl at the 5-
  • the 2-position of the oxazole ring may be unsubstituted but may be substituted, for example by a halogen atom or a suitable group which is bonded through a carbon, nitrogen, oxygen, or sulfur atom.
  • the 4-position of the oxazole ring may be unsubstituted but may be substituted, for example by a halogen atom or a suitable group which is bonded through a carbon, nitrogen, oxygen, or sulfur atom.
  • the substituent group bonded through a sulfinyl or sulfonyl moiety at the 5-position of the oxazole ring may be any group which is bonded through a sulfinyl group or a sulfonyl group. Such a group can be typically expressed by the formula:
  • R'-SfO R'-SfO),- wherein R 1 represents a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, or amino which may be substituted; n is 1 or 2 .
  • the halogen atom which can be used includes fluorine, chlorine, bromine, and iodine.
  • R a , R , and R c may be independently represents hydrogen, a hydrocarbon group which may be substituted, or a heterocyclic group which may be substituted. Where -NR a R exists as part of the substituent group, R a and R may be combine with the adjacent nitrogen atom to form a heterocyclic ring.
  • the hydrocarbon group for "the group bonded through a carbon atom" for the 2- or 4-substituent and the hydrocarbon group for R 1 , R a , R , or R c includes alkyl, alkenyl, alkinyl, cycloalkyl, aryl, aralkyl and bridged-ring hydrocarbon groups . Particularly preferred are C l hydrocarbon groups.
  • the alkyl group is preferably a straight-chain or branched alkyl group of 1-24 carbon atoms ( 1 . 2 i, alkyl).
  • the preferred alkyl group is a straight-chain or branched alkyl group of 1- 19 carbon atoms (C ⁇ alkyl) and the more preferred is a straight-chain or branched alkyl group of 1-12 carbon atoms (C,- 12 alkyl). Particularly preferred is a straight-chain or branched alkyl group of 1-6 carbon atoms (C,_ 6 alkyl) .
  • the alkenyl group is preferably a straight-chain or branched alkenyl group of 2-24 carbon atoms (C 2 _ 24 alkenyl), thus including vinyl, propeny(l-, 2-), butenyl(l-, 2-, 3-), pentenyl, octenyl, butadienyl(1, 3-), etc.
  • the preferred alkenyl is a straight-chain or branched alkenyl group of 2-19 carbon atoms (C 2 . 19 alkenyl) and the more preferred is a straight chain or branched alkenyl group of 2-12 carbon atoms (C 2 . 12 alkenyl). Particularly preferred is a straight-chain or branched alkenyl group of 2-6 carbon atoms (C 2 . 6 alkenyl) .
  • the alkinyl group is preferably a straight-chain or branched alkinyl group of 2-24 carbon atoms ( C 2 . 2i> alkinyl), thus including ethinyl, propinyl(l-, 2-), butinyl(l-, 2-, 3-), pentinyl, octinyl, decinyl, etc.
  • the preferred alkinyl is a straight-chain or branched alkinyl group of 2-19 carbon atoms (C 2 . ⁇ 9 alkinyl) and the more preferred is a straight chain or branched alkinyl group of 2-12 carbon atoms (C 2 . 12 alkinyl). Particularly preferred is a straight-chain or branched alkinyl group of 2-6 carbon atoms (C 2 . 6 alkinyl).
  • the cycloalkyl group is preferably a group of 3-10 carbon atoms (C 3 _ 10 cycloalkyl), thus including cyclo- propyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • the more preferred is a cycloalkyl group of 3-8 carbon atoms (C 3 . 8 cycloalkyl) .
  • Particularly preferred is a cycloalkyl group of 3-6 carbon atoms (C 3 . 6 cycloalkyl).
  • the aryl group may for example be a monocyclic group or a fused polycyclic group and is preferably a group containing 6-18 carbon atoms (C 6 . 18 aryl).
  • C 6 . 18 aryl a group containing 6-18 carbon atoms
  • phenyl, biphenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, etc. can be mentioned.
  • the preferred aryl group is a group of 6-14 carbon atoms (C 6 . aryl), such as phenyl and naphthyl.
  • aryl group of 6-12 carbon atoms (C 6 . 12 aryl) .
  • the aralkyl group may for example be an alkyl group substituted by a mono- to tri-cyclic aromatic hydrocarbon group and is preferably an alkyl group of
  • aryl group of 6-18 carbon atoms which has been substituted by an aryl group of 6-18 carbon atoms (C 6 . 18 aryl-C 1 . 2Z
  • aralkyl groups are benzyl, biphenylylmethyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4- phenylbutyl, 1-naphthylmethyl, 2-naphthylmethyl, etc.
  • C 7 . 19 aralkyl groups are preferred and C 7 . 13 aralkyl groups are particularly preferred.
  • the bridged-ring hydrocarbon group is preferably a group of 4-19 carbon atoms (C « _ 19 bridged-ring hydrocarbon group), thus including 1-adamantyl, 2- adamantyl, 2-norbornanyl and 5-norbornen-2-yl.
  • the more preferred is a bridged-ring hydrocarbon group of 4-12 carbon atoms (C. 12 bridged-ring hydrocarbon group) .
  • the heterocyclic group mentioned for the "group bonded through a carbon atom" for the 2- or 4- substituent and the heterocyclic group for R , R a , R and R° may for example be a 5- to 8-membered heterocyclic group containing 1-4 hetero-atoms selected from oxygen, sulfur and nitrogen in addition to carbon as ring members, or a condensed heterocyclic group thereof (e.g. a condensed heterocyclic group with a 6- to 8- membered carbocyclic or a heterocyclic group) .
  • the heterocyclic group includes 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 2-, 4- or 5- oxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isoxazolyl, 3-, 4- or 5-isothiazolyl, 3- or 5-(1,2,4-oxadiazolyl) , 1,3,4- oxadiazolyl, 3- or 5-(1,2,4-thiadiazolyl) , 1,3,4- thiadiazolyl, 4- or 5-(1,2,3-thiadiazolyl) , 1,2,5- thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, IH- or 2H-tetrazolyl, N-oxido-2-, 3- or 4-pyridyl, N-oxidetra
  • heterocyclic groups are 5- or 6-membered heterocyclic groups containing at least one nitrogen atom.
  • pyrimidinyl, thiazolyl and oxadiazolyl are preferred.
  • the substituent group for groups which may be present on the above-mentioned "hydrocarbon group” or “heterocyclic group” includes but is not limited to C,_ 12 alkyl groups (preferably C ⁇ alkyl, more preferably C ! . 4 alkyl, e.g. methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl), C 3 . 8 cycloalkyl (preferably C 3 . 6 cycloalkyl, e.g.
  • halogen e.g. fluorine, chlorine, bromine, and iodine
  • cyano cyano
  • hydroxyl which may be acylated preferably hydroxyl which may be acylated with Ci. 12 alkanoy
  • aralkanoyloxy e.g. benzylcarbonyloxy
  • alkoxy preferably C 1-6 alkoxy such as methoxy, ethoxy, propoxy, and butoxy
  • C 5 . 14 aryloxy e.g. phenyloxy, naphthyloxy, etc.
  • carboxyl Ci.1 2 alkoxy-carbonyl (preferably Cj.g alkoxy-carbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, and butoxycarbonyl), nitro, carbamoyl which may be substituted with Cn 2 alkyl (e.g. butylcarbamoyl) , C x .
  • alkanoyl preferably C ⁇ _ 6 alkanoyl such as formyl, acetyl, propionyl, and butyryl
  • C 6 . u aryl e.g. phenyl, naphthyl, etc.
  • C 6 _ 14 arylcarbonyl e.g. benzoyl, naphthoyl, etc.
  • C 7 . 13 aralkyl-carbonyl e-g- benzylcarbonyl
  • heterocyclic groups e.g.
  • R d and R ⁇ independently represents hydrogen, a hydro- carbon
  • said Cj-iz alkyl, C 3 . 8 cycloalkyl, and the alkyl moiety of said C 1 . l2 alkylthio, C 1 _ 12 alkylsulfinyl or alkylsulfonyl may be further substituted with, for example, C. 8 cycloalkyl (preferably C 3 . 6 cycloalkyl such as cyclopentyl and cyclohexyl), halogen (e.g. fluorine, chlorine, bromine, iodine), cyano, hydroxyl, C U12 alkoxy (preferably Ci.
  • C. 8 cycloalkyl preferably C 3 . 6 cycloalkyl such as cyclopentyl and cyclohexyl
  • halogen e.g. fluorine, chlorine, bromine, iodine
  • cyano hydroxyl
  • C U12 alkoxy preferably Ci.
  • Ci_ 12 alkoxy-carbonyl preferably Ci- ⁇ alkoxy-carbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, and butoxycarbonyl
  • nitro, amino, carbamoyl and C ⁇ _ 12 alkyl-carbonyl (preferably t _ 6 alkyl-carbonyl such as formyl, acetyl, propionyl, and butyryl).
  • said c 6 -m aryl and the C 6 . 14 aryl moiety of said C 6 . u aryl- carbonyl, C 6 . 12 arylthio, C 6 . 12 arylsulfinyl, or C 6 . 12 arylsulfonyl may be further substituted with, for example, Cj_ 6 alkyl (preferably Cj.., alkyl such as methyl, ethyl, propyl, and butyl), C 3 . 8 cycloalkyl (preferably C 3 _ 6 cycloalkyl such as cyclopentyl and cyclohexyl), halogen (e.g.
  • Cj_ 6 alkyl preferably Cj.., alkyl such as methyl, ethyl, propyl, and butyl
  • C 3 . 8 cycloalkyl preferably C 3 _ 6 cycloalkyl such as cyclopentyl and cyclohexy
  • said heterocyclic group may be further substituted by, for example, alkyl (preferably C ] .
  • alkyl such as methyl, ethyl, propyl, and butyl
  • C 3 . 8 cycloalkyl preferably C 3 . 6 cycloalkyl such as cyclopentyl and cyclohexyl
  • halogen e.g.
  • C ⁇ alkoxy preferably C,_ t, alkoxy such as methoxy, ethoxy, propoxy, and butoxy
  • carboxyl preferably Cj.* alkoxy- carbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, and butoxycarbonyl
  • nitro, amino, carbamoyl, C ⁇ alkanoyl preferably C A alkyl-carbonyl such as formyl, acetyl, propionyl, and butyryl.
  • the hydrocarbon group or heterocyclic group represented by R , R e , or R in the group of the formula -NR R B or -S0 7 - R may be the same as the hydrocarbon group or heterocyclic group defined for R hereinbefore.
  • R d and R e are combined with the adjacent nitrogen atom to form a heterocyclic ring, the ring (i.e.
  • the nitrogen-containing ring may be a 5- to 8- membered nitrogen-containing group optionally containing 1-4 atoms selected from carbon, nitrogen, oxygen, and sulfur in addition to said nitrogen atom as ring members, which nitrogen-containing ring may be further fused to a 6- to 8-membered carbocyclic or heterocyclic group.
  • R and R e are combined with the adjacent nitrogen atom to form a heterocyclic ring, the group of the formula -NR R e constitutes a cyclic amino group.
  • cyclic amino group there can be mentioned 1-pyrrolidinyl, 1- imidazolyl, piperidino (1-piperidyl), 1-pi ⁇ erazinyl, 3- oxazolidinyl, hexamethylenimino, heptamethylenimino, morpholino (4-morpholinyl) , 1-indolinyl, and phthalimido among others.
  • These cyclic amino groups may each be further substituted.
  • the substituents for the hydrocarbon group or the heterocyclic group, represented by R d or R e , or the cyclic amino group -NR R e may be, for example, C ⁇ _ 4 alkyl (e.g. methyl, ethyl, propyl, butyl, etc.), C 3 _ 8 cycloalkyl (preferably C 3 _ 6 cycloalkyl such as cyclopentyl and cyclohexyl), halogen (e.g. fluorine, chlorine, bromine, iodine), cyano, hydroxyl, C ⁇ alkoxy (e.g. methoxy, ethoxy, propoxy, butoxy, etc.), carboxyl, C,.
  • C ⁇ _ 4 alkyl e.g. methyl, ethyl, propyl, butyl, etc.
  • C 3 _ 8 cycloalkyl preferably C 3 _ 6 cycloalkyl such as cyclopentyl and
  • a alkoxy-carbonyl e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.
  • the above-mentioned C ⁇ alkyl and of said C 3 . 8 cycloalkyl may be further substituted with, for example, C 3 _ 8 cycloalkyl (preferably C 3 .
  • cycloalkyl such as cyclopentyl and cyclohexyl
  • halogen e.g. fluorine, chlorine, bromine, iodine
  • cyano hydroxyl
  • C j . 4 alkoxy e.g. methoxy, ethoxy, propoxy, butoxy
  • carboxyl C,./, alkoxy-carbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl), nitro, amino, carbamoyl, and C ⁇ _ 4 alkyl-carbonyl (e.g. formyl, acetyl, propionyl, butyryl).
  • C 6 cycloalkyl such as cyclopentyl and cyclohexyl
  • halogen e.g. fluorine, chlorine, bromine, iodine
  • cyano hydroxyl
  • C j . 4 alkoxy e.g.
  • Cj. 4 alkyl e.g. methyl, ethyl, propyl, butyl
  • C 3 _ 8 cycloalkyl preferably C 3 . 6 cycloalkyl such as cyclopentyl and cyclohexyl
  • halogen e.g. fluorine, chlorine, bromine, iodine
  • cyano hydroxyl
  • C alkoxy e.g. methoxy, ethoxy, propoxy, butoxy
  • carboxyl C ⁇ _,, alkoxy-carbonyl (e.g.
  • the ring formed by R and R combined with the adjacent nitrogen atom can be the same kind of ring as the ring formed by R and R e combined with the adjacent nitrogen atom.
  • the amino which may be substituted for R 1 may for example be a group of the formula -NR*R 5 , -NR a -C0-R b , -NR a -CO-NR 4 R 5 , -NR a -CS-NRV, -NR a -NRV, or -NR a -CO-OR b (where R a , R , R and R independently represents a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted; R and R 5 may be combined with the adjacent nitrogen atom to form a heterocyclic ring) .
  • the hydrocarbon group which may be substituted or the heterocyclic group which may be substituted, for R'' or R may be the same kind of group as "the hydrocarbon group which may be substituted" or "the heterocyclic group which may be substituted” for R a or R .
  • the ring formed by R and R combined with the adjacent nitrogen atom may be the same kind of ring as formed by R and R e combined with the adjacent nitrogen atom.
  • the "group bonded through a sulfinyl or sulfonyl moiety" at the 5- ⁇ osition of the oxazole ring in compound A according to the present invention is preferably a group of the formula R-S(0)n-.
  • R may for example be a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, or amino which may be substituted. Particularly preferred is a hydrocarbon group which may be substituted or amino which may be substituted. As to the value of n, both 1 and 2 are satisfactory but 2 is preferred.
  • the preferred substituent at the 2-position of compound A according to the present invention includes hydrogen, halogen, a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, a hydrocarbon-oxy group which may be substituted (for example, -0R a ) , amino which may be substituted (for example, -NR a R ) , carboxyl which may be esterified (for example, -COR a ) etc.
  • the preferred substituent at the 4-position of compound A according to the present invention includes hydrogen, cyano, acyl (-C0R a ), carbamoyl which may be substituted (-CO-NR ,6 suitcaseR7), thiocarbamoyl which may be substituted (-CS-NRR ), a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, amino which may be substituted (for example, -NR a -C00R ), carboxyl which may be esterified (for example, -C00R ) , etc.
  • cyano, acyl (-COR a ), carbamoyl which may be substituted (-CO-NR 6 R 7 ), thiocarbamoyl which may be substituted (-CS-NR 6 R 7 ), a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, and carboxyl which may be esterified (-C00R 8 ) are preferred.
  • the preferred substituent at the 5-position is a group of the formula R : -S(0)n-, where R is preferably one of the following groups (1)-
  • Ci.ig alkyl which may be substituted with (i) a 5- or 6-membered sulfur-containing heterocyclic group, (ii) a 5- or 6-membered oxygen- and nitrogen-containing heterocyclic group which may be substituted with C ⁇ alkyl or cyano, (iii) carboxyl, (iv) C 6 . arylcarbonyl, (v) cyano, (vi) carbamoyl which may be substituted with mono- or di-C 1 . 12 alkyl, or (vii) d_ 12 alkoxy-carbonyl.
  • C 6 _ 14 aryl which may be substituted with (i) halogen, (ii) C ⁇ _ 12 alkoxy, (iii) amino which may be substituted with (a) carbamoyl which may be substituted with C ! . 12 alkyl or C 3 _ 10 cycloalkyl, (b) C 6 . 14 arylsulfonyl which may be substituted with halogen, or ( c ) c ⁇ - ⁇ alkylsulfonyl, (iv) C x _ n alkyl which may be substituted with halogen, (v) nitro or (vi) hydroxyl.
  • alkyl which may be substituted with (a) C ⁇ _ 12 alkoxy-carbonyl, (b) mono- or di-C 1 _ 12 alkylamino or (c) a 5- or 6- membered nitrogen-containing heterocyclic group, (ii) C 7 . 19 aralkyl which may be substituted with halogen or C ⁇ . 12 alkoxy, (iii) C 4 . 12 bridged-ring hydrocarbon group, (iv) C 6 _ 14 aryl or (v) C 3 . 10 cycloalkyl.
  • R is more preferably one of the group of the following groups (1) - (12) .
  • c ⁇ -i 2 alkyl which may be substituted with (i) thienyl, (ii) oxazolyl which may be substituted with C y . 6 alkyl or cyano, (iii) carboxyl, (iv) C 6 _ 12 arylcarbonyl, (v) cyano, (vi) carbamoyl which may be substituted with mono- or di-C j . 6 alkyl, or (vii) C ⁇ alkoxy-carbonyl.
  • C 6 , 12 aryl which may be substituted with (i) halogen, (ii) Ci. 6 alkoxy, (iii) amino which may be substituted with (a) carbamoyl which is substituted with C ⁇ g alkyl or C 3 _ 8 cycloalkyl, (b) C 6 . 12 arylsulfonyl which may substituted with halogen or (c) C . 6 alkylsulfonyl, (iv) Cj.g alkyl which may be substituted with halogen (v) nitro or (vi) hydroxy. (6) C 7 .
  • aralkyl which may be substituted with (i) halogen, (ii) Ci_ 6 alkoxy, (iii) amino which may be substituted with (a) C 6 . 12 arylsulfonyl which may be substituted with C,_ 6 alkyl or (b) C ⁇ alkylsulfonyl, or (iv) nitro.
  • a heterocyclic group selected from the group consisting of pyrimidyl, piperidino, morpholino and 1- piperazinyl.
  • R is preferably one of the following groups:
  • C ⁇ . 6 alkyl which may be substituted with (i) 2- thienyl or (ii) carboxyl, (2) C 6 . 12 aryl which may be substituted with (i) halogen, (ii) C ⁇ g alkoxy or (iii) C x _ 6 alkylcarbamoyla ino, (3) C 7.13 aralkyl which may be substituted with nitro, (4) amino which may be substituted with (i) C ⁇ alkyl, (ii) C 6 . 12 aryl or (iii) C 3 - 8 cycloalkyl, or (5) morpholino.
  • the symbol n may represent whichever of 1 and 2 but 2 is particularly preferred.
  • R is preferably (1) C J . J Q alkyl which may be substituted with cyano, (2) C 2 _ 12 alkinyl, (3) C ⁇ . 8 cycloalkyl, (4) C 6 . 12 aryl with may be substituted with (i) halogen, (ii) amino which may be substituted with carbamoyl with substituted with C _ 6 alkyl, or (iii) C,_ 6 alkyl which may be substituted with halogen, or (5) pyrimidinyl.
  • the substituent at the 2-position is preferably one of the following groups (1)-(13).
  • C!_ 12 alkyl which may be substituted with a group selected from the group consisting of(i) amino which may be substituted with C 7 . 19 aralkyl or C 12 alkyl, (ii) a 5- or 6-membered saturated heterocyclic group containing 2 nitrogen atoms which may be substituted with C 6 . 14 aryl, (iii) phthalimido, (iv) C 6 . 14 arylsulfonyl which may substituted with C 1 , 12 alkyl, (v) hydroxyl which may be substituted with C).
  • the substituent at the 2-position is more preferably one of the following groups (1) - (13).
  • C 6 alkyl which may be substituted with (i) amino which may be substituted with C 7 . 13 aralkyl or C ⁇ alkyl, (ii) 1-piperazinyl which may be substituted with c 6 -i 2 ar yl, (i ⁇ ) phthalimide, (iv) C 6 . 12 arylsulfonyl which may be substituted with C ⁇ g alkyl, (v) hydroxyl which may be substituted with C t .
  • C 6 . 12 aryl which may be substituted with C ⁇ _ 6 alkoxy.
  • C 7 . 13 aralkyl which may be substituted with (i) amino, (ii) nitro, (iii) Cl-6 alkoxy, or (iv) halogen.
  • the substituent at the 2-position is preferably one of the following groups:
  • carbamoyl which may be substituted with (i) C 12 alkyl which may be substituted with a 5- or 6-membered nitrogen-containing heterocyclic group, (ii) alkoxy or (iii) C 7 . 19 aralkyl.
  • thiocarbamoyl which may be substituted with (i) C,_ 12 alkyl or (ii) C 7 . 19 aralkyl.
  • ( 7 ) c ⁇ -i 2 alkyl which may be substituted with a group selected from the group consisting of (i) hydroxyl which may be acylated with C 6 . 14 arylcarbonyl, (ii) halogen, (iii) carboxyl, (iv) cyano, (v) amino which may be substituted with alkyl which may be substituted with a 5- or 6-membered nitrogen-containing heterocyclic group or C 7 _ 19 aralkyl, (vi) a 5- or 6- me bered saturated heterocyclic group containing 2 nitrogen atoms, which may be substituted with C 6 _ ⁇ 4 aryl, (vii) phthalimido, (viii) C 6 _ 14 arylsulfonyl which may be substituted with C 2 alkyl, and (ix) C 6 . 14 aryloxy which may be substituted with halogen, . (8) C 7 . 19 aralkyl which may be substituted with halogen or
  • the substituent at the 2-position is more preferably one of the following groups (1) - (13).
  • carbamoyl which may be substituted with (i) C,. 6 alkyl which may be substituted with pyridyl, (ii) C 7 . n aralkyl or (iii) alkanoyl.
  • thiocarbamoyl which may be substituted with (i) C 1-6 alkyl or (ii) C 7 . 13 aralkyl.
  • Ci_ 6 alkyl which may be substituted with (i) hydroxy which may be acylated with C 6 . 12 arylcarbonyl, (ii) halogen, (iii) carboxyl, (iv) cyano, (v) amino which may substituted with (a) C 1-6 alkyl which may be substituted with pyridyl or (b) C 7 . 13 aralkyl, (vi) 1- piperazinyl which may be substituted with C 6 . 12 aryl, (vii) phthalimido, (viii) C 6 . 12 arylsulfonyl which may be substituted with C ⁇ alkyl, or (ix) C 6 . 12 aryloxy which may be substituted with halogen.
  • the more preferred substituent at the 4-position is cyano carbamoyl, thiocarbamoyl or C x _ 6 alkyl which may be substituted with halogen. Particularly pre erred is cyano or thiocarbamoyl.
  • the substituent at the 5-position is a group bonded through a sulfinyl moiety
  • the substituent at the 4-position is preferably (1) cyano, (2) C ⁇ alkyl which may be substituted with halogen or (3) thiocarbamoyl. Particularly preferred is cyano.
  • Compound (A) according to the present invention does not comprise the following compounds: (1) the compound having 4-methoxyphenyl or 4- methoxyphenylethinyl at the 2-position and nonafluorobutylsulfonyl at the 5-position, (2) the compound having phenyl at the 2-position and (2-phenyl- 5-thiazolyl)sulfonyl at the 5-position, and (3) the compound having 3-[5-(2,3-epoxy-5-hydroxy-4- methylhexyl)-3,4-dihydroxytetrahydropyran-2-yl]-2- methyl-l-(E)-propenyl at the 2-position and 4- methylphenylsulfonyl at the 5-position.
  • Compound A according to the present invention is a novel compound.
  • Compound A for use in the present invention is preferably a compound (I) of the following formula
  • R represents a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, or amino which may be substituted
  • n ⁇ represents 1 or 2
  • R represents hydrogen, cyano, acyl, carbamoyl which may be substituted, thiocarbamoyl which may be substituted, a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, or amino which may be substituted, carboxyl which may be esterified
  • R 3 represents hydrogen, halogen, a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, a hydrocarbon-oxy group which may be substituted, amino which may be substituted, carboxyl which may be esterified, or a group of the formula
  • R represents a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted; m represents 0, 1, or 2; exclusive of the compounds in which R is hydrogen and n is 2, wherein (1) R is 4-methoxyphenyl or 4-methoxyphenylethinyl and R is nonafluorobutyl, (2) R 3 is phenyl and R 1 is 5-(2- phenylthiazolyl) , and (3) R 3 is 3-[5-(2,3-epoxy-5- hydroxy-4-methylhexyl)-3,4-dihydroxytetrahydropyran-2- yl]-2-methyl-l-(E)-propenyl and R 1 is 4-methylphenyl.
  • the hydrocarbon group which may be substituted, heterocyclic group which may be substituted, and amino which may be substituted for R 1 have the same meanings as defined hereinbefore.
  • the amino which may be substituted for R may for example be a group of the formula -NR 4 R , wherein R and R independently represents hydrogen, a hydrocarbon group which may be substituted, or a heterocyclic group which may be substituted; R and R 5 may be combined with the adjacent nitrogen atom to form a heterocyclic ring.
  • the acyl for R may for example be a organic carboxylic acid-derived acyl group and is preferably an acyl group of 1-19 carbon atoms (C j . 19 alkanoyl) .
  • C j . 19 alkanoyl a acyl group of 1-19 carbon atoms
  • formyl, acetyl, ethylcarbonyl, propylcarbonyl, etc. can be mentioned.
  • Particularly preferred are acyl groups of 1-6 carbon atoms (C U6 alkanoyl) .
  • the carbamoyl which may be substituted for R 2 may for example be a group of the formula -CONR R , where R 6 and R independently represents hydrogen, acyl, a hydrocarbon group which may be substituted, or a heterocyclic group which may be substituted; R and R may be combined with the adjacent nitrogen atom to form a heterocyclic ring.
  • the thiocarbamoyl which may be substituted for R may for example be a group of the formula -CS-NR R wherein R and R independently represents hydrogen, a hydrocarbon group which may be substituted, or a heterocyclic group which may be substituted; R and R may be combined with the adjacent nitrogen atom to form a heterocyclic ring.
  • the carboxyl which may be esterified for R or R may for example be a group of the formula -COOR , where R 10 represents hydrogen, a hydrocarbon group which may be substituted, or a heterocyclic group which may be substituted.
  • the substituent for amino which may be substituted for R 2 may for example be C ⁇ . _ 12 alkoxy-carbonyl (preferably C j .g alkoxy-carbonyl) . Particularly preferred is buthoxycarbonyl.
  • the halogen for R may for example be fluorine, chlorine, bromine, or iodine.
  • the hydrocarbon-oxy which may be substituted may for example be a group of the formula -OR 11 , where R u represents a hydrocarbon group which may be substituted.
  • the "hydrocarbon group which may be substituted" for R, R z , R 3 , R 5 , R 6 , R 7 , R 10 , or R 11 can be the same as the "hydrocarbon group that may be substituted" which has been defined for R 1 .
  • heterocyclic group which may be substituted for R, R , R , R , R , R 6 , R 7 , or R 10 can be the same as the "heterocyclic group that may be substituted" which has been defined for R 1 .
  • the heterocyclic group which R 4 and R 5 , or R 6 and R , may be combined with the adjacent nitrogen atom to form a heterocyclic group can be the same as heterocyclic group formed by R d and R e which may be combined with the adjacent nitrogen atom.
  • the acyl for R 6 or R 7 can be the same as the acyl which has been defined for R 2 .
  • -S(0)m-R for R 3 includes C,_ 12 alkylthio (e.g. methylthio, ethylthio, etc.), C 6 . 14 arylthio (e.g. phenylthio etc.), C 6 . 14 aryl-C ⁇ _ 6 alkylthio (e.g. benzylthio etc.), C,_ 1A alkylsulfinyl (e.g. methylsulfinyl, ethylsulfinyl, etc.), C 6 . 14 arylsulfinyl (e.g. phenylsulfinyl etc.), C 6 .
  • aryl-C ⁇ alkylsulfinyl e.g. benzylsulfinyl etc.
  • C U12 alkylsulfonyl e.g. methylsulfonyl, ethylsulfonyl, etc.
  • C 5 _ 14 arylsulfonyl e.g. phenylsulfonyl etc.
  • C 6 . 14 aryl-C 6 alkylsulfonyl e.g. benzylsulfonyl etc.
  • R 1 may be the same as R of the group of the formula R 1 -S(0)n- at the 5-position described above.
  • R may be the same as the substituent at the 4-position described above.
  • R may be the same as the substituent at the 2-position described above.
  • compound (I) of the present invention all the compounds corresponding to the above combinations of R 1 , R 2 and R 3 are invariably preferred.
  • Compound (I) of the present invention does not include compounds such that R is hydrogen and n is equal to 2, wherein (1) R is 4-methoxyphenyl or 4- methoxyphenylethinyl and R 1 is nonafluorobutyl, (2) R3 is phenyl and R is 4-(2-phenylthiazolyl) , (3) R 3 is 3- [5-(2,3-epoxy-5-hydroxy-4-methylhexyl)-3,4- dihydroxytetrahydropyran-2-yl]-2-methyl-1-(E)-propeny1 and R is 4-methylphenyl.
  • Compound (I) is a novel compound.
  • Compound B for use in the present invention is an oxazole derivative having a group bonded through a sulfinyl (-SO-) or sulfonyl (-S0 2 -) moiety at the 5- position of the oxazole ring.
  • the 2-position of the oxazole ring may be unsubstituted but may be substituted by a certain group such as halogen or a group bonded through a carbon, nitrogen, oxygen, or sulfur atom.
  • the 4-position of the oxazole ring may be unsubstituted but may be substituted by a certain group such as halogen or a group bonded through a carbon, nitrogen, oxygen, or sulfur atom.
  • the substituent group bonded through a sulfinyl or sulfonyl moiety at the 5-position of the oxazole ring may be the same as the group bonded through a sulfinyl or sulfonyl moiety at the 5-position of the oxazole ring of compound A.
  • halogen atom or the group bonded through a carbon, nitrogen, oxygen, or sulfur atom at the 2- or 4-position of the oxazole ring may be the same as the halogen atom or the group bonded through a carbon, nitrogen, oxygen, or sulfur atom at the 2- or 4- position of compound A mentioned hereinbefore.
  • Compound B for use in the present invention includes the specific compounds excluded from compound A, namely the compounds having hydrogen at the 4- position wherein (1) the substituent at the 2-position is 4-methoxyphenyl or 4-methoxyphenylethinyl and the substituent at the 5-position is nonafluorobutylsulfonyl, (2) the substituent at the 2- position is phenyl and the substituent at the 5- position is (2-phenyl-5-thiazolyl)sulfonyl, and (3) the substituent at the 2-position is 3-[5-(2,3-epoxy-5- hydroxy-4-methylhexyl)-3,4-dihydroxytetrahydropyran-2- yl]-2-methyl-l-(E)-propenyl and the substituent at the 5-position is 4-methylphenylsulfonyl.
  • Compound B is preferably a compound of the formula
  • R represents a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, or amino which may be substituted
  • n 1 or 2
  • R represents hydrogen, cyano, acyl, carbamoyl which may be substituted, thiocarbamoyl which may be substituted, a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, amino which may be substituted or carboxyl which may be esterified
  • R 3 represents hydrogen, halogen, a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, a hydrocarbon-oxy group which may be substituted, amino which may be substituted, carboxyl which may be esterified or a group of the formula -S(0)m-R, where R represents a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted; m represents 0, 1, or 2.
  • R 1 and R 3 are as defined hereinbefore; R has the same meaning as R 2 defined hereinbefore.
  • the compound may form a salt with a suitable base or acid, and these salts are included in the compound of the invention.
  • the kind of salt is preferably a pharmacologically acceptable salt, for example, salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, and salts with basic or acidic amino acids.
  • the salt with an inorganic base includes alkali metal salts (e.g. sodium salt, potassium salt, etc.), alkaline earth metal salts (e.g.
  • the salt with an organic base includes salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, dicyclohexylamine, etc.
  • the salt with an inorganic acid includes salts with hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, etc.
  • the salt with an organic acid includes salts with formic acid, acetic acid, oxalic acid, fumaric acid, maleic acid, succinic acid, citric acid, trifluoroacetic acid, methanesulfonic acid, p- toluenesulfonic acid, etc.
  • the salt with a basic amino acid includes salts with arginine, lysine, ornithine, etc.
  • the salt with an acidic amino acid includes salts with aspartic acid, glutamic acid, etc.
  • Compound A of the present invention can be produced generally in the same manner as compound (I) of the invention which is described in detail below.
  • Compound (I) of the present invention can be produced typically by the following processes (l)-(4).
  • This process comprises oxidizing the oxazole derivative (II) to compound (I) of the invention. More particularly, the derivative (II) is dissolved in a solvent and reacted with an oxidizing agent to give compound (I) .
  • the oxidizing agent that can be used includes but is not limited to m-chloroperbenzoic acid, hydrogen peroxide, peracetic acid, t-butyl hydroperoxide, potassium peroxysulfate, potassium permanganate, sodium perborate, sodium periodate, sodium hypochlorite, and halogen.
  • the amount of the oxidizing agent is generally about 1-3 moles per mole of compound (II).
  • reaction solvent need not be critically chosen unless it reacts with the oxidizing agent used.
  • halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2- dichloroethane, etc.
  • aromatic hydrocarbons such as benzene, toluene, xylene, etc.
  • aliphatic hydrocarbons such as pentane, hexane, petrolen, ether, etc.
  • alcohols such as methanol, ethanol, isopropyl alcohol, t-butyl alcohol, etc.
  • carboxylic acids such as acetic acid, trifluoroacetic acid, etc.
  • ethers such as diethyl ether, tetrahydrofuran, dioxane, etc., aceto ⁇ nitrile, N,N-dimethylformamide, dimethyl sulfoxide, water, and mixtures thereof can be mentioned.
  • This oxidation reaction can be conducted in the presence of a catalyst such as vanadium pentoxide, benzeneselenic acid, ruthenium oxide, osmium oxide, or the like. While this reaction may be carried out under cooling, at room temperature, or under heating, it is usually conducted at room temperature or under heating.
  • the reaction time is generally about 1-20 hours and preferably about 1-10 hours.
  • the objective compound of high purity can be isolated by subjecting the reaction mixture to a known purification procedure such as solvent extraction, distillation, column chromatography, and recrystallization.
  • R 1 , R , R , and n are as defined hereinbefore;
  • R 12 represents lower alkyl or phenyl; n 1 represents 0,
  • M represents an alkali metal
  • the alkali metal for M in the above formula may for example be lithium, sodium, potassium, or cesium.
  • the reaction solvent is preferably a polar solvent.
  • halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, etc.
  • alcohols such as methanol, ethanol, isopropyl alcohol, t-butyl alcohol, etc., acetone, acetonitrile, N,N- dimethylformamide, dimethyl sulfoxide, hexamethylphosphoramide, water, and mixtures thereof can be employed.
  • This reaction is conducted under cooling, at room temperature, or under heating and the reaction time is generally about 1-20 hours and preferably about 1-10 hours .
  • the objective compound of high purity can be isolated by subjecting the reaction mixture to a known procedure such as solvent extraction, distillation, column chromatography, and recrystallization.
  • R , R , and R have the same respective meanings as R , R , and R defined above.
  • R , R 2 ' , and R ' have the same respective meanings as R 1 , R 2 , and R defined above.
  • R and R 1 ", R 2" and R 2'" , and R and R " may respectively be the same but at least one of the three pairs consists of dissimilar groups.
  • compound (I''') is produced by substituting 1-3 of R , R and R 3 of oxazole derivative (I'') or subjecting (I'') to functional transformation.
  • the substitution reaction and functional transformation reaction can be carried out by the routine procedures. As such routine procedures, the following methods can be typically mentioned.
  • R g , R , and R 1 independently represents a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted.
  • R 1 , R 2 , 3, R 12 , R 4 , R 5 , n, and M are as defined hereinbefore;
  • X represents a leaving group.
  • halogen such as chlorine, bromine, iodine, etc., p-toluenesulfonyloxy, or methanesulfonyloxy, for instance, is employed. Among them, halogen is preferred and chlorine is particularly suitable.
  • This process is directed to production of compound (VII), which is a species of compound (I) of the invention wherein R represents -NR R . More specifically, the process comprises reacting compound (III) with M 2 S, e.g.
  • the reaction solvent for use in the reaction with M 2 S in the above course of synthesis from compound (III) to compound (V) is preferably a polar solvent, e.g. halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, etc., alcohols such as methanol, ethanol, isopropyl alcohol, etc., acetone, acetonitrile, water, and mixture of such solvents.
  • This reaction is conducted under cooling, at room temperature, or under heating, and the reaction time is generally about 1-20 hours and preferably about 1-10 hours.
  • the acid that can be used in the acid treatment but generally an aqueous solution of hydrochloric acid, sulfuric acid, nitric acid, acetic acid, or the like is employed.
  • the base that can be used in the course of synthesis from compound (VI) to compound (VII) includes sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, triethylamine, pyridine, sodium methoxide, sodium ethoxide, potassium t-butoxide, sodium hydride, and sodium amide, among others.
  • the reaction solvent that can be used includes but is not limited to hydrogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2- dichloroethane, etc., aromatic hydrocarbons such as benzene, toluene, xylene, etc., aliphatic hydrocarbons such as pentane, hexane, petroleum ether, etc., ethers such as diethyl ether, tetrahydrofuran, dioxane, etc., acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, and mixtures thereof.
  • This reaction is conducted under cooling, at room temperature, or under heating and the reaction time is generally about 1-20 hours and preferably about 1-10 hours.
  • the objective compound of high purity can be isolated from the reaction mixture by the known procedures such as solvent extraction, distillation, column chromatography, and recrystallization.
  • the starting compound (II) for use in process (1) can be produced by the known technology or any method analogous thereto.
  • the known technology includes the process starting with 2-amino-3,3- dichloroacrylonitrile, in which the starting compound is converted to a 3,3-bis(substituted mercapto)derivative which, in turn, is cyclized with a silver salt [Matsumura et al. , Chem. Pharm. Bull. 24. p.912 (1976), ditto, p.948] and the process in which 5- mercapto-oxazole is S-alkylated [T. K. Vinogradova et al., Zh. Org. Khim. i£, 1864 (1982)].
  • the starting compound (II) can be obtained by the following process.
  • R 1 , R 2 , R 3 , and M are as defined hereinbefore;
  • X represents a leaving group.
  • R is preferably an electron-withdrawing group such as cyano, alkyloxycarbonyl, carbamoyl, or the like.
  • X preferably represents halogen, e.g. chlorine, bromine, or iodine, p-toluenesulfonyloxy, or methane- sulfonyloxy, for instance.
  • the reaction solvent is preferably a polar solvent.
  • a polar solvent for example, hydrogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, etc., alcohols such as methanol, ethanol, isopropyl alcohol, t-butyl alcohol, etc., acetone, acetonitrile, N,N- dimethylformamide, dimethyl sulfoxide, hexamethylphosphoramide, etc., water, and mixtures thereof can be employed.
  • This reaction is conducted under cooling, at room temperature, or under heating and the reaction time is generally about 1-20 hours and preferably about 1-10 hours.
  • the starting compound (II) can also be produced by the following process.
  • reaction solvent is preferably a polar solvent, e.g.
  • halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, etc., alcohols such as methanol, ethanol, isopropyl alcohol, t-butyl alcohol, etc., acetone, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphoramide, etc., water, and mixtures thereof.
  • the reaction is conducted under cooling, at room temperature, or under heating and the reaction time is generally about 1-20 hours and preferably 1-10 hours.
  • the base that can be used in process A includes but is not limited to sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, triethylamine, pyridine, sodium methoxide, sodium ethoxide, potassium t-butoxide, sodium hydride, and sodium amide. It is also possible to treat the thiol with a base and subject the resulting thiol anion (RS ⁇ ) to the reaction with compound (III).
  • Compound (II) thus obtained can be converted to compounds having different substituent groups by intro ⁇ ducing desired substituent groups for 1-3 of its substituents R , R , and R by the same procedure as described in connection with process (3) for producing compound (I) or subjecting it to functional transformation.
  • the starting compound (I'') for process (3) can be produced by process (1) or (2).
  • R represents 1) a C ⁇ _ 19 hydrocarbon group which may be substituted with (1) Ci. 12 alkyl which may be substituted with (a) C 3 . 8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) alkoxy, (f) carboxyl, (g) C M2 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) C ⁇ . 12 alkanoyl,
  • hydroxyl which may be acylated with (a) C ⁇ _ 12 alkanoyl, (b) C 6 . 1 arylcarbonyl or (c) C 7 . 19 aralkanoyl, (6) Cj., 2 alkoxy,
  • C 6 _u arylcarbonyl which may be substituted with (a) C 6 alkyl, (b) C 3 . 8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) C ⁇ . 6 alkoxy, (g) carboxyl, (h) C ⁇ g alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) C ⁇ . _ 6 alkanoyl,
  • R d' and R ⁇ ' independently represents (A) hydrogen, (B) a C j _ 19 hydrocarbon group which may be substituted with (a) C ⁇ alkyl which may be substituted with (i) C 3 .
  • hydrocarbon group which may be substituted with (a) C ⁇ _ 4 alkyl which may be substituted with (i) C 3 - 8 cycloalkyl, (ii) halogen, (iii) cyano, (iv) hydroxyl, (v) C w alkoxy, (vi) carboxyl, (vii) C,. 4 alkoxy-carbonyl, (viii) nitro, (ix) amino, (x) carbamoyl, or (xi) C ⁇ alkanoyl, (b) C 3 . 8 cycloalkyl which may be substituted with (i) C 3 .
  • R d' and R e' may be combined with the adjacent nitrogen atom to form a heterocyclic group selected from 1-pyrrolidinyl, 1- imidazolyl, piperidino, 1-piperazinyl, 3-oxazolidinyl, hexamethylenimino, heptamethylenimino, morpholono, 1- indolinyl and phthalimido, which may be substituted with (a) Cn alkyl which may be substituted with (i) C 8 cycloalkyl, (ii) halogen, (iii) cyano, (iv) hydroxyl, (v) Cj_ 4 alkoxy, (vi) carboxyl, (vii) C 4 alkoxy- carbonyl, (viii) nitro, (ix) amino, (x) carbamoyl, or (xi) C 1 .
  • a heterocyclic group selected from 1-pyrrolidinyl, 1- imidazolyl, piperidino, 1-pipe
  • alkanoyl (b) C 3 . 8 cycloalkyl which may be substituted with (i) C 3 . 8 cycloalkyl, (ii) halogen, (i ⁇ ) cyano, (iv) hydroxyl, (v) C ⁇ _ alkoxy, (vi) carboxyl, (vii) Ci_ 4 alkoxy-carbonyl, (viii) nitro, (ix) amino, (x) carbamoyl, or (xi) C ⁇ alkanoyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) C 4 alkoxy, (g) carboxyl, (h) C ⁇ alkoxy-carbonyl, (i) nitro, (j) di-C,.
  • Ci . ⁇ alkylthio which may be substituted with (a) C 3 - 8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) Ci. 12 alkoxy, (f) carboxyl, (g) C1 . .1 2 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) C l . l2 alkanoyl ,
  • Ci. ⁇ alkylsulfinyl which may be substituted with (a) C 3 - 8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C alkoxy, (f) carboxyl, (g) C,_ 12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) C ! . 12 alkanoyl,
  • C ! _ 12 alkylsulfonyl which may be substituted with (a) C 3 _ 8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C X - 12 alkoxy, (f) carboxyl, (g) Ci_ 12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) Ci_ 12 alkanoyl,
  • C 6 _ 14 arylsulfinyl which may be substituted with (a) C x . 6 alkyl, (b) C 3 . 8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) C 6 alkoxy, (g) carboxyl, (h) Cj. 6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) C ⁇ . _ 6 alkanoyl, or
  • (22) C 6 . 14 arylsulfonyl which may be substituted with (a) C ⁇ . _ 6 alkyl, (b) C 3 . 8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) C L6 alkoxy, (g) carboxyl, (h) C L6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cj.g alkanoyl,
  • C 3 _ 8 cycloalkyl which may be substituted with (a) C,. 8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C t . 12 alkoxy, (f) carboxyl, (g) C ⁇ _ 12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) C,. 12 alkanoyl, (3) halogen (4) cyano,
  • hydroxyl which may be acylated with (a) C x . 12 alkanoyl, (b) C 6 . 14 arylcarbonyl or (c) C 7 . 19 aralkanoyl,
  • C 6 . 14 aryloxy which may be substituted with (a) C 6 alkyl, (b) C 3 . 8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Cj.g alkoxy, (g) carboxyl, (h) C ⁇ alkoxy- carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) C ! _ 6 alkanoyl,
  • C 6 alkanoyl (14) C 6 _ 14 arylcarbonyl which may be substituted with (a) Ci- 6 alkyl, (b) C 3 _ 8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) C ⁇ 6 alkoxy, (g) carboxyl, (h) C,_ 6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) C ⁇ _ 6 alkanoyl, (15) a 3- to 8-membered heterocyclic group containing 1 to 4 hetero-atoms selected from nitrogen, oxygen and sulfur, or a condensed heterocyclic group thereof with a 6- to 8-membered carbocyclic group or a heterocyclic group, which may be substituted with (a) C ⁇ alkyl, (b) C 3 .
  • (1 7 ) c ⁇ -i 2 alkylthio which may be substituted with (a) 3 - 8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C,. 12 alkoxy, (f) carboxyl, (g) C 2 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) Cj. 12 alkanoyl,
  • C ⁇ _ 12 alkylsulfonyl which may be substituted with (a) C 3 _ 8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) x . n alkoxy, (f) carboxyl, (g) C 1 . i 2 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) Ci.i T. alkanoyl,
  • hydroxyl which may be acylated with (a) C . l2 alkanoyl, (b) C 6 . 14 arylcarbonyl or (c) C 7 _ 19 aralkanoyl,
  • ( 7 ) C 6 _ 14 aryloxy which may be substituted with (a) C 1-6 alkyl, (b) C 3 , 8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) C 6 alkoxy, (g) carboxyl, (h) C]. 6 alkoxy- carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cj. 6 alkanoyl,
  • C l2 alkanoyl (13) C 6 . 14 aryl which may be substituted with (a) C ⁇ _ 6 alkyl, (b) C 3 . 8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) C ⁇ g alkoxy, (g) carboxyl, (h) C 6 alkoxy- carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cj- 6 alkanoyl.
  • C 6 , 14 arylcarbonyl which may be substituted with (a) C LS alkyl, (b) C 3 .
  • C 1-12 alkylthio which may be substituted with (a) C 3 _ 8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, ( e ) C 1 - 12 alkoxy, (f) carboxyl, (g) C 12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) C 12 alkanoyl,
  • C ⁇ _i 2 alkylsulfinyl which may be substituted with (a) C 3 _ 8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C ⁇ . 12 alkoxy, (f) carboxyl, (g) C ⁇ . l 2 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) C LJJ alkanoyl,
  • C ⁇ _ 12 alkylsulfonyl which may be substituted with (a) C 3 _ 8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C,. 12 alkoxy, (f) carboxyl, (g) C j. _ 12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) C ⁇ _ 12 alkanoyl,
  • (22) C 6 . 14 arylsulfonyl which may be substituted with (a) C ! _ 6 alkyl, (b) C 3 . 8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) C,_ 6 alkoxy, (g) carboxyl, (h) C j _ 6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) C ⁇ 6 alkanoyl, or
  • C a 5- to 8-membered heterocyclic group containing 1 to 4 hetero-atoms selected from nitrogen, oxygen and sulfur, which may be substituted with (1) C N12 alkyl which may be substituted with (a) C 3 _ 8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C,. 12 alkoxy, (f) carboxyl, (g) Ci_ 12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) C ⁇ _ 12 alkanoyl, (2) C 3 _ 8 cycloalkyl which may be substituted with (a) C-,.
  • hydroxyl which may be acylated with (a) C ⁇ alkanoyl, (b) C 6 . 14 arylcarbonyl or (c) C 7 . 19 aralkanoyl,
  • C 6 . 14 aryl which may be substituted with (a) C N6 alkyl, (b) C 3 . 8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Ci_ 6 alkoxy, (g) carboxyl, (h) C 6 alkoxy- carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) C LS alkanoyl,
  • C 6 . 14 arylcarbonyl which may be substituted with (a) C ⁇ g alkyl, (b) C 3 . 8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) C ⁇ alkoxy, (g) carboxyl, (h) C ⁇ ft alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) C l . 6 alkanoyl,
  • Cj. 12 alkylthio which may be substituted with (a) C 3 _ 8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, ( e ) i. ⁇ .2 alkoxy, (f) carboxyl, (g) C ⁇ . 12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) C ⁇ alkanoyl,
  • C ⁇ _ 12 alkylsulfinyl which may be substituted with (a) C 3 . 8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C,_ 12 alkoxy, (f) carboxyl, (g) C ⁇ alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) C . l2 alkanoyl,
  • C i . n alkylsulfonyl which may be substituted with (a) C 3 . 8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C i . l2 alkoxy, (f) carboxyl, (g) C t . alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) d.1 2 alkanoyl,
  • (22) C 6 . 14 arylsulfonyl which may be substituted with (a) Cj- 6 alkyl, (b) C 3 . 8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Cj.g alkoxy, (g) carboxyl, (h) C !
  • R and R may be combined with the adjacent nitrogen atom to form a heterocyclic group selected from 1-pyrrolidinyl, 1- imidazolyl, piperidino, 1-piperazinyl, 3-oxazolidinyl, hexamethylenimino, heptamethylenimino, morpholono, 1- indolinyl and phthalimido, which may be substituted with (a) Ci.
  • R a and R b' independently represents (A) hydrogen, (B) a hydrocarbon group which may be substituted with (1) C,. 12 alkyl which may be substituted with (a) C 3 _ 8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C U12 alkoxy, (f) carboxyl, (9) C ⁇ - 12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) C ⁇ _ 12 alkanoyl,
  • hydroxyl which may be acylated with (a) C,. 1Z alkanoyl, (b) C 6 . 14 arylcarbonyl or (c) C 7 . 19 aralkanoyl,
  • C 6 . 14 aryloxy which may be substituted with (a) C ⁇ alkyl, (b) C 3 _ 8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) C ⁇ alkoxy, (g) carboxyl, (h) C ⁇ alkoxy- carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) C ⁇ . 6 alkanoyl,
  • C 6 . 14 aryl which may be substituted with (a) d_ 6 alkyl, (b) C 3 . 8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) d. 6 alkoxy, (g) carboxyl, (h) d- ⁇ alkoxy- carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Ci-g alkanoyl,
  • C 6 . 14 arylcarbonyl which may be substituted with (a) d- ⁇ alkyl, (b) C 3 . 8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) C ⁇ _ 6 alkoxy, (g) carboxyl, (h) d_ 6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) C,_ 6 alkanoyl,
  • (22) C 6 . 14 arylsulfonyl which may be substituted with (a) Ci. 6 alkyl, (b) C 3 . 8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) C ⁇ . 6 alkoxy, (g) carboxyl, (h) Cj. f i alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) C ⁇ _ 6 alkanoyl,
  • hydroxyl which may be acylated with (a) d- 12 alkanoyl, (b) C 6 _ 1A arylcarbonyl or (c) C 7 . 19 aralkanoyl,
  • C 6 . 14 aryloxy which may be substituted with (a) d. 6 alkyl, (b) C 3 . 8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Cj. 6 alkoxy, (g) carboxyl, (h) d. 6 alkoxy- carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cj. f i alkanoyl,
  • C 6 .j 4 aryl which may be substituted with (a) d. 6 alkyl, (b) C 3 . 8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) d_ 6 alkoxy, (g) carboxyl, (h) d. 6 alkoxy- carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cj. f i alkanoyl,
  • C f i. 14 arylcarbonyl which may be substituted with (a) C j . 6 alkyl, (b) C 3 . 8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) d_ 6 alkoxy, (g) carboxyl, (h) Cj. 6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) d_ 6 alkanoyl,
  • d_ 12 alkylsulfinyl which may be substituted with (a) C 3 _a cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) d- 12 alkoxy, (f) carboxyl, (g) Cj. 12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) Cj. 12 alkanoyl,
  • C j - 12 alkylsulfonyl which may be substituted with (a) C 3 . 8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C J . J2 alkoxy, (f) carboxyl, (g) Cj. 12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) Cj. 12 alkanoyl,
  • C 6 _ ⁇ 4 arylsulfinyl which may be substituted with (a) Cj. 6 alkyl, (b) C 3 . 8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) d_ 6 alkoxy, (g) carboxyl, (h) Cj. 6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) d. 6 alkanoyl, or
  • R 6 and R independently represents (A) hydrogen, (B) d. j? alkanoyl, (C) a Cj.j 9 hydrocarbon group which may be substituted with (1) Cj. 12 alkyl which may be substituted with (a) C 3 . 8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C . J2 alkoxy, (f) carboxyl, (g) Cj. 12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) Cj. 12 alkanoyl,
  • C 3 _a cycloalkyl which may be substituted with (a) C,. 8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e)
  • C 6 . 14 aryl which may be substituted with (a) C,. 6 alkyl, (b) C 3 . 8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) d_ 6 alkoxy, (g) carboxyl, (h) d_ 6 alkoxy- carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cj. 6 alkanoyl, (14) C 6 . 14 arylcarbonyl which may be substituted with (a) Cj. 6 alkyl, (b) C 3 .
  • d_ ⁇ 2 alkylthio which may be substituted with (a) C 3 _ 8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, ( e ) C . .- 2 alkoxy, (f) carboxyl, (g) d_ 12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) Cj.j 2 alkanoyl,
  • Cj. 12 alkylsulfinyl which may be substituted with (a) C 3 . 8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) d_ 12 alkoxy, (f) carboxyl, (g) d- 12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) C 12 alkanoyl,
  • Cj. 12 alkylsulfonyl which may be substituted with (a) C 3 . 8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) Cj. 12 alkoxy, (f) carboxyl, (g) d_ 12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) C ⁇ _ 12 alkanoyl,
  • C 6 .j 4 arylsulfinyl which may be substituted with (a) Cj. 6 alkyl, (b) C 3 . 8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Cj. 6 alkoxy, (g) carboxyl, (h) Cj. 6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cj. 6 alkanoyl, or
  • (22) C 6 . 14 arylsulfonyl which may be substituted with (a) Cj. 6 alkyl, (b) C 3 . 8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Cj. 6 alkoxy, (g) carboxyl, (h) Cj. 6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) d_ 6 alkanoyl, or
  • (1 7 ) c ⁇ -i 2 alkylthio which may be substituted with (a) 3 - 8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) d_ 12 alkoxy, (f) carboxyl, (g) d_ 12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) d_ 12 alkanoyl,
  • Cj. 12 alkylsulfinyl which may be substituted with (a) C 3 _ 8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) Cj. 12 alkoxy, (f) carboxyl, (g) Cj. 12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) Cj. 12 alkanoyl,
  • C 6 -j 4 arylthio which may be substituted with (a) C,- 6 alkyl, (b) C 3 _ 8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) d_ 6 alkoxy, (g) carboxyl, (h) Cj. 6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cj. 6 alkanoyl,
  • R and R may be combined with the adjacent nitrogen atom to form a heterocyclic group selected from 1-pyrrolidinyl, 1- imidazolyl, piperidino, 1-piperazinyl, 3-oxazolidinyl, hexamethylenimino, heptamethylenimino, morpholono, 1- indolinyl and phthalimido, which may be substituted with (a) Cj. 4 alkyl which may be substituted with (i) C 3 .
  • Cj.j 2 alkyl which may be substituted with (a) C 3 _ 8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) d_ 12 alkoxy, (f) carboxyl, (g) d_ ⁇ 2 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) Cj. 12 alkanoyl,
  • C 3 _ ⁇ cycloalkyl which may be substituted with (a) C-,. 8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) Cj. 12 alkoxy, (f) carboxyl, (g) C j . 12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) d- 12 alkanoyl,
  • hydroxyl which may be acylated with (a) d_ 12 alkanoyl, (b) C 6 .j 4 arylcarbonyl or (c) C 7 .j 9 aralkanoyl,
  • C 6 .j 4 aryloxy which may be substituted with (a) C j . 6 alkyl, (b) C 3 . 8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) d- 6 alkoxy, (g) carboxyl, (h) d_ 6 alkoxy- carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cj. 6 alkanoyl,
  • C 6 .j 4 aryl which may be substituted with (a) C,_ 6 alkyl, (b) C 3 _ 8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Cj. 6 alkoxy, (g) carboxyl, (h) d_ 6 alkoxy- carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) C. 6 alkanoyl,
  • C f i. 14 arylcarbonyl which may be substituted with (a) Cj. 6 alkyl, (b) C 3 . 8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Cj. 6 alkoxy, (g) carboxyl, (h) Cj. 6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) d_ 6 alkanoyl,
  • C ⁇ _i 2 alkylsulfonyl which may be substituted with (a) C 3 _ 8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C J . J2 alkoxy, (f) carboxyl, (g) C J . J2 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) d_ 12 alkanoyl,
  • C 6 .j 4 arylsulfinyl which may be substituted with (a) Cj. 6 alkyl, (b) C 3 . 8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) d_ 6 alkoxy, (g) carboxyl, (h) Cj. 6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) C 6 alkanoyl, or
  • (22) C 6 . 14 arylsulfonyl which may be substituted with (a) Cj. 6 alkyl, (b) C 3 . 8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Cj. 6 alkoxy, (g) carboxyl, (h) Cj. 6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cj. 6 alkanoyl,
  • C j . 12 alkyl which may be substituted with (a) C 3 . 8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) Cj. 12 alkoxy, (f) carboxyl, (9) c ⁇ - ⁇ alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) d_ 12 alkanoyl,
  • C f i. 14 aryl which may be substituted with (a) d_ 6 alkyl, (b) C 3 . 8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Cj_ 6 alkoxy, (g) carboxyl, (h) d. 6 alkoxy- carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cj. 6 alkanoyl,
  • C f i.ji arylcarbonyl which may be substituted with (a) Cj. 6 alkyl, (b) C 3 _ 8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Cj. 6 alkoxy, (g) carboxyl, (h) Cj. 6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) d_ 6 alkanoyl,
  • C.j 2 alkylthio which may be substituted with (a) d- ⁇ cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C. 12 alkoxy, (f) carboxyl, (g) Cj. 12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) Cj. 12 alkanoyl,
  • d_ 12 alkylsulfinyl which may be substituted with (a) C 3 . 8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) Cj. 12 alkoxy, (f) carboxyl, (g) Cj_ 12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) C j . 12 alkanoyl,
  • C J . J2 alkylsulfonyl which may be substituted with (a) C 3 . 8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C ⁇ _ 12 alkoxy, (f) carboxyl, (g) Cj.j 2 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) Cj. 12 alkanoyl,
  • C f i. 14 arylthio which may be substituted with (a) C,_ 6 alkyl, (b) C 3 . 8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) d_ 6 alkoxy, (g) carboxyl, (h) Cj. 6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cj. 6 alkanoyl,
  • C 6 . 14 arylsulfinyl which may be substituted with (a) Cj. 6 alkyl, (b) C 3 . 8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Cj. 6 alkoxy, (g) carboxyl, (h) j. 6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) C_ 6 alkanoyl, or
  • R represents 1) hydrogen, 2) halogen, 3) a Cj_ 19 hydrocarbon group which may be substituted with (1) C,. 12 alkyl which may be substituted with (a) C 3 . 8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) Cj.j 2 alkoxy, (f) carboxyl, (g) C J . J2 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) d_ 12 alkanoyl,
  • hydroxyl which may be acylated with (a) d_ 12 alkanoyl, (b) C 6 .j 4 arylcarbonyl or (c) C 7 . 19 aralkanoyl,
  • C 6 . 14 aryl which may be substituted with (a) d_ 6 alkyl, (b) C 3 . 8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) d_ 6 alkoxy, (g) carboxyl, (h) d_ 6 alkoxy- carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cj. 6 alkanoyl,
  • C 6 . 14 arylcarbonyl which may be substituted with (a) Cj. 6 alkyl, (b) C 3 . 8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Cj_ 6 alkoxy, (g) carboxyl, (h) Cj. 6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) d_ 6 alkanoyl,
  • Cj. 12 alkylthio which may be substituted with (a) C 3 - 8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) Cj. 12 alkoxy, (f) carboxyl, (g) Cj_ 12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) Cj_ 12 alkanoyl,
  • Cj. 12 alkylsulfonyl which may be substituted with (a) C 3 _ B cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) d_ 12 alkoxy, (f) carboxyl, (g) d- 12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) d- 12 alkanoyl,
  • C f i. 14 arylthio which may be substituted with (a) C,. 6 alkyl, (b) C 3 . 8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) d_ 6 alkoxy, (g) carboxyl, (h) C N6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or
  • C 6 .j 4 arylsulfinyl which may be substituted with (a) Cj. 6 alkyl, (b) C 3 . 8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) d_ 6 alkoxy, (g) carboxyl, (h) Cj. 6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cj. 6 alkanoyl, or
  • J2 alkyl which may be substituted with (a) C 3 . 8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) d_ 12 alkoxy, (f) carboxyl, (g) Cj. 12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) d_ 12 alkanoyl,
  • hydroxyl which may be acylated with (a) C J . J2 alkanoyl, (b) C 6 . 14 arylcarbonyl or (c) C 7 .j 9 aralkanoyl,
  • C 6 . 14 aryloxy which may be substituted with (a) d_ 6 alkyl, (b) C 3 . 8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Cj. 6 alkoxy, (g) carboxyl, (h) d_ 6 alkoxy- carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) C j . 6 alkanoyl, (8) carboxyl,
  • C 6 . j4 aryl which may be substituted with (a) d_ 6 alkyl, (b) C 3 . 8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) C j _ 6 alkoxy, (g) carboxyl, (h) Cj. 6 alkoxy- carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cj. 6 alkanoyl,
  • C 6 .j 4 arylcarbonyl which may be substituted with (a) C j . 6 alkyl, (b) C 3 . 8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) d_ 6 alkoxy, (g) carboxyl, (h) C. 6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cj. 6 alkanoyl,
  • Cj. 12 alkylthio which may be substituted with (a) C 3 . 8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) Cj. j2 alkoxy, (f) carboxyl, (g) d_ 12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) Cj. 12 alkanoyl,
  • Cj. 12 alkylsulfinyl which may be substituted with (a) C 3 . 8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) Cj. 12 alkoxy, (f) carboxyl, (g) d_ 12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) Cj. 12 alkanoyl,
  • Cj. 12 alkylsulfonyl which may be substituted with (a) C 3 . 8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) d- 12 alkoxy, (f) carboxyl, (g) Cj. 12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) C j .j 2 alkanoyl,
  • C f i. 14 arylthio which may be substituted with (a) C,_ 6 alkyl, (b) C 3 . 8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) d_ 6 alkoxy, (g) carboxyl, (h) Cj. 6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or
  • a d_ 19 hydrocarbon-oxy which may be substituted with (1) d_ ⁇ 2 alkyl which may be substituted with (a) C 3 . a cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) Cj. 12 alkoxy, (f) carboxyl, (g) Cj. 12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) d_ 12 alkanoyl,
  • d_ 6 alkanoyl (15) a 3- to 8-membered heterocyclic group containing 1 to 4 hetero-atoms selected from nitrogen, oxygen and sulfur, or a condensed heterocyclic group thereof with a 6- to 8-membered carbocyclic group or a heterocyclic group, which may be substituted with (a) d_ 6 alkyl, (b) C 3 .
  • Cj. 12 alkylthio which may be substituted with (a) C 3 _ 8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) Cj. 12 alkoxy, (f) carboxyl, (g) d_ 12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) C . 12 alkanoyl,
  • d_ 12 alkylsulfinyl which may be substituted with (a) C 3 . 8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) Cj. 12 alkoxy, (f) carboxyl, (g) C j . 12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) C . 12 alkanoyl,
  • C j . 12 alkylsulfonyl which may be substituted with (a) C 3 . 8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C J . J2 alkoxy, (f) carboxyl, (g) Cj.j 2 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) C J . J2 alkanoyl,
  • C 6 . j4 arylthio which may be substituted with (a) C,. 6 alkyl, (b) C 3 . 8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Cj. 6 alkoxy, (g) carboxyl, (h) Cj- 6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cj.g alkanoyl,
  • C 6 .j 4 arylsulfinyl which may be substituted with (a) C j .g alkyl, (b) C 3 . 8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) d_ 6 alkoxy, (g) carboxyl, (h) Cj.g alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) d_ 6 alkanoyl, or
  • R represents (A) a d_ 19 hydrocarbon group which may be substituted with (1) C J . J2 alkyl which may be substituted with (a) C 3 . 8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) d_ 12 alkoxy, (f) carboxyl, (g) Cj. 12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) d_ 12 alkanoyl,
  • hydroxyl which may be acylated with (a) Cj. 12 alkanoyl, (b) C 6 . 14 arylcarbonyl or (c) C 7 . 19 aralkanoyl,
  • ( 7 ) c 6 -u aryloxy which may be substituted with (a) Cj. 6 alkyl, (b) C 3 . 8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) d_ 6 alkoxy, (g) carboxyl, (h) d_ 6 alkoxy- carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cj.g alkanoyl,
  • C f i. 14 aryl which may be substituted with (a) d_ 6 alkyl, (b) C 3 . 8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) d_ 6 alkoxy, (g) carboxyl, (h) d- ⁇ alkoxy- carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cj.g alkanoyl,
  • C 6 . 14 arylcarbonyl which may be substituted with (a) Cj.6 alkyl, (b) C 3 . 8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) d_ 6 alkoxy, (g) carboxyl, (h) Cj.g alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) d- 6 alkanoyl,
  • C 3 . 8 cycloalkyl which may be substituted with (a) C 3 . 8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C J . J2 alkoxy, (f) carboxyl, (g) d_ 12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) d- 12 alkanoyl,
  • hydroxyl which may be acylated with (a) C J . J2 alkanoyl, (b) C 6 . 14 arylcarbonyl or (c) C 7 . 19 aralkanoyl,
  • C 6 .j 4 aryl which may be substituted with (a) C j . 6 alkyl, (b) C 3 . 8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) d_ 6 alkoxy, (g) carboxyl, (h) Cj. 6 alkoxy- carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) d_ 6 alkanoyl,
  • C 6 .j 4 arylcarbonyl which may be substituted with (a) Cj. 6 alkyl, (b) C 3 . 8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Cj. 6 alkoxy, (g) carboxyl, (h) Cj.g alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) d_ 6 alkanoyl,
  • Compound B particularly compound A, has excellent inhibitory activities of IL-6 activity and NO production of NOS inducible cells and low toxicity.
  • IL-6 activity or NO production in human and other mammalian animals (e.g. mouse, rat, guinea pig, rabbit, dog, cat, bovine, swine, sheep, monkey, chimpanzee, etc.).
  • mammalian animals e.g. mouse, rat, guinea pig, rabbit, dog, cat, bovine, swine, sheep, monkey, chimpanzee, etc.
  • compound B can be safely used as a drug, for example a prophylactic and a therapeutic drug for IL-6-associated diseases, namely heart diseases such as myocardiopathy, cardiac hypertrophy, myocardial infarction, angina pectoris, etc., various autoimmune diseases such as chronic rheumatoid arthritis, systemic lupus erythematosus, systemic scleroder a, rheumatic fever, polymyositis, periarteritis nodosa, Sj ⁇ gren's syndrome, Behcet's disease, Castleman's disease, autoimmune hemolytic anemia, etc., inflammatory diseases such as mesangial proliferative nephritis, IgA nephritis, lupus nephritis, osteoporosis, amyloidosis, bronchial asthma, atopic dermatitis, psoriasis, pleurisy, ulcerative colitis,
  • NO-associated diseases for example, atherosclerosis, myocarditis, myocardiopathy, ischemic brain disorder, Alzheimer's disease, multiple sclerosis, septicemia, rheumatoid arthritis, osteoarthritis, gastric ulcer, duodenal ulcer, ulcerative colitis, diabetes, glomerulonephritis, osteoporosis, pneumonia, hepatitis, graft rejection, pain, etc., in human and other mammalian animals (e.g. mouse, rat, guinea pig, rabbit, dog, cat, bovine, swine, sheep, monkey, chimpanzee, etc.).
  • mammalian animals e.g. mouse, rat, guinea pig, rabbit, dog, cat, bovine, swine, sheep, monkey, chimpanzee, etc.
  • compound B can be administered, either alone or in mixture with a pharmacologically acceptable carrier, excipient, or diluent, orally in such dosage forms as tablets, capsules, granules, powders, etc. or parenterally in such dosage forms as injections, among other forms.
  • a pharmacologically acceptable carrier e.g. hydroxypropyl- cellulose, hydroxypropylmethylcellulose, macrogols, etc.
  • disintegrators e.g. starch, carboxymethylcellulose calcium, etc.
  • excipients e.g. lactose, talc, etc.
  • lubricants e.g.
  • an aqueous medium e.g. distilled water
  • isotonic solutions e.g. saline. Ringer's solution
  • isotonizing agents e.g. glucose, D-sorbitol, D-mannitol, sodium chloride, etc.
  • stabi ⁇ lizers e.g. human serum albumin etc.
  • antiseptics e.g. benzyl alcohol, chlorobutanol, methyl p- hydroxybenzoate, propyl p-hydroxybenzoate, phenols, etc.
  • buffers e.g. phosphate buffer, sodium acetate buffer, etc.
  • local anesthetics e.g. benzalkonium chloride, procaine hydrochloride, etc.
  • the daily dosage of compound B depends on various factors such as species of mammals, diseases, clinical condition, etc.
  • about 0.1-10 mg, preferably about 0.1-5 mg, per kg body weight is administered once daily.
  • Example 2 To 0.93 g of the 2-methyl-5-methylsulfonyl-4- oxazolecarbonitrile synthesized in Example 1 was added 20 ml of methanol and the mixture was heated to provide a solution. To this solution was added 1.32 g of sodium sulfide nonahydrate. Then, 1.0 g of l-bromo-3- phenylpropane was added and the mixture was stirred at 50°C for 2 hours. Then, 100 ml of ethyl acetate was added and the mixture was washed with two 50 ml portions of water.
  • H-NMR (CDC1 3 ) ⁇ : 0.93 (t, J 7.2 Hz, 3H) , 1.38 ( ,
  • Example 68 the compound of Example 67 was synthesized.
  • Example 69 the compounds of Example 98 and Reference Examples 70 and 73 were respectively synthesized.
  • N-benzyl-2-methyl-5-methylsulfonyl-4-oxazole ⁇ carboxamide To 1.00 g of the 2-methyl-5-methylsulfonyl-4- oxazolecarboxylic acid synthesized in Example 68 was added 10 ml of thionyl chloride and the mixture was refluxed for 6 hours. The thionyl chloride was then distilled off and the solid residue was dissolved in 15 ml of dichloromethane. Then, a solution of benzylamine (0.57 g) and triethylamine (0.54 g) in dichloromethane (1 ml) was added dropwise with ice-cooling.
  • Example 87 the compound of Example 82 was synthesized.
  • Example 101 the compound of Example 97 was synthesized.
  • Example 104 the compound of Example 188 was synthesized.
  • Example 140 2-Methyl-5-phenylsulfonyl-4-oxazolecarboxylic acid The title compound was synthesized in the same manner as in Example 68 and the resulting oil was crystallized from methanol. H-NMR (CDCl 3 ) ⁇ : 2.59 (s, 3H) , 7.76-7.90 (m, 3H) , 8.14 (m, 2H).
  • Example 140 To 15 ml of t-butyl alcohol was added 0.65 g of the 2-methyl-5-phenylsulfonyl-4-oxazolecarboxylic acid synthesized in Example 140, followed by addition of 0.23 g of diphenylphosphorylazide (DPPA) and 0.09 g of triethylamine, and the mixture was refluxed for 2 hours. The solvent was then distilled off and the residue was dissolved in 30 ml of dichloromethane. This solution was washed with 5% aqueous citric acid solution and saturated aqueous NaHC0 3 solution in the order mentioned.
  • DPPA diphenylphosphorylazide
  • this crystal crop was dissolved in 50 ml of N,N- dimethylformamide and with ice-cooling, a solution of sodium sulfide nonahydrate (2.76 g) in water (5 ml) was added dropwise. The mixture was stirred for 5 minutes, after which 1.60 g of methyl iodide was added and the mixture was further stirred at room temperature for 1 hour. The reaction mixture was then concentrated under reduced pressure and the residue was diluted with 100 ml of ethyl acetate and 50 ml of water. The ethyl acetate layer was taken, washed with two 50 ml portions of water, dried, and concentrated.
  • Example 179 the compounds of Example 169- 178 were synthesized.
  • test compound was dissolved in N,N- dimethylformamide at a concentration of 10 mM and this solution was diluted with RPMI-1640 medium at a final concentration of 0.1 mM. Then, this dilution was further diluted serially with the same medium by the doubling dilution method to provide a concentration series from 20 ⁇ M to 0.16 ⁇ M for addition to the culture system.
  • the in ⁇ hibitory effect of the test compound on IL-6-dependent growth of cells was evaluated.
  • the cells were suspended in 10% inactivated fetal calf serum-RPMI-1640 medium at a density of 1x10 /mL and grown in a flask at 37°C under sparging with 5% C0 2 /95% air.
  • the cultured cells were seeded in a 96- well plate, at a density of 1x10* cells/0.1 mL/well. After the test compound preparation was added to the wells, IL-6 was added at a final concentration of 0.25 ng/mL.
  • test compound was found to effec ⁇ tively inhibit growth of MH60 cells.
  • the data are pre ⁇ sented in Table 26 in terms of IC 50 which is the concentration of the test compound causing 50% inhibition of growth. Table 26

Abstract

The present invention relates to oxazole derivatives having a group bonded through a sulfinyl or sulfonyl moiety at the 5-position of the oxazole ring, their production and use. The oxazole derivatives of the present invention have excellent IL-6 inhibitory activity and NO production inhibitory activity of NOS inducible cells, and can be used as a prophylactic or a therapeutic drug for IL-6-associated diseases or NO-associated diseases.

Description

DESCRIPTION OXAZOLE DERIVATIVES, THEIR PRODUCTION AND USE
[Technical Field] The present invention relates to oxazole deriva¬ tives having inhibitory activity of interleukin-6 (IL- 6) activity and that of nitrogen monoxide (NO) production of NOS inducible cells, which are of value as medicines for prophylaxis and therapy of heart diseases, autoimmune diseases, inflammatory diseases and diseases accompanied by granuloma, among other morbidities, to processes for its production, and to pharmaceutical compositions comprising said derivatives. [Background Art]
Interleukin-6 (hereinafter referred to briefly as IL-6) is a glycoprotein with a molecular mass of 26kDa as initially cloned as B-cell stimulatory factor. This cytokine is produced in T- and B-lymphocytes, onocytes, fibroblasts, keratinocytes, vascular endothelial cells, renal mesangial cells, brain astrocytes and osteoblasts. Its multifunctional physiological activity encompasses the immune system, hematopoietic system, cerebroneural system, inflammatory system, endocrine system, etc. Thus, IL-6 specifically functions as 1) antibody production inducing factor, 2) hybridoma/plasmacytoma/myeloma growth factor, 3) T-lymphocyte growth factor/killer T- cell differentiation factor, 4) hematopoietic stem cell growth factor, 5) megakaryocyte maturation factor/platelet proliferation factor, 6) nerve cell stimulating factor, 7) hepatocyte stimulatory factor, 8) osteoclast activating factor, 9) renal mesangial cell growth factor, and 10) ACTH production inducing factor, etc. [The Cytokine Handbook, 2nd Ed., Academic Press, USA., pp.145-168 (1994)]. Recently IL-6 has been to be involved in the various diseases, namely cardiac diseases such as myocardiopathy, cardiac hypertrophy, myocardial infarc¬ tion, angina pectoris, etc., various autoimmune diseases such as chronic rheumatoid arthritis, systemic lupus erythematosus, systemic scleroderma, rheumatic fever, poly yositis, periarteritis nodosa, Sjogren's syndrome, Behcet's disease, Castleman's disease, autoimmune hemolytic anemia, etc., inflammatory diseases such as mesangial proliferative nephritis, IgA nephritis, lupus nephritis, osteoporosis, bronchial asthma, atopic dermatitis, psoriasis, pleurisy, ulcerative colitis, atherosclerosis, active chronic hepatitis, alcoholic cirrhosis, gout, various types of encephalitis, etc., and diseases accompanied by granulo a such as multiple myeoloma, atrial myxoma, renal carcinoma, pulmonary adenocarcinoma, malignant mesothelioma, ovarian cancer, cancerous cachexia, and so on. In fact, in patients with chronic rheumatoid arthritis, high level of IL-6 is detected in the synovial fluid, with the definite expression of IL-6 mRNA in the synovial membrane. And administration of anti-IL-6 antibody to such patients resulted in symptomatic improvements [The Journal of Rheumatology, 20. 259-261 (1993)]. In regard to glo erulonephritis, while mesangial proliferative nephritis accompanied by advanced proteinurea was found in IL-6 transgenic mice, administration of anti-IL-6 antibody resulted in remission of the symptoms [Japanese Journal of Clinics, 50. 2840-2841 (1992)]. Moreover, in human proliferative glomerulonephritis inclusive of IgA nephritis, the urinary IL-6 level is elevated in proportion to the degree of progression of tissue damage and, therefore, IL-6 is utilized as a clinical marker. In postmenopausal osteoporosis with decreased estrogen production, IL-6 acts as osteoclast activating factor and exhibits potent bone resorption activity. In ovariectomized mice, osteoclasts proliferate but this proliferation is inhibited by anti-IL-6 antibody [Science, 257. 88-91 (1992)]. In IL-6 gene-deficient mice, no bone destruction took place even after ovariectomy. These reports indicate the involvement of IL-6 in the above-mentioned diseases and suggest that symptomatic improvements can be obtained by inhibiting the physiological activity of IL-6.
For inhibition of the physiological activity of IL-6, both inhibition of IL-6 production and inhibition of IL-6 activity can be contemplated. As regards the former approach, 4H-l-benzopyran-4-one derivatives have been reported to be inhibitors of IL-6 production
[Japanese laid-open patent application 49778/1990]. In contrast, the latter approach remains to be explored as yet (and is by nature a very singular approach), and most of the reports so far made in this area are concerned with macromolecular substances such as antibodies and peptides which are not suitable for administration [The European Journal of Immunology, 18. 951-956 (1988)].
Nitrogen monoxide (NO) is considered to play multi-faceted roles in the mammalian body, for example as a vasodilating factor in the vascular system [Pharmacol. Rev. li, 109-142 (1991)], as a factor having tumoricidal and germicidal activity in the leukocytic system [Curr. Opin. Immunol., 3., 65-70 (1991)], and as a neurotransmitter in the nervous system, among others [Neuron, £, 3-11 (1992)].
NO is produced from L-arginine by NO synthase (NOS). Today, three isozymes, namely neural NOS, vascular endothelial NOS and inducible NOS (iNOS), have been identified [Cell, ! , 705-707 (1992)]. Based on the mode of production, the former two isozymes are also known as constitutive NOS (cNOS) in antithesis to the third one iNOS. cNOS exists in the vascular endothelial cells and nerve cells. cNOS is calcium/calmodulin-dependent and activated by various receptor stimuli to produce a small amount of NO, thus carrying out the physiological modulations mentioned above. On the other hand, iNOS is induced by various cytokines and bacterial lipopolysaccharides (LPS) in the macrophages and neutrophils and it has been pointed out that because it produces a large amount of NO persistently, iNOS not only shows the above-mentioned physiological activities but, when produced locally, injures the cells and tissues [Immunol. Today, 13. 157-160 (1992)]. As the cells and tissues in which iNOS is expressed, not only the above-mentioned cells but also hepatocytes, Kupffer cells, gliacytes, vascular smooth muscle cells, vascular endothelial cells, heart muscle lining, myocardial cells, mesangial cells, chondrocytes, sinovial cells, pancreatic β cells and osteoclasts are known [FASEB J., £, 3051-3064 (1992), Arch Surg. , 12JB_, 396-401 (1993), J. Biol . Chem., 4_4, 27580-27588 (1994), J. Cell. Biochem., 57, 399-408 (1995)]. It is, therefore, conceivable that NO produced in these cells and tissues is involved in various diseases. Therefore, any substance that inhibits production and release of NO from cells in which iNOS has been induced is expected to be of value as a drug for prevention and therapy of various NO- associated diseases such as, for example, atherosclerosis, myocarditis, myocardiopathy, ischemic brain disorder, Alzheimer's disease, multiple sclerosis, septicemia, chronic rheumatoid arthritis, osteoarthritis, gastric ulcer, duodenal ulcer, ulcerative colitis, diabetes, glomerulonephritis, osteoporosis, pneumonia, hepatitis, graft rejection and pain. From the above points of view, L-arginine analogues [Pharmacol. Rev., ϋ, 109-142 (1991)], a ino- guanidine [Br. J. Pharmacol., 110. 963-968 (1993), and S-ethylisothiourea [J. Biol. Chem., 4_3_, 26669-26676 (1994)], among others, have been reported for use as inhibitors of iNOS. However, these compounds are either not sufficiently active or inhibit not only iNOS but also cNOS which is in charge of physiological functions. Various drugs have heretofore been used in the treatment of heart diseases, autoimmune diseases, inflammatory diseases, and diseases accompanied by granuloma but none of them are fully satisfactory in efficacy or in safety. Therefore, development of drugs improved in these aspects has been awaited for the prevention and treatment of heart diseases, autoimmune diseases, inflammatory diseases, and diseases accompanied by granuloma.
Some oxazole derivatives were described in Chem. Mater., 1994, 6(7) 1023-1032, Chem. Abs. 107:96787 and EP-A 879539. However, inhibition of IL-6 activity and NO production of the oxazole derivatives of this invention has not been disclosed anywhere.
[Disclosure of Invention]
After intensive research for solving the above- mentioned problems, the inventors of the present invention discovered surprisingly that oxazole derivatives having a group bonded through a sulfinyl or sulfonyl moiety at the 5-position of the oxazole ring have excellent IL-6 inhibitory activity and NO production inhibitory activity of NOS inducible cells and are effective in the prevention and therapy of heart diseases, autoimmune diseases, inflammatory diseases, and diseases accompanied by granuloma. The inventors thenceforth did further research and have completed the present invention.
The present invention accordingly provides:
1. An oxazole derivative having a group bonded through a sulfinyl or sulfonyl moiety at the 5-position of the oxazole ring, provided that when the substituent at the 4-position is hydrogen, (1) the compound which has 4-methoxyphenyl or 4-methoxyphenylethinyl at the 2- position and nonafluorobutylsulfonyl at the 5-position, (2) the compound which has phenyl at the 2-position and (2-phenyl-5-thiazolyl)sulfonyl at the 5-position, and (3) the compound which has 3-[5-(2,3-epoxy-5-hydroxy-4- methylhexyl)-3,4-dihydroxytetrahydropyran-2-yl]-2- methyl-l-(E)-propenyl at the 2-position and 4-methyl- phenylsulfonyl at the 5-position are excluded;
2. The oxazole derivative as described in 1, which has a halogen atom or a group bonded through a carbon, nitrogen, oxygen, or sulfur atom as a substituent at the 2-position of the oxazole ring;
3. The oxazole derivative as described in 1, which has a halogen atom or a group bonded through a carbon, nitrogen, oxygen, or sulfur atom as a substituent at the 4-position of the oxazole ring;
4. The oxazole derivative as described in 1 , which is a compound of the formula:
Figure imgf000008_0001
wherein R represents a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, or amino which may be substituted; n represents 1 or 2; R represents hydrogen, cyano, acyl, carbamoyl which may be substituted, thiocarbamoyl which may be substituted, a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, amino which may be substituted, or carboxyl which may be esterified; R represents hydrogen, halogen, a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, a hydrocarbon-oxy group which may be substituted, amino which may be substituted, carboxyl which may be esterified, or a group of the formula -S(0)m-R; where R represents a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted; m represents 0, 1, or 2;
5. The oxazole derivative as described in 4, wherein R represents a C^^ hydrocarbon group which may be substituted, a 5- to 8-membered heterocyclic group containing at least 1 atom selected from nitrogen, oxygen, and sulfur, which may be substituted, or amino which may be substituted;
R represents hydrogen, cyano, an organic carboxylic acid-derived acyl group, carbamoyl which may be substi¬ tuted, thiocarbamoyl which may be substituted, a C^,, hydrocarbon group which may be substituted, a 5- to 8- membered heterocyclic group containing at least 1 atom selected from nitrogen, oxygen, and sulfur, which may be substituted, amino which may be substituted, or carboxyl which may be esterified; R represents hydrogen, halogen, a CL_19 hydrocarbon group which may be substituted, a 5- to 8-membered heterocyclic group containing at least 1 atom selected from nitrogen, oxygen, and sulfur, which may be substituted, a C 19 hydrocarbon-oxy group which may be substituted, amino which may be substituted, carboxyl which may be esterified, or a group of the formula -S(0)m-R'; where R' represents a C,.19 hydrocarbon group which may be substituted or a 5- to 8-membered heterocyclic group containing at least 1 atom selected from nitrogen, oxygen, and sulfur, which may be substituted; m represents 0, 1, or 2;
6. The oxazole derivative as described in 4, wherein R represents
(1) C,.19 alkyl which may be substituted with (i) a 5- or 6-membered sulfur-containing heterocyclic group,
(ii) a 5- or 6-membered oxygen- and nitrogen-containing heterocyclic group which may be substituted with C._.z alkyl or cyano, (iii) carboxyl, (iv) C6. arylcarbonyl, (v) cyano, (vi) carbamoyl which may be mono- or di- substituted with C^^ alkyl, or (vii) Cx.l2 alkoxy- carbonyl,
(2) C2.12 alkenyl which may be substituted with mono- or alkylamino,
(3) C2-π alkinyl, (4) C3.10 cycloalkyl,
(5) C6. aryl which may be substituted with (i) halogen, (ii) C,_12 alkoxy, (iii) amino which may be substituted with (a) carbamoyl which may be substituted with C,_12 alkyl or C3.10 cycloalkyl, (b) C6.14 arylsulfonyl which may be substituted with halogen, or (c) cι-i2 alkylsulfonyl, (iv) C,_12 alkyl which may be substituted with halogen, (v) nitro or (vi) hydroxyl,
(6) C7.19 aralkyl which may be substituted with (i) halogen, (ii)
Figure imgf000010_0001
alkoxy, (iii) amino which may be substituted with (a) C6. arylsulfonyl which may be substituted with
Figure imgf000010_0002
alkyl or (b) Cj..12 alkylsulfonyl, or (iv) nitro,
(7) a 5- or 6-membered nitrogen- or oxgen-containing heterocyclic group, (8) amino which may be substituted with (i) Cι_12 alkyl which may be substituted with (a) C,_ι2 alkoxy-carbonyl, (b) mono- or
Figure imgf000011_0001
alkylamino or (c) a 5- or 6- membered nitrogen-containing heterocyclic group, (ii) C7_19 aralkyl which may be substituted with halogen or C._12 alkoxy, (iii) C4.12 bridged-ring hydrocarbon group, (iv) C6.u aryl or (v) C3.10 cycloalkyl or (9) thienopyrimidylhydrazino which may be substituted with C,_12 alkyl;
7. The oxazole derivative as described in 4, wherein R1 represents
(1) C 12 alkyl which may be substituted with (i) thienyl, (ii) oxazolyl which may be substituted with Ci_6 alkyl or cyano, (iii) carboxy, (iv) C6.12 arylcarbonyl, (v) cyano, (vi) carbamoyl which may be mono- or di-substituted with C,_6 alkyl, or (vii) C 6 alkoxy-carbonyl,
(2) C2.6 alkenyl which may be substituted with mono- or di-Cj.6 alkylamino, (3) C2.6 alkinyl,
(4) C3.8 cycloalkyl,
(5) C6.12 aryl which may be substituted with (i) halogen, (ii) C._6 alkoxy, (iii) amino which may be substituted with (a) carbamoyl which is substituted with Ci.s alkyl or C3_8 cycloalkyl, (b) C6.12 arylsulfonyl which may substituted with halogen or (c) C^ alkylsulfonyl, (iv) Cj.g alkyl which may be substituted with halogen (v) nitro or (vi) hydroxy,
(6) C7.13 aralkyl which may be substituted with (i) halogen, (ii) Cx.6 alkoxy, (iii) amino which may be substituted with (a) C6.12 arylsulfonyl which may be substituted with C^ alkyl or (b) C,_6 alkylsulfonyl, or (iv) nitro,
(7) a heterocyclic group selected from the group consisting of pyrimidyl, piperidino, morpholino and 1- piperazinyl,
(8) amino which may be substituted with (i) C,.6 alkyl which may be substituted with (a) Ct_6 alkoxy-carbonyl, (b) mono- or di-Cj.6 alkylamino or (c) pyridyl, (ii) C6_ 12 aryl, (iii) C7.13 aralkyl which may be substituted with halogen or Ci_6 alkoxy, (iv) adamantyl or (v) C3.8 cycloalkyl, or
(9) thienopyrimidylhydrazino which may be substituted with Ci-e alkyl;
8. The oxazole derivative as described in 4, wherein R represents (1) cyano, (2) Cj.,2 alkanoyl,
(3) carbamoyl which may be substituted with (i) Cι_12 alkyl which may be substituted with a 5- or 6-membered nitrogen-containing heterocyclic group, (ii) C,_12 alkoxy or (iii) C7_19 aralkyl, (4) a 5- or 6-membered saturated nitrogen-containing heterocyclic-carbonyl, which may be substituted with C6-ι« aryl,
(5) thiocarbamoyl which may be substituted with (i) Ct- 12 alkyl or (ii) C7.19 aralkyl, (6) a 5- or 6-membered saturated nitrogen-containing heterocyclic-thiocarbonyl,
(7) cι-i2 alkyl which may be substituted with a group selected from the group consisting of (i) hydroxyl which may be acylated with C6.1 arylcarbonyl, (ii) halogen, (iii) carboxyl, (iv) cyano, (v) amino which may be substituted with Cι_12 alkyl which may be substituted with a 5- or 6-membered nitrogen-containing heterocyclic group or C7.19 aralkyl, (vi) a 5- or 6- membered saturated heterocyclic group containing 2 nitrogen atoms, which may be substituted with C6.14 aryl, (vii) phthalimido, (viii) C6.14 arylsulfonyl which may be substituted with Cj.12 alkyl, and (ix) C6_1 aryloxy which may be substituted with halogen,
(8) C7.19 aralkyl which may be substituted with halogen or hydroxyl,
(9) a 5- or 6-membered nitrogen and sulfur-containing heterocyclic group, which may be substituted with (i) C 12 alkoxy-carbonyl or (ii) C6.14 aryl,
(10) amino which may be substituted with C^^ alkoxy- carbonyl,
(11) carboxyl, or
(12) C._12 alkoxy-carbonyl;
9. The oxazole derivative as described in 4, wherein R represents
(1) cyano,
(2) Cl_6 alkanoyl,
(3) carbamoyl which may be substituted with (i) C,.6 alkyl which may be substituted with pyridyl, (ii) C7_n aralkyl or (iii) C^ alkanoyl,
(4) piperidinocarbonyl,
(5) 1-piperazinylcarbonyl which may be substituted with C-6-12 aryl,
(6) thiocarbamoyl which may be substituted with (i) C,.fi alkyl or (ii) C7.13 aralkyl,
(7) piperidinothiocarbonyl,
(8) C,_6 alkyl which may be substituted with (i) hydroxy which may be acylated with C6.12 arylcarbonyl, (ii) halogen, (iii) carboxyl, (iv) cyano, (v) amino which may substituted with (a) C,_6 alkyl which may be substituted with pyridyl or (b) C7.13 aralkyl, (vi) 1- piperazinyl which may be substituted with C6.12 aryl, (vii) phthalimido, (viii) C6_12 arylsulfonyl which may be substituted with C,._6 alkyl, or (ix) C6_12 aryloxy which may be substituted with halogen. (9) c 7-i3 aralkyl which may be substituted with halogen or hydroxyl,
(10) thiazolyl which may be substituted with C].6 alkoxy-carbonyl or (b) C6.12 aryl, (11) amino which may be substituted with Cι_6 alkoxy- carbonyl,
(12) carboxyl, or
(13) Cι.6 alkoxy-carbonyl;
10. The oxazole derivative as described in 4, wherein R represents
(1) hydrogen,
(2) halogen,
(3) C!_12 alkyl which may be substituted with a group selected from the group consisting of (i) amino which may be substituted with C7.19 aralkyl or C._12 alkyl, (ii) a 5- or 6-membered saturated heterocyclic group containing 2 nitrogen atoms which may be substituted with C6_i4 aryl, (iii) phthalimido, (iv) C6. arylsulfonyl which may substituted with C l2 alkyl, (v) hydroxyl which may be substituted with Ci_12 alkanoyl, (vi) a 5- or 6-membered saturated nitrogen- and/or oxygen-containing heterocyclic group, (vii) halogen, (viii) C!_12 alkoxy-carbonyl, and (ix) a 5- to 6-membered unsaturated nitrogen- and/or oxgen-containing heterocyclic group, which may be substituted with C^ alkyl or cyano,
(4) C2_12 alkenyl which may be substituted with C6.u aryl, (5) C6.14 aryl which may be substituted with Cl. alkoxy,
(6) C7.19 aralkyl which may be substituted with (i) amino, (ii) nitro, (iii) CW2 alkoxy, or (iv) halogen,
(7) C3.10 cycloalkyl,
(8) C3_,0 cycloalkyl-C,.12 alkyl, (9) a C4.12 bridged-ring hydrocarbon group, (10) a 5- to 6-membered unsaturated nitrogen- and/or oxygen-containing heterocyclic group,
(11) C!_12 alkoxy,
(12) amino which may be substituted with (i) Ci.12 alkyl which may substituted with C1.12 alkoxy-carbonyl or (b) a 5- or 6-membered nitrogen-containing heterocyclic group or (ii) C7.19 aralkyl, or
(13) C 2 alkoxy-carbonyl;
11. The oxazole derivative as described in 4, wherein
3
R represents
(1) hydrogen,
(2) halogen,
(3) Cj.6 alkyl which may be substituted with (i) amino wwhhiicchh mmaayy be substituted with C7.13 aralkyl or Cι_6 aaall lkrvyll, . M(i'i i 1) 1 l --npii rpιperraa7zii nnvyll wwhhii rc-hh
Figure imgf000015_0001
Hboe csnubsstt-i i 1t- ιuι tt-oeHd wwii 1th C:6-ι2 aryl, (iii) phthalimide, (iv) C6.12 arylsulfonyl wrhhiicchh mmaayy bbee ssuubbssttiittuutteedd wwiitthh CC,,__66 aallkkyyll,, ((vv)) hhyyddrrooxxyyll which may bbee ssuubbssttiittuutteedd wwiitthh CCxx__66 aallkkaannooyyll,, ((vvii)) morpholino>,, ((vviiii)) ppiippeerriiddiinnoo,, ((vviiiiii)) hhaallooggeenn,, ((iixx)) C^ alkoxy-carbonyl, and (x) oxazolyl which may be substituted with Cj.g alkyl or cyano,
(4) C2.6 alkenyl which may be substituted with C6.12 aryl,
(5) C6.12 aryl which may be substituted with Cj_6 alkoxy,
(6) C7.13 aralkyl which may be substituted with (i) amino, (ii) nitro, (iii) Cl-6 alkoxy, or (iv) halogen,
(7) C3.8 cycloalkyl.
(8) C3.8 cycloalkyl-Cj.g alkyl (9) adamantyl,
(10) oxadiazolyl,
( \11Λ-)I C,_-66 aα.l.LkΛΛoJxΛyy,,
(12) amino which may be substituted with (i) C,.6 alkyl which may be substituted with C^6 alkoxy-carbonyl or pyridyl, or (ii) C7.13 aralkyl, or (13) Ci-s alkoxy-carbonyl;
12. The oxazole derivative as described in 4, wherein R represents (1) C 6 alkyl which may be substituted with (i) 2-thienyl or (ii) carboxyl, (2) C6.12 aryl which may be substituted with (i) halogen, (ii) C,_6 alkoxy or (iii) C alkylcarbamoylamino, (3) C7.13 aralkyl which may be substituted with nitro, (4) amino which may be substituted with (i) C^ alkyl, (ii) C6_12 aryl or (iii) C3.8 cycloalkyl, or (5) morpholino;
13. The oxazole derivative as described in 4, wherein R represents cyano, thiocarbamoyl, carbamoyl, or Cι_6 alkyl which may be substituted with halogen;
14. The oxazole derivative as described in 4, wherein R represents (1) hydrogen, (2) C^g alkyl which may be substituted with amino which may have Cl.β alkyl or C7_|5 aralkyl substituent, (3) C3_6 cycloalkyl, (4) C6.12 aryl which may be substituted with Cj_6 alkoxy or (5) C7.13 aralkyl which may be substituted with (i) halogen or (ii) C,_6 alkoxy;
15. The oxazole derivative as described in 4, wherein n is 2;
16. A process for producing the oxazole derivative as described in 4, which comprises (1) oxidizing a compound of the formula:
Figure imgf000016_0001
7/24340
15
wherein R 1, R2, and R 3 are as defined in 4 to obtain an oxazole derivative of the formula:
R'-S
Figure imgf000017_0001
wherein R , R , and R are as defined above, and n is as defined in 4,
(2) reacting a compound of the formula:
Figure imgf000017_0002
wherein R and R are as defined above; R12 represents lower alkyl or phenyl; n is 0, 1, or 2 with a compound of the formula:
Figure imgf000017_0003
wherein R is as defined above; M represents an alkali metal to obtain an oxazole derivative of the formula:
Figure imgf000017_0004
wherein R1, R2, and R are as defined above, or (3) reacting a compound of the formula:
Figure imgf000017_0005
wherein R2, R3, and n are as defined above; X represents a leaving group with a compound of the formula:
Figure imgf000018_0001
wherein R and R independently represent hydrogen, a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted; R4 and R5 may be combined with the adjacent nitrogen atom to form a heterocyclic group to obtain an oxazole derivative of the formula:
Figure imgf000018_0002
wherein R , _R3, n, R , and R are as defined above;
17. A process for producing a compound of the formula:
Figure imgf000018_0003
R3
wherein R 1, R2, and R3 are as defined in 4 which comprises
(1) reacting a compound of the formula:
Figure imgf000018_0004
wherein R and R are as defined above with a compound of the formula:
M2S wherein M represents an alkali metal and a compound of the formula:
RXX wherein R is as defined above; X represents a leaving group, or
(2) reacting a compound of the formula:
Rl
Figure imgf000019_0001
wherein R2 and R3 are as defined above; R12 represents lower alkyl or phenyl; n is 0, 1, or 2 with a compound of the formula:
RX-SH wherein R are as defined above, or (3) reacting a compound of the formula:
Figure imgf000019_0002
wherein R , R , R and n are as defined above with a compound of the formula:
M2S wherein M is as defined above and a compound of the formula:
R'X wherein R and X are as defined above;
18. A pharmaceutical composition comprising an oxazole derivative having a group bonded through a sulfinyl or sulfonyl moiety at the 5-position of the oxazole ring;
19. The pharmaceutical composition as described in 18, wherein the oxazole derivative is a compound of the formula: R'-S
Figure imgf000020_0001
.1 wherein R represents a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, or amino which may be substituted; n represents 1 or 2; R represents hydrogen, cyano, acyl, carbamoyl which may be substituted, thiocarbamoyl which may be substituted, a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, amino which may be substituted, or carboxyl which may be esterified; R represents hydrogen, halogen, a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, a hydrocarbon-oxy group which may be substituted, amino which may be substituted, carboxyl which may be esterified, or a group of the formula -S(0)m-R, where R represents a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted; m represents 0, 1, or 2;
20. The pharmaceutical composition as described in 18 or 19, which is a prophylactic or therapeutic pharmaceutical for cardiac diseases, autoimmune diseases, inflammatory diseases, or diseases accompanied by granuloma;
21. The pharmaceutical composition as described in 18 or 19, which is a prophylactic or therapeutic pharmaceutical for myocardiopathy, cardiac hypertrophy, myocardial infarction, angina pectoris, chronic rheumatoid arthritis, systemic lupus erythe atosus, systemic scleroderma, rheumatic fever, polymyositis, periarteritis nodosa, Sjδgren's syndrome, Behcet's disease, Castleman's disease, autoimmune hemolytic anemia, mesangial proliferative nephritis, IgA nephritis, lupus nephritis, osteoporosis, amyloidosis, bronchial asthma, atopic dermatitis, psoriasis, j pleurisy, ulcerative colitis, atherosclerosis, active chronic hepatitis, alcoholic cirrhosis, gout, encephalitis, multiple myeoloma, atrial myxoma, renal carcinoma, pulmonary adenocarcinoma, malignant mesothelioma, ovarian cancer or cancerous cachexia;
22. A composition for inhibition of interleukin-6 activity comprising an oxazole derivative having a group bonded through a sulfinyl or sulfonyl moiety at the 5-position of the oxazole ring;
23. The pharmaceutical composition as described in 18 or 19, which is a prophylactic or therapeutic pharmaceutical for atherosclerosis, myocarditis, myocardiopathy, ischemic brain disorder, Alzheimer's disease, multiple sclerosis, septicemia, chronic rheumatoid arthritis, osteoarthritis, gastric ulcer, duodenal ulcer, ulcerative colitis, diabetes, glomerulonephritis, osteoporosis, pneumonia, hepatitis, graft rejection or pain;
24. A composition for inhibition of nitrogen monoxide production comprising an oxazole derivative having a group bonded through a sulfinyl or sulfonyl moiety at the 5-position of the oxazole ring; 0
25. Use of an oxazole derivative having a group bonded through a sulfinyl or sulfonyl moiety at the 5-position of the oxazole ring, for the manufacture of a medicament for inhibiting interleukin-6 activity;
26. Use of an oxazole derivative having a group bonded through a sulfinyl or sulfonyl moiety at the 5-position of the oxazole ring, for the manufacture of a medicament for inhibiting nitrogen monoxide production;
27. A method for inhibiting interleukin-6 activity in human or mammal, which comprises administering an effective amount of an oxazole derivative having a group bonded through a sulfinyl or sulfonyl moiety at the 5-position of the oxazole ring, to human or the mammal;
28. A method for preventing or treating interleukin-6- associated diseases, which comprises administering an effective amount of an oxazole derivative having a group bonded through a sulfinyl or sulfonyl moiety at the 5-position of the oxazole ring, to human or the mammal;
29. A method for inhibiting a nitrogen monoxide production in human or mammal, which comprises administering an effective amount of an oxazole derivative having a group bonded through a sulfinyl or sulfonyl moiety at the 5-position of the oxazole ring, to human or the mammal; or
30. A method for preventing or treating nitrogen monoxide-associated diseases, which comprises administering an effective amount of an oxazole derivative having a group bonded through a sulfinyl or sulfonyl moiety at the 5-position of the oxazole ring, to human or the mammal.
The oxazole ring forming the skeletal structure of the compound of the present invention can be expressed by the following formula: /24340
21
Figure imgf000023_0001
1
Compound A according to the present invention is an oxazole derivative having a group bonded through a sulfinyl (-SO-) or sulfonyl (-S02-) moiety at the 5- position of the oxazole ring provided that when the substituent at the 4-position is hydrogen, (1) the compound which has 4-methoxyphenyl or 4-methoxy- phenylethinyl at the 2-position and nonafluorobutyl- sulfonyl at the 5-position, (2) the compound which has phenyl at the 2-position and (2-phenyl-5- thiazolyl)sulfonyl at the 5-position, and (3) the compound which has 3-[5-(2,3-epoxy-5-hydroxy-4-methyl- hexyl)-3,4-dihydroxytetrahydropyran-2-yl]-2-methyl-l- (E)-propenyl at the 2-position and 4-methyl- phenylsulfonyl at the 5-position are excluded. The 2-position of the oxazole ring may be unsubstituted but may be substituted, for example by a halogen atom or a suitable group which is bonded through a carbon, nitrogen, oxygen, or sulfur atom. The 4-position of the oxazole ring may be unsubstituted but may be substituted, for example by a halogen atom or a suitable group which is bonded through a carbon, nitrogen, oxygen, or sulfur atom.
The substituent group bonded through a sulfinyl or sulfonyl moiety at the 5-position of the oxazole ring may be any group which is bonded through a sulfinyl group or a sulfonyl group. Such a group can be typically expressed by the formula:
R'-SfO),- wherein R1 represents a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, or amino which may be substituted; n is 1 or 2 .
The halogen atom which can be used includes fluorine, chlorine, bromine, and iodine.
The substituent group bonded through a carbon atom at the 2- or 4-position of the oxazole ring may for example be a hydrocarbon group which may be substi¬ tuted, a heterocyclic group which may be substituted (this heterocyclic group is linked via a ring carbon atom at the 2- or 4-position of the oxazole ring), -CN- , -COORa, -C0-R% -C0-NRaRb, -CS-NRaR , -CO-SR -CS- SRa, -C0-NRa-C0-Rb, and -C(=NH)-NRaRb.
The substituent group bonded through a nitrogen atom at the 2- or 4-position may for example be -NRaRb, -NRa-CO-Rb, -NRa-CS-Rb, -NRc-C0-NRaRb, -NRc-CS-NRaRb, -NRΛ- CO-ORb, -NRa-CS-ORb, -NRa-CO-SRb, -NRa-CS-SRb, -NRr- C(=NH)-NRaRb, -NRa-S02Rb and -NRc-NRaRb.
The group bonded through an oxygen atom at the 2- or 4-position may for example be 0Ra, -0-C0-R3, -O-CS- Ra, -O-CO-OR3, -0-CO-NRaRb, and -0-C(=NH)-NRa. The substituent group bonded through a sulfur atom at the 2- or 4-position may for example be -SRa, -SO- Ra, -S02-Ra, -S02NRaRb, -S-CO-R3, -S-CS-R3, -S-C0-NRaRb, -S-CS-NRaRb, -S-C(=NH)NRaRb, and -SCN.
Ra, R , and Rc, mentioned above, may be independently represents hydrogen, a hydrocarbon group which may be substituted, or a heterocyclic group which may be substituted. Where -NRaR exists as part of the substituent group, Ra and R may be combine with the adjacent nitrogen atom to form a heterocyclic ring. The hydrocarbon group for "the group bonded through a carbon atom" for the 2- or 4-substituent and the hydrocarbon group for R1, Ra, R , or Rc includes alkyl, alkenyl, alkinyl, cycloalkyl, aryl, aralkyl and bridged-ring hydrocarbon groups . Particularly preferred are C l hydrocarbon groups. The alkyl group is preferably a straight-chain or branched alkyl group of 1-24 carbon atoms ( 1.2i, alkyl). Thus, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isoamyl, tert-amyl, n-hexyl, isohexyl, n-heptyl, n- octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n- tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n- heptadecyl, n-octadecyl, n-eicosyl, n-docosyl, n- tetracosyl, etc. can be mentioned. The preferred alkyl group is a straight-chain or branched alkyl group of 1- 19 carbon atoms (C^^ alkyl) and the more preferred is a straight-chain or branched alkyl group of 1-12 carbon atoms (C,-12 alkyl). Particularly preferred is a straight-chain or branched alkyl group of 1-6 carbon atoms (C,_6 alkyl) .
The alkenyl group is preferably a straight-chain or branched alkenyl group of 2-24 carbon atoms (C2_24 alkenyl), thus including vinyl, propeny(l-, 2-), butenyl(l-, 2-, 3-), pentenyl, octenyl, butadienyl(1, 3-), etc. The preferred alkenyl is a straight-chain or branched alkenyl group of 2-19 carbon atoms (C2.19 alkenyl) and the more preferred is a straight chain or branched alkenyl group of 2-12 carbon atoms (C2.12 alkenyl). Particularly preferred is a straight-chain or branched alkenyl group of 2-6 carbon atoms (C2.6 alkenyl) .
The alkinyl group is preferably a straight-chain or branched alkinyl group of 2-24 carbon atoms ( C2.2i> alkinyl), thus including ethinyl, propinyl(l-, 2-), butinyl(l-, 2-, 3-), pentinyl, octinyl, decinyl, etc. The preferred alkinyl is a straight-chain or branched alkinyl group of 2-19 carbon atoms (C2.ι9 alkinyl) and the more preferred is a straight chain or branched alkinyl group of 2-12 carbon atoms (C2.12 alkinyl). Particularly preferred is a straight-chain or branched alkinyl group of 2-6 carbon atoms (C2.6 alkinyl).
The cycloalkyl group is preferably a group of 3-10 carbon atoms (C3_10 cycloalkyl), thus including cyclo- propyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The more preferred is a cycloalkyl group of 3-8 carbon atoms (C3.8 cycloalkyl) . Particularly preferred is a cycloalkyl group of 3-6 carbon atoms (C3.6 cycloalkyl).
The aryl group may for example be a monocyclic group or a fused polycyclic group and is preferably a group containing 6-18 carbon atoms (C6.18 aryl). Thus, for example, phenyl, biphenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, etc. can be mentioned. The preferred aryl group is a group of 6-14 carbon atoms (C6. aryl), such as phenyl and naphthyl.
Particularly preferred is an aryl group of 6-12 carbon atoms (C6.12 aryl) .
The aralkyl group may for example be an alkyl group substituted by a mono- to tri-cyclic aromatic hydrocarbon group and is preferably an alkyl group of
1-24 carbon atoms which has been substituted by an aryl group of 6-18 carbon atoms (C6.18 aryl-C1.2Z| alkyl). Among such aralkyl groups are benzyl, biphenylylmethyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4- phenylbutyl, 1-naphthylmethyl, 2-naphthylmethyl, etc. Among them, C7.19 aralkyl groups are preferred and C7.13 aralkyl groups are particularly preferred.
The bridged-ring hydrocarbon group is preferably a group of 4-19 carbon atoms (C«_19 bridged-ring hydrocarbon group), thus including 1-adamantyl, 2- adamantyl, 2-norbornanyl and 5-norbornen-2-yl. The more preferred is a bridged-ring hydrocarbon group of 4-12 carbon atoms (C.12 bridged-ring hydrocarbon group) . The heterocyclic group mentioned for the "group bonded through a carbon atom" for the 2- or 4- substituent and the heterocyclic group for R , Ra, R and R° may for example be a 5- to 8-membered heterocyclic group containing 1-4 hetero-atoms selected from oxygen, sulfur and nitrogen in addition to carbon as ring members, or a condensed heterocyclic group thereof (e.g. a condensed heterocyclic group with a 6- to 8- membered carbocyclic or a heterocyclic group) .
Specifically, the heterocyclic group includes 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 2-, 4- or 5- oxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isoxazolyl, 3-, 4- or 5-isothiazolyl, 3- or 5-(1,2,4-oxadiazolyl) , 1,3,4- oxadiazolyl, 3- or 5-(1,2,4-thiadiazolyl) , 1,3,4- thiadiazolyl, 4- or 5-(1,2,3-thiadiazolyl) , 1,2,5- thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, IH- or 2H-tetrazolyl, N-oxido-2-, 3- or 4-pyridyl, N-oxido-2-, 4- or 5-pyrimidinyl, 3- or 4-pyridazinyl, pyrazinyl, N- oxido-3- or 4-pyridazinyl, benzofuryl, benzothiazolyl, benzoxazolyl, triazinyl, oxotriazinyl, tetrazolo[ 1,5- bjpyridazinyl, triazolof1,5-b]pyridazinyl, oxoimidazinyl, dioxotriazinyl, pyrrolidinyl, piperidinyl, pyranyl, thiopyranyl, 1,4-oxazinyl, morpholinyl, 1,4-thiazinyl, 1,3-thiazinyl, piperazinyl, benzimidazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, indolizinyl, quinolizinyl, 1,8-naphthyridinyl, purinyl, pteridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenanthridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, thienopyrimidinyl etc.
Preferred among those heterocyclic groups are 5- or 6-membered heterocyclic groups containing at least one nitrogen atom. In particular, pyrimidinyl, thiazolyl and oxadiazolyl are preferred.
The substituent group for groups which may be present on the above-mentioned "hydrocarbon group" or "heterocyclic group" includes but is not limited to C,_ 12 alkyl groups (preferably C^ alkyl, more preferably C!.4 alkyl, e.g. methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl), C3.8 cycloalkyl (preferably C3.6 cycloalkyl, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl) , halogen (e.g. fluorine, chlorine, bromine, and iodine), cyano, hydroxyl which may be acylated (preferably hydroxyl which may be acylated with Ci.12 alkanoyl, C6.)Λ arylcarbomyl or C7.,3 aralkanoyl such as carboxyl, Cx.l2 alkanoyloxy (e.g. acetyloxy) , C6. arylcarbonyloxy (e.g. benzoyloxy) and C7.13 aralkanoyloxy (e.g. benzylcarbonyloxy) ) , .γ. alkoxy (preferably C1-6 alkoxy such as methoxy, ethoxy, propoxy, and butoxy) , C5.14 aryloxy (e.g. phenyloxy, naphthyloxy, etc.), carboxyl, Ci.12 alkoxy-carbonyl (preferably Cj.g alkoxy-carbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, and butoxycarbonyl), nitro, carbamoyl which may be substituted with Cn2 alkyl (e.g. butylcarbamoyl) , Cx. 2 alkanoyl (preferably Cι_6 alkanoyl such as formyl, acetyl, propionyl, and butyryl), C6.u aryl (e.g. phenyl, naphthyl, etc.), C6_14 arylcarbonyl (e.g. benzoyl, naphthoyl, etc.), C7.13 aralkyl-carbonyl (e-g- benzylcarbonyl) heterocyclic groups [e.g. 3- to 8-membered heterocyclic groups containing 1-4 hetero- atoms selected from nitrogen, oxygen, and sulfur in addition to carbon as ring members and the condensed heterocyclic group thereof with a 6- to 8-membered carbocyclic or heterocyclic group, such as furyl(2-, 3- ), thienyl(2-, 3-), pyridyl(2-, 3-, 4-), thiazolyl, imidazolyl, benzothiazolyl, benzimidazolyl, oxazolyl (2-, 4, 5-) etc.], a group of the formula -NR Re (where Rd and Rβ independently represents hydrogen, a hydro- carbon group which may be substituted, a heterocyclic group which may be substituted, or -S02R where R represents a hydrocarbon group which may be substituted; R and Re may be combined with the adjacent nitrogen atom to form a heterocyclic ring, C). 12 alkylthio, Ci_12 alkylsulfinyl,
Figure imgf000029_0001
alkylsulfonyl, C6_ 14 arylthio, C6.14 arylsulfinyl, C6. arylsulfonyl, etc.
Among the above-mentioned substituent groups, said Cj-iz alkyl, C3.8 cycloalkyl, and the alkyl moiety of said C1.l2 alkylthio, C1_12 alkylsulfinyl or
Figure imgf000029_0002
alkylsulfonyl may be further substituted with, for example, C.8 cycloalkyl (preferably C3.6 cycloalkyl such as cyclopentyl and cyclohexyl), halogen (e.g. fluorine, chlorine, bromine, iodine), cyano, hydroxyl, CU12 alkoxy (preferably Ci.6 alkoxy such as methoxy, ethoxy, propoxy, and butoxy) , carboxyl, Ci_12 alkoxy-carbonyl (preferably Ci-β alkoxy-carbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, and butoxycarbonyl), nitro, amino, carbamoyl, and Cι_12 alkyl-carbonyl (preferably t_6 alkyl-carbonyl such as formyl, acetyl, propionyl, and butyryl).
Among the above-mentioned substituent groups, said c 6-m aryl and the C6.14 aryl moiety of said C6.u aryl- carbonyl, C6.12 arylthio, C6.12 arylsulfinyl, or C6.12 arylsulfonyl may be further substituted with, for example, Cj_6 alkyl (preferably Cj.., alkyl such as methyl, ethyl, propyl, and butyl), C3.8 cycloalkyl (preferably C3_6 cycloalkyl such as cyclopentyl and cyclohexyl), halogen (e.g. fluorine, chlorine, bromine, and iodine), cyano, hydroxyl, C,_6 alkoxy (preferably C,_ L, alkoxy such as methoxy, ethoxy, propoxy, and butoxy) , carboxyl, C .6 alkoxy-carbonyl (preferably Cj. alkoxy- carbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, and butoxycarbonyl), nitro, amino, carbamoyl, C 6 alkanoyl (preferably CM alkyl-carbonyl such as formyl, acetyl, propionyl, and butyryl) .
Among the above-mentioned substituent groups, said heterocyclic group may be further substituted by, for example,
Figure imgf000030_0001
alkyl (preferably C].A alkyl such as methyl, ethyl, propyl, and butyl), C3.8 cycloalkyl (preferably C3.6 cycloalkyl such as cyclopentyl and cyclohexyl), halogen (e.g. fluorine, chlorine, bromine, and iodine), cyano, hydroxyl, C^ alkoxy (preferably C,_ t, alkoxy such as methoxy, ethoxy, propoxy, and butoxy) , carboxyl, C^ alkoxy-carbonyl (preferably Cj.* alkoxy- carbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, and butoxycarbonyl), nitro, amino, carbamoyl, C^ alkanoyl (preferably C A alkyl-carbonyl such as formyl, acetyl, propionyl, and butyryl). Among the above-mentioned substituent groups, the hydrocarbon group or heterocyclic group represented by R , Re, or R in the group of the formula -NR RB or -S07- R may be the same as the hydrocarbon group or heterocyclic group defined for R hereinbefore. Where Rd and Re are combined with the adjacent nitrogen atom to form a heterocyclic ring, the ring (i.e. the nitrogen-containing ring) may be a 5- to 8- membered nitrogen-containing group optionally containing 1-4 atoms selected from carbon, nitrogen, oxygen, and sulfur in addition to said nitrogen atom as ring members, which nitrogen-containing ring may be further fused to a 6- to 8-membered carbocyclic or heterocyclic group. Where R and Re are combined with the adjacent nitrogen atom to form a heterocyclic ring, the group of the formula -NR Re constitutes a cyclic amino group. As specific examples of the cyclic amino group, there can be mentioned 1-pyrrolidinyl, 1- imidazolyl, piperidino (1-piperidyl), 1-piρerazinyl, 3- oxazolidinyl, hexamethylenimino, heptamethylenimino, morpholino (4-morpholinyl) , 1-indolinyl, and phthalimido among others. These cyclic amino groups may each be further substituted.
The substituents for the hydrocarbon group or the heterocyclic group, represented by Rd or Re, or the cyclic amino group -NR Re may be, for example, Cι_4 alkyl (e.g. methyl, ethyl, propyl, butyl, etc.), C3_8 cycloalkyl (preferably C3_6 cycloalkyl such as cyclopentyl and cyclohexyl), halogen (e.g. fluorine, chlorine, bromine, iodine), cyano, hydroxyl, Cμ alkoxy (e.g. methoxy, ethoxy, propoxy, butoxy, etc.), carboxyl, C,.A alkoxy-carbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.), nitro, amino, di-Cι-4 alkylamino, carbamoyl, C1 alkyl- carbonyl (e.g. formyl, acetyl, propionyl, and butyryl), C6.12 aryl (e.g. phenyl, naphthyl, etc.) and 2-pyridyl. The above-mentioned C^ alkyl and of said C3.8 cycloalkyl may be further substituted with, for example, C3_8 cycloalkyl (preferably C3.6 cycloalkyl such as cyclopentyl and cyclohexyl), halogen (e.g. fluorine, chlorine, bromine, iodine), cyano, hydroxyl, Cj.4 alkoxy (e.g. methoxy, ethoxy, propoxy, butoxy), carboxyl, C,./, alkoxy-carbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl), nitro, amino, carbamoyl, and Cι_4 alkyl-carbonyl (e.g. formyl, acetyl, propionyl, butyryl). The C6.12 aryl group mentioned above may also be further substituted by, for example, Cj.4 alkyl (e.g. methyl, ethyl, propyl, butyl), C3_8 cycloalkyl (preferably C3.6 cycloalkyl such as cyclopentyl and cyclohexyl), halogen (e.g. fluorine, chlorine, bromine, iodine), cyano, hydroxyl, C alkoxy (e.g. methoxy, ethoxy, propoxy, butoxy), carboxyl, C}_,, alkoxy-carbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl), nitro, amino, carbamoyl, and C^ alkyl-carbonyl (e.g. formyl, acetyl, propionyl, butyryl, etc.). The ring formed by R and R combined with the adjacent nitrogen atom can be the same kind of ring as the ring formed by R and Re combined with the adjacent nitrogen atom. The amino which may be substituted for R1 may for example be a group of the formula -NR*R5, -NRa-C0-Rb, -NRa-CO-NR4R5, -NRa-CS-NRV, -NRa-NRV, or -NRa-CO-ORb (where Ra, R , R and R independently represents a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted; R and R5 may be combined with the adjacent nitrogen atom to form a heterocyclic ring) .
The hydrocarbon group which may be substituted or the heterocyclic group which may be substituted, for R'' or R , may be the same kind of group as "the hydrocarbon group which may be substituted" or "the heterocyclic group which may be substituted" for Ra or R . The ring formed by R and R combined with the adjacent nitrogen atom may be the same kind of ring as formed by R and Re combined with the adjacent nitrogen atom.
The "group bonded through a sulfinyl or sulfonyl moiety" at the 5-ρosition of the oxazole ring in compound A according to the present invention is preferably a group of the formula R-S(0)n-.
Here R may for example be a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, or amino which may be substituted. Particularly preferred is a hydrocarbon group which may be substituted or amino which may be substituted. As to the value of n, both 1 and 2 are satisfactory but 2 is preferred.
The preferred substituent at the 2-position of compound A according to the present invention includes hydrogen, halogen, a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, a hydrocarbon-oxy group which may be substituted (for example, -0Ra) , amino which may be substituted (for example, -NRaR ) , carboxyl which may be esterified (for example, -CORa) etc.
The preferred substituent at the 4-position of compound A according to the present invention includes hydrogen, cyano, acyl (-C0Ra), carbamoyl which may be substituted (-CO-NR ,6„R7), thiocarbamoyl which may be substituted (-CS-NRR ), a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, amino which may be substituted (for example, -NRa-C00R ), carboxyl which may be esterified (for example, -C00R ) , etc. In particular, cyano, acyl (-CORa), carbamoyl which may be substituted (-CO-NR6R7), thiocarbamoyl which may be substituted (-CS-NR6R7), a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, and carboxyl which may be esterified (-C00R8) are preferred.
More specifically, the preferred substituent at the 5-position is a group of the formula R:-S(0)n-, where R is preferably one of the following groups (1)-
(9). (1) Ci.ig alkyl which may be substituted with (i) a 5- or 6-membered sulfur-containing heterocyclic group, (ii) a 5- or 6-membered oxygen- and nitrogen-containing heterocyclic group which may be substituted with C^^ alkyl or cyano, (iii) carboxyl, (iv) C6. arylcarbonyl, (v) cyano, (vi) carbamoyl which may be substituted with mono- or di-C1.12 alkyl, or (vii) d_12 alkoxy-carbonyl.
(2) C2.12 alkenyl which may be substituted with mono- or di-Cι_12 alkylamino.
(3) C2-12 alkinyl. ( 4 ) C3.10 cycloalkyl .
(5) C6_14 aryl which may be substituted with (i) halogen, (ii) Cι_12 alkoxy, (iii) amino which may be substituted with (a) carbamoyl which may be substituted with C!.12 alkyl or C3_10 cycloalkyl, (b) C6.14 arylsulfonyl which may be substituted with halogen, or (c) cι-π alkylsulfonyl, (iv) Cx_n alkyl which may be substituted with halogen, (v) nitro or (vi) hydroxyl.
(6) C7_19 aralkyl which may be substituted with (i) halogen, (ii) Ci.12 alkoxy, (iii) amino which may be substituted with (a) C6_14 arylsulfonyl which may be substituted with Cl.12 alkyl or (b) Cj.12 alkylsulfonyl, or (iv) nitro.
(7) a 5- or 6-membered nitrogen- or oxgen-containing heterocyclic group.
(8) amino which may be substituted with (i)
Figure imgf000034_0001
alkyl which may be substituted with (a) Cι_12 alkoxy-carbonyl, (b) mono- or di-C1_12 alkylamino or (c) a 5- or 6- membered nitrogen-containing heterocyclic group, (ii) C7.19 aralkyl which may be substituted with halogen or Cι.12 alkoxy, (iii) C4.12 bridged-ring hydrocarbon group, (iv) C6_14 aryl or (v) C3.10 cycloalkyl.
(9) thienopyrimidylhydrazino which may be substituted with C!_1Z alkyl. R is more preferably one of the group of the following groups (1) - (12) .
(1) cι-i2 alkyl which may be substituted with (i) thienyl, (ii) oxazolyl which may be substituted with Cy.6 alkyl or cyano, (iii) carboxyl, (iv) C6_12 arylcarbonyl, (v) cyano, (vi) carbamoyl which may be substituted with mono- or di-Cj.6 alkyl, or (vii) C^ alkoxy-carbonyl.
(2) C2.6 alkenyl which may be substituted with mono- or di-Cι_6 alkylamino. ( 3 ) C2.6 alkinyl .
( 4 ) C3.8 cycloalkyl .
(5) C6,12 aryl which may be substituted with (i) halogen, (ii) Ci.6 alkoxy, (iii) amino which may be substituted with (a) carbamoyl which is substituted with C^g alkyl or C3_8 cycloalkyl, (b) C6.12 arylsulfonyl which may substituted with halogen or (c) C .6 alkylsulfonyl, (iv) Cj.g alkyl which may be substituted with halogen (v) nitro or (vi) hydroxy. (6) C7.13 aralkyl which may be substituted with (i) halogen, (ii) Ci_6 alkoxy, (iii) amino which may be substituted with (a) C6.12 arylsulfonyl which may be substituted with C,_6 alkyl or (b) C^ alkylsulfonyl, or (iv) nitro. (7) a heterocyclic group selected from the group consisting of pyrimidyl, piperidino, morpholino and 1- piperazinyl.
(8) amino which may be substituted with (i) C1-6 alkyl which may be substituted with (a) C,_6 alkoxy-carbonyl, (b) mono- or di-C 6 alkylamino or (c) pyridyl, (ii) C6_ 12 aryl, (iii) C7.13 aralkyl which may be substituted with halogen or C^ alkoxy, (iv) adamantyl or (v) C3.8 cycloalkyl .
(9) thienopyrimidylhydrazino which may be substituted with Ci.6 alkyl.
Particularly, R is preferably one of the following groups:
(1) Cι.6 alkyl which may be substituted with (i) 2- thienyl or (ii) carboxyl, (2) C6.12 aryl which may be substituted with (i) halogen, (ii) C^g alkoxy or (iii) Cx_6 alkylcarbamoyla ino, (3) C7.13 aralkyl which may be substituted with nitro, (4) amino which may be substituted with (i) C^ alkyl, (ii) C6.12 aryl or (iii) C3-8 cycloalkyl, or (5) morpholino. The symbol n may represent whichever of 1 and 2 but 2 is particularly preferred.
When n is 1, R is preferably (1) CJ.JQ alkyl which may be substituted with cyano, (2) C2_12 alkinyl, (3) C^. 8 cycloalkyl, (4) C6.12 aryl with may be substituted with (i) halogen, (ii) amino which may be substituted with carbamoyl with substituted with C _6 alkyl, or (iii) C,_6 alkyl which may be substituted with halogen, or (5) pyrimidinyl. The substituent at the 2-position is preferably one of the following groups (1)-(13).
( 1) hydrogen.
(2) halogen.
(3) C!_12 alkyl which may be substituted with a group selected from the group consisting of(i) amino which may be substituted with C7.19 aralkyl or C 12 alkyl, (ii) a 5- or 6-membered saturated heterocyclic group containing 2 nitrogen atoms which may be substituted with C6.14 aryl, (iii) phthalimido, (iv) C6.14 arylsulfonyl which may substituted with C1,12 alkyl, (v) hydroxyl which may be substituted with C)..12 alkanoyl, (vi) a 5- or 6-membered saturated nitrogen- and/or oxygen-containing heterocyclic group, (vii) halogen, (viii) C!-12 alkoxy-carbonyl, and (ix) a 5- to 6-membered unsaturated nitrogen- and/or oxgen-containing heterocyclic group which may be substituted with Cι._6 alkyl or cyano.
(4) C2.12 alkenyl which may be substituted with C6.14 aryl. (5) C6.14 aryl which may be substituted with Cι_12 alkoxy.
(6) C7.i9 aralkyl which may be substituted with (i) amino, (ii) nitro, (iii) Cj.12 alkoxy, or (iv) halogen.
( 7 ) C3.10 cycloalkyl .
( 8 ) C3.10
Figure imgf000036_0001
alkyl . (9) a C4.12 bridged-ring hydrocarbon group. (10) a 5- to 6-membered unsaturated nitrogen- and/or oxygen-containing heterocyclic group.
(11) C 12 alkoxy.
(12) amino which may be substituted with (i) C^^ alkyl which may substituted with C^^ alkoxy-carbonyl or (b) a 5- or 6-membered nitrogen-containing heterocyclic group or (ii) C7.19 aralkyl.
( 13 ) Cx.12 alkoxy-carbonyl .
The substituent at the 2-position is more preferably one of the following groups (1) - (13).
(1) hydrogen.
(2) halogen.
(3) C 6 alkyl which may be substituted with (i) amino which may be substituted with C7.13 aralkyl or C^ alkyl, (ii) 1-piperazinyl which may be substituted with c 6-i2 aryl, (iϋ) phthalimide, (iv) C6.12 arylsulfonyl which may be substituted with C^g alkyl, (v) hydroxyl which may be substituted with Ct.6 alkanoyl, (vi) morpholino, (vii) piperidino, (viii) halogen, (ix) C (l alkoxy-carbonyl, and (x) oxazolyl which may be substituted with C^ alkyl or cyano.
(4) C2.6 alkenyl which may be substituted with C6.12 aryl .
(5) C6.12 aryl which may be substituted with Cι_6 alkoxy. (6) C7.13 aralkyl which may be substituted with (i) amino, (ii) nitro, (iii) Cl-6 alkoxy, or (iv) halogen.
(7) C3.8 cycloalkyl.
(8) C3-8 cycloalkyl-Ci.6 alkyl.
(9) adamantyl. (10) oxadiazolyl.
(11) C!_6 alkoxy.
(12) amino which may be substituted with (i) Cj.s alkyl which may be substituted with C 6 alkoxy-carbonyl or pyridyl, or (ii) C7.13 aralkyl. (13) Ci.β alkoxy-carbonyl.
Particularly, the substituent at the 2-position is preferably one of the following groups:
(1) hydrogen, (2) C^ alkyl which may be substituted with amino which may have C^ alkyl or C7.15 aralkyl substituent, (3) C3.6 cycloalkyl, (4) C5.12 aryl which may be substituted with Cj.6 alkoxy or (5) C7_13 aralkyl which may be substituted with (i) halogen or (ii) C^ alkoxy. When a group bonded through a sulfinyl moiety exists at the 5-position, the preferred group at the 2- position is (1) C 12 alkyl which may be substituted with Cl.12 alkoxy-carbonyl, (2) C2.12 alkenyl which may be substituted with C6_ι4 aryl, (3) C6.14 aryl which may be substituted with
Figure imgf000038_0001
alkoxy, (4) C7.j9 aralkyl, (5) C3-10 cycloalkyl, or (6) a 5- or 6-membered saturated nitrogen and/or sulfur containing heterocyclic group. The substituent at the 4-position is preferably one of the following groups (1) - (12). (1) cyano.
(2) Cx.12 alkanoyl.
(3) carbamoyl which may be substituted with (i) C 12 alkyl which may be substituted with a 5- or 6-membered nitrogen-containing heterocyclic group, (ii)
Figure imgf000038_0002
alkoxy or (iii) C7.19 aralkyl.
(4) a 5- or 6-membered saturated nitrogen-containing heterocyclic-carbonyl, which may be substituted with C6.14 aryl.
(5) thiocarbamoyl which may be substituted with (i) C,_ 12 alkyl or (ii) C7.19 aralkyl.
(6) a 5- or 6-membered saturated nitrogen-containing heterocyclic-thiocarbonyl.
(7) cι-i2 alkyl which may be substituted with a group selected from the group consisting of (i) hydroxyl which may be acylated with C6.14 arylcarbonyl, (ii) halogen, (iii) carboxyl, (iv) cyano, (v) amino which may be substituted with
Figure imgf000039_0001
alkyl which may be substituted with a 5- or 6-membered nitrogen-containing heterocyclic group or C7_19 aralkyl, (vi) a 5- or 6- me bered saturated heterocyclic group containing 2 nitrogen atoms, which may be substituted with C6_ι4 aryl, (vii) phthalimido, (viii) C6_14 arylsulfonyl which may be substituted with C 2 alkyl, and (ix) C6.14 aryloxy which may be substituted with halogen, . (8) C7.19 aralkyl which may be substituted with halogen or hydroxyl.
(9) a 5- or 6-membered nitrogen and sulfur-containing heterocyclic group, which may be substituted with (i) Ci_12 alkoxy-carbonyl or (ii) C6.14 aryl. (10) amino which may be substituted with C1_12 alkoxy- carbonyl.
(11) carboxyl.
(12) C{.ϊ2 alkoxy-carbonyl.
The substituent at the 2-position is more preferably one of the following groups (1) - (13).
(1) cyano.
(2) Cι_6 alkanoyl.
(3) carbamoyl which may be substituted with (i) C,.6 alkyl which may be substituted with pyridyl, (ii) C7.n aralkyl or (iii)
Figure imgf000039_0002
alkanoyl.
(4) piperidinocarbonyl.
(5) 1-piperazinylcarbonyl which may be substituted with C6.12 aryl.
(6) thiocarbamoyl which may be substituted with (i) C1-6 alkyl or (ii) C7.13 aralkyl.
(7) piperidinothiocarbonyl.
(8) Ci_6 alkyl which may be substituted with (i) hydroxy which may be acylated with C6.12 arylcarbonyl, (ii) halogen, (iii) carboxyl, (iv) cyano, (v) amino which may substituted with (a) C1-6 alkyl which may be substituted with pyridyl or (b) C7.13 aralkyl, (vi) 1- piperazinyl which may be substituted with C6.12 aryl, (vii) phthalimido, (viii) C6.12 arylsulfonyl which may be substituted with C^ alkyl, or (ix) C6.12 aryloxy which may be substituted with halogen.
(9) C7.13 aralkyl which may be substituted with halogen or hydroxyl.
(10) thiazolyl which may be substituted with C 6 alkoxy-carbonyl or (b) C5.12 aryl. (11) amino which may be substituted with C 6 alkoxy- carbonyl.
(12) carboxyl.
(13) Cj-e alkoxy-carbonyl.
The more preferred substituent at the 4-position is cyano carbamoyl, thiocarbamoyl or Cx_6 alkyl which may be substituted with halogen. Particularly pre erred is cyano or thiocarbamoyl.
Where the substituent at the 5-position is a group bonded through a sulfinyl moiety, the substituent at the 4-position is preferably (1) cyano, (2) C^^ alkyl which may be substituted with halogen or (3) thiocarbamoyl. Particularly preferred is cyano.
Compound (A) according to the present invention does not comprise the following compounds: (1) the compound having 4-methoxyphenyl or 4- methoxyphenylethinyl at the 2-position and nonafluorobutylsulfonyl at the 5-position, (2) the compound having phenyl at the 2-position and (2-phenyl- 5-thiazolyl)sulfonyl at the 5-position, and (3) the compound having 3-[5-(2,3-epoxy-5-hydroxy-4- methylhexyl)-3,4-dihydroxytetrahydropyran-2-yl]-2- methyl-l-(E)-propenyl at the 2-position and 4- methylphenylsulfonyl at the 5-position. Compound A according to the present invention is a novel compound. Compound A for use in the present invention is preferably a compound (I) of the following formula
Figure imgf000041_0001
wherein R represents a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, or amino which may be substituted; n ι represents 1 or 2; R represents hydrogen, cyano, acyl, carbamoyl which may be substituted, thiocarbamoyl which may be substituted, a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, or amino which may be substituted, carboxyl which may be esterified; R3 represents hydrogen, halogen, a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, a hydrocarbon-oxy group which may be substituted, amino which may be substituted, carboxyl which may be esterified, or a group of the formula
-S(0)m-R where R represents a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted; m represents 0, 1, or 2; exclusive of the compounds in which R is hydrogen and n is 2, wherein (1) R is 4-methoxyphenyl or 4-methoxyphenylethinyl and R is nonafluorobutyl, (2) R3 is phenyl and R1 is 5-(2- phenylthiazolyl) , and (3) R3 is 3-[5-(2,3-epoxy-5- hydroxy-4-methylhexyl)-3,4-dihydroxytetrahydropyran-2- yl]-2-methyl-l-(E)-propenyl and R1 is 4-methylphenyl. Referring to the above formula (I), the hydrocarbon group which may be substituted, heterocyclic group which may be substituted, and amino which may be substituted for R1 have the same meanings as defined hereinbefore. The amino which may be substituted for R may for example be a group of the formula -NR4R , wherein R and R independently represents hydrogen, a hydrocarbon group which may be substituted, or a heterocyclic group which may be substituted; R and R5 may be combined with the adjacent nitrogen atom to form a heterocyclic ring.
The acyl for R may for example be a organic carboxylic acid-derived acyl group and is preferably an acyl group of 1-19 carbon atoms (Cj.19 alkanoyl) . To be specific, formyl, acetyl, ethylcarbonyl, propylcarbonyl, etc. can be mentioned. Particularly preferred are acyl groups of 1-6 carbon atoms (CU6 alkanoyl) .
The carbamoyl which may be substituted for R2 may for example be a group of the formula -CONR R , where R6 and R independently represents hydrogen, acyl, a hydrocarbon group which may be substituted, or a heterocyclic group which may be substituted; R and R may be combined with the adjacent nitrogen atom to form a heterocyclic ring.
The thiocarbamoyl which may be substituted for R may for example be a group of the formula -CS-NR R wherein R and R independently represents hydrogen, a hydrocarbon group which may be substituted, or a heterocyclic group which may be substituted; R and R may be combined with the adjacent nitrogen atom to form a heterocyclic ring.
The carboxyl which may be esterified for R or R may for example be a group of the formula -COOR , where R10 represents hydrogen, a hydrocarbon group which may be substituted, or a heterocyclic group which may be substituted.
The substituent for amino which may be substituted for R2 may for example be Cι._12 alkoxy-carbonyl (preferably Cj.g alkoxy-carbonyl) . Particularly preferred is buthoxycarbonyl.
The halogen for R may for example be fluorine, chlorine, bromine, or iodine.
The hydrocarbon-oxy which may be substituted may for example be a group of the formula -OR11, where Ru represents a hydrocarbon group which may be substituted.
The "hydrocarbon group which may be substituted" for R, Rz, R3,
Figure imgf000043_0001
R5, R6, R7, R10, or R11 can be the same as the "hydrocarbon group that may be substituted" which has been defined for R1.
The "heterocyclic group which may be substituted" for R, R , R , R , R , R6, R7, or R10 can be the same as the "heterocyclic group that may be substituted" which has been defined for R1.
The heterocyclic group which R4 and R5, or R6 and R , may be combined with the adjacent nitrogen atom to form a heterocyclic group, can be the same as heterocyclic group formed by Rd and Re which may be combined with the adjacent nitrogen atom.
The acyl for R6 or R7 can be the same as the acyl which has been defined for R2.
-S(0)m-R for R3 includes C,_12 alkylthio (e.g. methylthio, ethylthio, etc.), C6.14 arylthio (e.g. phenylthio etc.), C6.14 aryl-Cι_6 alkylthio (e.g. benzylthio etc.), C,_1A alkylsulfinyl (e.g. methylsulfinyl, ethylsulfinyl, etc.), C6.14 arylsulfinyl (e.g. phenylsulfinyl etc.), C6.14 aryl-C^ alkylsulfinyl (e.g. benzylsulfinyl etc.), CU12 alkylsulfonyl (e.g. methylsulfonyl, ethylsulfonyl, etc.), C5_14 arylsulfonyl (e.g. phenylsulfonyl etc.), C6.14 aryl-C 6 alkylsulfonyl (e.g. benzylsulfonyl etc.), etc.
Referring to the above formula (I), R1 may be the same as R of the group of the formula R1-S(0)n- at the 5-position described above. R may be the same as the substituent at the 4-position described above. R may be the same as the substituent at the 2-position described above. As compound (I) of the present invention, all the compounds corresponding to the above combinations of R1, R2 and R3 are invariably preferred.
Compound (I) of the present invention does not include compounds such that R is hydrogen and n is equal to 2, wherein (1) R is 4-methoxyphenyl or 4- methoxyphenylethinyl and R 1 is nonafluorobutyl, (2) R3 is phenyl and R is 4-(2-phenylthiazolyl) , (3) R3 is 3- [5-(2,3-epoxy-5-hydroxy-4-methylhexyl)-3,4- dihydroxytetrahydropyran-2-yl]-2-methyl-1-(E)-propeny1 and R is 4-methylphenyl. Compound (I) is a novel compound.
Compound B for use in the present invention is an oxazole derivative having a group bonded through a sulfinyl (-SO-) or sulfonyl (-S02-) moiety at the 5- position of the oxazole ring.
The 2-position of the oxazole ring may be unsubstituted but may be substituted by a certain group such as halogen or a group bonded through a carbon, nitrogen, oxygen, or sulfur atom. The 4-position of the oxazole ring may be unsubstituted but may be substituted by a certain group such as halogen or a group bonded through a carbon, nitrogen, oxygen, or sulfur atom.
The substituent group bonded through a sulfinyl or sulfonyl moiety at the 5-position of the oxazole ring may be the same as the group bonded through a sulfinyl or sulfonyl moiety at the 5-position of the oxazole ring of compound A.
The halogen atom or the group bonded through a carbon, nitrogen, oxygen, or sulfur atom at the 2- or 4-position of the oxazole ring may be the same as the halogen atom or the group bonded through a carbon, nitrogen, oxygen, or sulfur atom at the 2- or 4- position of compound A mentioned hereinbefore. Compound B for use in the present invention includes the specific compounds excluded from compound A, namely the compounds having hydrogen at the 4- position wherein (1) the substituent at the 2-position is 4-methoxyphenyl or 4-methoxyphenylethinyl and the substituent at the 5-position is nonafluorobutylsulfonyl, (2) the substituent at the 2- position is phenyl and the substituent at the 5- position is (2-phenyl-5-thiazolyl)sulfonyl, and (3) the substituent at the 2-position is 3-[5-(2,3-epoxy-5- hydroxy-4-methylhexyl)-3,4-dihydroxytetrahydropyran-2- yl]-2-methyl-l-(E)-propenyl and the substituent at the 5-position is 4-methylphenylsulfonyl.
Compound B is preferably a compound of the formula
Figure imgf000045_0001
wherein R represents a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, or amino which may be substituted; n represents 1 or 2; R represents hydrogen, cyano, acyl, carbamoyl which may be substituted, thiocarbamoyl which may be substituted, a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, amino which may be substituted or carboxyl which may be esterified; R3 represents hydrogen, halogen, a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, a hydrocarbon-oxy group which may be substituted, amino which may be substituted, carboxyl which may be esterified or a group of the formula -S(0)m-R, where R represents a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted; m represents 0, 1, or 2.
In the above formula (I' ) , R1 and R3 are as defined hereinbefore; R has the same meaning as R2 defined hereinbefore.
Referring to compound A or B according to the present invention, where it has an acidic group (e.g. carboxyl, phenolic hydroxy, sulfo, etc.) or a basic group (e.g. amino) as a substituent, the compound may form a salt with a suitable base or acid, and these salts are included in the compound of the invention. The kind of salt is preferably a pharmacologically acceptable salt, for example, salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, and salts with basic or acidic amino acids. The salt with an inorganic base includes alkali metal salts (e.g. sodium salt, potassium salt, etc.), alkaline earth metal salts (e.g. calcium salt, magnesium salt, etc.), and ammonium salts. The salt with an organic base includes salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, dicyclohexylamine, etc. The salt with an inorganic acid includes salts with hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, etc. The salt with an organic acid includes salts with formic acid, acetic acid, oxalic acid, fumaric acid, maleic acid, succinic acid, citric acid, trifluoroacetic acid, methanesulfonic acid, p- toluenesulfonic acid, etc. The salt with a basic amino acid includes salts with arginine, lysine, ornithine, etc. The salt with an acidic amino acid includes salts with aspartic acid, glutamic acid, etc. [Best Mode for Carrying Out the Invention]
Compound A of the present invention can be produced generally in the same manner as compound (I) of the invention which is described in detail below. Compound (I) of the present invention can be produced typically by the following processes (l)-(4). (1)
Figure imgf000047_0001
wherein R , R , R , and n are as defined hereinbefore. This process comprises oxidizing the oxazole derivative (II) to compound (I) of the invention. More particularly, the derivative (II) is dissolved in a solvent and reacted with an oxidizing agent to give compound (I) .
The oxidizing agent that can be used includes but is not limited to m-chloroperbenzoic acid, hydrogen peroxide, peracetic acid, t-butyl hydroperoxide, potassium peroxysulfate, potassium permanganate, sodium perborate, sodium periodate, sodium hypochlorite, and halogen. The amount of the oxidizing agent is generally about 1-3 moles per mole of compound (II). Specifically, the oxidizing agent is used in a proportion of generally about 1-1.5 moles and preferably about 1-1.2 moles when n=l or generally about 2-3 moles and preferably about 2-2.5 moles when n=2.
The reaction solvent need not be critically chosen unless it reacts with the oxidizing agent used. Thus, for example, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2- dichloroethane, etc., aromatic hydrocarbons such as benzene, toluene, xylene, etc., aliphatic hydrocarbons such as pentane, hexane, petrolen, ether, etc., alcohols such as methanol, ethanol, isopropyl alcohol, t-butyl alcohol, etc., carboxylic acids such as acetic acid, trifluoroacetic acid, etc., ethers such as diethyl ether, tetrahydrofuran, dioxane, etc., aceto¬ nitrile, N,N-dimethylformamide, dimethyl sulfoxide, water, and mixtures thereof can be mentioned. This oxidation reaction can be conducted in the presence of a catalyst such as vanadium pentoxide, benzeneselenic acid, ruthenium oxide, osmium oxide, or the like. While this reaction may be carried out under cooling, at room temperature, or under heating, it is usually conducted at room temperature or under heating. The reaction time is generally about 1-20 hours and preferably about 1-10 hours.
After the reaction, the objective compound of high purity can be isolated by subjecting the reaction mixture to a known purification procedure such as solvent extraction, distillation, column chromatography, and recrystallization. (2)
Figure imgf000048_0001
(III) (IV) (] :n=2)
wherein R1, R , R , and n are as defined hereinbefore;
R12 represents lower alkyl or phenyl; n1 represents 0,
1, or 2; M represents an alkali metal.
The alkali metal for M in the above formula, may for example be lithium, sodium, potassium, or cesium. The lower alkyl for R12 includes
Figure imgf000048_0002
alkyl groups such as methyl, ethyl, propyl, etc. This process comprises reacting oxazole derivative (III) with sulfinic acid salt (IV) in a solvent to give compound (I) in which n=2.
The reaction solvent is preferably a polar solvent. Thus, for example, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, etc., alcohols such as methanol, ethanol, isopropyl alcohol, t-butyl alcohol, etc., acetone, acetonitrile, N,N- dimethylformamide, dimethyl sulfoxide, hexamethylphosphoramide, water, and mixtures thereof can be employed.
This reaction is conducted under cooling, at room temperature, or under heating and the reaction time is generally about 1-20 hours and preferably about 1-10 hours .
After the reaction, the objective compound of high purity can be isolated by subjecting the reaction mixture to a known procedure such as solvent extraction, distillation, column chromatography, and recrystallization. (3)
Figure imgf000049_0001
Cl") c r " )
wherein R , R , and R have the same respective meanings as R , R , and R defined above. R , R2 ' , and R ' have the same respective meanings as R1, R2, and R defined above. R and R1 ", R2" and R2'", and R and R " may respectively be the same but at least one of the three pairs consists of dissimilar groups. In this process, compound (I''') is produced by substituting 1-3 of R , R and R3 of oxazole derivative (I'') or subjecting (I'') to functional transformation. The substitution reaction and functional transformation reaction can be carried out by the routine procedures. As such routine procedures, the following methods can be typically mentioned.
[Table 1]
• halogenation H -> halogen OH
• substitution
Figure imgf000051_0001
hydrolysis C02R' -> C02H
CN
Figure imgf000051_0002
O-COR' → OH
NHCOR' ■ NH2
NR'COR' -> NHR' dehydration C0NH2 -> CN decarboxylation C02H -> H etherification OH -> OR* acylation OH - O-COR'
NH2 -> NH-COR'
NHR' -3> NR '-CORh
H "> COR'
[Table 2] • sulfonylation OH - 0-S02R»
NH2 - NH-S02R»
Figure imgf000052_0001
estrification C02H -> C02R« thiol- esterification C02H -> CO-SR' aπidation CONR-R'
Figure imgf000052_0002
thio-amidation C0NH2 -> CS-NH2
CONHR' ■ CS-NHR'
CONR'R"—- CS-NR«Rh CN ■ CS-NH2 synthesis of ketone CO-R'
Figure imgf000052_0003
• nitration H -> N02
• oxidation CH20H ■ CHO - C02H
SR" -> SO-R' - S02-Rg
• reduction C02R" -> CHO -> CH20H
NO, " NH,
[Table 3] • hydrogenation C≡C CH=CH -^ CH2CH2
Figure imgf000053_0001
NO i - NH2
0CH2Ph - OH NHCH2Ph" - NH2
NR'CH∑Ph- ->NHR' rearrangement C02H — CON, -> NH2 C0NH2 —
Figure imgf000053_0002
substitution via diazo group NH, OV)
Figure imgf000053_0003
synthesis of heterocyclic group
Figure imgf000053_0004
H Wherein Rg, R , and R1 independently represents a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted. (4)
R1
Figure imgf000054_0001
(III) (V)
Figure imgf000054_0002
(VI) (VII)
wherein R1, R2, 3, R12, R4, R5, n, and M are as defined hereinbefore; X represents a leaving group. For X in the above formula, halogen such as chlorine, bromine, iodine, etc., p-toluenesulfonyloxy, or methanesulfonyloxy, for instance, is employed. Among them, halogen is preferred and chlorine is particularly suitable. This process is directed to production of compound (VII), which is a species of compound (I) of the invention wherein R represents -NR R . More specifically, the process comprises reacting compound (III) with M2S, e.g. sodium sulfide or potassium sulfide, treating the reaction product with an acid to give a thiol intermediate (V), transforming (V) to an intermediate compound (VI) in the per se known method (Chem. Lett., 1992, p.1483), and reacting (VI) further with a primary or secondary amine in the presence of a base to give compound (VII). In this process, the intermediates (V) and (VI) can be respectively isolated and purified but this is not essential.
The reaction solvent for use in the reaction with M2S in the above course of synthesis from compound (III) to compound (V) is preferably a polar solvent, e.g. halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, etc., alcohols such as methanol, ethanol, isopropyl alcohol, etc., acetone, acetonitrile, water, and mixture of such solvents. This reaction is conducted under cooling, at room temperature, or under heating, and the reaction time is generally about 1-20 hours and preferably about 1-10 hours.
There is no particular limitation on the acid that can be used in the acid treatment but generally an aqueous solution of hydrochloric acid, sulfuric acid, nitric acid, acetic acid, or the like is employed.
The course of synthesis from compound (III) to compound (V) can be carried out using MSH, e.g. sodium hydrosulfide or potassium hydrosulfide, instead of M2S. While this reaction can be conducted under the same conditions as the reaction using M2S, the subsequent acid treatment is unnecessary.
The course of synthesis from compound (V) to compound (VI) can be carried out by the known procedure using sulfuryl chloride and a salt of nitric acid as described hereinbefore.
The base that can be used in the course of synthesis from compound (VI) to compound (VII) includes sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, triethylamine, pyridine, sodium methoxide, sodium ethoxide, potassium t-butoxide, sodium hydride, and sodium amide, among others. The reaction solvent that can be used includes but is not limited to hydrogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2- dichloroethane, etc., aromatic hydrocarbons such as benzene, toluene, xylene, etc., aliphatic hydrocarbons such as pentane, hexane, petroleum ether, etc., ethers such as diethyl ether, tetrahydrofuran, dioxane, etc., acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, and mixtures thereof. This reaction is conducted under cooling, at room temperature, or under heating and the reaction time is generally about 1-20 hours and preferably about 1-10 hours.
After the reaction, the objective compound of high purity can be isolated from the reaction mixture by the known procedures such as solvent extraction, distillation, column chromatography, and recrystallization.
The starting compound (II) for use in process (1) can be produced by the known technology or any method analogous thereto. The known technology includes the process starting with 2-amino-3,3- dichloroacrylonitrile, in which the starting compound is converted to a 3,3-bis(substituted mercapto)derivative which, in turn, is cyclized with a silver salt [Matsumura et al. , Chem. Pharm. Bull. 24. p.912 (1976), ditto, p.948] and the process in which 5- mercapto-oxazole is S-alkylated [T. K. Vinogradova et al., Zh. Org. Khim. i£, 1864 (1982)].
The starting compound (II) can be obtained by the following process.
Figure imgf000056_0001
(VIII) (ID
wherein R1, R2, R3, and M are as defined hereinbefore; X represents a leaving group.
Referring to the above formula, R is preferably an electron-withdrawing group such as cyano, alkyloxycarbonyl, carbamoyl, or the like. X preferably represents halogen, e.g. chlorine, bromine, or iodine, p-toluenesulfonyloxy, or methane- sulfonyloxy, for instance.
In this process, the compound (VIII) obtained by the process of Matsumura et al. [Chem. Pharm. Bull. 24. p.912 (1976)] or any process analogous thereto is reacted with M2S, such as sodium sulfide or potassium sulfide, in a solvent, and then treated with R3X to give compound (II).
The reaction solvent is preferably a polar solvent. Thus, for example, hydrogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, etc., alcohols such as methanol, ethanol, isopropyl alcohol, t-butyl alcohol, etc., acetone, acetonitrile, N,N- dimethylformamide, dimethyl sulfoxide, hexamethylphosphoramide, etc., water, and mixtures thereof can be employed. This reaction is conducted under cooling, at room temperature, or under heating and the reaction time is generally about 1-20 hours and preferably about 1-10 hours.
The starting compound (II) can also be produced by the following process.
Figure imgf000057_0001
2)R' X ( III) (I I)
wherein R1, R2, R , R12, n1, M, and X are respectively as defined hereinbefore. Thus, in a solvent, compound (III) is reacted with a thiol in the presence of a base (process A) or first reacted with M2S, e.g. sodium sulfide or potassium sulfide, and then treated with R3X (process B) to give compound (II). For both processes A and B, the reaction solvent is preferably a polar solvent, e.g. halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, etc., alcohols such as methanol, ethanol, isopropyl alcohol, t-butyl alcohol, etc., acetone, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphoramide, etc., water, and mixtures thereof. The reaction is conducted under cooling, at room temperature, or under heating and the reaction time is generally about 1-20 hours and preferably 1-10 hours.
The base that can be used in process A includes but is not limited to sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, triethylamine, pyridine, sodium methoxide, sodium ethoxide, potassium t-butoxide, sodium hydride, and sodium amide. It is also possible to treat the thiol with a base and subject the resulting thiol anion (RS~) to the reaction with compound (III).
Compound (II) thus obtained can be converted to compounds having different substituent groups by intro¬ ducing desired substituent groups for 1-3 of its substituents R , R , and R by the same procedure as described in connection with process (3) for producing compound (I) or subjecting it to functional transformation.
Among species of starting compound (III) for use in processes (2) and (4), the compound in which n =0 is subsumed in the category of said compound (II) and the compound in which n =1 and 2 is subsumed in the category of compound (I). Therefore, these compounds can be produced by procedures corresponding to the above production processes.
The starting compound (I'') for process (3) can be produced by process (1) or (2).
In this manner, the oxazole derivative (I) of the present invention can be provided.
Referring to the formula (I), desirably R represents 1) a Cι_19 hydrocarbon group which may be substituted with (1) Ci.12 alkyl which may be substituted with (a) C3.8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e)
Figure imgf000059_0001
alkoxy, (f) carboxyl, (g) CM2 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) Cι.12 alkanoyl,
(2) C3,8 cycloalkyl which may be substituted with (a) 3-8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) cι-n alkoxy, (f) carboxyl, (g) Cj.12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) Ci-12 alkanoyl,
(3) halogen
(4) cyano,
(5) hydroxyl which may be acylated with (a) Cι_12 alkanoyl, (b) C6.1 arylcarbonyl or (c) C7.19 aralkanoyl, (6) Cj.,2 alkoxy,
(7) C6_14 aryloxy which may be substituted with (a) Cj.6 alkyl, (b) C3_8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Ci-e alkoxy, (g) carboxyl, (h) C^ alkoxy- carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) CLS alkanoyl,
(8) carboxyl,
(9) C:.12 alkoxy-carbonyl,
(10) nitro,
(11) carbamoyl which may be substituted with C,_12 alkyl, (12) Ci_12 alkanoyl,
(13) C6.u aryl which may be substituted with (a) C 6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Cj.6 alkoxy, (g) carboxyl, (h) C 6 alkσxy- carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Ci-β alkanoyl,
(14) C6_u arylcarbonyl which may be substituted with (a) C 6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Cχ.6 alkoxy, (g) carboxyl, (h) C^g alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cι._6 alkanoyl,
(15) a 3- to 8-membered heterocyclic group containing 1 to 4 hetero-atoms selected from nitrogen, oxygen and sulfur, or a condensed heterocyclic group thereof with a 6- to 8-membered carbocyclic group or a heterocyclic group, which may be substituted with (a) Cι_6 alkyl, (b) c 3-β cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Cj.6 alkoxy, (g) carboxyl, (h) C^β alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) C^ alkanoyl,
(16) -NRdRβ', wherein Rd' and Rβ' independently represents (A) hydrogen, (B) a Cj_19 hydrocarbon group which may be substituted with (a) C^ alkyl which may be substituted with (i) C3.8 cycloalkyl, (ii) halogen, ( ϋ) cyano, (iv) hydroxyl, (v) C^ alkoxy, (vi) carboxyl, (vii) C _ alkoxy-carbonyl, (viii) nitro, (ix) amino, (x) carbamoyl, or (xi) C^, alkanoyl, (b) C3_8 cycloalkyl which may be substituted with (i) C3_8 cycloalkyl, (ii) halogen, (iii) cyano, (iv) hydroxyl, (v) Ci.4 alkoxy, (vi) carboxyl, (vii) Cι_4 alkoxy- carbonyl, (viii) nitro, (ix) amino, (x) carbamoyl, or (xi) C,_A alkanoyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) C,._4 alkoxy, (g) carboxyl, (h) Cj.4 alkoxy- carbonyl, (i) nitro, (j) di-C^ alkylamino, (k) carbamoyl, (1) C^ alkanoyl, (m) C6.12 aryl which may be substituted with (i) C,. alkyl, (ii) C3.8 cycloalkyl, (iii) halogen, (iv) cyano, (v) hydroxyl, (vi) Ci.i alkoxy, (vii) carboxyl, (viii) Cj_4 alkoxy-carbonyl, (ix) nitro, (x) amino, (xi) carbamoyl, or (xii) Cι_A alkanoyl, or (n) 2-pyridyl, (C) a heterocyclic group which may be substituted with (a) C^ alkyl which may be substituted with (i) C3.8 cycloalkyl, (ii) halogen, (iii) cyano, (iv) hydroxyl, (v) C^ alkoxy, (vi) carboxyl, (vii) C^ alkoxy-carbonyl, (viii) nitro, (ix) amino, (x) carbamoyl, or (xi) C^, alkanoyl, (b) Cj_8 cycloalkyl which may be substituted with (i) C3_8 cycloalkyl, (ii) halogen, (iii) cyano, (iv) hydroxyl, (v) Ci-4 alkoxy, (vi) carboxyl, (vii) Cw alkoxy- carbonyl, (viii) nitro, (ix) amino, (x) carbamoyl, or (xi) C 4 alkanoyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) C,_4 alkoxy, (g) carboxyl, (h) C^ alkoxy- carbonyl, (i) nitro, (j) di-C^ alkylamino, (k) carbamoyl, (1) Cι_4 alkanoyl, (m) C6.12 aryl which may be substituted with (i) C i alkyl, (ii) C3_8 cycloalkyl, (iii) halogen, (iv) cyano, (v) hydroxyl, (vi) Cι_4 alkoxy, (vii) carboxyl, (viii) C^ alkoxy-carbonyl, (ix) nitro, (x) amino, (xi) carbamoyl, or (xii) C^ alkanoyl, or (n) 2-pyridyl, or (D) -S02Rf , wherein R represents a Cι.1 hydrocarbon group which may be substituted with (a) Cι_4 alkyl which may be substituted with (i) C3-8 cycloalkyl, (ii) halogen, (iii) cyano, (iv) hydroxyl, (v) Cw alkoxy, (vi) carboxyl, (vii) C,.4 alkoxy-carbonyl, (viii) nitro, (ix) amino, (x) carbamoyl, or (xi) C^ alkanoyl, (b) C3.8 cycloalkyl which may be substituted with (i) C3.8 cycloalkyl, (ii) halogen, (iii) cyano, (iv) hydroxyl, (v) d_4 alkoxy, (vi) carboxyl, (vii) Cw alkoxy-carbonyl, (viii) nitro, (ix) amino, (x) carbamoyl, or (xi) C,_4 alkanoyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Cj_4 alkoxy, (g) carboxyl, (h) C^ alkoxy-carbonyl, (i) nitro, (j) di-C,. 4 alkylamino, (k) carbamoyl, (1) Cx.4 alkanoyl, (m) C6.I7 aryl which may be substituted with (i) C^ alkyl, (ii) C3.8 cycloalkyl, (iii) halogen, (iv) cyano, (v) hydroxyl, (vi) C^ alkoxy, (vii) carboxyl, (viii) C 4 alkoxy-carbonyl, (ix) nitro, (x) amino, (xi) carbamoyl, or (xii) Ci.4 alkanoyl, or (n) 2-pyridyl; Rd' and Re' may be combined with the adjacent nitrogen atom to form a heterocyclic group selected from 1-pyrrolidinyl, 1- imidazolyl, piperidino, 1-piperazinyl, 3-oxazolidinyl, hexamethylenimino, heptamethylenimino, morpholono, 1- indolinyl and phthalimido, which may be substituted with (a) Cn alkyl which may be substituted with (i) C 8 cycloalkyl, (ii) halogen, (iii) cyano, (iv) hydroxyl, (v) Cj_4 alkoxy, (vi) carboxyl, (vii) C 4 alkoxy- carbonyl, (viii) nitro, (ix) amino, (x) carbamoyl, or (xi) C1.l, alkanoyl, (b) C3.8 cycloalkyl which may be substituted with (i) C3.8 cycloalkyl, (ii) halogen, (iϋ) cyano, (iv) hydroxyl, (v) Cι_ alkoxy, (vi) carboxyl, (vii) Ci_4 alkoxy-carbonyl, (viii) nitro, (ix) amino, (x) carbamoyl, or (xi) C^ alkanoyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) C 4 alkoxy, (g) carboxyl, (h) C^ alkoxy-carbonyl, (i) nitro, (j) di-C,. 4 alkylamino, (k) carbamoyl, (1) C,_4 alkanoyl, (m) C6.]7 aryl which may be substituted with (i) Cj.z, alkyl, (ii) C3.8 cycloalkyl, (iii) halogen, (iv) cyano, (v) hydroxyl, (vi) C^ alkoxy, (vii) carboxyl, (viii) C^ alkoxy-carbonyl, (ix) nitro, (x) amino, (xi) carbamoyl, or (xii) C 4 alkanoyl, or (n) 2-pyridyl,
(17) Ci.^ alkylthio which may be substituted with (a) C3-8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) Ci.12 alkoxy, (f) carboxyl, (g) C1..12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) Cl.l2 alkanoyl ,
(18) Ci.^ alkylsulfinyl which may be substituted with (a) C3-8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C alkoxy, (f) carboxyl, (g) C,_12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) C!.12 alkanoyl,
(19) C!_12 alkylsulfonyl which may be substituted with (a) C3_8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) CX-12 alkoxy, (f) carboxyl, (g) Ci_12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) Ci_12 alkanoyl,
(20) C6.14 arylthio which may be substituted with (a) C,_ 6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Cx.6 alkoxy, (g) carboxyl, (h) C1,6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or
(1) Cι_6 alkanoyl,
(21) C6_14 arylsulfinyl which may be substituted with (a) Cx.6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) C 6 alkoxy, (g) carboxyl, (h) Cj.6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cι._6 alkanoyl, or
(22) C6.14 arylsulfonyl which may be substituted with (a) Cι._6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) CL6 alkoxy, (g) carboxyl, (h) CL6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cj.g alkanoyl,
2) a 5- to 8-membered heterocyclic group containing at least 1 atom selected from nitrogen, oxygen, and sulfur which may be substituted with (1) Cι_12 alkyl which may be substituted with (a) C3_8 cycloalkyl, (b) halogen,
(c) cyano, (d) hydroxyl, (e) Cι_12 alkoxy, (f) carboxyl, (9) Cι-12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) Cj.12 alkanoyl,
(2) C3_8 cycloalkyl which may be substituted with (a) C,. 8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) Ct.12 alkoxy, (f) carboxyl, (g) Cι_12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) C,.12 alkanoyl, (3) halogen (4) cyano,
(5) hydroxyl which may be acylated with (a) Cx.12 alkanoyl, (b) C6.14 arylcarbonyl or (c) C7.19 aralkanoyl,
(6) cι-ι2 alkoxy,
(7) C6.14 aryloxy which may be substituted with (a) C 6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Cj.g alkoxy, (g) carboxyl, (h) C^ alkoxy- carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) C!_6 alkanoyl,
(8) carboxyl, (9)
Figure imgf000064_0001
alkoxy-carbonyl,
(10) nitro,
(11) carbamoyl which may be substituted with Ci.i2 alkyl,
(12) C1.12 alkanoyl, (13) C6_14 aryl which may be substituted with (a) C^ alkyl, (b) C.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) C^ alkoxy, (g) carboxyl, (h) C,_6 alkoxy- carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cj.6 alkanoyl, (14) C6_14 arylcarbonyl which may be substituted with (a) Ci-6 alkyl, (b) C3_8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) C^6 alkoxy, (g) carboxyl, (h) C,_6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cι_6 alkanoyl, (15) a 3- to 8-membered heterocyclic group containing 1 to 4 hetero-atoms selected from nitrogen, oxygen and sulfur, or a condensed heterocyclic group thereof with a 6- to 8-membered carbocyclic group or a heterocyclic group, which may be substituted with (a) C^ alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Cj.j alkoxy, (g) carboxyl, (h) C^ alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) C^ alkanoyl, (16) -NR Re , wherein R and Ra have the same meanings as defined above,
(17) cι-i2 alkylthio which may be substituted with (a) 3-8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C,.12 alkoxy, (f) carboxyl, (g) C 2 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) Cj.12 alkanoyl,
(18) C!-12 alkylsulfinyl which may be substituted with (a) C3-8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) Cι_ϊ2 alkoxy, (f) carboxyl, (g) C,.,2 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) C!_12 alkanoyl,
(19) Cι_12 alkylsulfonyl which may be substituted with (a) C3_8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) x.n alkoxy, (f) carboxyl, (g) C1.i 2 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) Ci.iT. alkanoyl,
(20) C6.14 arylthio which may be substituted with (a) C,. 6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) C.._6 alkoxy, (g) carboxyl, (h) Cι_6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cj-6 alkanoyl,
(21) C6.14 arylsulfinyl which may be substituted with (a) Cj.g alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) C,_6 alkoxy, (g) carboxyl, (h) C,_6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cj.g alkanoyl, or
(22) C6.14 arylsulfonyl which may be substituted with (a) Cj_6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) CU6 alkoxy, (g) carboxyl, (h) Ci.6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) C1-6 alkanoyl, 3) -NR R5', wherein R4' and R5' independently represents (A) hydrogen, (B) a ^l9 hydrocarbon group which may be substituted with (1) Cx.12 alkyl which may be substituted with (a) C3_8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C^^ alkoxy, (f) carboxyl, (g) C 12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) C l2 alkanoyl, (2) C3-8 cycloalkyl which may be substituted with (a) C^ 8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) Cι-,2 alkoxy, (f) carboxyl, (g) C1_i2 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) Ci_12 alkanoyl, (3) halogen (4) cyano,
(5) hydroxyl which may be acylated with (a) C .l2 alkanoyl, (b) C6.14 arylcarbonyl or (c) C7_19 aralkanoyl,
(6) Ci-12 alkoxy,
(7) C6_14 aryloxy which may be substituted with (a) C1-6 alkyl, (b) C3,8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) C 6 alkoxy, (g) carboxyl, (h) C].6 alkoxy- carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cj.6 alkanoyl,
(8) carboxyl, (9) CW2 alkoxy-carbonyl,
(10) nitro,
(11) carbamoyl which may be substituted with Cl.i 2 alkyl,
(12) C l2 alkanoyl, (13) C6.14 aryl which may be substituted with (a) Cι_6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) C^g alkoxy, (g) carboxyl, (h) C 6 alkoxy- carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cj-6 alkanoyl. (14) C6,14 arylcarbonyl which may be substituted with (a) CLS alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) C^ alkoxy, (g) carboxyl, (h) Ci-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) C^ alkanoyl,
(15) a 3- to 8-membered heterocyclic group containing 1 to 4 hetero-atoms selected from nitrogen, oxygen and sulfur, or a condensed heterocyclic group thereof with a 6- to 8-membered carbocyclic group or a heterocyclic group, which may be substituted with (a) C^ alkyl, (b) 3-8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Ci_6 alkoxy, (g) carboxyl, (h) C,_6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) C^ alkanoyl, (16) -NR Re , wherein R and Re have the same meanings as defined above,
(17) C1-12 alkylthio which may be substituted with (a) C3_8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C1-12 alkoxy, (f) carboxyl, (g) C 12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) C 12 alkanoyl,
(18) Cι_i2 alkylsulfinyl which may be substituted with (a) C3_8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) Cι.12 alkoxy, (f) carboxyl, (g) Cι.l 2 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) CLJJ alkanoyl,
(19) Cι_12 alkylsulfonyl which may be substituted with (a) C3_8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C,.12 alkoxy, (f) carboxyl, (g) Cj._12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) Cι_12 alkanoyl,
(20) C6.14 arylthio which may be substituted with (a) C,_ 6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano,
(e) hydroxyl, (f) Cι._6 alkoxy, (g) carboxyl, (h) C,_6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cj-e alkanoyl,
(21) C6.14 arylsulfinyl which may be substituted with (a) C1-6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Cι_6 alkoxy, (g) carboxyl, (h) Cj.6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) C 6 alkanoyl, or
(22) C6.14 arylsulfonyl which may be substituted with (a) C!_6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) C,_6 alkoxy, (g) carboxyl, (h) Cj_6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) C^6 alkanoyl, or
(C) a 5- to 8-membered heterocyclic group containing 1 to 4 hetero-atoms selected from nitrogen, oxygen and sulfur, which may be substituted with (1) CN12 alkyl which may be substituted with (a) C3_8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C,.12 alkoxy, (f) carboxyl, (g) Ci_12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) Cι_12 alkanoyl, (2) C3_8 cycloalkyl which may be substituted with (a) C-,. 8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) Ci.ι.2 alkoxy, (f) carboxyl, (g) C1.12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) C1.12 alkanoyl, (3) halogen (4) cyano,
(5) hydroxyl which may be acylated with (a) C^^ alkanoyl, (b) C6.14 arylcarbonyl or (c) C7.19 aralkanoyl,
(6) Cn2 alkoxy,
(7) C6.14 aryloxy which may be substituted with (a) C^ alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) C,._6 alkoxy, (g) carboxyl, (h) Cj_6 alkoxy- carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cj-6 alkanoyl,
(8) carboxyl, ( 9 ) C L_ι2 alkoxy-carbonyl ,
( 10 ) nitro ,
(11) carbamoyl which may be substituted with C .12 alkyl, (12) Cι_12 alkanoyl,
(13) C6.14 aryl which may be substituted with (a) CN6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Ci_6 alkoxy, (g) carboxyl, (h) C 6 alkoxy- carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) CLS alkanoyl,
(14) C6.14 arylcarbonyl which may be substituted with (a) C^g alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) C^ alkoxy, (g) carboxyl, (h) C^ft alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cl.6 alkanoyl,
(15) a 3- to 8-membered heterocyclic group containing 1 to 4 hetero-atoms selected from nitrogen, oxygen and sulfur, or a condensed heterocyclic group thereof with a 6- to 8-membered carbocyclic group or a heterocyclic group, which may be substituted with (a) Cι_6 alkyl, (b) C3-8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) C!_6 alkoxy, (g) carboxyl, (h) Cι_6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) C^ alkanoyl, (16) -NR Re , wherein R and Re' have the same meanings as defined above,
(17) Cj.12 alkylthio which may be substituted with (a) C3_8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) i.ι.2 alkoxy, (f) carboxyl, (g) Cι.12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) C^^ alkanoyl,
(18) Cι_12 alkylsulfinyl which may be substituted with (a) C3.8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C,_12 alkoxy, (f) carboxyl, (g) C^^ alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) C .l2 alkanoyl,
(19) Ci.n alkylsulfonyl which may be substituted with (a) C3.8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) Ci.l2 alkoxy, (f) carboxyl, (g) Ct. alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) d.12 alkanoyl,
(20) C6.14 arylthio which may be substituted with (a) C,_ 6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) C^ alkoxy, (g) carboxyl, (h) C^ alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cj-6 alkanoyl,
(21) C6.14 arylsulfinyl which may be substituted with (a) C1.6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) C^ alkoxy, (g) carboxyl, (h) C 6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Ci.g alkanoyl, or
(22) C6.14 arylsulfonyl which may be substituted with (a) Cj-6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Cj.g alkoxy, (g) carboxyl, (h) C!_6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) C,_6 alkanoyl; R and R may be combined with the adjacent nitrogen atom to form a heterocyclic group selected from 1-pyrrolidinyl, 1- imidazolyl, piperidino, 1-piperazinyl, 3-oxazolidinyl, hexamethylenimino, heptamethylenimino, morpholono, 1- indolinyl and phthalimido, which may be substituted with (a) Ci.4 alkyl which may be substituted with (i) C a cycloalkyl, (ii) halogen, (iii) cyano, (iv) hydroxyl, (v) Ct._ϋ alkoxy, (vi) carboxyl, (vii) C 4 alkoxy- carbonyl, (viii) nitro, (ix) amino, (x) carbamoyl, or (xi) C,_4 alkanoyl, (b) C3_8 cycloalkyl which may be substituted with (i) C3.8 cycloalkyl, (ii) halogen, (iii) cyano, (iv) hydroxyl, (v) C,_4 alkoxy, (vi) carboxyl, (vii) C^ alkoxy-carbonyl, (viii) nitro, (ix) amino, (x) carbamoyl, or (xi) C^ alkanoyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Cj_4 alkoxy, (g) carboxyl, (h) C alkoxy-carbonyl, (i) nitro, (j) di-C,_ 4 alkylamino, (k) carbamoyl, (1) CL_4 alkanoyl, (m) C6.)7 aryl which may be substituted with (i) Cj.4 alkyl, (ii) C3-8 cycloalkyl, (iii) halogen, (iv) cyano, (v) hydroxyl, (vi) Cj_4 alkoxy, (vii) carboxyl, (viii) C 4 alkoxy-carbonyl, (ix) nitro, (x) amino, (xi) carbamoyl, or (xii) Ci.tl alkanoyl, or (n) 2-pyridyl,
4) -NR -CO-R , wherein Ra and Rb' independently represents (A) hydrogen, (B) a
Figure imgf000071_0001
hydrocarbon group which may be substituted with (1) C,.12 alkyl which may be substituted with (a) C3_8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) CU12 alkoxy, (f) carboxyl, (9) Cι-12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) Cι_12 alkanoyl,
(2) C3.8 cycloalkyl which may be substituted with (a) C 8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) Ci_12 alkoxy, (f) carboxyl, (g) C^^ alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) Cι_12 alkanoyl,
(3) halogen
(4) cyano,
(5) hydroxyl which may be acylated with (a) C,.1Z alkanoyl, (b) C6.14 arylcarbonyl or (c) C7.19 aralkanoyl,
(6) cι-i2 alkoxy,
(7) C6.14 aryloxy which may be substituted with (a) C^ alkyl, (b) C3_8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) C^ alkoxy, (g) carboxyl, (h) C^ alkoxy- carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cχ.6 alkanoyl,
(8) carboxyl,
(9) Ci.12 alkoxy-carbonyl,
(10) nitro. (11) carbamoyl which may be substituted with CU12 alkyl,
(12) d_12 alkanoyl,
(13) C6.14 aryl which may be substituted with (a) d_6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) d.6 alkoxy, (g) carboxyl, (h) d-β alkoxy- carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Ci-g alkanoyl,
(14) C6.14 arylcarbonyl which may be substituted with (a) d-β alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Cι_6 alkoxy, (g) carboxyl, (h) d_6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) C,_6 alkanoyl,
(15) a 3- to 8-membered heterocyclic group containing 1 to 4 hetero-atoms selected from nitrogen, oxygen and sulfur, or a condensed heterocyclic group thereof with a 6- to 8-membered carbocyclic group or a heterocyclic group, which may be substituted with (a) d.6 alkyl, (b) c 3-β cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) d_6 alkoxy, (g) carboxyl, (h) d_6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) d_6 alkanoyl,
(16) -NR R° , wherein R and Rβ have the same meanings as defined above, (17) Cι_12 alkylthio which may be substituted with (a) c 3-β cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C1.l2 alkoxy, (f) carboxyl, (g) d-ι2 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) C,.12 alkanoyl, (18) d_12 alkylsulfinyl which may be substituted with (a) C3.8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C1.12 alkoxy, (f) carboxyl, (g) C 2 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) d_12 alkanoyl, (19) d-12 alkylsulfonyl which may be substituted with (a) C3,8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C,.12 alkoxy, (f) carboxyl, (g) d_12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) d.ι2 alkanoyl,
(20) C6.14 arylthio which may be substituted with (a) C,. 6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) d-β alkoxy, (g) carboxyl, (h) d_6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) d_6 alkanoyl,
(21) C6.14 arylsulfinyl which may be substituted with (a) d_6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) d_6 alkoxy, (g) carboxyl, (h) d-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) d_6 alkanoyl, or
(22) C6.14 arylsulfonyl which may be substituted with (a) Ci.6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Cι.6 alkoxy, (g) carboxyl, (h) Cj.fi alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cι_6 alkanoyl,
(C) a 5- to 8-membered heterocyclic group containing 1 to 4 hetero-atoms selected from nitrogen, oxygen and sulfur, which may be substituted with (1) d_12 alkyl which may be substituted with (a) C3.8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) d-12 alkoxy, (f) carboxyl, (g) d_12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) d-12 alkanoyl,
(2) C3.8 cycloalkyl which may be substituted with (a) d_ 8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C,-12 alkoxy, (f) carboxyl, (g) C,_12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) d_12 alkanoyl,
(3) halogen
(4) cyano,
(5) hydroxyl which may be acylated with (a) d-12 alkanoyl, (b) C6_1A arylcarbonyl or (c) C7.19 aralkanoyl,
(6) d_12 alkoxy,
(7) C6.14 aryloxy which may be substituted with (a) d.6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Cj.6 alkoxy, (g) carboxyl, (h) d.6 alkoxy- carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cj.fi alkanoyl,
(8) carboxyl,
(9) C.12 alkoxy-carbonyl, (10) nitro,
(11) carbamoyl which may be substituted with Cj.ιz alkyl,
(12) C.12 alkanoyl,
(13) C6.j4 aryl which may be substituted with (a) d.6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) d_6 alkoxy, (g) carboxyl, (h) d.6 alkoxy- carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cj.fi alkanoyl,
(14) Cfi.14 arylcarbonyl which may be substituted with (a) Cj.6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) d_6 alkoxy, (g) carboxyl, (h) Cj.6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) d_6 alkanoyl,
(15) a 3- to 8-membered heterocyclic group containing 1 to 4 hetero-atoms selected from nitrogen, oxygen and sulfur, or a condensed heterocyclic group thereof with a 6- to 8-membered carbocyclic group or a heterocyclic group, which may be substituted with (a) d_6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Cj.6 alkoxy, (g) carboxyl, (h) d_6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cj_6 alkanoyl,
(16) -NRdRe', wherein R and Rβ' have the same meanings as defined above. (17) Cj-12 alkylthio which may be substituted with (a) C3_8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C...2 alkoxy, (f) carboxyl, (g) d_12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) CJ.J2 alkanoyl,
(18) d_12 alkylsulfinyl which may be substituted with (a) C3_a cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) d-12 alkoxy, (f) carboxyl, (g) Cj.12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) Cj.12 alkanoyl,
(19) Cj-12 alkylsulfonyl which may be substituted with (a) C3.8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) CJ.J2 alkoxy, (f) carboxyl, (g) Cj.12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) Cj.12 alkanoyl,
(20) C6.14 arylthio which may be substituted with (a) C,_ 6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) d_6 alkoxy, (g) carboxyl, (h) d_6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cj.6 alkanoyl,
(21) C6_ι4 arylsulfinyl which may be substituted with (a) Cj.6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) d_6 alkoxy, (g) carboxyl, (h) Cj.6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) d.6 alkanoyl, or
(22) Cfi.14 arylsulfonyl which may be substituted with (a) Cj.6 alkyl, (b) C3_8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) C .6 alkoxy, (g) carboxyl, (h) Cj.6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) d_6 alkanoyl,
5) -NRa'-CO-NR4V, wherein Ra', R and R5' have the same meanings as defined above, 6 6)) --NNRRa^'--CCSS--NNRRή^,'RR55'',, wwhheerreeiinn Ra', R4' and R5' have the same meanings as defined above, 7) -NRa -NR R ', wherein Ra', R4' and R5' have the same meanings as defined above, or
8) -NRa'-CO-ORb', wherein Ra' and Rb' have the same meanings as defined above; R2 represents 1) hydrogen, 2) cyano, 3) organic carboxylic acid-derived acyl, 4) -CONR6 R7', wherein R6 and R independently represents (A) hydrogen, (B) d.j? alkanoyl, (C) a Cj.j9 hydrocarbon group which may be substituted with (1) Cj.12 alkyl which may be substituted with (a) C3.8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C .J2 alkoxy, (f) carboxyl, (g) Cj.12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) Cj.12 alkanoyl,
(2) C3_a cycloalkyl which may be substituted with (a) C,. 8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e)
Cj.jz alkoxy, (f) carboxyl, (g) Cj.12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) d_12 alkanoyl,
(3) halogen
(4) cyano, (5) hydroxyl which may be acylated with (a) Cι_12 alkanoyl, (b) C6_ι4 arylcarbonyl or (c) C7_ι9 aralkanoyl,
(6) Cj.12 alkoxy,
(7) C 6-IA aryloxy which may be substituted with (a) d_6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Cj.6 alkoxy, (g) carboxyl, (h) d_6 alkoxy- carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) C.6 alkanoyl,
(8) carboxyl,
(9) Cj.12 alkoxy-carbonyl, (10) nitro,
(11) carbamoyl which may be substituted with d_12 alkyl,
(12) Cj.12 alkanoyl,
(13) C6.14 aryl which may be substituted with (a) C,.6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) d_6 alkoxy, (g) carboxyl, (h) d_6 alkoxy- carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cj.6 alkanoyl, (14) C6.14 arylcarbonyl which may be substituted with (a) Cj.6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Cj_6 alkoxy, (g) carboxyl, (h) Cj.6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) d_6 alkanoyl, (15) a 3- to 8-membered heterocyclic group containing 1 to 4 hetero-atoms selected from nitrogen, oxygen and sulfur, or a condensed heterocyclic group thereof with a 6- to 8-membered carbocyclic group or a heterocyclic group, which may be substituted with (a) d_6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Cj.6 alkoxy, (g) carboxyl, (h) d_6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cj.6 alkanoyl,
(16) -NR Re , wherein R and Re have the same meanings as defined above,
(17) d_ι2 alkylthio which may be substituted with (a) C3_8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C..-2 alkoxy, (f) carboxyl, (g) d_12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) Cj.j2 alkanoyl,
(18) Cj.12 alkylsulfinyl which may be substituted with (a) C3.8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) d_12 alkoxy, (f) carboxyl, (g) d-12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) C 12 alkanoyl,
(19) Cj.12 alkylsulfonyl which may be substituted with (a) C3.8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) Cj.12 alkoxy, (f) carboxyl, (g) d_12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) Cι_12 alkanoyl,
(20) C6.ι4 arylthio which may be substituted with (a) C,_ 6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) d_6 alkoxy, (g) carboxyl, (h) Cj.6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or
(1) Cj.6 alkanoyl,
(21) C6.j4 arylsulfinyl which may be substituted with (a) Cj.6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Cj.6 alkoxy, (g) carboxyl, (h) Cj.6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cj.6 alkanoyl, or
(22) C6.14 arylsulfonyl which may be substituted with (a) Cj.6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Cj.6 alkoxy, (g) carboxyl, (h) Cj.6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) d_6 alkanoyl, or
(D) a 5- to 8-membered heterocyclic group containing 1 to 4 hetero-atoms selected from nitrogen, oxygen and sulfur, which may be substituted with (1) Cj.12 alkyl which may be substituted with (a) C3_8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) Cj.12 alkoxy, (f) carboxyl, (g) CJ.J2 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) Cj.12 alkanoyl,
(2) C3_8 cycloalkyl which may be substituted with (a) _ 8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e)
Cj.12 alkoxy, (f) carboxyl, (g) CJ.J2 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) Cj.12 alkanoyl,
(3) halogen
(4) cyano, (5) hydroxyl which may be acylated with (a) d_12 alkanoyl, (b) C6.j4 arylcarbonyl or (c) C7.j9 aralkanoyl,
(6) Cj.12 alkoxy,
(7) C6.14 aryloxy which may be substituted with (a) Cι_6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Cj.6 alkoxy, (g) carboxyl, (h) Cj.6 alkoxy- carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cj.6 alkanoyl, (8) carboxyl, (9) cι-i2 alkoxy-carbonyl,
(10) nitro,
(11) carbamoyl which may be substituted with Cj.j2 alkyl,
(12) Cj.j2 alkanoyl, (13) C6.j4 aryl which may be substituted with (a) C 6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) d_6 alkoxy, (g) carboxyl, (h) d_6 alkoxy- carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cj.6 alkanoyl, (14) Cfi-u arylcarbonyl which may be substituted with (a) d.6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Cj.6 alkoxy, (g) carboxyl, (h) Cj.6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) d_6 alkanoyl, (15) a 3- to 8-membered heterocyclic group containing 1 to 4 hetero-atoms selected from nitrogen, oxygen and sulfur, or a condensed heterocyclic group thereof with a 6- to 8-membered carbocyclic group or a heterocyclic group, which may be substituted with (a) Cj.6 alkyl, (b) _β cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Cj.6 alkoxy, (g) carboxyl, (h) d_6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cj.6 alkanoyl,
(16) -NRd Re , wherein Rd and Rβ' have the same meanings as defined above,
(17) cι-i2 alkylthio which may be substituted with (a) 3-8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) d_12 alkoxy, (f) carboxyl, (g) d_12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) d_12 alkanoyl,
(18) Cj.12 alkylsulfinyl which may be substituted with (a) C3_8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) Cj.12 alkoxy, (f) carboxyl, (g) Cj.12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) Cj.12 alkanoyl,
(19) cι-π alkylsulfonyl which may be substituted with (a) C3.8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) Cj.12 alkoxy, (f) carboxyl, (g) d.j2 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) Cj,j2 alkanoyl,
(20) C6-j4 arylthio which may be substituted with (a) C,- 6 alkyl, (b) C3_8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) d_6 alkoxy, (g) carboxyl, (h) Cj.6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cj.6 alkanoyl,
(21) C6.14 arylsulfinyl which may be substituted with (a) Cj.6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Cj_6 alkoxy, (g) carboxyl, (h) Cj.6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) d_6 alkanoyl, or
(22) C6.j4 arylsulfonyl which may be substituted with (a) Cj.6 alkyl, (b) C3_8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Cj.6 alkoxy, (g) carboxyl, (h) Cj.6 alkoxy-carbonyl, (i) nitro, (j) amino, (k)
§» 7» carbamoyl or (1) C.6 alkanoyl; R and R may be combined with the adjacent nitrogen atom to form a heterocyclic group selected from 1-pyrrolidinyl, 1- imidazolyl, piperidino, 1-piperazinyl, 3-oxazolidinyl, hexamethylenimino, heptamethylenimino, morpholono, 1- indolinyl and phthalimido, which may be substituted with (a) Cj.4 alkyl which may be substituted with (i) C3.
8 cycloalkyl, (ii) halogen, (iii) cyano, (iv) hydroxyl,
(v) d_4 alkoxy, (vi) carboxyl, (vii) d_4 alkoxy- carbonyl, (viii) nitro, (ix) amino, (x) carbamoyl, or (xi) Cj_4 alkanoyl, (b) C3.8 cycloalkyl which may be substituted with (i) C3.8 cycloalkyl, (ii) halogen, (iii) cyano, (iv) hydroxyl, (v) d_4 alkoxy, (vi) carboxyl, (vii) d_4 alkoxy-carbonyl, (viii) nitro, (ix) amino, (x) carbamoyl, or (xi) Cj.4 alkanoyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) d_4 alkoxy, (g) carboxyl, (h) d_4 alkoxy-carbonyl, (i) nitro, (j) di-C,. 4 alkylamino, (k) carbamoyl, (1) d_4 alkanoyl, (m) C6_]7 aryl which may be substituted with (i) d_4 alkyl, (ii) C3_8 cycloalkyl, (iii) halogen, (iv) cyano, (v) hydroxyl, (vi) d_4 alkoxy, (vii) carboxyl, (viii) Cj.4 alkoxy-carbonyl, (ix) nitro, (x) amino, (xi) carbamoyl, or (xii) Cj.4 alkanoyl, or (n) 2-pyridyl, 5) -CSNR6 R , wherein Rδ and R7 have same meanings as defined above,
6) a CJ.J9 hydrocarbon group which may be substituted with (1) Cj.j2 alkyl which may be substituted with (a) C3_8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) d_12 alkoxy, (f) carboxyl, (g) d_ι2 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) Cj.12 alkanoyl,
(2) C3_β cycloalkyl which may be substituted with (a) C-,. 8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) Cj.12 alkoxy, (f) carboxyl, (g) Cj.12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) d-12 alkanoyl,
( 3) halogen
(4) cyano,
(5) hydroxyl which may be acylated with (a) d_12 alkanoyl, (b) C6.j4 arylcarbonyl or (c) C7.j9 aralkanoyl,
(6) Cj.12 alkoxy,
(7) C6.j4 aryloxy which may be substituted with (a) Cj.6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) d-6 alkoxy, (g) carboxyl, (h) d_6 alkoxy- carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cj.6 alkanoyl,
(8) carboxyl,
(9) cι-i2 alkoxy-carbonyl, (10) nitro,
(11) carbamoyl which may be substituted with Cj.12 alkyl,
(12) Cj.j2 alkanoyl,
(13) C6.j4 aryl which may be substituted with (a) C,_6 alkyl, (b) C3_8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Cj.6 alkoxy, (g) carboxyl, (h) d_6 alkoxy- carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) C.6 alkanoyl,
(14) Cfi.14 arylcarbonyl which may be substituted with (a) Cj.6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Cj.6 alkoxy, (g) carboxyl, (h) Cj.6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) d_6 alkanoyl,
(15) a 3- to 8-membered heterocyclic group containing 1 to 4 hetero-atoms selected from nitrogen, oxygen and sulfur, or a condensed heterocyclic group thereof with a 6- to 8-membered carbocyclic group or a heterocyclic group, which may be substituted with (a) Cj.6 alkyl, (b) C3-8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Cj.6 alkoxy, (g) carboxyl, (h) Cj.6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) d_6 alkanoyl,
(16) -NRdRe , wherein R and Rβ have the same meanings as defined above, (17) Cj.12 alkylthio which may be substituted with (a) C3.8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) cι-i2 alkoxy, (f) carboxyl, (g) CJ.J2 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) d_12 alkanoyl, (18) d_12 alkylsulfinyl which may be substituted with (a) C3.8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) CJ.J2 alkoxy, (f) carboxyl, (g) d_12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) d_i2 alkanoyl,
(19) Cι_i2 alkylsulfonyl which may be substituted with (a) C3_8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) CJ.J2 alkoxy, (f) carboxyl, (g) CJ.J2 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) d_12 alkanoyl,
(20) C6.14 arylthio which may be substituted with (a) C,_ 6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Cj.6 alkoxy, (g) carboxyl, (h) Cj.6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cj.6 alkanoyl,
(21) C6.j4 arylsulfinyl which may be substituted with (a) Cj.6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) d_6 alkoxy, (g) carboxyl, (h) Cj.6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) C 6 alkanoyl, or
(22) C6.14 arylsulfonyl which may be substituted with (a) Cj.6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Cj.6 alkoxy, (g) carboxyl, (h) Cj.6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cj.6 alkanoyl,
7) a 5- to 8-membered heterocyclic group containing at least 1 atom selected from nitrogen, oxygen, and sulfur which may be substituted with (1) Cj.12 alkyl which may be substituted with (a) C3.8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) Cj.12 alkoxy, (f) carboxyl, (9) cι-π alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) d_12 alkanoyl,
(2) C3.8 cycloalkyl which may be substituted with (a) C3- 8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) Cj.12 alkoxy , ( f ) carboxyl , ( g ) C J. J2 alkoxy-carbonyl , ( h ) nitro , ( i ) amino , ( j ) carbamoyl , or ( k ) CJ.J2 alkanoyl ,
(3) halogen
(4) cyano, (5) hydroxyl which may be acylated with (a) Cj.12 alkanoyl, (b) C6.j4 arylcarbonyl or (c) C7.j9 aralkanoyl ,
(6) Cj.j2 alkoxy,
(7) C6_j4 aryloxy which may be substituted with (a) Cj.6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) C,_6 alkoxy, (g) carboxyl, (h) Cj.6 alkoxy- carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cj.6 alkanoyl,
(8) carboxyl,
(9) Cj.12 alkoxy-carbonyl, (10) nitro,
(11) carbamoyl which may be substituted with CJ.J2 alkyl,
( 12 ) Cj.12 alkanoyl ,
(13) Cfi.14 aryl which may be substituted with (a) d_6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Cj_6 alkoxy, (g) carboxyl, (h) d.6 alkoxy- carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cj.6 alkanoyl,
(14) Cfi.ji arylcarbonyl which may be substituted with (a) Cj.6 alkyl, (b) C3_8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Cj.6 alkoxy, (g) carboxyl, (h) Cj.6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) d_6 alkanoyl,
(15) a 3- to 8-membered heterocyclic group containing 1 to 4 hetero-atoms selected from nitrogen, oxygen and sulfur, or a condensed heterocyclic group thereof with a 6- to 8-membered carbocyclic group or a heterocyclic group, which may be substituted with (a) d_6 alkyl, (b) C3_8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Cj.6 alkoxy, (g) carboxyl, (h) d_6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cj.6 alkanoyl,
(16) -NRdRe', wherein Rd' and Re' have the same meanings as defined above,
(17) C.j2 alkylthio which may be substituted with (a) d-β cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C.12 alkoxy, (f) carboxyl, (g) Cj.12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) Cj.12 alkanoyl,
(18) d_12 alkylsulfinyl which may be substituted with (a) C3.8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) Cj.12 alkoxy, (f) carboxyl, (g) Cj_12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) Cj.12 alkanoyl,
(19) CJ.J2 alkylsulfonyl which may be substituted with (a) C3.8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) Cι_12 alkoxy, (f) carboxyl, (g) Cj.j2 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) Cj.12 alkanoyl,
(20) Cfi.14 arylthio which may be substituted with (a) C,_ 6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) d_6 alkoxy, (g) carboxyl, (h) Cj.6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cj.6 alkanoyl,
(21) C6.14 arylsulfinyl which may be substituted with (a) Cj.6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Cj.6 alkoxy, (g) carboxyl, (h) j.6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) C_6 alkanoyl, or
(22) C6.j4 arylsulfonyl which may be substituted with (a) Cj.6 alkyl, (b) C3_8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) d_6 alkoxy, (g) carboxyl, (h) C.6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) d_6 alkanoyl,
8) amino which may be substituted with a C,_19 hydrocarbon-oxy, or
9) carboxyl which may be esterified; R represents 1) hydrogen, 2) halogen, 3) a Cj_19 hydrocarbon group which may be substituted with (1) C,. 12 alkyl which may be substituted with (a) C3.8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) Cj.j2 alkoxy, (f) carboxyl, (g) CJ.J2 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) d_12 alkanoyl,
(2) C3_8 cycloalkyl which may be substituted with (a) _ 8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) Cj.12 alkoxy, (f) carboxyl, (g) CJ.J2 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) Cj.12 alkanoyl, (3) halogen
(4) cyano,
(5) hydroxyl which may be acylated with (a) d_12 alkanoyl, (b) C6.j4 arylcarbonyl or (c) C7.19 aralkanoyl,
(6) Cj.12 alkoxy, (7) C6.j4 aryloxy which may be substituted with (a) d-β alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) d_6 alkoxy, (g) carboxyl, (h) d_6 alkoxy- carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cj.6 alkanoyl, (8) carboxyl,
( 9 ) CJ.J2 alkoxy-carbonyl ,
( 10 ) nitro ,
(11) carbamoyl which may be substituted with C,_12 alkyl, (12) Cj.12 alkanoyl,
(13) C6.14 aryl which may be substituted with (a) d_6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) d_6 alkoxy, (g) carboxyl, (h) d_6 alkoxy- carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cj.6 alkanoyl,
(14) C6.14 arylcarbonyl which may be substituted with (a) Cj.6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Cj_6 alkoxy, (g) carboxyl, (h) Cj.6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) d_6 alkanoyl,
(15) a 3- to 8-membered heterocyclic group containing 1 to 4 hetero-atoms selected from nitrogen, oxygen and sulfur, or a condensed heterocyclic group thereof with a 6- to 8-membered carbocyclic group or a heterocyclic group, which may be substituted with (a) C.6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Cj.6 alkoxy, (g) carboxyl, (h) Cj.6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cj.6 alkanoyl,
(16) -NR Re , wherein R and Re have the same meanings as defined above,
(17) Cj.12 alkylthio which may be substituted with (a) C3-8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) Cj.12 alkoxy, (f) carboxyl, (g) Cj_12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) Cj_12 alkanoyl,
(18) Cj.12 alkylsulfinyl which may be substituted with (a) c 3-β cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) Cj.12 alkoxy, (f) carboxyl, (g) Cj.12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) d_12 alkanoyl,
(19) Cj.12 alkylsulfonyl which may be substituted with (a) C3_B cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) d_12 alkoxy, (f) carboxyl, (g) d-12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) d-12 alkanoyl,
(20) Cfi.14 arylthio which may be substituted with (a) C,. 6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) d_6 alkoxy, (g) carboxyl, (h) CN6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or
(1) C.6 alkanoyl,
(21) C6.j4 arylsulfinyl which may be substituted with (a) Cj.6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) d_6 alkoxy, (g) carboxyl, (h) Cj.6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cj.6 alkanoyl, or
(22) C6.14 arylsulfonyl which may be substituted with (a) Cj.6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Cj.6 alkoxy, (g) carboxyl, (h) Cj.6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cj_6 alkanoyl, 4) a 5- to 8-membered heterocyclic group containing at least 1 atom selected from nitrogen, oxygen, and sulfur, which may be substituted with (1) CJ.J2 alkyl which may be substituted with (a) C3.8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) d_12 alkoxy, (f) carboxyl, (g) Cj.12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) d_12 alkanoyl,
(2) C3.8 cycloalkyl which may be substituted with (a) C-,. 8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C .J2 alkoxy, (f) carboxyl, (g) Cj.12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) Cj_12 alkanoyl, (3) halogen
(4) cyano ,
(5) hydroxyl which may be acylated with (a) CJ.J2 alkanoyl, (b) C6.14 arylcarbonyl or (c) C7.j9 aralkanoyl,
(6) cι-i2 alkoxy, (7) C6.14 aryloxy which may be substituted with (a) d_6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Cj.6 alkoxy, (g) carboxyl, (h) d_6 alkoxy- carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cj.6 alkanoyl, (8) carboxyl,
(9) cι-i2 alkoxy-carbonyl,
(10) nitro,
(11) carbamoyl which may be substituted with CJ-J2 alkyl,
(12) Cj.12 alkanoyl,
(13) C6.j4 aryl which may be substituted with (a) d_6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Cj_6 alkoxy, (g) carboxyl, (h) Cj.6 alkoxy- carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cj.6 alkanoyl,
(14) C6.j4 arylcarbonyl which may be substituted with (a) Cj.6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) d_6 alkoxy, (g) carboxyl, (h) C.6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cj.6 alkanoyl,
(15) a 3- to 8-membered heterocyclic group containing 1 to 4 hetero-atoms selected from nitrogen, oxygen and sulfur, or a condensed heterocyclic group thereof with a 6- to 8-membered carbocyclic group or a heterocyclic group, which may be substituted with (a) Cj.6 alkyl, (b) d-β cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Cj.6 alkoxy, (g) carboxyl, (h) Cj_6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cj_6 alkanoyl,
(16) -NR Re , wherein R and Re have the same meanings as defined above,
(17) Cj.12 alkylthio which may be substituted with (a) C3.8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) Cj.j2 alkoxy, (f) carboxyl, (g) d_12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) Cj.12 alkanoyl,
(18) Cj.12 alkylsulfinyl which may be substituted with (a) C3.8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) Cj.12 alkoxy, (f) carboxyl, (g) d_12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) Cj.12 alkanoyl,
(19) Cj.12 alkylsulfonyl which may be substituted with (a) C3.8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) d-12 alkoxy, (f) carboxyl, (g) Cj.12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) Cj.j2 alkanoyl,
(20) Cfi.14 arylthio which may be substituted with (a) C,_ 6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) d_6 alkoxy, (g) carboxyl, (h) Cj.6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or
(1) Cj.6 alkanoyl,
(21) C6.14 arylsulfinyl which may be substituted with (a) Cj.6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Cj.6 alkoxy, (g) carboxyl, (h) C.6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cj_6 alkanoyl, or
(22) Cfi.14 arylsulfonyl which may be substituted with (a) Cj.fi alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) d_6 alkoxy, (g) carboxyl, (h) Cj.6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cj_6 alkanoyl,
5) a d_19 hydrocarbon-oxy which may be substituted with (1) d_ι2 alkyl which may be substituted with (a) C3.a cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) Cj.12 alkoxy, (f) carboxyl, (g) Cj.12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) d_12 alkanoyl,
(2) C3.8 cycloalkyl which may be substituted with (a) C3_ 8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e)
Cj.12 alkoxy, (f) carboxyl, (g) CJ.J2 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) d_12 alkanoyl,
(3) halogen
(4) cyano, (5) hydroxyl which may be acylated with (a) Cj.12 alkanoyl, (b) C6.14 arylcarbonyl or (c) C7.19 aralkanoyl,
(6) Cj.12 alkoxy,
(7) C6.j4 aryloxy which may be substituted with (a) Cj.6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Cj_6 alkoxy, (g) carboxyl, (h) Cj.6 alkoxy- carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cj.g alkanoyl,
(8) carboxyl, ( 9 ) C J. JZ alkoxy-carbonyl ,
(10) nitro,
(11) carbamoyl which may be substituted with CJ.J2 alkyl,
(12) Cj.12 alkanoyl, (13) C6-j4 aryl which may be substituted with (a) d_6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Cj_6 alkoxy, (g) carboxyl, (h) Cj.6 alkoxy- carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cj.6 alkanoyl, (14) Cfi.i4 arylcarbonyl which may be substituted with (a) Cj.6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Cj.6 alkoxy, (g) carboxyl, (h) Cj.g alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) d_6 alkanoyl, (15) a 3- to 8-membered heterocyclic group containing 1 to 4 hetero-atoms selected from nitrogen, oxygen and sulfur, or a condensed heterocyclic group thereof with a 6- to 8-membered carbocyclic group or a heterocyclic group, which may be substituted with (a) d_6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Cj.6 alkoxy, (g) carboxyl, (h) C,_6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) d_6 alkanoyl, (16) -NR Re , wherein R and Re' have the same meanings as defined above,
(17) Cj.12 alkylthio which may be substituted with (a) C3_8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) Cj.12 alkoxy, (f) carboxyl, (g) d_12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) C .12 alkanoyl,
(18) d_12 alkylsulfinyl which may be substituted with (a) C3.8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) Cj.12 alkoxy, (f) carboxyl, (g) Cj.12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) C .12 alkanoyl,
(19) Cj.12 alkylsulfonyl which may be substituted with (a) C3.8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) CJ.J2 alkoxy, (f) carboxyl, (g) Cj.j2 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) CJ.J2 alkanoyl,
(20) C6.j4 arylthio which may be substituted with (a) C,. 6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Cj.6 alkoxy, (g) carboxyl, (h) Cj-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cj.g alkanoyl,
(21) C6.j4 arylsulfinyl which may be substituted with (a) Cj.g alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) d_6 alkoxy, (g) carboxyl, (h) Cj.g alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) d_6 alkanoyl, or
(22) Cfi.14 arylsulfonyl which may be substituted with (a) Cj.6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Cj.6 alkoxy, (g) carboxyl, (h) Cj.g alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) d_6 alkanoyl,
6) -NR4R5', wherein R and R5' have the same meanings as defined above,
7) carboxyl which may be esterified, 8) or a group of the formula -S(0)m-R", where R" represents (A) a d_19 hydrocarbon group which may be substituted with (1) CJ.J2 alkyl which may be substituted with (a) C3.8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) d_12 alkoxy, (f) carboxyl, (g) Cj.12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) d_12 alkanoyl,
(2) C3.8 cycloalkyl which may be substituted with (a) C3. 8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) CJ.J2 alkoxy, (f) carboxyl, (g) d_12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) Cj.12 alkanoyl,
(3) halogen
(4) cyano,
(5) hydroxyl which may be acylated with (a) Cj.12 alkanoyl, (b) C6.14 arylcarbonyl or (c) C7.19 aralkanoyl,
(6) cι-i2 alkoxy,
(7) c 6-u aryloxy which may be substituted with (a) Cj.6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) d_6 alkoxy, (g) carboxyl, (h) d_6 alkoxy- carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cj.g alkanoyl,
(8) carboxyl,
(9) Cj.12 alkoxy-carbonyl,
(10) nitro, (11) carbamoyl which may be substituted with d-12 alkyl,
(12) Cj.12 alkanoyl,
(13) Cfi.14 aryl which may be substituted with (a) d_6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) d_6 alkoxy, (g) carboxyl, (h) d-β alkoxy- carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cj.g alkanoyl,
(14) C6.14 arylcarbonyl which may be substituted with (a) Cj.6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) d_6 alkoxy, (g) carboxyl, (h) Cj.g alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) d-6 alkanoyl,
(15) a 3- to 8-membered heterocyclic group containing 1 to 4 hetero-atoms selected from nitrogen, oxygen and sulfur, or a condensed heterocyclic group thereof with a 6- to 8-merabered carbocyclic group or a heterocyclic group, which may be substituted with (a) Cj.6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Cj.6 alkoxy, (g) carboxyl, (h) d_6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cj.6 alkanoyl,
(16) -NR Re , wherein R and R* have the same meanings as defined above, (17) C.12 alkylthio which may be substituted with (a) C3.8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) cι-i2 alkoxy, (f) carboxyl, (g) Cj.12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) d_12 alkanoyl, (18) Cj.12 alkylsulfinyl which may be substituted with (a) C3.8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) Cj.12 alkoxy, (f) carboxyl, (g) d-12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) Cj.12 alkanoyl, (19) Cj.12 alkylsulfonyl which may be substituted with (a) C3_8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) d_12 alkoxy, (f) carboxyl, (g) Cj.12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) Cj.12 alkanoyl, (20) C6_ι4 arylthio which may be substituted with (a) C,_ 6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) d_6 alkoxy, (g) carboxyl, (h) d.6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cj.6 alkanoyl, (21) Cfi.j4 arylsulfinyl which may be substituted with (a) Cj.g alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Cj.6 alkoxy, (g) carboxyl, (h) Cj.6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cj.6 alkanoyl, or
(22) Cfi.1 arylsulfonyl which may be substituted with (a) Cj.6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Cj.6 alkoxy, (g) carboxyl, (h) Cj.6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cj.6 alkanoyl, or (B) a 5- to 8- membered heterocyclic group containing at least 1 atom selected from nitrogen, oxygen, and sulfur which may be substituted with (1) Cj.12 alkyl which may be substituted with (a) C3.8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C.12 alkoxy, (f) carboxyl, (g) Cj.12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) Cj.12 alkanoyl,
(2) C3.8 cycloalkyl which may be substituted with (a) C3. 8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) CJ.J2 alkoxy, (f) carboxyl, (g) d_12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) d-12 alkanoyl,
(3) halogen
(4) cyano,
(5) hydroxyl which may be acylated with (a) CJ.J2 alkanoyl, (b) C6.14 arylcarbonyl or (c) C7.19 aralkanoyl,
(6) cι-π alkoxy,
(7) C 6-IA aryloxy which may be substituted with (a) Cj.6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) d.6 alkoxy, (g) carboxyl, (h) Cj.6 alkoxy- carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cj.6 alkanoyl,
(8) carboxyl,
(9) d_12 alkoxy-carbonyl,
(10) nitro, (11) carbamoyl which may be substituted with d-12 alkyl,
(12) C.12 alkanoyl,
(13) C6.j4 aryl which may be substituted with (a) Cj.6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) d_6 alkoxy, (g) carboxyl, (h) Cj.6 alkoxy- carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) d_6 alkanoyl,
(14) C6.j4 arylcarbonyl which may be substituted with (a) Cj.6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Cj.6 alkoxy, (g) carboxyl, (h) Cj.g alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) d_6 alkanoyl,
(15) a 3- to 8-membered heterocyclic group containing 1 to 4 hetero-atoms selected from nitrogen, oxygen and sulfur, or a condensed heterocyclic group thereof with a 6- to 8-membered carbocyclic group or a heterocyclic group, which may be substituted with (a) d_6 alkyl, (b) C3-8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Cj.g alkoxy, (g) carboxyl, (h) Cj.6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cj.6 alkanoyl,
(16) -NRd Re , wherein R and Re have the same meanings as defined above, (17) C.12 alkylthio which may be substituted with (a) 3-8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) cι-i2 alkoxy, (f) carboxyl, (g) Cj.12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) CJ.J2 alkanoyl, (18) Cj.12 alkylsulfinyl which may be substituted with (a) C3.8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C.12 alkoxy, (f) carboxyl, (g) Cj.j2 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) CJ.J2 alkanoyl, (19) Cj.j2 alkylsulfonyl which may be substituted with (a) C3.8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) d_12 alkoxy, (f) carboxyl, (g) d_12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl, or (k) CJ.J2 alkanoyl,
(20) C6.14 arylthio which may be substituted with (a) C,_ 6 alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) d_6 alkoxy, (g) carboxyl, (h) C_6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) Cj.g alkanoyl,
(21) Cfi.j4 arylsulfinyl which may be substituted with (a) Cj.g alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) Cj.6 alkoxy, (g) carboxyl, (h) Cj.g alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) d_6 alkanoyl, or
(22) Cfi.j4 arylsulfonyl which may be substituted with (a) Cj.g alkyl, (b) C3.8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) d_6 alkoxy, (g) carboxyl, (h) Cj.g alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or (1) d_6 alkanoyl; m represents 0, 1, or 2.
[Industrial Application]
Compound B, particularly compound A, has excellent inhibitory activities of IL-6 activity and NO production of NOS inducible cells and low toxicity.
Therefore, it can be used as a safe inhibitor of IL-6 activity or NO production in human and other mammalian animals (e.g. mouse, rat, guinea pig, rabbit, dog, cat, bovine, swine, sheep, monkey, chimpanzee, etc.). Furthermore, compound B can be safely used as a drug, for example a prophylactic and a therapeutic drug for IL-6-associated diseases, namely heart diseases such as myocardiopathy, cardiac hypertrophy, myocardial infarction, angina pectoris, etc., various autoimmune diseases such as chronic rheumatoid arthritis, systemic lupus erythematosus, systemic scleroder a, rheumatic fever, polymyositis, periarteritis nodosa, Sjδgren's syndrome, Behcet's disease, Castleman's disease, autoimmune hemolytic anemia, etc., inflammatory diseases such as mesangial proliferative nephritis, IgA nephritis, lupus nephritis, osteoporosis, amyloidosis, bronchial asthma, atopic dermatitis, psoriasis, pleurisy, ulcerative colitis, atherosclerosis, active chronic hepatitis, alcoholic cirrhosis, gout, various types of encephalitis, etc., or diseases accompanied by granuloma such as multiple myeoloma, atrial myxoma, renal carcinoma, pulmonary adenocarcinoma, malignant mesothelioma, ovarian cancer, cancerous cachexia, etc. or NO-associated diseases, for example, atherosclerosis, myocarditis, myocardiopathy, ischemic brain disorder, Alzheimer's disease, multiple sclerosis, septicemia, rheumatoid arthritis, osteoarthritis, gastric ulcer, duodenal ulcer, ulcerative colitis, diabetes, glomerulonephritis, osteoporosis, pneumonia, hepatitis, graft rejection, pain, etc., in human and other mammalian animals (e.g. mouse, rat, guinea pig, rabbit, dog, cat, bovine, swine, sheep, monkey, chimpanzee, etc.).
For use as a drug, compound B can be administered, either alone or in mixture with a pharmacologically acceptable carrier, excipient, or diluent, orally in such dosage forms as tablets, capsules, granules, powders, etc. or parenterally in such dosage forms as injections, among other forms. For the manufacture of oral dosage forms, taking tablets as an example, binders (e.g hydroxypropyl- cellulose, hydroxypropylmethylcellulose, macrogols, etc.), disintegrators (e.g. starch, carboxymethylcellulose calcium, etc.), excipients (e.g. lactose, talc, etc.), and lubricants (e.g. magnesium stearate, talc, etc.) can be suitably formulated. For the manufacture of parenteral products, taking an injection as an example, an aqueous medium (e.g. distilled water), isotonic solutions (e.g. saline. Ringer's solution), isotonizing agents (e.g. glucose, D-sorbitol, D-mannitol, sodium chloride, etc.), stabi¬ lizers (e.g. human serum albumin etc.), antiseptics (e.g. benzyl alcohol, chlorobutanol, methyl p- hydroxybenzoate, propyl p-hydroxybenzoate, phenols, etc.), buffers (e.g. phosphate buffer, sodium acetate buffer, etc.), and local anesthetics (e.g. benzalkonium chloride, procaine hydrochloride, etc.) can be suitably formulated.
The daily dosage of compound B depends on various factors such as species of mammals, diseases, clinical condition, etc. For the usual daily oral dosage, about 1-100 mg, preferably about 1-50 mg, per kg body weight of both human and mammalian animals, is administered in 1-3 divided doses. For administration by routes other than peroral, about 0.1-10 mg, preferably about 0.1-5 mg, per kg body weight is administered once daily.
The following reference examples, examples, and experimental examples are intended to describe the present invention in further detail and should by no means be construed as defining the scope of the invention.
The compounds obtained in Reference Examples and Examples are shown in Table 4 - Table 25. The IR spectra were recorded by the liquid film method or the KBr disk method. In the table, Ph represents phenyl. [Reference Example 1]
3,3-Dichloro-2-hexanoylaminoacrylonitrile
In accordance with the method of Matsumura et al. [Chem. Pharm. Bull., 21, 924, (1976)], 50.0 g of 2- amino-3,3-dichloroacrylonitrile was reacted with 84.9 g of hexanoic anhydride using 0.5 ml of concentrated sulfuric acid as an acid catalyst to provide 81.4 g of the title compound as crude crystals.
XH-NMR (CDC13) δ: 0.91 (t, J=7.0 Hz, 3H) , 1.25-1.45 ( , 4H), 1.55-1.85 (m, 2H) , 2.35 (t, J=7.5 Hz, 2H) ,
6.83 (bs, IH) .
In the same manner, the compound of Reference Example 5 was synthesized. [Reference Example 2] 2-Benzoylamino-3,3-dichloroacrylonitrile
In 100 ml of dichloromethane was dissolved 5.00 g of 2-amino-3,3-dichloroacrylonitrile, and under ice- cooling, 5.64 g of benzoyl chloride and 5.36 g of anhydrous aluminum chloride were added in the order mentioned. The mixture was stirred at 0°C for 1 hour. This reaction mixture was diluted with 200 ml of water and extracted with 3 portions of dichloromethane. The combined extract was dried and concentrated and the residue was purified by column chromatography (silica gel; eluent: dichloromethane) and recrystallized from dichloromethane/n-hexane to provide 4.45 g of the title compound.
!H-NMR (CDC13) 8: 7.43-7.70 (m, 4H) , 7.84 (d, 2H) . Elemental analysis (%) (for C10H6N2OC12) Calcd.: C, 49.82; H, 2.51; N, 11.62
Found : C, 49.97; H, 2.27; N, 11.70
In the same manner, the compounds of Reference Examples 3 and 4 were synthesized. [Reference Example 6] 3,3-Dichloro-2-methoxycarbonylaminoacrylonitrile
To 200 ml of methyl chloroformate was added 20.0 g of 2-amino-3,3-dichloroacrylonitrile and the mixture was refluxed for 48 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the residue was recrystallized from ethyl acetate/n-hexane to provide 23.7 g of the title compound.
!H-NMR (CDC13) δ: 3.83 (s, 3H) , 6.26 (bs, IH) . Elemental analysis (%) (for C5H4N202C12)
Calcd.: C, 30.80; H, 2.07; N, 14.37 Found : C, 30.71; H, 2.14; N, 14.30 [Reference Example 7]
Butyl N'-(l-cyano-2,2-dichlorovinyl)ureidoacetate
In the same manner as Reference Example 2, 20.37 g of anhydrous aluminum chloride was permitted to act upon 20.92 g of 2-amino-3,3-dichloroacrylonitrile and 24.0 g of butyl isocyanatoacetate to provide 23.6 g of the title compound. ^-NMR (CDC13) δ: 0.94 (t, 3H) , 1.25-1.48 (m, 2H) ,
1.56-1.73 ( , 2H) , 4.05 (d, 2H) , 4.17 (t, 2H) , 6.12 (t, IH), 7.21 (bs, IH) .
Elemental analysis (%) (for C10H13N3O3Cl2)
Calcd.: C, 40.83; H, 4.45; N, 14.29
Found : C, 40.64; H, 4.55; N, 14.25 [Reference Example 8] 2-Acetylamino-3,3-bis(pentylthio)acrylonitrile
According to the method of Matsumura et al. [Chem. Pharm. Bull., 2±, 948, (1976)], 2.00 g of 2- acetylamino-3,3-dichloroacrylonitrile was reacted with 2.56 g of pentanethiol to provide 3.44 g of the title compound.
^-N R (CDC13) 6: 0.90 (t, J=7.3 Hz, 6H) , 1.15-1.50 ( ,
8H), 1.50-1.75 (m, 4H), 2.14 (s, 3H) , 2.85 (t,
J=7.4 Hz, 2H), 2.91 (t, J=7.5 Hz, 2H) , 7.30 (bs,
IH). Elemental analysis (%) (for Cj5H26N2OS2)
Calcd.: C, 57.28; H, 8.33; N, 8.91 Found : C, 57.06; H, 8.36; N, 8.67 In the same manner, the compounds of Reference Examples 9-13 and 16 were synthesized. [Reference Example 14] 3,3-Bis(methylthio)-2- chloroacetylaminoacrylonitrile
To a solution of 2-amino-3,3-bis(methyl- thio)acrylonitrile (9.98 g) in 100 ml of dichloromethane was added 7.39 g of chloroacetyl chloride and the mixture was stirred under ice-cooling for 10 minutes. Then, 8.72 g of aluminum chloride was added and the mixture was further stirred at room temperature for 1 hour. To this reaction mixture was added iced water to stop the reaction and the organic layer was washed with 3 portions of cold water. The organic layer was dried and concentrated and the residue was purified by column chromatography (silica gel; eluent: ethyl acetate/n-hexane = 3/1) and recrystallized from dichloromethane/n-hexane (1:2) to provide 8.86 g of the title compound. H-NMR (CDC13) δ: 2.47 (s, 3H) , 2.48 (s, 3H), 4.17 (s,
2H), 8.23 (bs, IH). Elemental analysis (%) (for C7H9N20S2C1)
Calcd.: C, 35.51; H, 3.83; N, 11.83 Found : C, 35.33; H, 3.74; N, 11.68
In the same manner, the compound of Reference Example 15 was synthesized. [Reference Example 17]
2-Methyl-5-pentylthio-4-oxazolecarbonitrile According to the method of Matsumura et al. [Chem. Pharm. Bull., 21, 924, (1976)], 6.98 g of silver carbonate was permitted to act upon 2-acetylamino-3,3- bis(pentylthio)acrylonitrile to provide 1.25 g of the title compound. 'H-NMR (CDC13) δ: 0.91 (t, J=7.2 Hz, 3H) , 1.24-1.52 (m, 4H), 1.67 (qin, J=7.0 Hz, 2H) , 2.50 (s, 3H) , 2.99 ( t, J=7 . 2 Hz , 2H ) . Elemental analysis ( % ) ( for Cj0H14N2OS )
Calcd . : C , 57 . 11 ; H , 6 . 71 ; N, 13 . 32
Found : C, 56.98; H, 6.72; N, 13.34 In the same manner, the compounds of Reference Examples 18-21 and 23-26 were synthesized. [Reference Example 27]
2-Methyl-5-phenethylthio-4-oxazolecarbonitrile
To a solution of phenethylmercaptan (0.98 g) in 20 ml of ethanol was added 0.41 g of sodium ethoxide and the mixture was stirred at room temperature for 15 minutes. The resulting solution was added gradually to a solution of 2-methyl-5-methylsulfonyl-4-oxazolecarbo- nitrile (1.0 g) in 20 ml of ethanol and the mixture was stirred at room temperature for 2.5 hours. The solvent was then distilled off and the residue was dissolved with ethyl acetate and washed with water to remove the salt. The organic layer was dried and concentrated to recover a yellow oil. This oil was purified by column chromatography (silica gel; eluent: ethyl acetate/n- hexane = 1/10) to provide 1.13 g of the title compound. *H-NMR (CDC13) δ: 2.45 (s, 3H), 2.99 (t, J=7.5 Hz, 2H) ,
3.25 (t, J=7.5 Hz, 2H), 7.15-7.35 (m, 5H) . Elemental analysis (%) (for C13H12N2OS) Calcd.: C, 63.91; H, 4.95; N, 11.47
Found : C, 63.89; H, 4.93; N, 11.44
In the same manner, the compounds of Reference Examples 30, 31, 53, 72, 85-103, 107, and 110 were synthesized. [Reference Example 28]
2-Methyl-5-(3-phenylpropylthio)-4- oxazolecarbonitrile
To 0.93 g of the 2-methyl-5-methylsulfonyl-4- oxazolecarbonitrile synthesized in Example 1 was added 20 ml of methanol and the mixture was heated to provide a solution. To this solution was added 1.32 g of sodium sulfide nonahydrate. Then, 1.0 g of l-bromo-3- phenylpropane was added and the mixture was stirred at 50°C for 2 hours. Then, 100 ml of ethyl acetate was added and the mixture was washed with two 50 ml portions of water. The organic layer was dried and concentrated and the residue was purified by column chromatography (silica gel; eluent: ethyl acetate/n- hexane = 1/3) to provide 0.72 g of the title compound. lH-NMR (CDC13) δ: 1.96 (t, 2H) , 2.47 (s, 3H) , 2.77 (t, 2H), 2.96 (t, 2H), 7.15-7.32 (m, 5H) . Elemental analysis (%) (for C14H14N2OS)
Calcd.: C, 65.09; H, 5.46; N, 10.84 Found : C, 65.12; H, 5.52; N, 10.74 In the same manner, the compounds of Reference Examples 29, 32-52, and 75-81 were synthesized. [Reference Example 54]
5-Methylthio-2-trifluoromethyl-4- oxazolecarbonitrile
In 60 ml of N,N-dimethylformamide was dissolved 5.8 g of 3,3-dichloro-2- trifluoroacetylaminoacrylonitrile. Then, a solution of 12.5 g sodium sulfide nonahydrate in 8 ml water was added dropwise with ice-cooling and the mixture was stirred for 30 minutes. Then, 7.5 g of methyl iodide was added and the mixture was stirred with ice-cooling for another 30 minutes. This reaction mixture was diluted with 200 ml of water and extracted with two 200 ml portions of ethyl acetate. The combined ethyl acetate layer was washed with 100 ml of water, dried, and concentrated and the residue was purified by column chromatography (silica gel; eluent: ethyl acetate/n- hexane = 1:3) to provide 4.98 g of the title compound. :H-NMR (CDC13) δ: 2.75 (s, 3H) Elemental analysis (%) (for C6H3N2OSF3) Calcd.: C, 34.62; H, 1.45; N, 13.46 Found : C, 34.51; H, 1.44; N, 13.17 In the same manner, the compounds of Reference Examples 22 and 55-60 were synthesized. [Reference Example 61]
5-Methylthio-2-phthalimidomethyl-4-oxazole- carbonitrile
To a solution of 2-chloromethyl-5-methylthio-4- oxazolecarbonitrile (0.20 g) in 20 ml of N,N- dimethylformaraide was added a solution of potassium phthalimide (0.22 g) in 10 ml of N,N-dimethylformamide gradually and the mixture was stirred at room temperature for 2 hours. This reaction mixture was diluted with 100 ml of water and extracted with 3 portions of ethyl acetate. The combined extract was dried and concentrated and the residue was purified by column chromatography (silica gel; eluent: ethyl acetate/n-hexane = 2/5) to provide 0.23 g of the title compound.
!H-NMR ( CDC13 ) δ : 2 . 61 ( s , 3H ) , 4 . 97 ( s , 2H ) , 7 . 75-7 . 85 (m, 2H) , 7 . 85-7 . 98 (m, 2H) . Elemental analysis ( % ) ( for C14H9N303S )
Calcd.: C, 56.18; H, 3.03; N, 14.04 Found : C, 56.01; H, 3.02; N, 13.72 [Reference Example 62]
4-Hydroxymethyl-2-methyl-5-methylthiooxazole In 25 ml of dry tetrahydrofuran was dissolved 2.00 g of the methyl 2-methyl-5-methylthio-4- oxazolecarboxylate synthesized in Reference Example 26, followed by addition of 0.34 g of lithium aluminum hydride in small portions under ice-cooling. The mixture was stirred under ice-cooling for 2 hours and, then, 0.34 ml of water, 0.34 ml of 15% aqueous sodium hydroxide solution, and 1 ml of water were successively added. The mixture was stirred for 30 minutes and filtered to remove insolubles. The filtrate was concentrated and the residue was purified by column chromatography (silica gel; eluent: ethyl acetate) to provide 0.73 g of the title compound.
!H-NMR (CDC13) δ: 2.37 (s, 3H) , 2.46 (s, 3H) , 3.25 (bs,
IH), 4.57 (d, J=4.2 Hz, 2H) . Elemental analysis (%) (for C6H9N02S) Calcd.: C, 45.27; H, 5.70; N, 8.80 Found : C, 45.42; H, 5.61; N, 8.79 In the same manner, the compound of Reference Example 67 was synthesized. [Reference Example 63] 2-Methyl-5-methylthio-4-oxazolylmethyl benzoate
In 10 ml of dichloromethane was dissolved 0.360 g of the 4-hydroxymethyl-2-methyl-5-methylthiooxazole synthesized in Reference Example 62 as well as 0.380 g of benzoyl chloride. To this solution under ice- cooling was added dropwise a solution of triethylamine (0.310 g) in dichloromethane (1 ml), and the mixture was stirred at room temperature overnight. To this reaction mixture was added an aqueous solution of sodium hydrogen carbonate and the mixture was extracted with two portions of dichloromethane. The combined extract was dried and concentrated and the residue was purified by column chromatography (silica gel; eluent: ethyl acetate/n-hexane = 1:2) to provide 0.533 g of the title compound. ^-NMR (CDC13) δ: 2.40 (s, 3H) , 2.48 (s, 3H) , 5.27 (s, 2H), 7.42 (t, J=7.5 Hz, 2H) , 7.55 (t, J=7.5 Hz, IH), 8.07 (d, J=7.5 Hz, 2H) . Elemental analysis (%) (for C13Hj3N03S)
Calcd.: C, 59.30; H, 4.98; N, 5.32 Found : C, 59.23; H, 5.11; N, 5.28 [Reference Example 64]
(A) 4-(4-Chlorophenyloxymethy1)-2-methyl-5-methy1thio- oxazole
(B) 4-(5-Chloro-2-hydroxyphenylmethyl)-2-methyl-5- methylthiooxazole
In 20 ml of dry tetrahydrofuran was dissolved 0.606 g of the 4-hydroxymethyl-2-methyl-5- methylthiooxazole synthesized in Reference Example 62 as well as 0.636 g of p-chlorophenol and 1.50 g of triphenylphosphine. Then, 0.995 g of diethyl azodicarboxylate was added dropwise under ice-cooling. The mixture was stirred under ice-cooling for 1 hour and then, concentrated. The residue was chromatographed columnwise twice (silica gel; 1st run = ethyl acetate/n-hexane = 1/2, 2nd run = dichloromethane) to provide 0.213 g (oil) of title compound (A) and 0.449 g (solid) of title compound (B) .
(B) was recrystallized from dichloromethane/n- hexane.
(A) XH-NMR (CDC13) δ: 2.37 (s, 3H) , 2.47 (s, 3H) , 4.93 (s, 2H), 6.95 (d, J=6.8 Hz, 2H) , 7.23 (d, J=6.8
Hz, 2H) .
(B) ^- R (CDC13) δ: 2.34 (s, 3H) , 2.43 (s, 3H) , 3.80
(s, 2H), 6.89 (d, J=9.0 Hz, IH) , 7.10 (m, 2H), 9.66 (s, IH) . Elemental analysis (%) (for Cj2H12N02SCl) Calcd.: C, 53.43; H, 4.48; N, 5.19 Found : C, 53.01; H, 4.39; N, 4.94 [Reference Example 65]
4-Bromomethyl-2-methyl-5-methylthiooxazole In 25 ml of dry tetrahydrofuran was dissolved 1.76 g of the 4-hydroxymethyl-2-methyl-5-methylthiooxazole synthesized in Reference Example 62 as well as 4.37 g of triphenylphosphine. After ice-cooling, 4.05 g of carbon tetrabromide was added and the mixture was stirred under ice-cooling for 1.5 hours. The insoluble matter was filtered off and the filtrate was concentrated. The residue was purified by column chromatography (silica gel; eluent: ethyl acetate/n- hexane = 1:2) to provide 1.95 g of the title compound. !H-NMR (CDC13) δ: 2.39 (s, 3H), 2.46 (s, 3H) , 4.41 (s, 2H) . [Reference Example 66]
Butyl 4-(2-methyl-5-methylthiooxazolyl) ketone In a dry ice-ethanol bath, 2.1 ml of 1.6M n-butyl- lithium-n-hexane was added to a solution of 2-methyl-5- methylthio-4-oxazolecarbonitrile (1.0 g) in 10 ml of N,N-dimethylformamide under nitrogen atmosphere with stirring. The temperature was then increased to room temperature in 1.5 hours, after which the mixture was further stirred for 10 minutes. The solvent was then distilled off and the residue was purified by column chromatography (silica gel; eluent: ethyl acetate/n- hexane = 1/9) to provide 0.23 g of the title compound. H-NMR (CDC13) δ: 0.93 (t, J=7.2 Hz, 3H) , 1.38 ( ,
J=7.4 Hz, 2H), 1.67 (qin, J=7.4 Hz, 2H) , 2.49 (s, 3H), 2.56 (s, 3H), 1.67 (t, J=7.5 Hz, 2H) .
Elemental analysis (%) (for Cj0H15N02S)
Calcd.: C, 56.31; H, 7.09; N, 6.57 Found : C, 56.16; H, 7.04; N, 6.86 [Reference Example 68] 4-Chloromethyl-2-methyl-5-phenylthiooxazole
In 50 ml of chloroform was dissolved 3.02 g of the 4-hydroxymethyl-2-methyl-5-phenylthiooxazole synthesized in Reference Example 67. Under ice- cooling, 3.24 g of thionyl chloride was added dropwise and the mixture was stirred under ice-cooling for 0.5 hour. The reaction mixture was then concentrated and the residue was purified by column chromatography (silica gel; eluent: ethyl acetate/n-hexane = 1/2) to provide 2.25 g of the title compound. ^-N R (CDC13) δ: 2.47 (s, 3H) , 4.55 (s, 2H) , 7.17-7.33 ( , 5H). Elemental analysis (%) (for CnHj0NOSCl)
Calcd.: C, 55.11; H, 4.20; N, 5.84 Found : C, 54.85; H, 4.12; N, 6.10 [Reference Example 69]
2-Methyl-5-phenylthio-4-oxazolylacetonitrile In 7 ml of dimethyl sulfoxide was dissolved 1.00 g of the 4-chloromethyl-2-methyl-5-phenylthiooxazole synthesized in Reference Example 68, followed by addition of 0.31 g of sodium cyanide, and the mixture was stirred at room temperature overnight. The reaction mixture was poured in aqueous sodium chloride solution and extracted with 3 portions of ethyl acetate. The combined extract was dried and concentrated and the residue was purified by column chromatography (silica gel; eluent: ethyl acetate/n- hexane = 1/2) to provide 0.656 g of the title compound.
!H-NMR (CDC13) δ: 2.48 (s, 3H) , 3.68 (s, 2H) , 7.19-7.34 (m, 5H). Elemental analysis (%) (for C12H10N2OS)
Calcd.: C, 62.59; H, 4.38; N, 12.16 Found : C, 62.32; H, 4.39; N, 11.93 [Reference Example 71]
N-isobutyl-(4-cyano-2-methyl-5-oxazolyl)thio- acetamide
In 16 ml of dichloromethane was dissolved 0.79 g of the (4-cyano-2-methyl-5-oxazolyl)thiogiycolic acid synthesized in Reference Example 70 and, then under ice-cooling, 0.60 g of 1-hydroxybenzotriazole (HOBt), 0.84 g of l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD-HC1), and 0.32 g of isobutylamine were added in that order. The mixture was stirred for 1 hour, after which it was concentrated under reduced pressure. The residue was purified by column chromato- graphy (silica gel; eluent: methanol/chloroform = 1/50) to provide 1.00 g of the title compound. αH-NMR (CDC13) δ: 0.92 (d, 6H) , 1.84 (m, IH) , 2.50 (s,
3H), 3.14 (t, 2H), 3.65 (s, 2H) , 6.55 (broad, IH) . Elemental analysis (%) (for CπH15N302S) Calcd.: C, 52.15; H, 5.97; N, 16.59 Found : C, 50.34; H, 5.84; N, 15.77 In the same manner, the compound of Reference Example 74 was synthesized. [Reference Example 82]
4-Cyano-5-methylthio-2-oxazolecarbohydrazide In 30 ml of methanol was dissolved 1.49 g of the methyl 4-cyano-5-methylthio-2-oxazolecarboxylate synthesized as in Reference Example 54. To this solution was added 1.87 g of hydrazine hydrate at room temperature. The mixture was stirred at room temperature for 1 hour and the crystals that formed were harvested by filtration and dried to provide 0.77 g of the title compound.
!H-NMR (CDC13) δ: 2.74 (s, 3H) , 4.09 (s, 2H) , 8.11 (s,
IH) . Elemental analysis (%) (for C6H6N402S)
Calcd.: C, 36.36; H, 3.05; N, 28.27
Found : C, 36.28; H, 3.06; N, 28.32 [Reference Example 83]
4-Cyano-N'-formyl-5-methylthio-2- oxazolecarbohydrazide
In 15 ml of formic acid was dissolved 1.18 g of the 4-cyano-5-methylthio-2-oxazolecarbohydrazide synthesized in Reference Example 82 and the mixture was refluxed for 1 hour. This reaction mixture was concentrated to dryness under reduced pressure and 50 ml of methanol was added to the residue, whereupon crystals separated out. This crystal crop was harvested by filtration and dried to provide 0.53 g of the title compound. !H-NMR (CDC13) δ: 2.75 (s, 3H) , 8.12 (s, IH) , 10.2 (s,
IH), 11.1 (s, IH). Elemental analysis (%) (for C7H6N403S)
Calcd.: C, 37.17; H, 2.67; N, 24.77
Found : C, 37.09; H, 2.66; N, 24.79 [Reference Example 84]
5-Methylthio-2-(2-[1,3,4]-oxadiazolyl)-4-oxazole- carbonitrile
To 1.12 g of the 4-cyano-N'-formyl-5-methylthio-2- oxazolecarbohydrazide synthesized in Reference Example 83 was added 250 ml of xylene and following addition of 0.7 g of phosphorus pentoxide, the mixture was refluxed for 3 hours with the dehydration by a Soxhlet's apparatus packed with molecular sieve 3A. The reaction mixture was distilled under reduced pressure. The ethyl acetate-soluble fraction was purified by column chromatography (silica gel; eluent: ethyl acetate/n- hexane = 1/2) to provide 0.17 g of the title compound. ^-NMR (CDC13) 6: 2.80 (s, 3H), 8.63 (s, IH) . Elemental analysis (%) (for C7H4N402S)
Calcd.: C, 40.38; H, 1.94; N, 26.91 Found : C, 40.08; H, 1.98; N, 26.80 [Reference Example 105] N-4-[5-(4-cyano-2- methyloxazolyl)thiojphenylmethanesulfonamide
In 10 ml of pyridine was dissolved 0.6 g of the 5- (4-aminophenylthio)-2-methyl-4-oxazolecarbonitrile synthesized in Reference Example 103, followed by addition of 0.39 g of methanesulfonyl chloride, and the mixture was stirred at room temperature for 7 hours. The pyridine was then distilled off under reduced pressure and the residue was dissolved in 50 ml of chloroform and washed with two 50 ml portions of water. The organic layer was dried and concentrated and the residue was purified by column chromatography (silica gel; eluent: chloroform/ethyl acetate = 10/1) and recrystallized from n-hexane-toluene to provide 0.62 g of the title compound. ^-NMR (CDC13) δ: 2.48 (s, 3H) , 3.06 (s, 3H) , 6.83 (b,
IH), 7.20-7.28 (m, 2H) , 7.50-7.56 (m, 2H) . Elemental analysis (%) (for C12Hn 3θ3S2) Calcd.: C, 46.59; H, 3.58; N, 13.58
Found : C, 46.65; H, 3.48; N, 13.55 In the same manner, the compound of Reference Example 106 was synthesized. [Reference Example 111]
N-3-[5-(4-cyano-2-methyloxazolyl)thio]phenyl-N'- propylurea
In 20 ml of chloroform was dissolved 0.5 g of the 5-(3-aminophenylthio)-2-methyl-4-oxazolecarbonitrile synthesized in Reference Example 110 as well as 0.84 g of n-propyl isocyanate. To this solution was added 0.04 g of aluminum chloride and the mixture was stirred at room temperature for a day. This reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel; eluent: dichloromethane/n-hexane/ethyl acetate = 2/2/1) and recrystallized from toluene to provide 0.57 g of the title compound. XH-NMR (CDC13) δ: 0.97 (t, 3H), 1.54-1.65 (m, 2H) , 2.46
(s, 3H), 3.26 (dt, 2H), 5.12 (b, IH) , 6.96-7.68
(m, 4H) , 8 .29 ( dd, IH) . Elemental analysis ( % ) ( for d5Hι6N402S )
Calcd.: C, 56.95; H, 5.10; N, 17.71
Found : C, 56.98; H, 5.06; N, 17.78
In the same manner, the compounds of Reference Examples 104, 108, and 109 were synthesized. [Example 1]
2-Methyl-5-methylsulfonyl-4-oxazolecarbonitrile
To 400 ml of chloroform was added 10.0 g of 2- methyl-5-methylthio-4-oxazolecarbonitrile. Then, 28.0 g of m-chloroperbenzoic acid was added under ice- cooling and the mixture was stirred at room temperature for 2 hours and then, refluxed for 4 hours. This reaction mixture was washed with 2 portions of 10% aqueous sodium thiosulfate solution and 3 portions of saturated aqueous NaHC03 solution. The organic layer was dried and concentrated and the residue was washed with diethyl ether and dried in vacuo, whereby 9.8 g of the title compound was obtained as crude crystals. A portion of this crude crystal crop was recrystallized from toluene to provide a pure product. XH-NMR (CDC13) δ: 2.65 (s, 3H) , 3.30 (s, 3H) . Elemental analysis (%) (for C6H6N203S)
Calcd.: C, 38.71; H, 3.25; N, 15.05 Found : C, 39.16; H, 3.31; N, 14.59 In the same manner, the compounds of Examples 2- 19, 21-55, 65, 75-78, 84-86, 99, 100, 116, 117, 119- 121, 123, 125-128, 130, 142-146, 148-154, 157, 159, 160, 162, 164, 165, 167, 181-183, and 185-187 were synthesized. [Example 20]
5-Methylsulfonyl-2-phenyl-4-oxazolecarboxamide To a solution of 5-methylthio-2-phenyl-4- oxazolecarboxamide (0.13 g) in 5 ml of acetic acid was added a mixture of 30% hydrogen peroxide (0.23 g)- acetic acid (25 ml) and the whole mixture was stirred on an oil bath at 70°C for 7 hours. After 0.5% aqueous sodium thiosulfate solution was added, the reaction mixture was extracted with 200 ml of ethyl acetate and the extract was dried and concentrated. The residue was recrystallized from methanol to provide 0.10 g of the title compound. JH-NMR (DMSO-dfi) δ: 2.52 (s, 3H) , 7.58-7.88 (m, 4H), 7.97 (bs, 2H), 8.06-8.18 (m, 2H) . Elemental analysis (%) (for CJJHJ0N2O4S)
Calcd.: C, 49.62; H, 3.79; N, 10.52 Found : C, 49.48; H, 3.54; N, 10.65 [Example 56]
(A) 5-Methylsulfonyl-2-(4-nitrobenzyl)-4-oxazole- carbonitrile
(B) 5-Methylsulfonyl-2-(2-nitrobenzyl)-4-oxazole- carbonitrile To a solution of sodium nitrate (0.39 g) in 6 ml of concentrated sulfuric acid was added 1.01 g of 2- benzyl-5-methylsulfonyl-4-oxazolecarbonitrile portionwise with stirring and ice-cooling. After 1 hour of stirring under ice-cooling, the reaction mixture was diluted with 50 g of iced water and extracted with 3 portions of dichloromethane. The combined extract was dried and concentrated and the residue was fractionated and purified by column chromatography (silica gel; eluent: ethyl acetate/n- hexane/dichloromethane = 1/1/1). The fractions were respectively recrystallized from dichloromethane/n- hexane (1:1) to provide 0.84 g of the title compound (A) and 0.37 g of the title compound (B).
(A) ^-NMR (CDC13) δ: 3.29 (s, 3H) , 4.35 (s, 2H) , 7.53
(d, J=8.7 Hz, 2H), 8.26 (d, J=8.7 Hz, 2H) . Elemental analysis (%) (for Cι2H9N305S)
Calcd.: C, 46.90; H, 2.95; N, 13.67 Found : C, 46.35; H, 2.89; N, 13.39
(B) !H-NMR (CDC13) δ: 3.31 (s, 3H) , 4.59 (s, 2H) ,
7.45-7.80 (m, 3H) , 8.15-8.30 (m, IH) . Elemental analysis (%) (for C12H9N305S)
Calcd.: C, 46.90; H, 2.95; N, 13.67 Found : C, 46.48; H, 3.10; N, 13.43 [Example 58]
2-Bromo-5-methylsulfonyl-4-oxazolecarbonitrile In a dry ice-ethanol bath, 1.2 ml of 1.6M n-butyl- lithium-n-hexane was added to a solution of 5- methylsulfonyl-4-oxazolecarbonitrile (0.30 g) in 30 ml of tetrahydrofuran under nitrogen atmosphere and the mixture was stirred for 30 minutes. Then, 0.31 g of bromine was added dropwise and the mixture was further stirred under the same conditions for 30 minutes. The reaction was then stopped by adding 10% aqueous sodium thiosulfate solution and the mixture was extracted with 3 portions of ethyl acetate. The combined extract was dried and concentrated and the residue was purified by column chromatography (silica gel; eluent: chloroform) to provide 0.07 g of the title compound. ^- MR (CDC13) δ: 3.34 (s, 3H) . Elemental analysis (%) (for C5H3N203SBr)
Calcd.: C, 23.92; H, 1.20; N, 11.16 Found : C, 24.00; H, 1.15; N, 11.05 [Example 59]
2-Methylamino-5-methylsulfonyl-4- oxazolecarbonitrile
To a solution of 2-bromo-5-methylsulfonyl-4- oxazolecarbonitrile (1.0 g) in 80 ml of dichloromethane was added a mixture of 40% methylamine-methanol (0.33 g) and triethylamine (0.42 g) dropwise under ice- cooling and the mixture was then stirred at room temperature for 2 hours. The solvent was then distilled off and the residue was purified by column chromatography (silica gel; eluent: ethyl acetate/n- hexane/dichloromethane = 1/1/1) to provide 0.68 g of the title compound.
^-NMR (CDC13) δ: 3.10 (d, J=5.1 Hz, 3H) , 3.23 (s, 3H) , 5.22 (bs, IH) .
Elemental analysis ( % ) ( for C6H7N303S )
Calcd.: C, 35.82; H, 3.51; N, 20.88 Found : C, 35.57; H, 3.53; N, 20.68 In the same manner, the compounds of Examples 60 and 61 were synthesized. [Example 62]
2-(N-benzyl-N-methylaminomethyl)-5-methylsulfonyl- 4-oxazolecarbonitrile
To a solution of 2-chloromethyl-5-methylsulfonyl- 4-oxazolecarbonitrile (0.23 g) in 60 ml of dichloromethane was added a solution of benzylmethylamine (0.15 g) and triethylamine (0.13 g) in 20 ml of dichloromethane gradually under ice-cooling and the mixture was refluxed overnight. The solvent was then distilled off and the yellow residue was purified by column chromatography (silica gel; eluent: ethyl acetate/n-hexane/dichloromethane = 1/1/1) to provide 0.03 g of the title compound.
*H-NMR (CDC13) δ: 2.43 (s, 3H) , 3.29 (s, 3H), 3.67 (s, 2H), 3.83 (s, 2H), 7.25-7.40 (m, 5H) . Elemental analysis (%) (for Cj4Hj5N303S)
Calcd.: C, 55.07; H, 4.95; N, 13.76 Found : C, 55.26; H, 4.96; N, 13.50 In the same manner, the compounds of Examples 131-
133 were synthesized. [Example 63]
5-Methylsulfonyl-2-(4-phenyl-l-piperazinylmethyl)-
4-oxazolecarbonitrile
To a solution of 2-chloromethyl-5-methylsulfonyl-
4-oxazolecarbonitrile (0.30 g) in 50 ml of acetonitrile were added 0.05 g of potassium iodide, 0.23 g of phenylpiperazine, and 0.20 g of potassium carbonate and the mixture was stirred at room temperature for 30 minutes. This reaction mixture was filtered and the solvent was distilled off. The yellow residue was purified by column chromatography (silica gel; eluent: ethyl acetate/n-hexane/dichloromethane = 1/1/1) and recrystallized from dichloromethane/n-hexane (1:1) to provide 0.48 g of the title compound.
Η-NMR (CDC13) δ: 2.78 (t, J=4.9 Hz, 4H) , 3.24 (t, J=5.0 Hz, 4H), 3.33 (s, 3H) , 3.89 (s, 2H) , 6.83- 7.00 ( , 3H), 7.22-7.33 (m, 2H) .
Elemental analysis (%) (for Cj6Hj8N403S)
Calcd.: C, 55.48; H, 5.24; N, 16.17 Found : C, 55.27; H, 5.25; N, 16.14 [Example 64]
(A) 2-(4-Methylphenylsulfonylmethyl)-5-methylsulfonyl- 4-oxazolecarbonitrile
(B) 5-(4-Methylphenylsulfonyl)-2-(4- methylphenylsulfonylmethyl)-4-oxazolecarbonitrile To a solution of 2-chloromethyl-5-methylsulfonyl- 4-oxazolecarbonitrile (0.16 g) in 30 ml of N,N- dimethylformamide was added 0.19 g of sodium p- toluenesulfinate with ice-cooling and the mixture was stirred at room temperature for 20 minutes. This reaction mixture was diluted with 100 ml of water and extracted with 3 portions of ethyl acetate. The combined extract was dried and concentrated and the residue was purified by column chromatography (silica gel; eluent: ethyl acetate/n-hexane = 1/2) and recrystallized from dichloromethane/n-hexane to provide 0.12 g of the title compound (A) and 0.03 g of the title compound (B).
(A) ^- MR (CDC13) 6: 2.50 (s, 3H) , 3.30 (s, 3H) , 4.64
(s, 2H), 7.42 (d, J=8.6 Hz, 2H) , 7.72 (d, J=8.6 Hz, 2H) . Elemental analysis (%) (for Cj3H12N205S)
Calcd.: C, 45.87; H, 3.55; N, 8.23 Found : C, 45.69; H, 3.56; N, 8.29
(B) !H-NMR (CDC13) δ: 2.48 (s, 3H) , 2.50 (s, 3H) , 4.54
(s, 2H), 7.32 (d, J=8.6 Hz, 2H) , 7.46 (d, J=8.6 Hz, 2H), 7.58 (d, J=8.6 Hz, 2H) , 7.95 (d, J=8.6
Hz, 2H) . Elemental analysis (%) (for Cj9Hι6N205S2)
Calcd.: C, 54.79; H, 3.87; N, 6.78 Found : C, 54.28; H, 3.84; N, 6.68 [Example 66]
2-Methyl-5-methylsulfonyl-4-oxazolecarboxamide To 3 ml of concentrated sulfuric acid was added 1.0 g of 2-methyl-5-methylsulfonyl-4- oxazolecarbonitrile portionwise with ice-cooling and the mixture was stirred at room temperature for 3 hours. To this reaction mixture was added 20 ml of iced water and the precipitate that formed was recovered by filtration, rinsed with a small amount of cold water, and dried in vacuo. This crystal crop was recrystallized from methanol to provide 0.49 g of the title compound. *H-NMR ( DMSO-dfi ) δ : 2 . 55 ( s , 3H ) , 3 . 56 ( s , 3H) , 7 . 92
(bs, IH), 8.02 (bs, IH) . Elemental analysis (%) (for C6H8N204S)
Calcd.: C, 35.29; H, 3.95; N, 13.72 Found : C, 35.30; H, 3.75; N, 13.75
In the same manner, the compound of Example 67 was synthesized. [Example 68]
2-Methyl-5-methylsulfonyl-4-oxazolecarboxylic acid To 3.44 g of the methyl 2-methyl-5-methylsulfonyl- 4-oxazolecarboxylate synthesized in Example 19 was added 4.61 g of 15% sodium hydroxide and 30 ml of water and the mixture was stirred at room temperature for 1 hour. This reaction mixture was made acidic with diluted sulfuric acid and extracted with 10 portions of ethyl acetate. The combined extract was dried and concentrated and the residue was recrystallized from methanol-diethyl ether-hexane to provide 2.66 g of the title compound. ^-NMR (DMSO-dfi) δ: 2.55 (s, 3H) , 3.50 (s, 3H) . Elemental analysis (%) (for C6H7N05S)
Calcd.: C, 35.12; H, 3.44; N, 6.83
Found : C, 35.16; H, 3.44; N, 6.90
In the same manner, the compounds of Example 98 and Reference Examples 70 and 73 were respectively synthesized. [Example 69]
N-benzyl-2-methyl-5-methylsulfonyl-4-oxazole¬ carboxamide To 1.00 g of the 2-methyl-5-methylsulfonyl-4- oxazolecarboxylic acid synthesized in Example 68 was added 10 ml of thionyl chloride and the mixture was refluxed for 6 hours. The thionyl chloride was then distilled off and the solid residue was dissolved in 15 ml of dichloromethane. Then, a solution of benzylamine (0.57 g) and triethylamine (0.54 g) in dichloromethane (1 ml) was added dropwise with ice-cooling. After 1 hour of stirring under ice-cooling, the reaction mixture was poured in water and extracted with 3 portions of dichloromethane. The combined extract was dried and concentrated and the residue was purified by column chromatography (silica gel; eluent: ethyl acetate) and recrystallized from ethanol to provide 1.36 g of the title compound.
*H-NMR (CDC13) 6: 2.55 (s, 3H) , 3.56 (s, 3H) , 4.61 (d, J=6.0 Hz, 2H), 7.34 (m, bs, 6H) . Elemental analysis (%) (for Cj3Hj4N204S)
Calcd.: C, 53.05; H, 4.79; N, 9.52 Found : C, 52.97; H, 4.80; N, 9.59 In the same manner, the compounds of Examples 70- 74 were synthesized. [Example 79]
4-(N-benzy1-N-methylaminomethy1)-2-methyl-5- methylsulfonyloxazole
In 15 ml of dichloromethane was dissolved 0.350 g of the 4-bromomethyl-2-methyl-5-methylsulfonyloxazole synthesized in Example 78. To this solution was added a solution of N-methylbenzylamine (0.217 g) and triethylamine (0.182 g) in dichloromethane ( 1 ml) dropwise under ice-cooling. The mixture was stirred under ice-cooling for 1 hour and at room temperature for another hour, after which it was concentrated. The residue was purified by column chromatography (silica gel; eluent: ethyl acetate) to provide 0.322 g of the title compound. JH-NMR (CDC13) δ: 2.55 (s, 3H) , 2.68 (s, 3H) , 3.17 (s, 3H), 3.64 (s, 2H), 3.78 (s, 2H) , 7.20-7.38 (m, 5H) .
In the same manner, the compounds of Examples 80 and 81 were synthesized. [Example 83]
2-Methyl-4-(4-methylphenylsulfonylmethyl)-5- methylsulfonyloxazole
In 5 ml of N,N-dimethylformamide was dissolved 0.250 g of the 4-bromomethyl-2-methyl-5- methylsulfonyloxazole synthesized in Example 78, followed by addition of 0.258 g of sodium p- toluenesulfinate tetrahydrate under ice-cooling. The mixture was stirred under ice-cooling for 1 hour and then, concentrated under reduced pressure. The residue was purified by column chromatography (silica gel; eluent: ethyl acetate) and recrystallized from dichloromethane/diethyl ether/n-hexane to provide 0.231 g of the title compound.
:H-NMR (CDC13) δ: 2.47 (s, 3H) , 2.58 (s, 3H) , 3.30 (s, 3H), 4.62 (s, 2H), 7.39 (d, J=8.4 Hz, 2H) , 7.82 (d, J=8.4 Hz, 2H) .
Elemental analysis (%) (for Cj3Hj5N05S2)
Calcd.: C, 47.40; H, 4.59; N, 4.25 Found : C, 47.16; H, 4.47; N, 4.37 In the same manner, the compound of Example 82 was synthesized. [Example 87]
2-Methyl-5-phenylsulfonyl-4-oxazolylacetic acid To 10 ml of concentrated sulfuric acid was added 0.200 g of the 2-methyl-5-phenylsulfonyl-4-oxazolyl- acetonitrile synthesized in Example 86 and the mixture was heated at 115°C for 2 hours. This reaction mixture was added in small portions to iced water and extracted with 2 portions of ethyl acetate. The combined extract was washed with aqueous sodium chloride solution once, dried, and concentrated. The residue was recrystallized from dichloromethane/n-hexane to provide 0.151 g of the title compound.
*H-NMR (CDC13) δ: 2.47 (s, 3H) , 4.06 (s, 2H) , 6.80 (b, IH), 7.50-7.72 ( , 3H) , 7.96-8.05 ( , 2H) . Elemental analysis (%) (for C12HnN05S)
Calcd.: C, 51.24; H, 3.94; N, 4.98 Found : C, 50.84; H, 3.88; N, 4.79 [Example 88]
2-Methyl-5-methylsulfonyl-4-oxazolecarbothioamide To 80 ml of dry tetrahydrofuran was added 2.00 g of the 2-methyl-5-methylsulfonyl-4-oxazolecarboxamide synthesized in Example 66 as well as 2.77 g of Lawesson's reagent and the mixture was refluxed for 6 hours. This reaction mixture was concentrated and the residue was purified by column chromatography (silica gel; eluent: ethyl acetate/n-hexane = 1/1) and recrystallized from ethyl acetate to provide 0.60 g of the title compound.
XH-NMR (DMSO-dfi) δ: 2.51 (s, 3H) , 3.49 (s, 3H) , 9.78 (bs, IH), 10.31 (bs, IH) . Elemental analysis (%) (for C6H8N203S2)
Calcd.: C, 32.72; H, 3.66; N, 12.72; S, 29.11 Found : C, 32.83; H, 3.55; N, 12.52; S, 28.75 In the same manner, the compounds of Examples 89- 92 were synthesized. [Example 93]
2-Methyl-5-pentylsulfonyl-4-oxazolecarbothioamide In 6.6 ml of tetrahydrofuran/water (10:1) was dissolved 0.170 g of the 2-methyl-5-pentylsulfonyl-4- oxazolecarboxamide synthesized in Example 4, followed by addition of 0.390 g of 0,0'-diethyl dithiophosphate, and the mixture was refluxed for 9 hours. This reaction mixture was concentrated and the residue was purified by column chromatography (silica gel; eluent: ethyl acetate/n-hexane = 1/1) to provide 0.108 g of the title compound.
^- MR (CDC13) δ: 0.90 (t, J=7.0 Hz, 3H) , 1.25-1.50 ( , 4H), 1.70-1.90 (m, 2H) , 2.60 (s, 3H) , 3.56-3.67 (m, 2H), 7.70 (bs, IH) , 8.60 (bs, IH) . MS m/z 276 (M+) In the same manner, the compounds of Examples 94, 95, and 135-139 were synthesized. [Example 96]
2-Methyl-5-methylsulfonyl-4-(4-phenylthiazolyl)- oxazole
In 20 ml of ethanol was dissolved 0.150 g of the 2-methyl-5-methylsulfonyl-4-oxazolecarbothioamide synthesized in Example 88 as well as 0.162 g of phenacyl bromide and the solution was refluxed for 1 hour. This reaction mixture was concentrated and the residue was purified by column chromatography (silica gel; eluent: ethyl acetate/n-hexane = 1/2) and recrystallized from dichloromethane/n-hexane to provide
0.112 g of the title compound.
!H-NMR (CDC13) δ: 2.64 (s, 3H), 3.67 (s, 3H) , 7.33-7.54
(m, 3H), 7.67 (s, IH) , 7.89-8.00 (m, 2H) . Elemental analysis (%) (for C14H12N203S2)
Calcd.: C, 52.48; H, 3.78; N, 8.74
Found : C, 52.18; H, 3.92; N, 8.82
In the same manner, the compound of Example 97 was synthesized. [Example 101]
(E)-5-(2-N,N-dimethylaminoethenylsulfonyl)-2- methyl-4-oxazolecarbonitrile
To a solution of 2-methyl-5-methylsulfonyl-4- oxazolecarbonitrile (1.0 g) in 10 ml of N,N- dimethylformamide was added 0.83 g of N,N- dimethylformamide dimethyl acetal and the mixture was stirred at room temperature for 4 hours and further on an oil bath at 50°C for 15 minutes. The solvent was then distilled off and the residue was purified by column chromatography (silica gel; eluent: ethyl acetate/n-hexane = 4/5) to provide 0.64 g of the title compound.
XH-NMR (CDC13) δ: 2.55 (s, 3H) , 2.88 (s, 3H) , 3.18 (s,
3H), 4.97 (d, J=12 Hz, IH) , 7.44 (d, J=12 Hz, IH) . Elemental analysis (%) (for C9HuN303S)
Calcd.: C, 44.80; H, 4.60; N, 17.42 Found : C, 44.63; H, 4.44; N, 17.24 [Example 102]
2-Methyl-5-(2-methyl-4-cyano-5-oxazolyl)methyl- sulfonyl-4-oxazolecarbonitrile In 20 ml of N,N-dimethylformamide was dissolved 0.93 g of the 2-methyl-5-methylsulfonyl-4- oxazolecarbonitrile synthesized in Example 1, followed by addition of 0.24 g of sodium hydride (ca. 60%) under ice-cooling. The mixture was stirred under ice-cooling for 1 hour and then at room temperature for another hour. This reaction mixture was diluted with 100 ml of ethyl acetate and washed with 50 ml of water twice. The organic layer was dried and concentrated and the residue was purified by column chromatography (silica gel; eluent: ethyl acetate/n-hexane = 1/2) and recrystallized from ethyl acetate/n-hexane to provide 0.12 g of the title compound.
^-N R (CDC13) δ: 2.58 (s, 3H) , 2.69 (s, 3H) , 4.77 (s, 2H) . Elemental analysis (%) (for CuH8N404S)
Calcd.: C, 45.21; H, 2.76; N, 19.17 Found : C, 45.17; H, 2.76; N, 19.20 In the same manner, the compound of Example 188 was synthesized. [Example 104]
2-Methyl-5-[2-(4-methylsulfonamidophenyl)ethyl¬ sulfonyl]-4-oxazolecarbonitrile
In 5 ml of pyridine was dissolved 0.25 g of the 2- methyl-5-[2-(4-aminophenyl)ethylsulfonyl]-4-oxazole- carbonitrile synthesized in Example 103, followed by addition of 0.12 g of methanesulfonyl chloride, and the mixture was stirred at room temperature for 1 hour. This reaction mixture was diluted with 50 ml of ethyl acetate and washed with two 50 ml portions of water. The organic layer was dried and concentrated and the residue was purified by column chromatography (silica gel; eluent: ethyl acetate/n-hexane = 1/2) and recrystallized from methanol to provide 0.20 g of the title compound. H-NMR (CDC13) δ: 2.56 (s, 3H) , 3.05 (s, 3H) , 3.20 (t, 2H), 3.65 (t, 2H), 6.04 (s, IH) , 7.16 (s, 2H) . Elemental analysis (%) (for Cj4H15N305S2)
Calcd.: C, 45.52; H, 4.09; N, 11.37 Found : C, 45.44; H, 4.07; N, 11.24 In the same manner, the compounds of Examples 105 and 106 were synthesized. [Example 107]
5-(4-Aminophenylsulfonyl)-2-methyl-4-oxazole- carbonitrile
In 10 ml of tetrahydrofuran was dissolved 0.20 g of the 2-methyl-5-(4-nitrophenylsulfonyl)-4-oxazole- carbonitrile synthesized in Example 40. Then, 1.3 ml of concentrated hydrochloric acid and 0.15 g of iron powder were added under ice-cooling. The mixture was stirred under ice-cooling for 1 hour and then, neutralized with saturated aqueous NaHC03 solution. The mixture was concentrated and the residue was diluted with 100 ml of ethyl acetate and washed with 15% aqueous NaOH solution. The organic layer was dried and concentrated and the residue was purified by column chromatography (silica gel; eluent: n-hexane/di- chloro ethane/ethyl acetate = 2/2/1) and recrystallized from n-hexane/toluene to provide 0.044 g of the title compound. H-NMR (CDC13) δ: 2.53 (s, 3H) , 4.20 (b, 2H) , 6.71-6.76 (m, 2H), 7.80-7.85 (m, 2H) .
In the same manner, the compounds of Examples 57 and 103 were synthesized. [Example 108]
N-isobutyl-4-cyano-2-methyl-5-oxazolesulfonamide In 20 ml of hot methanol was dissolved 1.00 g of the 2-methyl-5-methylsulfonyl-4-oxazolecarbonitrile synthesized in Example 1, followed by addition of 1.40 g of sodium sulfide nonahydrate. The mixture was stirred at room temperature for 1 hour and acidified to below pH=3 with 1N-HC1. This reaction mixture was concentrated to dryness under reduced pressure and 6 ml of acetonitrile was added. The insoluble matter was filtered off and the filtrate was cooled to -10°C. Then, 1.35 g of potassium nitrate and 1.81 g of thionyl chloride were added. The mixture was filtered to remove the insoluble matter. To the filtrate was added 40 ml of pyridine, followed by addition of 0.46 g of isobutylamine, and the mixture was stirred at room temperature for 1 hour. This reaction mixture was diluted with 200 ml of ethyl acetate and washed with two 100 ml portions of water. The organic layer was dried and concentrated and the residue was purified by column chromatography (silica gel; eluent: ethyl acetate/n-hexane = 1/3) and recrystallized from ethyl acetate/n-hexane to provide 0.095 g of the title compound.
^-NMR (CDC13) δ: 0.95 (d, 6H) , 1.84 (m, IH), 2.60 (s,
3H), 3.05 (t, 2H), 5.28 (t, IH) . Elemental analysis (%) (for C9Hj3N303S)
Calcd.: C, 44.43; H, 5.39; N, 17.27 Found : C, 44.15; H, 5.17; N, 17.15
In the same manner, the compounds of Examples 109- 112 and 189-205 were synthesized. [Example 113]
4-Bromomethyl-2-methyl-5-methylsulfinyloxazole In 30 ml of dichloromethane was dissolved 3.55 g of the 4-bromomethyl-2-methyl-5-methylthiooxazole synthesized in Reference Example 65, followed by addition of 2.76 g of m-chloroperbenzoic acid with ice- cooling. The mixture was stirred at room temperature for 1 hour and then washed with 10% aqueous sodium thiosulfate solution once and 2 portions of saturated aqueous NaHC03 solution. The organic layer was dried and concentrated and the residue was purified by column chromatography (silica gel; eluent: ethyl acetate) and recrystallized from dichloromethane/hexane to provide 1.10 g of the title compound.
!H-NMR (CDCI3) δ: 2.57 (s, 3H) , 3.01 (s, 3H) , 4.47 (s,
2H) . Elemental analysis ( % ) ( for C6H8N02SBr )
Calcd . : C , 30 . 27 ; H , 3 . 39 ; N , 5 . 88 Found : C , 30 . 01 ; H , 3 . 46 ; N , 5 . 86
In the same manner, the compounds of Examples 114, 115, 118, 122, 124, 129, 147, 155, 156, 158, 161, 163, 166 and 184 were synthesized. [Example 134] (A) 5-Methylsulfinyl-2-(2-[1,3,4]-oxadiazolyl)-4- oxazolecarbonitrile
(B) 5-Methylsulfonyl-2-(2-[1,3,4]-oxadiazolyl)-4- oxazolecarbonitrile
In chloroform was dissolved 0.90 g of the 5- methylthio-2-(2-[1,3,4]-oxadiazolyl)-4- oxazolecarbonitrile synthesized in Reference Example 84, followed by addition of 0.90 g of - chloroperbenzoic acid with cooling. The reaction was carried out at room temperature for 2 hours, after which the reaction mixture was washed with 2 portions of saturated aqueous NaHC03 solution. The chloroform layer was dried and concentrated and the residue was fractionated and purified by column chromatography (silica gel; eluent: ethyl acetate/n-hexane = 1/2) to provide 0.25 g of the title compound (A) and 0.057 g of the title compound (B).
(A) :H-NMR (CDC13) δ: 3.24 (s, 3H) , 8.71 (s, IH) . Elemental analysis (%) (for C7H4N403S)
Calcd.: C, 37.50; H, 1.80; N, 24.99 Found : C, 37.20; H, 1.94; N, 24.49
(B) H-NMR (CDC13) δ: 3.43 (s, 3H) , 8.73 (s, IH) . Elemental analysis ( % ) ( for C7H4N404S )
Calcd.: C, 35.00; H, 1.68; N, 23.33 Found : C, 35.42; H, 1.73; N, 23.34 [Example 140] 2-Methyl-5-phenylsulfonyl-4-oxazolecarboxylic acid The title compound was synthesized in the same manner as in Example 68 and the resulting oil was crystallized from methanol. H-NMR (CDCl3)δ: 2.59 (s, 3H) , 7.76-7.90 (m, 3H) , 8.14 (m, 2H).
Elemental analysis (%) (for CuH9N05S»CH3OH) Calcd.: C, 48.15; H, 4.38; N, 4.68 Found : C, 47.76; H, 4.13; N, 4.77 [Example 141] t-Butyl 4-(2-Methyl-5-phenylsulfonyloxazolyl)- carbamate
To 15 ml of t-butyl alcohol was added 0.65 g of the 2-methyl-5-phenylsulfonyl-4-oxazolecarboxylic acid synthesized in Example 140, followed by addition of 0.23 g of diphenylphosphorylazide (DPPA) and 0.09 g of triethylamine, and the mixture was refluxed for 2 hours. The solvent was then distilled off and the residue was dissolved in 30 ml of dichloromethane. This solution was washed with 5% aqueous citric acid solution and saturated aqueous NaHC03 solution in the order mentioned. The organic layer was dried and concentrated and the residue was purified by column chromatography (silica gel; eluent: ethyl acetate/n- hexane = 1/1) and recrystallized from dichloromethane/n-hexane to provide the title compound. H-NMR (CDC13) δ: 1.55 (s, 9H) , 2.48 (s, 3H) , 7.53-7.67
(m, 3H), 7.84 (bs, IH) , 7.93-8.00 (m, 2H) . Elemental analysis (%) (for Cj5H18N205S)
Calcd.: C, 53.24; H, 5.36; N, 8.28 Found : C, 53.18; H, 5.34; N, 8.29 [Example 168] 2-(2-Methoxybenzyl)-5-methylsulfonyl-4-oxazole- carbonitrile
To 1.86 g of 2-methoxyphenylacetic acid was added 8 ml of thionyl chloride and the mixture was refluxed for 1 hour. The thionyl chloride was distilled off and the residual oil was dissolved in 50 ml of ethyl acetate. To this solution was added 1.50 g of 2-amino- 3,3-dichloroacrylonitrile and the mixture was stirred at room temperature for 17 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the residue was recrystallized from diethyl ether/n-hexane to give 1.57 g of needles. Then, as in Reference Example 54, this crystal crop was dissolved in 50 ml of N,N- dimethylformamide and with ice-cooling, a solution of sodium sulfide nonahydrate (2.76 g) in water (5 ml) was added dropwise. The mixture was stirred for 5 minutes, after which 1.60 g of methyl iodide was added and the mixture was further stirred at room temperature for 1 hour. The reaction mixture was then concentrated under reduced pressure and the residue was diluted with 100 ml of ethyl acetate and 50 ml of water. The ethyl acetate layer was taken, washed with two 50 ml portions of water, dried, and concentrated. Then, as in Example 1, the oily residue was dissolved in 100 ml of chloroform, and after addition of 3.80 g of - chloroperbenzoic acid under ice-cooling, the mixture was refluxed for 4 hours. This reaction mixture was washed with 2 portions of 10% aqueous sodium thiosulfate solution twice and 3 portions of saturated aqueous NaHC03 solution. The organic layer was dried and concentrated and the residue was purified by column chromatography (silica gel; eluent: ethyl acetate/n- hexane = 1/2) and recrystallized from ethyl acetate/n- hexane (1:1) to provide 0.53 g of the title compound. H-NMR (CDC13) 6: 3.26 (s, 3H), 3.81 (s, 3H), 4.21 (s. 2H), 6.80-7.40 (m, 4H) . Elemental analysis (%) (for Cj3H12N204S)
Calcd.: C, 53.42; H, 4.14; N, 9.58 Found : C, 53.41; H, 4.11; N, 9.65 In the same manner, the compounds of Example 169- 178 were synthesized. [Example 179]
2-(3-Methoxybenzyl)-5-methylsulfonyl-4-oxazole- carbonitrile In 50 ml of ethyl acetate was dissolved 0.7 g of
2-amino-3,3-dichloroacrylonitrile, followed by addition of 0.98 g of 3-methoxyphenylacetyl chloride, and the mixture was stirred at room temperature for 17 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the residue was recrystallized from diethyl ether/n-hexane (1:3) to provide 1.1 g of needles. As in Reference Example 54, this crystal crop was dissolved in 50 ml of N,N- dimethylformamide, and under ice-cooling, a solution of sodium sulfide nonahydrate (1.95 g) in water (5 ml) was added dropwise. The mixture was stirred for 5 minutes, after which 1.2 g of methyl iodide was added and the mixture was further stirred at room temperature for 4 hours. This reaction mixture was concentrated under reduced pressure and the residue was diluted with 50 ml of water and extracted with 100 ml of ethyl acetate. The ethyl acetate layer was washed with two 50 ml portions of water, dried, and concentrated. As in Example 1, the oil thus obtained was dissolved in 100 ml of chloroform, and under ice-cooling, 2.34 g of m- chloroperbenzoic acid was added. The mixture was then refluxed for 4 hours. This reaction mixture was washed with 2 portions of 10% aqueous sodium thiosulfate solution and 3 portions of saturated aqueous NaHC03 solution. The organic layer was dried and concentrated and the residue was purified by column chromatography (silica gel; eluent: ethyl acetate/n-hexane = 1/2) and recrystallized from ethyl acetate/n-hexane (1:2) to provide 0.12 g of the title compound.
!H-NMR (CDC13) 6: 3.27 (s, 3H) , 3.82 (s, 3H) , 4.18 (s, 2H), 6.80-6.95 (m, 3H) , 7.20-7.40 (m, IH) .
Elemental analysis (%) (for Cj3H12N204S)
Calcd.: C, 53.42; H, 4.14; N, 9.58 Found : C, 53.56; H, 4.13; N, 9.47 In the same manner, the compound of Example 180 was synthesized.
129
[Table 4] Compounds of Reference Examples
Figure imgf000131_0001
Figure imgf000131_0002
97/24340
130
[Table 5] Compounds of Reference Examples
Figure imgf000132_0001
Figure imgf000132_0002
97/24340
131
Reference Examples and Examples
Figure imgf000133_0001
Figure imgf000133_0002
[Table 7]
Figure imgf000134_0001
Figure imgf000134_0002
O 97/24340
133
[Table 8]
Figure imgf000135_0001
Figure imgf000135_0002
97/24340
134
Figure imgf000136_0001
Figure imgf000136_0002
97/24340
135
[Table 10]
Figure imgf000137_0001
97/24340
136
[Table 11]
Figure imgf000138_0001
Figure imgf000138_0002
9
137
Figure imgf000139_0002
Figure imgf000139_0001
97/24340
138
Figure imgf000140_0001
Figure imgf000140_0002
97/24340
139
Figure imgf000141_0001
Figure imgf000141_0002
97/24340
140
Figure imgf000142_0001
Figure imgf000142_0002
97/24340
141
Figure imgf000143_0001
Figure imgf000143_0002
97/24340
142
[Table 17] R2
Figure imgf000144_0001
97/24340
143
[Table 18]
Figure imgf000145_0001
Figure imgf000145_0002
97/24340
144
Figure imgf000146_0002
Figure imgf000146_0001
97/24340
145
[Table 20]
Figure imgf000147_0001
Figure imgf000147_0002
O 97/24340
146
[Table 21]
Figure imgf000148_0001
97/24340
147
Figure imgf000149_0001
Figure imgf000149_0002
97/24340
148
Figure imgf000150_0002
Figure imgf000150_0001
149
Figure imgf000151_0002
Figure imgf000151_0001
97/24340
150
Figure imgf000152_0001
Figure imgf000152_0002
[Experimental Example 1] Inhibition of IL-6 activity
The test compoundwas dissolved in N,N- dimethylformamide at a concentration of 10 mM and this solution was diluted with RPMI-1640 medium at a final concentration of 0.1 mM. Then, this dilution was further diluted serially with the same medium by the doubling dilution method to provide a concentration series from 20 μM to 0.16 μM for addition to the culture system.
Using the IL-6-dependent cell line MH60, the in¬ hibitory effect of the test compound on IL-6-dependent growth of cells was evaluated. On the day immediately preceding the experiment, the cells were suspended in 10% inactivated fetal calf serum-RPMI-1640 medium at a density of 1x10 /mL and grown in a flask at 37°C under sparging with 5% C02/95% air. On the day of starting the experiment, the cultured cells were seeded in a 96- well plate, at a density of 1x10* cells/0.1 mL/well. After the test compound preparation was added to the wells, IL-6 was added at a final concentration of 0.25 ng/mL. After 2 days of incubation, 0.02 mL of solution of dimethylthiazolyl diphenyltetrazolium bromide (MTT) in PBS (5 mg/mL) was added to each well, and the plate was further incubated for 3 hours. Then, 0.1 mL of 10% sodium dodecyl sulfate 0.01N-HC1 solution was added to each well and the plate was further incubated at 37°C overnight. Then, using the Multi-Scan, the optical density at 560 nm was measured to estimate the viability of cells.
As a result, the test compound was found to effec¬ tively inhibit growth of MH60 cells. The data are pre¬ sented in Table 26 in terms of IC50 which is the concentration of the test compound causing 50% inhibition of growth. Table 26
Ex. No. of test compound IC50 (μM) 6 0.83
13 0.91
17 0.80
18 0.85 38 0.90 44 0.49
94 0.79
95 0.85 114 0.80 116 0.98 122 0.84
136 0.79
137 0.78
138 0.98
139 0.64 143 0.59
144 0.83
145 0.81
146 0.73
147 0.39 148 0.93
150 0.90
151 0.88
153 0.36
154 0.33 155 0.37
166 0.34
167 0.61 169 0.99 187 0.90 204 0.75
It is clear from the data shown in Table 26 that the oxazole derivatives of the present invention have excellent IL-6-inhibitory activity. [Experimental Example 2] Inhibition of acute-phase protein production
It is known that in the event of infection, tissue injury, development of a malignant tumor, or immunologic abnormality, the body reacts to such an event by producing acute-phase proteins and that IL-6 is the most crucial factor in the induction of such proteins. In amyloidosis secondary to chronic inflammatory diseases, the acute-phase protein serum amyloid A protein becomes fibrillated and is deposited extracellularly to elicit disorders of the organs. Then, effect of the test compound on the production of serum amyloid A protein was investigated in experi¬ mental animals.
Female C57BL/6 mice (6 weeks old) were acclimatized for 1 week, and divided into groups of 5 animals. Mice in the test group were given a single dose of the test compound suspended in 5% aqueous arabic gum solution by oral gavage. A control group was similarly treated with the vehicle only. One hour after administration, 0.25 mg of LPS, the outer membrane fraction of Gram-negative bacteria, was administered intraperitoneally to animals in both the test group and the control group. The blood was drawn 7 hours after administration of LPS, and serum amyloid A protein concentration was determined by the sandwich ELISA method. The result is set forth in Table 27. The asterisk denotes significant difference from control (p<0.01; student t-test) . [Table 27]
treatment dose Inhibition of serum amyloid
(mg/kg) A protein production (%) none 0 0 compound of
Ex. 6 50 54* compound of
Ex. 13 50 78*
It is clear from Table 27 that the oxazole deriva¬ tives of the present invention have excellent activity to inhibit the production of the acute-phase protein. [0151] [Experimental Example 3] Inhibition of NO production
Using the mouse macrophage-derived cell line RAW 264.7 as iNOS-induction cells, the inhibitory effect of the test compound on NO production was evaluated. The test compound was dissolved in N,N-dimethylformamide at a concentration of 10 mM and the solution was diluted with RPMI-1640 medium to 0.1 mM. This solution was further diluted serially with the same medium by the 10-fold dilution method to provide a concentration series from 10 μM to about 10 nM for addition to the culture system. On the day immediately preceding the experiment, cells were suspended in 10% inactivated fetal calf serum-RPMI-1640 medium at a density of 5xl05/ml and seeded in a 96-well plate, lxlO5 cells/0.2 ml/well. The plate was incubated at 37°C under aeration with 5% COz/95% air overnight and then the test compound preparation was added. LPS and gamma interferon were then added at final concentrations of 5 ng/ l and 1 U/ml, respectively, and the plate was incubated. After overnight culture, the nitrite ion (stable metabolite of NO) in the culture supernatant was determined as an indicator of NO production. The nitrite ion concentration was measured by adding 25 μl of 2,3-diaminonaphthalene (DAN) (20 μg/ l) to 50 μl of culture supernatant and measuring the fluorescent emission at 450 nm (exciting wavelength 365 nm) . The results are shown in Table 28. IC50 stands for the concentration of the test compound causing 50% inhibition of NO production. [Table 28]
Ex. No. of test compound IC50 (nM) 1 73
2 65
7 19
24 40
34 13 35 28
62 15
98 15
121 10
122 80 123 9.1
181 67
195 24
204 28
205 28
It is clear from Table 28 that the oxazole deriva¬ tive of the present invention strongly inhibits release of NO from RAW264.7 cells and thus has excellent NO production-inhibitory activity. [Experimental Example 4]
Effect against elevation of blood nitrogen oxide concentration
As NO is produced in the body as a defense against infection or immunologic abnormality, it is immediately metabolized into nitrous acid and nitric acid so that the blood nitrogen oxide (NOx) level is elevated. Therefore, using experimental animals, the effect of the test compound on this elevation of blood NOx concentration was evaluated.
Female BALB/c mice (6 weeks old) were acclimatized for 1 week, and divided into groups each consisting of 6-8 animals. The mice in the test group were intraperitoneally dosed with 30 mg/kg of the test compound (compound of Ex. 8, 88, 123 or 132) suspended in 0.5% aqueous methylcellulose solution. The control group received the vehicle only in the same manner. After 30 minutes, LPS (30 mg/kg) was administered intraperitoneally to animals in both the test group and the control group. The blood was drawn 6 hours after LPS administration and the serum concentration of nitrate ion + nitrite ion was measured. The nitrate ion was converted to nitrite ion with nitrate reductase and the total nitrite ion concentration was determined by the above-mentioned fluorometry using DAN. The test compounds showed significant inhibition compared with control (student's t-test). It is clear that the oxazole derivative of the present invention exerts excellent NO production- inhibitory activity in vivo as well.
The oxazole derivative of the present invention has excellent inhibitory activities of IL-6 activity and NO production can be used as a safe IL-6 activity inhibitor or NO production inhibitor in human and other mammalian animals (e.g. mouse, rat, guinea pig, rabbit, dog, cat, bovine, swine, sheep, monkey, chimpanzee) . Furthermore, the oxazole derivative (I') can be used as a medicine, such as a prophylactic and therapeutic drug for IL-6-associated diseases, for example, cardiac diseases such as myocardiopathy, cardiac hypertrophy, myocardial infarction, angina pectoris, etc., various autoimmune diseases such as chronic rheumatoid arthritis, systemic lupus erythematosus, systemic scleroderma, rheumatic fever, polymyositis, periarteritis nodosa, Sjogren's syndrome, Behcet's disease, Castleman's disease, autoimmune hemolytic anemia, etc., inflammatory diseases such as mesangial proliferative nephritis, IgA nephritis, lupus nephritis, osteoporosis, amyloidosis, bronchial asthma, atopic dermatitis, psoriasis, pleurisy, ulcerative colitis, atherosclerosis, active chronic hepatitis, alcoholic cirrhosis, gout, various types of encephalitis, etc., or diseases accompanied by granuloma such as multiple myeoloma, atrial myxoma, renal carcinoma, pulmonary adenocarcinoma, malignant mesothelioma, ovarian cancer, cancerous cachexia, etc., or NO-associated diseases, for example, atherosclerosis, myocarditis, myocardiopathy, ischemic brain disorder, Alzheimer's disease, multiple sclerosis, septicemia, rheumatoid arthritis, osteoarthritis, gastric ulcer, duodenal ulcer, ulcerative colitis, diabetes, glomerulonephritis, osteoporosis, pneumonia, hepatitis, graft rejection, pain, etc., with safety in human and other mammalian animals (e.g. mouse, rat, guinea pig, rabbit, dog, cat, bovine, swine, sheep, monkey, chimpanzee).

Claims

CLAIMSWhat is claimed is:
1. An oxazole derivative having a group bonded through a sulfinyl or sulfonyl moiety at the 5-position of the oxazole ring, provided that when the substituent at the 4-position is hydrogen, (1) the compound which has 4-methoxyphenyl or 4-methoxyphenylethinyl at the 2- position and nonafluorobutylsulfonyl at the 5-position,
(2) the compound which has phenyl at the 2-position and (2-phenyl-5-thiazolyl)sulfonyl at the 5-position, and
(3) the compound which has 3-[5-(2,3-epoxy-5-hydroxy-4- methylhexyl)-3,4-dihydroxytetrahydropyran-2-yl]-2- methyl-l-(E)-propenyl at the 2-position and 4-methyl- phenylsulfonyl at the 5-position are excluded.
2. The oxazole derivative according to claim 1, which has a halogen atom or a group bonded through a carbon, nitrogen, oxygen, or sulfur atom as a substituent at the 2-position of the oxazole ring.
3. The oxazole derivative according to claim 1, which has a halogen atom or a group bonded through a carbon, nitrogen, oxygen, or sulfur atom as a substituent at the 4-position of the oxazole ring.
4. The oxazole derivative according to claim 1, which is a compound of the formula:
Figure imgf000160_0001
wherein R1 represents a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, or amino which may be substituted; n represents 1 or 2; R represents hydrogen, cyano, acyl, carbamoyl which may be substituted, thiocarbamoyl which may be substituted, a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, amino which may be substituted, or carboxyl which may be esterified; R3 represents hydrogen, halogen, a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, a hydrocarbon-oxy group which may be substituted, amino which may be substituted, carboxyl which may be esterified, or a group of the formula -S(0)m-R; where R represents a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted; m represents 0, 1, or 2.
5. The oxazole derivative according to claim 4, wherein R1 represents a CW9 hydrocarbon group which may be substituted, a 5- to 8-membered heterocyclic group containing at least 1 atom selected from nitrogen, oxygen, and sulfur, which may be substituted, or amino which may be substituted;
R represents hydrogen, cyano, an organic carboxylic acid-derived acyl group, carbamoyl which may be substi¬ tuted, thiocarbamoyl which may be substituted, a Cι.19 hydrocarbon group which may be substituted, a 5- to 8- membered heterocyclic group containing at least 1 atom selected from nitrogen, oxygen, and sulfur, which may be substituted, amino which may be substituted, or carboxyl which may be esterified;
R represents hydrogen, halogen, a
Figure imgf000161_0001
hydrocarbon group which may be substituted, a 5- to 8-membered heterocyclic group containing at least 1 atom selected from nitrogen, oxygen, and sulfur, which may be substituted, a C^g hydrocarbon-oxy group which may be substituted, amino which may be substituted, carboxyl which may be esterified, or a group of the formula - S(0)m-R'; where R' represents a Cj.jg hydrocarbon group which may be substituted or a 5- to 8-membered heterocyclic group containing at least 1 atom selected from nitrogen, oxygen, and sulfur, which may be substituted; m represents 0, 1, or 2.
6. The oxazole derivative according to claim 4, wherein R represents
(1) Cx.l9 alkyl which may be substituted with (i) a 5- or 6-membered sulfur-containing heterocyclic group, (ii) a 5- or 6-membered oxygen- and nitrogen-containing heterocyclic group which may be substituted with CL12 alkyl or cyano, (iii) carboxyl, (iv) C6.u arylcarbonyl, (v) cyano, (vi) carbamoyl which may be mono- or di- substituted with C1_i2 alkyl, or (vii) Cι_l2 alkoxy- carbonyl,
(2) C2.12 alkenyl which may be substituted with mono- or alkylamino,
(3) C2_12 alkinyl,
(4) C3.10 cycloalkyl,
(5) C6. aryl which may be substituted with (i) halogen, (ii)
Figure imgf000162_0001
alkoxy, (iii) amino which may be substituted with (a) carbamoyl which may be substituted with Cj_i2 alkyl or C3.10 cycloalkyl, (b) C6.14 arylsulfonyl which may be substituted with halogen, or (c) cι-i2 alkylsulfonyl, (iv) Cl.12 alkyl which may be substituted with halogen, (v) nitro or (vi) hydroxyl,
(6) C7.19 aralkyl which may be substituted with (i) halogen, (ii) C1-12 alkoxy, (iii) amino which may be substituted with (a) C6. arylsulfonyl which may be substituted with
Figure imgf000162_0002
alkyl or (b) C1-12 alkylsulfonyl, or (iv) nitro,
(7) a 5- or 6-membered nitrogen- or oxgen-containing heterocyclic group,
(8) amino which may be substituted with (i) Cι_12 alkyl which may be substituted with (a) Cl. alkoxy-carbonyl, (b) mono- or di-C1.12 alkylamino or (c) a 5- or 6- membered nitrogen-containing heterocyclic group, (ii) C7.19 aralkyl which may be substituted with halogen or Cj_12 alkoxy, (iii) C4.12 bridged-ring hydrocarbon group, (iv) C6_ aryl or (v) C3.10 cycloalkyl or (9) thienopyrimidylhydrazino which may be substituted with C!_12 alkyl.
7. The oxazole derivative according to claim 4, wherein R1 represents
(1) j.lz alkyl which may be substituted with (i) thienyl, (ii) oxazolyl which may be substituted with Cj.g alkyl or cyano, (iii) carboxyl, (iv) C6.12 arylcarbonyl, (v) cyano, (vi) carbamoyl which may be mono- or di-substituted with C^ alkyl, or (vii) C^ alkoxy-carbonyl,
(2) C2-6 alkenyl which may be substituted with mono- or di-Ci.6 alkylamino,
(3) C2.6 alkinyl,
(4) C3_8 cycloalkyl,
(5) C6,12 aryl which may be substituted with (i) halogen, (ii) Cj.g alkoxy, (iii) amino which may be substituted with (a) carbamoyl which is substituted with Cj.g alkyl or C3-8 cycloalkyl, (b) C6.12 arylsulfonyl which may substituted with halogen or (c) C^ alkylsulfonyl, (iv) C^ alkyl which may be substituted with halogen (v) nitro or (vi) hydroxy,
(6) c 7-π aralkyl which may be substituted with (i) halogen, (ii) Cj.g alkoxy, (iii) amino which may be substituted with (a) C6_12 arylsulfonyl which may be substituted with C^ alkyl or (b) Cx_6 alkylsulfonyl, or (iv) nitro,
(7) a heterocyclic group selected from the group consisting of pyrimidyl, piperidino, morpholino and 1- piperazinyl,
(8) amino which may be substituted with (i) C _6 alkyl which may be substituted with (a) C 6 alkoxy-carbonyl, (b) mono- or di-C^g alkylamino or (c) pyridyl, (ii) C6_ 12 aryl, (iii) C7.13 aralkyl which may be substituted with halogen or C^ alkoxy, (iv) adamantyl or (v) C3.8 cycloalkyl, or
(9) thienopyrimidylhydrazino which may be substituted with Cj.6 alkyl.
8. The oxazole derivative according to claim 4, wherein R represents
(1) cyano,
(2) C1.12 alkanoyl,
(3) carbamoyl which may be substituted with (i) Cι_12 alkyl which may be substituted with a 5- or 6-membered nitrogen-containing heterocyclic group, (ii) C!_12 alkoxy or (iii) C7.19 aralkyl,
(4) a 5- or 6-membered saturated nitrogen-containing heterocyclic-carbonyl, which may be substituted with C-6-14 aryl,
(5) thiocarbamoyl which may be substituted with (i) C,. i2 alkyl or (ii) C7.19 aralkyl,
(6) a 5- or 6-membered saturated nitrogen-containing heterocyclic-thiocarbonyl,
(7) Ci_12 alkyl which may be substituted with a group selected from the group consisting of (i) hydroxyl which may be acylated with C6.1 arylcarbonyl, (ii) halogen, (iii) carboxyl, (iv) cyano, (v) amino which may be substituted with C[.12 alkyl which may be substituted with a 5- or 6-membered nitrogen-containing heterocyclic group or C7.19 aralkyl, (vi) a 5- or 6- membered saturated heterocyclic group containing 2 nitrogen atoms, which may be substituted with C6.1A aryl, (vii) phthalimido, (viii) C6.14 arylsulfonyl which may be substituted with C{.12 alkyl, and (ix) C6. aryloxy which may be substituted with halogen,
(8) C7.19 aralkyl which may be substituted with halogen or hydroxyl,
(9) a 5- or 6-membered nitrogen and sulfur-containing heterocyclic group, which may be substituted with (i) Cj_12 alkoxy-carbonyl or (ii) C6_n aryl,
(10) amino which may be substituted with Cj.12 alkoxy- carbonyl,
(11) carboxyl, or
(12) C!.12 alkoxy-carbonyl.
9. The oxazole derivative according to claim 4, wherein R2 represents
(1) cyano,
(2) Cj.6 alkanoyl,
(3) carbamoyl which may be substituted with (i) C1-6 alkyl which may be substituted with pyridyl, (ii) C7.n aralkyl or (iii) Cj.6 alkanoyl,
(4) piperidinocarbonyl,
(5) 1-piperazinylcarbonyl which may be substituted with C6.12 aryl,
(6) thiocarbamoyl which may be substituted with (i) C,,,, alkyl or (ii) C7.13 aralkyl,
(7) piperidinothiocarbonyl,
(8) Cj.6 alkyl which may be substituted with (i) hydroxy which may be acylated with C6.12 arylcarbonyl, (ii) halogen, (iii) carboxyl, (iv) cyano, (v) amino which may substituted with (a) Cj_6 alkyl which may be substituted with pyridyl or (b) C7.13 aralkyl, (vi) 1- piperazinyl which may be substituted with C6.12 aryl, (vii) phthalimido, (viii) C6.12 arylsulfonyl which may be substituted with C 6 alkyl, or (ix) C6_12 aryloxy which may be substituted with halogen. (9) C7.13 aralkyl which may be substituted with halogen or hydroxyl,
(10) thiazolyl which may be substituted with Cy_6 alkoxy-carbonyl or (b) C6.12 aryl,
(11) amino which may be substituted with C^ alkoxy- carbonyl,
(12) carboxyl, or
(13) Cj.g alkoxy-carbonyl.
10. The oxazole derivative according to claim 4, wherein R represents
(1) hydrogen,
(2) halogen,
(3) Cι_12 alkyl which may be substituted with a group selected from the group consisting of (i) amino which may be substituted with C7_19 aralkyl or Cj_12 alkyl, (ii) a 5- or 6-membered saturated heterocyclic group containing 2 nitrogen atoms which may be substituted with C6.14 aryl, (iii) phthalimido, (iv) C6.14 arylsulfonyl which may substituted with
Figure imgf000166_0001
alkyl, (v) hydroxyl which may be substituted with C1.n alkanoyl, (vi) a 5- or 6-membered saturated nitrogen- and/or oxygen-containing heterocyclic group, (vii) halogen, (viii) Cj_12 alkoxy-carbonyl, and (ix) a 5- to 6-membered unsaturated nitrogen- and/or oxgen-containing heterocyclic group, which may be substituted with C^ alkyl or cyano,
(4) c 2-ι2 alkenyl which may be substituted with C6.1Zl aryl,
(5) C6.14 aryl which may be substituted with Cj_12 alkoxy,
(6) C7.19 aralkyl which may be substituted with (i) amino, (ii) nitro, (iii) Ci_12 alkoxy, or (iv) halogen,
(7) C3.10 cycloalkyl,
(8) C3.10
Figure imgf000166_0002
alkyl,
(9) a C4.12 bridged-ring hydrocarbon group, (10) a 5- to 6-membered unsaturated nitrogen- and/or oxygen-containing heterocyclic group,
( 11) C i2 alkoxy,
(12) amino which may be substituted with (i) Cγ.n alkyl which may substituted with Ci_12 alkoxy-carbonyl or (b) a 5- or 6-membered nitrogen-containing heterocyclic group or (ii) C7.19 aralkyl, or
(13) C!-12 alkoxy-carbonyl.
11. The oxazole derivative according to claim 4, wherein R represents
(1) hydrogen,
(2) halogen,
(3) C!_6 alkyl which may be substituted with (i) amino which may be substituted with C7.13 aralkyl or C^ alkyl, (ii) 1-piperazinyl which may be substituted with c6-i2 aryl/ (iϋ) phthalimide, (iv) C6.12 arylsulfonyl which may be substituted with Cj.β alkyl, (v) hydroxyl which may be substituted with Ci_6 alkanoyl, (vi) morpholino, (vii) piperidino, (viii) halogen, (ix) Cι_6 alkoxy-carbonyl, and (x) oxazolyl which may be substituted with C,_6 alkyl or cyano,
(4) C2-6 alkenyl which may be substituted with C6.12 aryl,
(5) c 6-i2 aryl which may be substituted with C^ alkoxy,
(6) c 7-π aralkyl which may be substituted with (i) amino, (ii) nitro, (iii) Cl-6 alkoxy, or (iv) halogen,
(7) C3_8 cycloalkyl,
(8) C3.8 cycloalkyl-Cj.6 alkyl,
(9) adamantyl ,
(10) oxadiazolyl,
(11) Cn alkoxy,
(12) amino which may be substituted with (i) Cx_6 alkyl which may be substituted with C^g alkoxy-carbonyl or pyridyl, or (ii) C7.13 aralkyl, or (13) Ci.β alkoxy-carbonyl.
12. The oxazole derivative according to claim 4, wherein R1 represents (1) Cj.g alkyl which may be substituted with (i) 2-thienyl or (ii) carboxyl, (2) c 6-i2 aryl which may be substituted with (i) halogen, (ii) Cj.6 alkoxy or (iii) C^ alkylcarbamoylamino, (3) C7.13 aralkyl which may be substituted with nitro, (4) amino which may be substituted with (i) C^ alkyl, (ii) c 6-i2 aryl or (iii) C3_8 cycloalkyl, or (5) morpholino.
13. The oxazole derivative according to claim 4, wherein R represents cyano, thiocarbamoyl, carbamoyl, or Ci-s alkyl which may be substituted with halogen.
14. The oxazole derivative according to claim 4, wherein R3 represents (1) hydrogen, (2) C^g alkyl which may be substituted with amino which may have
Figure imgf000168_0001
alkyl or C7.15 aralkyl substituent, (3) C3.6 cycloalkyl, (4) Cfi_ 12 aryl which may be substituted with Cι.6 alkoxy or (5) C7.13 aralkyl which may be substituted with (i) halogen or (ii) Ci.6 alkoxy.
15. The oxazole derivative according to claim 4, wherein n is 2.
16. A process for producing the oxazole derivative according to claim 4, which comprises
(1) oxidizing a compound of the formula:
Figure imgf000168_0002
wherein R1, R2, and R are as defined in claim 4 to give an oxazole derivative of the formula:
Figure imgf000169_0001
wherein R 1, R2, and R3 are as defined above, and n is as defined in claim 4,
(2) reacting a compound of the formula:
Figure imgf000169_0002
wherein R2 and R are as defined above; R12 represents lower alkyl or phenyl; n is 0, 1, or 2 with a compound of the formula:
R -S02M wherein R is as defined above; M represents an alkali metal to obtain an oxazole derivative of the formula:
Figure imgf000169_0003
wherein R1, R2, and R are as defined above, or (3) reacting a compound of the formula:
Figure imgf000169_0004
wherein R2, R3, and n are as defined above; X represents a leaving group with a compound of the formula:
HNRV wherein R and R independently represent hydrogen, a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted; R4 and R5 may be combined with the adjacent nitrogen atom to form a heterocyclic group to obtain an oxazole derivative of the formula:
Figure imgf000170_0001
wherein R , R , n, R , and R are as defined above.
17. A process for producing a compound of the formula:
Figure imgf000170_0002
wherein R , R , and R are as defined in claim 4, which comprises
(1) reacting a compound of the formula: COR3
Figure imgf000170_0003
wherein R 2 and R3 are as defined above with a compound of the formula:
M2S wherein M represents an alkali metal and a compound of the formula:
R*X wherein R1 is as defined above; X represents a leaving group, or
(2) reacting a compound of the formula:
Rl
Figure imgf000171_0001
wherein R and R are as defined above; R represents lower alkyl or phenyl; n is 0, 1, or 2 with a compound of the formula:
R -SH wherein R are as defined above, or
(3) reacting a compound of the formula:
Rl
Figure imgf000171_0002
wherein R , R , R and n are as defined above with a compound of the formula:
M2S wherein M is as defined above and a compound of the formula:
R*X wherein R and X are as defined above.
18. A pharmaceutical composition comprising an oxazole derivative having a group bonded through a sulfinyl or sulfonyl moiety at the 5-position of the oxazole ring.
19. The pharmaceutical composition according to claim 18, wherein the oxazole derivative is a compound of the formula:
Figure imgf000172_0001
wherein R represents a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, or amino which may be substituted; n represents 1 or 2; R represents hydrogen, cyano, acyl, carbamoyl which may be substituted, thiocarbamoyl which may be substituted, a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, amino which may be substituted, or carboxyl which may be esterified; R3 represents hydrogen, halogen, a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, a hydrocarbon-oxy group which may be substituted, amino which may be substituted, carboxyl which may be esterified, or a group of the formula -S(0)m-R, where R represents a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted; m represents 0, 1, or 2.
20. The pharmaceutical composition according to claim 18 or 19, which is a prophylactic or therapeutic pharmaceutical for cardiac diseases, autoimmune diseases, inflammatory diseases, or diseases accompanied by granuloma.
21. The pharmaceutical composition according to claim 18 or 19, which is a prophylactic or therapeutic pharmaceutical for myocardiopathy, cardiac hypertrophy, myocardial infarction, angina pectoris, chronic rheumatoid arthritis, systemic lupus erythematosus, systemic scleroderma, rheumatic fever, polymyositis, periarteritis nodosa, Sjδgren's syndrome, Behcet's disease, Castleman's disease, autoimmune hemolytic anemia, mesangial proliferative nephritis, IgA nephritis, lupus nephritis, osteoporosis, amyloidosis, bronchial asthma, atopic dermatitis, psoriasis, pleurisy, ulcerative colitis, atherosclerosis, active chronic hepatitis, alcoholic cirrhosis, gout, encephalitis, multiple myeoloma, atrial myxo a, renal carcinoma, pulmonary adenocarcinoma, malignant mesothelioma, ovarian cancer or cancerous cachexia.
22. A composition for inhibition of interleukin-6 activity comprising an oxazole derivative having a group bonded through a sulfinyl or sulfonyl moiety at the 5-position of the oxazole ring.
23. The pharmaceutical composition according to claim 18 or 19, which is a prophylactic or therapeutic pharmaceutical for atherosclerosis, myocarditis, myocardiopathy, ischemic brain disorder, Alzheimer's disease, multiple sclerosis, septicemia, chronic rheumatoid arthritis, osteoarthritis, gastric ulcer, duodenal ulcer, ulcerative colitis, diabetes, glomerulonephritis, osteoporosis, pneumonia, hepatitis, graft rejection or pain.
24. A composition for inhibition of nitrogen monoxide production comprising an oxazole derivative having a group bonded through a sulfinyl or sulfonyl moiety at the 5-position of the oxazole ring.
25. Use of an oxazole derivative having a group bonded through a sulfinyl or sulfonyl moiety at the 5-position of the oxazole ring, for the manufacture of a medicament for inhibiting interleukin-6 activity.
26. Use of an oxazole derivative having a group bonded through a sulfinyl or sulfonyl moiety at the 5-position of the oxazole ring, for the manufacture of a medicament for inhibiting nitrogen monoxide production.
27. A method for inhibiting interleukin-6 activity in human or mammal, which comprises administering an effective amount of an oxazole derivative having a group bonded through a sulfinyl or sulfonyl moiety at the 5-position of the oxazole ring, to human or the mammal.
28. A method for preventing or treating interleukin-6- associated diseases, which comprises administering an effective amount of an oxazole derivative having a group bonded through a sulfinyl or sulfonyl moiety at the 5-position of the oxazole ring, to human or the mammal.
29. A method for inhibiting nitrogen monoxide production in human or mammal, which comprises administering an effective amount of an oxazole derivative having a group bonded through a sulfinyl or sulfonyl moiety at the 5-position of the oxazole ring, to human or the mammal.
30. A method for preventing or treating nitrogen monoxide-associated diseases, which comprises administering an effective amount of an oxazole derivative having a group bonded through a sulfinyl or sulfonyl moiety at the 5-position of the oxazole ring, to human or the mammal.
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998042377A1 (en) * 1997-03-21 1998-10-01 Chugai Seiyaku Kabushiki Kaisha Preventives or remedies for sensitized t cell-related diseases containing il-6 antagonists as the active ingredient
US7691884B2 (en) 2000-12-13 2010-04-06 Wyeth Heterocyclic sulfonamide inhibitors of β amyloid production
US7824674B2 (en) 1998-03-17 2010-11-02 Chugai Seiyaku Kabushiki Kaisha Preventive or therapeutic agent for inflammatory bowel disease comprising IL-6 antagonist as an active ingredient
US8492415B2 (en) * 2007-07-03 2013-07-23 Yale University Azoles and related derivatives as non-nucleoside reverse transcriptase inhibitors (NNRTIs) in antiviral therapy (HIV)
CN111868043A (en) * 2018-01-10 2020-10-30 庆北大学校产学协力团 Novel benzenesulfonyl oxazole derivatives and use thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0087953A2 (en) * 1982-02-27 1983-09-07 Beecham Group Plc Antibacterial 1-normon-2-yl-heterocyclic compounds
WO1995013067A1 (en) * 1993-11-08 1995-05-18 Smithkline Beecham Corporation Oxazoles for treating cytokine mediated diseases
WO1995024403A1 (en) * 1994-03-10 1995-09-14 Zeneca Limited (4,4-difluorobut-3-enylthio)-substituted heterocyclic or carbocyclic ring compounds having pesticidal activity

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0087953A2 (en) * 1982-02-27 1983-09-07 Beecham Group Plc Antibacterial 1-normon-2-yl-heterocyclic compounds
WO1995013067A1 (en) * 1993-11-08 1995-05-18 Smithkline Beecham Corporation Oxazoles for treating cytokine mediated diseases
WO1995024403A1 (en) * 1994-03-10 1995-09-14 Zeneca Limited (4,4-difluorobut-3-enylthio)-substituted heterocyclic or carbocyclic ring compounds having pesticidal activity

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
PAMELA BROWN ET AL: "The chemistry of pseudomonic acid.Synthesis and antibacterial activity of a series of 5-alkyl,5-alkenyl, and 5-heterosubstituted oxazoles", JOURNAL OF MEDICINAL CHEMISTRY, vol. 39, no. 2, 19 January 1996 (1996-01-19), WASHINGTON US, pages 446 - 457, XP002028007 *
ROBERT D.MILLER ET AL: "Substituted azole derivatives as nonlinear optical chromophores", CHEMISTRY OF MATERIALS, vol. 6, no. 7, 1994, WASHINGTON US, pages 1023 - 1032, XP002028006 *
V.S.BROVARETS ET AL: "Reactions of substituted phosphinomethylene containing 2-alkyl(or aryl)-4,5-dihydro-5-thioxo-4-oxazolylidene fragments", JOURNAL OF GENERAL CHEMISTRY USSR, vol. 56, no. 7, 1986, NEW YORK US, pages 1323 - 1332, XP002028005 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998042377A1 (en) * 1997-03-21 1998-10-01 Chugai Seiyaku Kabushiki Kaisha Preventives or remedies for sensitized t cell-related diseases containing il-6 antagonists as the active ingredient
US9017677B2 (en) 1997-03-21 2015-04-28 Chugai Seiyaku Kabushiki Kaisha Methods of treating a disease mediated by sensitized T cells
US7824674B2 (en) 1998-03-17 2010-11-02 Chugai Seiyaku Kabushiki Kaisha Preventive or therapeutic agent for inflammatory bowel disease comprising IL-6 antagonist as an active ingredient
US7691884B2 (en) 2000-12-13 2010-04-06 Wyeth Heterocyclic sulfonamide inhibitors of β amyloid production
US7842718B2 (en) 2000-12-13 2010-11-30 Wyeth Llc Heterocyclic sulfonamide inhibitors of beta amyloid production
US8492415B2 (en) * 2007-07-03 2013-07-23 Yale University Azoles and related derivatives as non-nucleoside reverse transcriptase inhibitors (NNRTIs) in antiviral therapy (HIV)
CN111868043A (en) * 2018-01-10 2020-10-30 庆北大学校产学协力团 Novel benzenesulfonyl oxazole derivatives and use thereof
CN111868043B (en) * 2018-01-10 2023-11-14 利索科技股份有限公司 Novel benzenesulfonyl oxazole derivative and use thereof

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