WO1999018942A1 - Use of csaidtm compounds for the management of uterine contractions - Google Patents

Use of csaidtm compounds for the management of uterine contractions Download PDF

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Publication number
WO1999018942A1
WO1999018942A1 PCT/GB1998/003015 GB9803015W WO9918942A1 WO 1999018942 A1 WO1999018942 A1 WO 1999018942A1 GB 9803015 W GB9803015 W GB 9803015W WO 9918942 A1 WO9918942 A1 WO 9918942A1
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alkyl
imidazole
optionally substituted
fluorophenyl
heterocyclyl
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PCT/GB1998/003015
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French (fr)
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Samir Ahmed Alvi
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Imperial College Innovations Ltd.
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Priority to EP98947651A priority Critical patent/EP1021173A1/en
Priority to JP2000515577A priority patent/JP2001519381A/en
Priority to CA002316296A priority patent/CA2316296A1/en
Priority to AU94493/98A priority patent/AU9449398A/en
Publication of WO1999018942A1 publication Critical patent/WO1999018942A1/en

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    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/4164—1,3-Diazoles
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/06—Antiabortive agents; Labour repressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to the treatment of inappropriate, excessive or undesirable uterine contractions, in a mammal.
  • Preterm labour is of major concern to both obstetricians and neonatologists. It affects approximately 10% of pregnancies and results in 30% of long term neonatal handicap and 85% of perinatal deaths.
  • the pathogenesis of preterm labour is incompletely understood at present, it is therefore difficult to both predict and treat effectively.
  • the underlying biochemical pathways involved in the initiation of parturition have not yet been fully elucidated. There are clear links between inflammatory processes and activation of the immune system in the maternal decidua. Prostaglandins, which have a well documented role in the initiation of labour, (Mitchell, MD., (1984) Journal of Developmental Physiology, 6, 107-118) and the inflammatory cytokines (Mitchell, MD., et al.
  • Interleukin- 1 ⁇ (IL-l ⁇ ) has been demonstrated to be the pivotal cytokine in the biochemical pathway leading to labour (Mitchell, MD., et al.(1993), supra). It has been shown to directly stimulate the production of prostaglandins which are the terminal products of the inflammatory response and direct initiators of labour (Romero, R., et al. (1992) Am. J. Reprod. Immunol, 33, 117-123; and Kent A.S.H., et al. (1993) Prostaglandins 46, 51-59).
  • IL-l ⁇ levels of IL-l ⁇ have been shown to rise following stimulation with bacterial endotoxin (Romero, R., et al. (1989) Am. J. Obstet and Gynaecol, 160, 1117) which implies a mediating role for this cytokine in the induction of labour in the presence of infection.
  • prostaglandin H synthase The production of prostaglandins is under the influence of two enzymes, phospholipase A2 and cyclo-oxygenase (COX) alternatively known as prostaglandin H synthase.
  • COX has been found to be present in two forms; type-1 COX is the constitutive form of the enzyme present in all tissues.
  • Type-2 COX is the inducible form of the enzyme that has been shown to be up-regulated near term (Macchia L., et al. (1997) Biochemical and Biophysical Research Communications, 233, 496-501).
  • IL-l ⁇ is able to increase the production of COX-2 in amnion (Trautman M.S., et al. (1996) Placenta, 17, 239-245).
  • PGE 2 prostaglandin E2
  • Tocolytic agents that completely suppress contractions are not yet available.
  • NSAID's Non- Steroidal Anti-inflammatory Drugs
  • oxytocin antagonists is used to try and suppress unwanted uterine activity.
  • the therapeutic cocktail does not fully address the management of preterm labor in patients, therefore a need still exists to find suitable small molecule inhibitors which will help modulate the contactile activity of the uterus in a mammal in need thereof.
  • the present invention is to the novel use of a cytokine inhibitor for the prophylatic treatment or management of excessive, undesired or inappropriate uterine activity in a mammal, which method comprises administering to said mammal an effective amount of a compound which inhibits the production, transcription or translation of a cytokine.
  • the cytokine is inhibited by inhibition of the kinase CSBP/p38/RK.
  • the preferred compounds for use as cytokine inhibitors are those compounds of Formula (I) as noted herein.
  • the preferred method of inhibition is the inhibition of the CSBP/p38 RK kinase pathway.
  • CSAIDTM compounds i.e. compounds that block cytokine production
  • CSAIDTM compounds can be a therapeuticially effective agent in modulating uterine contractile activity. Such modulation will help treat preterm labour in patients in need thereof.
  • the present invention is to the novel use of a cytokine inhibitor, in particular that of cytokine CSBP/p38, for the prophylactic treatment or management of excessive, undesired or inappropriate uterine activity in a mammal.
  • prostaglandin E2 PGE 2
  • PGE 2 prostaglandin E2
  • Tocolytic agents that completely suppress contractions are not yet available and there has been very little recent progress in the therapeutic modalities available to treat preterm labour.
  • the current treatment for preterm labour is a therapeutic cocktail consisting of betasypathomimetics, Non-Steroidal Anti-inflammatory Drugs (NSAID's), and oxytocin antagonists. This cocktail is used to try and suppress unwanted uterine activity.
  • PGE 2 production by fetal membranes has been shown to be inhibited by the use of NSAID's.
  • the efficacy in controlling uterine activity is however dependent on the specificity of the agent used and the treatments are not without their side-effects.
  • small molecule inhibitors which act on cytokine synthesis may also have a similar inhibitory effect on the production PGE 2 by inhibiting cytokine driven prostaglandin production and could therefore be useful in the treatment and prevention of preterm labour. Therefore, another aspect of the present invention is the use of cytokine inhibitors of the p38/CSPB RK pathway in the treatment of both preterm and term labour.
  • the CSAIDTM compound SKF86002 has effectively been used to modulate prostaglandin and interleukin production from gestational tissues.
  • the compound SKF 86002 has previously been shown to decrease the production of IL-l ⁇ from lipopolysaccharide (LPS) stimulated isolated human macrophages (Perregaux D. G., et al. (1995) Molecular pharmacology, 48, 433-442) and the production of prostaglandin H synthase from rat basophilic leukaemic cells (Griswold D.E., et al. (1987) Biochemical Pharmacology, 36, 3463-3470).
  • LPS lipopolysaccharide
  • inappropriate uterine activity includes, but is not limited to, diseases which are characterized by the presence of unwanted or excessive uterine activity prior to the completion of normal gestational period in a mammal. In the case of a human, for instance, this would be approximately a 40 week gestation.
  • excessive or increased uterine activity is characterized by the presence of abnormal uterine action during labour. Abnormal uterine action during labour is characterized by the excessive frequency, amplitude or duration of uterine contractions.
  • pre-term labour refers to the onset of labour before 37 weeks gestation. However, it is recognized that pre-term labour is a complex syndrome due to many aetiological factors. See for instance, Romero, et al., Ann NY Acad. Sci., 734, page 414 (1994).
  • dilatation, or ripening of the cervix is affected by the reorganization of collagen bundles in the cervix. This is believed to be under the control of the enzyme collagenase, produced by neutrophils (Osmers, et al., American Journal of Obstetrics & Gynecology, 166, pp 1455-1460 (1992)). Neutrophils migrate into the cervix from the surrounding tissues under the influence of chemotactic inflammatory cytokines such as IL-8. They are then stimulated by IL-8 to release collagenase which breaks down the collagen bundles in the cervix. IL-8 has also been shown to soften the cervix after topical application.
  • CSBP inhibitor should inhibit unwanted cervical ripening in a mammal.
  • An inhibitor of these cytokines such as CSAIDTM inhibitor, would therefore be able to prevent the unwanted rupture of the fetal membranes by preventing the release of inflammatory cytokines which stimulate the release of proteases, etc., which in turn destroy the integrity of the fetal membranes.
  • Eclampsia and pre-eclampsia are thought to result from the defective penetration of maternal blood vessels (the spiral arteries) into the trophoblast. Inflammatory cytokines are important in mediating this process. Many studies have implicated a variety of cytokine in the pathogenesis of pre-eclampsia. IL-4 has been shown to be elevated in the sera of pre-eclamptic women (Omu-Ae et al., Nutrition, l l(5Suppl), pp 688-91 (1995 -Sep-Oct).
  • pre-eclampsia/ intrauterine dystrophy is characterized by reduction of some cytokines within the amniotic fluid compartment and concomitant reactive augmentations of other cytokines within the maternal and fetal organism.
  • Stallmach et al. Reprod- Fertil-Dev. 1995; 7(6): 1573-80 (1995).
  • IL-6 levels have also been shown to be increased in pre-eclamptic patients (Greer et al., Obstet-Gynecol., 84(6) (1994).
  • a CSAIDTM inhibitor may therefore favourably modify the cytokine profile in pre-eclamptic and eclamptic patients by decreasing the severity of the disease.
  • Preferred compounds for use as cytokine inhibitors are those compounds of Formula (I) as noted herein. Synthetic chemistry and methods of pharmaceutical formulations thereof are also contained within each noted patent application. A description of the assay for inhibition of the cytokine specific binding protein (CSBP) is also found in WO95/07922, whose disclosure is incorporated by reference in its entirety.
  • CSBP cytokine specific binding protein
  • a preferred group of compounds for use herein are those compounds of the formula (I):
  • Rl is a pyrid-4-yl, pyrimidin-4-yl, pyridazin-4-yl, l,2,4-triazin-5-yl, quinol-4-yl, isoquinolinyl, quinazolin-4-yl, 1-imidazolyl or 1-benzimidazolyl ring, which ring is optionally substituted independently one to three times with Y, NHR a , optionally substituted Ci-4 alkyl, halogen, hydroxyl, optionally substituted Ci-4 alkoxy, optionally substituted C ⁇ _4 alkylthio, Ci-4 alkylsulfinyl, CH2OR12, amino, mono and di- Ci-6 alkyl substituted amino, or N(R ⁇ o)C(O)R D ;
  • Y is O-R a ;
  • R4 is phenyl, naphth-1-yl or naphth-2-yl, or heteroaryl, which is optionally substituted by one or two substituents, each of which is independently selected, and which, for a
  • 4-phenyl, 4-naphth-l-yl, 5-naphth-2-yl or 6-naphth-2-yl substituent, is halogen, cyano, nitro, C(Z)NR7R ⁇ , C(Z)ORi6, (CRioR20)vCORi2, SR5, SOR5, OR12, halo- substituted-Ci-4 alkyl, C1.4 ⁇ dkyl, ZC(Z)Ri2, NR ⁇ oC(Z)Ri6, or (CR ⁇ oR2 ⁇ )v Rl ⁇ R20 > and which, for other positions of substitution, is halogen, cyano, C(Z)NRi3Rl4, C(Z)OR3, (CR ⁇ oR2 ⁇ )m"COR3, S(O) m R3, OR3, halo- substituted-Ci-4 alkyl, C ⁇ .
  • R2 is hydrogen, (CRioR20)n' OR9, heterocyclyl, heterocyclylCi-io alkyl, C1 0 alkyl, halo-substituted Ci-io alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkylCi-io alkyl, C5.7 cycloalkenyl, C5.7 cycloalkenylCi-io alkyl, aryl, arylC ⁇ _ 10 alkyl, heteroaryl, heteroarylCi-io alkyl, (CRioR20)nORi 1, (CR ⁇ 0 R20)nS(O) m Ri8, (CRioR20)nNHS(O) 2 Rl8, (CRl ⁇ R2 ⁇ )nNRl3 l4, (CRioR20)nNO2, (CRioR20)nCN, (CR ⁇ oR2 ⁇ )n'
  • R a is a Ci-6 alkyl, aryl, arylCi-6 alkyl, heterocyclyl, heterocyclylCi-6 alkyl, heteroaryl, or heteroarylCi-6 alkyl moiety, and wherein each of these moieties may be optionally substituted;
  • R is hydrogen, Ci-6 alkyl, C3-7 cycloalkyl, aryl, arylCi-4 alkyl, heteroaryl, heteroarylCi-4 alkyl, heterocyclyl, or heterocyclylCi-4 alkyl;
  • R3 is heterocyclyl, heterocyclylCi-io alkyl or Kg;
  • R5 is hydrogen, -4 alkyl, C2-4 alkenyl, C2-4 alkynyl or NR7R17, excluding the moieties SR5 being SNR7R17 and SOR5 being SOH;
  • R6 is hydrogen, a pharmaceutically acceptable cation, Ci-io alkyl, C3.7 cyclo
  • RlO and R20 is each independently selected from hydrogen and C1.4 alkyl
  • Rl l is hydrogen, Ci-io alkyl, C3-7 cycloalkyl, heterocyclyl, heterocyclylCi-io alkyl, aryl, arylCl-io alkyl, heteroaryl or heteroarylCi-io alkyl;
  • Rl2 is hydrogen or Ri6,' R13 and R14 is each independently selected from hydrogen, optionally substituted Ci-4 alkyl, optionally substituted aryl and optionally substituted arylCi-4 alkyl; or together with the nitrogen to which they are attached R13 and R14 form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR9;
  • Ri5 is R ⁇ o or C(Z)-Ci-4 alkyl;
  • Rl6 is Cj-4 alkyl, halo-substituted-Ci-4 alkyl, or C3..7 cycloalkyl
  • Rl8 is Ci-io alkyl, C3-.7 cycloalkyl, heterocyclyl, aryl, arylCi-io alkyl, heterocyclyl, heterocyclylCl-10 alkyl, heteroaryl or heteroarylCi-io alkyl
  • Rl9 is hydrogen, cyano, C1.4 alkyl, C3-7 cycloalkyl or aryl; or a pharmaceutically acceptable salt thereof.
  • Ri is a substituted 4-pyridyl or 4-pyrimindyl. More suitably R ⁇ is substituted by an optionally substituted alkoxy, alkylthio, amino, methylamino, NHRa, or Y.
  • a preferred ring placement of the Ri substituent on the 4-pyridyl derivative is the 2- position, such as in 2-methoxy-4-pyridyl.
  • a preferred ring placement on the 4-pyrimidinyl ring is also at the 2-position, such as in 2-methoxy-pyrimidinyl.
  • R a is a Ci-6 alkyl, aryl, arylCi-6 alkyl, heterocyclyl, heterocyclylCi-6 alkyl, heteroaryl, or heteroarylCi-6 alkyl moiety, wherein each of these moieties may be optionally substituted.
  • R a is aryl
  • R a is preferably an optionally substituted phenyl or naphthyl.
  • R a is an arylalkyl, it is preferably an optionally substituted benzyl or naphthylmethyl.
  • the heterocyclic portion is preferably an optionally substituted ring which is pyrrolindinyl, piperidine, morpholino, tetrahydropyran, tetrahydrothiopyranyl, tetrahydrothipyran-sulfinyl, tetrahydrothio-pyransulfonyl, pyrrolindinyl, indole, or piperonyl.
  • the heterocyclic rings herein may contain unsaturation, such as in a tryptamine ring.
  • R a moieties in particular the aryl, may be optionally substituted, preferably 1 to 3 times, independently with halogen; Ci-4 alkyl, such as methyl, ethyl, propyl, isopropyl, or t-butyl; halosubstituted alkyl, such as CF3; hydroxy; hydroxy substituted Ci- 4 alkyl; Ci-4 alkoxy, such as methoxy or ethoxy; S(O) m alkyl and S(O)m aryl (wherein m is 0, 1, or 2); C(O)OR ⁇ 1, such as C(O)Ci-4 alkyl or C(O)OH moieties; C(O)R ⁇ 1;
  • OC(O)R c ; -O-(CH2)s-O-, such as in a ketal or dioxyalkylene bridge; amino; mono- and di- Ci-6 alkylsubstituted amino; N(Rio)C(O)R D ; C(O)NRioR20; cyano; nitro; or an N- heterocyclyl ring which ring has from 5 to 7 members and optionally contains an additional heteroatom selected from oxygen, sulfur or NR15; optionally substituted aryl, such as phenyl; optionally substituted arylalkyl, such as benzyl or phenethyl; optionally substituted aryloxy, such as phenoxy; or optionally substituted arylalkyloxy such as benzyloxy.
  • the aryl, arylalkyl, aryloxy, or arylalkyloxy optional substituents are as defined in the "optional substituent" definition herein.
  • R c is an optionally substituted Ci-6 alkyl, optionally substituted C3-7 cycloalkyl, optionally substituted aryl, optionally substituted arylCi-4 alkyl, optionally substituted heteroaryl, optionally substituted heteroarylCi-4 alkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylCi-4 alkyl moieties; and wherein the optional substituents are as defined in the "optional substituent" definition herein.
  • the R a groups include Ci .4 alkyl, benzyl, halosubstituted benzyl, naphthylmethyl, phenyl, halosubstituted phenyl, aminocarbonylphenyl, alkylphenyl, cyanophenyl, alkylthiophenyl, hydroxyphenyl, alkoxyphenyl, morpholinopropyl, piperonyl, piperidin-4-yl, alkyl substituted piperidine, such as 1-methylpiperidine, or 2,2,6,6-tetramethylpiperidin-4-yl.
  • R a is aryl, arylalkyl, halosubstituted arylalkyl, halosubstituted aryl, heterocyclyl alkyl, hydroxy alkyl, alkyl- 1-piperidine- carboxylate, heterocyclyl, alkyl substituted heterocyclyl, halosubstituted heterocyclyl, or aryl substituted heterocyclyl.
  • R a is benzyl, halosubstituted benzyl, naphthylmethyl, phenyl, halosubstituted phenyl, morpholinopropyl, 2-hydroxy ethyl, ethyl- 1-piperidinecarboxylate, piperonyl, piperidin-4-yl, alkyl substituted piperidine, chlorotryptamine, or tetrathiohydropyranyl.
  • R ⁇ substituent is an optionally substituted Ci-4 alkoxy or
  • Ci-4 alkylthio it is preferably a methoxy group. If the alkyl chain in these moieties is optionally substituted it is preferably substituted by halogen, such as fluorine, chlorine, bromine or iodine; hydroxy, such as hydroxyethoxy; Ci-io alkoxy, such as a methoxymethoxy, S(O)m alkyl, wherein m is 0, 1 or 2; amino, mono and di-substituted amino, such as in the NR7R17 group, i.e.
  • halogen such as fluorine, chlorine, bromine or iodine
  • hydroxy such as hydroxyethoxy
  • Ci-io alkoxy such as a methoxymethoxy, S(O)m alkyl, wherein m is 0, 1 or 2
  • amino, mono and di-substituted amino such as in the NR7R17 group, i.e.
  • R7R17 may together with the nitrogen to which they are attached cyclize to form a 5 to 7 membered ring which optionally includes an additional heteroatom selected from O/N/S; Ci-io alkyl, cycloalkyl, or cycloalkyl alkyl group, such as methyl, ethyl, propyl, isopropyl, t-butyl, etc. or cyclopropyl methyl; or halosubstituted Cj-io alkyl, such as CF3.
  • R4 is an optionally substituted phenyl.
  • the phenyl is substituted one or more times independently by halogen, SR5, S(O)R5, OR 12, halo- substituted-Ci-4 alkyl, or Ci -4 alkyl, preferably in the 4-position of the ring. More preferably R4 is a halosubstituted phenyl, more preferably in the 4-position; and most preferably by fluorine.
  • R2 is hydrogen, (CRioR20)n' OR9, heterocyclyl, heterocyclylCi-io alkyl, Ci-io alkyl, halo-substituted Ci-io alkyl, C2-10 alkenyl, C2-10 alkynyl, C3.7 cycloalkyl, C3.7 cycloalkylCi-io alkyl, C5-7 cycloalkenyl, C5.7 cycloalkenylCi-io alkyl, aryl, arylCi-io alkyl, heteroaryl, heteroarylCi -io alkyl, (CR ⁇ oR2 ⁇ )nORn, (CRioR20)nS(O) m Ri8, (CR ⁇ oR2 ⁇ )nNHS(O) 2 Rl8, (CRl ⁇ 2 ⁇ )nNRi3Rl4, (CR ⁇ 0 R20)nNO 2 , (CR ⁇ 0 R2 ⁇ )nCN, (CRioR
  • R2 is selected from hydrogen, optionally substituted Ci-io alkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylCi-io alkyl,
  • R2 is hydrogen, morpholino propyl, piperidine, N-methylpiperidine, N-benzylpiperidine, 2,2,6,6-tetramethylpiperidine, 4-aminopiperidine, 4-amino-2,2,6,6- tetramethylpiperidine, 4-hydroxycyclohexyl, 4-methyl-4-hydroxycyclohexyl, 4-pyrrolinindylcyclohexyl, 4-methyl-4-aminocyclohexyl, 4-methyl-4-acetamidocyclohexyl, 4-ketocyclohexyl, 4-oxiranyl, or 4-hydroxy-4-(l-propynyl)cyclohexyl.
  • R2 is an optionally substituted heterocyclyl ring, optionally substituted heterocyclylCi-io alkyl, optionally substituted aryl, (CRio 20)n Rl3Rl4, or (CRioR20)nC(Z)ORi 1 group.
  • R2 is an optionally substituted heterocyclyl ring, or optionally substituted heterocyclylCi-io alkyl.
  • the ring is preferably a morpholino, pyrrolidinyl, or a piperidinyl group.
  • the substituents may be directly attached to the free nitrogen, such as in the piperidinyl group or pyrrole ring, or on the ring itself.
  • the ring is a piperidine or pyrrole, more preferably piperidine.
  • the heterocyclyl ring may be optionally substituted one to four times independently by halogen; Ci-4 alkyl; aryl, such as phenyl; aryl alkyl, such as benzyl - wherein the aryl or aryl alkyl moieties themselves may be optionally substituted (as in the "optionally substituted” definition below); C(O)OR ⁇ 1, such as the C(O)Cl-4 alkyl or
  • C(O)OH moieties C(O)H; C(O)C ⁇ _4 alkyl; hydroxy substituted Ci-4 alkyl; Cj-4 alkoxy; S(O) m Ci-4 alkyl (wherein m is 0, 1, or 2); and NR10R2O (wherein Rio and R20 are independently hydrogen or C 1 _4alkyl) .
  • the ring is a piperidine
  • the ring is attached to the imidazole at the 4-position, and the substituents are directly on the available nitrogen, i.e. a l-formyl-4-piperidine, l-benzyl-4-piperidine, l-methyl-4-piperidine, or 1-ethoxycarbonyl- 4-piperidine.
  • the ring is substituted by an alkyl group and the ring is attached in the 4-position, it is preferably substituted in the 2- or 6- position or both, such as 2,2,6,6- tetramethyl-4-piperidine.
  • the ring is a pyrrole
  • the ring is attached to the imidazole at the 3-position, and the substituents are all directly on the available nitrogen.
  • R2 is an optionally substituted heterocyclylCi-io alkyl group
  • the ring is preferably a mo ⁇ holino, pyrrolidinyl, or a piperidinyl group.
  • the alkyl linking moiety is from 1 to 4, more preferably 3 or 4, and most preferably 3 carbons, such as in a propyl group.
  • Preferred heterocyclyl alkyl groups include but are not limited to, mo ⁇ holino ethyl, mo ⁇ holino propyl, pyrrolidinyl propyl, and piperidinyl propyl moieties.
  • the heterocyclic ring herein is also optionally substituted in a similar manner to that indicated above for the direct attachment of the heterocyclyl ring.
  • R2 is an optionally substituted C3.7 cycloalkyl, or an optionally substituted C3..7 cycloalkylCi-io alkyl
  • the cycloalkyl group is preferably a C4 or C6 ring, most preferably a C6 ring, which ring is optionally substituted.
  • the cycloalkyl ring may be optionally substituted one to three times independently by halogen, such as fluorine, chlorine, bromine or iodine; hydroxy; Ci-io alkoxy, such as methoxy or ethoxy; S(O) m alkyl, wherein m is 0, 1, or 2, such as methyl thio, methylsulfinyl or methyl sulfonyl; S(O) m aryl; cyano; nitro; amino; mono and di-C _ Q alkyl substituted amino, such as in the NR7R17 group, wherein R7 and R 17 are as defined in Formula (I), or where the R7R17 may cyclize together with the nitrogen to which they are attached to form a 5 to 7 membered ring which optionally includes an additional heteroatom selected from oxygen, sulfur or NR15; N(Rio)C(O)Xi, wherein Xi is C 1.4 alkyl, aryl or arylC
  • Rd is hydrogen, a pharmaceutically acceptable cation, aroyl or a Ci-io alkanoyl group.
  • R e is a 1,3-dioxyalkylene group of the formula -O-(CH2)s-O-, wherein s is 1 to 3, preferably s is 2 yielding a 1,3-dioxyethylene moiety, or ketal functionality.
  • R ⁇ ' is NRi9'R20'>' C ⁇ _6 alkyl; halosubstituted C g alkyl; hydroxy substituted C ⁇ _6 alkyl; C2-6 alkenyl; or an aryl or heteroaryl optionally substituted by halogen, C _6 alkyl, halosubstituted .g alkyl, hydroxyl, or C ⁇ g alkoxy.
  • R 9' is H or Cj.g alkyl.
  • the ring may be saturated or contain more than one unsaturated bond.
  • R6' is NRi9'R20' and Ri9' and R20' are preferably hydrogen.
  • R2 cycloalkyl moiety is substituted by a NR7R17 group, or NR7R17
  • Ci-io alkyl group, and the R7 and R17 are as defined in Formula (I), the substituent is preferably an amino, amino alkyl, or an optionally substituted pyrrolidinyl moiety.
  • a preferred ring placement on the cycloalkyl moiety is the 4-position, such as in a C ring.
  • the cycloalkyl ring is di-substituted it is preferably di-substituted at the 4 position, such as in:
  • R ⁇ ' and R ⁇ ' ⁇ e independently the optional substituents indicated above for R2.
  • R ⁇ and R ⁇ ' are hydrogen, hydroxy, alkyl, substituted alkyl, optionally substituted alkyne, aryl, arylalkyl, NR7R17, and N(R ⁇ o)C(O)R ⁇ 1.
  • the alkyl is a Ci-4 alkyl, such as methyl, ethyl, or isopropyl; NR7R17 and NR7R17 alkyl, such as amino, methylamino, aminomethyl, aminoethyl; substituted alkyl such as in cyanomethyl, cyanoethyl, nitroethyl, pyrrolidinyl; aryl such as in phenyl; arylalkyl, such as in benzyl; optionally substituted alkyne, such as ethyne or propynyl; or together R* and R2' ⁇ e a keto functionality.
  • Ci-4 alkyl such as methyl, ethyl, or isopropyl
  • NR7R17 and NR7R17 alkyl such as amino, methylamino, aminomethyl, aminoethyl
  • substituted alkyl such as in cyanomethyl, cyanoethyl, nitroethyl
  • R4 is an optionally substituted phenyl
  • R is an optionally substituted 4- pyridyl or 4-pyrimidinyl
  • R2 is an optionally substituted heterocyclyl, heterocyclyl Ci- 4 alkyl, a cycloalkyl or a cycloalkyl alkyl.
  • Rj is a 4-pyridyl or 4-pyrimidinyl subtituted by Y, NHRa, or C .4 alkoxy.
  • the unsaturated linkage i.e., the vinylene or acetylene linkage is preferably not directly attached to the nitrogen, oxygen or sulfur moieties, for instance in OR3, or for certain R2 moieties.
  • halogen such as fluorine, chlorine, bromine or iodine
  • hydroxy hydroxy substituted Ci-io alkyl
  • C ⁇ _ ⁇ o alkoxy such as methoxy or ethoxy
  • S(O)m alkyl such as methylthio, methylsulfinyl or methylsulfonyl
  • Ci-io alkyl, cycloalkyl, or cycloalkyl alkyl group such as methyl, ethyl, propyl, isopropyl, t-butyl, etc.
  • Ci-io alkyl such as CF3
  • an optionally substituted aryl such as phenyl, or an optionally substituted arylalkyl, such as benzyl or phenethyl, wherein these aryl moieties may also be substituted one to two times by halogen; hydroxy; hydroxy substituted alkyl; Ci-io alkoxy; S(O) m alkyl; amino, mono and di- Ci-io alkyl substituted amino, such as in the NR7R17 group; Ci-io alkyl; or halosubstituted alkyl, such as CF3.
  • Suitable pharmaceutically acceptable salts are well known to those skilled in the art and include basic salts of inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methane sulphonic acid, ethane sulphonic acid, acetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid.
  • pharmaceutically acceptable salts of compounds of Formula (I) may also be formed with a pharmaceutically acceptable cation, for instance, if a substituent group comprises a carboxy moiety.
  • Suitable pharmaceutically acceptable cations are well known to those skilled in the art and include alkaline, alkaline earth, ammonium and quaternary ammonium cations. The following terms, as used herein, refer to:
  • halo or halogens
  • halogens include the halogens: chloro, fluoro, bromo and iodo.
  • C _ ⁇ oal yl or "alkyl” - both straight and branched chain radicals of 1 to 10 carbon atoms, unless the chain length is otherwise limited, including, but not limited to, methyl, ethyl, n-propyl, w ⁇ -propyl, n-butyl, sec-butyl, wo-butyl, tert-butyl, n-pentyl and the like.
  • cycloalkyl is used herein to mean cyclic radicals, preferably of 3 to 8 carbons, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, and the like.
  • cycloalkenyl is used herein to mean cyclic radicals, preferably of 5 to 8 carbons, which have at least one double bond including but not limited to cyclopentenyl, cyclohexenyl, and the like.
  • alkenyl is used herein at all occurrences to mean straight or branched chain radical of 2-10 carbon atoms, unless the chain length is limited thereto, including, but not limited to ethenyl, 1-propenyl, 2-propenyl, 2-methyl-l-propenyl, 1-butenyl, 2-butenyl and the like. • "aryl” - phenyl and naphthyl;
  • heteroaryl (on its own or in any combination, such as “heteroaryloxy”, or “heteroarylalkyl”) - a 5-10 membered aromatic ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N, O or S, such as, but not limited, to pyrrole, pyrazole, furan, thiophene, quinoline, isoquinoline, quinazolinyl, pyridine, pyrimidine, oxazole, thiazole, thiadiazole, triazole, imidazole, or benzimidazole.
  • heterocyclyl (on its own or in any combination, such as “heterocyclylalkyl”) - a saturated or partially unsaturated 4-10 membered ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N, O, or S; such as, but not limited to, pyrrolidine, piperidine, piperazine, mo ⁇ holine, tetrahydropyran, or imidazolidine.
  • aralkyl or “heteroarylalkyl” or “heterocyclylalkyl” is used herein to mean Cj-4 alkyl as defined above attached to an aryl, heteroaryl or heterocyclyl moiety as also defined herein unless otherwise indicated.
  • sulfinyl - the oxide S(O) of the corresponding sulfide
  • thio refers to the sulfide
  • sulfonyl refers to the fully oxidized S(O)2 moiety.
  • alkanoyl - a C(O)C ⁇ _ ⁇ o alkyl wherein the alkyl is as defined above.
  • the compounds for use in the present invention may exist as stereoisomers, regioisomers, or diastereiomers. These compounds may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. All of these compounds are included within the scope of the present invention.
  • Specifically exemplified compounds of Formula (I) include: l-[3-(4-M ⁇ holinyl)propyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole; l-(3-Chloropropyl)-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole; l-(3-Azidopropyl)-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole; l-(3-Aminopropyl)-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole; l-(3-Methylsulfonamidopropyl)-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole; l-[3-(N-Phenylmethyl)amino
  • cytokine inhibitor compounds in particular those of Formula (I) or a pharmaceutically acceptable salt, can be used in the manufacture of a medicament for the prophylactic treatment or management of excessive, undesired or inappropriate uterine activity in a mammal, preferably a human, which activity is exacerbated or caused by excessive or unregulated cytokine production by such mammal.
  • the cytokine inhibitors of the p38/CSPB pathway are capable of inhibiting proinflammatory cytokines, such as JL-1, IL-6, IL-8 and TNF.
  • the cytokine inhibitors of the p38/CSPB pathway are administered in an amount sufficient to inhibit the cytokine, in particular IL-1, IL-6, IL-8 or TNF, production such that it is regulated down to normal levels, or in some cases to subnormal levels, so as to ameliorate or prevent the disease state.
  • Abnormal levels of IL-1, IL-6, E -8 or TNF for instance in the context of the present invention, constitute: (i) levels of free (not cell bound) IL-1, IL-6, J -8 or TNF greater than or equal to 1 picogram per ml; (ii) any cell associated IL-1, IL-6, IL-8 or TNF; or (iii) the presence of IL-1, IL-6, IL-8 or TNF mRNA above basal levels in cells or tissues in which IL-1, IL-6, IL-8 or TNF, respectively, is produced.
  • the term "inhibiting the production of IL-1 (IL-6, IL-8 or TNF)” refers to: a) a decrease of excessive in vivo levels of the cytol ⁇ ne (IL-1, EL-6, IL-8 or TNF) in a human to normal or sub-normal levels by inhibition of the in vivo release of the cytokine ⁇ by all cells, including but not limited to monocytes or macrophages; b) a down regulation, at the genomic level, of excessive in vivo levels of the cytokine (EL-1, IL-6, IL-8 or TNF) in a human to normal or sub-normal levels; c) a down regulation, by inhibition of the direct synthesis of the cytokine (IL-1, IL-6, IL-8 or TNF) as a postranslational event; or d) a down regulation, at the translational level, of excessive in vivo levels of the cytokine (IL-1, E -6, IL-8 or TNF)
  • cytokine refers to any secreted polypeptide that affects the functions of cells and is a molecule which modulates interactions between cells in the immune, inflammatory or hematopoietic response.
  • a cytokine includes, but is not limited to, monokines and lymphokines, regardless of which cells produce them.
  • a monokine is generally referred to as being produced and secreted by a mononuclear cell, such as a macrophage and/or monocyte.
  • Lymphokines are generally referred to as being produced by lymphocyte cells.
  • cytokines include, but are not limited to, Interleukin-1 (IL-1), Interleukin-6 (IL-6), Interleukin-8 (IL-8), Tumor Necrosis Factor-alpha (TNF- ⁇ ) and Tumor Necrosis Factor beta (TNF- ⁇ ).
  • cytokine interfering or "cytokine suppressive amount” refers to an effective amount of a compound of Formula (I) which will cause a decrease in the in vivo levels of the cytokine to normal or sub-normal levels, when given to a patient for the prophylaxis or treatment of a disease state which is exacerbated by, or caused by, excessive or unregulated cytokine production.
  • CSBP MAP kinase family
  • RK The MAP kinase family
  • CSBP MAP kinase family
  • Activation of this novel protein kinase via dual phosphorylation has been observed in different cell systems upon stimulation by a wide spectrum of stimuli, such as physiochemical stress and treatment with lipopolysaccharide or proinflammatory cytokines such as IL-1 and TNF.
  • the cytokine biosynthesis inhibitors for use in the present invention for instance compounds of Formula (I), have been determined to be potent and selective inhibitors of this CSBP/p38/RK kinase activity. These inhibitors are of aid in determining the signaling pathways involvement in inflammatory responses.
  • a definitive signal transduction pathway can be prescribed to the action of lipopolysaccharide in cytokine production in macrophages.
  • the CSBP protein is described in detail in Patent Application USSN 08/123175 Lee et al., filed September 1993; Lee et al., PCT/US94/10529 filed 16 September 1994; USSN 08/605002, filed 15 April 1996; USSN 08/469421, USSN 08/468902; and Lee et al., Nature 300, n(72), 739-746 ' (Dec. 1994).
  • Inhibitors of the variants and homologs of the CSBP protein are also considered as another aspect of the present invention.
  • Intracellular signal transduction is the means by which cells respond to extracellular stimuli. Regardless of the nature of the cell surface receptor (e.g. protein tyrosine kinase or seven-transmembrane G-protein coupled), protein kinases and phosphatases along with phopholipases are the essential machinery by which the signal is further transmitted within the cell [Marshall, J. C. CeU , 80, 179-278 (1995)].
  • protein kinases and phosphatases along with phopholipases are the essential machinery by which the signal is further transmitted within the cell [Marshall, J. C. CeU , 80, 179-278 (1995)].
  • Protein kinases can be categorized into five classes with the two major classes being, tyrosine kinases and serine / threonine kinases depending upon whether the enzyme phosphorylates its substrate(s) on specific tyrosine(s) or serine / threonine(s) residues [Hunter, T., Methods in Enzymology (Protein Kinase Classification) p. 3, Hunter, T.; Sefton, B. M.; eds. vol. 200, Academic Press; San Diego, 1991].
  • kinases For most biological responses, multiple intracellular kinases are involved and an individual kinase can be involved in more than one signaling event. These kinases are often cytosolic and can translocate to the nucleus or the ribosomes where they can affect transcriptional and translational events, respectively. The involvement of kinases in transcriptional control is presently much better understood than their effect on translation as illustrated by the studies on growth factor induced signal transduction involving MAP/ERK kinase [Marshall, C. J. Cell , 80, 179 (1995); Herskowitz, I. Cell, 80, 187 (1995); Hunter, T. Cell , 80, 225 (1995); Seger, R., and Krebs, E. G. FASEB J., 726-735 (1995)].
  • cytokines e.g., JL-1 and TNF
  • mediators of inflammation e.g., COX-2, and iNOS
  • LPS bacterial lippopolysaccharide
  • p38 identified murine p38 as a kinase which is tyrosine phosphorylated in response to LPS.
  • Definitive proof of the involvement of the p38 kinase in LPS-stimulated signal transduction pathway leading to the initiation of proinflammatory cytokine biosynthesis was provided by the independent discovery of p38 kinase by Lee [Lee; et al., Nature. 372, 739(1994)] as the molecular target for a novel class of anti- inflammatory agents.
  • the discovery of p38 (termed by Lee as CSBP 1 and 2) provided a mechanism of action of a class of anti-inflammatory compounds for which SK&F 86002 was the prototypic example.
  • CSBP/p38 is a one of several kinases involved in a stress-response signal transduction pathway which is parallel to and largely independent of the analogous mitogen-activated protein kinase (MAP) kinase cascade ( Figure 1).
  • Stress signals including LPS, pro-inflammatory cytokines, oxidants, UV light and osmotic stress, activate kinases upstream from CSBP/p38 which in turn phosphorylate CSBP/p38 at threonine 180 and tyrosine 182 resulting in CSBP/p38 activation.
  • MAPKAP kinase-2 and MAPKAP kinase-3 have been identified as downstream substrates of CSBP/p38 which in turn phosphorylate heat shock protein Hsp 27 ( Figure 2). It is not yet known whether MAPKAP-2, MAPKAP-3, Mnkl or Mnk2 are involved in cytokine biosynthesis or alternatively that inhibitors of CSBP/p38 kinase might regulate cytokine biosynthesis by blocking a yet unidentified substrate downstream from CSBP/p38 [Cohen, P. Trends Cell Biol.. 353-361(1997)].
  • CSBP/p38 kinase inhibitors (SK&F 86002 and SB 203580) also decrease the synthesis of a wide variety of pro-inflammatory proteins including, IL-6, IL-8, GM-CSF and COX-2.
  • Inhibitors of CSBP/p38 kinase have also been shown to suppress the TNF- induced expression of VCAM-1 on endothelial cells, the TNF-induced phosphorylation and activation of cytosolic PLA2 and the IL-1 -stimulated synthesis of collagenase and stromelysin.
  • cytokine biosynthesis inhibitors for use in the present invention will normally be formulated into a pharmaceutical composition in accordance with standard pharmaceutical practice, for example they will be formulated with a pharmaceutically acceptable diluent or carrier.
  • Cytokine biosynthesis inhibitors, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions inco ⁇ orating such may conveniently be administered by any of the routes conventionally used for drug administration, for instance, orally, topically, parenterally or by inhalation.
  • the cytokine biosynthesis inhibitors may be administered in conventional dosage forms prepared by combining a cytokine biosynthesis inhibitor with standard pharmaceutical carriers according to conventional procedures. Cytokine biosynthesis inhibitors may also be administered in conventional dosages in combination with a known, second therapeutically active compound.
  • the pharmaceutical carrier employed may be, for example, either a solid or liquid.
  • solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like.
  • liquid carriers are syrup, peanut oil, olive oil, water and the like.
  • the carrier or diluent may include time delay material well known to the art, such as glyceryl mono-stearate or glyceryl distearate alone or with a wax.
  • the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge.
  • the amount of solid carrier will vary widely but preferably will be from about 25mg to about lg.
  • the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampule or nonaqueous liquid suspension.
  • the cytokine biosynthesis inhibitors may be administered topically, that is by non- systemic administration. This includes the application of an inhibitor externally to the epidermis or the buccal cavity and the instillation of such a compound into the ear, eye and nose, such that the compound does not significantly enter the blood stream.
  • systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.
  • Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation such as liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose.
  • the active ingredient may comprise, for topical administration, from 0.001% to 10% w/w, for instance from 1% to 2% by weight of the formulation. It may however comprise as much as 10% w/w but preferably will comprise less than 5% w/w, more preferably from 0.1% to 1% w/w of the formulation.
  • Lotions according to the present invention include those suitable for application to the skin or eye.
  • An eye lotion may comprise a sterile aqueous solution optionally containing a bactericide and may be prepared by methods similar to those for the preparation of drops.
  • Lotions or liniments for application to the skin may also include an agent to hasten drying and to cool the skin, such as an alcohol or acetone, and/or a moisturizer such as glycerol or an oil such as castor oil or arachis oil.
  • Creams, ointments or pastes according to the present invention are semi-solid formulations of the active ingredient for external application.
  • the base may comprise hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap; a mucilage; an oil of natural origin such as almond, corn, arachis, castor or olive oil; wool fat or its derivatives or a fatty acid such as steric or oleic acid together with an alcohol such as propylene glycol or a macrogel.
  • hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap
  • a mucilage an oil of natural origin such as almond, corn, arachis, castor or olive oil
  • wool fat or its derivatives or a fatty acid such as steric or oleic acid together with an alcohol such as propylene glycol or a macrogel.
  • the formulation may inco ⁇ orate any suitable surface active agent such as an anionic, cationic or non-ionic surfactant such as a sorbitan ester or a polyoxyethylene derivative thereof.
  • suitable surface active agent such as an anionic, cationic or non-ionic surfactant such as a sorbitan ester or a polyoxyethylene derivative thereof.
  • Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as silicaceous silicas, and other ingredients such as lanolin, may also be included.
  • Drops according to the present invention may comprise sterile aqueous or oily solutions or suspensions and may be prepared by dissolving the active ingredient in a suitable aqueous solution of a bactericidal and/or fungicidal agent and/or any other suitable preservative, and preferably include a surface active agent.
  • the resulting solution may then be clarified by filtration, transferred to a suitable container which is then sealed and sterilized by autoclaving or maintaining at 98-100°C for half an hour.
  • the solution may be sterilized by filtration and transferred to the container by an aseptic technique.
  • bactericidal and fungicidal agents suitable for inclusion in the drops are phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%).
  • Suitable solvents for the preparation of an oily solution include glycerol, diluted alcohol and propylene glycol.
  • the cytokine biosynthesis inhibitors may be administered parenterally, that is by intravenous, intramuscular, subcutaneous intranasal, intrarectal, intravaginal or intraperitoneal administration.
  • the subcutaneous and intramuscular forms of parenteral administration are generally preferred.
  • Appropriate dosage forms for such administration may be prepared by conventional techniques.
  • the cytokine biosynthesis inhibitors may also be administered by inhalation, that is by intranasal and oral inhalation administration.
  • Appropriate dosage forms for such administration such as an aerosol formulation or a metered dose inhaler, may be prepared by conventional techniques.
  • the preferred, dosage regimen would be parenteral until contractions cease, and then as long as necessary to optimise fetal well-being prior to delivery, i.e. as near to term (37 weeks gestation) as is necessary.
  • daily parenteral dosage regimen will be from about 0.1 to about 80 mg/kg of total body weight, preferably from about 0.2 to about 30 mg/kg, and more preferably from about 0.5 mg to 15mg/kg.
  • the daily oral dosage regimen will preferably be from about 0.1 to about 80 mg/kg of total body weight, preferably from about 0.2 to 30 mg/kg, more preferably from about 0.5 mg to 15mg.
  • the daily topical dosage regimen such as may be applied to prevent cervical ripening, could be administered topically to the cervix to prevent cervical softening and delay fetal membrane rupture.
  • Such as topical dosage will preferably be in a formulation containing from 0.1 mg to 150 mg, administered one to four, preferably two or three times daily.
  • the daily inhalation dosage regimen if applicable, will preferably be from about 0.01 mg/kg to about 1 mg/kg per day.
  • the optimal quantity and spacing of individual dosages of cytokine biosynthesis inhibitor will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular patient being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e., the number of doses given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests.
  • cytokine-inhibiting effects of compounds for use in the present invention may be determined by the following in vitro assays: Assays for Interleukin- 1 (IL-1), Interleukin-8 (IL-8 ), and Tumour Necrosis
  • TNF Tumorin Factor
  • Interleukin - 1 (IL-1)
  • Human peripheral blood monocytes are isolated and purified from either fresh blood preparations from volunteer donors, or from blood bank buffy coats, according to the procedure of Colotta et al, J Immunol, 132, 936 (1984). These monocytes (1x10 ⁇ ) ⁇ e plated in 24- well plates at a concentration of 1-2 million/ml per well. The cells are allowed to adhere for 2 hours, after which time non-adherent cells are removed by gentle washing. Test compounds are then added to the cells for lh before the addition of lipopolysaccharide (50 ng/ml), and the cultures are incubated at 37°C for an additional 24h. At the end of this period, culture supernatants are removed and clarified of cells and all debris.
  • Culture supernatants are then immediately assayed for LL-1 biological activity, either by the method of Simon et a , J. Immunol. Methods, 84, 85, (1985) (based on ability of IL-1 to stimulate a Interleukin 2 producing cell line (EL-4) to secrete IL-2, in concert with A23187 ionophore) or the method of Lee et al, J. ImmunoTherapy, 6 (1), 1-12 (1990) (ELISA assay).
  • mice and rats are injected with LPS.
  • mice Male Balb/c mice from Charles River Laboratories are pretreated (30 minutes) with compound or vehicle. After the 30 min. pretreat time, the mice are given LPS (lipopolysaccharide from Esherichia coli Serotype 055-85, Sigma
  • mice 25 ug/mouse in 25 ul phosphate buffered saline (pH 7.0) intraperitoneally. Two hours later the mice are killed by CO2 inhalation and blood samples are collected by exsanguination into heparinized blood collection tubes and stored on ice. The blood samples are centrifuged and the plasma collected and stored at -20°C until assayed for TNF ⁇ by ELISA.
  • mice Male Lewis rats from Charles River Laboratories are pretreated at various times with compound or vehicle. After a determined pretreat time, the rats are given LPS (lipopolysaccharide from Esherichia coli Serotype 055-85, Sigma Chemical Co., St Louis, MO) 3.0 mg/kg intraperitoneally. The rats are killed by CO2 inhalation and heparinized whole blood is collected from each rat by cardiac puncture 90 minutes after the LPS injection. The blood samples are centrifuged and the plasma collected for analysis by ELISA for TNF ⁇ levels.
  • LPS lipopolysaccharide from Esherichia coli Serotype 055-85, Sigma Chemical Co., St Louis, MO
  • TNF ⁇ levels were measured using a sandwich ELISA, as described in Olivera et al., Circ. Shock, 37, 301-306, (1992), whose disclosure is inco ⁇ orated by reference in its entirety herein, using a hamster monoclonal antimurine TNF ⁇ (Genzyme, Boston, MA) as the capture antibody and a polyclonal rabbit antimurine TNFa (Genzyme) as the second antibody.
  • a peroxidase-conjugated goat antirabbit antibody Pierce, Rockford, EL
  • was added followed by a substrate for peroxidase (1 mg/ml orthophenylenediamine with 1% urea peroxide).
  • TNF ⁇ levels in the plasma samples from each animal were calculated from a standard curve generated with recombinant murine TNF ⁇ (Genzyme).
  • Test compound concentrations were prepared at 10 X concentrations and LPS prepared at 1 ug/ml (final cone, of 50 ng/ml LPS) and added in 50 uL volumes to 1.5 mL eppendorf tubes. Heparinized human whole blood was obtained from healthy volunteers and was dispensed into eppendorf tubes containing compounds and LPS in 0.4 mL volumes and the tubes incubated at 37 C. Following a 4 hour incubation, the tubes were centrifuged at 5000 rpm for 5 minutes in a TOMY microfuge, plasma was withdrawn and frozen at -80 C.
  • Cytokine measurement IL-I and/or TNF were quantified using a standardized ELISA technology. An in-house ELISA kit was used to detect human IL-1 and TNF. Concentrations of IL- 1 or TNF were determined from standard curves of the appropriate cytokine and IC50 values for test compound (concentration that inhibited 50% of LPS -stimulated cytokine production) were calculated by linear regression analysis.
  • a radiocompetitive binding assay was developed to provide a highly reproducible primary screen for structure-activity studies. This assay provides many advantages over the conventional bioassays which utilize freshly isolated human monocytes as a source of cytokines and ELISA assays to quantify them. Besides being a much more facile assay, the binding assay has been extensively validated to highly correlate with the results of the bioassay.
  • a specific and reproducible cytokine inhibitor binding assay was developed using soluble cystosolic fraction from THP.1 cells and a radiolabeled compound.
  • CSBP cytokine specific binding protein
  • the binding protein may be in isolated form in solution, or in immobilized form, or may be genetically engineered to be expressed on the surface of recombinant host cells such as in phage display system or as fusion proteins.
  • whole cells or cytosolic fractions comprising the CSBP may be employed in the screening protocol.
  • a plurality of compounds are contacted with the binding protein under conditions sufficient to form a compound/ binding protein complex and compound capable of forming, enhancing or interfering with said complexes are detected.
  • This assay measures the CSBP/p38-catalyzed transfer of 32p f ro m [a- 32p]ATP to threonine residue in an epidermal growth factor receptor (EGFR)-derived peptide (T669) with the following sequence: KRELVEPL7PSGEAPNQALLR (residues 661-681).
  • EGFR epidermal growth factor receptor
  • KRELVEPL7PSGEAPNQALLR residues 661-681.
  • Reactions were carried in round bottom 96 well plate (from Corning) in a 30 ml volume. Reactions contained (in final concentration): 25 mM Hepes, pH7.5; 8 mM MgCl2i 0.17 mM ATP (the KmrATP] of P 38 (see Lee et al., Nature 300, n72 pg 639-746 (Dec. 1994)); 2.5 uCi of [g-32P]ATP; 0.2 mM sodium orthovanadate; 1 mM DTT; 0.1% BSA; 10% glycerol; 0.67 mM T669 peptide; and 2-4 nM of yeast- expressed, activated and purified p38.
  • Reactions were initiated by the addition of [gamma-32P]Mg/ATP, and incubated for 25 min. at 37 °C. Inhibitors (dissolved in DMSO) were incubated with the reaction mixture on ice for 30 minutes prior to adding the 32P-ATP. Final DMSO concentration was 0.16%. Reactions were terminated by adding 10 ul of 0.3 M phosphoric acid, and phosphorylated peptide was isolated from the reactions by capturing it on p81 phosphocellulose filters. Filters were washed with 75 mM phosphoric acids, and inco ⁇ orated 32P was quantified using beta scintillation counter.
  • the specific activity of p38 was 400-450 pmol/pmol enzyme, and the activity was linear for up to 2 hr of incubation.
  • the kinase activity values were obtained after subtracting values generated in the absence of substrate which were 10-15% of total values.
  • Fetal membranes were obtained from term elective caesarean sections from uncomplicated pregnancies and washed in phosphate buffered saline containing 10% penicillin, streptomycin and L-glutamine. Whole membrane discs consisting of adherent amnion and chorio-decidua each measuring 1.5 cm were then cut and incubated overnight in multiwell tissue culture plates at 37°C, 95% air, 5% CO 2 in serum free medium 199 (Sigma) supplemented with insulin, transferrin and selenium. Following the addition of fresh medium 199 four experimental groups (A to D) were set up. Each experimental group consisted of identical triplicate tissue culture wells.
  • LPS (Sigma-E.coli Serotype 0114:B4) was used at a concentration of 10 8 g/dl.
  • SKF 86002 was dissolved in ethanol to provide a final concentration of 10 ⁇ M.
  • Group A consisted of control discs incubated in medium alone. Incubations were carried out for four, eight and twelve hours following which the supernatants were harvested and stored at -20°C for subsequent estimation of IL- l ⁇ and PGE 2 levels by ELISA ⁇ enzyme linked immunosorbent assay (Amersham) ⁇ .
  • Control wells consisting of ethanol and medium 199 with and without LPS were also included. Fetal membrance viability was assessed using the diaphorase histochemical method, see Aldred L.F., et al. (1983) J. Steroid Biochem., 18, 411-414.
  • IL-l ⁇ production Mixed model analysis of variance was used to analyse the data. The assumptions of the analysis of variance were checked and a log transformation was found to be the most appropriate. Data is presented on an untransformed original scale for ease of inte ⁇ retation.
  • Tissue viability was not compromised by the addition of the drug as tested by the diaphorase method. Ethanol alone did not significantly inhibit production of either PGE 2 or IL-l ⁇ from the fetal membranes.
  • CSAIDTM compounds have utility to modulate prostaglandin and interleukin production from gestational tissues.
  • the compound decreased basal PGE 2 and IL-l ⁇ production as well as production in response to LPS, this provides a basis for treatment of both infection driven and idiopathic pre-term labour.

Abstract

The present invention is to the novel use of a cytokine inhibitor for the prophylactic treatment, or management of excessive, undesired or inappropriate uterine activity, such as contractions, in a mammal in need thereof.

Description

Use of CSAID™ Compounds for the Management of Uterine Contractions
FIELD OF THE INVENTION
The present invention relates to the treatment of inappropriate, excessive or undesirable uterine contractions, in a mammal.
BACKGROUND OF THE INVENTION
Preterm labour is of major concern to both obstetricians and neonatologists. It affects approximately 10% of pregnancies and results in 30% of long term neonatal handicap and 85% of perinatal deaths. The pathogenesis of preterm labour is incompletely understood at present, it is therefore difficult to both predict and treat effectively. The underlying biochemical pathways involved in the initiation of parturition have not yet been fully elucidated. There are clear links between inflammatory processes and activation of the immune system in the maternal decidua. Prostaglandins, which have a well documented role in the initiation of labour, (Mitchell, MD., (1984) Journal of Developmental Physiology, 6, 107-118) and the inflammatory cytokines (Mitchell, MD., et al. (1993) Clinical Obs. and Gynaecol, 3, 553-575) have therefore both been implicated in the pathogenesis of labour. Interleukin- 1 β (IL-lβ) has been demonstrated to be the pivotal cytokine in the biochemical pathway leading to labour (Mitchell, MD., et al.(1993), supra). It has been shown to directly stimulate the production of prostaglandins which are the terminal products of the inflammatory response and direct initiators of labour (Romero, R., et al. (1992) Am. J. Reprod. Immunol, 33, 117-123; and Kent A.S.H., et al. (1993) Prostaglandins 46, 51-59). Levels of IL-lβ have been shown to rise following stimulation with bacterial endotoxin (Romero, R., et al. (1989) Am. J. Obstet and Gynaecol, 160, 1117) which implies a mediating role for this cytokine in the induction of labour in the presence of infection.
The production of prostaglandins is under the influence of two enzymes, phospholipase A2 and cyclo-oxygenase (COX) alternatively known as prostaglandin H synthase. COX has been found to be present in two forms; type-1 COX is the constitutive form of the enzyme present in all tissues. Type-2 COX is the inducible form of the enzyme that has been shown to be up-regulated near term (Macchia L., et al. (1997) Biochemical and Biophysical Research Communications, 233, 496-501). IL-lβ is able to increase the production of COX-2 in amnion (Trautman M.S., et al. (1996) Placenta, 17, 239-245).
By modulating the production of prostaglandin E2 (PGE2) the contractile activity of the uterus may be controlled. Tocolytic agents that completely suppress contractions are not yet available. There has been very little recent progress in the therapeutic modalities available to treat preterm labour. Currently a therapeutic cocktail consisting of betasypatho imetics, Non- Steroidal Anti-inflammatory Drugs (NSAID's), and oxytocin antagonists is used to try and suppress unwanted uterine activity.
The therapeutic cocktail does not fully address the management of preterm labor in patients, therefore a need still exists to find suitable small molecule inhibitors which will help modulate the contactile activity of the uterus in a mammal in need thereof.
SUMMARY OF THE INVENTION
The present invention is to the novel use of a cytokine inhibitor for the prophylatic treatment or management of excessive, undesired or inappropriate uterine activity in a mammal, which method comprises administering to said mammal an effective amount of a compound which inhibits the production, transcription or translation of a cytokine. Preferably, the cytokine is inhibited by inhibition of the kinase CSBP/p38/RK.
The preferred compounds for use as cytokine inhibitors are those compounds of Formula (I) as noted herein. The preferred method of inhibition is the inhibition of the CSBP/p38 RK kinase pathway.
DETAILED DESCRIPTION OF THE INVENTION
The current application teaches the novel finding that CSAID™ compounds, i.e. compounds that block cytokine production, can be a therapeuticially effective agent in modulating uterine contractile activity. Such modulation will help treat preterm labour in patients in need thereof.
The present invention is to the novel use of a cytokine inhibitor, in particular that of cytokine CSBP/p38, for the prophylactic treatment or management of excessive, undesired or inappropriate uterine activity in a mammal.
As noted above, by modulating the production of prostaglandin E2 (PGE2) the contractile activity of the uterus may be controlled. Tocolytic agents that completely suppress contractions are not yet available and there has been very little recent progress in the therapeutic modalities available to treat preterm labour. The current treatment for preterm labour is a therapeutic cocktail consisting of betasypathomimetics, Non-Steroidal Anti-inflammatory Drugs (NSAID's), and oxytocin antagonists. This cocktail is used to try and suppress unwanted uterine activity.
PGE2 production by fetal membranes has been shown to be inhibited by the use of NSAID's. The efficacy in controlling uterine activity is however dependent on the specificity of the agent used and the treatments are not without their side-effects. It has now been found that small molecule inhibitors which act on cytokine synthesis may also have a similar inhibitory effect on the production PGE2 by inhibiting cytokine driven prostaglandin production and could therefore be useful in the treatment and prevention of preterm labour. Therefore, another aspect of the present invention is the use of cytokine inhibitors of the p38/CSPB RK pathway in the treatment of both preterm and term labour.
As will be demonstrated herein in the Example section, the CSAID™ compound SKF86002 has effectively been used to modulate prostaglandin and interleukin production from gestational tissues. The compound SKF 86002 has previously been shown to decrease the production of IL-lβ from lipopolysaccharide (LPS) stimulated isolated human macrophages (Perregaux D. G., et al. (1995) Molecular pharmacology, 48, 433-442) and the production of prostaglandin H synthase from rat basophilic leukaemic cells (Griswold D.E., et al. (1987) Biochemical Pharmacology, 36, 3463-3470).
The term "inappropriate uterine activity "as used herein includes, but is not limited to, diseases which are characterized by the presence of unwanted or excessive uterine activity prior to the completion of normal gestational period in a mammal. In the case of a human, for instance, this would be approximately a 40 week gestation.
The term "excessive or increased uterine activity" as used herein is characterized by the presence of abnormal uterine action during labour. Abnormal uterine action during labour is characterized by the excessive frequency, amplitude or duration of uterine contractions. The term "pre-term labour" as used herein refers to the onset of labour before 37 weeks gestation. However, it is recognized that pre-term labour is a complex syndrome due to many aetiological factors. See for instance, Romero, et al., Ann NY Acad. Sci., 734, page 414 (1994).
Labour and pre-term labour are characterized by the presence of 1) sustained uterine contractions; 2) dilatation of the cervix; and 3) rupture of the fetal membranes
All three components of labour are mediated in part by the action of inflammatory cytokines, consequently use of a CSBP inhibitor would be of use in all these areas.
In particular, dilatation, or ripening of the cervix is affected by the reorganization of collagen bundles in the cervix. This is believed to be under the control of the enzyme collagenase, produced by neutrophils (Osmers, et al., American Journal of Obstetrics & Gynecology, 166, pp 1455-1460 (1992)). Neutrophils migrate into the cervix from the surrounding tissues under the influence of chemotactic inflammatory cytokines such as IL-8. They are then stimulated by IL-8 to release collagenase which breaks down the collagen bundles in the cervix. IL-8 has also been shown to soften the cervix after topical application. See, Chwalisz, et al., Human Reproduction, 9, pp 2173-2181 (1994); and El Maradny et al., American Journal of Obstetrics & Gynecology, 171, pp 77-83 (1994). Therefore, use of a CSBP inhibitor should inhibit unwanted cervical ripening in a mammal.
In preterm rupture of the fetal membrane (PROM) there is significant evidence which implicates infection and inflammation in the pathogenesis of fetal membrane rupture (French et al., Seminars in Perinatology, 20 pp 344-368 (1996)). Proteases produced in response to infection have been shown to be involved in a reduction in fetal membrane tensile strength (McGregor, et al., Obstet and Gynceol, 69, pp 167-174 (1987)). These proteases are under the influence of inflammatory cytokines such as IL-lα and IL-lβ, and TNF-α (Woessner, J. FASEB J, 5, pp 2145-2154 (1991). An inhibitor of these cytokines, such as CSAID™ inhibitor, would therefore be able to prevent the unwanted rupture of the fetal membranes by preventing the release of inflammatory cytokines which stimulate the release of proteases, etc., which in turn destroy the integrity of the fetal membranes.
Eclampsia and pre-eclampsia are thought to result from the defective penetration of maternal blood vessels (the spiral arteries) into the trophoblast. Inflammatory cytokines are important in mediating this process. Many studies have implicated a variety of cytokine in the pathogenesis of pre-eclampsia. IL-4 has been shown to be elevated in the sera of pre-eclamptic women (Omu-Ae et al., Nutrition, l l(5Suppl), pp 688-91 (1995 -Sep-Oct). Thus, pre-eclampsia/ intrauterine dystrophy is characterized by reduction of some cytokines within the amniotic fluid compartment and concomitant reactive augmentations of other cytokines within the maternal and fetal organism. Stallmach et al., Reprod- Fertil-Dev. 1995; 7(6): 1573-80 (1995). IL-6 levels have also been shown to be increased in pre-eclamptic patients (Greer et al., Obstet-Gynecol., 84(6) (1994). A CSAID™ inhibitor, may therefore favourably modify the cytokine profile in pre-eclamptic and eclamptic patients by decreasing the severity of the disease.
Other cytokine inhibitory compounds for use in the present invention include, but are not limited to, those described in USSN 08/091,491, published as WO95/02575; WO95/02591; US 5,593,992; US 5,663,334; US 5,670,527; WO96/21452; WO96/21654; US 5,658,903 and WO96/40143; US 5,739,143; WO96/21654; WO93/14081; US Patent 5,656,644; USSN 08/095,234; US 5,686,455; US 5,559,137; US 5,656,644 and WO95/03297; USSN 08/481,671; WO97/25048; WO97/25047; US 5,756,499 and WO97/25045; US 5,716,955 and WO97/25046; WO97/33883; WO92/10190; WO92/10498; WO98/06715; WO93/14082; WO95/13067; WO95/31451; WO 98/07425; PCT/US98/12387; WO97/05877; PCT/US98/12828; PCT/US98/13808; PCT/US97/23638; USSN 60/068,178; USSN 60/061351; WO92/12154; EP 0531901; US 5,670,503 and WO94/19350; WO97/05878; WO97/05877; WO97/05878; WO97/16441; WO97/16426; WO97/12876; US 5,717,100; WO97/45412; WO97/36587; and WO97/ 16442. Each of these references are incorporated by reference herein in their entirety.
Preferred compounds for use as cytokine inhibitors are those compounds of Formula (I) as noted herein. Synthetic chemistry and methods of pharmaceutical formulations thereof are also contained within each noted patent application. A description of the assay for inhibition of the cytokine specific binding protein (CSBP) is also found in WO95/07922, whose disclosure is incorporated by reference in its entirety.
A preferred group of compounds for use herein are those compounds of the formula (I):
Figure imgf000007_0001
wherein:
Rl is a pyrid-4-yl, pyrimidin-4-yl, pyridazin-4-yl, l,2,4-triazin-5-yl, quinol-4-yl, isoquinolinyl, quinazolin-4-yl, 1-imidazolyl or 1-benzimidazolyl ring, which ring is optionally substituted independently one to three times with Y, NHRa, optionally substituted Ci-4 alkyl, halogen, hydroxyl, optionally substituted Ci-4 alkoxy, optionally substituted Cι_4 alkylthio, Ci-4 alkylsulfinyl, CH2OR12, amino, mono and di- Ci-6 alkyl substituted amino, or N(Rιo)C(O)RD;
Y is O-Ra;
R4 is phenyl, naphth-1-yl or naphth-2-yl, or heteroaryl, which is optionally substituted by one or two substituents, each of which is independently selected, and which, for a
4-phenyl, 4-naphth-l-yl, 5-naphth-2-yl or 6-naphth-2-yl substituent, is halogen, cyano, nitro, C(Z)NR7Rπ, C(Z)ORi6, (CRioR20)vCORi2, SR5, SOR5, OR12, halo- substituted-Ci-4 alkyl, C1.4 ∑dkyl, ZC(Z)Ri2, NRιoC(Z)Ri6, or (CRιoR2θ)v RlθR20> and which, for other positions of substitution, is halogen, cyano, C(Z)NRi3Rl4, C(Z)OR3, (CRιoR2θ)m"COR3, S(O)mR3, OR3, halo- substituted-Ci-4 alkyl, C\. alkyl, (CRιoR2θ)m"NRlθC(Z)R3, NRιoS(O)m'R8, NRιoS(O)m'NR7Rl7, ZC(Z)R3 or (CRioR20)m"NRl3Rl4; v is 0, or an integer having a value of 1 or 2; n is an integer having a value of 1 to 10; n' is 0, or an integer having a value of 1 to 10; m is 0, or an integer having a value of 1 or 2; m' is an integer having a value of 1 or 2, m" is 0, or an integer having a value of 1 to 5;
R2 is hydrogen, (CRioR20)n' OR9, heterocyclyl, heterocyclylCi-io alkyl, C1 0 alkyl, halo-substituted Ci-io alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkylCi-io alkyl, C5.7 cycloalkenyl, C5.7 cycloalkenylCi-io alkyl, aryl, arylCι_ 10 alkyl, heteroaryl, heteroarylCi-io alkyl, (CRioR20)nORi 1, (CRι0R20)nS(O)mRi8, (CRioR20)nNHS(O)2Rl8, (CRlθR2θ)nNRl3 l4, (CRioR20)nNO2, (CRioR20)nCN, (CRιoR2θ)n'SO2Rl8, (CRιoR2θ)nS(O)m'NRi3Rl4, (CRι0R20)nC(Z)Rn, (CRι0R20)nOC(Z)Rι 1,
(CRioR20)nC(Z)ORi 1, (CRι0R20)nC(Z)NRι3Rl4, (CRι0R20)nC(Z)NRι 1OR9, (CRι0R20)nNRi0C(Z)Rι 1, (CRioR20)nNRioC(Z)NRi3Rl4, (CRιoR2θ)nN(OR6)C(Z)NRι3Rl4, (CRι0R20)nN(OR6)C(Z)Rι i, (CRioR20)nC(=NOR6)Rl 1, (CRι0R2θ)nNRiθC(=NRι9)NRι3Rl4, (CRioR20)nOC(Z)NRi3Rl4, (CRi0R2θ)nNRlθC(Z)NRι3Rl4,
(CRιoR2θ)nNRlθC(Z)ORio, 5-(Rι8)-l,2,4-oxadizaol-3-yl or 4-(R12)-5-(Rι8R19)-4,5- dihydro-l,2,4-oxadiazol-3-yl; wherein the aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaryl alkyl, heterocyclyl and heterocyclyl alkyl groups may be optionally substituted; Z is oxygen or sulfur;
Ra is a Ci-6 alkyl, aryl, arylCi-6 alkyl, heterocyclyl, heterocyclylCi-6 alkyl, heteroaryl, or heteroarylCi-6 alkyl moiety, and wherein each of these moieties may be optionally substituted; R is hydrogen, Ci-6 alkyl, C3-7 cycloalkyl, aryl, arylCi-4 alkyl, heteroaryl, heteroarylCi-4 alkyl, heterocyclyl, or heterocyclylCi-4 alkyl; R3 is heterocyclyl, heterocyclylCi-io alkyl or Kg; R5 is hydrogen, -4 alkyl, C2-4 alkenyl, C2-4 alkynyl or NR7R17, excluding the moieties SR5 being SNR7R17 and SOR5 being SOH; R6 is hydrogen, a pharmaceutically acceptable cation, Ci-io alkyl, C3.7 cycloalkyl, aryl, arylCi-4 alkyl, heteroaryl, heteroarylCi-4 alkyl, heterocyclyl, aroyl, or Ci-io alkanoyl; R7 and R17 is each independently selected from hydrogen or Ci-4 alkyl or R7 and R17 together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR15; R8 is a Ci-io alkyl, halo-substituted Ci-io alkyl, C2-10 alkenyl, C2-10 alkynyl, C3.7 cycloalkyl, C5-7 cycloalkenyl, aryl, arylCi-io alkyl, heteroaryl, heteroarylCi-io alkyl,
(CRl0R20)nORl l, (CRlθR2θ)nS(O)mRi8, (CRioR20)nNHS(O)2Rl8, or (CRioR20)n Rl3Rl4 moiety; wherein the aryl, arylalkyl, heteroaryl, heteroaryl alkyl moieties may be optionally substituted; R9 is hydrogen, C(Z)Rι 1 or optionally substituted Ci-io alkyl, S(O)2Rl8. optionally substituted aryl or optionally substituted arylC 1.4 alkyl;
RlO and R20 is each independently selected from hydrogen and C1.4 alkyl;
Rl l is hydrogen, Ci-io alkyl, C3-7 cycloalkyl, heterocyclyl, heterocyclylCi-io alkyl, aryl, arylCl-io alkyl, heteroaryl or heteroarylCi-io alkyl; Rl2 is hydrogen or Ri6,' R13 and R14 is each independently selected from hydrogen, optionally substituted Ci-4 alkyl, optionally substituted aryl and optionally substituted arylCi-4 alkyl; or together with the nitrogen to which they are attached R13 and R14 form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR9; Ri5 is Rιo or C(Z)-Ci-4 alkyl;
Rl6 is Cj-4 alkyl, halo-substituted-Ci-4 alkyl, or C3..7 cycloalkyl; Rl8 is Ci-io alkyl, C3-.7 cycloalkyl, heterocyclyl, aryl, arylCi-io alkyl, heterocyclyl, heterocyclylCl-10 alkyl, heteroaryl or heteroarylCi-io alkyl; Rl9 is hydrogen, cyano, C1.4 alkyl, C3-7 cycloalkyl or aryl; or a pharmaceutically acceptable salt thereof.
Suitably, Ri is a substituted 4-pyridyl or 4-pyrimindyl. More suitably Rι is substituted by an optionally substituted alkoxy, alkylthio, amino, methylamino, NHRa, or Y. A preferred ring placement of the Ri substituent on the 4-pyridyl derivative is the 2- position, such as in 2-methoxy-4-pyridyl. A preferred ring placement on the 4-pyrimidinyl ring is also at the 2-position, such as in 2-methoxy-pyrimidinyl.
Suitably, Ra is a Ci-6 alkyl, aryl, arylCi-6 alkyl, heterocyclyl, heterocyclylCi-6 alkyl, heteroaryl, or heteroarylCi-6 alkyl moiety, wherein each of these moieties may be optionally substituted.
When the substituent is Y, and Ra is aryl, it is preferably an optionally substituted phenyl or naphthyl. When Ra is an arylalkyl, it is preferably an optionally substituted benzyl or naphthylmethyl. When Ra is a heterocyclyl or heterocyclyl alkyl moiety, the heterocyclic portion is preferably an optionally substituted ring which is pyrrolindinyl, piperidine, morpholino, tetrahydropyran, tetrahydrothiopyranyl, tetrahydrothipyran-sulfinyl, tetrahydrothio-pyransulfonyl, pyrrolindinyl, indole, or piperonyl. It is noted that the heterocyclic rings herein may contain unsaturation, such as in a tryptamine ring.
The Ra moieties, in particular the aryl, may be optionally substituted, preferably 1 to 3 times, independently with halogen; Ci-4 alkyl, such as methyl, ethyl, propyl, isopropyl, or t-butyl; halosubstituted alkyl, such as CF3; hydroxy; hydroxy substituted Ci- 4 alkyl; Ci-4 alkoxy, such as methoxy or ethoxy; S(O)malkyl and S(O)m aryl (wherein m is 0, 1, or 2); C(O)ORι 1, such as C(O)Ci-4 alkyl or C(O)OH moieties; C(O)Rι 1;
OC(O)Rc; -O-(CH2)s-O-, such as in a ketal or dioxyalkylene bridge; amino; mono- and di- Ci-6 alkylsubstituted amino; N(Rio)C(O)RD; C(O)NRioR20; cyano; nitro; or an N- heterocyclyl ring which ring has from 5 to 7 members and optionally contains an additional heteroatom selected from oxygen, sulfur or NR15; optionally substituted aryl, such as phenyl; optionally substituted arylalkyl, such as benzyl or phenethyl; optionally substituted aryloxy, such as phenoxy; or optionally substituted arylalkyloxy such as benzyloxy. The aryl, arylalkyl, aryloxy, or arylalkyloxy optional substituents are as defined in the "optional substituent" definition herein.
Suitably, Rc is an optionally substituted Ci-6 alkyl, optionally substituted C3-7 cycloalkyl, optionally substituted aryl, optionally substituted arylCi-4 alkyl, optionally substituted heteroaryl, optionally substituted heteroarylCi-4 alkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylCi-4 alkyl moieties; and wherein the optional substituents are as defined in the "optional substituent" definition herein.
Preferably, the Ra groups include Ci .4 alkyl, benzyl, halosubstituted benzyl, naphthylmethyl, phenyl, halosubstituted phenyl, aminocarbonylphenyl, alkylphenyl, cyanophenyl, alkylthiophenyl, hydroxyphenyl, alkoxyphenyl, morpholinopropyl, piperonyl, piperidin-4-yl, alkyl substituted piperidine, such as 1-methylpiperidine, or 2,2,6,6-tetramethylpiperidin-4-yl.
Preferably, when the substituent is NHRa then Ra is aryl, arylalkyl, halosubstituted arylalkyl, halosubstituted aryl, heterocyclyl alkyl, hydroxy alkyl, alkyl- 1-piperidine- carboxylate, heterocyclyl, alkyl substituted heterocyclyl, halosubstituted heterocyclyl, or aryl substituted heterocyclyl. More preferably, Ra is benzyl, halosubstituted benzyl, naphthylmethyl, phenyl, halosubstituted phenyl, morpholinopropyl, 2-hydroxy ethyl, ethyl- 1-piperidinecarboxylate, piperonyl, piperidin-4-yl, alkyl substituted piperidine, chlorotryptamine, or tetrathiohydropyranyl. Preferably, when the R\ substituent is an optionally substituted Ci-4 alkoxy or
Ci-4 alkylthio, it is preferably a methoxy group. If the alkyl chain in these moieties is optionally substituted it is preferably substituted by halogen, such as fluorine, chlorine, bromine or iodine; hydroxy, such as hydroxyethoxy; Ci-io alkoxy, such as a methoxymethoxy, S(O)m alkyl, wherein m is 0, 1 or 2; amino, mono and di-substituted amino, such as in the NR7R17 group, i.e. tert-butylaminoethoxy; or where the R7R17 may together with the nitrogen to which they are attached cyclize to form a 5 to 7 membered ring which optionally includes an additional heteroatom selected from O/N/S; Ci-io alkyl, cycloalkyl, or cycloalkyl alkyl group, such as methyl, ethyl, propyl, isopropyl, t-butyl, etc. or cyclopropyl methyl; or halosubstituted Cj-io alkyl, such as CF3. Suitably, R4 is an optionally substituted phenyl. Preferably the phenyl is substituted one or more times independently by halogen, SR5, S(O)R5, OR 12, halo- substituted-Ci-4 alkyl, or Ci -4 alkyl, preferably in the 4-position of the ring. More preferably R4 is a halosubstituted phenyl, more preferably in the 4-position; and most preferably by fluorine. Suitably, R2 is hydrogen, (CRioR20)n' OR9, heterocyclyl, heterocyclylCi-io alkyl, Ci-io alkyl, halo-substituted Ci-io alkyl, C2-10 alkenyl, C2-10 alkynyl, C3.7 cycloalkyl, C3.7 cycloalkylCi-io alkyl, C5-7 cycloalkenyl, C5.7 cycloalkenylCi-io alkyl, aryl, arylCi-io alkyl, heteroaryl, heteroarylCi -io alkyl, (CRιoR2θ)nORn, (CRioR20)nS(O)mRi8, (CRιoR2θ)nNHS(O)2Rl8, (CRlθ 2θ)nNRi3Rl4, (CRι0R20)nNO2, (CRι0R2θ)nCN, (CRι0R2θ)n'SO Rl8, (CRιoR2θ)nS(O)m'NRi3Rl4, (CRi0R20)nC(Z)Rι 1, (CRi0R2θ)nOC(Z)Rι 1, (CRi0R2θ)nC(Z)ORι 1, (CRioR20)nC(Z)NRi3Ri4, (CRι0R20)nC(Z)NRι 1OR9, (CRιoR2θ)nNRlθC(Z)Rn, (CRι0R20)nNRl0C(Z)NRi3Rl4, (CRl0R20)nN(OR6)C(Z)NRi3Ri4, (CRi0R20)nN(OR6)C(Z)Rι i, (CRiθR2θ)nC(=NOR6)Rl 1,
(CRιoR2θ)nNRιoC(=NRi9)NRi3Rl4, (CRlθR2θ)nOC(Z)NRι3Rl4, (CRιoR2θ)nNRιoC(Z)NRi3Rl4, (CRlθR2θ)nNRlθC(Z)ORio, 5-(Rι8)-l,2,4-oxadizaol- 3-yl or 4-(Ri2)-5-(Rι8Ri9)-4,5-dihydro-l,2,4-oxadiazol-3-yl group, and wherein the aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaryl alkyl, heterocyclyl and heterocyclyl alkyl groups may be optionally substituted.
Suitably, R2 is hydrogen, optionally substituted heterocyclyl, optionally substituted heterocyclylCi-io alkyl, optionally substituted Ci-io alkyl, optionally substituted C3-7 cycloalkyl, optionally substituted C3-7 cycloalkylCi-io alkyl, (CRl0R20)nC(Z)ORn, (CRιoR2θ)nNRl3Rl4, (CRι0R20)nNHS(O)2Rl8, (CRιoR2θ)nS(O) Ri8, optionally substituted aryl, optionally substituted arylCi-io alkyl, (CRι0R20)nORl l, (CRι0R20)nC(Z)Rι 1, or (CRioR20)nC (=NOR6)Rl 1.
More suitably, R2 is selected from hydrogen, optionally substituted Ci-io alkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylCi-io alkyl,
(CRioR20)nNS(O)2Rl8, (CRlθR2θ)nS(O)mRι8, arylCi-io alkyl, (CRι0R2θ)nNRl3Rl4, optionally substituted C3-7 cycloalkyl, or optionally substituted C3-.7 cycloalkylCi-io alkyl.
Preferably R2 is hydrogen, morpholino propyl, piperidine, N-methylpiperidine, N-benzylpiperidine, 2,2,6,6-tetramethylpiperidine, 4-aminopiperidine, 4-amino-2,2,6,6- tetramethylpiperidine, 4-hydroxycyclohexyl, 4-methyl-4-hydroxycyclohexyl, 4-pyrrolinindylcyclohexyl, 4-methyl-4-aminocyclohexyl, 4-methyl-4-acetamidocyclohexyl, 4-ketocyclohexyl, 4-oxiranyl, or 4-hydroxy-4-(l-propynyl)cyclohexyl.
More preferably R2 is an optionally substituted heterocyclyl ring, optionally substituted heterocyclylCi-io alkyl, optionally substituted aryl, (CRio 20)n Rl3Rl4, or (CRioR20)nC(Z)ORi 1 group. Most preferably an optionally substituted heterocyclyl ring, or optionally substituted heterocyclylCi-io alkyl.
When R2 is optionally substituted heterocyclyl, the ring is preferably a morpholino, pyrrolidinyl, or a piperidinyl group. When the ring is optionally substituted, the substituents may be directly attached to the free nitrogen, such as in the piperidinyl group or pyrrole ring, or on the ring itself. Preferably the ring is a piperidine or pyrrole, more preferably piperidine. The heterocyclyl ring may be optionally substituted one to four times independently by halogen; Ci-4 alkyl; aryl, such as phenyl; aryl alkyl, such as benzyl - wherein the aryl or aryl alkyl moieties themselves may be optionally substituted (as in the "optionally substituted" definition below); C(O)ORι 1, such as the C(O)Cl-4 alkyl or
C(O)OH moieties; C(O)H; C(O)Cι_4 alkyl; hydroxy substituted Ci-4 alkyl; Cj-4 alkoxy; S(O)mCi-4 alkyl (wherein m is 0, 1, or 2); and NR10R2O (wherein Rio and R20 are independently hydrogen or C 1 _4alkyl) .
Preferably if the ring is a piperidine, the ring is attached to the imidazole at the 4-position, and the substituents are directly on the available nitrogen, i.e. a l-formyl-4-piperidine, l-benzyl-4-piperidine, l-methyl-4-piperidine, or 1-ethoxycarbonyl- 4-piperidine. If the ring is substituted by an alkyl group and the ring is attached in the 4-position, it is preferably substituted in the 2- or 6- position or both, such as 2,2,6,6- tetramethyl-4-piperidine. Similarly, if the ring is a pyrrole, the ring is attached to the imidazole at the 3-position, and the substituents are all directly on the available nitrogen. When R2 is an optionally substituted heterocyclylCi-io alkyl group, the ring is preferably a moφholino, pyrrolidinyl, or a piperidinyl group. Preferably the alkyl linking moiety is from 1 to 4, more preferably 3 or 4, and most preferably 3 carbons, such as in a propyl group. Preferred heterocyclyl alkyl groups include but are not limited to, moφholino ethyl, moφholino propyl, pyrrolidinyl propyl, and piperidinyl propyl moieties. The heterocyclic ring herein is also optionally substituted in a similar manner to that indicated above for the direct attachment of the heterocyclyl ring.
When R2 is an optionally substituted C3.7 cycloalkyl, or an optionally substituted C3..7 cycloalkylCi-io alkyl, the cycloalkyl group is preferably a C4 or C6 ring, most preferably a C6 ring, which ring is optionally substituted. The cycloalkyl ring may be optionally substituted one to three times independently by halogen, such as fluorine, chlorine, bromine or iodine; hydroxy; Ci-io alkoxy, such as methoxy or ethoxy; S(O)m alkyl, wherein m is 0, 1, or 2, such as methyl thio, methylsulfinyl or methyl sulfonyl; S(O)m aryl; cyano; nitro; amino; mono and di-C _ Q alkyl substituted amino, such as in the NR7R17 group, wherein R7 and R 17 are as defined in Formula (I), or where the R7R17 may cyclize together with the nitrogen to which they are attached to form a 5 to 7 membered ring which optionally includes an additional heteroatom selected from oxygen, sulfur or NR15; N(Rio)C(O)Xi, wherein Xi is C 1.4 alkyl, aryl or arylCi-4 alkyl; Ci-io alkyl, such as methyl, ethyl, propyl, isopropyl, or t-butyl; optionally substituted alkyl wherein the substituents are halogen, (such as CF3), hydroxy, nitro, cyano, amino, mono & di- Ci-io alkyl substituted amino; NR7R17; S(O)m alkyl and S(O)m aryl, wherein m is 0, 1 or 2; optionally substituted alkylene, such as ethylene or propylene; optionally substituted alkyne, such as ethyne; C(O)ORι 1; the group Re; C(O)H; =O; =N-ORι 1; N(H)-OH (or substituted alkyl or aryl derivatives thereof on the nitrogen or the oxime moiety); N(ORd)-C(O)-R6'; an optionally substituted aryl, such as phenyl; an optionally substituted arylCi-4 alkyl, such as benzyl or phenethyl; an optionally substituted heterocyclyl or heterocyclylCι.4 alkyl, and further wherein these aryl, arylalkyl, heterocyclyl, and heterocyclyl alkyl moieties are optionally substituted one to two times by halogen, hydroxy, Ci-io alkoxy, S(O)m alkyl, cyano, nitro, amino, mono and di-Cι_ιo alkyl substituted amino, alkyl, or halosubstituted alkyl.
Suitably Rd is hydrogen, a pharmaceutically acceptable cation, aroyl or a Ci-io alkanoyl group.
Suitably Re is a 1,3-dioxyalkylene group of the formula -O-(CH2)s-O-, wherein s is 1 to 3, preferably s is 2 yielding a 1,3-dioxyethylene moiety, or ketal functionality.
Suitably Rδ' is NRi9'R20'>' Cι_6 alkyl; halosubstituted C g alkyl; hydroxy substituted Cι_6 alkyl; C2-6 alkenyl; or an aryl or heteroaryl optionally substituted by halogen, C _6 alkyl, halosubstituted .g alkyl, hydroxyl, or Cμg alkoxy.
Suitably R 9' is H or Cj.g alkyl.
Suitably R20' is H, C _ alkyl, aryl, benzyl, heteroaryl, Cι_6 alkyl substituted by halogen or hydroxyl, or phenyl substituted by a member selected from the group consisting of halo, cyano, C _ 2 alkyl, C _g alkoxy, halosubstituted C\_ alkyl, Cι_g alkylthio, Cj.g alkylsulphonyl, or C g alkylsulfinyl; or R 9' and R20' may together with the nitrogen to which they are attached form a ring having 5 to 7 members, which members of the ring may be optionally replaced by a heteroatom selected from oxygen, sulfur or nitrogen. The ring may be saturated or contain more than one unsaturated bond. Preferably R6' is NRi9'R20' and Ri9' and R20' are preferably hydrogen. When the R2 cycloalkyl moiety is substituted by a NR7R17 group, or NR7R17
Ci-io alkyl group, and the R7 and R17 are as defined in Formula (I), the substituent is preferably an amino, amino alkyl, or an optionally substituted pyrrolidinyl moiety.
A preferred ring placement on the cycloalkyl moiety is the 4-position, such as in a C ring. When the cycloalkyl ring is di-substituted it is preferably di-substituted at the 4 position, such as in:
Figure imgf000014_0001
wherein R^' and R^' ^e independently the optional substituents indicated above for R2. Preferably, R^ and R^' are hydrogen, hydroxy, alkyl, substituted alkyl, optionally substituted alkyne, aryl, arylalkyl, NR7R17, and N(Rιo)C(O)Rι 1. Suitably, the alkyl is a Ci-4 alkyl, such as methyl, ethyl, or isopropyl; NR7R17 and NR7R17 alkyl, such as amino, methylamino, aminomethyl, aminoethyl; substituted alkyl such as in cyanomethyl, cyanoethyl, nitroethyl, pyrrolidinyl; aryl such as in phenyl; arylalkyl, such as in benzyl; optionally substituted alkyne, such as ethyne or propynyl; or together R* and R2' ^e a keto functionality.
Preferably R4 is an optionally substituted phenyl; R is an optionally substituted 4- pyridyl or 4-pyrimidinyl; and R2 is an optionally substituted heterocyclyl, heterocyclyl Ci- 4 alkyl, a cycloalkyl or a cycloalkyl alkyl. More preferably R2 is an optionally substituted C4 or C cycloalkyl, cyclopropyl methyl, moφholinyl butyl, moφholinyl propyl, moφholinyl ethyl, cyclohexyl substituted by methyl, phenyl, benzyl, amino, acetamide, aminomethyl, aminoethyl, cyanomethyl, cyanoethyl, hydroxy, nitroethyl, pyrrolidinyl, ethynyl, 1-propynyl, =O, -O-(CH2)2θ-, =NORι 1, wherein Ri 1 is hydrogen, alkyl or aryl, NHOH, or N(OH)-C(O)-NH2; or R2 is moφholinyl propyl, aminopropyl, piperidinyl, N- benzyl-4-piperidinyl, N-methyl-4-piperidinyl, 2,2,6,6-tetramethypiperidinyl, substituted piperidine, such as l-formyl-4-piperidine, or a l-ethoxycarbonyl-4-piperidine. More preferably Rj is a 4-pyridyl or 4-pyrimidinyl subtituted by Y, NHRa, or C .4 alkoxy. In all instances herein where there is an alkenyl or alkynyl moiety as a substituent group, the unsaturated linkage, i.e., the vinylene or acetylene linkage is preferably not directly attached to the nitrogen, oxygen or sulfur moieties, for instance in OR3, or for certain R2 moieties.
As used herein, "optionally substituted", unless specifically defined, shall mean such groups as halogen, such as fluorine, chlorine, bromine or iodine; hydroxy; hydroxy substituted Ci-io alkyl; Cι_ιo alkoxy, such as methoxy or ethoxy; S(O)m alkyl, wherein m is 0, 1 or 2, such as methylthio, methylsulfinyl or methylsulfonyl; amino, mono and di-Cι_ιo alkyl substituted amino, NR7R17 wherein the R7R17 may together with the nitrogen to which they are attached cyclize to form a 5 to 7 membered ring which optionally includes an additional heteroatom selected from O/N/S; Ci-io alkyl, cycloalkyl, or cycloalkyl alkyl group, such as methyl, ethyl, propyl, isopropyl, t-butyl, etc. or cyclopropyl methyl; halosubstituted Ci-io alkyl, such CF3; an optionally substituted aryl, such as phenyl, or an optionally substituted arylalkyl, such as benzyl or phenethyl, wherein these aryl moieties may also be substituted one to two times by halogen; hydroxy; hydroxy substituted alkyl; Ci-io alkoxy; S(O)m alkyl; amino, mono and di- Ci-io alkyl substituted amino, such as in the NR7R17 group; Ci-io alkyl; or halosubstituted alkyl, such as CF3.
Suitable pharmaceutically acceptable salts are well known to those skilled in the art and include basic salts of inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methane sulphonic acid, ethane sulphonic acid, acetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid. In addition, pharmaceutically acceptable salts of compounds of Formula (I) may also be formed with a pharmaceutically acceptable cation, for instance, if a substituent group comprises a carboxy moiety. Suitable pharmaceutically acceptable cations are well known to those skilled in the art and include alkaline, alkaline earth, ammonium and quaternary ammonium cations. The following terms, as used herein, refer to:
• "halo" or "halogens", include the halogens: chloro, fluoro, bromo and iodo.
• "C _ιoal yl" or "alkyl" - both straight and branched chain radicals of 1 to 10 carbon atoms, unless the chain length is otherwise limited, including, but not limited to, methyl, ethyl, n-propyl, wσ-propyl, n-butyl, sec-butyl, wo-butyl, tert-butyl, n-pentyl and the like.
• The term "cycloalkyl" is used herein to mean cyclic radicals, preferably of 3 to 8 carbons, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, and the like.
• The term "cycloalkenyl" is used herein to mean cyclic radicals, preferably of 5 to 8 carbons, which have at least one double bond including but not limited to cyclopentenyl, cyclohexenyl, and the like.
• The term "alkenyl" is used herein at all occurrences to mean straight or branched chain radical of 2-10 carbon atoms, unless the chain length is limited thereto, including, but not limited to ethenyl, 1-propenyl, 2-propenyl, 2-methyl-l-propenyl, 1-butenyl, 2-butenyl and the like. • "aryl" - phenyl and naphthyl;
• "heteroaryl" (on its own or in any combination, such as "heteroaryloxy", or "heteroarylalkyl") - a 5-10 membered aromatic ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N, O or S, such as, but not limited, to pyrrole, pyrazole, furan, thiophene, quinoline, isoquinoline, quinazolinyl, pyridine, pyrimidine, oxazole, thiazole, thiadiazole, triazole, imidazole, or benzimidazole.
• "heterocyclyl" (on its own or in any combination, such as "heterocyclylalkyl") - a saturated or partially unsaturated 4-10 membered ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N, O, or S; such as, but not limited to, pyrrolidine, piperidine, piperazine, moφholine, tetrahydropyran, or imidazolidine.
• The term "aralkyl" or "heteroarylalkyl" or "heterocyclylalkyl" is used herein to mean Cj-4 alkyl as defined above attached to an aryl, heteroaryl or heterocyclyl moiety as also defined herein unless otherwise indicated. • "sulfinyl" - the oxide S(O) of the corresponding sulfide, the term "thio" refers to the sulfide, and the term "sulfonyl" refers to the fully oxidized S(O)2 moiety. • "aroyl" - a C(O)Ar, wherein Ar is a phenyl, naphthyl, or aryl alkyl derivative such as defined above, such groups include but are not limited to benzyl and phenethyl.
• "alkanoyl" - a C(O)Cι_ιo alkyl wherein the alkyl is as defined above.
For the puφoses herein the "core" 4-pyrimidinyl moiety for Ri or R2 is referred to as the formula:
Figure imgf000017_0001
It is recognized that the compounds for use in the present invention may exist as stereoisomers, regioisomers, or diastereiomers. These compounds may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. All of these compounds are included within the scope of the present invention.
As noted previously, methods of making these compounds can be found in their respective patent applications as noted above.
Specifically exemplified compounds of Formula (I) include: l-[3-(4-Mθφholinyl)propyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole; l-(3-Chloropropyl)-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole; l-(3-Azidopropyl)-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole; l-(3-Aminopropyl)-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole; l-(3-Methylsulfonamidopropyl)-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole; l-[3-(N-Phenylmethyl)aminopropyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole; l-[3-(N-Phenylmethyl-N-methyl)aminopropyl]-4-(4-fluorophenyl)-5-(4- pyridyl)imidazole; l-[3-(l-Pyrrolidinyl)propyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole; l-(3-Diethylaminopropyl)-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole; l-[3-(l-Piperidinyl)propyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole; l-[3-(Methylthio)propyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole; l-[2-(4-Mθφholinyl)ethyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole; l-[3-(4-Moφholinyl)propyl]-4-(3-methylthiophenyl)-5-(4-pyridyl)imidazole; (+/-)- l-[3-(4-Moφholinyl)propyl]-4-(3-methylsulfinylphenyl)-5-(4-pyridyl)imidazole; l-[3-(N-Methyl-N-benzyl)aminopropyl]-4-(3-methylthiophenyl)-5-(4- pyridyl)imidazole; l-[3-(N-Methyl-N-benzyl)aminopropyl]-4-(3-methylsulfinylphenyl)-5-(4- pyridyl)imidazole; l-[4-(Methylthio)phenyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole; l-[4-(Methylsulfinyl)phenyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole; l-[3-(Methylthio)phenyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;
(+/-)- l-[3-(Methylsulfinyl)phenyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole; l-t2-(Methylthio)phenyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole; l-[2-(Methylsulfinyl)phenyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole; l-[4-(4-Moφholinyl)butyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole; l-Cyclopropyl-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole; l-Isopropyl-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole; 1 -Cyclopropylmethyl-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole; l-tert-Butyl-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole; l-(2,2-Diethoxyethyl)-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole; l-Formylmethyl-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole; l-Hydroxyiminylmethyl-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole; 1 -Cyanomethyl-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole; l-[3-(4-Moφholinyl)propyl)-4-(4-fluorophenyl)-5-(2-methylpyridin-4-yl)imidazole;
4-(4-Fluorophenyl)-l-[3-(4-moφholinyl)propyl]-5-(2-chloropyridin-4-yl)imidazole;
4-(4-Fluorophenyl)-l-[3-(4-moφholinyl)propyl]-5-(2-amino-4-pyridyl)imidazole; l-(4-Carboxymethyl)propyl-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole; 1 -(4-Carboxypropyl)-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole; l-(3-Carboxymethyl)ethyl-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole; l-(3-Carboxy)ethyl-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;
1 -( 1 -Benzylpiperidin-4-yl)-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;
5-(2-Aminopyrimidin-4-yl)-4-(4- fluorophenyl)- l-[3-(4-moφholinyl)propyl]imidazole; 5 -(2- Aminopyrimidin-4-yl)-4-(4-fluorophenyl)- 1 -( 1 -benzylpiperidin-4-y l)imidazole ;
5-(2-Aminopyrimidin-4-yl)-4-(4-fluorophenyl)-l-(2-propyl)imidazole;
5-(2-Aminopyrimidin-4-yl)-4-(4-fluorophenyl)-l-(cyclopropylmethyl)imidazole;
5-(2-Aminopyrimidin-4-yl)-4-(4-fluorophenyl)- 1 -( 1 -carboxyethyl-4- piperidinyl)imidazole; 5-(2-Aminopyrimidin-4-yl)-4-(4-fluorophenyl)- 1 -(4-piperidinyl)imidazole; l-Methyl-4-phenyl-5-(4-pyridyl)imidazole; l-Methyl-4-(3-chlorophenyl)-5-(4-pyridinyl)imidazole; l-Methyl-4-(3-methylthiophenyl)-5-(4-pyridyl)imidazole;
(+/-)-l-Methyl-4-(3-methylsulfinylphenyl)-5-(4-pyridyl)imidazole; (+/-)-4-(4-Fluorophenyl)-l-[3-(methylsulfinyl)propyl]-5-(4-pyridinyl)imidazole;
4-(4-Fluorophenyl)-l-[(3-methylsulfonyl)propyl]-5-(4-pyridinyl)imidazole; l-(3-Phenoxypropyl)-4-(4-fluorophenyl)-5-(4-pyridinyl)imidazole; l-[3-(Phenylthio)propyl]-4-(4-fluorophenyl)-5-(4-pyridinyl)imidazole; l-[3-(4-Moφholinyl)propyl]-4-(4-fluorophenyl)-5-(4-quinolyl)imidazole;
(+/-)- l-(3-Phenylsulfinylpropyl)-4-(4-fluorophenyl)-5-(4-pyridinyl)imidazole; l-(3-Ethoxypropyl)-4-(4-fluorophenyl)-5-(4-pyridinyl)imidazole; l-(3-Phenylsulfonylpropyl-4-(4-fluorophenyl)-5-(4-pyridinyl)imidazole; l-[3-(4-Mθφholinyl)propyl]-4-(3-chlorophenyl)-5-(4-pyridyl)imidazole; l-[3-(4-Moφholinyl)propyl]-4-(3,4-dichlorophenyl)-5-(4-pyridyl)imidazole;
4-[4-(4-Fluorophenyl)-l-[3-(4-moφholinyl)propyl]-5-(pyrimid-2-one-4-yl)imidazole;
4-(4-Fluorophenyl)-5-[2-(methylthio)-4-pyrimidinyl]-l-[3-(4-moφholinyl)propyl]- imidazole;
(+/-)-4-(4-Fluorophenyl)-5-[2-(methylsulfinyl)-4-pyrimidinyl]-l-[3-(4-moφholinyl)- propyl]imidazole;
(E)- 1 -( 1 -Propenyl)-4-(4-fluorophenyl)-5-(4-pyridinyl)imidazole; l-(2-Propenyl)-4-(4-fluorophenyl)-5-(4-pyridinyl)imidazole; 5-[(2-N,N-Dimethylamino)pyrimidin-4-yl]-4-(4-fluorophenyl)-l-[3-(4-moφholinyl)- propyl]imidazole; l-[3-(4-Mθφholinyl)propyl]-5-(4-pyridinyl)-4-[4-(trifluoromethyl)phenyl]imidazole; l-[3-(4-Mθφholinyl)propyl]-5-(4-pyridinyl)-4-[3-(trifluoromethyl)phenyl]imidazole; l-(Cyclopropylmethyl)-4-(3,4-dichlorophenyl)-5-(4-ρyridinyl)imidazole; l-(Cyclopropylmethyl)-4-(3-trifluoromethylphenyl)-5-(4-pyridinyl)imidazole; l-(Cyclopropylmethyl)-4-(4-fluorophenyl)-5-(2-methylpyrid-4-yl)imidazole; l-[3-(4-Moφholinyl)propyl]-5-(4-pyridinyl)-4-(3,5-bistrifluoromethylphenyl)- imidazole;
5-[4-(2-Aminopyrimidinyl)]-4-(4-fluorophenyl)-l-(2-carboxy-2,2- dimethylethyl)imidazole;
1 -( 1 -Formyl-4-piperidinyl)-4-(4-fluorophenyl)-5-(4-pyridinyl)imidazole;
5-(2-Amino-4-pyrimidinyl)-4-(4-fluorophenyl)- 1 -( 1 -methyl-4-piperidinyl)imidazole; l-(2,2-Dimethyl-3-mθφholin-4-yl)propyl-4-(4-fluorophenyl)-5-(2-amino-4- pyrimidinyl)imidazole; 4-(4-Fluorophenyl)-5-(4-pyridyl)-l-(2-acetoxyethyl)imidazole;
5-(2-Aminopyrimidin-4-yl)-4-(4-fluorophenyl)- 1-( 1 -benzylpyrrolin-3-yl)imidazole;
5-(2-Aminopyrimidin-4-yl)-4-(4-fluorophenyl)-l-(2,2,6,6-tetramethylpiperidin-4- yl)imidazole;
5-[4-(2-N-Methylamino)pyrimidinyl]-4-(4-fluorophenyl)-l-(4-N-methylpiperidine)- imidazole;
5-[4-(2-N-Methylamino)pyrimidinyl]-4-(4-fluorophenyl)- 1 -(4-N-moφholino- 1 - propyl)imidazole; -[4-(2-N-Methylamino)pyrimidinyl]-4-(4-fluorophenyl)-l-(4-piperidine)imidazole; -[(2-Ethylamino)pyrimidin-4-yl]-4-(4-fluorophenyl)- 1 -( l-methylpiperidin-4-yl)imidazole; -(4-Fluorophenyl)-5-[2-(isopropyl)aminopyrimidiny-4-yl]-l-(l-methylpiperidin-4- yl)imidazole; -(2-Acetamido-4-pyrimidinyl)-4-(4-fluorophenyl)- 1 -(4-N-moφholino- 1 -propyl)- imidazole; -(2-Acetamido-4-pyrimidinyl)-4-(4-fluorophenyl)- 1 -( 1 -methyl-4-piperidinyl)imidazole; -[4-(2-N-Methylthio)pyrimidinyl]-4-(4-fluorophenyl)-l-(4-piperidine)irnidazole; -(Fluorophenyl)-l-(methyl-4-piperidinyl)-5-(2-methylthio-4-pyrimidinyl)imidazole; -(Fluorophenyl)- 1 -(methyl-4-piperidinyl)-5-(2-methysulfinyl-4-pyrimidinyl)imidazole; l-tert-Butyl-4-(4-fluorophenyl)-5-(2-methysulfιnyl-4-pyrimidinyl)imidazole; -[4-(2-Aιninopyrirnidinyl)]-4-(4-fluorophenyl)-l-(2,2,6,6-tetramethyl-4- piperidinyl)imidazole ; -[4-(2-N-Methylamino-4-pyrimidinyl)]-4-(4-fluorophenyl)-l-(2,2,6,6-tetramethyl-4- piperidine)imidazole;
5-(2-Amino-4-pyrimidinyl)-4-(4-fluorophenyl)-l-(tetrahydro-4-thiopyranyl)imidazole; 5-(2-Amino-4-pyrimidinyl)-4-(4-fluorophenyl)-l-(tetrahydro-4-pyranyl)imidazole; 5-(2-Methylamino-4-pyrimidinyl)-4-(4-fluorophenyl)-l-(2-cyanoethyl)imidazole; 5-(2-Amino-4-pyrimidinyl)-4-(4-fluorophenyl)-l-(tetrahydro-4-sulfinylpyranyl)imidazole; 5-(2-Amino-4-pyrimidinyl)-4-(4-fluorophenyl)- 1 -(tetrahydro-4-sulfonylpyranyl)- imidazole; 5-(2-Methylamino-4-pyrimidinyl)-4-(4-fluorophenyl)-l-(2,2,2-trifluoroethyl-4- piperidinyl)imidazole; 5-(2-Amino-4-pyrimidinyl)-4-(4-fluorophenyl)-l-(trifluoroacetyl-4-piperidinyl)- imidazole;
5-(4-Pyridyl)-4-(4-fluorophenyl)- 1 -(4-piperidinyl)imidazole; 5-(4-Pyridyl)-4-(4-fluorophenyl)- 1 -( 1 -t-butoxy carbonyl-4-piperidinyl)imidazole; 4-(4-Fluorophenyl)-5-(4-pyridyl)imidazole; 4-(4-Fluorophenyl)-5-(2-methoxy-pyrimidin-4-yl)imidazole; 4-(4-Fluorophenyl)-5-(2-methylthio-pyrimidin-4-yl)imidazole;
5-[(2-Benzylamino)pyrimidin-4-yl]-4-(4-fluorophenyl)-l-(l-methylpiperidin-4- yl)imidazole; 4-(4-Fluorophenyl)- 1 -( 1 -methylpiperidin-4-yl)-5- [2-(4-tetrahydrothio- pyranyl)aminopyrimidin-4-yl]imidazole; 5-[(2-(3-Chlorobenzylamino))pyrimidin-4-yl]-4-(4-fluorophenyl)-l-(l-methyl-piperidin- 4-yl)imidazole; - [(2-( 1 -Naphthylmethylamino))pyrimidin-4-yl]-4-(4-fluorophenyl)- 1 -( 1 - methylpiperidin-4-yl)imidazole; -[(2-(l-Benzyl-4-piperidinylamino))pyrimidin-4-yl]-4-(4-fluorophenyl)-l-(l- methylpiperidin-4-yl)imidazole; -(4-Fluorophenyl)-l-(l-methylpiperdin-4-yl)-5-[2-[3-(moφholino)propyl]- aminopyrimidiny-4-yl]imidazole; -[2-[(3-Bromophenyl)amino]pyrimidin-4-yl]-4-(4-fluorophenyl)-l-(l-methylpiperidin-
4-yl)imidazole; -[(2-(Piperonylamino)pyrimidin-4-yl]-4-(4-fluorophenyl)- 1 -( 1 -methylpiperidin-4- yl)imidazole; -[(2-(4-Piperdinylamino))pyrimidin-4-yl]-4-(4-fluorophenyl)- 1 -( 1 -methylpiperidin-4- yl)imidazole; -[(2-(5-Chlorotryptamino))pyrimidin-4-yl]-4-(4-fluorophenyl)- 1 -( 1 -methylpiperidin-4- yl)imidazole; -[(2-(2,2,6,6-Tetramethylpiperidin-4-yl)amino)pyrimidin-4-yl]-4-(4-fluorophenyl)- 1 -( 1 - methylpiperidin-4-yl)imidazole; -[(2-( 1 -Ethoxycarbonyl))piperdin-4-yl]aminopyrimidin-4-yl]-4-(4-fluorophenyl)- 1 -( 1 - methylpiperidin-4-yl)imidazole; -[2-(Phenylamino)pyrimidin-4-yl]-4-(4-fluorophenyl)-l-(4-oxocyclohexyl)irnidazole; -[4-(2-Phenylamino)pyrimidin-4-yl]-4-(4-fluorophenyl)- 1 -(4-hydroxycyclohexyl)- imidazole; -(4-Fluorophenyl)-l-(l-methylpiperdin-4-yl)-5-[(2-phenylamino)pyrimidin-4-yl]- imidazole; -(4-Fluorophenyl)-l-(2,2,6,6-tetramethylpiperidin-4-yl)-5-[(2-phenylamino)pyrimidin- 4-yl] imidazole; -(4-Fluorophenyl)-5-[(2-phenylamino)pyrimidin-4-yl]-l-(piperidin-4-yl)imidazole; -(4-Fluorophenyl)-5-[2-[3-(imidazol-l-yl)propyl]aminopyrimidin-4-yl]-l-[(l-t- butoxycarbonyl)piperidin-4-yl]imidazole; -(4-Fluorophenyl)-5-[2-[3-(imidazol- 1 -yl)propyl]aminopyrimidin-4-yl]- 1 -(piperidin-4- yl)imidazole; l-(4-Piperidinyl)-4-(4-fluorophenyl)-5-(2-anilino-4-pyridinyl)imidazole; -(4-Thiomethylphenyl)-5-[(2-phenylamino)pyrimidin-4-yl]-l-(l-ethoxy carbonylpiperidin-4-yl)imidazole; -(4-Thiomethylphenyl)-5-[(2-phenylamino)pyrimidin-4-yl]-l-(piperidin-4- yl)imidazole; -(4-Methylsulfinylphenyl)-5-[(2-phenylamino)pyrimidin-4-yl]-l-(piperidin-4- yl)imidazole; -(4-Fluorophenyl)-5-[(2-(4-fluorophenyl)amino)pyrimidin-4-yl]-l-(piperidin-4- yl)imid<azole; -(4-Fluorophenyl)-5-[(2-(3-fluorophenyl)amino)pyrimidin-4-yl]-l-(piperidin-4- yl)imidazole; -(4-Fluorophenyl)-5-[(2-(2-fluorophenyl)amino)pyrimidin-4-yl]- 1 -(piperidin-4- yl)imidazole; -(4-Fluorophenyl)-5-[(2-(4-benzyloxyphenyl)amino)pyrimidin-4-yl]- 1 -( 1 - ethoxycarbonylpiperidin-4-yl)imidazole; -(4-Fluorophenyl)-5-[(2-(3-benzyloxyphenyl)amino)pyrimidin-4-yl]-l-(l- ethoxycarbonylpiperidin-4-yl)imidazole; -(4-Fluorophenyl)-5-[(2-(3-trifluoromethylphenyl)amino)pyrimidin-4-yl]-l-(piperidin-
4-yl)imidazole; -(4-Fluorophenyl)-5-[(2-(3,4-difluorophenyl)arnino)pyrimidin-4-yl]-l-(piperidin-4- yl)imidazole; -(4-Fluorophenyl)-5-[(2-(4-hydroxyphenyl)amino)pyrimidin-4-yl]-l-(piperidin-4- yl)imidazole; -(4-Fluorophenyl)-5-[(2-(3-hydroxyphenyl)amino)pyrimidin-4-yl]-l-(piperidin-4- yl)imidazole; 4-(4-Fluorophenyl)-5-[(2-(4-methoxyphenyl)amino)pyrimidin-4-yl]-l-(piperidin-4- yl)imidazole;
4-(4-Fluorophenyl)-5-[(2-(3-methoxyphenyl)amino)pyrimidin-4-yl]-l-(piperidin-4- yl)imidazole; 4-(4-Fluorophenyl)-5-[(2-(2-methoxyphenyl)amino)pyrimidin-4-yl]-l-(piperidin-4- yl)imidazole; 4-(4-Fluorophenyl)-5-[(2-(3-fluoro-2-methylphenyl)amino)pyrimidin-4-yl]-l- (piperidin-4-yl)imidazole; l-(4-Oxocyclohexyl)-4-(4-fluorophenyl)-5-[(2-methoxy)pyrimidin-4-yl]imidazole; cw -l-(4-Hydroxycyclohexyl)-4-(4-fluorophenyl)-5-[(2-methoxy)pyrimidin-4- yljimidazole; trans- 1 -(4-Hydroxycyclohexyl)-4-(4-fluorophenyl)-5- [(2-methoxy)pyrimidin-4- yl]imidazole; l-(4-Oxocyclohexyl)-4-(4-fluorophenyl)-5-[(2-methylthio)pyrimidin-4-yl]- imidazole; trαn5-l-(4-Hydroxycyclohexyl)-4-(4-fluorophenyl)-5-[(2-methylthio)pyrimidin-4- yl]imidazole; l-(4-Oxocyclohexyl)-4-(4-fluorophenyl)-5-[(2-hydroxy)pyrimidin-4-yl]imidazole; l-(4-Oxocyclohexyl)-4-(4-fluorophenyl)-5-[(2-isopropoxy)pyrimidin-4- yl]imidazole; 1 -(4-Hydroxycyclohexyl)-4-(4-fluorophenyl)-5- [(2-isopropoxy)pyrimidin-4- yl]imidazole; trøn.s-l-(4-Hydroxy-4-methylcyclohexyl)-4-(4-fluorophenyl)-5-[(2-methoxy)- pyrimidin-4-yl]imidazole; c/s-l-(4-Hydroxy-4-methylcyclohexyl)-4-(4-fluorophenyl)-5-[(2-methoxy)- pyrimidin-4-yl] imidazole ; trans- 1 -(4-Hydroxycyclohexyl)-4-(4-fluorophenyl)-5- [(2-ethoxy)pyrimidine-4- yljimidazole; l-Cycloheptyl-4-(4-fluorophenyl)-5-(2-methoxypyrimidin-4-yl)imidazole; l-Cyclopropyl-4-(4-fluorophenyl)-5-(2-methoxypyrimidin-4-yl)imidazole; l-Cyclobutyl-4-(4-fluorophenyl)-5-(2-methoxypyrimidin-4-yl)imidazole; l-Cyclopentyl-4-(4-fluorophenyl)-5-(2-methoxypyrimidin-4-yl)imidazole; l-Cyclohexyl-4-(4-fluorophenyl)-5-(2-methoxypyrimidin-4-yl)imidazole; trans-5-[4-(2-Methoxy)pyrimidinyl]-4-(4-fluorophenyl)- 1 -[4-(2-tetrahydropyranyl)- oxycyclohexyl] imidazole ; l-(4-Hydroxycyclohexyl)-4-(4-fluorophenyl)-5-[(2-hydroxy)pyrimidin-4- yl]imidazole cis-l-[(4-Hydroxy-4-methylcyclohexyl)]-4-(4-fluorophenyl)-5-(2-methoxy-4- pyrimidinyl)imidazole; trans-l-[(4-Hydroxy-4-methylcyclohexyl)]-4-(4-fluorophenyl)-5-(2-methoxy-4- pyrimidinyl)imidazole; trans- 1 -(4-Aminocyclohexyl)-4-(4-fluorophenyl)-5-(2-methoxy-4- pyrimidinyl)imidazole; trans-4-(4-Fluorophenyl)-5-[(2-methoxy)pyrimidin-4-yI]- 1 -[4-
((methylthio)methoxy)cyclohexyl]imidazole; cis- 1 -(4- Aminocyclohexyl)-4-(4-fluorophenyl)-5-(2-methoxy-4- pyrimidinyl)imidazole; trans-l-[(4-Butyryloxy)cyclohexyl]-4-(4-fluorophenyl)-5-[(2-methoxypyrimidin)-4- yl]imidazole; trans-4-(4-Fluorophenyl)-l-[4-(2-(N,N-dimethylamino)ethoxy)cyclohexyl]-5-[(2- methoxy)pyrimidin-4-yl]imidazole hydrochloride; cw/tra«5-l-(4-Hydroxy-4-hydroxymethylcyclohexyl)-4-(4-fluorophenyl)-5-[(2- methoxy)pyrimidin-4-yl]imidazole; l-(4-Piperidinyl)-4-(4-fluorophenyl)-5-(2-phenoxypyrimidin-4-yl)imidazole; l-(4-Piperidinyl)-4-(4-fluorophenyl)-5-(2-phenoxypyridin-4-yl)imidazole; l-(4-Piperidinyl)-4-(4-fluorophenyl)-5-[2-(4-methoxyphenoxy)pyridin-4-yl]imidazole; l-(4-Piperidinyl)-4-(4-fluorophenyl)-5-[2-(4-fluorophenoxy)pyridin-4-yl]imidazole; l-(Piperidin-4-yl)-4-(4-fluorophenyl)-5-[2-(4-methoxyphenoxy)pyrimidin-4-yl]- imidazole; l-(Piperidin-4-yl)-4-(4-fluorophenyl)-5-[2-(4-fluorophenoxy)pyrimidin-4-yl]imidazole; l-(Piperidin-4-yl)-4-(4-fluorophenyl)-5-[2-(4-aminocarbonylphenoxy)pyrimidin-4-yl]- imidazole; l-(Piperidin-4-yl)-4-(4-fluorophenyl)-5-[2-(4-ethylphenoxy)pyrimidin-4-yl]imidazole; l-(Piperidin-4-yl)-4-(4-fluorophenyl)-5-[2-(4-benzyloxyphenoxy)pyrimidin-4-yl]- imidazole; l-(Piperidin-4-yl)-4-(4-fluorophenyl)-5-[2-(4-cyanophenoxy)pyrimidin-4-yl]imidazole; l-(Piperidin-4-yl)-4-(4-fluorophenyl)-5-[2-(4-hydroxyphenoxy)pyrimidin-4- yl]imidazole; l-(4-Hydroxycyclohexyl)-4-(4-fluorophenyl)-5-[2-(phenoxy)pyrimidin-4- yl]imidazole; l-(Piperidin-4-yl)-4-(4-fluorophenyl)-5-[2-(2,6-dimethylphenoxy)pyridin-4- yl]imidazole; l-(Piperidin-4-yl)-4-(4-fluorophenyl)-5-[2-(4-methylphenoxy)pyridin-4-yl]imidazole; l-(Piperidin-4-yl)-4-(4-fluorophenyl)-5-[2-(4-chlorophenoxy)pyridin-4-yl]imidazole; l-[3-(N-Moφholino)propyl]-4-(4-fluorophenyl)-5-[2-(phenoxy)pyrimidin-4- yl]imidazole; l-(Piperidin-4-yl)-4-(4-fluorophenyl)-5-[2-(3-methoxyphenoxy)pyrimidin-4- yl]imidazole; l-(Piperidin-4-yl)-4-(4-fluorophenyl)-5-[2-(4-phenylphenoxy)pyrimidin-4- yljimidazole; l-(Piperidin-4-yl)-4-(4-fluorophenyl)-5-[2-(4-phenoxyphenoxy)pyrimidin-4- yl]imidazole; l-(Piperidin-4-yl)-4-(4-fluorophenyl)-5-[2-(3-hydroxyphenoxy)pyrimidin-4- yl]imidazole; l-(3-(N-Mθφholino)propyl)-4-(4-fluorophenyl)-5-[2-(4-fluorophenoxy)pyrimidin-4- yl] imidazole; l-(Piperidin-4-yl)-4-(4-fluorophenyl)-5-[2-(2-hydroxyphenoxy)pyrimidin-4- yl] imidazole; l-(Piperidin-4-yl)-4-(4-fluorophenyl)-5-[2-(3,4-methylenedioxyphenoxy)- pyrimidin-4-y 1] imidazole ; l-(Piperidin-4-yl)-4-(4-fluorophenyl)-5-[2-(3-fluorophenoxy)pyrimidin-4- yl]imidazole; l-(Piperidin-4-yl)-4-(4-fluorophenyl)-5-[2-(2-fluorophenoxy)pyrimidin-4- yl]imidazole; l-(Piperidin-4-yl)-4-(4-fluorophenyl)-5-[2-(2-methoxyphenoxy)pyrimidin-4- yl]imidazole; l-(Piperidin-4-yl)-4-(4-fluorophenyl)-5-[2-(3-trifluoromethylphenoxy)pyrimidin-4- yl]imidazole; l-(Piperidin-4-yl)-4-(4-fluorophenyl)-5-[2-(3,4-difluorophenoxy)pyrimidin-4- yl]imidazole; l-(Piperidin-4-yl)-4-(4-fluorophenyl)-5-[2-(4-methylsulfonylphenoxy)pyrimidin-4- yl] imidazole; l-(4-Piperidinyl)-4-(4-fluorophenyl)-5-(2-tWophenoxypyrimidin-4-yl)imidazole; 1 -(4-Piperidinyl)-4-(4-fluorophenyl)-5-[2-( 1 -methyltetrazol-5-ylthio)pyridin-4- yl]imidazole l-(4-Piperidinyl)-4-(4-fluorophenyl)-5-[(2-acetamidophenoxy)pyrimidin-4- yl] imidazole; l-(4-Piperidinyl)-4-(4-fluorophenyl)-5-[(3-propionaιrιidophenoxy)pyrimidin-4- yl]imidazole; l-Cyclohexyl-4-(4-fluorophenyl)-5-[(2-phenoxy)pyrimidin-4-yl]imidazole; l-(4-Piperidinyl)-4-(4-fluorophenyl)-5-[2-(2,6-dimethylphenoxy)pyrimidin-4- yl]imidazole; l-(4-Piperidinyl)-4-(4-fluorophenyl)-5-[2-(2-methylphenoxy)pyrimidin-4- yljimidazole; l-(4-Piperidinyl)-4-(4-fluorophenyl)-5-[2-(2,6-dimethyl-4-chlorophenoxy)- pyrimidin-4-yl]imidazole; l-(4-Piperidinyl)-4-(4-fluorophenyl)-5-[2-(indol-4-yloxy)pyrimidin-4-yl]imidazole; l-Cyclopropyl-4-(4-fluorophenyl)-5-(2-phenoxypyrimidin-4-yl)imidazole; l-Isopropyl-4-(4-fluorophenyl)-5-(2-phenoxypyrimidin-4-yl)imidazole; l-Cyclopentyl-4-(4-fluorophenyl)-5-(2-phenoxypyrimidin-4-yl)imidazole; (+/-)-l-(l-Hydroxyprop-2-yl)-4-(4-fluorophenyl)-5-(2-phenoxypyrimidin-4-yl)- imidazole; 3-[4-(4-Fluorophenyl)-5-[(2-phenoxy)pyrimidin-4-yl]imidazol-l-yl]propionitrile; (R)-(l-Hydroxy-3-phenylprop-2-yl)-4-(4-fluorophenyl)-5-(2-phenoxy)pyrimidin-4- yl)imidazole; (S)-(l-Hydroxy-3-phenylprop-2-yl)-4-(4-fluorophenyl)-5-(2-phenoxy)pyrimidin-4- yl)imidazole; (+/-)- 1-(1 -Phenoxyprop-2-yl)-4-(4-fluorophenyl)-5-(2-phenoxypyrimidin-4-yl)- imidazole; 1 -(4-Piperidinyl)-4-(4-fluorophenyl)-5-[2-(3-piperazin- 1 -ylacetamido)phenoxy- pyrimidin-4-yl] imidazole ; l-(4-Piperidinyl)-4-(4-fluorophenyl)-5-[2-(3-piperazin-l-ylamidophenoxy)- pyrimidin-4-yl] imidazole ; l-(4-Piperidinyl)-4-(4-fluorophenyl)-5-(2-isopropoxy-4-pyrimidinyl)imidazole; l-(4-Piperidinyl)-4-(4-fluorophenyl)-5-(2-methoxy-4-pyrirnidinyl)imidazole; 5-(2-Hydroxy-4-pyrimidinyl)-4-(4-fluorophenyl)-l-(4-piperidinyl)imidazole; 5-(2-Methoxy-4-pyridinyl)-4-(4-fluorophenyl)-l-(4-piperidinyl)imidazole; 5-(2-wo-Propoxy-4-pyridinyl)-4-(4-fluorophenyl)-l-(4-piperidinyl)imidazole; 5-(2-Methylthio-4-pyrimidinyl)-4-(4-fluorophenyl)- 1 -(4-piperidinyl)imidazole; 5-(2-Methylthio-4-pyrimidinyl)-4-(4-fluorophenyl)- 1 -[( 1 -methyl-4- piperidinyl]imidazole; 5-(2-Ethoxy-4-pyrimidinyl)-4-(4-fluorophenyl)-l-(4-piperidinyl)imidazole; l-(l-Ethylcarboxylpiperidin-4-yl)-3-(4-thiomethylphenyl)-5-[2-(thiomethyl)- pyrimidin-4-yl]imidazole;
1 -( 1 -Ethylcarbonylpiperidin-4-yl)-4-(4-methylsulfinylphenyl)-5-[2-methylsulfιnyl- pyrimidin-4-yl]imidazole; or pharmaceutically acceptable salts thereof.
METHODS OF TREATMENT
The cytokine inhibitor compounds, in particular those of Formula (I) or a pharmaceutically acceptable salt, can be used in the manufacture of a medicament for the prophylactic treatment or management of excessive, undesired or inappropriate uterine activity in a mammal, preferably a human, which activity is exacerbated or caused by excessive or unregulated cytokine production by such mammal.
The cytokine inhibitors of the p38/CSPB pathway are capable of inhibiting proinflammatory cytokines, such as JL-1, IL-6, IL-8 and TNF.
The cytokine inhibitors of the p38/CSPB pathway are administered in an amount sufficient to inhibit the cytokine, in particular IL-1, IL-6, IL-8 or TNF, production such that it is regulated down to normal levels, or in some cases to subnormal levels, so as to ameliorate or prevent the disease state. Abnormal levels of IL-1, IL-6, E -8 or TNF, for instance in the context of the present invention, constitute: (i) levels of free (not cell bound) IL-1, IL-6, J -8 or TNF greater than or equal to 1 picogram per ml; (ii) any cell associated IL-1, IL-6, IL-8 or TNF; or (iii) the presence of IL-1, IL-6, IL-8 or TNF mRNA above basal levels in cells or tissues in which IL-1, IL-6, IL-8 or TNF, respectively, is produced. As used herein, the term "inhibiting the production of IL-1 (IL-6, IL-8 or TNF)" refers to: a) a decrease of excessive in vivo levels of the cytolάne (IL-1, EL-6, IL-8 or TNF) in a human to normal or sub-normal levels by inhibition of the in vivo release of the cytokine ~ by all cells, including but not limited to monocytes or macrophages; b) a down regulation, at the genomic level, of excessive in vivo levels of the cytokine (EL-1, IL-6, IL-8 or TNF) in a human to normal or sub-normal levels; c) a down regulation, by inhibition of the direct synthesis of the cytokine (IL-1, IL-6, IL-8 or TNF) as a postranslational event; or d) a down regulation, at the translational level, of excessive in vivo levels of the cytokine (IL-1, E -6, IL-8 or TNF) in a human to normal or sub-normal levels. As used herein, the term "cytokine" refers to any secreted polypeptide that affects the functions of cells and is a molecule which modulates interactions between cells in the immune, inflammatory or hematopoietic response. A cytokine includes, but is not limited to, monokines and lymphokines, regardless of which cells produce them. For instance, a monokine is generally referred to as being produced and secreted by a mononuclear cell, such as a macrophage and/or monocyte. Many other cells, however, also produce monokines, such as natural killer cells, fibroblasts, basophils, neutrophils, endothelial cells, brain astrocytes, bone marrow stromal cells, epideral keratinocytes and B -lymphocytes. Lymphokines are generally referred to as being produced by lymphocyte cells. Examples of cytokines include, but are not limited to, Interleukin-1 (IL-1), Interleukin-6 (IL-6), Interleukin-8 (IL-8), Tumor Necrosis Factor-alpha (TNF-α) and Tumor Necrosis Factor beta (TNF-β).
As used herein, the term "cytokine interfering" or "cytokine suppressive amount" refers to an effective amount of a compound of Formula (I) which will cause a decrease in the in vivo levels of the cytokine to normal or sub-normal levels, when given to a patient for the prophylaxis or treatment of a disease state which is exacerbated by, or caused by, excessive or unregulated cytokine production.
The MAP kinase family, alternatively termed CSBP, p38, or RK, has been identified independently by several laboratories. Activation of this novel protein kinase via dual phosphorylation has been observed in different cell systems upon stimulation by a wide spectrum of stimuli, such as physiochemical stress and treatment with lipopolysaccharide or proinflammatory cytokines such as IL-1 and TNF. The cytokine biosynthesis inhibitors for use in the present invention, for instance compounds of Formula (I), have been determined to be potent and selective inhibitors of this CSBP/p38/RK kinase activity. These inhibitors are of aid in determining the signaling pathways involvement in inflammatory responses. In particular, for the first time a definitive signal transduction pathway can be prescribed to the action of lipopolysaccharide in cytokine production in macrophages. The CSBP protein is described in detail in Patent Application USSN 08/123175 Lee et al., filed September 1993; Lee et al., PCT/US94/10529 filed 16 September 1994; USSN 08/605002, filed 15 April 1996; USSN 08/469421, USSN 08/468902; and Lee et al., Nature 300, n(72), 739-746 ' (Dec. 1994). Inhibitors of the variants and homologs of the CSBP protein are also considered as another aspect of the present invention. One such variant is the p38 beta protein, as described in Jiang, Y., et al., J. Biol. Chem., 271, pp 17920-26 (1996); and variants in USSN 08/746788, filed 15 November 1996; whose disclosures are incoφorated by reference in their entirety herein.
Intracellular signal transduction is the means by which cells respond to extracellular stimuli. Regardless of the nature of the cell surface receptor (e.g. protein tyrosine kinase or seven-transmembrane G-protein coupled), protein kinases and phosphatases along with phopholipases are the essential machinery by which the signal is further transmitted within the cell [Marshall, J. C. CeU , 80, 179-278 (1995)]. Protein kinases can be categorized into five classes with the two major classes being, tyrosine kinases and serine / threonine kinases depending upon whether the enzyme phosphorylates its substrate(s) on specific tyrosine(s) or serine / threonine(s) residues [Hunter, T., Methods in Enzymology (Protein Kinase Classification) p. 3, Hunter, T.; Sefton, B. M.; eds. vol. 200, Academic Press; San Diego, 1991].
For most biological responses, multiple intracellular kinases are involved and an individual kinase can be involved in more than one signaling event. These kinases are often cytosolic and can translocate to the nucleus or the ribosomes where they can affect transcriptional and translational events, respectively. The involvement of kinases in transcriptional control is presently much better understood than their effect on translation as illustrated by the studies on growth factor induced signal transduction involving MAP/ERK kinase [Marshall, C. J. Cell , 80, 179 (1995); Herskowitz, I. Cell, 80, 187 (1995); Hunter, T. Cell , 80, 225 (1995); Seger, R., and Krebs, E. G. FASEB J., 726-735 (1995)].
While many signaling pathways are part of cell homeostasis, numerous cytokines (e.g., JL-1 and TNF) and certain other mediators of inflammation (e.g., COX-2, and iNOS) are produced only as a response to stress signals such as bacterial lippopolysaccharide (LPS). The first indications suggesting that the signal transduction pathway leading to LPS-induced cytokine biosynthesis involved protein kinases came from studies of Weinstein [Weinstein, et al., J. Immunol. 151, 3829(1993)] but the specific protein kinases involved were not identified. Working from a similar perspective, Han [Han, et al, Science. 265, 808(1994)] identified murine p38 as a kinase which is tyrosine phosphorylated in response to LPS. Definitive proof of the involvement of the p38 kinase in LPS-stimulated signal transduction pathway leading to the initiation of proinflammatory cytokine biosynthesis was provided by the independent discovery of p38 kinase by Lee [Lee; et al., Nature. 372, 739(1994)] as the molecular target for a novel class of anti- inflammatory agents. The discovery of p38 (termed by Lee as CSBP 1 and 2) provided a mechanism of action of a class of anti-inflammatory compounds for which SK&F 86002 was the prototypic example. These compounds inhibited IL-1 and TNF synthesis in human monocytes at concentrations in the low uM range [Lee, et al, Int. J. Immunopharmac. 10(7), 835(1988)] and exhibited activity in animal models which are refractory to cyclooxygenase inhibitors [Lee; et al., Annals N. Y. Acad. Sci., 696, 149(1993)].
ITOGEN AND STRESS ACTIVATED PROTEIN KINASE CASCADES
Figure imgf000029_0001
Figure 1
It is now firmly established that CSBP/p38 is a one of several kinases involved in a stress-response signal transduction pathway which is parallel to and largely independent of the analogous mitogen-activated protein kinase (MAP) kinase cascade (Figure 1). Stress signals, including LPS, pro-inflammatory cytokines, oxidants, UV light and osmotic stress, activate kinases upstream from CSBP/p38 which in turn phosphorylate CSBP/p38 at threonine 180 and tyrosine 182 resulting in CSBP/p38 activation. MAPKAP kinase-2 and MAPKAP kinase-3 have been identified as downstream substrates of CSBP/p38 which in turn phosphorylate heat shock protein Hsp 27 (Figure 2). It is not yet known whether MAPKAP-2, MAPKAP-3, Mnkl or Mnk2 are involved in cytokine biosynthesis or alternatively that inhibitors of CSBP/p38 kinase might regulate cytokine biosynthesis by blocking a yet unidentified substrate downstream from CSBP/p38 [Cohen, P. Trends Cell Biol.. 353-361(1997)].
p38 Kinase Pathway
LPS/IL-1/TNF stress/UV
Figure imgf000030_0001
Figure 2
What is known, however, is that in addition to inhibiting IL-1 and TNF, CSBP/p38 kinase inhibitors (SK&F 86002 and SB 203580) also decrease the synthesis of a wide variety of pro-inflammatory proteins including, IL-6, IL-8, GM-CSF and COX-2. Inhibitors of CSBP/p38 kinase have also been shown to suppress the TNF- induced expression of VCAM-1 on endothelial cells, the TNF-induced phosphorylation and activation of cytosolic PLA2 and the IL-1 -stimulated synthesis of collagenase and stromelysin. These and additional data demonstrate that CSBP/p38 is involved not only cytokine synthesis, but also in cytokine signaling [CSBP/P38 kinase reviewed in Cohen, P. Trends Cell Biol., 353-361(1997)].
Pharamaceutical Formulations
The cytokine biosynthesis inhibitors for use in the present invention will normally be formulated into a pharmaceutical composition in accordance with standard pharmaceutical practice, for example they will be formulated with a pharmaceutically acceptable diluent or carrier. Cytokine biosynthesis inhibitors, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions incoφorating such may conveniently be administered by any of the routes conventionally used for drug administration, for instance, orally, topically, parenterally or by inhalation. The cytokine biosynthesis inhibitors may be administered in conventional dosage forms prepared by combining a cytokine biosynthesis inhibitor with standard pharmaceutical carriers according to conventional procedures. Cytokine biosynthesis inhibitors may also be administered in conventional dosages in combination with a known, second therapeutically active compound. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation. It will be appreciated that the form and character of the pharmaceutically acceptable character or diluent is dictated by the amount of active ingredient with which it is to be combined, the route of administration and other well-known variables. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
The pharmaceutical carrier employed may be, for example, either a solid or liquid. Exemplary of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Exemplary of liquid carriers are syrup, peanut oil, olive oil, water and the like. Similarly, the carrier or diluent may include time delay material well known to the art, such as glyceryl mono-stearate or glyceryl distearate alone or with a wax.
A wide variety of pharmaceutical forms can be employed. Thus, if a solid carrier is used, the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge. The amount of solid carrier will vary widely but preferably will be from about 25mg to about lg. When a liquid carrier is used, the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampule or nonaqueous liquid suspension.
The cytokine biosynthesis inhibitors may be administered topically, that is by non- systemic administration. This includes the application of an inhibitor externally to the epidermis or the buccal cavity and the instillation of such a compound into the ear, eye and nose, such that the compound does not significantly enter the blood stream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.
Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation such as liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose. The active ingredient may comprise, for topical administration, from 0.001% to 10% w/w, for instance from 1% to 2% by weight of the formulation. It may however comprise as much as 10% w/w but preferably will comprise less than 5% w/w, more preferably from 0.1% to 1% w/w of the formulation.
Lotions according to the present invention include those suitable for application to the skin or eye. An eye lotion may comprise a sterile aqueous solution optionally containing a bactericide and may be prepared by methods similar to those for the preparation of drops. Lotions or liniments for application to the skin may also include an agent to hasten drying and to cool the skin, such as an alcohol or acetone, and/or a moisturizer such as glycerol or an oil such as castor oil or arachis oil. Creams, ointments or pastes according to the present invention are semi-solid formulations of the active ingredient for external application. They may be made by mixing the active ingredient in finely-divided or powdered form, alone or in solution or suspension in an aqueous or non-aqueous fluid, with the aid of suitable machinery, with a greasy or non-greasy base. The base may comprise hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap; a mucilage; an oil of natural origin such as almond, corn, arachis, castor or olive oil; wool fat or its derivatives or a fatty acid such as steric or oleic acid together with an alcohol such as propylene glycol or a macrogel. The formulation may incoφorate any suitable surface active agent such as an anionic, cationic or non-ionic surfactant such as a sorbitan ester or a polyoxyethylene derivative thereof. Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as silicaceous silicas, and other ingredients such as lanolin, may also be included.
Drops according to the present invention may comprise sterile aqueous or oily solutions or suspensions and may be prepared by dissolving the active ingredient in a suitable aqueous solution of a bactericidal and/or fungicidal agent and/or any other suitable preservative, and preferably include a surface active agent. The resulting solution may then be clarified by filtration, transferred to a suitable container which is then sealed and sterilized by autoclaving or maintaining at 98-100°C for half an hour. Alternatively, the solution may be sterilized by filtration and transferred to the container by an aseptic technique. Examples of bactericidal and fungicidal agents suitable for inclusion in the drops are phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%). Suitable solvents for the preparation of an oily solution include glycerol, diluted alcohol and propylene glycol.
The cytokine biosynthesis inhibitors may be administered parenterally, that is by intravenous, intramuscular, subcutaneous intranasal, intrarectal, intravaginal or intraperitoneal administration. The subcutaneous and intramuscular forms of parenteral administration are generally preferred. Appropriate dosage forms for such administration may be prepared by conventional techniques. The cytokine biosynthesis inhibitors may also be administered by inhalation, that is by intranasal and oral inhalation administration. Appropriate dosage forms for such administration, such as an aerosol formulation or a metered dose inhaler, may be prepared by conventional techniques.
For all methods of use disclosed herein for the cytokine biosynthesis inhibitors, including compounds of Formula (I), the preferred, dosage regimen would be parenteral until contractions cease, and then as long as necessary to optimise fetal well-being prior to delivery, i.e. as near to term (37 weeks gestation) as is necessary. In light of this, daily parenteral dosage regimen will be from about 0.1 to about 80 mg/kg of total body weight, preferably from about 0.2 to about 30 mg/kg, and more preferably from about 0.5 mg to 15mg/kg. The daily oral dosage regimen will preferably be from about 0.1 to about 80 mg/kg of total body weight, preferably from about 0.2 to 30 mg/kg, more preferably from about 0.5 mg to 15mg. The daily topical dosage regimen, such as may be applied to prevent cervical ripening, could be administered topically to the cervix to prevent cervical softening and delay fetal membrane rupture. Such as topical dosage will preferably be in a formulation containing from 0.1 mg to 150 mg, administered one to four, preferably two or three times daily. The daily inhalation dosage regimen, if applicable, will preferably be from about 0.01 mg/kg to about 1 mg/kg per day.
It will also be recognized by one of skill in the art that the optimal quantity and spacing of individual dosages of cytokine biosynthesis inhibitor will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular patient being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e., the number of doses given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests.
BIOLOGICAL EXAMPLES
The cytokine-inhibiting effects of compounds for use in the present invention, such as those noted above, may be determined by the following in vitro assays: Assays for Interleukin- 1 (IL-1), Interleukin-8 (IL-8 ), and Tumour Necrosis
Factor (TNF) are well known in the art, and may be found in a number of publications, and patents. Representative suitable assays for use herein are described in Adams et al., US 5,593,992, whose disclosure is incoφorated by reference in its entirety.
Interleukin - 1 (IL-1)
Human peripheral blood monocytes are isolated and purified from either fresh blood preparations from volunteer donors, or from blood bank buffy coats, according to the procedure of Colotta et al, J Immunol, 132, 936 (1984). These monocytes (1x10^) ^e plated in 24- well plates at a concentration of 1-2 million/ml per well. The cells are allowed to adhere for 2 hours, after which time non-adherent cells are removed by gentle washing. Test compounds are then added to the cells for lh before the addition of lipopolysaccharide (50 ng/ml), and the cultures are incubated at 37°C for an additional 24h. At the end of this period, culture supernatants are removed and clarified of cells and all debris. Culture supernatants are then immediately assayed for LL-1 biological activity, either by the method of Simon et a , J. Immunol. Methods, 84, 85, (1985) (based on ability of IL-1 to stimulate a Interleukin 2 producing cell line (EL-4) to secrete IL-2, in concert with A23187 ionophore) or the method of Lee et al, J. ImmunoTherapy, 6 (1), 1-12 (1990) (ELISA assay).
In vivo TNF assay:
(1) Griswold et al, Drugs Under Exp. and Clinical Res.,XIX (6). 243-248 (1993); or
(2) Boehm, et al, Journal Of Medicinal Chemistry 39, 3929-3937 (1996) whose disclosures are incoφorated by reference herein in their entirety.
LPS -induced TNFα Production in Mice and Rats In order to evaluate in vivo inhibition of LPS -induced TNFα production in rodents, both mice and rats are injected with LPS. Mouse Method
Male Balb/c mice from Charles River Laboratories are pretreated (30 minutes) with compound or vehicle. After the 30 min. pretreat time, the mice are given LPS (lipopolysaccharide from Esherichia coli Serotype 055-85, Sigma
Chemical Co., St Louis, MO) 25 ug/mouse in 25 ul phosphate buffered saline (pH 7.0) intraperitoneally. Two hours later the mice are killed by CO2 inhalation and blood samples are collected by exsanguination into heparinized blood collection tubes and stored on ice. The blood samples are centrifuged and the plasma collected and stored at -20°C until assayed for TNFα by ELISA.
Rat Method
Male Lewis rats from Charles River Laboratories are pretreated at various times with compound or vehicle. After a determined pretreat time, the rats are given LPS (lipopolysaccharide from Esherichia coli Serotype 055-85, Sigma Chemical Co., St Louis, MO) 3.0 mg/kg intraperitoneally. The rats are killed by CO2 inhalation and heparinized whole blood is collected from each rat by cardiac puncture 90 minutes after the LPS injection. The blood samples are centrifuged and the plasma collected for analysis by ELISA for TNFα levels.
ELISA Method TNFα levels were measured using a sandwich ELISA, as described in Olivera et al., Circ. Shock, 37, 301-306, (1992), whose disclosure is incoφorated by reference in its entirety herein, using a hamster monoclonal antimurine TNFα (Genzyme, Boston, MA) as the capture antibody and a polyclonal rabbit antimurine TNFa (Genzyme) as the second antibody. For detection, a peroxidase-conjugated goat antirabbit antibody (Pierce, Rockford, EL) was added, followed by a substrate for peroxidase (1 mg/ml orthophenylenediamine with 1% urea peroxide). TNFα levels in the plasma samples from each animal were calculated from a standard curve generated with recombinant murine TNFα (Genzyme).
LPS -Stimulated Cytokine Production in Human Whole Blood
Assay: Test compound concentrations were prepared at 10 X concentrations and LPS prepared at 1 ug/ml (final cone, of 50 ng/ml LPS) and added in 50 uL volumes to 1.5 mL eppendorf tubes. Heparinized human whole blood was obtained from healthy volunteers and was dispensed into eppendorf tubes containing compounds and LPS in 0.4 mL volumes and the tubes incubated at 37 C. Following a 4 hour incubation, the tubes were centrifuged at 5000 rpm for 5 minutes in a TOMY microfuge, plasma was withdrawn and frozen at -80 C.
Cytokine measurement: IL-I and/or TNF were quantified using a standardized ELISA technology. An in-house ELISA kit was used to detect human IL-1 and TNF. Concentrations of IL- 1 or TNF were determined from standard curves of the appropriate cytokine and IC50 values for test compound (concentration that inhibited 50% of LPS -stimulated cytokine production) were calculated by linear regression analysis.
Cytokine Specific Binding Protein Assay
A radiocompetitive binding assay was developed to provide a highly reproducible primary screen for structure-activity studies. This assay provides many advantages over the conventional bioassays which utilize freshly isolated human monocytes as a source of cytokines and ELISA assays to quantify them. Besides being a much more facile assay, the binding assay has been extensively validated to highly correlate with the results of the bioassay. A specific and reproducible cytokine inhibitor binding assay was developed using soluble cystosolic fraction from THP.1 cells and a radiolabeled compound. Patent Application USSN 08/123175 Lee et al., filed September 1993, US 5,783,644 and US 5,777,097 Lee et al., WO94/10529 filed 16 September 1994 and Lee et al., Nature 300, n(72), 739-746 (Dec. 1994) whose disclosures are incoφorated by reference herein in its entirety describes the above noted method for screening drugs to identify compounds which interact with and bind to the cytokine specific binding protein (hereinafter CSBP). However, for puφoses herein the binding protein may be in isolated form in solution, or in immobilized form, or may be genetically engineered to be expressed on the surface of recombinant host cells such as in phage display system or as fusion proteins. Alternatively, whole cells or cytosolic fractions comprising the CSBP may be employed in the screening protocol. Regardless of the form of the binding protein, a plurality of compounds are contacted with the binding protein under conditions sufficient to form a compound/ binding protein complex and compound capable of forming, enhancing or interfering with said complexes are detected.
CSBP/p38 Kinase Assay:
This assay measures the CSBP/p38-catalyzed transfer of 32p from [a- 32p]ATP to threonine residue in an epidermal growth factor receptor (EGFR)-derived peptide (T669) with the following sequence: KRELVEPL7PSGEAPNQALLR (residues 661-681). (See Gallagher et al., "Regulation of Stress Induced Cytokine Production by Pyridinyl Imidazoles: Inhibition of CSBP Kinase", BioOrganic & Medicinal Chemistry, 1997, 5, 49-64).
Reactions were carried in round bottom 96 well plate (from Corning) in a 30 ml volume. Reactions contained (in final concentration): 25 mM Hepes, pH7.5; 8 mM MgCl2i 0.17 mM ATP (the KmrATP] of P38 (see Lee et al., Nature 300, n72 pg 639-746 (Dec. 1994)); 2.5 uCi of [g-32P]ATP; 0.2 mM sodium orthovanadate; 1 mM DTT; 0.1% BSA; 10% glycerol; 0.67 mM T669 peptide; and 2-4 nM of yeast- expressed, activated and purified p38. Reactions were initiated by the addition of [gamma-32P]Mg/ATP, and incubated for 25 min. at 37 °C. Inhibitors (dissolved in DMSO) were incubated with the reaction mixture on ice for 30 minutes prior to adding the 32P-ATP. Final DMSO concentration was 0.16%. Reactions were terminated by adding 10 ul of 0.3 M phosphoric acid, and phosphorylated peptide was isolated from the reactions by capturing it on p81 phosphocellulose filters. Filters were washed with 75 mM phosphoric acids, and incoφorated 32P was quantified using beta scintillation counter. Under these conditions, the specific activity of p38 was 400-450 pmol/pmol enzyme, and the activity was linear for up to 2 hr of incubation. The kinase activity values were obtained after subtracting values generated in the absence of substrate which were 10-15% of total values.
Modulation of PGE2 and IL-lβ production The Examples below determine the effects of the CSAID™ compounds on the ability to modulate both PGE2 and IL-lβ production from fetal membranes.
Fetal membranes were obtained from term elective caesarean sections from uncomplicated pregnancies and washed in phosphate buffered saline containing 10% penicillin, streptomycin and L-glutamine. Whole membrane discs consisting of adherent amnion and chorio-decidua each measuring 1.5 cm were then cut and incubated overnight in multiwell tissue culture plates at 37°C, 95% air, 5% CO2 in serum free medium 199 (Sigma) supplemented with insulin, transferrin and selenium. Following the addition of fresh medium 199 four experimental groups (A to D) were set up. Each experimental group consisted of identical triplicate tissue culture wells.
Group Medium
A Control (Unstimulated)
B Control (Unstimulated) + SKF86002
C LPS
D LPS + SKF 86002
LPS (Sigma-E.coli Serotype 0114:B4) was used at a concentration of 108 g/dl. SKF 86002 was dissolved in ethanol to provide a final concentration of 10 μM. Group A consisted of control discs incubated in medium alone. Incubations were carried out for four, eight and twelve hours following which the supernatants were harvested and stored at -20°C for subsequent estimation of IL- lβ and PGE2 levels by ELISA {enzyme linked immunosorbent assay (Amersham) } .
Control wells consisting of ethanol and medium 199 with and without LPS were also included. Fetal membrance viability was assessed using the diaphorase histochemical method, see Aldred L.F., et al. (1983) J. Steroid Biochem., 18, 411-414.
RESULTS: IL-lβ production: Mixed model analysis of variance was used to analyse the data. The assumptions of the analysis of variance were checked and a log transformation was found to be the most appropriate. Data is presented on an untransformed original scale for ease of inteφretation.
Group:
Group A v Group B p=0.007
Difference = 25.5 95% CI (-2.3, 53.3)
Group C v Group D p=0.002
Difference 45.5 95% CI (17.9, 73.2)
Time:
4 hours v 12 hours p=0.08 Difference 22.7 95% CI (-3.0, 48.4)
PGE-, production:
Mixed model analysis of variance was used to analyse the data. The assumptions of the analysis of variance were checked and a log transformation was found to be the most appropriate. Data is presented on an untransformed scale for ease of inteφretation.
Group:
Group A v Group B p<0.001 Difference 109 95% CI (78.96, 139.9)
Group C v Group D p<0.001 Difference 161 95% CI (130.6, 191.9)
Tissue viability was not compromised by the addition of the drug as tested by the diaphorase method. Ethanol alone did not significantly inhibit production of either PGE2 or IL-lβ from the fetal membranes.
Conclusions The results indicate that following treatment with the prototype CSAID™ compound SKF 86002 [6-(4-fluorophenyl)-2,3-dihydro-5-(4- pyridinyl)imidazo[2,l-b]thiazole] there was a significant decrease in the production of both PGE2 and IL- 1 β from fetal membranes.
SKF 86002 reduced IL-lβ production from both control (p=0.07) and LPS stimulated wells (p=0.002). The effects of the agent appeared to diminish after 12 hours incubation. Maximal production of IL-lβ from all treatment groups occurred after 8 hours incubation. IL-lβ production was significantly lower at 12 hours compared to 4 hours in all treatment groups (p=0.08). SKF86002 reduced PGE2 production from both control (p<0.001) and LPS stimulated wells (p<0.001). The effects did not seem to diminish throughout the incubation period.
This data indicates that CSAID™ compounds have utility to modulate prostaglandin and interleukin production from gestational tissues. As the compound decreased basal PGE2 and IL-lβ production as well as production in response to LPS, this provides a basis for treatment of both infection driven and idiopathic pre-term labour.
All publications, including but not limited to patents and patent applications, cited in this specification are herein incoφorated by reference as if each individual publication were specifically and individually indicated to be incoφorated by reference herein as though fully set forth.
The above description fully discloses the invention including preferred embodiments thereof. Modifications and improvements of the embodiments specifically disclosed herein are within the scope of the following claims. Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. Therefore the
Examples herein are to be construed as merely illustrative and not a limitation of the scope of the present invention in any way. The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows.

Claims

What is Claimed is:
1. A method of prophylactic treatment or management of excessive, undesired or inappropriate uterine activity in a mammal, which method comprises administering to said mammal an effective amount of a compound which inhibits the production, transcription or translation of a cytokine.
2. The method according to Claim 1 wherein the cytokine is inhibited by inhibition of the kinase CSBP/p38/RK.
3. The method according to Claim 1 or 2 wherein the uterine activity is preterm labour which is infection driven.
4. The method according to Claim 1 or 2 wherein the uterine activity is idiopathic pre-term labour.
5. The method according to Claim 1 or 2 wherein the uterine activity is unwanted dilatation, or ripening of the cervix.
6. The method according to Claim 1 or 2 wherein the uterine activity is preterm rupture of the fetal membrane.
7. The method according to Claim 1 or 2 wherein the uterine activity is eclampsia or pre-eclampsia.
8. The method according to any one of the preceding claims wherein the compound is of the formula (I):
Figure imgf000040_0001
wherein:
Rl is a pyrid-4-yl, pyrimidin-4-yl, pyridazin-4-yl, l,2,4-triazin-5-yl, quinol-4-yl, isoquinolinyl, quinazolin-4-yl, 1-imidazolyl or 1-benzimidazolyl ring, which ring is optionally substituted independently one to three times with Y, NHRa, optionally substituted Ci-4 alkyl, halogen, hydroxyl, optionally substituted Ci-4 alkoxy, optionally substituted Ci-4 alkylthio, Ci-4 alkylsulfinyl, CH2ORi2┬╗ amino, mono and di- Ci-6 alkyl substituted amino, or N(Rio)C(O)Rt>;
Y is O-Ra;
R4 is phenyl, naphth-1-yl or naphth-2-yl, or heteroaryl, which is optionally substituted by one or two substituents, each of which is independently selected, and which, for a
4-phenyl, 4-naphth-l-yl, 5-naphth-2-yl or 6-naphth-2-yl substituent, is halogen, cyano, nitro, C(Z)NR7Ri7, C(Z)ORi6, (CR╬╣oR2╬╕)vCORi2, SR5, SOR5, OR12, halo- substituted-Ci-4 alkyl, C1-4 alkyl, ZC(Z)Ri2, NR╬╣oC(Z)Ri6, or (CRioR20)vNRioR20> and which, for other positions of substitution, is halogen, cyano, C(Z)NR RI4, C(Z)OR3, (CRioR20)m"COR3, S(O)mR3, OR3, halo- substituted-C╬╣.4 alkyl, Ci-4 alkyl, (CRioR2╬╕)m"NRl╬╕C(Z)R3, NR╬╣oS(O)m'R8, NR╬╣oS(O)m'NR7Rl7, ZC(Z)R3 or (CRioR2╬╕)m"NRl3Rl4; v is 0, or an integer having a value of 1 or 2; n is an integer having a value of 1 to 10; n' is 0, or an integer having a value of 1 to 10; m is 0, or an integer having a value of 1 or 2; m' is an integer having a value of 1 or 2, m" is 0, or an integer having a value of 1 to 5;
R2 is hydrogen, (CR╬╣oR2╬╕)n' OR9, heterocyclyl, heterocyclylCi-io alkyl, C MO alkyl, halo-substituted -io alkyl, C2-10 alkenyl, C2-10 alkynyl, C3.7 cycloalkyl, C3.7 cycloalkylCi-io alkyl, C5-.7 cycloalkenyl, C5-7 cycloalkenylCi-io alkyl, aryl, arylCi- 10 alkyl, heteroaryl, heteroarylCi-io alkyl, (CR╬╣oR2╬╕)nORn, (CRioR20)nS(O)mRi8, (CR╬╣oR2╬╕)nNHS(O)2Rl8, (CR╬╣0R20)nNRl3Rl4, (CRioR20)nNO2, (CRioR20)nCN, (CRioR20)n'SO2Rl8, (CRioR20)nS(O)m'NRi3Rl4, (CRl╬╕R2╬╕)nC(Z)Rn, (CRioR20)nOC(Z)Rn,
(CRi0R20)nC(Z)OR╬╣ i, (CRioR20)nC(Z)NRi Rl4, (CR╬╣0R20)nC(Z)NR╬╣ 1OR9, (CRioR20)nNRlOC(Z)Ri 1, (CR╬╣oR2╬╕)nNRl╬╕C(Z)NRi3Rl4, (CRioR2╬╕)nN(OR6)C(Z)NR╬╣3Ri4, (CR╬╣0R2╬╕)nN(OR6)C(Z)R╬╣ 1, (CRioR20)nC(=NOR6)Rl 1, (CR╬╣oR2╬╕)nNRi╬╕C(=NRi9)NR╬╣3Rl4, (CR╬╣oR2╬╕)nOC(Z)NRi3Rl4, (CRl╬╕R2╬╕)nNRl╬╕C(Z)NR╬╣3Rl4,
(CRioR20)nNRioC(Z)ORio, 5-(R╬╣8)-l,2,4-oxadizaol-3-yl or 4-(R12)-5-(R╬╣8R╬╣9)-4,5- dihydro-l,2,4-oxadiazol-3-yl; wherein the aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaryl alkyl, heterocyclyl and heterocyclyl alkyl groups may be optionally substituted; Z is oxygen or sulfur; Ra is a Ci-6 alkyl, aryl, arylCi-6 alkyl, heterocyclyl, heterocyclylCi-6 alkyl, heteroaryl, or heteroarylCi-6 alkyl moiety, and wherein each of these moieties may be optionally substituted;
R is hydrogen, Ci-6 alkyl, C3-7 cycloalkyl, aryl, arylCi-4 alkyl, heteroaryl, heteroarylC 1.4 alkyl, heterocyclyl, or heterocyclylC 1.4 alkyl;
R3 is heterocyclyl, heterocyclylC ╬╣_ 10 alkyl or Rs;
R5 is hydrogen, C╬╣_4 alkyl, C2-4 alkenyl, C2-4 alkynyl or NR7R17, excluding the moieties SR5 being SNR7R17 and SOR5 being SOH;
R6 is hydrogen, a pharmaceutically acceptable cation, Ci-io alkyl, C3.7 cycloalkyl, aryl, arylCi-4 alkyl, heteroaryl, heteroarylC 1.4 alkyl, heterocyclyl, aroyl, or Ci-io alkanoyl;
R7 and R17 is each independently selected from hydrogen or Ci-4 alkyl or R7 and R17 together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR 15 ;
R8 is a Ci-io alkyl, halo-substituted Ci-io alkyl, C2-10 alkenyl, C2-10 alkynyl, C3..7 cycloalkyl, C5-7 cycloalkenyl, aryl, arylCi-io alkyl, heteroaryl, heteroarylC ╬╣_ 10 alkyl, (CRioR20)nORl l, (CRioR20)nS(O)mRi8, (CR╬╣0R20)nNHS(O)2Rl8, or (CR╬╣oR2╬╕)nNRl3Rl4 moiety; wherein the aryl, arylalkyl, heteroaryl, heteroaryl alkyl moieties may be optionally substituted;
R9 is hydrogen, C(Z)R╬╣ 1 or optionally substituted Ci-io alkyl, S(O)2Rl84 optionally substituted aryl or optionally substituted arylCi-4 alkyl;
RlO and R20 is each independently selected from hydrogen and C╬╣_4 alkyl;
Rl l is hydrogen, Ci-io alkyl, C3-7 cycloalkyl, heterocyclyl, heterocyclylC l- 10 alkyl, aryl, arylCi-io alkyl, heteroaryl or heteroarylC i- 10 alkyl;
Rl2 is hydrogen or Ri6;
Rl3 and R14 is each independently selected from hydrogen, optionally substituted C1.4 alkyl, optionally substituted aryl or optionally substituted arylC╬╣.4 alkyl, or together with the nitrogen to which they are attached R13 and R14 form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR9;
Rl5 is Rio or C(Z)-C╬╣_4 alkyl;
Rl6 is Ci-4 alkyl, halo-substituted-Ci-4 alkyl, or C3-7 cycloalkyl;
Rl8 is Ci-io alkyl, C3-.7 cycloalkyl, heterocyclyl, aryl, arylCi-io alkyl, heterocyclyl, heterocyclylC i- 10 alkyl, heteroaryl or heteroarylC 1- 10 alkyl;
Rl9 is hydrogen, cyano, Ci-4 alkyl, C3-.7 cycloalkyl or aryl; or a pharmaceutically acceptable salt thereof.
9. The method according to Claim 8 wherein Ri is optionally substituted 4-pyridyl or 4-pyrimindyl.
10. The method according to Claim 8 or 9 wherein Ra is alkyl, aryl, arylalkyl, halosubstituted arylalkyl, halosubstituted aryl, heterocyclyl alkyl, hydroxyalkyl, alkyl- 1- piperidine-carboxylate, heterocyclyl, alkyl substituted heterocyclyl, halosubstituted heterocyclyl, or aryl substituted heterocyclyl.
11. The method according to Claim 10 wherein R is methyl, ethyl, iospropoxy, benzyl, halosubstituted benzyl, naphthylmethyl, phenyl, halosubstituted phenyl, moφholinopropyl, 2-hydroxyethyl, ethyl- 1-piperidinecarboxy late, piperonyl, piperidin-4-yl, alkyl substituted piperidine, chlorotryptamine, or tetrathiohydropyranyl.
12. The method according to any one of claims 8 to 11 wherein R4 is optionally substituted phenyl.
13. The method according to Claim 12 wherein the phenyl is substituted in the 4- position by halogen.
14. The method according to any one of claims 8 to 13 wherein R2 is selected from optionally substituted heterocyclyl, optionally substituted heterocyclylC ╬╣_ 10 alkyl, (CR╬╣0R20)nNS(O)2Rl8> (CRl╬╕R2╬╕)nS(O)mR╬╣8, arylCi- 10 alkyl, (CRioR20)nNRl3Rl4, optionally substituted C3.7 cycloalkyl, and optionally substituted C3..7 cycloalkylCi-io alkyl.
15. The method according to Claim 14 wherein R2 is moφholino propyl, piperidine, N-methylpiperidine, N-benz lpiperidine, 2,2,6,6-tetramethylpiperidine, 4-aminopiperidine, 4-amino-2,2,6,6-tetramethyl piperidine, 4-hydroxycyclohexyl, 4-methyl-4-hydroxycyclohexyl, 4-pyrrolinindylcyclohexyl, 4-methyl-4- aminocyclohexyl, 4-methyl-4-acetamidocyclohexyl, 4-ketocyclohexyl, 4-oxiranyl, or 4-hydroxy-4-( 1 -propynyl)cyclohexyl.
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