WO1992001683A1 - Benzodiazepine derivatives - Google Patents

Benzodiazepine derivatives Download PDF

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Publication number
WO1992001683A1
WO1992001683A1 PCT/JP1991/000952 JP9100952W WO9201683A1 WO 1992001683 A1 WO1992001683 A1 WO 1992001683A1 JP 9100952 W JP9100952 W JP 9100952W WO 9201683 A1 WO9201683 A1 WO 9201683A1
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Prior art keywords
compound
salt
group
formula
substituent
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PCT/JP1991/000952
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French (fr)
Inventor
Yoshinari Sato
Hiromichi Itani
Takatomo Ogahara
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Fujisawa Pharmaceutical Co., Ltd.
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Application filed by Fujisawa Pharmaceutical Co., Ltd. filed Critical Fujisawa Pharmaceutical Co., Ltd.
Priority to AU82171/91A priority Critical patent/AU650034B2/en
Publication of WO1992001683A1 publication Critical patent/WO1992001683A1/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D243/00Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/141,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
    • C07D243/161,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
    • C07D243/181,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
    • C07D243/24Oxygen atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D403/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D403/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings

Definitions

  • This invention relates to new benzodiazepin ⁇ derivatives and pharmaceutically acceptable salrs thereof which are useful as a medicament.
  • This invention relates to new benzodiazepine derivatives and pharmaceutically acceptable salts thereof,
  • benzodiazepine derivatives and pharmaceutically acceptable salts thereof which are cholecystokinin (CCK) antagonists and therefore useful as therapeutical and/or preventive agents for emesis, pancreatitis, disorders of appetite requlatory systems, pain, insulinoma, gastroparesis, carcinoma of pancreas, gallbladder disease (e.g. acute cholecystitis, calculus, e ⁇ c), disorders associated with intenstinal smooth muscle hyperactivity (e.g. irritable bowel syndrome, sphincter spasm, etc.), hyperinsulinemia, dyspepsia, nausea, etc.
  • CCK cholecystokinin
  • the benzodiazepine derivatives of this invention can be represented by the following formula (I) :
  • R is heterocyclic group which may have one or more suitable s bstituent(s) , or cyano,
  • 3 R is aryl which may have one or more suitable substituent(s)
  • 4 R is aryl which may have one or more suitable substituent(s) , ar(lower)alkenyl which may have one or more suitable substituent(s) , arylamino which may have one or more suitable substituent(s) , heteromonocyclic group which may have one or more suitable substituent(s) , qninolyl, isoquinolyl, cinnolinyl, indolyl, or guinoxalinyl, and
  • A is lower alkylene
  • R is tetrazolyl which may have one or more suitable substituent(s) and 3 R is halophenyl or ⁇ (ii) R is imidazolyl which may have one or more suitable substituent(s) ,
  • the new benzodiazepine derivatives (I) can be prepared by the processes which are illustrated in the following scheme, Process 1
  • R 1, R2, R3, R4 and A are each as defined above,
  • R 3. is heterocyclic group having a protected i ino group of the formula :
  • R is heterocyclic group having an imino group of the formula :
  • R is ar(lower)alkenyl having a nitro group
  • R is ar(lower)alkenyl having an amino group and X is an acid residue.
  • the starting co ⁇ pounds (II) and (IV) can be prepared by the following processes.
  • R 1, R2, R3, R4 and A are each as defined above, and
  • the starting compound (VII) or a salt thereof can be prepared by the methods disclosed in the Preparations 1-3, 6 and 7 described later or similar manners thereto .
  • Suitable pharmaceutically acceptable salts of the object compound (I) are conventional non-toxic salts and include a metal salt such as an alkali metal salt (e.g. sodium salt, potassium salt, etc.) and an alkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.), an ammonium salt, an organic base salt (e.g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.), an organic acid salt (e.g.
  • a metal salt such as an alkali metal salt (e.g. sodium salt, potassium salt, etc.) and an alkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.), an ammonium salt, an organic base salt (e.g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N'-dibenzy
  • heterocyclic group may include saturated or unsaturated, monocyclic or polycyclic heterocyclic group containing at least one hetero-atom such as an oxygen, sulfur, nitrogen atom and the like.
  • heterocyclic group may be heterocyclic group such as unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide, pyri idyl, pyrazinyl, pyridazinyl, dihydropyridazinyl, tetrahydropyridazinyl, triazolyl (e.g.
  • tetrazolyl e.g., lH-tetrazolyl, 2H-tetrazolyl, etc.
  • dihydrotriazinyl e.g., 4,5-dihydro-
  • Suitable "substituent" in the terms “heterocyclic group which may have one or more suitable substituent(s)” and “heteromonocyclic group which may have one or more suitable substituent( ⁇ )” may include amino, protected amino as exemplified below, oxo, hydroxy, imino protective group as exemplified below, lower alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, t-pentyl, hexyl, etc.) and the like.
  • lower alkyl e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, t-pentyl, hexyl, etc.
  • Suitable "protected amino” may include acylamino and the like.
  • Suitable “imino protective group” may include acyl, mono(or di or tri)phenyl(lower)alkyl (e.g. trityl, etc. ) tetrahydropyranyl and the like.
  • acyl and “acyl moiety” in the term “acylamino” may include aliphatic acyl group and acyl group containing an aromatic or heterocyclic ring. And, suitable examples of the said acyl may be lower alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl, etc. ) ; lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
  • lower alkanoyl e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl, etc.
  • lower alkoxycarbonyl e.g. methoxycarbonyl, ethoxycarbonyl
  • ar(lower)alkanoyl e.g. phenylacetyl, phenylpropionyl, etc.
  • ar(lower)alkoxycarbonyl e.g. benzyloxycarbonyl, phenethyloxycarbonyl, etc.
  • acyl moiety as stated above may have at least one suitable substituent(s) such as halogen (e.g. chlorine, bromine, fluorine and iodine), amino, protected amino
  • suitable substituent(s) such as halogen (e.g. chlorine, bromine, fluorine and iodine), amino, protected amino
  • Suitable "acid residue” may include halogen and the like.
  • Suitable "halogen” may include chlorine, bromine, fluorine and iodine.
  • aromatic alkenyl and “arylamino” may include phenyl, naphthyl and the like.
  • Suitable "substituent” in the terms "aryl which may have one or more suitable substituent(s)", ar(lower)alkenyl which may have one or more suitable substituent(s)” and “arylamino which may have one or more suitable substituent(s)” may include hydroxy, protected hydroxy as exemplified below, nitro, lower alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentyloxy, t-pentyloxy, hexyloxy, etc.), amino, protected amino as exemplified above, lower alkyl (e.g.
  • Suitable "lower alkenyl moiety" in the term “ar(lower)alkenyl” may include vinyl, allyl, 1-propenyl, 1 or 2 or 3-butenyl, 1 or 2 or 3 or 4-pentenyl, 1 or 2 or 3 or 4 or 5-hexenyl and the like.
  • heteromonocyclic group may include saturated or unsaturated heteromonocyclic group containing at least one hetero-atom such as an oxygen, sulfur, nitrogen atom and the like. And, especially preferable heteromonocyclic group may be heteromonocyclic group such as unsaturated 3 to 8-membered heteromonocyclc group containing 1 to 4 nitrogen atom( ⁇ ), for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide, pyrimidyl, pyrazinyl, pyridazinyl, dihydropyridazinyl, tetrahydropyridazinyl, triazolyl (e.g.
  • 1,2,4-triazolyl 1H-1,2,3-triazolyl, 2H-l,2,3-triazolyl, etc.
  • tetrazolyl e.g., lH-tetrazolyl, 2H-tetrazolyl, etc.
  • dihydrotriazinyl e.g., 4,5-dihydro-l,2,4- triazinyl, 2,5-dihydro-l,2,4-triazinyl, etc.
  • saturated 3 to*-8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s) for example, pyrrolidinyl, imidazolidmyl, piperidino, piperazinyl, etc.
  • 1,2,3-thiadiazolyl, etc. saturated 3 to 8-membered heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolidinyl, etc.; unsaturated 3 to 8-membered heteromonocyclic group containing an oxygen atom, for example furyl, etc.; unsaturated 3 to 8-membered heteromonocyclic group containing a sulfur atom, for example, thienyl, etc.; and the like.
  • Suitable "lower alkylene” may include straight or branched one having 1 to 6 carbon atom(s), such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene or the like, preferably one having 1 to 4 carbon atom(s).
  • heterocyclic group in the terms
  • H may include unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrroiyl, pyrrolinyl, imidazolyl, pyrazolyl, dihydropyridaziny "1 , tetrahydropyridazinyl, triazolyl (e.g.
  • tetrazolyl e.g., IH-tetrazolyl, 2H-tetrazolyl, etc.
  • dihydrotriazinyl e.g., 4,5-d
  • R is heterocyclic group (more preferably unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom( ⁇ ), most preferably tetrazolyl or imidazolyl) which may have one to three (more preferably one) suitable substituent( ⁇ ) [more preferably tetrazolyl or imidazolyl, each of which may have an imino protective group; most preferably tetrazolyl or imidazolyl, each of which may have monofor di or tri)phenyl(lower)alkyl] , or cyano;
  • 2 R is hydrogen; 3 R is aryl (more preferably phenyl) which may have one to three (more preferably one) suitable substituent( ⁇ )
  • R is aryl (more preferably phenyl or naphthyl) which may have one to three (more preferably one or two) suitable substituent( ⁇ ) [more preferably phenyl or naphthyl, each of which may have one or two substituent(s) selected from the group consisting of halogen and amino; most preferably naphthyl, dihalophenyl or phenyl having halogen and amino] , ar(lower)alkenyl (more preferably phenyl(lower)alkenyl) which may have one to three (more preferably one) suitable substituent( ⁇ ) [more preferably phenyl(lower)alkenyl which may have amino or nitro; most preferably nitrophenyl(lower)alkenyl or aminophenyl(lower)alkenyl] , arylamino (more preferably phenyla ino) which may have one to three (more preferably one) suitable substituent(s) [more preferably phenylamino
  • R is tetrazolyl and 3 R is halophenyl or
  • R is imidazolyl which may have mono(or di or tri)- phenyl(lower)alkyl
  • R is hhaalloopphheennyyl and is ethylene.
  • the compound (I) or a salt thereof can be prepared by reacting the compound (II) or its reactive derivative at the amino group or a salt thereof with the compound (III) or its reactive derivative or a salt thereof.
  • Suitable reactive derivative at the amino group of the compound (II) may include Schiff's base type imino or its tautomeric enamine type isomer formed by the reaction of the compound (II) with a carbonyl compound such as aldehyde, ketone or the like; a silyl derivative formed by the reaction of the compound (II) with a silyl compound such as N,0-bis(trimethylsilyl)acetamide, N-trimethylsilylacetamide or the like; a derivative formed by the reaction of the compound (II) with phosphorus trichloride or phosgene and the like.
  • Suitable salts of the compound (II) and (III) can be referred to the ones as exemplified for the compound (I).
  • Suitable reactive derivative of the compound (III) may include an acid halide, an acid anhydride, an activated amide, an activated ester, isocyanate and the like.
  • the suitable example may be an acid chloride, an acid azide; a mixed acid anhydride with an acid such as substituted phosphoric acid (e.g.
  • dialkylphosphoric acid phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated pho ⁇ phoric acid, etc.
  • dialkylpho ⁇ phorous acid sulfurous acid, thio ⁇ ulfuric acid,• alkanesulfonic acid (e.g. methanesulfonic acid, ethanesulfonic acid, etc.), ⁇ ulfuric acid, alkylcarbonic acid, aliphatic carboxylic acid (e.g. pivalic acid, pentanoic acid, i ⁇ opentanoic acid, 2-ethylbutyric acid, trichloroacetic acid, etc.) or aromatic carboxylic acid (e.g.
  • benzoic acid etc.
  • a ⁇ ymmetrical acid anhydride an activated amide with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole
  • an activated e ⁇ ter e.g.
  • These reactive derivatives can optionally be selected from them according to the kind of the compound (III) to be used.
  • the reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvents which do not adversely influence the reaction.
  • a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvents which do not adversely influence the reaction.
  • a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine
  • the reaction is preferably carried out in the presence of a conventional condensing agent such as N,N'-dicyclohexylcarbodiimide; N-cyclohexyl-N'-morpholinoethylcarbodiimide;
  • the reaction may al ⁇ o be carried out in the presence of an inorganic or organic ba ⁇ e such as an alkali metal bicarbonate, tri(lower)alkylamine, pyridine, N-(lower)alkylmorphorine, N,N-di(lower)alkylbenzylarain ⁇ , or the like.
  • an inorganic or organic ba ⁇ e such as an alkali metal bicarbonate, tri(lower)alkylamine, pyridine, N-(lower)alkylmorphorine, N,N-di(lower)alkylbenzylarain ⁇ , or the like.
  • the reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.
  • the compound (lb) or a salt thereof can be prepared by subjecting the compound (Ia) or a salt thereof to elimination reaction of the imino protective group.
  • Suitable method of this reaction may include conventional one such as hydrolysis, reduction and the like.
  • Suitable base may include an inorganic base and an organic base such as an alkali metal [e.g. sodium, potassium, etc.], the hydroxide or carbonate or bicarbonate thereof, trialkylamine [e.g. trimethylamine, triethylamine, etc.], picoline, 1,5-diazabicyclo[4.3.0]- non-5-ene, 1,4-diazabicyclo[2.2.2]octane, l,8-diazabicyclo[5.4.0]undec-7-ene, or the like.
  • an alkali metal e.g. sodium, potassium, etc.
  • trialkylamine e.g. trimethylamine, triethylamine, etc.
  • picoline 1,5-diazabicyclo[4.3.0]- non-5-ene
  • 1,4-diazabicyclo[2.2.2]octane 1,4-diazabicyclo[2.2.2]octane
  • Suitable acid may include an organic acid [e.g. formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.] and an inorganic acid [e.g. hydrochloric acid, hydrobromic acid, sulfuric acic, hydrogen chloride, hydrogen bromide, etc.].
  • organic acid e.g. formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.
  • an inorganic acid e.g. hydrochloric acid, hydrobromic acid, sulfuric acic, hydrogen chloride, hydrogen bromide, etc.
  • the elimination using Lewis acid ⁇ uch as trihaloacetic acid [e.g. trichloroacetic acid, trifluoroacetic acid, etc.] or the like is preferably carried out in the presence of cation trapping agent ⁇ [e.g. anisole, phenol, etc.].
  • the reaction is usually carried out in a solvent such as water, an alcohol [e.g. methanol, ethanol, etc.], N,N-dimethylformamide, methylene chloride, tetrahydrofuran, a mixture thereof or any other solvent which does not adversely influence the reaction.
  • a liquid base or acid can be also used as the solvent.
  • the reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
  • Reduction is carried out in a conventional manner, including chemical reduction and catalytic reduction.
  • Suitable reducing agents to be used in chemical reduction are a combination of a metal (e.g. tin, zinc, iron, etc.) or metallic compound (e.g. chromium chloride, chromium acetate, etc.) and an organic or inorganic acid (e.g. formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.).
  • a metal e.g. tin, zinc, iron, etc.
  • metallic compound e.g. chromium chloride, chromium acetate, etc.
  • organic or inorganic acid e.g. formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.
  • Suitable catalysts to be used in catalytic reduction are conventional one ⁇ such as platinum catalysts (e.g. platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.), palladium catalysts (e.g. spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate, etc.), nickel catalysts (e.g. reduced nickel, nickel oxide, Raney nickel, etc.), cobalt catalysts (e.g. reduced cobalt, Raney cobalt, etc.), iron catalysts (e.g. reduced iron, Raney iron, etc.), copper catalysts (e.g.
  • platinum catalysts e.g. platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.
  • palladium catalysts e.g. spongy palladium, palladium black, palladium oxide, palladium on
  • the reduction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, methanol, ethanol, propanol, N,N-dimethylformamide, tetrahydrofuran, or a mixture thereof.
  • a solvent which does not adversely influence the reaction
  • the above-mentioned acids to be u ⁇ ed in chemical reduction are in liquid, they can also be used as a solvent.
  • reaction temperature of this reduction is not critical and the reaction is u ⁇ ually carried out under cooling to heating.
  • the compound (Id) or a salt thereof can be prepared by subjecting the compound " (Ic) or a salt thereof to reduction reaction.
  • This reduction reaction can be . referred to that of the aforementioned Process 2.
  • the compound (I) or a salt thereof can be prepared by reacting the compound (IV) or a salt thereof with the compound (V) or a salt thereof.
  • Suitable salts of the compounds (IV) and (V) can be referred to the ones as exemplified for the compound (I) .
  • Suitable ba ⁇ e may include an inorganic ba ⁇ e ⁇ uch a ⁇ alkali metal hydride (e.g. sodium hydride, etc.), alkali metal hydroxide (e.g. sodium hydroxide, potas ⁇ ium hydroxide, etc.), alkaline earth metal hydroxide (e.g. magnesium hydroxide, calcium hydroxide, etc.), alkali metal carbonate (e.g. sodium carbonate, potassium carbonate, etc.), alkaline earth metal carbonate (e.g. magnesium carbonate, calcium carbonate, etc.), alkali metal bicarbonate (e.g. sodium bicarbonate, potas ⁇ ium bicarbonate, etc.
  • alkali metal bicarbonate e.g. sodium bicarbonate, potas ⁇ ium bicarbonate, etc.
  • alkali metal acetate e.g. ⁇ odium acetate, pota ⁇ sium acetate, etc.
  • alkaline earth metal phosphate e.g. magnesium phosphate, calcium phosphate, etc.
  • alkali metal hydrogen phosphate e.g. disodium hydrogen phosphate, dipotassium hydrogen phosphate, etc.
  • organic base such as trialkylamine (e.g. trimethylamin ⁇ , triethylamine, etc.), picoline, N-methylpyrrolidine, N-methylmorpholine or the like.
  • This reaction is usually carried out in a solvent such as alcohol (e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformamide, tetrahydrofuran, diethyl ether or any other solvent which does not adversely affect the reaction.
  • a solvent such as alcohol (e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformamide, tetrahydrofuran, diethyl ether or any other solvent which does not adversely affect the reaction.
  • the reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
  • the compound (If) or a ⁇ alt thereof can be prepared by reacting the compound (Ie) or a ⁇ alt thereof with the compound (VI) or a salt thereof.
  • Suitable salt ⁇ of the compounds (Ie) and (If) can be referred to the ones as exemplified for the compound (I).
  • Suitable salt ⁇ of the compound (VI) may include an alkali metal salt (e.g. sodium salt, potassium salt, etc.) and the like.
  • the reaction is usually carried out in a conventional ⁇ olvent such as l-methyl-2-pyrrolidinone, N,N-dimethylfor amide, dichloromethane, ethylene chloride or any other solvent which does not adversely influence the reaction.
  • a conventional ⁇ olvent such as l-methyl-2-pyrrolidinone, N,N-dimethylfor amide, dichloromethane, ethylene chloride or any other solvent which does not adversely influence the reaction.
  • the reaction temperature is not critical and the reaction is usually carried out under warming to heating.
  • the compound (II) or a salt thereof can be prepared by subjecting the compound (VII) or a salt thereof to elimination reaction of the amino protective group.
  • Suitable salt ⁇ of the compound (VII) can be referred to the ones as exemplified for the compound (I) .
  • the elimination reaction i ⁇ carried out in accordance with a conventional method ⁇ uch as hydrolysi ⁇ ; reduction; Edman' ⁇ method (phenyl isothiocyanate method); or the like.
  • the hydrolysis may include a method using an acid or base or hydrazine and the like. These methods may be selected depending on the kind of the protective groups to be eliminated. Among these methods, hydrolysis using an acid is one of the most common and preferable method for eliminating the protective groups such as substituted or unsubstituted alkoxycarbonyl, for example, tert-pentyloxycarbonyl, lower alkanoyl (e.g.
  • cycloalkoxycarbonyl substituted or unsubstituted aralkoxycarbonyl
  • aralkyl e.g. trityl
  • substituted phenylthio substituted phenylthio, sub ⁇ tituted aralkylidene, substituted alkylidene, substituted cycloalkylidene or the like.
  • Suitable acid includes an organic or inorganic acid such as formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid and the like, and the most suitable acid is an acid which can easily be removed from the reaction mixture by a conventional manner such as distillation under reduced pressure, for example, formic acid, trifluoroacetic acid, hydrochloric acid, etc.
  • the acids can be selected according to the kind of the protective group to be eliminated.
  • the elimination reaction reaction using trifluoroacetic acid may be carried out in the presence of anisole.
  • the hydrolysis using hydrazine is commonly applied for eliminating a phthaloyl, succinyl type amino-protective group.
  • Suitable ba ⁇ e may include an inorganic base and an organic base.
  • the reductive elimination is generally applied for eliminating the protective group, for example, haloalkoxycarbonyl (e.g. trichloroethoxycarbonyl, etc.), substituted or unsubstituted aralkoxycarbonyl (e.g. benzyloxycarbonyl, etc.), 2-pyridylmethoxycarbonyl, etc.
  • Suitable reduction may include, for example, reduction with an alkali metal borohydride (e.g. sodium borohydride, etc.), reduction with a combination of a metal (e.g. tin, zinc, iron, etc.) or the said metal together with a metal salt compound (e.g.
  • chromous-chloride chromous acetate, etc.
  • organic or inorganic acid e.g. acetic acid, propionic acid, hydrochloric acid, etc.
  • catalytic reduction e.g. acetic acid, propionic acid, hydrochloric acid, etc.
  • Suitable catalyst includes a conventional one, for example, Raney nickel, platinum oxide, palladium on carbon and the like.
  • the acyl group can generally be eliminated by hydrolysis.
  • halogen sub ⁇ tituted-alkoxycarbonyl and 8-quinolylox ⁇ carbonyl groups are usually eliminated by treating with a heavy metal such as copper, zinc, or the like.
  • the reaction is usually carried out in a conventional solvent such as water, chloroform, methylene chloride, alcohol (e.g., methanol, ethanol, etc.), tetrahydrofuran or any other organic solvent which does not adversely influence the reaction.
  • a conventional solvent such as water, chloroform, methylene chloride, alcohol (e.g., methanol, ethanol, etc.), tetrahydrofuran or any other organic solvent which does not adversely influence the reaction.
  • the reaction temperature is not critical and may suitably be selected in accordance with the kind of the amino protective group and the elimination method as mentioned above, and the reaction is usually carried out under a mild condition such as under cooling or at slightly elevated temperature.
  • the protective groups the acyl group derived from ⁇ -amino acid can be eliminated by Edman's method. Proce ⁇ s B
  • the compound (IV) or a salt thereof can be prepared by reacting the compound (VIII) or its reactive derivative at the amino group or a salt thereof with the compound (III) or its reactive derivative or a salt thereof.
  • the reaction is carried out by substantially the same method as that of Process 1, and therefore the reaction method and conditions are to be referred to said Process 1.
  • the object compound (I) and pharmaceutically acceptable salt ⁇ thereof are. CCK antagonists and therefore useful as therapeutical agents for emesis, pancreatitis, etc.
  • object compound (I) and pharmaceutically acceptable salts thereof have gastric antagonism and are useful as therapeutical and/or preventive agents for ulcers, excess gastric secretion, Zollinger-Ellison Syndrome, etc.
  • Test Compound (3S)-1,3-Dihydro-l-(4-imidazolylmethyl)-3-[ (E)-3-(2- aminophenyl)propenoylamino]-5-(2-fluorophenyl)-2H-l,4- benzodiazepin-2-one dihydrochloride [hereinafter referred to as test compound A]
  • the object compound (I) or pharmaceutically acceptable salt ⁇ thereof can usually be administered to mammals including human being in the form of a conventional pharmaceutical composition such as capsule, micro-capsule, tablet, granule, powder, troche, syrup, aerosol, inhalation, solution, injection, suspension, emulsion, suppository or the like, and the most suitable dosage form is injection.
  • a conventional pharmaceutical composition such as capsule, micro-capsule, tablet, granule, powder, troche, syrup, aerosol, inhalation, solution, injection, suspension, emulsion, suppository or the like, and the most suitable dosage form is injection.
  • the pharmaceutical composition of this invention can contain various organic or inorganic carrier materials, which are conventionally used for pharmaceutical purpose, such as excipient (e.g. sucrose, starch, annit, sorbit, lactose, glucose, cellulose, talc, calcium phosphate calcium carbonate, etc.), binding agent (cellulose, methyl cellulose, hydroxypropylcellulose, polypropylpyrrolidone, gelatin, gum arabic, polyethyleneglycol, sucrose, starch, etc.), disintegrator (e.g.
  • excipient e.g. sucrose, starch, annit, sorbit, lactose, glucose, cellulose, talc, calcium phosphate calcium carbonate, etc.
  • binding agent cellulose, methyl cellulose, hydroxypropylcellulose, polypropylpyrrolidone, gelatin, gum arabic, polyethyleneglycol, sucrose, starch, etc.
  • disintegrator e.g.
  • starch carboxymethyl cellulo ⁇ e, calcium salt of carboxymethyl cellulose, hydroxypropylstarch, sodium glycole-starch, ⁇ odium bicarbonate, calcium pho ⁇ phate, calcium citrate, etc.
  • lubricant e.g. magnesium stearate, talc, sodium laurylsulf te, etc.
  • flavoring agent e.g. citric acid, mentol, glycine, orange powders, etc.
  • preservative e.g. sodium benzoate, sodium bisulfite, methylparaben, propylparaben, etc.
  • stabilizer e.g. citric acid, sodium citrate, acetic acid, etc.
  • su ⁇ pending agent e.g.
  • methyl cellulose methyl cellulose, polyvinylpyrrolidone, aluminum ⁇ tearate, etc.
  • dispersing agent e.g. water
  • aqueous diluting agent e.g. water
  • base wax e.g. cacao butter, polyethyleneglycol, white petrolatum, etc.
  • the effective ingredient may u ⁇ ually be admini ⁇ tered with a unit dose of 0.01 mg/kg to 50 mg/kg, 1 to 4 times a day.
  • the above dosage may be increased or decreased according to age, weight, conditions of the patient or the administering method.
  • the fractions containing the other object compound were combin ⁇ d and ⁇ vaporat ⁇ d to giv ⁇ an amorphous mass, which was susp ⁇ nd ⁇ d in dii ⁇ opropyl ether and collect ⁇ d by filtration to giv ⁇ (3R)-3-[ ( (2S)-2-amino-3-ph ⁇ nyl- propanoyl)amino]-1,3-dihydro-5-(2-fluorophenyl)-!-[(1H- tetrazol-5-yl)methyl]-2H-l,4-benzodiaz ⁇ pin-2-on ⁇ (4.76 g) .
  • Th ⁇ resultant powder was collected by filtration and washed with diisopropyl eth ⁇ r to giv ⁇ (3 ⁇ )-3-[[(2S)-2- ⁇ N'-(ph ⁇ nyl)thioureido ⁇ -3-phenyl- propanoyl]amino]-l,3-dihydro-5-(2-fluoroph ⁇ yl)-l-[ (1H- t ⁇ trazol-5-yl)m ⁇ thyl]-2H- ⁇ ,4-b ⁇ nzodiaz ⁇ pin-2-on ⁇ (5.63 g) .
  • Th ⁇ product obtain ⁇ d abov ⁇ was ⁇ u ⁇ p ⁇ nd ⁇ d in tetrahydrofuran (35 ml) and * 4N-hydrogen chloride in ethyl acetate (33.5 ml) wa ⁇ added dropwise thereto under ice-cooling. The mixture was stirred, for 5 hours and then evaporated in vacuo to give a viscous oil, which wa ⁇ washed with ethyl acetat ⁇ by stirring for 3 hours.
  • the mixture was stirred for 3 hours and allowed to stand overnight.
  • the reaction mixture was poured into a mix-ture of ⁇ thyl acetate and water under stirring.
  • the ⁇ eparat ⁇ d organic lay ⁇ r was wa ⁇ hed with water twice and dried.
  • the solvent was removed under reduced pressur ⁇ to giv ⁇ an amorphous residue, which was purified by column chromatography on silica gel with an eluen-t of chloroform.
  • the fractions containing the desired product were combined and evaporated to afford an amorphous mass, which was pulverized and stirred for several hours in diisopropyl ether.
  • Example 3 To a solution of (3RS)-l,3-dihydro-l-[ (1- tritylimidazol-4-yl)methyl]-3-amino-5-(2-fluorophenyl)-2H- l,4-benzodiazepin-2-one (1.0 g) in methylene chloride (10 ml) were added successive ⁇ ively triethylamine (340 mg) and 2-naphthoyl chloride (320 mg) . The mixture wa ⁇ stirred for 1.5 hours. The reaction mixture was washed with water and dried. The solvent was removed under reduced pre ⁇ ur ⁇ to give an amorphous residue, which was purified by column chromatography on silica gel with an eluent of chloroform.
  • reaction mixture was filtered through celite and the filtered mass was washed with hot ethanol several times. From the filtrate and the washings, ethanol was removed under reduced pressure. To the residual mixture wa ⁇ added a ⁇ aturated aqueous ⁇ olution of ⁇ odium bicarbonate (100 ml) and the mixture was extracted with ethyl acetate (100 ml).
  • Acetic acid (2 ml) was added to the reaction mixture.
  • Th ⁇ r ⁇ sultant mixtur ⁇ was pour ⁇ d into a mixtur ⁇ of ⁇ thyl ac ⁇ tat ⁇ (200 ml) and wat ⁇ r (200 ml) und ⁇ r stirring.
  • Th ⁇ mixture was adjusted to pH 8 with an aqueous solution of sodium bicarbonate.
  • the s ⁇ parated organic layer was washed with water.
  • the solvent was r ⁇ mov ⁇ d und ⁇ r r ⁇ duced pressure to give an amorphous residue, which was purified by column chromatography on silica gel with an eluent of chloroform.
  • Example 9 To a solution of (3RS)-l,3-dihydro-3-(2-naphthoyl- amino)-5-(2-fluorophenyl)-2H-l,4-benzodiazepin-2-on ⁇ (1.25 g) in N,N-dimethylformamid ⁇ (31 ml) was add ⁇ d sodium hydrid ⁇ (60% susp ⁇ nsion in mineral oil, 130 mg) under stirring and cooling at 0 Q C in an ice-salt bath in a stream of nitrogen. After the mixture was stirred at room temperature for 45 minutes, a solution of chloroace onitril ⁇ (270 mg) in N,N-dim ⁇ thylformamide (5 ml) was added to the mixture at 0°C under stirring.
  • the resultant mixture was stirred overnight at room temperature. Acetic acid (0.5 g) was added to the reaction mixture. The resultant mixture was poured into a mixture of ethyl acetate (200 ml) and water (300 ml) under stirring. The mixture was adjusted to pH 8 with an aqueous solution of sodium bicarbonate. The separated organic layer was washed with water. The solvent was remov ⁇ d under reduced pressure to give amorphous residue, which was purified by column chromatography on silica gel with an ⁇ lu ⁇ nt of chloroform.
  • Example 11 To a solution of (3RS)-l,3-dihydro-l-[2-(1-trityl- imidazol-4-yl) ⁇ thyl]-3-(3-quinolylcarbonylamino)-5-(2- fluoroph ⁇ nyl)-2H-l,4-b ⁇ nzodiaz ⁇ pin-2-on ⁇ (740 mg) in N,N-dim ⁇ thylformamid ⁇ (7.4 ml) wa ⁇ added 6N-hydrochloric acid (5.18 ml) under ⁇ tirring and cooling in an ice-bath. The mixture was warmed to 60-70°C and stirred for one hour.
  • the r ⁇ sultant precipitates were collect ⁇ d by filtration, wash ⁇ d with wat ⁇ r and purified by column chromatography on ⁇ ilica gel with an eluent of chloroform. The fraction ⁇ containing the de ⁇ ired product were combined and ⁇ vaporated to afford an amorphous mass, which was pulverized and stirred for ⁇ everal hour ⁇ in diisopropyl ether. Collection by filtration, washing with dii ⁇ opropyl eth ⁇ r and drying und ⁇ r r ⁇ duced pressur ⁇ gave
  • Example 18 To a su ⁇ pension of 2-indolecarboxylic acid (161.2 g) in methylene chloride (3.25 ml) was added thionyl chloride (119.0 mg) and one drop of N,N-dimethylformamid ⁇ und ⁇ r stirring at ambient temperature. The mixture was reflux ⁇ d for 1 hour with stirring.
  • Example 19 the following compound was obtained according to a similar manner to that of Example 18.

Abstract

Benzodiazepine derivatives of formula (I), wherein R1 is heterocyclic group which may have one or more suitable substituent(s), or cyano, R2 is hydrogen or halogen, R3 is aryl which may have one or more suitable substituent(s), R4 is aryl which may have one or more suitable substituent(s), etc., and A is lower alkylene, and pharmaceutically acceptable salts thereof which are useful as a medicament.

Description

DESCRIPTION
BENZODIAZEPINE DERIVATIVES
TECHNICAL FIELD
This invention relates to new benzodiazepinε derivatives and pharmaceutically acceptable salrs thereof which are useful as a medicament.
BACKGROUND ART
Some benzodiazepine derivatives have been known as described, for example, in European Patent Application Publication No. 349949 and U.S. Patent 4,820,834.
DISCLOSURE OF INVENTION
This invention relates to new benzodiazepine derivatives and pharmaceutically acceptable salts thereof,
More particularly, it relates to new benzodiazepine derivatives and pharmaceutically acceptable salts thereof which are cholecystokinin (CCK) antagonists and therefore useful as therapeutical and/or preventive agents for emesis, pancreatitis, disorders of appetite requlatory systems, pain, insulinoma, gastroparesis, carcinoma of pancreas, gallbladder disease (e.g. acute cholecystitis, calculus, e~c), disorders associated with intenstinal smooth muscle hyperactivity (e.g. irritable bowel syndrome, sphincter spasm, etc.), hyperinsulinemia, dyspepsia, nausea, etc.
The benzodiazepine derivatives of this invention can be represented by the following formula (I) :
Figure imgf000004_0001
wherein R is heterocyclic group which may have one or more suitable s bstituent(s) , or cyano,
2 R is hydrogen or halogen,
3 R is aryl which may have one or more suitable substituent(s) , 4 R is aryl which may have one or more suitable substituent(s) , ar(lower)alkenyl which may have one or more suitable substituent(s) , arylamino which may have one or more suitable substituent(s) , heteromonocyclic group which may have one or more suitable substituent(s) , qninolyl, isoquinolyl, cinnolinyl, indolyl, or guinoxalinyl, and
A is lower alkylene,
4 with proviso that when R is mdolyl, then
(i) R is tetrazolyl which may have one or more suitable substituent(s) and 3 R is halophenyl or η (ii) R is imidazolyl which may have one or more suitable substituent(s) ,
3 R iiss hhaalloopphheenn^yl and is ethylene.
According to the present invention, the new benzodiazepine derivatives (I) can be prepared by the processes which are illustrated in the following scheme, Process 1
Figure imgf000005_0001
(III)
(ID or its reactive derivative or its reactive derivative, at the amino group, or a salt thereof or a salt thereof
Figure imgf000005_0002
(I) or a salt thereof
Process 2
Figure imgf000005_0003
(la) or a salt thereof Elimination reaction of the i ino protective group
Figure imgf000006_0001
(lb) or a salt thereof
Process 3
Figure imgf000006_0002
(Ic) or a salt thereof
Reduction
Figure imgf000007_0001
(Id) or a salt thereof
Process 4
Figure imgf000007_0002
(IV) or a salt thereof or a salt thereof
(I) or a salt thereof Process 5
Figure imgf000008_0001
( Ie) or a salt thereof or a salt thereof
Figure imgf000008_0002
(if) or a salt thereof
wherein R 1, R2, R3, R4 and A are each as defined above,
R 3. is heterocyclic group having a protected i ino group of the formula :
N-
(in which R is imino protective
Rl group)
in its hetero ring, which may have one or more suitable substituent(s ,
1
R, is heterocyclic group having an imino group of the formula :
H in its hetero ring, which may have one or more suitable substituent(s) , R is ar(lower)alkenyl having a nitro group,
R, is ar(lower)alkenyl having an amino group and X is an acid residue.
The starting coπpounds (II) and (IV) can be prepared by the following processes.
Process A
Figure imgf000009_0001
(VII) or a salt thereof
Elimination reaction of the amino protective group
Figure imgf000009_0002
(ID or a salt thereof Process B
Figure imgf000010_0001
or its reactive
(VIII) derivative, or its reactive derivative^ or a salt thereof at the amino group, or a salt thereof
Figure imgf000010_0002
(IV) or a salt thereof
wherein R 1, R2, R3, R4 and A are each as defined above, and
R ,7 i_s protected amino.
The starting compound (VII) or a salt thereof can be prepared by the methods disclosed in the Preparations 1-3, 6 and 7 described later or similar manners thereto .
With regard to the object compound (i), in case -char the compound (I) has the group of the formula : - -
Figure imgf000011_0001
in R , said group can also exist in the tautomeric form and such tautomeric equilibrium can be represented by the following scheme.
H
Figure imgf000011_0002
(A) (B)
Both of the above tautomeric isomerε are included within the scope of the present invention. In the present specification and claim, the compounds including the group of such tautomeric isomers are represented for the convenient sake by one expression of the group of the formula (A) .
Further, in case that the compound (I) has the group of the formula :
H N
Figure imgf000011_0003
N —N
in R , said group can also exist in the tautomeric form and such tautomeric equilibrium can be represented by the following scheme. H
N N
\ *" __/ ^ N
\\ // — \\ /
N — N N NH
( C) ( D )
Both of the above tautomeric isomers are included within the scope of the present invention. In the present specification and claim, the compounds including the group of such tautomeric isomers ar.e represented for the convenient sake by one expression of the group of the formula (C) .
Suitable pharmaceutically acceptable salts of the object compound (I) are conventional non-toxic salts and include a metal salt such as an alkali metal salt (e.g. sodium salt, potassium salt, etc.) and an alkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.), an ammonium salt, an organic base salt (e.g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.), an organic acid salt (e.g. acetate, maleate, tartrate,' methanesulfonate, benzenesulfonate, formate, toluenesulfonate, trifluoroacetate, etc.), an inorganic acid salt (e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.), a salt with an amino acid (e.g. arginine, aspartic acid, glutamic acid, etc.), and the like. In the above and subsequent descriptions of the present specification, suitable examples and illustrations of the various definitions which the present invention include within the scope thereof are explained in detail as follows. The term "lower" is intended to mean 1 to 6 carbon atom(s), unless otherwise indicated.
Suitable "heterocyclic group" may include saturated or unsaturated, monocyclic or polycyclic heterocyclic group containing at least one hetero-atom such as an oxygen, sulfur, nitrogen atom and the like. And especially preferable heterocyclic group may be heterocyclic group such as unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide, pyri idyl, pyrazinyl, pyridazinyl, dihydropyridazinyl, tetrahydropyridazinyl, triazolyl (e.g. 1,2,4-triazolyl, lH-l,2,3-triazolyl, 2H-l,2,3-triazolyl, etc.), tetrazolyl (e.g., lH-tetrazolyl, 2H-tetrazolyl, etc.)-, dihydrotriazinyl (e.g., 4,5-dihydro-l,2,4- triazinyl, 2,5-dihydro-l,2,4-triazinyl, etc.), etc.; saturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc. ; unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atom(s), for example, indolyl, isoindolyl, indolinyl, isoindolinyl, indolizynyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridyl, tetrazolopyridazinyl (e.g. tetrazolo-
E1,5-b]pyridazinyl, etc.), dihydrotriazolopyridazinyl, etc.; unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, oxazolyl, isoxazolyl, dihydroisoxazolyl, oxadiazolyl, (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1;2,5-oxadiazolyl, etc.) etc.; saturated 3 to 8-membered heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, morpholinyl, etc.; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, benzoxazolyl, benzoxadiazolyl, etc.; unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, 1,3-thiazolyl, 1,2-thiazolyl, thiazolinyl, thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-thiadiazolyl, etc.; saturated 3 to 8-membered heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolidinyl, etc.; unsaturated 3 to 8-membered heteromonocyclic group containing an oxygen atom, for example furyl, etc.; unsaturated 3 to 8-membered heteromonocyclic group containing a sulfur atom, for example, thienyl, etc.; unsaturated condensed heterocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, benzothiazolyl, behzothiadiazolyl, etc. and the like. Suitable "substituent" in the terms "heterocyclic group which may have one or more suitable substituent(s)" and "heteromonocyclic group which may have one or more suitable substituent(ε)" may include amino, protected amino as exemplified below, oxo, hydroxy, imino protective group as exemplified below, lower alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, t-pentyl, hexyl, etc.) and the like.
Suitable "protected amino" may include acylamino and the like.
Suitable "imino protective group" may include acyl, mono(or di or tri)phenyl(lower)alkyl (e.g. trityl, etc. ) tetrahydropyranyl and the like.
Suitable "acyl" and "acyl moiety" in the term "acylamino" may include aliphatic acyl group and acyl group containing an aromatic or heterocyclic ring. And, suitable examples of the said acyl may be lower alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl, etc. ) ; lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
1-cyclopropylethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc. ) ; lower alkanesulfonyl (e.g. esyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, butanesulfonyl, etc. ) ; arenesulfonyl (e.g. benzenesulfonyl, tosyl, etc.); aroyl (e.g. benzoyl, toluoyl, xyloyl, naphthoyl, phthaloyl, indancarbonyl, etc.); ar(lower)alkanoyl (e.g. phenylacetyl, phenylpropionyl, etc. ) ; ar(lower)alkoxycarbonyl (e.g. benzyloxycarbonyl, phenethyloxycarbonyl, etc. ) , and the like.
The acyl moiety as stated above may have at least one suitable substituent(s) such as halogen (e.g. chlorine, bromine, fluorine and iodine), amino, protected amino
(e.g. lower alkanoylamino, phenylthioureido, etc.), or the like.
Suitable "acid residue" may include halogen and the like.
Suitable "halogen" may include chlorine, bromine, fluorine and iodine.
Suitable "aryl" and "aryl moiety" in the terms
"ar(lower)alkenyl" and "arylamino" may include phenyl, naphthyl and the like.
Suitable "substituent" in the terms "aryl which may have one or more suitable substituent(s)", ar(lower)alkenyl which may have one or more suitable substituent(s)" and "arylamino which may have one or more suitable substituent(s)" may include hydroxy, protected hydroxy as exemplified below, nitro, lower alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentyloxy, t-pentyloxy, hexyloxy, etc.), amino, protected amino as exemplified above, lower alkyl (e.g. , methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, t-pentyl, hexyl, etc.), halogen as exemplified above, and the like.
Suitable "lower alkenyl moiety" in the term "ar(lower)alkenyl" may include vinyl, allyl, 1-propenyl, 1 or 2 or 3-butenyl, 1 or 2 or 3 or 4-pentenyl, 1 or 2 or 3 or 4 or 5-hexenyl and the like.
Suitable "heteromonocyclic group" may include saturated or unsaturated heteromonocyclic group containing at least one hetero-atom such as an oxygen, sulfur, nitrogen atom and the like. And, especially preferable heteromonocyclic group may be heteromonocyclic group such as unsaturated 3 to 8-membered heteromonocyclc group containing 1 to 4 nitrogen atom(ε), for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide, pyrimidyl, pyrazinyl, pyridazinyl, dihydropyridazinyl, tetrahydropyridazinyl, triazolyl (e.g. 1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-l,2,3-triazolyl, etc.), tetrazolyl (e.g., lH-tetrazolyl, 2H-tetrazolyl, etc.), dihydrotriazinyl (e.g., 4,5-dihydro-l,2,4- triazinyl, 2,5-dihydro-l,2,4-triazinyl, etc.), etc.; saturated 3 to*-8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolidinyl, imidazolidmyl, piperidino, piperazinyl, etc. unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, oxazolyl, isoxazolyl, dihydroisoxazolyl, oxadiazolyl, (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.) etc.; saturated 3 to 8-membered heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, morpholinyl, etc.; unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, 1,3-thiazolyl, 1,2-thiazolyl, thiazolinyl, thiadiazolyl (e.g., 1,2,4-thiadiazolyl,
1,3,4-thiadiazolγl, 1,2,5-thiadiazoylyl,
1,2,3-thiadiazolyl, etc.; saturated 3 to 8-membered heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolidinyl, etc.; unsaturated 3 to 8-membered heteromonocyclic group containing an oxygen atom, for example furyl, etc.; unsaturated 3 to 8-membered heteromonocyclic group containing a sulfur atom, for example, thienyl, etc.; and the like.
Suitable "lower alkylene" may include straight or branched one having 1 to 6 carbon atom(s), such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene or the like, preferably one having 1 to 4 carbon atom(s).
Preferable "heterocyclic group" in the terms
"heterocyclic group having a protected imino group of the formula : \xτ// N 6 j (in which R is imino protective group)
R6 in its hetero ring" and "heterocyclic group having an imino group of the formula : \N_/ in its hetero ring"
H may include unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrroiyl, pyrrolinyl, imidazolyl, pyrazolyl, dihydropyridaziny"1 , tetrahydropyridazinyl, triazolyl (e.g. 1,2,4-triazolyl, lH-l,2,3-triazolyl, 2H-l,2,3-triazolyl, etc.), tetrazolyl (e.g., IH-tetrazolyl, 2H-tetrazolyl, etc.), dihydrotriazinyl (e.g., 4,5-dihydro-l,2,4-tria'zinyl, 2,5-dihydro-l,2,4-triazinyl, etc.), etc.; saturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolidinyl, imidazolidmyl, piperidyl, piperazinyl, etc. ; and the like.
The preferred embodiments of the object, compound (I) are as follows.
R is heterocyclic group (more preferably unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(ε), most preferably tetrazolyl or imidazolyl) which may have one to three (more preferably one) suitable substituent(ε) [more preferably tetrazolyl or imidazolyl, each of which may have an imino protective group; most preferably tetrazolyl or imidazolyl, each of which may have monofor di or tri)phenyl(lower)alkyl] , or cyano;
2 R is hydrogen; 3 R is aryl (more preferably phenyl) which may have one to three (more preferably one) suitable substituent(ε)
[more preferably phenyl or halophenyl] ;
R is aryl (more preferably phenyl or naphthyl) which may have one to three (more preferably one or two) suitable substituent(ε) [more preferably phenyl or naphthyl, each of which may have one or two substituent(s) selected from the group consisting of halogen and amino; most preferably naphthyl, dihalophenyl or phenyl having halogen and amino] , ar(lower)alkenyl (more preferably phenyl(lower)alkenyl) which may have one to three (more preferably one) suitable substituent(ε) [more preferably phenyl(lower)alkenyl which may have amino or nitro; most preferably nitrophenyl(lower)alkenyl or aminophenyl(lower)alkenyl] , arylamino (more preferably phenyla ino) which may have one to three (more preferably one) suitable substituent(s) [more preferably phenylamino which may have lower alkyl or halogen; most preferably lower alkylphenylamino or halophenylamino] , heteromonocyclic group (more preferably pyridyl or tetrahydropyridazinyl) which may have one to three (more preferably one) suitable substituent(s) [more preferably pyridyl, or tetrahydropyridazinyl which may have an oxo group; moεt preferably pyridyl „ or tetrahydropyridazinyl having an oxo group], quinolyl, iεoquinolyl, cinnolinyl, indolyl or quinoxalinyl, and A is lower alkylene (more preferably C.-C, alkylene),
4 4 with proviso that when R s indolyl, then
(i) R is tetrazolyl and 3 R is halophenyl or
(ii) R is imidazolyl which may have mono(or di or tri)- phenyl(lower)alkyl,
3 R is hhaalloopphheennyyl and is ethylene.
The processes for preparing the object compound (I) and the starting compounds of the present invention are explained in detail in the following.
Process 1 :
The compound (I) or a salt thereof can be prepared by reacting the compound (II) or its reactive derivative at the amino group or a salt thereof with the compound (III) or its reactive derivative or a salt thereof.
Suitable reactive derivative at the amino group of the compound (II) may include Schiff's base type imino or its tautomeric enamine type isomer formed by the reaction of the compound (II) with a carbonyl compound such as aldehyde, ketone or the like; a silyl derivative formed by the reaction of the compound (II) with a silyl compound such as N,0-bis(trimethylsilyl)acetamide, N-trimethylsilylacetamide or the like; a derivative formed by the reaction of the compound (II) with phosphorus trichloride or phosgene and the like.
Suitable salts of the compound (II) and (III) can be referred to the ones as exemplified for the compound (I). Suitable reactive derivative of the compound (III) may include an acid halide, an acid anhydride, an activated amide, an activated ester, isocyanate and the like. The suitable example may be an acid chloride, an acid azide; a mixed acid anhydride with an acid such as substituted phosphoric acid (e.g. dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phoεphoric acid, etc.), dialkylphoεphorous acid, sulfurous acid, thioεulfuric acid,• alkanesulfonic acid (e.g. methanesulfonic acid, ethanesulfonic acid, etc.), εulfuric acid, alkylcarbonic acid, aliphatic carboxylic acid (e.g. pivalic acid, pentanoic acid, iεopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid, etc.) or aromatic carboxylic acid (e.g. benzoic acid, etc.); a εymmetrical acid anhydride; an activated amide with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole; or an activated eεter (e.g. cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl [
Figure imgf000020_0001
ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl eεter, pentachlorophenyl eεter, meεylphenyl ester, phenylazophenyl ester, phenyl thioester, p-nitrophenyl thioester, p-cresyl thioεster, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, etc.), or an ester with a N-hydroxy compound (e.g. N,N-dimethylhydroxylamine, l-hydroxy-2-(1H)-pyridone, N-hydroxysuccinimide, N-hydroxybenzotriazole, N-hydroxyphthalimide, l-hydroxy-6-chloro-lH-benzotriazole, etc.), isocyanate of the formula : R 5-N=C=0 (in which R5 is aryl which may have one or more suitable substituent(s) ) , and the like.
These reactive derivatives can optionally be selected from them according to the kind of the compound (III) to be used.
The reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvents which do not adversely influence the reaction. These conventional solvents may also be used in a mixture with water.
When the compound (III) is used in free acid form or its salt form in the reaction, the reaction is preferably carried out in the presence of a conventional condensing agent such as N,N'-dicyclohexylcarbodiimide; N-cyclohexyl-N'-morpholinoethylcarbodiimide;
N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide - N,N' -diethylcarbodiimide, N,N'-diisopropylcarbodiimide; N-ethy1- '-(3-dimethylaminopropyl)carbodiimide; N,N-carbonylbiε-(2-methylimidazole) ; pentamethyleneketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene; 1-alkoxy-l-chloroethylene; trialkyl phosphite; ethyl polyphεphate; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride) ; phosphorus trichloride; thionyl chloride; oxalyl chloride; triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt; 2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide intra-molecular salt; 1-(p-chlorobenzenesulfonyloxy)-6-chloro-lH-benzotrιazoie; so-called Vilsmeier reagent prepared by the reaction of N,N-dimethylforma_rιide with thionyl chloride, phosgene, phosphoruε oxychloride, etc.; or the like.
The reaction may alεo be carried out in the presence of an inorganic or organic baεe such as an alkali metal bicarbonate, tri(lower)alkylamine, pyridine, N-(lower)alkylmorphorine, N,N-di(lower)alkylbenzylarainε, or the like. The reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.
Process 2
The compound (lb) or a salt thereof can be prepared by subjecting the compound (Ia) or a salt thereof to elimination reaction of the imino protective group.
Suitable method of this reaction may include conventional one such as hydrolysis, reduction and the like.
(i) For Hydrolysis : The hydrolysiε iε preferably carried out in the presence of a baεe or an acid including Lewiε acid.
Suitable base may include an inorganic base and an organic base such as an alkali metal [e.g. sodium, potassium, etc.], the hydroxide or carbonate or bicarbonate thereof, trialkylamine [e.g. trimethylamine, triethylamine, etc.], picoline, 1,5-diazabicyclo[4.3.0]- non-5-ene, 1,4-diazabicyclo[2.2.2]octane, l,8-diazabicyclo[5.4.0]undec-7-ene, or the like.
Suitable acid may include an organic acid [e.g. formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.] and an inorganic acid [e.g. hydrochloric acid, hydrobromic acid, sulfuric acic, hydrogen chloride, hydrogen bromide, etc.]. The elimination using Lewis acid εuch as trihaloacetic acid [e.g. trichloroacetic acid, trifluoroacetic acid, etc.] or the like is preferably carried out in the presence of cation trapping agentε [e.g. anisole, phenol, etc.].
The reaction is usually carried out in a solvent such as water, an alcohol [e.g. methanol, ethanol, etc.], N,N-dimethylformamide, methylene chloride, tetrahydrofuran, a mixture thereof or any other solvent which does not adversely influence the reaction. A liquid base or acid can be also used as the solvent. The reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
(ii) For reduction :
Reduction is carried out in a conventional manner, including chemical reduction and catalytic reduction. Suitable reducing agents to be used in chemical reduction are a combination of a metal (e.g. tin, zinc, iron, etc.) or metallic compound (e.g. chromium chloride, chromium acetate, etc.) and an organic or inorganic acid (e.g. formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.).
Suitable catalysts to be used in catalytic reduction are conventional oneε such as platinum catalysts (e.g. platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.), palladium catalysts (e.g. spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate, etc.), nickel catalysts (e.g. reduced nickel, nickel oxide, Raney nickel, etc.), cobalt catalysts (e.g. reduced cobalt, Raney cobalt, etc.), iron catalysts (e.g. reduced iron, Raney iron, etc.), copper catalysts (e.g. reduced copper, Raney copper, Ullman copper, etc. ) and the like. The reduction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, methanol, ethanol, propanol, N,N-dimethylformamide, tetrahydrofuran, or a mixture thereof. Additionally, in case that the above-mentioned acids to be uεed in chemical reduction are in liquid, they can also be used as a solvent.
The reaction temperature of this reduction is not critical and the reaction is uεually carried out under cooling to heating.
Process 3
The compound (Id) or a salt thereof can be prepared by subjecting the compound "(Ic) or a salt thereof to reduction reaction. This reduction reaction can be . referred to that of the aforementioned Process 2.
Process 4
The compound (I) or a salt thereof can be prepared by reacting the compound (IV) or a salt thereof with the compound (V) or a salt thereof. Suitable salts of the compounds (IV) and (V) can be referred to the ones as exemplified for the compound (I) .
This reaction is uεually carried out in the preεence of base. Suitable baεe may include an inorganic baεe εuch aε alkali metal hydride (e.g. sodium hydride, etc.), alkali metal hydroxide (e.g. sodium hydroxide, potasεium hydroxide, etc.), alkaline earth metal hydroxide (e.g. magnesium hydroxide, calcium hydroxide, etc.), alkali metal carbonate (e.g. sodium carbonate, potassium carbonate, etc.), alkaline earth metal carbonate (e.g. magnesium carbonate, calcium carbonate, etc.), alkali metal bicarbonate (e.g. sodium bicarbonate, potasεium bicarbonate, etc. ) , alkali metal acetate (e.g. εodium acetate, potaεsium acetate, etc.), alkaline earth metal phosphate (e.g. magnesium phosphate, calcium phosphate, etc.), alkali metal hydrogen phosphate (e.g. disodium hydrogen phosphate, dipotassium hydrogen phosphate, etc.), or the like, and an organic base such as trialkylamine (e.g. trimethylaminε, triethylamine, etc.), picoline, N-methylpyrrolidine, N-methylmorpholine or the like.
This reaction is usually carried out in a solvent such as alcohol (e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformamide, tetrahydrofuran, diethyl ether or any other solvent which does not adversely affect the reaction.
The reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
Proceεε 5
The compound (If) or a εalt thereof can be prepared by reacting the compound (Ie) or a εalt thereof with the compound (VI) or a salt thereof.
Suitable saltε of the compounds (Ie) and (If) can be referred to the ones as exemplified for the compound (I). Suitable saltε of the compound (VI) may include an alkali metal salt (e.g. sodium salt, potassium salt, etc.) and the like.
The reaction is usually carried out in a conventional εolvent such as l-methyl-2-pyrrolidinone, N,N-dimethylfor amide, dichloromethane, ethylene chloride or any other solvent which does not adversely influence the reaction.
The reaction temperature is not critical and the reaction is usually carried out under warming to heating.
Process A
The compound (II) or a salt thereof can be prepared by subjecting the compound (VII) or a salt thereof to elimination reaction of the amino protective group. Suitable saltε of the compound (VII) can be referred to the ones as exemplified for the compound (I) .
The elimination reaction iε carried out in accordance with a conventional method εuch as hydrolysiε; reduction; Edman'ε method (phenyl isothiocyanate method); or the like. The hydrolysis may include a method using an acid or base or hydrazine and the like. These methods may be selected depending on the kind of the protective groups to be eliminated. Among these methods, hydrolysis using an acid is one of the most common and preferable method for eliminating the protective groups such as substituted or unsubstituted alkoxycarbonyl, for example, tert-pentyloxycarbonyl, lower alkanoyl (e.g. formyl, acetyl, etc.), cycloalkoxycarbonyl, substituted or unsubstituted aralkoxycarbonyl, aralkyl (e.g. trityl), substituted phenylthio, subεtituted aralkylidene, substituted alkylidene, substituted cycloalkylidene or the like.
Suitable acid includes an organic or inorganic acid such as formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid and the like, and the most suitable acid is an acid which can easily be removed from the reaction mixture by a conventional manner such as distillation under reduced pressure, for example, formic acid, trifluoroacetic acid, hydrochloric acid, etc. The acids can be selected according to the kind of the protective group to be eliminated.
The elimination reaction reaction using trifluoroacetic acid may be carried out in the presence of anisole. The hydrolysis using hydrazine is commonly applied for eliminating a phthaloyl, succinyl type amino-protective group.
The elimination using base is used for eliminating an acyl group such aε trifluoroacetyl. Suitable baεe may include an inorganic base and an organic base.
The reductive elimination is generally applied for eliminating the protective group, for example, haloalkoxycarbonyl (e.g. trichloroethoxycarbonyl, etc.), substituted or unsubstituted aralkoxycarbonyl (e.g. benzyloxycarbonyl, etc.), 2-pyridylmethoxycarbonyl, etc. Suitable reduction may include, for example, reduction with an alkali metal borohydride (e.g. sodium borohydride, etc.), reduction with a combination of a metal (e.g. tin, zinc, iron, etc.) or the said metal together with a metal salt compound (e.g. chromous-chloride, chromous acetate, etc.) and an organic or inorganic acid (e.g. acetic acid, propionic acid, hydrochloric acid, etc.); and catalytic reduction. Suitable catalyst includes a conventional one, for example, Raney nickel, platinum oxide, palladium on carbon and the like.
Among the protective groups, the acyl group can generally be eliminated by hydrolysis. Especially, halogen subεtituted-alkoxycarbonyl and 8-quinolyloxγcarbonyl groups are usually eliminated by treating with a heavy metal such as copper, zinc, or the like.
The reaction is usually carried out in a conventional solvent such as water, chloroform, methylene chloride, alcohol (e.g., methanol, ethanol, etc.), tetrahydrofuran or any other organic solvent which does not adversely influence the reaction.
The reaction temperature is not critical and may suitably be selected in accordance with the kind of the amino protective group and the elimination method as mentioned above, and the reaction is usually carried out under a mild condition such as under cooling or at slightly elevated temperature. Among the protective groups, the acyl group derived from α-amino acid can be eliminated by Edman's method. Proceεs B
The compound (IV) or a salt thereof can be prepared by reacting the compound (VIII) or its reactive derivative at the amino group or a salt thereof with the compound (III) or its reactive derivative or a salt thereof.
The reaction is carried out by substantially the same method as that of Process 1, and therefore the reaction method and conditions are to be referred to said Process 1. The object compound (I) and pharmaceutically acceptable saltε thereof are. CCK antagonists and therefore useful as therapeutical agents for emesis, pancreatitis, etc.
Further, it is expected that the object compound (I) and pharmaceutically acceptable salts thereof have gastric antagonism and are useful as therapeutical and/or preventive agents for ulcers, excess gastric secretion, Zollinger-Ellison Syndrome, etc.
In order to show the utility of the object compound (I), the pharmacological activity of the representative compound thereof is shown in the following.
[I] Test Compound : (3S)-1,3-Dihydro-l-(4-imidazolylmethyl)-3-[ (E)-3-(2- aminophenyl)propenoylamino]-5-(2-fluorophenyl)-2H-l,4- benzodiazepin-2-one dihydrochloride [hereinafter referred to as test compound A]
[II] Test :
CCK receptor antagonism in isolated fundic circular muscle from guinea pig stomach
Test Method The strip of circular muscle from guinea pig stomach was εuspended in 25 ml organ bath containing Krebs' bicarbonate solution (NaCl 118mM, KCl 4.8mM, H-PO. 1.2mM,
MgS04 1.2mM, CaCl2 2.5mM, NaHC03 25mM, glucose llmM and bovine serum albumin 0.1%) maintained at 37°C and gassed with 95% Q- and 5% C02- The strip was placed under an initial tension of 0.5 g and equilibrated for 60 minutes during which the bath volume was replaced every 15 minuteε. Iεometric contraction was measured using a force transducer. CCK-8
_7 (3.2 x 10 M) was added to the bathing solution and the contractile force was measured. After washing out CCK-8, it stood for about 15 minutes until contractile force became plateau. Then test compound A (1 x 10~ M) was added. 5 minutes later, CCK-8 was added and the contractile force was recorded. CCK antogonism- was calculated by comparing the contractile force induced by CCK in the abεence or presence of test compound A.
Test Result
Inhibition (%) : 89.9
The object compound (I) or pharmaceutically acceptable saltε thereof can usually be administered to mammals including human being in the form of a conventional pharmaceutical composition such as capsule, micro-capsule, tablet, granule, powder, troche, syrup, aerosol, inhalation, solution, injection, suspension, emulsion, suppository or the like, and the most suitable dosage form is injection.
The pharmaceutical composition of this invention can contain various organic or inorganic carrier materials, which are conventionally used for pharmaceutical purpose, such as excipient (e.g. sucrose, starch, annit, sorbit, lactose, glucose, cellulose, talc, calcium phosphate calcium carbonate, etc.), binding agent (cellulose, methyl cellulose, hydroxypropylcellulose, polypropylpyrrolidone, gelatin, gum arabic, polyethyleneglycol, sucrose, starch, etc.), disintegrator (e.g. starch, carboxymethyl celluloεe, calcium salt of carboxymethyl cellulose, hydroxypropylstarch, sodium glycole-starch, εodium bicarbonate, calcium phoεphate, calcium citrate, etc.), lubricant (e.g. magnesium stearate, talc, sodium laurylsulf te, etc.), flavoring agent (e.g. citric acid, mentol, glycine, orange powders, etc.), preservative (e.g. sodium benzoate, sodium bisulfite, methylparaben, propylparaben, etc.), stabilizer (e.g. citric acid, sodium citrate, acetic acid, etc.),. suεpending agent (e.g. methyl cellulose, polyvinylpyrrolidone, aluminum εtearate, etc. ) , dispersing agent, aqueous diluting agent (e.g. water), base wax (e.g. cacao butter, polyethyleneglycol, white petrolatum, etc.).
The effective ingredient may uεually be adminiεtered with a unit dose of 0.01 mg/kg to 50 mg/kg, 1 to 4 times a day. However, the above dosage may be increased or decreased according to age, weight, conditions of the patient or the administering method.
The following Preparations and Examples are given only for the purpose of illustrating the present invention in more detail.
Preparation 1
To a εolution of (3RS)-3-phthalimido-5-(2- fluorophenyl)-l,3-dihydro-2H-l,4-benzodiazepin-2-one (21.17 g) in N,N-dimethylformamide (400 ml) waε added gradually sodium hydride (2.0 g, 60% suspension in mineral oil) under cooling in an ice-bath and nitrogen atmosphere. The mixture was stirred under the εame conditionε for 0.5 hour and at ambient temperature for 1 hour. The mixture was cooled in ice-bath and a solution of chloroacetonitrile (3.48 ml) in N,N-dimethylformamide (5 ml) was added dropwise thereto. The mixture was stirred for 1 hour at the same temperature and at ambient temperature overnight. To the reaction mixture was added acetic acid (3.5 g) under cooling and the resultant mixture was poured into a mixture of ethyl acetate and water under stirring. The mixture was adjusted to pH 7.5 with aqueous sodium bicarbonate. The crystals were collected by filtration and washed with cold ethyl acetate to give (3RS)-3-phthalimido-l-cyanomethyl-l,3-dihydro-5- (2-fluorophenyl)-2H-l,4-benzodiazepin-2-one (20.9 g) . p : 260°C (dec.) -
IR (Nujol) : 2160, 1776, 1725, 1700, 1604 cm"1 NMR (DMSO-dg, δ) : 5.15 (2H, ABq, J=24.6Hz, 17.8Hz),
5.83 (1H, s), 7.2-8.1 (12H, )
Preparation 2
A mixture of (3RS)-3-phthalimido-l-cyanomethyl-l,3- dihydro-5-(2-fluorophenyl)-2H-l,4-benzodiazepin-2-one (20.0 g) , sodium azide (8.43 g) and triethylamine hydrochloride (8.92 g) in N-methyl-2-pyrrolidone (350 ml) was heated at 145°C under stirring for 3.5 hours. After cooling to ambient temperature, the mixture was poured into 5% hydrochloric acid (500 ml) and ice. The resultant precipitates were collected by filtration, washed with cold water several times and dried over phoεphoruε - -
pentoxide under reduced pressure to afford (3RS)-3- phthalimido-1,3-dihydro-5-(2-fluorophenyl)-1-[ (1H- tetrazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one (18.07 g). IR (Nujol) : 1778, 1720, 1693, 1610 cm"1
NMR (DMSO-dg, δ) : 5.46 (2H, s), 5.85 (1H, s),
7.2-8.0 (13H, m)
Preparation 3 To a solution of (3RS)-3-phthalimido-l,3-dihydro-5- (2-fluorophenyl)-l-[ (lH-tetrazol-5-yl)methyl]-2H-1,4- benzodiazepin-2-one (18.07 g) and trityl chloride (10.99 g) in N,N-dimethyIformamide (330 ml) was dropwise added a solution of triethylamine (4.6 g) in N,N-dimethylformamide (10 ml) under stirring and cooling in an ice-bath. The mixture was stirred for 20 minuteε under the same conditionε and at ambient temperature overnight. The reaction mixture was poured into an ice-water (500 ml), and the resultant precipitates were collected by filtration, washed with water and dried over phosphorus pentoxide under reduced pressure to afford (3RS)-3-phthalimido-l,3-dihydro-5-(2-fluorophenyl)-1- [ (l-trityl-lH-tetrazol-5-yl)methγl]-2H-l,4-benzodiazepin- 2-one (33.41 g) as white powder. IR (Nujol) : 1778, 1723, 1695, 1610 cm"1
NMR (DMSO-dg, δ) : 5.56 (2H, ABq, J=16.0Hz, 52.6Hz),
5.80 (1H, ε), 6.8-8.1 (27H, m)
Preparation 4 To a suεpension of (3RS)-3-phthalimido-l-[ (1-trityl- lH-tetrazol-5-γl)methyl]-5-(2-fluorophenyl)-1,3-dihydro- 2H-l,4-benzodiazepin-2-one (33.4 g) in tetrahydrofuran (500 ml) was added hydrazine hydrate (1.90 g) under stirring at ambient temperature. The mixture was stirred for 2 hours at the same temperature and refluxed under εtirring for 2 hours. The reaction mixture was cooled in an ice-bath and the resultant precipitates were filtered off. The filtrate and the waεhings were combined and evaporated to afford a residue, which was stirred in ethyl acetate and filtered. The filtrate and washings were combined and evaporated to give white powder (14.43 g) of (3RS)-3-amino-1,3-dihydro-5-(2-fluorophenyl)-1-[ (1- trityl-lH-tetrazol-5-yl)methyl]-2H-l,4-benzodiazepin-2- one. IR (Nujol) : 3350, 1686, 1597, 760, 700 cm"1
NMR (CDC13, δ) : 2.95 '( 2H, br s), 4.62 (1H, s) , 5.42 (2H, ABq, J=19.6Hz, 15.8Hz), 6.8-7.6 (23H, m)
Preparation 5 The following compound was obtained according to a similar manner to that of Preparation 4.
(3RS)-3-Amino-l,3-dihydro-5-phenyl-l-[ (1-trityl-lH- tetrazol-5-yl)methyl]-2H-l,4-benzodiazepin-2-one mp : 132-135°C
IR (Nujol) : 3375, 1680, 1595, 1575, 1560 cm"1 NMR (CDC13, δ) : 2.72 (2H, s), 4.55 (1H, s),
5.46 (2H, ABq, J=16Hz, 51Hz), 6.90-6.70 (6H, m) , 7.15-7.50 (18H, m)
Preparation 6
To a solution of (3RS)-3-amino-l,3-dihydro-5-(2- fluorophenyl)-l-[ (l-trityl-lH-tetrazol-5-yl)methyl]-2H- l,4-benzodiazepin-2-one (11.54 g) and N-t-butoxycarbonyl- L-phenylalanine (5.42 g) in N,N-dimethyIformamide (200 ml) were added successively 1-hydroxybenzotriazole (2.76 g) , l-ethyl-3-(3-dimethyla inopropyl)carbodiimide hydrochloride (3.91 g) and triεthylamine (2.36 g) u__der stirring at ambient temperature. The mixture was εtirred under the same conditionε for 4.5 hourε and then poured into water (1.5 ) under stirring. The mixture was adjusted to pH 8 with an aqueous solution of sodium bicarbonate. The reεultant prεcipitatεε were collected by filtration, waεhed with water and dried over phoεphorus pentoxide under rεduced pressure to give a mixture (16.29 g) of (3R)-3-[ ( (2S)-2-t-butoxycarbonylamino-3- phenylpropanoyl)amino]-l,3-dihydro-5-(2-fluorophenyl)-1- [ (l-trityl-lH-tetrazol-5-yl)methyl]-2H-l,4-benzodiazepin- 2-one and (3S)-3-[ ( (2S)-2-t-butoxycarbonylamino-3- phenylpropanoyl)amino]-1,3-dihydro-5-(2-fluorophenyl)-1- [ (l-trityl-lH-tetrazol-'5-yl)methyIj-2H-1,4-benzodiazεpin- 2-one. mp : 108-114°C
IR (Nujol) : 3330, 1700, 1690, 1675, 1610 cm"1 NMR (DMSO-dg, δ) : 1.28 (9H, s), 2.65-2.9 (1H, m) ,
3.0-3.2 (1H, m) , 4.40 (1H, m) , 5.33-5.41 (2H, m) , 5.39, 5.40 (1H, εach d, J=8Hz), 5.58 (2H, ABq, J=16.8Hz, 82.2Hz), 6.8-7.95 (14H, m) , 9.25, 9.37 (1H, each d, J=8Hz)
Preparation 7
A mixture of a mixture (16.2 g) of (3R)-3-[ ( (2S)-2-t- butoxycarbonylamino-3-phenylpropanoyl)amino]-1,3-dihydro- 5-(2-fluorophenyl)-1-[ (l-trityl-lH-tetrazol-5-yl)methyl]- 2H-l,4-benzodiazεpin-2-onε and (3S)-3-[ ( (2S)^-t-butoxy- carbonylamino-S-phenylpropanoyl)amino]-1,3-dihydro-5- (2-fluorophenyl)-1-[(l-tritγl-lH-tetrazol-5-yl)methyl]- 2H-l,4-benzodiazepin-2-onε and 4N solution of hydrogen chloride in ethyl acetate (200 ml) was stirred at ambient temperature for 5 hourε. The mixture waε concentratεd in vacuo to give a residue, which waε dissolved in methanol (100 ml) and neutralized with an ethanolic ammonia. The mixture was concentrated in vacuo to dryness. The residue was subjected to column chromatography on silica gel with an eluent (CHC1-.:CH30H = 10:1). The fractions containing thε object compound were combined and evaporated to give an amorphouε mass, which waε suspendεd in diiεopropyl εthεr and collected by filtration to give (3S)-3-[( (2S)-2-amino-3-phenylpropanoyl)amino]-l,3- dihydro-5-(2-fluorophenyl)-l-[ (lH-tetrazol-5-yl)methyl]- 2H-l,4-bεnzodiazεpin-2-onε (4.57 g) .
NMR (DMSO-dg, δ) : 2.91 (1H, dd, J=14.0Hz, 8.4Hz) , 3.20 (1H, dd, J=4Hz, 14.0Hz), 4.13 (1H, dd, J=4Hz, 8.4Hz), 5.26 (2H, ABq, J=15.4Hz, 3i.6Hz), 5.39 (1H, d, J=8.0Hz), 7.1-7.35 (10H, m) ,
7.52-7.66 (4H, m) , 7.96 (1H, d, J=8.4Hz), 9.77 (1H, d, J=8.0Hz)
The fractions containing the other object compound were combinεd and εvaporatεd to givε an amorphous mass, which was suspεndεd in diiεopropyl ether and collectεd by filtration to givε (3R)-3-[ ( (2S)-2-amino-3-phεnyl- propanoyl)amino]-1,3-dihydro-5-(2-fluorophenyl)-!-[(1H- tetrazol-5-yl)methyl]-2H-l,4-benzodiazεpin-2-onε (4.76 g) . NMR (DMSO-dg, δ) : 3.0-3.17 (1H, m) , 3.57-3.64 (1H, m), 3.0-4.1 (2H, broad), 4.21 (1H, t, J=4.2Hz), 5.19 (2H, ABq, J=15.6Hz, 70.1Hz), 5.38 (1H, d, J=8.3Hz), 7.16-7.4 (10H, m) , 7.51-7.67 (4H, m) , 7.97 (1H, d, J=8.2Hz), 9.78 (1H, d, J=8.3Hz)
Preparation 8
To a solution of (3S)-3-[ ( (2S)-2-amino-3- phεnylpropanoyl)amino]-1,3-dihydro-5-(2-fluorophenyl)-1- [ (lH-tetrazol-5-yl)methyl]-2H-l,4-benzodiazepin-2-one (4.57 g), and triethyla inε (0.974 g) in dried tetrahydrofuran (45 ml) was added phenyl isothiocyanate (2.54 g) under stirring at ambient temperature. Thε mixture was stirred for 2 hours at ambient temperature and for 1 hour at 50°C. To the reaction mixture was added lN-hydrochloric acid (9.64 ml) under ice cooling. Thε mixture was concentrated in vacuo to give a reεidue, which waε extracted with ethyl acetate. The extract was waεhed with water twice and dried over magnesium sulfate. Removal of the solvent in vacuo afforded an amorphous masε (7.23 g), which was powdered by stirring in diisopropyl ethεr for 3 hours. Thε resultant powder was collected by filtration and washed with diisopropyl ethεr to givε (3Ξ)-3-[[(2S)-2-{N'-(phεnyl)thioureido}-3-phenyl- propanoyl]amino]-l,3-dihydro-5-(2-fluorophεήyl)-l-[ (1H- tεtrazol-5-yl)mεthyl]-2H-ϊ,4-bεnzodiazεpin-2-onε (5.63 g) . Thε product obtainεd abovε was εuεpεndεd in tetrahydrofuran (35 ml) and*4N-hydrogen chloride in ethyl acetate (33.5 ml) waε added dropwise thereto under ice-cooling. The mixture was stirred, for 5 hours and then evaporated in vacuo to give a viscous oil, which waε washed with ethyl acetatε by stirring for 3 hours. The rεsultant powder was collectεd by filtration, and driεd under reduced pressure to give (3S)-3-amino-l,3-dihydro- 5-(2-fluorophenyl)-l-[(lH-tetrazol-5-yl)mεthyl]-2H-l,4- benzodiazepin-2-one hydrochloride (2.91 g) . [ ]^° = -36.36° (C=0.495, CH3OH)
Preparation 9
The following compound was obtained according to a similar manner to that of Preparation 8.
(3R)-3-Amino-l,3-dihydro-5-(2-fluorophenyl)-!-[(1H- tεtrazol-5-yl)mεthyl]-2H-l,4-bεnzodiazepin-2-one hydrochloridε α]^° = + 33.46° (C=0.505, CH3OH)
Preparation 10
To a εuspension of (3RS)-3-ammo-l,3-dihydrQ-5-(2- fluorophenyl)-2H-l,4-benzodiazepin-2-one (2.0 g) in methylene chloride (30 ml) waε added dropwiεe triεthylaminε (1.61 g) under stirring and cooling in an ice-bath. To the mixture was added 2-naphthoyl chloride (1.52 g) under the same conditions. The mixture was stirred for 2 hours at the same temperature. The resultant precipitate was collected by filtration and washed with methylenε chloride and water successively. The collected crystals were dried over phosphorus pentoxide under reduced pressure to give (3RS)-3-(2-naphthoylamino)-5-(2-fluorophenyl)-1,3- dihydro-2H-l,4-benzodiazepin-2-one (2.33 g) .
NMR (DMSO-dg, δ) : 5.6.0 (1H, d, J=7.7Hz), 7.22-7.39 (5H, m), 7.54-7.66 (5H, m) , 7.99-8.11 (4H, m) , 8.72 (1H, s), 9.74 (1H, d, J=7.7Hz), 11.05 (1H, m) MASS (m/e) : 423 (M+)
Preparation 11
The following compounds werε obtainεd according to a similar mannεr to that of Preparation 10.
(1) (3RS)-3-(3-Quinolylcarbonylamino)-5-(2-fluorophenyl)- l,3-dihydro-2H-l,4-benzodiazepin-2-one
IR (Nujol) : 3600, 1695, 1670, 1610, 1590, 1515 cm"1 NMR (DMSO-dg, δ) : 5.59 (1H, d, J=7.6Hz) , 7.23-7.40 (5H, m), 7.61-7.76 (4H, ) , 7.67-7.94 (1H, m) ,
8.1-8.16 (2H, m), 9.09 (1H, s), 9.40 (1H, d, J=2.1Hz), 10.1 (1H, d, J=7.6Hz), 11.08 (1H, s)
(2) (3RS)-3-(3,4-Dichlorobεnzoylamino)-5-(2- fluorophεnyl)-1,3-dihydro-2H-l,4-bεnzodiazεpin-2-one NMR (DMSO-dg, δ) : 5.49 (1H, d, J=7.6Hz) , 7.2-8.02 (11H, ) , 3.21 (1H, s), 9.93 (1H, d, J=7.6Hz) , 11.03 (1H, 8)
MASS (m/e) : 442 (M+) Examplε 1
To a εolution of (3S)-1,3-dihydro-5-(2-fluorophenyl)- 3-amino-l-[ (l-tritylimidazol-4-yl)methyl]-2H-l,4- benzodiazεpin-2-one (1.0 g) in N,N-dimethylformamide (10 ml) were added εuccessively (E)-3-(2-nitrophεnyl)propεnoic acid (330 g), 1-hydroxybεnzotriazolε (230 mg) , N-εthyl-N' -(3-dimethylaminopropyl)carbodiimide hydrochloride (320 mg) and triethylamine (170 mg) under stirring at ambient temperaturε. The mixture was stirred for 3 hours and allowed to stand overnight. The reaction mixture was poured into a mix-ture of εthyl acetate and water under stirring. The εeparatεd organic layεr was waεhed with water twice and dried. The solvent was removed under reduced pressurε to givε an amorphous residue, which was purified by column chromatography on silica gel with an eluen-t of chloroform. The fractions containing the desired product were combined and evaporated to afford an amorphous mass, which was pulverized and stirred for several hours in diisopropyl ether. Collection by filtration, washing with diisopropyl ether and drying under reduced pressure gave (3S)-l,3-dihydro-l-[ (l-tritylimidazol-4-yl)methyl]-3- [(E)-3-(2-nitrophenyl)propenoylamino]-5-(2-fluorophenyl)- 2H-l,4-benzodiazεpin-2-one (1.16 g) . NMR (CDC13, δ) : 5.07 (2H, br ε) , 5.66-5.7 (1H, m) ,
6.49-8.14 (32H, m)
Example 2
The following compounds were obtained according to a similar manner to that of Example 1.
(1) (3Ξ)-1,3-Dihydro-1-[ (l-tritylimidazol-4-yl)methyl]- 3-[ (2-amino-4-chlorobenzoyl)amino]-5- (2-fluorophenyl)-2H-l,4-benzodiazepin-2-one NMR (CDC13, δ) : 5.06 (2H, d, J=3.7Hz), 5.62-5.68 (3H, m) , 6.63-8.04 (29H, m) MASS (m/e) : 502 (M+-243)
(2) (3RS)-l,3-Dihydro-l-[(l-tritylimidazol-4-yl)methyl]- 3-[ (2,3,4,5-tetrahydro-3-oxopyridazin-6-yl)- carbonylamino]-5-(2-fluorophenyl)-2H-l,4- benzodiazepin-2-one
(3) (3RS)-l,3-Dihydro-l-[ (l-tritylimidazol-4-yl)methyl]- 3-(3,4-dichlorobεnzoylamino)-5-( 2-fluorophenyl) -2H-
1,4-bεnzodiazεpin-2-onε-
NMR (CDC13, δ) : 5.02 (1H, d, J=15Hz),
5.12 (1H, d, J=15Hz), 5.67 (1H, d, J=7.8Hz), 6.85-8.04 (29H, m)
(4) (3RS)-l,3-Dihydro-l-[ (l-tritylimidazol-4-yl)mεthyl]- 3-(3-quinolylcarbonylamino)-5-(2-fluorophenyl)-2H-
1,4-benzodiazεpin-2-onε NMR (DMSO-dg, δ) : 5.01-5.18 (2H, m) , 5.78 (1H, d, J=7.8Hz), 6.87-8.26 (30H, m) ,
8.72 (1H, d, J=1.9Hz), 9.44 (1H, d, J=2.2Hz) MASS (m/e) : 504 (M+-243), 424
( 5) ( 3RS)-1,3-Dihydro-l-[ (l-tritylimiazol-4-yl)methyl]- 3-(2-quinoxalinylcarbonylaird.no)-5-(2-fluorophenyl)-
2H-l,4-benzodiazepin-2-one
( 6) (3RS)-1,3-Dihydro-l-[ (l-tritylimidazol-4-yl)methyl]- 3-(4-cinnolinylcarbonylamino)-5-(2-fluorophenyl)- 2H-l,4-benzodiazepin-2-onε
NMR (CDC13, δ) : 5.09 (2H, s), 5.80 (1H, d,J=7.8Hz), 6.86-8.09 (28H, m) , 8.49-8.66 (2H, m) , 9.54 (1H, ε)
(7) (3RS)-l,3-Dihydro-l-[(l-tritylimidazol-4-yl)mεthyl]- 3-(1-iεoquinolylcarbonylamino)-5-(2-fluorophenyl)-
2H-1,4-benzodiazεpin-2-onε
NMR (CDC13, δ) : 5.11 (2H, s), 5.78 (1H, d,
J=8.3Hz), 6.89-7.89 (28H, m) , 8.05 (1H, d, J=8.2Hz), 8.59 (1H, d, J=*5.5Hz), 9.52-9.56 (1H, m), 9.93 (1H, d, J=8.2Hz)
(8) (3RS)-l,3-Dihydro-l-[ (l-tritylimidazol-4-yl)mεthyl]- 3-nicotinoylamino-5-(2-fluorophenyl)-2H-1,4- benzodiazepin-2-one
NMR (CDC13, δ) : 4.99-5.16 (4H, m) ,
5.71 (1H, d, J=7.7Hz), 6.85-9.18 (28H, m)
Example 3 To a solution of (3RS)-l,3-dihydro-l-[ (1- tritylimidazol-4-yl)methyl]-3-amino-5-(2-fluorophenyl)-2H- l,4-benzodiazepin-2-one (1.0 g) in methylene chloride (10 ml) were added succesεively triethylamine (340 mg) and 2-naphthoyl chloride (320 mg) . The mixture waε stirred for 1.5 hours. The reaction mixture was washed with water and dried. The solvent was removed under reduced preεεurε to give an amorphous residue, which was purified by column chromatography on silica gel with an eluent of chloroform. The fractions containing the desired product werε combined and evaporated to afford on oil, which was dried under reduced pressure to give (3RS)-l,3-dihydro-l-[ (1- tritylimidazol-4-yl)mεthyl]-3-(2-naphthoylamino)-5-(2- fluorophenyl)-2H-l,4-benzodiazεpin-2-onε (1.21 g) .
NMR (CDC13, δ) : 5.03 (2H, d, J=15Hz) , 5.15 (2H, d, J=15Hz), 5.79 (1H, d, J=8Hz), 6.89-8.07 (29H, ) , 8.22 (1H, d, J=8Hz), 8.47 (1H, s)
Examplε 4
To a solution of (3RS)-l,3-dihydro-l-[ (1- tritylimidazol-4-yl)mεthyl]-3-amino-5-(2-fluorophεnγl)-2H- l,4-benzodiazepin-2-one (1.5 g) in tεtrahydrofuran (23 ml) was added m-tolyl isocyanatε (0.35 g) under εtirring at ambient temperature. The mixture was stirred for 2 hours under the same condition. From the reaction mixture, the solvent was removed in vacuo to give crude product, which was recrystallized from a mixture of ethyl acetate and tetrahydrofuran to afford pure (3RS)-1,3- dihydro-l-[(l-tritylimidazol-4-yl)methyl]-3-[3-(3- methylphenyl)ureido]-5-(2-fluorophenyl)-2H-l,4- benzodiazepin-2-one (1.47 g) .
NMR (DMSO-dg, δ) : 2.2.4 (3H, s) , .85 (1H, d,
J=14.8Hz), 5.24-5.33 (2H, m) , 6.67-7.68 (29H, m), 7.91 (1H, d, J=8.2Hz), 8.97 (1H, s)
Example 5
To a suspended mixture of iron powdεr (1.1 g) and ammonium chloridε (0.13 g) in a mixturε of water (2.5 ml) and ethanol (7.5 ml) was added portionwise (3S)-1,3- dihydro-l-[(l-tritylimidazol-4-yl)methyl]-3-[(E)-3-(2- nitrophenyl)propenoylamino]-5-(2-fluorophenyl)-2H-l,4- benzodiazepin-2-one (1.1 g) under stirring and refluxing. After ethanol (7.5 ml) and water (2.5 ml) were added, the resultant mixture waε rεfluxed under stirring for 1.5 hours. The reaction mixture was filtered through celite and the filtered mass was washed with hot ethanol several times. From the filtrate and the washings, ethanol was removed under reduced pressure. To the residual mixture waε added a εaturated aqueous εolution of εodium bicarbonate (100 ml) and the mixture was extracted with ethyl acetate (100 ml). After washing with water and drying over magnesium sulfate, the extract was evaporated to give an amorphous residue, which was pulverized with diisopropyl ethεr and collected by filtration to afford (3S)-l,3-dihydro-l-[ (l-tritylimidazol-4-yl)methyl]-3- [ (E)-3-(2-aminophenyl)propenoylamino]-5-(2-fluorophenyl)- 2H-l,4-benzodiazepin-2-one (0.98 g).
NMR (CDC13, δ) : 3.71-4.07 (2H, br d) , 5:06 (2H, s),
5.68 (1H, d, J=8Hz), 6.47-7.99 (32H, m) MASS (m/e) : 476 (M+-260)
Example 6
To a solution of (3S)-l,3-dihydro-l-[(1- tritylimidazol-4-yl)mεthyl]-3-[ (E)-3-(2-aminophεnyl)- propenoylamino]-5-(2-fluorophenyl)-2H-l,4-benzodiazεpin- 2-one (0.49 g) in N,N-dimethylformamidε (4.9 ml) was added 6N-hydrochloric acid (3.4 mlX undεr stirring and cooling in an ice-bath. The mixture was warmed to 50°C and stirred for 1 hour. After cooling to room temperature, to the reaction mixture were added water and ethyl acetate under stirring. The mixture was adjusted to pH 8 with an aqueous solution of sodium bicarbonate. The separated organic layer was washed with water and dried. The solvent was removed under reduced pressure to give an amorphous residue, which was pulverized and stirred for several hours in diisopropyl ether. Collection by filtration, washing with diisopropyl ether and drying under reduced pressure gave (3S)-l,3-dihydro-l-(4- imidazolylmethyl)-3-[(E)-3-(2-aminophenyl)propenoylamino]- 5-(2-fluorophenyl)-2H-l,4-benzodiazepin-2-onε (350 mg) . To a solution of the product obtained above in chloroform (10 ml) was added 20%-hydrogen chloride in ethanol (5 ml) under cooling. The clear yellow solution was evaporated to dryness under reduced pressure. The rεsidue was pulverized and stirred for several hours in diisopropyl ether. Collection by filtration, washing with diisopropyl ether and drying under reduced prεssurε gave yellow powder (234 mg) of (3S)-l,3-dihydro-l-(4-imidazolylmethyl)-3- [ (E)-3-(2-aminophenyl)propεnoylamino]-5-(2-fluorophεnyl)- 2H-1,4-benzodiazepin-2-one dihydrochloride. IR (Nujol) : 3650-3050, 2700-2150, 1660, 1605 cm"1 NMR (CDC13, 6) : 3.8-4.8 (2H, b) , 5.15-5.56 (3H, m) , 7.04-7.81 (18H, m) , 9.03 (1H, s), 9.43 (1H, d, •J=8Hz ) MASS (m/e) : 494 (M+-73), 476
Example 7
The following compounds werε obtained according to a similar manner to that of Example 6.
(1) (3S)-l,3-Dihydro-l-(4-imidazolylmεthyl)-3-[ (2-amino- 4-chlorobenzoy1)amino]-5-(2-fluorophenyl)-2H-1,4- benzodiazepin-2-one mp : 180-220°C (dec.)
IR (Nujol) : 3500-3000, 1675, 1640 cm"1 NMR (CDC13, δ) : 4.93 (1H, d, J=15Hz), 5.20 (1H, d,
J=15Hz), 5.25-5.69 (3H, m) , 6.62-6.67 (2H, m) , 6.98-7.26 (6H, m) , 7.40-7.69 (5H, m) , 7.89-7.91 (2H, )
MASS (m/e) : 502 (M+)
(2) (3RS)-1,3-Dihydro-1-(4-imidazolylmethyl)-3-[(2,3,4,5- tεtrahydro-3-oxopyridazin-6-yl)carbonylamino]-5-(2- fluorophenyl)-2H-l,4-benzodiazepin-2-one dihydrochloride mp : 230-240°C (dεc.)
IR (Nujol) : 3650-3050, 2650, 2200, 1670, 1610,
1500 cm"1 NMR (DMSO-dg, δ) : 2.41-2.88 (4H, m) , 5.20 (1H, d, J=16Hz), 5.42 (1H, d, J=16Hz), 5.43 (1H, d, J=7.8Hz), 7.15-7.78 (9H, ) , 8.58 (1H, d,
J=7.8Hz), 9.02 (1H, s), 11.31 (1H, s), 14.67 (1H, br s) MASS (m/e) : 393 (M+-153)
(3) (3RS)-l,3-Dihydro-l-(4-imidazolylmethyl)-3-(3,4- dichlorobenzoylamino)-5-(2-fluorophenyl)-2H-1,4- benzodiazepin-2-one hydrochloride mp : 212-230°C (dec.)
IR (Nujol) : 3650, 3150, 2650-2000, 1650, 1600, 1510 cm"1
NMR (DMSO-dg, δ) : 5.20 (1H, d, J=16Hz),
5.43 (1H, d, J=16Hz), 5.61 (1H, d, J=7.3Hz), 7.19-7.82 (10H, m) , 7.98 (1H, dd, J=2Hz, 8Hz), 8.30 (1H, d, J=2Hz), 9.02 (1H, d, J=1.2Hz), 10.0 (1H, d, J=9.4Hz), 14.64 (1H, br ε)
MASS (m/e) : 521 (M+-37), 441
(4) (3RS)-1,3-Dihydro-1-(4-imidazolylmethyl)-3-(3- quinolylcarbonylamino)-5-(2-fluorophenyl)-2H-1,4- benzodiazεpin-2-one dihydrochloride mp : 230-233°C (dεc.) IR (Nujol) : 3600-3100, 2700-2100, 1670, 1610,
1510 cm"1 NMR (DMSO-dg, δ) : 5.24 (1H, d, J=16Hz), 5.47 (1H, d, J=16.1Hz), 5.71 (1H, d, J=7.2Hz),
7.2-8.39 (13H, m) , 9.05 (1H, d, J=l.lHz), 9.48 (1H, d, J=1.8Hz), 9.60 (1H, d, J=2Hz), 10.36 (1H, d, J=7.2Hz), 14.72 (1H, br ε) MASS (m/e) : 504 (M+-73), 424
(5) (3RS)-l,3-Dihydro-l-(4-imidazolylmethyl)-3-(2- quinoxalinylcarbonylamino)-5-(2-fluorophεnyl)-2H-1,4- bεnzodiazεpin-2-onε hydrochloride mp : 205-220°C (dec.) IR (Nujol) : 3600-3050, 2700-2000, 1670, 1600 cm"1 NMR (DMSO-dg, δ) : 5.25 (1H, d, J=16.1Hz),
5.48 (1H, d, J=16.1Hz), 5.68 (1H, d, J=7.8Hz) , 7.18-8.35 (13H, m) , 9.04 (1H, s), 9.53-9.61 (2H, m) , 14.63 (1H, m) MASS (m/e) : 505 (M+-36), 425 ( 6 ) ( 3RS ) -l , 3-Dihydro-l- ( 4-imidazolylmethyl ) -3- ( 4- cinnolinylcarbonylamino)-5-(2-fluorophenyl)-2H-1,4- benzodiazepin-2-one dihydrochloride p : 215-230°C (dec.)
IR (Nujol) : 3600-3100, 2700-2100, 1660, 1610 cm"1
NMR (DMSO-dg, δ) : 5.21-5.72 (3H, m) ,
7.18-8.61 (13H, m) , 9.01 (1H, s), 9.48 (1H, s), 10.46 (1H, d, J=7.lHz), 14.61 (1H, br s)
MASS (m/e) : 505 (M÷-73), 448
(7) (3RS)-1,3-Dihydro-l-(4-imidazolylmethyl)-3-(1- iεoquinolylcarbonylamino)-5-(2-fluorophenyl)-2H-1,4* benzodiazεpin-2-onε dihydrochloridε mp : 209-220°C (dec.) IR (Nujol) : 3600-3200, 2700-2100, 1670, 1610 cm"1 NMR (DMSO-dg, δ) : 5.2-5.55 (2H, m) ,
5.67 (ΪH, d, J=7.7Hz), 7.23-8.19 (13H, m) , 8.67 (1H, d, J=5.6Hz), 9.03 (1H, s), 9.19 (ΪH, d, J=8.4Hz), 9.9 (1H, d, J=7.7Hz), 14.62 (1H, br s)
MASS (m/ε) : 504 (M+-73), 424
(8) (3RS)-1,3-Dihydro-l-(4-imidazolylmεthyl)-3- nicotinoylamino-5-(2-fluorophenyl)-2H-1,4- benzodiazepin-2-onε dihydrochloridε mp : 220-235°C (dec.) NMR (DMSO-dg, δ) : 5.21 (1H, d, J=16.lHz),
5.45 (1H, d, J=16.1Hz), 5.64 (1H, d, J=7.2Hz), 7.2-8.0 (1H, m), 8.76-9.04 (2H, m) , 9.32 (1H, ε), 10.32 (1H, d, J=7.2Hz), 14.67 (1H, br ε)
MASS (m/e) : 454 (M+-73)
(9) (3RS)-1,3-Dihydro-l-(4-imidazolylmethyl)-3-(2- naphthoylamino)-5-(2-fluorophεnyl)-2H-l,4- bεnzodiazεpin-2-onε hydrochloridε mp : 220-230°C (dεc.)
IR (Nujol) : 3600-3050, 2800-2000, 1690, 1660, 1610 cm"1
NMR (DMSO-dg, δ) : 5.22 (1H, d, J=16Hz) ,
5.45 (1H, d, J=16Hz), 5.70 (1H, d, J=7.4Hz), 7.19-8.1 (15H, m), 8.70 (1H, s) , 9.03 (1H, s) , 9.78 (1H, d, J=7.4Hz), 14.61 (1H, br ε)
MASS (m/e) : 503 (M+-37), 427
(10) (3RS)-l,3-Dihydro-l-(4-imidazolylmethyl)-3-[3-(3- mεthylphenyl)ureido]-5-(2-fluorophenyl)-2H-1,4- benzodiazεpin-2-one hydrochloride mp : 210-225°C (dec.) IR (Nujol) : 3600-3050, 1680, 1610, 1555 cm"1 NMR (DMSO-dg, δ) : 2.24 (3H, s), 5.06 (2H, ε),
5.26 (1H, d, J=8.4Hz), 6.74 (1H, d, J=6.6Hz), . 6.87 (1H, s), 7.07-7.71 (13H, m) , 8.02 (1H, d, J=8.0Hz), 8.99 (1H, s)
Example 8
To a mixture of (3RS)-l,3-dihydro-3-(3-quinolyl- carbonylamino)-5-(2-fluorophεnyl)-2H-1,4-bεnzodiazεpin- 2-onε (850 mg) and l-trityl-4-(2-chloroethyl)imidazole monohydrochloride (900 mg) in N,N-dimethylformamide were added sodium hydride (60% suspension in mineral oil, 180 mg) and sodium iodide (3.98 g) under stirring and cooling at 0°C in an ice-salt bath in a stream of nitrogen. The mixture was stirred at room temperature for 1.5 hours and at 60-65°C for 6 hours. Acetic acid (2 ml) was added to the reaction mixture. Thε rεsultant mixturε was pourεd into a mixturε of εthyl acεtatε (200 ml) and watεr (200 ml) undεr stirring. Thε mixture was adjusted to pH 8 with an aqueous solution of sodium bicarbonate. The sεparated organic layer was washed with water. The solvent was rεmovεd undεr rεduced pressure to give an amorphous residue, which was purified by column chromatography on silica gel with an eluent of chloroform. The fractions containing the desirεd product were combined and evaporated to afford an amorphous mass, which was dried under reducεd pressure to give (3RS)-l,3-dihydro-l-[2-(l- tritylimidazol-4-yl)ethyl]-3-(3-quinolylcarbonylamino)-5- (2-fluorophenyl)-2H-l,4-benzodiazepin-2-one (750 mg) . NMR (DMSO-dg, δ) : 2.49-2.65 (2H, m) , 3.8-4.6 (2H, m), 5.62 (1H, d, J=7.48Hz), 6.70 (1H, s),
7.00-8.1 (28H, m),.9.05 (1H, ε), 9.35 (1H, d, J=2.2Hz), 10.0 (1H, d, J=7.64Hz)
Example 9 To a solution of (3RS)-l,3-dihydro-3-(2-naphthoyl- amino)-5-(2-fluorophenyl)-2H-l,4-benzodiazepin-2-onε (1.25 g) in N,N-dimethylformamidε (31 ml) was addεd sodium hydridε (60% suspεnsion in mineral oil, 130 mg) under stirring and cooling at 0QC in an ice-salt bath in a stream of nitrogen. After the mixture was stirred at room temperature for 45 minutes, a solution of chloroace onitrilε (270 mg) in N,N-dimεthylformamide (5 ml) was added to the mixture at 0°C under stirring. The resultant mixture was stirred overnight at room temperature. Acetic acid (0.5 g) was added to the reaction mixture. The resultant mixture was poured into a mixture of ethyl acetate (200 ml) and water (300 ml) under stirring. The mixture was adjusted to pH 8 with an aqueous solution of sodium bicarbonate. The separated organic layer was washed with water. The solvent was removεd under reduced pressure to give amorphous residue, which was purified by column chromatography on silica gel with an εluεnt of chloroform. Thε fractions containing thε desired product were combined and evaporated to afford an amorphous mass, which was dried under reduced pressurε to give (3RS)-l,3-dihydro-l-cyanomethyl-3-(2-naphthoyl- amino)-5-(2-fluorophεnyl)-2H-1,4-benzodiazepin-2-one (1.19 g).
NMR (DMSO-dg, δ) : 5.08-5.32 (2H, m) , 5.74 (1H, d, J=7.65Hz), 7.25-7.82 (14H, m) , 8.71 (1H, s),
9.95 (1H, d, J=7.68Hz)
Examplε 10
The following compounds werε obtainεd according to similar manners to those of Examples 8 and 9.
(1) (3RS)-1,3-Dihydro-3-( 3-quinolylcarbonylamino)-5-(2- fluorophεnyl)-l-[(lH-tetrazol-5-yl)methyl]-2H-l,4- benzodiazepin-2-one mp : 284-285°C
IR (Nujol) : 3400, 1695, 1650, 1600, 1525 cm"1 NMR (DMSO-dg, δ) : 5.4-5.62 ( 2H, m) , 5.76 (1H, d, J=7.74Hz), 7.23-7.39 (4H, m) , 7.63-7.79 (4H, m), 7.86-7.93 (2H, m) , 8.09-8.32 (2H, m) , 9.05 (1H, s), 9.37 (1H, d, J=2.36Hz), 10.12 (1H, d,
J=7.78Hz), 15.2-16.0 (1H, br ε) MASS (m/e) : 507 (M+) , 424 (M+-83)
(2) (3RS)-1,3-Dihydro-3-(3,4-dichlorobenzoylamino)-5-(2- fluorophεnyl)-l-[ (iH-tetrazol-5-yl)methyl]-2H-l,4- benzodiazepin-2-onε mp : 260-265°C (dεc.)
IR (Nujol) : 3600, 3050, 1650, 1600 cm"1
NMR (DMSO-dg, δ) : 3.83 ( 1H, br ε) , 5.2-5.4 (2H, m), 5.63 (1H, d, J=7.8Hz), 7.14-7.33 (5H, ), 7.55-7.67 (4H, m) , 7.77 (1H, d, J=8.4Hz), 7.97 (2H, d, J=8.4Hz), δ.?8 (1H, d, J=1.9Hz), 9.94 (1H, d, J=7.83Hz)
MASS (m/e) : 524 (M+) , 368 (M+-156) (3) (3RS)-1,3-Dihydro-3-(2-indolylcarbonylamino)-5-(2- fluorophεnyl)-l-[(lH-tetrazol-5-γl)methyl]-2H-l,4- benzodiazεpin-2-one p : 280-290°C (dec.) IR (Nujol) : 3150, 1640, 1540 cm"1 NMR (DMSO-d., δ) : 5.21-5.3 (2H, m) , 5.69 (1H, d, J=8.14Hz), 7.02-7.66 (13H, m) , 7.97 (1H, d, J=8.26Hz), 9.52 (1H, d, J=8.18Hz), 11.67 (1H, ε) MASS (m/e) : 351 (M+-144), 332 (M+-162)
(4) (3RS)-1,3-Dihydro-l-[2-(4-imidazolyl)ethyl]-3-(3- quinolylcarbonylamino)-5-(2-fluorophεnyl)-2H-1,4- benzodiazεpin-2-one mp : 165-175°C (dec.) IR (Nujol) : 3600-3000, 1650, 1600 cm"1
(5) (3S)-3-(2-Indolylcarbonylamino)-1,3-dihydro-5-( 2- fluorophenyl)-l-[(lH-tεtrazol-5-yl)methyl]-2H-l,4~ benzodiazεpin-2-one NMR (DMSO-dg, δ) : 5.49 (2H, ABq, J=16.4Hz, 24.8Hz),
5.73 (1H, d, J=8.0Hz), 7.0-7.91 (14H, m) , 9.60 (1H, d, J=8.0Hz), 11.65 (1H, s)
Example 11 To a solution of (3RS)-l,3-dihydro-l-[2-(1-trityl- imidazol-4-yl)εthyl]-3-(3-quinolylcarbonylamino)-5-(2- fluorophεnyl)-2H-l,4-bεnzodiazεpin-2-onε (740 mg) in N,N-dimεthylformamidε (7.4 ml) waε added 6N-hydrochloric acid (5.18 ml) under εtirring and cooling in an ice-bath. The mixture was warmed to 60-70°C and stirred for one hour. Aftεr cooling to room temperature, to the reaction mixturε wεrε added icε water and ethyl acetatε undεr stirring. The mixture was adjusted to pH 8 with an aqueous solution of sodium bicarbonate. The separated organic layer was washed with water and dried. Thε solvent was rεmovεd under reduced pressure to give an amorphous reεiduε, which was purifiεd by column chromatography on silica gεl with an eluent of chloroform. The fractions containing the desirεd product were combined and evaporatεd to afford an amorphouε mass, which was pulvεrized and stirred for sεveraϊ hours in diisopropyl ethεr. Thε prεcipitatε was collεctεd by filtration, washed with diisopropyl ether and dried under reducεd prεssurε to give (3RS)-l,3-dihydro-l-[2-(4-imidazolyl)- ethyl]-3-(3-quinolylcarbonylamino)-5-(2-fluorophεnyl)- 2H-l,4-benzodiazεpin-2-onε (0.25 g) . mp : 165-175°C (dec.)*
IR (Nujol) : 3600-3000, 1650, 1600 cm"1 NMR (DMSO-dg, δ) : 2.52-2.66 (2H, m) , 4.09-4.63 (2H, m) , 5.65 (1H, d, J=7.6Hz), 6.77 (1H, ε),
7.24-8.32 (13H, m) , 9.07 (1H, d, J=1.92Hz), 9.39 (1H, d, J=2.2Hz), 10.11 (1H, d, J=7.6Hz), 11.82 (1H, br s)
MASS (m/e) : 518 (M+)
Example 12
To a mixture of (3RS)-l,3-dihydro-3-(3,4-dichloro-- bεnzoylamino)-5-(2-fluorophεnyl)-2H-l,4-bεnzodiazepin-2- onε (500 mg) and l-trityl-4-(2-chloroethyl)imidazolε monohydrochloridε (295 mg) in N,N-dimethylformamide (7.5 ml) werε added sodium hydride (60% suspension in mineral oil, 99.5 mg) and sodium iodide (2.25 g) under stirring and cooling at 0°C in an ice-salt bath in a εtream of nitrogεn. After the mixture waε stirred at room temperature for 1.5 hourε and at 60-65°C for 6 hours. To the reaction mixture werε added acetic acid (1.1 ml) and 6N-hydrochloric acid (5 ml) and the mixturε waε stirred at 60-70°c for one hour. The resultant mixturε was poured into a mixture of ethyl acetatε (100 ml) and watεr (100 ml) under stirring. Thε mixture was adjusted to pH 8 with an aqueouε εolution of sodium bicarbonate. The separated organic layer was washεd with watεr and dried. The solvent was removed under reducεd prεssurε to givε an amorphous rεsiduε, which was purified by column chromatography on silica gel with an eluent of chloroform. The fractions containing the desired product were combined and evaporated to afford an amorphous mass, which was pulverized and stirred for several hourε in diiεopropyl ether. Collection by filtration, washing with diisopropyl ether and drying under reducεd prεssurε gavε
(3RS)-l,3-dihydro-l-[2-(4-imidazolyl)ethyl]-3-(3,4- dichlorobεnzoylamino)-5-(2-fluorophenyl)-2H-1,4- benzodiazepin-2-one (0.18 g) . mp : 149-159°C IR (Nujol) : 3600-3100, 1650, 1600 cm"1
NMR (DMSO-dg, δ) : 2.5-2.59 (2H, m) , 3.95-4.62 (2H, m), 5.5 (1H, d, J=7.52Hz), 6.77 (1H, br s), 7.23-8.32 (12H, m) , 9.99 (1H, br ε), 11.8 (1H, br s) MASS (m/ε) : 386 (M+-150)
Examplε 13
Thε following compounds were obtained according to a similar manner to that of Example 12.
(1) (3RS)-l,3-Dihydro-l-[2-(4-imidazolyl)ethyl]-3-(2- naphthoylamino)-5-(2-fluorophenyl)-2H-1,4- benzodiazepin-2-onε mp : 198-205°C (dεc.) IR (Nujol) : 3275, 1680, 1630, 1530 cm"1
NMR (DMSO-dg, δ) : 2.5-2.8 (2H, m) , 4.0-4.6 (2H, m) , 5.65 (1H, d, J=7.67Hz), 6.81 (1H, br s), 7.24-8.09 (15H, m) , 8.71 (1H, s), 9.78 (1H, d, J=7.7lHz), 11.8 (1H, br s) MASS (m/e) : 518 (M+) (2) (3RS)-l,3-Dihydro-l-[2-(4-imidazolyl)εthyl]-3-(2- indolylcarbonylamino)-5-(2-fluorophεnyl)-2H-1,4- benzodiazepin-2-one mp : 188-205°C (dec.)
IR (Nujol) : 3550-3100, 1640, 1540 cm"1 NMR (DMSO-dg, δ) : 2.51-2.65 (2H, m) , 4.01-4.08 (1H, m), 4.50-4.57 (1H, m) , 5.63 (1H, d, J=7.9Hz), 6.56 (1H, ε), 6.76-7.81 (14H, m) , 9.60 (1H, d, J=7.9Hz), 11.64 (1H, ε) , 11.81 (1H, br ε)
Example 14
(1) A mixture of (3RS)-l,3-dihydro-l-σyanomethyl-3-(2- naphthoylamino)-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2- one (1.15 g) , εodium azide (480 mg) and triethylamine monohydrochloridε (510 mg) in l-mεthyl-2-pyrrolidinonε (20 ml) was stirred at 145°C for 3.5 hours. The reaction mixturε was pourεd into 5°C hydrochloric acid (100 ml) under stirring. The rεsultant precipitates were collectεd by filtration, washεd with watεr and purified by column chromatography on εilica gel with an eluent of chloroform. The fractionε containing the deεired product were combined and εvaporated to afford an amorphous mass, which was pulverized and stirred for εeveral hourε in diisopropyl ether. Collection by filtration, washing with diiεopropyl ethεr and drying undεr rεduced pressurε gave
(3RS)-1,3-dihydro-3-(2-naphthoylamino)-5-(2-fluorophenyl)- l-[ (lH-tetrazol-5-γl)raethγl]-2H-l,4-benzodiazepin-2-one (540 mg). mp : 265-275°C (dεc.) IR (Nujol) : 3570-3100, 1650, 1490 cm"1
NMR (DMSO-dg, δ) : 5.33 (2H, ε), 5.73 (1H, d,
J=7.98Hz), 7.18-8.09 (15H. m) , 8.69 (1H, ε) , 9.72 (1H, d, J=8Hz) MASS (m/ε) : 505 (M+) Thε following compound was obtainεd according to a similar mannεr to that of Example 14(1).
(2) (3S)-3-(2-Indolylcarbonylamino)-1,3-dihydro-5-(2- fluorophenyl)-l-[ (lH-tetrazol-5-yl)methyl]-2H-I,4- bεnzodiazεpin-2-onε
NMR (DMSO-dg, δ) : 5.49 (2H, ABq, J=16.4Hz, 24.8Hz), 5.73 (1H, d, J=8.0Hz), 7.0-7.91 (14H, ) , 9.60 (1H, d, J=8Hz), 11.65 (1H, s)
Examplε 15
4-Chlorophεnyl isocyanatε (0.14 g) was addεd to a solution of (3RS)-3-amino-l,3-dihydro-5-phenyl-l-[ (1- trityl-lH-tetrazol-5-yl)methyl]-2H-l,4-benzodiazepin-2-one (0.50 g) in dry tetrahydrofuran (10 ml) at room temperature. After the mixture was stirred for 3 hours, 8.4N-ethanolic hydrogen chloride (1.5 ml) was added to the mixture at room temperature and then thε mixture was stirred for 3 hours. The solvent was removed under reduced pressurε. Thε rεsiduε was suspended with a mixture of ethanol and ethyl acetate and the resultant precipitate was collected by filtration to give (3RS)-1,3- dihydro-3-[3-(4-chlorophenyl)ureido]-5-phenyl-l-[ (1H- tεtrazol-5-yl)methyl]-2H-1,4-bεnzodiazεpin-2-onε monohydrochloridε (0.40 g) . mp : 205-208°C IR (Nujol) : 3325, 3250, 3190, 2725, 1690, 1600,
1545 cm"1 NMR (DMSO-dg, δ) : 5.30-5.50 (1H, m) , 5.46 (2H, ABq, J=17Hz, 24Hz), 7.20-7.85 (15H, m) , 9.0-11.0 (1H, broad), 9.42 (1H, s)
Examplε 16
Thε following compoundε wεrε obtainεd according to a similar manner to that of Example 15. (1) (3RS)-1,3-Dihydro-3-[3-(4-chlorophenyl)ureido]-5-(2- (fluorophenyl)-1-[(lH-tetrazol-5-yl)methyl]-2H-1,4- benzodiazepin-2-one monohydrochloridε mp : 203-205°C IR (Nujol) : 3320, 3250, 3190, 2720, 1695, 1605,
1525 cm"1 NMR (DMSO-dg, δ) : 5.30-5.40 (1H, m) , 5.48 (2H, ABq, J=17Hz, 21Hz), 7.20-7.80 (13H, m)," 8.0-10.5 (2H, broad), 9.37 (lH; Ξ)
(2) (3RS)-l,3-Dihydro-3-[3-(3-methylphenyl)ureido]-5- phenyl-l-[ (lH-tetrazol-5-γl)mεthyl]-2H-l,4- bεnzodiazepin-2-one monohydrochloride p : 188-194°C (dec.) IR (Nujol) : 3290, 2720, 2605, 1685, 1610, 1595,
1540 cm"1 NMR (DMSO-dg, δ) : .-2.24 (3H, s), 5.30-5.48 (1H, m), 5.46 (2H, ABq, J=17Hz, 25Hz) , 6.70-6.80 (1H, m) , 7.00-7.54 (12H, m) , 7.70-7.80 (2H, m) , 8.0-10.20 (2H, broad), 9.12 (1H, s)
(3) (3RS)-1,3-Dihydro-5-(2-fluorophenyl)-3-[3-(3- methylphenyl)ureido]-1-[(lH-tεtrazol-5-yl)methyl]-2H- 1,4-benzodiazepin-2-onε monohydrochloridε mp : 181-191°C (dec.)
IR (Nujol) : 3300, 2710, 2610, 1690, 1595, 1550 cm"1 NMR (DMSO-dg, δ) : 2.24 (3H, ε), 5.35-5.45 (1H, m) , 5.48 *(2H, ABq, J=llHz, 22Hz), 6.70-6.78 (1H, m) , 7.05-7.38 (7H, m) , 7.50-7.81 (6H, m) , 8.0-10.4 (2H, broad), 9.11 (1H, s)
Example 17
To a solution of (3S)-l,3-dihydro-l-[ (1- tritylimidazol-4-yl)mεthyl]-3-(3,4-dichlorobenzoylamino)- 5-(2-fluorophenyl)-2H-l,4-benzodiazepin-2-onε (20.34 g) in" N,N-dimethylformamide (204 ml) was added 6N-hydrochloric acid (157 ml) under stirring and cooling in an ice-bath. The mixture waε warmed to 70-80°C and εtirred for 1 hour. After cooling to room temperaturε, to the reaction mixture werε addεd ice water and ethyl acetate under stirring. The mixture was adjusted to pH 8.0 with an aqueous solution of sodium bicarbonate. The separated organic layer was washed with water and dried. The solvent was re ovεd under reduced presεure to givε an amorphous residue, which was purified by column chromatography on εilica gel with an eluent of chloroform. The fractions containing the desired product were combined and evaporated to afford an amorphous mass, which was dried under reduced pressure to give (3S)-l,3-dihydro-l-(4- imidazolylmethyl)-3-(3,4-dichlorobenzoylamino)-5-( 2- fluorophenyl)-2H-l,4-benzodiazepin-2-one. This was disεolved in chloroform (200 ml) and to thε rεsultant solution was added 20%-hydrogεn chloridε in εthanol (50 ml) undεr cooling. Thε clεar yellow solution was evaporated to dryness under rεduced pressurε to givε an amorphous mass, which was lyophirizεd to give (3S)-1,3- dihydro-1-(4-imidazolylmethyl)-3-(3,4-dichlorobεnzoyl- amino)-5-(2-fluorophenyl)-2H-1,4-benzodiazεpin-2-one hydrochloridε as yellow powder (12.97 g) . IR (CHC13) : 3000, 2900-2200, 1660, 1600, 1500 cm"1 NMR (DMSO-dg, δ) : 5.19 (1H, d, J=16Hz), 5-.43 (1H, d, J=16Hz), 5.61 (1H, d, J=7.3Hz), 7.19-7.39 (5H, m), 7.56-7.82 (5H, m) , 7.95-8.00 (1H, m) , 8.30 (1H, d, J=1.9Hz), 9.01 (1H, ε), 9.99 (1H, d, J=7.3Hz), 14.6 (1H, br ε)
MASS (m/e) : 521 (M+-37) [α]^° = -24.75° (C=0.832, CHjOH)
Example 18 To a suεpension of 2-indolecarboxylic acid (161.2 g) in methylene chloride (3.25 ml) was added thionyl chloride (119.0 mg) and one drop of N,N-dimethylformamidε undεr stirring at ambient temperature. The mixture was refluxεd for 1 hour with stirring. To a solution of (3S)-3-amino-l,3-dihydro-5-(2-fluorophεnyl)-1-[ (1H- tetrazol-5-yl)methyl]-2H-l,4-benzodiazεpin-2-onε hydrochloride (387.8 mg) and triεthylamine (506.0 mg) in methylene chloride (8 ml) was added dropwisε the εolution of 2-indolylcarbonyl chloride in mεthylenε chloride obtained above under icε-cooling and stirring. The mixture was stirred under the same conditions for 3 hourε. To the reaction mixture was" added chloroform. The mixture was washed with diluted hydrochloric acid and water successively and dried over magnεsium sulfatε. Rεmoval of thε solvent in vacuo afforded an amorphouε mass, which was suspendεd with stirring in diisopropyl ether. The resultant powder waε collected by filtration, washed with diisopropyl ether and dried under reduced pressure to give (3S)-3-(2-indolylcarbonylamino)-1,3-dihydro-5-( 2- fluorophenyl)-l-[ (lH-tεtrazol-5-yl)methyl]-2H-l,4- benzodiazepin-2-one. p : 270-271°C (dec.)
[α]^8*5 = -18.87° (C=0.62, tetrahydrofuran) NMR (DMSO-dg, δ) : 5.49 (2H, ABq, J=16.4Hz, 24.8Hz), 5.73 (1H, d, J=8.0Hz), 7.0-7.91 (14H, m) , 9.60
(1H, d, J=8.0Hz), 11.65 (1H, s) MASS (m/e) : 494 (M+)
Example 19 the following compound was obtained according to a similar manner to that of Example 18.
(3R)-3-(2-Indolylcarbonylamino)-1,3-dihydro-5-(2- fluorophenyl)-l-[(lH-tetrazol-5-yl)methyl]-2H-l,4- benzodiazεpin-2-onε mp : 270-271°C (dec.)
[α]^8,5 : +18.72° (C=0.625, tetrahydrofuran)
NMR (DMSO-dg, δ) : 5.49 (2H, ABq, J=16.3Hz, 24.7Hz),
5.73 (1H, d, J=8.0Hz), 7.0-7.91 (14H, m) , 9.60
(1H, d, J=8.0Hz), 11.65 (1H, s) MASS (m/e) : 494 (M+)
Example 20
The following compounds were obtained according to a similar manner to that of Example 1.
(1) (3S)-l,3-Dihydro-l-[ ( l-tritylimidazol-4-yl)mεthyl]- 3-(3 ,4-dichlorobεnzoylamino)-5-(2-fluorophεnyl)-2H- 1,4-bεnzodiazεpin-2-onε NMR (CDC13, δ) : 5.02 (1H, d, J=15Hz),
5.11 (1H, d, J=15Hz), 5.67 (1H, d, J=7.8Hz), 6.84-8.04 (29H, )
(2) (3RS)-1,3-Dihydro-1-[2-( 4-imidazolyl) thyl]-3-( 3- quinolylcarbonylamino)-5-(2-fluorophεnyl) -2H-1,4- benzodiazepin-2-onε mp : 165-175°C (dec.)
IR (Nujol) : 3600-3000, 1650, 1600 cm"1
Example 21
The following compound was obtained according to a similar manner to that of Example 11.
(3S)-3-(2-Indolylcarbonylamino)-1,3-dihydro-5-(2- fluorophenyl)-!-[ (lH-tetrazol-5-yl)mεthyl]-2H-l, 4- bεnzodiazepin-2-one
NMR (DMSO-dg, δ) : 5.49 (2H, ABq, J=16.4Hs, 24.8Hz), 5.73 (1H, d, J=8.0Hz), 7.0-7.91 (14H, ) , r-.60 (1H, d, J=8.0Hz), 11.65 (1H, ε)

Claims

C L A I M S
A compound of thε formula
Figure imgf000058_0001
whεrεin R is hεterocyclic group which may have one or more suitable substituent(s) , or cyano,
R is hydrogen or halogen,
R" is aryl which may have one or more suitable substituent(s) ,
R- is aryl which may have one or more suitable substituent(ε) ,
■war(lower)alkenyl which may have one or more εuitable substituent(s) , arylamino which may have one or more suitable substituent(s) , heteromonocyclic group which may have onε or orε εuitablε substituent(s) , quinolyl, isoquinolyl, cinnolinyl, indolyl, or quinoxalinyl, and
A is lowεr alkylεne,
4 with proviso that when R is indolyl, thεn
(i) R is tεtrazolyl which may havε onε or morε suitablε substituent(s) and 3 R is halophenyl or
(ii) R is imidazolyl which may have onε or more suitablε substituent(s) ,
R iε halophenyl and A iε εthylεne, and a pharmaceutically acceptablε salt thεrεof.
2. A compound of claim 1, whεrεin R is tεtrazolyl which may havε an imino protective group, imidazolyl which may have an imino protective group, or cyano,
3 R is phenyl or halophenyl,
4 R is phenyl or naphthyl, each of which may havε one or two substituent(s) selected from the group consisting of halogen and amino; phεnyl(lowεr)alkεhyl which may have amino or nitro; phenylamino which may have lower alkyl or halogen; pyridyl; tetrahydropyridazinyl which may have an oxo group; quinolyl; isoquinolyl; cinnolinyl; indolyl; or quinoxalinyl.
3. A compound of claim 2, wherein
R is tetrazolyl which may have mono(or di or tri)- phenyl(lowεr)alkyl, imidazolyl which may have mono(or di or tri)phenyl(lower)alkyl, or cyano, 4 R is naphthyl; dihalophenyl; phenyl having halogen and amino; nitrophenyl(lowεr)alkenyl; aminophεnyl(lowεr)alkenyl; lower alkylphenylamino; halophεnylamino; pyridyl; tεtrahydropyridazinyl having an oxo group; quinolyl; iεoquinolyl; cinnolinyl; indolyl; or quinoxalinyl.
4. A compound of claim 3, whεrεin
R is tεtrazolyl,
2 R is hydrogεn,
R is halophenyl ,
4 R is mdolyl and
A iε C- -C . alkylene . A compound of claim 4, which is
(3S)-3-(2-indolylcarbonylamino)-1,3-dihydro-5-(2- fluorophenyl)-l-[(lH-tetrazol-5-yl)methyl]-2H-1,4- benzodiazepin-2-one
A process for preparing a compound of the formula
Figure imgf000060_0001
wherein R1 is hetεrocyclic group which may havε onε or morε εuitablε substituεnt(s) , or cyano,
R is hydrogen or halogen,
3 R is aryl which may have onε or morε suitablε subεtituent(s) ,
R is aryl which may have one or more suitablε substituent(s) , ar(lower)alkenyl which may have one or more suitable substituent(ε) , arylamino which may have one or morε suitablε substituent(s) , heteromonocyclic group which may have one or more suitable subεtituent(ε) , quinolyl, iεoquinolyl, cinnolinyl, indolyl, or quinoxalinyl, and
A iε lower alkylene,
4 with proviεo that when R is indolyl, thεn
(i) R is tεtrazolyl which may havε onε or more suitable substituent(s) and
R3 is halophenyl or (ii) R iε imidazolyl which may have one or more suitable substituent(s) , 3 R is halophenyl and
A is ethylene, or a salt thereof, which comprises
1) reacting a compound of the formula :
Figure imgf000061_0001
whεrεin R 1, R2, R3 and A arε εach as defined above, or its reactive derivative at the amino group, or a salt thereof with a compound of the formu_a :
HO-C-R'
wherein R is aε definεd abovε, or its reactive derivative or a salt therεof to give a compound of thε formula :
Figure imgf000061_0002
1 2 3 4 whεrεin R , R , R , R and A are each as definεd abov , 60 -
-?•' or a salt thεreof, or
(2) subjecting a compound of the formula
Figure imgf000062_0001
whεrεin R 2 , R 3 , R 4 and A arε εach as defined abovε, and
Figure imgf000062_0002
i_•s heterocyclic group having a
15 protected imino group of the formula :
j (in which R is imino protective ■ R group) in its hetεro ring, which may havε onε
20 or more suitable substituent(s) , or a salt thεrεof to elimination reaction of thε imino protεctivε group to givε a compound of the formula :
Figure imgf000062_0003
30 wherein R 2 , R 3 , R 4 and A are each as defined abovε , and
R ,,1 i_s hεtεrocyclic group having an imino group of thε formula
35 N"
H in its hetεro ring, which may have onε or morε suitable substituent(s) ,
or a salt thεreof, or
(3) subjecting a compound of thε formula
Figure imgf000063_0001
wherein R 1, R2, R3 and A are each as definεd above, and 4 R= is ar(lowεr)alkεnyl having a nitro group, or a salt thεrεof to givε a compound of thε formula
Figure imgf000063_0002
whεrein R 1 , R2 , R 3 and A are each as defined above , and 4 R, is ar ( lower ) alkenyl having an ammo group , or a salt thereof, or
(4) reacting a compound of the formula - -
Figure imgf000064_0001
whεrein R 2, R3 and R4 are each aε defined above, or a salt thereof with a compound of the formula
X-A-RJ
wherein R and A are each as definεd above, and
X is an acid reεidue, or a salt therεof to give a compound of the formula
Figure imgf000064_0002
wherεin R 1, R2, R3, R4 and A are each as definεd above, or a salt thereof, or
(5) reacting a compound of the formula
Figure imgf000064_0003
2 3 4 wherein R , R , R and A are each as defined above, or a salt thεreof with a compound of thε formula
HN.
or a salt thereof to give a compound of the formula
H N—N
\\ -N
N
Figure imgf000065_0001
2 3 4 wherein R , R , R and A are each as defined above, or a salt thereof.
A compound of the formula :
Figure imgf000065_0002
wherεin R is tεtrazolyl which may have one or more suitable substituent( s) ,
R ,2 i.s hydrogen or halogen,
3 R is aarryyll wwhhiicchh mmaayy hhaavvee <one or more suitable substituent(s) , and A is lower alkylene, and a salt thereof.
8. A process for preparing a compound of the formula
5
Figure imgf000066_0001
1 wherein R is tetrazolyl which may have one or more suitable subεtituerit(s),
2
15 R is hydrogen or halogen,
3 R is aryl which may have one or more suitable substituent(s) , and
A is lowεr alkylenε, or a salt thereof,
20 which comprises subjecting a compound of the formula:
Figure imgf000066_0002
wherein R 1 ; R2, R3, and A are each as defined above, and
^0 R7 is protected ammo, or a salt thereof to elimination reaction of the amino protective group.
9. A pharmaceutical composition which comprises, as an
35 active ingredient, a compound of claim 1 or a pharmaceutically acceptable salt therεof in admixturε with pharmaceutically acceptable carriers.
10. A use of a compound of claim 1 or a pharmaceutically acceptable salt thereof aε a cholecyεtokinin antagonist.
11. A method for treating or preventing cholecyεtokinin-mediated diseases which comprises administering a compound of claim 1 or a pharmaceutically acceptable salt thereof to human or animals.
12. A process for preparing a pharmaceutical composition which comprises admixing a compound of claim 1 or a pharmaceutically acceptablε salt thεreof with a pharmaceutically acceptable carrier.
PCT/JP1991/000952 1990-07-19 1991-07-17 Benzodiazepine derivatives WO1992001683A1 (en)

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EP0508799A1 (en) * 1991-04-10 1992-10-14 Merck & Co. Inc. Cholecystokinin antagonists
EP0508797A1 (en) * 1991-04-10 1992-10-14 Merck & Co. Inc. Cholecystokinin antagonists
US5220017A (en) * 1991-04-10 1993-06-15 Merck & Co., Inc. Cholecystokinin antagonists
US5220018A (en) * 1991-04-10 1993-06-15 Merck & Co., Inc. Cholecystokinin antagonists
WO1993019052A1 (en) * 1992-03-24 1993-09-30 Merck Sharp & Dohme Limited 3-ureido substituted benzodiazepin-2-ones having cholecystokinin and/or gastrin antagonistic activity and their use in therapy
US5360802A (en) * 1992-05-11 1994-11-01 Merck Sharpe & Dohme Ltd. Benzodiazepine derivatives, compositions containing them and their use in therapy
WO1994026723A2 (en) * 1993-05-14 1994-11-24 Genentech, Inc. ras FARNESYL TRANSFERASE INHIBITORS
US5378838A (en) * 1993-01-13 1995-01-03 Merck & Co., Inc. Benzodiazepine cholecystokinin antagonists
WO1995003299A1 (en) * 1993-07-20 1995-02-02 Glaxo S.P.A. 1,5-benzodiazepine derivatives useful as cck or gastrin antagonists
WO1996004254A2 (en) * 1994-07-29 1996-02-15 Fujisawa Pharmaceutical Co., Ltd. Benzodiazepine derivatives
US5698691A (en) * 1993-09-24 1997-12-16 Takeda Chemical Industries, Ltd. Condensed cyclic compounds and their use
WO1998000406A1 (en) * 1996-07-02 1998-01-08 Merck & Co., Inc. Method for the treatment of preterm labor
US5929071A (en) * 1996-07-02 1999-07-27 Merck & Co., Inc. Method for the treatment of preterm labor
US6509331B1 (en) 1998-06-22 2003-01-21 Elan Pharmaceuticals, Inc. Deoxyamino acid compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
US6528505B1 (en) 1998-06-22 2003-03-04 Elan Pharmaceuticals, Inc. Cyclic amino acid compounds pharmaceutical compositions comprising same and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
US6541466B2 (en) 1996-12-23 2003-04-01 Athena Neurosciences, Inc. Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
US6569851B1 (en) 1998-06-22 2003-05-27 Elan Pharmaceutials, Inc. Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
US6683075B1 (en) 1996-12-23 2004-01-27 Athena Neurosciences, Inc. Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use
EP1398033A3 (en) * 1999-04-30 2004-06-30 The Regents Of The University Of Michigan Use of benzodiazepines for treating autoimmune diseases, inflammations, neoplasies, viral infections and atherosclerosis
US6774125B2 (en) 1998-06-22 2004-08-10 Elan Pharmaceuticals, Inc. Deoxyamino acid compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
US6838455B2 (en) 1998-06-22 2005-01-04 Athena Neurosciences, Inc. Deoxyamino acid compounds, pharmaceutical compositions comprising same, and methods for inhibiting beta-amyloid peptide release and/or its synthesis by use of such compounds
US6958330B1 (en) 1998-06-22 2005-10-25 Elan Pharmaceuticals, Inc. Polycyclic α-amino-ε-caprolactams and related compounds
US7572788B2 (en) 1999-04-30 2009-08-11 The Regents Of The University Of Michigan Compositions and methods relating to novel compounds and targets thereof
US7638624B2 (en) 2005-01-03 2009-12-29 The Regents Of The University Of Michigan Compositions and methods relating to novel benzodiazepine compounds and derivatives
US7683046B2 (en) 1999-04-30 2010-03-23 The Regents Of The University Of Michigan Benzodiazepine compositions for treating epidermal hyperplasia and related disorders
US9126978B2 (en) 2009-11-17 2015-09-08 The Regents Of The University Of Michigan 1,4-benzodiazepine-2,5-diones and related compounds with therapeutic properties

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Cited By (45)

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Publication number Priority date Publication date Assignee Title
EP0508799A1 (en) * 1991-04-10 1992-10-14 Merck & Co. Inc. Cholecystokinin antagonists
EP0508797A1 (en) * 1991-04-10 1992-10-14 Merck & Co. Inc. Cholecystokinin antagonists
US5218115A (en) * 1991-04-10 1993-06-08 Merck & Co., Inc. Cholecystokinin antagonists
US5218114A (en) * 1991-04-10 1993-06-08 Merck & Co., Inc. Cholecystokinin antagonists
US5220017A (en) * 1991-04-10 1993-06-15 Merck & Co., Inc. Cholecystokinin antagonists
US5220018A (en) * 1991-04-10 1993-06-15 Merck & Co., Inc. Cholecystokinin antagonists
US5681833A (en) * 1992-03-24 1997-10-28 Merck, Sharp & Dohme Ltd. Benzodiazepine derivatives
WO1993019052A1 (en) * 1992-03-24 1993-09-30 Merck Sharp & Dohme Limited 3-ureido substituted benzodiazepin-2-ones having cholecystokinin and/or gastrin antagonistic activity and their use in therapy
US5360802A (en) * 1992-05-11 1994-11-01 Merck Sharpe & Dohme Ltd. Benzodiazepine derivatives, compositions containing them and their use in therapy
US5378838A (en) * 1993-01-13 1995-01-03 Merck & Co., Inc. Benzodiazepine cholecystokinin antagonists
WO1994026723A2 (en) * 1993-05-14 1994-11-24 Genentech, Inc. ras FARNESYL TRANSFERASE INHIBITORS
WO1994026723A3 (en) * 1993-05-14 1995-02-02 Genentech Inc ras FARNESYL TRANSFERASE INHIBITORS
US5843941A (en) * 1993-05-14 1998-12-01 Genentech, Inc. Ras farnesyl transferase inhibitors
US5532359A (en) * 1993-05-14 1996-07-02 Genentech, Inc. Ras farnesyl transferase inhibitors
WO1995003299A1 (en) * 1993-07-20 1995-02-02 Glaxo S.P.A. 1,5-benzodiazepine derivatives useful as cck or gastrin antagonists
US5698691A (en) * 1993-09-24 1997-12-16 Takeda Chemical Industries, Ltd. Condensed cyclic compounds and their use
WO1996004254A3 (en) * 1994-07-29 1996-06-20 Fujisawa Pharmaceutical Co Benzodiazepine derivatives
WO1996004254A2 (en) * 1994-07-29 1996-02-15 Fujisawa Pharmaceutical Co., Ltd. Benzodiazepine derivatives
WO1998000406A1 (en) * 1996-07-02 1998-01-08 Merck & Co., Inc. Method for the treatment of preterm labor
US5929071A (en) * 1996-07-02 1999-07-27 Merck & Co., Inc. Method for the treatment of preterm labor
US6541466B2 (en) 1996-12-23 2003-04-01 Athena Neurosciences, Inc. Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
US6683075B1 (en) 1996-12-23 2004-01-27 Athena Neurosciences, Inc. Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use
US7153847B2 (en) 1996-12-23 2006-12-26 Athena Neurosciences, Inc. Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
US6544978B2 (en) 1996-12-23 2003-04-08 Athena Neurosciences, Inc. Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
US6559141B2 (en) 1996-12-23 2003-05-06 Athena Neurosciences, Inc. Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
US6951854B1 (en) 1996-12-23 2005-10-04 Athena Neurosciences, Inc. Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
US6579867B2 (en) 1996-12-23 2003-06-17 Athena Neurosciences, Inc. Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
US6632811B2 (en) 1996-12-23 2003-10-14 Athena Neurosciences, Inc. Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
US6653303B1 (en) 1996-12-23 2003-11-25 Athena Neurosciences, Inc. Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
US6667305B1 (en) 1996-12-23 2003-12-23 Athena Neurosciences, Inc. Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
US6774125B2 (en) 1998-06-22 2004-08-10 Elan Pharmaceuticals, Inc. Deoxyamino acid compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
US6958330B1 (en) 1998-06-22 2005-10-25 Elan Pharmaceuticals, Inc. Polycyclic α-amino-ε-caprolactams and related compounds
US6509331B1 (en) 1998-06-22 2003-01-21 Elan Pharmaceuticals, Inc. Deoxyamino acid compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
US6528505B1 (en) 1998-06-22 2003-03-04 Elan Pharmaceuticals, Inc. Cyclic amino acid compounds pharmaceutical compositions comprising same and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
US6838455B2 (en) 1998-06-22 2005-01-04 Athena Neurosciences, Inc. Deoxyamino acid compounds, pharmaceutical compositions comprising same, and methods for inhibiting beta-amyloid peptide release and/or its synthesis by use of such compounds
US6906056B2 (en) 1998-06-22 2005-06-14 Elan Pharmaceuticals, Inc. Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
US6569851B1 (en) 1998-06-22 2003-05-27 Elan Pharmaceutials, Inc. Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
US6696438B2 (en) 1998-06-22 2004-02-24 Elan Pharmaceuticals, Inc. Cyclic amino acid compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
EP1398033A3 (en) * 1999-04-30 2004-06-30 The Regents Of The University Of Michigan Use of benzodiazepines for treating autoimmune diseases, inflammations, neoplasies, viral infections and atherosclerosis
US7572788B2 (en) 1999-04-30 2009-08-11 The Regents Of The University Of Michigan Compositions and methods relating to novel compounds and targets thereof
US7683046B2 (en) 1999-04-30 2010-03-23 The Regents Of The University Of Michigan Benzodiazepine compositions for treating epidermal hyperplasia and related disorders
US8168626B2 (en) 1999-04-30 2012-05-01 The Regents Of The University Of Michigan Benzodiazepine compositions for treating epidermal hyperplasia and related disorders
US7638624B2 (en) 2005-01-03 2009-12-29 The Regents Of The University Of Michigan Compositions and methods relating to novel benzodiazepine compounds and derivatives
US9126978B2 (en) 2009-11-17 2015-09-08 The Regents Of The University Of Michigan 1,4-benzodiazepine-2,5-diones and related compounds with therapeutic properties
US9849138B2 (en) 2009-11-17 2017-12-26 The Regents Of The University Of Michigan 1,4-benzodiazepone-2,5-diones and related compounds with therapeutic properties

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ZA915423B (en) 1992-04-29
HUT63627A (en) 1993-09-28
IL98873A0 (en) 1992-07-15
CN1059141A (en) 1992-03-04
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JPH06502620A (en) 1994-03-24
PT98370A (en) 1992-05-29

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