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WO1994026719A1 - Derives de mercapto-amides utiles comme inhibiteurs de l'endopeptidase neutre et de l'eca - Google Patents

Derives de mercapto-amides utiles comme inhibiteurs de l'endopeptidase neutre et de l'eca Download PDF

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Publication number
WO1994026719A1
WO1994026719A1 PCT/JP1994/000784 JP9400784W WO9426719A1 WO 1994026719 A1 WO1994026719 A1 WO 1994026719A1 JP 9400784 W JP9400784 W JP 9400784W WO 9426719 A1 WO9426719 A1 WO 9426719A1
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WO
WIPO (PCT)
Prior art keywords
compound
oxo
tetrahydro
benzazepine
amino
Prior art date
Application number
PCT/JP1994/000784
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English (en)
Inventor
Youichi Shiokawa
Koichi Takimoto
Kohei Takenaka
Osamu Okitsu
Hiroaki Mizuno
Yuiko Kobayashi
Original Assignee
Fujisawa Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Fujisawa Pharmaceutical Co., Ltd. filed Critical Fujisawa Pharmaceutical Co., Ltd.
Priority to JP6525243A priority Critical patent/JPH07509257A/ja
Publication of WO1994026719A1 publication Critical patent/WO1994026719A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/16—Benzazepines; Hydrogenated benzazepines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D281/02—Seven-membered rings
    • C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D281/10—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • This invention relates to new mercapto-amide
  • Some mercapto-amide derivatives have been known as inhibitor of enkephalinase which is an enkephalin- degrading enzyme, and an angiotensin converting enzyme
  • This invention relates to new mercapto-amide
  • NEP neutral endopeptidase
  • endopeptidase EC 3. 4. 24. 11, and ACE to processes for the preparation thereof, to a pharmaceutical composition comprising the same and to a method for the treatment
  • cardiovascular disorders such as hypertension, heart failure, angina pectoris or the
  • the object compound is expected to be useful as therapeutical and/or preventive agents for glaucoma, asthma, inflammation, pain, epilepsy, dementia, obesity and gastrointestinal disorders
  • One object of this invention is to provide new and useful mercapto-amide derivatives which possess inhibitory activities against NEP and ACE.
  • Another object of this invention is to provide processes for the preparation of said mercapto-amide derivatives and salts thereof.
  • a further object of this invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising, as an active ingredient, said mercapto-amide derivatives and
  • Still further object of this invention is to provide a therapeutical method for the treatment and/or prevention of aforesaid diseases in human beings or animals, using said mercapto-amide derivatives and pharmaceutically acceptable salts thereof.
  • ANP atrial natriuretic peptide
  • enkephalin which is a endogenous morphine-like peptide.
  • inhibiting NEP are useful for the treatment and/or
  • cardiovascular disorders such as hypertension, heart failure, angina pectoris or the like, renal insufficiency, cyclic edema, hepatocirrhosis, hyperaldosteronism, hypercalciuria, and the other diseases mentioned above.
  • ACE is a peptidyl dipeptidase which catalyzes the conversion of angiotensin I to angiotensin II.
  • Angiotensin II is a vasoconstrictor which also stimulates aldosterone secretion by the adrenal cortex.
  • ACE inhibitors are also useful for the treatment and/or prevention of various cardiovascular disorders such as hypertension, heart failure or the like.
  • R 1 is hydrogen or a mercapto-protective group
  • R 2 is hydrogen or aryl optionally substituted with lower alkylenedioxy
  • R 3 is lower alkyl substituted with acyl
  • A is a single bond or lower alkylene
  • X is lower alkylene
  • Y is a single bond, O or S
  • Z is a single bond or lower alkylene, and n is 1 or 2,
  • the object compound [I] or its salt can be prepared by the following processes.
  • R 3 a is lower alkyl substituted with esterified carboxy
  • R 3 b is lower alkyl substituted with carboxy, R 1 a is a mercapto-protective group, and
  • R 1 , R 2 , R 3 , A, X, Y, Z and n are each as defined above.
  • lower is intended to mean a group having 1 to 6 carbon atom(s), unless otherwise provided.
  • ar( lower)alkyl and “lower alkoxy(lower)alkyl” may be a straight or branched one such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl or the like, in which preferable one is methyl or ethyl.
  • Suitable "cyclo(lower)alkyl” may be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • Suitable "aryl” may be phenyl, naphthyl, phenyl substituted with lower alkyl [e.g. tolyl, mesityl,
  • Suitable "ar(lower)alkyl” may be benzyl, phenethyl, diphenylmethyl, triphenylmethyl, naphthylmethyl, and the like, in which preferable one is benzyl.
  • Suitable lower alkoxy moiety in the term "lower alkoxy(lower)alkyl” may be methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy and the like, in which preferable one is methoxy.
  • Suitable "lower alkylene” may be a straight or branched one such as methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, hexamethylene, ethylethylene, or the like, in which preferable one is methylene or propylene.
  • Suitable "lower alkylenedioxy” may be a straight or branched one such as methylenedioxy, ethylenedioxy, trimethylenedioxy, dimethylmethylenedioxy, propylenedioxy, or the like, in which preferable one is methylenedioxy.
  • Suitable "mercapto-protective group” may be lower alkyl [e.g. tert-butyl, etc.], lower alkoxy(lower)alkyl [e.g. methoxymethyl, isobutoxymethyl, etc.], substituted or unsubstituted ar(lower)alkyl [e.g. benzyl,
  • substituted or unsubstituted aryl e.g. phenyl
  • acyl such as lower alkanoyl [e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexan ⁇ yl, etc.], lower alkanoyl [e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexan ⁇ yl, etc.], lower
  • alkoxycarbonyl e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.
  • aroyl e.g. benzoyl, etc.
  • ar(lower)alkoxycarbonyl e.g. benzyloxycarbonyl, methoxybenzyloxycarbonyl, etc.
  • preferable one is lower alkanoyl or aroyl and the most preferable one is acetyl or benzoyl.
  • acyl (lower)alkyl may include carboxy; esterified
  • substituent(s) selected from the group consisting of lower alkyl, cyclo( lower)alkyl, aryl, ar(lower)alkyl, lower alkoxy(lower)alkyl and a heterocyclic group; lower
  • alkanoyl alkanoyl; aroyl; a heterocycliccarbonyl; lower
  • alkylsulfonyl and the like, in which preferable one is carboxy or esterified carboxy.
  • the esterified carboxy may be substituted or
  • unsubstituted lower alkoxycarbonyl e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tert- butoxycarbonyl, hexyloxycarbonyl, 2-iodoethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, etc.
  • substituted or unsubstituted aryloxycarbonyl e.g. phenoxycarbonyl, 4-nitrophenoxycarbonyl, 2-naphthyloxycarbonyl, etc.] substituted or unsubstituted ar( lower)alkoxycarbonyl [e.g.
  • benzyloxycarbonyl phenethyloxycarbonyl, benzhydryloxycarbonyl, 4-nitrobenzyloxycarbonyl, etc.] and the like, in which preferable one is lower alkoxycarbonyl or ar(lower)alkoxycarbonyl [more preferably
  • the lower alkanoyl may be formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl and the like.
  • the aroyl may be benzoyl, naphthoyl, benzoyl
  • heterocycliccarbonyl may include saturated or
  • heterocyclic group may be unsaturated, 3 to 8-membered, more
  • oxygen atom(s) for example, benzofuranyl, etc.; or the like.
  • Preferable compound [I] is one which has hydrogen, lower alkanoyl or aroyl for R 1 , hydrogen or phenyl
  • alkylenedioxy (more preferably methylenedioxy) for R 2 , lower alkyl substituted with carboxy or esterified carboxy for R 3 , a single bond or lower alkylene (more preferably m ethylene) for A, lower alkylene (more preferably
  • n 1 or 2 for n.
  • More preferable compound [I] is one which has
  • A methylene for X, a single bond for Y, a single bond for Z , and 2 for n .
  • Suitable pharmaceutically acceptable salts of the object compound [I] are conventional non-toxic salts and include a metal salts 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 addition salt [e.g.
  • trimethylamine salt triethylamine salt, dicyclohexylamine salt, etc.] or the like.
  • the compound [I] or its salt can be prepared by reacting a compound [II] or its reactive derivative at the carboxy group or a salt thereof with a compound [III] or its salt.
  • Suitable salts of the compound [II] and its reactive derivative at the carboxy group can be referred to the same salt as exemplified for the compound [I].
  • Suitable salt of the compound [III] may be an acid addition salt such as an inorganic acid addition salt
  • an organic addition salt e.g. formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.] or the like.
  • Suitable reactive derivative at the carboxy group of the compound [II] may include an acid halide, an acid anhydride, an activated amide, an activated ester, and the like.
  • Suitable examples of the reactive derivatives may be an acid chloride; an acid azide; a mixed acid anhydride with an acid such as substituted phosphoric acid [e.g.
  • halogenated phosphoric acid, etc. dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, sulfonic acid [e.g. methanesulfonic acid, etc.], aliphatic carboxylic acid [e.g. acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid, etc.] or aromatic carboxylic acid [e.g. benzoic acid, etc.]; a symmetrical acid anhydride; an activated amide with imidazole, 4-substituted imidazole,
  • dimethylpyrazole, triazole or tetrazole or an activated ester
  • N-hydroxy compound e.g. N,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-1H-benzotriazole, etc.
  • reactive derivatives can optionally be selected from them according to the kind of the compound [II] to be used.
  • the reaction is usually carried out in a conventional solvent such as water, alcohol [e.g. methanol, ethanol, etc.], acetone, dioxane, acetonitrile, chloroform,
  • a conventional solvent such as water, alcohol [e.g. methanol, ethanol, etc.], acetone, dioxane, acetonitrile, chloroform,
  • 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-ethyl-N'-(3-dimethylaminopropyl)carbodiimide;
  • 1-alkoxy-1-chloroethylene 1-alkoxy-1-chloroethylene; trialkyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride); phosphorous
  • [III] having lower alkyl substituted with carboxy for R 3 is used as a starting compound, the reaction is preferably carried out in the presence of a silylation agent [e.g. N,O-bis(trimethylsilyl)acetamide, etc.].
  • a silylation agent e.g. N,O-bis(trimethylsilyl)acetamide, etc.
  • reaction may also be carried out in the presence of an inorganic or organic base such as an alkali metal bicarbonate, tri(lower)alkylamine, pyridine,
  • N-(lower)alkylmorpholine N,N-di(lower)alkylbenzylamine, or the like.
  • the reaction temperature is not critical, and the reaction is usually carried out under cooling to hating.
  • the compound [Ib] or its salt can be prepared by subjecting a compound [Ia] or its salt to deesterification reaction .
  • Suitable salts of the compound [Ia] and [Ib] may be the same as those exemplified for the compound [I].
  • the reaction is carried out in accordance with a conventional method such as hydrolysis or the like.
  • the hydrolysis is preferably carried out in the presence of a base or an acid including Lewis acid.
  • Suitable base may include an inorganic base and an organic base such as an alkali metal [e.g. sodium, potassium, etc.], an alkaline earth metal [e.g. magnesium, calcium, etc.], the hydroxide or carbonate or bicarbonate, thereof, ammonia, cysteamine, trialkylamine [e.g.
  • an alkali metal e.g. sodium, potassium, etc.
  • an alkaline earth metal e.g. magnesium, calcium, etc.
  • ammonia cysteamine
  • trialkylamine e.g.
  • 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 acid, 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 acid, etc.
  • trichloroacetic acid, trifluoroacetic acid, etc.] or the like is preferably carried out in the presence of cation trapping agents [e.g. anisole, phenyl, etc.].
  • cation trapping agents e.g. anisole, phenyl, etc.
  • the reaction is usually carried out in a solvent such as water, an alcohol [e.g. methanol, ethanol, etc.], 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 warming.
  • the compound [Id] or its salt can be prepared by subjecting a compound [Ic] or its salt to elimination reaction of the mercapto-protective group.
  • Suitable salts of the compounds [Ic] and [Id] may be the same as those exemplified for the compound [I].
  • reaction can be carried out in substantially the same manner as Process 2, and therefore the reaction mode and the reaction condition [e.g. solvent, reaction
  • the compound [Id] having lower alkyl substituted with carboxy for R 3 may be obtained according to reaction conditions. This case is also included within the scope of the present reaction.
  • the compounds obtained by the above processes can be isolated and purified by a conventional method such as pulverization, recrystallization, column chromatography, reprecipitation, or the like.
  • the compound [I] and the other compounds may include one or more stereoisomers due to asymmetric carbon atoms, and all of such isomers and mixture thereof are included within the scope of this invention.
  • the object compound [I] is expected to be useful as therapeutical and/or preventive agents for glaucoma, asthma, inflammation, pain, epilepsy, dementia, obesity and gastrointestinal disorders (especially diarrhoea and irritable bowel syndrome); the modulation of gastric acid secretion and the treatment of hyperreninaemia.
  • Test 1 the pharmacological data of the compound [I] are shown in the following. Test 1 :
  • NEP inhibitory activity was determined as follows.
  • the incubation mixture (total volume of 262 ⁇ l) contained 0.1 M Tris buffer (pH 7.4), 0.1 mg/rnl ⁇ -hANP ( ⁇ -human ANP), test compound (dissolved in 2 ⁇ l N,N-dimethylformamide) and NEP (45-50 U/ml).
  • the reaction mixture was incubated for 15 minutes at 37°C and was terminated with the addition of 50 ⁇ l 10% acetic acid.
  • reaction mixture Fifty microliters of the reaction mixture was injected into a HPLC and measured the hydrolysis of ⁇ -hANP by the reverse phase HPLC using C 18 column (YMC, ODS-A 200S).
  • NEP inhibitory activity was defined as the inhibition of hydrolysis of ⁇ -hANP.
  • Angiotensin converting enzyme (ACE) inhibitory activity is angiotensin converting enzyme (ACE) inhibitory activity
  • ACE inhibitory activities of the test compounds were measured according to the methods of Carmel and Yaron described in Eur. J. Biochem, Vol. 87, page 265-273
  • test compounds were dissolved in N,N-dimethylformamide (DMF) and were added to the assay mixture (0.4 Mm o-Aminobenzoyl-Gly-p-(NO 2 )Phe-Pro in 0.2 M Tris Hcl, Ph 8.0).
  • the reaction was started by adding the 50 ⁇ l of crude enzyme (guinea-pig serum). The reaction mixture was incubated for 20 minutes at 37°C, and the reaction was terminated by adding 2.0 ml of 0.1 M
  • EDTA-2Na The fluorescence measurements were performed with fluorescence spectrometer (HITACHI F-2000). The excitation and emission wave lengths were 360 nm and 410 nm, respectively. The ACE inhibitory activities were calculated from the difference of fluorescent intensity between assay mixture of test compounds and DMF control. Results :
  • the compound [I] of the present invention can be used in a form of pharmaceutical preparation containing one of said compounds, as an active ingredient, in admixture with a pharmaceutically
  • acceptable carrier such as an organic or inorganic solid, semi-solid or liquid excipient suitable for oral,
  • parenteral or external (topical) administration may be capsules, tablets, dragees, granules, suppositories, solution, lotion, suspension, emulsion, ointment, gel, or the like. If desired, there may be included in these preparations, auxiliary substances, stabilizing agents, wetting or emulsifying agents, buffers and other commonly used additives.
  • the dosage of the compound [I] will vary depending upon the age and condition of the patient, an average single dose of about 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and 1000 mg of the compound [I] may be effective for treating the above-mentioned diseases . In general, amounts between 0.1 mg/body and about 1,000 mg/body may be administered per day.
  • a salt (1.82 g) of 2(S)-acetylthiomethyl-3-phenylpropionic acid and 2(R)-isopropylamino-3-phenylpropanol was acidified with 5% hydrochloric acid, and extracted with dichloromethane. The extract was washed with brine, dried over anhydrous sodium sulfate, and then evaporated in vacuo.
  • the residual oil was purified by column-chromatography on silica gel (15 g) using a mixture of n-hexane, ethyl acetate and acetic acid (40:20:1) as an eluent to afford amorphous product of 4(S)-[(2(S)-acetylthio-1-oxo-3-phenylpropyl)amino]-3-oxo-1,3,4,5-tetrahydro-2H-2-benzazepine-2-acetic acid (0.40 g).

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Abstract

L'invention se rapporte à de nouveaux dérivés de mercapto-amides, qui possèdent des effets inhibiteurs contre l'endopeptidase neutre et contre l'enzyme de conversion de l'angiotensine (ECA) et qui sont représentés par la formule générale (I), où R1 représente hydrogène ou un groupe mercapto-protecteur, R2 représente hydrogène ou aryle éventuellement substitué par alkylènedioxy inférieur, R3 représente alkyle inférieur substitué par acyle, A représente une liaison simple ou alkylène inférieur, X représente alkylène inférieur, Y représente une liaison simple, O ou S, Z représente une liaison simple ou alkylène inférieur, et n est égal à 1 ou à 2, ainsi qu'à des sels pharmaceutiquement acceptables de ces dérivés, à des procédés pour leur préparation et à une composition pharmaceutique qui les contient.
PCT/JP1994/000784 1993-05-17 1994-05-12 Derives de mercapto-amides utiles comme inhibiteurs de l'endopeptidase neutre et de l'eca WO1994026719A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP6525243A JPH07509257A (ja) 1993-05-17 1994-05-12 中性エンドペプチダーゼおよびａｃｅ阻害剤として有用なメルカプトーアミド誘導体

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GB9310075.8 1993-05-17
GB939310075A GB9310075D0 (en) 1993-05-17 1993-05-17 New mercapto-amide derivatives,processes for the preparation thereof and pharmaceutical composition comprising the same

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0671172A1 (fr) * 1993-06-11 1995-09-13 Eisai Co., Ltd. Derive aminoacide
US5504080A (en) * 1992-10-28 1996-04-02 Bristol-Myers Squibb Co. Benzo-fused lactams
US5587375A (en) * 1995-02-17 1996-12-24 Bristol-Myers Squibb Company Azepinone compounds useful in the inhibition of ACE and NEP
US5635504A (en) * 1995-06-07 1997-06-03 Bristol-Myers Squibb Co. Diazepine containing dual action inhibitors
US5650408A (en) * 1995-06-07 1997-07-22 Karanewsky; Donald S. Thiazolo benzazepine containing dual action inhibitors
EP0830863A1 (fr) * 1996-09-18 1998-03-25 Solvay Pharmaceuticals GmbH Médicaments améliorateurs de l'irrigation sanguine gastrointestinale
FR2781483A1 (fr) * 1998-07-21 2000-01-28 Hoechst Marion Roussel Inc Derives de thioazepinone, procede de preparation et intermediaires de ce procede, application a titre de medicament et compositions pharmaceutiques les renfermant
US6140319A (en) * 1999-03-29 2000-10-31 Bristol-Myers Squibb Co. Vasopeptidase inhibitors to treat angina pectoris
US6235922B1 (en) 1995-05-17 2001-05-22 Bristol-Myers Squibb Co. Processes and intermediates for preparing benzo-fused azepinone and piperidinone compounds useful in the inhibition of ACE and NEP
US6544980B2 (en) * 1998-12-31 2003-04-08 Aventis Pharmaceuticals Inc. N-carboxymethyl substituted benzolactams as inhibitors of matrix metalloproteinase

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2045771A (en) * 1979-04-02 1980-11-05 Squibb & Sons Inc Mercaptoacyldipeptides
EP0072352A1 (fr) * 1981-08-11 1983-02-16 Ciba-Geigy Ag Benzazepin-2-ones, procédé pour leur préparation, préparations pharmaceutiques contenant ces composés ainsi que ces composés pour utilisation thérapeutique
FR2548184A1 (fr) * 1983-06-29 1985-01-04 Mitsui Toatsu Chemicals
US4548932A (en) * 1983-08-12 1985-10-22 Takeda Chemical Industries, Ltd. 3-Amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine derivatives
DE3426720A1 (de) * 1984-07-20 1986-01-23 Hoechst Ag, 6230 Frankfurt Benzthiazepinon- und benzthiazocinon-derivate, verfahren zu ihrer herstellung, diese enthaltende mittel und ihre verwendung, sowie zwischenprodukte bei ihrer herstellung
EP0481522A1 (fr) * 1990-10-18 1992-04-22 Merrell Pharmaceuticals Inc. Dérivés de mercaptoacétylamides utiles comme inhibiteurs de l'enképhalinase et de l'enzyme de conversion de l'angiotensine
EP0599444A1 (fr) * 1992-05-18 1994-06-01 E.R. SQUIBB & SONS, INC. Inhibiteurs à double effet

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2045771A (en) * 1979-04-02 1980-11-05 Squibb & Sons Inc Mercaptoacyldipeptides
EP0072352A1 (fr) * 1981-08-11 1983-02-16 Ciba-Geigy Ag Benzazepin-2-ones, procédé pour leur préparation, préparations pharmaceutiques contenant ces composés ainsi que ces composés pour utilisation thérapeutique
FR2548184A1 (fr) * 1983-06-29 1985-01-04 Mitsui Toatsu Chemicals
US4548932A (en) * 1983-08-12 1985-10-22 Takeda Chemical Industries, Ltd. 3-Amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine derivatives
DE3426720A1 (de) * 1984-07-20 1986-01-23 Hoechst Ag, 6230 Frankfurt Benzthiazepinon- und benzthiazocinon-derivate, verfahren zu ihrer herstellung, diese enthaltende mittel und ihre verwendung, sowie zwischenprodukte bei ihrer herstellung
EP0481522A1 (fr) * 1990-10-18 1992-04-22 Merrell Pharmaceuticals Inc. Dérivés de mercaptoacétylamides utiles comme inhibiteurs de l'enképhalinase et de l'enzyme de conversion de l'angiotensine
EP0599444A1 (fr) * 1992-05-18 1994-06-01 E.R. SQUIBB & SONS, INC. Inhibiteurs à double effet

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5504080A (en) * 1992-10-28 1996-04-02 Bristol-Myers Squibb Co. Benzo-fused lactams
EP0671172A1 (fr) * 1993-06-11 1995-09-13 Eisai Co., Ltd. Derive aminoacide
EP0671172A4 (fr) * 1993-06-11 1998-09-02 Eisai Co Ltd Derive aminoacide.
US5750687A (en) * 1995-02-17 1998-05-12 Bristol-Myers Squibb Company Azepinone compounds useful in the inhibition of ACE and NEP
US5587375A (en) * 1995-02-17 1996-12-24 Bristol-Myers Squibb Company Azepinone compounds useful in the inhibition of ACE and NEP
US5994537A (en) * 1995-02-17 1999-11-30 Bristol-Myers Squibb Co. Process for preparing azepinone compounds useful in the inhibition of ACE and NEP
US6235922B1 (en) 1995-05-17 2001-05-22 Bristol-Myers Squibb Co. Processes and intermediates for preparing benzo-fused azepinone and piperidinone compounds useful in the inhibition of ACE and NEP
US5650408A (en) * 1995-06-07 1997-07-22 Karanewsky; Donald S. Thiazolo benzazepine containing dual action inhibitors
US5635504A (en) * 1995-06-07 1997-06-03 Bristol-Myers Squibb Co. Diazepine containing dual action inhibitors
EP0830863A1 (fr) * 1996-09-18 1998-03-25 Solvay Pharmaceuticals GmbH Médicaments améliorateurs de l'irrigation sanguine gastrointestinale
FR2781483A1 (fr) * 1998-07-21 2000-01-28 Hoechst Marion Roussel Inc Derives de thioazepinone, procede de preparation et intermediaires de ce procede, application a titre de medicament et compositions pharmaceutiques les renfermant
WO2000005246A1 (fr) * 1998-07-21 2000-02-03 Hoechst Marion Roussel Derives de thioazepinone, procede de preparation et intermediaires de ce procede, application comme medicaments et compositions pharmaceutiques les contenant
US6544980B2 (en) * 1998-12-31 2003-04-08 Aventis Pharmaceuticals Inc. N-carboxymethyl substituted benzolactams as inhibitors of matrix metalloproteinase
US6140319A (en) * 1999-03-29 2000-10-31 Bristol-Myers Squibb Co. Vasopeptidase inhibitors to treat angina pectoris
EP1165088A1 (fr) * 1999-03-29 2002-01-02 Bristol-Myers Squibb Company Utilisation d'inhibiteurs de la vasopeptidase pour traiter l'angine de poitrine
EP1165088A4 (fr) * 1999-03-29 2002-09-04 Bristol Myers Squibb Co Utilisation d'inhibiteurs de la vasopeptidase pour traiter l'angine de poitrine
AU768880B2 (en) * 1999-03-29 2004-01-08 Bristol-Myers Squibb Company Use of vasopeptidase inhibitors to treat angina pectoris

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GB9310075D0 (en) 1993-06-30

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