WO1994026719A1 - Mercapto-amide derivatives useful as neutral endopeptidase and ace inhibitors - Google Patents

Mercapto-amide derivatives useful as neutral endopeptidase and ace inhibitors 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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Prior art keywords
compound
oxo
tetrahydro
benzazepine
amino
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PCT/JP1994/000784
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French (fr)
Inventor
Youichi Shiokawa
Koichi Takimoto
Kohei Takenaka
Osamu Okitsu
Hiroaki Mizuno
Yuiko Kobayashi
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Fujisawa Pharmaceutical Co., Ltd.
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Priority to JP6525243A priority Critical patent/JPH07509257A/en
Publication of WO1994026719A1 publication Critical patent/WO1994026719A1/en

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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).

Abstract

This invention relates to new mercapto-amide derivatives possessing inhibitory activities against the neutral endopeptidase and the angiotensin converting enzyme, and represented by general formula (I), wherein R1 is hydrogen or a mercapto-protective group, R2 is hydrogen or aryl optionally substituted with lower alkylenedioxy, R3 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, and pharmaceutically acceptable salts thereof, to processes for the preparation thereof and to a pharmaceutical composition comprising the same.

Description

DESCRIPTION
MERCAPTO-AMIDE DERIVATIVES USEFUL AS NEUTRAL ENDOPEPTIDASE AND ACE INHIBITORS TECHNICAL FIELD
This invention relates to new mercapto-amide
derivatives and pharmaceutically acceptable salts thereof which are useful as a medicament. BACKGROUND ART
Some mercapto-amide derivatives have been known as inhibitor of enkephalinase which is an enkephalin- degrading enzyme, and an angiotensin converting enzyme
(hereinafter ACE), for example, in EP Patent Application Publication No. 0 481 522.
DISCLOSURE OF INVENTION
This invention relates to new mercapto-amide
derivatives and pharmaceutically acceptable salts thereof.
More particularly, it relates to new mercapto-amide derivatives and pharmaceutically acceptable salts thereof which possess inhibitory activities against the neutral endopeptidase (hereinafter NEP), e.g. neutral
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
and/or prevention of various cardiovascular disorders such as hypertension, heart failure, angina pectoris or the
like, renal insufficiency, cyclic edema, hepatocirrhosis, hyperaldosteronism, hypercalciuria and the like in human beings or animals. Additionally, 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
(especially diarrhoea and irritable bowel syndrome); the modulation of gastric acid secretion and the treatment of hyperreninaemia.
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 comprising, as an active ingredient, said mercapto-amide derivatives and
pharmaceutically acceptable salts thereof.
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.
It is well known that NEP is involved in the
breakdown of several peptide hormones, including atrial natriuretic peptide (hereinafter, ANP) which has potent vasodilatory, diuretic and natriuretic activities, and enkephalin which is a endogenous morphine-like peptide. Thus, NEP inhibitors can potentiate the biological effects of ANP and enkephalin. Therefore, the compounds
inhibiting NEP are useful for the treatment and/or
prevention of various 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.
Additionally, it is well known that 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. Thus, ACE inhibitors are also useful for the treatment and/or prevention of various cardiovascular disorders such as hypertension, heart failure or the like.
The object mercapto-amide derivatives of this
invention are new and can be represented by the following general formula [I] :
Figure imgf000005_0001
wherein R1 is hydrogen or a mercapto-protective group,
R2 is hydrogen or aryl optionally substituted with lower alkylenedioxy,
R3 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,
and pharmaceutically acceptable salts thereof.
The object compound [I] or its salt can be prepared by the following processes.
Figure imgf000006_0001
Figure imgf000006_0002
Figure imgf000007_0002
Figure imgf000007_0001
wherein R3 a is lower alkyl substituted with esterified carboxy,
R3 b is lower alkyl substituted with carboxy, R1 a is a mercapto-protective group, and
R1, R2, R3, A, X, Y, Z and n are each as defined above. In the above and subsequent descriptions of the present specification, suitable examples of the various definitions to be included within the scope of the
invention are explained in detail in the following.
The term "lower" is intended to mean a group having 1 to 6 carbon atom(s), unless otherwise provided.
Suitable lower alkyl moiety in the terms
"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,
cumenyl, xylyl, diethylphenyl, diisopropylphenyl, di-tert-butylphenyl, etc.] and the like, in which preferable one is phenyl or tolyl.
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,
methoxybenzyl, nitrobenzyl, diphenylmethyl,
bis(methoxyphenyl)methyl, triphenylmethyl, etc.],
substituted or unsubstituted aryl [e.g. phenyl,
dinitrophenyl, etc.], acyl such as lower alkanoyl [e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanσyl, etc.], lower
alkoxycarbonyl [e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.], aroyl [e.g. benzoyl, etc.], substituted or unsubstituted ar(lower)alkoxycarbonyl [e.g. benzyloxycarbonyl, methoxybenzyloxycarbonyl, etc.], and the like, in which preferable one is lower alkanoyl or aroyl and the most preferable one is acetyl or benzoyl.
Suitable "acyl" and acyl moiety in the term
"acyl (lower)alkyl" may include carboxy; esterified
carboxy; carbamoyl optionally substituted with
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; 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
diphenyl(lower)alkoxycarbonyl].
The lower alkanoyl may be formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl and the like.
The aroyl may be benzoyl, naphthoyl, benzoyl
substituted with lower alkyl [e.g. toluoyl, xyloyl, etc.] and the like.
Suitable heterocyclic moiety in the term
"heterocycliccarbonyl" may include saturated or
unsaturated, monocyclic or polycyclic one containing at least one hetero atom such as nitrogen atom, oxygen atom or sulfur atom.
The preferred examples of thus defined "heterocyclic group" may be unsaturated, 3 to 8-membered, more
preferably 5 or 6-membered heteromonocyclic group
containing 1 to 4-nitrogen atom(s), for example, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridyl N-oxide,
dihydropyridyl, tetrahydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, triazolyl, tetrazinyl, tetrazolyl, etc.;
saturated, 3 to 8-membered, more preferably 5 or 6-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, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, 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, oxadiazolyl, etc.;
saturated, 3 to 8-membered heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, morpholino, sydnonyl, 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, thiazolyl, isothiazolyl,
thiadiazolyl, etc.;
unsaturated, 3 to 8-membered heteromonocyclic group containing 1 to 2 sulfur atom(s), 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, benzothiadiazolyl, etc.;
unsaturated, 3 to 8-membered heteromonocyclic group containing an oxygen atom, for example, furyl, etc.;
unsaturated, condensed heterocyclic group containing 1 to 2 sulfur atom(s), for example, benzothienyl, etc.; unsaturated, condensed heterocyclic group containing
1 to 2 oxygen atom(s), for example, benzofuranyl, etc.; or the like.
Preferable compound [I] is one which has hydrogen, lower alkanoyl or aroyl for R1, hydrogen or phenyl
optionally substituted with lower alkyl or lower
alkylenedioxy (more preferably methylenedioxy) for R2, lower alkyl substituted with carboxy or esterified carboxy for R3, a single bond or lower alkylene (more preferably methylene) for A, lower alkylene (more preferably
methylene or propylene) for X, a single bond or S for Y, a single bond or lower alkylene (more preferably methylene) for Z, and 1 or 2 for n.
More preferable compound [I] is one which has
hydrogen, acetyl or benzoyl for R1, phenyl for R2, lower alkyl substituted with carboxy for R3, a single bond for
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 processes for preparing the object compound [I] are explained in detail in the following.
Process 1
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
[e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.], 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.
dialkylphosphσric acid, phenylphosphoric acid,
diphenylphosphoric acid, dibenzylphosphoric acid,
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 [e.g. cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl [ (CH3 ) 2N=CH- ] ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenyl
thioester, p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, etc.], or an ester with an N-hydroxy compound [e.g. N,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-1H-benzotriazole, etc.], and the like. These 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,
methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction. These conventional solvent may also be used in a mixture with water.
In this reaction, when the compound [II] is used in a free acid form or its salt form, 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-ethyl-N'-(3-dimethylaminopropyl)carbodiimide;
N,N'-carbonylbis-(2-methylimidazole);
pentamethyleneketene-N-cyclohexylimine;
diphenylketene-N-cyclohexylimine; ethoxyacetylene;
1-alkoxy-1-chloroethylene; trialkyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride); phosphorous
trichloride; diphenyl phosphorylazide; diphenylphosphinic chloride; thionyl chloride; oxalyl chloride; lower alkyl haloformate [e.g. ethyl chloroformate, isopropyl
chloroformate, etc.]; triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt; 2-ethyl-5-(m- sulfophenyl)isoxazolium hydroxide intramolecular salt; 1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole; so-called Vilsmeier reagent prepared by the reaction of N,N-dimethylformamide with thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorus oxychloride, etc.; or the like.
Additionally, in this reaction that the compound
[III] having lower alkyl substituted with carboxy for R3 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.].
The 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.
Process 2
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.
trimethylamine, triethylamine, etc.], picoline, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]-octane, 1, 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 acid, etc.].
The reaction using trihaloacetic acid [e.g.
trichloroacetic acid, trifluoroacetic acid, etc.] or the like is preferably carried out in the presence of 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.
In this reaction, in case that the compound [Ia] having acyl for R1 is used as a starting compound, the compound [Ib] having hydrogen for R1 may be obtained according to reaction conditions. This case is also included within the scope of the present reaction. Process 3
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].
This 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
temperature, etc.] of this reaction are to be referred to those as explained in Process 2.
In this reaction, in case that the compound [Ic] having lower alkyl substituted with esterified carboxy for R3 is used as a starting compound, the compound [Id] having lower alkyl substituted with carboxy for R3 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.
It is to be noted that 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] and pharmaceutically
acceptable salts thereof possess inhibitory activities against NEP and ACE, and are useful for the treatment and/or prevention of various cardiovascular disorders such as hypertension, heart failure, angina pectoris or the like, renal insufficiency, cyclic edema, hepatocirrhosis, hyperaldosteronism, hypercalciuria and the like in human beings or animals. Additionally, 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.
In order to illustrate the usefulness of the object compound [I], the pharmacological data of the compound [I] are shown in the following. Test 1 :
Neutral endopeptidase (NEP) inhibitory activity
Method :
Purified NEP was used, which was prepared from male Sprague-Dawley rat kidney by the method of J.L. Sonnenberg et al. described in Peptide, Vol. 9, page 173-180 (1988).
NEP inhibitory activity was determined as follows.
The incubation mixture (total volume of 262 μl) contained 0.1 M Tris buffer (pH 7.4), 0.1 mg/rnl α-hANP (α-human ANP), test compound (dissolved in 2 μl 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 μl 10% acetic acid.
Fifty microliters of the reaction mixture was injected into a HPLC and measured the hydrolysis of α-hANP by the reverse phase HPLC using C18 column (YMC, ODS-A 200S).
A 15 minutes linear gradient elution from 0.05%
trifluoroacetic acid : 60% CH3CN (70:30) to 0.05%
trifluoroacetic acid : 60% CH3CN (54:46) was used.
NEP inhibitory activity was defined as the inhibition of hydrolysis of α-hANP. Results :
Figure imgf000018_0001
Test 2 :
Angiotensin converting enzyme (ACE) inhibitory activity
Method :
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
(1978).
The test compounds were dissolved in N,N-dimethylformamide (DMF) and were added to the assay mixture (0.4 Mm o-Aminobenzoyl-Gly-p-(NO2)Phe-Pro in 0.2 M Tris Hcl, Ph 8.0). The reaction was started by adding the 50 μl 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 :
Figure imgf000019_0001
For therapeutic purpose, 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. The pharmaceutical preparations 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.
While 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.
The following Preparations and Examples are given for the purpose of illustrating this invention.
Preparation 1 The following compounds were obtained according to a similar manner to that of preparing the compound 24 described in J. Med. Chem. 1992, 35, 833-846. 1) 3-Oxo-4(S)-ρhthalimido-1,3,4,5-tetrahydro-2H-2- benzazepine-2-acetic acid
mp :213-216°C
[α]D 20 : +9.4° (C=1.01, CH3OH)
IR (Nujol) : 1760, 1720, 1680, 1640 cm-1
NMR (CDCI3, δ) : 3.16 (1H, dd, J=4.3, 16.0Hz), 4.00
(1H, d, J=17.4Hz), 4.27 (1H, dd, J=13.0,
16.0Hz), 4.50 (1H, d, J=17.4Hz), 4.52 (1H, d, J=16.2Hz), 4.91 (1H, d, J=16.2Hz), 5.50 (1H, dd, J=4.3, 13.0Hz), 7.1-7.4 (4H, m), 7.7-7.8 (2H, m), 7.8-7.9 (2H, m)
MASS (m/z) : 364 (M+)
2) α(S)-Methyl-3-oxo-4(S)-ρhthalimido-1,3,4,5- tetrahydro-2H-2-benzazepine-2-acetic acid
mp : 178-179°C
[α]D 20 : -29.8° (C=1.02, CH3OH)
IR (Nujol) : 1770, 1700, 1635 cm-1
NMR (CDCI3, δ) : 1.33 (3H, d, J=7.1Hz), 3.22 (1H, dd, J=4.4, 15.8Hz), 4.01 (1H, dd, J=12.8,
15.8Hz), 4.62 (1H, d, J=16.1Hz), 4.78 (1H, d,
J=16.1Hz), 4.82 (1H, quartet, J=7.1Hz), 5.18 (1H, dd, J=4.4, 12.8Hz), 7.2-7.4 (4H, m), 7.8- 8.0 (4H, m), 12.5 (br s)
MASS (m/z) : 379 (M+1)
Preparation 2
To a solution of 3-oxo-4(S)-phthalimido-1,3,4,5-tetrahydro-2H-2-benzazepine-2-acetic acid (2.47 g) in ethyl acetate (50 ml) was added in small portions diphenyl diazomethane (1.98 g) at ambient temperature. The resulting mixture was stirred overnight at ambient
temperature and then evaporated in vacuo. The residue was purified by column-chromatography on silica gel (54 g) using a mixture of ethyl acetate and n-hexane (2:3), and then ethyl acetate as an eluent to afford diphenylmethyl 3-OXO-4(S)-phthalimido-1,3,4,5-tetrahydro-2H-2-benzazepine-2-acetate (2.91 g) .
mp : 170-172°C
[α]D 20 : +5.0° (C=0.50, CHCI3)
IR (Nujol) : 1750, 1710, 1660, 1630 cm-1
NMR (CDCI3, δ) : 3.14 (1H, dd, J=4.3, 15.8Hz),
4.24 (1H, d, J=17.3Hz), 4.25 (1H, dd, J=13.1, 15.8Hz), 4.53 (1H, d, J=17.3Hz), 4.55 (1H, d, J=16.1Hz), 4.80 (1H, d, J=16.1Hz), 5.47 (1H, dd, J=4.3, 13.1Hz), 6.89 (1H, s), 7.0-7.2 (14H, m),
7.6-7.8 (2H, m), 7.8-8.0 (2H, m)
MASS (m/z) : 530 (M+)
Preparation 3
The following compound was obtained according to a similar manner to that of Preparation 2.
Diphenylmethyl α(S)-methyl-3-oxo-4(S)-phthalimido-1,3,4,5-tetrahydro-2H-2-benzazepine-2-acetate
IR (Nujol) : 1710, 1670, 1640 cm-1
NMR (CDCI3, δ) : 1.49 (3H, d, J=7.2Hz), 3.05 (1H, dd, J=4.4, 15.5Hz), 4.19 (1H, dd, J=12.0,
15.5Hz), 4.46 (1H, d, J=16.0Hz), 4.67 (1H, d,
J=16.0Hz), 5.30 (1H, dd, J=4.4, 12.0Hz), 5.41 (1H, quartet, J=7.2Hz), 6.71 (1H, s), 7.0-7.4
(14H, m), 7.6-7.8 (2H, m), 7.8-8.0 (2H, m)
MASS (m/z) : 545 (M+1), 379
Preparation 4
A mixture of diphenylmethyl 3-oxo-4(S)-phth-limido- 1,3,4,5-tetrahydro-2H-2-benzazepine-2-acetate (2.80 g) and hydrazine hydrate (0.51 ml) in ethanol (10 ml) was heated under reflux for 15 minutes. The resulting mixture was cooled to ambient temperature and a precipitate was removed by filtration and washed with ethanol. The filtrate was concentrated in vacuo and the residue was purified by column-chromatography on silica gel (54 g) using a mixture of chloroform and methanol (50:1) to give white powders of diphenylmethyl 4(S)-amino-3-oxo-1,3,4,5-tetrahydro-2H-2-benzazepine-2-acetate (1.02 g).
mp : 97-99°C
[α]D 20 : +47.3° (C=1.06, CH3OH)
IR (Nujol) : 3350, 1710, 1640 cm-1
NMR (CDCI3, δ) : 1.78 (2H, s), 2.91 (1H, dd, J=12.7, 17.0Hz), 3.25 (1H, dd, J=4.3, 17.0Hz), 3.86 (1H, d, J=16.8Hz), 4.05 (1H, d, J=17.4Hz), 4.36 (1H, dd, J=4.3, 12.7Hz), 4.65 (1H, d, J=17.4Hz), 5.19 (1H, d, J=16.8Hz), 6.88 (1H, s), 6.9-7.4 (14H, m)
MASS (m/z) : 400 (M+)
Preparation 5
The following compound was obtained according to a similar manner to that of Preparation 4.
Diphenylmethyl 4(S)-amino-α(S)-methyl-3-oxo-1,3,4,5-tetrahydro-2H-2-benzazepine-2-acetate
IR (CHCI3) : 3350, 1730, 1650 cm-1
NMR (CDCI3, δ) : 1.45 (3H, d, J=7.1Hz), 1.77 (2H, br s), 2.86 (1H, dd, J=12.8, 16.9Hz), 3.16 (1H, dd,
J=4.1, 16.9Hz), 4.05 (1H, d, J=16.7Hz), 4.1-4.4 (1H, m), 4.90 (1H, d, J=16.7Hz), 5.38 (1H, quartet, J=7.1Hz), 6.44 (1H, s), 7.8-7.4 (14H, m)
MASS (m/z) : 414 (M+1) Preparation 6
A mixture of 3-oxo-4(S)-phthalimido-1,3,4,5-tetrahydro-2H-2-benzazepine-2-acetic acid (6.81 g) and hydrazine hydrate (2.73 ml) in ethanol (13.6 ml) was heated under reflux for 20 minutes. The resulting mixture was cooled to ambient temperature and diluted with
ethanol. A precipitate was removed by filtration and washed with ethanol. The filtrate was concentrated in vacuo and the residue dissolved in methanol was acidified with 4N hydrogen chloride in dioxane. The resulting solution was concentrated in vacuo and the residue was purified by HP-20 using 30% aqueous methanol as an eluent to afford white powders of 4(S)-amino-3-oxo-1,3,4,5-tetrahydro-2H-2-benzazepine-2-acetic acid (1.27 g).
[α]D 19 : -353.5° (C=0.49, H2O)
IR (Nujol) : 3370 (br), 1670, 1580 cm-1
NMR (D2O, δ) : 3.31 (1H, dd, J=12.8, 16.6Hz), 3.50
(1H, dd, J=5.1, 16.6Hz), 3.81 (1H, d, J=17.0Hz), 4.12 (1H, d, J=17.0Hz), 4.28 (1H, d, J=17.0Hz), 5.15 (1H, d, J=17.0Hz), 5.20 (1H, d, J=17.0Hz),
7.2-7.5 (4H, m)
MASS (m/z) : 234 (M+) preparation 7
The following compound was obtained according to a similar manner to that of Preparation 6.
4(S)-Amino-α(S)-methyl-3-oxo-1,3,4,5-tetrahydro-2H-2-benzazepine-2-acetic acid
[α]D 19 : -372.8° (C=0.57, H2O)
IR (Nujol) : 3350 (br), 1660, 1680 cm-1
NMR (D2O, δ) : 1.35 (3H, d, J=7.1Hz), 3.2-3.6 (2H, m), 4.23 (1H, d, J=17.1Hz), 4.6-5.2 (3H, m), 7.1-7.4 (4H, m)
MASS (m/z) : 249 (M+1) Preparation 8
To a solution of 2(S)-benzoylthio-3-phenylpropionic acid (10.0 g) in ethyl acetate (100 ml) was added a solution of dicyclohexylamine (6.3 ml) in ethyl acetate (100 ml) at 0°C under stirring. The reaction mixture was evaporated in vacuo. The residue was triturated with ethyl acetate to afford a colorless powder of
dicyclohexylammonium 2(S)-benzoylthio-3-phenylpropionate (9.67 g).
mp : 139-140°C
[α]D 18 : -43.66° (C=1.2, CHC13 )
IR (Nujol) : 1655, 1620 cm-1
NMR (CDCI3, δ) : 1.0-2.1 (20H, m), 2.8-3.0 (2H, m), 3.14 (1H, dd, J=6.2, 13.6Hz), 3.38 (1H, dd, J=8.1, 13.6Hz), 4.45 (1H, dd, J=6.2, 8.0Hz),
7.1-7.6 (10H, m), 7 . 93 (2H, d, J=7.1Hz)
Preparation 9
To a solution of potassium thioacetate (3.41 g) in N,N-dimethylformamide (34 ml) was added dropwise 2-chloro-3-(3,4-methylenedioxyphenyl)propionic acid (5.68 g) [this compound was obtained according to a method of T. Sohda et al. (Chem. Pharm. Bull., 1983, 31, 560-569)] at 0°C. The reaction mixture was stirred overnight at ambient
temperature, and poured into cold water (140 ml) and extracted with ethyl acetate (x 3). The organic layer was dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography using a mixture of dichloromethane and methanol (50:1 to 20:1) as an eluent to afford yellow oil of 2-acetylthio-3-(3,4-methylenedioxyphenyl)propionic acid (7.39 g).
IR (Film) : 2600-2400, 1710, 1670 cm-1
NMR (CDCI3, δ) : 2.33 (3H, s), 2.9-3.05 (1H, m), 3.15-3.3 (1H, m), 4.38 (1H, t, J=7.4Hz), 5.92 ( 2H , s ) , 6 . 65-6 . 8 ( 3H , m ) , 8 . 6 ( 1H , br s )
MASS ( m/ z ) : 251
Preparation 10
The following compound was obtained according to a similar manner to that of Preparation 9.
2-Acetylthio-3-(2-methylphenyl)propionic acid
IR (Film) : 2700-2400, 1715, 1660 cm-1
NMR (CDCl3, δ) : 2.32 (3H, s), 2.95-3.1 (1H, m),
3.3-3.55 (1H, m), 4.44 (1H, t, J=7.8Hz), 7.1- 7.25 (4H, m), 9.4 (1H, br s)
Preparation 11
To a suspension of sodium hydride (60% dispersion in mineral oil, 2.80 g) in N,N-dimethylformamide (115 ml) was added ethyl 2-chloroacetoacetate (9.68 ml) at 0°C. The reaction mixture was stirred for 20 minutes at the same temperature. Thereto was added dropwise a solution of α-bromo-o-xylene (9.38 ml) in N,N-dimethylformamide (12 ml) at 0°C. The reaction mixture was stirred overnight at ambient temperature, poured into ice-water (500 g) and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography using a mixture of n-hexane and ethyl acetate (50:1) as an eluent to afford a colorless oil of ethyl 2-chloro-2-(2-methylphenyl)methylacetoacetate (14.48 g).
IR (Film) : 1725 cm-1
NMR (CDCI3, δ) : 1.15 (3H, t, J=7.1Hz)), 2.27 (3H, s), 2.34 (3H, s), 3.59 (2H, s), 4.15-4.35 (2H, m), 7.1-7.2 (4H, m) Preparation 12 To a solution of ethyl 2-chloro-2-(2-methylphenyl)methylacetoacetate (14.29 g) in ethanol (143 ml) was added IN sodium hydroxide solution (56 ml) at ambient temperature. The reaction mixture was stirred for 30 minutes at the same temperature and washed with diethyl ether (x 2). The aqueous layer was acidified with
concentrated hydrochloric acid (6 ml) and extracted with ethyl acetate (x 3). The organic layer was dried over anhydrous magnesium sulfate and evaporated in vacuo to afford a colorless oil of 2-chloro-3-(2-methylphenyl)propionic acid (6.00 g) .
IR (Film) : 2800-2500, 1710 cm-1
NMR (CDCI3, δ) : 2.36 (3H, s), 3.20 (1H, dd, J=8.1, 14.4Hz), 3.43 (1H, dd, J=6.8, 14.4Hz), 4.48 (1H, dd, J=6.8, 8.1Hz), 7.18 (4H, br s), 9.14 (1H, br s)
FAB-MASS (m/z) : 197
Example 1
To a mixture of 2 (S)-acetylthio-3-phenylpropionic acid (1.55 g), 1-hydroxybenzotriazole hydrate (1.02 g), and 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide
hydrochloride (1.45 g) in dichloromethane (40 ml) was added dropwise under ice-cooling a solution of tert-butyl 3(S)-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetate (2.0 g) in dichloromethane (20 ml). The resulting mixture was stirred at ambient temperature for 3 hours, and then evaporated in vacuo. The residue was diluted with ethyl acetate, washed twice with water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by column-chromatography on silica gel (80 g) using a mixture of n-hexane and ethyl acetate (3:1) as an eluent to afford amorphous product of tert-butyl 3(S)-[(2(S)-acetylthio-1-oxo-3-phenylpropyl)amino]-2-oxo-2,3,4,5-tetrahydro-1H-1- benzazepine-1-acetate (2.18 g).
IR (Nujol) : 3320, 1735, 1680, 1650 cm-1
NMR (CDCI3, δ) : 1.41 (9H, s), 1.7-1.9 (1H, m), 2.31 (3H, s), 2.5-2.8 (2H, m), 2.94 (1H, dd, J=7.8, 14.1Hz), 3.1-3.4 (2H, m), 4.1-4.3 (1H, m), 4.23
(1H, d, J=17.0Hz), 4.3-4.5 (1H, m), 4.64 (1H, d, J=17.0Hz), 7.0-7.3 (10H, m)
MASS (m/z) : 497 (M+1) Example 2
The following compounds were obtained according to a similar manner to that of Example 1.
1) tert-Butyl 3(S)-[(2(R)-acetylthio-1-oxo-3- phenylpropyl)amino]-2-oxo-2,3,4,5-tetrahydro-1H-1- benzazepine-1-acetate
IR (CHCI3) : 3310, 1740, 1680, 1655 cm-1
NMR (CDCI3, δ) : 1.39 (9H, s), 1.6-1.8 (1H, m), 2.32 (3H, s), 2.4-2.7 (2H, m), 2.90 (1H, dd, J=6.6, 13.7Hz), 3.1-3.4 (1H, m), 3.25 (1H, dd, J=8.9,
13.7Hz), 4.1-4.2 (1H, m), 4.18 (1H, d, J=17.0Hz), 4.3-4.5 (1H, m), 4.69 (1H, d,
J=17.0Hz), 6.87 (1H, d, J=7.0Hz), 7.07 (1H, d, J=7.6Hz), 7.1-7.3 (8H, m)
MASS (m/z) : 497 (M+1)
2) tert-Butyl 3(R)-[(2(S)-acetylthio-1-oxo-3- phenylpropyl)amino]-2-oxo-2,3,4,5-tetrahydro-1H-1- benzazepine-1-acetate
IR (Nujol) : 3310, 1740, 1650 (br) cm-1
NMR (CDCI3, δ) : 1.40 (9H, s), 1.50-1.7 (1H, m), 2.32 (3H, s), 2.4-2.6 (2H, m), 2.90 (1H, dd, J=6.7, 13.7Hz), 3.2-3.3 (2H, m), 4.1-4.2 (2H, m), 4.3-4.5 (1H, m), 6.19 (1H, d, J=17.0Hz), 6.88 (1H, d, J=7.0Hz), 7.1-7.3 (9H, m) MASS (m/z ) : 497 ( M+1 )
3) tert-Butyl 3(R)-[(2(R)-acetylthio-1-oxo-3- phenylpropyl)amino]-2-oxo-2,3,4,5-tetrahydro-1H-1- benzazepine-1-acetate
IR (Nujol) : 3300, 1740 cm-1
NMR (CDCl3, δ) : 1.41 (9H, s), 1.7-1.9 (1H, m), 2.31 (3H, s), 2.5-2.8 (2H, m), 2.95 (1H, dd, J=7.7, 14.1Hz), 3.2-3.4 (2H, m), 4.2-4.3 (2H, m), 4.3- 4.5 (1H, m), 4.64 (1H, d, J=17.0Hz), 7.0-7.3
(10H, m)
MASS (m/z) : 497 (M+1)
4) tert-Butyl 3(S)-[(2(S)-acetylthio-1-oxo-3- methylbutyl)amino]-2-oxo-2,3,4,5-tetrahydro-1H-1- benzazepine-1-acetate
IR (Nujol) : 3320, 1730, 1670, 1650 cm-1
NMR (CDCI3, δ) : 0.95 (3H, d, J=6.4Hz), 0.98 (3H, d, J=6.4Hz), 1.42 (9H, s), 1.8-2.0 (1H, m), 2.1-2.3 (1H, m), 2.37 (3H, s), 2.5-2.8 (2H, m), 3.2-3.4
(1H, m), 3.83 (1H, d, J=7.3Hz), 4.23 (1H, d, J=17.0Hz), 4.4-4.6 (1H, m), 4.69 (1H, d,
J=17.0Hz), 7.00 (1H, d, J=7.1Hz), 7.1-7.4 (4H, m)
MASS (m/z) : 449 (M+1)
5) Ethyl 3(S)-[2(S)-acetylthiomethyl-1-oxo-3- phenylpropyl)amino]-2-oxo-2,3,4,5-tetrahydro-1H-1- benzazepine-1-acetate
IR (Nujol) : 3330, 1740, 1670 (br), 1650 (br) cm-1
NMR (CDCI3, δ) : 1.25 (3H, t, J=7.1Hz), 1.8-2.0 (1H, m), 2.32 (3H, s), 2.5-3.1 (7H, m), 3.2-3.4 (1H, m), 4.18 (2H, q, J=7.1Hz), 4.3-4.5 (2H, m), 4.70 (1H, d, J=17.1Hz), 6.45 (1H, d, J=6.5Hz), 7.1- 7.3 (9H, m) MASS ( m/ z ) : 483 (M+1 )
6) Ethyl 3(S)-[(2(S)-acetylthio-1-oxo-3- phenylpropyl)amino]-2-oxo-2,3,4,5-tetrahydro-1H-1- benzazepine-1-acetate
IR (Nujol) : 3360, 1740, 1675, 1650 cm-1
NMR (CDCI3, δ) : 1.24 (3H, t, J=7.1Hz), 1.7-2.0 (1H, m), 2.32 (3H, s), 2.5-2.8 (2H, m), 2.95 (1H, dd, J=7.8, 14.2Hz), 3.2-3.4 (2H, m), 4.1-4.5 (4H, m), 4.73 (1H, d, J=17.2Hz), 7.0-7.4 (11H, m)
MASS (m/z) : 469 (M+1)
Example 3
To a mixture of 2(S)-acetylthio-3-phenylpropionic acid (0.67 g), diphenylmethyl 4(S)-amino-3-oxo-1,3,4,5-tetrahydro-2H-2-benzazepine-2-acetate (1.20 g), and 1-hydroxybenzotriazole hydrate (0.41 g) in dichloromethane (12 ml) was 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (0.63 g) under ice-cooling. The resulting mixture was stirred at the same temperature for 5 minutes and at ambient temperature for an additional hour, and then evaporated in vacuo. The residue was partitioned between ethyl acetate and water. After being washed with 1N hydrochloric acid, water, saturated aqueous sodium bisulfate and brine successively, the organic layer was dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by column-chromatography on silica gel (40 g) using a mixture of n-hexane and ethyl acetate (3:1 to 2:1) as an eluent to afford amorphous product of diphenylmethyl 4(S)-[(2(S)-acetylthio-1-oxo-3-phenylpropyl)amino]-3-oxo-1,3,4,5-tetrahydro-2H-2-benzazepine-2-acetate (1.34 g).
IR (CHCI3) : 3370, 1730, 1680, 1650 cm-1
NMR (CDCI3, δ) : 2.35 (3H, s), 2.74 (1H, dd, J=12.9, 16.3Hz), 3.02 (1H, dd, J=7.8, 14.0Hz), 3.33 (1H, dd, J=7.4, 14.0Hz), 3.40 (1H, dd, J=4.1,
16.3Hz), 3.73 (1H, d, J=17.0Hz), 4.09 (1H, d, J=17.4Hz), 4.33 (1H, t-like, J=7.6Hz), 4.54 (1H, d, J=17.4Hz), 5.24 (1H, d, J=17.0Hz), 5.2-5.4 (1H, m), 6.86 (1H, s), 6.9-7.4 (20H, m)
MASS (m/z) : 607 (M+1), 441
Example 4
The following compounds were obtained according to a similar manner to that of Example 3.
1) Diphenylmethyl 4(S)-[(2(S)-acetylthio-1-oxo-3- phenylpropyl)amino]-α(S)-methyl-3-oxo-1,3,4,5- tetrahydro-2H-2-benzazepine-2-acetate
IR (Nujol) : 3370, 1730, 1680, 1650 cm-1
NMR (CDCl3, δ) : 1.44 (3H, d, J=7.2Hz), 2.38 (3H, s), 2.69 (1H, dd, J=12.3, 17.2Hz), 3.04 (1H, dd, 3=1 .1 , 14.0Hz), 3.2-3.5 (2H, m), 4.03 (1H, d, J=17.0Hz), 4.35 (1H, t-like, J=7.5Hz), 4.94 (1H, d, J=17.0Hz), 5.1-5.3 (1H, m), 5.33 (1H,
quartet, J=7.2Hz ), 6.41 (1H, s), 6.8-7.1 (4H, m), 7.1-7.5 (16H, m)
MASS (m/z) : 621 (M+1), 455 2) tert-Butyl 3(S)-[2-acetylthio-3-(3,4- methylenedioxyphenyl)-1-oxopropyl]amino-2-oxo- 2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetate
IR (Film) : 3360, 1735, 1680 (shoulder), 1655 cm-1 NMR (CDCI3, δ) : 1.40 and 1.41 (total 9H, each s), 1.75-1.95 (1H, m), 2.33 (3H, s), 2.5-2.95 (3H, m), 3.1-3.4 (2H, m), 4.1-4.3 (2H, m), 4.3-4.5 (1H, m), 4.67 (1H, dd, J=9.1, 17.0Hz), 5.92 (two peak, total 2H, each s), 6.55-6.75 (3H, m), 6.85-7.35 (5H, m)
MASS (m/z) : 541, 485 3) tert-Butyl 3(S)-[2-acetylthio-3-(2-methylphenyl)-1- oxopropyl]amino-2-oxo-2,3,4,5-tetrahydro-1H-1- benzazepine-1-acetate
IR (Film) : 3320, 1730, 1680, 1650 cm-1
NMR (CDCl3, δ) : 1.39 and 1.41 (total 9H, each s),
1.5-1.95 (1H, m), 2.30, 2.32 (two peak) and 2.35 (total 6H, each s), 2.45-2.8 (2H, m), 2.85-3.0 (1H, m), 3.15-3.4 (2H, m), 4.15-4.3 (2H, m), 4.35-4.5 (1H, m), 4.67 (1H, dd, J=6.0, 17.0Hz), 6.8-7.35 (9H, m)
MASS (m/z) : 511, 455
4) tert-Butyl 3(S)-[2(S)-benzoylthio-1-oxo-3- phenylpropyl]amino-2-oxo-2,3,4,5-tetrahydro-1H-1- benzazepine-1-acetate
IR (Film) : 3175, 1730, 1650 cm-1
NMR (CDCI3, δ) : 1.39 (9H, s), 1.7-2.0 (1H, m), 2.5- 2.85 (2H, m), 3.11 (1H, dd, J=7.5, 14.1Hz), 3.2- 3.3 (1H, m), 3.35 (1H, dd, J=7.5, 14.1Hz), 4.23 (1H, d, J=17.0Hz), 4.35-4.55 (2H, m), 4.63 (1H, d, J=17.0Hz), 7.05-7.7 (13H, m), 7.92 (2H, d, J=7.3Hz)
Example 5
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. To a mixture of 2(S)-acetylthio-3-phenylpropionic acid obtained above, 1-hydroxybenzotriazole hydrate (0.63 g), and tert-butyl 3(S)-amino-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetate (1.23 g) in dichloromethane (10 ml) was added 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (0.93 g) under ice-cooling. The resulting mixture was stirred at ambient temperature for 4 hours, washed with water, saturated aqueous sodium bicarbonate solution, and water, successively. The extract was dried over anhydrous sodium sulfate, and then evaporated in vacuo. The residue was purified by column-chromatography on silica gel (50 g) using a mixture of n-hexane and ethyl acetate (4:1 to 3:1) as an eluent to afford amorphous product of tert-butyl 3(S)-[2(S)-acetylthiomethyl-1-oxo-3-phenylpropyl)amino]-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetate (2.07 g).
IR (Nujol) : 3320, 1740, 1680, 1650 cm-1
NMR (CDCl3, δ) : 1.41 (9H, s), 1.7-2.0 (1H, m), 2.31
(3H, s), 2.5-3.1 (7H, m), 3.2-3.4 (1H, m), 4.22 (1H, d, J=17.0Hz), 4.3-4.5 (1H, m), 4.61 (1H, d,
J=17.0Hz), 6.48 (1H, d, J=6.7Hz), 7.0-7.4 (9H, m)
MASS (m/z) : 511 (M+1) Example 6
The following compounds were obtained according to a similar manner to that of Example 5.
1) tert-Butyl 3(S)-{[2(S)-acetylthiomethyl-3-(2- methylphenyl)-1-oxopropyl]amino}-2-oxo-2,3,4,5- tetrahydro-1H-1-benzazepine-1-acetate
IR (Nujol) : 3320, 1735, 1680, 1645 cm-1
NMR (CDCI3, δ) : 1.41 (9H, m), 1.8-2.0 (1H, m), 2.29 (3H, s), 2.32 (3H, s), 2.5-3.1 (7H, m), 3.2-3.4 (1H, m), 4.21 (1H, d, J=17.0Hz), 4.3-4.5 (1H, m), 4.61 (1H, d, J=17.0Hz), 6.43 (1H, d,
J=6.7Hz), 7.3-7.1 (8H, m)
MASS (m/z) : 525 (M+1) 2) tert-Butyl 3(S)-{[2(S)-acetylthiomethyl-3-(3,4- methylenedioxyphenyl)-1-oxopropyl]amino}-2-oxo- 2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetate
IR (Nujol) : 3300, 1735, 1670, 1650 cm-1
NMR (CDCI3, δ) : 1.41 (9H, s), 1.8-2.0 (1H, m), 2.32 (3H, s), 2.5-3.1 (7H, m), 3.2-3.4 (1H, m), 4.21 (1H, d, J=17.0Hz), 4.3-4.5 (1H, m), 4.64 (1H, d, J=17.0Hz), 5.93 (2H, s), 6.45 (1H, d, J=6.8Hz), 6.5-6.7 (3H, m), 7.0-7.4 (4H, m)
MASS (m/z) : 555 (M+1)
3) tert-Butyl 3(S)-[(2(S)-acetylthiomethyl-3-methyl-1- oxobutyl)amino]-2-oxo-2,3,4,5-tetrahydro-1H-1- benzazepine-1-acetate
IR (Nujol) : 3310, 1730, 1680, 1640 crn-1
NMR (CDCI3, δ) : 0.91 (3H, d, J=6.6Hz), 0.99 (3H, d,
J=6.7Hz), 1.42 (9H, s), 1.7-2.2 (3H, m) , 2.31 (3H, s), 2.5-2.9 (2H, m), 2.87 (1H, dd, J=10.4, 13.2Hz), 3.23 (1H, dd, J=3.9, 13.2Hz), 3.3-3.5 (1H, m), 4.24 (1H, d, J=17.0Hz), 4.4-4.6 (1H, m), 4.67 (1H, d, J=17.0Hz), 6.49 (1H, d,
J=7.1Hz), 7.0-7.4 (4H, m)
MASS (m/z) : 463 (M+1)
Example 7
To a solution of 2(S)-acetylthiomethyl-3-phenylpropionic acid (0.72 g) in dichloromethane (10.7 ml) was added thionyl chloride (0.65 ml) and N,N-dimethylformamide (1 drop) under ice-water cooling. The resulting mixture was stirred at ambient temperature for 2 hours, and then evaporated in vacuo. To a suspension of 4(S)-amino-3-oxo-1,3,4,5-tetrahydro-2H-2-benzazepine-2-acetic acid (0.59 g) in acetonitrile (2.9 ml) was added dropwise N,O-bis(trimethylsilyl)acetamide (1.85 ml) under ice-water cooling. The resulting mixture was stirred at the same temperature for 30 minutes and at ambient temperature for an additional hour, and then cooled again with ice-water bath. Thereto was added dropwise a solution of 2(S)-acetylthiomethyl-3-phenylpropionyl chloride (0.78 g) obtained above in acetonitrile (2 ml). The resulting mixture was stirred at ambient temperature for an hour, and then poured into ice-water. The organic layer was washed with IN hydrochloric acid and brine, dried over anhydrous magnesium sulfate, and then
evaporated in vacuo. The residue was purified by columnchromatography on silica gel (40 g) using a mixture of chloroform, methanol and acetic acid (50:2:1) as an eluent to afford amorphous product of 4(S)-[(2(S)-acetylthiomethyl-1-oxo-3-phenylpropyl)amino]-3-oxo-1,3,4,5-tetrahydro-2H-2-benzazepine-2-acetic acid (0.90 g).
IR (Nujol) : 3300, 1730, 1680, 1630 cm-1
NMR (DMSO-d6, δ) : 2.34 (3H, s), 2.6-3.2 (6H, m), 3.46 (1H, dd, J=4.2, 17.0Hz), 3.80 (1H, d, J=17.0Hz), 3.82 (1H, d, J=17.7Hz), 4.53 (1H, d, J=17.7Hz), 5.23 (1H, d, J=17.0Hz ), 5.2-5.5 (1H, m), 6.9-7.4 (10H, m)
MASS (m/z) : 454 (M+)
Example 8
The following compounds were obtained according to a similar manner to that of Example 7.
1) 4(S)-[(2(S)-Acetylthiomethyl-3-methyl-1- oxobutyl)amino]-3-oxo-1,3,4,5-tetrahydro-2H-2- benzazepine-2-acetic acid
IR (CHCl3) : 3320, 1720, 1680, 1650 cm-1
NMR (CDCI3, δ) : 0.90 (3H, d, J=6.7Hz), 0.97 (3H, d, J=6.7Hz), 1.7-2.0 (1H, m), 2.0-2.2 (1H, m), 2.28 (3H, s), 2.85 (1H, dd, J=12.6, 17.0Hz), 2.90 (1H, dd, J=10.3, 13.3Hz), 3.23 (1H, dd, J=3.9, 13.3Hz), 3.45 (1H, dd, J=4.2, 17.0Hz), 3.77 (1H, d, J=17.6Hz), 3.78 (1H, d, J=16.9Hz), 4.53 (1H, d, J=17.6Hz), 5.21 (1H, d, J=16.9Hz), 5.3-5.6 (1H, m), 6.9-7.3 (5H, m)
MASS (m/z) : 407 (M+l)
2) 4(S)-[(2(S)-Acetylthio-3-methyl-1-oxobutyl)amino]-3- oxo-1,3,4,5-tetrahydro-2H-2-benzazepine-2-acetic acid IR (Nujol) : 3350, 1710, 1680, 1650 cm-1
NMR (CDCl3, δ) : 1.00 (3H, d, J=6.8Hz), 1.04 (3H, d,
J=6.8Hz), 2.2-2.5 (1H, m), 2.41 (3H, s), 2.91 (1H, dd, J=12.6, 16.9Hz), 3.46 (1H, dd, J=4.1, 16.9Hz), 3.85 (1H, d, J=16.9Hz), 3.90 (1H, d, J=17.7Hz), 3.97 (1H, d, J=7.0Hz), 4.59 (1H, d, J=17.7Hz), 5.27 (1H, d, J=16.9Hz), 5.4-5.6 (1H, m), 6.9-7.3 (4H, m), 7.52 (1H, d, J=6.4Hz)
MASS (m/z) : 393 (M+1)
3) 4(S)-[(3-Acetylthio-2(S)-methyl-1-oxopropyl)amino]-3- oxo-1,3,4,5-tetrahydro-2H-2-benzazepine-2-acetic acid
IR (Nujol) : 3380, 1720, 1670, 1650 cm-1
NMR (DMSO-d6, δ) : 1.10 (3H, d, J=6.8Hz), 2.33 (3H, s), 2.6-2.8 (1H, m), 2.8-3.1 (3H, m), 3.15 (1H, dd, J=4.1, 17.1Hz), 3.94 (1H, d, J=17.3Hz), 4.16 (1H, d, J=17.4Hz), 4.24 (1H, d, J=17.4Hz), 5.22
(1H, d, J=17.3Hz), 5.2-5.5 (1H, m), 7.1-7.3 (4H, m), 8.17 (1H, d, J=17.4Hz), 12.2 (1H, br s) MASS (m/z) : 379 (M+1) 4) 4(S)-[2(S)-Acetylthiomethyl-1-oxo-3- phenylpropyl)amino]-α(S)-methyl-3-oxo-1,3,4,5- tetrahydro-2H-2-benzazepine-2-acetic acid
[α]D 19 : +9.0° (C=0.48, CH3OH)
IR (CHCI3) : 3375, 1715, 1680 cm-1
NMR (CDCI3, δ) : 1.26 (3H, d, J=7.1Hz), 2.30 (3H, s), 2.5-2.8 (1H, m), 2.8-3.1 (5H, m), 3.1-3.3 (1H, m), 4.17 (1H, d, J=17.1Hz), 4.82 (1H, quartet, J=7.1Hz), 5.12 (1H, d, J=17.1Hz), 5.2- 5.4 (1H, m), 7.0-7.4 (9H, m), 8.31 (1H, d, J=7.1Hz), 12.3 (1H, br s)
MASS (m/z) : 469 (M+1)
Example 9
To a solution of 2(S)-acetylthiomethyl-3-phenylpropionic acid (1.1 g) in dichloromethane (10 ml) was added thionyl chloride (1 ml) and N,N-dimethylformamide (2 drops) under ice-water cooling. The resulting mixture was stirred for an hour and 40 minutes, and then evaporated in vacuo. To a suspension of 3(R)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid hydrobromide (1.53 g) and N-methylmorpholine (0.5 ml) in acetonitrile (15 ml) was added dropwise N,O-bis(trimethylsilyl)acetamide (3.4 ml) under ice-water cooling. The resulting mixture was stirred at the same temperature for 30 minutes and at ambient temperature for an additional hour, and then cooled again with ice-water bath. Thereto was added dropwise a solution of 2(S)-acetylthiomethyl-3-phenylpropionyl chloride (1.17 g) obtained above in acetonitrile (3 ml). The mixture was stirred at the same temperature for an hour and evaporated in vacuo. The residue was partitioned between 1N
hydrochloric acid and ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then evaporated in vacuo. The residue was purified by column-chromatography on silica gel (50 g) using a mixture of n-hexane, ethyl acetate and acetic acid (40:20:1) as an eluent to afford amorphous product of 3(R)-[(2(S)-acetylthiomethyl-1-oxo-3-phenylpropyl)amino]-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid (1.2 g). mp : 139-141°C
[α]D 18 : -226° (C=0.51, CH3OH)
IR (Nujol) : 3300, 1680, 1650 cm-1
NMR (DMSO-D6, δ) : 2.24 (3H, s), 2.5-2.7 (1H, m), 2.7-3.1 (5H, m), 3.3-3.5 (1H, m), 3.80 (1H, d, J=16.8Hz), 4.4-4.6 (1H, m), 4.64 (1H, d,
J=16.8Hz), 7.1-7.4 (6H, m), 7.4-7.7 (3H, m), 8.55 (1H, d, J=8.2Hz), 12.8 (1H, br s)
MASS (m/z) : 473 (M+1)
Example 10
The following compound was obtained according to a similar manner to that of Example 9. 3(R)-[(2(S)-Acetylthio-1-oxo-3-phenylpropyl)amino]-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid mp : 159-161°C
IR (Nujol) : 3350, 1650 cm-1
NMR (DMSO-d6, δ) : 2.24 (3H, s), 2.75 (1H, dd,
J=8.0, 14.0Hz), 2.93 (1H, t-like, J=11.5Hz),
3.14 (1H, dd, J=6.8, 14.0Hz), 3.42 (1H, dd, J=6.6, 11.2Hz), 3.70 (1H, d, J=17.0Hz), 4.3-4.5 (2H, m), 4.63 (1H, d, J=17.0Hz), 7.1-7.4 (6H, m), 7.4-7.8 (3H, m), 8.54 (1H, d, J=7.9Hz) MASS (m/z) : 459 (M+1)
Example 11
To a solution of tert-butyl 3(S)-[(2(S)-acetylthio-1-oxo-3-phenylpropyl)amino]-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetate (1.95 g) in dichloromethane (60 ml) was added trifluoroacetic acid (9.1 ml). The resulting mixture was stirred at ambient temperature for 2 hours and evaporated in vacuo. The residual trifluoroacetic acid was removed azeotropically twice with toluene. The residue was pulverized with diisopropyl ether to give a white powder of 3(S)-[(2(S)-acetylthio-1-oxo-3-phenylpropyl)amino]-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetic acid (1.41 g) .
[α]D 20 : -204.10° (C =1.1, CHCl3)
IR (Nujol) : 3350, 1735, 1690, 1665, 1620, 1540,
1210 cm-1
NMR (CDCI3, δ) : 1.7-2.0 (1H, m), 2.29 (3H, s), 2.4- 2.8 (2H, m), 2.92 (1H, dd, J=7.8, 14.1Hz), 3.1- 3.4 (2H, m), 4.23 (1H, t, J=7.6Hz), 4.3-4.6 (1H, m), 4.40 (1H, d, J=17.3Hz), 4.68 (1H, d,
J=17.3Hz), 6.68 (1H, br s), 7.0-7.2 (9H, m) MASS (m/z) : 441 (M+1)
Example 12
The following compounds were obtained according to a similar manner to that of Example 11.
1) 3(S)-[(2(R)-Acetylthio-1-oxo-3-phenylpropyl)amino]-2- oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetic acid
[α]D 20 : -103.5° (C=1.03, CHCI3)
IR (Nujol) : 3340, 1725, 1685, 1665, 1630 cm-1
NMR (CDCI3, δ) : 1.5-1.8 (1H, m), 2.30 (3H, s), 2.3- 2.6 (2H, m), 2.89 (1H, dd, J=6.8, 13.7Hz), 3.1- 3.3 (1H, m), 3.22 (1H, dd, J=9.1, 13.7Hz), 4.18 (1H, dd, J=6.8, 9.1Hz), 4.3-4.5 (1H, m), 4.35
(1H, d, J=17.5Hz), 4.72 (1H, d, J=17.5Hz), 6.94 (1H, d, J=7.3Hz), 7.0-7.4 (9H, m)
MASS (m/z) : 441 (M+1) 2) 3(R)-[(2(S)-Acetylthio-1-oxo-3-phenylpropyl)amino]-2- oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetic acid IR (Nujol) : 3350, 1740, 1690, 1670, 1640 cm-1
NMR (CDCI3, δ) : 1.5-1.8 (1H, m), 2.31 (3H, s), 2.4- 2.7 (2H, m), 2.90 (1H, dd, J=6.7, 9.0Hz), 4.3- 4.6 (2H, m), 4.73 (1H, d, J=17.4Hz), 6.90 (1H, d, J=7.3Hz), 7.1-7.3 (9H, m)
MASS (m/z) : 441 (M+l) 3) 3(R)-[(2(R)-Acetylthio-1-oxo-3-phenylpropyl)amino]-2- oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetic acid
IR (Nujol) : 3330, 1735, 1690, 1665, 1620 cm-1
NMR (CDCl3, δ) : 1.7-2.0 (1H, m), 2.31 (3H, s), 2.5- 2.8 (2H, m), 2.94 (1H, dd, J=7.7, 14.2Hz), 3.1- 3.4 (2H, m), 4.23 (1H, t, J=7.7Hz), 4.3-4.5 (2H, m), 4.69 (1H, d, J=17.4Hz), 7.0-7.3 (10H, m) MASS (m/z) : 441 (M+1)
4) 3(S)-[2(S)-Acetylthio-1-oxo-3-methylbutyl)amino]-2- oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetic acid
[α]D 18 : -309.2° (C=1.1, CHCl3)
IR (Nujol) : 3360, 1740, 1700, 1675, 1635, 1620 cm-1 NMR (CDCI3, δ) : 0.93 (3H, d, J=6.5Hz), 0.96 (3H, d, J=6.5Hz), 1.8-2.0 (1H, m), 2.1-2.3 (1H, m), 2.36 (3H, s), 2.5-2.8 (2H, m), 3.1-3.4 (1H, m), 3.82
(1H, d, J=7.4Hz), 4.39 (1H, d, J=17.5Hz), 4.4- 4.6 (1H, m), 4.75 (1H, d, J=17.5Hz), 7.0-7.4 (5H, m), 8.45 (1H, br s)
MASS (m/z) : 393 (M+1)
5) 3(S)-[(2(S)-Acetylthiomethyl-1-oxo-3- phenylpropyl)amino]-2,3,4,5-tetrahydro-2-oxo-1H-1- benzazepine-1-acetic acid
IR (Nujol) : 3300, 1735, 1670, 1630 cm-1
NMR (CDCI3, δ) : 1.9-2.0 (1H, m), 2.29 (3H, s), 2.5- 3.3 (8H, m), 4.37 (1H, d, J=17.4Hz), 4.4-4.5 (1H, m), 4.66 (1H, d, J=17.4Hz), 6.69 (1H, d, J=7.1Hz), 7.0-7.3 (9H, m), 7.77 (1H, br s)
MASS (m/z) : 445 (M+1) 6) 3(S)-{[2(S)-Acetylthiomethyl-3-(2-methylphenyl)-1- oxopropyl]amino}-2-oxo-2,3,4,5-tetrahydro-1H-1- benzazepine-1-acetic acid
IR (Nujol) : 3300, 1740, 1680, 1660, 1630 cm-1
NMR (CDCl3, δ) : 1.8-2.0 (1H, m), 2.25 (3H, s), 2.30 (3H, s), 2.5-3.3 (8H, m), 4.3-4.5 (1H, m), 4.37 (1H, d, J=17.4Hz), 4.65 (1H, d, J=17.4Hz), 6.54 (1H, d, J=6.9Hz), 7.0-7.4 (8H, m)
MASS (m/z) : 469 (M+1)
7) 3(S)-{[2(S)-Acetylthiomethyl-3-(3,4- methylenedioxyphenyl)-1-oxopropyl]amino}-2-oxo- 2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetic acid IR (Nujol) : 3300, 1730, 1670 (br), 1635 (br) cm-1 NMR (CDCI3, δ) : 1.9-2.0 (1H, m), 2.29 (3H, s), 2.5- 3.3 (8H, m), 4.36 (1H, d, J=16.7Hz), 4.4-4.6 (1H, m), 4.58 (1H, d, J=16.7Hz), 5.87 (2H, s), 6.4-6.6 (5H, m), 7.1-7.3 (3H, m)
MASS (m/z) : 499 (M+1)
8 ) 3 ( S ) - [ ( 2 ( S ) -Acetylthiomethyl-3-methyl-1- oxobutyl)amino]-2-oxo-2,3,4,5-tetrahydro-1H-1- benzazepine-1-acetic acid
IR (Nujol) : 3280, 1730, 1690, 1620, 1550 cm-1
NMR (CDCI3, δ) : 0.88 (3H, d, J=6.6Hz), 0.96 (3H, d,
J=6.7Hz), 1.7-2.2 (3H, m), 2.31 (3H, s), 2.5-2.8 (2H, m), 2.87 (1H, dd, J=10.4, 13.3Hz), 3.21 (1H, dd, J=3.9, 13.3Hz), 3.1-3.4 (1H, m), 4.39 (1H, d, J=17.4Hz), 4.5-4.7 (1H, m), 4.75 (1H, d, J=17.4Hz), 6.67 (1H, d, 3=1.4Hz), 7.1-7.4 (4H, m)
MASS (m/z) : 407 (M+1)
9) 3(S)-[2(S)-Benzoylthio-1-oxo-3-phenylpropyl]amino-2- oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetic acid mp : 182-183°C
[α]D 18 : -238.6° (C=1.02, DMSO)
IR (Nujol) : 3370, 2800-2400, 1720, 1655, 1620,
1530 cm-1
NMR (CDCI3, δ) : 1.7-1.95 (1H, m), 2.4-2.8 (2H, m),
3.04 (1H, dd, J=7.6, 14.1Hz), 3.1-3.25 (1H, m), 3.32 (1H, dd, J=7.5, 14.1Hz), 4.38 (1H, d,
J=17.5Hz), 4.35-4.55 (2H, m), 4.68 (1H, d,
J=17.4Hz), 7.05-7.65 (13H, m), 7.85-7.95 (2H, m) MASS (m/z) : 503
Example 13
To a mixture of diphenylmethyl 4(S)-[(2(S)-acetylthio-1-oxo-3-phenylpropyl)amino]-3-oxo-1,3,4,5-tetrahydro-2H-2-benzazepine-2-acetate (0.90 g) and anisole (1.5 ml) was added trifluoroacetic acid (9.0 ml). The mixture was stirred at ambient temperature for an hour, and then trifluoroacetic acid was removed in vacuo. The residue was dissolved in ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate, and 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).
IR (CHCI3) : 3350, 1710, 1680, 1650 cm-1
NMR (CDCI3, δ) : 2.34 (3H, s), 2.84 (1H, dd, J=12.8, 16.8Hz), 3.02 (1H, dd, J=8.0, 14.1Hz), 3.32 (1H, dd, J=7.1, 14.1Hz), 3.42 (1H, dd, J=4.1,
16.8Hz), 3.84 (1H, d, J=17.1Hz), 3.86 (1H, d, J=17.7Hz), 3.35 (1H, t, J=7.5Hz), 4.54 (1H, d, J=17.7Hz), 5.23 (1H, d, J=17.1Hz), 5.3-5.5 (1H, m), 6.9-7.4 (9H, m), 7.48 (1H, d, J=6.3Hz)
MASS (m/z) : 441 (M+1) Example 14
The following compound was obtained according to a similar manner to that of Example 13. 4(S)-[(2(S)-Acetylthio-1-oxo-3-phenylpropyl)amino]-α(S)-methyl-3-oxo-1,3,4,5-tetrahydro-2H-2-benzazepine-2-acetic acid
IR (Nujol) : 3300, 1720, 1680, 1630 cm-1
NMR (CDCI3, δ) : 1.41 (3H, d, J=7.1Hz), 2.35 (3K, s), 2.85 (1H, dd, J=12.8, 16.9Hz), 3.02 (1H, dd,
J=7.9, 14.1Hz), 3.2-3.4 (2H, m), 4.02 (1H, d, J=17.1Hz), 4.35 (1H, t, J=7.6Hz), 4.96 (1H, quartet, J=7.1Hz), 5.03 (1H, d, J=17.1Hz), 5.2- 5.4 (1H, m), 6.9-7.4 (9H, m), 7.55 (1H, d,
J=6.5Hz)
MASS (m/z) : 455 (M+1)
Example 15
To a suspension of 3(S)-[(2(S)-acetylthio-1-oxo-3-phenylpropyl)amino]-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetic acid (0.70 g) in water (2.0 ml) was added 28% aqueous ammonia (1.0 ml) under nitrogen
atmosphere. The resulting solution was stirred at ambient temperature for 20 minutes and then poured into 5% aqueous potassium bisulfate solution (90 ml) to give a white precipitate, which was collected by filtration to afford 3(S)-[(2(S)-mercapto-1-oxo-3-phenylpropyl)amino]-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetic acid (0.58 g).
[α]D 20: -186.4° (C=1.04, CH3OH)
IR (Nujol) : 3300, 1730, 1630, 1200 cm-1
NMR (CDCI3, δ) : 1.8-2.2 (1H, m), 1.97 (1H, d,
J=8.7Hz), 2.4-2.8 (2H, m), 3.00 (1H, dd, J=7 . 2 , 13.8Hz), 3.1-3.4 (2H, m), 3.52 (1H, ddd, J=6.7, 7.2, 8.7Hz), 4.3-4.7 (1H, m), 4.39 (1H, d, J=17.4Hz), 4.62 (1H, d, J=17.4Hz), 6.9-7.5 (9H, m), 7.37 (1H, d, J=7.3Hz)
MASS (m/z) : 399 (M+1) Example 16
The following compounds were obtained according to a similar manner to that of Example 15.
1) 3(S)-[(2(R)-Mercapto-1-oxo-3-phenylpropyl)amino]-2- oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetic acid
[α]D 18 : -192.6° (C=0.87, CHCI3)
IR (Nujol) : 3300, 1735, 1640 cm-1
NMR (CDCI3, δ) : 1.5-1.8 (1H, m), 2.06 (1H, d,
J=9.1Hz), 2.3-2.7 (2H, m), 2.94 (1H, dd, J=6.7, 13.5Hz), 3.0-3.3 (2H, m), 3.40 (1H, ddd, J=6.7,
7.9, 9.1Hz), 4.3-4.6 (1H, m), 4.39 (1H, d,
J=17.4Hz), 4.66 (1H, d, J=17.4Hz), 6.6-7.4 (9H, m), 7.03 (1H, d, J=7.3Hz)
MASS (m/z) : 399 (M+1)
2) 3(R)-[(2(S)-Mercapto-1-oxo-3-phenylpropyl)amino]-2- oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetic acid
[α]D 20 : +231.5° (C=1.01, CH3OH)
IR (Nujol) : 3300, 1730, 1635 (br) cm-1
NMR (CDCI3, δ) : 1.5-1.8 (1H, m), 2.06 (1H, d,
J=9.0Hz), 2.4-2.8 (2H, m), 2.9-3.8 (4H, m), 4.40 (1H, d, J=17.4Hz), 4.3-4.6 (1H, m), 4.67 (1H, d, J=17.4Hz), 6.97 (1H, d, J=7.3Hz), 6.8-7.5 (9H, m)
MASS (m/z) : 399 (M+1)
3) 3(R)-[(2(R)-Mercapto-1-oxo-3-phenylpropyl)amino]-2- oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetic acid
[α]D 20 : +194.1° (C=1.01, CH3OH)
IR (Nujol) : 3300, 1730, 1635 cm-1 NMR (CDCI3, δ) : 1.9-2.0 (1H, m), 1.96 (1H, d,
J=8.7Hz), 2.5-2.7 (2H, m), 2.9-3.3 (3H, m), 3.4- 3.7 (1H, m), 4.3-4.6 (1H, m), 4.41 (1H, d,
J=17.4Hz), 4.65 (1H, d, J=17.4Hz), 7.1-7.4 (10H, m)
MASS (m/z) : 399 (M+l)
4) 3(S)-[2(S)-Mercapto-1-oxo-3-methylbutyl)amino]-2-oxo- 2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetic acid
[α]D 18 : -240.7° (C=1.03, CHCI3)
IR (Nujol) : 3300, 1725, 1630 cm-1
NMR (CDCI3, δ) : 0.92 (3H, d, J=6.4Hz), 0.95 (3H, d, J=6.4Hz), 1.84 (1H, d, J=8.7Hz), 1.9-2.3 (2H, m), 2.5-2.8 (2H, m), 3.11 (1H, dd, J=6.6,
8.7Hz), 3.2-3.4 (1H, m), 4.42 (1H, d, J=17.4Hz),
4.4-4.7 (1H, m), 4.68 (1H, d, J=17.4Hz), 7.1-7.5 (4H, m), 7.47 (1H, d, J=7.4Hz)
MASS (m/z) : 351 (M+1) 5) 3(S)-[(2(S)-Mercaptomethyl-1-oxo-3- phenylpropyl)amino]-2-oxo-2,3,4,5-tetrahydro-1H-1- benzazepine-1-acetic acid
[α]D 20 : -170.1° (C=1.01, CH3OH)
IR (Nujol) : 3300, 1730, 1655, 1630 cm-1
NMR (CDCI3, δ) : 1.43 (1H, t, J=8.4Hz), 1.9-2.1 (1H, m), 2.4-3.0 (7H, m), 3.1-3.3 (1H, m), 4.41 (1H, d, J=17.4Hz), 4.4-4.7 (1H, m), 4.67 (1H, d, J=17.4Hz), 6.73 (1H, d, J=7.2Hz), 7.0-7.4 (9H, m)
MASS (m/z) : 413 (M+1)
6) 3(S)-{[2(S)-Mercaptomethyl-3-(2-methylphenyl-1- oxopropyl]amino}-2-oxo-2,3,4,5-tetrahydro-1H-1- benzazepine-1-acetic acid
[α]D 20 : -164.9° (C=1.10, CH3OH) IR (Nujol) : 3300, 1730, 1630 (br) cm-1
NMR (CDCI3, δ) : 1.45 (1H, t, J=8.5Hz), 1.9-2.1 (1H, m), 2.25 (3H, s), 2.4-3.0 (7H, m), 3.1-3.3 (1H, m), 4.40 (1H, d, J=17.4Hz), 4.4-4.6 (1H, m), 4.68 (1H, d, J=17.4Hz), 6.65 (1H, d, J=7.2Hz),
7.0-7.4 (8H, m)
MASS (m/z) : 427 (M+1)
7) 3(S)-{[2(S)-Mercaptomethyl-3-(3,4- methylenedioxyphenyl)-1-oxopropyl]amino}-2-oxo- 2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetic acid
[α]D 20 : -138.3° (C=1.10, CH3OH)
IR (Nujol) : 3300, 1730, 1635 (br) cm-1
NMR (CDCI3, δ) : 1.43 (1H, t, J=8.4Hz), 1.9-2.1 (1H, m), 2.4-2.8 (7H, m), 3.2-3.3 (1H, m), 4.40 (1H, d, J=17.4Hz), 4.4-4.65 (1H, m), 4.67 (1H, d, J=17.4Hz), 5.90 (2H, s), 6.4-6.65 (3H, m), 6.82 (1H, d, J=7.5Hz), 7.1-7.4 (4H, m)
MASS (m/z) : 457 (M+1)
8) 3(S)-[(2(S)-Mercaptomethyl-3-methyl-1- oxobutyl)amino]-2-oxo-2,3,4,5-tetrahydro-1H-1- benzazepine-1-acetic acid
[α]D 20 : -271.4° (C=0.51, CH3OH)
IR (Nujol) : 3320, 1730, 1640, 1605 cm-1
NMR (DMSO-d6, δ) : 0.84 (3H, d, J=6.5Hz), 0.87 (3H, d, J=6.6Hz), 1.6-1.8 (1H, m), 1.99 (1H, t,
J=8.0Hz), 2.0-2.3 (3H, m), 2.5-2.87 (2H, m), 3.1-3.4 (2H, m), 4.2-4.4 (1H, m), 4.33 (1H, d, J=17.4Hz), 4.65 (1H, d, J=17.4Hz), 7.2-7.5 (4H, m), 8.18 (1H, d, J=7.9Hz)
MASS (m/z) : 365 (M+)
9) 4(S)-[(2(S)-Mercaptomethyl-3-methyl-1- oxobutyl)amino]-3-oxo-1,3,4,5-tetrahydro-2H-2- benzazepine-2-acetic acid
[α]D 20 : +52.8° (C=1.03, CH3OH)
IR (Nujol) : 3320, 1730, 1630, 1520 cm-1
NMR (CDCI3, δ) : 0.87 (3H, d, J=6.6Hz), 0.97 (3H, d, J=6.7Hz), 1.6-2.0 (1H, m), 2.12 (1H, t-like,
J=7.9Hz), 2.2-2.5 (1H, m), 2.5-2.8 (2H, m), 2.98 (1H, dd, J=12.8, 17.2Hz), 3.20 (1H, dd, J=4.4, 17.2Hz), 3.96 (1H, d, J=17.3Hz), 4.17 (1H, d, J=16.7Hz), 4.23 (1H, d, J=17.3Hz), 5.23 (1H, d, J=16.7Hz), 5.3-5.5 (1H, m), 7.0-7.3 (4H, m),
8.14 (1H, d, J=7.4Hz)
MASS (m/z) : 365 (M+1)
10) 4(S)-[(2(S)-Mercapto-1-oxo-3-phenylpropyl)amino]-3- oxo-1,3,4,5-tetrahydro-2H-2-benzazepine-2-acetic acid
[α]D 20 : +95.5° (C=0.47, CH3OH)
NMR (DMSO-d6, δ) : 2.6-3.4 (5H, m), 3.7-4.0 (2H, m), 4.14 (1H, d, J=17.6Hz), 4.24 (1H, d, J=17.2Hz), 5.1-5.5 (2H, m), 7.0-7.4 (9H, m), 8.32 (1H, d, J=6.9Hz)
MASS (m/z) : 399 (M+1)
11) 4(S)-[(2(S)-Mercapto-3-methyl-1-oxobutyl)amino]-3- oxo-1,3,4,5-tetrahydro-2H-2-benzazepine-2-acetic acid
[α]D 20 : +82.2° (C=0.51, CH3OH)
IR (Nujol) : 3310, 1730, 1630 cm-1
NMR (DMSO-d6, δ) : 0.94 (3H, d, J=6.6Hz), 0.99 (3H, d, J=6.7Hz), 1.8-2.1 (1H, m), 2.59 (1H, d,
J=9.5Hz), 2.92 (1H, dd, J=12.8, 16.9Hz), 3.20 (1H, dd, J=3.8, 16.9Hz), 3.3-3.5 (1H, m), 3.97
(1H, d, J=17.3Hz), 4.17 (1H, d, J=17.2Hz), 4.24 (1H, d, J=17.3Hz), 5.25 (1H, d, J=17.2Hz), 5.3- 5.5 (1H, m), 7.0-7.3 (4H, m), 8.31 (1H, d,
J=7.0Hz), 12.5 (1H, br s)
MASS (m/z) : 351 (M+1) 12) 4(S)-[(3-Mercapto-2(S)-methyl-1-oxopropyl)amino]-3- oxo-1,3,4,5-tetrahydro-2H-2-benzazepine-2-acetic acid
[α]D 20 : +52.6° (C=0.54, CH3OH)
IR (Nujol) : 3300, 1730, 1630 cm-1
NMR (DMSO-d6, δ) : 1.07 (3H, d, J=6.9Hz), 2.21 (1H, t-like, J=7.8Hz), 2.4-2.8 (3H, m), 2.90 (1H, dd, J=13.1, 17.2Hz), 3.20 (1H, dd, J=3.9, 17.2Hz), 3.95 (1H, d, J=17.3Hz), 4.17 (1H, d, J=16.6Hz), 4.25 (1H, d, J=17.3Hz), 5.23 (1H, d, J=16.6Hz), 5.3-5.5 (1H, m), 7.0-7.4 (4H, m), 8.14 (1H, d,
J=7.4Hz), 12.7 (1H, br s)
MASS (m/z) : 337 (M+1)
13) 4(S)-[(2(S)-Acetylthio-1-oxo-3-phenylpropyl)amino]- α(S)-methyl-3-oxo-1,3,4,5-tetrahydro-2H-2- benzazepine-2-acetic acid
[α]D 21 : + 55.7° (C=0.49, CH3OH)
IR (Nujol) : 3300, 1730, 1630 cm-1
NMR (DMSO-d6, δ) : 1.26 (3H, d, J=6.9Hz), 2.82 (1H, dd, J=7.6, 13.8Hz), 2.7-3.0 (1H, m), 3.19 (1H, dd, J=6.6, 13.8Hz), 3.1-3.4 (2H, m), 3.8-4.0 (1H, m), 4.16 (1H, d, J=17.2Hz), 4.84 (1H, quartet, J=6.9Hz), 5.14 (1H, d, J=17.2Hz), 5.1- 5.4 (1H, m), 7.0-7.4 (9H, m), 8.32 (1H, d,
J=6.8Hz), 12.4 (1H, br s)
MASS (m/z) : 413 (M+1)
14) 3(R)-[(2(S)-Mercapto-1-oxo-3-phenylpropyl)amino]-4- oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid
[α]D 19 : -202° (C=0.5, CH3OH)
IR (Nujol) : 3300, 1730, 1640, 1200 crn-1
NMR (DMSO-d6, δ) : 2.6-2.8 (2H, m), 2.9-3.2 (2H, m), 3.47 (1H, dd, J=6.7, 11.2Hz), 3.70 (1H, dd, J=7.4, 16.0Hz), 4.24 (1H, d, J=17.4Hz), 4.4-4.6 (1H, m), 4.63 (1H, d, J=17.4Hz), 7.1-7.4 (6H, m), 7.4-7.8 (3H, m), 8.55 (1H, d, J=8.2Hz) MASS (m/z) : 417 (M+l) 15) 3(R)-[(2(S)-Mercaptomethyl-1-oxo-3- phenylpropyl)amino]-4-oxo-2,3,4,5-tetrahydro-1,5benzothiazepine-5-acetic acid
IR (Nujol) : 3300, 1730, 1640, 1200 cm-1
NMR (DMSO-d6, δ) : 2.14 (1H, t, J=8.1Hz), 2.3-3.1 (6H, m), 3.4-3.6 (1H, m), 4.24 (1H, d,
J=17.3Hz), 4.4-4.7 (1H, m), 4.64 (1H, d,
J=17.3Hz), 7.0-7.4 (6H, m), 7.4-7.8 (3H, m), 8.53 (1H, d, J=8.4Hz), 12.8 (1H, br s) MASS (m/z) : 431 (M+1)
16) 4(S)-[(2(S)-Mercaptomethyl-1-oxo-3- phenylpropyl)amino]-α(S)-methyl-3-oxo-1,3,4,5- tetrahydro-2H-2-benzazepine-2-acetic acid
[α]D 19 : +61.4° (C=0.49, CH3OH)
IR (Nujol) : 1725, 1625 cm-1
NMR (CHCI3, δ) : 1.26 (3H, d, J=7.1Hz), 2.26 (1H, t, J=8.0Hz), 2.3-2.5 (1H, m), 2.5-2.8 (2H, m), 2.8- 3.1 (3H, m), 3.1-3.3 (1H, m), 4.18 (1H, d,
J=17.1Hz), 4.82 (1H, quartet, J=7.1Hz), 5.12 (1H, d, J=17.1Hz), 5.2-5.4 (1H, m), 6.8-7.2 (9H, m), 8.25 (1H, d, J=7.0Hz), 12.3 (1H, br s)
MASS (m/z) : 469 (M+1)
17) 3(S)-[2(S or R)-Mercapto-3-(3,4-methylenedioxyphenyl)-1-ox propyl]amino-2-oxo-2,3,4,5-tetrahydro- 1H-1-benzazepine-1-acetic acid (a single isomer) mp : 102-106°C (dec.)
[α]D 20 : -141.8° (C=0.50, MeOH)
IR (Nujol) : 3250, 2800-2500, 1720, 1650 (shoulder),
1630 cm-1 NMR (CDCI3, 6) : 1.8-2.1 (1H, m), 1.98 (1H, d,
J=8.9Hz), 2.55-2.8 (2H, m), 2.9-3.55 (4H, m), 4.43 (1H, d, J=17.4Hz), 4.65 (1H, d, J=17.4Hz), 4.4-4.6 (1H, m), 5.92 (2H, s), 6.5-6.75 (3H, m), 7.1-7.4 (5H, m)
MASS (m/z) : 443
18) 3(S)-[2(R or S)-Mercapto-3-(3,4-methylenedioxyphenyl)-1-oxopropyl]amino-2-oxo-2,3,4,5-tetrahydro- 1H-1-benzazepine-1-acetic acid (a single isomer) mp : 105-107°C (dec.)
[α]D 20 : -232.5° (C=0.52, MeOH)
IR (Nujol) : 3275, 2800-2500, 1720, 1625 cm-1
NMR (CDCI3, δ) : 1.65-1.85 (1H, m), 2.05 (1H, d,
J=9.1Hz), 2.45-2.75 (2H, m), 2.89 (1H, dd,
J=6.5, 13.6Hz), 3.0-3.45 (3H, m), 4.42 (1H, d, J=17.4Hz), 4.4-4.55 (1H, m), 4.68 (1H, d,
J=17.4Hz), 5.92 (2H, s), 6.55-6.8 (3H, m), 7.01 (1H, d, J=7.3Hz), 7.1-7.4 (4H, m)
MASS (m/z) : 443
19) 3(S)-[2(S or R)-Mercapto-3-(2-methylphenyl)-1- oxopropyl]amino-2-oxo-2,3,4,5-tetrahydro-1H-1- benzazepine-1-acetic acid (a single isomer)
mp : 98-103°C (dec.)
[α]D 20 : -164.9° (C=0.51, MeOH)
IR (Nujol) : 3280, 2850-2500, 1720, 1650 (shoulder),
1630 cm-1
NMR (CDCI3, δ) : 1.9-2.0 (1H, m), 2.01 (1H, d,
J=8.4Hz), 2.29 (3H, s), 2.5-2.8 (2H, m), 2.92
(1H, dd, J=7.8, 14.2Hz), 3.15-3.3 (2H, m), 3.45- 3.6 (1H, m), 4.42 (1H, d, J=17.4Hz), 4.4-4.5 (1H, m), 4.68 (1H, d, J=17.4Hz), 7.05-7.4 (9H, m)
MASS (m/z) : 413 20) 3(S)-[2(R or S)-Mercapto-3-(2-methylphenyl)-1- oxopropyl]amino-2-oxo-2,3,4,5-tetrahydro-1H-1- benzazepine-1-acetic acid (a single isomer)
mp : 100-104°C (dec.)
[α]D 20 : -257.8° (C=0.51, MeOH)
IR (Nujol) : 3275, 2800-2500, 1720, 1650 (shoulder),
1630 cm-1
NMR (CDCI3, δ) : 1.5-1.75 (1H, m), 2.12 (1H, d,
J=8.9Hz), 2.30 (3H, s), 2.4-2.7 (2H, m), 2.95 (1H, dd, J=6.5, 13.7Hz), 3.05-3.5 (3H, m), 4.41
(1H, d, J=17.4Hz), 4.4-4.55 (1H, m), 4.67 (1H, d, J=17.4Hz), 6.86 (1H, d, J=7.3Hz), 7.05-7.4 (8H, m)
MASS (m/z) : 413
Example 17
To a mixture of 4(S)-[(2(S)-acetylthiomethyl-1-oxo-3-phenylpropyl)amino]-3-oxo-1,3,4,5-tetrahydro-2H-2-benzazepine-2-acetic acid (0.85 g) in methanol (6.0 ml) was added 28% aqueous ammonia (1.14 ml) under nitrogen atmosphere. The resulting mixture was stirred under icewater cooling for 1.5 hours, poured into 5% aqueous potassium bisulfate solution (50 ml), and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by column-chromatography on silica gel (40 g) using a mixture of chloroform, methanol and acetic acid (50:2:1) as an eluent. The fractions containing the desired product were collected and
concentrated in vacuo, and the residue was pulverized with diethyl ether to afford a powder of 4(S)-[(2(S)-mercaptomethyl-1-oxo-3-phenylpropyl)amino]-3-oxo-1,3,4,5-tetrahydro-2H-2-benzazepine-2-acetic acid (0.56 g).
[α]D 20 : +117.1° (C=0.49, CH3OH)
IR (Nujol) : 3270, 1730, 1650, 1620, 1550 cm-1 NMR (DMSO-d6, δ) : 2.25 (1H, t, J=8.0Hz), 2.3-2.5
(1H, m), 2.5-2.8 (2H, m), 2.8-3.1 (3H, m), 3.23 (1H, dd, J=4.0, 17.0Hz), 3.95 (1H, d, J=17.3Hz), 4.17 (1H, d, J=16.6Hz), 4.25 (1H, d, J=17.3Hz), 5.23 (1H, d, J=16.6Hz), 5.3-5.5 (1H, m), 7.0-7.4
(9H, m), 8.25 (1H, d, J=7.3Hz), 12.7 (1H, br s)
MASS (m/z) : 412 (M+)
Example 18
To a mixture of dicyclohexylammonium 2(S)-benzoylthio-3-phenylpropionate (16.93 g), tert-butyl 3(S)-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetate (10.51 g) and 1-hydroxybenzotriazole hydrate (5.38 g) in dichloromethane (400 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (7.63 g) at 0°C. The reaction mixture was stirred overnight at ambient temperature. The precipitate was removed by filtration and washed with dichloromethane. The filtrate was
evaporated in vacuo. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was washed successively with saturated sodium bicarbonate solution, water and brine, dried over anhydrous magnesium sulfate and evaporated in vacuo to give colorless amorphous of tert-butyl 3(S)-[2(S)-benzoylthio-1-oxo-3-phenylpropyl]-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetate (18.56 g).
IR (Film) : 3175, 1730, 1650 cm-1
NMR (CDCI3, δ) : 1.39 (9H, s), 1.7-2.0 (1H, m), 2.5- 2.85 (2H, m), 3.11 (1H, dd, J=7.5, 14.1Hz), 3.2- 3.3 (1H, m), 3.35 (1H, dd, J=7.5, 14.1Hz), 4.23
(1H, d, J=17.0Hz), 4.35-4.55 (2H, m), 4.63 (1H, d, J=17.0Hz), 7.05-7.7 (13H, m), 7.92 (2H, d, J=7.3Hz) Example 19 To a solution of tert-butyl 3(S)-[2-acetylthio-3- (3,4-methylenedioxyphenyl)-1-oxopropyl]amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetate (1.85 g) in dichloromethane (37 ml) was added trifluoroacetic acid (3.92 ml) at 0°C. The reaction mixture was stirred overnight at ambient temperature and evaporated in vacuo. The residue was dissolved in toluene and evaporated azeotropically in vacuo for 'removal of excess
trifluoroacetic acid. The residue was purified twice by silica gel column chromatography using a mixture of n hexane, ethyl acetate and acetic acid (100:100:1) to ethyl acetate and acetic acid (100:1) as an eluent to afford two colorless amorphous of 3(S)-[2(S)-acetylthio-3-(3,4-methylenedioxyphenyl)-1-oxopropyl]amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetic acid and 3(S)-[2(R)-acetylthio-3-(3,4-methylenedioxyphenyl)-1-oxopropyl]amino-2-OXO-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetic acid (less polar compound, 0.79 g and more polar compound, 0.68 g).
A-isomer (less polar compound)
[α]D 15 : -145.4° (C=0.68, MeOH)
IR (Film) : 3350, 3000-2700, 1710 (shoulder),
1640 cm-1
NMR (CDCI3, δ) : 1.75-1.95 (1H, m), 2.31 (3H, s), 2.45-2.75 (2H, m), 2.84 (1H, dd, J=7.3 , 14.1Hz),
3.11 (1H, dd, J=7.6, 14.0Hz), 3.2-3.35 (1H, m), 4.15 (1H, t, J=7.5Hz), 4.41 (1H, d, J=17.3Hz), 4.4-4.55 (1H, m), 4.67 (1H, d, J=17.4Hz), 5.90 (2H, s), 6.55-6.75 (3H, m), 7.05-7.35 (5H, m) MASS (m/z) : 485
B-isomer (more polar compound)
[α]D 17 : -109.6° (C=0.74, MeOH)
IR (Film) : 3375, 3000-2700, 1720, 1670 (shoulder),
1650 cm-1 NMR (CDCI3, δ) : 1.65-1.9 (1H, m), 2.30 (3H, s),
2.4-2.7 (2H, m), 2.80 (1H, dd, J=6.6, 13.9Hz), 3.14 (1H, dd, J=9.0, 13.8Hz), 3.2-3.4 (1H, m), 4.11 (1H, dd, J=6.6, 8.9Hz), 4.36 (1H, d,
J=17.3Hz), 4.35-4.55 (1H, m), 4.67 (1H, d,
J=17.4Hz), 5.91 (2H, s), 6.6-6.75 (3H, m), 7.00 (1H, d, J=7.1Hz), 7.1-7.4 (4H, m)
MASS (m/z) : 485 Example 20
The following compounds were obtained according to a similar manner to that of Example 19.
3(S)-[2(S or R)-Acetylthio-3-(2-methylρhenyl)-1-oxopropyl]amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetic acid (A-isomer, less polar compound)
[α]D 17 : -190.7° (C=0.61, MeOH)
IR (Film) : 3350, 3000-2700, 1720, 1640 cm-1
NMR (CDCI3, δ) : 1.75-2.0 (1H, m), 2.29 (3H, s), 2.30 (3H, s), 2.45-2.8 (2H, m), 2.91 (1H, dd,
J=8.3, 14.4Hz), 3.15-3.35 (2H, m), 4.22 (1H, t, J=7.7Hz), 4.41 (1H, d, J=17.4Hz), 4.4-4.55 (1H, m), 4.68 (1H, d, J=17.4Hz), 7.0-7.4 (9H, m) MASS (m/z) : 455
3(S)-[2(R or S)-Acetylthio-3-(2-methylphenyl)-1-oxopropyl]amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetic acid (B-isomer, more polar compound)
[α]D 18 : -165.5° (C=0.6, MeOH)
IR (Film) : 3325, 3000-2600, 1720, 1675 (shoulder),
1640 cm-1
NMR (CDCI3, δ) : 1.55-1.75 (1H, m), 2.30 (3H, s), 2.33 (3H, s), 2.35-2.6 (2H, m), 2.91 (1H, d, J=6.8, 14.0Hz), 3.1-3.25 (1H, m), 3.24 (1H, dd, J=9.1, 14.0Hz), 4.18 (1H, dd, J=6.9, 9.0Hz), 4.36 (1H. d. J=17.5Hz), 4.35-4.55 (1H, m), 4.70 (1H, d, J=17.4Hz), 6.89 (1H, d, J=7.2Hz), 7.05- 7.4 (8H, m)
MASS (m/z) : 455

Claims

CLAIMS 1. A compound of the formula :
Figure imgf000055_0001
wherein R1 is hydrogen or a mercapto-protective
group,
R2 is hydrogen or aryl optionally substituted with lower alkylenedioxy,
R3 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,
and pharmaceutically acceptable salts thereof.
2. A compound according to claim 1,
wherein R1 is hydrogen, lower alkanoyl or aroyl, and
R3 is lower alkyl substituted with carboxy or esterified carboxy.
3. A compound according to claim 2,
wherein R2 is hydrogen.
4. A process for preparing a compound of the formula
Figure imgf000056_0003
wherein R1 is hydrogen or a mercapto-protective
group,
R2 is hydrogen or aryl optionally substituted with lower alkylenedioxy,
R3 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,
or salts thereof, which comprises, a) reacting a compound of the formula :
Figure imgf000056_0001
or its reactive derivative at the carboxy group or a salt thereof with a compound of the formula
Figure imgf000056_0002
or its salt to provide a compound of the formula
Figure imgf000057_0003
or its salt, in the above formulas,
R1, R2, R3 , A, X, Y, Z and n are each as defined
above, or b) subjecting a compound of the formula
Figure imgf000057_0002
or its salt to deesterification reaction to provide a compound of the formula :
Figure imgf000057_0001
or its salt, in the above formulas,
R1, R2, A, X, Y, Z and n are each as defined above.
Ra 3 is lower alkyl substituted with esterified carboxy, and
Rb 3 is lower alkyl substituted with carboxy, or c) subjecting a compound of the formula :
Figure imgf000058_0001
or its salt to elimination reaction of the mercapto- protective group to provide a compound of the formula :
Figure imgf000058_0002
or its salt, in the above formulas,
Ra 1 is a mercapto-protective group, and
R2, R3, A, X, Y, Z and n are each as defined above.
5. A pharmaceutical composition comprising a compound of claim 1, as an active ingredient, in association with a pharmaceutically acceptable, substantially non- toxic carrier or excipient.
6. A compound of claim 1 for use as a medicament,
7. Use of a compound of claim 1 for the manufacture of a medicament for the treatment and/or prevention of cardiovascular disorders, renal insufficiency, cyclic edema, hepatocirrhosis, hyperaldosteronism or hypercalciuria in human beings or animals.
PCT/JP1994/000784 1993-05-17 1994-05-12 Mercapto-amide derivatives useful as neutral endopeptidase and ace inhibitors WO1994026719A1 (en)

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JPH07509257A (en) 1995-10-12
GB9310075D0 (en) 1993-06-30

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