EP1073674A1 - Certains inhibiteurs thiol d'une enzyme de conversion d'endotheline - Google Patents

Certains inhibiteurs thiol d'une enzyme de conversion d'endotheline

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Publication number
EP1073674A1
EP1073674A1 EP99920729A EP99920729A EP1073674A1 EP 1073674 A1 EP1073674 A1 EP 1073674A1 EP 99920729 A EP99920729 A EP 99920729A EP 99920729 A EP99920729 A EP 99920729A EP 1073674 A1 EP1073674 A1 EP 1073674A1
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EP
European Patent Office
Prior art keywords
phenyl
alkyl
lower alkyl
aryl
substituted
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP99920729A
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German (de)
English (en)
Inventor
Stéphane De Lombaert
Cynthia Anne Fink
Fariborz Firooznia
Denton Wade Hoyer
Arco Yingcheu Jeng
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novartis Pharma GmbH
Novartis AG
Original Assignee
Novartis Erfindungen Verwaltungs GmbH
Novartis AG
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Publication of EP1073674A1 publication Critical patent/EP1073674A1/fr
Withdrawn legal-status Critical Current

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    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • 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
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • 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
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • 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
    • 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
    • A61P9/12—Antihypertensives
    • 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
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to the compounds of formula I below which have been discovered to be useful as endothelin-converting enzyme (ECE) inhibitors in mammals.
  • R represents monocyclic carbocyclic aryl substituted by cycloalkyl
  • R represents monocyclic carbocyclic aryl substituted by azacycloalkyl which is optionally substituted by lower alkyl or acyl;
  • Rj represents hydrogen or acyl
  • R 2 represents hydrogen, lower alkyl, carbocyclic or heterocyclic aryl, carbocyclic or heterocyclic aryl-lower alkyl, cycloalkyl, cycloalkyl-lower alkyl, biaryl, biaryl-lower alkyl,
  • R 3 represents hydrogen or lower alkyl; or R 2 and R 3 together with the carbon atom to which they are attached represent cycloalkylidene or benzo-fused cycloalkylidene;
  • a together with the carbon atom to which it is attached forms a ring and represents 3 to 10 membered cycloalkylidene or 5 to 10 membered cycloalkenylidene radical which may be substituted by lower alkyl or aryl-lower alkyl or may be fused to a saturated or unsaturated carbocyclic 5-7-membered ring; or A together with the carbon to which it is attached represents 5 to 6 membered oxacycloalkylidene, thiacycloalkylidene or azacycloalkylidene optionally substituted by lower alkyl, acyl or aryl-lower alkyl; or A together with the carbon atom to which it is attached represents 2,2-norbonylidene; m is zero or 1 -3;
  • Y represents 5-tetrazolyl, carboxyl or carboxyl derivatized in form of a pharmaceutically acceptable ester; disulfide derivatives derived from said compounds wherein Rj is hydrogen; or a pharmaceutically acceptable salts thereof; pharmaceutical compositions comprising said compounds; methods for preparation of said compounds; intermediates; and methods of treating disorders in mammals which are responsive to ECE inhibition by administration of said compounds to mammals in need of such treatment.
  • esters are preferably prodrug ester derivatives, such being convertible by solvolysis or under physiological conditions to the free carboxylic acids of formula I.
  • prodrug derivatives of compounds of the invention having a free carboxyl, sulfhydryl or hydroxyl group, said prodrug derivatives being convertible by solvolysis or under physiological conditions to the free carboxyl, sulfhydryl and/or hydroxyl compounds.
  • Prodrug derivatives are e.g. the esters of free carboxylic acids and S-acyl and O-acyl derivatives of thiols, or alcohols, wherein acyl has meaning as defined herein.
  • prodrug esters of carboxylic acids are preferably e.g. lower alkyl esters, cycloalkyl esters, lower alkenyl esters, aryl-lower alkyl esters, ⁇ -(lower alkanoyloxy)-lower alkyl esters such as the pivaloyloxy-methyl ester, and ⁇ -(lower alkoxycarbonyl- or di-lower alkylamino carbonyl-)-lower alkyl esters.
  • Pharmaceutically acceptable salts are salts derived from pharmaceutically acceptable bases for any acidic compounds of the invention, e.g. those wherein Y represents carboxyl.
  • Such are e.g. alkali metal salts (e.g. sodium, potassium salts), alkaline earth metal salts (e.g. magnesium, calcium salts), amine salts (e.g. tromethamine salts).
  • Preferred as endothelin converting enzyme inhibitors are the compounds with the S- configuration of formula II R
  • R represents benzothiophenyl, naphthyl, benzofuranyl, indolyl, or monocyclic carbocyclic aryl substituted by monocyclic carbocyclic aryl or by monocyclic heterocyclic aryl;
  • Ri represents hydrogen or carboxyl derived acyl;
  • R 2 represents lower alkyl, hydroxy-lower alkyl, (lower alkylthio- or lower alkoxy-)lower alkyl, carbocyclic or heterocyclic aryl, carbocyclic or heterocyclic aryl-lower alkyl, cycloalkyl, cycloalkyl-lower alkyl, or biaryl-lower alkyl;
  • Y represents 5-tetrazolyl, carboxyl or carboxyl derivatized in form of a pharmaceutically acceptable ester;
  • n represents 2-6, preferably 2, 4 or 5; disulfide derivatives derived from said compounds wherein R « is hydrogen; or a pharmaceutically
  • R ⁇ represents hydrogen, aryl-lower alkanoyl, lower alkanoyl, lower alkoxy-lower alkanoyl, or heterocyclic or carbocyclic aroyl
  • R 2 represents C 2 -C 4 alkyl interrupted by S or O, C 2 -C 5 -alkyl or cyclohexyl
  • Y represents 5-tetrazolyl, carboxyl, lower alkoxycarbonyl, carbocyclic or heterocyclic aryl-lower alkoxycarbonyl, ⁇ -(lower alkanoyloxy-, lower alkoxycarbonyl- or di- lower alkylaminocarbonyl-)lower alkoxycarbonyl
  • n is 2, 4 or 5; or a pharmaceutically acceptable salt thereof.
  • R represents benzothiophenyl, naphthyl, benzofuranyl, indolyl, or monocyclic carbocyclic aryl substituted by monocyclic carbocyclic aryl or by monocyclic heterocyclic aryl;
  • R t represents hydrogen, lower alkanoyl, methoxy-lower alkanoyl, benzoyl or pyridylcarbonyl;
  • R represents benzothiophenyl, naphthyl, benzofuranyl, indolyl or monocarbocyclic aryl substituted by monocyclic carbocyclic aryl or by monocyclic heterocyclic aryl;
  • R 2 represents C 2 -C 5 -alkyl, cyclohexyl or C 2 -C 4 -alkyl interrupted by O or S; - 6 -
  • Y represents 5-tetrazolyl, carboxyl, lower alkoxycarbonyl, benzyloxycarbonyl, pyridylmethoxycarbonyl, ⁇ -(lower alkanoyloxy-, lower alkoxycarbonyl- or di-lower alkylaminocarbonyl-) lower alkoxycarbonyl; or a pharmaceutically acceptable salt thereof.
  • a particular aspect of the invention is directed to the novel compounds of formulae I, II, III, Ilia and lllb wherein
  • R represents 3-indolyl, 4- (5-isoxazolyl)-phenyl, 4-(2- or 3-pyrrolyl)phenyl, 4-(2- or 3-furanyl)phenyl, 4-(2- or 3- thienyl)phenyl, 4-(2- or 3-pyridyl)-phenyl, piperidin-3-yl-phenyl which is N-unsubstituted or N- substituted by lower alkanoyl, or represents 4-(5-pyrimidinyl)-phenyi, naphthyl, 5,6,7,8- tetrahydro-naphthalen-1 -yl, 5,6,7,8-tetryhydro
  • Y is methoxycarbonyl, R « is acetyl, R 2 is n-propyl and R is 4-biphenylyl; and pharmaceutically acceptable salts thereof.
  • Y is carboxyl, R « is hydrogen, R 2 is isobutyl and R is 3-indolyl; and pharmaceutically acceptable salts thereof.
  • Y is methoxycarbonyl, R 2 is isobutyl and R is 3-indolyl.
  • Aryl represents carbocyclic or heterocyclic aryl, either monocyclic or bicyclic.
  • Monocyclic carbocyclic aryl represents optionally substituted phenyl, being preferably phenyl or phenyl substituted by one to three substituents, such being advantageously lower alkyl, hydroxy, lower alkoxy, acyloxy, halogen, cyano, trifluoromethyl, amino, lower alkanoylamino, lower alkyl-(thio, sulfinyl or sulfonyl), lower alkoxycarbonyl, mono- or di-lower alkylcarbamoyl, or mono- or di-lower alkylamino.
  • Bicyclic carbocyclic aryl represents 1 - or 2-naphthyl or 1 - or 2-naphthyl preferably substitued by lower alkyl, lower alkoxy or halogen.
  • Optionally substituted furanyl represents 2- or 3-furanyl or 2- or 3-furanyl preferably substituted by lower alkyl.
  • Optionally substituted pyridyl represents 2-, 3- or 4-pyridyl or 2-, 3- or 4-pyridyl preferably substituted by lower alkyl, halogen or cyano.
  • Optionally substituted thienyl represents 2- or 3-thienyl or 2- or 3-thienyl preferably substituted by lower alkyl or hydroxy-lower alkyl.
  • Optionally substituted thiazolyl represents e.g. 4-thiazolyl, or 4-thiazolyl substituted by lower alkyl.
  • Optionally substituted pyrimidinyl represents 2-, 4- or 5-pyridridinyl or 2-, 4- or 5- pyrimidinyl preferably substituted by lower alkyl.
  • Optionally substituted oxazolyl represents 2-, 4- or 5-oxazolyl or 2-, 4- or 5-oxazolyl preferably substituted by lower alkyl.
  • Optionally substituted pyrrolyl represents 1 -, 2- or 3-pyrrolyl or 1 -, 2- or 3- pyrrolyl preferably substituted by lower alkyl.
  • Optionally substituted imidazolyl represents 1 -, 2- or 4- imidazolyl or 1-, 2- or 4- imidazolyl preferably substituted by lower alkyl.
  • Optionally substituted oxadiazolyl represents 3- or 5- [1 , 2, 4] oxadiazolyl or 3- or 5- [1 , 2, 4] oxadiazolyl preferably substituted by lower alkyl.
  • Bicyclic heterocyclic aryl represents preferably benzothiophenyl, benzofuranyl, indolyl or benzothiazolyl optionally substituted by hydroxy, lower alkyl, lower alkoxy or halogen, advantageously 3-indolyl, 2-benzothiazolyl, 2-benzofuranyl or 3-benzo[b]thiophenyl.
  • Aryl in aryl-lower alkyl is preferably phenyl or phenyl substituted by one or two of lower alkyl, lower alkoxy, hydroxy, lower alkanoyloxy, halogen, trifluoromethyl, cyano, lower alkanoylamino or lower alkoxycarbonyl; also, optionally substituted naphthyl.
  • Aryl-lower alkyl is advantageously benzyl or 1- or 2-phenethyl optionally substituted on phenyl by one or two of lower alkyl, lower alkoxy, hydroxy, lower alkanoyloxy, halogen or trifluoromethyl.
  • lower referred to herein in connection with organic radicals or compounds respectively defines such with up to and including 7, preferably up toand including 4 and advantageously one or two carbon atoms. Such may be straight chain or branched.
  • a lower alkyl group preferably contains 1-4 carbon atoms and represents for example ethyl, propyl, butyl or advantageously methyl.
  • Cycloalkyl represents a saturated cyclic hydrocarbon radical which preferably contains 5 to 7 ring carbons, preferably cyclopentyl or cyclohexyl.
  • cycloalkyl(lower) alkyl represents preferably 1 - or 2-(cyclopentyl or cyclohexyl)ethyl, 1 -, 2- or 3-(cyclopentyl or cyclohexyl)propyl, or 1-, 2-, 3- or 4-(cyclopentyl or cyclohexyl)-butyl. - 10 -
  • a lower alkoxycarbonyl group preferably contains 1 to 4 carbon atoms in the alkoxy portion and represents, for example, methoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl or advantageously ethoxycarbonyl.
  • Cycloalkylidene is 3 to 10 membered, preferably 3, 5 or 6-membered, and represents a cycloalkane linking group e.g. cyclopropylidene, cyclopentylidene, cyclohexyiidene, cycloheptylidene or cyclooctylidene, in which the two attached groups are attached to the same carbon of the cycloalkane ring.
  • a cycloalkane linking group e.g. cyclopropylidene, cyclopentylidene, cyclohexyiidene, cycloheptylidene or cyclooctylidene, in which the two attached groups are attached to the same carbon of the cycloalkane ring.
  • Cycloalkylidene fused to a saturated carbocyclic ring represents e.g. perhydronaphthylidene.
  • Cycloalkylidene fused to an unsaturated carbocyclic ring represents e.g. 1 ,1 - or 2,2- tetralinylidene or 1 ,1- or 2,2-indanylidene.
  • Membered oxacycloalkylidene represents preferably a tetrahydrofuran or tetrahyd ropy ran linking group, e.g. tetrahydrofuranylidene or tetrahydropyranylidene, in which the two attached groups are attached to the same carbon atom of the respective rings, e.g. at the 3 or 4 position thereof.
  • Membered thiacycloalkylidene represents preferably a tetrahydrothiophene or tetrahydrothiopyran linking group in which the two attached groups are attached to the same carbon atom of the respective rings, e.g. at the 3 or 4 position thereof.
  • azacyloalkylidene represents preferably a pyrrolidine or piperidine linking groups in which the two attached groups are attached to the same carbon atom of the respective rings, e.g. at the 3 or 4 position thereof, and the nitrogen may be substituted by lower alkyl, e.g. methyl, or by aryl-lower alkyl, e.g. benzyl.
  • Acyl is derived from a carboxylic acid and represents preferably optionally substituted lower alkanoyl, cycloalkylcarbonyl, carbocyclic aryl-lower alkanoyl, aroyl, lower alkoxycarbonyl or aryl-lower alkoxycarbonyl, advantageously optionally substituted lower alkanoyl or aroyl.
  • Lower alkanoyl is preferably acetyl, propionyl, butanoyl, pentanoyl, or pivaloyl.
  • Aryl-lower alkoxycarbonyl is preferably monocyclic carbocyclic-lower alkoxycarbonyl, advantageously benzyloxycarbonyl.
  • Biaryl represents for example 4-biphenylyl.
  • the compounds of the invention are thus particularly useful in mammals for the treatment of e.g. hypertension and heart failure, cerebrovascular disorders, e.g. cerebral vasospasm and stroke, acute and chronic renal failure, penile erectile dysfunction, pulmonary disorders e.g. bronchial asthma, and complications associated with organ transplantation.
  • cerebrovascular disorders e.g. cerebral vasospasm and stroke
  • acute and chronic renal failure e.g. cerebral vasospasm and stroke
  • penile erectile dysfunction e.g. bronchial asthma
  • complications associated with organ transplantation e.g. hypertension and heart failure
  • cerebrovascular disorders e.g. cerebral vasospasm and stroke
  • penile erectile dysfunction e.g. bronchial asthma
  • complications associated with organ transplantation e.g. hypertension and heart failure
  • cerebrovascular disorders e.g. cerebral vasospasm and stroke
  • penile erectile dysfunction e.g. bronchi
  • the above-cited properties are demonstrable in vitro and in vivo tests, using advantageously mammals, e.g. mice, rats, dogs, monkeys or isolated organs, tissues and preparations thereof.
  • Said compounds can be applied in vitro in the form of solutions, e.g. preferably aqueous solutions, and in vivo either enterally, parenterally, advantageously intravenously, e.g. as a suspension or in aqueous solution.
  • the dosage in vitro may range between about 10 "5 molar and 10 "9 molar concentrations.
  • the dosage in vivo may range depending on the route of administration, between about 0.1 and 50 mg/kg, advantageously between about 1.0 and 25 mg/kg.
  • ECE inhibiton can be determined as described in Biochem. Mol. Biol. Int. 31, (5), 861 -867 (1993), by radioimmunoassay to measure ET-1 formed from big ET-1.
  • recombinant human ECE-1 (rhECE-1 ) can be used, as follows:
  • rhECE-1 Chinese hamster ovary cells expressing recombinant human endothelin converting enzyme-1 (rhECE-1 ; Kaw, S.; Emoto, N.; Jeng, A.; Yanagisawa, M. 4th Int. Conf. on Endothelin; April 23-25, London (UK), 1995; C6) are cultured in DMEM/F12 medium containing 10% fetal bovine serum and 1x antibiotic-antimycotic.
  • Cells are harvested by scraping, pelleted by centrifugation, and homogenized at 4 °C in a buffer containing 5 mM MgCI 2 , 1 ⁇ M pepstatin A, 100 ⁇ M leupeptin, 1 mM PMSF, and 20 mM Tris, pH 7.0, with a ratio of 2 mL of buffer/mL of cells.
  • the cell debris is removed by brief centrifugation, and the supernatant is centrifuged again at 100,000 x g for 30 minutes.
  • the resulting pellet is resuspended in a buffer containing 200 mM NaCI and 50 mM Tes, pH 7.0, at a protein concentration about 15 mg/mL and stored in aliquots at -80°C.
  • a concentration-response curve of each inhibitor is determined.
  • An IBM-compatible version of ALLFIT program is used to fit data to a one-site model.
  • the compound of Example 5j demonstrates an IC 50 of about 11 nM in the in vitro assay for rh-ECE-1 inhibition.
  • Endothelin converting enzyme inhibition can also be determined in vivo by measuring the inhibition of big ET-1 -induced pressor response in the anesthesized or conscious rat, as described below.
  • the effect of the inhibitors on the pressor response resulting from big ET- 1 challenge is measured in Sprague-Dawley rats as described in Biochem. Mol. Biol. Int. 31_, (5), 861 -867 (1993). Results are expressed as percent inhibition of the big ET-1 -induced pressor response as compared to vehicle.
  • mice Male Sprague-Dawley rats are anesthetized with Inactin (100 mg/kg i.p.) and instrumented with catheters in the femoral artery and vein to record mean arterial pressure (MAP) and administer compounds, respectively.
  • MAP mean arterial pressure
  • a tracheostomy is performed and a cannula inserted into the trachea to ensure airway patency.
  • the body temperature of the animals is maintained at 37 ⁇ 1 °C by means of a heating blanket.
  • MAP is allowed to stabilize before interrupting autonomic neurotransmission with chlorisondamine (3 mg/kg i.v.).
  • Rats are then treated with the test compound at 10 mg/kg i.v. or vehicle and challenged with big ET-1 (1 nmol/kg i.v.) 15 min and 90 min later.
  • big ET-1 (1 nmol/kg i.v.
  • mice Male Sprague-Dawley rats are anesthetized with methohexital sodium (75 mg/kg i.p.) and instrumented with catheters in the femoral artery and vein to measure mean arterial pressure (MAP) and administer drugs, respectively.
  • the catheters are threaded through a swivel system that enables the rats to move freely after regaining consciousness.
  • the rats are allowed to recover from this procedure for 24 h before initiating the study.
  • MAP is recorded via the femoral artery catheter and a test compound or vehicle is adminstered via the femoral vein. Animals are challenged with big ET-1 at 1 nmol/kg i.v. at various times after dosing.
  • animals can be re-tested at another dose of test compound or vehicle.
  • the data are reported as the change in MAP produced by big ET-1 at 2- minute intervals in animals treated with the test compound as compared to vehicle.
  • ECE inhibition can also be determined in vivo by measuring the inhibition of the big ET-1 induced pressor response in conscious spontaneously hypertensive rats (SHR), e.g. as described in Biochem. Biophys. Res. Commun. 204, 407-412 (1994).
  • SHR conscious spontaneously hypertensive rats
  • the combined effect is beneficial for e.g. the treatment of cardiovascular disorders in mammals such as hypertension, congestive heart failure and renal failure.
  • the compounds of the invention can generally be prepared according to methodology described in U.S. Patent 5,506,244, in particular using the processes described and illustrated below, e.g.
  • R, m, X and Y' have meaning as defined above;
  • Suitable protecting groups for the preparation of the 5-tetrazolyl compounds are the protecting groups customarily used in tetrazole chemistry, especially triphenylmethyl, unsubstituted or substituted, (for example nitro-substituted), benzyl such as 4-nitrobenzyl, lower alkoxymethyl such as methoxy- and ethoxymethyl, also 1 -ethoxyethyl, lower alkylthiomethyl such as methylthiomethyl, silyl such as tri-lower alkylsilyl, for example - 19 -
  • the displacement is carried out in an inert solvent, such as dimethylformamide, methylene chloride or THF in the presence of a base such as potassium carbonate, triethylamine, diisopropylethylamine, N-methylmorpholine, and the like at room or elevated temperatures.
  • an inert solvent such as dimethylformamide, methylene chloride or THF
  • a base such as potassium carbonate, triethylamine, diisopropylethylamine, N-methylmorpholine, and the like at room or elevated temperatures.
  • the starting materials of formula VIII can be prepared by reacting the amide derivative of formula IV with an acid of the formula
  • Acids of formula XII e.g. wherein Z is bromo, can be prepared from the corresponding ⁇ -aminoacids according to methods well known in the art.
  • active acids of formula XII can be obtained from optically active ⁇ -aminoacids as illustrated herein.
  • compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers.
  • adjuvants such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers.
  • the compositions may also contain other therapeutically valuable substances.
  • Said compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1 to 75%, preferably about 1 to 50%, of the active ingredient. - 30 -
  • R and S are used to indicate the absolute configuration at each asymmetric center.
  • L-Amino acids as used herein correspond to the S-configuration.
  • the stereo chemical configuration, as assigned to the products of the examples, is indicated in a conventional manner in the respective structural formulae.
  • the starting material is prepared as follows:
  • the starting material is prepared from ⁇ R-bromo- ⁇ S-hydroxybutanoic acid.
  • Ra ⁇ R-mercapto- ⁇ R-hydroxybutanoyl; mp 155-160 °C;
  • NBS N-bromosuccinimide
  • 2-methoxy-biphenyl-4-yl 2-methoxy-biphenyl-4-yl-methanol
  • triphenyl phosphine 2.0 g, 7.0 mmol
  • the cooling bath is removed and the reaction mixture is stirred at room temperature overnight.
  • the reaction mixture is then concentrated in vacuo, and the residue is purified by chromatography on silica gel (10% EtOAc/hexane) to furnish 4-bromomethy!-2-methoxy-biphenyl as a clear, colorless oil.
  • the 2-amino-3-(2-methoxybiphenyl-4-yl)-propionic acid methyl ester hydrochloride intermediate is prepared from 4-bromomethyl-2-methoxy-biphenyl according to the procedure reported by Williams and Im (J. Am. Chem. Soc. 1991 , 113, 9726). White solid; 1 H NMR (250 MHz, CD3OD) ⁇ 7.25-7.47 (m, 6 H), 6.96 (s, 1 H), 6.92 (d, 1 H), 4.39 (dd, 1 H), 3.86 (s, 3 H), 3.81 (s, 3 H), 3.19 (dd, 1/2 of CH2 ABX, 1 H, the other H buried under solvent peak).
  • the 4-bromomethyl-2-methoxy-biphenyl starting material is prepared as follows:
  • 3-Methoxy-4-trifluoromethanesulfonyloxybenzaldehyde is prepared from 4-hydroxy-3- methoxybenzaldehyde oil; 1 H NMR (250 MHz, CD3OD) 6 9.95 (s, 1 H), 7.55 (d, 1 H), 7.50 (dd, 1 H), 7.40 (d, 1 H), 3.97 (s, 3 H). Such is converted to 2-methoxy-biphenyl-4- carboxaldehyde according to the procedure reported in Chem. Rev.
  • 4-bromomethyl-2,2 ' -dimethoxy-biphenyl is prepared according to the procedure described above for the synthesis of 4-bromomethyl-2-methoxy-biphenyi; 1 H NMR (250 MHz, CDCI3) 6 7.35 (dt, 1 H), 7.20-7.28 (m, 2 H), 6.90-7.10 (m, 4 H), 4.53 (s, 2 H), 3.78 (s, 3 H), 3.76 (s, 3 H).
  • the starting material is prepared as follows:
  • Bisbenzoyl peroxide (560 mg, 0.232 mmol) is added to a solution of 2.17 g (13.65 mmol) of 5-(4-methyl-phenyl)-isoxazole (Lin, Y.-i.; Lang, Jr., S. A. J. Org. Chem. 1980, 45, 4857) and N-bromosuccinimide (2.43 g, 13.65 mmol) in 64 mL of CCI 4 , and the reaction mixture is heated at reflux overnight.
  • 2-Amino-3-(4-isoxazole-5-yl-phenyl)-propionic acid hydrochloride is prepared according to the procedure of Stork et al. (J. Org. Chem. 1976, 41, 3491 ) using NaHMDS as the base, from 5-(4-bromomethyl-phenyl)-isoxazole; white solid; 1 H NMR (300 MHz, CD 3 OD) ⁇ 8.43 (d, 1 H), 7.86 (d, 2H), 7.43 (d, 2 H), 6.81 (d, 1 H), 4.35 (t, 1 H), 4.25 (q, 2 H), 3.21-3.34 (m, 2 H), 1.23 (t, 3 H).
  • the starting material is prepared as follows:
  • Trifluoromethanesulfonic anhydride (7.1 mmol) is added slowly dropwise to a solution of 2-[(1 -te/ ⁇ -butoxycarbonylamino-cyclopentanecarbonyl)-amino]-3-(4-hydroxy- phenyl)-propionic acid ethyl ester (2.70 g, 6.4 mmol) and 0.7 mL (8.7 mmol) of pyridine in 20 mL of CH 2 CI 2 at 0 °C, and the solution is stirred at 0 °C for 1 hour. The reaction mixture is then partitioned between water and CH 2 CI 2 .
  • the Boc-protected boronophenylalanine reagent 2-(N-f-Boc-amino)-3-[4-(4,4,5,5- tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-phenyl]propionic acid ethyl ester (see Roberts et al., Tetrahedron Letters 1980, 21 , 3435) is condensed with 1 -acetoxy-2-iodobenzene in the Suzuki coupling reaction followed by coupling to N-f-Boc-cycloleucine methyl ester to obtain the intermediate

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Abstract

L'invention concerne les composés de la formule (I) comme inhibiteurs de l'enzyme de conversion d'endothéline, les variables ayant les significations données antérieurement.
EP99920729A 1998-04-23 1999-04-21 Certains inhibiteurs thiol d'une enzyme de conversion d'endotheline Withdrawn EP1073674A1 (fr)

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US6526598A 1998-04-23 1998-04-23
US65265 1998-04-23
PCT/EP1999/002690 WO1999055726A1 (fr) 1998-04-23 1999-04-21 Certains inhibiteurs thiol d'une enzyme de conversion d'endotheline

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US6426354B1 (en) 1998-04-23 2002-07-30 Novartis Ag Certain heteroaryl substituted thiol inhibitors of endothelin-converting enzyme
US6423727B1 (en) 1998-04-23 2002-07-23 Novartis Ag Certain thiol inhibitors of endothelin-converting enzyme
AU2001254776A1 (en) * 2000-04-06 2001-10-23 Novartis Ag Organic compounds
US6777443B2 (en) * 2001-05-15 2004-08-17 Novartis Ag Dipeptide derivatives
ATE342261T1 (de) * 2001-09-21 2006-11-15 Novartis Pharma Gmbh Pyranderivate als inhibitoren von ace und nep
US6919343B2 (en) 2002-02-08 2005-07-19 Merck & Co., Inc. N-biphenyl(substituted methyl) aminocycloalkane-carboxamide derivatives
EP1476419B1 (fr) 2002-02-08 2006-02-01 Merck & Co., Inc. Derives de n-biphenylmethyl aminocycloalcanecarboxamide
EP1481967B1 (fr) 2002-03-05 2011-05-04 Sumitomo Chemical Company, Limited Procede de preparation de composes biaryle
US20060183753A1 (en) * 2002-12-20 2006-08-17 Bayer Healthcare Ag Use of substituted 2,5-diamidoindoles for the treatment of urological diseases
US7427611B2 (en) 2003-09-26 2008-09-23 Solvay Pharmaceuticals Gmbh Amidomethyl-substituted 1-(carboxyalkyl)-cyclopentyl-carbonylamino-benzazepine-N-acetic acid compounds, process and intermediate products for their preparation and pharmaceutical compositions containing them
US7452875B2 (en) 2003-09-26 2008-11-18 Solvay Pharmaceuticals Gmbh Amidomethyl-substituted 1-(carboxyalkyl) cyclopentyl-carbonylamino-benzazepine-N-acetic acid compounds, process and intermediate products for their preparation and pharmaceutical compositions containing them
US7262184B2 (en) 2003-09-26 2007-08-28 Solvay Pharmaceuticals Gmbh Amidomethyl-substituted 1-(carboxyalkyl) cyclopentyl-carbonylamino-benzazepine-N-acetic acid compounds, process and intermediate products for their preparation and pharmaceutical compositions containing them
CA2551789C (fr) * 2004-01-12 2011-05-03 Solvay Pharmaceuticals B.V. Inhibiteurs de l'endopeptidase neutre (nep) et de l'endopeptidase soluble humaine (hsep) et traitement des troubles neurodegeneratifs
US8829209B2 (en) 2006-01-11 2014-09-09 Seikagaku Corporation Cycloalkylcarbonylamino acid ester derivative and process for producing the same
JP3975226B2 (ja) 2006-01-11 2007-09-12 生化学工業株式会社 シクロアルキルカルボニルアミノ酸誘導体及びその製造方法
JP4047365B2 (ja) 2006-01-11 2008-02-13 生化学工業株式会社 シクロアルカンカルボキサミド誘導体及びその製造方法
EP2543368A1 (fr) 2007-12-11 2013-01-09 Viamet Pharmaceuticals, Inc. Inhibiteurs de métalloenzymes utilisant des fractions de liaison à un métal en combinaison avec des fractions de ciblage
CN104725279B (zh) * 2015-02-12 2018-03-02 威海迪素制药有限公司 一种N‑Boc‑联苯丙氨酸衍生物的制备方法

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RU2126418C1 (ru) * 1993-11-01 1999-02-20 Циба-Гейги Джапан Димитед Антагонисты рецепторов эндотелина
PT655461E (pt) * 1993-11-16 2000-11-30 Novartis Ag Derivados ciclicos de aminoacidos
FR2745571B1 (fr) * 1996-03-04 1998-06-19 Inst Nat Sante Rech Med Nouveaux derives soufres comportant une liaison amide, leur procede de preparation, leur application a titre de medicaments, et les compositions pharmaceutiques les renfermant

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SK15812000A3 (sk) 2001-03-12
HUP0101640A2 (hu) 2001-09-28
CA2323691A1 (fr) 1999-11-04
BR9909805A (pt) 2000-12-26
WO1999055726A1 (fr) 1999-11-04
JP2002513032A (ja) 2002-05-08
HUP0101640A3 (en) 2002-10-28
AU3819999A (en) 1999-11-16
ZA200004680B (en) 2001-04-25
PL343594A1 (en) 2001-08-27
RU2000129510A (ru) 2002-11-10
CN1297453A (zh) 2001-05-30
NO20005293L (no) 2000-12-18
IL138246A0 (en) 2001-10-31
ID26822A (id) 2001-02-15
KR20010034816A (ko) 2001-04-25
JP4350306B2 (ja) 2009-10-21

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