JP2002513032A - Thiol-type inhibitors of endothelin converting enzymes - Google Patents

Abstract

(57) [Summary] Described as endothelin converting enzyme inhibitors are those of formula (I) Wherein the variables are as defined above.

Description

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds of the following formula I, which are mammalian endothelin converting enzymes (ECE)
) It was found to be useful as an inhibitor.

The thiol derivatives described herein inhibit the formation of endothelin, reduce plasma and tissue levels of endothelin, and inhibit the physiological effects of endothelin activity in mammals.

The present invention provides a method for inhibiting ECE and endothelin-dependent diseases or disorders using the following compounds, such as essential hypertension, vasoconstriction, congestive heart failure, pulmonary hypertension, cerebral ischemia (stroke), Subarachnoid hemorrhage, traumatic brain injury, acute and chronic renal failure, atherosclerosis, cerebral vasospasm, restenosis, Raynaud's disease, myocardial infarction, obesity; or respiratory diseases such as bronchial asthma; Gastrointestinal disorders such as inflammation, pancreatitis, vomiting; transplant rejection such as prostate hyperplasia, migraine, diabetes (diabetic nephropathy), preeclampsia, glaucoma, and aortic or solid organ transplantation in allogeneic or xenotransplantation And treatment and / or prevention of erectile dysfunction.

[0004] The present invention also relates to ECE inhibiting pharmaceutical compositions and novel compounds described herein.

[0005] Certain compounds that have been discovered to have novel ECE inhibitory uses are disclosed in US Pat. No. 5,506,24 as angiotensin converting enzymes and as neutral endopeptidase inhibitors.
No. 4 (incorporated herein by reference). Compounds of the following formula III wherein Y is carboxyl or esterified carboxyl, R is 4-biphenylyl, 3-indolyl or 5-hydroxy-3-indolyl, and R ₂ is isopropyl are exemplified in the patent. I have.

The present invention provides compounds of formula I

Embedded image Wherein R is a bicyclic carbocyclic aryl or a bicyclic heterocyclic aryl; or a fully or partially saturated form thereof; or R is a cycloalkyl-substituted monocyclic carbocycle R is a monocyclic carbocyclic aryl optionally substituted by lower alkyl or azabicyclo optionally substituted by acyl; or R is cycloalkyl substituted by cycloalkyl or azacycloalkyl; R ₁ is hydrogen or acyl; R ₂ is hydrogen, lower alkyl, carbocyclic or heterocyclic aryl, carbocyclic or heterocyclic aryl-lower alkyl, cycloalkyl, cycloalkyl-lower alkyl, biaryl, biaryl-lower Alkyl, (hydroxy, lower alkoxy or acyloxy) -lower alkyl, or lower Alkyl - (thio, sulfinyl or sulfonyl) - lower alkyl; - the fusion cycloalkylidene or R ₂ and R ₃ together with the carbon atom to which they are attached cycloalkylidene or benzo; R ₃ is hydrogen or lower alkyl A forms a ring with the carbon atom to which it is attached to form a 3- to 10-membered cycloalkylidene or 5- to 10-membered cycloalkenylidene group, which is substituted with lower alkyl or aryl-lower alkyl. Or A may be fused to a saturated or unsaturated carbocyclic 5- to 7-membered ring; or A together with the carbon atom to which it is attached, optionally lower alkyl, acyl or aryl-lower. 5- to 6-membered oxacycloalkylidene, thiacycloalkylidene optionally substituted with alkyl Or azacycloalkylidene; or A together with the carbon atom to which it is attached, refers to 2,2-norbornylidene; m is 0 or 1-3; Y is 5-tetrazolyl, carboxyl or pharmaceutically acceptable A disulfide derivative derived from the compound wherein R ₁ is hydrogen; or inhibition of endothelin converting enzyme using a pharmaceutically acceptable salt thereof; A method of treating a disease in a mammal responsive to ECE inhibition by administering the compound to a mammal in need of such treatment.

The pharmaceutically acceptable esters are preferably prodrug ester derivatives, which are convertible by solvolysis or under physiological conditions to the free carboxylic acids of the formula I.

[0008] Included in the present invention are any prodrug forms of the compounds of the present invention having a free carboxyl, sulfhydryl or hydroxyl group, wherein the prodrug derivative is free under solvolysis or physiological conditions. It can be converted to carboxyl, sulfhydryl and / or hydroxyl compounds. Prodrug derivatives are, for example, S-acyl or O-acyl derivatives of esters and thiols of free carboxylic acids, or alcohols, wherein acyl has the meaning defined herein.

[0009] The pharmaceutically acceptable prodrug esters of carboxylic acids are preferably α- (, such as, for example, lower alkyl esters, cycloalkyl esters, lower alkenyl esters, aryl-lower alkyl esters, pivaloyloxy-methyl esters. Lower alkanoyloxy) -lower alkyl, and α- (lower alkoxycarbonyl- or di-lower alkylaminocarbonyl-)-lower alkyl esters.

A pharmaceutically acceptable salt is a salt derived from a pharmaceutically acceptable base for any acidic compound of the invention, for example, where Y is carboxyl. This is, for example, an alkali metal salt (eg, sodium, potassium salt), an alkaline earth metal salt (eg, magnesium, calcium salt), an amine salt (eg, tromethamine salt).

The compounds of the formula I have one or more asymmetric carbon atoms, depending on the nature of the substituents. The resulting diastereomers and optical enantiomers are encompassed by the present invention. Preferred is a configuration in which the asymmetric carbon atom having the substituent Y has the S-configuration.

Preferred as endothelin converting enzyme inhibitors are those of formula II

Embedded image Wherein R is benzothiophenyl, naphthyl, benzofuranyl, indolyl, or monocyclic carbocyclic aryl substituted by monocyclic carbocyclic aryl or carbocyclic heterocyclic aryl; R ₁ is hydrogen or Carboxyl-derived acyl; R ₂ is 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 is 5-tetrazolyl, carboxyl or a carboxyl derivative in the form of a pharmaceutically acceptable ester;
Preferably 2, 4 or 5]; a disulfide derivative derived from the compound wherein R ₁ is hydrogen; or a pharmaceutically acceptable salt thereof.

More preferably, R has the meaning defined above; R ₁ is hydrogen, aryl-
Lower alkanoyl, lower alkanoyl, lower alkoxy-lower alkanoyl, or heterocyclic or carbocyclic aroyl; R ₂ is C ₂ -C ₄ alkyl interrupted by S or O, or heterocyclic aryl-lower alkoxycarbonyl; α- (lower alkanoyloxy-, lower alkoxycarbonyl- or di-lower alkylaminocarbonyl-) lower alkoxycarbonyl; n is 2, 4 or 5
Or a pharmaceutically acceptable salt thereof.

Particularly preferred as endothelin converting enzyme inhibitors are those of formula III

Embedded image And formula IIIa

Embedded image Wherein R is benzothiophenyl, naphthyl, benzofuranyl, indolyl, or monocyclic carbocyclic aryl substituted by monocyclic carbocyclic aryl or monocyclic heterocyclic aryl; R ₁ is hydrogen, Lower alkanoyl, methoxy-lower alkanoyl, benzoyl or pyridylcarbonyl; R ₂ is C ₂ -C ₅ -alkyl, cyclohexyl or C ₂ -C ₄ -alkyl interrupted by O or S; Y is 5-tetrazolyl, carboxyl, Lower alkoxycarbonyl, benzyloxycarbonyl, pyridylmethoxycarbonyl, α- (lower alkanoyloxy-, lower alkoxycarbonyl- or di-lower alkylaminocarbonyl-)
Lower alkoxycarbonyl], or a pharmaceutically acceptable salt thereof.

A further embodiment of the present invention provides a compound of formula IIIb

Embedded image Wherein R is benzothiophenyl, naphthyl, benzofuranyl, indolyl or a carbocyclic aryl substituted by a monocyclic carbocyclic aryl or a monocyclic heterocyclic aryl; W is CH ₂ , O, S or NR ₄ (wherein, R ₄ is hydrogen, acyl, lower alkyl or aryl - lower alkyl); R ₁ is hydrogen, lower alkanoyl, methoxy - lower alkanoyl, benzoyl or pyridylcarbonyl; R ₂ is C ₂ -C ₅ - alkyl , Cyclohexyl or C ₂ -C ₄ -alkyl interrupted by O or S; Y is 5-tetrazolyl, carboxyl, lower alkoxycarbonyl, benzyloxycarbonyl, pyridylmethoxycarbonyl, α- (lower alkanoyloxy-, lower alkoxycarbonyl -Or di-lower alkylaminocarboni -)
A lower alkoxycarbonyl], or a pharmaceutically acceptable salt thereof.

More preferably, R is 4-biphenylyl or 3-indolyl; R ₁ is hydrogen or lower alkanoyl; R ₂ is C ₃ -C ₅ -alkyl, Y is 5-tetrazolyl,
A carboxyl, lower alkoxycarbonyl, benzyloxycarbonyl, pyridylmethoxycarbonyl, α- (lower alkanoyloxy-, lower alkoxycarbonyl- or di-lower alkylaminocarbonyl-) lower alkoxycarbonyl of the formula II, III, IIIa or IIIb Or a pharmaceutically acceptable salt thereof.

Particularly preferred embodiments are those wherein R is 4-biphenylyl; R ₁ is hydrogen or lower alkanoyl; R ₂ is n-propyl, n-butyl or isobutyl; and Y is 5-tetrazolyl or particularly preferably carboxyl or lower alkoxy. Or a pharmaceutically acceptable salt thereof.

Particular embodiments of the present invention include: (a) monocyclic carbocyclic aryl wherein R is substituted with cycloalkyl; (b) optionally wherein R is optionally substituted at nitrogen with lower alkyl or acyl. Monocyclic carbocyclic aryl substituted by good azacycloalkyl; (c) R is cycloalkyl substituted by cycloalkyl; and other symbols have the meanings as defined above. I, II, III, IIIa and
IIIb.

Another aspect of the invention relates to novel compounds of formulas I, II, IIIa and IIIb, wherein Y is 5-tetrazolyl and the other symbols have the meanings as defined herein.

Preferred compounds of the present invention are those wherein Y is carboxy or lower alkoxycarbonyl; R ₁ is hydrogen or lower alkanoyl; R ₂ is lower alkyl, hydroxy, mercapto, phenyl, phenyl, lower alkoxy substituted with lower alkyl, Substituted with hydroxy, lower alkylthio, halogen, trifluoromethyl, and further each independently substituted with unsubstituted or lower alkyl, lower alkoxy, hydroxy, lower alkylthio, halogen, or trifluoromethyl, respectively. Lower alkyl substituted with phenyl or naphthyl, or cyclohexyl; and R is 3-indolyl, 4- (5-isoxazolyl) -phenyl, 4- (2- or 3-pyrrolyl) phenyl, 4- (2 -Or 3-f Lanyl) phenyl, 4- (2- or 3-thienyl) phenyl, 4- (2
-Or 3-pyridyl) -phenyl, piperidin-3-yl-phenyl N-unsubstituted or N-substituted by lower alkanoyl, or 4- (5-pyrimidinyl) -phenyl, naphthyl, 5,6,7,8 -Tetrahydro-naphthalen-1-yl, 5,6,7,8-tetrahydro-naphthalen-2-yl or 4-cyclohexyl-phenyl, or 4-biphenylyl or one or both benzene rings with lower alkyl, lower alkoxy, Formula III or III which is 4-biphenylyl substituted with hydroxy, lower alkylthio, halogen or trifluoromethyl
b) or a pharmaceutically acceptable salt thereof.

A preferred endothelin converting enzyme inhibiting compound of the present invention is a compound of the formula: wherein Y is 5-tetrazolyl, carboxyl or lower alkoxycarbonyl; R ₁ is hydrogen or lower alkanoyl; R ₂ is n-propyl, n-butyl, isobutyl, n-pentyl, methoxyethyl or methylthioethyl; and R is 3-indolyl, 4-
(5-isoxazolyl) -phenyl, 4- (2- or 3-furanyl) -phenyl,
4- (2- or 3-thienyl) -phenyl, 4-biphenylyl, 4- (2- or 3-pyridyl) -phenyl, 4- (5-pyrimidinyl) -phenyl, or lower one or both benzene rings Includes a compound of Formula III, or a pharmaceutically acceptable salt thereof, which is 4-biphenylyl substituted with alkyl, lower alkoxy, hydroxy, lower alkylthio, halogen or trifluoromethyl.

Particularly preferred are: (a) Y is carboxyl, R ₁ is hydrogen, R ₂ is n-propyl and R is 4-biphenylyl; (b) Y is methoxycarbonyl, R ₁ is acetyl, R ₂ is n-propyl and R is 4
- is biphenylyl; acceptable salts and to their pharmaceutically; and their pharmaceutically acceptable salts (c) Y is carboxyl, R ₁ is hydrogen, R ₂ is iso-butyl and R is 3-indolyl (d) A compound of formula III wherein Y is methoxycarbonyl, R ₂ is isobutyl and R is indolyl.

As used herein, the definitions themselves or combinations thereof, unless otherwise indicated, have the following meanings within the scope of the invention.

Aryl means monocyclic or heterocyclic carbocyclic or heterocyclic aryl. Monocyclic carbocyclic aryl is optionally substituted phenyl, preferably phenyl or phenyl substituted with one to three substituents,
The substituents are 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 means 1- or 2-naphthyl or 1- or 2-naphthyl, preferably substituted by alkyl, lower alkoxy or halogen.

Monocyclic heterocyclic aryl preferably means optionally substituted thiazolyl, thienyl, furanyl, pyridyl, pyrimidinyl, oxazolyl, isoxazolyl, pyrrolyl, imidazolyl or oxadiazolyl.

[0027] Denotes optionally substituted furanyl, 2- or 3-furanyl or 2- or 3-furanyl, preferably substituted with lower alkyl. Optionally substituted pyridyl may be 2-, 3- or 4-pyridyl or 2-, 3- or 4-pyridyl, preferably substituted by lower alkyl, halogen or cyano.
Meaning 3- or 4-pyridyl.

The optionally substituted thienyl is 2- or 3-thienyl, or preferably 2 substituted with lower alkyl or hydroxy-lower alkyl.
-Or 3-thienyl is meant. Optionally substituted thiazolyl means, for example, 4-thiazolyl or 4-thiazolyl substituted with lower alkyl.

The optionally substituted pyrimidinyl is 2-, 4- or 5-pyrimidinyl, or 2-, 4- or 5 preferably substituted with lower alkyl.
-Means pyrimidinyl. Oxazolyl, which is optionally substituted, is 2-, 4- or 5-oxazolyl or 2-, 4- or 5-substituted, preferably substituted by lower alkyl.
-Means oxazolyl.

By optionally substituted isoxazolyl is meant 3-, 4- or 5-isoxazolyl or 3-, 4- or 5-isoxazolyl which is preferably substituted with lower alkyl. An optionally substituted pyrrolyl refers to 1-, 2- or 3-pyrrolyl, or 1-, 2- or 3-pyrrolyl, which is preferably substituted with lower alkyl.

The optionally substituted imidazolyl is 1-, 2- or 4-imidazolyl, or 1-, 2- or 4-imidazolyl, preferably substituted by lower alkyl. The optionally substituted oxadiazolyl is 3- or 5- [1,2
, 4] oxadiazolyl or 3- or 5- [1,2,4] oxadiazolyl, preferably substituted by lower alkyl.

Bicyclic heterocyclic aryl preferably means benzothiophenyl, benzofuranyl, indolyl or benzothiazolyl optionally substituted with hydroxy, lower alkyl, lower alkoxy, advantageously 3-indolyl, 2-
Benzothiazolyl, 2-benzofuranyl or 3-benzo [b] thiophenyl.

The aryl in the aryl lower alkali is preferably phenyl or one or two lower alkyl, lower alkoxy, hydroxy, lower alkanoyloxy,
Phenyl which may be substituted with halogen, trifluoromethyl, cyano, lower alkanoylamino or lower alkoxycarbonyl; and naphthyl which may be optionally substituted. Aryl lower alkyl is advantageously 1- or 2-, optionally substituted benzyl or phenyl, with one or two lower alkyl, lower alkoxy, hydroxy, lower alkanoyloxy, halogen or trifluoromethyl.
Phenethyl.

The term “lower” as used herein in connection with an organic group or compound is up to seven (including seven), preferably up to four (including four), and advantageously Defined as having one or two carbon atoms. It can be straight or branched.

A lower alkyl group preferably contains 1-4 carbon atoms and means, for example, ethyl, propyl, butyl or advantageously methyl. Lower alkoxy groups preferably contain 1-4 carbon atoms and include, for example, methoxy,
Propoxy, isopropoxy or advantageously ethoxy is meant.

Cycloalkyl means a saturated cyclic hydrocarbon group preferably containing 5 to 7 ring carbons, preferably cyclopentyl or cyclohexyl. The term cycloalkyl (lower) alkyl is preferably 1- or 2- (cyclopentyl or cyclohexyl) ethyl, 1-, 2- or 3- (cyclopentyl or cyclohexyl) propyl, or 1-, 2-, 3- or 4 -Means (cyclopentyl or cyclohexyl) -butyl.

A lower alkoxycarbonyl group preferably contains 1 to 4 carbon atoms in the alkoxy moiety, for example, methoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl or advantageously ethoxycarbonyl.

The cycloalkylidene has a 3 to 10 membered ring, preferably 3, 5 or 6 members,
Cycloalkane linking groups, for example, cyclopropylidene, cyclopentylidene, cyclohexylidene, wherein two linking groups are attached to the same carbon of the cycloalkane ring,
Means cycloheptylidene or cyclooctylidene.

Cycloalkenylidene is a 5- to 10-membered, preferably 5- or 6-membered, meaning cycloalkene linking group wherein two bonders are attached to the same carbon atom of the cycloalkene ring. Cycloalkylidene fused to a saturated carbocyclic ring means, for example, perhydronaphthylidene.

Cycloalkylidene fused to an unsaturated carbocyclic ring means, for example, 1,1- or 2,2-tetralinylidene or 1,1- or 2,2-indanilidene.

The 5- or 6-membered oxacycloalkylidene is preferably a tetrahydrofuran or tetrahydropyridine bridging group wherein two linking groups are attached to the same carbon atom on each ring, eg, at the 3- or 4-position, for example, Means tetrahydrofuranylidene or tetrahydropyranylidene.

5- or 6-membered thiacycloalkylidene preferably means a tetrahydrothiophene or tetrahydropyran bridging group in which two linking groups are bonded to the same carbon atom in each ring, eg in the 3- or 4-position. I do.

5- or 6-membered azacycloalkylidene preferably means a pyrrolidine or piperidine linking group in which the two linking groups are bonded to the same carbon atom in each ring, eg in the 3- or 4-position, The nitrogen may be substituted by lower alkyl, such as methyl, or aryl-lower alkyl, such as benzyl.

Halogen (halo) preferably means fluorine or chlorine, but may also be bromine or iodine.

Acyl is derived from a carboxylic acid and preferably refers to optionally substituted lower alkanoyl, cycloalkylcarbonyl, carbocyclic aryl-lower alkanoyl, aroyl, lower alkoxycarbonyl or aryl-lower alkoxycarbonyl. , Preferably an optionally substituted alkanoyl or aroyl.

The lower alkanoyl is preferably acetyl, propionyl, butanoyl, pentanoyl or pivaloyl. Lower alkanoyl optionally substituted is, for example, lower alkanoyl or lower alkanoyl substituted with lower alkoxycarbonyl, lower alkanoyloxy, lower alkanoylthio, lower alkoxy or lower alkylthio; and also, for example, hydroxy, di Lower alkylamino, lower alkanoylamino, morpholino, piperidino, pyrrolidino or lower alkanoyl substituted with 1-lower alkylpiperazino.

Aroyl is carbocyclic or heterocyclic aroyl, preferably monocyclic carbocyclic or monocyclic heterocyclic aroyl. Monocyclic carbocyclic aroyl is preferably benzoyl or benzoyl substituted with lower alkyl, lower alkoxy, halogen or trifluoromethyl.

A monocyclic carbocyclic aryl substituted with a carbocyclic aryl is preferably
Optionally one or both benzene rings to one or more lower alkyl,
Biphenylyl optionally substituted with lower alkoxy, hydroxy, lower alkylthio, halogen, trifluoromethyl, amino, acylamino or nitro;
Preference is given to 4-biphenylyl.

A monocyclic carbocyclic aryl substituted with a heterocyclic aryl is a monocyclic heterocyclic aryl in the para position, preferably a thiazolyl optionally substituted.
Phenyl substituted with thienyl, furanyl, pyridyl, pyrimidinyl, oxazolyl or isoxazolyl, optionally substituted with lower alkyl, lower alkoxy, hydroxy, lower alkylthio, trifluoromethyl.

The monocyclic heterocyclic aroyl is preferably pyridylcarbonyl or thienylcarbonyl. Azacycloalkyl preferably means piperidyl, advantageously 3-piperidyl, optionally substituted on the nitrogen by lower alkyl or acyl.

Acyloxy is preferably optionally substituted lower alkanoyloxy, lower alkoxycarbonyloxy, monocyclic carbocyclic aroyloxy or monocyclic heterocyclic aroyloxy; also carbocyclic or heterocyclic aryl -A lower alkanoyloxy.

The optionally substituted lower alkanoyloxy is preferably a lower alkanoyloxy, such as acetyloxy, optionally substituted with any of the above groups with an optionally substituted alkanoyl. .

Aryl-lower alkoxycarbonyl is preferably monocyclic carbocyclic-lower alkoxycarbonyl, advantageously benzyloxycarbonyl.

Biaryl means, for example, 4-biphenylyl. Biaryl-lower alkyl is preferably 4-biphenylyl-lower alkyl,
Preference is given to 4-biphenylyl-methyl.

The novel compounds of the present invention are pharmacologically potent endothelin converting enzyme inhibitors and inhibit the formation of mammalian endothelin. They therefore inhibit the physiological effects of mammalian endothelin.

The compounds of the invention are therefore useful, for example, for hypertension and heart disease, cerebrovascular disease,
For example, it is particularly useful in mammals for the treatment of cerebral vasospasm and stroke, acute and chronic renal failure, penile erectile dysfunction, pulmonary diseases such as bronchial asthma and complications related to organ transplantation.

The above properties can be demonstrated in in vitro and in vivo tests, advantageously using mammals, such as mice, rats, dogs, monkeys or isolated organs, tissues and preparations thereof. The compounds can be administered in vitro in solution, for example, preferably in aqueous solutions, and in vivo enterally, parenterally, advantageously intravenously, for example, as suspensions or aqueous solutions. In vitro dosages are between about 10 ^-5 molar and 10 ^-6 molar. In vivo dosages may range from about 0.1 to 5 depending on the route of administration.
0 mg / kg, preferably between 1.0 and 25 mg / kg.

In vitro inhibition of endothelin converting enzyme can be demonstrated as follows: The test compound is dissolved in dimethyl sulfoxide or 0.25 M sodium bicarbonate and the solution is diluted to the desired concentration with a pH 7.4 buffer. .

Endothelin converting enzyme (ECE) was isolated from porcine major aortic endothelial cells by DE52 anion exchange column chromatography, and its activity was determined by Anal. Biochem.
, 434-436 (1993). Or,
The native enzyme can be a recombinant replacement of ECE, for example, as described in Cell 78, 473-485 (1994). Human ECE-1 has been described by several groups (Schmidt, M .;
et al. FEBS Letters, 1994, 356, 283-243; Kaw, s .; Emoto, N .; Jeng, A .; Y
anagisawa, M. 4th Int. Conf. of Endothelin; April 23-25, London (UK), 19
95; C6; Biophys. Res. Commun., 1995, 207, 807-812). ECE inhibition is Biochem. Mo
l. Biol. Int. 31, (5), 861-867 (1993).
Can be measured by a radioimmunoassay for the measurement of ET-1 formed from.

Alternatively, recombinant human ECE-1 (rhECE-1) can be used as follows: Recombinant human endothelin converting enzyme-1 (rhECE-1; Kawa, S .; Emoto, N .; Yanagisa
wa M., 4th Int. Conf.on Endothelin; April 23-25, London (UK), 1995; C6)
Hamster ovary cells expressing 10% fetal bovine serum and 1 ×
Culture in DMEM / F12 medium containing antibiotic-antimycotic. Cells are harvested by scraping, pelleted by centrifugation and at 4 ° C. in a buffer containing 5 mM MgCl ₂ , 1 μM pepstatin A, 100 μM leupeptin, 1 mM PMSF and 20 mM Tris, pH 7.0, 2 mL buffer / mL cell ratio. Homogenize. Cell debris is removed by short centrifugation, and the supernatant is centrifuged again at 100,000 × g for 30 minutes. The resulting pellet is concentrated to about 15 mg / ml and an aliquot is stored at -80 ° C.

To assess the effect of the inhibitor on ECE-1 activity, 10 μg of protein was combined with the desired concentration of compound for 20 minutes at room temperature in a 10 μL volume of 50 mM TES, pH
Pre-incubate in 7.5 and 0.005% Triton X-100. Human large ET-1 (
5 μL) was then added at a final concentration of 0.2 μM and the reaction mixture was further incubated for 2 hours at 37 ° C.
Incubate with The reaction is stopped by the addition of 500 μL of radioimmunoassay (RIA) buffer containing 0.1% Triton X-100, 0.2% bovine serum albumin, and 0.02% NaN ₃ in phosphate buffered saline. .

Dilution samples (200 μL) from the above enzyme assay were added at 4 ° C. overnight for 2 hours each.
Incubate with 5 μL of [ ¹²⁵ I] ET-1 (10,000 cpm / test tube) and 1: 20,000 dilution rabbit antibody that specifically recognizes the carboxyl-terminal tryptophan of ET-1. Goat anti-rabbit antibody conjugated to magnetic beads (70 μg) is then added to each tube and the reaction mixture is incubated for an additional 30 minutes at room temperature. Pellet the beads using a magnetic rack. The supernatant is decanted and the radioactivity of the pellet is counted with a gamma counter. Total and non-specific binding are measured in the absence of non-radioactive ET-1 and anti-ET antibodies, respectively. Under these conditions, ET-1 and large ET-1
[ ¹²⁵ I] ET-1 binding to the antibody was determined at 21 ± 2 and 260,000 ± 66,000 f, respectively.
Replace with the IC ₅₀ value of mol (mean ± SEM, n = 3-5).

To determine the IC ₅₀ value of an inhibitor, a concentration-response curve for each inhibitor is determined.
Fit the data to a one-sided model using the IBM compatible version of the ALLFIT program.

In vitro tests are most appropriate for compounds where Y is tetrazolyl or carboxyl.

As an illustration of the present invention, the compound of Example 5j demonstrates an IC ₅₀ of about 11 nM in an in vitro assay of rhECE-1 inhibition.

Endothelin converting enzyme inhibition can also be determined by measuring inhibition of the large ET-1 induced hyperactivity in anesthetized or awake rats as described below. The effect of the inhibitor of the hyperactive reaction by the large ET-1 attack was measured in SpragueDawley rats by Biochem.
It is measured as described in Mol. Biol. Int. 31, (5), 861-867 (1993). Result is,
It is shown as the percentage of inhibition of the large ET-1 induced hyperactivity compared to the vehicle.

[0067] Male Sprague-Dawley rats are anesthetized with inactin (100 mg / kg ip), equipped with a catheter in the femoral artery and vein, and recorded with mean arterial pressure (MAP) and compound administration, respectively. Make a tracheotomy and place the cannula into the trachea to ensure airway openness. The animal's body temperature is maintained at 37 ± 1 ° C. by means of a heating blanket. Following surgery, the MAP is stabilized before interruption of autonomic transmission with chlorisondamine (3 mg / kg iv). Rats are then treated with 10 mg / kg iv of test compound or vehicle and challenged with large ET-1 (1 nmol / kg iv) after 15 and 90 minutes. Generally, the data is reported as the maximum increase in MAP produced by large ET-1 in animals treated with the test compound or vehicle.

[0068] Male Sprague-Dawley rats are anesthetized with sodium methhexital (75 mg / kg ip) and equipped with a catheter in the femoral artery and vein to record mean arterial pressure (MAP) and compound administration, respectively. The catheter is passed through a swivel system that allows the rat to freely receive it after regaining wakefulness. Rats from this process
Allow 24 hours before the start of the experiment to recover. The following day, the MAP is recorded via the femoral artery catheter and the test compound or vehicle is administered via the femoral vein. Animals are challenged with 1 nmol / kg iv of large ET-1 at various times after dosing. After a suitable washing time,
Data are reported as changes in MAP produced by large ET-1 at 2 minute intervals in animals treated with test compound compared to vehicle, depending on dose and regimen.

ECE inhibition is also described, for example, in Biochem. Biophys. Res. Commum. 204, 407-412 (19
As described in 94), it can be determined by measuring the inhibition of large ET-1 induced hyperactivity in awake essential hypertensive rats (SHR).

Male SHRs (16-18 weeks of age) are administered test compound or vehicle (1 M NaHCO ₃ ) via a subcutaneously implanted osmotic minipump. On day 5, femoral arterial and venous catheters are placed in anesthetized rats for MAP measurement and test compound administration, respectively. After a recovery time of 48 hours, MAP is recorded via an arterial catheter connected to a pressure transducer (day 7). Blood pressure and heart rate are stabilized 30 minutes before ganglionic inhibition is performed using chlorisondamine (10 / kg iv).
After about 15 minutes, a bolus dose of large ET-1 (0.25 nmol / kg iv) is administered to both vehicle and compound treated rats. Changes in blood pressure in response to large ET-1 were then compared between the two groups of rats in two directions at 1, 5, 10, 15, 30, and 60 minutes post-dose.
Compare using ANOVA.

The compounds of the present invention inhibit cerebral vasoconstriction and are useful for treating and reducing cerebral spasm. They are therefore useful for treating and alleviating conditions in which cerebral vasospasm occurs. Such conditions include stroke, cerebral ischemia, acute and traumatic brain injury,
Includes cerebral hemorrhage, especially aneurysmal subarachnoid hemorrhage, and migraine.

Inhibition of cerebral vasospasm is demonstrated by measuring inhibition of experimentally induced contraction of the rabbit skull base cerebral artery (Caner et al., J. Neurosurg., 1996, 85, 917-922). Bronchial effects can be determined by measuring effects in a model of ET-1 induced bronchoconstriction.

The compounds of the present invention may also have angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP) inhibitory activity. Methods for their determination are described, for example, in US Pat. No. 5,506,244, which is incorporated herein by reference.

The combined effect is effective, for example, in treating mammalian cardiovascular diseases such as hypertension, congestive heart failure and renal failure.

The compounds of the present invention can generally be prepared by the methods described in US Pat. No. 5,506,244, and in particular, using the methods described below, such as (a) Formula IV

Embedded image Wherein the symbols R, m and A are as defined above and Y ′ is N-protected 5
-Tetrazolyl or esterified carboxyl];

Embedded image Wherein R ₂ and R ₃ are as defined above, and R ′ ₁ is an labile S-protecting group, for example, acyl, t-butyl or optionally substituted benzyl.
By condensation of a carboxylic acid, or a reactive functional derivative thereof; or

(B) Formula IV

Embedded image Wherein the symbols A, R ₁ ′, R ₂ and R ₃ have the meanings as defined above, or a reactive functional derivative thereof;

Embedded image Wherein R, m, X and Y ′ are as defined above; or

(C) Under basic conditions, the formula

Embedded image Wherein the symbols R, A, R ₂ , R ₃ and Y ′ are as defined above and Z is a reactive esterified hydroxyl group as a leaving group (eg, halo such as chlorine or bromine) And a compound of the formula R ₁ 'SH (IX) wherein R ₁ ' is an unstable S-protecting group, for example acyl, t-butyl or optionally substituted benzyl. Condensing;

[0078] Then, the R ₁ 'is obtained is benzyl which may be optionally substituted R ₁
Is hydrogen; and, in the above step, if the interfering reactive group was temporarily protected, the protecting group was removed, and the resulting compound of the invention was then isolated; and Optionally, converting the compound of the invention to another compound of the invention; and / or optionally converting the free carboxylic acid function to a pharmaceutically acceptable ester derivative or freeing the resulting ester. Converting the resulting free compound to a salt, or converting the resulting salt to a free compound or other salt, and / or optionally converting the resulting free compound to a salt. The resulting isomer or racemic mixture is separated into single isomers or racemates and / or, if desired, the resulting racemate is resolved into optical enantiomers.

In the starting compounds and intermediates that are converted to the compounds of the present invention by the methods described herein, the functional groups present, such as thiol, carboxyl, amino, and hydroxyl groups, if desired, Protected by common and conventional protecting groups.
Protected thiol, carboxyl, amino and hydroxyl groups are those which can be converted under mild conditions to free thiol, carboxyl, amino and hydroxyl groups without undesired side reactions.

The purpose of the insertion of the protecting group is to protect the functional group, preferably from internal reactions, under the reactive components and conditions used to effect the desired substitution of chemical components. The need and choice of protecting groups for a particular reaction are known to those skilled in the art, and the nature of the protecting functional group (thiol, carboxyl, amino group, etc.), the structure and stability of the molecule in which the substituent is a part And the reaction conditions.

Well-known protecting groups meeting these conditions and their insertion and removal are described, for example, in J. F.
W. McOmie, "Protective Groups in Organic Chemistry", Plenum Press, Lon
don, NY 1973, TW Greene and PGM Woots, "Protective Groups in O
rganic Synthesis ", Wiley, NY 1991," The Peptides ", Vol. I, Schroeder a
nd Luebke, Academic Press, London, NY, 1965 and also PJ Kocienski,
"Protecting Groups", Thieme, NY 1994.

Suitable protecting groups for the preparation of 5-tetrazolyl compounds are those protecting groups customarily used in tetrazole chemistry, especially triphenylmethyl, unsubstituted or substituted (eg nitro-substituted) benzyl, eg 4-nitrobenzyl Methoxy- and ethoxymethyl, also lower alkoxymethyl such as 1-ethoxymethyl, lower alkylthiomethyl such as methylthiomethyl, tri-lower alkylsilyl such as dimethyl-tert-butyl- and triisopropylsilyl, and also 2-cyanoethyl. And lower alkoxy-lower alkoxy-methyl such as 2-methoxyethoxymethyl, benzyloxymethyl and phenacyl.

The removal of the protecting group is performed according to a known method. For example, the triphenylmethyl group is customarily removed by hydrolysis, in particular in the presence of an acid, or by hydrogenolysis in the presence of a hydrogenation catalyst; 4-nitrobenzyl is, for example, present in the presence of a hydrogenation catalyst. Methoxy- or ethoxy-methyl is removed, for example, by treatment with a tri-lower alkyl-tin bromide such as triethyl or tributyl; methylthiomethyl is removed, for example, by trifluoroacetic acid Silyl groups are removed, for example, by treatment with a fluoride such as tetra-lower alkyl-ammonium fluoride, for example, tetrabutylammonium fluoride, or an alkali metal fluoride, for example, sodium fluoride. 2-cyanoethyl, for example, in sodium hydroxide solution, e.g. 2-methoxyethoxymethyl is removed, for example, with hydrochloric acid, for example, by hydrolysis; and benzyloxymethyl and sulfur are removed, for example, in the presence of a hydrogenation catalyst. It is removed by chemical decomposition.

The tetrazole protecting group, preferably inserted by conversion of a similarly protected amide that is polysulfur to the N-substituted tetrazole, is, for example, cyanoethyl, p-nitrophenylethyl, lower alkoxycarbonylethyl, phenylsulfonylethyl, etc. is there. Such tetrazole protecting groups are known as DBN (1,5-diazabicyclo [4.3.
0] none-5-ene), amidine, alkali metal carbonates or alkoxides, for example by reverse Michael deprotection in a inert solvent with a base such as potassium carbonate, t-butoxide carbonate, sodium methoxide. it can.

The amino protecting group is preferably t-butoxycarbonyl or benzyloxycarbonyl. The sulfhydryl protecting group is preferably lower alkanoyl, for example acetyl.

The preparation of the compounds according to the invention according to step (a) involving the condensation of an amino of the formula IV with an acid of the formula V or a functional reactive derivative thereof is carried out by methods well-known for peptide synthesis.

The condensation according to step (a) of a compound of the formula IV with a free carboxylic acid of the formula V is preferably carried out with dicyclohexylcarbodiimide or N- (3-dimethylaminopropyl)
-N'-ethylcarbodiimide, and hydroxybenzotriazole, 1-hydroxy-7-azabenzotriazole, chlorodimethyloxytriazine or benzotriazol-1-yloxy-tris- (dimethylamino) phosphonium hexafluorophosphate (BOP Reagent), And triethylamine or N
-In an inert solvent such as dimethylformamide or methylene chloride, preferably at room temperature, in the presence of a condensing agent such as methylmorpholine.

The condensation of a compound of formula IV with a reactive functional derivative of an acid of formula V in the form of an acid halide, preferably acid chloride, or mixed anhydride, is carried out in an inert solvent such as toluene or methylene chloride. It is advantageously carried out in the presence of a base, for example a directed base such as potassium carbonate or an organic base such as triethylamine, N-methylmorpholine or pyridine, preferably at room temperature.

The reactive functional derivative of the carboxylic acid of Formula V is preferably an acid halide (eg,
Acid chloride), and mixed anhydrides such as pivaloyl or isobutyloxycarbonyl anhydride, or activated esters such as benzotriazole, 7-azabenzotriazole or hexafluorophenyl esters.

The starting materials of formula IV can be prepared by the methods described herein and described in the examples.

The preparation of the starting material of formula IV is based on the formula X

Embedded image Wherein R and Y ′ are as defined above, of the formula XI

Embedded image Wherein A is as defined above and R ₅ is a labile amino protecting group, for example,
acylation with a suitably N-protected messenger amino acid (or a reactive functional derivative) to give the corresponding N-protected compound of formula IV.

The condensation of the compound of the formula X with the compound of the formula XI is carried out by methods known in the art of peptide synthesis, for example as described for the condensation of a compound of the formula IV with a compound of the formula V. The N-protecting group is
It is removed by methods well known in the art, for example, t-butoxycarbonyl is removed with an anhydride such as trifluoroacetic acid.

The starting amino acids and esters of the compounds of the formulas X and XI, if known or new, can be prepared by methods well known in the art, for example from the corresponding aldehydes or ketones. The α-amino acids of formula X are preferably obtained as —S-enantiomers. Resolution of the N-acyl amino acid ester can be performed by hydrolysis with an esterase, such as an alcalase, to give an S-amino acid.

The starting materials of the formula V are new or, if new, can be prepared by customary methods. Starting materials can be obtained, for example, by replacement of the corresponding racemic or optically active α-amino acid with an α-bromo derivative, followed by its appropriate thioacid or optionally substituted benzylthiol under basic conditions. For example, as described in European Patent Application No. 524,553, published Jan. 23, 1993. S-Debenzylation of the resulting end product is performed, for example, by base-catalyzed hydrolysis with dilute aqueous sodium hydroxide or lithium hydroxide.

The preparation of the compounds of the invention according to step (b) involving the condensation of an acid of formula VI with a compound of formula VII is carried out in a manner analogous to step (a). Similarly, the starting materials of formula VI, with an ester corresponding to cyclic amino acid of the acid of formula XI of the formula V (R ₅ is hydrogen), the similar conditions of the condensation, followed by a carboxyl or tetrazolyl protecting group Manufactured by removal of

The preparation of the compounds according to the invention in step (c) involving the replacement of the leaving group Z of the compounds of the formula VIII with the sulfhydryl derivatives R ₁ ′ -SH is carried out by methods known in the art.

The reactive esterified hydroxyl group represented by Z is a hydroxyl group esterified by a strong inorganic or organic acid. The corresponding Z groups are in particular halo, for example chloro, bromo or iodo, and also lower alkyl- or arylsulfonyl groups, for example sulfonyloxy groups such as (methane-, ethane-, benzene- or toluene-) sulfonyloxy groups, or It is a trifluoromethylsulfonyloxy group.

The substitution 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 temperature or elevated temperature.

Similarly, the starting material of formula VIII comprises an amide derivative of formula IV

Embedded image Wherein R ₂ and R ₂ and Z have the meanings as defined above, under the conditions described in step (a).

For example, acids of formula XII where Z is bromo can be prepared from the corresponding α-amino acid by methods well known in the art. The optionally active acid of Formula XII can be obtained from an optically active α-amino acid as described herein.

The following reaction sequence illustrates step (c).

[0102]

Embedded image

B: An alternative method for compounds where R is biaryl, for example N-Boc-cycloleucyl-biarylalanine derivative 7, is for example 2-[(1-tert-butoxycarbonylamino-cyclopentanecarbonyl) -amino] 3- (4-trifluoromethanesulfonyloxyphenyl) -propionic acid ethyl ester 14 and Carlson a
nd Shieh (J. Org. Chem. 1992, 57, 379) of various arylboronic acids by modification of the method reported by, PdCl ₂ a (dppf) as the catalyst, and K ₃ PO ₄ as base
This is a Suzuki binding reaction using DME or THF as a solvent. The synthesis of the final product is then completed as in Sequence A.

[0104]

Embedded image

C: Alternatively, for the synthesis of compounds where R is biaryl, the penultimate intermediate bromoester 11 can be converted to a standard linkage between bromate 17 and aminoester hydrochloride 5 (chloride as described above). Synthesized by DCC, HOAT, Et ₃ N) in methylene. The biarylaminoester hydrochloride is then, for example, 2- (benzhydridene-amino)-
Prepared from 3- [4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborane-2-yl-phenyl] -propionic acid ethyl ester 18 by Suzuki coupling and subsequent hydrolysis ( Satoh, Y .; Guide, C .: Cham, K .; Firooznia, F. Tetra
hedron Lett. 1997, 38, 7645).

[0106]

Embedded image

D: For compounds where R is biaryl, an alternative method of preparing N-Boc-cycloleucyl-biarylalanine ester intermediate 7 is, for example, 2-[(1-tert-butoxycarbonylamino-cyclopentanecarbonyl) -Amino] -3- (4-indophenyl) -propionic acid methyl ester and various arylboronic acids containing linkages according to the same reaction conditions as in Sequence B. Biaryl substituted intermediate 7 is also a palladium catalyzed reaction of iodophenyl substituted intermediate 19 with various aryl stannic acids.
Under the conditions of the Stille coupling reaction, it can be obtained using toluene or dioxane as a solvent.

[0108]

Embedded image

Compounds of the present invention wherein Y is 1H-5-tetrazolyl are prepared analogously, but with the formula X ′

Embedded image Wherein R _p is a tetrazolyl protecting group (such as 2-cyanoethyl).

The tetrazole starting material of formula X ′ is prepared from the corresponding N-acyl amino acid, initially by converting it to an N—R _p -substituted amide. The resulting amide is then purified under conditions known in the art of tetrazole ring formation, for example, Tetraherdon Lett
ers 1979, 491 and J. Org.Chem. 56, 2395 (1991), for example,
Treat in the presence of trimethylsilyl azide, diisopropyl azodicarboxylate and triphenylphosphine. Removal of the N-acyl group leads to the starting material of formula X '.

In the above described sequence of the reaction of step (c), the tetrazole protecting group is preferably removed after formation of the bromo intermediate and before reaction with, for example, potassium thioacetate.

Certain compounds and intermediates of the present invention can be converted by general reactions known in the art.

The free mercaptan is prepared by reacting the S-acyl derivative with a reactive derivative of a carboxylic acid such as an acid anhydride or the chloride (wherein R ₁ corresponds to acyl in formula I), preferably with cobalt chloride ( It can be converted in an inert solvent such as acetonitrile or methylene chloride in the presence of CoCl ₂ ).

Free mercaptans where R ₁ is hydrogen oxidize to the corresponding disulfide by, for example, air oxidation or use of a mild oxidizing agent such as iodine in an alcoholic solution. Conversely, disulfides can be reduced to the corresponding mercaptans with, for example, sodium, borohydride and reducing agents such as acetic acid or tributylphosphine.

Carboxylic esters are well known in the art from carboxylic acids, for example, by condensation with the corresponding halide to the esterified alcohol in the presence of a base, or by condensation with an excess of alcohol in the presence of an acid catalyst. The method can be used.

Carboxylic acid esters and S-acyl derivatives can be hydrolyzed with aqueous alkali such as, for example, alkali metal carbonates or hydroxides.

A carbocyclic or heterocyclic aromatic compound or intermediate can be reduced to the corresponding cycloaliphatic compound or intermediate by the methods described herein, for example, catalytic hydrogenation.

When mixtures of stereoisomers (eg, diastereomers) are obtained, they can be separated by known methods such as functional crystallization and chromatography (eg, thin layer, column, flash chromatography). . The racemic free acid can be decomposed into the optical enantiomer by fractional crystallization of d- or l- (α-methylbenzylamine, cinchonidine, cinchonine, quinine, quinidine, dehydroabiethylamine, brucine or strychnine) salts and the like. The racemic product, if not a diastereomer, is first converted to a diastereoisomer with an optically active reagent (such as an optically active alcohol to form an ester) that can then be separated as described above, e.g., Hydrolyzes to the individual enantiomers. Racemic products can also be resolved by chiral chromatography, for example, high performance liquid chromatography using a chiral adsorbent; or by enzymatic degradation of, for example, an ester with alcalase.

Each of the above reactions is preferably inert to the reagent and is in the presence or absence of a diluent, catalyst, alkali or product condensing agent that is a solvent, or the other reagent and / or an inert atmosphere. The reaction is carried out at lower, lower, room or elevated temperatures, preferably near the boiling point of the solvent used, at atmospheric or superatmospheric pressure.

The invention further relates to using the intermediate product obtained at any stage of the process as a starting material to perform the remaining steps, or to stop the process at any stage thereof, or to reduce the starting material to the reaction conditions. And the use of the reactive component in its salt or optically pure enantiomer form. Primarily, starting materials that result in the formation of the compounds indicated above as preferred should be used in the reaction.

The present invention further provides compounds of the present invention and pharmaceutically acceptable non-toxic acid addition salts or pharmaceutical compositions for the inhibition of endothelin converting enzymes and, for example, as described above. Endothelin-dependent diseases such as hypertension, heart failure, acute or chronic renal failure, cardiovascular diseases such as stroke and cerebral vasospasm, and bronchial asthma;
It relates to the use as a medicament for the treatment of erectile dysfunction and of complications associated with organ transplantation.

The present invention also relates to the use of a compound of the present invention for the manufacture of a pharmaceutical composition, especially a pharmaceutical composition having endothelin converting enzyme inhibitory activity.

The pharmaceutical compositions of the invention are suitable for enteral, transdermal and parenteral administration, such as oral or rectal, to mammals, including humans, for treating endothelin-dependent diseases, and in effective amounts. Of the present invention or a pharmaceutically acceptable salt thereof, alone or with one or more pharmaceutically acceptable carriers.

The pharmacologically active compounds of the present invention are useful in the manufacture of pharmaceutical compositions that contain an effective amount of it, together with or as a mixture, with excipients or carriers suitable for enteral or parenteral administration. Preferably, the active agent is a) a diluent such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine; b) a lubricant such as silica, talc, stearic acid, its magnesium or calcium salt and And / or polyethylene glycol; for tablets also c
A) binders such as aluminum magnesium silicate, starch paste, gelatin,
Tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; if desired, d) disintegrants such as starch, agar, alginic acid or its sodium salt, or an effervescent mixture; and / or e.
) Tablets and gelatin capsules containing with absorbents, pigments, flavoring and sweetening agents. Injectable compositions are preferably aqueous isotonic solutions or suspensions, and suppositories are advantageously made from fatty emulsions or suspensions. The compositions may be sterilized and / or contain adjuvants such as preserving, stabilizing, wetting or emulsifying agents, solution enhancers, salts for regulating the osmotic pressure and / or buffers. In addition, the composition may also include other therapeutically effective substances. The compositions can be prepared by conventional mixing, granulating or coating methods, respectively, and contain about 0.1 to 75%, preferably about 1 to 50%, of the active ingredient.

Formulations suitable for transdermal administration include an effective amount of a compound of the present invention with a carrier.
Advantageous carriers include readily absorbable pharmacologically acceptable solvents to assist passage through the skin of the host. Characteristically, the transdermal device comprises a backing portion, a reservoir containing the compound, optionally with a carrier, a rate-limiting barrier for delivering the compound to the host's skin at a controlled, predetermined rate, if desired over an extended period of time, and In the form of a bandage consisting of a means for securing the device to the skin.

A unit dose for a mammal of about 50 to 70 kg contains about 5 to 100 mg of the active ingredient. The dosage of the active compound depends on the species, body weight, age and individual condition of the warm-blooded animal (mammal) and the mode of administration.

The following examples are intended to illustrate the present invention and should not be construed as limiting. Temperatures are given in degrees Celsius. Unless otherwise stated, all evaporations are performed under reduced pressure, preferably at about 15 to 100 mmHg. Optical rotation is 58 at room temperature.
Measure at 9 nm (D line for sodium) or other wavelengths noted in the examples.

The prefixes R and S are used to indicate the absolute configuration of each asymmetric center. L-amino acids as used herein correspond to the S-configuration. The stereochemical configurations specified in the products of the examples are given in conventional manner for each structural formula.

Abbreviations used are standard in the art, for example, “BOP” reagent is an abbreviation for benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, HOAT is 1-hydroxy- 7-azabenzotriazole, HOBT is 1-hydroxybenzotriazole, EDCl is 1-ethyl-3- (
3-dimethylaminopropyl) carbodiimide hydrochloride, DCC stands for dicyclohexylcarbodiimide.

Example 1 (a) 5.00 g (38.1 mmol) of L-norleucine (αS-aminohexanoic acid) and 22.7 g (191 mmol) of potassium bromide are dissolved in 50 mL of water at room temperature. Then 10.8 mL (95.5 mmol) of aqueous 48% hydrobromic acid are added and the mixture is cooled to -12.
Cool to ° C with an ice / NaCl bath. The flask is then fitted with a funnel containing 3.16 g (45.7 mmol) of a 20 mL aqueous solution of sodium nitrite. The sodium nitrite solution is added dropwise to the reaction mixture over 30 minutes. After the addition of sodium nitrite is complete, the mixture is crushed for another 45 minutes, transferred to another funnel and diluted with ethyl acetate. The phases are separated and the aqueous phase is extracted twice with ethyl acetate. The combined ethyl acetate phases were washed three times with saturated aqueous sodium bisulfite (except yellow), dried over sodium sulfate and evaporated to dryness to give a clear oil which was dried under high vacuum to give αS Obtaining bromohexanoic acid.

[Table 1]

Also prepared are: (b) αR-bromohexanoic acid;

[Table 2] (C) αS-bromo-βR-methylvaleric acid;

[Table 3] (d) αS-bromo-βS-methylvaleric acid;

[Table 4]

(E) αR-bromo-βR-methylvaleric acid;

[Table 5] (f) αR-bromo-βS-methylvaleric acid;

[Table 6]

(G) αR-bromo-γ-methylvaleric acid;

[Table 7] (h) αS-bromo-γ-methylvaleric acid;

[Table 8] (i) αR-bromo-γ-thiomethylbutyric acid;

[Table 9]

(J) αS-bromo-γ-thiomethylbutyric acid;

[Table 10] (k) αR-bromovaleric acid;

[Table 11] (l) αS-bromovaleric acid;

[Table 12]

(M) αR-bromo-βR-methoxybutyric acid;

[Table 13] (n) αR-bromovaleric acid;

[Table 14] (o) αR-bromo-βS-hydroxybutyric acid;

[Table 15]

(P) αS-bromo-βR-hydroxybutyric acid;

[Table 16] (q) α-bromo-β-phenylvaleric acid 10;

[Table 17] (r) α-bromo-β-naphthalen-2-yl-valeric acid;

[Table 18]

(S) β-biphenyl-4-yl-α-bromovaleric acid;

[Table 19] (t) α-bromo-β-cyclohexyl-valeric acid; white solid;

[Table 20]

Example 2 (a) 2.54 g (4.67 mmol) of crude αS-bromohexanoylcycloleucyl-L
Dissolve biphenylalanine methyl ester in DMF at room temperature. 2 in this solution
.67 g (23.4 mmol) of potassium thioacetate are added. The reaction mixture is stirred for 4 hours, then diluted with ether, successively 4 times, 250 ml of water and 1 time, 200 ml
Wash with mL of saline. The ether phase is then dried over sodium sulfate and concentrated to give a brown residue. Purify the crude product by silica gel chromatography with 30% ethyl acetate / hexane to obtain αR- (acetylthio) -hexanoyl-cycloleucyl-L-biphenylalanine methyl ester as a white powder;

[Table 21]

The starting material is prepared as follows; 20.0 g (155 mmol) of cycloleucine (1-amino-1-cyclopentanecarboxylic acid) are taken up in 150 ml of anhydrous methanol at room temperature and a cloudy white Obtain a solution. Hydrogen chloride gas is then bubbled through the solution for 15 minutes, after which the flask is bubbled and the mixture is stirred for an additional 4 hours and 45 minutes at room temperature. The reaction mixture is concentrated to dryness and further dried under high vacuum for 30 minutes to give a white solid. The white powder is triturated with ether and then filtered. After further washing with ether, the white solid is dried under high vacuum overnight to give cycloleucine methyl ester hydrochloride.

27.0 g (151 mmol) of cycloleucine methyl ester hydrochloride are taken up in 250 ml of dichloromethane at room temperature to give a cloudy solution. The solution is cooled to 0 ° C. in an ice bath, then 44.3 mL (317 mmol) of triethylamine are added with rapid stirring for 5 minutes. Then 69.2 g (317 mmol) of di-tert-butyl dicarbonate are added as such, the mixture is warmed to room temperature and stirred for 16 hours. The crude reaction mixture is concentrated to dryness to give a white solid, which is then dissolved in 200 mL of 90% aqueous THF. To this clear colorless solution is added 25.6 mL (317 mmol) of pyridine and the mixture is stirred for 2 hours at room temperature. The reaction mixture is concentrated to give a light yellow residue, which is taken up in ethyl acetate and washed successively twice with water, twice with 1M hydrochloric acid, twice with saturated sodium bicarbonate and twice with brine. The organic phase is then dried over sodium sulfate and concentrated to give Nt-Boc-cycloleucine methyl ester;

[Table 22]

25.5 g (105 mmol) of Nt-Boc cycloleucine methyl ester was added to 900
Dissolve in mL of tetrahydrofuran at room temperature. Then, 420 mL (420 mmol) of 1
Add 0.0M aqueous lithium hydroxide with rapid stirring. After stirring for 16 hours, the tetrahydrofuran is removed on a rotary evaporator, after which the aqueous phase is washed twice with dichloromethane and then acidified to pH = 1 using concentrated hydrochloric acid. The product is extracted with ethyl acetate. The organic phase was dried over sodium sulfate and then concentrated to dryness to give a clear off-white oil which was dried under high vacuum to give Nt-
Obtain Boc-cycloleucine as a white amorphous foam;

[Table 23]

Dissolve 50.0 g (146 mmol) of Nt-Boc-L-biphenylalanine in 300 mL of anhydrous methanol at room temperature to obtain a clear and colorless solution. Hydrogen chloride gas is then bubbled through the solution for 15 minutes, turning the solution cloudy white. The flask is bubbled and the solution is stirred at room temperature for 3 hours. The reaction mixture was concentrated and then placed on high vacuum for 30 minutes to give a very bright yellow powder, which was sheared with 550 mL of ether and filtered to give a white solid, which was washed with 300 mL of additional ether I do. Drying the white powder under vacuum overnight to obtain L-biphenylalanine methyl ester hydrochloride;

[Table 24]

Dissolve 18.5 g (80.7 mmol) of Nt-Boc-cycloleucine in 400 mL of dichloromethane at room temperature. With rapid stirring, the following are continuously added: 25.9 g (88.7 mmol) of L-biphenylalanine methyl ester hydrochloride; 1
6.8 mL (121 mmol) of triethylamine, 12.1 g (88.7 mmol) of HOAt, and 30.9 g (161 mmol) of the water-soluble binding reagent EDCl. After stirring for 18 hours, the brown mixture is diluted with ether and washed three times with water, twice with 1 M hydrochloric acid, twice with saturated sodium bicarbonate, and twice with brine. The organic phase is then dried over sodium sulfate,
Concentrate and dry. The resulting white solid is then dried under high vacuum and the Nt-
Obtaining Boc-cycloleucyl-L-biphenylalanine methyl ester;

[Table 25]

Dissolve 36.0 g (77.1 mmol) of Nt-Boc-cycloleucyl-L-biphenylalanine methyl ester in 400 mL of 3: 1 dichloromethane / ether at room temperature to obtain a translucent solution. With rapid stirring, hydrogen chloride gas is bubbled through the solution for 15 minutes, turning the solution cloudy white. The flask is bubbled and the solution is stirred at room temperature for 3.5 hours. Concentrate the reaction mixture and then place under high vacuum for 30 minutes to obtain a light yellow amorphous solid. The solid is dissolved in warm dichloromethane and crystallized by the addition of hexane. The off-white solid precipitated from the solution is filtered, washed with cold hexane and dried under high vacuum to give cycloleucyl-L-biphenylalanine methyl ester hydrochloride;

[Table 26]

2.00 g (4.96 mmol) of cycloleucyl-L-biphenylalanine methyl ester hydrochloride, 1.06 g (5.46 mmol) of 2S-bromohexanoic acid and 743
mg (5.46 mmol) of HOAt are dissolved in 30 mL of dichloromethane at room temperature. To this solution, 1.18 mL (8.43 mmol) of triethylamine, 1.91 g (9.92 mmol 9
1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCl)
The binding reagent is added and the reaction mixture is stirred for 15 minutes. The reaction mixture is then washed with ether and washed successively three times with water, twice with 1 M hydrochloric acid, twice with saturated sodium bicarbonate, and twice with brine. The ether phase is then dried over sodium sulfate and concentrated to give αS-bromohexanoylcycloleucyl-L-biphenylalanine teleester as a light yellow solid.

(B) Similarly prepared is αS- (acetylthio) -pentanoyl-cycloleucyl-L-biphenylalanine methyl ester, mp 130 ° -134 ° C.

Example 3

Embedded image 189 mg (0.351 mmol) of 2R- (acetylthio) hexanoylcycloleucyl-L-biphenylalanine methyl ester are dissolved in 4 mL of methanol at room temperature. Then 1.4 g (1.4 mmol) of aqueous 1.00 M lithium hydroxide are added.
The clear colorless mixture is stirred for 2 hours and then acidified to pH = 1 with 1 M hydrochloric acid, forming a white precipitate. The white solid was extracted into ethyl acetate, washed with brine, dried over sodium sulfate and concentrated to dryness to give an off-white solid, which was further dried in a 50 ° C. oven under high vacuum to give 3- Biphenyl-4-yl-2-{[1- (
2R-mercapto-hexanoylamino) -cyclopentanecarbonyl] -amino}
-To obtain propionic acid; mp 104-107 ° C.

Embodiment 4

Embedded image Dissolve 500 mg (0.94 mmol) of αR-bromo-βS-hydroxybutanoylcycloleucyl-L-biphenylalanine phenyl ester in 3 mL of methanol and overnight with 530 mg (9.4 mmol) of sodium hydrogen sulfide hydrate. Treat at room temperature.
The reaction mixture was evaporated to dryness to give a yellow solid, which was taken up in ethyl acetate and the pH =
Acidify to 1 with 1M hydrochloric acid and separate the phases. The organic phase is washed with brine, dried over sodium sulfate, concentrated and dried to give a yellow oil. Then drying under high vacuum gives αS-mercapto-βS-hydroxybutanoyl-cycloleucyl-L-biphenylalanine methyl ester;

[Table 27] Starting materials are prepared from αR-bromo-βS-hydroxybutyric acid.

Example 5 Prepared analogously to the method described in the previous example is a compound of the following formula:

Embedded image

Wherein: (a) Ra = αS-mercaptohexanoyl; mp 159-162 ° C .; (b) Ra = αR-mercapto-βR-methylpentanoyl; mp 172-174
° C; (d) Ra = αR-mercapto-βS-methylpentanoyl; mp 108-116.
° C; (e) Ra = αS-mercapto-βS-methylpentanoyl; mp 142-145.
° C; (f) Ra = αS-mercapto-γ-methylpentanoyl; mp 187-189 ° C
(G) Ra = αR-mercapto-γ-methylpentanoyl; mp 120-124 ° C.
(H) Ra = αS-mercapto-γ-methylthiobutanoyl; mp 159-163
° C (i) Ra = αR-mercapto-γ-methylthiobutanoyl; mp 159-163
(J) Ra = αS-mercaptopentanoyl; mp 180-182 ° C .; (k) Ra = αR-mercaptopentanoyl; mp 77-85 ° C .; (1) Ra = αR-mercapto-βR-methoxybutanoyl Mp 130-132
C .; (m) Ra = αS-mercaptopropanoyl; mp 185-187 ° C .; (n) Ra = αS-mercapto-βS-hydroxybutanoyl; mp 120-12.
4 ° C .; (o) Ra = αR-mercapto-βR-hydroxybutanoyl; mp 155-16
0 ° C; (p) Ra = αS-mercapto-β-methylbutanoyl; mp 180-181 ° C.

Example 6 Produced analogously to the previous example: (a)

Embedded image 2-{[1- (2-Mercapto-3-methyl-butanoylamino) -cyclopentanecarbonyl] -amino} -3-naphthalen-2-yl-propionic acid; mp 197
-195 ° C.

(B)

Embedded image 2-{[1- (2-Mercapto-3-methyl-butanoylamino) -cyclopentanecarbonyl] -amino} -3-naphthalen-1-yl-propionic acid; mp 207
° C.

(C)

Embedded image 3-bicyclohexyl-4-yl-2-{[1-mercapto-3-methyl-butanoylamino) -cyclopentanecarbonyl] -amino} -propionic acid; mp 20
9-210 ° C.

A 2-bicyclohexyl-4-yl-2-tert-butoxycarbonylpropionic acid intermediate is prepared as follows: 3-biphenyl-4-yl-2-tert-butoxycarbonylaminopropionic acid (5. 45 psi 0 g) and EtOH suspension of 40mL of platinum oxide (0.625 g) and with H ₂
And stir at room temperature for 2 hours. The catalyst is filtered and washed twice with EtOH. The EtOH solution is then concentrated in vacuo and the residue is recrystallized from hexane to give the intermediate;

[Table 28]

(D)

Embedded image 3- (4-cyclohexyl-phenyl) -2-{[1- (2-mercapto-3-methylbutanoylamino) -cyclopentanecarbonyl] -amino} -propionic acid; m
p 201-202 <0> C.

The 3- (4-cyclohexyl-phenyl) -2-tert-butoxycarbonylamino-propionic acid intermediate is prepared as follows: 3-biphenyl-4-yl-2-tert-butoxycarbonylamino-propion A solution of the acid (1.0 g) and 5% Ph / C (0.25 g) in 10 mL of EtOH was added with H ₂ at 45 p.
Pressurize with si and stir at room temperature for 24 hours. The catalyst is filtered and washed twice with EtOH. Et
The OH phase is then concentrated in vacuo and the residue is chromatographed on silica gel (hexane: E
Purify with tOAc: AcOH 80: 20: 1) to give a white solid.

[Table 29]

(E)

Embedded image 3-biphenyl-4-yl-2-{[1- (2-mercapto-3-methylbutanoylamino) -indan-2-carbonyl] -amino} -propionic acid; mp 203
-205 ° C.

(F)

Embedded image 3-biphenyl-4-yl-2-{[1- (2-mercapto-3-methyl-butylamino) -indan-1-carbonyl] -amino} -propionic acid; mp 115-
120 ° C.

(G)

Embedded image 3-biphenyl-4-yl-2-{[1- (2-mercapto-3-phenyl-propionylamino) -cyclopentanecarbonyl] -amino} -propionic acid; mp
212-213 ° C.

(H)

Embedded image 3-biphenyl-4-yl-2-{[1- (2-mercapto-3-naphthalene-2
-Yl-propionylamino) -cyclopentanecarbonyl] -amino} -propionic acid; mp 166-168 ° C.

(I)

Embedded image 2-{[1-mercapto-3-methylbutanoylamino) -cyclopentanecarbonyl] -amino} -3- (5,6,7,8-tetrahydro-naphthalen-1-yl)-
Propionic acid; mp 158-164 ° C.

The 2-amino-3- (5,6,7,8-tetrahydro-naphthalen-1-yl) -propionic acid methyl ester hydrochloride intermediate is prepared as follows: 1-naphthylalanine methyl ester hydrochloride salt (500 mg, 1.79 mmol) and 20mLMeOH solution of platinum oxide (170 mg) for applying 3.5 hours pressurized with 42psi with H _2. The catalyst is filtered off and the filtrate is concentrated in vacuo to give the intermediate as a solid;

[Table 30]

(K)

Embedded image 2-{[1- (2-Mercapto-3-methylbutanoylamino) -cyclopentanecarbonyl] -amino} -3- (2-methoxybiphenyl-4-yl) -propionic acid; mp 121-123 ° C.

The 2-amino-3- (2-methoxybiphenyl-4-yl) -propionic acid methyl ester hydrochloride intermediate was converted from 4-bromomethyl-2-methoxy-biphenyl to
Prepared by the method reported by Williams and Im (J. Am. Chem. Soc. 1991, 113, 9726). White solid;

[Table 31]

The 4-bromomethyl-2-methoxy-biphenyl starting material is prepared as follows: 3-Methoxy-4-trifluoromethanesulfonylbenzaldehyde is converted to 4-
Prepared from hydroxy-3-methoxybenzaldehyde oil;

[Table 32] This was converted to 2-methoxy-biphenyl-4-carboxaldehyde, Chem. Rev. 1
995, 95, 2457-83, converted as reported for the coupling of tyrosine triflate to boronic acid to give a clear, colorless oil;

[Table 33]

A toluene solution of 10.0 mL of 1.0 M DIBAL-H (diisobutylaluminum hydrate) was added to 2-methoxy-biphenyl-4-carboxaldehyde (1.34 g, 6
(3 mmol) in a solution of 15 mL of THF. The cooling bath is removed and the half-yellow mixture is stirred for 30 minutes. The reaction was quenched by the addition of 3 mL of MeOH and the resulting mixture was combined with EtOAc and 1 liter.
Partition into N HCl. The organic phase was separated, washed with brine, dried over MgSO _4, filtered and concentrated to give 2-methoxy - obtaining methanol clear, colorless oil - biphenyl-4-yl).

[Table 34]

1.24 g (7.6 mmol) of NBS (N-bromosuccinimide) were added in small portions to (
2-methoxy-biphenyl-4-yl) -methanol (1.35 g, 6.3 mmol),
A solution of triphenylphosphine (2.0 g, 7.0 mmol) in 15 mL of CH ₂ Cl ₂ at 0 ° C. is added. 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 silica gel chromatography (10% EtOAc / hexane) to give 4-bromomethyl-2-methoxy-biphenyl as a clear, colorless oil.

[Table 35]

(L)

Embedded image 3-biphenyl-4-yl-2- {1- [3-biphenyl-4-yl-2-mercapto-propionylamino) -cyclopentanecarbonyl] -amino} -propionic acid; mp 187-189 ° C.

(M)

Embedded image 3-biphenyl-4-yl-2-{[4- (2-mercapto-3-methyl-butanoylamino) -tetrahydro-pyran-4-carbonyl] -amino} -propionic acid; 4-amino-tetrahydropyran- Made from 4-carboxylic acid (Lewis et al.,
J. Med. Chem. 1978, 21, 1070); mp 161-163 ° C.

(N)

Embedded image 3- (4-cyclohexyl-phenyl) -2- {1- (2-mercapto-3-phenyl-propionylamino) -cyclopentanecarbonyl] -amino} -propionic acid; mp 172-175 ° C.

(O)

Embedded image 3-biphenyl-4-yl-2-{[1- (2-mercapto-3-methyl-butanoylamino) -tetrahydro-tripyran-4-carbonyl] -amino} -propionic acid; 4-amino-tetrahydro-thiopyran Manufactured from -4-carboxylic acid (J.
Med. Chem. 1978, 21, 1070); mp 203-204 ° C.

(P)

Embedded image 3- (2,2'-dimethoxy-biphenyl-4-yl) -2-{[1- (2-mercapto-3-methyl-butanoylamino) -cyclopentanecarbonyl] -amino}-
Propionic acid; mp 173-175C.

Starting material. 4-Bromomethyl-2,2'-dimethoxybiphenyl is the above-mentioned 4-
Prepared according to the method described for the synthesis of bromomethyl-2-methoxy-biphenylyl;

[Table 36]

(Q)

Embedded image 3- (4-isoxazol-5-yl-phenyl) -2-{[1- (2-mercapto-
Pentanoylamino) -cyclopentanecarbonyl] -amino} -propionic acid; m
p 95-108 ° C.

The starting material is prepared as follows: 2.17 g (13.65 mmol) of bisbenzoyl peroxide (560 mg, 0.232 mmol)
) Of 5- (4-methyl-phenyl) -isoxazole (Lin, YI; Lang, Jr., SA
J. Org. Chem. 1980, 45, 4857) and N-bromosuccinimide (2.43 g,
(13.65 mmol) in a solution of 64 mL of CCl ₄ and the reaction mixture is heated to reflux overnight.
The reaction mixture is then concentrated in vacuo and the product is chromatographed on silica gel (
Purify with 20% EtOAc / hexane, R _f = 0.6) to give 5- (4-bromomethyl-phenyl) -isoxazole.

[Table 37]

2-Amino-3- (4-isoxazol-5-yl-phenyl) -propionic acid hydrochloride was converted to N according to the method of Stork et al. (J. Org. Chem. 1976, 41, 3491).
Prepared from 5- (4-bromomethyl-phenyl) -isoxazole using aHMDS as base; white solid;

[Table 38]

The conversion to ethyl 2-acetylamino-3- (4-isoxazol-5-yl-phenyl) -propionate following enzymatic hydrolysis is performed using (S) -2-acetylamino-
Produce 3- (4-isoquiazol-5-yl-phenyl) -propionic acid;

[Table 39]

(R)

Embedded image 3- (4-isoxazol-5-yl-phenyl) -2-{[1- (2-mercapto-
4-Methyl-pentanoylamino) -cyclopentanecarbonyl] -amino} -propionic acid; mp 104-110 ° C.

Example 7 Similarly prepared according to the method described above, is: (a)

Embedded image 2-{[1- (2-Mercapto-3-methyl-butanoylamino) -cyclopentanecarbonyl] -amino} -3- (4'-chloro-biphenyl-4-yl) -propionic acid; mp 177-179 ° C.

The starting material is prepared as follows: 3.0 g (12.2 mmol) of tyrosine ethyl ester hydrochloride and 2.8 g (12.2 mmol).
The N-Boc-cycloleucine for 2 mmol) is suspended in of CH ₂ Cl ₂ 100 mL. 1.65g (
12.2 mmol) HOBT, 3.02 g (14.6 mmol) DCC, and 1.7 mL (12.2 mm)
was added Et ₃ N in ol), the solution is stirred at room temperature overnight. The reaction mixture was filtered, CH ₂ Cl ₂
Is removed in vacuo. The residue was taken up in EtOAc, filtered and successively 1N HCl, water,
Wash with saturated aqueous NaHCO ₃ solution and brine, then dry over MgSO ₄ , filter,
Concentrate. The residue was purified by silica gel chromatography (50% EtOAc / hexane) to give 2-[(1-tert-butoxycarbonylamino-cyclopentanecarbonyl).
) -Amino] -3- (4-hydroxy-phenyl) -propionic acid ethyl ester;

[Table 40]

[0181] 1.2 mL of trifluoromethanesulfonic anhydride (7.1 mmol) was added to 2-[(1-te
rt-butoxycarbonylamino-cyclopentanecarbonyl) -amino] -3- (
4-Hydroxy-phenyl) -propionic acid ethyl ester (2.70 g, 6.4 mm
ol) and 0.7 mL (8.7 mmol) of pyridine in 20 mL of CH ₂ Cl ₂ at 0 ° C., and the solution is stirred at 0 ° C. for 1 hour. Then, the reaction mixture is partitioned between water and CH ₂ Cl _2.
The organic phase was separated, washed with saturated aqueous NaHCO ₃ solution, dried over MgSO ₄ , filtered and concentrated to give 2-[(1-tert-butoxycarbonylamino-cyclopentanecarbonyl.
) -Amino] -3- (4-trifluoromethanesulfonyloxy-phenyl) -propionic acid ethyl ester is obtained as a tan solid;

[Table 41]

2-[(1-tert-butoxycarbonylamino-cyclopentanecarbonyl)-
Amino] -3- (4-trifluoromethanesulfonyloxyphenyl) -propionic acid ethyl ester and p-chlorophenylboronic acid, Carlson and Shieh (J.
Org. Chem. 1992, 57, 379), a Suzuki bond using PdCl ₂ (dppf) as a catalyst, K ₃ PO ₄ as a base, and DME as a solvent gave 2- [(1-tert-butoxycarbonylamino-cyclopentanecarbonyl
) -Amino] -3- (4-chlorobiphenyl) -propionic acid ethyl ester is obtained.

(B)

Embedded image 2-{[1- (2-Mercapto-3-methyl-butanoylamino) -cyclopentanecarbonyl] -amino} -3- (4'-methoxy-biphenyl-4-yl) -propionic acid; mp 179-181 ° C.

(C)

Embedded image 2-{[1- (2-Mercapto-3-methyl-butanoylamino) -cyclopentanecarbonyl] -amino} -3- [4- (thiophen-3-yl) -phenyl] -propionic acid; mp 177- 179 ° C.

(D)

Embedded image 2-{[1- (2-mercapto-3-phenyl-propionylamino) -cyclopentanecarbonyl] -amino} -3- [4- (thiophen-3-yl) -phenyl] -propionic acid; mp 190-192. ° C.

(E)

Embedded image 2-{[1- (2-Mercapto-3-methyl-pentanoylamino) -cyclopentanecarbonyl] -amino} -3- [4- (thiophen-3-yl) -phenyl] -propionic acid; mp 99- 101 ° C.

Intermediate, 2-[(tert-butoxycarbonylamino-cyclopentanecarbonyl
) -Amino] -3- [4- (thiophen-3-yl) -phenyl] -propionic acid ethyl ester is prepared via the following Suzuki coupling reaction: 2-{(tert-butoxy) in a 25 mL round bottom flask. Carbonylamino-cyclopentanecarbonyl) -amino] -3- (4-trifluoromethanesulfonyloxy-phenyl) -propionic acid ethyl ester (500 mg, 0.905 mmol), thiophen-3-boronic acid (232 mg, 1.81 mmol), PdCl ₂ (dppf) (66 mg, 0.0905 mm
ol), K ₃ PO ₄ (768 mg, 3.62 mmol) and 9 mL of THF were added and the reaction mixture was
Heat to reflux for hours, then cool to room temperature. The reaction mixture was partitioned between EtOAc and water,
The aqueous phase is extracted with EtOAc. The combined organic phases were washed with brine, dried over MgSO _4, filtered and concentrated. The product is chromatographed on silica gel (30% EtOAc / He
Purify in x).

(F)

Embedded image 2-{[1- (2-Mercapto-3-methyl-butanoylamino) -cyclopentanecarbonyl] -amino} -3- [4- (thiophen-2-yl) -phenyl] -propionic acid; mp 179- 181 ° C.

(G)

Embedded image 2-{[1- (2-mercapto-3-phenyl-propionylamino) -cyclopentanecarbonyl] -amino} -3- (4′-trifluoromethyl-biphenyl-4-
Yl) -propionic acid; mp 222-225 ° C.

(H)

Embedded image 2-{[1- (2-mercapto-3-methylbutanoylamino) -cyclopentanecarbonyl] -amino} -3- (4'-trifluoromethyl-biphenyl-4-yl)
-Propionic acid; mp 235-236 <0> C.

(I)

Embedded image 3-biphenyl-3-yl-2-{[1- (2-mercapto-3-methylbutanoylamino) -cyclopentanecarbonyl] -amino} -propionic acid; mp 75-
78 ° C,

(J)

Embedded image 3- [4- (furan-2-yl) -phenyl] -2-{[1- (2-mercapto-3-
Methyl-butanoylamino) -cyclopentanecarbonyl] -amino} -propionic acid; mp 152-154 ° C.

The starting material, 2-[(1-tert-butoxycarbonylamino-cyclopentanecarbonyl) -amino] -3- [4- (furan-2-yl) -phenyl] -propionic acid ethyl ester, was treated with tri- Prepared from n-butyl-furan-2-yl-stannane as follows: 2-[(tert-butoxycarbonylamino-cyclopentanecarbonyl) -amino] -3- (4-iodo-phenyl) in a 25 mL round bottom flask. ) -Propionic acid methyl ester (250 mg, 0.48 mmol), tri-n-butyl-furan-2-yl-stannane (196 mg, 0.57 mmol), Pd ₂ (dba) ₃ (11 mg, 0.012 mmol), tri Phenylarsine (30 mg, 0.098 mmol) and 10 mL of toluene are charged and the reaction mixture is heated at reflux overnight, then cooled to room temperature. The reaction mixture is filtered, diluted with EtOAc and washed with half-saturated aqueous KF. The organic phase was washed with brine, dried over MgSO _4, filtered and concentrated. The product is chromatographed on silica gel (30% EtOAc /
Hex); mp 107-112 ° C.

(K)

Embedded image 2-{[1- (2-Mercapto-3-methyl-butanoylamino) -cyclopentanecarbonyl] -amino} -3- [4- (pyridin-3-yl) -phenyl] -propionic acid; mp 212- 214 ° C.

(L)

Embedded image 2-{[1- (2-Mercapto-3-methyl-pentanoylamino) -cyclopentanecarbonyl] -amino} -3- [4- (pyridin-3-yl) -phenyl] -propionic acid; mp 207- 208 ° C.

(M)

Embedded image 2-{[1- (2-Mercapto-3-methyl-pentanoylamino) -cyclopentanecarbonyl] -amino} -3- [4- (pyridin-3-yl) -phenyl] -propionic acid; mp 205- 207 ° C.

(N)

Embedded image 2-{[1- (2-Mercapto-3-methyl-pentanoylamino) -cyclopentanecarbonyl] -amino} -3- [4- (pyridin-3-yl) -phenyl] -propionic acid; mp 210- 211 ° C.

(O)

Embedded image 2-{[1- (2-mercapto-3-cyclohexyl-butanoylamino) -cyclopentanecarbonyl] -amino} -3- [4- (pyridin-3-yl) -phenyl]-
Propionic acid; mp 243-344 ° C.

(P)

Embedded image 3- [4- (1-acetyl-piperidin-3-yl) -phenyl] -2-{[1- (2
-Mercapto-3-methyl-butanoylamino) -cyclopentanecarbonyl]-
Amino} -propionic acid; mp 190-192 ° C.

The starting material is prepared as follows: 2-[(1-tert-butoxycarbonylamino-cyclopentanecarbonyl)-
Amino] -3- {4- (pyridin-3-yl) - phenyl - a MeOH suspension of 10mL of propionic acid ethyl ester (958 mg) and 10% Pt / C (958g) , in H ₂ 45
Pressurize to psi and stir at room temperature for 4 days. The catalyst is filtered off and washed with MeOH. The combined organic phases are concentrated in vacuo. The residue was chromatographed on silica gel (EtOAc: MeOH:
AcOH 80: 20: 1) to give 2-[(1-tert-butoxycarbonylamino-cyclopentanecarbonyl) -amino] -3- [4- (piperidin-3-yl)-.
[Phenyl] -propionic acid is obtained;

[Table 42]

Acetyl chloride (50 mL, 0.70 mmol) was added to 2-[(1-tert-butoxycarbonylamino-cyclopentanecarbonyl) -amino] -3- [4- (piperidin-3-
Yl) - phenyl] - Puropison acid ethyl ester (277 mg, 0.57 mmol) and slowly added to Et ₃ N solution of CH ₂ Cl ₂ 2mL of 11 mL (0.79 mmol). The reaction mixture is stirred at 0 ° C. for 2 hours, then partitioned between saturated aqueous NaHCO ₃ solution and CH ₂ Cl ₂ . The organic phase was washed with brine, dried over MgSO _4, filtered and concentrated. The residue was purified by silica gel chromatography (EtOAc) to give 2-[(1-tert-butoxycarbonylamino-cyclopentanecarbonyl) -amino] -3- [4- (1-acetyl-piperidin-3-yl) -phenyl ] -Propionic acid ester;

[Table 43]

Example 8 Partitioning of α-bromoacetylaminocyclopentane carboxylic acid and ester (a)

Embedded image 1- (2-Bromo-3-methyl-butanoylamino) -cyclopentanecarboxylic acid is prepared as follows: 5.60 g (18 mmol) of 1- (2-bromo-3-methyl-butanoylamino) −
Dissolve cyclopentanecarboxylic acid methyl ester in 40 mL MeOH. 37 mL of 1 N NaOH are added and the solution is stirred at room temperature for 5 hours. The solvent was removed in vacuo, the residue is dissolved in water and extracted three times with Et ₂ O. The aqueous phase was acidified with 40 mL of 1N HCl,
Filtering the product as a white solid;

[Table 44]

A 1- (2-bromo-3-methyl-butanoylamino) -cyclopentanecarboxylic acid methyl ester precursor is prepared as follows: 4.92 g (27 mmol) of cycloleucine methyl ester hydrochloride and 7 .72 (
27 mmol) of diisopropylammonium 2-bromo-3-methyl-butyrate in 5
Suspend in 0 mL CH ₂ Cl ₂ . 3.74 g (27 mmol) of HOAT and 6.20 g (30 mmol)
l) DCC is added and the solution is stirred at room temperature overnight. The reaction mixture was filtered to remove the CH ₂ Cl ₂ in vacuo. The residue was taken up in EtOAc, filtered, washed successively with 1N HCl, water, saturated aqueous NaHCO ₃ solution, and brine, then dried over MgSO ₄ , filtered,
Concentrate. The residue is purified by silica gel chromatography (30% EtOAc / hexane to give a white solid;

[Table 45]

The following compounds are prepared in a similar manner. (b)

Embedded image 1- (2-bromo-3-methyl-pentanoylamino) -cyclopentanecarboxylic acid; white solid;

[Table 46]

(C)

Embedded image 1- (2-bromo-3-methyl-pentanoylamino) -cyclopentanecarboxylic acid; white solid;

[Table 47]

Example 9 Synthesis of Biaryl Amino Acid Ester Step 1

Embedded image 2- (benzhydridene-amino) -3- [4- (4,4,5,5-tetramethyl- [1
, 2,3] Dioxaborolan-2-yl) -phenyl] -propionic acid ethyl ester was prepared via NaHM via the method reported by Stork (J. Org. Chem. 1976, 41, 3491).
Using DS as the base, 2- (4-bromomethyl-phenyl) -4,4,5,5-
Prepared from tetramethyl- [1,3,2] dioxaborolane. White solid; mp 12
0-121 ° C;

[Table 48]

Step 2

Embedded image 2- (benzhydridene-amino) -3- (4'-fluoro-biphenyl-4-yl
) -Propionic acid ethyl ester was prepared according to Satoh et al. (Tetraherdon Letter Vol. 4).
8, 7645 (1997)). In a 50 mL flask, the boronate intermediate of Step 1 (600 mg, 1.01 mmol), 1-fluoro-4-iodo-
Benzene (247 mg, 1.11 mmol), PdCl ₂ (dppf) (37 mg, 0.051 mmol), K ₃ P
Charge O ₄ (860 mg, 4.04 mmol) and 10 mL of DME. The reaction mixture is heated at reflux for 12 hours, then cooled to room temperature and partitioned between EtOAc and water. The organic phase was separated, washed with brine, dried over MgSO _4, filtered and concentrated. The residue is purified by silica gel chromatography (gradient elution with 5-10% EtOAc / hexane) to give the imine as a light brown oil.

[Table 49]

Step 3

Embedded image 2-Amino-3- (4'-fluoro-biphenyl-4-yl) -propionic acid ethyl ester hydrochloride is prepared as follows: In a 50 mL flask, 2- (benzhydridene-amino) -3- (4'- Fluoro-biphenyl-4-yl) -propionic acid ethyl ester (350 mg, 0.775 mmol)
Charge 10 mL of 1N HCl and 8 mL of Et ₂ O. The reaction mixture is stirred at room temperature for 12 hours, then partitioned between ether and water. Separate the aqueous phase and extract twice with ether, then concentrate in vacuo to give the product as a white solid;

[Table 50]

The biaryl-substituted amino acid ester starting materials leading to the end products described in the examples below can be prepared analogously.

Example 10 (a)

Embedded image 1- (2-bromo-3-methylbutanoylamino) -cyclopentanecarboxylic acid
Example 8 and 2-amino-3- (4'-fluorobiphenyl-4-yl) propionic acid ethyl ester hydrochloride (Example 9) by condensation using DCC, HOAT and triethylamine in methylene chloride. , 3- (4'-fluoro-biphenyl-4
-Yl) -2-{[1- (2-mercapto-3-methyl-butanoylamino) -cyclopentanecarbonyl] -amino} -propionic acid; mp 196-198 ° C.
.

[0211] Similarly prepared are: (b)

Embedded image 2-{[1- (2-mercapto-3-methyl-butanoylamino) -cyclopentanecarbonyl] -amino} -3- (4-pyridin-2-yl-phenyl-4-yl)-
Propionic acid (from 2-iodopyridine); mp 199-201 ° C.

(C)

Embedded image 2-{[1- (2-mercapto-3-methyl-butanoylamino) -cyclopentanecarbonyl] -amino} -3- (4-pyrimidin-5-yl-phenyl) -propionic acid (from 5-iodopyrimidine ); Mp 214-215 ° C.

(D)

Embedded image 2-{[1- (2-mercapto-3-methyl-pentanoylamino) -cyclopentanecarbonyl] -amino} -3- (4-pyrimidin-5-yl-phenyl) -propionic acid; mp 206-208 ° C. .

(E)

Embedded image 2-{[1- (2-Mercapto-3-methyl-pentanoylamino) -cyclopentanecarbonyl] -amino} -3- (4-pyrimidin-5-yl-phenyl) -propion hydrochloride; mp 170- 184 ° C.

(F)

Embedded image 2-{[1- (2-mercapto-4-methyl-pentanoylamino) -cyclopentanecarbonyl] -amino} -3- (4-pyrimidin-5-yl-phenyl) -propionic acid; mp 192-195 ° C .

(G)

Embedded image 2-{[1- (2-mercapto-3-methyl-butanoylamino) -cyclopentanecarbonyl] -amino} -3- (4-pyrimidin-4-yl-phenyl) -propionic acid (from 4-bromopyridine ); Mp 236-238 ° C.

(H)

Embedded image 3- [4- (5-hydroxymethyl-thiophen-3-yl) -phenyl] -2-{[
1- (2-Mercapto-3-methyl-butanoylamino) -cyclopentanecarbonyl] -amino} -propionic acid (starting from 4-bromo-2-thiophenecarboxaldehyde); mp 155-158 ° C.

(I)

Embedded image 2-{[1- (2-mercapto-3-methyl-butanoylamino) -cyclopentanecarbonyl] -amino} -3- (3'-methoxy-biphenyl-4-yl) -propionic acid (1-iodo- From 3-methoxybenzene); mp 159-160 ° C.

(J)

Embedded image 3- (2 ', 3'-dimethoxy-biphenyl-4-yl) -2-{[1- (2-mercapto-3-methyl-butanoylamino) -cyclopentanecarbonyl] -amino}-
Propionic acid (1-trifluoromethylsulfonyloxy-2,3-dimethoxy-
From benzene); mp 83-86 ° C.

(K)

Embedded image 3- (3 ', 5'-dimethoxy-biphenyl-4-yl) -2-{[1- (2-mercapto-3-methyl-butanoylamino) -cyclopentanecarbonyl] -amino}-
Propionic acid; mp 150-152 ° C.

Example 11 The following can be prepared in the same manner as described above: (a)

Embedded image 3- (2'-hydroxy-biphenyl-4-yl) -2-{[1- (2-mercapto-
4-Methyl-pentanoylamino) -cyclopentanecarbonyl] -amino} -propionic acid; mp 215-217 ° C.

The starting material is prepared as follows: Boc-protected boronophenylalanine reagent, 2- (Nt-Boc-amino) -3- [
4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl)-
Phenyl] propionic acid ethyl ester (Roberts et al., Tetraherdon Letters
1980, 21, 3435) with 1-acetoxy-2-iodobenzene in a Suzuki coupling reaction followed by coupling with Nt-Boc-cycloleucine methyl ester to form the intermediate

Embedded image Obtaining 2-[(1-tert-butoxycarbonylamino-cyclopentanecarbonyl) -amino] -3- (2′-hydroxy-biphenyl-4-yl) -propionic acid methyl ester;

[Table 51]

(B) 2- (2′-Fluoro-biphenyl-4-yl) -2-{[1- (2-mercapto-3
-Methyl-butanoylamino) -cyclopentanecarbonyl] -amino} -propionic acid (1-fluoro-2-iodobenzene); mp 171-173C.

(C)

Embedded image 3- (3'-Fluoro-biphenyl-4-yl) -2-{[1- (2-mercapto-4
-Methyl-pentanoylamino) -cyclopentanecarbonyl] -amino} -propionic acid (1-fluoro-3-iodobenzene); mp 125-128 ° C.

Example 12 Prepared analogously to the method described above, the following is (a)

Embedded image 2-{[1- (2-Mercapto-3-methyl-butanoylamino) -cyclopentanecarbonyl] -amino} -3- (2'-methoxy-biphenyl-4-yl) -propionic acid; mp 172-174 ° C.

Expression

Embedded image Of 1-[(1-tert-butoxycarbonylamino-cyclopentanecarbonyl) -amino] -3- (4-iodo-phenyl) -propionic acid methyl ester with N-Boc cycloleucine and 4- iodo - phenylalanine methyl ester is prepared by standard coupling conditions previously described _{(DCC, HOAT, Et 3 N} ); mp
137 ° C.

This condensation with 2-methoxyphenylboronic acid gives the formula

Embedded image To produce 2-[(1-tert-butoxycarbonylamino) -cyclopentanecarbonyl) -amino] -3- (2′-methoxy-biphenyl-4-yl) -propionic acid methyl ester;

[Table 52]

(B)

Embedded image 3- (4'-Fluoro-biphenyl-4-yl) -2-{[1- (2-mercapto-3
-Methyl-butanoylamino) -cyclopentanecarbonyl] -amino} -propionic acid (from 4-fluorophenyl-boronic acid) mp 106-108 ° C.

(C)

Embedded image 2-{[1- (2-mercapto-3-methyl-butanoylamino) -cyclopentanecarbonyl] -amino} -3- (3'-trifluoromethyl-biphenyl-4-yl
) -Propionic acid (from 4-fluorophenyl-boronic acid);
° C.

(E)

Embedded image 2-{[1- (2-mercapto-4-methyl-pentanoylamino) -cyclopentanecarbonyl] -amino} -3- (4′-naphthalen-1-yl-biphenyl-4-
Yl) -propionic acid (from naphthalen-1-ylboronic acid); mp 151-15
4 ° C.

(F)

Embedded image 2-{[1- (2-mercapto-4-methyl-pentanoylamino) -cyclopentanecarbonyl] -amino) -3- (4'-methylthio-biphenyl-4-yl) -propionic acid (4-methylthiophenyl -From boronic acid); mp 187-189 ° C.

Example 13 Also can be prepared as described above: (a) 2-{[1- (2-Mercapto-4-methyl-benzofuran-2-yl) -propionic acid Mp 115-117 ° C. The starting material 2-amino-3- (4,5,6,7-tetrafluoro-3-methyl-benzofuran-2-yl) -propionic acid methyl ester hydrochloride was prepared according to Stork et al.
al. (J. Org. Chem. 1976, 41, 3491) using 2-bromomethyl-4,5,6,7-tetrafluoro-3-, using NaHMDS as the base.
Prepared from methyl-benzofuran (prepared by reduction of the corresponding ethyl ester and conversion of the resulting alcohol to bromide);

[Table 53]

(B) 3- (1H-Indol-3-yl) -2-{[1- (2-mercapto-4-methyl-pentanoylamino) -cyclopentanecarbonyl] -amino} -propionic acid; mp 116-118 ° C. (c) 3- (1H-Indol-3-yl) -2-{[1- (2-mercapto-pentanoylamino) -cyclopentanecarbonyl] -amino} -propionic acid; mp 10
2-105 ° C.

(D) 2-({1- [3- (4-hydroxyphenyl) -2-mercapto-propionylamino] -cyclopentanecarbonyl} -amino) -3- (1H-indori-3-
Yl) -propionic acid;

[Table 54]

(E) 3-benzo [b] thiophen-3-yl-2-{[1- (2-mercapto-4-
Methyl-pentanoylamino) -cyclopentanecarbonyl] -amino} -propionic acid; mp 135-137 ° C. (f) 3- (1H-Indol-3-yl) -2-{[1- (2-mercapto-3-methylbutanoylamino) -cyclopentanecarbonyl] -amino} -propionic acid. (g) 3- (1H-Indol-3-yl) -2-{[1- (2-acetylthio-3-methylbutanoylamino) -cyclopentanecarbonyl] -amino} -propionic acid n-butyl ester; mp 111-112 ° C. (h) 3- (4-biphenylyl) -2-{[1- (2-mercapto-3-methylbutanoylamino) -cyclopentanecarbonyl] amino} -propionic acid; mp 180
-181 ° C.

──────────────────────────────────────────────────続 き Continuation of front page (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE ), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR , BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS , JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZA, ZW (72) Inventor Faribolds Filugina United States 10709 New York East Chester, Merritt Avenue No. 35 (72) Inventor Denton Wade Heuer, No. 3526, Noble Drive, Dexter, Michigan, United States 48130 U.S.A. 5th F term (reference) 4C084 AA01 BA01 BA08 BA14 BA24 MA01 NA14 ZA062 ZA082 ZA202 ZA332 ZA372 ZA392 ZA402 ZA422 ZA432 ZA452 ZA592 ZA662 ZA702 ZA712 ZA812 ZB072 ZC202 ZC352 4H045 AA10 BA11 DA55 EA20 FA20

Claims (17)

[Claims] 1. A compound of the formula I Wherein R is a bicyclic carbocyclic aryl or a bicyclic heterocyclic aryl; or a fully or partially saturated form thereof; or R is a cycloalkyl-substituted monocyclic carbocycle R is a monocyclic carbocyclic aryl optionally substituted by lower alkyl or azabicyclo optionally substituted by acyl; or R is cycloalkyl substituted by cycloalkyl or azacycloalkyl; R ₁ is hydrogen or acyl; R ₂ is hydrogen, lower alkyl, carbocyclic or heterocyclic aryl, carbocyclic or heterocyclic aryl-lower alkyl, cycloalkyl, cycloalkyl-lower alkyl, biaryl, biaryl-lower Alkyl, (hydroxy, lower alkoxy or acyloxy) -lower alkyl, or lower Alkyl - (thio, sulfinyl or sulfonyl) - lower alkyl; - the fusion cycloalkylidene or R ₂ and R ₃ together with the carbon atom to which they are attached cycloalkylidene or benzo; R ₃ is hydrogen or lower alkyl A forms a ring with the carbon atom to which it is attached to form a 3- to 10-membered cycloalkylidene or 5- to 10-membered cycloalkenylidene group, which is substituted with lower alkyl or aryl-lower alkyl. Or A may be fused to a saturated or unsaturated carbocyclic 5- to 7-membered ring; or A together with the carbon atom to which it is attached, optionally lower alkyl, acyl or aryl-lower. 5- to 6-membered oxacycloalkylidene, thiacycloalkylidene optionally substituted with alkyl Or azacycloalkylidene; or A together with the carbon atom to which it is attached, refers to 2,2-norbornylidene; m is 0 or 1-3; Y is 5-tetrazolyl, carboxyl or pharmaceutically acceptable Or a disulfide derivative derived from said compound wherein R ₁ is hydrogen; or a pharmaceutically acceptable salt thereof for endothelin converting enzyme inhibition in mammals or for endothelin dependence Use in the manufacture of a pharmaceutical composition for the treatment of a disease. 2. Use of a compound according to claim 1, wherein the asymmetric carbon atom in the substituent Y has the S-configuration. 3. The formula: Wherein R is benzothiophenyl, naphthyl, benzofuranyl, indolyl, or monocyclic carbocyclic aryl substituted by monocyclic carbocyclic aryl or carbocyclic heterocyclic aryl; R ₁ is hydrogen or Carboxyl-derived acyl; R ₂ is 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 is 5-tetrazolyl, carboxyl or a carboxyl derivative in the form of a pharmaceutically acceptable ester;
Preferably 2, 4, or 5], or a pharmaceutically acceptable salt thereof. 4. R has the meaning defined in claim 3; R ₁ is hydrogen, aryl-lower alkanoyl, lower alkanoyl, lower alkoxy-lower alkanoyl,
Or heterocyclic or carbocyclic aroyl; R ₂ is C ₂ -C ₄ alkyl interrupted by S or O, or heterocyclic aryl-lower alkoxycarbonyl, α-
(Lower alkanoyloxy-, lower alkoxycarbonyl- or di-lower alkylaminocarbonyl-) lower alkoxycarbonyl; n is 2, 4 or 5; the compound of claim 3; or a pharmaceutically acceptable salt thereof. use. 5. A compound of the formula And formula IIIa: Wherein R is benzothiophenyl, naphthyl, benzofuranyl, indolyl, or monocyclic carbocyclic aryl substituted by monocyclic carbocyclic aryl or monocyclic heterocyclic aryl; R ₁ is hydrogen, Lower alkanoyl, methoxy-lower alkanoyl, benzoyl or pyridylcarbonyl; R ₂ is C ₂ -C ₅ -alkyl, cyclohexyl or C ₂ -C ₄ -alkyl interrupted by O or S; Y is 5-tetrazolyl, carboxyl, Lower alkoxycarbonyl, benzyloxycarbonyl, pyridylmethoxycarbonyl, α- (lower alkanoyloxy-, lower alkoxycarbonyl- or di-lower alkylaminocarbonyl-)
Lower alkoxycarbonyl]. Use of the compound according to claim 3 or a pharmaceutically acceptable salt thereof. 6. Use of a compound according to claim 5 of formula III or a pharmaceutically acceptable salt thereof. 7. A compound of formula IIIb Wherein R is benzothiophenyl, naphthyl, benzofuranyl, indolyl or a carbocyclic aryl substituted by a monocyclic carbocyclic aryl or a monocyclic heterocyclic aryl; W is CH ₂ , O, S or NR ₄ (wherein, R ₄ is hydrogen, acyl, lower alkyl or aryl - lower alkyl); R ₁ is hydrogen, lower alkanoyl, methoxy - lower alkanoyl, benzoyl or pyridylcarbonyl; R ₂ is C ₂ -C ₅ - alkyl , Cyclohexyl or C ₂ -C ₄ -alkyl interrupted by O or S; Y is 5-tetrazolyl, carboxyl, lower alkoxycarbonyl, benzyloxycarbonyl, pyridylmethoxycarbonyl, α- (lower alkanoyloxy-, lower alkoxycarbonyl -Or di-lower alkylaminocarboni -)
A lower alkoxycarbonyl]; or a pharmaceutically acceptable salt thereof. 8. R is 4-biphenylyl or 3-indolyl; R ₁ is hydrogen or lower alkanoyl; R ₂ is C ₃ -C ₅ -alkyl, Y is 5-tetrazolyl, carboxyl, lower alkoxycarbonyl, benzyloxycarbonyl, The compound according to claim 3, which is pyridylmethoxycarbonyl, α- (lower alkanoyloxy-, lower alkoxycarbonyl- or di-lower alkylaminocarbonyl-) lower alkoxycarbonyl; or use of a pharmaceutically acceptable salt thereof. . 9. R is 4-biphenylyl; R ₁ is hydrogen or lower alkanoyl; R ₂ is n-propyl, n-butyl or isobutyl; and Y is 5-tetrazolyl or particularly preferred is carboxyl or lower alkoxycarbonyl. Use of a compound according to claim 3; or a pharmaceutically acceptable salt thereof. 10. R is 4-biphenylyl; R ₁ is hydrogen or lower alkanoyl; R ₂ is n-propyl, n-butyl or isobutyl; and Y is 5-tetrazolyl or particularly preferred is carboxyl or lower alkoxycarbonyl. Use of a compound according to claim 6; or a pharmaceutically acceptable salt thereof. 11. Use according to claim 1, for the manufacture of a pharmaceutical composition for the treatment of hypertension, heart failure, cerebral vasospasm, stroke, renal failure, bronchial asthma, complications related to organ transplantation, and erectile dysfunction. . 12. A compound of formula III Wherein R is benzothiophenyl, naphthyl, benzofuranyl, indolyl, or monocyclic carbocyclic aryl substituted by monocyclic carbocyclic aryl or monocyclic heterocyclic aryl; R ₁ is hydrogen, Lower alkanoyl, methoxy-lower alkanoyl, benzoyl or pyridylcarbonyl; R ₂ is C ₂ -C ₅ -alkyl, cyclohexyl or C ₂ -C ₄ -alkyl interrupted by O or S; Y is 5-tetrazolyl, carboxyl, Lower alkoxycarbonyl, benzyloxycarbonyl, pyridylmethoxycarbonyl, α- (lower alkanoyloxy-, lower alkoxycarbonyl- or di-lower alkylaminocarbonyl-)
A lower alkoxycarbonyl]. 13. A compound of formula III Or a compound of formula (IIIb) Wherein R is carboxy or lower alkoxycarbonyl; R ₁ is hydrogen or lower alkanoyl; R ₂ is lower alkyl, hydroxy, mercapto, phenyl, phenyl substituted with lower alkyl, lower alkoxy, hydroxy, lower alkylthio, halogen , Trifluoromethyl, and further unsubstituted or independently lower alkyl, lower alkoxy, hydroxy, lower alkylthio, lower alkyl substituted with phenyl or naphthyl optionally substituted with halogen or trifluoromethyl, or Cyclohexyl; and R is 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, N-unsubstituted or piperidine-N-substituted with lower alkanoyl-
3-yl-phenyl, or 4- (5-pyrimidinyl) -phenyl, naphthyl, 5
, 6,7,8-Tetrahydro-naphthalen-1-yl, 5,6,7,8-tetrahydro-naphthalen-2-yl or 4-cyclohexyl-phenyl, or 4-biphenylyl or one or both benzene rings Is substituted with lower alkyl, lower alkoxy, hydroxy, lower alkylthio, halogen or trifluoromethyl] or a pharmaceutically acceptable salt thereof. 14. Y is 5-tetrazolyl, carboxyl or lower alkoxycarbonyl; R ₁ is hydrogen or lower alkanoyl; R ₂ is n-propyl, n-butyl, isobutyl, n-pentyl, methoxyethyl or methylthioethyl; Is 3-indolyl, 4- (5-isoxazolyl) -phenyl, 4- (2- or 3-furanyl) -phenyl, 4- (2- or 3-thienyl) -phenyl,
-Biphenylyl, 4- (2- or 3-pyridyl) -phenyl, 4- (5-pyrimidinyl) -phenyl, or one or both benzene rings to lower alkyl, lower alkoxy, hydroxy, lower alkylthio, halogen or trifluoro A compound of formula III or pharmaceutically acceptable salt thereof, which is 4-biphenylyl substituted with methyl. 15. A compound of formula (III) wherein Y is carboxyl, R ₁ is hydrogen, R ₂ is n-propyl and R is 4-biphenylyl, or a pharmaceutically acceptable salt thereof; A compound of formula (III) wherein Y is methoxycarbonyl, R ₁ is acetyl, R ₂ is n-propyl and R is 4-biphenylyl, or a pharmaceutically acceptable salt thereof; (iii) Y is carboxyl, R ₁ is Hydrogen, a compound of formula (III) wherein R ₂ is isobutyl and R is 3-indolyl, or a pharmaceutically acceptable salt thereof; and (iv) the group consisting of Y is methoxycarbonyl, R ₂ is isobutyl and R is indolyl The compound according to claim 14, which is selected from: 16. A pharmaceutical composition for inhibiting endothelin converting enzyme, comprising the compound according to claim 13 or 14 and a carrier. 17. Use of a compound according to claim 13 or 14 in the manufacture of a pharmaceutical composition for inhibiting an endothelin converting enzyme or treating an endothelin-dependent disease in a mammal.