Dipeptide derivatives

Details Dipeptide derivatives Dipeptide derivatives

2002-05-09

2004-08-17

Lambkin, Deborah C. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

C514S541000, C514S542000, C560S170000, C560S159000, C560S105000

Reexamination Certificate

active

06777443

ABSTRACT:

SUMMARY OF THE INVENTION
The present invention directed to novel vasopeptidase inhibitors described below which are useful as dual inhibitors of both angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP, EC 3.4.24.11). The compounds of the invention are particularly useful for the treatment and/or the prevention of conditions which are responsive to ACE and NEP inhibition, particularly cardiovascular disorders, such as hypertension, isolated systolic hypertension, renal failure (including edema and salt retention), pulmonary edema, left ventricular hypertrophy, heart failure (including congestive heart failure) and atherosclerosis. The compounds of the invention are also useful for reducing elevated cholesterol plasma levels in mammals. Furthermore, they also inhibit endothelin converting enzyme (ECE) and are useful for the treatment and/or prevention of conditions which are responsive to ECE inhibition.
By virtue of their inhibition of neutral endopeptidase, the compounds of the invention may also be useful for the treatment of pain, depression, certain psychotic conditions, and cognitive disorders. Other potential indications include the treatment of angina, premenstrual syndrome, Meniere's disease, hyperaldosteronism, hypercalciuria, ascites, glaucoma, asthma and gastrointestinal disorders such as diarrhea, irritable bowel syndrome and gastric hyperacidity.
By virtue of their inhibition of ECE, the compounds of the invention may also be useful for the treatment and/or prevention of endothelin dependent conditions and diseases, including cerebral ischemia (stroke), subarachnoid hemorrhage, traumatic brain injury, cerebral vasospasm, arterial hypertrophy, restenosis, Raynaud's disease, myocardial infarction, obesity; also prostate hyperplasia, migraine, diabetes mellitus (diabetic nephropathy), preeclampsia, glaucoma, and transplantation rejection such as in aorta or solid organ transplantation; as well as erectile dysfunction.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to compounds of formula I
wherein
R represents hydrogen, lower alkyl, carbocyclic or heterocyclic aryl-lower alkyl or cycloalkyl-lower alkyl;
R
1
represents lower alkyl, cycloalkyl, carbocyclic or heterocyclic aryl, or biaryl; or R
1
represents (cycloalkyl, carbocyclic aryl, heterocyclic aryl or biaryl)-lower alkyl;
alk represents lower alkylene;
R
3
represents hydrogen or acyl;
R
4
represents hydrogen, optionally substituted lower alkyl, carbocyclic or heterocyclic aryl, (carbocyclic or heterocyclic aryl)-lower alkyl, cycloalkyl, cycloalkyl-lower alkyl, biaryl, biaryl-lower alkyl, oxacycloalkyl, thiacycloalkyl, azacycloalkyl, or (oxacycloalkyl, thiacycloalkyl or azacycloalkyl)-lower alkyl;
R
5
represents hydrogen or lower alkyl; or
R
4
and R
5
, together with the carbon atom to which they are attached, represent cycloalkylidene, benzo-fused cycloalkylidene; or 5- or 6-membered (oxacycloalkylidene, thiacycloalkylidene or azacycloalkylidene), each optionally substituted by lower alkyl or aryl-lower alkyl;
R
6
represents lower alkyl, carbocyclic or heterocyclic aryl, (carbocyclic or heterocyclic aryl)-lower alkyl, cycloalkyl, cycloalkyl-lower alkyl, biaryl or biaryl-lower alkyl;
R
7
represents lower alkyl, (carbocyclic or heterocyclic aryl)-lower alkyl, cycloalkyl-lower alkyl or biaryl-lower alkyl; or
R
6
and R
7
, together with the carbon atom to which they are attached, represent 3- to 10-membered cycloalkylidene which may be substituted by lower alkyl or aryl-lower alkyl or may be fused to a saturated or unsaturated carbocyclic 5- to 7-membered ring; or 5- or 6-membered (oxacycloalkylidene, thiacycloalkylidene or azacycloalkylidene), each optionally substituted by lower alkyl or aryl-lower alkyl; or 2,2-norbonylidene;
X represents —O—, —S(O)
n
—, —NHSO
2
—, or —NHCO—;
n is zero, one or two; and
COOR
2
represents carboxyl or carboxyl derivatized in form of a pharmaceutically acceptable ester;
disulfide derivatives derived from said compounds wherein R
3
is hydrogen; and pharmaceutically acceptable salts thereof.
The present invention is also directed to pharmaceutical compositions comprising said compounds; methods for preparation of said compounds; intermediates; and methods of treating disorders in mammals which are responsive to ACE and NEP inhibition by administration of said compounds to mammals in need of such treatment.
Encompassed by the instant invention are also any prodrug derivatives of compounds of the invention having a free carboxyl, sulfhydryl or hydroxy group, said prodrug derivatives being convertible by solvolysis or under physiological conditions to be the free carboxyl, sulfhydryl and/or hydroxy compounds. Prodrug derivatives are, e.g., the esters of free carboxylic acids and S-acyl and O-acyl derivatives of thiols, alcohols or phenols, wherein acyl has meaning as defined herein.
Pharmaceutically acceptable esters are preferably prodrug ester derivatives, such being convertible by solvolysis or under physiological conditions to the free carboxylic acids of formula I.
Pharmaceutically acceptable prodrug esters are preferably, e.g., lower alkyl esters, aryl-lower alkyl esters, &agr;-(lower alkanoyloxy)-lower alkyl esters such as the pivaloyloxymethyl ester, and &agr;-(lower alkoxycarbonyl, morpholinocarbonyl, piperidinocarbonyl, pyrrolidinocarbonyl or di-lower alkylaminocarbonyl)-lower alkyl esters.
Pharmaceutically acceptable salts are salts derived from pharmaceutically acceptable bases for any acidic compounds of the invention, e.g., those wherein COOR
2
represents carboxyl. Such are, e.g., alkali metal salts (e.g., sodium, potassium salts), alkaline earth metal salts (e.g., magnesium, calcium salts), amine salts (e.g., tromethamine salts).
Compounds of formula I, depending on the nature of substituents, possess two or more asymmetric carbon atoms. The resulting diastereomers and optical antipodes are encompassed by the instant invention. The preferred configuration is indicated in formula Ia.
wherein asymmetric carbons carrying the substituents -alk-X—R
1
and R
4
typically have the S-configuration.
Preferred are the compounds of formula I and Ia wherein R and R
5
represent hydrogen; R
1
represents lower alkyl, C
5
- or C
6
-cycloalkyl, carbocyclic or heterocyclic aryl, or (carbocyclic or heterocyclic aryl)-lower alkyl; alk represents lower alkylene; X represents —O— or —S(O)
n
wherein n represents zero or two; R
3
represents hydrogen or acyl; R
4
represents optionally substituted lower alkyl, oxacycloalkyl, oxacycloalkyl-lower alkyl, or (carbocyclic or heterocyclic aryl)-lower alkyl; R
5
represents hydrogen; or R
4
and R
5
combined with the carbon atom to which they are attached represent C
5
or C
6
-cycloalkylidene; R
6
and R
7
represent lower alkyl; or R
6
and R
7
, together with the carbon atom to which they are attached, represent 5- or 6-membered cycloalkylidene; COOR
2
represents carboxyl or carboxyl derivatized in form of a pharmaceutically acceptable ester; disulfide derivatives derived from said compounds wherein R
3
is hydrogen; and pharmaceutically acceptable salts thereof.
Further preferred are said compounds of formula I and Ia wherein R and R
5
represent hydrogen; R
1
represents carbocyclic or heterocyclic aryl or (carbocyclic or heterocyclic aryl)-lower alkyl; R
3
represents hydrogen or optionally substituted lower alkanoyl; R
4
represents lower alkyl, cycloalkyl, tetrahydropyranyl or C
1
-C
4
-lower alkoxy-lower alkyl; R
6
and R
7
both represent C
1
-C
4
-alkyl and are identical; X represents —O— or —S—; alk represents methylene; COOR
2
represents carboxyl, lower alkoxycarbonyl, (di-lower alkylaminocarbonyl)-lower alkoxycarbonyl or (morpholinocarbonyl, piperidinocarbonyl or pyrrolidinocarbonyl)-lower alkoxycarbonyl; and pharmaceutically acceptable salts thereof.
Particularly preferred are said compounds of formula I or Ia wherein R and R
5
represent hydrogen; R
1
represents carbocyclic aryl or carbocyclic aryl-lower alkyl in which carbocyclic aryl represents phenyl or phenyl substitut

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