Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-10-16
2002-07-30
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S354000, C514S019300, C546S001000, C546S279700, C549S083000
Reexamination Certificate
active
06426354
ABSTRACT:
The present invention relates to the novel compounds described below which are useful as endothelin-converting enzyme (ECE) inhibitors in mammals.
The thiol derivatives described herein inhibit the formation of endothelin, reduce the plasma and tissue levels of endothelin and inhibit the biological effects of endothelin activity in mammals.
The compounds of the invention are thus useful for the treatment and/or prevention of endothelin dependent conditions and diseases, e.g. cardio- and cerebro-vascular disorders 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, vasoconstriction, arterial hypertrophy, restenosis, Raynaud's disease, myocardial infarction, obesity; also respiratory disorders such as bronchial asthma; gastrointestinal disorders such as inflammatory bowel disease, pancreatitis, emesis; 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.
The present invention is directed to the novel thiol derivatives of formula I
or of the formula Ia
wherein
Het represents monocyclic heterocyclic aryl;
Ar represents carbocyclic or heterocyclic aryl;
R
1
represents hydrogen or acyl;
R
2
represents hydrogen, lower alkyl, carbocyclic or heterocyclic aryl, carbocyclic or heterocyclic aryl-lower alkyl, cycloalkyl, cycloalkyl-lower alkyl, biaryl, biaryl-lower alkyl, (hydroxy, lower alkoxy or acyloxy)-lower alkyl, or lower alkyl-(thio, sulfinyl or sulfonyl)-lower alkyl;
R
3
represents hydrogen or lower alkyl; or R
2
and R
3
together with the carbon atom to which they are attached represent cycloalkylidene or benzo-fused cycloalkylidene;
R
4
represents hydrogen, lower alkyl, substituted lower alkyl, aryl-lower alkyl or biaryl-lower alkyl;
R
5
represents lower alkyl, substituted lower alkyl, aryl-lower alkyl or biaryl-lower alkyl;
A together with the carbon atom to which it is attached forms a ring and represents 3 to 10 membered cycloalkylidene or 5 to 10 membered cycloalkenylidene radical which may be substituted by lower alkyl or aryl-lower alkyl or may be fused to a saturated or unsaturated carbocyclic 5-7-membered ring; or A together with the carbon to which it is attached represents 5 to 6 membered oxacycloalkylidene, thiacycloalkylidene or azacycloalkylidene optionally substituted by lower alkyl or aryl-lower alkyl; or A together with the carbon atom to which it is attached represents 2,2-norbonylidene;
m is zero or 1-3;
Y represents 5-tetrazolyl, carboxyl or carboxyl derivatized in form of a pharmaceutically acceptable ester;
disulfide derivatives derived from said compounds wherein R
1
is hydrogen; and
pharmaceutically acceptable salts thereof; pharmaceutical compositions comprising said compounds; methods for preparation of said compounds; intermediates; and methods of treating disorders in mammals which are responsive to ECE inhibition by administration of said compounds to mammals in need of such treatment.
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.
Encompassed by the instant invention are any prodrug derivatives of compounds of the invention having a free carboxyl, sulfhydryl or hydroxyl group, said prodrug derivatives being convertible by solvolysis or under physiological conditions to the free carboxyl, sulfhydryl and/or hydroxyl compounds. Prodrug derivatives are e.g. the esters of free carboxylic acids and S-acyl and O-acyl derivatives of thiols, or alcohols, wherein acyl has meaning as defined herein.
Pharmaceutically acceptable prodrug esters of carboxylic acids are preferably e.g. lower alkyl esters, cycloalkyl esters, lower alkenyl esters, aryl-lower alkyl esters, &agr;-(lower alkanoyloxy)-lower alkyl esters such as the pivaloyloxy-methyl ester, and &agr;-(lower alkoxycarbonyl- or di-lower alkylamino carbonyl-)-lower alkyl esters.
Pharmaceutically acceptable salts are salts derived from pharmaceutically acceptable bases for any acidic compounds of the invention, e.g. those wherein Y represents carboxyl. Such are e.g. alkali metal salts (e.g. sodium, potassium salts), alkaline earth metal salts (e.g. magnesium, calcium salts), amine salts (e.g. tromethamine salts).
Compounds of the invention, depending on the nature of substituents, possess one or more asymmetric carbon atoms. The resulting diastereomers and optical antipodes are encompassed by the instant invention. Preferred is the configuration wherein the asymmetric carbon with the substituent Y has the S-configuration.
Preferred as endothelin converting enzyme inhibitors are the compounds with the S-configuration of formula II
wherein Het represents monocyclic heterocyclic aryl; Ar represents monocyclic or bicyclic carbocyclic or heterocyclic aryl; R
1
represents hydrogen or carboxyl derived acyl; R
2
represents lower alkyl, hydroxy-lower alkyl, (lower alkylthio- or lower alkoxy-) lower alkyl, carbocyclic or heterocyclic aryl, carbocyclic or heterocyclic aryl-lower alkyl, cycloalkyl, cycloalkyl-lower alkyl, or biaryl-lower alkyl; Y represents 5-tetrazolyl, carboxyl or carboxyl derivatized in form of a pharmaceutically acceptable ester; n represents 2-6, preferably 2, 4 or 5; disulfide derivatives derived from said compounds wherein R
1
is hydrogen; and pharmaceutically acceptable salts thereof.
Further preferred are said compounds of formula II wherein Het is thienyl, furanyl, oxazolyl, pyridyl, thiazolyl or oxadiazolyl, each optionally substituted by lower alkyl; Ar is monocyclic carbocyclic aryl or monocyclic heterocyclic aryl; R
1
represents hydrogen, aryl-lower alkanoyl, lower alkanoyl, lower alkoxy-lower alkanoyl, or heterocyclic or carbocyclic aroyl; R
2
represents C
2
-C
4
alkyl interrupted by S or O, C
2
-C
5
-alkyl or cyclohexylmethyl; Y represents 5-trazolyl, carboxyl, lower alkoxycarbonyl, carbocyclic or heterocyclic aryl-lower alkoxycarbonyl, &agr;-(lower alkanoyloxy-, lower alkoxycarbonyl- or di-lower alkylaminocarbonyl-)lower alkoxycarbonyl; n is 2, 4 or 5; and pharmaceutically acceptable salts thereof.
Particularly preferred as endothelin converting enzyme inhibitors are said compounds with the S-configuration of formula III
and of formula IIIa
wherein
Het represents pyridyl, pyrimidinyl, thienyl, furanyl, oxazolyl, isoxazolyl, oxadiazolyl or thiazolyl, each optionally substituted by lower alkyl;
Ar represents monocyclic carbocyclic aryl or monocyclic heterocyclic aryl;
R
1
represents hydrogen, lower alkanoyl, methoxy-lower alkanoyl, benzoyl or pyridylcarbonyl;
R
2
represents C
2
-C
5
-alkyl, cyclohexylmethyl or C
2
-C
4
-alkyl interrupted by O or S;
R
4
and R
5
represent lower alkyl or lower alkyl substituted by lower alkoxycarbonyl, lower alkanoyloxy, lower alkanoylthio, lower alkoxy, lower alkylthio, hydroxy, di-lower alkylamino, lower alkanoylamino, morpholino, piperidino, pyrrolidino or 1-lower alkylpiperazino;
Y represents 5-tetrazolyl, carboxyl, lower alkoxycarbonyl, benzyloxycarbonyl, pyridylmethoxycarbonyl, &agr;-(lower alkanoyloxy-, lower alkoxycarbonyl- or di-lower alkylaminocarbonyl-) lower alkoxycarbonyl; and pharmaceutically acceptable salts thereof.
A further embodiment of the invention relates to the compounds with the S-configuration of formula IIIb
wherein
Het represents pyridyl, pyrimidinyl, thienyl, furanyl, oxazolyl, isoxazolyl, oxadiazolyl or thiazolyl, each optionally substituted by lower alkyl;
Ar represents monocyclic carbocyclic aryl or monocyclic heterocyclic aryl;
W represents CH
2
, O, S or NR
6
in which R
6
is hydrogen, acyl, lower alkyl or aryl-lower alkyl;
R
1
represents hydrogen, lower alkanoyl, methoxy-lower alkanoyl, benzoyl or pyridylcarbonyl;
R
2
represents C
2
-C
5
-alkyl, cyclohexylmethyl or C
2
-C
4
-alkyl interrupted by O or S;
Fink Cynthia Anne
Firooznia Fariborz
Gruenfeld Norbert
Novartis AG
Patel Sudhaker B.
Shah Mukund J.
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