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
2002-07-23
Geist, Gary (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S530000, C514S531000, C514S332000, C514S538000, C562S424000, C562S427000, C562S503000
Reexamination Certificate
active
06423727
ABSTRACT:
The present invention relates to the compounds of formula I below which have been discovered to be useful as endothelin-converting enzyme (ECE) inhibitors in mammals.
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 present invention provides a method of inhibiting ECE and a method of treating and/or preventing 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, 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 in either allo- or xeno- transplantation; as well as erectile dysfunction; using the compounds described below.
The present invention is also directed to ECE inhibiting pharmaceutical compositions and to novel compounds disclosed herein.
Certain compounds for which the new ECE inhibiting use has been discovered have been disclosed in U.S. Pat. No. 5,506,244 (which is incorporated herein by reference) as angiotensin converting enzyme and neutral endopeptidase inhibitors. Compounds of formula III below wherein Y represents carboxyl or esterified carboxyl, R is 4-biphenylyl, 3-indolyl or 5-hydroxy-3-indolyl, and R
2
is isopropyl, are examples in said patent.
The present invention relates to the inhibition of endothelin converting enzyme using a thiol derivative of formula I
wherein
R represents bicyclic carbocyclic aryl or bicyclic heterocyclic aryl; or a wholly or partially saturated form thereof; or
R represents monocyclic carbocyclic aryl substituted by carbocyclic aryl or by heterocyclic aryl; or
R represents monocyclic carbocyclic aryl substituted by cycloalkyl; or
R represents monocyclic carbocyclic aryl substituted by azacycloalkyl which is optionally substituted by lower alkyl or acyl; or
R represents cycloalkyl substituted by cycloalkyl or azacycloalkyl;
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;
A together with the carbon atom to which it is attached forms a ring and represents 3 to 10 membered cycloalkylidene or 5 to 10 membered cycloalkenylidene radical which may be substituted by lower alkyl or aryl-lower alkyl or may be fused to a saturated or unsaturated carbocyclic 5-7-membered ring; or A together with the carbon to which it is attached represents 5 to 6 membered oxacycloalkylidene, thiacycloalkylidene or azacycloalkylidene optionally substituted by lower alkyl, acyl or aryl-lower alkyl; or A together with the carbon atom to which it is attached represents 2,2-norbonylidene;
m is zero or 1-3;
Y represents 5-tetrazolyl, carboxyl or carboxyl derivatized in form of a pharmaceutically acceptable ester;
disulfide derivatives derived from said compounds wherein R
1
is hydrogen; or a pharmaceutically acceptable salts thereof; pharmaceutical compositions comprising said compounds; methods for preparation of said compounds; intermediates; and methods of treating disorders in mammals which are responsive to ECE inhibition by administration of said compounds to mammals in need of such treatment.
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 formula I, 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 R represents benzothiophenyl, naphthyl, benzofuranyl, indolyl, or monocyclic carbocyclic aryl substituted by monocyclic carbocyclic aryl or by monocyclic 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; or a pharmaceutically acceptable salt thereof.
Further preferred are said compounds of formula II wherein R has meaning as defined above; 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 cyclohexyl; Y represents 5-tetrazolyl, 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; or a pharmaceutically acceptable salt thereof.
Particularly preferred as endothelin converting enzyme inhibitors are said compounds with the S-configuration of formula III
and of formula IIIa
wherein
R represents benzothiophenyl, naphthyl, benzofuranyl, indolyl, or monocyclic carbocyclic aryl substituted by monocyclic carbocyclic aryl or by monocyclic heterocyclic aryl;
R
1
represents hydrogen, lower alkanoyl, methoxy-lower alkanoyl, benzoyl or pyridylcarbonyl;
R
2
represents C
2
-C
5
-alkyl, cyclohexyl or C
2
-C
4
-alkyl interrupted by O or S;
Y represents 5-tetrazolyl, carboxyl, lower alkoxycarbonyl, benzyloxycarbonyl, pyridylmethoxycarbonyl, &agr;-(lower alkanoyloxy-, lower alkoxycarbonyl- or di-lower alkylaminocarbonyl-) lower alkoxycarbonyl; or a pharmaceutically acceptable salt thereof.
A further embodiment of the invention relates to the compounds with the S-configuration of formula IIIb
wherein
R represents benzothiophenyl, naphthyl, benzofuranyl, indolyl or
De Lombaert Stephane
Fink Cynthia Anne
Firooznia Fariborz
Hoyer Denton Wade
Jeng Arco Yingcheu
Geist Gary
Gruenfeld Norbert
Novartis AG
Reyes Hector M
LandOfFree
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