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Pyrane derivatives as both ace- and nep-inhibitorsRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Peptide Containing (e.g., Protein, Peptones, Fibrinogen, Etc.) Doai, Cyclopeptides, 2 Peptide Repeating Units In Known Peptide ChainPyrane derivatives as both ace- and nep-inhibitors description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20060194742, Pyrane derivatives as both ace- and nep-inhibitors. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] The present invention is 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. It can be shown that the compounds of the invention also inhibit endothelin converting enzyme (ECE) and are useful for the treatment and/or prevention of conditions which are responsive to ECE inhibition. [0002] The present invention relates to the dual ACE and NEP inhibiting compounds of formula I wherein [0003] R represents hydrogen, lower alkyl, carbocyclic or heterocyclic aryl-lower alkyl or cycloalkyl-lower alkyl; [0004] R.sub.1 represents hydrogen, cycloalkyl, carbocyclic or heterocyclic aryl, or biaryl; [0005] alk represents lower alkylene; [0006] R.sub.3 represents hydrogen or acyl; [0007] R.sub.4 represents oxacycloalkyl, (thia-, oxothia- or diooxothia)-cycloalkyl, azacycloalkyl, or oxacycloalkyl-, (thia-, oxothia- or diooxothia)-cycloalkyl- or azacycloalkyl-lower alkyl; [0008] R.sub.5 represents hydrogen or lower alkyl; [0009] R.sub.6 represents lower alkyl, carbocyclic or heterocyclic aryl, (carbocyclic or heterocyclic aryl)-lower alkyl, cycloalkyl, cycloalkyl-lower alkyl, biaryl or biaryl-lower alkyl; [0010] R.sub.7 represents lower alkyl, (carbocyclic or heterocyclic aryl)-lower alkyl, cycloalkyl-lower alkyl or biaryl-lower alkyl; or [0011] R.sub.6 and R.sub.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; [0012] COOR.sub.2 represents carboxyl or carboxyl derivatized in form of a pharmaceutically acceptable ester; disulfide derivatives derived from said compounds wherein R.sub.3 is hydrogen; and pharmaceutically acceptable salts thereof. [0013] 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 and, optionally, ECE inhibition by administration of said compounds to mammals in need of such treatment. [0014] 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. [0015] 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. [0016] Pharmaceutically acceptable prodrug esters are preferably, e.g., lower alkyl esters, aryl-lower alkyl esters, .alpha.-(lower alkanoyloxy)-lower alkyl esters such as the pivaloyloxymethyl ester, and .alpha.-(lower alkoxycarbonyl, morpholinocarbonyl, piperidinocarbonyl, pyrolidinocarbonyl or di-lower alkylaminocarbonyl)-lower alkyl esters. [0017] Pharmaceutically acceptable salts are salts derived from pharmaceutically acceptable bases for any acidic compounds of the invention, e.g., those wherein COOR.sub.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). [0018] 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-R.sub.1 and R.sub.4 typically have the S-configuration. [0019] Preferred are the compounds of formula I and la wherein R and R.sub.5 represent hydrogen; R.sub.1 represents hydrogen, C.sub.5- or C.sub.6-cycloalkyl, carbocyclic or heterocyclic aryl, or biaryl; alk represents lower alkylene; R.sub.3 represents hydrogen or acyl; R.sub.4 represents oxacycloalkyl or oxacycloalkyl-lower alkyl; R.sub.6 and R.sub.7 represent lower alkyl; or R.sub.6 and R.sub.7, together with the carbon atom to which they are attached, represent 5- or 6-membered cycloalkylidene; COOR.sub.2 represents carboxyl or carboxyl derivatized in form of a pharmaceutically acceptable ester; disulfide derivatives derived from said compounds wherein R.sub.3 is hydrogen; and pharmaceutically acceptable salts thereof. [0020] Further preferred are said compounds of formula I and Ia wherein R and R.sub.5 represent hydrogen; R.sub.1 represents carbocyclic or heterocyclic aryl, or biaryl; R.sub.3 represents hydrogen or optionally substituted lower alkanoyl; R.sub.4 represents tetrahydropyranyl or 4-tetrahydropyranylmethyl; R.sub.6 and R.sub.7 represent C.sub.1-C.sub.4-alkyl and are identical; alk represents methylene or ethylene; COOR.sub.2 represents carboxyl, lower alkoxycarbonyl, (di-lower alkylaminocarbonyl)-lower alkoxycarbonyl or (morpholinocarbonyl, piperidinocarbonyl or pyrrolidinocarbonyl)-lower alkoxycarbonyl; and pharmaceutically acceptable salts thereof. [0021] Particularly preferred are said compounds of formula I or Ia wherein R and R.sub.5 represent hydrogen; R.sub.1 represents carbocyclic aryl or heterocyclic aryl in which carbocyclic aryl represents phenyl or phenyl substituted by one or two of hydroxy, lower alkanoyloxy, lower alkyl, lower alkoxy, trifluoromethyl, trifluoromethoxy or halo and in which heterocyclic aryl represents indolyl; R.sub.3 represents hydrogen or lower alkanoyl; R.sub.4 represents 4-tetrahydropyranyl; R.sub.6 and R.sub.7 represent methyl; alk represents methylene or ethylene; and COOR.sub.2 represents carboxyl or lower alkoxycarbonyl; and pharmaceutically acceptable salts thereof. [0022] Also preferred are the above compounds of formula I or Ia wherein R and R.sub.5 represent hydrogen; R.sub.1 represents phenyl, fluorophenyl, methoxyphenyl, 2-thienyl-5-pyridyl, 4-biphenylyl, or 3-indolyl; R.sub.3 represents hydrogen or lower alkanoyl; R.sub.4 represents 4-tetrahydropyranyl; R.sub.6 and R.sub.7 represent methyl; alk represents methylene or ethylene; and COOR.sub.2 represents carboxyl or lower alkoxycarbonyl; and pharmaceutically acceptable salts thereof. [0023] In particular preferred are compounds of formula Ia wherein R and R.sub.5 represent hydrogen; R.sub.1 represents phenyl wich is unsubstituted or substituted by phenyl or C.sub.1-C.sub.4 alkoxy; or R.sub.1 represents indolyl or pyridyl substituted by thienyl; R.sub.2 represents hydrogen or C.sub.1-C.sub.4 alkyl; R.sub.3 represents hydrogen or C.sub.2-C.sub.5 alkanoyl; R.sub.4 represents tetrahydropyranyl or 4-tetrahydropyranylmethyl; R.sub.6 and R.sub.7 represent C.sub.1-C.sub.4 alkyl; or R.sub.6 and R.sub.7, together with the carbon atom to which they are attached, represent cyclopentylidene; alk represents C.sub.1 to C.sub.2 alkylene; or a pharmaceutically acceptable salt thereof. [0024] The definitions as such or in combination as used herein, unless denoted otherwise, have the following meanings within the scope of the present invention. [0025] Aryl represents carbocyclic or heterocyclic aryl, either monocyclic or bicyclic. [0026] Monocyclic carbocyclic aryl represents optionally substituted phenyl, being preferably phenyl or phenyl substituted by one to three substitutents, such being advantageously lower alkyl, hydroxy, lower alkoxy, acyloxy, halogen, cyano, trifluoromethyl, trifluoromethoxy, amino, lower alkanoylamino, lower alkyl-(thio, sufinyl or sulfonyl), lower alkoxycarbonyl, mono- or di-lower alkylcarbamoyl, or mono- or di-lower alkylamino; or phenyl substituted by lower alkelenedioxy. [0027] Bicyclic carbocyclic aryl represents 1- or 2-naphthyl or 1- or 2-naphthyl preferably substituted by lower alkyl, lower alkoxy or halogen. [0028] Monocyclic heterocyclic aryl represents preferably thiazolyl, thienyl, furanyl, pyridyl, pyrimidinyl, oxazolyl, isoxazolyl, pyrrolyl, imidazolyl or oxadiazolyl, each being optionally substituted, e.g., by lower alkyl and the like. [0029] Optionally substituted furanyl represents 2- or 3-furanyl or 2- or 3-furanyl preferably substituted by lower alkyl. [0030] Optionally substituted pyridyl represents 2-, 3- or 4-pyridyl or 2-, 3- or 4-pyridyl preferably substituted by lower alkyl, halogen or cyano. [0031] Optionally substituted thienyl represents 2- or 3-thienyl or 2- or 3-thienyl preferably substituted by lower alkyl. [0032] Bicyclic heterocyclic aryl represents preferably indolyl or benzothiazolyl optionally substituted by hydroxy, lower alkyl, lower alkoxy or halogen, advantageously 3-indolyl or 2-benzothiazolyl. [0033] Aryl as in aryl-lower alkyl is preferably phenyl or phenyl substituted by one or two of lower alkyl, lower alkoxy, hydroxy, lower alkanoyloxy, halogen, trifluoromethyl, cyano, lower alkanoylamino or lower alkoxycarbonyl; also, optionally substituted naphthyl. [0034] Aryl-lower alkyl is advantageously benzyl or 1- or 2-phenethyl optionally substituted on phenyl by one or two of lower alkyl, lower alkoxy, hydroxy, lower alkanoyloxy, halogen or trifluoromethyl. 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