Abstract:
The invention relates to a method for preparing sulfanyl-type endothelin receptor antagonists of general formula (I) wherein R represents hydroxy, alkoxy, sulfonamidyl, amino; R represents alkyl, aryl or heteroaryl, optionally substituted, and R , R , R can be the same or different and are alkyl or aryl, optionally substituted, by means of nucleophilic reaction of a carboxylic acid derivative of formula (II) with a sulfide of formula (III), X being SR or SO2R and R being alkyl or aryl, optionally substituted.
Abstract:
Carboxylic acid derivatives have the formula (I), in which R1 stands for tetrazole or a group (a); R2 stands for hydrogen, hydroxy, NH¿2?, NH(C1-c4-alkyl), N(C1-C4-alkyl)2, halogen, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkinyl, C1-C4-halogenalkyl, C1-C4-alkoxy, C1-C4-halogenalkoxy or C1-C4-alkylthio, or CR?2¿ is linked with CR10, as indicated below, into a 5- or 6-membered ring; X stands for nitrogen or methine; Y stands for nitrogen or methine; Z stands for nitrogen or CR10, wherein R10 is hydrogen or C¿1?-C4-alkyl or CR?10¿ forms together with CR?2 or CR3¿ an optionally substituted 5- or 6-membered alkylene or alkenylene ring, and wherein one or more methylene groups can be substituted by oxygen, sulphur, -NH or -N(C¿1?-C4-alkyl); R?3¿ stands for hydrogen, hydroxy, NH¿2?, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, halogen, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkinyl, C1-C4-hydroxyalkyl, C1-C4-halogenalkyl, C1-C4-alkoxy, C1-C4-halogenalkoxy, C1-C4-alkylthio; or CR?3¿ is linked to CR10 as indicated above into a 5- or 6-membered ring, R?4 and R5¿ (which may be identical or different) stand for optionally substituted phenyl or naphthyl, or for phenyl or naphthyl which are linked to each other at the ortho-position by a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulphur atom or an SO¿2?, NH or N-alkyl group; optionally substituted C3-C8-cycloalkyl; R?6¿ stands for optionally substituted C¿3?-C8-cycloalkyl; optionally substituted phenyl or naphthyl, a 5- or 6-membered, optionally substituted heteroaromatic compound containing one to three nitrogen atoms and/or one sulphur or oxygen atom; W stands for sulphur or oxygen; Q is a spacer with a length that corresponds to a C2-C4 chain. Also disclosed are the physiologically tolerable salts of these compounds, as well as their pure enantiomer and diastereoisomer forms, their preparation and use as mixed ETA/ETB-receptor antagonists.
Abstract:
Heterocyclyl-substd. propanoic acids and their derivs., of formula (I), are new. R = formyl, tetrazolyl, nitrile, COOH or a gp. that can be hydrolysed to COOH; X = N or CR14; R2 = H, OH, NH2, alkylamino, dialkylamino, halo, alkyl, haloalkyl, alkoxy, haloalkoxy or alkylthio; R14 = H or 1-5 C alkyl; R3 = R2 or alkoxyimino; or CR3 + CR14 = 5 or 6 membered alkylene or alkenyl ring (opt. substd. by 1-2 alkyl) in which a methylene can be replaced by O, S, NH or alkylamino; R4, R5 = phenyl or naphthyl (both opt. substd. by one or more halo, NO2, CN, OH, alkyl, haloalkyl, alkoxy, haloalkyloxy, phenoxy, alkylthio, NH2, alkylamine or dialkylamino) or 3-7 C cycloalkyl; or the phenyl or naphthyl gps. are opt. bonded at the O- position (by a bond, CH2, O, S, SO2, ethylene, ethenylene or opt. alkylated amino); R6 = H, 1-8 C alkyl, 2-6 C alkenyl, 3-6 C alkynyl, 3-8 C cycloalkyl (all opt. substd. by 1 or more halo, NO2, CN, alkoxy 3-6 C alkenyloxy, 3-6 C alkynyloxy, alkylthio, haloalkoxy, alkylcarbonyl, alkoxycarbonyl, 3-8 C alkylcarbonylalkyl, alkylamino, dialkylamino, phenyl, Ph or OPh), Ar or Het; Y = S, O or bond; Q = S, O, SO, SO2 or bond; Ph = substd. phenyl, where substits. are halo, NO2, CN, alkyl, haloalkyl, alkoxy, haloalkoxy or alkylthio; Ar = phenyl or naphthyl (both opt. substd. by 1 or more halo, NO2, CN, OH, NH2, alkylamino, dialkylamino or OCH2CH2O); Het = 5 or 6 membered heteroaromatic with 1-3 N atoms and/or one S or O (opt. substd. by 1-4 halo and/or 1 or 2 alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, phenyl, phenoxy or phenyl carbonyl (where the phenyl is opt. substd. by 1-5 halo and/or 1-3 alkyl, haloalkyl, alkoxy, haloalkoxy and/or alkylthio)); alkyl and alkoxy have 1-4 C unless otherwise stated; provided that R6 is not H when Q = bond.
Abstract:
The invention relates to carboxylic acid derivatives of the formula Iwhere the radicals have the meanings stated in the description, and to their use as drugs.
Abstract:
An b-amino or b-azido carboxylic acid derivative has the formula (I) wherein: R1 is tetrazole or -C(=O)-R; R is OR4, -O-(CH2)p-S(O)k-R5, a 5 membered heteroaromatic system linked via a nitrogen atom, -NH-SO2-R5; A is NR7R8 or azido; W and Z are independently nitrogen or methine provided that Q is nitrogen if W and Z are methine; X is nitrogen or CR9; Y is nitrogen or CR10; Q is nitrogen or CR11 provided that if X is CR9 and Y is CR10 if Q is nitrogen; R2 and R3 are independently optionally substituted phenyl or naphthyl or phenyl or naphthyl is linked together in ortho position by a direct linkage, methylene, ethylene or ethenylene, oxygen, sulphur, SO2, NH or N-alkyl; R4 is H, alkali metal cation, alkaline earth metal cation, or a physiologically tolerated organic ammonium ion, optionally substituted cycloalkyl, alkyl or -CH2-phenyl. k is 0 to 2 and p is 1 to 4; R5 is alkyl, cycloalkyl, alkenyl, alkynyl or optionally substituted phenyl and R7 to R11 are defined in the specification. A pharmaceutical composition thereof is useful as an endothelin receptor antagonist. A compound of formula (II) A-C(R2)(R3)-CH(R1)-OH wherein A and R1 to R3 are as defined above s useful as a starting material to prepare the compounds of formula (I).
Abstract:
The invention relates to carboxylic acid derivatives of formula (I), wherein the substituents have the following meanings; R = tetrazole or a group (1); R = a radical OR (2), (3), a 5-membe red heteroaromatic bonded by a nitrogen atom such a pyrrolyl, pyrazolyl, imidazolyl and trizolyl; R , R = hydrogen, hydroxy, NH2, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, halogen, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkinyl, C1-C4-hydroxyalkyl, C1-C4-alkoxy, C1-C4-halogen alkyl, C1-C4-alkoxy, C1-C4-halogen alkoxy or C1-C4-alkythio; X = halogen, C1-C4-halogen alkyl, hydroxy; R and R = phenyl or naphthyl, C3-C7-cycloalkyl, phenyl or naphthyl which are bonded in ortho position by a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an SO2-NH or an N-alkyl group or a 5-membered or 6-membered heteroaromatic; R = hydrogen, phenyl or naphthyl, a five or six-membered heteroaromatic, C1-C8-alkyl, C3-C6-alkenyl, C3-C6-alkinyl or C3-C8-cycloalkyl, whereby said radicals can be substituted once or many times, with the proviso that R can only stand for hydrogen if Z does not represent a single bond; Z = sulfur, oxygen or a single bond, in addition to the physiologically compatible salts and the enantiomeric-pure and diastereomeric-pure forms. The novel compounds are suitable for combating diseases, especially as endothelin antagonists.
Abstract:
Heterocyclyl-substd. propanoic acids and their derivs., of formula (I), are new. R = formyl, tetrazolyl, nitrile, COOH or a gp. that can be hydrolysed to COOH; X = N or CR14; R2 = H, OH, NH2, alkylamino, dialkylamino, halo, alkyl, haloalkyl, alkoxy, haloalkoxy or alkylthio; R14 = H or 1-5 C alkyl; R3 = R2 or alkoxyimino; or CR3 + CR14 = 5 or 6 membered alkylene or alkenyl ring (opt. substd. by 1-2 alkyl) in which a methylene can be replaced by O, S, NH or alkylamino; R4, R5 = phenyl or naphthyl (both opt. substd. by one or more halo, NO2, CN, OH, alkyl, haloalkyl, alkoxy, haloalkyloxy, phenoxy, alkylthio, NH2, alkylamine or dialkylamino) or 3-7 C cycloalkyl; or the phenyl or naphthyl gps. are opt. bonded at the O- position (by a bond, CH2, O, S, SO2, ethylene, ethenylene or opt. alkylated amino); R6 = H, 1-8 C alkyl, 2-6 C alkenyl, 3-6 C alkynyl, 3-8 C cycloalkyl (all opt. substd. by 1 or more halo, NO2, CN, alkoxy 3-6 C alkenyloxy, 3-6 C alkynyloxy, alkylthio, haloalkoxy, alkylcarbonyl, alkoxycarbonyl, 3-8 C alkylcarbonylalkyl, alkylamino, dialkylamino, phenyl, Ph or OPh), Ar or Het; Y = S, O or bond; Q = S, O, SO, SO2 or bond; Ph = substd. phenyl, where substits. are halo, NO2, CN, alkyl, haloalkyl, alkoxy, haloalkoxy or alkylthio; Ar = phenyl or naphthyl (both opt. substd. by 1 or more halo, NO2, CN, OH, NH2, alkylamino, dialkylamino or OCH2CH2O); Het = 5 or 6 membered heteroaromatic with 1-3 N atoms and/or one S or O (opt. substd. by 1-4 halo and/or 1 or 2 alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, phenyl, phenoxy or phenyl carbonyl (where the phenyl is opt. substd. by 1-5 halo and/or 1-3 alkyl, haloalkyl, alkoxy, haloalkoxy and/or alkylthio)); alkyl and alkoxy have 1-4 C unless otherwise stated; provided that R6 is not H when Q = bond.
Abstract:
Heterocyclyl-substd. propanoic acids and their derivs., of formula (I), are new. R = formyl, tetrazolyl, nitrile, COOH or a gp. that can be hydrolysed to COOH; X = N or CR14; R2 = H, OH, NH2, alkylamino, dialkylamino, halo, alkyl, haloalkyl, alkoxy, haloalkoxy or alkylthio; R14 = H or 1-5 C alkyl; R3 = R2 or alkoxyimino; or CR3 + CR14 = 5 or 6 membered alkylene or alkenyl ring (opt. substd. by 1-2 alkyl) in which a methylene can be replaced by O, S, NH or alkylamino; R4, R5 = phenyl or naphthyl (both opt. substd. by one or more halo, NO2, CN, OH, alkyl, haloalkyl, alkoxy, haloalkyloxy, phenoxy, alkylthio, NH2, alkylamine or dialkylamino) or 3-7 C cycloalkyl; or the phenyl or naphthyl gps. are opt. bonded at the O- position (by a bond, CH2, O, S, SO2, ethylene, ethenylene or opt. alkylated amino); R6 = H, 1-8 C alkyl, 2-6 C alkenyl, 3-6 C alkynyl, 3-8 C cycloalkyl (all opt. substd. by 1 or more halo, NO2, CN, alkoxy 3-6 C alkenyloxy, 3-6 C alkynyloxy, alkylthio, haloalkoxy, alkylcarbonyl, alkoxycarbonyl, 3-8 C alkylcarbonylalkyl, alkylamino, dialkylamino, phenyl, Ph or OPh), Ar or Het; Y = S, O or bond; Q = S, O, SO, SO2 or bond; Ph = substd. phenyl, where substits. are halo, NO2, CN, alkyl, haloalkyl, alkoxy, haloalkoxy or alkylthio; Ar = phenyl or naphthyl (both opt. substd. by 1 or more halo, NO2, CN, OH, NH2, alkylamino, dialkylamino or OCH2CH2O); Het = 5 or 6 membered heteroaromatic with 1-3 N atoms and/or one S or O (opt. substd. by 1-4 halo and/or 1 or 2 alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, phenyl, phenoxy or phenyl carbonyl (where the phenyl is opt. substd. by 1-5 halo and/or 1-3 alkyl, haloalkyl, alkoxy, haloalkoxy and/or alkylthio)); alkyl and alkoxy have 1-4 C unless otherwise stated; provided that R6 is not H when Q = bond.
Abstract:
PCT No. PCT/EP96/03793 Sec. 371 Date Feb. 24, 1998 Sec. 102(e) Date Feb. 24, 1998 PCT Filed Aug. 29, 1996 PCT Pub. No. WO97/09294 PCT Pub. Date Mar. 13, 1997Carboxylic acid derivatives of the formula I here R1 is a tetrazole [sic], nitrile [sic], a group COOH or a radical which can be hydrolyzed to COOH, and the other substituents have the meaning explained in the description.
Abstract:
The invention relates to amino acid derivatives of the formula Iwhere the radicals have the meanings stated in the description, and to the use thereof as drugs.