MXPA98008197A - Derivatives of novel carboxylic acids, its preparation and its - Google Patents

Abstract

The present invention relates to the carboxylic acid derivatives of the formula (see formula) wherein the radicals have the meanings defined in the description, the preparation of these compounds and their use as mediation.

Description

ES $ DERIVATIVES OF NEW CARBOXYLIC ACIDS, ITS PREPARATION AND USE The present invention relates to novel carboxylic acid derivatives, their preparation and use. Endothelin is a peptide that is composed of 21 amino acids and is synthesized and released by the vascular endothelium. Endothelin exists in three isoforms, ET-1, ET-2 and ET-3. In the following document, "endothelin" or "ET" means one or all of the endothelin isoforms. Endothelin is a potent constrictor vessel and has a potent effect on vasal tone. It is known that this vasoconstriction is caused by the binding of endothelin to its receptor (Nature, 332, 411-415, 1988; FEBS Letters, 231, 440-444, 1988 and Biochem. Biophys., Res. Commun., 154, 868-875, 1988). The increased or abnormal release of endothelin causes persistent vasoconstriction in peripheral blood vessels, kidney and brain, which gives rise to diseases. It has been reported in the literature that endothelin is included in various diseases; these include hypertension, myocardial infarction, cardiac deficiency, renal deficiency, pulmonary hypertension, Raynaud's syndrome, cerebral vasospasm, atherosclerosis, infarction, benign prosthetic hypertrophy and asthma (Japan, J. Hypertension 12, 79 (1989), J. Vascular Med Biology 2, 207 (1990), J. Am. Med. Association 264, 2868 (1990), Nature 344, 11 (1990), N. Engl. J. Med. 322, 205 (1989), N. Engl.

Med. 328, 1732 (1993), Nephron 66, 373 (1994), Strake 25, 904 (1994), Nature 365, 759 (1993), J. Mol. Cell. Cardiol. 27, A234 (1995), Cancer Research 56, 663 (1996). Accordingly, substances that specifically inhibit the binding of endothelin to the receptor must also antagonize the various aforementioned physiological effects of endothelin and are therefore valuable drugs. The application of German Patent No. P 44 36 851.8 describes the following compounds as endothelin receptor antagonists: OCH3 C6H5 / I N- < HO CH_ > CH2 O C CH O - (O) I 1 »- C6H5 COOH QCH3 ? 6H5 G? HO CH2 CH O C I CH O (N O \) I I N \ C6H5 COOH OCH3 We have now found that certain carboxylic acid derivatives are good inhibitors of endothelin receptors and that these compounds at the same time have a relatively low plasma binding. The invention relates to the carboxylic acid derivatives of the formula I wherein R is a formyl, tetrazole, nitrile, a COOH group or a radical that can be hydrolyzed to COOH, and the other substituents have the following meanings: R 2 halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, alkoxy of C 1 -C 4, C 1 -C 4 haloalkoxy or C 1 -C 4 alkylthio; X Nitrogen or CR14, wherein R14 is hydrogen or C1-C5 alkyl, or CR14 forms together with CR3 a 5 or 6 membered alkylene or alkenylene ring which can be substituted by one or two C1-C4 alkyl groups and in the which in each case a methylene group can be substituted by oxygen, sulfur, -NH or alkyl-NC? -4; R3 is halogen, C1-C4 alkyl, C1-C4 haloalkyl. C1-C4 alkoxy, C1-C4 haloalkoxy, -NH-O-C1-4-alkyl, C1-C4 alkylthio or CR3 is attached to CR14 as indicated above to form a 5- or 6-membered ring; R4 and R5 (which may be the same or different): Phenyl or naphthyl, each of which may be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, C1-C4 alkyl, haloalkyl of C? -C 4, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, phenoxy, C 1 -C 4 alkylthio, amino, C 4 -C 4 alkylamino or C 4 -C 4 dialkylamino; Phenyl or naphthyl which are connected together in ortho positions by a direct bond, a methylene, ethylene or ethylene group, an oxygen or sulfur atom or an S02, NH or N-alkyl group, or C3-C7 cycloalkyl; R6 is C3-C10 alkyl, C3-C10 alkenyl, or C3-Cio alkynyl, each of the radicals being substituted once or twice - hydroxyl, mercapto, carboxyl, "N ^ CO- Rv where Rj z are, independently of one another, hydrogen or C 1 -C 5 alkyl, sulfonium, cyano, guanidino, Z sulfur or oxygen.

The compounds, and the intermediates for preparing them, for example, IV and VI, may have one or more asymmetrically substituted carbon atoms. These compounds can exist as pure enantiomers and pure diastereomers or as a mixture of both. The use of an enantiomerically pure compound as active substance is preferred. The invention further relates to the use of the aforementioned carboxylic acid derivatives to produce medicaments, in particular to produce inhibitors of the endothelin receptor. The compounds according to the invention are prepared starting from the epoxides IV, which is obtained in a conventional manner, for example, as described in J. March, Advanced Organic Chemistry, 2nd ed., 1983, p. 862 and 750 from ketones II or olefins III: The carboxylic acid derivatives of the general formula VI can be prepared by reacting the epoxides of the general formula IV (for example with R = ROOR10 [sic]) with alcohols or thiols of the general formula V wherein R6 and Z have the meanings which are mentioned in claim 1. R4 For this purpose, the compounds of the general formula IV are heated with a compound of the formula V in the molar ratio of approximately 1: 1 to 1: 7, preferably to 3 molar equivalents, of 50 to 200 ° C, preferably from 80 to 150 ° C. Other functional groups in R6 are initially protected in a conventional manner for reaction with the compounds of formula IV; for example, alcohols can be protected as acetates, diols as acetals and carboxyl groups as esters. The protecting group can be removed after the reaction of the compounds of the formula VI with VII. The reaction can also be carried out in the presence of a diluent. It is possible to use for this purpose all the solvents that are inert to the reagents used. Examples of these solvents or diluents are water, aliphatic, alicyclic and aromatic hydrocarbons which may in each case be chlorinated, such as hexane, cyclohexane, petroleum ether, naphtha, benzene, toluene, xylene, methylene chloride, chloroform, tetrachloride carbon, ethyl chloride and trichloro ethylene, ethers such as diisopropyl ether, dibutyl ether, methyl tertiary butyl ether, propylene oxide, dioctane and tetrahydrofuran, ketones such as acetone, methyl ethyl ketone, methyl isopropyl ketone and methyl isobutyl ketone, nitriles such as acetonitrile and propionitrile , alcohols such as methanol, ethanol, isopropanol, butanol and ethylene glycol, esters such as ethyl acetate and amyl acetate, amides such as dimethyl formamide and dimethyl acetamide, sulfoxides and sulphones, such as dimethyl sulfoxide and sulfolane, bases such as pyridine, N-methylpyrrolidone , cyclic ureas such as 1,3-dimethyl-2-imidazolidinone and 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone. The preferred reaction is carried out at a temperature in the range of 0 ° C to the boiling point of the solvent or the mixture of solvents. The presence of a catalyst can be advantageous. The catalysts suitable in this case are strong organic and inorganic acids and Lewis acids. Examples of these are, inter alia, sulfuric acid, hydrochloric acid, trifluoroacetic acid, p-toluensufonic acid and boron trifluoride etherate and titanium (IV) alcoholate. The compounds of the general formula VI can be obtained in entaniomerically pure form starting from enantiomerically pure compounds of the formula IV and reacting them with compounds of the formula V in the manner described. In addition it is possible to obtain enantiomerically pure compounds of formula VI by carrying out a resolution of classical racemate with racemic or diastereomeric compounds of formula VI using suitable enantiomerically pure bases such as brucine, strychnine, quinine, quinidine, chinchonidine [sic], chinchonine [sic] ] yohimbine, morphine, dehydroabietylamine, ephedrine (-), (+), deoxiefedrine (+), (-), threo-2-amino-l-) p-nitrophenyl) -1,3-propanediol (+), (-), threo-2-amino-1-phenyl-1,3-propanediol (+), (-), α-methylbenzylamine (+), (-), α- (1-naphthyl) ethylamine (+), (-), α- (2-naphthyl) ethylamine (+), (-), aminomethylpinone, N , N-dimethyl-1-phenylethylamine, N-methyl-1-phenylethylamine, 4-nitrophenylethylamine, pseudoephedrine, norephedrine, norseudoephedrine, amino acid derivatives, peptide derivatives. The compounds of the general formula I according to the invention can be prepared, for example by reacting the carboxylic acid derivatives of the general formula VI in which substituents have the stated meanings with the compounds of the general formula VII.

VII wherein Rls is halogen or Rld-S02-, wherein R16 may be C1-C4 alkyl, C9-C4 haloalkyl or phenyl. Preferably, the reaction is carried out in one of the aforementioned inert diluents with the addition of a suitable base, ie, a base that deprots intermediate VI, at a temperature in the range from room temperature to the point of boiling of the solvent. The compounds of formula VII are known and some of them can be purchased or can be prepared in a conventional manner. It is possible to use as a base an alkaline earth metal hydride such as sodium hydride, potassium hydride or calcium hydride, a carbonate such as an alkali metal carbonate, for example sodium or potassium carbonate, a hydroxide of alkali metal or alkaline earth metal such as sodium or potassium hydroxide, an organometallic compound such as butyl or an alkali metal amide, such as lithium diisopropylamide or lithium amide. The compounds of the formula I can also be prepared starting from the corresponding carboxylic acids, ie the compounds of the formula I wherein R1 is hydroxyl, and initially converting these into a conventional form in an activated form, such as a halide, an anhydride or imidazolide, and then react the latter with a suitable hydroxyl compound HOR10. This reaction can be carried out in conventional solvents and often require the addition of a base, in which case the above-mentioned ones are suitable. These two steps can also be simplified, for example by allowing the carboxylic acid to act on the hydroxyl compound in the presence of a dehydrating agent such as a carbodiimide. The compounds of the formula I can also be prepared starting from the salts of the appropriate carboxylic acids, ie, from the compounds of the formula I, wherein R is a group COR1 and R1 is OM, wherein M it can be an alkali metal cation or the equivalent of an alkaline earth metal cation. These salts can be reacted with many compounds of the formula R1-A wherein A is a conventional nucleofugic leaving group, for example halogen, such as chlorine, bromine, iodine or aryl- or alkyl sulfonyl which is unsubstituted or substituted by halogen , alkyl or haloalkyl, such as toluenesulfonyl and methylsulfonyl or other equivalent leaving group. The compounds of the formula R1-A with a reactive substituent A are known or can be obtained easily with general expert knowledge. This reaction can be carried out in conventional solvents and is advantageously carried out with the addition of a base, in which case those mentioned in the above are suitable.

The radical R in formula I can be varied widely. R is, for example, a group O C-R1 wherein R1 has the following meanings: a) hydrogen; b) a succinylimidoxy group: c) a 5-membered heteroaromatic system linked through a nitrogen atom, such as pyrrolyl, pyrazolyl, imidazolyl and triazolyl, which can carry one or two halogen atoms, in particular fluorine and chlorine and / or 1 or 2 of the following radicals: C 1 -C 4 alkyl, such as methyl, ethyl, 1-propyl, 2-propyl, 2-methyl-2-propyl, 2-methyl-1-propyl, 1-butyl , 2-butyl; C 1 -C 4 haloalkyl, in particular C 1 -C 2 haloalkyl such as fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trichloromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2 - trifluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl and pentafluoroethyl; C 1 -C 4 haloalkoxy, in particular C 1 -C 2 haloalkoxy difluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 2, 2-difluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2,2,2-trifluoroethoxy , 2-chloro-l, 1,2-trifluoroethoxy and pentafluoroethoxy, in particular trifluoromethoxy; C 1 -C 4 alkoxy such as methoxy, ethoxy, propoxy, 1-methyl-ethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, 1,1-dimethylethoxy, in particular methoxy, ethoxy and 1-methylethoxy; C 1 -C 4 alkylthio, such as methylthio, ethylthio, propylthio, 1-methylethylthio, butylthio, 1-ethylpropylthio, 2-methylpropylthio, 1/1-dimethylethylthio, in particular methylthio and ethylthio; d) R1 is also a radical: R7 (O). / í m \ wherein m is 0 or 1, and R7 and R8, which may be the same or different, have the following meanings: hydrogen, C? -C8 alkyl, in particular C? -C4 alkyl as already mentioned; C3-C6 alkenyl such as 2-propenyl, 2-butenyl, 3-butenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1- methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, l-methyl-3-butenyl, 2-methyl-3-butenium, 3-methyl-3-butenium-, 1, dimethyl-2-propenyl, 1,2-dimethyl-2-propenyl, l-ethyl-2-propenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, l-methyl-2-pentenyl, -methyl-2-pentenyl, 3-methy1-2-pentenyl, 4-methyl-2-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, l-methyl-4-pentenyl, 2-methyl -4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1, l-dimethyl-2-butenyl, 1, l-dimethyl-3-butenyl, 1,2-dimethyl-2-butenyl , 1,2-dimethyl-3-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-2-butenyl , 2, 3-dimethyl-3-butenyl, l-ethyl-2-butenyl, l-ethyl-3-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-tri -methyl-2-propenyl, l-ethyl-l-methyl-2-propenyl and 1-ethyl-2-methyl-2-propenyl, in particular 2-propenyl, 2-butenyl, 3-methyl-2-butenyl and 3-methyl-2-pentenyl; C3-C6 alkynyl, such as 2-propynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-3-butynyl, 2- methyl-3-butynyl, 1-methyl-2-butynyl, 1, 1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, l- methyl-2-pentynyl, l-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-4-pentynyl, 4-methyl- 2-pentynyl, 1, l-dimethyl-2-butynyl, 1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl, 2,2-dimethyl-3-butynyl, l-ethyl-2 -butynyl, l-ethyl-3-butynyl, 2-ethyl-3-butynyl and 1-ethyl-1-methyl-2-propynyl, preferably 2-propynyl, 2-butynyl, 1-methyl-2-propynyl and -methyl-2-butynyl, in particular 2-propynyl; C3-Ce cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, cyclooctyl, it being possible for these alkyl, cycloalkyl, alkenyl and alkynyl groups each to have from 1 to 5 halogen atoms, in particular fluorine or chlorine, and / or 1 or 2 of the following groups: C 1 -C 4 alkyl, C 1 -C 4 alkoxy / C 1 -C 4 alkylthio, C 1 -C 4 haloalkoxy as mentioned, C 3 -C 6 alkenyloxy / C 3 -C 6 alkenylthio C3-C6 alkynyloxy, C3-C6 alkynylthio wherein the alkenyl and alkynyl constituents present in these radicals preferably correspond to the above meanings; C 1 -C 4 alkylcarbonyl, such as, in particular, methylcarbonyl, ethylcarbonyl, propylcarbonyl, 1-methylethylcarbonyl, butylcarbonyl, 1-methylpropylcarbonyl, 2-methylpropylcarbonyl and 1,1-dimethylethylcarbonyl; C 1 -C 4 alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl, 1-ethylethoxycarbonyl, butyloxycarbonyl, 1-methylpropyloxycarbonyl, 2-methylpropyloxycarbonyl and 1,1-dimethylethoxycarbonyl; C3-C6 alkenylcarbonyl, C3-C6 alkynylcarbonyl, C3-C6 alkenyloxycarbonyl and C3-C6 alkynyloxycarbonyl, wherein the alkenyl and alkynyl radicals preferably have the definitions detailed above; phenyl, unsubstituted or substituted one or more times, for example, 1 to 3 times by halogen, nitro, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy C4 or C 1 -C alkylthio, such as 2-fluorophenyl, 3-chlorophenyl, 4-bromophenyl, 2-ethylphenyl, 3-nitrophenyl, 4-cyanophenyl, 2-trifluoromethylphenyl, 3-methoxyphenyl, 4-trifluoroethoxyphenyl, 2-methylthiophenyl , 2,4-dichlorophenyl, 2-methoxy-3-methyl-phenyl, 2,4-methoxyphenyl, 2-nitro-5-cyanophenyl and 2,3-diflurophenyl; C 1 -C 4 dialkylamino, such as, in particular, dimethylamino, dipropylamino, N-propyl-N-methylamino, N-propyl-N-ethylamino, diisopropylamino, N-isopropyl-N-methylano, N-isopropyl-N-ethylamino , N-isopropyl-N-propylamino; R7 and R8 further phenyl which may be substituted by one or more, for example, one to three of the following radicals: Halogen, nitro, cyano, C_-C4 alkyl, C1-C4 haloalkyl, C_-C4 alkoxy, haloalkoxy of C1-C4 or alkylthio of C1-C4 as already mentioned in particular; R7 and Re together form an alkylene chain of C4-C7 which closes to form a ring and is substituted or unsubstituted, for example, substituted by C4-C4 alkyl, and which may contain a heteroatom selected from the oxygen group, sulfur or nitrogen, such as - (CH2) 4-, - (CH2) 5-, - (CH2) 6-, - (CH2) 7-, - (CH2) 2-0- (CH2) 2, - CH2 -S- (CH2) 3 -, - (CH2) 2-0- (CH2) 3-, -NH- (CH2) 3-, -CH-NH- (CH2) -, -CH2-CH = CH-CH2 -, -CH = CH- (CH2) 3-; e) R1 is also a group: Go I ° - H2) p S R9 in which it takes the values 0, 1 and 2, p takes the values 1, 2, 3 and 4 and R9 is: C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 alkenyl, C3-C6 alkynyl or substituted or unsubstituted phenyl, as already mentioned in particular; f) R1 is also a radical OR10, where R10 is: hydrogen, the cation of an alkali metal such as lithium, sodium, potassium, or the cation of an alkaline earth metal such as calcium, magnesium and barium, or an ion of environmentally compatible organic ammonium, such as C1-C4 tertiary alkyl ammonium or ammonium ion; C3-C8 cycloalkyl as already mentioned, which can carry from 1 to 3 C1-C4 alkyl groups; C? -C8 alkyl such as, in particular, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, -methylbutyl, 1,2-dimethylpropyl, 1,1-di-ethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 1-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,1-trimethylpropyl, 1,1,2-trimethylpropyl, 1-ethylbutyl, 2-ethylbutyl, l-ethyl-2-methylpropyl, which can carry from 1 to 5 halogen atoms, in particular fluorine and chlorine, and / or one of the following radicals: C1-C4 alkoxy, C1-C4 alkylthio, cyano, C1-C4 alkylcarbonyl, C3-C8 cycloalkyl [sic], C1-C4 alkoxycarbonyl, phenyl, phenoxy or phenylcarbonyl, it being possible for the aromatic radicals each to have 1 to 5 halogen atoms and / or from 1 to 3 of the following radicals: nitro, cyano, alkyl of C 1 -C 4, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy and / or C 1 -C 4 alkylthio as already mentioned in particular; an alkyl group of C? -C8 as already mentioned, which can carry from 1 to 5 halogen atoms, in particular fluorine and / or chlorine, and which bears one of the following radicals: a 5-membered heteroaromatic system containing 1 to 3 nitrogen atoms or a 5-membered heteroaromatic system containing a nitrogen atom and an oxygen or sulfur atom, which system can carry from 1 to 4 halogen atoms and / or 1 or 2 of the following radicals: nitro , cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, phenyl, C 1 -C 4 haloalkoxy and / or C 1 -C 4 alkylthio. Specific mention may be made of: 1-pyrazolyl, 3-methyl-1-pyrazolyl, 4-methyl-1-pyrazolyl, 3, 5-dimethyl-1-pyrazolyl, 3, 5-dimethyl-1-pyrazolyl, 3-phenyl -l-pyrazolyl, 4-phenyl-1-pyrazolyl, 4-chloro-1-pyrazolyl, 4-bromo-1-pyrazolyl, 1-imidazolyl, 1-benzimidazolyl, 1, 2, 4-triazol-1-yl, 3 - methyl-1,2,4-triazol-1-yl, 5-methyl-1,2,4-triazol-1-yl, 1-benzotriazolyl, 3-isopropyl-5-isoxasolyl, 3-methyl-5-isoxasolyl , 2-oxasolyl, 2-thiazolyl, 2-imidazolyl, 3-ethyl-5-isoxasolyl, 3-phenyl-5-isoxasolyl, 3-tert-butyl-5-isoxasolyl; a C2-C6 alkyl group carrying in position 2 one of the following radicals: C1-C4 alkoxyimino, C3-C6 alkynyloxyimino, C3-C5 haloalkenyloximino or benzyloxy ino; a C3-C6 alkenyl or C3-C6 alkynyl group, it being possible for these groups in turn to carry from 1 to 5 halogen atoms; R 1 C is furthermore a phenyl radical which can carry from 1 to 5 halogen atoms and / or from 1 to 3 of the following radicals: nitro, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C1-C4 haloalkoxy and / or C1-C4 alkylthio as already mentioned, in particular; A 5-membered heteroaromatic system that binds through a nitrogen atom and contains 1 to 3 nitrogen atoms and that can carry 1 or 2 halogen atoms and / or 1 or 2 of the following radicals: C1- alkyl C4, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, phenyl, C 1 -C 4 haloalkoxy and / or C 1 -C 4 alkylthio. Specific mention may be made of: 1-pyrazolyl, 3-methyl-1-pyrazolyl, 4-methyl-1-pyrazolyl, 3,5-dimethyl-1-pyrazolyl, 3-phenyl-1-pyrazolyl, 4-phenyl-1-pyrazolyl , 4-chloro-l-pyrazolyl, 4-bromo-l-pyrazolyl, 1- i-idazolyl, 1-benzimidazolyl, 1, 2,4-triazol-l-yl, 3-methyl-1,2,4-triazole- l -yl, 5-methyl-1,2-triazol-1-yl, 1-benzotriazolyl, 3,4-dichloro-1-imidazolyl; R10 is also a group: 11 N wherein R 11 and R 12, which may be the same or different, are C 1 -Ce alkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl, C 3 -C 8 cycloalkyl, it being possible for these radicals to carry an alkoxy radical of C1-C4, C 1 -C 4 alkylthio and / or substituted or unsubstituted phenyl; phenyl which may be substituted by one or more, for example from 1 or 3 of the following radicals: halogen, nitro, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy or C 1 -C 4 alkylthio, wherein the radicals correspond to those mentioned above in particular; or R11 and R12 together form an alkylene chain of C3-C -1_2 which can carry 1 to 3 C_-C4 alkyl groups and can contain a heteroatom of the oxygen, sulfur and nitrogen group; R1 is also a radical: O IoI where R 13 is: C 1 -C 4 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl, C 3 -C 8 cycloalkyl, it being possible for these radicals to carry a C 1 -C 4 alkoxy radical, C 1 -C 4 alkylthio and / or phenyl; substituted or unsubstituted phenyl; h) R1 is a radical: OR where R13 has the meaning mentioned above. R can also be: Tetrazol or nitrile.

With a view to the biological effect, the preferred carboxylic acid derivatives of the formula I, as pure enantiomers or as pure diastereomers or as mixtures thereof, are those in which the substituents have the following meanings: R2 the alkyl groups of C1 -C4, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy and C1-C4 alkylthio and halogen atoms specified for R1, in particular chlorine, methyl, methoxy, ethoxy, difluoro methoxy and trifluoromethoxy; X Nitrogen or CR14, wherein R14 hydrogen or alkyl, or CR14 together with CR3 forms a 4 or 5 membered alkylene or alkenylene ring in which in each case, a methylene group can be substituted by oxygen or sulfur, such as - CH2-CH2-0-, -CH = CH-0-, -CH2-CH2-CH2-O-, CH = CH-CH20-, in particular, -CH2-CH2-O-, -CH (CH3) -CH (CH3) -0-, -C (CH3) = C (CH3) -0-, -CH = C (CH3) -0- or - C (CH3) -S; R3 the C1-C4 alkyl groups, C4-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy and C1-C4 alkylthio and halogen atoms mentioned for R1, in particular chlorine, methyl, methoxy, ethoxy, difluoro methoxy, trifluoro methoxy or binds to R14 as already mentioned to form a 5- or 6-membered ring; R 4 and R 5 are phenyl or naphthyl, each of which can be substituted by one or more, for example, 1 to 3 of the following radicals: halogen, nitro, cyano, hydroxyl, mercapto, amino, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 alkylthio, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino, C 1 -C 4 alkylcarbonyl, C 1 -C 4 alkoxycarbonyl; Phenyl or naphthyl which are connected together in ortho positions by a direct bond, a methylene, ethylene or ethenyl group, an oxygen or sulfur atom or a S02, NH or N-alkyl, or C3-C7 cycloalkyl group; R6 is C1-C4 alkyl, C3-C5 alkenyl, wherein the radicals are each substituted once or twice by hydroxyl, mercapto, carboxyl or cyano; Z sulfur or oxygen.

Particularly preferred compounds of the formula I, as pure enantiomers or as pure diastereomers or as a mixture of both, are those in which the substituents have the following meanings: R2 C1-C4 alkyl, C1-C4 alkoxy, X nitrogen or CR14 where R14 is hydrogen or alkyl, or CR14 together with CR3 forms a 4 or 5 membered alkylene or alkenylene ring, such as -CH2-CH2-CH2- or -CH = CH-CH2-, in which, in each case, a methylene group can be substituted by oxygen or sulfur, such as -CH2-CH2-0-, -CH = CH-0-, -CH2-CH2-CH2-0-, -CH = CH-CH20 -, in particular hydrogen, -CH2-CH2-0-, -CH (CH3) -CH (CH3) -0-, -C (CH3) -C (CH3) -O-, - CH = C (CH3) - 0- or -C (CH3) = C (CH3) -S; R3 the C3-C4 alkyl groups, C4-C4 alkoxy, C1-C4 alkylthio mentioned for R1, or binds to R14 as already mentioned to form a 5- or 6-membered ring; R 4 and R 5 phenyl (same or different), which may be substituted by 1 or more, for example 1 to 3 of the following radicals: halogen, nitro, hydroxyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 alkylthio -C4, or R4 and R5 are phenyl groups which are connected together in ortho positions by a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or a S02, NH or N-alkyl group; or R4 and R5 are C3-C7 cycloalkyl; R6 alkyl of C1-C3, C3-C4 alkenyl, wherein the radicals are each substituted once or twice by hydroxyl or are substituted once by carboxyl; Z sulfur or oxygen.

The compounds of the present invention provide a novel therapeutic potential for the treatment of hypertension, pulmonary hypertension, myocardial infarction, angina pectoris acute renal failure, renal insufficiency, vasoe. Brain disorders, cerebral izkemia, subarachnoid hemorrhages, migraine, asthma, atherosclerosis, endotoxic shock, endotoxin-induced organ deficiency, intravascular coagulation, restenosis after angioplasty, benign prosthetic hyperplasia or hypertension or renal deficiency caused by izchemia or intoxication and cancers , especially prostate and skin cancer. The invention further relates to the combination of the compounds of the formula I with renin-angiotensin system (RAS) inhibitors. The RAS inhibitors are described in, for example, EP 634 175. The combinations according to the invention are suitable for treating disorders for which the compounds of the formula I also show efficacy in themselves, especially for treating hypertomia [sic] and chronic heart failure. The good effect of the compounds can be demonstrated in the following tests: Receptor binding studies CHO cells expressing in the human ETA receptor cloned and cerebellar guinea pig membranes with > 60% of ETB receptors compared with ETA were used for binding studies.

Preparation of the membrane CHO cells expressing in the ETA receptor were developed in Fi2 medium containing 10% of fetal bovine serum, 1% of glutamine, 100 U / m of penicillin and 0.2% of streptomycin (Gibco BRL, Gaithersburg, MD, USA). After 48 h, the cells were washed with PBS and incubated with PBS containing 0.05% trypsin for 5 minutes. The neutralization was then carried out with F12 medium, and the cells were collected by centrifugation at 300 x g. To lyse the cells, the pack was briefly washed with lysis buffer (5 mM Tris-HCl, pH 7.4 with 10% glycerol) and then incubated at a concentration of 107 cells / ml of buffer for lysis at 4 ° C for 30 minutes. minutes The membranes were centrifuged at 20,000 x g for 10 min, and the package was stored in liquid nitrogen. Guinea pig cerebellums were homogenized in a Potter-Elvejhem homogenizer and obtained by differential centrifugation at 1000 x g for 10 min and repeated centrifugation of the supernatant at 20,000 x g for 10 min.

Bonding tests. For the binding assay of the ETA and ETB receptor, the membranes were suspended in a buffer solution for incubation (50 mM Tris-HCl, pH 7.4 with 5 mM MnCl, 40 μg / ml bacitracin and 0.2% BSA) at a concentration of 50 μg of protein per assay mixture and incubated with 25 pM [1251 [sic]] - ET? (assay of the ETA receptor) or 25 pM [1251 [sic]] - RZ3 (assay of the ETB receptor) in the presence and absence of the test substance at 25 ° C. The non-specific binding was determined using ET_ 10"7 M. After 30 minutes, filtration through glass fiber filters GF / B (Whatman, England) in a Skatron cell collector (Skatron, Lier, Norway) was The separated radioactivity collected on the filters was quantified using a Packard 2200 liquid scintillation counter, and the filters were washed with ice-cold buffer solution Tris-HCl, pH 7.4 with 0.2% BSA. AC.

In Vitro Functional Assay System for Searching for Endothelin Receptor Antagonists (Subtype A) This assay system is a functional cell-based assay for endothelin receptors. When certain cells are stimulated with endothelin 1 (ET1) they show an increase in intracellular calcium concentration. This increase can be measured in intact cells loaded with calcium-sensitive dyes. The 1-fibroblasts that have been isolated from rats and in which an endogenous endothelin receptor of subtype A have been detected were loaded with a fluorescent dye Fura-2-an as follows: after trypsinization, the cells were resuspended in buffer solution (120 mM NaCl, 5 mM KCl, 1.5 mM MgCl2, 1 mM CaCl2, 25 mM HEPES, 10 mM glucose, pH 7.4) to a density of 2 x 106 / ml and incubated with Fura-2-an (2 μM), Pluronics [sic] F-127 (0.04%) and DMSO (0.2%) at 37 ° C in the dark for 30 minutes. The cells were then washed twice with buffer a and resuspended at 2 x 106 / ml. The fluorescence signal of 2 x 10 5 cells per ml with Ex / Em 380/510 was continuously recorded at 30 ° C. The test substances and, after an incubation time of 30 min, ET1 were [lacuna] for the cells, the maximum change in fluorescence was determined. The response of the cells to ET1 without prior addition of a test substance was used as a control and was set equal to 100%.

Tests of ET in vivo antagonists Male SD rats weighing 250-300 g were anesthetized with amobarbital, artificially ventilated, vagotomized and the medulla removed. The carotid artery and the jugular vein were catheterized. In animal * - ntrol, the intravenous administration of 1 μg / kg of ET1 t t or a different elevation in blood pressure that persisted for a prolonged period. The test animals received an i.v. of the test compounds (1 ml / kg) 5 minutes before the administration of ET1. To determine ET antagonistic properties, the elevation in blood pressure in the test animals was compared with that in the control animals.

Sudden death induced by endothelin-1 in mice The principle of the test is the inhibition of sudden cardiac death caused in mice by endothelin, which is probably induced by constriction of the coronary vessels, by pretreatment with endothelin receptor antagonists. Intravenous injection of 10 nmol / kg of endothelin in a volume of 5 ml / kg of body weight results in the death of the animals in a few minutes. The lethal dose of endothelin-1 was verified in each case in a small group of animals. If the test substance was administered intravenously, the injection of endothelin-1 that was lethal in the reference group is usually carried out 5 minutes after this. In other modes of administration, the times before administration are extended, where it is adequate up to several hours. The average number of survivors is recorded, and the effective doses that protect 50% of the animals (ED 50) of cardiac death induced by endothelin for 24 h or more are determined.

Functional test in vessels for endothelin receptor antagonists Rabbit aortic segments are, after an initial tension of 2g and a relaxation time of lh in Krebs-Henseleit solution at 37 ° X and pH 7.3-7.4, first induced to contract with Kt. After washing, a dose-effect graph of endothelin is elaborated to the maximum. Potential endothelin antagonists are administered in other preparations of the same vessel 15 minutes before starting the dose-effect graph of endothelin. The effects of endothelin are calculated as percent of the contraction induced by Kt. Effective endothelin antagonists result in a shift to the right in the dose-effect graph of endothelin. The compounds according to the invention can be administered orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperitoneally) in a conventional manner. The administration can be carried out with vapors or sprays through the nasopharyngeal space.

The dose depends on the age, condition and weight of the patient and on the mode of administration. The daily dose of the active substance is, as a general rule, approximately 0. 5-50 mg / kg of body weight in oral administration and approximately 0.1-10 mg / kg of body weight in parenteral administration. The novel compounds can be used in conventional solid or liquid pharmaceutical administration forms, for example uncoated or coated tablets (films), capsules, powders, granules, suppositories, solutions, ointments, creams or aerosols. These are produced in a conventional manner. The active substances can, for this purpose, be processed with conventional pharmaceutical auxiliaries, such as binders for tablets, bulking agents, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, cleaning agents. slow release, antioxidants and / or propellant gases (see H. Sucker et al.: Pharmazeutische Technolgie, Thieme-Verlag, Stuttgart, 1991). The administration forms obtained in this manner will normally contain from 0.1 to 90% by weight of the active substance.

Synthetic examples Example 1 Methyl 3- (2-acetoxyethoxy) -2-hydroxy-3, 3-diphenylpropionate 7.95 g (31.3 mmol) of methyl 3,3-diphenyl-2,3-epoxypropionate were dissolved in 20 ml of diethyl ether with N2 and cooled to 0 ° C, and 5.87 ml (31.3 mmol) of 2-hydroxyethyl acetate (50% concentration) and 3 drops of BF3.Et20 were added. After removing the ice bath the mixture was stirred at RT for 2 h. The reaction solution was washed successively with NaCl solution and NaHCO 3 solution, and the organic phase was dried over MgSO 4 and concentrated. 12.3 g of a pale yellow oil were obtained and reacted without further purification and characterization.

Example 2 Methyl 3- (2-acetoxyethoxy) -2- (4-methoxy-6-methyl-2-pyrimidin-yloxy) -3,3-diphenylpropionate 4 g (11.1 mmol) of 3- (2-acetoxyethoxy) - Methyl 2-hydroxy-3, 3-diphenylpropionate were dissolved in 20 ml of DMF with N2, 770 mg (5.6 mmol) of K2C03 and 2.24 g (11.1 mmol) of 2-methanesulfonyl-4-methoxy-6-methylpyrimidine were added , and the mixture was stirred at 80 ° C for 2 h. Subsequently it was diluted with 20 ml of H20 and extracted twice with 30 ml of diethyl ether, the organic phase was dried over MgSO4 and concentrated, and the residue was purified by chromatography on silica gel with ethyl acetate / cyclohex mixtures. 4.8 g (90%) of a colorless oil were obtained ^ -R (CDC13) d: 2.10 (s, 3H); 2.35 (s, 3H); 3.50 (s, 3H); 3.85 (s, 6H); 4.00 (m, 2H); 4.30 (m, 2H); 6.00 (s, ÍH), 6.25 (s, ÍH); 7.20 - 7.50 (m, 10H) Example 3 3- (2-Hydroxyethoxy) -2- (4-methoxy-6-methyl-2-pyrimidinyloxy) -3,3-diphenylpropionic acid 4.8 g (10 mmol) of 3- (2-acetoxyethoxy) -2- ( 4-methoxy-6-methyl-2-pyrimidinyloxy (methyl 3, 3-diphenylpropionate [sic] were dissolved in 80 ml of dioxane and 40 ml of an IN solution of KOH and stirred at 90 ° C for 8 h. The solution was diluted with 50 ml of H20 and extracted with diethyl ether.The aqueous phase was neutralized with 10 ml of an IN solution of HCl and extracted twice with diethyl ether, and the organic phase was dried and concentrated. chromatography on silica gel with cyclohexane / ethyl acetate mixtures to yield 1.2 g (28%) of colorless crystals ^ - MR (CDC13) d: 2.25 (s, 3H); 3.55 (m, 2H); 3.65-3.85 (m, 3H); 3.90 (s, 6H); 6.10 (s, ÍH); 6.25 (s, ÍH); 6.40 (broad, ÍH), 7.20-7.60 (m, 10H) Example 4 Methyl 3- (2-hydroxy-2-methoxycarbonyl-l, 1-diphenylethoxy) -2,2-dimethylpropionate 12.7 g (50 mmol) of 3,3-diphenyl-2,3-epoxypropionate methyl were dissolved in 50 ml of diethyl ether, 6.6 g (50 mmol) of methyl 3-hydroxy-2, 2-dimethylpropionate and 1 ml of BF3 * Et2? were added, and the mixture was stirred at room temperature for 18 hours. The solvent was evaporated and the oily residue was reacted without purification or characterization.

Example 5 Methyl 3- [2-methoxycarbonyl-2- (4-methoxy-6-methyl-2-pyrimidinyloxy) -1, 1-diphenylethoxy] -2,2-dimethylpropionate 10 g (25.9 mmol) of 3- (2 methyl-hydroxy-2-methoxycarbonyl-l, 1-diphenylethoxy) -2,2-dimethylpropionate were dissolved in 40 ml of DMF with N2, 1.78 g (13 mmol) of K2C03 and 5.2 g (25.9 mmol) of 2-methanesulfonyl -4-methoxy-6-methylpyrimidine were added, and the mixture was stirred at 80 ° C for 2 h. This was subsequently diluted with 40 ml of H20 and extracted twice with 30 ml of diethyl ether, the organic phase was dried over MgSO4 and concentrated, and the residue was purified by chromatography on silica gel with ethyl acetate / cyclohexane mixtures. Crystallization from diethyl ether / hexane resulted in 11.8 g (90%) of the product as colorless crystals. Melting point: 143 ° C Example 6 3- [2-Carboxy-2- (4-methoxy-6-methyl-2-pyrimidinyloxy) -1,1-diphenylethoxy] -2,2-dimethylpropionic acid 10.1 g (20 mmol) of 3- [2- Methyl methoxycarbonyl-2- (4-methoxy-6-methyl-2-pyrimidinyloxy) -1, 1-diphenylethoxy] -2,2-dimethylpropionate were dissolved in 50 ml of dioxane and 50 ml of a 2N solution of NaOH and stirred at 80 ° C for 4 h. The solution was diluted with 300 ml of H0 and extracted with 100 ml of ethyl acetate. The aqueous phase was neutralized with IN HCl and extracted with ethyl acetate, and the organic phase was dried over MgSO4, filtered and concentrated. The oily residue was crystallized from diethylether / hexane to give 4.1 g (42%) of colorless crystals XH-NMR (CDC13) d 1.10 (s, 3H); 1.20 (s, 3H); 2.50 (s, 3H); 3.65 (d, ÍH); 3.80 (s, 3H); 3.90 (d, ÍH); 5.95 (s, ÍH); 6.25 (s, ÍH); 7.20-7.50 (m, 10H) The compounds listed in Table 1 can be prepared in similar ways.

Table i Table 1 (Continued) Table 1 (Continued) Table 1 (Continued) Table 1 (Continued) Table 1 (Continued) Table 1 (Continued) Table 1 (Continued) Table 1 (Continued) Table 1 (Continued) Table 1 (Continued) Table 1 (Continued) Table 1 (Continued) Table 1 (Continued)

Claims (1)

1. CLAIMS n derivative of carboxylic acid of the formula I where R is triazole, nitrile or a group c-o "^ - 0R1 and the other substituents have the following meanings: [sic] where R1 has the following meanings: a) hydrogen: b) succinylimidoxy group [sic]; c) a 5-membered heteroaromatic system linked through a nitrogen atom, such as pyrrolyl, pyrazolyl, imidazolyl and triazolyl, which can carry one or two halogen atoms, in particular fluorine and chlorine, and / or 1 or 2 of the following radicals: C? -C4 alkyl such as methyl, ethyl, 1- propyl, 2-propyl, 2-methyl-2-propyl, 2-methyl-1-propyl, 1-butyl, 2-butyl; haloalkyl of C1 -C4, in particular haloalkyl of C? -C2 such as fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trichloromethyl, 1-flurorethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2- chloro-2, 2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl and pentafluoroethyl; haloalkoxy of C 1 -C 4, in particular halo C-C oalkoxy such as difluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro- 1,2,2-trifluoroethoxy and pentafluoroethoxy, in particular trifluoromethoxy; C 1 -C 4 alkoxy such as methoxy, ethoxy propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, 1,1-dimethylethoxy, in particular methoxy, ethoxy and 1-methylethoxy; C 1 -C 4 alkylthio, such as methylthio, ethylthio, propylthio, 1-methylethylthio, butylthio, 1-methylpropylthio, 2-methylpropylthio, 1,1-dimethylethylthio, in particular methylthio and ethylthio; d) R1 is also a radical: R7 (O). / [m \ 8 where m is 0 or 1 and R7 and R8, which can be the same or different, have the following meanings: hydrogen, C? -C8 alkyl, C3-C6 alkenyl, C3-Cd alkynyl, cycloalkyl of C3-C8, it being possible for these alkyl, cycloalkyl, alkenyl and alkynyl groups each to carry from one to five halogen atoms, in particular fluorine or chlorine, and / or one or two of the following groups: C1-C4 alkyl , C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, C 1 -C 4 haloalkoxy as already mentioned, C 3 -C 6 alkenyloxy, C 3 -C 6 alkenylthio, C 3 -C 6 alkynyloxy, C 3 -C 6 alkynylthio, C 1 -C 6 alkylcarbonyl -C, C1-C4 alkoxycarbonyl, C3-C6 alkenylcarbonyl, C3-C6 alkenyloxycarbonyl, C3-C6 alkynyloxycarbonyl, phenyl, substituted or unsubstituted alkynylcarbonyl one or more times, for example one to three times, by halogen, nitro, cyano, C 1 -C alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy or C 1 -C 4 alkylthio, C 1 -C 4 dialkylamino 4, R7 and R8 are also phenyl which can be substituted by one or more of the following radicals: halogen, nitro, cyano, C1-C4 alkyl. C1-C4 haloalkyl, C1-C4 alkoxy, haloalkoxy C1-C4 or alkylthio of C.-C4, OR 'and RL together form an alkylene chain of C4-C7 which closes to form a ring and may contain a heteroatom selected from the group of oxygen, sulfur or nitrogen, e) R1 is in addition a group: 0- (CH2) p S R9 in the k it takes the values 0, 1 and 2, p takes the values-. 2, 3 and 4, and R9 is C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 alkenyl, C3-C6 alkynyl or substituted or unsubstituted phenyl, f) R1 is furthermore a radical or R10 where R10 is: hydrogen, cation of an alkali metal such as lithium, sodium, potassium or the cation of an alkaline earth metal such as calcium, magnesium and barium or an organic ammonium ion; C-C8 cycloalkyl which can carry from one to three C? -C4 alkyl groups; C.sub.1 -C.sub.8 alkyl which can carry from one to five halogen atoms and / or one of the following radicals: C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 alkylthio, cyano, C.sub.1 -C.sub.4 alkylcarbonyl, C.sub.3 -C.sub.i cycloalkyl < [sic], C 1 -C 4 alkoxycarbonyl, phenyl, phenoxy or phenylcarbonyl, it being possible for the aromatic radicals in turn to carry from one to five halogen atoms and / or from one to three of the following radicals: nitro, cyano, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy and / or C 1 -C 4 alkylthio; an alkyl group of C? -C8 which can carry one to five halogen atoms and bears one of the following radicals: a 5-membered heteroaromatic system containing 1 to 3 nitrogen atoms, or a 5-membered heteroaromatic system containing a nitrogen atom and an oxygen or sulfur atom, which system can carry from 1 to 4 halogen atoms and / or one or two of the following radicals: nitro, cyano, C_-C4 alkyl, haloalkyl of C_-c4 , C 1 -C 4 alkoxy, phenyl, C 1 -C 4 haloalkoxy and / or C 1 -C alkylthio; a C2-C6 alkyl group carried in the position 2 one of the following radicals: C 1 -C 4 alkoxyimino, C 3 -C 6 alkynyloxyimino, C 3 -C 6 haloalkenyloximino or benzyloximino; a C3-C6 alkenyl group or an alkynyl group of C3-C6, it being possible that these groups in turn carry from 1 to 5 halogen atoms; R10 is furthermore a phenyl radical which can carry from 1 to 5 halogen atoms and / or from 1 to 3 of the following radicals: nitro, cyano, Ci- C4 alkyl, C1-C4 halalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy and / or C1-C4 alkylthio; a 5-membered heteroaromatic system that binds through a nitrogen atom and contains 1 to 3 nitrogen atoms in which can take 1 or 2 halogen atoms and / or 1 or 2 of the following radicals, [lacuna] R10 is also a group: 11 N 12 wherein R 11 and R 12, which may be the same or different, are C 1 -C 8 alkyl, C 3 -C 6 alkenyl, alkynyl C3-C6, C3-C8 cycloalkyl, it being possible for these radicals to carry a C1-C4 alkoxy radical, C1-C4 alkylthio and / or a substituted or unsubstituted phenyl radical; phenyl which can be substituted by one or more of the following radicals: halogen, nitro, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C-C4 alkoxy, C-C4 haloalkoxy or C? -C4 alkylthio , or R11 and R12 together form an alkylene chain of C3-Ci2 which can carry from 1 to 3 alkyl groups of C1-C4 and may contain a heteroatom of the oxygen, sulfur and nitrogen group; g) R1 is also a radical: wherein R 13 is: C 1 -C 4 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl, C 3 -C 8 cycloalkyl, it being possible for these radicals to carry a C 1 -C 4 alkoxy radical, C 1 -C 4 alkylthio and / or phenyl; substituted or unsubstituted phenyl; h) R1 is a radical O where R13 has the meaning mentioned above. R ~ halogen, C1-C4 alkyl, C1-C haloalkyl, C1-C4 alkoxy, C?-C4 haloalkoxy or X-nitrogen alkylthio or CR14, wherein R14 is hydrogen or C1-C5 alkyl, or CR14 forms together with CR3 a 5 or 6 membered alkylene or alkenyl ring which can be substituted by 1 or 2 C1-C4 alkyl groups and in which in each case a methylene group can be substituted by oxygen, sulfur, -NH or -NC1 -4- alk 'R3 halo, C1-C4 alkyl, C1-C4 haloalkyl, C-C alkoxy, C1-C4 haloalkoxy, -NH-O-C1-4-alkyl, C1-C4 alkylthio or CR3 binds to CR14 as indicated above to form a 5- or 6-membered ring; R4 and R5 (which may be the same or different): phenyl or naphthyl, each of which may be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, C1-C4 alkyl, C1 haloalkyl -C4, C1-C4 alkoxy, C_-C haloalkoxy, phenoxy, C_-C4 alkylthio, amino, C 1 -C 4 alkylamino or phenyl dialkylamino or naphthyl which are connected together in ortho positions by a direct bond, a group methylene, ethylene or ethenylene, an oxygen or sulfur atom or an S02, NH or N-alkyl group, or C3-C7 cycloalkyl; R6 C1-C10 alkyl, C3-C? O alkenyl or C3-C10 alkynyl, the radicals each being substituted one TJ or more times by hydroxyl, mercapto, 2 N- CO- R where Ry and Rz are, independently from each other yes, hydrogen or C 1 -C 5 alkyl; sulfonyl, cyano, guanidino; Z sulfur or oxygen. The carboxylic acid derivative, as claimed in claim 1, wherein R is COOH. The carboxylic acid derivative, as claimed in any of the preceding claims, wherein at least one of the radicals R4 and R5 is phenyl. The carboxylic acid derivative, as claimed in claim 3, wherein R4 and R5 are both phenyl. The carboxylic acid derivative as claimed in any of the preceding claims, wherein R6 is C.sub.1 -Ce alkyl, substituted or unsubstituted by OH or C] -C.sub.4 alkoxy, and Z is 0. The acid derivative carboxylic acid, as claimed in any of the preceding claims, wherein X is CH. The carboxylic acid derivative, as claimed in any of the preceding claims, wherein at least one of the radicals R2 is C1-C alkyl. The use of the compounds, as claimed in any of claims 1 to 7, to produce medicines for the treatment of hypertension, pulmonary hypertension, acute and chronic renal failure, chronic heart failure, cerebral izkemia, restenosis after angioplasty, cancer of prostate. The use of a combination of a compound as claimed in any of claims 1 to 7 with a renin-angiotensin system (RAS) inhibitor.