MXPA02000616A - Novel carboxylic acid derivatives with 5,6 substituted pyrimidine ring, the production and utilization thereof as endothelin receptor antagonists. - Google Patents

Abstract

The invention relates to compounds of formula (I), whereby the substituents have the meaning cited in the description. The invention also relates to the utilization of said derivatives.

Description

'r DERIVATIVES OF CARBOXYLIC ACIDS, NOVEDOUS, WITH RING PIRIMIDINE REPLACED IN POSITIONS 5,6, SU PREPARATION AND USE AS ANTAGONISTS OF RECEIVERS FOR ENDOTHELIN The present invention relates to novel carboxylic acid derivatives, their preparation and use.

Endothelin is a peptide composed of 21 amino acids and is synthesized and released by vascular endothelium. Endothelin exists in three isoforms, ET-1, ET-2 and ET-3. "Endothelin" or "ET" hereinafter refers to one or all of the endothelin isoforms. Endothelin is a potent vasoconstrictor and has a strong effect on the tone of the vessels. It is known that this vasoconstriction is caused by the binding of endothelin to its receptor (Nature, 322, 411-415, 1998, FEBS Letters, 231, 440-444, 1998 and Biochem. Biophys. Res. Commun., 154, 868 -875, 1988).

The high or abnormal release of endothelin causes persistent vasoconstriction in the peripheral, renal and cerebral blood vessels, which can cause disorders. As reported in the literature, endothelin is involved in different disorders. These include: hypertension, acute myocardial infarction, pulmonary hypertension, Raynaud's syndrome, cerebral vasospasm, stroke, benign prostatic hypertrophy, atherosclerosis, asthma and 5 prostate cancer (J. Vascular Med. Biology 2_, 207 (1990), J Am. Med. Association 264, 2868 (1990), Nature 344, 114 (1990), N. Engl. J. Med. 322, 205 (1989), N.

• Engl. J. Med. 328, 1732 (1993), Nephron 66, 373 (1994), Stroke 25, 904 (1994), Nature 365, 759 (1993), J. Mol. 10 Cell. Cardiol. 27, A234 (1995); Cancer Research 56, 663 (1996), Nature Medicine 1, 944 (1995)).

At least two subtypes of endothelin receptors, the ETA and ETB receptors, are currently 15 described in the literature (Nature 348, 730 (1990), Nature 348, 732 (1990)). Therefore, substances that inhibit the binding of endothelin to one or both receptors must antagonize the physiological effects of endothelin and therefore represent valuable drugs.

The preparation and use of endothelin receptor antagonists have already been described in WO 95/26716, WO 96/11914, WO 97/09294, WO 97/12878, WO 97/38980, WO 97/38981, WO 97 / 38982, WO 98/09953, WO 25 98/27070, DE 19726146.9, DE 19748238.4, DE 19750529.5, DE 19806438.1, DE 19809144.3 and DE 19836044.4. Further investigation has shown that the compounds related to the pyrimidine ring substituted at position 5,6 have advantageous properties in relation to the affinity for the receptor and the receptor binding profile. The present patent refers to its preparation and use.

The invention relates to the carboxylic acid derivatives of the formula I: po 15 O II C-R in which R has the following meaning: 7 7 an OR radical in which R is: • hydrogen, the cation of an alkali metal, the cation of an alkaline earth metal, organic ammonium ion, physiologically tolerated, such as C? -Calcylammonium alkyl ammonium or the ammonium ion; 25 Illiiiili-MWlitoliMililllliilli C3-Cs cycloalkyl, Ci-Cs alkyl. CH2-phenyl which may be substituted by one or more of the following radicals: halogen, nitro, cyano, C-C-alkyl, C1-C4 haloalkyl, hydroxyl, C-C4 alkoxy, mercapto, C1-C4 alkylthio , amino, NH (C 1 -C 4 alkyl), N (C 1 -C 2) alkyl; • a C3-C6 alkenyl group, or a C3-C6 alkynyl group, it being possible that these groups in turn 10 carry from 1 to 5 halogen atoms; R can also be a phenyl radical which can carry from 1 to 5 halogen atoms and / or from 1 to 3 of the following radicals: nitro, cyano, Alkyl of ^ -04, haloalkyl of C1-C4, hydroxyl, alkoxy of C1-C4, mercapto, alkylthio of C1-C4, amino, NH (alkyl of C _.- C), N (alkyl of C? -C); b) a 5-member heteroaromatic system, as 20 being pyrrolyl, pyrazolyl, imidazolyl and triazolyl, • which is linked by a nitrogen atom and which can carry from 1 to 2 halogen atoms or from one to two C? -C alkyl groups or from one to two C1-C4 alkoxy groups; c) a group: in which k has the values 0, 1 and 2, p has the q values 1, 2, 3 and 4, and R is: • C 1 -C 4 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl or phenyl which may be 10 substituted by one more, for example from one to three, of the following radicals: halogen, nitro, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, hydroxyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio , mercapto, amino, • NH (C 1 -C 4 alkyl), N (C 1 -C 4 alkyl) 2; 15 of a radical: O S-R H 20 • in which R is: C1-C4 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C8 cycloalkyl, it being possible for These radicals have a C 1 -C 4 alkoxy group, C 1 -C 4 alkylthio and / or a phenyl radical as mentioned in c); phenyl which may be substituted by from one to three of the following radicals: halogen, nitro, cyano, C? -C4 alkyl, C? -C4 haloalkyl, hydroxyl, C? -C alkoxy, C? -C4 alkylthio , • mercapto, amino, NH (C? -C4 alkyl), N (C? -C) alkyl 2. The other substituents have the following meanings: • R is hydroxyl, NH2, NH (C? -C4 alkyl), N (alkyl), 15 C -C 4) 2 C 4 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 hydroxyalkyl, C 1 -C 4 haloalkyl, C 4 -C alkoxy, C 1 haloalkoxy C4, C? -C4 alkylthio, or CR 2 forms together with CR3 a 5 or 6 membered alkylene or alkenylene ring 20 which may be substituted by one or two C 1 -C 4 alkyl groups, in which in each case one or more methylene groups may be substituted by oxygen, sulfur, -NH or - N (C? -C4 alkyl).

R3 is hydroxyl, NH, NH (C? -C4 alkyl), N (C-C4 alkyl) 2, halogen, C? -C4 alkyl, C-C4 alkenyl, C2-C4 alkynyl, C3 alkenyloxy -C6, C? -C4 alkylcarbonyl, C? -C4 alkoxycarbonyl, C? -C4 hydroxyalkyl, C? -C4 haloalkyl, C? -C4 alkoxy, C? -C4 haloalkoxy, -NH-O- C -C 4 alkyl, C 1 -C 4 alkylthio or CR 3 forms, as indicated in R 2, together with CR 2 a 5 or 6 membered ring; 10 R 4 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, C? -C4 alkyl, C? -C4 haloalkyl, C alkoxy? ~ C4, C? -C4 haloalkoxy, phenoxy, C? -C4 alkylthio, amino, NH (C? -C4 alkyl), N (C? -C4 alkyl) 2; or phenyl or naphthyl that are connected to each other in 20 ortho positions by a direct link, a group # methylene, ethylene or ethenylene, an oxygen or sulfur atom or a SO2, NH or N-alkyl group; or C3-C7 cycloalkyl; 25 Rl is hydrogen, C? -Ce alkyl, C3-C6 alkenyl, C3-C6 alkynyl, or C-C8 cycloalkyl, it being possible for each of these radicals to be substituted one or more times by: hydroxyl, mercapto, carboxyl, halogen, nitro, cyano, C? -C4 alkoxy, alkenyloxy • of C3-C6, C3-C6 alkynyloxy, C? -C4 alkylthio, C? -C4 haloalkoxy, C? -C4 alkylcarbonyl, C 1 -C 4 alkoxycarbonyl, (C 1 -C) alkylcarbonyl, (C 1 -C 4) alkyl 2Ncarbonyl, C 3 -C 8 alkylcarbonylalkyl, amino, NH (C 1 -C 4 alkyl), N (C? -C4 alkyl) 2, phenoxy or phenyl, • it is possible that these aryl radicals are 15 substituted one or more times, for example, 1 to 3 times, by halogen, nitrogen, cyano, C? -C alkyl, C? -C4 haloalkyl, C? -C alkoxy, C? -C haloalkoxy. , mercapto, carboxy, hydroxyl, amino, R, C? -C-alkoxycarbonyl, NH (alkyl), 20 C? -C4), N (C? -C) alkyl, methylenedioxy, # ethylenedioxy, or phenyl or phenoxy substituted by C 1 -C 4 alkylthio; phenyl or naphthyl, each of which may be 25 substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, C? -C alkyl, C? -C4 haloalkyl, C? -C alkoxy, C-C haloalkoxy, phenoxy, alkylthio of C -C4, HN (C? -C4 alkyl), N (C? -C4 alkyl) 2 or methylenedioxy or ethylenedioxy; a 5- or 6-membered heteroaromatic system containing from 1 to 3 nitrogen atoms and / or a sulfur atom and which can carry from 1 to 4 halogen atoms and / or from 1 to 2 of the following radicals: C-alkyl -C4, haloalkyl of C? -C, alkoxy of C? -C4, haloalkoxy of C? -C4, alkylthio of C? -C4, phenyl, phenoxy or phenylcarbonyl, it being possible for the phenyl radicals themselves to carry from 1 up to 5 halogen atoms, phenyl, phenoxy or phenylcarbonyl, it being possible for the phenyl radicals in turn to carry from 1 to 5 halogen atoms and / or from 1 to 3 of the following radicals: C 1 -C 4 alkyl, haloalkyl C? -C4, C? -C4 alkoxy, C? -C4 haloalkoxy and / or C? -C4 alkylthio; R is C? -C alkyl, C? -C alkylthio, or alkoxy of C? -C, each of which bears one of the following radicals: hydroxyl, carboxyl, amino, NH (C? -C4 alkyl), N (C? -C4 alkyl) 2, carboxamide or CON (alkyl) C? -C4) 2; Z is sulfur or oxygen. 5 The following definitions apply here and now: • an alkali metal is, for example, lithium, sodium potassium; an alkaline earth metal is, for example, calcium, magnesium, barium; The organic ammonium ions are protonated amines such as for example ethanolamine, diethanolamine, ethylenediamine, diethylamine or piperazine; C3-C7 cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; • haloalkyl of C? -C4, can be linear or branched such as for example fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, diclofluoromethyl, 25 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 or pentafluoroethyl; C?-C 4 haloalkoxy can be linear or branched, for example, difluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, 1-fluoroethoxy, 2,2-difluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2,2,2-trifluoroethoxy, -chloro- 1, 1, 2-trifluoroethoxy, 2-fluoroethoxy or pentafluoroethoxy; C? -C4 alkyl can be linear or branched, for example, methyl, ethyl, 1-propyl, 2-propyl, 2-methyl-2-propyl, 2-methyl-1-propyl, 1-butyl or 2-butyl; C2-C4 alkenyl can be linear or branched, for example, ethenyl, l-propen-3-yl, l-propen-2-yl, 1-propen-1-yl, 2-methyl-l-propenyl, 1- butenyl or 2-butenyl; C2-C alkynyl can be linear or branched, for example, ethynyl, 1-propynyl-yl, l-propyne-3-yl, 1-butyne-4-yl or 2-butyne-4-yl; C 4 -C 4 alkoxy can be linear or branched, for example, methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1- -_ -. »YA-Í-t.J« t-a --_, - and-M- .-. »-.- m-y ^ .- ^^ a ,. methylpropoxy, 2-methylpropoxy or 1,1-dimethylethoxy; C3-C6 alkenyloxy may be linear or branched, for example, allyloxy, 2-buten-1-yloxy or 3-buten-2-yloxy; C3-C6 alkynyloxy may be linear or branched, for example, 2-propynyl-yloxy, 2-butynyl-yloxy or 3-butynyl-2-yloxy; C 1 -C 4 alkylthio may be linear or branched, for example, methylthio, ethylthio, propylthio, 1-methylethylthio, butylthio, 1-methylpropylthio, 2-methylpropylthio or 1,1-dimethylethylthio; C? -C alkylcarbonyl can be linear or branched, for example, acetyl, ethylcarbonyl or 2-propylcarbonyl; C 1 -C 4 alkoxycarbonyl can be linear or branched, for example, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl or n-butoxycarbonyl; C3-Ce alkylcarbonylalkyl may be linear or branched, for example, 2-oxoprop-1-yl, 3-oxobut-1-yl or 3-oxobut-2-yl; C? -Cg alkyl can be linear or branched, for example, C? -C4 alkyl, pentyl, hexyl, heptyl or octyl; 5 halogen is, for example, fluorine, chlorine, bromine, iodine.

The invention also relates to the compounds of • which can be released compounds of formula I (called prodrugs). Preferred prodrugs are those in which release occurs under conditions prevailing in certain compartments of the body, for example in the stomach, intestine, bloodstream, liver. The compounds and intermediates for their preparation, such as for example II and IV, can have one or more substituted asymmetric carbon atoms. Compounds of this type can be in the form of pure enantiomers or pure diastereomers or a mixture of • these. The use of a pure enantiomer compound as the active ingredient is preferred.

The invention further relates to the use of the aforementioned carboxylic acid derivatives for ____________ ÉÉÉ-Ía - Í - l - Í -.-, .. tyA A? S?, T. **? . i - yy-yy- ... - - > - y_y, - .. ^ ... y. > | . . ,. »_._.- -. _ Y _.."-__. -, and ... and- _. -_tA. It is necessary to produce drugs, in particular to produce inhibitors of endothelin receptors.

The compounds of the general formula IV in which Z is sulfur or oxygen (IV) can be prepared as described in WO 96/11914. 10 II III IV The compounds of the general formula III are known or can be synthesized, for example, by reducing the corresponding carboxylic acids or their esters, or by the generally known methods.

The compounds of the formula IV can be obtained in enantiomerically pure form by an acid catalyzed transesterification as described in WO 98/09953. • The enantiomerically pure compounds of formula IV can also be obtained by carrying out a resolution of racemates with racemic compounds 25 or diastereomers of formula IV, using convenient enantiomerically pure bases. Examples of suitable bases of this type are 4-chlorophenylethylamine and the bases mentioned in WO 96/11914. The novel compounds in which the substituents have the meanings mentioned for the general formula I can be prepared, for example, by reacting the carboxylic acid derivatives of the general formula IV in which the substituents have the meanings mentioned with the compounds of the general formula V: V is halogen or R 12-S02-, where R 12 may be C 1 -C alkyl, C 1 -C 4 haloalkyl or phenyl. The reaction of Preference to take place in an inert solvent or diluent • with the addition of a suitable base, that is, of a base that deprotonates intermediate IV, at a temperature in the range from room temperature to the boiling point of the solvent. If R is an ester, then compounds with R = COOH can be prepared by acid, basic or catalytic cleavage of the ester group. 5 Compounds of type I with R = COOH can also be obtained directly when the intermediate IV in which R means COOH is deprotonated with two • equivalents of a convenient base and the reaction with the compounds of the general formula V. In this case also the reaction takes place in an inert solvent and in a temperature range from room temperature to the boiling temperature of the solvent.

Examples of these solvents or diluents are Aliphatic, alicyclic and aromatic hydrocarbons, each of which may optionally be chlorinated, for example, hexane, cyclohexane, petroleum ether, naphtha, benzene, toluene, xylene, methylene chloride, chloroform, carbon tetrachloride, ethyl chloride Y Trichlorethylene, ethers such as, for example, diisopropyl ether, dibutyl ether, methyl terbutyl ether, propylene oxide, dioxane and tetrahydrofuran, nitriles such as, for example, acetonitrile, and propionitrile, amides, such as, for example, 25 dimethylformamide, dimethylacetamide and N-methylpyrrolidone, sulfoxides and sulphones such as, for example, dimethisulfoxide and sulfolane.

The compounds of formula V are known, and some of these may be purchased, or they may be prepared in a generally known manner. The base which may be used is an alkali metal or alkaline earth metal hydride such as sodium hydride, potassium hydride or calcium hydride, a carbonate such as alkali metal carbonate such as sodium carbonate or potassium carbonate, an alkali metal hydroxide or of alkaline earth metal such as sodium hydroxide or potassium hydroxide, an organometallic compound such as butyl lithium or an alkali metal amide such as lithium diisopropylamide.

The compounds of the formula I can also be prepared starting from the corresponding carboxylic acids, ie the compounds of the formula XI in which R is COOH, and converting these in a customary manner to an activated form such as a acid halide, an anhydride or imidazolide, and then reacting the latter with a suitable 7-hydroxyl compound HOR. This reaction can be carried out in conventional solvents and often requires the addition of a base such as, for example, triethylamine, pyridine, imidazole, or diazabicycloundecene. These two steps can also be simplified, for example, by allowing the carboxylic acid to act in the presence of a dehydrating agent such as carbodiimide on the hydroxyl compound.

It is also possible to prepare compounds of the formula I starting from the salts of the corresponding carboxylic acids, ie of compounds of the formula I in which R is a COOM group, where M can be an alkali metal cation or the equivalent of an alkaline earth metal cation. These salts can react with many compounds of the formula R -A, where A is a usual nucleofugic leaving group, for example halogen, such as chlorine, bromine, iodine or as a halogen-, alkyl- or haloalkylaryl-substituted option or alkylsulfonyl, such as, for example, toluenesulfonyl and methylsulfonyl or another leaving group 7 equivalent. The compounds of the formula R -A with a reactive substituent A are known and can be easily obtained with the general knowledge of an expert. This reaction can be carried out in normal solvents and is advantageously undertaken with the addition of a base, in which case the aforementioned ones are convenient.

In some cases, it is necessary to apply the generally known protective group techniques to prepare the novel compounds I. If, for example, R = 4-hydroxyphenyl, the hydroxyl group in the first place can be protected. as benzyl ether, which then dissociates at an appropriate stage in the reaction sequence.

The compounds of the formula I in which R is tetrazolyl can be prepared as described in WO 96/11914.

From the biological effect point of view, the preferred carboxylic acid derivatives of the formula I are those - as pure enantiomers or pure diastereomers or as a mixture of these - in which the substituents have the following meanings: 2 R is hydroxyl, NH (C? -C alkyl), N (20 C? -C4 alkyl) 2. C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C alkoxy, C 1 -C 4 haloalkoxy, 2 3 C 4 -C 4 alkylthio, or CR together with CR form an alkylene or alkenylene ring or 6 members which may be substituted by one or two C? -C alkyl groups, in each case one or more methylene groups IlÍÉ_i-MB-BH Ii-MÍ--. III -! __.-- A »*" * - »-. **., Z- - - ^ -m. *. *., ..,., ^.,, .... .... .. - ... - .... -y.yy..yJ .. »....--. yy ......, and» ..-- and ... jj-i it can be replaced by oxygen, sulfur, -NH or -N (C? -C4 alkyl); 3 R is hydroxyl, N (C 1 -C 4 alkyl) 2, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, 3 C 4 -C 4 haloalkoxy, C 1 alkylthio C4, halogen or CR form, as indicated in R 2, together with CR2 a ring of 5 or 6 • members; R and R phenyl or naphthyl, each of which may be substituted by one or more, for example from 1 to 3, of the following radicals: halogen, cyano,? hydroxyl, mercapto, amino, C? -C4 alkyl, C? -C4 haloalkyl, C? -C4 alkoxy, haloalkoxy 15 C? -C4, C? -C4 alkylthio, NH (C? -C4 alkyl), N (C? -C) alkyl, C? -C4 alkoxycarbonyl; phenyl or naphthyl which are connected to each other in ortho positions by a direct bond, a methylene group, ethylene or ethylene, an oxygen atom or • of sulfur or a SO2, NH or N-alkyl group of C? -C4, * or C3-C7 cycloalkyl; 25 j ^^^^ E | JH R is C? -C8 alkyl, C3-C6 alkenyl, C3-C6 alkynyl or C3-C8 cycloalkyl, it being possible for each of these radicals to be substituted one or more times by : halogen, hydroxyl, cyano, C? -C alkoxy, C3-C6 alkenyloxy, C3-C6 alkynyloxy, C? -C4 alkylthio, C? -C4 haloalkoxy, C? -C alkylcarbonyl, hydroxycarbonyl, • C? -C-alkoxycarbonyl, NH (C? -C alkyl), N (C-C4 alkyl) 2. phenoxy or phenyl, being possible That these aryl radicals are substituted one or more times, for example, 1 to 3 times, by halogen, C? -C4 alkyl, C? -C4 haloalkyl, C? -CXalkoxy X, C haloalkoxy? -C4, R, C? -C4 alkoxycarbonyl, methylenedioxy, ethylenedioxy, C? -C alkylthio, phenyl or phenoxy; phenyl or naphthyl, each of which may be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, amino, C? -C4 alkyl, C? -C haloalkyl, alkoxy • C? -C4, C-C4 haloalkoxy, phenoxy, C? -C4 alkylthio, HN (C? -C4 alkyl), (C? -C4 alkyl) 2; a heteroaromatic system of 5 or 6 members that 25 contains from 1 to 3 nitrogen atoms and / or a sulfur or oxygen atom and which can carry from 1 to 4 halogen atoms and / or from 1 to 2 of the following radicals: C 1 -C 4 alkyl, haloalkyl C? -C, C? -C alkoxy, C? -C4 haloalkoxy, C? -C alkylthio, phenyl, phenoxy or phenylcarbonyl, it being possible for the phenyl radicals in turn to carry from 1 to 5 halogen atoms and / or from 1 to 3 of the following radicals: C? -C alkyl, C? -C4 haloalkyl, C? -C alkoxy, C? -C4 haloalkoxy and / or C? -C4 alkylthio; R is C? -C alkyl, or C? -C4 alkoxy, each of which may carry one of the following radicals: hydroxyl, carbamoyl or CON (C? -C4 alkyl) 2; Z is sulfur or oxygen.

Particularly preferred compounds of the formula I are - as pure enantiomers or pure diastereomers or as a mixture thereof - those in which the substituents have the following meanings: R C?-C 4 alkyl, C?-C 4 alkoxy, in particular methyl, ethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy or CR 2 forms together with CR 3 a 5-membered alkylene or alkenylene ring which may be substituted by one or two methyl groups and in which in each case one or more methylene groups can be substituted by oxygen or sulfur; • 3 R C C alkyl, C 4 alkoxy, C 1 -C alkylthio, in particular methyl, ethyl, methoxy, ethoxy, 3-difluoromethoxy, trifluoromethoxy or CR form, as indicated in R 2, together with CR2 a 5-membered ring; R 4 and R 5 phenyl (identical or different) that may be 15 substituted by one or more, for example from 1 to 3 of the following radicals: halogen, hydroxyl, C? -C4 alkyl, C? -C4 alkoxy, C? -C alkylthio; R 4 and R 5 are phenyl groups that are connected to each other 20 in ortho positions by a direct link, a group • methylene, ethylene or ethenylene, an oxygen or sulfur atom or a group S02, NH or N- (C? -C alkyl); or R and R are cyclohexyl; R is C? -C8 alkyl, C3-C6 alkenyl or C3-C8 cycloalkyl, it being possible for each of these radicals to be substituted one or more times by: halogen, hydroxyl, cyano, C? -C alkoxy, C3-C6 alkenyloxy, C? -C4 alkylthio, phenoxy or phenyl, it being possible for these aryl radicals to be substituted one or more times, for example, 1 to 3 times, by halogen, C? -C4alkyl, alkoxy of C? -C4, methylenedioxy, ethylenedioxy, C? -C4 alkylthio; phenyl or naphthyl, each of which may be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, amino, C? -C alkyl, C? -C haloalkyl, C? C, C? -C4 haloalkoxy, phenoxy, C? -C4 alkylthio, C? -C4 alkylamino or C? -C4 dialkylamino; a 5- or 6-membered heteroaromatic system containing from a nitrogen atom and / or a sulfur or oxygen atom and which can carry from 1 to 4 halogen atoms and / or from 1 to 2 of the following radicals: C-alkyl ? -C, C? -C4 haloalkyl, C? -C4 alkoxy, C? -C4 alkylthio, phenyl, phenoxy or phenylcarbonyl, it being possible for the phenyl radicals themselves to carry from 1 to 5 halogen atoms and /? or from 1 to 3 of the following radicals: C? -C4 alkyl, C? -C haloalkyl, C? -C alkoxy and / or C? -C4 alkylthio; 5 Z is sulfur or oxygen.

The compounds of the present invention offer a • Novel therapeutic potential for the treatment of hypertension, pulmonary hypertension, infarction of 10 myocardium, angina pectoris, arrhythmia, acute / chronic renal failure, chronic heart failure, renal failure, cerebral vasospasm, cerebral ischemia, subarachnoid hemorrhages, migraine, asthma, • atherosclerosis, endotoxic shock, organ failure 15 induced by endotoxin, intravascular coagulation, restenosis after angioplasty and bypass operations, benign prostatic hyperplasia, liver cirrhosis, erectile dysfunction, ischemic renal failure and induced by intoxication or hypertension, metastasis and growth of 20 mesenchymal tumors, renal failure induced by the contrast medium, pancreatitis, in particular acute pancreatitis, gastrointestinal ulcers.

The invention further relates to combinations of the endothelin receptor antagonists of the formula I and the renin-angiotensin system inhibitors. Inhibitors of the renin-angiotensin system are renin inhibitors, angiotensin II antagonists and angiotensin converting enzyme (ACE) inhibitors. The combinations of the endothelin receptor antagonists of the formula I and the ACE inhibitors are preferred.

The invention further relates to combinations of endothelin receptor antagonists of formula I and beta blockers.

The invention also refers to the combinations * of the endothelin receptor antagonists of formula I and diuretics.

The invention furthermore relates to combinations of endothelin receptor antagonists of the formula I and substances that block the action of VEGF 20 (vascular endothelial growth factor). Examples of these substances are antibodies directed against VEGF or specific binding proteins or even low molecular weight substances that can specifically inhibit the release of VEGF or binding to the receptor. 25 - - - - - - - - - - - - - - - -. ^ y -.- .. ........ ^, .. y. _._._.,., ".. -. _ - "- __, _, J_, ....- yy, ..., ji-, 1.

The combinations mentioned above can be administered at the same time or in sequence. These can be used in a single pharmaceutical formulation or even in separate formulations. The form of administration may also differ, for example, endothelin receptor antagonists may be administered orally and parenterally administered VEGF inhibitors.

These products in combination are particularly suitable for treating and preventing hypertension and its sequelae, and for treating heart failure.

The good effect of the compounds can be demonstrated in the following tests: Receptor binding studies For the binding studies, cloned CHO cells expressing human ETA or ETB receptors were used.

Preparation of the membrane CHO cells expressing ETA or ETB receptors were grown in DMEM NUT MIX F? 2 medium (Gibco, No. 21331-020) with 10% fetal bovine serum (PAA Laboratories GmbH, Linz, NO.A15-022), 1 mM glutamine (Gibco No. 25030-024), 100 U / mL penicillin and 100 μg / mL streptomycin (Sigma No. P-0781). After 48 hours, the cells were washed with PBS and incubated with PBS containing 0.05% trypsin at 37 ° C for 5 minutes. This was followed by neutralization with medium, and the cells were harvested by centrifugation at 300 x g.

For the preparation of the membrane, the q cells were adjusted to a concentration of 10 cells / mL of buffer solution (50 mM Tris-HCl buffer, pH 7.4) and then disintegrated with ultrasound (Branson Sonifier 250, 40-70 seconds / constant output 20).

Bonding tests For the assay of binding to the ETA and ETB receptors, the membranes were suspended in the incubation buffer (50 mM Tris-HCl, pH 7.4 with MnCl2, 5 mM, 40 mg / mL of bacitracin and 0.2% of BSA) in a concentration of 50 μg of protein per test mixture and incubated with [125 I] -ET? (assay for the ETA receptor) 25 pM or [125I] -ET3 (assay of the ETB receptor) 25 pM in the presence and absence of the test substance at 25 ° C. The non-specific binding _7 was determined using 10 M ETx. After 30 minutes, filtration through glass fiber filters GF / B 5 (Whatman, England) in a Skatron cell harvester (Skatron, Lier, Norway) separated the free radioligand and the bound, and the filtrates were washed with buffer solution Tris-HCl pH 7.4 with 0.2% BSA cooled in ice. The radioactivity collected on the filters was quantified using a Packard 2200 CA liquid scintillation counter.

Functional test of the vessels for endothelin receptor antagonists 15 After pre-tensioning segments of rabbit aorta with 2 g and a relaxation time of one hour in Krebs-Henseleit solution at 37 ° C and a pH between 7.3 and 7.4, initially a contraction with K was induced. After the washing, a dose-effect graph of the • endothelin to the maximum.

Potential endothelin antagonists are administered to other copies of the same vessel 15 minutes 25 before beginning the dose / effect graph of endothelin. The effects of endothelin are calculated as a percentage of the contraction with K. With effective endothelin antagonists there is a shift to the right in the dose / effect graph of endothelin. 5 Tests of ET antagonists in vivo: • Male SD rats weighing 250-300 g were anesthetized with amobarbital, artificially ventilated, 10 vagotomized and prepared. The carotid artery and the jugular vein were catheterized.

Q? In control animals, intravenous administration of 1 μg / kg of ETx leads to a marked increase in blood pressure which persists for a prolonged period.

The test animals received iv injection (1 mL / kg) of the test compounds 30 minutes before the administration of ETx. To determine ET antagonist properties, changes in blood pressure in the test animals were compared with those in the control animals. 25 Oral tests of mixed ETA and ETB receptor antagonists Male normotensive rats (Sprague, Dawley, Janvier) weighing 250-350 g are pretreated with oral test substances. 80 minutes later, the animals are anesthetized with urethane, and the carotid artery (to measure blood pressure) and the jugular vein are catheterized (administration of large endothelin / endothelin 1).

After a stabilization period, large endothelin (20 μg / kg, administration volume 0.5 mL / kg) or ETX (0.3 μg / kg, administration volume 0.5 mL / kg) is given intravenously. Blood pressure and heart rate are continuously recorded for 30 minutes. Notable and lasting changes in blood pressure are calculated as the area under the curve (AUC). To determine the antagonistic effect of the test substances, the AUC for the animals tested with the substance is compared to the AUC of the control animals.

The novel compounds can be administered orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperitoneally) in a customary manner. The administration can also take place with vapors or rubbers through the nasopharyngeal space. 5 The dose depends on the age, condition and weight of the patient and the mode of administration. As a general rule, the daily dose of the active ingredient is from about 0.5 to 50 mg / kg of body weight with oral administration and from about 0.1 to 10 10 mg / kg body weight with parenteral administration.

The novel compounds can be administered in Q? usual solid or liquid pharmaceutical forms, for example, as uncovered or covered tablets (with 15 film), capsules, powders, granules, suppositories, solutions, ointments, creams or sprays. These occur in a usual way. The active ingredients can, for this purpose, be processed with normal pharmaceutical auxiliaries such as tablet binders, 20 diluents, preservatives, tablet disintegrators, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, slow release agents, antioxidants and / or propellant gases (see H. Sucker et al .: Pharmazeutische 25 Technologie, Thieme-Verlag, Stuttgart, 1991). The forms of administration obtained in this way usually contain from 0.1 to 90% by weight of the active ingredient. 5 Examples of synthesis Example 1 • 2-Methylsulfanyl-6,7-dihydro-5H-cyclopentapyrimidine 4.9 g (44 mmol) of 2-oxocyclopentancarbaldehyde, dissolved in 100 mL of water, were added over the course of one hour to a solution of 16.4 g of water. • potassium carbonate (119 mmol) and 42.3 g of S-15 methylisothiourea sulfate (152 mmol) and, after stirring at room temperature overnight, was heated at 65 ° C for 6 hours. The aqueous solution was extracted with pentane, the organic phase was concentrated and the residue was chromatographed on silica gel. 20 (heptane / ethyl acetate 8: 2), yielding 0.93 g of • objective compound as a solid. 25 Example 2 2-Methylsulfonyl-6,7-dihydro-5H-cyclopentapyrimidine 5 A solution of 9.9 g (16.1 mmol) of Oxone in 70 mL of water and a 4 M solution of sodium hydroxide were added in an alternating manner to a solution of 0.85 g. • (5.1 mmol) of 2-methylsulfanyl-6,7-dihydro-5H-cyclopentapyrimidine in 20 mL of methanol at 0 ° C to 10 maintain a pH of 2-3. After the addition was complete, the mixture was stirred at room temperature for 2 hours and then extracted with ethyl acetate, Q? The organic phase was dried over sodium sulfate and evaporated. The solid residue (0.93 g) was used without 15 additional purification.

Example 3 2- (6,7-dihydro-5H-cyclopentapyrimidin-2-yloxy) -3-methoxy-benzyl 3,3-diphenylpropionate • 0.6 g (1.6 mmol) of 2-hydroxy-3-methoxy-3, 3- Benzyl diphenyl propionate, dissolved in DMF, was added dropwise to a suspension of 0.1 g of NaH 25 (3.3 mmol, 80% in white oil) in 10 mL of DMF at 0 ° C.

After stirring the mixture for 30 minutes, 420 mg (2.1 mmol) of 2-methylsulfonyl-6,7-dihydro-5H-cyclopentapyrimidine in 10 mL of DMF was added, and the mixture was stirred at room temperature overnight. 5 Then it was poured into ice water and extracted three times with diethyl ether. The ether phases were dried with magnesium sulfate and then filtered, and the solvent was • dragged in vacuum. The yellow residue (0.54 g) was subjected to chromatography on silica gel, isolating 10 243 mg of the required product.

MS (API): 503 (M + Na; # Example 4 15 2- (6,7-Dihydro-5H-cyclopentapyrimidin-2-yloxy) -3-methoxy-3, 3-di-phenylpropionic acid (1-136) A solution of benzyl 2- (6,7-dihydro-5H-20 cyclopentapyrimidin-2-yloxy) -3-methoxy-3, 3-di-phenylpropionate in 15 mL of ethyl acetate / methanol 2: 1 was hydrogenated with hydrogen at atmospheric pressure, using 60 mg of palladium in active carbon (10%), at room temperature for 24 hours. The The mixture was filtered and concentrated and the residue (177 mg) was stirred in diethyl ether, filtered and then dried. 95 mg of the target product were isolated.

XH-NMR (d6-DMSO, 200 MHz): 8.3 (s, 1H), 7.2-7.4 (m, 10H), 6.15 (s, 1H); 3.3 (s, 3H); 2.8 (m, 4H), 2.1 (m, 2H).

Example 5 2-Chloro-4-methoxy-5-methylpyrimidine 10 A solution of 25 g of 2,4-dichloro-5-methylpyrimidine in methanol was cooled to 0 ° C, added • 28.5 mL of a sodium methoxide solution (30% in methanol) and the mixture was stirred first at 0 ° C for one 15 hours and then at room temperature for 2 hours. The resulting suspension was then freed from the solvent, taken up in water and extracted with ether, the organic phases were dried over sodium sulfate, filtered and then concentrated, and the resulting residue was subjected to 20 chromatography on silica gel, yielding 11.4 g of the • objective compound. 25 Example 6 2- (4-Methoxy-5-methylpyrimidin-2-yloxy) -3-isopropoxy-3, 3-diphenylpropionic acid (1-5) 5 0.76 g (2.5 mmol) of 2-hydroxy-3-isopropoxy acid 3, 3-diphenylpropionic, dissolved in DMF, drop was added • dropwise to a suspension of 0.23 g of sodium hydride (7.6 mmol, 80% in white oil) in 20 mL of DMF at 0 ° C. After the mixture had been stirred for 30 minutes, 0.6 g (3.8 mmol) of 2-chloro-4-methoxy-5-methylpyrimidine in 10 mL of DMF was added, then the Q? The mixture was stirred first at room temperature overnight and then at 40 ° C for 8 hours. Then it was poured in The ice water was adjusted to pH 1 with 2N HCl and extracted three times with diethyl ether. The ethereal phases were extracted with KOH IN, and the alkaline aqueous phase was again adjusted to pH 1 with 2N HCl and re-extracted with ether. The ethereal phases obtained in this way were dried 20 over magnesium sulfate and filtered, the solvent was drained in vacuo. The yellowish residue (0.8 g) was subjected to chromatography on silica gel, isolating 0.19 g of the required product.

H-NMR (CDCl 3, 200 MHz): 8.0 (s, 1H); 7.5.-7.6 (, 2H); 7.2-7.4 (m, 8H); 6.3 (s, 1H); 3.9 (m, 1H); 3.9 (s, 3H); 2.0 (2, 3H); 1.1 (m, 6H). 5 MS (API): 423 (M + H) Example 7 • 2-methylsulfanyl-4-methoxy-5-methylpyrimidine 7.2 g (102 mmol) of sodium thiomethanolate were added to a solution of 14.8 g (93 mmol) of 2-fl-chloro-4-methoxy-5-methylpyrimidine in 100 mL of acetonitrile, and the resulting suspension was refluxed for 4 hours. Then the solvent was removed and the residue was taken up in water and extracted with ether. The organic phases were dried over sodium sulfate, filtered and concentrated, and the resulting residue (13.4 g) was reacted without further purification. 20 • Example 8 2-methylsulfanyl-4-methoxy-5-methylpyrimidine 25 A solution of 62.4 g (101 mmol) of Oxone in water and a 4M solution of sodium hydroxide (approximately 40 mL) were added to a solution of 13.3 g (78.1 mmol) of 2-methylsulfanyl-4-methoxy-5- methylpyrimidine in 80 mL of methanol at 0 ° C in such a way that a pH of 2-3 was maintained. After the addition was complete, the mixture was stirred at room temperature for 2 hours and, after removing the methanol, it was extracted with ethyl acetate, • and the organic phase was dried over sodium sulfate and evaporated. The solid residue (14.7 g) was stirred in diethyl Ether for 2 hours, then filtered and dried, yielding 13.5 g of the pure objective product.

Example 9 15 2- (4-Methoxy-5-methylpyrimidin-2-yloxy) -3-benzyloxy-3, 3-diphenylpropionic acid (1-47) 1. 0 g (2.4 mmol) of 2-hydroxy-3-benzyloxy-3-diphenylpropionic acid dissolved in DMF was added dropwise 20 to a suspension of 0.27 g of sodium hydride (9 mmol, • 80% in white oil) in 20 mL of DMF at 0 ° C. After stirring the mixture for 30 minutes, 0.79 g (3.9 mmol) of 2-methylsulfonyl-4-methoxy-5-methylpyrimidine in 10 mL of DMF and the mixture was then stirred at room temperature 25 during the night. This was emptied in ice water, adjusted to pH 1 with 2N HCl and extracted three times with diethyl ether. The ether phases were extracted with 1N KOH, and the alkaline aqueous phase was again adjusted to pH 1 with 2N HCl and extracted with ether. The resulting ether phases were dried over magnesium sulfate and filtered, and the solvent was entrained in vacuo. The yellowish residue (1.2 g) was mixed with 10 mL of diethyl ether and stirred at room temperature for three hours, and then the precipitated solid was filtered off with suction and dried, yielding 0.6 g of the objective compound. 1 H-NMR (CDC13 200 MHz): 8.0 (s, 1H), 7.2-7.45 (m, 10H); • 6.2 (s, 1H); 4.7 (d, 1H); 4.55 (d, 1H); 3.85 (s, 3H); 2.1 (s, 3H). 15 MS (API): 472 (M + H) Example 10 20 2- (4-Methoxy-5-methylpyrimidin-2-yloxy) -3-hydroxy-3mW 3, 3-diphenylpropionic acid (1-29) A solution of 440 mg (0.94 mmol) of 2- (4-methoxy-5-methylpyrimidin-2-yloxy) -3-benzyloxy-3, 3-25-diphenylpropionic acid in 20 mL of ethyl acetate was added. --ty-t-dL -.--. J --- t --- y -, .. hydrogenated with hydrogen at atmospheric pressure at room temperature using 80 mg of palladium on activated carbon (10%) for 3 days. The mixture was filtered and concentrated, and the residue (430 mg) was subjected to chromatography on silica gel, isolating 39 mg of the desired target product. • 1H-NMR (d6-DMSO, 200 MHz): 8.0 (s, 1H); 7.6 (m, 2H); 7.0- 7.5 (, 8H); 5.6 (s, 1H); 3.8 (s, 3H); 1.9 (s, 3H). 10 Example 11 k (S) -2- (4-methoxy-5-methylpyrimidin-2-yloxy) -3-methoxy-3,3-diphenylpropionic acid (1-2) 15 g (36.7 mmol) of (S) -acid 2-hydroxy-3-methoxy-3,4-diphenylpropionic acid, dissolved in 40 mL of MDF, was added dropwise to a suspension of 3.3 g of sodium hydride (110 mmol, 80% in white oil) in 40 g. 20 mL of DMF at 0 ° C. After stirring the mixture for 60 • minutes, 9.6 g (47.7 mmol) of 2-methylsulfonyl-4-methoxy-5-methylpyrimidine in 20 mL of DMF was added, and the mixture was then stirred at room temperature overnight. This was poured into ice water, 25 adjusted to pH 1 with 2N HCl and extracted three times with Diethyl ether. The ethereal phases were extracted with KOH IN, and the alkaline aqueous phase was readjusted to pH 1 with 2N HCl, and extracted with ether. The resulting ether phases were dried over sodium sulfate and filtered, and the solvent was drained off in vacuo. The residue (17.1 g) was stirred in diethyl ether overnight, filtered and dried. The solid (12.1 g) obtained in this way was subjected to chromatography on silica gel, obtaining 11.4 g of the desired product. 10 1-NMR (CDC13, 270 MHz): 8.0 (s, 1H), 7.2-7.45 (m, 10H); 6.1 (s, 1H); 3.85 (s, 3H); 3.3 (s, 3H); 2.0 (s, 3H). p.f. 134 ° C (decomposition) 15 MS (ESI): 394 (M + H) The following compounds were prepared in the same manner as the aforementioned examples. 20 • Example 12 3-Ethoxy-2- (4-methoxy-5-methylpyrimidin-2-yloxy) -3,3-diphenylpropionic acid (1-4) ____ t_y_¿_ --- y-jy-yyi ---. ^ 1 H-NMR (CDCl 3, 200 MHz): 8.0 (s, 1H), 7.1-7.5 (m, 10H); 6.2 (s, 1H); 3.9 (s, 3H); 3.5 (m, 3H); 2.0 (s, 3H); 1.1 (t, 3H). 5 MS (ESI): 409 (M + H) + Example 13 3- [2- (3, 4-dimethoxyphenyl) ethoxy] -2- (4-methoxy-5-10 methylpyrimidin-2-yloxy) -3,3-diphenylpropionic acid 1 H-NMR (CDCl 3, 200 MHz): 8.0 (s, 1 H), 7.1-7.4 (m, 10 H); 6.6-6.8 (m, 3H); 6.3 (s, 1H); 3.9 (s, 3H); 3.8 (m, 7H); 3.5-3.65 (m, 1H); 2.7-2.9 (m, 2H); 2.0 (s, 3H); 1.1 (t, 3H). # 15 Example 14 3- [2- (3,4-Dimethoxyphenyl) ethoxy] -2- (9-methyl-9H-purin-2-yloxy) -3,3-diphenylpropionic acid (1-150) 1 H-NMR (CDC13, 200 MHz): 8.2 (s, 1H); 7.9 (s, 1H), 7.1-7.4 (m, 10H); 6.6-6.8 (m, 3H); 6.3 (s, 1H); 3.9 (s, 3H); 3.8 (m, 7H); • 3.5-3.65 (m, 1H); 2.7-2.9 (ra, 2H); 2.0 (s, 3H); 1.1 (t, 3H). 25 ¿Jgg! Example 15 3, 3-Bis (4-fluorophenyl) -3-methoxy-2- (4-methoxy-5-methylpyrimidin-2-yloxy) propionic acid (1-61) 1 H-NMR (CDCl 3 at 400 MHz): 8.0 (s, 1H), 7.4-7.5 (m, 2H); 7.25-7.3Í (m, 2H); 6.9-7.0 (m, 4H); 6.05 (s, 1H); 3.9 (s, 3H); 3.3 (s, 3H 2.05 (s, 3H).

• Example 16 10 3 (3,4-Dimethylbenzyloxy) -2- (4-methoxy-5-methylpyrimidin-2-yloxy) -3,3-diphenylpropionic acid (1-149) • 1 H-NMR (CDCl 3, 200 MHz): 8.0 (s, 1 H), 7.1-7.5 (m, 10 H); 6.2 (s, 1H); 4.6 (d, 1H); 4.4 (d, 1H); 3.85 (s, 3H); 2.2 < s, 6H); 2.0 (S, 3H). fifteen The compounds mentioned in Table 1 can be prepared in the same way.

Example 17 • The binding data of the receptor was measured using the binding assay described above for the compounds mentioned below. 25 The results are shown in Table 2 Table 2 5 Receptor binding data (Kx values) • • * 46 Table I 1 * • 47 1 48 10 15 49 10 15 • fifty 1

Claims (8)

1. A compound of the formula I wherein R is tetrazolyl or an O 10 II C-R group in which R has the following meaning: a) an OR 7 radical in which R7 is: Hydrogen, the cation of an alkali metal, the cation of an alkaline earth metal, organic ammonium ion, physiologically tolerated, such as C 1 -C 4 alkyl ammonium or the ammonium ion; 20 • C3-C8 cycloalkyl, C? -C8 alkyl, CH2-phenyl which may be substituted by one or more of the following radicals: halogen, nitro, cyano, C1-C4 alkyl, C1-C4 haloalkyl, 25 hydroxyl, C1-C4 alkoxy, mercapto, alkylthio - ^ ± j ^^ & z ^^ x? GJÍ * ¡^^^^^ j * j > ¡?? =? of C 1 -C 4, amino, NH (C 1 -C 4 alkyl), N (C 1 -C 4 alkyl) 2; an alkenyl group of C3 ~ C6, or a group C3-C6 alkynyl, it being possible for these groups in turn to carry from 1 to 5 halogen atoms; * 7 R can also be a phenyl radical that 10 can carry from 1 to 5 halogen atoms and / or from 1 to 3 of the following radicals: nitro, cyano, C1-C4 alkyl, C1-C4 haloalkyl, hydroxyl, C3-C4 alkoxy, mercapto, alkylthio of C1-C4, amino, NH 4 (C 1 -C 4 alkyl), N (C 1 -C 4 alkyl) 2; b) a 5-membered heteroaromatic system, such as pyrrolyl, pyrazolyl, imidazolyl and triazolyl, which is linked by a nitrogen atom and which can carry from 1 to 2 halogen atoms or from one to two alkyl groups of C? -C4 or from one to two C1-C4 alkoxy groups; a group: 25 in which k has the values 0, 1 and 2, p Q has the values 1, 2, 3 and 4, and R is: C-C alkyl, C3-C8 cycloalkyl, z > C3-C6 alkenyl, C3-C6 alkynyl or phenyl which may be substituted by one more, Examples of one to three of the following radicals: halogen, nitro, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, hydroxyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, mercapto, amino, NH ( C1-C4 alkyl), N (C? -C) alkyl 2; 15 d) a radical: 20 in which R is: C1-C4 alkyl, C3-C6 alkenyl, C3-Cg alkynyl, C3-C8 cycloalkyl, being possible 25 that these radicals bear a C1-C4 alkoxy group, C1-C4 alkylthio and / or a phenyl radical as mentioned in c); phenyl which may be substituted by from one to three of the following radicals: halogen, nitro, cyano, C1-C4 alkyl, C1-C4 haloalkyl, hydroxyl, C3-C4 alkoxy, C1-C4 alkylthio, mercapto, amino, NH (C 1 -C 4 alkyl), N (C 1 -C) alkyl 2. R 2 is hydroxyl, NH 2, NH (C 1 -C 4 alkyl), N (C 1 -C 4 alkyl) 2, C 1 -C 4 alkyl, C 2 -C alkenyl, C 2 -C 4 alkyl, C hydroxyalkyl; -C4, C1-C4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 alkylthio 2, or CR forms, together with CR, a 5 or 6 membered alkylene or alkenylene ring which may be substituted by one or two C1-6 alkyl groups C4, in which in each case one 20 or more methylene groups can be substituted by # oxygen, sulfur, -NH or -N (C 1 -C 4 alkyl). 3 R is hydroxyl, NH 2, NH (C 1 -C 4 alkyl), N (C 1 -C 4 alkyl), halogen, alkyl C1-C4, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 alkenyloxy, C1-C4 alkylcarbonyl, C1-C4 alkoxycarbonyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, C1 alkoxy -C 4, haloalkoxy of CI -CA I -NH-O-C-C 4 alkyl, 3-C 1 -C 4 alkylthio or CR form, as indicated 2 2 in R, together with CR a 5- or 6-membered ring; R 5 and R (which may be the same or different) are phenyl or naphthyl, each of which may be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, C? -C alkyl , C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, phenoxy, C 1 -C 4 alkylthio, amino, NH (C 1 -C 4 alkyl), N (C 1 -C 4 alkyl); or phenyl or naphthyl which are connected to each other in ortho positions by a direct link, a »Methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an S0, NH or N-alkyl group; 25 or C3-C7 cycloalkyl; R "is hydrogen, Ci-Cs alkyl, C3-C6 alkenyl, C3-C6 alkynyl or C3-C8 cycloalkyl, it being possible for each of these radicals to be substituted one or more times by: hydroxyl, mercapto, carboxyl, halogen, nitro, cyano, C1-C4 alkoxy, C3-C6 alkenyloxy, C3-C6 alkynyloxy, C1-C4 alkylthio, C1-C4 haloalkoxy, C 1 -C 4 alkylcarbonyl, C 1 -C 4 alkoxycarbonyl, C 1 -C 4 alkylcarbonyl, C 1 -C 4 alkyl 2Ncarbonyl, C 3 -C 8 alkylcarbonylalkyl, amino, NH (C? Alkyl) C4), * N (C? -C4 alkyl) 2, phenoxy or phenyl, being It is possible that these aryl radicals are substituted one or more times; phenyl or naphthyl, each of which may be substituted by one or more of the 20 following radicals: halogen, nitro, cyano, W hydroxyl, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C alkoxy, C 1 -C 4 haloalkoxy, phenoxy, C 1 -C 4 alkylthio, HN (C 1 -C 4 alkyl), N (C 1 -C 4 alkyl) ? -C4) 2 or methylenedioxy or Ethylene dioxy; a 5 or 6 membered heteroaromatic system containing from 1 to 3 nitrogen atoms and / or a sulfur atom and which can carry from 1 to 4 halogen atoms and / or from 1 to 5 of the following radicals: 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, phenyl, phenoxy or phenylcarbonyl, it being possible for the radicals phenyl in turn take from 1 to 10 5 halogen atoms, phenyl, phenoxy or phenylcarbonyl, it being possible for the phenyl radicals in turn to carry from 1 to 5 halogen atoms and / or from 1 to 3 of the following radicals: C 1 -C 4 alkyl, C? -C haloalkyl, C? -C alkoxy, C? -C4 haloalkoxy and / or C? -C4 alkylthio; Z is sulfur or oxygen 20 and the salts, the tautomeric forms, the enantiomeric and diastereomeric pure forms, physiologically tolerated.

2. The use of compounds I as claimed in claim 1 to treat diseases. ifttf -ÉiÉi *

3. The use of compounds I as claimed in claim 1 as endothelin receptor antagonists.

4. The use of the compounds I as claimed in claim 1 to produce medicaments for the treatment of diseases in which high concentrations of endothelin occur.

5. The use of the compounds I as claimed in claim 1 to produce medicaments for treating diseases in which endothelin contributes to the development and / or progress.

6. The use of compounds I as claimed in claim 1 for treating chronic heart failure, restenosis, high blood pressure, pulmonary hypertension, acute / chronic renal failure, cerebral ischemia, asthma, benign prostatic hyperplasia, 20 prostate cancer and acute pancreatitis.

7. A combination of the compounds I as claimed in claim 1 and one or more active ingredients selected from the inhibitors of the system 25 renin-angiotensin, such as inhibitors A ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^ angiotensin converting enzyme (ACE), combined ACE / neutral endopeptidase (NEP) inhibitors, 5 β-blockers, diuretics, calcium channel blockers, and VEGF blocking substances. •

8. A pharmaceutical preparation for oral or parenteral use, comprises at least one compound I 10 as claimed in claim 1 for individual dosage, in addition to usual pharmaceutical excipients. • ^^^^^^^ _ fe ^^^^ ___ ^^