ZA200200333B

ZA200200333B - Novel carboxylic acid derivatives with 5,6 substituted pyrimidine ring, the production and utilization thereof as endothelin receptor antagonists.

Info

Publication number: ZA200200333B
Application number: ZA200200333A
Authority: ZA
Inventors: Wilhelm Amberg; Georg Kettschau
Original assignee: Basf Ag
Priority date: 1999-07-20
Filing date: 2002-01-15
Publication date: 2003-04-30
Also published as: BR0012592A; BG106321A; NO20020254D0; AR030026A1; SK772002A3; CN1367778A; KR20020019550A; NO20020254L; JP2003505377A; IL147666A0; HUP0202646A2; AU6561500A; EP1196394A1; DE19933164A1; PL353165A1; TR200200622T2; WO2001005771A1; HUP0202646A3; TW555749B; CA2379545A1

Description

fh " x 4 o 0050/50501

Novel carboxylic acid derivatives with 5,6-substituted pyrimidine ring, their preparation and use as endothelin receptor antagonists

The present invention relates to novel carboxylic acid derivatives, their preparation and use.

Endothelin is a peptide which is composed of 21 aminoacids 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 isoforms of endothelin.

Endothelin is a potent vasoconstrictor and has a strong effect on vessel tone. It is known that this vasoconstriction is caused by binding endothelin to its receptor (Nature, 332, 411-415, 1988; FEBS Letters, 231, 440-444, 1988 and Biochem. Biophys. Res.

Commun., 154, 868-875, 1988).

Elevated or abnormal release of endothelin causes persistent vasoconstriction in peripheral, renal and cerebral blood vessels, which may result in disorders. As reported in the literature, endothelin is involved in a number of disorders. These include: hypertension, acute myocardial infarct, pulmonary hypertension, Raynaud's syndrome, cerebral vasospasms, stroke, benign prostate hypertrophy, atherosclerosis, asthma and 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. Cell. Cardiol. 27, A234 (1995); Cancer Research 56, 663 (1996), Nature

Medicine 1, 944,(1995)).

At least 2 endothelin receptor subtypes, ET, and ETg receptors, are currently described in the literature (Nature 348, 730 (1990), Nature 348, 732 (1990)). Accordingly, substances which inhibit the binding of endothelin to one or both receptors ought to antagonize the physiological effects of endothelin and therefore represent valuable drugs.

The preparation and use of endothelin receptor antagonists has already been described in WO 95/26716, WO 96/11914, WO 97/09294, WO097/12878, WO 97/38980,

WO097/38981, WO 97/38982, WO098/09953, WO098/27070, DE 19726146.9, DE 19748238.4, DE 19750529.5, DE 19806438.1, DE 19809144.3 and DE 19836044.4.

Further investigation has revealed that related compounds with 5,6-substituted pyrimidine ring has advantageous properties in relation to receptor affinity and receptor i]

AMENDED SHEET

® 0050/50501 -2.- binding profile. The present patent relates to their preparation and use.

The invention relates to carboxylic acid derivatives of the formula

R® a [ i: | N

R—z—c—C—o— Dg

KE 2 B= ; big

R in which R is tetrazolyl or a group

Cc . 1].

C—R in which R has the following meaning: : “ay anOR'radicatinwhichR'isr hydrogen, the cation of an alkali metal, the cation of an alkaline earth metal, a physiologically tolerated organic ammonium ion such as tertiary C4-C,- alkylammonium or the ammonium ion;

Cs-Cg-cycloalkyl, Cy-Cg-alkyl, CHp-phenyl which may be substituted by one or more of the following radicals: halogen, nitro, cyano, C,-Cy-alkyl, C4-C4-haloalkyl, hydroxyl, C4-C,-alkoxy, mercapto, C;-C,-alkylthio, amino,

NH(C;-Cy-alkyl), N(C4-Cs-alkyl),; a C;-Ce-alkenyl or a C;-Ce-alkynyl group, it being possible for these groups in turn to carry from one to five halogen atoms;

R’ can also be a phenyl radical which can carry from one to five halogen atoms and/or from one to three of the following radicals: nitro, cyano, C4-C4-alkyl, Cy-C,- haloalkyl, hydroxyl, C-Cs-alkoxy, mercapto, C;-C,-alkylthio, amino,

NH(C,-C,-alkyl), N(C+-Cs-alkyl)z;

SI

~ ‘0050/50501 -3- b) a 5-membered heteroaromatic system, such as pyrrolyl, pyrazolyl, imidazoly! and triazolyl, which is linked via a nitrogen atom and which may carry from one to two halogen atoms or from one to two C4-C,-alkyl or from one to two C;-Cs-alkoxy groups;

C) a group (Bs —0— (CB,),—S—R in which k has the values 0, 1 and 2, p has the values 1, 2, 3 and 4, and R® is

C4-Cy-alkyl, Cs-Cg-cycloalkyl, Cs-Cs-alkenyl, C3-Cg-alkynyl or phenyl which may be substituted by one or more, e.g. from one to three, of the following radicals: halogen, nitro, cyano, C4-Cy-alkyl, C,-Cs-haloalkyl, hydroxyl, C,-C4-alkoxy, C4-C4- i5 alkylthio, mercapto, amino, NH(C;-Cy-alkyl), N(C-Cg-alkyl),; d) a radical oO —¥—8— ®

I

C1-Cs-alkyl, C3-Cs-alkenyl, Cs-Cs-alkynyl, C3-Cg-cycloalkyl, it being possible for these radicals to carry a C4-C4-alkoxy, C4-C,-alkylthio and/or a phenyl radical as mentioned under C); phenyl which may be substituted by from one to three of the following radicals: halogen, nitro, cyano, C4-Cs-alkyl, C4-C4-haloalkyl, hydroxyl, C,-Cs-alkoxy, C4-C,- alkylthio, mercapto, amino, NH(C;-Cy4-alkyl), N(C4-Cs-alkyl)..

The other substituents have the following meanings:

LS A

~ '0050/50501 -4-

R? is hydroxyl, NH,, NH(C1-Cs-alkyl), N(C1-Cs-alkyl),, C-Cy-alkyl, C>-Cs-alkenyl, Co-

Cs-alkynyl, C4-C4-hydroxyalkyl, C;-C,-haloalkyl, C,-Cs-alkoxy, C;-Cs-haloalkoxy,

C1-Cs-alkylthio or CR? forms together with CR® a 5- or 6- membered alkylene or alkenylene ring which may be substituted by one or two C,-Cy-alkyl groups, in which in each case one or more methylene groups may be replaced by oxygen, sulfur, -NH or —N(C;-C,-alkyl).

R® is hydroxyl, NHz, NH(C:-Cy4-alkyl), N(C4-Cy4-alkyl),, halogen, C4-Cs-alkyl, C>-Cs- alkenyl, Co-Cy-alkynyl, Cs-Ce-alkenyloxy, C,-Cs-alkylcarbonyl, C4-Cqs- alkoxycarbonyl, C;-Cs-hydroxyalkyl, C4-Cs-haloalkyl, C,-C4-alkoxy, C;-C4- haloalkoxy, -NH-O-C;-C4-alkyl, C-C,-alkylthio or CR® forms, as indicated under

R?, together with CR? a 5- or 6-membered ring;

R* and R® (which may be identical or different) are: phenyl or naphthyl, each of which may be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, C4-C4-alkyl, C4-C4-haloalkyl,

C,-Cs-alkoxy, Cq-Cs-haloalkoxy, phenoxy, C;-Cs-alkylthio, amino, NH(C;-C,- alkyl), N(C4-Cs-alkyl),; or phenyl or naphthyl which are connected together in ortho positions by a direct linkage, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an SO., NH or N-alkyl group; or C3-C-cycloalkyl;

R® is hydrogen,

C,-Cg-alkyl, C3-Ce-alkenyl, Cs-Cg-alkynyl or C5-Cg-cycloalkyl, it being possible for each of these radicals to be substituted one or more times by: hydroxyl, mercapto, carboxyl, halogen, nitro, cyano, C,-Cs-alkoxy, Cs-Cs-alkenyloxy, Cs-Cs- alkynyloxy, C;-Cs-alkylthio, C;-Cs-haloalkoxy, C;-Cs-alkylcarbonyl, C;-C,- alkoxycarbonyl, (C4-Cs-alkyl)NHcarbonyl, (C;-Cs-alkyl)o.Ncarbonyl, Cs-C,- alkylcarbonylalkyl, amino, NH(C-Cy-alkyl), N(C4-Cs-alkyl),, phenoxy or phenyl, it being possible for said aryl radicals to be substituted one or more times, e.g. from one to three times, by halogen, nitro, cyano, Cy-C4-alkyl, C,-C,-haloalkyl, C4-C,-

AMENDED SHEET

® 0050/50501 -5- alkoxy, C;-Cs-haloalkoxy, mercapto, carboxy, hydroxyl, amino, R', C,-Cs alkoxycarbonyl, NH(C,-Cg4-alkyl), N(C4-C4-alkyl),, methylenedioxy, ethylenedioxy, or phenyl or phenoxy substituted by C;-Cs-alkylthio; 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, C4-Cs- haloalkyl, C;-Cs-alkoxy, Cy-Cs-haloalkoxy, phenoxy, Ci-Cs-alkylthio, NH(C4-Ca- alkyl), N(C4-C,-alkyl), or methylenedioxy or ethylenedioxy; a five- or six-membered heteroaromatic system which contains from one to three nitrogen atoms and/or a sulfur or oxygen atom and which may carry from one to four halogen atoms and/or from one to two of the following radicals: C4-Cg-alkyi,

C,-Cs-haloalkyl, C4-C4-alkoxy, C,-C,-haloatkoxy, C4-Cs-alkylthio, phenyl, phenoxy or phenylcarbonyl, it being possible for the phenyl radicals is turn to carry from one to five halogen atoms and/or from one to three of the following radicals: C;-

Cs-alkyl, C1-C4-haloalkyl, C;-C4-alkoxy, C4-Cs-haloalkoxy and/or C4-Cs-alkyithio;

R'™ is Cy-Cs-alkyl, Ci-Ca-alkylthio or Ci-Cs-alkoxy, each of which carry one of the following radicals: hydroxyl, carboxyl, amino, NH(C;-Cs-alkyl), N(C;-Cs-alkyl), carboxamide or CON(C-C4-alkyl)z; : y4 is sulfur or oxygen. : SEE

The following definitions apply herein and hereinafter: an alkali metal is, for example, lithium, sodium, potassium; Cn : an alkaline earth metal is, for example, calcium, magnesium, barium; : organic ammonium jons are protonated amines such as, for example, ethanolamine, diethanolamine, ethylenediamine, diethylamine or piperazine;

C,-Cr-cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl;

C,-Cs-haloalkyl can be linear or branched such as, for example, fluoromethyl, difluoromethyt, trifluoromethyl, - chlorodifluoromethyl, dichlorofiuoromethyl,

i

AMENDED SHEET

0050/50501 -6- 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;

C4-Cs-haloalkoxy can be linear or branched such as, for example, difluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, 1-fluoroethoxy, 2,2-difluoroethoxy, 1,1,2,2- tetrafluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-1,1,2-trifluoroethoxy, .2-fluoroethoxy or pentafluoroethoxy;

C,-Cs-alkyl can be linear or branched such as, for example, methyl, ethyl, 1-propyl, 2- propyl, 2-methyi-2-propyi, 2-methyi-i-propyi, 1-butyl or 2-butyl;

C,-Cs-alkenyl can be linear or branched such as, for example, ethenyl, i-propen-3-yl, i- propen-2-yl, 1-propen-1-yl, 2-methyl-i-propenyl, 1-butenyl or 2-butenyl;

C,-Cs-alkynyl can be linear or branched such as, for example, ethynyl, i-propyn-i-yl, i- propyn-3-yl, 1-butyn-4-yl or 2-butyn-4-yl; :

C:-C4-alkoxy can be linear or branched such as, for example, methoxy, ethoxy, propoxy, : 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or 1,1-dimethylethoxy;

Ci-Cs-alkenyloxy can be linear or branched such as, for example, allyloxy, 2-buten-1i- yloxy or 3-buten-2-yloxy,

Cs;-Cs-alkynyloxy can be linear or branched such as, for example, 2-propyn-1-yloxy, 2- butyn-1-yloxy or 3-butyn-2-yloxy,

C1-Cy-alkylthio can be linear or branched such as, for example, methylthio, ethylthio, propylthio, 1-methylethylthio, butylthio, 1-methyipropyithio, 2-methyipropylthio or 1,1i- dimethylethylthio,

C:-Cs-alkylcarbonyl can be linear or branched such as, for example, acetyl, ethylcarbonyl or 2-propyicarbonyl;

C4-Cs-alkoxycarbonyl can be linear or branched such as, for example, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl or n-butoxycarbonyi;

' 0050/5050 -7-

Cs-Cg-alkylcarbonylalkyl can be linear or branched such as, for example, 2-oxoprop-1-Yl, 3-oxobut-1-yl or 3-oxobut-2-yl;

C1-Cs-alkyl can be linear or branched such as, for example, C;-C4-alkyl, pentyl, hexyl, 5 heptyl or octyl; halogen is, for example, fluorine, chlorine, bromine, iodine. :

The invention further relates to compounds from which the compounds of the formula can be released (called prodrugs).

Preferred prodrugs are those in which the release occurs under conditions prevailing in certain compartments of the body, for example in the stomach, intestine, blood stream, liver. L

The compounds and the intermediates for their preparation, such as, for example, Il and

IV, may have one or more asymmetric substituted carbon atoms. Compounds of this type may be in the form of pure enantiomers or pure diastereomers or a mixture thereof.

The use of an enantiomerically pure compound as active ingredient is preferred.

The invention further relates to the use of the abovementioned carboxylic acid derivatives for producing drugs, in particular for producing 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. é

RB

Q 1

RE R 6 6 BH

SLANT Bogor > R —2Z C—o8 r® Rr r?

IZ ITX Iv

Compounds of the general formula Ill are either known or can be synthesized, for example, by reducing the corresponding carboxylic acids or their esters, or by other generally known methods. :

4 64 ~ ‘0050/50501 -8-

Compounds of the formula IV can be obtained in enantiomerically pure form by an acid- catalysed transetherification as described in WO 98/09953.

The enantiomerically pure compounds of the formula IV can also be obtained by carrying out a conventional racemate resolution with racemic or diastereomeric compounds of the formula IV, using suitable 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 stated for general formula | can be prepared, for example, by reacting the carboxylic acid derivatives of the general formula IV in which the substituents have the stated meaning with compounds of the general formula V.

B

2

IV + r* —( RR T

B® — . v rR’

R'" in formula V is halogen or R'>-SO,-, where R'? can be C;-Cj-alkyl, C;-C4-haloalkyl or phenyl. The reaction preferably takes place in an inert solvent or diluent with the addition of a suitable base, i.e. of a base that deprotonates the intermediate IV, at a temperature in the range from room temperature to the boiling point of the solvent.

If R' is an ester, then the compounds with R' = COOH can be prepared by acidic, basic or catalytic cleavage of the ester group.

Compounds of type | with R' = COOH may furthermore be obtained directly when the intermediate IV in which R' means COOH is deprotonated with two equivalents of a suitable base and reacted with compounds of the general formula V. Here too, the reaction takes places in an inert solvent and in a temperature range from room temperature to the boiling point of the solvent.

Examples of such solvents or diluents are aliphatic, alicyclic and aromatic hydrocarbons, each of which may optionally be chlorinated, such as, for example, hexane,

il

AMENDED SHEET

® 0050/50501 -9- cyclohexane, petroleum ether, naphtha, benzene, toluene, xylene, methylene chloride, chloroform, carbon tetrachloride, ethyl chloride and trichloroethylene, ethers such as, for example, diisopropyl! ether, dibutyl ether, methyl tert-butyl ether, propylene oxide, dioxane and tetrahydrofuran, nitriles such as, for example, acetonitrile and propionitrile, amides such as, for example, dimethylformamide, dimethylacetamide and N- methylpyrrolidone, sulfoxides and sulfones, such as, for example, dimethyl sulfoxide and sulfolane.

Compounds of the formula V are known, and some of them can be bought, or they can be prepared in a generally known manner.

The base which can 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, e.g. sodium carbonate or potassium carbonate, an alkali metal or alkaline . earth metal hydroxide such as sodium hydroxide or potassium hydroxide, an organometallic compound such as butyllithium or an alkali metal amide such as lithium diisopropylamide. )

Compounds of the formula | can also be prepared by starting from the corresponding carboxylic acids, i.e. compounds of the formula | in which ‘R' is COOH, and converting these in a conventional way into an activated form such as an acid halide, an anhydride or imidazolide, and then reacting the latter with an appropriate hydroxyl compound

HOR’. This reaction can be carried out in the conventional solvents and often requires : 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 a carbodiimide on the hydroxyl compound.

It is also possible to prepare compounds of the formula | by starting from the salts of the corresponding carboxylic acids, i.e. from 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 be reacted with many compounds of the formula R’-

A where A is a conventional nucleofugic leaving group, for example halogen such as chlorine, bromine, iodine or optionally halogen-, alkyl- or haloalkyl- substituted aryl- or alkyisulfonyl such as, for example, toluenesulfonyl and methylsulfonyl or another equivalent leaving group. Compounds of the formula R’-A with a reactive substituent A are known or can easily be obtained with general expert knowledge. This reaction can be

AMENDED SHEET

® 0050/50501 -10- carried out in the conventional solvents and is advantageously undertaken with the addition of a base, in which case those mentioned above are suitable.

In some cases it is necessary to apply generally known protective group techniques for preparing the novel compounds |. If, for example, R® = 4-hydroxyphenyl, the hydroxy! group can firstly be protected as benzyl ether, which is then cleaved at a suitable stage in the reaction sequence.

Compounds of the formula | in which R'is tetrazolyl can be prepared as described in

WO 96/11914.

With a view to the biological effect, preferred carboxylic acid derivatives of the general formula | are those — either as pure enantiomers or pure diastereomers or as mixture thereof — in which the substituents have the following meanings: :

R? hydroxyl, N(C:-Cs-alkyl)s, Ci-Cs-alkyl, Ci-Cs-haloalkyl, C-Cs-alkoxy, C4-Cs- haloalkoxy, Cs-Ca-alkylthio or CR? forms together with CR® a 5- or 6-membered alkylene or alkenylene ring which may be substituted by one or two C;-Cg-alkyl groups and in which in each case one or more methylene groups may be replaced by oxygen, sulfur, -NH or -N(C4-C4-alkyl);

R® hydroxyl, N(Ci-Cs-alkyl)s, C;-Cs-alkyl, Cy-Cs-haloalkyl, Ci-Cs-alkoxy, Ci-C,- haloalkoxy, C4-Cs4-alkylthio, halogen or CR?3 forms, as indicated for R?, together with CR? a 5- or 6-membered ring;

R* and R® phenyl or naphthyl, each of which may be substituted by one or more, e.g. from one to three, of the following radicals: halogen, cyano, hydroxyl, mercapto, amino, C;-Cgs-alkyl, C;-Cs-haloalkyl, C;-Cs-alkoxy, C;-Cs-haloalkoxy, C;-C,- alkylthio, NH(Cs-Cs-alkyl)z [sic], N(C4-Cs-alkyl)s, Ci-Cs-alkylcarbonyl, Ci-C,- alkoxycarbonyl; phenyl or naphthyl which are connected together in ortho positions by a direct linkage, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an SO,, NH or N(C4-Cs-alkyl) group, or C3-Cs-cycloalkyl;

AMENDED SHEET

® 0050/50501 -11 -

R® C4-Cg-alkyl, Cs-Cs-alkenyl, C3-Cs-alkynyl or C3-Cg-cycloalkyl, it being possible for each of these radicals to be substituted one or more times by: halogen, hydroxyl, cyano, Cy-Cs-alkoxy, Cs-Ces-alkenyloxy, Cs-Ce-alkynyloxy, C,-Cs-alkylthio, C4-Cs- haloalkoxy, C-C,-alkylcarbonyl, hydroxycarbonyl, C:-C4-alkoxycarbonyl, NH(C;-

Cs-alkyl), N(C-C4-alkyl),, phenoxy or phenyl, it being possible for said aryl radicals to be substituted one or more times, e.g. from one to three times by halogen, C:-Cs-alkyl, C-Cg4-haloalkyl, C,-Cs-alkoxy, Ci-Cs-haloalkoxy, R" C,-Cs alkoxycarbonyl, methylenedioxy, ethylenedioxy, C;-C4-alkylthio, phenyl or phenoxy; : phenyl or naphthyl which may be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, amino, C,-C4-alkyl, C-Cs-haloalkyl,

C,-Ca-alkoxy, C;-C4-haloalkoxy, phenoxy, C4-Ca-alkylthio, NH(C-Cg-alkyl), N(C+-Cs- alkyl); a five- or six-membered heteroaromatic system which contains from one to three nitrogen atoms and/or one sulfur or oxygen atom and which may carry from one to four halogen atoms and/or from one to two of the following radicals: C-Cs4- alkyl, C;-Cs-haloalkyl, C4-C4-alkoxy, C;-Cs-haloalkoxy, Ci-C,-alkyithio, phenyl, phenoxy or phenyicarbonyl, it being possible for the phenyl radicals in turn to carry from one to five halogen atoms and/or from one to three of the following radicals: Cy-Cs-alkyl, C;i-C,-haloalkyl, C1-Cs-alkoxy, C4-Cy-haloalkoxy and/or C;-

C,-alkyithio;

R'® C,-Csalkyl, Ci-Cs-alkoxy, which carry one of the following radicals: hydroxyl, carbamoyl or CON(C4-Cs,-alkyl),; :

Zz sulfur or oxygen.

Particularly preferred compounds of the formula | are those — either as pure enantiomers or pure diastereomers or as mixture thereof — in which the substituents have the following meanings:

R? C,-Csalkyl, C;-Csalkoxy, in particular methyl, ethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy or CR? forms together with CR® 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 may be

AMENDED SHEET

® 0050/50501 -12 - replaced by oxygen or sulfur;

R® C-Cs-alkyl, C4-C,-alkoxy, C4-Cs-alkylthio, in particular methyl, ethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy or CR® forms, as indicated for RZ, together with CR? a 5-membered ring; -

R* and R°® phenyl (identical or different) which may be substituted by one or more, e.g. from one to three, of the following radicals: halogen, hydroxyl, C,-Cs-alkyl,

C,-C,-alkoxy, C;-Cy-alkylthio or

R* and R® are phenyl groups which are connected together in ortho positions by a direct linkage, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an SO;, NH or N(C,-C,-alkyl) group; or R*and R°® are cyclohexyl;

R® C;-Cg-alkyl, Ca-Cg-alkenyl or Cs-Cg-cycloalkyl, it being possible for each of these radicals to be substituted one or more times by: halogen, hydroxyl, cyano, C4-C,- alkoxy, Cs-Cs-alkenyloxy, C-Cs-alkylthio, phenoxy or phenyl, it being possible for said aryl radicals to be substituted one or more times, e.g. from one to three times, by C;-Cy-alkyl, C¢-C4-alkoxy, methylenedioxy, ethylenedioxy, C;-Cs- alkylthio; phenyl or naphthyl which may be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, amino, C,-Cs-alkyl, C1-Cs-haloalkyl, C;-

Cs-alkoxy, C4-C4-haloalkoxy, phenoxy, C4-C4-alkylthio, C1-Cq-alkylamino or

C;-C,-dialkylamino; a five- or six-membered heteroaromatic system which contains one nitrogen atom and/or one sulfur or oxygen atom and which may carry from one to four halogen atoms and/or from one to two of the following radicals: C4-Cs-alkyl, C,- : Cg-haloalkyl, C4-C,-alkoxy, C4-Cg-atkylthio, phenyl, phenoxy or phenylcarbonyl, it being possible for the phenyl radicals in turn to carry from one to five halogen atoms and/or from one to three of the following radicals: C4-Cs-alkyl, C4-C,- haloalkyl, C4-C4-alkoxy and/or C,-Cs-alkylthio;

Zz sulfur or oxygen.

" fe

B '0050/50501 -13-

The compounds of the present invention offer a novel therapeutic potential for the treatment of hypertension, pulmonary hypertension, myocardial infarct, angina pectoris, arrhythmia, acute/chronic renal failure, chronic heart failure, renal insufficiency, cerebral vasospasms, cerebral ischemia, subarachnoid hemorrhages, migraine, asthma, atherosclerosis, endotoxic shock, endotoxin-induced organ failure, intravascular coagulation, restenosis after angioplasty and by-pass operations, benign prostate hyperplasia, cirrhosis of the liver, erectile dysfunction, ischemic and intoxication-induced renal failure or hypertension, metastasis and growth of mesenchymal tumors, contrast medium-induced renal failure, pancreatitis, in particular acute pancreatitis, gastrointestinal ulcers.

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

The invention further relates to combinations of endothelin receptor antagonists of the formula | and beta-blockers.

The invention further relates to combinations of endothelin receptor antagonists of the formula | and diuretics.

The invention further relates to combinations of endothelin receptor antagonists of the formula | and substances which block the action of VEGF (vascular endothelial growth factor). Examples of such substances are antibodies directed against VEGF or specific binding proteins or else low molecular weight substances which are able specifically to inhibit the VEGF release or receptor binding.

The aforementioned combinations may be administered simultaneously or sequentially.

They can be employed either in a single pharmaceutical formulation or else in separate formulations. The form of administration may also differ, for example the endothelin receptor antagonists may be administered orally and the VEGF inhibitors parenterally.

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

n

AMENDED SHEET

0050/50501 -14-

The good effect of the compounds can be shown in the following tests:

Receptor-binding studies

Cloned human ETa or ETg receptor-expressing CHO cells were employed for binding studies.

Membrane preparation

The ET, or ETs receptor-expressing CHO cells were grown in DMEM NUT MIX Fz medium (Gibco, No. 21331-020) with 10% fetal calf serum (PAA Laboratories GmbH,

Linz, No. A15-022), 1 mM glutamine (Gibco No. 25030-024), 100 U/ml penicillin and 100 ig/ml streptomycin (Sigma No. P-0781). After 48 hours, the cells were washed with PBS and incubated with 0.05% trypsin-containing PBS at 37°C for 5 minutes. This was followed by neutralization with medium, and the cells were collected by centrifugation at 300 x g.

For membrane preparation, the cells were adjusted to a concentration of 10° cells/ml of buffer (50 mM Tris—HCL buffer, pH 7.4) and then disintegrated with ultrasound (Branson

Sonifier 250, 40-70 seconds/constant output 20).

Binding assays :

For the ET, and ET receptor-binding assay, the membranes were suspended in incubation buffer (50 mM Tris—HCI, pH 7.4 with 5 mM MnCl, 40 mg/ml bacitracin and 0.2% BSA) in a concentration of 50 ug of protein per assay mixture and incubated with 25 pM [1251]-ET, (ETA receptor assay) or 25 pM [1251]-ET; (ETg receptor assay) in the presence and absence of test substance at 25°C. The nonspecific binding was determined using 107 M ET,. After 30 min, filtration through GF/B glass fiber filters (Whatman, England) in a Skatron cell harvester (Skatron, Lier, Norway) separated free and bound radio ligand, and the filters were washed with ice-cold Tris—HCI buffer, pH 7.4 with 0.2% BSA. The radioactivity collected on the filters was quantified using a Packard 2200 CA liquid scintillation counter.

i

AMENDED SHEET

® 0050/50501 -15-

Functional vessel test for endothelin receptor antagonists

After pretensioning rabbit aorta segments with 2 g and a relaxation time of 1 h in Krebs-

Henseleit solution at 37°C and a pH between 7.3 and 7.4, initially a contraction is induced with K*. After washing out, an endothelin dose-effect plot is constructed up to the maximum.

Potential endothelin antagonists are administered to other specimens of the same vessel 15 min before starting the endothelin dose-effect plot. The effects of the endothelin are calculated as a % of the K+ contraction. With effective endothelin antagonists there is a rightward shift in the endothelin dose-effect plot.

Testing of ET antagonists in vivo:

Male SD rats weighing 250 — 300 g were anesthetized with amobarbital, artificially ventilated, vagotomized and pithed. The carotid artery and jugular vein were catheterized.

In control animals, intravenous administration of 1 ng/kg ET1 results in a marked rise in blood pressure which persists for a lengthy period.

The test animals received i.v. injection (1 ml/kg) of the test compounds 30 min before administration of ET1. To determine the ET-antagonistic properties, the changes in blood pressure in the test animals were compared with those in the control animals.

Oral testing of mixed ETa and ETg receptor antagonists:

Male normotensive rats (Sprague Dawley, Janvier) weighing 250-350 g are pretreated with the test substances orally. 80 minutes later, the animals are anesthetized with urethane, and the carotid artery (for measuring the blood pressure) and the jugular vein (administration of big endothelin/endothelin 1) are catheterized.

After a stabilization period, big endothelin (20 pg/kg, admin. vol. 0.5 mikg) or ET1 (0.3 ng/kg, admin. vol. 0.5 ml/kg) is given intravenously. Blood pressure and heart rate are recorded continuously for 30 minutes. The marked and long-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 treated with

X . ~ 0050/5050 -16 - substance is compared with the AUC for the control animals.

The novel compounds can be administered orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperitoneally) in a conventional way. Administration can also take place with vapors or sprays through the nasopharyngeal space.

The dosage depends on the age, condition and weight of the patient and on the mode of administration. As a rule, the daily dose of active ingredient is from about 0.5 to 50 mg/kg of body weight on oral administration and from about 0.1 to 10 mg/kg of body weight on parenteral administration.

The novel compounds can be administered in conventional solid or liquid pharmaceutical forms, e.g. as uncoated or (fim-)coated tablets, capsules, powders, granules, suppositories, solutions, ointments, creams or sprays. These are produced in a conventional way. The active ingredients can for this purpose be processed with conventional pharmaceutical aids such as tablet binders, bulking agents, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, release-slowing agents, antioxidants and/or propellant gases (cf. H. Sucker et al.: Pharmazeutische Technologie, Thieme—Verlag, Stuttgart, 1991). The administration forms obtained in this way normally contain from 0.1 to 90% by weight of active ingredient.

Synthesis Examples

Example 1 2-Methylsulfanyl-6,7-dihydro-5H-cyclopentapyrimidine : 4.9 g (44 mmol) of 2-oxocyclopentanecarbaldehyde, dissolved in 100 ml of water, were added over the course of one hour to a solution of 16.4 g of potassium carbonate (119 mmol) and 42.3 g of S-methylisothiourea sulfate (152 mmol) and, after stirring at room temperature overnight, 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 (heptane/ethyl acetate 8:2), resulting in 0.93 g of the target compound as a solid.

N, . '0050/50501 -17 -

Example 2 2-Methylsulfonyl-6,7-dihydro-5H-cyclopentapyrimidine

A solution of 8.9 g (16.1 mmol) of Oxone in 70 ml of water and 4M sodium hydroxide solution were added alternately to a solution of 0.85 g (5.1 mmol) of 2-methylsulfanyl- 6,7-dihydro-5H-cyclopentapyrimidine in 20 mi of methanol at 0°C so that a pH of 2-3 was maintained. After the addition was complete, the mixture was stirred at room temperature for 2 hours and then extracted with ethyl acetate, the organic phase was dried over sodium sulfate and evaporated. The solid residue (0.93 g) was employed without further purification.

Example 3

Benzyl 2-(6,7-dihydro-5H-cyclopentapyrimidin-2-yloxy)-3-methoxy-3,3- diphenylpropionate 0.6 g (1.6 mmol) of benzyl 2-hydroxy-3-methoxy-3,3-diphenyl-propionate, dissolved in

DMF, was added dropwise to a suspension of 0.1 g of NaH (3.3 mmol, 80% in white oil) in 10 ml of DMF at 0°C. After the mixture had been stirred for 30 minutes, 420 mg (2.1 mmol) of 2-methylsulfonyl-6,7-dihydro-5H-cyclopentapyrimidine in 10 ml of DMF were added, and the mixture was stirred at room temperature overnight. It was then 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 stripped off in vacuo. The yellow residue (0.54 g) was chromatographed on silica gel, allowing 243 mg of the required product to be isolated. :

MS (API): 503 (M+Na)*

Example 4 2-(6,7-Dihydro-5H-cyclopentapyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropionic acid (I- 136)

A solution of 0.23 g of benzyl 2-(6,7-dihydro-5H-cyclopentapyrimidin-2-yloxy)-3-methoxy- 3,3-diphenylpropionate in 15 ml of ethyl acetate/methanol 2:1 was hydrogenated with hydrogen under atmospheric pressure, using 60 mg of palladium in active carbon (10%),

. 0050/50501 -18 - at room temperature for 24 hours. The mixture was filtered and concentrated, and the residue (177 mg) was stirred into diethyl ether, filtered and then dried. 95 mg of the target product were isolated. 1H-NMR (dg-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

A solution of 25 g of 2,4-dichloro-5-methylpyrimidine in methanol was cooled to 0°C, 28.5 ml of sodium methoxide solution (30% in methanol) were added, and the mixture was stirred firstly at 0°C for one hour and then at room temperature for 2 hours. The resulting suspension was then freed of 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 chromatographed on silica gel, resulting in 11.4 g of the target compound.

Example 6 2-(4-Methoxy-5-methylpyrimidin-2-yloxy)-3-isopropoxy-3,3-diphenylpropionic acid (I-5) 0.76 g (2.5 mmol) of 2-hydroxy-3-isopropoxy-3,3-diphenylpropionic acid, dissolved in

DMF, 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 mixture was stirred firstly at room temperature overnight and then at 40°C for 8 hours. It was then poured into ice-water, adjusted to pH 1 with 2N HCI 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 HCI and reextracted with ether. The ether phases obtained in this way were dried over magnesium sulfate and filtered, and the solvent was stripped off in vacuo. The yellowish residue (0.8 g) was chromatographed on silica gel, allowing 0.19 g of the required product to be isolated. 1H-NMR (CDCl3, 200 MHz): 8.0 (s, 1H); 7.5-7.6 (m, 2H); 7.2-7.4 (m, 8H); 6.3 (s, 1H); 3.9 (m, 1H); 3.9 (s, 3H); 2.0 (s, 3H); 1.1 (m, 6H). }

0

AMENDED SHEET

® 0050/50501 -19 -

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-chloro-4-methoxy-5-methylpyrimidine in 100 mi of acetonitrile, and the resulting suspension was refluxed for four hours. The solvent was then 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.

Example 8 2-Methylsulfanyl-4-methoxy-5-methylpyrimidine

A solution of 62.4 g (101 mmol) of Oxone in water and 4 M sodium hydroxide solution (about 40 ml) were added to a solution of 13.3 g (78.1 mmol) of 2-methylsulfanyl-4- methoxy-5-methylpyrimidine in 80 mi 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 removal of methanol, 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 two hours, then filtered and dried, resulting in 13.5 g of pure target product.

Example 9 2-(4-Methoxy-5-methylpyrimidin-2-yloxy)-3-benzyloxy-3,3-diphenylpropionic acid (1-47) 1.0 g (2.5 mmol) of 2-hydroxy-3-benzyloxy-3,3-diphenylpropionic acid, dissolved in DMF, was added dropwise to a suspension of 0.27 g of sodium hydride (8 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 were added, and the . mixture was then stirred at room temperature overnight. It was poured into ice-water adjusted to pH 1 with 2N HCI and extracted three times with diethyl ether. The ether

AMENDED SHEET

@ 0050/50501 - 20 - phases were extracted with IN KOH, and the alkaline aqueous phase was again adjusted to pH 1 with 2N HCI and extracted with ether. The resulting ether phases were dried over magnesium sulfate and filtered, and the solvent was stripped off in vacuo.

The yellowish residue (1.2 g) was mixed with 10 mi of diethyl ether and stirred at room temperature for 3 hours, and then the precipitated solid was filtered off with suction and dried, resulting in 0.6 g of the target compound. 1H-NMR (CDCl3, 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).

MS (API): 471 (M+H)*

Example 10 2-(4-Methoxy-5-methylpyrimidin-2-yloxy)-3-hydroxy-3,3-diphenylpropionic acid (I-29)

A solution of 440 mg (0.84 mmol) of 2-(4-methoxy-5-methylpyrimidin-2-yloxy)-3- benzyloxy-3,3-diphenylpropionic acid in 20 ml of ethyl acetate was hydrogenated with hydrogen under atmospheric pressure at room temperature using 80 mg of palladium on active carbon (10%) for 3 days. The mixture was filtered and concentrated, and the residue (430 mg) was chromatographed on silica gel, allowing 32 mg of the desired target product to be isolated. 1H-NMR (ds-DMSO, 200 MHz): 8.0 (s, 1H); 7.6 (m, 2H); 7.0-7.5 (m, 8H); 5.6 (s, 1H); 3.8 (s, 3H); 1.9 (s, 3H).

Example 11 (S5)-2-(4-Methoxy-5-methylpyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropionic acid (I-2) 10 g (36.7 mmol) of (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid, dissolved in 40 ml of DMF, were added dropwise to a suspension of 3.3 g of sodium hydride (110 mmol, 80% in white oil) in 40 ml of DMF at 0°C. After stirring the mixture for 60 minutes, 9.6 g (47.7 mmol) of 2-methyisulfonyl-4-methoxy-5-methylpyrimidine in 20 ml of DMF were added, and the mixture was then stirred at room temperature overnight. It was poured into ice-water, adjusted to pH 1 with 2N HCI and extracted three times with diethyl ether. The ether phases were extracted with IN KOH, and the alkaline aqueous

} 0050/50501 -21- phase was readjusted to pH 1 with 2N HCI and extracted with ether. The resulting ether phases were dried over sodium sulfate and filtered, and the solvent was stripped 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 chromatographed on silica gel, allowing 11.4 g of the desired product to be isolated. 1H-NMR (CDCl3, 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). m.p.: 134°C (decomposition)

MS (ESI): 394 (M+H)*

The following compounds were prepared analogously to the abovementioned examples 15.

Example 12 3-Ethoxy-2-(4-methoxy-5-methylpyrimidin-2-yloxy)-3,3-diphenylpropionic acid (1-4) 1H-NMR (CDCl, 200 MHz): 8.0 (s, 1H), 7.1-7.5 (m, 10H); 6.2 (s, 1H); 3.9 (s, 3H); 3.5 (m, 2H); 2.0 (s, 3H); 1.1 (t, 3H).

MS (API): 409 (M+H)*

Example 13 3-[2-(3,4-Dimethoxyphenyl)ethoxy]-2-(4-methoxy-5-methylpyrimidin-2-yloxy)-3,3- diphenylpropionic acid 1H-NMR (CDCls, 200 MHz): 8.0 (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 (m, 2H); 2.0 (s, 3H); 1.1 (t, 3H).

MS (ESI): 555 (M+H)*

Example 14 3-[2-(3,4-Dimethoxyphenyl)ethoxy]-2-(9-methyl-9H-purin-2-yloxy)-3,3-diphenylpropionic

Claims

0 AMENDED SHEET ® 0050/50501 - 37 - We claim:

1. A compound of the formula } r® B 8 H N AN 2 R—Z—-C—C—0— R lg I = R® R LA I R in which R'is tetrazolyl or a group Oo ll C—R i0 in which R has the following meaning: a) an OR’ radical in which R’ is: hydrogen, the cation of an alkali metal, the cation of an alkaline earth metal, a physiologically tolerated organic ammonium ion such as tertiary C;-C,- alkylammonium or the ammonium ion; Cs-Cg-cycloalkyl, C4-Cg-alkyl, CH»-phenyl which may be substituted by one or more of the following radicals: halogen, nitro, cyano, C;-Cs-alky!, C4-C4-haloalkyt, hydroxyl, C;-Cs4-alkoxy, mercapto, C4-Cs-alkylthio, amino, NH(C,-C,-alkyl), N(C;- Cs-alkyl)z; a Cs-Ce-alkenyl or a C5-Cg-alkynyl group, it being possible for these groups in turn to carry from one to five halogen atoms; R’ can also be a phenyl radical which can carry from one to five halogen atoms and/or from one to three of the following radicals: nitro, cyano, C;-C,-alkyl, C;-C,- haloalkyl, hydroxyl, C,-Cs-alkoxy, mercapto, C;-C;-alkylthio, amino, NH(C4-Cq-alkyl), N(C4-Cy-alkyl),;

. 0050/50501 - 38 - “

b) a 5-membered heteroaromatic system, such as pyrrolyl, pyrazolyl, imidazolyl and triazolyl, which is linked via a nitrogen atom and which may carry from one to two halogen atoms or from one to two C4-Cy-alkyl or from one to two C;-C,-alkoxy groups;

5 C) a group = —Q— (CB,), —8—R’

in which k has the values 0, 1 and 2, p has the values 1, 2, 3 and 4, and R® is C4-Cs-alkyl, Cs-Cg-cycloalkyl, Cs-Ce-alkenyl, Cs-Cg-alkynyl or phenyl which may be substituted by one or more, e.g. from one to three, of the following radicals: halogen, nitro, cyano, C,-Cs-alkyl, C4-C4-haloalkyl, hydroxyl, C;-Cg-alkoxy, C1-Cs-

alkylthio, mercapto, amino, NH(C;-C;-alkyl), N(C4-Cg-alkyl)z;

d) a radical

Lo]

re a s—g’ I 0 in which R? is:

C4-Cs-alkyl, C3-Ces-alkenyl, Cs-Cs-alkynyl, C;-Cg-cycloalkyl, it being possible for these radicals to carry a C,-Cs-alkoxy, C4-C4-alkylthio and/or a phenyl radical as mentioned under c); phenyl which may be substituted by from one to three of the following radicals: halogen, nitro, cyano, C;-Cy-alkyl, C;-C4-haloalkyl, hydroxyl, C;-C4-alkoxy, C4-C,- alkylthio, mercapto, amino, NH(C;-Cy-alkyl), N(C-Cs-alkyl),;

R? is hydroxyl, NHz, NH(C+-Cy-alkvl), N(C1-Cs-alkyl)s, C4-Cs-alkyl, Co-Cs-alkenyl, C,-

N 9050/50501 -39- Cs-alkynyl, C4-C4-hydroxyalkyl, C4-Cy-haloalkyl, C;-Cs-alkoxy, C;-C,-haloalkoxy, C1-C-alkylthio or CR? forms together with CR® a 5- or 6- membered alkylene or alkenylene ring which may be substituted by one or two C;-C,-alkyl groups, in which in each case one or more methylene groups may be replaced by oxygen, sulfur, -NH or —=N(C4-Cy-alkyl);

R® is hydroxyl, NH, NH(C;-Cgs-alkyl), N(C;-C,s-alkyl)z, halogen, C;-Cs-alkyl, Co-Cq- alkenyl, C,-Cy-alkynyl, Cs-Cs-alkenyloxy, C,-C,-alkylcarbonyl, Cy-Cs- alkoxycarbonyl, C,-C,-hydroxyalkyl, C;-Cs-haloalkyl, C;-Cs-alkoxy, C;-Cs-

haloalkoxy, -NH-O-C,-C4-alkyl, C4-C4-alkylthio or CR® forms, as indicated under R?, together with CR? a 5- or 6-membered ring;

R* and R® (which may be identical 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-Cs-alkyl, C4-C4-haloalky!, C4-Cs-alkoxy, C4-Cy4-haloalkoxy, phenoxy, C;-Cs-alkylthio, amino, NH(C4-C,-alkyl), N(C1-C4-alkyl),; or phenyl or naphthyl which are connected together in ortho positions by a direct linkage, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an SO,, NH or N-alkyl group; or C3-C-cycloalkyl;

R® is hydrogen,

C4-Cg-alkyl, C3-Cg-alkenyl, C3-Cg-alkynyl or Cs-Cg-cycloalkyl, it being possible for each of these radicals to be substituted one or more times by: hydroxyl,

mercapto, carboxyl, halogen, nitro, cyano, C1-Cs-alkoxy, Cs-Cs-alkenyloxy, Cs-Cs- alkynyloxy, Cs-Cs-alkylthio, C4-Cs-haloalkoxy, C;-Cs-alkylcarbonyl, C;-C,- alkoxycarbonyl, (C4-Cs-alkyl)NHcarbonyl, (Cy-Cs-alkyl).Ncarbonyl, C3-Cs- alkylcarbonylalkyl, amino, NH(C1-Cs-alkyl), N(C,-Cs-alkyl),, phenoxy or phenyl, it being possible for said aryl radicals to be substituted one or more times;

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,-

il AMENDED SHEET 0050/50501 - 40 - haloalkyl, C4-Cq-alkoxy, C;-Cs-haloalkoxy, phenoxy, Ci-Cs-alkylthio, NH(C;-C4- alkyl), N(C4-Cs-alkyl), or methylenedioxy or ethylenedioxy; a five- or six-membered heteroaromatic system which contains from one to three nitrogen atoms and/or a sulfur or oxygen atom and which may carry from one to four halogen atoms and/or from one to two of the following radicals: C,-C,-alkyl, C1-Cs-haloalkyl, C-Cy-alkoxy, C-C4-haloalkoxy, Cq-C,-alkylthio, phenyl, phenoxy or phenylcarbonyl, it being possible for the phenyl radicals in turn to carry from one to five halogen atoms and/or from one to three of the following radicals: C;- Cs-alkyl, C4~C,-haloalkyl, C4-Cs-alkoxy, C4-Cs-haloalkoxy and/or C4-C,-alkylthio; Z is sulfur or oxygen, and the physiologically tolerated salts, tautomeric forms and the enantiomerically pure and diastereomerically pure forms.

2. The use of compounds | as claimed in claim 1 for treating diseases.

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

4. The use of compounds | as claimed in claim 1 for producing drugs for treating diseases in which elevated endothelin levels occur.

5, The use of compounds | as claimed in claim 1 for producing drugs for treating diseases in which endothelin contributes to the development and/or progression.

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

7. A combination of compounds | as claimed in claim 1 and one or more active ingredients selected from inhibitors of the renin-angiotensin system such as renin inhibitors, angiotensin II antagonists, angiotensin converting enzyme (ACE) inhibitors, mixed ACE/neutral endopeptidase (NEP) inhibitors, B-blockers, diuretics, calcium channel blockers and VEGF-blocking substances.

0 AMENDED SHEET @ oos0/50501 41.

8. A pharmaceutical preparation for oral or parenteral use, comprising at least one compound | as claimed in claim 1 per single dose, in addition to conventional pharmaceutical excipients.

9. A compound of formula | as claimed in claim 1, substantially as hereinbefore described and exemplified.

10. A compound of formula | including any new and inventive integer or combination of integers, substantially as herein described.

11. The use of compounds of formula | as claimed in any one of claims 2 to 6, substantially as hereinbefore described and exemplified.

12. The use of compounds of formula | including any new and inventive integer or combination of integers, substantially as herein described.

13. A combination of compounds of formula | and one or more active ingredients as claimed in claim 7, substantially as hereinbefore described and exemplified.

14. A combination of compounds of formula | and one or more active ingredients including any new and inventive integer or combination of integers, substantially as herein described.

15. A pharmaceutical preparation as claimed in claim 8, substantially as hereinbefore described and exemplified.

16. A pharmaceutical preparation including any new and inventive integer or combination of integers, substantially as herein described.

17. A compound of formula I, or combination or pharmaceutical preparation comprising thereof as claimed in any one of claims 1, 7 to 10 and 13 to 16 whenever supplied with instructions for the use thereof in the treatment of diseases in which elevated endothelin levels occur, diseases in which endothelin contributes to the development and/or progression, chronic heart failure, restenosis, high blood pressure, pulmonary hypertension, acute/chronic renal failure, cerebral ischemia, asthma, benign prostate hyperplasia, prostate cancer and/or acute pancreatitis.

18. A compound of formula I, or composition or pharmaceutical preparation comprising thereof as claimed in claim 17 when the instructions are in printed or written form.

19. A compound of formula |, or combination or pharmaceutical preparation comprising thereof as claimed in claim 18 supplied in a package or container having the said instructions provided therein or thereon.