EP1286973A2

EP1286973A2 - Novel carbamates and carbamides, production and use thereof as endothelin receptor antagonists

Info

Publication number: EP1286973A2
Application number: EP01943411A
Authority: EP
Inventors: Wilhelm Amberg; Georg Kettschau
Original assignee: BASF SE
Current assignee: Abbott GmbH and Co KG
Priority date: 2000-05-25
Filing date: 2001-05-18
Publication date: 2003-03-05
Also published as: JP2003534329A; DE10025728A1; WO2001090079A2; CA2410304A1; AU2001265995A1; US20040034076A1; MXPA02011512A; WO2001090079A3

Abstract

The invention relates to carbamate and carbamide derivatives of formula (I), wherein the substituents have the meaning cited in the description. The invention also relates to the production and use thereof as endothelin receptor antagonists.

Description

New carbarates and ureas, their production and use as endothelin receptor antagonists

description

The present invention relates to new carbamate and urea derivatives, their production and use as endothelin receptor antagonists.

Endothelin receptor antagonists of the structure type of the 3,3-di-substituted propionic acids are described in numerous patent applications (WO 95/26716, WO 96/11914, WO 97/12878, WO 97/38980, WO 97/38981, WO 97/38982, WO 98/09953, WO 99/23078 and WO 99/42453). Other representatives of the 3, 3-disubstituted

Propionic acid derivatives have a herbicidal action and are therefore of interest as crop protection agents (WO 94/25442, WO 96/00219, DE 4035758, EP 0481512).

WO 98/58916 describes endothelin receptor antagonists of the 3, 3-disubstituted propionic acid type, on which C-3 is additionally functionalized by a nitrogen-containing group (such as azido or amino).

The object was to provide endothelin receptor antagonists which bind to the ET _A and / or the ET _B receptor subtypes. It was surprisingly found that compounds in which the above-mentioned nitrogen at C-3 is part of a carbamate or urea residue have advantageous pharmacological properties.

The invention relates to carbamate and urea derivatives of the formula 1

where R ¹ stands for tetrazole or for a group

O

II C ~ ^R in which R has the following meaning:

a) a radical OR ⁶ , in which R ⁶ denotes:

Hydrogen, the cation of an alkali metal, the cation of a

Alkaline earth metal, a physiologically acceptable organic ammonium ion such as tertiary Ci-C ^ alkylammonium or the ammonium ion;

C ₃ -C ₈ cycloalkyl, -CC ₈ alkyl, CH ₂ -phenyl, which can in each case be substituted by one or more radicals, preferably by halogen, nitro, cyano, C 1 -C ₄ -alkyl, C -C ₄ -Halogen- alkylj hydroxy, -CC alkoxy, mercapto, -CC ₄ -alkylthio, A ino, NH (-CC ₄ alkyl), N (-C ₄ alkyl) ₂ ;

A C ₂ -Cg alkenyl or a C ₃ -Cg alkynyl group, these groups in turn being able to carry one to five halogen atoms;

RG may furthermore be a phenyl radical which may be substituted, preferably a phenyl radical containing from one to five halogen atoms and / or can carry one to three of the following radicals: nitro, cyano, ~ C ₄ -alkyl, C ₄ -haloalkyl , Hydroxy, -C-alkoxy, mercapto, Cχ-C ₄ alkylthio, amino, NH (C -C ₄ alkyl), N (C ₁ -C ₄ alkyl) ₂ ;

b) pyrrolyl, pyrazolyl, imidazolyl and triazolyl, which can carry one to two halogen atoms or one to two Cx- alkyl or one to two -C-alkoxy groups;

c) a group

where k is 0, 1 and 2, p is 1, 2, 3 and 4 and R ^{7 is}

C _x -C ₄ alkyl, C ₃ -C ₈ cycloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ -alkynyl o _r _Ph eny _l which may optionally be substituted, preferably By J _he inen to three of the following:

Halogen, nitro, cyano, Cx- alkyl, -CC ₄ -haloalkyl, hydroxy, -C-C ₄ alkoxy, Cx- alkylthio, mercapto, amino, NH (C ₁ -C ₄ alkyl), N (Cι -C ₄ alkyl) ₂ ; d) a rest

wherein R ⁸ means: 0 -C ₄ alkyl, CC ₆ alkenyl, C ₂ -C ₅ alkynyl, C ₃ -C ₈ cycloalkyl, these radicals being a C ₁ -C ₄ alkoxy, C ₁ -C ₄ - Alkylthio and / or a phenyl radical as mentioned under c) can wear;

Phenyl, optionally substituted, preferably by one to three of the following 5 radicals: halogen, nitro, cyano, C 1 -C 4 -alkyl,

C 1 -C 6 -haloalkyl, hydroxy, C 1 -C ₄ alkoxy, C 1 -C ₄ alkylthio,

Mercapto, amino, NH (Cχ-C4-alkyl), N (Cι-C ₄ alkyl) ₂ ;

The other substituents have the following meaning: 0

R ² and R ³ (which may be the same or different):

Phenyl or naphthyl, which can be substituted by one or more of the following radicals: halogen, nitro, 5 cyano, hydroxy, mercapto, Cχ-C ₄ -alkyl, C ₂ -C ₄ -alkenyl,

C ₂ -C ₄ -alkynyl, Cχ-C ₄ -haloalkyl, Cχ-C ₄ -alkoxy, phenoxy, Cχ-C ₄ -haloalkoxy, Cχ-C ₄ -alkylthio, amino, NH (Cχ-C ₄ -alkyl), N (Cχ-C ₄ alkyl) ₂ or phenyl, which can be mono- or polysubstituted by halogen, nitro, cyano, Cχ-C ₄ alkyl, Cχ-C ₄ haloalkyl, Cχ-C ₄ alkoxy, Cχ_C ₄ _haloalkoxy or Cx-C ₄ -alkylth.i0; or

Phenyl or naphthyl, which are ortho-linked via a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an S0 ₂ -, NH or N-alkyl group;

C ₅ -C ₆ cycloalkyl;

R ^{4 is} hydrogen, Cχ-C ₄ alkyl;

R ⁵ Ci-Cs-alkyl, optionally substituted, preferably simply substituted by halogen, hydroxyl, Cχ-C4-alkoxy or phenyl, which in turn can carry one to three of the following substituents: halogen, cyano, CC ₄ -alkoxy, C -C _4- alkyl, Cχ-C ₄ -alkylthio, NH (C ₁ -C ₄ -alkyl), N (C-C4-alkyl) ₂ , amino, carboxy; C ₃ -C ₈ cycloalkyl, optionally substituted, preferably monosubstituted by radicals: cyano, carboxy, _{Cχ-C4-alkyl,} Cχ-C ₄ haloalkyl, hydroxy, .Cχ-C ₄ alkoxy, amino, NH (C - C ₄ alkyl), N (Cχ-C ₄ alkyl) ₂ ;

Phenyl or naphthyl, which can carry one to three of the following substituents: halogen, cyano, Cχ-C ₄ alkoxy,

Cχ-C ₄ alkyl, Cχ-C ₄ alkylthio, NH (Cχ-C ₄ alkyl), N (Cχ-C ₄ alkyl) ₂ , amino, carboxy;

or R ⁵ forms with NR ⁹ as indicated under R ⁹ a three- to seven-membered ring;

A oxygen or NR ⁹ with

R ^{9 is} hydrogen, Cχ-C ₄ ~ alkyl; or NR ⁹ forms with R ⁵ and a corresponding number of methylene groups a three- to seven-membered saturated ring which can be simply substituted by Cχ-C ₄ alkyl and in which up to two of the methylene groups by oxygen, sulfur, NH or N ( Cχ-C ₄ ~ alkyl) can be replaced;

W and Z (which can be the same or different):

Nitrogen or methine; with the proviso that if W and Z = methine, then Q = nitrogen;

X nitrogen or CR ¹⁰ ;

Y is nitrogen or CR ¹¹ ;

Q nitrogen or CR ¹² ; with the proviso that if Q = nitrogen, then X = CR ¹⁰ and Y = CR ¹¹ ;

furthermore the requirement applies that a maximum of three of the ring members denoted by W, X, Q, Y and Z represent nitrogen;

R ¹⁰ and R ¹¹ (which may be the same or different):

Hydrogen, halogen, Cχ-C ₄ -haloalkoxy, C ₃ -C ₅ -alkenyloxy, C3-C ₆ -alkynyloxy, Cχ-C ₄ -alkylthio,

Cχ-C ₄ alkylcarbonyl, Cι-C ₄ alkoxycarbonyl, hydroxy, NH ₂ , NH (Cι-C-alkyl), N ⁽ C ₁ -C ₄ alkyl) ₂ , carboxy; C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, where these radicals can be substituted one or more times by halogen, hydroxy, mercapto, carboxy, cyano, phenyl, C Phen-C ₄ -alkoxy;

Phenyl or, phenoxy, which can be mono- or disubstituted, preferably by halogen, nitro, cyano, Cχ-C ₄ alkyl, Cχ-C ₄ haloalkyl, Cχ-C ₄ alkoxy, Cχ-C ₄ haloalkoxy alkoxycarbonyl , Alkylcarbonyl, amino;

, C χ -C ₄ alkoxy, which radical may be mono- or polysubstituted, preferably by halogen, hydroxy, carboxy, _C _yano; or CR ¹⁰ or CR ¹¹ is linked to CR ¹² as stated under R ¹² to form a 5- or 6-membered ring;

R ^{12 is} hydrogen, halogen, Cχ-C ₄ -alkoxy, Cχ-C ₄ -haloalkoxy,

Cχ-C ₄ -alkylthio, Cχ-C ₄ -alkylcarbonyl, Cχ-C ₄ -alkoxycarbonyl, NH (Cχ-C ₄ -alkyl), N (Cχ-C -alkyl) ₂ , hydroxy, carboxy, cyano, amino, mercapto ;

Cχ-C ₄ alkyl, CC ₄ alkenyl, CC ₄ alkynyl, where these radicals can be mono- or polysubstituted by: halogen, hydroxy, mercapto, carboxy, cyano, amino, Cχ-C ₄ alkoxy;

or CR ¹² together with CR ¹⁰ or CR ¹¹ forms a 5- or 6-membered alkylene or alkenylene ring, which can be substituted by one or two Cχ_4-alkyl groups, and in each case one or more methylene groups by oxygen, sulfur, -NH or -N (Cχ C ₄ alkyl), can be replaced _^

The following definitions apply here and below:

An alkali metal is e.g. Lithium, sodium, potassium;

An alkaline earth metal is e.g. Calciu, magnesium, barium;

Organic ammonium ions are protonated amines such as e.g. Ethanol amine, diethanolamine, ethylenediamine, diethylamine, triethylamine or piperazine;

C ₃ -C ₈ cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl;

CC ₄ -haloalkyl can be linear or branched, such as fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trichloromethyl, 1-fluoroethyl, 2-fluoroethyl, 2, 2-difluoroethyl, 2, 2,2-trifluoroethyl, 2-chloro-2 , 2-difluoroethyl. 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl or pentafluoroethyl;

Cχ-C ₄ haloalkoxy can be linear or branched such as difluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, 1-fluoro-ethoxy, 2, 2-difluoroethoxy, 1, 1, 2, 2-tetrafluoroethoxy, 2,2,2-tri-fluoroethoxy , 2-chloro-l, 1,2-trifluoroethoxy, 2-fluoroethoxy or pentafluoroethoxy;

Cχ-C ₈ ~ alkyl can be linear or branched such as methyl, ethyl, 1-propyl, 2-propyl, 2-methyl-2-propyl, 2-methyl-l-propyl, 1-butyl, 2-butyl, n -Hexyl, 3-methyl-1-pentyl, 4-methyl-2-pentyl, 3-methyl-2-hexyl, n-octyl;

CC ₆ -alkenyl can be linear or branched, such as, for example, ethenyl, 1-propen-3-yl, 1-propen-2-yl, 1-propen-1-yl, 2-methyl-1-propenyl, 1-butenyl, 2 -Butenyl, l-penten-3-yl, l-hexen-5-yl;

CC ₆ ~ alkynyl can be linear or branched, such as ethynyl, 1-propyn-l-yl, l-propyn-3-yl, l-butyn-4-yl, 2-butyn-4-yl or l-hexyn-3 yl;

Cχ-C ₄ alkoxy can be linear or branched, such as methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or 1, 1-dimethylethyloxy;

C ₃ -C ₆ alkenyloxy can be linear or branched, for example allyloxy, 2-buten-1-yloxy or 3-butene-2-yloxy;

C ₃ -C ₆ alkynyloxy can be linear or branched, such as 2-propin-1-yloxy, 2-butyn-1-yloxy or 3-butyn-2-yloxy;

Cχ-C ₄ alkylthio can be linear or branched such as methyl thio, ethyl thio, propyl thio, 1-methyl ethyl thio, butyl thio, 1-methyl propyl thio, 2-methyl propyl thio or 1, 1-dimethyl ethyl thio;

Cχ-C ₄ alkylcarbonyl can be linear or branched such as acetyl, ethylcarbonyl or 2-propylcarbonyl;

Cχ-C ₄ alkoxycarbonyl can be linear or branched, such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl or n-butoxycarbonyl;

Halogen is, for example, fluorine, chlorine, bromine, iodine. The invention further relates to those compounds from which the compounds of the formula I with R ¹ = COOH can be released (so-called prodrugs).

Preference is given to those prodrugs in which the release takes place under conditions which prevail in certain body compartments, for example in the stomach, intestine, bloodstream, liver. A preferred embodiment for "prodrugs" are those compounds in which the radical R ¹ in formula (I) is in masked form and the activation to "drug" generates a COOH function for R ¹ . The masking of certain chemical groups of a compound as a prodrug is a process familiar to the person skilled in the art (see, for example, "A Textbook of Drug Design and Development", Krogsgard-Larsen and Bundgard, Harvwood Academic Publishers).

The invention further relates to the physiologically tolerable salts of compounds of the general formula I.

The compounds and also the intermediates for their preparation, e.g. II and III, can have one or more asymmetric substituted carbon atoms. Such compounds can exist as pure enantiomers or pure diastereomers or as a mixture thereof. The use of an enantiomerically pure compound as the active ingredient is preferred.

The invention furthermore relates to the use of the carbamate and urea derivatives mentioned above for the production of medicaments, in particular for the production of inhibitors for endothelin receptors.

As described in WO 98/58916, the compounds having the general formula III can be prepared by reducing the azido compounds of the general formula II. As an alternative to the reducing agents described there, trialkylphosphanes, for example tri (n-butyl) phosphane, can also be used with great success.

II III The compounds of the general formula I according to the invention in which A is oxygen (I) can be prepared, for example, by reacting the carboxylic acid derivatives of the general formula III with chloroformic acid esters of the general formula IV. For this purpose, the compounds mentioned are reacted in a molar ratio of about 1: 1 to 1: 5 in the presence of a base and a suitable diluent. All solvents which are inert to the reagents used can be used for this purpose.

III

Examples of the solvents or diluents mentioned above are aliphatic, alicyclic and aromatic hydrocarbons, each of which may optionally be chlorinated, such as, for example, hexane, cyclohexane, petroleum ether, ligroin, benzene, toluene, xylene, methylene chloride, chloroform, carbon tetrachloride, ethyl chloride and Trichlorethylene, ethers such as diisopropyl ether, dibutyl ether, methyl tert. butyl ether,

Dioxane and tetrahydrofuran, nitriles such as acetonitrile and propionitrile, acid amides such as dimethylformamide, dimethylacetamide and N-methylpyrrolidone, sulfoxides and sulfones such as dimethyl sulfoxide and sulfolane.

As the base, for example, tertiary aliphatic amines, such as triethylamine, diisopropylethylamine, N-methylmorpholine or N-methylpyrrolidine, as well as under the reaction conditions. erte aromatic nitrogen compounds such as pyridine can be used. The reaction is preferably carried out in a temperature range between 0 ° C. and the boiling point of the solvent or solvent mixture.

The compounds of the invention, in which general

Formula I in which A is NR ⁹ (Ib) can be prepared, for example, by first converting the carboxylic acid derivatives of the general formula III into an isocyanate V using phosgene or an equivalent thereof in the presence of one of the diluents mentioned above, and subsequently converted into the compounds of the general formula Ib according to the invention by reaction with R ⁵ R ⁹ NH. The second step is preferably carried out in the presence of one of the bases and diluents mentioned above.

R ^

N-H

9 '

Both reaction steps are preferably carried out in a temperature range between 0 ° C. and the boiling point of the solvent or solvent mixture. If R ^{1 is} an ester, the compounds with R ¹ = COOH can be prepared by acidic, basic or catalytic cleavage of the ester group.

Compounds of type I with R ¹ = COOH can furthermore be obtained directly by deprotonating an intermediate VI in which R ^{1 is} COOH with three equivalents of a suitable base and reacting it with compounds of the general formula VII. Here too, the reaction takes place in an inert solvent and in a temperature range from room temperature to the boiling point of the solvent.

As the base in this reaction step, an alkali or alkaline earth metal hydride such as sodium hydride, potassium hydride or calcium hydride, a carbonate such as alkali metal carbonate, e.g. Sodium or potassium carbonate, an alkali or alkaline earth metal hydroxide such as sodium or potassium hydroxide, an organometallic compound such as butyllithium or an alkali amide such as lithium diisopropylamide.

VI VII

y

In formula VII, R ^{13 is} halogen or R ¹⁴ -S0 ₂ - / where R ^{14 can be} Cχ-C ₄ alkyl, Cχ-C ₄ haloalkyl or phenyl, and for W, X, Q, Y and Z those mentioned above Conditions apply. The reaction preferably takes place in an inert solvent or diluent with the addition of a suitable base, ie a base which brings about a deprotonation of the intermediate VI, in a temperature range from room temperature to the boiling point of the solvent.

Compounds of the formula VII are known, some are commercially available or can be prepared in a generally known manner. Compounds of the formula I can also be prepared by starting from the corresponding carboxylic acids, ie compounds of the formula I in which R ^{1 is} COOH, and converting them first in the usual manner into an activated form such as an acid halide, an anhydride or Imidazolide transferred and then reacted with a corresponding hydroxyl compound HÖR ⁶ . This reaction can be carried out in the customary solvents and often requires the addition of a base such as triethylamine, pyridine, imidazole or diazabicycloundecane to be considered. These two steps can also be simplified, for example, by allowing the carboxylic acid to act on the hydroxyl compound in the presence of a water-releasing agent such as a carbodiimide.

In addition, compounds of the formula I can also be prepared by starting from the salts of the corresponding carboxylic acids, ie from compounds of the formula I in which R ^{1 represents} a group COOM, where M is an alkali metal cation or the equivalent of an alkaline earth metal cation can. These salts can be combined with many of the compounds

Bring formula R ⁶ -D to reaction, where D represents a conventional nucleofugic leaving group, for example halogen such as chlorine, bromine, iodine or optionally aryl- or alkylsulfonyl substituted by halogen, alkyl or haloalkyl, such as toluenesulfonyl and methylsulfonyl or another equivalent leaving group. Compounds of the formula R ⁶ -D with a reactive substituent D are known or are easy to obtain with the general specialist knowledge. This reaction can be carried out in the customary solvents and is advantageously carried out with the addition of a base, the above-mentioned being suitable.

Compounds of the formula I in which R ^{1 is} tetrazole can, as in WO 96/11914. described, manufactured; Further manufacturing procedures can be found in the chemical literature and can be found, for example, in Synthesis 767 (1993) and in J. Org. Chem. 56, 2395, (1991).

With regard to the biological action, carbamate and urea derivatives of the general formula I - both as pure enantiomers or pure diastereomers or as a mixture thereof - are preferred, in which the substituents have the following meaning:

where R ¹ stands for tetrazole or for a group

0

II

C-R

in which R has the following meaning:

a) a radical OR ⁶ , in which R ⁶ denotes:

Hydrogen, the cation of an alkali metal, the cation of an alkaline earth metal, a physiologically compatible organic ammonium ion such as tertiary Cχ-C ₄ alkylammonium or the ammonium ion;

C ₃ -C ₈ cycloalkyl, Cχ-C ₈ alkyl, CH ₂ phenyl, each of which can be substituted by one or more of the following radicals: halogen, Cχ-C ₄ alkyl, Cχ-C ₄ haloalkyl, hydroxy , Cχ-C ₄ alkoxy;

A CC ₆ alkenyl or a C ₃ -Cg alkynyl group, these groups in turn being able to carry one to five halogen atoms;

R ⁶ can also be a phenyl radical which is one to five

Halogen atoms and / or can carry one to three of the following radicals: Cχ-C ₄ alkyl, Cχ-C ₄ haloalkyl, hydroxy, Cχ-C ₄ alkoxy;

b) pyrrolyl, pyrazolyl, imidazolyl and triazolyl, which can carry one or two halogen atoms or one or two Cχ-C ₄ alkyl or one or two Cχ-C ₄ alkoxy groups;

c) a group

where k is 0, 1 and 2, p is 1, 2, 3 and 4 and R ^{7 is}

CC ₄ alkyl, C ₃ -C ₈ cycloalkyl or phenyl, which can be substituted by one to three of the following radicals: halogen, Cχ-C ₄ alkyl, Cχ-C ₄ haloalkyl, hydroxy, CC ₄ alkoxy ; d) a rest

where R ⁸ means:

Cχ-C ₄ alkyl, C ₃ -C ₈ cycloalkyl, where these radicals can carry a Cχ-C ₄ alkoxy, Cχ-C ₄ alkylthio and / or a phenyl radical as mentioned under c);

Phenyl, which can be substituted by one to three of the following radicals: halogen, -CC ₄ -alkyl, Cχ-C ₄ -haloalkyl, hydroxy, Cχ-C ₄ alkoxy;

^'The other substituents have the following meanings:

R ² and R ³ (which may be the same or different):

Phenyl which can be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxy, Cχ-C ₄ ~ alkyl, Cχ-C ₄ -haloalkyl, Cχ-C ₄ -alkoxy, phenoxy,

Cχ-C ₄ -haloalkoxy, amino, NH (Cχ-C ₄ -alkyl), N (Cχ-C4-alkyl) ₂ or phenyl, which can be substituted one or more times by halogen, Cχ-C ₄ -alkyl, Cχ -C ₄ haloalkyl, Cχ-C ₄ alkoxy, Cχ-C ₄ haloalkoxy;

R ^{4 is} hydrogen, Cχ-C ₄ alkyl;

R ⁵ Cχ-C ₈ ~ alkyl, which can be simply substituted by halogen, hydroxy, Cχ-C ₄ ~ alkoxy or phenyl, which in turn can carry one to three of the following substituents: halogen, cyano, Cχ-C ₄ alkoxy, Cχ-C ₄ alkyl or carboxy;

C ₃ -C ₈ cycloalkyl, which can be simply substituted by: carboxy, CC ₄ alkyl, hydroxy, Cχ-C ₄ alkoxy;

Phenyl or naphthyl, which can carry one to three of the following substituents: halogen, Cχ-C ₄ alkoxy, Cχ-C ₄ alkyl or carboxy;

or R ⁵ forms with NR ⁹ as indicated under R ⁹ a three- to seven-membered ring; A oxygen or NR ⁹ with

R ^{9 is} hydrogen, Ci-C ^ alkyl, or NR ⁹ forms with R ⁵ and a corresponding number of methylene groups a three- to seven-membered saturated ring, which can be simply substituted with Cχ-C ₄ alkyl and in which up to two the Me hylengruppen can be replaced by oxygen;

W and Z (which can be the same or different):

X nitrogen or CR ¹⁰ ;

Y is nitrogen or CR ¹¹ ;

the stipulation also applies that a maximum of three of the W, X, Q,

Y and Z denote ring members denoted nitrogen;

R ¹⁰ and R ^{1: 1} (which may be the same or different):

Hydrogen, halogen, Cχ-C ₄ -alkoxy, Cχ-C ₄ _alkylcarbonyl, Cχ-C ₄ -alkoxycarbonyl, hydroxy, NH ₂ , NH (Cχ-C ₄ -alkyl), N (Cχ_C-alkyl) ₂ , carboxy;

Cχ-C ₄ alkyl, which can be mono- or polysubstituted by halogen, hydroxy, carboxy, phenyl, Cχ-C ₄ alkoxy;

Phenyl or phenoxy, which can be mono- to disubstituted by halogen, Cχ-C ₄ alkyl, Cχ-C ₄ alkoxy, Cχ-C ₄ haloalkoxy alkoxycarbonyl; or CR ¹⁰ or CR ¹¹ is linked to CR ¹² as stated under R ¹² to form a 5- or 6-membered ring;

_R ^{12 is} hydrogen, halogen, Cχ ~ C ₄ alkoxy, NH (Cχ_C ₄ alkyl), N (Cχ— C ₄ alkyl) ₂ , hydroxy, carboxy, amino;

Cχ-C4-alkyl, which can be substituted one or more times by: hydroxy, carboxy, amino, Cχ- ~ C ₄ - alkoxy; or CR ¹² together with CR ¹⁰ or CR ¹¹ forms a 5- or 6-membered alkylene or alkenylene ring, which can be substituted by one or two C 1 -C ₄ -alkyl groups, and in which in each case one or more methylene groups are substituted by oxygen, NH or -N (Cχ ~ C ₄ alkyl), may be replaced;

Compounds of the formula I are particularly preferred - both as pure enantiomers or pure diastereomers or as a mixture thereof - in which the substituents have the following meaning:

where R ¹ stands for tetrazole or for a group

0

C-R

in which R has the following meaning:

a) a radical OR ⁵ , in which R ⁶ denotes:

C ₃ -C ₈ cycloalkyl, Cj-Cβ-alkyl, CH ₂ -phenyl, each of which can be substituted by one or more of the following radicals: halogen, C ₁ -C ₄ alkyl, Cχ-C ₄ haloalkyl, hydroxy , Cχ-C ₄ alkoxy;

R ⁶ can furthermore be a phenyl radical which can carry one to five halogen atoms and / or one to three of the following radicals: CC ₄ alkyl, CC ₄ alkoxy; 01/90079

16 b) a remainder

where R ⁸ means:

Cχ-C ₄ alkyl, C ₅ -C ₆ cycloalkyl;

Phenyl, which can be substituted by one to three of the following radicals: halogen, Cχ-C ₄ alkyl, Cχ-C ₄ alkoxy;

The other substituents have the following meaning:

R ² and R ³ (which may be the same or different):

Phenyl, which can be substituted by one or more of the following radicals: halogen, Cχ-C ₄ alkyl, CC ₄ alkoxy;

R ^{4 is} hydrogen;

R ⁵ Cχ-C ₄ alkyl, which can be simply substituted by hydroxy, Cχ-C ₄ alkoxy or phenyl, which in turn can carry one to three of the following substituents: halogen, Cχ-C ₄ alkoxy or Cχ-C ₄ alkyl;

C ₅ -C ₆ cycloalkyl which can carry a C ₁ -C ₄ alkyl group;

Phenyl which can carry one to three of the following substituents: halogen, Cχ-C ₄ -alkoxy or Cχ-C ₄ ~ alkyl;

or R ⁵ forms with NR ⁹ one of the cyclic groups indicated under R ⁹ ;

A oxygen or NR ⁹ with

R ^{9 is} hydrogen, Cχ-C ₄ alkyl;

or NR ⁹ forms with R ⁵ a pyrrolidinyl, piperidinyl,

Morpholinyl or N-methyl-piperazinyl;

W sticks toff;

X CR ¹⁰ ; Y CR ¹¹ ;

Z nitrogen or methine;

Q nitrogen or CR ¹² -

R ¹⁰ and R ¹¹ (which may be the same or different):

Hydrogen, halogen, Cχ-.C ₄ alkoxy;

Cχ-C ₄ alkyl, which can be simply substituted by hydroxy or carboxy;

trifluoromethyl;

Phenvl or phenoxy. which can be mono- to disubstituted by halogen, Cχ-C ₄ ~ alkyl, Cχ-C ₄ -alkoxy, Cχ-C ₄ ~ haloalkoxy _^ . Alkoxycarbonyl _;

or CR ¹⁰ or CR ¹¹ is linked to CR ¹² as stated under R ¹² to form a 5- or 6-membered ring;

R ^{12 is} hydrogen, halogen, Cχ-C ₄ alkoxy;

Cχ-C ₄ alkyl, which can be simply substituted by hydroxy;

or CR ¹² together with CR ¹⁰ or CR ¹¹ forms a 5- or 6-membered alkylene or alkenylene ring which can be substituted by one or two Cχ_-alkyl groups and in which a methylene group can be replaced by oxygen.

The compounds of the present invention offer new therapeutic potential for the treatment of hypertension, pulmonary hypertension, myocardial infarction, angina pectoris, arrhythmia, acute / chronic kidney syndrome, chronic • heart failure, renal failure, cerebral vasospasm, cerebral ischemia, subarachnoid hemorrhage, migraine, asthma, asthma , endotoxic shock, endotoxin-induced organ failure, intravascular coagulation, restenosis after angioplasty and by-pass surgery, benign prostate hyperplasia, erectile dysfunction, glaucoma, ischemic and intoxication-induced kidney failure or hypertension, metastasis and growth of mesenchymal tumors, liver Contrast-induced kidney failure, pancreatitis, gastrointestinal ulcers. The invention further relates to combinations of endothelin receptor antagonists of the formula I and inhibitors of the renin-angiotensin system. Inhibitors of the renin-angiotensin system are renin inhibitors, angiotensin II antagonists and angiotensin converting enzyme (ACE) inhibitors. Combinations of endothelin receptor antagonists of the formula I and ACE inhibitors are preferred.

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

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

The invention further relates to combinations of endothelin receptor antagonists of the formula I and calcium antagonists.

The invention further relates to combinations of endothelin receptor antagonists of the formula I and substances which block the action of VEGF (vascular endothelial growth factor). Such substances are, for example, antibodies directed against VEGF or specific binding proteins or also low molecular weight substances which can specifically inhibit VEGF release or receptor binding.

The combinations mentioned above can be administered simultaneously or sequentially in time. They can be used both in a single pharmaceutical formulation or in separate formulations. The form of administration can also be different, for example the endothelin receptor antagonists can be administered orally and VEGF inhibitors parenterally.

These combination products are particularly suitable for the treatment and prevention of hypertension and its complications, as well as for the treatment of heart failure.

The good effects of the compounds can be demonstrated in the following experiments:

Receptor binding studies

Cloned human ET _A or ET _B receptor-expressing CHO cells were used for binding studies. membrane preparation

The ET _A or ET _B receptor expressing CHO cells were in DMEM NUT MIX F ₁₂ 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 μg / l streptomycin (Gibco, Sigma No. P-0781) increased. After 48 hours, the cells were washed with PBS and incubated with 0.05% trypsin-containing PBS for 5 minutes at 37 ° C. The mixture was then neutralized with medium and the cells were collected by centrifugation at 300 x g.

For the membrane preparation, the cells were adjusted to a concentration of 10 ⁸ cells / ml buffer (50 mM Tris-HCl buffer, pH 7.4) and then disintegrated by ultrasound (Branson Sonifier 250, 40-70 seconds / constant / output 20).

binding assays

For the ET _A and ET _B receptor binding test, the membranes were incubated in incubation buffer (50 mM Tris-HCl, pH 7.4 with 5 mM MnCl, 40 mg / ml bacitracin and 0.2% BSA) in a concentration of 50 μg protein suspended per test batch and incubated at 25 ° C with 25 pM [125J] -ETχ (ET _A receptor test) or 25 pM [125J] -ET ₃ (ET _B receptor test) in the presence and absence of test substance. The non-specific binding was determined with 10 ^{~ 7} M ETx. After 30 min the free and bound radioligand were separated by filtration through GF / B glass fiber filters (Whatman, England) on a Skatron cell collector (Skatron, Lier, Norway) and the filters with ice-cold Tris-HCl buffer, pH 7.4 washed with 0.2% BSA. Radioactivity collected on the filters was quantified using a Packard 2200 CA liquid scintillation counter.

Functional vascular test for endothelin receptor antagonists

After a preload of 2 g and a relaxation time of 1 h in Krebs-Henseleit solution at 37 ° C and a pH value between 7.3 and 7.4, a K ⁺ contracture is first triggered on aortic segments of the rabbit. After washing out, an endothelin dose-response curve is drawn up to the maximum.

Potential othndothelin antagonists are applied to other preparations in the same vessel 15 minutes before the endothelin dose-response curve begins. The effects of endothelin are calculated in% of the K ⁺ contracture. With effective endothelin antagonists the endothelin dose-response curve is shifted to the right.

Testing the ET antagonists in vivo:

Male SD rats weighing 250-300 g were anesthetized with amino barbital, artificially ventilated, vagotized and despinalized. The carotid artery and jugular vein were cathetized.

In control animals, intravenous administration of 1 μg / kg ET-1 leads to a significant increase in blood pressure that persists over a longer period of time.

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

p.o. - Testing the ET antagonists:

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

After a stabilization phase, big endothelin (20 μg / kg, Appl. Vol. 0.5 ml / kg) or ET-1 (0.3 μg / kg, Appl. Vol. 0.5 ml / kg) is given intravenously. Blood pressure and heart rate are continuously recorded over 30 minutes. The significant 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 of the substance-treated animals is compared with the AUC of the control animals.

The compounds according to the invention can be administered in the usual way orally or parenterally (subcutaneously, intravenously, intramuscularly, intra-perotoneal). It can also be applied with vapors or sprays through the nasopharynx.

The dosage depends on the age, condition and weight of the patient and on the type of application. As a rule, the daily dose of active substance is between approximately 0.5 and 50 mg / kg body weight when administered orally and between approximately 0.1 and 10 mg / kg body weight when administered parenterally. The new compounds can be used in the customary pharmaceutical application forms in solid or liquid form, for example as tablets, film tablets, capsules, powders, granules, dragées, suppositories, solutions, ointments, creams or sprays. These are manufactured in the usual way. The active ingredients can be processed with the usual pharmaceutical auxiliaries such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, retardants, antioxidants and / or propellants (see H. Sucker et al. : Pharmaceutical Technology, Thieme-Verlag, Stuttgart, 1991). The administration forms obtained in this way normally contain the active ingredient in an amount of 0.1 to 90% by weight.

Synthesis Examples:

Example 1:

3-Azido-2- [(4, 6-dimethoxy-2-pyrimidinyl) oxy] -3, 3-diphenylpropionic acid methyl ester

A solution of 3-azido-2-hydroxy-3, 3-diphenylpropionic acid methyl ester (4.47 g; 15.0 mmol) and 4,6-dirnethoxy-2-methylsulfonylpyrimidine (3.61 g; 16. 5 mmol) in anhydrous dimethylformamide (20 mL) was mixed with potassium carbonate (1.04 g; 7.52 mmol) and stirred at 80 ° C for 3 hours. After cooling, the mixture was left to stir at room temperature for a further two days. The mixture was poured onto ice water (100 ml) and extracted with ethyl acetate (3x). The combined organic extracts were dried over magnesium sulfate and evaporated in vacuo. The remaining oil (8.30 g) was used without further purification.

ⁱ H-MR (270 MHz, CDC1 ₃ ): 7.2-7.5 (m, 10 H); 6.0 (s, 1H); 5.7 (s, 1H); 3.8 (s, 6H); 3.4 (s, 3H).

HPLC-MSD: M + H + = 436.

Example 2:

3-Amino-2- [(4, 6-dimethoxy-2-pyrimidinyl) oxy] -3, 3-diphenylpropionic acid methyl ester

3-Azido-2- [(4, 6-dimethoxy-2-pyrimidinyl) oxy] -3, 3-diphenylpropionic acid methyl ester (8.30 g; crude) was in a mixture of methanol (50 mL) and dichloromethane (30 mL) dissolved, mixed with a 10% palladium / activated carbon hydrogenation catalyst (approx. 1 g) and stirred for 20 hours under a hydrogen atmosphere at room temperature. The catalyst was then filtered off and concentrated. Stirring from dichloromethane / hexane gave the desired one Compound as a colorless solid (3.50 g; 8.55 mmol, 57% over 2 steps).

iH-NMR (270 MHz, CDC1 ₃ ): 7.2-7.6 (m, 10 H); 5.9 (s, 1H); 5.7 (s, 1H); 3.9 (s, 6H); 3.2 (s, 3H); 2.0-2.6 (s br, 2H).

Example 3:

3- [(Benzyloxycarbonyl) amino] -2- [(, 6 ~ dimethoxy-2-pyrimidinyl) - oxy] -3, 3-diphenylpropionic acid methyl ester

A solution of methyl 3-amino-2- [(4,6-dimethoxy-2-pyrimidinyl) oxy] -3,3-diphenylpropionate (300 mg; 730 μmol) in anhydrous dichloromethane (10 mL) was treated with benzyl chloroformate (115 μL; 810 μmol) and pyridine (150 μL; 1.83 mmol) were added and the mixture was stirred at room temperature. After two hours, benzyl chloroformate (115 μL, 810 μmol) and pyridine (150 μL, 1.83 mmol) were added again and the mixture was stirred for a further two hours. To complete the reaction, benzyl chloroformate (115 μL) and pyridine (150 μL) were added again, the mixture was stirred for 30 minutes and terminated by shaking the reaction mixture with saturated sodium hydrogen carbonate solution. The organic phase was washed with aqueous citric acid, dried over magnesium sulfate and concentrated. The remaining residue was purified by column chromatography; 280 mg (500 μmol with 96% purity, 68% yield) of the title compound were obtained.

HPLC-MSD: M + H ⁺ = 544.

Example 4: (1-140)

N- [(Benzyloxy) carbonyl] -2- [(4, 6-dimethoxy-2-pyrimidinyl) oxy] -3, 3-diphenyl-β-alanine

A solution of methyl 3- [(benzyloxycarbonyl) amino] -2- [(4, 6-dimethoxy-2-pyrimidinyl) oxy] -3, 3-diphenylpropionate (280 mg, 550 μmol at 96% purity) in a mixture of water (5 mL) and tetrahydrofuran (10 mL) were added with lithium hydroxide (25 mg, 1.04 mmol) and stirred for 24 hours at room temperature. The mixture was diluted with water and extracted with ether; the aqueous phase was acidified with citric acid and extracted again with ether. Since the target compound was contained in both organic extracts, these were combined, dried with magnesium sulfate and evaporated in vacuo. Stirring from dichloromethane / n-hexane gave the desired product in 95% purity as a colorless solid (100 mg, 180 μmol, 36% yield). ⁱ H-MR (360 MHz, CDC1 ₃ ): 7.5 (m, 2 H); 7.1-7.4 (, 13H); 6.4 (s, 2H); 5.7 (s, 1H); 5.0 (s, 2H); 3.8 (s, 6H).

ESI-MS: M ⁺ = 529.

Example 5:

3-Azido-2-hydroxy-3, 3-diphenylpropionic acid benzyl ester

A solution of methyl 3-azido-2-hydroxy-3,3-diphenylpropionate (2.00 g, 6.73 mmol) in water (10 mL) and tetrahydrofuran (20 mL) was washed with 1 molar sodium hydroxide solution (10, 0 mL) and stirred for three hours at room temperature. After dilution with water and acidification with dilute hydrochloric acid, the mixture was extracted with ether. The organic extracts were dried over magnesium sulfate and evaporated in vacuo. The crude oil which remained (2.42 g) was taken up in dimethylformamide (30 mL) without further purification, and potassium carbonate (2.79 g; 20.2 mmol) was added. After stirring at room temperature for 15, benzyl bromide (1.21 g; 0.84 mL; 7.07 mmol) was added dropwise and the mixture was stirred at room temperature for 16 hours. Then it was diluted with water, acidified with aqueous citric acid and extracted with ether. The combined ethereal extracts were washed back with water, dried over magnesium sulfate and evaporated in vacuo. The residue was crystallized from ether and gave 1.63 g (4.28 mmol; 64% yield) of the pure title compound.

HPLC-MSD: M + K ⁺ = 412.

Example 6:

3-Azido-2- [(4, 6-dimethoxy-2-pyrimidyl) oxy] -3, 3-diphenylpropionic acid benzyl ester

A mixture of benzyl 3-azido-2-hydroxy-3,3-diphenylpropionate (1.62 g; 4.28 mmol) and potassium carbonate (296 mg;

2.14 mmol) in dimethylformamide (15 mL), 4, 6-dimethoxy-2-methylsulfonylpyrimidine (1.03 g; 4.71 mmol) was added and the mixture was stirred at 80 ° C. for one hour. The mixture was left to stir at room temperature for two more days and the reaction was then stopped by dilution with water. The mixture was extracted with ethyl acetate and the combined organic extracts were washed with water, dried over magnesium sulfate and evaporated in vacuo. The crude residue (2.27 g; 4.26 mmol at 96% purity according to HPLC, 99% yield) was reacted further without further purification.

HPLC-MSD: M + H ⁺ = 512. Example 7:

3-Amino-2- [(4, 6-dimethoxy-2-pyrimidyl) oxy] -3, 3-diphenylpropionic acid benzyl ester

To a solution of benzyl 3-azido-2- [(4,6-dimethoxy-2-pyrimidyl) oxy] -3,3-diphenylpropionate (1.18 g; 2.21 mmol at 96% purity) in a 2: 1 - Mixture of ether and dichloromethane (30 mL) was given tri (n-butyl) phosphine (492 mg, 2.43 mmol). After stirring for one hour at room temperature, the reaction mixture was extracted three times with aqueous citric acid. The organic phase was dried over magnesium sulfate and evaporated in vacuo. The residue (1.75 g) was purified by column chromatography. 930 mg (1.92 mmol, 87% yield) of the pure amine were obtained.

^ ^• H NMR (270 MHz, CDC1 ₃ ): 7.4-7.5 (m, 4 H); 7.2-7.3 (m, 9H); 6.9 (m, 2H); 6.0 (s, 1H); 5.7 (s, 1H); 4.9 (d. 1H); 4.5 (d, 1H); 3.8 (s, 6H); 2.4 (s br, 2H).

ESI-MS: M ⁺ = 485.

Example 8:

2- [(4, 6-Dimethoxy-2-pyrimidinyl) oxy] -3- {[(4-methoxyphenoxy) carbonyl] amino} -3, 3-diphenylpropionic acid benzyl ester

Benzyl 3-amino-2- [(4, 6-dimethoxy-2-pyrimidyl) oxy] -3, 3-diphenylpropionate (368 mg, 0.76 mmol) was treated with a spatula tip of N, N-dimethylaminopyridine in anhydrous dichloromethane ( 10 mL) and pyridine (150 mg, 1.89 mmol) and 4-methoxyphenylchloroformate (212 mg; 1.14 mmol) were added in succession. The mixture was stirred for 30 minutes at room temperature. After the reaction had been terminated by shaking with sodium hydrogen carbonate solution, the organic phase was diluted with ether, washed three times with aqueous citric acid, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography; 286 mg (0.42 mmol with 94% purity, 56% yield) of the target compound were obtained.

HPLC-MSD: M + H ⁺ = 636, Example 9: (1-170)

2- [(4, 6-Dimethoxy-2-pyrimidinyl) oxy] -N- [(4-methoxyphenoxy) carbonyl] -3, 3-diphenyl-β-alanine

A solution of 2- [(4, 6-dimethoxy-2-pyrimidinyl) oxy] -3- {[(4-methoxy-phenoxy) carbonyl] amino} -3, 3-diphenylpropionic acid benzyl ester (286 mg, 0.42 mmol) in ethyl acetate (10 mL) was mixed with a spatula tip of a 10% palladium / activated carbon hydrogenation catalyst and stirred for one hour under a hydrogen atmosphere. The catalyst was then filtered off and concentrated in vacuo. Crystallization from dichloromethane / n-hexane provided the pure carboxylic acid (140 mg, 0.26 mmol, 61% yield).

ⁱ H-NMR (360 MHz, CDC1 ₃ ): 7.5-7.6 (d, 2 H); 7.2-7.4 (m, 10H); 6.9 (S br, 1H); 6.8 (d, 2H); 6.6 (s, 1H); 6.4 (s, 1H); 5.7 (s, 1H); 3.9 (s, 6H); 3.7 (s, 3H).

ESI-MS: M ⁺ = 545.

Example 10:

2- [(4, 6-Dimethoxy-2-pyrimidinyl) oxy] -3- ({[(4-methoxybenzyl) - (methyl) -amino] carbonyl} amino) -3, 3-diphenylpropionic acid methyl ester

A solution of 3-amino-2- [(4,6-dimethoxy-2-pyrimidinyl) oxy] -3,3-diphenylpropionic acid methyl ester (300 mg, 0.71 mmol, see Example 2) in 1,4-dioxane ( 10 mL) was mixed with triphosgene (222 mg, 0.75 mmol) and stirred at 80 ° C for one hour. After cooling to room temperature, a solution of N-ethyldiisopropylamine (0.31 L, 1.78 mmol) and N- (4-methoxybenzyl) -N-methylamine (124 mg, 0.82 mmol) in 1, 4-Dioxane (2 mL) added dropwise. The mixture was stirred again at 70 ° C. for two hours and then concentrated on a rotary evaporator. The residue was taken up in ethyl acetate and washed with saturated saline. The organic phase was dried over magnesium sulfate and evaporated in vacuo. The residue was taken up in dichloromethane and the product was precipitated by adding hexane. 443 mg of a colorless solid were obtained (0.69 mmol with 91% purity, 97% yield).

HPLC-MSD: M + H + = 587. Example 11: (1-23)

2- [(4, 6-Dimethoxy-2-pyrimidinyl) oxy] -N- {[(4-methoxybenzyl) -

(ethyl) amino] carbonyl} -3, 3-diphenyl-β-alanine

5 A solution of 2- [(4, 6-dimethoxy-2-pyrimidinyl) oxy] -3- ({[(4-methoxybenzyl) (methyl) amino] carbonyl} amino) -3, 3-diphenylpropionic acid methyl ester ( 443 mg, 0.69 mmol at 91% purity) were placed in a mixture of tetrahydrofuran (10 ml) and water (5 ml) and 1 molar sodium hydroxide solution (1.03 ml) was added. You let

10 Stir at room temperature for 16 hours and then stir at 40 ° C for two hours to complete the reaction. The reaction mixture was then diluted with water, acidified with citric acid and extracted with ether. The organic extracts were backwashed with water, dried over magnesium sulfate

15 and evaporated in vacuo. The residue was lyophilized; 290 mg (0.49 mmol, 72% yield) of the title compound were obtained.

iH-NMR (360 MHz, CDC1 ₃ ): 7.2-7.4 (m, 10 H); 6.9 (d, 2H); 6.8 (m, 3H); 5.7 (s, 1H); 5.6 (s br, 1H); 4.5 (d, 1H); 4.3 20 (d, 1H); 3.9 (s, 6H); 3.8 (s, 3H); 2.9 (s, 3H).

ESI-MS: M ⁺ = 572.

The following were prepared analogously to Example 4: 25

Example 12: (1-230)

2- [(4, 6-Dimethoxy-2-pyrimidinyl) oxy] -N- (methoxycarbonyl) -3, 3-diphenyl-ß-alanine 0 ⁱ H-NMR (400 MHz, d ₆ -DMSO): 8.1 (s br, 1H); 7, 5 (app d, 2 H); 7, 1-7, 4 (m, 8H); 6.4 (s br, 1H); 5, 8 (s, 1H); 3, 8 (s, 6H); 3, 4 (s, 3H).

¹³ C NMR (100 MHz, d ₆ -DMSO): 172.2 (s); 169.8 (s); 163.0 (s); 154.8 5 (s); 142.3 (s); 140.0 (s); 128.8 (d); 128.1 (d); 127.4 (d); 127.2

(d); 127.03 (d); 126.99 (d); 126.6 (d); 83.0 (d); 77.2 (d); 65.1 (s); 54.1 (q), 51.1 (q).

ESI-MS: M + = 453.0

5 Example 13: (1-266)

N- {[(4,5-Dimethoxy-2-nitrobenzyl) oxy] carbonyl} -2- [(4, 6-dimethoxy-

2-pyrimidinyl) oxy] -3, 3-diphenyl-β-alanine

³ H NMR (360 MHz, CDC1 ₃ ): 7.7 (s, 1 H); 7.6 (m, 2H); 7.2-7.4 (m, 8H); 6.9 (s br, 1H); 6.6 (s, 1H); 6.4 (s, 1H); 5.7 (s, 1H); 5.4 (s br, 2H); 3.9 (s, 3H); 3.8 (s, 9H).

ESI-MS: M ⁺ = 634.

The following was prepared analogously to Example 9:

Example 14: (1-168)

2- [(4, 6-Dimethoxy-2-pyrimidinyl) oxy] -N- [(3, 4-dimethylphenoxy) carbonyl] -3, 3-diphenyl-β-alanine

ⁱ H-MR (360 MHz, CDCI ₃ ): 7.5-7.6 (m app d, 2 H); 7.2-7.4 (.8H); 7.0 (d. 1H); 6.7 (s br, 2H); 6.6 (s, 1H); 6.4 (s, 1H); 5.7 (s, 1H); 3.8 (s, 6H); 2.2 (s, 6H).

ESI-MS: M + = 543.

The following were prepared analogously to Example 11:

Example 15: (1-86)

N- [(Diethylamino) carbonyl] -2- [(4, 6-dimethoxy-2-pyrimidinyl) oxy] - 3,3-diphenyl-ß-alanine

ⁱ H-NMR (360 MHz, CDCI ₃ ): 7.3-7.5 (, 10 H); 6.8 (s, 1H); 5.7 (s, 1H); 5.4 (s br, 1H); 3.9 (s, 6H); 3.2-3.4 (, 4H); 1.1 (t, 6H).

ESI-MS: M ⁺ = 494.

Example 16: (1-260)

N- {[Benzyl (methyl) amino] carbonyl} -2- [(4, 6-dimethoxy-2-pyrimidinyl) oxy] -3, 3-diphenyl-β-alanine

ⁱ H-NMR (360 MHz, CDCI ₃ ): 7.2-7.4 (m, 13 H); 7.0-7.1 (m, 2H); 6.9 (s, 1H); 5.7 (s, 1H); 5.6 (s br, 1H); 4.6 (d, 1H); 4.3 (d. 1H); 3.9 (s, 6H); 2.9 (s, 3H).

ESI-MS: M + = 542. Example 17: (1-155)

2- [(4, 6-dimethoxy-2-pyrimidinyl) oxy] -N- [(methylanilino) carbonyl] -

3,3-diphenyl-β-alanine

¹ H NMR (360 MHz, CDC1 ₃ ): 7.1-7.5 (m, 15 H); 7.0 (s, 1H); 5.7 (s, 1H); 5.3 (s, 1H); 3.9 (s, 6H); 3.2 (s, 3H).

ESI-MS: M ⁺ = 528.

Example 18: (1-11)

2- [(4, 6-Dimethoxy-2-pyrimidinyl) oxy] -N- [(di ethylamino) carbonyl] -3,3-diphenyl-β-alanine

iH-MR (360 MHz, CDCI ₃ ): 7.7 (m app d, 2 H); 7.2-7.5 (.8H); 6.6 (s, 1H); 6.2 (s, 1H), 5.7 (s, 1H); 3.8 (s, 6H); 3.0 (s, 6H).

ESI-MS: M ⁺ = 466.

Example 19: (1-121) 2- [(4, 6-Dimethoxy-2-pyrimidinyl) oxy] -N- {[4-methoxy (methyl) anilino] carbonyl} -3, 3-diphenyl-β-alanine

1H NMR (360 MHz, CDCI ₃ ): 7, 3-7, 4 (, 3 H); 7.15-7.3 (m /? H); 7.1 (m. 2H); 7.0 (m, 3H); 6.8 (d, 2H); 5.7 (s, 1H); 5.3 (s br, 1H); 3.9 (s, 6H); 3.8 (s, 3H); 3.2 (s, 3H).

ESI-MS: M ⁺ = 558.

Example 20: (1-194) 2- [(4, 6-dimethyl-2-pyrimidinyl) oxy] -N- {[(4-methoxybenzyl) - (methyl) amino] carbonyl} -3, 3-diphenyl-β alanine

ⁱ H-NMR (360 MHz, CDCI ₃ ): 7.2-7.4 (m, 10 H); 6.9-7.0 (m, 3H), 6.8 (d, 2H); 6.7 (s, 1H), 5.7 (s br, 1H); 4.5 (d, 1H); 4.3 (d. 1H); 3.8 (s, 3H); 2.8 (s, 3H), 2.3 (s, 6H).

ESI-MS: M + = 540.

Example 21: (1-75) 2- t (4,6-dimethyl-2-pyrimidinyl) oxy] -N- (4-morpholinylcarbonyl) -3,3-diphenyl-β-alanine

ⁱ H-MR (360 MHz, CDCI ₃ ): 7.5 (d, 2 H); 7.2-7.4 (m, 8H); 6.7 (s, 1H); 6.6 (s, 1H); 6.1 (s br, 1H); 3.5-3.7 (m, 4H); 3.3-3.5 (, 2H); 3.2-3.3 (, 2H); 2.3 (s, 6H).

ESI-MS: M ⁺ = 476. Example 22: (1-52)

2- [(4, 6-Dimethyl-2-pyrimidinyl) oxy] -3, 3-diphenyl-iV- (1-piperidinylcarbonyl) -ß-alanine

ⁱ H-NMR (360 MHz, CDC1 ₃ ): 7.5 (d, 2 H); 7.2-7.4 (.8H); 6.9

(s, 1H); 6.6 (s, 1H); 5.7 (s br, 1H); 3, 3-3, 5 (m, 2H); 3.2-3.3 (m, 2H); 2.3 (s, 6H); 1.3-1.7 (m, 6H).

ESI-MS: M ⁺ = 474.

Example 23: (1-26)

2- [(4, 6-Dimethyl-2-pyrimidinyl) oxy] -3, 3-diphenyl-N- (1-pyrrolidinylcarbonyl) -ß-alanine

ⁱ H-NMR (360 MHz, CDCI ₃ ): 7.5 (m, 2 H); 7.2-7.4 (m, 8H); 7.0 (s, 1H); 6.7 (s, 1H); 5.3 (s br, 1H); 3.3-3.4 (m, 4H); 2.3 (s, 6H); 1.8-2.0 (m, 4H).

ESI-MS: M ⁺ = 460.

Example 24: (1-202)

N- {[Cyclohexyl (methyl) amino] carbonyl} -2- [(4, 6-dimethyl-2-pyrimidinyl) oxy] -3, 3-diphenyl-β-alanine

ⁱ H-MR (400 MHz, CDCI ₃ ): 7.5 (d, 2 H); 7.2-7.4 (m, 8H); 6.8 (S, 1H); 6.6 (s, 1H); 6.1 (s br, 1H); 3.8-4.0 (m, 1H); 2.8 (s, 3H); 2.3 (s, 6H); 1.7-1.9 (m, 2H); 1.5-1.7 (m, 4H); 1.2-1.4 (m, 4H).

ESI-MS: M ⁺ = 502.

The compounds listed in Table 1 can be prepared analogously to the synthesis examples mentioned or as described in the general part.

ifc

0

rf

t

According to the binding test described in the general section, receptor binding data were measured for the compounds listed below.

The results are shown in Table 2.

Table 2

Receptor binding data (edge)

Claims

claims

1. Carbamate and urea derivatives of the formula I.

where the substituents have the following meaning:

R ¹ tetrazole or a group

O

II

C-R

in which R means:

a) a radical OR ⁶ , in which R ⁶ denotes:

Hydrogen, the cation of an alkali metal, the cation of an alkaline earth metal, a physiologically compatible organic ammonium ion such as tertiary C 1 -C ₄ -alkylammonium or the ammonium ion;

C ₃ -C ₈ cycloalkyl, Ci-Cs-alkyl, CH ₂ -phenyl, which can optionally be substituted,

A C ₂ -C ₆ alkenyl or a C ₃ -C ₆ alkynyl group, these groups in turn being able to carry one to five halogen atoms;

R ⁶ can also be an optionally substituted phenyl radical;

b) pyrrolyl, pyrazolyl, imidazolyl and triazolyl, which can carry one to two halogen atoms, or one to two C 1 -C alkyl or one to two C 1 -C 4 alkoxy groups; c) a group

O- with k = 0, 1 or 2;

P = 1, 2, 3 or 4; R ^? -C-C ₄ alkyl, C ₃ -C ₈ cycloalkyl, C ₂ -C ₆ alkenyl, CC ₆ alkynyl or phenyl, which can optionally be mono- or polysubstituted;

R8 Cι-C ₄ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ -cycloalkyl, these radicals being a _Cι-C4 alkoxy, Cι-C ₄ -Alkylthio- and / or an optionally substituted phenyl radical can wear;

Phenyl, optionally substituted; R2 and R ³ (which may be the same or different):

Phenyl or naphthyl which may be substituted by one or more • the following radicals: halogen, nitro, cyano, hydroxy, mercapto, Cι-C ₄ alkyl, C ₂ -C ₄ _Alkenyl, C ₂ -C ₄ alkynyl, Cι -C ₄ -Halogenalkyl, Cι_C ₄ _alkoxy, phenoxy, Cι_C -haloalkoxy, Cι-C ₄ -alkylthio, amino, NH (Cι-C ₄ -alkyl), N (Cι-C ₄ -alkyl) or phenyl, the one nitro, cyano, C ₄ -alkyl, C may be mono- or polysubstituted by halogen, _halo-4 alkyl, Cι_C ₄ alkoxy, Cι_C ₄ _Halogenalkoxy or Cι_C ₄ _Alkylthio;

C ₅ -C ₆ cycloalkyl; -O4

Hydrogen, Cχ-C alkyl;

Ci-Cβ-alkyl, optionally substituted;

C ₃ -C ₈ cycloalkyl, optionally substituted;

Phenyl or naphthyl, which can carry one to three of the following substituents: halogen, cyano, C ₄ -C ₄ alkoxy, C 1 -C ₄ alkyl, C ₄ -C ₄ alkylthio, NH (C 1 -C ₄ alkyl), N ( -CC ₄ alkyl) ₂ , amino or carboxy; or R ⁵ forms a three- to seven-membered ring with KR ⁹ as indicated under R ⁹ ;

Oxygen or NR ⁹ with

R ^{9 is} hydrogen, C ₁ -C ₄ alkyl;

or NR ⁹ forms with R ⁵ and a corresponding number of methylene groups a three- to seven-membered saturated ring, which may be substituted with

C 1 -C ₄ alkyl and in which up to two of the methylene groups can be replaced by oxygen, sulfur, NH or N (C 1 -C ₄ alkyl);

W and Z (which can be the same or different):

X nitrogen or CR ¹⁰ ;

Y is nitrogen or CR ¹¹ ;

Q nitrogen or CR ¹² ; with the proviso that if Q = nitrogen, then X = CR ¹⁰ and Y = CR ¹¹ ; with the proviso that a maximum of three of the ring members denoted by W, X, Q, Y and Z represent nitrogen,

R ¹⁰ and R ^{1: L} (which may be the same or different):

Hydrogen, halogen, C 1 -C ₄ haloalkoxy,

C ₃ _C ₆ alkenyloxy, Ca-Cς alkynyloxy, Cι_C ₄ _alkylthio, Cι_C ₄ _alkylcarbonyl, Cι-C ₄ -alkoxycarbonyl, hydroxy, NH ₂ , NH (Cι_C_Alkyl), N (Cι_C_Alkyl) ₂ , carboxy; C ₁ -C ₄ -alkyl, CC ₄ -alkenyl, C ₂ -C ₄ -alkynyl, where these radicals can be substituted one or more times by halogen, hydroxy, mercapto, carboxy, cyano, phenyl, C 1 -C ₄ -alkoxy;

Phenyl or phenoxy, optionally mono- or disubstituted;

C i -C ₄ alkoxy, optionally substituted; or CR ¹⁰ or CR ¹¹ is linked to CR ¹² as stated under R ¹² to form a 5- or 6-membered ring;

R ^{12 is} hydrogen, halogen, C ₄ C alkoxy, C ₄ C haloalkoxy,

C_C ₄ _Alkylthio, Cι_C ₄ -alkylcarbonyl, Cι-C ₄ -alkoxycarbonyl, NH (Cι_C ₄ _Alkyl), N (Cι_C_Alkyl) ₂ , hydroxy, carboxy, cyano, amino, mercapto;

C ₁ -C ₄ -alkyl, C ₂ -C ₄ -alkenyl, C ₂ -C ₄ -alkynyl, where these radicals can be substituted one or more times by: halogen, hydroxy, mercapto, carboxy, cyano, amino, C__C_alkoxy;

or CR ¹² forms together with CR ¹⁰ or CR ¹¹ a 5- or 6-membered alkylene or alkenylene ring, which can be substituted by one or two Cι_ ₄ alkyl groups, and in each case one or more methylene groups

Oxygen, sulfur, -NH or - (Cι_C_Alkyl), can be replaced

2. Use of the carbamate and urea derivatives I according to claim 1 for the manufacture of medicaments.

3. Use of the compounds I according to claim 2 as endothelin receptor antagonists.

4. Use according to claim 2 for the treatment of diseases in which elevated endothelin levels occur.

5. Use according to claim 2 for the treatment of diseases in which endothelin contributes to the development and / or progression.

6. Use according to claim 2 for the treatment of chronic heart failure, restenosis, high blood pressure, pulmonary high pressure, acute / chronic kidney say, erectile dysfunction, cirrhosis of the liver, cerebral ischemia, benign prostatic hyperplasia, acute pancreatitis and prostate cancer.

7. Combinations of carbamate and urea derivatives I according to claim 1 and one or more active substances, selected from inhibitors of the renin-angiotensin system, beta blockers, diuretics, calcium antagonists and VEGF-blocking substances for the treatment of high blood pressure.

8. Pharmaceutical preparations for oral and parenteral use, comprising, in addition to the usual pharmaceutical excipients, at least one carbamate or urea derivative I according to claim 1.