HRP980331A2 - New beta-amino and beta-azido carboxylic acid derivatives, the production and the use thereof as endothelin receptor antagonists - Google Patents

Description

The proposed invention relates to new carboxylic acid derivatives and their preparation and use.

Endothelin is a peptide made of 21 amino acids, which is synthesized and released by the vascular endothelium. Endothelin also exists in three isomeric forms, ET-1, ET-2 and ET-3. As used herein, the term "endothelin" or "ET" refers to one or all of the isomeric forms of endothelin. Endothelin is a strong vasoconstrictor and has a strong effect on blood vessel tone. It is known that this vasoconstriction is caused by the binding of endothelin to its receptor (Nature, 332, (1988) 411-415; FEBS Letters, 231, (1988) 440-444 and Biochem. Biophys. Res. Commun., 154, (1988) 868-875.

Elevated or abnormal release of endothelin causes permanent vasoconstriction in peripheral, renal, and cerebral blood vessels, which can lead to disease.

It is known from the literature that endothelin is involved in numerous diseases. These are hypertension, acute myocardial infarction, pulmonary hypertension, Raynaud's syndrome, cerebral vasospasm, stroke, benign prostatic hypertrophy, atherosclerosis, asthma and prostate cancer (J. Vascular Med. Biology 2, (1990) 207, J. Am. Med. Association 264, (1990) 2868), Nature 344, (1990) 114, N. Engl. J. Med. 322, (1989) 205, N. Engl. J. Med. Chem. 328, (1993) 1732, Nephron 66, (1994) 373, Stroke 25, (1994) 904, Nature 365, (1993), 759, J. Mol. Cell. Cardiol. 27, (1995) A234; Cancer Research 56, (1996) 663, Nature Medicine 1, (1995) 944).

So far, at least two subtypes of endothelin receptors, ETA and ETB receptors, have been described in the literature (Nature 348, (1990) 730, Nature 348, (1990) 732). Therefore, substances that inhibit the binding of endothelin to one or both receptors also antagonize the physiological effects of endothelin and therefore represent valuable drugs.

The object of the proposed invention is to provide endothelin receptor antagonists that bind to ETA and ETB receptors. The invention relates to β-amino and β-azido carboxylic acid derivatives of formula I

[image]

where

R1 represents a tetrazole or a group

[image]

where R has the following meaning:

a) radical OR4, where

R4 represents hydrogen, an alkali metal cation, an alkaline earth metal cation or a physiologically tolerable organic ammonium ion such as C1-C4-alkylammonium or ammonium ion;

C3-C8-cycloalkyl, C1-C8-alkyl, CH2-phenyl, which may be substituted with one or more of the following substituents: halogen, nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, hydroxyl, C1-C4 -Alkoxy, mercapto, C1-C4-alkylthio, amino, NH(C1-C4-alkyl), N(C1-C4-alkyl)2;

C3-C8-alkenyl or C3-C8-alkynyl, whereby these groups can carry one to five halogen atoms;

R4 can further be a phenyl radical which can carry one to five halogen atoms and/or one to three of the following radicals: nitro, cyano, C1-C4-alkyl, C1-C4-halogenoalkyl, hydroxyl, C1-C4-alkoxy, mercapto, C1 -Cd-alkylthio, amino, NH (C1-C4-alkyl), N(C1-C4-alkyl)2;

b) a five-membered heteroaromatic system such as pyrrolyl, pyrazolyl, imidazolyl and triazolyl connected via a nitrogen atom, which can carry one or two halogen atoms, or one or two C1-C4-alkyl or one or two C1-C4-alkoxy groups;

c) group

[image]

where

k has the value 0, 1 and 2,

p has the value 1, 2, 3 and 4, a

R5 represents C1-C4-alkyl, C3-C8-cycloalkyl, C3-C8-alkenyl, C3-C8-alkynyl or phenyl, which may be substituted with one or more, for example with one to three of the following radical residues:

d) radical

[image]

in which

R6 represents C1-C4-alkyl, C3-C8-alkenyl, C3-C8-alkynyl, C3-C8-cycloalkyl, whereby these radicals can carry C1-C4- alkoxy, C1-C4-alkylthio and/or a phenyl radical as mentioned under c);

C1-C4-haloalkyl or phenyl, unsubstituted or substituted, especially as specified under c).

Other substituents have the following meanings:

A is NR 7 R 8 or azido;

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

nitrogen or methine; provided that Q = nitrogen if W and Z are methine;

X is nitrogen or CR9;

Y is nitrogen or CR10;

Q is nitrogen or CR11; provided that X = CR9 and Y is CR10 if Q is nitrogen,

R2 and R3 (which can be the same or different) represent:

phenyl or naphthyl, each of which may be substituted with one or more of the following radicals: halonitro, cyano, hydroxyl, mercapto, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-hydroxyalkyl, C1-C4-Haloalkyl, C1-C4-Alkoxy, Phenoxy, C1-C4-HaloAlkoxy, C1-C4-Alkylthio, Amino, NH(C1-C4-Alkyl), N(C1-C4-Alkyl)2 or phenyl which may be mono- or multi-substituted, eg mono- to tri-halogen, nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy or C1-C4-alkylthio; or

phenyl or naphthyl, which are connected to each other in ortho positions via a direct bond, methylene, ethylene or ethenyl group, oxygen or sulfur atom or one SO2-, NH or N-alkyl group;

C5-C6-cycloalkyl, unsubstituted or substituted;

R7 represents hydrogen, C1-C8-alkyl, C3-C8-alkenyl or C3-C8-alkynyl, C1-C5-alkylcarbonyl, each of these radicals can be unsubstituted or substituted;

phenyl or naphthyl, unsubstituted or substituted; unsubstituted or substituted C3-C8-cycloalkyl;

or

R7 is linked to R8 via 4 or 5 CH2 groups to form a five- or six-membered ring;

R 8 represents hydrogen, C 1 -C 4 -alkyl; or

R8 is linked to R7 via 4 or 5 CH2 groups to form a five- or six-membered ring;

R9 and R10 (which may be the same or different) represent:

hydrogen, halogen, C1-C4-Alkoxy, C1-C4-HaloAlkoxy, C3-C6-Alkenyloxy, C3-C6-Alkynyloxy, C1-C4-Alkylthio, C1-C4-Alkylcarbonyl, C1-C4-Alkoxycarbonyl, Hydroxyl, NH2, NH (C1-C4-alkyl), N(C1-C4-alkyl)2, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, whereby these radicals can be unsubstituted or substituted;

or CR9 and CR10 are linked to CR11 as defined for R11 to form a five- or six-membered ring;

R11 is hydrogen, halogen, C1-C4-Alkoxy, C1-C4-halo-Alkoxy, C3-C6-Alkenyloxy, C3-C6-Alkynyloxy, C1-C4-Alkylthio, C1-C4-Alkylcarbonyl, C1-C4-Alkoxycarbonyl, NH ( C1-C4-alkyl), N(C1-C4-alkyl)2, hydroxyl, carboxyl, cyano, amino mercapto;

C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, whereby these radicals can be singly or multiply substituted with halogen, hydroxyl, mercapto, carboxyl, cyano, amino, C1-C4-alkoxy;

or CR11 together with CR9 or CR10 forms a five- or six-membered alkylene or alkenylene ring which can be substituted with one or two C1-C4-alkyl groups, and in which in each case one or more methylene groups can be substituted with oxygen, sulfur, - NH or -N(C1-C4-alkyl).

The following definitions apply here and below:

An alkali metal is, for example, lithium, sodium, potassium.

Alkaline earth metal is, for example, calcium, magnesium, barium.

Organic ammonium ions are protonated amines such as ethanolamine, diethanolamine, ethylenediamine, diethylamine or piperazine.

C3-C8-cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl;

C1-C4-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;

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

C1-C4-alkyl may be linear or branched such as methyl, ethyl, 1-propyl, 2-propyl, 2-methyl-2-propyl; 2-methyl-1-propyl, 1-butyl or 2-butyl;

C2-C4-alkenyl can be linear or branched such as ethenyl, 1-propen-3-yl, 1-propen-2-yl, 1-propen-1-yl, 2-methyl-1-propenyl, 1-butenyl or 2-butenyl;

C2-C4-alkynyl can be linear or branched, such as ethynyl, 1-propyn-1-yl, 1-propyn-3-yl, 1-butyn-4-yl or 2-butyn-4-yl;

C1-C4-Alkoxy can be linear or branched, such as methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or 1,1-dimethylethoxy;

C3-C6-alkenyloxy can be linear or branched, such as allyloxy, 2-buten-1-yloxy or 3-buten-2-yloxy;

C3-C6-alkynyloxy can be linear or branched, such as propyn-1-yloxy, 2-butyn-1-yloxy or 3-butyn-2-yloxy;

C1-C4-alkylthio can be linear or branched, such as methylthio, ethylthio, propylthio, 1-methylethylthio, butylthio, 1-methylpropylthio, 2-methylpropylthio or 1,1-dimethylethylthio;

C1-C5-alkylcarbonyl may be linear or branched, such as acetyl, ethylcarbonyl or 2-propylcarbonyl;

C1-C4-Alkoxycarbonyl can be linear or branched, such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl or n-butoxycarbonyl;

C3-C8-alkylcarbonylalkyl may be linear or branched, such as 2-oxo-prop-1-yl, 3-oxo-but-1-yl or 3-oxo-but-2-yl;

C1-C8-alkyl may be linear or branched, such as C1-C4-alkyl, pentyl, hexyl, heptyl or octyl;

C3-C8-alkenyl can be linear or branched, such as 1-propen-3-yl, 1-propen-2-yl, 1-propen-1-yl, 2-methyl-1-propenyl, 1-buten- 4-yl, 2-buten-3-yl, 1-penten-5-yl, 1-hexen-6-yl, 3-hexen-6-yl, 2-hepten-7-yl or 1-octen-8- or

C3-C8-alkynyl can be linear or branched, such as 1-propyn-1-yl, 1-propyn-3-yl, 1-butyn-4-yl or 2-butyn-4-yl, 2-pentyn- 5-yl, 3-hexen-6-yl, 3-heptyn-7-yl or 2-octyn-8-yl.

Halogen is, for example, fluorine, chlorine, bromine, iodine.

The invention further relates to those compounds from which the compounds of formula I can be released (so-called prodrugs). Preference is given to such prodrugs in which the release takes place under conditions such as those prevailing in certain parts of the body, eg in the stomach, intestines, bloodstream, liver.

Compounds I and intermediates for their production, such as II and III, may have one or more asymmetrically substituted carbon atoms. Such compounds may exist as pure enantiomers or pure diastereomers or as mixtures thereof. When used as an active substance, preference is given to using an enantiomerically pure compound.

The invention further relates to the use of the above-mentioned carboxylic acid derivatives for the production of drugs, especially for the production of ETA and/or ETB receptor inhibitors. The new compounds are suitable as antagonists as defined in the introduction.

The production of compounds of formula II, in which A represents an azido group (IIa) starts from epoxide III which can be synthesized, for example, as described in WO 96/11914.

These epoxides III can then be reacted with an azide such as sodium azide. This is done by reacting compounds of formula III with azide in a molar ratio of approx. 1:1 to 1:7 at 20 to 150°C, giving IIa.

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The reaction can be carried out in the presence of a diluent. For this purpose, all solvents that are inert to the reagents can be used.

Examples of such solvents, i.e. diluents, are aliphatic, alicyclic and aromatic hydrocarbons, which can be chlorinated if necessary, such as hexane, cyclohexane, petroleum ether, naphtha, benzene, toluene, xylene, methylene chloride, chloroform, ethyl chloride and trichloroethylene. , ethers, such as diisopropyl ether, dibutyl ether, methyl tert.butyl ether, dioxane and tetrahydrofuran, nitriles such as acetonitrile and propionitrile, amides such as dimethylformamide, dimethylacetamide and N-methyl-pyrrolidone, sulfoxides and sulfones, such as example dimethyl sulfoxide and sulfolane.

The reaction is preferably carried out at a temperature ranging from 0°C to the boiling point of the solvent or solvent mixture. The presence of a catalyst can be beneficial. Suitable catalysts are strong organic or inorganic acids and Lewis acids. Examples of these include sulfuric acid, hydrochloric acid, trifluoroacetic acid, p-toluenesulfonic acid, boron trifluoride etherate, and rare earth triflates.

New compounds of formula I, in which A represents an azido group (Ia), can be produced, for example, by the reaction of carboxylic acid derivatives of formula IIa where the substituents have the meanings specified for compounds of formula IV.

[image]

R12 in formula IV is halogen or R16-SO2-, where R13 can be C1-C4-alkyl, C1-C4-haloalkyl or phenyl, and W, X, Y, Z and Q have the meanings given in the introduction. The reaction takes place primarily in one of the above-mentioned inert solvents or diluents with the addition of a suitable base, i.e. a base that deprotonates intermediate IIa, in the temperature range from room temperature to the boiling point of the solvent.

Compounds of formula IV are known, some of them can be purchased or can be prepared in a generally known manner. Compounds of type Ia with R1 = COOH can be obtained directly by deprotonation of intermediate IIa, where R1 is COOH, with two equivalents of a suitable base, and reaction with compounds of formula IV. This reaction also takes place in an inert solvent and at a temperature ranging from room temperature to the boiling point of the solvent.

An alkali metal or alkaline earth metal hydride such as sodium hydride, potassium hydride or calcium hydride, a carbonate such as an alkali metal carbonate, for example sodium or potassium carbonate, an alkali metal or alkaline earth metal hydroxide such as sodium or potassium hydroxide, can also be used as a base. an organometallic compound such as butyllithium, or an alkali metal amide such as lithium diisopropylamide or lithium amide.

New compounds of formula I in which A represents an amino group (Ib) can be produced starting from compounds Ia. This is done by reacting compounds of formula Ia with hydrogen in the presence of a catalyst such as palladium or platinum in a solvent at a temperature of 20 to 100°C. Compounds Ia can also be converted to Ib in the presence of triphenylphosphine.

[image]

If R1 represents an ester, the amino group in Ib can be alkylated or converted to an amide by generally known methods. The ester group can be cleaved with an acid or base to give a carboxylic acid.

Compounds of formula II where A represents a substituted amino group (IIc) are also prepared directly from epoxide III by opening with an amine. Compounds IIc are then reacted with IV as described above to give new compounds I.

Compounds of formula I can also be prepared starting from the corresponding carboxylic acids, i.e. compounds of formula I in which R1 is COOH, first by converting that compound in the usual manner into an activated form, such as a halide, anhydride or imidazole, and then by reacting the latter with the appropriate with the hydroxyl compound HOR4 or with sulfonamide H2NSO2R6. This reaction can be carried out in common solvents and often requires the addition of a base, in which case the above are suitable. This two-step procedure can be simplified, for example by allowing the carboxylic acid to act on the hydroxyl compound or on the sulfonamide in the presence of a dehydrating agent such as carbodiimide.

Compounds of formula I can also be produced starting from salts of the corresponding carboxylic acids, i.e. from compounds of formula I in which R1 represents COOM, where M can be an alkali metal cation or the equivalent of an alkaline earth metal cation. These salts react with many compounds of the formula R-D where D represents a common nucleophilic leaving group, for example halogen such as chlorine, bromine, iodine or aryl- or alkylsulfonyl which is unsubstituted or substituted with halogen, alkyl or haloalkyl, for example toluenesulfonyl and methylsulfonyl , or some other equivalent starting group. Compounds of formula R-D with reactive substituent D are known or can be easily obtained based on general expert knowledge. This reaction can be carried out in common solvents and is preferably carried out with the addition of a base, whereby the ones mentioned above are suitable. Compounds of formula I in which R 1 is tetrazolyl can be prepared by methods similar to those described in WO 96/11914 from the corresponding carboxylic acids (formula I with R 1 = COOH).

In some cases, for the production of new compounds I, generally known methods of protecting groups should be applied. If, for example, A represents HOCH2CONH-, the hydroxyl group should first be protected as a benzyl ether, which is then cleaved off in a suitable reaction step.

Compounds of formulas I and II can be obtained in enantiomerically pure form by performing classical racemate resolution with suitable enantiomerically pure bases, as described for example in WO/11914, to racemic or diastereomeric compounds of formulas I and II.

As far as biological activity is concerned, preference is given to derivatives of carboxylic acids of the general formula I - also as pure enantiomers, i.e. pure diastereomers or as their mixtures -, in which the substituents have the following meaning:

A is NR 7 R 8 or azido;

W and Z (which may be the same or different) are: nitrogen or methine; provided that Q = nitrogen if W and Z are methine;

X is nitrogen or CR9

Y is nitrogen or CR10

Q is nitrogen or CR11; provided that X = CR9 and Y is CR10 if Q represents nitrogen, furthermore, for Q, in addition to the above conditions, the following applies: X is CR9, Y is CR10, if Q is CR11.

R2 and R3 (which can be the same or different) represent:

phenyl or naphthyl, which may be substituted with one or more of the following radicals: halogen, cyano, hydroxyl, mercapto, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, phenoxy, C1-C4-haloalkyl, C1 -C4-alkylthio, amino, NH (C1-C4-alkyl), N (C1-C4-alkyl)2 or phenyl which can be mono- or multi-substituted, e.g. mono to tri-substituted with halogen, cyano, C1-C4-alkyl , C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy or C1-C4-alkylthio; or

phenyl or naphthyl, which are connected to each other in the ortho position via a direct bond, a methylene, ethylene or ethenyl group, an oxygen or sulfur atom or one SO2-, NH- or N-alkyl group;

R7 is hydrogen, C1-C8-alkyl, C3-C8-alkenyl or C3-C8-alkynyl, C1-C5-alkylcarbonyl, where these radicals can be. substituted in each case one or more times with a substituent from the group consisting of halogen, hydroxyl, mercapto, carboxyl, amino, cyano, C1-C4-alkoxy, C3-C6-alkenyloxy, C3-C6-alkynyloxy, C1-C4-alkylthio, C1-C4-haloalkoxy, C1-C4-alkoxycarbonyl, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, C3-C8-cycloalkyl, hetaryloxy or hetaryl, five- or six-membered, containing one to three nitrogen atoms and/or a sulfur or oxygen atom, phenoxy or phenyl, whereby all mentioned aryl radicals are substituted singly or multiply, e.g., singly to triply, with a substituent from the group consisting of: halogen, hydroxyl, mercapto, carboxyl, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, amino NH(C1-C4-alkyl), N(C1-C4-alkyl)2, or C1 -C4-alkylthio;

phenyl or naphthyl, which in each case may be substituted with one or more of the following radicals: halogen, cyano, hydroxyl, amino, C1-C4-alkyl, C1-C4-haloalkyl, phenoxy, C1-C4- alkoxy, C1-C4- haloalkoxy, C1-C4-alkylthio, methylenedioxy, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, or ethylenedioxy;

C3-C8-cycloalkyl, wherein these radicals can be substituted in each case one or more times with halogen, hydroxyl, mercapto, carboxyl, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkenyl, C1-C4 -Alkoxy, C1-C4-alkylthio, C1-C4-haloalkyloxy;

R 8 is hydrogen;

R9 and R10 (which may be the same or different) represent:

hydrogen, halogens C1-C4-Alkoxy, C1-C4-Halo-Alkoxy, C1-C9-Alkylthio, NH(C1-C4-Alkyl), N(C1-C4-Alkyl)2;

C1-C4-alkyl, C2-C4-alkenyl, whereby these radicals can be substituted with halogen, hydroxyl, mercapto, cyano;

or R9 and R10 are linked to CR11 as defined for R11 to form a five- or six-membered ring;

R11 is hydrogen, halogen, C1-C4-Alkoxy, C1-C4-Halo-Alkoxy, C1-C4-Alkylthio, NH(C1-C4-Alkyl), N(C1-C4-Alkyl)2, Cyano, C1-C4-Alkyl , C2-C4-alkenyl, whereby these radicals can in any case be substituted one or more times with halogen, cyano, C1-C4-alkoxy;

or CR11 together with CR9 or CR10 forms a five- or six-membered alkylene or alkenylene ring which can be substituted with one or more C1-C4-alkyl groups, and in which in each case one or more methylene groups can be substituted with oxygen, sulfur, - NH or -N(C1-C4-alkyl).

Particularly preferred compounds of the general formula I - also as pure enantiomers, i.e. pure diastereomers or as their mixtures - are those in which the substituents have the following meanings:

A is NR 7 R 8 or azido;

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

nitrogen or methine; provided that Q is nitrogen if W and Z are methine;

X is nitrogen or CR9;

Y is nitrogen or CR10;

Q is nitrogen or CR11; provided that X = CR9 and Y is CR10, if Q is nitrogen, and X is CR9, Y is CR10, if Q is CR11;

R2 and R3 (which can be the same or different) represent:

phenyl which may be substituted with one or more of the following radicals: halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4- alkoxy, phenoxy, C1-C4-alkylthio, NH(C1-C4-alkyl), N (C1-C4-alkyl)2 or phenyl which may be mono- or poly-substituted, e.g. mono to tri-halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, or

C1-C4-alkylthio; or

phenyl groups connected to each other in the ortho position via a direct bond, methylene, ethylene or ethenyl group, oxygen or sulfur atom or one SO2-, NH or N-alkyl group;

R7 is hydrogen, C1-C8-alkyl, C3-C8-alkenyl or C3-C8-alkynyl, C1-C5-alkylcarbonyl, whereby these radicals can be substituted in each case one or more times with halogen, hydroxyl, carboxyl, amino , C1-C4-Alkoxy, C1-C4-Alkylthio, C1-C4-Alkoxycarbonyl, NH(C1-C4-Alkyl), N(C1-C4-Alkyl)2, C3-C8-cycloalkyl, Hetaryloxy or Hetaryl, Petro- or six-membered, containing one to three nitrogen atoms and/or a sulfur or oxygen atom, phenoxy or phenyl, whereby all mentioned aryl radicals are substituted singly or multiply, e.g. singly to triply, with halogen, hydroxyl, mercapto, carboxyl, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, amino, NH(C1-C4-alkyl), N(C1-C4-alkyl)2 or C1-C4-alkylthio;

phenyl or naphthyl, each of which may be substituted with one or more of the following radicals: halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, phenoxy, C1-C4-alkoxy, C1-C4-alkylthio, methylenedioxy or ethylenedioxy ;

C5-C6-cycloalkyl, whereby these radicals can be substituted in each case singly or multiply by C1-C4-alkyl, C1-C4-alkoxy;

R8 is hydrogen:

R9 and R10 (which may be the same or different) represent:

hydrogen, C1-C4-Alkoxy, C1-C4-Alkylthio, N(C1-C4-Alkyl)2;

C1-C4-alkyl, where these radicals can be substituted with halogen;

or R9 and R10 are connected to CR11 as defined for R11 to form a five- or six-membered ring

R 11 is hydrogen, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylthio, cyano;

C1-C4-alkyl, whereby these radicals can in any case be substituted one or more times with halogen;

or CR11 together with CR9 or CR10 forms a five- or six-membered alkylene or alkenyl ring which can be substituted with one or two C1-C4-alkyl groups, where in each case one or more methylene groups can be substituted with oxygen, sulfur, -NH or -N(C1-C4-alkyl).

The compounds of the proposed invention offer a new therapeutic option for the treatment of hypertension, pulmonary hypertension, myocardial infarction, chronic heart failure, angina pectoris, acute/chronic renal failure, renal failure, cerebral vasospasm, cerebral ischemia, subarachnoid hemorrhage, migraine, asthma, atherosclerosis, or endotoxic shock. organ failure induced by endotoxin, intravascular coagulation, restenosis after angioplasty, benign prostatic hyperplasia, ischemic and renal failure caused by intoxication, i.e. hypertension, renal failure induced by ciclosporin, metastasis and growth of mesenchymal tumors, cancer, prostate cancer, renal failure induced by a contrast medium, pancreatitis, gastrointestinal ulcers.

The invention further relates to combined products consisting of an endothelin receptor antagonist of formula I and an inhibitor of the renin-angiotensin system. Inhibitors of the renin-angiotensin system are renin inhibitors, angiotensin II antagonists, especially inhibitors of the enzyme that converts angiotensin (ACE, e. angiotensin converting enzyme).

The combinations can be given together in one pharmaceutical form or separated in time and space. Factors to be considered in dosage and route of administration are the same as for the corresponding substances outside the combination.

This combination of products is particularly suitable for the treatment and prevention of hypertension and its consequences, and for the treatment of heart failure.

The invention further relates to the use of new compounds for labeling the photoaffinity of the endothelin receptor. In particular, those compounds of formula I in which A represents azido are suitable for this purpose.

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

Study of receptor binding

Cloned CHO cells expressing the ETA or ETB receptor are used to study binding.

Preparation of membranes

CHO cells expressing ETA or ETB receptor were propagated in DMEM NUT MIX F12 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/ml streptomycin (Gibco, Sigma no. P-0781). After 48 hours the cells are washed with PBS and incubated for 5 minutes at 37ºC with PBS containing 0.05% trypsin. They are then neutralized with neutralization medium and the cells are collected by centrifugation at 300 x g.

To prepare membranes, cells are adjusted to a concentration of 108 cells/ml buffer (50 ml Tris HCl buffer, pH 7.4) and then disintegrated by ultrasound (Branson Sonifier 250, 40-70 seconds/power constant 20).

Binding tests

To test the binding of ETA and ETB receptors, membranes are suspended in incubation buffer (50 mM Tris-HCl, pH 7.4 with 5 mM MnCl2, 40 µg/ml bacitracin and 0.2% BSA) at a concentration of 50 µg of protein per test well. mixture and incubated at 25°C with 25 pM 125J-ET1 (ETA-receptor assay) or 25 pM 125J-RT3 (ETB receptor assay) in the presence and absence of the test substance. Non-specific binding is determined by 10-7 M ET1. After 30 minutes, free and bound radioligand are separated by filtration through a GF/B glass fiber filter (Whatman, England) on a Skatron cell harvester (Skatron, Lier, Norway) and the filter is washed with ice-cold Tris-HCl buffer, pH 7.4 with 0.2% BSA. Radioactivity collected on the filters was quantified using a Packard 2200 CA liquid scintillation counter.

Testing ET-antagonists in vivo

Male SD rats weighing 250-300 g were anesthetized with amobarbital, connected to artificial respiration, vagotomized and de-spinalized. The carotid and jugular veins were catheterized.

In a group of control animals, intravenous administration of 1 µg/kg ET1 led to a clear increase in blood pressure, which was sustained over a longer period of time.

Experimental animals, 30 minutes before the administration of ET1, were injected with the test compounds i.v. (1 mg/kg). To determine the ET-antagonistic properties, the increase in blood pressure in experimental animals was compared with that in control animals.

Oral testing of EZ receptor antagonists:

Male normotensive rats weighing 250-350 g (Sprague Dawley, Janvier) were first orally administered the test substances. 80 minutes later the animals were anesthetized with urethane, and the carotid (for blood pressure measurement) as well as the jugular vein (administration of large endothelin/endothelin 1) were catheterized.

After the stabilization phase, large endothelin (20 µg/kg, given volume 0.5 ml/kg) or ET1 (0.3 µg/kg, given volume 0.5 ml/kg) was given intravenously. Blood pressure and heart rate were registered continuously for 30 minutes. Clear and persistent changes in blood pressure were calculated as area under the curve (AUC). To determine the antagonistic effect of the test substances, the AUC of the animals that received the test substances was compared with the control animals.

The new compounds can be administered in the usual way orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperitoneally). Applications can also be made with vapors or sprays through the nasopharyngeal route.

The dosage depends on the patient's age, condition and weight, and on the method of administration. As a rule, the daily dose of the active substance is between 0.5 and 50 mg/kg of body weight for oral administration and between 0.1 and 10 mg/kg of body weight for parenteral administration.

The novel compounds may be provided in conventional solid or liquid pharmaceutical forms, eg as uncoated or (film)-coated tablets, capsules, powders, granules, suppositories, solutions, ointments, creams or sprays. They are prepared in the usual way. In doing so, the active substances can be processed with the usual pharmaceutical auxiliaries such as tablet binders, fillers, preservatives, tablet dissolving agents, flow control agents, plasticizers, wetting agents, dispersing agents, emulsifiers, solvents, release retarders active substances, antioxidants and/or propellants (cf. H. Sucker et al.; Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1991). The dosage forms thus obtained contain the active substance usually in an amount of 0.1 to 90 wt. %.

Examples of synthesis

Example 1

Methyl 2-hydroxy-3-azido-3,3-diphenylpropionate

3.8 g (59.0 mmol) of sodium azide and 3.1 g (59.0 mmol) of ammonium chloride are placed in 80 ml of methanol. 5 g (19.7 mmol) of methyl 3,3-diphenyl-2,3-epoxypropionate were added to this suspension, which was then stirred for 48 hours at room temperature. The mixture is thickened, water is added and the aqueous phase is extracted several times with ethyl acetate. Then the combined organic phases are dried over magnesium sulfate, the solvent is distilled off and the residue is purified by chromatography. 1.2 g (4 mmol, yield 21%) of the pure product was isolated.

Melting point: 102--103°C.

GH-NMR (200 MHz): 7.2 ppm (10 H, m); 5.1 (1H, d); 3.5 (3H, s); 3.4 (1H, d).

Example 2

Methyl 2-(4-methoxy-6-methyl-2-pyrimidinyloxy)-3-azido-3,3-diphenylpropionate

930 mg (6.7 mmol) of potassium carbonate, 1.4 g (6.7 mmol) of 4-methoxy-6-methyl-sulfonylpyrimidine and 2.0 g (6.7 mmol) of methyl 2-hydroxy-3-azido- 3,3-diphenylpropionate was mixed with 20 ml of DMF. The mixture is stirred for two hours at 80°C. It is cooled and water is added and then extracted with ethyl acetate. The combined organic phases are dried over magnesium sulfate and the solvent is distilled off. 2.9 g of crude oil was isolated and reacted immediately.

Example 3

Methyl 2-(4-methoxy-6-methyl-2-pyrimidinyloxy)-3-amino-3,3-diphenylpropionate

2.8 g (6.7 mmol) of methyl 2-(4-methoxy-6-methyl-2-pyrimidinyloxy)-3-azido-3,3-diphenylpropionate were dissolved in 20 ml/40 ml methanol/ethyl acetate and added with a teaspoon of palladium on charcoal. After flushing the apparatus with nitrogen and then with hydrogen, the solution is stirred for 3 hours under atmospheric pressure at room temperature. At the end of the conversion, the palladium on the charcoal is filtered off and the solvent is distilled off. 2.9 g of crystals were isolated, which immediately reacted further.

Example 4

2-(4-methoxy-b-methyl-2-pyrimidinyloxy)-3-amino-3,3-diphenylpropionic acid (I-375)

840 mg (2.1 mmol) of methyl 2-(4-methoxy-6-methyl-2-pyrimidinyloxy)-3-amino-3,3-diphenylpropionate was added to a mixture of 6.4 ml of dioxane and 3.2 ml of 1N potassium hydroxide solution and the mixture is stirred for two hours at 80°C. It is cooled, water is added and acidified and then extracted with ethyl acetate. The combined organic phases are dried over magnesium sulfate and the solvent is distilled off. The residue was mixed with ether, allowing 190 mg (0.5 mmol, yield 25%) of crystals to be isolated.

1H-NMR (360 MHz/DMSO/303K): 7.7 ppm (1 H, broad); 7.4 (4H, m); 7.2 (6H, m); 5.9 (1H, broad); 5.1 (1H, s); 3.2 (3H, broad), 2.1 (3H, s).

1H-NMR (360 MHz/DMSO/323K): 7.7 ppm (1 H, broad); 7.4 (4H, m); 7.2 (6H, m); 5.9 (1H, s); 5.1 (1H, S); 3.2 (3H, s); 2.1 (3H, s).

Example 5

2-(4,6-dimethoxy-2-pyrimidinyloxy)-3-azido-3,3-diphenyl)-propionic acid (I-542)

1.1 g (2.5 mmol) of 2-(4,6-dimethoxy-2-pyrimidinyl-oxy)-3-azido-3,3-diphenyl)-propionate was added to a mixture of 11 ml of dioxane and 5 ml of 1N of potassium hydroxide solution and stirred for three hours at 50°C. Cool, add water and acidify and then extract with ether. The combined organic phases are dried over magnesium sulfate and the solvent is distilled off. 900 mg (2.1 mmol, yield 85%) of crystals were isolated.

Melting point. 169 - 165°C

ESI-MS: M+ = 421

Example 6

Methyl 2-(4,6-dimethoxy-2-pyrimidinyloxy)-3-acetylamino-3,3-diphenyl-propionate

A catalytic amount of DMAP and 1 g (2.4 mmol) of methyl 2-(4,6-dimethoxy-2-pyrimidinyloxy)-3-amino-3,3-diphenyl-propionate were dissolved in 10 ml of pyridine. With cooling on ice, acetyl chloride (0.26 ml, 3.7 mmol) was added dropwise and the mixture was stirred for 12 hours at room temperature. Water is added and the mixture is extracted with ether. The combined organic phases are dried over magnesium sulfate and the solvent is distilled off. The residue is mixed with ether and the compound begins to crystallize after a short time (1 g, 2.2 mmol, yield 90%). The compound can be used without further cleaning.

Example 7

2-(4,6-dimethoxy-2-pyrimidinyloxy)-3-acetylamino-3,3-diphenyl-propionic acid (I-174)

1 g (2.2 mmol) of methyl 2-(4,6-dimethoxy-2-pyrimidinyloxy)-3-acetylamino-3,3-diphenylpropionate is added to a mixture of 8.8 ml of dioxane and 4.4 ml of 1N potassium hydroxide and stirred for one hour at 80°C. Cool, add water and then extract once with ether. It is then acidified and extracted with methyl tert.butyl ether. The combined organic phases are dried over magnesium sulfate and the solvent is distilled off. The residue was mixed with ether, which allowed the isolation of 640 mg (1.5 mmol, yield 67%) of crystals.

Melting point° 120-121°C

ESI-MS M+ = 43'7

Example 8

Methyl 2-(4-methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-yloxy)-3-azido-diphenylpropionate

7443 mg (5.4 mmol) of potassium carbonate, 2.5 g (10.8 mmol) of 4-methoxy-6,7-dihydro-5H-cyclopenta-2-methylsulfonyl-pyrimidine and 3.0 g (10.8 mmol ) of methyl 2-hydroxy-3-azido-3,3-diphenylpropionate was mixed in 20 ml of DMF. The mixture is stirred for three hours at 60°C. Cool and add water and then extract with ethyl acetate. The combined organic phases are dried over magnesium sulfate and then the solvent is distilled off. 3.7 g (8.3 mmol, yield 77%) of crystals were isolated, which immediately reacted further.

Example 9

2-(4-Methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-yloxy)-3-azido-diphenylpropionic acid (I-518)

3.7 g (8.3 mmol) of methyl 2-(4-methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-yloxy)-3-azido-diphenylpropionate was added to a mixture of 33 ml of dioxane and 17 ml of 1N potassium hydroxide solution and then the mixture is stirred first for two hours at 50°C and then for 12 hours at room temperature. Water is added and impurities are extracted with ether. It is acidified and then extracted with ether. The combined organic phases are dried over magnesium sulfate and the solvent is distilled off. The residue is crystallized from ether/n-hexane, which gives 2.6 g (5 mmol, yield 60%) of crystals. Melting point: 143-144°C

ESI-MS: M+ = 431

Example 10

The following compounds were produced in the same manner as described in the above examples.

2-(4,6-dimethoxy-2-pyrimidinyloxy)-3-amino-3,3-diphenyl-propionic acid (I-354)

Melting point: l59 -160°C

ESI-MS: M+ = 395

2-(4-methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-yloxy)-3-amino-3,3-diphenyl-propionic acid (I-334)

Melting point: 119-120°C

ESI-MS: M + =405

2-(4,6-dimethoxy-2-pyrimidinyloxy)-3-methoxyacetylamino-3,3-diphenyl-propionic acid (I-535)

Melting point: 187-188°C

ESI-MS: M+ = 467

2-(4,6-dimethoxy-2-pyrimidinyloxy)-3-(2,2-dimethyl-propylcarbonylamino)-3,3-diphenyl-propionic acid (I-388)

Melting point: 198-199°C

1H-NMR (200 MHz): 7.5 ppm, (2H, m); 7.2 (8H, m); 6.7 (1H, s); 6.5 (1H, s); 5.7 (1H, s); 3.8 (6H, s); 2.1 (2H, s); 1.0 (9H, s) .

2-(4,6-dimethoxy-2-pyrimidinyloxy)-3-cyclopropyl-carbonylamino)-3,3-diphenyl-propionic acid (I-227)

Melting point: 206-207°C

ESI-MS: M+ = 463

2-(4,6-dimethoxy-2-pyrimidinyloxy)-3-p-nitrobenzoylamino-3,3-diphenylpropionic acid (I-541)

Melting point: 219-220°C

ESI-MS: M+ = 544

In the same way or as described in the general part, the compounds listed in Table 1 can be produced.

Table I

[image]

[image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image]

Example 11

Receptor binding data were measured by the experiment described above for the following compounds listed below.

The results are shown in the following table 2.

Table 2

Receptor binding data (Ki--values)

[image]

Claims (10)

1. Derivative of β-amino or β-azido carboxylic acid of formula I [image] indicated by that R1 represents a tetrazole or a group [image] where R has the following meaning: a) radical OR4, where R 4 represents hydrogen, an alkali metal cation, an alkaline earth metal cation or a physiologically tolerable organic ammonium ion; C3-C8-cycloalkyl, C1-C8-alkyl, unsubstituted or substituted; CH2-phenyl, unsubstituted or substituted; C3-C8-alkenyl or C3-C8-alkynyl, unsubstituted or substituted; phenyl, unsubstituted or substituted; b) a five-membered heteroaromatic system connected via a nitrogen atom, c) group [image] where k has the value 0, 1 and 2, p has the value 1, 2, 3 and 4, a R5 represents C1-C4-alkyl, C3-C8-cycloalkyl, C3-C8-alkenyl, C3-C8-alkynyl or unsubstituted or substituted phenyl, d) radical [image] in which R6 represents C1-C4-alkyl, C3-C8-alkenyl, C3-C8-alkynyl, C3-C8-cycloalkyl, whereby these radicals can carry C1-C4- alkoxy, C1-C4-alkylthio and/or a phenyl radical; C1-C4-haloalkyl or phenyl, unsubstituted or substituted; A is NR 7 R 8 or azido; W and Z (which can be the same or different) are: nitrogen or methine; provided that Q = nitrogen if W and Z are methine; X is nitrogen or CR9 Y is nitrogen or CR10 Q is nitrogen or CR11; provided that X = CR9 and Y is CR10 if Q is nitrogen; R2 and R3 (which can be the same or different) represent: phenyl or naphthyl, unsubstituted or substituted, or phenyl or naphthyl, which are connected to each other in the ortho positions via a direct bond, methylene, ethylenic or ethenyl group, oxygen or sulfur atom or one SO2-, NH or N-alkyl group; C5-C6-cycloalkyl; whereby these radicals can be substituted in each case singly or multiply by halogen, hydroxyl, mercapto, carboxyl, nitro, cyano, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4- alkoxy, C1-C4-alkylthio or C1-C4-haloalkoxy; R7 represents hydrogen, Cl-C8-alkyl, C3-C8-alkenyl or C3-C8-alkynyl, C1-C5-alkylcarbonyl, whereby each of these radicals can in any case be substituted singly or multiply by a radical from the group consisting of: halogen, hydroxyl, mercapto, carboxyl, nitro, amino, cyano, C1-C4-Alkoxy, C3-C6-Alkenyloxy, C3-C6-Alkynyloxy, C1-C4-Alkylthio, C1-C4-Haloalkyloxy, C1-C4-Alkoxycarbonyl, C3-C8-alkylcarbonylalkyl, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, C3-C8-cycloalkyl, hetaryloxy or hetaryl, five- or six-membered, containing one to three nitrogen atoms and/or sulfur or oxygen atom, phenoxy or phenyl, wherein all said aryl radicals are in turn substituted singly or multiply, e.g. singly to triply, with halogen, hydroxyl, mercapto, carboxyl, nitro, cyano, C1-C4-alkyl, C1 -C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, amino, NH (C1-C4-alkyl), N(C1-C4-alkyl)2, phenyl or C1-C4-alkylthio; phenyl or naphthyl, which in each case may be substituted with one or more of the following radicals: halogen, nitro, cyano, hydroxyl, amino, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4- alkoxy, C1-C4- haloalkoxy, phenoxy, C1-C4-alkylthio, carboxyl, NH (C1-C4-alkyl), N(C1-C4-alkyl)2, methylenedioxy or ethylenedioxy; C3-C8-cycloalkyl, whereby these radicals can in any case be substituted singly or multiply with halogen, hydroxyl, mercapto, carboxyl, nitro, cyano, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkenyl, C1-C4-Alkoxy, C1-C4-Alkylthio, C1-C4-Halo-Alkoxy; or R7 is linked to R8 via 4 or 5 CH2 groups to form a five- or six-membered ring; R 8 represents hydrogen, C 1 -C 4 -alkyl; or R8 is linked to R7 via 4 or 5 CH2 groups to form a five- or six-membered ring; R9 and R10 (which may be the same or different) represent: hydrogen, halogen, C1-C4-Alkoxy, C1-C4-HaloAlkoxy, C3-C6-Alkenyloxy, C3-C6-Alkynyloxy, C1-C4-Alkylthio, C1-C4-Alkylcarbonyl, C1-C4-Alkoxycarbonyl, Hydroxyl, NH2, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, whereby these radicals can be substituted with halogen, hydroxyl, mercapto , carboxyl, cyano; or CR9 and CR10 are linked to CR11 as indicated below to form a five- or six-membered ring, R11 is hydrogen, halogen, C1-C4-Alkoxy, C1-C4-Halo-Alkoxy, C3-C6-Alkenyloxy, C3-C6-Alkynyloxy, C1-C4-Alkylthio, C1-C4-Alkylcarbonyl, C1-C4-Alkoxycarbonyl, NH(C1-C4-Alkyl), N(C1-C4-Alkyl)2, Hydroxyl, Carboxyl, Cyano, Amino, Mercapto; C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, whereby these radicals can be unsubstituted or substituted; or CR11 together with CR9 or CR10 forms a five- or six-membered alkylene or alkenylene ring which may be unsubstituted or substituted and in each case one or more methylene groups may be substituted with oxygen, sulfur, -NH or -N(C1-C4- alkyl); and their physiologically tolerable salts, and possible enantiomerically pure and diastereomerically pure forms. 2. The use of β-amino or β-azido carboxylic acid derivatives according to claim 1, characterized in that they are used for the treatment of diseases. 3. Use of compounds I according to claim 2, characterized in that they are used as endothelin receptor antagonists. 4. The use of β-amino or β-azido carboxylic acid derivatives according to claim 1, characterized in that they are used for the production of medicines or for the treatment of diseases in which an elevated level of endothelin appears. 5. The use of β-amino or β-azido carboxylic acid derivatives according to claim 1, characterized in that they are used for the treatment of chronic heart failure, restenosis, high blood pressure, pulmonary hypertension, acute/chronic kidney failure, cerebral ischemia, asthma, benign prostatic hyperplasia and prostate cancer. 6. Use of β-amino or β-azido carboxylic acid derivatives according to claim 1, characterized in that they are used in combination with inhibitors of the renin-angiotensin system such as renin inhibitors, angiotensin II angiotensin inhibitors such as renin inhibitors, angiotensin II antagonists and, in particular, angiotensin-converting enzyme (ACE) inhibitors; mixed ACE/neutral endopeptidase (NEP) inhibitors; β-blockers. 7. Drug preparations for oral, parenteral and intraperitoneal administration, characterized by the fact that, in addition to the usual pharmaceutical excipients, they contain at least one carboxylic acid derivative I according to claim 1. 8. Compound of formula II [image] characterized by the fact that the radicals R1, R2, R3 and A have the meanings specified in claim 1. 9. Use of compounds of formula II [image] in which the radicals R1, R2, R3 and A have the meanings stated in claim 1, indicated by the fact that they are used as starting material for the synthesis of endothelin receptor antagonists. 10. Structural fragment of the formula [image] in which the radicals R1, R2, R3 and A have the meanings stated in claim 1, indicated by the fact that it represents the structural element of the endothelin receptor antagonist.