CA2294050A1 - New .beta.-amino and .beta.-azidocarboxylic acid derivatives, the production thereof and the use thereof as endothelin receptor antagonists - Google Patents

Abstract

The invention relates to carboxylic acid derivatives of formula (I) wherein the constituents have the meaning given in the description. The invention also relates to the production of said derivatives, and to their use as endothelin receptor antagonists.

Description

NEW ~i-AMINO AND (3-AZIDOCARBOXYLIC ACID DERIVATIVES, THE
PRODUCTION THEREOF AND THE USE THEREOF AS ENDOTHELIN
RECEPTOR ANTAGONISTS
The present invention relates to novel carboxylic acid derivates, their preparation and use.
Endothelia is a peptide which is composed of 21 amino acids and which is synthesized and released by vascular endothelium.
Endothelia exists in three isoforms, ET-1, ET-2 and ET-3.
"Endothelia" or "ET" hereinafter refers to one or all isoforms of endothelia. Endothelia is a potent vasoconstrictor and has a strong effect on vessel tone. It is known that this vasoconstriction is caused by binding of endothelia to its receptor (Nature, 332 (1988) 411-415; FEBS Letters, 231, (1988) 440-444, and Biochem. Biophys. Res. Commun., 154, (1988) 868-875).
Increased or abnormal release of endothelia causes persistent vasoconstriction in peripheral, renal and cerebral blood vessels, which may lead to diseases. As reported in the literature, endothelia is involved in a number of diseases. These include:
hypertension, acute myocardial infarct, pulmonary hypertension, , Raynaud's syndrome, cerebral vasospasms, stroke, benign prostate hypertrophy, atherosclerosis, asthma and prostate cancer (J- Vascular Med. Biology 2_, (1990) 207, J. Am. Med. Association 264, (1990) 2868, Nature 344, (1990) 114, N. Engl. J. Med. 322, (1989) 205, N. Engl. J. Med. 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).
At least two endothelia receptor subtypes, ETA and ET$ receptors, have to date been described in the literature (Nature 348, (1990) 730, Nature 348, (1990) 732). Accordingly, substances which inhibit the binding of endothelia to one or both receptors should antogonize the physiological effects of endothelia and therefore represent valuable drugs.
It is an object of the present invention to provide endothelia receptor antagonists which bind to the ETA and/or ET$ receptor.
The invention relates to ~-amino and ~-azido carboxylic acid derivatives of the formula I

A C-CH-0-~~ Q
~ Z=Y

where R1 is tetrazole [sic] or a group O
C-R
I5 where R has the following meaning:
a) a radical OR4, where R4 is:
hydrogen, the cation of an alkali metal, the cation of an alkaline earth metal or a physiologically tolerated organic ammonium ion such as tertiary C1-C4-alkylammonium or the ammonium ion;
C3-Ce-cycloalkyl, C1-CB-alkyl, CHZ-phenyl, which may be substituted by one or more of the following radicals:
halogen, vitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, hydroxyl, C1-C4-alkoxy, mercapto, C1-CQ-alkylthio, amino, NH(C1-C4-alkyl), N(C1-C4-alkyl)2;
C3-Ce-alkenyl or C3-C8-alkynyl, it being possible for these groups in turn to carry one to five halogen atoms;
R4 can furthermore be phenyl which may carry one to five halogen atoms and/or one to three of the following radicals:
vitro, 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;
b) a 5-membered heteroaromatic system linked via a nitrogen atom, such as pyrrolyl, pyrazolyl, imidazolyl and triazolyl, which may carry one or two halogen atoms or one or two C1-C4-alkyl or one or two C1-C4-alkoxy groups;
c) a group (~~)k -O- ( CHZ )p S R5 where k can assume the values 0, 1 and 2, p the values 1, 2, 3 and 4, and R5 is C1-C4-alkyl, C3-C8-cycloalkyl, C3-C8-alkenyl, C3-CB-alkynyl or phenyl, which may be substituted by one or more, eg. one to three, of the following radicals:
d) a radical O

O

where R6 is C1-C4-alkyl, C3-C8-alkenyl, C3-Ce-alkynyl, C3-CB-cycloalkyl, it being possible for these radicals to carry a C1-C4-alkoxy, C1-CQ-alkylthio and/or a phenyl radical as mentioned under C);
C1-C4-haloalkyl or phenyl, unsubstituted or substituted in particular as mentioned under C).
The other substitutents have the following meanings:
A is NR~Re or azido;
f,,t and Z (which may be identical or different) are:
nitrogen or methine; with the proviso that Q = nitrogen if W
and Z = methine;
g is nitrogen or CR9;
Y is nitrogen or CRlo;
Q is nitrogen or CR11; with the proviso that X = CR9 and Y =
CRlo if Q = nitrogen R2 and R3 (which may be identical or different) are:
phenyl or naphthyl, each of which may substituted by one or more of the following radicals: halogen, vitro, cyano, hydroxyl, mercapto, C1-C4-alkyl, CZ-C4-alkenyl, C2-C4-alkynyl, C1-C4-hydroxyalkyl, C1-C4-haloalkyl, C1-CQ-alkoxy, phenoxy, C1-C4-haloalkoxy, C1-C4-alkylthio, amino, NH(C1-C4-alkyl), N(C1-C4-alkyl)z or phenyl which may be substituted one or more times, eg. one to three times, by halogen, vitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy or C1-C4-alkylthio; or phenyl or naphthyl which are linked together in ortho Positions by a direct linkage, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an 502, NH or N-alkyl group;
CS-C6-cycloalkyl, it being possible for these radicals to be substituted in each case one or more times by: halogen, hydroxyl, mercapto, carboxyl, vitro, cyano, C1-C4-alkyl, CZ_C4-alkenyl, CZ-C4-alkynyl, C1-C4-alkoxy, C1-C4-alkylthio, C1-C4-haloalkoxy;
R~ is hydrogen, C1-Ce-alkyl, C3-Cs-alkenyl or C3-CB-alkynyl, C1._C5-alkylcarbonyl, it being possible for these radicals to be substituted in each case one or more times by: halogen, hydroxyl, mercapto, carboxyl, vitro, amino, cyano, C1-C4-alkoxy, C3-C6-alkenyloxy, C3-C6-alkynyloxy, C1-C4-alkylthio, C1-C4-haloalkoxy, C1-C4-alkoxycarbonyl, C3-Ce-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 one sulfur or oxygen atom, phenoxy or phenyl, it being possible for all said aryl radicals in turn to be substituted one or more times, eg. one to three times, by halogen, hydroxyl, mercapto, carboxyl, vitro, cyano, C1-CQ-alkyl, C1-C4-haloalkyl, C1-CQ-alkoxy, C1-C4-haloalkoxy, amino, NH(C1-C4-alkyl), N(C1-C4-alkyl)z, phenyl, or C1-C4-alkylthio;
phenyl or naphthyl, which can in each case be substituted by one or more of the following radicals: halogen, vitro, cyano, hydroxyl, amino, C1-C4-alkyl, C1-CQ-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, phenoxy, C1-C4-alkylthio, carboxyl, NH(C1-C4-alkyl), N(C1-C4-alkyl)Z, dioxomethylene [sic] or dioxoethylene [sic];

C3-C$-cycloalkyl, it being possible for these radicals to be substituted in each case one or more times by: halogen, hydroxyl, mercapto, carboxyl, nitro, cyano, C1-C4-alkyl, Cz_C4-alkenyl, CZ-C4-alkynyl, C1-C4-alkoxy, C1-C4-alkylthio, 5 C1-C4-haloalkoxy or;
R~ is linked to R8 via 4 or 5 CH2 groups to give a 5- or 6-membered ring;
IO R8 is hydrogen, C1-C4-alkyl;
or RB is linked to R~ via 4 or 5 CHZ groups to give a 5- or 6-membered ring;

R9 and Rlo(which may be identical or different) are:
hydrogen, halogen, C1-C4-alkoxy, C1-CQ-haloalkoxy, C3_C6-alkenyloxy, C3-C6-alkynyloxy, C1-C4-alkylthio, 20 C1_C4-alkylcarbonyl, C1-C4-alkoxycarbonyl, hydroxyl, NHZ, NH(C1-C4-alkyl), N(C1-C4-alkyl)2 C1-C4-alkyl, CZ-C4-alkenyl, C2-C4-alkynyl, it being possible for these radicals to be substituted by halogen, hydroxyl, 25 mercapto, carboxyl, cyano;
or CR9 or CRlo is linked to CR11 as indicated for R11 to give a 5- or 6-membered ring, 30 R11 is hydrogen, halogen, C1-C4-alkoxy, C1-C4-haloalkoxy, C3-C6-alkenyloxy, C3-C6-alkynyloxy, C1-C4-alkylthio, C1-C4-alkylcarbonyl, C1-C4-alkoxycarbonyl, NH(C1-C4-alkyl), N(C1-C4-alkyl)Z, hydroxyl, carboxyl, cyano, amino, mercapto;
35 C1-C4-alkyl, C2-C4-alkenyl, CZ-C4-alkynyl, it being possible for these radicals to be substituted one or more times by:
halogen, hydroxyl, mercapto, carboxyl, cyano, amino, C1-C4-alkoxy;
or CR11 forms together with CR9 or CRlo a 5- or 6-membered alkylene- or alkenylene ring which may substituted by one or two C1-C4-alkyl groups, and in which in each case one or more methylene groups may be replaced by oxygen, sulfur, -NH or -N(C1-C4-alkyl)I

' 005048085 CA 02294050 1999-12-17 The definitions applying herein and hereafter are:
An alkali metal is, for example, lithium, sodium, potassium;
An alkaline earth metal is, for example, calcium, magnesium, barium;
organic ammonium ions are protonated amines such as ethanolamine, diethanolamine, ethylenediamine, diethylamine or piperazine;
C3-Ce-cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl;
I5 C1-CQ-haloalkyl can be linear or branched, eg. 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, 22,2-trichloroethyl or pentafluoroethyl;
C1-C4-haloalkoxy can be linear or branched, eg. difluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, 1-fluoroethoxy, 2~2'difluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-1,1,2-trifluoroethoxy, 2-fluoroethoxy or pentafluoroethoxy;
CI-C4-alkyl can be linear or branched, eg. methyl, ethyl, 1-Propyl, 2-propyl, 2-methyl-2-propyl, 2-methyl-1-propyl, 1-butyl or 2-butyl;
CZ-C4-alkenyl can be linear or branched, eg. ethenyl, 1-propen-3-yl, 1-propen-2-yl, 1-propen-1-yl, 2-methyl-1-propenyl, 1-butenyl or 2-butenyl;
Cz-C4-alkynyl can be linear or branched, eg. 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 eg. methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or 1,1-dimethylethoxy;
C3-C6-alkenyloxy can be linear or branched, eg. allyloxy, 2-buten-1-yloxy or 3-buten-2-yloxy;

' 0050/48085 CA 02294050 1999-12-17 C3-C6-alkynyloxy can be linear or branched eg. 2-propyn-1-yloxy, 2-butyn-1-yloxy or 3-butyn-2-yloxy;
C1-C4-alkylthio can be linear or branched eg. methylthio, ethylthio, propylthio, 1-methylethylthio, butylthio, 1-methylpropylthio, 2-methylpropylthio or 1,1-dimethylethylthio;
C1-C5-alkylcarbonyl can be linear or branched, eg. acetyl, ethylcarbonyl or 2-propylcarbonyl;
C1-CQ-alkoxycarbonyl can be linear or branched, eg.
metoxycarbonyl [sic], ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl or n-butoxycarbonyl;
C3-Ce-alkylcarbonylalkyl can be linear or branched eg.
2-oxo-1-propyl, 3-oxo-1-butyl or 3-oxo-2-butyl C1-CB_alkyl can be linear or branched eg. C1-C9-alkyl, pentyl, hexyl, heptyl or octyl;
C3-C8-alkenyl can be linear or branched, eg. 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-yl;
C3-C$-alkynyl can be linear or branched eg. 1-propyn-1-yl, 1-propyn-3-yl, 1-butyn-4-yl, 2-butyn-4-yl, 2-pentyn-5-yl, 3-hexyn-6-yl, 3-heptyn-7-yl, 2-octyn-8-yl;
Halogen is, for example, fluorine, chlorine, bromine, iodine.
The invention further relates to those compounds from which the compounds of the formula I can be liberated (called prodrugs).
Preferred prodrugs are those whose release takes place under conditions prevailing in certain compartments of the body, eg. in the stomach, intestine, blood circulation, liver.
The compounds I and the intermediates for preparing them, eg. II
and III, may have one or more asymmetrically substituted carbon atoms. Compounds of this type can exist as pure enantiomers or - ~ 005048085 CA 02294050 1999-12-17 pure diastereomers or as mixture thereof. It is preferred to use an enantiomerically pure compound as active ingredient.
The invention further relates to the use of the abovementioned carboxylic acid derivatives to produce drugs, in particular to produce inhibitors of ETA and/or ETB receptors. The novel compounds are suitable as antagonists as defined at the outset.
preparation of compounds of the formula II where A is an azido group (IIa) starts from the epoxides 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 the compounds of the formula III
I5 with the azide in the molar ratio of about 1:1 to 1:7 at from 20 -to 150°C to give IIa.

RZ O Ri H
+ N3Na --~ N3 C OH

III IIa The reaction may also take place in the presence of a diluent.
All solvents which are inert toward the reagents can be used for this purpose.
Examples of such solvents or diluents are aliphatic, alicyclic and aromatic hydrocarbons, each of which may be chlorinated, 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-methylpyrrolidone, sulfoxides and sulfones such as dimethyl sulfoxide and sulfolane.
The reaction is moreover preferably carried out at a temperature in the range from 0°C to the boiling point of the solvent or mixture of solvents.
The presence of a catalyst may be advantageous. Suitable catalysts are strong organic and inorganic acids, and Lewis acids. Examples thereof include sulfuric acid, hydrochloric acid, trifluoroacetic acid, p-toluenesulfonic acid, boron trifluoride etherate and triflates of the rare earths.
The preparation of the novel compounds of the formula I where A
is an azido group (Ia) can be prepared [sic], for example, by reacting the carboxylic acid derivatives of the formula IIa where the substituents have the stated meanings with compounds of the formula IV.
IO Rz W- X W- X
H
IIa + R12 --C/ ~Q ~ N3 C O~/ ~Q

IV Ia Rlz in formula IV is halogen or R13-SOz- where R13 can be C1-C4-alkyl, C1-CQ-haloalkyl or phenyl, and the conditions [sic]
specified at the outset apply to W,X,Y,Z and Q. The reaction Preferably takes place in an inert solvent or diluent with the addition of a suitable base, ie. a base which effects deprotonation of the intermediate IIa, at a temperature in the range from room temperature to the boiling point of the solvent.
Compounds of the formula IV are known, and some of them can be bought or can be prepared in a generally known manner.
Compounds of type Ia with R1 = COON can be obtained directly by deprotonating the intermediate IIa where R1 is COOH with two equivalents of a suitable base, and reacting with compounds of the formula IV. This reaction also takes place in an inert solvent and at a temperature in the range from room temperature to the boiling point of the solvent.
The base which can be used is an alkali metal or alkaline earth metal hydride such as sodium hydride, potassium hydride or calcium hydride, a carbonate such as alkali metal carbonate, eg.
sodium or potassium carbonate, an alkali metal or alkaline earth metal hydroxide such as sodium or potassium hydroxide, an organometallic compound such as butyllithium, or an alkali metal amide such as lithium diisopropylamide or lithium amide.
Novel compounds of the formula I where A is an amino group (Ib) are prepared starting from compounds Ia. This is done by reacting the compounds of the formula Ia with hydrogen in the presence of a catalyst such as palladium or platinum in a solvent at from 20 to 100°C. The compounds Ia can also be converted into Ib in the presence of triphenylphosphine.
5 Rz R2 W-X W-X
H
N3 C 0 ~~ \ Q ~ H2N C 0 --~~ \ Q
Z- Y
Ia R3 Rl Z Y Ib R3 R1 If R1 is an ester, the amino group in Ib can be alkylated or converted into the amide by generally known methods. The ester group can then be cleaved with acid or base to the carboxylic acid.
Compounds of the formula II where A is substituted amine [sic]
(IIc) can also be prepared directly from the epoxide III by opening with an amine. The substances IIc can then be reacted with IV as described above to give the novel compounds I.
Compounds of the formula I can also be prepared by starting from the corresponding carboxylic acids, ie. compounds of the formula I where R1 is COOH, and initially converting these in a conventional way into an activated form, such as a halide, an anhydride or imidazolide, and then reacting the latter with an appropriate hydroxyl compound HOR4 or sulfonamide H2NSOzR6. This reaction can be carried out in the usual solvents and often requires addition of a base, in which case those mentioned above are suitable. These two steps can also be simplified, for example, by allowing the carboxylic acid to act on the hydroxyl compound or the sulfonamide in the presence of a dehydrating agent such as a carbodiimide.
Compounds of the formula I can also be prepared in addition by starting from salts of the corresponding carboxylic acids, ie.
from compounds of the formula I where R1 is COR and R is OM [sic]
where M can be an alkali metal cation or the equivalent of an alkaline earth metal cation. These salts can be reacted with many compounds of the formula R-D where D is a usual nucleofugic leaving group, for example halogen such as chlorine, bromine, iodine or aryl- or alkylsulfonyl which is unsubstituted or substituted by halogen, alkyl or haloalkyl, eg. toluenesulfonyl and methylsulfonyl, or another equivalent leaving group.
Compounds of the formula R-D with a reactive substituent D are known or can easily be obtained with general expert knowledge.
This reaction can be carried out in conventional solvents, advantageously with the addition of a base, in which case those mentioned above are suitable. Compounds of the formula I where R1 is tetrazole [sic] can be prepared by methods similar to those described in WO 96/11914 from the corresponding carboxylic acids (formula I with R1 = COOH).
It is necessary in some cases to use generally known protective group techniques to prepare the novel compounds I. If, for example, A is to be HOCHZCONH-, the hydroxyl group can initially be protected as benzyl ether, which is then cleaved at a suitable stage in the reaction sequence.
Compounds of the formula I and II can be obtained in enantiomerically pure form by carrying out a classical racemate resolution with suitable enantiomerically pure bases, as described, for example, in WO 96/11914, on racemic or diastereomeric compounds of the formula I and II.
With a view to the biological effect, preferred carboxylic acid derivatives of the formula I, both as pure enantiomers and pure diastereomers or as mixture thereof, are those where the substituents have the following meanings:
A is NR~RB or azido;
w and Z, (which may be identical or different) are:
nitrogen or methine; with the proviso that Q = nitrogen if W
and Z = methine;
X is nitrogen or CR9;
Y is nitrogen or CRla;
Q is nitrogen or CR11; with the proviso that X = CR9 and Y =
CRlo if Q = nitrogen;
furthermore Q for which, in addition to the stated conditions, the following applies: Y = CR1~ or X = CR9 if Q = CR11.
R2 and R3 (which may be identical or different) are:
Phenyl or naphthyl, each of which may substituted by one or more of the following radicals: halogen, cyano, hydroxyl, mercapto, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, phenoxy, C1-C4-haloalkoxy, C1-C4-alkylthio, amino, NH(C1-C4-alkyl), _ ' 0050/48085 CA 02294050 1999-12-17 N(C1-C4-alkyl)2 or phenyl which may be substituted one or more times, eg. one to three times, by halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy or C1-C4-alkylthio; or phenyl or naphthyl which are linked together in orthopositions via a direct linkage, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an S02-, NH- or N-alkyl group;
IO
R~ is hydrogen, C1-Ce-alkyl, C3-Ce-alkenyl or C3-CB-alkynyl, C1_C5-alkylcarbonyl, it being possible for these radicals to be substituted in each case one or more times by: halogen, I5 hydroxyl, mercapto, carboxyl, amino, cyano, C1-C4-alkoxy, C3-C6-alkenyloxy, C3-C6-alkynyloxy, C1-C4-alkylthio, C1-CQ-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 20 and/or one sulfur or oxygen atom, phenoxy or phenyl, it being possible for all said aryl radicals in turn to be substituted one or more times, eg. one to three times, by halogen, hydroxyl, mercapto, carboxyl, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C9-haloalkoxy, amino, 25 NH(C1-C4-alkyl), N(C1-C4-alkyl)2, or C1-C4-alkylthio;
phenyl or naphthyl, which can in each case be substituted by one or more of the following radicals: halogen, cyano, hydroxyl, amino, C1-C4-alkyl, C1-C4-haloalkyl, phenoxy, 30 Ci-C4-alkoxy, C1-C4-haloalkoxy, C1-C4-alkylthio, dioxomethylene [sic], NH(C1-C4-alkyl), N(C1-C4-alkyl)Z or dioxoethylene (sic];
C3-CB-cycloalkyl, it being possible for these radicals to be 35 substituted in each case one or more times by: halogen, hydroxyl, mercapto, carboxyl, C1-C4-alkyl, Cz_CQ-alkenyl, Cz-C4-alkynyl, C1-C4-alkoxy, C1-CQ-alkylthio, C1-C4-haloalkoxy;
Re is hydrogen;
R9 and Rlo(which may be identical or different) hydrogen, halogen, C1_C4-alkoxy, C1-C4-haloalkoxy, Ci-C4-alkylthio, NH(C1-C4-alkyl), N(C1-C4-alkyl)2;

_ ~ 0050/480$5 CA 02294050 1999-12-17 C1-C4-alkyl, CZ-C4-alkenyl, it being possible for these radicals to be substituted by halogen, hydroxyl, mercapto, cyano;
or CR9 or CRlo is linked to CR11 as indicated for R11 to give a 5- or 6-membered ring;
R11 is hydrogen, halogen, C1_C4-alkoxy, C1-C4-haloalkoxy, IO C1-CQ-alkylthio, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, cyano;
C1-C4-alkyl, CZ-C4-alkenyl, it being possible for these radicals to be substituted in each case one or more times by:
halogen, cyano, C1-C4-alkoxy;
I5 or CR1I forms together with CR9 or CRlo a 5- or 6-membered alkylene or alkenylene ring which may be substuituted by one or two C1-C4-alkyl groups, and in which in each case one or more methylene groups can be replaced by oxygen, sulfur, -NH
or -N(C1-C4-alkyl);
Particularly preferred compounds of the formula I, both as pure enantiomers and pure diastereomers or as mixture thereof, are those where the substituents have the following meanings:
A is NR~RB or azido;
W and Z (which may be identical or different) are:
nitrogen or methine; with the proviso that Q = nitrogen if W
and Z = methine;
X is nitrogen or CR9;
Y is nitrogen or CRlo;
Q is nitrogen or CR11; with the proviso that X = CR9 and Y =
CRlo if Q = nitrogen, and Y = CRlo or X = CR9 if Q = CR11;
R2 and R3 (which may be identical or different) are:
phenyl which may be substituted by one or more of the following radicals: halogen, C1-CQ-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, phenoxy, C1-C4-alkylthio, NH(C1-C4-alkyl), N(C1-C4-alkyl)2 or phenyl which can be substituted one or more times, eg. one to three times, by halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy or C1-C4-alkylthio; or phenyl groups which are linked together in orthopositions by a direct linkage, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an S02, NH or N-alkyl group;
R7 is hydrogen, C1-Ce-alkyl, C3-Ce-alkenyl or C3-Ce-alkynyl, C1-CS-alkylcarbonyl, it being possible for these radicals to be substituted in each case one or more times by: halogen, hydroxyl, carboxyl, amino, C1-C4-alkoxy, C1-C4-alkylthio, C1-C4-alkoxycarbonyl, NH(C1-C4-alkyl), N(C1-C4-alkyl)z, C3-C8-cycloalkyl, hetaryloxy or hetaryl, five- or I5 six-membered, containing one to three nitrogen atoms and/or one sulfur or oxygen atom, phenoxy or phenyl, it being possible for said aryl radicals in turn to be substituted one or more times, eg. one to three times, by halogen, hydroxyl, mercapto, carboxyl, cyano, C1-CQ-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 can be substituted by one or more of the following radicals: halogen, cyano, Ci-Ca-alkyl, C1-C4-haloalkyl, phenoxy, C1-C4-alkoxy, C1-C4-alkylthio, dioxomethylene (sic] or dioxoethylene [sic];
C5-C6-cycloalkyl, it being possible for these radicals in each case to be substituted one or more times by: C1-C4-alkyl, C1-C4-alkoxy;
R8 is hydrogen;
R9 and R1~(which may be identical or different) are:
hydrogen, C1-C4-alkoxy, C1-CQ-alkylthio, N(C1-C4-alkyl)2;
C1-C4-alkyl, it being possible for these radicals to be substituted by halogen;
or CR9 or CR1~ is linked to CR11 as indicated for R11 to give a 5- or 6-membered ring;
R11 is hydrogen, C1-C4-alkoxy, C1-C4-alkylthio, cyano;

C1-C4-alkyl, it being possible for these radicals in each case to be substituted one or more times by halogen;
or CR11 forms together with CR9 or CR1~ a 5- or 6-membered 5 alkylene or alkenylene ring which may be substituted by one or two C1-C4-alkyl groups and in which, in each case, one or more methylene groups can be replaced by oxygen, sulfur, -NH
or -N(C1-C4-alkyl);

10 The compounds of the present invention offer a novel potential treatment of hypertension, pulmonary hypertension, myocardial infarct, chronic heart failure, angina pectoris, acute/chronic kidney failure, renal insufficiency, cerebral vasospasms, 15 cerebral ischemia, subarachnoid hemorrhages, migraine, asthma, atherosclerosis, endotoxic shock, endotoxin-induced organ failure, intravascular coagulation, restenosis after angioplasty, benign prostate hyperplasia, ischemic and intoxication-induced kidney failure or hypertension, cyclosporin-induced kidney failure, metastasis and growth of mesenchymal tumors, cancer, prostate cancer, contrast agent-induced kidney failure, pancreatitis, gastrointestinal ulcers.
The invention further relates to combination products consisting 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, in particular, angiotensin converting enzyme (ACE) inhibitors.
The combinations can be administered together in one pharmaceutical form or temporally and spatially separate.
The factors to be taken into account in respect of dosage and mode of administration are the same as for the corresponding single substances.
These combination products are particularly suitable for treating and preventing hypertension and its sequelae, and for treating heart failure.
The invention further relates to the use of the novel compounds for photoaffinity labeling of endothelin receptors. Particularly suitable for this purpose are those compounds of the formula I
where A is azido.

' 005048085 CA 02294050 1999-12-17 The good effect of the compounds can be shown in the following tests:
Receptor-binding studies Cloned human ETA or ETB receptor-expressing CHO cells were employed for binding studies.
Membrane preparation The ETA or ET$ receptor-expressing CHO cells were grown 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 ~.g/ml streptomycin (Gibco, Sigma No. P-0781). After 48 hours, the cells were washed with PBS and incubated with 0.05 trypsin-containing PBS at 37~C for 5 minutes. This was followed by neutralization with medium, and the cells were collected by centrifugation at 300 x g.
For membrane preparation, the cells were adjusted to a concentration of 10$ cells/ml of buffer (50 mM Tris~HC1 buffer, pH
7.4) and then disintegrated with ultrasound Branson Sonifier 250, 40-70 seconds/constant/output [sic] 20).
Binding assays For the ETA and ETB receptor-binding assay, the membranes were suspended in incubation buffer (50 mM Tris-HC1, pH 7.4 with 5 mM
MnClz, 40 ~,g/ml bacitracin and 0.2~ BSA) in a concentration of 50 ~g of protein per assay mixture and incubated with 25 pM
[125I]-ET1 (ETA-receptor assay) or 25 pM [125I]-ET3 (ETe receptor assay) in the presence and absence of test substance at 25~C. The nonspecific binding was determined using 10-~ M ET1. After 30 min, filtration through GF/B glass fiber filters (Whatman, England) in a Skatron cell collector (Skatron, Lier, Norway) separated free and bound radio ligand, and the filters were washed with ice-cold Tris-HC1 buffer, pH 7.4 with 0.2% BSA. The radioactivity collected on the filters was quantified using a Packard 2200 CA
liquid scintillation counter.

Testing of ET antagonists in vivo:
Male SD rats weighing 250 - 300 g were anesthetized with amobarbital, artificially ventilated, vagotomized and pithed. The carotid artery and jugular vein were cathetized.
In control animals, intravenous administration of 1 ~g/kg ET1 results in a marked rise in blood pressure which persists for a lengthy period.
The test animals received i.v. injection (1 ml/kg) of the test compounds 30 min before administration of ET1. To determine the ET-antagonistic properties, the changes in blood pressure in the test animals were compared with those in the control animals.
Oral testing of ET receptor antagonists:
Male normotensive rats (Sprague Dawley, Janvier) weighing 250-350 g are pretreated with the test substances orally.
80 minutes later, the animals are anesthetized with urethane, and the carotid artery (for measuring the blood pressure) and the jugular vein (administration of big endothelin/endothelin 1) are catheterized.
After a stabilization period, big endothelin (20 ~,g/kg, admin.
vol. 0.5 ml/kg) or ET1 (0.3 ~g/kg, admin. vol. 0.5 ml/kg) is given intravenously. Blood pressure and heart rate are recorded continuously for 30 minutes. The marked and long-lasting changes in blood pressure are calculated as the area under the curve (AUC). To determine the antagonistic effect of the test substances, the AUC for the animals treated with substance is compared with the AUC for the control animals.
The novel compounds can be administered orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperitoneally) in a conventional way. Administration can also take place with vapors or sprays through the nasopharyngeal space.
The dosage depends on the age, condition and weight of the patient and on the mode of administration. As a rule, the daily dose of active ingredient is from about 0.5 to 50 mg/kg of body weight on oral administration and from about 0.1 to 10 mg/kg of body weight on parenteral administration.

The novel compounds can be administered in conventional solid or liquid pharmaceutical forms, eg. as uncoated or (film-)coated tablets, capsules, powders, granules, suppositories, solutions, ointments, creams or sprays. These are produced in a conventional way. The active ingredients can for this purpose be processed with conventional pharmaceutical aids such as tablet binders, bulking agents, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, release-slowing agents, antioxidants and/or propellant gases (cf. H. Sucker et al.: Pharmazeutische Technologic, Thieme-Verlag, Stuttgart, 1991). The administration forms obtained in this way normally contain from 0.1 to 90% by weight of active ingredient.
Synthesis Examples Example 1:
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 were introduced into 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 at room temperature for 48 hours. The mixture was concentrated, water was added, and the aqueous phase was extracted several times with ethyl acetate.
The combined organic phases were then dried over magnesium sulfate, the solvent was distilled off, and the residue was purified by chromatography. 1.2 g (4 mmol, 21% yield) of pure product were isolated.
Melting point: 102-103°C
iH-NMR (200 MHz): 7.2 ppm (10 H, m), 5.1 (1 H, d), 3.5 (3 H, s), 3.4 (1 H, 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-2-methylsulfonylpyrimidine and 2.0 g (6.7 mmol) of methyl 2-hydroxy-3-azido-3,3-diphenylpropionate were mixed in 20 ml of DMF. The mixture was stirred at 80°C far two hours. Cooling and addition of water were followed by extraction with ethyl acetate. The combined organic phases were dried over magnesium sulfate, and the solvent was distilled off.
2.9 g of a crude oil were isolated and were immediately reacted further.
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 of methanol/ethyl acetate, and a spatula tip of palladium on carbon was added. After the apparatus had been flushed with nitrogen and then with hydrogen, the solution was stirred under atmospheric pressure at room temperature for three hours. After conversion was complete, the palladium on carbon was filtered off and the solvent was distilled off. 2.9 g of crystals were isolated and immediately reacted further.
Example 4:
2_(4-Methoxy-6-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 were added to a mixture of 6.4 ml of dioxane and 3.2 ml of 1 N potassium hydroxide solution, and the mixture was stirred at 80°C for two hours. Cooling, addition of water and acidification were followed by extraction with ethyl acetate. The combined organic phases were dried over magnesium sulfate, and the solvent was distilled off. The residue was stirred with ether, which allowed 190 mg (0.5 mmol, 25~ yield) of crystals to be isolated.
1H-NMR(360 MHz/DMSO/303K): 7.7 ppm (1 H, broad), 7.4 (4 H, m), 7.2 (6 H, m), 5.9 1 H, broad), 5.1 (1 H, s), 3.2 (3 H, broad), 2.1 (3 H, s).
1H-NMR (360 MHz/DMSO/323 K): 7.7 PPm [sicJ (1 H, broad), 7.4 (4 H, m), 7.2 (6 H, m), 5.9 (1 H, s), 5.1 (1 H, s), 3.2 (3 H, s), 2.1 (3 H, s).

Example 5:
2-(4,6-Dimethoxy-2-pyrimidinyloxy)-3-azido-3,3-diphenylpropionic acid (I-542) 1.1 g (2.5 mmol) of methyl 2-(4,6-dimethoxy-2-pyrimidinyloxy)-3-azido-3,3-diphenylpropionate were added to a mixture of 11 ml of dioxane and 5 ml of 1 N potassium hydroxide solution, and the 10 mixture was stirred at 50°C for three hours. Cooling, addition of water and acidification were followed by extraction with ether.
The combined organic phases were dried over magnesium sulfate, and the solvent was distilled off. 900 mg (2.1 mmol, 85~ yield) of crystals were isolated.
Melting point: 164-165°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-diphenylpropionate were dissolved in 10 ml of pyridine. While cooling in ice, 0.26 ml (3.7 mmol) of acetyl chloride was added dropwise, and the mixture was stirred at room temperature for 12 hours. Water was added, and the mixture was extracted with ether. The combined organic phases were dried over magnesium sulfate, and the solvent was distilled off. The residue was mixed with ether, and the compound starts to crystallize out after a short time (1 g, 2~2 mmol, 90o yield). The compound could be used further without further purification.
Example 7:
2_(4,6-Dimethoxy-2-pyrimidinyloxy)-3-acetylamino-3,3-diphenylpropionic acid (I-174) 1 g (2.2 mmol) methyl 2-(4,6-dimethoxy-2-pyrimidinyloxy)-3-acetylamino-3,3-diphenylpropionate was added to a mixture of 8.8 ml of dioxane and 4.4 ml of 1 N potassium hydroxide solution, and the mixture was stirred at 80°C for one hour. Cooling and addition of water were followed by extraction once with ether.
Acidification was then followed by extraction with methyl tert -butyl ether. The combined organic phases were dried over magnesium sulfate, and the solvent was distilled off. The residue was stirred with ether to allow isolation of 640 mg (1.5 mmol, 67~ yield) of crystals.
Melting point: 120-121°C
ESI-MS: M* = 437 Example 8:
Methyl 2-(4-methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-yloxy)-3-azido-3,3-diphenylpropionate 743 mg (5.4 mmol) of potassium carbonate, 2.5 g (10.8 mmol) of 4-methoxy-6,7-dihydro-5H-cyclopenta-2-methylsulfonylpyrimidine and 3.0 g (10.8 mmol) of methyl 2-hydroxy-3-azido-3,3-diphenylpropionate were mixed in 20 ml of DMF. The mixture was stirred at 60°C for three hours. Cooling and addition of water were followed by extraction with ethyl acetate. The combined organic phases were dried over magnesium sulfate, and the solvent was distilled off. 3.7 g (8.3 mmol, 77~ yield) of crystals were isolated and were immediately reacted further.
Example 9:
2-(4-Methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-yloxy)-3-azido-3,3-diphenylpropionic acid (I-518) 3.7 g (8.3 mmol) of methyl 2-(4-methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-yloxy)-3-azido-3,3-diphenylpropionate were added to a mixture of 33 ml of dioxane and 17 ml of 1 N potassium hydroxide solution, and the mixture was stirred firstly at 50°C
for two hour [sic] and then at room temperature for 12 hours.
Water was added, and impurities were extracted with ether.
Acidification was then followed by extraction with ether. The combined organic phases were dried over magnesium sulfate, and the solvent was distilled off. The residue was crystallized from ether/n-hexane, allowing 2.6 g (5 mmol, 60~ yield) of crystals to be isolated.
Melting point: 143-144°C

ESI-MS: M* = 431 Example 10:
The following compounds were prepared in a similar way to the examples described above.
2-(4,6-Dimethoxy-2-pyrimidinyloxy)-3-amino-3,3-diphenylpropionic acid (I-354) Melting point: 159-160°C
ESI-MS: M+ = 395 2-(4-Methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-yloxy)-3-amino-3,3-diphenylpropionic acid (I-334) Melting point: 119-120°C
ESI-MS: M+ = 405 2-(4,6-Dimethoxy-2-pyrimidinyloxy)-3-methoxyacetylamino-3,3-diphenylpropionic 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-diphenylpropionic [sic] acid (I-388) Melting point: 198-199°C
1H-NMR(200 MHz): 7.5 ppm (2 H, m), 7.2 (8 H, m), 6.7 (1H, s), 6.5 (1 H, s), 5.7 (1 H, s), 3.8 (6 H, s), 2.1 (2 H, s), 1.0 (9 H, s).
2-(4,6-Dimethoxy-2-pyrimidinyloxy)-3-cyclopropylcarbonylamino-3,3-diphenylpropionic 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 [sic]

_ ~ 005048085 CA 02294050 1999-12-17 ESI-MS: M+ = 544 The compounds listed in Table 1 can be prepared in a similar way or as described in the general part.
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Example 11 Receptor binding data were measured by the binding assay described above for the compounds listed below.
The results are shown in Table 2.
Table 2 Receptor binding data (Ki values) Compound ETA (nM/1] ETB [nM/1]

I-174 83 >7000 I_354 50 >6400 I-541 1000 >7000

Claims (10)

We claim:

1. A .beta.-amino or .beta.-azido carboxylic acid derivative of the formula I

where R1 is tetrazole [sic] or a group where R has the following meaning:
a) a radical OR4, where R4 is:
hydrogen, the cation of an alkali metal,, the cation of an alkaline earth metal or a physiologically tolerated organic ammonium ion;
C3-C8-cycloalkyl, C1-C8-alkyl, unsubstituted or substituted, CH2-phenyl, unsubstituted or substituted, C3-C8-alkenyl or a C3-C8-alkynyl, unsubstituted or substituted, or phenyl, unsubstituted or substituted, b) a 5-membered heteroaromatic system linked via a nitrogen atom, c) a group where k can assume the values 0, 1 and 2, p the values 1, 2, 3 and 4, and R5 is C1-C4-alkyl, C3-C8-cycloalkyl, C3-C8-alkenyl, C3-C8-alkynyl or unsubstituted or substituted phenyl, d) a radical where R6 is:
C1-C4-alkyl, C3-C8-alkenyl, C3-C8-alkynyl, C3-C8-cycloalkyl, it being possible for these radicals to carry a C1-C4-alkoxy, C1-C4-alkylthio and/or a phenyl radical;
C1-C4-haloalkyl or phenyl, unsubstituted or substituted.
A is NR7R8 or azido;
W and Z (which may be identical or different) are:
nitrogen or methine; with the proviso that Q = nitrogen if W and Z = methine;
X is nitrogen or CR9;
Y is nitrogen or CR10;
Q is nitrogen or CR11; with the proviso that X = CR9 and Y =
CR10 if Q = nitrogen;

R2 and R3 (which may be identical or different) are:
phenyl or naphthyl, unsubstituted or substituted, or phenyl or naphthyl which are linked together in ortho positions by a direct linkage, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an SO2, NH
or N-alkyl group, C5-C6-cycloalkyl, unsubstituted or substituted;
R7 is hydrogen, C1-C8-alkyl, C3-C8-alkenyl, C3-C8-alkynyl, C1-C5-alkylcarbonyl, it being possible for these radicals to 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 give a 5- or 6-membered ring;
R8 is hydrogen, C1-C4-alkyl;
or R8 is linked to R7 via 4 or 5 CH2 groups to give a 5- or 6-membered ring;
R9 and R10 (which may identical or different) are:
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, it being possible for these radicals to be unsubstituted or substituted;
or CR9 or CR10 is linked to CR11 as indicated below to give a 5- or 6-membered ring, R11 is hydrogen, halogen, C1-C4-alkoxy, C1-C4-haloalkoxy, 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, it being possible for these radicals to be unsubstituted or substituted;
or CR11 forms together with CR9 or CR10 a 5- or 6-membered alkylene or alkenylene ring which may unsubstituted or substituted, and in which in each case one or more methylene groups may be replaced by oxygen, sulfur, -NH
or -N(C1-C4-alkyl);
and the pysiologically tolerated salts, and the possible enantiomerically pure and diastereoisomerically pure forms.

2. The use of a .beta.-amino or .beta.-azido carboxylic acid derivative as claimed in claim 1 for treating diseases.

3. The use of compounds I as claimed in claim 2 as endothelin receptor antagonists.

4. The use of a .beta.-amino or .beta.-azido carboxylic acid derivative I
as claimed in claim 1 for producing drugs for treating diseases in which elevated endothelia levels occur.

5. The use of a .beta.-amino or .beta.-azido carboxylic acid derivative I
as claimed in claim 1 for treating chronic heart failure, restenosis, high blood pressure, pulmonary hypertension, acute/chronic kidney failure, cerebral ischemia, benign prostate hyperplasia and prostate cancer.

6. The use of a .beta.-amino and .beta.-azido carboxylic acid derivative I
as claimed in claim 1 in combination with: inhibitors of the renin-angiotensin system such as renin inhibitors, angiotensin II antagonists and, in particular, angiotensin converting enzyme (ACE) inhibitors; mixed ACE/neutral endopeptidase (NEP) inhibitors; .beta. blockers.

7. A drug formulation for oral, parenteral or intraperenteral [sic] administration comprising per single dose, besides conventional pharmaceutical auxiliaries, at least one carboxylic acid derivative I as claimed in claim 1.

8. A compound of the formula II
where the radicals R1, R2, R3 and A have the meanings stated in claim 1.

9. The use of compounds of the formula II, where the radicals R1, R2, R3 and A have the meanings stated in claim 1, as starting material for synthesizing endothelia receptor antagonists.

10. A structural fragment of the formula where the radicals R1, R2, R3 and A have the meanings stated in claim 1, as structural element in an endothelia receptor antagonist.