CA2302350A1

CA2302350A1 - Novel carboxylic acid derivatives, their production and their use as mixed eta/etb endothelin-receptor antagonists

Info

Publication number: CA2302350A1
Application number: CA002302350A
Authority: CA
Inventors: Wilhelm Amberg; Rolf Jansen; Dagmar Klinge; Hartmut Riechers; Stefan Hergenroder; Manfred Raschack; Liliane Unger
Original assignee: Individual
Current assignee: Abbott GmbH and Co KG
Priority date: 1997-09-04
Filing date: 1998-08-24
Publication date: 1999-03-11
Also published as: AU748610B2; AR017052A1; BR9811631A; CN1269792A; CO4970738A1; PL338954A1; JP2001514254A; HUP0004935A3; BG104222A; WO1999011629A1; KR20010023615A; NO20001077D0; TW546295B; SK1522000A3; HRP980484A2; EP1009741A1; IL134276A0; NO20001077L; ID25620A; TR200000602T2

Abstract

The invention relates to carboxylic acid derivatives of formula (I) wherein the radicals are defined in the description, and to the use of these derivatives as ETA/ETB endothelin-receptor antagonists.

Description

NOVEL CARBOXYLIC ACID DERIVATIVES, THEIR PRODUCTION AND
THEIR USE AS MIXED ETp/ETB ENDOTHELIN-RECEPTOR ANTAGONISTS
The present invention relates to novel carboxylic acid derivatives, their preparation and use.
Endothelia is a peptide which is composed of 21 amino acids and 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 vascular tone. It is known that this vasoconstriction is caused bY the 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 disorders. It is reported in the literature that endothelia is involved in a number of disorders. These include: hypertension, acute myocardial infarct, pulmonary hypertension, Raynaud's syndrome, cerebral vasospasms, stroke, benign prostate hypertrophy, atherosclerosis and asthma (J. Vascular Med. Biology 2_ (1990) 207, J. Am. Med. Association 264 (1990) 2868, Nature 344 (1990) 114, N. eg.. J. Med. 322 (1989) 205, N. eg.. J. Med. 328 (1993) 1732, Nephron 66 (1994) 373, Stroke ~ (1994) 904, Nature 365 (1993) 759, J. Mol. Cell.
Cardiol. 27 (1995) A234; Cancer Research 56 (1996) 663).
The literature at present describes at least two subtypes of endothelia receptors, ETA and ETB receptors, (Nature 348 (1990) 730 and 732). According to this, substances which inhibit the binding of endothelia to the two receptors ought to antagonize the physiological effects of endothelia and therefore represent valuable drugs.
WO 96/11914 describes carboxylic acid derivatives which, however, bind with high affinity to the ETA receptor and with a considerably lower affinity to the ETB receptor (called ETA-specific antagonists).
We~refer here to antagonists as ETA-specific when their affinity for the ETA receptor is at least ten times higher than their affinity for the ETB receptor.
It is an object of the present invention to provide endothelia 0050/48312 ca o23o23so 2000-o2-2s receptor antagonists which bind with roughly the same affinity to the ETA and the ETB receptors (called mixed antagonists).
Roughly the same affinity for the receptors means that the ratio of the affinities is greater than 0.1 and less than 10.
The invention relates to carboxylic acid derivatives of the formula I carboxylic acid derivatives of the formula I [sic]

R6-- Z-C- CH - O - Het I
B R

where the substituents have the following meanings:
R is tetrazole [sic] or a group O
~ C-Ri Ri is a radical ORS
in which R~ is:
hydrogen, the cation of an alkali metal, the cation of an alkaline earth metal or a physiologically tolerated organic ammonium ion;
C3-CB-~cycloalkyl, C1-Ce-alkyl, CH2-phenyl, unsubstituted or substituted, C3-C6-alkenyl or a C3-C6-alkynyl group, unsubstituted or substituted, or phenyl, unsubstituted or substituted, R2 is hydrogen, hydroxyl, NH2, NH(Ci-C9-alkyl), N(Ci-C4-alkyl)2, halogen, C1-C4-alkyl, C2-CQ-alkenyl, CZ-C4-alkynyl, C1-C4-haloalkyl, Ci-C4-alkoxy, C1-CQ-haloalkoxy or C1-C4-alkylthio, or CRZ is linked to CRio as indicated below to give a 5- or 6-membered ring, or, if Het is a five-membered ring, CR2 can together with CR3 be a 5- or - 6-membered alkenyl or alkylenyl [sic] ring which is ' ' 0050/48312 ca o23o23so 2000-o2-2s unsubstituted or substituted;
X is nitrogen or methine;
Y is nitrogen or methine;
W is nitrogen or CR1~, where Rlo is hydrogen or C1_4-alkyl, or CRlo forms together with CR2 or CR3 a 5- or 6-membered alkylene or alkenylene ring which is unsubstituted or substituted and in which in each case one or more methylene groups can be replaced by oxygen, sulfur, -NH or -N(C1_C4_alkyl);
R3 is hydrogen, hydroxyl, NH2, NH(C1-C4-alkyl), N(C1-C4-alkyl)Z, halogen, C1-Cq-alkyl, CZ-C4-alkenyl, CZ-C4-alkynyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1_C4-haloalkoxy, C1-C4-alkylthio; or CR3 is linked to CR1~ as indicated above to give a 5- or 6-membered ring;
R4 and R5 (which may be identical or different) are:
phenyl or naphthyl, unsubstituted or substituted, or phenyl or naphthyl which are linked together in the 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 C3-Cs-cycloalkyl, unsubstituted or substituted;
R6 is hydrogen, C1-CB-alkyl, C3-C8-alkenyl or C3-C$-alkynyl, it being possible for each of these radicals to be substituted 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-alkylcarbonyl, C1-C9-alkoxycarbonyl, C3_8-alkylcarbonylalkyl, NH(C1-C4-alkyl), N(C1-C4-alkyl)Z, 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 said aryl radicals in turn to be substitued one or more times, eg. one to three times, by halogen, hydroxyl, mercapto, carboxyl, vitro, 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-Cq-alkylthio;
phenyl or naphthyl, each of which can be substituted by one 0050/48312 ca o23o23so 2000-o2-2s or more of the following radicals: halogen, nitro, cyano, hydroxyl, amino, Ci-C4-alkyl, C1-C4-haloalkyl, C1-CQ-alkoxy, C1-C4-haloalkoxy, phenoxy, C1-C4-alkylthio, C1-C4-alkylamino, C1-C4-dialkylamino, dioxomethylene [sic] or dioxoethylene [sic];
a five- or six-membered heteroaromatic system comprising one to three nitrogen atoms and/or one sulfur or oxygen atom, which may carry one to four halogen atoms and/or one to two 10 of the following radicals: C1-C4-alkyl, C1-C4-haloalkyl, CI-C4-alkoxy, C1-C4-haloalkoxy, C1-C4-alkylthio, phenyl, phenoxy or phenylcarbonyl, it being possible for the phenyl radicals in turn to carry one to five halogen atoms and/or one to three of the following radicals: C1-C4-alkyl, 15 C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy and/or C1-C4-alkylthio;
C3-CB-cycloalkyl, it being possible for these radicals to be substituted one or more times by: halogen, hydroxyl, 20 mercapto, carboxyl, nitro, cyano, C1-C4-alkyl, CZ-CQ-alkenyl, C2-C4-alkynyl, C1-C4-alkoxy, C1-CQ-alkoxy, C1-C4-alkylthio, C1-CQ-haloalkoxy;
Z is sulfur or oxygen;
B is CZ-C4-alkylene Het is a heterocyclic radical of the formula Ia or Ib N RZ y ~C ~ -C _ W

Ia Ib with T = 0, S, NRs Re is C1-C6-alkyl and the physiologically tolerated salts and the enantiomerically pure forms.
In this connection and hereinafter, the following definitions apply:
An alkali metal is, for example, lithium, sodium, potassium;

'. 0050/48312 ca o23o23so 2000-o2-2s An alkaline earth metal is, for example, calcium, magnesium, barium;
C3-Ce-cycloalkyl is, for example, cyclopropyl, cyclobutyl, 5 cyclopentyl, cyclohexyl, cycloheptyl oder cyclooctyl;
C1-C4-haloalkyl can be linear or branched, such as fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trichlorornethyl, 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;
C1-CQ-haloalkoxy can be linear or branched, such as difluoromethoxy, trifluoromethody, 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;
C1-C4-alkyl can 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-rnethylpropoxy, 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 2-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-C4-alkylcarbonyl can be linear or branched, such as acetyl, ethylcarbonyl or 2-propylcarbonyl;

- '~ 0050/48312 CA 023023s0 2000-o2-Zs C1-C4-alkoxycarbonyl can be linear or branched, such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl or n-butoxycarbonyl;
C3-Ce-alkylcarbonylalkyl can be linear or branched, for example 2-oxo-1-propyl, 3-oxo-1-butyl or 3-oxo-2-butyl C1-C8-alkyl can be linear or branched, such as C1-C4-alkyl, pentyl, hexyl, heptyl or octyl;
halogen ist, for example, fluorine, chlorine, bromine, iodine.
The invention further relates to compounds from which compounds of the formula I can be released (called prodrugs).
Preferred prodrugs are those where the release takes place under conditions like those prevailing in certain compartments of the body, eg. in the stomach, intestine, bloodstream, liver.
The compounds and the intermediates for preparing them, such as II, III and IV, may have one or more asymmetrically substituted carbon atoms. Compounds of this type may exist as pure enantiomers or pure diastereomers or as mixtures 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 for producing drugs, in particular for producing inhibitors of ETA and ETB receptors. The compounds according to the invention are particularly suitable as mixed antagonists as defined at the outset.
Compounds with the formula IV where Z is sulfur or oxygen can be prepared, also in enantiomerically pure form, as described in WO 96/11914.

C~ + R6- Z- H -~ R'S- Z- ~ -CH- OH
B B R
R' II III IV RS
Compounds of the formula III either are known or can be synthesized for example by reducing the corresponding carboxylic acids or esters thereof, or by other generally known methods.

' ~~ 0050/48312 ca o23o23so 2000-o2-2s The compounds according to the invention where the substituents have the meanings stated under formula I can be prepared, for example, by reacting the carboxylic acid derivatives of the formula IV, where the substituents have the stated meaning, with compounds of the formula V.
IV + R11 - Het ~ I
V
R11 in formula V is halogen or R12-SOZ-, where R12 can be C1-C4-alkyl, C1-C4-haloalkyl or phenyl. In addition, at least one of the ring members X or Y or Z is nitrogen. The reaction preferably takes place in an inert solvent or diluent with the addition of a suitable base, i.e. of a base which deprotonates the intermediate IV, at a temperature in the range from room temperature to the boiling point of the solvent.
Compounds of type I with R = COOH can furthermore be obtained directly when the intermediate IV where R is COOH is deprotonated with two equivalents of a suitable base and reacted with compounds of the formula V. 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.
Examples of such solvents and 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, carbon tetrachloride, ethyl chloride and trichloroethylene, ethers such as diisopropyl ether, dibutyl ether, methyl tert-butyl ether, propylene oxide, 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.
Compounds of the formula V are known or, in some cases, can be bought or prepared in a generally known manner.
It is possible to use as base 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.

' ~ 0050/48312 CA 02302350 2000-02-25 Compounds of the formula I can also be prepared by starting from the corresponding carboxylic acids, i.e. compounds of the formula I where R1 is COON, and converting them initially in a conventional way into an activated form, such as an acid halide, anhydride or imidazolide, and then reacting the latter with an appropriate hydroxyl compound HORS. This reaction can be carried out in conventional solvents and often requires addition of a base, in which case those mentioned above are suitable. These two steps can, for example, also be simplified by allowing the carboxylic acid to act on the hydroxyl compound in the presence of a dehydrating agent such as a carbodiimide.
It is additionally possible to prepare compounds of the formula I
by starting from salts of the appropriate carboxylic acids, i.e.
from compounds of the formula I where R1 is a group COR and R is OM where M can be an alkali metal cation or the equivalent of an alkaline earth metal cation. These salts can be reacted with many compounds of the formula R-A, where A is a conventional nucleofugic leaving group, for example halogen such as chlorine, bromine, iodine or unsubstituted or halogen-, alkyl- or haloalkyl-substituted aryl or alkylsulfonyl such as toluenesulfonyl and methylsulfonyl, or another equivalent leaving group. Compounds of the formula R-A with a reactive substituent A
are known or can easily be obtained with general expert knowledge. This reaction can be carried out in conventional solvents and is advantageously carried out with the addition of a base, in which case those mentioned above are suitable.
With a view to the biological effect, preferred carboxylic acid derivatives of the formula I, both as pure enantiomers and pure diastereomers and as mixture thereof, are those where the substituents have the following meanings:
R1 COORS in which R~ is:
hydrogen, the cation of an alkali metal, the cation of an alkaline earth metal or a physiologically tolerated organic ammonium ion;
C3-CB-cycloalkyl, C1-C8-alkyl, CH2-phenyl, unsubstituted or substituted, C3-C6-alkenyl or a C3-C6-alkynyl group, unsubstituted or substituted, or phenyl, unsubstituted or substituted. [sic]

' ' 0050/48312 CA 023023s0 2000-o2-Zs RZ hydrogen, hydroxyl, halogen, N(C1-C4-alkyl)2, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkylthio, C1-C4-haloalkyl, C1-C4-haloalkoxy, or CRZ is linked to CRlo as indicated below to form a 5- or 6-membered ring, or, if Het is a five-membered ring, CRZ can together with CR3 be a 5- or 6-membered alkenyl or alkylenyl [sic] ring which is unsubstituted or substituted;
X nitrogen or methine;
Y nitrogen or methine;
W nitrogen or CRlo, where Rlo is hydrogen or C1_4-alkyl, or CRlo forms together with CR2 or CR3 a 5- or 6-membered alkylene or alkenylene ring which may be substituted by one or two methyl groups and in which in each case a methylene group can be replaced by oxygen or sulfur, such as -CH2-CHZ-0-, -CHZ-CHZ-CHZ-0-, -CH=CH-O-, -CH=CH-CH20-, -CH(CH3)-CH(CH3)-O-, -CH=C(CH3)-O-, -C(CH3)=C(CHg)-O-, Or -C(CH3)=C(CH3)-S;
At least one of the ring members X, Y or W is nitrogen.
R3 hydrogen, hydroxyl, halogen, N(C1-CQ-alkyl)2, Cl-C4-alkyl, C1-C4-alkoxy, C1-C4-alkylthio, C1-C4-haloalkyl, C1-C4-haloalkoxy, or CR3 is linked to CR1~ as indicated above to give a 5- or 6-membered ring, or, if Het is a five-membered ring, CRZ can together with CR3 be a 5- or 6-membered alkenyl or alkylenyl [sicj ring which is unsubstituted or substituted;
R4 and R5 (which may be identical or different):
phenyl or naphthyl, each of which may be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, mercapto, amino, C1-CQ-alkyl, C1-CQ-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, phenoxy, C1-C4-alkylthio, NH(C1-C4-alkyl) or N(C1-C4-alkyl)2 or phenyl which may be substituted one or more times, eg. one to three times, by 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 together in ortho positions by a direct linkage, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an S02, NH or N-alkyl group C3-C$-cycloalkyl;

' ~ 0050/48312 R6 C3-C8-cycloalkyl, it being possible for these radicals to be substituted one or more times by: halogen, hydroxyl, mercapto, carboxyl, nitro, cyano, C1-C4-alkoxy, C1-C4-alkyl, 5 C2-C4-alkenyl, C2-C4-alkynyl, C3-C6-alkenyloxy, C3-C6-alkynyloxy, C1-C4-alkylthio, C1-C4-haloalkoxy, C1-C4-alkylcarbonyl, C1-C4-alkoxycarbonyl, NH(C1-C4-alkyl), N(C1-C4-alkyl)2 or phenyl which can be substituted one or more times, for example one to three times, by halogen, nitro, 10 cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy or C1-C4-alkylthio;
phenyl or naphthyl, each of which can be substituted by one or more of the following radicals: halogen, nitro, mercapto, carboxyl, cyano, hydroxyl, amino, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C3-C6-alkenyloxy, C1-CQ-haloalkyl, C3-C6-alkynyloxy, C1-C4-alkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-alkoxy, Cl-C4-haloalkoxy, phenoxy, C1-CQ-alkylthio, NH(C1-CQ-alkyl), N(Cl-C4-alkyl)2, dioxomethylene [sicj, dioxoethylene [sic] or phenyl which may be substituted one or more times, eg. one to three times, by halogen, nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy or C1-C4-alkylthio;
a five- or six-membered heteroaromatic system comprising one to three nitrogen atoms and/or one sulfur or oxygen atom, which may carry one to four halogen atoms and/or one to two of the following radicals: C1-C4-alkyl, C1-C4-haloalkyl, C1-CQ-alkoxy, C1-C4-haloalkoxy, C1-C4-alkylthio, phenyl, phenoxy or phenylcarbonyl, it being possible for the phenyl radicals in turn to carry one to five halogen atoms and/or one to three of the following radicals: C1-Cq-alkyl, C1-CQ-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy and/or C1-C4-alkylthio;
Z sulfur or oxygen;
B C2-C4 alkylene Het a heterocyclic group of the formula Ia or Ib with T = 0, S.
Particularly preferred compounds of the formula I, both as pure enantiomers and pure diastereomers and as mixture thereof, are those where the substituents have the following meanings:
R' COOH;
X,Y N;

' 0050/48312 CA 023023s0 2000-o2-Zs w cRla;
R2,R3 hydrogen, hydroxyl, NHZ, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, halogen, C1-C4-alkyl, C2-C4-alkenyl, CZ-C4-alkynyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy or C1-C4-alkylthio, or CRZ is linked to CR1~ as indicated below to give a 5- or 6-membered ring, or, if Het is a five-membered ring, CRZ can together with CR3 be a 5- or 6-membered alkylene or alkylenyl [sic] ring which is unsubstituted or substituted;
R4 phenyl which may be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, mercapto, amino, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, phenoxy, C1-C4-alkylthio, NH(C1-C4-alkyl) or N(C1-C4-alkyl)Z or phenyl which may be substituted one or more times, eg. one to three times, by halogen, nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy or C1-C4-alkylthio; or R5 phenyl or 3,4-dimethoxyphenyl R6 CS-C~-cycloalkyl, it being possible for these radicals in each case to be substituted one or more times by: C1-C4-alkoxy, C1-C4-alkyl, C1-C4-alkylthio, halogen, hydroxyl, carboxyl, cyano, trifluoromethyl, acetyl, 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;
phenyl or naphthyl, each of which may be substituted by one or more of the following radicals: halogen, nitro, mercapto, carboxyl, cyano, hydroxyl, amino, C1-C4-alkyl, C1-C4-haloalkyl, acetyl, C1-C4-alkoxycarbonyl, C1-C9-alkoxy, C1-CQ-haloalkoxy, phenoxy, C1-C4-alkylthio, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, dioxomethylene [sic], dioxoethylene [sic] or phenyl which may be substituted one or more times, eg. one to three times, by halogen, nitro, cyano, C1-CQ-alkyl, C1-C4-haloalkyl, C1-CQ-alkoxy, C1-CQ-haloalkoxy or C1-C4-alkylthio;
a five- or six-membered heteroaromatic system comprising one to three nitrogen atoms and/or one sulfur or oxygen atom, which may carry one to four halogen atoms and/or one to two of the following radicals: C1-C9-alkyl, C1-C4-haloalkyl, C1-CQ-alkoxy, trifluoromethoxy, C1-C4-alkylthio, phenyl or phenoxy, it being possible for the phenyl radicals in turn to carry one to five halogen atoms and/or one to three of the following radicals: C1-C4-alkyl, C1-C4-haloalkyl, C1-CQ-alkoxy, C1-C4-haloalkoxy and/or C1-CQ-alkylthio;
Z sulfur or oxygen;
B C3-alkylene Het Ia with R2 and R3 methyl and T = O, S.
The compounds of the present invention provide a novel therapeutic potential for treating hypertension, pulmonary hypertension, myocardial infarct, angina pectoris, acute/chronic kidney failure, renal insufficiency, cerebral vasospasms, cerebral ischemia, subarachnoid hemorrhages, migraine, asthma, atherosclerosis, endotoxic shock, endotoxin-induced organ failure, intravascular coagulation, restenosis after angioplasty, benign prostate hypoplasia, ischemic and intoxication-induced kidney failure and hypotension, metastasis and growth of mesenchymal tumors, contrast agent-induced kidney failure, pancreatitis, gastrointestinal ulcers.
The invention further relates to combination protiucts comprising endothelia 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.
These combination products are particularly suitable for treating and preventing hypertension and its sequelae, and for treating heart failure.
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 ETB 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, [sic] 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 collection of the cells by centrifugation at 300 x g.
For the membrane preparation, the cells were adjusted to a concentration of 108 cells/ml of buffer (50 mM tris~HCL buffer, pH 7.4) and then disintegrated by ultrasound (Branson Sonifier 250, 40-70 seconds/constant/output [sic] 20).
Binding assays For the ETA and ETB receptor binding assays, the membranes were suspended in the 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 at 25~C with pM [125I [sic]]-ET1 (ETA receptor assay) or 25 pM [125I
[sic]]-ET3 (ETB receptor assay) in the presence and absence of a test substance. The nonspecific binding was determined with 10-~ M
20 ET1. After 30 min, filtration through GF/B glass fiber filters (Whatman, England} in a Skatron cell collector (Skatron, Lier, Norway) separated free from bound radioligand, 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 25 Packard 2200 CA liquid scintillation counter.
Tests on the 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 [sic].
Intravenous administration of 1 ~g/kg ET1 to control animals led to a distinct rise in blood pressure which persisted for a lengthy period.
The test animals received i.v, injections (1 ml/kg) of the test compounds 30 min before the ET1 administration. To determine the ET-antagonistic properties, the changes in blood pressure of the test animals were compared with those for the control animals.
Oral testing of the mixed ETA and ETB antagonists:
Male normotensive rats (Sprague Dawley, Janvier) weighing 250-350 g are pretreated orally with the test substances.
80 minutes later, the animals are anesthetized with urethane, and the carotid artery (for measuring the blood pressure) and the ~ CA 02302350 2000-02-25 jugular vein (administration of big endothelin/endothelin 1) are catheterized.
After a stabilization period, big endothelin (20 ~g/kg, volume administered 0.5 ml/kg) or ET1 (0.3 ~g/kg, volume administered 0.5 ml/kg) is given intravenously. The blood pressure and heart rate are recorded continuously for 30 minutes. The pronounced and long-lasting changes in blood pressure are calculated as area under the curve (AUC). To determine the antagonistic effect of the test substances, the AUC for animals treated with the substance is compared with the AUC for the control animals.
The compounds according to the invention can be administered orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperotoneally [sic]) 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 about 0.5-SO mg/kg of bodyweight on oral administration and about 0.1-10 mg/kg of bodyweight on parenteral administration.
The novel compounds can be used 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 auxiliaries 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 2,3-epoxy-3,6-diphenylhexanoate 1.4 g (31 mmol) of 50% sodium hydride were added in portions over the course of 8 hours to a soluton of 4 g (17.8 mmol) of 1,4-diphenyl-1-butanone and 2.7 ml (31 mmol) of methyl 0050/48312 CA o23o23so 2000-o2-2s chloroacetate in 60 ml of THF. After the ketone had completely reacted, the reaction mixture was added to ice-water and extracted ether. The organic phase was dried over magnesium sulfate and, after the solvent had been distilled off, it was 5 possible to isolate 5.5 g of an oil which was reacted further.
Example 2:
Methyl 2-hydroxy-3-methoxy-3,6-diphenylhexanoate 2 g (6.75 mmol) of methyl 2,3-epoxy-3,6-diphenylhexanoate were introduced with 0.5 ml of methanol into 20 ml of dichloromethane, and 5 drops of boron trifluoride etherate were added. After 2 hours, the mixture was concentrated and the residue was purified by MPLC (cyclohexane/ethyl acetate gradient) to isolate 530 mg of one diastereomer, 720 mg of the second diastereomer and 800 mg of a mixed fraction.
Example 3:
2-Hydroxy-3-methoxy-3,6-diphenylhexanoic acid (one diastereomer, stereochemistry unknown) The second diastereomer (720 mg, 2.2 mmol) was dissolved in 9 ml of dioxane, and 4.5 ml of 1N sodium hydroxide solution were added. The mixture was stirred for 16 hours and then, after addition of water, extracted with ether. The aqueous phase was acidified with citric acid and extracted with ether, the organic phase was dried with [sic] over magnesium sulfate, and the solvent was distilled off. 936 mg of an oil were isolated and were immediately reacted further.
Example 4:
2-(4-Methoxy-6-methyl-2-pyrimidinyloxy)-3-methoxy-3,6-diphenyl-hexanoic acid (one diastereomer) 195 mg (4.4 mmol) of 50% sodium hydride, 465 mg (1.5 mmol) of 2-hydroxy-3-methoxy-3,6-diphenylhexanoic acid and 291 mg (1.5 mmol) of 3,4-dimethyl-2-methylsulfonepyrimidine [sic] were mixed in 20 ml of DMF and stirred at room temperature for 2 hours. The reaction mixture was added to 100 ml of ice-water, acidified with citric acid and extracted with ether. The organic phase was dried with magnesium sulfate, and the solvent was distilled off. The residue was purified by MPLC (cyclohexane/
ethyl acetate gradient) to isolate 103 mg of one diastereomer.

' ' 0050/48312 CA o23o23so 2000-o2-2s S

1H-NMR (200 MHz, CDC13): 7.1-7.5 ppm (10 H, m), 6.2 (1 H, s), 5.6 (1 H, s), 3.8 (3 H, s), 3.3 (3 H, s), 2.5-2.8 (3 H, m), 2.3 (3 H, s), 2.0 (1 H, m), 1.5-1.8 (2 H, m).
ESI MS: M+ = 436 Example 5:
Methyl 2,3-epoxy-3-phenyl-6-(3,4-methoxyphenyl)hexanoate [sic]
(mixture of diastereomers):
12.6 g (44 mmol) of 1-phenyl-4-(3,4-dimethoxy)phenyl-1-butanone [sic] were dissolved together with 8.3 g of methyl chloroacetate in 50 ml of DMF and, at room temperature, 3.7 g of 50~ sodium hydride suspension were added in portions over the course of 1 hour. Reaction of the precursor was complete after a total of 1.5 hours, and the reaction solution was added to 300 m1 of ice-water. The aqueous phase was acidified with citric acid and extracted several times with ether, and the organic phase was separated off, washed and dried over magnesium sulfate. The solvent was distilled off to isolate 13 g of an oil which could be immediately reacted further.
Example 6:
Methyl 2-hydroxy-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3-phenyl-6-(3,4-dimethoxyphenyl)hexanoate A mixture of 3.6 g (10 mmol) of methyl 2,3-epoxy-3-phenyl-6-(3,4-methoxyphenyl)hexanoate [sic], 1.8 g (10 mmol) of 2-(3,4-dimethoxy)ethanol [sic] and 100 mg of p-toluenesulfonic acid in 50 ml of dichloromethane was stirred for one hour while cooling in ice. The reaction solution was added to a saturated sodium bicarbonate solution, and the organic phase was separated off and dried over magnesium sulfate. The solvent was distilled off, and 4.7 g of residue was purified by MPLC (gradient:
cyclohexane/ethyl acetate) to isolate 750 mg of a mixture of diastereomers.
Example 7:
2-Hydroxy-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3-phenyl-6-(3,4-dimethoxyphenyl)hexanoic acid 2.1 ml of 1N sodium hydroxide solution were added to 750 mg (1.4 mmol) of methyl 2-hydroxy-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3-phenyl-6-(3,4-dimethoxyphenyl)hexanoate dissolved in 4.2 ml of ' 0050/48312 ca o23o23so 2000-o2-2s dioxane, and the mixture was stirred at room temperature for 16 hours. 100 ml of water were added to the mixture, which was then extracted with ether. It was subsequently neutralized with hydrochloric acid, the aqueous phase was extracted with ether, the ether phase was dried with magnesium sulfate, and the solvent was distilled off. 620 mg of an oil were isolated and were immediately employed further.
Example 8:
2-(4,6-Dimethyl-2-pyrimidinyloxy)-3-(2-(3,4-dimethoxyphenyl)-ethoxy)-3-phenyl-6-(3,4-dimethoxyphenyl)hexanoic acid 164 mg (3.42 mmol) of sodium hydride, 600 mg (1.14 mmol) of 2-hydroxy-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3-phenyl-6-(3,4-dimethoxyphenyl)hexanoic acid and 223 mg (1.2 mmol) of 3,4-dimethyl-2-methylsulfonepyrimidine [sic] were mixed in 10 ml of DMF and stirred at room temperature for 6 hours. The reaction mixture was added to 100 ml of ice-water, acidified with citric acid and extracted with ether. The organic phase was dried with magnesium sulfate, and the solvent was distilled off. The residue was purified by flash chromatography (cyclohexane/ethyl acetate gradient) to isolate 115 mg of one crystalline diastereomer.
Diast. I:
Melting point: 93-~6~C
ESI MS: M+ = 630 Example 9:
2-(4,6-Dimethyl-2-pyrimidinyloxy)-3-(3,4-dimethoxybenzyloxy)-3-phenyl-6-(3,4-dimethoxyphenyl)hexanoic acid Diast. I:
Melting point: 130-133~C
ESI MS: M+ = 616 Example 10:
2-(4,6-Dimethyl-2-pyrimidinyloxy)-3-(4-methoxyphenoxy)-3-phenyl-6-(3,4-dimethoxyphenyl)hexanoic acid Diast. I:
Melting point: 118-122~C
ESI MS: M+ = 572 ' ' 0050/48312 Example 11:
2-(4,6-Dimethyl-2-pyrimidinyloxy)-3-methoxy-3-phenyl-6-(3,4-di-methoxyphenyl)hexanoic acid Diast. I:
Melting point: 135-138°C
ESI MS: M+ = 480 Diast. II:
Melting point: 128-134°C
ESI MS: M+ = 480 Example 12:
2-(4,6-Dimethyl-2-pyrimidinyloxy)-3-methoxy-3,6-diphenylhexanoic acid 1H-NMR (200 MHz, CDC13): 7.1-7.5 ppm (10 H, m), 6.7 (1 H, s), 5.8 (1 H, s), 3.3 (3 H, s), 2.5-2.7 (3 H, m), 2.3 (6 H, s), 2.0-2.1 (1 H, m), 1.6-1.8 (2 H, m).
ESI MS: M+ = 420 Example 13:
2-(4,6-Dimethyl-2-pyrimidinyloxy)-3-hex-3E-enoxy-3,6-diphenyl-hexanoic [sic] acid Diast. I:
Melting point: 110-114°C
ESI MS: M+ = 488 Diast. II:
ESI MS: M+ = 488 Example 14:
2-(4,6-Dimethyl-2-pyrimidinyloxy)-3-(2-(3,4-dimethoxyphenyl)-ethoxy)-3,6-diphenylhexanoic acid Diast. I:
Melting point: 87-88°C
ESI MS: M+ = 570 Diast. II:
Melting point: 87-88°C

ESI MS: M+ = 570 Example 15:
2-(4-Methoxy-6-methyl-2-pyrimidinyloxy)-3-(2-(3,4-dimethoxy-phenyl)ethoxy)-3,6-diphenylhexanoic acid Diast. I:
Melting point: 141-142~C
ESI MS: M+ = 586 Example 16:
2-(4,6-Dimethyl-2-pyrimidinyloxy)-3-(3,4-dimethoxybenzyloxy)-3,6-diphenylhexanoic acid Diast. I:
1H-NMR (200 MHz, CDC13): 7.1-7.5 ppm (10 H, m), 6.9 (3 H, m),6.7 (1 H, s), 5.8 (1 H, s), 4.4 (1 H, d), 4.3 (1 H, d), 3.9 (3 H, s), 3.85 (3 H, s), 2.5-2.7 (3 H, m), 2.3 (6 H, s), 2.0-2.3 (1 H, m), 1.7-1.9 (2 H, m).
ESI MS: M+ = 556 Example 17:
2-(4-Methoxy-6-methyl-2-pyrimidinyloxy)-3-(3,4-dimethoxybenzyl-oxy)-3,6-diphenylhexanoic acid Diast. I:
1H-NMR (200 MHz, CDC13): 7.1-7.5 ppm (10 H, m), 6.9 (3 H, m),6.25 (1 H, s), 5.75 (1 H, s), 4.45 (1 H, d), 4.35 (1 H, d), 3.9 (3 H, s), 3.85 (6 H, s), 2.4-2.7 (3 H, m), 2.3 (6 H, s), 2.0-2.2 (1 H, m), 1.7-1.9 (2 H, m).
ESI MS: M+ = 572 Example 18:
2-(4-Methoxy-6-methyl-2-pyrimidinyloxy)-3-(2-(2-thiophenyl-ethoxy)-3,6-diphenylhexanoic [sic] acid 3:1 mixture of diastereomers:
Decomposition: 85~C
ESI MS: M+ = 532 Example 19:
2-(4,6-Dimethyl-2-pyrimidinyloxy)-3-(2-(3,4,5-trimethoxyphenyl)-ethoxy)-3,6-diphenylhexanoic acid Diast. I:
1H-NMR (200 MHz, CDC13): 7.0-7.3 ppm (10 H, m), 6.65 (1 H, m),6.4 (2 H, s), 5.75 (1 H, s), 3.9 (3 H, s), 3.85 (6 H, s),3.5-3.7 (2 H, m), 2.8-2.9 (2 H, m), 2.3-2.5 (3 H, m), 2.3 (6 H, s}, 2.0-2.3 10 (1 H, m), 1.5-1.7 (2 H, m).
ESI MS: M+ = 600 Example 20:
2-(4-Methoxy-6-methyl-2-pyrimidinyloxy)-3-(2-(3,4,5-trimethoxy-phenyl)ethoxy)-3,6-diphenylhexanoic acid Diast. I:
Melting point: 153-155~C
ESI MS: M+ = 616 Example 21:
2-(4,6-Dimethyl-2-pyrimidinyloxy)-3-(2-(4-hydroxy-3-methoxy-phenyl)ethoxy)-3,6-diphenylhexanoic acid Diast. I:
1H-NMR (200 MHz, CDC13): 7.0-7.4 ppm (10 H, m), 6.9 (1 H, dm),6.6-6.75 (3 H, m), 5.8 (1 H, s), 5.5 (OH), 3.9 (3 H, s), 3.85 (3 H, s), 3.5-3.7 (2 H, m), 2.8-2.9 (2 H, tr), 2.3-2.5 (3 H, m), 2.3 (6 H, s), 2.0-2.3 (1 H, m), 1.5-1.7 (2 H, m).
ESI MS: M+ = 556 Diast. II:
ESI MS: M+ = 556 Example 22:
2-(4-Methoxy-6-methyl-2-pyrimidinyloxy}-3-(2-(4-hydroxy-3-methoxyphenyl)ethoxy)-3,6-diphenylhexanoic acid Diast. I:
Melting point: 154-157~C
ESI MS: M+ = 572 ' ' 0050/48312 ca o23o23so 2000-o2-2s Example 23:
2-(4,6-Dimethyl-2-pyrimidinyloxy)-3-(4-carboxybenzyloxy)-3,6-diphenylhexanoic acid Diast. I:
1H-NMR (200 MHz, CDC13): 8.0 (2 H, d), 7.1-7.5 ppm (12 H, m), 6.8 (1 H, m),6.8 (1 H, s), 4.6 (1 H, d), 4.5 (1 H, d), 2.5-2.7 (3 H, m), 2.3 (6 H, s), 2.1-2.25 (1 H, m), 1.5-1.7 (2 H, m).
ESI MS: M+ = 540 Diast. II:
Melting point: 160-167~C
ESI MS: M+ = 540 Example 24:
2-(4-Methoxy-6-methyl-2-pyrimidinyloxy)-3-(4-carboxybenzyloxy)-3,6-diphenylhexanoic acid Diast. I:
1H-NMR (200 MHz, CDC13): 8.0 (2 H, d), 7.1-7.5 ppm (12 H, m), 6.2 (1 H, m),5.6 (1 H, s), 4.55 (1 H, d), 4.45 (1 H, d), 3.9 (3 H,s), 2.5-2.7 (3 H, m), 2.3 (3 H, s), 2.1-2.25 (1 H, m), 1.6-1.8 (2 H, m).
ESI MS: M+ = 556 Diast. II:
ESI MS: M+ = 556 Example 25:
2-(4,6-Dimethyl-2-pyrimidinyloxy)-3-(4-methoxyphenoxy)-3,6-diphenylhexanoic acid Diast. I:
1H-NMR (200 MHz, CDC13): 7.1-7.5 ppm (10 H, m), 6.5-6.8 (5 H, m),5.9 (1 H, s), 3.75 (3 H, s), 2.2-2.7 (4 H, m), 2.3 (6 H, s), 1.5-1.7 (2 H, m).
ESI MS: M+ = 512 Diast. II:
ESI MS: M+ = 512 ' 0050148312 Example 26:
2-(4-Methoxy-6-methyl-2-pyrimidinyloxy)-3-(4-methoxyphenoxy)-3,6-diphenylhexanoic acid Diast. I:
1H-NMR (200 MHz, CDC13): 7.1-7.5 ppm (10 H, m), 6.5-6.9 (4 H, m),6.2 (1 H, s), 5.75 (1 H, s), 3.8 (3 H, s), 3.75 (3 H, s), 2.2-2.7 (4 H, m), 2.3 (3 H, s), 1.5-1.7 (2 H, m).
ESI MS: M+ = 528 Diast. II:
ESI MS: M+ = 528 Example 27:
2-(4,6-Dimethyl-2-pyrimidinyloxy)-3-(3-(3,4,5-trimethoxyphenyl)-2E-propenoxy)-3,6-diphenylhexanoic [sic] acid zo Diast. I:
1H-NMR (200 MHz, CDC13}: 7.1-7.4 ppm (10 H, m), 6.6 (1 H, s), 6.55 (2 H, s}, 6.3 (1 H, s), 6.2 (1 H, dtr), 5.9 (1 H, d), 4.0 4.2 (1 H, m), 3.85 (3 H, s), 3.8 (3 H, s), 3.75 (3 H, s), 3.4 (1 .~.5 H,m), 2.4-2.7 (3 H, m), 2.3 (6 H, s), 2.0-2.1 (1 H, m), 1.5-1.7 (2 H, m).
ESI MS: M+ = 612 30 The compounds listed in Table 1 can be prepared in a similar way or as described in the general part.

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'' ooso~4a3i2 Example 12 Receptor binding data were measured by the binding assay 5 described above for the compounds listed below.
The results are shown in Table 2.
Table 2 Receptor binding data (Ki values) Compound ETA Ki[nM] ETB Ki [nM]

I-2 one diast. 43 345 I-224 one diast. 33 6.8 I-171 one diast. 15.7 26.4 I-145 one diast. 1100 13.6 I-137 one diast. 60 11 I-1 one diast. 190 495 I-88 one diast. 50 10 I-89 one diast. 25 17 I-35 one diast. 400 250 I-36 one diast. 300 250 I-128 one diast. 46 9 I-129 one diast. 23 10 I-44 one diast. 205 365 I-45 one diast. 40 255 I-89 one diast. 35 93 I_10 one diast. 65 190 I-116 one diast. 9 43 I-290 one diast. 22 700 I-292 one diast. 1.8 170 I-293 one diast. 13 15 I-295 one diast. 215 1400 ~

Claims

We claim:

1. A carboxylic acid derivative of the formula I

where the substituents have the following meanings:
R is tetrazole [sic] or a group R1 is a radical OR7 in which R7 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, CH2-phenyl, unsubstituted or substituted, C3-C6-alkenyl or a C3-C6-alkynyl group, unsubstituted or substituted, or phenyl, unsubstituted or substituted, R2 is hydrogen, hydroxyl, NH2, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, halogen, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy or C1-C4-alkylthio, or CR2 is linked to CR10 as indicated below to give a 5- or 6-membered ring, or, if Het is a five-membered ring, CR2 can together with CR3 be a 5- or 6-membered alkenyl or alkylenyl [sic] ring which is unsubstituted or substituted;
X is nitrogen or methine;
Y is nitrogen or methine;

W is nitrogen or CR10, where R10 is hydrogen, halogen or C1-4-alkyl, or CR10 forms together with CR2 or CR3 a 5- or 6-membered alkylene or alkenylene ring which is unsubstituted or substituted and in which in each case one or more methylene groups can be replaced by oxygen, sulfur, -NH or -N(C1-C4-alkyl);
R3 is hydrogen, hydroxyl, NH2, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, halogen, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, C1-C4-alkylthio; or CR3 is linked to CR10 as indicated above to give a 5- or 6-membered ring;
R4 and R5 (which may be identical or different) are:
phenyl or naphthyl, unsubstituted or substituted, or phenyl or naphthyl which are linked together in the 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 C3-C8-cycloalkyl, unsubstituted or substituted;
R6 is hydrogen, C1-C8-alkyl, C3-C8-alkenyl or C3-C8-alkynyl, it being possible for each of these radicals to be substituted one or more times by: halogen, hydroxyl, mercapto, carboxyl, nitro, amino, cyano, C1-C4-alkoxy, C3-C6-alkenyloxy, C3-C6-alkynyloxy, C1-C4-alkylthio, C1-C4-haloalkoxy, C1-C4-alkylcarbonyl, C1-C4-alkoxycarbonyl, C3-8-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 said aryl radicals in turn to be substitued one or more times, eg. one to three times, by 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 or C1-C4-alkylthio;
phenyl or naphthyl, each of which can be substituted by 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, C1-C4-alkylamino, C1-C4-dialkylamino, dioxomethylene [sic] or dioxoethylene [sic];

a five- or six-membered heteroaromatic system comprising one to three nitrogen atoms and/or one sulfur or oxygen atom, which may carry one to four halogen atoms and/or one to two of the following radicals: C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, C1-C4-alkylthio, phenyl, phenoxy or phenylcarbonyl, it being possible for the phenyl radicals in turn to carry one to five halogen atoms and/or one to three of the following radicals: C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy and/or C1-C4-alkylthio;
C3-C8-cycloalkyl, it being possible for these radicals to be substituted one or more times by: halogen, hydroxyl, mercapto, carboxyl, vitro, cyano, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-alkoxy, C1-C4-alkylthio, C1-C4-haloalkoxy;
Z is sulfur or oxygen;
B is C2-C4-alkylene Het is a heterocyclic radical of the formula Ia or Ib with T = O, S, NR8 R8 is C1-C6 alkyl and the physiologically tolerated salts and the enantiomerically pure forms.

2. The use of a carboxylic acid derivative as claimed in claim 1 for producing drugs.