Carboxylic acid derivatives, their production and use

Details Carboxylic acid derivatives, their production and use Carboxylic acid derivatives, their production and use

1998-10-08

2003-08-26

Raymond, Richard L. (Department: 1611)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S274000, C544S315000, C544S318000, C544S219000

Reexamination Certificate

active

06610691

ABSTRACT:

The present invention relates to new carboxylic acid derivatives, their preparation and use.
Endothelin is a peptide which is composed of 21 amino acids and is synthesized and released by the vascular endothelium. Endothelin exists in three isoforms, ET-1, ET-2 and ET-3. In the following text, “endothelin” or “ET” signifies one or all isoforms of endothelin. Endothelin is a potent vasoconstrictor and has a potent effect on vessel tone. It is known that this vasoconstriction is caused by binding of endothelin to its receptor (Nature, 332, 411-415, 1988; FEBS Letters, 231, 440-444, 1988 and Biochem. Biophys. Res. Commun., 154, 868-875, 1988).
Increased or abnormal release of endothelin causes persistent vasoconstriction in the peripheral, renal and cerebral blood vessels, which may lead to illnesses. It has been reported in the literature that endothelin is involved in a number of illnesses; these include hypertension, myocardial infarct, heart failure, kidney failure, pulmonary hypertension, Raynaud's syndrome, cerebral vasospasms, atherosclerosis, stroke, benign prostate hypertrophy and asthma (Japan J. Hypertension 12, 79 (1989), J. Vascular Med. Biology 2, 207 (1990), J. Am. Med. Association 264, 2868 (1990), Nature 344, 11 (1990), N. Engl. J. Med. 322, 205 (1989), N. Engl. J. Med.328, 1732 (1993), Nephron 66, 373 (1994), Strake 25, 904 (1994), Nature 365, 759 (1993), J. Mol. Cell. Cardiol. 27, A234 (1995), Cancer Research 56, 663 (1996)).
Accordingly, substances which specifically inhibit the binding of endothelin to the receptor ought also to antagonize the various abovementioned physiological effects of endothelin and therefore be valuable drugs.
The German Patent Application with the file number P 44 36 851.8 describes the following compounds as endothelin receptor antagonists:
We have now found that certain carboxylic acid derivatives are good inhibitors of endothelin receptors and that these compounds simultaneously have a relatively low plasma binding.
The invention relates to carboxylic acid derivatives of the formula I
where R is a formyl group, tetrazole [sic], nitrile [sic], a group COOH or a radical which can be hydrolyzed to COOH, and the other substituents have the following meanings:
R
2
halogen, C
1
-C
4
-alkyl, C
1
-C
4
-haloalkyl, C
1
-C
4
-alkoxy, C
1
-C
4
-haloalkoxy or C
1
-C
4
-alkylthio;
X nitrogen or CR
14
, where R
14
is hydrogen or C
1-5
-alkyl, or CR
14
forms together with CR
3
a 5- or 6-membered alkylene or alkenylene ring which can be substituted by one or two C
1-4
-alkyl groups and in which in each case one methylene group can be replaced by oxygen, sulfur, —NH or —NC
1-4
-alkyl;
R
3
halogen, C
1
-C
4
-alkyl, C
1
-C
4
-haloalkyl, C
1
-C
4
-alkoxy, C
1
-C
4
-haloalkoxy, —NH—O—C
1-4
-alkyl, C
1
-C
4
-alkylthio or CR
3
is linked to CR
14
as indicated above to form a 5- or 6-membered ring;
R
4
and R
5
(which may be identical or different):
phenyl or naphthyl, each of which can be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, C
1
-C
4
-alkyl, C
1
-C
4
-haloalkyl, C
1
-C
4
-alkoxy, C
1
-C
4
-haloalkoxy, phenoxy, C
1
-C
4
-alkylthio, amino, C
1
-C
4
-alkylamino or C
1
-C
4
-dialkylamino;
phenyl or naphthyl which are connected together in ortho positions by a direct linkage, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an SO
2
, NH or N-alkyl group, or C
3
-C
7
-cycloalkyl;
R
6
C
1
-C
10
-alkyl, C
3
-C
10
-alkenyl or C
3
-C
10
-alkynyl, the radicals each being substituted one or more times by hydroxyl, mercapto, carboxy,
 where R
y
and R
z
are, independently of one another, hydrogen or C
1
-C
5
-alkyl; sulfonyl, cyano, guanidino;
Z sulfur or oxygen.
The compounds, and the intermediates for preparing them, eg. IV and VI, may have one or more asymmetrically substituted carbon atoms. Such compounds may exist as pure enantiomers and pure diastereomers or as a mixture thereof. The use of an enantiomerically pure compound as active substance is preferred.
The invention furthermore relates to the use of the abovementioned carboxylic acid derivatives for producing drugs, in particular for producing endothelin-receptor inhibitors.
The compounds according to the invention are prepared starting from the epoxides IV, which are obtained in a conventional way, eg. as described in J. March, Advanced Organic Chemistry, 2nd Ed., 1983, pages 862 and 750 from the ketones II or the olefins III:
Carboxylic acid derivatives of the general formula VI can be prepared by reacting the epoxides of the general formula IV (eg. with R=ROOR
10
[sic] with alcohols or thiols of the general formula V where R
6
and Z have the meanings stated in claim 1.
For this purpose, compounds of the general formula IV are heated with a compound of the formula V in the molar ratio of about 1:1 to 1:7, preferably 1 to 3 mol equivalents, at from 50 to 200° C., preferably 80 to 150° C.
Other functional groups in R
6
are initially protected in a conventional way for the reaction with compounds of the formula IV; for example, alcohols can be protected as acetates, diols as acetals and carboxyl groups as esters. The protective groups can be eliminated after the reaction of compounds of the formula VI with VII.
The reaction may also take place in the presence of a diluent. It is possible to use for this purpose all solvents which are inert toward the reagents used.
Examples of such solvents or diluents are water, aliphatic, alicyclic and aromatic hydrocarbons, which may in each case 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, ketones such as acetone, methyl ethyl ketone, methyl isopropyl ketone and methyl isobutyl ketone, nitrites such as acetonitrile and propionitrile, alcohols such as methanol, ethanol, isopropanol, butanol and ethylene glycol, esters such as ethyl acetate and amyl acetate, amides such as dimethylformamide and dimethylacetamide, sulfoxides and sulfones, such as dimethyl sulfoxide and sulfolane, bases such as pyridine, N-methylpyrrolidone, cyclic ureas such as 1,3-dimethyl-2-imidazolidinone and 1,3-dimethyl-3,4,5,6-tetra-hydro-2(1H) pyrimidinone.
The reaction is 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 in this case are strong organic and inorganic acids, and Lewis acids. Examples thereof are, inter alia, sulfuric acid, hydrochloric acid, trifluoroacetic acid, p-toluenesulfonic acid, boron trifluoride etherate and titanium(IV) alcoholates.
Compounds of the general formula VI can be obtained in enantiomerically pure form by starting from enantiomerically pure compounds of the formula IV and reacting them with compounds of the formula V in the manner described.
It is furthermore possible to obtain enantiomerically pure compounds of the formula VI by carrying out a classical racemate resolution with racemic or diastereomeric compounds of the formula VI using suitable enantiomerically pure bases such as brucine, strychnine, quinine, quinidine, chinchonidine [sic], chinchonine [sic], yohimbine, morphine, dehydroabietylamine, ephedrine (−), (+), deoxyephedrine (+), (−), threo-2-amino-1-(p-nitrophenyl)-1,3-propanediol (+), (−), threo-2-(N,N-dimethylamino)-1-(p-nitrophenyl)-1,3-propanediol (+), (−), threo-2-amino-1-phenyl-1,3-propanediol (+), (−), &agr;-methylbenzylamine (+), (−), &agr;-(1-naphthyl)ethylamine (+), (−), &agr;-(2-naphthyl)ethylamine (+), (−), aminomethylpinone, N,N-dimethyl-1-phenylethylamine, N-methyl-1-phenylethylamine, 4-nitrophenylethylamine, pseudoephedrine, norephedrine, norpseudoephedrine, amino acid derivatives, peptide derivativ

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