Carboxylic acid derivatives, their preparation and use

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

2000-12-27

2003-07-29

Kifle, Bruck (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Four or more ring nitrogens in the bicyclo ring system

C544S278000, C544S279000, C544S280000, C544S283000, C544S286000

Reexamination Certificate

active

06600043

ABSTRACT:

THE PRESENT INVENTION RELATES TO NOVEL 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, (1988) 411-415; FEBS Letters, 231, (1988) 440-444 and Biochem. Biophys. Res. Commun., 154, (1988) 868-875).
Increased or abnormal release of endothelin causes persistent vasoconstruction in the peripheral, renal and cerebral blood vessels, which may lead to illnesses. It has been reported in the literature that elevated plasma levels of endothelin were found in patients with hypertension, acute myocardial infarct, pulmonary hypertension, Raynaud's syndrome, atherosclerosis and in the airways of asthmatics (Japan J. Hypertension, 12, (1989) 79, J. Vascular Med. Biology 2, (1990) 207, J. Am. Med. Association 264, (1990) 2868).
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.
We have found that certain carboxylic acid derivatives are good inhibitors of endothelin receptors.
The invention relates to carboxylic acid derivatives of the formula I
where R is formyl, tetrazole, nitrile, a COOH group or a radical which can be hydrolyzed to COOH, and the other substituents have the following meanings:
R
2
hydrogen, hydroxyl, NH
2
, NH(C
1
-C
4
-alkyl), N(C
1
-C
4
-alkyl)
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 a methylene group can be replaced by oxygen, sulfur, —NH or —NC
1-4
-alkyl;
R
3
hydrogen, hydroxyl, NH
2
, NH(C
1
-C
4
-Alkyl), N(C
1
-C
4
-alkyl)
2
, 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 give a 5- or 6-membered ring;
R
4
and R
5
(which can be identical or different):
phenyl or naphthyl, 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; or
phenyl or naphthyl, which are connected together in the ortho positions via 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
hydrogen, C
1
-C
8
-alkyl, C
3
-C
6
-alkenyl, C
3
-C
6
-alkynyl or C
3
-C
8
-cycloalkyl, where each of these radicals can be substituted one or more times by: halogen, nitro, cyano, C
1
-C
4
-alkoxy, C
3
-C
6
-alkenyloxy, C
3
-C
6
-alkynyloxy, C
1
-C
4
-alkylthio, C
1
-C
4
-haloalkoxy, C
1
-C
4
-alkylcarbonyl, C
1
-C
4
-alkoxycarbonyl, C
3-8
-alkylcarbonylalkyl, C
1
-C
4
-alkylamino, di-C
1
-C
4
-alkylamino, phenyl or phenyl or phenoxy which is substituted one or more times, eg. one to three times, by halogen, mitro, cyano, 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;
phenyl or naphthyl, each of which can be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, amino, 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, C
1
-C
4
-alkylamino, C
1
-C
4
-dialkylamino, dioxomethylene or dioxoethylene;
a five- or six-membered heteroaromatic moiety containing one to three nitrogen atoms and/or one sulfur or oxygen atom, which can carry one to four halogen atoms and/or one or two of the following radicals: C
1
-C
4
-alkyl, C
1
-C
4
-haloalkyl, C
1
-C
4
-alkoxy, C
1
-C
4
-haloalkoxy, C
1
-C
4
-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: C
1
-C
4
-alkyl, C
1
-C
4
-haloalkyl, C
1
-C
4
-alkoxy, C
1
-C
4
-haloalkoxy and/or C
1
-C
4
-alkylthio;
with the proviso that R
6
can be hydrogen only when Z is not a single bond;
Y sulfur or oxygen or a single bond;
Z sulfur or oxygen or a single bond.
The compounds, and the intermediates for preparing them, such as IV and VI, may have one or more asymmetrical substituted carbon atoms. Such compounds may be in the form of the pure enantiomers or pure diastereomers or 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 invention furthermore relates to the preparation of the compounds of the formula IV in enantiomerically pure form. Enantio-selective epoxidation of an olefin with two phenyl substituents is known (J. Org. Chem. 59, 1994, 4378-4380). We have now found, surprisingly, that even ester groups in these systems permit epoxidation in high optical purity.
The preparation of the compounds according to the invention where Z is sulfur or oxygen starts from the epoxides IV, which are obtained in a conventional manner, eg. as described in J. March, Advanced Organic Chemistry, 2nd ed., 1983, page 862 and page 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
with alcohols or thiols of the general formula V where R
6
and Z have the meanings stated in claim 1.
To do this, compounds of the general formula IV are heated with compounds of the formula V, in the molar ratio of about 1:1 to 1:7, preferably 1 to 3 mole equivalents, to 50-200° C., preferably 80-150° C.
The reaction can also take place in the presence of a diluent. All solvents which are inert toward the reagents used can be used for this purpose.
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, dimethylacetamide and N-methyl-pyrrolidone, sulfoxides and sulfones, such as dimethyl sulfoxide and sulfolane, bases such as pyridine, cyclic ureas such as 1,3-dimethylimidazolidin-2-one and 1,3-dimethyl-3,4,5,6-tetrahydro-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 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 formula VI where R
4
and R
5
are cycloalkyl can also be prepared by subjecting compounds of the formula VI where R
4
and R
5
are phenyl, naphthyl, or phenyl or naphthyl substituted as described above,

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