US20110178294A1

US20110178294A1 - Novel carboxylic acid derivatives, their preparation and use

Info

Publication number: US20110178294A1
Application number: US12/959,849
Authority: US
Inventors: Hartmut Riechers; Dagmar Klinge; Wilhelm Amberg; Andreas Kling; Stefan Muller; Ernst Baumann; Joachim Rheinheimer; Uwe Vogelbacher; Wolfgang Wernet; Andrea Hager-Wernet; Liliane Unger; Manfred Raschack
Original assignee: Abbott GmbH and Co KG
Current assignee: AbbVie Deutschland GmbH and Co KG
Priority date: 1994-10-14
Filing date: 2010-12-03
Publication date: 2011-07-21
Also published as: JP2007137893A; US6600043B2; JP2007169295A; US20120088911A1; NO308846B1; HRP950517B1; FI971529A; FR08C0041I1; US20060160808A1; KR970707103A; CN1293059C; IL115560A; USRE42462E1; USRE42477E1; US8349843B2; HRP20040364B1; PT785926E; FI971529A0; PL319655A1; US7109205B2

Abstract

Carboxylic acid derivatives

where R—R⁶, X, Y and Z have the meanings stated in the description, and the preparation thereof, are described. The novel compounds are suitable for controlling diseases.

Description

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 [sic], nitrile [sic], a COOH group or a radical which can be hydrolyzed to COOH, and the other substituents have the following meanings:

R²hydrogen, hydroxyl, NH₂, NH(C₁-C₄-alkyl), N(C₁-C₄-alkyl)₂, halogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy or C₁-C₄-alkylthio;
X nitrogen or CR¹⁴where R¹⁴is hydrogen or C_1-5-alkyl, or CR¹⁴forms together with CR³a 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;
R³hydrogen, hydroxyl, NH₂, NH(C₁-C₄-Alkyl), N(C₁-C₄-alkyl)₂, halogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, C₁-C₄-alkylthio or CR³is linked to CR¹⁴as indicated above to give a 5- or 6-membered ring;
R⁴and R⁵(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, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, phenoxy, C₁-C₄-alkylthio, amino, C₁-C₄-alkylamino or C₁-C₄-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 SO₂—, NH— or N-alkyl group, or C₃-C₇-cycloalkyl;
R⁶hydrogen, C₁-C₈-alkyl, C₃-C₆-alkenyl, C₃-C₆-alkynyl or C₃-C₈-cycloalkyl, where each of these radicals can be substituted one or more times by: halogen, nitro, cyano, C₁-C₄-alkoxy, C₃-C₆-alkenyloxy, C₃-C₆-alkynyloxy, C₁-C₄-haloalkoxy, C₁-C₄-alkylcarbonyl, C₁-C₄-alkoxycarbonyl, C_3-8-alkylcarbonylalkyl, di-C₁-C₄-alkylamino, phenyl or phenyl or phenoxy which is substituted one or more times, eg. one to three times, by halogen, mitro, cyano, 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, cyano, hydroxyl, amino, C₁-C₄-alkyl, 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 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: 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;
- with the proviso that R⁶can 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. Enantioselective 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═ROOR¹⁰[sic]) with alcohols or thiols of the general formula V where R⁶and 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, nitriles 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-methylpyrrolidone, 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-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 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 R⁴and R⁵are cycloalkyl can also be prepared by subjecting compounds of the formula VI where R⁴and R⁵are phenyl, naphthyl, or phenyl or naphthyl substituted as described above, to a nuclear hydrogenation.
Compounds of the formula VI can be obtained in enantiomerically pure form by starting from enantiomerically pure compounds of the formula IV and reacting them in the manner described with compounds of the formula V.
It is furthermore possible to obtain enantiomerically-pure compounds of the formula VI by carrying out a classical racemate resolution on 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-(pnitrophenyl)-1,3-propanediol (+), (−) threo-2-amino-1-phenyl-1,3-propanediol (+), (−), α-methylbenzylamine (+), (−), α-(1-naphthyl)ethylamine (+), (−), α-(2-naphthyl)ethylamine (+), (−), aminomethylpinane, N,N-dimethyl-1-phenylethylamine, N-methyl-1-phenylethylamine, 4-nitrophenylethylamine, pseudoephedrine, norephedrine, norpseudoephedrine, amino acid derivatives, peptide derivatives.
The compounds according to the invention where Y is oxygen, and the remaining substituents have the meanings stated under the general formula I, can be prepared, for example, by reacting the carboxylic acid derivatives of the general formula VI where the substituents have the stated meanings with compounds of the general formula VII
where R¹⁵is halogen or R¹⁶—SO₂—, where R¹⁶can be C₁-C₄-alkyl, C₁-C₄-haloalkyl or phenyl. The reaction preferably takes place in one of the abovementioned inert diluents with the addition of a suitable base, ie. of a base which deprotonates the intermediate VI, in a temperature range from room temperature to the boiling point of the solvent.
Compounds of the formula VII are known, some of them can be bought, or they can be 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 an 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.
The compounds according to the invention where Y is sulfur, and the remaining substituents have the meanings stated under the general formula I, can be prepared, for example, by reacting carboxylic acid derivatives of the general formula VIII, which can be obtained in a known manner from compounds of the general formula VI and in which the substituents have the abovementioned meanings, with compounds of the general formula IX, where R², R³and X have the meanings stated under general formula I.
The reaction preferably takes place in one of the abovementioned inert diluents with the addition of a suitable base, ie. a base which deprotonates the intermediate IX, in a temperature range from room temperature to the boiling point of the solvent.
It is possible to use as base, besides those mentioned above, organic bases such as triethylamine, pyridine, imidazole or diazabicycloundecane [sic].
Carboxylic acid derivatives of the formula VIa (Z in formula VI=direct linkage) can be prepared by reacting epoxides of the formula IV with cuprates of the formula XI:
The cuprates can be prepared as described in Tetrahedron Letters 23, (1982) 3755.
Compounds of the formula I can also be prepared by starting from the corresponding carboxylic acids, ie. compounds of the formula I where R is COOH, and initially converting these in a conventional manner into an activated form, such as a halide, an anhydride or imidazolide, and then reacting the latter with an appropriate hydroxy compound HOR¹⁰. 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 hydroxy compound in the presence of a dehydrating agent such as a carbodiimide.
In addition, it is also possible for compounds of the formula I to be prepared by starting from the salts of the corresponding carboxylic acids, ie. from compounds of the formula I where R is COR¹and R¹is 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 R¹-A where A is a conventional 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, such as toluenesulfonyl and methylsulfonyl, or another equivalent leaving group. Compounds of the formula R¹-A with a reactive substituent A are known or can be easily obtained with general expert knowledge. This reaction can be carried out in conventional solvents and advantageously takes place with the addition of a base, in which case those mentioned above are suitable.
The radical R in formula I may vary widely. For example, R is a group
where R¹has the following meanings:

a) hydrogen;
b) succinylimidoxy [sic];
c) a five-membered heteroaromatic moiety linked by a nitrogen atom, such as pyrrolyl, pyrazolyl, imidazolyl and triazolyl, which may carry one or two halogen atoms, in particular fluorine and chlorine and/or one or two of the following radicals:
- C₁-C₄-alkyl such as methyl, ethyl, 1-propyl, 2-propyl, 2-methyl-2-propyl, 2-methyl-1-propyl, 1-butyl, 2-butyl;
- C₁-C₄-haloalkyl, in particular C₁-C₂-haloalkyl such as fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trichloromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro2-fluoroethyl, 2,2,2-trichloroethyl and pentafluoroethyl;
- C₁-C₄-haloalkoxy, in particular C₁-C₂-haloalkoxy such as difluoromethoxy, trifluoromethoxy, chloradifluoromethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-1,1,2-trifluoroethoxy and pentafluoroethoxy, in particular trifluoromethoxy;
- C₁-C₄-alkoxy such as methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, 1,1-dimethylethoxy, in particular methoxy, ethoxy, 1-methylethoxy;
- C₁-C₄-alkylthio such as methylthio, ethylthio, propylthio, 1-methylethylthio, butylthio, 1-methylpropylthio, 2-methylpropylthio, 1,1-dimethylethylthio, . . . in particular methylthio and ethylthio;
d) R¹furthermore a radical

- where m is 0 or 1 and R⁷and R⁸, which can be identical or different, have the following meanings:
- hydrogen
- C₁-C₈-alkyl, in particular C₁-C₄-alkyl as mentioned above;
- C₃-C₆-alkenyl such as 2-propenyl, 2-butenyl, 3-butenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-2-butenyl, 2-methyl2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-2-propenyl; 1-ethyl-2-propenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl2-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl and 1-ethyl-2-methyl-2-propenyl, in particular 2-propenyl, 2-butenyl, 3-methyl-2-butenyl and 3-methyl-2-pentenyl;
- C₃-C₆-alkynyl such as 2-propynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-methyl-2-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-2-pentynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 1-methyl-4-pêntynyl, 2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-4-pentynyl, 4-methyl-2-pentynyl, 1,1-dimethyl-2-butynyl, 1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl, 2,2-dimethyl-3-butynyl, 1-ethyl-2-butynyl, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl and 1-ethyl-1-methyl-2-propynyl, preferably 2-propynyl, 2-butynyl, 1-methyl-2-propynyl and 1-methyl-2-butynyl, in particular 2-propynyl
- C₃-C₈-cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, cyclooctyl, where these alkyl, cycloalkyl, alkenyl and alkynyl groups can each carry one to five halogen atoms, in particular fluorine or chlorine and/or one or two of the following groups:
- C₁-C₄-alkyl, C₁-C₄-alkoxy, C₁-C₄-alkylthio, C₁-C₄-haloalkoxy as mentioned above, C₃-C₆-alkenyloxy, C₃-C₆-alkenylthio, C₃-C₆-alkynyloxy, C₃-C₆-alkynylthio, where the alkenyl and alkynyl constituents present in these radicals preferably have the abovementioned meanings;
- C₁-C₄-alkylcarbonyl such as, in particular, methylcarbonyl, ethylcarbonyl, propylcarbonyl, 1-methylethylcarbonyl, butyl-carbonyl, 1-methylpropylcarbonyl, 2-methylpropylcarbonyl, 1,1-dimethylethylcarbonyl;
- C₁-C₄-alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl, 1-methylethoxycarbonyl, butyloxycarbonyl, 1-methylpropyloxycarbonyl, 2-methylpropyloxycarbonyl, 1,1-dimethylethoxycarbonyl;
- C₃-C₈-alkenylcarbonyl, C₃-C₆-alkynylcarbonyl, C₃-C₈-alkenyloxycarbonyl and C₃-C₆-alkynyloxycarbonyl, where the alkenyl and alkynyl radicals are preferably defined as detailed above;
- phenyl, unsubstituted or 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, such as 2-fluorophenyl, 3-chlorophenyl, 4-bromophenyl, 2-methylphenyl, 3-nitrophenyl, 4-cyanophenyl, 2-trifluoromethylphenyl, 3-methoxyphenyl, 4-trifluoroethoxyphenyl, 2-methylthiophenyl, 2,4-dichlorophenyl, 2-methoxy-3-methylphenyl, 2,4-dimethoxyphenyl, 2-nitro-5-cyanophenyl, 2,6-difluorophenyl;
- di-C₁-C₄-alkylamino such as, in particular, dimethylamino, dipropylamino, N-propyl-N-methylamino, N-propyl-N-ethylamino, diisopropylamino, N-isopropyl-N-methylamino, N-isopropylN-ethylamino, N-isopropyl-N-propylamino;
- R⁷and R⁸furthermore phenyl which can be substituted by one or more, eg. one to three, of the following radicals: halogen, nitro, cyano, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy or C₁-C₄-alkylthio, as mentioned above in particular;
- or R⁷and R⁹together form a C₄-C₇-alkylene chain which is closed to form a ring, is unsubstituted or substituted, eg. substituted by C₁-C₄-alkyl, and may contain a heteroatom selected from the group consisting of oxygen, sulfur or nitrogen, such as —(CH₂)₄—, —(CH₂)₅—, —(CH₂)₆—, —(CH₂)₇—, —(CH₂)₂—O—(CH₂)₂—, —CH₂—S—(CH₂)₃—, —(CH₂)₂—O—(CH₂)₃—, —NH—(CH₂)₃—, —CH₂—NH—(CH₂)₂—, —CH₂—CH═CH—CH₂—, —CH═CH—(CH₂)₃—;
e) R¹furthermore a group

- where k is 0, 1 and 2, p is 1, 2, 3 and 4 and R⁹is
- C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₃-C₆-alkenyl, C₃-C₆-alkynyl or unsubstituted or substituted phenyl, as mentioned above in particular.
f) R¹furthermore a radical OR₁₀, where R¹⁰is:
- hydrogen, the cation of an alkali metal such as. lithium, sodium, potassium or the cation of an alkaline earth metal such as calcium, magnesium and barium or an environmentally compatible organic ammonium ion such as tertiary C₁-C₄-alkylammonium or the ammonium ion;
- C₃-C₈-cycloalkyl as mentioned above, which may carry one to three C₁-C₄-alkyl groups;
- C₁-C₈-alkyl such as, in particular, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 1,1-dimethyl-inaty-1,-2,2-dimethylbutyl, 3,3-dimethylbutyl, thylpropyl, 1,2,2-trimethylpropyl, 1-ethylbutyl, 2-ethylbutyl, 1-ethyl-2-methylpropyl, which can carry one to five halogen atoms, in particular fluorine and chlorine and/or one of the following radicals:
- C₁-C₄-alkoxy, C₁-C₄-alkylthio, cyano, C₁-C₄-alkylcarbonyl, C₃-C₉-cycloalkyl, C₁-C₄-alkoxycarbonyl, phenyl, phenoxy or phenylcarbonyl, where the aromatic radicals in turn can carry in each case one to five halogen atoms and/or one to three of the following radicals: nitro, cyano, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy and/or C₁-C₄-alkylthio, as mentioned above in particular;
- a C₁-C₈-alkyl as mentioned above, which can carry one to five halogen atoms, in particular fluorine and/or chlorine, and carries one of the following radicals: a 5-membered heteroaromatic moiety containing one to three nitrogen atoms, or a 5-membered heteroaromatic moiety containing a nitrogen atom and an oxygen or sulfur atom, which can carry one to four halogen atoms and/or one or two of the following radicals:
- nitro, cyano, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, phenyl, C₁-C₄-haloalkoxy and/or C₁-C₄-alkylthio. Particular mention may be made of: 1-pyrazolyl, 3-methyl-1-pyrazolyl, 4-methyl-1-pyrazolyl, 3,5-dimethyl-1-pyrazolyl, 3-phenyl-1-pyrazolyl, 4-phenyl-1-pyrazolyl, 4-chloro-1-pyrazolyl, 4-bromo-1-pyrazolyl, 1-imidazolyl, 1-benzimidazolyl, 1,2,4-triazol-1-yl, 3-methyl-1,2,4-triazol-1-yl, 5-methyl-1,2,4-triazol-1-yl, 1-benzotriazolyl, 3-isopropyl-5-isoxazolyl, 3-methyl-5-isoxazolyl, 2-oxazolyl, 2-thiazolyl, 2-imidazolyl, 3-ethyl-5-isokazolyl, 3-phenyl5-isoxazolyl, 3-tert-butyl-5-isoxazolyl;
- a C₂-C₆-alkyl group which carries one of the following radicals in position 2: C₁-C₄-alkoxyimino, C₃-C₆-alkynyloxyimino, C₃-C₆-haloalkenyloxylmino or benzyloxyimino;
- a C₃-C₆-alkenyl or C₃-C₆-alkynyl group, it being possible for these groups in turn to carry one to five halogen atoms;
- R¹⁰furthermore a phenyl radical which can carry one to five halogen atoms and/or one to three of the following radicals: nitro, cyano, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy and/or C₁-C₄-alkylthio, as mentioned above in particular;
- a 5-membered heteroaromatic moiety which is linked via a nitrogen atom, contains one to three nitrogen atoms and can carry one or two halogen atoms and/or one or two of the following radicals: C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, phenyl, C₁-C₄-haloalkoxy and/or C₁-C₄-alkylthio. Particular mention may be made of: 1-pyrazolyl, 3-methyl-1-pyrazolyl, 4-methyl-1-pyrazolyl, 3,5-dimethyl-1-pyrazolyl, 3-phenyl-1-pyrazolyl, 4-phenyl-1-pyrazolyl, 4-chloro-1-pyrazolyl, 4-bromo-1-pyrazolyl, 1-imidazolyl, 1-benzimidazolyl, 1,2,4-triazol-1-yl, 3-methyl-1,2,4-triazol-1-yl, 5-methyl-1,2,4-triazol-1-yl4-1-benzotriazolyl, 3,4-dichloro-1-imidazolyl;
- R¹⁰furthermore a group

- where R¹¹and R¹², which can be identical or different, are:
- C₁-C₈-alkyl, C₃-C₆-alkenyl, C₃-C₆-alkynyl, C₃-C₈-cycloalkyl, it being possible for these radicals to carry a C₁-C₄-alkoxy, C₁-C₄-alkylthio and/or an unsubstituted or substituted phenyl radical, as mentioned above in particular;
- phenyl which can be substituted by one or more, eg. one to three, of the following radicals: halogen, nitro, cyano, C₁-C₄-alkyl, C₁-C₁-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy or C₁-C₄-alkylthio, where these radicals are, in particular, those mentioned above;
- or R¹¹and R¹²together form a C₃-C₁₂-alkylene chain which can carry one to three C₁-C₄-alkyl groups and contain a heteroatom from the group consisting of oxygen, sulfur and nitrogen, as mentioned in particular for R⁷and R⁸.
g) R¹furthermore a radical

- where R¹³is:
- C₁-C₄-alkyl, C₃-C₆-alkenyl, C₃-C₆-alkynyl, C₃-C₈-cycloalkyl as mentioned above in particular, it being possible for these radicals to carry a C₁-C₄-alkoxy, C₁-C₄-alkylthio and/or a phenyl radical as mentioned above;
- phenyl, unsubstituted or substituted, in particular as mentioned above.
h) R¹a radical

- where R¹³has the abovementioned meaning.
R can furthermore be:
- tetrazole [sic] or nitrile [sic].

In respect of the biological effect, preferred carboxylic acid derivatives of the general formula I, both as pure enantiomers and pure diastereomers or as mixture thereof, are those where the substituents have the following meanings:

R²hydrogen, hydroxyl, N(C₁-C₄-alkyl)₂, the C₁-C₄alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, C₁-C₄-alkylthio groups and halogen atoms mentioned in detail for R¹, especially chlorine, methyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy;
X nitrogen or CR¹⁴where
R¹⁴is hydrogen or alkyl, or CR¹⁴forms together with CR³a 4- to 5-memberedalkylene or alkenylene ring in which, in each case, a methylene group can be replaced by oxygen or sulfur, such as —CH₂—CH₂—O—, —CH═CH—O—, —CH₂—CH₂—CH₂—O—, —CH═CH—CH₂O—, in particular hydrogen, —CH₂—CH₂—O—, —CH(CH₃)—CH(CH₃)—O0-, —C(CH₃)═C(CH₃)—O—, —CH═C(CH₃)—O— or —C(CH₃)═C(CH₃)—S;
R3 the hydrogen, hydroxyl, N(C₁-C₄-alkyl)₂, C₁-C₄haloalkyl, C₁-C₄alkoxy, C₁-C₄-haloalkoxy, C₁-C₄-alkylthio groups and halogen atoms mentioned for R¹, especially chlorine, methyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy or is linked to R¹⁴as mentioned above to give a 5- or 6-membered ring;
R⁴and R⁵phenyl or naphthyl, which can be substituted by one or more, eg. one to three, of the following radicals: halogen, nitro, cyano, hydroxyl, mercapto, amino, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄alkoxy, C₁-C₄-haloalkoxy, C₁-C₄-alkylamino, di-C₁-C₄-alkylamino, C₁-C₄alkylcarbonyl, C₁-C₄alkoxycarbonyl; phenyl or naphthyl, which are connected 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, or C₃-C₇-cycloalkyl;
R⁶C₁-C₈-alkyl, C₃-C₆-alkenyl, C₃-C₆-alkynyl or C₂-C₈-cycloalkyl as mentioned above in particular, it being possible for these radicals in each case to be substituted one or more times by: halogen, hydroxyl, nitro, cyano, C₁-C₄-alkoxy, C₃-C₆-alkenyloxy, C₃-C₆-alkyhyloxy, C₁-C₄-alkylthio, C₁-C₄-haloalkoxy, C₁-C₄-alkylcarbonyl, hydroxycarbonyl, C₂-C₄-alkoxycarbonyl, C₁-C₄-alkylamino, di-C₁-C₄-alkylamino or unsubstituted or substituted phenyl or phenoxy, as mentioned above in particular;
- phenyl or naphthyl, 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 [sic] or C₂-C₄-dialkylamino, as mentioned in particular for R⁷and R⁴;
- a five- or six-membered heteroaromatic moiety which contains one to three nitrogen atoms and/or one sulfur or oxygen atom and which can carry one to four halogen atoms and/or one or 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, as mentioned for R⁴in particular;
Y sulfur, oxygen or a single bond;
Z sulfur, oxygen, —SO—, —SO₂— or a single bond.

Particularly preferred compounds of the formula I, both as pure enantiomers and pure diastereomers or as mixture thereof, are those in which the substituents have the following meanings:

R²C₁-C₄-alkyl, C₁-C₄-alkoxy
X nitrogen or CR¹⁴, where
R¹⁴is hydrogen or alkyl, or CR¹⁴forms together with CR³a 4- or 5-membered alkylene or alkenylene ring such as —CH₂—CH₂—CH₂—, —CH═CH—CH₂—, in which in each case a methylene group can be replaced by oxygen or sulfur, such as —CH₂—CH₂—O—, —CH═CH—O—, —CH₂—CH₂—CH₂—O—, —CH═CH—CH₂O—, in particular hydrogen, —CH₂—CH₂—O—, —CH(CH₃)—CH(CH₃)—O—, —C(CH₃)═C(CH₃)—O—, —CH═C(CH₃)—O— or —C(CH₃)═C(CH₃)—S;
R³the C₁-C₄-alkyl, C₁-C₄-alkoxy, C₁-C₄-alkylthio groups mentioned for R¹, or is linked to R¹⁴as mentioned above to give a 5- or 6-membered ring;
R⁴and R⁵phenyl (identical or different) which can be substituted by one or more, eg. one to three, of the following radicals: halogen, nitro, hydroxyl, C₁-C₄-alkyl, C₁-C₄-alkoxy, C₁-C₄-alkylthio or
R⁴and R⁵are phenyl groups which are connected 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; or
R⁴and R⁵are C₃-C₇-cycloalkyl;
R⁶C₁-C₈-alkyl, C₃-C₆-alkenyl or C₃-C₈-cycloalkyl, it being possible for these radicals in each case to be substituted one or more times by: halogen, hydroxyl, nitro, cyano, C₁-C₄-alkoxy, C₃-C₆-alkenyloxy, C₁-C₄-alkylthio; phenyl or naphthyl, 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-alkowy, C₁-C₄-haloalkoxy, phenoxy, C₁-C₄-alkylthio, C₁-C₄-alkylamino [sic] or C₁-C₄-dialkylamino;
- a five- or six-membered heteroaromatic moiety which contains a nitrogen atom and/or a sulfur or oxygen atom and which can carry one to four halogen atoms and/or one or two of the following radicals: C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, 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 and/or C₁-C₄-alkylthio;
Y sulfur, oxygen or a single bond;
Z sulfur, oxygen, —SO—, —SO₂— or a single bond.

The compounds of the present invention provide a novel therapeutic potential for the treatment of hypertension, pulmonary hypertension, myocardial infarct, angina pectoris, acute kidney failure, renal insufficiency, cerebral vasospasms, cerebral ischemia, subarachnoid hemorrhages, migraine, asthma, atherosclerosis, endotoxic shock, endotoxin-induced organ failure, intra vascular coagulation, restenosis after angioplasty, benign prostate hyperplasia, or hypertension or kidney failure caused by ischemia or intoxication.
The good effect of the compounds can be shown in the following tests:

Receptor Binding Studies

Cloned human ET_Areceptor-expressing CHO cells and guinea pig cerebellar membranes with >60% ET_Bcompared with ET_Areceptors were used for binding studies.
The ET_Areceptor-expressing CHO cells were grown in F₁₂medium containing 10% fetal calf serum, 1% glutamine, 100 U/ml penicillin and 0.2% streptomycin (Gibco BRL, Gaithersburg, Md., USA). After 48 h, the cells were washed with PBS and incubated with 0.05% trypsin-containing PBS for 5 min. Neutralization was then carried out with F₁₂medium, and the cells were collected by centrifugation at 300×g. To lyze the cells, the pellet was briefly washed with lysis buffer (5 mM Tris-HCl, pH 7.4 with 10% glycerol) and then incubated at a concentration of 10⁷cells/ml of lysis buffer at 4° C. for 30 min. The membranes were centrifuged at 20,000 xsg-for 10 min, and the pellet was stored in liquid nitrogen.
Guinea pig cerebella were homogenized in a Potter-Elvejhem homogenizer and [lacuna] obtained by differential centrifugation at 1000×g for 10 min and repeated centrifugation of the supernatant at 20,000×g for 10 min.

Binding Assays

For the ET_Aand ET_Breceptor binding assay, the membranes were suspended in incubation buffer (50 mM Tris-HCl, pH 7.4 with 5 mM MnCl₂, 40 μg/ml bacitracin and 0.2% BSA) at a concentration of 50 Rg of protein per assay mixture and incubated with 25 pM [125I)-ET₁(ET_Areceptor assay) or 25 pM [125I]-RZ₃(ET_Breceptor assay) in the presence and absence of test substance at 25° C. The nonspecific binding was determined using 10⁻⁷M ET₁. After 30 min, the free and bound radioligand were separated by filtration through GF/B glass fiber filters (Whatman, England) on a Skatron cell collector (Skatron, Lier, Norway) and the filters were washed with ice-cold Tris-HCl buffer, pH 7.4 with 0.2% BSA. The radioactivity collected on the filters was quantified using a Packard 2200 CA liquid scintillation counter.

Functional In Vitro Assay System to Look for Endothelin Receptor (Subtype A) Antagonists

This assay system is a functional, cell-based assay for endothelin receptors. When certain cells are stimulated with endothelin 1 (ET1) they show an increase in the intracellular calcium concentration. This increase Can be measured in intact cells loaded with calcium-sensitive dyes.
1-Fibroblasts which had been isolated from rats and in which an endogenous endothelin receptor of the A subtype had been detected were loaded with the fluorescent dye Fura 2-an as follows: after trypsinization, the cells were resuspended in buffer A (120 mM NaCl, 5 mM KCl, 1.5 mM MgCl₂, 1 mM CaCl₂, 25 mM HEPES, 10 mM glucose, pH, 7.4.) to a density of 2×10⁶/ml and incubated with Fura 2-am (2 μM), Pluronics F-127 (0.04%) and DMSO (0.2%) at 37° C. in the dark for 30 min. The cells were then washed twice with buffer A and resuspended at 2×10⁶/ml.
The fluorescence signal from 2×10⁵cells per ml with Ex/Em 380/510 was recorded continuously at 30° C. The test substances and, after an incubation time of 3 min, ET1 [lacuna] to the cells, the maximum change in the fluorescence was determined. The response of the cells to ET1 without previous addition of a test substance was used as control and was set equal to 100%.

Testing of ET Antagonists In Vivo

Male SD rats weighting 250-300 g were anesthetized with amobarbital, artificially ventilated, vagotomized and pithed. The carotid artery and jugular vein were cathetized [sic].
In control animals, intravenous administration of 1 μg/kg ET1 led to a distinct rise in blood pressure which persisted for a lengthy period.
The test animals received an i.v. injection of the test compounds (1 ml/kg) 5 min before the administration of ET1. To determine the ET-antagonistic properties, the rise in blood pressure in the test animals was compared with that in the control animals.

Endothelin-1-Induced Sudden Death in Mice

The principle of the-test is the inhibition of the sudden heart death caused in mice by endothelin, which is probably induced by constriction of the coronary vessels, by pretreatment with endothelin receptor antagonists. Intravenous injection of 10 nmol/kg endothelin in a volume of 5 ml/kg of body weight results in death of the animals within a few minutes.
The lethal endothelin-1 dose is checked in each case on a small group of animals. If the test substance is administered intravenously, the endothelin-1 injection which was lethal in the reference group usually takes place 5 min thereafter. With other modes of administration, the times before administration are extended, where appropriate up to several hours.
The survival rate is recorded, and effective doses which protect 50% of the animals (ED 50) from endothelin-induced heart death for 24 h or longer are determined.

Functional Test on Vessels for Endothelin Receptor Antagonists

Segments of rabbit aorta are, after an initial tension of 2 g and a relaxation time of 1 h in Krebs-Henseleit solution at 37° C. and pH-7.3-7.4, first induced to contract with K+. After washing out, an endothelin dose-effect plot up to the maximum is constructed.
Potential endothelin antagonists are administered to other preparations of the same vessel 15 min before starting the endothelin dose-effect plot. The effects of the endothelin are calibrated as a % of the K+-induced contraction. Effective endothelin antagonists result in a shift to the right in the endothelin dose-effect plot.
The compounds according to the invention can be administered orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperotoneally) 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. The daily dose of active substance is, as a rule, about 0.5-50 mg/kg of body weight on oral administration and about 0.1-10 mg/kg of body weight 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 substances can for this purpose be processed with conventional pharmaceutical aids such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, release-slowing agents, antioxidants and/or propellent gases (cf. H. Sucker. et al.: Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1991). The administration forms obtained in this way normally contain from 0.1 to 90% by weight of the active substance.

SYNTHESIS EXAMPLES

Example 1

Methyl 2-hydroxy-3-methoxy-3,3-diphenylpropionate

5 g (19.6 mmol) of methyl 3,3-diphenyl-2,3-epoxypropionate were dissolved in 50 M1 of absolute methanol and, at 0° C., 0.1 ml of boron trifluoride etherate was added. The mixture was stirred at 0° C. for 2 h and at room temperature for a further 12 h. The solvent was distilled out, the residue was taken up in ethyl acetate, washed with sodium bicarbonate solution and water and dried over magnesium sulfate. After removal of the solvent by distillation there remained 5.5 g (88%) of a, pale yellow oil.

Example 2

Methyl 2-hydroxy-3-phenoxy-3,3-diphenylpropionate

5 g (19.6 mmol) of methyl 3,3-diphenyl-2,3-epoxypropionate and 5.6 g (60 mmol) of phenol were heated together at 100° C. for 6 h. Removal of the excess phenol by distillation under high vacuum and purification of the residue by chromatography on silica gel with hexane/ethyl acetate mixtures resulted in 4.9 g (77%) of a pale yellow oil.

Example 3

Methyl 2-(4,6-dimethoxy-pyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropionate

2.86 g (10 mmol) of methyl 2-hydroxy-3-methoxy-3,3-diphenylpropionate were dissolved in 40 ml of dimethylformamide, and 0.3 g (12 mmol) of sodium hydride was added. The mixture was stirred for 1 h and then 2.2 g (10 mmol) of 4,6-dimethoxy-2-methylsulfonylpyrimidine were added. After stirring at room temperature for 24 h, cautious hydrolysis was carried out with 10 ml of water, the pH was adjusted to 5 with acetic acid, and the solvent was removed by distillation under high vacuum. The residue was taken up in 100 ml of ethyl acetate, washed with water and dried over magnesium sulfate, and the solvent was distilled out. The residue was mixed with 10 ml of ether, and the resulting precipitate was filtered off with suction. After drying, 3.48 g (82%) of a white powder remained.
Melting point 81° C.

Example 4

2-(4,6-Dimethoxy-pyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropionic acid

2.12 g (5 mmol) of methyl 2-(4,6-dimethoxy-pyriMidin-2-yloxy)-3-methoxy-3,3-diphenylpropionate were dissolved in 50 ml of dioxane, 10 ml of 1 N KOH solution were added, and the mixture was stirred at 100° C. for 3 h. The solution was diluted with 300 ml of water and extracted with ethyl acetate to remove unreacted ester. The aqueous phase was then adjusted to pH 1-2 with dilute hydrochloric acid and extracted with ethyl acetate. After drying over magnesium sulfate and removal of the solvent by distillation, the residue was mixed with an ether/hexane mixture, and the precipitate which formed was filtered off with suction. After drying, 1.85 g (90%) of a white powder remained.
Melting-point 16-7° C.

Example 5

2-(4,6-Dimethoxy-2-pyrimidinyloxy)-3-methoxy-3,3-diphenyl sodium [sic] propionate

1.68 g (4 mmol) of 2-(4,6-dimethoxy-2-pyrimidinyloxy)-3-methoxy-3,3-diphenylpropionic acid are dissolved in 4 ml of 1N NaOH 4 100 ml of water. The solution is freeze-dried, and the sodium salt of the carboxylic acid used is obtained quantitatively.
10 g (34.9 mmol) of methyl 2-hydroxy-3-methoxy-3,3-diphenylpropionate were dissolved in 50 ml each of methanol and glacial acetic acid, 1 ml of RuO(OH)₂in dioxane was added, and hydrogenation was carried out with H₂in an autoclave at 100° C. under 100 bar for 30 h. The catalyst was filtered off, the mixture was concentrated, mixed with ether and washed with NaCl solution, and the organic phase was dried and concentrated. 10.1 g of methyl 3,3-dicyclohexyl-2-hydroxy-3-methoxypropionate were obtained as an oil.

Example 7

Methyl 2-[(4,6-dimethoxy-pyrimidin-2-yl)thio]-3-methoxy-3,3-diphenylpropionate [sic]

7.16 g (25 mmol) of methyl 2-hydroxy-3-methoxy-3,3-diphenylpropionate were dissolved in 50 ml, of dichloromethane, 3 g (30 mmol) of triethylamine were added, and 3.2 g (28 mmol) of methanesulfonyl chloride were added dropwise while stirring. The mixture was stirred at room temperature for 2 h, washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was taken up in DMF and added dropwise at 0° C. to a suspension of 12.9 g (75 mmol) of 4,6-dimethoxypyrimidine-2-thiol and 8.4 g (100 mmol) of sodium bicarbonate in 100 ml of DMF. After stirring at room temperature for 2 h and at 60° C. for a further 2 h, the mixture was poured into 1 liter of ice-water, and the resulting precipitate was filtered off with suction. After drying, 3.19 g (29%) of a white powder remained.

Example 8

Methyl 2-hydroxy-3,3-diphenylbutyrate

1.5 g (5.9 mmol) of methyl 3,3-diphenyl-2,3-epoxypropionate dissolved in 10 ml of absolute ether were added dropwise to a cup-rate solution which had been prepared from 635 mg (7 mmol) of copper(I) cyanide dissolved in 10 ml of absolute ether and 8.14 ml (13 mmol) of a 1.6 normal methyllithium solution and had been cooled to −78° C. The solution was stirred at −78° C. for 1 h and then allowed to warm to room temperature. It was subsequently diluted with 100 ml of ether and 100 ml of water, and the ether phase was washed with dilute citric acid and with sodium bicarbonate solution and dried over magnesium sulfate. The crude product was purified by chromatography on silica gel with cyclohexane/ethyl acetate mixtures to result in 250 mg (16%) of a pale yellow oil.

Example 9

2-Hydroxy-3-methoxy-3,3-diphenylpropionic acid

91.11 g (0.5 mol) of benzophenone and 45.92 g (0.85 mol) of sodium methoxide were suspended in 150 ml of methyl tert-butyl ether (MTB) at room temperature. After cooling to −10° C., 92.24 g (0.85 mol) of methyl chloroacetate were added in such a way that the internal temperature rose to 40° C. while continuing to cool in a bath at −10° C. The mixture was then stirred without cooling at the autogenous temperature for one hour. After addition of 250 ml of water, and brief stirring, the aqueous phase was separated off. The MTB phase was washed with 250 ml of dilute sodium chloride solution. After the solvent had been changed to methanol (250 ml), a solution of 1 g of p-toluenesulfonic acid in 10 ml of methanol was added at room temperature. The mixture was stirred at autogenous temperature for one hour and then heated to reflux. While distilling out the methanol, 400 g of a 10% strength sodium hydroxide solution was added dropwise, and finally 60 ml of water were added. The methanol was distilled out until the bottom temperature reached 97° C. After cooling to 55° C., 190 ml of MTB were added and the mixture was acidified to pH 2 with about 77 ml of concentrated HCl. After cooling to room temperature, the aqueous phase was separated off and the organic phase was concentrated, by distilling, out 60 ml of MtB [sic]. The product was crystallized by adding 500 ml of heptane and slowly cooling to room temperature. The coarsely crystalline solid was filtered off with suction, washed with heptane and dried to constant weight in a vacuum oven at 40° C.
Yield: 108.9 g (80%), HPLC >99.5% area.

Example 10

S-2-Hydroxy-3-methoxy-3,3-diphenylpropionic acid (facemate resolution with L-proline methyl ester)

148.8 g of a 30% strength methanolic sodium methanolate solution (0.826 mol) were added dropwise to 240 g of a 57.% strength methanolic L-proline methyl ester hydrochloride solution (0.826 mol) at room temperature, and 2.4 l of MTB and 225 g (0.826 mol) of 2-hydroxy-3-Methoxy-3,3-diphenylpropionic acid were added. After 2680 ml of MTB/methanol mixture had been distilled out with simultaneous dropwise addition of 2.4 l of MTB, the mixture was slowly cooled to room temperature, the crystals (R-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid×L-proline methyl ester) were filtered off with suction, and the solid was washed with 150 ml of MTB. The filtrate was concentrated by distilling out 1.5 l of MTB, and 1.0 l of water was added. The pH was adjusted to 1.2 with concentrated hydrochloric acid at room temperature and, after stirring and phase separation, the aqueous phase was separated off and extracted with 0.4 l of MTB. The combined organic phases were extracted with 0.4 l of water. The residue after the MTB had been stripped off was dissolved in 650 ml of toluene under reflux, and the product was crystallized by seeding and slow cooling. Filtration with suction, washing with toluene and drying in a vacuum oven resulted in 78.7 g of S-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid (yield 35% based on the racemate).
Chiral HPLC: 100% pure
HPLC: 99.8%

Example 11

S-2-Hydroxy-3-methoxy-3,3-diphenylpropionic acid (racemate resolution with (S)-1-(4-nitrophenyl)ethylamine)

30.5 g J0.184 mol) of (S)-1-(4-nitrophenyl)ethylamine were added to 100 g (0.368 mol) of 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid in 750 ml of acetone and 750 ml of MTB under reflux, the mixture was seeded, boiled under reflux for one hour and slowly cooled to room temperature for crystallization. The crystals (S-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid×(S)-1-(4-nitrophenyl)ethylamine) were filtered off with suction and washed with MTB. The residue was suspended in 500 ml of water and 350 ml of MTB and then the pH was adjusted to 1.2 with concentrated hydrochloric acid at room temperature, and, after stirring and phase separation, the aqueous phase was separated off and extracted with 150 ml of MTB. The combined organic phases were extracted with 100 ml of water. 370 ml of MTB were distilled out and then 390 ml of n-heptane were added under reflux, and the mixture was slowly cooled to room temperature while the product crystallized. Filtration with suction, washing with n-heptane and drying in a vacuum oven resulted in 35.0 g of S-2-hydrory-3-methoxy-3,3-diphenylpropionic acid (yield 35% based on the race-mate).
Chiral HPLC: 100% pure
HPLC: 99.8%

Example 12

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

24.48 g (90 mmol) of 3-methoxy-3,3-diphenyl-2-hydroxypropionic acid were dissolved in 150 ml of DMF, and 13.7 g (99 mmol) of potassium carbonate were added. The suspension was stirred at room temperature for 30. min. Then 10.7 ml (90 mmol) of benzyl bromide were added dropwise over the course of 5 min, and the mixture was stirred for 1 h, during which the temperature rose to 32° C.
To this mixture were successively added 24.84 g (180 mmol) of K₂CO₃and 20.52 g (90 mmol) of 2-methanesulfonyl-4-methoxy6,7-dihydro-5H-cyclopentapyridine [sic], and the mixture was stirred at 80° C. for 3 h.
For workup, the contents of the flask were diluted with about 600 ml of H₂O and cautiously acidified with concentrated HCl, and 250 ml of ethyl acetate were added. 31.4 g of pure product precipitated and were filtered off.
The ethyl acetate phase was separated from the mother liquor, the aqueous phase was extracted again with ethyl acetate, and the combined organic phases were concentrated. The oily residue (19 g) was purified by chromatography (cyclohexane/ethyl acetate=9/1) to result in a further 10.5 g of pure product.
Total yield: 41.9 g (82.2 mmol)=191%
Melting point 143-147° C.
MS: MH⁺=511

Example 13

3-Methoxy-2-(4-inethoxy-(6,7-dihydro-5H-cyclopeniapyrimidin-2-yloxy)-3,3-diphenylpropionic [sic] acid

40 g (78.4 mmol) of benzyl 3-methoxy-2-(4-methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-yloxy)-3,3-diphenylpropionate were dissolved in 400 ml of ethyl acetate/methanol (4:1), about 500 mg of palladium on active carbon (10%) were added, and the mixture was exposed to a hydrogen atmosphere until no further gas was taken up. The Catalyst was-filtered off, the solution was evaporated, and the residue was crystallized from ether.

Example 14

Ethyl 2S-3,3-diphenyloxirane-2-carboxylate

2.57 g (10.2 mmol) of ethyl 3,3-diphenylacrylate and 464 mg of 4-phenylpyridine N-oxide were dissolved in 24 ml of methylene chloride, and 432 mg (6.5 mol %) of (5,5)-(+)-N,N′-bis(3,5-ditert-butylsalicylidene)-1,2-cyclohexanediaminomanganese(III) chloride were added. While cooling in ice, 6.4 ml of a 12% strength sodium hypochloride [sic] solution were added, and the mixture was stirred while cooling in ice for 30 min and at room temperature overnight. The solution was diluted to 200 ml with water, extracted with ether, dried and evaporated. 2.85 g of a colorless oil were obtained. Purification by NPLC [sic] (cyclohexane:ethyl acetate=9:1) resulted in 1.12 g of oil with an enantiomer ratio of about 8:1 in favor of the S configuration.
¹H-NMR [CDCl₃],
δ=1.0 (t, 3H); 3.9 (m, 3H); 7.3 (m, 10H)

Example 15

2-Methylsulfonyl-6,7-dihydro-5H-cyclopentapyrimidin-4-ol [sic]

46.9 g (330 mmol) of methyl cyclopentanone-2-carboxylate and 53.5 g (192 mmol) of 5-methylisothiourea [sic] sulfate were successively added to 29.6 g (528 mmol) of KOH in 396 ml of methanol, and the mixture was stirred at room temperature overnight, acidified with 1N hydrochloric acid and diluted with water. The crystals which separated out were filtered off with suction and dried. 20 g of crystals were obtained.

Example 16

sulfanyl 4-Chloro-2-methyl-6,7-dihydro-5H-cyclopentapyrimidine [sic]

255 ml of phosphorus oxychloride were added to 20 g (110 mmol) [lacuna], and the mixture was stirred at 80° C. for 3 hours. Phosphorus oxychloride was evaporated off, ice was added to the residue, and the crystals which separated out were filtered off with suction. 18.5 g of a brownish solid were obtained.

Example 17

4-Methoxy-2-methylsulfonyl-6,7-dihydro-5H-cyclopenipyrimidine [sic]

18.05 g (90 mmol) of 4-chloro-2-methylsulfonyl-6,7-dihydro-5H-cyclopentapyrimidine [sic] were dissolved in 200 ml of methanol. At 45° C., 16.7 g of sodium methoxide (as 30% strength solutions [sic] in methanol) were added dropwise, and the mixture was stirred for 2 hours. The solution was evaporated, taken up in ethyl acetate and acidified with dilute hydrochloric acid, and the ethyl acetate extract was evaporated. 15.5 g of an oil remained.
¹H-NMR [DMSO],
δ=2.1 (quintet, 2H); 2.5 (s, 3H);
2.8 (dt, 4H); 3.9 (s, 3H) ppm.

Example 18

2-methylsulfonyl-4-methoxy-6,7-dihydro-5H-cyclopentopyrimidine [sic]

15 g (76.2 mmol) of 4-methoxy-2-methylsulfonyl-6,7-dihydro-5Hcyclopentapyrimidine [sic] were dissolved in 160 ml of glacial acetic acid/methylene chloride (1:1), and 1.3 g of sodium tungstate were added. At 35° C., 17.5 ml (170 ml [sic]) of a 30% strength H202 solution were added dropwise. The mixture was then diluted with 500 ml of water and 100 ml of methylene chloride, and the organic phase was separated off, dried and evaporated. 14 g of oil remained and were crystallized from ether.
¹H-NMR [CDCl₃],
δ=2.2 (quintet, 2H); 3.0 (dt., 4H);
3.3 (s, 3H); 4.1 (s, 3H) ppm

Example 19

1-Benzenesulfonyl-3-(4,6-dimethoxy-2-pyrimidinyloxy)-4-methoxy-4,4-diphenyl-2-butanone

0.37 g (2.4 mmol) of phenyl methane [sic] sulfone were dissolved in 10 ml of dry THE and then, at −70° C., 2 eq. of butyllithium (2.94. ml; 1.6 molar solution in hexane) were added dropwise. After 1 h at −70° C., 1 g (2.4 mmol) of methyl 2-(4,6-dimethoxy-2-pyrimidinyloxy)-3-methoxy-3,3-diphenylpropynoate [sic] dissolved in 5 ml of THF was added dropwise. The reaction mixture was then stirred at −70° C. for 1 h and at −10° C. for 1 h and then warmed to room temperature.
For workup, about 10 ml of saturated NH₄Cl solution were added dropwise, thorough extraction with ethyl acetate was carried out, and the-combined organic phases [lacuna] with saturated N—Cl [sic] solution and dried over Na₂SO₄. The residue obtained after drying and concentration was purified by chromatography on silica gel (n-heptane/ethyl acetate 15%→30%) and subsequently MPLC on RP silica gel (acetonitrile/H₂O+TFA); 0.3 g of a white amorphous powder was obtained as product.

Example 20

3,3-Diphenyloxiram-2-carbonitrile [sic]

3.1 g (54.9 mmol) of sodium methoxide were suspended in 20 ml of dry THF and then, at −10° C., a mixture of 5-g (27.4 mmol) of benzophenone and 4.2 g (54.9 mmol) of chloroacetonitrile was added dropwise.
The reaction mixture was stirred at −10° C. for about 2 h, then poured into water and extracted several times with ethyl acetate. The combined organic phases were dried over Na₂SO₄and concentrated, and the residue was purified by chromatography on silica gel (n-heptane/ethyl acetate).
Yield: 1.2 g (20%)
¹H-NMR (CDCl₃],
δ=3.9 (s, 1H); 7.4-7.5 (m, 10H) ppm

Example 21

2-Hydroxy-3-methoxy-3,3-diphenylpropionitrile

6.5 [lacuna] (29.4 mmol) of 3,3-diphenyloxirane-2-carbonitrile were dissolved in 60 ml of methanol and, at 0° C., about 2 ml of boron trifluoride etherate solution were added. The mixture was stirred further at 0° C. for 1 h and then at room temperature overnight. For workup it was diluted with diethyl ether and washed with saturated NaCl solution, and the organic phase was dried over Na2SO4 and concentrated. The residue comprised 7.3 g of a white amorphous powder which was used directly in the subsequent reactions.
¹H-NMR.[CDCl₃],
δ=2.95 (broad s, OH), 3.15 (s, 3H),⁻
5.3 (s, 1H), 7.3-7.5 (m, 10) ppm

Example 22

2-(4,6-Dimethoxy-2-nyrimidinyloxy)-3-methoxy-3,3-diphenylpropionitrile

7.3 g (28.8 mmol) of 2-hydroxy-3-methoxy-3,3-diphenylpropionitrile were dissolved in 90 ml of DMF, and 4 g (28.8 mmol) of K₂CO₃and 6.3 g (28 mmol) of 2-methanesulfonyl-4,6-dimethoxypyrimidine were added. The mixture was stirred at room temperature for about 12 h, then poured into water and extracted with ethyl acetate. The combined organic phases were washed again with H₂O, dried and concentrated. The residue obtained in this way was then purified by chromatography on silica gel (n-hepane/ethyl acetate.
Yield: 6.9 g of white amorphous powder
FAB-MS: 392 (M+H⁺)
¹H-NMR [CDCl₃],
δ=3.3 (s, 3H); 4.95 (s, 6H), 5.85 (s, 1H);
6.3 (s, 1H); 7.3-7.5 (m, 10H) ppm

Example 23

5-[2-(4,6-Dimethoxy-2-pyrimidinyloxy)-3-methoxy-3,3-diphenyl)-propyl]-1H-tetrazole [sic]

0.5 g (1.3 mmol) of nitrile was dissolved in-10 ml of toluene, and 85 mg (1.3 mmol) of NaN₃and 460 mg (1.4 mmol) of Bu₃SnCl were successively added, and then the mixture was refluxed for about 40 h. Cooling was followed by dilution with ethyl acetate and washing with 10% aqueous KF solution and with NaCl solution. After drying over MgSO₄and concentration there remained 1.0 g of a yellow oil, which was purified by chromatography on silica gel (n-heptane/ethyl acetate).
Concentration of the fractions resulted in 60 mg of the 1H-tetra; zole and 110 mg of the 1-methyltetrazole, each as amorphous white solids.

5-12-(4,6-Dimethoxy-2-pyrimidinyloxy)-3-methoxy-3,3-diphenyl)-propyl]-1H-tetrazole [sic]

Electrospray-MS: 435 (M+H⁺)
¹H-NMR (CDCl₃):
δ (ppm) 3.28 (s, 3H), 3.85 (s, 6H), 5.75 (s, 1H), 7.25-7.40
(m, 10H), 7.50 (s, 1H).

5-[2-(4,6-Dimethoxy-2-pyrimidinyloxy)-3-methoxy-3,3-diphenyl)-propyl]-1-methyltetrazole [sic]

Electrospray-MS; 471 (M+H⁺)
¹H-NMR (CDCl₃):
δ (ppm) 3.0 (s, 3H), 3.35 (s, 3H9 [sic], 3.80 (s, 6H), 5.75 (s, 1H), 7.30-7.40 (m, 11H).

Example 24

2-(4,6-Dimethoxy-2-pyrimidinyloxy)-3-methylsulfinyl-3,3-diphenylpropionic acid

1.2 g (2.9 mmol) of 2-(4,6-dimethoxy-2-pyrimidinyloxy)-3-methylsulfonyl-3,3-diphenylpropionic [sic] acid were introduced into 15 ml of glacial acetic acid at 0° C. and 294 μl of 30% strength H₂0₂were added dropwise. The mixture was stirred at room temperature overnight, poured into water, extracted with CH₂Cl₂and washed with sodium thiosulfate solution and brine. After drying, 1 g of substance was isolated as a white foam.

Example 25

2-(4,6-Dimethoxy-2-pyrimidinyloxy)-3-methylsulfonyl-3,3-diphenylpropionic acid

0.6 g (1.45 mmol) of 2-(4,6-dimethoxy-2-pyrimidinyloxy)-3-methylsulfonyl-3,3-diphenylpropionic [sic] acid was introduced into 15 ml of glacial acetic acid at room temperature, and 294 μl of 30% strength H₂O₂were added dropwise. The mixture was stirred at room temperature overnight, heated at 50° C. for a further 3 h, poured into water and washed with sodium thiosulfate solution and brine. After drying, 400 mg were isolated as a white solid.
The compounds listed in Table 1 [sic] can be prepared in a similar way.

TABLE I

No	R¹	R⁴, R⁵	R⁶	R²	R³	X	Y	Z	m.p. [° C.]

I-195	OMe	Phenyl	Methyl	OMe	OMe	CH	O	O	61
I-196	OH	Phenyl	Methyl	OMe	OMe	CH	O	O	167
I-197	OH	Phenyl	CH₂—CH₂—S—CH₃	OMe	OMe	CH	O	O
I-198	OH	Phenyl	Ethyl	OMe	OMe	CH	O	O	81
									(decomp.)
I-199	OH	Phenyl	iso-Propyl	OMe	OMe	CH	O	O	182
I-200	OH	Phenyl	Methyl	OMe	OMe	CH	O	S	163
I-201	OH	Phenyl	CH₂—CH₂—SO₂—CH(CH₃)₂	OMe	OMe	CH	O	O
I-202	OH	Phenyl	CH₂—CH₂—SO₂—CH(CH₃)₂	OMe	OMe	CH	S	O
I-203	OH	Phenyl	CH₂—CH₂—SO₂—CH(CH₃)₂	OMe	OMe	C—CH(CH₃)₂	O	O
I-204	OH	Phenyl	CH₂—CH₂—SO₂—CH(CH₃)₂	OMe	OMe	C—CH(CH₃)₃	O	O
I-205	OH	Phenyl	CH₂—CH₂—SO₂—CH(CH₃)₂	OMe	NH—OCH₃	CH	O	O
I-206	OH	Phenyl	n-Propyl	OMe	OMe	CH	O	O	174
I-207	OMe	Phenyl	n-Propyl	OMe	OMe	CH	O	O
I-208	OH	Phenyl	n-Propyl	OEt	OEt	CH	O	O
I-209	OH	Phenyl	n-Butyl	OMe	OMe	CH	O	O
I-210	OH	Phenyl	iso-Butyl	OMe	OMe	CH	O	O

I-211

OH

Phenyl

iso-Butyl

OMe

O—CH₂—CH₂—C

O

I-212	OH	Phenyl	tert-Butyl	OMe	OMe	CH	O	O
I-213	OH	Phenyl	Cyclopropyl	OMe	OMe	CH	O	O
I-214	OH	Phenyl	Cyclopentyl	OMe	OMe	CH	O	O
I-215	OH	Phenyl	Cyclohexyl	OMe	OMe	CH	O	O
I-216	OH	Phenyl	(CH₃)₃C—CH₂—CH₂	OEt	OEt	CH	O	O
I-217	OH	Phenyl	(CH₃)₂CH—CH₂—CH₂—CH₂	OMe	OMe	CH	O	O	173
I-218	OH	Phenyl	HO—CH₂—CH₂	OMe	OMe	CH	O	O
I-219	OH	Phenyl	HO₂C—(CH₂)₂—	OMe	OMe	CH	O	O
I-220	OH	Phenyl	Cyclopropylmethylene	OMe	OMe	CH	O	O	115
			[sic]
I-221	OH	Phenyl	H	OMe	OMe	CH	O	O
I-222	OH	Phenyl	Methyl	OMe	OMe	CH	O	—
I-223	OH	Phenyl	Phenyl	OMe	OMe	CH	O	O	136

I-224

OH

Phenyl

OMe

O—CH(CH₃)—CH₂—C

O

I-225	OMe	Phenyl	Phenyl	OMe	OMe	CH	O	O
I-226	OH	Phenyl	4-Isopropyl-Phenyl	OMe	OMe	CH	O	O
I-227	OH	Phenyl	4-Me-S-Phenyl	OMe	OMe	CH	O	O
I-228	OH	Phenyl	4-Me-O-Phenyl	OMe	OMe	CH	O	O
I-229	OH	Phenyl	3-Et-Phenyl	OMe	OMe	CH	O	O
I-230	OH	Phenyl	2-Me-Phenyl	OMe	OMe	CH	O	O
I-231	OH	Phenyl	2-Cl-Phenyl	OMe	OMe	CH	O	O
I-232	OH	Phenyl	3-Br-Phenyl	OMe	OMe	CH	O	O
I-233	OH	Phenyl	4-F-Phenyl	OMe	OMe	CH	O	O
I-234	OH	Phenyl	4-F-Phenyl	OMe	OMe	CH	S	O
I-235	OH	Phenyl	4-CH₃-Phenyl	OMe	OMe	CH	O	O
I-236	OH	Phenyl	3-NO₂-Phenyl	OMe	OMe	CH	O	O
I-237	OH	Phenyl	2-HO-Phenyl	OMe	OMe	CH	O	O
I-238	OH	Phenyl	3,4-Dimethoxyphenyl	OMe	OMe	CH	O	O
I-239	OH	Phenyl	3,4-Dioxomethylenephenyl	OMe	OMe	CH	O	O
			[sic]
I-240	OH	Phenyl	3,4,5-Trimethoxyphenyl	OMe	OMe	CH	O	O
I-241	OH	Phenyl	Benzyl	OMe	OMe	CH	O	O
I-242	OH	Phenyl	2-Cl-Benzyl	OMe	OMe	CH	O	O
I-243	OH	Phenyl	3-Br-Benzyl	OMe	OMe	CH	O	O
I-244	OH	Phenyl	4-F-Benzyl	OMe	OMe	CH	O	O
I-245	OH	Phenyl	2-Me-Benzyl	OMe	OMe	CH	O	O

I-246

OH

Phenyl

2-Me-Benzyl

OMe

O—CH═CH—C

O

I-247	OH	Phenyl	3-Et-Benzyl	OMe	OMe	CH	O	O
I-248	OH	Phenyl	4-iso-Propyl-Benzyl	OMe	OMe	CH	O	O
I-249	OH	Phenyl	4-NO₂-Propyl-Benzyl	OMe	OMe	CH	O	O
I-250	OH	Phenyl	2-Me-5-Propyl-Benzyl	OMe	OMe	CH	O	O
I-251	OH	Phenyl	2-Me-5-Propyl-Benzyl	OEt	OEt	CH	O	O
I-252	OH	Phenyl	4-Me-2-Propyl-Benzyl	OMe	OMe	CH	O	O
I-253	OH	Phenyl	3,4-Dioxomethylene-	OMe	OMe	CH	O	O
			benzyl [sic]
I-254	OH	4-F-Phenyl	Methyl	OMe	OMe	CH	O	O	163-165
									(decomp.)
I-255	OMe	4-F-Phenyl	Methyl	OEt	OEt	CH	O	O
I-256	OH	4-Cl-Phenyl	Methyl	OMe	OMe	CH	O	O
I-257	OH	4-Me—O-Phenyl	Methyl	OMe	OMe	CH	O	O
I-258	OH	4-Me—O-Phenyl	Ethyl	OMe	OMe	CH	O	O
I-259	OH	4-Me-Phenyl	Methyl	OMe	OMe	CH	O	O

I-260

OH

4-Me-Phenyl

Methyl

OMe

O—CH₂—CH₂—C

O

I-261

OH

3-CF₃-Phenyl

n-Propyl

OMe

CH

O

I-262

OH

3-CF₃-Phenyl

n-Propyl

OMe

O—CH(CH₂)—CH₂—C

O

I-263

OH

4-NO₂-Phenyl

Methyl

OMe

CH

O

I-264

OH

4-NO₂-Phenyl

Methyl

OMe

O—CH═CH—C

O

I-265	OH	3-Cl-Phenyl	Ethyl	OMe	OMe	CH	O	O
I-266	OH	2-F-Phenyl	Methyl	OMe	OMe	CH	O	O	193-194
									(decomp.)
I-267	OH	2-F-Phenyl	Methyl	OMe	OMe	CH	S	O
I-268	OH	2-Me—O-Phenyl	Methyl	OMe	OMe	CH	O	O
I-269	OH	2-Me—O-Phenyl	Methyl	OMe	OMe	CH	O	S
I-270	OH	3,4-Dimethoxyphenyl	Methyl	OMe	OMe	CH	O	O
I-271	OH	3,4-Dioxomethylenephenyl	Methyl	OMe	OMe	CH	O	O
		[sic]
I-272	OH	p-CF₃-Phenyl	Methyl	OMe	OMe	CH	O	O
I-273	OH	Phenyl	Methyl	OMe	OEt	CH	O	O
I-274	OMe	Phenyl	Methyl	OMe	OEt	CH	S	O
I-275	OH	Phenyl	Ethyl	OMe	NH—OMe	CH	O	O
I-276	OH	p-Me—O-Phenyl	n-Propyl	OMe	OCF₃	CH	O	O
I-277	OH	Phenyl	Methyl	OMe	CF₃	CH	O	O
I-278	OH	Phenyl	Methyl	OMe	CF₃	N	O	O
I-279	OH	3,4-Dimethoxyphenyl	Benzyl	Me	Me		O	O

I-280	OH	3,4-Dimethoxyphenyl	Methyl	OMe	O—CH₂—CH₂—C	O	O
I-281	OH	Phenyl	Methyl	OMe	O—CH₂—CH₂—C	O	O	126
								(decomp.)
I-282	OH	Phenyl	Methyl	OMe	O—CH(CH₃)—CH₂—C	O	O
I-283	OH	Phenyl	Methyl	OMe	N(CH₃)—CH═CH—C	O	O	118
I-284	OH	Phenyl	Methyl	OMe	S—C(CH₃)═C(CH₃)—C	O	O
I-285	OH	Phenyl	Methyl	OMe	O—C(CH₃)═CH—C	O	O
I-286	OH	Phenyl	Methyl	Me	O—C(CH₃)═C—C	O	O
I-287	OH	Phenyl	Methyl	Me	O—CH═CH—C	O	O
I-288	OH	4-F-phenyl	Methyl	Me	S—CH═CH—C	O	O

I-289

OH

4-F-phenyl

H

OMe

CH

O

I-290	OH	Phenyl	Methyl	OMe	CH₂—CH₂—CH₂—C	O	O	149-151
								(decomp.)
I-291	OH	Phenyl	Methyl	Methyl	CH₂—CH₂—CH₂—C	O	O	157
								(decomp.)
I-292	OH	Phenyl	Methyl	Ethyl	CH₂—CH₂—CH₂—CH₂—C	O	O
I-293	OH	Phenyl	Methyl	OMe	CH₂—CH₂—CH₂—CH₂—C	O	O

I-294	OH	Phenyl	Methyl	Me	Me	CH	O	O
I-295	OH	Phenyl	Methyl	Et	Et	CH	O	O
I-296	OH	Phenyl	Methyl	Me	Me	C—CH₃	O	O
I-297	OH	Phenyl	Methyl	OMe	Me	CH	O	O
I-298	OH	Cyclohexyl	Methyl	OMe	OMe	CH	O	O

I-299

OH

Cyclohexyl

Methyl

OMe

CH₂—CH₂—CH₂—C

O

I-300	OH	Phenyl	Methyl	OCH₃	OCH₃	CH	S	S
I-301	OH	Phenyl	Methyl	OCH₃	OCH₃	CH	O	S	134
I-302	OCH₃	Phenyl	Methyl	OCH₃	OCH₃	CH	S	S
I-303	OH	Phenyl	Methyl	OCH₃	OCH₃	CH	O	O
I-304	OCH₃	2-Fluorophenyl	Methyl	OCH₃	OCH₃	CH	O	O
I-305	OC₂H₅	3-Chlorophenyl	Methyl	OCH₃	OCH₃	N	O	O
I-306	ON(CH₃)₂	4-Bromophenyl	Methyl	CF₃	CF₃	CH	S	O
I-307	O—CH₂—C═CH	Phenyl	Ethyl	OCH₃	CF₃	CH	O	O
I-308	OH	Phenyl	Propyl	OCH₃	OCF₃	CH	O	S
I-309	OCH₃	Phenyl	i-Propyl	OCH₃	CH₃	CH	O	O
I-310	OC₂H₅	Phenyl	s-Butyl	OCH₃	Cl	CH	S	O
I-311	ON(CH₃)₂	2-Methylphenyl	Methyl	OCH₃	OCH₃	CH	O	O
I-312	ON(CH₃)₂	3-Methoxyphenyl	Methyl	OCH₃	OCH₃	CH	O	O
I-313	ON═C(CH₃)₂	4-Nitrophenyl	Methyl	OCH₃	OCH₃	CH	O	O
I-314	ON(CH₃)₂	Phenyl	1-Phenylpropyn-3-yl	OCH₃	OCF₃	N	O	S
I-315	ON═C(CH₃)₂	2-Hydroxyphenyl	Methyl	OCH₃	CH₃	N	O	O
I-316	ONSO₂C₆H₅	3-Trifluoromethylphenyl	Methyl	OCH₃	Cl	N	O	O
I-317	NHPhenyl	4-Dimethylaminophenyl	Methyl	OCH₃	OCH₃	CH	S	O
I-318	OC₂H₅	Phenyl	Trifluoroethyl	CH₃	CH₃	CH	O	O
I-319	ON(CH₃)₂	Phenyl	Benzyl	Cl	Cl	CH	O	O

I-320

ON(CH₃)₂

Phenyl

2-Methoxyethyl

OCH₃

—O—CH₂—CH₂—

S

O

I-321

OH

Phenyl

OCH₃

CH

O

I-322

OH

Phenyl

OCH₃

—O—CH₂—CH₂—

O

I-323	OH	Phenyl	Phenyl	OCH₃	OCH₃	N	O	O
I-324	OH	Phenyl	Phenyl	OCH₃	OCH₃	CH	S	O
I-325	OH	Phenyl	Phenyl	OCH₃	OCH₃	CH	S	S
I-326	OH	Phenyl	Phenyl	OCH₃	OCH₃	CH	O	S
I-327	OH	Phenyl	Phenyl	OCH₃	OCH₃	CH	O	O
I-328	OH	Phenyl	Phenyl	OCH₃	OCH₃	CH	O	O
I-329	OH	—(CH₂)₅—	Phenyl	Phenyl	OCH₃	CH	O	O
I-330	OH	Phenyl	2-Thiazolyl	OCH₃	OCH₃	CH	O	O
I-331	OCH₃	2-Fluorophenyl	Phenyl	OCH₃	OCH₃	CH	O	O
I-332	OC₂H₅	3-Chlorophenyl	Phenyl	OCH₃	OCH₃	N	O	O
I-333	ON(CH₃)₂	4-Bromophenyl	Phenyl	CF₃	CF₃	CH	O	O
I-334	O—CH₂≡CH	Phenyl	2-Fluorophenyl	OCH₃	CF₃	CH	O	O
I-335	OH	Phenyl	3-Chlorophenyl	OCH₃	OCF₃	CH	O	S
I-336	OCH₃	Phenyl	4-Bromophenyl	OCH₃	CH₃	CH	O	O
I-337	OC₂H₅	Phenyl	4-Thiazolyl	OCH₃	Cl	CH	S	O
I-338	ON(CH₃)₂	2-Methylphenyl	Phenyl	OCH₃	OCH₃	CH	O	O
I-339	ON═C(CH₃)₂	3-Methoxyphenyl	Phenyl	OCH₃	OCH₃	CH	O	O

I-340

OH

Phenyl

Methyl

OCH₃

—CH₂—CH₂—CH₂—C

O

I-341	OH	4-Fluorophenyl	Methyl	OCH₃	OCH₃	CH	O	O	168
									(decomp.)

I-342

OH

4-Fluorophenyl

Methyl

OCH₃

—CH₂—CH₂—CH₂—C

O

I-343

NH—SO—C₆H₅

4-Nitrophenyl

Phenyl

OCH₃

CH

O

I-344

OCH₃

Phenyl

3-Imidazolyl

OCH₃

—O—CH₂—CH₂

O

I-345	OC₂H₅	Phenyl	4-Imidazolyl	OCH₃	CF₃	N	S	O
I-346	ON(CH₃)₂	Phenyl	2-Pyrazolyl	OCH₃	OCF₃	N	O	S
I-347	ON═C(CH₃)₂	2-Hydroxyphenyl	Phenyl	OCH₃	CH₃	N	O	O
I-348	NH—SO₂—C₆H₅	3-Trifluoromethylphenyl	Phenyl	OCH₃	Cl	N	O	O
I-349	NHPhenyl	4-Dimethylaminophenyl	Phenyl	OCH₃	OCH₃	CH	S	O
I-350	ONa	Phenyl	Phenyl	OCH₃	OCH₃	CH	S	S
I-351	O—CH₂—C≡C	Phenyl	Phenyl	OCH₃	OCH₃	N	S	S
I-352	OH	Phenyl	Phenyl	CF₃	CF₃	CH	O	S
I-353	OCH₃	Phenyl	Phenyl	OCF₃	OCF₃	CH	O	O
I-354	OC₂H₅	Phenyl	2-Dimethylaminophenyl	CH₃	CH₃	CH	O	O
I-355	ON(CH₃)₂	Phenyl	3-Hydroxyphenyl	Cl	Cl	CH	O	O

I-356

ON═C(CH₃)₂

Phenyl

4-Trifluoromethylphenyl

OCH₃

—O—CH₂—CH₂—

S

O

I-357	NH—SO₂—C₆H₅	Phenyl	2-Oxazolyl	OCH₃	CF₃	N	S	S
I-358	OH	Phenyl	Methyl	CH₃	CH₃	CH	O	O
I-359	OH	Cyclohexyl	Methyl	OCH₃	OCH₃	CH	O	O

I-360

OH

Cyclohexyl

Methyl

OCH₃

—CH₂—CH₂—CH—C

O

I-361	OH	Phenyl	Methyl	N(CH₃)₂	N(CH₃)₂	CH	O	O
I-362	OH	Phenyl	Methyl	OCH₃	OCH₃	CH	O	SO₂
I-363	OH	Phenyl	Methyl	OCH₃	OCH₃	CH	O	SO₂
I-364	OH	3-F-Phenyl	Me	OMe	OMe	CH	O	O

I-365	OH	3-F-Phenyl	Me	OMe	CH₂—CH₂—CH₂—C	O	O
I-366	OH	4-F-Phenyl	Me	OMe	CH₂—CH₂—CH₂—C	O	O	142-143
								191° C.
I-367	OH	3-MeO-Phenyl	Me	OMe	CH₂—CH₂—CH₂—C	O	O	158-161
								(decomp.)

I-368

OH

3-MeO-Phenyl

Me

OMe

CH

O

I-369	OH	3-MeO-Phenyl	Et	OMe	CH₂—CH₂—CH₂—C	O	O
I-370	OH	Phenyl	HO—CH₂—CH₂	OMe	CH₂—CH₂—CH₂—C	O	O

I-371	OH	Phenyl	Me	NMe₂	NMe₂	N	O	O	181
I-372	OH	Phenyl	Me	OMe	OMe	N	O	O
I-373	OH
I-374	NH—SO₂-Phenyl	Phenyl	Me	OMe	OMe	CH	O	O
I-375	NH—SO₂—Me	Phenyl	Me	OMe	OMe	CH	O	O
I-376	CH₂—SO₂-Phenyl	Phenyl	Me	OMe	OMe	CH	O	O
I-377	CH₂—SO₂—Me	Phenyl	Me	OMe	OMe	CH	O	O
I-378	—CN	Phenyl	Me	OMe	OMe	CH	O	O
I-379	Tetrazole [sic]	Phenyl	Me	OMe	OMe	CH	O	O
I-380	NH—SO₂-Phenyl	Phenyl	Me	OMe	OMe	CH	O	O	167
I-381	N-Methyltetra-	Phenyl	Me	OMe	OMe	CH	O	O
	zole [sic]

I-382	ONa	Phenyl	Me	OMe	—O—CH₂—CH₂—C—	O	O	122-139
								(zers.)
I-383	OH	o-F-Phenyl	Me	OMe	—O—CH₂—CH₂—C—	O	O	140-144
								(decomp.)

I-384

OH

m-Me-Phenyl

Me

OMe

CH

O

169-177

I-385	OH	m-Me-Phenyl	Me	OMe	—O—CH₂—CH₂—C—	O	O	119-135
								(decomp.)

I-386	OH	p-F-Phenyl	Me	OMe	Me	CH	O	O	137-140
									(decomp.)

I-387	OH	m-F-Phenyl	Me	Me	—O—CH₂—CH₂—C—	O	O	150-152
I-388	OH	p-F-Phenyl	Me	Me	—O—CH₂—CH₂—C—	O	O	169-170

TABLE II

No.	R¹	A	R⁶	R²	R³	X	Y	Z	m.p. [° C.]

II-1	OH	Bond	Methyl	OMe	OMe	CH	O	O	96-98
II-2	OH	CH₂	Methyl	OMe	OMe	CH	O	O
II-3	OH	CH₂—CH₂	Methyl	OMe	OMe	CH	O	O
II-4	OH	CH═CH	Methyl	OMe	OMe	CH	O	O
II-5	OH	O	Methyl	OMe	OMe	CH	O	O
II-6	OH	S	Methyl	OMe	OMe	CH	O	O
II-7	OH	NH(CH₃)	Methyl	OMe	OMe	CH	O	O
II-8	OH	Bond	Isopropyl	OMe	OMe	CH	O	O	137-139
II-9	OH	Bond	p-Isopropylphenyl	OMe	OMe	CH	O	O
II-10	OH	Bond	Benzyl	OMe	OMe	CH	O	O
II-11	OH	CH═CH	Ethyl	OMe	OMe	CH	O	O
II-12	OH	CH═CH	(CH₃)₂—CH₂—CH₂	OMe	OMe	CH	O	O
II-13	OH	CH═CH	Cyclopropylmethylene [sic]	OMe	OMe	CH	O	O

II-14	OH	CH═CH	Methyl	OMe	O—CH₂—CH₂—C	O	O
II-15	OH	CH₂—CH₂	Ethyl	OMe	O—CH═CH—C	O	O
II-16	OH	CH₂—CH₂	Methyl	OMe	CH₂—CH₂—CH₂—C	O	O
II-17	OH	Bond	Methyl	OMe	CH₂—CH₂—CH₂—C	O	O	147

Example 35

Receptor binding data were measured by the binding assay described above for the compounds listed below.
The results are shown in Table 2 [sic].

TABLE 2 [sic]

Receptor binding data (K_ivalues)

	Compound	ET_A[nM]	ET_B[nM]

I-2	6	34
I-29	86	180
I-5	12	160
I-4	7	2500
I-87	1	57
I.89	86	9300
I-103	0.4	29
I-107	3	485
I-12	19	1700
I-26	23	2000
I-23	209	1100
I-47	150	1500
I-60	33	970
I-96	0.6	56
II-3	107	7300
II-1	28	2300

Claims

1. A carboxylic acid derivative of the formula I

where R is formyl, tetrazole [sic], nitrile [sic], a COOH group or a radical which can be hydrolyzed to COOH, and the other substituents have the following meanings:

R²hydrogen, hydroxyl, NH2, NH(C₁-C₄alkyl), N(C₁-C₄-alkyl)₂halogen, C₁-C₄-alkyl, C₁-C₄-fialoalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy or C₁-C₄-alkylthio;

X nitrogen or CR¹⁴where R¹⁴is hydrogen or C_1-5-alkyl, or CR¹⁴forms together with CR³a 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; hydrogen, hydroxyl, NH2, NH(C₁-C₄-Alkyl), N(C₁-C₄-alkyl)₂, halogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, —NH—O—C_1-4-alkyl, C₁-C₄-alkylthio or CR³is linked to CR¹⁴as indicated above to give a 5- or 6-membered ring;

R⁴and R⁵(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, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, phenoxy, C₁-C₄-alkylthio, amino, C₁-C₄-alkylamino or C₁-C₄-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 SO₂, NH or N-alkyl group or C₃-C₇-cycloalkyl;

R⁶hydrogen, C₁-C₈-alkyl, C₃-C₆-alkenyl, C₃-C₈-alkynyl or C₃-C₈-cycloalkyl, where each of these radicals can be substituted one or more times by: halogen, nitro, cyano, C₁-C₄-alkoxy, C₃-C₆-alkenyloxy, C₃-C₆-alkynyloxy, C₁-C₄-alkylthio, C₁-C₄-haloalkoxy, C₁-C₄-alkylcarbonyl, C₁-C₄-alkoxycarbonyl, C_3-8-alkylcarbonylalkyl, C₁-C₄-alkylamino, di-C₁-C₄-alkylamino, phenyl or phenyl or phenoxy which is substituted one or more times, eg. one to three times, by halogen, nitro, cyano, 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, cyano, hydroxyl, amino, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxyl C₁-C₄-haloalkoxy, phenoxy, C₁-C₄-alkylthio, C₁-C₄-alkylamino, C₁-C₄-dialkylamino or dioxomethylene [sic] or dioxoethylene [sic];

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: 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;

with the proviso that R⁶can be hydrogen only when Z is not a single bond;

Y sulfur or oxygen or a single bond;

z sulfur, oxygen, —SO—, —SO2- or a single bond.

Novel carboxylic acid derivatives, their preparation and use