HK1066541B - New carboxylic acid derivatives, their preparation and their use - Google Patents

Description

Carboxylic acid derivatives, their preparation and use

The present invention relates to novel carboxylic acid derivatives, their preparation and use.

Endothelin is a peptide consisting of 21 amino acids, which is synthesized and released by the endothelium of blood vessels. Endothelin exists in three isoforms, ET-1, ET-2 and ET-3. Hereinafter "endothelin" or "ET" means one or all endothelin isomers. Endothelin is a potent vasoconstrictor and has a strong effect on vascular tone. It is known that endothelin binding to its receptor causes such vasoconstriction (Nature)332411-415, 1988; FEBS communications (Letters),231440-444, 1988 and the publication of Biochemical and biophysical research (biochem. Biophys-Res. Commun.),154，868-875，1988)。

increased or abnormal endothelin release causes sustained vasoconstriction in peripheral, renal and cerebral vessels, which can lead to disease. As reported in the literature, increased plasma levels of endothelin have been found in patients with hypertension, acute myocardial infarction, pulmonary hypertension, raynaud's syndrome, atherosclerosis and airway spasm (Japan j. hypertension,12，79(1989)，J.Vascular Med.Biology 2，207(1990)，J.Am.Med.Association 264，2868(1990))。

thus, substances which specifically inhibit the binding of endothelin to receptors should also antagonize the above-mentioned different physiological effects of endothelin and are therefore valuable pharmaceuticals.

It has now been found that certain carboxylic acid derivatives are good inhibitors of endothelin receptors.

The invention relates to carboxylic acid derivatives of formula I

In which R is a formyl, tetrazolyl, cyano, -COOH or a pair of COOH hydrolyzable radicals and the remaining substituents have the following meanings:

R²is hydrogen, hydroxy, NH₂，NH(C₁-C₄Alkyl), N (C)₁-C₄-alkyl groups)₂Halogen, C₁-C₄-alkyl radical, C₁-C₄Haloalkyl, C₁-C₄-alkoxy radical, C₁-C₄-haloalkoxy or C₁-C₄An alkyl sulfide;

x is nitrogen or CR¹⁴Wherein R is¹⁴Is hydrogen or C_1-5Alkyl or CR¹⁴And CR³Forming a 5-or 6-membered alkylene or alkenylene ring which may be interrupted by one or two C₁-C₄Alkyl substituted and in which one methylene group may be always replaced by oxygen, sulfur, -NH or-N (C)₁-C₄-alkyl) substitution;

R³is hydrogen, hydroxy, NH₂，NH(C₁-C₄Alkyl), N (C)₁-C₄-alkyl groups)₂Halogen, C₁-C₄-alkyl radical, C₁-C₄-haloalkyl radical, C₁-C₄-alkoxy radical, C₁-C₄-haloalkoxy, -NH-O-C₁-₄-alkyl radical, C₁-C₄Alkylthio or CR as defined above³And CR¹⁴To form a 5-or 6-membered ring;

R⁴and R⁵(II)Which may be the same or different) are:

phenyl or naphthyl, both of which may be substituted by one or more of the following groups: halogen, nitro, cyano, hydroxy, C₁-C₄-alkyl radical, C₁-C₄-haloalkyl radical, C₁-C₄-alkoxy radical, C₁-C₄Halogenoalkoxy, phenoxy, C₁-C₄Alkyl sulfur, amino, C₁-C₄-alkylamino or C₁-C₄-a dialkylamino group; or

Phenyl or naphthyl, both ortho-fixed via a direct bond, methylene, ethylene or vinylene, an oxygen or sulfur atom or an SO₂-, NH-or N-alkyl radicals in combination or C₃-C₇-a cycloalkyl group;

R⁶is hydrogen, C₁-C₈-alkyl radical, C₃-C₆-alkenyl radical, C₃-C₆-alkynyl or C₃-C₈Cycloalkyl, where these radicals may be substituted one or more times by: halogen, nitro, cyano, C₁-C₄-alkoxy radical, C₃-C₆An alkenyloxy radical, C₃-C₆-alkynyloxy radical, C₁-C₄Alkyl sulfur, C₁-C₄-haloalkoxy, C₁-C₄-alkylcarbonyl group, C₁-C₄Alkoxycarbonyl radical, C₃-C₈-alkylcarbonylalkyl, C₁-C₄Alkylamino, di-C₁-C₄Alkylamino, phenyl or one or more, e.g. one to three, passes through halogen, nitro, cyano, C₁-C₄-alkyl radical, C₁-C₄-haloalkyl radical, C₁-C₄-alkoxy radical, C₁-C₄-haloalkoxy or C₁-C₄-an alkylthio-substituted phenyl or phenoxy group;

phenyl or naphthyl, both of which may be substituted by one or more of the following groups: halogen, nitro, cyano, hydroxy, amino, C₁-C₄-alkanesBase, C₁-C₄-haloalkyl radical, C₁-C₄-alkoxy radical, C₁-C₄Halogenoalkoxy, phenoxy, C₁-C₄Alkyl sulfur, C₁-C₄-alkylamino radical, C₁-C₄-dialkylamino, dioxymethylene or dioxyethylene;

a 5-or 6-membered heteroarene compound containing one to three nitrogen atoms and/or one sulphur atom or oxygen atom, which arene can carry 1 to 4 halogen atoms and/or 1 to 2 of the following groups: c₁-C₄-alkyl radical, C₁-C₄-haloalkyl radical, C₁-C₄-alkoxy radical, C₁-C₄-haloalkoxy, C₁-C₄Alkylthio, phenyl, phenoxy or phenylcarbonyl, where the phenyl radical may bear from 1 to 5 halogen atoms and/or from 1 to 3 of the following radicals: c₁-C₄-alkyl radical, C₁-C₄-haloalkyl radical, C₁-C₄-alkoxy radical, C₁-C₄-haloalkoxy and/or C₁-C₄-an alkyl sulfide;

with the additional condition that: if Z is not a single bond, then R⁶May be hydrogen only;

y is sulfur or oxygen or a single bond;

z is sulfur or oxygen or a single bond.

The compounds and intermediates in their preparation, such as IV and VI, may have 1 or more asymmetrically substituted carbon atoms. Such compounds may exist as pure enantiomers or diastereomers or as mixtures thereof. The use of enantiomerically pure compounds is preferred as active substance.

The invention further relates to the use of the above-mentioned carboxylic acid derivatives for producing medicaments, in particular for producing endothelin receptor inhibitors.

Another subject of the invention is the preparation of the compound of formula IV in the form of a pure enantiomer. Enantioselective epoxidation of biphenylene-substituted olefins is known (someJournal of organic chemistry (j. orgchem)1994,59,4378-4380). It has now been unexpectedly found that both ester groups can be epoxidized in this system in high optical purity.

The preparation of the compounds of the invention, in which Z is sulfur or oxygen, starts from epoxides IV obtained in a generally known manner, for example, from ketones II or olefins III, as described in J.March, advanced organic chemistry, second edition, 1983, pages 862 and 750:

carboxylic acid derivatives of formula VI are prepared by reacting epoxides of formula IV (e.g. R ═ ROOR)¹⁰) With alcohols or thiols of formula V (wherein R is⁶And Z has the meaning mentioned in claim 1).

The compound of the formula IV is heated to a temperature of from 50 to 200 ℃ preferably from 80 to 150 ℃ in a molar ratio of approximately from 1: 1 to 1: 7, preferably from 1 to 3, molar equivalents, of the compound of the formula V.

The reaction may also be carried out in the presence of a diluent. All solvents which are inert to the reactants used can be used for this purpose.

Examples of such solvents or diluents are water, aliphatic, alicyclic and aromatic hydrocarbons which may be chlorinated if desired, such as hexane, cyclohexane, petroleum ether, naphtha, benzene, toluene, xylene, dichloromethane, chloroform, carbon tetrachloride, dichloroethane and trichloroethylene, ethers, such as diisopropyl ether, dibutyl ether, methyl-tert-butyl-ether-1, 2-epoxypropane, dioxane and tetrahydrofuran, ketones, such as acetone, methyl ethyl ketone, methyl isopropyl ketone and methyl isobutyl ketone, alkylcyanides, 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, alkyl 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.

While the reaction is preferably carried out at a temperature ranging from 0 ℃ to the boiling point of the solvent or solvent mixture.

The presence of a reaction catalyst is beneficial. In this case, strong organic and inorganic acids and also Lewis acids are suitable as catalysts. Further examples here are sulfuric acid, hydrochloric acid, trifluoroacetic acid, p-toluenesulfonic acid, boron trifluoride etherate and titanium (IV) -alcoholate.

A compound of formula VI (wherein R⁴And R⁵Is cycloalkyl) can also be prepared by subjecting a compound of formula VI, wherein R is⁴And R⁵Is phenyl, naphthyl or substituted phenyl or naphthyl as described above.

The compounds of the formula VI can be obtained in the form of the pure enantiomers starting from the pure enantiomer of the formula IV and converting it in the manner described with the compounds of the formula V.

Pure enantiomeric compounds of formula VI can additionally be obtained by a conventional racemic decomposition of a racemic or diastereomeric compound of formula VI with a suitable pure enantiomeric base, for example brucine, quinine, quinidine, demethoxyquinine, 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 (+), (-), α -methyl-benzylamine (+), (-), α - (1-naphthyl) ethylamine (+), (-), α - (2-naphthyl) ethylamine, aminomethyl pinane, N-dimethyl-1-phenylethylamine, N-methyl-1-phenylethylamine, 4-nitrophenylethylamine, pseudoephedrine, norephedrine, norpseudoephedrine, amino acid derivatives, peptide derivatives.

The compounds according to the invention, in which Y is oxygen and the remaining substituents have the meanings already given for the formula I, can be prepared, for example, by reacting carboxylic acid derivatives of the formula VI, in which the substituents have the meanings already given, with compounds of the formula VII,

in the formula R¹⁵Is halogen or R¹⁶-SO₂-, wherein R¹⁶Is C₁-C₄-alkyl radical, C₁-C₄-haloalkyl or phenyl. The reaction is preferably carried out in an inert diluent as listed above, with addition of a suitable base, that is to say a base which brings about deprotonation of the intermediate product VI, at a temperature ranging from room temperature up to the boiling point of the solvent.

The compounds of the formula VII are known, partly commercially available or can be prepared in a manner known in general.

Alkali metal hydrides or alkaline earth metal hydrides such as sodium hydride, potassium hydride or calcium hydride, carbonates such as alkali metal carbonates, for example sodium carbonate or potassium carbonate, alkali metal hydroxides or alkaline earth metal hydroxides such as sodium hydroxide or potassium hydroxide, metal organic compounds such as butyllithium or alkali metal amides such as lithium diisopropylamide can be used as bases.

The compounds of the invention, in which Y is sulfur and the remaining substituents have the meanings stated in the formula I, can be prepared, for example, by: reacting a carboxylic acid derivative of the formula VIII, which is obtainable in a known manner from a compound of the formula VI and in which the substituents have the meanings already stated, with a compound of the formula IX, in which R has²，R³And X has the meaning already stated for the formula I).

The reaction is preferably carried out in an inert diluent as described above with the addition of a suitable base, that is to say a base which brings about deprotonation of the intermediate product IX, at a temperature in the range from room temperature up to the boiling point of the solvent.

In addition to the above-mentioned bases, organic bases such as triethylamine, pyridine, imidazole or diazabicycloundecane may be used as the base.

Carboxylic acid derivatives of formula VIa (Z ═ direct bond in formula VI) are prepared by reacting an epoxide of formula IV with a cuprate of formula XI:

cuprates can communicate in tetrahedrons (Tetrahedron Letters)233755 (1982).

The compounds of formula I can also be prepared by the following process: starting from the corresponding carboxylic acid, that is to say the compound of the formula I in which R is COOH, and first converting this carboxylic acid in the usual manner into an activated form such as an acid halide, anhydride or imidazolidine and then reacting this compound with a corresponding hydroxy compound HOR¹⁰The transformation is carried out. This conversion can be carried out in customary solvents and is frequently carried out with addition of a base, in which case the bases mentioned above are taken into account. These two steps can also be simplified, for example, by the following method: the carboxylic acid is allowed to act on the hydroxy compound in the presence of a dehydrating agent such as carbodiimide.

The compounds of the formula I can furthermore be prepared by the following process: from the salts of the corresponding carboxylic acids, that is to say from compounds of the formula I in which R is COR¹And R¹Is OM, while M may be an alkali metal cation or the equivalent of an alkaline earth metal cation. Such salts may be reacted with a compound of formula R¹A number of compounds of formula (I) A, wherein A is a usual nucleofugic leaving group, e.g. halogen such as chlorine, bromine, iodine or, if desired, fluorinePerhalo-, alkyl-or haloalkyl-substituted arylsulfonyl or alkylsulfonyl groups such as tosyl and methylsulfonyl or one other equivalent leaving group. With a reactive substituent A of the formula R¹The compounds of formula (I) are known or readily available with ordinary expertise. This conversion can be carried out in customary solvents and advantageously with addition of a base, in which case the bases mentioned above are taken into account.

In formula I the radicals R are widely varied, e.g. R is a radical

In the formula R¹Has the following meanings:

a) hydrogen;

b) a succinimide oxy group;

c) a 5-membered heteroaromatic compound which is linked via a nitrogen atom, such as pyrrolyl, pyrazolyl, imidazolyl and triazolyl, which may carry one to two halogen atoms, in particular fluorine and chlorine, and/or one to two of the following groups:

C₁-C₄alkyl radicals such as the methyl, ethyl, 1-propyl, 2-methyl-2-propyl, 2-methyl-1-propyl, 1-butyl, 2-butyl radical;

C₁-C₄haloalkyl, especially C₁-C₂Haloalkyl groups such as fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trichloromethyl, 1-fluoroethyl, 2, 2-difluoroethyl, 2, 2, 2-trifluoroethyl, 2-chloro-2, 2-difluoroethyl, 2, 2-dichloro-2-fluoroethyl, 2, 2, 2-trichloroethyl and pentafluoroethyl;

C₁-C₄haloalkoxy, especially C₁-C₂Haloalkoxy such as difluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, 1-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-C₄alkoxy radicals such as the methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, 1, 1-dimethylethoxy radical, in particular the methoxy, ethoxy, 1-methylethoxy radical;

C₁-C₄alkylthio such as methylthio, ethylthio, propylthio, 1-methylethylthio, butylthio, 1-methylpropylthio, 2-methylpropylthio, 1, 1-dimethylethylthio, in particular methylthio and ethylthio;

d) in addition, R¹Is a group

Wherein m is 0 or 1 and R⁷And R⁸Which may be identical or different, have the following meanings:

hydrogen

C₁-C₈Alkyl, especially C as mentioned above₁-C₄-an alkyl group;

C₃-C₆alkenyl groups such as 2-propenyl, 2-butenyl, 3-butenyl, 1-methyl-2-propenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-2-butenyl, 2-methyl-2-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-methyl-2-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-pentenyl2-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-ethyl-2-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-C₆alkynyl groups 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-3-pentynyl, 1-methyl-4-pentynyl, 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-C₈Cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, where these alkyl, cycloalkyl, alkenyl, alkynyl groups may each carry from 1 to 5 halogen atoms, in particular fluorine or chlorine, and/or from 1 to 2 of the following groups:

C₁-C₄-alkyl radical, C₁-C₄-alkoxy radical, C₁-C₄Alkyl sulfur, C₁-C₄Haloalkoxy as mentioned above, C₃-C₆An alkenyloxy radical, C₃-C₆Alkenylsulfur, C₃-C₆-alkynyloxy、C₃-C₆Alkynylthio, wherein the alkenyl and alkynyl moieties present in these radicals preferably correspond to the meanings mentioned above;

C₁-C₄alkylcarbonyl such as, in particular, methylcarbonyl, ethylcarbonyl, propylcarbonyl, 1-methylethylcarbonyl, butylcarbonyl, 1-methylpropylcarbonyl, 2-methylpropylcarbonyl, 1, 1-dimethylethylcarbonyl;

C₁-C₄alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1-methylethoxycarbonyl, butoxycarbonyl, 1-methylpropoxycarbonyl, 2-methylpropoxycarbonyl, 1, 1-dimethylethoxycarbonyl;

C₃-C₆-alkenylcarbonyl group, C₃-C₆-alkynylcarbonyl, C₃-C₆-alkenyloxycarbonyl and C₃-C₆Alkynyloxycarbonyl, where alkenyl or alkynyl is preferably as defined above;

phenyl, if desired once or more than once, e.g. one to three times, through halogen, nitro, cyano, C₁-C₄-alkyl radical, C₁-C₄-haloalkyl radical, C₁-C₄-alkoxy radical, C₁-C₄-haloalkoxy or C₁-C₄Alkylthio substituted, 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-methoxyphenyl, 2-nitro-5-cyanophenyl, 2, 6-difluorophenyl;

di-C₁-C₄Alkylamino is especially such as dimethylamino, dipropylamino, N-propyl-N-methylamino, N-propyl-N-ethylamino, diisopropylamino, N-isopropyl-N-methylamino, N-isopropyl-N-ethylamino, N-isopropyl-N-propylamino;

in addition, R⁷And R⁸Is benzeneA group which may be substituted by one or more, for example 1 to 3, of the following groups: halogen, nitro, cyano, C₁-C₄-alkyl radical, C₁-C₄-haloalkyl radical, C₁-C₄-alkoxy radical, C₁-C₄-haloalkoxy or C₁-C₄Alkylthio, in particular as listed above;

or R⁷And R⁸Together forming a ring-closed, optionally substituted, e.g. by C₁-C₄-alkyl substituted C₄-C₇An alkylene chain which may contain a heteroatom selected from oxygen, sulphur or nitrogen, e.g. - (CH)₂)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) In addition, R¹Is a group

In which k is 0, 1 and 2, p is 1, 2, 3 and 4 and R⁹Is C₁-C₄-alkyl radical, C₁-C₄-haloalkyl radical, C₃-C₆-alkenyl radical, C₃-C₆Alkynyl or optionally substituted phenyl, in particular as mentioned above.

f) In addition, R¹Is a radical OR¹⁰In the formula, R¹⁰Comprises the following steps:

hydrogen, an alkali metal cation such as lithium, sodium, potassium or an alkaline earth metal cation such as calcium, magnesium, barium or an environmentally compatible organic ammonium ion such as t-C₁-C₄Alkyl ammoniumOr an ammonium ion;

C₃-C₈cycloalkyl is as mentioned above, which may bear 1 to 3C₁-C₄-an alkyl group;

C₁-C₈alkyl radicals such as, in particular, methyl, ethyl, propyl, 1-methyl-ethyl, 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-dimethylbutyl, 2, 2-dimethylbutyl, 3, 3-dimethylbutyl, 1, 1, 2-trimethylpropyl, 1, 2, 2-trimethylpropyl, 1-ethylbutyl, 2-ethylbutyl, 1-ethyl-2-methylpropyl, which radicals may carry from 1 to 5 halogen atoms, in particular fluorine or chlorine, and/or one of the following radicals:

C₁-C₄-alkoxy radical, C₁-C₄Alkyl sulfide, cyano, C₁-C₄-alkylcarbonyl group, C₃-C₈-cycloalkyl radical, C₁-C₄Alkoxycarbonyl, phenyl, phenoxy or phenylcarbonyl, where the aryl radicals can each bear from 1 to 5 halogen atoms and/or from 1 to 3 of the following radicals: nitro, cyano, C₁-C₄-alkyl radical, C₁-C₄-haloalkyl radical, C₁-C₄-alkoxy radical, C₁-C₄-haloalkoxy and/or C₁-C₄Alkyl sulfides, in particular as mentioned above;

a C₁-C₈Alkyl as mentioned above, such a radical may carry from 1 to 5 halogen atoms, in particular fluorine and/or chlorine, and one of the following radicals: a 5-membered heteroaromatic compound containing 1 to 3 nitrogen atoms or a 5-membered heteroaromatic compound containing one nitrogen atom and one oxygen atom or sulfur atom, which may carry 1 to 4 halogen atoms and/or 1 to 2 groups described below;

nitro, cyano, C₁-C₄-alkyl radical, C₁-C₄-haloalkyl radical, C₁-C₄Alkoxy, phenyl, C₁-C₄-haloalkoxy and/or C₁-C₄-an alkyl sulfide. Mention may be made in particular of: 1-pyrazolyl, 3-methyl-1-pyrazolyl, 4-methyl-1-pyrazolyl, 3, 5-dimethyl-1-pyrazolyl, 3-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-isopropylisoxazol-5-yl, 3-methylisoxazol-5-yl, oxazol-2-yl, thiazol-2-yl, imidazol-2-yl, 3-ethylisoxazol-5-yl, 3-phenyl-isoxazol-5-yl, 3-tert-butylisoxazol-5-yl;

a C₂-C₆-an alkyl group bearing in the 2-position one of the following groups: c₁-C₄-alkoxyimino group, C₃-C₆Alkinyloxyimino radical, C₃-C₆-haloalkenyloxyimino or benzyloxyimino;

a C₃-C₆-alkenyl or a C₃-C₆Alkynyl, where these radicals may carry from 1 to 5 halogen atoms;

in addition, R¹⁰Is a phenyl radical which may carry 1 to 5 halogen atoms and/or 1 to 3 radicals: nitro, cyano, C₁-C₄-alkyl radical, C₁-C₄-haloalkyl radical, C₁-C₄-alkoxy radical, C₁-C₄-haloalkoxy and/or C₁-C₄Alkyl sulfides, in particular as mentioned above;

a 5-membered heteroaromatic compound containing 1 to 3 nitrogen atoms which is linked via a nitrogen atom and which can carry 1 to 2 halogen atoms and/or 1 to 2 radicals: c₁-C₄-alkyl radical, C₁-C₄-haloalkyl radical, C₁-C₄Alkoxy, phenyl, C₁-C₄Alkyl halidesOxy and/or C₁-C₄-an alkyl sulfide. Mention may be made in particular of: 1-pyrazolyl, 3-methyl-1-pyrazolyl, 4-methyl-1-pyrazolyl, 3, 5-dimethyl-1-pyrazolyl, 3-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, 4-dichloro-imidazol-1-yl;

in addition, R¹⁰Is a radical

In the formula R¹¹And R¹²(which may be the same or different) are:

C₁-C₈-alkyl radical, C₃-C₆-alkenyl radical, C₃-C₆-alkynyl, C₃-C₈Cycloalkyl, where these radicals may bear a C₁-C₄-alkoxy radical, C₁-C₄Alkylthio and/or an optionally substituted phenyl radical, in particular as mentioned above;

phenyl, which may be substituted by one or more, for example 1 to 3, of the following groups: halogen, nitro, cyano, C₁-C₄-alkyl radical, C₁-C₄-haloalkyl radical, C₁-C₄-alkoxy radical, C₁-C₄-haloalkoxy or C₁-C₄Alkylthio, where these radicals are particularly suitable for the abovementioned radicals;

or R¹¹And R¹²Together form a C₃-C₁₂An alkylene chain which may carry from 1 to 3C₁-C₄Alkyl and may contain a heteroatom of oxygen, sulfur and nitrogen, as in R⁷And R⁸As mentioned.

g) In addition, R¹Is a radical

In the formula R¹³Comprises the following steps:

C₁-C₄-alkyl radical, C₃-C₆-alkenyl radical, C₃-C₆-alkynyl, C₃-C₈Cycloalkyl radicals, in particular as mentioned above, wherein these radicals may bear a C₁-C₄-alkoxy radical, C₁-C₄-an alkylthio group and/or one of the phenyl groups mentioned above;

phenyl, optionally substituted, in particular as mentioned above.

h)R¹Is a radical

In the formula R¹³Have the meaning mentioned above.

R may additionally be: tetrazole or nitrile.

In view of the fact that biologically active carboxylic acid derivatives of the general formula I are preferred (not only as pure enantiomers or pure diastereomers but also as mixtures thereof), wherein the substituents have the following meanings:

R²is hydrogen, hydroxy, N (C)₁-C₄-alkyl groups)₂At R¹C mentioned in detail₁-C₄-alkyl radical, C₁-C₄-haloalkyl radical, C₁-C₄-alkoxy radical, C₁-C₄-haloalkoxy, C₁-C₄Alkylthio and halogen atoms, in particular chlorine, methyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy;

x is nitrogen or CR¹⁴Wherein

R¹⁴Is hydrogen or alkyl, or CR¹⁴And CR³Together form a 4-to 5-membered alkylene or alkenylene ring in which one methylene group, e.g. -CH, may be replaced by oxygen or sulfur at a time₂-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 (CH)₃)＝C(CH₃)-S；

R³Is at R¹Hydrogen, hydroxy, N (C) as mentioned₁-C₄-alkyl groups)₂，C₁-C₄-alkyl radical, C₁-C₄-haloalkyl radical, C₁-C₄-alkoxy radical, C₁-C₄-haloalkyl radical, C₁-C₄Alkylthio and halogen atoms, especially chlorine, methyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy or with R¹⁴As mentioned above, to form a 5-or 6-membered ring;

R⁴and R⁵Is phenyl or naphthyl, which may be substituted by one or more, for example 1 to 3, of the following groups: halogen, nitro, cyano, hydroxy, mercapto, amino, C₁-C₄-alkyl radical, C₁-C₄-haloalkyl radical, C₁-C₄-alkoxy radical, C₁-C₄-haloalkoxy, C₁-C₄Alkyl sulfur, C₁-C₄Alkylamino, di-C₁-C₄-alkylamino radical, C₁-C₄-alkylcarbonyl group, C₁-C₄-an alkoxycarbonyl group;

phenyl or naphthyl, which is ortho-fixed via a direct bond, methylene, ethylene or vinylene, oxygen or sulfur atom or-SO₂-, NH-or N-alkyl radicals bonded to one another, or C₃-C₇-a cycloalkyl group;

R⁶is C₁-C₈-alkyl radical, C₃-C₆-alkenyl radical, C₃-C₆-alkynyl or C₃-C₈Cycloalkyl is in particular as mentioned above, wherein these radicals may be substituted one or more times by: halogen, hydroxy, nitro, cyano, C₁-C₄-alkoxy radical, C₃-C₆An alkenyloxy radical, C₃-C₆-alkynyloxy radical, C₁-C₄Alkyl sulfur, C₁-C₄-haloalkoxy, C₁-C₄-alkylcarbonyl, hydroxycarbonyl, C₁-C₄Alkoxycarbonyl radical, C₁-C₄Alkylamino, di-C₁-C₄-alkylamino or optionally substituted phenyl or phenoxy, in particular as mentioned previously;

phenyl or naphthyl, which may be substituted by one or more of the following groups: halogen, nitro, cyano, hydroxy, amino, C₁-C₄-alkyl radical, C₁-C₄-haloalkyl radical, C₁-C₄-alkoxy radical, C₁-C₄Halogenoalkoxy, phenoxy, C₁-C₄Alkyl sulfur, C₁-C₄-alkylamino or C₁-C₄Dialkylamino, especially as in R⁷And R⁸As mentioned above;

a 5-or 6-membered heteroaromatic compound containing 1 to 3 nitrogen atoms and/or one sulfur or oxygen atom, which may carry 1 to 4 halogen atoms and/or 1 to 2 of the following radicals: c₁-C₄-alkyl radical, C₁-C₄-haloalkyl radical, C₁-C₄-alkoxy radical, C₁-C₄-haloalkoxy, C₁-C₄Alkylthio, phenyl, phenoxy or phenylcarbonyl, where the phenyl radical may bear from 1 to 5 halogen atoms and/or from 1 to 3 of the following radicals: c₁-C₄-alkyl radical, C₁-C₄-haloalkyl radical, C₁-C₄-alkoxy radical, C₁-C₄-haloalkoxy and/or C₁-C₄-an alkyl sulfide. In particular as in R⁴As mentioned above;

y is sulfur, oxygen or a single bond;

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

Particularly preferred compounds of the formula I (not only as pure enantiomers or pure diastereomers or as mixtures thereof) are those whose substituents have the following meanings:

R²is C₁-C₄-alkyl radical, C₁-C₄-an alkoxy group,

x is nitrogen or CR¹⁴Wherein

R¹⁴Is hydrogen or alkyl, or CR¹⁴And CR³Together form a 4-to 5-membered alkylene or alkenylene ring, e.g. -CH₂-CH₂-CH₂-，-CH＝CH-CH₂-, where one methylene group may be replaced by oxygen or sulfur in general, e.g. -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 (CH)₃)＝C(CH₃)-S；

R³Is at R¹C mentioned at the time₁-C₄-alkyl radical, C₁-C₄-alkoxy radical, C₁-C₄-alkylthio or with R¹⁴As mentioned above to form a 5-or 6-membered ring;

R⁴and R⁵Is phenyl (the same or different) which may be substituted by 1 or more, for example 1 to 3, of the following groups: halogen, nitro, hydroxy, C₁-C₄-alkyl radical, C₁-C₄-alkoxy radical, C₁-C₄Alkyl sulfur or

R⁴And R⁵Is phenyl, which is fixed in the ortho position via a direct bond, methylene, ethylene or vinylene, an oxygen or sulfur atom or-SO₂-NH-or N-alkyl are linked to each other; or

R⁴And R⁵Is C₃-C₇-a cycloalkyl group;

R⁶is C₁-C₈-alkyl radical, C₃-C₆-alkenyl or C₃-C₈Cycloalkyl, where these radicals may each be substituted one or more times by: halogen, hydroxy, nitro, cyano, C₁-C₄-alkoxy radical, C₃-C₆An alkenyloxy radical, C₁-C₄-an alkyl sulfide;

phenyl or naphthyl, which may be substituted by one or more of the following groups: halogen, nitro, cyano, hydroxy, amino, C₁-C₄-alkyl radical, C₁-C₄-haloalkyl radical, C₁-C₄-alkoxy radical, C₁-C₄Halogenoalkoxy, phenoxy, C₁-C₄Alkyl sulfur, C₁-C₄-alkylamino or C₁-C₄-a dialkylamino group;

a 5-or 6-membered heteroaromatic compound containing one nitrogen atom and/or one sulfur atom or oxygen atom, which may carry 1 to 4 halogen atoms and/or 1 to 2 of the following radicals: c₁-C₄-alkyl radical, C₁-C₄-haloalkyl radical, C₁-C₄-alkoxy radical, C₁-C₄Alkylthio, phenyl, phenoxy or phenylcarbonyl, where the phenyl radical may bear from 1 to 5 halogen atoms and/or from 1 to 3 of the following radicals: c₁-C₄-alkyl radical, C₁-C₄-haloalkyl radical, C₁-C₄-alkoxy and/or C₁-C₄-an alkyl sulfide;

y is sulfur, oxygen or a single bond;

z is sulfur, oxygen, -SO-, -SO-₂-or a single bond.

The compounds of the invention provide a new therapeutic possibility for the treatment of hypertension, pulmonary hypertension, myocardial infarction, angina pectoris, acute renal failure, renal insufficiency, cerebral vasospasm, cerebral ischemia, subarachnoid hemorrhage, migraine, asthma, atherosclerosis, endotoxic shock, endotoxically-induced organ failure, intravascular coagulation, restenosis following angioplasty, benign prostatic hypertrophy, ischemic and poisoning-induced renal failure or hypertension.

The good effect of the compounds can be shown in the following tests:

receptor binding studies

Expression of cloned human ET for binding studies_ACHO cells of the receptor and ET_A-receptor has > 60% ET compared to_BGuinea pig meninges of the recipient.

Membrane preparation

Make expression of ET_ACHO-cells of the receptor in F with 10% fetal bovine serum, 1% glutamine, 100E/ml penicillin and 0.2 streptomycin (Gibco BRL, Gaithersburg, Md., USA)₁₂Propagation in culture medium. After 48 hours the cells were washed with PBS and incubated with 0.05% trypsin in PBS for 5 minutes. Thereafter with F₁₂The medium was neutralized and the cells were harvested at 300 Xg by centrifugation. For cell lysis the granulate is briefly washed with lysis buffer (5mM tri-HCl, pH7.4, with 10% glycerol) and then at 4 ℃ at a concentration of 10 ℃⁷Cells/ml lysis buffer for 30 min. The membranes were centrifuged at 20,000 Xg for 10 minutes and the pellets were stored in liquid nitrogen.

Guinea pig cerebellum was homogenized in a Potter-Elvejhem-homogenizer and was obtained by differential centrifugation at 1.000 × g for 10 minutes and repeated centrifugation at 20,000 × g for 10 minutes of the supernatant.

Binding assay

Is ET_A-and ET_BReceptor binding assay membranes were suspended in incubation buffer (50mM Tris-HCl, pH7.4, with 5 m) at a concentration of 50. mu.g protein per assay solutionM MnCl₂40. mu.g/ml bacitracin and 0.2% BSA) and at 25 ℃ with 25pm [ 125J ] -ET₁(ET_A-receptor assay) or 25pm [ 125J ] -RZ₃(ET_BReceptor assay) is incubated in the presence or absence of the test substance. By 10^-7M ET₁Nonspecific binding was determined. After 30 minutes, free and bound radioligand was separated by filtration through a GF/B glass fiber filter (Whatman, England) in a Schartron cell harvester (Skatron, Lier, Norwegen) and the filter was washed with ice-cold tri-HCl-buffer (pH7.4 with 0.2% BSA). Radioactivity collected on the filters was measured using a cypress 2200CA liquid scintillation counter.

To find the function of endothelin-receptor (subtype A) -antagonists in an in vitro test system

This test system is a functional, cell-based assay for endothelin receptors. When endothelin 1 (ET) is used₁) When the cells are stimulated, a certain number of cells show an increase in intracellular calcium concentration. This increase was detectable in intact cells (cells loaded with calcium-sensitive dyes).

1-fiber cells isolated from mice, in which an endogenous A-subtype of endothelin receptor was confirmed, were loaded with the fluorescent dye Fule 2-an (Fura 2-an) as follows: after trypsinization, cells were suspended in buffer A (120mM NaCl, 5mM KCl, 1.5mM MgCl)₂，1mM CaCl₂25mM HEPES, 10mM glucose, pH7.4) to a density of 2X 10⁶Perml and incubated with Fule 2-am (Fura 2-am) (2 μm), Prulanic F-127 (0.04%) and dimethyl sulfoxide (0.2%) in the dark at 37 ℃ within 30 minutes. Thereafter the cells were washed twice with buffer A and resuspended to 2X 10⁶/ml。

2X 10 at 30 ℃ recorded consecutively at Ex/Em 380/510⁵Fluorescence signal of cells/ml. The test substance and ET1 after 3 minutes incubation were included in the cells and the maximum change in fluorescence was determined. The reaction of cells to ET1 without the addition of test substance beforehand was used as a controlThe sum is made equal to 100%.

In vivo testing of ET-knot inhibitors

Male SD-mice weighing 250-. Carotid arteries and jugular veins were catheterized.

Intravenous infusion of 1 μ g/kg ET1 in the monitoring resulted in a significant increase in blood pressure that lasted for a longer period of time.

Test animals were injected with test compound (1mg/kg) in turn 5 minutes prior to ET1 infusion. To determine the performance of the ET-knot antagonists, the blood pressure increase in the test animals was compared with that of the control animals.

Endothelin-1 causing "sudden death" in mice

The principle of the assay was to suppress sudden cardiac death in mice caused by isoendothelin, most likely due to narrowing of the coronary vessels, by pretreatment with endothelin receptor antagonists. Animals died within a few minutes after intravenous injection of 10hmol/kg endothelin at a volume of 5ml/kg body weight.

One small herd of animals was tested for the lethal dose of endothelin-1 at a time. If the test substance is injected intravenously, the lethal endothelin-1 injection of the control group is usually performed 5 minutes thereafter. In other administration methods, the time is expected to be extended, if necessary up to several hours.

Survival was recorded and the effective dose to protect 50% of the animals from endothelin heart death for 24 hours or longer was determined.

Functional vascular assay for endothelin-receptor antagonists

K is first triggered on the aortic segment of rabbits in a Klebsiella-Shasselt solution at 37 ℃ and a pH between 7.3 and 7.4 after a prestressing and relaxation time of 1 hour of 2g⁺-contracture. After washing, an endothelin-dose curve was generated up to a maximum.

The potential endothelin-antagonist is administered 15 minutes before the start of the endothelin-dose curve to the other formulations in the same container. Effect of endothelin measured by K⁺The% of contracture calculation, a right shift of the hemogram of the endothelin dose curve in the case of effective endothelin antagonists.

The compounds of the invention can be administered orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperitoneally) in the usual manner, and also by steam or spray through the naso-pharyngeal space.

The dosage is related to the age, physical condition and weight of the patient and the method of administration. In general, the daily effective dose is between 0.5 and 50mg/kg body weight (oral) and between about 0.1 and 10mg/kg body weight (parenteral).

The novel compounds can be used in the usual administration forms formulated as a solid or liquid: for example tablets, film-coated tablets, capsules, powders, granules, dragees, suppositories, solutions, ointments, salves or sprays. These drugs are prepared by a conventional method. The active substances can be processed with the customary formulary auxiliaries such as tablet binders, fillers, preservatives, tablet-splitting agents, flow-control agents, softeners, wetting agents, dispersants, emulsifiers, solvents, retardants, antioxidants and/or drive gases (vgl. h. summer et al: pharmaceutical technology, Thieme-Verlag, Stuttgart, 1991). The administration forms thus obtained generally contain an active substance in an amount of 0.1 to 90% by weight.

Synthetic examples

Example 1

2-hydroxy-3-methoxy-3, 3-diphenylpropanoic acid methyl ester

5g (19.6mmol) of methyl 3, 3-diphenyl-2, 3-epoxypropionate are dissolved in 50ml of dry methanol and 0.1ml of boron trifluoride etherate are added at 0 ℃. Stirring was continued at 0 ℃ for 2 hours and at room temperature for 12 hours, the solvent was distilled off, the residue was taken up in ethyl acetate, washed with sodium hydrogencarbonate solution and water and dried over magnesium sulfate. After distilling off the solvent, 5.5g (88%) of a pale yellow oil remained.

Example 2

2-hydroxy-3-phenoxy-3, 3-diphenylpropanoic acid methyl ester

5g (19.6mmol) of methyl 3, 3-diphenyl-2, 3-epoxypropionate and 5.6g (60mmol) of phenol are heated together at 100 ℃ for 6 hours. The excess phenol was distilled off under high vacuum and the residue was chromatographed on silica gel using a hexane/ethyl acetate mixture to give 4.9g (77%) of a pale yellow oil.

Example 3

2- (4, 6-dimethoxy-pyrimidin-2-yloxy) -3-methoxy-3, 3-diphenylpropanoic acid methyl ester

2.86g (10mmol) of methyl 2-hydroxy-3-methoxy-3, 3-diphenyl-propionate are dissolved in 40ml of dimethylformamide and 0.3g (12mmol) of sodium hydride are added. Stirring was carried out for 1 hour and 2.2g (10mmol) of 4, 6-dimethoxy-2-methylsulfonylpyrimidine were then added. After stirring for 24 hours at room temperature, hydrolysis is carried out carefully with 10ml of water, the pH is adjusted to 5 with acetic acid and the solvent is distilled off under high vacuum, the residue is taken up in 100ml of ethyl acetate, washed with water, dried over magnesium sulfate and the solvent is distilled off. The residue was taken up in 10ml of ether and the resulting precipitate was aspirated off. After drying, 3.48g (82%) of a white powder remained.

Melting point: 81 deg.C

Example 4

2- (4, 6-dimethoxy-pyrimidin-2-yloxy) -3-methoxy-3, 3-diphenyl-propionic acid

2.12g (5mmol) of 2- (4, 6-dimethoxy-pyrimidin-2-yloxy) -3-methoxy-3, 3-diphenyl-propionic acid methyl ester are dissolved in 50ml of dioxane, admixed with 10ml of a solution of 1N in KOH and stirred at 100 ℃ for 3 hours. The solution was diluted with 300ml of water and the unconverted ester was removed by extraction with ethyl acetate. The aqueous phase is then adjusted to pH 1-2 with dilute hydrochloric acid and extracted with ethyl acetate. After drying over magnesium sulfate and distillation of the solvent, the residue was admixed with an ether/hexane mixture and the precipitate formed was aspirated off. After drying, 1.85g (90%) of a white powder remained.

Melting point: 167 deg.C

Example 5

2- (4, 6-dimethoxy-pyrimidin-2-yloxy) 3-methoxy-3, 3-diphenyl-propionic acid sodium salt

1.68g (4mmol)2- (4, 6-dimethoxy-pyrimidin-2-yloxy) -3-methoxy-3, 3-diphenyl-propionic acid was dissolved in 4ml 1N NaOH and 100ml water, the solution was freeze-dried and the sodium salt to which the carboxylic acid was added was quantitatively obtained.

Example 6

10g (34.9mmol) methyl 2-hydroxy-3-methoxy-3, 3-diphenylpropionate are dissolved in 50ml each of methanol and glacial acetic acid, 1ml of RuO (OH) in dioxane are incorporated₂And H was added in an autoclave at 100 bar and 100 ℃₂Hydrogenation was carried out for 30 hours. The catalyst is filtered off, the solution is concentrated, ether is incorporated, the organic phase is washed with NaCl solution, dried and concentrated. 10.1g of methyl 3, 3-dicyclohexyl-2-hydroxy-3-methoxypropionate are obtained as an oil.

Example 7

2- [ (4, 6-dimethoxy-pyrimidin-2-yl) thio ] -3-methoxy-3, 3-diphenylpropanoic acid methyl ester

7.16g (25mmol) of methyl 2-hydroxy-3-methoxy-3, 3-diphenyl-propionate were dissolved in 50ml of dichloromethane, 3g (30mmol) of triethylamine were added and 3.2g (28mmol) of methanesulfonic acid chloride were added dropwise with stirring. Stir at room temperature for 2 hours, wash with water, dry over magnesium sulfate and concentrate in vacuo. The residue is dissolved in dimethylformamide and added dropwise at 0 ℃ to a suspension of 12.9g (75mmol) of 4, 6-dimethoxy-pyrimidine-2-thiol and 8.4g (100mmol) of sodium hydrogencarbonate in 100ml of dimethylformamide. After stirring at room temperature for 2 hours and further stirring at 60 ℃ for 2 hours, the mixture was poured into 1 l of ice water and the precipitate formed was aspirated off, leaving after drying 3.19g (29%) of a white powder.

Example 8

2-hydroxy-3, 3-diphenyl-butyric acid methyl ester

1.5g (5.9mmol) of methyl 3, 3-diphenyl-2, 3-epoxypropionate are dissolved in 10ml of dry ether and added dropwise to a copper-carboxylate solution cooled to-78 ℃ and composed of 635mg (7mmol) of copper-I-cyanide dissolved in 10ml of dry ether and 8.14mg (13mmol) of 1.6 equivalents of methyllithium solution. Stir at-78 ℃ for 1 hour and then heat the solution to room temperature. It is then diluted with 100ml of ether and 100ml of water, the ether phase is washed with diluted citric acid and with sodium bicarbonate solution and dried over magnesium sulfate, and the crude product is chromatographed on silica gel using a cyclohexane/ethyl acetate mixture to give 250mg (16%) of a pale yellow oil.

Example 9

2-hydroxy-3-methoxy-3, 3-diphenylpropanoic acid

91.11g (0.5mol) of phenolic ketone and 45.92g (0.85mol) of sodium methylate are suspended at room temperature in 150ml of methyl tert-butyl ether (MTB). After cooling to-10 ℃ 92.24g (0.85mol) of methyl chloroacetate were added, the internal temperature was raised to 40 ℃ while further cooling with a-10 ℃ bath. Followed by stirring at the original temperature for 1 hour without cooling. The aqueous phase was separated after addition of 250ml of water and short stirring. The MTB phase was washed with 250ml of dilute sodium chloride solution and, after the solvent had been exchanged for methanol (250ml), a solution of 1g of p-toluenesulfonic acid in 10ml of methanol was added at room temperature. Stirred at the original temperature for 1 hour and then heated under reflux. 400g of 10% sodium hydroxide solution were added dropwise with distilling off methanol, followed by addition of 60ml of water. Methanol was distilled off until the bottom temperature reached 97 ℃. After cooling to 55 ℃ 190ml MTB were added and acidified to pH 2 with about 77ml concentrated HCl. After cooling to room temperature, the aqueous phase is separated and the organic phase is concentrated by distillation to 60ml MTB. The product crystallizes out by adding 500ml of heptane and slowly cooling to room temperature. The crude crystalline solid was aspirated, washed with heptane and dried in a vacuum oven at 40 ℃ to constant weight. Yield 108.9g (80%), HPLC > 99.5% (area)

Example 10

S-2-hydroxy-3-methoxy-3, 3-diphenylpropanoic acid (racemate cleavage with L-proline methyl ester)

To 240g of a 57% methanol solution of L-proline methyl ester-hydrochloride (0.826mol) were added dropwise 148.8g of a 30% methanol sodium methoxide solution (0.826mol) at room temperature, 2.4L of MTB and 225g (0.826mol) of 2-hydroxy-3-methoxy-3, 3-diphenylpropanoic acid. After 2680ml of MTB-methanol mixture had been distilled off and simultaneously 2.4 l of MTB had been added dropwise, cooling was slowly carried out to room temperature, the crystals (R-2-hydroxy-3-methoxy-3, 3-diphenylpropionic acid XL-proline methyl ester) were aspirated and the solid was washed with 15ml of MTB. The filtrate was concentrated by distilling off 1.5 l of MTB and spiked with 1.0 l of water. The pH is adjusted to 1.2 at room temperature with concentrated hydrochloric acid, the aqueous phase is separated off after stirring and phase separation and is reextracted with 0.4 l of MTB. The combined organic phases were extracted with 0.4 l of water. After withdrawal of MTB, the residue is taken up under reflux in 650ml of toluene and the product is crystallized by denaturation and slow cooling. After aspiration, washing with toluene and drying in a vacuum oven, 78.7g S-2-hydroxy-3-methoxy-3, 3-diphenylpropanoic acid (yield 35%, based on the racemate) was obtained.

Chiral HPLC: 100 percent

HPLC：99.8％

Example 11

S-2-hydroxy-3-methoxy-3, 3-diphenylpropanoic acid (cleavage of the racemate with (S) -1- (4-nitrophenyl) ethylamine)

100g (0.368mol) of 2-hydroxy-3-methoxy-3, 3-diphenylpropanoic acid are admixed with 30.5g (0.184mol) of (S) -1- (4-nitrophenyl) ethylamine in 750ml of acetone and 750ml of MTB under reflux, denatured, boiled under reflux for 1 hour and slowly cooled to room temperature with crystallization. The crystals (S-2-hydroxy-3-methoxy-3, 3-diphenylpropanoic acid X (S) -1- (4-nitrophenyl) ethylamine) were aspirated and washed with MTB. After suspending the residue in 500ml of water and 350ml of MTB, the pH is adjusted to 1.2 at room temperature with concentrated hydrochloric acid, the aqueous phase is separated off after stirring and phase separation and is reextracted with 150ml of MTB. The combined organic phases were extracted with 100ml of water. After 370ml of MTB had been distilled off, 390ml of n-heptane were admixed under reflux and slowly cooled to room temperature with crystallization of the product. After aspiration, rinsing with n-heptane and drying in a vacuum oven, 35.0g S-2-hydroxy-3-methoxy-3, 3-diphenylpropanoic acid (yield 35%, based on the racemate) was obtained.

Chiral HPLC: 100 percent

HPLC：99.8％

Example 12

3-methoxy-2- (4-methoxy-6, 7-dihydro-5H-cyclopentapyrimidin-2-yloxy) -3, 3-diphenyl-propionic acid benzyl ester

24.48g (90mmol) of 3-methoxy-3, 3-diphenyl-2-hydroxypropionic acid are dissolved in 150ml of dimethylformamide and 13.7g (99mmol) of potassium carbonate are incorporated. The suspension was stirred at room temperature for 30 minutes. 10.7ml (90mmol) of benzyl bromide are then added dropwise over a period of 5 minutes and stirred for a further 1 hour, while the temperature is increased to 32 ℃.

To this solution 24.84g (180mmol) K were added successively₂CO₃And 20.52g (90mmol) of 2-methanesulfonyl-4-methoxy-6, 7-dihydro-5H-cyclopentylpyridine were stirred at 80 ℃ for 3 hours.

About 600ml H was used for dilution for processing₂The contents were diluted O, carefully acidified with concentrated HCl and 250ml ethyl acetate was added. 31.4g of pure product precipitated and the product was filtered.

The ethyl acetate phase is separated from the mother liquor, the aqueous phase is extracted with ethyl acetate and the combined organic phases are concentrated. The oily residue (19g) was chromatographed (cyclohexane/ethyl acetate 9/1) to give a further 10.5g of pure product.

Total yield: 41.9g (82.2mmol)91％

Melting point: 143 ℃ C

MS：MH⁺＝511

Example 13

3-methoxy-2- (4-methoxy- (6, 7-dihydro-5H-cyclopentapyrimidin-2-yloxy) -3, 3-diphenylpropanoic acid

40g (78.4mmol) of 3-methoxy-2- (4-methoxy-6, 7-dihydro-5H-cyclopentapyrimidin-2-yloxy) -3, 3-diphenyl-propionic acid benzyl ester were dissolved in 400ml of ethyl acetate/methanol (4: 1), admixed with about 500mg of palladium on charcoal (10%) and placed under a hydrogen atmosphere until no more gas was absorbed. The catalyst is filtered off, the solution is concentrated by evaporation and the residue is crystallized from ether.

Example 14

2S-3, 3-Diphenyl-oxirane-2-carboxylic acid ethyl ester

2.57g (10.2mmol) of ethyl 3, 3-diphenyl-acrylate and 464mg of 4-phenylpyridine-N-oxide are dissolved in 24ml of dichloromethane and 432mg (6.5 mol%) of (5, 5) - (+) -N, N' -bis (3, 5-di-tert-butyl-salicylidene) -1, 2-cyclohexanediamino-manganese (III) chloride are incorporated. 6.4ml of 12% sodium hypochlorite solution was added under ice-cooling, stirred for 30 minutes under ice-cooling and left overnight at room temperature. The reaction solution was diluted with water to 200ml, extracted with ether, dried and concentrated by evaporation. 2.85g of a colorless oil were obtained. After purification by NPLC (cyclohexane: ethyl acetate: 9: 1) 1.12g of an oil with an enantiomeric ratio of approximately 8: 1 favouring the S-configuration are obtained.

¹H-NMR〔CDCl₃〕，

δ＝1.0(t_r，3H)；3.9(m，3H)；7.3(m，10H)

Example 15

2-methylsulfonyl-6, 7-dihydro-5H-cyclopentapyrimidin-4-ol

To 29.6g (528mmol) KOH in 396ml methanol were added 46.9g (330mmol) methyl cyclopentanone-2-carboxylate followed by 53.5g (192mmol) 5-methylisothiourea-sulfate and stirred at room temperature overnight. The reaction mixture was acidified with 1N hydrochloric acid and diluted with water. The precipitated crystals were aspirated and dried to obtain 20g of crystals.

Example 16

4-chloro-2-methylsulfonyl-6, 7-dihydro-5H-cyclopentapyrimidine

255ml of phosphorus oxychloride were added to 20g (110mmol) and stirred at 80 ℃ for 3 hours. The phosphorus oxychloride was evaporated, the residue was decomposed with ice and the precipitated crystals were aspirated off. 18.5g of a brownish solid are obtained.

Example 17

4-methoxy-2-methylsulfonyl-6, 7-dihydro-5H-cyclopentapyrimidine

18.05g (90mmol) 4-chloro-2-methylsulfonyl-6, 7-dihydro-5H-cyclopentapyrimidine are dissolved in 200ml methanol. 16.7g of sodium methyl (as a 30% solution in methanol) are added dropwise at 45 ℃ and stirred for a further 2 hours. The reaction solution was concentrated by evaporation, taken up in ethyl acetate, acidified with dilute hydrochloric acid and the ethyl acetate extract concentrated by evaporation, leaving 15.5g of oil.

¹H-NMR〔DMSO〕，

δ — 2.1 (quintuple, 2H); 2.5(S, 3H); 2.8 (dt)_r，4H)；3.9(S，3H)ppm

Example 18

2-methylsulfonyl-4-methoxy-6, 7-dihydro-5H-cyclopentapyrimidine

15g (76.2mmol) of 4-methoxy-2-methylsulfonyl-6, 7-dihydro-5H-cyclopentapyrimidine are dissolved in 160ml of glacial acetic acid/dichloromethane (1: 1) and 1.3g of the sodium tungstate salt are incorporated. 17.5ml (170ml) of 30% H was added dropwise at 35 deg.C₂O₂And (3) solution. The mixture is subsequently diluted with 500ml of water and 100ml of dichloromethane, the organic phase is separated off, dried and concentrated by evaporation, leaving 14g of oil which crystallizes from ether.

¹H-NMR〔CDCl₃〕，

δ — 2.2 (quintuple, 2H); 3.0 (dt)_r.，4H)；3.3(S，3H)；4.1(S，3H)ppm

Example 19

1-benzenesulfonyl-3- (4, 6-dimethoxypyrimidin-2-yloxy) -4-methoxy-4, 4-diphenyl-butan-2-one

0.37g (2.4mmol) of phenylmethanesulfone are dissolved in 10ml of dry tetrahydrofuran; 2 equivalents of butyllithium (2.94 ml; 1.6 mol in hexane) were then added dropwise at-70 ℃. After 1 hour at-70 ℃ 1g (2.4mmol) of methyl 2- (4, 6-dimethoxypyrimidin-2-yloxy) -3-methoxy-3, 3-diphenylpropanoate (dissolved in 5ml of tetrahydrofuran) were added dropwise. The reaction mixture was stirred at-70 ℃ for 1 hour each at-10 ℃ and then warmed to room temperature.

About 10ml of saturated NH are added dropwise for processing₄Cl solution, extracted thoroughly with ethyl acetate and the combined organic phases taken up with saturated N-Cl solution (stripped) and over Na₂SO₄The residue obtained after drying, drying and concentration is purified by chromatography on silica gel (n-heptane/ethyl acetate 15% -30%) and then on RP-silica gel (acetonitrile/H)₂O + trifluoroacetic acid) was purified by MPLC; as a product, 0.3g of a white amorphous powder was obtained.

Example 20

3, 3-Diphenyl-oxirane-2-carbonitriles

3.1g (54.9mmol) of the methyl sodium salt are suspended in 20ml of dry tetrahydrofuran and subsequently a mixture of 5g (27.4mmol) of benzophenone and 4.2g (54.9mmol) of chloroacetonitrile is added dropwise at-10 ℃.

The reaction mixture was stirred at-10 ℃ for about 2 hours, then poured into water and extracted several times with ethyl acetate. The combined organic phases are passed over Na₂SO₄Dried, concentrated and the residue left is purified by chromatography on silica gel (n-heptane/ethyl acetate).

Yield: 1.2g (20%)

¹H-NMR〔CDCl₃〕，

δ＝3.9(S，1H)；7.4-7.5(m，10H)ppm

Example 21

2-hydroxy-3-methoxy-3, 3-diphenyl-propionitrile

6.5g (29.4mmol) of 3, 3-diphenyl-oxirane-2-carbonitrile are dissolved in 60ml of methanol and admixed with about 2ml of boron trifluoride etherate solution at 0 ℃. The reaction mixture was stirred at 0 ℃ for another 1 hour and then at room temperature overnight. For the work-up, the solution is diluted with diethyl ether, washed with saturated NaCl-solution and the organic phase is passed over NaSO₄Dried and concentrated. 7.3g of a white amorphous powder remained as residue, which was used directly for further conversion.

¹H-NMR(CDCl₃)，

δ 2.95 (width S, OH), 3.15(S, 3H), 5.3(S, 1H), 7.3-7.5(m, 10) ppm

Example 22

2- (4, 6-dimethoxy-pyrimidin-2-yloxy) -3-methoxy-3, 3-diphenyl-propionitrile

7.3g (28.8mmol) 2-hydroxy-3-methoxy-3, 3-diphenylpropanenitrile are dissolved in 90ml DMF and 4g (28.8mmol) K are admixed₂CO₃And 6.3g (28.8mmol) 2-methanesulfonyl-4, 6-dimethoxy-pyrimidine. The mixture was stirred at room temperature for about 12 hours, then poured into water and extracted with ethyl acetate. The combined organic phases are washed again with water, dried and concentrated. The residue thus obtained is then purified by chromatography on silica gel (n-heptane/ethyl acetate).

Yield: 6.9g 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

S- [ 2- (4, 6-dimethoxy-pyrimidin-2-yloxy) -3-methoxy-3, 3-diphenyl) -propyl ] -1H-tetrazole

0.5g (1.3mmol) of nitrileDissolved in 10ml of toluene and admixed with 85mg (1.3mmol) of NaN₃And 460mg (1.4mmol) of Bu₃SnCl and then the mixture was heated at reflux for about 40 hours. After cooling, it is diluted with ethyl acetate, washed with 10% aqueous KF-solution and with NaCl-solution, over MgSO₄After drying and concentration 1.0g of a yellow oil remains which is purified by chromatography on silica gel (n-heptane/ethyl acetate).

After concentration of the fractions 60mg of 1H-tetrazole and 110mg of 1-methyl-tetrazole (each in amorphous white) are obtained as solids.

5- [ 2- (4, 6-dimethoxy-pyrimidin-2-yloxy) -3-methoxy-3, 3-diphenyl) -propyl ] -1H-tetrazole

electron-beam-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-pyrimidin-2-yloxy) -3-methoxy-3, 3-diphenyl) -propyl ] -1-methyl-tetrazole

electron-beam-MS: 471(M + H)⁺)

¹H-NMR(CDCl₃)；

δ(ppm)3.0(S，3H)，3.35(S，3H)，3.80(S，6H)，5.75(S，1H)，7.30-7.40(m，11H)

Example 24

2- (4, 6-dimethoxy-pyrimidin-2-yloxy) -3-methylsulfinyl-3, 3-diphenyl-propionic acid

1.2g (2.9mmol)2- (4, 6-dimethoxy-pyrimidin-2-yloxy) -3-methylsulfonyl-3, 3-diphenyl-propionic acid are placed in 15ml glacial acetic acid at 0 ℃ and 294. mu.l 30% H are added dropwise₂O₂. Stirring overnight at room temperature, pouring into water, and adding CH₂Cl₂Extracted and washed with sodium thiosulfate solution and common salt solution. Drying and separating out1g of white foam.

Example 25

2- (4, 6-dimethoxy-pyrimidin-2-yloxy) -3-methylsulfonyl-3, 3-diphenyl-propionic acid

0.6g (1.45mmol)2- (4, 6-dimethoxy-pyrimidin-2-yloxy) -3-methylsulfonyl-3, 3-diphenyl-propionic acid are placed in 15ml glacial acetic acid at room temperature and 294. mu.l 30% H are added dropwise₂O₂. Stirring was carried out overnight at room temperature, heating was continued at 50 ℃ for 3 hours, pouring into water and washing with sodium thiosulfate solution and common salt solution. After drying, 400mg of a white solid were isolated.

The compounds listed in table 1 can be prepared analogously.

TABLE I

Nr.	R1	R4，R5	R6	R2	R3	X	Y	Z	Melting Point [. degree.C. ]]
										I-1	OMe	Phenyl radical	Methyl radical	OMe	OMe	CH	O	O	81
I-2	OH	Phenyl radical	Methyl radical	OMe	OMe	CH	O	O	167
										I-3	OH	Phenyl radical	CH2-CH2-S-CH3	OMe	OMe	CH	O	O
I-4	OH	Phenyl radical	Ethyl radical	OMe	OMe	CH	O	O	81 (decomposition)
										I-5	OH	Phenyl radical	Isopropyl group	OMe	OMe	CH	O	O	182
I-6	OH	Phenyl radical	Methyl radical	OMe	OMe	CH	O	S	168
										I-7	OH	Phenyl radical	CH2-CH2-SO2-CH(CH3)2	OMe	OMe	CH	O	O
I-8	OH	Phenyl radical	CH2-CH2-SO2-CH(CH3)2	OMe	OMe	CH	S	O
										I-9	OH	Phenyl radical	CH2-CH2-SO2-CH(CH3)2	OMe	OMe	C-CH(CH3)2	O	O
I-10	OH	Phenyl radical	CH2-CH2-SO2-CH(CH3)2	OMe	OMe	C-CH(CH3)3	O	O
										I-11	OH	Phenyl radical	CH2-CH2-SO2-CH(CH3)2	OMe	NH-OCH3	CH	O	O
I-12	OH	Phenyl radical	N-propyl radical	OMe	OMe	CH	O	O	174
										I-13	OMe	Phenyl radical	N-propyl radical	OMe	OMe	CH	O	O
I-14	OH	Phenyl radical	N-propyl radical	OEt	OEt	CH	O	O

Nr.	R1	R4，R5	R6	R2	R3	X	Y	Z	Melting Point [. degree.C. ]]
										I-15	OH	Phenyl radical	N-butyl	OMe	OMe	CH	O	O
I-16	OH	Phenyl radical	Isobutyl radical	OMe	OMe	CH	O	O
										I-17	OH	Phenyl radical	Isobutyl radical	OMe	O-CH2-CH2-C		O	O
I-18	OH	Phenyl radical	Tert-butyl	OMe	OMe	CH	O	O
										I-19	OH	Phenyl radical	Cyclopropyl group	OMe	OMe	CH	O	O
I-20	OH	Phenyl radical	Cyclopentyl group	OMe	OMe	CH	O	O
										I-21	OH	Phenyl radical	Cyclohexyl radical	OMe	OMe	CH	O	O
I-22	OH	Phenyl radical	(CH3)3C-CH2-CH2	OEt	OEt	CH	O	O
										I-23	OH	Phenyl radical	(CH3)2CH-CH2-CH2-CH2	OMe	OMe	CH	O	O	173
I-24	OH	Phenyl radical	HO-CH2-CH2	OMe	OMe	CH	O	O
										I-25	OH	Phenyl radical	HO2C-(CH2)2-	OMe	OMe	CH	O	O
I-26	OH	Phenyl radical	Cyclopropyl methylene group	OMe	OMe	CH	O	O	115
										I-27	OH	Phenyl radical	H	OMe	OMe	CH	O	O
I-28	OH	Phenyl radical	Methyl radical	OMe	OMe	CH	O	-
										I-29	OH	Phenyl radical	Phenyl radical	OMe	OMe	CH	O	O	136
I-30	OH	Phenyl radical	Phenyl radical	OMe	O-CH(CH3)-CH2-C		O	O
										I-31	OMe	Phenyl radical	Phenyl radical	OMe	OMe	CH	O	O
I-32	OH	Phenyl radical	4-isopropylphenyl group	OMe	OMe	CH	O	O
										I-33	OH	Phenyl radical	4-Me-S-phenyl	OMe	OMe	CH	O	O
I-34	OH	Phenyl radical	4-Me-O-phenyl	OMe	OMe	CH	O	O
										I-35	OH	Phenyl radical	3-Et-phenyl	OMe	OMe	CH	O	O
I-36	OH	Phenyl radical	2-Me-phenyl	OMe	OMe	CH	O	O

Nr.	R1	R4，R5	R6	R2	R3	X	Y	Z	Melting Point [. degree.C. ]]
										I-37	OH	Phenyl radical	2-Cl-phenyl	OMe	OMe	CH	O	O
I-38	OH	Phenyl radical	3-Br-phenyl	OMe	OMe	CH	O	O
										I-39	OH	Phenyl radical	4-F-phenyl	OMe	OMe	CH	O	O
I-40	OH	Phenyl radical	4-F-phenyl	OMe	OMe	CH	S	O
										I-41	OH	Phenyl radical	4-CH3-phenyl radical	OMe	OMe	CH	O	O
I-42	OH	Phenyl radical	3-NO2-phenyl radical	OMe	OMe	CH	O	O
										I-43	OH	Phenyl radical	2-HO-phenyl	OMe	OMe	CH	O	O
I-44	OH	Phenyl radical	3, 4-Dimethoxyphenyl	OMe	OMe	CH	O	O
										I-45	OH	Phenyl radical	3, 4-Dioxymethylenephenyl	OMe	OMe	CH	O	O
I-46	OH	Phenyl radical	3, 4, 5-trimethoxyphenyl	OMe	OMe	CH	O	O
										I-47	OH	Phenyl radical	Benzyl radical	OMe	OMe	CH	O	O
I-48	OH	Phenyl radical	2-Cl-benzyl	OMe	OMe	CH	O	O
										I-49	OH	Phenyl radical	3-Br-benzyl	OMe	OMe	CH	O	O
I-50	OH	Phenyl radical	4-F-benzyl	OMe	OMe	CH	O	O
										I-51	OH	Phenyl radical	2-Me-benzyl	OMe	OMe	CH	O	O
I-52	OH	Phenyl radical	2-Me-benzyl	OMe	O-CH＝CH-C		O	O
										I-53	OH	Phenyl radical	3-Et-benzyl	OMe	OMe	CH	O	O
I-54	OH	Phenyl radical	4-Isopropylbenzyl	OMe	OMe	CH	O	O
										I-55	OH	Phenyl radical	4-NO2-propylbenzyl	OMe	OMe	CH	O	O
I-56	OH	Phenyl radical	2-Me-5-propylbenzyl	OMe	OMe	CH	O	O
										I-57	OH	Phenyl radical	2-Me-5-propylbenzyl	OEt	OEt	CH	O	O
I-58	OH	Phenyl radical	4-Me-2-propylbenzyl	OMe	OMe	CH	O	O

Nr.	R1	R4，R5	R6	R2	R3	X	Y	Z	Melting Point [. degree.C. ]]
										I-59	OH	Phenyl radical	3, 4-Dioxymethylenebenzyl	OMe	OMe	CH	O	O
I-60	OH	4-F-phenyl	Methyl radical	OMe	OMe	CH	O	O	163-165 (decomposition)
										I-61	OMe	4-F-phenyl	Methyl radical	OEt	OEt	CH	O	O
I-62	OH	4-Cl-phenyl	Methyl radical	OMe	OMe	CH	O	O
										I-63	OH	4-Me-O-phenyl	Methyl radical	OMe	OMe	CH	O	O
I-64	OH	4-Me-O-phenyl	Ethyl radical	OMe	OMe	CH	O	O
										I-65	OH	4-Me-phenyl	Methyl radical	OMe	OMe	CH	O	O
I-66	OH	4-Me-phenyl	Methyl radical	OMe	O-CH2-CH2-C		O	O
										I-67	OH	3-CF3-phenyl radical	N-propyl radical	OMe	OMe	CH	O	O
I-68	OH	3-CF3-phenyl radical	N-propyl radical	OMe	O-CH(CH3)-CH2-C		O	O
										I-69	OH	4-NO2-phenyl radical	Methyl radical	OMe	OMe	CH	O	O
I-70	OH	4-NO2-phenyl radical	Methyl radical	OMe	O-CH＝CH-C		O	O
										I-71	OH	3-Cl-phenyl	Ethyl radical	OMe	OMe	CH	O	O
I-72	OH	2-F-phenyl	Methyl radical	OMe	OMe	CH	O	O	193-
										I-73	OH	2-F-phenyl	Methyl radical	OMe	OMe	CH	S	O
I-74	OH	2-Me-O-phenyl	Methyl radical	OMe	OMe	CH	O	O
										I-75	OH	2-Me-O-phenyl	Methyl radical	OMe	OMe	CH	O	S
I-76	OH	3, 4-Dimethoxyphenyl	Methyl radical	OMe	OMe	CH	O	O
										I-77	OH	3, 4-Dioxymethylenephenyl	Methyl radical	OMe	OMe	CH	O	O
I-78	OH	p-CF3-phenyl radical	Methyl radical	OMe	OMe	CH	O	O
										I-79	OH	Phenyl radical	Methyl radical	OMe	OEt	CH	O	O
I-80	OMe	Phenyl radical	Methyl radical	OMe	OEt	CH	S	O

Nr.	R1	R4，R5	R6	R2	R3	X	Y	Z	Melting Point [. degree.C. ]]
										I-81	OH	Phenyl radical	Ethyl radical	OMe	NH-OMe	CH	O	O
I-82	OH	p-Me-O-phenyl	N-propyl radical	OMe	OCF3	CH	O	O
										I-83	OH	Phenyl radical	Methyl radical	OMe	CF3	CH	O	O
I-84	OH	Phenyl radical	Methyl radical	OMe	CF3	N	O	O
										I-85	OH	3, 4-Dimethoxyphenyl	Benzyl radical	Me	Me		O	O
I-86	OH	3, 4-Dimethoxyphenyl	Methyl radical	OMe	O-CH2-CH2-C		O	O
										I-87	OH	Phenyl radical	Methyl radical	OMe	O-CH2-CH2-C		O	O	126 (decomposition)
I-88	OH	Phenyl radical	Methyl radical	OMe	O-CH(CH3)-CH2-C		O	O
										I-89	OH	Phenyl radical	Methyl radical	OMe	N(CH3-CH＝CH-C		O	O	118
I-90	OH	Phenyl radical	Methyl radical	OMe	S-C(CH3)＝C(CH3)-C		O	O
										I-91	OH	Phenyl radical	Methyl radical	OMe	O-C(CH3)＝CH-C		O	O
I-92	OH	Phenyl radical	Methyl radical	Me	O-C(CH3)＝CH-C		O	O
										I-93	OH	Phenyl radical	Methyl radical	Me	O-CH＝CH-C		O	O
I-94	OH	4-F-phenyl	Methyl radical	Me	S-CH＝CH-C		O	O
										I-95	OH	4-F-phenyl	H	OMe	OMe	CH	O	O
I-96	OH	Phenyl radical	Methyl radical	OMe	CH2-CH2-CH2-C		O	O	149-
										I-97	OH	Phenyl radical	Methyl radical	Methyl	CH2-CH2-CH2-C		O	O	157 (decomposition)
I-98	OH	Phenyl radical	Methyl radical	Ethryl	CH2-CH2-CH2-CH2-C		O	O
										I-99	OH	Phenyl radical	Methyl radical	OMe	CH2-CH2-CH2-CH2-C		O	O
I-100	OH	Phenyl radical	Methyl radical	Me	Me	CH	O	O
										I-101	OH	Phenyl radical	Methyl radical	Et	Et	CH	O	O
I-102	OH	Phenyl radical	Methyl radical	Me	Me	C-CH3	O	O

Nr.	R1	R4，R5	R6	R2	R3	X	Y	Z	Melting Point [. degree.C. ]]
										I-103	OH	Phenyl radical	Methyl radical	OMe	Me	CH	O	O
I-104	OH	Cyclohexyl radical	Methyl radical	OMe	OMe	CH	O	O
										I-105	OH	Cyclohexyl radical	Methyl radical	OMe	CH2-CH2-CH2-C		O	O
I-106	OH	Phenyl radical	Methyl radical	OCH3	OCH3	CH	S	S
										I-107	OH	Phenyl radical	Methyl radical	OCH3	OCH3	CH	O	S	134
I-108	OCH3	Phenyl radical	Methyl radical	OCH3	OCH3	CH	S	S
										I-109	OH	Phenyl radical	Methyl radical	OCH3	OCH3	CH	O	O
I-110	OCH3	2-fluorophenyl group	Methyl radical	OCH3	OCH3	CH	O	O
										I-111	OC2H5	3-chlorophenyl group	Methyl radical	OCH3	OCH3	N	O	O
I-112	ON(CH3)2	4-bromophenyl radical	Methyl radical	CF3	CF3	CH	S	O
										I-113	O-CH2-C＝CH	Phenyl radical	Ethyl radical	OCH3	CF3	CH	O	O
I-114	OH	Phenyl radical	Propyl radical	OCH3	OCF3	CH	O	S
										I-115	OCH3	Phenyl radical	i-isopropyl group	OCH3	CH3	CH	O	O
I-116	OC2H5	Phenyl radical	s-sec-butyl	OCH3	Cl	CH	S	O
										I-117	ON(CH3)2	2-methylphenyl radical	Methyl radical	OCH3	OCH3	CH	O	O
I-118	ON(CH3)2	3-methoxyphenyl group	Methyl radical	OCH3	OCH3	CH	O	O
										I-119	ON＝C(CH3)2	4-Nitrophenyl radical	Methyl radical	OCH3	OCH3	CH	O	O
I-120	ON(CH3)2	Phenyl radical	1-phenyl-propyn-3-yl	OCH3	OCF3	N	O	S
										I-121	ON＝C(CH3)2	2-hydroxyphenyl group	Methyl radical	OCH3	CH3	N	O	O
I-122	ONSO2C6H5	3-trifluoromethylphenyl group	Methyl radical	OCH3	Cl	N	O	O
										I-123	NHPhenyl	4-dimethylaminophenyl radical	Methyl radical	OCH3	OCH3	CH	S	O
I-124	OC2H5	Phenyl radical	Trifluoroethyl radical	CH3	CH3	CH	O	O

Nr.	R1	R4，R5	R6	R2	R3	X	Y	Z	Melting Point [. degree.C. ]]
										I-125	ON(CH3)2	Phenyl radical	Benzyl radical	Cl	Cl	CH	O	O
I-126	ON(CH3)2	Phenyl radical	2-methoxyethyl group	OCH3	-O-CH2-CH2-		S	O
										I-127	OH	Phenyl radical	Phenyl radical	OCH3	OCH3	CH	O	O
I-128	OH	Phenyl radical	Phenyl radical	OCH3	-O-CH2-CH2-		O	O
										I-129	OH	Phenyl radical	Phenyl radical	OCH3	OCH3	N	O	O
I-130	OH	Phenyl radical	Phenyl radical	OCH3	OCH3	CH	S	O
										I-131	OH	Phenyl radical	Phenyl radical	OCH3	OCH3	CH	S	S
I-132	OH	Phenyl radical	Phenyl radical	OCH3	OCH3	CH	O	S
										I-133	OH	Phenyl radical	Phenyl radical	OCH3	OCH3	CH	O	O
I-134	OH	Phenyl radical	Phenyl radical	OCH3	OCH3	CH	O	O
										I-135	OH	-(CH2)5-	Phenyl radical	Phenyl	OCH3	CH	O	O
I-136	OH	Phenyl radical	2-thiazolyl group	OCH3	OCH3	CH	O	O
										I-137	OCH3	2-fluorophenyl group	Phenyl radical	OCH3	OCH3	CH	O	O
I-138	OC2H5	3-chlorophenyl group	Phenyl radical	OCH3	OCH3	N	O	O
										I-139	ON(CH3)2	4-bromophenyl radical	Phenyl radical	CF3	CF3	CH	O	O
I-140	O-CH2＝CH	Phenyl radical	2-fluorophenyl group	OCH3	CF3	CH	O	O
										I-141	OH	Phenyl radical	3-chlorophenyl group	OCH3	OCF3	CH	O	S
I-142	OCH3	Phenyl radical	4-bromophenyl radical	OCH3	CH3	CH	O	O
										I-143	OC2H5	Phenyl radical	4-thiazolyl group	OCH3	Cl	CH	S	O
I-144	ON(CH3)2	2-methylphenyl radical	Phenyl radical	OCH3	OCH3	CH	O	O
										I-145	ON＝C(CH3)2	3-methoxyphenyl group	Phenyl radical	OCH3	OCH3	CH	O	O
I-146	OH	Phenyl radical	Methyl radical	OCH3	-CH2-CH2-CH2-C		O	O

Nr.	R1	R4，R5	R6	R2	R3	X	Y	Z	Melting Point [. degree.C. ]]
										I-147	OH	4-fluorophenyl group	Methyl radical	OCH3	OCH3	CH	O	O	168 (decomposition)
I-148	OH	4-fluorophenyl group	Methyl radical	OCH3	-CH2-CH2-CH2-C		O	O
										I-149	NH-SO-C6H5	4-Nitrophenyl radical	Phenyl radical	OCH3	OCH3	CH	O	O
I-150	OCH3	Phenyl radical	3-imidazolyl	OCH3	-O-CH2-CH2		O	O
										I-151	OC2H5	Phenyl radical	4-imidazolyl	OCH3	CF3	N	S	O
I-152	ON(CH3)2	Phenyl radical	2-pyrazolyl radical	OCH3	OCF3	N	O	S
										I-153	ON＝C(CH3)2	2-hydroxyphenyl group	Phenyl radical	OCH3	CH3	N	O	O
I-154	NH-SO2-C6H5	3-trifluoromethylphenyl group	Phenyl radical	OCH3	Cl	N	O	O
										I-155	NH phenyl	4-dimethylaminophenyl radical	Phenyl radical	OCH3	OCH3	CH	S	O
I-156	ONa	Phenyl radical	Phenyl radical	OCH3	OCH3	CH	S	S
										I-157	O-CH2-C≡C	Phenyl radical	Phenyl radical	OCH3	OCH3	N	S	S
I-158	OH	Phenyl radical	Phenyl radical	CF3	CF3	CH	O	S
										I-159	OCH3	Phenyl radical	Phenyl radical	OCF3	OCF3	CH	O	O
I-160	OC2H5	Phenyl radical	2-dimethylaminophenyl radical	CH3	CH3	CH	O	O
										I-161	ON(CH3)2	Phenyl radical	3-hydroxyphenyl group	Cl	Cl	CH	O	O
I-162	ON＝C(CH3)2	Phenyl radical	4-trifluoromethylphenyl group	OCH3	-O-CH2-CH2-		S	O
										I-163	NH-SO2-C6H5	Phenyl radical	2-oxazolyl radical	OCH3	CF3	N	S	S
I-164	OH	Phenyl radical	Methyl radical	CH3	CH3	CH	O	O
										I-165	OH	Cyclohexyl radical	Methyl radical	OCH3	OCH3	CH	O	O
I-166	OH	Cyclohexyl radical	Methyl radical	OCH3	CH2-CH2-CH-C		O	O
										I-167	OH	Phenyl radical	Methyl radical	N(CH3)2	N(CH3)2	CH	O	O
I-168	OH	Phenyl radical	Methyl radical	OCH3	OCH3	CH	O	SO2

Nr.	R1	R4，R5	R6	R2	R3	X	Y	Z	Melting Point [. degree.C. ]]
										I-169	OH	Phenyl radical	Methyl radical	OCH3	OCH3	CH	O	SO2
I-170	OH	3-F-phenyl	Me	OMe	OMe	CH	O	O
										I-171	OH	3-F-phenyl	Me	OMe	CH2-CH2-CH2-C		O	O
I-172	OH	4-F-phenyl	Me	OMe	CH2-CH2-CH2-C		O	O	142-143191℃
										I-173	OH	3-MeO-phenyl	Me	OMe	CH2-CH2-CH2-C		O	O	158-161 (decomposition)
I-174	OH	3-MeO-phenyl	Me	OMe	OMe	CH	O	O
										I-175	OH	3-MeO-phenyl	Et	OMe	CH2-CH2-CH2-C		O	O
I-176	OH	Phenyl radical	HO-CH2-CH2	OMe	CH2-CH2-CH2-C		O	O
										I-177	OH	Phenyl radical	Me	NMe2	NMe2	N	O	O	181
I-178	OH	Phenyl radical	Me	OMe	OMe	N	O	O
										I-179	OH	3-F-phenyl	Me	OMe	Me	CH	O	O
I-180	NH-SO2-phenyl radical	Phenyl radical	Me	OMe	OMe	CH	O	O
										I-181	NH-SO2-Me	Phenyl radical	Me	OMe	OMe	CH	O	O
I-182	CH2-SO2-phenyl radical	Phenyl radical	Me	OMe	OMe	CH	O	O
										I-183	CH2-SO2-Me	Phenyl radical	Me	OMe	OMe	CH	O	O
I-184	-CN	Phenyl radical	Me	OMe	OMe	CH	O	O
										I-185	Tetrazole derivatives	Phenyl radical	Me	OMe	OMe	CH	O	O
I-186	NH-SO2-phenyl radical	Phenyl radical	Me	OMe	OMe	CH	O	O	167
										I-187	N-methyltetrazole ol	Phenyl radical	Me	OMe	OMe	CH	O	O
I-188	ONa	Phenyl radical	Me	OMe	-O-CH2-CH2-C-		O	O	122-
										I-189	OH	o-F-phenyl	Me	OMe	-O-CH2-CH2-C-		O	O	140-144 (decomposition)
I-190	OH	m-Me-phenyl	Me	OMe	OMe	CH	O	O	169-177

Nr.	R1	R4，R5	R6	R2	R3	X	Y	Z	Melting Point [. degree.C. ]]
										I-191	OH	m-Me-phenyl	Me	OMe	-O-CH2-CH2-C-		O	O	119-135 (decomposition)
I-192	OH	p-F-phenyl	Me	OMe	Me	CH	O	O	137-
										I-193	OH	m-F-phenyl	Me	Me	-O-CH2-CH2-C-		O	O	150-152
I-194	OH	p-F-phenyl	Me	Me	-O-OH2-CH2-C-		O	O	169-170

TABLE II

Nr.	R1	A	R6	R2	R3	X	Y	Z	Melting Point [. degree.C. ]]
										II-1	OH	Key with a key body	Methyl radical	OMe	OMe	CH	O	O	96-98
II-2	OH	CH2	Methyl radical	OMe	OMe	CH	O	O
										II-3	OH	CH2-CH2	Methyl radical	OMe	OMe	CH	O	O
II-4	OH	CH＝CH	Methyl radical	OMe	OMe	CH	O	O
										II-5	OH	O	Methyl radical	OMe	OMe	CH	O	O
II-6	OH	S	Methyl radical	OMe	OMe	CH	O	O
										II-7	OH	NH(CH3)	Methyl radical	OMe	OMe	CH	O	O
II-8	OH	Key with a key body	Isopropyl group	OMe	OMe	CH	O	O	137-139

Nr.	R1	A	R6	R2	R3	X	Y	Z	Melting Point [. degree.C. ]]
										II-9	OH	Key with a key body	P-isopropylphenyl	OMe	OMe	CH	O	O
II-10	OH	Key with a key body	Benzyl radical	OMe	OMe	CH	O	O
										II-11	OH	CH＝CH	Ethyl radical	OMe	OMe	CH	O	O
II-12	OH	CH＝CH	(CH3)2-CH2-CH2	OMe	OMe	CH	O	O
										II-13	OH	CH＝CH	Cyclopropyl methylene group	OMe	OMe	CH	O	O
II-14	OH	CH＝CH	Methyl radical	OMe	O-CH2-CH2-C		O	O
										II-15	OH	CH2-CH2	Ethyl radical	OMe	O-CH＝CH-C		O	O
II-16	OH	CH2＝CH2	Methyl radical	OMe	CH2-CH2-CH2-C		O	O
										II-17	OH	Key with a key body	Methyl radical	OMe	CH2-CH2-CH2-C		O	O	147

Example 35

Receptor binding data were determined for the compounds listed below according to the binding assay described above.

The results are loaded in table 2.

Table 2: receptor binding data (Ki-values)

Compound (I)	ETA[nM]	ETB[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 (7)

1. Compounds having the following general formula (I) and salts thereof:

wherein:

x is CH;

y is O;

z is O;

r is CO₂H；

R²Is a methoxy group;

R³is a methoxy group；

R⁴Is phenyl;

R⁵is phenyl; and

R⁶is methyl.

2. A pharmaceutical formulation comprising a compound having a salt of a compound of formula (I) dispersed in a pharmaceutically acceptable buffer, diluent and excipient

A compound of the following general formula (I):

wherein:

x is CH;

y is O;

z is O;

r is CO₂H；

R²Is a methoxy group;

R³is a methoxy group;

R⁴is phenyl;

R⁵is phenyl; and

R⁶is methyl.

3. The medicament according to claim 2, formulated for administration by oral, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, sublingual, transdermal and pernasal pharyngeal routes.

4. The medicament according to claim 2, wherein the medicament is in solid form.

5. The medicament according to claim 2, wherein the medicament is in liquid form.

6. The medicament according to claim 2, wherein the medicament is formulated as an uncoated tablet, a coated tablet, a capsule, a powder, a granule, a suppository, a solution, a colloid, an ointment, a paste, an aerosol or a spray.

7. The medicament of claim 2, further comprising one or more of the following: tablet binder, filler, preservative, tablet disintegrant, flow modifier, softener, wetting agent, dispersing agent, emulsifier, solvent, sustained release agent, antioxidant or driving gas.