MXPA96004448A - Use of carboxylic acid derivatives comomedicamen - Google Patents

Abstract

The present invention relates to the use of carboxylic acid derivatives of the general formula I: wherein R means a formyl group, a group CO2H, R2 halogen, C1-C4 alkyl and others, X nitrogen or CR14 and others, R3 halogen, C1-C4-alkyl and others, R4 a C1-C10-alkyl group and others, a C1-C10-alkyl group, which carries one to five halo atoms and other radicals, a C3-C12-cycloalkyl or C3-C12-cycloalkenyl group , which may contain an oxygen or sulfur atom and carry one to five halo atoms and other radicals, a C3-C6-alkenyl or C3-C6-alkynyl group, which may each carry one to five halo atoms and / or one of the following radicals: C1-C4-alkyl, C1-C4-alkoxy and others, a heteroaromatic of five or six members, containing one to three nitrogen atoms and / or one sulfur or oxygen atom, which can carry one to four halogen atoms and / or one to two of the following radicals: C1-C4-alkyl and others, phenyl or naft ilo, which may be substituted by one or more radicals: halogen, nitro, cyano, hydroxy, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, phenoxy, C1-C4- alkylthio, amino, C1-C4-alkylamino or C1-C4-dialkylamino; R4 and R5 form together with the neighboring carbon atom a ring of 3 to 8 members, which may contain an oxygen or sulfur atom and carry one to three radicals; C1-C4-alkyl and others, R5 hydrogen, C1-C4-alkyl and others, R6 C1-C8-alkyl, C3-C6-alkenyl, C3-C6-alkynyl or C3-C8-cycloalkyl, whose radicals may be mono or polysubstituted, phenyl or naphthyl, which may be substituted each time by one or several radicals: halogen and others, a heteroaromatic of five or six members, containing one to three nitrogen atoms and / or one atom of sulfur or oxygen, which may carry one up to four halo atoms and / or one to two of the following radicals: C1-C4 alkyl and otr

Description

Use of carboxylic acid derivatives as medicines Description The present invention relates to the use of certain carboxylic acid derivatives as medicaments.

Endothelin is a peptide composed of 21 amino acids, which is synthesized and released by the vascular endothelium. Endote-lina exists in three isomeric forms. ET-1, ET-2 and ET-3. Hereinafter, the term "in otelin" or "ET" will encompass one or more isomeric forms of endothelin. Endothelin is a potent vasoconstrictor and has a strong effect on vascular tone. AND? It is known that this vascular constriction is produced by the binding of endothelin with its receptor (Nature, 332, 411-415, 1988; FEBS Letters, 2 1, 440-444, 1988 and Biochem. Biophys., Res. Comroun., 1 £ 4, 868-875, 1988).

An increased or abnormal libration of endothelin will cause prolonged contraction of the peripheral, renal and cerebral vessels, a phenomenon that can result in diseases. According to the literature, high levels of endothelin are found in the plasma in patients suffering from hypertonia, acute myocardial infacet, pulmonary hypertension, Raynaud's syndrome, acerosclerosis, and in the respiratory tract of asthmatics. { Japan J, Hypertension, 12., 79 (1989), J. Vascular Med. Biology 2, 207 (1990), J. Am. Med. Association 264, 2868 (1990)).

Thus, substances that specifically inhibit endothelial ligation with the receptor must antagonize the different physiological effects of endothelin, which is why they are valuable drugs.

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

The object of the present invention is the use of carboxylic acid derivatives, which correspond to formula I below, for the production of drugs, especially for obtaining inhibitors for endothelin receptors.

Carboxylic acid derivatives of the general formula i wherein R means a formyl group, a co-H group or a hydrolysable radical in COOH and the other substituents have the following meanings: R "halogen, Cj-C.i-alkyl, d-C, -halogenoalkyl, C? -C4-alkoxy, Ci-Cj-halogenoalkoxy or d-C ^ -alkylthio; X nitrogen 'or CR14, where 1 * means hydrogen or form together with R: an alkylene or alkenyl chain with 3 to 4 members, in which a methylene group respectively is substituted by oxygen; R3 halogen, Ci-Ca-haloalkyl, C1-C4-alkoxy, C? -C "-haloalcoal? I, C? -C: -alkylthio or R3 is attached with R14, as indicated above, forming a ring of 5 6 6 members; R *? N group C? -Cln-aikyl, which can carry one to five halogen atoms / or one of the following radicals: C? -C ~ alkoxy, C] .- C -? - alkylthio, cyano, Ci-? Ct-alkylcarbonyl, C] .- Ca-alkoxycarbonyl, phenyl, phenoxy or phenylcarbonyl, the phenyl radicals being capable of carrying one to five halogen atoms and / or one to three of the following radicals: Ci-C -alkyl, Ci-d.-halogenoalkyl, Cj-Ci-alkoxy, C: -C4 -haiogenoalkoxy and / or C? -C4-alkylthio; l-? fftupo Ci-Cic-alkyl, which carries one to five halogen atoms and one of the following radicals: a five-membered heteroaromatic containing one to three nitrogen atoms and / or a sulfur or oxygen atom, which can carry one to four halogen atoms and / or one to do3 of the following radicals: c -.- C, -alkyl, Ci-Cd-halogencalkyl, Ci-Cj-alkoxy, C? -C4-halogenoalkoxy, C? -C4- alkylthio and / or phenyl; a group which may contain an oxygen or sulfur atom and carry one to five halogen atoms and / or one of the following radicals: Ci-Cj-alkyl, C1-C4-alkoxy, C? -C4-alkylthio, cyano, Ci -C, -alkylcarbonyl, C? -C6-alkoxycarbonyl, phenyl, phenoxy or phenylcarbonyl, whose phenyl radicals can in turn carry one to five halogen atoms and / or one to three of the following radicals: 5 C- -Cj-alkyl, C: ~ Cis-halogen, C: .- C4-alkoyl, C: -C'4-halogenoalkyl, and / or C-, -C_-alkylthio; a C3-C-alkenyl group or C:, - C.- ~ alkynyl, which can each carry one to five halogen atoms and / or one of the following 10 radicals: C.-C -.- alkyl, CC, -alkoxy, C? -C4-alkylthio, cyano, Ci-C? -alkylcarbonyl, C? Cg-alkoxycarbonyl, phenyl, phenoxy or phenylcarbonyl, whose phenyl radicals can in turn carry one to five halogen atoms and / or one to three of the following radicals: C-Cí-alkyl, C: -C -halogenalkyl, d-C4-alkoxy, Ci-Ci-haloalkoxy and C-Cz-alkylthio; a heteroaromatic of five or six members, containing one to three nitrogen atoms and / or one sulfur atom or oxygen, which can carry one to four halogen atoms and / or one to two of the following radicals: C-C4-alkyl, Ci-d-haloalkyl, C- | -C < -alkoxy, c1-c4-halogenoalkoxy, C ^ -C ^ -alquiltis, phenyl, phenoxy or phenylcarbonyl, whose phenyl radicals can carry parts one to five halogen atoms and / or one to three of the following radicals: C: ~ C ~ alkyl, Ci-Cí-haloalkyl, C 1 -C 4 -alkoxy, Ci-Ci-halogenoalkoxy and / or Ci-Ci- alkylthio; Phenyl or naphthyl, which may be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxy, Ci-C-alkyl, C-Cj-haloalkyl, C! -C4-lcoxy, C? -C4 -halogen Ieoxi, phenoxy, C: -C < -alkyl-r.io, amino, Cj-Cj-alkylamino or Ci-Ci-dialkylamino; R4 and R- 'together form with the neighboring carbon atom a ring of 3 to 8 members, which may contain an oxygen or sulfur atom and carry one to three of the following radicals: CN-C ^ -alkyl, halogen, Cι-C 4 -halogenalkyl, C?-C 4 -alkoxy, d-C'-haloalkoxy and / or C ?C 4 -alkylthio; R- 'hydrogen, Ci- -alkyl, Crj-Cr-alkenyl, Cv.-Cf, -alkynyl, C3-C;: - cycloalkyl ?, C: -C4-haloalkyl, C? -C4-alkoxyalkyl, Ci -C ^ -alkylthioalkyl, phenyl, or R5 is linked with R'3, a as indicated above, forming a ring of 3 to 8 members; R'.sub.5 -C.-C, -alkyl, C -.-C.-ayenyl, C.-Cg-alkynyl or C3-C0-cycloaikyl, the radicals of which may be mono- or polysubstituted by: halogen, nitro , cyano, d ^ -alco i, C -C-alkykennyloxy, C -.- C ^ -alkynyloxy, C? -C < -alkylthio, C? -C,? -haloalkoxy, C? -C? -alkylcarbonyl, C? -C4-alkoxycarbonyl, C: -C4-alkylamino, di-Ci-Cj-alkylamino, phenyl, mono or polysustitutes, eg mono to trisubstituted by halogen, nitro, cyano, C -, - C4-alkyl, Ci-C ^ -halogenoalkyl, Ci-Cj-alkoxy, C? -4-haloalkoxy or phenyl substituted by C - Ci-alkylthio, or phenoxy; phenyl or naphthyl, which may be substituted each time by one or more of the following radicals: halogen, nitro, cyano, hydroxy, amino, C 1 -C 4 -alkyl, C: -C 4 -halogenalkyl, C-. -C¿-alkoxy, C; -C, α-haloalkoxy, phenoxy, Cj-C-aL-alkylthio, C; -C¿-alkylamino or Ci-Q-dialkylamino; a heteroaromatic of five or six members, containing one to three nitrogen atoms and / or one sulfur or oxygen atom, which may carry one to four halogen atoms and / or one up to doe of the following radicals: C-C-alkyl, C? -C,; -halogenoalkyl, C-, -C4-alkoxy, dC.-halogenoalkoxy, Ci-Ci-alkylthio, phenyl, phenoxy or pheylcarbonyl, whose phenyl radicals can carry their part one to five halogen atoms and / or one to three of the following radicals: C? -C4-alkyl, C? -C4-alkoxy, C? -c < -halogenoalkoxy and / or C? -C4 -alkyi; And sulfur or oxygen or a simple bond; Z dufre or oxygen.

For the preparation of the compounds of the invention, starting from the IV epoxies, which are prepared in a known manner, for example in the manner described in J. March, Advanced Organic Chemistry, 2nd ed. , 1983, p. 862 and p. 750, from aldehydes or ketones II or olefins III; The carboxylic acid derivatives of the general formula VI can be prepared by reacting the epoxides of the general formula IV (for example with R = C00Rlü) with alcohols or thioles of the general formula V, in which R6 and Z have the meaning indicated in claim 1, R4 6 IV + RÓZH * > R Z C s: CH OH VI v 'i' R For this, the compounds of the general formula IV are heated with an excess of the compounds of the formula v, eg 1.2-7, preferably 2-5 mol equivalents, at a temperature of 50-200 C , preferably 80-150 ° C.

The reaction can also take place in the presence of a diluent. For this purpose, all inert solvents can be used against the reagents used.

Examples of the solvents or diluents are: water, aiiphatic, alicyclic and aromatic hydrocarbons, which in each case may be chlorinated, such as, for example, hexane, cyclohexane, petroether, ligroin, benzene, toluene, xylene, methylene chloride, chloroform, carbon tetrachloride, ethylenic chloride and tpchlorethylene, ethers, such as, for example, diisopropyl ether, dibutyl ether, propylene oxide, dioxane and tetrahydrofuran, cer. such as, for example, acetone, methyl ethyl ketone, methyl isopropyl ketone and methyl isobutyl ketone, nitriles, co or P-ex. acetonitrile and propionitrile, alcohols, such as, for example, methanol, ethanol, isopropanol, butanol and ethylene glycol, esters, such as, for example, ethyl acetate and amyl acetate, acid amides, e.g. di methylformamide and dimethylacetamide, sulfoxides and suifones, such as, for example, dimethyl sulfoxide and sulfolane and bases, with, for example, pyridine.

The reaction can be carried out preferably in a temperature range of between 0 ° C and the boiling point of the solvent or solvent mixture.

The presence of a reaction catalyst can be advantageous. As catalysts sor. appropriate strong organic and inorganic acids, as well as Lewis acids. Examples are: sulfuric acid, hydrochloric acid, trifluoroacetic acid, boric trifluoride etherate and the titanium (IV) alcoholates.

The computates of the invention in which Y means oxygen and the other solvents have the meaning indicated for the general formula i, they can be prepared, for example, in such a way that the carboxylic acid derivatives of the general formula VI, where the substituents have the indicated meaning, they are reacted with compounds of the general formula vil, VII wherein R1S stands for halogen or R1 (1- S-2-, representing R * 6 C? -C4-alkyl) C? ~ c, -halogenoalkyl or phenyl The reaction preferably takes place in one of the diluents mentioned above, adding an appropriate base, namely, a base, which produces the deprotonation of intermediate VI, at a temperature range from room temperature to the boiling point of the solvent.

As the base, an alkali metal or alkaline-iron hydride, such as or, may be used. ex. sodium hydride, potassium hydride or calcium hydroxide, a carbonate, such as, for example, an alkali metal carbonate, eg sodium carbonate or potassium carbonate, an organic metal compound, such as p. ex. but..lite or an alkaline amide, as p. ex. lithium diisopropylamide.

The compounds of the invention, in which Y means sulfur and the other substituents have the meaning indicated for the general formula I, can be prepared, for example, by reacting carboxylic acid derivatives of the general formula VIII, obtained in a known manner from starting from compounds of the general formula VI, and in which the substituents 0 they have the meanings indicated above, with compounds of the general formula IX, in which R-, R3 and x have the meanings indicated for the general formula I.

The reaction is preferably lauded in one of the diluents mentioned above, adding an appropriate base, namely a base which produces the deprotonation of intermediate IX, in a temperature range of between room temperature and the boiling temperature of the product. solvent.

As bases are appropriate in addition to the bases mentioned above, also organic bases, such as tertiary amines, p.sj. triethylamine, pyridine, imidazole or diasabicycloundecene.

The compounds of the formula I can also be prepared, starting from the corresponding carboxylic acids, to form compounds of the formula I, wherein R 1 is hydroxyl, and these are first converted, in a customary manner, into an activated form, such as A halide, an anhydride or imidaso-lide, and reacting this, then, with a corresponding hydrixyl compound H0R1C. This reaction can be carried out in customary solvents, and frequently requires the addition of a base, the abovementioned being suitable as such. These two steps can be simplified, for example by activating the carboxylic acid in the presence of a water separating agent, such as a carbodiimide, on the hydroxyl compound.

In addition, the compounds of the formula I can also be obtained, starting from the corresponding carboxylic acids, ie, compounds of the formula I, wherein R represents a group C0Rt and R1 means OM, where M can be an alkali metal cation or the equivalent of an alkali-iron metal cation. These salts can be reacted with a number of compounds of the formula R-A, meaning A a customary non-halogen dispersible group, such as, for example, chlorine, bromine, iodine or arylsulfonyl or alkylsulfonyl optionally substituted by halogen, alkyl or haloalkyl, such as, for example, toluenesulfo-nyl and methylsulfonyl or another equivalent dissociative group.

Compounds of the formula R.sup.-A with a reactive Y substituent are known or can easily be obtained by applying general professional knowledge. This reaction can be carried out in customary solvents and is carried out, preferably, by adding a base, the bases indicated above being lent.

The radical R in formula i can have a widely variable meaning. For example, R can mean a group Q C-R1 where R1 has the following meanings: a) hydrogen; b) a sucoinimidyloxy group; c) a five-membered heteroaromatic linked via a nitrogen atom, such as, for example, pyrrolyl, pyrazolyl, imidazoiyl and triazolyl, which can carry one to two halogen atoms, especially fluorine and chlorine and / or one to two of the following radicals: Ci-C-alkyl, eg methyl, ethyl, 1-propyl, 2-propyl, 2-methyl-2-propyl], 2-methyl-1-propyl, 1-butyl, 2-butyl; C 4 -Chaloalkyl, especially C 1 -C 2 -haloalkyl, such as, for example, fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, chlorofluoromethyl, trichloromethyl, 1-fluoroethyl, 3-flylmethyl, 2, 2-difluoroethyl, , 2,2-trifluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl and pentafluoroethyl; C 1 -C 4 -haloalkoxy, especially C 1 -C 2 -haloalkoxy, eg difluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, i-fluoroethoxy, 2-fluoroethoxy, 2,2-di-toluoroethoxy, 1, 1,2, 2-tetrafluoroethoxy,, 2, -trifluoroethoxy, 2-chloro-l, 1,2-trifluoroethoxy and pentafluoroethoxy, especially trifluoromethoxy; Ci-Cj-alkoxy with, for example, methoxy, ethoxy, propoxy, 1-methyloxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, 1,1-dimethylethoxy, especially methoxy, ethoxy, 1- methylethoxy; C-J-C4"alkyl, methylthio, ethyl, propylthio, 1-methyl ethylthio, butylthio, 1-methylpropylthio, 2-methylpropylthio, 1,1-dimethylethylthio, especially methylthio and ethylthio; d) R7 where m is 0 or 1 and R7 and Rs, which may be identical or different, have the following meanings: hydrogen C.-C3-alkyl, especially Ci-d-alkyl, as the above-mentioned; CjC.; - alkenyl, p.-ej ... 2-propenyl, 2-butenyl, 3-butenyl, 1-methy1-2-propenyl, 2-methyl-2-propenyl, 2-pentenenyl, 3-pentenyl, 4-? Entenyl, l-methyl-2-butenyl, 2-methyl-2-butenyl, 3-metii-2-butenyl, 1-methyl-1-butenyl, 2-methyl-3-butenyl , 3-methyl-3-butenyl, 1, l-dimethyl-2-propenyl, 1, 2-dimethyl-2-propenyl »l-ethyl-2-propenyl, 2-hexenyl, 3-hexenyl, 4 -hexenyl, 5-hexenyl, l-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, l-methyl-4- pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenenyl, 4-methyl-4-penteryl, 1,1-dimethyl-2-butenyl, 1,1-dimethy. .3-butenium, 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-ba enue, l-etü-2-butenyl, l-ethyl-3-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, l-ethyl-l-methyl-2-propepyl and l-ethyl-2 -methyl-propenyl, especially 2-propenyl, 2-butenyl, 5-methyl-2-butenyl and 3-methyl-2-pentenyl; C -, - C (5-alkenyl), eg 2-propinyl, 2-butinyl, 3-butylene, 1-me-L-2-propinyl, 2-pentynyl, 3-pentynyl, 4-? entinyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-methyl-2-butynyl, 1, 1-dimethyl-2-pypinyl, 1-ethyl-2-propynyl, 2-Hexynyl, 3-Hexynyl, 4-Hexynyl, 5-Hexynyl, 1-Methyl-2-Pentnyl, 1-Methyl-3-Pentynyl, 1-Methyl-4-Pentyne-1-methyl-3-Pentynyl , 2-methyl-4-peptinyl, 3-methyl-4-pentynyl, 4-methyl-2-pentynyl, 1, ld? Methyl-2-butynyl, 1, l-din? Et? L- 3-butynyl, 1,2-dimethyl-3-butynyl, 2,2-d? Methyl-3-butynyl, l-ethyl-2-butynyl, l-ethyl-3-butynyl, 2-ethyl-3- butynyl and l-ethyl-l-methyl-2-propynyl, preferably 2-propynyl, 2-butynyl, l-methyl-2-propynyl and l-methyl-2-butyl, especially 2-propynyl Cr.-C? -cycloalkyl, eg cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, whose alkyl, cycloalkyl, alkenyl and alkynyl groups can each carry one to five halogen atoms, especially fluoro or chlorine and / or one to two of the following groups: 25 C -C4-alkyl, C_-C4-alkoxy, C? -C4-alkylthio, C? -C4-halogenoalkoxy, with the abovementioned, C3-C4 -alkenylsxy, CC? -alkenylthio, Cj-C-alkyloxy, Cs-Cj-alkynedis, having the alkenyl and alkynyl components present The radicals preferably have the meanings indicated above; C_-C_-alkylcarbonyl, e.g., especially methylcarbonyl, ethylcarbonyl, propylcarbonyl, 1-methyethylcarbonyl, butylcaibonyl, 1-methylpropycarbonyl, 2-methylpropycarbonyl, 1,1-dimethyl-ethylcarbonyl; C-Cj-alkoxycarbonyl, eg methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl, 1-methylethoxycarbonium, butyloxycarbonyl, 1-methylpropylcarbonyl, 2-methylpropyloxycarbonyl, 1,1-dimethylethoxycarbonyl; C-C,; -alkylcarbonyl, C3-C (-; - alkynylcarbonyl, C?, - C: -alkenyloxycarbonyl and C3-C6-alkynyloxycarbonyl, the alkenyl or alkynyl radicals of which are preferably as defined above; phenyl, optionally mono- or polysubstituted, eg mono-trisubstituted by halogen, nitro, cyano, C? -C4-alkylo, C? -C4-haloalkyl, C? -C4-alC? xi, C-? C-halogenoalkoxy or C: ~ C? -alkylthio, such as, for example, 2-fluorophenoyl, 3-chlorophenyl, 4-bromophenyl, 2-methylphhenyl, 3-nitr-ofenyl, 4-cyanophenyl, 2-trifluoromethylphenyl, 3-methoxy-phenyl, 4-trifluoroethoxyphenyl, 2-methylthiophenyl, 2,4-di-chlorophenyl, 2-methoxy-3-methylphyl, 2-dimethoxypyl, 2-nitro-5-cyanophenyl, 2,6-difluorophenyl; di-Ci-Ci-alkylamino, eg, especially dimethylamino, diprop lamino, N-propyl-N-methylamino, N-propyl-N-ethylamino, diisopropylcimino, N-isopropyl-N-methylamino, N-iso - propyl-N-ethylamino, N-isopropyl-N-propylamino; "and Re mean, in addition, phenyl, which may be substituted by one or more, eg one to three of the following radicals: halogen, nitro, cyano, C1-C4-alkyl, C -! - C4-hal? genoa.lkyl, C- | -C-alkoxy, Ci-Cj-halogenoalkoxy or C-C4-alkylthio, such as especially those mentioned above; or Rv and R5 together form a chain of C4-C, -alkylene closed in ring form and optionally substituted for example by Ci-C-alkyl, and which may contain a hetero atom selected from the group oxygen, sulfur or nitrogen, eg - (CH2) 4-, - (CH2) s-, - (CH5) e ~, - (CH2) 7-, - (CH2) -0- (CH2); - f -CH2 -S- i Crl-¿) 3-, -. { CH2) 2-0- (CH2) 3-, - H-. { CH2) 3-, -CH2-NH- (CH) 2-, -CH2-CH = CH-CH2-, -CH-CH- (CH ^), -? -, • e) (O) O:? -: R ' where k has the values 0, 1 and 2, p the values 1, 2, 3 and 4 and R5 means Cx-Cí-alkyl, Ci-Cc-halogenoalkyl, C¡-Cf; -alkenyl, C3-Cf-alkynyl or optionally substituted phenyl, eg especially the above mentioned.

R 'also means a radical OR10, where R1'1 signifies; hydrogen, the cation of an alkali metal, eg lithium, sodium, potassium or the cation of an alkaline earth metal, eg calcium, magnesium and barium or an organic ammonium ion harmless to the environment, eg C1-C4-tertiary alkylammonium or the ammonium ion; C-jCN-cycloalkyl, eg those mentioned above, and which can carry one to three C? -C4-alkyl groups; Ci-Cn-alkyl, e.g., especially, methyl, ethyl, propyl, 1-melethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, per.ethyl, -I-butyl, 2-methylbutyl, 3- and ilbuyl, 1, -dimethylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methyl-pentyl, 2-methylpentyl , 3-methylpentyl, 4-methylpentyl, -dimethylbutyl, 1, -dimethylbutyl, 2,3-dimethyl-1, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3, 3-dimethylbutyl, 1,2-trimethylpropyl, 1,2,4-dimethylbutyl -trimethylpropyl, 1-ethylbutyl, 2-ethylbutyl, I-ethyl-2-methylpropyl, which can carry up to five halogen atoms, especially fluoro and chloro, and / or no of the following radicals: C -, - C4-alkoxy, C- | -C-alkylthio, cyano, C? -C4-alkylcarbonyl, C ', -C, cycloalkyl, C: -C, i-alkoxycarbonyl, phenyl, phenoxy or phenylcarbonyl, whose aromatic radicals can each carry one to five carbon atoms Halogen and / or one to three of the following radicals: nitro, cyano, Ci-Ci-alkyl, C-Cj-haloalkyl, C: -C.-alkoxy, C? -C, -haloalkoxy and / or C? C4-alkylthio,, e.g. especially the above mentioned; a C? -C? -alkyl group, eg those mentioned above, and carrying one to five halogen atoms, especially fluoro / or chlorine and one of the following radicals: a five-membered heteroaromatic, containing one to three nitrogen atoms, or a 5-membered heteroaromatic containing a nitrogen atom and an oxygen or sulfur atom, and which may carry one to four halogen atoms and / or one to two of the following radicals: nitro, cyano, C: -C, -alkyl, C; -C.? -halogenoalkyl, C? -C, -alkoxy, phenyl, C-Cj-haloalkoxy and / or C? -C4-allylthio. They are mentioned, especially: 1-pyrazole, 3-methyl-1-pyrazolyl, 4-methyl-1-pyrazolyl, 3,5-dimethyl-1-pyrazole, 3-phenyl-1-pyrazolyl , 4-phenyl-1-pyrazyl-lyl, 4-chloro-lp-razolyl, 4-bromo-1-pyrazolyl, 1-imidazolyl, 1-benzimidazolyl, 1,2,4-triazol-1-yl, 3 -me-ti1-1, 2, -triazol-l-yl, 5-methyl-l, 2,4-triazol-l-yl, 1-benztriazolyl, 3-isopropylisoxazol-5-yl, 3-methylisoxazole-zol- 5-yl, oxazol-2-yl ?, thiazole-2-ÜO, imidazol-2-yl, 2-ethylisoxazol-b-yl, 3-phenylisoxazol-5-yl, 3-tert-bu-yl isoxasol-5 ilo; a C6-C, -alkyl group, which carries in the 2-position one of the following radicals: Ci-Ci-alkoimino, C-C6-alkyloxyimino, C3-C? -haloalkenyloxyimino or benzyloxy-imino; a C3-Cfi-alkenyl group or whose groups can in turn carry one to five halogen atoms; R1 * -1 also means a phenyl radical, which can carry one to five halogen atoms and / or one to three of the following radicals: nitro, cyano, Ci-C-alkyl, C? -C,? haloalkyl, C [alpha] -C4-alkoxy, Ci-C [alpha] -haloalkoxy and / or C [beta] -4-alkytiio, for example, especially those mentioned above; a five-membered heteroaromatic linked via a nitrogen atom, containing up to three nitrogen atoms, and which can carry one up to two halogen atoms and / or one to two of the following radicals: C? -c4-aikyl, C 1 -C 4 -halogen-alkyl, C 4 -C-alkoxy, phenyl, C 4 -C 4 -halogencalcyl, and / or C 1 -C 4, -alkylthio. They are mentioned, especially: 1-pyrazolyl, 3-methyl-1-pyrazolyl, 4-methyl-1-pyrrazolyl, 3, 5-dimethyl-1-pyrazolyl, 3-phenyl-1-pi-razolyl, 4-phen Pyrazolium, 4-chloro-1-pyrazolyl, 4-b-omo-1-pyrazolyl, 1-midazolyl, 1-benzimidazolyl, 1,2,4-triazol-1-yl, 3-methyl-1,2,4-triazol-1-yl, 5-methyl-1, 4-triazol-1-yl, 1-benstriasolyl, 3 , 4-dichloroimi- dazol-1-i] o; R1 'also means a group where P i and R ^, which may be identical or different, mean: Ci-CV-alkyl, C3-Cg-alkenyl, Cs-Cs-alkynyl, C2-Cs-cycloalkyl, whose radicals can carry C? -C4-alkoxy, C: -C? -alkylthio and / or a phenyl radical optionally substituted, for example, in particular, as mentioned above; phenyl, which may be substituted by one or more, eg one to three of the following radicals: halogen, nitro, cyano, C? -C.-alkyl, Ci-Cj-haloalkyl, C? -C4-al -c? xi, C? -C-halogenoalco? io C | -C4-alkytio, whose radicals co respond, especially to those mentioned above; or R11 and 12 together form a chain of Cj-C? 2-alkylen, which may contain one to three chyl groups and one heteroatom of the group oxygen, sulfur and nitrogen, eg especially those mentioned for R 'and R «.

RJ- means, in addition, a radical -NH II R 13 OR where R1- means: C? -C4-alkyl, -C3-C? -alkenyl, Cj-CV-alkynyl, C'j-C3-cycloalkyl, as especially those mentioned above, whose radicals can carry a C? -C4-alkoxy radical, C? -C'4-al? Iui.ltio and / or phenyl, as those mentioned above; phenyl, optionally substituted, as especially those mentioned above.

With respect to their biological action, the carboxylic acid derivatives of the general formula I are preferred, in which the substituents have the following meanings: R ~ the C] -C4-alkyl, C ': - C_-halogenoalkyl, C3. ~ C4-alkoxy, Ci-Cj-halogenoalkoxy, Ci-Cr-alkylthio groups mentioned in detail for R1 and halogen atoms, especially chlorine, methyl, methoxy, ethoxy, difluoromethoxy, trifluoromethate, especially methoxy; X nitrogen or C 34, where K is hydrogen or together with R3 forms an alkylene or alkenylene chain with 4 to 5 members, in which each time a methylene group is replaced by oxygen, eg -CH¿-CH-0-, -CH = CH-0-, -CH-CHj-CH2-0-, -CH = CH-CH20-, especially hydrogen and -CH1-CH2-0-; R- 'means the groups C? -4-alkyl, C? -C4-haloalkyl, Ci-C? -alkyl, C? -C4-haloalkynoalkoxy, C? -C4-alkylthio mentioned for R1 and halogen atoms, especially chloro, methyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, or form with H1 *, as indicated above, a 5- or 6-membered ring; R means, above all, methoxy; C - C -, -, - alkyl, eg those mentioned in detail for Ri, and which can carry up to five halogen atoms, eg fluoro, chloro, bromo, iodo, especially fluoro and chloro and / or one of the following radicals: alkoxy, alkylthio, cyano, alkycarbonyl, alkoxycarbonyl, phenyl, phenoyl, phenyleptopyl, eg those mentioned generally and especially for R1; -Cio-alkyl, eg those mentioned above, and which can take up to five halogen atoms, eg those mentioned above, especially fluoro and chloro, and a heteroaromatic optionally substituted with 5 members, e.g. eg one of the above mentioned for R1; C-~ C ': -cycloalkyl? > , especially C3-C7-cycloalkyl or Ci-Ci-cycloalkenyl, especially C4-C7-cycloalkenyl, wherein in the saturated or unsaturated ring an eti-iene group may be substituted by an oxygen or sulfur atom, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuranyl, tetrahydro-triemyl, tetrahydropyranyl, tetrahydrothiopyranyl, cyclo-propenyl, dihydrofuranyl, dihydrothienyl, dihydropyranyl, dihydrotopyranyl, whose cycloalkyl or cycloalkenyl radicals may be substituted by one to five halogen atoms, eg those mentioned above, especially fluoro or chloro and / or one of the following radicals: C? -C4-alkyl ?, Ci-Ci-alkoxy, C? -C4-alkylthi ?, cyano, C C -C-alkylcarbonyl, Ci-Ce-alkoxycarbonyl, phenyl, phenoxy, phenylcarbonyl, eg those mentioned above and especially; C; -C7-alkenyl or G > -C,; -alkynyl, eg the encylo- scripts 5 for R "-, and which can carry one to five halogen atoms, eg those mentioned above, especially fluorc and chlorine and / or one of the following radicals : C] -C4-alkyl, Ci-C4-alkoxy, C-C4-alkylthio, cyano, Q C -? - Ctf-alkylenecarbonyl, Ci-Cg-alkoxycarbonyl, phenylene, phenoxy, phenylcarbonyl, eg the above mentioned generally and specifically; a five or six membered heteroaryl, eg furyl, thienyl, pyrryl, pyrazolyl, idol, triazolyl, iso azolyl, oxazolyl, isothiazolyl, thiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triaeinyl, example, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl. 3-isoxasolyl, 4-isoxasolyl, 5-issxazo-20 lyl, 3-isoL.-aiazolyl, 4-isothiazolyl, 5-icothiazole, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiao-olyl, 2-ylidazolyl, 4-imidazsyl, 5-imi - dazolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, oxa-2,4-diazolyl, oxa-3 , 4-diazoylyl, thia-, 4-diazolyl, thia-3, 4-diazolium and triazolyl, whose heteroaromatics can carry one to five halogen atoms, eg those mentioned above, especially fluoro and chloro and / or one up to three of the following radicals: C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 4 -C alkylthio, cyano, nitro, C x -C g alkylcarbonyl, C 3 -C 6 alkoxycarbonyl, phenyl, phenoxy, phenylcarbonyl, eg the above mentioned generally and especially; R'- further denotes phenyl or naphthyl, which may be substituted by one or more, eg one to three of the following radicals: halogen, nitro, cyano, hydroxy, mercapto, amino, C? -C -alkyl, C? -C4-halogensalkyl, C | -C4 ~ -alkoxy, C'i-Ci-halogenoalkoxy, C? -C4 -alkyl, C: -C4-alkylamino, di-C? -C4-alkylamino, C? -C4-alkylcarbo-nyl, C? ~ C4-alkoxycarbonyls, especially, eg those mentioned for R7 and Rr ', such as, for example, 3-hydroxyphenyl, 4-dimethylaminophenyl, 2-mercapto-phenyl, 3-methoxycarbsnyl-phenyl, 4-acetylphenyl, 1-naphtyl, 2-naphthyl, 3-bromo-naphthyl, 4-methyl-1-naphthyl, 5-methoxy-1-naphthyl, 6 ~ trifluoromethyl-l-naphthyl, 7-chloro-l-naphyl, 8-hi-droxy-1-naph il ?; or Rc and R together form with the neighboring carbon atom a ring with 3 to 6 members, which may contain an oxygen or sulfur atom and which is unsubstituted, or which, depending on the size of the ring, carries one to three The following radicals: Ci-Ci-alkyl, Cr-C4-alkoxy, C 1 -C 4 -haloalkyl ?, C 1 -C 4 -halogenoalkoxy, C 1 -C 4 -alkylthio, p. ex. the above mentioned generally and especially; Rfi hydrogen, Ci -C ^ -alkyl, C3-C-lkenyl, C-C-alkynyl, C3-Cfi-cy-cloalqui lü, C? -C4-hai Ógehoalquí l? , C: -C'4-alkoxial ~ q? ilo, C.?--C4-aIc?uiltioalsuilo or phenyl, p. ex. especially those mentioned for R; Rc C -, - Cy-alkyl, Cv-Cf-alkenylc, Cj-Cg-alkynyl or C3-Cfi-cycloalkyl, eg especially those mentioned above, and q? E may in each case be mono or polysustitides by : halogen, nitro, cyano, Cj-C4-alkoxy, C -., - C?; - lkenyloxy, Cj-Cinylalkyloxy; C.-C_-alkylthio, d-Cj-halogenoalco?, C? -C4-alkylcarbonyl, C-C4-alkoxycarbonyl, C'i-C? -alkylamino, di-CC-alkylamino, or phenyl or phenoxy optionally substituted, eg especially those mentioned above; phenyl or naphthiio, which may be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxy, amir.o, C? -C4-alkyl, Cj-C-haloalkyl, C? -C. : -alkoxy C1-C4-halogenoalkoxy, phenoxy, Cj-Ca-alkylthio, Ci- -alkylamino or C? -C4-dialkylamino, eg, especially those mentioned for Rv and R4; a heteroaromatic of five or six members, containing one to three nitrogen atoms and / or one sulfur or oxygen atom, and which may carry one to four halogen atoms and / or one to two of the following radicals: C1-C4 -alkyl, CL-C, -halogenoalkyl, Ci-Clycoxy, C 1 -C 4 -haloalkoxy, C. -C 4 -alkylthio, phenyl, phenoxy or phenylcarbonyl, the phenyl radicals of which may contain one to five halogen atoms and / or one to three of the following radicals: C | -C4-alkyl, Cx-C-haloalkyl, C C 4 -alkoxy, Ci-Cj-halogenoalkoxy and C 1 -alkylthio, eg, especially those mentioned * for R 4; And sulfur, oxygen or a simple bond Z sulfur or oxygen.

Especially preferred are compounds of formula I, wherein R2 and 3 mean methoxy and X is CH. In addition, compounds of the formula i are preferred, wherein R 2 and R 3 signify methoxy, X signifies CH, Y and Z signify oxygen and R- 'is C 1 -C 4 -alkyl. An especially preferred radical in the case of R.sub.1 is the group R.sub.R "', wherein R.sub.10 denotes hydrogen or C.sub.C.-C.

R 4 K "1 represents, especially Ci-Cj-alkyl, optionally substituted phenyl or a heterocyclic radical containing a heteroatom, for example fucyl or thienyl.

R6 represents, in particular, phenyl, optionally mono- to trisubstituted by halogen, 1-C4 -alkyl, C1-Cj-alkoxy and / or C? -C /? -alkyl -i or.

Examples of preferred compounds are indicated in the following table.

Parß? L US ° SeSÜn in-ión «b stacar, especially, compounds 4.42 and 4.58 (ßjempio 10, table 4).

Table - 0 The compounds according to the present invention offer a new therapeutic potential for the treatment of hypertonia, pulmonary hypertension, myocardial infarction, angina pectoris, acute renal failure, renal insufficiency, cerebral vasospasm, cerebral ischemia, subarachnoid hemorrhages, migraine, asthma, atherosclerosis, endopoxic shock, organic failure induced by endotoxin, intravascular coagulation, restenosis after angioplasty and renal insufficiency induced by cyclosporine, or hypertonia.

The good action of the compounds can be demonstrated by the following tests: Linkage studies to the receptor For the linkage studies, human CHO cells, cloned, ETA receptor expressor and guinea pig membranes from guinea pigs with > 60% ETB, compared to ET receivers Preparation of the membrane CHO cells with expression of ETA receptors were multiplied in the medium of F; - with 10% fetal calf serum, 1% glutamine, 100 ü / ml penicillin and 0.2% streptomycin (Gibco BRL , Gaithersburg, MD, USA). After 48 h the cells were washed with PBS and incubated for 5 minutes with 0.05% PBS containing trypsin. Then, it was neutralized with F medium; and the cells were collected by centrifugation at 300 x g. For the lysis of the cells the pellet was washed briefly with lysis buffer. { 5 mM Tris-HCl, pH 7.4 with 10% glycine) and then incubated for 30 min at 4UC at a concentration of 10 v cells / ml of lysis buffer. The membranes were centrifuged for 10 min at 20,000 x g and the pellet was stored in liquid nitrogen.

The cerebellum of the guinea pigs were homogenized in the Potter-Elvejhem homogenizer and generated by differential centrifugation of 10 min at 1,000 x g and repeated centrifugation of the supernatant for 10 min at 20,000 x g.

Linkage assays For the linkage assay with the ETA and ET & amp; the membranes were suspended in the incubation buffer (50 mM Tris-HCl, pH 7.4, with MnCl, 5 mM, 40 μg / ml bacitracin and 0.2% BSA) in a concentration of 50 μg of protein per Test substance, and incubated at 25 ° C with 25 pM of [125J] -ET? (assay with ETA receptor) or 25 pM of [125J] -RZ (assay with ETp receptor ..}., in the presence or absence of the test substance.The specific binding was determined with 10"7 M ETi. of 30 min the free radioligand and the radioligand were separated by filtration on a GF / B glass fiber filter (whatmap, England) in a Skatron cell collector (S atron, 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 by means of a pac ard 2200 CA liquid scintillation counter.

The K values were determined by regression analysis, using the L1GAND program.

Table A shows the action of the compounds of formula i determined in the test equipment as K value, [mol / 1].

Table A Functional in vitro assay system for finding endothelin receptor antagonists (subtype A) This test system is a functional test for endothelin receptors, which is based on cells. Certain cells exhibit an increase in intracellular calcium concentration when stimulated with endothelin 1 (ET1). This increase can be measured in intact cells, loaded with calcium-sensitive dyes. 1-fibroblasts isolated from rats, in which an endogenous endothelin receptor of subtype A was detected were loaded with the fluorescent dye fura 2-am in the following manner: after trypsinization the cells were resuspended in buffer A (120 mM NaCl, 5 mM KCl, 1.5 mM MgCl, 1 M CaCl, 25 mM HEPES, 10 mM glucose, pH 7.4) to a density of 2 x 10 5 / ml and incubated for 30 minutes. min at 37 ° C in the dark with fura 2-am (2 μM), Pluro-nics F-127 (0.04%) and DMSO (0.2%). Then, the cells were washed twice with buffer A and resuspended at 2 x 10 ml.

The fluorescence signal of 2 x 10 - cells per ml was recorded continuously at 30: 'C with? X / EI? I 380/510. The test substances were added to the cells and after a 3 min incubation time with ET1 the maximum change in fluorescence was determined. Controlling the response of the cells to ET1 without prior addition of a test substance, and this response was set equal to 100%.

Table B shows the action determined in this test in the compounds composed of the formula? as IC50 value [mol / 1].

Table B Assay of ET antagonists in vivo Male SD rats of 250-300 g were narcotized with obar-btal A, connected to artificial respiration, vagotomized and de-nalized. The carotid artery and the jugularis vein were probed.

In control animals the intravenous administration of 1 μg / kg of ET1 produced a marked increase in blood pressure, which lasted for a prolonged period.

The test animals were injected (1 ml / kg) intravenously 5 min before the administration of ET1 to the test animals. To determine ET antagonist properties, the increase in blood pressure in the test animals was compared with that of the control animals.

"Sudden death" induced by endothelin in rats The principle of the assay is based on the inhibition of the sudden cardiac death of the mouse produced by endothelin, which is probably due to a constriction of the coronary arteries, by pretreatment with endothelin receptor antagonists. After intravenous injection of 10 nmol / kg of endo-telin in the volume of 5 ml / kg of body weight, the death of the animals occurs within a few minutes.

The lethal dose of in otelin-1 is examined each time in a small collective of animals. When the test substance is applied intravenously, injection of lethal endothelin-1 into the reference group is generally applied 5 minutes later. In the other types of application, the lethal application is carried out, if necessary, until a few hours later.

The percentage of survival is documented and the active doses that protect 50% of the animals 24 hours or more of sudden cardiac death induced by endothelin (ED 50) are determined.

Functional assay of vessels for endothelin receptor antagonists In segments of the rabbit aorta, after a pretension of 2 g and a relaxation time of 1 h in Krebs-Her.se conductive solution at 37 C and a pK value of between 7.3 and 7.4, first , a contraction of K +. After washing, a curve of endothelin effect is drawn up to the maximum.

Potential endothelin antagonists are applied in other preparations of the same vessel 15 min before the beginning of the endothelin dose-effect curve. The effects of endothelin are calculated in% of the K + contraction. With efficient endothelin antagonists, a shift to the right of the endothelin dose-effect curve occurs.

The compounds of the invention can be administered in a customary manner orally or parenterally. (subcutaneous, intravenous, intramuscular, intraperitoneally). They can also be applied by means of vapors or sprays through the na-sofaringe cavity.

The dose depends on the age, the state and weight of the patient, as well as the way of application. As a general rule, the daily dose of active substance is increased to between approx. 0.5 and 50 mg / kg of body weight in oral administration, and at between approx. 0.1 and 10 mg / kg of body weight in the parenteral administration.

The new compounds can be used in the usual solid and liquid galenic application forms, eg as primers, film tablets, capsules, powders, granules, dragees, suppositories, solutions, ointments, creams or sprays. . These are prepared in a customary manner, being able to prepare the active substances with customary galenic auxiliaries, such as tablet excipients, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, humectants, dispersants, solvent emulsifiers, retarders, antioxidants. and / or gasses (see H. Sucker et al .: Pharmazeutische Tech-nologie, Thieme-verlag, Stuttgart, 1991). The application forms thus obtained contain the active substance, usually in an amount of 0.1 to 90% by weight.

Synthesis examples Synthesis of compounds of the general formula VT Example 1 Methyl ether of 3- ethoxy-3- (3-methoxyphenyl) -2-hydroxybutyric acid 19.5 g (88 nmol) of 3- (3-methoxyphenyl) -2,3-epo-butyric acid methyl ester are dissolved in 200 ml of absolute methanol and mixed with 0.1 ml of boric trifluoride etherate. Stir 12 hours at room temperature and then distill the solvent. The residue is absorbed in acetic ester, washed with sodium carbonate solution and water, and dried over sodium sulfate. The solvent having been distilled, 21.1 g of a lightly liquid oil remain.

Yield: 94% (diastereomeric mixture 1: 1) Example 2 Methyl ester of 3-benzyloxy-3-phenyl-2-hydroxybutyric acid 9.6 g (50 mmoles) of methyl ester of 3-f ni1-2, 3-epoxybutyric acid are dissolved in 150 ml of benzyl alcohol and mixed with 0.5 ml of concentrated sulfuric acid. The mixture is stirred at 50 ° C. for 6 hours and then allowed to cool to room temperature After neutralization with sodium bicarbonate solution, the excess benzyl alcohol is distilled in a high vacuum and the residue is purified by flash chromatography on silica gel with n- hexane / acetic ester 9: 1. Having distilled the solvent, 6.5 g of a colorless oil remain.

Yield: 43% (diastereose mixture was 3: 2) The compounds indicated in Table 1 are prepared analogously.

Table 1: Intermediate products of the formula VI with Rl s CH- R4 R6-O C-CH-OH R COOCH3 DO NOT. R * R5 DV * 1.1 P.f. ["C] methyl-1-oxyphenyl methyl 1: 1 1.2 benzyl phenyl methyl 3: 2 oil 1.3 methyl oil: > -fluorophene methyl 1: 1 1.4 methyl 4-i-propylphenyl methyl methyl 2-methylphenyl methyl 2: 1 1 .6 methyl omega 3-methylfenyl methyl-1,7-methyl-methyl-phenyl-methyl 3: 2 1,8-methyl-3-nitrophenyl-methyl-1,9-methyl-4-bromofyl-methyl-methyl-3: 1-methyl. 2-furyl methyl 1, 11 methy], or 3-furyl methyl, 12 meyl 2- methyl 1, methyl, 3-thienyl, methyl, 1,14, methyl, 2-pyridyl, methyl, 1,15, methyl, 3-pyridyl, methyl, 1,16, methyl, 4-pyridyl, methyl. methyl 2-thiazolyl methyl 1.18 methyl-isoxazolyl methyl .19 methyl 4-imidazolyl methyl .20 methyl 2-pyrazolyl methyl .21 methyl 4 4-chlorophenyl methyl 2: 1 .22 benzyl oil 3-methylphenyl methyl 1: 1 oil .2: methyl 4-fluorophenyl methyl 1: 1 oil .24 benzyl 4-bromophenyl methyl 1: 1 oil .25 benzyl 4-chlorophenyl methyl 3: 2 oil .26 benzyl 4-f luorophenyl methyl 1: 1 oil .27 methyl phenyl ethyl ITT oil * ratio diastereór.iera Synthesis of the compounds of general formula I: Example 3: 3-benzyloxy-3-eneyl-2- (4,6-dimethoxy-pyrimidin-2-yl) -oxibutyric acid methyl ester 3 g (10 mmol) of 3-benzyloxy-3-phe nyl-2-hydroxybuiric acid methyl ester (see 1.2) are dissolved in 40 ml of dimethylformamide and mixed with 0.3 g (12 mimols) of Sodium hydride The mixture is stirred for one hour and then 2.2 g (10 mol.) Of 4,6-di? R, ethoxy-2-methyl-sulphonylpyrimidine are added, and after stirring for 24 hours at room temperature, it is carefully hydrolyzed with 10 ml of water, a pH value of 5 is adjusted with acetic acid and the solvent is distilled in a high vacuum, the residue is taken up in 100 ml of acetic acid ester, washed with water, dried over sodium sulfate and the solvent is distilled. with 10 ml methyl-t-butyl ether and the precipitate is filtered off by suction, after drying 2,4 g of a white powder remain.

Yield: 55% (diastereose mixture was 1: 1) p.f. : 115-117? C Example 4 3-Benzyl acid? I-3-phenyl-2- (4,? -dimetho? Ipyrimidin-2-yl) oxy-butyric acid 1.4 g (3 mmoles) of 3-benzyloxy-3-eneyl-2-acid. { 4,6-dimethoxy-pyrimidin-2-yl) -oxibutyric acid (Ex 3) are dissolved in 20 ml of methanol and 20 ml of tetrahydrofuran and mixed with 3.7 g of 10% NaOH solution. The mixture is stirred at ßO ° C for 12 hours and 12 hours at room temperature, the solvents are distilled off in vacuo and the residue is taken up in 100 ml of water. Now it is extracted with acetic ester to remove unreacted ester. Then, the aqueous phase is adjusted with dilute hydrochloric acid to pH 1-2 and extracted with acetic ester. After drying the sodium sulphate and distilling off the solvent, the residue is mixed with a little acetone and the precipitate formed is filtered off with suction. After drying, 1.2 g of a white powder remain.

Yield: 83% diastereomeric mixture 3: 2 p.f .: 165 ° C (decomposition) Example 5 3-Benzyloxy-3-phenyl-2- [(4,6-dimetho-i-pyrimidin-2-yl) thio] -butyric acid methyl ester 11 g (25 mmol) of 3-benzyloxy-3-phenyl-2-hydroxybutyric acid methyl ester (Compound 1.2) are dissolved in 50 ml of dichloroethane, 3 g (30 mmol) of tritylamine are added and under stirring 3.2 g (28 mmol) of methanesulfonic acid chloride are added dropwise. It is stirred for two hours at room temperature, washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue is absorbed in DMF and added at 0 ° C to a suspension of 12.9 g (75 mmol) of 4,6-di-methoxyp? imi in-2-thiol and 8.4 g (loo mmoles) of sodium hydrogencarbonate in 100 ml of DMF. After stirring for two hours at room temperature and another two hours at 60 ° C, pour over 1 1 of ice water and filter the precipitate formed by suction. After drying, 3.2 g of a white powder remain.

Yield: 29% l diastereomeric mixture 1: 1) In analogy to the examples described above, the compounds listed in Table 2 are prepared.

Table 2 Synthesis of compounds of the general formula VI Example 6 3-phenoxy-3-phenyl-2-hydroxybutyric acid methyl ester 28.2 g (0.3 mol) of phenol and 19.2 g (0.1 mol) of methyl ester of 3-phenyl-2,3-epoxybutyric acid are heated together for 6 hours at 100 ° C. Having distilled the excess phenol in high vacuum and purified the residue by chromatography on silica gel with hexane / acetic ester mixture, 17.9 g of a slightly yellow oil are obtained.

Performance: 62.5% 7 Methyl ester of 3- (4-bromophen? L) or? I-3-phenyl-2-hydro? I-butyric acid 51.9 g (0.3 mol) of 4-bromophenol and 19.2 g (0.1 mol) of 3-phenyl-2,3-epoxybutyric acid methyl ester are stirred for 8 h at 100 ° C and 12 h room temperature. Having distilled the excessive phenol, the residue is purified by flash chromatography (silica gel, n-hexans-acetic ester 9: 1) 7.2 g of a white solid are obtained.

Yield: 20% p.f .: 133 - 135 ° C In analogy the compounds indicated in the Table were prepared 3: Table .- Intermediate products of the formula VI with R * = CH3 R * I Rb O C - CH - OH R 'COOCH3 Synthesis of the compounds of the general formula I: Example 8 Methyl ester of 3-phenoyl-i-3-phenyl-2- (4,6-dimethoxypropyl?) - din-2-yl) oxybutyric acid 4.4 g (15.4 mmol) of the methyl ester of 3-phenoxy-3-phe nyl-2-hydroxybutyl acid. 1.1) are dissolved in 40 ml of ida di-methylformate and mixed with 0.46 g (18.4 mmol) of sodium hydride. The mixture is stirred for one hour and then 3.4 g (15.4 mmoles) of 4,6-dimetho-i-2-rcethylsulphonylpyrin.idine are added. After stirring for 24 hours at room temperature, it is hydrolyzed carefully with 10 ml of water, a pH value of 5 is adjusted with acetic acid and the solvent is distilled under high vacuum, the residue is taken up in 100 ml of acetic ester, it is washed with water, dried over sodium sulfate and the solvent is distilled. The residue is mixed with 10 ml of methyl-1-t-bu il ether and the precipitate is filtered off by suction. After drying Queaan 1.6 g of a white powder.

Yield: 24.5% p.f .: 143 - 145 »C Example 9 3-Phenoxy-3-phenyl-2- (4,6-dimethoxypyrimidin-2-yl) oxybutyl acid 1.3 g of the 3-phenoxy-3-phenyl-2- (4,6-dimethoxypyrimidin-2-yl) oxybutyric acid methyl ester (Ex. 8) are dissolved in 20 ml of MeOH and 40 ml of tetrahydrofuran. , and mixed with 3.7 g of 10% NaOH solution. The mixture is stirred for 6 hours at 60 ° C and 12 hours at room temperature, the solvent is distilled off under vacuum and the residue is taken up in 10 ml of water. The unreacted ester is extracted with acetic acid. Then, the aqueous phase is adjusted with hydrochloric acid to pH 1-2 and extracted with acetic ester. After drying over magnesium sulfate and distilling off the solvent, 1.0 g of a white powder remain.

Yield: 79.7% p.f. : 50 - 55 ° C Example 10 Methyl ester of 3-phenoxy-3-femyl-2-f (4,6-dimethoxy-pyrimidin-2-yl) io] butyric acid 7.2 g (25 mmol) of the methyl ester of 3-phenoxy-3-phe nyl-2-hydroxybutyric acid are dissolved in 50 ml of dichloromethane, 3 g of 0 mmol) of triethylamine are added and stirring is added dropwise. 3.2 g (28 mmolee) of methanesulphonic acid chloride. Stir 2 hours at room temperature, wash with water, dry over magnesium sulfate and concentrate in vacuo. The residue is taken up in 100 ml DMF and added dropwise at 0 ° C to a suspension of 12.9 g (75 mmol) of 4,6-di-methoxypyrimidin-2-thiol and 8.4 g (100 mmol) of sodium hydrogencarbonate in 100 ml of DMF. After stirring for 2 hours at room temperature and another two hours at 60 ° C, it is poured into 1 liter of ice water and the precipitate is filtered by suction. After drying, 4.2 g of a white powder remain.

Performance; 38% Analogously to the examples described above, the compounds indicated in Table 4 are prepared. Table 4

Claims (1)

1. Claiming Use of carboxylic acid derivatives of the general formula I wherein R means a formyl group, a C02H group or a hydrolysable radical in COOH and the other substituents have the following meanings: R2 halogen, C? -C, -alkyl, C? -C4-haloalkyl, C? -C,? -alkoxy, C? -C4-haloalkoxy or C? -C4-alkylthio; x nitrogen or CR1 /; where R14 means hydrogen or together with R3 forms an alkylene or alkenyl chain with 3 to 4 members, in which a methylene group respectively is replaced by oxygen; R3 halogen, C? -C4 alkyl, C? -C4-haloalkyl, coxy, C? -C4-haloalkoxy, Ci-C? -alkylthio or R3 is linked with RiI, as indicated above, forming a ring of 5 or 6 members; R4 a C? -C? -alkyl group, which can carry one to five halogen atoms and / or one of the following radicals: C? -Ci-alkoxy, C: -C4-alkylthio, cyano, Ci-Cg -alkylcarbonyl, Ci-Ce-alkoxycarbonyl, phenyl, phenoxy or phenylcarbonyl, the phenyl radicals being capable of carrying one to five halogen atoms and / or one to three of the following radicals: Cj-Cí-alquüo, C? C4-alkoxy, C? -C4-halogenoalkoxy and / or C; i-C4-alkylthio; a C? -C? -alkyl group, which carries one to five halogen atoms and one of the following radicals: a five-membered heteroaromatic containing one to three nitrogen atoms and / or a sulfur or oxygen atom, which can carry one to four halogen atoms and / or one to two of the following radicals: C? -C4-aikyl, C? -C4-haloalkyl, Ci-Ci-alkoxy, C? -C4-halogenoalkoxy, C? -C α-alkylthio and / or phenyl; a C3-C? 2-cycloalkyl or Ci-Cjj-cycloalkenyl group, which may contain an oxygen or sulfur atom and carry one to five halogen atoms and / or one of the following radicals: C? ~ C, -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -lichthio, cyano, C ?Ce-alkylcarbonyl, Ci-Cι-alkoxycarbonyl, phenyl, phenoxy or phenylcarbonyl, whose phenyl radicals can carry one to five on the other hand halogen atoms and / or one to three of the following radicals: C? -C4? alkyl, C: -C-haloalkyl, Cj-d-alkoxy, C? -C4-haloalkoxy and / or C? -C4-alkylthi?; a C group: - C6-ahenynyl or C3-C6-alkynyl, which may each carry one to five halogen atoms and / or one of the following radicals: C? -C4-alkyl, C? -C4-alkoxy, C?-C4-alkylthio, cyano, Ci-Cs-alkylcarbonyl, C?-C§-alkoxycarbonyl, phenyl, phenoxy or phenylcarbonyl, whose phenyl radicals can in turn carry one to five halogen atoms and / or one to three of the following radicals: C? -C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C? -C4-haloalkoxy and / or C; -C4-alkylthi ?; a heteroaromatic of five or six members, containing 5 one to three nitrogen atoms and / or one sulfur or oxygen atom, which can carry one to four halogen atoms and / or one to two of the following radicals: Ci-C4 -alkyl, c-, - C4-halogenoalkyl, C? -C4-alkoxy, Cl-C4-halogenoalkoxy, C: -C4-alkylthio, phenyl, pheno? -io-nylcarbonyl, whose phenyl radicals can in turn carry one up to five halogen atoms and / or one to three of the radicals: Ci-Ca-alkyl, C-rC4-haloalkyl, C-c4-alkoxy, Ci-Ci-halogenoalcoy, and / or Ci- Cj-alkylthio; Phenyl or nayl, which may be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxy, C: -4-alkyl, C? -C4-haloalkyl, C? -C4-alkoxy, C? C 1 -haloalkoxy, phenoxy, C 1 -C 4 -alkylthio, amino, Ci-C 4 -alkylamino or C] .- C 4 -diarykylamino; 20 R < I and R5 together form with the neighboring carbon atom a ring of 3 to S members, which may contain an oxygen or sulfur atom and carry one to three of the following radicals: C < -C-alkyl, halogen, C? -C, i-halogenoalkyl, Ci-C4-aico?, C? -C4-halogenoalco? And / or d-c4-alkenylthio; R5 is hydrogen, Ci-Ca-alkyl, Cs-Cg-alkenyl, C3-C6-alkynyl, C3-Cg-cycloalkyl, C? -C4-alkoxyalkyl, C? -C-alkylarylthioacyl, phenyl, or R5 is attached with 30, as indicated above, forming a ring of 3 to 8 members; R6 Ci-Cβ-alkyl, C3-Ci- alkenyl, Cj-Cß-alkynyl or C3-CG-cycloalkyl, the radicals of which may be mono- or polysubstituted by: halogen, nitro, cyano, C? -C4-alkoxy , C3-C6-alkenyloxy, C3-C6-alkynyl?, C? -C4-alkylthio, C? -C4-halogenoalkoxy, C-C4-alkylcarbonyl, C? -C4-alkoxycarbonyl, C1- C4-alkylamino, di-C? -C4-alkylamino, phenyl, Mono- or polysubstituted, eg mono to trisubstituted by halogen, nitro, cyano, C? -C4-alkyl, Cx-Ci-halogenoalkyl, C? -C4-alkoxy, Ci-C-halogenoalkoxy or phenyl substituted by C? -C4 ~ alkylthio, or phenoxy; phenyl or naphthyl, which may be substituted each time 15 by one or more of the following radicals: halogen, nitro, cyano, hydroxy, amino, C? C4-alkyl, C? -4-halogenoalkyl, d-Ci-alkoxy, d-d-halogenoalkoxy, phenoxy, C? -C4-alkylthio, Ci-Cj-aiquiiamino or C? -C4-dialkylamino; A heteroaromatic of five or six members, containing one to three nitrogen atoms and / or one sulfur or oxygen atom, which can carry one to four halogen atoms and / or one to two of the following radicals. C-alkyl, C-Ci-haloalkyl, C? -C4-alko?, C1-C4-h.alogenoal.coxy, C: -C4-alkylthio, phenyl, phenoxy or phe- 25 nylcarbonyl, whose phenyl radicals can carry for its part one to five halogen atoms and / or one to three of the following radicals: C: -C4-alkyl, Ci-Ci-haloalkyl, C? -C4-alco? i, C? ~ C4-halogenoalkoxy and / or C1-C4-alkylthio; 30 And sulfur or oxygen or a single bond, - Z sulfur or oxygen; for obtaining medicines. Summary of the Invention Use of carboxylic acid derivatives of the general formula i wherein R means a formyl group, a C0H group or a hydrolysable radical in COOH and the other substituents have the following meanings: K? -halogen, C: -C 4 -alkyl, C? -C4-haloalkyl, C: -C 4 -alkoxy, C? -C4-halogen-C xi or C: -C_-alkylthio; x nitrogen or CR 1 ', where R 14 signifies hydrogen or forms together with R:' a chain of alkylene o or alkenyl with 3 to 4 members, in which a methylene group respectively is substituted by oxygen; R3 halogen, dC / -alkyl, C? -C4 -haloger.alkyl, C -.- C ^ -alkoxy, Ci-Ca-haloalkoxy, Ci-c4-alkylthio or R3 is linked with R1, as indicated above, forming a ring of 5 or 6 members; R4 is a C? -C-alkyl group, which can contain up to five halogen atoms and / or one of the following radicals: C? -C4-alkoxy, C? -C4-alkylthio, cyano, C: -C3-alkylcarbo - nilo, C -C? -alkoxycarbonyl, phenyl, phenoxy or phenylsarbonyl, the phenyl radicals can on the one hand carry one to five halogen atoms and / or one to three of the following radicals: C.-Ca-alkyl, C? -C4-haloalkyl , Ci-C-a coxy, and / or C? -C4-alkylthio; a group Cj.-C? -alkyl, which carries one to five halogen atoms and one of the following radicals: a five-membered heteroaromatic containing one to three nitrogen atoms and / or a sulfur or oxygen atom, which can carry one up to four halogen atoms and / or one up to two of the? following radicals: C: -C4 ~ alkyl, C-C4-halogen? alkyl, C? -C4-alkoxy, C? -C4-halogenoalkoxy, C: -Ci-a.-alkylthio and / or phenyl; a c., - C?, -; -? cloalkyl or C3-Ci2-cycloalkenyl group, which may contain an oxygen or sulfur atom and carry one to five halogen atoms and / or one of the following radicals: C1- c4-aikyl, C? -C4-alkoxy, C? -C4-alkylthio, cyano, C: -C3-alkylcarbonyl, Ci-Cg-alkoxycarbonyl, phenyl, phenoxy or phenylcarbonyl, whose phenyl radicals can carry per part one to five halogen atoms and / or one to three of the following radicals: C: -Cj-alkyl, C.-C4-haloalkyl ?, C? -C? -alkoxy, Ci-Ci-haloalkoxy and / or Ci -Cy-alkylthio; a C3-C6-aikenyl or C3-C6-alkynyl group, which can each carry up to five halogen atoms and / or one of the following radicals: C? -C4-alkyl, C? -C4-alkoxy, -Ci-alkylthio, cyano, Ci-Cg-alkylcarbonyl, Ci-Cg-alkoxycarbonyl, phenyl, phenoxy or phenylcarbonyl, whose phenyl radicals can in turn carry one to five halogen atoms and / or one to three of the following radicals: d-Ci-alkyl, Ci-CV-alkoalkyl, C? -C4-alkoxy, C? -C? -haloalkoxy and / or C »-C4-alkylthi ?; a heteroaromatic of five or six members, containing one to three nitrogen atoms and one atom of sulfur or oxygen, which can carry one to four halogen atoms and / or one to two of the following radicals: Ci-C4-alkyl , C? -C4-halogenoalkyl, C? ~ C4-alkoxy, CC? -halogenoalkoxy, C? -C4-alkylo, phenyl, phenoxy or fe¬ Nylcarbonyl, whose phenyl radicals can in turn carry one to five halogen atoms and / or one to three of the following radicals: C? -C4-to uyl, C: -C4-haloalkyl, C? -C4-alkoxy, C? -C4"-halogenoalkoxy and / or C? -C4-alkylthio; phenyl or naphthyl, which may be substituted by one or 15 several of the following radicals: halogen, nitro, cyano, hydroxy, C? -c4-alkyl, C? -C4-haloalkyl, C? -C4-alkoxy, C? -C4-haloalkoxy, phenoxy, C? -C4- alkylthio, amino, C? -C4-alkylamino or C? -C < -dialkylamino; 20 R and RB form together with the neighboring carbon atom a ring of 3 to 8 members, which may contain an oxygen or sulfur atom and carry one to three of the following radicals: C? -C4-alkyl, halogen, C ~ C-halogenalkyl, d-C'-alkoxy, Ci-Ca-halogenoalkoxy and / or C? -C4-alkylthio, -25 R5 hydrogen, C - (- C -alkyl, C3-C3-alkenyl, c3-C6-alkynyl, Cj-Cfl-cycloalkyl, C? -C4-haloalkyl, C? -C4-alkoxyalkyl, C? _ C4 -alkyl alkyl phenyl, or R5 is linked with R '1, a as indicated above, forming a ring of 3 to 8 members; R'-C? -C .-; - alkyl, C:, - C-alkenyl, C3-C6-alkylene or C3-Ca-cycloalkyl, the radicals of which may be mono- or polysubstituted by; halogen, nitro, cyano, C? -C4-alkoxy, c3-C6-alkenyloxy, c3-Ci- alkyloxy ?, C! -C4-alkylthio, Cj-C4-halogenoalco?, C; -C4-alkylcarbonyl , C? -C4-alkoxycarbonyl, C: -C4-alkylamino, di-C? -C4-alkylamino, phenyl, mono- or polysubstituted, eg mono to trisubstituted by halogen, nitro, cyano, C? -C4 -alkyl, C? ~ C4-halogenoalkyl, C? -C4-alkoxy, C? ~ C4-halogen lco or phenyl substituted by C? -c4-alkylthio, or phenoxy; phenyl or naphthyl, which may be substituted each time by one or more of the following radicals: halogen, nitro, cyano, hydroxy, amino, C? -C4-alkyl, C? -C4-halogenoalkyl, C-Ci-alkoxy , C? -C4-halogenoalkoxy, phenoxy, C? -C4-aicytthio, C-Cj-alkylamino or C? -C4-dialkylamino; a heteroaromatic of five or six members, containing one to three nitrogen atoms and / or one atom of sulfur or oxygen, which can carry one to four halogen atoms / or one to two of the following radicals: C | -C4- alkyl, C?-C4-haloalkyl, C?-C4-alkoxy, Ci-C4-haloalkoxy, C?-C4-alkylthio, phenyl, phenoxy or phenylcarbonyl, whose phenyl radicals can in turn carry one to five halogen atoms and / or one to three of the following radicals: C? -C4-alkyl, C? -C4-haloalkyl, C-C-alkoxy, C? -C4-halogenoalkoxy and / or d-C-alkylthio and sulfur or oxygen a simple link; z sulfur or oxygen; for obtaining medicines.