Heterocyclic carboxylic acid derivatives, the production and use thereof as endothelin receptor antagonists

Abstract

The present invention relates to carboxylic acid derivatives of the formula I where the substituents have the meanings explained in the description, and to preparation and use as endothelin receptor antagonists.

Description

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

Endothelin is a peptide made up of 21 amino acids, which is synthesized and released by vascular endothelin. Endothelin exists in three isoforms, ET-1, ET-2 and ET-3. In the following, endothelin or ET designates one or all isoforms of endothelin. Endothelin is a potent vasoconstrictor and has a strong effect on the vascular tone. It is known that this vasoconstriction is caused by the binding of endothelin to its receptor (Nature, 332 (1988), 411-415; FEBS Letters, 231 (1988), 440-444, and Biochem. Biophys. Res. Commun., 154 (1988), 868-875).

Increased or abnormal release of endothelin causes a lasting vascular contraction in peripheral, renal and cerebral blood vessels which can lead to illnesses. As reported in the literature, endothelin is involved in a number of illnesses. These include: hypertension, acute myocardial infarct, pulmonary hypertension, Raynaud's Syndrome, cerebral vasospasms, stroke, benign prostate hypertrophy, atherosclerosis and asthma (J. Vascular Med. Biology 2 (1990), 207, J. Am. Med. Association 264 (1990), 2868, Nature 344 (1990), 114, N. Engl. J. Med. 322 (1989), 205, N. Engl. J. Med. 328 (1993), 1732, Nephron 66 (1994), 373, Stroke 25 (1994), 904, Nature 365 (1993), 759, J. Mol. Cell. Cardiol. 27 (1995), A234; Cancer Research 56 (1996), 663).

At least two endothelin receptor subtypes, ET A and ET B receptors, are at present described in the literature (Nature 348 (1990), 730, Nature 348 (1990), 732). Accordingly, substances which inhibit the binding of endothelin to one or to both receptors should antagonize physiological effects of endothelin and therefore be useful pharmaceuticals.

It is an object of the present invention to make available endothelin receptor antagonists which bind to the ET A and/or the ET B receptors.

The invention relates to carboxylic acid derivatives of the formula I

[lacuna] R 1 is tetrazole or a group

where R has the following meanings:

a) a radical OR 6 , where R 6 is:

hydrogen, the cation of an alkali metal, the cation of an alkaline earth metal, a physiologically tolerable organic ammonium ion such as tertiary C 1 -C 4 -alkylammonium or the ammonium ion;

C 3 -C 8 -cycloalkyl, C 1 --C 8 -alkyl, CH 2 -phenyl which can be substituted by one or more of the following radicals: halogen, nitro, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, hydroxyl, C 1 -C 4 -alkoxy, mercapto, C 1 -C 4 -alkylthio, amino, NH(C 1 -C 4 -alkyl), N(C 1 -C 4 -alkyl) 2 ;

a C 3 -C 8 -alkenyl or a C 3 -C 8 -alkynyl group, it being possible for these groups in turn to carry one to five halogen atoms;

R 6 can furthermore be a phenyl radical which can carry one to five halogen atoms and/or one to three of the following radicals: nitro, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, hydroxyl, C 1 -C 4 -alkoxy, mercapto, C 1 -C 4 -alkylthio, amino, NH(C 1 -C 4 -alkyl), N(C 1 -C 4 -alkyl) 2 ;

b) a 5-membered heteroaromatic linked via a nitrogen atom, such as pyrrolyl, pyrazolyl, imidazolyl or triazolyl, which can carry one to two halogen atoms, or one to two C 1 -C 4 -alkyl or one to two C 1 -C 4 -alkoxy groups;

c) a group

where k [lacuna] assume the values 0, 1 and 2, p can assume the values 1, 2, 3 and 4 and R 7 is

C 1 -C 4 -alkyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -alkenyl, C 3 -C 8 -alkynyl or phenyl, which can be substituted by one or more, eg. one to three, of the following radicals: halogen, nitro, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, hydroxyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylthio, mercapto, amino, NH(C 1 -C 4 -alkyl), N(C 1 -C 4 -alkyl) 2 ;

d) a radical

where R 8 is:

C 1 -C 4 -alkyl, C 3 -C 8 -alkenyl, C 3 -C 8 -alkynyl, C 3 -C 8 -cycloalkyl, it being possible for these radicals to carry a C 1 -C 4 -alkoxy, C 1 -C 4 -alkylthio and/or a phenyl radical as mentioned under c);

C 1 -C 4 -haloalkyl or unsubstituted or substituted phenyl, in particular as mentioned under c).

The other substituents have the following meanings:

X is nitrogen or methine; with the proviso that if X=nitrogen then Z=nitrogen and if X=methine then at least one of the ring members Y or Z is nitrogen;

Y is nitrogen or CR 9 ;

Z is nitrogen or CR 10 ;

R 2 is C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, it being possible for these radicals each to be mono- or polysubstituted by: halogen, hydroxyl, mercapto, carboxyl, cyano, amino, C 1 -C 4 -alkoxy;

hydrogen, halogen, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, C 3 -C 6 -alkenyloxy, C 3 -C 6 -alkynyloxy, C 1 -C 4 -alkylthio, C 1 -C 4 -alkylcarbonyl, C 1 -C 4 -alkoxycarbonyl, NH(C 1 -C 4 -alkyl), N(C 1 -C 4 -alkyl) 2, hydroxyl, carboxyl, cyano, amino, mercapto;

or CR 2 together with CR 9 or CR 10 forms a 5- or 6-membered alkylene or alkenylene ring which can be substituted by one or two C 1 -C 4 -alkyl groups, and where in each case one or more methylene groups can be replaced by oxygen, sulfur, —NH or —N(C 1 -C 4 -alkyl);

R 3 and R 4 (which can be identical or different) are:

phenyl or naphthyl, which can be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, mercapto, C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, phenoxy, C 1 -C 4 -haloalkoxy, C 1 -C 4 -alkylthio, amino, NH(C 1 -C 4 -alkyl), N(C 1 -C 4 -alkyl) 2 or phenyl, which can be mono- or polysubstituted, eg. mono- to trisubstituted by halogen, nitro, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy or C 1 -C 4 -alkylthio; or

phenyl or naphthyl, which are connected to one another in the ortho position via a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an SO 2 —, NH— or N-alkyl group;

C 3 -C 8 -cycloalkyl, it being possible for these radicals in each case to be mono- or polysubstituted by: halogen, hydroxyl, mercapto, carboxyl, nitro, cyano, C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylthio, C 1 -C 4 -haloalkoxy;

R 5 is hydrogen, C 1 -C 8 -alkyl, C 3 -C 8 -alkenyl or C 3 -C 8 -alkynyl, it being possible for these radicals in each case to be mono- or polysubstituted by: halogen, hydroxyl, mercapto, carboxyl, nitro, amino, cyano, C 1 -C 4 -alkoxy, C 3 -C 6 -alkenyloxy, C 3 -C 6 -alkynyloxy, C 1 -C 4 -alkylthio, C 1 -C 4 -haloalkoxy, C 1 -C 4 -alkylcarbonyl, C 1 -C 4 -alkoxycarbonyl, C 3 -C 8 -alkylcarbonylalkyl, NH(C 1 -C 4 -alkyl), N(C 1 -C 4 -alkyl) 2 ,

C 3 -C 8 -cycloalkyl, heteroaryloxy or heteroaryl, which is five-or six-membered, comprising one to three nitrogen atoms and/or a sulfur or oxygen atom, phenoxy or phenyl, it being possible for the aryl radicals mentioned in turn to be mono- or polysubstituted, eg. mono- to trisubstituted by halogen, hydroxyl, mercapto, carboxyl, nitro, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, amino, NH(C 1 -C 4 -alkyl), N(C 1 -C 4 -alkyl) 2 or C 1 -C 4 -alkylthio;

phenyl or naphthyl, which in each case can be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, amino, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, phenoxy, C 1 -C 4 -alkylthio, C 1 -C 4 -alkylamino, C 1 -C 4 -dialkylamino, dioxomethylene or dioxoethylene;

a five- or six-membered heteroaromatic, comprising 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 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, C 1 -C 4 -alkylthio, phenyl, phenoxy or phenylcarbonyl, it being possible for the phenyl radicals in turn to carry one to five halogen atoms and/or one to three of the following radicals: C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy and/or C 1 -C 4 -alkylthio;

C 3 -C 8 -cycloalkyl, it being possible for these radicals in each case to be mono- or polysubstituted by: halogen, hydroxyl, mercapto, carboxyl, nitro, cyano, C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylthio, C 1 -C 4 -haloalkoxy;

R 9 and R 10 (which can be identical or different) are:

hydrogen, halogen, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, C 3 -C 6 -alkenyloxy, C 3 -C 6 -alkynyloxy, C 1 -C 4 -alkylthio, C 1 -C 4 -alkylcarbonyl, C 1 -C 4 -alkoxycarbonyl, NH 2 , NH(C 1 -C 4 -alkyl), N(C 1 -C 4 -alkyl) 2 ;

C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, it being possible for these radicals to be substituted by halogen, hydroxyl, mercapto, carboxyl, cyano;

or CR 9 or CR 10 is linked with CR 2 as indicated under R 2 to give a 5- or 6-membered ring;

W is sulfur, oxygen or a single bond;

Q is oxygen or nitrogen; with the proviso that if Q=nitrogen then W is a single bond.

In this context and subsequently the following definitions apply:

an alkali metal is, for example, lithium, sodium, potassium;

an alkaline earth metal is, for example, calcium, magnesium, barium;

organic ammonium ions are protonated amines such as, for example, ethanolamine, diethanolamine, ethylendiamine diethylamine or piperazine;

C 3 -C 8 -cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl;

C 1 -C 4 -haloalkyl can be linear or branched such as, for example, fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trichloromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl or pentafluoroethyl;

C 1 -C 4 -haloalkoxy can be linear or branched such as, for example, difluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, 1-fluoroethoxy, 2,2-difluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-1,1,2-trifluoroethoxy, 2-fluoroethoxy or pentafluoroethoxy;

C 1 -C 4 -alkyl can be linear or branched such as, for example, ethyl, ethyl, 1-propyl, 2-propyl, 2-methyl-2-propyl, 2-methyl-1-propyl, 1-butyl or 2-butyl;

C 2 -C 4 -alkenyl can be linear or branched such as, for example, ethenyl, 1-propen-3-yl, 1-propen-2-yl, 1-propen-1-yl, 2-methyl-1-propenyl, 1-butenyl or 2-butenyl;

C 2 -C 4 -alkynyl can be linear or branched such as, for example, ethynyl, 1-propyn-1-yl, 1-propyn-3-yl, 1-butyn-4-yl or 2-butyn-4-yl;

C 1 -C 4 -alkoxy can be linear or branched such as, for example, methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or 1,1-dimethylethoxy;

C 3 -C 6 -alkenyloxy can be linear or branched such as, for example, allyloxy, 2-buten-1-yloxy or 3-buten-2-yloxy;

C 3 -C 6 -alkynyloxy can be linear or branched such as, for example, 2-propyn-1-yloxy, 2-butyn-1-yloxy or 3-butyn-2-yloxy;

C 1 -C 4 -alkylthio can be linear or branched such as, for example, methylthio, ethylthio, propylthio, 1-methylethylthio, butylthio, 1-methylpropylthio, 2-methylpropylthio or 1,1-dimethylethylthio;

C 1 -C 4 -alkylcarbonyl can be linear or branched such as, for example, acetyl, ethylcarbonyl or 2-propylcarbonyl;

C 1 -C 4 -alkoxycarbonyl can be linear or branched such as, for example, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl or n-butoxycarbonyl;

C 3 -C 8 -alkylcarbonylalkyl can be linear or branched, for example 2-oxoprop-1-yl, 3-oxobut-1-yl or 3-oxobut-2-yl;

C 1 -C 8 -alkyl can be linear or branched such as, for example, C 1 -C 4 -alkyl, pentyl, hexyl, heptyl or octyl; C 3 -C 8 -alkenyl can be linear or branched such as, for example, 1-propen-3-yl, 1-propen-2-yl, 1-propen-1-yl, 2-methyl-1-propenyl, 1-buten-4-yl, 2-buten-3-yl, 1-penten-5-yl, 1-hexen-6-yl, 3-hexen-6-yl, 2-hepten-7-yl or 1-octen-8-yl;

C 3 -C 8 -alkynyl can be linear or branched such as, for example, 1-propyn-1-yl, 1-propyn-3-yl, 1-butyn-4-yl, 2-butyn-4-yl, 2-pentyn-5-yl, 3-hexyn-6-yl, 3-heptyn-7-yl, 2-octyn-8-yl;

halogen is, for example, fluorine, chlorine, bromine, iodine.

The invention further relates to those compounds from which the compounds of the formula I can be released (prodrugs).

Those prodrugs are preferred in which the release proceeds under conditions of the type which prevail in certain body compartments, eg. in the stomach, intestine, blood circulation, liver.

The compounds I and also the intermediates for their preparation, such as, for example, II, III, IV and V, can have one or more asymmetrically substituted carbon atoms. Compounds of this type can be present as pure enantiomers or pure diastereomers or as a mixture thereof. The use of an enantiomeric pure compound as the active compound is preferred.

The invention further relates to the use of the abovementioned carboxylic acid derivatives for the production of drugs, in particular for the production of inhibitors for ET A and/or ET B receptors. The compounds according to the invention are suitable as antagonists, as were defined at the outset.

The preparation of the compounds of the general formula IV, where W is sulfur or oxygen and Q is oxygen (IVa) can be carried out, also in enantiomerically pure form, as described in WO 96/11914.

Compounds of the general formula III are either known or can be synthesized, for example, by reduction of the corresponding carboxylic acids or their esters, or by other generally known methods.

The compounds of the general formula IV, where W is a single bond and Q is oxygen (VIb), can be prepared both in racemic and in enantiomerically pure form as described in DE 19614533.3.

On the other hand, the compounds of the general formula IV, where W is a single bond and Q is nitrogen (IVc) can be prepared both in racemic form and in enantiomerically pure form as described in DE 19536891.6.

The compounds according to the invention, where the substituents have the meanings indicated under the general formula I, can be prepared, for example, by reacting the carboxylic acid derivatives of the general formula IV, in which the substituents have the meanings indicated, with compounds of the general formula VII.

In formula VII, R 11 is halogen or R 12 —SO 2 —, it being possible for R 12 to be C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl or phenyl, and for X, Y and Z the conditions mentioned at the outset apply. The reaction preferably takes place in an inert solvent or diluent with addition of a suitable base, ie. of a base which brings about deprotonation of the intermediate IV, in a temperature range from room temperature up to the boiling point of the solvent.

Compounds of the type I where R 1 =COOH can furthermore be obtained directly if the intermediate IV, where R 1 is COOH, is deprotonated using two equivalents of a suitable base and reacted with compounds of the general formula V. Here also, the reaction takes place in an inert solvent and in a temperature range from room temperature up to the boiling point of the solvent.

Examples of solvents or diluents of this type are aliphatic, alicyclic and aromatic hydrocarbons, which in each case can be free or chlorinated, such as, for example, hexane, cyclohexane, petroleum ether, naphtha, benzene, toluene, xylene, methylene chloride, chloroform, carbon tetrachloride, ethyl chloride and trichloroethylene, ethers, such as, for example, diisopropyl ether, dibutyl ether, methyl tert-butyl ether, propylene oxide, dioxane and tetrahydrofuran, nitrites, such as, for example, acetonitrile and propionitrile, acid amides, such as, for example, dimethylformamide, dimethylacetamide and N-methylpyrrolidone, sulfoxides and sulfones, such as, for example, dimethyl sulfoxide and sulfolane.

Compounds of the formula VII are known, in some cases commercially available or can be prepared in a generally known manner (eg. in a similar manner to J. Org. Chem. 52 (1987), 4280).

The base used can be an alkali metal or alkaline earth metal hydride, such as sodium hydride, potassium hydride or calcium hydride, a carbonate such as an alkali metal carbonate, eg. sodium or potassium carbonate, an alkali metal or alkaline earth metal hydroxide such as sodium or potassium hydroxide, an organometallic compound such as butyllithium or an alkali metal amide such as lithium diisopropylamide or lithium amide.

Compounds of the formula I can also be prepared by starting from the corresponding carboxylic acids, ie. compounds of the formula I where R 1 is COOH, and first converting these in a customary manner into an activated form such as an acid halide, an anhydride or imidazolide and then reacting this with an appropriate hydroxyl compound HOR 7 . This reaction can be carried out in the customary solvents and often requires the addition of a base, those mentioned above being suitable. These two steps can also be simplified, for example, by allowing the carboxylic acid to act on the hydroxyl compound in the presence of a dehydrating agent such as a carbodiimide.

Moreover, compounds of the formula I can also be prepared by starting from the salts of the corresponding carboxylic acids, ie. from compounds of the formula I where R 1 is COR and R is OM, it being possible for M to be an alkali metal cation or the equivalent of an alkaline earth metal cation. These salts can be reacted with many compounds of the formula R-A, A being a customary nucleofugic leaving group, for example halogen such as chlorine, bromine, iodine or, if desired, aryl- or alkylsulfonyl substituted by halogen, alkyl or haloalkyl, such as, for example, toluenesulfonyl and methylsulfonyl or another equivalent leaving group. Compounds of the formula R-A having a reactive substituent A are known or easy to obtain using the general expert knowledge. This reaction can be carried out in the customary solvents and is advantageously performed with addition of a base, those mentioned above being suitable.

Compounds of the formula I where R 1 is tetrazole can be prepared as described in WO 96/11914.

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

X is nitrogen or methine; with the proviso that if X=nitrogen then Z=nitrogen and if X=methine then at least one of the ring members Y or Z=nitrogen;

Y is nitrogen or CR 9 ;

Z is nitrogen or CR 10 ;

R 2 is C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl, it being possible for these radicals each to be mono- to trisubstituted by: halogen, hydroxyl, mercapto;

hydrogen, halogen, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, C 1 -C 4 -alkylthio, C 1 -C 4 -alkoxycarbonyl, NH(C 1 -C 4 -alkyl), N(C 1 -C 4 -alkyl) 2, hydroxyl;

or CR 2 , together with CR 9 or CR 10 , forms a 5- or 6-membered alkylene or alkenylene ring which can be substituted by one or two C 1 -C 4 -alkyl groups, and where in each case one or more methylene groups can be replaced by oxygen, sulfur, —NH or —N(C 1 -C 4 -alkyl);

R 3 and R 4 (which can be identical or different) are:

phenyl or naphthyl, it being possible for these radicals to be mono- to trisubstituted by: halogen, cyano, hydroxyl, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, C 1 -C 4 -alkylthio, amino, NH(C 1 -C 4 -alkyl), N(C 1 -C 4 -alkyl) 2 or phenyl, which can be mono- to trisubstituted by halogen, nitro, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy or C 1 -C 4 -alkylthio; or

phenyl or naphthyl, which are bonded to one another in the ortho position via a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an SO 2 —, NH— or N-alkyl group;

C 3 -C 8 -cycloalkyl, it being possible for these radicals in each case to be mono- to trisubstituted by: halogen, hydroxyl, mercapto, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylthio, C 1 -C 4 -haloalkoxy;

R 5 is hydrogen, C 1 -C 8 -alkyl, C 3 -C 8 -alkenyl or C 3 -C 8 -alkynyl, it being possible for these radicals in each case to be mono- to trisubstituted by: halogen, hydroxyl, mercapto, carboxyl, amino, cyano, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylthio, C 1 -C 4 -haloalkoxy, C 1 -C 4 -alkylcarbonyl, C 1 -C 4 -alkoxycarbonyl, NH(C 1 -C 4 -alkyl), N(C 1 -C 4 -alkyl) 2 , C 3 -C 8 -cycloalkyl, heteroaryloxy or heteroaryl, five- or six-membered, comprising one to three nitrogen atoms and/or a sulfur or oxygen atom, phenoxy or phenyl, it being possible for the aryl radicals mentioned in turn to be mono- to trisubstituted by halogen, hydroxyl, mercapto, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, C 1 -C 4 -alkylthio, NH(C 1 -C 4 -alkyl) or N(C 1 -C 4 -alkyl) 2 ;

phenyl or naphthyl, which in each case can be mono- to trisubstituted by: halogen, cyano, hydroxyl, amino, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, phenoxy, C 1 -C 4 -alkylthio, NH(C 1 -C 4 -alkyl), N(C 1 -C 4 -alkyl) 2 , dioxomethylene or dioxoethylene;

a five- or six-membered heteroaromatic, comprising 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 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, C 1 -C 4 -alkylthio, phenyl, phenoxy or phenylcarbonyl, it being possible for the phenyl radicals in turn to carry one to five halogen atoms and/or one to three of the following radicals: C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C l -C 4 -alkoxy, C 1 -C 4 -haloalkoxy and/or C 1 -C 4 -alkylthio;

C 3 -C 8 -cycloalkyl, it being possible for these radicals in each case to be mono- to trisubstituted by: halogen, hydroxyl, mercapto, C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylthio, C 1 -C 4 -haloalkoxy;

R 9 and R 10 (which can be identical or different) are:

hydrogen, halogen, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, C 1 -C 4 -alkylthio, C 1 -C 4 -alkylcarbonyl, C 1 -C 4 -alkoxycarbonyl, NH 2 , NH(C 1 -C 4 -alkyl), N(C 1 -C 4 -alkyl) 2 , hydroxyl;

C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, it being possible for these radicals to be substituted by halogen, hydroxyl, mercapto, cyano;

or CR 9 or CR 10 is linked to CR 2 as indicated under R 2 to give a 5- or 6-membered ring;

W is sulfur, oxygen or a single bond;

Q is oxygen or nitrogen, with the proviso that if Q=nitrogen then W is a single bond.

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

X is nitrogen or methine; with the proviso that if X=nitrogen then Z=nitrogen and Y=CR 9 and if X=methine then Y=nitrogen and Z=CR 10 or Y=CR 9 and Z=nitrogen;

Y is nitrogen or CR 9 ;

Z is nitrogen or CR 10 ;

R 2 is C 1 -C 4 -alkyl, trifluoromethyl, hydrogen, fluorine, C 1 -C 4 -alkoxy, trifluoromethoxy, C 1 -C 4 -alkylthio;

or CR 2 , together with CR 9 or CR 10 , forms a 5- or 6-membered alkylene or alkenylene ring, which can be substituted by one or two C 1 -C 4 -alkyl groups, and where in each case one or more methylene groups can be replaced by oxygen or sulfur;

R 3 and R 4 (which can be identical or different) are:

phenyl or naphthyl, which can be substituted by one or more of the following radicals: halogen, cyano, C 1 -C 4 -alkyl, trifluoromethyl, C 1 -C 4 -alkoxy, trifluoromethoxy, C 1 -C 4 -alkylthio or phenyl, which can be mono- to trisubstituted by halogen, C 1 -C 4 -alkyl, trifluoromethyl, C 1 -C 4 -alkoxy or C 1 -C 4 -alkylthio; or

phenyl or naphthyl, which are connected in the ortho position via a direct bond, a methylene, ethylene or ethenylene group;

C 5 -C 6 -cycloalkyl, it being possible for these radicals in each case to be mono- to trisubstituted by: halogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylthio;

R 5 is hydrogen, C 1 -C 8 -alkyl, C 3 -C 8 -alkenyl or C 3 -C 8 -alkynyl, it being possible for these radicals in each case to be mono- to trisubstituted by: halogen, hydroxyl, mercapto, carboxyl, cyano, amino, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylthio, C 1 -C 4 -alkoxycarbonyl, NH(C 1 -C 4 -alkyl), N(C 1 -C 4 -alkyl) 2 , C 3 -C 8 -cycloalkyl, heteroaryloxy or heteroaryl, five- or six-membered, comprising one to three nitrogen atoms and/or a sulfur or oxygen atom, phenoxy or phenyl, it being possible for the aryl radicals mentioned in turn to be mono- to trisubstituted by halogen, cyano, hydroxyl, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, C 1 -C 4 -alkylthio or N(C 1 -C 4 -alkyl) 2;

phenyl or naphthyl, which in each case can be mono- to trisubstituted by: halogen, C 1 -C 4 -alkyl, trifluoromethyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, phenoxy, C 1 -C4 4 -alkylthio, dioxomethylene or dioxoethylene;

a five- or six-membered heteroaromatic, comprising 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 1 -C 4 -alkyl, trifluoromethyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylthio, phenyl, phenoxy, it being possible for the phenyl radicals in turn to carry one to five halogen atoms and/or one to three of the following radicals: C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy or C 1 -C 4 -alkylthio;

C 3 -C 8 -cycloalkyl, it being possible for these radicals in each case to be mono- to trisubstituted by: halogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylthio;

R 9 and R 10 (which can be identical or different) are:

trifluoromethyl, trifluoromethoxy, hydrogen, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylthio, NH(C 1 -C 4 -alkyl), N(C 1 -C 4 -alkyl) 2 , C 1 -C 4 -alkyl, vinyl;

or CR 9 or CR 10 is linked to CR 2 as indicated under R 2 to give a 5- or 6-membered ring;

W is sulfur, oxygen or a single bond;

Q is oxygen or nitrogen; with the proviso that if Q=nitrogen then W is a single bond.

SYNTHEIS EXAMPLES

For the synthesis of 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid and 2-hydroxy-3,3-diphenylbutyric acid see WO 96/11914 and DE 19614533.3.

Example 1

2-(6-Methylpyridazin-3-yloxy)-3-methoxy-3,3-diphenylpropionic acid (I-517)

1.3 g (4.8 mmol) of 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid dissolved in DMF were added dropwise to a suspension of 0.43 g of NaH (14.3 mmol, 80% in white oil) in 10 ml of DMF. After stirring to room temperature for 30 minutes, the mixture was treated with 0.6 g (4.8 mmol) of 3-chloro-6-methylpyridazine in 10 ml of DMF and stirred overnight at room temperature. To complete the reaction, 0.6 g (4.8 mmol) of 3-chloro-6-methylpyridazine were then added again and the mixture was kept at 60° C. for 5 hours. It was poured onto ice water, extracted three times with ethyl acetate, the aqueous phase was brought to pH 2 with half-concentrated hydrochloric acid and the precipitate which was deposited was extracted with ethyl acetate. These ethyl acetate phases were dried with magnesium sulfate and then filtered and the solvent was stripped off under reduced pressure. 800 mg of the brown residue (1.19 g) were purified by means of MPLC, it being possible to isolate 199 mg of the desired product as a white solid.

1 H—NMR (200 MHz, DMSO): 7.5 ppm (1 H, d), 7.2-7.3 (10 H, m), 7.1 (1 H, d), 6.3 (1 H, s), 3.3 (3 H, s), 2.5 (3 H, S).

FAB-MS: 365 (M+H + )

Example 2

The following compounds were prepared similarly to Example 1:

2-(6-Methoxypyrazin-2-yloxy)-3-methoxy-3,3-diphenylpropionic acid (I-384)

1 H—NMR (200 MHz, DMSO): 7.9 ppm (1 H, s), 7.8 ppm (1 H, s), 7.2-7.3 (10 H, m), 6.1 (1 H, s), 3.9 (3 H, s), 3.3 (3 H, s).

FAB-MS: 380 (M+H + )

2-(6-Methoxypyridazin-3-yloxy)-3,3-diphenylbutyric acid

1H—NMR (200 MHz, DMSO): 12.3-12.6 ppm (broad, 1 H), 7.0-7.4 (12 H, m), 6.0 (1 H, s), 3.9 (3 H, s), 1.8 (3 H, s).

FAB-MS: 365 (M+H + )

The compounds listed in Table 1 can be prepared in a similar manner or as described in the general section.

TABLE I
	I
No.	R 1	R 3 , R 4	R 5	X	Y	R 2	Z	Q	W
I-1	COOH	phenyl	methyl	N	C-Me	Me	N	O	S
I-2	COOH	4-Cl-phenyl	methyl	N	C—OMe	Me	N	O	O
I-3	COOH	phenyl	methyl	CH	N	Me	C-ethyl	O	—
I-4	COOH	phenyl	methyl	CH	N	Me	C—SMe	O	—
I-5	COOH	4-F-phenyl	methyl	N	C-Me	OMe	N	O	O
I-6	COOH	4-F-phenyl	methyl	N	C-ethyl	Me	N	O	O
I-7	COOH	4-Cl-phenyl	methyl	N	C—OMe	H	N	O	O
I-8	COOH	phenyl	4-OMe-phenyl-(CH 2 ) 2 —	N	C—CH 2 —CH 2 —CH 2	N	O	O
I-9	COOH	phenyl	4-OMe-phenyl-(CH 2 ) 2 —	N	C-Me	ethyl	N	O	O
I-10	COOH	4-Me-phenyl	methyl	N	C—O—CH 2 —O	N	O	O
I-11	COOMe	phenyl	methyl	N	C—O—CH 2 —CH 2	N	O	O
I-12	COOH	phenyl	methyl	CH	N	Me	C—OMe	O	—
I-13	COOH	phenyl	methyl	CH	N	OMe	C-Me	O	—
I-14	COOH	cyclohexyl	methyl	CH	CH	Me	N	O	O
I-15	COOH	phenyl	propyl	CH	CH	OMe	N	O	O
I-16	COOH	phenyl	2-cyclopropyleth-1-yl	CH	C-Me	Me	N	O	O
I-17	COOH	phenyl	4-OMe-phenyl-(CH 2 ) 2 —	N	C-Me	Me	N	O	O
I-18	COOH	phenyl	4-OMe-phenyl-(CH 2 ) 2 —	N	C—OMe	Me	N	O	O
I-19	COOH	phenyl	cyclohexyl-(CH 2 ) 2 —	CH	C—OMe	Me	N	O	O
I-20	COOH	4-F-phenyl	methyl	CH	C—OMe	OMe	N	O	O
I-21	COOH	phenyl	methyl	CH	N	Me	CH	O	—
I-22	COOH	phenyl	methyl	CH	N	Me	C-Me	O	—
I-23	COOH	4-F-phenyl	methyl	CH	C-Me	OMe	N	O	O
I-24	COOH	phenyl	methyl	CH	C-Ethyl	Me	N	O	S
I-25	COOH	phenyl	methyl	CH	C—OMe	H	N	O	S
I-26	COOH	phenyl	3,4-di-OMe-phenyl-(CH 2 ) 2 —	CH	N	Me	C—CH 2 —OH	O	O
I-27	COOH	phenyl	3,4-di-OMe-phenyl-(CH 2 ) 2 —	CH	N	Me	C—N(CH 3 ) 2	O	O
I-28	tetrazole	phenyl	methyl	CH	C—O—CH 2 —O	N	O	O
I-29	COOH	4-Me-phenyl	methyl	CH	C—O—CH 2 —CH 2	N	O	O
I-30	COOH	phenyl	methyl	CH	C—N(CH 3 ) 2	Me	N	O	—
I-31	COOH	phenyl	methyl	CH	C—NH(CH 3 )	OMe	N	O	—
I-32	COOH	4-F-phenyl	methyl	CH	C—OMe	CF 3	N	O	O
I-33	COOH	4-Cl-phenyl	methyl	CH	C-Me	ethyl	N	O	O
I-34	COOH	phenyl	methyl	CH	C-ethyl	CF 3	N	O	O
I-35	COOH	phenyl	3,4-di-OMe-phenyl-(CH 2 ) 2 —	CH	N	CH 2 —CH 2 —O—C	O	O
I-36	COOH	phenyl	3,4-di-OMe-phenyl-(CH 2 ) 2 —	CH	N	F	C—OMe	O	O
I-37	COOH	phenyl	propyl	CH	C—CH 2 —OH	Me	N	O	O
I-38	COOH	cyclohexyl	methyl	CH	C—N(CH 3 ) 2	Me	N	O	O
I-39	COOH	phenyl	methyl	CH	C-ethyl	F	N	O	—
I-40	COOH	phenyl	methyl	CH	C—CH 2 —OH	Me	N	O	—
I-41	tetrazole	phenyl	methyl	CH	C—NH(CH 3 )	OMe	N	O	O
I-42	COOH	phenyl	cyclopentyl	CH	N	Me	CH	O	O
I-43	COOH	phenyl	methyl	CH	N	H	C—OCF 3	O	O
I-44	COOH	phenyl	3,4-di-OMe-phenyl-(CH 2 ) 2 —	CH	N	Me	C-ethyl	O	O
I-45	COOH	phenyl	3,4-di-OMe-phenyl-(CH 2 ) 2 —	CH	N	O—CH 2 —CH 2 —C	O	O
I-46	COOH	phenyl	methyl	CH	N	Me	C-Me	O	S
I-47	COOH	phenyl	methyl	CH	N	Me	C—OMe	O	S
I-48	COOH	phenyl	methyl	CH	C-Me	F	N	O	—
I-49	COOH	phenyl	methyl	CH	C—CH 2 —CH 2 —CH 2	N	O	—
I-50	COOH	4-F-phenyl	methyl	CH	N	OMe	C—OMe	O	O
I-51	COOH	4-OMe-phenyl	methyl	CH	N	OMe	C-Me	O	O
I-52	COOH	phenyl	methyl	CH	N	Me	C-ethyl	O	S
I-53	COOH	phenyl	3,4-di-OMe-phenyl-(CH 2 ) 2 —	CH	N	Me	C—OMe	O	O
I-54	COOH	phenyl	3,4-di-OMe-phenyl-(CH 2 ) 2 —	CH	N	F	C-Me	O	O
I-55	COOH	phenyl	cyclopentyl-(CH 2 ) 2 —	CH	N	H	C—OMe	O	O
I-56	COOH	phenyl	methyl	CH	N	CH 2 —CH 2 —S—C	O	O
I-57	COOH	phenyl	methyl	CH	C—O—CH 2 —O	N	O	—
I-58	COOH	phenyl	methyl	CH	C—O—CH 2 —CH 2	N	O	—
I-59	COOH	4-Br-phenyl	methyl	CH	N	CH 2 —CH 2 —CH 2 —C	O	O
I-60	COOMe	phenyl	methyl	CH	N	O—CH 2 —CH 2 —C	O	O
I-61	COOH	4-Me-phenyl	methyl	CH	N	CH 2 —CH 2 —O—C	O	O
I-62	COOH	phenyl	3,4-di-OMe-phenyl-(CH 2 ) 2 —	CH	C—N(CH 3 ) 2	Me	N	O	O
I-63	COOH	phenyl	3,4-di-OMe-phenyl-(CH 2 ) 2 —	CH	N	Me	C-Me	O	O
I-64	COOH	3-Cl-phenyl	methyl	CH	N	F	C—OMe	O	O
I-65	COOH	phenyl	3,4-di-OMe-phenyl-	CH	N	ethyl	C-Me	O	O
I-66	COOH	phenyl	methyl	CH	C-ethyl	Me	N	O	—
I-67	COOH	phenyl	methyl	CH	C—OMe	H	N	O	—
I-68	COOH	phenyl	4-OMe-phenyl-	CH	N	OMe	C-ethyl	O	O
I-69	COOH	phenyl	4-Me-phenyl-	CH	N	Me	C—CH 2 —OH	O	O
I-70	COOH	4-F-phenyl	methyl	CH	N	Me	C—N(CH 3 ) 2	O	O
I-71	COOH	phenyl	3,4-di-OMe-phenyl-(CH 2 ) 2 —	CH	C—O—CH 2 —CH 2	N	O	O
I-72	COOH	phenyl	3,4-di-OMe-phenyl-(CH 2 ) 2 —	CH	C—CH 2 —OH	Me	N	O	O
I-73	tetrazole	phenyl	methyl	CH	N	OMe	C—NH(CH 3 )	O	O
I-74	COOH	phenyl	3,4-di-OMe-phenyl-	N	C-Me	Me	N	O	O
I-75	COOH	phenyl	methyl	CH	C—OMe	OMe	N	O	—
I-76	COOH	phenyl	methyl	CH	C—NH 2	OMe	N	O	—
I-77	COOH	phenyl	3,4-di-OMe-phenyl-	N	C—OMe	Me	N	O	O
I-78	COOH	phenyl	4-OMe-phenyl-	N	C—CH 2 —CH 2 —CH 2	N	O	O
I-79	COOH	phenyl	cyclopentyl-(CH 2 ) 2 —	N	C-Me	OMe	N	O	O
I-80	COOH	phenyl	3,4-di-OMe-phenyl-(CH 2 ) 2 —	CH	C—OMe	Me	N	O	O
I-81	COOH	phenyl	3,4-di-OMe-phenyl-(CH 2 ) 2 —	CH	C—CH 2 —CH 2 —CH 2	N	O	O
I-82	COOH	phenyl	cyclohexyl-(CH 2 ) 2 —	N	C—O—CH 2 —O	N	O	O
I-83	COOH	4-F-phenyl	ethyl	CH	C—NH(CH 3 )	Me	N	O	O
I-84	COOH	phenyl	methyl	CH	C-Me	Me	N	O	—
I-85	COOH	phenyl	methyl	CH	C—OMe	Me	N	O	—
I-86	COOH	cyclohexyl	propyl	CH	C-Me	Me	N	O	O
I-87	COOH	4-Cl-phenyl	i-propyl	CH	C—OMe	Me	N	O	O
I-88	COOH	4-F-phenyl	ethyl	CH	C—OMe	NH 2	N	O	O
I-89	COOH	phenyl	3,4-di-OMe-phenyl-(CH 2 ) 2 —	CH	C—NH(CH 3 )	Me	N	O	O
I-90	COOH	phenyl	3,4-di-OMe-phenyl-(CH 2 ) 2 —	CH	C-Me	Me	N	O	O
I-91	COOH	phenyl	ethyl	CH	C-ethyl	ethyl	N	O	S
I-92	COOH	phenyl	ethyl	CH	C—CH 2 —CH 2 —CH 2	N	O	S
I-93	COOH	phenyl	methyl	CH	CH	Me	N	O	—
I-94	COOH	phenyl	methyl	CH	C—N(CH 3 ) 2	Me	N	O	—
I-95	COOH	phenyl	ethyl	CH	C—O—CH 2 —CH 2	N	O	S
I-96	COOH	phenyl	ethyl	CH	C-Me	F	N	O	S
I-97	COOH	4-Me-phenyl	ethyl	CH	C—CH 2 —OH	Me	N	O	O
I-98	COOH	phenyl	3,4-di-OMe-phenyl-(CH 2 ) 2 —	N	C-Me	OMe	N	O	O
I-99	COOH	phenyl	3,4-di-OMe-phenyl-(CH 2 ) 2 —	N	C—O—CH 2 —O	N	O	O
I-100	COOH	4-OCF 3 -phenyl	ethyl	CH	C—N(CH 3 ) 2	Me	N	O	O
I-101	COOH	phenyl	propyl	CH	N	Me	CH	O	O
I-102	COOH	phenyl	methyl	N	C—O—CH 2 —O	N	O	—
I-103	COOH	phenyl	methyl	N	C—O—CH 2 —CH 2	N	O	—
I-104	COOEt	phenyl	ethyl	CH	N	OMe	CH	O	O
I-105	COOH	4-Et-phenyl	ethyl	CH	N	Me	C-Me	O	O
I-106	COOH	phenyl	4-i-propyl-phenyl-	CH	N	Me	C—OMe	O	O
I-107	COOH	phenyl	3,4-di-OMe-phenyl-(CH 2 ) 2 —	N	C—OMe	Me	N	O	O
I-108	COOH	phenyl	3,4-di-OMe-phenyl-(CH 2 ) 2 —	N	C—CH 2 —CH 2 —CH 2	N	O	O
I-109	COOH	phenyl	4-i-propyl-phenyl-(CH 2 ) 2 —	CH	N	ethyl	C-Me	O	O
I-110	COOH	phenyl	3,4-di-Me-phenyl-(CH 2 ) 2 —	CH	N	Me	C-ethyl	O	O
I-111	COOH	phenyl	methyl	N	C-ethyl	Me	N	O	—
I-112	COOH	phenyl	methyl	N	C—OMe	H	N	O	—
I-113	COOH	phenyl	3,4-di-Me-phenyl-(CH 2 ) 2 —	CH	N	O—CH 2 —CH 2 —C	O	O
I-114	COOH	phenyl	4-SMe-phenyl-(CH 2 ) 2 —	CH	N	CH 2 —CH 2 —O—C	O	O
I-115	COOH	4-F-phenyl	ethyl	CH	N	F	C—OMe	O	O
I-116	COOH	phenyl	HO—CH 2 —CH 2 —	CH	N	OMe	C-ethyl	O	O
I-117	COOH	phenyl	3,4-di-OMe-phenyl-(CH 2 ) 2 —	N	C-Me	Me	N	O	O
I-118	COOH	phenyl	3-hexen-1-yl	CH	N	OMe	C-ethyl	O	O
I-119	COOH	phenyl	3-hepten-1-yl	CH	N	Me	C—CH 2 —OH	O	O
I-120	COOH	phenyl	methyl	N	C—OMe	Me	N	O	—
I-121	COOH	phenyl	methyl	N	C—CH 2 —CH 2 —CH 2	N	O	—
I-122	COOH	4-Cl-phenyl	ethyl	CH	N	Me	C—N(CH 3 ) 2	O	O
I-123	COOH	phenyl	HO—CH 2 —(CH—OH)—CH 2 —	N	C-Me	Me	N	O	O
I-124	COOH	phenyl	HO—CH 2 —(CH—OH)—CH 2 —	N	C—OMe	Me	N	O	O
I-125	COOH	phenyl	HO—CH 2 —CH 2 —	CH	N	CH 2 —CH 2 —CH 2 —C	O	O
I-126	COOH	phenyl	HO—CH 2 —CH 2 —	CH	N	F	C—OMe	O	O
I-127	COOH	phenyl	HO—CH 2 —(CH—OH)—CH 2 —	N	C—CH 2 —CH 2 —CH 2	N	O	O
I-128	COOH	phenyl	phenyl-O—(CH 2 ) 2 —	CH	C-Me	Me	N	O	O
I-129	COOH	phenyl	ethyl	CH	N	Me	C—N(CH 3 ) 2	N	—
I-130	COOH	phenyl	methyl	N	C-Me	Me	N	O	—
I-131	COOH	phenyl	4-OMe-phenyl-O—(CH 2 ) 2 —	CH	C—OMe	Me	N	O	O
I-132	COOH	4-F-phenyl	HO—CH 2 —CH 2 —	CH	C-Ethyl	ethyl	N	O	O
I-133	COOH	phenyl	HO—CH 2 —CH 2 —	CH	C—CH 2 —CH 2 —S	N	O	O
I-134	COOH	phenyl	HO—CH 2 —CH 2 —	CH	N	ethyl	C-Me	O	O
I-135	COOH	phenyl	HO—CH 2 —CH 2 —	CH	N	Me	C-ethyl	O	O
I-136	COOMe	phenyl	HO—CH 2 —CH 2 —	CH	C—O—CH 2 —CH 2	N	O	O
I-137	COOH	4-F-phenyl	HO—CH 2 —CH 2 —	CH	C-Me	F	N	O	O
I-138	COOH	phenyl	ethyl	CH	N	O—CH 2 —O—C	N	—
I-139	COOH	phenyl	ethyl	CH	N	CH 2 —CH 2 —CH 2 —C	N	—
I-140	COOH	4-F-phenyl	HO—CH 2 —CH 2 —	CH	C—CH 2 —OH	Me	N	O	O
I-141	COOH	phenyl	HO—CH 2 —CH 2 —CH 2 —	CH	N	Me	C-Me	O	O
I-142	COOH	phenyl	HO—CH 2 —CH 2 —CH 2 —	CH	N	Me	C—OMe	O	O
I-143	COOH	phenyl	HO—CH 2 —CH 2 —	CH	N	Me	C-Me	O	O
I-144	COOH	phenyl	HO—CH 2 —CH 2 —	CH	N	Me	C—OMe	O	O
I-145	COOH	4-Br-phenyl	HO—CH 2 —CH 2 —	CH	N	ethyl	C-Me	O	O
I-146	COOH	4-Me-phenyl	HO—CH 2 —CH 2 —	CH	N	Me	C-ethyl	O	O
I-147	COOH	phenyl	ethyl	CH	N	OMe	C-Me	N	—
I-148	COOH	phenyl	ethyl	CH	N	Me	C-ethyl	N	—
I-149	COOH	2-Me-phenyl	HO—CH 2 —CH 2 —	CH	N	CH 2 —CH 2 —CH 2 —C	O	O
I-150	COOH	2-Me-phenyl	HO—CH 2 —CH 2 —CH 2 —	CH	N	F	C—OMe	O	O
I-151	COOH	phenyl	HO—CH 2 —(CH—OH)—CH 2 —	CH	N	OMe	C-ethyl	O	O
I-152	COOH	phenyl	HO—CH 2 —CH 2 —	CH	C-Me	F	N	O	O
I-153	COOH	phenyl	HO—CH 2 —CH 2 —	CH	C—CH 2 —OH	Me	N	O	O
I-154	COOH	phenyl	3,4,5-tri-OMe-phenyl-(CH 2 ) 2 —	N	C-Me	Me	N	O	O
I-155	COOH	phenyl	3,4,5-tri-OMe-phenyl-(CH 2 ) 2 —	N	C—OMe	Me	N	O	O
I-156	COOH	phenyl	ethyl	CH	N	Me	C-Me	N	—
I-157	COOH	phenyl	ethyl	CH	N	Me	C—OMe	N	—
I-158	COOH	phenyl	3,4-di-Cl-phenyl-(CH 2 ) 2 —	N	C—CH 2 —CH 2 —CH 2	N	O	O
I-159	COOH	phenyl	4-Cl-phenyl-(CH 2 ) 2 —	N	C-Me	OMe	N	O	O
I-160	COOH	phenyl	3,4-di-Cl-phenyl-(CH 2 ) 2 —	N	C—O—CH 2 —O	N	O	O
I-161	COOH	phenyl	HO—CH 2 —CH 2 —	CH	C—CH 2 —CH 2 —CH 2	N	O	O
I-162	COOH	phenyl	HO—CH 2 —CH 2 —	CH	C—O—CH 2 —CH 2	N	O	O
I-163	COOH	phenyl	3,4-di-OMe-phenyl-(CH 2 ) 3 —	CH	C—NH(CH 3 )	Me	N	O	O
I-164	COOH	4-F-phenyl	3,4-di-OMe-phenyl-(CH 2 ) 2 —	CH	C-Me	Me	N	O	O
I-165	COOH	phenyl	ethyl	CH	C-Me	ethyl	N	N	—
I-166	COOH	phenyl	ethyl	CH	C-ethyl	OMe	N	N	—
I-167	COOH	phenyl	3,4,5-tri-OMe-phenyl-(CH 2 ) 2 —	CH	C—OMe	Me	N	O	O
I-168	COOH	4-Cl-phenyl	3,4-di-OMe-phenyl-(CH 2 ) 2 —	CH	C—CH 2 —CH 2 —CH 2	N	O	O
I-169	COOH	phenyl	3,4-di-OMe-phenyl-(CH 2 ) 3 —	CH	C—O—CH 2 —CH 2	N	O	O
I-170	COOH	phenyl	HO—CH 2 —CH 2 —	CH	C—OMe	Me	N	O	O
I-171	COOH	phenyl	HO—CH 2 —CH 2 —	CH	C-ethyl	ethyl	N	O	O
I-172	COOH	phenyl	4-Br-phenyl-(CH 2 ) 2 —	CH	C—CH 2 —OH	Me	N	O	O
I-173	COOH	phenyl	3,4-di-Me-phenyl-(CH 2 ) 2 —	CH	C—N(CH 3 ) 2	Me	N	O	O
I-174	COOH	phenyl	ethyl	CH	C—CH 2 —CH 2 —CH 2	N	N	—
I-175	COOH	phenyl	ethyl	CH	C—O—CH 2 —CH 2	N	N	—
I-176	COOH	phenyl	3,4-di-Me-phenyl-(CH 2 ) 2 —	CH	N	Me	C-Me	O	O
I-177	COOH	phenyl	3,4-di-OMe-phenyl-(CH 2 ) 2 —	CH	N	Me	C—OMe	O	S
I-178	COOH	phenyl	3,4-di-OMe-phenyl-(CH 2 ) 2 —	CH	N	F	C-Me	O	S
I-179	COOH	phenyl	HO—CH 2 —CH 2 —	N	C—CH 2 —CH 2 —CH 2	N	O	O
I-180	COOH	phenyl	HO—CH 2 —CH 2 —	CH	C-Me	Me	N	O	O
I-181	COOH	phenyl	3,4-di-OMe-phenyl-(CH 2 ) 2 —	CH	N	Me	C-ethyl	O	S
I-182	COOH	4-F-phenyl	3,4-di-OMe-phenyl-(CH 2 ) 2 —	CH	N	O—CH 2 —CH 2 —C	O	O
I-183	COOH	phenyl	ethyl	CH	C-Me	Me	N	N	—
I-184	COOH	phenyl	ethyl	CH	C—OMe	Me	N	N	—
I-185	COOH	4-F-phenyl	3,4-di-OMe-phenyl-(CH 2 ) 2 —	CH	N	CH 2 —CH 2 —O—C	O	O
I-186	COOH	phenyl	3,4-di-Cl-phenyl-(CH 2 ) 2 —	CH	N	F	C—OMe	O	O
I-187	COOH	phenyl	4-Cl-phenyl-(CH 2 ) 2 —	CH	N	Me	C—CH 2 —OH	O	O
I-188	COOH	phenyl	HO—CH 2 —CH 2 —	N	C-Me	Me	N	O	O
I-189	COOH	phenyl	HO—CH 2 —CH 2 —	N	C—OMe	Me	N	O	O
I-190	COOH	4-Cl-phenyl	3,4-di-OMe-phenyl-(CH 2 ) 2 —	CH	N	Me	C—N(CH 3 ) 2	O	O
I-191	COOH	Phenyl	4-i-propyl-phenyl-(CH 2 ) 2 —	N	C-Me	Me	N	O	O
I-192	COOH	phenyl	ethyl	N	C-ethyl	Me	N	N	—
I-193	COOH	phenyl	ethyl	N	C—O—CH 2 —CH 2	N	N	—
I-194	COOH	phenyl	4-i-propyl-phenyl-(CH 2 ) 2 —	N	C—OMe	Me	N	O	O
I-195	COOH	phenyl	4-ethyl-phenyl-(CH 2 ) 2 —	N	C—CH 2 —CH 2 —CH 2	N	O	O
I-196	COOH	phenyl	4-OMe-phenyl-(CH 2 ) 2 —	N	C-Me	ethyl	N	O	S
I-197	COOH	phenyl	ethyl	CH	N	Me	C—CH 2 —OH	O	O
I-198	COOH	phenyl	ethyl	CH	N	Me	C—N(CH 3 ) 2	O	O
I-199	COOH	phenyl	4-ethyl-phenyl-(CH 2 ) 2 —	N	C—O—CH 2 —O	N	O	O
I-200	COOH	4-F-phenyl	4-OMe-phenyl-(CH 2 ) 2 —	CH	C—NH(CH 3 )	Me	N	O	O
I-201	COOH	phenyl	ethyl	N	C-Me	Me	N	N	—
I-202	COOH	phenyl	ethyl	N	C—OMe	Me	N	N	—
I-203	COOH	phenyl	4-Br-phenyl-(CH 2 ) 2 —	CH	C-Me	Me	N	O	O
I-204	COOH	phenyl	4-i-propyl-phenyl-(CH 2 ) 2 —	CH	C—OMe	Me	N	O	O
I-205	COOH	phenyl	4-ethyl-phenyl-(CH 2 ) 2 —	CH	C—CH 2 —CH 2 —CH 2	N	O	S
I-206	COOH	phenyl	ethyl	CH	N	F	C—OMe	O	O
I-207	COOH	phenyl	ethyl	CH	N	OMe	C-ethyl	O	O
I-208	COOH	4-Cl-phenyl	4-OMe-phenyl-(CH 2 ) 2 —	CH	C—O—CH 2 —CH 2	N	O	O
I-209	COOH	4-Me-phenyl	4-OMe-phenyl-(CH 2 ) 2 —	CH	C—CH 2 —OH	Me	N	O	O
I-210	COOH	phenyl	methyl	CH	N	OMe	C-ethyl	N	—
I-211	COOH	phenyl	methyl	CH	N	Me	C—N(CH 3 ) 2	N	—
I-212	COOH	phenyl	4-OMe-phenyl-(CH 2 ) 2 —	CH	C—N(CH 3 ) 2	Me	N	O	S
I-213	COOH	phenyl	4-propyl-phenyl-(CH 2 ) 2 —	CH	N	Me	C-Me	O	O
I-214	COOH	phenyl	3,5-di-OMe-phenyl-(CH 2 ) 2 —	CH	N	Me	C—OMe	O	O
I-215	COOH	phenyl	ethyl	CH	N	O—CH 2 —CH 2 —C	O	O
I-216	COOH	phenyl	ethyl	CH	N	CH 2 —CH 2 —O—C	O	O
I-217	COOH	phenyl	3,5-di-OMe-phenyl-(CH 2 ) 2 —	CH	N	F	C-Me	O	O
I-218	COOH	phenyl	3,5-di-OMe-phenyl-(CH 2 ) 2 —	CH	N	Me	C-ethyl	O	O
I-219	COOH	phenyl	methyl	CH	N	O—CH 2 —CH 2 —C	N	—
I-220	COOH	phenyl	methyl	CH	N	CH 2 —CH 2 —O—C	N	—
I-221	COOH	phenyl	3,5-di-OMe-phenyl-(CH 2 ) 2 —	CH	N	CH 2 —CH 2 —CH 2 —C	O	O
I-222	COOH	phenyl	3,5-di-OMe-phenyl-(CH 2 ) 2 —	CH	N	O—CH 2 —CH 2 —C	O	O
I-223	COOH	phenyl	4-OMe-phenyl-(CH 2 ) 2 —	CH	N	F	C—OMe	O	S
I-224	COOH	phenyl	ethyl	CH	N	ethyl	C-Me	O	O
I-225	COOH	phenyl	ethyl	CH	N	Me	C-ethyl	O	O
I-226	COOH	phenyl	4-propyl-phenyl-(CH 2 ) 2 —	CH	N	Me	C—CH 2 —OH	O	O
I-227	COOH	phenyl	4-N(CH 3 ) 2 -phenyl-(CH 2 ) 2 —	CH	N	Me	C—N(CH 3 ) 2	O	O
I-228	COOH	phenyl	methyl	CH	N	O—CH 2 —O—C	N	—
I-229	COOH	phenyl	methyl	CH	N	CH 2 —CH 2 —CH 2 —C	N	—
I-230	COOH	phenyl	4-Cl-phenyl-CH 2 —	N	C-Me	Me	N	O	O
I-231	COOH	phenyl	4-Me-phenyl-CH 2 —	N	C—OMe	Me	N	O	O
I-232	COOH	phenyl	3,4-di-Me-phenyl-CH 2 —	N	C—CH 2 —CH 2 —CH 2	N	O	O
I-233	COOH	phenyl	ethyl	CH	N	Me	C-Me	O	O
I-234	COOH	phenyl	ethyl	CH	N	Me	C—OMe	O	O
I-235	COOH	phenyl	4-OMe-phenyl-CH 2 —	N	C-Me	ethyl	N	O	S
I-236	COOH	4-F-Phenyl	4-OMe-phenyl-CH 2 —	N	C—O—CH 2 —O	N	O	O
I-237	COOH	phenyl	methyl	CH	N	OMe	C-Me	N	—
I-238	COOH	phenyl	methyl	CH	N	Me	C-ethyl	N	—
I-239	COOH	4-F-phenyl	4-OMe-phenyl-CH 2 —	CH	Cl	Me	N	O	O
I-240	COOH	phenyl	4-OMe-phenyl-CH 2 —	CH	C-Me	Me	N	O	S
I-241	COOH	phenyl	4-OMe-phenyl-CH 2 —	CH	C—OMe	Me	N	O	S
I-242	COOH	phenyl	ethyl	CH	N	Me	CH	O	O
I-243	COOH	phenyl	ethyl	CH	N	OMe	CH	O	O
I-244	COOH	phenyl	4-Cl-phenyl-CH 2 —	CH	C—CH 2 —CH 2 —CH 2	N	O	O
I-245	COOH	phenyl	4-Cl-phenyl-CH 2 —	CH	C—O—CH 2 —CH 2	N	O	O
I-246	COOH	phenyl	methyl	CH	N	Me	C-Me	N	—
I-247	COOH	phenyl	methyl	CH	N	Me	C—OMe	N	—
I-248	COOH	4-Cl-phenyl	4-OMe-phenyl-CH 2 —	CH	C—CH 2 —OH	Me	N	O	O
I-249	COOH	phenyl	HO—CH 2 —	CH	N	Me	C—N(CH 3 ) 2	O	—
I-250	COOH	4-Cl-phenyl	4-OMe-phenyl-CH 2 —	CH	C—N(CH 3 ) 2	Me	N	O	O
I-251	COOH	phenyl	4-OMe-phenyl-CH 2 —	CH	N	CF 3	C-Me	O	O
I-252	COOH	phenyl	ethyl	CH	C—CH 2 —OH	Me	N	O	O
I-253	COOH	phenyl	ethyl	CH	C—N(CH 3 ) 2	Me	N	O	O
I-254	COOH	phenyl	4-OMe-phenyl-CH 2 —	CH	N	CF 3	C—OMe	O	O
I-255	COOH	phenyl	4-Br-phenyl-CH 2 —	CH	N	F	C-Me	O	O
I-256	COOH	phenyl	methyl	CH	C-Ethyl	OMe	N	N	—
I-257	COOH	phenyl	methyl	CH	C—N(CH 3 ) 2	Me	N	N	—
I-258	COOH	phenyl	4-i-propyl-phenyl-CH 2 —	CH	N	Me	C-ethyl	O	O
I-259	COOH	phenyl	HO—CH 2 —	CH	N	CH 2 —CH 2 —CH 2 —C	O	—
I-260	COOH	phenyl	HO—CH 2 —	CH	N	OMe	C-ethyl	O	—
I-261	COOH	phenyl	4-ethyl-phenyl-CH 2 —	CH	N	CH 2 —CH 2 —CH 2 —C	O	O
I-262	COOH	phenyl	4-i-propyl-phenyl-CH 2 —	CH	N	O—CH 2 —CH 2 —C	O	O
I-263	COOH	phenyl	ethyl	CH	C—O—CH 2 —CH 2	N	O	O
I-264	COOH	phenyl	ethyl	CH	C-Me	F	N	O	O
I-265	COOH	phenyl	4-phenyl-phenyl-CH 2 —	CH	N	F	C—OMe	O	O
I-266	COOH	4-F-phenyl	4-OMe-phenyl-CH 2 —	CH	N	Me	C—CH 2 —OH	O	O
I-267	COOH	phenyl	methyl	CH	C—OMe	F	N	N	—
I-268	COOH	phenyl	methyl	CH	C-Me	ethyl	N	N	—
I-269	COOH	4-F-phenyl	4-OMe-phenyl-CH 2 —	CH	N	Me	C—N(CH 3 ) 2	O	O
I-270	COOH	phenyl	HO—CH 2 —	CH	N	Me	C-ethyl	O	—
I-271	COOH	phenyl	HO—CH 2 —	CH	N	O—CH 2 —O—C	O	—
I-272	COOH	phenyl	methyl	N	C-Me	CF 3	N	N	—
I-273	COOH	4-OMe-phenyl	methyl	N	C—OMe	Me	N	N	—
I-274	COOH	phenyl	ethyl	CH	C-ethyl	ethyl	N	O	O
I-275	COOH	phenyl	ethyl	CH	C—CH 2 —CH 2 —CH 2	N	O	O
I-276	COOH	4-Me-phenyl	methyl	N	C-Me	OMe	N	N	—
I-277	COOH	4-OMe-phenyl	methyl	N	C-ethyl	Me	N	N	—
I-278	COOH	phenyl	methyl	CH	C—O—CH 2 —O	N	N	—
I-279	COOH	phenyl	methyl	CH	C—O—CH 2 —CH 2	N	N	—
I-280	COOH	phenyl	4-OMe-phenyl-CH 2 —	N	C—O—CH 2 —O	N	N	—
I-281	COOH	phenyl	HO—CH 2 —	CH	N	Me	C—OMe	O	—
I-282	COOH	phenyl	HO—CH 2 —	CH	N	OMe	C-Me	O	—
I-283	COOH	phenyl	4-OMe-phenyl-CH 2 —	N	C—O—CH 2 —CH 2	N	N	—
I-284	COOH	phenyl	phenyl-O—CH 2 —	CH	C-Me	Me	N	N	—
I-285	COOH	phenyl	ethyl	CH	C—OMe	Me	N	O	O
I-286	COOH	phenyl	ethyl	CH	C—OMe	NH 2	N	O	O
I-287	COOH	phenyl	3,4-di-OMe-phenyl-CH 2 —	CH	C—OMe	Me	N	N	—
I-288	COOH	phenyl	3,4-di-OMe-phenyl-CH 2 —	CH	C-Me	OMe	N	N	—
I-289	COOH	phenyl	methyl	CH	C-Me	OMe	N	N	—
I-290	COOH	phenyl	methyl	CH	C-ethyl	Me	N	N	—
I-291	COOH	phenyl	phenyl-CH 2 —O—CH 2 —	CH	C-ethyl	Me	N	N	—
I-292	COOH	phenyl	HO—CH 2 —	CH	C—CH 2 —CH 2 —CH 2	N	O	—
I-293	COOH	phenyl	HO—CH 2 —	CH	N	Me	C-Me	O	—
I-294	COOH	phenyl	HO—CH 2 —	CH	C—O—CH 2 —O	N	N	—
I-295	COOH	phenyl	HO—CH 2 —	CH	C—O—CH 2 —CH 2	N	N	—
I-296	COOH	phenyl	ethyl	CH	C—NH(CH 3 )	Me	N	O	O
I-297	COOH	phenyl	ethyl	CH	C-Me	Me	N	O	O
I-298	COOH	phenyl	methyl	CH	C—OMe	CF 3	N	N	—
I-299	COOH	phenyl	3,4-di-Me-phenyl-CH 2 —	CH	C-Me	ethyl	N	N	—
I-300	COOH	phenyl	methyl	CH	C-Me	Me	N	N	—
I-301	COOH	phenyl	methyl	CH	C—OMe	Me	N	N	—
I-302	COOH	4-Me-phenyl	methyl	CH	C-ethyl	OMe	N	N	—
I-303	COOH	phenyl	HO—CH 2 —	CH	C—OMe	H	N	O	—
I-304	COOH	phenyl	HO—CH 2 —	CH	C—O—CH 2 —CH 2	N	O	—
I-305	COOH	4-OMe-phenyl	methyl	CH	C—N(CH 3 ) 2	Me	N	N	—
I-306	COOH	phenyl	methyl	CH	N	CF 3	C-Me	N	—
I-307	COOH	phenyl	ethyl	N	C-Me	OMe	N	O	O
I-308	COOH	phenyl	ethyl	N	C—O—CH 2 —O	N	O	O
I-309	COOH	phenyl	4-OMe-phenyl-CH 2 —	CH	N	Me	C—OMe	N	—
I-310	COOH	phenyl	HO—CH 2 —	CH	N	OMe	C-Me	N	—
I-311	COOH	phenyl	methyl	N	C—O—CH 2 —O	N	N	—
I-312	COOH	phenyl	methyl	N	C—O—CH 2 —CH 2	N	N	—
I-313	COOH	phenyl	4-Me-phenyl-CH 2 —	CH	N	Me	C-ethyl	N	—
I-314	COOH	phenyl	HO—CH 2 —	CH	C—OMe	Me	N	O	—
I-315	COOH	phenyl	HO—CH 2 —	CH	C-ethyl	Me	N	O	—
I-316	COOH	phenyl	4-Me-phenyl-CH 2 —	CH	N	O—CH 2 —O—C	N	—
I-317	COOMe	phenyl	methyl	CH	N	CH 2 —CH 2 —CH 2 —C	N	—
I-318	COOH	phenyl	ethyl	N	C—OMe	Me	N	O	O
I-319	COOH	phenyl	ethyl	N	C—CH 2 —CH 2 —CH 2	N	O	O
I-320	COOH	4-OMe-phenyl	methyl	CH	N	O—CH 2 —CH 2 —C	N	—
I-321	COOH	4-Me-phenyl	methyl	CH	N	CH 2 —CH 2 —O—C	N	—
I-322	COOH	phenyl	methyl	N	C-Me	OMe	N	N	—
I-323	COOH	phenyl	methyl	N	C-ethyl	Me	N	N	—
I-324	COOH	phenyl	4-OMe-phenyl-CH 2 —	CH	N	OMe	C-ethyl	N	—
I-325	COOH	phenyl	HO—CH 2 —	N	C-ethyl	Me	N	O	—
I-326	COOH	phenyl	HO—CH 2 —	CH	C-Me	Me	N	O	—
I-327	COOH	phenyl	3,4-di-OMe-phenyl-CH 2 —	CH	N	Me	C—N(CH 3 ) 2	N	—
I-328	COOH	phenyl	4-OMe-phenyl-(CH 2 ) 2 —	N	C-Me	Me	N	N	—
I-329	COOH	phenyl	methyl	CH	N	OMe	C—NH(CH 3 )	O	O
I-330	COOH	phenyl	ethyl	N	C-Me	Me	N	O	O
I-331	COOH	phenyl	4-OMe-phenyl-(CH 2 ) 2 —	N	C—OMe	Me	N	N	—
I-332	COOH	phenyl	ethyl	N	C-ethyl	CF 3	N	N	—
I-333	COOH	phenyl	methyl	N	C-Me	Me	N	N	—
I-334	COOH	phenyl	methyl	N	C—OMe	Me	N	N	—
I-335	COOH	phenyl	HO—CH 2 —CH 2 —	N	C—O—CH 2 —CH 2	N	N	—
I-336	COOH	phenyl	HO—CH 2 —	N	C—OMe	Me	N	O	—
I-337	COOH	phenyl	HO—CH 2 —	N	C—CH 2 —CH 2 —CH 2	N	O	—
I-338	COOH	phenyl	HO—CH 2 —CH 2 —	CH	C-Me	Me	N	N	—
I-339	COOH	phenyl	phenyl-CH 2 —O—(CH 2 ) 2 —	CH	C—OMe	Me	N	N	—
I-340	COOH	phenyl	methyl	CH	N	Me	C—CH 2 —OH	O	O
I-341	COOH	phenyl	methyl	CH	N	Me	C—N(CH 3 ) 2	O	O
I-342	COOH	phenyl	phenyl-O—(CH 2 ) 2 —	CH	C—CH 2 —CH 2 —CH 2	N	N	—
I-343	COOH	phenyl	3,4-di-OMe-phenyl-O—(CH 2 ) 2	CH	C—O—CH 2 —CH 2	N	N	—
I-344	COOH	phenyl	4-OMe-phenyl-CH 2 —	CH	N	Me	C—CH 2 —OH	O	O
I-345	COOH	phenyl	4-OMe-phenyl-CH 2 —	CH	N	Me	C—N(CH 3 ) 2	O	O
I-346	COOH	phenyl	3,4-di-OMe-phenyl-O—(CH 2 ) 2 —	CH	C-Me	ethyl	N	N	—
I-347	COOH	phenyl	ethyl	CH	N	OMe	C—NH(CH 3 )	O	—
I-348	COOH	phenyl	HO—CH 2 —	N	C-Me	Me	N	O	—
I-349	COOH	phenyl	HO—CH 2 —CH 2 —	CH	C-ethyl	OMe	N	N	—
I-350	COOH	phenyl	propyl	CH	N	Me	C-Me	N	—
I-351	COOH	phenyl	methyl	CH	N	Ethyl	C-Me	O	O
I-352	COOH	phenyl	methyl	CH	N	OMe	C-ethyl	O	O
I-353	COOH	phenyl	3,4-di-OMe-phenyl-(CH 2 ) 3 —	CH	N	Me	C—OMe	N	—
I-354	COOH	phenyl	3,4-di-OMe-phenyl-(CH 2 ) 3 —	CH	N	OMe	C-Me	N	—
I-355	COOH	phenyl	4-OMe-phenyl-CH 2 —	CH	N	O—CH 2 —CH 2 —C	O	O
I-356	COOH	phenyl	4-OMe-phenyl-CH 2 —	CH	N	F	C—OMe	O	O
I-357	COOH	phenyl	n-butyl	CH	N	Me	C-ethyl	N	—
I-358	COOH	phenyl	ethyl	CH	N	Me	C—CH 2 —OH	O	—
I-359	COOH	phenyl	ethyl	CH	N	Me	C—N(CH 3 ) 2	O	—
I-360	COOH	phenyl	n-hexyl	CH	N	O—CH 2 —O—C	N	—
I-361	COOH	4-Me-phenyl	ethyl	CH	N	CH 2 —CH 2 —CH 2 —C	N	—
I-362	COOH	phenyl	methyl	CH	N	CH 2 —CH 2 —O—C	O	O
I-363	COOH	phenyl	methyl	CH	N	F	C—OMe	O	O
I-364	COOH	phenyl	ethyl	CH	N	CF 3	C—N(CH 3 ) 2	N	—
I-365	COOH	phenyl	4-OMe-phenyl-CH 2 —	N	C-Me	Me	N	O	—
I-366	COOH	phenyl	4-OMe-phenyl-CH 2 —	CH	N	Me	C-ethyl	O	O
I-367	COOH	phenyl	4-OMe-phenyl-CH 2 —	CH	N	CH 2 —CH 2 —CH 2 —C	O	O
I-368	COOH	phenyl	3,4-di-Me-phenyl-CH 2 —	N	C—OMe	Me	N	O	—
I-369	COOH	phenyl	ethyl	CH	N	CH 2 —CH 2 —CH 2 —C	O	—
I-370	COOH	phenyl	ethyl	CH	N	OMe	C-ethyl	O	—
I-371	COOH	phenyl	4-Me-phenyl-CH 2 —	N	C—CH 2 —CH 2 —CH 2	N	O	—
I-372	COOH	4-OMe-phenyl	methyl	N	C-ethyl	Me	N	O	—
I-373	COOH	phenyl	methyl	CH	N	CH 2 —CH 2 —CH 2 —C	O	O
I-374	COOH	phenyl	methyl	CH	N	O—CH 2 —CH 2 —C	O	O
I-375	COOH	4-OMe-phenyl	methyl	N	C—OMe	H	N	O	—
I-376	COOH	phenyl	4-i-propyl-phenyl-CH 2 —	N	C—O—CH 2 —O	N	O	—
I-377	COOH	phenyl	4-OMe-phenyl-CH 2 —	CH	N	Me	C—OMe	O	O
I-378	COOH	phenyl	4-OMe-phenyl-CH 2 —	CH	N	F	C-Me	O	O
I-379	COOH	phenyl	3,4,5-tri-OMe-phenyl-CH 2 —	N	C—O—CH 2 —CH 2	N	O	—
I-380	COOH	phenyl	ethyl	CH	N	Me	C-ethyl	O	—
I-381	COOH	phenyl	ethyl	CH	N	O—CH 2 —O—C	O	—
I-382	COOH	4-OMe-phenyl	methyl	CH	CH	Me	N	O	—
I-383	COOH	phenyl	3,4,5-tri-OMe-phenyl-CH 2 —	CH	C—N(CH 3 ) 2	Me	N	O	—
I-384	COOH	phenyl	methyl	CH	N	H	C—OMe	O	O
I-385	COOH	phenyl	methyl	CH	N	O—CH 2 —O—C	O	O
I-386	COOH	cyclohexyl	methyl	CH	C-Me	Me	N	O	—
I-387	COOH	phenyl	4-Me-phenyl-CH 2 —	CH	C—OMe	Me	N	O	—
I-388	COOH	phenyl	4-OMe-phenyl-CH 2 —	CH	C—N(CH 3 ) 2	Me	N	O	O
I-389	COOH	phenyl	4-OMe-phenyl-CH 2 —	CH	N	Me	C-Me	O	O
I-390	COOH	phenyl	2-OMe-phenyl-CH 2 —	CH	C—OMe	OMe	N	O	—
I-391	COOH	phenyl	ethyl	CH	N	Me	C—OMe	O	—
I-392	COOH	phenyl	ethyl	CH	N	OMe	C-Me	O	—
I-393	COOH	phenyl	4-Cl-phenyl-CH 2 —	CH	C—NH 2	OMe	N	O	—
I-394	COOH	phenyl	methyl	CH	C-ethyl	CF 3	N	O	—
I-395	COOH	phenyl	methyl	CH	N	OMe	C-Me	O	O
I-396	COOH	phenyl	methyl	CH	N	Me	C-ethyl	O	O
I-397	COOH	4-OMe-phenyl	methyl	CH	C—OMe	H	N	O	—
I-398	COOH	phenyl	3,4-di-Cl-phenyl-CH 2 —	CH	C—O—CH 2 —O	N	O	—
I-399	COOH	phenyl	4-OMe-phenyl-CH 2 —	CH	C—O—CH 2 —CH 2	N	O	O
I-400	COOH	phenyl	4-OMe-phenyl-CH 2 —	CH	C—CH 2 —OH	Me	N	O	O
I-401	COOH	phenyl	cyclopentyl-CH 2 —	CH	C—O—CH 2 —CH 2	N	O	—
I-402	COOH	phenyl	ethyl	CH	C—N(CH 3 ) 2	Me	N	O	—
I-403	COOH	phenyl	ethyl	CH	N	Me	C-Me	O	—
I-404	COOH	4-OMe-phenyl	methyl	CH	C-Me	F	N	O	—
I-405	COOH	phenyl	4-F-phenyl-CH 2 —	CH	C—CH 2 —CH 2 —CH 2	N	O	—
I-406	COOH	phenyl	methyl	CH	N	Me	C—OMe	O	O
I-407	COOH	phenyl	methyl	CH	N	OMe	C—OMe	O	O
I-408	COOH	phenyl	4-Cl-phenyl-CH 2 —	CH	C-ethyl	F	N	O	—
I-409	COOMe	phenyl	methyl	CH	C—CH 2 —OH	Me	N	O	—
I-410	COOH	phenyl	4-OMe-phenyl-CH 2 —	CH	C—OMe	Me	N	O	O
I-411	COOH	phenyl	4-OMe-phenyl-CH 2 —	CH	C—CH 2 —CH 2 —CH 2	N	O	O
I-412	COOH	phenyl	phenyl-O—CH 2 —	CH	C—N(CH 3 ) 2	Me	N	O	—
I-413	COOH	phenyl	ethyl	CH	C—CH 2 —CH 2 —CH 2	N	O	—
I-414	COOH	phenyl	ethyl	CH	C—CH 2 —OH	Me	N	O	—
I-415	COOH	phenyl	4-Br-phenyl-CH 2 —	CH	C—NH(CH 3 )	OMe	N	O	—
I-416	COOH	4-OMe-phenyl	methyl	CH	N	Me	CH	O	—
I-417	COOH	phenyl	methyl	CH	N	OMe	CH	O	O
I-418	COOH	phenyl	methyl	CH	N	Me	C-Me	O
I-419	COOH	phenyl	methyl	CH	N	CF 3	C-Me	O	—
I-420	COOH	phenyl	4-OMe-phenyl-CH 2 —	CH	N	Me	C—OMe	O	—
I-421	COOH	phenyl	4-OMe-phenyl-CH 2 —	CH	C—NH(CH 3 )	Me	N	O	O
I-422	COOH	phenyl	4-OMe-phenyl-CH 2 —	CH	C-Me	Me	N	O	O
I-423	COOH	phenyl	3,4-dioxomethylenephenyl-CH 2 —	CH	N	OMe	C-Me	O	—
I-424	COOH	phenyl	ethyl	CH	C—O—CH 2 —CH 2	N	O	—
I-425	COOH	phenyl	ethyl	CH	C-Me	F	N	O	—
I-426	COOH	phenyl	3-Cl-phenyl-CH 2 —	CH	N	Me	C-ethyl	O	—
I-427	COOH	phenyl	methyl	CH	N	Me	C—OCF 3	O	—
I-428	COOH	phenyl	methyl	CH	C—NH(CH 3 )	OMe	N	O	O
I-429	COOH	phenyl	methyl	CH	N	Me	CH	O	O
I-430	COOH	4-OMe-phenyl	methyl	CH	N	O—CH 2 —O—C	O	—
I-431	COOH	4-Me-phenyl	methyl	CH	N	CH 2 —CH 2 —CH 2 —C	O	—
I-432	COOH	phenyl	4-OMe-phenyl-CH 2 —	N	C-Me	ethyl	N	O	O
I-433	COOH	phenyl	4-OMe-phenyl-CH 2 —	N	C—O—CH 2 —O	N	O	O
I-434	COOH	phenyl	2-Cl-phenyl-CH 2 —	CH	N	O—CH 2 —CH 2 —C	O	—
I-435	COOH	phenyl	ethyl	CH	C-ethyl	Me	N	O	—
I-436	COOH	phenyl	ethyl	CH	C—OMe	H	N	O	—
I-437	COOH	phenyl	3-OMe-phenyl-CH 2 —	CH	N	CH 2 —CH 2 —O—C	O	—
I-438	COOH	phenyl	3,5-di-OMe-phenyl-CH 2 —	CH	N	F	C—OMe	O	—
I-439	COOH	phenyl	methyl	CH	C—CH 2 —OH	Me	N	O	O
I-440	COOH	phenyl	methyl	CH	C—N(CH 3 ) 2	Me	N	O	O
I-441	COOH	4-OMe-phenyl	methyl	CH	N	Me	C—NH(CH 3 )	O	—
I-442	COOH	phenyl	2-Br-phenyl-CH 2 —	CH	N	OMe	C-ethyl	O	—
I-443	COOH	phenyl	4-OMe-phenyl-CH 2 —	N	C—OMe	Me	N	O	O
I-444	COOH	phenyl	4-OMe-phenyl-CH 2 —	N	C—CH 2 —CH 2 —CH 2	N	O	O
I-445	COOH	phenyl	2-Cl-phenyl-CH 2 —	CH	N	Me	C—CH 2 —OH	O	—
I-446	COOH	phenyl	ethyl	CH	C-OMe	Me	N	O	—
I-447	COOH	phenyl	ethyl	CH	C—NH 2	OMe	N	O	—
I-448	COOH	phenyl	4-i-propyl-phenyl-CH 2 —	CH	N	Me	C—N(CH 3 ) 2	O	—
I-449	COOH	4-OMe-phenyl	methyl	CH	N	OMe	C—NH(CH 3 )	O	—
I-450	COOH	phenyl	methyl	CH	C-Me	ethyl	N	O	O
I-451	COOH	phenyl	methyl	CH	C-ethyl	OMe	N	O	O
I-452	tetrazole	phenyl	ethyl	N	C-Me	Me	N	O	—
I-453	COOH	phenyl	3,4-di-OMe-phenyl-(CH 2 ) 2 —	N	C—OMe	Me	N	O	—
I-454	COOH	phenyl	4-OMe-phenyl-(CH 2 ) 2 —	CH	N	Me	C—N(CH 3 ) 2	O	O
I-455	COOH	phenyl	4-OMe-phenyl-CH 2 —	N	C-Me	Me	N	O	O
I-456	COOH	phenyl	3,4-di-OMe-phenyl-(CH 2 ) 3 —	N	C—CH 2 —CH 2 —CH 2	N	O	—
I-457	COOH	phenyl	ethyl	CH	C—N(CH 3 ) 2	Me	N	O	—
I-458	COOH	phenyl	ethyl	CH	C-Me	Me	N	O	—
I-459	COOH	phenyl	3,4-di-OMe-phenyl-(CH 2 ) 3 —	N	C-ethyl	Me	N	O	—
I-460	COOH	phenyl	4-OMe-phenyl-(CH 2 ) 3 —	CH	C—N(CH 3 ) 2	Me	N	O	—
I-461	COOH	phenyl	methyl	CH	C—O—CH 2 —CH 2	N	O	O
I-462	COOH	phenyl	methyl	CH	C—OMe	F	N	O	O
I-463	COOH	phenyl	3-Cl-phenyl-(CH 2 ) 2 —	CH	C-Me	Me	N	O	—
I-464	COOH	phenyl	3,4-di-OMe-phenyl-(CH 2 ) 3 —	CH	C—OMe	Me	N	O	—
I-465	COOH	phenyl	4-OMe-phenyl-(CH 2 ) 2 —	CH	N	F	C—OMe	O	O
I-466	COOH	phenyl	4-OMe-phenyl-(CH 2 ) 2 —	CH	N	Me	C—CH 2 —OH	O	O
I-467	COOH	phenyl	3,4-di-OMe-phenyl-(CH 2 ) 3 —	CH	C—NH 2	OMe	N	O	—
I-468	COOH	phenyl	ethyl	N	C—CH 2 —CH 2 —CH 2	N	O	—
I-469	COOH	phenyl	ethyl	N	C-ethyl	Me	N	O	—
I-470	COOH	phenyl	4-Me-phenyl-(CH 2 ) 3 —	CH	C-ethyl	Me	N	O	—
I-471	COOH	phenyl	4-OH-phenyl-(CH 2 ) 3 —	CH	C—OMe	H	N	O	—
I-472	COOH	phenyl	methyl	CH	C—OMe	H	N	O	O
I-473	COOH	phenyl	methyl	CH	C—O—CH 2 —O	N	O	O
I-474	COOH	phenyl	4-OH-phenyl-(CH 2 ) 2 —	CH	C—O—CH 2 —CH 2	N	O	—
I-475	COOH	phenyl	3,4-dioxomethylenephenyl-(CH 2 ) 2 —	CH	C-Me	F	N	O	—
I-476	COOH	phenyl	4-OMe-phenyl-(CH 2 ) 2 —	CH	N	CH 2 —CH 2 —CH 2 —C	O	O
I-477	COOH	phenyl	4-OMe-phenyl-(CH 2 ) 2 —	CH	N	O—CH 2 —CH 2 —C	O	O
I-478	COOH	phenyl	4-Me-phenyl-(CH 2 ) 2 —	CH	C—CH 2 —CH 2 —CH 2	N	O	—
I-479	COOH	phenyl	ethyl	N	C-Me	Me	N	O	—
I-480	COOH	phenyl	ethyl	N	C—OMe	Me	N	O	—
I-481	COOH	phenyl	2-Cl-phenyl-(CH 2 ) 2 —	CH	C—CH 2 —OH	Me	N	O	—
I-482	COOH	phenyl	3,5-di-OMe-phenyl-(CH 2 ) 2 —	CH	C—N(CH 3 ) 2	Me	N	O	—
I-483	COOH	phenyl	methyl	CH	C-Me	OMe	N	O	O
I-484	COOH	phenyl	methyl	CH	C-ethyl	Me	N	O	O
I-485	COOH	phenyl	HO—CH 2 —CH 2 —	CH	N	Me	C-Me	O	—
I-486	COOH	phenyl	HO—CH 2 —CH 2 —	CH	N	Me	C—OMe	O	—
I-487	COOH	phenyl	4-OMe-phenyl-(CH 2 ) 2 —	CH	N	F	C-Me	O	O
I-488	COOH	phenyl	4-OMe-phenyl-(CH 2 ) 2 —	CH	N	Me	C-ethyl	O	O
I-489	COOH	phenyl	HO—CH 2 —CH 2 —	CH	N	OMe	C-Me	O	—
I-490	COOH	phenyl	methyl	CH	N	Me	C—N(CH 3 ) 2	O	—
I-491	COOH	phenyl	methyl	CH	N	OMe	C—NH(CH 3 )	O	—
I-492	COOH	phenyl	ethyl	CH	N	CF 3	C-ethyl	O	—
I-493	COOH	4-OMe-phenyl	ethyl	CH	N	O—CH 2 —O—C	O	—
I-494	COOH	phenyl	methyl	CH	C—OMe	Me	N	O	O
I-495	COOH	phenyl	methyl	CH	C—OMe	OMe	N	O	O
I-496	COOH	phenyl	4-Br-phenyl-(CH 2 ) 2 —	CH	N	C—CH 2 —CH 2 —CH 2	O	—
I-497	COOH	phenyl	4-OH-phenyl-(CH 2 ) 2 —	CH	N	OMe	C-ethyl	O	—
I-498	COOH	phenyl	4-OMe-phenyl-(CH 2 ) 2 —	CH	N	Me	C-Me	O	O
I-499	COOH	phenyl	4-OMe-phenyl-(CH 2 ) 2 —	CH	N	Me	C—OMe	O	O
I-500	COOH	phenyl	3,4-di-OMe-phenyl-(CH 2 ) 3 —	CH	N	Me	C—CH 2 —OH	O	—
I-501	COOH	phenyl	methyl	CH	N	OMe	C-ethyl	O	—
I-502	COOH	phenyl	methyl	CH	N	Me	C—CH 2 —OH	O	—
I-503	COOHI	phenyl	3,4-di-OMe-phenyl-(CH 2 ) 3 —	CH	N	Me	C—N(CH 3 ) 2	O	—
I-504	COOH	phenyl	propyl	CH	N	OMe	C—NH(CH 3 )	O	—
I-505	COOH	phenyl	methyl	CH	CH	OMe	N	O	O
I-506	COOH	phenyl	methyl	CH	C-Me	Me	N	O	O
I-507	COOH	phenyl	HO—CH 2 —CH 2 —	N	C-Me	Me	N	O	—
I-508	COOH	phenyl	HO—CH 2 —CH 2 —	N	C—OMe	Me	N	O	—
I-509	COOH	phenyl	4-OMe-phenyl-(CH 2 ) 2 —	CH	C—CH 2 —OH	Me	N	O	O
I-510	COOH	phenyl	4-OMe-phenyl-(CH 2 ) 2 —	CH	C—N(CH 3 ) 2	Me	N	O	O
I-511	COOH	4-OMe-phenyl	HO—CH 2 —	N	C—CH 2 —CH 2 —CH 2	N	O	—
I-512	COOH	phenyl	methyl	CH	N	F	C—OMe	O	—
I-513	COOH	phenyl	methyl	CH	N	Me	C—NH(CH 3 )	O	—
I-514	COOH	phenyl	HO—CH 2 —	N	C-ethyl	CF 3	N	O	—
I-515	COOH	phenyl	propyl	CH	C-Me	Me	N	O	—
I-516	COOH	phenyl	methyl	N	C—O—CH 2 —CH 2	N	O	O
I-517	COOH	phenyl	methyl	CH	CH	Me	N	O	O
I-518	COOH	phenyl	butyl	CH	C—OMe	Me	N	O	—
I-519	COOH	phenyl	i-butyl	CH	C-ethyl	Me	N	O	—
I-520	COOH	phenyl	4-OMe-phenyl-(CH 2 ) 2 —	CH	C—CH 2 —CH 2 —CH 2	N	O	O
I-521	COOH	phenyl	4-OMe-phenyl-(CH 2 ) 2 —	CH	C—O—CH 2 —CH 2	N	O	O
I-522	COOH	phenyl	propyl	CH	C—OMe	H	N	O	—
I-523	COOH	phenyl	methyl	CH	N	O—CH 2 —CH 2 —C	O	—
I-524	COOH	phenyl	methyl	CH	N	CH 2 —CH 2 —O—C	O	—
I-525	COOH	phenyl	HO—CH 2 —CH 2 —	CH	C—O—CH 2 —CH 2	N	O	—
I-526	COOH	phenyl	4-OMe-phenyl-CH 2 —O—CH 2 —	CH	C—CH 2 —CH 2 —CH 2	N	O	—
I-527	COOH	phenyl	methyl	N	C—OMe	H	N	O	O
I-528	COOH	phenyl	methyl	N	C—O—CH 2 —O	N	O	O
I-529	COOH	phenyl	4-OMe-phenyl-CH 2 —O—CH 2 —	CH	N	Me	C-Me	O	—
I-530	COOH	phenyl	3,4-di-OMe-phenyl-CH 2 —O—CH 2 —	CH	N	Me	C—OMe	O	—
I-531	COOH	phenyl	4-OMe-phenyl-(CH 2 ) 2 —	CH	C-Me	Me	N	O	O
I-532	COOH	phenyl	4-OMe-phenyl-(CH 2 ) 2 —	CH	C—OMe	Me	N	O	O
I-533	COOH	phenyl	3,4-di-OMe-phenyl-CH 2 —O—CH 2 —	CH	N	OMe	C-Me	O	—
I-534	COOH	phenyl	methyl	CH	N	O—CH 2 —O—C	O	—
I-535	COOH	phenyl	methyl	CH	N	CH 2 —CH 2 —CH 2 —C	O	—
I-536	COOH	phenyl	4-Cl-phenyl-CH 2 —O—CH 2 —	CH	N	Me	C-ethyl	O	—
I-537	COOH	phenyl	HO—CH 2 —CH 2 —	CH	N	O—CH 2 —O—C	O	—
I-538	COOH	phenyl	methyl	N	C-Me	OMe	N	O	O
I-539	COOH	phenyl	methyl	N	C-ethyl	Me	N	O	O
I-540	COOH	phenyl	phenyl-CH 2 —O—CH 2 —	CH	N	CH 2 —CH 2 —CH 2 —C	O	—
I-541	COOH	phenyl	4-OMe-phenyl-(CH 2 ) 2 —	N	C—O—CH 2 —O	N	O	O
I-542	COOH	phenyl	4-OMe-phenyl-(CH 2 ) 2 —	CH	C—NH(CH 3 )	Me	N	O	O
I-543	COOH	phenyl	HO—CH 2 —	CH	N	CF 3	C-ethyl	O	—
I-544	COOH	phenyl	propyl	CH	N	Me	C—N(CH 3 ) 2	O	—
I-545	COOH	phenyl	methyl	N	C-Me	Me	N	O	O
I-546	COOH	phenyl	methyl	N	C—OMe	Me	N	O	O
I-547	COOH	phenyl, naphthyl	methyl	CH	N	Me	C-Me	O	O
I-548	COOH	phenyl-4-Cl-	ethyl	CH	N	CF 3	C-ethyl	O	O
		phenyl
I-549	COOH	4-F-phenyl,	propyl	CH	C-ethyl	Me	N	O	O
		4-Cl-phenyl
I-550	COOH	naphthyl, 4-Cl-	methyl	CH	C—OMe	Me	N	O	O
		phenyl
I-551	COOH	4-Me-phenyl,	3,4-di-OMe-phenyl-(CH 2 ) 2 —	CH	C-Me	H	N	O	O
		phenyl
I-552	COOH	naphthyl, naph-	methyl	CH	C—CH 2 —CH 2 —CH 2	N	O	O
		thyl

The compounds of the present invention offer a new therapeutic potential for the treatment of hypertension, pulmonary high blood pressure, myocardial infarct, angina pectoris, arrhythmia, acute/chronic kidney failure, chronic cardiac insufficiency, renal insufficiency, cerebral vasospasms, cerebral ischemia, subarachnoid hemorrhages, migraine, asthma, atherosclerosis, endotoxic shock, endotoxin-induced organ failure, intravascular coagulation, restenosis after angioplasty and bypass operations, benign prostate hyperplasia, ischemic kidney failure and kidney failure or hypertension caused by intoxication, metastasis and growth of mesenchymal tumors such as prostate carcinoma, contrast agent-induced kidney failure, pancreatitis, gastrointestinal ulcers.

The invention further relates to combinations of endothelin receptor antagonists of the formula I and inhibitors of the renin-angiotensin system. Inhibitors of the renin-angiotensin system are renin inhibitors, angiotensin II antagonists and angiotensin-converting enzyme (ACE) inhibitors. Combinations of endothelin receptor antagonists of the formula I and ACE inhibitors are preferred.

The invention further relates to combinations of endothelin receptor antagonists of the formula I and calcium antagonists such as verapamil.

The invention further relates to combinations of endothelin receptor antagonists of the formula I and beta-blockers.

The invention further relates to combinations of endothelin receptor antagonists of the formula I and diuretics.

The invention further relates to combinations of endothelin receptor antagonists of the formula I and substances which block the action of VEGF (vascular endothelial growth factor). Substances of this type are, for example, antibodies directed against VEGF or specific binding proteins or alternatively low molecular weight substances which can specifically inhibit VEGF release or receptor binding.

The abovementioned combinations can be administered simultaneously or sequentially one after the other. They can be employed either in a single pharmaceutical formulation or alternatively in separate formulations. The administration form can also be different, for example the endothelin receptor antagonists can be administered orally and VEGF inhibitors can be administered parenterally.

These combination preparations are especially suitable for the treatment and prevention of hypertension and its sequelae, and for the treatment of cardiac insufficiency.

The good action of the compounds can be shown in the following experiments:

Receptor binding studies

For binding studies cloned human ET A - or ET B receptor-expressing CHO cells were employed.

Membrane preparation

The ET A or ET B receptor-expressing CHO cells were proliferated in DMEM NUT MIX F 12 medium (Gibco, No. 21331-020) with 10% fetal calf serum (PAA Laboratories GmbH, Linz, No. A15-022), 1 mM glutamine (Gibco No. 25030-024), 100 U/ml of penicillin and 100 μg/ml of streptomycin (Sigma No P 0781). After 48 hours, the cells were washed with PBS and incubated for 5 minutes at 37° C. with 0.05% trypsin-containing PBS. The mixture was then neutralized with medium and the cells collected by centrifugation at 300 x g.

For the membrane preparation, the cells were adjusted to a concentration of 10 8 cells/ml of buffer (50 mM tris HCL buffer, pH 7.4) and then disintegrated by ultrasound Branson Sonifier 250, 40-70 seconds/constant/output [sic] 20).

Binding tests

For the ET A and ET B receptor binding test, the membranes were suspended in an incubation buffer (50 mM tris HC 1 , pH 7.4 with 5 mM MnCl 2 40 mg/ml of bacitracin and 0.2% BSA) in a concentration of 50 μg of protein per test batch and incubated at 25° C. with 25 pM [ 125 I]-ET 1 (ET A receptor test) or 25 pM [ 125 I]-ET 3 (ET B receptor test) in the presence and absence of test substance. The nonspecific binding was determined with 10- 7 M ET 1 . After 30 min, the free and the bound radioligand were separated by filtration through GF/B glass fiber filters (Whatman, England) on a Skatron cell collector (Skatron, Lier, Norway) and the filters were washed with ice-cold tris HCl buffer, pH 7.4 with 0.2% BSA.

The radioactivity collected on the filters was quantified using a Packard 2200 CA liquid scintillation counter.

Testing of the ET antagonists in vivo:

Male SD rats 250-300 g in weight were anesthetized with amobarbital, artificially respirated, vagotomized and pithed. The carotid artery and jugular vein were catheterized.

In control animals, the intravenous administration of 1 mg/kg of ET 1 [sic] leads to a marked blood pressure increase, which lasts for a relatively long period of time.

The test animals were injected i.v. (1 ml/kg) with the test compounds 30 min before ET1 [sic] administration. To determine the ET-antagonistic properties, the blood pressure changes in the test animals were compared with those in the control animals.

p.o. Testing of the ET receptor antagonists:

Male normotensive rats (Sprague Dawley, Janvier) 250-350 g in weight are orally pretreated with the test substances. 80 minutes later, the animals are anesthetized with urethane and the carotid artery (for blood pressure measurements) and the jugular vein (administration of big endothelin/endothelin 1) are catheterized.

After a stabilization phase, big endothelin (20 μg/kg, administration vol. 0.5 ml/kg) or ET1 [sic] (0.3 μg/kg, administration vol. 0.5 ml/kg) is given intravenously. Blood pressure and heart rates are recorded continuously for 30 minutes. The marked and long-lasting blood pressure changes are calculated as the area under the curve (AUC). To determine the antagonistic action of the test substances, the AUCs of the substance-treated animals are compared with the AUC of the control animals.

The compounds according to the invention can be administered orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperitoneally) in a customary manner. Administration can also be carried out through the nasopharynx using vapors or sprays.

The dosage depends on the age, condition and weight of the patient and on the type of administration. As a rule, the daily dose of active compound is from approx. 0.5 to 100 mg/kg of body weight in the case of oral administration and from approx. 0.1 to 30 mg/kg of body weight in the case of parenteral administration.

The novel compounds can be used liquid or solid in the customary pharmaceutical administration forms, eg. as tablets, film-coated tablets, capsules, powders, granules, coated tablets, suppositories, solutions, ointments, creams or sprays. These are prepared in a customary manner. The active compounds can in this case be processed with the customary pharmaceutical auxiliaries such as tablet binders, fillers, preservatives, tablet disintegrants, flow-regulating agents, plasticizers, wetting agents, dispersants, emulsifiers, solvents, release-delaying agents, antioxidants and/or propellants (cf. H. Sucker et al.: Pharmazeutische Technologie [Pharmaceutical Technology], Thieme-Verlag, Stuttgart, 1991). The administration forms thus obtained normally contain the active compound in an amount from 0.1 to 90% by weight.

Claims

1. A compound of formula I whereR1 is tetrazole or a group where R has the following meanings:a) a radical OR6 where R6 is: hydrogen, the cation of an alkali metal, the cation of an alkaline earth metal of a physiologically tolerable organic ammonium ion; C3-C8-cycloalkyl, C1-C8-alkyl, unsubstituted or substituted CH2-phenyl, unsubstituted or substituted C3-C8-alkenyl or C3-C8-alkynyl or unsubstituted or substituted phenyl; b) a 5-membered heteroaromatic linked via a nitrogen atom; c) a group where k can assume the values of 0, 1 and 2, p the values 1, 2, 3 and 4 and R7 is C1-C4-alkyl, C3-C8-cycloalkyl, C3-C,-alkenyl, C3-C8-alkynyl or unsubstituted or substituted phenyl;d) a radical where R8 is C1-C4-alkyl, C3-C8-alkenyl, C3-C8-alkynyl, C3-C8-cycloalkyl, it being possible for these radicals to carry a C1-C4-alkoxy, C1-C4-alkylthio and/or a phenyl radical; C1-C4-haloalkyl or unsubstituted or substituted phenyl;X is nitrogen or methine; Y is nitrogen if X is methine and Y is CR9 if X is nitrogen; Z is nitrogen; R2 is C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, it being possible for these radicals to be unsubstituted or substituted; hydrogen, halogen, C1-C4-alkoxy, C1-C4-haloalkyl, C3-C6-alkenyloxy, C3-C6-alkynyloxy, C1-C4-alkylthio, C1-C4-alkylcarbonyl, C1-C4-alkoxycarbonyl, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, hydroxyl, carboxyl, amino; or CR2 together with CR9 forms a 5- or 6-membered alkylene or alkenylene ring which can be unsubstituted or substituted, and where in each case one or more methylene group can be replaced by oxygen, sulfur, —NH or N(C1-C4-alkyl); R3 and R4 (which can be identical or different) are: phenyl or naphthyl, unsubstituted or substituted, or phenyl or naphthyl which are connected to one another in the ortho position via a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an SO2—, NH— or N-alkyl group; unsubstituted or substituted C3-C8-cycloalkyl; R5 is hydrogen, C1-C8-alkyl, C3-C8-alkenyl or C3-C8-alkynyl, it being possible for these radicals to be unsubstituted or substituted; unsubstituted or substituted phenyl or naphthyl; a 5- or 6-membered heteroaromatic, having one to three nitrogen atoms and/or a sulfur or oxygen atom, and which can be unsubstituted or substituted; unsubstituted or substituted C3-C8-cycloalkyl; R9 is hydrogen, hydroxyl, NH2, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, halogen, C1-C4-alkoxy, C1-C4-haloalkoxy or C1--C4-alkylthio; C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, it being possible for these radicals to be unsubstituted or substituted; or CR9 is linked with CR2 as indicated above to give a 5- or 6-membered ring; W is sulfur, oxygen or a single bond; Q is oxygen or NH, with the proviso that if Q=NH, then W is a single bond or the physiologically tolerable salts, or the enantiomerically pure and diastereomerically pure forms.

2. A drug preparation for oral and parenteral administration, comprising per individual dose, customary drug auxiliaries, and at least one compound of formula I as claimed in claim 1.

3. A combination of the compound of formula I as claimed in claim 1 and one or more active compounds selected from inhibitors of the renin-angiotensin system.

4. The combination claimed in claim 3, wherein the inhibitors of the renin-angiotensin system are renin inhibitors, angiotensin II antagonists, angiotensin-converting enzyme (ACE) inhibitors, mixed ACE/neutral endopeptidase (NEP) inhibitors β-blockers, diuretics, calcium antagonists and VEGF-blocking substances.

5. A method of treating high blood pressure, pulmonary high blood pressure, myocardial infarct, angina pectoris, restenosis, arrhythmia, acute/chronic kidney failure, chronic cardiac insufficiency, renal insufficiency, cerebral vasospasms, cerebral ischemia, subarachnoid hemorrhages, migraine, asthma, atherosclerosis, endotoxic shock, endotoxin-induced kidney failure, kidney failure or hypertension caused by intoxication, metastasis and growth of mesenchymal tumors, contrast agent-induced kidney failure, pancreatitis, gastrointestinal ulcers, stroke, benign prostate hyperplasia or Raynaud's Syndrome caused or aggravated by abnormal release of endothelin, said method comprising administering to a human or animal in need of such treatment an effective amount of the compound of formula I as claimed in claim 1.

6. The method of treating illnesses as defined in claim 5, wherein said illness is selected from the group consisting of chronic cardiac insufficiency, restenosis, high blood pressure, pulmonary high blood pressure, acute/chronic kidney failure, cerebral ischemia and benign prostate hyperplasia.