AU765345B2

AU765345B2 - Novel carboxylic acid derivatives comprising aryl-substituted nitrogen heterocycles, their production and their use as endothelin receptor antagonists

Info

Publication number: AU765345B2
Application number: AU53959/00A
Authority: AU
Inventors: Wilhelm Amberg; Georg Kettschau
Original assignee: BASF SE
Current assignee: BASF SE
Priority date: 1999-06-01
Filing date: 2000-05-19
Publication date: 2003-09-18
Anticipated expiration: 2020-05-19
Also published as: EP1181281A2; AU5395900A; BR0011105A; KR20020006049A; PL355112A1; TR200103475T2; WO2000073276A2; IL146800A0; BG106154A; JP2003500476A; AR022047A1; SK17552001A3; HUP0201387A3; WO2000073276A3; DE19924892A1; CN1359376A; CZ20014312A3; NO20015762L; CA2375666A1; HK1047102A1

Description

0050/50031 Novel carboxylic acid derivatives with aryl-substituted nitrogen heterocycles, their preparation and use as endothelin receptor antagonists The present invention relates to novel carboxylic acid derivatives, their preparation and use.

Endothelin is a peptide composed of 21 amino acids, which is synthesized and released by vascular endothelium. 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 vessel tone. It is known that this vasoconstriction is caused by the binding of endothelin to its receptor (Nature, 332, 411-415, 1988; FEBS Letters, 231, 440-444, 1988 and Biochem. Biophys. Res. Commun., 154, 868-875, 1988).

Increased or abnormal release of endothelin causes persistent vasoconstriction in peripheral, renal and cerebral blood vessels, which may lead to diseases. As reported in the literature, endothelin is involved in a number of diseases. These include: hypertension, acute mycocardial infarct, pulmonary hypertension, Raynaud's syndrome, cerebral vasospasms, stroke, benign prostate hypertrophy, atherosclerosis, asthma and prostate cancer (J.

Vascular Med. Biology 2, 207 (1990), J. Am. Med. Association 26A, 2868 (1990), Nature 344, 114 (1990), N. Engl. J. Med. 322, 205 (1989), N. Engl. J. Med. 328, 1732 (1993), Nephron 66, 373 (1994), Stroke 25, 904 (1994), Nature 35., 759 (1993), J. Mol.

Cell. Cardiol. 21, A234 (1995); Cancer Research 56, 663 (1996), Nature Medicine 1, 944,(1995)).

At least two endothelin receptor sub.types, ETA and ETB receptors, have to date been described in the literature (Nature 348, 730 (1990), Nature 348, 732 (1990)). Accordingly, substances which inhibit the binding of endothelin to one or both receptors should antagonize the physiological effects of endothelin and therefore represent valuable drugs.

The preparation and use of endothelin receptor antagonists has already been described in WO 95/26716, WO 96/11914, WO 97/38980, WO 97/38982, W098/09953, W098/27070, WO 98/58916, WO 99/11629, DE 19748238.4, DE 19806438.1, DE 19809144.3 and DE 19836044.4.

These are compounds which each comprise a heteroaromatic system with at least one nitrogen but no phenyl substitution.

.A S 0050/50031 2 It is an object of the present invention to provide further endothelin receptor antagonists with valuable pharmacological properties.

The invention relates to carboxylic acid derivatives of the formula I 4

RX-Q

I H -Q

R

5

R

1 R R

R

in which R 1 is tetrazolyl or a group 0

II

C-R

in which R has the following meaning: a) a radical OR 6 in which R 6 is: hydrogen, the cation of an alkali metal, the cation of an alkaline earth metal, a physiologically tolerated 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 may be substituted by one or more of the following radicals: halogen, nitro, cyano, C 1

-C

4 -alkyl, Ci-C 4 -haloalkyl, hydroxyl, Ci-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 2

-C

6 -alkenyl or C 3

-C

6 -alkynyl group, it being possible for these groups in turn to carry one to five halogen atoms;

R

6 can also be a phenyl radical which may carry one to five halogen atoms and/or one to three of the following radicals: nitro, cyano, C 1

-C

4 -alkyl, Ci-C 4 -haloalkyl, hydroxyl, C 1

-C

4 -alkoxy, mercapto, C 1

-C

4 -alkylthio, amino, NH(Cl-C 4 -alkyl), N(C 1

-C

4 -alkyl) 2 b) a 5-membered heteroaromatic system which is linked via a nitrogen atom, such as pyrrolyl, pyrazolyl, imidazolyl and triazolyl, which may.carry one to two halogen atoms -f -t 0,050/50031 3 or one to two Cl-C 4 -alkyl or one to two Cl-C 4 -alkoxy groups; c) a group (CH -S-R 7 in which k assumes the values 0, 1 and 2, p assumes the values 1, 2, 3 and 4, and R 7 is Cl-C 4 -alkyl, C 3 -C8-cycloalkyl, C 2

-C

6 -alkenyl, C 2

-C

6 -alkynyl or phenyl which may be substituted by one or more, for example one to three, of the following radicals: halogen, nitro, cyano, Cl-C 4 -alkyl, Cl-C 4 -haloalkyl, hydroxyl, Cl-C 4 -alkoxy, Cl-C 4 -alkylthio, mercapto, amino, NH(Cl-C 4 -alkyl) N(Cl-C 4 -alkyl) 2 d) a radical 0 11

-N-S-R

H 1 250 in which R 8 is: Cl-C 4 -alkyl, C 2

-C

6 -alkenyl, C 2

-C

6 -alkynyl, C 3 -C-cycloalkyl, it being possible for these radicals to carry a Cl-C 4 -alkoxy, Cl-C 4 -alkylthio and/or a phenyl radical as mentioned under c); phenyl which may be substituted by one to three of the following radicals: halogen, nitro, cyano, Cl-C 4 -alkyl, Cl-C 4 -haloalkyl, hydroxyl, Cl-C 4 -alkoxy, C.

1

-C

4 -alkylthio, rnercapto, amino, NH(Cl-C 4 -alkyl), N(Cl-C 4 -alkyl) 2 The other substituents have the following meanings:

R

2 phenyl or phenoxy, benzyl, benzyloxy, it being possible for all the aryl radicals to carry one to five halogen atoms and/or one to three of the following radicals: hydroxyl, mercapto, carboxyl, nitro, cyano, Cl-C 4 -alkyl, Cl-C4-haloalkyl, Cl-C 4 -alkoxy, C3-C6-alkenyloxy,

C

3

-C

6 -alkynyloxy, Cl-C 4 -alkylthio, Cl-C 4 -haloalkoxy, Cl-C 4 -alkylcarbonyl, R 9 Cl-C4-alkoxycarbonyl, (Cl-C 4 -alkyl)NHcarbonyl, (C 1

C

4 -alkyl) 2 Ncarbonyl, f.10050/50031 4

C

3

-C

8 -alkylcarbonylalkyl, amino, NH (Cl-C 4 -alkyl), N(Cl-C 4 -alkyl) 2 phenoxy or phenyl, it being possible for said aryl radicals in turn to be substituted once to three times by halogen, Cl-C 4 -alkyl, Cl-C 4 -haloalkyl, Cl-C 4 -alkoxy, Cl-C 4 -haloalkoxy, methylenedioxy, ethylenedioxy, Cl-C 4 -alkylthio; a five- or six-membered heteroaromatic system which contains 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: Cl-C 4 -alkyl, Cl-C 4 -haloalkyl, Cl-C 4 -alkoxy, Cl-C 4 -haloalkoxy, Cl-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: Cl-C 4 -alkyl, Cl-C 4 -haloalkyl, Cl-C 4 -alkoxy, Cl-C 4 -haloalkoxy and/or Cl-C 4 -alkylthio; C3-C 8 -cycloalkyl which may carry one to three of the following radicals: Cl-C 4 -alkyl, Cl-C 4 -haloalkyl, Cl-C 4 -alkoxy, Cl-C 4 -haloalkoxy, Cl-C 4 -alkylthio.

R

3 hydrogen; Cl-C-alkyl, C 3

-C

6 -alkenyl, C 3

-C

6 -alkynyl or C 3

-C

8 -cycloalkyl, it being possible for each of these radicals to be substituted one or more times by: hydroxyl, mercapto, carboxyl, halogen, nitro, cyano, Cl-C 4 -alkoxy, C3-C 6 -alkenyloxy, C 3

-C

6 -alkynyloxy, Cl-C 4 -alkylthio, Cl-C 4 -haloalkoxy, Cl-C 4 -alkylcarbonyl, Cl-C 4 -alkoxycarbonyl, (Cl-C 4 -alkyl) NHcarbonyl, (Cl-C 4 -alkyl) 2 Ncarbonyl,

C

3

-C

8 -alkylcarbonylalkyl, amino, NH(Cl-C 4 -alkyl), N(Cl-C 4 -alkyl) 2 phenoxy, phenyl or hetaryl, five- or six-membered, containing one to three nitrogen atoms and/or one sulfur or oxygen atom, it being possible for all said aryl and hetaryl radicals to be su bstituted once to three times by: halogen, nitro, cyano, Cl-C 4 -alkyl, Cl-C 4 -haloalkyl, Cl-C 4 -alkoxy, Cl-C 4 -haloalkoxy, mercapto, carboxyl, hydroxyl, amino, R 9 Cl-C 4 -alkoxycarbonyl, NH(Cl-C 4 -alkyl), N(Cl-C 4 -alkyl) 2 methylenedioxy, ethylenedioxy, Cl-C 4 -alkyithio, phenyl or phenoxy; phenyl or naphthyl, each of which may be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, amino, Cl-C 4 -alkyl,. Cl-C 4 -haloalkyl, Cl-C 4 -alkoxy, Q50/50031 Ci-C 4 -haloalkoxy, phenoxy, C 4 -alkylthio, NH(Cl-C 4 -alkyl) N(Cl-C 4 -alkyl) 2 or methylenedioxy or ethylenedioxy; a five- or six-membered heteroaromatic system which contains 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: Cl-C 4 -alkyl, Cl-C 4 -haloalkyl, Cl-C 4 -alkoxy, Cl-C 4 -haloalkoxy, Cl-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: Cl-C 4 -alkyl, Cl-C 4 -haloalkyl, Cl-C 4 -alkoxy, Cl-C 4 -haloalkoxy and/or Cl-C 4 -alkylthio.

R

4 and R 5 (which may be identical or different): phenyl or naphthyl, each of which may be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, Cl-C 4 -alkyl, Cl-C 4 -haloalkyl, Cl-C 4 -alkoxy, Ci-C 4 -haloalkoxy, phenoxy, Cl-C 4 -alkylthio, amino, NH (Cl-C 4 -alkyl) N (Cl-C 4 -alkyl) 2 or phenyl or naphthyl which are connected together in ortho positions by a direct linkage, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an SO 2 NH or N-alkyl group; or C 3

-C

7 -cycloalkyl.

X and Y (which may be identical or different): nitrogen or methine; with the proviso that if X Y methine then Z nitrogen.

Z nitrogen or CR 10 Q nitrogen or CR 1 1 with the proviso *that if X Y Z= nitrogen then Q CR1 1

R

9

CI-C

4 -alkyl, Cl-C 4 -alkylthio, Cl-C 4 -alkoxy, each of which carry one of the following radicals: hydroxyl, carboxyl, amino, NH(CI-C 4 -alkyl), N(C3 1

-C

4 -alkyl) 2' carbarnoyl or CON (C-C 4 -alkyl) 2

R

10 hydrogen, halogen, hydroxyl, NH 2 NH(Cl-C 4 -alkyl), N (Cl-C 4 -alkyl) 2' Cl-C 4 -alkyl, C 2

-C

4 -alkenyl, C 2

-C

4 -alkynyl, Cl-C 4 -hydroxyalkyl, Cl-C 4 -haloalkyl, Cl-C 4 -alkoxy, Cl-C 4 -haloalkoxy or Cl-C 4 -alkylthio, or CR1. forms together 0050/50031 6 with CR 11 a 5- or 6-membered alkylene or alkenylene ring which may be substituted by one or two Cl-C 4 -alkyl groups arnd in which in each case one or more methylene groups can be replaced by oxygen, sulfur, -NH or -N (Cl-C 4 -alkyl); phenyl which may carry one to three of the following radicals: Cl-C 4 -alkyl, Cl-C 4 -haloalkyl, Cl-C 4 -alkoxy, Ci-C 4 -haloalkoxy, Cl-C 4 -alkylthio.

R

11 hydrogen, hydroxyl, NH 2 NH (Cl-C 4 -alkyl) N (Cl-C 4 -alkyl) 2 halogen, Cl-C 4 -alkyl, C 2

-C

4 -alkenyl, C 2

-C

4 -alkynyl, C3-C 6 -alkenyloxy, Cl-C 4 -alkylcarbonyl, Cl-C 4 -alkoxycarbonyl, Cl-C 4 -hydroxyalkyl, Cl-C 4 -haloalkyl, Cl-C 4 -alkoxy, Cl-C 4 -haloalkoxy, -NH-O-Cl-C 4 -alkyl, Cl-C 4 -alkyl thio, C3-C-cycloalkyl or CR 11 forms together with CR 10 and as indicated f or R 10 a 5- or 6-membered ring; phenyl or phenoxy, each of which may carry one to five halogen atoms and/or one to three of the following radicals: hydroxyl, mercapto, carboxyl, nitro, cyano, Cl-C 4 -alkyl, Ci-C 4 -haloalkyl, Cl-C 4 -alkoxy, C 3

-C

6 -alkenyloxy, C3-C 6 -alkynyloxy, Cl-C 4 -alkylthio, Cl-C 4 -haloalkoxy, Cl-C 4 -alkylcarbonyl, R 9 Cl-C 4 -alkoxycarbonyl, (Cl-C 4 -alkyl )NHcarbonyl, (Cl-C 4 -alkyl) 2 Ncarbonyl, C3-CB-alkylcarbonylalkyl, amino, NH.(Cl-C 4 -alkyl),

N(C

1

-C

4 -alkyl) 2 phenoxy or phenyl, it being possible for said.

aryl. radicals in turn to be substituted once to three times by halogen, Cl-C 4 -alkyl, Cl-C 4 -haloalkyl, Cl-C 4 -alkoxy, Cl-C 4 haloalkoxy, methylenedioxy, ethylenedioxy, Cl-C 4 -alkylthio; a five- or six-membered heteroaromatic system which contains 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: CI-C 4 -alkyl, Cl-C 4 -haloalkyl, Cl-C 4 -alkoxy, Cl-C 4 -haloalkoxy, Cl-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: Cl-C 4 -alkyl, Cl-C 4 -haloalkyl, Cl-C 4 -alkoxy, Cl-C 4 -haloalkoxy and/or Cl-C 4 -alkylthio.

A sulfur or oxygen.

The following definitions apply in this connection and hereinafter: 1 0050/50031 7 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, ethylenediamine, diethylamine or piperazime;

C

3 -CB-cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl;

CI-C

4 -haloalkyl can be linear or branched, such as, for example, f luoromethyl, difluoromethyl, trifluoromethyl, chlorodif luoromethyl, dichlorof luoromethyl, trichloromethyl, 1-f luoroethyl,'2-f luoroethyl, 2, 2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2, 2-trichloroethyl or pentaf luoroethyl; Cl-C 4 -haloalkoxy can be linear or branched, such as, for example, difluoromethoxy, trif luoromethoxy, chiorodifluoromethoxy, 1-f luoroethoxy, 2, 2-difluoroethoxy, 1,1,2, 2-tetrafluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-1, 1, 2-trifluoroethoxy, 2-f luoroethoxy or pentafluoroethoxy;

C

2

-C

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

C

2

-C

4 -alkenyl can b e 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; Cl-C 4 -alkoxy can be linear or branched, such as, for example, methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methyipropoxy, 2-methylpropoxy or 1, 1 -dime thyl ethoxy; C3-C6-alkenyloxy can be linear or branched, such as, for example, allyloxy, 2-buten-1-yloxy or 3-buten-2-y loxy; 0050/50031 8 C3-C 6 -alkynyloxy can be linear or branched, such as, for example, 2-propyn-l-yloxy, 2-butyn-l-yloxy or 3-butyn-2-yloxy;

C

1

-C

4 -alkylthio can be linear or branched, such as, for example, methylthio, ethylthio, propylthio, l-methylethylthio, butylthio, 1-methylpropylthio, 2-methylpropylthio or 1,1-dimethylethylthio; Ci-C 4 -alkylcarbonyl can be linear or branched, such as, for example, acetyl, ethylcarbonyl or 2-propylcarbonyl; Ci-C 4 -alkoxycarbonyl can be linear or branched, such as, for example, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl or n-butoxycarbonyl; C3-Ca-alkylcarbonylalkyl can be linear or branched, for example 2-oxoprop-l-yl, 3-oxobut-l-yl or 3-oxobut-2-yl; Ci-Ce-alkyl can be linear or branched, such as, for example, Ci-C 4 -alkyl, pentyl, hexyl, heptyl or octyl; halogen is, for example, fluorine, chlorine, bromine, iodine.

The invention further relates to compounds from which the compounds of the formula I can be liberated (called prodrugs), for example amides of the acids embraced by formula I.

Preferred prodrugs are those with which the liberation takes place under conditions like those prevailing in particular compartments of the body, for example in the stomach, intestine, bloodstream, liver.

The compounds, and the intermediates for preparing them, such as, for example, II and IV, may have one or more asymmetric substituted carbon atoms. Compounds of this type may be in the form of pure enantiomers or pure diastereomers or a mixture thereof. The use of an enantiomerically pure compound as active ingredient is preferred.

The invention further relates to the use of the abovementioned carboxylic acid derivatives for producing drugs, in particular for producing inhibitors for endothelin receptors.

Compounds of the general formula IV in which Z is sulfur or oxygen (IV) can be prepared as described in WO 96/11914.

e L1~1~---*i~l~.lrXa9IXUYUIl~ O,o/5oo31 9 4 4 4 O 1 R 4

R

4 R R 3 H R -Z-H R A C-OH II III IV Compounds of the general formula III either are known or can be synthesized, for example, by reducing the corresponding carboxylic acids or esters thereof, or by other generally known methods.

Compounds of the formula IV can be obtained in enantiomerically pure form by acid-catalyzed transesterification as described in WO 98/09953.

It is also possible to obtain enantiomerically pure compounds of the formula IV by carrying out a conventional racemate resolution of racemic or diastereomeric compounds of the formula IV using suitable enantiomerically pure bases. Examples of suitable bases of this type are 4-chlorophenylethylamine and the bases mentioned in WO 96/11914.

The compounds according to the invention in which the substituents have the meaning indicated for 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 stated meaning with compounds of the general formula V.

X-Q

IV R12- Z I V

R

12 in formula V is halogen or R 13 -S0 2 where R 13 can be

C

1

-C

4 -alkyl, C 1

-C

4 -haloalkyl or phenyl. The reaction preferably takes place in an inert solvent or diluent with the addition of a suitable base, i.e. a base which deprotonates the intermediate IV, at a temperature in the range from room temperature to the boiling point of the solvent.

If R 1 is an ester, the compounds with R 1 COOH can be prepared by acidic, basic or catalytic cleavage of the ester group.

S.00,50/50031 Compounds of type I with R 1 COOH can also be obtained directly by deprotonating the intermediate IV in which R 1 is COOH with two equivalents of a suitable base, and reacting with compounds of the general formula V. This reaction also takes place in an inert solvent and at a temperature in the range from room temperature to the boiling point of the solvent.

Examples of such solvents or diluents are aliphatic, alicyclic and aromatic hydrocarbons, each of which may optionally by 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, nitriles such as, for example, acetonitrile and propionitrile, 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 V are known, some of them can be bought, or they can be prepared in a generally known manner.

It is possible to use as base an alkali metal or alkaline earth metal hydride such as sodium hydride, potassium hydride or calcium hydride, a carbonate such as alkali metal carbonate, for example 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.

Compounds of the formula I can also be prepared by starting from the corresponding carboxylic acids, i.e. compounds of the formula I in which R 1 is COOH, and initially converting these in a conventional way into an activated form such as an acid halide, anhydride or imidazolide, and then reacting this with an appropriate hydroxyl compound HOR 7 This reaction can be carried out in the conventional solvents and often requires addition of a base such as, for example, triethylamine, pyridine, imidazole or diazabicycloundecene. These two steps can also be simplified, for example, by allowing the carboxylic acid to act in the presence of a dehydrating agent such as a carbodiimide on the hydroxyl compound.

It is also possible to prepare compounds of the formula I by starting from salts of the corresponding carboxylic acids, i.e.

from compounds of the formula I in which R 1 is a COOM group, where n~ 0050/50031 11 M can be an alkali metal cation or the equivalent of an alkaline earth metal cation. These salts can be reacted with many compounds of the formula R 1 -D where D is a conventional nucleofugic leaving group, for example halogen such as chlorine, bromine, iodine or optionally halogen-, alkyl- or haloalkyl-substituted aryl- or alkylsulfonyl such as, for example, toluenesulfonyl and methylsulfonyl or another equivalent leaving group. Compounds of the formula R 1 -D with a reactive substituent D are known or can easily be obtained with general expert knowledge. This reaction can be carried out in conventional solvents and is advantageously effected with addition of a base, in which case those mentioned above are suitable.

In a few cases it is necessary to use generally known protective group techniques to prepare the compounds I according to the invention. If, for example, R 6 4-hydroxyphenyl, the hydroxyl group can initially be protected as the benzyl ether, which is then cleaved at a suitable stage in the reaction sequence.

Compounds of the formula I in which R 1 is tetrazolyl can be prepared as described in WO 96/11914. Further possibilities are mentioned, for example, in: Synthesis, 767 (1993); J. Org. chem.

2395 (1991).

With a view to the biological effect, preferred carboxylic acid derivatives of the general formula I both as pure enantiomers and pure diastereomers or as mixtures thereof are those in which the substituents have the following meanings:

R

2 phenyl or phenoxy, each of which may carry one to three of the following radicals: halogen, C 1

-C

4 -alkyl, C 1

-C

4 -haloalkyl,

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,

(C

1

-C

4 -alkyl)-NHcarbonyl, (C 1

-C

4 -alkyl) 2 Ncarbonyl,

NH(C

1

-C

4 -alkyl), N(C 1

-C

4 -alkyl) 2 a five- or six-membered heteroaromatic system which contains one nitrogen atom and/or one sulfur or oxygen atom and which may carry one to two of the following radicals: halogen,

C

1

-C

4 -alkyl, C 1

-C

4 -haloalkyl, C 1

-C

4 -alkoxy, C 1

-C

4 -haloalkoxy, C1-C 4 -alkylthio, phenyl which in turn may carry one to three of the following radicals: halogen, Ci-C 4 -alkyl, C1-C 4 -haloalkyl, C 1

-C

4 -alkoxy, C1-C 4 -haloalkoxy,

C

1

-C

4 -alkylthio; 0050/50031 12 Cs-Cs-cycloalkyl.

R

3 hydrogen;

C

1

-C

8 -alkyl, C 3 -C-alkenyl, C 3

-C

6 -alkynyl or C 3 -CB-cycloalkyl, it being possible for each of these radicals to be substituted one or more times by: hydroxyl, halogen,

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, (Cl-C 4 -alkyl)NHcarbonyl, (C 1

-C

4 -alkyl) 2 Ncarbonyl, amino,

NH(C

1

-C

4 -alkyl), N(C 1

-C

4 -alkyl) 2 phenoxy or phenyl, hetaryl, five- or six-membered, containing one to three nitrogen atoms and/or one sulfur or oxygen atom, it being possible for said aryl and hetaryl radicals to be substituted once to three times by: halogen, C 1

-C

4 -alkyl, C 1

-C

4 -haloalkyl, C 1

-C

4 -alkoxy,

C

1

-C

4 -haloalkoxy, R 9

C

1

-C

4 -alkoxycarbonyl, NH(C 1

-C

4 -alkyl),

N(C

1

-C

4 -alkyl) 2 methylenedioxy, ethylenedioxy,

C

1

-C

4 -alkylthio; phenyl or naphthyl, each of which can be substituted by one or more of the following radicals: halogen, 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), N(C 1

-C

4 -alkyl) 2 methylenedioxy or ethylenedioxy; a five- or six-membered heteroaromatic system which contains one to three nitrogen atoms and/or one sulfur or oxygen atom and which may carry 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, Cl-C 4 -alkylthio, phenyl which may in turn 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,

C

1

-C

4 -alkylthio.

R

4 and Rs (which may be identical or different): phenyl or naphthyl, each of which can be substituted by one or more of the following radicals: halogen, C 1

-C

4 -alkyl,

C

1

-C

4 -haloalkyl, C 1

-C

4 -alkoxy, C 1

-C

4 -haloalkoxy, Cl-C 4 -alkylthio; or phenyl or naphthyl which are linked together in ortho positions by a direct linkage, a methylene, ethylene or ethenylene group; or cyclohexyl.

i~nr~s- i-.;-u-NCISr

UUU/.,UUJI

13 X and Y (which may be identical or different): nitrogen or methine; with the proviso that if X Y methine then Z nitrogen.

Z nitrogen or CR 10 with the proviso that if Z nitrogen then Q CR 1 1 Q nitrogen or CR 11

R

9 C1-C 4 -alkyl, C 1

-C

4 -alkylthio, C 1

-C

4 -alkoxy, which carry one of the following radicals: hydroxyl, carbamoyl or

CON(C

1

-C

4 -alkyl) 2

R

10 o hydrogen, halogen, C 1

-C

4 -alkyl, C 1

-C

4 -haloalkyl, C 1

-C

4 -alkoxy,

C

1

-C

4 -haloalkoxy or C 1

-C

4 -alkylthio, or CRio forms together with CR 11 a 5- or 6-membered alkylene or alkenylene ring which may be substituted by one or two methyl groups and in which in each case one or more methylene groups can be replaced by oxygen or sulfur.

R

1 1 hydrogen, NH(C 1

-C

4 -alkyl), N(C 1

-C

4 -alkyl) 2

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, Cs-Cs-cycloalkyl or CR 1 forms together with CRo as indicated under Ro 10 a 5- or 6-membered ring; phenyl or phenoxy, each of which may carry one to three of the following radicals: halogen, C 1

-C

4 -alkoxy, C1-C 4 -alkylthio, C 1

-C

4 -haloalkoxy, C 1

-C

4 -alkylcarbonyl, C1-C 4 -alkoxycarbonyl, (C 1

-C

4 -alkyl)NHcarbonyl, (C1-C 4 -alkyl) 2 Ncarbonyl, NH(C 1

-C

4 -alkyl), N(C 1

-C

4 -alkyl)2; a five- or six-membered heteroaromatic system which contains one nitrogen atom and/or one sulfur or oxygen atom and which may carry one to two of the following radicals: halogen,

C

1

-C

4 -alkyl, Cl-C 4 -haloalkyl, C 1

-C

4 -alkoxy, C 1

-C

4 -haloalkoxy,

C

1

-C

4 -alkylthio, phenyl which may in turn carry one to three of the following radicals: halogen, 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.

A sulfur or oxygen.

Particularly preferred compounds of the formula I both as pure enantiomers and pure diastereomers or as mixtures thereof are those in which the substituents have the following meanings: R I~-ncl- j K 6~rPsr ra 3 iW ann aa 0050/50031 14

R

-C

4 -alkyl, C 1

-C

4 -haloalkyl,

C

1

-C

4 -alkoxy, C 1

-C

4 -alkylthio, C 1

-C

4 -haloalkoxy; a five- or six-membered heteroaromatic system which contains one nitrogen atom and/or one sulfur or oxygen atom and which may carry one to two of the following radicals: halogen, C1-C 4 -alkyl, C 1

-C

4 -haloalkyl, C 1

-C

4 -alkoxy, C 1

-C

4 -haloalkoxy,

C

1

-C

4 -alkylthio; Cs-Cs-cycloalkyl.

R

3 hydrogen;

C

1

-C

8 -alkyl or C 3

-C

6 -cycloalkyl, it being possible for each of these radicals to be substituted once to three times by: hydroxyl, halogen, C 1

-C

4 -alkoxy, C 1

-C

4 -alkylthio, C1-C 4 -haloalkoxy, phenoxy, phenyl, hetaryl, five- or six-membered, containing one nitrogen atom and/or one sulfur or oxygen atom, it being possible for said aryl and hetaryl radicals to be substituted once to three times by: halogen,

C

1

-C

4 -alkyl, C 1

-C

4 -haloalkyl, C 1

-C

4 -alkoxy, C 1

-C

4 -haloalkoxy,

R

9 methylenedioxy, ethylenedioxy, C 1

-C

4 -alkylthio; phenyl or naphthyl, each of which may be substituted by one or more of the following radicals: halogen, 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, methylenedioxy or ethylenedioxy; a five-membered heteroaromatic system which contains one sulfur or oxygen atom and which may carry one to two of the following radicals: C 1

-C

4 -alkyl, C 1

-C

4 -haloalkyl, C1-C 4 -alkoxy, C 1

-C

4 -haloalkoxy, C 1

-C

4 -alkylthio.

R

4 and Rs (which may be identical or different): phenyl or naphthyl, each of which may be substituted by one or more of the following radicals: halogen, C 1

-C

4 -alkyl, C1-C 4 -haloalkyl, C 1

-C

4 -alkoxy, C 1

-C

4 -haloalkoxy, C1-C 4 -alkylthio; or phenyl or naphthyl which are connected in ortho positions by a direct linkage or a methylene group.

0050/50031 X and Y (which may be identical or different): nitrogen or methine; with the proviso that if X Y methine then Z nitrogen; Z nitrogen or CR 10 Q CR 11

R

9

C

1

-C

4 -alkyl, C1-C 4 -alkylthio, C1-C 4 -alkoxy, each of which may carry a hydroxyl group.

R

10 hydrogen, halogen, methyl, trifluoromethyl, methoxy, or CR 1 0 forms together with CR 11 a 5- or 6-membered alkylene ring which may be substituted by one or two methyl groups and in which in each case one or more methylene groups may be replaced by oxygen or sulfur.

R

11 hydrogen, C1-C 4 -alkyl, Ci-C 4 -haloalkyl, C 1

-C

4 -alkoxy,

C

1

-C

4 -haloalkoxy, C1-C 4 -alkylthio, C 5

-C

6 -cycloalkyl or CR 11 forms together with CR i 0 as indicated under R 10 a 5- or 6-membered ring.

A sulfur or oxygen.

The compounds of the present invention offer a novel potential treatment of hypertension, pulmonary hypertension, myocardial infarct, angina pectoris, arrhythmia, acute/chronic kidney failure, chronic heart failure, 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, erectile dysfunction, glaucoma, ischemic and intoxication-induced kidney failure or hypertension, metastasis and growth of mesenchymal tumors, 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.

aI a Y *r S0050/50031 16 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). Examples of such substances are antibodies directed against VEGF or specific binding proteins or else low molecular weight substances capable of specific inhibition of VEGF release or receptor binding.

The aforementioned combinations can be administered concurrently or sequentially. They can be employed either in a single pharmaceutical formulation or else in separate formulations. The administration form may also differ; for example, the endothelin receptor antagonists can be administered orally, and VEGF inhibitors can be administered parenterally.

These combination products are particularly suitable for treating and preventing hypertension and its sequelae, and for treating heart failure.

The good effect of the compounds can be shown in the following tests: Receptor-binding studies Cloned human ETA or ETB receptor-expressing CHO cells were employed for binding studies.

Membrane preparation The ETA or ET B receptor-expressing CHO cells were grown 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 penicillin and 100 gg/ml streptomycin (Sigma No. P-0781). After 48 hours, the cells were washed with PBS and incubated with 0.05% trypsin-containing PBS at 37 0 C for 5 minutes. This was followed by neutralization with medium, and the cells were collected by centrifugation at 300 x g.

0060/50031 17 For membrane preparation, the cells were adjusted to a concentration of 108 cells/ml of buffer (50 mM Tris-HC1 buffer, pH 7.4) and then disintegrated with ultrasound (Branson Sonifier 250, 40-70 seconds/constant output Binding assays For the ETA and ETB receptor-binding assay, the membranes were suspended in incubation buffer (50 mM Tris-HC1, pH 7.4 with 5 mM MnC1 2 40 mg/ml bacitracin and 0.2% BSA) in a concentration of gg of protein per assay mixture and incubated with 25 pM [125I]-ETi (ETA receptor assay) or 25 pM [125I]-ET 3 (ETB receptor assay) in the presence and absence of test substance at 250C. The nonspecific binding was determined using 10- 7 M ET 1 After 30 min, filtration through GF/B glass fiber filters (Whatman, England) in a Skatron cell harvester (Skatron, Lier, Norway) separated free and bound radioligand, and the filters were washed with ice-cold Tris-HC1 buffer, pH 7.4 with 0.2% BSA. The radioactivity collected on the filters was quantified using a Packard 2200 CA liquid scintillation counter.

Functional test on vessels for endothelin receptor antagonists Segments of rabbit aorta are, after an initial tension of 2 g and a relaxation time of 1 h in Krebs-Henseleit solution at 37°C and pH 7.3-7.4, first induced to contract with After washing out, an endothelin dose-effect plot up to the maximum is constructed.

Potential endothelin antagonists are administered to other preparations of the same vessel 15 min before starting the endothelin dose-effect plot. The effects of the endothelin are calculated as percent of the K--induced contraction. Effective endothelin antagonists result in a shift to the right in the endothelin dose-effect plot.

Testing of ET antagonists in vivo: Male SD rats weighing 250 300 g were anesthetized with amobarbital, artificially ventilated, vagotomized and pithed. The carotid artery and jugular vein were catheterized.

In control animals, intravenous administration of 1 pg/kg ET1 results in a marked rise in blood pressure which persists for a lengthy period.

S4 P. 4 -4 ~~R 0050/50031 18 The test animals received i.v. injection (1 ml/kg) of the test compounds 30 min before administration of ET1. To determine the ET-antagonistic properties, the changes in blood pressure in the test animals were compared with those in the control animals.

Oral testing of mixed ETA and ETB antagonists: Male normotensive rats (Sprague Dawley, Janvier) weighing 250-350 g are pretreated with the test substances orally. minutes later, the animals are anesthetized with urethane, and the carotid artery (for measuring the blood pressure) and the jugular vein (administration of big endothelin/endothelin 1) are catheterized.

After a stabilization period, big endothelin (20 pg/kg, admin.

vol. 0.5 ml/kg) or ET1 (0.3 jig/kg, admin. vol. 0.5 ml/kg) is given intravenously. Blood pressure and heart rate are recorded continuously for 30 minutes. The marked and long-lasting changes in blood pressure are calculated as the area under the curve (AUC). To determine the antagonistic effect of the test substances, the AUC for the animals treated with substance is compared with the AUC for the control animals.

The novel compounds can be administered orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperitoneally) in a conventional way. Administration can also take place with vapors or sprays through the nasopharyngeal space.

The dosage depends on the age, condition and weight of the patient and on the mode of administration. As a rule, the daily dose of active ingredient is from about 0.5 to 50 mg/kg of body weight on oral administration and from about 0.1 to 10 mg/kg of body weight on parenteral administration.

The novel compounds can be administered in conventional solid or liquid pharmaceutical forms, e.g. as uncoated or (film-)coated tablets, capsules, powders, granules, suppositories, solutions, ointments, creams or sprays. These are produced in a conventional way. The active ingredients can for this purpose be processed with conventional pharmaceutical aids such as tablet binders, bulking agents, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, release-slowing agents, antioxidants and/or propellant gases (cf. H. Sucker et al.: Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1991). The administration a srP~- l 0050/50031 19 forms obtained in this way normally contain from 0.1 to 90% by weight of active ingredient.

Synthesis examples: Example 1: 4-Methyl-2-methylsulfanyl-6-phenylpyrimidine 1 molar sodium hydroxide solution (4.10 ml; 4.10 mmol) and iodomethane (86 pI; 194 mg; 1.37 mmol) were successively added to a solution of 4-methyl-6-phenylpyrimidine-2-thiol (300 mg; 1.37 mmol with 92% purity; synthesized by the method of D.J.

Brown et al., Aust. J. Chem. 1984, 37, 155) in methanol (15 ml).

The mixture was stirred at room temperature for 16 hours; it was then diluted with water (50 ml) and acidified with hydrochloric acid. The mixture was extracted with ethyl acetate the combined organic phases were dried over magnesium sulfate, and the solvent was removed in vacuo. 290 mg (1.24 mmol, 91% yield, HPLC purity 93%) of the required pyrimidine were obtained.

Example 2: 2-Methanesulfonyl-4-methyl-6-phenylpyrimidine Oxone® (Aldrich; 973 mg; 1.58 mmol) and 4 molar sodium hydroxide solution (0.85 ml; 3.33 mmol) were simultaneously added to a solution of 4-methyl-2-methylsulfanyl-6-phenylpyrimidine (278 mg, 1.19 mmol with 93% purity) in methanol (10 ml) and water (10 ml) while cooling in ice in such a way that the pH was always pH 2-3.

The mixture was then stirred at room temperature for 16 h, and the reaction was then stopped by dilution with water (75 ml). The mixture was extracted with ether (2x) and then with ethyl acetate the combined organic phases were dried over magnesium sulfate, and the solvent was removed in vacuo. 290 mg (1.11 mmol, 93% yield, HPLC purity 95%) of the required sulfonylpyrimidine were obtained; it was used further without further purification.

Example 3: 3-Ethoxy-2-(4-methyl-6-phenylpyrimidin-2-yloxy)-3,3-diphenylpropionic acid (1-180) sodium hydride (72 mg, 1.51 mmol) and then a solution of 3-ethoxy-2-hydroxy-3,3-diphenylpropionic acid (150 mg, 0.50 mmol; synthesis described in WO 96/11914) in dimethyl formamide were added to a solution of 2-methanesulfonyl-4-methyl-6-phenyl- 0050/50031 pyrimidine (145 mg; 0.55 mmol with 95% purity) in anhydrous dimethylformamide (10 ml), and the mixture was stirred at room temperature. After 3 hours, the sulfonylpyrimidine was completely consumed but the hydroxy acid had not yet reacted completely, so that a further 30 mg of the sulfonylpyrimidine were added. After stirring at room temperature for a further hour, the reaction was virtually complete and it was stopped by adding water.

Acidification with hydrochloric acid was followed by extraction with ether The ethereal extracts were extracted with 1 molar potassium hydroxide solution; the aqueous alkaline extracts were combined and again acidified and extracted three times with ether. The ethereal extracts resulting from this were dried over magnesium sulfate and evaporated. The remaining crude product was purified by flash chromatography on silica gel and isolated by freeze drying. 47 mg of the target compound (0.09 mmol; 19% yield) were obtained.

1 H-NMR (200 MHz, CDC1 3 7.9-8.1 2 7.1-7.7 14 1 3.3-3.7 2 2.5 3 1.2 3 H).

ESI-MS: M 454.

Example 4: 3-Methoxy-2-(4-methyl-6-phenylpyrimidin-2-yloxy)-3,3-diphenylpropionic acid (1-58) 1 H-NMR (200 MHz, CDC1 3 7.9-8.1 2 7.2-7.7 14 6.4 1 3.3 3 2.5 3 H).

ESI-MS: M 440.

Example 2 -Methylsulfanyl-6-phenylpyrimidin-4-ol 1 molar sodium hydroxide solution (15.0 ml; 15.0 mmol) and iodomethane (0.33 ml; 735 mg; 5.18 mmol) were successively added to a solution of 2-mercapto-6-phenylpyrimidin-4-ol (1.06 g; 5.18 mmol; synthesized by the method of H.I. Skulnick et al., J.

Med. Chem. 1986, 29 1499) in methanol (10 ml). The mixture was stirred at room temperature for 30 minutes; it was then diluted with water (100 ml) and acidified with hydrochloric acid.

The mixture was extracted with ethyl acetate the combined organic phases were dried over magnesium sulfate, and the solvent T -a W r -as-^^^^E-iaSW^BM^^ 0050/50031 21 was removed in vacuo. 750 mg (3.44 mmol, 66% yield) of the required product were obtained.

Example 6: 4-Chloro-2-methylsulfanyl-6-phenylpyrimidine A solution of 2-methylsulfanyl-6-phenylpyrimidin-4-ol (854 mg; 3.91 mmol) in phosphorus oxychloride (10.0 ml) was heated with stirring to 80 0 C and stirred at this temperature for 2 hours.

After cooling, the phosphorus oxychloride was removed in vacuo; the residue was taken up in ethyl acetate and washed with water The organic phase was dried over magnesium sulfate, and the solvent was evaporated off in vacuo. Evaporation once again with toluene afforded the required chloropyrimidine in 95% purity (950 mg; 3.81 mmol; 97% yield).

Example 7: 4-Methoxy-2-methylsulfanyl-6-phenylpyrimidine strength methanolic sodium methanolate solution (4.50 ml) was added to a mixture of 4-chloro-2-methylsulfanyl-6-phenylpyrimidine (950 mg, 3.81 mmol with 95% purity) in anhydrous methanol (15 ml) under a nitrogen atmosphere. The resulting mixture was heated to boiling and refluxed at this temperature for 90 minutes. It was then stirred at room temperature for 16 hours, and the solvent was evaporated off. The residue was mixed with water and extracted with ethyl acetate The organic phase was dried over magnesium sulfate and evaporated. The required compound was obtained in the form of yellow crystals (854 mg; 3.60 mmol; 94%).

Example 8: 2-Methanesulfonyl-4-methoxy-6-phenylpyrimidine Oxone® (Aldrich; 3.32 g; 5.40 mmol) and 4 molar sodium hydroxide solution (2.50 ml; 10.0 mmol) were simultaneously added to a solution of 4-methoxy-2-methylsulfanyl-6-phenylpyrimidine (854 mg, 3.60 mmol) in methanol (15 ml) and water (15 ml) while cooling in ice in such a way that the pH was always at pH 2-3.

The mixture was then stirred at room temperature for 16 h, and the reaction was then stopped by dilution with water (75 ml). The mixture was extracted with ethyl acetate the combined organic phases were dried over magnesium sulfate, and the solvent was removed in vacuo. 928 mg (3.17 mmol, 88% yield, HPLC purity l-~I 0050/50031 22 of the required sulfonylpyrimidine were obtained; it was used further without further purification.

Example 9: 3-Methoxy-2-(4-methoxy-6-phenylpyrimidin-2-yloxy)-3,3-diphenylpropionic acid (1-64) sodium hydride (106 mg; 2.20 mmol) was added to a stirred solution of 3-methoxy-2-hydroxy-3,3-diphenylpropionic acid (200 mg; 0.73 mmol; synthesis described in WO 96/11914) in anhydrous dimethylformamide (10 ml) while cooling in ice under a nitrogen atmosphere. After 10 minutes, 2-methanesulfonyl-4-methoxy-6-phenylpyrimidine (320 mg; 1.09 mmol with 90% purity) dissolved in a little dimethylformamide was added. The cooling bath was removed, and the mixture was stirred at room temperature for 16 hours. The reaction was then stopped by cautious addition of water, followed by acidification with hydrochloric acid and extraction with ether The ethereal extracts were extracted with 1 molar potassium hydroxide solution; the aqueous alkaline extracts were combined and again acidified and extracted three times with ether. The ethereal extracts obtained thereby were dried over magnesium sulfate and, after addition of some hexane, evaporated at low temperature.

317 mg (0.67 mmol; 92% yield) of the target compound were obtained.

1 H-NMR (200 MHz, CDC13): 7.9-8.1 2 7.2-7.6 13 6.8 1 6.3 1 3.9 3 3.3 3 H).

Melting point: 110-115 0

C.

Example 3-Ethoxy-2-(4-methoxy-6-phenylpyrimidin-2-yloxy)-3,3-diphenylpropionic acid (1-95) Example 11: 3-Methoxy-2-[4-methoxy-6-(4-trifluoromethylphenyl)pyrimidin-2yloxy]-3,3-diphenylpropionic acid (1-6) 1 H-NMR (200 MHz, d 6 -DMSO): 8.3 2 7.8 2 7.4 (m app t, 4 7,1 1 7.0-7.3 6 6.3 1 3.9 (s, 3 3.4 3 H).

MM

0050/50031 23 ESI-MS: M 524.

Example 12: 3-Ethoxy-2-[4-methoxy-6-(4-trifluoromethylphenyl)pyrimidin-2yloxy]-3,3-diphenyipropionic acid (1-159) 1 H-NMR (200 MHz, CDC1 3 8.0 2 7.7 2 7.6 2 H); 7.2-7.5 8 6.8 1 6.4 1 4.0 3 (mc, 2 1.3 3 H).

ESI-MS: M 538.

Example 13: 2-[4-(4-Isopropylphenyl)-6-methoxypyrimidin-2-yloxy]-3-methoxy- 3,3-diphenylpropionic acid (1-87) 1H-NMR (200 MHz, CDC1 3 7.9 2 7.6 (m app d, 2 7.2-7.4 10 6.8 1 6.4 1 3.9 3 3.3 3 2.9 (sept, 1 1.3 6 H).

ESI-MS: M 498.

Example 14: 2,4-Dichloro-6-ethyl-[1,3,5]-triazine A 2 molar solution of ethylmagnesium chloride in tetrahydrofuran (100 ml; 200 mmol) was added dropwise over the course of minutes to a solution of cyanuric chloride (23.1 g; 184 mmol) in anhydrous toluene (200 ml) while cooling in ice under a nitrogen atmosphere. The temperature gradually rose to 15 0 C during this; after completion of the addition, the mixture was stirred at room temperature for 2 hours. To stop the reaction, water (40 ml) was very cautiously (NB) added to the mixture and, after addition of solid magnesium sulfate (40 it was filtered. The filtrate was evaporated and the residue was extracted with hexane. Evaporation of the hexane was followed by purification by flash chromatography on silica gel; 8.80 g (49.4 mmol; 40% yield) of an oil were obtained.

Example 2-Chloro-4-ethyl-6-phenyl-[1,3,5] -triazine 0050/50031 24 A solution of 2,4-dichloro-6-ethyl-[1,3,5]-triazine (1.78 g; 10.0 mmol) in anhydrous dichloromethane (50 ml) was cooled to to -20 0 C under a nitrogen atmosphere and a 2 molar solution of phenylmagnesium chloride in tetrahydrofuran (5.50 ml; 11.0 mmol) was added over the course of 5 minutes. The mixture was allowed to warm to room temperature and was then stirred at room temperature for 1 hour. The reaction was stopped by cautious addition of water (3 ml); this was followed by addition of 3 g of solid magnesium sulfate. After removal of insolubles by filtration, the solvent was evaporated off and the remaining oil was purified by chromatography. 1.35 g of an oil were obtained; despite chromatography, its HPLC purity was only 66% (4.07 mmol; 41% yield).

Example 16: Benzyl 3-ethoxy-2-hydroxy-3,3-diphenylpropionate Absolute ethanol (10.0 ml) and boron trifluoride etherate (3-4 drops) were successively added to a solution of benzyl 3,3-diphenyloxirane-2-carboxylate (10.0 g; 30.3 mmol with 92% purity) in anhydrous ether (100 ml) while cooling in ice under a nitrogen atmosphere. The cooling bath was removed, and the mixture was stirred at room temperature for 2 hours. Washing with saturated sodium bicarbonate solution and water was followed by drying over magnesium sulfate and evaporation. The residue was purified by crystallization from ether/n-hexane; 6.60 g (17.5 mmol; 58% yield) of the pure hydroxy ester were obtained.

1 H-NMR (270 MHz, CDC1 3 7.2-7.5 15 5.2 1 5.0 (s, 2 3.4 1 3.2 1 3.0 1 1.1 3 H).

Example 17: Benzyl 3-ethoxy-2-(4-ethyl-6-phenyl-[1,3,5 -triazin-2-yloxy)-3,3diphenylpropionate (1-17) A solution of benzyl 3-ethoxy-2-hydroxy-3,3-diphenylpropionate (376 mg; 1.00 mmol) and 2-chloro-4-ethyl-6-phenyl-[1,3,5]triazine (497 mg; 1.50 mmol with 66% purity) in anhydrous dimethylformamide (30 ml) was mixed with potassium carbonate (276 mg; 2.00 mmol) and stirred at room temperature for 16 hours.

The mixture was diluted with water (150 ml), acidified with citric acid and extracted with ether The combined ethereal extracts were dried over magnesium sulfate, and the solvent was removed in vacuo; the oily residue was purified by flash 0050/50031 chromatography. 431 mg (0.77 mmol, 77% yield) of the pure target compound were obtained.

Example 18: 3-Ethoxy-2-(4-ethyl-6-phenyl-[1,3,5]-triazin-2-yloxy)-3,3diphenylpropionic acid (1-102) A solution of benzyl 3-ethoxy-2-(4-ethyl-6-phenyl-[1,3,5]triazin-2-yloxy)-3,3-diphenylpropionate (430 mg; 0.77 mmol) in ethyl acetate (60 ml) was mixed under protective gas with a palladium/carbon hydrogenation catalyst and then stirred under a hydrogen atmosphere at room temperature for 3 days. The mixture was then filtered to remove catalyst and was evaporated.

Crystallization of the oily residue from n-hexane afforded 187 mg (0.40 mmol; 52% yield) of the pure carboxylic acid.

1 H-NMR (200 MHz, CDC13): 8.4 2 7.2-7.7 13 1 3.5-3.7 1 3.25-3.45 1 2.9 2 H); 1.2-1.4 6 H).

ESI-MS: M* 469.

The following were prepared analogously: Example 19: 2-(4-Ethyl-6-phenyl-[1,3,5]-triazin-2-yloxy)-3-methoxy-3,3diphenylpropionic acid (1-109) 1 H-NMR (200 MHz, CDC13): 8.5 2 7.2-7.7 13 1 3.3 3 2.9 2 1.3 3 H).

ESI-MS: M* 455.

Example 2-[4-Ethyl-6- (4-methoxyphenyl)- 3,5]-triazin-2-yloxy] -3methoxy-3,3-diphenylpropionic acid (I-23) 1 H-NMR (200 MHz, CDC1 3 8.4 2 7.5-7.6 2 7.2-7.5 8 7.0 2 6.4 1 3.9 3 3.3 3 H); 2.9 2 1.3 3 H).

ESI-MS: M- 485.

~ics^- L~l~n*woui Example 21: 3-Ethoxy-2- [4-ethyl-6- (4-methoxyphenyl) 3, 5] -triazin-2-yloxy] 3, 3-diphenyipropionic acid (1-147) 1 H-NMR (200 MHz, CDCl 3 8.4 2 7.5-7.6 (in, 2 7.2-7.5 (mn, 8 7. 0 2 6.5 1 H) 3.9 3 3.3-3.7 (mn, 2 2.8 2 H) 1. 35 3 H) 1 .2 5 3 H) ESI-MS: MI 499.

Example 22: 2-(4,6-Diphenyl)-[1,3,5]-triazifl-2-yloxy]-3-mfethoxy-3,3-diphenylpropionic acid (1-29) 1 H-NMR (200 MHz, CDCl3) 8.6 4 H) T.2-7.7 (mn, 16 H) 1 3.3 3 H).

ESI-MS: M+ 503.

Example 23: 2 6-Diphenyl) 1,3, 5 tr ia zin- 2-yloxy 3 ethoxy-3, 3 -diphenl propionic acid (1-41) 1 H-NMR (200 MHz, CDCl 3 8.6 4 7.2-7.7 (in, 16 6.6 1 H) 3.3-3.7 (mn, 2 1. 3 3 H) ESI-MS: M4+ 517.

The compounds listed in Tables I and II can be prepared analogously or as described in the general section.

Table I R

X-Q

R

No. R 1

R

4

R

5 R3R 2 x V y Z Q A I-1 COOGH 3 3-Ci-Phenyl- H Benzyl- N N CH C-OMe 0 1-2 COOH 4-OMe-Phenyl- Methyl Phenyl- N N CH C-Me 0 1-3 COOH 4-Me-Phenyl- Ethyl Phenyl-O&- N N CH C-OMe 0 1-4 COOH 4-CF 3 O-Phenyl- i-Propyl 3-F-Phenyl- N N CH C-OMe 0 COOH 3-HO-Phenyl- CH 2 =CH-CH27 2,3-Di-Ci-Phenyl- N N CH COMe 0 1- 6 COOH Phenyl Methyl 4-F 3 C-Phenyl- N N CH C-OMe 0 1-7 COONa 3-SWe-Phenyl-- (CH 3 2 C=CH-CH2- 4-HO-Phenyl- N N N C-Me 0 1-8 COOH 4-H 2 N-Phenyl- CH 3 2 4-OMe-Phenyl- N N CHI CH 0 1-9 COOH Phenyl Cyclopropyl- 4-OMe--Phenyl--0- N N CH C-CF 3 0 1-10 COOH Phenyl icyclopentyl- 3,A-Di-OWe-Phenyl- N N CH C-NHOMe 0 I-11I COONa Phenyl HO-CH 2 -CH2- 3-SWe-Phenyl-- N N CH C-SMe 0 1-12 COOH Phenyl CHr-CH(SH)-H2 4-CF 3 7-Phenyl- N N CHI C-Et 0 1-1 3 COOH Phenyl HQOC-CHr-CH2- 3-(HOOC-CH 2 )-Phenyl N N CH C-OEt 0 1-44 COOH Phenyl CF 3

-CH

2 7- 3-CH 3 CO--Phenyl- N IN ICH C-NHOMe 0 1-15 COOCH 3 Phenyl 4-Me-Cyclohexyl- 2-CH 3 00C-Phenyl- N N CHI C-Et 0 1-16 COOH Phenyl CH 3

-O-CH

2 -CHZ- 3-H 2 N--Phenyl-- N N C C-Me IsI No. RiR 4 Rs 312 X Y Z Q A 1-17 COOH Phenyl Ethyl Phenyl- N N N C-Et 0 1-18 COOH Phenyl CH 3

-CH

2

-S--CH

2 -CHr- 4-H 2 NOC-Phenyl- N N CHI C-OMe 0 1-19 COOH Phenyl CF 3 -O3-CH 2

-CH

2 3-(Acetyl--CH 2 )-Phenyl,- N IN CH C-Me 0 1-20 COOH 4-CI-Phenyl- CH 3 00C-CH 2

-CH

2 2-Thieny],- N IN CH 0-OMe 0 1-21 COOH 3-Me-4-F-Phenyl- H 2

NCO-CH

2

-CH

2 3-Fury],- N N CH C-Me 0 1-22 COOH 4-Me-Phenyl-- (Butyl) 2

NCO-CH

2

-CH

2 2-Pyfrolyl N N N C-NHMe 0 11-23 COOH Phenyl Methiyl 4 -~-Phenyl- N N N C-Et 0 1--24 COOH 4-Ci--Phenyl-- Cyclohexyl-CH 2 -CH2-CH2- 3-Me--2-Furyl N N N C-N(Me) 2 0 1-25 COOH 3-F-Phenyl- Cyclopentyl-CH-CH-CH27- 3-F 3 C-2-Thienyl N N CHI 0-OMe 0 1-26 C0OH 2-F-Phenyl- Phenyl-CH--CH-CH2- 3-Thienyl-- N N CH C-Me 0 1-27 COOH 2-Me-Phenyl- Phenyl-O-CII 2 -CH2- 4-OMo,-2-Furyl N IN CH C-OEt 01 1-28 COOH Phenyl 2-Thienyl-CH 2

-CH

2 4-Thiazolyl- N N CH G-Allyl 0 1-29 CO0H Phenyl Methyl Phenyl- N N N C-Phenyl 0 1-30 C0OH Phenyl 3-Furyl--CHr-CH2- 5-Oxazolyl- N N CH C-OMe S 1-31 CO0H Phenyl 2-Thiazolyl-CH-3-CH2)- 3-OMe--Phenyl N N CHI 0-OMe 0 1-32 C0OH Phenyl 4-F-Phenyl-CH2-CHr- 2-OMe-Phenyl N N CH C-OPropyl 0 1-33 COOH Phenyl 3,4-Di-OMe-Phenyl-CI 2 -CH7- 2-Et-Phenyl,- N N CH C-Et 01 1-34 C0OH Phenyl 3-NC-Phenyl-CH 2 -CH2-- 3-Mo-4-OMeAPhenyl- N IN CH C-Me 0 1-35 ,COONa Phenyl Methyl 4-OMe-Phenyl- N CHI N C-OMe 0' 1-36 C0NHSO 2

CH

3 Phenyl Methyl Phenyl- N CH N OMe 0 1-37 CO0H Phenyl 4-Me-Phenyl-CH2- 3-Et-Phenyl N N CH C-OMe 1-38 C0OH Phenyl 4-OEt-Phenyl--CH 2 14-OMe-Cyclohexyl- N N CHI C-OMe No. iR 4

R

5 R3R 2 x Y Z Q A 1-39 COOH Phenyl 3-C1-4Me-Phenyl-CH 2 Cyclopropyl- N N CHI G-Me 0 1-40 COOCH 3 Phenyl 2-CF 3 7 Phenyl-CHZ-CH 2 Cyclopentyl- N N CH C-Me 0 1-41 COOH Phenyl Ethyl Phenyl- N N N C-Phenyl 0 1-42 COOH Phenyl 4-CF 3 -O -Phenyl-CH 2 -CH2-CH27- 3-M&-Cyclohexyl N N CHI C-OMe 0- 1-43 Tetrazolyl Phenyl Methyl 4-F-Phenyl- N N CHI OMe 0 COOH 3-Me-Phenyl Methyl 3-CI--Phenyl- N N N OMe 0 1-45 COOH Phenyl 3-HS--Phenyl-CH 2 -CIHr- 4-i-Propyl-Phenyl N N C-CH 2

-CH

2

-CH

2 -C 0- 1-46 C0OH Phenyl 4-HOOC-Phenyl-O-CI 2

CH

2 3-OEt-4-M&-Phenyl- N N C-CH 2

-CH

2 0 1-47 COOII Phenyl 2-HO-Phenyl-CII2-- 4-F 3 G-Phenyl- N N C-CII 2 -CHr-S--C 0 1-48 COOH Phenyl 3-H 2 N-Phenyl-CH 2

CI

2 2-SMe-Phenyl- N N CHI C-CF 3 0 1-49 COOH Phenyl 4-(IIOOC-CH 2 )-Phenyl-CH 2 4-Me--Phenyl- N N CHI C-OMe 0 1-50 C00H 4-F-Phenyl MethylI 3-Br-Phenyl- N N C-Me C-Me 0 1-51 COOLI Phenyl Methyl 4-OMe-Phenyl- N CII N -C-Et 01 1-52 C0OH 2-Me-Phenyl 3-CH 3 00C-Phenyl-CH 2

CH

2 3-OMe--Phenyl-- N N N C-Et s 1-53 COOII Phenyl 4-Me-2-Fwyl-CH2- Benzyl N N CHI C-Me 0' 1-54 COOH Phenyl 3,4-Methylenedioxyphenyl-CH2- 4-OMe-Phenyl-O- N N. CHI CH. 0 1-55 COOH Phenyl 3,4-Ethylenedioxyphenyl-CH2- 3-Me--Phenyl-0D- N N CHI C-OMe 0

CII

2 1-56 C0OH Phenyl 3-Me-4-SMe--Phenyl-CH 2

-CII

2 Beazyl- N N CH C-OMe 0 1-57 CO0H Phenyl Methyl 4-Et-Phenyl- N N CH N 0 1-58 C00H Phenyl Methyl Phenyl- N N CII C-Me 0 1-59 COOII Phenyl Phenyl- Phenyl- N N CHI G-Oet 101 COOH IPhenyl 12-Naplithyl- Phenyl-O- N N CHI C-SMe No. RIR 4 RsR

R

2 x Y ZQ A 1-61 COOH 4-Ci--Phenyl- 4-Ci-Phenyl- 3-F-Phenyl- N N N C-N(Me) 2 0 1-62 COOH 3-Me--F-Phenyl- 3-NC-Phenyl- 2,3-Di-Ci-Phenyl- N N CH C-Et s 1-63 COOH 4-Me-Phenyl- 3-HO-Phenyl- 4-HO-Phenyl- N N CH C-Me 0 1-64 COOH Phenyl Methlyl Phenyl- N N CH C-OMe 0 1-65 C0OH 4-Ci-Phenyl- 3,4,5-Thi-Mo-Phenyl- 4-OMe--Phenyl- N N CH C-OMe 0 1-66 COOH 3-F-Pheny1- 4-H 2 N-Phenyl- 4-OMe-Phenyl-O- N N CH C-Me 0 COOH 2-F--Phenyl-- 3-F 3 C--henyl- 3,4-Di-OWe-Phenyl- N N CH C-CF 3 0 1-68 COOH 2-Me-Phenyl- 3,A-Di-OMe-Phenyl- 3-SWe-Phenyl- N N CH C-OMe 0 1-69 COOH Phenyl 4-(F 2 HC)-O-Phenyl- 4-CF 3 Phenyl- N N CH C-OMe 0 1-70 COOC 2 H5 Phenyl Methyl 3-Me--Phenyl- N N CH C-Me 0 1-71 COOH Phenyl Methyl 4-OMe--Phenyl- N N CH C-Me 0 1-72 COOH Phenyl 3-SWe4-OWe-Phenyl 3-CH 3 -CO-Phenyl- N N CH C-OMe 0 1--73 COOH Phenyl 3-MeNH-Phenyl- 3-(HOOC-CH 2 )-Phenyl N N CH C-Me 0 1--74 COOH Phenyl 3,4-Mediylenedioxyphenyl- 2-CH 3 00C-Phenyl- N N N C-N(Me) 2 0 1-75 COOH Phenyl 3,4-Ethylenedioxyphenyl- 3-H 2 N--Phenyl- N N CH C-Me 0 1-76 COOH Phenyl 4---2-Naphthyl 4-H 2 N0C-Phenyl- N N CH C-Oet 0 1-77 COOH Cyclohexyl Methyl 2-OWe-Phenyl- N CHI CH N 0 1-78 COOH Phenyl Methyl 3,A-Methylenedioxy- N CH CH N S phenyl___ 1-79 COOH Phenyl H 3-(Acetyl-CH 2 )-Phenyl- N IN CH C-Et 0 1-80 COOH Phenyl CHr-CH(CH3)-CH2- 2-Thienyl- N N CH C-OMe 0 1-81 COOH Phenyl i--Propyl 3-Furyl-- N N CH C-Et 0 1-82 COOH Phenyl Butyl 2-Pyrrolyl N N CH C-OMe 0 Lii Lii 0D No. R 1

R

4 Rs R3 R2 xZ Q A 1-83 COOH 4-F-Phenyl CH 3 -CH=CH-CHz- 3-Me-2-Furyl N N CH C-OMe 0 1-4 COOH 3-F-Phenyl Methyl 3,4-Di-Me-Phenyl- N N CH N 0 1-85 1COOH 3-OMe-Phenyl Methyl 4-Me--Phenyl- N N CH N 0 1-86 ICOOCH 3 4--F-Phenyl (CH 3 2

C=CH-CH--CH

2 3-F 3 C--2-Thienyl N N CH C-Et 0 1-7 COOH Phenyl Methyl 4-i-Propyl-Phenyl- N N CH C-OMe 0 1-88 COOH 4-C1--Phenyl CH 3 -CHZ-C>C-CH2- 3-Thienyl- N N CH C-OMe 0 1-9 COOH 4-Me-Phenyl Cyclopropyl- 4-OMe-2-Furyl N N CH C-OMe 0 1-90 COOH 4-OWe-Phenyl 3-Me-Cyclopentyl1- 4-Thiazolyl- N N CH C-OMe 0 1-91 COOH 4-Me-Phenyl HO-CH-CH(OH)-CH27 5-Oxazolyl- N N CH C-Me 0 1-92 COOH Phenyl Methyl 3-Me-Phenyl- N CH CH C-CF 3 0 1-93 COOH 3-F-Phenyl Methyl 4-Et-Phenyl1- CH CH N C-Me 0 1-94 COOH Phenyl HS-CH 2 7-CH 2 7-CH2 3-OMe,-Phenyl N N CH C-Et 0 1-95 CO0H Phenyl Ethyl Phenyl- N N CH C-OMe 0 1-96 COOH 3-CF 3 -Phenyl UCf-F- 2-OMe-Phenyl N N CH 0-OMe 0 1-97 COOH Phenyl HOOC-CH 2

CH

2

-CH

2 2-Et-Phenyl- N N CH C-Me 0 1-98 C0OH 4-F-Phenyl 4-Me--Cyclohexyl- 3-Me-4-OW-Phenyl- N N CH C-Me 0 1-99 COOH Phenyl CHT-CHr-O-CH2-C12- 3-Et-Phenyl N N CH C-Me 0 1-100 COOH Phenyl Methyl 4-OMe-Phenyl CH CH IN C-OMe 0 1-101 CONHSO 2

CH

3 Phenyl Methyl 3,4-Di-OMe-Phenyl- CH N N C-Et 0 1-102 C0OH Phenyl Ethyl Phenyl- N N N C-Et 0 1-103 CO0CH 3 Phenyl CH 3 -S-CHZ-CH2- 4-OMe-Cyclohexyl- N N CH C-OMe Is 1-104 C0OH 3-CI--Phenyl CF 3

-O-CH

2

-CH

2 Cyclopropyl- N N ICH C-OEt 0 No. RiR 4

,R

5 R3 R2x Y Z Q A 1-405 COOC 2

H

5 Phenyl Ethyl 3-OEt--4--OMe-Phenyl- N N CH C-OMe 0 1-106 COOH Phenyl Ethyl 4-F 3 C-Phenyl- N N CH G-OMe 0 1-407 COOH 2-Fr-Phenyl CH 3 00C-CH 2 -CH2--CH2- Cyclopentyl- N IN CH C-OEt 0 1-108 C0OH 2-F-Phenyl H 2

NCO-CH

2

-CH

2

CH

2 3-Me-Cyclohexyl N N CH C-Propyl 0 1-109 COOH Phenyl Methyl Phenyl- N N N C-Et 0 I-110 COON 2-Me-Phenyl (Butyl) 2

NCO-CH

2

CH

2 -CH2-- 4-i-Propyl--Phenyl N N CH C-Et 0 1-111 COON Phenyl Methyl "-Me--henyl- N N jCH "-Me 0 1-112 COOCH 3 2-f-Phenyl Methyl 3-OMe--Phenyl N N CH CH 0, 1-113 COON Phenyl 4-0Me-yclohexyl-CH2-CH2- 3-OEt-4-OMe-Phenyl-- N N CH C-Et 0 1-114 COON Phenyl Cyclopentyl-CH2-CH2- 4-F 3 C-Phenyl-- N N ICH C-OMe 0 1-115 COON Phenyl Ethyl 2-SMe-Phenyl- N N CH C-OMe 0 1-116 COON 4-Cl--Phenyl Ethyl 4-Me-Phenyl- N N CH CHI 0 1-117 COOH 4-CF 3 -Phenyl 3-Cl--Phenyl-CH=CH-CH2- 2-SMe-Phenyl- N N CHI 0-OMe 0 1-118 COON Phenyl 4-OMO-Phenyl-O-C 2 -CH2- 4-Moe-Phenyl-- N N CHI G-OMe 0 1-119 COOH Phenyl 3-Thienyl-CHr-CH2-- 3-OMe--Phenyl- N N CH C-Me 1-420 COOC 2

H

5 3-CI--Phenyl Methyl 4-F 3 C-Phenyl- N N CH C-Et 0 1-121 COOCH 3 Phenyl Methyl 3-OMe--Phenyl- N N CHI C-OEt 0 1-122 COOCH 3 Phenyl 4-Moe-3-FuryI-CH 2 -CH2- Benzyl N N CH C-OMe 0 1-123 COOH Phenyl 4-Thiazolyl-CH 2 CH2-- 4-OMe--Phenyl-O- N N CH C-Me 0 1-124 COON 4-OCF 3 -Phenyl 4-Br-Phenyl-CH 2 -CH2- 3-Me--Phenyb-O-- N N CHI C-OCF 3 0 1-125 COOH Phenyl 3-OMe-4-OEt-Phenyl-CH2-CH2- Benzyl- N N CHI C-OCF 3 s 1-126 COON Phenyl 3-N0 2 -Phenyl-CH 2 -CH2- IPhenyl- N]N CH C-CF 3 0 No. RiR 4

R

5

R

3

R

2 x V Z Q A 1-427 COOC 2

H

5 Phenyl Methyl 4-OMe--Phenyl- N N CHI C--Cl 0 1-128 COOH 4-F-Phenyl Methyl 3-Mo--Phenyl- N N CH C-OMe 0 1-429 CO0H 4-F-Phenyl 3,4-Di-Me--Phenyl-C112- Phenyl-O-- N N CH C-Me 0 1-430 COOH Phenyl 3-OEt-Phenyl-CH27 3-F-Phenyl- N N CH C-Me 0 1-131 CO0H Phenyl Ethyl 3-OMe-Phenyl- N N CH C-Me 0 1-132 COOH Phenyl Methyl Phenyl- N N CHI C-Me 0 1-433 COOH Phenyl Methyl Cyclopentyl- N N CH C-OMe 0 IA134 COOH Phenyl 3,4-Di-Cl--Pheny-CH2-- 2,3-Di--C-Phenyl- N N CH C-OMe 0 1-13 5 COOH Phenyl 2-F-Phenyl-CH 2 -CH2 4-HO-Phenyl- N N CH C-Me 0 1-136 COOH Phenyl 4-Cl--Pheny-CH 2 -CH-CH2-- 4-OMa--Phenyl- N N CH C-OMe 0 1-137 C0NHS02Phenyl 4-F-Phenyl Methyl 4-OMe-Phenyl- N N CHI C-OMe 0 1-138 CO0C 2 H5 Phenyl Methyl 4-OMe--Phenyl-- N N CHI C-CF 3 0 1-139 CO0H Phenyl 3-HS-Phenyl-O-CH2-CH2- 4-OM&e-PhenyIl-O- N N CH C-Et 0 1-140 CO0H Phenyl 4-HOOC-Phenyl-CH2-CH2- 3,4-Di--OMe--Phenyl-- N N CH C-Et 0 1-141 COOH Phenyl 12-HO-Phenyl-CH2-CH2- 3-SMe-Phenyl-- N N CHI C-Et s 1-142 COOH Phenyl 3-H 2 N-Phenyl-CH2- 4-CF 3 -Phenyl- N N CH C-Et s 1-143 COOH Phenyl 4-(H 2

NOC-CH

2 )-Phenyl-CH 2 3-CH 3 CO-Phenyl-- N N CHI C-OMe 0 1-144 CONHSO 2 PhenyI 4-F-Phenyl Methyl Phenyl- N N CH C-Me 0 1-145 CO0CH 3 Phenyl Methyl 0-Phenyl-- N N CH C-CF 3 0 1-146 COOH Phenyl 4-CH 3 00C-Phenyl-CH 2 -CH2 3-(HO0C-CH 2 )-Phenyl N N CH C-OMe 0 117COOH Phenyl Ethyl I4-OWe-Phenyl- N N N C-Et 0 1-148 COOH Phenyl 3-Me-2-Furyl-CH27- 12-CH 3 00C-Phenyl- N N CH C-OMe 01 No. lR 4

R

5 R3R 2 x Y Z Q A 1-149 COOH Phenyl 3,4-Methylenedioxyphenyl-CH2- 3-H 2 N-Phenyl- N N CH C-Me 0 IA150 COOH 4-F-Phenyl 3,4-Ethylenedioxyphenyl-CH27- 4-H 2 NOC-Phenyl- N N CH C-OMe 0 1-151 COOH Phnl3-Me-4-SMe-Phenyl-CH2-CH2- 3-(Acetyl-CH 2 )-Pheny1- N N CH C-Me s 1-152 COOH Phenyl Ethyl Benzyl N N CH C-Me s 1-153 COOH Phenyl Ethyl 4-OMe--Phenyl-0- N N CH C-OMe 0 1-454 COOH Phenyl 4-OMe-Phenyl- 2-Thienyl- N N CH C-Me 0 1-155 COOH 4-F-Phenyl 2-Naphthyl- 3-Furyl-- N N CHI C-OMe 0 1-156 COOH Phenyl 3,4-Di-Ci-Phenyl- 2-Pyrrolyl N N CHI G-OMe 0 IA157 COOH Phenyl 4-NC-Phenyl- 3-Me-2-Furyl N N ICH C-Me 0 1-158 COOH Phenyl 4--HO-Phenyl- 3-F 3 C-2-Thienyl N N CHI C-Et 0 1-159 COOII Phenyl Ethyl 4-F 3 C-Phenyl- N N CH C-OMe 0 1-160 COOH Phenyl Ethyl 3-Me--Phenyl-O- N N CH C-OMe 0 1-161 C0OH Phenyl Methyl 4-OM&-Phenyl N CHI N C-OMe s 1-162 CO0H Phenyl 3,5-Di-Me--Phenyl- 3-Tluienyl- N N N N(Me) 2 0 1-163 COOII Phenyl 3-H 2 N-Phenyl- 4-OMe-2-Furyl N N CHI C-OMe 0 1-164 C0OH Cyclohexyl 4-F 3 C-Phenyl- 4-Thiazolyl- N N CH C-ODMe 0 1-165 COOII Phenyl 3,4-Di-OMe-Phenyl- 5--Oxazolyl- N N jCHI C-Me 0 1-166 COOCH 3 2-F-Phenyl 4--CF 3 -OC)-Phenyl- 3-OMe-Phenyl N N CHI C-OMe 0 1-167 C00H Phenyl Methyl 3,4-OMe-Phenyl- N CH N C-OMe 0 1-168 C0OH Phenyl Methyl 4-Me-Phenyl- N CH N C-OMe 0 1-169 C00C 2 Hs 3-CI-Phenyl 3-SMe-4-OEt-Phenyl- 2-OMe -Phenyl N N CH C-CF 3 0 1-170 C0OH Phenyl 4-MeNH-Phenyl-- 2-Et-Phenyl- N N CII C-CF 2

CF

3 s No. R1R 4 9Rs' R3 R2x Y Z Q A 1-171 CQOCH 3 Phenyl 3,4-Methylenedioxyphenyl 3-Me-4-OMe-Phenyl- N N CH 0-OMe 0 1-1 72 COOC 2

H

5 Phenyl 3 ,4-Ethylenedioxyphenyl 3-Et-Phenyl N N CH C-Cl 0 1-173 COOH 3-CF 3 -Phenyl 2-Me--3-Furyl- 4-OMe--Cyclohexyl- N IN CH C-Me S 1-174 COOH Phenyl Methyl 3-Furyl-- N N CH CH 0 1-175 COOH Phenyl Methyl 4-i-Propyl- N IN CH C-Me 0 1-176 COOH Phenyl 2-Thienyl Cyclopropyl N N CH C-Me s 1-177 COOH Phenyl Methyl Cyclopentyl- N N CH C-OEt 0 1-178 COOH 4-CI-Phenyl Ethyl 3-Me-Cyclohexyl N N CH C-OMe 0 1-179 COOH Phenyl Ethyl 44i-Propyl-TPhenyl N N CH Vinyl 0 1-480 COOH Phenyl Ethyl IPhenyl- N N CH C-Me 0 V V V V V V V V V V *V V V V V V

V

V V V V *V *V 0 V V V V. *V *V Table II R x

I

0 R3 No. R R, R5 D R 3 R12 x IY Z Q A I,,COOH Phenyl Bond Methyl Phenyl N N CH G-OMe 0 11-2 COOH Phenyl Bond Methyl Phenyl- N N CH C-Me 0 113COOH Phenyl Bond Ethyl 4-OWe-Phenyl- N N CH C-OMe 0 11- C0OH Phenyl Bond. i-Propyl 34F-henyl-- N N CH C-OMe 0 Phenyl Bond CH 2 =CH-CH2- 4---opyl-Phenyl- N N CH COMe 0 11- COOH Phenyl Bond Methyl 4-F 3 C-Phenyt- N N CH 0-OMe 0 ]_7COOMa Phenyl Bond (CH 3 )C=H-CHr- 4-OMe--Phenyl- N N N C-Et 0 11- COGH Phenyl CH2 Methyl 4-OWe-Phenyl- N N CH CH 0 11- COOH Phenyl CH2 Methyl 4-0M6Phenyl-- N N CH C-CF 3 0 ][1-101 COOH Phenyl CH2 Cyclopentyl- 3,4-i-OWe-Phenyl- N N CH C-NHOMe 0 ]:I1 COOH Phenyl CH2 H0-CH 2 -CH2-- 3-Me-P henyl- N N CH C-SMe 0 1111COOH Phenyl CH2 CH 3 -CH(SH)-CH2 4-CFr-Phenyl- N N CH C-Et 0 11-113 COOH Phenyl CH2 Ethyl- 3-Me--Phenyl-- N N CH C-Me0 U1-14 COOH Phenyl CH2 HOOC-CH! 2 -CHz- -HPhylN N 0050/50031 37 Example 24: The binding assay described above was used to measure receptor binding data for the compounds listed below.

The results are shown in Table 2.

Table 2 Receptor binding data (Ki values) Compound ETA [nM] 1-180 83 I-102 130 I-109 133 1-23 1-147 14

JI~

37a Comprises/comprising and grammatical variations thereof when used in this specification are to be taken to specify the presence of stated features, integers, steps or components or groups thereof, but do not preclude the presence or addition of one or more other features, integers, steps, components or groups thereof.

t *oooo

Claims

1. A carboxylic acid derivative of the formula I R 4 I H X-Q R-A-C- C- 0- I Rl 5 1 Y I R R R R in which R 1 is tetrazolyl or a group 0 I C-R in which R has the following meaning: a) a radical OR 6 in which R 6 is: hydrogen, the cation of an alkali metal, the cation of an alkaline earth metal, a physiologically tolerated 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 may be substituted by one or more of the following radicals: halogen, nitro, cyano, C 1 -C 4 -alkyl, Cl-C 4 -haloalkyl, hydroxyl, C 1 -C 4 -alkoxy, mercapto, Cl-C 4 -alkylthio, amino, NH(C 1 -C 4 -alkyl), N(C 1 -C 4 -alkyl)2; A C 2 -C 6 -alkenyl or C 3 -C 6 -alkynyl group, it being possible for these groups in turn to carry one to five halogen atoms; R 6 can also be a phenyl radical which may 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, CI-C 4 -alkoxy, mercapto, C 1 -C 4 -alkylthio, amino, NH(C 1 -C 4 -alkyl), N(Cl-C 4 -alkyl)2; b) a 5-membered heteroaromatic system which is linked via a nitrogen atom, such as pyrrolyl, pyrazolyl, imidazolyl and triazolyl, which may 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; a~a c) a group (O)k 0- (CH 2 )p S R in which k assumes the values 0, 1 and 2, p assumes the values 1, 2, 3 and 4, and R 7 is Cl-C 4 -alkyl, C 3 -C8-cycloalkyl, 0 3 -0 6 -alkenyl, C 3 -C 6 -alkynyl or phenyl which may be substituted by one or more, for example one to three, of the following radicals: halogen, nitro, cyano, Cl-0 4 -alkyl, Cl-C 4 -haloalkyl, hydroxyl, CI-0 4 -alkoxy, Cl-C 4 -alkylthio, mercapto, amino, NH(0 1 -C 4 -alkyl), N(Cl-C 4 -alkyl) 2 d) a radical 0 N S R 8 H in which R 8 is: Cl-C 4 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 -C 8 -cycloalkyl, it being possible for these radicals to carry a 0 1 -C 4 -alkoxy, Cl-C 4 -alkylthio and/or a phenyl radical as mentioned under c); phenyl which may be substituted by one to three of the following radicals: halogen, nitro, cyano, Cl-G 4 -alkyl, Cl-0 4 -haloalkyl, hydroxyl, CI-C 4 -alkoxy, Cl-C 4 -alkylthio, mercapto, amino, NH(Cl-C 4 -alkyl), N(Cl-C 4 -alkyl) 2 R2 is phenyl or phenoxy, benzyl, benzyloxy, it being possible for all the aryl radicals to carry one to five halogen atoms and/or one to three of the following radicals: hydroxyl, mercapto, carboxyl, nitro, cyano, Cl-0 4 -alkyl, C 1 -C 4 -haloal kyl, Cl -C 4 -al koxy, C 3 -C 6 -al kenyloxy, C 3 -C 6 -al kynyloxy, 01-04- alkylthio, Cl-C 4 -haloalkoxy, 0 1 -C 4 -alkylcarbonyl, R 9 0 1 -0 4 -alkoxycarbonyl, (Cl-C 4 -alkyl)NHcarbonyl, (Cl-0 4 -alkyl) 2 Ncarbonyl, C 3 -C 8 -alkylcarbonylalkyl, amino NH(Cl-C 4 -alkyl), N(Cl-C 4 -alkyl) 2 phenoxy or phenyl, it being possible for said aryl radicals in turn to be substituted once to three times by halogen, Cl-C 4 -alkyl, Cl-0 4 -haloalkyl, C 1 -C 4 -alkoxy, Cl-C 4 -haloalkoxy, methylenedioxy, ethylenedioxy, Cl-C 4 -alkylthio; a five- or six-membered heteroaromatic system which contains 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: 0 1 -C 4 -alkyl, 0 1 -C 4 -haloalkyl, 0 1 -C 4 -alkoxy, Cl-0 4 -haloalkoxy, 01-04- 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: Cl-0 4 -alkyl, 0 1 -0 4 -haloalkyl, Cl-C 4 -alkoxy, Cl-C 4 -haloalkoxy and/or Cl-C 4 -alkylthio; 0 3 -C 8 -cycloalkyl which may carry one to three of the following radicals: Cj- C 4 -alkyl, Cl-C 4 -haloalkyl, Cl-C 4 -alkoxy, Cl-C 4 -haloalkoxy, Cl-C 4 -alkylthio; R R 3 is hydrogen; 01 -C 8 -al kyl, C 3 -C 6 -al kenyl, C 3 -C 6 -alkynyl or C 3 -C 8 -cycloalkyl, it being possible for each of these radicals to be substituted one or more times by: hydroxyl, mercapto, carboxyl, halogen, nitro, cyano, Cl-C 4 -alkoxy, 03-06- alkenyloxy, C 3 -C 6 -alkynyloxy, Cl-C 4 -alkylthio, Cl-C 4 -haloalkoxy, Cl-C 4 alkylcarbonyl, Cl-C 4 -alkoxycarbonyl, (Cl-C 4 -alkyl)NHcarbonyl, (Cl-C 4 VO alkyl) 2 -Ncarbonyl, C 3 -C 8 -alkylcarbonylalkyl, amino, NH(Cl-C 4 -alkyl), N(Cj- C 4 -alkyl) 2 phenoxy or phenyl, hetaryl, five- or six-membered, containing one to three nitrogen atoms and/or one sulfur or oxygen atom, it being possible for all said aryl and hetaryl radicals to be substituted once to three 41 times by: halogen, nitro, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, mercapto, carboxyl, hydroxyl, amino, R 9 0 1 -C 4 alkoxycarbonyl, NH(C1-C 4 -alkyl), N(C1-C 4 -alkyl) 2 methylenedioxy, ethylenedioxy, C 1 -C 4 -alkylthio, phenyl or phenoxy; or phenyl or naphthyl, each of which may be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, amino, C 1 -C 4 -alkyl, C-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(C1-C 4 -alkyl) 2 or methylenedioxy or ethylenedioxy; or a five- or six-membered heteroaromatic system which contains 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: 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-C 4 -alkoxy, C 1 -C 4 -haloalkoxy and/or C 1 -C 4 -alkylthio; R 4 and R 5 (which may be identical or different) are: phenyl or naphthyl, each of which may be substituted by one or more of O. the following radicals: halogen, nitro, cyano, hydroxyl, C 1 -C 4 -alkyl, C1-C4- haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, phenoxy, C 1 -C 4 -alkylthio, amino, NH(C1-C 4 -alkyl), N(Cl-C 4 -alkyl) 2 or phenyl or naphthyl which are connected together in ortho positions by a direct linkage, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an SO 2 NH or N-alkyl group; or C 3 -C 7 -cycloalkyl; X and Y (which can be identical or different) are: nitrogen or methine; with the proviso that if X Y methine then Z nitrogen; l~a rrsn~i--- Z is nitrogen or CR 1 0 0 is nitrogen or CR 11 with the proviso that if X Y Z nitrogen then Z= CR 11 R 1 0 is hydrogen, halogen, hydroxyl, NH 2 NH(Cl-C 4 -alkyl), N(Cl-C 4 -alkyl) 2 Cl- C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, Cl-C 4 -hydroxyalkyl, Cl-C 4 -haloalkyl, Cl-C 4 -alkoxy, Cl-C 4 -haloalkoxy or Cl-C 4 -alkylthio, or CR 1 0 forms together with CR 1 1 a 5- or 6-membered alkylene or alkenylene ring which may be substituted by one or two Cl-C 4 -alkyl groups and in which in case one or more methylene groups can be replaced by oxygen, sulfur, -NH or -N(Cli- C 4 -alkyl); or phenyl which may carry one to three of the following radicals: Cl-C 4 -alkyl, Cl-C 4 -haloalkyl, Cl-C 4 -alkoxy, Cl-C 4 -haloalkoxy, Cl-C 4 -alkylthio; R 1 1 is hydrogen, hydroxyl, NH 2 NH(Cl-C 4 -alkyl), N(Cl-C 4 -alkyl) 2 halogen, C 1 C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, C 3 -C 6 -al kenyloxy, C 1 -04- alkylcarbonyl, Cl-C 4 -alkoxycarbonyl, Cl-C 4 -hydroxyalkyl, Cl-C 4 -haloalkyl, Cl-C 4 -alkoxy, C 1 -C 4 -haloalkoxy, -NH-O-Cl-C 4 -alkyl, Cl-C 4 -alkylthio, C 3 -C 8 :::.cycloalkyl or CR 11 forms, as indicated under R 10 together with CR 1 0 a 5- or **:6-membered ring; phenyl or phenoxy, each of which may carry one to five halogen atoms :and/or one to three of the following radicals: hydroxyl, mercapto, carboxyl, nitro, cyano, Cl-C 4 -alkyl, C 1 -C 4 -haloalkyl, Cl-C 4 -alkoxy, C 3 -C 6 -alkenyloxy, C3-C 6 -alkynyloxy, C 1 -C 4 -alkylthio, Cl-C 4 -haloalkoxy, Cl-C 4 -alkylcarbonyl, R 9 Cl-C 4 -alkoxycarbonyl, (Cl-C 4 -alkyl)NHcarbonyl, (C 1 -C 4 ~*.alkyl) 2 Ncarbonyl, C 3 -C 8 -alkylcarbonylalkyl, amino, NH(Cl-C 4 -alkyl), N(Cj- C 4 -alkyl) 2 phenoxy or phenyl, it being possible for said aryl radicals in turn to be substituted once to three times by halogen, Cl-C 4 -alkyl, C1-C 4 haloalkyl, Cl-C 4 -alkoxy, Cl-C 4 -haloalkoxy, methylenedioxy, ethylenedioxy, :C1-C4-alkylthio; or S a five- or six-membered heteroaromatic system which contains 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: C 1 -C 4 -alkyl, C1-C 4 -haloalkyl, C 1 -C 4 -alkoxy, C1-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: Ci-C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, Ci-C 4 -haloalkoxy and/or C 1 -C 4 -alkylthio; A is sulfur or oxygen; and the physiologically tolerated salts, and the enantiomerically pure and diastereomerically pure forms.

2. The use of a carboxylic acid derivative I as claimed in claim 1 for treating diseases.

3. The use of a compound I as claimed in claim 1 as endothelin receptor antagonist.

4. The use of a carboxylic acid derivative I as claimed in claim 1 for producing drugs for treating diseases in which elevated endothelin levels occur.

5. The use of a carboxylic acid derivative I as claimed in claimi for producing drugs for treating diseases in which endothelin contributes to the development and/or progression.

6. The use of a carboxylic acid derivative I as claimed in claim 1 for the treatment of chronic heart failure, restenosis, high blood pressure, pulmonary hypertension, acute/chronic kidney failure, cerebral ischemia, asthma, benign prostate hyperplasia and prostate cancer. *o 'i 7. A combination of a carboxylic acid derivative of the formula I as claimed in claim 1 and one or more active ingredients selected from inhibitors of the renin- hr~~ u n~ 44 angiotensin system such as renin inhibitors, angiotensin II antagonists, angiotensin converting enzyme (ACE) inhibitors, mixed ACE/neutral endopeptidase (NEP) inhibitors, p blockers, diuretics, calcium channel blockers and VEGF-blocking substances.

8. A pharmaceutical preparation for oral, parenteral or intraperitoneal use, comprising at least one carboxylic acid derivative I as claimed in claim 1, per single dose, in addition to conventional pharmaceutical excipients.

9. A method of treatment of diseases in which elevated endothelin levels occur, comprising administering to a patient in need of such treatment an efficacious amount of a derivative as claimed in claim 1, a combination as claimed in claim 7 or a preparation as claimed in claim 8. A method of treatment of diseases in which endothelin contributes to the development and/or progression, comprising administering to a patient in need of such treatment an efficacious amount of a derivative as claimed in claim 1, a combination as claimed in claim 7 or a preparation as claimed in claim 8.

11. A method of treatment of chronic heart failure, restenosis, high blood pressure, pulmonary hypertension, acute/chronic kidney failure, cerebral ischemia, asthma, benign prostate hyperplasia and prostate cancer, comprising administering to a patient in need of such treatment an efficacious amount of a derivative as claimed in claim 1, a combination as claimed in claim 7 or a preparation as claimed in claim 8.

12. A derivative as claimed in claim 1 substantially as hereinbefore described with reference to any one of the examples.

13. The use as claimed in any one of claims 2 to 6 substantially as hereinbefore described with reference to any one of the examples.

14. A combination as claimed in claim 7 substantially as hereinbefore described with reference to any one of the examples. A preparation as claimed in claim 8 substantially as hereinbefore described with reference to any one of the examples. DATED this 22 nd day of July, 2003 BASF AKTIENGESELLSCHAFT WATERMARK PATENT TRADE MARK ATTORNEYS 290 BURWOOD ROAD HAWTHORN VICTORIA 3122 AUSTRALIA P20619AU00 CJH/EXE/SIG S 6** 6* li;