AU748610B2

AU748610B2 - Novel carboxylic acid derivatives, their production and their their use as mixed ETa/ETb endothelin-receptor antagonists

Info

Publication number: AU748610B2
Application number: AU95333/98A
Authority: AU
Inventors: Wilhelm Amberg; Stefan Hergenroder; Rolf Jansen; Dagmar Klinge; Manfred Raschack; Hartmut Riechers; Liliane Unger
Original assignee: BASF SE
Current assignee: BASF SE
Priority date: 1997-09-04
Filing date: 1998-08-24
Publication date: 2002-06-06
Anticipated expiration: 2018-08-24
Also published as: HUP0004935A3; TW546295B; WO1999011629A1; EP1009741A1; BG104222A; SK1522000A3; JP2001514254A; PL338954A1; CO4970738A1; KR20010023615A; NZ502660A; HUP0004935A2; NO20001077L; AU9533398A; BR9811631A; CN1269792A; IL134276A0; ID25620A; AR017052A1; CA2302350A1

Description

0050/48312 Novel carboxylic acid derivatives, their preparation and use as mixed ETA/ETB receptor antagonists The present invention relates to novel carboxylic acid derivatives, their preparation and use.

Endothelin is a peptide which is composed of 21 amino acids and is synthesized and released by vascular endothelium. Endothelin exists in three isoforms, ET-1, ET-2 and ET-3. "Endothelin" or "ET" hereinafter refers to one or all isoforms of endothelin.

Endothelin is a potent vasoconstrictor and has a strong effect on 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 persistent vasoconstriction in peripheral, renal and cerebral blood vessels, which may lead to disorders. It is reported in the literature that endothelin is involved in a number of disorders. These include: hypertension, acute myocardial infarct, pulmonary hypertension, Raynaud's syndrome, cerebral vasospasms, stroke, benign prostate hypertrophy, atherosclerosis and asthma Vascular Med. Biology 2 (1990) 207, J. Am. Med. Association 264 (1990) 2868, Nature 344 (1990) 114, N. eg.. J. Med. 322 (1989) 205, N. eg.. 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).

The literature at present describes at least two subtypes of endothelin receptors, ETA and ETB receptors, (Nature 348 (1990) 730 and 732). According to this, substances which inhibit the binding of endothelin to the two receptors ought to antagonize the physiological effects of endothelin and therefore represent valuable drugs.

WO 96/11914 describes carboxylic acid derivatives which, however, bind with high affinity to the ETA receptor and with a considerably lower affinity to the ETB receptor (called ETA-specific antagonists).

We refer here to antagonists as ETA-specific when their affinity for the ETA receptor is at least ten times higher than their affinity for the ETB receptor.

SIt is an object of the present invention to provide endothelin 0050/48312 2 receptor antagonists which bind with roughly the same affinity to the ETA and the ETB receptors (called mixed antagonists).

Roughly the same affinity for the receptors means that the ratio of the affinities is greater than 0.1 and less than The invention relates to carboxylic acid derivatives of the formula I carboxylic acid derivatives of the formula I [sic] R4 R6-Z-C-CH- 0--Het I I

I

B R where the substituents have the following meanings: R is tetrazole [sic] or a group 0

SC-R

1

R

1 is a radical OR 7 in which R 7 is: hydrogen, the cation of an alkali metal, the cation of an alkaline earth metal or a physiologically tolerated organic ammonium ion;

C

3 -Cs-cycloalkyl, Ci-C 8 -alkyl,

CH

2 -phenyl, unsubstituted or substituted,

C

3

-C

6 -alkenyl or a C 3

-C

6 -alkynyl group, unsubstituted or substituted, or phenyl, unsubstituted or substituted,

R

2 is hydrogen, hydroxyl, NH 2

NH(C

1

-C

4 -alkyl), N(C 1

-C

4 -alkyl) 2 halogen, C 1

-C

4 -alkyl, C 2

-C

4 -alkenyl, C 2

-C

4 -alkynyl, Ci-C 4 -haloalkyl, Ci-C 4 -alkoxy, C 1

-C

4 -haloalkoxy or Ci-C 4 -alkylthio, or CR 2 is linked to CR 10 as indicated below to give a 5- or 6-membered ring, or, if Het is a five-membered ring, CR 2 can together with CR 3 be a 5- or S 6-membered alkenyl or alkylenyl [sic] ring which is 0050/48312 3 unsubstituted or substituted; X is nitrogen or methine; Y is nitrogen or methine; W is nitrogen or CR' 0 where R1 0 is hydrogen or Cl..

4 -alkyl, or CR'O forms together with CR 2 or CR 3 a 5- or 6-membered alkylene or alkenylene ring which is unsubstituted or substituted and in which in each case one or more methylene groups can be replaced by oxygen, sulfur, -NH or

-N(C..C

4 alkyl);

R

3 is 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, C,1-C 4 -haloalkyl, Cl-C 4 -alkoxy, Cl..C 4 -haloalkoxy, Cl-C 4 -alkylthio; or CR 3 is Linked to CR'O as indicated above to give a 5- or 6-membered ring;

R

4 and R 5 (which may be identical or different) are: phenyl or naphthyl, unsubstituted or substituted, or phenyl or naphthyl which are linked together in the 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

C

3

-C

8 -cycloalkyl, unsubstituted or substituted;

R

6 is hydrogen, Cl-C 8 -alkyl, C 3

-C

8 -alkenyl or C 3

-C

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

-C

6 -alkenyloxy,

C

3

-C

6 -alkynyloxy, Cl-C 4 -alkylthio, Cl-C 4 -haloalkoxy, Cl-C 4 -alkylcarbonyl, Cl-C 4 -alkoxycarbonyl,

C

3 8 -alkylcarbonylalkyl, NH(Cl-C 4 -alkyl), N(Cl-C 4 -alkyl) 2

C

3 -CB-cycloalkyl, hetaryloxy or hetaryl, five- or six-memibered, containing one to three nitrogen atoms and/or one sulfur or oxygen atom, phenoxy or phenyl, it being possible for said aryl radicals in turn to be substitued one or more times, eg. one to three times, by halogen, hydroxyl, mercapto, carboxyl, nitro, cyano, Cl-C 4 -alkyl, Cl-C 4 -haloalkyl, Cl-C 4 -alkoxy, Cl-C 4 -haloalkoxy, amino,

NH(C

1

-C

4 -alkyl), N(Cl-C 4 -alkyl) 2 or Cl-C 4 -alkylthio; phenyl or naphthyl, each of which can be substituted by one 0050/48312 4 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, Ci-C 4 -dialkylamino, dioxomethylene [sic] or dioxoethylene [sic]; a five- or six-membered heteroaromatic system comprising one to three nitrogen atoms and/or one sulfur or oxygen atom, which may carry one to four halogen atoms and/or one to two of the following radicals: Ci-C 4 -alkyl, Ci-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 Ci-C 4 -alkylthio;

C

3 -Cs-cycloalkyl, it being possible for these radicals to be substituted one or more times 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 -alkoxy, C 1

-C

4 -alkylthio, Ci-C 4 -haloalkoxy; Z is sulfur or oxygen; B is C 2

-C

4 -alkylene Het is a heterocyclic radical of the formula Ia or Ib

R

2 N R2 T R3 R3 Ia Ib with T O, S, NR 8

R

8 is C 1

-C

6 -alkyl and the physiologically tolerated salts and the enantiomerically pure forms.

In this connection and hereinafter, the following definitions apply: An alkali metal is, for example, lithium, sodium, potassium; 0050/48312 An alkaline earth metal is, for example, calcium, magnesium, barium;

C

3 -CB-cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl oder cyclooctyl; Cl-C 4 -haloalkyl can be linear or branched, such as f luoromethyl, difluoromethyl, trifluoromethyl, chiorodifluoromethyl, dichiorofluoromethyl, 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 pentafluoroethyl; Cl-C 4 -haloalkoxy can be linear or branched, such as difluoromethoxy, trifluoromethody, chiorodifluoromethoxy, 1-f luoroethoxy, 2 ,2-difluoroethoxy, 1,1, 2,2-tetrafluoroethoxy, 2,2, 2-trifluoroethoxy, 2-chloro-l, 1,2-trifluoroethoxy, 2 -fluoroethoxy or pentafluoroethoxy;

CI-C

4 -alkyl can be linear or branched, such as 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 be linear or branched, such as ethenyl, 1-propen-3-yl, 1-propen-2-yl, I-propen-I-yl, 2-methyl-1-propenyl, 1-butenyl or 2-butenyl;

C

2

-C

4 -alkynyl can be linear or branched, such as 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 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 allyloxy, 2-buten-1-yloxy or 3-buten-2-yloxy;

C

3

-C

6 -alkynyloxy can be linear or branched, such as 2-propyn- 1-yloxy, 2-butyn-1-yloxy or 3-butyn-2-yloxy; Cl-C 4 -alkylthio can be linear or branched, such as methylthio, ethylthio, propylthio, 1-methylethylthio, butylthio, 1-methylpropylthio, 2-methylpropylthio or 1, 1-dimethylethylthio; Cl-C 4 -alkylcarbonyl can be linear or branched, such as acetyl, ethylcarbonyl or 2-propylcarbonyl; 0050/48312 6 Ci-C 4 -alkoxycarbonyl can be linear or branched, such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl or n-butoxycarbonyl;

C

3

-C

8 -alkylcarbonylalkyl can be linear or branched, for example 2-oxo-l-propyl, 3-oxo-l-butyl or 3-oxo-2-butyl

C

1

-C

8 -alkyl can be linear or branched, such as Ci-C 4 -alkyl, pentyl, hexyl, heptyl or octyl; halogen ist, for example, fluorine, chlorine, bromine, iodine.

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

Preferred prodrugs are those where the release takes place under conditions like those prevailing in certain compartments of the body, eg. in the stomach, intestine, bloodstream, liver.

The compounds and the intermediates for preparing them, such as II, III and IV, may have one or more asymmetrically substituted carbon atoms. Compounds of this type may exist as pure enantiomers or pure diastereomers or as mixtures thereof. It is preferred to use an enantiomerically pure compound as active ingredient.

The invention further relates to the use of the abovementioned carboxylic acid derivatives for producing drugs, in particular for producing inhibitors of ETA and ETB receptors. The compounds according to the invention are particularly suitable as mixed antagonists as defined at the outset.

Compounds with the formula IV where Z is sulfur or oxygen can be prepared, also in enantiomerically pure form, as described in WO 96/11914.

R4 0 RR4 C R 6 Z- H R 6

-Z--C-CH--OH

B B R R II III IV R Compounds of the 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.

0050/48312 7 The compounds according to the invention where the substituents have the meanings stated under formula I can be prepared, for example, by reacting the carboxylic acid derivatives of the formula IV, where the substituents have the stated meaning, with compounds of the formula V.

IV R 11 Het I

V

R

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

C

1

-C

4 -alkyl, C 1

-C

4 -haloalkyl or phenyl. In addition, at least one of the ring members X or Y or Z is nitrogen. The reaction preferably takes place in an inert solvent or diluent with the addition of a suitable base, i.e. of a base which deprotonates the intermediate IV, at a temperature in the range from room temperature to the boiling point of the solvent.

Compounds of type I with R COOH can furthermore be obtained directly when the intermediate IV where R is COOH is deprotonated with two equivalents of a suitable base and reacted with compounds of the 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 and diluents are aliphatic, alicyclic and aromatic hydrocarbons, each of which may be chlorinated, such as hexane, cyclohexane, petroleum ether, naphtha, benzene, toluene, xylene, methylene chloride, chloroform, carbon tetrachloride, ethyl chloride and trichloroethylene, ethers such as diisopropyl ether, dibutyl ether, methyl tert-butyl ether, propylene oxide, dioxane and tetrahydrofuran, nitriles such as acetonitrile and propionitrile, amides such as dimethylformamide, dimethylacetamide and N-methylpyrrolidone, sulfoxides and sulfones such as dimethyl sulfoxide and sulfolane.

Compounds of the formula V are known or, in some cases, can be bought or 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, 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.

UUVU/ VV/J.L 8 Compounds of the formula I can also be prepared by starting from the corresponding carboxylic acids, i.e. compounds of the formula I where R 1 is COOH, and converting them initially in a conventional way into an activated form, such as an acid halide, anhydride or imidazolide, and then reacting the latter with an appropriate hydroxyl compound HOR 7 This reaction can be carried out in conventional solvents and often requires addition of a base, in which case those mentioned above are suitable. These two steps can, for example, also be simplified by allowing the carboxylic acid to act on the hydroxyl compound in the presence of a dehydrating agent such as a carbodiimide.

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

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

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

R

1

COOR

7 in which R 7 is: hydrogen, the cation of an alkali metal, the cation of an alkaline earth metal or a physiologically tolerated organic ammonium ion; C3-C 8 -cycloalkyl, C 1

-C

8 -alkyl,

CH

2 -phenyl, unsubstituted or substituted, C3-C 6 -alkenyl or a C 3

-C

6 -alkynyl group, unsubstituted or substituted, or phenyl, unsubstituted or substituted. [sic] VUU7UWiJLA 9

R

2 hydrogen, hydroxyl, halogen, N(C 1

-C

4 -alkyl) 2 Cl-C 4 -alkyl, Cl-C 4 -alkoxy, Cl-C 4 -alkylthio, Cl-C 4 -haloalkyl, Cl-C 4 -haloalkoxy, or CR 2 is linked to CR10 as indicated below to form a 5- or 6-membered ring, or, if Het is a five-membered ring, CR 2 can together with CR 3 be a 5- or 6-membered alkenyl or alkylenyl [sic] ring which is unsubstituted or substituted; X nitrogen or methine; Y nitrogen or methine; W nitrogen or CR' 0 where RIO is hydrogen or 4 -alkyl, or CR'O forms together with CR 2 or CR 3 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 a methylene group can be replaced by oxygen or sulfur, such as -CH 2

-CH

2

-CH

2

-CH

2

-CH

2 -CH=CH-O-, -CH=CH-CH 2 -CH (CH 3 )-CH (CH 3

-CH=C(CH

3

-C(CH

3

)=C(CH

3 or -C(CH 3

)=C(CH

3 At least one of the ring members X, Y or W is nitrogen.

R

3 hydrogen, hydroxyl, halogen, N(Cl-C 4 -alkyl) 2 Cl-C 4 -alkyl, Cl-C 4 -alkoxy, Cl-C 4 -alkylthio, Cl-C 4 -haloalkyl, Cl-C 4 -haloalkoxy, or CR 3 is linked to CR' 0 as indicated above to give a 5- or 6-membered ring, or, if Het is a five-membered ring, CR 2 can together with CR 3 be a 5- or 6-membered alkenyl or alkylenyl [sic] ring which is unsubstituted or substituted;

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, mercapto, amino, Cl-C 4 -alkyl, Cl-C 4 -haloalkyl, Cl-C 4 -alkoxy, Cl-C 4 -haloalkoxy, phenoxy, Cl-C 4 -alkylthio, NH(Cl-C 4 -alkyl) or N(Cl-C 4 -alkyl) 2 or phenyl which may be substituted one or more times, eg. one to three times, by halogen, nitro, cyano, Cl-C 4 -alkyl, Cl-C 4 -haloalkyl, Cl-C 4 -alkoxy, Cl-C 4 -haloalkoxy or Cl-C 4 -alkylthio; 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 S0 2 NH or N-alkyl group C3-C 8 -cycloalkyl; VU2VfC4&zJ.

R

6

C

3 -CB-cycloalkyl, it being possible for these radicals to be substituted one or more times by: halogen, hydroxyl, mercapto, carboxyl, nitro, cyano, Cl-C 4 alkoxy, Cl-C 4 -alkyl,

C

2

-C

4 -alkenyl, C 2

-C

4 -alkynyl, C 3

-C

6 -alkenyloxy,

C

3

-C

6 -alkynyloxy, Cl-C 4 alkylthio, Cl-C 4 -haloalkoxy, Cl-C 4 -alkylcarbonyl, Cl-C 4 -alkoxycarbonyl, NH(Cl-C 4 -alkyl), N(Cl-C 4 -alkyl) 2 or phenyl which can be substituted one or more times, for example one to three times, by halogen, nitro, cyano, Cl-C 4 -alkyl, Cl-C 4 -haloalkyl, Cl-C 4 -alkoxy, Cl-C 4 -haloalkoxy or Cl-C 4 -alkylthio; phenyl or naphthyl, each of which can be substituted by one or more of the following radicals: halogen, nitro, mercapto, carboxyl, cyano, hydroxyl, amino, Cl-C 4 -alkyl, C 2

-C

4 -alkenyl,

C

2

-C

4 -alkynyl, C 3

-C

6 -alkenyloxy, Cl-C 4 -haloalkyl,

C

3

-C

6 -alkynyloxy, Cl-C 4 -alkylcarbonyl, Cl-C 4 -alkoxycarbonyl, Cl-C 4 -alkoxy, Cl-C 4 -haloalkoxy, phenoxy, Cl-C 4 -alkylthio,

NH(C-C

4 -alkyl), N(Cl-C 4 -alkyl) 2 dioxomethylene [sic], dioxoethylene [sic] or phenyl which may be substituted one or more times, eg. one to three times, by halogen, nitro, cyano, Cl-C 4 -alkyl, Cl-C 4 -haloalkyl, Cl-C 4 -alkoxy, Cl-C 4 -haloalkoxy or Cl-C 4 -alkylthio; a five- or six-membered heteroaromatic system comprising one to three nitrogen atoms and/or one sulfur or oxygen atom, 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; Z sulfur or oxygen; B C 2

-C

4 alkylene Het a heterocyclic group of the formula Ia or lb with T 0, S.

Particularly preferred compounds of the formula I, both as pure enantiomers and pure diastereomers and as mixture thereof, are those where the substituents have the following meanings: R' COOH; X,Y N; 0050/43312 W CR 10

R

2

,R

3 hydrogen, hydroxyl, NH 2

NH(C

1

-C

4 -alkyl), N(Cl-C 4 -alkyl) 2 halogen, Cl-C 4 -alkyl, C 2

-C

4 -alkenyl, C 2

-C

4 -alkynyl, Cj-C 4 -haloalkyl, Cl-C 4 -alkoxy, Cl-C 4 -haloalkoxy or Cl-C 4 -alkylthio, or CR 2 is linked to CR 10 as indicated below to give a 5- or 6-membered ring, or, if Het is a five-membered ring, CR 2 can together with CR 3 be a 5- or 6-membered alkylene or alkylenyl [sic] ring which is unsubstituted or substituted;

R

4 phenyl which may be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, mercapto, amino, Cl-C 4 -alkyl, Cl-C 4 -haloalkyl, Cl-C 4 -alkoxy, Cl-C 4 -haloalkoxy, phenoxy, Cl-C 4 -alkylthio, NH(Cl-C 4 -alkyl) or N(Cl-C 4 -alkyl) 2 or phenyl which may be substituted one or more times, eg. one to three times, by halogen, nitro, cyano, Cl-C 4 -alkyl, Cl-C 4 -haloalkyl, Cl-C 4 -alkoxy, Cl-C 4 -haloalkoxy or Cl-C 4 -alkylthio; or

R

5 phenyl or 3,4-dimethoxyphenyl

R

6

C

5

-C

7 -cycloalkyl, it being possible for these radicals in each case to be substituted one or more times by: Cl-C 4 -alkoxy, Cl-C 4 -alkyl, Cl-C 4 -alkylthio, halogen, hydroxyl, carboxyl, cyano, trifluoromethyl, acetyl, or phenyl which may be substituted one or more times, eg. one to three times, by halogen, cyano, Cl-C 4 -alkyl, Cl-C 4 -haloalkyl, Cl-C 4 -alkoxy, Cl-C 4 -haloalkoxy or Cl-C 4 -alkylthio; phenyl or naphthyl, each of which may be substituted by one or more of the following radicals: halogen, nitro, mercapto, carboxyl, cyano, hydroxyl, amino, Cl-C 4 -alkyl, Cl-C 4 -haloalkyl, acetyl, Cl-C 4 -alkoxycarbonyl, Cl-C 4 -alkoxy, Cl-C 4 -haloalkoxy, phenoxy, Cl-C 4 -alkylthio, NH(Cl-C 4 -alkyl), N(Cl-C 4 -alkyl) 2 dioxomethylene [sic], dioxoethylene [sic] or phenyl which may be substituted one or more times, eg. one to three times, by halogen, nitro, cyano, CI-C 4 -alkyl, Cl-C 4 -haloalkyl, CI-C 4 -alkoxy, Cl-C 4 -haloalkoxy or Cl-C 4 -alkylthio; a five- or six-membered heteroaromatic system comprising one to three nitrogen atoms and/or one sulfur or oxygen atom, 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, trifluoromethoxy, Cl-C 4 -alkylthio, phenyl or phenoxy, it being possible for the phenyl radicals in turn to carry one to five halogen atoms and/or one to three of the UU3U/5jj.1L 12 following radicals: C 1

-C

4 -alkyl, C 1

-C

4 -haloalkyl, C1-C 4 -alkoxy, Ci-C 4 -haloalkoxy and/or C 1

-C

4 -alkylthio; Z sulfur or oxygen; B C 3 -alkylene Het Ia with R 2 and R 3 methyl and T O, S.

The compounds of the present invention provide a novel therapeutic potential for treating hypertension, pulmonary hypertension, myocardial infarct, angina pectoris, acute/chronic kidney failure, renal insufficiency, cerebral vasospasms, cerebral ischemia, subarachnoid hemorrhages, migraine, asthma, atherosclerosis, endotoxic shock, endotoxin-induced organ failure, intravascular coagulation, restenosis after angioplasty, benign prostate hypoplasia, ischemic and intoxication-induced kidney failure and hypotension, metastasis and growth of mesenchymal tumors, contrast agent-induced kidney failure, pancreatitis, gastrointestinal ulcers.

The invention further relates to combination products comprising endothelin receptor antagonists of the formula I and inhibitors of the renin-angiotensin system. Inhibitors of the reninangiotensin system are renin inhibitors, angiotensin II antagonists and, in particular, angiotensin converting enzyme (ACE) inhibitors.

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 ETB 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 Vg/ml streptomycin (Gibco, [sic] Sigma No. P-0781). After 48 hours, the UUU/4UJ1Z 13 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 collection of the cells by centrifugation at 300 x g.

For the membrane preparation, the cells were adjusted to a concentration of 108 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] Binding assays For the ETA and ETB receptor binding assays, the membranes were suspended in the incubation buffer (50 mM tris-HCl, pH 7.4 with 5 mM MnC12, 40 pg/ml bacitracin and 0.2% BSA) in a concentration of 50 Rg of protein per assay mixture and incubated at 25 0 C with pM [1251 [sic]]-ET 1 (ETA receptor assay) or 25 pM [1251 [sic]]-ET 3 (ETB receptor assay) in the presence and absence of a test substance. The nonspecific binding was determined with 10- 7

M

ET

1 After 30 min, filtration through GF/B glass fiber filters (Whatman, England) in a Skatron cell collector (Skatron, Lier, Norway) separated free from bound radioligand, 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.

Tests on the 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 cathetized [sic].

Intravenous administration of 1 [g/kg ET1 to control animals led to a distinct rise in blood pressure which persisted for a lengthy period.

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

Oral testing of the mixed ETA and ETB antagonists: Male normotensive rats (Sprague Dawley, Janvier) weighing 250-350 g are pretreated orally with the test substances.

minutes later, the animals are anesthetized with urethane, and the carotid artery (for measuring the blood pressure) and the

UUDU/QUSIZ

14 jugular vein (administration of big endothelin/endothelin 1) are catheterized.

After a stabilization period, big endothelin (20 g/kg, volume administered 0.5 ml/kg) or ET1 (0.3 Rg/kg, volume administered ml/kg) is given intravenously. The blood pressure and heart rate are recorded continuously for 30 minutes. The pronounced and long-lasting changes in blood pressure are calculated as area under the curve (AUC). To determine the antagonistic effect of the test substances, the AUC for animals treated with the substance is compared with the AUC for the control animals.

The compounds according to the invention can be administered orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperotoneally [sic]) 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 about 0.5-50 mg/kg of bodyweight on oral administration and about 0.1-10 mg/kg of bodyweight on parenteral administration.

The novel compounds can be used in conventional solid or liquid pharmaceutical forms, eg. as uncoated or (film-)coated tablets, capsules, powders, granules, suppositories, solutions, ointments, creams or sprays. These are produced in a conventional way. The active ingredients can for this purpose be processed with conventional pharmaceutical auxiliaries 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 forms obtained in this way normally contain from 0.1 to 90% by weight of active ingredient.

Synthesis examples Example 1: Methyl 2,3-epoxy-3,6-diphenylhexanoate 1.4 g (31 mmol) of 50% sodium hydride were added in portions over the course of 8 hours to a soluton of 4 g (17.8 mmol) of 1,4-diphenyl-l-butanone and 2.7 ml (31 mmol) of methyl UU3U/% 0J.z chloroacetate in 60 ml of THF. After the ketone had completely reacted, the reaction mixture was added to ice-water and extracted ether. The organic phase was dried over magnesium sulfate and, after the solvent had been distilled off, it was possible to isolate 5.5 g of an oil which was reacted further.

Example 2: Methyl 2-hydroxy-3-methoxy-3,6-diphenylhexanoate 2 g (6.75 mmol) of methyl 2,3-epoxy-3,6-diphenylhexanoate were introduced with 0.5 ml of methanol into 20 ml of dichloromethane, and 5 drops of boron trifluoride etherate were added. After 2 hours, the mixture was concentrated and the residue was purified by MPLC (cyclohexane/ethyl acetate gradient) to isolate 530 mg of one diastereomer, 720 mg of the second diastereomer and 800 mg of a mixed fraction.

Example 3: 2-Hydroxy-3-methoxy-3,6-diphenylhexanoic acid (one diastereomer, stereochemistry unknown) The second diastereomer (720 mg, 2.2 mmol) was dissolved in 9 ml of dioxane, and 4.5 ml of IN sodium hydroxide solution were added. The mixture was stirred for 16 hours and then, after addition of water, extracted with ether. The aqueous phase was acidified with citric acid and extracted with ether, the organic phase was dried with [sic] over magnesium sulfate, and the solvent was distilled off. 936 mg of an oil were isolated and were immediately reacted further.

Example 4: 2-(4-Methoxy-6-methyl-2-pyrimidinyloxy)-3-methoxy-3,6-diphenylhexanoic acid (one diastereomer) 195 mg (4.4 mmol) of 50% sodium hydride, 465 mg (1.5 mmol) of 2-hydroxy-3-methoxy-3,6-diphenylhexanoic acid and 291 mg (1.5 mmol) of 3,4-dimethyl-2-methylsulfonepyrimidine [sic] were mixed in 20 ml of DMF and stirred at room temperature for 2 hours. The reaction mixture was added to 100 ml of ice-water, acidified with citric acid and extracted with ether. The organic phase was dried with magnesium sulfate, and the solvent was distilled off. The residue was purified by MPLC (cyclohexane/ ethyl acetate gradient) to isolate 103 mg of one diastereomer.

1H-NMR (200 MHz, CDC13): 7.1-7.5 ppm (10 H, 6.2 (1 H, 5.6 (1 H, 3.8 (3 H, 3.3 (3 H, 2.5-2.8 (3 H, 2.3 (3 H, 2.0 (1 H, 1.5-1.8 (2 H, m).

ESI MS: M+ 436 Example Methyl 2,3-epoxy-3-phenyl-6-(3,4-methoxyphenyl)hexanoate [sic] (mixture of diastereomers): 12.6 g (44 mmol) of l-phenyl-4-(3,4-dimethoxy)phenyl-l-butanone [sic] were dissolved together with 8.3 g of methyl chloroacetate in 50 ml of DMF and, at room temperature, 3.7 g of 50% sodium hydride suspension were added in portions over the course of 1 hour. Reaction of the precursor was complete after a total of hours, and the reaction solution was added to 300 ml of ice-water. The aqueous phase was acidified with citric acid and extracted several times with ether, and the organic phase was separated off, washed and dried over magnesium sulfate. The solvent was distilled off to isolate 13 g of an oil which could be immediately reacted further.

Example 6: Methyl 2-hydroxy-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3-phenyl- 6-(3,4-dimethoxyphenyl)hexanoate A mixture of 3.6 g (10 mmol) of methyl 2,3-epoxy-3-phenyl- 6-(3,4-methoxyphenyl)hexanoate [sic], 1.8 g (10 mmol) of 2-(3,4-dimethoxy)ethanol [sic] and 100 mg of p-toluenesulfonic acid in 50 ml of dichloromethane was stirred for one hour while cooling in ice. The reaction solution was added to a saturated sodium bicarbonate solution, and the organic phase was separated off and dried over magnesium sulfate. The solvent was distilled off, and 4.7 g of residue was purified by MPLC (gradient: cyclohexane/ethyl acetate) to isolate 750 mg of a mixture of diastereomers.

Example 7: 2-Hydroxy-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3-phenyl- 6-(3,4-dimethoxyphenyl)hexanoic acid 2.1 ml of IN sodium hydroxide solution were added to 750 mg (1.4 mmol) of methyl 2-hydroxy-3-(2-(3,4-dimethoxyphenyl)ethoxy)- 3-phenyl-6-(3,4-dimethoxyphenyl)hexanoate dissolved in 4.2 ml of 0050/48312 17 dioxane, and the mixture was stirred at room temperature for 16 hours. 100 ml of water were added to the mixture, which was then extracted with ether. It was subsequently neutralized with hydrochloric acid, the aqueous phase was extracted with ether, the ether phase was dried with magnesium sulfate, and the solvent was distilled off. 620 mg of an oil were isolated and were immediately employed further.

Example 8: 2-(4,6-Dimethyl-2-pyrimidinyloxy)-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3-phenyl-6-(3,4-dimethoxyphenyl)hexanoic acid 164 mg (3.42 mmol) of sodium hydride, 600 mg (1.14 mmol) of 2-hydroxy-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3-phenyl- 6-(3,4-dimethoxyphenyl)hexanoic acid and 223 mg (1.2 mmol) of 3,4-dimethyl-2-methylsulfonepyrimidine [sic] were mixed in 10 ml of DMF and stirred at room temperature for 6 hours. The reaction mixture was added to 100 ml of ice-water, acidified with citric acid and extracted with ether. The organic phase was dried with magnesium sulfate, and the solvent was distilled off. The residue was purified by flash chromatography (cyclohexane/ethyl acetate gradient) to isolate 115 mg of one crystalline diastereomer.

Diast. I: Melting point: 93-96 0

C

ESI MS: M+ 630 Example 9: 2-(4,6-Dimethyl-2-pyrimidinyloxy)-3-(3,4-dimethoxybenzyloxy)- 3-phenyl-6-(3,4-dimethoxyphenyl)hexanoic acid Diast. I: Melting point: 130-133 0

C

ESI MS: M+ 616 Example 2-(4,6-Dimethyl-2-pyrimidinyloxy)-3-(4-methoxyphenoxy)-3-phenyl- 6-(3,4-dimethoxyphenyl)hexanoic acid Diast. I: Melting point: 118-1220C ESI MS: M+ 572 uaufI *53.5.

18 Example 11: 6-Dimethyl-2-pyrimidinyloxy)-3-methoxy-3-phenyl-6-(3, 4-dimethoxyphenyl )hexanoic acid Diast. I: Melting point: 135-138 0

C

ESI MS: M+ 480 Diast. II: Melting point: 128-1340C ESI MS: M+ 480 Example 12: 2- 6-Dimethyl-2-pyrimidinyloxy) -3-methoxy-3 ,6-diphenylhexanoic acid 1H-NMR (200 MHz, CDCl3): 7.1-7.5 ppm (10 H, mn), 6.7 (1 H, 5.8 (1 H, 3.3 (3 H, 2.5-2.7 (3 H, in), 2.3 (6 H, 2.0-2.1 (1 H, in), 1.6-1.8 (2 H, in).

ESI MS: M+ 420 Example 13: 4, 6-Dimethyl-2-pyrinidinyloxy) -3-hex-3E-enoxy-3, 6-diphenylhexanoic [sic] acid Diast. I: Melting point: 110-114 0

C

ESI MS: M+ 488 Diast. II: ESI MS: M+ 488 Example 14: 2- (4,6 -Dimethyl -2 -pyriinidinyloxy) (3,4 -diinethoxyphenyl) ethoxy) 6-diphenylhexanoic acid Diast. I: Melting point: 87-88 0

C

ESI MS: M+ 570 Diast. [I: Melting point: 87-880C UUvUI '*@JI 19 ESI MS: M+ 570 Example 2- (4-Methoxy-6-methyl-2-pyrimidinyloxy) 4-dimethoxyphenyl )ethoxy) 6-diphenyihexanoic acid Diast. I: Melting point: 141-1420C ESI MS: MI 586 Example 16: 2- 6-Dimethyl-2-pyrimidiriyloxy) 4-dimethoxybenzyloxy) 3,6-diphenylhexanoic acid Diast. I: 1H-NMR (200 MHz, CDC13): 7.1-7.5 ppm (10 H, in), 6.9 (3 H, m),6.7 (1 H, 5.8 (1 H, 4.4 (1 H, 4.3 (1 H, 3.9 (3 H, s), 3.85 (3 H, 2.5-2.7 (3 H, in), 2.3 (6 H, 2.0-2.3 (1 H, in), 1.7-1.9 (2 H, in).

ESI MS: M+ 556 Example 17: 4-Methoxy-6-methyl-2-pyrimidinyloxy) ,4-dimethoxybenzyloxy) 6-diphenylhexanoic acid Diast. I: 1H-NMR (200 MHz, CDCl3): 7.1-7.5 ppm (10 H, in), 6.9 (3 H, m),6.25 (1 H, 5.75 (1 H, 4.45 (1 H, 4.35 (1 H, 3.9 (3 H, 3.85 (6 H, 2.4-2.7 (3 H, mn), 2.3 (6 H, 2.0-2.2 (1 H, mn), 1.7-1.9 (2 H, in).

ESI MS: M+ 572 Example 18: 4-Methoxy-6-inethyl-2-pyrimidinyloxy) 2-thiophenylethoxy) 6-diphenylhexanoic [sic] acid 3:1 mixture of diastereoners: Decomposition: 85 0

C

ESI MS: M+ 532 Vw~uI 'Oa.L& Example 19: 2-(4 ,6-Dimethyl-2-pyrimidinyloxy)-3-( ethoxy) 6-diphenyihexanoic acid Diast. I: 1H-NMR (200 MHz, CDCl3): 7.0-7.3 ppm (10 H, mn), 6.65 (1 H, m),6.4 (2 H, 5.75 (1 H, 3.9 (3 H, 3.85 (6 H, s),3.5-3.7 (2 H, mn), 2.8-2.9 (2 H, mn), 2.3-2.5 (3 H, in), 2.3 (6 H, 2.0-2.3 (1 H, mn), 1.5-1.7 (2 H, in).

ESI MS: M+ 600 Example 4-Methoxy-6-methyl-2-pyrimidinyloxy)-3-(2-( 3,4, phenyl )ethoxy) 6-diphenyihexanoic acid Diast. I: Melting point: 153-155 0

C

ESI MS: M+ 616 Example 21: 4, 6-Dimethyl-2-pyrimidinyloxy) 4-hydroxy-3-methoxyphenyl)ethoxy)-3, 6-diphenyihexanoic acid Diast. I: 1H-NMR (200 MHz, CDCl3): 7.0-7.4 ppm (10 H, in), 6.9 (1 H, dm),6.6-6.75 (3 H, in), 5.8 (1 H, 5.5 3.9 (3 H, 3.85 (3 H, 3.5-3.7 (2 H, mn), 2.8-2.9 (2 H, tr), 2.3-2.5 (3 H, in), 2.3 (6 H, 2.0-2.3 (1 H, in), 1.5-1.7 (2 H, in).

ESI MS: M+ 556 Diast. II: ESI MS: M+ 556 Example 22: 4-Methoxy-6-methyl-2-pyrinidinyloxy) 4-hydroxy- 3-inethoxyphenyl )ethoxy) 6-diphenylhexanoic acid Diast. I: Melting point: 154-1570C ESI MS: M+ =572 Wwul 21 Example 23: 2- 6-Dimethyl-2-pyrimidinyloxy) (4-carboxybenzyloxy) 3, 6-diphenyihexanoic acid Diast. I: 1H-NMR (200 MHz, CDCl3): 8.0 (2 H, 7.1-7.5 ppm (12 H, mn), 6.8 (1 H, m),6.8 (1 H, 4.6 (1 H, 4.5 (1 H, 2.5-2.7 (3 H, in), 2.3 (6 H, 2.1-2.25 (1 H, in), 1.5-1.7 (2 H, in).

ESI MS: M+ 540 Diast. II: Melting point: 160-1670C ESI MS: M+ 540 Example 24: 2- (4-Methoxy-6-methyl-2-pyriinidinyloxy) (4-carboxybenzyloxy) 3,6-diphenylhexanoic acid Diast. I: 1H-NMR (200 MHz, CDCl3): 8.0 (2 H, 7.1-7.5 ppm (12 H, in), 6.2 (1 H, mn),5.6 (1 H, 4.55 (1 H, 4.45 (1 H, 3.9 (3 H,s), 2.5-2.7 (3 H, in), 2.3 (3 H, 2.1-2.25 (1 H, in), 1.6-1.8 (2 H, in).

ESI MS: M+ 556 Diast. II: ESI MS: M+ 556 Example 4, 6-Diinethyl-2-pyriinidinyloxy) 4-methoxyphenoxy) 3, 6-diphenylhexanoic acid Diast. I: 1H-NMR (200 MHz, CDCl3): 7.1-7.5 ppm (10 H, in), 6.5-6.8 (5 H, m),5.9 (1 H, 3.75 (3 H, 2.2-2.7 (4 H, in), 2.3 (6 H, s), 1.5-1.7 (2 H, in).

ESI MS: M+ 512 Diast. II: ESI MS: M+ 512 UUOUI G.SIZ 22 Example 26: 2- (4-Methoxy-6-methyl-2-pyrimidinyloxy) (4-methoxyphenoxy) 3, 6-diphenyihexanoic acid Diast. I: 1H-NMR (200 MHz, CDC13): 7.1-7.5 ppm (10 H, in), 6.5-6.9 (4 H, m),6.2 (1 H, 5.75 (1 H, 3.8 (3 H, 3.75 (3 H, s), 2.2-2.7 (4 H, mn), 2.3 (3 H, 1.5-1.7 (2 H, in).

ESI MS: M+ 528 Diast. II: ESI MS: M+ 528 Example 27: 2-(4 ,6-Dimethyl-2-pyrimidinyloxy) 3,4, 2E-propenoxy) 6-diphenyihexanoic [sic] acid Diast. I: IH-NMR (200 MHz, CDC13): 7.1-7.4 ppm (10 H, in), 6.6 (1 H, s), 6.55 (2 H, 6.3 (1 H, 6.2 (1 H, dtr), 5.9 (1 H, 4.2 (1 H, in), 3.85 (3 H, 3.8 (3 H, 3.75 (3 H, 3.4 (1 2.4-2.7 (3 H, in), 2.3 (6 H, 2.0-2.1 (1 H, mn), 1.5-1.7 (2 H, in).

ESI MS: M+ 612 The compounds listed in Table 1 can be prepared in a similar way or as described in the general part.

R

6 Z CH -O-Het B R

R

6 Z \W B RR 3 Nr. R R4 R 5

R

6 Z B R 2

R

3 W X JY Het I-1 COOH Phenyl Phenyl Me 0 CH 2

CH

2

CH

2 Me Me CH N N 1-2 COOH Phenyl Phenyl Me 0 CH 2

CH

2

CH

2 OMe Me CH N N 1-3 COOH Phenyl Phenyl Me S ICH 2

CH

2

CH

2

CF

3 Me ICH N N 1-4 COOH Phenyl Phenyl Me 0 CH 2

CH

2

CH

2 OMe (CH 2

CH

2

CH

2 C) N IN COOH Phenyl Phenyl Me 0 CH 2

CH

2

CH

2 OMe (OCH 2

CH

2 C) N N 1-6 COOH Phenyl Phenyl Me 0 CH 2

CH

2

CH

2 1).

1-7 COOH Phenyl Phenyl Me 0 1CH 2

CH

2

CH

2 2)2* 1-8 COOH Phenyl Phenyl 4-OMe-Phenyl 0 CH 2

CH

2

CH

2 1) 1* 1-9 COOH Phenyl Phenyl 4-OMe-Phenyl 0 CH 2

CH

2

CH

2 Me Me CH N N COOH Phenyl Phenyl 4-OMe-Phenyl 0 CH 2

CH

2

CH

2 OMe Me CH N N I-11 COOH Phenyl Phenyl 4-OMe-Phenyl 0 ICH 2

CH

2

CH

2 2)2* 1-12 COOH Phenyl Phenyl 4-OMe-Phenyl 0 CH 2

CH

2

CH

2 1OMe I(CH 2

CH

2

CH

2 C) N N 1-13 JCOOH Phenyl IPhenyl 4-OMe-Phenyl 0 1CH 2

CH

2

CH

2 I0Me I(OCH 2

CH

2 C) N N Nr. R R4 R6Z B R R3 W X Y Het 1-14 COOH Phenyl Phenyl 3,4-Di-OMe-Phenyl 0 CH 2

CH

2

CH

2 Me Me CH N N 1-15 COOH Phenyl Phenyl 3,4-Di-OMe-Phenyl 0 CH 2

CH

2

CH

2 OMe Me CH N N 1-16 1COOH Phenyl Phenyl 3,4-Di-OMe-Phenyl 0 ICH 2

CH

2

CH

2 F F 1)1*1 1-17 COOH Phenyl Phenyl 3,4-Di-OMe-Phenyl 0 CH 2

CH

2

CH

2 OMe (CH 2

CH

2

CH

2 C) N N 1-18 COOH Phenyl Phenyl 4-Ci-Phenyl 0 CH 2

CH

2

CH

2 OMe Me CH N N 1-19 COOH Phenyl Phenyl 4-Cl-Phenyl 0 CH 2

CH

2

CH

2 Me Me CH N N 1-20 COOH Phenyl Phenyl 4-Ci-Phenyl 0 CH 2

CH

2

CH

2 1) 1-21 COOH Phenyl Phenyl 4-Ci-Phenyl 0 CH 2

CH

2

CH

2 2) 1-22 COOH Phenyl Phenyl 4-Cl-Phenyl 0 CH 2

CH

2

CH

2 OMe (OCH 2

CH

2 C) N N 1-23 COOH Phenyl Phenyl 4-Me-Phenyl 0 CH 2

CH

2

CH

2 Me Me CH N N 1-24 COOH Phenyl Phenyl 4-Me-Phenyl 0 CH 2

CH

2

CH

2 OMe Me jCH N IN I 1-25 COOH Phenyl Phenyl 4-Me-Phenyl 0 CH 2

CH

2

CH

2 1- 1- 1) 1 1-26 COOH Phenyl Phenyl 4-Me-Phenyl 0 CH 2

CH

2

CH

2 OMe (OCH 2

CH

2 C) N N 1-27 COOH Phenyl Phenyl 4-Me-Phenyl 0 CH 2

CH

2

CH

2 OMe (CH 2

CH

2

CH

2 C) N N 1-28 COOH Phenyl Phenyl 4-Me-Phenyl 0 CH 2

CH

2

CH

2 2) 1-29 COOH Phenyl Phenyl 4-OMe-Benzyl 0 CH 2

CH

2

CH

2 OMe Me JCH N IN 1-30 COOH Phenyl Phenyl 4-OMe-Benzyl 0 CH 2

CH

2

CH

2 Me Me ICH N N 1-31 COOH Phenyl Phenyl 4-OMe-Benzyl 0 1CH 2

CH

2

CH

2 OMe (CH 2

CH

2

CH

2 C) N N 1-32 COOH Phenyl Phenyl 4-OMe-Benzyl 0 ICH 2

CH

2

CH

2 OMe (QCH 2

CH

2 C) N N 1-33 COQEt Phenyl 1Phenyl 14-OMe-Benzyl 0 1CH 2

CH

2

CH

2 I-34 1COOH Phenyl IPhenyl 14-0Me-Benzyl 0 1CH 2

CH

2

CH

2 1 2) Nr. R R4 R 5 R6Z B R2 R 3 W X Y Het 1-35 COOH Phenyl Phenyl 3,4-Di-QMe-Benzyl 0 CH 2

CH

2

CH

2 Me Me Ch N N 1-36 COOH Phenyl Phenyl 3,4-Di-OMe-Benzyl 0 CH 2

CH

2

CH

2 OMe Me CH N N 1-37 COOH Phenyl Phenyl 3,4-Di-OMe-Benzyl 0 CH 2

CH

2

CH

2 OMe (CH 2

CH

2

CH

2 C) NN 1-38 COOH Phenyl Phenyl 3,4-Di-OMe-Benzyl 0 jCH 2

CH

2

CH

2 OMe (QCH 2

CH

2 C) N N 1-39 COOH Phenyl Phenyl 3,4-Di-OMe-Benzyl 0 CH 2

CH

2

CH

2 1 1-40 COOH Phenyl Phenyl 3,4-Di-OMe-Benzyl 0 CH 2

CH

2

CH

2 2) 1-41 COOH Phenyl Phenyl 4-Me-Benzyl 0 CH 2

CH

2

CH

2 Me Me CH N N 1-42 COOH Phenyl Phenyl 4-Me-Benzyl 0 CH 2

CH

2

CH

2 OMe Me CH N N 1-43 COOH Phenyl Phenyl 4-Me-Benzyl 0 CH 2

CH

2

CH

2 2) 1-44 COOH Phenyl Phenyl 4-COOH-Benzyl 0 CH 2

CH

2

CH

2 Me Me CH N IN 1-45 COOH Phenyl Phenyl 4-COOH-Benzyl 0 CH 2

CH

2

CH

2 0Me Me CH N IN 1-46 COOH Phenyl Phenyl 4-COOH-Benzyl 0 CH 2

CH

2

CH

2 0Me (CH 2

CH

2

CH

2 C) N N 1-47 COOH Phenyl Phenyl 4-COOH-Benzyl 0 CH 2

CH

2

CH

2 OMe (0CH 2

CH

2 C) N N 1-48 COOH Phenyl Phenyl 4-COOH-Benzyl 0 jCH 2

CH

2

CH

2 1) 1-49 COOH Phenyl Phenyl 4-COOH-Benzyl 0 CH 2

CH

2

CH

2 2) 1-50 COOH Phenyl Phenyl 4-Cl-Benzyl 0 CH 2

CH

2

CH

2 Me Me CH N N 1-51 COOH Phenyl Phenyl 4-Cl-Benzyl 0 CH 2

CH

2

CH

2 OMe Me CH N N 1-52 COOH Phenyl Phenyl 4-C1-Benzyl 0 jCH 2

CH

2

CH

2 2) 1-53 COOH Phenyl Phenyl 4-SMe-Benzyl 0O CH 2

CH

2

CH

2 Me Me CH N N 1-54 COOH Phenyl Phenyl 4-SMe-Benzyl 10 CH 2

CH

2

CH

2 OMe Me CH N N COOH Phenyl Phenyl 4-SMe-Benzyl [0 CH 2

CH

2

CH

2 2) Nr. R R R5R 6 Z B R R3 W X Y Het 1-56 COOH Phenyl Phenyl 3-COQH-Benzyl 0 CH 2

CH

2

CH

2 Me Me CH N N 1-57 COOH Phenyl Phenyl 3-COOH-Benzyl 0 CH 2

CH

2

CH

2 OMe Me CH N N 1-58 COOH Phenyl Phenyl 3-COQH-Benzyl 0 CH 2

CH

2

CH

2 I- F 2) 1-59 COOH Phenyl Phenyl 4-COOH-3-OMeBenzyl 0 CH 2

CH

2

CH

2 Me Me ICH N IN 1-60 COOH Phenyl Phenyl 4-COOH-3-OMeBenzyl 0 CH 2

CH

2

CH

2 OMe Me CH N N 1-61 COOH Phenyl Phenyl 4-COOH-3-OMeBenzyl 0 CH 2

CH

2

CH

2 2) 1-62 COOH Phenyl Phenyl 4-COOH-3-OMeBenzyl 0 CH 2

CH

2

CH

2 Ethyl Me CHI N N 1-63 COOH Phenyl Phenyl 4-COOH-3-QMeBenzyJ. 0 CH 2

CH

2

CH

2

CF

3 Me CHI N N 1-64 COOH Phenyl Phenyl 4-C0OH-3-OMeBenzyl 0 CH 2

CH

2

CH

2 1 1-65 COOH Phenyl Phenyl 4-C0OH-3-MeBenzyl 0 CH 2

CH

2

CH

2 Me Me CHI N N 1-66 COOH Phenyl Phenyl 4-COOH-3-MeBenzyl 0 CH 2

CH

2

CH

2 OMe Me CH N N 1-67 COOH Phenyl Phenyl 4-COOH-3-MeBenzyl 0 CH 2

CH

2

CH

2 I- 2) 1-68 COOH Phenyl Phenyl 4-C00H-3-MeBenzyl 0 CH 2

CH

2

CH

2 OMe (CH 2

CH

2

CH

2 C) N N 1-69 COOH Phenyl Phenyl 4-Ethyl-Benzyl 0 CH 2

CH

2

CH

2 Me Me CHI N N 1-70 COOH Phenyl Phenyl 4-Ethyl-Benzyl 0 CH 2

CH

2

CH

2 OMe Me CHI N N 1-71 COOH Phenyl Phenyl 4-Ethyl-Benzyl 0 CH 2

CH

2

CH

2 2) 1-72 COOH Phenyl Phenyl 2-Phenyl-Ethyl 0 CII 2

CI

2

CII

2 Me Me CHI N N 1-73 COOH Phenyl Phenyl 2-Phenyl-Ethyl 0 CH 2

CH

2

CH

2 OMe Me CHI N N 1-74 COOH Phenyl Phenyl 2-Phenyl-Ethyl 0 CII 2

CII

2

CI

2 1 2) 1-75 COOH Phenyl Phenyl 2-(4-Me-Phenyl)-Ethyl 0 CH 2

CH

2

CH

2 Me Me CHI N N 1-76 COOH Phenyl Phenyl 2-(4-Me-Phenyl)-Ethyl 0 CII 2

CII

2

CI

2 0Me Me ICI N N Nr. R R R5R 6 Z B R 2 R3 IwX Y Het 1-77 COOH Phenyl Phenyl 2-(4-Me-Phenyl)-Ethyl 0 CH 2

CH

2

CH

2 OMe (OCH 2

CH

2 C) N N 1-78 COOH Phenyl Phenyl 2-(4-Me-Phenyl)-Ethyl 0 CH 2

CH

2

CH

2 OMe (CH 2

CH

2

CH

2 C) N N 1-79 COOH Phenyl Phenyl 2-(4-Me-Phenyl)-Ethyl 0 ICH 2

CH

2

CH

2 1) 1-80 COOH Phenyl Phenyl 2-(4-Me-Phenyl)-Ethyl 0 CH 2

CH

2

CH

2 2) 1-81 COOH Phenyl Phenyl 2-(4-0Me-Phenyl)-Ethyl 0 CH 2

CH

2

CH

2 Me Me CH N N 1-82 ICOOH Phenyl Phenyl 2-(4-OMe-Phenyl)-Ethyl 0 CH 2

CH

2

CH

2 OMe Me ICH N N 1-83 COOH Phenyl Phenyl 2-(4-OMe-Phenyl)-Ethyl 0 CH 2

CH

2

CH

2 OMe (CH 2

CH

2

CH

2 C) N N 1-84 COOH Phenyl Phenyl 2-(4-OMe-Phenyl)-Ethyl 0 CH 2

CH

2

CH

2 OMe (OCH 2

CH

2 C) N N 1-85 COOH Phenyl Phenyl 2-(4-OMe-Phenyl)-Ethyl 0 CH 2

CH

2

CH

2 1) 1-86 COOH Phenyl Phenyl 2-(4-OMe-Phenyl)-Ethyl 0 CH 2

CH

2

CH

2 2) 1-87 COOH Phenyl Phenyl 2-(4-0Me-Phenyl)-Ethyl 0 CH 2

CH

2

CH

2

CF

3 Me CH N N 1-88 COOH Phenyl Phenyl 2-(3,4-Di0Me- 0 CH 2

CH

2

CH

2 Me Me CH N N )-Ethyl 1-89 COOH Phenyl Phenyl 2-(3,4-DiOMe- 0 CH 2

CH

2

CH

2 OMe Me CH N N )-EthylI 1-90 COOH Phenyl Phenyl 2-(3,4-DiOMe- 0 CH 2

CH

2

CH

2 OMe (CH 2

CH

2

CH

2 C) N N Phenyl)-Ethyl 1-91 COOH Phenyl Phenyl 2-(3,4-DiOMe- 0 ICH 2

CH

2

CH

2 OMe (OCH 2

CH

2 C) N N 1-92 COOH Phenyl Phenyl 2-(3,4-DiOMe- 0 CH 2

CH

2

CH

2 1 -Ethyl I 1:-3 COOH Phenyl Phenyl 2-(3,4-DiOMe- 0 CH 2

CH

2 CH 2) Phenyl) -Ethyl._ Nr. R R4 R6Z B R2 R 3 W X Y Het 1-94 COOH Phenyl Phenyl 2-(4-COOH-Phenyl)-Ethyl 0 CH 2

CH

2

CH

2 Me Me CH N N 1-95 COOH Phenyl Phenyl 2-(4-CO0H-Phenyl)-Ethyl 0 CH 2

CH

2

CH

2 OMe Me CH N N 1-96 1COOH Phenyl IPhenyl 2-(4-C00H-Phenyl)-Ethyl 0 CH 2

CH

2

CH

2 OMe (CH 2

CH

2

CH

2 C) N N 1-97 COOH Phenyl Phenyl 2-(4-C0OH-Phenyl)-Ethyl 0 CH 2

CH

2

CH

2 OMe (OCH 2

CH

2 C) N N 1-98 COOH Phenyl Phenyl 2-(4-COOH-Phenyl)-Ethyl 0 CH 2

CH

2

CH

2 1) 1-99 COOH Phenyl Phenyl 2-(4-COOH-Phenyl)-Ethyl 0 CH 2

CH

2

CH

2 2) I-100 COOH Phenyl Phenyl 2-(4-SMe-Phenyl)-Ethyl 0 CH 2

CH

2

CH

2 Me Me CH N N I-101 COOH Phenyl Phenyl 2-(4-SMe-Phenyl)-Ethyl 0 CH 2

CH

2

CH

2 OMe Me CH N N 1-102 COOH Phenyl Phenyl 2-(4-SMe-Phenyl)-Ethyl 0 CH 2

CH

2

CH

2 2) 1-103 COOH Phenyl Phenyl 2-(4-Cl-Phenyl)-Ethyl 0 CH 2

CH

2

CH

2 Me Me CH N N 1-104 COOH Phenyl Phenyl 2-(4-Cl-Phenyl)-Ethyl 0 CH 2

CH

2

CH

2 OMe Me CH N N 1-105 COOH Phenyl Phenyl 2-(4-Cl-Phenyl)-Ethyl 0 CH 2

CH

2

CH

2 2) 1-106 COOH Phenyl Phenyl 2-(3,4-DiCl- 0 CH 2

CH

2

CH

2 Me Me CH N N -Ethyl 1-107 COOH Phenyl Phenyl 2-(3,4-DiCl- 0 CH 2

CH

2

CH

2 OMe Me CH N N ____Phenyl )-EthylII 1-108 COOH Phenyl Phenyl 2-(3,4-DiCl- 0 jCH 2

CH

2

CH

2 OMe (OCH 2

CH

2 C) N N -Ethyl___ 1-109 COOH Phenyl Phenyl 2-(3,4-DiCl- 0 CH 2

CH

2

CH

2 2) 1 1 Phenyl )-Ethyl_ I-110 ICOOH IPhenyl IPhenyl 12-(4-CO0H-3-0Me- 0 CH 2

CH

2

CH

2 Me Me ICH N N Phenyl )-Ethyl I_ Nr. R R4 R 5 R6ZB R R3 W X Y Het I-111 COOH Phenyl Phenyl 2-(4-COOH-3-OMe- 0 CH 2

CH

2

CH

2 OMe Me CH N N -Ethyl_ 1-112 GOGH Phenyl Phenyl 2-(4-COOH-3-OMe- 0 CH 2

CH

2

CH

2 2) Phenyl )-Ethyl 1-113 GOGH Phenyl Phenyl 3-Phenyl-Propyl 0 CH 2

CH

2

CH

2 Me Me CH N N 1-114 GOOH Phenyl Phenyl 3-Phenyl-Propyl 0 CH 2

CH

2

CH

2 OMe Me CH N N 1-115 GOGH Phenyl Phenyl 3-Phenyl-Propyl 0 CH 2

CH

2

CH

2 2) 1-116 GOOH Phenyl Phenyl 3-(3,4,5-triOMe- 0 CH 2

CH

2

CH

2 Me Me CH N N )Prop-2E-enyl

I__I

1-117 GOGH Phenyl Phenyl 3-(3,4,5-triMe- 0 CH 2

CH

2

CH

2 OMe Me CH N N )Prop-2E-enyl_ 1-118 GOGH Phenyl Phenyl 3-(3,4,5-triOMe- 0 CH 2

CH

2

CH

2 2) 1-119 GOGH Phenyl Phenyl 2-(3,4-methylenedioxy- 0 CH 2

CH

2

CH

2 Me Me CH N N phenyl)-Ethyl_____ 1-120 GOGH Phenyl Phenyl 2-(3,4-methylenedioxy- 0 CH 2

CH

2

CH

2 OMe Me CH N N phenyl) -Ethyl___ 1-121 GOGH Phenyl Phenyl 2-(3,4-methylenedioxy- 0 CH 2

CH

2

CH

2 2) phenyl 1-122 GOGH Phenyl Phenyl 2-(4-DiMethyl-amino- 0 CH 2

CH

2 CH2 Me Me CH N N Phenyl)-Ethyl______ 1-123 COGH Phenyl Phenyl 2-(4-DiMethyl-amino- 0 CH 2

CH

2

CH

2 OMe Me CH N N ~Phenyl)-Ethyl______ 1-2 COGH Phenyl Phenyl 2-(4-DiMethyl-amino- 0 CH 2

CH

2

CH

2 2) Phenyl)-Ethyl I I_ Nr. R R4 R 5

R

6 Z B R2 R 3 W X Y Het 1-125 COOH Phenyl Phenyl 2-(4-Hydroxy- 0 CH 2

CH

2

CH

2 Me Me CH N N Phenyl) -Ethyl 1-126 COOH Phenyl Phenyl 2-(4-Hydroxy- 0 CH 2

CH

2

CH

2 OMe Me OH N N Phenyl)-Ethyl_ 1-127 COOH Phenyl Phenyl 2-(4-Hydroxy- 0 CH 2

CH

2

CH

2 1-128 COOH Phenyl Phenyl 2-(4-Hydroxy-3-0Me- 0 CH 2

CH

2

CH

2 Me Me OH N N Phenyl)-Ethyl_ 1-129 COOH Phenyl Phenyl 2-(4-Hydroxy-3-0Me- 0 CH 2

CH

2

CH

2 OMe Me CH N IN 1-130 COOH Phenyl Phenyl 2-(4-Hydroxy-3-0Me- 0 CH 2

CH

2

CH

2 2 1-131 COOH Phenyl Phenyl 2-(4-Ethoxy-3-Methoxy- 0 CH 2

CH

2

CH

2 Me Me CH N N ___Phenyl)-Ethyl 1-132 COOH Phenyl Phenyl 2-(4-Ethoxy-3-Methoxy- 0 CH 2

CH

2

CH

2 0Me Me CH N N ______Phenyl 1-133 COOH Phenyl Phenyl 2-(4-Ethoxy-3-Methoxy- 0 CH 2

CH

2

CH

2 1 Phenyl )-Ethyl__ 1-134 COOH Phenyl Phenyl 2-(3,5-DiOMe- 0 CH 2

CH

2

CH

2 Me Me CH N N Phenyl) 1-135 COOH Phenyl Phenyl 2-(3,5-DiOMe- 0 CH 2

CH

2

CH

2 0Me Me OH N N ~Phenyl) 1-136 COOH Phenyl Phenyl 2-(3,5-DiOMe- 0 CH 2

CH

2

CH

2 2) Phenyl )-Ethyl 17 COOH Phenyl 3,4-DiOMe- Me 0 CH 2

CH

2

CH

2 Me Me OH NN- Phenyl I I_ Nr. R R4 R 5

R

6 Z B R2 R 3 W X Y Het 1-138 COOH Phenyl 3,4-DiOMe- Me 0 CH 2

CH

2

CH

2 OMe Me CH N N Phenyl__ 1-139 COOH Phenyl 3,4-DiOMe- Me 0 CH 2

CH

2

CH

2

CF

3 Me CH N N Phenyl 1-140 COOH Phenyl 3,4-DiOMe- Me 0 CH 2

CH

2

CH

2 OMe (CH 2

CH

2

CH

2 C) N N Phenyl 1-141 COOH Phenyl 3,4-DiOMe- Me 0 CH 2

CH

2

CH

2 OMe (OCH 2

CH

2 C) N N Phenyl____ 1-142 COOH Phenyl 3,4-DiOMe- Me 0 CH 2

CH

2

CH

2 1) Phenyl____ 1-143 COOH Phenyl 3,4-DiOMe- Me 0 CH 2

CH

2

CH

2 2)2* Phenyl 1-14 4 COOH Phenyl 3,4-DiOMe- 4-OMe-Phenyl 0 CH 2

CH

2

CH

2 1) 1* Phenyl_____ 1-145 COOH Phenyl 3,4-DiOMe- 4-OMe-Phenyl 0 CH 2

CH

2

CH

2 Me Me CH N N Phenyl_____ 1-146 COOH Phenyl 3,4-DiOMe- 4-OMe-Phenyl 0 CH 2

CH

2

CH

2 OMe Me CHI N N Phenyl___ 1-147 COOH Phenyl 3,4-DiOMe- 4-OMe-Phenyl 0 CH 2

CH

2

CH

2 2)2* 1-148 COOH Phenyl 3,4-DiOMe- 4-OMe-Phenyl 0 CH 2

CH

2

CH

2 OMe (CH 2

CH

2

CH

2 C) N N _____Phenyl 1-149 COOH Phenyl 3,4-DiOMe- 4-OMe-Phenyl 0 CH 2

CH

2

CH

2 OMe (OCH 2

CH

2 C) N N IIPhenyl 1-150 COOH Phenyl 3,4-DiOMe- 3,4-Di-OMe-Phenyl 0 CH 2

CH

2

CH

2 Me Me C Phenyl I I Nr. R R4 R 5 R6ZB R R3 W X Y Het 1-151 COOH Phenyl 3,4-DiOMe- 3,4-Di-OMe-Phenyl 0 CH 2

CH

2

CH

2 OMe Me CH N N- Phenyl 1-152 COOH Phenyl 3,4-DiOMe- 3, 4-Di-OMe-Phenyl 0 CH 2

CH

2

CH

2 1)* PhenylI 1-153 COOH Phenyl 3,4-DiOMe- 3,4-Di-OMe-Phenyl 0 CH 2

CH

2

CH

2 OMe (CH 2

CH

2

CH

2 C) N N- Phenyl_____ 1-154 COOH Phenyl 3,4-DiOMe- 4-Ci-Phenyl 0 CH 2

CH

2

CH

2 OMe Me CH N N- 1-155 COOH Phenyl 3,4-DiOMe- 4-Ci-Phenyl 0 CH 2

CH

2

CH

2 Me Me CH N N- Phenyl 1-156 COOH Phenyl 3,4-DiOMe- 4-Ci-Phenyl 0 CH 2

CH

2

CH

2 1 Phenyl 1-157 COOH Phenyl 3,4-DiOMe- 4-Ci-Phenyl 0 CH 2

CH

2

CH

2 2) Phenyl 1-158 COOH Phenyl 3,4-DiOMe- 4-Ci-Phenyl 0 CH 2

CH

2

CH

2 OMe (OCH 2

CH

2 C) N IN 1-159 COOH Phenyl 3,4-DiOMe- 4-Me-Phenyl 0 CH 2

CH

2

CH

2 Me Me CHI N N- 1-160 COOH Phenyl 3,4-DiOMe- 4-Me-Phenyl 0 CH 2

CH

2

CH

2 OMe Me CHI N N- Phenyl 1-161 COOH Phenyl 3,4-DiOMe- 4-Me-Phenyl 0 CH 2

CH

2

CH

2 1 1-162 COOH Phenyl 3,4-DiOMe- 4-Me-Phenyl 0 CH 2

CH

2

CH

2 OMe (OCH 2

CH

2 C) N N- Phenyl -63COOH Phenyl 13,4-DiOMe- 4-Me-Phenyl 0 CH 2

CH

2

CH

2 OMe (CH 2

CH

2

CH

2 C) N N- Phenyl Nr. R R R5R 6 Z B R 2 R3 W X Y Het 1-164 COOH Phenyl 3,4-DiOMe- 4-Me-Phenyl 0 CH 2

CH

2

CH

2 2) Phenyl 1-165 COOH Phenyl 3,4-DiOMe- 4-OMe-Benzyl 0 CH 2

CH

2

CH

2 OMe Me CH N N PhenylIIII 1-166 GOGH Phenyl 3,4-DiOMe- 4-OMe-Benzyl 0 CH 2

CH

2

CH

2 Me Me CH N N 1-167 GOGH Phenyl 3,4-DiOMe- 4-QMe-Benzyl 0 CH 2

CH

2

CH

2 OMe (CH 2

CH

2

CH

2 C) N N Phenyl 1-168 GOGH Phenyl 3,4-DiGMe- 4-OMe-Benzyl 0 CH 2

CH

2

CH

2 OMe (OCH 2

CH

2 C) N N Phenyl 1-169 GOGH Phenyl 3,4-DiGMe- 4-OMe-Benzyl 0 CH 2

CH

2

CH

2 1) _______Phenyl 1-170 GOGH Phenyl 3,4-DiOMe- 4-OMe-Benzyl 0 CH 2

CH

2

CH

2 2) 1-171 GOGH Phenyl 3,4-DiOMe- 3,4-Di-OMe-Benzyl 0 CH 2

CH

2

CH

2 Me Me Ch N N _____Phenyl 1-172 GOGH Phenyl 3,4-DiOMe- 3, 4-Di-OMe-Benzyl 0 CH 2

CH

2

CH

2 OMe Me CH N N 1-173 COGH Phenyl 3,4-DiOMe- 3,4-Di-OMe-Benzyl 0 CH 2

CH

2

CH

2 OMe (CH 2

CH

2

CH

2 C) N N Phenyl 1-174 GOGH Phenyl 3,4-DiOMe- 3,4-Di-OMe-Benzyl 0 CH 2

CH

2

CH

2 OMe (OCH 2

CH

2 C) N N Phenyl 1-175 GOGH Phenyl 3,4-DiOMe- 3, 4-Di-OMe-Benzyl 0 CH 2

CH

2

CH

2 1) PhenylI 1-176 GOGH Phenyl 3,4-DiGMe- 3,4-Di-OMe-Benzyl 0 CH 2

CH

2

CH

2 2) Phenyl I Nr. R R4 R 5

R

6 Z B R2 R 3 W X JY Het 1-177 COOH Phenyl 3,4-DiOMe- 4-Me-Benzyl 0 CH 2

CH

2

CH

2 Me Me CHI N N Phenyl 1-178 COOH Phenyl 3,4-DiOMe- 4-Me-Benzyl 0 CH 2

CH

2

CH

2 OMe Me CHI N N PhenylIII 1-179 COOH Phenyl 3,4-DiOMe- 4-Me-Benzyl 0 CH 2

CH

2

CH

2 2) Phenyl 1-180 COOH Phenyl 3,4-DiOMe- 4-COOH-Benzyl 0 CH 2

CH

2

CH

2 Me Me CHI N N Phenyl 1-181 COOH Phenyl 3,4-DiOMe- 4-COOH-Benzyl 0 CH 2

CH

2

CH

2 OMe Me CH N N PhenylIII 1-182 COOH Phenyl 3,4-DiOMe- 4-COOH-Benzyl 0 CH 2

CH

2

CH

2 OMe (CH 2

CH

2

CH

2 C) N N 1-183 COOH Phenyl 3,4-DiOMe- 4-COOH-Benzyl 0 CH 2

CH

2

CH

2 OMe (OCH 2

CH

2 C) N N Phenyl 1-184 COOH Phenyl 3,4-DiOMe- 4-COOH-Benzyl 0 CH 2

CH

2

CH

2 1) Phenyl 1-185 COGH Phenyl 3,4-DiOMe- 4-COOH-Benzyl 0 CH 2

CH

2

CH

2 2) Phenyl_______ 1-186 COOH Phenyl 3,4-DiOMe- 4-Cl-Benzyl 0 CH 2

CH

2

CH

2 Me Me CHI N N PhenylI 1-187 COOH Phenyl 3,4-DiOMe- 4-C1-Benzyl 0 CH 2

CH

2

CH

2 OMe Me CH N N PhenylII 1-188 COOH Phenyl 3,4-DiOMe- 4-C1-Benzyl 0 CH 2

CH

2

CH

2 2) 1 Phenyl -19COOH Phenyl 13,4-DiOMe- 4-SMe-Benzyl 0 CH 2

CH

2

CH

2 Me Me CHI NN I Phenyl Nr. R R4 R 5

R

6 Z B R2 R 3 W X Y Het 1-190 COOH Phenyl 3,4-DiOMe- 4-SMe-Benzyl 0 CH 2

CH

2

CH

2 OMe Me CH N N Phenyl 1-191 COOH Phenyl 3,4-DiOMe- 4-SMe-Benzyl 0 CH 2

CH

2

CH

2 2) 1-192 COOH Phenyl 3,4-DiOMe- 3-COOH-Benzyl 0 CH 2

CH

2

CH

2 Me Me CH N N PhenylI 1-193 COOH Phenyl 3,4-DiOMe- 3-COOH-Benzyl 0 CH 2

CH

2

CH

2 OMe Me CH N N Phenyl 1-194 COOH Phenyl 3,4-DiOMe- 3-COOH-Benzyl 0 CH 2

CH

2

CH

2 2) Phenyl 1-195 COOH Phenyl 3,4-DiOMe- 4-CO0H-3-OMeBenzyl 0 CH 2

CH

2

CH

2 Me Me CH N N Phenyl 1-196 COOH Phenyl 3,4-DiOMe- 4-COOH-3-OMeBenzyl 0 CH 2

CH

2

CH

2 OMe Me CH N N Phenyl 1-197 COOH Phenyl 3,4-DiOMe- 4-C0OH-3-OMeBenzyl 0 CH 2

CH

2

CH

2 2) Phenyl 1-198 COOH Phenyl 3,4-DiOMe- 4-COOH-3-OMeBenzyl 0 CH 2

CH

2

CH

2 Ethyl Me CH N N Phenyl 1-199 COOH Phenyl 3,4-DiOMe- 4-C00H-3-OMeBenzyl 0 CH 2

CH

2

CH

2

CF

3 Me CH N N 1-200 COOH Phenyl 3,4-DiOMe- 4-C0OH-3-OMeBenzyl 0 CH 2

CH

2

CH

2 1 Phenyl 1-201 COOH Phenyl 3,4-DiOMe- 4-C00H-3-MeBenzyl 0 CH 2

CH

2

CH

2 Me Me CH N N I_ Phenyl 1-202 COOH Phenyl 3,4-DiOMe- 4-C00H-3-MeBenzyl 0 CH 2

CH

2

CH

2 OMe Me CH N N Phenyl I I I I__ Nr. R R4 R6Z B R R3 W X Y Het 1-203 COGH Phenyl 3,4-DiOMe- 4-COQH-3-MeBenzyl 0 CH 2

CH

2

CH

2 2) 1-204 COOH Phenyl 3,4-DiOMe- 4-COOH-3-MeBenzyl 0 CH 2

CH

2

CH

2 OMe (CH 2

CH

2

CH

2 C) N N PhenylIII 1-205 COOH Phenyl 3,4-DiOMe- 4-Ethyl-Benzyl 0 CH 2

CH

2

CH

2 Me Me CH N N _____Phenyl 1-206 COOH Phenyl 3,4-DiOMe- 4-Ethyl-Benzyl 0 CH 2

CH

2

CH

2 OMe Me CH N N Phenyl 1-2 07 COOH Phenyl 3,4-DiOMe- 4-Ethyl-Benzyl 0 CH 2

CH

2

CH

2 2) Phenyl____ 1-208 COOH Phenyl 3,4-DiOMe- 2-Phenyl-Ethyl 0 CH 2

CH

2

CH

2 Me Me CH N N ~~Phenyl___ 1-209 GOGH Phenyl 3,4-DiOMe- 2-Phenyl-Ethyl 0 CH 2

CH

2

CH

2 OMe Me CH N N Phenyl 1-210 GOGH Phenyl 3,4-DiOMe- 2-Phenyl-Ethyl 0 CH 2

CH

2

CH

2 2) 1-211 GOGH Phenyl 3,4-DiOMe- 2-(4-Me-Phenyl)-Ethyl 0 CH 2

CH

2

CH

2 Me Me CHl N N 1-212 COOH Phenyl 3,4-DiOMe- 2-(4-Me-Phenyl)-Ethyl 0 CH 2

CH

2

CH

2 OMe Me CH N N IPhenyl 1-213 GOGH Phenyl 3,4-DiOMe- 2-(4-Me-Phenyl)-Ethyl 0 CH 2

CH

2

CH

2 OMe (OCH 2

CH

2 C) N IN 1-214 GOGH Phenyl 3,4-DiOMe- 2-(4-Me-Phenyl)-Ethyl 0 CH 2

CH

2

CH

2 OMe (CH 2

CH

2

CH

2 C) N N 1-215 GOGH Phenyl 3,4-DiOMe- 2-(4-Me-Phenyl)-Ethyl 10 ICH 2

CH

2

CH

2 I- -1 I Phenyl Nr. R R4 R 5

R

6 Z B R R3 W X Y Het 1-216 COOH Phenyl 3,4-DiOMe- 2-(4-Me-Phenyl)-Ethyl 0 CH 2

CH

2

CH

2 2) Phenyl 1-217 COOH Phenyl 3,4-DiOMe- 2-(4-OMe-Phenyl)-Ethyl 0 CH 2

CH

2

CH

2 Me Me CH N N Phenyl 1-218 COOH Phenyl 3,4-DiOMe- 2-(4-OMe-Phenyl)-Ethyl 0 CH 2

CH

2

CH

2 OMe Me CH N N _____PhenylI 1-219 COOH Phenyl 3,4-DiOMe- 2-(4-0Me-Phenyl)-Ethyl 0 CH 2

CH

2

CH

2 OMe (CH 2

CH

2

CH

2 C) N N Phenyl 1-220 COOH Phenyl 3,4-DiOMe- 2-(4-OMe-Phenyl)-Ethyl 0 CH 2

CH

2

CH

2 OMe (0CH 2

CH

2 C) N N 1-221 COOH Phenyl 3,4-DiOMe- 2-(4-OMe-Phenyl)-Ethyl 0 CH 2

CH

2

CH

2 1) 1-222 COOH Phenyl 3,4-DiOMe- 2-(4-OMe-Phenyl)-Ethyl 0 CH 2

CII

2

CH

2 2) Phenyl 1-223 COOH Phenyl 3,4-DiOMe- 2-(4-0Me-Phenyl)-Ethyl 0 CH 2

CH

2

CH

2

CF

3 Me CH N N 1-224 COGH Phenyl 3,4-DiOMe- 2-(3,4-DiOMe- 0 CH 2

CH

2

CH

2 Me Me CH N IN Phenyl Phenyl) -Ethyl__ 1-225 COOH Phenyl 3,4-DiOMe- 2-(3,4-Di0Me- 0 CH 2

CH

2

CH

2 OMe Me CH N N Phenyl Phenyl) -Ethyl 1-226 COOH Phenyl 3,4-DiOMe- 2-(3,4-Di0Me- 0 CH 2

CH

2

CH

2 0Me (CH 2

CH

2

CH

2 C) N N Phenyl Phenyl 1-227 COOH Phenyl 3,4-DiOMe- 2-(3,4-Di0Me- 0 CH 2

CH

2

CH

2 OMe (OCH 2

CH

2 C) N N Phenyl Phenyl) 1-228 COOH Phenyl 3,4-DiOMe- 2-(3,4-Di0Me- 0 CH 2

CH

2

CH

2 I -1 IIIPhenyl lPhenyl) -Ethyl I 1 &fl\1 q Nr. R R R5R 6 Z B R2 R 3 W X Y Het 1-229 COOH Phenyl 3,4-DiOMe- 2-(3,4-DiOMe- 0 CH 2

CH

2

CH

2 2) Phenyl Phenyl) -Ethyl 1-230 COOH Phenyl 3,4-DiOMe- 2-(4-COOH-Phenyl)-Ethyl 0 CH 2

CH

2

CH

2 Me Me CH N N Phenyl I I 1-231 COOH Phenyl 3,4-DiOMe- 2-(4-COOH-Phenyl)-Ethyl 0 CH 2

CH

2

CH

2 OMe Me CH N N Phenyl 1-232 COOH Phenyl 3,4-DiOMe- 2-(4-CO0H-Phenyl)-Ethyl 0 CH 2

CH

2

CH

2 OMe (CH 2

CH

2

CH

2 C) N N Phenyl 1-233 COOH Phenyl 3,4-DiOMe- 2-(4-CO0H-Phenyl)-Ethyl 0 CH 2

CH

2

CH

2 OMe (OCH 2

CH

2 C) N N IPhenyl 1-234 COOH Phenyl 3,4-DiOMe- 2-(4-COOH-Phenyl)-Ethyl 0 CH 2

CH

2

CH

2 1) Phenyl 1-235 COOH Phenyl 3,4-DiOMe- 2-(4-COOH-Phenyl)-Ethyl 0 CH 2

CH

2

CH

2 2) Phenyl 1-236 COOH Phenyl 3,4-DiOMe- 2-(4-SMe-Phenyl)-Ethyl 0 CH 2

CH

2

CH

2 Me Me CH N N 1-237 COOH Phenyl 3,4-DiOMe- 2-(4-SMe-Phenyl)-Ethyl 10 CH 2

CH

2

CH

2 OMe Me CH N N Phenyl__ 1-238 COOH Phenyl 3,4-DiOMe- 2-(4-SMe-Phenyl)-Ethyl 0 CH 2

CH

2

CH

2 2) Phenyl__ 1-239 COOH Phenyl 3,4-DiOMe- 2-(4-Cl-Phenyl)-Ethyl 0 CH 2

CH

2

CH

2 Me Me CH N N IPhenyl 1-240 COOH Phenyl 3,4-DiOMe- 2-(4-Cl-Phenyl)-Ethyl 0 CH 2

CH

2

CH

2 OMe Me CH N N 1-241 COOH Phenyl 3,4-DiOMe- 2-(4-Cl-Phenyl)-Ethyl 0 jCH 2

CH

2

CH

2 F-2) Phenyl I Nr. R R4 R6Z B R2 R 3 W X Y Het 1-242 COOH Phenyl 3,4-DiOMe- 2-(3,4-DiCl- 0 CH 2

CH

2

CH

2 Me Me CH N N Phenyl Phenyl) -Ethyl 1-243 COOH Phenyl 3,4-DiOMe- 2-(3,4-DiCl- 0 CH 2

CH

2

CH

2 OMe Me CH N N IPhenyl Phenyl )-Ethyl 1-244 COOH Phenyl 3,4-DiOMe- 2-(3,4-DiCl- 0 CH 2

CH

2

CH

2 OMe (OCH 2

CH

2 C) N N Phenyl Phenyl) -Ethyl 1-245 COOH Phenyl 3,4-DiOMe- 2-(3,4-DiCl- 0 CH 2

CH

2

CH

2 2 Phenyl Phenyl 1-246 COOH Phenyl 3,4-DiOMe- 2-(4-COOH-3-OMe- 0 CH 2

CH

2

CH

2 Me Me CH N N Phenyl Phenyl) 1-247 COOH Phenyl 3,4-DiOMe- 2-(4-C0OH-3-OMe- 0 CH 2

CH

2

CH

2 OMe Me CH N N Phenyl Phenyl )-Ethyl 1-248 COOH Phenyl 3,4-DiOMe- 2-(4-COOH-3-0Me- 0 CH 2

CH

2

CH

2 2) Phenyl Phenyl) -Ethyl 1-249 COOH Phenyl 3,4-DiOMe- 3-Phenyl-Propyl 0 CH 2

CH

2

CH

2 Me Me CHI N IN Phenyl 1-250 COOH Phenyl 3,4-DiOMe- 3-Phenyl-Propyl 0 CH 2

CH

2

CH

2 OMe Me CH N N 1-251 COOH Phenyl 3,4-DiOMe- 3-Phenyl-Propyl 0 CH 2

CH

2

CH

2 2) Phenyl 1-252 COOH Phenyl 3,4-DiOMe- 3-(3,4,5-triOMe- 0 CH 2

CH

2

CH

2 Me Me CH N N Phenyl Phenyl )Prop-2E-enyl 1-253 COOH Phenyl 3,4-DiOMe- 3-(3,4,5-triMe- 0 CH 2

CH

2

CH

2 OMe Me CHI N N Phenyl Phenyl )Prop-2E-enyl_____ 154COOH Phenyl 3,4-DiOMe- 3-(3,4,5-trioMe- 0CH 2

CH

2

CH

2 1 2) Phenyl Phenyl )Prop-2E-enyl to Nr. R R4 R6Z B R2 R 3 W X Y Het 1-255 COOH Phenyl 3,4-DiOMe- 2-(3,4-methylenedioxy- 0 CH 2

CH

2

CH

2 Me Me CH N N Phenyl phenyl )-Ethyl 1-256 COOH Phenyl 3,4-DiOMe- 2-(3,4-methylenedioxy- 0 CH 2

CH

2

CH

2 OMe Me CH N N Phenyl phenyl )-Ethyl 1-257 COOH Phenyl 3,4-DiOMe- 2-(3,4-methylenedioxy- 0 CH 2

CH

2

CH

2 2) Phenyl phenyl )-Ethyl 1-258 COOH Phenyl 3,4-DiOMe- 2-(4-DiMethyl-amino- 0 CH 2

CH

2

CH

2 Me Me CH N N Phenyl Phenyl )-Ethyl 1-259 COGH Phenyl 3,4-DiOMe- 2-(4-DiMethyl-amino- 0 CH 2

CH

2

CH

2 OMe Me CH N IN Phenyl Phenyl )-Ethyl 1-260 COOH Phenyl 3,4-DiOMe- 2-(4-DiMethyl-amino- 0 CH 2

CH

2

CH

2 2) Phenyl Phenyl )-Ethyl 1-261 COOH Phenyl 3,4-DiOMe- 2-(4-Hydroxy- 0 CH 2

CH

2

CH

2 Me Me CH N N Phenyl Phenyl) -Ethyl 1-262 COOH Phenyl 3,4-DiOMe- 2-(4-Hydroxy- 0 CH 2

CH

2

CH

2 OMe Me CH N N Phenyl Phenyl )-EthylI 1-263 COOH Phenyl 3,4-DiOMe- 2-(4-Hydroxy- 0 CH 2

CH

2

CH

2 Phenyl Phenyl) -Ethyl 1-264 COOH Phenyl 3,4-DiOMe- 2-(4-Hydroxy-3-QMe- 0 CH 2

CH

2

CH

2 Me Me CH N N IPhenyl Phenyl )-EthylII 1-265 COOH Phenyl 3,4-DiOMe- 2-(4-Hydroxy-3-OMe- 0 jCH 2

CH

2

CH

2 OMe Me CH N N Phenyl Phenyl) -Ethyl_____ 1-266 COOH Phenyl 3,4-DiOMe- 2-(4-Hydroxy-3-OMe- 0 jCH 2

CH

2

CH

2 1 2) 11Phenyl lPhenyl )-Ethyl nql~ Nr. R R R5R 6 Z B R2 R3X Y Het 1-267 COOH Phenyl 3,4-DiOMe- 2-(4-Ethoxy-3-Methoxy- 0 CH 2

CH

2

CH

2 Me Me CH N IN Phenyl Phenyl) -Ethyl 1-268 COOH Phenyl 3,4-DiOMe- 2-(4-Ethoxy-3-Methoxy- 0 CH 2

CH

2

CH

2 OMe Me CH N IN Phenyl Phenyl )-Ethyl 1-269 COOH Phenyl 3,4-DiOMe- 2-(4-Ethoxy-3-Methoxy- 0 CH 2

CH

2

CH

2 1 Phenyl Phenyl )-Ethyl 1-270 COOH Phenyl 3,4-DiOMe- 2-(3,5-DiOMe- 0 CH 2

CH

2

CH

2 Me Me CH N N Phenyl Phenyl) -Ethyl 1-271 COOH Phenyl 3,4-DiOMe- 2-(3,5-DiOMe- 0 CH 2

CH

2

CH

2 OMe Me CH N IN Phenyl Phenyl) -Ethyl 1-272 COOH Phenyl 3,4-DiOMe- 2-(3,5-DiOMe- 0 CH 2

CH

2

CH

2 -2) Phenyl Phenyl )-Ethyl 1-273 COOH Phenyl Phenyl Me 0OCH 2

CH

2 Me Me ICH N N 1-274 COOH Phenyl Phenyl Me 0 CH 2

CH

2 OMe Me ICH N IN 1-275 COOH Phenyl Phenyl Me 0 CH 2

CH

2 OMe (CH 2

CH

2

CH

2 C) N N 1-276 COOH Phenyl Phenyl Me 0 JCH 2

CH

2 OMe (OCH 2

CH

2 C) N N 1-277 COOH Phenyl Phenyl Me 0 CH 2

CH

2 Ethyl Me CH N N 1-27 8 COOH Phenyl Phenyl Me 0OCH 2

CH

2 F 1) 1-279 COOH Phenyl Phenyl Me 0 CH 2

CH

2 2) 1-280 COOH 4-OMe Phenyl Me 0OCH 2

CH

2 Me Me CH N IN Phenyl 1-281 1COOH 4-OMe Phenyl Me 0 CH 2

CH

2 0Me Me C-fH N IN I Phenyl Nr. R R4 R6Z B R 2

R

3 W X Y Het 1-282 COOH 4-OMe Phenyl Me 0 CH 2

CH

2 2) 1-283 COOH 4-OMe Phenyl Me 0 CH 2

CH

2

CH

2 Me Me CH N N _____Phenyl 1-284 COOH 4-OMe Phenyl Me 0 CH 2

CH

2

CH

2 OMe Me CH N N Phenyl 1-285 COGH 4-OMe Phenyl Me 0 CH 2

CH

2

CH

2 1 Phenyl__ 1-286 COOH 4-OMe Phenyl 2(3,4-DiOMe- 0 CH 2

CH

2

CH

2 Me Me CH N N Phenyl Phenyl )-Ethyl

I__I

1-287 COOH 4-OMe Phenyl 2(3,4-DiOMe- 0 CH 2

CH

2

CH

2 OMe Me CH N N Phenyl Phenyl 1-288 COOH 4-OMe Phenyl 2(3,4-DiOMe- 0 CH 2

CH

2

CH

2 2) Phenyl Phenyl )-Ethyl 1-289 COOH Phenyl Phenyl 2-("Thiophenyl)-Ethyl 0 CH 2

CH

2

CH

2 Me Me CH N IN [sic]_ 1-290 COOH Phenyl Phenyl "Thiophenyl)-Ethyl 0 CH 2

CH

2

CH

2 OMe Me CH N N [sic] 1-291 COOH Phenyl Phenyl 2-("Thiophenyl)-Ethyl 0 CH 2

CH

2

CH

2 2) 1_ [sic] I_ 1-292 COOH Phenyl Phenyl 2-(3,4,5-Tri OMe- 0 CH 2

CH

2

CH

2 Me Me CH N N _______Phenyl)-Ethyl

I___I

1-293 COOH Phenyl Phenyl 2-(3,4,5-Tri 0Me- 0 CH 2

CH

2

CH

2 OMe Me CH N N 1-294 COOH Phenyl Phenyl 2-(3,4,5-Tri OMe- 0 CH 2

CH

2

CH

2 2) Phenyl)-Ethyl I I_ Nr. R R4 R6Z B R 2

R

3 wX Y Het 1-295 COOH Phenyl Phenyl Hex-3E-enyl 0 CH 2

CH

2

CH

2 Me Me CH N N 1-296 COOH Phenyl Phenyl Hex-3E-enyl 0 CH 2

CH

2

CH

2 OMe Me CH N N 1-297 COOH Phenyl Phenyl Hex-3E-enyl 0 CH 2

CH

2

CH

2 OMe (CH 2

CH

2

CH

2 C) N IN 1-298 COOH Phenyl Phenyl Hex-3E-enyl 0 CH 2

CH

2

CH

2 OMe (OCH 2

CH

2 C) N N 1-299 COOH Phenyl Phenyl Hex-3E-enyl 0 CH 2

CH

2

CH

2 OMe OMe CH N N 1-300 COOH Phenyl Phenyl Hex-3E-enyl 0 CH 2

CH

2

CH

2 1 1-301 COOH Phenyl Phenyl Hex-3E-enyl 0 CH 2

CH

2

CH

2 2) 1-302 COOH Phenyl 3,4-DiOMe- 2-(3,4-Di OMe-Phenyl)- 0 CH 2

CH

2

CH

2 Me Me CH N N IPhenyl Ethyl I- I_ I_ 1* 2-(4,5-dimethyloxazolyl) 2* 2-(4,5-dimethylthiazolyl) 0050/48312 44 Example 12 Receptor binding data were measured by the binding assay described above for the compounds listed below.

The results are shown in Table 2.

Table 2 Receptor binding data (Ki values) Compound ETA Ki[nM] ETB Ki [nM] I-2 one diast. 43 345 1-224 one diast. 33 6.8 1-171 one diast. 15.7 26.4 1-145 one diast. 1100 13.6 1-137 one diast. 60 11 I-i one diast. 190 495 1-88 one diast. 50 1-89 one diast. 25 17 1-35 one diast. 400 250 1-36 one diast. 300 250 1-128 one diast. 46 9 1-129 one diast. 23 1-44 one diast. 205 365 1-45 one diast. 40 255 1-89 one diast. 35 93 1-10 one diast. 65 190 I-116 one diast. 9 43 1-290 one diast. 22 700 1-292 one diast. 1.8 170 1-293 one diast. 13 1-295 one diast. 215 1400

Claims

1. A carboxylic acid derivative of the formula I R 4 R 6 -Z-C-CH- 0- Het I I I B R where the substituents have the following meanings: R is tetrazole or a group O J- .C-RI R 1 is a radical OR 7 in which R 7 is: hydrogen, the cation of an alkali metal, the cation of an alkaline earth metal or a physiologically tolerated organic ammonium ion; Se C 3 -C-cycloalkyl, CI-C 8 -alkyl, CH 2 -phenyl, unsubstituted or substituted, C 3 -C 6 -alkenyl or a C 3 -C 6 -alkynyl group, unsubstituted or Ssubstituted, or phenyl, unsubstituted or substituted, eo R 2 is hydrogen, hydroxyl, NH 2 NH(C1-C 4 -alkyl), N(C 1 -C 4 -alkyl) 2 halogen, C1-C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, Cl-C 4 -haloalkyl, CI-C 4 -alkoxy, Ci-C 4 -haloalkoxy or C-C 4 -alkylthio, or CR 2 is linked to CRio as indicated below 40 to give a 5- or 6-membered ring, or, if Het is a o: five-membered ring, CR 2 can together with CR 3 be a 5- or

6-membered alkenyl or alkylenyl ring which is unsubstituted or substituted; X is nitrogen or methine; SY is nitrogen or methine; W is nitrogen or CR' 0 where R1 0 is hydrogen, halogen or Cl.. 4 -alkyl, or CR' 0 forms together with CR 2 or CR 3 a 5- or 6-membered alkylene or alkenylene ring which is unsubstituted or substituted and in which in each case one or more methylene groups can be replaced by oxygen, sulfur, -NH or -N(ClC 4 alkyl); R 3 is hydrogen, *hydroxyl, NH 2 NH(Cl-C 4 -alkyl), N(Cl-C 4 -alkyl) 2 halogen, CI-C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, Cl-C 4 -haloalkyl, Cl-C 4 -alkoxy, ClC 4 -haloalkoxy, Cl-C 4 -alkylthio; or CR 3 is linked to CR'O as indicated above to give a 5- or 6-membered ring; R 4 and R 5 (which may be identical or different) are: phenyl or naphthyl, unsubstituted or substituted, or phenyl or naphthyl which are linked together in the ortho positions by a direct linkage, a methylene, ethylene, or ethenylene group, an oxygen or sulfur atom or an S0 2 NH or N-alkyl group C 3 -C 8 -cycloalkyl, unsubstituted or substituted; *R 6 is hydrogen, Cl-C 8 -alkyl, C 3 -CB-alkenyl or C 3 -C 8 -alkynyl, it *:being possible for each of these radicals to be substituted one or more times by: halogen, hydroxyl, mercapto, carboxyl, nitro, amino, cyano, C 1 -C 4 -alkoxy, C 3 -C 6 -alkenyloxy, C 3 -C 6 -alkynyloxy, Cl-C 4 -alkylthio, C 1 -C 4 -haloalkoxy, Cl-C 4 -alkylcarbonyl, Cl-C 4 -alkoxycarbonyl, C 3 8 -alkylcarbonylalkyl, NH(C,-C 4 -alkyl), N(Cl-C 4 -alkyl) 2 C 3 -C 8 -cycloalkyl, hetaryloxy or hetaryl, five- or six-membered, containing one to three nitrogen atoms and/or one sulfur or oxygen atom, phenoxy or phenyl, it being possible for said aryl radicals in turn to be substitued one more times, eg. one to three times, by halogen, hydroxyl, mercapto, carboxyl, nitro, cyano, C-C 4 -alkyl, aio NH(C 1 -C 4 -alkyl), N(Cl-C 4 -alkyl) 2 or Cl-C 4 -alkylthio; phenyl or naphthyl, each of which can be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, amino, CI-C 4 -alkyl, Cl-C 4 -haloalkyl, Cl-C 4 -alkoxy, Cl-C 4 -haloalkoxy, phenoxy, Cl-C 4 -alkylthio, Cl-C 4 -alkylamino, C 1 -C 4 -dialkylamino, dioxomethylene .or dioxoethylene; 0050/48312 47 a five- or six-membered heteroaromatic system comprising one to three nitrogen atoms and/or one sulfur or oxygen atom, which may carry one to four halogen atoms and/or one to two of the following radicals: C 1 -C 4 -alkyl, Cl-C 4 -haloalkyl, Ci-C 4 -alkoxy, Ci-C 4 -haloalkoxy, Ci-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, Ci-C 4 -haloalkoxy and/or C1-C 4 -alkylthio; C 3 -C 8 -cycloalkyl, it being possible for these radicals to be substituted one or more times 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, Ci-C 4 -alkylthio, C 1 -C 4 -haloalkoxy; Z is sulfur or oxygen; B is C 2 -C 4 -alkylene Het is a heterocyclic radical of the formula Ia or Ib R 2 N R 2 Y4, V T R 3 X R 3 Ia Ib with T O, S, NR 8 R 8 is CI-C 6 alkyl and the physiologically tolerated salts and the enantiomerically pure forms. 2. The use of a carboxylic acid derivative as claimed in claim 1 for producing drugs. 0050/48312 Novel carboxylic acid derivatives, their preparation and use as mixed ETA/ETB receptor antagonists Abstract The invention relates to carboxylic acid derivatives of the formula I R 6 Z-C-CH- 0-Het B R where the radicals have the meanings stated in the description, and to the use thereof as drugs.