NZ502319A

NZ502319A - 3-Beta-amino and beta-azidocarboxylic acid derivates useful as endothelin receptor antagonists

Info

Publication number: NZ502319A
Application number: NZ502319A
Authority: NZ
Inventors: Wilhelm Amberg; Andreas Kling; Dagmar Klinge; Hartmut Riechers; Stefan Hergenroder; Manfred Raschack; Liliane Unger
Original assignee: Basf Ag
Priority date: 1997-06-19
Filing date: 1998-06-05
Publication date: 2002-03-01
Also published as: NO996268D0; HRP980331A2; HUP0002714A3; ZA985277B; CO4950605A1; CA2294050A1; KR20010013981A; WO1998058916A1; HUP0002714A2; SK176299A3; ID24346A; BG104022A; TR199903159T2; PL337507A1; DE19726146A1; EP0994861A1; AU8213398A; JP2002504130A; BR9810182A; CN1261352A

Abstract

An b-amino or b-azido carboxylic acid derivative has the formula (I) wherein: R1 is tetrazole or -C(=O)-R; R is OR4, -O-(CH2)p-S(O)k-R5, a 5 membered heteroaromatic system linked via a nitrogen atom, -NH-SO2-R5; A is NR7R8 or azido; W and Z are independently nitrogen or methine provided that Q is nitrogen if W and Z are methine; X is nitrogen or CR9; Y is nitrogen or CR10; Q is nitrogen or CR11 provided that if X is CR9 and Y is CR10 if Q is nitrogen; R2 and R3 are independently optionally substituted phenyl or naphthyl or phenyl or naphthyl is linked together in ortho position by a direct linkage, methylene, ethylene or ethenylene, oxygen, sulphur, SO2, NH or N-alkyl; R4 is H, alkali metal cation, alkaline earth metal cation, or a physiologically tolerated organic ammonium ion, optionally substituted cycloalkyl, alkyl or -CH2-phenyl. k is 0 to 2 and p is 1 to 4; R5 is alkyl, cycloalkyl, alkenyl, alkynyl or optionally substituted phenyl and R7 to R11 are defined in the specification. A pharmaceutical composition thereof is useful as an endothelin receptor antagonist. A compound of formula (II) A-C(R2)(R3)-CH(R1)-OH wherein A and R1 to R3 are as defined above s useful as a starting material to prepare the compounds of formula (I).

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number 502319 1 502319 Novel (3-amino and P-azido carboxylic acid derivatives, their preparation and use as endothelin receptor antagonists The present invention relates to novel carboxylic acid derivates, their preparation and use. Endothelin is a peptide which is composed of 21 amino acids and which 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 vessel tone. It is known that this vasoconstriction is caused by 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 diseases. As reported in the literature, endothelin is involved in a number of diseases. These include: hypertension, acute myocardial infarct, pulmonary hypertension, , Raynaud's syndrome, cerebral vasospasms, stroke, benign prostate hypertrophy, atherosclerosis, asthma and prostate cancer (J. Vascular Med. Biology 2, (1990) 207, J. Am. Med. Association 264. (1990) 2868, Nature 344, (1990) 114, N. Engl. J. Med. 322, (1989) 205, N. Engl. J. Med. 328, (1993) 1732, Nephron 66., (1994) 373, Stroke 25, (1994) 904, Nature 365, (1993) 759, J. Mol. Cell. Cardiol. 27, (1995) A234; Cancer Research 56, (1996) 663, Nature Medicine 1, (1995) 944). At least two endothelin receptor subtypes, ETA and ETB receptors, have to date been described in the literature (Nature 348, (1990) 730, Nature 348, (1990) 732). Accordingly, substances which inhibit the binding of endothelin to one or both receptors should antogonize the physiological effects of endothelin and therefore represent valuable drugs. It is an object of the present invention to provide endothelin receptor antagonists which bind to the ETAand/or ETBreceptor or to at least provide the public with a useful choice. The invention relates to p-amino and P-azido carboxylic acid derivatives of the formula I intellectual property office of n.z. - 1 OCT 2001 received 5023^9 R2 A C CH 0 I I R3 R1 where R1 is tetrazole or a group 0 1 where R has the following meaning: a) a radical OR4, where R4 is: hydrogen, the cation of an alkali metal, the cation of an alkaline earth metal or a physiologically tolerated organic ammonium ion such as tertiary Ci-C^-alkylammonium or the ammonium ion; Cj-Cg-cycloalkyl, C-L-Cg-alkyl, CH2-phenyl, which may be substituted by one or more of the following radicals: halogen, nitro, cyano, Cx-C^-alkyl, C^-C^-haloalkyl, hydroxyl, Ci-Q-alkoxy, mercapto, C1-C4-alkylthio, amino, NH (C1-C4-alkyl) , N (Ci-CValkyl) 2; C3-C8-alkenyl or C3-C8-alkynyl, it being possible for these groups in turn to carry one to five halogen atoms; R4 can furthermore be phenyl which may carry one to five halogen atoms and/or one to three of the following radicals: nitro, cyano, Cx-Cj-alkyl, Ci-^-haloalkyl, hydroxyl, ^-04-alkoxy, mercapto, Ci-Q-alkylthio, amino, NH (C1-C4-alkyl) , N(C1-C4-alkyl)2; b) a 5-membered heteroaromatic system linked via a nitrogen atom, such as pyrrolyl, pyrazolyl, imidazolyl and triazolyl, which may carry one or two halogen atoms or one or two C1-Ci-alkyl or one or two Ci-C^-alkoxy groups; c) a group w-x // * Z-Y Q intellectual property office of n.z. - 1 OCT 2001 received 5 10 15 20 25 30 35 40 45 0050/48085 3 (f)k —o—(CH2)p — s — R5 where k can assume the values 0, 1 and 2, p the values 1, 2, 3 and 4, and R5 is Ci-C4-alkyl, C3-C8-cycloalkyl, C3-C8-alkenyl, C3-C8-alkynyl or phenyl, which may be substituted by one or more, eg. one to three, of the following radicals: d) a radical 0 — NH—S R6 0 where R6 is: Ci-C4-alkyl, C3-C8-alkenyl, C3-C8-alkynyl, C3-C8-cycloalkyl, it being possible for these radicals to carry a Ci-C4-alkoxy, Cj-C4-alkylthio and/or a phenyl radical as mentioned under C); Ci-C4-haloalkyl or phenyl, unsubstituted or substituted in particular as mentioned under C). The other substitutents have the following meanings: A is NR7R8 or azido; W and Z (which may be identical or different) are: nitrogen or methine; with the proviso that Q = nitrogen if W and Z = methine; X is nitrogen or CR9; Y is nitrogen or CR10; Q is nitrogen or CR11; with the proviso that X = CR9 and Y = CR10 if Q = nitrogen 5023a9 R2 and R3 (which may be identical or different) are: phenyl or naphthyl, each of which may substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, mercapto, C-L-C^-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, Ci-Cj-hydroxyalkyl, Cj-C4-haloalkyl, C^-C^-alkoxy, phenoxy, Cx-C4-haloalkoxy, C^^-alkylthio, amino, NH(Ci-Q-alkyl) , N(C1-C4-alkyl)2 or phenyl which may be substituted one or more times, eg. one to three times, by halogen, nitro, cyano, Ci-Q-alkyl, Ca-C4-haloalkyl, Cj-C4-alkoxy, Ci-Qj-haloalkoxy or Cj-C^ alkylthio; or phenyl or naphthyl which are linked together in ortho positions by a direct linkage, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an S02, NH or N-alkyl group; C5-C6-cycloalkyl, it being possible for these radicals to be substituted in each case one or more times by: halogen, hydroxyl, mercapto, carboxyl, nitro, cyano, Cj.-C.j-alkyl, C2.C4-alkenyl, C2-C4-alkynyl, Q-^-alkoxy, C^Q-alkylthio, C^C*-haloalkoxy; R7 is hydrogen, C^-Ca-alkyl, C3-C8-alkenyl or C3-C8-alkynyl, C^Cs-alkylcarbonyl, it being possible for these radicals to be substituted in each case one or more times by: halogen, hydroxyl, mercapto, carboxyl, nitro, amino, cyano, alkoxy, C3-Cs-alkenyloxy, C3-C6-alkynyloxy, C^-Q-alkylthio, C^-C4-haloalkoxy, Ci-Q-alkoxycarbonyl, C3-C8-alkylcarbonylalkyl, NH (C1-C4-alkyl) , N (Cx - C4 - alky 1) 2, C3-C8-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 all said aryl radicals in turn to be substituted one or more times, eg. one to three times, by halogen, hydroxyl, mercapto, carboxyl, nitro, cyano, alkyl, Ci-Qj-haloalkyl, Ci-C^-alkoxy, C-L-C^-haloalkoxy, amino, NH (C1-C4-alkyl) , N(Ci-Q-alkyl) 2, phenyl, or Ci-^-alkylthio; phenyl or naphthyl, which can in each case be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, amino, Ci-C^-alkyl, Ci-Cj-haloalkyl, C^-Qj-alkoxy, Ct-C4-haloalkoxy, phenoxy, C^C^-alkylthio, carboxyl, NH (C^-C^-alkyl) , N (Ci-^-alkyl) 2, dioxomethylene or dioxoethylene; intellectual property office of nz. - 1 OCT 2001 received 0050/48085 10 40 5 c3-c8-cycloalkyl, it being possible for these radicals to be substituted in each case one or more times by: halogen, hydroxyl, mercapto, carboxyl, nitro, cyano, Ci-c4-alkyl, C2_C4-alkenyl, C2-C4-alkynyl, Ci-C4-alkoxy, Ci-C4-alkylthio, Ci-C4-haloalkoxy or; R7 is linked to R8 via 4 or 5 CH2 groups to give a 5- or 6-membered ring; R8 is hydrogen, C1-C4-alkyl; or R8 is linked to R7 via 4 or 5 CH2 groups to give a 5- or 6-membered ring; 15 R9 and R10(which may be identical or different) are: hydrogen, halogen, Ci-C4-alkoxy, C1-C4-haloalkoxy, C3_C6-alkenyloxy, C3-C6-alkynyloxy, Ci-C4-alkylthio, 20 Ci_C4-alkylcarbonyl, Ci-C4-alkoxycarbonyl, hydroxyl, NH2, NH(Ci-C4-alkyl), N(Ci-C4-alkyl)2 Ci-C4-alkyl/ C2-C4-alkenyl, C2-C4-alkynyl, it being possible for these radicals to be substituted by halogen, hydroxyl, 25 mercapto, carboxyl, cyano; or CR9 or CR10 is linked to CR11 as indicated for R11 to give a 5- or 6-membered ring, 30 Rii is hydrogen, halogen, Ci-C4-alkoxy, Ci-C4-haloalkoxy, C3-C6-alkenyloxy, C3-C6-alkynyloxy, Ci-C4-alkylthio, Ci-C4-alkylcarbonyl, Ci-C4-alkoxycarbonyl, NH(Ci-C4-alkyl), N(Ci-C4-alkyl)2, hydroxyl, carboxyl, cyano, amino, mercapto; 35 Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, it being possible for these radicals to be substituted one or more times by: halogen, hydroxyl, mercapto, carboxyl, cyano, amino, Ci-C4-alkoxy; 45 or CR11 forms together with CR9 or CR10 a 5- or 6-membered alkylene- or alkenylene ring which may substituted by one or two Ci-C4-alkyl groups, and in which in each case one or more methylene groups may be replaced by oxygen, sulfur, -NH or -N(Ci-C4-alkyl); 0050/48085 6 The definitions applying herein and hereafter are: 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 ethanolamine, 10 diethanolamine, ethylenediamine, diethylamine or piperazine; C3-C8-cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; Ci-C4-haloalkyl can be linear or branched, eg. fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trichloromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 20 2,2,2-trichloroethyl or pentafluoroethyl; C1-c4-haloalkoxy can be linear or branched, eg. difluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, 1-fluoroethoxy, 2,2-difluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2 5 2,2,2-trifluoroethoxy, 2-chloro-1,1,2-trifluoroethoxy, 2-fluoroethoxy or pentafluoroethoxy; Ci-C4-alkyl can be linear or branched, eg. methyl, ethyl, 30 1-propyl, 2-propyl, 2-methy1-2-propyl, 2-methyl-l-propyl, 1-butyl or 2-butyl; C2-C4-alkenyl can be linear or branched, eg. ethenyl, l-propen-3-yl, l-propen-2-yl, 1-propen-l-yl, 2-methyl-1-propenyl, 35 l-butenyl or 2-butenyl; c2-C4-alkynyl can be linear or branched, eg. ethynyl, 1-propyn-l-yl, l-propyn-3-yl, l-butyn-4-yl or 2-butyn-4-yl; Ci-C4-alkoxy can be linear or branched eg. methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or 1,1-dimethylethoxy; C3-C6-alkenyloxy can be linear or branched, eg. allyloxy, 45 2-buten-l-yloxy or 3-buten-2-yloxy; 7 50 231 C3-C6-alkynyloxy can be linear or branched eg. 2-propyn-l-yloxy, 2-butyn-l-yloxy or 3-butyn-2-yloxy; Cx-Q-alkylthio can be linear or branched eg. methylthio, ethylthio, propylthio, l-methylethylthio, butylthio, 1-methylpropylthio, 2-methylpropylthio or 1,1-dimethylethylthio; Ci-Cj-alkylcarbonyl can be linear or branched, eg. acetyl, ethylcarbonyl or 2-propylcarbonyl; Ci-^-alkoxycarbonyl can be linear or branched, eg. metoxycarbonyl [sic], ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl or n-butoxycarbonyl; C3-Cs-alkylcarbonylalkyl can be linear or branched eg. 2-oxo- 1-propyl, 3-oxo-l-butyl or 3-oxo-2-butyl Ci-Cg-alkyl can be linear or branched eg. C-L-Q-alkyl, pentyl, hexyl, heptyl or octyl; C3-C8-alkenyl can be linear or branched, eg. l-propen-3-yl, l-propen-2-yl, 1-propen-l-yl, 2-methyl-1-propenyl, l-buten-4-yl, 2-buten-3-yl, l-penten-5-yl, l-hexen-6-yl, 3-hexen-6-yl, 2-hepten-7-yl or l-octen-8-yl; C3-C8-alkynyl can be linear or branched eg. 1-propyn-l-yl, l-propyn-3-yl, l-butyn-4-yl, 2-butyn-4-yl, 2-pentyn-5-yl, 3-hexyn-6-yl, 3-heptyn-7-yl, 2-octyn-8-yl; Halogen is, for example, fluorine, chlorine, bromine, iodine. The invention further relates to those compounds from which the compounds of the formula I can be liberated (called prodrugs). Preferred prodrugs are those whose release takes place under conditions prevailing in certain compartments of the body, eg,, in the stomach, intestine, blood circulation, liver. The compounds I and the intermediates for preparing them, eg. II and III, may have one or more asymmetrically substituted carbon atoms. Compounds of this type can exist as pure enantiomers or intellectual property office of n.z. 1 1 DEC 2001 received 0050/48085 8 pure diastereomers or as mixture 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 to produce drugs, in particular to produce inhibitors of ETA and/or ETB receptors. The novel compounds are suitable as antagonists as defined at the outset. ^ Preparation of compounds of the formula II where A is an azido group (Ila) starts from the epoxides III which can be synthesized, for example, as described in WO 96/11914. These epoxides III can then be reacted with an azide such as sodium azide. This is done by reacting the compounds of the formula III ^ with the azide in the molar ratio of about 1:1 to 1:7 at from 20 to 150°C to give Ila. H C OH R1 25 The reaction may also take place in the presence of a diluent. All solvents which are inert toward the reagents can be used for this purpose. Examples of such solvents or 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, ethyl chloride and trichloroethylene, ethers such as diisopropyl ether, dibutyl ether, methyl tert-butyl ether, 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. The reaction is moreover preferably carried out at a temperature in the range from 0°C to the boiling point of the solvent or mixture of solvents. The presence of a catalyst may be advantageous. Suitable 45 catalysts are strong organic and inorganic acids, and Lewis acids. Examples thereof include sulfuric acid, hydrochloric acid, 20 R2 R3 0 Rl III + N3Na > N-, R2 R3 Ila 9 502319 trifluoroacetic acid, p-toluenesulfonic acid, boron trifluoride etherate and triflates of the rare earths. The preparation of the novel compounds of the formula I where A is an azido group (la) can be prepared, for example, by reacting the carboxylic acid derivatives of the formula Ila where the substituents have the stated meanings with compounds of the formula IV. Ila + R12 IV w '/ X \\ Z = Y N, la R2 H C R3 R1 0 w '/ X \\ R12 in formula IV is halogen or R13-S02- where R13 can be C^-C^-alky!, C-t-Q-haloalkyl or phenyl, and the conditions [sic] specified at the outset apply to W,X,Y,Z and Q. The reaction preferably takes place in an inert solvent or diluent with the addition of a suitable base, ie. a base which effects deprotonation of the intermediate Ila, at a temperature in the range from room temperature to the boiling point of the solvent. Compounds of the formula IV are known, and some of them can be bought or can be prepared in a generally known manner. Compounds of type la with R1 = COOH can be obtained directly by deprotonating the intermediate Ila where R1 is COOH with two equivalents of a suitable base, and reacting with compounds of the formula IV. 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. The base which can be used is 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. Novel compounds of the formula I where A is an amino group (lb) are prepared starting from compounds la. This is done by reacting the compounds of the formula la with hydrogen in the presence of intellectual property office of n.z. - 1 OCT 2001 received 5023^ a catalyst such as palladium or platinum in a solvent at from 20 to 100_C. The compounds la can also be converted into lb in the presence of triphenylphosphine. n, la R2 h — c- I r3 r1 r2 0 w- x '/ v z = y Q h2n-lb h C r3 r1 W // x \\ z = y If R1 is an ester, the amino group in lb can be alkylated or converted into the amide by generally known methods. The ester group can then be cleaved with acid or base to the carboxylic acid. Compounds of the formula II where A is substituted amine (lie) can also be prepared directly from the epoxide III by opening with an amine. The substances lie can then be reacted with IV as described above to give the novel compounds I. Compounds of the formula I can also be prepared by starting from the corresponding carboxylic acids, ie. compounds of the formula I where R1 is COOH, and initially converting these in a conventional way into an activated form, such as a halide, an anhydride or imidazolide, and then reacting the latter with an appropriate hydroxyl compound HOR4 or sulfonamide H2NS02Rs. This reaction can be carried out in the usual solvents and often requires addition of a base, in which case those mentioned above are suitable. These two steps can also be simplified, for example, by allowing the carboxylic acid to act on the hydroxyl compound or the sulfonamide in the presence of a dehydrating agent such as a carbodiimide. Compounds of the formula I can also be prepared in addition by starting from salts of the corresponding carboxylic acids, ie. from compounds of the formula I where R1 is COR and R is OH 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-D where D is a usual nucleofugic leaving group, for example halogen such as chlorine, bromine, iodine or aryl- or alkylsulfonyl which is unsubstituted or substituted by halogen, alkyl or haloalkyl, eg. toluenesulfonyl and methylsulfonyl, or another equivalent leaving group. Compounds of the formula R-D with a reactive substituent D are known or can easily be obtained with general expert knowledge. intellectual property office of n.z. - 1 OCT 2001 RECEIVED 11 advantageously with the addition of a base, in which case those mentioned above are suitable. Compounds of the formula I where R1 is tetrazole can be prepared by methods similar to those described in WO 96/11914 from the corresponding carboxylic acids (formula I with R1 = COOH) . It is necessary in some cases to use generally known protective group techniques to prepare the novel compounds I. If, for example, A is to be HOCH2CONH-, the hydroxyl group can initially be protected as benzyl ether, which is then cleaved at a suitable stage in the reaction sequence. Compounds of the formula I and II can be obtained in enantiomerically pure form by carrying out a classical racemate resolution with suitable enantiomerically pure bases, as described, for example, in WO 96/11914, on racemic or diastereomeric compounds of the formula I and II. With a view to the biological effect, preferred carboxylic acid derivatives of the formula I, both as pure enantiomers and pure diastereomers or as mixture thereof, are those where the substituents have the following meanings: A is NR7R8 or azido; W and Z, (which may be identical or different) are: nitrogen or methine; with the proviso that Q = nitrogen if W and Z = methine; X is nitrogen or CR9; Y is nitrogen or CR10; Q is nitrogen or CR11; with the proviso that X = CR9 and Y = CR10 if Q = nitrogen; furthermore Q for which, in addition to the stated conditions, the following applies: Y = CR10 or X = CR9 if Q = CR11. R2 and R3 (which may be identical or different) are: phenyl or naphthyl, each of which may substituted by one or more of the following radicals: halogen, cyano, hydroxyl, mercapto, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, phenoxy, C1-C4-haloalkoxy, C1-C4-alkylthio, amino, NH (C1-C4-alkyl) , N(Cj- intellectual property office of n.z. - 1 OCT 2001 D C P r in r > 12 1 9 C4-alkyl)2 or phenyl which may be substJwired %fte^>r more times, eg. one to three times, by halogen, cyano, Q-^-alkyl, C1-C4-haloalkyl, Ci-C^alkoxy, Ci-C^haloalkoxy or C^-CV alkylthio; or phenyl or naphthyl which are linked together in orthopositions via a direct linkage, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an S02-, NH- or N-alkyl group; is hydrogen, C^-Ca-alkyl, C3-C8-alkenyl or C3-C8-alkynyl, C^CV alkylcarbonyl, it being possible for these radicals to be substituted in each case one or more times by: halogen, hydroxyl, mercapto, carboxyl, amino, cyano, C^Q-alkoxy, C3-C6-alkenyloxy, C3-C6-alkynyloxy, Cj-Q-alkylthio, Ci-C,,-haloalkoxy, Qi-C^alkoxycarbonyl, NH(C1-C4-alkyl) , N(C;,.-C4-alkyl)2, C3-C8-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 all said aryl radicals in turn to be substituted one or more times, eg. one to three times, by halogen, hydroxyl, mercapto, carboxyl, cyano, C^Q-alkyl, Cx-C4-haloalkyl, Ci-C^-alkoxy, C^-CVhaloalkoxy, amino, NH (Cx-C4-alkyl) , N (Ci-Q-alkyl) 2, or C-L-C^alkylthio; phenyl or naphthyl, which can in each case be substituted by one or more of the following radicals: halogen, cyano, hydroxyl, amino, Ci-C^-alkyl, C^-C^-haloalkyl, phenoxy, C^-C^ alkoxy, C^-C^-haloalkoxy, C^-C^-alkylthio, dioxomethylene, NH (Cj-Q-alkyl) , N (C^Q-alky!) 2 or dioxoethylene; C3-C8-cycloalkyl, it being possible for these radicals to be substituted in each case one or more times by: halogen, hydroxyl, mercapto, carboxyl, C^-Cj-alkyl, C2.C4-alkenyl, C2-C4-alkynyl, Cj-C^-alkoxy, Q-Q-alkylthio, Cj-C^-haloalkoxy; is hydrogen; and R10 (which may be identical or different) : hydrogen, halogen, C^Q-alkoxy, Ci-^-haloalkoxy, C^C,,-alkylthio, NH (C^Q-alky!) , N(C1-C4-alkyl) 2; intellectual property office of n.z. - 1 OCT 2001 DCPCIlirn 0050/48085 13 5 RH 10 15 20 Particularly preferred compounds of the formula I, both as pure enantiomers and pure diastereomers or as mixture thereof, are those where the substituents have the following meanings: 25 A is NR7R8 or azido; W and Z (which may be identical or different) are: 30 nitrogen or methine; with the proviso that Q = nitrogen if W and Z = methine; X is nitrogen or CR9; 35 Y is nitrogen or CR10; Q is nitrogen or CR11; with the proviso that X = CR9 and Y = CR10 if Q = nitrogen, and Y = CR10 or X = CR9 if Q = CR11; 40 R2 and R3 (which may be identical or different) are: phenyl which may be substituted by one or more of the following radicals: halogen, Ci-C4-alkyl, Ci-C4-haloalkyl, ^ Ci-C4-alkoxy, phenoxy, C1-C4-alkylthio, NH(Ci-C4-alkyl), N(Ci-C4-alkyl)2 or phenyl which can be substituted one or more Ci-C4-alkyl, C2-C4-alkenyl, it being possible for these radicals to be substituted by halogen, hydroxyl, mercapto, cyano; or CR9 or CR10 is linked to CR11 as indicated for R11 to give a 5- or 6-membered ring; is hydrogen, halogen, Ci_C4-alkoxy, Ci-C4-haloalkoxy, Ci-C4-alkylthio, NH(Ci-C4-alkyl), N(Ci-C4-alkyl)2, cyano; Ci-C4-alkyl, C2-C4-alkenyl, it being possible for these radicals to be substituted in each case one or more times by: halogen, cyano, Ci-C4-alkoxy; or CR11 forms together with CR9 or CR10 a 5- or 6-membered alkylene or alkenylene ring which may be substuituted by one or two Ci-C4-alkyl groups, and in which in each case one or more methylene groups can be replaced by oxygen, sulfur, -NH or -N(Ci-C4-alkyl); 50231< times, eg. one to three times, by halogen, Ci-C^-alkyl, Ci-Ct-haloalkyl, ^-Q-alkoxy or C1-C4-alkylthio; or phenyl groups which are linked a direct linkage, a methylene, an oxygen or sulfur atom or an together in orthopositions by ethylene or ethenylene group, S02, NH or N-alkyl group; is hydrogen, C^Cg-alkyl, C3-C8-alkenyl or C3-C8-alkynyl, C1-C5-alkylcarbonyl_, it being possible for these radicals to be substituted in each case one or more times by: halogen, hydroxyl, carboxyl, amino, Ci-C^-alkoxy, C-L-Q-alkylthio, C^C,-alkoxycarbonyl, NH (Ci-C^-alkyl) , N (C-L-Qj-alkyl) 2, C3-C8-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 substituted one or more times, eg. one to three times, by halogen, hydroxyl, mercapto, carboxyl, cyano, Cj-Q-alkyl, Ci-C^-haloalkyl, C^-C^-alkoxy, amino, NH (Ci-C^-alkyl) , N (C^-C^-alky!) 2, or Cj-C^-alkylthio ; phenyl or naphthyl, each of which can be substituted by one or more of the following radicals: halogen, cyano, C^-Q-alkyl, Ci-C^-haloalkyl, phenoxy, Ci-C^-alkoxy, Ci-Q-alkylthio, dioxomethylene or dioxoethylene ,- C5-C6-cycloalkyl, it being possible for these radicals in each case to be substituted one or more times by: C^-C^-alkyl, Cx-C4-alkoxy ; R8 is hydrogen; and R10 (which may be identical or different) are: hydrogen, C^-Ca-alkoxy, Ci-C^-alkylthio, N(Cx-Q-alkyl) 2; C^-Qj-alkyl, it being possible for these radicals to be substituted by halogen; or CR9 or CR10 is linked to CR11 as indicated for R11 to give a 5- or 6-membered ring; is hydrogen, Ci-C^-alkoxy, Ci-^-alkylthio, cyano; intellectual property office of n.z. - 1 OCT 2001 received 0050/48085 15 Ci-C4~alkyl, it being possible for these radicals in each case to be substituted one or more times by halogen; 10 15 20 or CR11 forms together with CR9 or CR10 a 5- or 6-membered alkylene or alkenylene ring which may be substituted by one or two Ci-c4-alkyl groups and in which, in each case, one or more methylene groups can be replaced by oxygen, sulfur, -NH or -N(Ci-c4-alkyl); The compounds of the present invention offer a novel potential treatment of hypertension, pulmonary hypertension, myocardial infarct, chronic heart failure, 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 hyperplasia, ischemic and intoxication-induced kidney failure or hypertension, cyclosporin-induced kidney failure, metastasis and growth of mesenchymal tumors, cancer, prostate cancer, contrast agent-induced kidney failure, pancreatitis, gastrointestinal ulcers. The invention further relates to combination products consisting 25 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, in particular, angiotensin converting enzyme (ACE) inhibitors. 30 The combinations can be administered together in one pharmaceutical form or temporally and spatially separate. The factors to be taken into account in respect of dosage and mode of administration are the same as for the corresponding single substances. These combination products are particularly suitable for treating and preventing hypertension and its sequelae, and for treating heart failure. The invention further relates to the use of the novel compounds for photoaffinity labeling of endothelin receptors. Particularly 45 suitable for this purpose are those compounds of the formula I where A is azido. 16 The good effect of the compounds can be shown in the following tests: Receptor-binding studies Cloned human ETA or ETBreceptor-expressing CHO cells were employed for binding studies. Membrane preparation The ETa or ETB receptor-expressing CHO cells were grown in DMEM NUT MIX F12 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 mg/ml streptomycin (Gibco, Sigma No. P-0781). After 48 hours, the cells were washed with PBS and incubated with 0.05% trypsin-containing PBS at 37°C for 5 minutes. This was followed by neutralization with medium, and the cells were collected by centrifugation at 3 00 x g. 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 20). Binding assays For the ETA and ETBreceptor-binding assay, the membranes were suspended in incubation buffer (50 mM Tris-HCl, pH 7.4 with 5 mM MnCl2, 40 mg/ml bacitracin and 0.2% BSA) in a concentration of 50 mg of protein per assay mixture and incubated with 25 pM [1251]-ETX (ETA-receptor assay) or 25 pM [1251]-ET3 (ETB receptor assay) in the presence and absence of test substance at 25°C. The nonspecific binding was determined using 10~7 M ETX. After 30 min, filtration through GF/B glass fiber filters (Whatman, England) in a Skatron cell collector (Skatron, Lier, Norway) separated free and bound radio ligand, 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. intellectual property office of n.z. - 1 OCT 2001 received 0050/48085 17 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 cathetized. In control animals, intravenous administration of 1 ng/kg ETl results in a marked rise in blood pressure which persists for a lengthy period. The test animals received i.v. injection (1 ml/kg) of the test compounds 30 min before administration of ETl. To determine the ET-antagonistic properties, the changes in blood pressure in the 15 test animals were compared with those in the control animals. Oral testing of ET receptor antagonists: Male normotensive rats (Sprague Dawley, Janvier) weighing 20 250-350 g are pretreated with the test substances orally. 80 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. 25 After a stabilization period, big endothelin (20 fig/kg, admin, vol. 0.5 ml/kg) or ETl (0.3 \ig/kg, admin, vol. 0.5 ml/kg) is given intravenously. Blood pressure and heart rate are recorded 2Q 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. 35 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 40 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 45 weight on oral administration and from about 0.1 to 10 mg/kg of body weight on parenteral administration. 0050/48085 18 The novel compounds can be administered 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 5 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 10 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. 15 Synthesis Examples Example 1: 20 Methyl 2-hydroxy-3-azido-3,3-diphenylpropionate 3.8 g (59.0 mmol) of sodium azide and 3.1 g (59.0 mmol) of ammonium chloride were introduced into 80 ml of methanol. 5 g (19.7 mmol) of methyl 3,3-diphenyl-2,3-epoxypropionate were added 25 to this suspension, which was then stirred at room temperature for 48 hours. The mixture was concentrated, water was added, and the aqueous phase was extracted several times with ethyl acetate. The combined organic phases were then dried over magnesium sulfate, the solvent was distilled off, and the residue was 30 purified by chromatography. 1.2 g (4 mmol, 21% yield) of pure product were isolated. Melting point: 102-103°C 35 , I-H-NMR (200 MHz): 7.2 ppm (10 H, m) , 5.1 (1 H, d) , 3.5 (3 H, s), 3.4 (1 H, d). Example 2: 40 Methyl 2-(4-methoxy-6-methyl-2-pyrimidinyloxy)-3-azido-3,3-diphenylpropionate 930 mg (6.7 mmol) of potassium carbonate, 1.4 g (6.7 mmol) of 45 4-methoxy-6-methyl-2-methylsulfonylpyrimidine and 2.0 g (6.7 mmol) of methyl 2-hydroxy-3-azido-3,3-diphenylpropionate were mixed in 20 ml of DMF. The mixture was stirred at 80°C for 0050/48085 19 two hours. Cooling and addition of water were followed by extraction with ethyl acetate. The combined organic phases were dried over magnesium sulfate, and the solvent was distilled off. 2.9 g of a crude oil were isolated and were immediately reacted 5 further. Example 3: Methyl 2-(4-methoxy-6-methyl-2-pyrimidinyloxy)-3-amino-3,3-diphenylpropionate 2.8 g (6.7 mmol) of methyl 2-(4-methoxy-6-methyl-2-pyrimidinyloxy)-3-azido-3,3-diphenylpropionate were dissolved in 15 20 ml/40 ml of methanol/ethyl acetate, and a spatula tip of palladium on carbon was added. After the apparatus had been flushed with nitrogen and then with hydrogen, the solution was stirred under atmospheric pressure at room temperature for three hours. After conversion was complete, the palladium on carbon was 20 filtered off and the solvent was distilled off. 2.9 g of crystals were isolated and immediately reacted further. Example 4: OC 2-(4-Methoxy-6-methyl-2-pyrimidinyloxy)-3-amino-3,3-diphenylpropionic acid (1-375) 840 mg (2.1 mmol) of methyl 2-(4-methoxy-6-methyl-3Q 2-pyrimidinyloxy)-3-amino-3,3-diphenylpropionate were added to a mixture of 6.4 ml of dioxane and 3.2 ml of 1 N potassium hydroxide solution, and the mixture was stirred at 80°C for two hours. Cooling, addition of water and acidification were followed by extraction with ethyl acetate. The combined organic phases 35 were dried over magnesium sulfate, and the solvent was distilled off. The residue was stirred with ether, which allowed 190 mg (0.5 mmol, 25% yield) of crystals to be isolated. ^•H-NMRf 360 MHz/DMSC>/303K) : 7.7 ppm (1 H, broad), 7.4 (4 H, m), 7.2 40 (6 H, m), 5.9 1 H, broad), 5.1 (1 H, s), 3.2 (3 H, broad), 2.1 (3 H, s). iH-NMR (360 MHz/DMSO/323 K): 7.7 PPm [sic] (1 H, broad), 7.4 (4 H, m), 7.2 (6 H, m), 5.9 (1 H, s), 5.1 (1 H, s), 3.2 (3 H, s), 45 2.1 (3 H, s). Example 5: 20 5023'iC 2-(4,6-Dimethoxy-2-pyrimidinyloxy)-3-azido-3,3-diphenylpropionic acid (1-542) 5 1.1 g (2.5 mmol) of methyl 2-(4,6-dimethoxy-2-pyrimidinyloxy)-3-azido-3,3-diphenylpropionate were added to a mixture of 11 ml of dioxane and 5 ml of 1 N potassium hydroxide solution, and the ^ mixture was stirred at 50°C for three hours. Cooling, addition of water and acidification were followed by extraction with ether. The combined organic phases were dried over magnesium sulfate, and the solvent was distilled off. 900 mg (2.1 mmol, 85% yield) of crystals were isolated. 15 Melting point: 164-165°C ESI-MS: M+ = 421 Example 6: 20 Methyl 2-(4,6-dimethoxy-2-pyrimidinyloxy)-3-acetylamino-3,3-diphenylpropionate 25 A catalytic amount of DMAP and 1 g (2.4 mmol) of methyl 2-(4,6-dimethoxy-2-pyrimidinyloxy)-3-amino-3,3-diphenylpropionate were dissolved in 10 ml of pyridine. While cooling in ice, 0.26 ml (3.7 mmol) of acetyl chloride was added dropwise, and the 30 mixture was stirred at room temperature for 12 hours. Water was added, and the mixture was extracted with ether. The combined organic phases were dried over magnesium sulfate, and the solvent was distilled off. The residue was mixed with ether, and the compound starts to crystallize out after a short time (1 g, 35 2.2 mmol, 90% yield). The compound could be used further without further purification. Example 7: 40 2-(4, 6-Dimethoxy-2-pyrimidinyloxy)-3-acetylamino-3,3-diphenylpropionic acid (1-174) 1 g (2.2 mmol) methyl 2-(4,6-dimethoxy-2-pyrimidinyloxy)-3-acetylamino-3,3-diphenylpropionate was added to a mixture of 8.8 ml of dioxane and 4.4 ml of 1 N potassium hydroxide solution, and the mixture was stirred at 80°C for one hour. Cooling and intellectual property office of n.z. - 1 OCT 2001 received 50 2 3• addition of water were followed by extraction once with ether. Acidification was then followed by extraction with methyl fcerfc -butyl ether. The combined organic phases were dried over magnesium sulfate, and the solvent was distilled off. The residue 5 was stirred with ether to allow isolation of 640 mg (1.5 mmol, 67% yield) of crystals. Melting point: 120-121°C ESI-MS: M+ = 437 10 Example 8: Methyl 2-(4-methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-15 yloxy)-3-azido-3,3-diphenylpropionate 743 mg (5.4 mmol) of potassium carbonate, 2.5 g (10.8 mmol) of 4-methoxy-6,7-dihydro-5H-cyclopenta-2-methylsulfonylpyrimidine and 3.0 g (10.8 mmol) of methyl 2-hydroxy-3-azido-3,3- on diphenylpropionate were mixed m 20 ml of DMF. The mixture was stirred at 60°C for three hours. Cooling and addition of water were followed by extraction with ethyl acetate. The combined organic phases were dried over magnesium sulfate, and the solvent was distilled off. 3.7 g (8.3 mmol, 77% yield) of crystals were 2 5 isolated and were immediately reacted further. Example 9: 30 2-(4-Methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-yloxy)-3-azido-3,3-diphenylpropionic acid (1-518) 3.7 g (8.3 mmol) of methyl 2-(4-methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-yloxy)-3-azido-3,3-diphenylpropionate were 35 added to a mixture of 33 ml of dioxane and 17 ml of 1 N potassium hydroxide solution, and the mixture was stirred firstly at 50°C for two hours and then at room temperature for 12 hours. Water was added, and impurities were extracted with ether. Acidification was then followed by extraction with ether. The 40 combined organic phases were dried over magnesium sulfate, and the solvent was distilled off. The residue was crystallized from ether/n-hexane, allowing 2.6 g (5 mmol, 60% yield) of crystals to be isolated. ^ Melting point: 143-144°C intellectual property office of n.z. - 1 OCT 2001 received 22 ESI-MS: M+ = 431 Example 10: 5 The following compounds were prepared in a similar way to the examples described above. 2-(4,6-Dimethoxy-2-pyrimidinyloxy)-3-amino-3,3-diphenylpropionic 10 acid (1-354) Melting point: 159-160°C ESI-MS: M+ = 395 15 2-(4-Methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-yloxy)-3-amino-3,3-diphenylpropionic acid (1-334) Melting point: 119-120°C 20 ESI-MS: M+ = 405 50 23 1 ^ 2-(4,6-Dimethoxy-2-pyrimidinyloxy)-3-methoxyacetylamino-3,3-diphenylpropionic acid (1-535) Melting point: 187-188°C ESI-MS: M+ = 467 2-(4,6-Dimethoxy-2-pyrimidinyloxy)-3-(2,2-dimethyl-30 propylcarbonylamino)-3,3-diphenylpropionic acid (1-3 88) Melting point: 198-199°C 1H-NMR(200 MHz): 7.5 ppm (2 H, m), 7.2 (8 H, m) , 6.7 (1H, s), 6.5 35 (1 H, S), 5.7 (1 H, s), 3.8 (6 H, s), 2.1 (2 H, s), 1.0 (9 H, s). 2-(4,6-Dimethoxy-2-pyrimidinyloxy)-3-cyclopropylcarbonylamino-3,3-diphenylpropionic acid (1-227) 40 Melting point: 206-207°C ESI-MS: M+ = 463 2-(4, 6-Dimethoxy-2-pyrimidinyloxy)-3-p-nitrobenzoylamino-3,3-42 diphenylpropionic acid (1-541) Melting point: 219-220°C intellectual property office of n.z. - 1 OCT 2001 received 23 ESI-MS: M+ = 544 5023l9 The compounds listed in Table 1 can be prepared in a similar way or as described in the general part. 5 10 15 20 25 30 35 40 45 intellectual property office of n.z. - 1 OCT 2001 received Table I R2 | W -x a c ch 0 q i i z=y' r3 r1 No. r1 r2,r3 A W X Q Y Z 1-1 COOH Phenyl cf3conh- CH C-Me N C-Me N 1-2 COOH Phenyl cf3conh- CH C-OMe N C-Me N 1-3 COOH 4-F-Phenyl n3 CH C-Me N C-OMe N 1-4 COOH 4-F-Phenyl n3 CH C-Ethyl N C-Me n 1-5 COOH Phenyl 3,4-Di-OMe-Phenyl-CH2-CONH- n N C-Me C-OMe CH 1-6 COOH Phenyl 3,4-Di-OMe-Phenyl-CH2-CONH- n C-OMe C-Me N CH 1-7 COOH 4-Cl-Phenyl n3 n C-Me CH C-Me n 1-8 COOH 4-F-Phenyl n3 n C-Me n C-OMe n 1-9 COOH 4-F-Phenyl n3 n C-Ethyl n C-Me n i-10 COOH 4-Me-Phenyl n3 n C-OMe CH C-Me n 1-11 COOH Phenyl n3 n c-cf3 CH C-OMe n 1-12 COOH Phenyl Ethyl-CONH- n C-Ethyl CH C-Me N No. R1 R2, R3 A w X Q Y Z 1-13 COOH Phenyl Ethyl-CONH- N C-CH2-CH2-CH2-C C-OMe N 1-14 COOH Phenyl n3 N C-SMe CH C-Me N 1-15 COOH Phenyl n3 N C-ch2-ch2-ch2-ch2-C C-OMe n 1-16 COOH Phenyl 3-OMe-4-OH-Phenyl-CH2-CONH- CH C-Me N C-OMe n 1-17 COOH Phenyl 3-OMe-4-OH-Phenyl-ch2-CONH- CH C-Ethyl N C-Me N 1-18 COOH Phenyl n3 n C-S-ch2-ch2-C C-OMe n 1-19 COOH 4-Cl-Phenyl n3 N C-Me n C-Me N 1-20 COOH Phenyl n3 N C-NH(CH3) N C-NH(CH3) n 1-21 COOH Phenyl cf3conh- N C-OMe C-Me N CH 1-22 COOH Phenyl cf3conh- N N C-Me C-OMe n 1-23 COOH Phenyl n3 n C-Ethyl n C-Ethyl n 1-24 COOH Phenyl n3 N n CH C-OMe CH 1-25 COOH Phenyl 3,4-Di-OMe-Phenyl-CH2-CONH- N C-Me n C-OMe n 1-26 COOH Phenyl 3,4-Di-OMe-Phenyl-CH2-CONH- n C-Ethyl n C-Me n 1-27 COOH Phenyl n3 N C-OMe CH n CH 1-28 COOH 4-F-Phenyl n3 N C-O-ch2-ch2-C C-OMe n 1-29 COOH 4-F-Phenyl n3 N C-Me n C-Me n 1-30 COOH 4-Me-Phenyl n3 N N C-Me C-OMe N 1-31 COOH Phenyl n3 CH C-Ethyl n C-Me CH 1-32 COOH Phenyl Ethyl-CONH- N C-OMe CH C-Me N 1-33 COOH Phenyl Ethyl-CONH- N C-OMe CH C-OMe N 1-34 COOH Phenyl n3 CH C-Me n C-Ethyl n # No. R1 R2, R3 A W X Q Y Z 1-35 COOH 4-Cl-Phenyl n3 CH C-OMe N C-Me N 1-36 COOH Phenyl 3-OMe-4-OH-Phenyl-CH2-CONH- CH C-Me N C-Me N 1-37 COOH Phenyl 3-OMe-4-OH-Phenyl-ch2-CONH- CH C-OMe N C-Me N 1-38 COOMe Phenyl n3 CH C-Me N C-OMe N 1-39 COOH Phenyl n3 CH C-OMe N C-OMe N 1-40 COOH 4-F-Phenyl h2n- n C-Me CH C-Me CH 1-41 COOH Phenyl cf3conh- n C-Ethyl N C-Me N 1-42 COOH Phenyl cf3conh- n N C-Me C-OMe CH 1-43 COOH 4-F-Phenyl h2n- n C-Me CH C-Me N 1-44 COOH 4-Cl-Phenyl h2n- n C-OMe CH C-Me N 1-45 COOH Phenyl 3,4-Di-OMe-Phenyl-CH2-CONH- n C-O-ch2-ch2-C C-OMe N 1-46 COOH Phenyl 3,4-Di-OMe-Phenyl-CH2-CONH- n C-Me n C-Me n 1-47 COOH Phenyl H2N- n C-CF3 CH C-OMe n 1-48 COOH 4-F-Phenyl n3 n C-Ethyl CH C-Me n 1-49 COOH 4-F-Phenyl n3 n C-CH2-CH2-CH2-C C-OMe n 1-50 COOH Phenyl h2n- n C-Ethyl CH c-cf3 n 1-51 COOH Phenyl h2n- n C-CH2-CH2-CH2-C C-Ethyl N 1-52 COOH Phenyl ch3conh- CH C-Ethyl n C-Me N 1-53 COOH Phenyl Ethyl-CONH- n C-Me CH C-Me n 1-54 COOH Phenyl h2n- n C-O-ch2-ch2-C C-Ethyl n 1-55 COOH 2-F-Phenyl h2n- n C-Me n C-Me N 1-56 COOH Phenyl 3-OMe-4-OH-Phenyl-ch2-CONH- n N C-Me C-OMe n o o ut o s. rt* 00 o 00 U1 Is) C\ No. R1 R2,R3 A w X Q Y Z 1-57 COOH Phenyl 3-OMe-4-OH-Phenyl-ch2-CONH- CH C-Me N C-Me CH 1-58 COOH Phenyl h2n- n C-Me N C-SMe N 1-59 COOH Phenyl h2n- n C-Ethyl n C-CF3 n 1-60 COOH Phenyl h2n- N N CH C-OMe CH 1-61 COOH Phenyl cf3conh- n C-Me N C-Me N 1-62 COOH Phenyl cf3conh- N C-Me N C-OMe N 1-63 COOH Phenyl h2n- N C-OMe CH N CH 1-64 COOH Phenyl h2n- N C-Me C-Me N N 1-65 COOH Phenyl 3,4-Di-OMe-Phenyl-CH2 -CONH- n C-Ethyl CH C-Me N 1-66 COOH Phenyl 3,4-Di-OMe-Phenyl-CH2-CONH- N c-ch2-ch2-ch2-c C-OMe N 1-67 COOH 4-F-Phenyl h2n- N N C-Me C-OMe N 1-68 COOH 4-F-Phenyl n3 N C-OMe CH C-Me N 1-69 COOH 4-F-Phenyl n3 N C-OMe CH C-OMe N 1-70 COOH Phenyl h2n- N C-Me CH C-Me CH 1-71 COOH 4-Cl-Phenyl h2n- CH C-Me N C-Me N 1-72 COOH Phenyl ch3conh- CH C-Me N C-Me CH 1-73 COOH Phenyl ch3conh- CH C-Me n C-Me N 1-74 COOH Phenyl ch3conh- CH C-OMe N C-Me n 1-75 COOH Phenyl ch3conh- CH C-Me N C-OMe N 1-76 COOH Phenyl h2n- CH C-OMe n C-OMe N 1-77 COOH Phenyl h2n- CH C-Me n C-Ethyl N 1-78 COOH Phenyl 3-OMe-4-OH-Phenyl-CH2-CONH- N N C-Me C-OMe CH o o Ul o s if* 00 o 00 Ul to No. r1 r2,r3 A W X Q Y Z 1-79 COOH Phenyl 3-OMe-4-OH-Phenyl-CH2-CONH- n C-OMe C-Me N CH 1-80 COOH Phenyl h2n- N C-N(CH3)2 N C-N(CH3)2 N 1-81 COOH 4-F-Phenyl ch3conh- N C-Me CH C-Me N 1-82 COOH 4-F-Phenyl ch3conh- N C-OMe CH C-Me N 1-83 COOH Phenyl CF3CONH- N c-ch2-ch2-ch2-c C-OMe N 1-84 COOH Phenyl cf3conh- N C-0-CH2-CH2-C C-OMe N 1-85 COOH 4-Cl-Phenyl ch3conh- N C-OMe CH c-cf3 N 1-86 COOH Phenyl ch3conh- N C-Ethyl CH C-Me N 1-87 COOH Phenyl 3,4-Di-OMe-Phenyl-CH2-CONH- N C-OMe CH C-Me N 1-88 COOH Phenyl 3,4-Di-OMe-Phenyl-CH2-CONH- N C-OMe CH C-OMe n 1-89 COOH Phenyl ch3conh- N C-CH2-CH2-CH2-C C-Me N 1-90 COOH Phenyl 4-OMe-PhenyI-CONH- CH C-Ethyl n C-Me n 1-91 COOH 4-F-Phenyl n3 N C-Me CH C-Me N 1-92 COOH Phenyl ch3conh- N C-0-CH2-CH2-C C-Me N 1-93 COOH Phenyl ch3conh- N c-cf3 N C-Me n 1-94 COOH Phenyl ch3conh- n C-OMe C-Me n CH 1-95 COOH Phenyl CH3CONH- N N C-Me C-OMe N 1-96 COOH 4-F-Phenyl ch3conh- N C-Me N C-OMe N 1-97 COOH 4-F-Phenyl ch3conh- N C-Ethyl n C-Me N 1-98 COOH Phenyl 3-OMe-4-OH-Phenyl-ch2-CONH- N C-Me N C-OMe n 1-99 COOH Phenyl 3-OMe-4-OH-Phenyl-ch2-CONH- N C-Ethyl n C-Me N 1-100 COOH Phenyl ch3conh- N C-Me C-Me CH CH o o Ul o s 00 o 00 Ul to 00 No. r1 r2,r3 A W X Q Y Z 1-101 cooh Phenyl ch3conh- n ch c-Me n ch 1-102 cooh Phenyl ch3conh- n n c-Me c-Me n 1-103 cooh Phenyl cf3conh- n c-OMe ch c-OMe n 1-104 cooh Phenyl cf3conh- N C-Ethyl ch C-Me N 1-105 cooh Phenyl ch3conh- n C-Me ch C-Me ch 1-106 cooh Phenyl ch3conh- ch C-Me C-Me ch n 1-107 cooh Phenyl Cyclopropy 1 -CONH- ch C-Ethyl N C-Me N 1-108 cooh Phenyl 3,4-Di-OMe-Phenyl-CH2-CONH- N C-Me ch C-Me n 1-109 COOH 4-Cl-Phenyl ch3conh- CH C-OMe N C-Me N 1-110 COOH Phenyl 4-OMe-Phenyl-CONH- CH C-Me N C-Me n 1-111 COOH Phenyl 4-OMe-Phenyl-CONH- CH C-OMe n C-Me n 1-112 COOH 4-Me-Phenyl ch3conh- CH C-Me n C-OMe N 1-113 COOH 4-CF3-Phenyl ch3conh- CH C-Ethyl N C-Me n 1-114 COOH Phenyl ch3conh- N C-Ethyl N C-Me n 1-115 COOH Phenyl ch3conh- n N C-Me C-OMe CH 1-116 COOH Phenyl HO-(CH2)2-CONH- n C-Me CH C-Me n 1-117 COOH Phenyl Benzyl-0-(CH2)2-C0NH- n C-OMe CH C-Me N 1-118 COOH Phenyl 3-OMe-4-OH-Phenyl-CH2-CONH- N c-o-ch2-ch2-c C-OMe n 1-119 COOH Phenyl 3-OMe-4-OH-Phenyl- ch2-conh- N C-Me N C-Me N 1-120 COOH 4-F-Phenyl Ethyl-CONH- N C-OMe CH C-OMe N 1-121 COOH 4-F-Phenyl Ethyl-CONH- N C-Ethyl CH C-Me N 1-122 COOH 4-Cl-Phenyl Ethyl-CONH- n c-ch2-ch2-ch2-c C-OMe N 1-123 COOH Phenyl cf3conh- N C-Me CH C-Me n o o Ul o It* CO o 00 Ul NJ vo No. r1 r2,r3 A W X Q Y Z 1-124 COOH Phenyl cf3conh- N C-OMe CH C-Me N 1-125 COOMe Phenyl Ethyl-CONH- N C-0-CH2-CH2-C C-OMe N 1-126 COOH Phenyl HO-(CH2)2-CONH- N C-Me N C-Me N 1-127 COOH Phenyl Cyclopropyl-CONH- CH C-Me N C-Me N 1-128 COOH Phenyl Cyclopropyl-CONH- CH C-OMe N C-Me N 1-129 COOH Phenyl HO-(CH2)2-CONH- N C-Me N C-OMe N 1-130 COOH Phenyl 4-OMe-Phenyl-CONH- N C-OMe C-Me N CH 1-131 COOH Phenyl 4-OMe-Phenyl-CONH- N N C-Me C-OMe N 1-132 COOH Phenyl Benzyl-0-(CH2)2-C0NH- N C-Ethyl N C-Me N 1-133 COOH Phenyl Benzyl-0-(CH2)2-C0NH- N N C-Me C-OMe CH 1-134 COOH Phenyl ch3conh- n C-Me n C-Me n 1-135 COOH Phenyl CH3CONH- n C-Me N C-OMe n 1-136 COOH 4-F-Phenyl Ethyl-CONH- n C-OMe C-Me N CH 1-137 COOH Phenyl HO-(CH2)2-CONH- n N C-Me C-OMe n 1-138 COOH Phenyl 3-OMe-4-OH-Phenyl- ch2-conh- n C-Ethyl CH C-Me n 1-139 COOH Phenyl 3-OMe-4-OH-Phenyl- ch2-conh- n c-ch2-ch2-ch2-c C-OMe N 1-140 COOH Phenyl Ethyl-CONH- CH C-Me n C-Me CH 1-141 COOH Phenyl Ethyl-CONH- CH C-cf3 n C-cf3 n 1-142 COOH Phenyl HO-(CH2)2-CONH- CH C-OMe CH C-Me n 1-143 COOH Phenyl (CH3)2N- CH C-OMe n C-Me n 1-144 COOH Phenyl (CH3)2N- CH C-Ethyl n C-Me n 1-145 COOH Phenyl Ethyl-CONH- CH C-cf3 n C-OMe N 1-146 COOH Phenyl HO-(CH2)2-CONH- CH C-Ethyl n C-Me N No. r1 r2,r3 A W X Q Y Z 1-147 COOH Phenyl Cyclopropyl-CONH- N C-OMe C-Me N CH 1-148 COOH Phenyl Cyclopropyl-CONH- N N C-Me C-OMe N 1-149 COOH 4-Cl-Phenyl CH3NH- N C-Me CH C-cf3 N 1-150 COOH Phenyl 4-OMe-Phenyl-CONH- N C-Ethyl N C-Me N 1-151 COOH Phenyl 4-OMe-Phenyl-CONH- N N C-Me C-OMe CH 1-152 COOH Phenyl CH3NH- N C-SMe CH C-Me n 1-153 COOH Phenyl ch3nh- N C-OMe CH C-Ethyl N 1-154 COOH Phenyl ch3conh- n C-CH2-CH2-CH2-C C-OMe n 1-155 COOH Phenyl ch3conh- n C-O-ch2-ch2-C C-OMe N 1-156 COOH Phenyl ch3nh- n C-Ethyl CH C-Me n 1-157 COOH Phenyl ch3nh- n C-CH2-CH2-CH2-C C-Me N 1-158 COOH Phenyl 3-OMe-4-OH-Phenyl-ch2-CONH- N C-OMe CH C-Me N 1-159 COOH Phenyl 3-OMe-4-OH-Phenyl-ch2-CONH- n C-OMe CH C-OMe N 1-160 COOH Phenyl ch3nh- n C-S-ch2-ch2-C C-OMe N 1-161 COOH 4-F-Phenyl ch3nh- n C-Me N C-Me n 1-162 COOH 4-F-Phenyl CH3NH- n C-Me n C-OMe n 1-163 COOH Phenyl (CH3)2N- n N C-Me C-OMe N 1-164 COOH Phenyl (CH3)2N- CH C-Me n C-Me n 1-165 COOH Phenyl ch3nh- n C-Ethyl n C-Ethyl N 1-166 COOH Phenyl ch3nh- n N CH C-OMe CH 1-167 COOH Phenyl Cyclopropyl-CONH- n C-Ethyl n C-Me n 1-168 COOH Phenyl Cyclopropyl-CONH- n N C-Me C-OMe CH 1-169 COOH Phenyl Ethyl-NH- n C-OMe C-Me N CH No. r1 r2,r3 A w X Q y Z 1-170 COOH Phenyl 4-OMe-Phenyl-CONH- N C-Me N C-Me N 1-171 COOH Phenyl 4-OMe-Phenyl-CONH- N C-Me N C-OMe N 1-172 COOH Phenyl Ethyl-NH- N N C-Me C-OMe N 1-173 COOH Phenyl CH3NH- CH C-Me N C-Ethyl N 1-174 COOH Phenyl ch3conh- N C-OMe CH C-OMe N 1-175 COOH Phenyl ch3conh- N C-Ethyl CH C-Me N 1-176 COOH 4-F-Phenyl ch3nh- CH C-Me N C-OMe N 1-177 COOH 4-CI-Phenyl ch3nh- CH C-Ethyl N C-Me N 1-178 COOH Phenyl Benzyl-NH- CH C-Ethyl N C-Me N 1-179 COOH Phenyl 3-OMe-4-OH-Phenyl-ch2-CONH- N C-Me CH C-Me N 1-180 COOH Phenyl (CH2)5N- N C-Me CH C-Me N 1-181 COOH Phenyl (CH3)2N- N C-SMe CH C-Me N 1-182 COOH Phenyl (CH3)2N- N C-Ethyl CH C-Ethyl N 1-183 COOH Phenyl (CH3)2N- N N C-Me C-OMe CH 1-184 COOH Phenyl (CH3)2N- N C-OMe C-Me N CH 1-185 COOH 4-F-Phenyl (CH3)2N- N C-Ethyl CH C-Me N 1-186 COOH Phenyl (CH3)2N- N c-ch2-ch2-ch2-c C-Ethyl N 1-187 COOH Phenyl Cyclopropyl-CONH- N C-Me N C-Me N 1-188 COOH Phenyl Cyclopropyl-CONH- N C-Me N C-OMe N 1-189 COOH Phenyl (CH3)2N- N c-o-ch2-ch2-c C-Me N 1-190 COOH Phenyl 4-OMe-Phenyl-CONH- N c-ch2-ch2-ch2-c C-OMe N 1-191 COOH Phenyl 4-OMe-Phenyl-CONH- N c-o-ch2-ch2-c C-OMe N 1-192 COOH Phenyl (CH3)2N- N C-NH(CH3) N C-NH(CH3) N » No. R1 R2, R3 A w X Q Y Z 1-193 COOH Phenyl (CH3)2N- N C-N(CH3)2 N C-N(CH3)2 N 1-194 COOH Phenyl ch3conh- N C-Me CH C-Me N 1-195 COOH Phenyl ch3conh- N C-OMe CH C-Me N 1-196 COOH Phenyl (CH3)2N- N C-Ethyl N C-Ethyl N 1-197 COOH Phenyl (CH3)2N- N N CH C-OMe CH 1-198 COOH Phenyl Benzyl-NH- CH C-Me N C-Me N 1-199 COOH Phenyl Benzyl-NH- CH C-Me N C-OMe N 1-200 COOH 4-F-Phenyl (CH3)2N- N C-OMe C-Me N CH 1-201 COOH 4-F-Phenyl (CH3)2N- N N C-Me C-OMe N 1-202 COOH Phenyl (CH2)4N- CH C-Me N C-Me N 1-203 COOH Phenyl (CH3)2N- N C-Me N C-OMe N 1-204 COOH Phenyl (CH3)2N- N C-Ethyl N C-Me N 1-205 COOH Phenyl (CH3)2N- CH C-OMe N c-cf3 N 1-206 COOH Phenyl (CH3)2N- CH C-Ethyl N C-Ethyl N 1-207 COOH Phenyl Cyclopropyl-CONH- N C-CH2-CH2-CH2-C C-OMe N 1-208 COOH Phenyl Cyclopropyl-CONH- N c-o-ch2-ch2-c C-OMe N 1-209 COOH Phenyl cci3conh- N C-Me CH C-Me N 1-210 COOH Phenyl 4-OMe-Phenyl-CONH- n C-OMe CH C-OMe N 1-211 COOH Phenyl 4-OMe-Phenyl-CONH- n C-Ethyl CH C-Me n 1-212 COOH Phenyl CF3CONH- N C-OH C-F C-Me N 1-213 COOH Phenyl cf3conh- n C-OMe C-Me C-OMe n 1-214 COOH Phenyl h2n- CH C-Me n C-OMe n 1-215 COOH Phenyl h2n- CH C-Ethyl n C-Me n 1-216 COOH Phenyl cf3conh- n C-Ethyl C-Me CH N o o Ul o N 00 o 00 Ul w Ul No. R1 R2,R3 A W X Q Y Z 1-217 cooh Phenyl cf3conh- N c-ch2-ch2-ch2-ch2-c C-OMe N 1-218 cooh Phenyl Benzyl-NH- N C-OMe C-Me N ch 1-219 cooh Phenyl Benzyl-NH- N N C-Me C-OMe N 1-220 cooh Phenyl cf3conh- N c-o-ch2-ch2-c C-Ethyl N 1-221 cooh Phenyl cf3conh- N C-Ethyl N C-Ethyl N 1-222 COOH Phenyl cf3conh- N C-Me C-Me CH CH 1-223 COOH Phenyl (CH3)2N- N c-o-ch2-ch2-c C-OMe N 1-224 COOH Phenyl (CH3)2N- N C-Me N C-Me N 1-225 COOH Phenyl cf3conh- N C-CH=CH-CH=CH-C C-Me N 1-226 COOH 4-F-Phenyl cf3conh- N N C-Me C-OMe CH 1-227 COOH Phenyl Cyclopropy 1 -CONH- N C-OMe CH C-OMe N 1-228 COOH Phenyl Cyclopropyl-CONH- N C-Ethyl CH C-Me N 1-229 COOH 4-F-Phenyl cf3conh- N C-OMe C-Me N CH 1-230 COOH Phenyl 4-OMe-Phenyl-CONH- N C-Me CH C-Me N 1-231 COOH Phenyl 4-OMe-Phenyl-CONH- N C-OMe CH C-Me N 1-232 COOH 4-Cl-Phenyl cf3conh- n n C-Me C-OMe N 1-233 COOMe Phenyl cf3conh- CH C-Me N C-Me N 1-234 COOH Phenyl h2n- CH C-Me n C-Me N 1-235 COOH Phenyl h2n- CH C-OMe N C-Me N 1-236 COOH 4-F-Phenyl cf3conh- CH C-OMe N C-Me N 1-237 COOH 4-F-Phenyl cf3conh- CH C-Me N C-OMe N 1-238 COOH Phenyl Benzyl-NH- N C-Ethyl N C-Me N 1-239 COOH Phenyl Benzyl-NH- N N C-Me C-OMe CH 1-240 COOH Phenyl cf3conh- CH C-Ethyl N C-Ethyl N » No. r1 r2,r3 A w X Q Y Z 1-241 COOH Phenyl Ethyl-OCH2CONH- n C-Me CH C-Me n 1-242 COOH Phenyl Phenyl-OCH2CONH- N C-OMe CH C-Me N 1-243 COOH Phenyl (CH3)2N- N C-Ethyl CH C-Me N 1-244 COOH Phenyl (ch3)2n- N C-CH2-CH2-CH2-C C-OMe n 1-245 COOH Phenyl 4-OMe-Phenyl-OCH2CONH- N C-OMe CH C-OMe N 1-246 COOH Phenyl i-Propyl-OCH2CONH- N C-Ethyl CH C-Me n 1-247 COOH Phenyl Cyclopropyl-CONH- n C-Me CH C-Me N 1-248 COOH Phenyl Cyclopropyl-CONH- N C-OMe CH C-Me N 1-249 COOH Phenyl MeOCH2CONH- n C-CH2-CH2-CH2-C C-Me N 1-250 COOH Phenyl HOCH2CONH- CH C-Me n C-OMe n 1-251 COOH Phenyl hoch2conh- CH C-Ethyl N C-Me n 1-252 COOH Phenyl MeOCH2CONH- N C-0-CH2-CH2-C C-Ethyl N 1-253 COOH Phenyl Ethyl-OCH2CONH- N C-Me N C-Me n 1-254 COOH Phenyl H2N- N n C-Me C-OMe N 1-255 COOH Phenyl h2n- CH C-Me N C-Me CH 1-256 COOH Phenyl 3,4-Di-OMe-Phenyl- o-ch2conh- N C-Me n C-OMe N 1-257 COOH 4-F-Phenyl MeOCH2 CONH- N C-Ethyl n C-Me N 1-258 COOH Phenyl Benzyl-NH- n C-Me n C-Me N 1-259 COOH Phenyl Benzyl-NH- N C-Me n C-OMe n 1-260 COOH 4-F-Phenyl MeOCH2CONH- N n C-Me C-OMe CH 1-261 COOH Phenyl 4-Cl-Phenyl-OCH2CONH- N C-OMe C-Me N CH 1-262 COOH Phenyl i-Propyl-OCH2CONH- n N C-Me C-OMe n 1-263 COOH Phenyl (CH3)2N- n C-OMe CH C-Me N o o Ul o N It* 00 o 00 Ul Ul Ul No. R1 R2, R3 A W X Q Y Z 1-264 COOH Phenyl (CH3)2N- N C-OMe CH C-OMe N 1-265 COOH Phenyl n-ButyI-OCH2CONH- CH C-Me N C-Me CH 1-266 COOH Phenyl n-Propyl-OCH2CONH- CH C-Me N C-Me N 1-267 COOH Phenyl t- Bu-CH2CONH- CH C-Me N C-OMe N 1-268 COOH Phenyl t- Bu-CH2CONH- CH C-Ethyl N C-Me N 1-269 COOH Phenyl i-Propyl-OCH2CONH- CH C-OMe N C-Me N 1-270 COOH Phenyl HOCH2CONH- CH C-Me N C-Me N 1-271 COOH Phenyl hoch2conh- CH C-OMe N C-Me N 1-272 COOH Phenyl 3,4-Di-OMe-Phenyl- o-ch2conh- CH C-Me N C-Ethyl N 1-273 COOH Phenyl 3,4-Di-OMe-Phenyl- o-ch2conh- CH C-Ethyl N C-Me N 1-274 COOH Phenyl h2n- N C-OMe C-Me N CH 1-275 COOH Phenyl h2n- N C-OMe CH N N 1-276 COOH Phenyl n-Butyl-CONH- N C-Me CH C-Me N 1-277 COOH Phenyl n-Butyl-CONH- N C-OMe CH C-Me N 1-278 COOH Phenyl Benzyl-NH- n C-CH2-CH2-CH2-C C-OMe N 1-279 COOH Phenyl Benzyl-NH- N c-o-ch2-ch2-c C-OMe N 1-280 COOH Phenyl n-Propyl-CONH- N C-OMe CH C-OMe N 1-281 COOH Phenyl i-Propyl-CONH- N C-Ethyl CH C-Me N 1-282 COOH Phenyl i-Propyl-CONH- N c-ch2-ch2-ch2-c C-OMe N 1-283 COOH Phenyl CH3NH- CH C-Ethyl N C-Me N 1-284 COOH Phenyl (CH3)2N- N C-Me CH C-Me N 1-285 COOH Phenyl Cyclohexyl-CONH- N c-o-ch2-ch2-c C-OMe N 1-286 COOH Phenyl Cyclohexyl-CONH- N C-Me N C-Me N No. r1 r2,r3 A W X Q Y Z 1-287 COOH Phenyl t- Bu-CH2CONH- N N C-Me C-OMe N 1-288 COOH Phenyl t- Bu-CH2CONH- CH C-Me N C-Me N 1-289 COOH Phenyl n-Hexyl-CONH- N C-Me N C-OMe N 1-290 COOH Phenyl HOCH2CONH- N N C-Me C-OMe N 1-291 COOH Phenyl hoch2conh- CH C-Me N C-Me CH 1-292 COOH Phenyl 3-Hexen-l-yl-CONH- N C-Ethyl N C-Me N 1-293 COOH Phenyl ch3-ch=ch-conh- N N C-Me C-OMe CH 1-294 COOH Phenyl h2n- n C-Ethyl N C-Me N 1-295 COOH Phenyl h2n- N N C-Me C-OMe CH 1-296 COOH Phenyl ch3-ch=ch-conh- n C-OMe C-Me n CH 1-297 COOH Phenyl n-Propyl-CONH- n n C-Me C-OMe N 1-298 COOH Phenyl Benzyl-NH- n C-OMe CH C-OMe N 1-299 COOH Phenyl Benzyl-NH- N C-Ethyl CH C-Me N 1-300 COOH Phenyl n-Propyl-CONH- CH C-Me N C-Me N 1-301 COOH Phenyl 3-Hexen-l-yl-CONH- CH C-Me N C-OMe n 1-302 COOH 4-F-Phenyl t- Bu-CH2CONH- CH C-Ethyl N C-Me N 1-303 COOH Phenyl ch3nh- CH C-Me N C-Me N 1-304 COOH Phenyl ch3nh- CH C-Me N C-OMe N 1-305 COOH Phenyl Cyclobutyl-CONH- N C-Me CH C-Me N 1-306 COOH Phenyl Cyclobutyl-CONH- N C-OMe CH C-Me n 1-307 COOH Phenyl t- Bu-CH2CONH- N N C-Me C-OMe CH 1-308 COOH Phenyl t- Bu-CH2CONH- N C-OMe C-Me n CH 1-309 COOH Phenyl Cyclopentyl-CONH- N C-OMe CH C-OMe N 1-310 COOH Phenyl hoch2conh- N N C-Me C-OMe CH No. R1 R2, R3 A W X Q Y Z 1-311 COOH Phenyl HOCH2CONH- N C-OMe C-Me N CH 1-312 COOH Phenyl Cyclopentyl-CONH- n C-Ethyl CH C-Me N 1-313 COOH Phenyl Cyclohexyl-CONH- N C-CH2-CH2-CH2-C C-OMe n 1-314 COOH Phenyl h2n- N C-Me N C-Me n 1-315 COOH Phenyl h2n- n C-Me n C-OMe n 1-316 COOH Phenyl Cyclopropyl-CONH- n c-o-ch2-ch2-c C-Ethyl N 1-317 COOH Phenyl Cyclopropyl-CONH- n C-Ethyl n C-Ethyl n 1-318 COOH Phenyl Benzyl-NH- n C-Me CH C-Me n 1-319 COOH Phenyl Benzyl-NH- n C-OMe CH C-Me N 1-320 COOH 4-F-Phenyl Cyclopropyl-CONH- n C-Me n C-OMe N 1-321 COOH 4-F-Phenyl Cyclopropyl-CONH- n C-Ethyl N C-Me n 1-322 COOH Phenyl Cyclobutyl-CONH- n n C-Me C-OMe CH 1-323 COOH Phenyl CH3NH- n C-OMe C-Me N CH 1-324 COOH Phenyl ch3nh- N N C-Me C-OMe N 1-325 COOH Phenyl Cyclobutyl-CONH- n C-OMe C-Me n CH 1-326 COOH Phenyl Cyclopentyl-CONH- N N C-Me C-OMe N 1-327 COOH Phenyl t- Bu-CH2CONH- n C-Me N C-OMe n 1-328 COOH Phenyl t- Bu-CH2CONH- N C-Ethyl N C-Me N 1-329 COOH Phenyl Cyclopentyl-CONH- CH C-Me n C-Me n 1-330 COOH Phenyl HOCH2CONH- N C-Me n C-OMe n 1-331 COOH Phenyl hoch2conh- n C-Ethyl n C-Me N 1-332 COOH Phenyl Cyclohexyl-CONH- CH C-OMe n C-Me N 1-333 COOH Phenyl Cyclohexyl-CONH- CH C-Ethyl N C-Me N 1-334 COOH Phenyl H2N- n c-ch2-ch2-ch2-c C-OMe N No. R1 R2,R3 A W X Q Y Z 1-335 COOH Phenyl h2n- n C-0-CH2-CH2-C C-OMe N 1-336 COOH Phenyl 3,4-Di-CI-Phenyl-CH2-CONH- N C-Me CH C-Me N 1-337 COOH Phenyl 3,4-Di-Cl-Phenyl-CH2-CONH- n C-OMe CH C-Me N 1-338 COOH Phenyl 3,4-Di-OMe-Phenyl-(CH2)2-NH- CH C-Me N C-OMe n 1-339 COOH Phenyl 3,4-Di-OMe-Phenyl-(CH2)2-NH- CH C-Ethyl N C-Me n 1-340 COOH 4-F-Phenyl 3,4-Di-OMe-Phenyl-CH2-CONH- N C-OMe CH C-OMe N 1-341 COOH Phenyl 3,4-Di-Me-Phenyl-CH2-CONH- n C-Ethyl CH C-Me N 1-342 COOH Phenyl 3,4-Di-Me-Phenyl-CH2-CONH- N C-CH2-CH2-CH2-C C-OMe N 1-343 COOH Phenyl CH3NH- N C-Ethyl N C-Me N 1-344 COOH Phenyl ch3nh- n n C-Me C-OMe CH 1-345 COOH Phenyl 3,4-Di-Cl-Phenyl-CH2-CONH- n c-o-ch2-ch2-c C-OMe N 1-346 COOH Phenyl 3,4-Di-Me-Phenyl-CH2-CONH- n C-Me N C-Me N 1-347 COOH Phenyl t- Bu-CH2CONH- n c-o-ch2-ch2-c C-OMe N 1-348 COOH Phenyl t- Bu-CH2CONH- N C-Me N C-Me N 1-349 COOH Phenyl 3,5-Di-OMe-Phenyl-CH2-CONH- N C-Me N C-OMe n 1-350 COOH Phenyl HOCH2CONH- N c-o-ch2-ch2-c C-OMe N 1-351 COOH Phenyl hoch2conh- N C-Me N C-Me N 1-352 COOH Phenyl 3,5-Di-OMe-Phenyl-CH2-CONH- N C-Ethyl N C-Me n 1-353 COOH Phenyl 2,3-Di-OMe-Phenyl-CH2-CONH- N N C-Me C-OMe CH 1-354 COOH Phenyl H2N- N C-OMe CH C-OMe N 1-355 COOH Phenyl h2n- N C-Ethyl CH C-Me N 1-356 COOH Phenyl 3,5-Di-Me-Phenyl-CH2-CONH- N C-OMe C-Me N CH 1-357 COOH Phenyl 3,5-Di-OMe-Phenyl-CH2-CONH- N N C-Me C-OMe N 1-358 COOH Phenyl 3,4-Di-OMe-Phenyl-(CH2)2-NH- CH C-Me N C-Me n o o Ul o N tfk 00 o 00 Ul Ul vo No. r1 r2,r3 A W X Q Y Z 1-359 COOH Phenyl 3,4-Di-OMe-Phenyl-(CH2)2-NH- CH C-OMe N C-Me N 1-360 COOH Phenyl 2,5-Di-OMe-Phenyl-CH2-CONH- CH C-Me N C-Me CH 1-361 COOH Phenyl 3,5-Di-OMe-Phenyl-CH2-CONH- CH C-Me N C-Me N 1-362 COOH Phenyl 2,4-Di-OMe-Phenyl-CH2-CONH- CH C-OMe N C-Me N 1-363 COOH Phenyl CH3NH- n C-Me n C-Me n 1-364 COOH Phenyl ch3nh- n C-Me n C-OMe n 1-365 COOH Phenyl 3,4,5-Tri-OMe-PhenyI- ch2-conh- CH C-Me N C-OMe n 1-366 COOH Phenyl 3,4,5-Tri-OMe-Phenyl- ch2-conh- CH C-Ethyl N C-Me n 1-367 COOH Phenyl t- Bu-CH2CONH- n C-Ethyl CH C-Me n 1-368 COOH Phenyl t- Bu-CH2CONH- n C-CH2-CH2-CH2-C C-OMe n 1-369 COOH Phenyl 3,4-Di-Cl-Phenyl-(CH2)2-NH- n C-Me CH C-Me n 1-370 COOH Phenyl HOCH2CONH- n C-Ethyl CH C-Me n 1-371 COOH Phenyl hoch2conh- n C-CH2-CH2-CH2-C C-OMe n 1-372 COOH Phenyl 3,4-Di-Cl-Phenyl-(CH2)2-NH- n C-OMe CH C-Me n 1-373 COOH Phenyl 3,4-Di-Me-Phenyl-(CH2)2-NH- N C-OMe CH C-OMe n 1-374 COOH Phenyl H2N- N C-Me CH C-Me N 1-375 COOH Phenyl h2n- n C-OMe CH C-Me n 1-376 COOH Phenyl 3,4-Di-Me-Phenyl-(CH2)2-NH- n C-Ethyl CH C-Me n 1-377 COOH Phenyl 2,4-Di-OMe-Phenyl-(CH2)2-NH- n C-CH2-CH2-CH2-C C-OMe N 1-378 COOH Phenyl 3,4-Di-OMe-Phenyl-(CH2)2-NH- n C-OMe C-Me n CH 1-379 COOH Phenyl 3,4-Di-OMe-Phenyl-(CH2)2-NH- N n C-Me C-OMe n 1-380 COOH Phenyl 3,4,5-Tri-OMe-Phe-nyl-(CH2)2-NH- n c-o-ch2-ch2-c C-OMe N o o Ul o v. 00 o 00 Ul I* o No. r1 r2,r3 A w X Q y Z 1-381 COOH Phenyl 3,4,5-Tri-OMe-Phe-nyl-(CH2)2-NH- n C-Me n C-Me N 1-382 COOH Phenyl 3,4-Di-Me-Phenyl-(CH2)2-NH- n C-Me N C-OMe n 1-383 COOH Phenyl CH3NH- n C-CH2-CH2-CH2-C C-OMe n 1-384 COOH Phenyl ch3nh- n c-o-ch2-ch2-c C-OMe n 1-385 COOH Phenyl 3,5-Di-OMe-Phenyl-(CH2)2-NH- n C-Ethyl n C-Me n 1-386 COOH Phenyl 3,5-Di-OMe-Phenyl-(CH2)2-NH- N N C-Me C-OMe CH 1-387 COOH Phenyl t- Bu-CH2CONH- n C-OMe CH C-Me n 1-388 COOH Phenyl t- Bu-CH2CONH- n C-OMe CH C-OMe N 1-389 COOH Phenyl 2,4-Di-OMe-Phenyl-(CH2)2-NH- n C-OMe C-Me n CH 1-390 COOH Phenyl HOCH2CONH- N C-OMe CH C-Me n 1-391 COOH Phenyl HOCH2CONH- N C-OMe C1I C-OMe n 1-392 COOH Phenyl 3,4-Di-Me-Phenyl-(CH2)2-NH- n n C-Me C-OMe N 1-393 COOH Phenyl 3,4-Di-Me-Phenyl-(CH2)2-NH- CH C-Me n C-Me n 1-394 COOH Phenyl n3 CH C-Ethyl n C-Me n 1-395 COOH Phenyl h2n- n C-Me CH C-Me CH 1-396 COOH 4-F-Phenyl 3,4-Di-OMe-Phenyl-(CH2)2-NH- CH C-OMe n C-Me n 1-397 COOH 4-F-Phenyl 3,4-Di-OMe-Phenyl-(CH2)2-NH- CH C-Me n C-OMe N 1-398 COOH Phenyl 3,4-Di-OMe-Phenyl-(CH2)2-NH- n C-Ethyl n C-Me n 1-399 COOH Phenyl 3,4-Di-OMe-Phenyl-(CH2)2-NH- n N C-Me C-OMe CH 1-400 COOH Phenyl 3,4-Di-Me-Phenyl-(CH2)2-NH- CH C-Ethyl N C-Me N 1-401 COOH Phenyl 4-OMe-Benzyl-NH- n C-Me CH C-Me N 1-402 COOH Phenyl 3,4-Di-OMe-Benzyl-NH- N C-OMe CH C-Me N 1-403 COOH Phenyl CH3NH- n C-OMe CH C-OMe n No. R1 R2, R3 A W X Q Y Z 1-404 COOH Phenyl CH3NH- N C-Ethyl CH C-Me N 1-405 COOH Phenyl 4-Cl-Benzyl-NH- N C-OMe CH C-OMe N 1-406 COOH Phenyl 4-OH-Benzyl-NH- N C-Ethyl CH C-Me N 1-407 COOH Phenyl MeOCH2CONH- CH C-OMe N C-Me N 1-408 COOH Phenyl MeOCH2CONH- CH C-Me N C-OMe N 1-409 COOH Phenyl MeOCH2CONH- CH C-Ethyl N C-Me N 1-410 COOH Phenyl t- Bu-CH2CONH- N C-Me CH C-Me N 1-411 COOH Phenyl 3,4-Di-OMe-Benzyl-NH- N c-ch2-ch2-ch2-c C-OMe N 1-412 COOH Phenyl Phenyl-NH- CH C-Ethyl N C-Me N 1-413 COOH Phenyl HOCH2CONH- N C-Me CH C-Me N 1-414 COOH Phenyl 4-OMe-Benzyl-NH- N C-0-CH2-CH2-C C-OMe N 1-415 COOH Phenyl 3-OMe-4-OH-Benzyl-NH- N C-Me N C-Me N 1-416 COOH Phenyl n3 CH C-OMe N C-Me N 1-417 COOH Phenyl n3 CH C-Me N C-OMe N 1-418 COOH Phenyl 4-Me-Benzyl-NH- N C-Me N C-OMe N 1-419 COOH Phenyl 3,4-Di-Me-Benzyl-NH- N C-Ethyl N C-Me N 1-420 COOH Phenyl 3,4-Di-OMe-Phenyl-(CH2)2-NH- N C-Me N C-Me N 1-421 COOH Phenyl 3,4-Di-OMe-Phenyl-(CH2)2-NH- N C-Me N C-OMe N 1-422 COOH Phenyl 4-Me-Benzyl-NH- N N C-Me C-OMe CH 1-423 COOH Phenyl 3-Cl-Benzyl-NH- N C-OMe C-Me N CH 1-424 COOH Phenyl 2-Cl-Benzyl-NH- N N C-Me C-OMe N 1-425 COOH Phenyl CH3NH- N C-Me CH C-Me n 1-426 COOH Phenyl ch3nh- N C-OMe CH C-Me n 1-427 COOH Phenyl 3,5-Di-OMe-BenzyI-NH- CH C-Me N C-Me N No. R1 R2, R3 A W X Q Y Z 1-428 COOH 4-F-Phenyl Benzyl-NH- CH C-Me N C-OMe N 1-429 COOH Phenyl MeOCH2CONH- CH C-Me N C-Me CH 1-430 COOH Phenyl MeOCH2CONH- CH C-Me N C-Me N 1-431 COOH 4-F-Phenyl Benzyl-NH- CH C-Ethyl N C-Me N 1-432 COOH Phenyl Phenyl-NH- CH C-Me n C-Me N 1-433 COOH Phenyl Phenyl-NH- CH C-OMe N C-Me N 1-434 COOH Phenyl 3-Cl-4-OH-Phenyl-CH2-CONH- N C-Me CH C-Me N 1-435 COOH Phenyl 3-Cl-4-OH-Phenyl-CH2-CONH- N C-OMe CH C-Me n 1-436 COOH Phenyl n3 CH C-Me N C-Me CH 1-437 COOH Phenyl n3 CH C-Me N C-Me N 1-438 COOH Phenyl 3-Me-4-OH-Phenyl-CH2-CONH- N C-OMe CH C-OMe N 1-439 COOH Phenyl 3-Me-4-OH-Phenyl-CH2-CONH- N C-Ethyl CH C-Me N 1-440 COOH Phenyl 3,4-Di-OMe-Phenyl-(CH2)2-NH- N C-CH2-CH2-CH2-C C-OMe N 1-441 COOH Phenyl 3,4-Dt-OMe-Phenyl-(CH2)2-NH- N c-o-ch2-ch2-c C-OMe N 1-442 COOH Phenyl 3-OMe-4-OH-Phenyl- ch2-conh- N c-ch2-ch2-ch2-c C-Ethyl N 1-443 COOH Phenyl 3-OMe-4-OH-Phenyl- ch2-conh- N c-o-ch2-ch2-c C-Me N 1-444 COOH Phenyl 2-OMe-4-OH-Pheryl-ch2-CONH- n C-Me n C-Me n 1-445 COOH Phenyl Ethyl-CONH- CH C-Me n C-OMe n 1-446 COOH Phenyl Ethyl-CONH- CH C-Ethyl N C-Me N 1-447 COOH Phenyl 3-Cl-4-OH-Phenyl-CH2-CONH- N C-Me n C-OMe n 1-448 COOH Phenyl 3,4-Di-OH-Phenyl-CH2~CONH- n C-Ethyl N C-Me N 1-449 COOH Phenyl MeOCH2CONH- N C-OMe C-Me n CH o o Ul o s *> 00 o 00 Ul •fk Ul No. R1 R2, R3 A W X Q Y Z 1-450 COOH Phenyl MeOCH2CONH- N N C-Me C-OMe N 1-451 COOH Phenyl 3,4-Di-OH-PhenyI-CH2-CONH- N N C-Me C-OMe CH 1-452 COOH Phenyl Phenyl-NH- N C-OMe C-Me N CH 1-453 COOH Phenyl Phenyl-NH- N N C-Me C-OMe N 1-454 COOH Phenyl 3-OH-4-OMe-Phenyl- ch2-conh- N C-OMe C-Me N CH 1-455 COOH Phenyl 3-OH-4-OMe-Phenyl-CH2-CONH- N N C-Me C-OMe N 1-456 COOH Phenyl n3 N C-OMe C-Me N CH 1-457 COOH Phenyl n3 N N C-Me C-OMe n 1-458 COOH Phenyl 2-Cl-4-OH-Pheny 1-CH2 -CONH- CH C-Me n C-Me CH 1-459 COOH Phenyl 3-Cl-4-OH-Phenyl-CH2-CONH- CH C-Me n C-Me n 1-460 COOH Phenyl 3,4-Di-OMe-Phenyl-(CH2)2-NH- n C-OMe CH C-OMe n 1-461 COOH Phenyl 3,4-Di-OMe-Phenyl-(CH2)2-NH- n C-Ethyl CH C-Me n 1-462 COOH Phenyl 3-OMe-4-SMe-Phenyl- ch2-conh- CH C-OMe N C-Me n 1-463 COOH Phenyl 3-OMe-4-SMe-Phenyl- ch2-conh- CH C-Me n C-OMe n 1-464 COOH Phenyl 3,4-Di-OH-Phenyl-CH2-CONH- CH C-Ethyl n C-Me n 1-465 COOH Phenyl Ethyl-CONH- CH C-Me N C-Me n 1-466 COOH Phenyl Ethyl-CONH- CH C-OMe N C-Me N 1-467 COOH Phenyl Phenyl-NH- n C-cf3 CH C-Me N 1-468 COOH 4-F-Phenyl Phenyl-NH- N C-OMe CH C-Me N 1-469 COOH Phenyl MeOCH2CONH- n C-Ethyl n C-Me N 1-470 COOH Phenyl MeOCH2CONH- n N C-Me C-OMe CH o o Ul o N lt> 00 o 00 Ul it* No. R1 R2, R3 A W X Q Y Z 1-471 COOH 4-Cl-Phenyl Phenyl-NH- N C-OMe CH C-OMe N 1-472 COOH Phenyl Phenyl-NH- N C-Ethyl N C-Me N 1-473 COOH Phenyl Phenyl-NH- N N C-Me C-OMe CH 1-474 COOH 4-Me-Phenyl Phenyl-NH- N C-Ethyl CH C-Me N 1-475 COOH Phenyl Phenyl-NH- N C-CH2-CH2-CH2-C C-Me N 1-476 COOH Phenyl n3 N C-Ethyl N C-Me N 1-477 COOH Phenyl n3 N N C-Me C-OMe CH 1-478 COOH Phenyl Phenyl-NH- N C-O-ch2-ch2-C C-Me N 1-479 COOH Phenyl Phenyl-NH- N C-N(CH3)2 N C-N(CH3)2 N 1-480 COOH Phenyl 3,4-Di-OMe-Phenyl-(CH2)2-NH- N C-Me CH C-Me N 1-481 COOH Phenyl 3,4-Di-OMe-Phenyl-(CH2)2-NH- N C-OMe CH C-Me N 1-482 COOH Phenyl Phenyl-NH- N C-Ethyl N C-Ethyl N 1-483 COOH Phenyl Phenyl-NH- CH C-Ethyl CH C-Me N 1-484 COOH Phenyl Phenyl-NH- N N C-OMe CH CH 1-485 COOH Phenyl Ethyl-CONH- N N C-Me C-OMe N 1-486 COOH Phenyl Ethyl-CONH- CH C-Me n C-Me CH 1-487 COOH 4-F-Phenyl Phenyl-NH- N C-OMe C-Me N CH 1-488 COOH 4-F-Phenyl Phenyl-NH- N N C-Me C-OMe N 1-489 COOH Phenyl MeOCH2CONH- N C-Me N C-Me N 1-490 COOH Phenyl MeOCH2CONH- N C-Me N C-OMe N 1-491 COOMe Phenyl Phenyl-NH- CH C-Me N C-Me N 1-492 COOH Phenyl Phenyl-NH- N C-Me N C-Me N 1-493 COOH Phenyl Phenyl-NH- N C-Me N C-OMe N 1-494 COOH Phenyl Phenyl-NH- CH C-OMe N C-Ethyl N 1-495 COOH Phenyl 4-Cl-Phenyl-NH- CH C-Ethyl N C-Me N o o Ul o N 00 o 00 Ul Ul No. r1 r2,r3 A w X Q Y Z 1-496 COOH Phenyl n3 N C-Me N C-Me N 1-497 COOH Phenyl n3 N C-Me n C-OMe N 1-498 COOH Phenyl Benzyl-OCH2CONH- N C-Me CH C-Me N 1-499 COOH Phenyl Benzyl-OCH2CONH- N C-OMe CH C-Me N 1-500 COOH Phenyl 3,4-Di-OMe-Phenyl-CH2-CONH- CH C-Me N C-OMe N 1-501 COOH Phenyl 3,4-Di-OMe-Phenyl-CH2-CONH- CH C-Ethyl n C-Me N 1-502 COOH 4-F-Phenyl HOCH2CONH- N C-OMe CH C-OMe N 1-503 COOH 4-F-Phenyl n3 CH C-Me N C-Me N 1-504 COOH 4-F-Phenyl n3 CH C-OMe N C-Me N 1-505 COOH 4-F-Phenyl hoch2conh- N C-Ethyl CH C-Me N 1-506 COOH Phenyl hoch2conh- N C-CH2 -CH2 -CH2 -C C-Me N 1-507 COOH Phenyl Ethyl-CONH- N N C-Me C-OMe CH 1-508 COOH Phenyl Ethyl-CONH- N C-OMe C-Me N CH 1-509 COOH Phenyl HOCH2CONH- N c-s-ch2-ch2-c C-OMe N 1-510 COOH Phenyl Benzyl-OCH2CONH- n C-Me N C-Me N 1-511 COOH Phenyl MeOCH2CONH- n c-ch2-ch2-ch2-c C-OMe n 1-512 COOH Phenyl MeOCH2CONH- N c-o-ch2-ch2-c C-OMe n 1-513 COOH 4-Me-Phenyl HOCH2CONH- n C-Me N C-OMe N 1-514 COOH Phenyl Phenyl-NH- N c-ch2-ch2-ch2-c C-OMe N 1-515 COOH Phenyl Phenyl-NH- n c-o-ch2-ch2-c C-OMe n 1-516 COOH Phenyl hoch2conh- N C-Ethyl N C-Ethyl n 1-517 COOH Phenyl 4-OMe-Benzyl-OCH2CONH- N n C-Me C-OMe CH 1-518 COOH Phenyl n3 N c-ch2-ch2-ch2-c C-OMe N 1-519 COOH Phenyl n3 N c-o-ch2-ch2-c C-OMe N o o Ul o v. Ifk 00 o 00 Ul o> No. r1 r2,r3 A vv X Q Y Z 1-520 COOH Phenyl 4-OMe-Benzyl-OCH2CONH- N C-OMe C-Me N CH 1-521 COOH 4-F-Phenyl HOCH2CONH- N N C-Me C-OMe N 1-522 COOH Phenyl 3,4-Di-OMe-Phenyl-CH2-CONH- CH C-Me N C-Me N 1-523 COOH Phenyl 3,4-Di-OMe-Phenyl-CH2-CONH- CH C-OMe N C-Me N 1-524 COOH 4-Cl-Phenyl HOCH2CONH- CH C-Me N C-Me CH 1-525 COOH 4-F-Phenyl n3 N N C-Me C-OMe N 1-526 COOH 4-F-Phenyl n3 CH C-Me N C-Me CH 1-527 COOH Phenyl Phenyl-OCH2CONH- CH C-Me N C-Me N 1-528 COOH Phenyl 4-OMe-Phenyl-OCH2CONH- CH C-OMe N C-Me N 1-529 COOH Phenyl Ethyl-CONH- N C-Me N C-OMe N 1-530 COOH Phenyl Ethyl-CONH- N C-Ethyl N C-Me n 1-531 COOH Phenyl Benzyl-OCH2CONH- CH C-Me N C-OMe N 1-532 COOH 4-F-Phenyl HOCH2CONH- CH C-Ethyl N C-Me N 1-533 COOH Phenyl MeOCH2CONH- N C-Me CH C-Me N 1-534 COOH Phenyl MeOCH2CONH- N C-OMe CH C-Me N 1-535 COOH Phenyl MeOCH2CONH- N C-OMe CH C-OMe N 1-536 COOH Phenyl MeOCH2CONH- N C-Ethyl CH C-Me N 1-537 COOH Phenyl 4-OH-Phenyl-CONH- N C-Me CH C-Me N 1-538 COOH Phenyl Phenyl-NH- N C-OMe CH C-OMe N 1-539 COOH Phenyl Phenyl-NH- N C-Ethyl CH C-Me N 1-540 COOH Phenyl 4-SMe-Phenyl-CONH- N C-OMe CH C-Me n 1-541 COOH Phenyl 4-N02-Phenyl-C0NH- N C-OMe CH C-OMe N 1-542 COOH Phenyl n3 N C-OMe CH C-OMe N 1-543 COOH Phenyl n3 N C-Ethyl CH C-Me N No. r1 r2,r3 A W X Q Y Z 1-544 COOH Phenyl 4-Cl-Phenyl-CONH- N C-Ethyl CH C-Me N 1-545 COOH Phenyl 4-Ethyl-Phenyl-CONH- N C-CH2-CH2-CH2-C C-OMe N 1-546 COOH Phenyl 3,4-Di-OMe-Phenyl-CH2-CONH- N N C-Me C-OMe N 1-547 COOH Phenyl 3,4-Di-OMe-Phenyl-CH2-CONH- CH C-Me N C-Me CH 1-548 COOH 4-F-Phenyl 4-OMe-Phenyl-CONH- N c-o-ch2-ch2-c C-OMe N 1-549 COOH 4-F-Phenyl n3 N N C-Me C-OMe CH 1-550 COOH 4-F-Phenyl n3 N C-OMe C-Me N CH 1-551 COOH Phenyl 4-Cl-Phenyl-CONH- N C-Me N C-Me N 1-552 COOH Phenyl 3,4-Di-OMe-Phenyl-CONH- N C-Me n C-OMe N 1-553 COOH Phenyl Ethyl-CONH- N c-o-ch2-ch2-c C-OMe N 1-554 COOH Phenyl Ethyl-CONH- N C-Me N C-Me N 1-555 COOH Phenyl 3,4-Di-OMe-Phenyl-CONH- N C-Ethyl N C-Me N 1-556 COOH Phenyl 4-Cl-Phenyl-CONH- N N C-Me C-OMe CH 1-557 COOH Phenyl cf3conh- CH C-Me N C-OMe N 1-558 COOH Phenyl cf3conh- CH C-Ethyl N C-Me N 1-559 COOH Phenyl 3,4-Di-CI-Phenyl-CONH- N C-OMe C-Me N CH 1-560 COOH Phenyl Phenyl-NH- N C-Me CH C-Me N 1-561 COOH Phenyl Phenyl-NH- N C-OMe CH C-Me N 1-562 COOH Phenyl 3-OMe-4-OH-Phenyl-CONH- N N C-Me C-OMe N 1-563 COOH Phenyl 3-Cl-Phenyl-CONH- CH C-Me N C-Me N 1-564 COOH Phenyl n3 N C-Me CH C-Me N 1-565 COOH Phenyl n3 N C-OMe CH C-Me N 1-566 COOH Phenyl 2-Cl-Phenyl-CONH- CH C-OMe N C-Me N 1-567 COOH Phenyl 4-N02-Phenyl-C0NH- CH C-Ethyl N C-Me N 0050/48085 49 Example 11 Receptor binding data were measured by the binding assay described above for the compounds listed below. The results are shown in Table 2. 10 Table 2 Receptor binding data (Kx values) 15 20 25 Compound ETA [nM/1] ETb [nM/1] 1-174 83 >7000 1-227 225 2800 1-334 600 6400 1-354 50 >6400 1-375 300 7300 1-388 1000 7000 1-518 14 460 1-535 35 7000 1-541 1000 >7000 1-542 60 2200 30 35 40 45 </div>

Claims

<div class="application article clearfix printTableText" id="claims"> 0050/48085 5 %7 Novel P-amino and P-azidocarboxylic acid derivatives, their preparation and use as endothelin receptor antagonists 5 Abstract Carboxylic acid derivatives of the formula I r2 10 , w-x // a c ch 0—\ q ii z=y' r3 r1 15 where the substituents have the meanings explained in the description are used as endothelin receptor antagonists. 20 25 30 35 40 45 502319 We claim:

1. A P-amino or P-azido carboxylic acid derivative of the formula I R2 i w~x* A C CH 0 ( | I Z = Y R3 R1 where R1 is tetrazole or a group 0 C —R where R has the following meaning: a) a radical OR4, where R4is: hydrogen, the cation of an alkali metal, the cation of an alkaline earth metal or a physiologically tolerated organic ammonium ion; C3-Ce-cycloalkyl, Ci-Cg-alkyl, unsubstituted or substituted, CH2-phenyl, unsubstituted or substituted, C3-C8-alkenyl or a C3-C8-alkynyl, unsubstituted or substituted, or phenyl, unsubstituted or substituted, b) a 5-membered heteroaromatic system linked via a nitrogen atom, c) a group intellectual property office of n.z. - 1 OCT 2001 received 51 50 Tk —o—(CH2)p s R5 where k can assume the values 0, 1 and 2, p the values 1, 2, 3 and 4, and Rs is Ci-C.j-alkyl, C3-C8-cycloalkyl, C3-C8-alkenyl, C3-C8-alkynyl or unsubstituted or substituted phenyl, d) a radical where R6 is: C1-C4-alkyl, C3-C3-alkenyl, C3-Cs-alkynyl, C3-C8-cycloalkyl, it being possible for these radicals to carry a Ci-C,-alkoxy, Ci-C^-alkylthio and/or a phenyl radical; Cj-Q-haloalkyl or phenyl, unsubstituted or substituted. A is NR7Rs or azido; W and Z (which may be identical or different) are: nitrogen or methine; with the proviso that Q = nitrogen if W and Z = methine; X is nitrogen or CR9; Y is nitrogen or CR10; Q is nitrogen or CR11; with the proviso that X = CR9 and Y = CR10 if Q = nitrogen; 0 NH —S R6 O 52 -y 50 1 R2 and R3 (which may be identical or different) are: phenyl or naphthyl, unsubstituted or substituted, or phenyl or naphthyl which are linked together in ortho positions by a direct linkage, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an S02, NH or N-alkyl group, C5-Cs-cycloalkyl, unsubstituted or substituted; R7 is hydrogen, Ci-Cg-alkyl, C3-C8-alkenyl, C3-C8-alkynyl, Cx-Cs-alkylcarbonyl, it being possible for these radicals to be unsubstituted or substituted; phenyl or naphthyl, unsubstituted or substituted; unsubstituted or substituted C3-C8-cycloalkyl; or R7 is linked to R8 via 4 or 5 CH2 groups to give a 5-or 6-membered ring; R8 is hydrogen, Ci-C^-alkyl; or R8 is linked to R7 via 4 or 5 CH2 groups to give a 5-or 6-membered ring; R9 and R10 (which may identical or different) are: hydrogen, halogen, Ci-Qj-alkoxy, C1-C4-haloalkoxy, C3-C6-alkenyloxy, C3-C6-alkynyloxy, Cj-C^alkylthio, C^C,,-alkylcarbonyl, Ci-Qj-alkoxycarbonyl, hydroxyl, NH2, NH^-C4-alkyl) , N(Cx-Q-alkyl) 2 Q-C^-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, it being possible for these radicals to be unsubstituted or substituted; or CR9 or CR10 is linked to CR11 as indicated below to give a 5- or 6-membered ring, R11 is hydrogen, halogen, C^-CValkoxy, Ci-C^-haloalkoxy, C3-C6-alkenyloxy, C3-C6-alkynyloxy, C-L-C^alkylthio, C^C,,-alkylcarbonyl, Ci-Q-alkoxycarbonyl, NH (C^Q-alky!) , INTiLLiCTUAL PROPERTY OFFICE OF N.Z. - 1 OCT 2001 received 50 2 319 NtCi-C^-alkyl)a, hydroxyl, carboxyl, cyano, amino, mercapto; Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, it being possible for these radicals to be unsubstituted or substituted; or CR11 forms together with CR9 or CR10 a 5- or 6-membered alkylene or alkenylene ring which may unsubstituted or substituted, and in which in each case one or more methylene groups may be replaced by oxygen, sulfur, -NH or -N(Ci-C^-alkyl) ; and the pysiologically tolerated salts, and the possible enantiomerically pure and diastereoisomerically pure forms.

2. The use of a fe-amino or S-azido carboxylic acid derivative as claimed in claim 1 in the manufacture of a medicament for treating diseases.

3 . The use of compounds I as claimed in claim 2 in the manufacture of a medicament for use as endothelin receptor antagonists.

4. The use of a B-amino or fi-azido 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 S-amino or S-azido carboxylic acid derivative I as claimed in claim 1 in the manufacture of a medicament for treating chronic heart failure, restenosis, high blood pressure, pulmonary hypertension, acute/chronic kidney failure, cerebral ischemia, benign prostate hyperplasia and prostate cancer.

6. The use of a S-amino and S-azido carboxylic acid derivative I as claimed in claim 1 in the manufacture of a medicament for use in combination with: inhibitors of the renin-angiotensin system such as renin inhibitors, angiotensin II antagonists and, in particular, angiotensin converting enzyme (ACE) inhibitors; mixed ACE/neutral endopeptidase (NEP) inhibitors; £ blockers.

7. A drug formulation for oral, parenteral or intraperenteral administration comprising per single dose, besides intellectual property office of n.z. - 1 OCT 2001 Dcrciucn 54 - - 5 A 9 7 « U £ U [! conventional pharmaceutical auxiliaries, at least one carboxylic acid derivative I as claimed m claim 1.

8. A compound of the formula II R2 1 A C CH OH | i R3 R1 where the radicals R1, R2, R3 and A have the meanings stated in claim 1.

9. The use of compounds of the formula II, R2 A C CH OH i I R3 R1 where the radicals R1, R2, R3 and A have the meanings stated in claim 1, as starting material for synthesizing endothelin receptor antagonists.

10. A derivative of claim 1 as specifically set forth herein.

11. A drug formulation of claim 7 as specifically set forth herein.

12. A compound of claim 8 as specifically set forth herein.

13 . The use of claim 9 substantially as described herein with reference to the Examples. intellectual property office of nz. 1 ' DEC 2001 Received </div>