TREA

Azinyloxy, and phenoxy-diaryl-carboxylic acid derivatives, their preparation and use as mixed ETA/ETB endothelin receptor antagonists

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Information

  • Patent Grant
  • 6670367
  • Patent Number
    6,670,367
  • Date Filed
    Monday, March 1, 1999
    25 years ago
  • Date Issued
    Tuesday, December 30, 2003
    20 years ago
Information
Abstract
The invention relates to carboxylic acid derivatives of the formula I where the radicals have the meanings stated in the description, and to their use as drugs.
Description




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




Endothelin is a peptide which consists 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 means one or all isoforms of endothelin. Endothelin is a potent vasoconstrictor and has a great 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 vessels, which may lead to disorders. As reported in the literature, 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 (J. Vascular Med. Biology 2, (1990) 207, J. Am. Med. Association 264, (1990) 2868, Nature 344, (1990) 114, N. Engl. J. Med. 322, (1989) 205, N. Engl. J. Med. 328, (1993) 1732, Nephron 66, (1994) 373, Stroke 25, (1994) 904, Nature 365, (1993) 759, J. Mol. Cell. Cardiol. 27, (1995) A234; Cancer Research 56, (1996) 663).




At least two endothelin receptor subtypes, ET


A


and ET


B


receptors, have been described in the literature (Nature 348, (1990) 730, Nature 348, (1990) 732). Accordingly, substances which inhibit the binding of endothelin to the two receptors ought to antagonize the physiological effects of endothelin and therefore be valuable drugs.




WO 96/11914 describes carboxylic acid derivatives which, however, bind with high affinity to the ET


A


receptor and with considerably less affinity to the ET


B


receptor (called ET


A


-specific antagonists).




ET


A


-specific antagonists mean here those antagonists whose affinity for the ET


A


receptor is at least twenty times higher than their affinity for the ET


B


receptor.




It is an object of the present invention to provide endothelin receptor antagonists which bind with approximately the same affinity to the ET


A


and ET


B


receptors (called mixed antagonists).




Approximately the same affinity for the receptors means that the ET


A


:ET


B


affinity ratio is greater than 0.1 and less than 20, preferably less than 10.




We have found that this object is achieved by carboxylic acid derivatives of the formula I











where R


1


is tetrazole [sic] or a group











where R has the following meaning:




a) a radical OR


7


where R


7


is:




hydrogen, the cation of an alkali metal, the cation of an alkaline earth metal, a physiologically tolerated organic ammonium ion such as C


1


-C


4


-alkylammonium or the ammonium ion;




C


3


-C


8


-cycloalkyl, C


1


-C


8


-alkyl, CH


2


-phenyl which can be substituted by one or more of the following radicals: halogen, nitro, cyano, C


1


-C


4


-alkyl, C


1


-C


4


-haloalkyl, hydroxyl, C


1


-C


4


-alkoxy, mercapto, C


1


-C


4


-alkylthio, amino, carboxyl, NH(C


1


-C


4


-alkyl), N(C


1


-C


4


-alkyl)


2


;




C


3


-C


6


-alkenyl or C


3


-C


6


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




R


7


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


1


-C


4


-alkyl, C


1


-C


4


-haloalkyl, hydroxyl, C


1


-C


4


-alkoxy, mercapto, C


1


-C


4


-alkylthio, amino, NH(C


1


-C


4


-alkyl), N(C


1


-C


4


-alkyl)


2


;




b) a 5-membered heteroaromatic system which is linked via a nitrogen atom, such as pyrrolyl, pyrazolyl, imidazolyl and triazolyl, which may carry one to two halogen atoms or one to two C


1


-C


4


-alkyl or one to two C


1


-C


4


-alkoxy groups;




c) a group











 where k is 0, 1 and 2, p is 1, 2, 3 and 4 and R


8


is




C


1


-C


4


-alkyl, C


3


-C


8


-cycloalkyl, C


3


-C


6


-alkenyl, C


3


-C


6


-alkynyl or phenyl which can be substituted by one or more, eg. one to three, of the following radicals: halogen, nitro, cyano, C


1


-C


4


-alkyl, C


1


-C


4


-haloalkyl, hydroxyl, C


1


-C


4


-alkoxy, C


1


-C


4


-alkylthio, mercapto, amino, carboxyl, NH(C


1


-C


4


-alkyl), N(C


1


-C


4


-alkyl)


2


;




d) a radical











 in which R


9


is:




C


1


-C


4


-alkyl, C


3


-C


6


-alkenyl, C


3


-C


6


-alkynyl, C


3


-C


8


-cycloalkyl, C


1


-C


4


-haloalkyl, it being possible for these radicals to carry a C


1


-C


4


-alkoxy, C


1


-C


4


-alkylthio and/or a phenyl radical as mentioned under c);




phenyl, unsubstituted or substituted, in particular as mentioned above,




e) R


1


can furthermore be











 where R


13


and R


14


can be identical or different and have the following meanings:




hydrogen, C


1


-C


8


-alkyl, C


3


-C


8


-cycloalkyl, C


3


-C


8


-alkenyl, C


3


-C


8


-alkynyl, benzyl, phenyl which may carry one to five halogen atoms and/or one to three of the following radicals: nitro, cyano, C


1


-C


4


-alkyl, C


1


-C


4


-haloalkyl, hydroxyl, C


1


-C


4


-alkoxy, mercapto, C


1


-C


4


-alkylthio, amino, NH(C


1


-C


4


-alkyl), N(C


1


-C


4


-alkyl)


2


,




or R


13


and R


14


together form a C


4


-C


7


-alkylene chain which is closed to form a ring and which may be substituted by C


1


-C


4


-alkyl and in which an alkylene group may be replaced by oxygen, sulfur or nitrogen, such as —(CH


2


)


4


—, —(CH


2


)


5


—, —(CH


2


)


6


—, —(CH


2


)


2


—O—(CH


2


)


2


—, —(CH


2


)


7


—, —CH


2


—S—(CH


2


)


2


—, —CH


2


—NH—(CH


2


)


2


—, —(CH


2


)


2


—N—(CH


2


)


2


—;




R


2


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, C


1


-C


4


-hydroxyalkyl, C


1


-C


4


-haloalkyl, C


1


-C


4


-alkoxy, C


1


-C


4


-haloalkoxy or C


1


-C


4


-alkylthio, or CR


2


is linked to CR


10


as indicated below to give a 5- or 6-membered ring.




X nitrogen or methine.




Y nitrogen or methine.




Z nitrogen or CR


10


, where R


10


is hydrogen or C


1


-C


4


-alkyl, or CR


10


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 C


1


-C


4


-alkyl groups and in which in each case one or more methylene groups can be replaced by oxygen, sulfur, —NH or N(C


1


-C


4


-alkyl)


2


.




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




R


3


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, C


1


-C


4


-haloalkyl, C


1


-C


4


-alkoxy, C


1


-C


4


-haloalkoxy, C


1


-C


4


-hydroxyalkyl or C


1


-C


4


-alkylthio, or CR


3


is linked to CR


10


as indicated above to give a 5- or 6-membered ring.




R


4


and R


5


(which may be identical or different):




phenyl or naphthyl, which may be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, mercapto, C


1


-C


4


-alkyl, C


2


-C


4


-alkenyl, C


1


-C


4


-hydroxyalkyl, C


2


-C


4


-alkynyl, C


1


-C


4


-haloalkyl, C


1


-C


4


-alkoxy, phenoxy, carboxyl, C


1


-C


4


-haloalkoxy, C


1


-C


4


-alkylthio, amino, NH(C


1


-C


4


-alkyl), N(C


1


-C


4


-alkyl)


2


or phenyl which can be substituted one or more times, eg. one to three times by halogen, nitro, cyano, C


1


-C


4


-alkyl, C


1


-C


4


-haloalkyl, C


1


-C


4


-alkoxy, C


1


-C


4


-haloalkoxy or C


1


-C


4


-alkylthio; 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.




R


6


C


3


-C


8


-Cycloalkyl, it being possible for these radicals in each case to be substituted one or more times by: halogen, hydroxyl, mercapto, carboxyl, nitro, cyano, C


1


-C


4


-alkoxy, C


1


-C


4


-alkyl, C


2


-C


4


-alkenyl, C


2


-C


4


-alkynyl, C


3


-C


6


-alkenyloxy, C


3


-C


6


-alkynyloxy, C


1


-C


4


-alkylthio, C


1


-C


4


-haloalkoxy, C


1


-C


4


-alkylcarbonyl, C


1


-C


4


-alkoxycarbonyl, C


3


-C


8


-alkyl-carbonylalkyl, NH(C


1


-C


4


-alkyl), N(C


1


-C


4


-alkyl)


2


, or phenyl which can be substituted one or more times, eg. one to three times, by halogen, nitro, cyano, C


1


-C


4


-alkyl, C


1


-C


4


-haloalkyl, C


1


-C


4


-alkoxy, C


1


-C


4


-haloalkoxy or C


1


-C


4


-alkylthio;




phenyl or naphthyl, each of which can be substituted by one or more of the following radicals: halogen, R


15


, nitro, mercapto, carboxyl, cyano, hydroxyl, amino, C


1


-C


4


-alkyl, C


2


-C


4


-alkenyl, C


2


-C


4


-alkynyl, C


3


-C


6


-alkenyloxy, C


1


-C


4


-haloalkyl, C


3


-C


6


-alkynyloxy, C


1


-C


4


-alkylcarbonyl, C


1


-C


4


-alkoxycarbonyl, C


1


-C


4


-alkoxy, C


1


-C


4


-haloalkoxy, phenoxy, C


1


-C


4


-alkylthio, NH(C


1


-C


4


-alkyl), N(C


1


-C


4


-alkyl)


2


, dioxomethylene [sic], dioxoethylene [sic] or phenyl which can be substituted one or more times, eg. one to three times, by halogen, nitro, cyano, C


1


-C


4


-alkyl, C


1


-C


4


-haloalkyl, C


1


-C


4


-alkoxy, C


1


-C


4


-haloalkoxy or C


1


-C


4


-alkylthio;




a five- or six-membered heteroaromatic system containing 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, C


2


-C


4


-alkenyl, C


1


-C


4


-haloalkyl, C


1


-C


4


-alkoxy, C


1


-C


4


-haloalkoxy, C


1


-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 following radicals: C


1


-C


4


-alkyl, C


1


-C


4


-haloalkyl, C


1


-C


4


-alkoxy, C


1


-C


4


-haloalkoxy and/or C


1


-C


4


-alkylthio;




R


15


is C


1


-C


4


-alkyl, C


1


-C


4


-alkylthio or C


1


-C


4


-alkoxy which carry one of the following radicals: hydroxyl, carboxyl, amino, NH(C


1


-C


4


-alkyl), N(C


1


-C


4


-alkyl)


2


, carboxamide [sic] or CON(C


1


-C


4


-alkyl)


2


;




W sulfur or oxygen.




Q a spacer whose length corresponds to that of a C


2


-C


4


chain. The function of Q is to produce a defined distance between the groups R


6


and W in the compounds of the formula I. The distance should correspond to the length of a C


2


-C


4


-alkyl chain. This can be achieved by a large number of chemical radicals, for example with C


2


-C


4


-alkyl, C


3


-C


4


-alkenyl, C


3


-C


4


-alkynyl, —S—CH


2


—CH


2


—, —O—CH


2


—CH


2


—, —N—CO—CH


2


—O—, it being possible for each of these radicals to be substituted one or more times by: halogen, hydroxyl, mercapto, C


1


-C


4


-alkyl, C


2


-C


4


-alkenyl, C


2


-C


4


-alkynyl, carboxyl, nitro, cyano, C


1


-C


4


-alkoxy, C


3


-C


6


-alkenyloxy, C


3


-C


6


-alkynyloxy, C


1


-C


4


-alkylthio, C


1


-C


4


-haloalkoxy, C


1


-C


4


-alkylcarbonyl, C


1


-C


4


-alkoxycarbonyl, C


3


-C


8


-alkylcarbonylalkyl, NH(C


1


-C


4


-alkyl), N(C


1


-C


4


-alkyl)


2


, phenyl which can be substituted one or more times, eg. one to three times, by halogen, nitro, cyano, C


1


-C


4


-alkyl, C


1


-C


4


-haloalkyl, C


1


-C


4


-alkoxy, C


1


-C


4


-haloalkoxy or C


1


-C


4


-alkylthio.




Or the spacer Q is part of a 5-7-membered heterocyclic or carbocyclic ring to which R


6


is fused.




The following definitions apply thereto and hereinafter:




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




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




C


3


-C


8


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




C


1


-C


4


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




C


1


-C


4


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




C


1


-C


4


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




C


2


-C


4


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




C


1


-C


4


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




C


3


-C


6


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




C


1


-C


4


-hydroxyalkyl can be linear or branched, such as, for example, hydroxymethyl, 1-hydroxyether-2-yl,




C


3


-C


6


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




C


1


-C


4


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




C


1


-C


4


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




C


1


-C


4


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




C


3


-C


8


-alkylcarbonylalkyl can be linear or branched, such as, for example, 2-oxo-1-propyl, 3-oxo-1-butyl or 3-oxo-2-butyl




C


1


-C


8


-alkyl can be linear or branched, such as, for example, C


1


-C


4


-alkyl, pentyl, hexyl, heptyl or octyl;




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




The invention furthermore relates to those compounds from which compounds of the formula I can be liberated (called prodrugs).




Preferred prodrugs are those with which 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. Such compounds can be in the form of pure enantiomers or pure diastereomers or mixture thereof. An enantiomerically pure compound is preferably used as active substance.




The invention furthermore relates to the use of the abovementioned carboxylic acid derivatives for producing drugs, in particular for producing inhibitors of ET


A


and ET


B


receptors. The compounds according to the invention are particularly suitable as mixed antagonists as defined at the outset.




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











Compounds of the formula III are known or can be synthesized, for example, by reducing the corresponding carboxylic acids or esters thereof or by other conventional methods.




Carboxylic acid derivatives of the formula IV [sic] can also be prepared by reacting a compound of the formula IVa with an alcohol or thiol of the formula VII with acid catalysis.











The indicated radicals have the following meanings:




R


1


has the meaning indicated for formula I




R


16


and R


17


, which may be identical or different, hydrogen or alkyl, alkenyl, alkynyl, phenyl, naphthyl, cycloalkyl, in each case unsubstituted or substituted,




R


18


hydrogen or alkyl, alkenyl, alkynyl, phenyl, naphthyl, cycloalkyl, in each case unsubstituted or substituted,




R


19


hydrogen or alkyl, alkenyl, alkynyl, phenyl, naphthyl, cycloalkyl, in each case unsubstituted or substituted,




and the radicals preferably have the following meanings:




R


1


COOR


7






R


16


and R


17


, which may be identical or different, alkyl, phenyl, naphthyl, cycloalkyl, in each case unsubstituted or substituted,




R


18


alkyl, phenyl, cycloalkyl, in each case unsubstituted or substituted,




R


19


alkyl, alkenyl, alkynyl, phenyl, cycloalkyl, in each case unsubstituted or substituted,




and the following radicals are particularly preferred:




R


1


COOCH


3






R


16


R


4






R


17


R


5






R


18


alkyl, unsubstituted or substituted, in particular methyl




R


19


R


6


—Q.




The carboxylic acid derivatives of the formula IV can be prepared by this process by reacting a compound of the formula IVa with an alcohol or thiol of the formula III with acid catalysis











For this purpose, the compounds IVa and III are mixed without diluent or in a solvent which is inert for this reaction, and catalytic amounts of an acid such as p-toluenesulfonic acid are added. Examples of inert solvents are methylene chloride, benzene or toluene. Also suitable are those inert solvents which form an azeotrope with the alcohol R


18


OH. In the case of methanol (R


18


═CH


3


), examples of these are chloroform or methyl acetate.




The reaction mixture is then stirred at from room temperature to the boiling point of the solvent. The resulting alcohol R


18


OH is removed by distilling out or reducing the pressure. This method is also suitable for preparing enantiomerically pure IV if the IVa starting material is enantiomerically pure.




Compounds of the formula IVa are known and are described, for example, in WO 96/11914.




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











In formula V, R


11


is halogen or R


12


—SO


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, ie. 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


1


=COOH can furthermore be obtained directly by deprotonating the intermediate IV where R


1


is COOH with two equivalents of a suitable base, and reacting 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, for example dimethyl sulfoxide and sulfolane.




Compounds of the formula V are known, and in some cases can be bought or prepared in a conventional way.




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 an alkali metal carbonate, eg. sodium or potassium carbonate, an alkali metal or alkaline earth metal hydroxide such as sodium or potassium hydroxide, an organometallic compound such as butyllithium or an alkali metal amide such as lithium diisopropylamide or lithium amide.




Compounds of the formula I can also be prepared by starting from the corresponding carboxylic acids, ie. compounds of the formula I where R


1


is COOH, and converting first them 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 HOR


7


. This reaction can be carried out in conventional solvents and often requires the 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 in the presence of a dehydrating agent such as a carbodiimide.




It is also possible to prepare compounds of the formula I by starting from the salts of the appropriate carboxylic acids, ie. from compounds of the formula I where R


1


is COR and R is OM [sic] 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 halogens such as chlorine, bromine, iodine, or aryl- or alkylsulfonyl which is unsubstituted or substituted by halogen, alkyl or haloalkyl, 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 undertaken with the addition of a base, in which case those mentioned above are suitable.




In some cases it is necessary to use generally known protective group techniques to prepare compounds I according to the invention. If, for example, R


6


is to be 4-hydroxyphenyl, it is possible first to protect the hydroxyl group as benzyl ether, which is then cleaved at a suitable stage in the reaction sequence.




Compounds of the formula I where R


1


is tetrazole [sic] can be prepared as described in WO 96/11914.




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




R


2


hydrogen, hydroxyl, halogen, N(C


1


-C


4


-alkyl)


2


, C


1


-C


4


-alkyl, C


1


-C


4


-alkoxy, C


1


-C


4


-alkylthio, C


1


-C


4


-haloalkyl, C


1


-C


4


-haloalkoxy, or CR


2


is linked to CR


10


as indicated below to give a 5- or 6-membered ring;




X nitrogen or methine;




Y nitrogen or methine;




Z nitrogen or CR


10


, where R


10


is hydrogen or C


1


-C


4


-alkyl, or CR


10


forms together with CR


2


or CR


3


a 5- or 6-membered alkylene or alkenylene ring which can be substituted by one or two methyl groups and in which, in each case, one methylene group can be replaced by oxygen or sulfur, such as —CH


2


—CH


2


—O—, —CH


2


—CH


2


—CH


2


—O—, —CH═CH—O—, —CH═CH—CH


2


O—, —CH(CH


3


)—CH(CH


3


)—O—, —CH=C(CH


3


)—O—, —C(CH


3


)═C(CH


3


)—O—, or —C(CH


3


)═C(CH


3


)—S;




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




R


3


hydrogen, hydroxyl, halogen, N(C


1


-C


4


-alkyl)


2


, C


1


-C


4


-alkyl, C


1


-C


4


-alkoxy, C


1


-C


4


-alkylthio, C


1


-C


4


-haloalkyl, C


1


-C


4


-haloalkoxy, or CR


3


is linked to CR


10


as indicated above to give a 5- or 6-membered ring;




R


4


and R


5


(which can be identical or different):




phenyl or naphthyl, which can be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, mercapto, amino, C


1


-C


4


-alkyl, C


1


-C


4


-haloalkyl, carboxyl, C


1


-C


4


-alkoxy, C


1


-C


4


-haloalkoxy, phenoxy, C


1


-C


4


-alkylthio, NH(C


1


-C


4


-alkyl) or N(C


1


-C


4


-alkyl)


2


or phenyl which can be substituted one or more times, eg. one to three times, by halogen, nitro, cyano, C


1


-C


4


-alkyl, C


1


-C


4


-haloalkyl, C


1


-C


4


-alkoxy, C


1


-C


4


-haloalkoxy or C


1


-C


4


-alkylthio; or




phenyl or naphthyl, which are connected 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;




R


6


C


3


-C


8


-cycloalkyl, it being possible for these radicals in each case to be substituted one or more times by: halogen, hydroxyl, mercapto, carboxyl, nitro, cyano, C


1


-C


4


-alkoxy, C


1


-C


4


-alkyl, C


2


-C


4


-alkenyl, C


2


-C


4


-alkynyl, C


3


-C


6


-alkenyloxy, C


3


-C


6


-alkynyloxy, C


1


-C


4


-alkylthio, C


1


-C


4


-haloalkoxy, C


1


-C


4


-alkylcarbonyl, C


1


-C


4


-alkoxycarbonyl, NH(C


1


-C


4


-alkyl), N(C


1


-C


4


-alkyl)


2


or phenyl which can be substituted one or more times, eg. one to three times, by halogen, nitro, cyano, C


1


-C


4


-alkyl, C


1


-C


4


-haloalkyl, C


1


-C


4


-alkoxy, C


1


-C


4


-haloalkoxy or C


1


-C


4


-alkylthio;




phenyl or naphthyl, each of which can be substituted by one or more of the following radicals: halogen, R


15


, nitro, mercapto, carboxyl, cyano, hydroxyl, amino, C


1


-C


4


-alkyl, C


2


-C


4


-alkenyl, C


2


-C


4


-alkynyl, C


3


-C


6


-alkenyloxy, C


1


-C


4


-haloalkyl, C


3


-C


6


-alkynyloxy, C


1


-C


4


-alkylcarbonyl, C


1


-C


4


-alkoxycarbonyl, C


1


-C


4


-alkoxy, C


1


-C


4


-haloalkoxy, phenoxy, C


1


-C


4


-alkylthio, NH(C


1


-C


4


-alkyl), N(C


1


-C


4


-alkyl)


2


, dioxomethylene [sic], dioxoethylene [sic] or phenyl which can be substituted one or more times, eg. one to three times, by halogen, nitro, cyano, C


1


-C


4


-alkyl, C


1


-C


4


-haloalkyl, C


1


-C


4


-alkoxy, C


1


-C


4


-haloalkoxy or C


1


-C


4


-alkylthio;




a five- or six-membered heteroaromatic system containing one to three nitrogen atoms and/or one sulfur or oxygen atom, which can carry one to four halogen atoms and/or one to two of the following radicals: C


1


-C


4


-alkyl, C


1


-C


4


-haloalkyl, C


1


-C


4


-alkoxy, C


1


-C


4


-haloalkoxy, C


1


-C


4


-alkylthio, phenyl, phenoxy or phenylcarbonyl, where the phenyl radicals in turn can carry one to five halogen atoms and/or one to three of the following radicals: C


1


-C


4


-alkyl, C


1


-C


4


-haloalkyl, C


1


-C


4


-alkoxy, C


1


-C


4


-haloalkoxy and/or C


1


-C


4


-alkylthio;




R


15


methyl, ethyl, methoxy or ethoxy which carry one of the following radicals: hydroxyl, carboxyl, amino, NH(C


1


-C


4


-alkyl), N(C


1


-C


4


-alkyl)


2


, carboxamide [sic] or CON(C


1


-C


4


-alkyl)


2


;




W sulfur or oxygen;




Q C


2


-C


4


-alkyl, C


3


-C


4


-alkenyl, C


3


-C


4


-alkynyl, —S—CH


2


—CH


2


—, —O—CH


2


—CH


2


—, it being possible for each of these radicals to be substituted one or more times by: halogen, hydroxyl, mercapto, carboxyl, nitro, cyano, C


1


-C


4


-alkyl, C


1


-C


4


-alkoxy, C


1


-C


4


-alkylthio, C


1


-C


4


-haloalkoxy, C


1


-C


4


-alkoxycarbonyl, NH(C


1


-C


4


-alkyl), N(C


1


-C


4


-alkyl)


2


or phenyl which can be substituted one or more times, eg. one to three times, by halogen, nitro, cyano, C


1


-C


4


-alkyl, C


1


-C


4


-haloalkyl, C


1


-C


4


-alkoxy, C


1


-C


4


-haloalkoxy or C


1


-C


4


-alkylthio




or Q forms together with R


6


the following ring systems: 2-indanyl, 3-indanyl, 1,2,3,4-tetrahydro-2-naphthyl, 1,2,3,4-tetrahydro-3-naphthyl, it being possible for the phenyl rings in each case to be substituted by: halogen, hydroxyl, mercapto, carboxyl, nitro, cyano, C


1


-C


4


-alkoxy, C


1


-C


4


-alkyl, C


2


-C


4


-alkenyl, C


2


-C


4


-alkynyl, C


3


-C


6


-alkenyloxy, C


3


-C


6


-alkynyloxy, C


1


-C


4


-alkylthio, C


1


-C


4


-haloalkoxy, C


1


-C


4


-alkylcarbonyl, C


1


-C


4


-alkoxycarbonyl, amino, NH(C


1


-C


4


-alkyl), N(C


1


-C


4


-alkyl)


2


or phenyl.




Particularly preferred compounds of the formula I, both as pure enantiomers and pure diastereomers or mixtures thereof, are those where the substituents have the following meanings:




R


2


trifluoromethyl, C


1


-C


4


-alkyl, C


1


-C


4


-alkoxy, C


1


-C


4


-alkylthio, or CR


2


is linked to CR


10


as indicated below to give a 5- or 6-membered ring;




X nitrogen or methine;




Y nitrogen or methine;




Z nitrogen or CR


10


where R


10


is hydrogen or C


1


-C


4


-alkyl, or CR


10


forms together with CR


2


or CR


3


a 5- or 6-membered alkylene or alkenylene ring which can 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


—O—, —CH


2


—CH


2


—CH


2


—O—, —CH═CH—O—, —CH═CH—CH


2


O—, —CH(CH


3


)—CH(CH


3


)—O—, —CH=C(CH


3


)—O—, —C(CH


3


)═C(CH


3


)—O—, or —C(CH


3


)═C(CH


3


)—S;




At least one of the ring members X, Y or Z is nitrogen




R


3


trifluoromethyl, C


1


-C


4


-alkyl, C


1


-C


4


-alkoxy, C


1


-C


4


-alkylthio, or CR


3


is linked to CR


10


as indicated above to give a 5- or 6-membered ring;




R


4


and R


5


(which can be identical or different):




phenyl or naphthyl, which can be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, mercapto, amino, C


1


-C


4


-alkyl, C


1


-C


4


-haloalkyl, C


1


-C


4


-alkoxy, C


1


-C


4


-haloalkoxy, phenoxy, C


1


-C


4


-alkylthio, NH(C


1


-C


4


-alkyl) or N(C


1


-C


4


-alkyl)


2


or phenyl which can be substituted one or more times, eg. one to three times, by halogen, nitro, cyano, C


1


-C


4


-alkyl, C


1


-C


4


-haloalkyl, C


1


-C


4


-alkoxy, C


1


-C


4


-haloalkoxy or C


1


-C


4


-alkylthio; or




phenyl or naphthyl, which are connected 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


5


-C


7


-cycloalkyl;




R


6


C


5


-C


7


-cycloalkyl, it being possible for these radicals in each case to be substituted one or more times by: C


1


-C


4


-alkoxy,




C


1


-C


4


-alkyl, C


1


-C


4


-alkylthio, halogen, hydroxyl, carboxyl, cyano, trifluoromethyl, acetyl, or phenyl which can be substituted one or more times, eg. one to three times, by halogen, cyano, C


1


-C


4


-alkyl, C


1


-C


4


-haloalkyl, C


1


-C


4


-alkoxy, C


1


-C


4


-haloalkoxy or C


1


-C


4


-alkylthio;




phenyl or naphthyl, each of which can be substituted by one or more of the following radicals: halogen, R


15


, nitro, mercapto, carboxyl, cyano, hydroxyl, amino, C


1


-C


4


-alkyl, C


1


-C


4


-haloalkyl, acetyl, C


1


-C


4


-alkoxycarbonyl, C


1


-C


4


-alkoxy, C


1


-C


4


-haloalkoxy, phenoxy, C


1


-C


4


-alkylthio, NH(C


1


-C


4


-alkyl), N(C


1


-C


4


-alkyl)


2


, dioxomethylene [sic], dioxoethylene [sic] or




phenyl which can be substituted one or more times, eg. one to three times, by halogen, nitro, cyano, C


1


-C


4


-alkyl, C


1


-C


4


-haloalkyl, C


1


-C


4


-alkoxy, C


1


-C


4


-haloalkoxy or C


1


-C


4


-alkylthio;




a five- or six-membered heteroaromatic system containing one to three nitrogen atoms and/or one sulfur or oxygen atom, which can carry one to four halogen atoms and/or one to two of the following radicals: C


1


-C


4


-alkyl, C


1


-C


4


-haloalkyl, C


1


-C


4


-alkoxy, trifluoromethoxy, C


1


-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 following radicals: C


1


-C


4


-alkyl, C


1


-C


4


-haloalkyl, C


1


-C


4


-alkoxy, C


1


-C


4


-haloalkoxy and/or C


1


-C


4


-alkylthio;




R


15


methoxy or ethoxy which carry one of the following radicals: hydroxyl, carboxyl, amino, NH(C


1


-C


4


-alkyl), N(C


1


-C


4


-alkyl)


2


, carboxamide [sic] or CON(C


1


-C


4


-alkyl)


2


;




W sulfur or oxygen;




Q C


2


-C


4


-alkyl, C


3


-C


4


-alkenyl, C


3


-C


4


-alkynyl, —S—CH


2


—CH


2


—, —O—CH


2


—CH


2


—, it being possible for each of these radicals to be substituted one or more times by: halogen, hydroxyl, mercapto, carboxyl, C


1


-C


4


-alkyl, C


1


-C


4


-alkoxy, C


1


-C


4


-alkylthio, or phenyl which can be substituted one or more times, eg. one to three times, by halogen, nitro, cyano, C


1


-C


4


-alkyl, C


1


-C


4


-haloalkyl, C


1


-C


4


-alkoxy, C


1


-C


4


-haloalkoxy or C


1


-C


4


-alkylthio




or Q forms together with R


6


the following ring systems: 2-indanyl, 3-indanyl, 1,2,3,4-tetrahydro-2-naphthyl, 1,2,3,4-tetrahydro-3-naphthyl, it being possible for the phenyl rings in each case to be substituted by: halogen, hydroxyl, mercapto, carboxyl, cyano, C


1


-C


4


-alkoxy, C


1


-C


4


-alkyl, C


2


-C


4


-alkenyl, C


2


-C


4


-alkynyl, C


3


-C


6


-alkenyloxy, C


3


-C


6


-alkynyloxy, C


1


-C


4


-alkylthio, C


1


-C


4


-haloalkoxy, C


1


-C


4


-alkoxycarbonyl, NH(C


1


-C


4


-alkyl), N(C


1


-C


4


-alkyl)


2


or phenyl.




The compounds of the present invention offer a novel therapeutic potential for the 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, kidney failure and hypertension caused by ischemia and intoxication, metastasis and growth of mesenchymal tumors, kidney failure induced by contrast agents, pancreatitis, gastrointestinal ulcers.




The compounds according to the invention surprisingly also show in some cases an antagonistic action on the neurokinin receptor.




This is particularly true of compounds of the formula I where R


1


is











The invention furthermore relates to combination products consisting 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.




The invention further relates to combination products of β blockers and the abovementioned endothelin receptor antagonists, and of mixed ACE/neutral endopeptidase (NEP) inhibitors and the abovementioned endothelin receptor antagonists.




The combination products can be administered in a single pharmaceutical form or else in spatially separate forms. Administration may take place simultaneously or sequentially.




The dosage of the combination may be up to the maximum single dose in each case. However, it is also possible to employ lower doses than in the single therapy in each case.




These combination products are particularly suitable for the treatment and prevention of hypertension and its sequelae, and for the treatment of heart failure.




The good effect of the compounds can be shown in the following tests:




Receptor Binding Studies




Cloned human ET


A


or ET


B


receptor-expressing CHO cells were employed for binding studies.




Membrane Preparation




The ET


A


or ET


B


receptor-expressing CHO cells were grown in DMEM NUT MIX F


12


medium (Gibco, No. 21331-020) with 10% fetal calf serum (PAA Laboratories GmbH, Linz, No. A15-022), 1 mM glutamine (Gibco No. 25030-024), 100 U/ml penicillin and 100 μg/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. Neutralization with medium was then carried out, and the cells were collected by centrifugation at 300×g.




For the membrane preparation, the cells were adjusted to a concentration of 10


8


cells/ml of buffer (50 mM tris.HCL buffer, pH 7.4) and then disintegrated by ultrasound (Branson Sonifier 250, 40-70 seconds/constant/output 20).




Binding Assays




For the ET


A


and ET


B


receptor binding assays, the membranes were suspended in incubation buffer (50 mM tris-HCl, pH 7,4 with 5 mM MnCl


2


, 40 μg/ml bacitracin and 0.2% BSA) at a concentration of 50 μg of protein per assay mixture, and incubated with 25 pM


125


I-ET


1


(ET


A


receptor assay) or 25 pM


125


I-ET


3


(ET


B


receptor assay) in the presence and absence of test substance at 25° C. The nonspecific binding was determined with 10


−7


M ET


1


. Filtration was carried out after 30 min through GF/B glassfiber filters (Whatman, England) in a Skatron cell collector (Skatron, Lier, Norway) to separate free and bound radio ligands, and the filters were washed with ice-cold tris-HCl buffer, pH 7.4 with 0.2% BSA. The radioactivity collected on the filters was quantified using a




Packard 2200 CA liquid scintillation counter.




Testing of the ET antagonists in vivo:




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




Intravenous administration of 1 μg/kg ET1 to control animals led to a marked rise in blood pressure, which persisted for a lengthy period.




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




Oral testing of the mixed ET


A


and ET


B


antagonists:




Normotensive male rats (Sprague Dawley, Janvier) weighing 250-350 g are pretreated orally with the test substances. 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.




After a stabilization period, big endothelin (20 μg/kg, administration volume 0.5 ml/kg) or ET1 (0.3 μg/kg, administration volume 0.5 ml/kg) is given intravenously. The blood pressure and heartrate are recorded continuously for 30 minutes. The marked 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 the 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, intraperitoneally) in a conventional way. Administration may 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 substance 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. For this purpose, the active substances can 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 substance.











SYNTHESIS EXAMPLES




Example 1




Methyl 2-Hydroxy-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-diphenylpropionate




7 g (27.5 mmol) of methyl 3,3-diphenyl-2,3-epoxypropionate and 5.5 g (30.2 mmol) of 2-(3,4-dimethoxyphenyl)ethanol were dissolved in 20 ml of dichloromethane and, at room temperature, 5 drops of boron trifluoride etherate were added. The solution was stirred for 2 hours. The solvent was then distilled off, and the residue (10.7 g, 89%) was immediately reacted further.




Example 2




2-Hydroxy-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-diphenylpropionic Acid




12 g (27.5 mmol) of methyl 2-hydroxy-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-diphenylpropionate were dissolved in 110 ml of dioxane, and 55 ml of 1 N NaOH solution were added. The mixture was stirred at 80° C. for 2 hours. Water was added to the mixture, and the aqueous phase was extracted twice with ether. The aqueous phase was acidified with 1 N aqueous HCl and extracted with ether, the organic phase was dried over magnesium sulfate, and the solvent was distilled off. The residue was recrystallized from ether/n-hexane, and 10.2 g (87%) of colorless crystals were isolated.




Melting point: 133-135° C.




Example 3




2-(4-Methoxy-6-methyl-2-pyrimidinyloxy)-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-diphenylpropionic Acid (I-482)




1 g (2.3 mmol) of 2-hydroxy-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-diphenylpropionic acid was introduced into 10 ml of DMF, and 340 mg of NaH (50% suspension) were added. After the mixture had been stirred for 15 minutes, 526 mg of 4-methoxy-6-methyl-2-methylsulfonylpyrimidine were added, and the mixture was stirred at room temperature for 3 hours. Water was added to the mixture, which was then extracted with ether. The aqueous phase was acidified with 1 N aqueous HCl, extracted with ether and dried over magnesium sulfate. The solvent was distilled off, the residue was purified by MPLC, and 655 mg (52%) of colorless powder were isolated after recrystallization from ether/n-hexane.






1


H-NMR (200 MHz): 7.2 ppm (10H, m), 6.8 (3H, m), 6.2 (1H, s), 6.18 (1H, s), 3.9 (9H, m), 3.8 (1H, m), 3.7 (1H, m), 2.85 (2H, tr), 2.2 (3H, s). EI-MS: M


+


=544.




Example 4




Methyl 3,3-di(4-Ethylphenyl)-2,3-epoxypropionate




A solution of 15 ml (168 mmol) of methyl chloroacetate and 20 g (84 mmol) of 4,4′-diethylbenzophenone in 20 ml of THF was added dropwise to a suspension of 9.1 g (168 mmol) of sodium ethanolate in 80 ml of THF at −10° C. The mixture was warmed to room temperature and stirred for 2 hours. The mixture was added to water and extracted with ether. The organic phase was washed with sodium bicarbonate solution and citric acid solution and dried over magnesium sulfate, and the solvent was distilled off. 15.4 g of a crude oil were isolated and were immediately employed further.




Example 5




Methyl 2-Hydroxy-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-di-(4-ethyl-phenyl)propionate




6 g (19.3 mmol) of methyl 3,3-di(4-ethylphenyl)-2,3-epoxypropionate (crude) and 3.52 g (19.3 mmol) of 2-(3,4-dimethoxyphenyl)ethanol were dissolved in 20 ml of dichloromethane and, at room temperature, 5 drops of boron trifluoride etherate were added. The solution was stirred for 1.5 hours. The solvent was then distilled off, and the residue, a pale yellow oil (8.66 g, 91%), was immediately reacted further.




Example 6




2-Hydroxy-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-di(4-ethylphenyl)propionic Acid




9.2 g (19.3 mmol) of methyl 2-hydroxy-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-di(4-ethylphenyl)propionate were dissolved in 26 ml of dioxane, and 13 ml of 3 N NaOH solution were added. The mixture was stirred at 60° C. for 3 hours. Water was added to the mixture, and the aqueous phase was extracted twice with ether. The aqueous phase was acidified with 1 N aqueous HCl and extracted with ether, the organic phase was dried over magnesium sulfate, and the solvent was distilled off. 6.5 g (71%) of a yellowish oil were isolated and were immediately reacted further.




Example 7




2-(4-Methoxy-6-methyl-2-pyrimidinyloxy)-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-di(4-ethylphenyl)propionic Acid (I-116)




1.8 g (3.8 mmol) of 2-hydroxy-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-di(4-ethylphenyl)propionic acid were introduced into 20 ml of DMF, and 554 mg of NaH (50% suspension) were added. After the mixture had stirred for 15 minutes, 855 mg (4.2 mmol) of 4-methoxy-6-methyl-2-methylsulfonylpyrimidine were added, and the mixture was stirred at room temperature for 3 hours. Water was added to the mixture, which was then extracted with ether. The aqueous phase was acidified with 1 N aqueous HCl, extracted with ether and dried over magnesium sulfate. The solvent was distilled off and 540 mg (23%) of colorless powder were isolated after recrystallization from ether/n-hexane.






1


H-NMR (200 MHz): 7.0-7.4 ppm (10H, m), 6.8 (2H, d), 6.2 (1H, s), 6.15 (1H, s), 3.9 (3H, s), 3.8 (3H, s), 3.7 (1H, m), 3.5 (1H, m), 2.9 (2H, tr), 2.6 (4H, m), 2.3 (3H, s), 1.2 (6H, m). EI-MS: M


+


=600.




Example 8




2-(4,6-Dimethyl-2-pyrimidinyloxy)-3-(3-phenyl-(2E)-propenoxy)-3,3-diphenylpropionic Acid (I-27)




1.12 g (3 mmol) of 2-hydroxy-3-(3-phenyl-(2E)-propenoxy)-3,3-diphenylpropionic acid were added to a suspension of 432 mg (9 mmol, 50%) of NaH in 20 ml of DMF, and the mixture was stirred at room temperature for 10 minutes. 614 mg (3.3 mmol) of 4,6-dimethyl-1-methylsulfonylpyrimidine were added, and the mixture was stirred for 16 hours, then diluted with 200 ml of water, acidified with 1 N hydrochloric acid and extracted with ether. The ether phase was extracted with 1 N sodium hydroxide solution, the aqueous phase was again acidified, and the product was extracted with ether. The organic phase was dried over magnesium sulfate and filtered, and the solvent was distilled off. The residue was recrystallized from ether/hexane, and 927 mg (65%) of crystalline product were isolated.




Melting point: 128-133° C.;


1


H-NMR (200 MHz): 7.3 ppm (15H, m), 6.74 (1H, s), 6.7 (1H, d), 6.3 (1H, s), 6.2 (1H, dtr, 4.3 (1H, dd), 4.1 (1H, dd), 2.3 (6H, s). EI-MS: M


+


=480.




Example 9




4,6-Dimethyl-1-methylthiopyrimidine




15 g (107 mmol) of 4,6-dimethyl-1-mercaptopyrimidine and 5.14 g of NaOH were dissolved in 175 ml of water. 12 ml (128 mmol) of dimethyl sulfate were added dropwise to this mixture at room temperature over the course of 10 minutes. After 1 hour, the aqueous phase was extracted 3 times with ether and dried over magnesium sulfate, and the solvent was distilled off. 15.9 g (97%) of crude product were isolated.


1


H-NMR (270 MHz): 6.7 ppm (1H, s), 2.5 (3H, s), 2.3 (6H, s).




Example 10




4,6-Dimethyl-1-methylsulfonylpyrimidine




15.9 g (103 mmol) of 4,6-dimethyl-1-methylthiopyrimidine were introduced into 120 ml of dichloromethane and 110 ml of water. Chlorine gas was passed into saturation (yellow coloration) at 0° C. After the conversion was complete, excess chlorine was driven out with nitrogen, the aqueous phase was extracted with dichloromethane, and the collected organic phases were dried over magnesium sulfate. The solution was concentrated, and the product (14 g, 73%) was crystallized by adding ether.




Melting point: 79-80° C.


1


H-NMR (270 MHz): 7.2 ppm (1H, s), 3.4 (3H, s), 2.6 (6H, s).




Example 11




Methyl (S)-2-Hydroxy-3-methoxy-3,3-diphenylpropionate




54.4 g (200 mmol) of (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid were introduced with 10.8 g (200 mmol) of sodium methoxide into 300 ml of DMF. 21 ml (210 mmol) of dimethylsulfate were added dropwise to this suspension over 15 minutes, during which the temperature rises to 50° C. and the suspension becomes mobile. The mixture was stirred overnight and then added to 1.5 l of water and ice. The aqueous phase was extracted twice with 500 ml of ether, and the ether phase was in turn washed with 200 ml of water twice. The organic phase was dried over magnesium sulfate, the desiccant was filtered off, and the solvent was distilled off. 55.8 g of an oil were isolated and were immediately processed further.




Example 12




Methyl (S)-2-Hydroxy-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-diphenylpropionate




Variant A:




27.9 g of methyl (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionate (100 mmol) were mixed with 1 g of p-toluenesulfonic acid and 18.2 g of 2-(3,4-dimethoxyphenyl)ethanol (100 mmol) in a flask and heated to 60° C. The pressure in the flask is reduced in order to distill out the methanol which is produced, and the mixture is stirred at 60° C. for a further 5 hours. For workup, the mixture is cooled and diluted with 300 ml of ether, and the organic phase is washed first with sodium bicarbonate solution and then several times with water. It is then dried with magnesium sulfate, and the desiccant is filtered off and the solvent is distilled off. A residue of 43 g of oil was isolated and could be employed immediately for the subsequent synthesis.




Variant B:




27.9 g of methyl (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionate (100 mmol), 1 g of p-toluenesulfonic acid and 18.2 g (100 mmol) of 2-(3,4-dimethoxyphenyl)ethanol were dissolved in 75 ml of dichloromethane in a flask. The solution was heated and the dichloromethane was distilled out while simultaneously adding dichloromethane dropwise, in order to distill out the methanol which was produced, and the mixture was stirred at 60° C. for a further 5 hours. For workup, the mixture is cooled and diluted with 300 ml of ether, and the organic phase is washed first with sodium bicarbonate solution and then several times with water. It is then dried with magnesium sulfate, and the desiccant is filtered off and the solvent is distilled off. A residue of 43 g of oil was isolated and could be used immediately in the subsequent synthesis.




Example 13




(S)-2-Hydroxy-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-diphenylpropionic Acid




255 ml of 1 N sodium hydroxide solution were added to a solution of 74 g (170 mmol) of methyl (S)-2-hydroxy-3-(2-(3,4-dimethoxyphenyl)ethoxy-3,3-diphenylpropionate in 510 ml of dioxane, and the suspension was stirred at 50° C. for two hours. The mixture was diluted with 2.5 l of water and neutralized with citric acid. The aqueous phase was extracted twice with 500 ml of ether. The organic phase was then washed with water, dried over magnesium sulfate and filtered, and then the ether was distilled off. The residue was purified by crystallization from ether/n-hexane, and 70 g of crystals were isolated.






1


H-NMR (200 MHz): 7.3 ppm (10H, m), 6.8 (1H, dbr), 6.7 (1H, dbr), 6.6 (1H, sbr), 5.0 (1H, s), 3.9 (3H, s), 3.85 (3H, s), 3.6 (1H, dt), 3.4 (1H, OH), 3.2 (1H, dt), 2.8 (2H, t). [α]


20


=8.3 (1; ethanol).




Example 14




2-(4,6-(Dimethylpyrimidin-2-yloxy)-3-(2-(3,4-dimethoxyphenyl)ethoxy-3,3-diphenylpropionic Acid (I-445) and




(S)-2-(4,6-Dimethylpyrimidin-2-yloxy)-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-diphenylpropionic Acid (I-445 (S) Enantiomer) 55 g (130 mmol) of 2-hydroxy-3-(2-(3,4-dimethoxyphenyl)ethoxy-3,3-diphenylpropionic acid, dissolved in 150 ml of DMF, were added over the course of 15 minutes to 9 g (390 mmol) of lithium amide in 35 ml of DMF. 25 g (137 mmol) of 2-methylsulfone-4,6-dimethylpyrimidine [sic], dissolved in 75 ml of DMF, were slowly added dropwise to this, and the mixture was stirred at room temperature for 18 hours. For workup, the mixture was added to 2 l of ice-water and citric acid for neutralization. The crystals which separated out were filtered off with suction and washed with water. The moist crystals were dissolved in dichloromethane, the solution was dried over magnesium sulfate and filtered, and the solvent was distilled off. The oily residue was taken up in ether and extracted with 130 ml of 1 N sodium hydroxide solution, and the aqueous phase was neutralized with 130 ml of 1 N hydrochloric acid, whereupon crystals separated out. 64 g of product were isolated after drying.






1


H-NMR (200 MHz): 7.3 ppm (10H, m), 6.7 (4H, m), 6.3 (1H, s), 3.9 (3H, s), 3.85 (3H, s), 3.7 (1H, dt), 3.6 (1H, dt), 2.8 (2H, t), 2.3 (6H, s).




Melting point: 125-130° C. decomposition EI-MS: M


+


=528.




(S)-2-(4,6-dimethylpyrimidin-2-yloxy)-3-(2-(3,4-dimethoxyphenyl)ethoxy-3,3-diphenylpropionic acid was prepared in a similar way from (S)-2-hydroxy-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-diphenylpropionic acid and 2-methylsulfone-4,6-dimethylpyrimidine [sic] in the presence of lithium amide. [α]


20


=111 (1; ethanol).




Example 15




The following compounds were prepared as in Example 8




2-(4-Methoxy-6-methyl-2-pyrimidinyloxy)-3-(2-(4-methoxyphenyl)ethoxy)-3,3-di(4-ethylphenyl)propionic Acid (I-147)




Melting point: 150-155° C. EI-MS: M


+


=570.




2-(4-Methoxy-5,6-dihydrofuro(2,3d)-2-pyrimidinyloxy)-3-(2-(4-chlorophenyl)ethoxy)-3,3-diphenylpropionic Acid (I-651)




Melting point: 150-152° C. EI-MS: M


+


=546.




2-(4,6-Dimethyl-2-pyrimidinyloxy)-3-(2-(4-chlorophenyl)ethoxy)-3,3-diphenylpropionic Acid (I-713)




Melting point: 108° C. Decomposition EI-MS: M


+


=502.




2-(4,6-Dimethoxy-2-pyrimidinyloxy)-3-(2-(4-chlorophenyl)ethoxy)-3,3-diphenylpropionic Acid




Melting point: 165-167° C. EI-MS: M


+


=534.




2-(4-Methoxy-6-methyl-2-pyrimidinyloxy)-3-(2-(4-chlorophenyl)ethoxy)-3,3-diphenylpropionic Acid (I-746)




Melting point: 93-98° C. EI-MS: M


+


=518.




2-(4,6-Dimethyl-2-pyrimidinyloxy)-3-(2-(4-methoxyphenyl)ethoxy)-3,3-di(4-ethylphenyl)propionic Acid (I-148)




Melting point: 130-133° C. EI-MS: M


+


=554.




2-(4-Methoxy-6-methyl-2-pyrimidinyloxy)-3-(2-(4-methylphenyl)ethoxy)-3,3-di(4-chlorophenyl)propionic Acid (I-710)




Melting point: 90-100° C. EI-MS: M


+


=566.




2-(4-Methoxy-6-methyl-2-pyrimidinyloxy)-3-(3,3-diphenylpropoxy)-3,3-di(4-chlorophenyl)propionic Acid






1


H-NMR(200 MHz): 7.3 ppm (18H, m), 6.25 (1H, s), 6.0 (1H, s), 4.0 (1H, tr), 3.8 (3H, s), 3.4 (2H, m), 2.2 (5H, m). EI-MS: M


+


=642.




2-(4-Methoxy-6-methyl-2-pyrimidinyloxy)-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-di(4-chlorophenyl)propionic Acid (I-699)




Melting point: 100-110° C. EI-MS: M


+


=612.




2-(4-Methoxy-6-methyl-2-pyrimidinyloxy)-3-(2-(2-methoxyphenyl)ethoxy)-3,3-di(4-chlorophenyl)propionic Acid (I-487)




Melting point: 85-90° C. EI-MS: M


+


=582.




2-(4-Methoxy-5,6-dihydrofuro(2,3d)-2-pyrimidinyloxy)-3-(2-(3-methoxyphenyl)ethoxy)-3,3-di(4-chlorophenyl)propionic Acid (I-486)




Melting point: 190-195° C. EI-MS: M


+


=610.




2-(4-Methoxy-5,6-dihydrofuro(2,3d)-2-pyrimidinyloxy)-3-(2-phenylethylthio)-3,3-di(4-chlorophenyl)propionic Acid




Melting point: 173-175° C.


1


H-NMR (200): 7.0-7.4 ppm (13H, m), 6.0 (1H, s), 4.7 (2H, tr), 3.8 (3H, s), 3.1 (2H, tr), 2.5 (4H, m).




2-(4-Methoxy-5,6-dihydrofuro(2,3d)-2-pyrimidinyloxy)-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-di(4-chlorophenyl)propionic Acid (I-635)




Melting point: 100-110° C. EI-MS: M


+


=640.




2-(4-Methoxy-5,6-dihydrofuro(2,3d)-2-pyrimidinyloxy)-3-(2-(3,5-dimethoxyphenyl)ethoxy)-3,3-di(4-chlorophenyl)propionic Acid (1-593)




Melting point: 90-100° C. EI-MS: M


+


=640.




2-(4-Methoxy-5,6-dihydrofuro(2,3d)-2-pyrimidinyloxy)-3-(2-(2-methoxyphenyl)ethoxy)-3,3-di(4-chlorophenyl)propionic Acid (I-164)




Melting point: 135-145° C. EI-MS: M


+


=610.




2-(4-Methoxy-5,6-dihydrofuro(2,3d)-2-pyrimidinyloxy)-3-(3,3-diphenylpropoxy)-3,3-di(4-chlorophenyl)propionic Acid




Melting point: 125-127° C. EI-MS: M


+


=670.




2-(4-Methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-yloxy)-3-(3,3-diphenylpropoxy)-3,3-di(4-chlorophenyl)propionic Acid




Melting point: 135-140° C. EI-MS: M


+


=668.




2-(4-Methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-yloxy)-3-(2-phenylethylthio)-3,3-di(4-chlorophenyl)propionic Acid




Melting point: 135-140° C.


1


H-NMR (200): 7.0-7.5 ppm (13H, m), 5.9 (1H, s), 3.9 (3H, s), 2.6-2.8 (8H, m), 2.1 (2H, m).




2-(4-Methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-yloxy)-3-(2-(2-methoxyphenyl)ethoxy)-3,3-di(4-chlorophenyl)propionic Acid




Melting point: 105-115° C. EI-MS: M


+


=608.




2-(4-Methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-yloxy)-3-(2-(3-methoxyphenyl)ethoxy)-3,3-di(4-chlorophenyl)propionic Acid




Melting point: 110-120° C. EI-MS: M


+


=608.




2-(4-Methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-yloxy)-3-(2-(4-dimethylaminophenyl)ethoxy)-3,3-di(4-chlorophenyl)propionic Acid




Melting point: 135-140° C. EI-MS: M


+


=621.




2-(4-Methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-yloxy)-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-di(4-chlorophenyl)propionic Acid




Melting point: 125-130° C. EI-MS: M


+


=638.




2-(4-Methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-yloxy)-3-(2-(3,5-dimethoxyphenyl)ethoxy)-3,3-di(4-chlorophenyl)propionic Acid




Melting point: 125-130° C. EI-MS: M


+


=638.




2-(4-Methoxy-5,6-dihydrofuro(2,3d)-2-pyrimidinyloxy)-3-(2-(4-methylphenyl)ethoxy)-3,3-diphenylpropionic Acid (I-370)




Melting point: 128-130° C. EI-MS: M


+


=526.




2-(4-Methoxy-6-methyl-2-pyrimidinyloxy)-3-(2-phenylethoxy)-3,3-diphenylpropionic Acid (I-719)




Melting point: 155° C. Decomposition EI-MS: M


+


=484.




2-(4,6-Dimethoxy-2-pyrimidinyloxy)-3-(2-phenylethoxy)-3,3-diphenylpropionic Acid




Melting point: 203° C. Decomposition EI-MS: M


+


=500.




2-(4,6-Dimethyl-2-pyrimidinyloxy)-3-(2-phenylethoxy)-3,3-diphenyl propionic Acid (I-720)




Melting point: 130-133° C. EI-MS: M


+


=468.




2-(4-Methoxy-5,6-dihydrofuro(2,3d)-2-pyrimidinyloxy)-3-(2-phenylethoxy)-3,3-diphenylpropionic Acid (I-657)




Melting point: 138-142° C. EI-MS: M


+


=512.




2-(4,6-Dimethoxy-2-pyrimidinyloxy)-3-(2-(4-methylphenyl)ethoxy)-3,3-diphenylpropionic Acid




Melting point: 155-158° C. EI-MS: M


+


=514.




2-(4-Methoxy-6-methyl-2-pyrimidinyloxy)-3-(2-(4-methylphenyl)ethoxy)-3,3-diphenylpropionic Acid (I-465)




Melting point: 145-147° C. EI-MS: M


+


=498.




2-(4-Methoxy-6-methyl-2-pyrimidinyloxy)-3-(3-(4-methoxyphenyl)propoxy)-3,3-diphenylpropionic Acid (I-554)




Melting point: 160-165° C. EI-MS: M


+


=528.




2-(4,6-Dimethyl-2-pyrimidinyloxy)-3-(3-(4-methoxyphenyl)propoxy)-3,3-diphenylpropionic Acid (I-555)




Melting point: 165-170° C. EI-MS: M


+


=512.




2-(4-Methoxy-6-methyl-2-pyrimidinyloxy)-3-(3-(3,4,5-trimethoxyphenyl)propoxy)-3,3-diphenylpropionic Acid (I-335)






1


H-NMR (200): 7.2-7.4 ppm (10H, m), 6.3 (2H, s), 6.2 (2H, s), 3.8 (3H, s), 3.75 (10H, s), 3.4 (2H, m), 2.6 (2H, m), 2.25 (3H, s), 1.9 (2H, m). EI-MS: M


+


=588.




2-(4,6-Dimethyl-2-pyrimidinyloxy)-3-(3-(3,4,5-trimethoxyphenyl)propoxy)-3,3-diphenylpropionic Acid (I-336)






1


H-NMR (200): 7.2-7.5 ppm (10H, m), 6.6 (1H, s), 6.3 (3H, S), 3.8 (9H, s), 3.4 (2H, m), 2.6 (2H, m), 2.3 (6H, s), 1.9 (2H, m). EI-MS: M


+


=572.




2-(4-Methoxy-6-methyl-2-pyrimidinyloxy)-3-(3-(2-chlorophenyl)propoxy)-3,3-diphenylpropionic Acid (I-383)






1


H-NMR (200): 7.1-7.5 ppm (14H, m), 6.24 (1H, s), 6.23 (1H, s), 3.8 (3H, s), 3.4 (2H, m), 2.75 (2H, m), 2.25 (3H, s), 1.9 (2H, m). EI-MS: M


+


=532.




2-(4,6-Dimethyl-2-pyrimidinyloxy)-3-(3-(2-chlorophenyl)propoxy)-3,3-diphenylpropionic Acid (I-384)




Melting point: 172-178° C. EI-MS: M


+


=516.




2-(4,6-Dimethyl-2-pyrimidinyloxy)-3-(3-(4-chlorophenyl)propoxy)-3,3-diphenylpropionic Acid (I-251)






1


H-NMR (200): 7.0-7.4 ppm (14H, m), 6.6 (1H, s), 6.3 (1H, s), 3.5 (2H, m), 2.7 (2H, m), 2.3 (6H, s), 1.9 (2H, m). EI-MS: M


+


=516.




2-(4,6-Dimethyl-2-pyrimidinyloxy)-3-(3-(3,4-dimethoxyphenyl)propoxy)-3,3-diphenylpropionic Acid (I-490))






1


H-NMR (200): 7.1-7.5 ppm (10H, m), 6.74 (1H, s), 6.7 (3H, S), 6.3 (1H, s), 3.8 (6H, s), 3.5 (2H, m), 2.7 (2H, m), 2.3 (6H, s), 1.9 (2H, m). EI-MS: M


+


=542.




2-(4-Methoxy-6-methyl-2-pyrimidinyloxy)-3-(2-(4-propoxyphenyl)ethoxy)-3,3-diphenylpropionic Acid (I-69)




Melting point: 115-119° C. EI-MS: M


+


=542.




2-(4-Methoxy-6-methyl-2-pyrimidinyloxy)-3-(2-(4-butoxyphenyl)ethoxy)-3,3-diphenylpropionic Acid (I-71)




Melting point: 118-122° C. EI-MS: M


+


=556.




2-(4,6-Dimethyl-2-pyrimidinyloxy)-3-(2-(4-butoxyphenyl)ethoxy)-3,3-diphenylpropionic Acid (I-70)




Melting point: 122-125° C. EI-MS: M


+


=540.




2-(4-Methoxy-6-methyl-2-pyrimidinyloxy)-3-(3-phenyl-(2E)-propenoxy)-3,3-diphenylpropionic Acid (I-44)




Melting point: 171-174° C. EI-MS: M


+


=496.




2-(4-Methoxy-6-methyl-2-pyrimidinyloxy)-3-(3-(2-methylphenyl)propoxy)-3,3-diphenylpropionic Acid (I-107)




Decomposition: 144-146° C. EI-MS: M


+


=512.




2-(4,6-Dimethyl-2-pyrimidinyloxy)-3-(3-(2-methylphenyl)propoxy)-3,3-diphenylpropionic Acid (I-90)




Decomposition: 173-176° C. EI-MS: M


+


=496.




2-(4-Methoxy-6-methyl-2-pyrimidinyloxy)-3-(3-(4-methylphenyl)propoxy)-3,3-diphenylpropionic Acid (1-363)




Decomposition: 158-161° C. EI-MS: M


+


=512.




2-(4,6-Dimethyl-2-pyrimidinyloxy)-3-(3-(4-methylphenyl)propoxy)-3,3-diphenylpropionic Acid (I-346)




Decomposition: 163-167° C. EI-MS: M


+


=496.




2-(4-Methoxy-6-methyl-2-pyrimidinyloxy)-3-(2-(4-methylthiophenyl)ethoxy)-3,3-diphenylpropionic Acid (I-246)




Decomposition: 136-138° C. EI-MS: M


+


=530.




2-(4,6-Dimethyl-2-pyrimidinyloxy)-3-(2-(4-methylthiophenyl)ethoxy)-3,3-diphenylpropionic Acid (I-217)




Decomposition: 166-169° C. EI-MS: M


+


=514.




2-(4-Methoxy-6-methyl-2-pyrimidinyloxy)-3-(2-(4-ethoxy-3-methoxyphenyl)ethoxy)-3,3-diphenylpropionic Acid (1-145)




Decomposition: 141-145° C. EI-MS: M


+


=558.




2-(4-Methoxy-6-methyl-2-pyrimidinyloxy)-3-(2-(4-ethoxyphenyl)ethoxy)-3,3-diphenylpropionic Acid (I-510)




Decomposition: 131-135° C. EI-MS: M


+


=528.




2-(4-Methoxy-6-methyl-2-pyrimidinyloxy)-3-(2-(4-i-propylphenyl)ethoxy)-3,3-diphenylpropionic Acid (I-705)






1


H-NMR (200 MHz, DMSO): 7.0-7.35 ppm (14H, m), 6.35 (1H, s), 6.1 (1H, s), 4.0 (1H, m), 3.9 (3H, s), 3.8 (3H, s), 3.7 (1H, m), 2.9 (3H, m), 2.2 (3H, s), 1.1 (6H, d). EI-MS: M


+


=526.




2-(4-Methoxy-6-methyl-2-pyrimidinyloxy)-3-(2-(3,4-methylenedioxyphenyl)ethoxy)-3,3-diphenylpropionic Acid (1-568)




Decomposition: 146-148° C. EI-MS: M


+


=528.




2-(4-Methoxy-5,6-dihydrofuro(2,3d)-2-pyrimidinyloxy)-3-(2-(3,4-methylenedioxyphenyl)ethoxy)-3,3-diphenylpropionic Acid (I-501)




Decomposition: 145-149° C. EI-MS: M


+


=556.




2-(4-Methoxy-5,6-dihydrofuro(2,3d)-2-pyrimidinyloxy)-3-(2-(4-ethoxy-3-methoxyphenyl)ethoxy)-3,3-diphenylpropionic Acid (I-735)






1


H-NMR (270 MHz, DMSO): 7.1-7.4 ppm (10H, m), 6.85 (2H, m), 6.7 (1H, d), 6.1 (1H, s), 4.6 (2H, tr), 4.0 (3H, m), 3.85 (3H, s), 3.75 (3H, s), 3.65 (1H, m), 3.05 (2H, tr), 2.8 (2H, m), 1.25 (3H, m). EI-MS: M


+


=586.




2-(4-Methoxy-5,6-dihydrofuro(2,3d)-2-pyrimidinyloxy)-3-(2-(4-ethoxyphenyl)ethoxy)-3,3-diphenylpropionic Acid (I-407)






1


H-NMR (270 MHz, DMSO): 7.1-7.4 ppm (12H, m), 6.8 (2H, d), 6.1 (1H, s), 4.65 (2H, tr), 3.95 (3H, m), 3.8 (3H, s), 3.65 (1H, m), 3.05 (2H, tr), 2.8 (2H, m), 1.25 (3H, m). EI-MS: M


+


=556.




2-(4,6-Dimethyl-2-pyrimidinyloxy)-3-(2-(4-ethoxy-3-methoxyphenyl)ethoxy)-3,3-diphenylpropionic Acid (1-146)




Decomposition: 129-134° C. EI-MS: M


+


=542.




2-(4,6-Dimethyl-2-pyrimidinyloxy)-3-(2-(3,4-methylenedioxyphenyl)ethoxy)-3,3-diphenylpropionic Acid (I-569)






1


H-NMR (270 MHz, DMSO): 7.1-7.4 ppm (10H, m), 6.9 (1H, s), 6.8 (2H, m), 6.7 (1H, d), 6.2 (1H, s), 6.0 (2H, s), 3.95 (3H, m), 3.65 (1H, m), 2.8 (2H, m), 2.3 (6H, s). EI-MS: M


+


=512.




2-(4,6-Dimethyl-2-pyrimidinyloxy)-3-(2-(4-ethoxyphenyl)ethoxy)-3,3-diphenylpropionic Acid (I-473)




Decomposition: 145-148° C. EI-MS: M


+


=512.




2-(4-Methoxy-5,6-dihydrofuro(2,3d)-2-pyrimidinyloxy)-3-(2-(4-i-propylphenyl)ethoxy)-3,3-diphenylpropionic Acid (I-604)






1


H-NMR (270 MHz, DMSO): 7.1-7.4 ppm (14H, m), 6.1 (1H, s), 4.6 (2H, tr), 3.9 (1H, m), 3.8 (3H, s), 3.6 (1H, m), 3.0 (2H, tr), 2.8 (3H, m), 1.1 (6H, d). EI-MS: M


+


=554.




2-(4,6-Dimethyl-2-pyrimidinyloxy)-3-(2-(4-i-propylphenyl)ethoxy)-3,3-diphenylpropionic Acid (I-672)




Decomposition: 156-160° C. EI-MS: M


+


=510.




2-(4-Methoxy-5,6-dihydrofuro(2,3d)-2-pyrimidinyloxy)-3-(2-(4-methoxyphenyl)ethoxy)-3,3-di(4-methylphenyl)propionic Acid (I-517)






1


H-NMR (200 MHz, DMSO): 7.0-7.3 ppm (10H, m), 6.8 (2H, d), 6.0 (1H, s), 4.6 (2H, tr), 3.85 (3H, s), 3.8 (1H, m), 3.7 (3H, s), 3.6 (1H, m), 3.0 (2H, tr), 2.8 (2H, tr), 1.1 (6H, d). EI-MS: M


+


=570.




2-(4-Methoxy-6-methyl-2-pyrimidinyloxy)-3-(2-(4-methoxyphenyl)ethoxy)-3,3-diphenylpropionic Acid (I-622)






1


H-NMR (270 MHz, DMSO): 7.1-7.4 ppm (12H, m), 6.8 (2H, d), 6.4 (1H, s), 6.1 (1H, s), 4.0 (1H, m), 3.7 (3H, s), 3.7 (1H, m), 2.8 (2H, tr), 2.3 (3H, s). EI-MS: M


+


=514.




2-(4,6-Dimethyl-2-pyrimidinyloxy)-3-(2-(4-methoxyphenyl)ethoxy)-3,3-diphenylpropionic Acid (I-585)






1


H-NMR (200 MHz, DMSO): 7.1-7.4 ppm (12H, m), 6.8 (3H, m), 6.1 (1H, s), 4.0 (1H, m), 3.7 (3H, s), 3.6 (1H, m), 2.8 (2H, r), 2.3 (6H, s). EI-MS: M


+


=498.




2-(4-Methoxy-6-methyl-2-pyrimidinyloxy)-3-(3-phenylpropoxy)-3,3-diphenylpropionic Acid (I-499)




Decomposition: 153-155° C. EI-MS: M


+


=498.




2-(4,6-Dimethyl-2-pyrimidinyloxy)-3-(3-phenylpropoxy)-3,3-diphenylpropionic Acid (I-500)




Decomposition: 148-151° C. EI-MS: M


+


=482.




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













TABLE I











[sic]




I










































No.




R


1






R


4


, R


5






Q




R


6






R


2






R


3






Z




X




Y




W









I-1




COOH




phenyl




—CH


2


—CH


2


—




phenyl




OMe




Me




CH




N




N




S






I-2




COOMe




phenyl




—CH


2


—CH


2


—




phenyl




CF


3






Me




CH




N




N




O






I-3




COOH




4-Br-phenyl




—CH


2


—CH


2


—




phenyl




OMe




OMe




CH




N




N




O






I-4




COOH




phenyl




—CH


2


—C(CH


3


)


2


—




phenyl




OMe




Me




CH




N




N




O






I-5




COOH




4-Cl-phenyl




—CH


2


—CH


2


—CH


2


—




3,4-di-OMe-phenyl




Me




Me




CH




N




N




O






I-6




COOH




4-Cl-phenyl




—CH


2


—CH


2


—CH


2


—




3,4-di-OMe-phenyl




Me




Me




N




N




N




O






I-7




COOH




phenyl




—CH


2


—CH


2


—




3,4-di-Cl-phenyl




Me




Me




CH




N




N




O






I-8




COOH




phenyl




—CH


2


—CH


2


—




phenyl




Me




Me




N




N




CH




O






I-9




COOH




phenyl




—CH


2


—CH


2


—




phenyl




ethyl




Me




N




N




N




O






I-10




COOH




phenyl




—CH═CH—CH


2


—




phenyl




ethyl




Me




CH




N




N




O




















I-11




COOH




phenyl




—CH═CH—CH


2


—




phenyl




OMe




CH


2


—CH


2


—CH


2


—C




N




N




O






I-12




COOH




phenyl




—CH═CH—CH


2


—




phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O






I-13




COOH




phenyl




—CH


2


—CH


2


—




phenyl




OMe




CH


2


—CH


2


—CH


2


—C




N




N




S






I-14




COOEt




phenyl




—CH


2


—CH


2


—




phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-15




COOH




4-Et-phenyl




—CH


2


—CH


2


—




4-SMe-phenyl




Me




Me




CH




N




N




O






I-16




COOH




4-Et-phenyl




—CH


2


—CH


2


—




4-SMe-phenyl




Me




Me




N




N




N




O






I-17




COOMe




phenyl




—CH


2


—CH


2


—




4-OMe-phenyl




OMe




Me




CH




N




N




O






I-18




COOEt




phenyl




—CH


2


—CH


2


—




4-OMe-phenyl




Me




Me




CH




N




N




S




















I-19




tetrazole




phenyl




—CH


2


—CH


2


—




4-OMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O







[sic]






I-20




COOH




phenyl




—C(CH


3


)


2


—CH


2


—




4-OMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O






I-21




COOH




phenyl




—CH


2


—C(CH


3


)


2


—




4-OMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O






I-22




COOH




4-Cl-phenyl




—CH


2


—CH


2


—CH


2


—




4-OMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-23




COOH




4-Cl-phenyl




—CH


2


—CH


2


—CH


2


—




3,4-di-OMe-phenyl




OMe




Me




CH




N




N




O






I-24




COOH




4-Br-phenyl




—CH


2


—CH


2


—




4-OMe-phenyl




OMe




OMe




CH




N




N




O






I-25




COOH




phenyl




—CH


2


—CH


2


—




4-OMe-phenyl




OMe




Me




N




N




N




O






I-26




COOH




phenyl




—CH


2


—CH


2


—




4-OMe-phenyl




Me




Me




N




N




CH




O






I-27




COOH




phenyl




—CH═CH—CH


2


—




phenyl




Me




Me




CH




N




N




O






I-28




COOH




phenyl




—CH═CH—CH


2


—




phenyl




Me




Me




N




N




N




O






I-29




COOH




phenyl




—CH


2


—CH


2


—




4-OMe-phenyl




ethyl




Me




N




N




N




O




















I-30




COOH




phenyl




—CH


2


—CH


2


—




4-OMe-phenyl




OMe




CH


2


—CH


2


—CH


2


—C




N




N




S






I-31




COOH




4-Et-phenyl




—CH


2


—CH


2


—




3-OMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-32




COOH




4-Et-phenyl




—CH


2


—CH


2


—




4-SMe-phenyl




OMe




Me




CH




N




N




O




















I-33




COOEt




phenyl




—CH


2


—CH


2


—




4-OMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O






I-34




COOH




phenyl




—CH


2


—CH


2


—




3,4-di-OMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




S





















I-35




COOMe




phenyl




—C(CH


3


)


2


—CH


2


—




3,4-di-OMe-phenyl




OMe




Me




N




N




CH




S






I-36




COOH




phenyl




—C(CH


3


)


2


—CH


2


—




3,4-di-OMe-phenyl




ethyl




Me




CH




N




N




O






I-37




COOH




4-Br-phenyl




—CH


2


—CH


2


—




3,4-di-OMe-phenyl




CF


3






Me




CH




N




N




O






I-38




COOH




4-Cl-phenyl




—CH


2


—CH


2


—CH


2


—




4-OMe-phenyl




Me




Me




N




N




N




O






I-39




COOH




4-Cl-phenyl




—CH


2


—CH


2


—CH


2


—




4-OMe-phenyl




ethyl




Me




CH




N




N




O






I-40




COOH




phenyl




—CH


2


—CH


2


—




3,4-di-Me-phenyl




OMe




Me




CH




N




N




O






I-41




COOH




phenyl




—CH


2


—CH


2


—




3,4-di-OMe-phenyl




SMe




Me




CH




N




N




O






I-42




COOH




phenyl




—CH


2


—CH


2


—




3,4-di-OMe-phenyl




Me




Me




N




N




CH




O






I-43




COOH




phenyl




—CH═CH—CH


2


—




phenyl




CF


3






Me




CH




N




N




O






I-44




COOH




phenyl




—CH═CH—CH


2


—




phenyl




OMe




Me




CH




N




N




O






I-45




COOH




phenyl




—CH


2


—CH


2


—




3,4-di-OMe-phenyl




ethyl




Me




CH




N




N




S




















I-46




COOBzl




phenyl




—CH


2


—CH


2


—




3,4-di-OMe-phenyl




OMe




CH


2


—CH


2


—CH


2


—C




N




N




O





















I-47




COOH




4-Et-phenyl




—CH


2


—CH


2


—




3-OMe-phenyl




Me




Me




N




N




N




O






I-48




COOH




4-Et-phenyl




—CH


2


—CH


2


—




3-OMe-phenyl




ethyl




Me




CH




N




N




O




















I-49




COOH




4-F-phenyl




—CH


2


—CH


2


—




3,4-di-OMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-50




COOH




phenyl




—C(CH


3


)


2


—CH


2


—




3,4,5-tri-OMe-phenyl




CF


3






Me




CH




N




N




O






I-51




COOH




phenyl




—CH


2


—CH


2


—




3-Me-4-Et-phenyl




OMe




CF


3






CH




N




N




O






I-52




COOH




phenyl




—CH


2


—CH


2


—




3-Me-4-Et-phenyl




OMe




Me




CH




N




N




O






I-53




COOH




4-F-phenyl




—CH


2


—CH


2


—




4-Br-phenyl




Me




Me




N




N




N




O






I-54




COOH




4-Cl-phenyl




—CH


2


—CH


2


—CH


2


—




4-OMe-phenyl




OMe




Me




CH




N




N




O






I-55




COOH




4-Cl-phenyl




—CH


2


—CH


2


—CH


2


—




4-OMe-phenyl




Me




Me




CH




N




N




O






I-56




COOH




phenyl




—CH


2


—CH


2


—




4-Br-phenyl




Me




Me




N




N




CH




O






I-57




COOH




phenyl




—CH


2


—CH


2


—




3-Br-phenyl




ethyl




Me




CH




N




N




S




















I-58




COOH




phenyl




—CH


2


—CH


2


—




2-Me-phenyl




OMe




CH


2


—CH


2


—CH


2


—C




N




N




O






I-59




COOH




phenyl




—CH═CH—CH


2


—




4-Me-phenyl




OMe




CH


2


—CH


2


—CH


2


—C




N




N




O






I-60




COOH




phenyl




—CH═CH—CH


2


—




4-Me-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O






I-61




COOH




4-F-phenyl




—CH


2


—CH


2


—




3-Me-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-62




COOH




phenyl




—CH


2


—CH


2


—




3-Me-4-SMe-phenyl




CF


3






Me




CH




N




N




O






I-63




COOH




4-Et-phenyl




—CH


2


—CH


2


—




3-OMe-phenyl




OMe




Me




CH




N




N




O






I-64




COOH




4-Et-phenyl




—CH


2


—CH


2


—




3-OMe-phenyl




Me




Me




CH




N




N




O






I-65




tetrazole




phenyl




—CH


2


—CH


2


—




4-SMe-phenyl




Me




OMe




CH




N




N




O







[sic]






I-66




COOH




3-OMe-phenyl




—CH


2


—CH


2


—




4-SMe-phenyl




OMe




Me




CH




N




N




O






I-67




COOH




phenyl




—O—CH


2


—CH


2


—




4-SMe-phenyl




Me




Me




CH




N




N




O






I-68




COOH




phenyl




—CH


2


—CH


2


—




4-n-propoxy-phenyl




Me




Me




CH




N




N




O






I-69




COOH




phenyl




—CH


2


—CH


2


—




4-n-propoxy-phenyl




OMe




Me




CH




N




N




O






I-70




COOH




phenyl




—CH


2


—CH


2


—




4-n-butoxy-phenyl




Me




Me




CH




N




N




O






I-71




COOH




phenyl




—CH


2


—CH


2


—




4-n-butoxy-phenyl




OMe




Me




CH




N




N




O






I-72




COOH




phenyl




—O—CH


2


—CH


2


—




4-SMe-phenyl




Me




Me




CH




N




CH




O






I-73




COOH




phenyl




—O—CH


2


—CH


2


—




4-SMe-phenyl




ethyl




Me




CH




N




N




S






I-74




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




2-Me-phenyl




ethyl




Me




CH




N




N




O




















I-75




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




2-Me-phenyl




OMe




CH


2


—CH


2


—CH


2


—C




N




N




O






I-76




COOH




phenyl




—CH


2


—CH


2


—




2-Me-4-SMe-phenyl




OMe




CH


2


—CH


2


—CH


2


—C




N




N




O






I-77




COOH




phenyl




—C(CH


3


)


2


—CH


2


—




4-SMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-78




COOMe




phenyl




—CH


2


—CH


2


—




4-OEt-3-OMe-phenyl




CF


3






Me




CH




N




N




O






I-79




COOH




phenyl




—CH═CH—CH


2


—




4-Me-phenyl




Me




Me




N




N




N




O






I-80




COOH




phenyl




—CH═CH—CH


2


—




4-Me-phenyl




ethyl




Me




CH




N




N




O




















I-81




COOH




phenyl




—CH


2


—CH


2


—




4-(di-Me-amino)-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-82




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




4-OMe-phenyl




OMe




Me




CH




N




N




O






I-83




COOH




4-Et-phenyl




—CH


2


—CH


2


—




3,4-di-OMe-phenyl




ethyl




Me




CH




N




N




O




















I-84




COOH




4-Et-phenyl




—CH


2


—CH


2


—




3,4-di-OMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-85




COOH




3-OMe-phenyl




—CH


2


—CH


2


—




4-OEt-3-OMe-phenyl




OMe




Me




CH




N




N




O






I-86




COOH




phenyl




—O—CH


2


—CH


2


—




4-OEt-3-OMe-phenyl




Me




Me




CH




N




N




O






I-87




COOH




phenyl




—S—CH


2


—CH


2


—




3-OMe-4-Cl-phenyl




Me




Me




CH




N




N




O






I-88




COOH




phenyl




—CH


2


—CH


2


—




3-OMe-4-Cl-phenyl




ethyl




Me




CH




N




N




O




















I-89




COOH




3-Me-phenyl




—CH


2


—CH


2


—




3-OMe-4-Cl-phenyl




OMe




CH


2


—CH


2


—CH


2


—C




N




N




O





















I-90




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




2-Me-phenyl




Me




Me




CH




N




N




O






I-91




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




2-Me-phenyl




Me




Me




N




N




N




O




















I-92




COOH




phenyl




—CH


2


—CH


2


—




4-OEt-3-OMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




S





















I-93




COOMe




phenyl




—CH


2


—CH


2


—




4-iPr-phenyl




CF


3






Me




CH




N




N




O






I-94




COOH




2-Me-phenyl




—CH


2


—CH


2


—




4-F-phenyl




OMe




Me




CH




N




N




O






I-95




COOH




phenyl




—CH═CH—CH


2


—




4-Me-phenyl




OMe




Me




CH




N




N




O






I-96




COOH




phenyl




—CH═CH—CH


2


—




4-Me-phenyl




Me




Me




CH




N




N




O






I-97




COOH




2-Me-phenyl




—CH


2


—CH


2


—




4-iPr-phenyl




Me




Me




CH




N




N




O






I-98




COOH




phenyl




—O—CH


2


—CH


2


—




phenyl




Me




Me




N




N




N




O






I-99




COOH




4-Et-phenyl




—CH


2


—CH


2


—




3,4-di-OMe-phenyl




Me




Me




CH




N




N




O






I-100




COOH




4-Et-phenyl




—CH


2


—CH


2


—




3,4-di-OMe-phenyl




Me




Me




N




N




N




O






I-101




COOH




phenyl




—CH


2


—CH


2


—




4-(di-Me-amino)-phenyl




Me




Me




N




N




N




O






I-102




COOH




phenyl




—CH


2


—CH


2


—




4-(di-Me-amino)-phenyl




ethyl




Me




CH




N




N




O






I-103




COOH




2-Me-phenyl




—CH


2


—CH


2


—




4-Cl-phenyl




ethyl




Me




CH




N




N




O




















I-104




COOH




4-F-phenyl




—CH


2


—CH


2


—




4-OMe-phenyl




OMe




CH


2


—CH


2


—CH


2


—C




N




N




O






I-105




COOH




phenyl




—C(CH


3


)


2


—CH


2


—




3-Cl-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-106




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




2-Me-phenyl




CF


3






Me




CH




N




N




O






I-107




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




2-Me-phenyl




OMe




Me




CH




N




N




O






I-108




COOH




phenyl




—CH


2


—CH


2


—




3,4-methylenedioxyphenyl




Me




Me




N




N




CH




O






I-109




COOMe




phenyl




—CH


2


—CH


2


—




3,4-methylenedioxyphenyl




OMe




Me




CH




N




N




O






I-110




COOH




phenyl




—CH


2


—CH


2


—




3,4-methylenedioxyphenyl




Me




Me




CH




N




N




S




















I-111




COOH




phenyl




—CH═CH—CH


2


—




4-iPr-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-112




COOH




phenyl




—CH═CH—CH


2


—




4-Me-phenyl




CF


3






Me




CH




N




N




O






I-113




COOH




phenyl




—CH


2


—CH


2


—




3,4-di-Me-phenyl




Me




Me




CH




N




N




O






I-114




COOH




phenyl




—O—CH


2


—CH


2


—




3,4-di-Me-phenyl




ethyl




Me




CH




N




N




O




















I-115




COOH




4-Et-phenyl




—CH


2


—CH


2


—




4-OMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-116




COOH




4-Et-phenyl




—CH


2


—CH


2


—




3,4-di-OMe-phenyl




OMe




Me




CH




N




N




O




















I-117




COO-




phenyl




—CH


2


—CH


2


—




3,4-methylenedioxyphenyl




OMe




CH


2


—CH


2


—CH


2


—C




N




N




O







i-Propyl






I-118




COOH




phenyl




—CH


2


—CH


2


—




3,4-di-Me-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-119




COOH




phenyl




—CH


2


—CH


2


—




4-(di-Me-amino)-phenyl




OMe




Me




CH




N




N




O






I-120




COOH




phenyl




—CH


2


—CH


2


—




4-(di-Me-amino)-phenyl




Me




Me




CH




N




N




O






I-121




COOH




4-F-phenyl




—CH


2


—CH


2


—




4-Me-phenyl




CF


3






Me




CH




N




N




O






I-122




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




3-OMe-phenyl




ethyl




Me




CH




N




N




O




















I-123




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




3-OMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-124




COOH




phenyl




—S—CH


2


—CH


2


—




4-Me-phenyl




OMe




Me




CH




N




N




O






I-125




COOH




phenyl




—CH(OH)—CH


2


—




4-Me-phenyl




Me




Me




CH




N




N




O






I-126




COOH




phenyl




—CH


2


—CH


2


—




3-OMe-4-Me-phenyl




Me




Me




CH




N




N




O






I-127




COOH




phenyl




—CH═CH—CH


2


—




4-iPr-phenyl




ethyl




Me




CH




N




N




O






I-128




COOH




phenyl




—CH═CH—CH


2


—




4-iPr-phenyl




OMe




Me




CH




N




N




O






I-129




COOH




phenyl




—CH


2


—CH


2


—




4-Me-phenyl




ethyl




Me




N




N




CH




O




















I-130




COOH




phenyl




—CH


2


—CH


2


—




3-OMe-4-Me-phenyl




OMe




CH


2


—CH


2


—CH


2


—C




N




N




O





















I-131




COOH




4-Et-phenyl




—CH


2


—CH


2


—




4-OMe-phenyl




Me




Me




N




N




N




O






I-132




COOH




4-Et-phenyl




—CH


2


—CH


2


—




4-OMe-phenyl




ethyl




Me




CH




N




N




O




















I-133




COOH




phenyl




—CH


2


—CH


2


—




4-Me-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




S





















I-134




COOButyl




phenyl




—CH


2


—CH


2


—




4-Et-phenyl




CF


3






Me




CH




N




N




O






I-135




COOH




4-I-phenyl




—CH


2


—CH


2


—




4-Et-phenyl




OMe




Me




CH




N




N




O






I-136




COOH




phenyl




—CH(OH)—CH


2


—




4-Et-phenyl




Me




Me




CH




N




N




O




















I-137




COOH




phenyl




—CH


2


—CH


2


—




2-OMe-phenyl




OMe




CH


2


—CH


2


—CH


2


—C




N




N




O





















I-138




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




3-OMe-phenyl




Me




Me




CH




N




N




O






I-139




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




3-OMe-phenyl




Me




Me




N




N




N




O




















I-140




COOH




phenyl




—CH


2


—CH


2


—




2-OMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-141




COOH




phenyl




—CH


2


—CH


2


—




3-OMe-4-Et-phenyl




Me




Me




N




N




N




O






I-142




COOH




phenyl




—CH


2


—CH


2


—




4-Et-phenyl




ethyl




Me




N




N




N




O






I-143




COOH




phenyl




—CH═CH—CH


2


—




4-Cl-phenyl




ethyl




Me




CH




N




N




O




















I-144




COOH




phenyl




—CH═CH—CH


2


—




4-Cl-phenyl




OMe




CH


2


—CH


2


—CH


2


—C




N




N




O





















I-145




COOH




phenyl




—CH


2


—CH


2


—




4-OEt-3-OMe-phenyl




OMe




Me




CH




N




N




O






I-146




COOH




phenyl




—CH


2


—CH


2


—




4-OEt-3-OMe-phenyl




Me




Me




CH




N




N




O






I-147




COOH




4-Et-phenyl




—CH


2


—CH


2


—




4-OMe-phenyl




OMe




Me




CH




N




N




O






I-148




COOH




4-Et-phenyl




—CH


2


—CH


2


—




4-OMe-phenyl




Me




Me




CH




N




N




O




















I-149




COOH




phenyl




—CH


2


—CH


2


—




3-OMe-4-Et-phenyl




OMe




O—CH═CH—C




N




N




O






I-150




COOH




phenyl




—CH


2


—CH


2


—




3-OMe-4-Et-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-151




COOH




4-Me-phenyl




—CH


2


—CH


2


—




cyclohexyl




CF


3






Me




CH




N




N




O






I-152




COOH




phenyl




—CH


2


—CH


2


—




cyclohexyl




OMe




ethyl




CH




N




N




O






I-153




COOMe




phenyl




—CH


2


—CH


2


—




cyclohexyl




OMe




Me




CH




N




N




O






I-154




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




3-OMe-phenyl




CF


3






Me




CH




N




N




O






I-155




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




3-OMe-phenyl




OMe




Me




CH




N




N




O






I-156




COOH




phenyl




—CH


2


—CH


2


—




cyclohexyl




Me




Me




CH




N




CH




O






I-157




COOH




phenyl




—CH


2


—CH


2


—




cyclohexyl




Me




Me




N




N




CH




O






I-158




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




cyclohexyl




ethyl




Me




CH




N




N




O






I-159




COOH




phenyl




—CH═CH—CH


2


—




4-Cl-phenyl




Me




Me




CH




N




N




O






I-160




COOH




phenyl




—CH═CH—CH


2


—




4-Cl-phenyl




Me




Me




N




N




N




O






I-161




COOH




phenyl




—CH


2


—CH


2


—




2-OMe-phenyl




Me




Me




N




N




N




O






I-162




COOH




phenyl




—CH


2


—CH


2


—




2-OMe-phenyl




ethyl




Me




CH




N




N




O






I-163




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




2-OMe-phenyl




ethyl




Me




CH




N




N




O




















I-164




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




2-OMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O






I-165




COOH




4-Et-phenyl




—CH


2


—CH


2


—




cyclohexyl




OMe




CH


2


—CH


2


—CH


2


—C




N




N




O






I-166




COOH




phenyl




—CH


2


—CH


2


—




cyclohexyl




OMe




O—CH


2


—CH


2


—C




N




N




S






I-167




COOH




phenyl




—CH


2


—CH


2


—




4-SMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-168




COOH




phenyl




—CH


2


—CH


2


—




4-OEt-3-OMe-phenyl




CF


3






Me




CH




N




N




O






I-169




COOH




phenyl




—CH


2


—CH


2


—




3-Me-4-Cl-phenyl




CF


3






Me




CH




N




N




O






I-170




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




4-OEt-phenyl




ethyl




Me




CH




N




N




O




















I-171




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




4-OEt-phenyl




OMe




CH


2


—CH


2


—CH


2


—C




N




N




O





















I-172




COOH




phenyl




—CH


2


—CH


2


—




4-Cl-phenyl




OMe




Me




CH




N




N




S






I-173




COOH




3-Me-phenyl




—CH


2


—CH


2


—




4-Cl-phenyl




Me




Me




CH




N




N




O






I-174




COOH




phenyl




—O—CH


2


—CH


2


—




4-Cl-phenyl




ethyl




Me




N




N




N




O






I-175




COOH




phenyl




—CH═CH—CH


2


—




4-Cl-phenyl




CF


3






Me




CH




N




N




O






I-176




COOH




phenyl




—CH═CH—CH


2


—




4-Cl-phenyl




OMe




Me




CH




N




N




O






I-177




COOH




phenyl




—CH


2


—CH


2


—




2-Me-4-Cl-phenyl




SMe




Me




CH




N




N




O




















I-178




COOH




phenyl




—CH


2


—CH


2


—




cyclohexyl




OMe




CH


2


—CH


2


—CH


2


—C




N




N




O





















I-179




COOH




4-CF


3


-phenyl




—CH


2


—CH


2


—




3-OMe-phenyl




Me




Me




CH




N




N




O






I-180




COOH




4-CF


3


-phenyl




—CH


2


—CH


2


—




3-OMe-phenyl




Me




Me




N




N




N




O




















I-181




COOH




phenyl




—CH


2


—CH


2


—




cyclohexyl




OMe




O—CH


2


—CH


2


—C




N




N




O






I-182




COOBzl




phenyl




—CH


2


—CH


2


—




4-Cl-phenyl




OMe




CH


2


—CH


2


—CH


2


—C




N




N




O






I-183




COOH




phenyl




—CH


2


—CH


2


—




2-Me-4-Cl-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-184




COOH




phenyl




—CH(OH)—CH


2


—




naphth-2-yl




CF


3






Me




CH




N




N




O






I-185




COOH




phenyl




—CH


2


—CH


2


—




2-OMe-phenyl




OMe




Me




CH




N




N




O






I-186




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




4-OEt-phenyl




Me




Me




CH




N




N




O






I-187




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




4-OEt-phenyl




Me




Me




N




N




N




O






I-188




COOH




phenyl




—CH


2


—CH


2


—




2-OMe-phenyl




Me




Me




CH




N




N




O






I-189




COOH




2-Me-phenyl




—CH


2


—CH


2


—




naphth-2-yl




OMe




Me




CH




N




N




O






I-190




COOH




phenyl




—CH


2


—CH


2


—




naphth-2-yl




Me




Me




CH




N




N




S




















I-191




COOH




phenyl




—CH═CH—CH


2


—




4-Cl-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-192




COOH




phenyl




—CH═CH—CH


2


—




4-iPr-phenyl




Me




Me




CH




N




N




O






I-193




COOH




phenyl




—CH


2


—CH


2


—




4-SMe-phenyl




ethyl




Me




CH




N




N




O




















I-194




COOH




phenyl




—CH


2


—CH


2


—




4-SMe-phenyl




OMe




CH


2


—CH


2


—CH


2


—C




N




N




O






I-195




COOH




4-CF


3


-phenyl




—CH


2


—CH


2


—




3,4-di-OMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-196




COOH




4-CF


3


-phenyl




—CH


2


—CH


2


—




3-OMe-phenyl




OMe




Me




CH




N




N




O






I-197




COOH




phenyl




—CH


2


—CH


2


—




naphth-2-yl




Me




Me




N




N




CH




O






I-198




COOH




phenyl




—CH


2


—CH


2


—




1-Me-naphth-2-yl




ethyl




Me




CH




N




N




O




















I-199




COOH




phenyl




—CH


2


—CH


2


—




1-Me-naphth-2-yl




OMe




CH


2


—CH


2


—CH


2


—C




N




N




O






I-200




COOMe




phenyl




—CH


2


—CH


2


—




naphth-2-yl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-201




COOEt




phenyl




—CH


2


—CH


2


—




4-OEt-phenyl




CF


3






Me




CH




N




N




O






I-202




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




4-OEt-phenyl




CF


3






Me




CH




N




N




O






I-203




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




4-OEt-phenyl




OMe




Me




CH




N




N




O






I-204




COOH




phenyl




—CH


2


—CH


2


—




cyclohexyl




Me




Me




N




N




N




O






I-205




COOH




phenyl




—CH


2


—CH


2


—




cyclohexyl




ethyl




Me




CH




N




N




O






I-206




tetrazole




phenyl




—CH


2


—CH


2


—




4-OEt-phenyl




OMe




Me




CH




N




N




O







[sic]






I-207




COOH




phenyl




—CH═CH—CH


2


—




3,4-di-OMe-phenyl




ethyl




Me




CH




N




N




O




















I-208




COOH




phenyl




—CH═CH—CH


2


—




3,4-di-OMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-209




COOH




phenyl




—CH


2


—CH


2


—




4-OH-phenyl




Me




Me




CH




N




N




O






I-210




COOH




phenyl




—CH


2


—CH


2


—




4-OH-phenyl




ethyl




Me




N




N




CH




O






I-211




COOH




4-CF


3


-phenyl




—CH


2


—CH


2


—




3,4-di-OMe-phenyl




Me




Me




N




N




N




O






I-212




COOH




4-CF


3


-phenyl




—CH


2


—CH


2


—




3,4-di-OMe-phenyl




ethyl




Me




CH




N




N




O




















I-213




COOH




phenyl




—CH


2


—CH


2


—




3-OMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-214




COOH




phenyl




—CH


2


—CH


2


—




2-OMe-phenyl




CF


3






Me




CH




N




N




O






I-215




COOH




phenyl




—CH


2


—CH


2


—




4-OEt-phenyl




ethyl




Me




CH




N




N




S




















I-216




COOH




phenyl




—C(CH


3


)


2


—CH


2


—




4-OEt-phenyl




OMe




CH


2


—CH


2


—CH


2


—C




N




N




O





















I-217




COOH




phenyl




—CH


2


—CH


2


—




4-SMe-phenyl




Me




Me




CH




N




N




O




















I-218




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




4-Cl-phenyl




OMe




CH


2


—CH


2


—CH


2


—C




N




N




O






I-219




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




4-Cl-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-220




COOH




phenyl




—CH


2


—CH


2


—




4-SMe-phenyl




Me




Me




N




N




N




O




















I-221




COOH




phenyl




—O—CH


2


—CH


2


—




4-OEt-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-222




COOH




4-Br-phenyl




—CH


2


—CH


2


—




3,5-di-OMe-phenyl




CF


3






Me




N




N




CH




O






I-223




COOH




phenyl




—CH═CH—CH


2


—




3,4-di-OMe-phenyl




Me




Me




CH




N




N




O






I-224




COOH




phenyl




—CH═CH—CH


2


—




3,4-di-OMe-phenyl




Me




Me




N




N




N




O






I-225




COOH




4-I-phenyl




—CH


2


—CH


2


—




3,5-di-OMe-phenyl




OMe




Me




CH




N




N




O






I-226




COOH




phenyl




—CH


2


—CH


2


—




3,5-di-OMe-phenyl




Me




Me




CH




N




CH




O






I-227




COOH




4-CF


3


-phenyl




—CH


2


—CH


2


—




3,4-di-OMe-phenyl




OMe




Me




CH




N




N




O






I-228




COOH




4-CF


3


-phenyl




—CH


2


—CH


2


—




3,4-di-OMe-phenyl




Me




Me




CH




N




N




O






I-229




COOH




phenyl




—CH


2


—CH


2


—




3,5-di-OMe-phenyl




ethyl




Me




N




N




N




O






I-230




COOH




phenyl




—CH


2


—CH


2


—




cyclohexyl




OMe




Me




CH




N




N




O






I-231




COOH




phenyl




—CH


2


—CH


2


—




cyclohexyl




Me




Me




CH




N




N




O






I-232




COOH




phenyl




—CH(OH)—CH


2


—




3,5-di-OMe-phenyl




ethyl




Me




CH




N




N




O




















I-233




COOH




phenyl




—CH


2


—CH


2


—




3,5-di-OMe-4-Cl-phenyl




OMe




CH


2


—CH


2


—CH


2


—C




N




N




O





















I-234




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




4-Cl-phenyl




Me




Me




N




N




N




O






I-235




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




4-Cl-phenyl




ethyl




Me




CH




N




N




O




















I-236




COOMe




phenyl




—CH


2


—CH


2


—




3,5-di-OMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-237




COOH




phenyl




—CH


2


—CH


2


—




3-OMe-phenyl




ethyl




Me




CH




N




N




O




















I-238




COOH




phenyl




—CH


2


—CH


2


—




3-OMe-phenyl




OMe




CH


2


—CH


2


—CH


2


—C




N




N




O





















I-239




COOH




phenyl




—CH═CH—CH


2


—




3,4-di-OMe-phenyl




CF


3






Me




CH




N




N




O






I-240




COOH




phenyl




—CH═CH—CH


2


—




3,4-di-OMe-phenyl




OMe




Me




CH




N




N




O






I-241




COOH




phenyl




—CH


2


—CH


2


—




2-Me-3-OMe-phenyl




CF


3






Me




CH




N




N




O






I-242




COOH




phenyl




—CH


2


—CH


2


—




3-OMe-phenyl




OMe




Me




N




N




N




O






I-243




COOH




4-CF


3


-phenyl




—CH


2


—CH


2


—




4-OMe-phenyl




ethyl




Me




CH




N




N




O




















I-244




COOH




4-CF


3


-phenyl




—CH


2


—CH


2


—




4-OMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-245




COOH




phenyl




—CH


2


—CH


2


—




4-SMe-phenyl




OMe




OMe




CH




N




N




O






I-246




COOH




phenyl




—CH


2


—CH


2


—




4-SMe-phenyl




OMe




Me




CH




N




N




O






I-247




COOH




phenyl




—CH


2


—CH


2


—




3-OMe-phenyl




Me




Me




CH




N




CH




O






I-248




COOH




phenyl




—CH


2


—CH


2


—




3-OMe-phenyl




Me




Me




N




N




CH




O






I-249




COOH




phenyl




—CH


2


—CH


2


—




3-OMe-phenyl




ethyl




Me




CH




N




N




S






I-250




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




4-Cl-phenyl




OMe




Me




CH




N




N




O






I-251




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




4-Cl-phenyl




Me




Me




CH




N




N




O




















I-252




COOH




4-F-phenyl




—CH


2


—CH


2


—




3-OMe-phenyl




OMe




CH


2


—CH


2


—CH


2


—C




N




N




O






I-253




COOH




phenyl




—CH


2


—CH(CH


3


)—




3-OMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-254




COOH




phenyl




—CH


2


—CH


2


—




cyclohexyl




CF


3






Me




CH




N




N




O




















I-255




COOH




phenyl




—CH═CH—CH


2


—




4-OMe-phenyl




OMe




CH


2


—CH


2


—CH


2


—C




N




N




O






I-256




COOH




phenyl




—CH═CH—CH


2


—




4-OMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-257




COOH




phenyl




—CH


2


—CH


2


—




cyclohexyl




OMe




OMe




CH




N




N




O






I-258




tetrazole




phenyl




—CH


2


—CH


2


—




2-OMe-phenyl




CF


3






Me




CH




N




N




O







[sic]






I-259




COOH




4-CF


3


-phenyl




—CH


2


—CH


2


—




4-OMe-phenyl




Me




Me




CH




N




N




O






I-260




COOH




4-CF


3


-phenyl




—CH


2


—CH


2


—




4-OMe-phenyl




Me




Me




N




N




N




O






I-261




COOH




phenyl




—CH(2-OMe-phenyl)-CH


2


—




2-OMe-phenyl




OMe




Me




CH




N




N




O






I-262




COOH




phenyl




—CH


2


—CH


2


—




2-OMe-4-Br-phenyl




Me




Me




CH




N




N




O






I-263




COOH




phenyl




—CH


2


—CH


2


—




3-OMe-phenyl




Me




Me




CH




N




N




O






I-264




COOH




phenyl




—CH


2


—CH


2


—




3-OMe-phenyl




Me




Me




N




N




N




O






I-265




COOH




phenyl




—CH


2


—CH


2


—




2-OMe-phenyl




Me




Me




N




N




CH




O




















I-266




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




4-Et-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-267




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




4-Cl-phenyl




CF


3






Me




CH




N




N




O






I-268




COOH




phenyl




—CH


2


—CH


2


—




2-OMe-phenyl




ethyl




Me




CH




N




N




S




















I-269




COOH




phenyl




—CH


2


—CH


2


—




3,4,5-tri-OMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-270




COOH




phenyl




—CH


2


—CH


2


—




4-SMe-phenyl




CF


3






Me




CH




N




N




O






I-271




COOH




phenyl




—CH═CH—CH


2


—




4-OMe-phenyl




Me




Me




N




N




N




O






I-272




COOH




phenyl




—CH═CH—CH


2


—




4-OMe-phenyl




ethyl




Me




CH




N




N




O




















I-273




COOH




4-Br-phenyl




—CH


2


—CH


2


—




2-OMe-phenyl




OMe




CH


2


—CH


2


—CH


2


—C




N




N




O






I-274




COOH




phenyl




—CH(OH)—CH


2


—




2-OMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O






I-275




COOH




4-Et-phenyl




—CH


2


—CH


2


—




4-Me-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-276




COOH




4-CF


3


-phenyl




—CH


2


—CH


2


—




4-OMe-phenyl




OMe




Me




CH




N




N




O






I-277




COOH




4-Cl-phenyl




—CH(4-OMe-phenyl)—CH


2


—




4-OMe-phenyl




OMe




Me




CH




N




N




O






I-278




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




3-Me-4-OMe-phenyl




Me




Me




CH




N




N




O






I-279




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




3,4-methylenedioxyphenyl




Me




Me




CH




N




N




O






I-280




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




3,4-methylenedioxyphenyl




Me




Me




N




N




N




O






I-281




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




4-OMe-phenyl




ethyl




Me




N




N




N




O






I-282




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




4-Et-phenyl




ethyl




Me




CH




N




N




O




















I-283




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




4-Et-phenyl




OMe




CH


2


—CH


2


—CH


2


—C




N




N




O






I-284




COOH




phenyl




—CH


2


—CH


2


—




4-Et-phenyl




OMe




CH


2


—CH


2


—CH


2


—C




N




N




O






I-285




COOH




phenyl




—CH


2


—CH


2


—




4-Et-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-286




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




4-OMe-phenyl




ethyl




Me




CH




N




N




S






I-287




COOH




phenyl




—CH═CH—CH


2


—




4-OMe-phenyl




OMe




Me




CH




N




N




O






I-288




COOH




phenyl




—CH═CH—CH


2


—




4-OMe-phenyl




Me




Me




CH




N




N




O




















I-289




COOH




3,4-di-Cl-phenyl




—CH


2


—CH


2


—




4-OMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-290




COOEt




4-Cl-phenyl




—CH(OH)—CH


2


—




3,4-di-OMe-phenyl




OMe




Me




CH




N




N




O






I-291




COOH




4-Et-phenyl




—CH


2


—CH


2


—




4-Me-phenyl




Me




Me




N




N




N




O






I-292




COOH




4-Et-phenyl




—CH


2


—CH


2


—




4-Me-phenyl




ethyl




Me




CH




N




N




O






I-293




COOH




phenyl




—CH


2


—CH


2


—




3-OMe-phenyl




CF


3






Me




CH




N




N




O






I-294




COOH




phenyl




—CH


2


—CH


2


—




3-OMe-phenyl




OMe




Me




CH




N




N




O






I-295




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




3,4-di-OMe-phenyl




Me




Me




CH




N




CH




O






I-296




COOH




4-Cl-phenyl




—C(CH


3


)


2


—CH


2


—




3,4-di-OMe-phenyl




Me




Me




N




N




N




O






I-297




COOH




phenyl




—CH


2


—CH


2


—




3,4,5-tri-OMe-phenyl




ethyl




Me




CH




N




N




O






I-298




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




4-Et-phenyl




Me




Me




CH




N




N




O






I-299




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




4-Et-phenyl




Me




Me




N




N




N




O




















I-300




COOH




phenyl




—CH


2


—CH


2


—




3,4,5-tri-OMe-phenyl




OMe




CH


2


—CH


2


—CH


2


—C




N




N




O





















I-301




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




3,4-di-OMe-phenyl




ethyl




Me




N




N




N




O




















I-302




COOH




3,4-di-Cl-phenyl




—CH


2


—CH


2


—




3,4-di-OMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O






I-303




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




3,4,5-tri-OMe-phenyl




OMe




CH


2


—CH


2


—CH


2


—C




N




N




O





















I-304




COOH




phenyl




—CH═CH—CH


2


—




4-OMe-phenyl




CF


3






Me




CH




N




N




O






I-305




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




3-Me-4-Et-phenyl




OMe




Me




CH




N




N




O






I-306




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




3-Me-4-Et-phenyl




SMe




Me




CH




N




N




O






I-307




COOH




4-Et-phenyl




—CH


2


—CH


2


—




4-Me-phenyl




OMe




Me




CH




N




N




O






I-308




COOH




4-Et-phenyl




—CH


2


—CH


2


—




4-Me-phenyl




Me




Me




CH




N




N




O




















I-309




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




4-iPr-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-310




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




3,4-methylenedioxyphenyl




OMe




Me




CH




N




N




O






I-311




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




4-Br-phenyl




Me




Me




N




N




N




O






I-312




COOH




phenyl




—CH


2


—CH


2


—




4-Et-phenyl




Me




Me




N




N




N




O






I-313




COOH




phenyl




—CH


2


—CH


2


—




4-Et-phenyl




ethyl




Me




CH




N




N




O






I-314




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




4-Et-phenyl




CF


3






Me




CH




N




N




O






I-315




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




4-Et-phenyl




OMe




Me




CH




N




N




O






I-316




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




4-Br-phenyl




ethyl




Me




N




N




N




O




















I-317




COOH




4-Cl-phenyl




—CH(4-Br-phenyl)—CH


2


—




4-Br-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-318




COOH




4-Cl-phenyl




—CH(OH)—CH


2


—




4-SMe-phenyl




OMe




Me




CH




N




N




O






I-319




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




3,4,5-tri-OMe-phenyl




Me




Me




N




N




N




O






I-320




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




3,4,5-tri-OMe-phenyl




ethyl




Me




CH




N




N




O




















I-321




COOH




phenyl




—CH


2


—CH


2


—




3,5-di-OMe-phenyl




OMe




CH


2


—CH


2


—CH


2


—C




N




N




O






I-322




COOH




phenyl




—CH


2


—CH


2


—




3,5-di-OMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-323




COOH




4-Et-phenyl




—CH


2


—CH


2


—




4-SMe-phenyl




ethyl




Me




CH




N




N




O




















I-324




COOH




4-Et-phenyl




—CH


2


—CH


2


—




4-SMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-325




COOH




4-Cl-phenyl




—C(CH


3


)


2


—CH


2


—




4-SMe-phenyl




Me




Me




CH




N




CH




O






I-326




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




4-SMe-phenyl




Me




Me




N




N




N




S






I-327




COOH




phenyl




—CH


2


—CH


2


—




3,4,5-tri-OMe-phenyl




Me




Me




CH




N




N




O






I-328




COOH




phenyl




—CH


2


—CH


2


—




3,4,5-tri-OMe-phenyl




Me




Me




N




N




N




O






I-329




COOH




4-Cl-phenyl




—O—CH


2


—CH


2


—




4-SMe-phenyl




ethyl




Me




CH




N




N




O






I-330




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




4-Me-phenyl




ethyl




Me




CH




N




N




O




















I-331




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




4-Me-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O






I-332




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




4-SMe-phenyl




OMe




O—CH═CH—C




N




N




O





















I-333




COOH




4-Cl-phenyl




—CH(OH)—CH


2


—




4-OEt-3-OMe-phenyl




OMe




Me




CH




N




N




O






I-334




COOH




4-Cl-phenyl




—CH(4-SMe-phenyl)—CH


2


—




4-SMe-phenyl




Me




Me




CH




N




N




O






I-335




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




3,4,5-tri-OMe-phenyl




OMe




Me




CH




N




N




O






I-336




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




3,4,5-tri-OMe-phenyl




Me




Me




CH




N




N




O






I-337




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




4-iPr-phenyl




Me




Me




N




N




N




O






I-338




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




4-iPr-phenyl




ethyl




Me




CH




N




N




O






I-339




COOH




4-Me-phenyl




—CH


2


—CH


2


—




3,4-di-OMe-phenyl




Me




Me




CH




N




N




O






I-340




COOH




4-Me-phenyl




—CH


2


—CH


2


—




3,4-di-OMe-phenyl




Me




Me




N




N




N




O






I-341




COOH




3,4-di-Cl-phenyl




—CH


2


—CH


2


—




4-OEt-3-OMe-phenyl




Me




Me




N




N




N




O






I-342




COOH




phenyl




—CH


2


—CH


2


—




4-Et-phenyl




OMe




Me




CH




N




N




O






I-343




COOH




phenyl




—CH


2


—CH


2


—




4-Et-phenyl




Me




Me




CH




N




N




O






I-344




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




4-OEt-3-OMe-phenyl




ethyl




Me




CH




N




N




S






I-345




COOH




4-Cl-phenyl




—CH(4-Me-phenyl)—CH


2


—




4-Me-phenyl




OMe




Me




CH




N




N




O






I-346




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




4-Me-phenyl




Me




Me




CH




N




N




O






I-347




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




4-Me-phenyl




Me




Me




N




N




N




O






I-348




COOMe




4-Cl-phenyl




—CH


2


—CH


2


—




4-Me-phenyl




Me




Me




CH




N




CH




O






I-349




COOH




phenyl




—CH


2


—CH


2


—




3,5-di-OMe-phenyl




Me




Me




N




N




N




O






I-350




COOH




phenyl




—CH


2


—CH


2


—




3,5-di-OMe-phenyl




ethyl




Me




CH




N




N




O




















I-351




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




2-Cl-phenyl




OMe




CH


2


—CH


2


—CH


2


—C




N




N




O





















I-352




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




3,4,5-tri-OMe-phenyl




CF


3






Me




CH




N




N




O






I-353




COOH




4-Cl-phenyl




—CH(OH)—CH


2


—




4-Me-phenyl




Me




Me




N




N




N




O






I-354




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




3,4-di-Me-phenyl




ethyl




Me




CH




N




N




O




















I-355




COOH




4-Me-phenyl




—CH


2


—CH


2


—




4-OMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-356




COOH




4-Me-phenyl




—CH


2


—CH


2


—




3,4-di-OMe-phenyl




OMe




Me




CH




N




N




O






I-357




COOH




phenyl




—CH


2


—CH


2


—




3,4,5-tri-OMe-phenyl




OMe




OMe




CH




N




N




O






I-358




COOH




phenyl




—CH


2


—CH


2


—




3,4,5-tri-OMe-phenyl




OMe




Me




CH




N




N




O




















I-359




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




4-Me-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




S





















I-360




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




4-Et-phenyl




OMe




Me




CH




N




N




S






I-361




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




4-Et-phenyl




Me




Me




CH




N




CH




O






I-362




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




4-Me-phenyl




CF


3






Me




CH




N




N




O






I-363




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




4-Me-phenyl




OMe




Me




CH




N




N




O






I-364




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




4-Et-phenyl




ethyl




Me




N




N




N




O






I-365




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




4-iPr-phenyl




OMe




Me




CH




N




N




O






I-366




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




4-iPr-phenyl




Me




Me




CH




N




N




O






I-367




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




2-Cl-phenyl




Me




Me




N




N




N




O






I-368




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




2-Cl-phenyl




ethyl




Me




CH




N




N




O






I-369




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




4-Et-phenyl




SMe




Me




CH




N




N




O




















I-370




COOH




phenyl




—CH


2


—CH


2


—




4-Me-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-371




COOH




4-Me-phenyl




—CH


2


—CH


2


—




4-OMe-phenyl




Me




Me




N




N




N




O






I-372




COOH




4-Me-phenyl




—CH


2


—CH


2


—




4-OMe-phenyl




ethyl




Me




CH




N




N




O






I-373




COOH




phenyl




—CH


2


—CH


2


—




4-Et-phenyl




CF


3






Me




CH




N




N




O




















I-374




COOH




4-Cl-phenyl




—C(CH


3


)


2


—CH


2


—




4-Et-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-375




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




4-Cl-phenyl




OMe




Me




CH




N




N




S






I-376




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




1-Me-naphth-2-yl




OMe




Me




CH




N




N




O






I-377




COOH




phenyl




—CH


2


—CH


2


—




3,5-di-OMe-phenyl




OMe




Me




CH




N




N




O






I-378




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




3,4-methylenedioxyphenyl




ethyl




Me




CH




N




N




O




















I-379




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




3,4-methylenedioxyphenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-380




COOH




phenyl




—CH


2


—CH


2


—




3,5-di-OMe-phenyl




Me




Me




CH




N




N




O






I-381




COOH




4-Cl-phenyl




—CH(4-OEt-phenyl)—CH


2


—




4-OEt-phenyl




OMe




Me




CH




N




N




O






I-382




COOH




4-Cl-phenyl




—CH(OH)—CH


2


—




4-OEt-phenyl




Me




Me




CH




N




N




O






I-383




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




2-Cl-phenyl




OMe




Me




CH




N




N




O






I-384




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




2-Cl-phenyl




Me




Me




CH




N




N




O




















I-385




COOH




phenyl




—CH


2


—CH


2


—




3,4-di-OMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-386




COOH




phenyl




—CH


2


—CH


2


—




3,4,5-tri-OMe-phenyl




CF


3






Me




CH




N




N




O






I-387




COOH




4-Me-phenyl




—CH


2


—CH


2


—




4-OMe-phenyl




OMe




Me




CH




N




N




O






I-388




COOH




4-Me-phenyl




—CH


2


—CH


2


—




4-OMe-phenyl




Me




Me




CH




N




N




O






I-389




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




4-OEt-phenyl




ethyl




Me




N




N




CH




O






I-390




COOH




3,4-di-Cl-phenyl




—CH


2


—CH


2


—




3,5-di-OMe-phenyl




OMe




Me




CH




N




N




O






I-391




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




3,5-di-OMe-4-Cl-phenyl




Me




Me




CH




N




N




O






I-392




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




3,5-di-OMe-phenyl




Me




Me




N




N




CH




O






I-393




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




4-OEt-3-OMe-phenyl




ethyl




Me




CH




N




N




O






I-394




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




3,4-methylenedioxyphenyl




Me




Me




CH




N




N




O






I-395




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




3,4-methylenedioxyphenyl




Me




Me




N




N




N




O




















I-396




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




4-OEt-3-OMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-397




COOH




4-Cl-phenyl




—C(CH


3


)


2


—CH


2


—




3-OMe-phenyl




CF


3






Me




CH




N




N




O






I-398




COOH




phenyl




—CH


2


—CH


2


—




4-Me-phenyl




ethyl




Me




CH




N




N




O






I-399




COOH




4-Me-phenyl




—CH


2


—CH


2


—CH


2


—




4-Me-phenyl




ethyl




Me




CH




N




N




O






I-400




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




2-Cl-phenyl




CF


3






Me




CH




N




N




O




















I-401




COOH




phenyl




—CH


2


—CH


2


—




4-Me-phenyl




OMe




CH


2


—CH


2


—CH


2


—C




N




N




O





















I-402




COOH




4-Cl-phenyl




—C(CH


3


)


2


—CH


2


—




3-OMe-phenyl




Me




Me




CH




N




N




O






I-403




COOH




4-CF


3


-phenyl




—CH


2


—CH


2


—




4-Me-phenyl




ethyl




Me




CH




N




N




O




















I-404




COOH




4-CF


3


-phenyl




—CH


2


—CH


2


—




4-Me-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-405




COOH




4-Et-phenyl




—CH


2


—CH


2


—




4-OMe-phenyl




OMe




Me




CH




N




N




S






I-406




COOH




4-Et-phenyl




—CH


2


—CH


2


—




3-Me-4-OMe-phenyl




Me




Me




CH




N




N




O




















I-407




COOH




phenyl




—CH


2


—CH


2


—




4-OEt-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-408




COOH




phenyl




—CH


2


—CH


2


—




3,5-di-OMe-phenyl




CF


3






Me




CH




N




N




O






I-409




COOH




4-Et-phenyl




—CH


2


—CH


2


—




3-Me-4-OMe-phenyl




Me




Me




N




N




CH




O






I-410




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




3,4-methylenedioxyphenyl




CF


3






Me




CH




N




N




O






I-411




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




3,4-methylenedioxyphenyl




OMe




Me




CH




N




N




O






I-412




COOH




4-Et-phenyl




—CH


2


—CH


2


—




4-OMe-phenyl




ethyl




Me




CH




CH




N




O






I-413




COOH




phenyl




—CH


2


—CH


2


—




3,4-di-OMe-phenyl




ethyl




Me




CH




N




N




O




















I-414




COOH




phenyl




—CH


2


—CH


2


—




3,4-di-OMe-phenyl




OMe




CH


2


—CH


2


—CH


2


—C




N




N




O





















I-415




COOH




4-Me-phenyl




—CH


2


—CH


2


—CH


2


—




4-Me-phenyl




Me




Me




CH




N




N




O






I-416




COOH




4-Me-phenyl




—CH


2


—CH


2


—CH


2


—




4-Me-phenyl




Me




Me




N




N




N




O






I-417




COOH




4-Et-phenyl




—CH


2


—CH


2


—




3,4-di-OMe-phenyl




SMe




Me




CH




N




N




O






I-418




COOMe




4-Et-phenyl




—CH


2


—CH


2


—




3,4-di-OMe-phenyl




Me




Me




CH




N




N




O






I-419




COOH




4-CF


3


-phenyl




—CH


2


—CH


2


—




4-Me-phenyl




Me




Me




CH




N




N




O






I-420




COOH




4-CF


3


-phenyl




—CH


2


—CH


2


—




4-Me-phenyl




Me




Me




N




N




N




O






I-421




COOH




4-Et-phenyl




—CH


2


—CH


2


—




3,4-di-OMe-phenyl




Me




Me




N




N




N




S






I-422




COOH




4-Et-phenyl




—CH


2


—CH


2


—




3,4-di-OMe-phenyl




ethyl




Me




CH




CH




N




O






I-423




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




4-OEt-3-OMe-phenyl




Me




Me




CH




N




N




O






I-424




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




4-OEt-3-OMe-phenyl




Me




Me




N




N




N




O




















I-425




COOH




4-Et-phenyl




—CH


2


—CH


2


—




3,4-di-OMe-phenyl




OMe




O—CH═CH—C




N




N




O





















I-426




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




4-SMe-phenyl




ethyl




Me




CH




N




N




O




















I-427




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




4-SMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-428




COOH




phenyl




—CH


2


—CH


2


—




4-Me-phenyl




Me




Me




CH




N




N




O






I-429




COOH




phenyl




—CH


2


—CH


2


—




4-Me-phenyl




Me




Me




N




N




N




O






I-430




COOH




4-Et-phenyl




—CH


2


—CH


2


—




3-OMe-phenyl




OMe




CF


3






CH




N




N




O






I-431




COOH




4-Me-phenyl




—CH


2


—CH


2


—CH


2


—




4-SMe-phenyl




OMe




Me




CH




N




N




O




















I-432




COOH




4-Me-phenyl




—CH


2


—CH


2


—CH


2


—




4-SMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-433




COOH




4-Et-phenyl




—CH(3-OMe-phenyl)—CH


2


—




3-OMe-phenyl




Me




Me




CH




N




N




O






I-434




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




naphth-2-yl




Me




Me




CH




N




N




O




















I-435




COOH




4-CF


3


-phenyl




—CH


2


—CH


2


—




4-SMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-436




COOH




4-CF


3


-phenyl




—CH


2


—CH


2


—




4-Me-phenyl




OMe




Me




CH




N




N




O






I-437




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




naphth-2-yl




Me




Me




N




N




N




O






I-438




COOH




4-Et-phenyl




—CH(OH)—CH


2


—




3-OMe-phenyl




Me




Me




N




N




N




O






I-439




COOH




phenyl




—CH


2


—CH


2


—




4-OEt-phenyl




ethyl




Me




CH




N




N




O




















I-440




COOH




phenyl




—CH


2


—CH


2


—




4-OEt-phenyl




OMe




CH


2


—CH


2


—CH


2


—C




N




N




O





















I-441




COOH




4-Et-phenyl




—CH


2


—CH


2


—




3-OMe-phenyl




Me




Me




CH




N




CH




O






I-442




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




4-SMe-phenyl




Me




Me




CH




N




N




O






I-443




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




4-SMe-phenyl




Me




Me




N




N




N




O




















I-444




COOH




4-Et-phenyl




—C(CH


3


)


2


—CH


2


—




3-OMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-445




COOH




phenyl




—CH


2


—CH


2


—




3,4-di-OMe-phenyl




Me




Me




CH




N




N




O






I-446




COOH




phenyl




—CH


2


—CH


2


—




3,4-di-OMe-phenyl




Me




Me




N




N




N




O






I-447




COOH




4-Me-phenyl




—CH


2


—CH


2


—CH


2


—-




3,4-di-OMe-phenyl




ethyl




Me




CH




N




N




O




















I-448




COOH




4-Me-phenyl




—CH


2


—CH


2


—CH


2


—




3-OMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-449




COOH




4-Et-phenyl




—CH


2


—CH


2


—




4-SMe-phenyl




OMe




Me




CH




N




N




S






I-450




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




2-OMe-phenyl




Me




Me




CH




N




N




O






I-451




COOH




4-CF


3


-phenyl




—CH


2


—CH


2


—




4-SMe-phenyl




Me




Me




N




N




N




O






I-452




COOH




4-CF


3


-phenyl




—CH


2


—CH


2


—




4-SMe-phenyl




ethyl




Me




CH




N




N




O






I-453




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




2-OMe-phenyl




Me




Me




N




N




N




O






I-454




COOBzl




4-Et-phenyl




—CH


2


—CH


2


—




4-SMe-phenyl




Me




Me




CH




N




N




O






I-455




COOH




4-Et-phenyl




—CH


2


—CH


2


—




4-SMe-phenyl




ethyl




Me




CH




CH




N




O






I-456




COOH




4-Et-phenyl




—CH


2


—CH


2


—




4-Me-phenyl




OMe




Me




N




N




N




O




















I-457




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




4-SMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-458




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




4-SMe-phenyl




CF


3






Me




CH




N




N




O






I-459




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




4-SMe-phenyl




OMe




Me




CH




N




N




O






I-460




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




4-OEt-3-OMe-phenyl




OMe




Me




CH




N




N




O






I-461




COOH




4-CF


3


-phenyl




—CH


2


—CH


2


—




4-OMe-phenyl




Me




Me




N




CH




N




O






I-462




COOH




phenyl




—CH


2


—CH


2


—




4-Me-phenyl




CF


3






Me




CH




N




N




O






I-463




COOH




4-Me-phenyl




—CH


2


—CH


2


—CH


2


—




3,4-di-OMe-phenyl




OMe




Me




CH




N




N




O






I-464




COOH




4-Me-phenyl




—CH


2


—CH


2


—CH


2


—




3,4-di-OMe-phenyl




Me




Me




CH




N




N




O






I-465




COOH




phenyl




—CH


2


—CH


2


—




4-Me-phenyl




OMe




Me




CH




N




N




O






I-466




COOH




4-CF


3


-phenyl




—C(CH


3


)


2


—CH


2


—




4-OMe-phenyl




ethyl




Me




CH




N




N




O






I-467




COOH




4-CF


3


-phenyl




—CH


2


—CH


2


—




4-SMe-phenyl




OMe




Me




CH




N




N




O






I-468




COOH




4-CF


3


-phenyl




—CH


2


—CH


2


—




4-SMe-phenyl




Me




Me




CH




N




N




O






I-469




COOH




4-CF


3


-phenyl




—CH


2


—CH


2


—




3,4-di-OMe-phenyl




ethyl




Me




CH




CH




N




O




















I-470




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




4-Cl-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-471




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




naphth-2-yl




OMe




Me




CH




N




N




O




















I-472




COOH




4-CF


3


-phenyl




—CH


2


—CH


2


—




3,4-di-OMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




S





















I-473




COOH




phenyl




—CH


2


—CH


2


—




4-OEt-phenyl




Me




Me




CH




N




N




O






I-474




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




3,4-di-OMe-phenyl




ethyl




Me




CH




N




N




O




















I-475




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




3,4-di-OMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-476




COOH




phenyl




—CH


2


—CH


2


—




4-OEt-phenyl




Me




Me




N




N




N




O






I-477




COOH




4-CF


3


-phenyl




—CH


2


—CH


2


—




3-OMe-phenyl




ethyl




Me




N




N




N




O




















I-478




COOH




4-CF


3


-phenyl




—CH


2


—CH


2


—




2-Me-3-OMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-479




COOH




4-Me-phenyl




—CH


2


—CH


2


—CH


2


—




4-OMe-phenyl




ethyl




Me




CH




N




N




O




















I-480




COOH




4-Me-phenyl




—CH


2


—CH


2


—CH


2


—




4-OMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-481




COOH




phenyl




—CH


2


—CH


2


—




3,4-di-OMe-phenyl




OMe




OMe




CH




N




N




O






I-482




COOH




phenyl




—CH


2


—CH


2


—




3,4-di-OMe-phenyl




OMe




Me




CH




N




N




O






I-483




COOH




4-CF


3


-phenyl




—CH


2


—CH


2


—




3-OMe-phenyl




ethyl




Me




CH




N




N




O




















I-484




COOH




4-CF


3


-phenyl




—CH


2


—CH


2


—




3-OMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-485




COOH




4-CF


3


-phenyl




—CH


2


—CH


2


—




3-Me-4-SMe-phenyl




OMe




Me




CH




N




N




O




















I-486




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




3-OMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-487




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




2-OMe-phenyl




OMe




Me




CH




N




N




O






I-488




COOH




4-CF


3


-phenyl




—CH


2


—CH


2


—




cyclohexyl




OMe




Me




CH




N




N




O






I-489




COOH




4-CF


3


-phenyl




—CH


2


—CH


2


—




4-Me-phenyl




Me




Me




CH




N




N




S






I-490




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




3,4-di-OMe-phenyl




Me




Me




CH




N




N




O






I-491




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




3,4-di-OMe-phenyl




Me




Me




N




N




N




O






I-492




COOH




4-Me-phenyl




—CH


2


—CH


2


—




cyclohexyl




OMe




Me




CH




N




N




O






I-493




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




4-SMe-phenyl




Me




Me




N




N




N




O






I-494




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




4-SMe-phenyl




ethyl




Me




CH




N




N




O




















I-495




COOH




4-CF


3


-phenyl




—CH


2


—CH


2


—CH


2


—




4-Me-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-496




COOH




4-Me-phenyl




—CH


2


—CH


2


—CH


2


—




4-OMe-phenyl




OMe




Me




CH




N




N




O






I-497




COOH




4-Me-phenyl




—CH


2


—CH


2


—




4-OMe-phenyl




Me




Me




CH




N




N




S




















I-498




COOH




phenyl




—CH


2


—CH


2


—




3,4-methylenedioxyphenyl




OMe




CH


2


—CH


2


—CH


2


—C




N




N




O





















I-499




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




phenyl




OMe




Me




CH




N




N




O






I-500




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




phenyl




Me




Me




CH




N




N




O




















I-501




COOH




phenyl




—CH


2


—CH


2


—




3,4-methylenedioxyphenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-502




COOH




4-Me-phenyl




—CH


2


—CH


2


—




3,4-di-OMe-phenyl




Me




Me




N




CH




N




O






I-503




COOH




4-Me-phenyl




—CH


2


—CH


2


—




3,4-di-OMe-phenyl




ethyl




Me




CH




N




N




S






I-504




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




4-Cl-phenyl




Me




Me




N




N




N




O






I-505




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




4-Cl-phenyl




ethyl




Me




CH




N




N




O






I-506




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




3,4-di-OMe-phenyl




CF


3






Me




CH




N




N




O






I-507




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




3,4-di-OMe-phenyl




OMe




Me




CH




N




N




O






I-508




COOH




4-Me-phenyl




—CH


2


—CH


2


—




cyclopentyl




OMe




Me




CH




N




N




O






I-509




COOH




phenyl




—CH


2


—CH


2


—




4-OEt-phenyl




CF


3






Me




CH




N




N




O






I-510




COOH




phenyl




—CH


2


—CH


2


—




4-OEt-phenyl




OMe




Me




CH




N




N




O






I-511




COOH




4-CF


3


-phenyl




—CH


2


—CH


2


—CH


2


—




4-Me-phenyl




Me




Me




N




N




N




O






I-512




COOH




4-CF


3


-phenyl




—CH


2


—CH


2


—CH


2


—




4-Me-phenyl




ethyl




Me




CH




N




N




O






I-513




COOH




4-Me-phenyl




—CH


2


—CH


2


—




4-SMe-phenyl




OMe




Me




CH




N




N




S






I-514




COOH




4-Me-phenyl




—CH


2


—CH


2


—




4-SMe-phenyl




ethyl




Me




N




N




N




O




















I-515




COOH




4-Me-phenyl




—CH


2


—CH


2


—




4-Me-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-516




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




phenyl




CF


3






Me




CH




N




N




O




















I-517




COOH




phenyl




—CH


2


—CH


2


—




4-OMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-518




COOH




phenyl




—CH


2


—CH


2


—




3,4-di-OMe-phenyl




CF


3






Me




CH




N




N




O






I-519




COOH




4-Me-phenyl




—CH


2


—CH


2


—




4-SMe-phenyl




ethyl




Me




CH




CH




N




O






I-520




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




3-OMe-phenyl




Me




Me




N




N




N




O






I-521




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




3-OMe-phenyl




ethyl




Me




CH




N




N




O




















I-522




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




4-OMe-phenyl




OMe




CH


2


—CH


2


—CH


2


—C




N




N




O






I-523




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




4-OMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O






I-524




COOMe




4-Me-phenyl




—CH


2


—CH


2


—




4-Me-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-525




COOMe




phenyl




—CH


2


—CH


2


—CH


2


—




phenyl




CF


3






Me




CH




N




N




O






I-526




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




phenyl




OMe




Me




CH




N




N




S






I-527




COOH




4-CF


3


-phenyl




—CH


2


—CH


2


—CH


2


—




4-SMe-phenyl




ethyl




Me




CH




N




N




O




















I-528




COOH




4-CF


3


-phenyl




—CH


2


—CH


2


—CH


2


—




4-SMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-529




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




4-SMe-phenyl




OMe




Me




CH




N




N




O






I-530




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




4-SMe-phenyl




Me




Me




CH




N




N




O






I-531




COOH




4-Me-phenyl




—CH


2


—CH


2


—




4-Me-phenyl




Me




Me




N




N




N




O






I-532




COOH




4-Me-phenyl




—CH


2


—CH


2


—




4-Me-phenyl




ethyl




Me




CH




N




N




O






I-533




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




4-F-phenyl




Me




Me




CH




N




N




O






I-534




COOH




phenyl




—CH


2


—CH


2


—




3,4-methylenedioxyphenyl




Me




Me




N




N




N




O






I-535




COOH




phenyl




—CH


2


—CH


2


—




3,4-methylenedioxyphenyl




ethyl




Me




CH




N




N




O






I-536




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




phenyl




Me




Me




N




N




CH




O






I-537




COOH




4-Br-phenyl




—CH


2


—CH


2


—CH


2


—




phenyl




ethyl




Me




CH




N




N




O






I-538




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




4-OMe-phenyl




Me




Me




N




N




N




O






I-539




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




4-OMe-phenyl




ethyl




Me




CH




N




N




O






I-540




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




4-Cl-phenyl




OMe




Me




CH




N




N




O






I-541




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




4-Cl-phenyl




Me




Me




CH




N




N




O




















I-542




COOH




4-F-phenyl




—CH


2


—CH


2


—CH


2


—




phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O






I-543




COOH




4-CF


3


-phenyl




—CH


2


—CH


2


—CH


2


—




3-OMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-544




COOH




4-CF


3


-phenyl




—CH


2


—CH


2


—CH


2


—




4-SMe-phenyl




OMe




Me




CH




N




N




O




















I-545




COOH




phenyl




—CH


2


—CH


2


—




naphth-2-yl




OMe




CH


2


—CH


2


—CH


2


—C




N




N




O






I-546




COOH




phenyl




—CH


2


—CH


2


—




naphth-2-yl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-547




COOH




4-Me-phenyl




—CH


2


—CH


2


—




4-Me-phenyl




OMe




Me




CH




N




N




O






I-548




COOH




4-Me-phenyl




—CH


2


—CH


2


—




4-Me-phenyl




Me




Me




CH




N




N




O






I-549




COOMe




phenyl




—CH(phenyl)—CH


2


—CH


2


—




phenyl




CF


3






Me




CH




N




N




O






I-550




COOH




4-F-phenyl




—CH(phenyl)—CH


2


—CH


2


—




phenyl




OMe




Me




CH




N




N




O






I-551




COOH




phenyl




—CH


2


—CH


2


—




4-OMe-phenyl




ethyl




Me




CH




N




N




O




















I-552




COOH




phenyl




—CH


2


—CH


2


—




4-OMe-phenyl




OMe




CH


2


—CH


2


—CH


2


—C




N




N




O





















I-553




COOH




phenyl




—CH(phenyl)—CH


2


—CH


2


—




phenyl




Me




Me




CH




CH




N




O






I-554




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




4-OMe-phenyl




OMe




Me




CH




N




N




O






I-555




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




4-OMe-phenyl




Me




Me




CH




N




N




O






I-556




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




3-OMe-phenyl




OMe




Me




CH




N




N




O






I-557




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




3-OMe-phenyl




Me




Me




CH




N




N




O






I-558




COOH




phenyl




—CH(phenyl)—CH


2


—CH


2


—




phenyl




OMe




Me




N




N




N




O




















I-559




COOH




4-CF


3


-phenyl




—CH


2


—CH


2


—CH


2


—




3,4-di-OMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-560




COOH




4-CF


3


-phenyl




—CH


2


—CH


2


—CH


2


—




3-OMe-phenyl




ethyl




Me




CH




N




N




O






I-561




COOH




phenyl




—CH(phenyl)—CH


2


—CH


2


—




phenyl




ethyl




Me




N




N




N




O






I-562




COOMe




phenyl




—CH


2


—CH


2


—CH


2


—




4-OMe-phenyl




CF


3






Me




CH




N




N




O






I-563




COOH




4-Me-phenyl




—CH


2


—CH


2


—




4-SMe-phenyl




ethyl




Me




CH




N




N




O




















I-564




COOH




4-Me-phenyl




—CH


2


—CH


2


—




4-SMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-565




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




3,4,5-tri-OMe-phenyl




ethyl




Me




CH




N




N




O




















I-566




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




3,4,5-tri-OMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-567




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




4-OMe-phenyl




OMe




Me




CH




N




N




S






I-568




COOH




phenyl




—CH


2


—CH


2


—




3,4-methylenedioxyphenyl




OMe




Me




CH




N




N




O






I-569




COOH




phenyl




—CH


2


—CH


2


—




3,4-methylenedioxyphenyl




Me




Me




CH




N




N




O




















I-570




COOH




phenyl




—CH(phenyl)—CH


2


—CH


2


—




phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-571




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




4-OMe-phenyl




CF


3






Me




CH




N




N




O






I-572




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




4-OMe-phenyl




Me




Me




CH




N




CH




O






I-573




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




4-OMe-phenyl




ethyl




Me




N




N




N




O






I-574




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




4-Et-phenyl




ethyl




Me




CH




N




N




O






I-575




COOH




4-CF


3


-phenyl




—CH


2


—CH


2


—CH


2


—




3,4-di-OMe-phenyl




OMe




Me




CH




N




N




O






I-576




COOH




4-CF


3


-phenyl




—CH


2


—CH


2


—CH


2


—




3,4-di-OMe-phenyl




ethyl




Me




CH




N




N




O




















I-577




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




4-Et-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-578




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




3-Cl-4-OMe-phenyl




ethyl




Me




CH




N




N




O






I-579




COOH




4-Me-phenyl




—CH


2


—CH


2


—




4-SMe-phenyl




Me




Me




CH




N




N




O






I-580




COOH




4-Me-phenyl




—CH


2


—CH


2


—




4-SMe-phenyl




Me




Me




N




N




N




O






I-581




COOH




phenyl




—CH


2


—CH


2


—




naphth-2-yl




Me




Me




N




N




N




O






I-582




COOH




phenyl




—CH


2


—CH


2


—




naphth-2-yl




ethyl




Me




CH




N




N




O




















I-583




COOH




4-F-phenyl




—CH


2


—CH


2


—CH


2


—




4-OMe-phenyl




OMe




CH


2


—CH


2


—CH


2


—C




N




N




O






I-584




COOH




4-F-phenyl




—CH


2


—CH


2


—CH


2


—




4-OMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-585




COOH




phenyl




—CH


2


—CH


2


—




4-OMe-phenyl




Me




Me




CH




N




N




O






I-586




COOH




phenyl




—CH(phenyl)—CH


2


—CH


2


—




phenyl




Me




Me




N




N




N




O






I-587




COOH




phenyl




—CH(phenyl)—CH


2


—CH


2


—




phenyl




ethyl




Me




CH




N




N




O






I-588




COOH




phenyl




—CH


2


—CH


2


—




4-OMe-phenyl




Me




Me




N




N




N




O






I-589




COOH




4-F-phenyl




—CH


2


—CH


2


—CH


2


—




3,4-di-OMe-phenyl




CF


3






Me




CH




N




N




O






I-590




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




3,5-di-OMe-phenyl




ethyl




Me




CH




N




N




O




















I-591




COOH




4-Et-phenyl




—CH


2


—CH


2


—CH


2


—




4-Me-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O






I-592




COOH




4- CF


3


-phenyl




—CH


2


—CH


2


—CH


2


—




4-OMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O






I-593




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




3,5-di-OMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-594




COOH




phenyl




—CH(OH)—CH(OH)—CH


2


—




3,4-di-OMe-phenyl




OMe




Me




CH




N




N




O




















I-595




COOH




4-Me-phenyl




—CH


2


—CH


2


—




3-OMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-596




COOH




4-Me-phenyl




—CH


2


—CH


2


—




4-SMe-phenyl




OMe




Me




CH




N




N




O






I-597




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




3,4-di-OMe-phenyl




Me




Me




CH




N




N




S






I-598




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




3,4-di-OMe-phenyl




Me




Me




N




CH




N




O






I-599




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




3,4,5-tri-OMe-phenyl




Me




Me




CH




N




N




O






I-600




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




3,4,5-tri-OMe-phenyl




Me




Me




N




N




N




O






I-601




COOEt




phenyl




—CH


2


—CH


2


—CH


2


—




3,4-di-OMe-phenyl




ethyl




Me




CH




N




N




O






I-602




COOH




phenyl




—CH(phenyl)—CH


2


—CH


2


—




phenyl




OMe




Me




CH




N




N




O






I-603




COOH




phenyl




—CH(phenyl)—CH


2


—CH


2


—




phenyl




Me




Me




CH




N




N




O




















I-604




COOH




phenyl




—CH


2


—CH


2


—




4-iPr-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-605




COOH




phenyl




—CH


2


—CH


2


—




3,4-methylenedioxyphenyl




CF


3






Me




CH




N




N




O




















I-606




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




3,4-di-OMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




S






I-607




COOH




4-Et-phenyl




—CH


2


—CH


2


—CH


2


—




4-SMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-608




COOH




4-Et-phenyl




—CH


2


—CH


2


—CH


2


—




4-Me-phenyl




OMe




Me




CH




N




N




O






I-609




COOH




4-Br-phenyl




—CH


2


—CH


2


—CH


2


—




4-SMe-phenyl




OMe




Me




CH




N




N




O






I-610




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




4-Et-phenyl




Me




Me




CH




N




N




O






I-611




COOH




4-Me-phenyl




—CH


2


—CH


2


—




3-OMe-phenyl




Me




Me




N




N




N




O






I-612




COOH




4-Me-phenyl




—CH


2


—CH


2


—




3-OMe-phenyl




ethyl




Me




CH




N




N




O






I-613




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




4-Et-phenyl




Me




Me




N




N




N




O






I-614




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




4-SMe-phenyl




ethyl




Me




N




CH




N




O






I-615




COOH




phenyl




—CH


2


—CH


2


—




naphth-2-yl




OMe




Me




CH




N




N




O






I-616




COOH




phenyl




—CH


2


—CH


2


—




naphth-2-yl




Me




Me




CH




N




N




O




















I-617




COOH




phenyl




—CH(OH)—CH(OH)—CH


2


—




4-SMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O






I-618




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-619




COOH




phenyl




—CH(phenyl)—CH


2


—CH


2


—




phenyl




CF


3






Me




CH




N




N




O






I-620




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




4-Me-phenyl




Me




Me




N




N




CH




O






I-621




COOH




phenyl




—CH


2


—CH


2


—




4-OMe-phenyl




OMe




OMe




CH




N




N




O






I-622




COOH




phenyl




—CH


2


—CH


2


—




4-OMe-phenyl




OMe




Me




CH




N




N




O






I-623




COOH




4-Et-phenyl




—CH


2


—CH


2


—CH


2


—




4-SMe-phenyl




Me




Me




CH




N




N




O






I-624




COOH




4-Et-phenyl




—CH


2


—CH


2


—CH


2


—




4-SMe-phenyl




ethyl




Me




CH




N




N




O






I-625




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




4-Me-phenyl




CF


3






Me




CH




N




N




S






I-626




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




3,5-di-OMe-phenyl




Me




Me




CH




N




N




O






I-627




COOH




4-Me-phenyl




—CH


2


—CH


2


—




3-OMe-phenyl




OMe




Me




CH




N




N




O






I-628




COOH




4-Me-phenyl




—CH


2


—CH


2


—




3-OMe-phenyl




Me




Me




CH




N




N




O






I-629




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




3,5-di-OMe-phenyl




Me




Me




N




N




N




O






I-630




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




4-Me-phenyl




OMe




Me




N




N




N




O






I-631




COOH




phenyl




—CH(OH)—CH(OH)—CH


2


—




4-Me-phenyl




Me




Me




CH




N




N




O






I-632




COOH




4-Cl-phenyl




—CH


2


—CH


2


—CH


2


—




4-Et-phenyl




ethyl




Me




CH




N




N




O




















I-633




COOH




4-Cl-phenyl




—CH


2


—CH


2


—CH


2


—




4-Et-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-634




COOH




4-F-phenyl




—CH


2


—CH


2


—CH


2


—




4-Me-phenyl




Me




Me




N




N




N




O




















I-635




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




3,4-di-OMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-636




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




phenyl




Me




Me




N




N




N




O






I-637




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




phenyl




ethyl




Me




CH




N




N




O






I-638




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




3,4,5-tri-OMe-phenyl




OMe




Me




CH




N




N




O






I-639




COOH




4-F-phenyl




—CH


2


—CH


2


—CH


2


—




4-Me-phenyl




ethyl




Me




CH




N




N




O






I-640




COOH




phenyl




—CH


2


—CH


2


—




4-iPr-phenyl




ethyl




Me




CH




N




N




O






I-641




COOH




4-Et-phenyl




—CH


2


—CH


2


—CH


2


—




3-OMe-phenyl




ethyl




Me




CH




N




N




O




















I-642




COOH




4-Et-phenyl




—CH


2


—CH


2


—CH


2


—




3-OMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O






I-643




COOH




phenyl




—CH


2


—CH


2


—




4-iPr-phenyl




OMe




CH


2


—CH


2


—CH


2


—C




N




N




O






I-644




COOH




4-F-phenyl




—CH


2


—CH


2


—CH


2


—




4-Me-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-645




COOH




4-Me-phenyl




—CH


2


—CH


2


—




3,4-di-OMe-phenyl




ethyl




Me




CH




N




N




O




















I-646




COOH




4-Me-phenyl




—CH


2


—CH


2


—




3,4-di-OMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-647




COOH




4-F-phenyl




—CH


2


—CH


2


—CH


2


—




4-Et-phenyl




CF


3






Me




CH




N




N




O




















I-648




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




4-Me-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-649




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




4-Et-phenyl




OMe




Me




CH




N




N




O






I-650




COOMe




phenyl




—CH


2


—CH


2


—CH


2


—




4-Et-phenyl




OMe




Me




CH




N




N




O




















I-651




COOH




phenyl




—CH


2


—CH


2


—




4-Cl-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-652




COOH




4-Cl-phenyl




—CH


2


—CH


2


—CH


2


—




4-Me-phenyl




ethyl




Me




CH




N




N




O






I-653




COOH




4-Cl-phenyl




—CH


2


—CH


2


—CH


2


—




4-Et-phenyl




OMe




Me




CH




N




N




O






I-654




COOH




phenyl




—CH


2


—CH


2


—




naphth-2-yl




CF


3






Me




CH




N




N




O






I-655




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




3,4-di-Cl-phenyl




Me




Me




N




N




N




O






I-656




COOH




4-F-phenyl




—CH


2


—CH


2


—CH


2


—




4-Cl-phenyl




ethyl




Me




CH




N




N




O




















I-657




COOH




phenyl




—CH


2


—CH


2


—




phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-658




COOH




phenyl




—CH


2


—CH


2


—




4-OMe-phenyl




CF


3






Me




CH




N




N




O




















I-659




COOH




4-Et-phenyl




—CH


2


—CH


2


—CH


2


—




3,4-di-OMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-660




COOH




4-Et-phenyl




—CH


2


—CH


2


—CH


2


—




3-OMe-phenyl




OMe




Me




CH




N




N




O




















I-661




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




4-Cl-phenyl




OMe




CH


2


—CH


2


—CH


2


—C




N




N




S






I-662




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




4-OEt-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-663




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




3,5-di-OMe-phenyl




OMe




Me




CH




N




N




O






I-664




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




3-OMe-phenyl




ethyl




Me




N




CH




N




O






I-665




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




3-OMe-phenyl




OMe




Me




N




N




N




O






I-666




COOH




4-Cl-phenyl




—CH


2


—CH


2


—CH


2


—




4-Me-phenyl




OMe




Me




CH




N




N




O






I-667




COOH




4-Cl-phenyl




—CH


2


—CH


2


—CH


2


—




4-Me-phenyl




Me




Me




N




N




N




O




















I-668




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




2,3-di-OMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-669




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




3,4-di-OMe-phenyl




Me




Me




N




N




N




O






I-670




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




3,4-di-OMe-phenyl




ethyl




Me




CH




N




N




O






I-671




COOH




3,4-di-Cl-phenyl




—CH


2


—CH


2


—CH


2


—




4-OMe-phenyl




OMe




Me




CH




N




N




O






I-672




COOH




phenyl




—CH


2


—CH


2


—




4-iPr-phenyl




Me




Me




CH




N




N




O






I-673




COOH




4-Et-phenyl




—CH


2


—CH


2


—CH


2


—




3,4-di-OMe-phenyl




Me




Me




CH




N




N




O






I-674




COOH




4-Et-phenyl




—CH


2


—CH


2


—CH


2


—




3,4-di-OMe-phenyl




ethyl




Me




CH




N




N




O






I-675




COOH




phenyl




—CH


2


—CH


2


—




4-iPr-phenyl




Me




Me




N




N




N




O






I-676




COOH




3,4-di-Cl-phenyl




—CH


2


—CH


2


—CH


2


—




4-OMe-phenyl




Me




Me




CH




N




N




O






I-677




COOH




3,4-di-Cl-phenyl




—CH


2


—CH


2


—CH


2


—




4-OMe-phenyl




ethyl




Me




CH




N




N




O






I-678




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




4-Me-phenyl




Me




Me




N




N




N




O






I-679




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




4-Me-phenyl




ethyl




Me




CH




N




N




O






I-680




COOH




4-Cl-phenyl




—CH


2


—CH


2


—CH


2


—




3,4-methylenedioxyphenyl




Me




Me




CH




N




N




O




















I-681




COOH




4-Cl-phenyl




—CH


2


—CH


2


—CH


2


—




3,4-methylenedioxyphenyl




OMe




O—CH


2


—CH


2


—C




N




N




O






I-682




COOH




3,4-di-Cl-phenyl




—CH


2


—CH


2


—CH


2


—




4-OMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-683




COOH




phenyl




—CH


2


—CH


2


—




4-Cl-phenyl




ethyl




Me




CH




N




N




O




















I-684




COOH




phenyl




—CH


2


—CH


2


—




4-Cl-phenyl




OMe




CH


2


—CH


2


—CH


2


—C




N




N




O





















I-685




COOH




phenyl




—CH(OH)—CH(OH)—CH


2


—




2-Cl-phenyl




OMe




Me




CH




N




N




O






I-686




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




2-Cl-phenyl




Me




Me




CH




CH




N




O




















I-687




COOH




4-Et-phenyl




—CH


2


—CH


2


—CH


2


—




4-OMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-688




COOH




4-Et-phenyl




—CH


2


—CH


2


—CH


2


—




3,4-di-OMe-phenyl




OMe




Me




CH




N




N




O






I-689




COOH




phenyl




—CH


2


—CH


2


—




phenyl




Me




Me




N




N




N




O






I-690




COOH




phenyl




—CH


2


—CH


2


—




phenyl




ethyl




Me




CH




N




N




O






I-691




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




2-Cl-phenyl




Me




Me




N




N




N




S






I-692




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




4-OEt-phenyl




Me




Me




N




N




N




O






I-693




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




4-OEt-phenyl




ethyl




Me




CH




N




N




O






I-694




COOH




4-Cl-phenyl




—CH


2


—CH


2


—CH


2


—




4-iPr-phenyl




ethyl




Me




CH




N




N




O






I-695




COOH




4-Cl-phenyl




—CH


2


—CH


2


—CH


2


—




3,4-methylenedioxyphenyl




OMe




Me




CH




N




N




O






I-696




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




2-Cl-phenyl




ethyl




Me




CH




N




N




S




















I-697




COOMe




phenyl




—CH


2


—CH


2


—CH


2


—




2-Cl-phenyl




OMe




CH


2


—CH


2


—CH


2


—C




N




N




O





















I-698




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




3,5-di-OMe-4-Cl-phenyl




OMe




Me




CH




N




N




O






I-699




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




3,4-di-OMe-phenyl




OMe




Me




CH




N




N




O






I-700




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




3,4-di-OMe-phenyl




Me




Me




CH




N




N




O




















I-701




COOH




4-Cl-phenyl




—CH


2


—CH


2


—CH


2


—




3-OMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-702




COOH




4-Et-phenyl




—CH


2


—CH


2


—CH


2


—




4-OMe-phenyl




ethyl




Me




CH




N




N




O






I-703




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




3,5-di-OMe-4-Cl-phenyl




Me




Me




CH




N




N




O






I-704




COOH




phenyl




—CH


2


—CH


2


—




4-iPr-phenyl




CF


3






Me




CH




N




N




O






I-705




COOH




phenyl




—CH


2


—CH


2


—




4-iPr-phenyl




OMe




Me




CH




N




N




O






I-706




COOH




phenyl




—CH═CH—CH


2


—




4-OMe-phenyl




OMe




Me




CH




N




N




S






I-707




COOMe




phenyl




—CH═CH—CH


2


—




4-OMe-phenyl




Me




Me




CH




N




N




O




















I-708




COOH




4-Cl-phenyl




—CH


2


—CH


2


—CH


2


—




4-OEt, 3-OMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-709




COOH




4-Cl-phenyl




—CH


2


—CH


2


—CH


2


—




4-iPr-phenyl




Me




Me




N




N




N




O






I-710




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




4-Me-phenyl




OMe




Me




CH




N




N




O






I-711




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




4-Me-phenyl




Me




Me




CH




N




N




O






I-712




COOH




phenyl




—CH═CH—CH


2


—




4-OMe-phenyl




Me




Me




N




CH




N




O






I-713




COOH




phenyl




—CH


2


—CH


2


—




4-Cl-phenyl




Me




Me




CH




N




N




O






I-714




COOH




phenyl




—CH


2


—CH


2


—




4-Cl-phenyl




Me




Me




N




N




N




O






I-715




COOH




4-Cl-phenyl




—CH


2


—CH


2


—CH


2


—




3-OMe-phenyl




Me




Me




N




N




N




O






I-716




COOH




4-Cl-phenyl




—CH


2


—CH


2


—CH


2


—




3-OMe-phenyl




ethyl




Me




CH




N




N




O






I-717




COOH




phenyl




—CH═CH—CH


2


—




3-Cl-4-OMe-phenyl




ethyl




Me




CH




N




N




O




















I-718




COOH




phenyl




—CH═CH—CH


2


—




3-Cl-4-OMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-719




COOH




phenyl




—CH


2


—CH


2


—




phenyl




OMe




Me




CH




N




N




O






I-720




COOH




phenyl




—CH


2


—CH


2


—




phenyl




Me




Me




CH




N




N




O






I-721




COOH




4-F-phenyl




—CH═CH—CH


2


—




3,4-di-OMe-phenyl




OMe




Me




CH




N




N




O




















I-722




COOH




4-Cl-phenyl




—CH


2


—CH


2


—CH


2


—




4-SMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-723




COOH




4-Cl-phenyl




—CH


2


—CH


2


—CH


2


—




4-OEt, 3-OMe-phenyl




OMe




Me




CH




N




N




O






I-724




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




4-OEt-phenyl




OMe




Me




CH




N




N




O






I-725




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




4-OEt-phenyl




Me




Me




CH




N




N




O






I-726




COOMe




phenyl




—CH═CH—CH


2


—




3,4-di-OMe-phenyl




Me




Me




CH




N




N




O






I-727




COOH




phenyl




—CH═CH—CH


2


—




3,4-di-OMe-phenyl




Me




Me




N




CH




N




O




















I-728




COOH




phenyl




—CH═CH—CH


2


—




3,4-di-OMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




S





















I-729




COOH




4-Cl-phenyl




—CH


2


—CH


2


—CH


2


—




3-OMe-phenyl




OMe




Me




CH




N




N




O






I-730




COOH




4-Cl-phenyl




—CH


2


—CH


2


—CH


2


—




3-OMe-phenyl




Me




Me




CH




N




N




O






I-731




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




4-OMe-phenyl




ethyl




Me




CH




N




N




O




















I-732




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




4-OMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-733




COOH




phenyl




—CH═CH—CH


2


—




cyclohexyl




OMe




Me




CH




N




N




O




















I-734




COOH




phenyl




—CH


2


—CH


2


—




4-OEt-3-OMe-phenyl




OMe




CH


2


—CH


2


—CH


2


—C




N




N




O






I-735




COOH




phenyl




—CH


2


—CH


2


—




4-OEt-3-OMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-736




COOH




4-Cl-phenyl




—CH


2


—CH


2


—CH


2


—




4-SMe-phenyl




Me




Me




N




N




N




O






I-737




COOH




4-Cl-phenyl




—CH


2


—CH


2


—CH


2


—




4-SMe-phenyl




ethyl




Me




CH




N




N




O






I-738




COOH




phenyl




—CH═CH—CH


2


—




cyclohexyl




Me




Me




CH




N




N




O






I-739




COOH




phenyl




—CH═CH—CH


2


—




4-Me-phenyl




Me




Me




N




N




N




S






I-740




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




3,4-methylenedioxyphenyl




ethyl




Me




CH




N




N




O




















I-741




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




3,4-methylenedioxyphenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-742




COOH




phenyl




—C(phenyl)═CH—CH


2


—




phenyl




OMe




Me




CH




N




N




O






I-743




COOH




4-Cl-phenyl




—CH


2


—CH


2


—CH


2


—




3,5-di-OMe-phenyl




OMe




Me




CH




N




N




O






I-744




COOH




4-Cl-phenyl




—CH


2


—CH


2


—CH


2


—




3,5-di-OMe-phenyl




Me




Me




CH




N




N




O






I-745




COOH




phenyl




—CH


2


—CH


2


—




4-Cl-phenyl




CF


3






Me




CH




N




N




O






I-746




COOH




phenyl




—CH


2


—CH


2


—




4-Cl-phenyl




OMe




Me




CH




N




N




O






I-747




COOH




4-F-phenyl




—CH═CH—CH


2


—




phenyl




Me




Me




CH




N




N




O






I-748




COOH




4-F-phenyl




—CH═CH—CH


2


—




phenyl




Me




Me




N




N




N




O






I-749




COOH




phenyl




—CH


2


—CH


2


—




4-OEt-3-OMe-phenyl




Me




Me




N




N




N




O






I-750




COOH




4-Cl-phenyl




—CH


2


—CH


2


—CH


2


—




4-SMe-phenyl




OMe




Me




CH




N




N




O






I-751




COOH




4-Cl-phenyl




—CH


2


—CH


2


—CH


2


—




4-SMe-phenyl




Me




Me




CH




N




N




O






I-752




COOH




phenyl




—CH


2


—CH


2


—




4-OEt-3-OMe-phenyl




ethyl




Me




CH




N




N




O






I-753




COOH




phenyl




—C(phenyl)═CH—CH


2


—




phenyl




ethyl




Me




CH




N




N




O






I-754




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




naphth-2-yl




ethyl




Me




CH




N




N




O




















I-755




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




naphth-2-yl




OMe




O—CH


2


—CH


2


—C




N




N




O






I-756




COOH




phenyl




—CH═CH—CH


2


—




phenyl




OMe




O—CH


2


—CH


2


—C




N




N




S





















I-757




COOH




4-Cl-phenyl




—CH


2


—CH


2


—CH


2


—




4-OEt-phenyl




Me




Me




CH




N




N




O






I-758




COOH




4-Cl-phenyl




—CH


2


—CH


2


—CH


2


—




4-OEt-phenyl




ethyl




Me




CH




N




N




O






l-759




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




4-OEt-phenyl




CF


3






Me




CH




N




N




O






I-760




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




4-OEt-phenyl




OMe




Me




CH




N




N




O






I-761




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




4-OMe-phenyl




Me




Me




CH




N




N




O






I-762




COOH




4-Cl-phenyl




—CH


2


—CH


2


—




4-OMe-phenyl




Me




Me




N




N




N




O






I-763




COOH




4-Cl-phenyl




—CH


2


—CH


2


—CH


2


—




3,4-di-OMe-phenyl




ethyl




Me




CH




N




N




O




















I-764




COOH




4-Cl-phenyl




—CH


2


—CH


2


—CH


2


—




3,4-di-OMe-phenyl




OMe




O—CH


2


—CH


2


—C




N




N




O





















I-765




COOH




phenyl




—CH


2


—CH


2


—CH


2


—




4-OEt-phenyl




Me




Me




CH




N




N




O














Example 16




Receptor binding data were measured by the binding assay described above for the compounds listed hereinafter.




The results are shown in Table 2.












TABLE 2











Receptor binding data (K


i


values)















Compound




ET


A


[nM/l] [sic]




ET


B


[nM/l] [sic]



















I-116




35




35







I-140




575




460







I-146




4




29







I-321




340




290







I-355




132




82







I-370




11




54







I-445




3.5




7.2







I-445 (S) enantiomer




1.3




4.1







I-445 (R) enantiomer




65




140







I-482




2




14







I-499




31




135







I-585




6




23







I-593




300




160







I-622




3




23







I-635




210




126







I-672




60




185







I-699




230




130







I-713




20




96














Claims
  • 1. A carboxylic acid compound of the formula I where R1 is a group where R isa radical OR7 where R7 is hydrogen, the cation of an alkali metal, the cation of an alkaline earth metal or a physiologically tolerated organic ammonium ion; R2 is hydrogen, hydroxyl, NH2, NH(C1-C4-alkyl, N(C1-C4-alkyl)2, halogen, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy or C1-C4-alkylthio; X is nitrogen; Y is nitrogen; Z is CR10, where R10 is hydrogen or C1-C4-alkyl; R3 is hydrogen, hydroxyl, NH2, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, halogen, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-hydroxyalkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy or C1-C4-alkylthio, or CR3 is linked to CR10 as indicated above to give a 5- or 6-membered ring; R4 and R5, which may be identical or different, are phenyl or naphthyl, unsubstituted or substituted; R6 is substituted phenyl; W is oxygen; Q is a spacer whose length corresponds to that of a C2-C4 chain, or the physiologically tolerated salts, and the enantiomerically pure and diastereoisomerically pure forms thereof wherein the compound has an ETA:ETB affinity ratio of greater than 0.1 and less than 20.
  • 2. A pharmaceutical preparation for peroral, parenteral or intraparenteral use, comprising at least one carboxylic acid compound as claimed in claim 1, and conventional pharmaceutical ancillary substances.
  • 3. The method of treating a disease selected from the group consisting of chronic heart failure, restenosis, high blood pressure, pulmonary hypertension, acute/chronic kidney failure, cerebral ischemia, asthma, benign prostate hyperplasia and prostate cancer comprising administering an effective amount of a compound of claim 1 to a patient in need of such treatment.
  • 4. The method of claim 3 further comprising administering inhibitors of the rennin-angiotensin system mixed ACE/neutral endopeptidase (NEP) inhibitors and/or β blockers.
  • 5. The carboxylic acid derivative of claim 1, wherein Q is C2-C4-alkyl, C3-C4-alkenyl, C3-C4-alkynyl, —S—CH2—CH2—, or —O—CH2—CH2—, each of these radicals being unsubstituted or substituted one or more times by halogen, hydroxyl, mercapto, carboxyl, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkylthio, or phenyl which is unsubstituted or substituted one or more times by halogen, nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy or C1-C4-alkylthio;or Q forms together with R6 2-indanyl, 3-indanyl, 1,2,3,4-tetrahydro-2-naphthyl, or 1,2,3,4-tetrahydro-3-naphthyl, it being possible for the phenyl rings in each case to be substituted by halogen, hydroxyl, mercapto, carboxyl, cyano, C1-C4-alkoxy, C1-C4-alkyl, C2-C4-alkynyl, C3-C6-alkenyloxy, C3-C6-alkynyloxy, C1-C4-alkylthio, C1-C4-haloalkoxy, C1-C4-alkoxycarbonyl, NH(C1-C4-alkyl), N(C1-C4-alkyl)2 or phenyl.
Priority Claims (1)
Number Date Country Kind
196 36 046 Sep 1996 DE
PCT Information
Filing Document Filing Date Country Kind
PCT/EP97/04688 WO 00
Publishing Document Publishing Date Country Kind
WO98/09953 3/12/1998 WO A
US Referenced Citations (4)
Number Name Date Kind
5661106 Baumann et al. Aug 1997 A
5703017 Baumann et al. Dec 1997 A
5932730 Riechers et al. Aug 1999 A
5969134 Riechers et al. Oct 1999 A
Foreign Referenced Citations (7)
Number Date Country
3804595 May 1996 AU
43 35 950 Apr 1995 DE
195 33 023 Apr 1996 DE
94 25442 Nov 1994 WO
9526716 Oct 1995 WO
9611914 Apr 1996 WO
9712878 Apr 1997 WO
Non-Patent Literature Citations (1)
Entry
J. Med. Chem. 1996, 39, 2123-2128, Riechers et a. Inhibitors of Endothelin, Webb et al.,002-052.