MXPA97003146A - Derivatives of propenoic acid substituted conheterocicle as n antagonists - Google Patents

Abstract

The present invention relates to a compound of the formula: wherein Z is hydrogen-CH3; X is represented by -OH; Y is represented by -OH; R1 is represented by 1 to 3 substituents, independently selected from the group: hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, halogen, -CF3, oOCF3; G is a radical selected from the group R2 is represented by 1 to 2 substituents, independently selected from the group: hydrogen or alkyl of 1 to 4 carbon atoms, R3 is represented by 1 to 2 substituents, independently selected from the group hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, halogen, and pharmaceutically acceptable addition salts of the same

Description

DERIVATIVES OF PROPENOIC ACID SUBSTITUTED WITH HETEROCICLE AS NMDA ANTAGONISTS DESCRIPTION OF THE INVENTION The present invention is directed to a new class of excitatory amino acid antagonists and intermediates thereof. These new antagonists, propenoic acid derivatives substituted with heterocycle, are useful as NMDA (N-methyl-D-aspartate) antagonists. They are preferably linked to the strychnine-insensitive glycine binding site in the NMDA receptor complex associated with the treatment of a number of disease states. Another aspect of the invention is directed to its use in the treatment of a number of diseases, as well as to pharmaceutical compositions containing these excitatory amino acid antagonists. In accordance with the present invention, a new class of NMDA antagonists has been discovered, which can be described by the formula: (I) wherein: Z is hydrogen or -CH 3; X is represented by -OH, a physiologically acceptable ester, or a physiologically acceptable amide; Y is represented by -OH, a physiologically acceptable ester, or a physiologically acceptable amide; Ri is represented by from 1 to 3 substituents, independently selected from the group consisting of: hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, -CF 3, or -OCF 3; G is a radical selected from the group, wherein: R2 is represented by 1 to 2 substituents, independently selected from the group consisting of: hydrogen or C? -C alkyl; R3 is represented by from 1 to 2 substituents, independently selected from the group consisting of: hydrogen, C? -C alkyl, C? -C alkoxy, or halogen; and pharmaceutically acceptable addition salts thereof. As used in this application: a) the term "C? -C4 alkyl" refers to a straight or branched chain alkyl radical containing from 1-4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and the like; b) the term "C 1 -C alkoxy" refers to a straight or branched chain alkoxy radical containing 1 -4 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and the like, c) the term "halogen" refers to a fluorine atom, a gold atom, a bromine atom, or an iodine atom, d) the term "physiologically acceptable ester" refers to any Non-toxic or any prodrug that allows the compounds of this application to function as NMDA antagonists: these physiologically acceptable esters can be selected from, but not limited to, compounds wherein X and Y can each be represented by -OR4, -OCH2OR4 lo -O- (CH2) pN RsRβ, wherein R4 is represented by C?-C4 alkyl, phenyl, substituted phenyl, or a phenylalkyl substituent, such as benzyl, wherein the phenyl ring may be optionally substituted; is 2 or 3, and R5 and Rß each independently is repr ested by an alkyl of C? -C4 or together with the adjacent nitrogen atom forms a ring -CH2-CH2-Z-CH2-CH2-, where Z is a bond, O, S, or N R7, wherein R7 is hydrogen or C? -C4 alkyl; said rings include, but are not limited to, piperidino, morpholino, thiomorpholino, piperazino, N-methylpiperazino, or pyrrolidino; and their pharmaceutically acceptable addition salts; e) the term "physiologically acceptable amide" refers to any non-toxic amide or any prodrug that allows the compounds of this application to function as NMDA antagonists: these physiologically acceptable amides may be selected from, but are not limited to, compounds in where X and Y each can be independently represented by -NR8R9¡ wherein R8 and Rg each is independently represented by hydrogen, phenyl, substituted phenyl, phenylalkyl, or a Ci-C alkyl; or Rt and R g are taken together with the adjacent nitrogen atom to form a ring -CH 2 -CH 2 -Z-CH 2 -CH 2 -, where Z is a bond, O, S, or N R 7, wherein R 7 is hydrogen or C? -C alkyl; said rings include, but are not limited to, piperidino, morpholino, thiomorpholino, piperazino, N-methylpiperazino, or pyrrolidino, and their pharmaceutically acceptable addition salts; f) designation, It is also understood that when the radical is attached to the 2-position, the substituent or substituents represented by R can be attached to the 2-position or 3-position. any of positions 3, 4, or 5, and that when the radical is attached to the 3-position, the substituent or substituents represented by R can be attached to any of positions 2, 4, or 5; g) the designation, it refers to furyl, furanyl, or furan, and it is understood that the radical is attached to the 2-position or the 3-position, furthermore it is understood that when the radical is attached to the 2-position, the substituent or substituted te is represented by R, they can be attached to any of positions 3, 4, or 5, and that when the radical is attached at position 3, the substituent or substituents represented by R, can be attached to any of positions 2, 4, or 5; h) the designation "C (O)" refers to a carbonyl group of the formula: ) The designation, it refers to pyridine, pyridinyl or pyridyl, and it is understood that the radical can be attached to any of positions 2-, 3-, or 4-, it is further understood that when the radical is attached at position 2, the substituent or substituents represented by R, they can be attached at any of the positions, 3, 4, 5, or 6, that when the radical is attached at the 3-position, the substituent or substituents represented by R, can be attached at any of positions 2, 4 , 5, or 6, and that when the radical is attached at position 4, the substituent or substituents represented by R, can be attached at any of positions 2, 3, 5, or 6; j) the designation "?? G" refers to a link for which the stereochemistry is not designated; k) the term "pharmaceutically acceptable addition salts" refers to any acid addition salt or a basic addition salt. The expression "pharmaceutically acceptable acid addition salts" is intended to be applied to any acid salt of organic or inorganic addition of the base compounds represented by the formula (I) or any of its intermediates. Illustrative inorganic acids, which form suitable salts, include hydrochloric, hydrobromic, sulfuric and phosphoric acid, and acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Illustrative organic acids, which form suitable salts, include mono-, di-, and tricarboxylic acids. Illustrative of said acids are, for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymelic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic, 2- phenoxy-benzoic, and sulfonic acids such as p-toluenesulfonic acid, methanesulfonic acid and 2-hydroxyethane sulfonic acid. Said salts can exist in a hydrated or substantially anhydrous form. In general, the acid addition salts of these compounds are soluble in water and various hydrophilic organic solvents, and which in comparison to their free base forms, generally demonstrate higher melting points. The term "pharmaceutically acceptable basic addition salts" is intended to be applied to any non-toxic organic or inorganic basic addition salt of the compounds represented by formula (I) or any of its intermediates. Illustrative bases which form suitable salts include alkali metal or alkaline earth metal hydroxides such as sodium, potassium, calcium, magnesium, or barium hydroxides; ammonia and organic aliphatic, cyclic, or aromatic amines, such as methylamine, dimethylamine, trimethylamine, and picoline.

The compounds of the formula (I) exist as geometric isomers. Any reference in this application to any of the compounds of the formula (I) means that it encompasses either a specific geometric isomer or a mixture of isomers. The specific isomers can be separated and recovered by techniques known in the art, such as chromatography and selective crystallization. Illustrative examples of compounds encompassed by the present invention include: (E) -2-Bromo-3- (1-p-toluene-sulfonyl-2-c-arboethoxy-4,6-dichloroindol-3-y) t-butyl ester propenoic; (Z) -2-Bromo-3- (1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindol-3-yl) propenoic acid t-butyl ester; (E) -2- (Thien-3-yl) -3- (1-p-toluene-sulfonyl-2-carboethoxy-4,6-dichloroindol-3-yl) propenoic acid t-butyl ester; (Z) -2- (Thien-3-yl) -3- (1-p-toluene-sulfonyl-2-carboethoxy-4,6-dichloroindol-3-yl) propenoic acid t-butyl ester; (E) -2- (Thien-3-yl) -3- (1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloro-indol-3-yl) propenoic acid; (Z) -2- (Thien-3-yl) -3- (1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloro-indol-3-yl) propenoic acid; t-butyl ester of (E) -2- (Thien-2-yl) -3- (1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindol-3-yl) propenoic acid ester; t-butyl ester of (Z) -2- (Thien-2-yl) -3- (1-p-toluenesulfonyl-2-carboethoxy-4,6-dioxide roindol-3-yl) propenoic acid ester; (E) -2- (Thien-2-yl) -3- (1-p-toluene sulfonyl-2-carboethoxy-4,6-d-chloro-indol-3-yl) propenoic acid; (Z) -2- (Thien-2-yl) -3- (1-p-toluenesulfonyl-2-carboethoxy-4, β-dichloro-indol-3-yl) propenoic acid; t-butyl ester of (E) -2- (Fur-2-yl) -3- (1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindol-3-yl) propenoic acid ester; (Z) -2- (Fur-2-yl) -3- (1-p-toluene-sulfonyl-2-carboethoxy-4,6-dichloroindol-3-yl) propenoic acid t-butyl ester; (E) -2- (Fur-2-yl) -3- (1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloro-indol-3-yl) propenoic acid; (Z) -2- (Fur-2-yl) -3- (1-p-toluene sulfonyl-2-carboethoxy-4,6-dichloro-indol-3-yl) propenoic acid; t-butyl ester of (E) -2- (Fur-3-M) -3- (1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindol-3-yl) propenoic acid ester; (Z) -2- (Fur-3-yl) -3- (1-p-toluene-sulfonyl-2-carboethoxy-4,6-dichloroindol-3-yl) propenoic acid t-butyl ester; (E) -2- (Fu r-3-M) -3- (1-p-toluenesulfonyl-2-carboethoxy-4,6-d-chloro-indo I-3-yl) propenoic acid; (Z) -2- (Fur-3-yl) -3- (1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloro-indol-3-yl) propenoic acid; (E) -2- (Pyrid-4-yl) -3- (2-carboethoxy-4,6-dichloroindol-3-yl) propene nitrile; (Z) -2- (Pyrid-4-yl) -3- (2-carboethoxy-4,6-d-chloroindol-3-yl) propene-nitrile; (E) -2- (Pyrid-3-yl) -3- (2-carboethoxy-4,6-dichloroindol-3-yl) propenonitrile; (Z) -2- (Pyrid-3-yl) -3- (2-carboethoxy-4,6-dichloroindol-3-yl) propenonitrile; (E) -2- (Pyrid-2-yl) -3- (2-carboethoxy-4,6-dichloroindol-3-yl) propenonitrile; (Z) -2- (Pyrid-2-yl) -3- (2-carboethoxy-4,6-dichloroindol-3-yl) propenonitrile; Acid (Z) -2- (Pyrid-4-yl) -3- (4,6-dichloroindol-3-yl-2-carboxylic acid) propenoic acid; acid imide (Z) -2- (Pyrid-3-yl) -3- (4,6-dichloroindol-3-yl-2-carboxylic acid) propenoic acid; acid imide (Z) -2- (Pyrid-2-yl) -3- (4,6-dichloroindol-3-yl-2-carboxylic acid) propenoic acid; (E) -2- (Thien-3-yl) -3- (4,6-dichloroindol-3-yl-2-carboxylic acid) propenoic acid; (Z) -2- (Thien-3-yl) -3- (4,6-dichloroindol-3-yl-2-carboxylic acid) propenoic acid; (E) -2- (Thien-2-yl) -3- (4,6-dichloroindol-3-yl-2-carboxylic acid) propenoic acid; (Z) -2- (Thien-2-yl) -3- (4,6-dichloroindol-3-yl-2-carboxylic acid) propenoic acid; (E) -2- (Fur-2-yl) -3- (4,6-dichloroindol-3-yl-2-carboxylic acid) propenoic acid; (Z) -2- (Fur-2-yl) -3- (4,6-dichloroindol-3-yl-2-carboxylic acid) propenoic acid; (E) -2- (Fur-3-yl) -3- (4,6-dichloroindol-3-yl-2-carboxylic acid) propenoic acid; (Z) -2- (Fur-3-yl) -3- (4,6-dichloroindol-3-yl-2-carboxylic acid) propenoic acid; (E) -2- (Pyrid-4-yl) -3- (4,6-dichloroindol-3-yl-2-carboxylic acid) propenoic acid; (Z) -2- (Pyrid-4-yl) -3- (4,6-dichloroindol-3-yl-2-carboxylic acid) propenoic acid; (E) -2- (Pyrid-3-yl) -3- (4,6-dichloroindol-3-yl-2-carboxylic acid) propenoic acid; (Z) -2- (Pyrid-3-yl) -3- (4,6-dichloroindol-3-yl-2-carboxylic acid) propenoic acid; (E) -2- (Pyrid-2-yl) -3- (4,6-dichloroindol-3-yl-2-carboxylic acid) propenoic acid; (Z) -2- (Pyrid-2-yl) -3- (4,6-dichloroindol-3-yl-2-carboxylic acid) propenoic acid The compounds of the formula (I) can be prepared as described in Reaction Scheme 1. All substituents, unless otherwise indicated, are previously defined. Reagents and starting materials are readily available to one skilled in the art.

REACTION SCHEME 1 As described in Reaction Scheme 1, the compounds of formula (I) can be prepared by subjecting an appropriate indole (1) to a Wittig-type reaction, to give an ester of 2-bromo-3- (indole) acid. 3-yl) propenoic of structure (2), a Suzuki coupling reaction with an appropriate arylboronic acid, GB (OH) 2 > to give the compound (3), and deprotection and functionalization to give a compound of the formula (I). In preparing the compounds of the formula (I), wherein G is thienyl or furyl, the method described in Reaction Scheme 1 is preferred. In Reaction Scheme 1, step 1, an appropriate indole of structure (1) is contacted with an appropriate organophosphorus ylide in a Wittig-type reaction to give an ester of 2-bromo-2- (indole-3) acid. -il) propenoic of the structure (2). An appropriate indole compound of structure (1) is one in which R L and Z are as desired in the final product of formula (I), Pgi is X as desired in the final product of formula (I) or gives rise, after deprotection and functionalization according to X, as desired in the final product of formula (I), and Pg3 is a protective group, which is easily removed to give the final product of formula (I) or allows selective deprotection and functionalization as required to incorporate X and Y desired in the final product of formula (I). The appropriate characters of the structure (1) are readily prepared by methods well known in the art, such as the synthesis of Fischer indole, the introduction of a carbonyl substituent of the 3-position, and protection of the indole nitrogen. An appropriate organophosphorus ion is one which converts the carbonyl of the 3-position of an indole of the structure (1) to a 2-bromopropenoic acid ester of the structure (2), wherein Pg2 is Y, as desired in the final product of formula (I) or gives rise, after deprotection and functionalization, as required, to Y as desired in the final product of formula (I). An appropriate organophosphorus ylide is formed by contacting an appropriate organophosphorus reagent, such as diethylphosphonobromo-t-butyl acetate or ethyl diethylphosphonobromoacetate, with a suitable base, such as lithium diisopropylamide, sodium hydride, lithium bis (trimethylsilyl) amide. , or potassium t-butoxide. Suitable organophosphorus reagents and the use of appropriate organophosphate reagents are well known and appreciated in the art. For example, an appropriate organophosphorus reagent is contacted with a suitable base such as lithium diisopropylamide, sodium hydride, lithium bis (trimethylsilyl) amide or potassium t-butoxide. The formation of the ilido is carried out in a suitable solvent, such as tetrahydrofuran, benzene, or diethyl ether. The formation of the ilido is generally carried out at a temperature of -78 ° C at room temperature. An appropriate organophosphorous lycopene is contacted with an appropriate indole of structure (1). The reaction is carried out in a suitable solvent, such as tetrahydrofuran, benzene or diethyl ether. Generally, the reaction is carried out in the same solvent used to form the appropriate organophosphorous ylide. The reaction is carried out at temperatures of -78 ° C at the reflux temperature of the solvent. The reaction usually requires 1 hour to 48 hours. The product can be isolated through techniques well known in the art, such as extraction and evaporation. Then, the product can be purified by techniques well known in the art, such as distillation, chromatography or recrystallization. In Reaction Scheme 1, step 2, an ester of 2-bromo-3- (bromo-3-yl) propenoic acid of structure (2) is contacted with an appropriate arylboronic acid in a Suzuki coupling to give a composed of the structure (3). N. Miyaura et al. , J. Pray Chem .. 51_, 5467-5471 (1986); Y. Hoshino et al .. Bull. Chem. Soc. Japan. 61 3008-3010 (1988); N. Miyaura et al. , J. Am. Chem. Soc. üi, 314-321 (1989); W. J. Thompson et al .. J. Org. Chem .. 53-2052-2055 (1988); and T. Y. Wallow and B. M. Novak, J. Org. Chem. 59, 5034-5037 (1994). A suitable arylboronic acid, G-B (OH) 2, is one in which G is as desired in the final product of the formula (I). The preparation and use of arylboronic acids is well known and appreciated in the art. W.J. Thompson and J. Gaudino. J .Org. Chem. 49. 5237-5243 (1984). Arylboronic acids are frequently contaminated with their corresponding anhydrides, which do not work well in Suzuki coupling. Material contaminated by harmful amounts of anhydride can be converted to the corresponding acid through hydrolysis. The hydrolysis is carried out, if required, by briefly boiling in water, and the arylboronic acid is recovered by filtration. For example, an ester of 2-bromo-3- (indol-3-yl) propenoic acid of structure (2) is contacted with an appropriate arylboronic acid. The Suzuki coupling reaction is carried out in a suitable solvent, such as toluene or tetrahydrofuran. The reaction is carried out using from about 1.1 to about 3 molar equivalents of an appropriate arylboronic acid. The reaction is carried out in the presence of about 1 to about 3 molar equivalents of a suitable base, such as potassium carbonate, sodium carbonate. The coupling is performed using a suitable palladium catalyst, such as tetrakis < trif in the phosphine) palladium (0), bis (acetonitrile) palladium chloride (I I), palladium chloride (I I), palladium acetoacetate (I I), and tris (dibenzylidene ketone) dipalladium (0). The suitable palladium catalyst chosen can be modified through the use of ligands, such as tri (fur-2-yl) phosphine and tri (o-toluene) phosphine. V. Fariña and B. Krishnan, J .Am. Chem. Soc, 1 13. 9586-9595 (1991). The coupling is carried out at a temperature ranging from 0 ° C to the reflux temperature of the solvent. The reactions of the coupling represented in Reaction 1, generally require from 6 hours to 14 days. The product (3) of the coupling reaction can be isolated and purified using techniques well known in the art. These techniques include extraction, evaporation, chromatography and recrystallization. In Reaction Scheme 1, step 3, the compound of structure (3) obtained from the coupling reaction is deprotected and functionalized using techniques well known in the art to give compounds of formula (I). These techniques include the hydrolysis of esters, selective hydrolysis of esters, transesterification, removal of indole protecting groups, amidation of active ester leaving groups, and esterification of activated ester leaving groups. As appreciated by one skilled in the art, in Scheme 1, the number and order of deprotection, functionalization and protection steps performed will depend on the compound of formula (I), which is desired as the product of the Scheme. 1. The selection, use and removal of the protecting groups, using suitable protective groups such as those described in Protecting Groups in Organic Svnthesis by T. Greene, Wiley-lnterscience (1981), are well known and appreciated in the art. . As described in Reaction Scheme 1, step 3, the compounds of the formula (I) can be prepared by subjecting a compound (3) to an appropriate functionalization reaction, which introduces the appropriate functionality at the 2-position of the nucleus of indole and / or in the 1-position of the propenoic acid, thus producing one of the desired compounds of the formula (I). In structure (3), Z, Ri, and G are as defined in formula (I), Pg3 is represented by an indole-nitrogen protecting group, and Pgi and Pg2 are each independently represented by groups such as alkyl of C? -C, or other active ester leaving groups known in the art, physiologically acceptable ester or physiologically acceptable amide. Functionalization reactions can be performed using techniques well known in the art. For example, ester functionalities can be added to position 2 of the indole core and / or position 1 of the propenoic acid, using a variety of esterification techniques. A suitable esterification technique comprises contacting the appropriate compound of structure (3), wherein Pgi and Pg2 are C? -C4 alkyl functions, with an excess of an appropriate alcohol. An appropriate alcohol is one that gives rise to groups X and Y, as desired in the final product of the formula (I). The reaction is typically carried out in the presence of an excess of a base such as potassium carbonate. The reaction is typically carried out at a temperature ranging from room temperature to reflux, for a period ranging from 1 hour to 24 hours. After the reaction is complete, the desired product of the formula (I) can be recovered through organic extraction and evaporation. Then, it can be purified by flash chromatography and recrystallization, as is known in the art. Amides can also be easily prepared by contacting a structure (3) in which Pgi and Pg2 are Ci-C alkyls, with excess ammonia or a mono- or dialkylamine corresponding to X and Y desired in the final product. of the formula (I). The reaction is carried out at a temperature of 0-100 ° C, for a period ranging from 1 -48 hours, using the amine as a solvent or in an inert solvent such as tetrahydrofuran. The resulting amide derivatives of formula (I) can then be isolated and purified by techniques known in the art. As is readily apparent as those skilled in the art, if X and Y are not represented by the same function in the final product, then it will be necessary to carry out deprotection and functionalization reactions in a sequential manner, using suitable protecting groups such as those described in Protecting Groups in Organic Svnthesis. T. Greene. This can be done using techniques known to those skilled in the art.; D. B. Bryan et al, J .Am. Chem. Soc. 99. 2353 (1977); E. Wuensch, Methoden der Organischen Chemie (Houben-Weyl), E. Mueller, Ed., George Theime Verlag, Stuttgart, 1974, Vol. 15; M.G. Saulnierand and G. W. Gribble, J. Org. Chem. 47, 2810 (1982); Y. Egawa et al, Chem. Pharm. Bull .. 7. 896 (1963); R. Adams and L. H. Ulich, J. Am. Chem. Soc. 42. 599 (1920); and J. Szmuszkoviocz, J. Gold. Chem. 29, 834 (1964). The formation and use of active ester leaving groups, used in functionalization reactions, are well known and appreciated in the art. Active ester leaving groups include, but are not limited to, anhydrides, mixed anhydrides, acid chlorides, acid bromides, 1-hydroxybenzo-triazole esters, 1-hydroxysuccinimide esters, or activated intermediates formed in the presence of reactants coupling, such as dicyclohexycarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbo-diimide, and 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinolone. The active ester leaving groups can be prepared and isolated before use, or they can be prepared and used without isolation to form physiologically acceptable esters or physiologically acceptable amides. For example, a compound of formula (I), wherein Y is a physiologically acceptable amide and X is a physiologically acceptable ester or -OH, can be prepared from a compound of structure (3) wherein Pg2 is t -butyl and Pg, is a physiologically acceptable ester other than t-butyl, or a hydrolyzable ester. Selective removal of the t-butyl group gives a compound of structure (3), where Pg2 is -OH and Pg! is a physiologically acceptable ester other than t-butyl, or a hydrolyzable ester, which can be amidated through the formation of a leaving group of active ester followed by the addition of a suitable amine, as is well known in the art . A suitable amine is one which gives a physiologically acceptable amide, Y, as desired in the final product of the formula (I). Suitable amines include, but are not limited to, methylamine, dimethylamine, ethylamine, diethylamine, propylamine, butylamine, aniline, 4-chloroaniline, N-methylaniline, benzylamine, phenethylamine, morpholine, piperazine, piperidine, N-methylpiperazine, thiomorpholine, pyrrolidine, and N-methylbenzylamine. The formation of an active ester leaving group requires the protection of the NH indole, using a suitable protecting group, such as benzenesulfonyl, p-toluenesulfonyl, tri-methylsulfonyl, trimethylsilylethoxymethyl, and the like. Additional functionalization or hydrolysis yields a compound of the formula (I), wherein Y is a physiologically acceptable amide and X is a physiologically acceptable ester or -OH. After removing the functionalization of the indole N H, the protecting group gives a compound of the formula (I). Similarly, a compound of the formula (I), wherein X is a physiologically acceptable amide and Y is a physiologically acceptable ester or -OH, can be prepared from a compound of structure (3), wherein Pgi is t- butyl and Pg is a physiologically acceptable ester other than t-butyl, or a hydrolysable ester. The compounds of the formula (I), wherein X and Y are -OH, can be prepared from a compound of structure (3), wherein Pgi and Pg2 are C? -Calkoxy, or a leaving group of active ester, by deprotection using a molar excess of a suitable reagent, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate, or potassium carbonate, with lithium hydroxide being preferred, sodium hydroxide, potassium hydroxide, and lithium hydroxide being very preferred. These deprotections are carried out in a suitable solvent, such as mixtures of tetrahydrofuran and water, or water. The reaction is typically carried out at a temperature ranging from room temperature to reflux, for a period ranging from 1 hour to 24 hours. After the reaction is completed, the desired product of formula (I) can be recovered by techniques well known in the art, such as evaporation, precipitation, by adjusting the pH of the solution with a suitable acid such as hydrochloric acid, sodium bisulfate, potassium bisulfate , acetic acid, etc. , extraction and recrystallization. Alternatively, some of the compounds of formula (I) can be prepared as described in Reaction Scheme 2. All substituents, unless otherwise indicated, have been previously defined. Reagents and starting materials are readily available to one skilled in the art.

REACTION SCHEME 2 As described in Reaction Scheme 2, the compounds of the formula (I) can be prepared by subjecting an appropriate indole (1) to a condensation reaction to give a 2-aryl-3- (indol-3-yl) propenenitrile of structure (4), hydrolysis to give a compound (5), and deprotection, and / or functionalization, to give a compound of formula (I). In the preparation of the compounds of the formula (I), wherein G is pyridyl, the method described in Reaction Scheme 2 is preferred. In Reaction Scheme 2, step 1, an appropriate indole of the structure (1) it is contacted with an appropriate aryl acetonitrile in a condensation reaction to give a 2-aryl-3- (indol-3-yl) -propenenitrile of structure (4). An appropriate indole compound of structure (1) is one in which Ri, and Z are as desired in the final product of formula (I), Pgi is X as desired in the final product of formula (I) , or gives rise, after deprotection and functionalization as required, to X as desired in the final product of formula (I), and Pg3 is hydrogen or a protecting group, which is easily removed to give a final product of the formula (I), or allows selective deprotection and functionalization, as may be required, to incorporate desired X and Y into the final product of the formula (I). The appropriate characters of structure (1) are readily prepared by methods well known in the art, such as Fischer indole synthesis, introduction of a 3-carbonyl substituent, and if required, indole protection. -nitrogen. A suitable ar-acetonitrile, G-CH2-CN, is one in which G is as desired in the final product of the formula (I). For example, an appropriate indole of structure (1) is contacted with an appropriate aryl acetonitrile. The reaction is carried out in a suitable solvent, such as tetrahydrofuran, ethanol, or methanol. The reaction is carried out using a suitable base, such as piperidine, triethylamine, sodium hydride, or sodium carbonate. The reaction is generally carried out at temperatures from room temperature to the reflux temperature of the solvent. The reaction usually requires 1 hour to 120 hours. The product can be isolated through techniques well known in the art, such as extraction and evaporation. The product can then be purified by techniques well known in the art, such as distillation, chromatography, or recrystallization. In Reaction Scheme 2, step 2, an appropriate 2-aryl-3- (indol-3-yl) -propenonityl of structure (4) is hydrolyzed to give a compound of structure (5), wherein Yi is -OH, or -NH2. It is understood that such hydrolysis can be carried out through a number of steps, through intermediates such as imides. In Reaction Scheme 2, step 3, the compound of structure (5), obtained from the hydrolysis reaction, can be optionally protected, deprotected, and functionalized using techniques well known in the art, and described in the Reaction Scheme. 1, step 3, to give compounds of the formula (I). These techniques include the formation of esters to give a compound of structure (3), hydrolysis of esters, selective hydrolysis of esters, transesterification, removal of indole protecting groups, amidation of active ester leaving groups, and esterification of leaving groups of activated ester. The following preparations represent typical procedures for preparing starting materials used in the example. The following examples present typical syntheses, as described in Reaction Scheme 1, and Reaction Scheme 2. These preparations and examples are understood to be illustrative only, and are not intended to limit the scope of the invention. As used in the following preparations and examples, the following terms have the following indicated meanings: "kg" refers to kilograms, "g" refers to grams, "mg" refers to milligrams, "mol" refers to moles , "mmol" refers to millimoles, "L" refers to liters, "mi" refers to milliliters, "° C" refers to degrees Celsius, "M" refers to molar, "pf" refers to point of fusion, "dec" refers to decomposition.PREPARATION 1 .1 3-Formyl-1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloro-indole Combine 3,5-dichlorophenylhydrazine (300 g) and ethanol (2 L).

Add ethyl pyruvate (153.6 ml) and sulfuric acid (25 ml). After 3 hours, evaporate in vacuo to obtain a residue. Cover the residue with ethyl acetate and water. Add solid sodium bicarbonate until the aqueous layer is neutralized. Separate the layers and extract the aqueous layer with ethyl acetate. Combine the organic layers, dry over MgSO, filter, and evaporate in vacuo to give ethyl pyruvate 3,5-dichlorophenylhydrazone. Combine ethyl pyruvate 3, 5-dichlorophenylhydrazone (100 g) and polyphosphoric acid (2 kg). Heat over a steam bath. After 5 hours, stop the heating and slowly add ice (100 g) to thin the solution. Empty the reaction mixture on ice to give an aqueous suspension. Extract the aqueous suspension three times with ethyl acetate. Combine the organic layers, dry over MgSO, filter, and evaporate in vacuo to give a solid. Titrate the solid with diethyl ether, filter and dry to give 2-carboethoxy-4,6-dichloroindole. Combine 2-carboethoxy-4,6-dichloroindole (20.0 g, 0.077 mole), and dimethylformamide (9.0 ml, 0.1 mole) in dichloroethane (100 ml). Add phosphoryl chloride (18.0 g, 0.117 mmol). Heat to reflux. After 3.5 hours, cool the reaction mixture to room temperature to obtain a solid. Collect the solid by filtration, rinse with water. Combine the solid with 1 M of an aqueous solution of sodium acetate and stir. After 1 hour, filter, rinse with water, and dry to give 3-formyl-2-carboethoxy-4,6-dichloroindole. Combine 3-formyl-2-carboethoxy-4,6-dichloroindole (46.3 g, 162 mmol) and anhydrous potassium carbonate (44.9 g, 325 mmol) in dimethylformamide (600 mL). Add p-toluenesulfonyl chloride (42.9g, 225 mmol). After 18 hours, pour the reaction mixture into water (3 L) and stir to give a solid. Filter, rinse with water and diethyl ether, and recrystallize from acetonitrile / dichloroethane to give the title compound.

PREPARATION 1.2 3-For mil-1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindole Combine 2-carboethoxy-4,6-dichloroindole (10.0 g, 0.039 mole), and dimethylformamide (4.5 mL, 0 057 mole) in dichloroethane (20 mL).

Add phosphoryl chloride (8.9 g, 0.058 mmol). Heat at 80 ° C.

After 18 hours, cool the reaction mixture to room temperature and combine with an aqueous solution of 1 M sodium acetate and stir. After 18 hours, filter, rinse with water and dry to give 3-formyl-2-carboethoxy-4,6-dichloroindole. Reacting 3-formyl-2-carboethoxy-4,6-dichloroindole with p-toluenesulfonyl chloride, as described in Preparation 1.1, to give the title compound.

PREPARATION 2 3-Acetyl-1-p-toluenesulfonyl-2-carboethoxy-indole It is prepared through the method of Preparation 1 .1. , using 3-acetyl-2-carboethoxy-indole, Y. Murakami, and others, Heterocvcles 22. 241 -244 (1984) and Y. Murakami, and others, Heterocvcles 14. 1939-1941 (1980) and p-chloride toluenesulfonyl to give the title compound.

PREPARATION 3 Furan-2-boronic acid According to the method of M.J. Arco and others, J. Org. Chem .. 41 2075-2083 (1976), combine furan (10 g, 147 mmol) and tetrahydrofuran (50 ml). Cool to -30 ° C. Add a solution of n-butyllithium (59 ml, 2.5 M in hexane, 147 mmol). After the addition is complete, heat the reaction mixture to -15 ° C. After 4 hours, add triisopropyl borate (56.4 g, 300 mmol) and warm to room temperature. After 24 hours, divide the reaction mixture by 0.5 m of an aqueous solution of hydrochloric acid and diethyl ester. Separate the organic layer, dry over MgSO1, filter and dry in vacuo to give a residue. Recrystallize the residue from water, filter and dry to give the title compound.

PREPARATION 4 Furan-3-boronic acid Cool a solution of n-butyllithium (25.4 ml, 2.5 M in hexane, 63. 6 mmole) at -78 ° C. Add a solution of 3-bromofuran (7.8 g, 53 mmol) in tetrahydrofuran (20 ml). After 10 minutes, add triisopropyl borate (20 g, 106 mmol) and heat to room temperature. After 24 hours, divide the reaction mixture by 0.5 M of an aqueous solution of hydrochloric acid and diethyl ether. Separate the organic layer, dry over MgSO 4, filter and dry in vacuo to give a residue. Recrystallize the residue from water, filter and dry to give the title compound.

PREPARATION 5 T-Butyl Diethylphosfonobromoacetate Combine sodium hydroxide (65 g, 1.6 moles) and water (195 ml). Cool to -10 ° C. Add bromine dropwise (142 ml, 0.81 mol) at such a rate that the reaction temperature did not increase above 0 ° C. Add t-butyl diethylphosphonoacetate (46.5 g, 184 mmol) at such a rate that the temperature of the reaction did not increase above 0 ° C. After 90 minutes, extract the reaction mixture 3 times with chloroform. Combine the organic layers and extract with water, dry over MgSO4, filter and evaporate in vacuo to give t-butyl diethylphosphonodibromoacetate. Combine t-butyl diethylphosphonomodibromoacetate (75.6 g, 184 mmol) and isopropanol (190 ml). Cool to 0 ° C. Add a solution of tin chloride (I I) (33.2 g, 175 mmol) in water (190 ml). After completing the addition, extract the reaction mixture three times with chloroform. Combine the organic layers and extract with water, dry over MgSO 4, filter and evaporate in vacuo to give the title compound.

PREPARATION 6 (E) v (Z) -2-Bromo-3- (1-p-toluenesulfonyl-2-carboethoxy-4,6-dichlorolndol-3-yl) propenoic acid t-butyl ester Combine t-butyl diethylphosphonibibromoacetate 45.4 g, 137 mmol) and tetrahydrofuran (550 ml). Cool to -78 ° C. Add dropwise a solution of lithium bis (trimethylsilyl) amide (137 ml, 1.0 M in tetrahydrofuran, 137 mmol). Add, in portions for 30 minutes, 3-formyl-1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindole (38.4 g, 87.2 mmol). After completing the addition, heat to room temperature. After 18 hours, add water and evaporate in vacuo to remove the tetrahydrofuran. Extract with dichloromethane. Dry the organic layer over MgSO 4, filter and evaporate in vacuo to give a residue. Recrystallize the powder from ethyl acetate / cyclohexane, filter and dry to give the (Z) isomer: mp 131-1 132 ° C. 1 H NMR (CDCl 3) d 8.21 (s, 1 H), 7.95 (m, 3 H), 7.30 (m, 3 H), 4.42 (q, 2 H, J = 7.2 Hz), 2.41 (s, 3 H), 1 .56 (s, 9H), 1 .36 (t, 3H, J = 7.15 Hz). Elemental analysis calculated for C 25 H 24 BrCl 2 NO 6 S: C, 48.64; H, 3.92; N, 2.26. It was found: C, 48.44; H, 3.90; N, 2.22. Apply chromatography a mixture of isomers (E) and (Z) on silica gel. Evaporate the early elution fractions to give a residue enriched in the (E) isomer. Recrystallize the residue from diethyl ether / pentane, and cool to -20 ° C to give the isomer (E) .1H NMR (CDCl3) d 7.99 (d, 1H, J = 1.7 Hz), 7.96 (d, 2H, J = 8.7 Hz), 7.50 (s, 1H), 7.33 (d, 2H, J = 8.7 Hz), 7.27 (d, 1H, J = 1.7 Hz), 4.42 (q, 2H, J = 7.2 Hz), 2.42 (s, 3H), 1.39 (t, 3H, J = 7.2 Hz), 1.00 (s, 9H).

PREPARATION 7 (Z) -2-Bromo-3-methyl-3- (1-p-toluenesulfonyl-2-carboethoxy-indol-3-ip) propenoic acid t-butyl ester Prepared by the method of Preparation 6 using 3-acetyl-1-p-toiuenesulfonyl-2-carboethoxy-indole to give the title compound.

EXAMPLE 1 Preparation of Acid. E) -2-.thien-3-n-3- (4,6-dichloroindol-3-yl-2-carboxylic acid) propenoic acid 1. 1 Synthesis of t-butyl acid ester -E) -2- .thien-3-yl) -3-M-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindol-3-ihpropenoic acid.

Combine tris (dibenzylideneacetone) dipalladium (0) (204 mg, 0.223 mmol) and tri- (fur-2-yl) phosphine (413 mg, 1.78 mmol) in tetrahydrofuran (60 mL). After 5 minutes, add (Z) -2-bromo-3- (1-p-toluenesulfonyl-2-carboethoxy) t-butyl ester., 6-dichloroindol-3-yl) propenoic acid (1.85 g, 3.0 mmol), thiophene-3-boronic acid (1.16 g, 9.2 mmol). Heat at 60 ° C. After 6 days, add thiophene-3-boronic acid (744 mg, 5.8 mmol), tri- (fur-2-yl) phosphine (206 mg, 0.887 mmol), tris (dibenzylideneacetone) -dipaladium (0) (102 mg, 0.111 mmol), and powdered potassium carbonate (800 mg, 5.80 mmol). After three more days, dilute the reaction mixture with cyclohexane (60 ml) and apply chromatography on silica gel eluting with 3/1 cyclohexane / ether to give the title compound. 1 H NMR (CDCl 3) d 7.94 (d, 1 H, J = 1.7 Hz), 7.74 (d, 2 H, J = 84 Hz), 7.72 (s, 1 H), 7.26 (d, 2 H, J = 8.0 Hz), 7.24 (d, 1H, J = 1.7 Hz), 7.03 (d, 1H, J = 4.4 Hz), 7.02 (d, 1H, J = 1.5 Hz), 6.77 (dd, 1H, J = 4.7, 1.6 Hz), 4.20 (q, 2H, J = 7.15 Hz), 2.40 (s, 3H), 1.55 (s, 9H), 1.28 (t, 3H, J = 7.15 Hz). 1. 2 Synthesis of (E) -2- (thien-3-in-3-M-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindol-3-yl) propenoic acid.

Combine (E) -2- (thien-3-yl) -3- (1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindol-3-yl) propenoic acid, t-butyl ester and trifluoroacetic acid (10) ml). After 45 minutes, evaporate in vacuo to obtain a residue. Dissolve the residue in ethyl acetate and extract with water. Evaporate the organic layer under vacuum to obtain a residue. Holder with pentane, which contains a small amount of ether, to give a solid. Recrystallize the solid from cyclohexane / ethyl acetate, filter, and dry to give the title compound: mp 197-200 ° C (dec); 1 H NMR (CDCl 3) d 8.00 (s, 1 H), 7.95 (d, 1 H, J = 1.7 Hz), 7.74 (d, 2 H, J = 8.5 Hz), 7.27 (d, 2 H, J = 8.5 Hz), 7.25 (d, 1H, J = 1.7 Hz), 7.08 (d, 1H, J = 2.8 Hz), 7.08 (d, 1H, J = 3.6 Hz), 6.81 (dd, 1H, J = 3.6, 2.8 Hz), 4.22 (q, 2H, J = 7.2 Hz), 2.40 (s, 3H), 1.28 (t, 3H, J = 7.2 Hz); 1 H NMR (DMSO-d 6) d 13.07 (br s, 1 H), 7.88 (d, 1 h, J = 1.7 Hz), 7.74 (d, 2 H, J = 8.4 Hz), 7.66 (s, 1 H), 7.57 (d , 1H, J = 1.7 Hz), 7.44 (d, 2H, J = 8.4 Hz), 7.27 (dd, 1H, J = 5.0, 2.9 Hz), 7.09 (dd, 1 H, J = 2.9, 1 .2 Hz ), 6.63 (dd, 1 H, J = 5.0, 1.2 Hz), 4.1 1 (q, 2H, J = 7.1 Hz), 2.36 (s, 3H), 1 .14 (t, 3H, J = 7.1 Hz). Elemental analysis calculated for C2SH? 9CI2NOßS2: Found: C, 52.80; H, 3.19; N, 2.29. 1. 3 Synthesis of (E) -2-ithien-3-in-3- (4,6-dichloroindon-3-yl-2-carboxylic-propenoic acid.

Combine (E) -2- (thien-3-yl) -3- (1-p-toluenesulfonii-2-carbo-ethoxy-4,6-dichloroindol-3-yl) propenoic acid (1.15 g, 2.03 mmol) ) and lithium hydroxide hydrate (288 mg, 6.86 mmol) in 1/1 tetrahydrofuran / water (22 ml). Heat to reflux. After four hours, cool to room temperature, evaporate in vacuo to remove most of the tetrahydrofuran, dilute with water, and acidify using an aqueous solution of sodium bisulfate. Extract with ethyl acetate. Dry the organic layer over MgSO 4, filter, and evaporate in vacuo to give a solid. Recrystallize the solid from cyclohexane / ethyl acetate / acetone, filter and dry under vacuum with heating to give the title compound: mp 228-232 ° C (dec). 1 H NMR (DMSO-d 6) d 13.3 (br s, 1 H), 12.8 (br s, 1 H), 12.24 (s, 1 H), 8.01 (s, 1 H), 7.37 (d, 1 H, J = 1.7 Hz), 7.20 (dd, 1H, J = 5.0, 3.0 Hz), 7.12 (d, 1H, J = 1.7 Hz), 7.03 (dd, 1H, J = 3.0, 1.2 Hz), 6.66 (dd, 1H, J = 5.0, 1.2 Hz). Analysis calculated for C 16 H 9 Cl 2 NO 4 S: Found: C, 50.01; H, 2.56; N, 3.57.

EXAMPLE 2 Preparation of (E) -2- (Thien-2-in-3- (4-dichloroindol-3-yl-2-carboxylic acid? Propenoic acid 2. 1 Synthesis of butyl ester of acid (E -2- (thien-2-in-3- (1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindol-3-yl) propenoic acid.

Combine tris (dibenzylideneacetone) dipalladium (0) (412 mg, 0.450 mmol) and tri- (fur-2-yl) phosphine (837 mg, 3.60 mmol) in tetrahydrofuran (60 ml). After 5 minutes, add (Z) -2-bromo-3- (1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindol-3-yl) propenoic acid t-butyl ester (1.85 g, 3.0 mmoles), thiophene-2-boronic acid (1.12 g, 9.20 mmol), and powdered potassium carbonate (1.27 g, 9.2 mmol). Heat at 60 ° C. After 8 days, dilute the reaction mixture with cyclohexane (120 ml) and apply chromatography on silica gel eluting with 3/1 cyclohexane / ether to give the title compound 1 H NMR (CDCl 3) d 7.97 (d, 1H, J = 1.7 Hz), 7.80 (d, 2H, J = 8.5 Hz), 7.64 (s, 1H), 7.27 (d, 2H, J = 8.5 Hz), 7.23 (d, 1H, J = 1.7 Hz), 7.16 (dd, 1H, J = 5.1, 1.2 Hz), 6.83 (dd, 1H, J = 3.7, 1.2 Hz), 6.75 (dd, 1H, J = 5.1, 3.7 Hz), 4.24 (q, 2H, J = 7.1 Hz), 2.39 (s, 3H), 1.57 (s, 9H), 1.26 (t, 3H, J = 7.1 Hz). 2. 2 Synthesis of (E) -2-ithien-2-in-3- (1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindol-3-yl) propenoic acid.

Combine (t) -2- (thien-2-yl) -3- (1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindol-3-yl) propenoic acid t-butyl ester, and formic acid ( 96%, 20 ml). After 2 hours, evaporate in vacuo to obtain a residue. Holder with pentane, which contains a small amount of diethyl ether to obtain a solid. Recrystallize the solid from cyclohexane / ethyl acetate / acetone, filter, and dry to give the title compound: mp 184-187 ° C (dec). 1 H NMR (DMSO-d 6) d 13.2 (br s, 1 H), 7.92 (d, 1 H, J = 1.7 Hz), 7.80 (d, 2 H, J = 8.4 Hz), 7.60 (s, 1 H), 7.57 (d , 1H, J = 1.7 Hz), 7.44 (d, 2H, J = 8.4 Hz), 7.40 (dd, 1H, J = 4.7, 1.5 Hz), 6.84-6.8 (m, 2H), 4.14 (q, 2H, J = 7.1 Hz), 2.37 (s, 3H), 1.13 (t, 3H, J = 7.1 Hz). Elemental analysis calculated for C25H19CI2NO6S2: C, 53.20; H, 3.39; N, 2.48. Found: C, 53.30; H, 3.40; N, 2.41. 2. 3 Synthesis of acid .E) -2- (t-ene-2-n-3-.4,6-dichloroindol-3-yl-2-carboxylic-propenoic acid.

Combine (E) -2- (thien-2-yl) -3- (1-p-toluenesulfonyl-2-carbo-ethoxy-4,6-dichloroindol-3-yl) propenoic acid (1.24 g, 2.20 mmol) lithium hydroxide hydrate (313 mg, 7.46 mmol) in 1/1 tetrahydrofuran / water (24 ml). Heat to reflux. After 4 hours, cool to room temperature, evaporate in vacuo to remove most of the tetrahydrofuran, dilute with water, and acidify using an aqueous solution of sodium bisulfate. Extract with ethyl acetate. Dry the organic layer over MgSO, filter and evaporate to give a solid. Recrystallize the solid from cyclohexane / ethyl acetate / acetone, filter and dry to give the title compound: mp 239-244 ° C (dec). 1 H NMR (DMSO-dβ) d 7.92 (s, 1H), 7.38 (d, 1H, J = 1.7 Hz), 7.28 (dd, 1H, J = 5.1, 1.2 Hz), 7.12 (d, 1H, J = 1.7 Hz), 6.87 (dd, 1H, J = 3.7, 1.2 Hz), 6.77 (dd, 1H, J = 5.1, 3.7 Hz). Elemental analysis calculated for C? ßH9Cl2NO4S: C, 50.28; H, 2.37; N, 3.65. It was found: C, 50.31; H, 2.58; N.3.51.

EXAMPLE 3 Preparation of (E) -2- (fur-2-ih-3- (4,6-dichloroindol-3-yl-2-propenoic acid carboxylic acid 3. 1 Synthesis of (E) -2- (fur-2-ih-3- (1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindol-3-yl) propenoic acid t-butyl ester.

Combine butyl ester of (Z) -2-bromo-3-1 - (1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindol-3-yl) propenoic acid ester (1 .00 g, 1.6 mmoles) ), furan-2-boronic acid (0.27 g, 2.4 mmol), and cesium carbonate (1.00 g, 3.2 mmol) in toluene (15 ml). Spray with nitrogen for 15 minutes. Add tetrakis (triphenylphosphine) α-aladium (O) (50 mg). Heat at 90 ° C. After 3 days, partition the reaction mixture between ethyl acetate and water. Separate the layers. Dry the organic layer over MgSO, filter and evaporate in vacuo to give a residue. Apply chromatography to the residue on silica gel eluting with 15% diethyl ether / hexane to give the title compound. 3. 2 Synthesis of (E) -2- (fur-2-yl) -3- (1-p-toluenesulfonyl-2-carbo-ethoxy-4,6-dichloroindol-3-ippropenoic acid.

Combine t-butyl ester of (E) -2- (fur-2-yl) -3- (1-p-toluensulfonyl-2-carbo-ethoxy-4,6-d icloroind or l-3-i) I) propenoic (12 mg, 0.19 mmol) and trifluoroacetic acid (2 ml) in dichloromethane (5 ml). After 2 hours, evaporate in vacuo, add dichloromethane and evaporate in vacuo to give the title compound. 3. 3 Synthesis of acid -E) -2- (fur-2-n-3- (4,6-dichloroindol-3-yl-2-carboxylic-propenoic acid.

Combine (E) -2- (fur-2-yl) -3- (1-p-toluenesulfonyl-2-carbo-ethoxy-4,6-dichloroindol-3-yl) propenoic acid (0.1 g, 0.18 mmol) and an aqueous solution of lithium hydroxide (2 ml, 1 M in water, 2 mmol) in tetrahydrofuran (2 ml). Heat to reflux. After 24 hours, cool to room temperature, dilute with water, and acidify using an aqueous solution of hydrochloric acid to give a solid. Filter, and dry under vacuum to give the title compound: mp 237-239 ° C (dec). 1H NRM (DMSO-d6) d 13.3 (bs, 1H), 12.95 (bs, 1H), 12.32 (s, 1H), 7.90 (s, 1H), 7.40 (d, 1H, J = 1.8 Hz), 7.29 ( dd, 1H, J = 1.7, 0.6 Hz), 7.12 (d, 1H, J = 1.8 Hz), 6.43 (d, 1H, J = 3.4 Hz), 6.3.1 (dd, 1H, J = 3.4, 1.8 Hz ).

EXAMPLE 4 Preparation of (E) -2- (fur-3-in-3- (4,6-dichloroindol-3-yl-2-carboxylic acid? Propenoic acid. 4. 1 Synthesis of (E) -2- (fur-3-iH-3- (1-p-toluenesulfonyl-2-carbo-ethoxy-4,6-dichloroindol-3-ippropenoic) t-butyl ester.

Prepare by a method similar to Example 3.1 using furan-3-boronic acid to give the title compound. 4. 2 Synthesis of acid. E) -2-.fur-3-yl. 3- (1-p-toluenesulfonyl-2-carbo-ethoxy-4-β-dichloroindol-3-yl) propenoic acid.

Prepare by a method similar to Example 3.2 using (E) -2- (fur-3-yl) -3- (1-p-toluenesulfonyl-2-carbo-ethoxy-4,6-dichloroindole) t-butyl ester. 3-yl) propenoic to give the title compound. 4. 3 Synthesis of (E) -2- (fur-3-n-3- (4,6-dichloroindol-3-yl-2-carboxylic-propenoic acid.

Prepare by a method similar to Example 3.3 using (E) -2- (fur-3-yl) -3- (1-p-toluenesulfonyl-2-carbo-ethoxy-4,6-dichloroindol-3-yl) propenoic acid. to give the title compound: mp 223-225 ° C (dec). 1 H NMR (DMSO-d 6) d 13.0 (bs, 2H), 12.35 (s, 1 H), 7.94 (s, 1 H), 7.48 (m, 1 H), 7.42 (d, 1 H, J = 1. 7 Hz), 7.34 (m, 1 H), 7.15 (d, 1 H, J = 1 .7 Hz), 5.77 (m, 1 H).

EXAMPLE 5 Preparation of (E) -2- (pyrid-3-yl) -3- (4,6-dichloroindol-3-yl-2-carboxylic acid propenoic acid. . 1 Synthesis of (Z) -2- (pyrid-3-n-3- (2-carboethoxy-4,6-dichloroindol-3-iDpropenon itryl.

Combi 2-carboethoxy-4,6-dichloroindole (1.43 g, 5.0 mmol), pyrid-3-yl-acetonitrile (0.59 g, 5.0 mmol), piperidine (0.2 ml) and ethanol (30 ml). Heat to reflux. After 16 hours, cool to room temperature. Add diethyl ether to give a solid. Filter, rinse with diethyl ether, dry, recrystallize from acetone / water, filter and dry to give the title compound: mp 233-234 ° C (dec). 1 H NMR (DMSO-d 6) d 12.41 (br s, 1 H), 8.86 (s, 1 H), 8.57 (d, 1 H, J = 1 Hz), 8.16 (s, 1 H), 7.94 (d, 1 H, J = 6.1 Hz), 7.41-7.36 (m, 1H), 7.41 (s, 1H), 7.06 (m, 1H), 4.30 (q, 2H, J = 7.05 Hz), 1.23 (t, 3H, J = 7.05 Hz) . . 2 Synthesis of (Z) -2- (pyrid-3-in-3-.4. Beta-dichloroindol-3-yl-2-carboxylic acid) acid imide) propenoic acid.

Combine (Z) -2- (pyrid-3-yl) -3- (2-carboethoxy-4,6-dichloroindol-3-yl) propenonitrile (0.5 g, 1.3 mmol), sulfuric acid (6 ml), acetic acid (6 tnl), and water (0.3 ml). Heat to approximately 80 ° C. After 16 hours, pour the reaction mixture over water to give a solid. Filter a solid and combine with lithium hydroxide (91.0 mg, 2.6 mmol) in tetrahydrofuran / water (1/1, 10 ml) and heat at 60 ° C. After 16 hours, filter the solid and recrystallize from acetone / water to give the title compound. 1 H NMR (300 MHz, DMSO-dβ) d 13.25 (s, 1 H, NH), 11.92 (s, 1 H, NH), 8.66 (m, 1 H), 8.57 (m, 1 H), 8.43 (s, 1 H), 7.91 (m, 1H), 7.57 (s, 1H), 7.45 (overlapping m, 2H). . 3 Synthesis of (E) -2-.pyrid-3-in-3-.4,6-dichloroindol-3-yl-2-carboxylic acid propenoic acid.

Combine acid (Z) -2- (pyrid-3-yl) -3- (4,6-dichloroindol-3-yl-2-carboxylic acid) propenoic acid (152 mg, 0.42 mmol), an aqueous solution of M sodium hydroxide (6 ml), and tetrahydrofuran (2 ml). Heat at 60 ° C. After 48 hours, cool the reaction mixture to room temperature and evaporate in vacuo to remove the tetrahydrofuran. Dilute the reaction mixture with water (20 ml) and acidify to a pH of 2 with an aqueous solution of 12 M hydrochloric acid to give a solid. Filter, rinse with water, and dry to give the title compound: mp 285-286 ° C (dec). 1 H NMR (300 MHz), DMSO-dβ) d 13.18 (br m, 2 H), 12.28 (s, 1 H), 8.26 (m, 1 H), 8.22 (s, 1 H), 8.09 (m, 1 H), 7.39 ( d, 1H, J = 1.8 Hz), 7.35 (s, 1H), 7.19 (overlapping m, 2H).

EXAMPLE 6 Preparation of (E) -2- (pyrid-3-in-3- (4,6-dichloroindol-3-yl-2-carboxylic acid) propenoic acid. 6. 1 Synthesis of (Z) -2- (pyrid-2-yl-3-.2-carboethoxy-4-β-dichloroindol-3-yl) propenonitrile.

Combine 2-carboethoxy-4,6-dichloroindole (1.43 g, 5.0 mmol), pyrid-2-yl-acetonitrile (0.59 g, 5.0 mmol), piperidine (0.2 mL), and ethanol (30 mL). Heat to reflux. After 16 hours, cool to room temperature. Add diethyl ether to give a solid. Filter, rinse with diethyl ether, dry, recrystallize from acetone / water, filter, and dry to give the title compound: mp 250-254 ° C (dec). 1H NMR (DMSO-d6) d 12.9 (br, s, 1H), 8.86 (s, 1H), 8.70 (d, 1H, J = 1 Hz), 8.00 (m, 1H), 7.82 (d, 1H, J = 7.2 Hz), 7.55 (s, 1H), 7.48 (m, 1H), 7.48 (m, 1H), 7.34 (s, 1H), 4.35 (q, 2H, J = 7.1 Hz), 1.25 (t, 3H) , J = 7.1 Hz). .2 Synthesis of acid imide (Z) -2- (pyrid-2-p -3- (4,6-dichloroindol-2-carboxylic acid propenoic acid.

Combine (Z) -2- (pyrid-2-yl) -3- (2-carboethoxy-4,6-dichloroindol-3-yl) propenenitrile (1.0 g, 2.6 mmol), sulfuric acid (15 mL), acetic acid (15 ml), and water (0.3 ml). Heat to approximately 80 ° C. After 16 hours, cool to room temperature and pour the reaction mixture into water (50 ml) to obtain a solid. Filter the solid, rinse with water. Recrystallize from acetone / water, filter, and dry to give the title compound as the sulfuric acid salt: mp >300 ° C. 1 H NMR (DMSO-d 6) d 13.47 (br s, 1 H), 12.14 (m, 1 H), 8.90-8.83 (m, 1 H), 8.83 (s, 1 H), 8.02 (d, 1 H, J = 7.7 Hz) , 7.81 (m, 1H), 7.60 (s, 1H), 7.43 (s, 1H), 7.48 (m, 1H), 7.34 (s, 1H). Combine the sulfuric acid salt with (Z) -2- (pyrid-2-yl) -3- (4,6-dichloroindol-3-yl-2-carboxylic acid) propene ico acid (285 mg, 0.65 mmole), lithium hydroxide (67 mg, 1.6 mmole), and tetrahydrofuran / water (1/1, 10 ml). Heat at 60 ° C. After 16 hours, filter, rinse with water, and dry to give the title compound. 6. 3 Synthesis of acid (E) -2-. pyrid-2-yl) -3- (4,6-dichloroindol-3-yl-2-carboly-xylene-propenoic acid.

Prepare by a method similar to Example 5.3 using (Z) -2- (pyrid-2-yl) -3- (4,6-dichloroindol-3-yl-2-carboxylic acid) propenoic acid imide (0.5 g, 1.3 mmole) to give the title compound.

EXAMPLE 7 Preparation of (E) -2- (pyrid-4-in-3- (4,6-dichloroindol-3-yl-2-carboxylic acid) propenoic acid. 7. 1 Synthesis of (Z) -2-.pyrid-4-n-3- (2-carboethoxy-4,6-dichloroindol-3-yl) propenonitrile.

Prepare by a method similar to Example 5.1 using pyrid-4-yl-acetonitrile hydrochloride salt and triethylamine to give the title compound: mp 265 ° C (dec). 1 H NMR (DMSO-dβ) d 11.97 (br s, 1 H), 8.74 (m, 3 H), 7.76 (d, 2 H, J = 4.7 Hz), 7.56 (s, 1 H), 7.39 (m, 1 H), 4.35 (q, 2H, J = 6.8 Hz), 1.24 (t, 3H, J = 6.8 Hz). .2 Synthesis of (Z) -2- (pyrid-4-yl) -3- (4,6-dichloroindol-yl-2-carboxylic acid) acid imide) propenoic acid.

Prepare by a similar method Example 5.2 using (Z) -2- (pyrid-4-yl) -2-carboethoxy-4,6-dichloroindol-3-yl) propenonitrile to give the title compound. 7. 3 Synthesis of (E) -2- (pyrid-4-yl) -3- (4,6-dichloroindol-3-yl-2-carboxylic-propenoic acid.

Prepare by a method similar to Example 5.3 using (Z) -2- (pyrid-4-yl) -3- (4,6-dichloroindol-3-yl-2-carboxylic acid) propenoic acid imide to give the Title.

EXAMPLE 8 Preparation of (E) -2- (thien-2-iM-3-methyl-3- (indol-3-yl-2-carboxylic acid) lycopropenoic acid. 8. 1 Synthesis of butyl ester of (E) -2- (thien-2-ih-3-methyl-3-M-p-toluenesulfonyl-2-carboethoxy-indol-3-yl) propenoic acid ester.

Prepare by the method of Example 2.1 using (Z) -2-bromo-3-methyl-3- (1-p-toluenesulfonyl-2-carbo-ethoxy-indol-3-yl) propenoic acid t-butyl ester to give the title compound. .2 Synthesis of (E) -2- (thien-2-yl) -3-methyl-3- (1-p-toluenesulfonyl-carboethoxy-indole-3-propanenoic acid.

Prepare by the method of Example 2.2 using (E) -2- (thien-2-yl) -3-methyl-3- (1-p-toluenesulfonyl-2-carboethoxy-indol-3-y) t-butyl ester. ) propenoic to give the title compound. 8. 3 Synthesis of (E) and (Z) -2-ftien-2-in-3-methyl-3- (indol-3-yl-2-carboxylic acid).

Prepare by the method of Example 2.3 using (E) and (Z) -2- (thien-2-yl) -3-methyl-3 - (- 1-p-toluenesulfonyl-2-carboethoxy-indol-3-yl) acid. ) propenoic to give the title compound.

The compounds of Formula (I) are excitatory amino acid antagonists. These antagonize the eff that excitatory amino acids have on the NMDA receptor complex. Preferentially they bind to the strychnine-insensitive glycine binding site on the NMDA receptor complex associated with the treatment of a number of disease states. See, Palfreyman, M. G. and B. M. Barón. Excitatori Amino Acid Antagonists. B.S. Meldrum Ed., Blackwell Scientific, 101-129 (1991); and, Kemp, J .A. , and P. D. Leeson, Trends in Pharmacological Sciences. 14. 20-25 (1993). The affinity for the strychnine-insensitive glycine binding site of the brain on the NMDA receptor complex can be determined in the following manner. Approximately 50 to 60 young male rats, Sprague-Dawley (strain C-D), were sacrificed by decapitation and their cerebral cortices and hippocampi were removed. The two regions of the brain were combined and homogenized in 15 volumes of 0.32 M of ice-cooled sucrose, using a Teflon glass homogenizer (10 steps at 400 rpm). The homogenates were centrifuged at 1000 x g. for 10 minutes and the supernatants were transferred and centrifuged again at 44,000 x g. during 20 minutes. The white upper part of the pellets was resuspended with a pipette in ice-cold water and homogenized with a polytron (setting 6 for 10 seconds) and centrifuged at 44.degree., 000 x g. during 15 minutes. The pellets were then resuspended in 6 volumes of water and placed in a dry ice / methanol bath until freezing, followed by thawing at 37 ° C in a shaking water bath. The freeze / thaw procedure is repeated and the final volumes of the suspensions were adjusted to 15 volumes with water and centrifuged at 44,000 x g. during 15 minutes. The resulting pellets were resuspended in 15 volumes of 10 mM H EPES-KOH (N-2-hydroxyethyl-piperazine-N'-2-ethanesulfonic acid-potassium hydroxide) at a pH of 7.4 containing 0.04% Triton X -100 (v / v), incubated at 37 ° C for 15 minutes and centrifuged at 44,000 x g. during 15 minutes. Then, the pellets were resuspended in 15 volumes in 10 mM H EPES-KOH at a pH of 7.4 with a polytron (setting 6 for 10 seconds) and centrifuged at 44,000 x g. during 15 minutes. Repeat this resuspension / centrifugation procedure twice more. Then, the membranes were resuspended in 3 volumes of 10 mM H EPES and stored frozen at -80 ° C. When the assay is to be performed, the membranes are thawed at room temperature and diluted with 9 volumes of 10 mM H EPES-KOH, pH 7.4, and incubated at 25 ° C for 15 minutes. This is followed by centrifugation at 44,000 x g. for 15 minutes, then resuspended with 10 mM HEPES-KOH at a pH of 7.4, using a polytron. The incubation / resuspension / centrifugation procedure was repeated two more times, and the final pellet was resuspended in 6 volumes of 50 mM HEPES-KOH at a pH of 7.4. Incubation flasks in triplicate received 50 μL of 200 nM [3 H] -glycine, 50 μL of 1000 nM strychnine, 50 μL of various concentrations of the test compounds diluted with 50 mM HEPES-KOH at a pH of 7.4 , and 200 μL of membrane suspension (400 μg protein / aliquot) in a final volume of 0.5 ml. Incubations were performed at 4 ° C for 30 minutes, and were terminated by centrifugation at 46,000 x g. for 10 minutes. The supernatants were decanted and the pellets were rinsed rapidly with 2 ml of 50 mM H EPES-KOH, cooled with ice, to a pH of 7.4, then dissolved in 4 ml of Ready Protein (Beckman Instruments) and counted through of liquid scintillation spectrometry. The specific binding of [3 H] -glycine was measured as the minimum binding of total radioactivity that binds to the receptors in the presence of 0.1 mM M D-serine. The total membrane binding radioactivity is less than 2% of that added to the test bottles. Since these conditions limit the total binding to less than 10% of the radioactivity, the concentration of free ligand does not change appreciably during the assay. The results of this test are represented as an IC50, which is the molar concentration of a compound that causes a 50% bition of ligand binding.

Compound No. 1, is the compound of Example 1, (E) and (Z) -2- (thien-3-yl) -3- (4,6-dichloroindol-3-yl-2-carboxylic acid) propenoic; Compound No. 2, is the compound of Example 2, (E) and (Z) -2- (thien-2-yl) -3- (4,6-dichloroindol-3-yl-2-carboxylic acid) propenoic acid; Compound No. 3, is the compound of Example 3, (E) and (Z) -2- (fur-2-yl) -3- (4,6-dichloroindol-3-yl-2-carboxylic acid) propenoic; Compound No. 4 is the compound of Example 4, (E) and (Z) -2- (fur-3-yl) -3- (4,6-dichloroindol-3-yl-2-carboxylic acid ) propenoic. The compounds exhibit anticonvulsant properties and are useful in the treatment of major malignant attacks (epilepsy gravior), minor attacks, psychomotor attacks, autonomic attacks, etc.

One method to demonstrate its antiepileptic properties is through its ability to inhibit attacks that are caused by the administration of quinolinic acid. This test can be conducted in the following way. One group, containing ten mice, were administered 0.01-100 micrograms of the test compound, intracerebroventricularly, in a volume of 5 microliters of saline. A second control group, containing the same number of mice, was administered an equal volume of saline as a control. Approximately 5 minutes later, both groups were administered, intracerebroventricularly, 7.7 micrograms of quinolinic acid, in a volume of 5 microliters of saline. The animals were observed for 15 minutes for signs of tonic seizures. The control group will have a statistically higher regime of tonic attacks, than the one that will be in the test group. Another method to demonstrate the antiepileptic properties of these compounds is through their ability to inhibit audiogenic convulsions in DBA / 2J mice. This test can be conducted in the following way. Typically, a group of 6-8 male, audiogenic mice, DBA / 2J, were administered from about 0.01 micrograms to about 10 micrograms of the test compound to the lateral ventricle of the brain, or from about 0.1 milligrams to about 300 milligrams, intraperitoneally . A second group of mice were administered an equal volume of a saline control through the same route. Five minutes to 4 hours later, the mice were placed individually in glass containers and exposed to a sound of 1 10 decibels for 30 seconds. Each mouse was observed during exposure to sound for signs of attack activity. The control group will have a statistically higher incidence of attacks than the group receiving the test compound. The compounds of Formula (I) are useful to avoid or minimize damage, which nervous tissues contained within the CNS, suffer under exposure to either ischemic, traumatic or hypoglycemic conditions, including strokes or strokes, cardiovascular surgery , concussions, hyperinsulinemia, cardiac arrest, drowning, suffocation, and neonatal anoxic trauma. The compounds must be administered to the patient within 24 hours of the onset of the hypoxic, ischemic, traumatic, or hypoglycemic condition in order to minimize the damage to the CNS, which the patient will experience. The compounds of Formula (I) minimize or prevent damage to the CNS after ischemia. These anti-ischemic properties can be demonstrated by the ability of the compounds of Formula (I) to reduce the infarct volume in rats subjected to middle cerebral artery occlusion, as follows. Sprague-Dawley male rat rats were subjected to inclusion in the middle cerebral artery through an adaptation of the H method. Memezawa et al., Ischemia Penumbra in a Model of Reversible Meddle Brain Artery Occlusion in the Rat, Experimental Brain Research. 89, 65-78 (1992). The rat was anesthetized with halothane in a mixture of O2 and NO (ratio 1: 2) and a midline incision was made in the ventral region of the neck. An inherent venous catheter was placed in the jugular vein. Under a dissection microscope, the left common carotid artery was identified in its bifurcation in the external carotid artery and the external carotid artery. 2 ligatures were placed on the external carotid artery. The internal carotid artery was exposed far to the point of its bifurcation towards the intracranial internal carotid artery and the pterygopalatine artery. A small cut was made in the distant segment of the external carotid artery, and a 3-0 nylon monofilament was introduced into the lumen of the external carotid artery. Two ligatures, previously placed, were tightened around the monofilament. The external carotid artery was cut and reflected caudally, so that the monofilament was advanced towards the internal carotid artery, past the bifurcation of the distant internal carotid artery / pterygopalatine artery, and continuing towards the intranial segment of the internal carotid artery at a distance of 20 mm, at which point, the origin of the middle cerebral artery was occluded. The ligatures were tightened later and the wound closed. The compound or vehicle was only administered intravenously at a predetermined time of post-ischemia and the dosage can be single, multiple, or by continuous infusion. The animals were fed and given water, and allowed to survive for 24 hours. Before slaughter, the rat was weighed and given a battery of 4 neurological tests to measure muscle strength, behaviors, postural reflexes and sensory-motor integration, as described by C.G. Markgraf et al., Sensorimotor and Cognitive Consequences of Middle Cerebral Artery Occiusion in Rats, Brain Research. 575. 238-246 (1992). The animal was then decapitated, the brain removed, sliced into six sections and incubated in 2% 2,3,5-triphenyl tetrazolium chloride for 30 minutes, as described by K. Isayama et al., Evaluation of 2 , 3, 5-Triphenyltetrazolium Chioride Stains to Delineate Rat Brain Infarts, Stoke 22. 1394-1398 (1991). The infarct area is clearly visible. The area of infarction is determined through computer aided image analysis, for each of the six sections and integrated on the anterior-posterior part of the brain to produce the infarct volume. The mean + SE groups were determined for the infarct volume and for the four behavioral tests, and compared with the groups using ANOVA with orthogonal contraster. Another method for demonstrating the ability of the compounds of Formula (I) minimizes or prevents damage to the CNS after ischemia as follows: An adult male rat, weighing 200-300 g, was anesthetized with halothane in a mixture of O2 and NO (ratio 1: 2) and a midline incision was made in the ventral region of the neck. An inherent venous catheter was placed in the jugular vein. The common carotid artery was exposed and divided free from the vagus nerve and the cervical sympathetic nerves. A 4-0 silk suture ligature joined securely. The animal was placed in a constriction, so that the right side of the head looks up. The area was gummed with betadiene and then an incision was made through the skin and temporal muscle, in order to expose the skull. Care must be taken not to cut the Lagre vein that is visible through the muscle. Once the skull is exposed, the middle carotid artery can be seen through the skull. Using a Foredom microdrill with a 4 mm drill bit, a small hole (approximately 8 mm) was made in the skull directly above the middle carotid artery. After piercing through the skull, there usually exists a thin layer of skull that remains, which is carefully removed with fine forceps. Remove the dura, if required, away from the area directly above the middle carotid artery. Then, occlusion of the right middle cerebral artery was performed by electrocoagulation without damaging the brain. The middle cerebral artery was cauterized immediately away from the inferior cortical vein, then, a small piece of foam gel was placed in the area and the muscle and skin were sutured with 3-0 silk thread. The compound or vehicle was only administered intravenously at a predetermined post-ischemia time and the dosage can be single, multiple, or by continuous infusion. The animals were fed and given water, and allowed to survive for 24 hours. The animal was then decapitated, the brain removed, sliced into six sections and incubated in 2% 2,3,5-triphenyl tetrazolium chloride for 30 minutes, as described by K. Isayama et al., Evaluation of 2 , 3, 5- Triphenyltetrazolium Chioride Stains to Delineate Rat Brain Infarts, Stoke 22. 1394-1398 (1991). The infarct area is clearly visible. The area of infarction is determined through computer aided image analysis, for each of the six sections and integrated on the anterior-posterior part of the brain to produce the infarct volume. The mean + SE groups were determined for the infarct volume and for the four behavioral tests, and compared with the groups using ANOVA with orthogonal contrasts. The compounds are also useful in the treatment of neurodegenerative diseases such as Huntington's disease, Alzheimer's disease, senile dementia, glutaric acidemia type I, multiple infarct dementia, amyotrophic lateral sclerosis, and neuronal damage associated with uncontrolled attacks. The administration of these compounds to a patient, who experiences such conditions, will serve either to prevent the patient from experiencing another neurodegeneration or to reduce the rate at which neurodegeneration occurs. As is evident to those skilled in the art, the compounds will not correct any damage to the CNS that has already occurred as the result of any disease, physical injury, or lack of oxygen or sugar. As used in this application, the term "treat" refers to the ability of the compounds to avoid any damage or delay of the regime at which any additional damage occurs. The compounds exhibit an anxiolytic effect and thus are useful in the treatment of anxiety. These anxiolytic properties can be demonstrated by their ability to block distress vocalizations in rat pups. This test is based on the phenomenon that when a baby rat is removed from its bait, it will emit an ultrasonic vocalization. It was discovered that anxiolytic agents block these vocalizations. The test methods have been described by Gadner, C. R., Distress Vocalization in Rat Pups: A Simple Screening Method for Anxiolytic Drugs, J ^ Pharmacol. Methods. 14. 181 -87 (1996) and Insel et al., Rat Pup Isolation Calis: Possible Mediation by the Benzodiazepine Receptor Complex, Pharmacol. Biochem. Behav .. 24. 1263-67 (1986). The compounds also exhibit an analgesic effect and are useful for controlling pain. The compounds are also effective in the treatment of migraine. In order to exhibit these therapeutic properties, the compounds need to be administered in an amount sufficient to inhibit the effect that the excitatory amino acids have on the NMDA receptor complex. The dosage scale, at which these compounds exhibit this antagonistic effect, can vary widely depending on the disease to be treated, the severity of the patient's disease, the patient, the particular compound to be administered, the route of administration and the presence of other underlying disease states, etc. Typically, an effective dose of the compounds will vary from about 0.1 mg / kg / day to about 50 mg / kg / day, for any of the diseases or conditions listed above. Repetitive daily administration may be desirable, and will vary according to the conditions outlined above. The compounds of the present invention can be administered through a variety of routes. These are effective if they are administered orally. The compounds can also be administered parenterally (i.e., subcutaneous, intravenous, intramuscular, intraperitoneally or intrathecally). Using techniques well known in the art, pharmaceutical compositions can be made. Typically, a therapeutic amount of the compound will be mixed with a pharmaceutically acceptable carrier. For oral administration, the compounds can be formulated in solid or liquid preparations, such as capsules, pills, pills, troches, fusions, powders, suspensions, or emulsions. The liquid unit dosage forms can be ordinary gelatin-type capsules containing, for example, surfactants, lubricants and inert fillers, such as lactose, sucrose and corn starch, or they can be sustained release preparations. In another embodiment, the compounds of Formula (I) can be formed as tablets, with conventional tablet bases, such as lactose, sucrose, and corn starch, in combination with binders, such as acacia, corn starch, or gelatin , disintegrating agents, such as potato starch or alginic acid, and a lubricant, such as stearic acid or magnesium stearate. Liquid preparations are prepared by dissolving the active ingredient in an aqueous or non-aqueous pharmaceutically acceptable solvent, which may also contain suspending agents, sweetening agents, flavoring agents and preservatives, as are known in the art. For parenteral administration, the compounds can be dissolved in a physiologically acceptable pharmaceutical carrier and administered either as a solution or as a suspension. Examples of suitable pharmaceutical carriers are water, saline, dextrose solutions, fructose solutions, ethanol, or oils of animal, vegetable or synthetic origin. The pharmaceutical vehicle may also contain preservatives, pH regulators, etc. , as is well known in the art. When the compounds are to be administered intrathecally, they can also be dissolved in cerebrospinal fluid, as is known in the art. The compounds of this invention can also be administered topically. This can be achieved by simply preparing a solution of the compound to be administered, preferably using a solvent known to promote transdermal absorption, such as ethanol or dimethyl sulfoxide (DMSO) with or without other excipients. Preferably, topical administration will be achieved using a patch of either a reservoir or porous membrane type, or a variety of solid matrix.

Some suitable transdermal devices are described in the patents of E.U.A. Nos. 3,742, 951; 3,797,494; 3,996,934; and 4, 031, 894. These devices generally contain a backing member, which defines one of its face surfaces, an adhesive layer permeable to the active agent defining the other face surface, and at least one reservoir containing the active agent, interposed between the surfaces of expensive. Alternatively, the active agent may be contained in a plurality of microcapsules distributed throughout the permeable adhesive layer. In any case, the active agent is continuously supplied from the reservoir or microcapsules through a membrane to the active agent permeable adhesive, which is in contact with the skin or mucosa of the container. If the active agent is absorbed through the skin, a controlled and predetermined flow of the active agent is administered to the container. In the case of microcapsules, the encapsulating agent can also function as the membrane. In another device for transdermally administering the compounds, according to the invention, the pharmaceutically active compound is contained in a matrix, from which it is delivered in the gradual, constant and controlled, desired regime. The matrix is permeable to the release of the compound through diffusion or microporous flow. The release is controlled in its speed. Said system, which does not require any membrane, is described in the patent of E. U.A. No. 3, 921, 636. At least two types of release are possible in these systems. Release by diffusion occurs when the matrix is non-porous. The pharmaceutically effective compound dissolves in and diffuses through the same matrix. Release by microporous flow occurs when the pharmaceutically effective compound is transported through a liquid phase in the pores of the matrix. Since the invention has been described together with its specific embodiments, it will be understood that it is capable of other modifications, and this application is intended to cover any variations, uses or adaptations of the invention, following, in general, the principles of the invention and including such outputs of the present disclosure so as to enter into the known practice or of custom in the art. As used in this application: aa) the "patient" refers to blood-warm animals such as, for example, guinea pigs, mice, rats, cats, rabbits, dogs, monkeys, chimpanzees, and humans; bb) the term "treat" refers to the ability of the compounds to either decrease, alleviate, or reduce the progression of the patient's disease; ce) the term "neu-cogeneration" refers to a death or progressive disappearance of a population of nerve cells that occurs in a manner characteristic of a particular disease state and leads to brain damage. The compounds of Formula (I) can also be mixed with any inert vehicle and used in laboratory tests in order to determine the concentration of the compound within the serum, urine, etc. , of the patient, as is known in the art. Neurodegenerative diseases are typically associated with a loss of NMDA receptors. In this way, the compounds of Formula (I) can be used in diagnostic procedures to assist physicians with the diagnosis of neurodegenerative diseases. The compounds can be labeled with imaging agents known in the art, such as isotopic ions, and administered to a patient in order to determine whether the patient is exhibiting a reduced number of NMDA receptors and the rate at which said is occurring. lost.

Claims (5)

1. - A compound of the formula: wherein: Z is hydrogen or -CH3; X is represented by -OH, a physiologically acceptable ester, or a physiologically acceptable amide; Y is represented by -OH, a physiologically acceptable ester, or a physiologically acceptable amide; R is represented by from 1 to 3 substituents, independently selected from the group consisting of: hydrogen, C? -C4 alkyl, C? -C4 halogen alkoxy, -CF3, or -OCF3; G is a radical selected from the group, wherein: R2 is represented by 1 to 2 substituents, independently selected from the group consisting of: hydrogen or C? -C alkyl; R 3 is represented by 1 to 2 substituents, independently selected from the group consisting of: hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or halogen; and pharmaceutically acceptable addition salts thereof,

2. A compound according to claim 1, wherein Z is hydrogen.

3. A compound according to claim 2, wherein Ri is 4,6-dichloro. 4 - A compound according to claim 3, wherein X and Y are -OH. 5. The compound according to claim 1, wherein the compound is (E) or (Z) -2- (thien-3-yl) -3- (4,6-dichloro-indol-3-yl) acid. -2-carboxylic acid) propenoic and mixtures thereof. 6. The compound according to claim 1, wherein the compound is (E) or (Z) -2- (thien-2-yl) -3- (4,6-dichloro-indol-3-yl) acid. -2-carboxylic acid) propenoic and mixtures thereof. 7. The compound according to claim 1, wherein the compound is (E) or (Z) -2- (fur-2-yl) -3- (4,6-dichloro-indol-3-yl) acid. -2-carboxylic acid) propenoic and mixtures thereof. 8. The compound according to claim 1, wherein the compound is (E) or (Z) -2- (fur-3-yl) -3- (4,6-dichloro-indol-3-yl) -2-carboxylic acid) propenoic and mixtures thereof. 9 - The compound according to claim 1, wherein the compound is (E) or (Z) -2- (pyrid-3-yl) -3- (4,6-dichloro-indole-3-yl-) acid. 2- carboxylic acid) propenoic and mixtures thereof. 10. The use in the manufacture of a drug of the compound according to claim 1, for antagonizing the effects of excitatory amino acids by the N-MDA receptor complex. 1. The use in the manufacture of a drug of the compound according to claim 1, for the treatment of neurodegenerative diseases. 12 - The use in the manufacture of a drug of the compound according to claim 1, to avoid ischemic / hypoxic / hypoglycemic damage to brain tissue. 13. The use in the manufacture of a drug of the compound according to claim 1, for the treatment of anxiety. 1

4. The use in the manufacture of a drug of the compound according to claim 1, to produce an analgesic effect. 1

5. A pharmaceutical composition comprising a compound according to claim 1 in admixture with a pharmaceutically acceptable carrier.