MXPA99002983A - Nmda (n-methyl-d-aspartate) antagonists - Google Patents

Abstract

The present invention is new excitatory amino acid antagonists (herein referred to as compounds of formula (1)). These new antagonists are useful as NMDA (N-methyl-D-aspartate) antagonists.

Description

ANTAGON ISTAS OF NMDA (N-M ETI L-D-ASPARTATE) The present invention is directed to novel excitatory amino acid antagonists (hereinafter referred to as compounds of formula (1)). These new antagonists are useful as NMDA antagonists (N-methyl-D-aspartate) and preferably bind to the strychnine-insensitive glycine binding site in the NMDA receptor complex associated with the treatment of a number of immune states. diseases. Another aspect of the invention is directed to the use of compounds of formula (1) in the treatment of a number of diseases, as well as to pharmaceutical compositions containing these excitatory amino acid antagonists.

BRIEF DESCRIPTION OF THE INVENTION In accordance with the present invention, a new class of NMDA antagonists has been discovered, which is described by the formula ( 1 ) : N (01 J H; wherein X is hydroxy, forms with the adjacent C (O) a physiologically acceptable ester, or forms with the adjacent C (O) a physiologically acceptable amide; Y is hydroxy, forms with the adjacent C (O) a physiologically acceptable ester, or forms with the adjacent C (O) a physiologically acceptable amide; R is from 1 to 3 substituents independently chosen from the group consisting of hydrogen, C1-C alkyl, halogen CrC4 alkoxy, -CF3, and -OCF3; R, is selected from the group consisting of hydrogen and C! -C alkyl; R2 is a radical chosen from the group consisting of wherein R 3 is selected from the group consisting of hydrogen and C 1 -C 4 alkyl; R 4 is 1 to 2 substituents independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C alkoxy, halogen and -CF 3; R 5 is C 1 -C 4 alkyl, R 6 is C 1 -C 4 alkyl, R r is 1 to 2 substituents independently selected from the group consisting of hydrogen Ci-C alkyl, C 1 -C 4 alkoxy, halogen and -CF 3 , and pharmaceutically acceptable addition salts thereof.

As used in this application a) the term "C1-C 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, secbutyl, isobutyl, t-butyl and the like, b) the term "C?-C4 alkoxy" refers to a straight or branched chain alkoxy radical containing from 1-4 carbon atoms, such as such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, secbutoxy, isobutoxy, t-butoxy and the like, c) the term "halogen" refers to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, d) the term "physiologically acceptable ester" refers to any non-toxic ester or any prodrug that allows the compounds of this application to function as an NMDA antagonist; these physiologically acceptable esters may be chosen from, but are not limited to, compounds where X and Y can be independently represented by -OR8, -OCH OR8 or -O- (CH2) p-NR9R10I in which R8 is represented by C1-C1alkyl, phenyl, substituted phenyl or a phenylalkyl substituent, in which the phenyl ring may be optionally substituted , p is 2 or 3, R9 and R10 are each independently represented by a C! -C alkyl or together with the nitrogen atom to which they are attached they form a ring -CH2-CH2-Z1-CH2-CH2-, where Z is a bond, O, S or NR ,, in which Rn is hydrogen or alkyl of C, -C such rings include, but are not limited to, pipepdi, morpholino, thiomorphol, piperazmo, N-methylpiperazmo, or pyrro dmo, 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 chosen from, but are not limited to, compounds where X and Y can each be independently represented by -N R1 2 R13, R12 is represented by hydrogen or an alkyl of C ^ C », and R1 3 is represented by hydrogen, phenyl, substituted phenyl, phenylalkyl, or a C1-C4 alkyl, or R12 and R1 3 are taken together with the nitrogen atom to which they are attached to form a -CH2-C ring H2-Z2-CH2-CH2-, wherein Z2 is a bond, O, S, or NR14 in which R1 4 is hydrogen or C1-C4 alkyl, such rings include, but are not bound to, pipepdino , morpholmo, thiomorphol, piperazmo, N-methylpi perazmo, or pyrro dino, f) the term "phenyl" or "Ph" refers to a phenyl portion (C6H5) of the formula g) the term "feni substituted" refers to a phenyl portion of the formula which may have 1 to 3 substituents, Q ,, Q2, Q3 each independently chosen from the group hydrogen, halogens, alkyl of C? -C, alkoxy of C ^ Cs, -CF3, -OCF3, -OH, -CN, and -NO2 These substituents can be the same or different and can be located in any of the positions ortho, meta or para, h) the term "phenylalkyl substituent" or "phenylalkyl" refers to the following structure, - (CH2) m-C6HxZy, wherein m is an integer of 1-3 The phenyl ring may be substituted in the manner described in (g), i) the designation "vw -. *" refers to a ligature for which the stereochemistry is not designated j) as used in the preparations and examples, the term "mg" refers to milligrams, the term "g" is refers to grams, the term "kg" refers to kilograms, the term "mol" refers to moles, the term "ml" refers to milliliters, the term "L" refers to effers to liters, the term "° C" refers to degrees Celsius the term "mp" refers to the melting point, the term "dec" refers to decomposition, the term "R" refers to the retention factor, the term "M" refers to molar, the term "kg / cm2" refers to kilograms per square centimeter, the term "brine" refers to a saturated aqueous solution of sodium chloride, k) the term "pharmaceutically addition salts" "acceptable" refers to either an acid addition salt or a basic addition salt. The term "pharmaceutically acceptable acid addition salts" is intended to be applied to any non-toxic organic or inorganic acid addition salt of the base compounds represented by Formula (1) or any of its intermediates Illustrative inorganic acids, which form suitable salts, include hydrochloric, bromohydric, sulfuric and phosphoric acid and acid metal salts, such as monohydrogyl orthophosphate Sodium Acid and Potassium Acid Sulfate Illustrative organic acids, which form suitable salts include mono-, di-, and t-carboxylic acids Illustrative of such acids are, for example, acetic, glycolic, lactic, pyruvic, malonic, succinic acids glutpac, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymelic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, sahcyl, 2-phenoxybenzoic and sulfonic, such as p-toluenesulfonic acid, methane sulphonic acid and 2-hydroxyethane sulfonic acid Such salts may exist in either hydrated or substantially anhydrous form In general, the acid addition salts of these compounds are soluble in water and in vain hydrophilic organic solvents and which in comparison with their free base forms , generally show higher melting points The term "pharmaceutically acceptable basic addition salts" is intended to apply to any non-toxic organic or inorganic base addition salt of the compounds represented by the formula (1) or any of its intermediates Illustrative bases, which form suitable salts, include alkali metal hydroxides or alkanothermal metals such as sodium, potassium hydroxides , calcium, magnesium or barium, ammonia and aliphatic, cyclic or aromatic organic amines, such as methylamine, dimeththamine, tmethylamine and picoline The compounds of the formula (1) exist as geometric isomers Any reference in this application to one of the compounds of formula (1) means that it encompasses either a specific geometric isomer or a mixture of isomers. Specific isomers can be separated and recovered by techniques known in the art, such as chromatography, and selective crystallization As with any group of structurally related compounds which It has a particular generic utility, it is preferred n certain groups and configurations for the compounds of the formula (1) in their end use application. The preferred embodiments of the formula (1) are given below 1) Preferred are compounds wherein X is hydroxy, C, - ^ alkoxy, or NH2 2) More compounds are preferred wherein X is hydroxy, methoxy, ethoxy, or NH2 3) Compounds in which X is hydroxy, 4) compounds are preferred in which Y is hydroxy, C1-C4 alkoxy, or NH2 5) More compounds are preferred where Y is hydroxy, methoxy, ethoxy or NH2 6) Compounds where Y is hydroxy, 7) Preferred are compounds where R, is hydrogen, 8) Compounds where -NR, R2 is at the 3, 9 position are preferred. R2 is a radical selected from the group consisting of OO wherein R3, and R5 are as defined herein It is understood that more preferred embodiments of formula (1) may be selected by requiring one or more of preferred embodiments 1 to 9 of formula (1) or by reference to the examples given in the present illustrative examples of compounds encompassed by the formula (1) include the following. The examples are understood to encompass both the (E) -isomer and the (Z) -isomer of the compound and mixtures thereof This list is representative only and is not intended to mimic the scope of the invention in any way 2- (3-acetam-dofenyl) -3- (2-carboethoxy-4,6-d-chloro) methyl ester β-3-? l) -propene? co, methyl ester of 2- (3-prop? onam? dofen? l) -3- (2-carboethox? -4,6-d? chloro? ndol-3) methyl ester -? l) -propene? co, methyl ester of 2- (3-but? roam? dofen? l) -3- (2-carboethoxy? -4,6-d? chloro? ndol-3-? l) -propene? co, methyl ester of 2- (3-benzam? dofen? l) -3- (2-carboethox? -4,6-d? chloro? ndol-3? l) -propene? co acid, Methacrylic acid ester 2- (3- (N-carbomethoxyl amine) phenol) -3- (2-carboethoxy? -4,6-d? chloro? nd ol -3-? ) -propene? co, 2- (3- (N-carboet? lox? am? no) phen?) -3- (2-carboethoxy? -4,6-d? chloro? ndol-3) methyl ester -? l) -propene? co, methyl ester of 2- (3- (N-carboprop? lox? am? no) phen?) -3- (2-carboethoxy? -4,6-d? chloro? ndol-3-? l) -propene? co, 2- (3- (N-carboisopropyloxyamino) phenyl) -3- (2-carboethoxy? -4,6-d? chloro? ndol-3) methyl ester -? l) -propene? co, acid methyl ester 2- (3- (N-carbobut? Lox? Amino) phen? L) -3- (2-carboethoxy-4,6-d? Chloro? Ndol-3? L) -propene? Co, methyl ester of acid 2- (3-methersulphonamidophenyl) -3- (2-carboethoxy? -4,6-d? Chloro? Ndol-3? L) -propene? Co, methyl ester of 2- (3) acid -et? lsulfon? lam? dofen? l) -3- (2-carboethoxy? -4,6-d icio roí ndo l-3-? I) -propene? Co, methyl ester of 2- (3-prop? Lsulfon? Lam? Dofen? L) -3- (2-carboethox? -4,6-d? Chloro? Ndol-3-? L) -propene? co, 2- (3-but? lysulfon? lam? dofen? l) -3- (2-carboethox? -4,6-d? chloro? ndol-3-? l) -propene methyl ester Co, 2- (3-benzenesulfon? lam? dofen? l) -3- (2-carboethoxy? -4,6-d? chloro? ndol-3? l) -propene? -methyl ester, ester 2- (4-acetam-dofenyl) -3- (2-carboethoxy? -4,6-d? chloro? ndol-3? l) -propene? co acid methyl ester, 2- (2-methyl) methyl ester 4-benzamidophene) -3- (2-carboethoxy? -4,6-d? Chloro? Ndol-3-? L) -propene? Co, methyl ester of 2- (4- (N-carbomet ? lox? am? no) phen? l) -3- (2-carboethoxy? -4,6-d? chloro? ndol-3? l) -propene? co, methyl ester of 2- (4- ( N-carboethoxyamino) phenyl) -3- (2-carboethoxy? -4,6-d? Chloro? Ndol-3-? L) -propenoic acid 2- (4- (N-carboisopropyloxyamino) phenyl) methyl ester ) -3- (2-carboethoxy-4,6-d? Chloro? Ndol-3? L) -propenoic acid; 2- (4-Methylsulfone? lamidophenyl) -3- (2-carboethoxy-4,6-d? chloroindol-3? l) -propene? co-methyl ester, 2- (4-benzenesulfonyl) -methyl ester Dophenyl) -3- (2-carboethoxy-4,6-d? chloro? ndol-3? l) -propene? co, 2- (2-acetamidophenyl) -3- (2-carboethoxy) methyl ester 4,6-d? Chloro? Ndol-3-? L) -propene? Co, 2- (2-benzamidophen? L) -3- (2-carboethoxy-4,6-d? Chloro? Ndol) methyl ester -3-? L) -propene? Co, 2- (2- (N-carbomethaloxyamino) phenyl) -3- (2-carboethoxy? -4,6-d? Chloro? Ndol -3) methyl ester ?) -propene? co, 2- (2- (N-carboetheloxyamino) phenol) -3- (2-carboethoxy-4,6-d? chloro? ndol-3? ) -propene? co, 2- (2- (N-carboisopropyloxyamido) phenol) -3- (2-carboethoxy? -4,6-d? chloro? ndol-3-? l) methyl ester -propene? co; 2- (2-methylsulfon? lamidophenyl) methyl ester -3- (2-carboethoxy-4), 6-d? Chloro? Ndol-3-? L) -propene? Co, 2- (2-benzenesulfone? Lam? Dofen? L) methyl ester -3- (2-carboethoxy? -4,6-d) chloro? ndol-3-? l) -propene? co, ethyl ester of 2- (3-acetam? dofen? l) -3- (2-carboethox? -4,6-d? chloro? ndol) - 3-?) -propene? 2- (3-prop? Onam? Dofen? L) -3- (2-carboethoxy? -4,6-d? Chloro? Ndol-3? ) -propene? co, ethyl ester of 2- (3-but? roam? dofen? l) -3- (2-carboethoxy? -4,6-d? chloro? ndol-3-? l) -propene? co, 2- (3-benzamidopen?) -3- (2-carboethoxy? -4,6-d? chloro? ndol-3?) -propene? ethyl acid ethyl ester, ethyl ester of acid 2- (3- (N-carbomethoxyl amine) phenol) -3- (2-carboethoxy? -4,6-d? Chloro? Ndol-3-? L) -propene? Co, ester Ethyl 2- (3- (N-carboet? lox? am? no) phen?) -3- (2-carboethoxy? -4,6-d? chloro? ndol-3-? l) -propene? co, 2- (3- (N-carboprop? lox? am? no) phen?) -3- (2-carboethoxy? -4,6-d? chloro? ndol-3-? l) ethyl ester -propene? co, ethyl ester of 2- (3- (N-carbo? soprop? lox? am? no) phen? l) -3- (2-carboethoxy? -4,6-d? chloro? ndol- 3-? L) -propene? Co, ethyl ester of 2- (3- (N-carbobut? lox? am? no) phen?) -3- (2-carboethoxy? -4,6-d? chloro? ndol-3-? l) -propene Co, ethyl ester of 2- (3-methylsulfonyl lamofenyl) -3- (2-carboethoxy? -4,6-d? chloro? ndol-3? l) -propene? ethyl ester of 2- (3-et? lsulfon? lam? dofen? l) -3- (2-carboethoxy? -4,6-d? chloro? ndol-3? l) -propene? co ester ethyl acid 2- (3-prop? lsulfon? lam? dofen? l) -3- (2-carboethoxy? -4,6-d? chloro? ndol-3? l) -propene? co, ethyl ester of 2- (3-Butyl? sulfon? lam? dofen?) -3- (2-carboethoxy? -4,6-d? chloro? ndol-3-? l) -propene? co acid ethyl ester 2 - (3-benzenesulfon? Lam? Dofen? L) -3- (2-carboethoxy? -4,6-dichloroindo l-3-? l) -propene? co, ethyl ester of 2- (4-acetam? dofen? l) -3- (2-carboethoxy? -4,6-d? chloro? ndol-3-? l) -propene? , ethyl ester of 2- (4-benzamidopen?) -3- (2-carboethoxy? -4,6-d? chloro? ndol-3-? l) -propene? co acid ethyl ester 2 - (4- (N-carbomethoxyl amine) phenol) -3- (2-carboethoxy? -4,6-d? Chloro? Ndol-3? L) -propene? Co, ethyl ester 2- (4- (N-carboet? lox? am? no) phen?) -3- (2-carboethoxy? -4,6-d? chloro? ndol-3? l) -propene? , ethyl ester of 2- (4- (N-carbo? soprop? lox? am? no) phen? l) -3- (2-carboethoxy? -4,6-d? chloro? ndol-3? ) -propene? co, ethyl ester of 2- (4-meth? lsulfone? lam? dofeml) -3- (2-carboethoxy? -4,6-d? chloro? ndol-3-? l) -propene? co, 2- (4-benzenesulfon? lam? dofen? l) -3- (2-carboethoxy? -4,6-d? chloro? ndol-3? l) -propene? ethyl ester, ethyl ester 2- (2-Acetam-Dophenol) -3- (2-carboethoxy? -4,6-d? chloro? ndol-3-? l) -propene? co acid, 2- (2-ethyl) ethyl ester -benzam? dofen?) -3- (2-carboethoxy? -4,6-d? chloro? ndol-3-? l) -propene? co, ethyl ester of 2- (2- (N-carbo methoxyl amine) phenol) -3- (2-carboethoxy? -4,6-d? chloro? ndol-3? l) -propene? co, 2- (2-ethyl) ethyl ester (N-carboet? Lox? Am? No) phen? L) -3- (2-carboethoxy? -4,6-d? Chloro? Ndol-3? L) -propene? Co, ethyl ester of 2-acid (2- (N-carbo? Soprop? Lox? Am? No) phen? L) -3- (2-carboethoxy? -4,6-d? Chloro? Ndol-3? L) -propene? Co, ester Ethyl acid 2- (2-methylsulfon? lam? dofen? l) -3- (2-carboethoxy? -4,6-d? chloro? ndol-3-? l) -propene? co, ethyl ester of 2- (2-benzenesulfone? lam? dofen? l) -3 - (2-carboethoxy? -4,6-d? Chloro? Ndol-3? L) -propene? Co, 2- (3-acetam? Dofen? L) -3- (4,6-d? Chloro) β-3-α-2-carboxylic acid) -propenoic acid 2- (3-prop? onam? dofen? l) -3- (4,6-d? chloro? ndol-3? -2-carboxylic acid) -propenoic acid, 2- (3-butyloam? Dofen? L) -3- (4,6-d? Chloro? Ndol-3? L-2-carboxylic acid) ) -propenoic acid, 2- (3-benzamidoben?) -3- (4,6-d? chloro? ndol-3? l-2-carboxylic acid) -propenoic acid, 2- (3-benzamido) acid - (4-methox? Benzamido) phen? L) -3- (4,6-d? Chloro? Ndol-3? L-2-carboxy? Co) -propene? Acid 2- ( 3- (4-chlorobenzamido) phen? L) -3- (4,6-d? Chloro? Ndol-3? L-2-carboxy? -acetic acid) -propene? Acid 2- (3- (4-met? Lbenzamide) phen? L) -3- (4,6-d? Chloro? Ndol-3? L-2-carboxy? Co) -propene? Acid 2 - (3- (4-fl uorobenzamido) phen? L) -3- (4,6-d? Chloro? Ndol-3? L-2-carboxy? -acetic acid) -propene? 2- (3- (4-tr? f or orobenzamido) phenol) -3- (4,6-d? chloro? ndol-3? l-2-carboxy? co) -propene? co 2- (3- (N-carbomet? lox? am? no) phen?) -3- (4,6-d? chloro? ndol-3? l-2-ac? do carboxyl? co) -propene? co, 2- (3- (N-carboet? lox? am? no) phen? l) -3- (4,6-d? chloro? ndol-3? l-2-carboxy? co-acid) -propene? co, 2- (3- (N-carboprop? lox? am? no) phen? l) -3- (4,6-d? chloro? ndol-3-? l-2-ac? o) carboxyl? co) -propene? co, 2- (3- (N-carbo? soprop? lox? am? no) phen? l) -3- (4,6-d? chloro? ndol-3-? l- 2-carboxylic acid) -propene? Co, 2- (3- (N-carbobut? Lox? Am? No) phen?) -3- (4,6-d? Chloro? Ndol) -3-? L-2-carboxylic acid? Co) -propene? Acid 2- (3-methylsulfon? Lam? Dofen? L) -3- (4,6-d? Chloro? Ndol-3) (2-carboxylic acid) -propene-2- (3-ethersulphonamidophenol) -3- (4 6-d? chloro? ndol-3-? l- 2-carboxylic acid) -propene-co-acid 2- (3-prop? Lsulfon? Lam? Dofen? L) -3- (4,6-d? Chloro? Ndol-3-? L-2 -acetic carboxylic acid) -propene-2- (3-butylsulphonamidophenol) -3- (4,6-d? chloro? ndol-3? -l-2- acid carboxy? co) -propene? co acid 2- (3-benzenesu-lone? lam? dofen? l) -3- (4,6-d? chloro? ndol-3? l-2-ac? do carbox ? -co? -propene? co-acid 2- (3- (4-methoxy? benzenesulfon? lam? do) phen? l) -3- (4,6-d? chloro? ndol-3? l-2 carboxylic acid) -prop eno? co, acid 2- (3- (4-chloro benzenesulfone? lam? do) phen? l) -3- (4,6-dioxide ro? ndol-3? l-2-acido ca rbox? l? co) -prope no? co am ida of acid 2- (3-acetam? dofen? l) -3- (4,6-d? chloro? ndol-3? l-2-ác? do carboxíl? co) -propene? co, 2- (3-prop? onam? dofen? l) -3- (4,6-d? chloro? ndol-3? l-2-carboxylic acid amide) ) -propene? co, 2- (3-but? roam? dofen? l) -3- (4,6-d? chloro? ndol-3? l-2-carboxylic acid amide) -propene? co, 2- (3-benzam? dofen? l) -3- (4,6-d? chloro? ndol-3? l-2-carboxy? co) -propene acid amide? co, 2- (3- (4-methox? benzamido) -amino acid) -3- (4,6-d? chloro? ndol-3? l-2-carboxylic acid? co) - propene? co, 2- (3- (4-chlorobenzamido) phenol) -3- (4,6-d? chloro? ndol-3? l-2-carboxylic acid? propene? co, 2- (3- (4-met? lbenzamide) femido) -3- (4,6-d? chloro? ndol-3? l-2-carboxylic acid amide) co) - propene? co, 2- (3- (4-fluorobenzamido) phenol) -3- (4,6-d? chloro? ndol-3? l-2-carboxylic acid amide) co) - propene? co, 2- (3- (4-trifluorobenzamido) phenol) -3- (4,6-d? chloro? ndol-3? l-2-carboxylic acid amide) ) -propene? co, acid amide 2- (3- (N -carbomet? lox? am? no) phenol) -3- (4,6-d? chloro? ndol-3? -l-2-carboxylic acid) -propene? co, ammonium acid 2- (3- (N-? carboet? lox? am? no) phen? l) -3- (4,6-d? chloro? ndol-3? l-2-carboxylic acid? co) -propene? co, 2- (3 - (N-carboprop? Lox? Am? No) phen? L) -3- (4,6-d? Chloro? Ndol-3? L-2-ac? Do ca rbox? co?) -propene? co, 2- (3- (N-carbo? soprop? lox? am? no) phenol) -3- (4,6-d? chloro? ndol-3) (2-carboxylic acid) -propene? co, 2- (3- (N-carbobutyloxamino) phenyl) -3- (4,6-d? chloro? ndol-) acid amide 3-? L-2-carboxylic acid? Co) -propene? Co, 2- (3-meth? Lsulfon? Lam? Dofen? L) -3- (4,6-d? Chloro? Ndol-3) acid amide -? - 2-carboxylic acid? -propene? co, 2- (3-et? lsulfone? lam? dofen?) acid amide -3- (4,6-d? chloro? ndol-? 3-? L-2-carboxy? Co-acid) -propene? Co, 2- (3-prop? Lsulfon? Lam? Dofen?) Acid amide) -3- (4,6-d? Chloro? Ndol) -3-? L-2-carboxylic acid? Co) -propene? Co, 2- (3-but? Lysulfon? Lam? Dofen? L) -3- (4,6-d? Chloro? Ndol-) acid amide 3- (2-carboxylic acid) -propene, 2- (3-benzenesulfonyl-lamethofenyl) -3- (4,6-d? Chloro? Ndol-3) acid amide -? l-2-carboxylic acid? co) -propene? co, amido of 2- (3- (4-methox? benzenesulfon? lam? do) phen?) -3- (4,6-d? chloro? ndol-3-? l-2-carboxy? co-acid) -propene? co, 2- (3- (4-chlorobenzenesulfoan? lam? do) phen?) -3- (4, 6-di chloro indo l-3-? L-2-ac rboxyl? co) -propene? co, 2- (4-acetam? dofen? l) -3- (4,6-d? chloro? ndol-3? l-2-carboxylic acid) -propenoic acid 2- (4-proponase? dofen? l) -3- (4,6-d? chloro? ndol-3-? l-2-carboxylic acid) -propenoic acid 2- (4-but? roam? d ofen? l) -3- (4,6-d? chloro? ndol-3-? l-2-carboxylic acid) -pro pen oi co 2- (4-benzam? dofen? l) -3- (4,6-d? Chloro? Ndol-3-? L-2-carboxylic acid) -propenoic acid, 2- (4- (N-carbomet? Lox? Am? No) phen? L) -3- (4,6-d? Chloro? Ndol-3? L-2-carboxy? Co) -propene? Co, 2- (4- (N-carboet? Lox? Am? No) acid) fen? l) -3- (4,6-d? chloro? ndol-3? l-2-carboxy? co) -propene? co, 2- (4- (N-carboprop? lox? am? no) phen? l) -3- (4,6-d? chloro? ndol-3? l-2-carboxy? co) -propene? co, 2- (4- (N-? carbo? soprop? lox? am? no) fen? l) -3- (4, 6-d? Chloro? Ndol-3? -l-2-carboxylic acid) -propene? Co, 2- (4-met? L sulfon? Lam? Dofen? L) -3- ( 4,6-d? Chloro? Ndol-3? L-2-carboxylic acid) -propene? Co, 2- (4-benzenesulfon? Lam? Dofen? L) -3- (4 , 6-d? Chloro? Ndol-3-? L-2-carboxylic acid) -propene? Co, 2- (2-acetam? Dofen? L) -3- (4,6- d? chloro? ndol-3-? l-2-carboxylic acid) -propenoic acid, 2- (2-benzam? dofen? l) -3- (4,6-d? chloro? ndol-3? l-2-carboxylic acid) -propenoic acid, 2- (2- (N-carbomethaloxamino) phen? l) -3- (4,6-d? chloro? ndol-3? l-2-carboxylic acid) -propene? 2- (2- (N-carboet? lox? am? no) phen?) -3- (4,6-d? chloro? ndol-3-? l-2-carboxylic acid) -propene? co, 2- (2- (N-carboprop? lox? am? no) phen?) -3- (46- d? chloro? ndol-3-? l-2-carboxylic acid) -propene? 2- (2- (N-carbo? soprop? lox? am? no) phen? l) - 3- (4,6-d? Chloro? Ndol-3-? L-2-carboxy? Co-acid) -propene? Co, 2- (2-methylsulfon? Lam? Dofen? L) -3 acid - (4,6-d? Chloro? Ndol-3? L-2-carboxy? Co-acid) -propene? Co, 2- (2-benzenesulfone? Lam? Dofen? L) -3- (4 , 6-d? Chloro? Ndol-3-? L-2-ac? Ca rboxyl? co) -propene? co, 2- (3-acetam? dofen? l) -3- (5,6-d? chloro? ndol-3? l-2-carboxylic acid) -propenoic acid, 2- (3-benzamidopen?) -3- (5,6-d? chloro? ndol-3-? l-2-carboxylic acid) -propenoic acid, 2- (3- (N-) acid carbomethoxyl amine) phenol) -3- (5,6-d? chloro? ndol-3-? l-2-carboxy? co) -propene? co, 2- (3 - (N-carboet? Lox? Am? No) phen? L) -3- (5,6-d? Chloro? Ndol-3? L-2-carboxy? Co) -propene? Acid 2 - (3- (N-carboprop? Lox? Am? no) phenol) -3- (5,6-d? chloro? ndol-3-? l-2-carboxy? -acetic acid) -propene? co, 2- (3- (N-? carbo? soprop? lox? am? no) phen? l) -3- (5,6-d? chloro? ndol-3? l-2-carboxyl? -acetic acid) -propene? co, acid 2- (3-methersulfon-lame-dofen?) -3- (5,6-d? Chloro? Ndol-3? L-2-carboxylic acid) -propene? Acid 2 - (3-benzenesu lfon? Lam? Dofen? L) -3- (5,6-d? Chloro? Nd ol -3? L-2-carboxyl? -acetic acid) -propene? Acid 2 - (3-acetam-dofen? L) -3- (6-chloro-ndol-3-? L-2-carboxylic acid) -propenoic acid 2- (3-benzam? Dofen? L) -3- ( 6-d? Chloro? Ndol-3-? L-2-carboxylic acid) -propenoic acid, 2- (3- (N-carbomet? Lox? Am? No) phen?) -3- (6 - d? cioro? ndol-3-? l-2-ác? do carboxíl? co) -propeno? co, acid 2- (3- (N-carboet? lox? am? no) fen? l) -3- (6-d? Chloro? Ndol-3-? L-2-carboxy? Co-acid) -propene? Co, 2- (3- (N-carboprop? Lox? Am? No) phen?) - 3- (6-d? Chloro? Ndol-3-? L-2-carboxy? Co) -propene? Co, 2- (3- (N-carbo? Soprop? Lox? Am? No) phen (l) -3- (6-d? chloro? ndol-3-? l-2-carboxy? co) -propene? co, 2- (3-met? l sulfone? lam? dofen? l) - 3- (6-d? Chloro? Ndol-3-? L-2-carboxylic acid) -propene yl, 2- (3-benzenesulfone? Lam? Dofen? L) -3- (6-d) chloro-3-dol-2-carboxylic acid) -propene oi co, 2- (3-acetam-dofen? l) -3- (? ndol-3-? l-2-) acid acid carboxy? co) -propene? co, 2- (3- (N-carbomet? lox? am? no) phen?) -3- (? ndol-3-? l-2-ac? carboxylic acid) -propenoic acid 2- (3-met? lsulfon? lam? dofen? l) -3- (? ndol-3-? l-2-carboxylic acid) -propenoic acid 2- (3-benzenesu lfon? lam? dofen? l) -3- ( carboxylic acid-3- (2-carboxylic acid) -propenoic acid 2- (3-acetam-dodene) -3- (7-et? l-5-bromo? ndol-3-? l- 2-carboxylic acid) -propenoic acid 2- (3-benzamidophene) -3- (7-et? L-5-bromo? Ndol-3-? L-2-ac? Do carboxy l ico) -propen oi co 2- (3- (N-carbomet? lox? am? no) phen? l) -3- (7-et? l-5-bromo? ndol-3-? l- 2-carboxylic acid) -propene? Co, 2- (3- (N-carboet? Lox? Am? No) phen?) -3- (7-et? L-5-bromo? ndol-3-? l-2-carboxy? co-acid) -propene? co, 2- (3- (N-carboprop? lox? am? no) phen?) -3- (7-et? l-5-bromo? ndol-3-? l-2-carboxylic acid) -pro pentao, 2- (3- (N-carbo? soprop? lox? am? no) phen? l ) -3- (7-et? L-5-bromo? Ndol-3? L-2-carboxylic acid? Co) -propene? Co, 2- (3-met? L sulfone? Lam? Dofen? L) -3- (7-et? L-5-bromo? Ndol-3-yl-2-carboxylic acid? Co) -propene? Co, 2- (3-benzenesu lfon? Lam? Dofen? L) -3- (7-et? L-5-bromo? Ndol-3-? L-2-carboxylic acid) -prope no ico acid 2- (3 -acetam? dofen?) -3- (5-et? l-7-bromo? ndol-3-? l-2-carboxylic acid) -propenoic acid, 2- (3-benzam? dofen? l) -3- (5-et? l-7-bromo? ndol-3-? l-2-carboxylic acid) -propene? co, 2- (3- (N-carbomethoxyl) ? am? no) phen? l) -3- (5-et? l-7-bromo? ndol-3-? l-2-carboxylic acid) -pro pentanec, acid 2- ( 3- (N-carboet? Lox? Am? No) phen? L) -3- (5-et? l-7-bromo? ndol-3-? l-2-ác? do carbox? l? co) -propene? 2- (3- (N-carboprop? lox? am? no) phen? l) -3- (5-et? l-7-bromo? ndol-3-? l-2-carboxy I acid) ico) -pro peno i coacid 2- (3- (N-carbo? soprop? lox? am? no) phen? l) -3- (5-et? l-7-bromo? ndol-3-? l-2-acid or carboxyl) -prope no? co, 2- (3-meth? lsulfone? lam? dofen? l) -3- (5-et? l-7-bromo? ndol-3-? l-2-carboxylic acid) -propene ico acid , 2- (3-benzenesulfoan? lam? dofen? l) -3- (5-et? l-7-bromo? ndol-3-? l-2-carboxylic acid) -pro penoic acid, 2- (3-Acetam-Dophenol) -3- (5-fluoro-7-chloro-n-dol-3-l-2-carboxylic acid) -prope no ico, acid 2- ( 3-benzamidoben?) -3- (5-fluoro-7-chloro-n-dol-3-l-2-carboxylic acid) -propene? Co, 2- (3- (N-) acid -carbomet? lox? am? no) phen? l) -3- (5-fluoro-7-chloro? ndol-3? l-2-carboxylic acid? co) -propene? co, 2- (3- (N-carboet? Lox? Am? No) phen? L) -3- (5-fluoro-7-chloro? Ndol-3? L-2-carboxylic acid) -propene? Co, acid 2- (3- (N-carboprop? Lox? Am? No) phen? L) -3- (5-fluoro-7-chloro? Ndol-3-tl-2-carboxylic acid? Co) -propene? Co, 2- (3- (N-carbo? soprop? lox? am? no) phen? l) -3- (5-fluoro-7-chloro? ndol-3? l-2-carboxylic acid? co) - propene? - 2- (3-methylsulfon? lam? dofen? l) -3- (5-fluoro-7-chloro? ndol-3? l-2-ac? do carbox? l? co) - propene? co 2- (3-benzenesu lfon? lam? dofen? l) -3- (5-fluoro-7-c) parol? ndol-3-? l-2-carboxylic acid) -propene? acid 2- (3-acetam? dofen? l) -3- (7-fl uoro-5-chloro? ndol -3-? L-2-ác? Do carbox? l-co) -propene-co-acid 2- (3-benzam-dofen? l) -3- (7-fluoro-5-chloro-ndol-3-? l-2-ac? do carbox? l? co) -propene? 2- (3- (N-carbomethaloxamino) phenol) -3- (7-fluoro-5-chloro-ndol-3-? l-2-carboxylic acid? co) -propene Co, 2- (3- (N-carboet? lox? am? no) phen? l) -3- (7-fluoro-5-chloro? ndol-3? l-2-carboxylic acid) ? co) -propene? co, 2- (3- (N-carboprop? lox? am? no) phen?) -3- (7-fl uoro-5-chloro? ndol-3-? l-2) -carboxylic acid? co) -propene? co, 2- (3- (N-carbo? soprop? lox? am? no) phen? l) -3- (7-fluoro-5-chloro? ndol-3) l-2-carboxylic acid? co) -propene? co, 2- (3-methylsulfon? lam? dofen? l) -3- (7-fluoro-5-chloro? ndol-3-? l- 2-carboxy acid? Co) -propene? Co, 2- (3-benzenesulfan? Lam? Dofen? L) -3- (7-fluoro-5-chloro? Ndol-3-? L-2-ac carboxy? co) -propene? co, 2- (3-acetam? dofen? l) -3- (5,7-d? bromo? ndol-3? l-2-carboxylic acid) ) -propenoic acid, 2- (3-benzamidopen?) -3- (5,7-d? bromo? ndol-3-? l-2-carboxy-co-carboxy) -propenoic acid, 2- ( 3- (N-carbomethoxyl? No) phen? L) -3- (5 7-d? Bromo? Ndol-3? L-2-carboxylic acid) -propene? acid 2- (3- (N-carboet? lox? am? no) phen? l) -3- (5J-d? bromo? ndol-3-? l-2-ac? rboxyl? co) -propene? co-acid 2- (3- (N-carboprop? lox? am? no) phen? l) -3- (5 7-d? bromo? ndol-3-? l-2-ác? do carbox? co?) -propene? acid 2- (3- (N-carbo? soprop? lox? am? no) phen? l) -3- (5,7-d? bromo? ndol-3-? l- 2-carboxylic acid) -pro pe no? Co, 2- (3-methylsulfonylamidophenyl) -3- (5J-di bromoindol-3-yl-2-carboxylic acid) -propenoic acid; 2- (3-benzenesulfonylamidophenyl) -3- (5J-dibromoindol-3-yl-2-carboxylic acid) -propenoic acid.

A general synthetic process for preparing these compounds of formula (1) is set forth in Reaction Scheme 1. In Reaction Scheme 1, the reagents and starting materials are readily available to someone of ordinary skill in the art. In Reaction Scheme 1, all substituents, unless otherwise indicated, as previously defined.

REACTION SCHEME 1 In Reaction Scheme 1, optional step 1, an appropriate derivative of 2- (am? Nofen? L) -3- (? Ndol-3? L) -propene? Co of structure (2) is alkylated to give a 2- (N-alkylamidophenol) -3- (? ndol-3? l) -propene? co derivative of structure (2a), in which R, is C ^ alkyl Ct An appropriate derivative of 2- (amnofen? L) -3 - (? Ndol-3? L) -propenoic of structure (2) can be alkylated upon contact with an appropriate alkylating agent, reductive amination or reduction of a 2- (amidophenyl) -3- (? ndol-3? l) -propene? co derivative of structure (3) using a suitable reducing agent. A suitable derivative of 2- ( amnofen?) -3- (? ndol? l -3? l) -propenoic of structure (2) is one in which R is as desired in the final product of formula (1), Pg, is X as desired in the final product of formula (1) or increases after deprotection and / or functionalization as required for X as desired in the final product of formula (1), Pg2 is Y as e) desired in the final product of formula (1) or increases after deprotection and / or functionalization as required for Y as desired in the final product of formula (1), and Pg3 is hydrogen or a protecting group, which is removed to give a final product of formula (1) or allows for selective deprotection and functionalization as may be required to incorporate desired X and Y into the final product of formula (1) The appropriate derivatives of 2- (amidophen) acid ?) -3- (? ndol-3? l) -propenoic of structure (2) are easily prepared as described herein and in US Patent No. 5, 51 9, 048, which is incorporated herein. in the reference by reference An appropriate alkylating agent is that which allows the transfer of an alkyl group of C, -C4. Suitable alkylating agents include alkyl halides, for example, methyl iodide, ethyl iodide, propyl, butyl iodide, ethyl bromide, propyl bromide, bromide butyl, propyl chloride, butyl chloride An appropriate aldehyde is that which forms an alkylamine of CT-C, on reductive alkylation, for example, formaldehyde, acetaldehyde, propionaldehyde and butyraldehyde. For example, a derivative is contacted of 2- (amnofen? l) -3 - (? ndol-3? l) -propene? co of structure (2) with 1 to 2 molar equivalents of an appropriate alkyl halide The reaction is carried out in a suitable solvent such as chloroform, dimethylformamide or acetonitoplo The reaction is carried out using a suitable base, such as tetylamine, dnsopropylethylamine or sodium bicarbonate. Generally, the reaction is carried out at temperatures from room temperature to the reflux temperature of the solvent. , the reaction requires from 1 hour to 1 20 hours. The product can be isolated by techniques well known in the art, such as extraction and evaporation. The product can then be purified by technical means. are well known in the art, such as chromatography, grinding or recutting. For example, alternatively, an appropriate derivative of 2-8am? nofen? l) -3- (? ndol-3? l) -propene? co of structure (2) is contacted with an appropriate aldehyde in a reductive amination Reductive amine using amines and aldehyde. The reactions are carried out using a molar excess of sodium borohydride or sodium cyanoborohydride, with sodium cyanoborohydride being preferred. The reaction is carried out in a suitable solvent, such as methanol., dimethylformamide or ethanol The pH of the reaction mixture may require adjustment as described in RF Borch et al, J Am Chem Soc 2897-2904 (1 971) The reaction is carried out at temperatures from 0 ° C to 50 ° C. it is generally required 2 to 24 hours. The product can be isolated and purified by techniques well known in the art, such as extraction, evaporation, chromatography and recrystallization. Alternatively, a derivative of 2- (N-alkaline) acid ? nofen? l) -3- (? ndol-3-? l) -propene? co of structure (2a), in which Ri is dC alkyl, can be prepared by reduction of an appropriate derivative of 2- (am. ? nofen? l) -3- (? ndol-3? l) -propene? co acylated structure (3), where R 2 is formyl, acetyl, propionyl, butyl and the like A suitable derivative of acid 2- (amnofen? l) -3- (? ndol-3? l) -propene? co acylated structure (3) can be prepared as described in Reaction Scheme 1 step 2, below For example, the deriv acid 2- (am? nofen? l) -3- (? ndol-3? l) -propene? co acylated structure (3), wherein R2 is formyl, acetyl, propionyl and butyl, can be reduced to give the N-methyl N- derivatives ethyl, N-propyl, and N-butyl, respectively, of 2- (N-alk? lam? nofen? l) -3- (? ndol-3? l) -propene? co derivatives The reaction is carried out using a molar excess of a suitable reducing agent such as borane or a borane complex, such as borane dimethylsulfide. The reaction is carried out using a suitable solvent, such as diethyl ether or tetrahydrofuran. The reaction is carried out at temperatures from ambient temperatures up to the temperature of reflux of the solvent The reaction generally requires 2 to 48 hours. The product can be isolated and purified by techniques well known in the art, such as, quenching, extraction, evaporation, chromatography and recrystallization. In Reaction Scheme 1, step 2, contacts an appropriate derivative of 2- (amnofen? l) -3 - (? ndol-3? l) -propene? co of structure (2) or an appropriate derivative of 2- (N-alk? lamofonyl) -2-? ndol-3? l) -propene? co of structure (2a) with an appropriate acylating agent , sulfonation agent or carbamoylating agent, to give a derivative of 2- (amidophen? l) -3- (? ndol-3? l) -propene? co structure (3) An appropriate derivative of 2- (amidophenyl) -3 - (? Ndol-3? L) -propenoic acid of structure (2) or an appropriate derivative of 2- (alk? Lam? Nofen? L) acid -3- (? Ndol-3? L) -propene? Co of structure (2a) is as described in Reaction Scheme 1, optional step 1, above Suitable acylation agents, sulphonation agents and carbamoylating agents are those that transfer the group R2 as desired in the final product of the formula (1) Suitable acylating agents include acid halides, acid anhydrides and activated formic acid esters, carboxylic acids of C, -C4 alkyl, benzoic acid and substituted benzoic acid, for example, acetic acid anhydride of formic acid, acetic anhydride, acetyl chloride, acetyl bromide, n-propionic chloride, isopropionic chloride n-butyl chloride, s-butyl chloride, t -butyl, Acetyl, Droxtsuccinate and the like, benzoyl chloride, benzoyl bromide, 4-fluorochloride for example, 4-chlorobenzoyl chloride, 4-bromobenzoyl chloride, 4-tr? fluoromethoxybenzoyl chloride, 4-methylbenzoyl chloride, 3,4,5-tr? methoxyl chloride? benzoyl, 2,4-dichlorobenzoyl chloride, and the like Suitable sulfonation agents include C 1 -C 4 alkylsulfonyl chloride, benzenesulfonyl chloride and substituted benzenesulfonyl chlorides, for example, methanesulfonyl chloride, ethanesulfonyl chloride, propanesulfonyl chloride , butanesulfonyl chloride, benzenesulfonyl chloride, 4-methoxybenzenesulfonyl chloride, 4-chlorobenzenesulfonyl chloride, 4-methoxybenzenesulfonyl chloride, 4-trifluoromethylbenzenesulfonyl chloride, and Similar suitable carbamoylating agents include C-C4 alkyl chloroformates, for example, methyl chloroformate, ethyl chloroformate, n-propyl chloroformate, isopropyl chloroformate, n-butyl chloroformate, s-butyl chloroformate, t-butyl chloroformate and the like For example, a d suitable erivado of 2- (amnofen? l) -3 - (? ndol-3? l) -propene? co of structure (2) or an appropriate derivative of 2- (N-alk? latoppnofen? ) -3- (? Ndol-3? L) -propene? Co of structure (2a) is contacted with an acylating agent, its binding agent or carbamizing agent or appropriate reaction The reaction is carried out in a Suitable solvent such as tetrahydrofuran, dichloromethane, chloroform, dimethyl formamide or acetonyl chloride The reaction is carried out using a suitable base such as pi pepd ma, pipdin N-methylmorpholine, tetylamine dnsopropy letilamine potassium carbonate potassium bicarbonate sodium bicarbonate or sodium carbonate. The reaction is generally carried out at temperatures from room temperature to the reflux temperature of the solvent. Generally, the reaction requires from 1 hour to 120 hours. The product can be isolated by 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 chromatography, trituration or recrystallization. In Reaction Scheme 1, optional step 3, the product of structure (3) can be deprotected and / or functionalized using well-known techniques. in the art to give compounds of formula (1). These techniques include hydrolysis of esters, selective hydrolysis of esters, transestepfication, amidation of groups leaving activated ester, and esterification of groups leaving activated ester. As described in Reaction Scheme 1, the compounds of formula (1) can be prepared by subjecting a compound (3) to an appropriate functionalization reaction, which introduces the appropriate functionality at the 2-position of the indole nucleus and / or in position 1 of the propenoic acid, thereby producing the desired compound of formula (1). The functional reactions can be performed using techniques well known in the art. For example, ester functionalities can be added to the 2-position of the indole core and / or in the position 1 of propenoic acid using a variety of techniques of estepficación A suitable technique of estepficación comprises putting in contact the appropriate compound of structure (3), in which Pg, and Pg2 are alkyl functions of d-Ci with an excess of an alcohol of the formula XOH or YOH, wherein X and Y are the same defined for the formula (1) Normally, the reaction is performed in the presence of an excess of a base, such as potassium carbonate. The reaction is usually carried out at a temperature ranging from room temperature to reflux for a period ranging from 1 hour to 24 hours. The product can be isolated and purified by techniques well known in the art, such as, extinction, extraction, evaporation, chromatography and rection. The amides can also be easily prepared by contacting a compound of structure (3), in which Pg, and Pg2 are alkyls of CT- C, with an excess of ammonia or a corresponding mono- or dialkylamine for the desired X or Y substituent, at a temperature from 0-100 ° C for a period ranging from 1-48 hours, using the amine as solvent or in a inert solvent, such as, tetrahydrofuran The resultant amide derivatives of formula (1) can be isolated and purified by techniques known in the art, such as, extraction, evaporation, chromatography and recrystallization. Alternatively, the amide can be formed by the use of groups leaving active ester Formation and use of groups leaving active ester used in functionalization reactions is well known and appreciated in the art Groups leaving active ester include, but are not limited to, anhydrides, mixed anhydrides, acid chlorides, acid bromides, 1-hydroxyl benzotrol azol esters, 1-hydroxysuccinimide esters or activated intermediates formed in the presence of coupling reagents, such as dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) ) -3-ethylcarbodiimide, and 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinolone. Groups leaving active ester can be prepared and isolated before use or can be prepared and used without isolation to form physiologically acceptable esters or physiologically acceptable amides. As is readily apparent to those skilled in the art, if X and Y are not both represented by the same functionality in the final product, then it will be necessary to perform the deprotection and functionalization reactions in a sequential manner, using suitable protecting groups, such as those described in Protectinq Groups m Organic Synthesis, 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 Orqanischen Chemie (Houben-Weyl), E Mueller, Ed., George Theime Verlag Stuttgart, 1974 Vol. 15; M G. Saulnierand and G W. Gpbble, J. Orq. 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 Szumszkoviocz, J Org Chem., 29, 834 (1964) For example, a compound of formula (1), in which Y is a physiologically acceptable amide and X is a physiologically acceptable ester or -OH, can be prepared from of a compound of structure (3), in which Pg2 is t-butlO- and Pg, is a physiologically acceptable ester other than t-butyl or a hydrolysable ester The selective removal of the t-butyl group gives a structure compound (3), in which Pg2 is -OH and Pg, is a physiologically acceptable ester other than t-but? 10- or a hydrolyzable ester, which can be amidated through the formation of a group leaving activated ester followed by the addition of a suitable amine, as is well known in the art A suitable amine is that which gives a physiologically acceptable amide, Y, as desired in the final product of formula (1) Suitable amines include, but are not limited to a, ammonia, methylamma, dimethylamine, ethylamine, diethylamine, propylamine a, butylamma, aniline, 4-chloroanalone, N-methylanilma, benzylamine, phenethylamine, morpholma, piperazma, pipepdma, N-methylpiperazine, thiomorfolma, pyrrolidine, and N-methylbenzylamine The formation of a group leaving active ester may require protection of NHol mdol using a suitable protecting group, such as, benzenesulfonyl, p-toluenesulfonyl, tpmethylsilyl, tpmethylsilylethoxy methyl, and the like In cases in which NH indole requires protection, this is best done before the removal of the Pg2 butyl In addition, functionalization or hydrolysis yields a compound of formula (1) in which Y is a physiologically acceptable amide and X is a physiologically acceptable ester or -OH After functionalization, the removal of the indole protecting group NH gives a compound of formula (1) In a similar manner a compound of formula (1), in which X is a physiologically acceptable amide and Y is a physiologically acceptable ester or -OH can be prepared from a Structure item (3) in which Pg, is t-but? lO- and Pg2 is a physiologically acceptable ester other than t-but? 10- or a hydrolysable ester The compounds of formula (1), in which X and And they are -OH, can be prepared from a compound of structure (3), in which Pgi and Pg2 are C, -C4 alkoxy, or a group leaving activated ester, by deprotection using a molar excess of a reagent suitable, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate or potassium carbonate, with preference being given to lithium hydroxide, sodium hydroxide, potassium hydroxide, and lithium hydroxide being the most preferred . These deprotections are carried out in a suitable solvent, such as methanol, ethanol, mixtures of methanol and water, mixtures of ethanol and water, mixture of tetrahydrofuran and water, or water. The reaction is usually 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 (1) 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, acetic, etc., extraction and recrystallization. The following examples and preparations present the typical synthesis of the compounds of formula (1). It is understood that these examples are illustrative only and are not intended to limit the scope of the invention in any way. 33 PREPARATION 1 1 3-form? L-2-carboethox? -4,6-d? Chloro? Ndol Combine 3,5-d? Chlorophen? Lh? Draz? Na (300 g) and ethanol (2 I) Add pyruvate from ethyl (1536 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 4, filter and evaporate in vacuo to give ethyl p-ruvato-3,5-d? chlorophenolithrazole Combine p-ruvate-3,5-d ? chlorofen? lh? drazone of ethyl (100 g) and polisfosfopco acid (2 kg) Heat on a current bath After 5 hours, stop 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 4, filter and evaporate in vacuo to give a solid. Crush the solid with diethyl ether, filter and dry to give 2-carboethoxy-4,6-d-chloro- ndol Combine 2-carboethoxy-4,6-d-chloro-n-dol ( 200 g, 0077 mol), and dimethylformamide (90 ml, 0117 mol) in dichloroethane (100 ml). Add phospho-chloride (180 g, 0117 mmol) Heat at reflux After 35 hours cool the reaction mixture at room temperature to obtain a solid Collect the solid by filtration, rinse with dichloromethane Combine the solid with 1 M aqueous sodium acetate solution and stir. After 1 hour, filter, rinse with water, and dry to give the title compound PREPARATION 1 2 3-form L-2-carboethoxy? -4,6-d? chloro? ndol Combine 2-carboethoxy? -4,6-d? chloro? ndol (100 g, 0039 mol), and dimethylformamide (45 ml, 0057 mol) in dichloroethane (20 ml) Add phospho-chloride (89 g, 0058 mmol) Heat at 80 ° C After 18 hours, cool the reaction mixture to room temperature to give a solid filter. Extract and combine with 1M aqueous sodium acetate solution and stir. After 18 hours, filter, rinse with water, and dry to give the title compound mp 216-217 ° C, Rf = 024 (silica gel, 1 / 1 ether / hexane) 1 H NMR (CDCl 3) d 1080 (s, 1 H), 940 (br s, 1 H), 739 (s, 1 H), 735 (s, 1 H), 452 (q, 2 H, J = 72 Hz ), 1 47 (t, 3H, J = 7 1 Hz) PREPARATION 2 3-Methoxyl-2- (3-n? Trofen? L) -propene? -methyl methyl ester Combine (3-n? Trofen?) Acetic acid (200 g, 110 mmol) and anhydrous methanol (125 ml) Add 7 drops of concentrated sulfuric acid Heat at 50 ° C After 14 hours, cool to room temperature Evaporate in vacuo to give a residue Partition the residue between water and diethyl ether Separate the organic layer and extract with saturated aqueous solution of sodium bicarbonate and brine Dry the organic layer over MgSO4 and filter Evaporate slowly to give (3-n-trophene) methyl acetate 1H NMR (CDCl3) 58 17 (d, 1H, J = 1 1 Hz), 814 (dd, 1H, J = 1 0, 77 Hz) 763 (dd 1H J = 1 1, 77 Hz) 752 (t 1H, J = 77 Hz) 375 (s 2H) 373 (s 3H) Combine fresh sodium methoxide prepared (9.3 g, 172 mmol) and tetrahydrofuran (125 ml). Cool to 0 ° C. Add methyl formate (10.6 ml, 172 mmol). Add a solution of methyl (3-nitrophenyl) acetate (15.3 g, 78.2 mmol) in tetrahydrofuran (125 mL) as drops. After the addition is complete, heat the reaction mixture to room temperature. After 16 hours, evaporate in vacuo to give a residue. Dissolve the residue in dimethylformamide (125 ml). Add methyl iodide drops (19.5 ml, 313 mmol) in the form of drops. After 4 hours, dilute the reaction mixture with ethyl acetate and extract with water, saturated aqueous solution of sodium thiosulfate and brine. Dry over MgSO 4, filter through a plug of silica gel, levigating with dichloromethane to give the title compound: mp; 101-103 ° C.

EXAMPLE 1 Methyl ester of (E) and (Z) -2- (3-nitropheni0-3- (2-carboethoxy-4,6-dichloroindol-3-yl) -propenoic acid ester) Combine 3-methoxyl-2- (3-n? Trofen? L) -propene? Co methyl ester (139 g), 588 mmol) and 1,2-d-chloroethane (100 ml) Add tpmethylsilyl tpf lactide (11 4 ml, 585 mmol) in the form of drops by syringe. After 15 minutes, add 2-carboethoxy as drops. 4,6-dichloroeindole (11 7 g, 452 mmol) Heat at 70 ° C After 16 hours, cool to room temperature Add saturated aqueous sodium bicarbonate solution Extract with ethyl acetate Separate the organic layer and extract with water and brine Dry the organic layer over MgSO4, filter and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel, levigating with 1/3 ethyl acetate / hexane to give the title compound Rf = 05 (30%) acetate. ethyl acetate / cyclohexane) Separate the isomers by fractional recrystallization from ethyl acetate / cyclohexane Initially, mainly the Z isomer precipitates as a yellow powder, which can then be recrystallized from ether / cyclohexane to obtain the Z-isomer mp 178-180 ° C, IR (KBr) vmax 3408, 3316, 1715, 1530, 1443, 1350, 1319 1238, 1209, 1182 cm 1, 1H NMR (DMSO-d6) d 1246 (bs, 1H), 827 (t 1H J = 1 9 Hz) 822 (dm, 1H, J = 82 Hz) 792 (dm, 1H, J = 80 Hz), 771 (t 1H J = 80 Hz) 760 (s, 1H), 744 (d, 1H, J = 1 7 Hz), 717 (d, 1H, J = 1 7 Hz) 426 (q 2H J = 71 Hz), 341 (s, 3H), 1 23 (t, 3H, J = 71 Hz) Elemental analysis calculated for C21H, 6Cl2N206C, 5444H, 348, N, 605 Found C 5441, H, 354, N, 603 The E-isomer is then precipitated to give the E isomer mp 173- 175 ° C IR (KBr) 3399, 3304 1715, 1556, 1532, 1437, 1350, 1321, 1300, 1242 cm "1; 1H NMR (DMSO-d6) d 12.35, (bs, 1H), 8.25 (s, 1H), 7.96 (dm, 1H, J = 7.6 Hz), 7.86 (m, 1H), 739 (t, 1H, J = 7.6 Hz), 7.36 (dm, 1H, J = 7.6 Hz), 7.33 (d, 1H, J = 1.7 Hz), 7.14 (d, 1H, J = 1.7 Hz), 4.18 (q, 2H, J = 7.1 Hz ), 3.81 (s, 3H), 1.23 (t, 3H, J = 7.1 Hz) Elemental analysis calculated for C21H16CI2N2O6: C, 54.44; H, 348; N, 6.05 Found: C, 54.55, H, 3.41; N, 593 EXAMPLE 2 Methyl ester of (E) and (Z) -2- (3-aminophenyl) -3- (2-carboethoxy-4,6-dichloro-ndol-3-yl) -propenoic acid ester Combine the methyl ester of (E) and (Z) -2- (3-nitrophenol) -3- (2-carboethoxy? -4,6-d? Chloro? Ndol-3-yl) -propenoic acid (162) g, 35 mmol) and ethyl acetate / 175 ml). Add tin (II) chloride dihydrate in portions (472 g, 209 mmol). Heat at reflux. After 4 hours, cool the reaction mixture to room temperature. Slowly add saturated aqueous sodium bicarbonate solution. Add water and ethyl acetate. Separate the aqueous layer and extract three times with ethyl acetate. Combine the organic layers and extract with saturated aqueous sodium solution. Dry over MgSO, filter and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel by levigating with 1/2 ethyl acetate / hexane to give the title compound: mp 249-251 ° C; 1 H NMR (DMSO-d 6) d 12.36 (s, 1 H), 7.45 (d, 1 H, J = 1 J Hz), 7.32 (s, 1 H), 7.22 (d, 1 H, J = 1.7 Hz), 7.05 (t, 1H, J = 7.8 Hz), 6.67 (d, 1H, j = 1.9 Hz), 6.55-6.62 (m, 2H), 5.16 (s, 1H), 4.27 (q, 2H, j = 7.1 Hz), 3.39 ( s, 3H), 1.25 (t, 3H, J = 7.1). The elemental analysis calculated for C21H, 8CI2N2O4 • 2H2O: C, 57.09; H, 4.22; N, 6.34. Found: C, 56.94; H, 4.04; N, 6.15.

EXAMPLE 3 Methyl ester of (E) and (Z) -2- (3-acetamidophenyl) -3- (2-carboethoxy-4,6-dichloroindol-3-yl) -propenoic acid ester ? Combine the (E) and (Z) -2- (3-aminophenyl) -3- (2-carboethoxy-4,6-dichloroindol-3-yl) -propenoic acid methyl ester (2.0 g, 4.6 mmol) and triethylamine (1.9 ml, 14 mmol) in dichloromethane (45 ml). Add acetyl chloride (0.82 ml, 12 mmol). After 20 hours, quench with methanol and dilute with dichloromethane. Extract the diluted reaction mixture with brine. Separate the organic layer, dry over MgSO 4, filter and evaporate in vacuo to give the title compound.

EXAMPLE 4 Acid (E) v (Z) -2- (3-Acetamidophenyl) -3- (4,6-dichloroindol-3-yl-2-carboxylic acid) -propenoic acid Combine the methyl ester of (E) and (Z) -2- (3-acetamidophenyl) -3- (2-carboethoxy-4,6-dichloroindol-3-yl) -propenoic acid (2.39 g, 4.62 mmol) in tetrahydrofuran (25 ml) and water (20 ml). Add lithium hydroxide hydrate (664 mg, 27.7 mmol). Heat at 70 ° C. After 16 hours, dilute the reaction mixture with water (150 ml) and acidify with 1M hydrochloric acid. Extract with ethyl acetate and dry the organic layer with MgSO4. Evaporate vacuum and obtain a residue. Form a paste with the residue in hot ethyl acetate, filter and dry to give the title compound: mp 270-271 ° C (dec); IR (KBr) vmax 3414, 3279, 1688, 1613, 1557, 1242 cm "1; 1 H NMR (DMSO-d 6) d 12.14 (s, 1 H), 9.73 (s, 1 H), 8.03 (s, 1 H), 7.39 (dd, 1 H, J = 2.0, 1.1 Hz), 7.13 (d , 1H, J = 1.5 Hz), 6.94 (t, 1H, J = 7.7 Hz), 6.57 (dd, 1H, J = 1.0, 1.1 Hz), 1.94 (s, 3H). Elemental analysis Calculated for C20H, 4CI2N2O5 • 0.5 HOAc • 0.5 ethyl acetate: C, 54.45; H, 3.97; N, 5.52. Found: C, 54.13; H, 3.81; N, 5.76.

EXAMPLE 5 Methyl ester of (E) and (Z) -2- (3-benzamidopheni0-3- (2-carboethoxy-4,6-dichloroindol-3-yl) -propenoic acid ester) Combine (E) and (Z) -2- (3-aminophenyl) -3- (2-caboethoxy-4,6-dichloroindol-3-yl) -propenoic acid methyl ester (866 mg, 2.0 mmol), and triethylamine (0.84 ml, 6.0 mmol) in dichloromethane (20 ml). Add benzoyl chloride (0.58 ml, 5.0 mmol). After 20 hours, quench with methanol and dilute with dichloromethane. Extract the diluted reaction mixture with brine. Separate the organic layer, dry over MgSO 4, filter and evaporate in vacuo to give the title compound.

EXAMPLE 6 Acid (E) and (Z) -2- (3-benzamidophenyl) -3- (4,6-dichloro-undol-3-yl-2-carboxylic acid) -propene ico Combine the (E) and (Z) -2- (3-benzamidophenyl) -3- (2-carboethoxy-4,6-dichloroindol-3-yl) -propenoic acid methyl ester (920 mg, 1.43 mmol) in tetrahydrofuran (12 ml) and water (8 ml). Add lithium hydroxide hydrate (205 mg, 8.58 mmol). Heat at 70 ° C. After 16 hours, dilute the reaction mixture with water (150 ml) and acidify with 1M hydrochloric acid. Extract with ethyl acetate, dry the organic layer with MgSO 4, and evaporate in vacuo and obtain a residue. Subject to recrystallization the residue from ethyl acetate / hexane to give the title compound: mp 237-238 ° C (dec), IR (KBr) vmax 3420, 3275, 1686, 1611, 1537, 1234, 1225 cm " 1; 1H NMR (DMSO-ds) d 12 16, (s, 1H), 1007 (s, 1H), 8.06 (s, 1H), 7.95-7.85 (m, 2H), 760-7.45 (, 4H), 731 ( d, 1H, J = 1 8 Hz), 7.13 (d, 1H, J = 1 8 Hz), 6.94 (t, 1 H, J = 7.7), 665 (dd, 1H, J = 1 0, 77 Hz) EXAMPLE 7 5 Methyl ester of (E) and (Z) -2- (3- (N-carbomethaloxyamino) phenyl) -3- (2-carboethoxy-4,6-dichloro-ndol-3-yl) - propene? co Combine the methyl ester of (E) and (Z) -2- (3-aminophen?) -3- (2- 15 carboethoxy? -4,6-d? Chloro? Ndol-3-yl) -propenoic acid ester ( 1 19 g, 2.74 mmol) and pyridine (027 ml, 33 mmol) in dichloromethane (10 ml). Add methyl chloroformate (025 ml, 33 mmol). After 20 hours, quench with water and dilute with dichloromethane. Extract the diluted reaction mixture twice with dichloromethane. Combine the organic layers, extract with water, dry. over MgSO 4, filter and evaporate in vacuo to obtain a residue. Retract the residue from dichloromethane, filter, retain the mother liquors and dry to obtain the E isomer mp 192-194 ° C, IR (KBr) vmax 3293, 1742 , 1705, 1611, 1553, 1441, 1321, 1300, 1285, 1240 cm "1, 1 H NMR (CDCl 3) d 1061 (bs, 1 H), 8 16 (s, 1 H), 725 (d, 1H, J = 1 7 Hz), 7 19 (bs, 1")> H), 704 (bs, 1 H), 701 (d, 1H, J = 1 7 Hz), 693 (t, 1H, J = 1 7 Hz), 664 (d 1H, J = 7.6 Hz ), 4.21 (q, 2H, J = 7.1 Hz), 3.79 (s, 3H), 3.64 (s, 3H), 2.19 (bs, 1H), 1.28 (t, 3H, J = 7.1 Hz). for C23H2oCI2N2O6: C, 56.23; H, 4.10; N, 5.70. Found: C, 56.12; H, 4.08; N, 5.67 Evaporate the retained mother liquors and chromatograph on silica gel, levigating with cyclohexane / ethyl acetate , 2/1 to give the title compound: mp 87-92 ° C; IR (KBr) vmax 3337, 1705, 1611, 1555, 1545, 1443, 1319, 1300, 1283, 1238 cm "1; 1 H NMR (CDCl 3) d 9.34 (bs, 1 H), 9.15 (bs, 1 H), 8.20 (s, 1 H), 7.53 (bt, 1 H, J = 1.7 Hz), 7.44 (m, 1 H), 7.43 (s, 1 H), 7.34 (t, 1H, J = 8.0 Hz), 7.21 (dt, 1H, J = 7.6, 1.4 Hz), 7.18 and 7.16 (2d, 3 H, J = 1.7 Hz), 7.10 (d, 2H, J = 1.7 Hz), 7.08 (bt, 1H, J = 1.7 Hz), 7.00 (t, 1H, J = 8.0 Hz), 6.76 (bs, 1 H), 6.73 (dt, 1H, J = 7.7, 1.3 Hz), 6.50 (bs, 1 H), 4.33 (q, 2H, J = 7.1 Hz), 4.28 (q, 2H, J = 7.1 Hz), 3.85 (s, 3 H), 3.79 (s) , 3H), 3.68 (s, 3H), 3.56 (bs, 3 H), 1.34 (t, 3H, J = 7.1 Hz), 1.31 (t, 3H, J = 7.1 Hz).

EXAMPLE 8 Acid (E) and (Z) -2- (3- (N-Carbomethyloxyamino) phenyl) -3- (4,6-dichloroindol-3-yl-2-carboxylic acid) -propenoic acid "< CH: Combine the methyl ester of (E) and (Z) -2- (3- (N-carbomethyloxyamino) phenyl) -3- (2-carboethoxy-4,6-dichloroindol-3-yl) -propenoic acid (1.11 g, 2.26 mmol) in tetrahydrofuran (24 ml) and water (16 ml). Add lithium hydroxide hydrate (410 mg, 17.2 mmol). Heat at 70 ° C. After 16 hours, dilute the reaction mixture with water (150 ml) and acidify with 1M hydrochloric acid. Extract with ethyl acetate, dry the organic layer with MgSO, and evaporate in vacuo to obtain a residue. Chromatograph the residue on silica gel by levigating with dichloromethane / acetic acid, 9/1 to give a second residue. Recrystallize the second residue from ethyl acetate / cyclohexane to give the title compound: mp 250 ° C (dec); IR (KBr) vmax 3372, 3081, 1688, 1609, 1589, 1539, 1443, 1294, 1240, 1175 cm "1; 1H NMR (DMSO-d6) d 12.86 (bs, 2 H), 12.10 (s, 1 H ), 9.43 (s, 1 H), 8.05 (s, 1 H), 7.32 (d, 1H, J = 1.8 Hz), 7.2 (m, 2 H), 7.12 (d, 1H, J = 1.8 Hz), 6.96 (t, 1H, J = 7.9 Hz), 6.59 (dt, 1 H, J = 7.7, 1.3 Hz), 3.59 (s, 3 H).

EXAMPLE 9 (E) and (Z) -2- (3-Methylsulfonylamidophenyl) -3- (2-carboethoxy-4,6-dichloro-undol-3-yl) -propenoic acid methyl ester Combine the (E) and (Z) -2- (3-aminophenyl) -3- (2-carboethoxy-4,6-dichloroindol-3-yl) -propenoic acid methyl ester (1.12 g, 2.58 mmol) and pyridine (0.25 ml, 3.1 mmol) in dichloromethane (10 ml). Cool to 0 ° C using an ice bath. Add methanesulfonyl chloride (0.24 ml, 3.1 mmol). After 90 minutes, dilute with water and dichloromethane. Separate the organic layer, extract with water, dry over MgSO 4, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel, levigating with dichloromethane / ethyl acetate, 7/1, to give the title compound: IR (KBr) vmax 3410, 3297, 1703, 1609, 1437, 1321, 1240, 1152, 980 cm "1; 1 H NMR (CDCl 3) d isomer E: 9.37 (bs, 1 H), 8.24 (s, 1 H), 7.22 (d, 1 H, J = 1.7 Hz), 7.07 (d, 1 H, J = 1.7 Hz), 7.0-6.9 (m, 4 H), 6.65 (bs, 1 H), 4.31 (q, 2H, J = 7.2 Hz), 3.87 (s, 3H), 2.60 (s, 3H), 1.36 ( t, 3H, J = 7.2 Hz), Z isomer: 9.32 (bs, 1 H), 7.48 (s, 1 H), 7.4-7.3 (m, 4 H), 7.25 (d, 1H, J = 1.7 Hz) , 7.12 (d, 1H, J = 1.7 Hz), 7.10 (m, 1 H), 4.35 (q, 2H, J = 7.2 Hz), 3.53 (s, 3 H), 3.06 (s, 3 H), 1.32 (t, 3H, J = 7.2 Hz).

EXAMPLE 10 Acid (E) and (Z) -2- (3-methylsulfonylamodiphenyl) -3- (4,6-dichloroindol-3-yl-2-carboxylic acid) -propenoic acid 4 Prepare, by the method of Example 4 using (E) and (Z) -2- (3-methylsulfonylamidophenyl) -3- (2-carboethoxy-4,6-dichloroindol-3-yl) -propenoic acid methyl ester (1.17) g, 2.29 mmol) to give the title compound: mp > 270 ° C; IR (KBr) vmax 3418, 3300, 3200, 3094, 1686, 1615, 1319, 1306, 1240, 1140, 980 cm "1; 1H NMR (DMSO-d6) d 12.93 (bs, 2H), 12.18 (s, 1 H), 9.44 (s, 1H), 8.07 (s, 1 H), 7.32 (d, 1 H, J = 1.7 Hz), 7.13 (d, 1H, J = 1.7 Hz), 7.08 (dt, 1H, J = 7.7, 0.7 Hz), 6.9 (m, 2 H), 6.80 (dm, 1H, J = 7.7 Hz), 2.48 (s, 3H), Elemental analysis calculated for C? 9H14CI2N2O6S: C, 38.63; H, 3.01; N, 5.97, Found: C, 48.67; H, 3.18; N, 5.71.

EXAMPLE 11 (E) and (Z) -2- (3- (N-carboethyloxyamino) phenyl-3- (2-carboethoxy-4,6-dichloroindol-3-yl) -propenoic acid methyl ester Prepare by the method of Example 7 using methyl ester of (E) and (Z) -2- (3-aminophenyl) -3- (2-carboethoxy-4,6-dichloroindol-3-yl) -propenoic acid ester and chloroformate. ethyl to give the title compound. MS (CI / NH3) N + NH4 + / e 522. Elemental analysis calculated for C24H22CI2N206: C, 57.04; H, 4.39; N, 5.54, Found: C, 56.86; H, 4.35; N, 5.25.

EXAMPLE 12 Acid (E) v (Z) -2- (3- (N-carboethyloxyamino) phenyl) -3- (4,6-dichloroindol-3-yl-2-carboxylic acid) -propenoic acid Prepare by the method of Example 8 using (E) and (Z) -2- (3- (N-carboethyloxyamino) phenyl) -3- (2-carboethoxy-4,6-dichloroindol-3-yl) -propenoic acid for give the title compound. MS (CI / NH3) M + NH + / e 480.

EXAMPLE 13 Methyl ester of (E) and (Z) -2- (3- (N-carboisopropyloxyamino) phenyl) -3- (2-carboethoxy-4,6-dichloroindol-3-yl) -propenoic acid ester Prepare by the method of Example 7 using methyl ester of (E) and (Z) -2- (3-aminophenyl) -3- (2-carboethoxy-4,6-dichloroindol-3-yl) -propenoic acid ester and chloroformate. isopropyl to give the title compound. MS (CI / NH3) M + NH4 + / e 536. Elemental analysis calculated for C 25 H 24 Cl 2 N 2 O 6: C, 57.81; H, 4.66; N, 5.39. Found: C, 58.14; H, 4.76; N, 5.33.

EXAMPLE 14 Acid (E) and (Z) -2- (3- (N-carbo-isopropyloxyamino) phenyl) -3- (4,6-dichloroindol-3-yl-2-carboxylic acid) -propenoic acid Prepare by the method of Example 8 (E) and (Z) -2- (3- (N-carboisopropyloxyamino) phenyl) -3- (2-carboethoxy-4,6-dichloroindol-3-yl) methyl ester. propenoic to give the title compound. MS (CI / NH3) M + NH4 + / e 494.496.

EXAMPLE 15 Methyl ester of (E) and (Z) -2- (3-benzenesulfonylamidophenyl) -3- (2-carboethoxy-4,6-dichloroindol-3-yl) -propenoic acid ester Prepare by the method of Example 9 using (E) and (Z) -2- (3-aminophenyl) -3- (2-carboethoxy-4,6-dichloroindol-3-yl) -propenoic acid methyl ester and chloride of benzenesulfoni to give the title compound.

EJ EM PLO 16 Acid (E) and (Z) -2- (3-benzenesulfonyl-idophenyl) -3- (4,6-dichloroindol-3-yl-2-carboxylic acid) -propenoic acid Prepare by the method of Example 4 using methyl ester of (E) and (Z) -2- (3-benzenesulfomamidene) -3- (2-carboethoxy-4,6-d? Chloro? Ndol- 3-? L) -propene? Co to give the title compound EXAMPLE 17 (E) and (Z) -2- (4-n? Trofen? L) -3- (2-carboethoxy-4,6-d? Chloro? Ndol-3-yl) -propenon? Tr? Lo Combine 3-formyl-2-carboethoxy-4,6-dichlorodolin (50 g, 1748 mmol), 4-n-trophon-laceton-tot (283 g, 1748 mmol), pipepdma (0.2 ml) and ethanol (50 mL) Heat to reflux After 16 hours, cool to room temperature Cool to 0 ° C to give a solid. Filter and dry to give the title compound IR (KBr) vmax 3402, 3283, 2224, 1709, 1684, 1609 , 1522 1344, 1238 cm 1, 1 H NMR (DMSO-d 6) d 1292 (s, 1 H), 8.65 (s, 1 H), 836 (d 1 H, J = 89 Hz), 803 (d, 1 H, J = 89 Hz), 753 (d, 1H, J = 1.6 Hz), 737 (d 1H J = 1 6 Hz), 434 (q, 2H, J = 7 1 Hz), 1 24 (t, 3H, J = 7 1 ) Elemental analysis calculated for C2oH13CI2N3? 4 C, 5583, H, 305, N, 977 Found C 5565 H, 270, N, 967 5 EXAMPLE 18 (EJ_ (Z) -2- (4-am mofen? H -3- (2-carboethoxy? -4.6-d? Chloro? Ndol-3-? L) -propenonitplo Combine (E) and (Z) -2- (4-n? Trofen? L) -3- (2-carboethoxy? -4, 6-d? Chloro? Ndol-3-? L) -propene? Trol (693 g, 161 mmol) and ethanol (50 ml) Add portions of tin (II) chloride dihydrate (182 g, 805 mmol) Heat at 70 ° C After 4 hours, cool the reaction mixture to room temperature Evaporate in vacuum Add water and slowly add saturated aqueous sodium bicarbonate solution until the pH is approximately 75. Extract 2 times with ethyl acetate Combine the organic layers and extract with brine. Dry over MgSO 4, filter and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel, levigating with 2/1 hexane / ethyl acetate to give the title compound IR (KBr ) v 3385, 3302, 2222, 1690 1622, 1609 1514, 1238 cm 1, 1H NMR (DMSO-d6) d 1015 (s, 1H) 785 (s 1H), 752 (d, 1H, J = 74 Hz), 731 (s, 1H), 7 14 (d, 1H J = 1 3 Hz), 674 (d 1H, J = 74 Hz) 436 (q, 2H, J = 7 1 Hz), 1 27 (t, 3H, J = 7 1) Elemental analysis calculated for C2oH, 5CI2N302 C, 6002, H, 378, N, 1050 Found C 5965, H 348, N, 1007 EXAMPLE 19 Amide acid (E) and (Z) -2- (4-am? nofen? l) -3- (2-carboethoxy? -4,6-d? chloro) ? ndol 3-? L) -propene? Co Combine (E) and (Z) -2- (4-aminophen?) -3- (2-carboethoxy? -4,6-d? Chloro? Ndol-3? L) -propenon? Tplo (620 g, 155 mmol), sulfuric acid (20 ml) and acetic acid (20 ml) Warm to about 70 ° C. After 3 hours, cool in an ice / water bath to give a solid. Collect by filtration to give the title compound. titer 1H NMR (DMSO-d6) d 1224-1220 (s, 1H), 764 (s, 1H 740 (m, 2H), 72 (s, 2H), 684 (d, 2H), 680 (d, 2H) , 420 (q 2H), 44-34 (bs, 2H), 1 25 (t, 3H) EXAMPLE 20 Amide acid (E) and (Z) -2- (4- (N-carbomethoxyl amine) phenol) -3- (2-carboethoxy? -4,6-d? Chloro? ndol-3-? l) -propene? co Prepare by the method of Example 7 using (E) and (Z) -2- (4-am? Nofen? L) -3- (2-carboethoxy? -4,6-d? Chloro? Ndol-3? ) -propenon? tplo to give the title compound EXAMPLE 21 Amide of acid (E) v (Z) -2- (4- (N-carbomethoxyl amine) phenol) -3- (4,6-d? Chloro? Ndol-3? l-2-carboxy acid? co) -propene? co Prepare by the method of Example 8 using acid amide (E) and (Z) -2- (4- (N-carbomethoxyl amine) phenol) -3- (46-d? Chloro? Ndol-3-? L-2-ac? O) carboxyl? co) -propene? co to give the title compound EXAMPLE 22 Acid _ £ E) (Z) -2- (4-aminophenyl) -3- (4,6-dichloroindol-3-yl-2-carboxylic acid) -propenoic acid Combine (E) and (Z) -2- (4-aminophenyl) -3- (2-carboethoxy-4,6-dichloroindol-3-yl) -propenoic acid amide (1.90 g, 5.38 mmol) and aqueous solution of 6 M sodium hydroxide (20 ml). Heat at 105 ° C. After 14 hours, cool to 0 ° C and acidify to pH 3 with 6 M hydrochloric acid aqueous solution to form a solid. Collect the solid by filtration to give the title compound: IR (KBr) vmax 3395, 3271, 1724, 1612, 1176, 1082 cm "1; 1H NMR (DMSO-d6) d 12.12 (s, 1H), 7.87 (s) , 1H), 7.33 (d, 1H, J = 1.8 Hz), 7.10 (d, 1H, J = 1.8 Hz), 6.62 (d, 2H, J = 8.6 Hz), 6.23 (d, 2H, J = 8.6 Hz ).

EXAMPLE 23 Methyl ester of (E) v (Z) -2- (4-aminophenyl) -3- (2-carbomethoxy-4,6-dichloro indol-3-yl) -propenoic acid ester Combine (E) and (Z) -2- (4-aminophenyl) -3- (4,6-dichloroindol-3-yl-2-carboxylic acid) -propenoic acid (1.0 mole) and methanol (50 ml) . Add sulfuric acid (1 ml). After 24 hours, concentrate in vacuo to approximately 20 ml. Dilute the reaction mixture with dichloromethane and extract with saturated aqueous sodium carbonate solution. Separate the organic layer, dry over MgSO, and evaporate in vacuo to give the title compound.

EXAMPLE 24 Methyl ester of (E) and (Z) -2- (4-acetamidophenyl) -3- (2-carbomethoxy-4,6-dichloroindol-3-yl) -propenoic acid ester P repair by the method of Example 3 using (E) and (Z) -2- (4-aminophenyl) -3- (2-carbomethoxy-4,6-dichloroindol-3-yl) -propene methyl ester. to give the title compound.

EXAMPLE 25 Acid (E) and (Z) -2- (4-acetamidophenyl) -3- (4,6-dichloroindol-3-yl-2-carboxylic acid) -propene? Co Prepare by the method of Example 4 using (E) and (Z) -2- (4-acetamidophenyl) -3- (2-carbomethoxy-4,6-dichloroindol-3-yl) -propenoic acid methyl ester to give the composed of the title.

EXAMPLE 26 Methyl ester of (E) and (Z) -2- (4- (N-carbomethyloxyamino) phenyl) -3- (2-carbomethoxy-4,6-dichloroindol-3-yl) -propenoic acid C (0) OCH3 Prepare by the method of Example 7 using (E) and (Z) -2- (4-aminophenyl) -3- (2-carbomethoxy-4,6-dichloroindol-3-yl) -propenoic acid methyl ester to give the composed of the title.

EXAMPLE 27 Acid (E) v (Z) -2- (4- (N-carbomethyloxyamino) phenyl) -3- (4,6-dichloroindol-3-yl-2-carboxylic acid) -propenoic acid Prepare by the method of Example 8 using methyl ester of (E) and (Z) -2- (4- (N-carbomethyloxyamino) phenyl) -3- (2-carbomethoxy-4,6-dichloroindol-3-yl) -propenoic to give the title compound.

EXAMPLE 28 (E) and (Z) -2- (3-nitrophenyl) -3- (2-carboethoxy-4,6-dichloroindol-3-yl) -propenenitrile Combine 3-formyl-2-carboethoxy-4,6-dichloroindole (13.95 g, 0.49 mol), 4-nitrophenylacetonitrile (7.9 g, 10.49 mol), piperidine (1.5 ml) and ethanol (500 ml). Heat to reflux. After 4 days, cool to room temperature. Cool to 0 ° C to give a solid. Filter, rinse with ethanol and methyl t-butyl ether and dry to give the title compound: Rf = 0.60 (silica gel, 50% ethyl acetate / heptane) Elemental analysis calculated for C20H13CI2N3O4: C, 55.83, H, 305; N, 9.77 Found: C, 55.69, H, 307, N, 966 EXAMPLE 29 (Z) -2- (3-aminophen?) -3- (2-carboethoxy? -4,6-d? Chloro? Ndol-3-? L) -propenonitplo Combine (E) and (Z) -2- (3-nitrophenyl) -3- (2-carboethoxy? -4,6-d? Chloro? Ndol-3? L) -propene? Trol (258 g, 0042 mmol), tin (II) chloride dihydrate (68 g, 021 mmol) in ethyl acetate (120 mL) Heat at reflux After 3 hours, cool the reaction mixture to room temperature. Slowly add the saturated aqueous solution of sodium bicarbonate (150 ml) Add water (300 ml) Extract twice with ethyl acetate Combine the organic layers, dry over MgSO 4, filter and evaporate in vacuo to give the title compound Rf = 045 (silica gel, 50% ethyl acetate / heptane) Elemental analysis calculated for C2oH15Cl2N302 C, 6002 H, 378, N, 1050 Found C, 5970, H, 378, N, 1020 EXAMPLE 30 Acid Amide (E) v (Z) -2- (3-aminophenyl) -3- (2- carboethoxy-4,6-dichloroindol-3-yl) -propenoic acid Combine (E) and (Z) -2- (3-aminophenyl) -3- (2-carboethoxy-4,6-dichloroindol-3-yl) -propenenitrile (788 g, 0.20 mmol), sulfuric acid (25 g). ml) and acetic acid (25 ml). Heat to approximately 90 ° C. After 2 hours, cool the reaction mixture and slowly adjust the pH to 5, using a 6M aqueous sodium hydroxide solution. Cool to 0 ° C to give a solid. After 1 hour, collect by filtration. Combine the solid and ethyl acetate (1 I) and heat to reflux. After 1 hour, cool, filter and extract with water. Dry the organic layer over MgSO 4, filter and evaporate in vacuo to give the title compound.

EXAMPLE 31 Ammonium acid (E) and (Z) -2- (3- (N-carbomethyloxyamino) phenyl) -3- (2-carboethoxy-4,6-dichloroindole-3?) - propenoic Prepare by the method of Example 7 using (E) and (Z) -2- (3-aminophenyl) -3- (2-carboethoxy-4,6-dichloroindol-3-yl) -propenenitrile to give the compound of Title.

EXAMPLE 32 Amide acid (E) and (Z) -2- (3- (N-carbomethyloxyamino) phenyl) -3- (4,6-dichloroindol-3-yl-2-carboxylic acid) -propenoic acid Prepare by the method of Example 8 using acid amide (E) and (Z) -2- (3- (N-carbomethyloxyamino) phenyl) -3- (2-carboethoxy-4,6-dichloroindol-3-yl) ) -prope noico to give the compound of the title.

EXAMPLE 33 Amide acid (E) and (Z) -2- (3-acetamidophenyl) -3- (2-carboethoxy-4,6-dichloroindol-3-yl) -propenoic acid Prepare by the method of Example 3 using (E) and (Z) -2- (3-aminophenyl) -3- (2-carboethoxy-4,6-dichloroindol-3-yl) -propenenitrile to give the title compound.

EXAMPLE 34 Amide acid (E) and (Z) -2- (3-acetamidophenyl) -3- (4,6-dichloroindol-3-yl-2-carboxylic acid) propenoic acid Prepare by the method of Example 4 using (E) and (Z) -2- (3-acetamidophenyl) -3- (2-carboethoxy-4,6-d? Chloroindol-3?) -propenoic acid amide. to give the title compound PREPARATION 3 Mether of 3-methoxy-2- (2-nitrophenyl) -propene acid. Prepare by the method of Preparation 2 using (2-n-trophenyl) acetic acid to give the title compound.

EXAMPLE 35 Methyl ester of (E) and (Z) -2- (2-n? Trofen? L) -3- (2-carboethoxy? -4,6-dichloro? Ndol-3? L) -propene? Prepare by the method of Example 1 using 3-methoxy-2- (2-n-trophyl) -1-propene-co-methyl ester to give the title compound.

EXAMPLE 36 Acid methyl ester (E) and (Z) -2- (2-aminophen?) -3- (2-carboethoxy? -4,6-d? Chloro? Ndol-3-? L) - propene? co Prepare by the method of Example 2 using (E) and (Z) -2- (2-nitrophenyl) -3- (2-carboethoxy-4,6-dichloroindol-3-yl) -propenoic acid methyl ester to give the composed of the title.

EXAMPLE 37 Methyl ester of (E) and (Z) -2- (2-acetamidophenyl) -3- (2-carboethoxy-4,6-dichloro-ndol-3-yl) -propenoic acid ester OR Prepare by the method of Example 3 using methyl ester of (E) and (Z) -2- (2-am? Nofen? L) -3- (2-carboethoxy-4,6-dichloro? Ndol-3? l) -propenoic to give the title compound EXAMPLE 38 Acid (E) and (Z) -2- (2-acetamidophenyl) -3- (4,6-dichloroindol-3-yl-2-carboxylic acid) - propenoic Prepare by the method of Example 4 using (E) and (Z) -2- (2-acetamidophenyl) -3- (2-carboethoxy-4,6-dichloroindol-3-yl) -propenoic acid methyl ester to give the composed of the title.

EXAMPLE 39 Methyl ester of (E) and (Z) -2- (3- (Formamidophenyl) -3- (2-carboethoxy-4,6-dichloroindol-3-yl) -propenoic acid ester Combine methyl ester of (E) and (Z) -2- (3-aminophenyl) -3- (2-carboethoxy-4,6-dichlorindole-3?) -propene? Co (5.45 g, 12.6 mmol) and linden format (800 ml). After 20 hours, evaporate in vacuo to give a residue. Dilute the residue with ethyl acetate and extract with brine. Separate the organic layer, dry over MgSO 4, filter and evaporate in vacuo to give the title compound.

EXAMPLE 40 Methyl ester of (E) and (Z) -2- (3- (N-methylacetamidophenyl) -3- (2-carboethoxy-4,6-d? Chloroindol-3-yl) -propene? Combine methyl ester of (E) and (Z) -2- (3- (formamidophenyl) -3- (2-carboethoxy? -46-d? Chloro? Ndol-3-yl) -propene? Co (5.5) g, 12 mmol) and tetrahydrofuran (30 ml) Add a solution of borane dimethylsulfide complex in tetrahydrofuran (15 ml, 2M, 30 mmol) Heat at 60 ° C After 15 minutes, cool to room temperature and carefully quench with methanol Evaporate in vacuo to give a residue. Substitute the residue by chromatography on silica gel, levigating with 30% ethyl acetate / cyclohexane to give (E) and (Z) -2- (3- (N-methylaminophenyl) methyl ester. ) -3- (2-carboethoxy-4,6-dichloroindol-3-yl) -propenoic acid MS (CI / CH4) M + C2H5 + / e 457.477. Combine methyl ester of acid (E) and (Z) -2- (3- (N-methylaminophenyl) -3- (2-carboethoxy-4,6-dichloroindol-3-yl) -propenoic acid (4.6 mmol) and triethylamine (1.9 ml, 14 mmol) in dichloromethane (45 ml). of acetyl (0.82 ml, 12 mmol) After 20 hours, quench with methanol and dilute with dichloromethane. diluted reaction mixture with brine. Separate the organic layer, dry over MgSO 4, filter and evaporate in vacuo to give the title compound.

EXAMPLE 41 Acid (E) v (Z) -2- (3- (N-Methylacetamidophenyl) -3- (4,6-dichloroindol-3-yl-2-carboxylic acid) -propenoic acid Prepare by the method of Example 4 using (E) and (Z) -2- (3- (N-methylacetamidophenyl) -3- (2-carboethoxy-4,6-dichloroindol-3-yl) -propenoic acid methyl ester to give the title compound.

EXAMPLE 42 Methyl ester of (E) v (Z) -2- (3-N-methyl-N-carbomethyloxyminophenyl) -3- (2-carboethoxy-4,6-dichloroindol-3-yl) -propenoic acid ester Prepare by the method of Example 7 using methyl ester of (E) and (Z) -2- (3- (N-methylaminophenyl) -3- (2-carboethoxy-4,6-dichloroindol-3-yl) -prope noico to give the title compound.

EXAMPLE 43 Acid (E) and (Z) -2- (3- (N-methylacetam idophenyl) -3- (4,6-dichloroindol-3-yl-2-carboxylic acid) -propenoic acid 7 Prepare by the method of Example 8 using methyl ester of (E) and (Z) -2- (3- (N-meth? N -carbomethyl? Lox? Am? Nofen? L) -3- (2-carboethoxy? -4,6-d? Chloro? Ndol-3-? L) -propene? Co to give the title compound The compounds of formula (1) are excitatory amino acid antagonists. Antagonize the effects of excitatory amino acids on the NMDA receptor complex. They are preferably ligated to the strychnine-insensitive glycine binding site in the NMDA receptor complex associated with the treatment. from a number of disease states See Palfreyman, MG and BM Baron, Excitatory Ammo acid Antagonists, BS Meldrum ed, Blackwell Scientific, 01 01-21 (1 991), and, JA Kemp and PD Leeson, Trends m Pharmacological Sciences, 1 4, 20-25 (1 993), AJ Cárter, Drugs of the Future. 1 7, 595-61 3 (1992), and P D Leeson and L L Iverson, J Med Chem. 37, 4053-4067 (1994) The affinity for the strychnine-insensitive glycine binding site in the NMDA receptor complex can be determined in the following manner Approximately 50 to 60 young male Sprague-Dawley rats (CD strain) are sacrificed by decapitation and their cerebral cortexes and hypocampus are removed. The two brain regions are mixed and homogenized in 15 volumes of frozen 32 M sucrose using a Teflon glass homogenizer (10 steps at 400 rpm). centrifuge at 100 x gravity for 10 minutes and the supernatants are transferred and recentrifuged at 44,000 x gravity for 20 minutes. The upper white part of the pellets is re-suspended with a pipette in ice water and homogenize with a "polytron" (adjusting 6 for 10 seconds) and centrifuge at 44, 000 x gravity for 15 minutes Then, the pellets are resuspended in 6 volumes of water and placed in a dry ice / methanol bath until they are frozen, followed by thawing at 37 ° C in a water bath with agitation The freeze / thaw process is repeated and the final volumes of the suspensions are adjusted to 15 volumes with water and centrifuged at 44,000 x gravity for 15 minutes. The resulting pellets are resuspended in 15 volumes of HEPES-KOH (N-acid). -2-h? Drox? Et? Lp? Peraz? Na-N'-2-ethanesulfon? Co-potassium hydroxide) 10 mM at pH 74 containing 004% Triton X-100 (v / v), incubated at 37 ° C for 15 minutes and centrifuged at 44,000 x gravity for 15 minutes. The pellets are then resuspended in 15 volumes of 10 mM HEPES-KOH at pH 74 with a polytron (setting 6 for 10 seconds) and centrifuged at 44,000 x gravity for 15 minutes Repeat this process of resuspension / centpfugacion about 2 additional times The membranes are resuspended in 3 volumes of 10 mM HEPES and stored frozen at -80 ° C. When this test is to be performed, the membranes are thawed at room temperature and diluted with 9 volumes of 10 mM HEPES-KOH. pH 74 and incubated at 25 ° C for 15 minutes. This is followed by centrifugation at 44,000 x gravity for 15 minutes, then resuspension with 10 mM HEPES-KOH at pH 74 using a polytron. The process of mcubation / resuspension / centpfugation is Repeat an additional 2 times and the final pellet is resuspended in 6 volumes of 50 mM HEPES-KOH at pH 7.4. Incubation flasks in triplicate receive 50 μl of 200 nM [3 H] -glycine, 50 μl of 1 000 nM strychnine, 50 μl of various concentrations of test compounds diluted with 50 μM HEPES-KOH at pH 7.4, and 200 μl of membrane suspension (400 μg protein / aliquot) in a final volume of 0.5 ml. Incubations are performed at 4 ° C for 30 minutes and are terminated by centrifugation at 46,000 x gravity for 10 minutes. The supernatants are decanted and the pellets rinsed rapidly with 2 ml of ice cold 50 mM HEPES-KOH at pH 7.4, then dissolved in 4 ml of Ready Protein (Beckman I nstruments) and counted by liquid scintillation spectrometry. The specific binding of [3 H] -glycine is measured as the total radioactivity bound minus the ligand to the receptors in the presence of 0.1 M M D-serine. The radioactivity bound to the total membrane 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 test. The results of this test are expressed as an IC50, ie the molar concentration of a compound which causes 50% inhibition of ligation ligands. Compounds exhibit anticonvulsant properties and are useful in the treatment of seizure disorders, such as , attacks of great evils, attacks of small males, psychomotor attacks, autonomic attacks, etc. One method to demonstrate its antiepileptic properties is by means of its capacity to inhibit the attacks that are provoked by the administration of quinolinic acid. The test can be conducted in the following manner. A group containing ten mice or 01 -100 micrograms of test compound is intracerebrovenpularly administered in a volume of 5 microliters of saline A to a second control group containing an equal number of mice are administered an equal volume of saline as a control Approximately 5 minutes later, at both g A total of 7 7 micrograms of quinolinic acid are administered intracerebroventpularly in a volume of 5 micrograms of saline solution. The animals are observed for 15 minutes later for signs of tonic attack. The control group will have a statistically higher speed of Tonic attacks that the test group will have Another method to demonstrate the antiepileptic properties of these compounds is by their ability to inhibit audiogenic seizures in DBA / 2J mice This test can be conducted as follows Normally, a group of 6-8 DBA / 2J audionogenic male mice is administered from about 0.01 micrograms to about 10 micrograms of the test compound in the lateral ventricle of the brain or from about 0.100 igres to about 300 micrograms. Intrapeptoneal milligrams A second mouse segment is given an equal volume of saline control by the same route Five minutes after 4 hours, the mice are placed individually in glass jars and are exposed to a sound of 1 1 0 decibels for 30 seconds Each mouse is observed during sound exposure for signs of attack activity. The control group will have a statistically greater incidence of attacks than the group, which receives the test compound. Compounds of formula (1) are useful for preventing or minimizing CNS damage after ischemia. These anti-ischemia properties can be demonstrated by the ability of the compounds of formula (1) to reduce infarct volume in rats. subjected to central cerebral artery occlusion as follows Male Sprague-Dawley rats are subjected to occlusion of the central cerebral artery by an adaptation of the H Memezawa et al method, Ischemica Penumbra ma Model of Reversible Middle Cerebral Artery Occlusion m the Rat, Experimental Brain Research, 89, 67-78 (1992) The rat is anesthetized with halothane in a mixture of O 2 and NO (ratio 1 2) and a midline incision is made in the region of the ventral neck A catheter is placed venous resident in the jugular vein Under a dissecting microscope, the left common carotid artery is identified at its bifurcation to the external carotid artery and the internal carotid artery. located two bonds in the external carotid artery The internal carotid artery is exposed d istalmente to the point of its bifurcation towards the internal carotid artery mtracranial and the artery ptepgopalatina. A small cut is made in the distal segment of the external carotid artery and a 3-0 nylon monofilament is inserted into the lumen of the external carotid artery. The two previously placed clamps fit around the monofilament artery. External carotid artery is cut and reflected caudally, so that the monofilament can be advanced into the internal carotid artery, past the bifurcation of the distal internal carotid artery / artpa ptepglopalatine and continuing into the intranial segment of the internal carotid artery at a distance of 20 mm, at which point the origin of the central cerebral artery is occluded. The attachments are then adjusted and the wound closed. The compound or vehicle is only administered intravenously at a pre-determined time post-ischemia and the dosage can be simple, multiple or by continuous infusion Animals are provided with food and water and allowed to survive for 24 hours before slaughter. The rat is weighed and given a battery of four neurological tests to measure muscular strength, grooming skills, postural reflexes and sensorimotor integration, as described by CG Markgraf et al, Sensor / motor and Cognitive Consequences of Middle Cerebral Artery Occlusion m Rats, Bram Research 575, 238-246 (1992) The animal is then beheaded, the brain is removed, sliced into six sections and incubated in 2% chloride of 2, 3,5- tpfen? ltetrazole for 30 minutes, as described by K Isayama et al. Evaluation of 2, 3, 5-Tr? phenyltetrazole? um Chionde Stams to Delineate Rat Bram Infarcts, Stroke 22. 1 394-1 398 81 991) The area The infarct area is clearly visible The area of infarction is determined by computer-assisted image analysis for each of the six sections and is integrated over the antepor-postepor degree of the brain to produce the infarct volume. the group means ± SE by the number of the infarct and by the s four behavioral tests and groups compared using ANOVA with orthogonal contrasts Another method to demonstrate the ability of the compounds of formula (1) to minimize or prevent CNS damage after ischemia is as follows U na adult male rat weighing 200 -300 g is anesthetized with halothane in a mixture of O2 and NO (proportion 1 2) and a midline incision is made in the region of the ventral neck A venous catheter is placed in the jugular vein The common carotid artery is exposed and it is dissected free of the cervical sympathetic nerves and vagus A 4-0 silk suture ligature fits securely The animal is placed in a confinement, so that the right side of the head is upwards The area is rubbed with betadiene and then the incision is made through the skin and the temporal muscle in order to expose the skull Care must be taken not to cut the vein g rande q that is visible through the muscle Once the skull is exposed, the central carotid artery is visible through the skull Using a Foredom micro drill with a 4 mm burr, a small hole is made (approximately 8 mm) in the skull directly above the central carotid artery After drilling through the skull, there is usually a thin layer of the skull that remains, which is carefully removed with fine forceps Remove the dura, as required, away from the area directly above the central carotid artery The right central cerebral artery occlusion is then performed by electrocoagulation if it does not damage the brain The central cerebral artery l cauterizes immediately distal to the inferior cortical vein A small piece of foam gel is then placed in the area and the muscle and skin sutured with 3-0 silk Compound or vehicle is administered only intravenously at a pre-determined time post - ischemia and the dosage can be simple, multiple or by continuous infusion. The animals are given food and water and allowed to survive for 24 h Then the animal is decapitated, the brain is removed, sliced into six sections and incubated in 2% chloride 2, 3, 5-tpfen? ltetrazol? or for 30 minutes, as described by KI sayama et al, Evaluation of 2, 3, 5-Tr? phenyltetrazole? um Chlonde Stams to Delineate Rat Brain Infarcts , Stroke 22, 1 394- 1 398 (1 991) The area of infarction is clearly visible The area of infarction is determined by computer-aided image analysis for each of the six sections and is related to the degree antepor-postepor of the brain to produce go the volume of the infarct The means of the group ± SE for infarct volume and for the four behavioral tests are determined and the groups are compared using ANOVA with orthogonal contrasts. The compounds are also useful in the treatment of neurodegenerative diseases. finished "neurodegeneration" refers to a progressive death and disappearance of a population of nerve cells that occur in a manner characteristic of a particular disease state and that leads to brain damage. The term neurodegenerative diseases include H untington's disease. , Alzheimer's disease, senile dementia, acidem ia g lutapca ti po I dementia of m ulti-infarct am iotrophic lateral sclerosis and neuronal damage associated with non-controlled ataq ues 7 administering these compounds to a patient undergoing such a condition will serve to either prevent the patient from experiencing further neurodegeneration or decrease the rate at which neurodegeneration occurs. As is clear to those skilled in the art, the compounds do not correct any damage to the CNS that has already occurred, as the result of any illness, physical injury, or a lack of oxygen or sugar. As used in this application, the term "treat" refers to the ability of the compounds to prevent further damage or delaying the rate 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 the vocalizations of affliction in rat pups. The proof is based on the phenomenon that when a baby rat is removed from its bait, It will be found that anxiolytic vocalization is found to block these vocalizations. Test methods have been described by Gardner, CR Distress Vocalization m Rat Pups A Simple Screenmg Method for Anxiolytic Drugs, J Pharmacol Methods, 14, 1 81 -87 (1 986) and I nsel et al Rat Pup Isolation Calis Possibie Mediation by the Benzodiazepme Receptor Complex, Pharmacol Biochem Behav, 24, 1 263-67 (1986) The compounds also exhibit an analgesic effect and are useful for controlling odor. are effective in the treatment of migraine As excitatory amino acid antagonists, the compounds of formula (1) are useful in the treatment of diseases and conditions mediated by excitatory amino acids, including neurodegenerative diseases, seizure disorders, ischemic / hypoxic / hypoglycemic damage to brain tissue , anxiety, pain, migraine, and others known to those skilled in the art In a modali Further, as excitatory amino acid antagonists, the present invention provides a method for treating diseases and conditions mediated by excitatory amino acids, including neurodegenerative diseases, seizure disorders, ischemic / hypoxic / hypoglycemic damage to brain tissue, anxiety, pain and migraine in a patient in need of the same, comprising administering said patient a therapeutically effective amount of a compound of formula (1). As used herein, the term "patient" refers to a warm-blooded animal, such as a mammal. , which is afflicted with a particular allergic disease It is understood that the guinea pigs, dogs, cats, rats, mice, horses, cattle, sheep, monkeys, chima pances and humans are examples of animals within the scope of the sig Term Definition As used herein, the term "therapeutically effective amount" of a compound of formula (1) refers to an amount which is effective to treat the diseases and conditions described herein. This term is intended to refer to all processes in which an ad ism inution, interruption, arrest or suspension of the progression of the diseases and conditions described herein, but does not necessarily indicate a total elimination of all symptoms of the disease, and is intended to include the prophylactic treatment of diseases and conditions. A therapeutically effective amount can be readily determined by the attending physician, as one skilled in the art, by the use of conventional techniques and by observing the results obtained under analogous circumstances. To determine the therapeutically effective amount, the dose, a number of factors are considered by the attending physician, including, but not limited to: mammalian species, their size, age, and general health; the specific disease or condition involved, the degree of involvement or severity of the disease, the response of the individual patient; the particular compound administered, the mode of administration; the bioavailability characteristics of the preparation administered, the dose regimen selected, the use of concomitant medication, and other relevant circumstances. A therapeutically effective amount of a compound of formula (1) is expected to vary from about 0. 1 ml. branch per kilogram of body weight per day (mg / kg / day) to about 50 mg / kg / day The preferred amounts are capable of being determined by a person skilled in the art to carry out the treatment of a Patient afflicted with diseases and conditions described herein, a formulation of formula (1) can be admired in any form or manner, which makes the compound bioavailable in an effective amount, including oral and parenteral routes. For example, the compounds of formula (1) can be administered orally, subcutaneously, intramuscularly, intravenously, transdermally, rectally, topically and the like. One skilled in the art of preparing formulations can easily select the proper form and manner of administration, depending on the particular characteristics of the selected compound, the disease or condition to be treated, the stage of the disease or condition and other relevant circumstances (Remington's Pharmaceutical Sciences, 18th edition, Mack Publ ishing Co (1990)) The compounds of the present invention can be administered alone or in the form of a pharmaceutical composition, in combination with pharmaceutically acceptable carriers or excipients, the proportion and nature of which are determined by the chemical and solubility properties of the selected com pound, the chosen route of administration and standard pharmaceutical practice. The compounds of the present invention, while effective themselves, can be formulated and administered in the form of their pharmaceutically acceptable salts, such as acid addition salts or base addition salts, for stability purposes, Convenience of crystallization, solubility, and similarities In another embodiment, the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula (1) in admixture or otherwise in association with or not or more pharmaceutically acceptable carriers or excipients. The pharmaceutical compositions are prepared in a manner well known in the pharmaceutical art. The carrier or excipient may be a solid, semi-solid or liquid material, which may serve as a vehicle or medium for the active ingredient Suitable carriers or excipients are well known in the art The pharmaceutical composition IICA can be adapted for oral, parenteral or topical use and can be administered to the patient in the form of tablets, capsules, suppositories, solution, suspensions or the like. The compounds of the present invention can be administered orally, for example, with a diluent. Inert or with an edible carrier Can be enclosed in gelatin capsules or compressed into tablets For the purpose of oral therapeutic administration, the compounds can be incorporated with excipients and used in the form of tablets, troches, capsules, Ixires, suspensions, syrups, wafers, chewing gums and the like These preparations should contain at least 4% of the compound of the present invention, the active ingredient, but should be varied depending on the particular form and may conveniently be between 4% to about 70% of the weight of the unit The amount of the compound present in compositions is such that an adequate dosage must be obtained. preferred compositions and preparations according to the present invention, can be determined by any person skilled in the art Tablets, pills, troches and similar capsules may also contain one or more of the following auxiliary binders, such as microcpstalin cellulose, gum tragacanth or gelatin, excipients such as , starch or lactose, disintegrating agents, such as, algic acid, Pmmogel, corn starch and similar, lubricants, such as, magnesium stearate or Sterotex, brighteners, such as colloidal silicon dioxide, and sweetening agents, such as, sucrose or saccharin can be added or a sabotage agent, such as, mint, methyl salicylate or orange flavoring agent. When the dosage unit form is a capsule, it can contain, in addition to materials of the above type, a carrier lq such as, polyethylene glycol or a fatty oil Other forms of dosage unit may contain various other materials, which modify the physical form of the product. The dosage unit, for example, as coatings In this way, the tablets or pills can be coated with sugar, lacquer or other enteric coating agents. A syrup can contain, in addition to the present compounds, sucrose as a sweetening agent and certain preservatives, dyes and dyes and flavors The materials used to prepare these various compositions should be pharmaceutically pure and non-toxic in the amounts used. For the purpose of parenteral therapeutic administration, the compounds of the present invention can be incorporated into a solution or suspension. preparations should contain at least 0 1% of a compound of the invention, but can be varied to be between 0 1 and approximately 80% by weight thereof The amount of the formula (1) present in such combinations It is such that adequate dosage will be obtained. Preferred com positions and preparations are able to be determined. The solutions or suspensions may also include one or more of the following auxiliaries: sterile diluents, such as, water for injection, saline, fixed oils, polyethylene glycols, glycerin, propylene glycol, or other solvents. synthetic; antibacterial agents, such as benzyl alcohol or methyl paraben; antioxidants, such as, ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; buffers, such as acetates, citrates or phosphate and agents for tonicity adjustment, such as, sodium chloride or dextrose. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. The compounds of the present invention can also be administered topically, and when this is done, the carrier can suitably comprise a gel base ointment or solution. The base, for example, may comprise one or more of the following: petrolatum, lanolin, polyethylene glycols, beeswax, mineral oil, diluents, such as water and alcohol, and emulsifiers and stabilizers. Topical formulations may contain a concentration of formula (1) or its pharmaceutically acceptable salt, from about 0. 1 to about 20% w / v (weight per volume unit). The compounds of the present invention can be administered topically 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 os in other excipients.

Preferably, topical administration will be achieved using a patch either of the reservoir type or porous membrane, or of a variety of solid matrix. Some sule transdermal devices are described in US Patent Nos. 3,742,951, 3,797, 494, 3, 996,934, and 4,031 , 894 These devices generally contain a support member, which defines one of its faces, an adhesive layer permeable to the active agent, which defines the other face and at least one reservoir containing the active agent interposed enters the surfaces of The faces Alternatively, the active agent may be contained in a plurality of microcapsules distributed along the permeable adhesive layer. In either case, the active agent is continuously delivered from the reservoir or microcapsules through a membrane in the adhesive. permeable to the active agent, which is in contact with the skin or mucosa of the receptor If the active agent is absorbed through the skin , a controlled and predetermined fl ow of the active agent is administered to the receptor. 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 present invention, the The pharmaceutically active compound is contained in a trace, from which it is delivered at the desired steady, constant and controlled rate. The matrix is permeable for the release of the compound through diffusion or microporous flow. The release is of controlled velocity. Such a system which does not require a membrane is described in the patent no idense 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 matrix by itself. Release by microporous flow occurs when the pharmaceutically effective compound is transported through a liquid phase in the pores of the matrix. Although the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variation, use or adaptation of the invention by following, in general, the principles of the invention including such departures from the present description, as they fall within the known or customary practice within the art. Normally, neurodegenerative diseases are associated with a loss of N M DA receptors. In this way, the compounds of formula (1) 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 for the purpose of determining whether the patient is exhibiting a decreased number of N-MDA receptors and the rate at which they are present. happening that loss.

Claims (1)

1. CLAIMS 1 A compound of the formula wherein X is hydroxy, forms with the adjacent C (O) a physiologically acceptable ester, wherein X can be represented by -OR8, -OCH2OR8 or -O- (CH2) p-NR R, or, in which R8 is represented by C, -C 4 alkyl, phenyl, substituted phenyl or a phenylalkyl substituent, in which the phenyl ring may be optionally substituted, p is 2 or 3, R 9 and R 10 are each independently represented by a C alkyl, -C or together with the nitrogen atom to which they are attached form a ring -CH2-CH2-Z1-CH2-CH2-, where Z is a bond, O, S or NR ,, in which Rn is hydrogen or C, -C4 alkyl, or X is hydroxy, forms with the adjacent C (O) a physiologically acceptable amide, wherein X can be represented by -NR, 2R13l R, 2 is represented by hydrogen or a C, - alkyl C4I and R3 are represented by hydrogen, phenyl, substituted phenyl, phenylalkyl or a C, -C4 alkyl, or R12 and R3 are taken together with the nitrogen atom to which they are attached. n ring -CH2-CH2-Z2-CH2-CH2-, wherein Z2 is a bond, O, S or NR, 4, wherein R14 is hydrogen or C, -C4 alkyl, Y is hydroxy, form with C ( O) adjacent to a physiologically acceptable ester, wherein Y can be represented by -OR8, -OCH2OR8 or -O- (CH2) p-NR9R, or, in which R8 is represented by C, -C, alkyl, substituted phenyl or a phenylalkyl substituent, in which the phenyl ring may be optionally substituted, p is 2 or 3, R9 and R10 are each independently represented by a C, -C4 alkyl or together with the nitrogen atom to which they are attached; united form a ring -CH2-CH2-Z, -CH2-CH2-, wherein Z, is a bond, O, S or NR ,,, in which R ,, is hydrogen or C, -C4 alkyl, or Y is hydroxy, forms with the adjacent C (O) a physiologically acceptable amide, where Y can be represented by -NR, 2R, 3, R12 is represented by hydrogen or an alkyl of C, -C4, and R, 3 is represented by hydrogen, phenyl, substituted phenyl, phenyl alkyl or an alkyl of C, -C4, or R, 2 and R13 are taken together with the nitrogen atom to which they are attached of a ring -CH2-CH2-Z2-CH2-CH2- wherein Z2 is a bond, OR , S or NR, 4, wherein R, 4 is hydrogen or C, -C 4 alkyl, or forms with the C (O) adjacent a physiologically acceptable amide, R is from 1 to 3 substituents independently chosen from the group consisting of hydrogen, C, -C 4 alkyl, C, -C 4 alkoxy, halogen CF 3 R, is selected from the group consisting of hydrogen and d-C 4 alkyl R 2 is a radical selected from the group consisting of wherein R3 is selected from the group consisting of hydrogen and d-C4 alkyl, R4 is from 1 to 2 substituents independently selected from the group consisting of hydrogen, C? -C4 alkyl, C, -C, halogen alkoxy and -CF3, R5 is C, -C4 alkyl, R6 is C, -C, alkyl, R7 is 1 to 2 substituents independently chosen from the group consisting of hydrogen, C, -C, C, -C4 alkoxy , halogen and -CF3, and pharmaceutically acceptable addition salts thereof A compound of claim 1, wherein R2 is a radical selected from the group consisting of wherein R 3 is selected from the group consisting of hydrogen and C, -C 4 alkyl, and R 5 is C, -C 4 alkyl, A compound of claim 1, wherein X is selected from the group consisting of hydroxy, C, -C, and -NH2 4 A compound of claim 1, wherein Y is selected from the group consisting of hydroxy C1-C4 alkoxy and -NH2 A compound of claim 3, wherein X is selected from the group which consists of hydroxy methoxy, ethoxy and -NH 2 6 A compound of claim 4, wherein Y is selected from the group consisting of hydroxy methoxy, ethoxy and -NH 2 A compound of claim 3, wherein X is hydroxy The compound of claim 4, wherein Y is hydroxy A compound of claim 1, wherein the compound is methyl ester of acid (E) or (Z) -2- (3-acetam? dofen? l) -3- (2-carboethoxy? -4, 6-d? Chloro? Ndol-3-? L) -propene? Co or a mixture thereof A compound of claim 1, wherein the compound is methyl ester of acid (E) or (Z) -2 - (3-benzamidophene) -3- (2-carboethoxy? -4,6-d? Chloro? Ndol-3? L) -propene? Co or a mixture thereof A compound of the claim 1, wherein the compound is a methyl ester of (E) and (Z) -2- (3- (N-carbomethaloxamino) phenol) -3- (2-carboethoxy? -4) , 6-d? Chloro? Ndol-3-? L) -propene? Co or a mixture thereof 12 A compound of claim 1, wherein the compound is methyl ester of (E) or (Z) -2- (3- (N-carboet? Lox? Am? No) phen?) -3- (2 -carboetox? -4,6-d? chloro? ndol-3? l) -propene? co or a mixture thereof 13 A compound of claim 1, wherein the compound is methyl ester of (E) or (Z) -2- (3- (N-carbo? Soprop? Lox? Am? No) phen? L) ~ 3- (2-carboethoxy? -4,6-d? Chloro? Ndol-3-? L) -propene? co or a mixture thereof A compound of claim 1, wherein the compound is methyl ester of (E) or (Z) -2- (3-methylsulfon? lam? dofen? l) -3- (2-carboethoxy? -4,6-d? Chloro? Ndol-3? L) -propene? Co or a mixture thereof A compound of claim 1, wherein the compound is acid (E ) -2- (3-acetam? Dofen? L) -3- (4,6-d? Chloro? Ndol-3? L-2-carboxylic acid) -propenoic acid 16 A compound of claim 1 , wherein the compound is (E) -2- (3-benzam? dofen? l) -3- (4,6-d? chloro? ndol-3? l-2-carboxylic acid) -propenoic 17 A compound of the claim n 1, wherein the compound is (E) -2- (3- (N-carbomethaloxamino) phen? I) -3- (4,6-d? chloro? ndol-3? l-2-carboxylic acid) -propene? co A compound of claim 1, wherein the compound is (E) -2- (3- (N-carboet? lox? am? no. ) fen? l) -3- (4,6-d? chloro? ndol-3? l-2-ac? do carbox? l? co) -propene? co A compound of claim 1, wherein the compound is (E) -2- (3- (N-carbo? soprop? lox? am? no) phen? l) -3- (4,6-d? chlorotondo-3? l-2-carboxylic acid) ? co) -propene? co A compound of claim 1, wherein the compound is (E) -2- (3-met? lsulfon? lam? dofen? l) -3- (4,6-d? chloro? ndol-3-? l-2-carboxylic acid? co) -propene? co A compound of claim 1, wherein the compound is (Z) -2- (3-acetam? dofen? l) - 3- (4,6-d? Chloro? Ndol-3-? L-2-carboxylic acid) -propenoic acid 22 A compound of claim 1, wherein the compound is (Z) -2- (3- benzamidophene) -3- (4,6-d? chloro? ndol-3-? l-2-carboxylic acid) -propenoic acid 23 A compound of claim 1 , wherein the compound is (Z) -2- (3- (N-carbomethaloxamino) phen? I) -3- (4,6-d? chloro? ndol-3-? l- 2-carboxy acid? Co) -propene? Co A compound of claim 1, wherein the compound is (Z) -2- (3- (N-carboet? Lox? Am? No) phen? ) -3- (4,6-d? Chloro-ndol-3? -l-2-acid-box-11-ico) -propene ico A compound of claim 1, wherein the compound is acid (Z) -2- (3- (N-carbo? Soprop? Lox? Am? No) phen? L) -3- (4,6-d? Chloro? Ndol-3? L-2-carboxylic acid? Co) - propene? co 26 A compound of claim 1, wherein the compound is (Z) -2- (3-met? lsulfone? lam? dofen? l) -3- (4,6-d? chloro? ndol-? 3-? L-2-carboxylic acid) -propene? Co A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 A pharmaceutical composition comprising a therapeutically effective amount of a compound according to the claim 1 in admixture with a pharmaceutically acceptable carrier 29 A method for the treatment of neurodegenerative diseases comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 1 A method for preventing ischemic damage / hypoxic / hypoglycemic to brain tissue comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 1. A method for the treatment of anxiety comprising administering a therapeutically effective amount of a compound of According to claim 1, a method for producing an analgesic effect comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 1. The use of a com position of the claim. 1, optionally in combination with a cover or pharmaceutically acceptable, for the preparation of a pharmaceutic composition to treat neurodegenerative diseases 34. The use of a compound of claim 1, optionally in combination with a pharmaceutically acceptable carrier, for the preparation of a pharmaceutical composition for preventing ischemic / hypoxic / hypoglycemic damage to brain tissue. 35. The use of a compound of claim 1, optionally in combination with a pharmaceutically acceptable carrier, for the preparation of a pharmaceutical composition for treating anxiety. 36. The use of a compound of claim 1, optionally in combination with a pharmaceutically acceptable carrier, for the preparation of a pharmaceutical composition to produce an analgesic effect. 37. The use of a compound of claim 1, as a pharmaceutically active compound.