MXPA99011973A

MXPA99011973A - Process for preparing 4-substituted-1h-indole-3-glyoxamides

Info

Publication number: MXPA99011973A
Application number: MXPA/A/1999/011973A
Authority: MX
Inventors: Van Khau Vien; Matthew Pawlak Joseph; John Martinelli Michel
Original assignee: Eli Lilly And Company
Priority date: 1997-06-26
Filing date: 1999-12-17
Publication date: 2000-09-04

Abstract

A process for preparing 1H-indole-3-glyoxamides useful for inhibiting SPLA2 and novel intermediates useful in the preparation of such compounds.

Description

PROCESS FOR PREPARING SUBSTITUTE 1H-INDOL-3-GLIOXAMIDES IN POSITION 4 FIELD OF THE INVENTION This invention relates to the process for preparing certain lH-indol-3-glyoxamides useful for inhibiting the sPLA2 mediated release of fatty acids for conditions such as septic shock.

BACKGROUND OF THE INVENTION It is known that certain lH-indole-3-glyoxamides are potent and selective inhibitors of mammalian sPLA2 useful for treating diseases such as. septic shock, "adult respiratory distress syndrome, pancreatitis, trauma, bronchial asthma, allergic rhinitis, rheumatoid arthritis and related sPLA2-induced diseases." The EPO 'publication number 0675110, for example, describes such compounds.Several patents and publications describe process for elaborate indole-3-glyoxamides The article, "Recherch.es in series indolique. VI sur tryptamines substituees ", by Arch Julia, Jean Igolen and Hanne Igolen, Bull, Soc. Chim. France, 1962, pp. 1060-1068, describes REF .: 32346 certain indole-3-glyoxamides and their conversion to tryptamine derivatives The article "2-Aryl-3-Indoleglyoxylamides (FGIN-1): A New Class of Potent and Specific Ligands for the Mitochondrial DBI Receptor (MDR)" by E. Romeo, et al., The Journal of Pharmacolocry and Experimental Therapeutics , Vol. 262, No. 3, (pp. 971-978) describes certain 2-aryl-3-indolglyoxylamides which have applications in research in the central nervous systems of mammals.The summary "Fragmentation of N-benzylindoles in ass Spectrometry ", Chemical Abstracts, Vol. 67, 1967, 73028h, reports several benzyl-substituted phenols including those having glyoxylamide groups in the 3-position of the indole nucleus US Patent No. 3,449,363 discloses trifluoromethylindoles having glyoxylamide groups in position 3 of the indole nucleus U.S. Patent No. 3,351,630 discloses alpha 3-indolyl acetic acid substituted compounds and their preparation including glyoxylamide intermediates U.S. Patent No. 2,825,734 describes the preparation of 3- (2 -amino-1-idroxyethyl) Índoles using 3-indolglyoxylamide intermediates such as 1-phenethyl-2-ethyl-6-carboxy-N-propyl-3-indolglyoxylamide (see example 30).

U.S. Patent No. 4,397,850 prepares isoxazolyl indolamines using glyoxylamide Índoles as intermediates. U.S. Patent No. 3,801,594 discloses prepared analgesic intermediates of 3-indolglyoxylamide. The article "No. 565. - Inhibiteurs d'enzymes, XII- -Preparation of (propargylamino-2-ethyl) -3 Índoles" by. Alemanhy, E. Fernandez Alvarez, O. Nieto Lopey and M.E. Rubio Herraez; Bulletin of the Societe Chimique De France, 1974, No. 12, pp. 2883-2888, describes various indolyl-3-glyoxamides which have substituted hydrogen in the 6-membered ring of the indole nucleus. The article "Indol-Umlagerung von 1-Diphenylamino-2, 3-dihydro-2, 3-pyrrolidonen" by G.ert Kollenz and Christa Labes; Liebigs Ann. Chem., 1975, pp. 1979-1983, describes 3-glyoxylamides substituted with phenyl. U.S. Application Serial No. 08/469954, incorporated herein by reference in its entirety, discloses a process for preparing 4-substituted-lH-indol-3-glyoxamide derivatives comprising reacting a 4-methoxyindole appropriately substituted (prepared as described by Clark, RD et al., Synthesis, 1991, pp 871-878, the description of which is incorporated herein by reference) with sodium hydride in dimethylformamide at room temperature (20-25 ° C) and then treating the arylmethyl halide at room temperatures to provide l-arylmethylindole which is O-demethylated using boron tribromide in methylene chloride (Tsung-Ying Shem and Charles A. Winter, Adv. Drug Res., 1977, 12, 176, the description of which is incorporated herein by reference) to provide 4-hydroxyindole. The alkylation is obtained with an ester of alphabromoalkanoic acid in dimethylformamide using sodium hydride as a base. The conversion of gloxamide is obtained by reacting the ester of - [(indol-4-yl) oxy] alkanoic acid first with oxalyl chloride, then with ammonia, followed by hydrolysis with sodium hydroxide in methanol. The process for preparing 4-substituted-1H-indol-3-glyoxamide derivatives, as stated above, has utility. However, this process uses expensive reagents and environmentally hazardous organic solvents, produces byproducts containing furan and results in a relatively low yield of desired product. The present invention provides an improved process for preparing 4-substituted-lH-indol-3-glyoxatin derivatives. The process of the present invention can be carried out with inexpensive, readily available reagents, using aqueous solvent systems and resulting in better performance such that at the same time they avoid the production of furan by-products. Other objects, features and advantages of the present invention will become apparent from the subsequent description and the appended claims.

BRIEF DESCRIPTION OF THE INVENTION The present invention provides a process for preparing a compound of the formula I or a pharmaceutically acceptable salt or prodrug derivative thereof; wherein: R1 is selected from the group consisting of alkyl * -7 * -2 wherein R10 is selected from the group consisting of halo, C-C-L-alkyl, C-L-C ^ alkoxy, -S- (alkyl), C? ~ C10) and C-C ^ haloalkyl and t is an integer from 0 to 5, including both; R 2 is selected from the group consisting of hydrogen, halo, C 1 -C 4 alkyl, C 3 -C 4 cycloalkyl, C 3 -C 4 cycloalkenyl, -O- (C-Ca alkyl), -S-alkyl Ci-Ca), aryl, aryloxy and HET; R4 is selected from the group consisting of -C02H, -S03H, and -P (O) (OH) 2 or a salt or prodrug derivative thereof; and R5, R6 and R7 are each independently selected from the group consisting of hydrogen, CJL-CS alkoxy, C-C haloalkoxy, C2-C6 haloalkyl, bromine, chlorine, fluorine, iodine and aryl; process which includes the stages of: a) halogenating a compound of formula X X wherein R8 is aryl alkyl or HET; with S02C12 to form a compound of formula IX IX b) hydrolyzing and decarboxylating a compound of the formula IX IX to form a compound of formula VIII Or a VIII c) renting a compound of formula VII with a compound of formula VIII VIII to form a compound of formula VI d) Aminating and dehydrating a compound of formula VI with an amine of the formula R ^ - Ha in the presence of a solvent forming an azeotrope with water to form a compound of formula V; e) oxidizing a compound of formula V by subjecting the reflux in a polar hydrocarbon solvent having a boiling point of at least 150 ° C and a dielectric constant of at least 10 in the presence of a catalyst to form a compound of formula IV f) renting a compound of formula IV with an alkylating agent of the formula XCH2R4 wherein X is a leaving group and R4a is -C02R4b, -S03R4b, -P (O) (OR4b) 2 or -P (O) (0R4b) H, wherein R4b is a acid protecting group to form a compound of formula III III g) reacting a compound of formula III III with oxalyl chloride and ammonia to form a compound of formula II h) optionally hydrolyzing a compound of formula II II to form a compound of formula I; Y i) optionally salifying a compound of formula I. In another embodiment of the invention there is provided a process for preparing a compound of formula I comprising the steps of: a) oxidizing a compound of the formula V when refluxing in a. polar hydrocarbon solvent having a boiling point of at least 150 ° C and a dielectric constant of at least 10 in the presence of a catalyst to form a compound of formula IV IV b) renting a compound of the formula IV with an alkylating agent of the formula XCH2R4 wherein X is a leaving group and R4a is -C02R4b, -S03Rb, -P (O) or -P (O) (0R4b) H, wherein R4b is an acid protecting group to form a compound of formula III c) reacting a compound of formula III III with oxalyl chloride and ammonia to form a compound of formula II d) optionally hydrolyzing a compound of formula II II to form a compound of formula I; Y e). optionally salifying a compound of formula I. The present invention also provides novel intermediate compounds of formula IV IV wherein: R1 is selected from the group consisting of alkyl of ~ 7 ^ -20 wherein R.sup.10 is selected from the group consisting of halo, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.2 alkoxy, -S- (C.sub.1 -C.sub.10 alkyl) and C.sub.1 -C.sub.10 haloalkyl, and t is an integer from 0 to 5, including both; R 2 is selected from the group consisting of hydrogen, halo, C 1 -C 4 alkyl, C 3 -C 4 cycloalkyl, C 3 -C 4 cycloalkenyl, -0- (C 1 -C 2 alkyl), -S-C 1 -C 6 alkyl C2), aryl, aryloxy and HET; R5, Rs and R7 are each independently selected from the group consisting of hydrogen, Ci-Cg alkoxy alkyl, C2-C3 haloalkoxy halo, bromo, chloro, fluoro, iodo and aryl. The compounds of formula IV are useful as intermediates for preparing the compounds of formula I. The present invention also provides a process for preparing a compound of formula IV which comprises the stages of a) halogenating a compound of formula X X wherein R8 is Cx-Cß alkyl, aryl or HET; with S02C12 to form a compound of formula IX b) hydrolyzing and decarboxylating a compound of the formula IX IX to form a compound of formula VIII O Cl VIII rent a compound of formula VII with a compound of formula VIII VIII to form a compound of formula VI d) Aminating and dehydrating a compound of formula VI with an amine of the formula in the presence of a solvent that forms an azeotrope with water to form a compound of formula V; e) oxidizing a compound of formula V by refluxing in a polar hydrocarbon solvent having a boiling point of at least 150 ° C and a dielectric constant of at least 10 'in the presence of a catalyst.

In another embodiment, the present invention provides a process for preparing a compound of formula IV comprising: oxidizing a compound of formula V V by refluxing in a polar hydrocarbon solvent having a boiling point of at least 150 ° C and a dielectric constant of at least 10 in the presence of a catalyst.

DETAILED DESCRIPTION OF THE INVENTION The lH-indol-3-glyoxylamides of the invention use certain defining terms as follows: As used herein, the term "alkyl" by itself or as part of another substituent means, unless otherwise defined, a straight or branched chain monovalent hydrocarbon radical such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tertiary butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, heptyl, hexyl, octyl, nonyl, decyl and the like.

The term "0.-0 ^ alkoxy" as used herein, denotes a group such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, n-pentoxy, isopentoxy, neopentoxy, heptoxy , hexoxy, octoxy, nonoxy, decoxy and similar groups, attached to the rest of the molecule by the oxygen atom. The term "C3-C4 cycloalkyl" includes cyclopropyl and cyclobutyl groups. The term "C3-C4 cycloalkenyl" includes a cycloprenyl or cyclobutenyl ring having a double bond in the 1 or 2 position. The term "halo" means fluorine, chlorine, bromine or iodine. The term "haloalkyl of C 1 -C 6" means a C 1 -C 4 alkyl group substituted with 1 to 3 halo atoms, attached to the remainder of the molecule by the alkyl group. The term "haloalkyl" means the term "haloalkyl" C2-C6 The term "C2-C6 haloalkoxy" 'means an alkoxy group substituted with halo, which group is attached to the rest of the molecule in the oxygen of the alkoxy The term "aryl" means a group having the structure of ring characteristic of benzene, pentalene, indene, naphthalene, azulene, heptalene, phenanthrene, anthracene, etc. The aryl group can be substituted with 1 to 3 substituents which are selected from the group consisting of alkyl or halo (preferably fluorine or chlorine) The term "aryloxy" means an aryl group attached to the rest of the molecule by an oxygen binder The term "leaving group" means a substituent with a non-shared electron pair that deviates from the substrate in a substitution reaction. Nucleophilic ion The term "leaving group" includes halo, sulfonate, acetate and the like. The term HET includes pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, pyrazole, furan, thiophene, thiazole, isothiazole, oxadiazole, thiadiazole, imidazole, triazole and tetrazole. The heterocyclic ring can be attached to the rest of the molecule by any carbon in the heterocyclic ring. The salts of the compounds of formula I are a further aspect of the invention. In those instances in which the compounds of the invention possess acid functional groups, various salts can be formed which are more water soluble and physiologically suitable than the parent compound. Representative pharmaceutically acceptable salts include, but are not limited to alkaline and alkaline earth salts such as lithium, sodium, potassium, calcium, magnesium, aluminum and the like. The salts are conveniently prepared from the free acid by treating the acid in solution with a base or by exposing the acid to an ion exchange resin. Included within the definition of pharmaceutically acceptable salts are the relatively non-toxic inorganic and organic base addition salts of compounds of the present invention, for example ammonium, quaternary ammonium and amine cations, nitrogenous base derivatives of sufficient basicity to form salts with the compounds of this invention (see, for example, S. Berge, et al., "Pharmaceutical Salts" J. Phar. Sci. 66: 1-19 (1977)). The prodrugs are derivatives of the compounds of the invention which are chemically or metabolically cleavable groups and are converted, by solvolysis or under physiological coalitions, to the compounds of the invention which are pharmaceutically active in vivo .. Derivatives of the compounds of this invention. invention have activity in both their acid and base derivative forms, but the acid derivative form often provides solubility, tissue compatibility or delayed release advantages in a mammalian organism (see, Bundgard, H., Desicrn of Prodrucrs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). The prodrugs include well-known acid derivatives who practice the art, such as, for example, esters prepared by reaction of the parent acid compound with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a suitable amine. Simple aliphatic or aromatic esters derived from pendant acid groups in the compounds of this invention are the preferred prodrugs. In some cases, it is desirable to prepare double ester type prodrugs such as (acyloxy) alkyl esters or ((alkoxycarbonyl) oxy) alkyl esters. The term "acid protecting group" is used herein as it is frequently used in synthetic organic chemistry, to refer to a group which will prevent an acid group from participating in a reaction carried out on some other functional group of the molecule, but which can be removed when you want to do so. Such groups are discussed by T. Greene in Chapter 5 of Protective Groups in Orcranic Synthesis, John Wiley and Sons, York, 1981, incorporated herein by reference in its entirety. Examples of acid protecting groups include ester or amide derivatives of the acid group, such as methyl, methoxymethyl, methylthiomethyl, tetrahydroranyl, methoxyethoxymethyl, benzyloxymethyl, phenylaryl, ethyl, 2,2,2-trichloroethyl, 2-methylthioethyl. , t-butyl, cyclopentyl, triphenylmethyl, p-bromobenzyl, trimethylsilyl, N, N-dimethyl, pyrrolidinyl, piperidinyl or o-nitroanilido. A preferred acid protecting group is methyl.

Preferred Compounds Processed by the Invention Process A preferred group of compounds of formula I prepared by the process of the present invention are those in which: R 1 is R2 is halo, cyclopropyl, methyl, ethyl, propyl, O-ethyl or S-methyl; R4 is -C02H; and Rs, R6 and R7 are H. Compounds which can be made by the process of the present invention include: ((3- (2-amino-1,2-dioxyethyl) -2-methyl-1- (phenylmethyl) ) -lH-indol-4-yl) oxy) acetic acid; dl-2- ((3- (2-amino-1,2-dioxyethyl) -2-methyl-1- (phenylmethyl) -lH-indol-4-yl) oxy) propanoic acid; ((3- (2-amino-1,2-dioxyethyl) -1- (((1,1'-biphenyl) -2-ylmethyl) -2-methyl-1H-indol-4-yl) oxy) acetic acid ((3- (2-amino-1,2-dioxyethyl) -1- ((1,1'-biphenyl) -3-ylmethyl-1H-indol-4-yl) oxy) acetic acid; ((3- (2-amino-1,2-dioxyethyl) -1- ((1,1 '-bifinyl) -4-ylmethyl) -2-methyl-1H-indol-4-yl) oxy) acetic acid; (3- (2-amino-1,2-dioxyethyl) -1- ((2,6-dichlorophenyl) methyl) -2-methyl-1H-indol-4-yl) oxy) acetic acid; ((3 - (2-amino-1,2-dioxyethyl) -1- (4-fluorophenyl) methyl) -2-methyl-1H-indol-4-yl) oxy) acetic acid; ((3- (2-amino-1, 2-dioxyethyl) -2-methyl-1- ((naph to the enyl) methyl) -lH-indol-4-yl) oxy) acetic acid; ((3- (2-amino-1,2-dioxyethyl) -2-ethyl-1- (phenylmethyl) -lH-indol-4-yl) oxy) acetic acid; ((3 - (2-amino-1,2-dioxyethyl) -1- ((3-chlorofenylmethyl) -2-ethyl-lH-indol-4-yl) oxy) acetic acid ((3- (2)) -amino-l, 2-dioxyethyl) -1- ((1,1'-biphenyl) -2-ylmethyl) -2-ethyl-lH-indol-4-yl) oxy) acetic acid ((3- (2 -amino-l, 2-dioxyethyl) -1- ((1,1'-biphenyl) -2-ylmethyl) -2-propyl-1H-indol-4-yl) oxy) acetic acid ((3- (2 -amino-l, 2-dioxyethyl) -2-cyclopropyl-1- (phenylmethyl) -1H-indol-4-yl) oxy) acetic acid ((3- (2-amino-1,2-dioxyethyl) -1) - ((1,1'-biphenyl) -2-ylmethyl) -2-cyclopropyl-1H-indol-4-yl) oxy) acetic acid, 4- ((3- (2-amino-1,2-dioxyethyl) ) -2-ethyl-l- (phenylmethyl) -lH-indol-4-yl) oxy) utanoic acid ((3- (2-amino-1,2-dioxyethyl) -2-ethyl-1- (phenylmethyl) -lH-indol-4-yl) oxyacetic acid; (3- (2-amino-1,2-dioxyethyl) -2-ethyl-6-methyl-1- (phenylmethyl) -lH-indol-4-yl) oxy) acetic acid; (3- (2-amino-1,2-dioxyethyl) -2,6-dimethyl-1- (phenylmethyl) -lH-indol-4-yl) oxy) acetic acid; ((3- (2-amino-1,2-dioxyethyl) -2-methyl-1- (phenylmethyl) -lH-indol-4-yl) oxy) acetic acid; (3- (2-amino-1,2-dioxyethyl) -6-ethyl-2-methyl-1- (phenylmethyl) -lH-indol-4-yl) oxy) acetic acid; (3- (2-amino-1,2-dioxyethyl) -2,6-diethyl-1- (phenylmethyl) -lH-indol-4-yl) oxy) acetic acid; (3- (2-amino-1,2-dioxyethyl) -2-methyl-6-phenoxy-1- (phenylmethyl) -lH-indol-4-yl) oxy) acetic acid; (3- (2-Aminooxoacetyl) -2-ethyl-6-methyl-1- (phenylmethyl) -lH-indol-4-yl) oxy) acetic acid; and ((3- (2-amino-1,2-dioxyethyl) -2-ethyl-6-phenoxy-1- (phenylmethyl) -lH-indol-4-yl) oxy) acetic acid, or a pharmaceutically acceptable salt of the same. Of these compounds, preferred compounds include: ((3- (2-amino-1,2-dioxyethyl) -2-ethyl-1- (phenylmethyl) -lH-indol-4-yl) oxyacetic acid; - (2-amino-1,2-dioxyethyl) -2-ethyl-6-methyl-1- (phenylmethyl) -lH-indol-4-yl) oxy) acetic acid ((3- (2-amino-1) , 2-dioxyethyl) -2,6-dimethyl-1- (phenylmethyl) -lH-indol-4-yl) oxy) acetic acid; ((3- (2-amino-1,2-dioxyethyl) -2-methyl-1- (phenylmethyl) -lH-indol-4-yl) oxy) acetic acid; ((3- (2-amino-1, 2-dioxyethyl) -6-ethyl-1- (phenylmethyl) -lH-indol-4-yl) oxy) acetic acid; (3- (2-amino-1,2-dioxyethyl) -2,6-diethyl-1- (phenylmethyl) -lH-indol-4-yl) oxy) acetic acid; (3- (2-amino-1,2-dioxyethyl) -2-methyl-6-phenoxy-1- (phenylmethyl) -lH-indol-4-yl) oxy) acetic acid; (3- (2-Aminooxoacetyl) -6-methyl-1-phenyl-1H-indol-4-yl) oxy) acetic acid; and ((3- (2-amino-1,2-dioxyethyl) -2-ethyl-6-phenoxy-1-phenylmethyl) -lH-indol-4-yl) oxy) acetic acid, or a pharmaceutically salt thereof. Of these compounds, ((3- (2-amino-1,2-dioxyethyl) -2-methyl-1- (phenylmethyl) -1H-indol-4-yl) oxy) acetic acid and ((3 - (2-amino-1,2-dioxyethyl) -2-ethyl-1- (phenylmethyl) -lH-indol-4-yl) oxyacetic acid The most preferred compound which can be prepared by the present process is the acid ((3- (2-amino-1,2-dioxyethyl) -2-ethyl-1- (phenylmethyl) -lH-indol-4-yl) -oxyacetic acid or a pharmaceutically acceptable salt thereof The compounds of formula I, in the one that R1 is R2 is halo, cyclopropyl, methyl, ethyl, propyl, 0-methyl or S-methyl and Rs, R6 and R7 are H are preferred intermediates in the process for making the compounds of formula I. The most preferred compound of formula IV is 2-ethyl-1- (phenylmethyl) -4-hydroxy-1H-indole. Additional typical examples of compounds of formula IV which are useful in the present invention include: 2-chloro-1- (3-methylphenylethyl) -4-hydroxy-6-methoxy-1H-indole, -2-cyclopropyl-1- (4-ethylthiophenylmethyl) -4-hydroxy-5- (2-fluorobutoxy) -1H-indole; 2- (cycloprop-1-enyl) -1- (5-chloroheptylphenylethyl) -4-hydroxy-5,7-difluoro-1H-indole; 2-methoxy-1- (3-butylphenylmethyl) -4-hydroxy-7-phenyl-1H-indole; 2-methylthio-l- (4-phenylethylphenylmethyl ') -4-hydroxy-6-iodo-1H-indole; 2-phenyl-1-heptyl-4-hydroxy-1H-indole; 2-naphthyl-1-octyl-4-hydroxy-6-hexyl-1H-indole; 2-cyclobutyl-1-dedocyl-4-hydroxy-1H-indole; 2- (cyclobut-1-enyl) -1- (2-chlorophenylmethyl) -4-hydroxy-7-butoxy-1H-indole; 2-cyclopropyl-l-octadecyl-4-hydroxy-5- (3-fluorohexoxy) -1H-indole; 2- (cycloprop-1-enyl) -1- (3-pentoxyphenylethyl) -4-hydroxy-6-methyl-1H-indole; 2-methoxy-1- (2-phenylmethylphenylmethyl) -4-hydroxy-7- (2-chloroethyl) -1H-indole; 2-ethylthio-1-tetradecyl-4-hydroxy-5, -7-dibromo-1H-indole; PROCESS OF THE INVENTION The process of the present invention provides an improved method for the synthesis of compounds of formula I using inexpensive and readily available reagents, as shown in Scheme Reaction I as follows: REACTION SCHEME I (V) (IV) (III) II) (I) A compound of formula V is dissolved in a polar hydrocarbon solvent, which has a boiling point of at least 150 ° C and a dielectric constant of at least ° C, such as diethylene glycol, Cellosolve ™, Carbitol ™, glyme, diglyme or triglyme. Carbitol is preferred in the present process. The amount of solvent used should be sufficient to ensure that all the compounds remain in solution until the desired reaction is completed. Solvents having a boiling point of 150 ° C to 250 ° C and a dielectric constant of 10 to 20 are preferred. Further preferred are solvents with a boiling point in the range of 150 ° C to 220 ° C and a constant dielectric from 12 to 18. Examples of other suitable solvents include m-dichlorobenzene, bromobenzene, m-toluidine, o-toluidine, trans-3-methylcyclohexanol, 1,1,2,2-tetrachloroethane, 2-heptanol, 2-butoxyethanol , o-dichlorobenzene, cresol, 1-octanol, 3-methylcyclohexanol, benzyl alcohol, 2-methylcyclohexanol, 4-methylcyclohexanol, octanenitrile, hexanonitrile, alpha-tolunitrile, 1,1,2,2-tetramethylurea and triethylene glycol. The solution is preferably heated to the reflux temperature of the selected solvent. It is desirable to carry out the reaction in the presence of a catalyst such as Pd / C, Pt / C, PdO, Pt02, V20s, CuO, NiO, DDQ, or Mn02. Palladium in carbon and palladium oxide are preferred. The reaction ends substantially in about 30 minutes to 24 hours. The indole (IV) can then be easily alkylated with an alkylating agent of the formula XCH2R4a wherein X is a suitable leaving group and R4a is a protected carboxy group, sulfonyl or phosphonyl acid, preferably protected with an ester group, in the presence of a base. A preferred alkylating agent is methyl bromoacetate. Suitable bases include potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate or potassium hydroxide. Potassium carbonate is preferred. The amount of alkylating agent is not critical, however, the reaction is best carried out using a molar excess of alkylating agent in relation to the initial material. Preferably the reaction is carried out in an organic solvent such as acetone, acetonitrile or dimethylformamide. Other suitable solvents include tetrahydrofuran, methyl ethyl ketone, acetonitrile or t-butyl methyl ether. The reaction is carried out at temperatures from about 0 ° C to 100 ° C, preferably at room temperature, and is substantially complete in about 1 to 24 hours, based on the reagents used under the conditions and reaction temperature. Optionally, a phase transfer reagent such as tetrabutylammonium bromide can be used. The preparation of glyoxamide II is easily carried out in a two-step process by first treating intermediate III with oxalyl chloride at concentrations from about 0.2 to 1.5 mmol, preferably at equimolar concentrations relative to the initial material. Solvents such as methylene chloride, chloroform, trichlorethylene, carbon tetrachloride, ether or toluene are preferred. Temperatures from about -20 ° C to room temperature, preferably about -5 ° C, are suitable.

In the second stage, the solution is treated with ammonia; either bubbled as a gas, or preferably, using a molar excess of 30% aqueous ammonia. The reaction is typically carried out at temperature from about -25 ° C to 25 ° C, preferably to about -2 ° C to 0 ° C, and is substantially complete in 10 minutes to 1 hour. The hydrolysis of II is obtained using a base such as potassium hydroxide, lithium hydroxide or sodium hydroxide, preferably sodium hydroxide, in a lower alcohol solvent such as methanol, ethanol, isopropanol, etc., or solvents such as tetrahydrofuran. , dioxane and acetone. Through the use of standard analytical techniques, such as CLAP, the reactions of Scheme I can be monitored to determine when the initial materials and intermediaries have been converted into products. The initial material V is prepared according to the following procedure.

REACTION SCHEME II X IX R8 is alkyl or aryl. First, an appropriately substituted propionylacetate X is halogenated by treatment with sulfuryl chloride, preferably at equimolar concentrations relative to the initial material, at temperatures from about 0 ° C to 25 ° C, preferably less than 15 ° C, to prepare IX. hydrolysis and decarboxylation of IX is obtained by refluxing with an aqueous acid, such as hydrochloric acid, for 1 to 24 hours.The solution containing the decarboxylated product VIII 'is neutralized to adjust the pH to about 7.0-7.5, and then it is reacted with the cyclohexanedione VII (preferably at equimolar concentrations) and a base, preferably sodium hydroxide, to provide the tricetone VI monohydrate as a precipitate which can be nullified and isolated, if desired. performed at temperatures from -20 ° C to room temperature and is substantially complete in about 1 to 2 4 hours The above reactions are preferably carried out as a "container" process with the reagents added to the reaction vessel in the order indicated above. Preferably, the reaction is allowed to be carried out without isolating the compounds of formula IX or VIII, thus avoiding exposure to these volatile tear-off agents. The preparation of V is obtained by refluxing VI in a nonpolar solvent with a high boiling point which forms an azeotrope with water, preferably toluene, with an equimolar amount of an amine of the formula R1NH2 wherein R1 is as it is defined before. Solvents with a boiling point of at least 100 ° C, such as toluene, xylene, cymene, benzene, 1,2-dichloroethane, are preferred. 0 mesitylene, thus eliminating the need for a pressure reactor. Sufficient solvent should be used to ensure that all compounds remain in solution until the reaction is substantially complete at approximately 1 to 24 hours. Alternatively, intermediate IV can be prepared from VI in a container process without isolating intermediate V by heating VI with palladium on carbon and an appropriately substituted amine of formula R1NH2 in a polar hydrocarbon solvent such as CarbitolHR, as described in Reaction Scheme I above. The reaction is preferably carried out at reflux and considered substantially complete in 1 to 24 hours.

METHOD FOR DEVELOPING THE INTERMEDIARY COMPOUND OF FORMULA IV Intermediate IV can be prepared as described in the above Schemes I, Step a and II. The intermediate hydroxyindole IV can be purified using standard crystallization procedures. For example, filtration of the reaction product on diatomaceous earth followed by rinsing with t-butyl methyl ether effectively removes the catalyst. The filtrate can then be diluted with additional t-butylmethylether and rinsed, preferably with water. The organic phase is collected, dried and concentrated by conventional means. The concentrate is preferably dissolved in methylene chloride / hexanes, filtered over silicon dioxide and reconcentrated. Standard analytical techniques, such as CLAP, can be used to monitor reactions in order to determine when the initial material and intermediaries become a product. It will be readily appreciated by those skilled in the art that the starting materials for all of the above processes are commercially available or can be easily prepared by known techniques from commercial starting materials. For example, the initial material X can be easily prepared as described by D.W. Brookks et al., Anaew. Chem. Int. De. Enq.1979. 18, 72. Other preparations are described by R-. J. Cregge et al., Tetrahedron Lett. 1973, 26, 2425; M.W. Rathke, et al., J. Am. Chem. Soc. 1971, 93, 2318; . Hirama, et al., Tetrahedron Lett. 1986, 27, 5281; D.F. Taber et al., J. Am. Chem. Soc. 1987, 109, 7488; and T. Hanken, Chem. Ind. 1973, 325. The preparation of the starting material VII can be carried out, for example, in a Dieckman cyclization as described by Gramatiga P, et al., Heterocycles 24 (3), 743-750 (1986) or Frank RL et al., J. Am. Chem. Soc. 72, p. 1645, 1950. Additional preparations can be found, among others, in Venkar Y. D. Et al., Tetrahedron Lett. 28, p. 551, 1987; H.E. Zimmerman et al., J. Am. Chem. Soc. 107 (25), p. 7732, 1985; Hosangadi B.D. et al. , Indian J. Chem .. 20, mp. 63, 1981; Zenyuk A.A. et al. , Zh Ora Khim 26 (10). 2232-2233 (1990); or Berry N. et al., Synthesis-S uttaart (6), 476-480 (1986). The following examples further illustrate the process of the present invention. The examples also illustrate the preparation of the intermediary compounds of this invention. The examples are illustrative only and are not intended to limit the scope of the invention in any way. The following abbreviations are used in the examples below: HCl is hydrochloric acid NaOH is sodium hydroxide Pd / C is palladium on carbon t-BuOMe is t-butylmethylether MgSO4 is magnesium sulfate CH2C12 is dichloromethane Si02 is silicon dioxide K2C03 is potassium carbonate i-PrOH is isopropyl alcohol NH3 (g ) is gaseous ammonia MeOH is methanol EtOH is ethanol MTBE is ter-butylmethylether Preparation of 2-ethyl- (phenylmethyl) -lH-indol-4-ol 750 g (4.12 moles) of 2- (2-oxobutyl) -1,3-cyclohexanedione are added to a 22L flask, followed by 75 g of 10% Pd / C and then 7.5 1 of carbitol (lot 119WC7) with agitation. To the flask, 462 g (4.32 moles) of benzylamine are added and heated at 200 ° C for about 1 hour. The reaction is allowed to reflux (at 197 ° C) for 1 hour. The CCD does not show initial material. The reaction is cooled to room temperature, filtered through Celite to remove the catalyst, the solids are washed with 6.0 1 of toluene and then 2 1 of water. 12 1 of toluene and 6 1 of water are added to the filtrate. The mixture is stirred and the layers separated. The aqueous layer is back-extracted with 2 x 4 1 methylene chloride. All the organic layers are combined and concentrated to an oil weighing 1008 g. This oil is filtered through a plug of silica gel using methylene chloride to elute product from silica. All fractions containing product are combined and concentrated to a solid (775 g). The solid is dissolved in 2 l of toluene at 65 ° C, stirred for 15 minutes and then diluted with 15 1 of cyclohexane, and stirred 10 minutes at 65-70 ° C. After cooling to room temperature, the product is crystallized and placed in a refrigerator (0 ° C) overnight, then stirred cold for 15-30 minutes, filtered and filtered. wash with 2.0 1 of cyclohexane. The product is dried under vacuum to a constant weight. 547.4 g. Yield = 52.9%.

Example 1 ((3-Aminooxoacetyl) -2-ethyl-1- (phenylmethyl) -lH-indol-4-yl) oxy) acetic acid A. Preparation of 2- (2-oxobutyl) -1, 3-cyclohexanedione Methyl propionylacetate (130.15 g, 1.0 mol) is placed in a 2 1 Morton flask with a mechanical stirrer, a nitrogen inlet and a thermocouple. External cooling is applied until the internal temperature is 10 ° C. Sulfuryl chloride (135 g, 1.0 mol) is added dropwise at a rate to maintain the temperature < 15 ° C. Upon completion of the addition, the chromatographic analysis indicates the total conversion to the desired chlorine compound. Then 205 ml of 1M HCl is added and the reaction mixture is stirred at reflux for 18 hours.

After cooling to room temperature, 4N NaOH is added to adjust the pH from 7.0 to 7.5. cyclohexanedione is added (112.13 g, 1.0 mol), and the mixture is cooled in an ice bath. Then 5N NaOH (200 ml, 1.0 mol) is added dropwise and the reaction is stirred for 18 hours at room temperature. The resulting thick precipitate is filtered, rinsed with water and dried in vacuo to provide the subtitle tricetone monohydrate, 101 g, 56%. P.f. = 96-98 ° C Rf = 0.63 (Si02 / 9: 1 CH2C12: í-PrOH). XH NMR (CDC13) 6 1.04 (t, 3H, J = 7.2 Hz), 1.93 (m, 2H), 2.35 (m, 2H), 2.50 (m, 2H), 2.63 (c, 2H, J = 7.2 Hz) , 3.51 (s, 2H), 9.97 (s, 1H). IR (CHCl3) 3018, 1707, 1613, 1380, 1189, 1127 crn "1. UV (EtOH)? Max (e) = 262 (14500) EA theory: C, 59.98 H, 8.05 found: C, 59.71 H, 7.82 MS for C 10 H 14 O 3: m / z = 183 (m + 1) B. Preparation of 2-ethyl-l, 5, 6, 7-tetrahydro-1- (phenylmethyl) -4H-indol-4-one The tricetone obtained above, 101.14 g (0.51 mol) is placed in a 200 ml flask equipped with a Dean-Stark water separator, a mechanical stirrer and a dropping funnel. 600 ml of toluene are added and the mixture is heated to reflux until the distillate becomes clear and all the water is removed. The reaction mixture is cooled slightly, while benzylamine is added dropwise (55 g, 0.51 moles) which causes an exothermic reaction with the generation of water. Upon complete addition, the reaction is brought to reflux with continuous azeotropic water removal (3 hours) . Chromatographic analysis indicates that tricetone is completely consumed. The light yellow solution is then cooled to room temperature, after which the color changes to coffee. The toluene solution is concentrated to dryness and the resulting brown oil (133.8 g) is used directly in the subsequent oxidation. P.f. 59-610 ° C Rf = 0.37 (SiO2 / 2: 1: 1 hexane: CH2C12: EtOAc). XH NMR (CDC13) d 1.91 (t, 2H, J = 7.4 Hz), 2.80-2.12 (m, 2H), 2.42-2.48 (m, 4H), 2.60-2.64 (m, 2H), 5.03 (s, 2H) ), 6.38 (s, 1H), 6.89-6.91 (m, 2H), 7.28-7.32 (, 3H). 13C NMR (DMSO-dg) d 12.9, 19.2, 21.9, 23.9, 38.0, 46.9, 101.7, 119.7, 126.4, 127.7, 129.3, 137.0, 138.0, 144.4, 192.8. IR (KBr) 1640, 1453, 1175, 1137 crn "1. UV (EtOH)? Aax (e) = 284 (7500), 252 (11000), 208 (199000) Theoretical EA: C, 80.60 H, 7.56 N, 5.53 found: C, 80.80 H, 7.67 N, 5.56 EM for C17H19NO: m / z = 253 C. Preparation of 2-ethyl- (phenylmethyl) -lH-indol-4-ol A 200 ml 3-neck Morton flask is equipped with a mechanical stirrer, a reflux condenser and a stopper. The flask is charged with 10% Pd / C (26.8 g), followed by a solution of the compound from step B above, (133.8 g) in Carbitol ™ (800 ml, 2-ethoxy (ethoxy) ethanol). The resulting mixture is then refluxed for 18 hours. After cooling, the filtration over diatomaceous earth followed by rinsing with t-BuOMe effectively removes the catalyst. The filtrate is diluted with a total of 1 1 of t-BuOMe and rinsed with water (3 x 2 1). The organic phase is dried over MgSO4 and concentrated to provide 166 g of a dark brown oil. The oil is dissolved in CH2C12: hexanes (3: 1) and filtered on Si02 (325 g), eluting with an additional solvent until colorless. The concentration provides 132.7 g of the indole of the subtitle. P.f. 98.5-100 ° C R £ = 0.74 (SiO2 / 2: 1: 1 hexanes: CH2C12: EtOAc). H NMR (CDC13) d 1.32 (t, 3H, J = 7.4 Hz), 2.67 (c, 2H, J = 7.4 Hz), 4.96 (s, 1H), 5.29 (s, 2H), 6.39 (s, 1H) , 6.51 (d, 1H, J = 7.9 Hz), 6.82 (d, 1H, J = 8.2 Hz), 6.94-6.99 (m, 3H), 7.23-7.26 (m, 3H). 13C NMR (DMS0-d6) d 13.1, 19.9, '46.4 ', 96.2, 101.8, 104.3, 118.0, 122.1, 126.6, 127.5, 129.1, 139.2, 139.5, 141.0, 150.6. IR (KBr) 1586, 1467, 1351, 1250 cm "1. UV (EtOH)? Max (e) = 296 (6700), 287 (6500), 269 (8200), 223 (35000) .Theoretical EA: C, 81.24 H, 6.82 N, 5.57, found: C, 80.98 H, 6.90 N, 5.59 MS for C17H17NO: m / z = 251.

D. Preparation of ((2-ethyl-1- (phenylmethyl) -lH-indol-4-yl) oxy) acetic acid methyl ester.

The compound from part C above (3.0, 12.0 mmol), K2C03 (3.31 g, 24.0 mol) and acetone (24 ml) is charged to a 100 ml round bottom flask equipped with a magnetic stirrer. The heterogeneous reaction mixture is stirred at room temperature for 20 minutes. Methyl bromoacetate (1.7 ml, 18.0 mmol) is added dropwise via syringe and the reaction mixture is stirred for an additional 15 hours. The reaction mixture is filtered on a Büchner funnel, the solid is washed with acetone and the filtrate is passed over corrugated filter paper. The acetone is concentrated in vacuo to provide 4.1 g as a white solid. Crystallization from i-PrOH (30 ml) provides 3.28 g (84.5%) of the desired substituted intermediate as a colorless crystalline solid. P.f. 95.5-97 ° C Rf = 0.74 (Si02 / CH2C12). XH NMR (CDC13) d 1.32 (t, 3H, J = 7.4 Hz), 2.67 (c, 2H, J = 7.4 Hz), 4.96 (s, 1H), 5.29 (s, 2H), 6.39 (s, 1H) , 6.51 (d, 1H, J = 7.9 Hz), 6.82 (d, 1H, J = 8.2? Z), 6.94-6.99 (m, 3H), .7.23-7.26 (m, 3H). 13 C NMR (CDCl 3) d 12.6, 20.0, 46.7, 52.2, 65.9, 96.0, 101.1, 104.0, 118.8, 121.4, 125.9, 126.0, 127.3, 128.8, 137.9, 139.1, 141.9, 151.1, 169.9. IR (CHCl3) 3009, 1761, 1739, 1498, 1453, 1184, 1112 cm "1. UV (EtOH)? Max (e) = 221 (36500), 271 (9600), 283 (7800), 293 (7700) Theoretical EA: C, 74.28 H, 6.55 N, 4.33 found: C, 73.32 H, 6.64 N, 4.19 EM for C20H21NO3: m / z = 324 (m + 1).

E. Preparation of ((3- (2-amino-1,2-dioxyethyl) -2-ethyl-1- (phenylmethyl) -lH-indol-4-yl) oxy) -acetic acid methyl ester Charge the compound of part D above (4.0 g, 0.0124 mol) to a 100 ml three-necked round bottom flask equipped with an N2 inlet, magnetic stirrer and a gas dispersion tube connected to a gas tank. NH3. 28 ml of dichloromethane are added, resulting in a yellow solution, which is cooled by means of a bath with ice. To the cooled solution, pure oxalyl chloride (1.1 ml, 0.012 mol) is slowly added via a syringe to form a dark colored solution. After stirring the reaction solution for 20 minutes at an ice bath temperature, chromatographic analysis (CCD on SiO2, CH2C12) indicates the absence of starting material. NH3 (g) is then introduced through a gas dispersion tube for 15 minutes, after which the dark green solution becomes a light yellow precipitate, which is stirred at the temperature of the ice bath for 20 minutes. additional minutes The reaction is diluted with CH2C12 (56 mL), filtered over diatomacea earth, washed with CH2C12 (50 mL) and the filtrate concentrated in vacuo to provide 4.65 g as a yellow solid. Recrystallization from MeOH (15 volumes) gives 3.0 g (61.3%) as light yellow needles. P.f. 179-181 ° C Rf = 0.16 (Si02 / 95: 5 CH2C12: MeOH). XH NMR (CDC13) d 1.20 (t, 3H, J = 7.5 Hz), 2.94 (c, 2H, J = 7.54 Hz), 3.78 (s, 3H), 4.7.4 (s, 2H), 5.35 (s) , 2H), . 66 (broad s, 1H), 6.54 (d, 1H, J = 8.0 Hz), 6.58 (s broad, 1H), 6.87 (d, 1H, J = 8.5 Hz), 7.02-7.07 (m, 3H), 7.25-7.29 (m, 3H). • 13C NMR (CDC13) d 14.4, 19.1, 47.0, 52.1, 65.9, 104.6, 104.8, 110.0, 117.0, 123.7, 126.1, 127.8, 129.0, 136.3, 138.3, 150.2, 151.9, 167.6, 169.7, 188.1. IR (CHC13) 3399, 1761, 1700, 1646, 1519, 1452, 1151 cm "UV (EtOH)? Max (e) = 218 (32300), 258 (126000), 333 (5500) Theoretical EA: C, 66. 99 H, 5.62 N, 7.10 found: C, 66. 06 H, 5.64 N, 7.61 MS for C22H22N2Os: m / z = 395 (m + 1).

F. Preparation of ((3- (2-amino-1,2-dioxyethyl) -2-ethyl-1- (phenylmethyl) -1H-indol-4-yl) oxy) acetic acid sodium salt The compound of part F above is charged into a 500 ml three-necked round bottom flask equipped with a mechanical stirrer and a reflux condenser. The solid is suspended in EtOH (150 ml). While the suspension is stirred vigorously at room temperature, 5N NaOH (9.1 ml, 45.7 mmol) is added. The reaction mixture is heated to reflux to form a thick white precipitate. The reaction is refluxed for 20 minutes and then cooled to room temperature. EtOH (150 ml) is added, the solid is filtered on a Buchner funnel and dried in a high vacuum oven at 60 ° C for 4 hours to provide 13.67 g (89.3%) of the title compound. P.f. 296 ° C XH NMR (D20) d 1.11 (t, 3H, J = 7.6 Hz), 2.96 (c, 3H, J = 7.6 Hz), 4.51 (S, 2H), 5.45 (s, 2H), 6.55 (d , 1H, J = 8 Hz), 6.91-7.25 (m, 8H). 13 C NMR (DMSO-dg) d 14.3, 18.3, 45.9, 68.3, 103.0, 103. 8, 110.1, 115.8, 123.1, 126.0, 127.3, 128.6, 137.3, 137.5, 148. 1, 152.8, 169.4, 171.8, 190.0. IR (CHC13) 3028, 1649, 1411, 1276, 722 cm "1. UV (EtOH)? Max (e) = 218 (34900), 258 (14900), 337 (5836). Theoretical EA: C, 62. 68 H, 4. 76 N, 6 96 found: C, 62 .43 H, 4. 78 N, 6. 69 MS for C21H19N2OsNa: m / z = 381 (m-21, Na / + H).

Example 2 Sodium salt of ((3- (2-aminooxoacetyl) -2-ethyl-6-methyl-1- (phenylmethyl) -lH-indol-4-yl) oxy) acetic acid A. Preparation of the sodium enolate of 4-ethoxycarbonyl-5-methyl-1,3-cyclodexnedione In a 250 ml flask of trellis, ethyl crotonate (32.26 g, 1.06 mol) and ethyl acetoacetate (35.45 g, 1.02 mol) are combined. Sodium ethoxide is added with stirring for 2 minutes. The mixture is heated to 78 ° C and maintained at this temperature for 1 hour and 45 minutes. The reaction is allowed to cool slowly and then is further cooled in an ice / water bath at 14 ° C. The reaction is filtered, rinsed twice with ethanol and then dried under vacuum to recover 36.7 g (63.7%) of the subtitle compound.

B. Preparation of 5-methylcyclohexanedione Into a 5-liter flask, 495.9 g (2.25 moles) of the compound of part A above and a solution of potassium hydroxide (311.0 g in 1250 ml of water) are heated to reflux. After 6.5 hours, 6M HCl (11) is added over 25 minutes and the mixture is allowed to reflux until no more gas is produced, about 1 hour. Another 75 ml of 6M HCl is added and again the reaction is allowed to reach the reflux temperature until gas is no longer produced. Add final 75 ml of 6M HCl and change color from orange to yellow. The reaction mixture is allowed to cool to 56 ° C and the liquid is evaporated to provide 2728 g of material. 2.6 1 of ethyl acetate are added and the solution is transferred to an exit-bottom flask of 22 1 and rinsed with 500 ml of ethyl acetate followed by 500 ml of MTBE and 500 ml of water. After shaking, the layers are allowed to separate. The organic layer is washed with brine (1.5 1) and then dried over sodium sulfate and filtered and the organic fractions are stripped by distillation to form 377 g of a slurry. The suspension is filtered and rinsed with 6.5 1 pentane and the minimum amount of ethyl acetate needed to remove the yellow color. The resulting product is dried in a vacuum oven to provide 161.7 g (56.9%) of the subtitle product. P.f. 126-128 ° C C. Preparation of ((3- (2-aminooxoacetyl) -2-ethyl-6-methyl-1- (phenylmethyl) -lH-indol-4-yl) oxy) acetic acid Following the procedure described in steps A-F, Example 1, above, using 160.5 g of the compound of part B, 7.62 g (91.2%) of the title compound is prepared with the sodium salt.

"Elemental analysis for theoretical C22H21H205Na C, 63.46 H, 5.08 N, 6.72 found C, 63.69 H, 5.16 N, 6.79 NMR (CD30D) d 1.15 (t, 3H, J = 7/2 Hz) ', 2.33 (s, 3H ), 2.95 (c, 2H, J = 7.2 Hz), 4.52 (s, 2H), 5.44 (s, 2H), 6.43 (s, 1H), 6.74 (s, 1H), 7.04 (m, 2H), 7.28 (m, 3H) It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects or products to which it refers.

Claims

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. A process for preparing a compound of the formula I or a pharmaceutically acceptable salt or prodrug derivative thereof; wherein: R1 is selected from the group consisting of: -C7-C20 alkyl; wherein R 10 is selected from the group consisting of halo, C 1 Cm alkyl, C 1 -C 4 alkoxy, C? ~ C10) and haloalkyl of C ^ C ^ and t is an integer from 0 to 5, including both; R2 is selected from the group consisting of hydrogen, halo, C-L-C, alkyl. C3-C4 cycloalkyl, C3-C4 cycloalkenyl, -0- (C ^ OJ alkyl), -S-alkyl, aryl, aryloxy and HET; R4 is selected from the group consisting of -C02H, -S03H, and -P (0) (OH) 2 or salts or derivatives of prodrugs thereof; and R5, R6 and R7 are each independently selected from the group consisting of hydrogen, Ci-Cg alkyl, Cx-C6 alkoxy, C1-C6 haloalkoxy, C2-C6 haloalkyl, bromine, chlorine, fluoro, iodine and aril; process which is characterized in that it comprises the steps of: a) halogenating a compound of formula X X wherein R8 is aryl alkyl or HET; with S02C12 to form a compound of formula IX b) hydrolyzing and decarboxylating a compound of the formula IX IX to form a compound of formula VIII VIII c) renting a compound of formula VII 15 with a compound of formula VIII VIII 20 to form a compound of formula VI D) Aminating and dehydrating a compound of formula VI with an amine of the formula RXNH2 in the presence of a solvent that forms an azeotrope with water to form a compound of formula V; e) oxidizing a compound of formula V by subjecting the reflux in a polar hydrocarbon solvent having a boiling point of at least 150 ° C and a dielectric constant of at least 10 in the presence of a catalyst to form a compound of formula IV f) renting a compound of formula IV 10 15 with an alkylating agent of the formula XCH2R4a wherein X is a leaving group and R4a is -C02R4b, -S03R4b, -P (O) (0R4b) 2 or -P (0) (0R4b) H, wherein 'R4b is an acid protecting group to form a compound of 20 formula III g) reacting a compound of formula III III with oxalyl chloride and ammonia to form a compound of formula II h) optionally hydrolyzing a compound of formula II II to form a compound of formula I; Y i) optionally salifying a compound of formula I.

2. A process for preparing a compound of formula I or a pharmaceutically acceptable salt or prodrug thereof wherein: R1 is selected from the group consisting of: -C7-C20 alkyl; wherein R10 is selected from the group consisting of halo, Cx-C10 alkyl, -S- (-alkyl, C _.- C10) and haloalkyl of C-L-C ^ and t is an integer from 0 to 5, inclusive both; R 2 is selected from the group consisting of hydrogen, halo, alkyl, (C 3 -C 4) cycloalkyl, C 3 -C 4 cycloalkenyl, -0- (C 1 -C 6 alkyl, C 1 -C 6 alkyl) , aryl, aryloxy and HET, R4 is selected from the group consisting of -C02H, -S03H, and -P (0) (0H) 2 or salts or derivatives of prodrugs thereof, and R5, Rs and R7 are selected each one independently of the group consisting of hydrogen, C1-C3 alkoxy alkyl, C2-C6 haloalkoxy halo, bromo, chloro, fluoro, iodo and aryl; process which is characterized in that it comprises the steps of: a) oxidizing a compound of formula V by subjecting the reflux in a polar hydrocarbon solvent having a boiling point of at least 150 ° C and a dielectric constant of at least 10 in the presence of a catalyst to form a compound of formula IV b) renting a compound of formula IV IV with an alkylating agent of the formula XCH2R4 in which X is a leaving group and R4a is -C02R4b, -S03R4b, -PÍO) (0R4b) 2 or -P (0) (0R4b) H, wherein R4b is a group acid protector to form a compound of formula III Or reacting a compound of formula III III with oxalyl chloride and ammonia to form a 20 compound of formula II D) optionally hydrolyzing a compound of formula II II to form a compound of formula I, - and e) optionally salifying a compound of formula I

3. The process according to claim 1 or 2, characterized in that the azeotrope is toluene and the polar hydrocarbon solvent has a boiling point of 150-250 ° C and a dielectric constant of 10-20.

4. The process according to claim 1 or 2, characterized in that the azeotrope is toluene and the polar hydrocarbon solvent has a boiling point of 150-220 ° C and a dielectric constant of 12-18.

5. The process according to any of claims 1 to 4, characterized in that ((3- (2-amino-1, 2-dioxyethyl) -2-ethyl-1- (phenylmethyl) -1H-indole-4-acid is prepared. il) oxy) acetic.

A compound characterized in that it is of formula IV wherein: R1 is selected from the group consisting of: -C7-C20 alkyl; Y wherein R10 is selected from the group consisting of halo, C-t_-C10 alkoxy alkyl, -S- (alkyl C? ~ C10) and haloalkyl of C -C ^ and t is an integer from 0 to 5, including both; R2 is selected from the group consisting of hydrogen, halo, C1-C3 alkyl, C3-C4 cycloalkyl, C3-C4 cycloalkenyl, -0- (C4 alkyl), -S-C alkyl], - ^), aryl, aryloxy and HET; and R5, R6 and R7 are each independently selected from the group consisting of hydrogen, C2-C6 haloalkoxy haloalkoxy alkyl, bromo, chloro, fluoro, iodo and aryl.

7. The compound according to claim 6, characterized in that it is 2-ethyl-1- (phenylmethyl) -4-hydroxy-1H-indole.

8. A process for preparing a compound of formula wherein: R1 is selected from the group consisting of: -C7-C20 alkyl; wherein R10 is selected from the group consisting of halo, dC- ^ alkyl, C ± -C10 alkoxy, -S- (? -C10 alkyl) and CLChaloalkyl ^ and t is an integer from 0 to 5, including both; R 2 is selected from the group consisting of hydrogen, halo, C 1 -C 4 alkyl, C 3 -C 4 cycloalkyl, C 3 -C 4 cycloalkenyl, -0- (d- alkyl), -S-C 2 -C 2 alkyl) , aryl ', aryloxy and HET; and Rs, Rs and R7 are each independently selected from the group consisting of hydrogen, Ci-Cg alkoxy alkyl, C2-C6 haloalkoxy halo, bromo, chloro, fluoro, iodo and aryl; the process is characterized in that it comprises the steps of: a) halogenating a compound of formula X X wherein R8 is aryl alkyl or HET; with S02C12 to form a compound of formula IX b) hydrolyzing and decarboxylating a compound of the formula IX to form a compound of formula VIII VIII 20 c) alkylating a compound of formula VII 25 with a compound of formula VIII VIII to form a compound of formula VI D) Aminating and dehydrating a compound of formula VI with an amine of the formula R ^ -NH ^ in the presence of a solvent that forms an azeotrope with water to form A compound of formula V; e) oxidizing a compound of formula V by subjecting the reflux in a polar hydrocarbon solvent having a boiling point of at least 150 ° C and a dielectric constant of at least 10 in the presence of a catalyst.

A process for preparing a compound of formula IV wherein: R1 is selected from the group consisting of: -C7-C20 alkyl; wherein R10 is selected from the group consisting of halo, dC ^ alkyl, dC ^ alkoxy, -S- (C? -C10 alkyl) and CLC haloalkyl ^ and t is an integer from 0 to 5, including both; R 2 is selected from the group consisting of hydrogen, halo, C 1 -C 3 alkyl, C 3 -C 4 cycloalkyl, C 3 -C 4 cycloalkenyl, -O- (d-C alkyl,), -S-alkyl C -Cz), aryl, aryloxy and HET; and R5, R6 and R7 are each independently selected from the group consisting of hydrogen, d-Cg alkyl, Ci-C8 alkoxy, C2-C3 haloalkoxy / bromine, chloro, fluoro, iodo and aryl haloalkoxy; the process is characterized in that it comprises oxidizing a compound of formula V by refluxing in a polar hydrocarbon solvent having a boiling point of at least 150 ° C and a dielectric constant of at least 10 in the presence of a catalyst.

10. The process according to claim 8 or 9, characterized in that the azeotrope is toluene and the polar hydrocarbon solvent has a boiling point of 150-250 ° C and a dielectric constant of 10-20.

11. The process according to claim 7 or 8, characterized in that the azeotrope is toluene and the polar hydrocarbon solvent has a boiling point of 150-220 ° C and a dielectric constant of 12-18.

12. The process according to any of claims 8 to 11, characterized in that the compound 2-ethyl-1- (phenylmethyl) -4-hydroxy-1H-indole is prepared.

13. A process for preparing a compound of the formula I or a pharmaceutically acceptable salt or prodrug derivative thereof: in which: _ _ _. R1 is selected from the group consisting of: -C7-C20 alkyl; Y wherein R 10 is selected from the group consisting of halo, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C? -C10) and Ci-C10 haloalkyl and t is an integer from 0 to 5, including both; R2 is selected from the group consisting of hydrogen, halo, C3-C4 cycloalkyl, C3-C4 cycloalkenyl, -O- (Ci-Ca alkyl), -S-Ci-Ca alkyl), aryl, aryloxy and HET; R4 is selected from the group consisting of -C02H, -S03H, and -P (0) (OH) 2 or salts or derivatives of prodrugs thereof; and Rs, Rs and R7 are each independently selected from the group consisting of hydrogen, Ci-C6 alkyl, C6-C6 alkoxy, Ci-Cg haloalkoxy, C2-C6 haloalkyl, bromine, chlorine, fluoro, iodine and aryl; process which is characterized in that it comprises the steps of: a) halogenating a compound of formula X X wherein R8 is C6-C6 alkyl, aryl or HET; with S02C12 to form a compound of formula IX b) hydrolyzing and decarboxylating a compound of formula IX 20 to form a compound of formula VIII VIII to rent a compound of formula VII with a compound of formula VIII 10 O Cl. VIII 15 to form a compound of formula VI d) Aminating and dehydrating and oxidizing a compound of formula VI by refluxing in a polar hydrocarbon solvent having a boiling point of at least 150 ° C and a dielectric constant of at least 10 minus 10 in the presence of a catalyst and an amine of the formula R1NH2; to form a compound of formula IV e) renting a compound of the formula IV 25 with an alkylating agent of the formula XCH2R4a wherein X is a leaving group and R4a is -C02R4b, -S03R4b, -P (0) (0R4b) 2 or -P (0) (0R4b) H, wherein R4b is an acid protecting group to form a compound of formula III reacting a compound of formula III 'III 20 with oxalyl chloride and ammonia to form a compound of formula II g) optionally hydrolyzing a compound of formula II II to form a compound of formula I, - and h) optionally salifying a compound of formula I

14. A process for preparing a compound of formula I or a pharmaceutically acceptable salt or prodrug thereof, wherein: R1 is selected from the group consisting of: -C7-C20 alkyl; wherein R10 is selected from the group consisting of halo, Ci-C10 alkyl, Ci-C10 alkoxy, -S- ( C? -C10) and Ci-C10 haloalkyl and t is an integer from 0 to 5, including both; R2 is selected from the group consisting of hydrogen, halo, Ci-Cj alkyl, C3-C4 cycloalkyl, C3-C4 cycloalkenyl, -O- (Ci-C2 alkyl), -S-Ci- alkyl-; ), aryl, aryloxy and HET; R4 is selected from the group consisting of -COzH, -S03H, and -P (O) (OH) 2 or salts or derivatives of prodrugs thereof; and R5, R6 and R7 are each independently selected from the group consisting of hydrogen, Ci-C3 alkyl, Ci-Cg alkoxy, Ci-C6 haloalkoxy, C2-C6 haloalkyl, bromine, chlorine, fluoro, iodine and arilo, • process which is characterized by comprising the steps of: a) Aminating, dehydrating and oxidizing a compound of the formula VI. VI when refluxing in a polar hydrocarbon solvent having a boiling point of at least 150 ° C and a dielectric constant of at least 10 in the presence of a catalyst and an amine of the formula R1NH2 to form a compound of formula IV b) renting a compound of formula IV 20 with an alkylating agent of the formula XCH2R4 wherein X is a leaving group and R4a is -C02R4b, -S03R4b, -P (O) (ORb) 2 or -P (0) (0R4b) H, wherein R4b is an acid protecting group for forming a compound of formula III or reacting a compound of formula III III with oxalyl chloride and. ammonia to form a compound of formula II d) optionally hydrolyzing a compound of formula II II to form a compound of formula I; Y optionally salifying a compound of formula I

15. The process according to claim 13 or 14, characterized in that the polar hydrocarbon solvent has a boiling point of 150-250 ° C and a dielectric constant of 10-20 ..

16. The process according to claim 13 or 14, characterized in that the polar hydrocarbon solvent has a boiling point of 150-220 ° C and a dielectric constant of 12-18.

17. The process according to any of claims 13 to 16, characterized in that the ((3- (2-amino-1, 2-dioxyethyl) -2-ethyl-1- (phenylmethyl) -1H-indole-4 acid is prepared. -yl) oxy) acetic.

18. A process for preparing a compound of formula wherein: R1 is selected from the group consisting of: -C7-C20 alkyl; wherein R10 is selected from the group consisting of halo, Ci-C10 alkyl, Ci-C10 alkoxy, -S- ( C? ~ C10) and Ci-C10 haloalkyl and t is an integer from 0 to 5, including both; R2 is selected from the group consisting of hydrogen, halo, Cx-C3 alkyl, C3-C4 cycloalkyl, C3-C4 cycloalkenyl, -O- (C? -C2 alkyl), -S-C? Alkyl? C2), aryl, aryloxy and HET; and R5, Rs and R7 are each independently selected from the group consisting of hydrogen, Ci-C6 alkyl, Ci-Cg alkoxy, C?-C3 haloalkoxy, C2-C6 haloalkyl, bromine, chlorine, fluoro, iodine and aryl, the process is characterized in that it comprises the steps of: a) halogenating a compound of formula X X wherein R8 is Ci-C6 alkyl, aryl or HET; with S02C12 to form a compound of formula IX b) hydrolyzing and decarboxylating a compound of the formula IX 10 15 to form a compound of formula VIII VIII 20 c) alkylating a compound of formula VII VII with a compound of formula VIII VIII to form a compound of formula VI d) Aminating and dehydrating and oxidizing a compound of 15 formula VI by refluxing in a polar hydrocarbon solvent having a boiling point of at least 150 ° C and a dielectric constant of at least 10 in the presence of a catalyst and an amine of the formula R1NH2. 1 .

A process for preparing a compound of formula wherein: R1 is selected from the group consisting of: -C7-C20 alkyl; wherein R10 is selected from the group consisting of halo, C? -C? 0 alkyl, Cx-C10 alkoxy, -S- (C? -C? alkyl) and haloalkyl of yt is an integer of 0 to 5, including both; R2 is selected from the group consisting of hydrogen, halo, Ci-C3 alkyl, C3-C4 cycloalkyl, C2-C4 cycloalkenyl, -O- (Ci-C2 alkyl), -S-Ci-C2 alkyl) , aryl, aryloxy and HET; and Rs, R6 and R7 are each independently selected from the group consisting of hydrogen, Ci-C6 alkyl, Ci-Cg alkoxy, Ci-Ce haloalkoxy, C2-C3 haloalkyl, bromine, chlorine, fluoro, iodine and aril; the process is characterized in that it comprises • aminating, dehydrating and oxidizing a compound of formula V by refluxing in a polar hydrocarbon solvent having a boiling point of at least 150 ° C and a dielectric constant of at least 10 in the presence of a catalyst and an amine of the formula RXNH2.

20. . The process according to claim 18 or 19, characterized in that the azeotrope is toluene and the polar hydrocarbon solvent has a boiling point of 150-220 ° C and a dielectric constant of 12-18.

21. The process according to one of claims 18 to 20, characterized in that the compound 2-ethyl-1- (phenylmethyl) -4-hydroxy-1H-indole is prepared.