MXPA99003587A - Triciclic composites substitui - Google Patents

Abstract

The present invention relates to: A compound, characterized in that it is selected from the group consisting of [9-benzyl-5-carbamoyl-i-fluorocarbazol-4-yl] oxyacetic acid, acid. { 9 - [(phenyl) methyl] -5-carbamoylcarbazol-4-IL] oxyacetic acid, acid. { 9 - [(3-fluorophenyl) methyl] -5-carbamoylcarbazole-4-i} oxyacetic, acid. { 9 - [(3-chlorophenyl) methyl] -5-carbamoylcarbazol-4-IL} oxyacetic, sodium salt of acid. { 9 - [(3-trifluoromethylphenyl) methyl] -5-carbamolylcarbazol-4-IL} oxyacetic, sodium salt of acid. { 9- [2-methylphenyl) methyl] -5-carbamoylcarbazol-4-IL} oxyacetic, sodium salt of acid. { 9 - [(3-methylphenyl) methyl] -5-carbaniukcarbazik-4-IL} oxyacetic, sodium salt of acid. { 9 - [(3-trifluoromethoxyphenyl) methyl] -5-carbamoylcarbazol-4-IL} oxyacetic acid, [9-benzyl-5-carbamoyl-i-fluorocarbazol-4-IL] oxyacetic acid, [9 - [(cyclohexyl) methyl] -5-carbamoylcarbazol-4-y] oxyacetic acid and [9 - [(cyclopentyl)] methyl] -5-carbamoylcarbazole-IL] -5-carbamoylcarbazol-4-IL] oxyacetic acid or one of its racemates, solvates, tautomers, isomers, pharmaceutically acceptable salts or prodrugs

Description

SUBSTITUTE TRIKYCLIC COMPOUNDS Field of the Invention This invention relates to new tricyclic substituted organic compounds useful for inhibiting the release of fatty acids induced by sPLA2, for disorders such as septic shock. BACKGROUND OF THE INVENTION The structure and physical properties of human non-pancreatic secretory phospholipase A2 (hereinafter referred to as "sPLA2") has been thoroughly described in two articles, namely, "Cloning and Recombinant Expression of Phospholipase A2 Present in Rheumatoid Arthritic Synovial Fluid "by Seilhamer, Jeffrey J.; Pruzanski, aldemar; Vadas Peter; Plant, Shelley; Miller, Judy A .; Kloss, Jean; and Johnson, Lorin K.; The Journal of Biological Chemistry, Vol. 264, No. 10, Published on April 5, p. 5335-5338, 1989; and "Structure and Properties of a Human Non-Pancreatic Phospholipase A2" by Kramer, Ruth M.; Hession, Catherine; Johansen, Berit; Hayes, Gretchen; McGray, Paula; Cho, E. Pingchang; Tizard, Richard; and Pepinsky, R. Blake; The Journal of Biological Chemistry. Vol. 264, No. 107 Published on April 5, p. 5768-5775, 1989; whose descriptions REF .: 29910 incorporated here as a reference. Brief Description of the Invention It is believed that sPLA2 is a rate-limiting enzyme in the arachidonic acid cascade that hydrolyzes membrane phospholipids. Thus, it is important to create compounds that inhibit the release of fatty acids indicted by sPLA2 (eg, arachidonic acid). Such compounds would be valuable in the general treatment of disorders induced and / or maintained by the overproduction of sPLA2 such as septic shock, respiratory distress syndrome in adults, pancreatitis, trauma-induced shock, bronchial asthma, allergic rhinitis, rheumatoid arthritis and disorders. Similar. It is desirable to create new compounds and treatments for diseases induced by sPLA2. Description of the Invention The tricyclic compounds effective to inhibit the release of fatty acids induced by human sPLA2 are represented in the general formula (I) shown below: in which; Z is cyclohexenyl or phenyl, R20 is selected from groups (a), (b) and (c), wherein; (a) is -alkyl of 5 to 20 carbon atoms, -alkenyl of 5 to 20 carbon atoms, -alkynyl of 5 to 20 carbon atoms, carbocyclic radicals or heterocyclic radicals, or (b) is a member of (a) ) substituted with one or more non-interfering substituents, independently selected; or (c) is the group - (L) -R80; where (L) - a divalent linking group of 1 to 12 atoms, selected from carbon, hydrogen, oxygen, nitrogen and sulfur; selecting the combination of atoms in - (L) - from the group consisting of (i) only carbon and hydrogen, (ii) only one sulfur, (iii) only one oxygen, (iv) only one or two nitrogens and hydrogen, (v) ) carbon, hydrogen and only one sulfur, and (vi) one carbon, hydrogen and only oxygen; and wherein R80 is a group selected from (a) or (b); R21 is a non-interfering substituent in which f is 1-3; R1 is -NHNH2, -NH2 or -CONH2; R2 'is selected from the group consisting of -OH and -0 (CH2) tR5' where R5 'is H, -CN, -NH2, -CONH2, -CONR9R10, -NHS02R15; -CONHS02R15, where R15 is -alkyl (C-Cg) or -CF3; phenyl or phenyl substituted with -C02H or -C02-alkyl (Ci-C; and - (La) - (acid group), where - (La) - is an acid-binding group having an acid-linking group length from 1 to 7, and t is 1-5; R3 'is selected from non-interfering substituents, carbocyclic radicals, carbocyclic radicals substituted with non-interfering substituents, heterocyclic radicals and heterocyclic radicals substituted with non-interfering substituents, or one of their racemates, solvates, tautomers, optical isomers, prodrug derivatives or pharmaceutically acceptable salts.

The compounds of Formula I contemplated by the present invention are selected from the group consisting of [9-benzyl-5-carbamoyl-1-f-luorocarbazol-4-yl] oxyacetic acid., acid. { 9- [(phenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic, acid. { 9- [(3-fluorophenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic, acid. { 9- [(3-chloro-enyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic, sodium salt of acid. { 9- [(3-trifluoromethylphenyl) methyl] -5-carbamoylcarbazole-4-yl} oxyacetic, sodium salt of acid. { 9- [(2-methylphenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic, sodium salt of acid. { 9- [(3-Methylf-enyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic, sodium salt of acid. { 9- [(3-trif luoromethoxyphenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid, [9-benzyl-5-carbamoyl-l-chlorocarbazol-4-yl] oxyacetic acid, [9- [(cyclohexyl) methyl] -5-carbamoylcarbazol-4-yl] oxyacetic acid, [9- [(cyclopentyl)] ) -methyl] -5-carbamoylcarbazol-4-yl] oxyacetic acid or one of its racemates, solvates, tautomers, optical isomers, prodrug derivatives or pharmaceutically acceptable salts. This invention also relates to a pharmaceutical formulation comprising a compound selected from the group consisting of [9-benzyl-5-carbamoyl-1-fluorocarbazol-4-yl] oxyacetic acid, acid. { 9- [(phenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic, acid. { 9 - [(3-fluorophenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic, acid. { 9- [(3-chlorophenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic, sodium salt of acid. { 9- [(3-trifluoromethylphenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic, sodium salt of acid. { 9- [(2-methylphenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic, sodium salt of acid. { 9- [(3-methylphenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic, sodium salt of acid. { 9- [(3-trifluoromethoxyphenyl) methyl] -5-carbamoylcarbazole-4-yl} oxyacetic acid, [9-benzyl-5-carbamoyl-l-chlorocarbazol-4-yl] oxyacetic acid, [9- [(ciciohexyl) methyl] -5-carbamoylcarbazol-4-yl] oxyacetic acid and [9- [(cyclopentyl)] ) -methyl] -5-carbamoylcarbazol-4-yl] oxyacetic acid, associated with one or more pharmaceutically acceptable diluents, vehicles and excipients. This invention also relates to a method for inhibiting sPLA2, which comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound selected from the group consisting of [9-benzyl-5-carbamoyl-1-fluorocarbazole-4] il] oxyacetic acid. { 9- [(phenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic, acid. { 9- [(3-fluorophenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic, acid. { 9- [(3-Chlorophenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic, sodium salt of acid. { 9- [(3-trifluoromethylphenyl) methyl] -5-carbamoylcarbazole-4-yl} oxyacetic, sodium salt of acid. { 9- [(2-methylphenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic, sodium salt of acid. { 9- [(3-methylphenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic, sodium salt of acid. { 9- [(3-trifluoromethoxyphenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid, [9-benzyl-5-carbamoyl-l-chlorocarbazol-4-yl] oxyacetic acid, [9- [(ciciohexyl) methyl] -5-carbamoylcarbazol-4-yl] oxyacetic acid and [9 - [(cyclopentyl)] ) -methyl] -5-carbamoylcarbazol-4-yl] oxyacetic acid. According to a further aspect of the present invention, there is provided a method of selectively inhibiting sPLA2 in a mammal in need of such treatment, comprising administering to said mammal a therapeutically effective amount of a compound selected from the group consisting of acid [9]. -benzyl-5-carbamoyl-l-fluorocarbazol-4-yl] oxyacetic acid, acid. { 9- [(phenyl) methyl] -5-carbamoylcarbazole-4-yl} oxyacetic, acid. { 9 - [(3-fluorophenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic, acid. { 9- [(3-chlorophenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid, sodium salt of acid . { 9- [(3-trif luoromethyl-enyl) methyl] -5-carbamoylcarbazole-4-yl} oxyacetic, sodium salt of acid. { 9- [(2-Methylf-enyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic, sodium salt of acid. { 9- [(3-methylphenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic, sodium salt of acid. { 9- [(3-trifluoromethoxyphenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic, [9-benzyl-5-carbamoyl-l-chlorocarbazol-4-yl] oxyacetic acid, [9- [(ciciohexyl) methyl] -5-carbamoyl-carbazol-4-yl] oxyacetic acid and [9 - [( cyclopentyl) methyl] -5-carbamoylcarbazol-4-yl] oxyacetic acid. This invention further provides a compound selected from the group consisting of [9-benzyl-5-carbamoyl-1-f luorocarbazol-4-yl] oxyacetic acid, acid. { 9- [(phenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic I, acid . { 9- [(3-Fluoro-phenyl) -methyl] -5-carbamoylcarbazole-4-yl} oxyacetic, acid. { 9- [(3-chloro-enyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic, sodium salt of acid. { 9- [(3-trifluoromethylphenyl) methyl] -5-carbamoylcarbazole-4-yl} oxyacetic, sodium salt of acid. { 9 - [(2-methylphenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic, sodium salt of acid. { 9- [(3-methylphenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic, sodium salt of acid. { 9- [(3-trifluoromethoxyphenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid, [9-benzyl-5-carbamoyl-l-chlorocarbazol-4-yl] oxyacetic acid, [9- [(ciciohexyl) methyl] -5-carbamoylcarbazol-4-yl] oxyacetic acid and [9 - [(cyclopentyl)] ) methyl] -5-carbamoylcarbazol-4-yl] oxyacetic acid for use as a medicament in the treatment of inflammatory diseases such as septic shock, respiratory distress syndrome in adults, pancreatitis, shock induced by trauma, bronchial asthma, allergic rhinitis, arthritis rheumatoid, cystic fibrosis, stroke, acute bronchitis, chronic bronchitis, acute bronchiolitis, chronic bronchiolitis, osteoarthritis, gout, spondylarthropathy, ankylosing spondylitis, Reiter syndrome, psoriatic arthropathy, enteropatric spondylitis, juvenile arthropathy or juvenile ankylosing spondylitis, reactive arthropathy, infectious arthritis or after infection, gonococcal arthritis, tuberculous arthritis, viral arthritis, fungal arthritis, syphilitic arthritis, Lyme disease, arthritis associated with on "vasculitis syndromes", nodular polyarteritis, hypersensitivity vasculitis, Luegenec granulomatosis, polymyalgia rheumatica, joint cell arteritis, arthropathy due to calcium crystals deposition, pseudogout, non-joint rheumatism, bursitis, tenosynovitis, epicondylitis (elbow) tennis), carpal tunnel syndrome, repetitive use injury (typing), various forms of arthritis, neuropathic joint disease (Charcot's joint), hemarthrosis (hemarthrosis), Henoch-Schonlein purpura, hypertrophic osteoarthropathy, multicentric reticulohistiocytosis , arthritis associated with certain diseases, sulcoilosis, hemochromatosis, sickle cell disease and other hemog 1 obinopathies, hyper 1 ipoproteinemia, hypogammaglobulinemia, hyperparathyroidism, acromegaly, familial Mediterranean fever, Behat's disease, systemic lupus erythematosus or polychondritis co relapses and related diseases, which comprises administering to a mammal in need of such treatment, a therapeutically effective amount of the compound of formula I in an amount sufficient to inhibit the release of fatty acids induced by sPLA2 and thereby inhibit or prevent the cascade of arachidonic acid and its harmful products. Other objects, features and advantages of the present invention will become apparent from the following imprescription and the appended claims: Definitions: As used herein, the term "alkyl", by itself or as part of another substituent, means, unless otherwise indicated, a straight or branched monovalent hydrocarbon radical, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tertiary butyl, isobutyl, sec-butyl, tere-butyl, n-pentyl, isopentyl, neopentyl, heptyl, hexyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl and the like The term "alkyl" includes -alkyl of 1 to 2 carbon atoms, -alkyl of 1 to 4 atoms of carbon, -alkyl of 1 to 6 carbon atoms, -alkyl of 5 to 14 carbon atoms and -alkyl of 1 to 10 carbon atoms.The term "alkenyl", as used herein, represents a group linear or branched olefinically unsaturated that has at least It's a double bond. Examples of such groups include radicals such as vinyl, allyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2- heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, as well as linear and branched chain and dienes, The term "alkynyl" represents radicals such as ethinyl, propinyl, butinyl, pentynyl, hexynyl, heptinyl, as di- and tri-inos. The term "halo" means chlorine, fluorine, bromine or iodine.

The term "-alkoxy of 1 to 4 carbon atoms", as used herein, represents a group such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy and the like, attached to the remainder of the molecule by the oxygen atom. The term "phenylalkyl of 1 to 4 carbon atoms" refers to a straight or branched chain alkyl group having one to four carbon atoms attached to a phenyl ring, which chain is attached to the remainder of the molecule. Typical phenylalkyl groups include benzyl, phenylethyl, phenylpropyl, phenylisopropyl and phenylbutyl. The term "-alkylthio of 1 to 4 carbon atoms" defines a linear or branched alkyl chain having from one to four carbon atoms attached to the rest of the molecule by a sulfur atom. Typical -alkylthio (C3-C4) groups include methylthio, ethylthio, propylthio, butylthio, and the like. The term "-Cycloalkyl of 3 to 14 carbon atoms" includes groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, cyclotridecyl, cyclotetradecyl, and the like. to 14 carbon atoms) "includes -cycloalkyl of 3 to 7 carbon atoms The term" heterocyclic radical "refers to radicals derived from monocyclic or polycyclic heterocyclic, saturated or unsaturated, substituted or unsubstituted, heterocyclic nuclei, having 5 to 14 atoms in the ring and containing 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur Typical heterocyclic radicals are pyridyl, thienyl, fluorenyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, phenylimidazolyl, triazolyl, isoxazolyl , oxazolyl, thiazolyl, thiadiazolyl, indolyl, carbazolyl, norharmanyl, azaindolyl, benzofuranyl, dibenzofuranyl, aunt naphtheneyl, dibenzothiophenyl, indazolyl, imidazo (1.2-A) pyridinyl, benzotriazolyl, anthranilyl, 1,2-benzoisoxazolyl, benzoxazolyl, benzothiazolyl, purinyl, pyridinyl, dipyridyl, phenylpyridinyl, benzylpyridinyl, pyrimidinyl, phenylpyrimidinyl, pyrazinyl, 1,3,5- triazinyl, quinolinyl, phthalazinyl, quinazolinyl and quinoxalinyl. The term "carbocyclic radical" refers to radicals derived from an organic core of 5 to 14 links, substituted or unsubstituted, saturated or unsaturated, whose ring-forming atoms (other than hydrogen) are only carbon atoms. Typical carbocyclic radicals are cycloalkyl, cycloalkenyl, phenyl, naphthyl, norbornyl, bicycloheptadienyl, tolulyl, xylenyl, indenyl, stilbenyl, terphenylyl, diphenylethylene, phenylcyclohexenyl, acenaphthylenyl and anthracenyl, biphenyl, bibencyl and related bibencyl homologs represented by the formula (bb) , n being an integer from 1 to 8. The term "non-interfering substituent" refers to radicals suitable for substitution in the positions 1, 2, 3, 7 and / or 8 in the tricyclic core (as represented in Formula III) and suitable radical (s) for the substitution in the heterocyclic radical and the carbocyclic radical as defined above. Illustrative non-interfering radicals are hydrogen, -alkyl 1 to 14 carbon atoms -alkenyl of 2 to 6 carbon atoms, -alkynyl of 2 to 6 carbon atoms, -aralkyl of 7 to 12 carbon atoms, -alkylaryl of 7-12 carbon atoms), -cycloalkyl of 3 to 8 carbon atoms, -cycloalkenyl of 3 to 8 carbon atoms, phenyl, tolulyl, xylenyl, biphenyl, -alkoxy of 1 to 6 atoms, -alkenyloxy of 2 to 6 carbon atoms, -alkynyloxy of 2 to 6 atoms of carbon), -alkoxyalkyl of 1 to 12 carbon atoms, -alkoxyalkyloxy of 1 to 12 carbon atoms, -alkylcarbonyl of 1 to 12 carbon atoms, -alkylcarbonyl-amino of 1 to 12 carbon atoms, -alkoxyamide of 12 carbon atoms, -alkoxyaminocarbonyl of 1 to 12 carbon atoms), -alkylamino of 1 to 12 carbon atoms, -alkylthio of 1 to 6 carbon atoms, -alkyl-thiocarbonyl of 1 to 12 carbon atoms, -alkylsulfinyl of 1 to 6 carbon atoms), -alkylsulfonyl of 1 to 6 carbon atoms, -haloalkoxy of 1 to 6 atoms of carbon, -haloalkylsulfonyl of 1 to 6 carbon atoms, -haloalkyl of 1 to 6 carbon atoms, -hydroxyalkyl of 1 to 6 atoms, - (CH2) nCN, - (CH2) nNR9R10, -C (0) 0 (alkyl of 1 to 6 carbon atoms), - (CH2) n0 (alkyl of 1 to 6 carbon atoms), benzyloxy, phenoxy, phenylthio; .- (C0NHS02) R15, where R15 is -alkyl 6 carbon atoms; -CF3, naphthyl (CH2) sphenyl, where s 0-5; -CHO, -CF3, -0CF3, pyridyl, amino, amidino, halo, carbamyl, carboxyl, carbalkoxy, (CH2) pC02H, cyano, cyanoguanidinyl, guanidino, hydrazide, hydrazino, hydrazido, hydroxy, hydroxyamino, nitro, phosphono, -S03H , thioacetal, thiocarbonyl, furyl, thiophenyl, -COR9, -CONR9R10, -NR9R10, -NCHCOR9, -S02R9, -OR9, -SR9, CH2S02R9, tetrazolyl or tetrazolyl substituted with -alkyl- of 1 to 6 carbon atoms, phenyl or -alkylphenyl of 1 to 4 carbon atoms, - (CH 2) n 0 Si-alkyl of 1 to 6 carbon atoms and alkylcarbonyl of 1 to 6 carbon atoms; wherein n is from 1 to 8 and R9 and R10 being independently hydrogen, -CF3, phenyl, -alkyl of 1 to 4 carbon atoms), -alkylphenyl of 1 to 4 carbon atoms or -phenyl-alkyl of 1 to 4 carbon atoms; carbon The term "acid group" means an organic group which, when bound to a tricyclic core, through suitable binding atoms (hereinafter referred to as "acid-binding group"), acts as a proton donor capable of forming bonds of hydrogen. Illustrative of an acid group are the following: -C02H, -5-tetrazolyl, -SO3H, n being 1 to 8, R89 a metal or -alkyl of 1 to 10 carbon atoms and R99 hydrogen or -alkyl of 1 to 10 carbon atoms. The term "acid-binding group" refers to a divalent linking group symbolized as, - (La) -, which has the function of linking position 5 or 6 of the tricyclic nucleus to an acid group in the general relation: (tricyclic nucleus) - (La) - acid group The term "acid-binding group length" refers to the number of atoms (excluding hydrogens) in the shortest chain of the linking group - (La) - which connects the 5 or 6 position of the tricyclic core with the acid group . The presence of a carbocyclic ring in - (La) - represents the number of atoms approximately equivalent to the calculated diameter of the carbocyclic ring. Thus, a ring of benzene or cydohexane in the acid-binding group represents 2 atoms in the calculation of the length of - (La) -. They are illustrative acid binding groups, - where t is 1 to 5, Q is selected from the group - (CH2) -, -O-, -NH- and -S-, and each of R84 and R85 is independently selected from hydrogen, -alkyl from 1 to 10 atoms carbon, aryl, -alkylaryl of 1 to 10 carbon atoms, -aralkyl of 1 to 10 carbon atoms, carboxy, carbalkoxy and halo, when t is one (1), groups (a), (b), ( c) and (d) have lengths of the acid-binding group of 3, 3, 2 and 2, respectively. Those skilled in the art will appreciate that the position of the double bond in the centered 5-ring depends on the position of the nitrogen atom as depicted below.

The salts of the above tricyclic compounds are a further aspect of the invention. In cases where the compounds of the invention possess acid functional groups, various salts can be formed that are more water soluble and physiologically suitable than the parent compound. Representative pharmaceutically acceptable salts include, but are not limited to, the alkali metal salts and alkaline earth metals 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. of the pharmaceutically acceptable salts include the addition salts of relatively non-toxic organic and inorganic bases of compounds of the present invention, for example, ammonium, quaternary ammonium and amine cations, derived from nitrogenous bases of sufficient basicity to form salts with the compounds of this invention (see, for example, SM Berge , et al., "Pharmaceutical Salts", J. Phar. Sci .. 66: 1-19 (1977)). The compounds of the invention can have chiral centers and exist in optically active forms. This invention contemplates the R and S isomers and the racemic mixtures. A particular stereoisomer can be prepared by known procedures using stereospecific reactions with starting materials containing unsolved asymmetric centers or, as an alternative, by the subsequent resolution of mixtures of stereoisomers using known methods. Prodrugs are derivatives of the compounds of the invention that have groups that can be broken chemically or metabolically and that are converted, by solvolysis or under physiological conditions, into the compounds of the invention that are pharmaceutically active in vivo. Derivatives of the compounds of this invention have activity in their acid and base derived forms, but the acid derivative form often offers solubility, tissue compatibility or delayed release advantages in a mammalian organism (see, Bundgard, H. , Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives, such as esters prepared by the reaction of the parent acid compound with a suitable alcohol, or amides prepared by the reaction of the parent acid compound with a suitable amine. Preferred prodrugs are simple aliphatic esters (eg, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl) or aromatic esters derived from pendant acid groups present in the compounds of this invention. Other preferred esters include mo r f o 1 i not e t i 1 x i, d i e t i 1 g 1 i c o 1 a m i d a and diethylaminocarbonyl ethoxy. In some cases, it is desirable to prepare prodrugs of the double ester type as esters of (acyloxy) alkyl or esters of ((alkoxycarbonyl) oxy) alkyl. The term "acid protecting group" is used herein as it is frequently used in synthetic organic chemistry, to refer to a group that will prevent the participation of an acid group in a reaction performed in some other functional group of the molecule, but you can withdraw when you want. Such groups are discussed by T. W. Greene in Chapter 5 of Protective Groups in Organic Synthesis, John Wiley and Sons, New York, 1981, incorporated herein by reference in its entirety. Examples of the acid protecting groups include ester or amide derivatives of the acid group, such as methyl, methoxymethyl, methyl-thiomethyl, tetrahydropyranyl, methoxyethoxymethyl, benzyloxymethyl, phenyl, aryl, ethyl, 2,2,2-trichloroethyl, 2-methylthioethyl, t-butyl, cyclopentyl, triphenylmethyl, diphenylmethyl, benzyl, trimethylsilyl, N, N-dimethyl, pyrrolidinyl, piperidinyl or o-nitroanilide. A preferred acid protecting group is methyl. The compounds of formula I wherein Z is cyclohexene are prepared according to the following reaction schemes I (a) - (b) and II. Scheme I (a) where: R1 is -NH2, R3 (a) is H, -O-alkyl of 1 to 4 carbon atoms, halo, -alkyl of 1 to 6 carbon atoms, phenyl, -alkylphenyl of 1 to 4 carbon atoms; phenyl substituted with -alkyl of 1 to 6 carbon atoms, halo 0 -. 0 -CF3; -CH2OSi-alkyl of 1 to 6 carbon atoms, furyl, thiophenyl, -hydroxyalkyl of 1 to 6 carbon atoms, -alkoxy of 1 to 6 carbon atoms, -alkyl of 1 to 6 carbon atoms, -alkoxy of 1 to 6 carbon atoms, -alkenyl of 1 to 6 carbon atoms; or - (CH2) nR8, where R8 is H, -C0NH2, -NR9R10, -CN or phenyl, where R9 and R10 are independently hydrogen, -CF3, phenyl, -alkyl of 1 to 4 carbon atoms, -alkylphenyl of 1 to 4. carbon atoms or p-phenylalkyl of 1 to 4 carbon atoms and n being from 1 to 8; when R1 is -NHNH2, R3 (a) is H, -O-alkyl of 1 to 4 carbon atoms, halo, -alkyl of 1 to 6 carbon atoms, phenyl, -alkylphenyl of 1 to 4 carbon atoms; phenyl substituted with -alkyl of 1 to 6 carbon atoms, halo or -CF3; -CH20Si-alkyl of 1 to 6 carbon atoms, furyl, thiophenyl, -hydroxyalkyl of 1 to 6 carbon atoms, -alkoxy of 1 to 6 carbon atoms, -alkyl of 1 to 6 carbon atoms, -alkoxy of 1 to 6 carbon atoms, -alkenyl of 1 to 6 carbon atoms; or (CH2) nR8 where R8 is H, -NR9R10, -CN or phenyl, where R9 and R10 are independently hydrogen, -CF3, phenyl, -alkyl of 1 to 4 carbon atoms, -alkyl-phenyl of 1 to 4 carbon atoms; or p-phenylalkyl of 1 to 4 carbon atoms and n being from 1 to 8; R2 (a) is -OCH3 or -OH. An appropriately substituted nitrobenzene (1) can be reduced to the aniline (2) by treatment with a reducing agent, such as hydrogen, in the presence of Pd / C, preferably at room temperature. Compound (2) is N-alkylated at temperatures of about 0 to 20 ° C using an alkylating agent, such as an appropriately substituted aldehyde and sodium cyanoborohydride, to form (3). Alternatively, an appropriately substituted benzyl halide can be used for the first alkylation step. The resulting intermediate is further N-alkylated by treatment with 2-carboethoxy-6-bromocyclohexanone, preferably at temperatures of about 80 ° C, providing (4) or by treatment of potassium hexamethyldisilazide and the bromo ketoester. The product (4) is cyclized to tetrahydrocarbazole (5) by refluxing with ZnCl 2 in benzene, for about 1 to 2 days, preferably at 80 ° C. (Ref 1) The compound (5) is converted to the hydrazide (6) by treatment with hydrazine at temperatures of about 100 ° C, or in the amide (7) by reaction with methylchloroaluminum amide in benzene. (Ref. 2) As an alternative, (7) can be produced by treatment of (6) with an active Raney nickel catalyst. It will be readily appreciated that when R3 (a) is: 0 (CH2) n-C0-alkyl (GL-C) the conversion to the amide in this process can also be achieved. The compounds (6) and (7) can be dealkylated, preferably at a temperature of 0 ° C at room temperature, with a dealkylating agent such as boron tribromide or sodium thioethoxide, to give the compound (7) where R 2 is> -OH, which can then be further converted to compound (9), by realkylation with a base, such as sodium hydride, and an alkylating agent, such as Br (CH2) mR5, where R5 is the carboxylate, the phosphonic diester or the nitrile as It has been defined previously. The conversion of R2 to the carboxylic acid can be carried out by treatment with an aqueous base. When R2 is nitrile, conversion to the tetrazole can be achieved by reaction with tri-butyl tin azide or conversion to the carboxamide can be achieved by reaction with basic hydrogen peroxide. When R2 is the phosphonic diester, conversion to the acid can be achieved by reaction with a dealkylating agent such as trimethylsilyl bromide. The monoester can be achieved by reacting the diester with an aqueous base. When both R 2 and R 3 are methoxy, the selective demethylation can be carried out by treatment with sodium ethanethiolate in dimethylformamide at 100 ° C. Ref 1. Julia,.; Lenzi, J. Preparation d'acides tetrahydro-1, 2, 3, 4-carbazole-l- ou -4. Bull. Soc. Chim. France, 1962, 2262-2263.

Ref 2. Levin, J.I .; Turos, E .; Weinreb, S.M. An alternative procedure for the aluminum-mediated conversion of esters to amides. Syn. I used to eat. , 1982, 12, 989-993. In Scheme I (b) below, an alternative synthesis of the intermediate (5) is shown.

Scheme I (b) where PG is a protective group; R3a is as defined in Scheme 1, above. bromocyclohexanone in dimethylformamide, in the presence of sodium bicarbonate, for 8-24 hours at 50 ° C. Preferred protecting groups include methyl, carbonate and silyl groups, such as t-butyldimethylsilyl. The reaction product (4 ') is cyclized to (5') using the ZnCl2 under the benzene conditions described in Scheme (a) above. The N-alkylation of (5 ') by providing (5) is carried out by treatment with sodium hydride and the appropriate alkyl halide in dimethylformamide at room temperature for 4-8 hours.

Scheme II R3 (a) is as defined in Scheme I. As described in Scheme I above, carbazole (5) is hydrolysed to the carboxylic acid (10) by treatment with an aqueous base, preferably from room temperature to about 100 ° C. The intermediate is then converted to an acid chloride using, for example, oxalyl chloride and dimethylformamide and then further reacted with a lithium salt of (S) or (R) -4-alkyl-2-oxazolidine at a temperature about -75 ° C, to give (lia) and (llb), which can be separated by chromatography. The diastereomers are converted into the corresponding enantiomeric benzylic esters (12) by brief treatment at temperatures of about 0 ° C at room temperature with benzyl lithium oxide. (Ref 3) The esters (12) are then converted to (7), preferably by treatment with methylchloroaluminum amide (Ref 2, above) or, alternatively, by hydrogenation using, for example, hydrogen and palladium on carbon, as described above, to obtain the acid and then by reaction with an acyl azide, such as diphenylphosphoryl azide, followed by treatment with ammonia. Using the procedure described above in Scheme I, compounds (9a) or (9b) can be obtained. Ref 3. Evans, D.A.; Ennis, M.D.; Mathre, D. J. Asymmetric alkylation reactions of chiral imide enolates. A practical approach to the enantioselective synthesis of alpha-substituted carboxylic acid derivatives. J ". Am. ~ Chem. Soc., 1982, 104, 1737-1738.

The compounds of formula I in which Z is phenyl, can be prepared as shown below in Schemes III (a) to (g). Scheme III (a) (13) (14) A 1, 2, 3, 4-tetrahydrocarbazole-4-carboxamide or 4-carboxyhydrazide (13) is dehydrogenated by refluxing in a solvent such as carbitol, in the presence of Pd / C, to give the carbazole-4-carboxamide. Alternatively, treatment of (13) with DDQ in an appropriate solvent such as dioxane produces carbozol (14). Depending on the model of substituent, the oxidation described above can produce the dealkylation of nitrogen. For example, when R3 is substituted at the 8-position with methyl, the oxidation produces the dealkylation of the nitrogen that can be realked by treatment with sodium hydride and the appropriate alkyl halide, as described in Scheme I (a) above, to prepare the desired product (14). Intermediates and final products can be isolated and purified by conventional techniques, for example, by concentration of the solvents, followed by washing the residue with water and then purification by conventional techniques, such as chromatography and recrystallization. It will be readily appreciated by those skilled in the art that the starting materials are commercially available or can be easily prepared by known techniques from commercially available starting materials. All other reagents used to prepare the compounds in the present invention are commercially available.

Scheme III ü_l- (16) (25) (24) The benzoic acid derivative (16) in which X is preferably chlorine, bromine or iodine and the protective group is preferably -CH3, is reduced to the corresponding aniline (25) with a reducing agent, such as stannous chloride, in the presence of acid, under the general conditions of Sakamoto et al., Chem. Pharm. Bull. 35 (5), 1823-1828 (1987).

As an alternative, the reduction with sodium dithionite in the presence of a base, such as sodium carbonate, in a non-interfering solvent, such as water, ethanol and / or tetrahydrofuran, produces the starting material (16). Alternatively, reduction by hydrogenation over a sulfided platinum catalyst supported on carbon, with hydrogen at 1.01 x 10 5 to 6.078 x 10 6 Pa, in a non-interfering solvent, preferably ethyl acetate, forms a starting material (16) . The reactions are carried out at temperatures of about 0 to 100 ° C, preferably at room temperature, and are completed substantially in about 1 to 48 hours, depending on the conditions. The aniline (25) and the dione (15) are condensed under dehydration conditions, for example, using the general procedure of lida, et al., (Ref 5), with or without a non-interfering solvent, such as toluene, benzene or methylene chloride, under dehydration conditions, at a temperature of about 10 to 150 ° C. The water formed in the process can be removed by distillation, azeotropic removal by a Dean-Stark apparatus, or the addition of a drying agent, such as molecular sieves, magnesium sulfate, calcium carbonate, sodium sulfate and the like. The process can be carried out with or without a catalytic amount of an acid, such as p-toluenesulfonic acid or methanesulfonic acid. Other examples of suitable catalysts include hydrochloric acid, phenylsulfonic acid, calcium chloride and acetic acid. Examples of other suitable solvents include tetrahydrofuran, ethyl acetate, methanol, ethanol, 1,1,2,2-tetrachloroethane, chlorobenzene, bromobenzene, xylenes and carbon tetrachloride. The condensation of the present process is preferably carried out without solvent, at a temperature of about 100 to 150 ° C, the resulting water being removed by distillation through a stream of inert gas, such as nitrogen or argon. The reaction is completed substantially in about 30 minutes to 24 hours. Intermediate (26) can then be readily cyclized in the presence of a palladium catalyst, such as Pd (OAc) 2 or Pd (PPh3) 4 and the like, a phosphine, preferably a trialkyl- or triarylphosphine, such as triphenylphosphine, tri-o-tolylphosphine or tricyclohexylphosphine and the like, a base, such as sodium bicarbonate, triethylamine or diisopropylethylamine, in a non-interfering solvent, such as acetonitrile, triethylamine or toluene, at a temperature of about 25 to 200 ° C to form (19). Examples of other suitable solvents include tetrahydrofuran, benzene, dimethyl sulfoxide or dimethylformamide. Examples of other suitable palladium catalysts include Pd (PPh3) Cl2, Pd (OCOCF3) 2, [(CH3C6H4) 3P] 2PdCl2, [(CH3CH2) 3P] 2PdCl2, [(C6H11) 3P] 2PdCl2 and [(C6HS) 3P ] 2PdBr2. Examples of other suitable phosphines include triisopropylphosphine, triethylphosphine, tricyclopentylphosphine, 1,2-bis (diphenylphosphino) ethane, 1,3-bis (diphenylphosphino) propane and 1,4-bis (diphenylphosphino) butane. Examples of other suitable bases include tripropylamine, 2, 2, 6,6-tetramethylpiperidine, 1,5-diazabicyclo [2.2.2] octane (DABCO), 1,8 diazabicyclo [5.4.0] undec-7-ene (DBU) ), 1.5 diazabicyclo [4.3.0] non-5-ene (DBN), sodium carbonate, potassium carbonate and potassium bicarbonate. The cyclization of the present process is preferably carried out with palladium (II) acetate as catalyst in the presence of triphenylphosphine, tri-o-tolylphosphine, 1,3-bis (diphenylphosphino) propane or tricyclohexylphosphine, in acetonitrile as solvent and triethylamine as the base, a temperature of approximately 50 to 150 ° C. The reaction is completed substantially in about 1 hour to 14 days.

Alternatively, a preferred method for cyclization is the reaction of intermediate (26) with a palladium cyclic catalyst, such as trans-di (μ-acetate) -bis [o- (di-o-tolylphosphino) benzyl] dipalladium ( II), in a solvent, such as dimethylacetamide (DMAC), at 120-140 ° C, in the presence of a base such as sodium acetate. The intermediate (19) can be alkylated with an alkylating agent XCH2R4, where X is halo, in the presence of a base to form (20). Suitable bases include potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, potassium hydroxide, sodium hydroxide, sodium hydride, potassium hydride, lithium hydride and Triton B (N-benzyltrimethylammonium hydroxide). The reaction may or may not be carried out in the presence of a crown ether. Potassium carbonate and Triton B are preferred. The amount of alkylating agent is not critical, however, the reaction is performed in the best way using an excess of alkyl halide with respect to the starting material. A catalytic amount of an iodide, such as sodium iodide or lithium iodide, may or may not be added to the reaction mixture. The reaction is preferably carried out in an organic solvent, such as acetone, dimethylformamide, dimethisulfoxide or acetonitrile. Other suitable solvents include tetrahydrofuran, methyl ethyl ketone and t-butyl methyl ether. The reaction is carried out at temperatures of about -10 to 100 ° C, preferably at room temperature, and is completed substantially in about 1 to 48 hours depending on the conditions. Optionally, a phase transfer reagent, such as tetrabutylammonium bromide or tetrabutylammonium chloride, may be employed.

Intermediate (20) can be dehydrogenated by oxidation with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in a non-interfering solvent to form (21). Suitable solvents include methylene chloride, chloroform, carbon tetrachloride, diethyl ether, methyl ethyl ketone and t-butyl methyl ether. Preferred solvents are toluene, benzene, dioxane and tetrahydrofuran. The reaction is carried out at a temperature of about 0 to 120 ° C. Temperatures of 50 to 120 ° C are preferred. The reaction is completed substantially in about 1 to 48 hours, depending on the conditions.

The intermediate (21) can be aminated with ammonia in the presence of a non-interfering solvent, to form (22).

The ammonia may be in the form of gaseous ammonia or as an ammonium salt, such as ammonium hydroxide, ammonium acetate, ammonium trifluoroacetate, ammonium chloride, and the like. Suitable solvents include ethanol, methanol, propanol, butanol, tetrahydrofuran, dioxane and water. In the present process, a mixture of concentrated aqueous ammonium hydroxide and tetrahydrofuran or methanol is preferred. The reaction is carried out at a temperature of about -20 to 100 ° C.

Temperatures of 50 to 60 ° C are preferred. The reaction is completed substantially in about 1 to 48 hours, depending on the conditions. The alkylation of (22) is achieved by treatment with an alkylating agent of the formula XCH2R9, where X is halo and R70 -C02R71, -S03R71, -P (0) (OR71) 2 or -P (0) - (OR71) H , where R71 is an acid protecting group or a functional group of the prodrug, in the presence of a base, in a non-interfering solvent, to form (23). Preferred alkylating agents are methyl bromoacetate and t-butyl bromoacetate. Suitable bases include potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, potassium hydroxide, sodium hydroxide, sodium hydride, potassium hydride, lithium hydride and Triton B (N-benzyltrimethylammonium hydroxide). The reaction may or may not be carried out in the presence of a crown ether. Cesium carbonate and Triton B are preferred. The amount of alkylating agent is not critical, however, the reaction is performed in the best way using an excess of alkyl halide with respect to the starting material. The reaction is preferably carried out in an organic solvent, such as acetone, dimethylformamide, dimethisulfoxide or acetonitrile. Other suitable solvents include tetrahydrofuran, methyl ethyl ketone and t-butyl methyl ether. The reaction is carried out at temperatures of about -10 to 100 ° C, preferably at room temperature, and is substantially complete in about 1 to 48 hours, depending on the conditions. Optionally, a phase transfer reagent such as tetrabutylammonium bromide or tetrabutylammonium chloride can be employed. The intermediate (23) can optionally be hydrolysed with a base or acid to form the desired product (24) and optionally salified. Hydrolysis of (23) is achieved using a base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, aqueous potassium carbonate, aqueous sodium carbonate, aqueous lithium carbonate, aqueous potassium bicarbonate, aqueous sodium bicarbonate or aqueous lithium bicarbonate, preferably hydroxide sodium and a lower alcohol as solvent, such as methanol, ethanol, isopropanol and the like. Other suitable solvents include acetone, tetrahydrofuran and dioxane. Alternatively, the acid protecting group can be removed by organic and inorganic acids, such as trifluoroacetic acid and hydrochloric acid, with or without a non-interfering solvent. Suitable solvents include methylene chloride, tetrahydrofuran, dioxane and acetone. Preferably, the t-butyl esters are removed by the use of pure trifluoroacetic acid. The reaction is carried out at temperatures of about -10 ° C to 100 ° C, preferably at room temperature, and is completed substantially in about 1 to 48 hours, depending on the conditions. The starting material (16) is prepared by esterification of the compound (15) with an alkyl halide = XPG; X halo and PG being an acid protecting group, in the presence of a base, preferably potassium carbonate or sodium carbonate, in a non-interfering solvent, preferably dimethylformamide or dimethisulfoxide. • The preferred alkyl halide is methyl iodide. The reaction is carried out at temperatures of about 0 to 100 ° C, preferably at room temperature, and is substantially complete in about 1 to 48 hours, depending on the conditions. Alternatively, the starting material (16) can be prepared by condensation with a HOPG alcohol, with PG being an acid protecting group, in the presence of a dehydrating catalyst, such as dicyclohexylcarbodiimide (DCC) or carbonyl diimidazole. In addition, U.S. Patent No. 4,885,338 and Japanese Patent Kokai Tokkyo Koho 05286912, November 1993 Hesei, describe a process for the preparation of 2-fluoro-5-methoxyaniline derivatives. Scheme III (c) R is as defined in scheme III (b). R3 (a) is as defined in Scheme I (a), above; and X is halo. The benzoic acid derivatives (16) (X = Cl, Br or 1) and the boronic acid derivative (27) (commercially available or readily preparable by known techniques from commercially available starting materials) are condensed under the general procedure of Miyaura, et al., (Ref 8a) or Trecourt, et al. , (Ref 8b) in the presence of a palladium catalyst, such as Pd (Ph3P) 4, a base, such as sodium bicarbonate, in an inert solvent, such as THF, toluene or ethanol, to provide the compound (28). The compound (28) is converted to the carbazole product (29) by treatment with a trialkyl or triaryl phosphite or phosphine, such as triethylphosphite or triphenyl phosphine, according to the general procedure of Cadogan, et al (Ref. 6). The compound (29) is N-alkylated with an appropriately substituted alkyl or aryl halide, XCH2R4, in the presence of a base, such as sodium hydride or potassium carbonate, in a non-interfering solvent, such as toluene, dimethylformamide or dimethisulfoxide, providing carbazole ( 30).

The compound (30) is converted to the corresponding amide (22) by treatment with boron tribromide or sodium thioethoxide, followed by ammonia or an ammonium salt, such as ammonium acetate, in an inert solvent, such as water or alcohol, or with amide of methylchloroaluminum in an inert solvent, such as toluene, at a temperature between 0 and 110 ° C. When R3 (a) is substituted at position 8 with chlorine, dealkylation of (30) with boron tribromide results in the debenzylation of nitrogen as described above. The alkylation can be easily carried out in a two-step process. First, an O-alkylation by treatment with a haloalkyl acetate such as methyl bromoacetate, using sodium hydride in tetrahydrofuran, followed by N-alkylation using, for example, a base such as sodium hydride and an appropriately substituted alkyl or aryl halide. in dimethoxy formamide. The compound (22) can be converted into the product carbazole (24) as previously described in Scheme III (b) above. The conversion to the desired prodrug can be carried out by techniques known to those skilled in the art, such as, for example, by treatment with a primary or secondary halide, to obtain an ester prodrug. Scheme III (d) (29) As an alternative, the reduction of the nitro group of the compound (28) with a reducing agent, such as hydrogen, in the presence of palladium on carbon, in a non-interfering solvent, such as ethanol, at 1-60 atmospheres, at a temperature of 0 to 60 ° C, produces the corresponding aniline (32). The compound (32) is converted to the carbazole (29) according to the general procedure described by Trecourt, et al. (Ref. 8b). The aniline is treated with sulfuric acid and sodium nitrite, followed by sodium azide to form an intermediate azide which is cyclized to obtain a carbazole (29) by heating in an inert solvent, such as toluene.

The compound (29) is converted to the carbazole (24) product as previously described in Schemes III (b) and III (c). References: 8) a. N. Miyaura, et al., Synth. Commun. 11, 513 (1981) b. F. Trecourt, et al., Tetrahedron, 51, 11743 6) 6) J. Cadogan et al, J. Chem. Soc. , 4831 (1965) Scheme III (e) In an aprotic solvent, preferably tetrahydrofuran, the reduction of (40) is achieved using a reducing agent such as aluminum trihydride. Preferably, the reaction is carried out under an inert atmosphere, such as nitrogen, at room temperature. The sulfonylation can be carried out with an appropriate acylating agent, in the presence of an acid acceptor such as triethylamine. Scheme III (fl e n H -NSO 2R. (51) In a two-step procedure, in a single vessel, intermediate (50), prepared as described in Scheme I (a) above, is first activated with an activation agent such as carbonyl diimidazole. The reaction is preferably carried out in a polar or non-polar aprotic solvent, such as tetrahydrofuran. The acylation with the activated intermediate is carried out by reaction with H2NSOR15 in the presence of a base, preferably diazabicycloundecene. Scheme III (s) (20) (60) (63) (64) PG is an acid protecting group; . R22 is alkoxy of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms of alkenyl of 1 to 6 carbon atoms.

The starting material (20) is O-alkylated with an alkyl halide or alkenyl halide, using a base such as NaH, in a polar aprotic solvent, preferably anhydrous DMF, at room temperature under a nitrogen atmosphere. The aromatization process from a cyclohexanone functional group to a phenol functional group can be carried out by treatment of the tetrahydrocarbazole intermediate (60) with a base such as NaH, in the presence of methyl benzenesulphinate, in an anhydrous solvent, such as 1,4-dioxane. or DMF, forming the ketosulfoxide derivative. After heating to about 100 ° C for 1-2 hours, the ketosulfoxide derivative (60) is converted to the phenol derivative (61). The conversion of the ester (61) to the amide (62) can be achieved by treating a solution of (61) in a polar aprotic solvent, such as tetrahydrofuran with gaseous ammonia. The phenolic O-alkylation of (62) with, for example, methyl bromoacetate can be carried out in anhydrous DMF, at room temperature, using Cs2C03 or K2C03 as a base to form (63). The desired product (64) can be obtained by basic hydrolysis of the ester (63) using LiOH or NaOH as a base, in a solution of H 2? / CH 3 OH / THF, at 50 ° C, "for 1-2 hours.

When R22 is -alkoxy of 1 to 6 carbon atoms -alkenyl of 1 to 6 carbon atoms, the hydrogenation of the double bond can be carried out by treating (63) in THF using Pt02 as a catalyst, under a hydrogen atmosphere. The desired product can then be obtained as described above in Scheme III (g) by basic hydrolysis of the ester (63) using LiOH or NaOH as a base, in a solution of H20 / CH30H / THF, at 50 ° C for 1 hour. -2 hours . In the Examples and Preparations the following list of abbreviations is used. HCl = hydrochloric acid EtOAc = ethyl acetate DMF = dimethylformamide THF = tetrahydrofuran Et20 diethyl ether H20 = water NaOH sodium hydroxide EtOH ethanol Na2S04 = sodium sulfate NaHC03 = sodium bicarbonate celite = diatomaceous earth CH2C12 = methylene chloride H2S04 = sulfuric acid MeOH = methanol Rh / Al203 = rhodium on alum DDQ = 2,3-dichloro-5,6-dicyano-1,4-benzoquinone TLC = thin layer chromatography NaH = sodium hydride NH4OH = ammonium hydroxide LiOH = lithium hydroxide NNHH3, = ammonia Cs2C03 = cesium carbonate NH40Ac = ammonium acetate a = width The following intermediate preparations and examples of the final products further illustrate the preparation of the compounds of this invention. The examples are merely illustrative and are not intended to limit the scope of the invention in any way. Preparation 1 Preparation of 5-carbomethoxy-l, 2-dihydro-9H-carbazol-4 (3H) -one from 2-bromo-3-nitrobenzoic acid a) Methyl 2-bromo-3-nitrobenzoate A solution of 2-bromo-3-nitrobenzoic acid (28.4 g, 115.0 mM), iodomethane (18.0 g, 127 mM) and potassium carbonate was stirred ( 19.0 g, 137.4 mM) in 100 ml of DMF at room temperature for 72 hours. The mixture was poured into 1.5 liters of H20. The resulting precipitate was collected by filtration and dried under vacuum to provide 28.79 g (96%) of methyl 2-bromo-3-nitrobenzoate as a white solid. NMR of _I (DMSO-d6) d 8.3 (dd, 1H, J = 1 and 8 Hz), 7.9 (dd, 1H, J = 1 and 8 Hz), 7.7 (t, 1H, J = 8 Hz) and 3.9 (s, 3H). IR (KBr, cur1) 2950, 1738, 1541, 1435, 1364, 1298 and 1142. EM (FD) m / e 259, 261. Elemental Analysis for Calculated C8H6N04Br: C, 36, 95; H, 2, 33; N, 5, 39 Found: C, 37.1; H, 2.37; N, 5.45 b) Methyl 2-Bromo-3-aminobenzoate Hydrogen gas was passed through a solution of methyl 2-bromo-3-nitrobenzoate (0.20 g, 0.77 mM) and 0.1 g of 3% sulfided platinum on carbon in 25 ml of ethyl acetate for 24 hours at room temperature. The catalyst was removed by filtration through celite. The concentration of the filtrate produced 0, 175 g (99%) of methyl 2-bromo-3-aminobenzoate in the form of a yellow oil. 1 H NMR (CDC13) d 7.15 (t, 1H, J = 8 Hz), 7.1 (dd, 1H, J = 1 and 8 Hz), 6.8 (dd, 1H, J = 1 and 8 Hz) and 3.95 (s, 3H). IR (CHC13, cm "1) 3550, 3380, 2980, 2900, 1729, 1613, 1465, 1451, 1434, 1324, 1266 and 1025. MS (FD) m / e 230, 232. Elemental Analysis for C8H8N02Br: Calculated: C, 41.77; H, 3.51; N, 6.09. Found; C, 42.01; H, 3.29; N, 6.00. b ') In an alternative procedure, methyl 2-bromo-3-aminobenzoate was prepared as follows A solution of stannous chloride (15.0 g, 76.1 mM) in 30 ml of concentrated hydrochloric acid was slowly added to a solution of methyl 2-bromo-3-nitrobenzoate (4.0 g, 15.4 mM) in 90 ml of ethanol at 15-30 ° C for 1 hour The mixture was then heated to 50-60 ° C for 15 hours. The mixture was cooled to room temperature and made alkaline by the slow addition of solid sodium hydroxide while maintaining a temperature of 30-35 ° C. The resulting mixture was extracted three times with chloroform.The extracts were washed with brine, dried Sodium sulfate, filtered and concentrated to give 3.51 g (99%) of methyl 2-bromo-3-aminobenzoate as a yellow oil, identical in all respects to the material obtained by the catalytic hydrogenation described above. c) 3- (3-Carbomethoxy-2-bromoanilino) cyclohex-2-en-l-one Are heated A mixture of methyl 2-bromo-3-aminobenzoate (13.2 g, 60.0 mM) and 1,3-cyclohexanedione (8.4 g, 75 mM) was added at 125 ° C under a stream of nitrogen for 4 hours. hours. The resulting solid was purified by HPLC on silica gel (elution with methylene chloride / ethyl acetate) to provide 17.2 g (88%) of 3- (3-carbomethoxy-2-bromoanilino) cyclohex-2-en-1 -one in the form of a brown foam. NMR of _ (DMS0-d6) d 8.75 (s, 1H), 7.6-7.4 (m, 3H), 4.65 (s, 1H), 3.85 (s, 3H), 2 , 6 (t, 2H, J = 6 Hz), 2.15 (t, 2H, J = 6 Hz) and 1.9 (m, 2H). IR (CHCl3, cnr1) 3400, 3004, 2954, 1732, 1607, 1588, 1573, 1513, 1464, 1436, -1412, 1308, 1249, 1177 and 1144. MS (ES) m / e 322, 324, 326.

Elemental Analysis for C14H14N03Br: Calculated: C, 51, 85; H, 4, 32; N, 4, 32 Found: C, 53.60; H, 4.73; N, 4.09 d) 5-Carbomethoxy-1,2-dihydro-9H-carbazole-4 (3H) -one A suspension of 3- (3-carbomethoxy-2-bromoanilino) cyclohex- was heated at reflux for 8 hours. 2-en-l-one (15.8 g, 48.8 mM), palladium acetate (1.12 g, 5.0 mM), tri-o-tolylphosphine (3.1 g, 10.0 mM) and triethylamine (6.3 g, 62.0 mM) in 120 ml of acetonitrile. The solvent was removed in vacuo. The residue was dissolved in methylene chloride, washed twice with 1N HCl, twice with H20, once with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give 17 g of a clear brown foam. . Purification by HPLC on silica gel (elution with a gradient of methylene chloride / ethyl acetate) yielded 9.2 g (78%) of the 5-carbomethoxy-1,2-dihydro-9H-carbazole-4 (3H ) -one in the form of a yellow solid, identical to the material obtained from the 3- (3-carbomethoxy-2-chloroanilino) cyclohex-2-en-l-one described above. NMR of? (DMS0-d6) d 7.5 (d, 1H, J = 8 Hz), 7.25-7.1 (m, 2H), 5.7 (s, 1H), 3.8 (s, 3H) , 2.95 (t, 2H, J = 6 Hz), 274 (t, 2H, J = 6 Hz) and 2.1 (, 2H). MS (ES) m / e 242, 244.

Example 1 Preparation of the sodium salt of the acid. { 9- [(phenyl) methyl] -5- carbamoylcarbazol-4-yl} oxyacetic A. 9- [(Phenyl) methyl] -5-carbomethoxy-1,2-dihydrocarbazole -4 (3H) -one A suspension of 5-carbomethoxy-1,2-dihydro-9H-carbazole-4 (3H) was stirred. -one (300 mg, 1.23 mM), benzyl bromide (210 mg, 1.23 mM) and potassium carbonate (170 mg, 1.23 mM) in 15 ml of DMF at room temperature for 6 hours. The mixture was diluted with 80 ml of H20 and cooled in the refrigerator. The resulting white precipitate was collected by filtration, washed with H20 and dried under vacuum to provide 325 mg (79%) of the 9- [(phenyl) methyl] -5-carbomethoxy-1,2-dihydrocarbazole-4 (3H -one in the form of a white solid. 1 H NMR (DMS0-d6) d 7.7 (dd, 1H, J = 1 and 8 Hz), 7.45-7.0 (m, 7H), 5.6 (s, 2H), 3.8 (s, 3H), 3.05 (t, 2H, J = 6 Hz), 2.5 (t, 2H, J = 6 Hz) and 2.2 (m, 2H). IR (KBr, cm "1) 3421, 1726, 1676, 1636, 1473, 1450, 1435, 1288, 1122, 764, 745 and 706. MS (ES) m / e 334. Elemental Analysis for C21H19N03: Calculated: C, 75, 68; H, 5, 71; N, 4, 20 Found: C, 70.85; H, 5.53; N, 4.49 B. 9- [(Phenyl) methyl] -4-hydroxy-5-carbomethoxy carbazole (a) A solution of 9- [(phenyl) methyl] was stirred at 80-90 ° C for 6 hours. - -hydroxy-5-carbomethoxy-1,2-dihydrocarbazole-4 (3H) -one (1.5 g, 4.5 mM) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone ( 1.12 g, 5.0 mM) in 25 ml of toluene. The mixture was purified directly by column chromatography on silica gel (elution with methylene chloride / ethyl acetate) to give 420 mg (28%) of 9- [(phenyl) methyl] -4-hydroxy-5-carbomethoxy carbazole as a yellow solid. NMR of -I (DMSO-d6) d 10.25 (s, 1H), 7.7 (d, 1H, J = 8 Hz), 7.4 (t, 1H, J = 8 Hz), 7.4-7.0 (m, 8H), 6.6 (d, 1H, J = 8 Hz), 5.6 (s, 2H) and 3.8 (s, 3H). IR (CHC13, cm. "1723, 1685, 1621, 1597," 1568, 1496, 1453, 1442, 1392, 1286, 1267, 1156 and 1138. MS (ES) m / e 330, 332. Elemental Analysis for C22H17N03: Calculated: C, 76, 13; H, 5, 14; N, 4, 23 Found: C, 75.90; H, 5.20; N, 4.46 (b) To a solution of 9- [(phenyl) methyl] -5-carbomethoxy-1,2-dihydrocarbazole-4 (3H) -one (2.87 g, 8.61 mM) in 29 ml of dioxane, 60% sodium hydride in mineral oil (0.79 g, 19.8 mM) was added. The reaction was stirred for 8 minutes, then methyl benzene sulfinate (1.80 ml, 13.8 mM) was added. The reaction was stirred for an additional 1.5 hours, then diluted with 43 ml of dioxane and 1.13 ml of acetic acid. The mixture was refluxed for 1 hour, diluted with ethyl acetate and extracted twice with saturated NaHCO 3 and then with brine. After drying (NaS04), evaporation in vacuo gave 4.90 g. The mixture was purified by column chromatography on silica gel (elution with toluene / methylene chloride) to provide 2.31 g (81%) of the 9- [(phenyl) methyl] -4-hydroxy-5-carbomethoxy carbazole. NMR of I (DMSO-d6) d 10.25 (s, 1H), 7.7 (d, 1H, J = 8 Hz), 7.4 (t, 1H, J = 8 Hz), 7.4- 7.0 (m, 8H), 6.6 (d, 1H, J = 8 Hz), 5.6 (s, 2H) and 3.8 (s, 3H). IR (CHCl3, cm "1) 1723, 1685," 1621, 1597, 1568, 1496, 1453, 1442, 1392, 1286, 1267, 1156 and 1138. MS (ES) m / e 330, 332 Elemental Analysis for C21H17N03: Calculated: C, 76, 13; H, 5, 14; N, 4, 23 Found: C, 75.90; H, 5.20; N, 4.46. C. 9- [(Phenyl) methyl] -4-hydroxy-5-carbamoyl carbazole A solution of 9- [(phenyl) methyl] -4-hydroxy-5-carbomethoxy was sonicated for 30 h at 40-50 ° C. carbazole (200 mg, 0.6 mM) in 4 ml of MeOH and 40 ml of concentrated aqueous ammonium hydroxide. The mixture was diluted with ethyl acetate and acidified to pH 1 with 5 N HCl. The aqueous layer was extracted three times with ethyl acetate. The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (elution with a gradient of methylene chloride / ethyl acetate) to give 50 mg (26%) of the 9- [(phenyl) methyl] -4-hydroxy-5-carbamoyl Carbazole in the form of a white solid. NMR of I (DMS0-d6) d 10.5 (s, 1H), 8.8 (sa, 1H), 8.4 (sa, 1H), 7.85 (dd, 1H, J = 1 and 8 Hz ), 7.5-7.1 (m, 9H), 6, 6 (d, 1H, J = 8 Hz) and 5.8 (s, 2H). IR (KBr, cm "1) 3428, 3198, 3063, 1631, 1599, 1579," 1562, 1496, 1442, 1330, 1261, 1215, 775 and 697. MS (ES) m / e 315, 317.

Elemental Analysis for C20H16N2O2: Calculated: C, 75, 95; H, 5, 06; N, 8, 86 Found: C, 74.88; H, 5.40; N, 7.78. D. Methyl acid ester. { 9- [(phenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic 40% methanolic Triton B (0.11 ml, 0.24 mM) was added to a solution of 9- [(phenyl) methyl] -4-hydroxy-5-carbamoyl carbazole (70 mg, 0.22 mM) in 20 ml of DMF at 0 ° C. After 15 minutes, methyl bromoacetate (70 mg, 0.44 mM) was added and the resulting mixture was stirred at room temperature for 5 hours. The mixture was diluted with ethyl acetate, washed with 1 N HCl, H20 and saturated brine, dried over magnesium sulfate, filtered and concentrated. The residue was combined with the crude material derived from a similar experiment using 45 mg (0.14 mM [a total of 0.46 mM]) of 9 - [(phenyl) methyl] -4-hydroxy-5-carbamoyl carbazole. The combined residues were purified by column chromatography on silica gel (elution with ethyl acetate) to give 76 mg (54%) of the methyl ester of the acid. { 9- [(phenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic in the form of a white solid. NMR of _I (DMS0-d6) d 7.65 (d, 1H, J = 8 ~ Hz), 7.5 (sa, 1H), 7.4-7.15 (m, 9H), 7.1 ( d, 1H, J = 8 Hz), 6.6 (d, 1H, J = 8 Hz), 5.7 (s, 2H), 4.9 (s, 2H) and 3.75 (s, 3H) . IR (KBr, cm "1) 3367, 3200, 1760, 1643, 1579, 1496, 1452, 1427, 1216, 1157, 772 and 716. MS (FD) m / e 388. Elemental Analysis for C23H20N2O4: Calculated: C, 71.13; H, 5.15; N, 7.22 Found: C, 70.77; H, 5.49; N, 6.79, E. Sodium salt of acid {9- [(phenyl) methyl] -5-carbamoylcarbazol-4-yl.} oxyacetic acid A solution of the methyl ester of. {9- [(phenyl) methyl] -5-carbamoylcarbazol-4-yl was stirred for 16 hours at 25 ° C. Oxyacetic acid (10.1 mg, 0.025 mM) and 0.025 ml (0.025 mM) of 1 N NaOH in 3 ml of ethanol The resulting white precipitate was collected by filtration, washed with a small amount of EtOH and then dried under vacuum providing 7.1 mg (70%) of the sodium salt of the acid. {9- [(phenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid in the form of a white powder. (DMSO-d6) d 7.6 (d, 1H, J = 8 Hz), 7.5-7.05 (m, 11H), 6.55 (d, 1H, J = 8 Hz), 5.75 (s, 2H) and 4.3 (s, 2H).

IR (KBr, crn'1) 3471, 1657, 1615, 1591, 1496, 1453, 1412, 1330, 1272 and 1151. MS (S) m / e 373, 375, 397. Elemental Analysis for C22H17N204Na_: C, 66, 67; H, 4.29; N, 7.07. Found: C, 66.75; H, 4.55; N, 6.83.

Example 2 Preparation of [9-benzyl-4-carbamoyl-8-fluoro-1,2,3,4-tetrahydrocarbazol-5-yl] oxyacetic acid 'Preparation of (2-chloro-4-fluorophenyl) ethyl carbonate Chilled a solution of 19.16 g of 2-chloro-4-fluorophenol in 65.4 ml of 2N aqueous sodium hydroxide solution in an ice bath was treated dropwise with 16.3 ml of ethyl chloroformate. After stirring at room temperature overnight, the two-phase reaction mixture was diluted with 100 ml of water and extracted with 300 ml of a 1: 1 mixture of pentane / ether. The extract was washed three times with 0.02 N sodium hydroxide solution, with water and then with brine. After drying and evaporation, 27.63 g (97%) of the subtitle compound was obtained. NMR (300 MHz, CDC13): d 7.23-7.18 (m, 2H), 7.00 (dt, J = 8.4, 2.7, 1H), 4.35 (q, J = 7 , 1, 2H), 1.40 (t, J = 7.1, 3H). B. Preparation of (2-chloro-4-fluoro-5-nitrophenyl) -ethyl carbonate A solution of 27.63 g of (2-chloro-4-fluorophenyl) -ethyl carbonate in 60 ml of dichloromethane was cooled in an ice bath and treated dropwise with 31.86 g of a 1: 2 mixture of fuming nitric acid (90%) and concentrated sulfuric acid. The reaction was stirred for 2 hours at room temperature and then cooled with ice and treated with another 4.5 g of the same nitration mixture. The reaction was stirred overnight at room temperature, poured into 200 ml of ice and water and extracted twice with dichloromethane. The extracts were washed with water and then with brine, dried over magnesium sulfate and concentrated to give 33.01 (99%) of the subtitle compound, m.p. 50-51 ° C. Calculated Elementary Analysis: C, 41.01; H, 2.68; N, 5.31; Cl 13.45 Found: C, 41.03; H, 2.59; N, 5.38; Cl, 13.71 C. Preparation of 2-chloro-4-fluoro-5-nitroanisole A solution of 15.0 g of (2-chloro-4-fluoro-5-nitrophenyl) -ethyl carbonate in 100 ml was treated. of dimethylformamide with 18.6 g of cesium carbonate, 7.1 ml of iodomethane and 7 ml of methanol and stirred overnight at room temperature. The reaction mixture was poured into water and extracted twice with ether. The extracts were washed twice with water and then with brine, dried over magnesium sulfate and concentrated to give 11.4 g of the subtitle compound, m.p. 69-70 ° C. Ex. 57, C. Calculated Elementary Analysis: C, 40.90; H, 2.45; N, 6.81; Cl, 17,25, Found; C, 41.20; H, 2.48; N, 6.70; Cl, 17.44 D. Preparation of 2-fluoro-5-methoxyaniline A solution of 5.63 g of 2-chloro-4-fluoro-5-nitroanisole in 90 ml of ethanol and 5 ml of triethylamine was hydrogenated to a room temperature under 414 kPa with 1.0 g of 5% palladium on carbon for four hours. The catalyst was removed by filtration and the solvent was evaporated. The residue was suspended in chloroform and filtered through a plug of silica gel and then evaporated. This residue was chromatographed on silica gel using hexane / chloroform mixtures to provide 2.77 g (72%) of the subtitle compound, m.p. 253-254 ° C. NMR (300 MHz, CDC13): d 6.88 (dd, J = 10.6, 8.9, 1H), 6.32 (dd, J = 7.4, 3.0, 1H), 6.20 (dt, J = 8.9, 3.2, 1H), 3.73 (s, 3H), 3.72 (a, 2H). E. Preparation of N-benzyl-2-fluoro-5-methoxyaniline This procedure was designed after that of Tietze and Grote, Chem Ber. 126 (12), 2733 (1993). A solution of 2.73 g of 2-fluoro-5-methoxyaniline and 2.67 g of benzaldehyde in 48 ml of methanol was treated with 3.43 g of zinc chloride and then cooled in an ice bath. Sodium cyanoborohydride (1.58 g) was added in small portions at room temperature for 30 minutes and the reaction was stirred for five hours at room temperature. After evaporation of the solvent, the residue was suspended in 40 ml of a 1 N solution of sodium hydroxide and then extracted twice with ether. The extracts were washed with water and then with brine, dried over magnesium sulfate and concentrated. The residue was recrystallized from hexane to give 2.61 g and the mother liquor was chromatographed on silica gel using 20: 1 hexane / ether to give another 1.4 g of the subtitle compound (90%). 56-58 ° C. Calculated Elementary Analysis: C, 72.71; H, 6.10; N, 6.06. Found: C, 72.51; H, 6.06; N, 5.99 F. Preparation of ethyl 9-benzyl-5-methoxy-8-fluoro-1,2,3,4-tetrahydrocarbazole-4-carboxylate A solution of 0.62 g of N-benzyl was cooled. 2-fluoro-5-methoxyaniline in 20 ml of dry tetrahydrofuran in an ice bath and treated with 11.3 ml of 0.5 M potassium bis (trimethylsilyl) amide in toluene. After stirring for 30 minutes, 0.74 g of 2-carboethoxy-6-bromocyclohexanone (Sheeman and Mumaw, JACS, 72, 2127 (1950)) in 4 ml of tetrahydrofuran was added and the reaction allowed to warm slowly to room temperature for 2 hours. The reaction was quenched with saturated ammonium chloride solution and extracted twice with ether. The extracts were washed with water and then with brine, dried over magnesium sulfate and concentrated. This residue was chromatographed on silica gel using hexane / ether mixtures to provide 0.796 g (74%) of N-alkylated intermediate diastereomers. This mixture was heated to reflux in 20 ml of benzene with 0.99 g of zinc chloride overnight. The solvent was evaporated and the residue was partitioned between 25 ml of 1 N HCl and 25 ml of ethyl acetate and then extracted once more with ethyl acetate. The organic layers were washed with water and then with brine, dried over magnesium sulfate and concentrated to give 0.734 g (96%) of the subtitle compound. ESIMS m / e 382 (M ++ l). Calculated Elementary Analysis: C, 72.42; H, 6.34; N, 3.67, Found: C, 72.20; H, 6.26; N, 3.70. Preparation of 9-benzyl-5-methoxy-8-fluoro-1,2,3,4-tetrahydrocarbazole-4-carboxamide 9-benzyl-5-methoxy-8-fluoro-1,2,3,4-tetrahydrocarbazole was treated Ethyl 4-carboxylate (0.722 g) in a manner similar to that described in Example 49, Part C and chromatographed on silica gel using 1% methanol in dichloromethane to give 0.482 g (72%) of the subtitle compound. ESIMS m / e 353 (M ++ l). Calculated Elemental Analysis: C, 71.57; H, 6.01; N, 7.95. Found: C, 71.42; H, 5.83; N, 7.75. H. Preparation of [9-benzyl-4-carbamoyl-8-fluoro-l, 2,3,4-tetrahydrocarbazol-5-yl] oxyacetic acid methyl ester 9-benzyl-5-methoxy-8-fluoro- 1, 2, 3, 4-tetrahydrocarbazole-4-carboxamide (0.170 g), similar to that described in Example 49, Part D, and chromatographed on silica gel using 0-1% methanol in dichloromethane to provide mg (50%) of the subtitle compound, mp 183-185 ° C. Calculated Elementary Analysis: C, 67.31; H, 5.65; N, 6.82 Found: C, 67.58; H, 5.48; N, 6.95 Preparation of [9-benzyl-4-carbamoyl-8-fluoro-1,2,3,4-tetrahydrocarbazol-5-yl] oxyacetic acid [9-Benzyl-4-carbamoyl] methyl ester was hydrolyzed -8-fluoro-l, 2, 3, 4-tetrahydrocarbazol-5-yl] sxiacético (71 mg) in a manner similar to that described in Example 50, Part D, giving 65 mg of the title compound. ESIMS m / e 397 (M ++ l), 395 (M + -l). NMR (300 MHz, DMSO-d6): d 13.03 (a, 1H), 7.31-7.19 (m, 3H) 6.97 (d, J = 7.4, 2H), 6.95 (a, 1H), 6.70 (d, J = 3.8, 1H), 6.67 (dd, J = 12.4, 3.9, 1H), 6.28 (dd, J = 8.5, 2.6, 1H), 5.39 (ABq , 2H), 4.64 (s, 2H), 3.92 (a, 1H), 2.71 (m, 1H), 2.44 (m, 1H), 2.02 (m, 2H), 1 76 (m, 2H) Example 3 Preparation of [9-benzyl-5-carbamoyl-1-fluorocarbazol-4-yl] oxyacetic acid A. Preparation of 9-benzyl-5-carbamoyl-4-methoxy-1-fluorocarbazole. solution of 0.458 g of 9-benzyl-5-methoxy-8-fluoro-1,2,3,4-tetrahydrocarbazole-4-carboxamide in 13 ml of dry dioxane under nitrogen with 0.59 g of 2,3-dichloro- 5,6-dicyano-1,4-benzoquinone and heated to reflux for one hour. The reaction mixture was cooled and filtered and the precipitate was washed with 15 ml of dioxane. The filtrate and washings were poured into a saturated solution of sodium bicarbonate and extracted three times with ethyl acetate. The extracts were washed with saturated sodium bicarbonate, with water and then with brine; dried over magnesium sulfate and concentrated. This residue was chromatographed on silica gel using dichloromethane / 0-2% methanol to afford 0.45 g of the subtitle compound. ESIMS m / e 349 (M ++ l) Calculated Elemental Analysis: C, 72.42; H, 4.92; N, 8.04 Found: C, 72.35; H, 4.81; N, 7.88. B. Preparation of [9-benzyl-5-carbamoyl-1-fluorocarbazol-4-yl] oxyacetic acid methyl ester. A solution of 0.45 g of 9-benzyl-5-carbamoyl-4-methoxy-1 was treated. Fluorocarbazole in 25 ml of dichloromethane was cooled in an ice bath, dropwise with 12 ml of 1.0 M solution of boron tribromide in dichloromethane. The reaction was allowed to slowly warm to room temperature for 2 hours and then was quenched by pouring on ice and then adding 50 ml of 1 N HCl. The mixture was extracted with dichloromethane (3 x 200 ml), the extracts were dried over magnesium sulfate and concentrated giving 0.35 g (78%) of the demethylated intermediate. This intermediate (0.215 g) was alkylated and purified in a manner similar to that of Example GH1, Part D, giving 0.166 g (64%) of the subtitle compound, m.p. 190-191 ° C. Calculated Elementary Analysis: C, 67.97; H, 4.71; N, 6.89. Found: C, 67.81; H, 4.94; N, 6.96 C. Preparation of [9-benzyl-5-carbamoyl-1-fluorocarbazol-4-yl] oxyacetic acid. The [9-benzyl-5-carbamoyl-1-fluorocarbazole-4] methyl ester was hydrolysed il] oxyacetic acid (56 mg) and isolated in a similar manner to that described in Example 50, Part D, giving 54 mg of the title compound. FDMS m / e 392 (M +); ESIMS m / e 393 (M ++ 1), 391 (M + -l). NMR (300 MHz, DMS0-ds): d 12.92 (a, 1H), 7.70 (m, 2H), 7.45 (t, J = 7.5, 1H), 7.39 (a, 1H), 7.28-7.17 (m, 4H), 7.12 (d, J = 7.2, 1H), 7.07 (d, J = 7.0, 2H), 6.51 ( dd, J = 8.8, 2.7, 1H), 5.77 (s, 2H), 4.80 (s, 2H). Calculated Elementary Analysis: C, 67.34; H, 4.37; N, 7.14 Found: C, 66.92; H, 4.49; N, 6.77, Example 4 Preparation of acid. { 9- [(3-fluorophenyl) methyl] -5- carbamoylcarbazol-4-yl} oxyacetic A. 9- [(3-Fluorophenyl) methyl] -5-carbomethoxy-1,2-dihydrocarbazole-4 (3H) -one. 40% Methanolic Triton B (2.06 ml, 4.53) was slowly added dropwise. mM) to a solution of 5-carbomethoxy-1,2-dihydro-9H-carbazole-4 (3H) -one (930.0 mg, 3.82 mM) in 5 ml of DMF at 0 ° C. After 5 minutes, 3-fluorobenzyl chloride (664.0 mg, 4.59 M) was added and the resulting mixture was stirred at 0 ° C for 3 hours and then at room temperature for 20 hours. The mixture was diluted with ethyl acetate, washed three times with 1 N HCl, once with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (elution with a gradient of methylene chloride / ethyl acetate) to provide 502.3 mg (37%) of the 9- [(3-fluorophenyl) methyl] -5- carbomethoxy-1, 2-dihydrocarbazole-4 (3H) -one in the form of a yellow foam. NMR of I (CDC13) d 7.4-7.2 (m, 4H), 6.9 (m, 1H), 6.7 (m, 2H), 5.35 (s, 2H), 4.05 (s, 3H), 2.9 (t, 2H, J = 6 Hz), 2.65 (t, 2H, J = 6 Hz) and 2.3 (m, 2H). IR (CHC13, cm ') 3050, 2950, 1725, 1654, 1464, 1451, 1440, 1288 and 1119. MS (ES) m / e 350, 352. Elemental Analysis for C21H18N03F: Calculated: C, 71.78; H, 5.16; N, 3.99 Found: C, 72.00; H, 4.95; N, 4.11. B. 9 - [(3-Fluorophenyl) methyl] -4-hydroxy-5-carbomethoxy carbazole A solution of 9- [(3-fluorophenyl) methyl] -5-carbomethoxy-1,2-dihydrocarbazole-4 ( 3H) -one (434.0 mg, 1.23 mM) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (324.0 mg, 1.42 mM) in 20 ml of toluene between 70-80 ° C for 5 hours. The mixture was purified directly by column chromatography on silica gel (elution with methylene chloride ble) to provide 137.0 mg (32%) of the 9- [(3-fluorophenyl) methyl] -4-hydroxy-5-carbomethoxy carbazole in shape of a yellow foam. NMR of? (DMS0-d6) d 10.2 (s, 1H), 7.7 (d, 1H, J = 8 Hz), 7.4 (t, 1H, J = 8 Hz), 7.3 (m, 2H ), 7.2 (d, 1H, J = 8 Hz), 7.1 (d, 1H, J = 8 Hz), 7.05-6.85 (, 3H), 6.6 (d, 1H, J = 8 Hz), 5.65 (s, 2H) and 3.85 (s, 3H). IR (CHCl3, hearing1) 3200 (a), 1687, 1597, 1452, 1442, 1285 and 1267. MS (ES) m / e 348, 350. Elemental Analysis for C21H16N03F: Calculated: C, 72.20; H, 4.62; N, 4.01. Found: C, 72.30; H, 4.66; N, 4.04. C. 9- [(3-Fluorophenyl) methyl] -4-hydroxy-5-carbamoyl carbazole A solution of 9 - [(3-fluorophenyl) methyl] -4-hydroxy-5-carbomethoxy carbazole (130.8 mg, 0.37 mM) in 5 ml of water was sonicated for 5 hours at 40-50 ° C. THF and 20 ml of concentrated aqueous ammonium hydroxide. The mixture was diluted with ethyl acetate and acidified to pH 1 with 5 N HCl. The aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (elution with a gradient of methylene chloride / ethyl acetate) to provide 57.4 mg (45%) of the 9- [- (3-fluorophenyl) methyl] -4- hydroxy-5-carbamoyl carbazole in the form of a white solid. NMR of _? (DMS0-d6) d 10.5 (s, 1H), 8.8 (s at, 1H), 8.4 (s, 1H), 7.8 (dd, 1H, J = 1 and 8 Hz), 7 , 5 (m, 2H), 7.3 (m, 2H), 7.15-7.0 (m, 2H), 6.95 (d, 1H, J = 8 Hz), 6.85 (d, 1H, J = 8 Hz), 6.6 (d, 1H, J = 8 Hz) and 5.7 (s, 2H). IR (CHC13, cm "1) 3431, 3200 (a), 1628, 1614, 1600, 1580, 1546, 1488, 1448, 1329, 1261 and 776. MS (S) m / e 333, 335. Elemental Analysis for C20H15N2O2F : Calculated: C, 71.85; H, 4.52; N, 8.38 Found: C, 74.45; H, 6.01; N, 8.48 D. Tert-butyl acid ester. 9- [(3-Fluorophenyl) -methyl] -5-carbamoylcarbazol-4-yl.} Oxyacetic acid 40% methanolic Triton B (0.086 ml, 0.19 mM) was added to a solution of 9- [(3 -fluorophenyl) methyl] -4-hydroxy-5-carbamoyl carbazole (51.9 mg, 0.155 mM) in 3 ml of DMF at room temperature After 3 minutes, t-butyl bromoacetate (87.8 mg, 0.44 mM) and the resulting mixture was stirred at room temperature for 5 hours.The mixture was diluted with ethyl acetate, washed four times with H20 and saturated brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (elution with a gradient of methylene chloride / ethyl acetate) providing 44.0 mg (63%) of the tert-butyl ester of the acid. { 9- [(3-fluorophenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic, in the form of a white solid. NMR of _I (DMSO-dg) d 7.6 (d, 1H, J = 8 Hz), 7.5-6.8 (m, 10H), 6.55 (d, 1H, J = 8 Hz), 5.7 (S, 2H), 4.8 (s, 2H) and 1.45 (s, 9H). IR (CHC13, cm "1) 3450, 3400, 1746, 1674, 1592, 1457, 1369 and 1151. MS (FD) m / e 448. Elemental Analysis for C26H25N204F: Calculated: C, 69.63; H, 5, 62; N, 6.25 Found: C, 69.35; H, 5.44; N, 6.23, E. Acid {9- [(3-fluorophenyl) methyl] -5-carbamoylcarbazole-4- Oxyacetic acid A solution of tert-butyl ester of {9- [(3-fluorophenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid ester (40.0 mg, 0.089 mM) was stirred. in 2 ml of trifluoroacetic acid at room temperature for 5 hours.The solvent was removed in vacuo.The residue was triturated with ethyl ether and then dried under vacuum to provide 35.0 g (100%) of the acid. (3-fluorophenyl) methyl] -5-carbamoylcarbazol-4-yl.} Oxyacetic acid in the form of a white powder NMR of D (DMSO-ds) d 13.0 (br s, 1H), 7.75 (s, 1H), 7.6 (d, 1H, J = 8 Hz), 7.5-7.25 (m, 5H), 7.2-6.8 (m, 4H), 6.6 (d, 1H , J = 8 Hz), 5.7 (s, 2H) and 4.8 (s, 2H). IR (KBr, crn "1) 3423, 3400, 1736, 1637, 1615, 1589, 1499, 148 7, 1450, 1436, 1331, 1250 and 1156. MS (ES) m / e 391, 393. Elemental Analysis for C22H17N204F: Calculated: C, 67.34; H, 4.37; N, 7.14 Found: C, 67.63; H, 4.22; N, 7.35 Example 5 Preparation of acid. { 9- [(3-chlorophenyl) methyl] -5- carbamoylcarbazol-4-yl} oxyacetic A. 9- [(3-Chlorophenyl) methyl] -5-carbomethoxy-1,2-dihydrocarbazole-4 (3H) -one A suspension of 5-carbomethoxy-1,2-dihydroxylate was stirred at room temperature for 150 hours. 9H-carbazole-4 (3H) -one (527.0 mg, 2.17 mM), 3-chlorobenzyl bromide (802.2 mg, 3.90 mM), a catalytic amount of sodium iodide (approximate amount 1 mg ) and potassium carbonate (500.0 mg, 3.62 mM). The mixture was diluted with ethyl acetate, washed five times with H20, once with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (elution with a gradient of methylene chloride / ethyl acetate) to provide 537, 1 mg (67%) of the 9 - [(3-chlorophenyl) methyl] -5-carbomethoxy-1,2-dihydrocarbazole-4 (3H) -one as a yellow foam. NMR of I (CDC13) d 7.5-7.2 (m, 5H), 7.1 (s, 1H), 6.85 (m, 1H), 5.35 (s, 2H), 4.05 (s, 3H), 2.9 (t, 2H, J = 6 Hz), 2.65 (t, 2H, J - 6 Hz) and 2.3 (m, 2H). IR (CHC13, cm'1) 3050, 2950, 1725, 1654, 1464, 1444, 1432, 1288 and 1120. MS (ES) m / e 366, 368, 370. Elemental Analysis for C21H18N03C1: Calculated: C, 68, 57; H, 4.93; N, 3.81. Found: C, 68.61; H, 4.92; N, 3.70. B. 9- [(3-Chlorophenyl) methyl] -4-hydroxy-5-carbomethoxy carbazole A "solution of 9- [(3-chlorophenyl) methyl] -5- was stirred at 70-80 ° C for 3 hours. carbomethoxy-1, 2-dihydrocarbazole-4 (3H) -one (480.5 mg, 1.31 mM) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (325.7 mg, 1 43 mM) in 50 ml of toluene The mixture was purified directly by column chromatography on silica gel (elution with methylene chloride) to give 172.6 mg (36%) of the 9 - [(3-chlorophenyl) methyl] -4-hydroxy-5-carbomethoxy carbazole in the form of a yellow foam NMR of I (CDC13) d 10.4 (s, 1H), 8.05 (d, 1H, J = 8 Hz), 7.6 ( d, 1H, J = 8 Hz), 7.4 (m, 2H), 7.3-7.1 (m, 3H), 6, 9 -6, 1 (m, 3H), 5.55 (s , 2H) and 4.15 (s, 3H). IR (CHCl3, cm "1) 3200 (a), 1684, 1598, 1442, 1428, 1331, 1285 and 1267. MS (ES) m / e 364, 366 , 368. Elemental Analysis for C21H16N03C1: Calculated: C, 68.95; H, 4.41; N, 3.83. Found: C, 69.23; H, 4.52; N, 3.98. C. 9- [(3-Chlorophenyl) methyl] -4-hydroxy-5-carbamoyl carbazole A solution of 9 - [(3-chlorophenyl) methyl] -4-hydroxy-5-carbomethoxy carbazole (156.2 mg, 0.43 mM) in 5 ml of water was sonicated for 5 hours at 40-50 ° C. THF and 20 ml of concentrated aqueous ammonium hydroxide. The mixture was diluted with ethyl acetate and acidified to pH 1 with 5 N HCl. The aqueous layer was extracted twice with ethyl acetate.The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, The residue was purified by column chromatography on silica gel (elution with a gradient of methylene chloride / ethyl acetate) to give 69.7 mg (47%) of 9- [(3-chlorophenyl) methyl. ] -4-hydroxy-5-carbamoyl carbazole in the form of a white solid NMR of _I (DMS0-d6) d 10.5 (s, 1H), 8.8 (s at, 1H), 8.4 (s, 1H), 7.8 (dd, 1H, J = 1 and 8 Hz), 7.45 (m, 2H), 7.3 (m, 3H), 7.2 (s, 1H), 7.1 ( d, 1H, J = 8 Hz), 6.95 (s, 1H), 6.6 (d, 1H, J = 8 Hz) and 5.7 (s, 2H). IR (CHC13, crrr1) 3433, 3202 (a), 1630, 1600, 1580, 1564, 1433, 1330, 1261 and 776. MS (ES) m / e 349, 351, 353. Elemental Analysis for C20H15N2O2Cl: Calculated: C, 68.48; H, 4 , 31; N, 7.99, Found: C, 68.64; H, 4.55; N, 7.93. tert-butyl acid acid. { 9- [(3-chlorophenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic 40% methanolic Triton B (0.053 ml, 0.12 mM) was added to a solution of 9 - [(3-chlorophenyl) methyl] -4-hydroxy-5-carbamoyl carbazole (33.2 mg, 0.12 mM) in 12 ml of DMF at room temperature. After 3 minutes, t-butyl bromoacetate (53.8 mg, 0.27 mM) was added and the resulting mixture was stirred at room temperature for 20 h.The mixture was diluted with ethyl acetate, washed four times. H20 and once with saturated brine, dried over magnesium sulfate, filtered and concentrated, The residue was purified by column chromatography on silica gel (gradient elution of methylene chloride / ethyl acetate) to provide 4.21 mg (95%) of. {9- [(3-chlorophenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid tert-butyl ester as a white solid. (DMSO-ds) d 7.6 (d, 1H, J = 8 Hz), 7.5-6.8 (m, 10H), 6.55 (d, 1H, J = 8 Hz), 5.7 (s, 2H), 4.8 (s, 2H) and 1.45 (s, 9H). IR (CHCl3, cm-1) 3450, 3400, 1744, 1676, 1591, 1457, 1369 and 1150. MS ( FD) m / e 464, 466. Elemental Analysis for C26H25N204C1: Calculated: C, 67.17; H, 5.42; N, 6.03 Found: C, 67.17; H, 5.65; N, 5.97 E. Acid. 9- [(3-Chlorophenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid A solution of the tert-butyl ester of the acid was stirred at room temperature for 6 hours. { 9 - [(3-chlorophenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid (35.6 mg, 0.77 mM) in 2 ml of trifluoroacetic acid. The solvent was removed in vacuo. The residue was triturated with ethyl acetate and then dried under vacuum to provide 31.4 mg (100%) of the acid. { 9- [(3-chlorophenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic in the form of a white powder. NMR of I (DMS0-ds) d 13.0 (sa, 1H), 7.75 (s, 1H), 7.6 (d, 1H, J = 8 Hz), 7.4-7.25 (m , 7H), 7.2 (d, 1H, J = 8 Hz), 7.0 (ta, 1H), 6, 6 (d, 1H, J = 8 Hz), 5.7 (s, 2H) and 4.8 (s, 2H). IR (KBr, cm "1) 3456, 3416, 3335, 1735, 1638, 1617, 1580, 1499, 1452, 1431, 1431, 1329, 1255, 1157, 772, 764 and 717. MS (S) m / e 407 , 109, 411. Elemental Analysis for C22H17N204C1: Calculated: C, 64.63; H, 4.19; N, 6.85 Found: C, 64.55; H, 4.12; N, 6.74. 6 Preparation of the sodium salt of the acid. {9 - [(3- trifluoromethylphenylmethyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid A. 9 - [(3-Trifluoromethylphenyl) methyl] -5-carbomethoxy-1,2-dihydrocarbazole-4 (3H) -one. 40% Methanolic Triton B (2.18 ml, 4.8 mM) was slowly added dropwise to a solution of 5-carbomethoxy-1,2-dihydro-9H-carbazole-4 (3H) -one (973 mg , 4.0 mM) in 10 ml of DMF at -10 ° C. After 30 minutes, 3- (trifluoromethyl) benzyl chloride (1.53 g, 6.0 mM) and sodium iodide were added. (900 mg, 6.0 mM) and the resulting mixture was stirred at room temperature for 25 hours. The mixture was diluted with ethyl acetate, washed five times with H20, 1 N HCl, H20, NaHC03 sat. and saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated and dried in vacuo. The residue was purified by column chromatography on silica gel (gradient elution of methylene chloride / ethyl acetate) to provide 1.02 g (63%) of the 9- [(3-trifluoromethylphenyl) methyl] -5-carborne t-oxy-1,2-dihydrocarbazole-4 (3H) -one as a tan solid. NMR of I (CDC13) d 7.6 (d, 1H, J = 8 Hz), 7.45-7.2 (m, 5H), 7.0 (d, 1H, J = 8 Hz), 5, 4 (s, 2H), 4.05 (s, 3H), 2.85 (t, 2H, J = 6 Hz), 2.6 (t, 2H, J = 6 Hz) and 2.2 (m, 2H). IR (KBr, crn "1) 1727 and 1652. MS (ES) m / e 400, 402. Elemental Analysis for C22H18N03F3: Calculated: C, 65.83; H, 4.52; N, 3.49; F, 14.20 Found: C, 65.63; H, 4.58; N, 3.39; F, 14.14.

B. 9- [(3 -Trif luoromethylphenyl) methyl] -4-hydroxy-5-carbomethoxy carbazole A solution of 9- [(3-trifluoromethylphenyl) methyl] -5 was stirred at 80-90 ° C for 7 hours. -carbomethoxy-l, 2-dihydrocarbazole-4 (3H) -one (1.21 g, 3.00 mM) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (764 mg, 3, 3 mM) in 25 ml of toluene. The mixture was purified directly by column chromatography on silica gel (elution with methylene chloride) to provide 340.0 g (28%) of 9 - [(3-trifluoromethylphenyl) methyl] -4-hydroxy-5-carbomethoxycarbazole in shape of a yellow solid. NMR of I (CDCl3) "d 10.35 (s, 1H), 8.0 (d, 1H, J = 8 Hz), 7.6-7.3 (m, 6H), 7.05 (d, 1H, J = 8 Hz), 6.85 (m, 2H), 5.6 (s, 2H) and 4.1 (s, 3H). IR (CHC13, cm "1) 3378 and 1712. MS (ES) ) m / e 398, 400. Elemental Analysis for C22H16N03F3: Calculated: C, 66.17; H, 4.04; N, 3.51 Found: C, 66.99; H, 4.12; N, 3.53; FC 9 - [(3-Trifluoromethylphenyl) methyl] -4-hydroxy-5-carbamoyl carbazole A solution of 9 - [(3-trifluoromethylphenyl) methyl] -4-hydroxy was sonicated for 30 hours at 40-50 ° C. -5-carbomethoxy carbazole (250 mg, 0.625 mM) in 5 ml of THF and 20 ml of concentrated aqueous ammonium hydroxide. The mixture was diluted with ethyl acetate and acidified to pH 1 with 5 N HCl. The aqueous layer was extracted three times with ethyl acetate. The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (gradient elution of methylene chloride / ethyl acetate) yielding 120 mg (50%) of 9 - [(3-trifluoromethylphenyl) methyl] -4-hydroxy-5- Carbamoyl carbazole in the form of a white solid. NMR of _I (DMSO-d6) d 10.5 (s, 1H), 8.8 (sa, 1H), 8.4 (sa, 1H), 7.8 (d, 1H, J = 8 Hz), 7.6-7.5 (m, 5H), 7.3 (t, 1H, J = 8 Hz), 7.15 (d, 1H, J = 8 Hz), 7.1 (d, 1H, J = 8 Hz), 6.6 (d, 1H, J = 8 Hz) and 5.8 (s, 2H). IR (KBr, cm "1) 3429, 3206 and 1630. MS (ES) m / e 383, 385. Elemental Analysis for C21H15N202F3: Calculated: C, 65.62; H, 3.93; N, 7.29. Found: C, 67.50; H, 4.00; N, 7.19 D Acid methyl ester. {9- [(3 trif luoromet il feni 1) me ti 1] - 5 - carbamoi lcarbazole - 4-yl. Oxyacetic acid 40% Methanolic Triton B (0.18 ml, 0.4 mM) was added to a solution of 9 - [(3-trifluoromethylphenyl) methyl] -4-hydroxy-5-carbamoyl carbazole ( 115 mg, 0.3 mM) in 5 ml of DMF at room temperature After 15 minutes, methyl bromoacetate (95 mg, 0.6 mM) was added and the resulting mixture was stirred at room temperature for 22 hours. The mixture was diluted with ethyl acetate, washed four times with H20, 1 N HCl, sat.H20 NaHCO3 and saturated brine, dried over magnesium sulfate, filtered and concentrated.The residue was purified by gel column chromatography. of silica (elution with ethyl acetate) yielding 120 mg (88%) of the methyl ester of the acid ". { 9 - [(3-trif luoromet ilf enyl) met il] -5-carbamoylcarbazol-4-yl} oxyacetic in the form of a white solid. NMR of -I (CDC13) d 7.5-7.2 (m, 7H), 7.1 (d, 1H, J = 8 Hz), 7.0 (d, 1H, J = 8 Hz), 6 , 6 (d, 1H, J = 8 Hz), 6.4 (sa, 1H), 6.0 (sa, 1H), 5.55 (s, 2H), 4.9 (s, 2H) and 3 , 9 (s, 3H). IR (KBr, cm "1) 1763 and 1673. MS (ES) m / e 457. Elemental Analysis for C24H19N204F3: Calculated: C, 63.16; H, 4.20; N, 6.14 Found: C, 61 , 37; H, 4.19; N, 5.77, E *. Sodium salt of {9- [(3-trifluoromethylphenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid. 17 hours at 25 ° C a solution of methyl {. 9 - [(3-trifluoromethylphenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid methyl ester (91 mg, 0.153 mM) and 0.22 ml (0.22 mM) of 1 N NaOH in 8 ml of ethanol. The ethanol was removed in vacuo. The resulting white precipitate was collected by filtration, washed with small amounts of EtOH and diethyl ether and then dried under vacuum to give 75 mg (81%) of the sodium salt of the acid. { 9 - [(3-trif luoromet i 1 phenyl) met il] -5-carbamoi 1 carbazol-4-yl} oxyacetic in the form of a white powder. NMR of -i (DMS0-d6) d 7.65 (s, 1H), 7.6 (m, 4H), 7.45 (t, 1H, J = 8 Hz), 7.35 (t, 1H, J = 8 Hz), 7.3 (t, 1H, J = 8 Hz), 7.2 (d, 1H, J = 8 Hz), 7.1 (d, 1H, J = 8 Hz), 7, 05 (d, 1H, J = 8 Hz), 6.5 (d, 1H, J = 8 Hz), 5.75 (s, 2H) and 4.3 (s, 2H). IR (KBr, cm'1) 1665 and 1618. MS (ES) m / e 441 and .443. Elemental Analysis for C23H16N204F3Na: Calculated: C, 59.49; H, 3.47; N, 6.03 Found: C, 60.69; H, 3.78; N, 5.75. Example 7 Preparation of the sodium salt of the acid. { 9 - [(2-methylphenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic A. 9- [(2-Methylphenyl) methyl] -5-carbomethoxy-1,2-dihydrocarbazole-4 (3H) -one A suspension of 5-carbomethoxy-1,2-dihydroxypropyl ether was stirred at room temperature for 20 hours. 9H-carbazole-4 (3H) -one (870 mg, 3.58 mM), a-bromo-o-xylene (662 mg, "3.58 mM) and potassium carbonate (500 mg, 3.61 mM) in 20 ml of DMF The mixture was diluted with ethyl acetate, washed with H20 and saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give 1.21 g (98%) of the 9- [ (2-methylphenyl) methyl] -5-carbomethoxy-1,2-dihydrocarbazole-4 (3H) -one in the form of a dark oil, NMR of I (DMS0-d6) d 7.5-7.2 (m, 4H), 7.15 (t, 1H, J = 8 Hz), 7.0 (t, 1H, J = 8 Hz), 6.15 (d, 1H, J = 8 Hz), 5.55 (s) , 2H), 3.85 (s, 3H), 2.6 (m, 2H), 2.4 (m, 2H), 2.4 (s, 3H) and 2.1 (m, 2H). IR (CHC13, cm "1) 3010, 2952, 1724, 1671, 1653, 1604, 1460, 1444, 1290, 1174 and 1122. MS (ES) m / e 348.5. Elemental Analysis for C22H21N03: Calculated: C, 76.08; H, 6.05; N, 4.03 Found: C, 73.33; H, 6.36; N, 4.30 B. 9- [(2-Methylphenyl) methyl] -4-hydroxy -5-Carbomethoxy carbazole A solution of 9- [(2-methylphenyl) methyl] -5-carbomethoxy-1,2-dihydrocarbazole-4 (3H) -one (1) was stirred at 80-90 ° C for 5 hours. 2 g, 3.5 mM) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (800 mg, 3.6 mM) in 70 ml of toluene The mixture was purified directly by column chromatography on silica gel (elution with methylene chloride) affording 260 mg (22%) of the 9- [(2-methylphenyl) methyl] -4-hydroxy-5-carbomethoxy carbazole as a yellow solid. (DMSO-dg) d 10.25 (s, 1H), 7.5 (d, 1H, J = 8 Hz), 7.4 (t, 1H, J = 8 Hz), 7.3-7.1 (m, 4H), 6.9 (m, 2H), 6.6 (d, 1H, J = 8 Hz), 6.1 (d, 1H, J = 8 Hz), 5.65 (s, 2H) ), 3.8 (s, 3H) and 2.5 (s, 3H). IR (KBr, cm "1) 3200, 1672, 1440, 1426, 1332, 1302, 1265, 1216, 1141, 761, 749 and 718. MS (ES) m / e 344, 346. Elemental Analysis for C22H19? 03: Calculated: C, 76.52; H, 5.51; ?, 4.06 Found: C, 76.44; H, 5.66; ?, 3.94. C. 9- [(2-Methylphenyl) methyl] -4-hydroxy-5-carbamoylcarbazole A solution of 9 - [(2-methylphenyl) methyl] -4-hydroxy-5-carbomethoxy carbazole (260 mg, 0.75 mM) in 10 ml of THF was sonicated for 5 hours at 40-50 ° C. 30 ml of concentrated aqueous ammonium hydroxide. The mixture was diluted with ethyl acetate and acidified to pH 1 with 5? HCl. The aqueous layer was extracted three times with ethyl acetate. The combined organic extracts were washed with H20 and saturated brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (gradient elution of hexanes / ethyl acetate) to give 90 mg "(36%) of 9- [(2-methylphenyl) methyl] -4-hydroxy-5-carbamoyl Carbazole in the form of a chestnut solid NMR of -I (DMSO-ds) d 10.5 (s, 1H), 8.8 (sa, 1H), 8.4 (sa, 1H), 7.7 (m, 1H), 7.5 (m, 2H), 7.3 (m, 2H), 7.1 (t, 1H, J = 8 Hz), 6.95 (d, 1H, J = 8 Hz), 6.85 (t, 1H, J = 8 Hz), 6.6 (d, 1H, J = 8 Hz), 5, 95 (d, 1H, J = 8 Hz), • 5.7 (s, 2H) and 2.5 (s, 3H). IR (KBr, cm "1) 3451, 3191, 1627, 1600, 1584, 1562, 1435, 1329, 1322, 1263 and 774. MS (ES) m / e 329, 331. Elemental Analysis for C21H18N202: Calculated: C, 76.36; H, 5.45; N, 8.48 Found: C, 75.66; H, 5.79; N, 8.07. D. Methyl acid ester. { 9- [(2-methylphenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic 40% Methanolic Triton B (0.45 ml, 0.99 mM) was added to a solution of 9 - [(2-methylphenyl) methyl] -4-hydroxy-5-carbamoyl carbazole (80 mg, 0.24) mM) in 80 ml of DMF at room temperature. After 3 minutes, methyl bromoacetate (115 mg, 0.72 mM) was added and the resulting mixture was stirred at room temperature for 48 hours. The mixture was diluted with ethyl acetate, washed with H20, 1 N HCl, H20 and saturated brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (elution with ethyl acetate) to give 80 mg (82%) of the methyl ester of. {9- [(2-methylphenyl) methyl] -5-carbamoylcarbazole- 4-yl) oxyacetic acid in the form of a white solid, γ NMR (DMSO-d6) d 7.56 (br, 1H), 7.5-7.1 (m, 9H), 6.9 (t , 1H, J = 8 Hz), 6.6 (d, 1H, J = 8 Hz), 5.65 (s, 2H), 4.9 (s, 2H), 3.8 (s, 3H) and 2.5 (s, 3H). IR (KBr, cm'1) 3367, 3153, 1760, 1740, 1672, 1644, 1619, 1591, 1578, 1498, 1456, 1425, 1327, 1200, 1153, 1109, 1100 and 777. MS (FD) m / e 402. Elemental Analysis for C24H22N204: Calculated: C, 71.64; H, 5.47; N, 6.96 Found: C, 71.51; H, 5.56 N, 6.67, E. Sodium salt of {9- [(2-methylphenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid. A suspension of the suspension was stirred for 24 hours at 25 ° C {9 - [(2-methylphenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid methyl ester (15.5 mg, 0.039 mM) and 0.04 ml (0.04 mM) of NaOH 1 N in 5 ml of ethanol. The resulting white precipitate was collected by filtration, washed with a small amount of EtOH and then dried in vacuo to give 10 mg (63%) of the sodium salt of the acid. { 9 - [(2-methylphenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic in the form of a white powder. 1 H NMR (DMSO-d 6) d 7.55 (br s, 1H), 7.5-7.0 (m, 7H), 6.9 (d, 1H, J = 8 Hz), 6.85 (t , 1H, J = .8 Hz), 6.6 (d, 1H, J = 8 Hz), 6.2 (d, 1H, J = 8 Hz), 5.6 (s, 2H), 4.35 (s, 2H) and 2.5 (s, 3H) -. IR (KBr, cm'1) 3390, 1656, 1613, 1595, 1573, 1498, 1455, 1408, 1325, 1332 and 719. MS (S) m / e 387, 389. Elemental Analysis for C23H19N2? 4: Calculated: C, 67.32; H, 4.63; N, 6.83 Found: C, 64.72; H, 4.44; N, 6.40 Example 8 Preparation of the sodium salt of the acid. { 9 - [(3-methylphenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic A. 9- [(3-Methylf-enyl) methyl] -5-carbora-ethoxy-1,2-dihydrocarbazole-4 (3H) -one A suspension of 5-carbomethoxy-1, 2- was stirred at room temperature for 16 hours. dihydro-9H-carbazole-4 (3H) -one (870 mg, 3.58 mM), a-bromo-ir.-xylene (662 mg, 3.58 mM) and potassium carbonate (500 mg, 3.61 mM) ) in 20 ml of DMF. The mixture was diluted with ethyl acetate, washed with H20 and saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give 1.18 g (95%) of the 9- [(3-methylphenyl) methyl. ] - 5-carbomethoxy-1,2-dihydrocarbazole -4 (3H) -one in the form of a dark oil. NMR of _I (DMSO-d6) d 7.65 (dd, 1H, J = 1 and 8 Hz), 7.3-7.1 (m, 3H), 7.05 (d, 1H, J = 8 Hz ), 7.0 (s, 1H), 6.85 (d, 1H, J = 8 Hz), 5.5 (s, 2H), 3.38 (s, 3H), 3.0 (m, 2H) ), 2.45 (m, 2H), 2.3 (s, 3H) and 2.1 (m, 2H). IR (CHC13, crn "1) 3010, 2953, 1724, 1652, 1605, 1465, 1442, 1288, 1174 and 1119. MS (ES) m / e 348.5.Analysis for C22H21N03: Calculated: C, 76, 08; H, 6.05; N, 4.03 Found: C, 74.53; H, 6.03; N, 3.68, B, 9- [(3-methylphenyl) methyl] -4-hydroxy- 5-carbomethoxy carbazole A solution of 9 - [(3-methylphenyl) methyl] -5-carbomethoxy-1,2-dihydrocarbazole-4 (3H) -one (1.18 g, 3%) was stirred at 80-90 ° C for 6 hours. 4 mM) and 2,3-dichloro-5,6-dicyan-1,4-benzoquinone (800 mg, 3.6 mM) in 70 ml of toluene. The mixture was purified directly by column chromatography on silica gel (elution with methylene chloride) to afford 300 mg (26%) of the 9- [(3-methylphenyl) methyl] -4-hydroxy-5-carbomethoxycarbazole in the form of a yellow solid. NMR of -I (DMSO-d6) d 10.2 (s, 1H), 7.65 (d, 1H, J = 8 Hz), 7.35 (t, 1H, J = 8 Hz), 7.25 (t, 1H, J = 8 Hz), 7.2-7.0 (m, 4H), 6.9 (m, 2H), 6.6 (d, 1H, J = 8 Hz), 5.6 (s, 2H), 3.85 (s, 3H) and 2.2 (s, 3H). IR (KBr, cm'1) 3200, 1673, 1596, 1440, 1426, 1394, 1265, 1216, 1152, 750, 711 and 694. MS (S) m / e 344, 346. Elemental Analysis for C22H19N03: Calculated: C, 76.52; H, 5.51; N, 4.06 Found: C, 76.22; H, 5.55; N, 3.97. C. 9- [(3-Methylphenyl) methyl] -4-hydroxy-5-carbamoyl carbazole A 9- [(3-methylphenyl) methyl] -4- solution was sonicated for 5 hours at 40-50 ° C. hydroxy-5-carbomethoxy carbazole (300 mg, 0.87 mM) in 10 ml of THF and 30 ml of concentrated aqueous ammonium hydroxide. The mixture was diluted with ethyl acetate and acidified to pH 1 with 5 N HCl. The aqueous layer was extracted three times with ethyl acetate. The combined organic extracts were washed with H20 and saturated brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (gradient elution of hexanes / ethyl acetate) - yielding 114 mg (40%) of 9 - [(3-methylphenyl) methyl] -4-hydroxy-5-carbamoyl carbazole in the form of a whitish solid. NMR of I (DMSO-d6) d 10.5 (s, 1H), 8.8 (sa, 1H), 8.4 (sa, 1H), 7.8 (dd, 1H, J = 1 and 8 Hz ), 7.4 (m, 2H), 7.3 (t, 1H, J = 8 Hz), 7.15-7.0 (m, 3H), 6.85 (d, 1H, J = 8 Hz ), 6, 6 (d, 1H, J = 8 Hz), 5.95 (d, 1H, J = 8 Hz), 5.65 (s, 2H) and 2.25 (s, 3H). IR (KBr, cm "1) 3434, 3203, 1629, 1599, 1579, 1552, 1443, 1330, 1262, 1214 and 776. MS (S) m / e 329, 331. Elemental Analysis for C21H18N202: Calculated: C, 76.36; H, 5.45; N, 8.48 Found: C, 77.56; H, 5.67; N, 8.26 D. Methyl acid ester {9- [(3 -methylphenyl) methyl] -5-carbamoylcarbazol-4-yl.} oxyacetic acid 40% methanolic Triton B (0.45 ml, 0.99 mM) was added to a solution of 9 - [(3-methylphenyl) methyl] 4-hydroxy-5-carbamoyl carbazole (100 mg, 0.30 mM) in 8 ml of DMF at room temperature After 3 minutes, methyl bromoacetate (115 mg, 0.72 mM) and the resulting mixture were added. it was stirred at room temperature for 24 hours.

The mixture was diluted with ethyl acetate, washed with H20 and saturated brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (elution with ethyl acetate) to give 80 mg (66%) of the methyl ester of the acid. { 9- [(3-methylphenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic in the form of a white solid. NMR of _I (DMSO-d6) d 7, 6 (d, 1H, J = 8 Hz), 7.55 (sa, 1H), 7.45-7.0 (m, 8H), 6.9 (d, 1H, J = 8 Hz), 6 , 6 (d, 1H, J = 8 Hz), 5.65 (s, 2H), 4.9 (s, 2H), 3.75 (s, 3H) and 2.2 (s, 3H). IR (KBr, cm'1) 3367, 3157, 1760, 1642, 1589, 1499, 1455, 1424, 1328, 1216, 1151, 1102, 772 and 714. MS (ES) m / e 402. Elemental Analysis for C24H22N204: Calculated: C, 71.64; H, 5.47; N, 6.96. Found: C, 71.01; H, 5.60; N, 6.66. E. Sodium salt of acid. { 9- [(3-methylphenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid A suspension of the methyl ester of the acid was stirred for 24 hours at 25 ° C. { 9 - [(3-methylphenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid (15.8 mg, 0.039 mM) and 0.04 ml (0.04 mM) of 1 N NaOH in 5 ml of ethanol. The resulting white precipitate was collected by filtration, washed with a small amount of EtOH and then dried in vacuo to give 10 mg (62%) of the sodium salt of the acid. {9 - [(3-methylphenyl) methyl] -5-carbamoylcarbazol-4-yl.} Oxyacetic acid in the form of a white powder NMR of I (DMSO-d6) d 7.55 (d, 1H, J = 8 Hz), 7.5-7.0 ( m, 9H), 6.85 (d, 1H, J = 8 Hz), 6.55 (d, 1H, J = 8 Hz), 5.6 (s, 2H), 4.35 (s, 2H) and 2.2 (s, 3H). IR (KBr, CITG1) 3390, 1656, 1613, 1595, 1573, 1498, 1455, 1408, 1325, 1332 and 719. MS (ES) m / e 387, 389. Analysis Elemental for C23H19N204Na: Calculated: C, 67.32; H, 4.63; N, 6.83 Found: C, 61.20; H, 4.64; N, 6.06 Example 9 Preparation of the salt acid sodium. {9 - [(3-trifluoromethoxyphenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid OCF, A. 9 - [(3-Trifluoromethoxyphenyl) methyl] -5-carbomethoxy-1,2-dihydrocarbazole-4 (3H) -one A suspension of 5-carbomethoxy-2, 2 was stirred at room temperature for 17 hours. dihydro-9H-carbazole-4 (3H) -one (935 mg, 3.85 mM), 3-trifluoromethoxybenzyl bromide (1.0 g, 3.93 mM) and potassium carbonate (531 mg, 3.85 mM) in 230 ml of DMF. The mixture was diluted with ethyl acetate, washed with H20 and saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give 1.6 g (100%) of the 9- [(3-trifluoromethoxyphenyl) methyl ] -5-carbomethoxy-l, 2-dihydrocarbazole-4 (3H) -one in the form of a foam. 1H NMR (DMSO-dg) d 7.7 (dd, 1H, J = 1 and 8 Hz), 7.45 (t, 1H, J = 8 Hz), 7.3-7.1 (m, 4H), 7.05 (d, 1H, J = 8 Hz), 5.6 (s, 2H), 3.8 (s, 3H), 3, 0 (m, 2H), 2.45 (m, 2H) and 2.1 (m, 2H). IR (CHC13, crn "1) 1729, 1647, 1439, 1259, 1176 and 1116. MS (ES) m / e 418. Elemental Analysis for C22H18N04F3: Calculated: C, 63.31; H, 4.32; N, 3.36 Found: C, 63.12, H, 4.35, N, 3.31, B, 9 - [(3-Tri f-loromethoxy f eni l) met il] -4-hydroxy-5-carbomethoxy carbazole A solution of 9- [(3-trifluoromethoxyphenyl) methyl] -5-carbomethoxy-1,2-dihydrocarbazole-4 (3H) -one (0.75 g, 1.8 mM) was stirred at reflux for 6 hours. ) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (490 mg, 2.16 mM) in 70 ml of toluene The mixture was purified directly by column chromatography on silica gel (elution with methylene chloride) yielding 300 mg (40%) of 9 - [(3-trifluoromethoxyphenyl) methyl] -4-hydroxy-5-carbomethoxy carbazole as a yellow solid NMR of -I (DMSO-d6) d 10, 25 (s, 1H), 7.7 (d, 1H, J = 8 Hz), 7.5-7.0 (m, 8H), 6.6 (d, 1H, J = 8 Hz), 5, 7 (s, 2H) and 3.85 (s, 3H). IR (KBr, cm'1) 3200, 1673, 1441, 1268, 1217, 1173 and 753. MS (ES) m / e 414, 4 16. Elemental Analysis for C22H16N03F3: Calculated: C, 63.61; H, 3.86; N, 3.37. Found: C, 63, 40; H, 3, 99; N, 3, 43 C. 9- [(3-Trifluoromethoxyphenyl) methyl] -4-hydroxy-5-carbamoyl carbazole A solution of 9 - [(3-trifluoromethoxyphenyl) methyl] -4-hydroxy-5-carbomethoxy carbazole (260 mg) was vigorously stirred for 132 hours. , 0.62 mM) in 10 ml of THF and 30 ml of concentrated aqueous ammonium hydroxide. The mixture was diluted with ethyl acetate and acidified to pH 1 with 5 N HCl. The aqueous layer was extracted three times with ethyl acetate. The combined organic extracts were washed with H20 and saturated brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (elution with a gradient of hexanes / ethyl acetate) to give 150 mg (60%) of the 9- [(3-trifluoromethoxyphenyl) methyl] -4-hydroxy -5- carbamoi 1 carbazole in the form of a whitish solid. NMR of -I (DMSO- d5) d 10.5 (s, 1H), 8.8 (sa, 1H), 8.4 (sa, 1H), 7.85 (dd, 1H, J = 1 and 8 Hz), 7.5-7.15 (m, 5H), 7.1 (d, 1H, J = 8 Hz), 7.0 (d, 1H, J = 8 Hz), 6.6 (d, 1H, J = 8 Hz), 5.95 (d, 1H, J = 8 Hz) and 5.65 (s, 2H). IR (KBr, crn "1) 3431, 3203, 1629, 1601, 1580, 1548, 1446, 1330, 1261, 1215 and 777. MS (S) m / e 399, 401. Elemental Analysis for C21H15N202F3: Calculated: C, 63.00; H, 3.75; N, 7.0 Found: C, 63.15; H, 4.07; N, 6.84 D. Methyl acid ester {9 - [(3 trifluoromethoxyphenyl) met il] -5-carbamoylcarbazol-4-yl.} oxyacetic acid. 40% Methanolic Triton B (0.15 ml, 0.34 mM) was added to a solution of 9 - [(3-trifluoromethoxyphenyl) methyl] -4-hydroxy-5-carbamoyl carbazole (115 mg, 0.28 mM) in 8 ml of DMF at room temperature After 3 minutes, methyl bromoacetate (65 mg, 0.41 mM) was added and the The resulting mixture was stirred at room temperature for 23 hours.The mixture was diluted with ethyl acetate, washed with H20 and saturated brine, dried over magnesium sulfate, filtered and concentrated.The residue was purified by column chromatography on silica gel (elution with ethyl acetate) yielding 112 mg (83%) of the ester acid methyl. 9- [(3-trifluoromethoxyphenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic in the form of a white solid. NMR of -I (DMSO-ds) d 7.6 (d, 1H, J = 8 Hz), 7.55 (sa, 1H), 7.5-7.0 (m, 9H), 6.6 ( d, 1H, J = 8 Hz), 5.7 (s, 2H), 4.9 (s, 2H) and 3.75 (s, 3H). IR (KBr, crn "1) 3488, 3141, 1763, 1674, 1501, 1444, 1269, 1215, 1178, 1102, 772 and 714. MS (ES) m / e 472. Elemental Analysis for C24H19? 205F3: Calculated: C, 61.02; H, 4.03; ?, 5.93. Found: C, 61.05; H, 4.17; ?, 5.81. E. Sodium salt of acid. { 9- [(3-trifluoromethoxyphenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid A suspension of the methyl ester of the acid was stirred for 24 hours at 25 ° C. { 9- [(3-trifluoromethoxyphenyl) -methyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid (22.4 mg, 0.047 mM) and 0.065 ml (0.065 mM) of 1 N NaOH in 5 ml of ethanol. The solvent was removed in vacuo and the residue was suspended in EtOH. The resulting white precipitate was collected by filtration, washed with a small amount of EtOH and then dried in vacuo to give 9 mg (41%) of the sodium salt of the acid. { 9- [(3-trifluoromethoxyphenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic in the form of a white powder. MS (ES) m / e 457, 459. EXAMPLE 10 Preparation of [9-benzyl-5-carbamoyl-1-methylcarbazol-4-yl] oxyacetic acid A. Preparation of 5-carbamoyl-4-methoxy-1-methylcarbazole treated with 1.1 g of 5% palladium on carbon and a solution of 0.805 g of 9-benzyl-5-methoxy-8-methyl-1, 2, 3, 4- was heated at reflux for 6 hours to the air. tetrahydrocarbazole-4-carboxamide in 24 ml of carbitol. After cooling, the solution was filtered through a pad of celite and the layer was washed with ethyl acetate. The filtrates were diluted with ether, washed four times with water and dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel using 0-4% methanol in dichloromethane to yield 0.166 g (28%) of the debenzylated carbazole. ESIMS m / e 255 (M ++ l), 253 (M + -l). NMR (300 MHz, CDC13): d 8.13 (a, 1H), 7.51 (d, J = 8.1, 1H), 7.40 (t, J = 7.6, 1H), 7, 32 (d, J = 7.2, 1H), 7.18 (d, J = 7.8, 1H), 6.60 (d, J = 8, 1H), 5.68 (a, 2H), 3.99 (s, 3H), 2.50 (s, 3H). B. Preparation of 9-benzyl-5-carbamoyl-4-methoxy-1-methylcarbazole A solution of 0.148 g of 5-carbamoyl-4-methoxy-1-methylcarbazole in 1.1 ml of dimethylformamide was added to 0.026 g of hydride Sodium (60% in mineral oil) in 0.4 ml of dimethylformamide and stirred for 60 minutes at room temperature. Then benzyl bromide (0.076 ml) was added and the reaction was stirred overnight. The reaction mixture was poured into 20 ml of a saturated solution of ammonium chloride and then extracted twice with ethyl acetate. The extracts were washed with water and then with brine, dried over magnesium sulfate and concentrated. The residue was rinsed with hexane and dissolved in dichloromethane, filtered and concentrated to give 0.21 g of the subtitle compound. FDMS m / e 344 (M +) Calculated Elemental Analysis: C, 76.72; H, 5.85; N, 8.13. Found: C, 75.20; H, 6.19; N, 7.54. C. Preparation of [9-benzyl-5-carbamoyl-1-methylcarbazol-4-yl] oxyacetic acid methyl ester A solution of 0.23 g of 9-benzyl-5-carbamoyl-4-methoxy-1- was added. methylcarbazole in ml of dimethylformamide in 1 ml of sodium thiolate ethane solution (prepared from 0.116 of 60% sodium hydride dispersion and 0.22 ml of ethanethiol under nitrogen) and heated at 110 ° C for 15 hours. The reaction mixture was cooled, poured into 20 ml of 1 N HCl and extracted twice with ethyl acetate. The extracts were washed twice with water and then with brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel using 0-1% methanol in dichloromethane to give 0.146 g (66%) of the demethylated intermediate. A solution of 0.146 g of this intermediate in 1.5 ml of dimethylformamide was added to 0.021 g of sodium hydride (60% in mineral oil) in 0.5 ml of dimethylformamide. After stirring for 10 minutes at room temperature, 0.054 ml of methyl bromoacetate was added. After stirring for 5 hours at room temperature, the reaction mixture was poured into water and extracted twice with ethyl acetate. The extracts were washed with water and then with brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel using 0-2% methanol in dichloromethane to afford 0.10 g (56%) of the subtitle compound, m.p. 228-230 ° C. ESIMS m / e 403 (M ++ l).

Calculated Elemental Analysis: C, 71.63; H, 5.51; N, 6.96. Found; C, 71.34; H, 5.60; N, 6.70 D. Preparation of [9-benzyl-5-carbamoyl-1-methylcarbazol-4-yl] oxyacetic acid. A suspension of 32 mg was treated with 0.3 ml of a 2N aqueous solution of sodium hydroxide. , 0.795 mmol) of [9-benzyl-5-carbamoyl-1-methylcarbazol-4-yl] oxyacetic acid methyl ester in 1 ml of tetrahydrofuran and 3.5 ml of methanol and stirred overnight at room temperature. The solvent was evaporated and the residue was partitioned between ethyl acetate / tetrahydrofuran 1: 1 and 0.2 N HCl solution. After another extraction with 1: 1 ethyl acetate / tetrahydrofuran, the extracts were washed with brine, dried over magnesium sulfate and concentrated to give (27 mg) of the title compound. p.f. 253-254 ° C. ESIMS m / e 389 (M ++ 1), 387 (M + -l); . NMR (300 MHz, d6-DMSO): d 12.83 (a, 1H), 7.75 (a, 1H), 7.53 (d, J = 8.2, 1H), 7.41-7, 34 (m, 2H), 7.28-7.17 (m, 3H), 7.07 (m, 2H), 6.90 (d, J = 7.2, 2H), 6.49 (d, J = 8.1 1H), 5.89 (s, 2H), 4.79 (s, 2H), 2.52 (s, 3H). Example 11 Preparation of [9-benzyl-4-carbamoyl-8-fluoro-1,2,3,4-tetrahydrocarbazol-5-yl] oxyacetic acid A. Preparation of (2-chloro-4-fluorophenyl) -ethyl carbonate A solution of 19.16 g of 2-chloro-4-fluorophenol in 65.4 ml of 2N aqueous sodium hydroxide solution was cooled in an ice bath and treated dropwise with 16.3 ml of ethyl chloroformate. . After stirring at room temperature overnight, the two-phase reaction mixture was diluted with 100 ml of water and extracted with 300 ml of a 1: 1 mixture of pentane / ether. The extract was washed three times with 0.02 N sodium hydroxide solution, with water and then with brine. After drying and evaporation, 27.63 g (97%) of the subtitle compound was obtained. NMR (300 MHz, CDC13): d 7.23-7.18 (m, 2H), 7.00 (dt, J = 8.4, 2.7, 1H), 4.35 (q, J = 7, 1, 2H), 1.40 (t, J = 7.1, 3H). B. Preparation of (2-chloro-4-fluoro-5-nitrophenyl) -ethyl carbonate A solution of 27.63 g of (2-chloro-4-fluorophenyl) -ethyl carbonate in 60 ml of dichloromethane was cooled in an ice bath and treated dropwise with 31.86 g of a 1: 2 mixture of fuming nitric acid (90%) and concentrated sulfuric acid. The reaction was stirred for 2 hours at room temperature and then cooled with ice and treated with another 4.5 g of the same nitration mixture. The reaction was stirred overnight at room temperature, poured into 200 ml of ice and water and extracted twice with dichloromethane. The extracts were washed with water and then with brine, dried over magnesium sulfate and concentrated to give 33.01 (99%) of the subtitle compound, m.p. 50-5l ° C. Calculated Elemental Analysis: C, 41.01; H, 2.68; N, 5.31; Cl 13.45 Found: C, 41.03; H, 2.59; N, 5.38; Cl, 13.71 C. Preparation of 2-chloro-4-fluoro-5-nitroanisole A solution of 15.0 g of (2-chloro-4-fluoro-5-nitrophenyl) -ethyl carbonate in 100 ml was treated. of dimethylformamide with 18.6 g of cesium carbonate, 7.1 ml of iodomethane and 7 ml of methanol and stirred overnight at room temperature. The reaction mixture was poured into water and extracted twice with ether. The extracts were washed twice with water and then with brine, dried over magnesium sulfate and concentrated to give 11.4 g of the subtitle compound, e.g. f. 69-70 ° C. Ex. 57, C. Calculated Elementary Analysis: C, 40.90; H, 2.45; N, 6.81; Cl, 17,25. Found: C, 41.20; H, 2.48; N, 6.70; Cl, 17,44.

D. Preparation of 2-fluoro-5-methoxyaniline A solution of 5.63 g of 2-chloro-4-fluoro-5-nitroanisole in 90 ml of ethanol and 5 ml of triethylamine at room temperature under 414 kPa was subjected to hydrogenation. with 1.0 g of 5% palladium on carbon for four hours. The catalyst was removed by filtration and the solvent was evaporated. The residue was suspended in chloroform and filtered through a plug of silica gel and then evaporated. This residue was chromatographed on silica gel using hexane / chloroform mixtures to provide 2.77 g (72%) of the subtitle compound, m.p. 253-254 ° C. NMR (300"MHz, CDCl 3): d 6.88 (dd, J = 10.6, 8.9, 1H), 6.32 (dd, J = 7.4, 3.0, 1H), 6, 20 (dt, J = 8.9, 3.2, 1H), 3.73 (s, 3H), 3.72 (a, 2H) E. Preparation of N-benzyl-2-fluoro-5-methoxyaniline This procedure was designed after that of Tietze and Grote, Chem Ber, 126 (12), 2733 (1993), a solution of 2.73 g of 2-fluoro-5-methoxyaniline and 2.67 g of benzaldehyde in 48 ml of Methanol was treated with 3.43 g of zinc chloride and then cooled in an ice bath.Sodium cyanoborohydride (1.58 g) was added in small portions at room temperature for 30 minutes and the reaction was stirred for five hours at room temperature. After evaporation of the solvent, the residue was suspended in 40 ml of a 1 N sodium hydroxide solution and then extracted twice with ether.The extracts were washed with water and then with brine, dried over sodium sulfate, magnesium and concentrated, the residue was recrystallized from hexane to give 2.61 g The mother liquor was chromatographed on silica gel using 20: 1 hexane / ether to give another 1.4 g of the subtitle compound (90%). 56-58 ° C. Calculated Elementary Analysis: C, 72.71; H, 6.10; N, 6.06 Found: C, 72.51; H, 6.06; N, 5.99. Preparation of ethyl 9-benzyl-5-methoxy-8-fluoro-1,2,3,4-tetrahydrocarbazole-4-carboxylate A solution of 0.62 g of N-benzyl-2-fluoro-5-methoxyaniline was cooled. in 20 ml of dry tetrahydrofuran in an ice bath and treated with 11.3 ml of 0.5 M potassium bis (trimethylsilyl) amide in toluene. After stirring for 30 minutes, 0.74 g of 2-carboethoxy-6-bromocyclohexanone (Sheeman and Muma, JACS, 72, 2127 (1950)) was added in 4 ml of tetrahydrofuran and the reaction allowed to slowly warm to room temperature. environment for 2 hours. The reaction was quenched with saturated ammonium chloride solution and extracted twice with ether. The extracts were washed with water and then with brine, dried over magnesium sulfate and concentrated. This residue was chromatographed on silica gel using hexane / ether mixtures to provide 0.796 g (74%) of N-alkylated intermediate diastereomers. This mixture was heated to reflux in 20 ml of benzene with 0.99 g of zinc chloride overnight. The solvent was evaporated and the residue was partitioned between 25 ml of 1 N HCl and 25 ml of ethyl acetate and then extracted once more with ethyl acetate. The organic layers were washed with water and then with brine, dried over magnesium sulfate and concentrated to give 0.734 g (96%) of the subtitle compound. ESIMS m / e 382 (M ++ l). Calculated Elementary Analysis: C, 72.42; H, 6.34; N, 3.67. Found: C, 72.20; H, 6.26; N, 3.70. G. Preparation of 9-benzyl-5-methoxy-8-fluoro-1,2,3,4-tetrahydrocarbazole-4-carboxamide. 9-Benzyl-5-methoxy-8-fluoro-l, 2, 3, 4 was treated. Ethyl tetrahydrocarbazole-4-carboxylate (0.722 g) in a similar manner to that described in Example 49, Part C and chromatographed on silica gel using 1% methanol in dichloromethane to give 0.482 g (72%) of the subtitle compound . ESIMS m / e 353 (M ++ l). Calculated Elemental Analysis: C, 71.57; H, 6.01; N, 7.95. Found: C, 71.42; H, 5.83; N, 7.75 H. Preparation of [9-benzyl-4-carbamoyl-8-fluoro-l, 2,3,4-tetrahydrocarbazol-5-yl] oxyacetic acid methyl ester 9-Benzyl-5-methoxy-8-fluoro-1,2,3,4-tetrahydrocarbazole-4-carboxamide (0.170 g) was converted, similarly to that described in Example 49, Part D, and was cytomatographed using 0-1% methanol in dichloromethane giving 85 mg (50%) of the subtitle compound, mp 183-185 ° C. Calculated Elemental Analysis: C, 67.31; H, 5.65; N, 6.82. Found: C, 67.58; H, 5.48; N, 6.95. I. Preparation of [9-benzyl-4-carbamoyl-8-fluoro-1,2,4,4-tetrahydrocarbazol-5-yl] oxyacetic acid [9-benzyl-4-carbamoyl-8-] methyl ester fluoro-l, 2,3,4-tetrahydrocarbazol-5-yl] oxyacetic acid (71 mg) in a manner similar to that described in Example 50, Part D, giving 65 mg of the title compound. ESIMS m / e 397 (M ++ l), 395 (M + -l). NMR (300 MHz, DMSO-d6): d 13.03 (a, 1H), 7.31-7.19 (m, 3H) 6.97 (d, J = 7.4, 2H), 6.95 (a, 1H), -6.70 (d, J = 3.8, 1H), 6.67 (dd, J = 12.4, 3.9, 1H), 6.28 (dd, J = 8.5, 2.6, 1H), 5.39 (ABq, 2H), 4.64 (s, 2H), 3.92 (a, 1H), 2.71 ( m, 1H), 2.44 (m, 1H), 2.02 (m, 2H), 1.76. (m, 2H).

Example 12 Preparation of [9-benzyl-5-carbamoyl-1-chlorocarbazol-4-yl] oxyacetic acid A. Preparation of 9-benzyl-5-carbamoyl-4-methoxy-1-chlorocarbazole A solution of 1.0 was oxidized g of 9-benzyl-5-methoxy-8-methyl-1,2,3,4-tetrahydrocarbazole-4-carboxamide in a manner similar to that of Example 51, Part A and chromatographed on silica gel using dichloromethane / methanol 0-1% providing 0.66 g (67%) of the subtitle compound. FDMS m / e 364 (M +). Calculated Elementary Analysis: C, 69.14; H, 4.70; N, 7.68; Cl, 9.72 Found: C, 69.40; H, 4.64; N, 7.49; Cl, 9.98. B. Preparation of 5-carbamoyl-4-hydroxy-1-chlorocarbazole A solution of 0.66 of 9-benzyl-5-carbamoyl-4-methoxy-1-chlorocarbazole in 40 ml of dichloromethane was cooled in an ice bath and it was treated dropwise with 14 ml of 1.0 M boron tribromide solution in dichloromethane. The reaction was allowed to slowly warm to room temperature for 2 hours and then was quenched by pouring on ice and then adding 50 ml of 1 N HCl. The mixture was extracted with dichloromethane (3 x 200 ml) and the extracts were washed with brine, dried with magnesium sulfate and concentrated. The aqueous layers showed a precipitate and then extracted twice with ethyl acetate, washed with brine, dried over magnesium sulfate and concentrated to give 0.287 of the subtitle compound. The first residue was chromatographed on silica gel using 0.5% methanol in dichloromethane to give another 93 mg of the subtitle compound, (total yield 80%). ESIMS m / e 259 (M + -l). NMR (300 MHz, DMSO-d6): d 11.79 (s, 1H), 10.76 (s, 1H), 8.87 (sa, 1H), 8.41 (sa, 1H), 7.77. (t, J = 4.6, 1H), 7.48 (d, J = 4.2 2H), 7.34 (d, J = 8.5, 1H), 6.54 (d, J = 8) , 5, 1H). C. Preparation of [5-carbamoyl-l-chlorocarbazol-4-yl] oxyacetic acid methyl ester A solution of 0.28 g of 5-carbamoyl-4-hydroxy-1-chlorocarbazole in 6 ml of tetrahydrofuran was added to 0.043 g of sodium hydride (60% in mineral oil) in 1 ml of tetrahydrofuran and stirred for 60 minutes at room temperature. Then methyl bromoacetate (0.11 ml) was added and the reaction was stirred overnight. The reaction mixture was poured into 20 ml of saturated ammonium chloride solution and then extracted twice with ethyl acetate. The extracts were washed with water and then with brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel, eluting with chloroform and then with chloroform / ethyl acetate 2: 1, yielding 0.16 g (45%) of the subtitle compound.

ESIMS m / e 333 (M ++ l), 335 (M ++ 3), 331 (M + -l). NMR (300 MHz, d6-DMSO): d 11.73 (s, 1H), 7.56 (d, J = 8.1, 1H), 7.50 (sa, 1H), 7.43-7, 35 (m, 2H), 7.18 (sa, 1H), 7.06 (d, J = 7.8, 1H), 6.56 (d, J = 8.6, 1H), 4.90 ( s, 2H), 3.70 (s, 3H).

D. Preparation of [9-benzyl-5-carbamoyl-1-chlorocarbazol-4-yl] oxyacetic acid methyl ester A solution of 78 mg of [5-carbamoyl-1-chlorocarbazole-4-yl] methyl ester was added. ] oxyacetic acid in 0.8 ml of dry dimethylformamide to 10 mg of sodium hydride (60% in mineral oil) in 0.2 ml of dimethylformamide and stirred for 15 minutes. Then benzyl bromide was added (0.031 ml) and the reaction was stirred overnight. The reaction mixture was poured into water, acidified with 1 ml of 1 N HCl solution and extracted twice with ethyl acetate. The extracts were washed with water (3 x) and then with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was chromatographed on silica gel eluting with methanol / 0-2% in dichloromethane to give 40 mg of the subtitled compound. ESIMS m / e 423 (M ++ l), 425 (M ++ 3). NMR (300 MHz, CDC13): d 7.43-7.22 (m, 7H) ", 7.06 (s, J = 7.3, 2H), 6.51 (d, J = 8.6, 1H), 6.05 (s, 2H), 5.80 (a, 2H), 4.88 (s, 2H), 3.83 (s, 3H) E. Preparation of the acid [9-benzyl-5 -carbamoyl-1-chlorocarbazol-4-yl] oxyacetic acid The [9-benzyl-5-carbamoyl-1-chlorocarbazol-4-yl] oxyacetic acid methyl ester (15 mg) was hydrolysed in a similar manner to that described in Example 50, Part D giving 14 mg of the title compound, mp 240-2 ° C ESIMS m / e 409 (M ++ l), 407 (M ++ 3). NMR (300 MHz, d6-DMS0): d? 2.94 (a, 1H), 7.70 (a, 1H), 7.61 (d, J = 8.3, 1H), 7.43 (t, J = 7.8, 1H), 7.36 (m, 2H), 7.28-7.19 (m, 3H), 7.13 (d, J = 7.2, 1H), 6.99 (d, J = 7.4, 2H ), 6.63 (d, J = 8.6, 1H), 6.08 (s, 2H), 4.83 (s, 2H) Example 13 Preparation of the acid [9- [(cyclohexyl) methyl] - 5- carbamoylcarbazol-4-yl] oxyacetic acid A. 9- [(Cichlorhexyl) methyl] -5-carbomethoxy-1,2-dihydrocarbazole-4 (3H) -one. A suspension at 0 ° C was treated with cyclohexylmethyl bromide (0.631 ml, 4.52 mmol). of 5-carbomethoxy-1, 2-dihydro-9H-carbazole-4 (3H) -one (1.0 g, 4.11 mmol), a catalytic amount of Nal (approximately 10 mg) and K2C03 (1.1 g, 8.22 mmol) in 10 ml of DMF. After stirring overnight at room temperature, an additional 0.63 ml of cyclohexylmethyl bromide was added and the resulting mixture was heated at 60 ° C for 3 hours. The mixture was poured into H20 (30 mL) and extracted with EtOAc (2 x 25 mL). The combined organic layers were washed with H20 (4 x 50 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by radial chromatography on silica gel (elution with a gradient of 20 to 40% EtOAc / hexanes) to yield 1.36 g (4.01 mmol, 97%) of 9- [(cyclohexyl) methyl] - 5-carbomethoxy-1,2-dihydrocarbazole-4 (3H) -one in the form of a white foam. IR (CHC13, cm "1) 3011, 2932, 2857, 1725, 1649, 1469, 1146, 1288 and 1120. MS (ES) m / e 340 (M ++ 1), 453 (M + AcO"). FAB HRMS m / e, Calculated for C21H26N03: 340.1913. Found; 340.1916 (M + l). Elemental Analysis for C21H25N03: Calculated: C, 74.31; H, 7.42; N, 4.13 Found: C, 72.65; H, 7.39; N, 4.70 B. 9- [(Cicyclohexyl) methyl] -4-hydroxy-5-carbomethoxycarbazole A solution of 9 - [(cyclohexyl) methyl] -5-carbomethoxy-1,2-dihydrocarbazole-4 (3H) -one (1.16 g, 3.42 mmol) was heated at 80 ° C for 3 hours. , 3-dichloro-5,6-dicyano-1,4-benzoquinone (853 mg, 3.76 mmol) in 20 ml of toluene. The mixture was purified directly by column chromatography on silica gel (elution with CH2C12) yielding 259 mg (0.768 mmol, 22%) of 9- [(cyclohexyl) methyl] -4-hydroxy-5-carbomethoxy carbazole in the form of a yellow oil that solidified slowly. MS (ES) m / e 338 (M + 1), 336 (M-1). Elemental Analysis for C21H23N03: Calculated: C, 74.75; H, 6.87; N, 4.15. Found: C, 74.95; H, 6.99; N, 4.42. C. 9- [(Cichlorhexyl) methyl] -4-hydroxy-5-carbamoyl carbazole It was treated with a stream of gaseous NH3 to ensure saturation a solution of 9- [(cyclohexyl) methyl] -4-hydroxy-5-carbomethoxy carbazole (205 mg, 0.608 mmol) in 5 ml of THF and 20 ml of concentrated aqueous ammonium hydroxide. The reaction vessel was capped and the mixture was heated to 35 ° C with stirring until the tic indicated complete consumption of the starting material (20 hours). The THF was evaporated and the aqueous layer was filtered. The precipitated green solid was dissolved in THF and purified by radial chromatography on silica gel (elution with CH2C12). The resulting foam was triturated with ether to give 138 mg (70%) of the title compound as an off-white solid. IR (KBr, cm "1) 3418, 3200, 3131, 1629, 1600, 1443, 1261, 778. 'FAB HRMS m / e, Calculated for C20H23N2O2: 323.1760. Found: 323.1760 (M + l). D. [9- [(Ccyohexyl) methyl] -5-carbamoylcarbazol-4-yl] oxyacetic acid methyl ester Methyl bromoacetate (0.023 ml); 0.242 mmoles) a mixture of 9- [(cyclohexyl) methyl] -4-hydroxy-5-carbamoyl carbazole (60 mg, 0.186 mmol) and Cs2CO3 (150 mg, 0.460 mmol) in 2 ml of DMF. The reaction was stirred for 2 hours at room temperature and then diluted with EtOAc and H20 (10 ml of each). The aqueous layer was saturated with solid NaCl and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with H20 (2 x 25 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Purification of the crude residue by flash chromatography on silica gel (elution with a gradient of 0% to 90% EtOAc / hexanes), followed by trituration with Et20 / EtOAc afforded 45 mg (0.114 mmol, 61%) of the compound of the title in the form of a whitish solid. MS (ES) m / e 395 (M + 1), 378 (M + H-NH 3), 453 (M + AcO "). Elemental Analysis for C23H26N204 • 0.3 H20 Calculated: C, 69, 08; H, 6, 71; N, 7, 01. Found: C, 69.13; H, 6.71; N, 7.09 E. Acid [9- [(cyclohexyl) methyl] -5-carbamoylcarbazol-4-yl] oxyacetic acid A suspension of [9- [(cyclohexyl) methyl] -5-carbamoylcarbazol-4-yl] -oxyacetic acid methyl ester (20 mg) was treated with 0.1 ml of 1 N aq. LiOH (0.1 mmol). 0.051 mmol) in 0.3 ml of THF and 0.1 ml of MeOH and the mixture was stirred at room temperature for 2 hours.The reaction was acidified with 0.2 N HCl and the organics were removed in vacuo. it was filtered off from the aqueous layer and rinsed with Et20 to give 16 mg (0.042 mmol, 83%) of the title acid as a white powder, MS (ES) m / e 381 (M + 1), 364 ( M + H-NH3), 379 (Ml) Elemental Analysis for C 22 H 24 N 2 O 4: Calculated: C, 69.46; H, 6.36; N, 7.36. " Found: C, 69.34; H, 6.35; N, 7.29, Example 14 Preparation of [9- [(cyclopentyl) methyl] -5- carbamoylcarbazol-4-yl] oxyacetic acid A. 9- [(Cyclopentyl) methyl] -5-carbomethoxy-1,2-dihydrocarbazole-4 (3H) -one Was treated with cyclopentylmethyl chloride (JOC, 1964, 29, 421-423, 400 mg, 3.37 mmoles) a suspension of 5-carbomethoxy-l, 2-dihydro-9H-carbazole-4 (3H) -one (820 g, 3.37 mmol), a catalytic amount of Nal (approximately 10 mg) and K2C03 (930 mg, 6.74 mmol) in 6 ml of DMF. After stirring overnight at room temperature, an additional 800 mg of cyclopentylmethyl chloride and 1 g of Nal were added, and the resulting mixture was heated at 80 ° C overnight. An additional 800 mg of cyclopentylmethyl chloride and 2.2 g of Cs 2 CO 3 were added and the reaction mixture was heated at 80 ° C for 24 hours. An additional 1.6 g of cyclopentylmethyl chloride was added and the reaction mixture was heated at 80 ° C for 3 days. The mixture was poured into H20 (30 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over anhydrous Na 2 SO 4, filtered and concentrated in vacuo. The residue was purified by radial chromatography on silica gel (elution with a gradient of 10% to 40% EtOAc / hexanes) affording 775 mg (2.38 mmol, 71%) of 9 - [(cyclopentyl) methyl] -5-carbomethoxy-1,2-dihydrocarbazole-4 ( 3H) -one in the form of a brown foam. MS (ES) m / e 326 (M + l), 384 (M + AcO-). Elemental Analysis for C20H23NO3: Calculated: C, 73.82; H, 7.12; N, 4.30. Found: C, 74.12; H, 7.21; N, 4.45 B. 9- [(Cyclopentyl) methyl] -4-hydroxy-5-carbomethoxy carbazole A solution of 9 - [(cyclopentyl) methyl] -5-carbomethoxy-l was heated at 80 ° C for 3 hours. , 2-dihydrocarbazole-4 (3H) -one (730 mg, 2.24 mmol) and 2,3-dichloro-5,6-dicyan-1,4-benzoquinone (560 mg, 2.47 mmol) in 20 ml of toluene. The mixture was purified directly by column chromatography on silica gel (elution with CH2C12) to provide 140 mg (0.433 mmol, 19%) of 9- [(cyclopentyl) methyl] -4-hydroxy-5-carbomethoxy carbazole in the form of a yellow oil that solidified slowly. MS (ES) m / e 324 (M + 1), 322 (M-1). Elemental Analysis for C20H21NO3 - 0, 3H20: Calculated: C, 73.06; H, 6.62; N, 4.26 Found: C, 73.19; H, 6.44; N, 4.40. C. 9- [(Cyclopentyl) methyl] -4-hydroxy-5-carbamoyl carbazole A solution of 9 - [(cyclopentyl) methyl] -4-hydroxy-5-carbomethoxy carbazole (110 mg, 0.34 mmol) in 3 ml of THF and 20 ml of concentrated aqueous ammonium hydroxide were treated with a stream of gaseous NH3 to ensure saturation. The reaction vessel was capped and the mixture was heated to 35 ° C with stirring until the tic indicated complete consumption of the starting material (20 h). The THF was evaporated and the aqueous layer was filtered. The resulting solid was triturated with ether to give 50 mg (0.162, 48%) of the title compound as a white-green solid. IR (KBr, cm "1) 3416, 3199, 3126, 1630, 1599, 1442, 1262, 778. FAB HRMS (High resolution mass spectrum, Fast atom bombardment) m / e, calculated for C20H21N2O2: 309.1603 Found: 309.1607 (M + I: D. [9- [(Cyclopentyl) methyl] -5-carbamoylcarbazol-4-yl] oxyacetic acid methyl ester A mixture of 9- [(cyclopentyl) methyl] -4-hydroxy-5- carbamoyl carbazole (45 mg, 0.146 mmol) and Cs2CO3 '(120 mg; 0.365 mmoles) in 2 ml of DMF with methyl bromoacetate (0.018 ml, 0.19 mmol). The reaction was stirred for 2 hours at room temperature and then diluted with EtOAc and H20 (10 ml of each). The aqueous layer was saturated with solid NaCl and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with H20 (2 x 25 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Purification of the crude residue by flash chromatography on silica gel (elution with a gradient of 0% to 100% EtOAc / hexanes) followed by trituration with Et20 / EtOAc afforded 26 mg (0.0683 mmol, 47%) of the title in the form of a solid chestnut. MS (ES) m / e 381 (M + l), 364 (M + H-NH3), 439 (M + AcO ") Elemental Analysis for C23H26N204 • 0.1 H20: Calculated: C, 69.13; H, 6.38; N, 7.33. Found: C, 68.99; H, 6.39; N, 7.41. E. [9- [(Cyclopentyl) methyl] -5-carbamoylcarbazol-4-yl] oxyacetic acid A suspension of [9- [(cyclopentyl) methyl] -5-carbamoylcarbazol-4-yl] oxyacetic acid methyl ester was treated. (20 mg, 0.065 mmol) in 0.3 ml of THF and 0.1 ml of MeOH with 0.1 ml of aq. LiOH (0.1 mmol) and the mixture was stirred at room temperature for 2 hours. The reaction was acidified with 0.2 N HCl and the organics were removed in vacuo. The white precipitate was filtered off from the aqueous layer and rinsed with Et20 to give 15 mg (0.0409 mmole, 63%) of the title acid as a white powder. MS (ES) m / e 367 (M + 1), 350 (M + H-NH 3), 365 (M-1). Elemental Analysis for C21H22N204 • 0.3 H20: Calculated: C, 67.84; H, 6.13; N, 7.53. Found: C, 67.73; H, 5.97; N, 7.70. It is believed that the compounds described herein achieve their beneficial therapeutic action primarily by direct inhibition of human sPLA2, and not by acting as antagonists of arachidonic acid or other active agents below the arachidonic acid in the arachidonic acid cascade , such as 5-lipoxygenases, cyclooxygenases, etc. The method of the invention for inhibiting the release of fatty acids induced by sPLAβ comprises contacting the sPLA2 with a therapeutically effective amount of the compound of Formula (I) selected from the group consisting of [9-benzyl-5-carbamoyl- L-fluorocarbazol-4-yl] oxyacetic acid, acid. { 9- [(phenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic, acid. { 9- [(3-fluorophenyl) methyl] -5- • carbamoylcarbazol-4-yl} oxyacetic, acid. { 9 - [(3-chlorophenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic, sodium salt of acid. { 9- [(3-trifluoromethylphenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic, sodium salt of acid. { 9- [(2-methylphenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic, sodium salt of acid. { 9- [(3-methylphenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic, sodium salt of acid. { 9- [(3-trifluoromethoxy-phenyl) -methyl] -5-carbamoylcarbazole-4-yl} oxyacetic acid, [9-benzyl-5-carbamoyl-1-chlorocarbazol-4-yl] oxyacetic acid, [9 - [(cyclohexyl) met yl] -5-carbamoylcarbazol-4-yl] oxyacetic acid, [9- [( cyclopentyl) -methyl] -5-carbamoylcarbazol-4-yl] oxyacetic acid or its pharmaceutically acceptable salts. The compounds of the invention can be used in a method of treating a mammal (e.g., a human) to alleviate the pathological effects of septic shock, respiratory distress syndrome in "the adult, pancreatitis, trauma, bronchial asthma, allergic rhinitis. and rheumatoid arthritis, the method comprising administering to the mammal a compound of formula (I) in a therapeutically effective amount.A "therapeutically effective" amount is an amount sufficient to inhibit the release of fatty acids induced by sPLA2 and, thereby, inhibit or preventing the cascade of arachidonic acid and its harmful products The therapeutic amount of the compound of the invention necessary to inhibit sPLA2 can be easily determined by taking a samof body fluid and testing it with respect to the content of sPLA2 by conventional procedures. all this document, the person or animal to be treated was described It will be known as a "mammal" and it will be understood that the most preferred subject is a human being. However, it should be noted that the study of adverse conditions of the central nervous system in non-human animals is only beginning and some cases of such treatments are beginning to be used. Accordingly, the use of the present compounds in non-human animals is contemplated. It will be understood that the dosage ranges for other animals will necessarily be quite different from the doses administered to humans and, consequently, that the dosage ranges described will be recalculated, for exam a small dog may have only one tenth of the typical size of a human being and, therefore, it will be necessary to use a much smaller dose. The determination of an effective amount for a non-human animal is performed in the same manner as described below in the case of humans, and veterinarians are very accustomed to such determinations. As previously indicated, the compounds of this invention are useful for inhibiting the release of fatty acids induced by sPLA2 such as arachidonic acid. By the term "inhibit" is meant the prevention or therapeutically significant reduction in the release of fatty acids initiated by sPLA2 by the compounds of the invention. By "pharmaceutically acceptable" it is meant that the vehicle, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. In general, the compounds of the invention are administered, most desirably, in a dose which, in general, produces effective results without causing any serious side effects and can be administered as a single unit dose or, if desired, Dosage can be divided into convenient subunits administered at appropriate times throughout the day. The specific dose of a compound administered according to this invention to obtain therapeutic or prophylactic effects, of course, will be determined by the particular circumstances surrounding the case, including, for example, the route of administration, age, weight and response of the individual patient, the disorder to be treated and the severity of the patient's symptoms. Typical daily doses will contain a non-toxic dosage level of from about 0.01 mg / kg to about 50 mg / kg of body weight of an active compound of this invention. Preferably, the pharmaceutical formulation is in unit dosage form. The unit dosage form may be a capsule or tablet, or the appropriate number of any of these. The amount of active ingredient in a unit dose of composition can be varied or adjusted from about 0.1 to about 1000 milligrams or more, in accordance with the particular treatment involved. It will be appreciated that it may be necessary to make routine variations to the dose depending on the age and condition of the patient. The dose will also depend on the route of administration.

A "chronic" disorder means a deteriorating disorder of slow progress and prolonged permanence.

As such, it is treated when it is diagnosed and the treatment throughout the course of the disease. A "acute" disorder is an exacerbation of short course followed for a period of remission. In an acute case, the compound is administered at the onset of symptoms and is interrupted when the symptoms disappear.

Pancreatitis, trauma-induced shock, bronchial asthma, allergic rhinitis, and rheumatoid arthritis may occur as an acute case or as a chronic case.

Thus, the treatment of these disorders contemplates both acute and chronic forms. Septic shock and Respiratory distress in the adult, on the other hand, are acute disorders treated when diagnosed.

The compound can be administered by a variety of I pathways including oral, aerosol, rectal, transdermal, subcutaneous, intravenous, intramuscular and intranasal.

The pharmaceutical formulations of the invention are prepare by combining (eg, mixing) a therapeutically effective amount of the compounds of the invention together with a pharmaceutically acceptable carrier or diluent therefor. The present pharmaceutical formulations are prepared by known procedures using well-known and readily available ingredients. To prepare the compositions of the present invention, the active ingredient will normally be mixed with a vehicle, diluted by a vehicle or enclosed within a vehicle which may be in the form of a capsule, sachet, paper or other container. When the vehicle serves as a diluent, it can be a solid, semi-solid or liquid material that acts as a vehicle, or it can be in the form of tablets, pills, powders, tablets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (in solid form). or in a liquid medium) or ointments, containing, for example, up to 10% by weight of the active compound. The compounds of the present invention are preferably formulated before administration. In the case of pharmaceutical formulations, any suitable vehicle known in the art can be used. In such formulations, the carrier may be solid, liquid or a mixture of a solid and a liquid. Formulations in solid form include powders, tablets and capsules. A solid carrier may be one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, binders, tablet disintegrating agents and encapsulating materials.

Tablets for oral administration may contain suitable excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, together with disintegrating agents such as corn, starch or alginic acid, and / or binding agents, for example, gelatin or gum arabic, and lubricating agents such as magnesium stearate, stearic acid or talc. In the powders, the carrier is a finely divided solid that is mixed with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary binding properties in suitable proportions and compacted in the desired shape and size. The powders and tablets preferably contain from about 1 to about 99 weight percent of the active ingredient which is the new compound of this invention. Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, hypromellose, sodium carboxymethylcellulose, low melting point waxes and cocoa butter. Sterile liquid form formulations include suspensions, emulsions, syrups and elixirs. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable vehicle, as sterile water, a sterile organic solvent or a mixture of both. The active ingredient can often be dissolved in a suitable organic solvent, for example, aqueous propylene glycol. Other compositions can be obtained by dispersing the finely divided active ingredient in aqueous starch or sodium carboxymethyl cellulose solution or in a suitable oil. The following pharmaceutical formulations 1 to 8 are merely illustrative and are not intended to limit the scope of the invention in any way. "Active ingredient" refers to a compound according to Formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof. Formulation 1 Hard gelatin capsules are prepared using the following ingredients: Quantity (mg / capsule) Compound of Example 1 250 Starch, dried 200 Magnesium stearate 10 Total 460 mg Formulation 2 A tablet is prepared using the ingredients indicated below: Amount (mg / tablet) Compound of Example 2 250 Cellulose, microcrystalline 400 Silicon dioxide, pyrolysis 10 Stearic acid Total 665 mg The components are mixed and compressed to form tablets each weighing 665 mg.

Formulation 3 An aerosol solution is prepared which contains the following components: Weight Compound of Example 3 0,, 25 Ethanol 25,, 75 Propellant 22 (Clorodifluoromethane) 74,, 00 Total 100,, 00 The active compound is mixed with ethanol and the mixture is added to a portion of the propellant 22, cooled to -30 ° C and transferred to a filling device. The necessary amount is then introduced into a stainless steel container and diluted with the rest of the propellant. Then the valve units are adjusted to the container. Formulation 4 Tablets are prepared, each with 60 mg of active ingredient, as follows: Compound of Example 4 60 mg Starch 45 mg Microcrystalline cellulose 35 mg Polyvinylpyrrolidone (as a 10% solution in water) 4 mg Sodium 4-carboxymethylstarch - 5 mg Magnesium stearate 0,, 5 Talc 1 mg Total 150 mg The active ingredient, starch and cellulose are passed through a U.S. mesh screen. No. 45 and they are mixed homogeneously. The aqueous solution containing polyvinylpyrrolidone is mixed with the resulting powder and the mixture is then passed through a U.S. No. 14. The granules thus produced are dried at 50 ° C and passed through a US No. 18 mesh screen. Then the sodium carboxymethyl starch, magnesium stearate and talc, previously passed through a US mesh screen No. 60, to the granules which, after mixing, are compressed in a tabletting machine, providing tablets each weighing 150 mg. Formulation 5 Capsules are prepared, each containing 80 mg of active ingredient, as follows: Compound of Example 5 80 mg Starch 59 mg Microcrystalline cellulose 59 mg Magnesium stearate 2 mg Total 2O0 mg The active ingredient, cellulose, starch and magnesium stearate are mixed, passed through a U.S. mesh screen. No. 45 and are introduced into hard gelatin capsules in amounts of 200 mg. Formulation 6 Suppositories are prepared, each containing 225 mg of active ingredient, as follows: Compound of Example 6 225 mg Glycerides of saturated fatty acids 2,000 mg Total 2,225 mg The active ingredient is passed through a U.S. mesh screen. No. 60 and is suspended in the glycerides of saturated fatty acids previously melted using the minimum necessary heat. The mixture is then poured into a suppository mold of nominal 2 g capacity and allowed to cool. Formulation 7 Suspensions are prepared, each containing 50 mg of active ingredient per 5 ml dose, as follows: Compound of Example 7 50 mg Carboxymethylcellulose sodium 50 mg Syrup 1.25 ml Benzoic acid solution 0.10 ml Aromatizante c.s. Colorant c.s. Purified water, c.s.p. 5 ml The active ingredient is passed through a U.S. mesh screen. No. 45 and mixed with the sodium carboxymethylcellulose and the syrup to form a uniform paste. The benzoic acid, flavoring and coloring solution is diluted with a part of the water and added, with stirring. Then enough water is added providing the necessary volume. Formulation 8 An intravenous formulation can be prepared as follows: Compound of Example 8 100 mg isotonic saline solution i.oos ml The solution of the above ingredients is generally administered intravenously to a subject at a rate of 1 ml per minute. Test experiments Test Example 1 The following chromogenic assay procedure was used to identify and evaluate inhibitors of recombinant human secreted phospholipase A2. The assay described herein has been adapted for high volume screening using 96-well microtiter plates. A general description of this test procedure is found in the article "Análysis of Human Synovial Fluid Phospholipase A2 on Short Chain Phosphatidylcholine-Mixed Micelles: Development of a Spectrophotometric Assay Suitable for a Microtiterplate Reader", by Laure J. Reynolds, Lori L. Hughes, and Edward A. Dennis, Analytical Biochemistry, 204, p. 190-197, 1992 (the disclosure of which is incorporated herein by reference): Reagents: REACTION TAMPON CaCl2.2H20 (1.47 g / 1) KCl (7.455 g / 1) Bovine Serum Albumin (free of fatty acids) ( 1 g / 1) (Sigma A-7030, product of Sigma Chemical Co. St. Louis MO, USA) TRIS HCl (3.94 g / 1) pH 7.5 (adjust with NaOH) ENZYME TAMPON - NaOAc-3H20 0.05, pH 4.5 NaCl 0.2 Adjust pH to 4.5 with acetic acid DTNB 5,5 '-dithiobis-2-nitrobenzoic acid DIHEPTANOIL TIO - PC RACEMICO 1,2-bis (heptanoiltio) -1, Racemic 2-dideoxy-s-glycero-3-phosphorylcholine TRITON X-100 ™ prepared at 6.249 mg / ml in reaction buffer to be 10 μM. TRITON X-100 ™ is a non-ionic polyoxyethylene detergent supplied by Pierce Chemical Company 3747 N. Meridian Road, Rockford, Illinois 61101. REACTION MIXTURE - A measured volume of racemic diheptanoyl thio PC supplied in chloroform at a concentration of 100 mg / ml is brought to dryness and redissolved in TRITON X-100 ™ 10 millimolar aqueous non-ionic detergent solution. Reaction buffer is added to the solution and then DTNB to give the Reaction Mixture. The reaction mixture thus obtained contains 1 mM diheptanoyl thio-PC substrate, 0.29 mM Triton X-100 ™ detergent and 0.12 mM DTMB in a buffered aqueous solution at pH 7.5. Test Procedure: 1. Add 0.2 ml of reaction mixture to all wells; 2. Add 10 μl of test compound (or blank with solvent) to the appropriate wells, mix for 20 seconds; 3. Add 50 nanograms of sPLA2 (10 microliters) to the appropriate wells; 4. Incubate the plate at 40 ° C for 30 minutes; 5. Read the absorbance of the wells at 405 nanometers with an automatic plate reader. All compounds were tested in triplicate. Typically, the compounds were tested at a final concentration of 5 μg / ml. Compounds were considered active when they showed an inhibition of 40% or greater compared to uninhibited control reactions, measuring at 405 nanometers. The absence of color appearance at 405 nanometers showed inhibition. The compounds found initially active were re-tested to confirm their activity and, if they were sufficiently active, the IC50 values were determined. Typically, IC50 values (see Table I below) were determined by diluting the serial test compound in half in such a way that the final concentration of the reaction varied between 45 μg / ml and 0.35 μg. / ml. The most potent inhibitors required a significantly higher dilution. In all cases, the% inhibition measured at 405 nanometers generated by the enzymatic reactions containing inhibitors was determined with respect to the non-inhibited control reactions. Each sample was assessed in triplicate and the values of the results were averaged for the representation and calculation of IC 50 values. The IC50 were determined by representing the log of the concentration against the inhibition values in a range of inhibition of 10 to 90%. The compounds of the present invention were tested in Test Example 1 and were found to be effective at concentrations less than 100 μM. Test Example 2 Procedure: Male Hartley lineage guinea-pigs were sacrificed (500-700 g) by cervical dislocation, the intact lungs and hearts were removed and placed in Aerated Krebs (95% of 02: 5% of C02). Dorsal pleural strips (4x1x25 mm) of intact parenchymal segments (8x4x25 mm) cut parallel to the outer edge of the lower pulmonary lobes were dissected. Two adjacent pleural strips, obtained from a single lobe and representing a single tissue sample, were ligated at one end and independently attached to a metal supporting rod. A rod was attached to a force-displacement transducer Grass Model FT03C, product of Grass Medical Instruments Co., Quincy, MA, USA. Changes in isometric tension were shown on a monitor and thermal recorder (product of Modular Instruments, Malvern, PA). All tissues were placed in 10 ml tissue baths with a "heated jacket" maintained at 37 ° C. Tissue baths were continuously aerated and contained modified Krebs solution of the following composition (millimolar) NaCl, 118.2, KCl, 4.6, CaCl2-2H20, 2.5, MgSO4-7H20, 1.2, NaHCO3, 24.8, KH2P04, 1.0, and dextrose, 10.0.Pleural strips were used from the opposite lobes of the lung. Conducting matched experiments The preliminary data generated from the tension / response curves showed that the optimal resting tension was 800 mg The tissues were left to equilibrate for 45 minutes as the bath fluid was periodically changed. cumulative response Initially, the tissues were exposed 3 times to KCl (40 mM) to test the viability of the tissues and obtain a coherent response. After recording the maximum response to KCl, the tissues were washed and allowed to return to the initial state before the next exposure. Cumulative concentration-response curves were obtained from the pleural strips by increasing the concentration of agonist (sPLA2) in the tissue bath in 10-log half-log increments, while the previous concentration remained in contact with the tissues (Ref. 1, supra). The concentration of agonists was increased after reaching the plateau of the contraction produced by the previous concentration. A concentration-response curve of each tissue was obtained. To minimize the variability between tissues obtained from different animals, contractile responses were expressed as a percentage of the maximum response obtained with the final exposure to KCl. When the effects of various drugs on the contractile effects of sPLA2 were studied, the compounds and their respective vehicles were added to the tissues 30 minutes before beginning the sPLA concentration-response curves.

Statistical analysis: Data from different experiments were collected and presented as a percentage of the maximum KCl responses (mean + standard error). To estimate the rightward shifts induced by the drug in the concentration-response curves, the curves were analyzed simultaneously using nonlinear statistical modeling procedures similar to those described by Waud (1976), Equation 26, p. 163, (Ref. 2). The model includes four parameters: the maximum response of the tissue, which was considered equal for all the curves, the ED50 for the control curve, the slope of the curves and the pA2, the concentration of antagonist that requires an increase of twice the agonist to get an equivalent answer. It was determined that Schild's slope was 1, using nonlinear statistical modeling procedures similar to those described by Waud (1976), Equation 27, p. 164 (Ref. 2). A slope of Schild equal to 1 indicates that the model is consistent with the assumptions of a competitive antagonist; therefore, pA2 can be interpreted as the apparent KB, the dissociation constant of the inhibitor. To estimate the drug-induced suppression of the maximum responses, sPLA2 responses (10 μg / ml) were determined in the absence and in the presence of the drug, and the percentage of suppression was calculated for each pair of tissues. Representative examples of the inhibitory activities are presented in Table 2 below. Ref. 1 - Van, J. M.: Cumulative dose-response curves. II. Technique for the making of dose-response curves in isolated organs and the evaluation of drug parameters. Arch. Int. Pharmacodyn. Ther. , 143: 299-330, 1963. Ref. 2 - Waud, D.: Analysis of dose-response relationships. in Advances in General and Cellular Pharmacology eds Narahashi, Bianchi 1: 145-178, 1976. The compounds of the present invention were tested in Test Example 2 and were found to be effective at concentrations below 20 μM. Test Example 3 sPLA2 Assay in Transgenic Mice Materials and Methods The mice used in these studies were adult transgenic mice, 6-8 months old, stimulated with ZnSO4, from the hemizygous line 2608a (Fox et al., 1996). Transgenic mice of this line express human sPLA2 in the liver and other tissues and typically reach levels of human sPLA2 in their circulation of approximately 173 + 10 ng / ml when maximally stimulated with ZnSO4 (Fox, et al., 1996). The mice were caged under constant humidity and temperature and received food and water ad libi tum. The illumination of the animal room was maintained in a light / dark cycle of 12 hours and all the experiments were carried out at the same time of day during the early morning period. For the intravenous assay, compounds or vehicle were administered in the form of intravenous injection through the tail vein in a volume of 0.15 ml. The vehicle consisted of 1-5% dimethisulfoxide, 1-5% ethanol and 300% polyethylene glycol at 10-20% in H20; the concentrations of these ingredients were adjusted according to the solubility of the compound. The mice were bled by the retro-orbital route before drug or vehicle administration and 30 minutes, 2 and 4 hours later. Three to six mice were used for each dose. The catalytic activity of PLA2 in the serum was tested with a modified mixed micellar assay of phosphatidylcholine / deoxycholine (Fox, et al., 1996, Schadlich, et al., 1987) using 3 mM sodium deoxycholate and 1-palmitoyl-2-oleoyl- sn-glycero-3-phosphocholine 1 mM.

For the oral test, the compounds were dissolved in 1-5% ethanol / 10-30% polyethylene glycol 300 in H20 or suspended in 5% dextrose in H20 and administered by oral garage. Serum was prepared from the retro-orbital blood and tested for the catalytic activity of PLA2 as indicated above. References Fox, N., M. Song, J. Schrementi, J.D. Sharp, D. L. White, D. W. Snyder, L.W. Hartley, D. G. Carlsoñ, N. J. Bach, R. Dillard, S. Draheim, J. L. Bobbitt, L. Fisher and E. D. Míhelich. 1996. Eur. J. Pharmacol. 308: 195. Schadlich, H. R., M. Buchler, and H. G. Beger, 1987, J. Clin. Chem. Clin. Biochem. 25, 505. The compounds of the present invention were tested in Test Example 3 and were considered effective. Although the present invention has been illustrated above by certain specific examples, it should not be construed that these specific examples limit the scope of the invention, as described in the appended claims. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, the contents of the following are declared as property

Claims (23)

1. CLAIMS 1. A compound, characterized in that it is selected from the group consisting of [9-benzyl-5-carbamoyl-1-fluorocarbazol-4-yl] oxyacetic acid, acid. { 9- [(phenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic, acid. { 9 - [(3-fluorophenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic, acid. { 9- [(3-Chlorophenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic, sodium salt of acid. { 9- [(3-trifluoromethylphenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic, sodium salt of acid. { 9- [(2-methylphenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic, sodium salt of acid. { 9- [(3-methylphenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic, sodium salt of acid. { 9- [(3-trifluoromethoxyphenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid, [9-benzyl-5-carbamoyl-1-chlorocarbazol-4-yl] oxyacetic acid, [9 - [(cyclohexyl) met yl] -5-carbamoylcarbazole-4-yl] oxyacetic acid and [9 - [( cyclopentyl) methyl] -5-carbamoylcarbazol-4-yl] oxyacetic acid or one of its racemates, solvates, tautomers, optical isomers, prodrug derivatives or pharmaceutically acceptable salts.
2. 2. A compound according to claim 1, characterized in that it is the acid. { 9- [(phenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic, or one of its racemates, solvates, tautomers, optical isomers, prodrug derivatives or pharmaceutically acceptable salts.
3. 3. A compound according to claim 1, characterized in that it is [9-benzyl-5-carbamoyl-1-fluorocarbazol-4-yl] oxyacetic acid, or one of its racemates, solvates, tautomers, optical isomers, prodrug derivatives or pharmaceutically acceptable salts.
4. 4. A compound according to claim 1, characterized in that it is the acid. { 9- [(3-fluorophenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic, or one of its racemates, solvates, tautomers, optical isomers, prodrug derivatives or pharmaceutically acceptable salts.
5. 5. A compound according to claim 1, characterized in that it is the acid. { 9- [(3-chlorophenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic, or one of its racemates, solvates, tautomers, optical isomers, prodrug derivatives or pharmaceutically acceptable salts.
6. 6. A compound according to claim 1, characterized in that it is the sodium salt of the acid. { 9 - [(3-trif luoromet ilf enyl) met il] -5-carbamoylcarbazole-4-yl} oxyacetic, or one of its racemates, solvates, "tautomers, optical isomers, prodrug derivatives or pharmaceutically acceptable salts
7. 7. A compound according to claim 1, characterized in that it is the sodium salt of the acid. {9 - [(2-methylphenyl ) methyl] -5-carbamoylcarbazol-4-yl.} oxyacetic acid, or one of its racemates, solvates, tautomers, optical isomers, prodrug derivatives or pharmaceutically acceptable salts.
8. 8. A compound according to claim 1, characterized in that it is the sodium salt of the acid. { 9 - [(3-methylphenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic, or one of its racemates, solvates, tautomers, optical isomers, prodrug derivatives or pharmaceutically acceptable salts.
9. 9. A compound according to claim 1, characterized in that it is the sodium salt of the acid. { 9 - [(3-trifluoromethoxyphenyl) met il] -5-carbamoylcarbazol-4-yl} oxyacetic acid, or one of its racerotates, solvates, tautomers, optical isomers, prodrug derivatives or pharmaceutically acceptable salts.
10. A compound according to claim 1, characterized in that it is [9-benzyl-5-carbamoyl-1-chlorocarbazol-4-yl] oxyacetic acid, or one of its racemates, solvates, tautomers, optical isomers, prodrug derivatives or salts pharmaceutically acceptable
11. 11. A compound according to claim 1, characterized in that it is [9- [(ciciohexyl) methyl] -5-carbamoylcarbazol-4-yl] oxyacetic acid, or one of its racemates, solvates, tautomers, optical isomers, prodrug derivatives or pharmaceutically salts acceptable
12. 12. A compound according to claim 1, characterized in that it is [9- [(cyclopentyl) methyl] -5-carbamoylcarbazol-4-yl] oxyacetic acid, or one of its racemates, solvates, tautomers, optical isomers, prodrug derivatives or pharmaceutically acceptable salts.
13. 13. A compound according to any one of claims 1 to 12, characterized in that the prodrug derivative is an ester of methyl, ethyl, propyl, isopropyl, butyl, morpholinoethyl or diethylglycolamide.
14. 14. A compound according to any one of claims 1 to 12, characterized in that the salt is sodium.
15. 15. A pharmaceutical formulation, characterized in that it comprises a compound according to any one of claims 1 to 12, together with a pharmaceutically acceptable carrier or diluent therefor.
16. 16. A pharmaceutical formulation adapted to the treatment of a disorder associated with the inhibition of sPLA2, characterized in that it contains a compound according to any one of claims 1 to 12, together with a pharmaceutically acceptable carrier or diluent therefor.
17. 17. A method for selectively inhibiting sPLA2 in a mammal in need of such treatment, characterized in that it comprises administering to said mammal a therapeutically effective amount of a compound according to any one of claims 1 to 12.
18. 18. A method according to claim 17 , characterized in that the mammal is a human being.
19. 19. A method for alleviating the pathological effects of diseases related to sPLA2, characterized in that it comprises administering to a mammal in need of said treatment a compound according to any one of claims 1 to 12, in an amount sufficient to inhibit the release of induced fatty acids by sPLA2 and, in this way, inhibit or prevent the cascade of arachidonic acid and its harmful products.
20. 20. Use of a compound of formula I "according to any one of claims 1 to 12, for manufacturing a medicament for alleviating the pathological effects of diseases related to sPLA2, characterized in that it comprises administering a compound of formula I to a mammal in need thereof.
21. 21. A method for inhibiting sPLA2, characterized in that it comprises contacting sPLA2 with a compound according to any one of claims 1 to 12.
22. 22. A method for treating septicemia, septic shock, rheumatoid arthritis, osteoarthritis, apoplexy, apoptosis, asthma, chronic bronchitis, acute bronchitis, cystic fibrosis, inflammatory bowel disease or pancreatitis, characterized in that it comprises administering to a subject in need of such treatment, a therapeutically effective amount of a compound according to any one of claims 1 to 12.
23. 23. A method according to claim 21, characterized by alleviating the pathological effects of septicemia, septic shock, respiratory distress syndrome in adults, pancreatitis, shock induced by trauma, bronchial asthma, allergic rhinitis, rheumatoid arthritis, cystic fibrosis, stroke, acute bronchitis , chronic bronchitis, acute bronchiolitis, chronic bronchiolitis, osteoarthritis, gout, spondylarthropathy, ankylosing spondylitis, Reiter's syndrome, psoriatic arthropathy, enteropatric spondylitis, juvenile arthropathy or juvenile ankylosing spondylitis, reactive arthropathy, infectious arthritis or after infection, gonococcal arthritis, tuberculous arthritis, viral arthritis, fungal arthritis, syphilitic arthritis, Lyme disease, arthritis associated with "vasculitis syndromes", polyarteritis nodosa, hypersensitivity vasculitis, Luegenec's granulomatosis, polymyalgia rheumatica, arthritis of the cells of the joints, arthritis opathy due to calcium crystals deposition, pseudogout, non-articular rheumatism, bursitis, tenosynovitis, epicondylitis (tennis elbow), carpal tunnel syndrome, repetitive use injury (typing), various forms of arthritis, neuropathic joint disease (joint de Charcot), hemarthrosis (hemarthrosis), Henoch-Schonlein purpura, hypertrophic osteoarthropathy, multicentric reticulohistiocytosis, arthritis associated with certain diseases, sulcoilosis, hemochromatosis, sickle cell disease and other hemoglobinopathies, hyperlipoproteinemia, hypogammaglobulinemia, hyperparathyroidism, acromegaly, familial Mediterranean fever , Behat's disease, systemic lupus erythematosus or polychondritis with relapses and related diseases.