MXPA99003588A

MXPA99003588A - Triciclic composites substitui

Info

Publication number: MXPA99003588A
Application number: MXPA/A/1999/003588A
Authority: MX
Inventors: John Martinelli Michael; David Mihelich Edward; Jon Sall Daniel; James Bach Nicholas; Scott Sawyer Jason; Dean Kinnick Michael; Michael Morin John Jr; Anne Bastian Jolie; Wade Beight Douglas
Original assignee: Eli Lilly And Company
Priority date: 1998-04-17
Filing date: 1999-04-16
Publication date: 2000-07-01

Abstract

A class of novel tricyclic compounds is described along with the use of such compounds to inhibit the release of fatty acid mediated by sPLA2 for the treatment of conditions such as septic shock.

Description

SUBSTITUTE TRICKS COMPOUNDS Field of the Invention This invention relates to novel substituted tricyclic organic compounds useful for inhibiting sPLA2 / mediated slashing of fatty acids for conditions 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, Waldemar; Vadas Peter; Plant, Shelley; Miller, Judy A .; Kloss, Jean; and Johnson, Lorin K.; The Journal of Biological Chemistry, Vol. 264, No. 10, Number of April 5, p. 5335-5338, 1989; and "Structure and Properties of a Human Non-Pancreatic Phospholipase A2" by Kraer, Ruth M.; Hession, Catherine; Johansen, Berit; Hayes, Gretchen; McGray, Paula; Chow, E. Pingchang; Tizard, Richard; and Pepinsky, T. Blake; The Journal of Biological Chemistry, Vol. 264, No. 10, Number of April 5, p. 5768-5775, REF .: 29930 1989; whose descriptions are incorporated herein by reference. 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 sPLA2-mediated release of qrase acids (eg, arachidonic acid). Such compounds would be valuable in the general treatment of conditions induced and / or maintained by the overproduction of sPLA2 such as septic shock, respiratory distress syndrome in adults, pancreatitis, shock induced by trauma, bronchial asthma, allergic rhinitis, rheumatoid arthritis, etc. . It is desirable to create new compounds and treatments for diseases induced by sPLA2. Alexander, et al. , U.S. Patent Nos. 3,939,177 and 3,979,391, describe 1,2,3,4-tetrahydrocarbazoles useful as antibacterial agents. Description of the Invention This invention provides tricyclic compounds as represented in the general formula (I) shown below: in which; A is phenyl or pyridyl, where the nitrocene is in the position 5 67 7 -u 87 one of B or D is nitrogen and the other is carbon; Z is cyclohexenyl, phenyl, pyridyl, where the nitrogen is in the 1-, 2r d 3 ~, or a 6-membered heterocyclic ring having a heteroatom selected from the group consisting of sulfur or oxygen in the 1- 2- position 6 37 and nitrogen in the position I7 2 3 ~ or 47 is a single or double bond; , 20 is selected between groups (a), (b) and (c), where; (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 - (T,) - R80; where (T,) - is a divalent linking group - from 1 to 12 atoms, selected from carbon, hydrogen, oxygen, nitrocene and sulfur; where the combination of atoms in - (L) - is selected 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) carbon, hydrogen and only oxygen; and where Rso is a group selected from (a) or (b); R21 is substituting and not interfering; R1 'is -NHNH2, -NH2 or -C0NH2; R2 'is selected from the group consisting of -OH and -0 (CH2) tR5' where R5 'where is H, -Cn, -NH2, -C0NH2, -C0NR9R10, -NHS02R15; -CONHSO2R15, where R15 is -alkyl of 1 to 6 carbon atoms or -CF3; phenyl or phenyl substituted with -C02H or -C? 2 ~ alkyl of 1 to 4 carbon atoms; and (La) - (acid group), where - (La) - is an acidic linker having an acid linker length of 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 a racemate, solvate, tautomer, optical isomer, prodrug derivative or pharmaceutically acceptable salt thereof; with the proviso that one of A or Z is a heterocyclic ring; and when D is nitrogen, the heteroatom of Z is selected from the group consisting of sulfur or oxygen in the 1-, 2- or 3- position and nitrogen in the 1-, 2-, 3- or 4- position. These substituted tricyclic compounds are effective in inhibiting the release of fatty acids mediated by sPLA2. This invention is also a pharmaceutical formulation comprising a compound of formula I in association with one or more pharmaceutically acceptable diluents, carriers and excipients. This invention is also a method for inhibiting sPLA2 which comprises administering to a mammal in need of such treatment, a therapeutically effective amount of a compound of formula I. In accordance with another aspect of the present invention, a method for selectively inhibiting sPLA2 is provided. in a mammal in need of such treatment, comprising administering to said mammal a therapeutically effective amount of a compound of formula I.

This invention further provides a method to alleviate the pathological effects of sepsis, septic shock, respiratory distress syndrome in adults, pancreatitis, shock induced trauma, bronchial asthma, allergic rhinitis, rheumatoid arthritis, cystic fibrosis, cerebrovascular accidents, acute bronchitis, chronic bronchitis, acute bronchitis, chronic bronchitis, osteoarthritis, qota, spondylarthropathy, ankylosing spondylitis, Reiter's syndrome, psoriatic arthropathy, enteropatric spondylitis, juvenile arthropathy or juvenile ankylosing spondylitis, reactive arthropathy, infectious or post-infection arthritis, gonorrhea arthritis, arthritis tuberculosa, viral arthritis, fungal arthritis, syphilitic arthritis, Lyme disease, arthritis associated with "vasculitis syndromes", polyarteritis nodosa, hypersensitivity vasculitis, Luegenec granulomatosis, polymialgina rheumatica, arteritis of the cells of the joints Arthropathies of calcium deposition, pseudogout, non-articular rheumatism, bursitis, tenosynovitis, epicondylitis (tennis elbow), carpal tunnel syndrome, repetitive use injury (typing), various forms of arthritis, neuropathic disease of the joints (Charcot joint), hermarthrosis (hemarthrosis), Henoch purpura- Schonlein, hypertrophic osteoarthropathy, multicentric reticulohistiocytosis, arthritis associated with certain diseases' sulcoilosis, hemochromatosis, sickle cell disease and other hemoglobin diseases, hyperlipoproteinemia, hypogammaglobulinemia, hyperparathyroidism, acromegaly, familial Mediterranean fever, Behat's disease, systemic lupus erythematosus or relapsed polychondritis 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 mediated by sPLA2 and, therefore, inhibit or prevent the cascade of the arachidonic acid and its harmful products. Other objects, features and advantages of the present invention will become apparent from the following description and the appended claims. Definitions:; As used herein, the term "alkyl", by itself or as part of another substituent, means, unless otherwise defined, a straight or branched monovalent hydrocarbon radical, such as methyl, ethyl, n- propyl, isopropyl, n-butyl, tertiary butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, heptyl, hexyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl and the like. The term "alkyl" includes -alkyl of 1 to 2 carbon atoms, -alkyl of 1 to 4 carbon atoms, -alkyl of 1 to ß 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 linear or branched olefinically unsaturated group having at least one 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, heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, as well as dienes and trienes of straight and branched chains. The term "alkynyl" denotes radicals such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, as well as di- and tri-ions. The term "halo" means chlorine, fluorine, bromine or iodine. The term "-alkoxy of 1 to 4 carbon atoms", as used herein, denotes a group such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy and similar, linked to the rest 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 alkyl groups of from 1 to 4 carbon atoms include methylthio, ethylthio, propylthio, butylthio, and the like. The term "cycloalkyl of 3 to 14 carbon atoms" includes such groups as cyclopropyl, cyclobutyl, cyclopentyl, ciciohexilo, cicioheptilo, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, cyclotridecyl, cyclotetradecyl and the like. The term "-cycloalkyl of 3 to 14 carbon atoms" includes -cycloalkyl of 3 to 7 carbon atoms.

The term "heterocyclic radical" derived from polycyclic, saturated or unsaturated, substituted or unsubstituted monocyclic nuclei radicals having 5 to 14 ring atoms and containing from 1 to 3 heteroatoms selected from the group consisting of nitrogen is concerned, 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, tianaphteneyl, dibenzothiophenyl, indazolyl. , imidazo (1.2-A) pyridinyl, benzotriazolyl, anthranilyl, 1,2-benzisoxazolyl, benzoxazolyl, benzothiazolyl, purinyl, pyridinyl, dipiridililo, 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. The carbocyclic radicals. Typical are cycloalkyl, cycloalkenyl, phenyl, naphthyl, norbornanyl, bicycloheptadienyl, tolulilo, xylenyl, indenyl, stilbenyl, terphenylyl, diphenylethylenyl, fenilciclohexenilo, acenaphthylenyl and anthracenyl, biphenyl, bibenzylyl and related bibenzylyl homologues represented by the formula (bb), in which 'n is an integer from 1 to 8. The term "non-interfering substituent" refers to radicals suitable for substitution at positions 1, 2, 3, 7 and / or 8 in the tricyclic core (as represented in Formula III) and suitable radical (s) for substitution in the heterocyclic radical and the carbocyclic radical as defined above. Illustrative non-interfering radicals are hydrogen, -alkyl of 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, -alcarilo 7 to 12 carbon atoms cycloalkyl from 3 to 8 carbon atoms, cycloalkenyl of 3 to 8 carbon atoms, phenyl tolulilo, xylenyl, biphenyl, alkoxy of 1 to 6 carbon atoms, -alkenyloxy of 2 to 6 carbon atoms, -alkynyloxy of 2 to 6 carbon atoms, alkoxyalkyl of 1 to 12 carbon atoms, -alkoxyalkyloxy of 1 to 12 carbon atoms -alkyl of 1 to 12 carbon atoms carbonaceous carbon, -alkyl of 1 to 12 carbon atoms, carbonylamino, -alkoxyamino of 1 to 12 carbon atoms, -alkoxy of 1 to 12 carbon atoms, aminocarbonyl, -alkylamino of 1 to 12 carbon atoms, alkylthio of 1 to 6 arbon atoms, -alkyl of 1 to 12 carbon atoms, thiocarbonyl, alkylsulfinyl of 1 to 6 carbon atoms, -alkyl of 1 to 12 carbon atoms, thiocarbonyl, alkylsulfinyl of 1 to 6 carbon atoms, -alkylsulfonyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, haloalkylsulfonyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, -hydroxyalkyl of 1 to 6 carbon 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; - (CONHS02) R15, where R15 is -alkyl of 1 to 6 carbon atoms; -CF3, naphthyl or - (CH2) sphenyl, where s is 0-5; -CHO, CF3, -OCF3, pyridyl, amino, amidino, halo, carbamyl, carboxyl, carbalkoxy, - (CH) nC02H, cyano, cyanoguanidinyl, guan? Dino, hydrazide, hydrazino, hydrazido, hydroxy, hydroxyamino, nitro phosfono, - 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 from 1 to 6 carbon atoms, - (CH 2) nOSi-alkyl of 1 to 6 carbon atoms and alkyl of 1 to 6 carbon atoms carbonyl; where n is from 1 to 8 and R9 and R10 are independently hydrogen, -CF3, phenyl, -alkyl of 1 to 4 carbon atoms, alkylphenyl of 1 to 4 carbon atoms or -phenylalkyl of 1 to 4 carbon atoms. The term "acid group" means an organic group that when bound to a tricyclic core, through suitable binding atoms (hereinafter referred to as "acidic linker"), acts as a proton donor capable of forming hydrogen bonds. The following are illustrative of an acid group: -C02H, -5-tetrazolyl, -S03H, ^ 99 -? - ° - (CH2'n- -N- Bflß OH R8 fifteen twenty where n is 1 to 8, R89 is a metal or -alkyl of 1 to 10 carbon atoms and Rg9 is hydrogen or -alkyl of 1 to 10 carbon atoms. The term "acid linker" 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 link length" refers to the number of atoms (excluding hydrogens) in the shortest chain of the linking group - (La) - which connects the 5 6 6 position of the tricyclic core with the acid group. The presence of a carbocyclic ring in - (La) - contributes the number of atoms approximately equivalent to the calculated diameter of the carbocyclic ring. Thus, a ring of benzene or cyclohexane in the acidic connector provides 2 atoms in the calculation of the length of - (La) -. They are illustrative acid connector groups; (to) where t is 1 to 5, Q is selected from the group - (CH2) -, -O-, -NH- and -S-, and each of R4 and Res is independently selected from hydrogen, alkyl of 1 to 10 atoms carbon, aryl, -alkaryl 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 acid connector lengths of 3, 3, 2 and 2, respectively.

The person skilled in the art will appreciate that the position of the double bond in the 5-membered central ring depends on the position of the nitrogen atom as shown below.

The salts of the above tricyclic compounds are a further aspect of the invention. In cases where the compounds of the invention possess acidic functional groups, various salts can be formed which are more water soluble and physiologically suitable than the parent compound. Representative pharmaceutically acceptable salts include, but are not limited to, the alkali and alkaline earth metal salts such as lithium, sodium, potassium, calcium, magnesium, aluminum and the like. The salts are conveniently prepared from the free acid by treating the acid in solution with a base or by exposing the acid to an ion exchange resin.

Within the definition of the pharmaceutically acceptable salts include the relatively non-toxic organic and inorganic base addition salts of compounds of the present invention, for example, ammonium, quaternary ammonium and amine cations, derived from basicity nitrogenous bases sufficient 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 methods 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. The term "acid protecting group" is used herein as 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 treated by T. 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, methylthioethyl, t-butyl, cyclopentyl, triphenylmethyl, diphenylmethyl, benzyl, trimethylsilyl, N, N-dimethyl, pyrrolidinyl, piperidinyl or o-nitroanilide. A preferred acid protecting group is methyl. Prodrugs are derivatives of the compounds of the invention which have chemically or metabolically cleavable groups and which are converted, by solvolysis or under physiological conditions, to the compounds of the invention which are pharmaceutically active in vivo. Derivatives of the compounds of this invention have activity in their acid and basic derivative forms, but the acid derivative form often offers solubility, tissue compatibility or delayed release benefits 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 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 morpholinoethyloxy, diethylglycolamide and diethylaminocarbonylmethoxy. In some cases, it is desirable to prepare prodrugs of the double ester type such as (acyloxy) alkyl esters or ((alkoxycarbonyl) oxy) alkyl esters.

Preferred Subgroups of the Formula Compounds (i: A preferred subclass of compounds of formula (I) are those in which R21 is selected from the group of hydrogen, halo, -alkyl of 1 to 3 carbon atoms, -cycloalkyl of 3 to 4 carbon atoms, cycloalkenyl of 3 to 4 carbon atoms, -O-alkyl of 1 to 2 carbon atoms and -S-alkyl of 1 to 2 carbon atoms.

Another preferred subclass of compounds of formula (I) are those in which for R20, the group R80 is selected from the group consisting of cycloalkyl, cycloalkenyl, phenyl, naphthyl, norbornyl, bicycloheptadienyl, tolulyl, xylenyl, indenyl, stilbenyl, terphenylyl, diphenylethylene, phenyl-cyclohexenyl, acenaphthylenyl and anthracenyl, biphenyl, bibencyl and related bibencyl homologs represented by the formula (bb), wherein n is a number from 1 to 8. Particularly preferred are compounds wherein R20 is selected from the group consisting of fi ~ - «a,) o-r- _ / where R 11 is a radical independently selected from halo, -alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, -S- (alkyl of 1 to 10 carbon atoms) and -haloalkyl of 1 to 10 atoms carbon, and w is a number from 0 to 5.

Another preferred subclass of compounds of formula (I) are those wherein R2 'is a substituent having an acid linker with an acid linker length of 2 or 3. The most preferred are those compounds in which the acid group is selected between -C02H, • 5- etrazolyl, -S03H, ? 99? - O- (CH,) ,, - N-R »I OH > where n is 1 to 8, Rss is a metal or -alkyl of 1 to 10 carbon atoms and R99 is hydrogen or -alkyl of 1 to 10 carbon atoms. Particularly preferred are compounds wherein the acidic group of R2 'is selected from; C ° 2H - SO3H P (O) (OH) 2 or a salt and prodrug derivatives (e.g., ester) thereof. Another preferred subclass of compounds of formula (I) are those wherein R2 'is a substituent having an acid linker with an acid linker length of 2 or 3 and the acid linker group, - (La) -, for R2 ', is selected from a group represented by the formula; wherein Q is selected from the group - (CH2) -, -O-, -NH- and -S-, and each of R4 and Res is independently selected from hydroquin, -alkyl from 1 to 10 carbon atoms, aryl, -alkylaryl of 1 to 10 carbon atoms, arylalkyl of 1 to 10 carbon atoms, carboxy, carbalkoxy and halo. Even more preferred are compounds in which the acidic conjugate, - (La) - for R2 'is selected from the specific groups; , Another preferred subclass of compounds of formula (I) are those wherein R2 'is a substituent having an acid linker with an acid linker length of 3 to 8 atoms and the acid linker group, - (La) -, to R2 'is selected from; where r is a number from 2 to 7, s is O or l and Q is selected from the group - (CH2) -, -O-, -NH- and -S-, and each one of Rs4 and Rss is independently selected from hydrogen, -alkyl of 1 to 10 carbon atoms, aryl, -alkylaryl of 1 to 10 carbon atoms, arylalkyl of 1 to 10 carbon atoms, carboxy, carbalkoxy and halo. Even more preferred are compounds in which the acidic conjugate, - (La) -, for R2 'is selected from the specific groups; - -tCH,),., - ^ wherein each of R84 and Rss is independently selected from hydrogen, -alkyl of 1 to 10 carbon atoms, aryl, -alkaryl of 1 to 10 carbon atoms, aralkyl of 1 to 19 carbon atoms, aralkyl of 1 to 10 carbon atoms, carboxy, carbalkoxy and halo. Another preferred subclass of compounds of formula (III) are those in which R3 'is selected from hydrogen and non-interfering substituents, the non-interfering substituents being selected from the group consisting of hydrogen, -alkyl of 1 to 6 carbon atoms, -alkenyl of 2 to 6 carbon atoms, -alkynyl of 2 to 6 carbon atoms, aralkyl of 7 to 12 carbon atoms, -alcaryl of 7 to 12 carbon atoms, -cycloalkyl of 3 to 8 carbon atoms, -cycloalkenyl from 3 to 8 carbon atoms, phenyl, tolulyl, xylenyl, biphenyl, -alkoxy of 1 to 6 carbon atoms carbon, -alkenyloxy of 2 to 6 carbon atoms, alkynyloxy of 2 to 6 carbon atoms, -alkoxyalkyl of 1 to 12 carbon atoms, -alkoxyalkyloxy of 1 to 12 carbon atoms -alkyl of 1 to 12 carbon atoms carbonyl , -alkyl of 1 to 12 carbon atoms, aminocarbonyl, -alkylamino of 1 to 12 carbon atoms, -alkylthio of 1 to 6 carbon atoms, alkyl of 1 to 12 carbon atoms, thiocarbonyl, -alkylsulfinyl of 1 to 6 carbon atoms , -alkyl-sulfonyl of 1 to 6 carbon atoms, -haloalkoxy of 1 to 6 carbon atoms, haloalkylsulfonyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, -C (0) 0 (alkyl of 1 to 6 carbon atoms), (CH2) n0 (alkyl of 1 to 6 carbon atoms), -benzyloxy, halo or CF3; furyl, thiophenyl, - (CH2) nCN, (CH2) nR8 where R8 is H, -CONH2, -NR9R10, -CN or phenyl wherein R9 and R10 are independently -alkyl of 1 to 4 carbon atoms or phenyl of 1 to 4 carbon atoms; -CHO, amino, amidino, carbamyl, carboxyl, carbalkoxy, - (CH2) nC02H, cyano, cyanoguanidinyl, guanidinium, hydrazide, hydrazino, hydrazido, hydroxy, hydroxyamino, nitro, phosphono, -S03H, thioacetal, thiocarbonyl and -alkyl. to 6 carbon atoms carbonyl; where n is from 1 to 8.

Another preferred group of stents for R3 'includes H, -O-alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 10 carbon atoms, phenyl, -alkylphenyl of 1 to 4 carbon atoms; phenyl substituted with -alkyl of 1 to 6 atoms, halo or -CF3; -CH2Osi -alkyl of 1 to 6 carbon atoms, furyl, thiophenyl, -hydroxyalkyl of 1 to 6 carbon atoms or - (CH2) nR8, where R8 is H, -NR9R10, -CN or phenyl, where R9 and R10 are independently - alkyl of 1 to 4 carbon atoms or - phenylalkyl of 1 to 4 carbon atoms and n is 1 to 8. Another preferred group includes 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 atoms, halo or -CF3; -CH2Osi -alkyl of 1 to 6 carbon atoms, furyl, thiophenyl, -hydroxyalkyl of 1 to 6 carbon atoms or - (CH2) nR8, where R8 is H, -NR9R10, -CN or phenyl, where R9 and R10 are Independently - at least 1 to 4 carbon atoms or - phenylalkyl of 1 to 4 carbon atoms and n is 1 to 8. Preferred compounds of the invention are those having the general formula (II) (II) in which; R1 is -NHNH2 or -NH; R2 is selected from the group consisting of -OH and -0 (CH2) mR5, where R5 is H, -C0H, -C02 (to the quill of 1 to 4 carbon atoms); -P (O) (R6R7), wherein one of R6 and R7 is independently -OH or -O-alkyl of 1 to 4 carbon atoms; -S03H, -S03 (alkyl of 1 to 4 carbon atoms), 'tetrazolyl, -CN, NH2, -NHS02R15; -C0NHS02R15, where R15 is alkyl of 1 to 6 carbon atoms or -CF3, phenyl or phenyl substituted with C02H or -C02-alkyl of 1 to 4 carbon atoms where m is 1-3; R3 is H, -O-alkyl of 1 to 4 carbon atoms, halo, -alkyl of 1 to 6 carbon atoms, phenyl substituted with -alkyl of 1 to 6 carbon atoms, halo or -CF3; -CH20S- alkyl of 1 to 6 carbon atoms, furyl, thiophenyl, -hydroxyalkyl of 1 to 6 carbon atoms; or - (CH2) nR8, where R8 is H, -C0NH2, -NR9R10, -CN or phenyl, where R9 and R10 are independently - alkyl of 1 to 4 carbon atoms 0 -. 0-phenylalkyl of 1 to 4 carbon atoms and n is 1 to 8; R 4 is H, -alkyl gives from 5 to 14 carbon atoms, -cycloalkyl from 3 to 14 carbon atoms, pyridyl, phenyl or phenyl substituted with -alkyl of 1 to 6 carbon atoms, halo, CF 3, -OCF 3, -alkoxy from 1 to 4 carbon atoms, -CN, -alkylthio of 1 to 4 carbon atoms, phenylalkyl of 1 to 4 carbon atoms, -alkylphenyl of 1 to 4 carbon atoms, phenyl, phenoxy or naphthyl; A is phenyl or pyridyl, where the nitrogen is in the 5-, 6-, 7- or 8- position; Z is cyclohexenyl, phenyl, pyridyl, where the nitrogen is in the 1-, 2- or 3- position, or a 6-membered heterocyclic ring having a heteroatom selected from the group consisting of sulfur or oxygen in the 1- position, 2- or 3-, and nitrogen in the 1-, 2-, 3- or 4- position, or where a carbon in the heterocyclic ring is optionally substituted with = 0, or a racemate, solvate, tautomer, optical isomer, derivative pharmaceutically acceptable prodrug or salt thereof; with the proviso that one of A or Z is a heterocyclic ring. Preferred substituents of the compounds of formula I and II include the following: (a) R1 is -NH2, -NHNH2; (b) R1 is -NH2; (c) R2 is -0 (CH2) mR5 where R5 is -H, -C02H or -P (0) (R6R7), where R6 and R7 are -OH; (d) R2 is -OH; (e) R2 is -0 (CH2) mR5, where Rs is -H, -C02 (alkyl of 1 to 4 carbon atoms, phenyl or phenyl substituted with -C02H or -C02 (alkyl of 1 to 4 carbon atoms) (f) R2 is -0 (CH2) mR5, where R5 is -P (0) (R6R7) and R6 and R7 are -O (alkyl of 1 to 4 carbon atoms), or when one of R6 and R7 is -O (alkyl of 1 to 4 carbon atoms), the other is -OH; (g) R3 is -H, -O (alkyl of 1 to 4 carbon atoms) or - (CH2) nR8, where n = 2 and R8 is H or phenyl; (h) R3 is H? -O (at 1 to 4 carbon atoms); (i) R3 is - (CH2) nR8, where R8 is -NR9R10, -C (0) ) NH2 or -CN, where R9 and R10 are -alkyl of 1 to 4 carbon atoms; (j) R4 is phenyl; (k) R4 is phenyl substituted in position 2 and 6 of the phenyl ring with -alkyl from 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, halo or phenyl; (1) R 4 is phenyl substituted at the 2 or 6 position of the phenyl ring with -alkyl of 1 to 4 carbon atoms, -alkoxy of 1 to 4 carbon atoms, halo or phenyl; (m) R 4 is phenyl substituted at the 3 or 5 position of the phenyl ring with -alkyl of 1 to 4 carbon atoms, -alkoxy of 1 to 4 carbon atoms, halo or phenyl; (n) R 4 is -alkyl of 6 to 14 carbon atoms or -cycloalkyl of 6 to 14 carbon atoms; (o) Z is cyclohexenyl; (p) R5 is H, -C02H, -C02 (alkyl of 1 to 4 sarbone atoms), -P (0) (R6R7), -NHS02 -alkyl of 1 to 6 carbon atoms, -CONHS02-alkyl of 1 to 6 carbon atoms, tetrazolyl, phenyl or phenyl substituted with -C02H or -C02 (alkyl of 1 to 4 carbon atoms) wherein each of R6 and R7 is independently selected from -OH or -O (alkyl from 1 to 4 carbon atoms and m is 1-3; (q) R5, is H, -C02H, -C02 (alkyl of 1 to 4 carbon atoms), -P (O) (R6R7), phenyl or phenyl substituted with -C02H or -C02 (alkyl of 1 to 4 carbon atoms) where each of R6 and R7 is independently selected between -OH or -O (alkyl of 1 to 4 carbon atoms and m is 1-3; (r) Z is cyclohexenyl, phenyl, pyridyl, where the nitrogen is in the 1-, 2- or 3- position, or a 6-membered heterocyclic ring having one heteroatom selected from the group consisting of sulfur or oxygen in the 1-, 2- or 3- position, and nitrogen in the 1-, 2-, 3- or 4- position, where one carbon in the heterocyclic ring is optionally substituted with -C (0): (s) Z is cyclohexenyl or phenyl, or a pharmaceutically acceptable salt, racemate or optical isomer thereof, with the proviso that when R3 is H, R4 is phenyl, is 1 or 2 and R2 is substituted in the 6-position, R5 can not be H; (t) A is phenyl; (u) A is pyridium, where the nitrogen is in the 5-, 6-, 7- or 8-position - (v) R5 is H, -C02H, -C02 (alkyl of 1 to 4 carbon atoms), -P (0) (R6R7), where each of R6 and R7 are independently -OH or -O-alkyl from 1 to 4 carbon atoms; -S03H, -S03 (alkyl of 1 to 4 atom carbon atoms), tetrazolyl, -CN, NH2, -NHS02R15; -C0NHS02R15, where R15 is -alkyl of 1 to 6 atoms of carbon or -CF3, phenyl or phenyl substituted with -C02H 0 -. 0 -C02-alkyl of 1 to 4 carbon atoms where m is 1-3; and (w) R3 is H, -O-alkyl of 1 to 4 carbon atoms, haloalkyl 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, -CH2Osi-alkyl of 1 to 6 carbon atoms, furyl, thiophenyl, -hydroxyalkyl of 1 to 6 carbon atoms, -alkoxy of 1 to 6 carbon atoms carbon alkyl of 1 to 6 carbon atoms, -alkoxy of 1 to 6 carbon atoms-alkenyl 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, -CONH2, -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 atoms of carbon or p-phenylalkyl of 1 to 4 carbon atoms and n is 1 to 8. Other typical examples of compounds of formula I which are useful in the present invention include: 2- [4-oxo-5-carboxamido-9- (2-methylbenzyl) -9H-pyrido [3,4-Jb] indolyl] acetic acid; 2 - [4 - oxo - 5 - carboxydopido - 9 - (3 - methylbenzyl) - 9 H - pyrido acid [3, 4 - £ > ] indolyl] acetic; 2- [4-oxo-carboxamido-9- (4-methylbenzyl) -9H-pyrido [3,4-jb] indolyl] acetic acid; 2- [4-oxo-5-carboxamido-9- (4- tert -butylbenzyl) -9H-pyrido [3,4- £ > ] indolyl] acetic; 2- [4-oxo-5-carboxamido-9-pentafluorobenzyl-9J? -pyrido [3,4-Jb] indolyl] acetic acid; 2- [4-oxo-5-carboxamido-9- (2-fluorobenzyl) -9H-pyrido [3,4-jb] indolyl] acetic acid; 2- [4-oxo-5-carboxamido-9- (3-fluorobenzyl) -9H-pyrido [3,4-Jb] indolyl] acetic acid; 2- [4-oxo-5-carboxamido-9- (4-fluorobenzyl) -9H-pyrido [3,4-b] indolyl] acetic acid; 2- [4-oxo-5-carboxamido-9- (2,6-difluorobenzyl) -9H-pyrido [3,4-Jb] indolyl] acetic acid; 2- [4-oxo-5-carboxamido-9- (3, 4-difluorobenzyl) -9H-pyrido [3,4-b] indolyl] acetic acid; 2- [4-oxo-5-carboxamido-9- (2, 5-difluorobenzyl) -9H- acid pyrido [3,4-Jb] indolyl] acetic; 2- [4-oxo-5-carboxamido-9- (3, 5-difluorobenzyl) -9H-pyrido [3, 4-Jb] indolyl] acetic acid; 2- [4-oxo-5-carbsxamido-9- (2,4-difluorobenzyl) -9H-pyrido [3, 4-Jb] indolyl] acetic acid; 2- [4-oxo-5-carboxamido-9- (2, 3-difluorobenzyl) -9H-pyrido [3,4-b] indolyl] acetic acid; 2 - [4-oxo-5-carboxamido-9- [2- (trifluoromethyl) benzyl] -9i? -pyrido [3,4-Jb] indolyl] acetic acid; 2 - [4-oxo-5-carboxamido-9- [3- (trifluoromethyl) benzyl] -9-pyrido [3,4-Jb] indolyl] acetic acid; 2 - [4-oxo-5-carboxamido-9- [4- (trifluoromethyl) benzyl] -9H-pyrido [3,4-Jb] indolyl] acetic acid; 2- [4-oxo-5-carboxamido-9- [3,5-bis- (trifluoromethyl) benzyl] -9-pyrido [3,4- £ > ] indolyl] acetic; 2- [4-oxo-5-carboxamido-9- [2,4-bis- (trifluoromethyl) benzyl] -9-pyrido [3,4-i?] indolyl] acetic acid; 2- [4-oxo-5-carboxamido-9- (a-methylnaphyl) -9H-pyrido [3,4-b] indolyl] acetic acid; 2- [4-oxo-5-carboxamido-9- (b-methylnaphyl) -9H-pyrido [3,4-b] indolyl] acetic acid; 2- [4-oxo-5-carboxamido-9- (3, 5-dimethylbenzyl) -9H-pyrido [3,4-Jb] indolyl] acetic acid; 2- [4-oxo-5-carboxamido-9- (2,4-dimethylbenzyl) -9H-pyrido [3,4-Jb] indolyl] acetic acid; 2- [4-oxo-5-carboxamido-9- (2-f-enylbenzyl) -9H- acid pyrido [3, 4-Jb] indolyl] acetic acid; 2- [4-oxo-5-carboxamido-9- (3-f-enylbericyl) -9H-pyrido [3, 4-2 > ] indolyl] acetic; 2- [4-oxo-5-carboxamido-9- (4-f-enylbenzyl) -9H-pyrido [3,4-Jb] indolyl] acetic acid; 2- [4-oxo-5-carboxamido-9- (1-fluorenylmethyl) -9H-pyrido [3,4-b] indolyl] acetic acid; 2- [4-oxo-5-carboxamido-9- (2-fluoro-3-methylbenzyl) -9H-pyrido [3,4-Jb] indolyl] acetic acid; 2- [4-oxo-5-carboxyamido-9- (3-benzoylbenzyl) -9H-pyrido [3,4-Jb] indolyl] acetic acid; 2- [4-oxo-5-carboxamido-9- (2-f-enoxobenzyl) -9H-pyrido [3, 4-Jb] indolyl] acetic acid; 2- [4-oxo-5-carboxamido-9- (3-f-enoxobenzyl) -9H-pyrido [3,4-Jb] indolyl] acetic acid; 2- [4-oxo-5-carboxamido-9- (4-f-enoxobenzyl) -9H-pyrido [3,4-Jb] indolyl] acetic acid; 2- [4-oxo-5-carboxamido-9- [3- [2- (f luorofenoxi) -benzyl]] - 9H-pyrido [3,4-Jb] indolyl] acetic acid; 2 - [4 - oxo - 5 - carboxamido - 9 - [3 - [4 - (f luorofenoxi) benzyl]] - 9 H - pyrido [3,4 - b] indolyl] acetic acid - 2- [4 - oxo-5-carboxamido-9 - [2-fluoro-3- (trifluoromethyl) benzyl] -9H-pyrid [3,4-Jb] indolyl] acetic acid; 2- [4-Oxo-5-carboxamido-9 - [2-fluoro-4- (rif-loromethyl) -benzyl] -9-pyrido [3,4-b] indolyl] -acetic acid; 2- [4-oxo-5-carboxamido-9- [2-fluoro-5-] acid (trifluoromethyl) benzyl] -9-ff-pyrido [3,4-Jb] indolyl] acetic acid; 2- [4-oxo-5-carboxyamido-9 - [3-fluoro-5- (trifluoromethyl) benzyl] -9H-pyrido [3,4-Jb] indolyl] acetic acid; 2- [4-oxo-5-carboxyamido- [4-fluoro-2- (trifluoromethyl) benzyl] -9H-pyrido [3,4-Jb] indolyl] acetic acid; 2- [4-oxo-5-carboxyamido-9 - [4-fluoro-3- (trifluoromethyl) benzyl] -9H-pyrido [3,4-Jb] indolyl] acetic acid; 2- [4-oxo-5-carboxamido-9 - [2-fluoro-6- (trifluoromethyl) benzyl] -9H-pyrido [3,4-Jb] indolyl] acetic acid; 2 - [4 - oxo - 5 - carboxamido - 9 - (2, 3, 6 - trifluorobenzyl) - 9 H - pyrido [3,4 - Jb] indolyl] acetic acid; 2 - [4 - oxo - 5 - carboxamido - 9 - (2, 3, 5 - trifluorobenzyl) - 9 H - pyrido [3,4 - Jb] indolyl] acetic acid; 2 - [4-oxo-5-carboxamido-9- (2,4,5-trifluorobenzyl) -9H-pyrido [3,4-Jb] indolyl] acetic acid; 2 - [4-oxo-5-carboxamido-9- (2,4,6-trifluorobenzyl) -9H-pyrido [3, 4-Jb] indolyl] acetic acid; 2 - [4 - oxo - 5 - carboxamido - 9 - (2, 3, 4 - trifluorobenzyl) - 9 H - pyrido [3,4 - Jb] indolyl] acetic acid; 2 - [4-oxo-5-carboxamido-9- (3,4,5-trifluorobenzyl) -9H-pyrido [3,4-Jb] indolyl] acetic acid; 2- [4-oxo-5-carboxamido-9- [3- (trifluoromethoxy) encyl] -9H-pyrido [3,4-Jb] indolyl] acetic acid; 2- [4-oxo-5-carboxamido-9- [4- (trifluoromethoxy) benzyl] -9H-pyrido [3,4- £ > ] indolyl] acetic; 2 - [4 - oxo - 5 - carboxamido - 9 - [4 -] acid methoxy (tetraf luoro) benzyl] -9H-pyrido [3,4-Jb] indolyl] acetic acid; 2- [4-oxo-5-carboxamido-9- (2-methoxybenzyl) -9H-pyrido [3,4-Jb] indolyl] acetic acid; 2- [4-oxo-5-carboxamido-9- (3-methoxybenzyl) -9H-pyrido [3,4-Jb] indolyl] acetic acid; 2 - [4-oxo-5-carboxamido-9- (4-methoxybenzyl) -9H-pyrido [3,4-Jb] indolyl] acetic acid; 2 - [4 -oxo-5-carboxamido-9 - (4-ethylbenzyl) -9H-pyrido [3,4-Jb] indolyl] acetic acid; 2- [4-oxo-5-carboxamido-9- (4-isopropylbenzyl) -9H-pyrido [3,4-Jb] indolyl] acetic acid; 2 - [4-oxo-5-carboxamido-9- (3,4,5-trimethoxybenzyl) -9H-pyrido [3,4-b] indolyl] acetic acid; 2- [4-oxo-5-carboxamido-9- (3,4-methylenedioxybenzyl) -9H-pyrido [3,4-Jb] indolyl] acetic acid; 2- [4-oxo-5-carboxamido-9- (4-methoxy-3-methylbenzyl) -9H-pyrido [3,4-Jb] indolyl] acetic acid; 2- [4-oxo-5-carboxamido-9- (3, 5-dimethoxybenzyl) -9H-pyrido [3,4-Jb] indolyl] acetic acid; 2- [4-oxo-5-carboxamido-9- (2,5-dimethoxybenzyl) -9H-pyrido [3,4-b] indolyl] acetic acid; 2- [4-oxo-5-carboxatnido-9- (4-ethoxy-4-cyclic) -9H-pyrido [3,4-b] indolyl] acetic acid; 2- [4-oxo-5-carboxamido-9- (cyclohexylmethyl) -9H-pyrido [3,4-Jb] indolyl] acetic acid; 2- [4-oxo-5-carboxamido-9- (cyclopentylmethyl) -9H- acid pyrido [3, 4-Jb] indolyl] acetic; 2- [4-oxo-5-carboxamido-9-ethyl-9ií-pyrido [3,4-Jb] indolyl] acetic acid; 2- [4-oxo-5-carboxamido-9- (1-propyl) -9H-pyrido [3,4-Jb] indolyl] acetic acid; 2- [4-oxo-5-carboxamido-9- (2-propyl) -9H-pyrido [3, 4-Jb] indolyl] acetic acid; 2- [4-oxo-5-carboxamido-9- (1-butyl) -9tf-pyrido [3,4-b] indolyl] acetic acid; 2- [4-oxo-5-carboxamido-9- (2-butyl) -9H-pyrido [3,4-Jb] indolyl] acetic acid; 2- [4-oxo-5-carboxamido-9-isobutyl-9H-pyrido [3,4-i > ] indolyl] acetic; 2- [4-oxo-5-carboxamido-9- [2- (1-phenylethyl)] -9H-pyrido [3, 4-Jb] indolyl] acetic acid; 2- [4-oxo-5-carboxamido-9- [3- (1-phenylpropyl)] -9H-pyrido [3,4-Jb] indolyl] acetic acid; 2- [4-oxo-5-carboxamido-9- [3- (1-phenylbutyl)] -9H-pyrido [3,4-b] indolyl] acetic acid; 2- [4-oxo-5-carboxamido-9- (1-pentyl) -9J-pyrido [3,4-Jb] indolyl] acetic acid; 2- [4-oxo-5-carboxamido-9- (1-hexyl) -9H-pyrido [3,4-] indolyl] acetic acid; or a pharmaceutically acceptable racemate, solvate, tautomer, optical isomer, derivatized prodrug derivative or salt thereof.

The compounds of formula I in which ring A is phenyl and the heteroatom in Z is sulfur, oxygen or nitrogen, can be prepared as described in Schemes I (a) - (f), shown below: Scheme Ka) PG is a protective group of acids. X is halo. 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; -CH2Osi-alkyl of 1 to 6 carbon atoms, furyl, thiophenyl, -hydroxyalkyl of 1 to 6 carbon atoms; or (CH2) nR8 where R8 is H, -NR9R10, -CN or phenyl, where R9 and Rxo are independently -alkyl of 1 to 4 carbon atoms or -phenyl-alkyl of 1 to 4 carbon atoms and n is 1 to 8; An indole-3-acetic ester (191), Ref.10, is alkyl by treatment with alkali metal amide and bcycyloxymethyl chloride to give (102), which is converted to the alcohol (103) by catalytic hydrogenation. The alcohol was alkyl to produce the formaldehyde acetal (104), which is cyclized by a Lewis acid to produce the pyran [3,4-b] indole (105). The ester is converted to the amide (106) by methylchloroaluminum amide and then in the phenol (107) with boron tribromide. The phenol is 0 -alkylated to give (108), which is hydrolysed to the acid (109).

) Dillard, R., Et al., J. Med. Chem. Vol. 39, No. 26, 5119-5136.

Scheme I fb) PG is an acid protecting group W is halo, alkyl or aryl sulfonyl 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; -CH2Osi-alkyl of 1 to 6 carbon atoms, furyl, thiophenyl, -hydroxyalkyl of 1 to 6 carbon atoms; or (CH2) nR8 where R8 is H, -NR9R10, -CN or phenyl, where R9 and R10 are independently -alkyl of 1 to 4 carbon atoms or -phenyl-alkyl of 1 to 4 carbon atoms and n is 1 to 8; The reaction of this alcohol (103) with aldehyde and acid produces the pyranoindol (110). The conversion of the hydroxyl function of (103) to a halide or sulfate functionality is achieved by treatment with triphenylphosphine and CH3X (where X is a halogen) to obtain compounds of formula (111) wherein X is a halide; or by treatment with • triethylamine and methanesulfonyl chloride to obtain the sulfonate. The displacement with the sodium salt of the thiol acetic acid gives (114), which in turn is hydrolyzed by a base to the thiol (115) which is reacted with an appropriately substituted aldehyde and an acid to produce the thiopyranoindoles (116). The intermediate (111) can also be reacted with sodium azide to give the azide derivative (112), which it is reduced by hydrogen catalytically to give the amine, which is converted to the carboline (113) with aldehyde and acid. Intermediates (113), (110) and (116) can be N-alkylated using sodium hydride and an appropriately substituted XCHR4 alkyl halide.

Scheme I (c) (131) The 4-methoxyindole (117) is converted to the indole acetic acid derivative (118) by alkylation with an epoxy propionate. The treatment of (118) with. a brominating reagent produces the mixture of bromine (119) and (120) isomers which give the spiro compound (121) after basic treatment. Heating (121) with benzyl bromide provides a mixture of the isomeric bromine compounds (122) and (123) which are reacted with potassium thioacetate to give a mixture of isomers from which it can be separated (124). The thioester solvolysis produces the thiol (125) which is alkyl to give (126). The Lewis acids convert (126 to the thiopyran [3,4-b] indole (127) .The ester function is converted to amide using methylchloroaluminum amide, the methyl ether is cleaved by boron tribromide and the phenolic product is O- alkylate with bromoacetic ester to give (130), which is hydrolyzed to (131).

Scheme I (d) X is halo R3 (a) is as defined in Scheme T (a) above; and R is - (CH2) mR5, Protection of the Oxygen by treatment of (132) with tert-butyldimethylsilyl chloride and imidazole in a polar aprotic solvent such as tetrahydrofuran or methylene chloride, yields (133). The alkylation in position 3 of the indole (133) is carried out by treatment with n-butyllithium and then with zinc chloride at temperatures starting at about 10 ° C, and warming to room temperature followed by reaction with a haloalkyl. suitable ester such as methyl or ethyl bromoacetate. The reaction is preferably carried out at room temperature in a polar aprotic solvent such as tetrahydrofuran. The alkylation of the indole-nitrocene can then be carried out by reaction of (134) with a suitable alkyl halide in the presence of potassium bis (trimethylsilyl) amide to prepare (135).

I The ester functionality of (135) is converted to a trimethylsilyl ketene acetal (136) by treatment with potassium bis (trimethylsilyl) amide and trimethylsilyl chloride. The treatment of ketene acetal (136) with bis (chloromethyl) sulfide and zinc bromide in methylene chloride yields the cyclized product (137). The conversion to amide (138) can be carried out by a reaction of einreb with methylchloroaluminum amide. Removal of the oxygen protecting group with a fluorine source, such as tetrabutylammonium fluoride (TBAF), and the combined reaction of the resulting anion with, for example, ethyl bromoacetate, yields the ester (139). Deprotection of the ester produces the desired acid (140).

Scheme I (e) R (a) is as described for Scheme T (a) and R is as described in Scheme III (b). The treatment of ketene acetal (136) with bis (chloromethyl) ether and zinc bromide in methylene chloride yields the cyclized product (141). The conversion to the amide (142) can be carried out by Weinreb reaction with methylchloroaluminum amide. Removal of the oxygen protecting group with a fluoride source, such as tetrabutylammonium fluoride, and the concomitant reaction of the resulting anion with ethyl bromoacetate, yield ester (143). Deprotection of the ester produces the desired acid (144).

Scheme I (f) (236) twenty (241) (242) N-alkylation of the 4-methoxy indole (231) commercially available under basic conditions using an alkyl halide produces the N-alkyl indole (232). Acylation with a suitable acid chloride produces the product glyoxalate ester (233), which can be reduced with a variety of hydride reducing agents to give the intermediate alcohols (234). The conversion of the alcohol to a suitable leaving group and the displacement with nucleophiles of sulfur produces the thioether product (235). The conversion of acid chloride and spontaneous cyclization produces the thioketone product (236). Ester cleavage can be carried out under basic conditions to give the corresponding acid which, upon formation of the acid chloride and reaction with an appropriate amine, yields the amide product (237). Excision of the methyl ether yields the phenol (238) which can be alkylated under basic conditions using alkyl halides to give the O-alkylated product (239). Cleavage of the ester under basic conditions gives the desired product (240). Alternatively, the reduction of the benzylic ketone with a hydride reducing agent and the subsequent deoxygenation of the resulting alcohol gives the deoxygenated product '(244). The cleavage of the oxyacetic ester is carried out under basic conditions to give the desired oxyacetic acid (242).

Compounds wherein Z is an aromatic or heterocyclic ring containing nitrocene, can be prepared as described in Schemes II (a) - (e), shown below.

Scheme II (a) (145) (146) The Substituted haloaniline (145) is condensed with N-benzyl-3-piperidone to provide enamine (146). The closure of the ring is carried out by treating (146) with palladium (II) acetate and the resulting product is converted to (147) by treatment with cyanogen bromide. The alkylation of (147) is carried out by treatment with the appropriate alkyl bromide using sodium hydride as a base. Hydrolysis of this N-alkylated product with basic hydroquinone peroxide under conventional conditions, produces (148). The demethylation of (148) is carried out by treatment with boron tribromide in methylene chloride. The resulting phenol (149) is transformed by the conventional sequence of O-alkylation with methyl bromoacetate in the presence of a base, hydrolysis with hydroxide to provide the intermediate salt, which is then deprotonated in aqueous acid to produce the desired d-carboline (150).

Scheme II (b) twenty X is halo, R is as defined in Scheme I (d), and R3 (a) is as defined in Scheme I (a). The ketene acetal (136), prepared as described in Scheme I (d), is reacted with benzyl bis (methoxymethyl) amine in the presence of zinc chloride to give the tetrahydro-beta-carbonyl (151) . Treatment of (151) with lithium hydroxide, neutralization with hydrochloric acid and subsequent treatment with 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and ammonia, provides the desilylated amide (152) in which R20 is hydrogen , which can be alkylated with, for example, ethyl bromoacetate, to give the ester (153). Alternatively, treatment of (115) with the appropriate Weinreb reagent provides the amide (152) (R20 is t-butyldimethylsilyl), which is desilylated with tetra-n-butylammonium fluoride and alkylated with, for example, ethyl bromoacetate , to give the ester (153). The hydrolysis mediated by lithium hydroxide gives the acid (154), which can be hydrogenated over an appropriate catalyst in the presence of hydrochloric acid to give the tetrahydro-beta-carboline in the form of the hydrochloride salt (155; The compound (155), in turn, can be aromatized by refluxing in carbitol with palladium on carbon to provide beta-carboline (156).

Scheme II (c) (164) X is halo, R is as defined in Scheme I (d); Y R3 < a) is co or has been defined in Scheme T (a). In a single vessel reaction, indole (133) is treated successively with an equivalent of n-butyllithium, gaseous carbon dioxide, an equivalent of t-butyl-lithium and l-dimethylamino-2-nitroethene to give (157) . Nitroalkene (157) is reduced with lithium aluminum hydride to amine (158), which is cyclized with methyl glyoxylate (Ref. 9) in refluxing ethanol to give tetrahydrocarboline (159). The alkylation of the two nitrogens of (159) leads to intermediate (160), which is treated with the appropriate Weinreb reagent to provide the amide (161). Fluoride-assisted desilylation and alkylation with, for example, ethyl iodoacetate, provides the ester (162), which can be hydrogenated over a suitable catalyst and hydrolyzed with base to give the acid (163). The aromatization of (163) to carbonyl (164) is carried out by reflux in carbitol in the presence of palladium on carbon. Reference 9: Kelley, T. R .; Schmidt, T. E .; Haggerty, J. G. A Convenient preparation of methyl and ethyl glyoxylate, Synthesis, 1972,544-545.

Scheme II (d) The commercially available acid (170) is reduced with lithium aluminum hydride, oxidized with pyridinium chlorochromate and silylated with t-butyldimethylsilyl chloride to give (171). The treatment with sodium azide gives the azide (172), which is reacted with nitromethane and potassium hydroxide in ethanol, followed by treatment with acetic anhydride and pyridine to give the nitroolefin (173). Heating in xylene induces cyclization to produce indole (174). Alkylation with, for example, benzyl iodide and sodium hydride, provides (175), which is hydrogenated in the presence of palladium on carbon to give the amine (176). The acylation with the acid chloride of the commercially available monoacetic ester of oxalacetic acid gives (177), which is thermally cycled to the lactam (178). The selective reduction of the carbonyl lactam can be carried out by treatment with NaBH2S3 to provide the amine (179).

The protection of the amine (179) with di-t-butyl dicarbonate and pyridine produces (180), which is converted by means of the appropriate Weinreb reagent into the amide (181).

Fluoride-assisted desilylation, alkylation with, for example, ethyl iodoacetate and potassium carbonate, basic hydrolysis and acid hydrolysis yields tetrahydro-alpha-carboline (182).

Alternatively, the amine (179) can be flavored by refluxing in carbitol or some other suitable high boiling solvent to give the alpha-carboline (183), which is converted by the appropriate Weinreb reagent into the amide (184). ). Fluoride-assisted disililaicon, alkylation with ethyl iodoacetate and potassium carbonate and basic hydrolysis as described above, provides alpha-carboline (185).

Scheme II (e) (193) (192) (197) X is halo R3 (a, is as defined above) Scheme II (e) provides the d-carboline (198) by the sequence of reactions indicated N-alkylation of 2-carboethoxyindole (1890), followed by a conventional sequence of two carbon homologation, provides the 2- (3-propenoic acid) Índoles (194) In this sequence, the condensation of the aldehyde (193) with malonic acid used a mixture of pyridine and piperidine as a base. formation of methyl ester and hydrogenation (195), ring closure (196) was carried out by treatment with bis (2,2,2-trichloroethyl) azodicarboxylate (BTCEAD) followed by zinc in acetic acid The reduction of the cyclic amide with lithium aluminum hydride followed by treatment with trimethylsilylisocyanate provided the urea (197) Conversion to the desired d-carboline (198) was carried out under the usual demethylation conditions and the subsequent alkylation and hydrolysis steps of The inverse characters, that is, the compounds in which B is carbon and D is nitrogen, can be prepared as described in Scheme III, shown below.

Scheme III The aryl hydrazines (200) are condensed with substituted propionaldehydes to form hydrazones which are cyclized to indoles (201) by treatment with phosphorus trichloride at room temperature (Ref. 1). The Índoles are N-alkylated in the reaction with a base, such as sodium hydride, and an alpha-bromo ester to give indoles (202) which are cyclized to tetrahydrocarbazoles (203) by Lewis acids (eg, aluminum chloride) or by radical initiators (eg, tributyltin hydride). The compounds (203) can be converted to carbazoles by, for example, heating to reflux in a solvent such as carbitol in the presence of pd / C. The compounds of formula I in which A is pyridyl can be prepared as described in Schemes IV (a) - (b), shown below.

Scheme IV (a) X is halo and R is (CH2) mR5 The commercially available 4-chloroindole (210) is treated with 3 equivalents of t-butyl lithium, followed by carbon dioxide, 1 equivalent of n-butyl lithium, 1-dimethylamino-2-nitroethene and acid, to provide carboxylic acid (211), which can be esterified to give (212). Alkylation at position 1 followed by hydrogenation yields aminoethyl indole (214). Cyclization with phosgene a (215) followed by aromatization gives the carboline (216). Treatment of (216) with the appropriate Weinreb reagent provides the amide (217), which can be alkylated with, for example, ethyl bromoacetate and saponified with sodium hydroxide to give the carboline (218).

Essuema IV (b) R3 (a) is co or defined in Scheme T (a), X is halo, and R is (CH2) mR5. The 1,3-dione structures (228) are commercially available or easily prepared by known techniques from starting materials acquirable in the market. The preparation of the aniline derivatives (220) (X = Cl, Br or I) is carried out by reduction of an appropriately substituted benzoic acid derivative to give the aniline correpsondant by treatment with a reducing agent such as SnCl2 in hydrochloric acid, in an inert solvent such as ethanol, or by hydrogenation using gaseous hydrogen and sulphurated platinum or carbon or palladium on carbon. The amino group of (228) is protected with an appropriate protecting group, such as the protecting group carboethoxy, benzyl, CBZ (benzyloxycarbonyl) or BOC (tert-butoxycarbonyl) and the like. The dione (228) and the aniline derivative (220) are condensed according to the general procedure of Chen, et al., (Ref.10) or Yang, et al., (Ref. 11) with or without a solvent non-interfering such as methanol, toluene or methylene chloride, with or without an acid, such as p-toluenesulfonic acid or trifluoroacetic acid, with or without N-chlorosuccinimide and dimethyl sulfide, to produce the coupled product (221). The compound (221) is cyclized under basic conditions with a copper (I) salt in an inert solvent according to with the general procedure of Yang, et al., (Ref. 8). The derivative (221) is treated with a base, such as sodium hydride, in an inert solvent, such as HMPA, at a temperature comprised between 0 and 25 ° C. A copper (I) salt, such as copper iodide (I), is added, and the resulting mixture is stirred at a temperature between 25 and 150 ° C for 1 to 48 hours, to produce the compound (222). The compound (221) can also be cyclized according to the general procedure of Chen, et al., (Ref. 10). The derivative (221) is treated with a base, such as sodium bicarbonate and a palladium catalyst, such as Pd (PPh3) 4, in an inert solvent, such as HMPA, at a temperature comprised between 25 and 150 ° C, for produce the compound (222). In a preferred process, intermediate (171) is treated with a transition metal catalyst, such as Pd (Oac) 2 (O-tol) 3P, in the presence of a base such as triethylamine, using a DMF / acetonitrile cosolvent to prepare (222). The compound (222) is N-alkylated with an appropriately substituted benzyl halide in the presence of a base, such as sodium hydride or potassium carbonate, in a non-interfering solvent, such as dimethylformamide or dimethyl sulfoxide, for; produce the ketone (223). In a two-stage process in a single vessel, (222) is aromatized by treatment with acetic acid and palladium on carbon in a non-interfering solvent, such as carbitol or cymene, followed by treatment with gaseous hydrogen and palladium on carbon to cleave the nitrogen-protecting group and produce the phenolic derivative (224). The ester (224) is converted to the corresponding amide (225) under conventional conditions with ammonia (preferably) or an ammonium salt, such as ammonium acetate, in an inert solvent, such as water or alcohol, preferably methane, or MeClAlNH2 in an inert solvent, such as toluene, at a temperature between 0 and 110 ° C. The alkylation of phenolic oxygen of compound 38 with an appropriate haloester, such as methyl bromoacetate, in the presence of a base, such as methyl bromoacetate, in the presence of a base, such as cesium carbonate, potassium carbonate or sodium, in a Inert solvent, such as dimethylformamide or dimethyl sulfoxide, produces the ester-amide (226). Other haloesters, such as ethyl bromoacetate, propyl bromoacetate, butyl bromoacetate, and the like, can also be used to prepare the corresponding esters.

Saponification of the compound (226), with lithium hydroxide in an inert solvent, such as methanol-water, yields (227). The intermediate and final products can be isolated and purified by conventional techniques such as chromatography or recrystallization. Regioisomeric and intermediate products can be separated by standard procedures, such as recrystallization or chromatography.

References: ) L.-C. Chen et al., Synthesis 385 (1995) 11) S.-C. Yang et al., Heterocycles, 32, 2399 (1991).

The following examples further illustrate the preparation of the compounds of this invention. The examples are illustrative only and should not be considered as limiting the scope of the invention in any way.

Example 1 Preparation of (-R, S) - (9-benzyl-4-carbamoyl-1-oxo-3-thia-1,2,3,4-tetrahydrocarbazol-5-yl) oxyacetic acid A. l-benzyl-4-methoxyindole NaH (7.7 g, 191.7 mmol) was added portionwise to a 0 ° C solution of 4-methoxyindole (21.7 g, 147 mmol) in 750 mL of anhydrous DMF. After 15 minutes, the suspension was treated with benzyl bromide (17.5 ml, 147 mmol). The reaction mixture was allowed to warm up the room temperature and stirred overnight. The reaction mixture was poured into 1 L of H20. The layers were separated and the aqueous phase was extracted with EtOAc (2 x 200 ml). The combined organic layers were washed with H20 (4 x 500 ml), dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by flash chromatography (Si02, hexanes) to give 32.9 g (138.6 mmol, 94%) of the title compound as a white solid. Electroneubilization MS 238 (M + 1); Elemental Analysis for CieHisNO: Calculated: C, 80.98; H, 6.37; N, 5.90. Found: C, 81.20; H, 6.09; N, 5.83. B. (methyl l-Benzyl-4-methoxyindol-3-yl) oxoacetate A solution at 0 ° C of l-benzyl-4-methoindole (31.9 q, 134.4 mmol) in 500 ml of CH2C12 and pyridine (21.7 ml, 268.8 mmol) was treated with methyl oxalyl chloride (13.6 ml, 147.9 mmol). After 1.5 hours a. 0 ° C, 500 ml of a saturated solution of NaHCO 3 was added. The aqueous layer was extracted with CHC13 (1 x 200ml, 2 x 50 ml). The combined organic layers were concentrated in vacuo to give a tan solid, which was triturated with EtOAc / hexanes to give 29.8 g (92.1 mmol, 69%) of the title compound as an off-white solid. Electronebulization MS 324 (M + l); Elemental Analysis for C? 9H? 7N04: Calculated: C, 70.58; H, 5.30; N, 4.33. Found: C, 70.86; H, 5.42; N, 4.49. C. (R, S) - methyl (l-Benzyl-4-methoxyindol-3-yl) hydroxyacetate A solution of methyl (l-benzyl-4-methoxyindol-3-yl) oxoacetate (10 g, 30.9 mmol) in 300 mL of MeOh was treated with NaBH 4 (1.46 g, 38.6 mmol). After stirring overnight, EtOAc and H2O (20 ml each) were added. The aqueous layer was extracted with EtOAc (2 x 25 ml). The combined organic layers were dried over Na 2 SO 4, filtered and concentrated in vacuo. The crude residue was recrystallized with EtOAc / hexanes to give 9.1 g (28.0 mmol, 91%) of the title compound as a white powder. FDMS 325 (M +); Elemental Analysis for C19H19NO4: Calculated: C, 70.14; H, 5.89; N, 4.30. Found: C, 70.42; H, 5.93; N, 4.41. D. Acid (i?, S) - [l-benzyl-4-methoxyindol-3-yl] (carbomethoxy) methyl] thioacetic A 0 ° C suspension of methyl (R, S) - (1-benzyl-4-methoxyindol-3-yl) hydroxyacetate (3.5 g, 10.8 mmol) and K2C03 (2.2 g, 16%). 1 mmol) in 50 ml of CHC12 was treated with TEA (0.075 ml, 0.54 mmol). After 15 minutes, MsCl (1.25 ml, 16.1 mmol) was added. After stirring for 2 h at 0 ° C, mercaptoacetic acid (3 mL, 43 mmol) was added and the reaction was heated to reflux overnight. The reaction mixture was poured into 25 ml of a saturated solution of NaHCO 3. The aqueous layer was extracted with 25 ml of CHC13, acidified with 1 N HCl and extracted again with CHC13 (3 x 25 ml). The acidified extracts were combined, dried over Na 2 SO 4, filtered and concentrated in vacuo. The oily residue was purified by ultrafast chromatography (Si02, glacial acetic acid gradient from 0% to 2% in 1: 1 EtOAc / hexanes) to give 2.58 g (6.46 mmol, 60%) of the title compound in the form of a transparent oil that solidified after resting. FDMS 399 (M +); Elemental Analysis for C2? H21NO5S * 0.2 H20 - Calculated: C, 62.58; H, 5.35; N, 3.48. Found: C, 62.57; H, 5.26; N, 3.55. E. (R, S) - [9-benzyl-5-methoxy-l-oxo-3-thia-l, 2,3,3-tetrahydrocarbazol-5-yl) carboxylic acid methyl ester A solution of the carboxylic acid from Part D above (2.32 g, 5.81 mmol) in 50 ml of 1,2-dichloroethane was treated with oxalyl chloride (2.0 ml, 22.9 mmol) and 1 drop of DMF. The resulting mixture was allowed to sit at room temperature for 3 hours and then concentrated in vacuo. The crude residue was purified by ultrafast chromatography (SiO2, 0% to 5% EtOAc gradient and 10% / hexanes) to give 1.39 g (3.64 mmol, 63%) of the title compound as a light yellow powder. FDMS 381 (M +); Elemental Analysis for C2? H? 9N0S: Calculated: C, 66.12; H, 5.02; N, 3.67. Found: C, 66.00; H, 5.26; N, 3.63. F. (R, S) - [9-benzyl-5-methoxy-1-oxo-3-thia-l, 2, 3, 4-tetrahydrocarbazol-5-yl) carboxamide methyl A solution of methyl (R, S) - (9-benzyl-54-methoxy-l-oxo-3-thia-1,2,3,4-tetrahydrocarbazol-5-yl) carboxylate (1.1 g, , 88 mmol) in 25 ml of THF / MeOH / H20 (3: 1: 1) was treated with LiOH (83 mg, 3.46 mmol) and allowed to stir at room temperature overnight. The aqueous layer was extracted with 25 ml of CH2C12, acidified with 1 N HCl and extracted again with CH2C12 (2 x 25 ml). The acidified extracts were combined, dried over Na 2 SO 4, filtered and concentrated in vacuo. The crude intermediate acid was dissolved in 20 ml of 1,2-dichloroethane and treated with (COCl) 2 (0.77 ml, 8.82 mmol). After 4 hours, the reaction mixture was concentrated in vacuo and resuspended in 20 ml of 1,2-dichloroethane. Ammonia was bubbled through the solution for about 10 min., Then the reaction mixture was capped and allowed to stand for 1.5 hours. The crude amide was concentrated in vacuo and recrystallized from EtOAc / hexanes) to give 780 mg (2.13 mmol, 74%) of the title compound as a light tan solid. FDMS 366 (M +); Elemental Analysis for C20Hi8 204S O, 2H2? Calculated: C, 64, 92; H, 5, 01; N, 7, 57. Found: C, 64.95; H, 5.04; N, 7.78. G. (R, S) - [9-benzyl-5-hydroxy-l-oxo-3-thia-1,2,3-tetrahydrocarbazol-5-yl) carboxamide A 0 ° C solution of methyl (R, S) - (9-benzyl-5-methoxy-l-oxo-3-thia-1,2,3,4-tetrahydrocarbazol-5-yl) carboxamide in 10 ml of 1,2-dichloroethane, was treated with BBr3 (2.4 ml, 24.9 mmol). After 3 hours, the reaction mixture was quenched with cold MeOH and poured into 20 ml of a saturated solution of NaHCO 3. The aqueous layer was extracted with CHC13 (4 x 50 ml). The combined organic layers were dried over Na 2 SO, filtered and concentrated in vacuo. Purification of the crude residue by radial chromatography (Si02; MeOH gradient of the 0% to 2% MeOH / CHCl 3) to give 162 mg (0.46 mmol, 28%) of the title compound as a brown foam. FDMS 352 (M +); Elemental Analysis for Ci9H? 6N2O3 * 0, 8 H20 Calculated: C, 62.21; H, 4.84; N, 7.64. Found: C, 62.57; H, 4.50; N, 7.27. H. (R, S) - [9-benzyl-4-carbamoyl-l-oxo-3-thia-l, 2, 3, 4-tetrahydrocarbazol-5-yl) oxyacetate ethyl A suspension of (R, S) - (9-benzyl-5-hydroxy-l-oxo-3-thia-1,2,3,4-tetrahydrocarbazol-5-yl) carboxamide (145 mg, 0.411 mmol) and Cs2C03 (400 mg, 1.23 mmol) in 5 ml of DMF was treated with ethyl bromoacetate (0.046 ml, 0.411 mmol). After stirring overnight, the reaction mixture was poured into 20 ml of H20. The aqueous layer was extracted with EtOAc (4 x 50 ml). The combined organic layers were washed with H20 (3 x 100 ml), dried over Na2SO4, filtered and concentrated in vacuo. Purification of the crude product by radial chromatography (Si02; 0% to 0.5% MeOH / CHCl 3 gradient) yielded 120 mg (0.274 mmol, 67%) of the title compound as a light brown foam. FDMS 438 (M +); Elemental Analysis for C23H22N2? 5SO, 3H2O-0.4C13: Calculated: C, 57.16; H, 4.72; N, 5.70. Found: C, 57.18; H, 4.61; N, 5.68. I. Acid (R, S) - [9-benzyl-4-carbamoyl-l-oxo-3-thia-l, 2,3,4-tetrahydrocarbazol-5-yl) oxyacetic acid A solution of (R, S) - (Ethyl 9-benzyl-4-carbamoyl-l-oxo-3-thia-1,2,3,4-tetrahydrocarbazol-5-yl) oxyacetate (20 mg, 0.0456 mmol) in 0.5 mL of THF / MeOH / H20 (3: 1: 1) was treated with LiOH (1.3 mq, • 0.0547 mmol). The solution rapidly turned a light orange color and, after 45 minutes the aqueous layer was extracted with 10 ml of CHCI3, acidified with 1 N HCl and extracted again with CHCl3 (3 x 20 ml). The acidified extracts were combined, dried over Na 2 SO 4, filtered and concentrated in vacuo to yield an orange solid. The crude acid was purified on a pipette column (Si02, 0% to 2% MeOH / CHCl3 gradient, traces of glacial acetic acid) to yield 10 mg (0.0244 mmol, 53%) of the title in the form of a light brown solid. FABHRMS: m / e for C21H19N2O5S: '411.1015. Found: 411.1010 (M + 1). Example 2 Preparation of (R, S) - (9-benzyl-4-carbamoyl-l-oxo-3-thia-1,2,3,4-tetrahydrocarbazol-5-yl) oxyacetic acid A. (JR, S) - ethyl (9-benzyl-4-carbamoyl-3-thia-l, 2,3,4-tetrahydro-carbazol-5-yl) oxyacetate A suspension of ethyl (R, S) - (9-benzyl-4-carbamoyl-l-oxo-3-thia-1,2,3,4-tetrahydrocarbazol-5-yl) oxyacetate (75 mg, 0.171 mmol) in 1 ml of MeOH and 1.5 ml of THF (for solubility) was treated with NaBH 4 (8 mg, 0.214 mmol). After 20 minutes, the reaction mixture was quenched with 10 ml of H20. The layers were separated and the aqueous layer was extracted with EtOAc (3 x 20 ml). The combined organic layers were dried over K2CO3, filtered and concentrated in vacuo. The crude intermediate alcohol was immediately dissolved in 2 ml of 1,2-dichloroethane. The resulting solution was treated with EtsSiH (0.19 mL, 1.2 mmol). After cooling to 0 ° C, TFA (0.13 ml, 1.7 mmol) was added dropwise. After 1 hour, the reaction mixture was poured into 25 ml of saturated aqueous NaHCO3. The layers were separated and the aqueous layer was extracted with EtOAc (3 x 25 ml). The combined organic layers were dried over Na 2 SO 4, filtered and concentrated in vacuo. Purification of the crude residue by ultrafast chromatography (Si02; MeOH gradient from 0% to 0.5% / CHCl 3) afforded 38 mg (0.895 mmol, 52%) of the title compound as an off-white solid. FDMS424 (M +); Elemental Analysis for C23H24N2O4S-0.3H2O '0.6 CHC13: Calculated: C, 56.51; H, 5.06; N, 5.59.

Found: C, 56.61; H, 4.87; N, 5.60. B. Acid (-R, S) - [9-benzyl-4-carbamoyl-l-oxo-3-thia-l, 2,3,4-tetrahydrocarbazol-5-yl) oxyacetic acid A solution of (R, S) Ethyl (9-benzyl-4-carbamoyl-3-thia-l, 2,3,4-tetrahydrocarbazol-5-yl) oxyacetate (28 mg, 0.066 mmol) in 0.5 ml of THF / MeOH / H20 ( 3: 1: 1) was treated with LiOH (1.9 mg, 0.079 mmol). After 1 hour, the aqueous layer was extracted with 10 ml of CHC13, acidified with 1 N HCl and extracted again with CHC13 (3 x 20 ml). The combined organic extracts were dried over Na 2 SO 4, filtered and concentrated in vacuo. The crude acid was purified on a pipette column (Si02, 0% to 1% MeOH / CHC13 gradient, traces of glacial acetic acid) to yield 18 mg (0.045 mmol, 69%) of the title compound as a whitish solid. FABHRMS: m / e, calculated for C21H2? N204S: 397.1222. Found: 397.1216 (m + 1). Example 3 2- (4-Oxo-5-carboxamido-9-benzyl-9-pyrido [3, 4- £>] indolyl) acetic acid hydrochloride A. Preparation of N- [5- (l-benzyl-3-oxo-l, 2,3,6-tetrahydropyridinyl)] -2-bromo-3-carbomethoxyaniline To a mixture of 2-bromo-3-carbomethoxyaniline (12 , 0 g, 52.2 mmol) and pyridinium p-toluenesulfonate (13.8 g, 54.9 mmol) in toluene / dioxane 2: 1 (300 mL), l-benzyl-3, 5-piperidinedione was added (13.0 g, 70.2 mmol, Chen, L.-C; Yang, S.-C. Heterocycles 1990, 31, 911-916). The apparatus was equipped with a Dean-Star e-trap and the mixture was heated to reflux for 10 h. The mixture was concentrated in vacuo and the residue was dissolved in chloroform. This solution was washed three times with water, once with saturated sodium chloride solution, dried (sodium sulfate), filtered and concentrated in vacuo to yield a dark oil. Chromatography (silica gel, chloroform to 4% methanol / 96% chloroform) yielded 2.0 g (9%) of the title product as a foam that could crystallize from acetonitrile: m.p. 156-158 ° C. * H NMR (CDC13) d 7.55 (m, 2H), 7.40 (, 6H), 5.55 (s, 1H), 3.94 (s, 3H), 3.85 (m, 2H) , 3.56 (m, 2H), 3.30 (br s, 2H). MS ES + m / e 414.9 (p), 416.9 (p); IR (KBr, cm "1) 3185, 2944, 1728, 1603, 1544, 1306. Elemental Analysis for C20H? 9BrN2? 3: Calculated: C, 57.84; H, 4.61; N, 6.75. : C, 58.13; H, 4.49; N, 6.91.

B. Preparation of 2-benzyl-4-oxo-5-carbomethoxy-1,2,3,4-tetrahydro-Si-pyrido [3,4-J Jindol. A mixture of N- [5- (l-benzyl-3-oxo-1,2,3,6, tetrahydropyridinyl)] -2-bromo-3-carbomethoxyaniline (2.07 g, 4.98 mmol), palladium (II) (0.112 g, 0.499 mmol), tri-o-tolylphosphine (0.304 g, 0.999 mmol), triethylamine (1.3 mL, 9.3 mmol) and N, N-dimethylformamide (3 mL) in acetonitrile ( 12 ml) was placed in a tube and purged with argon. The tube was sealed and heated at 100 ° C for 16 h. The mixture was cooled to room temperature, diluted with ethyl acetate, filtered and the filtrate was concentrated in vacuo to give a dark oil. Chromatography (silica gel, chloroform at 4% methanol / 96% chloroform) yielded 1.28 g (77%) of an oil that crystallized upon storage at 10 ° C: recrystallized from EtOAc / hexane, m.p. 174-176 ° C. 1 H NMR (CDC13) d 9.25 (sa, 1H), 7.38 (d, J = 9 Hz, 2H), 7.30 (m, 5H), 7.23 (t, J = 8 Hz, 1H ) 3.97 (s, 3H), 3.75 (s, .2H), 3.72 (s, 2H), 3.61 (s, 2H); MS ES + m / e 335 (p + 1); IR (KBr, 'cm' 1) 3080, 1721, 1628, 1476, 1294, "1138. Elemental Analysis for C2oH? 8N2? 3 Calculated: C, 71.84; H, 5.43; N, 8.38. Found: C, 72.06; H, 5.31; N, 8.31.

C. Preparation of 2,3-dibenzyl-4-oxo-5-carbomethoxy-1,2,3,4-tetrahydro-9i? -pyrido [3,4-Jb] indole. To a solution of 2-benzyl-4-oxo-5-carbomethoxyll, 2,3,4-tetrahydro-9H-pyrido [3,4-b] indole. (0.928 g, 2.78 mmol) in dry tetrahydrofuran (5 mL) was added 60% sodium hydride in oil (III mg). The resulting mixture was stirred at room temperature until the evolution of qas ceased. A solution of benzyl iodide (0.606 g, 2.78 mmol) in dry tetrahydrofuran (5 ml) was added to the reaction mixture and the resulting solution was stirred at room temperature for 60 hours. The mixture was diluted with methylene chloride and washed twice with saturated sodium chloride solution. The organic layer was dried (magnesium sulfate), filtered and concentrated in vacuo. The residue was triturated with ethyl acetate resulting in a yellow precipitate (163 mg). The filtrate was concentrated in vacuo and chromatographed (silica gel, 5% methanol / 95% methylene chloride) to yield 580 mg more of the title compound (743 mg total, 63%) as a crystalline solid: pf 198-199 ° C. 1K NMR (CDC13) d 7.43 (d, J = 7 Hz, 1H), 7.36 (d, J = 8 Hz, 1H), 7.25 (m, 9H), 6.95 (m, 2H ), 5.24 (s, 2H), 4.01 (s, 3H), 3.78 (m, 4H), 3.40 (s, 2H); MS ES + m / e 425 (p + 1); IR (KBr, cm "1) 1726, 1648, 1449, 1134, 1107. Elemental Analysis for C2H24N2? 3: Calculated: C, 76.40; H, 5.70; N, 6.60 Found: C, 76 , 11; H, 5.45; N, 6.54.

D. Preparation of 4-hydroxy-5-carbomethoxy-9-benzyl-9i? -pyrido [3,4-b] indole A mixture of 2,9-dibenzyl-4-oxo-5-carbomethoxy-2, 3,4-tetrahydro-9H-pyrido [3,4-b] indole (521 mg, 1.23 'mmole) and 10% palladium on carbon (250 mg) in acetic acid (15 ml) was heated to reflux for 4 h. The reaction flask was cooled to room temperature and purged with nitrogen. The flask was placed under a positive pressure of hydrogen and heated at 75 ° C for 16 hours. The mixture was cooled to room temperature, filtered and concentrated in vacuo to provide an orange solid. Chromatography (silica gel, 4% methanol / 96% methylene chloride) gave 271 mg (60%) of the title compound as a yellow powder monohydrate: m.p. > 250 ° C. ? E NMR (CDC13) d 8.46 (s, 1H), 8.22 (s, 1H), 8.09 (d, J = 8 Hz, 1H), 7.70 (d, J = 8 Hz, 1H), 7.56 (t, J = 8 Hz, 1H), 7.23 (m, 3H), 7.08 (m, 2H), 5.60 (s, 2H), 4.11 (s, 3H); MS ES + m / e 333 (p + 1). Elemental Analysis for C2oH? 6N203 • H20: Calculated: C, 68.60; H, 4.98; N, 7.91. Found: C, 68.56; H, 5.18; N, 8.00.

E. Preparation of 4-hydroxy-5-carboxamido-9-benzyl-5J? -pyrido [3,4-b] indole. 4-Hydroxy-5-carboxamido-9-benzyl-9H-pyrido [3,4-b] indole (200 mg, 0.618 mmol) was dissolved in a 2M methanolic ammonia solution (10 ml) and placed in a tube open. The solution was saturated with gaseous ammonia for 10 minutes. The tube was sealed and heated to 60-65 ° C for 8 hours. The reaction mixture was cooled to room temperature and the resulting precipitate was collected in vacuo to provide 0.12 g (61%) of the title compound as a yellow solid: m.p. > 250 ° C. 1 H NMR (DMSO-d 6) d 10.99 (s, 1H, -OH), 8.99 (br s, 1H, -NH), 8.59 (s, 1H), 8.55 (s, a, 1H , -NH), 7.96 (d, J = 7 Hz, 1 H), 7.94 (s, 1H), 7.64 (t, J = 8Hz, 1H), 7.57 (d, J = 7 Hz, 1H), 7.22 (m, 3H), 7.12 (d, J = 7 Hz, 2H), 5.80 (s, 2H); MS ES + m / e 318 (p + 1). Elemental Analysis for Ci9H? S 302: Calculated: C, 71.91; H, 4.76; N, 13.24.

Found: C, 72.20; H, 4.57; N, 13.48.

F. Preparation of 2-4-oxo-5-carboxamido-9-benzyl-5Ji-pyrido [3,4-b] indole) acetic acid hydrochloride. A mixture of 4-hydroxy-5-carboxamido-9-benzyl-Pi? -pyrido [3,4-Jb] indole (57 mg, 0.18 mmol) methyl bromoacetate (51 ml, 0.54 mmol) and carbonate of cesium (114 mg, 0.349 mmol) in N, N-dimethylformamide (2 ml) was stirred at room temperature for 45 minutes. The mixture was treated with a minimum of water and methanol and concentrated in vacuo. The residue was dissolved in dilute aqueous hydrochloric acid and purified by reverse phase HPLC, followed by lyophilization, to provide 28.5 mg (38%) of the title product. X H NMR (DMSO-d 6) d 12.85 (br s, 1 H), 9.41 (s, 1 H), 9.11 (s, 1 H), 8.66 (s, 1 H), 8.30 (s, 1H), 8.10 (d, J = 8Hz, 1H), 7.85 (t, J = 8Hz, 1H), 7.76 (d, J = 7 Hz, 1H), 7.27 (m, 3H), 7.19 (m, 2H), 5.88 (s, 2H), 5.37 (s, 2H); MS ES + m / e 375 (p + 1). Elemental Analysis for C2? H? 7N304 • HCl • O, 5H20: Calculated: C, 60.58; H, 4.47; N, 10.09. Found: C, 60.39; H, 4.35; N, 9.69. Example 4 Preparation of [N-benzyl-1-carbamoyl-l-aza-1,2,3,4-tetrahydrocarbazol-8-yl) oxyacetic acid A. Preparation of methyl N-benzyl-4-methoxyindole-2-carboxylate 6 were dissolved, 15 g of methyl 4-methoxyindole-2-carboxylate in 30 ml of dimethylformamide, the mixture was added to a suspension of 12 g of cesium carbonate in 20 ml of dimethylformamide and heated to 40-45 ° C for 1 hour . After cooling, benzyl bromide was added in the same solvent and stirred overnight at room temperature. The treatment was carried out by adding water cooled with ice and extracting twice with ether. The ether layer was washed with water and brine, dried over magnesium sulfate, filtered and concentrated to dryness. 8.6 g (97%). Mass Spectrum: M + + 1 (296), p.f. 104-105 ° C. B. Preparation of N-benzyl-2-hydroxymethyl-4-methoxyindole To a suspension of 0.31 g of lithium aluminum hydride (8.2 mmol) in 25 ml of ether at 0-10 ° C, methyl N-benzyl-4-methoxyindole-2-carboxylate (2M) was added. , 95 g) dissolved in 10 ml of the same solvent. The mixture was stirred at t.a. for 2 hours, it was inactivated under the conventional procedure of Fieser and Fieser, filtered through a pad of celite and concentrated to dryness to give 2.8 g of alcohol. Mass Spectrum: M + + 1 (268), p.f. 142-143 ° C. C. Preparation of N-benzyl-4-methoxyindole-2-carboxaldehyde A mixture of 3.2 g of N-benzyl-2-hydroxymethyl-4-methoxyindole (12 mmole) and 15 g of manganese dioxide (172 mmole) in 50 ml of dichloromethane, heated to reflux for 6 hours, cooled to rt and filtered through celite. Concentration to dryness yielded 3.6 g of a yellow solid. P.f. 130-131 ° C. D. Preparation of methyl N-benzyl-4-methoxyindole-2-propionate 3.1 g (11.7 mmol) of N-benzyl-4-methoxyindole-2-carboxaldehyde in 20 ml of pyridine were combined with 3.65 g (35.1 mmoles) of malonic acid and 0.4 g of piperidine; The mixture was heated at 100 ° C for 2 hours, concentrated vacuum up to one third of the volume and acidified with 1 N HCl. The solid was filtered off, washed with water and dried under vacuum to give 3.0 g of product (85%). Mass Spectrum: M + + 1 (308), p.f. 208-210 ° C. This material was dissolved in 30 ml of methanol and 1 ml of sulfuric acid, heated to reflux for 2 hours, cooled to t.a and concentrated to a small volume. The resulting solid was isolated by filtration. This material was hydrogenated in methanol-tetrahydrofuran with 5% Pd on carbon to yield the title compound (2.5 g) with a total yield of 66%. Mass Spectrum: M + + 1 (324), p.f. 195-196 ° C. E. Preparation of N-benzyl-1-aza- (3, 4-dihydro) -8-methoxycarbazol-2-one 2.5 g of methyl N-benzyl-4-methoxyindole-2-propionate (7, 7 ml) in 25 ml of ether and 2 equivalents (5.86 g) of bis (2,2,2-trichloroethyl) azodicarboxylate were added portionwise over half an hour; the mixture was stirred at t.a. overnight, it was filtered and concentrated to dryness. This compound was dissolved in a small amount of ether and filtered to give 3.2 q of a green solid. 1 g of this complex was reduced in 5 ml of acetic acid with 1 g of activated zinc. The temperature is kept at 10 ° C for 1 hour, allowed to warm up to the t.a. and stirred overnight. Water was added and basified with 1 N sodium hydroxide. Extraction with tetrahydrofuran and ethyl acetate, washing, drying and concentration yielded a brown oil which crystallized from isopropyl alcohol. 300 mg of crude and 130 mg after crystallization. Mass Spectrum: M + + 1 (307), p.f. 206-208 ° C. F. Preparation of N-benzyl-l-carbamoyl-l-aza-8-methoxy-1,2,3,4-tetrahydrocarbazole 500mg of N-benzyl-1-aza- (3,4-dihydro) -8 was treated - methoxycarbazol-2-one in tetrahydrofuran with 82 mg of lithium aluminum hydride at rt, and then the mixture was heated to 50 ° C. The treatment was carried out according to the procedure of Fieser and Fieser (The Agents for Organic Synthesis, Fiesr, L. Et al., John Willey and Sons, • NY 1967, p 583), the mixture was filtered through celite and concentrated to dryness. 420 mg of crude product.

This product without further purification was treated with trimethylsilyl isocyanate in tetrahydrofuran for two hours and then concentrated to dryness. Ether was added and the amorphous solid was isolated by filtration. 360 mg. Spectrum e Masses: M + + 1 (336).

G. Preparation of the methyl ester [N-benzyl-1-carbamoyl-l-aza-1,2,3,4-tetrahydrocarbazol-8-yl] oxyacetic acid. 300 mg of N-benzyl-1-carbamoyl-1-aza-8-methoxy-l, 2,3,4-tetrahydrocarbazole were dissolved in 10 ml of dichloromethane and the mixture was cooled to -20 ° C. 10 ml of a solution of 1 M boron tribromide in the same solvent was added dropwise. It was stirred at t.a. for three hours and poured into 1 N HCl-ice. This material was extracted in ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered and concentrated to dryness to give 190 mq. This material was dissolved in 5 ml of dimethylformamide and a slight excess of cesium carbonate was added. After heating at 35 ° C for 10 minutes, methyl bromoacetate was added and stirred at r.t. during one night. Water was added, extracted with ethyl acetate, washed, dried over magnesium sulfate, filtered and concentrated to dryness. Ultrafast purification using 3: 1 chloroform-ethyl acetate yielded 45 mg of product. Mass Spectrum: M + 1 (394). NMR (CDC13) 7.3 (m, 5H), 7.9 (m, 1H), 6.95 (d, 1H), 6.4 (d, 1H), 5.25 (s, 2H), 5 , 2 (a, 2H), 4.8 (s, 2H), 3.8 (s, 3H), 2.75 (a, 2H), 2.1 (a, 2H), 1.25 (2, 2H).

H. Preparation of [N-benzyl-1-carbamoyl-l-aza-1,2,3,4-tetrahydrocarbazol-8-yl] oxyacetic acid. 15 mq of [N-benzyl-l-carbamoyl-1-aza-1,2,3,4-tetrahydrocarbazol-8-yl] oxyacetic acid methyl ester in 10 ml of 7: 1 tetrahydrofuran: methanol were dissolved and added 0.5 ml of 1 N sodium hydroxide. After stirring at overnight, the solvents were removed by distillation, the residue was acidified with 1 N HCl and the solid was filtered. This was washed with water and dried under vacuum. Mass spectrum: M + + 1 (380) Example 5 Preparation of 4-methoxy-6-methoxycarbonyl-10-phenylmethyl-6,7,8,9-tetrahydropyrido [1,2-a] indole A. Preparation of 3-phenylmethyl-7-methoxyindole. 1 A mixture of 15 g (0.086 moles) of 2-methoxyphenylhydrazine hydrochloride and 12 ml (0.09 moles of 3- phenylpropionaldehyde in 300 ml of toluene, was heated to reflux for 1.5 hours with azeotropic removal of the water. The suspension was cooled, evaporated in vacuo and the residue was dissolved in 500 ml of dichloromethane and stirred with 9 ml (0.09 mole) of phosphorus trichloride for 18 hours. The solution was poured into ice-cooled water, stirred well and made basic with sodium bicarbonate. The organic phase was washed with saturated sodium chloride, dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a gradient of hexane / ethyl ether of 5-15% to give the product, 8.0 g, 40%, as a viscous oil. 1 HOUR NMR (CDC13) d: 3.95 (s, 3H), 4.10 (s, 2H), 6.65 (d, 1H), 6.90 (s, 1H), 7.00 (t, 1H) , 7.10 (d, 1H), 7.20 (m, 1H), 7.30 (m, 4H), 8.20 (br s, 1H). B. Preparation of methyl 2- [3-phenylmethyl-7-methoxyindol-l-yl] -5-chloropentanoate A solution of 2.7 g (11 mmol) of the product of Part A in 75 ml of dimethyl sulfoxide and a few ml of tetrahydrofuran, treated in portions with 480 mg of sodium hydride (60% in mineral oil, 12 mmol), stirred for 10 minutes and then for 16.5 hours after the addition of 0.3 g of 18-crown -6 and 1.7 g (13 mmol) of methyl 2-bromo-5-chloropentanoate. The The solution was diluted with ethyl acetate and water. The organic phase was washed with water, washed with saturated sodium chloride, dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a 10-25% hexane / ethyl ether granule to give the product, 1.7 g, 40%, as an oil. X H NMR (DMSO-dβ) d: 1.35 (m, 1 H), 1.60 (m, 1 H), 2.10 (m, 1 H =, 2.20 (m, 1 H), 3.55 (t , 2H), 3.60 (s, 3H), 3.80 (s, 3H), 4.00 (s, 2H), 6.60 (d, 1H), 6.85 (t, 1H), 7 , 00 (d, 1H), 7.10 (m, 1H), 7.15 (s, 1H), 7.20 (m, 4H) C. Preparation of 4-methoxy-6-methoxycarbonyl-10-phenylmethyl. -6,7, 8, 9-tetrahydropyrido [1, 2, -a] indole A solution of 1.8 g (4.7 mmoles) of the product from part B and 4 ml (15 mmoles) of trihydride -n-butyltin in 50 ml of toluene was heated to reflux and treated dropwise with a solution of 85 mg (0.5 mmol) of 2,2'-azobis (2-methylpropionitrile) .The solution was heated to reflux for 1 hour after the addition, it was cooled and evaporated in vacuo, suspended in ethyl acetate, stirred with aqueous potassium fluoride and filtered, the organic phase was washed with saturated sodium chloride, dried over sodium sulfate and evaporated in vacuo to give a mixture of 4-methoxy-6-methoxycarbonyl-10-phenylmethyl-6,7,8-tetrahydropyrido [1,2-a] ndol and 2- [3-phenylmethyl-7- methyl methoxyindole-l-yl] pentanoate which was dissolved in 25 ml of dioxane and added with 450 mq (2 mmoles) of dichlorodicyanoquinone for 30 minutes. The solution was evaporated in vacuo, suspended in dichloromethane, filtered through florisil and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a gradient of hexane / 10-20% ethyl ether to give the title compound, 75 mg, 5%, as an amorphous solid. X H NMR (CDCl 3) d: 1.70 (m, 1 H), 1.85 (m, 1 H), 2.20 (m, 1 H), 2.35 (m, 1 H), 2.70 (m, 1H), 3.00 (m, 1H), 3.70 (s, 3H), 3.80 (s, 3H), 4.00 (q, 2H), 5.65 (m, 1H), 6, 50 (d, 1H), 6.90 (t, 1H), 7.00 (d, 1H), 7.10 (m, 1H), 7.20 (m, 4H). Example 6 Preparation of the acid (4-carboxamido-9-phenylmethyl-4,5-dihydrothiopyrano [3,4-b] indol-5-yl) oxyacetic acid A. Preparation of methyl 3- (4-methoxyindol-3-yl) lactane.

To a solution of 4-methoxyindole (200 mq, 1.36 mmole) and methyl-2,3-epoxypropionate (258 mg, 2.22 mmole) in 40 ml of carbon tetrachloride, qota was added to qota stannic chloride (0.16 ml, 1.39 mmole) at a temperature of -5 to -10 ° C. The reaction mixture was added at this temperature for one hour, warmed to room temperature slowly and continued to be quenched.

The reaction mixture was diluted with ethyl acetate and sodium bicarbonate solution, washed with brine, dried over sodium sulfate and evaporated in vacuo to give 210 mg of a yellow oil which was subjected to flash column chromatography (2: 1 to 1: 1 hexanes: ethyl acetate) to give the product, 157 mg, 44% as an amine foam XE NMR (CDC13) d: 1.20 (t, 3H), 3.15 (dd, 1H), 3.49 (dd, 1H), 3.95 (s, 3H), 4.12 (q, 2H), 4.49 (dd, 1H), 5.27 (s, 2H), 6.50 (d, 1H), 6.83 (d, 1H), 7.08 (m, 2H), 7.31 (m, 5H). B. Preparation of a mixture of methyl 2-bromo-3- (4-methoxyindol-3-yl) propionate and methyl 2-bromomethyl-3- (4-methoxyindol-3-yl) acetate. To a solution of the product of Part A (29 mg, 0.11 mmol) and triphenylphosphine (57.7 mg, 0.22 mmol) in 2 ml of 1,2-dichloroethane, was added a solution of 1,2- dibromotetrachloroethane, (71.6 mg, 0.22 mmol) in 1 ml of 1,2-dichloroethane, at -10 ° C. The reaction mixture was warmed to room temperature and stirred for an additional 10-15 minutes. It was then concentrated in vacuo and subjected to flash column chromatography (2: 1 hexanes: ethyl ether) to give 31 mg, 86%, of a mixture of 2-bromo-3- (4-methoxyindol-3-yl) methyl propionate and methyl 2-bromomethyl-3- (4-methoxyindol-3-yl) acetate in the form of a yellow oil. XH NMR (CDC13) d: 1.20 (t, 3H), 3.15, 8dd, 1H), 3.49 (dd, 1H), 3.95 (s, 3H), 4.12 (q, 2H) , 4.49 (dd, 1H), 5.27 (s, 2H), 6.50 (d, 1H), 6.83 (d, 1H), 7.08 (m, 2H), 7.31 ( m, 5H). C. Preparation of a mixture of methyl 2-bromo-3- (1-phenylmethyl-4-methoxyindol-3-yl) propionate and 2-bromomethyl-3- (l-phenylmethyl-4-methoxyindol-3-yl) acetate of methyl. The product mixture of Part B was dissolved in 5 ml of acetonitrile and 1 equivalent of potassium carbonate was added. This mixture was heated to reflux overnight to form methyl 2- [4-methoxyindol-3,3-yl] spirocyclopropane carboxylate. To this reaction mixture 2 equivalents of benzyl bromide were added and the mixture was heated to reflux overnight. The mixture was filtered and concentrated. The residue was purified by flash column chromatography (97.1 of hexanes: ether) to give 29 mg, 66%, of a mixture of about 1: 9 of methyl 2-bromo-3- (l-phenylmethyl-4-methoxyindol-3-yl) propionate and 2-bromomethyl-3 - Methyl (1-phenylmethyl-4-methoxyindol-3-yl) acetate. XH NMR (CDC13) d: 1.28 (t, 3H), 3.82 (d, 2H), 3.96 (s, 3H), 4.26 (q, 2H), 4.81 (t, 1H ), 5.25 (s, 2H), 6.53 (d, 1H), 6.89 (d, 1H), 7.02-7.18 (m, 7H). D. Preparation of a mixture of methyl 2-acetylthiomethyl-3- (1-phenylmethyl-4-methoxyindol-3-yl) acetate. A solution of the product mixture from Part C (2.87 g, 7.0 mmol) in 15 ml of tetrahydrofuran and 40 ml of dimethylformamide was added 18-crown-6 (0.31 g) and potassium thioacetate (12, 2 g 0.11 mmol) and then it was added at 50 ° C for 2 hours. The mixture was diluted with ethyl acetate and brine. The organic phase was washed, dried and concentrated. The residue was purified by HPLC and yielded 1.8 g, 64.2% product. X H NMR (CDCl 3): 1.19 (t, 3 H), 2.28 (s, 3 H), 3.54 (dd, 2 H), 3.91 (s, 3 H), 4.52 (t, 1 H) , 5.22 (s, 2H), 6.53 (d, 1H), 6.82 (d, 1H), 7.00 (s, 1H), 7.11 8m, 3H), 7.28 (m , 3H). E. Preparation of methyl 2-mercaptomethyl-3- (l-phenylmethyl-4-methoxyindol-3-yl) acetate To a solution of the product from Part d (0.84 g 2.0 mmol) in ethanol (70 ml ), carbonate was added potassium (4.1 g, 30 mmol). The reaction mixture was stirred at room temperature for 1,5 hours. It was quenched with hydrochloric acid solution and extracted with ethyl acetate, dried and concentrated to give the product, 0.74 g, 98%. 1 H NMR (CDC13) d: 1.21 (t, 3 H), 1.55 (t, 1 H), 3.03 (m, 2 H), 3.91 (s, 1 H), 4.19 (q, 2 H) ), 4.50 (t, 1H), 5.22 (s, 3H), 6.48 (d, 1H), 6.83 (d, 1H), 6.98 (s, 1H), 7.10 (m, 3H), 7.27 (m, 3H). F. Preparation of methyl 2-methoxymethylmercaptomethyl-3- (1-phenylmethyl-4-methoxyindol-3-yl) acetate To a solution of the product from Part E (0.71 q, 1.92 mmol) in tetrahydrofuran (45 ml) were added a few mg of 18-crown-6 and potassium hexamethyldisilazide (4.54 ml, 0.5 M in toluene) at -75 ° C. The solution was stirred at -75 ° C for 3 minutes and then iodomethyl methyl ether (0.28 ml, mmol) was added and stirred for 20 minutes at -75 ° C. The reaction mixture was poured into a mixture of ethyl acetate and brine. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (3: 1 hexanes: ethyl acetate) to give the product, 650 mg, 82%, as a light yellow oil. lE NMR (CDC13) d: 1.23 (t, 3H), 3.14 (m, 2H), 3.35 (s, 3H), 3.91 (s, 3H), 4.22 (q, 2H), 4.65 (d, 1H), 4.66 (t, 1H), 4.75 (d, 1H), 5.22 (s, 2H), 6.51 (d, 1H), 6.90 (d, 1H), 7.00 (s, 1H) , 7.07 (m, 3H), 7.28 (m, 3H). G. Preparation of 4-methoxycarbonyl-5-methoxy-9-phenylmethyl-4,5-dihydrothiopyrano [3,4-b] indole. To a solution of the product of Part F (518 mq, 1.25 mmol in dichloromethane (10 ml) was added a zinc bromide spatula rapidly.The mixture was stirred at room temperature for 4.5 hours. It was taken up in ethyl acetate and sodium bicarbonate solution, the organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo, the residue was purified by column chromatography (3: 1 hexanes: ethyl acetate). yield 269 mg, 56.4%, of the product as a yellow oil.1H NMR (CDCl3) d: 1.22 (t, 3H), 320 (dd, 1H), 3.59 (d, 1H), 3.72 (d, 1H), 3.83 (s, 3H), 4.21 (m, 3H), 4.53 (t, 1H), 5.18 (d, 1H), 5.24 (d , 1H), 6.43 (d, 1H), 6.82 (d, 1H), 6.98 (d, 1H), 7.09 (t, 1H), 7.22 (m, 4H). Preparation of 4-carboxamido-5-methoxy-9-phenylmethyl-4,5-dihydrothiopyrano [3,4-b] -indole To a solution of the product from Part G (120 mg, 0.31 mmol) in benzene ( 15 ml) freshly prepared methylchloroaluminum amide (0 67 M, 9.3 ml) The mixture was stirred at 50 ° C overnight. It cooled, it added 1 N hydrochloric acid and diluted with ethyl acetate and brine. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by column chromatography (3: 1 hexanes: ethyl acetate to ethyl acetate and 1% methanol in dichloromethane) to give the product, 49.3 mg, 45% MS FIA 353.4 (M + 1) ) Elemental Analysis for C2oH2oN202S: • Calculated: C, 68.16; H, 5.72; N, 7.95 Found: C, 68.31; H, 5.83; N, 8.05 I. Preparation of [Ethyl 4-carboxamido-9-phenylmethyl-4,5-dihydrothiopyrano [3,4-b] indol-5-yl] oxyacetate To a solution of the product of Part H (210 mg, 0.60 mmol) in dichloromethane (30 ml) was added boron tribromide (10 ml, 1M in dichloromethane) The mixture was stirred for 0.5 h The reaction mixture was poured into ice water, extracted with 1% methanol in dichloromethane was washed with brine, dried and concentrated The crude 4-carboxamido-5-hydroxy-9-phenylmethyl-4,5-dihydrothio [3, 4-b] indole was dissolved in 13 ml of DMF and the resulting solution was treated with sodium hydride (50 mg, 60% in mineral oil, 1.25 mmol) for 5 minutes and then with ethyl bromoacetate (0.09 ml, 1.2 mmol) for 1.5 hours. The reaction mixture is diluted with ethyl acetate and brine. The organic layer was washed, dried and concentrated. The residue was purified by column chromatography (10% methanol in dichloromethane) to give the product, 79 mg, 31%, as a yellow foam. MS FIA 425.2 (M + l) Elemental Analysis for C23H2N204S: Calculated: C, 65.07; H, 5.57; N, 6.47 Found: C, 65.88; H, 5.57; N, 6.47. J. Preparation of (4-carboxamido-9-phenylmethyl) -4,5-dihydrothiopyrano [3,4-b] -indol-5-yl) oxyacetic acid To a solution of the product of Part I (53.7 mg, 0.13 mmol) in a mixture of solvents (5 ml, tetrahydrofuran: methanol: water, 3: 1: 1), lithium hydroxide (~ 2.5 equivalents) was added. The solution was added overnight, acidified to a pH ~ 2 and extracted with ethyl acetate. The organic solution was dried over sodium sulfate and evaporated in vacuo to give the title compound, 37 mg, 74%, as a yellow solid. MS FIA 397.1 (M + l) Elemental Analysis for C2? H2ON204S: Calculated: C, 63.62; H, 5.08; N, 7.07. Found: C, 63.83; H, 5.33; N, 6.87.

Example 7 3,4-Dihydro-4-carboxamidol-5-methoxy-9-phenylmethylpyrano [3,4-b] indole A. Preparation of ethyl [4-methoxyindol-3-yl] acetate. To a solution of 2.94 g (20 mmol) of 4-methoxyindole in 150 ml of tetrahydrofuran, 13 ml of n-butyl lithium (1.6 M in hexane, 20 mmol) was added slowly followed by the slow addition of 20 ml of zinc chloride (1.0 M in ethyl ether, 20 mmol) at 0-5 ° C. The cooling bath was removed, the solution was stirred for 2 hours and then treated with 2.1 ml (25 mmol) of ethyl bromoacetate for 19 hours, diluted with ethyl acetate, washed with water, washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a gradient of hexane / ethyl ether 10-50% to give the starting material (40%) and then the product, 2.3 g, 50%, in the form of? N. oil. X H NMR (CDCl 3) d 1.25 (t, 3 H), 3.85 (s, 3 H), 3.90 (s, 2 H), 4.10 (q, 2 H), 6.45 (d, 1 H) , 6.90 (d, 1H), 6.95 (s, 1H), 7.05 (t, 1H), 8.00 (sa, 1H).

B. Preparation of Ethyl [4-methoxy-l-phenylmethylindol-3-yl] acetate A solution of 1.6 g (6.9 mmol) of the product of part A in 75 ml of dimethylformamide and 10 ml of tetrahydrofuran, it was treated in portions with 300 mg of sodium hydride (60% in mineral oil, 7.5 mmol), then with 1.0 ml (8.4 mmol) of benzyl bromide for 4 hours, and then diluted with ethyl acetate. ethyl and water. The organic phase was washed with water, washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a gradient of hexane / 10-20% ethyl ether to give the product, 1.0 g, 45%, as an oil. aH NMR (CDCl 3) d: 1.25 (t, 3H), 3.85 (s, 3H), 3.90 (s, 2H), 4.19 (q, 2H), 5.25 (s, 2H), 6.50 (d, 1H), 6.85 (d, 1H), 6.95 (s, 1H), 7.05 (t, 1H), 7.10 (d, 2H), 7, 25 (m, 3H). MS ES + 324.0 (M + l). C. Preparation of ethyl 2- [4-methoxy-l-phenylmethylindol-3-yl] -3-phenylmethoxypropionate. To an added solution of the product from Part B (1.4 q 4.3 mmoles) in 50 ml of tetrahydrofuran was added slowly potassium hexamethyldisilazide (9.54 ml, 0.5 M in toluene, 4.77 mmol at -75 ° C under nitrogen.) The resulting reaction mixture was stirred for a couple of minutes and treated with chloromethyl benzyl ether (1). , 7 g, 8.6 mmol) at -75 ° C. The reaction mixture was stirred at -75 ° C. for 0.5 hour and poured into a mixture of brine and ethyl acetate. brine, dried and concentrated in vacuo The residue was purified by flash column chromatography (3: 1 hexanes: ethyl acetate) to give the product as a yellow oil, 1.34 g, 70.3% X H NMR (CDC13): 1.22 (t, 3 H), 3.88 (s, 3 H), 3.94 (dd, 1 H), 4.21 (m, 3 H), 4.56 (s, 2 H) ), 4.75 (dd, 1H), 5.20 (s, 2H), 6.40 (d, 1H), 6.81 (d, 1H), 7.02-7.34 (m, 7H) D. Preparation of ethyl 2- [4-methoxy-l-phenylmethylindol-3-yl] -3-hydroxypropionate To a stirred solution of the product from part C (0.33 g) in ethyl acetate (50 ml) was added 5% Pd / C (0.17 g) and 1 ml of 1 N hydrochloric acid. The reaction mixture was stirred under about 1 atmosphere of hydrogen at room temperature overnight. The reaction mixture was filtered, neutralized with sodium bicarbonate solution and washed with brine. The organic layer was dried over sodium sulfate and concentrated vacuum to give the product, 0.23 g, 89%, in the form of a yellow oil. XH NMR (CT> C13) d: 1.21 (t, 3H), 3.87 (s, 3H), 3.92 (dd, 1H), 4.20 8m, 3H), 4.44 (dd) , 1H), 5.21 (s, 2H), 6.43 (d, 1H), 6.84 (d, 1H), 6.98 (s, 1H), 7.00 (m, 3H), 7 , 30 (m, 3H). E. Preparation of ethyl 2- [4-methoxy-l-phenylmethylindol-3-yl] -3-methoxypropionate. To a stirred solution of the product of Part D (0.26 g, 0.74 mmol) in 18 ml of tetrahydrofuran was slowly added potassium hexamethyldisilazide. (1.63 ml, 0.5 M in toluene, 0.815 mmol) at -75 ° C. To the reaction mixture was added iodomethyl methyl ether (0.13 mL, 1.48 mmol) at -75 ° C after stirring for 2 minutes at the same temperature. The mixture was diluted with brine and ethyl acetate after 15 minutes at -75 ° C. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (4: 1 to 3.1 hexanes.ethyl acetate) to give the product, 0.23 g, 79.3%, as a yellow oil. XH NMR (CDC13) d: 1. 21 (t, 3H), 3.35 (s, 3H), 3.91 (s, 3H), 9.95 (m, 2H), 4. 22 (q, 2H), 4.65 (s, 2H), 4.72 (dd, 1H), 5.21 (s, 2H), 6.41 (d, 1H), 6.82 (d, 1H) ), 7.04 (m, 4H), 7.24 (m, 3H).

F. Preparation of 3,4-dihydro-4-ethoxycarbonyl-5-methoxy-9-phenylmethylpyrano [3,4-b] iridol. To a solution of boron trifluoride etherate (0.071 ml, 0.55 mmol) in dichloromethane (6 ml), a solution of the product from Part E was slowly added. (148 mg, 0.37 mmol) in dichloromethane (4 ml) at 0-5 ° C. The reaction mixture was warmed to room temperature and stirred for 0.5 hour to complete the reaction. The reaction mixture was diluted with ethyl acetate and brine. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel (1: 1 hexanes: ethyl ether) to give the product, 49.3 mg, 36.2%, as a white solid. XH NMR (CDC13): 1.21 (t, 3H), 3.88 (s, 3H), 4.05 (dd, 1H), 4.15 (, 1H), 4.24 (, 3H), 4.60 (d, 1H), 4.78 (d, 1H), 5.04 (d, 1H), 5.18 (d, 1H), 6.44 (d, 1H), 6.82 (d, 1H), 7.01 (m, 3H), 7.22 (m, 3H). G. Preparation of 3,4-dihydro-4-carboxamidol-5-methoxy-9-phenylmethylpyrano [3,4-b] indole To a solution of the product from Part F (490 mg, 1.34 mmol) in benzene ( 60-80 ml) freshly prepared methylchloroaluminum amide (0.67 M, 60 ml, 40 mmoles). The reaction mixture was stirred at 50 ° C for 24 hours, cooled, decomposed by the addition of 1 N hydrochloric acid and diluted with ethyl acetate and brine. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel eluting with a gradient of 1-2% dichloromethane-7-methanol to give the product, 335 mg, 74.6%. MS FIA 337.2 (M + l) Elemental Analysis for C20H2oN203S: Calculated: C, 71.41; H, 5.99; N, 8.33. Found: C, 71.51; H, 6.19; N, 8.26. Example 8 Preparation of 2- [(2,9-bis-benzyl-4-carbamoyl-1,2,3,4-tetrahydro-beta-carbolin-5-yl) oxy] acetic acid A. Preparation of 4- (tert-butyldimethylsilyl) oxindole. Imidazole (15.3 g, 225 mmol) was added to a solution of 4-hydroxyindole (20 g, 150 mmol) in 300 mL of anhydrous methylene chloride at room temperature. The resulting mixture was treated with tert-butyldimethylsilyl chloride (25 g, 165 mmol). After stirring overnight at room temperature, the reaction mixture was poured into 300 ml of water. The layers were separated and the aqueous phase was extracted with methylene (2 x 100 ml). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give a black oil. The crude residue was purified on a Prep 500 (silica gel; 0% to 5% ethyl acetate / hexanes) to give the title compound as a clear purple waxy solid with a quantitative yield. MS (electrospray, NH4OAc) m / e [M + 1] + 248, [M-1] ~ 246. Elemental Analysis for C? 4H2? NOSi: Calculated: C, 67.96; H, 8.55; N, 5.66. Found: C, 69.10; H, 8.79; N, 5.70. B. Preparation of ethyl [4- (tert-H-butyldimethylsilyl) oxindole] -3-acetic acid. A solution of indole (78) (247 mq, 1.00 mmol) in dry tetrahydrofuran (2 ml) under a nitrogen atmosphere was cooled to -10 ° C and then added qota by drop, for 30 seconds, by medium of a syringe, n-butyl-lithium (0.625 ml, 1.00 mmol) 1.6 M in hexanes. The resulting solution was stirred for 15 minutes and zinc chloride (1.0 mL, 1.0 mmol), 1 M in ether was added all at once. The solution was stirred for 2 hours while heating to room temperature. To this solution was added ethyl iodoacetate (0.118 ml, 1.00 mmoles, all at once. The mixture was added for 3 hours at room temperature and concentrated in vacuo. The residue was purified directly over that of silica (30 x 35 mm column) eluting with methylene chloride. Concentration of the appropriate fractions yielded 192 mq (57.8%) of the title product as a white solid. MS (electrospray, NH40Ac) m / e '[M + l] + 334, [M-l] "332. Elemental Analysis for Ci8H2N03Si: Calculated: C, 64.86; H, 8.11; N, 4.20. Found: C, 65.11; H, 8.02; N, 4.24. C. Preparation of Ethyl [2,9-bis-benzyl-5- (tert-butyldimethylsilyl) oxy-1,2,3,4-tetrahydro-beta-carboline] -4-acetic acid] -3-acetic acid. A solution of the ester (79) (5.08 g, 15.2 mmol) in dry tetrahydrofuran (100 ml) was cooled to -78 ° C and then treated qota to qota with potassium bis (trimethylsilyl) amide 0.5 M in toluene (32 ml, 16 mmol). The resulting solution was added for 10 minutes and then benzyl iodide (3.32 q, 15.2 mmol) was added once. The cooling bath was removed, the mixture was rapidly heated to 0 ° C and then slowly to room temperature. After stirring for 75 minutes at room temperature, the mixture was concentrated in vacuo. The residue was suspended in ether and washed successively with 10% aqueous citric acid, water and saturated sodium bicarbonate solution. The ether solution was dried over magnesium sulfate and concentrated in vacuo. The residue was purified on silica gel (70 x 130-mm column) eluting with 500 ml of methylene chloride. The appropriate fractions were combined and concentrated in vacuo to yield 5.90 g (91%) of ethyl [l-benzyl-4- (tert-butyldimethylsilyl) oxindole] -3-acetic acid in the form of a brown oil. Benzyl amine (2.14 g, 20.0 mmol) and paraformaldehyde (1.80 g, 120 mmol, and refluxing in anhydrous methanol (10 mL) for 2 hours were combined.The mixture was concentrated in vacuo and dried under vacuum for 30 minutes to produce crude benzyl bis (methoxymethyl) amine as an aqueous white oil.This material was used immediately without purification.To a cooled solution of ethyl [l-benzyl-4- (tert-butyldimethylsilyl) oxindole] ] -3-acetic acid 8190 mg, 0.45 mmol) in dry tetrahydrofuran (2 ml), potassium bis (trimethylsilyl) amide was added dropwise and by syringe. (0.98 mL, 0.49 mmol), 0.5 M in toluene. After stirring the mixture for 10 minutes, it was added all at once trimethylsilyl chloride (0.057 ml, 0.45 mmol). The mixture was allowed to warm to room temperature and then concentrated in vacuo. The residue was dried for 30 minutes in vacuo to yield the trimethylsilyl ketene acetal (81). The residual ketene acetal (81) was immediately dissolved in methylene chloride (30 ml), to which freshly prepared benzyl bis (methoxymethyl-9amine (175 mg, 0.90 mmol) was added.The mixture was cooled to -78 ° C and it was treated with 1 M zinc chloride in ether (0.9 ml, 0.9 mmol) The mixture was allowed to warm to room temperature and was added for an additional 45 minutes, the mixture was washed with saturated sodium bicarbonate and then passed through a plug of silica gel eluting with 1: 4 ethyl acetate / hexane.The desired fractions were combined and concentrated in vacuo and then further purified on an SCX cartridge (lg, Varian). ) with methanol and ammonia The desired fractions were combined, concentrated and purified on silica gel eluting with methylene chloride to yield 34 mg (14%) of the title tricyclic indole MS (electrospray, NH0Ac) m / e [ M + l] + 555. Elemental Analysis for 3H42N2? 3Yes: Calculated: C, 73, 64; H, 7.58; N, 5.05.

Found: C, 73, 42; H, 7.61; N, 5.15.

D. Preparation of ethyl 2- [(2,9-bis-benzyl-4-carbamoyl-1,2,3,4-tetrahydro-beta-carbolin-5-yl) oxy] acetyl acid. A solution of 565 mg (1.02 mmol) of the Part C compound in 10 ml of 1: 1 methanol-7-tetrahydrofuran was treated with 5 ml (5 mmol) of 1 N lithium hydroxide under a nitrogen atmosphere. The mixture was briefly heated, allowed to stir at room temperature for 2 hours and then concentrated in vacuo to about 5 ml. The pH of the solution was adjusted to -5-6 with 1 N hydrochloric acid. The resulting precipitate was collected and dried to yield 430 mg (102%) of hydroxy acid. This product was suspended with hydroxybenzotriazole (160 mg), 1.19 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (940 mg, 2.30 mmol) in 30 ml of 1: 1 tetrahydrofuran / chloride of ethylene. The mixture was stirred vigorously for 10 minutes, saturated with ammonia gas, stirred vigorously for 1 hour and then concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The ethyl acetate solution was dried over magnesium sulfate Anhydrous, filtered and concentrated in vacuo. The residue was passed through a plug of silica gel with ethyl acetate. The eluent was evaporated to yield 175 mg (43%) of the carboxamide. This compound was dissolved in 3 ml of dry tetrahydrofuran, cooled to -70 ° C and treated with 0.5 M potassium bis (trimethylsilyl) amide in toluene. (0.85 mL, 0.425 mmol). The solution was stirred for 10 minutes and then ethyl bromoacetate was added at once. The reaction was stirred for 6 hours while heating to room temperature. The mixture was concentrated in vacuo and the residue was purified on silica gel eluting with ethyl acetate to yield 86 mg (41%) of the title compound. MS (electrospray, NH4OAc) m / e [M + 1] + 498. Elemental Analysis for C3oH3iN30: Calculated: C, 72, 43; H, 6.24; N, 8.45. Found: C, 72, 54; H, 6.36; N, 8.64.

E. Preparation of 2- [2,9-bis-benzyl-4-carbamoyl-1,2,3,4-tetrahydro-beta-carbol-5-yl) oxy] acetic acid. A solution of the Part D compound (78 mg, 0.16 mmol) in 2 ml of 1: 1 tetrahydrofuran-7-methanol was stirred with 1 M lithium hydroxide (0.63 ml, 0.63 mmol). during 3 hours. The mixture was concentrated in vacuo to give a white solid. The solid was suspended in 2 ml of water and the pH was adjusted to ~ 5-6 with 1N hydrochloric acid to form a somewhat different white solid. The new solid was collected by filtration and dried under vacuum to yield 68 mg (93%) of the title compound. MS (electrospray, NH40Ac) m / e [M + 1] + 470. Elemental Analysis for C28H27 3? 4- 0.8 H20: Calculated: C, 69, 49; H, 5.96; N, 8.68. Found: C, 69, 50; H, 5.64; N, 8.54.

F. Preparation of 2- [(9-benzyl-4-carbamoyl-1,2,3,4-tetrahydro-beta-carbolin-5-yl) oxy] acetic acid hydrochloride. A suspension of the compound from Part E (68 mg, 0.14 mmol) was treated with 3-4 drops of 1 N HCl to effect the solution. To the solution was added 10% palladium on carbon (70 mg). The flask was purged appropriately with nitrogen and hydrogen and then stirred under a hydrogen atmosphere for 18 hours. The mixture was filtered and the solids were thoroughly washed with methanol. The filtrate was concentrated in vacuo to yield a mixture of acid and methyl ester. The mixture was treated with aqueous 1 N LiOH (0.3 ml) in approximately 2 ml of methanol for 2 hours. The mixture was concentrated in vacuo and the residue acidified to pH = 5 with 1 N HCl causing the formation of a precipitate. The precipitate was collected by filtration. The filtrate was concentrated in vacuo to leave a residue. The collected solid and residue were purified by reverse phase chromatography to yield 31 mg (68%) of the title compound as the HCL salt. MS (electrospray) m / e [M + l] + 380. IR (KBr, cm "1) 3393 (a), 3100-2500 (COOH), 1735, 1671, 1638, 1615, 1445, 1263, 1133, 731 , 722. Therapeutic Use of Tricyclic Compounds It is believed that the compounds described herein conserve their beneficial therapeutic action mainly by direct inhibition of human sPLA2, and not by acting as antagonists of arachidonic acid or other active agents below arachidonic acid in the arachidonic acid cascade, such as 5-lipooxyqases, cyclooxygenases, etc. The method of the invention for inhibiting the release of fatty acids mediated by sPLA2 comprises contacting the sPLA2 with an amount Therapeutically effective of the compound of Formula (I) or its salt. 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 adults, pancreatitis, trauma, bronchial asthma, allergic rhinitis and arthritis. rheumatoid wherein the method comprises 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 mediated by sPLA2 and, therefore, to inhibit or prevent the cascade of arachidonic acid and its deleterious products. The therapeutic amount of the compound of the invention necessary to inhibit sPLA2 can be easily determined by taking a sample of body fluid and assaying it for the content of sPLA2 by conventional methods. Throughout this document, the person or animal to be treated will be described 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 animals does not Human is only in the beginning and that they are beginning to use some cases of such treatments. 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, therefore, that the described dosage ranges will be recalculated. For example, a small dog may only have one-tenth 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.

Pharmaceutical Formulations of the Invention As previously indicated, the compounds of this invention are useful for inhibiting the release of fatty acids mediated by sPLA2 such as arachidonic acid. By the term "inhibition" is meant the prevention or therapeutically significant reduction in the release of qrase acids initiated by sPLA2 by the compounds of the invention. By "pharmaceutically acceptable" it is meant that the carrier, diluent or excipient has to be compatible with the other ingredients of the formulation and not detrimental to the recipient thereof. In general, the compounds of the invention are administered, most desirably, at a dose that generally produces effective results without causing any serious side effects and can be administered as a single unit dose or, if desired, the dose 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 condition 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 can be a capsule or tablet, or the appropriate number of any of these. The amount of active ingredient in a unit dose of composition may be varied or adjusted from about 0.1 to about 1000 milli 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" condition signifies a deteriorating condition of slow progress and prolonged stay. As such, it is treated when the treatment is diagnosed and continued throughout the course of the disease. An "acute" condition is a short-course exacerbation followed by a period of remission. In an acute case, the compound is administered at the beginning of the 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 conditions includes both acute and Chronicles. Septic shock and respiratory failure in adults, on the other hand, are acute conditions treated when diagnosed. The compound can be administered by a variety of routes including the oral, aerosol, rectal, transdermal, subcutaneous, intravenous, intramuscular and intranasal routes. The pharmaceutical formulations of the invention are prepared by the combination (e.g., mixture) of 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 ingredients and readily available. To make 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, dragees, 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 vehicle is a finely divided solid that is mixed with the active ingredient finely divided. In the 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, lactose sugar, 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 carrier, such as water, sterile, 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 illustrative only and are not intended to limit the scope of the invention in any way. "Active ingredient" refers to a compound according to Formula (III) or a pharmaceutically acceptable salt, solvate or prodrug thereof. Formulation 1 Hard gelatin capsules are prepared using the following ingredients: Quantity (mg / capsule) 2- [4-Oxo-5-carboxamido -9- (4-Methylbenzyl) -Si? -pyrido [3,4-Jb] indolyl] acetic acid 250 Starch, dried 200 Magnesium stearate 10 Total 460 mg Formulation 2 Prepared One tablet using the ingredients indicated below: Amount (mg / tablet) 2- [4-Oxo-5-carboxamido-9- [4- (trifluoromethyl) benzyl) -5-pyrido [3,4-Jb] indolyl] acetic acid 250 Cellulose, microcrystalline '400 Silicon dioxide, non-volatile 10 Stearic acid 5 Total 665 mg The components are mixed and compressed to form tablets weighing, each, 665 mg. Formulation 3 An aerosol solution containing the following components is prepared: Weight Acid 2- [4-oxo-5-carboxamido-9- [3- (benzoylbenzyl) -9H-pyrido [3, -b] indolyl] acetic 0 , 25 Ethanol 25.75 Propellant 22 (Chlorodifluoro methane) 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. Then the necessary amount is introduced into a container of stainless steel and diluted with the rest of the propellant. Then the valve units are adjusted to the container. Formulation 4 Tablets are made, each with 60 mg of active ingredient, as indicated below: 2- [4-Oxo-5-carboxamido-9- (2,4,6-trifluorobenzyl) -9E-pyrido [3 , 4-Jb] indolyl] acetic 60 mg Starch 45 mg Microcrystalline cellulose 35 mg Polyvinylpyrrolidone (as a 10% solution in water) 4 mg Sodium carboxymethyl starch 4.5 mg Magnesium stearate 0.5 mg Talc 1 mg Total 150 mg The active ingredient, starch and cellulose are passed through US mesh in sieve. No. 45 and they mix badly. The aqueous solution containing polyvinylpyrrolidone is mixed with the resulting powder and the mixture is then passed through a US mesh screen. No. 14. The granules thus produced are dried at 50 ° C and passed through a US mesh screen. No. 18. Then the sodium carboxymethyl starch, the 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 to produce tablets each weighing 150 mg. Formulation 5 Capsules are made, each containing 80 mq of active ingredient, as follows: 2- [4-Oxo-5-carboxamido -9- (2-fluorobenzyl) -5i-pyrido [3,4 -b] indolyl] acetic 80 mg Starch 59 mg Microcrystalline cellulose 59 mg Stearate 2 mg Total 200 mg The active ingredient, cellulose, starch and magnesium stearate are mixed, passed through a mesh screen of EE. No. 45 and are filled into hard gelatin capsules in amounts of 200 mg Formulation 6 Suppositories are made, each containing 225 mg of active ingredient, as follows: 2- [4-oxo-5- carboxamido-9-pentafluorobenzyl) -3H-pyrido [3, 4-b] indolyl] acetic 225 mg Glycerides of saturated fatty acids 2,000 mg Total 2,225 mg The active ingredient is passed through a US 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 made, each containing 50 mg of active ingredient per 5 ml dose, as follows: 2- [4-Oxo-5-carboxamido-9- (3, 4, 5-trimethoxybenzyl) - 9i? -pyrid [3, -b] indolyl] acetic 50 mg Sodium carboxymethylcellulose 50 mg Syrup 1.25 ml Benzoic acid solution 0.10 ml Aromatizante c.v. Color C.V. Purified water up to the total 5 ml The active ingredient is passed through a US 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 to produce the necessary volume. Formulation 8 An intravenous formulation can be prepared as follows: 2- [4-Oxo-5-carboxamido -9- (3, 5-difluorobenzyl) -9ff-pyrido [3,4-b] indolyl] acetic acid 100 mg Saline isotonic solution 1,000 ml The solution of the above ingredients is generally administered intravenously to a subject at a rate of 1 ml per minute. Test Example 1 The following chromogenic assay procedure was used to identify and evaluate the deenzyme inhibitors to identify and evaluate inhibitors of recombinant human secreted phospholipase A2. The assay described in this document has been adapted for high volume screening using 96-well microtiter plates. A general description of this test procedure is found in the article "Analysis 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 Bimistry, 204, p. . 190-197, 1992 (the description of which is incorporated herein by reference): Reagents: • REACTION TAMPON CaCl2.2H20 (1.47 g / 1) KCl (7.455 g / 1) Bovine serum albumin (without 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 0.05 NaOAc. 3H20, pH 4.5 0.2 NaCl Adjust pH to 4.5 with acetic acid DTNB - 5,5'-dithiobis-2-nitrobenzoic acid DIHEPTANOIL TIO - RACEMIC PC 1, 2-bis (heptanoylthio) -1, 2 -dideoxy-sn-glycero-3-racemic phosphorylcholine TRITON X-100 ™ prepared at 6.249 mg / ml in reaction buffer to equal 10 M TRITON X-100 ™ is a non-ionic polyoxyethylene detergent supplied by Pierce Chemical Company 3747 N. Meridian Road, Rockford, Illinois 61101. MIXTURE OF REACTION A measured volume of racemic diheptanoyl thio PC supplied in chloroform at a concentration of 100 μg / ml is brought to dryness and redissolved in 10 μm TRITON X-100 ™ 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 μM diheptanoyl thio-PC substrate, 0.29 μM Triton X-100 ™ detergent and 0.12 μM DTMB detergent 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 L of test compound (or white solvent) to the appropriate wells, mix for 20 seconds; 3. Add 50 nanograms sPLA2 (10 microliters) to the appropriate wells; 4. Incubate the plate at 40 ° C for 30 minutes; . - Read the absorbance of the wells at 405 nanometers with an automatic plate reader. All the 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. It was initially observed that the compounds were active when they were retested to confirm their activity and, when they were sufficiently active, the CI values were determined. 'Typically, the IC 50 values (see Table I shown below) were determined by diluting the The test compound was serially doubled 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 was determined by the enzymatic reactions containing inhibitors, with respect to the non-inhibited control reactions. Each sample was concentrated in triplicate and the result values were averaged for representation and calculation of the CI5o values- The IC50's were determined by representing the loq of the concentration against the inhibition values in an inhibition range of 10 to 90%. The compounds of the present invention (Examples 1-19) were tested in Test Example 1 and were considered effective at concentrations less than 100 μM. Test Example 2 Procedure: Guinea pigs of the male Hartley strain (500-700 q) were sacrificed by cervical dislocation, the lungs and intact hearts were removed and placed in aerated Krebs buffer (95% 02: 5% C02). ): Dorsal pleural strips (4 x 1 x 25 mm) were dissected from intact parenchymal segments (8 x 4 x 25 mm) cut parallel to the outer edge of the lower pulmonary lobes. Two adjacent pleural strips, obtained from a single lobe and representing a single tissue sample, were attached at one end and independently attached to a metal supporting rod. A rod was attached to a Grass force displacement transducer Model FT03C, product of Grass Medical Instruments Co., Quinci, MA, USA). The changes of the Isometric voltage was represented in a monitor and thermal recorder (product of Modular Instruments, Malvern, PA). All tissues were placed in 10 ml tissue baths with a heating jacket kept at 37 ° C. The tissue baths were continuously aerated and contained modified Krebs solution of the following millimolar composition) NaCl, 118.2; KCl, 4.6; CaCl2-2H20, 2.5; MgSO4 «7H20, 1.2; NaHCO 3, 24.8; KH2P04, 1.0; and dextrose, 10.0. Pleural strips were used from the opposite lobes of the lung to perform experiments in pairs. The preliminary data generated from the tension / response curves showed that the resting tension of 800 mg was optimal. The tissues were allowed to equilibrate for 45 minutes as the bath fluid was periodically changed Cumulative concentration-response curves Initially, the tissues were exposed 3 times to KCl (40 μM) to test the viability of the tissues and obtain a consistent 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-response concentration curves were obtained from the pleural strips increasing the concentration of agonists (sPLA2) in the tissue bath in semilogarithmic increments, while the previous concentration remained in contact with the tissues (Ref. 1 above). The concentration of aqonists 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, the 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 concentration-response curves of sPLA2. Statistical analysis: Data from different experiments were gathered and presented as a percentage of the maximum KCl proposals (mean + E.E.). To estimate the drug-induced shifts to the right 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.). The model It includes four parameters: the maximum response of the tissue, which was considered to be iqual 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 achieve an equivalent answer It was determined that Schild's slope was I, using procedures of non-linear statistical models similar to those described by aud (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 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 Avdances in General and Cellular Pharmacology eds Narahashi, Bianchi 1: 145-178, 1976. The compounds of the present invention (Examples 1-19) were tested in Test Example 2 and were found to be effective at concentrations below 20. μM. Test Example 3 Assay of sPLA2 in Transgenic Mice Materials and Methods The mice used in these studies were mature 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 libitum. 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 as an IV bolus through the tail vein in a volume of 0.15 ml. The vehicle consisted of 1-5% dimethyl-fufoxide, 1-5% ethanol and 10-30% polyethylene glycol 300 in H20; the concentrations of these ingredients were adjusted according to the solubility of the compound. Blood was extracted from the mice 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 M. For the oral assay, the compounds were dissolved n 1-5% ethanol / 10-30% polyethylene glycol 300 in H20 or suspended in 5% dextrose in H20 and administered by an oral probe 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. Carlson, N. J. Bach, R. D. Dillard, S. E. Drahei, J. L. Bobbitt, L. Fisher and E. D. Mihelich. 1996. Eur. J. Pharmacol. 308: 195 .. Schadlich, H. R., M. Buchler, and H. G. Beger, 1987, J. Clin. Chem. Clim. Biochem. 25, 505. The compounds of the present invention were tested in Test Example 3 and were considered effective. It is noted that in relation to this date, the best method known to the applicant to carry out the ementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, property is claimed as contained in the following:

Claims

RE IVIND I CAC I ONE S

1. A compound of the formula (I) characterized in that; A is phenyl or pyridyl, where the nitrocene is in the 5-, 6-, 7- or 8- position; one of B or D is nitrogen and the other is carbon; Z is cyclohexenyl, phenyl, pyridyl, where the nitrogen is in the 1-, 2- or 3- position, or a 6-membered heterocyclic indigo having a heteroatom selected from the group consisting of sulfur or oxygen in the 1- position, 2- or 3-, and nitrogen in the 1-, 2-, 3- or 4- position; it is a single or double link; R20 is selected from groups (a), (b) and (c), where; (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) - is a divalent linking group of 1 to 12 atoms, selected from carbon, hydrogen, oxygen, nitrogen and sulfur; where the combination of atoms in - (L) - is selected 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) carbon, hydrogen and only oxygen; and where R80 is a group selected from (a) or (b); R21 is a non-interfering substituent; R1 'is -NHNH2, -NH2 or -CONH2; R2 'is selected from the group consisting of -OH and -0 (CH2) tR5' where R5 'where is H, -Cn, -NH2, -CONH2, -CONR9R10, -NHS02R15; -C0NHS02R15, where R15 is -alkyl of 1 to 6 carbon atoms or -CF3; phenyl or phenyl substituted with -C02H or -C02-alkyl of 1 to 4 carbon atoms; and (La) - (acid group), where - (La) - is an acidic linker having an acid link length of 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 a pharmaceutically acceptable racemate, solvate, tautomer, optical isomer, prodrug derivative or salt thereof; with the proviso that one of A or Z is a heterocyclic ring; and when D is nitrocene, the heteroatom of Z is selected from the group consisting of sulfur or oxygen in the 1-, 2- or 3- position and nitrogen in the 1-, 2-, 3- or 4- position.

2. A compound of the formula (II) (II) characterized in that; R1 is -NHNH2 or -NH2; R is selected from the group consisting of -OH and -0 (CH2) mRs, where R5 is H, -C02H, -C02 (alkyl of 1 to 4 carbon atoms); -P (0) (R6R7), wherein each of R6 and R7 is independently -OH or '-O-alkyl of 1 to 4 carbon atoms; -S03H, -S03 (alkyl of 1 to 4 carbon atoms, tetrazolyl, -CN, NH2, -NHS02R1S; -C0NHS02R15, where R15 is alkyl of 1 to 6 carbon atoms or -CF3, phenyl or phenyl substituted with C02H or -C02-C 1-4 -alkyl wherein m is 1-3; R 3 'is H, -O-C 1-4 -alkyl, halo, -alkyl of 1 to 6 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; or - (CH2) nR8 / where R8 is H, -C0NH2, -NR9R10, -CN or phenyl, where R9 and R10 are independently -alkyl of 1 to 4 carbon atoms 0 -. 0-phenylalkyl of 1 to 4 carbon atoms and n is 1 to 8; R 4 is H, -alkyl of 5 to 14 carbon atoms, -cycloalkyl of 3 to 14 carbon atoms, pyridyl, phenyl or phenyl substituted with -alkyl of 1 to 6 carbon atoms, halo, CF 3, -OCF 3, - alkoxy- of 1 to 4 carbon atoms, -CN, -alkylthio of 1 to 4 carbon atoms, phenylalkyl of 1 to 4 carbon atoms, -alkylphenyl of 1 to 4 carbon atoms, phenyl, phenoxy or naphthyl; A is phenyl or pyridyl, where the nitrocene is in the 5-, 6-, 7- or 8- position; Z is cyclohexenyl, phenyl, pyridyl, where the nitrocene is in the 1-, 2-, or 3- position, or a 6-membered heterocyclic ring having one heteroatom selected from the group consisting of sulfur or oxycene in the 1,2-position. or 3, and nitroquinone at the 1, 2, 3 6 4 position, or where a carbon in the heterocyclic ring is optionally substituted with = 0, or a pharmaceutically acceptable racemate, solvate, tautomer, optical isomer, prodrug derivative or pharmaceutically acceptable salt thereof; with the proviso that one of A or Z is a heterocyclic ring.

3. A compound according to claim 2, characterized in that it is selected from the group consisting of the acid (R, S) - (9-benzyl-4-carbamoyl-1-oxo-3-thia-1, 2, 3, 4 , -tetrahydrocarbazol-5-yl) oxyacetic acid; (R, S) - (9-Benzyl-4-carbamoyl-1-oxo-3-thia-1,2,3,4-tetrahydrocarbazol-5-yl) oxyacetic acid; [N-benzyl-l-carbamoyl-l-aza-1,2,3,4-tetrahydrocarbazol-8-yl] oxyacetic acid; 4-methoxy-6-ethoxycarbonyl-10-phenylmethyl-6,7,8,9-tetrahydropyrido [1,2-a] indole; (4-carboxamido-9-phenylmethyl-4,5-dihydrothiopyran [3,4-] b] indol-5-yl) oxyacetic acid; 3,4-dihydro-4-carboxamidol-5-methoxy-9-phenylmethylpyrano [3,4-b] indole; 2 - [(2,9-bis-benzyl-4-carbamoyl-1, 2,3,4-tetrahydro-beta-carbolin-5-yl) oxy] acetic acid or a racemate, solvate, tautomer, optical isomer, derivative prodrug or pharmaceutically acceptable salt thereof.

4. A pharmaceutical formulation, characterized in that it comprises a compound of formula I according to claim 1, together with a pharmaceutically acceptable carrier or diluent therefor.

5. A pharmaceutical formulation, characterized by comprising a compound of formula II according to claim 2, together with a pharmaceutically acceptable carrier or diluent therefor.

6. A pharmaceutical formulation adapted for the treatment of a condition associated with the inhibition of sPLA2, characterized in that it contains a compound of formula I according to claim 1, together with a pharmaceutically acceptable carrier or diluent therefor.

7. A pharmaceutical formulation adapted for the treatment of a condition associated with the inhibition of sPLA2, characterized in that it contains a compound of formula II according to claim 2, together with a pharmaceutically acceptable carrier or diluent therefor.

8. 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 of formula (I) in which; A is phenyl or pyridyl, where the nitrocene is in the 5 ~, 7- or 87 position, one of B or D is nitrogen and the other is carbon; Z is cyclohexenyl, phenyl, pyridyl, where the nitrogen is in the 1-, 2-, or 3-position or a 6-membered heterocyclic indigo having a heteroatom selected from the group consisting of sulfur or oxygen in the 1, 2, or 3 position , and nitroquinone in the 1-, 2r, 3"or 47 position is a single or double bond, R20 is selected between groups (a), (b) and (c), where: (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) - is a divalent linking group of 1 to 12 atoms, selected from carbon, hydrogen, oxygen, nitrogen and sulfur, where the combination of atoms in - (L) - is selected from the group consisting of (i) only carbon and hydrogen, (ii) only one sulfur, (iii) only one ox oxygen, (iv) only one or two nitrogens and hydrogen, (v) carbon, hydrogen and only one sulfur, and (vi) carbon, hydrogen and only oxygen; and where R80 is a group selected from (a) or (b); R21 is a non-interfering substituent; R1 'is -NHNH2, -NH2 or -C0NH2; R2 'is selected from the group consisting of -OH and -0 (CH2) tR5' where R5 'where is H, -Cn, -NH2, -C0NH2, -CONR9R10, -NHS02R15; -CONHS02R15, where R15 is -alkyl of 1 to 6 carbon atoms or -CF3; phenyl or phenyl substituted with -C02H or -C02-alkyl of 1 to 4 carbon atoms; and (La) - (acid group), where - (La) - is an acidic linker having a length of acidic co-reactor 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 a pharmaceutically acceptable racemate, solvate, tautomer, optical isomer, prodrug derivative or salt thereof; with the proviso that one of A or Z is a heterocyclic ring; and when D is nitrocene, the heteroatom of Z is selected from the group consisting of sulfur or oxygen in the position -tr, 2- or 3-- and the nitrogen in the position 1-, 2- 3 or 4-w

9. 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 of formula (II) 'according to claim 2. (II) in which; R1 is -NHNH2 or -NH2; R2 is selected from the group consisting of -OH and -OÍCH ^ R5, where R5 is H, -C02H, -C02 (alkyl of 1 to 4 carbon atoms); -P (0) (R6R7), wherein one of R6 and R7 is independently -OH or -O-alkyl of 1 to 4 carbon atoms; -S03H, -S03 (alkyl of 1 to 4 carbon atoms, tetrazolyl, -CN, NH2, -NHS02R15; -C0NHS02R15, where R1S is alkyl of 1 to 6 carbon atoms or -CF3, phenyl or phenyl substituted with C02H or -C02-alkyl of 1 to 4 carbon atoms where m is 1-3; R3 is H > -O-to the quilo of 1 to 4 carbon atoms, halo, -alkyl of 1 to 6 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; or - (CH2) nR8, where R8 is H, -CONH2, -NR9R10, -CN or phenyl, where R9 and R10 are independently -alkyl of 1 to 4 carbon atoms or -phenylalkyl of 1 to 4 carbon atoms and n is 1 to 8; R 4 is H, -alkyl of 5 to 14 carbon atoms, -cycloalkyl of 3 to 14 carbon atoms, pyridyl, phenyl or phenyl substituted with -alkyl of 1 to 6 carbon atoms, halo, CF 3, -OCF 3, -alkoxy from 1 to 4 carbon atoms, -CN, -alkylthio of 1 to 4 carbon atoms, phenylalkyl of 1 to 4 carbon atoms, -alkylphenyl of 1 to 4 carbon atoms, phenyl, phenoxy or naphthyl; A is phenyl or pyridyl, where the nitrocene is in the 5-, 6 > 7-u Qf Z is cyclohexenyl, phenyl, pyridyl, where the nitrogen is in the 1-, 2r or 3- position, or a 6-membered heterocyclic ring having a heteroatom selected from the group consisting of sulfur or oxygen in the position I7 2-6 3 and nitrogen in the position I7 2-, 3- or 4? or wherein a carbon in the heterocyclic ring is optionally substituted with = 0, or a racemate, solvate, tautomer, optical isomer, prodrug derivative or pharmaceutically acceptable salt thereof; with the proviso that one of A or Z is a heterocyclic ring.

10. A method according to claim 8, characterized in that the mammal is a human being.

11. A method according to claim 9, characterized in that the mammal is a human being.

12. A method for alleviating the pathological effects of diseases related to sPLA2, characterized in that it comprises administering to a mammal in need of such treatment a compound of formula I according to claim 1, in an amount sufficient to inhibit the release of fatty acids mediated by sPLA2 and, therefore, inhibit or prevent the cascade of arachidonic acid and its harmful products.

13. A method for alleviating the pathological effects of diseases related to sPLA2, characterized in that it comprises administering to a mammal in need of such treatment a compound of formula II according to claim 2, in an amount sufficient to inhibit the release of fatty acids mediated by sPLA2 and, therefore, inhibit or prevent the cascade of arachidonic acid and its harmful products.

14. The use of a compound according to claim 1, for the manufacture of a medicament for alleviating the pathological effects of diseases related to sPLA2, characterized in that it comprises administering to a mammal in need of such treatment a compound of formula I.

15. A process of claim 8, characterized in that the compound is selected from the group consisting of acid (R, S) - (9-benzyl-4-carbamoyl-l-oxo-3-thia-1, 2, 3, 4, -tetrahydrocarbazol-5-yl) oxyacetic acid; (R, S) - (9-benzyl-4-carbamoyl-l-oxo-3-thia-l, 2,3,4-tetrahydrocarbazol-5-yl) oxyacetic acid; [N-benzyl-1-carbamoyl-l-aza-1,2,3,4-tetrahydrocarbazole-8- acid] il] oxyacetic; 4-methoxy-6-methoxycarbonyl-10-phenylmethyl-6,7,8,9-tetrahydropyrido [1,2-a] indole; (4-carboxamido-9-phenylmethyl-4,5-dihydrothiopyrano [3,4-b] indol-5-yl) oxyacetic acid; 3, 4-dihydro-4-carboxamidol-5-methoxy-9-phenylmethylpyrano [3,4-b] indole; 2 - [(2,9-bis-benzyl-4-carbamoyl-1,2,4,4-tetrahydro-beta-carbolin-5-yl) oxy] acetic acid or a racemate, solvate, tautomer, optical isomer, derivative prodrug or pharmaceutically acceptable salt thereof.

16. A method of claim 9, characterized in that the compound is selected from the group consisting of acid (R, S) - (9-benzyl-4-carbamoyl-1-oxo-3-thia-1, 2, 3, 4, -tetrahydrocarbazol-5-yl) oxyacetic acid; (-R, S) - (9-benzyl-4-carbamoyl-l-oxo-3-thia-l, 2,3,4-tetrahydrocarbazol-5-yl) oxyacetic acid; [N-benzyl-1-carbamoyl-l-aza-1,2,3-tetrahydrocarbazol-8-yl] oxyacetic acid; 4-methoxy-6-methoxycarbonyl-10-phenylmethyl-6,7,8,9-tetrahydropyrido [1,2-a] indole; (4-carboxamido-9-phenylmethyl-4,5-dihydrothiopyrano [3,4-b] indol-5-yl) oxyacetic acid; 3,4-dihydro-4-carboxamidol-5-methoxy-9-phenylmethylpyrano [3,4-b] indole; 2 - [(2,9-bis-benzyl-4-carbamoyl-1, 2,3,4-tetrahydro-beta-carbolin-5-yl) oxy] acetic acid or a racemate, solvate, tautomer, isomer optical, prodrug derivative thereof, pharmaceutically acceptable.

17. A method for inhibiting sPLA2, characterized in that it comprises contacting sPLA2 with a compound of formula II according to claim 1.

18. A method for inhibiting sPLA2, characterized in that it comprises contacting sPLA2 with a compound of formula II according to claim 2.

19. A method of treating sepsis, septic shock, rheumatoid arthritis, osteoarthritis, cerebrovascular accidents, 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 of formula in which; A is phenyl or pyridyl, where the nitrocene is in the 5,6, 7 or 8 position; one of B or D is nitrogen and the other is carbon; Z is cyclohexenyl, phenyl, pyridyl, where the nitrogen is in the 1-, 2- or 3- position, or a 6-membered heterocyclic ring having a heteroatom selected from the group consisting of sulfur or oxygen in the 1- position, 2- or 3-, and nitrogen in the 1-, 2-, 3- or 4- position; it is a single or double link; R20 is selected from groups (a), (b) and (c), where; (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 (s) is the group - (T -) - R80; where (T,) - is a divalent linking group of 1 to 12 atoms, selected from carbon, hydrogen, oxygen, nitrogen and sulfur; where the combination of atoms in - (L) - is selected 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) carbon, hydrogen and only oxygen; and where R80 is a group selected from (a) or (b); > 21 is not stupid and not interfering; R1 is -NHNH2, -NH2 or -CONH ,; R2 'is selessiona between the group consisting of -OH and -0 (CH2) tR5' where R5 'where is H, -Cn, -NH2, -C0NH2, -C0NR9R10, -NHS02R15; -C0NHS02R15, where R15 is -alkyl of 1 to 6 carbon atoms or -CF3; phenyl or phenyl substituted with -C02H or -C02-alkyl of 1 to 4 carbon atoms; and (La) - (acid group), where - (La) - is an acidic linker having an acid link length of 1 to 7, and t is 1-5; R3'se > selects between non-interfering substituents, carbocyclic radicals, carbocyclic radicals substituted with non-interfering substituents, heterocyclic radicals and heterocyclic radicals substituted with non-interfering substituents; or a racemate, solvate, tautomer, optical isomer, prodrug derivative or pharmaceutically acceptable salt thereof; with the proviso that one of A or Z is a heterocyclic ring; and when D is nitrocene, the heteroatom of Z 'is selected from the group consisting of sulfur or oxycene in the 1-, 2- or 3- position and the nitrocene in the 1-, 2-, 3- or 4- position,

20. A method of treating sepsis, septic shock, rheumatoid arthritis, osteoarthritis, cerebrovascular accidents, apoptosis, asthma, chronic bronchitis, bronchitis aquda, 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 of formula (II) in which; R1 is -NHNH2 or -NH2; R2 is selected from the group given by -OH and -0 (CH2) mR5, where R5 is H, -C02H, -C02 (alkyl of 1 to 4 carbon atoms); -P (0) (R6R7), wherein each of R6 and R7 is independently -OH or -O-alkyl of 1 to 4 carbon atoms; -S03H, -SO3 (C 1 -C 4 alkyl, tetrazolyl, -CN, NH 2, -NHSO 2 R 15; -CONHS 0 2 R 15, wherein R 15 is C 1 -C 6 alkyl or -CF 3, phenyl or phenyl substituted with C0 2 H or -C02-alkyl of 1 to 4 carbon atoms where m is 1-3; R3 is H, -O-alkyl of 1 to 4 carbon atoms, halo, -alkyl of 1 to 6 carbon atoms, phenyl substituted with - alkyl of 1 to 6 carbon atoms, halo or -CF3; -CH2OSi-alkyl of 1 to 6 carbon atoms, furyl, thiophenyl, -hydroxyalkyl of 1 to 6 carbon atoms; or - (CH2) nR8 - where R8 is H, -CONH2, -NR9R10, -CN or phenyl, where R9 and R10 are independently -alkyl of 1 to 4 carbon atoms or -phenylalkyl of 1 to 4 carbon atoms and n is 1 to 8; R4 is H, - alkyl of 5 to 14 carbon atoms, -cycloalkyl of 3 to 14 carbon atoms, pyridyl, phenyl or phenyl substituted with -alkyl of 1 to 6 carbon atoms, halo, CF3, -0CF3, -alkoxy of 1 to 4 atoms from carbon, -CN, -alkylthio of 1 to 4 carbon atoms, phenylalkyl of 1 to 4 carbon atoms, -alkylphenyl of 1 to 4 carbon atoms, phenyl, phenoxy or naphthyl; A is phenyl or pyridyl, where the nitrocene is in the 5-, 6-, 7- or 8- position; Z is cyclohexenyl, phenyl, pyridyl, where the nitrogen is in the 1-, 2- or 3- position, or a 6-membered heterocyclic ring having a heteroatom selected from the group consisting of sulfur or oxygen in the 1- position, 2- or 3-, and nitrogen in the 1-, 2-, 3- or 4- position, or where a carbon in the heterocyclic ring is optionally substituted with = 0, or a racemate, solvate, tautomer, optical isomer, derivative pharmaceutically acceptable prodrug or salt thereof; with the proviso that one of A or Z is a heterocyclic ring.

21. A method of claim 8 for alleviating the pathological effects of sepsis, septic shock, respiratory distress syndrome in adults, pancreatitis, trauma induced shock, bronchial asthma, allergic rhinitis, rheumatoid arthritis, cystic fibrosis, cerebrovascular accidents, acute bronchitis, chronic bronchitis, bronchitis, bronchitis chronic, osteoarthritis, qota, spondylarthropathy, ankylosing spondylitis, Reiter's syndrome, psoriatic arthropathy, enteropatric spondylitis, juvenile arthropathy or juvenile ankylosing spondylitis, reactive arthropathy, infectious or post-infection arthritis, gonococcal arthritis, tuberculous arthritis, viral arthritis, fungal arthritis , syphilitic arthritis, Lyme disease, arthritis associated with "vasculitis syndromes", polyarteritis nodosa, hypersensitivity vasculitis, Luegenec granulomatosis, rheumatic polymialgina, joint cell arteritis, arthropathies of calcium crystals deposition, pseudogout, rheumatism non-joint, bursitis, tenosynovitis, epicondylitis (tennis elbow), carpal tunnel syndrome, repetitive use injury (typing), various forms of arthritis, neuropathic joint disease (Charcot's joint), hermarthrosis (hemarthrosis), purpura from Henoch-Schonlein, 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, lupus systemic erythematosus or polychondritis with relapses and related diseases, characterized in that it comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula I.

22. A method of claim 9 for relieving patolóqicos effects of sepsis, septic shock, respiratory distress syndrome in adults, pancreatitis, trauma-induced shock, bronchial asthma, alérqica rhinitis, rheumatoid arthritis, cystic fibrosis, stroke, aquda bronchitis, chronic bronchitis, aquda bronchiolitis, chronic bronchiolitis, osteoarthritis, Qota, espondialartropatía, ankylosing spondylitis, Reiter's syndrome, psoriatic arthropathy, enterapathric spondylitis, juvenile arthropathy or juvenile ankylosing spondylitis, reactive arthropathy, infectious arthritis or post-infection, qonocócia arthritis; tuberculosis, viral arthritis, fungal arthritis, syphilitic arthritis, Lyme disease, arthritis associated with "vasculitic syndromes", polyarteritis nodosa, hypersensitivity vasculitis, Luegenec's granulomatosis, polymyalgin rheumatica, arteritis joint cells, Hip replacement deposition calcium crystals, pseudogout, non-articular rheumatism, bursitis, tenosynovitis, epicondylitis (tennis elbow), carpal tunnel syndrome, repetitive use injury (typing), various forms of arthritis, neuropathic joint disease (Charcot's joint) , hermarthrosis (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, characterized in that it comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula II.

23. The use of a compound of the formula I according to claim 1 for the manufacture of a medicament for the treatment of sepsis, septic shock, respiratory distress syndrome in adults, pancreatitis, shock induced by trauma, bronchial asthma, rhinitis allergic, rheumatoid arthritis, cystic fibrosis, stroke, acute bronchitis, chronic bronchitis, acute bronchiolitis, chronic bronchiolitis, osteoarthritis, gout, espondialartropatía, ankylosing spondylitis, Reiter's syndrome, psoriatic arthropathy, enterapathric spondylitis, juvenile arthropathy or juvenile anquilosante_ spondylitis, Reactive arthropathy, infectious arthritis or later to a infection, qonocócia arthritis, tuberculous arthritis, viral arthritis, fúnqica arthritis, syphilitic arthritis, Lyme disease, arthritis associated with "vasculitic syndromes", polyarteritis nodosa, hypersensitivity vasculitis, granulomatosis Luegenec, polymyalgin rheumatica, arteritis cells joints, arthropathies of deposition of calcium crystals, pseudogout, non-articular rheumatism, bursitis, tenosynovitis, epicondylitis (tennis elbow), carpal tunnel syndrome, repetitive use injury (typing), various forms of arthritis, neuropathic disease of the ar ticulaciones (charco and joint), hermartrosis (hemarthrosic), Henoch-Schonlein, hypertrophic osteoarthropathy, multicentric reticulohistiocytosis, arthritis associated with certain diseases surcoilosis, 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, characterized in that it comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula I.