MXPA01005932A - 4,5-pyrazinoxindoles as protein kinase inhibitors - Google Patents

4,5-pyrazinoxindoles having formula (I), inhibit or modulate protein kinases, in particular JNK protein kinases and are useful as anti-inflammatory agents, particularly in the treatment of rheumatoid arthritis.

4,5-PIRAZINOXINDOLES Description of the Invention Protein kinases are a class of proteins that regulate a certain number of cellular functions. This takes place by the phosphorylation of specific protein amino acids or substrates, which results in the alteration of the structure of the substrate protein. The structural change modulates the activity of the substrate or its capacity to interact with other groups of union. The enzymatic activity of the protein kinase is related to the speed at which the kinase adds phosphate groups to the substrate. This can be measured, for example, by determining the amount of substrate that has become a given product, as a function of time. The phosphorylation of a substrate takes place in the active site of a protein kinase. The JNK protein kinases (Jun N-terminal kinase) (also known as "stress-activated protein kinases" or "SAPK"), are members of the mitogen-activated protein kinase (MAP) see, for example, S. Gupta et al. , EMBO J., vol 15 no 11 (1996) pp. 2760-2770; and Yang et al., Nature, vol. 289 (October 23, 1997) pp. 865-870. At least, ten JNK isoforms are commonly known. See Gupta, id. REF .: 130116 As its name suggests, one of the substrates of the JNK is the c-Jan. JNK phosphorylates the activation domain of the NH2 terminal of c-Jun in Ser63 and Ser73, causing an increase in the transcriptional activity of cJun. See Gupta, id. In turn, c-Jun is an AP-1 transcription factor that induces gene expression in an ediata-pronta form. See, for example, A. Minden et al., Biochimica et Biophysica Acta 1333 (1997) F85-F104; and A. Karin, Biochimica et Biophysica Acta, vol. 172 (1991) pp. 129-157. JNK proteinoguanase is strongly activated in response to treatment of cells with pro-inflammatory cytokines or exposure to environmental stress. In this way, JNK induces the effect of extracellular stimuli on c-Jun. See Gupta, above; and Minden, see above. Consequently, JNK is a physiological regulator of the transcriptional activity of AP-1. In this way, the inhibition of JNK activity will inhibit the transcription induced by AP-1 of inflammatory and immunological mediators that are involved in pathological proliferative conditions, for example, in inflammatory diseases and neurodegenerative diseases, in particular, rheumatoid arthritis. . See, for example, Swantek et al., Molecular and Cellular Biology, vol 17 (1997) pp. 6274-6282; Maroney et al., J. Neuroscience, vol. 18 (January 1, 1998) pp. 104-111; and Minden, see above in F92. The homologue in the rat, of the JNK, is also called SAPK (stress-activated protein kinase) ("protein kinase activated by stress"). The SAPK isoforms share a significant sequence identity (> 90%) with the corresponding JNK isoforms (see Kyriakis et al., Nature, vol 369 (12 May 1994) pp. 156-160 and Gupta et al., See more above). Both the JNK and the SAPK are capable of phosphony of the cJun substrate, so that they have a very similar enzymatic activity. The JNK and SAPK are part of a protein kinase cascade that is activated by several extracellular stimuli. See for example, Minden above; and Kyriakis et al., BioEssays vol. 18 (1996) pp. 567-577. The JNK and SAPK can each be activated by phosphorylation in specific threonine and tyrosine residues by the dual specificity MAP kinase of kinases such as MKK4, SEK-1, or MKK7. See Kyriakis et al., Above; and Tournier et al., Proceedings of the National Academy of Sciences USA, vol. 94 (July 1997), pp. 7337-7342). The kinases with dual MAP kinase specificity, can be activated by phosphorylation in serine residues and / or threonine by MAP kinase kinases such as MEKK-1. In this way, the measurement of the enzymatic activity of the JNK or SAPK can be enhanced by the activation of the above or preceding kinases. In addition, the extent of inhibition of SAPK is intimately correlated with inhibition of JNK. Inhibitors of the catalytic activity of the protein kinase are already known in the art. See WO 98/24432 (indoline compounds that inhibit FLK protein kinase); WO 97/45409 (analogs of tetrallymethylene substituted oxindole that inhibit tyrosine kinase). In particular, small molecule inhibitors typically block substrate binding through close interaction with the protein kinase ATP binding site (or "active site"). See WO 98/24432. It is desirable to identify the small molecule compounds which can be easily synthesized and are effective for the inhibition of the catalytic activity of the protein kinases, in particular of the JNK protein kinases. The indolinone compounds (also known as oxindole), known to be useful for regulating abnormal cell proliferation through Tyrosine kinase inhibition are described, for example, in patents WO 96/40116, WO 98/07695, WO 95/01349, WO 96/32380, WO 96/22976, WO 96/16964 and WO 98/50356 (derivatives of 2-indolinone as modulators, of the protein kinase activity); Mohammadi et al., Science, vol. 276, May 9, 1997, pp. 955-960. The oxindol derivatives have also been described for several other therapeutic uses: 5,206,261 (improvement of brain function); WO 92/07830, (peptide antagonists); EP 580 502 Al (antioxidants). It remains a necessity to have readily synthesizable, small molecule compounds effective in inhibiting JNK proteinoguinase and therefore useful in the treatment or control of pathological proliferative conditions, for example inflammatory diseases and neurodegenerative diseases, in particular , rheumatoid arthritis. It is therefore an object of this invention to provide said compounds and compositions containing said compounds. The present invention relates to certain 4,5-pyrazinoxindoles capable of inhibiting the activity of one or more JNK protein kinases. These compounds are useful for the treatment of diseases inflammatory and neurodegenerative diseases. In particular, the compounds of the present invention are especially useful in the treatment or control of rheumatoid arthritis. The compounds of the present invention are the 4,5-pyrazinoxindoles having the following formula: and the pharmaceutically acceptable salts thereof; wherein R1 and R2 are independently selected from the group consisting of hydrogen -OR4, -COR4, -COOR ", -CONR ^ R6, -NR5R6, lower alkyl, which may be substituted with a member of group (a), consisting of -OR4, -NR5R6, halogen, -COR4, -COOR4, -0C0R4, -C0NR5R6, -CN, -S02R4, -S02NR5R6; or with cycloalkyl, heterocycle, aryl and heteroaryl, wherein the cycloalkyl and the heterocycle each, may be substituted with the group R11 and the aryl and heteroaryl may each be substituted, with the group R12, cycloalkyl, which may be substituted with a member of group (a) as defined above, or with lower alkyl, heterocycle, aryl and heteroaryl, wherein the lower alkyl and heterocycle each may be substituted with the group R11 and the aryl and heteroaryl each may be be substituted with the group R12, heterocycle, which may be substituted with a member of group (a) as defined above, or with lower alkyl, cycloalkyl, aryl, and heteroaryl, wherein the lower alkyl and cycloalkyl each, may be substituted with the group R11 and the aryl and heteroaryl each, may be optionally substituted with the group R12, aryl, which may be substituted with a member of the group (b) for by -OR4, -NR5R6, halogen, -N02 / perfluoroalkyl, -COR4, -COOR4, -0C0R4, -C0NR5R6, -CN, -S02R4, -S02NR5R6; or with lower alkyl, cycloalkyl, heterocycle, aryl and heteroaryl, and wherein the lower alkyl, cycloalkyl and heterocycle each, may be substituted with the group R11 and the aryl and heteroaryl each may be substituted with the group R12, heteroaryl, which may be substituted with a member of group (b) as defined above, or with lower alkyl, cycloalkyl, heterocycle, aryl and heteroaryl, and wherein the lower alkyl, cycloalkyl and heterocycle each, may be optionally substituted with the group R11 and the aryl and Leteroaryl each, may be substituted with the group R12, or alternatively, R1 and R2 may form a ring of 5-7 atoms, said ring optionally including one or more heteroatoms and being optionally substituted with a member of the group formed by -OR8, -COR7, -COOR7, -0C0R4, -CONR7R9, -NR8R9, or lower alkyl, which may be substituted with the group R11; R3 is hydrogen, -OR4, -COR4, -COOR4, -0C0R4, -CONR5R6, halogen, -CN, perfluoroalkyl -NR5R6, or lower alkyl which may be substituted with -OR4, -0C0R4, or -NR5R6; R4 is hydrogen, lower alkyl, which may be substituted with a member of group (c) formed by -OR8, -COOR7, -COR7, -CONR5R6, -NR5R6, S02R7, S02NR5R6; or with cycloalkyl, heterocycle, aryl and heteroaryl, and wherein the cycloalkyl and heterocycle each may be substituted with the group R11 and the aryl and heteroaryl each may be substituted with the group R12. cycloalkyl, which may be substituted with a member of group (c) as defined above, or with lower alkyl, heterocycle, aryl and heteroaryl, wherein the lower alkyl and heterocycle each may be substituted with the group R11 and the aryl and heteroaryl each may be substituted with the group R12, heterocycle, which may be substituted with a member of group (c) as defined above, or with cycloalkyl, lower alkyl, aryl, and heteroaryl, and wherein the cycloalkyl and the lower alkyl each, may each be substituted with the group R11 and the aryl and heteroaryl, may be optionally substituted with the group R12, aryl, - which may be substituted with a member of the group (d) formed by -OR8, -COOR7, -COR7, -CONR5R6, -NR5R6, -N02, halogen, perfluoroalkyl, S02R7, -S02NR5R6; or with lower alkyl, cycloalkyl, heterocycle, aryl and heteroaryl, and wherein the lower alkyl, cycloalkyl and heterocycle each may be substituted with the group R11, and the aryl and heteroaryl each may be substituted with the group R12, and heteroaryl, which may be substituted with a member of group (d) as defined above or with cycloalkyl, lower alkyl, heterocycle, aryl and heteroaryl, and wherein the lower alkyl, cycloalkyl and heterocycle each, may be substituted with the group R11 and the aryl and heteroaryl each may be substituted with the group R12; R5 and R6 are each, independently of each other, hydrogen -COR7, -COOR7, -CONR7R9, lower alkyl, which may be substituted with a member of group (e), formed by -OR8, -COOR7, -COR7, - CONR7R8, -NR7R8, -S02R7, -S02NR7R8; or with cycloalkyl, heterocycle, aryl and heteroaryl, and wherein the cycloalkyl and heterocycle each, may be substituted with the group R11 and the aryl and heteroaryl each may be substituted with the group R12, cycloalkyl, which may be substituted with a member of group (e) as defined above, or with lower alkyl, heterocycle, aryl and heteroaryl, and wherein the lower alkyl and heterocycle each may be substituted with the group R11 / aryl and heteroaryl each may be substituted with the group R12, heterocycle, which may be substituted with a member of group (e) as defined above, or with cycloalkyl, lower alkyl, aryl, and heteroaryl, and wherein the cycloalkyl and lower alkyl each may be substituted with the group R11 and the aryl and heteroaryl each, may be optionally substituted with the group R12, arilc, which may be substituted with a member of the group (f) formed by -OR8, -COOR7, -COR7, -C0NR7R8, -NR7R8, -N02, halogen, perfluoroalkyl, -S02R7, -S02NR R8; or with lower alkyl, cycloalkyl, heterocycle, aryl, and heteroaryl, and wherein the lower alkyl, cycloalkyl, and heterocycle may each be substituted with the group R11 and the aryl and heteroaryl each may be substituted with the group R12, and heteroaryl, which may be substituted with a member of group (f) as defined above or with, lower alkyl, cycloalkyl, heterocycle, aryl and heteroaryl, and wherein the lower alkyl, cycloalkyl and heterocycle each may be substituted with the group R11 and the aryl and heteroaryl each may be substituted with the group R12; or alternatively, -NR5R6 can form a ring of 3 to 7 carbon atoms, said ring optionally including one or more additional heteroatoms and optionally being substituted with lower alkyl, -OR8, -COR7, -COOR7, -C0NR7R9 or - NR8R9; R7 is hydrogen or lower alkyl which may be substituted with a member of the group consisting of cycloalkyl, heterocycle, aryl, heteroaryl, -OR9, or -NR8R9; R8 is hydrogen, -COR9, -CONR10R9, or lower alkyl which may be substituted with R11; R9 and R10 are each independently of one another, hydrogen or lower alkyl; R11 is -OR9, -COR9, -COOR9, -OCOR9, -CONR9R10, -NR9R10, -N (COR9) R10, -S02R9, or -S02NR9R10; R12 is -OR9, -COR9, -COOR9, -OCOR9, -C0NR9R10, -NR9R10, -N (COR9) R10, - S02R9, - S02NR9R1 0, halogen, -CN, -N02 / or perfluoroalkyl lo; and X e s N or CH. The present invention further relates to pharmaceutical compositions comprising a pharmaceutically effective amount of any one or more of the compounds described above and a pharmaceutically acceptable carrier or excipient. The present invention also relates to new intermediate products, useful in the synthesis of the compounds described above. The present invention also relates to the use of a compound of formula I, and / or the pharmaceutically active salts, prodrugs or metabolites thereof, in the preparation of a medicament for the treatment and / or control of inflammatory and neurodegenerative diseases, particularly of rheumatoid arthritis, or for the treatment of solid tumors, in particular breast or colon tumors. As used herein, the following terms have the following definitions: "Aryo" means an aromatic group of 5 to 10 atoms consisting of one or two rings. Examples of aryl groups include phenyl and 1- or 2-naphthyl. "Cycloalkyl" means a hydrocarbon group cyclic aliphatic, non-aromatic, partially or completely saturated, containing 3 to 8 atoms. Examples of cycloalkyl groups include cyclopropyl, cyclopentyl and cyclohexyl. "Effective amount" means an amount of at least one compound of formula I, or a pharmaceutically acceptable salt, prodrug or metabolite thereof, that inhibits the development or proliferation of (1) an inflammatory disease or its response, and / or ( 2) a neurodegenerative disease or its response, such as, for example, and not as a limitation, rheumatoid arthritis. "Halogen" means fluorine, chlorine, bromine or iodine. "Heteroaryl" groups are aromatic groups of 5 to 10 atoms, one or 2 rings, and containing one or more heteroatoms. Examples of heteroaryl groups are 2-, 3- or 4-pyridyl, tetrazoyl, oxadiazolyl, pyrazinyl, quinolyl, pyrrolyl, and imidazolyl. "Heteroatom" means an atom selected from N, O and S. "Heterocycle" means a hydrocarbon group of 3 to 10 members, partially or completely saturated, non-aromatic, such as tetrahydroquinolyl, containing one or two rings and at least one heteroatom "IC5o" means the concentration of a 4.5- pyrazinox particular indole, necessary to inhibit 50% of the cJun phosphorylation, which is a measure of the inhibition of SAPK activity. The IC50 can be measured, among other ways, using the assay described here in example 7, below. "Lower alkyl" means a straight or branched chain saturated aliphatic hydrocarbon, from 1 to 6, preferably 1 to 4, carbon atoms. Typical lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, t-butyl, 2-butyl, pentyl, hexyl, and the like. "Pharmaceutically acceptable salt" means acid addition salts or conventional basic addition salts, which retain the biological effectiveness and properties of the compounds of formula I and are formed of suitable non-toxic organic or inorganic acids, or inorganic bases. Acid addition salts of sample include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfuric acid, phosphoric acid and nitric acid and derivatives of organic acids such as p-acid. phonic toluensul, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, and Similar. Basic sample addition salts include those derived from the ammonium, potassium, sodium and quaternary ammonium hydroxides, such as for example tetramethylammonium hydroxide. "Pharmaceutically acceptable", such as a pharmaceutically acceptable carrier, excipient, prodrug, etc., means pharmacologically acceptable and substantially non-toxic to the individual to whom the particular compound is administered. "Pharmaceutically active metabolite" means a metabolic product of a compound of formula I, which is pharmaceutically acceptable and effective. "Prodrug" means a compound that can be converted, under physiological conditions or by solvolysis, into any one of the compounds of formula: or a pharmaceutically acceptable salt of a compound of formula I. A prodrug can be inactive when administered to a individual but becomes in vi in an active compound of formula I. "Substituted", as for example "substituted alkyl" means that the substitution can be made in one or more positions and, unless otherwise indicated, that the Substituents are independently selected from specific options.

Preferred perfluoroalkyls, according to the present invention, include -CF3. In a preferred embodiment of the compounds of formula I, R1 and R2 are, independently of each other, hydrogen -NR5 R6, lower alkyl, which may be substituted with R11, cycloalkyl, heterocycle, aryl and heteroaryl, wherein the cycloalkyl and heterocycle they may be substituted with R11, and the aryl and heteroaryl may be substituted with R12; cycloalkyl, which can be substituted with R11, lower alkyl, heterocycle, aryl, and heteroaryl, wherein the lower alkyl and heterocycle may be substituted with R11, and the aryl and heteroaryl may be substituted with R12; heterocycle, which can be replaced with R11, lower alkyl, cycloalkyl, aryl and heteroaryl, wherein the lower alkyl and cycloalkyl may be substituted with R11, and the aryl and heteroaryl may be substituted with R12; arylc, which may be substituted with R12 'lower alkyl, cycloalkyl, heterocycle, aryl and heteroaryl, wherein the lower alkyl and heterocycle and cycloalkyl may be substituted with R11, and the aryl and heteroaryl can be substituted with R12; heteroaryl, which may be substituted with R 12, lower alkyl, cycloalkyl, heterocycle, aryl and heteroaryl wherein the lower alkyl, cycloalkyl and heterocycle may be substituted R 11, and the aryl and heteroaryl, may be substituted with R 12; or alternatively, R1 and R2 may form a ring of 5 to 7 atoms and optionally be substituted with a group selected from -OR8, COR7, -COOR7, -CONR7R9, and lower alkyl, which may be substituted with R11. More preferably, R1 and R2 are independently from each other, lower alkyl, aryl, particularly phenyl, or heterocycle, particularly furanyl, or R1 and R2 together form a ring of 5-7 atoms, particularly a cyclohexane ring. In another preferred embodiment of the compounds of formula I, R3 is hydrogen, -OR4, -NR5R6, or lower alkyl, which may be substituted with the group consisting of -OR4 and NR5R6. In another preferred embodiment of the compounds of formula I, R3 is hydrogen, -0R4, -NR5R6 or lower alkyl which may be substituted with the group consisting of -OR4 and -NR5R6. In another preferred version of the compounds of Formula I, R3 is hydrogen, -OR9 or lower alkyl which may be substituted with the group consisting of OR9 and -NR9R10. More preferably R3 is lower alkoxy. The following are examples of the preferred compounds of formula I: (Z) -7, 9-dihydro-2,3-dimethyl-9 - [(3-methoxy-1H-pyrrol-2-yl) methylene] -8H-pyrrolo- [3, 2-f] quinoxalin-8- ona (A). (Z) -3-Butyl-7,9-dihydro-9 - [(3-methoxy-lH-pyrrol-2-yl) ethylene] -2-methyl-1H-pyrrolo- [3, 2-f) quinoxalin -8-one, and (Z) -2-butyl-7, 9-dihydro-9 - [(3-methoxy-lH-pyrrol-2-yl) ethylene] -3-methyl-8H-pyrrolo- [3, 2-f] quinoxalin-8-one (B), (Z) -7, 9-dihydro-9 - [(3-methoxy-lH-pyrrol-2-yl) ethylene] -2-met i 1-3- phenyl-8H-pyrrolo- [3, 2-f] quinoxal in- 8-one, and (Z) -7, 9-dihydro-9 - [(3-methoxy-lH-pyrrol-2-yl) methylene] - 3-methyl-2-phenyl-8H-pyrrolo- [3,2-f] quinoxalin-8-one (C), (Z) -7, 9-dihydro-2,3-di- (2-furanyl) - 9- [(3-methoxy-1H-pyrrol-2-yl) ethylene] -8H-pyrrolo- [3, 2-f] quinoxalin-8-one (D), (Z) -1, 3, 5, 6 , 7, 8-hexahydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-pyrrolo- [3, 2-f] phenazin-2-one (E).

The compound described herein and exemplified with the above formulas may exhibit tautomerism or structural isomerism. It is intended that the invention encompass any tautomeric or structural isomeric form of these compounds or mixtures of said forms, without thereby being limited to any one of these tautomeric or structural isomeric forms used within the formulas mentioned above. The compounds of formula I can be prepared by methods known in the art. In the examples that follow, suitable processes for the synthesis of these compounds are described. Generally, these compounds can be prepared according to the following synthesis schemes: Step A Step B He passed Step D Step E In an alternative embodiment, the present invention relates to pharmaceutical compositions containing at least one compound of formula I or a prodrug thereof, or a pharmaceutically accele salt of a compound of formula I or a prodrug thereof. These pharmaceutical compositions can be administered orally, for example in the form of tablets, coated tablets, dragees, hard or soft gelatine capsules, solutions, emulsions or suspensions. They can also be administered rectally, for example, in the form of suppositories, or parenterally, for example, in the form of solutions for injection. The pharmaceutical compositions of the present invention, which contain compounds of formula I, prodrugs of such compounds, or salts thereof, can be prepared in a manner known from the art. specialty, for example, by means of conventional mixing, encapsulation, dissolution, granulation, emulsion, occlusion, preparation of dragees or lyophilization processes. These pharmaceutical preparations i.cas can be formulated with inorganic or organic, therapeutically inert supports. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts, can be used as supports for tablets, coated tablets, dragees and hard gelatine capsules. Suitable supports for soft gelatine capsules are vegetable oils, waxes, fats, semi-solid or liquid "poly". Depending on the nature of the active substance, no support is generally necessary in the case of soft gelatin capsules. Suitable supports for the development of solutions and syrups are water, polyols, sucrose, invert sugar and glucose. Suitable supports for injection are water, alcohols, polyols, glycerin, vegetable oils, phospholipids and surfactants. Suitable substrates for suppositories are natural or hardened oils, waxes, fats and polyols are illiquid. The pharmaceutical preparations may also contain preserving agents, solubilizing agents, stabilizing agents, wetting agents, agents emulsifiers, sweetening agents, coloring agents, flavoring agents, salts for varying the osmotic pressure, buffers, coating agents or anti-oxidants. They may also contain other substances of therapeutic value, including additional active ingredients other than those of formula I. As mentioned above, the compounds of formula I, prodrugs thereof, and their salts and compositions containing these compounds, are useful in the treatment or control of inflammatory diseases and neurodegenerative diseases, in particular in the treatment or control of rheumatoid arthritis. A therapeutically effective amount of a compound according to this invention means an amount of compound that is effective in preventing, alleviating or ameliorating symptoms of the disease. The determination of the therapeutically effective amount falls within the skill of the specialty. The therapeutically effective amount or dosage of a compound of formula I can vary within wide limits and will be adjusted to the individual requirements of each particular case. In general, in the case of oral administration or parenteral to adult humans with a weight of about 70 kgs, a daily dosage of about 10 mg to about 10,000 mg, preferably from about 200 mg to about 1,000 mg, should be adequate, although the upper limit may be exceeded when indicated. The daily dosage can be administered as a single dose or in divided doses, or for parenteral administration, it can take the form of a continuous infusion. The compounds of the present invention can be synthesized according to known techniques, such as for example the general scheme given above. The following examples illustrate the preferred methods for the synthesis of the compounds and formulations of the present invention. As used hereinafter, t.a. is room temperature, EtOH is ethanol, MeOH is methanol and THF is tetrahydrofuran. Example 1: General Methods of Synthesis and Starting Materials General Method A: Preparation of (Z) -7,9-dihydro-9- [3-methoxy-lH-pyrrole-2-yl] methylene] -8H-pyrrolo [3, .2-f] quinoxalin-8-ones To a suspension of the starting diamine derivative (60 mg, 0.22 mmol) (starting material 5), in EtOH (3 ml) were added 10 equivalents of diketone. After heating, the suspension became a dense orange solid. The mixture was cooled to t.a. and the precipitate was collected by filtration by suction, and then dried overnight in a vacuum oven. The asymmetric diketones provided a mixture of regioisomers. Starting material 1; 1,3-dihydro-4-fluoro-2H-indol-2-one 6-Fluoro-2-nitrobenzyl cyanide (23.10 g, 0.12 mole) (prepared according to A. Kalir et al., Synthesis, 1987, 514-515), was dissolved in 10: 1 MeOH / H20 (250 ml ), and the solution was cooled in an ice water bath. HBr gas was bubbled through the cold mixture for 75 minutes. The solution was allowed to warm to t.a. and then concentrated to half volume at reduced pressure. THF (100 ml), water (100 ml) and conc. HCl were added successively. (6 ml), at t.a. and stirring was maintained for 75 minutes. The mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with water, saturated aqueous NaHC03, and brine, then dried with sodium sulfate and concentrated under reduced pressure.

This material (20.9 g) was dissolved in acetic acid (200 ml) and hydrogenated for 2 hours in an apparatus Parr at 50 Psi in the presence of Pd 10% / C (4.33 9). The reaction mixture was filtered through a cake of Celite® (Fischer Scientific) and the cake was washed with acetic acid. The solution was concentrated under reduced pressure and dissolved in MeOH (300 mL) containing IN NaOH (15 mL). This mixture was poured into NaCl sol. sat./H20 2: 1 (600 ml) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried with sodium sulfate and concentrated. The crude residue was triturated with ether to obtain 5.8 (first harvest) of 1, 3-dihydro-4-fluoro-2H-indol-2-one pure. The mother liquor was chromatographed on silica gel (230-400 mesh, eluted with 40% ethyl acetate in hexane), obtaining an additional 1.6 g of product (total cyanide yield: 41%). Starting material 2: 1, 3-dihydro-4-fluoro-5-nitro-2H-indol-2-one 1,3-dihydro-4-fluoro-2H-indol-2-one (6.29 g, 41.6 mmol) (starting material 1, above) was dissolved in 100 ml of H2SO4 with stirring. This mixture was cooled in a dry ice-acetone bath at -20 ° C to which a solution of 2.6 ml (41.6 mmoles) of HN03 in 10 ml of H2SO4 was added slowly over 30 minutes. Then, the reaction mixture was stirred at -20 ° C for 45 minutes (TLC: 50% ethyl acetate in hexaro, showed that the reaction was complete after 30 minutes), then it was poured into 1 liter of ice and water, extracted with 2x200 ml of ethyl acetate, washed with 2 x 200 ml of saturated NaCl solution, it was dried with Na 2 SO, filtered and concentrated at 45 ° C under high vacuum to obtain a brown solid (7.87 g). This material was recrystallized from ethyl acetate to obtain 3.94 g (first harvest only) of the pure product. The mother liquor was chromatographed on silica gel (230-400 mesh, eluted with 50% ethyl acetate in hexane) to obtain 1.91 g of additional material (total yield: 5.85 g, 71.7%). Starting material 3: (Z) -1, 3-dihydro-4-fluoro-3- [(3-methoxy-lH-pyrrol-2-yl) ethylene] -5-ni tro-2H-indo1-2-one 1, 3-dihydro-4-fluoro-5-nitro-2H-indol-2-one (5.25 g, 26.8 mmol) (starting material 2), was suspended in 110 ml of 1.35% piperidine solution (Aldrich) in 2-propanol (Fisher). 3-Methoxy-2-pyrrole carboxaldehyde (3.68 g 29.4 mmoles, 1.1 equivalents) (prepared according to F. Bellamy et al., J. Chem. Research (S) 1979, 18-19; J. Chem. Research (M) 1979, 0101-0116), and the mixture was heated at 60 ° C for 3.5 hours (TLC: 50% ethyl acetate in hexane). The reaction mixture was poured into 1 liter of a mixture of water and ice, and the precipitated solid was filtered, washed with water and dried at 50 ° C under high vacuum to give the product as a brown solid. orange (yield 6.6 g 81%). Starting material 4: (Z) -4-azido-l, 3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) ethylene] -5-nitro-2H-indol-2-one (Z) -1,3-dihydro-fluoro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -5-nitro-2H-indol-2-one (6.60 g, 21.8 mmol) (starting material 3, above), suspended in 330 mL of THF and 165 mL of ethanol: To this mixture was added diipropylethylamine (56.9 mL, 326 mmol) (Aldrich) and trimethylsilyl azide (28.6 mL, 216 mmol) (Aldrich). The reaction mixture was heated to reflux overnight, and then poured into 2 liters of ice mixture and IN solution of HCl. The solid precipitate was filtered, washed with water and dried at 50 ° C under high vacuum to obtain (Z) -4-azido-1,3-dihydro-3- [(3-methoxy-H-pyrrol-2-yl. Methylene] -5-nitro-2H-indol-2-one as a dark red solid (yield 6.44 g, 90%). Starting material 5: (Z) -4,5-diamino-1,3-dihydro-3- [(3-methoxy-1H-pyrrol-2-yl) methylene] -2H-indol-2-one (Z) -4-azido-l, 3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -5-nitro-2H-indol-2-one (2.08g, 6.37 mmoles ) (starting material 4, see above) was dissolved in THF (16Q ml) at t.a. Ammonium hydroxide (2 ml) was added followed by a catalytic amount of depleted platinum on carbon (Pt 5% / Cl / 2S, 300 mg) (Engelhard Ind). The reaction mixture was hydrogenated in a Parr pump to SO psi of hydrogen for 12 hours. The mixture was filtered through a cake of Celite®, the cake was washed twice with THF, and the filtrate was concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (230-400 mesh, eluted with 75% ethyl acetate in hexane), yielding (Z) -4,5-diamino-1,3-dihydro-3- [(3-) methoxy-lH-pi-rrol-2-yl) methylene] -2H-indol-2-one (yield 1.} .44 g, 84%). Example 2: (Z) -7, 9-dihydro-2,3-dimethyl-9 - [(3-methoxy-lH-pyrrol-2-yl) methylene] -8H-pyrrolo [3, 2-f] quinoxalin- 8-one (A) Using method A (see above), (Z) -4,5-diamino-l, 3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) ethylene] -2H- was condensed indole-2-one (60 mg, 0.22 mmol) (starting material 5), with 2,3-butanedione (135 μl) (Aldrich) in ethanol (3 ml) at reflux to obtain (Z) -7, 9 -dihydro-2, 3-dimethyl-9 - [(3-methoxy-lH-pyrrol-2-yl) methylene] -8H-pyrrolo- [3, 2-f] guinoxalin-8-one with 100% yield . Example 3: Mixture of (Z) -3-butyl-7,9-dihydro-9 - [(3-methoxy-lH-pyrrol-2-yl) methylene] -2-methyl-8H-pyrrolo- [3, 2 -f] quinoxalin-8-one and (Z) -2-butyl-7,9-dihydro-9 - [(3-methoxy-lH-pyrrol-2-yl) ethylene] -3-methyl-8H-pyrrolo- [3, 2-f] quinoxalin-8-one (B) Using method A above, the (Z) -, 5-di-amino-1,3-dihydro-3- [(3-metho-lH-pyrrol-2-yl) ethylene] -2H-indol-2-one (60 mg, 0.22 mmol) ) (starting material 5), with 2, 3-heptanedione (282 μl) (Lancaster) in ethanol (3 ml) under reflux to give a mixture of (Z) -3-butyl-7,9-dihydro-9 - [(3-methoxy-lH-pyrrol-2-yl) methylene] -2-methyl-8H-pyrrolo- [3,2-f] quinoxalin-8-one and (Z) -2-butyl-, 9- dihydro-9 - [(3-methoxy-lH-pyrrol-2-yl) methylene] -3-methyl-8H-pyrrolo- [3, 2-f] quinoxalin-8-one with 88% yield. Example 4: Mixture of (Z) -7,9-dihydro-9 - [(3-methoxy-lH-pyrrol-2-yl) methylene] -2-methyl-phenyl-8H-pyrrolo- [3,2-f ] quinoxalin-8-, ona and (Z.) -7, 9-dihydro-9 - [(3-methoxy-lH-pyrrol-2-yl) methylene] -3-methy1-2-phenyl-8H-pyrrolo- [3,2-f] quinoxalin-8-one (C) Using method A above, the (Z) -4,5-di-amino-1,3-dihydro-3- [(3-methoxy-1H-pyrrole-2-) was condensed. il)) methylene] -2H-indol-2-one (60 mg, 0.22 mmol) (starting material 5), with l-phenyl-1,2-propanedione (326 μl) (Aldrich) in ethanol (3 ml) under reflux to give a mixture of (Z) -7,9-dihydro-9- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2-methyl-3-phenyl-8H-pyrrolo [3, 2-f] quinoxalin-8-one and (Z) -7,9-dihydro -9- [(3-methoxy-lH-pyrrol-2-yl) -methylene] -3-methyl-2-phenyl-dH-pyrrolo [3,2-f] quinoxalin-8-one with 46% yield . Example 5: (Z) -7,9-dihydro-2,3-di- (2-furanyl) -9 [(3-methoxy-lH-pyrrol-2-yl) ethylene] -8H-pyrrolo- [3, 2, f] quinoxalin-8-one (D) Using method A above, (Z) -4,5-diamino-l, 3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indole-2 was condensed ona (60 mg, 0.22 mmol) (starting material 5), with furyl (200 mg) (Aldrich) in ethanol (3 ml) under reflux to give (Z) -7, 9-dihic.ro-2,3-di- (2-furanyl) -9- [(3-methoxy-lH-pyrrol- 2-yl) methylene] -8H-pyrrolo- [3, 2-f] quinoxalin-8-one, with a yield of 86%. Example 6: (Z) -l, 3,5,6,7,8-hexahydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-pyrrolo [3, 2-a] Phenazin-2-one (E) Using method A above, (Z) -4, -diamino- 1, 3-dihydro-3 [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indole-2 was condensed nona (60 mg, 0.22 mmoles) starting material 5), with 1,2-cyclohexanedione (248 mg) (Aldrich) in ethanol (3 ml) under reflux to give the (Z) -1, 3, 5, 6 , 7, 8-hexahydro-3- ([3-methoxy-lH-pyrrol-2-yl) methylene] -2H-pyrrolo- [3, 2-a] phenazin-2-one, with a yield of 18%. Example 7: Inhibitory activity of SAPK The inhibitory activity of SAPK of the compounds of the invention is demonstrated below. These The effects indicate that the compounds of the present invention are useful in the treatment of inflammatory diseases such as, for example, rheumatoid arthritis. SAPK flash plate assay Human JNK is highly homologous to the SAPK of the rat. To measure the inhibitory activity of the test compounds, the compounds were tested with the rat SAPK assay. For the SAPK assay, they were coated with purified GST-cJUN (a chimeric protein containing cJun, a natural substrate of the JNK), 96-well flash plates (New England Nuclear, Boston, V. A). The purified rat SAPK was preincubated (isoform ß, Kyriakis et al., see above) with preparations containing MEKK-1 and MKK4 for 30 minutes at 37 ° C in assay buffer containing 25 mM Hepes, pH 7.5, 150 mM NaCl, 20 mM2 MgCl2, 2 mM DTT, 0.001% of Tween 20, 1 mM of ATP, newly added.

In the preincubation step, MEKK-1 phosphorylates and activates MKK-4, which in turn phosphorylates and activates the SAPK. The activated SAPK was then added to the flash plates coated with cJun together with 33P-ATP (0.32 μCi per reaction) and the test compounds. The plates were incubated for 30 minutes at 37 ° C, then they were washed with PBS, 0.01% Tween 20, and counted with the Topcount scintillation counter (Packard Instrument Co., Downers Grove, IL). The dilutions of the compounds were analyzed in duplicate in each assay. The percent inhibition of fostorilation of cJun (a measure of the inhibition of SAPK activity), was determined by the following formula: 100 X 1 - test compound - non-specific J total - non-specific in which, "test compound" means the average of counts per minute of the tests in duplicate "non-specific" means the average of accounts per minute when SAPK has not been added, and "total" means the average of counts per minute when no compound has been added. In Table I, below, the results of the SAPK assay are summarized with several test compounds.

Table 1 Example 8: Formulation of tablets Compound 1 represents a compound of this invention. Preparation procedure: 1. Mix items 1,2 and 3 in a suitable mixer for 15 minutes. 2. Granulate the powder mixture from step 1, with a 20% solution of Povidone K30 (item 4). 3. Dry the granulate from step 2 at 50 ° C. 4. Pass the granulate from step 3 through suitable grinding equipment. 5. Add item 5 to the ground granulate from step 4 and mix for 3 minutes. 6. Compress the granulate from step 5 in a suitable press.

Example 9: Formulation of capsules * Compound 1 represents a compound of this invention.

Preparation procedure: 1. Mix items 1, 2 and 3 in a suitable mixer for 15 minutes. 2. Add items 4 and 5 and mix for 3 minutes. 3. Fill suitable capsules.

Example 10: Solution for injection / Preparation of an emulsion Compound 1 represents a compound of the invention Elaboration procedure: 1. Dissolve item 1 in item 2. 2. Add items 3,4 and 5 to item 6 and mix until dispersion, then homogenei: .ar. 3. Add the solution from step 1 to the mixture from step 2 homogenize until the dispersion is translucent. 4. Filter sterile through a 0.2 μm filter and fill the vials.

Example 11: Solution for injection / Preparation of the emulsion compound 1 represents a compound of the invention Preparation procedure Dissolve item 1 in item 2 2. Add items 3, 4 and 5 to item 6 and mix until dispersion, then homogenize. 3. Add the solution from step 1 to the mixture from step 2 and homogenize until the dispersion is translucent. 4. filter sterile through a 0.2 μm filter and fill the vials.

It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects to which it relates.

1. R E I V I N D I C A I N N E S Having described the invention as above, the content of the following claims is claimed as property: 1. A compound of the formula: characterized in that R1 and R2 are independently selected from the group consisting of hydrogen -OR4, -COR5, -COOR4, -CON: 5R6, -NR5R6, lower alkyl, which may be substituted with a member of group (a), formed by - OR4, -NR5R6, halogen, -COR4, -COOR4, -OCOR4, -C0NR5R6, -CN, -S02R4, -S02NR5R6; or with cycloalkyl, heterocycle, aryl and heteroaryl, wherein the cycloalkyl and the heterocycle each, may be substituted with the group R11 and the aryl and heteroaryl may each be substituted, with the group R12, cycloalkyl, which may be substituted with a member of group (a) as defined above, or with lower alkyl, heterocycle, aryl and heteroaryl, wherein the lower alkyl and heterocycle each may be substituted with the group R11 and the aryl and heteroaryl each may be be substituted with the group R12, heterocycle, which may be substituted with a member of group (a) as defined above, or with lower alkyl, cycloalkyl, aryl, and heteroaryl, wherein the lower alkyl and cycloalkyl each, may be substituted with the group R11 and the aryl and heteroaryl each, may be optionally substituted with the group R12, aryl, which may be substituted with a member of group (b) for by -OR4, -NR5R6, halogen, -N02, perfluoroalkyl, -COR4, -COOR4, -OCOR4, -C0NR5R6, -CN, -S02R4, -S02NR5R6; or with lower alkyl, cycloalkyl, heterocycle, aryl and heteroaryl, and where the lower alkyl, cycloalkyl and heterocycle each may be substituted with the group R11 and the aryl and heteroaryl each may be substituted with the group R12, heteroaryl, which may be substituted with a member of group (b) as defined above, or with lower alkyl, cycloalkyl, heterocycle, aryl and heteroaryl, and wherein the lower alkyl, cycloalkyl and heterocycle each, may be optionally substituted with the group R11 and the aryl and heteroaryl each, may be substituted with the group R12, or alternatively, R1 and R2 can form a ring of 5-7 atoms, said ring optionally including one or more heteroatoms and being optionally substituted with a member of the group consisting of -OR8, -COR7, -COOR7, -OCOR4, -CONR7R9, -NR8R9, or lower alkyl, which may be substituted with the group R11; R3 is hydrogen, -OR4, -COR4, -COOR4, -OCOR4, -C0NR5R6, halogen, -CN, perfluoroalkyl -NR5R6, or lower alkyl which may be substituted with -OR4, -OCOR4 / or -NR5R6; R 4 is hydrogen, lower alkyl, which may be substituted with a member of group (c) formed by -OR 8, -COOR 7, -COR7, -C0NR5R6, -NR5R6, S02R7, S02NR5R6; or with cycloalkyl, heterocycle, aryl, and heteroaryl, and wherein each cycloalkyl and heterocycle may be substituted with the group R11 and the aryl and heteroaryl each may be substituted with the group R12, cycloalkyl, which may be substituted with a member of group (c) as defined above, or with lower alkyl, heterocycle, aryl and heteroaryl, wherein the lower alkyl and heterocycle each may be substituted with the group R11 and the aryl and heteroaryl each they may be substituted with the group R12, heterocycle, which may be substituted with a member of group (c) as defined above, or with cycloalkyl, lower alkyl, aryl, and heteroaryl, and wherein the cycloalkyl and lower alkyl each, can be substituted with the group R11 and the aryl and heteroaryl each, can be optionally substituted with the group aryl, which may be substituted with a member of the group (d) formed by -OR8, -COOR7, -COR7, -CONR5R6, -NR5R6, -N02, halogen, perfluoroalkyl, S02R7, • S02NR5R6, with lower alkyl, cycloalkyl, heterocycle, aryl and heteroaryl, and wherein the lower alkyl, cycloalkyl and heterocycle each, may be substituted with the group R11, and the aryl and heteroaryl each may be substituted with the group R12, and heteroaryl, which may be substituted with a member of group (d) as defined above or with cycloalkyl, lower alkyl, heterocycle, aryl and heteroaryl, and wherein the lower alkyl, cycloalkyl and heterocycle each, may be substituted with the group R11 and the aryl and heteroary can each be substituted with the group R12; R5 and R6 are each, independently of each other, hydrogen -COR ", -COOR7, -CONR7R9, lower alkyl, which may be substituted with a member of group (e), formed by -OR8, -COOR7, -COR7, -CONR R8, -NR7R8, -S02R7, -S02NR7R8, or with cycloalkyl, heterocycle, aryl and heteroaryl, and wherein each cycloalkyl and heterocycle may be substituted with the group R11 and the aryl and heteroaryl each can be substituted with the R12 cycloalkyl group, which may be substituted with a member of group (e) as defined above, or with lower alkyl, heterocycle, aryl and heteroaryl, and wherein the lower alkyl and heterocycle may each be substituted with the R11 group and the aryl and heteroaryl each may be substituted with the group R12, heterocycle, which may be substituted with a member of group (e) as defined above, or with cycloalkyl, lower alkyl, aryl, and heteroaryl, and wherein the cycloalkyl and lower alkyl each may be substituted with the group R11 and the aryl and heteroaryl each, may be optionally substituted with the group R12, aryl, which may be substituted with a member of the group (f) formed by -OR8, -COOR7, -COR7, -C0NR7R8, -NR7R8, -N02, halogen, perfluoroalkyl, -S02R7, -S02NR7R8; or with lower alkyl, cycloalkyl, heterocycle, aryl and heteroaryl, and wherein the lower alkyl, cycloalkyl and heterocycle each, may be substituted with the group R11 and the aryl and heteroaryl each may be substituted with the group R12, and heteroaryl , which can be replaced with a member of group (f) as defined above or with, lower alkyl, cycloalguyl, heterocycle, aryl and heteroaryl, and wherein the lower alkyl, cycloalkyl and heterocycle each, may be substituted with the group R11 and the aryl and heteroaryl each may be substituted with the group R12; or alternatively, -NR5R6 can form a ring of 3 to 7 carbon atoms, said ring optionally including one or more additional heteroatoms and being optionally substituted with lower alkyl, -OR8, -COR7, -COOR7, -C0NR7R9 or -NR8R9; R7 is hydrogen or lower alkyl which may be substituted with a member of the group consisting of cycloalkyl, heterocycle, aryl, heteroaryl, -OR9, or -NR8R9; R8 is hydrogen, -COR9, -CONR10R9, or lower alkyl which may be substituted with R11; R9 and R10 are each independently of one another, hydrogen or lower alkyl; R11 is -OR9, -COR9, -COOR9, -OCOR9, -CONR9R10, -NR9R10, -M (COR9) R10, -S02R9, or -S02NR9R10; R12 is -OR9, -COR9, -COOR9, -OCOR9, -CONR9R10, -NR9R10, -N (COR9) R10, -S02R9, -S02NR9R10, halogen, -CN, -N02, or perfluoroalkyl; Y X is N or CH. and pharmaceutically active prodrugs and metabolites of compounds of formula I; and the pharmaceutically acceptable salts of the above compounds.

2. 2. A compound of claim 1, characterized in that R1 and R2 are, independently of each other, hydrogen -NR5 R6, lower alkyl, which may be substituted with R11, cycloalguyl, heterocycle, aryl and heteroaryl, wherein the cycloalkyl and heterocycle they may be substituted with R11, and the aryl and heteroaryl may be substituted with R12; cycloalkyl, which can be substituted with R11, lower alkyl, heterocycle, aryl, and heteroaryl, wherein the lower alkyl and heterocycle may be substituted with R11, and the aryl and heteroaryl may be substituted with R12; heterocycle, which can be replaced with R11, lower alkyl, cycloalkyl, aryl and heteroaryl, wherein the lower alkyl and cycloalkyl may be substituted with R11, and the aryl and heteroaryl may be substituted with R12; aryl, which may be substituted with R 12 'lower alkyl, cycloalkyl, heterocycle, aryl and heteroaryl, wherein the lower alkyl and heterocycle and cycloalkyl may be substituted with R 11, and the aryl and heteroaryl may be substituted with R 12; heteroaryl, which may be substituted with R 12, lower alkyl, cycloalkyl, heterocycle, aryl, and heteroaryl wherein the lower alkyl, cycloalkyl, and heterocycle may be substituted R 11, and the aryl and heteroaryl, may be substituted with R 12; or alternatively, R1 and R2 may form a ring of 5 to 7 atoms and optionally be substituted with a group selected from -OR8, -COR7, -COOR7, -CONR7R9, and lower alkyl, which may be substituted with R11.

3. 3. The compound of claim 2, characterized in that R3 is hydrogen, -OR4, -NR5R6, or lower alkyl, which may be substituted with the group consisting of -OR4 and -NR5R6'

4. 4. The compound of claim 2, characterized in that R3 is hydrogen, -OR9 or lower alkyl, which may be substituted with the group formed per -OR9 and -NR9R10-

5. 5. The compound of claim 1, characterized in that it is (Z) -7, 9-dihydro- 2, 3-dimethyl-9- [. (3-methoxy: .- lH-pyrrol-2-yl) methylene] -8H-pyrrolo [3, 2-f] quinoxali -8-one.

6. 6. The compound of claim 1, characterized in that it is (Z) -3-butyl-7,9-dihydro-9 - [(3-methoxy-lH-pyrrol-2-yl) methylene] -2-methyl-8H -pyrrolo [3,2-f] quinoxalin-8-one.

7. 7. The compound of claim 1, characterized in that it is (Z) -2-butyl-7,9-dihydro-9 - [(3-methoxy-lH-pyrrol-2-yl) methylene] -3- methyl-8H-pyrrolo [3,2-f] quinoxalin-8-one.

8. 8. The compound of claim 1, characterized in that it is (Z) -7, 9-dihydro-9 - [(3-methoxy-lH-pyrrol-2-yl) methylene] -2-methyl-3-phenyl-BH -pyrrolo [3,2-f) quinoxa in-8-one.

9. 9. The compound of claim 1, characterized in that it is (Z) -7,9-dihydro-9 - [(3-methoxy-lH-p rrol-2-yl) methylene] -3-methyl-2-phenyl -8H-pyrrolo [3,2-f] quinoxalin-8-one.

10. The compound of claim 1, characterized in that it is (Z) -7,9-dihydro-2,3-di- (2-furanyl) -9- [(3-methoxy-lH-pyrrole-2-yl) methylene] -8H-pyrrolo [3, 2-f] quinoxalin-8-one.

11. 11. The compound of claim 1, characterized in that it is (Z) -1, 3, 5, 6, 7, 8-hexahydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H -pirrolo [(3,2-a] phenazinone.

12. 12. A pharmaceutical composition characterized in that it contains as an active ingredient a compound of any one of claims 1 to 11 and a pharmaceutically acceptable excipient carrier.

13. 13. A compound of any one of claims 1 to 11, for use as a medicament, particularly for the treatment and / or control of inflammation and neurovegetative diseases, in particular rheumatoid arthritis, or for the treatment of solid tumors, in particular breast or colon tumors.

14. 14. The use of a compound of formula I or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 11, in the preparation of a medicament containing the compound, for the treatment and / or control of inflammation and neurodegenerative diseases, in particular rheumatoid arthritis, or for the treatment of solid tumors, in particular breast or colon tumors.