FR2887550A1 - New 1-benzylpyrazole-3-acetamide compounds are cannabinoids receptor antagonists useful to treat/prevent immune disorders, pain, gastrointestinal disturbances, cardiovascular/kidney disorders and in cancer chemotherapy - Google Patents

Abstract

1-Benzylpyrazole-3-acetamide compound (I) and their salts or solvates are new. 1-Benzylpyrazole-3-acetamide compound of formula (I) and their salts or solvates are new. R1H or 1-4C alkyl; R2, R4H or halo, 1-4C alkyl, 1-4C alkoxy or CF3; R3, R5halo, 1-4C alkyl, 1-4C alkoxy, CF3 or S(O)n-Alk; R6(2-8C) alkyl, 3-12C non aromatic carbocyclic radical (optionally substituted by 1-4C alkyl); n : 0-2; and Alk : 1-4C alkyl; R7H or (1-4C) alkyl. Independent claims are included for: (1) the preparation of (I); and (2) 1-benzylpyrazole-3-acetamid of formula (II). Y1halo, OH or CN. [Image] [Image] ACTIVITY : Analgesic; Gastrointestinal-Gen.; Cardiovascular-Gen.; Nephrotropic; Cytostatic. MECHANISM OF ACTION : Cannabinoids receptor antagonist. The ability of (I) to antagonize cannabinoids receptor was tested using biological assays. The results showed that the median inhibitory concentration value of (I) was 0.1-500 nM.

Description

(I)

  1-BENZYLPYRAZOLE-3-ACETAMIDE DERIVATIVES, THEIR PREPARATION AND THERAPEUTIC USE THEREOF

  The present invention relates to 1-benzylpyrazole-3-acetamide derivatives, their preparation and their therapeutic application.

  1-Benzylpyrazole-3-carboxamide derivatives are known in the literature, in particular European Patent EP-B-868,420 and its US equivalent US 5,925,768 describe compounds of formula: (A) These compounds have an affinity for human CB2 receptors.

  The subject of the present invention is compounds corresponding to formula (I): (I) in which: R1 represents a hydrogen atom or a (C1C4) alkyl group; R2 and R4 are each independently of one another a hydrogen or halogen atom, or a (C1-C4) alkyl, (C1-C4) alkoxy or trifluoromethyl group; R3 and R5 are each independently of each other halogen, (C1-C4) alkyl, (C1-C4) alkoxy or trifluoromethyl, or S (O) nAlk; R6 represents a group selected from: - (C2-C8) alkyl; a non-aromatic C 3 -C 12 carbocyclic radical which is unsubstituted or substituted one or more times with a (C 1 -C 4) alkyl group; R7 represents a hydrogen atom or a (C1-C4) alkyl group; - nest0, 1 or 2; Alk represents a (C1-C4) alkyl.

  The compounds of formula (I) may exist in the form of bases or addition salts with acids. Such addition salts are part of the invention.

  These salts are advantageously prepared with pharmaceutically acceptable acids, but the salts of other acids that are useful, for example, for the purification or the isolation of the compounds of formula (I) are also part of the invention.

  The compounds of formula (I) may also exist in the form of hydrates or solvates, namely in the form of associations or combinations with one or more molecules of water or with solvent. Such hydrates and solvates are also part of the invention.

  In the context of the present invention, the following are meant: a halogen atom: a fluorine, a chlorine, a bromine or an iodine, chlorine and fluorine being preferred; a (C1-C4) alkyl or (C2-C8) alkyl group: a saturated linear or branched aliphatic group, respectively with C1-C4, or with C2-C8. By way of example, mention may be made of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, heptyl and octyl groups; a (C1-C4) alkoxy group: an O-alkyl radical in which the alkyl group is as previously described; a non-aromatic C 3 -C 12 carbocyclic radical: a monocyclic radical or a di- or tricyclic radical condensed or bridged; monocyclic radical is understood to mean a cycloalkyl, that is to say a cyclic alkyl group, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; By condensed or bridged di- or tricyclic radical is meant, for example, bicyclo [2.2.1] heptyl, bicyclo [3.2.1] octyl.

  Among the compounds of formula (I) which are subjects of the invention, mention may be made of the preferred compounds which comprise one or more substituents defined below: R 1 represents hydrogen; R2 and R3 represent two chlorine atoms in 3 and in 4; and R4 and R5 represent a methyl group or a 4-chlorine atom and a 3-chlorine or hydrogen atom; R2 represents a methylthio or methylsulfonyl group at 4 and R3 represents a hydrogen atom; and R4 and R5 represent two chlorine atoms at 2 and 4; R6 represents a propyl, isopropyl, isobutyl, sec-butyl or tert-butyl group, or a cyclopropyl, bicyclo [2. 2.1] heptyl or 1,3,3-trimethylbicyclo [2.2.1] heptyl or bicyclo [3.2.1] octyl; R7 represents a hydrogen atom or a methyl or isopropyl group.

  Among the compounds of formula (I) which are subjects of the invention, mention may notably be made of the following compounds: N- (tert-butyl) -2- (1- (3-chloro-4-methylbenzyl) -5- (3 4-dichlorophenyl) -1H-pyrazol-3-yl) acetamide; N-bicyclo [3.2.1] oct-3-yl-2- (1- (3-chloro-4-methylbenzyl) -5- (3,4-dichlorophenyl) -1H-pyrazol-3-yl) acetamide; 2- (1- (3-chloro-4-methylbenzyl) -5- (3,4-dichlorophenyl) -1H-pyrazol-3-yl) -N- (1,3,3-trimethylbicyclo [2.2.1] hept-2 yl) acetamide.

  N- (tert-butyl) -2- (1- (2,4-dichlorobenzyl) -5- (4-methylthiophenyl) -1Hpyrazol-3-yl) acetamide; N-bicyclo [3.2.1] oct-3-yl-2- (1- (2,4-dichlorobenzyl) -5- (4-methylsulfonylphenyl) -1H-pyrazol-3-yl) acetamide. N- (tert-butyl) -2- (1- (4-chlorobenzyl) -5- (3,4-dichlorobenzyl) -1Hpyrazol-3-yl) acetamide.

  2- (1- (4-Chlorobenzyl) -5- (3,4-dichlorophenyl) -1H-pyrazol-3-yl-Nisopropyl-N-methylacetamide.

  2- (1- (4-Chlorobenzyl) -5- (3,4-dichlorophenyl) -1H-pyrazol-3-yl-Nisopropyl-N-isopropylacetamide.

  N-sec-butyl-2- (1- (4-chlorobenzyl) -5- (3,4-dichlorophenyl) -1H-pyrazol-3-yl) acetamide.

  According to the invention, the compounds of formula (I) can be prepared according to the following process. This process is characterized in that: a functional derivative of the acid of formula: in which R 1, R 2, R 3, R 4, R 5 are as defined above for the compounds of formula (I) with an amine of formula R6R7NH (III).

  By functional derivative of an acid of formula (II) is meant an acid chloride, an anhydride or the free acid suitably activated for example with benzotriazolyloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP).

  The reaction is carried out in an aprotic solvent such as dichloromethane, THF or DMF, in basic medium and in the presence of a coupling agent such as BOP or dicyclohexylcarbodiimide (DCC).

  The compounds of formula (I) in which R3 and / or R5 represent a group SOAIk or SO2Alk may be prepared from equivalent compounds of formula (I) in which R3 and / or R5 represent a group SAlk by action of an agent oxidant such as hydrogen peroxide or metachloroperbenzoic acid.

  The compounds of formula (II) are prepared according to the following reaction scheme: SCHEME 1 KOH (II) (VII) Hal: halogen atom, preferentially Cl or Br.

  In the first step, the ester of formula (IV) is reduced by the action of a reducing agent such as LiAlH 4.

  In the next step, the hydroxymethyl derivative (V) obtained is treated with an agent such as PC15, PBr3, HBr or BBr3 to form the halomethylated derivative of formula (VI). This is treated with a metal cyanide, for example, potassium cyanide to form the compound of formula (VII).

  Finally, the action of a strong base such as potassium hydroxide makes it possible to obtain the acid of formula (II).

  The compounds of formula (IV) are known and their method of preparation is described in patent EP-B-868,420.

  The compounds of formula (V), (VI), (VII) and the compounds of formula (II) are new.

  Thus the invention, according to another of its aspects, also relates to the compounds of formula (VIII): (VIII) in which: - Y represents a halogen atom, a hydroxyl group or cyano; R1 represents a hydrogen atom or a (C1-C4) alkyl group; R 2 and R 4 each independently represent a hydrogen or halogen atom, or a (C 1 -C 4) alkyl, (C 1 -C 4) alkoxy or trifluoromethyl group; R 3 and R 5 each independently represent a halogen atom, a (C 1 -C 4) alkyl, (C 1 -C 4) alkoxy or trifluoromethyl group, or a S (O) nAlk group; n is 0, 1 or 2; Alk represents a (C1-C4) alkyl.

  The compounds of formula (VIII) may exist in the form of bases or addition salts with acids. Such addition salts are part of the invention.

  The compounds of formula (VIII) may also exist in the form of hydrates or solvates, namely in the form of associations or combinations with one or more molecules of water or with solvent. Such hydrates and solvates are also part of the invention.

  These compounds are useful as synthesis intermediates for the compounds of formula (I) according to the invention.

  The following example describes the preparation of certain compounds according to the invention. This example is not limiting and only illustrates the present invention. The numbers of the compounds exemplified refer to those given in the table below, which illustrates the chemical structures and the physical properties of some compounds according to the invention.

  In the Example the following abbreviations are used: TA: room temperature (dec): decomposition THF: tetrahydrofuran DMF: dimethylformamide DCM: dichloromethane DMSO: dimethylsulfoxide BOP: benzotriazol-1-yloxytris (dimethylamino) phosphonium / hexafluorophosphate K2SO4 / KHSO4: buffer pH 0.8 (0.12 M KHSO4 and K2SO4 0.185 M) AcOEt: ethyl acetate For nuclear magnetic resonance spectra (NMR), the observed signals are expressed as follows: d: doublet; of: expanded doublet; d. of d .: doublet of doublet; s: singlet; it is: widened singlet; t: triplet.

  The compounds according to the invention are analyzed by LC / UVIMS coupling (liquid chromatography / UV detection / mass spectrometry). The molecular peak (MH +) and the retention time (t) are measured in minutes.

  Conditions: A Symmetry C18 column of 2.1 x 50 mm, 3.5 m, is used at 30 C, flow rate 0.4 mL / min.

  The eluent is composed as follows: solvent A: 0.005% trifluoroacetic acid (TFA) in water at pH 3.15; solvent B: 0.005% of TFA in acetonitrile.

  Gradient: Time (min)% A% B 0 100 0 10 90 10 90 16 100 0 100 0 Column temperature: 30 C, flow rate 0.4 ml / min.

  The UV detection is carried out at a, = 210 nM and the mass detection in ESI (Electro Spray Ionization) chemical ionization mode is positive.

Example 1: compound 3

  N- (tert-butyl) -2- (1- (3-chloro-4-methylbenzyl) -5- (3,4-dichlorophenyl) -1H-pyrazol-3-yl) acetamide.

  A) (1- (3-chloro-4-methylbenzyl) -5- (3,4-dichlorophenyl) -1H-pyrazol-3-yl) methanol.

  4 g of methyl 1- (3-chloro-4-methylbenzyl) 5- (3,4-dichlorophenyl) -1Hpyrazole-3-carboxylate are dissolved in 100 ml of THF and cooled between 0.degree. C. and -5.degree. 0.6 g of LiAlH4 is added in small increments maintaining the same low temperature. It is allowed to return to RT and stir 30 minutes. It is hydrolyzed at 0 ° C. with N NaOH (100 ml). The mixture is filtered and the filtrate is washed with THF and evaporated. The oil obtained is taken up in ether, washed with water, with NaCl solution, then dried over Na 2 SO 4 and evaporated to dryness to obtain 3.5 g of the expected compound.

  NMR (200 MHz) in DMSO-d6: 7.7 ppm: d: 1H; 7.6 ppm: d: 1H; 7.4 ppm: dded: 1H, 7.3ppm: d: 1H, 7ppm: d: 1H; 6.8 ppm: d of d: 1H; 6.4 ppm: s: 1H; 5, 3 ppm: s: 2H; 5.1 ppm: t: 1H, 4.4 ppm: d: 2H, 2.2 ppm: s: 3H.

  B) 3- (bromomethyl) -1- (3-chloro-4-methylbenzyl) -5- (3,4-dichlorophenyl) -1H-pyrazole.

  5.8 g of the compound obtained in the preceding step are dissolved in 150 ml of dry DCM and cooled to 0 ° C. and then 17.4 ml of molar solution of BBr3 in 150 ml of DCM are added dropwise. After stirring for 2 hours at 0 ° C., the mixture is allowed to return to RT and the stirring is continued for 4 days. The reaction medium is poured into a water + ice mixture and then extracted with DCM.

  The organic phase is dried over Na 2 SO 4 and then evaporated to dryness. The residue is purified by chromatography on silica eluting with an AcOEt / cyclohexane mixture (10/90; v / v). 5 g of the expected compound are obtained. F = 76 C.

  C) (1- (3-chloro-4-methylbenzyl) -5- (3,4-dichlorophenyl) -1H-pyrazol-3-yl) acetonitrile.

  2.42 g of the compound of the preceding step are dissolved in 75 ml of ethanol and a mixture containing 2 g of KCN in 25 ml of water is added. After stirring for 48 hours, the reaction medium is poured into water and extracted with AcOEt. The insoluble material is filtered and then washed with water, the organic phase is dried over Na 2 SO 4 and evaporated to dryness. Purified by chromatography on silica eluting with AcOEt / cyclohexane (20/80, v / v) to obtain 1.54 g of the expected compound. Mp = 59 C. D) (1- (3-Chloro-4-methylbenzyl) -5- (3,4-dichlorophenyl) -1H-pyrazol-3-yl) acetic acid.

  1.5 g of the compound of the preceding step are dissolved in 150 ml of ethanol and a mixture containing 426 mg of KOH in 50 ml of water is added. The mixture is refluxed for 7 hours and then allowed to warm to RT and acidified to pH = 2 by addition of 6N HCl. Extracted with AcOEt, the organic phase dried over Na 2 SO 4 to obtain 1.50 g of the expected compound which crystallizes. F = 105 C.

  E) N- (tert-butyl) -2- (1- (3-chloro-4-methylbenzyl) -5- (3,4-dichlorophenyl) -1H-pyrazol-3-yl) acetamide.

  340 mg of the acid obtained in the preceding step are dissolved in 60 ml of DMF, 78 mg of tert-butylamine and 476 mg of BOP are added and then adjusted to pH = 9 by addition of triethylamine and left for 18 hours. with stirring at RT. The solvent is evaporated under vacuum and then 50 ml of AcOEt are added and the mixture is washed with a saturated solution of NaHCO 3, a solution of K 2 SO 4 / KHSO 4 and then water. It is dried over Na 2 SO 4 and then evaporated to dryness. The residue is purified by chromatography on silica eluting with an AcOEt / cyclohexane mixture (60/40, v / v). 220 mg of the expected compound are obtained. Mp = 92C.

  Proceeding as described in steps A, B, C and D above, the following are prepared: [1 - (4-chlorobenzyl) -5- (3,4-dichlorophenyl) -1H-pyrazol) yl] acetic acid, mp = 71 ° C (1- (2,4-dichlorobenzyl) -5- (4-methylthiophenyl) -1H-pyrazol-3-yl) acetic acid, mp = 61 ° C.

  The latter compound is oxidized with metachloroperbenzoic acid to obtain (1- (2,4-dichlorobenzyl) -5- (4-methylsulfonylphenyl) -1Hpyrazol-3-yl) acetic acid, m.p. 155 C.

  The following table illustrates the chemical structures and the physical properties of some compounds according to the invention. In the table, Me, Pr, iPr, secBu and tBu respectively represent methyl, propyl, isopropyl, sec-butyl and tert-butyl groups.

9 TABLE 1 (I)

  Compounds R2, R3 R4, R5 R6 R7 Characterization 1 3,4-diCl 3 -Cl, 4-Me endo HF = 130 C 2 3,4-diCl 3 -Cl, 4-Me Me HF = 57 C Me Me (1S endo) 3 3,4-diCi 3Cl, 4-Me t-Bu HF = 92 C 4 4 SO 2 Me 2,4-diCl endo HF = 135 C 4 -MMe 2,4diCl tBu HF = 45 C 6 3,4- diCl 4 -Cl tHu HF = 105 C 7 3,4-diCl 4 -Cl iPr Me MH = 449 t = 10.73 min 8 3,4-diCl 4 -Cl iPr HF = 122C 9 3,4-diCl 4 -Cl sec-Bu HF = 96 C racemic 3,4-diCl 4-Cl iBu HF = 118 C 11 3,4-diCi 4Cl Pr Me Mie = 449 t = 10.29 min 12 3,4-diCl 4-Cl tBu ME-1-1- = 543 t = 13, 12 min. 13 3,4-diCl 4 -Cl HF = 137 C 14 3,4-diCl 4-Cl and HF = 131 C The compounds of formula (I) possess a very good in vitro affinity for cannabinoid CB2 receptors, under the experimental conditions described by M. Rinaldi-Carmona in J. Pharmacol. Exp. Therap. 1998, 287, 644-650. More particularly, the compounds of the present invention or their optional salts are strong and selective CB2 cannabinoid receptor ligands, having an IC 50 generally of between 0.1 and 500 nM. They are generally between 10 and 1000 times more active on CB2 than on CB1 receptors. In addition, the antagonistic nature of the compounds of formula (I) has been demonstrated by the results obtained in the models of the inhibition of adenylate cyclase.

  Thus, according to another of these aspects, the invention relates to medicaments for human or veterinary medicine which comprise a compound of formula (I) or an addition salt thereof to a pharmaceutically acceptable acid or a hydrate or a solvate. These drugs find their therapeutic use in the treatment or prevention of pathologies involving the cells of the immune system or immune disorders such as autoimmune diseases, diseases associated with organ transplants, infectious diseases, allergic diseases, diseases of the gastrointestinal system, diseases of inflammatory origin. More particularly, mention may be made of the following autoimmune diseases: systemic lupus erythematosus, connective tissue diseases, Sjdgren's syndrome, ankylosing spondylitis, reactive arthritis, rheumatoid arthritis, undifferentiated spondyloarthritis, Behcet's disease, hemolytic autoimmune anemias, multiple sclerosis, amyotrophic lateral sclerosis, Charcot's disease, psoriasis. The allergic diseases to be treated may be of the immediate hypersensitivity type or asthma, allergic rhinitis, allergic conjunctivitis or contact dermatitis. Similarly, the compounds and their possible pharmaceutically acceptable salts can be used to treat vasculitis, parasitic infections, viral infections (AIDS), bacterial infections (meningitis), amyloidosis, diseases affecting lymphohematopoietic system lineages.

  The compound of formula (I) according to the invention can be used as a medicament in the treatment or prevention of pain: neuropathic pain, peripheral acute pain, chronic pain of inflammatory origin. The following inflammatory diseases can be mentioned: arthritis, rheumatoid arthritis, osteoathritis, spondylitis, gout, Crohn's disease, ulcerative colitis, irritable bowel disease (IBS) or inflamed (IBD) ), acute pancreatitis.

  The compounds of formula (I) may also be used in the treatment of bone diseases and osteoporosis.

  In addition, the compound of formula (I) according to the invention may be used as a medicament in the treatment or prevention of gastrointestinal disorders, diarrheal disorders, ulcers, vomiting, bladder and urinary disorders, renal ischemia, nephritis, endocrine disorders, cardiovascular disorders, hemorrhagic shock, septic shock, chronic cirrhosis of the liver, asthma, Raynaud's disease, glaucoma, fertility, as well as as a drug for cancer chemotherapy (cancer of the skin, prostate or cerebral origin). The compound of formula (I) according to the invention can be used as a medicament for the treatment of appetite disorders and / or eating behaviors, in particular for the treatment of cachexia.

  In addition, the compound of formula (I) may be useful as a neuroprotector, in the treatment of ischemia, head trauma and the treatment of neurodegenerative diseases: including chorea, Huntington's disease, Tourrette.

  The compound of formula (I) according to the invention can be used as a medicament for the treatment or prevention of migraine, stress, psychosomatic diseases, panic attacks, epilepsy, movement disorders.

  The compound of formula (I) according to the invention can be used as a medicament in the treatment or prevention of diseases of the respiratory system such as chronic bronchitis, chronic obstructive bronchitis (COPD) or emphysema.

  Thus the compounds of formula (I) according to the present invention are particularly useful for the preparation of medicaments for the treatment and prevention of immune disorders, pain, gastrointestinal disorders, cardiovascular or renal disorders, and or useful in cancer chemotherapy.

  According to another of its aspects, the present invention relates to pharmaceutical compositions comprising, as active ingredient, at least one compound according to the invention. These pharmaceutical compositions contain an effective dose of a compound according to the invention, or a pharmaceutically acceptable salt, a hydrate or solvate of said compound, as well as one or more pharmaceutically acceptable excipients.

  Said excipients are chosen according to the pharmaceutical form and the desired mode of administration, from the usual excipients which are known to those skilled in the art.

  In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration, the active ingredient of formula (I) above, or its Any salt, solvate or hydrate may be administered in unit dosage form, in admixture with conventional pharmaceutical excipients, to animals and humans for the prophylaxis or treatment of the above disorders or diseases.

  Suitable unit dosage forms include oral forms such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, sublingual, oral, intratracheal, intraocular, intranasal forms of administration. by inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration forms, rectal administration forms and implants. For topical application, the compounds according to the invention can be used in creams, ointments or lotions.

  Orally, the dose of active ingredient administered per day can reach 0.01 to 100 mg / kg, in one or more doses, preferably from 0.1 to 50 mg / kg.

  There may be special cases where higher or lower dosages are appropriate; such dosages are not outside the scope of the invention. According to the usual practice, the dosage appropriate to each patient is determined by the physician according to the mode of administration, the weight and the response of said patient.

  The present invention, according to another of its aspects, also relates to a method of treatment of the pathologies indicated above which comprises the administration to a patient of an effective dose of a compound according to the invention, or one of its pharmaceutically acceptable salts or hydrates or solvates.

Claims (1)

13 Claims   1. Compounds corresponding to formula (I): R CH2 (I) in which: R1 represents a hydrogen atom or a (C1-C4) alkyl group; R 2 and R 4 each independently represent a hydrogen or halogen atom, or a (C 1 -C 4) alkyl, (C 1 -C 4) alkoxy or trifluoromethyl group; R 3 and R 5 each independently represent a halogen atom, a (C 1 -C 4) alkyl, (C 1 -C 4) alkoxy or trifluoromethyl group, or a S (O) nAlk group; R6 represents a group chosen from: a (C2-C8) alkyl; a non-aromatic C 3 -C 12 carbocyclic radical which is unsubstituted or substituted one or more times with a (C 1 -C 4) alkyl group; R7 represents a hydrogen atom or a (C1-C4) alkyl group; - n is 0, 1 or 2; Alk represents a (C1-C4) alkyl; in the form of base or addition salts and in the state of hydrates or solvates. 2. Process for the preparation of the compounds of formula (I) according to claim 1, characterized in that: a functional derivative of the acid of formula: in which R1, R2, R3, R4, R5 are as defined for compounds of formula (I) in claim 1 with an amine of formula R6R7NH (III) wherein R6 and R7 are as defined for compounds of formula (I) in claim 1.   3. Compounds of formula (VIII): (VIII) in which: Y represents a halogen atom, a hydroxyl or cyano group; R1 represents a hydrogen atom or a (C1-C4) alkyl group; R 2 and R 4 each independently represent a hydrogen or halogen atom, or a (C 1 -C 4) alkyl, (C 1 -C 4) alkoxy or trifluoromethyl group; R 3 and R 5 each independently represent a halogen atom, a (C 1 -C 4) alkyl, (C 1 -C 4) alkoxy or trifluoromethyl group, or an S (O) nAlk group; n is 0, 1 or 2; Alk represents a (C1-C4) alkyl; in the form of base or addition salts as well as hydrates or solvates.   4. Medicament, characterized in that it comprises a compound of formula (I) according to claim 1, or an addition salt of this compound to a pharmaceutically acceptable acid, or a hydrate or a solvate of the compound of formula ( I).   5. Pharmaceutical composition, characterized in that it comprises a compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt, a hydrate or a solvate of this compound, and at least one pharmaceutically acceptable excipient.   6. Use of a compound of formula (I) according to claim 1 for the preparation of a medicament for the treatment and prevention of immune disorders, pain, gastrointestinal disorders, cardiovascular or renal disorders, and or useful in cancer chemotherapy.