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Definitions

• the invention relates to 5-membered azaspiranylalkylcarbamate derivatives of 5-membered heterocycles, their preparation and their therapeutic application.
• the compounds of the invention fulfill this purpose.
• the compounds of the invention have the general formula (D:
• R 2 represents a hydrogen, fluorine atom or a hydroxyl, cyano, trifluoromethyl, C 1-6 alkyl, C 1-6 alkoxy, NR 8 R 9 group ;
• n, o and p represent, independently of one another, an integer of 0, 1, 2 or 3;
• A represents a covalent bond or a C1- ⁇ -alkylene group; represents a group R 5 optionally substituted with one or more R 6 and / or R 7 groups ;
• R 5 represents a group selected from phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, naphthalenyl, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, cinnolinyl, naphthyridinyl;
• R 6 represents a halogen atom, a cyano group, -CH 2 CN, nitro, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 -thioalkyl, C 1-6 -haloalkyl, C 1-6 -haloalkoxy, CI_ 6 - halothioal kyle, C 3-7 -cycloal kyle, C 3-7 -cycloal kyle- -C 3 -al Kylene, C 3-7 -cycloal kyle--C 3 -al Kylene-0-, NR 8 R 9 ,
• R 7 represents a group selected from furanyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazole, thiadiazole, phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazine, naphthalenyl, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, cinnolinyl, naphthyridinyl, imidazopyrimidinyl, thienopyrimidinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, indolyl
• R 3 represents a hydrogen atom, fluorine, a C 1-6 alkyl group or a trifluoromethyl group
• R 4 represents a group selected from furanyl, pyrrolyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl, tetrazolyl; this group being optionally substituted by one or more substituents selected from a halogen atom, a Ci- 6 group - alkyl, hereinafter 6 -haloalkyl, C 3 - 7 -cycloalkyl, C 3 _ 7 -cycloalkyle-
• R 8 and R 9 represent, independently of one another, a hydrogen atom or a C 1-6 alkyl group, or form, with the atom or atoms bearing them, in the case of NR 8 R 9 , a chosen cycle among the azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, azepine, oxazepine or piperazine rings, this ring being optionally substituted by a C 1-6 alkyl or benzyl group; in the case of NR 8 COR 9 , a lactam ring; in the case of NR 8 CO 2 R 9 , an oxazolidinone, oxazinone or oxazepinone ring; in the case of NR 8 SO 2 R 9 , a sultame cycle; in the case of NR 8 SO 2 NR 8 R 9 , a thiazolidine dioxide or thiadiazinane dioxide ring;
• Ri o and Rn independently of one another represent a hydrogen atom or a C 1-6 alkyl group.
• a first subgroup of compounds consists of compounds for which R 2 represents a hydrogen atom.
• a second subgroup of compounds is composed of compounds for which the group
• R 2 being as defined in the general formula (I).
• a third subgroup of compounds is composed of compounds for which the group
• R 2 being as defined in the general formula (I).
• a fourth subgroup of compounds is composed of compounds for which A represents a covalent bond or a C1-s-alkylene group, more particularly a methylene group.
• a fifth subgroup of compounds is composed of compounds for which R 1 represents a group R 5 optionally substituted with one or more R 6 and / or R 7 groups ;
• R 5 represents a pyrimidinyl, pyrazinyl, pyridinyl or quinolinyl group
• R 6 represents a halogen atom, more particularly a bromine, fluorine or chlorine atom, a C 1-6 -haloalkyl group, more particularly a trifluoromethyl group or a C 1-6 -alkyl group, more particularly an isobutyl group;
• R 7 represents a phenyl which may be substituted with one or more R 6 groups which are identical or different from one another.
• a sixth subgroup of compounds is composed of compounds for which R 1 represents a group R 5 optionally substituted with one or more groups R 6 and / or R 7 ; R 5 represents a pyridinyl or quinolinyl group;
• R 6 represents a halogen atom, more particularly a bromine, fluorine or chlorine atom, or a C 1-6 -haloalkyl group, more particularly trifluoromethyl;
• R 7 represents a phenyl which may be substituted with one or more R 6 groups which are identical or different, one of The other.
• a seventh subgroup of compounds consists of compounds for which R 3 represents a hydrogen atom.
• an eighth subgroup of compounds is composed of compounds for which R 4 represents a group selected from thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl; this group being optionally substituted by one or more substituents selected from C 1-6 alkyl, CONR 8 R 9 , CON (R 8 ) (C 1-3 alkylene NR 6 R) or phenyl; the phenyl group being optionally substituted with one or more substituents selected from a halogen atom;
• R 8 , R 9 , Rio and Ru represent, independently of one another, a hydrogen atom or a C 1-6 alkyl group, more particularly methyl.
• a ninth subgroup of compounds is composed of compounds for which R 4 represents a group selected from a thiazolyl, an oxazolyl, an isoxazolyl; this group being optionally substituted by one or more groups CONR 8 R 9 ;
• R 8 and R 9 independently of one another represent a hydrogen atom or a C 1-6 alkyl group, more particularly methyl.
• a tenth subgroup of compounds is constituted by the compounds of general formula (I) in which both R 1 and / or R 2 and / or R 3 and / or R 4 and / or n and / or m and / or o and / or p and / or A are as defined in the groups above.
• the compounds of general formula (I) the following compounds may be mentioned (IUPAC nomenclature generated by AutoNom software):
• the compounds of general formula (I) may comprise one or more asymmetric carbons. They can exist as enantiomers or diastereoisomers.
• the compounds of general formula (I) may also exist in the form of cis or trans stereoisomers. These stereoisomers, enantiomers and diastereoisomers, as well as their mixtures, including racemic mixtures, form part of the invention.
• 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.
• 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.
• t and z may take the values from 1 to 8, a carbon chain which can have from t to z carbon atoms, for example a chain -C 3 carbon which may have 1 to 3 carbon atoms; alkyl, a saturated, linear or branched aliphatic group; for example a C 1-6 alkyl group represents a linear or branched carbon chain of 1 to 6 carbon atoms, more particularly a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl; alkylene group, a saturated divalent alkyl, linear or branched, for example a group -C 3 -alkylene is a divalent carbon chain of 1 to 3 carbon atoms, linear or branched, more particularly a methylene, ethylene, 1-methylethylene or propylene ; cycloalkyl,
• a C 3-7 -cycloalkyl represents a cyclic carbon group of 3 to 7 carbon atoms, more particularly a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl; alkoxy, a -O-alkyl group with saturated aliphatic chain, linear or branched; thioalkyl, a -S-alkyl group with saturated aliphatic chain, linear or branched; haloalkyl, an alkyl group of which one or more hydrogen atoms have been substituted with a halogen atom; haloalkoxy, an alkoxy group of which one or more hydrogen atoms have been substituted by a halogen atom; halothioalkyl, a thioalkyl group of which one or more hydrogen atoms have been substituted with a halogen atom; halogen atom, fluorine, chlorine, bromine or i
• the compounds of the invention can be prepared according to various methods, illustrated by the following diagrams.
• a first method consists in reacting an amine of general formula (II), in which A, Ri, R 2 , m, n, o and p are as defined in general formula (I) defined herein. above, with a carbonate of general formula (III) in which Z represents a hydrogen atom or a nitro group, R 3 and R 4 are as defined in the general formula (I) defined above, in the presence of a base such as triethylamine, pyridine, N, N-dimethylaminopyridine or diisopropylethylamine, in a solvent such as toluene or dichloroethane, at a temperature between room temperature and the reflux temperature of the solvent.
• a base such as triethylamine, pyridine, N, N-dimethylaminopyridine or diisopropylethylamine
• An alternative for obtaining the compounds of general formula (I) (scheme 1) consists in reacting an amine of general formula (II), as defined above, with phenyl or 4-nitro-phenyl chloroformate, in the presence of a base such as triethylamine or diisopropylethylamine, in a solvent such as dichloromethane or tetrahydrofuran, at a temperature between 0 ° C. and room temperature, to yield the carbamate derivative of general formula (IV), in which A, R 1, R 2 , m, n, o and p are as defined in the general formula (I) defined above, and Z represents a hydrogen atom or a nitro group.
• a base such as triethylamine or diisopropylethylamine
• a solvent such as dichloromethane or tetrahydrofuran
• the carbamate derivative of general formula (IV) thus obtained is then converted into a compound of general formula (I) by the action of an alcohol of general formula HOCHR 3 R 4 (HIa), in which R 3 and R 4 are such that defined in the general formula (I) defined above, in the presence of a base such as triethylamine, pyridine, N, N-dimethylaminopyridine or diisopropylethylamine, in a solvent such as toluene or dichloroethane, at a temperature between room temperature and the reflux temperature of the solvent.
• a base such as triethylamine, pyridine, N, N-dimethylaminopyridine or diisopropylethylamine
• a second method (scheme 2 - route A) consists in reacting, in a first step, an amine of general formula (IIa), in which A, R 2 , m, n, o and p are as defined in the general formula ( I) defined above, and PG represents a protecting group such as a Boc (tert-butyloxycarbonyl), a Cbz (benzyloxycarbonyl), a benzyl or a benzhydrile, with a carbonate of general formula (III) as defined above.
• a variant of obtaining (scheme 2 - variant route A) intermediates of general formula (Ia) consists in reacting an amine of general formula (IIa), as defined above, with phenyl chloroformate or 4- nitro-phenyl, in the presence of a base such as triethylamine or diisopropylethylamine, in a solvent such as dichloromethane or tetrahydrofuran, at a temperature between 0 ° C. and room temperature, to yield the carbamate derivative of general formula (IVa), in which
• A, R 2 , m, n, o and p are as defined in the general formula (I) defined above, PG is as defined above and Z represents a hydrogen atom or a group nitro.
• the carbamate derivative of general formula (IVa) thus obtained is then converted into a compound of general formula (Ia) by the action of an alcohol of general formula HOCHR 3 R 4 (HIa), as defined above, in the presence of a base such as triethylamine, pyridine, N, N-dimethylaminopyridine or diisopropylethylamine, in a solvent such as toluene or dichloroethane, at a temperature between room temperature and the reflux temperature of the solvent, followed by a deprotection reaction, for example in the presence of a solution of hydrochloric acid (5N) in isopropanol or dioxane.
• a base such as triethylamine, pyridine, N, N-dimethylaminopyridine
• the compound of general formula (I) is then obtained by reaction of the compound of general formula (Ia) with a derivative of general formula Ri-Ui (V), in which R 1 is as defined in the general formula (I) and Ui represents a halogen atom or an O-triflate group, using the reaction conditions of aromatic or heteroaromatic nucleophilic substitution, for example by means of a base such as triethylamine, diisopropylethylamine, pyridine or N, N-dimethylaminopyridine in a solvent such as dichloromethane, dichloroethane, acetonitrile, N, N dimethylformamide, dioxane or tetrahydrofuran, at a temperature of between 0 ° C. and the reflux temperature of the solvent.
• This transformation can also be carried out using the N-arylation or N-heteroarylation conditions of Buchwald, for example by means of a palladium or copper catalyst.
• U 2 being in the position where it is desired to introduce the group R 6 or R 7 : either by a Suzuki-type reaction, for example by means of a boronic acid of alkyl, cycloalkyl, aryl or heteroaryl, either according to a Stille-type reaction, for example by using a tri-alkylstannous aryl or heteroaryl derivative or by a Nministershi-type reaction, for example by using a zincate derivative of alkyl halide, cycloalkyl , aryl or heteroaryl.
• a Suzuki-type reaction for example by means of a boronic acid of alkyl, cycloalkyl, aryl or heteroaryl, either according to a Stille-type reaction, for example by using a tri-alkylstannous aryl or heteroaryl derivative or by a Ngorgeshi-type reaction, for example by using a zincate derivative of alkyl halide, cycloalkyl , aryl or heteroaryl.
• the intermediary of general formula (Ib) as defined above is obtained beforehand by reacting an amine of general formula (Ia) as defined above with a derivative of general formula U2-R5-U1 (Va), in which R 5 , U 1 and U 2 are as defined above using the aromatic nucleophilic, heteroaromatic or N-arylation, Buchwald N-heteroarylation substitution reactions, for example by means of a palladium or copper catalyst.
• An alternative for obtaining intermediates of general formula (Ib) (Scheme 2 - variant of route B) consists in reacting initially an amine of general formula (Hb), in which A, R 5 , R 2 , m, n, o and p are as defined in the general formula (I) defined above, and U 2 is as defined above, with a carbonate of general formula (III) as defined above, in the conditions described above in the reaction of the amine of general formula (II) with the carbonate of general formula (III), to obtain the intermediate of general formula (Ib), wherein A, R 5 , R 2 , R 3 , R 4 , m, n, o and p are as defined in the general formula (I), and U 2 is as defined above.
• Another subject of the present invention relates to a compound of formula (Ia) as described above. Another object of the present invention relates to a compound of formula (Ic) as described above. Another subject of the present invention relates to a compound of formula (II) as described above. Another subject of the present invention relates to a compound of formula (IV) as described above.
• the carbonate of general formula (III) can be prepared according to any method described in the literature, for example by reaction of an alcohol of general formula HOCHR 3 R 4 (IIIa), in which R 3 and R 4 are such that defined in the general formula (I) as defined above, with phenyl chloroformate or 4-nitrophenyl, in the presence of a base such as triethylamine, N-methylmorpholine or diisopropylethylamine, in a solvent such as dichloromethane or tetrahydrofuran at a temperature of between 0 ° C. and room temperature.
• a base such as triethylamine, N-methylmorpholine or diisopropylethylamine
• R f indicates the retention time obtained by TLC analysis (Thin Layer Chromatography).
• aqueous phase is separated and then extracted three times with dichloromethane, the combined organic phases are washed with saturated aqueous sodium chloride solution and dried over sodium sulfate. After evaporation of the solvent, 3.62 g of product is obtained in the form of an oil used as it is in the next step.
• the aqueous phase is separated off, extracted twice with dichloromethane, the combined organic phases are washed with saturated aqueous ammonium chloride solution and then with saturated aqueous sodium chloride solution and dried over sodium sulphate. and we concentrate the filtrate under reduced pressure.
• the oil obtained is triturated in diisopropyl ether. The solid thus obtained is filtered and then rinsed thoroughly with ether. After drying under vacuum at approximately 40 ° C., 0.195 g of pure product is obtained in the form of a beige powder.
• step 2.5 From 0.364 g (0.86 mmol) of tert-butyl 2- [3- (methylcarbamoyl) -isoxazol-5-ylmethoxycarbonylamino] -7-aza-spiro [3.5] nonane-7-carboxylate, obtained from step 4.2., and 3.25 mL (12.92 mmol) of a solution of 4N hydrochloric acid in dioxane, 0.32 g of product as hydrochloride used as such in the next step.
• LC-MS: M + H 359
• step 2.4 From 0.50 g (1.19 mmol) of tert-butyl 2 - [(4-nitro-phenoxycarbonylamino) -methyl] -7-aza-spiro [3.5] nonane-7-carboxylate, prepared from step 5.2., 0.337 g (2.38 mmol) of N, N-diisopropylethylamine, 0.073 g (0.60 mmol) of N, N-dimethylaminopyridine and 0.169 g (1.19 mmol) of 3-carbamoyl. isoxazol-5-ylmethanol, 0.50 g of product is obtained in the form of an oil used as it is in the next step.
• aqueous phase is separated, extracted twice with ethyl acetate, the combined organic phases are washed with a saturated aqueous solution of ammonium chloride and dried over sodium sulfate. After evaporation of the solvent, 0.380 g of product is obtained in the form of an orange oil used as it is in the next step.
• Example 1 The procedure is as described in Example 1 (step 1.3). From 0.45 g (1.04 mmol) of 5- (6-aza-spiro [3.4] oct-2- trifluoroacetate ethylcarbamoyloxymethyl) -isoxazole-3-carboxylate, described in step 6.6, of 0.198 g (1.04 mmol) of 2-fluoro-5- (4-fluoro-phenyl) -pyridine, prepared in accordance with step 6.7.
• step 8.4 0.16 g (0.88 mmol) of 2-fluoro-5- (4-fluorophenyl) pyridine, prepared in step 6.7. and 0.38 g (2.92 mmol) of N, N-diisopropylethylamine, and after purification by chromatography on silica gel, eluting with a 98/2 / 0.2 mixture of dichloromethane and methanol and aqueous ammonia, 0.07 g of pure product is thus obtained in the form of a white solid.
• LC-MS: M + H 494
• Example 1 The procedure is as described in Example 1 (step 1.3). From 0.33 g (0.76 mmol) of 3- (methylcarbamoyl) -isoxazol-5-ylmethyl (6-Aza-spiro [3.4] oct-2-ylmethyl) -carbamate trifluoroacetate, described in US Pat. step 9.3., 0.174 g (0.91 mmol) of 2-fluoro-5- (4-fluorophenyl) pyridine, prepared in step 6.7.
• step 6.3. From 7.66 g (19.62 mmol) of 7- [5- (4-fluoro-phenyl) -pyridin-2-yl] -7-aza-spiro [3.5] non-2-yl methanesulfonate, prepared in step 10.3., and 3.83 g (58.85 mmol) of sodium azide in 28 mL of N, N- dimethylformamide. After evaporation of the solvent, 6.60 g of product is obtained in the form of a brown oil.
• step 10.5. 1.34 g (4.16 mmol) of 3- (methylcarbamoyl) -isoxazol-5-ylmethyl 4-nitro-phenylcarbonate, obtained in step 4.1., from 1 12 g (8.67 mmol) of N, N-diisopropylethylamine and 0.212 g (1.73 mmol) of N, N-dimethylaminopyridine and after purification by chromatography on silica gel eluting with a 98/2 mixture of dichloromethane and methanol, 0.847 g of pure product is thus obtained in the form of a white solid.
• PF ( 0 C): 219-221 ° C LC-MS: M + H 493
• the solution obtained is filtered on celite and rinsed abundantly with water and with ether.
• the aqueous phase is then separated, extracted several times with ether.
• the combined organic phases are dried over sodium sulfate and the filtrate is concentrated under reduced pressure. After evaporation of the solvent, the product obtained in the form of a brown oil is used as it is in the next step.
• the filtrate is evaporated to dryness.
• the residue obtained is taken up in water and extracted several times with ethyl acetate.
• the combined organic phases are dried over sodium sulfate and the filtrate is concentrated under reduced pressure.
• the residue obtained is purified by chromatography on silica gel, eluting with a 90/10 mixture of cyclohexane and ethyl acetate. 1.78 g of pure product are thus obtained in the form of a white powder.
• tert-butyl 2-methanesulfonyloxy-6-aza-spiro [3.4] octane-6-carboxylate isomers 1 and 2, prepared according to the method described in Example 6 (step 6.2.), Are separated by chromatography column. on silica gel eluting with a cyclohexane / ethyl acetate mixture from 100/0 to 80/20.
• Example 6 The procedure is as described in Example 6 (step 6.3). From 1.62 g (5.30 mmol) of 2-methanesulfonyloxy-6-aza-spiro [3.4] octane-6-carboxylate (isomer 1), described in Example 12 (step 12.1) and from 68 g (10.61 mmol) of sodium azide, the product is obtained in the form of a yellow oil used as such in the next step.
• reaction medium is taken up with a saturated solution of sodium chloride and dichloromethane, the aqueous phase is separated off, extracted with dichloromethane and the combined organic phases are dried over sodium sulphate. After evaporation under reduced pressure and purification on a column of silica gel, eluting with a mixture of 100/0/0 to 96/4 / 0.4 of dichloromethane, methanol and 28% ammonia, 0.27 g is obtained. of expected product in the form of wax.
• LC-MS: M + H 274
• Example 16 [6- (4-Trifluoromethyl-pyrimidin-2-yl) -6-aza-spiro [2.5] oct-1-yl] -carbamoyl-isoxazol-5-ylmethyl carbamate
• Table 1 which follows illustrates the chemical structures and the physical properties of some compounds according to the invention. In this table: all compounds are in free base form; Compounds Nos. 10 and 11 are mixtures of isomers. Compound No. 12 is in the form of isomer I while compound No. 13 is in the form of isomer II. Compound No. 17 is in the form of isomer I while compound No. 18 is in the form of isomer II. Compounds 16, 21 and 22 are in the form of an isomer. These isomers correspond to positional isomers of the -A-NH- chain with respect to the - (CH 2 ) n N- chain. the "PF ( 0 C)" column gives the product melting points in degrees Celsius ( 0 C).
• Compound 26 is in salt form.
• the compounds of the invention have been the subject of pharmacological tests to determine their inhibitory effect of the enzyme FAAH (Fatty Acid Amide Hydrolase).
• reaction buffer supplemented with bovine serum albumin without fatty acids (BSA, 1 mg / mL) is used for the enzymatic reaction, the dilution of the compounds and of anandamide [ethanolamine 1- 3 H].
• BSA bovine serum albumin without fatty acids
• the most active compounds of the invention exhibit IC 50 (50% concentration inhibiting the enzymatic activity controlling FAAH) of between 0.001 and 1 ⁇ M, for example compounds No. 4 and No. 6 , No. 8, No. 10, No. 12, No. 19, No. 25, No. 31, No. 40 have respective IC 50 of 0.0082, 0.00025, 0.00072, 0.0023, 0.00085, 0.0018, 0.0017, 0.0043, 0.0005 ⁇ M.
• the in vivo activity of the compounds of the invention was evaluated in an analgesia test.
• the compounds tested are administered orally (p.o.) or intraperitoneally
• the most potent compounds of the invention reduce by 35 to 80% the number of stretching induced by the PBQ, in a dose range of between 1 and 30 mg / kg.
• compound No. 5 of Table 1 reduces the number of PBQ-induced stretches by 50% at a dose of 30 mg / kg p.o. to 120 minutes.
• the enzyme FAAH (Chemistry and Physics of Lipids, (2000), 108, 107-121) catalyzes the hydrolysis of endogenous derivatives of amides and esters of different fatty acids such as N-arachidonoylethanolamine (anandamide), N-palmitoyl ethanolamine, N-oleoylethanolamine, oleamide or 2-arachidonoylglycerol. These derivatives exert different pharmacological activities by interacting, inter alia, with the cannabinoid and vanilloid receptors.
• the compounds of the invention block this degradation pathway and increase the tissue level of these endogenous substances. They can be used for this purpose in the prevention and treatment of pathologies in which the endogenous cannabinoids and / or any other substrates metabolized by the enzyme FAAH, are involved.
• pain particularly acute or chronic pain of the neurogenic type: migraine, neuropathic pain, including forms associated with the herpes virus and diabetes, and chemotherapy, acute or chronic pain associated with inflammatory diseases: arthritis, rheumatoid arthritis, osteoarthritis, spondylitis, gout, vasculitis, Crohn's disease, irritable bowel syndrome, acute or chronic peripheral pain, dizziness, vomiting, nausea in particularly those following chemotherapy, eating disorders, particularly anorexia and cachexia of various kinds, neurological and psychiatric pathologies: tremor, dyskinesia, dystonia, spasticity, compulsive and obsessive behavior, Tourette's syndrome, all forms of depression and anxiety of any kind and origin, mood disorders, psychoses, acute and chronic neuro-degenerative diseases: Parkinson's disease, Alzheimer's disease, senile dementia, Huntington's chorea, brain ischemia-related lesions and cranial and spinal injuries, the epil e
• the subject of the invention is also medicaments which comprise a compound of formula (I), or an addition salt with an acid, or a pharmaceutically acceptable hydrate or solvate of the compound of formula (I).
• These drugs find their use in therapy, especially in the treatment of the above-mentioned pathologies.
• the present invention relates to pharmaceutical compositions containing, 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 an addition salt with an acid, or a hydrate, or a pharmaceutically acceptable solvate. said compound, and optionally 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.
• compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intrathecal, intranasal, transdermal, pulmonary, ocular or rectal administration the active ingredient of formula (I) above, or its acid addition 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 disorders or diseases above.
• Suitable unit dosage forms include oral forms such as tablets, soft or hard capsules, powders, granules, chewing gums and oral solutions or suspensions, sublingual, oral, Intratracheal, intraocular, intranasal, inhalation, subcutaneous, intramuscular or intravenous administration forms and rectal or vaginal administration forms.
• oral forms such as tablets, soft or hard capsules, powders, granules, chewing gums and oral solutions or suspensions, sublingual, oral, Intratracheal, intraocular, intranasal, inhalation, subcutaneous, intramuscular or intravenous administration forms and rectal or vaginal administration forms.
• the compounds according to the invention can be used in creams, ointments or lotions.
• a unitary form of administration of a compound according to the invention in tablet form may comprise the following components:
• Said unit forms are dosed to allow a daily administration of 0.01 to 20 mg of active ingredient per kg of body weight, according to the dosage form.
• dosages There may be special cases where higher or lower dosages are appropriate, such dosages also belong to the invention.
• 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 invention according to another of its aspects, also relates to a method of treatment of the pathologies indicated above which comprises the administration of an effective dose of a compound according to the invention, one of its addition salts a pharmaceutically acceptable acid, a solvate or a hydrate of said compound.

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