EP2146992A1 - Triazolopyridine carboxamide derivatives and triazolopyrimidine carboxamide derivatives, preparation thereof and therapeutic use thereof - Google Patents

Triazolopyridine carboxamide derivatives and triazolopyrimidine carboxamide derivatives, preparation thereof and therapeutic use thereof

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Publication number
EP2146992A1
EP2146992A1 EP08787965A EP08787965A EP2146992A1 EP 2146992 A1 EP2146992 A1 EP 2146992A1 EP 08787965 A EP08787965 A EP 08787965A EP 08787965 A EP08787965 A EP 08787965A EP 2146992 A1 EP2146992 A1 EP 2146992A1
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compound
formula
diseases
phenyl
group
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German (de)
French (fr)
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Luc Even
Christian Hoornaert
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Sanofi SA
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Sanofi Aventis France
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to triazolopyridine-carboxamide and triazolopyrimidine-carboxamide derivatives, to their preparation and to their therapeutic application.
  • a and X represent, independently of one another, a nitrogen atom or a CH group
  • R 1 represents an aryl or heteroaryl group optionally substituted by one or more groups selected from a halogen atom, a (C -, - C 6) alkyl, halo (Ci-C 6) alky e, (C r C 6! ) alkoxy, halo (C r C 6) alkoxy,
  • R 2 represents an aryl group, optionally substituted with one or more groups selected from a halogen atom, a methyl group, trifluoromethyl, methoxy, trifluoromethoxy.
  • the compounds of formula (I) may comprise one or more asymmetric carbon atoms. They can therefore exist as enantiomers or diastereoisomers. These enantiomers, diastereoisomers, as well as their mixtures, including the 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 can be 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 water molecules or with a solvent. Such hydrates and solvates are also part of the invention.
  • Ci -3 can characterize a carbon chain having from 1 to 3 carbon atoms ;
  • halogen atom a fluorine, a chlorine, a bromine or an iodine
  • alkyl group a saturated linear or branched aliphatic group.
  • alkyl group a saturated linear or branched aliphatic group.
  • haloalkyl group an alkyl group in which one or more hydrogen atoms have been substituted by a fluorine atom;
  • an alkoxy group an -O-alkyl radical in which the alkyl group is as previously defined;
  • a haloalkoxy group an alkoxy group in which one or more hydrogen atoms have been substituted with a halogen atom;
  • aryl group a cyclic aromatic group comprising between 5 and 14 carbon atoms.
  • aryl groups mention may be made of phenyl or naphthyl;
  • heteroaryl group an aromatic heterocyclic group comprising either 5 or 6 carbon atoms and comprising from 1 to 4 heteroatoms, such as nitrogen, oxygen or sulfur.
  • heteroaryl groups mention may be made of pyrrole, furan, thiophene, pyrazole, imidazole, triazole, tetrazole, oxazole, isoxazole, oxadiazole, thiazole, isothiazole, thiadiazole, pyridine, pyrimidine, pyrazine, pyridazine and triazine.
  • a first group of compounds consists of the compounds for which:
  • A represents a nitrogen atom
  • X represents a CH group.
  • a second group of compounds consists of the compounds for which:
  • Ft 1 represents an aryl or heteroaryl group optionally substituted by one or more groups selected from a halogen atom, a (C 1 - C 6) alkyl, halo (CrC 6) alkyl, (C-rC ⁇ Jalcoxy, halo (C r C 6 ) alkoxy,
  • a third group of compounds consists of the compounds for which:
  • R 1 represents a phenyl, furan, thiophene or naphthalene group, optionally substituted by a halogen atom.
  • a protective group Pg is understood to mean a group that makes it possible, on the one hand, to protect a reactive function such as a hydroxyl or an amine during a synthesis and, on the other hand, to regenerate the intact reactive function. at the end of synthesis.
  • Examples of protecting groups and methods of protection and deprotection are given in "Protective Groups in Organic Synthesis", Green et al., 2nd Edition (John Wiley & Sons, Inc., New York), 1991.
  • leaving group is meant, in what follows, a group that can be easily cleaved from a molecule by breaking a heterolytic bond, with departure from an electronic pair. This group can thus be easily replaced by another group during a substitution reaction, for example.
  • Such leaving groups are, for example, halogens or an activated hydroxy group such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, triflate, acetate, etc. Examples of leaving groups as well as references for their preparation are given in Advances in Organic Chemistry, J. March, 3 rd Edition, Wiley Interscience, 1985, p. 310-316.
  • the compounds of general formula (I) can be prepared according to the process illustrated in the following scheme 1.
  • the compounds of general formula (II), in which X is as defined above, are converted into compounds of general formula (III) in which X and R 1 are such that defined above.
  • the transformation is carried out by a coupling reaction with a boronic acid or a boronate of the respective general formulas (IV) or (V), in which R 1 is as defined above, and (OR ") 2 represents a pinacol group, catalyzed by a palladium complex.
  • the compounds of general formula (III), in which X and R 1 are as defined above, are converted into compounds of general formula (VI), in which R 1 , R 2, X and A are as defined above, by reaction with a carbamoyl chloride of general formula (VII).
  • the reaction is carried out in a solvent such as N, N-dimethylformamide or N-methylpyrrolidone in the presence of a base such as sodium hydride or potassium tert-butoxide or ferf-pentoxide.
  • the compounds of general formula (VI) are converted into compounds of general formula (VIII) in which R 2 , A, R 1 and X are as defined above, by reduction of a nitro group to an amino group.
  • the reaction can be carried out by various methods described in the literature or known to those skilled in the art, such as, for example, hydrogenation in the presence of a catalyst based on palladium, platinum or nickel and their variants.
  • the compounds of general formula are converted (VIII) to compounds of general formula (I) by a diazotization-cyclization reaction.
  • the reaction can be carried out using a nitrite, for example sodium or potassium nitrite in an acid medium or isoamyl or tert-butyl nitrite, in solvents such as water or tetrahydrofuran or their mixture.
  • a nitrite for example sodium or potassium nitrite in an acid medium or isoamyl or tert-butyl nitrite, in solvents such as water or tetrahydrofuran or their mixture.
  • Lane B of Scheme 1 illustrates an alternative method for preparing the compounds of formula (I).
  • the compounds of general formula (II) are converted into compounds of general formula (IX) by reaction with a carbamoyl chloride of general formula (VII), as defined above.
  • the compounds of general formula (IX) are converted into compounds of general formula (VI) by a reaction with a boronic acid or a boronate of general formula (IV) or (V), as defined above.
  • the compounds of general formula (II), (IV) and (V) are commercially available.
  • the carbamoyl chlorides of general formula (VII), if they are not commercially available, may be prepared by any method described in the literature or known to those skilled in the art, for example from the corresponding amines by reaction. with phosgene, diphosgene or triphosgene.
  • Lane A alternatively, 4- (3-trifluoromethyl-phenyl) -piperazine-1-carboxylic acid, [6- (4-chloro-phenyl) -3-nitro-pyridin-2-yl] -amide may be prepared as follows. Under a nitrogen atmosphere, 1 g (5.76 mmol) of 2-amino-6-chloro-3-nitro-pyridine, 1.26 g (8.07 mmol) of 4-chlorobenzeneboronic acid, 7.2 ml are mixed.
  • step 1.1 This product is employed as in step 1.1 to obtain 4- (3-trifluoromethyl-phenyl) -piperazine-1-carboxylic acid, [6- (4-chloro-phenyl) -3-nitro-pyridin-2 yl] amide.
  • Table 1 which follows illustrates the chemical structures and the physical properties of some examples of compounds according to the invention.
  • Table 1 which follows illustrates the chemical structures and the physical properties of some examples of compounds according to the invention. In this table :
  • Ph represents a phenyl group.
  • the compounds according to the invention surprisingly exhibit an inhibitory effect on the MGL enzyme (monoacyl glycerol lipase).
  • the MGL enzyme catalyzes the hydrolysis of endogenous derivatives of monoglyceride esters of different fatty acids (FEBS Letters 1998, 429, 152-156) and in particular the hydrolysis of 2-arachidonoylglycerol (2-AG) and 1 (3 ) -arachidonoylglycerol (1 (3) -AG) (J. Biol Chem 1987, 272 (48), 27218-27223, Proc Natl Acad Sci USA 2002, 99 (16), 10819-10824; Pharmacol 2004, 67, 1381-1387, Mol Pharmacol 2004, 66 (5), 1260-1264).
  • the 2-AG and 1 (3) -AG derivatives in particular interact with the cannabinoid receptors (J. Biol Chem 1999, 274 (5), 2794-2801, J. Biol Chem 2000, 275 (1), 605-612, British J. Pharmacol 2001, 134, 664-672).
  • the compounds of the invention block this degradation pathway and increase the tissue levels of these derivatives and in particular 2-AG and / or 1 (3) -AG. As such, they can be used in the prevention and treatment of pathologies in which 2-AG and / or 1 (3) -AG in particular and / or any other substrate metabolized by the MGL enzyme (Progress) are involved. Lipid Research 2006, 45, 405-446).
  • the compounds according to the invention may also have an additional inhibitory effect on the enzyme FAAH (Fatty Acid Amide Hydrolase).
  • 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 ⁇ / -arachidonoylethanolamine (anandamide), ⁇ -palmitoylethanolamine, ⁇ -O-triethanolamine or oleamide. These derivatives exert different pharmacological activities by interacting, inter alia, with the cannabinoid and vanilloid receptors.
  • the compounds of the invention block this pathway of degradation and increase the tissue level of these endogenous substances. They can be used as such in the prevention and treatment of pathologies in which the endogenous cannabinoids and / or any other substrate metabolized by the enzyme FAAH, are involved. Trials consisted of measuring the in vitro activity of the compounds of the invention on the MGL enzyme.
  • Inhibitory activity was measured in a radioenzyme assay based on the measurement of the hydrolysis product of 2-Oleoyl Glycerol ([ 3 H] 2-OG) by MGL.
  • the hydrolysis products of [ 3 H] 2-OG, labeled on glycerol, are oleic acid and [ 3 H] glycerol and the MGL enzyme source is a mouse brain homogenate where the cerebellum and the spinal bulb have been eliminated.
  • the mouse brains are removed, stored at -80 ° C.
  • the dilution range of the compounds is made from stock solutions at 20 mM in 100% DMSO.
  • the first dilution of this range is carried out in 100% DMSO then the second in the enzyme reaction buffer (50 mM phosphate, 0.1% BSA) resulting in the achievement of a concentration range 10 times concentrated.
  • the test compounds are preincubated at the selected concentration for 20 minutes with the mouse brain homogenate preparation.
  • the final concentration of DMSO in the enzymatic reaction does not exceed 0.1%.
  • the assay of the MGL activity is carried out in a 96-well microplate in a final reaction volume of 100 ⁇ l. Briefly, 75 ⁇ g of protein, preincubated with the test compounds, are diluted in 50 mM phosphate buffer containing 0.1% BSA and incubated for 20 minutes at room temperature, in the presence of 50 ⁇ M of 2-OG containing amount of [ 3 H] 2-OG of 0.027 ⁇ Ci / well (specific activity of 20 Ci / mmol). The reaction is stopped and the products formed are separated by the addition and the mixture of 100 ⁇ l of chloroform / methanol (1/1).
  • the microplate After stirring for 10 minutes, the microplate is centrifuged for 15 minutes at 4000 g and an aliquot of 30 ⁇ l of the aqueous phase containing the [ 3 H] glycerol product is removed and then counted for 5 minutes by liquid scintillation (Wallac 1450 Microbeta).
  • the inhibitory activity against MGL is given by the concentration which inhibits 50% of the MGL activity.
  • the most active compounds of the invention have a Cl 50 (concentration inhibiting 50% MGL control enzyme activity) of between 0.001 and 0.1 ⁇ M.
  • Inhibitory activity was measured in a radioenzymatic assay based on the measurement of the hydrolysis product (ethanolamine [1-3H]) of anandamide by FAAH (Life Science (1995), 56, 1999-2005 and Journal of Pharmacology and Experimented Therapeutics (1997), 283, 729-734).
  • the hydrolysis products of ethanolamine-labeled T [ 3 H] anandamide are arachidonic acid and T [ 3 H] ethanolamine and the enzyme source FAAH is a mouse brain homogenate where the cerebellum and the spinal bulb have been eliminated. The mouse brains are removed, stored at -80 ° C.
  • the dilution range of the compounds is made from stock solutions at 20 mM in 100% DMSO.
  • the first dilution of this range is carried out in 100% DMSO then the second in the enzyme reaction buffer (10 mM Tris-HCl, 15 mM NaCl, 1 mM EDTA (pH 8), 0.1% BSA) resulting in the production of concentration range 10 times concentrated.
  • the test compounds are preincubated at the selected concentration for 20 minutes with the mouse brain homogenate preparation. The final concentration of DMSO in the enzymatic reaction does not exceed 0.1%.
  • the assay of the FAAH activity is carried out in a 96-well microplate in a final reaction volume of 70 ⁇ L. Briefly, 200 ⁇ g of mouse brain homogenate, preincubated with the test compounds, are diluted in 10 mM Tris-HCl, NaCl. 15 mM, 1 mM EDTA (pH8) containing 0.1% BSA and incubated for 20 minutes at room temperature in the presence of 10 ⁇ M of anandamide containing a quantity of [ 3 H] -anandamide of 0.01 ⁇ Ci / well ( Specific activity of 60 Ci / mmole). The reaction is stopped and the products formed are separated by the addition and the mixture of 140 ⁇ l of chloroform / methanol (2/1).
  • the microplate After 10 minutes After stirring, the microplate is centrifuged for 15 minutes at 4000 g and an aliquot of 30 ⁇ l of the aqueous phase containing P [ 3 H] ethanolamine produced is taken and then counted for 5 minutes by liquid scintillation (Wallac 1450 Microbeta).
  • the most active compounds of the invention have a Cl 50 (50% concentration inhibiting the enzymatic activity controlling FAAH) of between 0.001 and 0.1 ⁇ M.
  • Cl 50 50% concentration inhibiting the enzymatic activity controlling FAAH
  • compound No. 3 showed a Cl 50 of 0.002 ⁇ M.
  • the compounds according to the invention have a selective inhibitory activity with respect to MGL or mixed with respect to MGL and FAAH.
  • the compounds according to the invention can therefore be used for the preparation of medicaments, in particular drugs which inhibit the MGL enzyme or the MGL and FAAH enzymes.
  • the subject of the invention is medicaments which comprise a compound of formula (I), or an addition salt thereof to a pharmaceutically acceptable acid, or a hydrate or a solvate of compound of formula (I).
  • These drugs find their therapeutic use, particularly in the treatment and prevention of: pain including acute or chronic pain of neurogenic type: migraine, neuropathic pain including forms associated with the herpes virus and diabetes; 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 especially those following chemotherapy; eating disorders, particularly anorexia and cachexia of various natures; metabolic syndrome and its manifestations, including obesity; dyslipidemias and their manifestations, including atherosclerosis and coronary heart disease; neurological and psychiatric pathologies: tremor, dyskinesia, dystonia, spasticity, compulsive and obsessive behavior, Tourette's syndrome, all forms of depression and anxiety of all kinds and origins, mood disorders, psychoses; acute and chronic neuro-degenerative diseases: Parkinson's disease, Alzheimer's disease, senile dementia
  • Epilepsy sleep disorders including sleep apnea; cardiovascular diseases especially hypertension, cardiac arrhythmias, arteriosclerosis, heart attack, ischemic heart disease; renal ischemia; cancers: benign tumors of the skin, papillomas and brain tumors, prostate tumors, brain tumors (glioblastomas, medulloepitheliomas, medulloblastomas, neuroblastomas, embryonic origin tumors, astrocytomas, astroblastomas, ependyomas, oligodendrogliomas, plexus tumors, neuroepitheliomas, epiphysis tumor, ependymoblastomas, malignant meningiomas, sarcomatoses, malignant melanomas, schwénnomes); disorders of the immune system, including autoimmune diseases: psoriasis, lupus erythematosus, connective tissue diseases or connective tissue diseases, Sjögren's syndrome, ankylosing spond
  • the present invention relates to pharmaceutical compositions comprising, as active principle, a compound according to the invention.
  • These pharmaceutical compositions contain an effective dose of at least one compound according to the invention, or a pharmaceutically acceptable salt, a hydrate or solvate of said compound, as well as at least one pharmaceutically acceptable excipient.
  • 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, infra-venous, topical, local, intratracheal, intranasal, transdermal or rectal administration the active ingredient of formula (I) above, or its 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.
  • the compounds according to the invention can be used in creams, gels, ointments or lotions.
  • a unitary form of administration of a compound according to the invention in tablet form may comprise the following components: Compound according to the invention 50.0 mg
  • the present invention 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.

Abstract

The invention relates to the triazolopyridine carboxamide derivatives and triazolopyrimidine carboxamide derivatives of general formula (I) in which A and X are, independently of one another, a nitrogen atom or a CH group, R1 is an aryl or heteroaryl group optionally substituted with one or more groups selected from a halogen atom or a (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkoxy or halo(C1-C6)alkoxy group, R2 is an aryl group optionally substituted with one or more groups selected from a halogen atom or a methyl, trifluoromethyl, methoxy or trifluoromethoxy group. Process for the preparation thereof and therapeutic use thereof.

Description

DÉRIVÉS DE TRIAZOLOPYRIDINE-CARBOXAMIDES ET TRIAZOLOPYRIMIDINE-CARBOXAMIDES, LEUR PRÉPARATION ET LEUR APPLICATION EN THÉRAPEUTIQUE TRIAZOLOPYRIDINE CARBOXAMIDE AND TRIAZOLOPYRIMIDINE CARBOXAMIDE DERIVATIVES, PREPARATION THEREOF AND THERAPEUTIC USE THEREOF
La présente invention se rapporte à des dérivés de triazolopyridine- carboxamides et triazolopyrimidine-carboxamides, à leur préparation et à leur application en thérapeutique.The present invention relates to triazolopyridine-carboxamide and triazolopyrimidine-carboxamide derivatives, to their preparation and to their therapeutic application.
La présente invention a pour objet les composés répondant à la formule (I)The subject of the present invention is the compounds corresponding to formula (I)
(I) dans laquelle :(I) in which:
A et X représentent indépendamment l'un de l'autre, un atome d'azote ou un groupement CH,A and X represent, independently of one another, a nitrogen atom or a CH group,
R1 représente un groupement aryle ou hétéroaryle, éventuellement substitué par un ou plusieurs groupes choisis parmi un atome d'halogène, un groupe (C-,- C6)alkyle, halo(CrC6)alky!e, (CrC6)alcoxy, halo(CrC6)alcoxy,R 1 represents an aryl or heteroaryl group optionally substituted by one or more groups selected from a halogen atom, a (C -, - C 6) alkyl, halo (Ci-C 6) alky e, (C r C 6! ) alkoxy, halo (C r C 6) alkoxy,
R2 représente un groupement aryle, éventuellement substitué par un ou plusieurs groupes choisis parmi un atome d'halogène, un groupe méthyle, trifluorométhyle, méthoxy, trifluorométhoxy.R 2 represents an aryl group, optionally substituted with one or more groups selected from a halogen atom, a methyl group, trifluoromethyl, methoxy, trifluoromethoxy.
Les composés de formule (I) peuvent comporter un ou plusieurs atomes de carbone asymétriques. Ils peuvent donc exister sous forme d'énantiomères ou de diastéréoisomères. Ces énantiomères, diastéréoisomères, ainsi que leurs mélanges, y compris les mélanges racémiques, font partie de l'invention.The compounds of formula (I) may comprise one or more asymmetric carbon atoms. They can therefore exist as enantiomers or diastereoisomers. These enantiomers, diastereoisomers, as well as their mixtures, including the racemic mixtures, form part of the invention.
Les composés de formule (I) peuvent exister à l'état de bases ou de sels d'addition à des acides. De tels sels d'addition font partie de l'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.
Ces sels peuvent être préparés avec des acides pharmaceutiquement acceptables, mais les sels d'autres acides utiles, par exemple, pour la purification ou l'isolement des composés de formule (I) font également partie de l'invention.These salts can be 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.
Les composés de formule (I) peuvent également exister sous forme d'hydrates ou de solvatees, à savoir sous forme d'associations ou de combinaisons avec une ou plusieurs molécules d'eau ou avec un solvant. De tels hydrates et solvatees font également partie de l'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 water molecules or with a solvent. Such hydrates and solvates are also part of the invention.
Dans le cadre de la présente invention, on entend par :In the context of the present invention, the following terms mean:
- Ct-Z où t et z peuvent prendre les valeurs de 1 à 7, une chaîne ou un cycle carboné pouvant avoir de t à z atomes de carbone, par exemple Ci-3 peut caractériser une chaîne carbonée ayant de 1 à 3 atomes de carbone;- tZ C where t and z may take the values from 1 to 7, a chain or carbon ring possibly containing from t to z carbon atoms, for example Ci -3 can characterize a carbon chain having from 1 to 3 carbon atoms ;
- un atome d'halogène : un fluor, un chlore, un brome ou un iode ;a halogen atom: a fluorine, a chlorine, a bromine or an iodine;
- un groupe alkyle : un groupe aliphatique saturé linéaire ou ramifié. A titre d'exemples, on peut citer les groupes méthyle, éthyle, propyle, isopropyle, butyle, isobutyle, tertbutyle, pentyle, etc ;an alkyl group: a saturated linear or branched aliphatic group. By way of examples, mention may be made of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, and the like;
- un groupe haloalkyle : un groupe alkyle dont un ou plusieurs atomes d'hydrogène ont été substitués par un atome de fluor ;a haloalkyl group: an alkyl group in which one or more hydrogen atoms have been substituted by a fluorine atom;
- un groupe alcoxy : un radical -O-alkyle où le groupe alkyle est tel que précédemment défini ;an alkoxy group: an -O-alkyl radical in which the alkyl group is as previously defined;
- un groupe haloalcoxy : un groupe alcoxy dont un ou plusieurs atomes d'hydrogène ont été substitués par un atome d'halogène ;a haloalkoxy group: an alkoxy group in which one or more hydrogen atoms have been substituted with a halogen atom;
- un groupe aryle : un groupe aromatique cyclique comprenant entre 5 et 14 atomes de carbone. A titre d'exemples de groupes aryles, on peut citer phényle ou naphthyle;an aryl group: a cyclic aromatic group comprising between 5 and 14 carbon atoms. As examples of aryl groups, mention may be made of phenyl or naphthyl;
- un groupe hétéroaryle : un groupe hétérocyclique aromatique comprenant soit 5 soit 6 atomes de carbone et comprenant de 1 à 4 hétéroatomes, tels que l'azote, l'oxygène ou le soufre. A titre d'exemples de groupes hétéroaryles, on peut citer pyrrole, furane, thiophene, pyrazole, imidazole, triazole, tetrazole, oxazole, isoxazole, oxadiazole, thiazole, isothiazole, thiadiazole, pyridine, pyrimidine, pyrazine, pyridazine, triazine.a heteroaryl group: an aromatic heterocyclic group comprising either 5 or 6 carbon atoms and comprising from 1 to 4 heteroatoms, such as nitrogen, oxygen or sulfur. As examples of heteroaryl groups, mention may be made of pyrrole, furan, thiophene, pyrazole, imidazole, triazole, tetrazole, oxazole, isoxazole, oxadiazole, thiazole, isothiazole, thiadiazole, pyridine, pyrimidine, pyrazine, pyridazine and triazine.
Dans les différents groupes tel que définis ci-dessous, les groupes A, X, R1 et R2 lorsqu'ils ne sont pas définis, ont les mêmes définitions que celles mentionnées ci- dessus.In the different groups as defined below, the groups A, X, R 1 and R 2, when they are not defined, have the same definitions as those mentioned above.
Parmi les composés de formule (I) objets de l'invention, un premier groupe de composés est constitué par les composés pour lesquels :Among the compounds of formula (I) that are the subject of the invention, a first group of compounds consists of the compounds for which:
A représente un atome d'azote,A represents a nitrogen atom,
X représente un groupement CH. Parmi les composés de formule (I) objets de l'invention, un second groupe de composés est constitué par les composés pour lesquels :X represents a CH group. Among the compounds of formula (I) that are the subject of the invention, a second group of compounds consists of the compounds for which:
Ft1 représente un groupe aryle ou hétéroaryle éventuellement substitué par un ou plusieurs groupes choisis parmi un atome d'halogène, un groupe (C1- C6)alkyle, halo(CrC6)alkyle, (C-rCβJalcoxy, halo(CrC6)alcoxy,Ft 1 represents an aryl or heteroaryl group optionally substituted by one or more groups selected from a halogen atom, a (C 1 - C 6) alkyl, halo (CrC 6) alkyl, (C-rCβJalcoxy, halo (C r C 6 ) alkoxy,
Parmi les composés de formule (I) objets de l'invention, un troisième groupe de composés est constitué par les composés pour lesquels :Among the compounds of formula (I) that are the subject of the invention, a third group of compounds consists of the compounds for which:
R1 représente un groupe phényle, furane, thiophène, ou naphtalène, éventuellement substitué par un atome d'halogène.R 1 represents a phenyl, furan, thiophene or naphthalene group, optionally substituted by a halogen atom.
Les combinaisons des groupes un à trois tels que définis ci dessus font également partie de l'invention.The combinations of groups one to three as defined above are also part of the invention.
Parmi les composés de formule (I) objets de l'invention, on peut notamment citer les composés suivants :Among the compounds of formula (I) that are subjects of the invention, mention may be made especially of the following compounds:
- [5-(2-Chloro-phényl)-[1,2,3]triazolo[4,5-b]pyridin-3-yl]-[4-(3-trifluorométhyl-phényl)- pipérazin-1-yl]-méthanone ;- [5- (2-Chloro-phenyl) - [1,2,3] triazolo [4,5-b] pyridin-3-yl] - [4- (3-trifluoromethyl-phenyl) -piperazin-1-yl] ] -methanone;
- [5-(3-Chloro-phényl)-[1,2,3]tria2o!o[4,5-b]pyridin-3-yl]-[4-(3-trifluorométhyl-phényl)- pipérazin-1 -yl]-méthanone ;- [5- (3-Chloro-phenyl) - [1,2,3] triazo [4,5-b] pyridin-3-yl] - [4- (3-trifluoromethyl-phenyl) -piperazin-1 -yl] -methanone;
- [5-(4-Chloro-phényl)-[1,2,3]triazolo[4,5-b]pyridin-3-yl]-[4-(3-trifluorométhyl-phényl)- pipérazin-1-yl]-méthanone ;[5- (4-Chloro-phenyl) - [1,2,3] triazolo [4,5-b] pyridin-3-yl] - [4- (3-trifluoromethyl-phenyl) -piperazin-1-yl] ] -methanone;
- (5-Furan-3-yl-[1 ,2,3]triazolo[4,5-b]pyridin-3-yl)-[4-(3-trifluorométhyl-phényl)- pipérazin-1-y!]-méthanone ;(5-Furan-3-yl- [1,2,3] triazolo [4,5-b] pyridin-3-yl) - [4- (3-trifluoromethyl-phenyl) piperazin-1-yl] -methanone;
- (5-Thiophèn-3-yl-[1 ,2,3]triazolo[4,5-b]pyridin-3-yl)-[4-(3-trifluorométhyl-phényl)- pipérazin-1-yl]-méthanone ;(5-Thiophen-3-yl- [1,2,3] triazolo [4,5-b] pyridin-3-yl) - [4- (3-trifluoromethyl-phenyl) -piperazin-1-yl] - methanone;
- (5-Naphthalèn-2-yl-[1 ,2,3]triazolo[4,5-b]pyridin-3-yl)-[4-(3-trifluorométhyl-phényl)- pipérazin-1-yl]-méthanone ;(5-Naphthalen-2-yl- [1,2,3] triazolo [4,5-b] pyridin-3-yl) - [4- (3-trifluoromethyl-phenyl) -piperazin-1-yl] - methanone;
- (5-Naphthalèn-1 -yl-[1 ,2,3]triazolo[4,5-b]pyridin-3-ylH4-(3-trifluorométhyl-phényl)- pipérazin-1 -yl]-méthanone.(5-Naphthalen-1-yl [1,2,3] triazolo [4,5-b] pyridin-3-yl] -4- (3-trifluoromethyl-phenyl) piperazin-1-yl] -methanone.
Dans ce qui suit, on entend par groupe protecteur Pg un groupe qui permet, d'une part, de protéger une fonction réactive telle qu'un hydroxy ou une aminé pendant une synthèse et, d'autre part, de régénérer la fonction réactive intacte en fin de synthèse. Des exemples de groupes protecteurs ainsi que des méthodes de protection et de déprotection sont données dans « Protective Groups in Organic Synthesis », Green et al., 2nd Edition (John Wiley & Sons, Inc., New York), 1991. On entend par groupe partant, dans ce qui suit, un groupe pouvant être facilement clivé d'une molécule par rupture d'une liaison hétérolytique, avec départ d'une paire électronique. Ce groupe peut ainsi être remplacé facilement par un autre groupe lors d'une réaction de substitution, par exemple. De tels groupes partants sont, par exemple, les halogènes ou un groupe hydroxy activé tel qu'un méthanesulfonate, benzènesulfonate, p-toluènesulfonate, triflate, acétate, etc. Des exemples de groupes partants ainsi que des références pour leur préparation sont donnés dans « Advances in Organic Chemistry », J. March, 3rd Edition, Wiley Interscience, 1985, p. 310-316.In what follows, a protective group Pg is understood to mean a group that makes it possible, on the one hand, to protect a reactive function such as a hydroxyl or an amine during a synthesis and, on the other hand, to regenerate the intact reactive function. at the end of synthesis. Examples of protecting groups and methods of protection and deprotection are given in "Protective Groups in Organic Synthesis", Green et al., 2nd Edition (John Wiley & Sons, Inc., New York), 1991. By leaving group is meant, in what follows, a group that can be easily cleaved from a molecule by breaking a heterolytic bond, with departure from an electronic pair. This group can thus be easily replaced by another group during a substitution reaction, for example. Such leaving groups are, for example, halogens or an activated hydroxy group such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, triflate, acetate, etc. Examples of leaving groups as well as references for their preparation are given in Advances in Organic Chemistry, J. March, 3 rd Edition, Wiley Interscience, 1985, p. 310-316.
Conformément à l'invention, on peut préparer les composés de formule générale (I) selon le procédé illustré sur le schéma 1 qui suit.According to the invention, the compounds of general formula (I) can be prepared according to the process illustrated in the following scheme 1.
• Selon la voie A, on transforme, dans une première étape, les composés de formule générale (II), dans laquelle X est tel que défini ci-dessus, en composés de formule générale (III) dans laquelle X et Ri sont tels que définis ci-dessus. La transformation est réalisée par une réaction de couplage avec un acide boronique ou un boronate de formules générales respectives (IV) ou (V), dans lesquelles Ri est tel que défini précédemment, et (OR")2 représente un groupement pinacol, catalysée par un complexe de palladium.According to Route A, in a first step, the compounds of general formula (II), in which X is as defined above, are converted into compounds of general formula (III) in which X and R 1 are such that defined above. The transformation is carried out by a coupling reaction with a boronic acid or a boronate of the respective general formulas (IV) or (V), in which R 1 is as defined above, and (OR ") 2 represents a pinacol group, catalyzed by a palladium complex.
Dans une deuxième étape, on transforme les composés de formule générale (III), dans laquelle X et R1 sont tels que définis ci-dessus, en composés de formule générale (Vl), dans laquelle R1, R2, X et A sont tels que définis ci-dessus, par réaction avec un chlorure de carbamoyle de formule générale (VII). La réaction est conduite dans un solvant tel que le N,N-diméthylformamide ou le N- méthylpyrrolidone en présence d'une base telle que l'hydrure de sodium ou le tert- butoxyde ou ferf-pentoxyde de potassium.In a second step, the compounds of general formula (III), in which X and R 1 are as defined above, are converted into compounds of general formula (VI), in which R 1 , R 2, X and A are as defined above, by reaction with a carbamoyl chloride of general formula (VII). The reaction is carried out in a solvent such as N, N-dimethylformamide or N-methylpyrrolidone in the presence of a base such as sodium hydride or potassium tert-butoxide or ferf-pentoxide.
Dans une troisième étape, on transforme les composés de formule générale (Vl) en composés de formule générale (VIII) dans laquelle R2, A, Ri et X sont tels que définis ci-dessus, par réduction de groupement nitro en groupement amino. La réaction peut être conduite par différentes méthodes décrites dans la littérature ou connues de l'homme de métier, comme par exemple l'hydrogénation en présence d'un catalyseur à base de palladium, platine ou nickel et leurs variantes.In a third step, the compounds of general formula (VI) are converted into compounds of general formula (VIII) in which R 2 , A, R 1 and X are as defined above, by reduction of a nitro group to an amino group. The reaction can be carried out by various methods described in the literature or known to those skilled in the art, such as, for example, hydrogenation in the presence of a catalyst based on palladium, platinum or nickel and their variants.
Dans la quatrième étape, on transforme les composés de formule générale (VIII) en composés de formule générale (I) par une réaction de diazotation- cyclisation. La réaction peut être conduite en utilisant un nitrite, par exemple Ie nitrite de sodium ou de potassium en milieu acide ou le nitrite d'isoamyle ou de tert- butyle, dans des solvants tels que l'eau ou le tétrahydrofurane ou leur mélange. Schéma 1In the fourth step, the compounds of general formula are converted (VIII) to compounds of general formula (I) by a diazotization-cyclization reaction. The reaction can be carried out using a nitrite, for example sodium or potassium nitrite in an acid medium or isoamyl or tert-butyl nitrite, in solvents such as water or tetrahydrofuran or their mixture. Diagram 1
(V)(V)
(Vl) (VI)
(VIII)(VIII)
La voie B du schéma 1 illustre une méthode alternative de préparation des composés de formule (I).Lane B of Scheme 1 illustrates an alternative method for preparing the compounds of formula (I).
Dans une première étape, on transforme les composés de formule générale (II) en composés de formule générale (IX) par réaction avec un chlorure de carbamoyle de formule générale (VII), comme défini précédemment. Dans une deuxième étape, on transforme les composés de formule générale (IX) en composés de formule générale (Vl) par une réaction avec un acide boronique ou un boronate de formule générale (IV) ou (V), comme défini précédemment. On transforme ensuite les composés de formule générale (Vl) en composés de formule générale (VIII) puis en composés de formule générale (I) comme précisé précédemment.In a first step, the compounds of general formula (II) are converted into compounds of general formula (IX) by reaction with a carbamoyl chloride of general formula (VII), as defined above. In a second step, the compounds of general formula (IX) are converted into compounds of general formula (VI) by a reaction with a boronic acid or a boronate of general formula (IV) or (V), as defined above. We then converts the compounds of general formula (VI) into compounds of general formula (VIII) and then into compounds of general formula (I) as specified above.
Les composés de formule générale (II), (IV) et (V) sont disponibles dans le commerce. Les chlorures de carbamoyles de formule générale (VII), s'ils ne sont pas disponibles dans le commerce, peuvent être préparés par toute méthode décrite dans la littérature ou connues de l'homme de métier, par exemple à partir des aminés correspondantes par réaction avec le phosgène, le diphosgène ou le triphosgène.The compounds of general formula (II), (IV) and (V) are commercially available. The carbamoyl chlorides of general formula (VII), if they are not commercially available, may be prepared by any method described in the literature or known to those skilled in the art, for example from the corresponding amines by reaction. with phosgene, diphosgene or triphosgene.
Les exemples qui suivent illustrent la préparation de quelques composés de l'invention. Ces exemples ne sont pas limitatifs et ne font qu'illustrer l'invention. Les microanalyses, les spectres IR et RMN et ou les LC-MS confirment les structures et les puretés des composés obtenus. Les points de fusion (PF) sont indiqués en degrés Celsius.The following examples illustrate the preparation of some compounds of the invention. These examples are not limiting and only illustrate the invention. Microanalyses, IR and NMR spectra and or LC-MS confirm the structures and purities of the compounds obtained. Melting points (PF) are given in degrees Celsius.
Exemple 1 (composé N0 3 du tableau)Example 1 (compound N 0 3 of the table)
[5-(4-chloro-phényl)-[1 ,2,3]triazolo[4,5-jb]pyridin-3-yl]-[4-(3-trifluorométhyl-phényl)- pipérazin-1 -yl]-méthanone[5- (4-Chloro-phenyl) - [1,2,3] triazolo [4,5-b] pyridin-3-yl] - [4- (3-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone
1.1. 4-(3-trifluorométhyl-phényl)-pipérazine-1-carboxylique acide, (6-chloro-3-nitro- pyridin-2-yl)-amide Voie B :1.1. 4- (3-Trifluoromethyl-phenyl) -piperazine-1-carboxylic acid, (6-chloro-3-nitropyridin-2-yl) -amide Lane B:
Sous atmosphère d'Argon, on ajoute par portion 0,55 g (13,83 mmoles) d'hydrure de sodium à 60% dans l'huile à une solution de 1 g (5,76 mmoles) de 2-amino-6- chloro-3-nitro-pyridine et de 2 g (6,91 mmoles) de chlorure 4-(3-trifluorométhyl- phényl)-1-pipérazinecarbonyle (préparé à partir de 1-(3-trifluorométhyl- phényl)pipérazine et de triphosgène) dans 11 mL de diméthylformamide refroidie par un bain de glace. On poursuit l'agitation du mélange réactionnel à la température du bain de glace pendant 15 minutes puis à température ambiante pendant 2 heures. On refroidit par un bain de glace et on ajoute goutte à goutte 40 mL d'une solution aqueuse 1 M d'acide chlorhydrique. On ajoute 40 ml d'acétate d'éthyle et on agite le mélange vigoureusement pendant 15 minutes. On ajuste à pH basique par addition d'une solution aqueuse 1M de soude. On décante Ia phase organique, on la lave par 25 mL d'eau et 25 mL d'une solution aqueuse saturée en R2008/000536Under an argon atmosphere, 0.55 g (13.83 mmol) of 60% sodium hydride in oil is added portionwise to a solution of 1 g (5.76 mmol) of 2-amino-6. chloro-3-nitro-pyridine and 2 g (6.91 mmol) of 4- (3-trifluoromethylphenyl) -1-piperazinecarbonyl chloride (prepared from 1- (3-trifluoromethylphenyl) piperazine and triphosgene) in 11 mL of dimethylformamide cooled by an ice bath. Stirring of the reaction mixture is continued at the temperature of the ice bath for 15 minutes and then at room temperature for 2 hours. It is cooled by an ice bath and 40 ml of a 1M aqueous hydrochloric acid solution are added dropwise. 40 ml of ethyl acetate are added and the mixture is stirred vigorously for 15 minutes. It is adjusted to basic pH by addition of a 1M aqueous solution of sodium hydroxide. The organic phase is decanted, washed with 25 ml of water and 25 ml of a saturated aqueous solution. R2008 / 000536
chlorure de sodium. On sèche sur sulfate de sodium et on évapore à sec. On purifie le produit par chromatographie sur gel de silice en éluant par un mélange 80:20 puis 60:40 de cyclohexane et d'acétate d'éthyle. On obtient 1 ,54 g (Rdt : 62%) de produit sous forme de gomme orange.sodium chloride. It is dried over sodium sulphate and evaporated to dryness. The product is purified by chromatography on silica gel, eluting with an 80:20 mixture and then 60:40 of cyclohexane and ethyl acetate. 1.54 g (yield: 62%) of product are obtained in the form of an orange gum.
1H-RMN (DMSO-d6, δ ppm) : 8,65 (d, 1H), 7,40-7,75 (m+d, 4H), 7,35 (d, 1 H), 3,90 (m, 4H), 3,50 (m, 4H). 1 H-NMR (DMSO-d 6 , δ ppm): 8.65 (d, 1H), 7.40-7.75 (m + d, 4H), 7.35 (d, 1H), 3, 90 (m, 4H), 3.50 (m, 4H).
1.2. 4-(3-trifluorométhyl-phényl)-pipérazine-1-carboxylique acide, [6-(4-chloro- phényl)-3-nitro-pyridin-2-yl]-amide Voie B :1.2. 4- (3-Trifluoromethyl-phenyl) -piperazine-1-carboxylic acid, [6- (4-chlorophenyl) -3-nitro-pyridin-2-yl] -amide Lane B:
Sous atmosphère d'azote, on mélange 0,64 g (1,50 mmole) de 4-(3- trifluorométhyl-phényl)-pipérazine-1-carboxylique acide, (6-chloro-3-nitro-pyridin-2- yl)-amide obtenu à l'étape 1.1. (voie B), 0,33 g (2,1 mmole) d'acide 4- chrorobenzèneboronique, 1,87 ml (3,75 mmoles) d'une solution aqueuse 2M de carbonate de sodium et 0,18 g (4,26 mmoles) de chlorure de lithium dans 100 ml d'un mélange préalablement dégazé d'éthanol/toluène/eau (v/v : 1/1/0,4). On ajoute 0,08 g (0,07 mmole) de tetrakis(triphenylphosphine)palladium (0). On chauffe à 900C sous agitation pendant 8 heures. On refroidit à température ambiante puis on dilue avec 50 ml de dichlorométhane et 25 ml d'eau. On décante la phase organique, on la lave par 25 ml d'eau et 25 ml d'une solution saturée en chlorure de sodium. On sèche sur sulfate de sodium et on évapore à sec. On purifie le produit par chromatographie sur gel de silice en éluant par un mélange 80:20 puis 60:40 de cyclohexane et d'acétate d'éthyle. On obtient 0,6 g (Rdt : 79%) de produit sous forme d'huile.Under a nitrogen atmosphere, 0.64 g (1.50 mmol) of 4- (3-trifluoromethyl-phenyl) -piperazine-1-carboxylic acid, (6-chloro-3-nitro-pyridin-2-yl) are added. ) -amide obtained in step 1.1. (Route B), 0.33 g (2.1 mmol) of 4-chlorobenzeneboronic acid, 1.87 ml (3.75 mmol) of a 2M aqueous solution of sodium carbonate and 0.18 g (4, 26 mmol) of lithium chloride in 100 ml of a previously degassed mixture of ethanol / toluene / water (v / v: 1/1 / 0.4). 0.08 g (0.07 mmol) of tetrakis (triphenylphosphine) palladium (0) is added. The mixture is heated at 90 ° C. with stirring for 8 hours. It is cooled to ambient temperature and then diluted with 50 ml of dichloromethane and 25 ml of water. The organic phase is decanted, washed with 25 ml of water and 25 ml of a saturated solution of sodium chloride. It is dried over sodium sulphate and evaporated to dryness. The product is purified by chromatography on silica gel, eluting with an 80:20 mixture and then 60:40 of cyclohexane and ethyl acetate. 0.6 g (yield: 79%) of product is obtained in the form of an oil.
1H-RMN (DMSO-CZ6, δ ppm) : 8,55 (d, 1H), 8,30 (d, 2H), 8,00 (d, 1H), 7,80 (d, 2H), 7,80 (m, 1H), 7,60 (m, 1H), 7,40 (m, 2H), 7,20 (m, 1H), 3,8 (m, 4H), 3,50 (m, 4H). 1 H-NMR (DMSO-CZ 6 , δ ppm): 8.55 (d, 1H), 8.30 (d, 2H), 8.00 (d, 1H), 7.80 (d, 2H), 7.80 (m, 1H), 7.60 (m, 1H), 7.40 (m, 2H), 7.20 (m, 1H), 3.8 (m, 4H), 3.50 (m). , 4H).
Voie A : alternativement, on peut préparer le 4-(3-trifluorométhyl-phényl)-pipérazine- 1-carboxylique acide, [6-(4-chloro-phényl)-3-nitro-pyridin-2-yl]-amide comme suit. Sous atmosphère d'azote, on mélange 1 g (5,76 mmoles) de 2-amino-6-chloro-3- nitro-pyridine, 1 ,26 g (8.07 mmoles) d'acide 4-chrorobenzèneboronique, 7,2 ml (14,4 mmoles) d'une solution aqueuse 2M de carbonate de sodium et 0,7 g (16,36 mmoles) de chlorure de lithium dans 44 ml d'un mélange préalablement dégazé d'éthanol/toluène/eau (v/v : 1/1/0,4). On ajoute 0,34 g (0,29 mmole) de tetrakis(triphenylphosphine)palladium (0). On chauffe à 900C sous agitation pendant 18 heures. On refroidit à température ambiante puis on dilue avec 50 ml de dichlorométhane et 25 ml d'eau. On décante la phase organique, on la lave par 25 ml d'eau et 25 ml d'une solution saturée en chlorure de sodium. On sèche sur sulfate de sodium et on évapore à sec. On purifie le produit par chromatographie sur gel de silice en éluant par un mélange 50:50 puis 80:20 de dichlorométhane et de cyclohexane. On obtient 0,395 g (Rdt : 27%) de 6-(4-chloro-phényI)-3-nitro- pyridin-2-ylamine sous forme de poudre blanche.Lane A: alternatively, 4- (3-trifluoromethyl-phenyl) -piperazine-1-carboxylic acid, [6- (4-chloro-phenyl) -3-nitro-pyridin-2-yl] -amide may be prepared as follows. Under a nitrogen atmosphere, 1 g (5.76 mmol) of 2-amino-6-chloro-3-nitro-pyridine, 1.26 g (8.07 mmol) of 4-chlorobenzeneboronic acid, 7.2 ml are mixed. (14.4 mmol) of a 2M aqueous solution of sodium carbonate and 0.7 g (16.36 mmol) of lithium chloride in 44 ml of a previously degassed mixture of ethanol / toluene / water (v / v: 1/1 / 0.4). 0.34 g (0.29 mmol) of tetrakis (triphenylphosphine) palladium (0) are added. Heated at 90 ° C. with stirring for 18 hours. It is cooled to ambient temperature and then diluted with 50 ml of dichloromethane and 25 ml of water. The organic phase is decanted, washed with 25 ml of water and 25 ml of a saturated solution of sodium chloride. It is dried over sodium sulphate and evaporated to dryness. The product is purified by chromatography on silica gel, eluting with a 50:50 mixture and then 80:20 of dichloromethane and cyclohexane. 0.395 g (yield 27%) of 6- (4-chlorophenyl) -3-nitro-pyridin-2-ylamine are obtained in the form of a white powder.
LC-MS (m/z) : 250 (MH+)LC-MS (m / z): 250 (MH +)
1H-RMN (DUSO-d6, δ ppm) : 8,45 (d, 1 H), 8,15 (d, 1 H), 7,95 (m, 2H), 7,60 (d, 1H), 7,30 (d, 1H), 7,20 (d,1 H). 1 H-NMR (DUSO-d 6 , δ ppm): 8.45 (d, 1H), 8.15 (d, 1H), 7.95 (m, 2H), 7.60 (d, 1H) ), 7.30 (d, 1H), 7.20 (d, 1H).
Ce produit est engagé comme dans l'étape 1.1 pour l'obtention du 4-(3- trifluorométhyl-phényl)-pipérazine-1 -carboxylique acide, [6-(4-chloro-phényl)-3-nitro- pyridin-2-yl]-amide.This product is employed as in step 1.1 to obtain 4- (3-trifluoromethyl-phenyl) -piperazine-1-carboxylic acid, [6- (4-chloro-phenyl) -3-nitro-pyridin-2 yl] amide.
1.3. 4-(3-trifluorométhyl-phényl)-pipérazine-1 -carboxylique acide, [3-amino-6-(4- chloro-phényl)-pyridin-2-yl]-amide1.3. 4- (3-Trifluoromethyl-phenyl) -piperazine-1-carboxylic acid, [3-amino-6- (4-chloro-phenyl) -pyridin-2-yl] -amide
Dans une fiole à hydrogénation, on dissout 0,72 g (1 ,44 mmole) de 4-(3- trifluorométhyl-phényl)-pipérazine-1 -carboxylique acide, [6-(4-chloro-phényl)-3-nitro- pyridin-2-yl]-amide obtenu à l'étape 1.2 (voie A ou B), dans un mélange de 250 mL d'éthanol et 1 ,44 mL d'une solution aqueuse 1M d'acide chlorhydrique (1 ,44 mmole). On ajoute 0,13 g de Platine (0,72 mmole) à 10% sur charbon. On agite le mélange sous atmosphère d'hydrogène à la pression de 40 Psi (2,5 bars) pendant 2 heures. On ajoute 5 ml d'une solution 5N d'acide chlorhydrique dans l'isopropanol, on filtre sur célite et on lave avec de l'éthanol. On évapore le filtrat pour obtenir 0,57 g (Rdt : 84%) de produit sous forme de poudre rouge.In a hydrogenation flask, 0.72 g (1.44 mmol) of 4- (3-trifluoromethyl-phenyl) -piperazine-1-carboxylic acid, [6- (4-chloro-phenyl) -3-nitro - pyridin-2-yl] -amide obtained in step 1.2 (route A or B), in a mixture of 250 mL of ethanol and 1.44 mL of a 1M aqueous solution of hydrochloric acid (1, 44 mmol). 0.13 g of 10% platinum (0.72 mmol) on charcoal is added. The mixture is stirred under a hydrogen atmosphere at a pressure of 40 psi (2.5 bar) for 2 hours. 5 ml of a 5N solution of hydrochloric acid in isopropanol is added, filtered through celite and washed with ethanol. The filtrate is evaporated to obtain 0.57 g (yield: 84%) of product in the form of a red powder.
LC-MS (m/z) : 476 (MH+)LC-MS (m / z): 476 (MH +)
1H-RMN (DMSO-CZ6, δ ppm) : 7,90 (d, 2H), 7,65 (d, 2H), 7,50 (m, 3H), 7,35 (m, 1 H), 7,20 (m, 2H), 7,00 (m, 1H), 3,60 (m, 4H), 3,25 (m, 4H). 1 H-NMR (DMSO-CZ 6 , δ ppm): 7.90 (d, 2H), 7.65 (d, 2H), 7.50 (m, 3H), 7.35 (m, 1H) , 7.20 (m, 2H), 7.00 (m, 1H), 3.60 (m, 4H), 3.25 (m, 4H).
1.4. [5-(4-chloro-phényl)-[1 ,2,3]triazolo[4,5-i)]pyridin-3-yl]-[4-(3-trifluorométhyl- phényl)-pipérazin-1 -yl]-méthanone1.4. [5- (4-Chloro-phenyl) - [1,2,3] triazolo [4,5-i)] pyridin-3-yl] - [4- (3-trifluoromethyl-phenyl) -piperazin-1-yl] ] -methanone
Dans un tricol de 100 ml, on dissout 0,55 g (1 ,17 mmole) de 4-(3-trifiuorométhyl- phényl)-pipérazine-1 -carboxylique acide, [3-amino-6-(4-chloro-phényl)-pyridin-2-yl]- amide obtenu à l'étape 1.3., dans un mélange de 5 ml d'eau et 5 ml d'acide chlorhydrique aqueux à 37%, refroidi par un bain de glace. A l'aide d'une ampoule à brome, on ajoute goutte à goutte 0,24 g (3,50 mmoles) de nitrite de sodium dissous dans 4 ml d'eau. On agite le mélange pendant deux heures à 00C. On laisse reposer une heure dans le bain de glace puis on filtre le solide. On le lave par 3x1 OmI d'eau pour obtenir un solide beige. On le sèche sous vide en présence de pentoxyde de phosphore. On purifie le produit par chromatographie sur gel de silice en éluant par un mélange 80:20 puis 60:40 de cyclohexane et d'acétate d'éthyle. On cristallise l'huile obtenue dans du pentane pour obtenir 0,15 g (Rdt : 26%) de produit sous forme d'une poudre jaune claire.In a 100 ml three-necked flask, 0.55 g (1.17 mmol) of 4- (3-trifluoromethylphenyl) -piperazine-1-carboxylic acid, [3-amino-6- (4-chlorophenyl) ) -pyridin-2-yl] -amide obtained in step 1.3., in a mixture of 5 ml of water and 5 ml of acid 37% aqueous hydrochloric acid, cooled by an ice bath. With the aid of a dropping funnel, 0.24 g (3.50 mmol) of sodium nitrite dissolved in 4 ml of water are added dropwise. The mixture is stirred for two hours at 0 ° C. It is allowed to stand for one hour in the ice bath and then the solid is filtered off. It is washed with 3x1 OmI of water to obtain a beige solid. It is dried under vacuum in the presence of phosphorus pentoxide. The product is purified by chromatography on silica gel, eluting with an 80:20 mixture and then 60:40 of cyclohexane and ethyl acetate. The oil obtained is crystallized from pentane to give 0.15 g (yield: 26%) of product in the form of a light yellow powder.
Point de fusion (0C) : 139-1410CMelting point ( 0 C): 139-141 0 C
LC-MS (m Iz) : 487 (MH+)LC-MS (m Iz): 487 (MH +)
IR (KBr, cm"1) : 1718, 1591IR (KBr, cm- 1 ): 1718, 1591
1H-RMN (DMSO-CZ6, δ ppm) : 8,80 (d, 1H), 8,25 (dd, 3H), 7,60 (d, 2H), 7,45 (t, 1H), 7,25 (d, 1H), 7,20 (s, 1H), 7,10 (d, 1 H), 3,30-4,00 (m, 8H). 1 H-NMR (DMSO-CZ 6 , δ ppm): 8.80 (d, 1H), 8.25 (dd, 3H), 7.60 (d, 2H), 7.45 (t, 1H), 7.25 (d, 1H), 7.20 (s, 1H), 7.10 (d, 1H), 3.30-4.00 (m, 8H).
Le tableau 1 qui suit illustre les structures chimiques et les propriétés physiques de quelques exemples de composés selon l'invention. Dans ce tableau :Table 1 which follows illustrates the chemical structures and the physical properties of some examples of compounds according to the invention. In this table :
- dans la colonne « sel », « - » représente un composé sous forme de base libre, alors que « HCI » représente un composé sous forme de chlorhydrate;in the "salt" column, "-" represents a compound in free base form, while "HCl" represents a compound in the hydrochloride form;
- Ph représente un groupe phényle.Ph represents a phenyl group.
Tableau 1Table 1
(D (D
Les composés selon l'invention présentent de façon surprenante un effet inhibiteur sur l'enzyme MGL (monoacyl glycerol lipase). L'enzyme MGL catalyse l'hydrolyse de dérivés endogènes d'esters monoglycérides de différents acides gras (FEBS Letters 1998, 429, 152-156) et en particulier l'hydrolyse du 2-arachidonoylglycérol (2-AG) et du 1(3)-arachidonoylglycérol (1(3)-AG) (J. Biol. Chem. 1987, 272 (48), 27218-27223 ; Proc. Natl. Acad. Sci. USA 2002, 99 (16), 10819-10824 ; Biochem. Pharmacol. 2004, 67, 1381-1387 ; Mol. Pharmacol. 2004, 66 (5), 1260-1264). Les dérivés 2-AG et 1(3)-AG en particulier interagissent avec les récepteurs cannabinoïdes (J. Biol. Chem. 1999, 274 (5), 2794-2801 ; J. Biol. Chem. 2000, 275 (1), 605-612 ; British. J. Pharmacol. 2001, 134, 664-672).The compounds according to the invention surprisingly exhibit an inhibitory effect on the MGL enzyme (monoacyl glycerol lipase). The MGL enzyme catalyzes the hydrolysis of endogenous derivatives of monoglyceride esters of different fatty acids (FEBS Letters 1998, 429, 152-156) and in particular the hydrolysis of 2-arachidonoylglycerol (2-AG) and 1 (3 ) -arachidonoylglycerol (1 (3) -AG) (J. Biol Chem 1987, 272 (48), 27218-27223, Proc Natl Acad Sci USA 2002, 99 (16), 10819-10824; Pharmacol 2004, 67, 1381-1387, Mol Pharmacol 2004, 66 (5), 1260-1264). The 2-AG and 1 (3) -AG derivatives in particular interact with the cannabinoid receptors (J. Biol Chem 1999, 274 (5), 2794-2801, J. Biol Chem 2000, 275 (1), 605-612, British J. Pharmacol 2001, 134, 664-672).
Les composés de l'invention bloquent cette voie de dégradation et augmentent les taux tissulaires de ces dérivés et en particulier du 2-AG et/ou du 1(3)-AG. A ce titre, ils peuvent être utilisés dans la prévention et le traitement de pathologies dans lesquelles sont impliqués le 2-AG et/ou le 1 (3)-AG en particulier et/ou tout autre substrat métabolisé par l'enzyme MGL (Progress Lipid Research 2006, 45, 405-446).The compounds of the invention block this degradation pathway and increase the tissue levels of these derivatives and in particular 2-AG and / or 1 (3) -AG. As such, they can be used in the prevention and treatment of pathologies in which 2-AG and / or 1 (3) -AG in particular and / or any other substrate metabolized by the MGL enzyme (Progress) are involved. Lipid Research 2006, 45, 405-446).
Les composés selon l'invention peuvent également avoir de façon additionnelle un effet inhibiteur sur l'enzyme FAAH (Fatty Acid Amide Hydrolase). L'enzyme FAAH (Chemistry and Physics of Lipids, (2000), 108, 107-121) catalyse l'hydrolyse de dérivés endogènes d'amides et d'esters de différents acides gras tels que la Λ/-arachidonoyléthanolamine (anandamide), la /V-palmitoyléthanolamine, la Λ/-o!éoyléthanolamine ou l'oléamide. Ces dérivés exercent différentes activités pharmacologiques en interagissant, entre autres, avec les récepteurs cannabinoïdes et vanilloïdes.The compounds according to the invention may also have an additional inhibitory effect on the enzyme FAAH (Fatty Acid Amide Hydrolase). 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 Λ / -arachidonoylethanolamine (anandamide), α-palmitoylethanolamine, Λ-O-triethanolamine or oleamide. These derivatives exert different pharmacological activities by interacting, inter alia, with the cannabinoid and vanilloid receptors.
Les composés de l'invention bloquent cette voie de dégradation et augmentent le taux tissulaire de ces substances endogènes. Ils peuvent être utilisés à ce titre dans la prévention et le traitement des pathologies dans lesquelles les cannabinoïdes endogènes et/ou tout autre substrat métabolisé par l'enzyme FAAH, sont impliqués. Des essais ont consisté à mesurer l'activité in vitro des composés de l'invention sur l'enzyme MGL.The compounds of the invention block this pathway of degradation and increase the tissue level of these endogenous substances. They can be used as such in the prevention and treatment of pathologies in which the endogenous cannabinoids and / or any other substrate metabolized by the enzyme FAAH, are involved. Trials consisted of measuring the in vitro activity of the compounds of the invention on the MGL enzyme.
L'activité inhibitrice a été mesurée dans un test radio-enzymatique basé sur la mesure du produit d'hydrolyse du 2-Oléoyl Glycérol ([3H] 2-OG) par la MGL. Les produits d'hydrolyse du [3H] 2-OG, marqué sur le glycérol, sont l'acide oléïque et le [3H]glycérol et la source d'enzyme MGL est un homogénat de cerveau de souris où le cervelet et le bulbe rachidien ont été éliminés. Les cerveaux de souris sont prélevés, stockés à -8O0C jusqu'à leur utilisation ou homogénéisés immédiatement 2 fois 5 secondes à l'aide de l'appareil Precellys à 5000 rpm (Bertin) dans un tampon Tris-HCI 10 mM, NaCI 15OmM, EDTA 1mM (pH8) à 40C. La concentration des homogénats est ensuite ajustée à 7,5 μg/μL.Inhibitory activity was measured in a radioenzyme assay based on the measurement of the hydrolysis product of 2-Oleoyl Glycerol ([ 3 H] 2-OG) by MGL. The hydrolysis products of [ 3 H] 2-OG, labeled on glycerol, are oleic acid and [ 3 H] glycerol and the MGL enzyme source is a mouse brain homogenate where the cerebellum and the spinal bulb have been eliminated. The mouse brains are removed, stored at -80 ° C. until use or homogenized immediately 2 times 5 seconds using the Precellys device at 5000 rpm (Bertin) in a 10 mM Tris-HCl buffer, NaCl 15 mM, 1 mM EDTA (pH8) at 40 ° C. The concentration of the homogenates is then adjusted to 7.5 μg /.
La gamme de dilution des composés est réalisée à partir de solutions stocks à 20 mM en 100 % DMSO. La première dilution de cette gamme est réalisée en 100 % DMSO puis la deuxième dans le tampon de réaction enzymatique (50 mM phosphate, BSA 0,1 %) aboutissant à la réalisation d'une gamme de concentration 10 fois concentrée. Les composés à tester sont préincubés à la concentration choisie pendant 20 minutes avec la préparation d'homogénat de cerveaux de souris. La concentration finale de DMSO dans la réaction enzymatique n'excède pas 0,1%.The dilution range of the compounds is made from stock solutions at 20 mM in 100% DMSO. The first dilution of this range is carried out in 100% DMSO then the second in the enzyme reaction buffer (50 mM phosphate, 0.1% BSA) resulting in the achievement of a concentration range 10 times concentrated. The test compounds are preincubated at the selected concentration for 20 minutes with the mouse brain homogenate preparation. The final concentration of DMSO in the enzymatic reaction does not exceed 0.1%.
Le dosage de l'activité MGL est réalisée en microplaque 96 puits dans un volume réactionnel final de 100 μL. Brièvement, 75 μg de protéines, préincubés avec les composés à tester, sont dilués dans 50 mM de tampon phosphate contenant 0,1 % de BSA et incubés, pendant 20 minutes à température ambiante, en présence de 50 μM de 2-OG contenant une quantité de [3H] 2-OG de 0,027 μCi/puits (Activité spécifique de 20 Ci/mmole). La réaction est arrêtée et les produits formés sont séparés par l'addition et le mélange de 100 μL de chloroforme/méthanol (1/1). Après 10 minutes d'agitation, la microplaque est centrifugée pendant 15 minutes à 4000g et un aliquot de 30 μL de la phase aqueuse contenant le [3H]glycérol produit est prélevé puis compté pendant 5 minutes par scintillation liquide (Wallac 1450 Microbeta).The assay of the MGL activity is carried out in a 96-well microplate in a final reaction volume of 100 μl. Briefly, 75 μg of protein, preincubated with the test compounds, are diluted in 50 mM phosphate buffer containing 0.1% BSA and incubated for 20 minutes at room temperature, in the presence of 50 μM of 2-OG containing amount of [ 3 H] 2-OG of 0.027 μCi / well (specific activity of 20 Ci / mmol). The reaction is stopped and the products formed are separated by the addition and the mixture of 100 μl of chloroform / methanol (1/1). After stirring for 10 minutes, the microplate is centrifuged for 15 minutes at 4000 g and an aliquot of 30 μl of the aqueous phase containing the [ 3 H] glycerol product is removed and then counted for 5 minutes by liquid scintillation (Wallac 1450 Microbeta).
L'activité inhibitrice vis-à-vis de MGL est donnée par la concentration qui inhibe 50% de l'activité de MGL. Dans ces conditions, les composés les plus actifs de l'invention présentent une Cl50 (concentration inhibant de 50% l'activité enzymatique contrôle de la MGL) comprise entre 0,001 et 0,1 μM.The inhibitory activity against MGL is given by the concentration which inhibits 50% of the MGL activity. Under these conditions, the most active compounds of the invention have a Cl 50 (concentration inhibiting 50% MGL control enzyme activity) of between 0.001 and 0.1 μM.
Par exemple, les composés n° 3 et 5 et ont montré une Cl50 de respectivement 0,002 et 0,007 μM.For example, Compounds Nos. 3 and 5 and showed an IC 50 of 0.002 and 0.007 μM, respectively.
Des essais ont consisté à mesurer l'activité in vitro des composés de l'invention sur l'enzyme FAAH.Trials consisted in measuring the in vitro activity of the compounds of the invention on the enzyme FAAH.
L'activité inhibitrice a été mesurée dans un test radioenzymatique basé sur la mesure du produit d'hydrolyse (éthanolamine [1-3H]) de l'anandamide par la FAAH (Life Science (1995), 56, 1999-2005 et Journal of Pharmacology and Experimented Therapeutics (1997), 283, 729-734). Les produits d'hydrolyse de T[3H] anandamide, marqué sur l'éthanolamine, sont l'acide arachidonique et T[3H] éthanolamine et la source d'enzyme FAAH est un homogénat de cerveau de souris où le cervelet et le bulbe rachidien ont été éliminés. Les cerveaux de souris sont prélevés, stockés à -8O0C jusqu'à leur utilisation ou homogénéisés immédiatement 2 fois 5 secondes à l'aide de l'appareil Precellys à 5000 rpm (Bertin) dans un tampon Tris-HCI 10 mM, NaCI 15OmM, EDTA 1mM (pH8) à 40C. La concentration des homogénats est ensuite ajustée à une concentration de 20 μg/μL.Inhibitory activity was measured in a radioenzymatic assay based on the measurement of the hydrolysis product (ethanolamine [1-3H]) of anandamide by FAAH (Life Science (1995), 56, 1999-2005 and Journal of Pharmacology and Experimented Therapeutics (1997), 283, 729-734). The hydrolysis products of ethanolamine-labeled T [ 3 H] anandamide are arachidonic acid and T [ 3 H] ethanolamine and the enzyme source FAAH is a mouse brain homogenate where the cerebellum and the spinal bulb have been eliminated. The mouse brains are removed, stored at -80 ° C. until use or homogenized immediately 2 times 5 seconds using the Precellys device at 5000 rpm (Bertin) in a 10 mM Tris-HCl buffer, NaCl 15 mM, 1 mM EDTA (pH8) at 40 ° C. The concentration of the homogenates is then adjusted to a concentration of 20 μg / μL.
La gamme de dilution des composés est réalisée à partir de solutions stocks à 20 mM en 100 % DMSO. La première dilution de cette gamme est réalisée en 100 % DMSO puis la deuxième dans le tampon de réaction enzymatique (Tris-HCI 10 mM, NaCI 15OmM, EDTA 1mM (pH8), BSA 0,1 %) aboutissant à la réalisation d'une gamme de concentration 10 fois concentrée. Les composés à tester sont préincubés à la concentration choisie pendant 20 minutes avec la préparation d'homogénat de cerveaux de souris. La concentration finale de DMSO dans la réaction enzymatique n'excède pas 0,1%.The dilution range of the compounds is made from stock solutions at 20 mM in 100% DMSO. The first dilution of this range is carried out in 100% DMSO then the second in the enzyme reaction buffer (10 mM Tris-HCl, 15 mM NaCl, 1 mM EDTA (pH 8), 0.1% BSA) resulting in the production of concentration range 10 times concentrated. The test compounds are preincubated at the selected concentration for 20 minutes with the mouse brain homogenate preparation. The final concentration of DMSO in the enzymatic reaction does not exceed 0.1%.
Le dosage de l'activité FAAH est réalisée en microplaque 96 puits dans un volume réactionnel final de 70 μL Brièvement, 200 μg d'homogénat de cerveau de souris, préincubés avec les composés à tester, sont dilués dans Tris-HCI 10 mM, NaCI 15OmM, EDTA 1mM (pH8) contenant 0,1 % de BSA et incubés, pendant 20 minutes à température ambiante, en présence de 10 μM d'anandamide contenant une quantité de [3H]-anandamide de 0,01 μCi/puits (Activité spécifique de 60 Ci/mmole). La réaction est arrêtée et les produits formés sont séparés par l'addition et le mélange de 140 μL de chloroforme/méthanol (2/1). Après 10 minutes d'agitation, la microplaque est centrifugée pendant 15 minutes à 4000g et un aliquot de 30 μl_ de la phase aqueuse contenant P[3H]éthanolamine produit est prélevé puis compté pendant 5 minutes par scintillation liquide (Wallac 1450 Microbeta).The assay of the FAAH activity is carried out in a 96-well microplate in a final reaction volume of 70 μL. Briefly, 200 μg of mouse brain homogenate, preincubated with the test compounds, are diluted in 10 mM Tris-HCl, NaCl. 15 mM, 1 mM EDTA (pH8) containing 0.1% BSA and incubated for 20 minutes at room temperature in the presence of 10 μM of anandamide containing a quantity of [ 3 H] -anandamide of 0.01 μCi / well ( Specific activity of 60 Ci / mmole). The reaction is stopped and the products formed are separated by the addition and the mixture of 140 μl of chloroform / methanol (2/1). After 10 minutes After stirring, the microplate is centrifuged for 15 minutes at 4000 g and an aliquot of 30 μl of the aqueous phase containing P [ 3 H] ethanolamine produced is taken and then counted for 5 minutes by liquid scintillation (Wallac 1450 Microbeta).
Dans ces conditions, les composés les plus actifs de l'invention présentent une Cl50 (concentration inhibant de 50% l'activité enzymatique contrôle de la FAAH) comprise entre 0,001 et 0,1 μM. Par exemple, le composé n° 3 a montré une Cl50 de 0,002 μM.Under these conditions, the most active compounds of the invention have a Cl 50 (50% concentration inhibiting the enzymatic activity controlling FAAH) of between 0.001 and 0.1 μM. For example, compound No. 3 showed a Cl 50 of 0.002 μM.
Il apparaît donc que les composés selon l'invention ont une activité inhibitrice sélective vis-à-vis de MGL ou mixte vis-à-vis de MGL et FAAH.It therefore appears that the compounds according to the invention have a selective inhibitory activity with respect to MGL or mixed with respect to MGL and FAAH.
Les composés selon l'invention peuvent donc être utilisés pour la préparation de médicaments, en particulier de médicaments inhibiteurs de l'enzyme MGL ou des enzymes MGL et FAAH.The compounds according to the invention can therefore be used for the preparation of medicaments, in particular drugs which inhibit the MGL enzyme or the MGL and FAAH enzymes.
Ainsi, selon un autre de ses aspects, l'invention a pour objet des médicaments qui comprennent un composé de formule (I), ou un sel d'addition de ce dernier à un acide pharmaceutiquement acceptable, ou encore un hydrate ou un solvate du composé de formule (I).Thus, according to another of its aspects, the subject of the invention is medicaments which comprise a compound of formula (I), or an addition salt thereof to a pharmaceutically acceptable acid, or a hydrate or a solvate of compound of formula (I).
Ces médicaments trouvent leur emploi en thérapeutique, notamment dans le traitement et la prévention de : la douleur notamment les douleurs aiguës ou chroniques de type neurogène : migraine, douleurs neuropathiques incluant les formes associées au virus de l'herpès et au diabète ; les douleurs aiguës ou chroniques associées aux maladies inflammatoires : arthrite, arthrite rhumatoïde, ostéoarthrite, spondylite, goutte, vascularite, maladie de Crohn, syndrome du colon irritable ; les douleurs aiguës ou chroniques périphériques ; les vertiges, les vomissements, les nausées en particulier celles consécutives à une chimiothérapie ; les troubles du comportement alimentaire en particulier les anorexies et cachexies de diverses natures ; le syndrome métabolique et ses manifestations, incluant l'obésité ; les dyslipidémies et leurs manifestations, incluant l'athérosclérose et les maladies coronariennes ; les pathologies neurologiques et psychiatriques : tremblements, dyskinésies, dystonies, spasticité, comportements compulsifs et obsessionnels, syndrome de Tourette, toutes les formes de dépression et d'anxiété de toute nature et origine, troubles de l'humeur, psychoses ; les maladies neuro-dégénératives aiguës et chroniques : maladie de Parkinson, maladie d'Alzheimer, démence sénile, chorée de Huntington, lésions liées à l'ischémie cérébrale et aux traumatismes crâniens et médullaires, la sclérose latérale amyotrophique ;These drugs find their therapeutic use, particularly in the treatment and prevention of: pain including acute or chronic pain of neurogenic type: migraine, neuropathic pain including forms associated with the herpes virus and diabetes; 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 especially those following chemotherapy; eating disorders, particularly anorexia and cachexia of various natures; metabolic syndrome and its manifestations, including obesity; dyslipidemias and their manifestations, including atherosclerosis and coronary heart disease; neurological and psychiatric pathologies: tremor, dyskinesia, dystonia, spasticity, compulsive and obsessive behavior, Tourette's syndrome, all forms of depression and anxiety of all kinds and origins, mood disorders, psychoses; acute and chronic neuro-degenerative diseases: Parkinson's disease, Alzheimer's disease, senile dementia, Huntington's chorea, lesions related to cerebral ischemia and cranial and medullary traumas, amyotrophic lateral sclerosis;
Pépilepsie ; les troubles du sommeil incluant les apnées du sommeil ; les maladies cardiovasculaires en particulier hypertension, arythmies cardiaques, artériosclérose, crise cardiaque, ischémies cardiaques ; l'ischémie rénale ; les cancers : tumeurs bénignes de la peau, papillomes et tumeurs cérébrales, tumeurs de la prostate, tumeurs cérébrales (glioblastomes, médullo- épithéliomes, médulloblastomes, neuroblastomes, tumeurs d'origine embryonnaires, astrocytomes, astroblastomes, épendyomes, oligodendrogliomes, tumeur du plexus, neuroepithéliomes, tumeur de l'épiphyse, épendymoblastomes, méningiomes malins, sarcomatoses, mélanomes malins, schwénnomes) ; les désordres du système immunitaire, notamment les maladies auto- immunes : psoriasis, lupus érythémateux, maladies du tissu conjonctif ou connectivités, syndrome de Sjôgren's, spondylarthrite ankylosante, spondylarthrite indifférenciée, maladie de Behcet's, anémies auto-immunes hémolytiques, sclérose en plaques, sclérose latérale amyotrophique, amyloses, rejet de greffes, maladies affectant la lignée plasmocytaire ; les maladies allergiques : l'hypersensibilité immédiate ou retardée, rhinites ou conjonctivites allergiques, dermatites de contact ; les maladies infectieuses parasitaires, virales ou bactériennes : SIDA, méningites ; les maladies inflammatoires, notamment les maladies articulaires : arthrite, arthrite rhumatoïde, ostéoarthrite, spondylite, goutte, vascularite, maladie de Crohn, syndrome du colon irritable ; l'ostéoporose ; les affections oculaires : hypertension oculaire, glaucome ; les affections pulmonaires : maladies des voies respiratoires, bronchospasmes, toux, asthme, bronchite chronique, obstruction chronique des voies respiratoires, emphysème ; les maladies gastro-intestinales: syndrome du colon irritable, désordres inflammatoires intestinaux, ulcères, diarrhées ; l'incontinence urinaire et l'inflammation vésicale.Epilepsy; sleep disorders including sleep apnea; cardiovascular diseases especially hypertension, cardiac arrhythmias, arteriosclerosis, heart attack, ischemic heart disease; renal ischemia; cancers: benign tumors of the skin, papillomas and brain tumors, prostate tumors, brain tumors (glioblastomas, medulloepitheliomas, medulloblastomas, neuroblastomas, embryonic origin tumors, astrocytomas, astroblastomas, ependyomas, oligodendrogliomas, plexus tumors, neuroepitheliomas, epiphysis tumor, ependymoblastomas, malignant meningiomas, sarcomatoses, malignant melanomas, schwénnomes); disorders of the immune system, including autoimmune diseases: psoriasis, lupus erythematosus, connective tissue diseases or connective tissue diseases, Sjögren's syndrome, ankylosing spondylitis, undifferentiated spondyloarthritis, Behcet's disease, hemolytic autoimmune anemias, multiple sclerosis, multiple sclerosis amyotrophic lateral, amyloidosis, graft rejection, diseases affecting the plasmocytic lineage; allergic diseases: immediate or delayed hypersensitivity, allergic rhinitis or conjunctivitis, contact dermatitis; parasitic, viral or bacterial infectious diseases: AIDS, meningitis; inflammatory diseases, including joint diseases: arthritis, rheumatoid arthritis, osteoarthritis, spondylitis, gout, vasculitis, Crohn's disease, irritable bowel syndrome; osteoporosis; eye conditions: ocular hypertension, glaucoma; lung diseases: diseases of the respiratory tract, bronchospasm, cough, asthma, chronic bronchitis, chronic obstruction of the respiratory tract, emphysema; gastrointestinal diseases: irritable bowel syndrome, inflammatory bowel disorders, ulcers, diarrhea; urinary incontinence and bladder inflammation.
Selon un autre de ses aspects, la présente invention concerne des compositions pharmaceutiques comprenant, en tant que principe actif, un composé selon l'invention. Ces compositions pharmaceutiques contiennent une dose efficace d'au moins un composé selon l'invention, ou un sel pharmaceutiquement acceptable, un hydrate ou solvatee dudit composé, ainsi qu'au moins un excipient pharmaceutiquement acceptable.According to another of its aspects, the present invention relates to pharmaceutical compositions comprising, as active principle, a compound according to the invention. These pharmaceutical compositions contain an effective dose of at least one compound according to the invention, or a pharmaceutically acceptable salt, a hydrate or solvate of said compound, as well as at least one pharmaceutically acceptable excipient.
Lesdits excipients sont choisis selon la forme pharmaceutique et le mode d'administration souhaité, parmi les excipients habituels qui sont connus de l'homme du métier.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.
Dans les compositions pharmaceutiques de la présente invention pour l'administration orale, sublinguale, sous-cutanée, intramusculaire, infra-veineuse, topique, locale, intratrachéale, intranasale, transdermique ou rectale, le principe actif de formule (I) ci-dessus, ou son sel, solvate ou hydrate éventuel, peut être administré sous forme unitaire d'administration, en mélange avec des excipients pharmaceutiques classiques, aux animaux et aux êtres humains pour la prophylaxie ou le traitement des troubles ou des maladies ci-dessus.In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, infra-venous, topical, local, intratracheal, intranasal, transdermal or rectal administration, the active ingredient of formula (I) above, or its 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.
Les formes unitaires d'administration appropriées comprennent les formes par voie orale telles que les comprimés, les gélules molles ou dures, les poudres, les granules et les solutions ou suspensions orales, les formes d'administration sublinguale, buccale, intratrachéale, intraoculaire, intranasale, par inhalation, les formes d'administration topique, transdermique, sous-cutanée, intramusculaire ou intraveineuse, les formes d'administration rectale et les implants. Pour l'application topique, on peut utiliser les composés selon l'invention dans des crèmes, gels, pommades ou lotions.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, gels, ointments or lotions.
A titre d'exemple, une forme unitaire d'administration d'un composé selon l'invention sous forme de comprimé peut comprendre les composants suivants : Composé selon l'invention 50,0 mgBy way of example, a unitary form of administration of a compound according to the invention in tablet form may comprise the following components: Compound according to the invention 50.0 mg
Mannitol 223,75 mgMannitol 223.75 mg
Croscarmellose sodique 6,0 mgCroscarmellose sodium 6.0 mg
Amidon de maïs 15,0 mgCorn starch 15.0 mg
Hydroxypropyl-méthylcellulose 2,25 mgHydroxypropyl methylcellulose 2.25 mg
Stéarate de magnésium 3,0 mgMagnesium stearate 3.0 mg
La présente invention, selon un autre de ses aspects, concerne également une méthode de traitement des pathologies ci-dessus indiquées qui comprend l'administration, à un patient, d'une dose efficace d'un composé selon l'invention, ou un de ses sels pharmaceutiquement acceptables ou hydrates ou solvates. 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

REVENDICATIONS
1. Composé répondant à la formule (I)1. Compound corresponding to formula (I)
dans laquelle : in which :
A et X représentent indépendamment l'un de l'autre, un atome d'azote ou un groupement CH,A and X represent, independently of one another, a nitrogen atom or a CH group,
R1 représente un groupement aryle ou hétéroaryle, éventuellement substitué par un ou plusieurs groupes choisis parmi un atome d'halogène, un groupe (C-r C6)alkyle, halo(CrC6)alkyle, (CrC6)alcoxy, halo(CrC6)alcoxy,R 1 represents an aryl or heteroaryl group, optionally substituted by one or more groups selected from a halogen atom, a (Cr C 6 ) alkyl, halo (C 1 -C 6 ) alkyl, (C r C 6 ) alkoxy, halo ( C r C 6 ) alkoxy,
R2 représente un groupement aryle, éventuellement substitué par un ou plusieurs groupes choisis parmi un atome d'halogène, un groupe méthyle, trifluorométhyle, méthoxy, trifluorométhoxy, à l'état de base ou de sel d'addition à un acide, ainsi qu'à l'état d'hydrate ou de solvate.R 2 represents an aryl group, optionally substituted by one or more groups chosen from a halogen atom, a methyl, trifluoromethyl, methoxy or trifluoromethoxy group, in the form of a base or of an addition salt with an acid, as well as in the hydrate or solvate state.
2. Composé de formule (I) selon la revendication 1 , caractérisé en ce que A représente un atome d'azote,2. Compound of formula (I) according to claim 1, characterized in that A represents a nitrogen atom,
X représente un groupement CH, à l'état de base ou de sel d'addition à un acide, ainsi qu'à l'état d'hydrate ou de solvate.X represents a CH group, in the form of a base or of an addition salt with an acid, and in the hydrate or solvate state.
3. Composé de formule (I) selon l'une des revendications 1 ou 2, caractérisé en ce que3. Compound of formula (I) according to one of claims 1 or 2, characterized in that
R1 représente un groupe aryle ou hétéroaryle éventuellement substitué par un ou plusieurs groupes choisis parmi un atome d'halogène, un groupe (C1- C6)alkyle, halo(CrC6)alkyle, (CrC6)alcoxy, halo(CrC6)alcoxy, à l'état de base ou de sel d'addition à un acide, ainsi qu'à l'état d'hydrate ou de solvate.R 1 represents an aryl or heteroaryl group optionally substituted with one or more groups chosen from a halogen atom, a (C 1 -C 6 ) alkyl group, a halo (C r C 6 ) alkyl group, (C r C 6 ) alkoxy group; , halo (C r C 6) alkoxy, with the base or of an addition salt with an acid, and in the hydrate or solvate form.
4. Composé de formule (I) selon l'une des revendications 1 à 3, caractérisé en ce que4. Compound of formula (I) according to one of claims 1 to 3, characterized in that
R1 représente un groupe phényle, furane, thiophène ou naphtalène, éventuellement substitué par un atome d'halogène, à l'état de base ou de sel d'addition à un acide, ainsi qu'à l'état d'hydrate ou de solvate.R 1 represents a phenyl, furan, thiophene or naphthalene group, optionally substituted with a halogen atom, in the form of a base or of addition salt with an acid, and in the hydrate or solvate state.
5. Composé de formule (I) selon l'une des revendications 1 à 4, caractérisé en ce qu'il est choisi parmi :5. Compound of formula (I) according to one of claims 1 to 4, characterized in that it is chosen from:
- [5-(2-Chloro-phényl)-[1 ,2,3]triazolo[4,5-b]pyridin-3-yl]-[4-(3-trifluorométhyl-phényl)- pipérazin-1 ~yl]-méthanone[5- (2-Chloro-phenyl) - [1,2,3] triazolo [4,5-b] pyridin-3-yl] - [4- (3-trifluoromethyl-phenyl) -piperazin-1-yl] ] -methanone
- [5-(3-Chloro-phényl)-[1 ,2,3]triazolo[4,5-b]pyridin-3-yl]-[4-(3-trifluorométhyl-phényl)- pipérazin-1 -yl]-méthanone- [5- (3-Chloro-phenyl) - [1,2,3] triazolo [4,5-b] pyridin-3-yl] - [4- (3-trifluoromethyl-phenyl) -piperazin-1-yl] ] -methanone
- [5-(4-Chloro-phényl)-[1 ,2,3]triazolo[4,5-b]pyridin-3-yl]-[4-(3-trifluorométhyl-phényl)- pipérazin-1 -yl]-méthanone- [5- (4-Chloro-phenyl) - [1,2,3] triazolo [4,5-b] pyridin-3-yl] - [4- (3-trifluoromethyl-phenyl) -piperazin-1-yl] ] -methanone
- (5-Furan-3-yl-[1 ,2,3]triazolo[4J5-b]pyridin-3-yl)-[4-(3-trifluorométhyl-phényl)- pipérazin-1 -yl]-méthanone- (5-Furan-3-yl- [1, 2,3] triazolo [4 J 5-b] pyridin-3-yl) - [4- (3-trifluoromethyl-phenyl) - piperazin-1-yl] - methanone
- (5-Thiophèn-3-yl-[1 ,2,3]triazolo[4,5-b]pyridin-3-yl)-[4-(3-trifluorométhyl-phényl)- pipérazin-1 -yl]-méthanone(5-Thiophen-3-yl- [1,2,3] triazolo [4,5-b] pyridin-3-yl) - [4- (3-trifluoromethyl-phenyl) piperazin-1-yl] - methanone
- (5-Naphthalèn-2-yl-[1 ,2,3]triazolo[4,5-b]pyridin-3-yl)-[4-(3-trifluorométhyl-phényl)- pipérazin-1 -yl]-méthanone(5-Naphthalen-2-yl- [1,2,3] triazolo [4,5-b] pyridin-3-yl) - [4- (3-trifluoromethyl-phenyl) piperazin-1-yl] - methanone
- (5-Naphthalèn-1-yl-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-[4-(3-trifluorométhyl-phényl)- pipérazin-1 -yl]-méthanone.(5-Naphthalen-1-yl- [1,2,3] triazolo [4,5-b] pyridin-3-yl) - [4- (3-trifluoromethyl-phenyl) piperazin-1-yl] - methanone.
6. Procédé de préparation d'un composé de formule (I) selon l'une quelconque des revendications 1 à 5, caractérisé en ce que l'on transforme un composé de formule générale (VIII)6. Process for the preparation of a compound of formula (I) according to any one of claims 1 to 5, characterized in that one converts a compound of general formula (VIII)
(VlII) dans laquelle, R-i, R2, X et A sont tels que définis dans la formule (I) selon la revendication 1 , en composé de formule générale (I), par une réaction de diazotation-cyclisation, sous l'action d'un nitrite.(VIII) wherein, R 1, R 2 , X and A are as defined in formula (I) according to claim 1, compound of general formula (I), by a diazotization-cyclization reaction, under the action of a nitrite.
7. Médicament, caractérisé en ce qu'il comprend un composé de formule (I) selon l'une quelconque des revendications 1 à 5, ou un sel d'addition de ce composé à un acide pharmaceutiquement acceptable, ou encore un hydrate ou un solvate du composé de formule (I). 7. Medicament, characterized in that it comprises a compound of formula (I) according to any one of claims 1 to 5, or a salt of addition of this compound to a pharmaceutically acceptable acid, or a hydrate or a solvate of the compound of formula (I).
8. Composition pharmaceutique, caractérisée en ce qu'elle comprend un composé de formule (I) selon l'une quelconque des revendications 1 à 5, ou un sel pharmaceutiquement acceptable, un hydrate ou un solvate de ce composé, ainsi qu'au moins un excipient pharmaceutiquement acceptable.8. Pharmaceutical composition, characterized in that it comprises a compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, a hydrate or a solvate of this compound, and at least a pharmaceutically acceptable excipient.
9. Utilisation d'un composé de formule (I) selon l'une quelconque des revendications 1 à 5 pour la préparation d'un médicament destiné au traitement et à la prévention d'une pathologie dans laquelle le 2-arachidonoylglycérol (2-AG) et le 1 (3)-arachidonoylglycérol endogènes et/ou tout autre substrat métabolisé par l'enzyme MGL sont impliqués.9. Use of a compound of formula (I) according to any one of claims 1 to 5 for the preparation of a medicament for the treatment and prevention of a pathology in which 2-arachidonoylglycerol (2-AG ) and endogenous 1 (3) -arachidonoylglycerol and / or any other substrate metabolized by the MGL enzyme are involved.
10. Utilisation d'un composé de formule (I) selon l'une quelconque des revendications 1 à 5 pour la préparation d'un médicament destiné au traitement et à la prévention d'une pathologie dans laquelle l'anandamide endogène et/ou tout autre substrat métabolisé par l'enzyme FAAH sont impliqués.Use of a compound of formula (I) according to any one of claims 1 to 5 for the preparation of a medicament for the treatment and prevention of a pathology in which the endogenous anandamide and / or any other substrate metabolized by the enzyme FAAH are involved.
11. Utilisation d'un composé de formule (I) selon l'une quelconque des revendications 1 à 5, à l'état de base, d'hydrate ou de solvate pharmaceutiquement acceptable, pour la préparation d'un médicament destiné à prévenir ou à traiter les douleurs aiguës ou chroniques, les vertiges, les vomissements, les nausées, les troubles du comportement alimentaire, le syndrome métabolique, les dyslipidémies, les pathologies neurologiques et psychiatriques, les maladies neuro-dégénératives aiguës ou chroniques, l'épilepsie, les troubles du sommeil, les maladies cardiovasculaires, l'ischémie rénale, les cancers, les désordres du système immunitaire, les maladies allergiques, les maladies infectieuses parasitaires, virales ou bactériennes, les maladies inflammatoires, l'ostéoporose, les affections oculaires, les affections pulmonaires, les maladies gastro-intestinales, l'incontinence urinaire, l'inflammation vésicale.11. Use of a compound of formula (I) according to any one of claims 1 to 5, in the form of base, hydrate or solvate pharmaceutically acceptable for the preparation of a medicament for preventing or to treat acute or chronic pain, dizziness, vomiting, nausea, eating disorders, metabolic syndrome, dyslipidemia, neurological and psychiatric pathologies, acute or chronic neuro-degenerative diseases, epilepsy, sleep disorders, cardiovascular diseases, renal ischemia, cancers, immune system disorders, allergic diseases, parasitic, viral or bacterial infectious diseases, inflammatory diseases, osteoporosis, eye diseases, lung diseases , gastrointestinal diseases, urinary incontinence, bladder inflammation.
12. Composé de formule (I) selon l'une quelconque des revendications 1 à 5, à l'état de base, d'hydrate ou de solvate pharmaceutiquement acceptable, pour la prévention ou le traitement des douleurs aiguës ou chroniques, des vertiges, des vomissements, des nausées, des troubles du comportement alimentaire, du syndrome métabolique, des dyslipidémies, des pathologies neurologiques et psychiatriques, des maladies neuro-dégénératives aiguës ou chroniques, de l'épilepsie, des troubles du sommeil, des maladies cardiovasculaires, de l'ischémie rénale, des cancers, des désordres du système immunitaire, des maladies allergiques, des maladies infectieuses parasitaires, virales ou bactériennes, des maladies inflammatoires, de l'ostéoporose, des affections oculaires, des affections pulmonaires, des maladies gastro-intestinales, de l'incontinence urinaire, de l'inflammation vésicale. 12. Compound of formula (I) according to any one of claims 1 to 5, in the form of base, hydrate or solvate pharmaceutically acceptable, for the prevention or treatment of acute or chronic pain, vertigo, vomiting, nausea, eating disorders, metabolic syndrome, dyslipidemia, neurological and psychiatric diseases, acute or chronic neuro-degenerative diseases, epilepsy, sleep disorders, cardiovascular diseases, kidney ischemia, cancers, immune system disorders, diseases allergic, parasitic, viral or bacterial infectious diseases, inflammatory diseases, osteoporosis, ocular affections, pulmonary diseases, gastrointestinal diseases, urinary incontinence, bladder inflammation.
EP08787965A 2007-04-18 2008-04-16 Triazolopyridine carboxamide derivatives and triazolopyrimidine carboxamide derivatives, preparation thereof and therapeutic use thereof Withdrawn EP2146992A1 (en)

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FR0702808A FR2915198B1 (en) 2007-04-18 2007-04-18 TRIAZOLOPYRIDINE CARBOXAMIDE AND TRIAZOLOPYRIDINE -CARBOXAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC USE.
PCT/FR2008/000536 WO2008145843A1 (en) 2007-04-18 2008-04-16 Triazolopyridine carboxamide derivatives and triazolopyrimidine carboxamide derivatives, preparation thereof and therapeutic use thereof

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CL2008001103A1 (en) 2009-01-16
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FR2915198A1 (en) 2008-10-24
CN101663304A (en) 2010-03-03
UY31037A1 (en) 2008-11-28
TW200901992A (en) 2009-01-16
KR20090130061A (en) 2009-12-17
US20110071162A1 (en) 2011-03-24
US20100041670A1 (en) 2010-02-18
WO2008145843A1 (en) 2008-12-04
RU2009142434A (en) 2011-05-27
CA2683936A1 (en) 2008-12-04
AR066104A1 (en) 2009-07-22
MX2009011213A (en) 2009-11-02
US7863279B2 (en) 2011-01-04
JP2010524908A (en) 2010-07-22
IL201471A0 (en) 2010-05-31
BRPI0810412A2 (en) 2014-10-14

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