WO2006064375A9 - Composes heterocycliques a noyau a cinq elements a substitution aminoaryle pour le traitement de maladies - Google Patents

Composes heterocycliques a noyau a cinq elements a substitution aminoaryle pour le traitement de maladies Download PDF

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WO2006064375A9
WO2006064375A9 PCT/IB2005/004031 IB2005004031W WO2006064375A9 WO 2006064375 A9 WO2006064375 A9 WO 2006064375A9 IB 2005004031 W IB2005004031 W IB 2005004031W WO 2006064375 A9 WO2006064375 A9 WO 2006064375A9
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alkyl
group
formula
aryl
heteroaryl
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PCT/IB2005/004031
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WO2006064375A2 (fr
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Marco Ciufolini
Abdellah Benjahad
Bruno Giethlen
Alain Moussy
Camille Wermuth
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Ab Science
Marco Ciufolini
Abdellah Benjahad
Bruno Giethlen
Alain Moussy
Camille Wermuth
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Publication of WO2006064375A2 publication Critical patent/WO2006064375A2/fr
Publication of WO2006064375A9 publication Critical patent/WO2006064375A9/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
    • C07D271/113—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
    • C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • C07D285/135—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • Aminoaryl substituted five-membered ring heterocyclic compounds for the treatment of diseases
  • the present invention relates to novel compounds selected from aminoaryl five- membered ring heterocycles that selectively modulate, regulate, and/or inhibit signal transduction mediated by native and/or mutant tyrosine kinases implicated in a variety of human and animal diseases such as cell proliferative, metabolic, allergic, inflammatory and degenerative disorders.
  • Tyrosine kinases are receptor type or non-receptor type proteins, which transfer the terminal phosphate of ATP to tyrosine residues of proteins thereby activating or inactivating signal transduction pathways. These proteins are known to be involved in many cellular mechanisms, which in case of disruption, lead to disorders such as abnormal cell proliferation and migration as well as inflammation.
  • VEGF receptors As of today, there are about 58 known receptor tyrosine kinases. Included are the well- known VEGF receptors (Kim et al, Nature 362, pp. 841-844, 1993), PDGF receptors, c-kit, Flt-3 and the FLK family. These receptors can transmit signals to other tyrosine kinases including Src, Raf, Frk, Btk, Csk, AbI, Fes/Fps, Fak, Jak, Ack, etc.
  • tyrosine kinase receptors some are of special interest and have been shown to be directly or indirectly implicated in numerous pathologies for which the Applicant filed WO 03/004007, WO 03/004006, WO 03/003006, WO 03/003004, WO 03/002114, WO 03/002109, WO 03/002108, WO 03/002107, WO 03/002106, WO 03/002105, WO 03/039550, WO 03/035050, WO 03/035049, WO 03/0720090, WO 03/072106 and WO 2004/014903.
  • tyrosine kinase inhibitors for example, bis monocyclic, bicyclic or heterocyclic aryl compounds (WO 92/20642), vinyl ene-azaindole derivatives (WO 94/14808), l-cyclopropyl-4-pyridyl-quinolones (US 5,330,992), styryl compounds (US 5,217,999), styryl-substituted pyridyl compounds (US 5,302,606), selenoindoles and selenides (WO 94/03427), tricyclic polyhydroxylic compounds (WO 92/21660), benzylphosphonic acid compounds (WO 91/15495), pyrimidine derivatives (US 5,521,184 and WO 99/03854), indolinone derivatives and pyrrole-substituted indolinones (US 5,792,783, EP 934 931, US 5,834,504, US 5,883,116, US
  • the present invention relates to compounds belonging to the aminoaryl five-membered ring heterocycles. These compounds are capable of selectively inhibiting signal transduction involving the tyrosine phosphokinase, for example VEGF receptors, PDGF receptors, c-kit, Flt-3 and the FLK family, Src, Raf, Frk, Btk, Csk, AbI, Fes/Fps, Fak, Jak, Ack ; and mutant forms thereof.
  • the invention is aimed at compounds of formula I, which may represent either free base forms of the substances or pharmaceutically acceptable salts thereof:
  • A is selected from the group consisting of: - Imidazole (formula 1-1)
  • Rl, R2, R3 and R4 each independently are selected from hydrogen, halogen (selected from F, Cl, Br or I), a linear or branched alkyl group containing from 1 to 10 carbon atoms and optionally substituted with one or more hetereoatoms such as halogen
  • R5 and R8 are one of the following: (i) hydrogen, or
  • an aryl group such as phenyl or a substituted variant thereof bearing any combination, at any one ring position, of one or more substituents such as halogen (selected from F, Cl, Br or I), alkyl groups containing from 1 to 10 carbon atoms and optionally substituted with one or more hetereoatoms such as halogen (selected from F, Cl, Br or I), oxygen, and nitrogen, the latter optionally in the form of an amino group; as well as trifluoromethyl, C 1-6 alkyloxy, carboxyl, cyano, nitro, formyl, hydroxy, C 1-6 alkylamino, di(C 1-6 alkyl)amino, and amino, the latter nitrogen substituents optionally in the form of an amino group; as well as CO-R, COO-R, CONH-R, S02-R, and SO2NH-R wherein R is a linear or branched alkyl group containing from 1 to 10 carbon atoms and optionally substituted with at any
  • R6 and R7 each independently are selected from: i) hydrogen, a halogen (selected from F, Cl, Br or I), or ii) an alkyl 1 group defined as a linear, branched or cycloalkyl group containing from 1 to 10 carbon atoms, or from 2 or 3 to 10 carbon atoms, (for example methyl, ethyl, propyl, butyl, pentyl, hexyl%) and optionally substituted with one or more hetereoatoms such as halogen (selected from F, Cl, Br or I), oxygen, and nitrogen (the latter optionally in the form of an amino group); as well as trifluoromethyl, carboxyl, cyano, nitro, formyl; as well as CO-R, COO-R, CONH-R, S02-R, and SO2NH-R wherein R is a linear or branched alkyl group containing 1 to 10 carbon atoms, or from 2 or 3 to 10 carbon atoms,
  • an alkyl 1 group a cycloalkyl, aryl or heteroaryl group optionally substituted by an amino group
  • R corresponds to hydrogen, alkyl 1 , aryl or heteroaryl, or
  • a heteroaryl 1 group defined as a pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, -heterocycleyl, pyrazolyl, pyrrolyl, furanyl, -heterocycleyl, is- heterocycleyl , triazolyl, tetrazolyl, indolyl, benz-heterocycle, quinolinyl group, which may additionally bear any combination, at any one ring position, of one or more substituents such as
  • an O-aryl 1 , or NH-aryl 1 , or O-heteroaryl 1 or NH-heteroaryl 1 group (vi) trifluoromethyl, O-alkyl 1 , carboxyl, cyano, nitro, formyl, hydroxy, NH-alkyl 1 , N(alkyl 1 )(alkyl 1 ), and amino, the latter nitrogen substituents optionally in the form of an amino group, or (vi) NHCO-R or NHCOO-R or NHCONH-R or NHS02-R or NHSO2NH-R or CO-R or COO-R or CONH-R or S02-R or S02NH-R wherein R corresponds to hydrogen, alkyl 1 , aryl or heteroaryl.
  • R9 and / or RlO are hydrogen or: i) an alkyl 1 group, CF3 or ii) an aryl 1 , heteroaryl 1 or cycloalkyl group optionally substituted by a an amino group, or iii) a CO-R, COO-R, CON-RR'or S02-R, where R and R' are a hydrogen, alkyl 1 , aryl 1 or heteroaryl 1 , optionally substituted by an amino group; or:
  • R9 and / or RlO are hydrogen or: i) an alkyl 1 group, CF3 or ii) an aryl 1 , heteroaryl 1 or cycloalkyl group optionally substituted by a an amino group, or
  • X may also be Alkyl 1 .
  • the invention is directed to heterocycle A-yl-benzene- 1,3 -diamine compounds of the following formula II:
  • Y and Z represents an hydrogen, an aryl 1 or a heteroaryl 1 group, optionally substituted by an amino group.
  • A, Rl, R2, R3 and R4 have the meaning as depicted above. Examples:
  • R represent an hydrogen, an alkyl 1 , aryl 1 or a heteroaryl 1 group.
  • A, Rl, R2, R3, and R4 have the meaning as defined above in formula I.
  • W is selected from O, S and Z corresponds to H, alkyl 1 , NRaRb, or OR wherein Ra and Rb and R are independently chosen from H or alkyl 1 or aryl 1 or heteroaryl 1 , optionally substituted by an amino group.
  • A, Rl, R2, R3, R4 and R5 have the meaning described above for formula I.
  • Ra, Rb are independently chosen from H or alkyl 1 or aryl 1 or heteroaryl 1 , optionally substituted by an amino group.
  • A, Rl, R2, R3, R4 and W have the meaning described above.
  • B is aryl 1 or heteroaryl 1 and
  • R is independently alkyl 1 , aryl 1 or heteroaryl 1 .
  • A, Rl, R2, R3, R4 and R5 have the meaning described above for formula I.
  • Rl, R2, R3, R4 and alkyl 1 have the meaning as defined above.
  • Y is selected from NRaRb, NHNRaRb, alkyl 1 , aryl 1 , or OR wherein Ra, Rb and R are independently chosen from H or alkyl 1 or aryl 1 or heteroaryl 1 , optionally substituted by an amino group.
  • A, Rl, R2, R3 and R4 have the meaning described above for formula I.
  • alkyl 1 , A, Rl, R2, R3 and R4 have the meaning as defined for formula I above.
  • the optional substitution by an amino group may be represented for example by the structures a to k and m shown below, wherein the wavy line and the arrow line correspond to the point of attachment to core structure of formula I-X.
  • the arrow may include a point of attachment to the core structure via a phenyl group.
  • Group 1 above is an alternative encompassed herein.
  • the amino group may be a saturated cyclic amino group which may be substituted by a group consisting of alkyl, alkoxycarbonyl, halogen, haloalkyl, hydroxyalkyl, amino, monoalkylamino, dialkylamino, carbamoyl, monoalkylcarbamoyl and dialkylcarbamoyl.
  • Intermediate (2) are commercially available or can prepared by reaction of an appropriate amine (10) with a reagent like phosgene or triphosgene in a solvent such as dichloromethane.
  • Intermediate (1) are commercially available or can prepared by reaction of an appropriate ester with hydrazine monohydrate in a solvent such as EtOH.
  • Intermediate (4) are commercially available or can prepared by reaction of an appropriate amine (10) with a reagent like thiophosgene, 1,1 '-thiocarbonyldiimidazole or l,r-thiocarbonyldi-2(lH)-pyridone in a solvent such as dichloromethane.
  • a reagent like thiophosgene, 1,1 '-thiocarbonyldiimidazole or l,r-thiocarbonyldi-2(lH)-pyridone
  • Reaction of intermediate (5) with the commercially chloroacetaldehyde in the presence of 4 equivalents of HCl (ION) in a solvent such EtOH or dioxane yields compound (7).
  • Aminopyrazole (7) was coupled with an appropriate boronic acid in the presence of a suitable catalyst such as Cu(OAc) 2 in a solvent such dichloromethane to give the pyrazole 1-5.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound as depicted above.
  • Such medicament can take the form of a pharmaceutical composition adapted for oral administration, which can be formulated using pharmaceutically acceptable carriers well known in the art in suitable dosages.
  • Such carriers enable the pharmaceutical compositions to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for ingestion by the patient.
  • these pharmaceutical compositions may contain suitable pharmaceutically-acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Further details on techniques for formulation and administration may be found in the latest edition of Remington's Pharmaceutical Sciences (Maack Publishing Co., Easton, Pa.).
  • composition of the invention can also take the form of a pharmaceutical or cosmetic composition for topical administration.
  • compositions may be presented in the form of a gel, paste, ointment, cream, lotion, liquid suspension aqueous, aqueous-alcoholic or, oily solutions, or dispersions of the lotion or serum type, or anhydrous or lipophilic gels, or emulsions of liquid or semi-solid consistency of the milk type, obtained by dispersing a fatty phase in an aqueous phase or vice versa, or of suspensions or emulsions of soft, semi-solid consistency of the cream or gel type, or alternatively of microemulsions, of microcapsules, of microparticles or of vesicular dispersions to the ionic and/or nonionic type.
  • These compositions are prepared according to standard methods.
  • composition according to the invention comprises any ingredient commonly used in dermatology and cosmetic. It may comprise at least one ingredient selected from hydrophilic or lipophilic gelling agents, hydrophilic or lipophilic active agents, preservatives, emollients, viscosity enhancing polymers, humectants, surfactants, preservatives, antioxidants, solvents, and fillers, antioxidants, solvents, perfumes, fillers, screening agents, bactericides, odor absorbers and coloring matter.
  • oils which can be used in the invention mineral oils (liquid paraffin), vegetable oils (liquid fraction of shea butter, sunflower oil), animal oils, synthetic oils, silicone oils (cyclomethicone) and fluorinated oils may be mentioned. Fatty alcohols, fatty acids (stearic acid) and waxes (paraffin, carnauba, beeswax) may also be used as fatty substances.
  • glycerol stearate, polysorbate 60 and the PEG-6/PEG-32/glycol stearate mixture are contemplated.
  • hydrophilic gelling agents carboxyvinyl polymers (carbomer), acrylic copolymers such as acrylate/alkylacrylate copolymers, polyacrylamides, polysaccharides such as hydroxypropylcellulose, clays and natural gums may be mentioned, and as lipophilic gelling agents, modified clays such as bentones, metal salts of fatty acids such as aluminum stearates and hydrophobic silica, or alternatively ethylcellulose and polyethylene may be mentioned.
  • hydrophilic active agents proteins or protein hydrolysates, amino acids, polyols, urea, allantoin, sugars and sugar derivatives, vitamins, starch and plant extracts, in particular those of Aloe vera may be used.
  • agents As lipophilic active, agents, retinol (vitamin A) and its derivatives, tocopherol (vitamin E) and its derivatives, essential fatty acids, ceramides and essential oils may be used. These agents add extra moisturizing or skin softening features when utilized.
  • a surfactant can be included in the composition so as to provide deeper penetration of the compound capable of depleting mast cells, such as a tyrosine kinase inhibitor, preferably a c-kit and/or a bcr-abl inhibitor.
  • the invention embraces penetration enhancing agents selected for example from the group consisting of mineral oil, water, ethanol, triacetin, glycerin and propylene glycol; cohesion agents selected for example from the group consisting of polyisobutylene, polyvinyl acetate and polyvinyl alcohol, and thickening agents.
  • compounds with penetration enhancing properties include sodium lauryl sulfate (Dugard, P. H. and Sheuplein, R. J., "Effects of Ionic Surfactants on the Permeability of Human Epidermis: An Electrometric Study," J. Ivest. Dermatol., V.60, pp. 263-69, 1973), lauryl amine oxide (Johnson et. al., US 4,411,893), azone (Rajadhyaksha, US 4,405,616 and 3,989,816) and decylmethyl sulfoxide (Sekura, D. L.
  • a second class of chemical enhancers are generally referred to as co-solvents. These materials are absorbed topically relatively easily, and, by a variety of mechanisms, achieve permeation enhancement for some drugs. Ethanol (Gale et. al., U.S. Pat. No.
  • compositions of the invention can also be intended for administration with aerosolized formulation to target areas of a patient's respiratory tract.
  • Devices and methodologies for delivering aerosolized bursts of a formulation of a drug is disclosed in US 5,906,202.
  • Formulations are preferably solutions, e.g. aqueous solutions, ethanoic solutions, aqueous/ethanoic solutions, saline solutions, colloidal suspensions and microcrystalline suspensions.
  • aerosolized particles comprise the active ingredient mentioned above and a carrier, (e.g., a pharmaceutically active respiratory drug and carrier) which are formed upon forcing the formulation through a nozzle which nozzle is preferably in the form of a flexible porous membrane.
  • the particles have a size which is sufficiently small such that when the particles are formed they remain suspended in the air for a sufficient amount of time such that the patient can inhale the particles into the patient's lungs.
  • the invention encompasses the systems described in US 5,556,611 :
  • a liquefied gas is used as propellent gas (e.g. low-boiling FCHC or propane, butane) in a pressure container,
  • propellent gas e.g. low-boiling FCHC or propane, butane
  • a - pressurized gas system (a compressed gas such as nitrogen, carbon dioxide, dinitrogen monoxide, air is used.
  • the pharmaceutical preparation is made in that the active substance is dissolved or dispersed in a suitable nontoxic medium and said solution or dispersion atomized to an aerosol, i.e. distributed extremely finely in a carrier gas.
  • aerosol i.e. distributed extremely finely in a carrier gas.
  • the invention is also directed to aerosol devices comprising the compound as defined above and such a formulation, preferably with metered dose valves.
  • compositions of the invention can also be intended for intranasal administration.
  • pharmaceutically acceptable carriers for administering the compound to the nasal mucosal surfaces will be readily appreciated by the ordinary artisan. These carriers are described in the Remington's Pharmaceutical Sciences” 16th edition, 1980, Ed. By Arthur Osol, the disclosure of which is incorporated herein by reference.
  • the composition can be formulated into a solution, e.g., water or isotonic saline, buffered or unbuffered, or as a suspension, for intranasal administration as drops or as a spray.
  • a solution e.g., water or isotonic saline, buffered or unbuffered, or as a suspension
  • such solutions or suspensions are isotonic relative to nasal secretions and of about the same pH, ranging e.g., from about pH 4.0 to about pH 7.4 or, from pH 6.0 to pH 7.0.
  • Buffers should be physiologically compatible and include, simply by way of example, phosphate buffers.
  • a representative nasal decongestant is described as being buffered to a pH of about 6.2 (Remington's, Id. at page 1445).
  • a suitable saline content and pH for an innocuous aqueous carrier for nasal and/or upper respiratory administration is described as being buffered to a pH of about 6.2 (Remington's, Id. at page 1445).
  • the ordinary artisan can readily determine a suitable saline content and pH for an innocuous aqueous carrier for nasal and/or upper respiratory administration.
  • Common intranasal carriers include nasal gels, creams, pastes or ointments with a viscosity of, e.g., from about 10 to about 3000 cps, or from about 2500 to 6500 cps, or greater, may also be used to provide a more sustained contact with the nasal mucosal surfaces.
  • Such carrier viscous formulations may be based upon, simply by way of example, alkylcelluloses and/or other biocompatible carriers of high viscosity well known to the art (see e.g., Remington's, cited supra.
  • a preferred alkylcelmlose is, e.g., methylcellulose in a concentration ranging from about 5 to about 1000 or more mg per 100 ml of carrier.
  • a more preferred concentration of methyl cellulose is, simply by way of example, from about 25 to about mg per 100 ml of carrier.
  • ingredients such as art known preservatives, colorants, lubricating or viscous mineral or vegetable oils, perfumes, natural or synthetic plant extracts such as aromatic oils, and humectants and viscosity enhancers such as, e.g., glycerol, can also be included to provide additional viscosity, moisture retention and a pleasant texture and odor for the formulation.
  • various devices are available in the art for the generation of drops, droplets and sprays.
  • a premeasured unit dosage dispenser including a dropper or spray device containing a solution or suspension for delivery as drops or as a spray is prepared containing one or more doses of the drug to be administered and is another object of the invention.
  • the invention also includes a kit containing one or more unit dehydrated doses of the compound, together with any required salts and/or buffer agents, preservatives, colorants and the like, ready for preparation of a solution or suspension by the addition of a suitable amount of water.
  • the invention embraces a method for treating a disease related to unregulated c-kit transduction comprising administering an effective amount of a compound as defined above to a mammal in need of such treatment. It also relates to a method for treating a disease related bcr-abl and/or Flt-3 comprising administering an effective amount of a compound as defined above to a mammal in need of such treatment.
  • the invention is aimed at a method for treating a disease selected from autoimmune diseases, allergic diseases, bone loss, cancers such as leukemia and GIST, tumor angiogenesis, inflammatory diseases, inflammatory bowel diseases (EBD), interstitial cystitis, mastocytosis, infections diseases, metabolic disorders, fibrosis, diabetes and CNS disorders comprising administering an effective amount a compound depicted above to a mammal in need of such treatment.
  • a disease selected from autoimmune diseases, allergic diseases, bone loss, cancers such as leukemia and GIST, tumor angiogenesis, inflammatory diseases, inflammatory bowel diseases (EBD), interstitial cystitis, mastocytosis, infections diseases, metabolic disorders, fibrosis, diabetes and CNS disorders
  • a disease selected from autoimmune diseases, allergic diseases, bone loss, cancers such as leukemia and GIST, tumor angiogenesis, inflammatory diseases, inflammatory bowel diseases (EBD), interstitial cystitis, mastocytosis, infections diseases, metabolic disorders, fibrosis
  • - neoplastic diseases such as mastocytosis, canine mastocytoma, solid tumours, human gastrointestinal stromal tumor (“GIST”), small cell lung cancer, non- small cell lung cancer, acute myelocytic leukemia, acute lymphocytic leukemia, myelodysplastic syndrome, chronic myelogenous leukemia, colorectal carcinomas, gastric carcinomas, gastrointestinal stromal tumors, testicular cancers, glioblastomas, solid tumors and astrocytomas.
  • - tumor angiogenesis such as mastocytosis, canine mastocytoma, solid tumours, human gastrointestinal stromal tumor (“GIST”), small cell lung cancer, non- small cell lung cancer, acute myelocytic leukemia, acute lymphocytic leukemia, myelodysplastic syndrome, chronic myelogenous leukemia, colorectal carcinomas, gastric carcinomas, gastrointestinal stromal tumors, testicular cancers, glioblasto
  • - metabolic diseases such as diabetes mellitus and its chronic complications; obesity; type II diabetes; hyperlipidemias and dyslipidemias; atherosclerosis; hypertension; and cardiovascular disease, allergic diseases such as asthma, allergic rhinitis, allergic sinusitis, anaphylactic syndrome, urticaria, angioedema, atopic dermatitis, allergic contact dermatitis, erythema nodosum, erythema multiforme, cutaneous necrotizing venulitis and insect bite skin inflammation and blood sucking parasitic infestation, interstitial cystitis. - bone loss (osteoporosis).
  • allergic diseases such as asthma, allergic rhinitis, allergic sinusitis, anaphylactic syndrome, urticaria, angioedema, atopic dermatitis, allergic contact dermatitis, erythema nodosum, erythema multiforme, cutaneous necrotizing venulitis and insect bite skin inflammation and blood sucking parasitic infestation, interstitial cystitis
  • inflammatory diseases such as rheumatoid arthritis, conjunctivitis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions as well as inflammatory muscle disorders; autoimmune diseases such as multiple sclerosis, psoriasis, intestine inflammatory disease, ulcerative colitis, Crohn's disease, rheumatoid arthritis and polyarthritis, local and systemic scleroderma, systemic lupus erythematosus, discoid lupus erythematosus, cutaneous lupus, dermatomyositis, polymyositis, Sjogren's syndrome, nodular panarteritis, autoimmune enteropathy, as well as proliferative glomerulonephritis.
  • autoimmune diseases such as multiple sclerosis, psoriasis, intestine inflammatory disease, ulcerative colitis, Crohn's disease, rhe
  • - graft- versus-host disease or graft rejection in any organ transplantation including kidney, pancreas, liver, heart, lung, and bone marrow.
  • Other autoimmune diseases embraced by the invention active chronic hepatitis and chronic fatigue syndrome, subepidermal blistering disorders such as pemphigus. - Vasculitis.
  • HIV infection - Plasmodium infection.
  • melanocyte dysfunction associated diseases such as hypermelanosis resulting from melanocyte dysfunction and including lentigines, solar and senile lentigo, Dubreuilh melanosis, moles as well as malignant melanomas.
  • the invention embraces the use of the compounds defined above to manufacture a medicament or a cosmetic composition for whitening human skin.
  • CNS disorders such as psychiatric disorders, migraine, pain, memory loss and nerve cells degeneracy. More particularly, the method according to the invention is useful for the treatment of the following disorders: Depression including dysthymic disorder, cyclothymic disorder, bipolar depression, severe or "melancholic" depression, atypical depression, refractory depression, seasonal depression, anorexia, bulimia, premenstrual syndrome, post- menopause syndrome, other syndromes such as mental slowing and loss of concentration, pessimistic worry, agitation, self-deprecation, decreased libido, pain including, acute pain, postoperative pain, chronic pain, nociceptive pain, cancer pain, neuropathic pain, psychogenic pain syndromes, anxiety disorders including anxiety associated with hyperventilation and cardiac arrhythmias, phobic disorders, obsessive-compulsive disorder, posttraumatic stress disorder, acute stress disorder, generalized anxiety disorder, psychiatric emergencies such as panic attacks, including psychosis, delusional disorders,
  • Alzheimer's disease Parkinson's disease, Huntington's disease, the prion diseases, Motor Neurone Disease
  • MND Amyotrophic Lateral Sclerosis
  • substance use disorders include but are not limited to drug addiction, drug abuse, drug habituation, drug dependence, withdrawal syndrome and overdose. Cerebral ischemia - Fibrosis
  • the invention contemplates the use of the compounds as defined above for treating the different categories which can be classified as follows:
  • the category I is composed by two sub-categories (IA and IB).
  • Category IA is made by diseases in which mast cell infiltration is strictly localized to the skin. This category represents the most frequent form of the disease and includes : i) urticaria pigmentosa, the most common form of cutaneous mastocytosis, particularly encountered in children, ii) diffuse cutaneous mastocytosis, iii) solitary mastocytoma and iv) some rare subtypes like bullous, erythrodermic and telangiectatic mastocytosis. These forms are characterized by their excellent prognosis with spontaneous remissions in children and a very indolent course in adults.
  • Category IB is represented by indolent systemic disease (SM) with or without cutaneous involvement. These forms are much more usual in adults than in children. The course of the disease is often indolent, but sometimes signs of aggressive or malignant mastocytosis can occur, leading to progressive impaired organ function.
  • the category II includes mastocytosis with an associated hematological disorder, such as a myeloproliferative or myelodysplastic syndrome, or acute leukemia. These malignant mastocytosis does not usually involve the skin. The progression of the disease depends generally on the type of associated hematological disorder that conditiones the prognosis.
  • the category III is represented by aggressive systemic mastocytosis in which massive infiltration of multiple organs by abnormal mast cells is common. In patients who pursue this kind of aggressive clinical course, peripheral blood features suggestive of a myeloproliferative disorder are more prominent. The progression of the disease can be very rapid, similar to acute leukemia, or some patients can show a longer survival time.
  • mast cell leukemia characterized by the presence of circulating mast cells and mast cell progenitors representing more than 10% of the white blood cells. This entity represents probably the rarest type of leukemia in humans, and has a very poor prognosis, similar to the rapidly progressing variant of malignant mastocytosis. Mast cell leukemia can occur either de novo or as the terminal phase of urticaria pigmentosa or systemic mastocytosis.
  • the invention also contemplates the method as depicted for the treatment of recurrent bacterial infections, resurging infections after asymptomatic periods such as bacterial cystitis. More particularly, the invention can be practiced for treating FimH expressing bacteria infections such as Gram-negative enterobacteria including E. coli, Klebsiella pneumoniae, Serratia marcescens, Citrobactor freudii and Salmonella typhimurium.
  • FimH expressing bacteria infections such as Gram-negative enterobacteria including E. coli, Klebsiella pneumoniae, Serratia marcescens, Citrobactor freudii and Salmonella typhimurium.
  • the invention is directed to a method for treating neoplastic diseases such as mastocytosis, canine mastocytoma, solid tumours, human gastrointestinal stromal tumor ("GIST"), small cell lung cancer, non-small cell lung cancer, acute myelocytic leukemia, acute lymphocytic leukemia, myelodysplastic syndrome, chronic myelogenous leukemia, colorectal carcinomas, gastric carcinomas, gastrointestinal stromal tumors, testicular cancers, glioblastomas, and astrocytomas comprising administering a compound as defined herein to a human or mammal, especially dogs and cats, in need of such treatment.
  • GIST human gastrointestinal stromal tumor
  • the invention is directed to a method for treating allergic diseases such as asthma, allergic rhinitis, allergic sinusitis, anaphylactic syndrome, urticaria, angioedema, atopic dermatitis, allergic contact dermatitis, erythema nodosum, erythema multiforme, cutaneous necrotizing venulitis and insect bite skin inflammation and blood sucking parasitic infestation
  • allergic diseases such as asthma, allergic rhinitis, allergic sinusitis, anaphylactic syndrome, urticaria, angioedema, atopic dermatitis, allergic contact dermatitis, erythema nodosum, erythema multiforme, cutaneous necrotizing venulitis and insect bite skin inflammation and blood sucking parasitic infestation
  • administering a compound as defined herein to a human or mammal, especially dogs and cats, in need of such treatment.
  • the invention is directed to a method for treating inflammatory diseases such as rheumatoid arthritis, conjunctivitis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions comprising administering a compound as defined herein to a human in need of such treatment.
  • inflammatory diseases such as rheumatoid arthritis, conjunctivitis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions
  • the invention is directed to a method for treating autoimmune diseases such as multiple sclerosis, psoriasis, intestine inflammatory disease, ulcerative colitis, Crohn's disease, rheumatoid arthritis and polyarthritis, local and systemic scleroderma, systemic lupus erythematosus, discoid lupus erythematosus, cutaneous lupus, dermatomyositis, polymyositis, Sjogren's syndrome, nodular panarteritis, autoimmune enteropathy, as well as proliferative glomerulonephritis comprising administering a compound as defined herein to a human in need of such treatment.
  • autoimmune diseases such as multiple sclerosis, psoriasis, intestine inflammatory disease, ulcerative colitis, Crohn's disease, rheumatoid arthritis and polyarthritis
  • local and systemic scleroderma systemic lupus ery
  • the invention is directed to a method for treating graft-versus-host disease or graft rejection in any organ transplantation including kidney, pancreas, liver, heart, lung, and bone marrow comprising administering a compound as defined herein to a human in need of such treatment.
  • the FMA3 and P815 cell lines are mastocytoma cells expressing endogenous mutated forms of Kit, i.e., frame deletion in the murine juxtamembrane coding region of the receptor-codons 573 to 579.
  • the human leukaemic MC line HMC-I expresses mutations JM-V560G; Immunoprecipitation assays and western blotting analysis For each assay, 5.106 Ba/F3 cells and Ba/F3 -derived cells with various c-kit mutations were lysed and immunoprecipitated as described (Beslu et al., 1996), excepted that cells were stimulated with 250 ng / ml of rmKL.

Abstract

La présente invention concerne de nouveaux composés choisis parmi des hétérocycles à noyau à cinq éléments aminoaryle modulant, régulant et/ou inhibant sélectivement la transduction de signal médiée par certaines tyrosine kinases natives et/ou mutantes impliquées dans une pluralité de maladies humaines et animales, telles que les maladies prolifératives, métaboliques, allergiques et dégénératives.
PCT/IB2005/004031 2004-12-16 2005-12-16 Composes heterocycliques a noyau a cinq elements a substitution aminoaryle pour le traitement de maladies WO2006064375A2 (fr)

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JO3019B1 (ar) 2006-04-19 2016-09-05 Janssen Pharmaceutica Nv ثلاثي مستبدل 4،2،1-ثلاثي زولات
SI2091948T1 (sl) * 2006-11-30 2012-07-31 Probiodrug Ag Novi inhibitorji glutaminil ciklaze
JO2784B1 (en) 2007-10-18 2014-03-15 شركة جانسين فارماسوتيكا ان. في 5,3,1 - Triazole substitute derivative
CN101827836B (zh) 2007-10-18 2014-02-19 詹森药业有限公司 三取代的1,2,4-***化合物
US20110105436A1 (en) * 2008-03-10 2011-05-05 Auckland Uniservices Limited Heteroaryl compounds, compositions, and methods of use in cancer treatment
MY152486A (en) 2008-03-19 2014-10-15 Janssen Pharmaceutica Nv Trisubstituted 1,2,4 - triazoles as nicotinic acetylcholine receptor modulators
UA103319C2 (en) 2008-05-06 2013-10-10 Глаксосмитклайн Ллк Thiazole- and oxazole-benzene sulfonamide compounds
WO2009135944A1 (fr) 2008-05-09 2009-11-12 Janssen Pharmaceutica Nv Pyrazoles trisubstitués en tant que modulateurs des récepteurs de l'acétylcholine
DE102008038222A1 (de) 2008-08-18 2010-02-25 Merck Patent Gmbh Indazol-5-carbonsäurehydrazid-derivate
DE102008038220A1 (de) 2008-08-18 2010-02-25 Merck Patent Gmbh Oxadiazolderivate
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CA2891412A1 (fr) 2012-11-20 2014-05-30 Vertex Pharmaceuticals Incorporated Composes utiles comme inhibiteurs de l'indoleamine 2,3-dioxygenase
CN106397432B (zh) * 2015-08-03 2018-03-16 南昌弘益科技有限公司 作为jak抑制剂的一类化合物

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EP1624873A2 (fr) * 2003-04-28 2006-02-15 AB Science Utilisation d'inhibiteurs de tyrosine kinase pour le traitement de l'ischemie cerebrale
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