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  • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• the present invention relates to novel 6-O-cycloalkyl or -6-NH-cycloalkyl-triazolopyridazine-sulfanyl benzothiazole and benzimidazole derivatives, process for their preparation, novel intermediates obtained, their use as medicaments, and pharmaceutical compositions containing them. and the novel use of such 6-triazolopyridazin-sulfanyl benzothiazole and benzimidazole derivatives.
• the present invention relates more particularly to novel 6-O-cycloalkyl or 6-NH-cycloalkyl-triazolopyridazine-sulfanyl benzothiazole and benzimidazole derivatives, exhibiting anticancer activity, via the modulation of the activity of proteins, in particular kinases.
• protein kinases play an important role in the regulation of a wide variety of cellular processes, including metabolism, proliferation cell adhesion and motility, cell differentiation or cell survival, with some protein kinases playing a central role in the initiation, development and completion of cell cycle events.
• the present invention relates to novel derivatives with inhibitory effects vis-à-vis protein kinases.
• the products according to the present invention can thus notably be used for the prevention or the treatment of diseases that can be modulated by the inhibition of protein kinases.
• the products according to the present invention exhibit in particular an anticancer activity, via the modulation of the activity of kinases.
• kinases for which modulation of activity is desired MET as well as MET protein mutants are preferred.
• the present invention also relates to the use of said derivatives for the preparation of a medicament for the treatment of humans.
• one of the objects of the present invention is to provide compositions having anticancer activity, acting in particular vis-à-vis kinases.
• MET is preferred.
• MET or Hepatocyte Growth Factor Receptor
• HGF Hepatocyte Growth Factor
• MET is a receptor with tyrosine kinase activity expressed in particular by epithelial and endothelial cells.
• HGF Hepatocyte Growth Factor
• HGF is described as the specific ligand of MET.
• HGF is secreted by the mesenchymal cells and activates the MET receptor that moderates. As a consequence, the receptor autophosphorylates on tyrosines of catalytic domain Y1230, Y1234 and Y1235.
• MET stimulation by HGF induces proliferation, scattering (or dispersion), cell motility, resistance to apoptosis, invasion and angiogenesis.
• MET like HGF, are found to be overexpressed in many human tumors and a wide variety of cancers. MET is also found amplified in gastric tumors and glioblastomas. Numerous point mutations of the MET gene have also been described in tumors, in particular in the kinase domain, but also in the juxtamembrane domain and the SEMA domain. Overexpression, amplification or mutations cause constitutive activation of the receptor and deregulation of its functions.
• the present invention thus relates in particular to novel inhibitors of the MET protein kinase and its mutants, which can be used for an anti-proliferative and anti-metastatic treatment, especially in oncology.
• the present invention also relates to novel inhibitors of the MET protein kinase and its mutants, which can be used for anti-angiogenic treatment, in particular in oncology.
• Ra represents a radical -O-cycloalkyl, or a radical -NH-cycloalkyl all optionally substituted
• X represents S, SO or SO2;
• A represents NH or S;
• W represents a hydrogen atom; an alkyl radical optionally substituted with alkoxy, heterocycloalkyl or NR3R4; or the radical COR in which R represents:
• a cycloalkyl radical or an alkyl radical, optionally substituted by a halogen atom or a cycloalkyl, NR3R4, alkoxy, hydroxy, phenyl, heteroaryl or heterocycloalkyl radical, themselves optionally substituted;
• R1 and R2 are such that one of R1 and R2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical and the other of R1 and R2 represents a hydrogen atom, a cycloalkyl radical, a heterocycloalkyl radical or an alkyl radical optionally substituted with one or more identical or different radicals chosen from hydroxyl, alkoxy, heteroaryl, heterocycloalkyl, NR3R4, optionally substituted phenyl radicals or R1 and R2 radicals form with the atom; nitrogen to which they are attached a cyclic radical containing from 3 to 10 members and optionally one or more other heteroatoms selected from O, S, N and NH, with the optional S possibly being in SO or SO2 form; this radical including the possible NH it contains being optionally substituted; with R3 and R4, which may be identical or different, represent a hydrogen atom, an alkyl radical, a cycloalkyl radical,
• R5 and R5 ' which may be identical or different, represent an alkyl or cycloalkyl radical containing at most 6 carbon atoms; alk represents an alkyl radical containing at most 4 carbon atoms; it being understood that W does not represent H when A represents S, X represents S, Ra represents the O-cyclohexyl radical or the unsubstituted NH-cyclohexyl radical and represents a double bond, said products of formula (I) being in all forms racemic isomers, enantiomers and diastereoisomers, as well as addition salts with mineral and organic acids or with the inorganic and organic bases of said products of formula (I).
• Ra represents an optionally substituted -O-cycloalkyl radical or -NH-cycloalkyl radical
• X is S, SO or SO 2
• A is NH or S
• W represents a hydrogen atom, an alkyl radical optionally substituted with alkoxy, heterocycloalkyl or NR3R4; or the radical COR in which R represents:
• a cycloalkyl radical or an alkyl radical optionally substituted by a halogen atom or a cycloalkyl radical, NR3R4, alkoxy, hydroxy, phenyl, heteroaryl, or heterocycloalkyl themselves optionally substituted;
• R1 and R2 are such that one of R1 and R2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical and the other of R1 and R2 represents a hydrogen atom, a cycloalkyl radical, a heterocycloalkyl radical or an alkyl radical optionally substituted with one or more identical or different radicals chosen from hydroxyl, alkoxy, heteroaryl, heterocycloalkyl, NR3R4, optionally substituted phenyl radicals or R1 and R2 radicals form with the atom; nitrogen to which they are attached a cyclic radical containing from 3 to 10 members and optionally one or more other heteroatoms selected from O, S, N and NH, with the optional S possibly being in SO or SO2 form, this radical including any NH that it contains being optionally substituted; with R3 and R4, which may be identical or different, represent a hydrogen atom, an alkyl radical, a cycloalkyl radical,
• R5 represents an alkyl or cycloalkyl radical containing at most 6 carbon atoms; said products of formula (I) being in all possible isomeric racemic, enantiomeric and diastereoisomeric forms, as well as the addition salts with mineral and organic acids or with the inorganic and organic bases of said products of formula (I).
• the subject of the present invention is the products of formula (I) as defined above or below in which zzz , Ra and X have the values defined in any of the other claims and:
• A represents NH or S
• W represents a hydrogen atom; an alkyl radical optionally substituted with alkoxy, heterocycloalkyl or NR3R4; or the radical COR in which R represents:
• R 1 and R 2 are such that one of R 1 and R 2 represents a hydrogen atom or an alkyl radical and the other of R 1 and R 2 represents a hydrogen atom or a cycloalkyl radical; a heterocycloalkyl radical or an alkyl radical optionally substituted with an alkoxy, heterocycloalkyl or NR3R4 radical; or R1 and R2 together with the nitrogen atom to which they are attached form a cyclic radical containing 3 to 10 members and optionally one or more other heteroatoms chosen from O, S, N and NH, this radical including the optional NH it contains being optionally substituted;
• R 3 and R 4 which may be identical or different, represent a hydrogen atom or an alkyl radical or a heterocycloalkyl radical, all optionally substituted with one or more identical or different radicals chosen from alkoxy, heterocycloalkyl or NH 2, NHAIk radicals; or N (Alk) 2; or R3 and R4 together with the nitrogen atom to which they are attached form a cyclic radical containing from 3 to 10 members and optionally one or more other heteroatoms chosen from O, S, N and NH, this radical including the optional NH it contains being optionally substituted; all the cycloalkyl, heterocycloalkyl and phenyl radicals as well as the cyclic radicals that can be formed by R1 and R2 or R3 and R4 with the nitrogen atom to which they are bonded, defined above, being optionally substituted by one or more radicals chosen from halogen atoms, hydroxyl, alkoxy, NH2, NHaIk,
• these radicals optionally containing one or more other heteroatoms selected from O, S, N and NH, with 1 any possible S possibly being in SO or SO2 form; these radicals, including any NH they contain, may therefore be optionally substituted, in particular with a radical chosen from alkyl, alkoxy, cycloalkyl or heterocycloalkyl, themselves optionally substituted with one or more radicals chosen from halogen atoms and radicals; alkyl, alkoxy, NH 2, NHAIk or N (Alk) 2;
• Ra represents a radical -O-cycloalkyl, or a radical -NH-cycloalkyl all optionally substituted
• X represents S, SO or SO2;
• A represents NH or S;
• W represents a hydrogen atom; an alkyl radical optionally substituted with alkoxy, heterocycloalkyl or NR3R4; or the radical COR in which R represents:
• a cycloalkyl radical or an alkyl radical, optionally substituted by a radical NR3R4, alkoxy, hydroxy, phenyl, heteroaryl, or heterocycloalkyl, themselves optionally substituted;
• R1 and R2 are such that one of R1 and R2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical and the other of R1 and R2 represents a hydrogen atom, a cycloalkyl radical, or an alkyl radical optionally substituted with one or more identical or different radicals chosen from hydroxyl, alkoxy, heteroaryl, heterocycloalkyl, NR3R4, optionally substituted phenyl radicals or else R1 and R2 form with the nitrogen atom to which they are attached a cyclic radical containing from 3 to 10 members and optionally one or more other heteroatoms chosen from O, S, N and NH, this radical including the possible NH that it contains being optionally substituted; with R3 and R4, identical or different, represent a hydrogen atom, an alkyl radical, a cycloalkyl radical, a heteroaryl radical or a phenyl radical, all optionally substituted or else R3 and R
• R5 and R5 ' which may be identical or different, represent an alkyl or cycloalkyl radical containing at most 6 carbon atoms; alk represents an alkyl radical containing at most 4 carbon atoms; it being understood that W does not represent H when A represents S, X represents S, Ra represents the O-cyclohexyl radical or the unsubstituted NH-cyclohexyl radical and represents a double bond, said products of formula (I) being in all forms racemic isomers, enantiomers and diastereoisomers, as well as addition salts with mineral and organic acids or with the inorganic and organic bases of said products of formula (I).
• Ra represents an optionally substituted -O-cycloalkyl radical or -NH-cycloalkyl radical
• X is S, SO or SO 2
• A is NH or S
• W represents a hydrogen atom, an alkyl radical optionally substituted with alkoxy, heterocycloalkyl or NR3R4; or the radical COR in which R represents:
• a cycloalkyl radical or an alkyl radical, optionally substituted by a radical NR3R4, alkoxy, hydroxy, phenyl, heteroaryl, or heterocycloalkyl, themselves optionally substituted;
• R1 and R2 are such that one of R1 and R2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical and the other of R1 and R2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical optionally substituted with one or more identical or different radicals chosen from hydroxyl, alkoxy, heteroaryl, heterocycloalkyl, NR3R4, optionally substituted phenyl radicals or R1 and R2 together with the nitrogen atom to which they are attached form a cyclic radical containing from 3 to 10 members; and optionally one or more other heteroatoms selected from O, S, N and NH, this radical including the optional NH it contains being optionally substituted; with R3 and R4, which may be identical or different, represent a hydrogen atom, an alkyl radical, a cycloalkyl radical, a heteroaryl radical or an optionally substituted phenyl radical or else R3 and R4
• R5 represents an alkyl or cycloalkyl radical containing at most 6 carbon atoms; said products of formula (I) being in all isomeric forms possible racemic, enantiomers and diastereoisomers, as well as addition salts with the inorganic and organic acids or with the inorganic and organic bases of said products of formula (I).
• A represents NH or S
• W represents a hydrogen atom; an alkyl radical optionally substituted with alkoxy, heterocycloalkyl or NR3R4; or the radical COR in which R represents:
• R 1 and R 2 are such that one of R 1 and R 2 represents a hydrogen atom or an alkyl radical and the other of R 1 and R 2 represents a hydrogen atom or a cycloalkyl radical; or an alkyl radical optionally substituted with an alkoxy, heterocycloalkyl or NR3R4 radical; or R1 and R2 together with the nitrogen atom to which they are attached form a cyclic radical containing 3 to 10 members and optionally one or more other heteroatoms chosen from O, S, N and NH, this radical including the optional NH it contains being optionally substituted; with NR3R4, such that R3 and R4, which are identical or different, represent a hydrogen atom or an alkyl radical or else R3 and R4 form, with the nitrogen atom to which they are bonded, a cyclic radical containing from 3 to 10 members and, if appropriate, one or more other heteroatoms chosen from O, S, N and NH, this radical including the optional NH
• A represents NH or S
• W represents a hydrogen atom; an alkyl radical optionally substituted by a heterocycloalkyl radical or NR3R4; or the radical COR in which R represents:
• R 1 and R 2 are such that one of R 1 and R 2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical and the other of R 1 and R 2 represents a hydrogen atom; , an alkyl radical optionally substituted with a heterocyclic radical or NR3R4, or else R1 and R2 form, with the nitrogen atom to which they are bonded, a cyclic radical optionally containing one or more other heteroatoms chosen from O, S, N and NH, this radical including the optional NH it contains being optionally substituted; with NR3R4, such that R3 and R4, which may be identical or different, represent a hydrogen atom or an alkyl radical or else R3 and R4 form, with the nitrogen atom to which they are bonded, a cyclic radical optionally containing one
• the subject of the present invention is the products of formula (I) as defined above or below, in which A represents NH, the substituents zzz , Ra, X and W being chosen from all the values defined for these radicals at any of the other claims, said products of formula (I) being in all possible isomeric racemic, enantiomeric and diastereoisomeric forms, as well as addition salts with mineral and organic acids or with the mineral and organic bases of said products. of formula (I).
• the subject of the present invention is the products of formula (I) as defined above or below, in which A represents S, the substituents zzz , Ra, X and W being chosen from among all the values defined for these radicals. any of the other claims, said products of formula (I) being in all possible isomeric racemic, enantiomeric and diastereoisomeric forms, as well as addition salts with mineral and organic acids or with the mineral and organic bases of said products. of formula (I).
• Ra and W are selected from the meaning indicated in any one of the other claims, said products of formula (Ia) and (Ib) being in all possible isomeric racemic, enantiomeric and diastereoisomeric forms, as well as salts addition with the mineral and organic acids or with the inorganic and organic bases of said products of formula (Ia) and (Ib).
• the subject of the present invention is the products of formula (I) as defined above or below, in which represents a single bond corresponding to the products of formula (I 1 ):
• the subject of the present invention is the products of formula (I) as defined above or below, in which represents a single bond corresponding to the products of formula (Ia '):
• Ra and W are selected from the meaning indicated in any one of the other claims, said products of formula (a) being in all possible isomeric racemic, enantiomeric and diastereoisomeric forms, as well as the addition salts with inorganic and organic acids or with the inorganic and organic bases of said products of formula (a).
• Ra and W are selected from the meaning indicated in any one of the other claims, said products of formula (I “a) being in all possible isomeric racemic, enantiomeric and diastereoisomeric forms, as well as the addition salts with inorganic and organic acids or with the inorganic and organic bases of said products of formula (I "a).
• the subject of the present invention is the products of formula (I) as defined above or hereinafter in which zzz represents a single bond corresponding to the products of formula (b):
• Ra and W are selected from the meaning indicated in any one of the other claims, said products of formula (b) being in all possible isomeric racemic, enantiomeric and diastereoisomeric forms, as well as the addition salts with the inorganic and organic acids or with the inorganic and organic bases of said products of formula (b).
• Ra and W are selected from the meaning indicated in any one of the other claims, said products of formula (I “b) being in all possible isomeric racemic, enantiomeric and diastereoisomeric forms, as well as the addition salts with inorganic and organic acids or with the inorganic and organic bases of said products of formula (I "b).
• alkyl radical denotes the radicals, linear and, if appropriate, branched, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl and also heptyl, octyl, nonyl and decyl and their linear or branched positional isomers: alkyl radicals containing from 1 to 6 carbon atoms and more particularly radicals are preferred alkyl containing 1 to 4 carbon atoms from the above list;
• alkoxy radical denotes the linear and, if appropriate, branched, methoxy, ethoxy, propoxy, isopropoxy, linear butoxy, secondary or tertiary, pentoxy or hexoxy radicals, as well as their linear or branched positional isomers: the alkoxy radicals containing 1 to 4 carbon atoms from the above list;
• halogen atom denotes the chlorine, bromine, iodine or fluorine atoms and preferably the chlorine, bromine or fluorine atom.
• cycloalkyl radical denotes a saturated carbocyclic radical containing 3 to 10 carbon atoms and thus particularly denotes the cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl radicals and especially the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl radicals;
• heterocycloalkyl radical thus denotes a monocyclic or bicyclic carbocyclic radical containing from 3 to 10 members interrupted by one or more heteroatoms, which may be identical or different, chosen from oxygen, nitrogen or sulfur atoms; for example, morpholinyl, thiomorpholinyl, aziridyl, azetidyl, piperazinyl, piperidyl, homopiperazinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, oxodihydropyridazinyl radicals, or alternatively oxetanyl or thietanyl radicals, these radicals being optionally substituted; it may be noted that these heterocycloalkyl radicals may comprise a bridge formed from two links to form, for example, morpholin
• aryl and heteroaryl denote unsaturated or partially unsaturated, respectively carbocyclic and heterocyclic, monocyclic or bicyclic radicals, containing at most 12 members, which may optionally contain a -C (O) - chain, heterocyclic radicals containing one or more identical heteroatoms or different selected from O, N, or S with N, if appropriate, optionally substituted;
• aryl radical thus denotes monocyclic or bicyclic radicals containing 6 to 12 members, such as, for example, the phenyl, naphthyl, biphenyl, indenyl, fluorenyl and anthracenyl radicals, more particularly the phenyl and naphthyl radicals and even more particularly the phenyl radical.
• a carbocyclic radical containing a -C (O) - linkage is, for example, the tetralone radical;
• heteroaryl radical thus denotes monocyclic or bicyclic radicals containing 5 to 12 ring members: monocyclic heteroaryl radicals such as, for example, thienyl radicals such as 2-thienyl and 3-thienyl, furyl such as 2-furyl, 3-furyl, pyrannyl, pyrrolyl, pyrrolinyl, pyrazolinyl, imidazolyl, pyrazolyl, pyridyl such as 2-pyhdyl, 3-pyridyl and 4-pyhdyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl, isothiazolyl, diazolyl, thiadiazolyl, thiatriazolyl, oxadiazolyl, isoxazolyl as 3- or 4-isoxazolyl, furazannyl, free or salt tetrazolyl,
• heteroaryl or bicyclic radicals there may be mentioned more particularly the pyrimidinyl, pyridyl, pyrrolyl, azaindolyl, indazolyl or pyrazolyl radicals, optionally substituted by one or more identical or different substituents as indicated above.
• the carboxyl group (s) of the products of formula (I) may be salified or esterified with the various groups known to those skilled in the art, among which may be mentioned, for example:
• mineral bases such as, for example, one equivalent of sodium, potassium, lithium, calcium, magnesium or ammonium or organic bases such as, for example, methylamine, propylamine, trimethylamine, diethylamine, triethylamine, N, N-dimethylethanolamine, tris (hydroxymethyl) amino methane, ethanolamine, pyridine, picoline, dicyclohexylamine, morpholine, benzylamine, procaine, lysine , arginine, histidine, N-methylglucamine,
• the alkyl radicals to form alkoxycarbonyl groups such as, for example, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl, these alkyl radicals being able to be substituted by radicals chosen, for example, from the atoms of halogen, hydroxyl, alkoxy, acyl, acyloxy, alkylthio, amino or aryl radicals such as in groups chloromethyl, hydroxypropyl, methoxynethyl, propionyloxymethyl, methylthionethyl, dimethylanninoethyl, benzyl or phenethyl.
• the addition salts with the mineral or organic acids of the products of formula (I) can be, for example, the salts formed with hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, propionic, acetic, trifluoroacetic, formic acids, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, ascorbic, alkylmonosulphonic acids such as, for example, methanesulfonic acid, ethanesulphonic acid, propanesulphonic acid, alkylsulphonic acids such as, for example, methanedisulfonic acid, alpha, beta-ethanedisulfonic acid, arylmonosulfonic acids such as benzenesulphonic acid and aryldisulphonic acids.
• hydrochloric hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, propionic,
• stereoisomerism can be defined in its broad sense as the isomerism of compounds having the same developed formulas, but whose different groups are arranged differently in space, such as in particular in monosubstituted cyclohexanes whose substituent can be in axial or equatorial position, and the different possible rotational conformations of the ethane derivatives.
• stereoisomerism due to the different spatial arrangements of fixed substituents, either on double bonds or on rings, often called geometric isomerism or cis-trans isomerism.
• stereoisomers is used in the present application in its broadest sense and therefore relates to all of the compounds indicated above.
• the cyclic radicals that R 1 and R 2 can form on the one hand with the nitrogen atom to which they are bonded and on the other hand R 3 and R 4 with the nitrogen atom to which they are bonded, are optionally substituted with one or several radicals chosen from those indicated above for the possible substituents of heterocycloalkyl radicals, ie one or more radicals selected from halogen atoms, hydroxyl, oxo, alkoxy, NH 2 radicals; NHaIk, N (alk) 2, and the radicals alkyl, heterocycloalkyl, CH2-heterocycloalkyl, phenyl, CH2-phenyl, heteroaryl, and CO-phenyl, such that in these latter radicals the alkyl, heterocycloalkyl and phenyl radicals are themselves optionally substituted with one or more radicals selected from halogen atoms and hydroxyl, oxo, alkyl and alkoxy radicals having 1 to 4 carbon atoms, NH
• the cyclic radicals that can be formed on the one hand R 1 and R 2 with the nitrogen atom to which they are bonded and on the other hand R 3 and R 4 with the nitrogen atom to which they are bonded, are in particular optionally substituted by a or more identical or different radicals chosen from halogen atoms and alkyl, hydroxyl, alkoxy, CH 2 -pyrrolidinyl, CH 2 -phenyl, heteroaryl and phenyl radicals, in which the alkyl, pyrrolidinyl and phenyl radicals are themselves optionally substituted by one or more identical or different radicals chosen from halogen atoms and alkyl, hydroxyl, oxo and alkoxy radicals.
• heterocycloalkyl radicals as defined above represent, in particular, the azepanyl, morpholinyl and pyrrolidinyl, piperidyl and piperazinyl radicals themselves optionally substituted, as defined above or hereinafter.
• NR1 R2 or NR3R4 forms a ring as defined above
• such an amine ring may be chosen in particular from pyrrolidinyl, pyrazolidinyl, pyrazolinyl, piperidyl, azepinyl, morpholinyl or piperazinyl radicals, these radicals themselves being optionally substituted as indicated.
• radicals chosen from halogen atoms and alkyl, hydroxyl, alkoxy, phenyl and CH 2 -phenyl radicals for example by one or more identical or different radicals chosen from halogen atoms and alkyl, hydroxyl, alkoxy, phenyl and CH 2 -phenyl radicals, the alkyl or phenyl radicals being themselves optionally substituted by one or several identical or different radicals chosen from halogen atoms and alkyl, hydroxyl and alkoxy radicals.
• the NR 1 R 2 or NR 3 R 4 ring may more particularly be chosen from pyrrolidinyl and morpholinyl radicals, optionally substituted by one or two alkyl or piperazinyl radicals, optionally substituted on the second nitrogen atom by an alkyl, phenyl or CH 2 -phenyl radical, themselves optionally substituted by one or more identical or different radicals chosen from halogen atoms and alkyl, hydroxyl and alkoxy radicals.
• Ra represents a -O-cycloalkyl radical, or a -NH-cycloalkyl radical optionally substituted with a hydroxyl, alkoxy or -O-CO-R5 radical;
• X is S; A represents S;
• W represents a hydrogen atom or an alkyl radical optionally substituted with heterocycloalkyl or the COR radical in which R represents:
• a cycloalkyl radical or an alkyl radical, optionally substituted with an NR 3 R 4 radical, or alkoxy radical; an O-phenyl radical;
• R1 and R2 are such that one represents a hydrogen atom and the other represents an alkyl radical optionally substituted with a heterocycloalkyl radical; with NR3R4 such that R3 and R4, which may be identical or different, represent a hydrogen atom or an alkyl radical; R5 represents an alkyl or cycloalkyl radical containing at most 6 carbon atoms; said products of formula (I) being in all possible isomeric racemic, enantiomeric and diastereoisomeric forms, as well as the addition salts with mineral and organic acids or with the inorganic and organic bases of said products of formula (I).
• the cycloalkyl radicals may represent a cycloheptyl, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl radical;
• heterocycloalkyl radicals may represent a morpholinyl or pyrrolidinyl radical.
• the subject of the present invention is also any process for the preparation of the products of formula (I) as defined above
• the subject of the present invention is thus any process for the preparation of the products of formula (I) as defined above in which A represents NH.
• the subject of the present invention is thus any process for the preparation of the products of formula (I) as defined above in which A represents S.
• the products according to the invention can be prepared from conventional methods of organic chemistry.
• Schemes 1, 2, 3, 4, 5 and 6 below are illustrative of the methods used for the preparation of the products of formula (I). As such, it can not constitute a limitation of the scope of the invention, as regards the methods of preparation of the claimed compounds.
• the products of formula (I) as defined above according to the present invention can thus be prepared in particular according to the processes described in Schemes 1, 2, 2bis, 3, 4, 5 and 6 below.
• the present invention thus also relates to the process for the preparation of products of formula (I) according to Scheme 1 as defined below.
• the present invention thus also relates to the process for preparing products of formula (I) according to Scheme 2 as defined below.
• the present invention thus also relates to the process for preparing products of formula (I) according to Scheme 2bis as defined below.
• the present invention thus also relates to the process for the preparation of products of formula (I) according to Scheme 3 as defined below
• the present invention thus also relates to the process for preparing products of formula (I) according to Scheme 4 as defined below
• the present invention thus also relates to the process for the preparation of products of formula (I) according to Scheme 5 as defined below
• the present invention thus also relates to the process for the preparation of products of formula (I) according to Scheme 6 as defined below
• the products of formula (V) which represent the products of formula (I) in which represents a bond are defined simple and the products of formula (I ") which represent the products of formula (I) in which zzz ⁇ represents a double bond, likewise for synthetic intermediates as defined below of formulas (a), (b) (c), (d), (e) and (f) wherein represents a single or double bond, the compounds of formulas (a 1 ), (b 1 ), (c 1 ), (d 1 ) are defined , (e 1 ) and (f) in which zzz ⁇ represents a single bond, and the compounds of formulas (a "), (b"), (c “), (d"), (e ") and (f) in which represents a double bond.
• the substituent Ra can take the meanings indicated above for the products of formula (I 1 ) and (I "), the substituent R 5, in the compounds of formulas (J), (1a). 1 ) and (1 a ") represents an alkyl radical and the substituent R 6 in the compounds of formulas (O), (1d ') and (1d") represents an alkyl radical optionally substituted with NR 3 R 4 (a radical - ( CH2) n-NR3R4), alkoxy, hydroxy, heterocycloalkyl, phenyl, - (CH2) n- phenyl, with optionally substituted phenyl and n represents an integer of 1 to 4.
• the substituent R 7 in the compounds of formulas (P) and (1 e ') / (1 e ") represents a cycloalkyl or alkyl radical optionally substituted with a radical NR3R4, alkoxy, hydroxy phenyl, heteroaryl, or heterocycloalkyl, themselves optionally substituted.
• the benzimidazoles of the general formula (1a “), (1b"), (1c “), (1d") and (1e ") and their reduced analogues of the general formula ( 1 to 1 ), (1 b 1 ), (1c '), (1cT) and (1 e 1 ) can be prepared from 3,6-dichloro [1,2,4] triazolo [4,3 commercial pyridazine of formula (S).
• the compounds (E) can be obtained, for example, by reacting alcohols or amines in the presence or absence of a base on the compound (S). The reaction is carried out, for example, at a temperature in the region of 20 ° C. to 80 ° C.
• Compounds (G) can be obtained, for example, by reaction of 3-amino-4-nitro-benzenethiol of formula (F) with compounds of formula (E).
• the compounds of formula (F) are obtained by in situ reduction of 3-amino-4-nitrophenyl thiocyanate (Q) (commercial compound), by for example, in the presence of sodium borohydride in a solvent such as N, N-dimethylformamide, at a temperature in the region of 20 ° C.
• the compounds (H ") as represented by a double bond can be obtained, for example, by reduction with iron (O) on the compounds of formula (G), in a solvent such as methanol, in the presence of acetic acid, at a temperature in the region of 70 ° C.
• the compounds (H ') such that zz 1 are a single bond can be obtained, for example, by reduction with zinc (O) on the compounds of formula (G), in the presence of acetic acid, at a temperature close to 20 ° C.
• the carbamates of general formula (1 a ') and (1 a ") can be prepared in particular as described in patent WO03028721A2, from a 3,4-diamino phenyl sulfide of formula (H') and (H ") and a pseudothiourea of formula (J), in the presence of acetic acid and in a protic solvent such as methanol, at a temperature of 80 0 C.
• the benzimidazoles of general formula (1b ') and (1b ") can be prepared respectively by reaction of an amine NHR1 R2 of formula (R) (with R1 and R2 as defined above) on a carbamate of formula (1 a ') and (1 a "), for example in the presence of an aprotic solvent such as 1-methyl-2-pyrrolidinone.
• the reaction is carried out, for example, a temperature close to 120 ° C., in a tube sealed under microwaves.
• the 2-amino benzimidazoles of general formula (1c ') and (1c ") can be prepared, for example, by reaction of cyanogen bromide with a compound of formula (H') and (H") respectively, in presence of a protic solvent such as ethanol. The reaction is carried out at a temperature in the region of 80 ° C.
• carboxamides (1 ') and (1e ") can be obtained respectively from the amines of general formula (1c') and (1c")
• the benzothiazoles of the general formula (2a "), (2b"), (2c ") and (2d") as well as their reduced analogues of the general formula (2a 1 ), (2b 1 ), (2c 1 ) and (2cT) can be prepared from 2-amino-1,3-benzothiazol-6-yl (K) thiocyanate (commercial compound).
• the carboxamides (L3) can be obtained by acylation of the amine (K)
• the glycidic acids (P ') can be prepared from bromoacetic acid and amines HNR3R4 under conditions similar to those described by D. T. Witiak et.al .; J. Med. Chem. 1985, 28, 1228.
• the amines (2d ') and (2d ") can be treated with chloroacetyl chloride in the presence of a base such as pyridine, triethylamine or N-methylmorpholine, in a solvent such as dichloromethane at a temperature in the region of 0 ° C. to 20 ° C.
• a base such as pyridine, triethylamine or N-methylmorpholine
• dichloromethane a temperature in the region of 0 ° C. to 20 ° C.
• the alpha-chloroacetamides (2e72e) thus formed can react with amines of the HNR3R4 type, as defined above, in a solvent such as pyridine at a temperature of 20 0 C, to give the derivatives (2c72c ") as defined in Scheme 2a above.
• the compounds of general formula (M1), (M2) and (M3) can be obtained, for example, by reduction of compounds of general formula (L1), (L2), (L3) with DL-dithiotreitol, in the presence of sodium dihydrogen carbonate in a solvent such as ethanol and at a temperature in the region of 80 ° C.
• the compound of general formula (N) can be prepared in situ by reduction of the compound of formula (K), for example with sodium borohydride in a solvent such as N, N-dimethylformamide, in the presence of a base such as triethylamine and at a temperature in the region of 95 ° C. or between 20 ° C. and 95 ° C.
• a chlorocarbonate of formula (O) (X Cl)
• the benzothiazoles of general formula (2a "), (2b"), (2c ") and (2d") as well as their reduced analogues of general formula (2a '), (2b 1 ), (2c 1 ) and (2d ') can be prepared for example: 1) or by coupling a compound of formula (E) with derivatives (M1), (M2) and (M3) and (N) generated in situ by reduction of derivatives (L1), (L2), (L3) and (K) with sodium borohydride, in a solvent such as N, N-dimethylformamide and in the presence of a base such as thylamine, at a temperature in the region of 95 ° C or between 50 ° C and 95 ° C .
• the substituent R8 represents a cycloalkyl radical as defined above for the products of formula (I)
• the compounds of formula (E) can be obtained, for example, as shown in scheme 3 above, from commercially available 3,6-dichloro [1,2,4] thazolo [4,3-b] pyridazine of formula (S).
• the compounds of formula (E) in which Ra represents an OR8 radical can be obtained by treatment of 3,6-dichloro [1,2,4] thazolo [4,3-b] pyridazine (S) at a temperature of a temperature of about 20 0 C to 80 0 C and in a solvent such as tetrahydrofuran with an alkoxide of formula (U), itself obtained by treatment of an alcohol (HOR8) with, for example, sodium hydride in a solvent such as tetrahydrofuran at a temperature in the region of 0 ° C. to 20 ° C.,
• the compounds of formula (E) wherein Ra represents an R8NH radical can be obtained by treatment of 3,6-dichloro [1,2,4] thazolo [4,3-b] pyhdazine (S) with a amine of formula (R8NH2), at a temperature in the region of 20 ° C to 50 ° C and in a solvent such as N, N-dimethylformamide.
• the benzothiazoles of general formula (2e 1 ) and (2e ") can be prepared respectively from the compounds of formulas (2a 1 ) and (2a").
• the substituent OR6 is preferably O-t-butyl.
• the substituent R 9 represents an alkyl or cycloalkyl radical optionally substituted with an alkoxy, heterocycloalkyl or NR 3 R 4 radical (R 3 and R 4 as defined above).
• the compounds of general formula (2e 1 ) and (2e ") can be obtained respectively by treatment of the compounds (T) and (T ") isolated, for example, with trifluoroacetic acid, in a solvent such as dichloromethane, at a temperature in the region of 20 ° C.,
• the compounds of general formula (2e ") can be obtained directly by reaction of the compounds of formula (L4) and (E), via the compound (T") formed in situ, for example, in the presence of DL-dithiotreitol and of sodium dihydrogen carbonate, in a solvent such as ethanol and at a temperature of about 80 ° C., optionally followed by an in situ treatment with trifluoroacetic acid at 20 ° C. if necessary.
• the carbamates of general formula (L4) can be obtained by reaction of carbamates of general formula (L1), for example with alkyl halides of formula (W), in a solvent such as N, N-dimethylformamide, in the presence sodium hydride, at a temperature of between 20 and 90 ° C.
• the benzothiazoles of general formula (2e ") can be prepared from the compounds of formulas (L6) and (E), for example, in the presence of DL-dithiotreitol and sodium dihydrogen carbonate in a solvent such as ethanol and at a temperature in the region of 80 ° C.
• the benzothiazoles of general formula (2e 1 ) can be prepared from compounds of formula (2e "), according to the methods described below for the preparation of compounds (I 1 ) from compounds (I").
• the compounds of formulas (L6) can be prepared from the 2-bromo benzothiazole derivative (L5) by treatment with an NH 2 R 9 derivative, for example, in a solvent such as tetrahydrofuran, at a temperature in the region of 20 ° C.
• the substituent R 9 represents an alkyl or cycloalkyl radical optionally substituted with an alkoxy, heterocycloalkyl or NR 3 R 4 radical (R 3 and R 4 as defined above).
• the compounds of formulas (L5) can be prepared from 2-amino-1,3-benzothiazol-6-yl (K) thiocyanate (commercial compound), for example by treatment with an alkyl nitrite and bromide. cuprous in a solvent such as acetonitrile, at a temperature of 0-20 ° C, according to the method described by Jagabandhu Das et. al. in J. Med. Chem. 2006, 49, 6819-6832.
• the benzothiazoles of general formula (T) may also be prepared, starting from the compounds of formula (I "), by reduction, for example, with sodium borohydride, in a solvent such as ethanol, at a temperature of about 80 0 C or by reduction with zinc (0) in the presence of acetic acid, at a temperature of 20 ° C.
• the compounds (I 1 ) can also be prepared from compounds of formula (E ') by coupling with compounds of type M1, M2, M3 or N, obtained as intermediates by reduction of compounds L1, L2. , L3 or K in situ, as described above in Scheme 2.
• the M1, M2 or M3 type compounds can also be isolated and used for coupling with (E ').
• the compounds (E ') can be obtained from the compounds of formula (E) by reduction, for example, by reduction with zinc (O) in the presence of acetic acid, at a temperature in the region of 20 ° C.
• the compounds (I ') may also be prepared from other compounds (T) by transformation of the group W into a group W of the same nature as defined above for W and according to the type of reactions defined in scheme 2: transformations of 2d '/ 2d "into 2a' / 2a" and into 2c '/ 2c ", the transformations of 2a' / 2a" into 2d '/ 2d "and into 2b' / 2b".
• sulfur S can be oxidized to sulfoxide SO or sulfone SO 2 according to the methods known to those skilled in the art and, if necessary, protecting the optionally reactive groups by appropriate protective groups.
• the hydroxyl groups may be protected, for example, by alkyl radicals such as tert-butyl, thmethylsilyl, tert-butyldimethylsilyl, methoxymethyl, tetrahydropyranyl, benzyl or acetyl,
• amino groups may be protected for example by the acetyl, trityl, benzyl, tert-butoxycarbonyl, BOC, benzyloxycarbonyl, phthalimido or other radicals known in peptide chemistry,
• esters formed with easily cleavable esters such as benzyl or tert-butyl esters or esters known in peptide chemistry.
• intermediate products or products of formula (I) thus obtained can be subjected, if desired and if necessary, to the processes described above, to obtain other intermediates or other products of formula (I), one or more reactions of transformations known to those skilled in the art such as for example: a) an esterification reaction of acid function, b) a saponification reaction of ester function in acid function, c) a reduction reaction of the free or esterified carboxy function as a function of alcohol, d) an alkoxy function-to-hydroxyl function conversion reaction, or also an alkoxy-functional hydroxyl function, e) an elimination reaction of the protective groups that the protected reactive functions, f) a salification reaction with a mineral or organic acid or a base to obtain the corresponding salt, g) a resolving reaction of the racemic forms into split products, said products of formula (I) thus obtained being in any isomeric possible racemic, enantiomeric and diastereoisomeric forms.
• the saponification reaction can be carried out according to the usual methods known to those skilled in the art, such as, for example, in a solvent such as methanol or ethanol, dioxane or dimethoxyethane, in the presence of sodium hydroxide or potassium hydroxide.
• a solvent such as methanol or ethanol, dioxane or dimethoxyethane
• the optional free or esterified carboxy functions of the products described above may, if desired, be reduced in alcohol function by the methods known to those skilled in the art: the optional esterified carboxy functions may, if desired, be reduced depending on the alcohol by the methods known to those skilled in the art and in particular by lithium hydride and aluminum in a solvent such as for example tetrahydrofuran or dioxane or ethyl ether.
• the optional free carboxy functions of the products described above may, if desired, be reduced in particular alcohol function by boron hydride.
• the optional alkoxy functions, such as methoxy in particular, of the products described above may, if desired, be converted into hydroxyl function under the usual conditions known to those skilled in the art, for example by boron tribromide in a solvent such as For example, methylene chloride, with hydrobromide or pyridine hydrochloride or with hydrobromic or hydrochloric acid in water or trifluoroacetic acid under reflux.
• a solvent such as For example, methylene chloride, with hydrobromide or pyridine hydrochloride or with hydrobromic or hydrochloric acid in water or trifluoroacetic acid under reflux.
• the phthalimido group can be removed by hydrazine.
• the products described above may, if desired, be the subject of salification reactions, for example by a mineral or organic acid or by a mineral or organic base according to the usual methods known to those skilled in the art: such salification reaction can be carried out for example in the presence of hydrochloric acid for example or tartaric acid, citric or methanesulfonic acid in an alcohol such as for example ethanol or methanol.
• hydrochloric acid for example or tartaric acid, citric or methanesulfonic acid in an alcohol such as for example ethanol or methanol.
• the products of the present invention are especially useful for tumor therapy.
• the products of the invention can also increase the therapeutic effects of commonly used anti-tumor agents.
• the subject of the invention is, as medicaments, the products corresponding to the following formulas:
• the invention also relates to pharmaceutical compositions containing as active principle at least one of the products of formula (I) as defined above or a pharmaceutically acceptable salt of this product or a prodrug of this product and, where appropriate, optionally, a pharmaceutically acceptable carrier.
• the invention thus extends to pharmaceutical compositions containing as active principle at least one of the drugs as defined above.
• compositions of the present invention may also, where appropriate, contain active ingredients of other antimitotic drugs such as in particular those based on taxol, cisplatin, intercalating DNA agents and others.
• compositions may be administered orally, parenterally or locally by topical application to the skin and mucous membranes or by intravenous or intramuscular injection.
• compositions may be solid or liquid and may be in any of the pharmaceutical forms commonly used in human medicine, such as, for example, simple or coated tablets, pills, lozenges, capsules, drops, granules, injectable preparations, ointments, creams or gels; they are prepared according to the usual methods.
• the active ingredient can be incorporated into the excipients usually employed in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous vehicles or not, the fatty substances of animal or vegetable origin, paraffinic derivatives, glycols, various wetting agents, dispersing or emulsifying agents, preservatives.
• the usual dosage, variable according to the product used, the subject treated and the condition in question, may be, for example, from 0.05 to 5 g per day in the adult, or preferably from 0.1 to 2 g. per day.
• the subject of the present invention is also the use of the products of formula (I) as defined above or of pharmaceutically acceptable salts of these products for the preparation of a medicament intended for inhibiting the activity of a protein kinase.
• the subject of the present invention is also the use of products of formula (I) as defined above for the preparation of a medicament intended for the treatment or prevention of a disease characterized by the dysregulation of a protein kinase.
• a medicament may especially be intended for the treatment or prevention of a disease in a mammal.
• the present invention also relates to the use defined above in which the protein kinase is a protein tyrosine kinase.
• the subject of the present invention is also the use defined above in which the protein tyrosine kinase is MET or its mutant forms.
• the present invention also relates to the use defined above in which the protein kinase is in a cell culture.
• the present invention also relates to the use defined above in which the protein kinase is in a mammal.
• the present invention particularly relates to the use of a product of formula (I) as defined above for the preparation of a medicament for the prevention or treatment of diseases related to uncontrolled proliferation.
• the present invention particularly relates to the use of a product of formula (I) as defined above for the preparation of a medicament for the treatment or prevention of a disease selected from the following group: disorders proliferation of blood vessels, fibrotic disorders, mesangial cell proliferation disorders, metabolic disorders, allergies, asthma, thrombosis, nervous system diseases, retinopathy, psoriasis, rheumatoid arthritis, diabetes, muscle degeneration and cancers.
• a disease selected from the following group: disorders proliferation of blood vessels, fibrotic disorders, mesangial cell proliferation disorders, metabolic disorders, allergies, asthma, thrombosis, nervous system diseases, retinopathy, psoriasis, rheumatoid arthritis, diabetes, muscle degeneration and cancers.
• the present invention thus particularly relates to the use of a product of formula (I) as defined above for the preparation of a medicament for the treatment or prevention of diseases in oncology and in particular for treatment of cancers.
• the products of the present invention cited can in particular be used for the treatment of primary tumors and / or metastases, in particular in gastric, hepatic, renal, ovarian, colon, prostate, lung (NSCLC and SCLC) cancers, glioblastomas, thyroid, bladder, breast, melanoma, lymphoid or myeloid hematopoietic tumors, sarcomas, brain, larynx, lymphatic system, bone and pancreas.
• NSCLC and SCLC lung
• the subject of the present invention is also the use of the products of formula (I) as defined above for the preparation of medicaments intended for the chemotherapy of cancers.
• Such drugs for cancer chemotherapy may be used alone or in combination.
• the products of the present application can in particular be administered alone or in combination with chemotherapy or radiotherapy or in combination with other therapeutic agents, for example.
• Such therapeutic agents may be commonly used anti-tumor agents.
• kinase inhibitors there may be mentioned butyrolactone, flavopiridol and 2 (2-hydroxyethylamino) -6-benzylamino-9-methylpurine called olomucine.
• the subject of the present invention is also, as new industrial products, the synthetic intermediates of formulas E ', M1, M2, M3 and N as defined above and recalled hereinafter:
• the N- (6 - ⁇ [6- (cyclohexyloxy) [1,2,4] tetrazolo [4,3-b] pyridazin-3-yl] sulfanyl ⁇ -1,3-benzothiazol-2-yl) cyclopropanecarboxamide may be prepared in the following manner: at 2 cm 3 of pyridine at 20 0 C are added 75 mg of 6 - ⁇ [6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl ⁇ -1,3-Benzothiazol-2-amine and 20 ⁇ l of
• N- (6 - ⁇ [6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl ⁇ -1,3-benzothiazol-2-yl) acetamide may be prepared in the following manner: at 2 cm 3 of pyridine at 20 ° C. are added 0.276 cm 3 of acetic anhydride and 160 mg of 6 - ⁇ [6- (cyclohexyloxy) [1,2,4] thazolo [4,3-b] ] pyridazin-3-yl] sulfanyl ⁇ -1,3-benzothiazol-2-amine (1b).
• Phenyl (6 - ⁇ [6- (cyclohexyloxy) [1,2,4] tertzolo [4,3-b] pyridazin-3-yl] sulfanyl ⁇ -1,3-benzothiazol-2-yl) carbamate may be prepared as follows: to 200mg of 6 - ⁇ [6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl ⁇ -1,3-benzothiazol-2-amine (1b) in 5cm 3 of pyridine is added at 20 0 C, 0.13 cm 3 of phenyl chlorocarbonate.
• the reaction medium is stirred for 18 h at 20 ° C. and then the suspension is concentrated to dryness under reduced pressure.
• the oily brown residue obtained is taken up in 20 cm 3 of ethanol.
• the mixture is degassed by bubbling argon for 5 min at 20 ° C., then 5 mg of potassium dihydrogenphosphate are added in 0.2 cm 3 of water followed by 617 mg of DL-Dithiothreitol and 253 mg of 3-chloro-6- (cyclohexyloxy).
• [1,2,4] triazolo [4,3-b] pyhdazine (1c) After 23 hours under reflux, the red suspension is concentrated to dryness under reduced pressure.
• the residue is purified by dry deposition on Biotage Quad 25M (KP-SIL, 60, 32-63 ⁇ M) eluting with a gradient of 95: 5 to 85:15 of dichloromethane / (dichloromethane: 38 / methanol: 17 / aqueous ammonia: 2).
• the yellow solid obtained is washed with ether and with pentane. 218 mg of 6 - ⁇ [6- (cyclohexyloxy) [1,2,4] thazolo [4,3-b] pyridazin-3-yl] sulfanyl ⁇ -N- [2- (pyrrolidin-1-yl) are thus obtained.
• N- (6 - ⁇ [6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl ⁇ -1,3-benzothiazol-2-yl) -2- methoxyacetamide can be prepared in a manner similar to Example 1a but from 200 mg of 6 - ⁇ [6- (cyclohexyloxy) [1,2,4] thazolo [4,3-b] pyridazin-3-yl] sulfanyl ⁇ -1,3-benzothiazol-2-amine (1b) in 5cm 3 of pyridine with 0.165 cm 3 of methoxyacetyl chloride after 23h of reaction at 20 ° C.
• N- (6 - ⁇ [6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl ⁇ -1,3-benzothiazol-2-yl) -N 2 N 2 -dimethylglycinamide can be prepared in a manner similar to Example 1a, but from 100 mg of 6 - ⁇ [6- (cyclohexyloxy) [1,2,4] tetrazolo [4,3-b] pyridazin).
• N- (6 - ⁇ [6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl ⁇ -1,3-benzothiazol-2-yl) -3- methylbutanannide can be prepared in a manner similar to Example 1a but from 102 mg of 6 - ⁇ [6-
• N- (6 - ⁇ [6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl ⁇ -1,3-benzothiazol-2-yl) -3- methoxypropanamide can be prepared in a manner similar to Example 1a but from 146 mg of 6 - ⁇ [6- (cyclohexyloxy) [1,2,4] thazolo [4,3-b] pyridazin-3-yl] sulfanyl ⁇ -1,3-benzothiazol-2-amine (1b) in 5cm 3 of pyridine with 0.191 cm 3 of 3-methoxypropanoyl chloride after 23h of reaction at 20 ° C.
• 6 - ⁇ [6- (cyclopentyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl ⁇ -1,3-benzothiazol-2-amine a)
• the 6 - ⁇ [6 (cyclopentyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl ⁇ -1,3-benzothiazol-2-amine can be prepared in a manner similar to Example 1b but from 889 mg of 3-chloro-6-
• N- (6 - ⁇ [6- (cyclopentyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl ⁇ -1,3-benzothiazol-2-yl) cyclopropanecarboxamide may be prepared in a manner similar to Example 1a but from 300 mg of 6 - ⁇ [6- (cyclopentyloxy) [1,2,4] thazolo [4,3-b] pyridazin-3-yl] sulfanyl ⁇ - 1, 3-benzothiazol-2-amine (11a) in 5 cm 3 of pyridine with 0.140 cm 3 of cyclopropane carboxylic acid chloride after 3 hours of reaction at 20 ° C.
• N- (6 - ⁇ [6- (cyclopentyloxy) [1,2,4] tetrazolo [4,3-b] pyridazin-3-yl] sulfanyl ⁇ -1,3-benzothiazol-2-yl) acetamide may be prepared in a manner similar to Example 1a but from 250 mg of 6 - ⁇ [6- (cyclopentyloxy) [1,2,4] thazolo [4,3-b] pyridazin-3-yl] sulfanyl ⁇ - 1, 3-benzothiazol-2-amine 11a in 5 cm 3 of pyridine with 2.5 cm 3 of acetic anhydride after 48h of reaction at 20 0 C.
• 6 - ⁇ [6- (cycloheptyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl ⁇ -1,3-benzothiazol-2-amine can be prepared in a manner similar to Example 1b but starting from 249 mg of 3-chloro-6- (cycloheptyloxy) [1,2,4] triazolo [4,3-b] pyridazine (15b) in 5 cm 3 of degassed ethanol, 5 mg of potassium dihydrogenphosphate in 0.1 cm 3 of water, 432 mg of DL-dithiothreitol and 193 mg of 2-amino-1,3-benzothiazol-6-yl thiocyanate after 24 hours at 80 ° C. 260 mg is thus obtained from 6 - ⁇ [6-
• N- (6 - ⁇ [6- (cycloheptyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl ⁇ -1,3-benzothiazol-2-yl) acetamide may be prepared in a manner similar to Example 1a but from 85 mg of 6 - ⁇ [6- (cycloheptyloxy) [1,2,4] thazolo [4,3-b] pyridazin-3-yl] sulfanyl ⁇ - 1,3-benzothiazol-2-amine (16a) in 5 cm 3 of pyridine with 0.160 cm 3 of acetic anhydride after 24 hours of reaction at 20
• the N- (6 - ⁇ [6- (cyclohexylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl ⁇ -1,3-benzothiazol-2-yl) acetamide may be prepared in a manner similar to Example 1a but from 150 mg of 3 - [(2-amino-1,3-benzothiazol-6-yl) sulfanyl] -N-cyclohexyl [1,2,4] thazolo [4] , 3-b] pyridazin-6-amine in 1 cm 3 of pyridine with 0.5 cm 3 of acetic anhydride after 18h
• the resulting mixture is then stirred at 20 ° C. for 20 h and then extracted with 2x150 cm 3 of ethyl acetate.
• the organic phases are combined and then washed with 3X50 cm 3 of a saturated aqueous solution of sodium hydrogencarbonate.
• the organic phase obtained is dried over magnesium sulphate and then concentrated to dryness under reduced pressure. The residue is taken up in 50 cm 3 of water and then filtered off and dried under vacuum at 20 ° C.
• pyrimidazin-6-yl] amino ⁇ cyclohexyl may be prepared in a manner similar to Example 1a but from 300 mg of trans-4 - ( ⁇ 3 - [(2-amino-1,3-benzothiazol-6-yl) sulfanyl] [1,2,4] tetrazolo [4,3-b] pyridazin-6-yl ⁇ amino ) cyclohexanol in 2.1 cm 3 of pyridine with 0,133cm 3 of the chloride of cyclopropanecarboxylic acid after 18 hours of reaction at 20 0 C.
• N- (6 - ⁇ [6- (cyclohexylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl ⁇ -1,3-benzothiazol-2-yl) cyclopropanecarboxamide may be prepared in a manner similar to Example 1a but from 300 mg of 3 - [(2-amino-1,3-benzothiazol-6-yl) sulfanyl] -N-cyclohexyl [1,2,4] thazolo [ 4,3-b] pyridazin-6-amine (18b) in 2.1 cm 3 of pyridine with 3 0,14cm chloride of cyclopropanecarboxylic acid, after 18h of reaction at 20 0 C.
• N- [6 - ( ⁇ 6 - [(trans-4-hydroxycyclohexyl) amino] [1,2,4] triazolo [4,3-b] pyridazin-3-yl ⁇ sulfanyl) 1,3-Benzothiazol-2-yl] acetamide can be prepared as follows: to a solution of 114 mg of trans-4 - ( ⁇ 3 - [(2-amino-1,3-benzothiazol-6-yl) sulfanyl) ] [1,2,4] thazolo [4,3-b] pyridazin-6-yl ⁇ amino) cyclohexanol (20b) in 2 cm 3
• N- [6 - ( ⁇ 6 - [(trans-4-hydroxycyclohexyl) amino] [1,2,4] triazolo [4,3-b] pyridazin-3-yl ⁇ sulfanyl) -1,3-benzothiazole 2-yl] cyclopropanecarboxamide can be prepared in a manner similar to Example 1a but from 300 mg of trans-4 - ( ⁇ 3 - [(2-amino-1,3-benzothiazol-6-yl) sulfanyl] [1,2,4] triazolo [4,3-b] pyridazin-6-yl) amino) cyclohexanol (20b) in 3cm 3 of pyridine with 0.235cm 3 of cyclopropane carboxylic acid chloride, after 16h of reaction at 20 0 C.
• Example 25 N- (6 - ⁇ [6- (Cyclopropylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl ⁇ -1,3-benzothiazol-2-yl) acetamide
• the N- (6 - ⁇ [6- (cyclopropylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl ⁇ -1,3-benzothiazol-2-yl) acetamide may be prepared in a manner similar to Example 1a but from 300 mg of 3 - [(2-amino-1,3-benzothiazol-6-yl) sulfanyl] -N-cyclopropyl [1,2,4] triazolo [4] , 3-b] pyridazin-6-amine (24a) in 2.1 cm 3 of pyridine with 1. 04 cm 3 of acetic anhydr
• 1,3-benzothiazol-2-yl) cyclopropanecarboxamide a) N- (6 - ⁇ [6- (Cyclopropylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl ⁇ - 1,3-Benzothiazol-2-yl) cyclopropanecarboxamide may be prepared in a manner similar to Example 1a but from 300 mg of 3 - [(2-amino-1,3-benzothiazol-6-yl) sulfanyl] N-cyclopropyl [1,2,4] triazolo [4,3-b] py ⁇ dazin-6-amine (24a) in 3 cm 3 of pyridine with 0.16 cm 3 of cyclopropane carboxylic acid chloride, after 18 hours of reaction at 20 ° C.
• N- (6 - ⁇ [6- (cyclopropylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl ⁇ -1,3-benzothiazol-2-yl) -3-methoxypropanamide may be prepared in a manner similar to Example 1a but from 220 mg of 3 - [(2-amino-1,3-benzothiazol-6-yl) sulfanyl] -N-cyclopropyl [1,2,4] triazolo [4] , 3-b] py ⁇ dazin-6-amine (24a) in 7cm 3 of pyridine with 0.2 cm 3 of 3-methoxypropanoyl chloride after 18h of reaction at 20 ° C.
• Ethyl (6 - ⁇ [6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl ⁇ -1,3-benzothiazol-2-yl) carbamate can be prepared in the following way:
• MASS SPECTRUM Waters UPLC-SQD:
• N- (6 - ⁇ [6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl ⁇ -1,3-benzothiazol-2-yl) -N 2 -cyclopropylglycinamide can be prepared in the following manner: at 280mg of 2-chloro-N- (6 - ⁇ [6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3 - yl] sulfanyl ⁇ -1,3-benzothiazol-2-y
• 6 - ⁇ [6- (cyclobutyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl ⁇ -1,3-benzothiazol-2-amine a)
• the 6 - ⁇ [6 - (Cyclobutyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl ⁇ -1,3-benzothiazol-2-amine can be prepared in a manner similar to Example 1b but starting from 1.07 g of 2-amino-1,3-benzothiazol-6-yl thiocyanate, 15 cm 3 of degassed ethanol, 20 mg of potassium dihydrogenphosphate in 0.1 cm 3 of water, 1 g.
• N- (6 - ⁇ [6- (cyclobutyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl ⁇ -1, 3-Benzothiazol-2-yl) -2- (4-ethylpiperazin-1-yl) acetamide can be prepared in the following manner: a mixture of 273 mg of (4-ethylpiperazin-1-yl) acetic acid (commercial), 0.28cm 3 of diisopropyl ethylamine and 411 mg of O- (7-azabenzotriazol-1-yl) -N,
• N 2 -dialylglycinamide can be prepared in the following manner: a mixture of 827 mg of sodium (diethylamino) acetate (commercial) in 5.5 cm 3 of a 2N solution of hydrogen chloride in the The ether is stirred for 1 h at 20 ° C.
• the residue is taken up in water and the mixture is extracted with ethyl acetate and then evaporated to dryness.
• the residue is purified by dry deposition on silica and chromatographed on Biotage Quad 12/25 (KP-SIL, 6OA, 32-63 ⁇ M), eluting with a dichloromethane / methanol gradient of 100/0 to 98/2.
• MASS SPECTRUM Waters UPLC-SQD:
• racemic pyhdazine can be prepared in a manner similar to that described in Example 1c but from 0.628 g of a 1/1 mixture of racemic cis- and trans-3-methylcyclohexanol in solution in 6 cm 3 tetrahydrofuran under an argon stream to which is added at a temperature of 0 0 C, 0.220 g of 60% sodium hydride in the oil.
• the reaction medium is maintained at a temperature in the region of 0 ° C. for 15 minutes and then 0.650 g of 3,6-dichloro [1,2,4] thazolo [4,3-b] pyridazine is added.
• 10 cm 3 of a saturated aqueous ammonium chloride solution and 20 cm 3 of ethyl acetate are added.
• the organic phase is washed successively with 2 times 10 cm 3 of distilled water and 15 cm 3 of a saturated solution of sodium chloride and is then dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure.
• N- (6-sulfanyl-1,3-benzothiazol-2-yl) cyclopropanecarboxamide can be prepared in a manner similar to that described in Example 2b but from 14.0 g of 2 - [(cyclopropylcarbonyl) thiocyanate ) amino] -1,3-benzothiazol-6-yl, 22.44 g of DL-dithiothreitol, a solution of 0.235 g of potassium dihydrogenphosphate in 60 cm 3 of distilled water and 450 cm 3 of ethanol.
• the solid formed is filtered on a VF3 filter and then washed with 5 times 70 cm 3 of ice water before drying in an oven under reduced pressure (2.7 kPa) at 40 ° C. for 10 h to give 19 g of 2 - [( cyclopropylcarbonyl) amino] -1,3-benzothiazol-6-yl as a pink solid whose characteristics are as follows:
• N- (6 - ⁇ [6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl ⁇ -1,3-benzothiazol-2-yl) -3- (Piperidin-1-yl) azetidine-1-carboxamide can be prepared in a manner similar to Example 5 but from 185 mg of (6 - ⁇ [6- (cyclohexyloxy) [1,2,4] thazolo [ Phenyl 4,3-b] pyridazin-3-yl] sulfanyl ⁇ -1,3-benzothiazol-2-yl) carbamate (4) in 10cm 3 of THF and 10cm 3 of DMF with 75mg of 1 - (azetidin) dihydrochloride.
• MASS SPECTRUM Electron emission on WATERS UPLC - SQD: [M + H] +: m / z 565; [M-H] -: m / z 563.
• N- (6 - ⁇ [6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl ⁇ -1,3-benzothiazol-2-yl) -2- oxa-6-azaspiro [3.3] heptane-6-carboxamide can be prepared in a manner similar to that described in Example 5 but from 150 mg of (6 - ⁇ [6- (cyclohexyloxy) [1, 2, 4] thazolo [4,3-b] pyridazin-3-yl] sulfanyl ⁇ -1,3-benzothiazol-2-yl) phenyl carbamate (4), 65 mg of mono oxalate of 2-oxa-6-aza-spiro [3.3] heptane, 0.144 cm 3 of triethylamine and 10 cm 3 of tetrahydrofuran. After stirring for 15 hours at a temperature in the
• oxalate monooxalate of 2-oxa-6-aza-spiro [3.3] heptane can be prepared as described by Georg Wunschik, Mark Rogers-Evans, Andreas Buckl, Maurizio
• N- (6 - ⁇ [6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl ⁇ -1,3-benzothiazol-2-yl) -3- (morpholin-4-yl) azetidine-1-carboxamide can be prepared in a manner similar to Example 5 but from 182 mg of (6- ⁇ [6- (cyclohexyloxy) [1,2,4] triazolo [ Phenyl 4,3-b] pyridazin-3-yl] sulfanyl ⁇ -1,3-benzothiazol-2-yl) carbamate (4) in 10cm 3 THF, 106mg 4- (azetidin-3-yl) dihydrochloride ) morpholine and 0.167 cm 3 of triethylamine, after 22 hours of reaction at 20 ° C.
• N- (6 - ⁇ [6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyhdazin-3-yl] sulfanyl ⁇ -1,3-benzothiazol-2-yl) -3- methoxyazetidine-1-carboxamide can be prepared in a manner similar to Example 5 but from 192 mg of (6 - ⁇ [6- (cyclohexyloxy) [1,2,4] thazolo [4,3-b] pyridazine Phenyl-3-yl] sulfanyl ⁇ -1,3-benzothiazol-2-yl) carbamate (4) in 5 cm 3 of dimethylformamide, 69 mg of 3-methoxyazetidine hydrochloride and 0.078 cm 3 of the methylamine after 20 hours of reaction with 20 0 C.
• MASS SPECTRUM Electron-ray on WATERS UPLC - SQD: [M + H] +: m / z 498; [M-H] -: m / z 496.
• Example 78 Pharmaceutical composition Tablets having the following formula were prepared:
• Examples 1 and 4 are taken as examples of a pharmaceutical preparation, this preparation can be carried out if desired with other products as examples in the present application.
• Recombinant His-Tev-MET (956-1390) DNA in pFastBac (Invitrogen) is transfected into insect cells and after several viral amplification steps, the final baculovirus stock is tested for protein expression. interest.
• the SF21 cell cultures are harvested by centrifugation and the cell pellets are stored at -80 ° C. Purification:
• the cell pellets are resuspended in lysis buffer (buffer A [50 mM HEPES, pH 7.5, 250 mM NaCl, 10% glycerol, 1 mM TECP] + Roche Diagnostics protease inhibitor cocktail without EDTA, ref. 1873580), stirred at 4 ° C. until homogeneous, then mechanically lysed using a "Dounce" type apparatus.
• buffer A 50 mM HEPES, pH 7.5, 250 mM NaCl, 10% glycerol, 1 mM TECP] + Roche Diagnostics protease inhibitor cocktail without EDTA, ref. 1873580
• the lysing supernatant is incubated for 2 hours at 4 ° C with Nickel Chelate resin (His-Trap 6 Fast Flow TM, GE HealthCare). After washing with 20 volumes of Tp A, the suspension is packaged in a column, and the proteins are eluted by a gradient of buffer B (TpA + 290 mM imidazole).
• the fractions containing the protein of interest in view of the electrophoretic analysis are pooled, concentrated by Ultrafiltration (cut-off 1 OkDa) and injected on an exclusion chromatography column (Superdex TM 200, GE HealthCare). balanced in buffer A. After enzymatic cleavage of the Histidine tag, the protein is reinjected onto a new IMAC Nickel Chelate chromatography column (His-Trap 6 Fast Flow TM, GE HealthCare) equilibrated in Buffer A. The fractions eluted by a buffer B gradient and containing the protein after electrophoresis (SDS PAGE), are finally collected and stored at -80 ° C.
• the preceding fractions are incubated for 1 h at room temperature after addition of 2 mM ATP, 2 mM MgCl 2, and Na 3 VO 4. 4 mM.
• the reaction mixture is injected onto a HiPrep desalting column (GE HealthCare) previously equilibrated with 4mM A + Na3VO4 buffer, the fractions containing the protein of interest (SDS PAGE analysis) are pooled. and stored at -80 ° C.
• the phosphorylation level is verified by mass spectrometry (LC-MS), and by peptide mapping.
• Test A HTRF MET assay in 96-well format
• final 5 nM MET is incubated in the presence of the test molecule (for a final concentration range of 0.17 nM to 10 ⁇ M, final DMSO 3%) in MOPS 1 OmM buffer pH 7.4, DTT 1 mM, Tween 20 0.01%.
• the reaction is initiated by the substrate solution to obtain the final concentrations of poly- (GAT) 1 ⁇ g / ml, 10 ⁇ M ATP and 5mM MgCl 2.
• the reaction is stopped by a 30 ⁇ l mix to obtain a final solution of 50 mM Hepes pH 7.5, 50 mM potassium fluoride, 0.1% BSA and 133 mM EDTA in the presence of 80 ng Streptavidin. 61 SAXLB Cis-Bio Int. and 18ng anti-Phosphotyrosine Mab PT66-Europium Cryptate per well. After 2 hours incubation at room temperature, the reading is made at 2 wavelengths 620 nm and 665 nm on a reader for the TRACE / HTRF technique and the% inhibition is calculated according to the 665/620 ratios.
• Test B Inhibition of MET autophosphorylation; ELISA technique (pppY1230,1234,1235) a) Cell lysates: Inoculate MKN45 cells in 96-well plate (CeII coat BD polylysine) at 20,000 cells / well under 200 ⁇ l in RPMI medium + 10% FCS + 1% L-glutamine. Allow 24 hours to adhere to the incubator.
• the cells are treated the day after seeding with the products at 6 concentrations in duplicate for 1 h. At least 3 control wells are treated with the same amount of final DMSO.
• Lysis buffer 1 OmM Tris, pH 7.4 HCl, 10 mM NaCl, 1 mM EDTA, 1 mM EGTA, 1% Triton X- 100, 10% glycerol, 0.1% SDS, 0.5% deoxycholate, 20mM NaF, 2mM Na3VO4, 1mM PMSF and anti protease cocktail.
• kit plate In each well of the kit plate, add 70 ⁇ l of kit dilution buffer + 30 ⁇ l of cell lysate or 30 ⁇ l of lysis buffer for the blanks. Incubate for 2h with gentle shaking at room temperature.
• kit wash buffer Incubate with 10 ⁇ l of anti-phospho MET antibody for 1h at room temperature.
• kit wash buffer Put 100 ⁇ L of chromogen and incubate 30minutes in the dark at room temperature.
• Test C Measurement of Cell Proliferation Using 14C-Thymidine
• the cells are seeded in 96-well Cytostar plates at 180 ⁇ l for 4 hours at 37 ° C. and 5% CO 2: HCT116 cells at a rate of 2500 cells per well in DMEM medium + 10% fetal calf serum + 1% L Glutamine and MKN45 cells at the rate of 7500 cells per well in RPMI medium + 10% fetal calf serum + 1% L-Glutamine.
• HCT116 cells at a rate of 2500 cells per well in DMEM medium + 10% fetal calf serum + 1% L Glutamine
• MKN45 cells at the rate of 7500 cells per well in RPMI medium + 10% fetal calf serum + 1% L-Glutamine.
• the products are added under 10 ⁇ l in 20-fold concentrated solution according to the dilution method mentioned for the ELISA.
• the products are tested at 10 concentrations in duplicate from 1000OnM to 0.3nM with a pitch of 3.
• results obtained by this test B for the products of formula (I) as examples in the experimental part are such that IC50 less than 10 microM and in particular to i microM.
• results obtained for the exemplary products in the experimental part are given in the table of pharmacological results below, as follows: for test A, the sign + corresponds to less than 50 nm and the sign ++ corresponds to less than 100 nm. . for test B the sign + corresponds to less than 50OnM and the sign ++ corresponds to less than 10OnM. for the C test the + sign corresponds to less than 10 microM and the sign ++ corresponds to less than I microM.
• Ra represents a radical -O-cycloalkyl, or a radical -NH-cycloalkyl all optionally substituted
• X represents S, SO or SO2;
• A represents NH or S;
• W represents a hydrogen atom; an alkyl radical optionally substituted with alkoxy, heterocycloalkyl or NR3R4; or the radical COR in which R represents:
• a cycloalkyl radical or an alkyl radical, optionally substituted by a halogen atom or a cycloalkyl, NR3R4, alkoxy, hydroxy, phenyl, heteroaryl or heterocycloalkyl radical, themselves optionally substituted;
• R1 and R2 are such that one of R1 and R2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical and the other of R1 and R2 represents a hydrogen atom,

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