EP2393793A1 - Derives de 6-(6-substitue-triazolopyridazine-sulfanyl) 5-fluoro-benzothiazoles et 5-fluoro-benzimidazoles : preparation, application comme medicaments et utilisation comme inhibiteurs de met - Google Patents
Derives de 6-(6-substitue-triazolopyridazine-sulfanyl) 5-fluoro-benzothiazoles et 5-fluoro-benzimidazoles : preparation, application comme medicaments et utilisation comme inhibiteurs de metInfo
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- EP2393793A1 EP2393793A1 EP10708280A EP10708280A EP2393793A1 EP 2393793 A1 EP2393793 A1 EP 2393793A1 EP 10708280 A EP10708280 A EP 10708280A EP 10708280 A EP10708280 A EP 10708280A EP 2393793 A1 EP2393793 A1 EP 2393793A1
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- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
- C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
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- C07D403/02—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
- 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
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Definitions
- the present invention relates to novel 6- (6-substituted-triazolopyridazin-sulfanyl) 5-fluoro-benzothiazole and 5-fluorobenzimidazole derivatives, process for their preparation, novel intermediates obtained, their use as medicaments, compositions containing them and the new use of such 6- (6-substituted-triazolopyhdazine-sulfanyl) 5-fluoro-benzothiazoles and 5-fluorobenzimidazoles derivatives.
- the present invention relates more particularly to novel derivatives of 6- (6-substituted-triazolopyhdazine-sulfanyl) 5-fluoro-benzothiazoles and 5-fluorobenzimidazoles exhibiting anticancer activity, via the modulation of the activity of proteins, in particular proteins. kinases.
- Protein kinase is a family of enzymes that catalyze the phosphorylation of hydroxyl groups of specific protein residues such as tyrosine, serine or threonine residues.
- 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.
- some processes represent attractive targets for treating certain diseases. Examples include angiogenesis and cell cycle control as well as cell proliferation, in which protein kinases can play a critical role.
- inhibitory molecules of such kinases are able to limit unwanted cell proliferations such as those observed in cancers, and may intervene in the prevention, control and treatment of cancer. regulation or treatment of neurodegenerative diseases such as Alzheimer's disease or neuronal apoptosis.
- 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.
- the products of the present application thus inhibit, in particular, the autophosphorylation activity of MET and the proliferation of cells whose growth depends on MET. or its mutant forms.
- MET or Hepatocyte Growth Factor Receptor, is a receptor with tyrosine kinase activity expressed in particular by epithelial and endothelial cells.
- HGF Hepatocyte Growth Factor
- 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 new inhibitors of the MET protein kinase and its mutants, which can be used for 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 hydrogen atom; a halogen atom; an alkoxy radical optionally substituted with a chlorine atom, a hydroxyl radical or a heterocycloalkyl radical which is itself optionally substituted; a radical -O-cycloalkyl, -O-heterocycloalkyl; -NH-cycloalkyl and -NH- heterocycloalkyl all optionally substituted; an optionally substituted heteroaryl radical; an optionally substituted phenyl radical; an NHCOalkyl or NHCOcycloalkyl radical; or an NR1 radical R2 as defined below;
- X is S, SO or SO 2
- A is NH or S
- W represents a hydrogen atom; an alkyl, cycloalkyl or heterocycloalkyl radical optionally substituted with alkoxy, heterocycloalkyl or NR3R4; or the radical COR in which R represents:
- R1 and R2 are such that one of R1 and R2 represents a hydrogen atom or an alkyl radical and the other of R1 and R2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical optionally substituted by 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 chosen 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 a phenyl radical, all optionally substituted with one or more identical or different radicals chosen from hydroxyl
- F represents a fluorine atom.
- the present invention relates in particular to the products of formula (I) in which Ra represents a hydrogen atom; a halogen atom; an alkoxy radical optionally substituted with a heterocycloalkyl radical which is itself optionally substituted; an optionally substituted heteroaryl radical; an optionally substituted phenyl radical; an optionally substituted cycloalkyl radical; O-heterocycloalkyl optionally substituted; -NH-cycloalkyl optionally substituted; -NH-heterocycloalkyl optionally substituted; an -NHCOalkyl or -NHCOcycloalkyl radical; or a radical NR1 R2 as defined above or hereinafter. the other substituents of said products of formula (I) having any of the meanings indicated above or below.
- Ra represents an alkoxy radical optionally substituted with a chlorine atom, a hydroxyl radical or a heterocycloalkyl radical which is itself optionally substituted; a -O-cycloalkyl radical; a radical -NHCOaIk; or a radical -NR 1 aR 2 a; as R1a and R2a represents a hydrogen atom, a cycloalkyl radical or an alkyl radical optionally substituted with one or more identical or different radicals chosen from radicals hydroxyl, alkoxy, heteroaryl, heterocycloalkyl, NR3R4 and optionally substituted phenyl; and W represents a hydrogen atom; an alkyl radical optionally substituted with alkoxy, heterocycloalkyl or NR3R4; or the radical COR in which R represents:
- alkoxy radical optionally substituted by NR 3 R 4, alkoxy, hydroxy or by heterocycloalkyl; an O-phenyl radical or a radical
- R1 and R2 are such that one of R1 and R2 represents a hydrogen atom or an alkyl radical and the other of R1 and R2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical optionally substituted by 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 chosen 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 a phenyl radical, all optionally substituted with one or more identical or different radicals chosen from hydroxyl
- Ra represents an alkoxy radical optionally substituted with a heterocycloalkyl radical which is itself optionally substituted; an NHCOaIk radical or an NR1 aR2a radical; such that R1a and R2a 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 and optionally substituted phenyl radicals; and W represents a hydrogen atom; an alkyl radical optionally substituted with alkoxy, heterocycloalkyl or NR3R4; or the radical COR in which R represents:
- R1 and R2 are such that one of R1 and R2 represents a hydrogen atom or an alkyl radical and the other of R1 and R2 represents a hydrogen atom, or an alkyl radical; optionally substituted by one or more identical or different radicals selected from hydroxyl, alkoxy, heteroaryl, heterocycloalkyl, NR3R4, optionally substituted phenyl or R1 and R2 together with the nitrogen atom to which they are attached form a cyclic radical containing from 3 to 10-membered ring 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 R3 and R4, which may be identical or different, represent a hydrogen atom, an alkyl radical, a cycloalkyl radical, a heteroaryl radical or a phenyl radical, all optionally substituted with one or more identical or different radicals chosen from hydroxyl and alkoxy radicals;
- this radical including the optional NH it contains being optionally substituted; all the radicals defined above heterocycloalkyl, heteroaryl and phenyl as well as the cyclic radicals that can form R1 and R2 or R3 and R4 with the nitrogen atom to which they are attached, being optionally substituted by one or more radicals chosen from halogen atoms, hydroxyl, oxo, alkoxy, NH 2, NHaIk, N (alk) 2 radicals and alkyl, cycloalkyl, heterocycloalkyl, CH 2 -heterocycloalkyl, phenyl, CH 2 -phenyl, heteroaryl, CO-phenyl and S-heteroaryl radicals; , such that, in the latter radicals, the alkyl, heterocycloalkyl, phenyl and heteroaryl radicals are themselves optionally substituted by one or more radicals chosen from halogen atoms and hydroxyl,
- Ra represents a hydrogen atom; a halogen atom; an alkoxy radical optionally substituted with a heterocycloalkyl radical which is itself optionally substituted; an optionally substituted heteroaryl radical; an optionally substituted phenyl radical; an NHCOalkyl or NHCOcycloalkyl radical; or an NR1 radical R2 as defined below;
- 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 an NR 3 R 4, alkoxy, hydroxy, phenyl, heteroaryl or heterocycloalkyl radical, themselves optionally substituted;
- alkoxy radical optionally substituted by NR 3 R 4, alkoxy, hydroxy or by heterocycloalkyl; an O-phenyl radical or a radical
- R1 and R2 are such that one of R1 and R2 represents a hydrogen atom or an alkyl radical and the other of R1 and R2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical optionally substituted by 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, identical or different , represent a hydrogen atom, an alkyl radical, a cycloalkyl radical, a heterocycloalkyl radical, a heteroaryl radical or a phenyl radical, all optionally substituted with one or more radicals
- products of formula (I) being in all possible isomeric forms racemic, 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).
- the present invention which therefore relates to the products of formula (I) as defined above in which represents a single or double bond, therefore relates precisely to the products of formula (I 1 ) which represent the products of formula (I) in which zzz ⁇ represents a single bond and the products of formula (I ") which represent the products of formula (I) in which represents a double bond, thus all the products of formula (I) as defined above or below. especially represent products of formula (T) in which represents a single bond.
- the present invention relates to the products of formula (I) as defined above or below in which zzz ⁇ , Ra and X have the values defined above or below and:
- A represents NH or S
- W represents a hydrogen atom; an alkyl radical optionally substituted by alkoxy or heterocycloalkyl; 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 NR 3 R 4 or by alkoxy, or else R 1 and R 2 form, with the nitrogen atom to which they are bonded, a cyclic radical containing from 3 to 10 ring 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 selected from O, S, N and NH, this radical including the optional NH it contains
- the subject of the present invention is therefore the products of formula (I) as defined above in which zz ⁇ , Ra, X, A and W have any of the values defined above or below, and the radical NR1 R2 is such that one of R1 and R2 represents a hydrogen atom or an alkyl radical and the other of R1 and R2 represents a hydrogen atom or an alkyl radical optionally substituted by NR3R4 or by alkoxy, or R1 and R2 together with the nitrogen atom to which they are bonded 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 1 any NH it contains being optionally substituted; all other substituents having the definitions indicated above; 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).
- Ra represents a hydrogen atom or a halogen atom or an optionally substituted phenyl radical
- X is S, SO or SO2 A is NH or S; W represents a hydrogen atom or the COR radical in which R represents:
- O- (CH2) n-NR3R4 an O-phenyl radical or an O- (CH 2) n-phenyl radical with optionally substituted phenyl and n represents an integer of 1 to 4;
- R1 and R2 are such that one of R1 and R2 represents a hydrogen atom or an alkyl radical and the other of
- R1 and R2 represents 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 form with the atom nitrogen to which they are attached 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 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 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; all the radicals defined above heterocyclo
- A represents NH or S
- W represents a hydrogen atom or an alkyl radical or the COR radical in which R represents:
- alkyl radical optionally substituted with OCH 3 or NR 3 R 4; a cycloalkyl radical
- 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 an optionally alkyl radical; substituted by NR3R4, or R1 and R2 together with the nitrogen atom to which they are attached form a cyclic radical optionally containing one or more other heteroatoms chosen from O, S, N and NH, this radical including the any NH that 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 or more other heteroatoms chosen (s) from O, S, N and NH, this radical including the optional NH it contains being optionally substituted; the phenyl radicals as well as the cyclic radicals that can be formed by
- A represents NH or S
- W represents a hydrogen atom or the COR radical in which R represents: an alkyl radical optionally substituted with NR3R4; an alkoxy radical optionally substituted with NR 3 R 4, ie an O- (CH 2) n -NR 3 R 4 radical, an O-phenyl or O- (CH 2) n -phenyl radical, with optionally substituted phenyl and n represents an integer of 1 to 2; or the radical NR1 R2, wherein R1 and R2 are such that one of R1 and
- R2 represents a hydrogen atom or an alkyl radical and the other of R1 and R2 represents an alkyl radical optionally substituted with 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 selected 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 or more other heteroatoms chosen (s) from O, S, N and NH, this radical including the optional NH it contains being optionally substituted; the 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
- Rb represents a halogen atom or an S-heteroaryl radical optionally substituted by a radical chosen from halogen atoms and hydroxyl, alkyl and alkoxy radicals containing from 1 to 4 carbon atoms, NH2, NHaIk and N (alk ) 2, said products of formula (I) being in all the possible isomeric forms racemic, enantiomers and diastereoisomers, as well as the addition salts with mineral and organic acids or with the inorganic and organic bases of said products of formula (I) .
- 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; In the products of formula (I) and in the following:
- 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 as well as their linear or branched positional isomers: alkyl radicals containing from 1 to 6 carbon atoms and more particularly the alkyl radicals containing from 1 to 4 carbon atoms of the above list are preferred.
- 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: alkoxy radicals containing 1 to 4 carbon atoms from the above list; the term “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, cyclopentyl and cyclohexyl 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, oxodihydropyridazinyl, or oxetanyl or thietanyl radicals, all of which radicals are optionally substituted; it may be noted that these heterocycloalkyl radicals may comprise a bridge formed from two links to form, for example, an oxa-5-azabicyclo [
- 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, pyranyl, pyrrolyl, pyrrolinyl, pyrazolinyl, imidazolyl, pyrazolyl, pyridyl such as 2-pyhdyl, 3-pyhdyl and 4-pyhdyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl, isothiazolyl, diazolyl, thiadiazolyl, thiatriazolyl, oxadiazolyl, isoxazolyl such as 3- or 4-isoxazolyl, furazannyl, free or salt tetrazoly
- 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, for example, in chloromethyl, hydroxypropyl, methoxymethyl, propionyloxymethyl, methylthiomethyl, dimethylaminoethyl, benzyl or phenethyl groups.
- 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
- the addition salts with the mineral or organic acids of the products of formula (I) may be, for example, the salts formed with the hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, propionic, acetic, trifluoroacetic, formic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, ascorbic acids, alkylmonosulphonic acids such as, for example, methanesulfonic acid, ethanesulphonic acid, propanesulphonic acid, alkylsulphonic acids such as, for example, methanedisulphonic acid, alpha, beta-ethanedisulphonic acid, arylmonosulphonic acids such as benzenesulphonic acid and aryldisulphonic acids.
- 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 chosen from halogen atoms, hydroxyl, oxo, alkoxy and 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 by one or more radicals chosen from halogen atoms and hydroxyl, oxo, alkyl and alkoxy radicals containing from 1 to 4 carbon atoms,
- 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.
- NR 1 R 2 or NR 3 R 4 forms a ring as defined above
- such an amine ring may be chosen in particular from pyrrolidinyl, pyrazolidinyl, pyrazolinyl, piperidyl, azepinyl, morpholino or piperazinyl radicals, these radicals themselves being optionally substituted as indicated above.
- the NR 1 R 2 or NR 3 R 4 ring may more particularly be chosen from pyrrolidinyl and morpholino radicals optionally substituted by one or two alkyl or piperazinyl radicals optionally substituted on the second nitrogen atom by an alkyl, phenyl or or CH 2 -phenyl radical, -Same optionally substituted with one or more identical or different radicals selected from halogen atoms and alkyl, hydroxyl and alkoxy radicals.
- the subject of the present invention is in particular the products of formula (I) in which A represents NH, the substituents Ra, X and W being chosen from all the values defined for these radicals above or below, said products of formula ( I) being in all isomeric forms possible racemic, 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).
- the subject of the present invention is in particular the products of formula (I) in which A represents S, the substituents Ra, X and W being chosen from all the values defined for these radicals above or below, said products of formula ( I) being in all isomeric forms possible racemic, 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).
- the present invention relates to the products of formula (I) corresponding to formula (Ia) or (Ib):
- Ra and W are selected from any of the meanings given above or below, said products of formula (Ia) and (Ib) 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 (la ) and (Ib).
- the present invention therefore particularly relates to products of formula
- the present invention therefore particularly relates to products of formula
- the present invention therefore particularly relates to products of formula
- Ra and W are selected from any of the meanings given above or hereafter, 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).
- the present invention therefore particularly relates to products of formula
- Ra and W are selected from any of the meanings given above or hereafter, said products of formula (I “a) being in any isomeric possible 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 present invention therefore particularly relates to products of formula
- Ra and W are selected from any of the meanings indicated above or hereafter, 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).
- the present invention therefore particularly relates to products of formula
- Ra represents the radical:
- Rb is in particular in para position.
- Rb defined above represents a halogen atom
- Rb especially represents fluorine
- 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, 2bis, 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 subject of the present invention is therefore also the process for preparing products of formula (I) according to Scheme 4 as defined below.
- the subject of the present invention is therefore also the process for the preparation of products of formula (I) according to schema 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 zzz ⁇ represents a single or double bond, the compounds of formulas (a 1 ), (b 1 ), (c 1 ), (d 1 ), (e 1 ) and (f) in which zzz ⁇ represents a single bond, and compounds of formulas (a "), (b"), (c “), (d"), (e ") and (f) wherein - represents a double bond.
- COR6 and COR7 which constitute W, can take the values of W as defined above for the products of formula (I 1 ) and (I "), when W ⁇ H
- the benzimidazoles of the general formula (1a “), (1b"), (1c “), (1d") and (1e ") and their reduced analogues of the general formula ( 1a 1 ), (1b 1 ), (1c '), (1cT) and (1e 1 ) can be prepared from 3,6-dichloro [1,2,4] triazolo [4,3- b] Commercial pyridazine of formula (S).
- the compounds (G) can be obtained, for example, by reaction of 2-fluoro-4-nitro-5-amino-benzenethiol of formula (F) with the compounds of formula (E).
- the compound of formula (F) can be obtained by introducing the thiol function on the 2-nitro-4,5-difluoroaniline derivative (Q) (commercial compound), for example, in the presence of potassium thioacetate 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) of compounds of formula (G), in a solvent such as methanol, in the presence of acetic acid, with a temperature close to 70 ° C.
- the compounds (H ') as represent a single bond can be obtained, for example, by reduction with zinc (0) compounds of formula (G), in the presence of acetic acid, at a temperature in the region of 20 ° C.
- the carbamates of general formula (1 to 1 ) and (1a ") can be prepared in particular as described in patent WO03028721A2, but from respectively a 2-fluoro-4,5-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 to 1 ) 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.
- the carboxamides (1 ') and (1 e ") can be obtained respectively from the amines of general formula (1c') and (1c")
- the substituent Ra has the meanings given above for the products of formula (I 1 ) and (I ") and the groups CONR 1 R 2, COR 6 and COR 7, which constitute W, can take the values of W as defined above for the products of formula (I 1 ) and (I "), when W ⁇ H.
- yl (K) in a solvent such as tetrahydrofuran, in the presence of a base such as sodium hydrogencarbonate, at a temperature in the region of 20 ° C.
- the carboxamides (L3) can be obtained by acylation of the amine (K)
- the carboxamides (2c ') and (2c ") can be obtained respectively from the amines (2d') and (2d" ).
- 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.degree. C at 20 ° C.
- a base such as pyridine, triethylamine or N-methylmorpholine
- dichloromethane a solvent
- the alpha-chloroacetamides (2e '/ 2e ") thus formed can react with amines of HNR3R4 type, as defined above, in a solvent such as pyridine at a temperature in the region of 20 ° C. to give the derivatives (2c '/ 2c ") 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-dimethylformanide, in the presence of a base such as thylamine and at a temperature in the region of 95 ° C or between 20 ° C and 95 ° C, or, alternatively, for example 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.
- a chlorocarbonate of formula (O) (X Cl)
- benzothiazoles of general formula (2a "), (2b"), (2c ") and (2d") as well as their reduced analogues of general formula (2a '), (2b'), (2c ') and (2d ') can be prepared for example: 1) by coupling a compound of formula (E) with derivatives (M1),
- the substituents Ra, R 1 and R 2 have the meanings indicated above for the products of formula (I 1 ) and (I ").
- the substituent R 7 represents an alkyl or cycloalkyl radical. represent : or an alkyl radical optionally substituted with a chlorine atom, a hydroxyl radical or a heterocycloalkyl radical which is itself optionally substituted,
- 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 temperature close to 80 0 C and in a solvent such as N, N-dimethylformamide with an alkoxide of formula (U), itself obtained by treatment of the corresponding alcohol with a base such as sodium hydride at a similar temperature 0 0 C to 20 0 C.
- the compounds of formula (E) wherein Ra represents a radical NRiR 2 can be obtained by the treatment of 3,6-dichloro [1,2,4] thazolo [4,3-b] pyhdazine (S) with an amine of formula (R), at a temperature of 20 ° C and in a solvent such as N 1 N -dimethylformamide or, in the case NR1 R2 is NH2, with aqueous ammonia, in a solvent such as dioxane in a sealed tube at a temperature between 70 0 C and 90 ° C.
- 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, cycloalkyl or heterocycloalkyl radical optionally substituted by 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 compounds (T) and (T") isolated, for example, with trifluoroacetic acid, in a solvent such as dichloromethane, at a temperature of 20 0 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 sodium dihydrogen carbonate, in a solvent such as ethanol and at a temperature in the region of 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 between 20 and 90 ° C.
- the benzothiazoles of the 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 R 9 substituent represents an alkyl or cycloalkyl radical optionally substituted with an alkoxy, heterocycloalkyl or NR3R4 radical (R3 and R4 as defined above).
- the compounds of formulas (L5) can be prepared from 2-amino-5-fluoro-1,3-benzothiazol-6-yl thiocyanate (K), 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 (I 1 ) can also be prepared from the compounds of formula (I ") by reduction, for example with sodium borohydride, in a solvent such as ethanol, at a temperature in the region of 80 ° C. or by reduction with zinc (0) in the presence of acetic acid, at a temperature in the region of 20 ° C.
- the compounds (V) 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 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 of 20 ° C.
- the compounds (I ') can also be prepared from other compounds (I') 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: the transformations of 2d '/ 2d "into 2a' / 2a" and into 2c '/ 2c ", the transformations from 2a' / 2a" into 2d '/ 2d "and into 2b' / 2b".
- the sulfur S can be oxidized to SO 2 or SO 2 sulfone by methods known to those skilled in the art and, if necessary, protecting the optionally reactive groups with the appropriate protecting groups.
- B, D, J, K, O, P, P ', Q, R, S, U, V, W are known and can be obtained either commercially or according to the usual known methods. those skilled in the art, for example from commercial products.
- hydroxyl groups may be protected, for example, by alkyl radicals such as tert-butyl, thmethylsilyl, tert-butyldimethylsilyl, methoxymethyl, tetrahydropyranyl, benzyl or acetyl,
- 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.
- 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 alkoxy functions, such as in particular methoxy, 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.
- the products of formula (I) as defined above and their addition salts with acids have interesting pharmacological properties, in particular because of their kinase inhibiting properties as indicated above.
- 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 of formula (I) as defined above, corresponding to the following formulas: 1- (6 - ⁇ [6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl ⁇ -5-fluoro-1,3-benzothiazol-2-yl ) -3- [2- (morpholin-4-yl) ethyl] urea
- 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, if appropriate, contain active principles of other antimitotic drugs such as in particular those based on taxol, cisplatin, intercalating agents of DNA and others.
- These pharmaceutical 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.
- Such 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 the proliferation of blood vessels, disorders fibrotic disorders, mesangial cell proliferation disorders, metabolic disorders, allergies, asthma, thrombosis, diseases of the nervous system, 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 cancers
- glioblastomas thyroid, bladder, breast, melanoma
- lymphoid or myeloid hematopoietic tumors sarcomas
- brain larynx
- lymphatic system bone and pancreas.
- 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-methylpuhne called olomucine.
- the subject of the present invention is also, as new industrial products, the synthetic intermediates of formulas M1, M2, M3 and N as defined above and recalled hereinafter:
- N, N "- [disulfanediylbis (5-fluoro-1,3-benzothiazole-6,2-diyl)] bis ⁇ 3- [2- (morpholin-4-yl) ethyl] urea ⁇ can be prepared in the following manner: to 322 mg of phenyl (5-fluoro-6-thiocyanato-1,3-benzothiazol-2-yl) carbamate in 10 cm 3 of tetrahydrofuran at 20 ° C., 0.24 cm 3 is added of 2- (morpholin-1-yl) ethanamine and 0.39 cm 3 of triethylamine The reaction medium is heated at 60 ° C.
- the brown suspension is stirred for 22 h while gradually returning to 20 ° C.
- the reaction mixture is poured into ice water and the mixture is extracted with ethyl acetate. After concentrating the organic phase to dryness under vacuum, a brown oil is obtained.
- the oily residue is chromatographed on Biotage Quad 12/25 (KP-SIL, 60A, 32-63 ⁇ M) eluting with a cyclohexane / ethyl acetate gradient of 95/5 to 65/35.
- reaction mixture is poured into water, the dichloromethane is decanted and the aqueous phase is extracted with ethyl acetate. The combined organic phases are concentrated under reduced pressure. The yellow solid residue is washed with ether and dried under vacuum.
- 5-Fluoro-6 - ⁇ [6- (4-fluorophenyl) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl ⁇ -1,3-benzothiazol-2-amine may be prepared in the following manner: to a mixture of 157 mg of (5-fluoro-6 - ⁇ [6- (4-fluorophenyl) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] 2-methylpropan-2-yl sulfanyl ⁇ -1,3-benzothiazol-2-yl) carbamate in 5 cm 3 of dichloromethane at 20 ° C., 0.9 cm 3 of trifluoroacetic acid (at 10%) are added gradually.
- Example 4 (5-Fluoro-6 - ⁇ [6- (4-fluorophenyl) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl ⁇ -1,3-benzothiazol-2- yl) -3- [2- (morpholin-4-yl) ethyl] urea a) 1- (5-Fluoro-6 - ⁇ [6- (4-fluorophenyl) [1,2,4] triazolo [4, 3-b] pyridazin-3-yl] sulfanyl ⁇ -1,3-benzothiazol-2-yl) -3- [2- (morpholin-4-yl) ethyl] urea can be prepared in the following manner: solution of 217 mg of N, N "- [disulfanediylbis (5-fluoro-1,3-benzothiazole-6,2-diyl)] bis (3- [2- (morph
- the resulting solution is dried over magnesium sulfate, filtered and then evaporated to dryness in vacuo.
- the brown residue is purified on SPOT II by chromatography on a silica cartridge (SVF D26 Si60, 15-40 ⁇ M, 25 g) eluting with a gradient of 97.4: 2.6 to 90:10 of dichloromethane / methanol.
- N- (6 - ⁇ [6- (Cyclobutyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl 5-fluoro-1,3-benzothiazol-2-yl) -2- (4-cyclopropylpiperazin-1-yl) acetamide can be prepared in a manner similar to Example 2a but from 266 mg.
- N- ⁇ 6 - [(6-ethoxy [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl ⁇ -5- Fluoro-1,3-benzothiazol-2-yl ⁇ -2- (4-ethylpiperazin-1-yl) acetamide may be prepared in a manner similar to Example 2a but from 353 mg of 2 - ⁇ [(4-ethylpiperazin-1-yl) acetyl] amino ⁇ -5-fluoro-1,3-benzothiazol-6-yl thiocyanate ( 9b
- Example 10 N- (6 - ⁇ [6- (cyclobutyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl ⁇ -5-fluoro-1,3-benzothiazol-2-yl) 2- (4-ethylpiperazin-1-yl) acetamide a) N- (6 - ⁇ [6- (Cyclobutyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl 5-Fluoro-1,3-benzothiazol-2-yl) -2- (4-ethylpiperazin-1-yl) acetannide can be prepared in a manner similar to Example 2a but from 355 mg of 2 - ⁇ [(4-ethylpiperazin-1-yl) acetyl] amino ⁇ -5-fluoro-1,3-benzothiazol-6-yl
- MASS SPECTRUM Waters UPLC-SQD: [M + H] +: m / z 557; [M + 2H] 2 +: m / z 279 (base peak); [MH] -: m / z 555 b) 3-Chloro-6- (oxetan-3-yloxy) [1,2,4] thazolo [4,3-b] pyhdazine can be prepared in a manner similar to Example 1e but starting from 1, 96g of oxetan-3-ol, 634mg of sodium hydride at 60% in oil and 2g of 3,6-dichloro [1,2,4] triazolo [4.3-b] pyridazine (commercial) in 20cm 3 of tetrahydrofuran.
- Example 12 Rac-2- (4-cyclopropylpiperazin-1-yl) -N- (5-fluoro-6 - ⁇ [6- (tetrahydrofuran-3-yloxy) [1,2,4] triazolo [4,3- b] pyridazin-3-yl] sulfanyl ⁇ -1,3-benzothiazol-2-yl) acetamide a) Rac-2- (4-cyclopropylpiperazin-1-yl) -N- (5-fluoro-6 - [[ 6
- Examples 1 and ⁇ are taken as examples of pharmaceutical preparation, this preparation can be carried out if desired with other products examples in the present application.
- the SF21 cell cultures are harvested by centrifugation and the cell pellets are stored at -80 ° C.
- the cell pellets are resuspended in the 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
- 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 1OkDa) 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 incubation hours 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
- 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. Dilution of the products: Stock at 1 ⁇ M in pure DMSO - Range of 1 ⁇ M at 30 ⁇ M with a step of 3 in pure DMSO - Dilutions intermediate to 1/50 in culture medium then 10 ⁇ l sample directly added to the cells (200 ⁇ l) : final range of 10000 to 3OnM.
- 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 mM PMSF and anti protease cocktail.
- the 10 ⁇ l of lysates are transferred into a V-bottom polypropylene plate and the ELISA is carried out immediately or the plate is frozen at -80 ° C.
- kit plate b) ELISA PhosphoMET BioSource Kit KHO0281
- 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 30 minutes in the dark at room temperature.
- Test C Measurement of Cell Proliferation Using 14 C-Thymidine Cells are inoculated 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 7500 cells per well in RPMI medium + 10% fetal calf serum + 1% L-Glutamine. After these 4 hours of incubation, 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 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.
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Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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FR0900514A FR2941952B1 (fr) | 2009-02-06 | 2009-02-06 | Derives de 6-(6-substitue-triazolopyridazine-sulfanyl) 5-fluoro-benzothiazoles et 5-fluoro-benzimidazoles : preparation, application comme medicaments et utilisation comme inhibiteurs de met. |
PCT/FR2010/050180 WO2010089509A1 (fr) | 2009-02-06 | 2010-02-04 | Derives de 6-(6-substitue-triazolopyridazine-sulfanyl) 5-fluoro-benzothiazoles et 5-fluoro-benzimidazoles : preparation, application comme medicaments et utilisation comme inhibiteurs de met |
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EP2393793A1 true EP2393793A1 (fr) | 2011-12-14 |
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EP10708280A Withdrawn EP2393793A1 (fr) | 2009-02-06 | 2010-02-04 | Derives de 6-(6-substitue-triazolopyridazine-sulfanyl) 5-fluoro-benzothiazoles et 5-fluoro-benzimidazoles : preparation, application comme medicaments et utilisation comme inhibiteurs de met |
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US (1) | US20120165326A1 (fr) |
EP (1) | EP2393793A1 (fr) |
JP (1) | JP2012517410A (fr) |
KR (1) | KR20110126659A (fr) |
CN (1) | CN102369191A (fr) |
AR (1) | AR075251A1 (fr) |
AU (1) | AU2010212234A1 (fr) |
BR (1) | BRPI1008019A2 (fr) |
CA (1) | CA2751474A1 (fr) |
CO (1) | CO6420339A2 (fr) |
EA (1) | EA201171012A1 (fr) |
FR (1) | FR2941952B1 (fr) |
IL (1) | IL214408A0 (fr) |
MA (1) | MA33103B1 (fr) |
MX (1) | MX2011008290A (fr) |
SG (1) | SG173561A1 (fr) |
TW (1) | TW201036977A (fr) |
UY (1) | UY32422A (fr) |
WO (1) | WO2010089509A1 (fr) |
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FR2966151B1 (fr) * | 2010-10-14 | 2012-11-09 | Sanofi Aventis | Derives de 6-(alkyl- ou cycloalkyl-triazolopyridazine-sulfanyl) benzothiazoles: preparation, application comme medicaments et utilisation comme inhibiteurs de met |
ES2691650T3 (es) | 2011-09-15 | 2018-11-28 | Novartis Ag | 3-(quinolin-6-il-tio)-[1,2,4]-triazolo-[4,3-a]-piridinas 6-sustituidas como inhibidores de tirosina quinasa c-Met |
US11324729B2 (en) | 2017-12-07 | 2022-05-10 | The Regents Of The University Of Michigan | NSD family inhibitors and methods of treatment therewith |
AU2020242287A1 (en) | 2019-03-21 | 2021-09-02 | INSERM (Institut National de la Santé et de la Recherche Médicale) | A Dbait molecule in combination with kinase inhibitor for the treatment of cancer |
CN114761006A (zh) | 2019-11-08 | 2022-07-15 | Inserm(法国国家健康医学研究院) | 对激酶抑制剂产生耐药性的癌症的治疗方法 |
WO2021148581A1 (fr) | 2020-01-22 | 2021-07-29 | Onxeo | Nouvelle molécule dbait et son utilisation |
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EP1298125A1 (fr) | 2001-09-26 | 2003-04-02 | Aventis Pharma S.A. | Benzimidazoles substitués et leur usage comme traitement du cancer |
AU2006320580B2 (en) * | 2005-11-30 | 2011-06-23 | Vertex Pharmaceuticals Incorporated | Inhibitors of c-Met and uses thereof |
BRPI0620292B1 (pt) * | 2005-12-21 | 2021-08-24 | Janssen Pharmaceutica N. V. | Compostos de triazolopiridazinas como moduladores da cinase, composição, uso, combinação e processo de preparo do referido composto |
EP2032578A2 (fr) * | 2006-05-30 | 2009-03-11 | Pfizer Products Incorporated | Dérivés de la triazolopyridazine |
PE20121506A1 (es) * | 2006-07-14 | 2012-11-26 | Amgen Inc | Compuestos triazolopiridinas como inhibidores de c-met |
PL2084162T3 (pl) * | 2006-10-23 | 2013-01-31 | Sgx Pharmaceuticals Inc | Bicykliczne triazole jako modulatory kinaz białkowych |
PA8792501A1 (es) * | 2007-08-09 | 2009-04-23 | Sanofi Aventis | Nuevos derivados de 6-triazolopiridacina-sulfanil benzotiazol y bencimidazol,su procedimiento de preparación,su aplicación como medicamentos,composiciones farmacéuticas y nueva utilización principalmente como inhibidores de met. |
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2009
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2010
- 2010-02-04 CA CA2751474A patent/CA2751474A1/fr not_active Abandoned
- 2010-02-04 MA MA34148A patent/MA33103B1/fr unknown
- 2010-02-04 MX MX2011008290A patent/MX2011008290A/es not_active Application Discontinuation
- 2010-02-04 AU AU2010212234A patent/AU2010212234A1/en not_active Abandoned
- 2010-02-04 CN CN2010800155638A patent/CN102369191A/zh active Pending
- 2010-02-04 JP JP2011548753A patent/JP2012517410A/ja not_active Withdrawn
- 2010-02-04 EP EP10708280A patent/EP2393793A1/fr not_active Withdrawn
- 2010-02-04 EA EA201171012A patent/EA201171012A1/ru unknown
- 2010-02-04 BR BRPI1008019A patent/BRPI1008019A2/pt not_active Application Discontinuation
- 2010-02-04 US US13/147,644 patent/US20120165326A1/en not_active Abandoned
- 2010-02-04 SG SG2011056504A patent/SG173561A1/en unknown
- 2010-02-04 KR KR1020117020675A patent/KR20110126659A/ko not_active Application Discontinuation
- 2010-02-04 WO PCT/FR2010/050180 patent/WO2010089509A1/fr active Application Filing
- 2010-02-05 AR ARP100100319A patent/AR075251A1/es unknown
- 2010-02-05 UY UY0001032422A patent/UY32422A/es not_active Application Discontinuation
- 2010-02-05 TW TW099103557A patent/TW201036977A/zh unknown
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2011
- 2011-08-02 IL IL214408A patent/IL214408A0/en unknown
- 2011-08-05 CO CO11099118A patent/CO6420339A2/es not_active Application Discontinuation
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Also Published As
Publication number | Publication date |
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MX2011008290A (es) | 2011-11-04 |
SG173561A1 (en) | 2011-09-29 |
FR2941952B1 (fr) | 2011-04-01 |
AR075251A1 (es) | 2011-03-16 |
JP2012517410A (ja) | 2012-08-02 |
TW201036977A (en) | 2010-10-16 |
IL214408A0 (en) | 2011-09-27 |
EA201171012A1 (ru) | 2012-03-30 |
CA2751474A1 (fr) | 2010-08-12 |
US20120165326A1 (en) | 2012-06-28 |
FR2941952A1 (fr) | 2010-08-13 |
UY32422A (es) | 2010-09-30 |
CO6420339A2 (es) | 2012-04-16 |
MA33103B1 (fr) | 2012-03-01 |
CN102369191A (zh) | 2012-03-07 |
BRPI1008019A2 (pt) | 2016-03-15 |
WO2010089509A1 (fr) | 2010-08-12 |
KR20110126659A (ko) | 2011-11-23 |
AU2010212234A1 (en) | 2011-08-25 |
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