EP2310366A2 - NOUVEAUX DERIVES TRIAZOLO(4,3-a)PYRIDINE,LEUR PROCEDE DE PREPARATION,LEUR APPLICATION A TITRE DE MEDICAMENTS,COMPOSITIONS PHARMACEUTIQUES ET NOUVELLE UTILISATION NOTAMMENT COMME INHIBITEURS DE MET - Google Patents

NOUVEAUX DERIVES TRIAZOLO(4,3-a)PYRIDINE,LEUR PROCEDE DE PREPARATION,LEUR APPLICATION A TITRE DE MEDICAMENTS,COMPOSITIONS PHARMACEUTIQUES ET NOUVELLE UTILISATION NOTAMMENT COMME INHIBITEURS DE MET

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Publication number
EP2310366A2
EP2310366A2 EP09736253A EP09736253A EP2310366A2 EP 2310366 A2 EP2310366 A2 EP 2310366A2 EP 09736253 A EP09736253 A EP 09736253A EP 09736253 A EP09736253 A EP 09736253A EP 2310366 A2 EP2310366 A2 EP 2310366A2
Authority
EP
European Patent Office
Prior art keywords
radical
radicals
optionally substituted
alkyl
products
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP09736253A
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German (de)
English (en)
French (fr)
Inventor
Eric Bacque
Dominique Damour
Conception Nemecek
Patrick Nemecek
Sylvie Wentzler
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sanofi SA
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Sanofi Aventis France
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Priority claimed from FR0804084A external-priority patent/FR2933980B1/fr
Priority claimed from FR0900245A external-priority patent/FR2941229B1/fr
Application filed by Sanofi Aventis France filed Critical Sanofi Aventis France
Publication of EP2310366A2 publication Critical patent/EP2310366A2/fr
Withdrawn legal-status Critical Current

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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
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    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • protein kinases play an important role in the regulation of a wide variety of cellular processes, including metabolism, cell 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 present invention also relates to the use of said derivatives for the preparation of a medicament for the treatment of humans.
  • Rb represents a hydrogen atom, a -CO-Rc radical or a -CO-NRcRd radical; with Rc represents an alkyl or cycloalkyl radical optionally substituted by one or more radicals chosen from hydroxyl, alkoxy and NR1 R2 radicals; Rd represents a hydrogen atom;
  • Ra represents a hydrogen atom; a halogen atom; an aryl radical; or a heteroaryl radical, these aryl and heteroaryl radicals being optionally substituted as indicated below;
  • NR3R4 being such that: either, R3 and R4 being identical or different, one of R3 and R4 represents a hydrogen atom or an alkyl radical and the other of R3 and R4 represents a hydrogen atom, a cycloalkyl radical; or a radical alkyl optionally substituted by one or more identical or different radicals chosen from hydroxyl, alkoxy, heterocycloalkyl, heteroaryl or phenyl radicals themselves optionally substituted, or R3 and R4 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; the cyclic radicals that can be formed by R 1 and R 2 or R 3 and R 4 respectively with the nitrogen atom to which they are bonded, being optionally substituted by one or more identical or different radicals chosen from halogen atoms, hydroxyl radicals, alkoxy radicals
  • Rb represents a hydrogen atom, a -CO-Rc radical or a -CO-NRcRd radical; with Rc represents an alkyl or cycloalkyl radical, both optionally substituted with one or more radicals chosen from the hydroxyl, alkoxy, NR1 R2 and phenyl radicals, optionally substituted with one or more radicals selected from halogen atoms, hydroxyl, alkoxy, alkyl, NH2, NHaIk and N (alk) 2 radicals;
  • 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, NR3R4 or phenyl radicals themselves optionally substituted; or R1 and R2 form, with the nitrogen atom to which they are bonded, a cyclic radical containing from 4 to 7 members and optionally another heteroatom selected from O, S, N and NH, this radical including the optional NH that it contains being optionally substituted;
  • Ra represents a hydrogen atom; a halogen atom; or a phenyl radical optionally substituted by a halogen atom
  • Rb represents a hydrogen atom, a -CO-Rc radical or a -CO-NRcRd radical
  • Rc represents an alkyl or cycloalkyl radical optionally substituted by one or more radicals chosen from hydroxyl, alkoxy and NR1 R2 radicals
  • Rd represents a hydrogen atom
  • 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;
  • 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, homomorpholinyl, aziridyl, azetidyl, piperazinyl, piperidyl, homopiperazinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuryl, tetrahydrothienyl, tetrahydropyranyl, tetrahydropyran, oxodihydropyridazinyl radicals, or alternatively oxetanyl, all these radicals being optionally substituted; mention may in particular be made of tetrahydropyranyl, morpholinyl, thiomorpholinyl, homomorpholin
  • 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;
  • 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, thiathazolyl, oxadiazolyl, isoxazolyl as 3- or 4-isoxazolyl, furazannyl, free or salified tetrazoly
  • 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-methylglucanin,
  • 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
  • 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 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,
  • Rd represents a hydrogen atom
  • NR 1 R 2 being such that either R 1 and R 2, which are identical or different, represent a hydrogen atom or an alkyl radical, or R 1 and R 2 form, with the nitrogen atom to which they are bonded, a morpholinyl or piperazinyl radical optionally substituted on the second atom; azole with an alkyl radical; the above alkyl or alkoxy radicals containing from 1 to 4 carbon atoms, 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).
  • 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.
  • boronic acids of formula Ra-B (OH) 2 in the presence of sodium hydrogen carbonate and palladium tetrakistriphenylphosphine in a solvent such as dimethylsulfoxide or dioxane at a temperature in the region of 80.degree. from the boronic esters Ra-B (OR) 2 in the presence of palladium dichloro-bis (triphenylphosphine) in a solvent such as, for example, 1,2-dimethoxyethane, in the presence of a base such as sodium hydroxide 1 N, at a temperature of about 80 ° C.
  • ester function transformations in acid function of the products described above may, if desired, be carried out under the usual conditions known to those skilled in the art, in particular by hydrolysis acid or alkali for example with sodium hydroxide or potassium hydroxide in an alcoholic medium such as, for example, in methanol or with hydrochloric or sulfuric acid.
  • 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 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 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 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.
  • 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.
  • 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, tablets, capsules, drops, granules, preparations and the like. injectables, 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 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 therapeutic agents may be commonly used anti-tumor agents.
  • Example 1b 4 - ([1,2,4] triazolo [4,3-a] pyhdin-3-ylsulfanyl) aniline
  • the compound can be prepared in the following manner: To a solution of 6.21 g of stannous chloride, dihydrate in 8 ml of ethanol is added 1.5 g of 3 - [(4-nitrophenyl) sulfanyl] [1,2,4] thazolo [4,3-a ] pyhdine. The orange solution obtained is brought to around 60 ° C. 8.2 ml of a 10N aqueous solution of hydrochloric acid is poured dropwise at this temperature and the reaction mixture is stirred for approximately 30 minutes at this same temperature.
  • Example 2a ⁇ - [6 - ([1,2,4] triazolo [4,3-a] pyridin-3-ylsulfanyl) -1,3-benzothiazol-2-yl] cyclopropanecarboxamide
  • the compound can be prepared from following way:
  • Example 2b 2 - [(cyclopropylcarbonyl) amino] -1,3-benzothiazole-6-diazonium tetrafluoroborate
  • Example 3 1- [2- (Morpholin-4-yl) ethyl] -3- [6 - ([1,2,4] triazolo [4,3-a] pyridin-3-ylsulfanyl) -1.3- benzothiazol-2-yl] urea
  • Example 3a 1- [2- (Morpholin-4-yl) ethyl] -3- [6 - ([1,2,4] triazolo [4,3-a] pyridin-3-ylsulfanyl) -1,3 benzothiazol-2-yl] urea
  • Example 4 1- [2- (4-methylpiperazin-1-yl) ethyl] -3- [6 - ([1,2,4] triazolo [4,3-a] pyridin-3-ylsulfanyl) -1, 3-benzothiazol-2-yl] urea.
  • the compound can be prepared as in Example 3a but from 0.2 g of [[6 - ([1,2,4] thalzolo [4,3-a] pyhdin-3-ylsulfanyl) -1,3 phenylbenzothiazol-2-yl] carbamate and 75.15 mg of 2- (4-methylpiperazin-1-yl) ethanamine.
  • Example 6a 6 - [(6-iodo [1,2,4] triazolo [4,3-a] pyhdin-3-yl) sulfanyl] -1,3-benzothiazol-2-amine
  • the compound can be prepared as in Example 1b from 4.02 g of stannous chloride, dihydrate, 60 ml of ethanol, and 1.89 g of 6-iodo-3- [(4-nitrophenyl) sulfanyl] [1,2,4] triazolo [4,3-a] pyridine and 4.45 ml of a 12N aqueous solution of hydrochloric acid. 0.23 g of 4 - [(6-iodo [1,2,4] triazolo [4,3-a] pyridin-3-yl) sulfanyl] aniline are thus obtained in the form of an orange-brown solid.
  • Example 6c 6-iodo-3 - [(4-nitrophenyl) sulfanyl] [1,2,4] thazolo [4,3-a] pyridine
  • the compound can be obtained as described in patent WO 2006/114213, example 32A page 40.
  • Example 7 6 - ⁇ [6- (4-fluorophenyl) [1,2,4] triazolo [4,3-a] pyridin-3-yl] sulfanyl ⁇ -1,3-benzothiazol-2-amine
  • Example 7a 6 - ⁇ [6- (4-fluorophenyl) [1,2,4] triazolo [4,3-a] pyridin-3-yl] sulfanyl ⁇ -1,3-benzothiazol-2-amine
  • the compound can be prepared as described in Example 1a from 0.24 g of 4 - ⁇ [6- (4-fluorophenyl) [1,2,4] triazolo [4,3-a] pyridin-3-yl] sulfanyl ⁇ aniline, 10 ml of acetic acid, 0.28 g of potassium thiocyanate and 37 .mu.l of bromine diluted in 2 ml of glacial acetic acid.
  • the compound 6 - ⁇ [6- (4-fluorophenyl) [1,2,4] triazolo [4,3-a] pyridin-3-yl] sulfanyl ⁇ -1,3-benzothiazol-2-amine can also be obtained as follows: To a solution of 20 mg of 6 - [(6-iodo [1,2,4] triazolo [4,3-a] pyridin-3-yl) sulfanyl] -1,3-benzothiazol-2 -amine and 1 ml of dimethylsulfoxide are added 35 mg of potassium phosphate, 80 mg of 4-fluorophenylboronic acid and 3 mg of palladium tetrakistriphenylphosphine.
  • the reaction medium is heated at 80 ° C. for 18 hours. 5 mg of palladium tetrakistriphenylphosphine are then added and the medium is again brought to 80 ° C. for 2 days. After cooling the reaction medium with an ice bath, 15 ml of water are added and the medium is kept under cold stirring for one hour and then for 18 hours at room temperature. The aqueous phase is extracted with 3 times 30 ml of ethyl acetate, the combined organic phases are dried over sodium sulfate, filtered and concentrated by evaporation under reduced pressure.
  • Example 7b 4 - ⁇ [6- (4-fluorophenyl) [1,2,4] triazolo [4,3-a] pyridin-3-yl] sulfanyl ⁇ aniline
  • the compound can be prepared as in Example 1b from 1.88 g of stannous chloride, dihydrate, 25 ml of ethanol, 0.61 g of 6- (4-fluorophenyl) -3 - [(4 -Nitrophenyl) sulfanyl] [1,2,4] thazolo [4,3-a] pyridine and 2.06 ml of a 10N aqueous solution of hydrochloric acid. 0.24 g of 4 - ⁇ [6- (4-fluorophenyl) [1,2,4] triazolo [4,3-a] pyhdin-3-yl] sulfanyl ⁇ aniline are thus obtained in the form of a yellow solid. .
  • the compound can be prepared as in Example 1c from 0.83 g of 6- (4-fluorophenyl) - [1,2,4] triazolo [4,3-a] pyridine-3-thiol, from 8 ml of dimethylsulfoxide and 0.80 g of 4-nitrobenzenediazonium tetrafluoroborate. 0.61 g of 6- (4-fluorophenyl) -3 - [(4-nitrophenyl) sulfanyl] [1,2,4] thazolo [4,3-a] pyhidine are thus obtained in the form of a brown meringue.
  • Example 7d 6- (4-fluorophenyl) - [1,2,4] triazolo [4,3-a] pyridine-3-thiol
  • the compound can be prepared in the following manner:
  • Example 7e 5- (4-Fluorophenyl) -2-hydroxyrazine
  • the compound can be prepared as described by R. Church et al., Journal of Organic Chemistry (1995), 60 (12), 3750-8.
  • the compound can be prepared in the following manner:
  • the compound can be prepared as in Example 2 from 0.13 g of 6 - ⁇ [6- (1-methyl-1H-pyrazol-4-yl) [1,2,4] triazolo [4, 3-a] pyhdin-3-yl] sulfanyl ⁇ -1,3-benzothiazol-2-amine, 0.034 ml of cyclopropanecarbonyl chloride and 2 ml of pyridine.
  • 0.1 g of ⁇ - (6 - ⁇ [6- (1-methyl-1H-pyrazol-4-yl) [1,2,4] triazolo [4,3-a] pyhdin-3 are thus obtained.
  • -yl] sulfanyl ⁇ -1,3-benzothiazol-2-yl) cyclopropanecarboxamide as a pale yellow solid.
  • the compound can be prepared in the following manner: To a solution of 10 g of 2-amino-1,3-benzothiazol-6-yl thiocyanate (commercial product) and 100 ml of pyridine is added 5.3 ml of cyclopropanecarbonyl chloride while maintaining the temperature of 20 0 C. The reaction medium is stirred for 4 hours and then 500 ml of water are added. The precipitate formed is filtered on sintered glass, washed well with water, drained and then dried. 13 g of (6-thiocyanato-1,3-benzothiazol-2-yl) cyclopropanecarboxamide are thus obtained in the form of a pale yellow solid which is used as it is in the subsequent steps.
  • Example 11 d 3-bromo-6- (1H-pyrazol-4-yl) - [1,2,4] triazolo [4,3-a] pyhidine
  • the compound can be prepared in the following manner: A solution of 170 mg of 6- (1H-pyrazol-4-yl) - [1,2,4] triazolo [4,3-a] pyhidine in 4 ml of ethanol is added a solution of 0.058 ml of bromine and 2 ml of water. The reaction mixture is stirred for about 2 days at a temperature in the region of 20 ° C. and then 20 ml of a saturated aqueous solution of sodium hydrogencarbonate are added.
  • the compound can be prepared in the following manner:
  • Example 13 ⁇ - (6 - ⁇ [6- (3-fluorophenyl) [1,2,4] triazolo [4,3-a] pyridin-3-yl] sulfanyl ⁇ -1,3-benzothiazol-2 yl) cyclopropanecarboxamide
  • Example 13a ⁇ - (6 - ⁇ [6- (3-fluorophenyl) [1,2,4] triazolo [4,3-a] pyridin-3-yl] sulfanyl ⁇ -1,3-benzothiazol-2 yl) cyclopropanecarboxamide
  • the compound can be prepared as in Example 11a from 480 mg of 3-bromo-6- (3-fluorophenyl) - [1,2,4] triazolo [4,3-a] pyridine, 411 mg (6-sulfanyl-1,3-benzothiazol-2-yl) cyclopropanecarboxamide, 454 mg of potassium carbonate and 10 ml of dimethylsulfoxide.
  • the compound can be prepared as in Example 12b from 360 mg of 6- (3-fluorophenyl) - [1,2,4] triazolo [4,3-a] pyhidine, 10 ml of chloroform and 300 mg N-bromosuccinimide. 480 mg of 3-bromo-6- (3-fluorophenyl) - [1,2,4] thazolo [4,3-a] pyhdine are thus obtained in the form of an ocher solid.
  • Example 13c 6- (3-fluorophenyl) - [1,2,4] triazolo [4,3-a] pyhidine
  • the compound can be prepared as in Example 12c from 400 mg of 6-bromo- [1] , 2,4] triazolo [4,3-a] pyhdine (commercial product), 8 ml of dimethysulfoxide, 69 mg of palladium tetrakistriphenylphosphine, 424 mg of sodium carbonate dissolved in 2 ml of water and 345 mg of (3-fluorophenyl) boronic acid. 361 mg of 6 - ((3-fluoro, 4-methyl) phenyl) - [1,2,4] triazolo [4,3-a] pyhidine are thus obtained in the form of a white solid.
  • Example 14a ⁇ - (6 - ⁇ [6- (1- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl] -1H-pyrazol-4-yl) [1,2,4] triazolo [4,3-a] pyridin-3-yl] sulfanyl ⁇ -1,3-benzothiazol-2-yl) cyclopropanecarboxamide
  • the compound can be prepared as in Example 11a from 240 mg of 3-bromo-6- (1- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl] -1H-pyrazol-4 yl)
  • Example 14b 3-Bromo-6- (1- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl] -1H-pyrazol-4-yl) [1,2,4] triazolo [4.3
  • the compound can be prepared as in Example 12b starting from 440 mg of 6- (1- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl] -1H-pyrazol-4-ol. yl)
  • Example 14c 6- (1- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl] -1H-pyrazol-4-yl) [1,2,4] triazolo [4,3-a] pyridine
  • the compound can be prepared as in Example 9 from 320 mg of 6-bromo- [1,2,4] triazolo [4,3-a] pyridine (commercial product), 15 ml of 1 -
  • Example 14d 1- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl] -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H pyrazole.
  • the compound can be prepared as described in US2007 / 0265272, p. 39.
  • the compound can be prepared in the following manner:
  • the resin is added to complete the reaction (followed by LC / MS), ie successively 45 mg, 40 mg and then 150 mg of resin while stirring at a temperature of 20 0 C and over a total period of 4 days.
  • the reaction medium is then filtered and the resin is washed with 4 times 15 ml of a 28% CH 2 Cl 2 / MeOH / NH 4 OH mixture (12/3 / 0.5 by volume).
  • the filtrate obtained is concentrated by evaporation under reduced pressure.
  • Example 16 ⁇ - (6 - ⁇ [6- (1-Piperidin-4-yl-1H-pyrazol-4-yl) [1,2,4] triazolo [4,3-a] pyridin-3- yl] sulfanyl ⁇ -1,3-benzothiazol-2-yl) cyclopropanecarboxamide
  • Example 16a ⁇ - (6 - ⁇ [6- (1-piperidin-4-yl-1H-pyrazol-4-yl) [1,2,4] triazolo [4,3-a] pyridin-3- yl] sulfanyl ⁇ -1,3-benzothiazol-2-yl) cyclopropanecarboxamide
  • the compound can be prepared as in Example 11a from 134 mg of 4- ⁇ 4 - [(3-bromo [1,2,4] triazolo [4,3-a] pyhdin) -6-yl] 2-methylpropan-2-yl 3H-pyrazol-1-yl ⁇ piperidine-1-carboxylate, 83 mg of (6-sulfanyl-1,3-benzothiazol-2-yl) cyclopropanecarboxamide, 83 mg of potassium and 3.5 ml of dimethylsulfoxide.
  • Example 16c 4- ⁇ 4 - [(3-bromo [1,2,4] triazolo [4,3-a] pyhdin) -6-yl] -1H-pyrazol-1-yl ⁇ piperidine-1-carboxylate 2-methylpropan-2-yl
  • the compound can be prepared as in Example 12b from 120 mg of 4- [4 - ([1,2,4] triazolo [4,3-a] pyridin-6-yl) -1H-pyrazol 2-methylpropan-2-yl 1-yl] piperidine-1-carboxylate, 5 ml chloroform and 58 mg N-bromosuccinimide. 134 mg of 4- ⁇ 4 - [(3-bromo [1,2,4] triazolo [4,3-a] pyridin-6-yl] -1H-pyrazol-1-yl ⁇ piperidine are thus obtained.
  • Example 7 is taken as an example 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 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 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 of interest after electrophoresis (SDS PAGE), are finally collected and stored at -80 ° C.
  • the previous fractions are incubated for 1 h at room temperature after addition of 2 mM ATP, 2 mM MgCl 2, and 4 mM Na3VO4.
  • 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.
  • Tests A and B A) 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.
  • 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.
  • 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 greater 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 microM.

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EP09736253A 2008-07-18 2009-07-16 NOUVEAUX DERIVES TRIAZOLO(4,3-a)PYRIDINE,LEUR PROCEDE DE PREPARATION,LEUR APPLICATION A TITRE DE MEDICAMENTS,COMPOSITIONS PHARMACEUTIQUES ET NOUVELLE UTILISATION NOTAMMENT COMME INHIBITEURS DE MET Withdrawn EP2310366A2 (fr)

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