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Definitions

• the subject of the present invention is certain derivatives of benzothiazole-4,7-diones and of benzoxazole-4,7-diones substituted in position 5 or in position 6, which inhibit the Cdc25 phosphatases, in particular the Cdc25-C phosphatase, and / or CD45 phosphatase as well as a process for the preparation of such derivatives and synthesis intermediates useful in the implementation of this process.
• kinases The control of the transition between the different phases of the cell cycle during mitosis or meiosis is ensured by a set of proteins whose enzymatic activities are associated with different states of phosphorylation. These states are controlled by two main classes of enzymes: kinases and phosphatases.
• CDKs cyclin-dependent kinases
• the enzymatic activity of these different CDKs is controlled by two other families of enzymes which work in opposition (Jessus and Ozon, Prog. Cell Cycle Res. (1995), 1, 215-228).
• the first groups kinases such as Weel and Mikl which deactivate CDKs by phosphorylating certain amino acids (Den Haese et al., Mol. Biol Cell (1995), 6, 371-385).
• the second groups together phosphatases such as Cdc25 which activate CDKs by dephosphorylating tyrosine and threonitic residues of CDKs (Gould et al., Science (1990), 250, 1573-1576).
• Phosphatases are classified into 3 groups: serines / threonines phosphatases (PPases), tyrosine phosphatases (PTPases) and double specificity phosphatases (DSPases). These phosphatases play an important role in the regulation of many cellular functions.
• Cdc25-A, Cdc25-B and Cdc25-C code for the proteins Cdc25.
• variants resulting from alternative splicing of the Cdc25 genes have been identified (cf. for example Baldin et al., Oncogene (1997), 14, 2485-2495).
• Cdc25 phosphatases The role of Cdc25 phosphatases in oncogenesis is now better understood and the mechanisms of action of these phosphatases are illustrated in particular in the following references: Gal forceov et al., Science (1995), 269, 1575-1577; Gal forceov et al., Nature (1996), 382, 511-517; & Mailand et al., Science (2000), 288, 1425-1429.
• Cdc25 phosphatases also play a role in neurodegenerative diseases such as Alzheimer's disease (cf. Zhou et al., Cell Mol. Life Sel (1999), 56 (9-10), 788-806; Ding et al. , Am. J. Pathol. (2000), 157 (6), 1983-90; Vincent et al., Neuroscience (2001), 105 (3), 639-50) so that one can also consider use compounds with inhibitory activity against these phosphatases to treat these diseases.
• Alzheimer's disease cf. Zhou et al., Cell Mol. Life Sel (1999), 56 (9-10), 788-806
• Ding et al. Am. J. Pathol. (2000), 157 (6), 1983-90
• Vincent et al. Neuroscience (2001), 105 (3), 639-50) so that one can also consider use compounds with inhibitory activity against these phosphatases to treat these diseases.
• Another problem to which the invention is addressed is the search for medicaments intended to prevent or treat the rejection of organ transplants or else to treat autoimmune diseases.
• these disorders / diseases inappropriate activation of lymphocytes and monocytes / macrophages is involved.
• the immunosuppressive drugs known to date have side effects which could be decreased or modified by products specifically targeting the signaling pathways in hematopoietic cells that initiate and maintain inflammation.
• Phosphatase CD45 plays a crucial role in the transmission of signals from receptors on T lymphocytes by regulating phosphorylation and the activity of tyrosine kinases of the src family, from which it is capable of dephosphorylating the negative regulation sites p56 lck and p59 fyn .
• CD45 phosphatase is therefore a potential target in the treatment of immune diseases. Indeed, blocking of the CD45 phosphatase by an anti-CD45 antibody inhibits the activation of T lymphocytes in vitro (Prickett and Hart, Immunology (1 90), 69, 250-256). Likewise, T lymphocytes from transgenic mice not expressing CD45 (CD45 knockout mice) do not respond to stimulation by an antigen (Trowbridge and Thomas, Annu. Rev. Immunol. (1994), 12, 85-116 ).
• CD45 would be able to dephosphorylate a subunit associated with Lyn, which would trigger a flow of calcium and activation of mast cells.
• Hamaguchi et al. Bioorg. Med. Chem. Lett. (2000), 10,2657-2660 have shown that a particular CD45 inhibitor (CI 50 equal to 280 nM) would suppress the release of histamine from rat peritoneal mast cells and protect anaphylactic shock mice.
• CD45 phosphatase inhibitors therefore appears obvious in particular when one is interested in: - obtaining an immunosuppressive effect in general, and in particular: • in the context of the treatment of autoimmune diseases (Zong et al. ., J. Mol. Med. (1998), 76 (8), 572-580) such as for example multiple sclerosis or autoimmune encephalitis (Yacyshyn et al., Dig. Dis. Sci. (1996) , 41 (12), 2493-8) and diabetes (Shimada et al., J. Autoimmun.
• the invention provides inhibitors of phosphatases, Cdc25 (in particular phosphatase Cdc25-C), and / or phosphatase CD 45, which are derivatives of benzothiazole-4,7-diones and benzoxazole-4,7- diones corresponding to the general formulas (I), (II) and (III) defined below.
• Cdc25 in particular phosphatase Cdc25-C
• CD 45 phosphatases
• autoimmune diseases such as multiple sclerosis and rheumatoid arthritis: and • diabetes.
• the compounds of the present invention are also, due to their inhibitory properties for Cdc25 phosphatases, capable of being used to inhibit the proliferation of microorganisms, in particular yeasts.
• One of the advantages of these compounds is their low toxicity on healthy cells.
• patent GB 1,534,275 relates to herbicides, the active principle of which is a compound corresponding to one of the general formulas.
• R 1 represents in particular a hydrogen atom or an alkyl or cycloalkyl radical
• R 2 represents in particular a hydrogen atom, an alkyl or cycloalkyl radical
• X represents in particular a halogen atom or an alkoxy radical
• Y and Z can in particular represent together with the carbon atoms which carry them a thiazole ring optionally substituted by an alkyl radical;
• R represents in particular an alkyl radical.
• PCT patent application WO 99/32115 describes the compounds of general formula (A3)
• the substituents R 2 -R 6 are chosen from the group consisting of a hydrogen atom, electron donor substituents, electron attracting substituents and electron modulating substituents; and Y 5 and Y are in particular chosen from the group consisting of a hydrogen atom, electron donor substituents, electron attracting substituents and electron modulating substituents.
• the term “electron donor substituent” refers to a functional group which tends to give electron density; the substituents alkyl, alkenyl and alkynyl are cited. Also in this patent application, “electron withdrawing substituent” refers to a functional group which tends to attract electronic density; the substituents cyano, acyl, carbonyl, fluoro, nitro, sulfonyl and trihalomethyl are mentioned. Finally, an “electron modulator substituent” is defined in this application as a functional group which tends to modulate the electron density, which can both attract and donate electrons and is therefore such that it can stabilize a cationic intermediate.
• amino substituents for example -NH 2 , alkylamino or dialkylamino
• hydroxy for example -NH 2 , alkylamino or dialkylamino
• alkoxy for example aryl
• heterocyclic substituents for example -NH 2 , alkylamino or dialkylamino
• halogen atoms etc.
• the compounds of general formula (A3) are presented as modulators of the ryanodine receptors which can be used as pesticides or as therapeutic agents, for example in the treatment of congestive heart failure, migraine headaches , hypertension, Parkinson's disease or Alzheimer's disease or in the prevention of premature abortion.
• the benzoxazole-4,7-diones derivatives of general formula (A4) are presented as modulators of the ryanodine receptors which can be used as pesticides or as therapeutic agents, for example in the treatment of congestive heart failure, migraine headaches , hypertension, Parkinson's disease or Alzheimer's disease or in the prevention of premature abortion.
• Ar 1 represents an optionally substituted aryl radical
• each of Q 1 and Q 2 represents in particular O, are described as active constituents of photosensitive layers of photoreceptors.
• R 1 represents a hydrogen atom or an alkyl, alkoxyalkyl, alkylthioalkyl or cycloalkyl radical.
• R, 36 together form with the carbon atom which carries them an indanyl or tetralinyl radical, or alternatively R 35 and R 36 together form with the carbon atom which carries them a saturated heterocycle with 5 to 7 members and 1 with 2 heteroatoms chosen from O, N and S, the nitrogen atoms of said heterocycle being optionally substituted by radicals chosen from alkyl radicals and the benzyl radical, R 1 can also, when W represents O, also represent a carbocyclic aryl radical optionally substituted 1 to 3 times with substituents chosen independently from a halogen atom and an alkyl, haloalkyl or alkoxy radical, X representing a bond or an alkylene radical linear or branched with 1 to 5 carbon atoms,
• Y representing a saturated carbon ring system having 1 to 3 condensed rings independently chosen from 3 to 7-membered rings, or Y representing a saturated heterocycle having 1 to 2 heteroatoms chosen independently from O, N and S and attached to the radical X by an N or CH link, said saturated heterocycle also counting from 2 to 6 additional links chosen independently from -CHR -, -CO-, -NR -, -O- and -S-, R representing a hydrogen atom or an alkyl radical and
• R representing a hydrogen atom or an alkyl or aralkyl radical, or alternatively Y representing a carbocyclic or heterocyclic aryl radical optionally substituted 1 to 3 times with substituents chosen independently from the group consisting of a halogen atom, an alkyl radical, a haloalkyl radical, an alkoxy radical, a haloalkoxy radical, a hydroxy radical, a nitro radical, a cyano radical, the phenyl radical, an SO 2 NHR 9 radical and a NR 10 R ⁇ radical, R 9 representing a hydrogen atom or an alkyl or phenyl radical, and R 10 and R 11 independently representing alkyl radicals, Z representing a bond or a linear or branched alkylene radical having 1 to 5 carbon atoms,
• R 5 and R being independently chosen from a hydrogen atom, an alkyl, aralkyl or - (CH 2 ) n -OH radical in which n represents an integer from 1 to 6, or R 5 representing an alkoxycarbonyl, haloalkoxycarbonyl or aralkoxycarbonyl radical and R representing a hydrogen atom or a methyl radical, or alternatively R 5 and R 6 forming, together with the nitrogen atom, a 4- to 7-membered heterocycle comprising from 1 to 2 heteroatoms, the members necessary to complete the heterocycle being independently selected from the radicals -CR 12 R 13 -, -O-, -S- and -NR 14 -, R 12 and R 13 independently representing each time they intervene a hydrogen atom or an alkyl radical , and R 14 representing a hydrogen atom or an alkyl or aralkyl radical, or alternatively R 14 representing a phenyl radical optionally substituted from 1 to 3 times with substituents independently chosen from a
• R 3 represents a hydrogen atom, a halogen atom, or an alkyl, haloalkyl, alkoxy or alkylthio radical;
• R 4 represents an alkyl, cycloalkyl, cycloalkylalkyl, cyano, amino radical, -CH 2 -COOR 18 , -CH 2 -CO-NR 19 R 20 or -CH 2 -NR 21 R 22 , or else R 4 represents an aryl radical carbocyclic or heterocyclic optionally substituted from 1 to 4 times by substituents chosen independently from a halogen atom and an alkyl, haloalkyl, alkoxy, haloalkoxy or NR 37 R 38 radical, or alternatively R 4 represents a phenyl radical having two substituents which together form a methylenedioxy or ethylenedioxy radical,
• R 18 representing a hydrogen atom or an alkyl radical
• R 19 representing a hydrogen atom, an alkyl radical or an aralkyl radical in which the aryl group is optionally substituted from 1 to 3 times by substituents chosen independently from the group consisting of a halogen atom, an alkyl radical, a haloalkyl radical, an alkoxy radical, a haloalkoxy radical, a hydroxy radical, a nitro radical, a cyano radical, the phenyl radical, an SO 2 NHR 23 radical and a NR R radical, R representing a hydrogen atom or an alkyl or phenyl radical, and R and R 25 independently representing alkyl radicals, R representing a hydrogen atom or an alkyl radical, or alternatively R 19 and R 20 forming together with the nitrogen atom a 4 to 7 membered heterocycle comprising from 1 to 2 heteroatoms, the links necessary to complete the heterocycle being chosen independently from the radicals -CR 2 R 2 -, -O-, -S- and -NR -,
• W represents O or S
• Cdc25 phosphatase inhibitors and in particular inhibitors of Cdc25-C phosphatase, and / or CD 45 phosphatase.
• Said compounds can therefore be used to prepare a medicament intended to inhibit Cdc25 phosphatases, and in particular Cdc25-C phosphatase, and / or CD 45 phosphatase.
• alkyl when no further details are given, is meant a linear or branched alkyl radical containing from 1 to 12 carbon atoms, preferably from 1 to 10 carbon atoms and more preferably from 1 to 8 carbon atoms (and in particular from 1 to 6 carbon atoms).
• cycloalkyl when it is not given more precision, is meant a cycloalkyl radical having 3 to 7 carbon atoms.
• carbocyclic or heterocyclic aryl is meant a carbocyclic or heterocyclic system of 1 to 3 condensed rings comprising at least one aromatic ring, a system being said to be heterocyclic when at least one of the rings which compose it comprises a heteroatom (O, N or S); when a carbocyclic or heterocyclic aryl radical is said to be substituted without being given any further details, it is understood that said carbocyclic or heterocyclic aryl radical is substituted from 1 to 3 times, and preferably from 1 to 2 times, by different radicals a hydrogen atom which, if they are not specified, are chosen from a halogen atom and the alkyl or alkoxy radicals; moreover, when is not given more precision, aryl means a carbocyclic aryl exclusively.
• haloalkyl is meant an alkyl radical in which at least one of the hydrogen atoms (and possibly all) is replaced by a halogen atom.
• cycloalkylalkyl, alkoxy, haloalkyl, haloalkoxy and aralkyl radicals is meant respectively the cycloalkylalkyl, alkoxy, haloalkyl, haloalkoxy and aralkyl radicals, the alkyl, cycloalkyl and aryl radicals of which have the meanings indicated above.
• a radical is optionally substituted from 1 to 3 times, it is preferably optionally substituted from 1 to 2 times and more preferably optionally substituted once.
• linear or branched alkyl having from 1 to 6 carbon atoms is meant in particular the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, pentyl, neopentyl, isopentyl, hexyl, isohexyl radicals.
• haloalkyl means in particular the trifluoromethyl radical.
• haloalkoxy means in particular the trifluoromethoxy radical.
• carbocyclic aryl is meant in particular the phenyl and naphthyl radicals.
• aralkyl in particular the phenylalkyl radicals, and in particular the benzyl radical.
• saturated carbon ring system containing 1 to 3 condensed rings independently chosen from 3 to 7 membered rings means in particular the cyclopropyl, cyclobutyl, cyclohexyl and adamantyl radicals.
• heterocyclic or heteroaryl aryl is meant in particular the thienyl, furanyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl and pyridyl radicals.
• halogen is meant the fluorine, chlorine, bromine or iodine atoms.
• pharmaceutically acceptable salt is intended to mean in particular addition salts of inorganic acids such as hydrochloride, hydrobromide, iodhydrate, sulfate, phosphate, diphosphate and nitrate or of organic acids such as acetate, maleate, fumarate, tartrate, succinate, citrate , lactate, methanesulfonate, p-toluenesulfonate, pamoate and stearate. Also falling within the scope of the present invention, when they can be used, the salts formed from bases such as sodium or potassium hydroxide. For other examples of pharmaceutically acceptable salts, reference may be made to "Knows selection for basic drugs", Int. J. Pharm. (1986), 33, 201-217.
• the compounds according to the present invention may contain asymmetric carbon atoms. Consequently, the compounds according to the present invention have two possible enantiomeric forms, that is to say the “R” and “S” configurations.
• the present invention includes the two enantiomeric forms and all combinations of these forms, including the "RS” racemic mixtures. For the sake of simplicity, when no specific configuration is indicated in the structural formulas, it should be understood that the two enantiomeric forms and their mixtures are represented.
• the compounds of general formula (I) ⁇ or (I) 2 , or their pharmaceutically acceptable salts may therefore be used to prepare a medicament intended to inhibit the Cdc25 phosphatases, and in particular the Cdc25-C phosphatase, and / or the phosphatase CD45.
• the compounds of general formula (1) 3 or (I) 4 , or their pharmaceutically acceptable salts can be used to prepare a medicament intended to inhibit the phosphatases Cdc25, and in particular the phosphatase Cdc25-C, and / or CD45 phosphatase.
• the compounds of general formula (I), (I) ⁇ , (I) 2 , (1) 3 or (I) used to prepare a medicament intended to inhibit the phosphatases Cdc25, and in particular the phosphatase Cdc25-C will include at least one of the following characteristics:
• R 1 representing an alkyl, cycloalkyl, alkoxyalkyl, - (CH 2 ) -XY, - (CH 2 ) -Z-NR 5 R 6 or-CHR 35 R 36 radical;
• R 2 representing a hydrogen atom or the methyl, ethyl or benzyl radical
• R 1 and R 2 forming together with the nitrogen atom a heterocycle of 4 to 8 members (preferably 5 to 7 members, and in particular 6 members) comprising from 1 to 2 heteroatoms (and preferably 2 heteroatoms) , the links necessary to complete the heterocycle being chosen independently from the radicals -CH -, -O- and -NR 17 (and preferably from the radicals -CH 2 - and -NR 17 -), R 17 representing a methyl or benzyl radical;
• R representing a hydrogen atom, a halogen atom or an alkyl, alkoxy or alkylthio radical
• R 4 representing an alkyl radical, -CH 2 -COOR 18 or -CH 2 -CO-NR 19 R 20 or 91 99 -CH 2 -NR R or else a carbocyclic or heterocyclic aryl radical optionally substituted from 1 to 4 times ( and in particular from 1 to 3 times) with substituents independently chosen from a halogen atom and an alkyl, haloalkyl, alkoxy or NR 37 R 38 radical.
• the compounds of general formula (I) in which W represents a sulfur atom will be preferred.
• Another interesting alternative for use in preparing a medicament intended to inhibit Cdc25 phosphatases, and in particular Cdc25-C phosphatase will nevertheless consist in using the compounds of general formula (I) in which W represents an oxygen atom.
• the radical X will preferably represent a bond or a linear alkylene radical containing from 1 to 5 carbon atoms.
• the radical Y will represent a saturated carbon ring system having 1 to 3 condensed rings independently chosen from 3 to 7-membered rings, or Y will represent an optionally substituted carbocyclic aryl radical (preferably optionally substituted by 1 to 3 radicals chosen from a halogen atom and an alkyl, haloalkyl, alkoxy, haloalkoxy, SO NHR 9 or NR 10 R ⁇ radical, and more preferably optionally substituted by 1 to 3 radicals chosen from a halogen atom and an alkyl, alkoxy, SO 2 NHR radical 9 or NR 10 R H ) or Y will represent an optionally substituted heterocyclic aryl radical, said heterocyclic aryl radical preferably being chosen from 5-membered aryl radicals (and in particular from imidazolyl, thienyl or pyridiny
• the radical Z will preferably represent an alkylene radical having 1 to 5 carbon atoms, and in particular a radical - (CH) P - in which p represents a integer from 1 to 3 (p preferably being equal to 1 or 2 and more preferably equal to 1).
• R and R will be independently chosen from a hydrogen atom and an alkyl radical, or alternatively R 5 and R 6 will form, together with the nitrogen atom which carries them, a 4 to 7 membered heterocycle comprising from 1 with 2 heteroatoms, said heterocycle then preferably being one of the azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, morpholinyl and thiomorpholinyl radicals optionally substituted with 1 to 3 alkyl radicals (and preferably with 1 to 3 methyl radicals); even more preferably, R 5 and R 6 will be independently chosen from alkyl or alkoxycarbonyl radicals (and in particular R 5 and R will each be a methyl or t ⁇ rt-butoxycarbonyl radical) or R and R will form together with the atom of nitrogen which carries them a 4- to 7-membered heterocycle comprising from 1 to 2 heteroatoms, said heterocycle then preferably being one
• radicals R 7 , R 12 , R 13 , R 15 , R 16 , R 26 , R 27 , R 39 and R 40 will preferably be chosen independently from a hydrogen atom and a methyl radical and the ⁇ - R 14 17 9R 41 radicals R, R, R, R and R will preferably be chosen independently from a hydrogen atom and a methyl or benzyl radical.
• R 19 and R 20 preference will be given to the cases in which R 19 represents a hydrogen atom, an alkyl radical or a benzyl radical and R 20 represents a hydrogen atom or the methyl radical, as well that those in which R 19 and R 20 form, together with the nitrogen atom which carries them, a 4- to 7-membered heterocycle comprising from 1 to 2 heteroatoms, said heterocycle then preferably being one of the azetidinyl and pyrrolidinyl radicals, piperidinyl, piperazinyl, homopiperazinyl, morpholinyl and thiomorpholinyl optionally substituted with 1 to 3 alkyl radicals (and preferably optionally substituted with 1 to 3 methyl radicals).
• R represents a hydrogen atom, an alkyl radical or a benzyl radical and R 22 represents a hydrogen atom or the methyl radical, as well as those in which R 21 99 and R form together with the nitrogen atom which carries them a 4 to 7-membered heterocycle comprising from 1 to 2 heteroatoms, said heterocycle then preferably being one of the azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl radicals , homopiperazinyl, morpholinyl and thiomorpholinyl optionally substituted.
• R and R these will preferably be such that R and R are independently chosen from a hydrogen atom and an alkyl radical and preferably from a hydrogen atom and a methyl radical (R 32 and R 33 even more preferably both representing hydrogen atoms) and that R 34 represents a hydrogen atom, an alkyl radical or a phenyl radical optionally substituted 1 to 3 times with substituents independently chosen from a halogen atom and an alkyl or alkoxy radical (R 34 even more preferably representing an atom hydrogen or a methyl or phenyl radical).
• R and R we will prefer the cases in which R and R form together with the carbon atom which carries them an indanyl radical or R 3 and R form together with the carbon atom which carries them a saturated heterocycle with 5 to 7 members and 1 to 2 heteroatoms chosen from O, N and S, the nitrogen atoms of said heterocycle being optionally substituted by radicals chosen from alkyl radicals and the benzyl radical.
• R and R preference will be given to the cases in which R and R independently represent radicals chosen from alkyl radicals.
• R 4 is a carbocyclic or heterocyclic aryl radical optionally substituted from 1 to 4 times, it is preferred that it is chosen from the group consisting of carbocyclic and heterocyclic aryl radicals optionally substituted from 1 to 3 times with substituents independently chosen from a halogen atom and an alkyl, haloalkyl, alkoxy, haloalkoxy or NR 37 R 38 radical (and in particular from 1 to 3 times by substituents independently chosen from a halogen atom and an alkyl, haloalkyl, alkoxy or haloalkoxy radical) and the 2,3,4,5-tetrafluorophenyl radical.
• R 4 when R 4 is a carbocyclic or heterocyclic aryl radical optionally substituted from 1 to 4 times, R 4 will be chosen from the group consisting of carbocyclic and heterocyclic aryl radicals optionally substituted from 1 to 2 times with substituents independently chosen from an atom halogen, an alkyl, haloalkyl, alkoxy, haloalkoxy or NR 37 R 38 radical (and in particular 1 to 2 times by substituents chosen independently from a halogen atom and an alkyl, haloalkyl, alkoxy or haloalkoxy radical), a radical 3,4 , 5-trihalophenyl and the 2,3,4,5-tetrafluorophenyl radical.
• the compounds of general formula (I), (I) ⁇ , (I) 2 , (I) 3 or (I) 4 used to prepare a medicament intended to inhibit the Cdc25 phosphatases, and in particular the Cdc25- phosphatase C will include at least one of the following:
• R 1 representing an alkyl, cycloalkyl, or - (CH 2 ) -Z-NR 5 R 6 radical; • R representing a hydrogen atom or the methyl radical;
• R representing a hydrogen atom, a halogen atom or the methoxy radical
• R 4 representing an alkyl radical, -CH -NR 21 R 22 , or also a carbocyclic or heterocyclic aryl radical optionally substituted from 1 to 4 times (and in particular from 1 to 3 times) by substituents chosen independently from a halogen atom and an alkyl radical, or NR 37 R 38 .
• the compounds of general formula (I), (I) ', (I) ", (I) ⁇ , (I) 2 , (1) 3 or (I) 4 used according to the invention will include at least one of the following:
• R 1 representing a radical - (CH 2 ) -Z-NR 5 R 6 ;
• R representing a hydrogen atom or a halogen atom (said halogen atom preferably being a chlorine or bromine atom);
• R representing an alkyl radical or a phenyl, pyridyl, thienyl or furanyl radical optionally substituted by 1 to 4 (preferably 1 to 3) halogen atoms or by a NR 37 R 38 radical.
• the compounds of general formula (I), (I) ⁇ . (1) 2, (1) 3 or (I) used to prepare a medicament intended to inhibit Cdc25 phosphatases, and in particular Cdc25-C phosphatase will include at least one of the following characteristics:
• R representing a hydrogen atom or a chlorine atom (and more preferably a hydrogen atom);
• R 4 representing an alkyl radical or a phenyl, pyridyl, thienyl furannyl radical optionally substituted by 1 to 4 (preferably 1 to 3) halogen atoms (and in particular R 4 representing an alkyl radical, and preferably an alkyl radical counting from 1 to 4 carbon atoms, and more preferably still a methyl or ethyl radical).
• W represents O.
• R 1 represents an aryl radical, and in particular a phenyl radical, optionally substituted 1 to 3 times with substituents chosen independently from a halogen atom and an alkyl, haloalkyl or alkoxy radical. More preferably, always when W represents O, it will be preferred that R 1 represents a phenyl radical optionally substituted by a halogen atom (said halogen atom preferably being a fluorine atom).
• R 4 will represent a phenyl radical or a heterocyclic aryl radical of 5 to 6 members optionally substituted 1 to 4 times (and preferably 1 to 3 times) by substituents chosen from the group consisting into halogen atoms, the trifluoromethyl radical and the trifluoromethoxy radical (and preferably chosen from the group consisting of halogen atoms and the trifluoromethyl radical).
• said optionally substituted 5 to 6 membered heterocyclic aryl will be an optionally substituted pyridine, thiophene, furar or pyrrole ring.
• the compounds of general formula (I), (I) ⁇ , (1) 2 , (1) 3 or (I) or their pharmaceutically acceptable salts will be used to prepare a medicament intended to treat a disease chosen from among the diseases following / the following disorders: proliferative tumor diseases, and in particular cancer, non-tumor proliferative diseases, neurodegenerative diseases, parasitic diseases, viral infections, spontaneous alopecia, alopecia induced by exogenous products, l radiation-induced alopecia, autoimmune diseases, transplant rejection, inflammatory diseases and allergies.
• a disease chosen from among the diseases following / the following disorders: proliferative tumor diseases, and in particular cancer, non-tumor proliferative diseases, neurodegenerative diseases, parasitic diseases, viral infections, spontaneous alopecia, alopecia induced by exogenous products, l radiation-induced alopecia, autoimmune diseases, transplant rejection, inflammatory diseases and allergies.
• the compounds of general formula (I), (I) ⁇ , (I) 2 , (1) 3 or (I) or their pharmaceutically acceptable salts may be used to prepare a medicament intended for treating cancer, and in particular breast cancer, lymphoma, neck and head cancer, lung cancer, colon cancer, prostate cancer and pancreatic cancer.
• the compounds of general formula (I), (I) ⁇ , (1) 2, (1) 3 or (I) or their pharmaceutically acceptable salts can be used to prepare a medicine intended to treat spontaneous alopecia, alopecia induced by exogenous products or radio-induced alopecia.
• An object of the invention relates to a compound of general formula (II)
• R 1 represents a hydrogen atom or an alkyl, alkoxyalkyl, alkylthioalkyl, cycloalkyl, - (CH 2 ) -XY, ⁇ (CH 2 ) -Z-NR 5 R 6 radical or a -CHR 35 R 36 radical in which R 35 and R 36 together form with the carbon atom which carries them an indanyl or tetralinyl radical, or alternatively R 35 and R 36 together form with the carbon atom which carries them 1 a saturated heterocycle having 5 to 7 members and from 1 to 2 heteroatoms chosen from O, N and S, the nitrogen atoms of said heterocycle being optionally substituted by radicals chosen from alkyl radicals and the benzyl radical,
• R 1 can also, when W represents O, also represent a carbocyclic aryl radical optionally substituted 1 to 3 times with substituents chosen independently from a halogen atom and an alkyl, haloalkyl or alkoxy radical, X representing a bond or an alkylene radical linear or branched with 1 to 5 carbon atoms,
• Y representing a saturated carbon ring system having 1 to 3 condensed rings independently chosen from 3 to 7-membered rings, or Y representing a saturated heterocycle having 1 to 2 heteroatoms chosen independently from O, N and S and attached to the radical X by an N or CH link, said saturated heterocycle also counting from 2 to 6 additional links chosen independently from -CHR -, -CO-, -NR 8 -, -O- and -S-, R 7 representing an atom d hydrogen or an alkyl radical and R 8 representing a hydrogen atom or an alkyl or aralkyl radical, or alternatively Y representing a carbocyclic or heterocyclic aryl radical optionally substituted 1 to 3 times with substituents chosen independently from the group consisting of a halogen atom, an alkyl radical, a haloalkyl radical, an alkoxy radical, a haloalkoxy radical, a hydroxy radical, a nitro radical, a cyano radical, the phenyl radical
• Z representing a bond or a linear or branched alkylene radical having 1 to 5 carbon atoms
• R 5 and R being independently chosen from a hydrogen atom, an alkyl, aralkyl or - (CH 2 ) n -OH radical in which n represents an integer from 1 to 6, or R 5 representing an alkoxycarbonyl, haloalkoxycarbonyl or aralkoxycarbonyl radical and R 6 representing a hydrogen atom or a methyl radical, or alternatively R 5 and R 6 forming together with the nitrogen atom a 4- to 7-membered heterocycle comprising from 1 to 2 heteroatoms, the links necessary to complete the heterocycle being chosen independently from the radicals -CR 12 R 13 -, -O-, -S- and -NR 14 -, R 12 and R 13 independently representing each time they intervene a hydrogen atom or an alkyl radical, and R 14 representing a hydrogen atom or an alkyl or aralkyl radical, or alternatively R 14 representing
• R 3 represents a hydrogen atom, a halogen atom, or an alkyl, haloalkyl, alkoxy or alkylthio radical;
• R 4 represents a radical -CH -Ar in which Ar represents an aryl radical optionally substituted from 1 to 4 times (and in particular from 1 to 3 times) by substituents chosen independently from a halogen atom and an alkyl, haloalkyl, alkoxy radical , haloalkoxy or NR 42 R 43 , or also R 4 represents a biphenyl radical,
• R 42 and R 43 being independently chosen from a hydrogen atom and an alkyl radical or R 42 and R 43 forming together with the nitrogen atom a 4 to 7 membered heterocycle comprising from 1 to 2 heteroatoms, the necessary members to complete the heterocycle being independently chosen from the radicals -CR 44 R 45 -, -O-, -S- and -NR 4 -, R 44 and R 45 representing each time independently a hydrogen atom or an alkyl radical, and R 46 representing a hydrogen atom or an alkyl radical; and the salts of compounds of general formula (II) defined above
• Cdc25 phosphatase inhibitors can be used as Cdc25 phosphatase inhibitors, and in particular inhibitors of Cdc25-C phosphatase, and / or of CD 45 phosphatase.
• the invention also relates, as medicaments, to the compounds of general formula (II) or their pharmaceutically acceptable salts. It further relates to pharmaceutical compositions comprising, as active principle, one of the compounds of general formula (II) or a pharmaceutically acceptable salt thereof, as well as at least one pharmaceutically acceptable excipient.
• said compounds or their pharmaceutically acceptable salts will be used to prepare a medicament intended to treat a disease chosen from the following diseases / the following disorders: proliferative tumor diseases, and in particular cancer, non-tumor proliferative diseases, neurodegenerative diseases, parasitic diseases, viral infections, spontaneous alopecia, alopecia induced by exogenous products, radio-induced alopecia, autoimmune diseases, transplant rejection, inflammatory diseases and allergies.
• said compounds or their pharmaceutically acceptable salts may be used to prepare a medicament intended to treat cancer, and in particular breast cancer, lymphomas, neck and head cancers, lung cancer, cancer of the colon, prostate cancer and pancreatic cancer.
• the compounds of general formula (II) also correspond to the general sub-formula (II) 2
• the compounds of general formula (II) also correspond to the general sub-formula (II) 3
• ⁇ R.4 will represent a radical -CH -Ar according to one of the possible variants for the compounds of general formula (II).
• R 4 represents a radical -CH 2 -Ar in which Ar represents an aryl radical optionally substituted from 1 to 4 times by substituents chosen independently from a halogen atom and an alkyl, haloalkyl or alkoxy radical. or haloalkoxy.
• R 4 will represent a radical -CH 2 -Ar in which Ar represents an aryl radical optionally substituted from 1 to 4 times by substituents chosen independently from a halogen atom and an alkyl or haloalkyl radical.
• R 4 will represent a radical -CH -Ar in which Ar represents an aryl radical optionally substituted optionally substituted 1 to 4 times (in particular 1 to 3 times and more particularly 1 to 2 times) with halogen atoms (which will preferably be chosen from chlorine and fluorine atoms).
• R 4 will represent a biphenyl radical, and in particular the 4-phenyl-phenyl radical.
• R 1 , R 2 , R 3 and W are as defined in the general formula (I) and R 4 is either as defined in the general formula (I), or as defined in the general formula (II).
• the compounds of general formula (III) also correspond to the general sub-formula (III) ⁇
• the compounds of general formula (III) also correspond to the general sub-formula (III)
• R 1 representing an alkyl, cycloalkyl, alkoxyalkyl, - (CH 2 ) -XY, - (CH 2 ) -Z-NR 5 R 6 or-CHR 35 R 36 radical;
• R 2 representing a hydrogen atom or the methyl, ethyl or benzyl radical
• R 1 and R 2 forming together with the nitrogen atom a heterocycle of 4 to 8 members (preferably 5 to 7 members, and in particular 6 members) comprising from 1 to 2 heteroatoms (and preferably 2 heteroatoms) , the links necessary to complete the heterocycle being chosen independently from the radicals -CH-, -O- and -NR 17 (and preferably from the radicals -CH 2 - and -NR 17 -), R 17 representing a methyl radical or benzyl;
• R 3 representing a hydrogen atom, a halogen atom or an alkyl, alkoxy or alkylthio radical
• R 4 representing an alkyl radical, -CH 2 -COOR 18 or -CH 2 -CO-NR 19 R 20 or -CH 2 -NR 21 R 22 , a carbocyclic or heterocyclic aryl radical optionally substituted from 1 to 4 times (and in particular from 1 to 3 times) with substituents chosen independently from a halogen atom and an alkyl, haloalkyl, alkoxy or NR 37 R 38 radical or alternatively R 4 representing a radical -CH 2 -Ar in which Ar represents an optionally substituted aryl radical from 1 to 4 times with substituents independently chosen from a halogen atom and an alkyl, haloalkyl, alkoxy or haloalkoxy radical.
• R 1 representing a radical - (CH 2 ) -Z-NR 5 R 6 ;
• R 3 representing a hydrogen atom or a halogen atom (said halogen atom preferably being a chlorine or bromine atom);
• R 4 representing an alkyl radical or a phenyl, pyridyl, thienyl or furanyl radical optionally substituted by 1 to 4 (preferably 1 to 3) halogen atoms or by a radical NR 37 or also R representing a radical -CH 2 -Ar in which Ar represents a phenyl or naphthyl radical optionally substituted from 1 to 4 times (and preferably from 1 to 3 times) by substituents chosen independently from a halogen atom and an alkyl, haloalkyl, alkoxy or haloalkoxy radical.
• R 3 representing a hydrogen atom or a chlorine atom (and more preferably a hydrogen atom);
• R 4 representing an alkyl radical or a phenyl, pyridyl, thienyl, furannyl, benzyl or naphthylmethyl radical optionally substituted by 1 to 4 (preferably 1 to 3 -) - halogen atoms-on the aromatic-du ⁇ .adical part .
• the compounds of general formula (III), (HI) ⁇ , (111) 2, (HI) 3 or (111) 4 (and in particular the compounds of general formula (t), (I) ⁇ , () 2 , or (1) or the compounds of general formula (II), (II) ⁇ , (II) 2 , (H) 3 or (II) 4 ) can be prepared according to an oriented preparation process.
• Said method makes it possible to substitute either position 5 or position 6 of the benzothiazole-4,7-dione or benzoxazole-4,7-dione nucleus and therefore to obtain a compound of general formula (III) and not the compound of formula general (HI) 3 corresponding (or vice versa), or a compound of general formula (111) 2 and not the compound of general formula HI) 4 corresponding (or vice versa).
• the invention therefore relates firstly to a process for the preparation of a compound of general formula (III) ⁇ or (111) 2 as defined above in which R 3 represents a hydrogen atom, said process being characterized in that the compound of general formula (A) is reacted
• W represents a sulfur atom or an oxygen atom and R 4 has the same meaning as in the general formula (III) ⁇ or (111) 2 with an amine of formula 1 9 general RR NH in a protic solvent at a temperature preferably between 20 ° C and the boiling point of the solvent.
• the invention relates in particular to a process for the preparation of a compound of general formula (I) ⁇ or (I) 2 as defined above in which R 3 represents a hydrogen atom, said process being characterized in that the the compound of general formula (A) is reacted
• W represents a sulfur atom or an oxygen atom and R 4 has the same meaning as in the general formula (I) ⁇ or (1) 2 with an amine of formula 1 9 general RR NH in a protic solvent with a temperature preferably between 20 ° C. and the boiling point of the solvent.
• the protic solvent for the abovementioned processes will be chosen from ethanol and methanol.
• the invention also relates to a process for the preparation of a compound of general formula (111) 3 or (III) 4 as defined above in which R 3 represents a hydrogen atom, said process being characterized in that one reacts the compound of general formula (K)
• W represents a sulfur atom or an oxygen atom and R 4 has the same meaning as in general formula (111) 3 or (III) 4 with an amine of formula general R ⁇ R 2 NH in a protic solvent at a temperature preferably between 20 ° C and the boiling point of the solvent.
• the invention relates in particular to a process for the preparation of a compound of general formula (I) 3 or (I) 4 as defined above in which R 3 represents a hydrogen atom, said process being characterized in that the the compound of general formula (K) is reacted
• W represents a sulfur atom or an oxygen atom and R 4 has the same meaning as in general formula (1) 3 or (I) 4 with an amine of general formula 1 9 RR NH in a protic solvent with a temperature preferably between 20 ° C. and the boiling point of the solvent.
• the protic solvent for the abovementioned processes will be chosen from ethanol and methanol.
• the invention also relates, as new products, to the compounds of general formula (A) in which W and R 4 have the meaning indicated above, it being understood however that if W represents a sulfur atom then R 4 is not methyl, as well as the salts thereof.
• the invention thus relates in particular, as new products, the compounds of general formula (A) in which W represents an oxygen atom (hereinafter respectively the compounds of general formula (A ')), as well as the salts of these.
• the invention therefore relates in particular, as new products, to the compounds of general formula (K) in which W represents an oxygen atom (hereinafter respectively the compounds of general formulas (K ')), as well as the salts of these.
• the invention also relates to the compounds of general formula (III) chosen from the following compounds:
• the invention also relates, as medicaments, to said compounds of general formula (I), (II) or (III) or to their pharmaceutically acceptable salts. It further relates to pharmaceutical compositions comprising, as active principle, one of said compounds of general formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, as well as at least one pharmaceutically acceptable excipient.
• said compounds or their pharmaceutically acceptable salts will be used to prepare a medicament intended to treat a disease chosen from the following diseases / the following disorders: proliferative tumoral diseases, and in particular cancer , non-tumor proliferative diseases, neurodegenerative diseases, parasitic diseases, viral infections, spontaneous alopecia, alopecia induced by exogenous products, radio-induced alopecia, autoimmune diseases, transplant rejection , inflammatory diseases and allergies.
• said compounds or their pharmaceutically acceptable salts may be used to prepare a medicament intended for treating cancer, and in particular breast cancer, lymphomas, neck and head cancers, lung cancer, cancer of the colon, prostate cancer and pancreatic cancer.
• the compounds of the invention can also be used in a treatment method proliferative tumor diseases, and in particular cancer, non-tumor proliferative diseases, neurodegenerative diseases, parasitic diseases, viral infections, spontaneous alopecia, alopecia induced by exogenous products, radio alopecia -induced, autoimmune diseases, transplant rejection, inflammatory diseases and allergies, said method comprising the administration of a therapeutically effective dose of a compound of general formula (I), (I) 15 (1 ), (1) 3 or (I) 4 , (II), (H) ⁇ . (H) 2, (II) 3 or (II) 4 or (III), (III) !, (HI) 2 , (
• compositions containing a compound of the invention can be in the form of solids, for example powders, granules, tablets, capsules, liposomes or suppositories.
• Suitable solid carriers can be, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, carboxymethyl cellulose sodium, polyvinylpyrrolidine and wax.
• compositions containing a compound of the invention can also appear as liquid form, for example, solutions, emulsions, suspensions or syrups.
• suitable liquid carriers can be, for example, water, organic solvents such as glycerol or glycols, as well as their mixtures, in varying proportions, in water.
• the administration of a medicament according to the invention can be done by topical, oral, parenteral route, by intramuscular injection, etc.
• the administration dose envisaged for a compound of general formula (I), (I) ⁇ , (1) 2, (I) 3 or (I) 4 , (II), (II) ⁇ , (II) 2 , (II) 3 or (II) 4 or (III), (III) !, (III) 2 , (III) 3 or (III) 4 is between 0.1 mg to 10 g depending on the type of active compound used .
• the following methods can be used to obtain exclusively a compound of general formula (III) ⁇ and not the corresponding compound of general formula (111) 3 (or vice versa), or even a compound of general formula (111) 2 and not the corresponding compound of general formula (111) 4 (or vice versa).
• This process can obviously be used mutatis mutandis to obtain the compounds of general formula (I) and (II) regioselectively. Only the methods for obtaining the compounds of general formula (III) will therefore be described below.
• the compounds of general formula (III) ! or (111) 2 in which R 3 represents H can be prepared according to the method illustrated in scheme 1 below.
• W, R 1 , R 2 and R 4 are as defined above and R 3 represents H, are obtained by treatment of the compounds of general formula (A) with amines of general formula
• R ! R 2 NH in a practical solvent such as methanol or ethanol, at a temperature of preferably between 25 ° C and the boiling point of the solvent (Yasuyuki Kita et al., J. Org. Chem. (1996), 61, 223-227).
• W represents a sulfur atom
• the compounds of general formula (A) in which R 4 is as defined above can be obtained by oxidative demethylation of the compounds of general formula (B), for example by treatment with chromium oxide (NI) in l acetic acid (JM by L. Nanderlei et al., Tetrahedron: Asymmetry (1997), 8 (16), 2781-2785), or by treatment with a 50% solution of hydrogen peroxide in the presence of phosphomolybdic acid and formic acid (AS Chida et al., Synth Commun (2001), 5, 657-660), or by treatment with dichlorodicyanoquinone (DDQ) in an H 2 O / THF mixture (K.
• NI chromium oxide
• JM chromium oxide
• JM chromium oxide
• a 50% solution of hydrogen peroxide in the presence of phosphomolybdic acid and formic acid AS Chida et al.
• nitro compound of general formula (Bi) can be obtained by treating the compound of general formula (B) with cerium and ammonium nitrate (CAN).
• the compound of general formula (A) can then be obtained after reduction of the nitro group by the action of hydrogen in the presence of palladium on carbon or by the action of tin chloride to obtain the intermediate of general formula (B.ii) which is then oxidized to finally give the quinone of general formula (A) by the action of cerium and ammonium nitrate (cf. diagram 3 below; K. Mohri et al., Chem Pharm Bull, (1998), 12, 1872-1877).
• the compounds of general formula (B), in which R 4 is as defined above, can be obtained in 3 steps (MA Lyon et al., J. Chem. Soc, Perkin Trans 1, (1999), 437- 442) from 3,5-dimethoxyaniline successively transformed into amide (D) by the action of the corresponding acid chloride according to conventional methods known to those skilled in the art.
• the amides of general formula (D) are then transformed into thioamides of general formula (C) by treatment with Lawesson's reagent in dry toluene at a temperature preferably between 80 ° C. and reflux for a period preferably between 2 hours and 18 hours, or with potassium pentasulfide in DME at a temperature preferably between 85 ° C. and reflux.
• the compounds of general formula (A), in which R 4 is as defined above, can be obtained in 3 steps from 4-methoxy-2,6-dinitrophenol (described in particular by P. Cotelle and J.- P. Catteau, Synth. Commun., 26, (1996), 4105-4112), which once esterified to give the intermediate of general formula (Fi) according to the usual methods known to those skilled in the art can be subjected to the action of a reducing agent under dehydrating conditions (such as, for example, tin and hydrogen chloride in ethanol described by YAM Marghlani et al. Pakistan J. Sci. Ind. Res.
• a reducing agent under dehydrating conditions such as, for example, tin and hydrogen chloride in ethanol described by YAM Marghlani et al. Pakistan J. Sci. Ind. Res.
• 4-methoxy-2,6-dinitrophenol can be reduced, for example by the action of hydrogen in the presence of palladium on carbon, then without isolating the intermediate (F.ii), can be condensed with a thioimidate of general formula (T) in a protic solvent such as ethanol at a temperature between 25 ° C and the boiling temperature of the solvent (according to the method described in particular by S. Rostamizadeh et al. J.
• RR NH in a protic solvent such as methanol or ethanol, at a temperature preferably between 25 ° C and the boiling temperature of the solvent (Yasuyuki Kita et al., J. Org. Chem. (1996), 61, 223-227).
• W represents a sulfur atom
• Diagram 6 The compounds of general formula (K) in which R is as defined above can be obtained according to a process analogous to that described for the preparation of intermediates of general formula (A) (cf. diagrams 2 and 3), the product starting material being 2,4-dimethoxyaniline (commercial).
• 6-methoxy-1,3-benzothiazol-2-amine (commercial) is transformed, according to the Sandmeyer method, known to those skilled in the art, into 2-bromo -6-methoxy-1,3-benzothiazole, itself nitrated according to the methods known to those skilled in the art to obtain 2-bromo-6-methoxy-7-nitro-1,3-benzothiazole.
• the intermediate of general formula (K-ii) is then obtained by condensation with boronic acids, according to the method of Suzuki, known to those skilled in the art.
• the intermediates of general formula (K) are obtained after reduction of the nitro group by the action of hydrogen in the presence of palladium on carbon or by the action of tin chloride to obtain the intermediate of general formula (Ki) which is then oxidized to obtain the quinone of general formula (K) by action of Frémy salt in acetone in the presence of a sodium hydrogen phosphate solution (GR Allen Jr et al., J Med Chem (1967), 10, 23).
• ii) W represents an oxygen atom:
• 5-methoxy-2-nitrophenol (commercial) is transformed into a 6-methoxy-benzoxazole derivative of general formula (S), either using an esterification / dehydrating reduction reaction such as that presented in diagram 4, either by reduction followed by condensation described above.
• the intermediate of general formula (S) is then nitrated and reduced to the corresponding amine of general formula (R) according to the process presented in scheme 3, then oxidized as previously to quinone of general formula (K).
• the term “approximately XX ° C.” indicates that the temperature in question corresponds to an interval of plus or minus 10 ° C. around the temperature of XX ° C., and preferably at an interval of plus or minus 5 ° C around the temperature of XX ° C.
• the compounds are characterized by their retention time (tr), expressed in minutes, determined by liquid chromatography (CL), and their molecular peak (MH +) determined by mass spectrometry (SM), a simple quadrupole mass spectrometer (Micromass, Platform model) equipped with an electrospray source is used with a resolution of 0.8 da at 50% of valley.
• elution conditions corresponding to the results indicated are as follows: elution with an acetonitrile-water-trifluoroacetic acid mixture 50-950-0.2 (A) for 1 minute, then passage of the mixture A to an acetonitrile-water mixture 950-50 (B) by a linear gradient over a period of 7.5 minutes, then elution with pure mixture B for 2 minutes.
• RM ⁇ 1H (DMSO d ⁇ , 400 MHz, ⁇ ): 7.65 (m, 1H, H arom.); 7.36 - 7.31 (m, 3H, H arom.); 6.75 (m, 1H, H arom.); 3.96 (s, 3H, CH 3 ); 3.87 (s, 3H, CH 3 ).
• Examples 2 to 7 are obtained in a similar manner to that described for Example 1, the adequate acyl chlorides replacing 2,6-difluorobenzoyl chloride in the first step and N- (2-aminoethyl) pyrrolidine replacing N, N-dimethylethylenediamine in the last step for Examples 3, 5 and 7.
• the protocol is identical to that described for step 1.5 of Example 1, the 2- (4-fluorophenyl) -6-methoxy- 1, 3 -benzothiazole-4,7-dione replacing the 2- (2,6-difluorophenyl) -5-methoxy-l, 3-benzothiazole-4,7-dione.
• the expected compound is obtained in the form of a red powder. Melting point: 246-247 ° C.
• Example 12 2- (2-chloro-6-fluorophenyl) -6 - ⁇ [2- (dimethylamino) ethyl] amino ⁇ - 1,3-benzothiazole-4,7-dione:
• the protocol is identical to that described for step 1.5 of Example 1, 6-methoxy- 2- (2-naphthyl) -1,3-benzothiazol-4,7-dione replacing 2- (2.6 -difluorophenyl) - 5-methoxy-1,3-benzothiazol-4,7-dione.
• the expected compound is obtained in the form of a red powder. Melting point: 167-168 ° C.
• Example 14 The compound of Example 14 is obtained in a similar manner to that described for Example 13, the 2,5-difluorophenylboronic acid replacing the 2-naphthalene boronic acid in the third step.
• Examples 16 to 23 are obtained in a similar manner to that described for Example 15, the appropriate methyl carbimidothioate replacing the methyl 2,5-difluorobenzenecarbimidothioate iodhydrate in the third step.
• Examples 24 to 26 are obtained in a similar manner to that described for Example 15, the appropriate methyl carbimidothioate replacing methyl 2,5-difluorobenzenecarbimidothioate iodhydrate in the third stage and N- (2-aminoethyl ) pyrrolidine replacing N, N-dimethylethylenediamine in the last step.
• the expected compound is obtained in the form of a red powder. Melting point: 182-183 ° C.
• the expected compound is obtained in the form of a black powder. Melting point: 193-194 ° C.
• Examples 28 to 44 are obtained in a similar manner to that described for Example 27, the appropriate methyl carbimidothioate replacing the methyl 2,5-difluorobenzenecarbimidothioate iodhydrate in the third step.
• the expected compound is obtained in the form of a pink powder. Melting point: 147-148 ° C.
• the expected compound is obtained in the form of a red powder. Melting point: 178-179 ° C.
• Example 36 6 - ⁇ [2- (dimethylamino) ethyl] amino ⁇ -2- (3,4,5-trifluorophenyl) - 1,3-benzoxazole-4,7-dione:
• the expected compound is obtained in the form of a red powder. Melting point: 188-189 ° C.
• the expected compound is obtained in the form of a red powder. Melting point: 165-166 ° C.
• the expected compound is obtained in the form of a red powder. Melting point: 151-152 ° C.
• the expected compound is obtained in the form of a red powder. Melting point: 163-164 ° C.
• the expected compound is obtained in the form of a black powder. Melting point: 181-182 ° C.
• the expected compound is obtained in the form of a red powder. Melting point: 172-173 ° C.
• the expected compound is obtained in the form of a red powder. Melting point: 178-179 ° C.
• the expected compound is obtained in the form of a red powder. Melting point: 153-154 ° C.
• Example 45 2- (2-bromophenyl) -6 - [(2-pyrrolidin-1-ylethyl) amino] - 1,3-benzoxazole-4,7-dione:
• the expected compound is obtained in the form of a red powder. Melting point: 198.5-199.5 ° C.
• the expected compound is obtained in the form of a red powder. Melting point: 173-174 ° C.
• the expected compound is obtained in the form of a brown powder. Melting point: 171-172 ° C.
• Example 60 The compound of Example 60 is obtained in a similar manner to that described for Example 13, the n-hexylboronic acid replacing the 2-naphthalene boronic acid in the third step.
• the phosphatase activity of the protein MBP-Cdc25C is evaluated by the dephosphorylation of 3-O-methylfluorescein phosphate (OMFP) to 3-O-methylfluorescein (OMF) with a determination of the fluorescence at 475 nm from the reaction product. This test makes it possible to identify inhibitors of the recombinant enzyme Cdc25.
• the preparation of the fusion protein MBP-Cdc25C is described in PCT patent application WO 01/44467.
• the reaction is carried out in 384-well plate format with a final volume of 50 ⁇ l.
• the MBP-Cdc25C protein (prepared as described above) is stored in the following elution buffer: 20 mM Tris-HCl pH 7.4; 250 mM NaCl; ImM EDTA; 1 mM dithiotlireitol (DTT); 10 mM maltose. It is diluted to a concentration of 60 ⁇ M in the following reaction buffer: 50 mM Tris-HCl pH 8.2; 50 mM NaCl; 1 mM DTT; 20% glycerol.
• the background noise measurement is carried out with the buffer without addition of the enzyme. The products are tested at decreasing concentrations from 40 ⁇ M.
• the reaction is initiated by the addition of a final 500 ⁇ M OMFP solution (prepared extemporaneously from a 12.5 mM stock solution in 100% DMSO (Sigma # M2629)). After 4 hours at 30 ° C. in a 384-well disposable plate, the fluorescence measured at OD 475 nm is read using a Victor plate reader (EGG-Wallac). The determination of the concentration inhibiting the enzymatic reaction by 50% is calculated from three independent experiments. Only the values contained in the linear part of the sigmoid are used for the linear regression analysis. ii) Measurement of the tyrosine phosphatase activity of the CD45 enzyme:
• the measurement of the tyrosine phosphatase activity of CD45 is based on the dephosphorylation by CD45 of the peptide pp60 c "src .
• the substrate is a synthetic peptide based on the negative regulatory domain sequence of pp60 c "src .
• the released phosphate is measured by a reagent of the green malachite type.
• the reaction is carried out in 384-well plate format with a final volume of 20 ⁇ l.
• the pp60 c "src substrate (P-301, BIOMOL, Madison Meeting, PA, USA) is diluted to a concentration of 925 ⁇ M in the following reaction buffer: 50 mM Hepes pH 7.2;
• DU145 human prostate cancer cells
• Mia-PaCa2 human pancreatic cancer cells
• the quantification of proliferation cell is evaluated by colorimetric test based on the cleavage of the tetrazolium salt WST1 by mitochondrial dehydrogenases in viable cells leading to the formation of formazan (Boehringer Mannheim, Meylan, France). These tests are carried out in duplicate with 8 determinations per concentration tested. For each compound to be tested, the values included in the linear part of the sigmoid were used for a linear regression analysis and used to estimate the inhibitory concentration IC 5 o. The products are dissolved in dimethylsulfoxide (DMSO) at 10 "2 M and used in culture with 0.1% DMSO in the end.
• DMSO dimethylsulfoxide
• the compounds of Examples 1 to 60 have an IC 5 o less than or equal to 10 microM of the phosphatase activity of the recombinant enzyme Cdc25-C purified.
• the compounds of Examples 1 to 60 have an IC 5 o less than or equal to 10 microM on cell proliferation lines Mia-Paca2.
• the compounds of Examples 1 to 60 have an IC 5 o less than or equal to 10 microM on cell proliferation of DU-145 cell lines.

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• 2003
  • 2003-06-25 FR FR0307648A patent/FR2856686A1/fr active Pending
• 2004
  • 2004-06-24 AU AU2004251912A patent/AU2004251912A1/en not_active Abandoned
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