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Definitions

• the present invention relates to pyrazolo-pyrazine derivatives. These compounds are inhibitors of G proteins. They are therefore particularly interesting for treating pathologies that result from the involvement of the heterotrimeric G protein.
• the invention also relates to pharmaceutical compositions containing said products and their use for the preparation of a medicament.
• G proteins are in fact the structural association of three distinct subunits called ⁇ , ⁇ and ⁇ , but function as dissociable entities consisting of ⁇ subunits on one side and ⁇ / ⁇ dimers on the other. .
• G-proteins participate in the transmission of signals from the outside of the cell through their interactions with receptors with seven transmembrane domains inward through different effectors including adenylate cyclase, phospholipase C or ion channels.
• the adenylate cyclase enzyme generates cyclic AMP (cAMP) (see Gilman, A.G. Biosci.Rep 15, 65-97 (1995)).
• cAMP cyclic AMP
• ⁇ / ⁇ dimers can directly activate effectors leading to the activation of kinases regulated by extracellular signals (ERKs) or MAP kinases.
• ERKs extracellular signals
• MAP kinases kinases regulated by extracellular signals
• a direct link between the ⁇ / ⁇ subunits and the src or src like kinases has been demonstrated (see Gutkind, J.S. J.Biol.Chem.273, 1839-1842 (1998)).
• bacterial toxins such as Vibrio cholera and Bortella pertussis
• peptides such as mastoparan and suramin
• G proteins see Freissmuth, M., Boehm, S., Beindl, W. Mol., Pharmacol., 49, 602-611 (1996), Boehm, S., Huck, S., Motejlek, A., et al., Journal of Negrochemistry 66, 1019-1026 (1996), Cachera, TG. , Rigual, R., Rocher, A.
• cholera toxin subunit modifies oc s G protein by adding an ADP-ribose from NAD to a specific arginine acceptor site. This completely blocks the activity of GTPase, causing persistent stimulation of its effector following adenylate cyclase and leading to overproduction of cAMP.
• cAMP cAMP-like kinase kinase
• the adverse effects of an abnormal level of cAMP include the following biological functions or disorders: smell, taste, light perception, neurotransmission, neurodegeneration, functioning of the endocrine and exocrine glands, autocrine regulation and paracrine, blood pressure, embryogenesis, benign cell proliferation, oncogenesis, viral infection and immunological functions, diabetes, obesity and pain.
• Z represents a hydrogen atom or a radical of general formula
• R 1 and R 2 represent, independently, a hydrogen atom, an aryl or heteroaryl radical, the aryl and heteroaryl radicals being optionally substituted by one or more idenic or different substituents chosen from: halo, hydroxy, alkyl, haloalkyl, alkoxy, haloalkoxy, aryl, aryloxy, -NRR 1 , -C (O) -NRR 1 , -NR N -C (O) R 1 , -SO 2 -R, -SiRR 1 R "or a heterocycloalkyl, or a radical of formula
• R 1 and R 2 together with the carbon atoms to which they are attached form a cycloalkyl or heterocycloalkyl radical
• R 3 represents a radical (CrC ⁇ ) alkyl or a cycloalkylalkyl, aryl or arylalkyl radical, the aryl group of the aryl and arylalkyl radicals being optionally substituted by one or more idenic or different substituents chosen from: halo, hydroxy, alkyl, haloalkyl, alkoxy, haloalkoxy, aryl, aryloxy, -NRR 1 , -C (O) -NRR ", -NR N -C (O) R", -SO 2 -R, -SiRR 1 R "or a heterocycloalkyl;
• R N represents a hydrogen atom or an alkyl radical
• R, R 1 and R represent, independently, an alkyl or aryl radical
• R 4 represents a hydrogen atom or a radical of formula -CO-OR 5 ;
• R 5 represents an alkyl or arylalkyl radical
• n the integer 1 or 2;
• X represents a sulfur atom or a selenium atom; or a pharmaceutically acceptable salt thereof.
• halo represents the fluoro, chloro, bromo or iodo radical, preferably fluoro, chloro or bromo.
• alkyl when not more precise is meant a linear or branched alkyl radical of 1 to 6 carbon atoms, for example the methyl, ethyl, propyl, isopropyl, butyl, isobutyl or sec-butyl radicals. and tert-butyl, pentyl, neopentyl, isopentyl, hexyl, isohexyl.
• (C r C 8 ) alkyl denotes an alkyl radical having from 1 to 8 carbon atoms, linear or branched, such radicals containing from 1 to 6 carbon atoms as defined above but also the linear or branched radicals containing 7 or 8 carbon atoms, for example heptyl, octyl, 1,1,2,2-tetramethylpropyl, 1,1,3,3-tetramethylbutyl.
• C4-C8 alkyl means an alkyl radical as defined above and containing from 4 to 8 carbon atoms.
• Haloalkyl means an alkyl radical of which at least one of the hydrogen atoms (and possibly all) is replaced by a halo radical such as trifluoromethyl, dichloroethyl.
• alkoxy denotes radicals in which the alkyl radical is as defined above such as, for example, methoxy, ethoxy, propyloxy or isopropyloxy radicals, but also linear, secondary or tertiary butoxy, pentyloxy radicals.
• haloalkoxy is meant an alkoxy radical in which at least one of the hydrogen atoms (and possibly all) is replaced by a halo radical such as trifluoromethoxy, dichloroethoxy.
• cycloalkyl refers to a saturated carbon monocyclic system comprising from 3 to 7 carbon atoms, and preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl rings.
• cycloalkylalkyl preferably refers to radicals in which the cycloalkyl and alkyl radicals are as defined above such as for example cyclohexyl-methyl, cyclohexyl-ethyl, cyclopropyl-methyl.
• heterocycloalkyl denotes a fused monocyclic or bicyclic saturated system comprising from 2 to 6 carbon atoms and at least one heteroatom.
• This radical can contain several identical or different heteroatoms.
• the heteroatoms are selected from oxygen, sulfur or nitrogen.
• heterocycloalkyl examples include pyrrolidine, imidazolidine, pyrrazolidine, isothiazolidine, thiazolidine, isoxazolidine, oxazolidine, piperidine, piperazine, azepane (azacycloheptane), azacyclooctane, diazepane, morpholine, decahydroisoquinoline (or decahydroquinoline), tetrahydrofuran or tetrahydrothiophene.
• aryl represents an aromatic radical consisting of one ring or from 2 to 3 fused rings, for example the phenyl, naphthyl or fluorenyl radical.
• aralkyl preferably refers to radicals in which the aryl and alkyl radicals are as defined above such as, for example, benzyl, homobenzyl or phenethyl.
• arylalkoxy preferably denotes radicals in which the aryl and alkoxy radicals are as defined above such as, for example, benzyloxy or phenylethoxy.
• heteroaryl refers to an aromatic radical, consisting of one ring or 2 to 3 fused rings, with at least one ring containing one or more identical or different heteroatoms selected from sulfur, nitrogen or oxygen.
• a heteroaryl radical mention may be made of the pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, thiazolyl, isoxazolyl, oxazolyl, triazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, quinoxalinyl, indolyl, benzoxadiazoyl, carbazolyl, purinyl or triazinyl radicals.
• pyrrazolo-pyrimidyl but also thienyl, benzothienyl, furyl, benzofuryl or pyranyl, and preferably thienyl, furanyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, thiazolyl, oxazolyl and pyridyl.
• the subject of the present invention is also compounds of general formula I as defined above, or one of its diastereoisomers, as well as one of its pharmaceutically acceptable salts in which
• R1 or R2 independently represents a hydrogen atom, an aryl radical or a heteroaryl radical, optionally substituted 1 to 3 times (and preferably 1 to 2 times) by a halogen atom, by an alkyl radical or by an alkoxy radical; ;
• R 1 and R 2 taken together may also form a ring or heterocycle
• R 3 represents a C1-C8 alkyl radical or a cycloalkylalkyl radical or an aryl or arylalkyl radical;
• R 4 represents a hydrogen atom or a -CO-OR 5 radical with R 5 being either a linear or branched alkyl radical or a methylfluorene or benzyl radical;
• n the integer 1 or 2;
• X represents a sulfur atom or a selenium atom
• Z represents a hydrogen atom or a radical of general formula below
• a radical is optionally substituted from 1 to 3 times, it is preferably optionally substituted 1 to 2 times and more preferably optionally substituted once.
• the invention preferably relates to compounds of formula I as defined above and characterized in that Z represents a hydrogen atom; or a pharmaceutically acceptable salt thereof.
• the invention relates to compounds of formula I as defined above and characterized in that Z represents a radical of general formula
• the invention relates to compounds of formula I as defined above and characterized in that X represents a sulfur atom; or a pharmaceutically acceptable salt thereof.
• the invention relates to compounds of formula I as defined above and characterized in that X represents a selenium atom; or a pharmaceutically acceptable salt thereof.
• the invention relates to compounds of formula I as defined above and characterized in that R 2 represents a hydrogen atom; or a pharmaceutically acceptable salt thereof.
• the invention relates to compounds of formula I as defined above and characterized in that R 4 represents a hydrogen atom or a radical of formula -CO-OR 5 and R 5 represents an alkyl radical; or a pharmaceutically acceptable salt thereof.
• the compound according to the invention of general formula (I) has a radical R 4 which represents a hydrogen atom.
• the invention relates to compounds of formula I as defined above and characterized in that n is 1; or a pharmaceutically acceptable salt thereof.
• the invention relates to compounds of formula I as defined above and characterized in that R 1 represents an aryl or heteroaryl radical, the aryl radical being optionally substituted with one or more identical or different substituents chosen from halo. and alkoxy,
• the invention relates to compounds of general formula (I) characterized in that R 1 represents a carbocyclic aryl radical or a heteroaryl radical, optionally substituted 1 to 3 times (and preferably 1 to 2 times) by a hydrogen atom. halogen, with an alkyl radical or with an alkoxy radical.
• the invention relates to compounds of formula I as defined above and characterized in that R 3 represents a C 4 -C 8 alkyl, arylalkyl or cycloalkylalkyl radical; or a pharmaceutically acceptable salt thereof.
• the invention relates to compounds of formula I as defined above and characterized in that R 2 and R 4 represent a hydrogen atom; or a pharmaceutically acceptable salt thereof.
• the invention relates to compounds of formula I as defined above and characterized in that R 3 represents a cycloalkylalkyl or arylalkyl radical; or a pharmaceutically acceptable salt thereof.
• R 3 represents a cycloalkylalkyl or arylalkyl radical; or a pharmaceutically acceptable salt thereof.
• the invention relates to compounds of formula I as defined above and characterized in that R 1 represents an aryl or heteroaryl radical, the aryl radical being optionally substituted by one or more haloidentic or different substituents; or a pharmaceutically acceptable salt thereof.
• the invention relates to compounds of formula I as defined above and characterized in that R 1 represents a heteroaryl radical; or a pharmaceutically acceptable salt thereof.
• the invention relates to compounds of formula I as defined above and characterized in that they comprise at least one of the following characteristics:
• the cycloalkyl radical of the cycloalkyl and cycloalkylalkyl groups is the hexyl radical
• the aryl radical of the aryl and arylalkyl groups is the phenyl radical
• heteroaryl is chosen from the following radicals; furyl, thienyl, pyridinyl; or a pharmaceutically acceptable salt thereof.
• the invention relates to a compound of general formula (I) or a salt thereof and selected from the following compounds:
• the invention relates more particularly to a compound of general formula (I) chosen from the following compounds:
• the compounds according to the present invention comprise asymmetric centers. Therefore, the compounds according to the present invention have several possible epimeric forms, i.e. the "Ff or" S “configurations of said asymmetric centers.
• the present invention includes all diastereomeric forms and combinations thereof, For simplicity, when no specific configuration is indicated in the structural formulas, it is to be understood that all diastereoisomeric forms and mixtures thereof are shown and described.
• salt of a compound is meant the addition salts of said compound with an organic or inorganic acid or, where appropriate, with a base, and in particular the pharmaceutically acceptable salts of said compound.
• salt in particular inorganic acid addition salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, diphosphate and nitrate or organic acids such as acetate, maleate, fumarate, tartrate, succinate, citrate. , lactate, methanesulfonate, p-toluenesulfonate, pamoate and stearate.
• salts formed from bases such as sodium or potassium hydroxide.
• variable groups R 4 and Z the compounds of the present invention may be prepared according to the various procedures described below.
• the compounds of general formula (I) in which R 4 represents a radical of formula -CO-OR 5 can be prepared under so-called peptide coupling conditions (Montalbetti et al., Tetrahedron 2005, 61, 10827), by reacting a carboxylic acid of general formula (VII) (c / -protected cystine or seleno-cystine / V-protected) in which R 5 is as defined above, with a compound of general formula (VI) at a temperature between 0 0 C and 30 ° C (preferably at room temperature) in an aprotic solvent such as for example DCM, DCE, THF or MeCN.
• aprotic solvent such as for example DCM, DCE, THF or MeCN.
• the compounds of general formula (I) in which R 4 represents a hydrogen atom may be prepared by treating a compound of general formula (I) in which R 4 represents a radical of formula -CO-OR 5 , under conditions deprotection. These conditions are, for example, an acid treatment (TFA, HCl, HCOOH) for tert-butoxycarbonyl (Boc), a treatment with a secondary amine (piperidine) for the 9-fluorenylmethyloxycarbonyl (Fmoc) group, at a temperature between 0 ° C. and 30 ° C., and preferably at room temperature.
• TFA tert-butoxycarbonyl
• piperidine secondary amine
• Fmoc 9-fluorenylmethyloxycarbonyl
• the compounds of general formula (I) in which Z represents hydrogen can be prepared by treating the corresponding compounds of general formula (I) in which Z does not represent the hydrogen atom, under reducing conditions. such as, for example, sodium borohydride or dithiothreitol in a protic solvent such as, for example, methanol or ethanol.
• a protic solvent such as, for example, methanol or ethanol.
• the compounds of formula (VI) can be obtained from the compound of formula (IV) either indirectly via synthesis of the intermediate compound (V) or directly.
• the compounds of the general formula (V) can be prepared by treating a compound of the general formula (IV) under acidic conditions in order to remove the Boc protecting group and then by adding a base to neutralize the acidity and promote the condensation. of the free amine with the carbonyl radical carrying the radical R 3 .
• the deprotection is carried out for example in a mixture of TFA and DCM, or in formic acid, at a temperature of between 0 ° C. and 30 ° C., preferably at room temperature.
• Neutralization can be achieved, for example, by adding TEA to the reaction medium.
• the compounds of general formula (VI) can be obtained by reducing to amine the imine function of the compounds of general formula (V). This reaction is generally carried out with sodium borohydride in MeOH or EtOH at a temperature of between 0 ° C. and 30 ° C. This reaction can also be carried out under asymmetric transfer hydrogenation conditions, in such a way that the compound ( Vl) is obtained with a strong enantiomeric excess.
• An example of such a transformation is described by Williams GD et al. Org. Lett. 2003, 5, 4227.
• the deprotection of the compound (IV) can be obtained by treatment with an acid such as, for example, trifluoroacetic acid or formic acid, without a solvent or in a solvent such as, for example, dichloromethane, THF or acetonitrile. , at a temperature between 0 0 C and 50 0 C and preferably at room temperature.
• the imine formation conditions (V) and the amine reduction (VI) are known to those skilled in the art as reductive amination and can be obtained in various ways such as for example cyanoborohydride. sodium in acetonitrile, sodium triacetoxyborohydride or, for cyclic imines such as the compounds of formula (V), sodium borohydride in methanol.
• the reductive amination is made from a ketone as in the compounds of formula (V), there is formation of a chiral center and it is then interesting that the reduction of imine is made in favor of one of two possible epimers relating to this chiral center.
• asymmetric transfer hydrogenation conditions Such a conversion of imines into amines can be obtained under so-called asymmetric transfer hydrogenation conditions.
• the hydrogen source is then preferably formic acid or a salt thereof such as, for example, sodium formate, the solvent may be formic acid in the presence of a base such as, for example, the triétylamine.
• the reaction is catalyzed by a ruthenium complex obtained by reaction between bis (( ⁇ 6 -p-cymene) dichlororuthenium) and a tosylated asymmetric diamine as a chiral auxiliary such as, for example, (1, f, 2fl). - / V- (p-toluenesulfonyl) -1,2-diphenylethylenediamine ((f1, fl) -TsDPEN).
• a ruthenium complex obtained by reaction between bis (( ⁇ 6 -p-cymene) dichlororuthenium) and a tosylated asymmetric diamine as a chiral auxiliary such as, for example, (1, f, 2fl).
• - / V- (p-toluenesulfonyl) -1,2-diphenylethylenediamine ((f1, fl) -TsDPEN) Examples of such catalysts employed for the
• the compounds of general formula (IV) can be prepared by reacting a compound of general formula (III) with an organometallic reagent of formula general R 3 M wherein R 3 is as defined above and M represents for example Li or Mg (MgBr or MgCl), these reagents may be of commercial origin or generated in situ according to methods known to man of the job. This reaction is carried out in an aprotic solvent such as, for example, THF, at a temperature of between -80 ° C. and 0 ° C. for organolithium compounds and between 0 ° C. and 60 ° C., and preferably at room temperature for organomagnesium.
• an aprotic solvent such as, for example, THF
• the derivatives of general formula (III) can be prepared under so-called peptide coupling conditions (Montalbetti et al., Tetrahedron 2005, 61, 10827), by reacting the carboxylic acid (II) with ⁇ , O-dimethylhydroxylamine. , at a temperature between 0 0 C and 100 0 C (preferably at room temperature), in an inert solvent such as for example dichloromethane (DCM), THF or DMF.
• DCM dichloromethane
• THF DMF
• the intermediate thus obtained may then be alkylated with tert-butyl (2-chloroethyl) carbamate or tert-butyl (3-bromopropyl) carbamate in the presence of a base such as sodium carbonate or tert-butyl potassium.
• a base such as sodium carbonate or tert-butyl potassium.
• butoxide optionally combined with a phase transfer agent such as tetrabutylammonium bromide, at a temperature between room temperature and 110 0 C and in an aprotic solvent, such as, for example, at 60 0 C in THF, at 80 ° C in MeCN or at 110 ° C in DMF.
• the carboxylic acids (II) are generally commercial products or can be prepared by standard methods known to those skilled in the art.
• the subject of the invention is also a process for preparing a compound of formula (I) as defined above, characterized in that a compound of formula (VI) is reacted
• the subject of the invention is also a compound of general formula (VI)
• the subject of the invention is also a process for the preparation of a compound of formula (VI) as defined above, characterized in that the compound (IV) is subjected
• the present invention also relates to a compound of general formula (I) as defined above or a pharmaceutically acceptable salt of such a compound, for use as a therapeutically active substance.
• the subject of the present invention is also a pharmaceutical composition
• a pharmaceutical composition comprising, as active principle, a compound of general formula (I) as defined above, or a pharmaceutically acceptable salt of such a compound, with at least one pharmaceutically acceptable excipient. acceptable.
• the subject of the present invention is also, as a medicament, a compound of general formula (I) as defined above, or a pharmaceutically acceptable salt of such a compound.
• the subject of the present invention is also the use of at least one compound of general formula (I) as defined above or a pharmaceutically acceptable salt thereof, for preparing a medicament intended to prevent or treat a disease or a disorder chosen from the following diseases or the following disorders: cancers, non-tumoral proliferative diseases, proliferative tumoral diseases, neurodegenerative diseases, parasitic diseases, viral infections, spontaneous alopecia, alopecia induced by exogenous products, radiation-induced alopecia, autoimmune diseases, rejection of grafts, inflammatory diseases, allergies or pain.
• a disease or a disorder chosen from the following diseases or the following disorders: cancers, non-tumoral proliferative diseases, proliferative tumoral diseases, neurodegenerative diseases, parasitic diseases, viral infections, spontaneous alopecia, alopecia induced by exogenous products, radiation-induced alopecia, autoimmune diseases, rejection of grafts, inflammatory diseases, allergies or pain.
• the subject of the present invention is preferably the use of at least one compound of general formula (I) as defined above or a pharmaceutically acceptable salt thereof, for preparing a medicament intended to treat or prevent cancers,
• the compound of general formula (I) or its salt used according to the invention or the combination according to the invention may be in the form of a solid, for example powders, granules, tablets, capsules, liposomes or suppositories.
• Suitable solid carriers may be, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, carboxymethyl cellulose sodium, polyvinylpyrrolidine and wax.
• the compound of general formula (I) or its salt used according to the invention or the combination according to the invention may also be in liquid form, for example solutions, emulsions, suspensions or syrups.
• suitable liquid carriers may be, for example, water, organic solvents such as glycerol or glycols, as well as their mixtures, in varying proportions, in water.
• a compound of general formula (I) or its salt used according to the invention or the combination according to the invention may be carried out topically, orally, parenterally, by intramuscular injection, subcutaneously.
• the dose of a product according to the present invention varies according to the mode of administration, the age and the body weight of the subject to be treated as well as the state of the latter, and it will ultimately be decided by the attending physician or veterinarian.
• Such a quantity determined by the attending physician or veterinarian is herein called "therapeutically effective amount”.
• the envisaged administration dose for a drug according to the invention is between 0.1 mg and 10 g depending on the type of active compound used.
• variable groups R 1, R 2, R 3, R 4, R 5, X and Z the compounds of the invention may be prepared according to the various procedures described above.
• Example 1 tert-Butyl ⁇ (1 H) -1 - [( ⁇ (2 H) -2 - [(tert-butoxycarbonyl) amino] -3 - [(4 H) -4- (cyclohexylmethyl) - 2-phenyl-6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] -3-oxopropyl ⁇ dithio) methyl] -2 - [(4A?
• Example 1a The compound of Example 1a (4.58 g, 19.8 mmol) in DMF (80 mL) is reacted with tert-butyl (2-chloroethyl) carbamate (4.27 g, 23.8 mmol, 1, 2 eq.) In the presence of sodium carbonate (3.01 g, 21.8 mmol, 1.1 eq.). The reaction medium is heated to
• Example 1b 60/40) to obtain the compound of Example 1b (6.4 g, 86%) as a translucent oil.
• Example 1c (1.62 g, 49%) as a white solid.
• Example 2 Fert-butyl ⁇ (1 fl) -1 - [( ⁇ (2 fl) -2 - [(f) t-butoxycarbonyl) amino] -3-oxo-3 - [(4 F) -2-phenyl-4 (2-phenylethyl) -6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] propyl ⁇ dithio) methyl] -2-oxo-2 - [(4S) -2) phenyl-4- (2-phenylethyl) -6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] ethyl ⁇ carbamate
• Example 2 The compound of Example 2 is synthesized according to a method analogous to that described in Example 1f.
• Example 3 tert-butyl ⁇ (1 H) -1 - [( ⁇ (2 H) -2 - [(tert-butoxycarbonyl) amino] -3-oxo-3 - [(4 H) -4 (2-phenylethyl) -2-pyridin-4-yl-6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] propyl ⁇ dithio) methyl] -2-oxo-2- [ (4S) -4- (2-phenylethyl) -2-pyridin-4-yl-6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4W) -yl] ethyl ⁇ carbamate
• Example 3 The compound of Example 3 is synthesized according to a method analogous to that described in Example 1f.
• Example 4 tert-Butyl ⁇ (1H) -1 - [( ⁇ (2H) -2 - [(tert-butoxycarbonyl) amino] -3-oxo-3- [(4H) S) -4 (2-phenylethyl) -2-pyridin-3-yl-6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4W) -yl] propyl ⁇ dithio) methyl] -2-oxo-2- [ (4S) -4- (2-phenylethyl) -2-pyridin-3-yl-6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4M) -yl] ethyl ⁇ carbamate
• Example 4 The compound of Example 4 is synthesized according to a method analogous to that described in Example 1f.
• Example 5 tert-butyl ⁇ (1H) -2 - [(4H) -2- (1,3-benzodioxol-5-yl) -4- (2-phenylethyl) -6,7-dihydropyrazolo ⁇ [1, 5-a] pyrazin-5 (4H) -yl] -1 - [( ⁇ (2f) -3 - [(4 S) -2- (1,3-benzodioxol-5-yl) -4- ( 2-phenylethyl) -6,7-dihydropyrazolo [1,5-a] pyrazin 5 (4W) -yl] -2 - [(tert-butoxycarbonyl) amino] -3-oxopropyl ⁇ dithio) methyl] -2-oxoethyl ⁇ carbamate
• Example 6 tert-butyl ⁇ (1 H) -1 - [( ⁇ (2 fl) -2 - [(tert-butoxycarbonyl) amino] -3-oxo-3 - [(4 H) S) -4- 2-phenylethyl) -2- (3,4,5-trimethoxyphenyl) -6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] propyl ⁇ dithio) methyl] -2-oxo-2 - [(4S) -4- (2-phenylethyl) -2- (3,4,5-trimethoxyphenyl) -6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] ethyl ⁇ carbamate
• Example 6 The compound of Example 6 is synthesized according to a method analogous to that described in Example 1f.
• Example 7 tert-butyl ⁇ (1H) -1- [( ⁇ (2f) -2 - [(tert-butoxycarbonyl) amino] -3-oxo-3 - [(4H, s) -4- (2-phenylethyl) -2- (2-thienyl) -6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] propyl ⁇ dithio) methyl] -2-oxo-2 - [(4HS) -4) (2-phenylethyl) -2- (2-thienyl) -6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] ethyl ⁇ carbamate
• Example 7 The compound of Example 7 is synthesized according to a method analogous to that described in Example 1f.
• Example 8 tert-butyl ⁇ (1 fl) -1 - [( ⁇ (2ff) -2 - [(tert-butoxycarbonyl) amino] -3 - [(4H) -s- 2- (2-furyl) - 4- (2-phenylethyl) -6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] -3-oxopropyl ⁇ dithio) methyl] -2 - [(4f-S) -2- (2-Furyl) -4- (2-phenylethyl) -6,7-dihydro-pyrazolo [1,5-a] pyrazin-5 (4H) -yl] -2-oxoethyl ⁇ carbamate
• Example 8 The compound of Example 8 is synthesized according to a method analogous to that described in Example 1f.
• Example 9 tert-Butyl ⁇ (1 R) -1 - [( ⁇ (2 R) -2 - [(tert-butoxycarbonyl) amino] -3-oxo-3 - [(4 S) -4-pentyl-2-phenyl 6,6-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] propyl ⁇ dithio) methyl] -2-oxo-2 - [(4H, 7S) -4-pentyl-2-phenyl) 6,7-Dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] ethyl ⁇ carbamate
• Example 10 tert-butyl ⁇ (1H) -1 - [( ⁇ (2H) -2 - [(tert-butoxycarbonyl) amino] -3 - [(4H) -4-butyl-2-phenyl 6,6-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] -3-oxopropyl ⁇ dithio) methyl] -2 - [(4H) -4-butyl-2-phenyl) 6,7-Dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] -2-oxoethyl ⁇ carbamate
• Example 10 The compound of Example 10 is synthesized according to a method analogous to that described in Example 1f.
• Example 11 tert-Butyl ⁇ (1 H) -NH- [1H] -N-butoxycarbonylamino] -N- [1H] -N- [1- (dichlorophenyl) -1H-phenylethyl] -4-dihydropyrazolothiazol-5 (4H) -yl ] -3-oxopropyl ⁇ dithio) methyl] -2 - [(4 H) -2- (2,4-dichlorophenyl) -4- (2-phenylethyl) -6,7-dihydropyrazolo [1,5-a] pyrazine) 5 (4H) -yl] -2-oxoethyl ⁇ carbamate
• Example 11 The compound of Example 11 is synthesized according to a method analogous to that described in Example 1f. Yellow solid
• Example 12 (2 R) -3 - ( ⁇ (2 fl) -2-Amino-3 - [(4 H) -4- (cyclohexylmethyl) -2-phenyl-6,7-dihydropyrazolo [1.5] a] pyrazin-5 (4H) -yl] -3-oxopropyl ⁇ dithio) -1 - [(4H) -4- (cyclohexylmethyl) -2-phenyl-6,7-dihydropyrazolo [1,5-de] a] pyrazin-5 (4H) -yl] -1-oxopropan-2-amine hydrochloride
• Example 13 (2f) -3 - ( ⁇ (2f) -2-Amino-3-oxo-3 - [(4H) -2-phenyl-4- (2-phenylethyl) -6,7-dihydropyrazolo [1, 5-a] pyrazin-5 (4H) -yl] propyl ⁇ dithio) -1-oxo-1 - [(4H) -2-phenyl-4- (2-phenylethyl) -6,7 Dihydropyrazolo [1,5-a] pyrazin-5 (4W) -yl] propan-2-amine hydrochloride
• Example 14 (2 R) -3 - ( ⁇ (2 R) -2-amino-3-oxo-3 - [(4H) -4- (2-phenylethyl) -2-pyridin-4 -yl-6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4A) -yl] propyl ⁇ dithio) -1-oxo-1 - [(4 / 7S) -4- (2-phenylethyl) -2-pyridin-4-yl-6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] propan-2-amine hydrochloride
• Example 16 (2/7) -3 - ( ⁇ (2/7) -2-amino-3 - [(4H, 7S) -2- (1,3-benzodioxol-5-yl) -4- phenylethyl) -6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] -3-oxopropyl ⁇ dithio) -1 - [(4H) -2- (1,3-benzodioxol) -5 -yl) -4- (2-phenylethyl) -6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4W) -yl] -1-oxopropan-2-amine hydrochloride
• Example 17 (2f) -3 - ( ⁇ (2f) -2-amino-3-oxo-3 - [(4H) -4- (2-phenylethyl) -2- (3,4,5-d); trimethoxyphenyl) -6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] propyl ⁇ dithio) -1-oxo-1 - [(4H, 7S) -4- (2-phenylethyl) - 2- (3,4,5-trimethoxyphenyl) -6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] propan-2-amine hydrochloride
• Example 18 (2/7) -3 - ( ⁇ (2ff) -2-amino-3-oxo-3 - [(4H) -4- (2-phenylethyl) -2- (2-thienyl) -6, 7-Dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] propyl ⁇ dithio) -1-oxo-1 - [(4H) -4- (2-phenylethyl) -2- -thienyl) -6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4W) -yl] propan-2-amine hydrochloride
• Example 19 (2/7) -3 - ( ⁇ (2f) -2-amino-3 - [(4H) -2- (2-furyl) -4- (2-phenylethyl) -6,7 dihydropyrazolo [1,5-a] pyrazin-5 (4W) -yl] -3-oxopropyl ⁇ dithio) -1 - [(4H) -2- (2-furyl) -4- (2-phenylethyl) -6- 7-Dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] -1-oxopropan-2-amine hydrochloride
• Example 20 (2f) -3 - ( ⁇ (2f) -2-Amino-3-oxo-3 - [(4H) -4-pentyl-2-phenyl-6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] propyl ⁇ dithio) -1-oxo-1 - [(4H, 7S) -4-pentyl-2-phenyl-6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4ft) -yl] propan-2-amine hydrochloride
• Example 21 (2 R) -3 - ( ⁇ (2 R) -2-amino-3 - [(4H) -4-butyl-2-phenyl-6,7-dihydro-pyrazolo [1, 5-a] pyrazin-5 (4W) -yl] -3-oxopropyl ⁇ dithio) -1 - [(4H) -4-butyl-2-phenyl-6,7-dihydropyrazolo [1,5-a] ] pyrazin-5 (4W) -yl] -1-oxopropan-2-amine hydrochloride
• Example 22 (2/7) -3 - ( ⁇ (2 ") - 2-amino-3 - [(4H) -2- (2,4-dichlorophenyl) -4- (2-phenylethyl) - 6,7-Dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] -3-oxopropyl ⁇ dithio) -1- [(4F) -2- (2,4-dichlorophenyl) -4- phenylethyl) -6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4W) -yl] -1-oxopropan-2-amine hydrochloride
• Example 23 tert-butyl ⁇ (1 fl) -1 - [( ⁇ (2 fl) -2 - [(f-butoxycarbonyl) amino] -3 - [(4S) -4 - (cyclohexylmethyl) -2-phenyl 6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] -3-oxopropyl ⁇ dithio) methyl] -2 - [(4S) -4- (cyclohexylmethyl) -2-phenyl) -6 7-Dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] -2-oxoethyl ⁇ carbamate
• the reaction medium is cooled to 0 ° C. and trethylamine (10.9 ml, 75 mmol, 3.6 vol) is added dropwise and the temperature is allowed to return to ambient temperature.
• the hydrogen transfer catalyst is prepared by stirring under argon for 40 minutes at 28 ° C. in anhydrous acetonitrile (4 ml) of bis (( ⁇ 6 -p-cymene) dichlororuthenium) (3 mg, 5 ⁇ mol).
• the formamide derivative can be hydrolyzed to the compound of Example 23a by refluxing in ethanol in the presence of 10% hydrochloric acid without significant loss of enantiomeric purity.
• Example 24 (2f) -3 - ( ⁇ (2f) -2-amino-3 - [(4S) -4- (cyclohexylmethyl) -2-phenyl-6,7-dihydropyrazolo [1,5-a] pyrazine) 5 (4H) -yl] -3-oxopropyl ⁇ dithio) -1 - [(4S) -4- (cyclohexylmethyl) -2-phenyl-6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] -1-oxopropan-2-amine hydrochloride
• Example 25 tert-Butyl ⁇ (1/7) -1 - [( ⁇ (2ff) -2 - [(tert-butoxycarbonyl) amino] -3 - [(4 H) -4- (cyclohexylmethyl) -2-phenyl) 6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] -3-oxopropyl ⁇ dithio) methyl] -2 - [(4H) -4- (cyclohexylmethyl) -2-phenyl-6, 7-dihydropyrazolo [1,5-a] pyrazin-5 (4W) -yl] -2-oxoethyl ⁇ carbamate
• Example 23a The procedure is analogous to the preparation of Example 23a using (1S, 2S) -TsDPEN instead of (1/2, 2f) -ZDPEN. A white solid is obtained; Melting point: 117-118 ° C
• Example 26 (1 R) -3 - ( ⁇ (2 R) -2-amino-3 - [(4H) -4- (cyclohexylmethyl) -2-phenyl-6,7-dihydropyrazolo [1,5-a] ] pyrazin-5 (4H) -yl] -3-oxopropyl ⁇ dithio) -1 - [(4 ⁇ ) -4- (cyclohexylmethyl) -2-phenyl-6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] -1-oxopropan-2-amine hydrochloride
• Example 27 tert-Butyl ⁇ (1 R) -1 - [( ⁇ (2 R) -2 - [(tert-butoxycarbonyl) amino] -3 - [(4H) -4- (cyclohexylmethyl) - 2-phenyl-7,8-dihydro-4H-pyrazolo [1,5-a] [1,4] diazepin-5 (6H) -yl] -3-oxopropyl ⁇ dithio) methyl] -2 - [(4fIS)) 4- (cyclohexylmethyl) -2-phenyl-7,8-dihydro-4H-pyrazolo [1,5-a] [1,4] diazepin-5 (6H) -yl] -2-oxoethyl ⁇ carbamate
• Example 27a 60/40) to obtain the compound of Example 27a (3.93 g, 72%) as a translucent oil.
• Example 1c The procedure is analogous to the preparation of Example 1c. A yellow oil is obtained.
• Example 28 ⁇ (1 R) -1 - [( ⁇ (2 R) -2-amino-3 - [(4H) -4- (cyclohexylmethyl) -2-phenyl-7,8-dihydro-4W- pyrazolo [1,5-a] [1,4] diazepin-5 (6W) -yl] -3-oxopropyl ⁇ dithio) methyl] -2 - [(4H) -4- (cyclohexylmethyl) -2- phenyl-7,8-dihydro-4H-pyrazolo [1,5-a] [1,4] diazepin-5 (6H) -yl] -2-oxoethyl ⁇ amine hydrochloride
• Example 19 The compound of Example 19 (93.7 mg, 0.100 mmol) is dissolved in ethanol, dithiothreitol (23 mg, 0.150 mmol) is added and the reaction is heated at reflux for 5 hours under a vacuum. argon, then at room temperature for 12h. The reaction is cooled to 5 ° C., then TBME and then TEt 2 O are added. The precipitate is collected on a fry and washed at 1 ° and 2 ° , and then dried under vacuum, to obtain a beige solid (85 ° C.). mg, 90%).
• Example 30 tert-butyl ⁇ (1 fl) -1 - [( ⁇ (2 fl) -2 - [(tert-butoxycarbonyl) amino] -3 - [(4 H) -4- (cyclohexylmethyl) -2-phenyl 6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] -3-oxopropyl) diselanyl) methyl] -2 - [(4SH) -4- (cyclohexylmethyl) -2-phenyl-6) 7-Dihydropyrazolo [1,5-a] pyrazin-5 (4f) -yl] -2-oxoethyl ⁇ carbamate
• EXAMPLE 31 ⁇ (1 R) -1 - [( ⁇ (2 R) -2-amino-3 - [(4H) -4- (cyclohexylmethyl) -2-phenyl-6,7-dihydropyrazolo [1, 5-a] pyrazin-5 (4H) -yl] -3-oxopropyl-diselanyl) methyl] -2 - [(4H) -4- (cyclohexylmethyl) -2-phenyl-6,7-dihydropyrazolo [1] 5-a] pyrazin-5 (4rt) -yl] -2-oxoethyl ⁇ amine hydrochloride
• the cells were treated on day 1 for 96 hours with increasing concentrations of each of the test compounds up to 10 ⁇ M. At the end of this period, quantification of cell proliferation is evaluated by colorimetric assay based on cleavage of tetrazolium salt WST1 by mitochondrial dehydrogenases in viable cells leading to formazan formation (Boehringer Mannheim, Meylan, France). ). These tests are performed in duplicate with 8 determinations per concentration tested. For each test compound, the values included in the linear part of the sigmoid were retained for a linear regression analysis and used to estimate the Cl 50 inhibitory concentration. The products are solubilized in dimethylsulfoxide (DMSO) 10 '2 M and used in culture with 0.1% DMSO final.
• DMSO dimethylsulfoxide

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