HK1125361A

HK1125361A - Novel isoindole derivatives, compositions containing same, preparation thereof and pharmaceutical uses thereof in particular as inhibitors of chaperone protein hsp90 activities

Info

Publication number: HK1125361A
Application number: HK09103207.4A
Authority: HK
Inventors: Patrick Mailliet; Luc Bertin; Didier Benard; Chantal Carrez; François VALLEE; Eric Bacque
Original assignee: Aventis Pharma Sa
Priority date: 2005-04-08
Filing date: 2006-04-05
Publication date: 2009-08-07

Description

Novel isoindole derivatives, compositions containing them, their preparation and their pharmaceutical use, in particular as inhibitors of the chaperone activity of Hsp90

The present invention relates to novel chemical compounds which are indole derivatives, as well as compositions containing them, their use as medicaments.

More particularly, the invention relates to their pharmaceutical use, in particular as inhibitors of Hsp90 chaperone activity.

Such derivatives of the invention may in particular be the following: 1- (benzimidazol-2-yl) -2, 3, 4, 6-tetrahydro-2H-pyridine [2, 1-a ] isoindole or 1- (azabenzimidazol-2-yl) -2, 3, 4, 6-tetrahydro-2H-pyridine [2, 1-a ] isoindole or 1- (benzimidazol-2-yl) -2, 5-dihydro-3H-pyrrolo [2, 1-a ] isoindole or 1- (azabenzimidazol-2-yl) -2, 5-dihydro-3H-pyrrolo [2, 1-a ] isoindole.

More particularly, according to a first aspect, the present invention relates to novel benzisoxazole derivatives.

The compounds of the invention have in particular anticancer activity, in particular Hsp90 chaperone inhibitory activity, more particularly ATPasique-like catalytic activity by inhibiting Hsp90 chaperone.

Chaperonin

The molecular chaperones of the Heat Shock Proteins (HSPs) family are classified according to their molecular weight (Hsp27, Hsp70, Hsp90, etc.), which are key elements in the balance between this synthesis and the degradation of cellular proteins that determine the rational folding of the proteins. They play an extremely important role in cellular stress. These HSPs, in particular Hsp90, are also involved in the regulation of various major functions of cells by their association with various user proteins involved in their proliferation or apoptosis (JoIIy C. and Morimoto R.I., [ J.N.cancer Inst. (2000), 92, 1564-72; Smith D.F. et al, [ pharmaceutical Rev., (1998), 50, 493- & 513; Smith D.F., [ Molecular chapters in the Cell ] & 165- & 178, Oxford university Press 2001).

Various pathologies in humans are the result of unreasonable folding of key proteins, particularly neurodegenerative diseases caused by aggregation of certain proteins, such as in Alzheimer's disease and chorea or diseases associated with infectious protein microparticles (Tytell M. and Hooper P.L., (Emerging ther targets. (2001), 5, 3788-. In these pathologies, methods aimed at disrupting or interfering with the functioning of these partners may be beneficial.

Hsp90 chaperones

Hsp90 chaperones, which are 1-2% of the protein content of this cell, have recently proven to be particularly promising targets in anticancer therapy (see: Moloney Ar and Workman P., expert Opin biol., E., (2002), 2(1), 3-24; Choisis et al, Drug discovery today, (2004), 9, 881 888). This benefit is particularly relevant to cytoplasmic interactions of Hsp90 with the major client proteins of Hsp90 (i.e., proteins involved in six mechanisms of tumor development), such as those defined by Hanahan d. and Weinberg r.a. (Cell (2002), 100, 57-70), namely:

-proliferative capacity in the absence of growth factors: EGFR-R/HER2, Src, Akt, Raf, MEK, Bcr-Abl, Flt-3, and the like,

ability to avoid apoptosis: p53, Akt, survivin mutant forms, etc.,

insensitivity to stop proliferation signal: cdk4, Plk, Weel, etc.,

-having the ability to activate angiogenesis: VEGF-R, FAK, HIF-1, Akt, etc.,

ability to proliferate without replication restriction: hTert, and the like,

-having the ability to circumvent new organization and metastasis: c-Met.

Among other client proteins of Hsp90, steroid hormone receptors, such as estrogen receptors or androgen receptors, are also of great interest in anticancer therapy.

It has recently been demonstrated that the alpha form of Hsp90 also has an extracellular role through interaction with MMP-2 metalloproteases, which are itself involved in tumor invasion (eutace b.k. et al, Nature Cell Biology, (2004), 6, 507-.

Hsp90 is composed of two N-and C-terminal domains separated by a strongly charged region. The kinetic interaction between these two domains, coordinated by nucleotide and co-partner immobilization, determines the partner conformation and its activation state. Client protein association depends primarily on the nature of Hsp70/Hsp40, the Hop60 co-chaperone, etc., the nature of the ADP or ATP nucleotides attached to the Hsp 90N-terminal domain. The hydrolysis of ATP to ADP and ADP/ATP exchange factors thus controls the entire chaperone mechanism, and it has also been demonstrated that ATPasique activity sufficient to prevent ATP hydrolysis to ADP-Hsp 90-in order to release the client proteins in the cytoplasm, where they are degraded in the proteasome (Neckers L and Neckers K, Expert Optin. Emerging Drugs, (2002), 7, 277, Neckers L, Current mcial Chemistry, (2003), 10, 733 739; Piper P.W., Current Optin. Invest. New Drugs, (2001), 2, 1606-one 1610).

Hsp90 inhibitors

The first known inhibitor of Hsp90 is a compound of the class of amsamycines, specifically geldanamycin (1) and herbimycin a. X-ray studies have shown that geldanamycin is linked to the ATP site of the terminal domain of Hsp90N, where it inhibits the ATPasique activity of this partner (Prodromou C. et al, Cell, (1997), 90, 65-75).

Indeed, NIH and Kosan BioSciences ensured the clinical development of 17AAG (2), an Hsp90 inhibitor derived from geldanamycin (1), which geldanamycin (1) blocks ATPasique activity of Hsp90 while being linked to the N-terminal recognition site of ATP. The results of phase I clinical trials of 17AAG (1) led to the start of phase II trials today, but these studies were also directed to more soluble derivatives such as analogue 3 (17 DMAG from Kosan BioSciences), a transporter for the dimethylamine chain, instead of the methoxy residue, and to an optimized formulation of 17AAG (CNF 1010 from Conforma Therapeutics):

radicicol (4) is also an Hsp90 inhibitor of natural origin (Roe s.m. et al, j.med chem. (1999), 42, 260-66). However, if it is far from a good in vitro inhibitor of Hsp90, its metabolic instability towards nucleophiles makes it difficult to use in vivo. Oxime derivatives with very good stability were developed by Kyowa Hakko Kogyo, such as KF 55823(5) or KF 25706(Soga et al, Cancer Research (1999), 59, 2931-.

Structures belonging to natural sources of radicicol have also recently been described, such as the zaral orphone (6) from Conforma therapeutics (WO 03041643) or the compounds (7-9).

The naturally derived Hsp90 inhibitor, novobiocin (10), was linked to a different ATP site located in the C-terminal domain of the protein (Itoh h et al, Biochem j, (1999), 343, 697-703).

Depsipeptides (depsipeptides), the name Pipalomycin or ICI101, have recently been described as non-competitive inhibitors of the ATP site of Hsp90 (J.Pharmacol. Exp.Ther. (2004), 370, 1288-1295).

Purines, such as PU3(11) compounds (Chiosis et al, chem. biol., (2001), 8, 289-299) and PU24FC1(12) (Chiosis et al, curr. cane. drug Targets., (2003), 3, 371-376) have also been described as inhibitors of Hsp 90.

Patent application WO2004/072080(Cellular Genomics) claims 8-heteroaryl-6-phenyl-imidazo [1, 2-a ] pyrazines as hsp90 activity modulators.

Patent application WO2004/050087(Ribotarget/Vernalis) claims a class of pyrazoles which are useful in the treatment of pathologies associated with the inhibition of heat shock proteins (e.g. the Hsp90 chaperone).

Patent application WO2004/056782(Vernalis) claims a new class of pyrazoles which are useful in the treatment of pathologies associated with the inhibition of heat shock proteins (e.g. the Hsp90 chaperone).

Patent application WO2004/07051(Vernalis) claims arylisoxazole derivatives which are useful in the treatment of pathologies associated with the inhibition of heat shock proteins, such as the Hsp90 chaperone.

Patent application WO2004/096212(Vernalis) claims pyrazoles of a third type, which are useful for the treatment of pathologies associated with the inhibition of heat shock proteins, such as the Hsp90 chaperone.

Patent application WO2005/00300(Vernalis) more generally claims 5-membered heterocycles substituted with aryl groups for the treatment of pathologies associated with the inhibition of heat shock proteins, such as the Hsp90 chaperone.

Finally, patent application WO2005/00778(Kyowa Hakko Kogyo) claims a class of benzophenone derivatives as HsP90 inhibitors, which are useful for the treatment of tumors.

The object of the present invention is therefore a product of formula (I):

in the formula:

a1, A2, A3 and A4, identical or different, represent CRa or N;

n represents an integer of 1 or 2;

r1 represents an oxygen or sulphur atom or an NRb group;

r2 is independently selected from H, halogen, CF3, nitro, cyano, methyl, ethyl, hydroxy, mercapto, amino, methoxy, thiomethoxy, methylamino, dimethylamino, acetylamino, carboxy, and carboxamido;

ra is selected from H, halogen, CF3, hydroxy, mercapto, nitro, amino, OR3, SR3, NR3R4, NH-OH, NH-CO-H, NH-CO-OH, NH-CO-NH2, carboxy, cyano, carboxamide, Y- (CH2) p-alkyl, Y- (CH2) p-cycloalkyl, Y- (CH2) p-heterocycloalkyl, Y- (CH2) p-aryl OR Y- (CH2) p-heteroaryl, wherein Y ═ O, S, NH, OC (O), c (O) -NH, NH-c (O), NH-S (O) OR NH-S (O)2, wherein p ═ 1, 2 OR3, and wherein the aryl contains 6 to 10 mer, the cycloalkyl contains 3 to 10 mer, the heteroaryl OR heterocycloalkyl contains 4 to 10 mer, wherein 1-3 heteroatoms are selected from O, N or S; all of these groups are optionally substituted,

r3 and R4 are independently selected from a hydrogen atom or an alkyl, alkenyl, alkynyl, aryl or heteroaryl, aralkyl or heteroaralkyl group; all of the above alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl or heteroaralkyl groups are optionally substituted;

rb is selected from H, (CH2) m-cycloalkyl, (CH2) m-heterocycloalkyl, (CH2) m-aryl or (CH2) m-heteroaryl, wherein m is 0, 1, 2, all of which are optionally substituted,

said product of formula (I) being in any of the possible racemic, enantiomeric and diastereomeric isomeric forms, and also addition salts of said product of formula (I) with inorganic and organic acids or with inorganic and organic bases.

In these products of formula (I) and in what follows, the terms indicated have the following meanings:

the term halogen denotes a fluorine, chlorine, bromine or iodine atom, preferably a chlorine or bromine atom.

The term alkyl denotes a straight-chain or branched-chain radical containing up to 12 carbon atoms, selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, tert-pentyl, neopentyl, hexyl, isohexyl, sec-hexyl, tert-hexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl, and also their straight-chain or branched-chain positional isomers. More particular mention may be made of alkyl groups containing up to 6 carbon atoms, in particular methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, straight-chain or branched pentyl, straight-chain or branched hexyl.

The term alkenyl denotes a straight or branched chain radical containing up to 12 carbon atoms, preferably 4 carbon atoms, which is selected, for example, from the following values: vinyl, propenyl or allyl, 1-propenyl, n-butenyl, i-butenyl, 3-methylbut-2-enyl, n-pentenyl, hexenyl, heptenyl, octenyl, cyclohexylbutenyl and decenyl and their linear or branched positional isomers. Among these alkenyl values, more specifically allyl or butenyl values are cited.

The term alkynyl denotes a straight or branched chain radical containing up to 12 carbon atoms, preferably 4 carbon atoms, which is selected, for example, from the following values: ethynyl, propynyl, butynyl, n-butynyl, i-butynyl, 3-methylbut-2-ynyl, pentynyl or hexynyl and also their straight-chain or branched positional isomers. Among these alkynyl values, propynyl is more specifically exemplified.

The term alkoxy, which may for example represent OR3, represents a linear OR branched radical containing up to 12 carbon atoms, preferably 6 carbon atoms, for example chosen from methoxy, ethoxy, propoxy, isopropoxy, secondary OR tertiary linear butoxy, pentoxy, hexoxy and heptoxy radicals and their linear OR branched positional isomers.

The term alkylthio or alkyl-S-, which may for example represent SR3, represents a straight-chain or branched radical containing up to 12 carbon atoms, and represents in particular methylthio, ethylthio, isopropylthio and heptylthio. In the radicals containing sulfur atoms, the sulfur atoms can be oxidized to the radicals SO or S (O) 2.

The term acyl or R-CO-denotes a straight-chain or branched radical containing up to 12 carbon atoms, where the radical R represents a hydrogen atom, an alkyl, cycloalkyl, cycloalkenyl, cycloalkyl, heterocycloalkyl or aryl radical, these radicals having the values indicated above and being optionally substituted as indicated: examples include formyl, acetyl, propionyl, butyryl or benzoyl, or pentanoyl, hexanoyl, acryloyl, crotonyl or carbamoyl.

The term cycloalkyl denotes a mono-or bicyclic carbocyclic ring containing 3 to 10 mer, in particular cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl,

the term cycloalkylalkyl denotes a radical wherein cycloalkyl and alkyl are selected from the values indicated above: this gene here denotes, for example, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl.

Acyloxy is understood to mean an acyl-O-group in which the acyl group has the meaning indicated above: examples thereof include acetoxy and propionyloxy.

By acylamino is understood an acyl-N-group in which the acyl group has the meaning indicated above.

The term aryl denotes a monocyclic unsaturated radical or a radical consisting of carbocyclic fused rings. As an example of such an aryl group, a phenyl group or a naphthyl group is cited, and more specifically a phenyl group is cited.

Arylalkyl is understood to mean a radical resulting from the combination of the optionally substituted alkyl radicals listed above with the optionally substituted aryl radicals also listed above: examples are benzyl, phenylethyl, 2-phenylethyl, triphenylmethyl or naphthylmethyl.

The term heterocyclyl denotes a saturated (heterocycloalkyl) or unsaturated (heteroaryl) carbocyclyl consisting of up to 6 mer, these mer being separated by one or more identical or different heteroatoms selected from oxygen, nitrogen or sulfur.

As heterocycloalkyl, mention may in particular be made of ditolylenyl (dioxolane), dioxanyl, dithienoalkyl (dithiolane), thiomolylenyl, thioxoalkyl, oxetanyl, oxolanyl, dioxolanyl, piperazinyl, piperidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, morpholinyl or tetrahydrofuranyl, tetrahydrothienyl, chromanyl, dihydrobenzofuranyl, indolinyl, piperidinyl, perhydropyranyl, pirindolylalkyl (pyridinolinyl), tetrahydroquinolinyl, tetrahydroisoquinolinyl or thiopyrrolidinyl (thioalidinyl), all of these groups being optionally substituted.

Among these heterocycloalkyl groups, mention may in particular be made of optionally substituted piperazinyl, optionally substituted piperidinyl, optionally substituted pyrrolidinyl, imidazolidinyl, pyrazolidinyl, morpholinyl or thiopyrrolyl.

By heterocycloalkyl alkyl is understood a radical in which both the heterocycloalkyl and the alkyl residue have the meaning indicated above.

Among the heteroaryl groups having 5 units, mention may be made of furyl, such as 2-furyl, thienyl, such as 2-thienyl and 3-thienyl, pyrrolyl, oxadiazolyl, thiazolyl, thiadiazolyl, thiatriazolyl, isothiazolyl, oxazolyl, oxadiazolyl, 3-or 4-isoxazolyl, imidazolyl, pyrazolyl, isoxazolyl.

Among the heteroaryl groups having 6 members, particular mention may be made of pyridyl groups, such as 2-pyridyl, 3-pyridyl and 4-pyridyl, pyrimidinyl, pyrimidinylalkyl, pyridazinyl, pyrazinyl and tetrazolyl.

As the fused heteroaryl group containing at least one hetero atom selected from sulfur, nitrogen and oxygen, for example, a benzothienyl group such as a 3-benzothienyl group, a benzofuranyl group, a benzopyrolyl group, a benzimidazolyl group, a benzoxazolyl group, a thionaphthyl group, an indolyl group, a purinyl group, a quinolyl group, an isoquinolyl group and a naphthyridinyl group can be cited.

Among the fused heteroaryl groups, mention may be made more particularly of benzothienyl, benzofuranyl, indolyl or quinolinyl, benzimidazolyl, benzothiazolyl, furanyl, imidazolyl, indolizinyl (indolizinyl), isoxazolyl, isoquinolyl, isothiazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, 1, 3, 4-thiadiazolyl, thiazolyl, thienyl and triazolyl groups, as indicated for heteroaryl, these groups being optionally substituted.

The term cyclic amine, which may for example denote NR3R4, denotes cycloalkyl containing 3 to 8 mer in which the carbon atoms are substituted by nitrogen atoms, cycloalkyl having the meaning indicated above and may also contain one or more further heteroatoms selected from O, S, SO2, N or NR3, wherein R3 is as defined above, and as such examples of cyclic amines, pyrrolidinyl, piperidinylalkyl, morpholinyl, piperazinyl, indolinyl, pirndolyl or tetrahydroquinolinyl may be mentioned.

The term patient refers to humans, but also to other mammals.

The term "prodrug" denotes a product which can be converted in vivo by metabolic mechanisms (e.g. hydrolysis) into the product of formula (I). For example, the product ester of formula (I) containing a hydroxyl group may be converted to its parent molecule by in vivo hydrolysis. Or the product esters of formula (I) containing carboxyl groups can be converted to their parent molecules by in vivo hydrolysis.

As examples of esters of the product of formula (I) containing hydroxyl groups, it is possible to cite, for example, the acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-b-hydroxynaphthoates, glycocholates, ethanolsulfonates, di-p-toluoyltartrates, methane sulfonates, ethane sulfonates, benzene sulfonates, p-toluene sulfonates, cyclohexyl sulfamates and quinic acid esters.

Particularly useful esters of the product of formula (I) containing hydroxyl groups may be prepared using acid residues as described, for example, in Bundgaard et al, J.Med.chem., 1989, 32, pages 2503-2507: these esters include in particular substituted (aminomethyl) -benzoates, dialkylamino-methylbenzates, in which the two alkyl groups can be linked together or can be separated by an oxygen atom or an optionally substituted nitrogen atom (i.e. a nitrogen atom containing an alkyl group), or (morpholinyl-methyl) benzoates, for example 3-or 4- (morpholinyl-methyl) -benzoates, and (4-alkylpiperazin-1-yl) benzoates, for example 3-or 4- (4-alkylpiperazin-1-yl) benzoates.

One or more of the carboxyl groups of the product of formula (I) may be salified or esterified using various groups known to those skilled in the art, among which the following compounds may be cited as non-limiting examples.

Among the salt-forming compounds, inorganic bases, such as, for example, sodium, potassium, lithium, calcium, magnesium or ammonium equivalents, or organic bases, such as, for example, methylamine, propylamine, triethylamine, diethylamine, triethylamine, N-dimethylethanolamine, tris (hydroxymethyl) aminomethane, ethanolamine, pyridine, picoline, dicyclohexylamine, morpholine, benzylamine, procaine, lysine, arginine, histidine, N-methylglucamine,

in the esterification of compounds, an alkoxycarbonyl group is formed, for example an alkyl group such as methoxycarbonyl, ethoxycarbonyl, tert-butoxy-carbonyl or benzyloxycarbonyl, which alkyl group may be substituted, for example, by a group selected from: halogen atoms, hydroxyl, alkoxy, acyl, acyloxy, alkylthio, amino or aryl groups, such as for example in the chloromethyl, hydroxypropyl, methoxy-methyl, propionyloxymethyl, methylthiomethyl, dimethyl-aminoethyl, benzyl or phenethyl group.

Esterified carboxyl is understood to be, for example, radicals such as alkoxycarbonyl, for example methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butyl or tert-butoxycarbonyl, cyclobutoxycarbonyl, cyclopentyloxycarbonyl or cyclohexyloxycarbonyl.

Examples thereof include groups which are formed with an ester residue which is easily cleaved, such as methoxymethyl group, ethoxymethyl group; acyloxyalkyl, such as valeryloxymethyl, valeryloxyethyl, acetoxymethyl or acetoxyethyl; alkoxycarbonyloxyalkyl, such as methoxycarbonyloxymethyl or ethyl, isopropoxycarbonyloxymethyl or ethyl.

A list of such ester groups is found, for example, in European patent EP 0034536.

Amidated carboxyl groups are understood to be, for example, groups of the type-CONR 3R4, in which R3 and R4 have the meanings indicated above.

Alkylamino is understood to be those radicals in which the alkyl radical is chosen from the alkyl radicals listed above. Alkyl groups having up to 4 carbon atoms are preferred, and for example, straight-chain or branched methylamino, ethylamino, propylamino or butylamino groups may be cited.

Dialkylamino is understood to mean these radicals in which the alkyl radicals, identical or different, are chosen from the alkyl radicals listed above. As indicated above, alkyl groups having up to 4 carbon atoms are preferred, and for example dimethylamino, diethylamino, straight-chain or branched methylethylamino groups may be cited.

The NR3R4 radical may also represent a heterocyclic ring, which may or may not contain additional heteroatoms. Mention may be made of pyrrolyl, imidazolyl, indolyl, piperidinyl, morpholinyl and piperazinyl. Piperidinyl, morpholinyl or piperazinyl are preferred.

Salt-forming carboxyl groups are understood to be, for example, salts with sodium, potassium, lithium, calcium, magnesium or ammonium equivalents. Salts with these organic bases such as methylamine, propylamine, trimethylamine, diethylamine and triethylamine can also be cited. Sodium salts are preferred.

When the products of formula (I) contain amino groups which are salifiable with acid, it is to be clearly understood that these acid salts are also part of the present invention. Examples thereof include salts obtained with hydrochloric acid or methanesulfonic acid.

The addition salts of the products of formula (I) with inorganic or organic acids may be, for example, the salts formed with the following acids: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, propionic acid, acetic acid, trifluoroacetic acid, formic acid, benzoic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, oxalic acid, glyoxylic acid, aspartic acid, ascorbic acid; alkyl monosulfonic acids, such as, for example, methane sulfonic acid, ethane sulfonic acid, propane sulfonic acid; alkyl disulfonic acids, such as, for example, methane disulfonic acid, alpha, beta-ethane disulfonic acid; aryl monosulfonic acids, such as benzenesulfonic acid and aryl disulfonic acids.

It may be mentioned that this stereoisomer may be defined in a broad sense as an isomer of the compound having the same expanded form, but that these different groups are arranged in different isomers in space, for example in particular in monosubstituted cyclohexane, whose substituents may be in axial or equatorial positions, but also as possible different rotational conformations of the ethane derivative. However, other types of stereoisomers exist due to different spatial arrangements of fixed substituents, either at the double bond or at the ring, and are often referred to as geometric isomers or cis-trans isomers. The present application uses the term stereoisomer in the broadest sense and thus relates to all the compounds indicated above.

In the products of formula (I) as defined above and below, the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl groups may be optionally substituted by one or more identical or different groups chosen from halogen atoms; a hydroxyl group; cycloalkyl containing up to 6 mer; acyl containing up to 7 carbon atoms; a cyano group; a nitro group; free, salified or esterified carboxyl groups; a tetrazolyl group; -NH2, -NH (alk), -n (alk) and (alk); SO 2-NH-CO-NH-alkyl; SO 2-NH-CO-NH-phenyl; -c (o) -NH 2; -C (O) -NH (alk); -C (O) -N (alk) - (alk), -NH-C (O) - (alk), -N (alk) - (C (O) - (alk)); a thienyl group; phenyl, alkyl, alkylthio, alkoxy and phenoxy groups, which are themselves optionally substituted by one or more groups selected from halogen atoms and hydroxy, alkoxy, alkyl, -NH2, -NH (alk) and-N (alk) alkyl.

More particularly, in the products of formula (I) as defined before and after, the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl groups may be optionally substituted by one or more identical or different groups chosen from halogen atoms; a hydroxyl group; free, salified or esterified carboxyl groups; -NH2, -NH (alk), -n (alk) and (alk); phenyl, alkyl and alkoxy, which are themselves optionally substituted by one or more groups selected from halogen atoms and hydroxyl, alkoxy, alkyl, -NH2, -NH (alk) and-N (alk).

Still more particularly, in the products of formula (I) as defined above and below, the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl groups may be optionally substituted by one or more identical or different radicals chosen from halogen atoms, hydroxyl groups and alkoxy groups.

In particular, the invention relates to a product of formula (I) as defined above, in which:

the same or different A1, A2, A3 and A4 are such that the same or different A1 and A4 represent CRa, while A2 and A3 represent N or CRa,

these substituents n, Ra, R1 and R2 have the meanings indicated above; said product of formula (I) being in any of the possible racemic, enantiomeric and diastereomeric isomeric forms, and also addition salts of said product of formula (I) with inorganic and organic acids or with inorganic and organic bases.

a1, A2, A3 and A4, which are identical or different, are such that A1 and A4, which are identical or different, represent CRa and A2 and A3 represent N or CRa, where Ra represents H or OH,

these substituents n, R1 and R2 have the meanings indicated above;

a1, A2, A3 and A4 are such that A1 and A4 represent CH, while A2 and A3, which are identical or different, represent N, CH or COH,

these substituents n, R1 and R2 have the meanings indicated above;

r1 represents an oxygen atom or a NRb group, wherein Rb represents H or (CH2) m-heteroaryl, wherein m is 0, 1, 2,

these substituents A1, A2, A3, A4, n and R2 have the meanings indicated above;

The invention relates in particular to the values for Rb, where Rb represents (CH2) m-heteroaryl, where m represents 1 and heteroaryl represents pyridyl, which is optionally substituted by amino groups NR3R4, where R3 and R4 are as defined above and the other substituents A1, A2, A3, A4, n and R2 have the meanings indicated above;

In particular, the invention relates to a product of formula (I) as defined above, in which n represents 2,

these substituents A1, A2, A3, A4, R1 and R2 have the meanings indicated above;

a1, A2 and A4 represent CH, A3 represents N, CH or COH,

n represents an integer of 2;

r1 represents an oxygen atom;

r2 represents a hydrogen atom or a hydrogen atom,

Very particularly, the invention relates to a product of formula (I) as defined above, having the following name:

-1- { 3-H-imidazo [4, 5-c ] pyridin-2-yl } -3, 4-dihydro-2H-pyridin [2, 1-a ] isoindol-6-one,

-1- { 1-H-6-hydroxy-benzoimidazol-2-yl } -3, 4-dihydro-2H-pyridin [2, 1-a ] isoindol-6-one,

Another subject of the invention is a process for the preparation of the products of formula (I) according to the invention.

Few 2, 3, 4, 6-tetrahydro-2H-pyrido [2, 1-a ] are described in the literature]Synthesis of isoindole ring

Several substituted derivatives of this ring at position 1 are known, such as the derivatives listed below:

gourves j.p. et al (eur.j.org.chem.1999, 3489) describe a synthetic method to perform intramolecular cyclization by means of the Horner-Wadworth-Emmons reaction as a key step:

patent JP 49102699 describes the preparation of 1-thiophenyl-and 1-tert-butylthio-6-oxo-2, 3, 4, 6-tetrahydropyridine [2, 1-a ] isoindole in a rather similar manner but with a cyclisation step induced by photochemical irradiation of N- (4-phenyl-or 4-tert-butylthio-butyl) phthalimide:

Deok-Chan et al (Tetrahedron Lett., 1996, 37, 2577-80) describe the synthesis of 6-oxo-2, 3, 4, 6-tetrahydropyridine [2, 1-a ] isoindole ring by reductive cyclization of N- (4-iodo-butylsulfanyl-butyl) phthalimide with samarium iodide:

earl r.a. and Volhardt P.C. ("heterocycles, 1982, 19, 265-71) describe the synthesis of 6-oxo-2, 3, 4, 6-tetrahydropyridine [2, 1-a ] isoindole rings by the trans-eneimino Diels-Alder reaction:

mazzochi et al (Tetrahedron letters, 1983, 24, 143-46) describe the synthesis of 6-oxo-2, 3, 4, 6-tetrahydropyridine [2, 1-a ] isoindole rings by intramolecular reaction of Paterno-Buchi:

finally, Malaria M. et al (Organic letters, 2003, 5, 5095-97) describe the synthesis of 6-oxo-2, 3, 4, 6-tetrahydropyridine [2, 1-a ] isoindole rings by a cascade configuration free radical cyclization:

2, 3, 4, 6-tetrahydro-2H-pyrido [2, 1-a ] isoindole skeletons are sometimes also found in more complex tetracyclic structures, for example in the cyanine derivatives described in patent IT671447, the semiporphyrazine derivatives described in patent SU 178001, or dyes used as copolymers in the production of synthetic textile fibers, for example in the dyes described in patents DE 2128326, BE662237, US3221041 or NL 6504566.

2, 5-dihydro-3H-pyrrolo [2, 1-a ] is not widely described in the literature]Synthesis of isoindole ring

Several substituted derivatives of this ring in position 1 are known, such as the derivatives listed below:

petter r.c. et al (journal of organic chemistry, 1990, 55, 3088-:

muchovski et al (Tetrahedron Lett., 1980, 21, 4585-88) describe the synthesis of triphenylphosphonium ring-opening of cyclic propionates with phtalimie:

Deok-Chan et al (Tetrahedron letter., 1996, 37, 2577-80) describe the synthesis of N- (4-iodo-butylsulfanyl-butyl) phthalimide by reductive cyclization with samarium iodide:

yoon et al (J.Amer. chem.Soc., 1995, 117, 2698-2710) describe the synthesis of cyclizing azomethine ylides (aryl d' azomthine) with acrylates, followed by dehydration of the diene polymer in an acidic medium:

sato et al (Liebigs an. chem., 1985, 1099-1108) describe the synthesis of a photochemical irradiation-induced cyclization step using N- (4-phenyl-or 4-tert-butylsulfanyl-butyl) phthalimide:

furthermore, the 2, 5-dihydro-3H-pyrrolo [2, 1-a ] isoindole skeleton is found in many tetracyclic compounds.

General method of Synthesis

The first original general procedure described in general scheme 1, which was suggested by the above work, and which appears to be particularly advantageous within the scope of the present invention, has been developed, in particular for the synthesis of 6-oxo-2, 3, 4, 6-tetrahydropyridine [2, 1-a ] isoindole derivatives:

scheme 1

The group O as defined in formula (I) may be converted into the group R1 according to general methods known to those skilled in the art, in particular the methods described below:

comprehensive organic Chemistry, part D, Barton et al (Pergamon Press);

advanced organic Chemistry, j.

A second general synthetic approach was developed from methyl 6-oxo-2, 3, 4, 6-tetrahydro-1H-pyridine [2, 1-a ] isoindole-1-carboxylate or methyl 6-oxo-2, 5-dihydro-3H-pyrrolo [2, 1-a ] isoindole-1-carboxylate by formation of a benzimidazole-like ring. Within the scope of the invention, it has been found to be particularly advantageous to carry out the process according to scheme 2 in two successive steps:

flow chart 2

The object of the invention has interesting pharmacological properties: they were observed to have especially inhibitory properties on the activity of the chaperone protein ATPasique. Among these proteins, HSP90 can be cited in particular.

An object of the present invention is therefore the use of a pharmaceutically acceptable product of formula (I) as a medicament.

More particularly, the object of the invention is the use of the product of the following name as a medicament:

and prodrugs thereof, in any of the possible racemic, enantiomeric and diastereomeric isomeric forms, and addition salts thereof with pharmaceutically acceptable inorganic or organic acids or with inorganic or organic bases.

These products can be administered by parenteral, oral, lingual, rectal or topical routes.

Another subject of the invention are these pharmaceutical compositions, characterized in that they contain, as active ingredient, at least one drug of formula (I).

The object of the present invention are these pharmaceutical compositions as defined above, characterized in that they are useful as medicaments, in particular as medicaments for the chemotherapy of cancer.

The object of the present invention is therefore these pharmaceutical compositions as defined above, which also contain the active ingredients of other anticancer chemotherapeutic drugs.

These compositions may be in the form of injection solutions or suspensions, tablets, sugar-coated tablets, capsules, syrups, suppositories, ointments and lotions. These pharmaceutical dosage forms can be prepared according to conventional methods. The active ingredient may be incorporated in excipients conventionally used in these compositions, such as aqueous or non-aqueous excipients, talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, fats of animal or vegetable origin, paraffin derivatives, glycols, various softening, dispersing or emulsifying agents, preservatives.

A usual dosage which may vary depending on the patient to be treated and the disease concerned may be, for example, 10mg to 500mg per day orally administered to a human.

The products of formula (I) according to the preceding definition thus have an inhibitory activity of the important Hsp90 chaperone.

A further object of the invention is the use of a product of formula (I) as defined above or of a pharmaceutically acceptable salt of said product of formula (I) for the preparation of a medicament for the prevention or treatment of diseases characterized by an abnormal activity of HSP90 protein.

An object of the present invention is therefore the use of a product of formula (I) as defined above or of a pharmaceutically acceptable salt of said product of formula (I) for the preparation of a medicament for inhibiting the activity of HSP90 protein.

An object of the present invention is therefore a product of formula (I) as defined above or the use of said product of formula (I) in a pharmaceutically acceptable salt, wherein the disease to be prevented or treated is a disease of a mammal.

The tests given in the experimental section below illustrate the inhibitory activity of the products of the invention on such proteins.

A further object of the invention is the use of a product of formula (I) as defined above or of a pharmaceutically acceptable salt of said product of formula (I) for the preparation of a medicament for the treatment of cancer.

A further object of the invention is a product of formula (I) as defined above or the use of said product of formula (I) in pharmaceutically acceptable salts, wherein the disease to be treated is solid or liquid tumour cancer.

The properties of the product of formula (I) according to the invention therefore make it particularly useful as a medicament for the treatment of malignant tumors.

Of these cancers, the present invention is of particular interest for the treatment of solid tumors and for the treatment of cancers that are resistant to cytotoxic agents.

A further object of the invention is a product of formula (I) as defined above or the use of said product of formula (I) in pharmaceutically acceptable salts, wherein the disease to be treated is cancer against cytotoxic agents.

Another object of the invention is the use of a product of formula (I) as defined above or of a pharmaceutically acceptable salt of said product of formula (I) for the preparation of a medicament for the treatment of a cancer selected from: lung, breast and ovarian cancer, glioblastoma, chronic myelogenous leukemia, acute lymphocytic leukemia, prostate, pancreatic and colon cancer, metastatic melanoma, thyroid tumor, and renal cancer.

Thus, among the main possible indications for Hsp90 inhibitors, mention may be made, without limitation, of:

"non-small cell" lung cancer, breast cancer, ovarian cancer and glioblastoma, which overexpress EGF-R or HER 2;

-chronic myeloid leukemia, which overexpresses Bcr-Abl;

-acute lymphoblastic leukemia, which overexpresses Flt-3;

-breast, prostate, lung, pancreatic, colon or ovarian cancer that overexpresses Akt;

metastatic melanoma and thyroid tumors, which overexpress mutant forms of the B-Raf protein;

-androgen-dependent and androgen-independent prostate cancer;

-estrogen-dependent and estrogen-independent breast cancer;

renal cancers, which overexpress HIF-Ia or mutein c-met etc.

The invention also relates to the use of a product of formula (I) as defined above or of a pharmaceutically acceptable salt of said product of formula (I) in the manufacture of a medicament for the chemotherapy of cancer.

As the medicament of the invention for the chemotherapy of cancer, the product of formula (I) of the invention can be used alone or in combination with chemotherapy or radiotherapy, or alternatively in combination with other therapeutic agents.

A further object of the invention is therefore the use of a product of formula (I) as defined above or of a pharmaceutically acceptable salt of said product of formula (I) for the preparation of a medicament for the chemotherapy of cancer, alone or in combination.

The invention therefore relates in particular to these pharmaceutical compositions as defined above, which also contain the active ingredients of other anticancer chemotherapeutic agents.

Such therapeutic agents may be commonly used antineoplastic agents.

Thus, another object of the invention is the use of a product of formula (I) as defined above or of a pharmaceutically acceptable salt of said product of formula (I) for the preparation of a medicament intended to be used alone or in combination with chemotherapy or radiotherapy, or alternatively in combination with other therapeutic agents.

Thus, another object of the invention is the use of the product of formula (I) as defined above, or of said product of formula (I) in pharmaceutically acceptable salts, wherein these therapeutic agents can be commonly used antitumor agents.

As examples of known inhibitors of protein kinases, mention may in particular be made of butyrolactone, flavopiridol, 2- (2-hydroxyethylamino) -6-benzylamino-9-methylpurine, olomcutine, gleevec and lressa.

The use of the product of formula (I) according to the invention in combination with an antiproliferative agent may therefore be very advantageous: as examples of such antiproliferative agents, but not limited to this list, aromatase inhibitors, antiestrogens, topoisomerase I inhibitors, topoisomerase II inhibitors, microtubule active agents, alkylating agents, histone deacetylase inhibitors, farnesyl transferase inhibitors, COX-2 inhibitors, MMP inhibitors, mTOR inhibitors, antitumor antimetabolites, platinum compounds, compounds capable of decreasing the activity of protein kinases and anti-angiogenic compounds, gonadotropin releasing hormone agonists, anti-androgens, bengamides, bisphosphonates and trastuzumab may be mentioned.

Thus, by way of example, anti-microtubule agents, such as taxanes, thermocarba-alkaloids, alkylating agents, such as cyclophosphamide, DNA-intercalating agents, such as cis-platinum, interactive agents of topoisomerase, such as camptothecin with derivatives, anthracyclines, such as doxorubicin, antimetabolites, such as 5-fluorouracil with derivatives and analogues may be cited.

The invention therefore relates to the use of the products of formula (I) in any of the possible isomeric forms, racemic, enantiomeric and diastereomeric, and their addition salts with pharmaceutically acceptable inorganic and organic acids or with pharmaceutically acceptable inorganic and organic bases, and their prodrugs, as protein kinase inhibitors.

The invention relates in particular to the use of a product of formula (I) as defined above in any possible racemic, enantiomeric and diastereomeric isomeric form as HSP90 inhibitor, and to the addition salts of said product of formula (I) with pharmaceutically acceptable inorganic and organic acids or with pharmaceutically acceptable inorganic and organic bases and their prodrugs.

The products of formula (I) according to the invention can be prepared by using known methods or adapting known methods, in particular methods described in the literature, such as, for example, the methods described by R.C. Larock in Comprehensive Organic Transformations, VCHpublishers, 1989.

In the reactions described below, it may be necessary to protect reactive functional groups, such as, for example, hydroxyl, amino, imino, thio-or carboxyl groups, when they are desired in the final product, but not when they are desired to participate in the synthesis of the product of formula (1). The usual protecting Groups can be used according to usual standard practice, such as described, for example, in T.W.Greene and P.G.M.Wuts protecting Groups in organic chemistry, "Protective Groups in organic chemistry," John Wiley and Sons, 1991.

The following preparation examples illustrate the invention without limiting its scope.

Description of embodiments of the invention

Example 1: 1- { 3-H-imidazo [4, 5-c]Pyridin-2-yl } -3, 4-dihydro-2H-pyridine [2, 1-a ]]Isoindol-6-ones

In a 250ml round bottom flask, 4g pyridine-3, 4-diamine and 9.5g 5- (1, 3-dioxo-1, 3-dihydro-isoindol-2-yl) pentanoic acid are added followed by 45g polyphosphoric acid (PPA). The solid mixture was heated with an oil bath at 210 ℃. During the reaction, the 2- {4- (3H-imidazo [4, 5-c ] pyridin-2-yl) butyl } isoindole-1, 3-dione, which is formed briefly, was recorded. After 16 hours of heating, the reaction was complete. After cooling the reaction mixture was dissolved in water. These impurities were removed by extraction with ethyl acetate. The aqueous phase is neutralized with 2N sodium hydroxide solution (pH 7). The product was recovered after 6 successive extractions with a mixture of ethyl acetate and methanol (9/1 by volume). After flash chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (95/5 by volume), 1.46g of 1- { 3-H-imidazo [4, 5-c ] pyridin-2-yl } -3, 4-dihydro-2H-pyridin [2, 1-a ] isoindol-6-one are obtained as a white solid, characterized as follows:

-¹h NMR (400MHz, DMSO-d 6): 2.08(m, 2H); 2.88(t, J ═ 6.0Hz, 2H); 3.81(t, J ═ 6.0Hz, 2H), 7.54(m, 2H); 7.60(d, J ═ 5.5Hz, 1H); 7.78(m, 1H); 7.95 (width m, 1H); 8.34(d, J ═ 5.5Hz, 1H); 8.97(s, 1H); 12.95 (very broadened m, 1H).

-mass spectrum (E/l): m/z 302(M +).

Example 2: 1- { 1-H-6-hydroxy-benzoimidazol-2-yl } -3, 4-dihydro-2H-pyridine [2, 1-a ]]Isoindol-6-ones

Step 1: 942mg of methyl 3, 4-dihydro-2H-pyridine [2, 1-a ] isoindol-6-one-1-carboxylate (obtained according to eur.j.org.chem., 1999, 3489) was dissolved in 10ml of dioxane in a 25ml three-necked flask, and 168mg of lithium hydroxide monohydrate was added. After stirring at room temperature for 6 hours, dioxane was evaporated off, and dissolved in 20mL of water, followed by addition of 1M aqueous hydrochloric acid to adjust pH 2. The precipitate formed was dehydrated, washed with water and then dried in a vacuum oven at 50 ℃. This gave 820mg of 3, 4-dihydro-2H-pyrido [2, 1-a ] isoindol-6-one-1-carboxylic acid as a white powder which was used as such in the subsequent step.

Step 2: in a 25mL three-necked flask, 442.5mg of 3, 4-dihydro-2H-pyridin [2, 1-a ] isoindol-6-one-1-carboxylic acid was dissolved in 20mL of dichloromethane, and then 400mg of 1- (3-dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride (EDCl) and 270mg of 1-hydroxybenzotriazole were added and stirred at room temperature for 1 hour. After concentrating the solvent under reduced pressure, 10mL of tetrahydrofuran and 276mg of 4-methoxybenzene-1, 2-diamine were successively added, and the mixture was heated at 70 ℃ for 5 hours. The reaction medium is evaporated off, thus obtaining 680mg of a mixture of the two regioisomers (regicoiseure), which is used as such in the subsequent steps.

And step 3: in a 100mL three-necked flask, 118mg of the mixture of regioisomers obtained above were dissolved in 5mL of trifluoroacetic acid and 0.5mL of trifluoroacetic anhydride and heated at 85 ℃ for 2.5 hours. After concentration under reduced pressure, the residue was purified by flash chromatography on silica gel eluting with a mixture of isopropyl ether and methanol (95/5 by volume). This gave 97mg of 1- { 1-H-6-methoxy-benzoimidazol-2-yl } -3, 4-dihydro-2H-pyridin [2, 1-a ] isoindol-6-one as a pale beige powder, which is characterized as follows:

-mass spectrum (E/l): 331(M +) for M/z

And 4, step 4: in a 25ml three-necked flask, a solution of 61mg of 1- { 1-H-6-methoxy-benzoimidazol-2-yl } -3, 4-dihydro-2H-pyridin [2, 1-a ] isoindol-6-one in 2ml of acetic acid and 3ml of 48% aqueous hydrobromic acid was stirred at room temperature for 20 hours. The reaction medium is sparged into 100mL of water and neutralized with a saturated sodium bicarbonate solution in the presence of 25mL of dichloromethane. The aqueous phase is back extracted 2 times with 20mL portions of dichloromethane. The combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure. The crude product was obtained and purified by flash chromatography on silica gel eluting with a mixture of dichloromethane and methanol (95/5 and then 90/10 by volume) to give 49mg of 1- { 1-H-6-hydroxy-benzoimidazol-2-yl } -3, 4-dihydro-2H-pyridin [2, 1-a ] isoindol-6-one as white copied protein characterized as follows:

-mass spectrum (E/l): 317(M +), M/z.

-¹H NMR (400MHz, DMSO-d 6): 2.04(m, 2H); 2.83(t, J ═ 6.0Hz, 2H); 3.80(t, J ═ 6.0Hz, 2H), 6.74 (width d, J ═ 8.5Hz, 1H); 6.90 (width m, 1H); 7.42 (width m, 1H); 7.53(m, 2H); 7.75(m, 1H); 8.02 (width m, 1H); 9.22 (spread m, 1H); 12.4 (very broadened m, 1H).

Example 3: pharmaceutical composition

Tablets were prepared according to the following formulation:

example 1 product 0.2g

Excipients to 1g tablet

(specific excipients: lactose, talc, starch, magnesium stearate).

Biological assays capable of biologically characterizing the invention

Inorganic phosphate released during ATP hydrolysis by the ATPasique activity of Hsp82 was quantified using the malachite green method. In the presence of this reagent, an inorganic phosphate-molybdate-malachite green complex is formed, the absorption wavelength of which is 620 nm.

These products to be evaluated were incubated in a 30. mu.l reaction volume in the presence of 1. mu.M Hsp82 and 250. mu.M medium (ATP) in a buffer consisting of 50mM Hepes-NaOH (pH7.5), 1mM DTT, 5mM MgCl2 and 50mM KCl at 37 ℃ for 60 minutes. Meanwhile, there is 1-40. mu.M of inorganic phosphate in this same buffer. Then 60. mu.l of biomolgreen reagent (Tebu) was added to reveal ATPasique activity. After incubation at room temperature for 20 minutes, the absorbance of the different wells was measured at 620nm using a microplate reader. The inorganic phosphate concentration of each sample was then calculated using the calibration curve. The ATPasique activity of Hsp82 is expressed in terms of the concentration of inorganic phosphate produced over a period of 60 minutes. The effect of the different test products is expressed as a percentage inhibition of the ATPasique activity.

ADP generated as a result of ATPasique activity of Hsp82 was used to develop another method for evaluating the enzymatic activity of the enzyme by employing an enzyme-coupled system involving Pyruvate Kinase (PK) and Lactate Dehydrogenase (LDH). In this kinetic class of spectrophotometric methods, PK catalyzes the production of ATP and pyruvate from phosphoenolpyruvate carboxylate (PEP), and ADP is produced by HSP 82. The pyruvate formed, i.e. the matrix for the LDH, is then converted into lactate in the presence of NADH. In this case, the decrease in NADH concentration, measured by the decrease in absorbance at a wavelength of 340nm, is proportional to the ADP concentration produced by HSP 82.

These test products were incubated in a reaction volume of 100. mu.l of a buffer consisting of 100mM Hepes-NaOH (pH7.5), 5mM MgCl2, 1mM DTT, 150mM KCl, 0.3mM NADH, 2.5mM PEP and 250. mu.M ATP. This mixture was pre-incubated at 37 ℃ for 30 minutes before the addition of 3.77 units LDH and 3.77 units PK. This reaction was initiated by the addition of various concentrations of the product to be evaluated and Hsp82 at a concentration of 1 μ M. The enzymatic activity of Hsp82 was then measured continuously at a wavelength of 340nm at 37 ℃ using a microplate reader. The reaction initiation rate was obtained by measuring the tangent slope at the beginning of the recorded curve. The enzyme activity is expressed in μ M per minute of ADP produced. The effect of the different test products is expressed as a percentage inhibition of ATPasique activity according to the following coefficient:

-A：IC50＜1μM

-B：1μM＜IC50＜10μM

-C：10μM＜IC50＜100μM

results table

Claims

1) A product of formula (I):

in the formula: a1, A2, A3 and A4, identical or different, represent CRa or N;

n represents an integer of 1 or 2;

r1 represents an oxygen or sulphur atom or an NRb group;

ra is selected from H, halogen, CF3, hydroxyl, mercapto, nitro, amino, OR3, SR3, NR3R4, NH-OH, NH-CO-H, NH-CO-OH, NH-CO-NH2, carboxyl, cyano, carboxamido, Y- (CH2) p-alkyl, Y- (CH2) p-cycloalkyl, Y- (CH2) p-heterocycloalkyl, Y- (CH2) p-aryl OR Y- (CH2) p-heteroaryl, wherein Y ═ O, S, NH, O-C (O), C (O) -NH, NH-C O), NH-S (O) OR NH-S (O)2, wherein p ═ 1, 2 OR3, and wherein aryl contains 6 to 10 mer, cycloalkyl contains 3 to 10 mer, and heteroaryl OR heterocycloalkyl contains 4 to 10 mer, wherein 1-3 heteroatoms are selected from O, N or S; all of these groups are optionally substituted,

2) A product of formula (I) according to any one of the other claims, wherein:

the substituents n, Ra, R1 and R2 have the meanings indicated in any of the other claims,

3) A product of formula (I) according to any one of the other claims, wherein:

the substituents n, R1 and R2 have the meanings indicated in any of the other claims,

4) A product of formula (I) according to any one of the other claims, wherein:

these substituents n, R1 and R2 have the meanings indicated in any of the other claims,

5) A product of formula (I) according to any one of the other claims, wherein:

r1 represents an oxygen atom or an NRb group, wherein Rb represents H or (CH2) m-heteroaryl, wherein m is 0, 1, 2;

the substituents A1, A2, A3, A4, n and R2 have the meanings indicated in any one of the other claims;

6) A product of formula (I) according to any one of the other claims, wherein:

n represents a number of 2 and n represents a number of 2,

the substituents A1, A2, A3, A4, R1 and R2 have the meanings indicated in any of the other claims,

7) The product of formula (I) according to claim 1, wherein:

a1, A2 and A4 represent CH, A3 represents N, CH or COH,

n represents an integer of 2;

r1 represents an oxygen atom;

r2 represents a hydrogen atom or a hydrogen atom,

8) The product of formula (I) according to any of the preceding claims, having the following name:

-1- { 3-H-imidazo [4, 5-c ] pyridin-2-yl } -3, 4-dihydro-2H-pyrido [2, 1-a ] isoindol-6-one

-1- { 1-H-6-hydroxy-benzoimidazol-2-yl } -3, 4-dihydro-2H-pyrido [2, 1-a ] isoindol-6-one

9) The product of formula (I) according to any one of claims 1 to 7, in any of its possible racemic, enantiomeric and diastereomeric isomeric forms, and their addition salts with pharmaceutically acceptable inorganic and organic acids or with pharmaceutically acceptable inorganic and organic bases, as well as their prodrugs, as a medicament.

10) The products of formula (I) according to claim 8 in any possible racemic, enantiomeric and diastereomeric isomeric form, and their prodrugs, as medicaments, their addition salts with pharmaceutically acceptable inorganic or organic acids or with pharmaceutically acceptable inorganic or organic bases.

11) Pharmaceutical compositions containing at least one pharmaceutical according to any one of claims 9 to 10 as active ingredient.

12) Pharmaceutical compositions according to any of the preceding claims, characterized in that they are used as medicaments, in particular as cancer chemotherapy medicaments.

13) Pharmaceutical compositions according to any of the preceding claims, which also contain the active ingredients of other drugs against cancer chemotherapy.

14) Use of a product of formula (I) according to any one of the preceding claims or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the prevention or treatment of a disease characterized by an abnormal activity of HSP90 protein.

15) Use of a product of formula (I) according to any one of the preceding claims or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting HSP90 protein activity.

16) Use of a product of formula (I) according to any of the preceding claims in the treatment or prevention of a disease in a mammal.

17) Use of a product of formula (I) according to any one of the preceding claims or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of cancer.

18) Use of a product of formula (I) according to the preceding claim for the treatment of solid or liquid tumor cancers.

19) Use of a product of formula (I) according to the preceding claim in cancer whose disease to be treated is an anti-cytotoxic agent.

20) Use of a product of formula (I) according to any one of the preceding claims or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a cancer selected from: lung, breast and ovarian cancer, glioblastoma, chronic myelogenous leukemia, acute lymphocytic leukemia, prostate, pancreatic and colon cancer, metastatic melanoma, thyroid tumor, and renal cancer.

21) Use of a product of formula (I) according to any one of the preceding claims or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use alone or in combination in cancer chemotherapy.

22) Use of a product of formula (I) according to any one of the preceding claims or of a pharmaceutically acceptable salt thereof, for the preparation of a medicament intended to be used alone or in combination with chemotherapy or radiotherapy, or alternatively in combination with other therapeutic agents.

23) Use of the products of formula (I) according to the preceding claims in such therapeutic agents that can be commonly used antineoplastic agents.

24) A product of formula (I) according to any one of claims 1 to 10 in any of its possible racemic, enantiomeric and diastereomeric isomeric forms, as an inhibitor of HSP90, addition salts thereof with pharmaceutically acceptable inorganic or organic acids or with inorganic or organic bases and prodrugs thereof.