FR2793796A1 - Imidazole derivatives having Src SH2 receptor antagonist activity for the prevention and treatment of osteoporosis, auto-immune diseases, proliferative diseases, cancers, allergies and other disorders - Google Patents

Abstract

Imidazole derivatives (I) in all possible isomeric forms, their salts and prodrugs, and their preparation are new. Imidazole derivatives of formula (I) in all possible isomeric forms, their salts and prodrugs are new: V' = R3, OR3, or SR3; (A0) = -C(Ra)(Rb)n-CO-NRi- or -C(Ra)(Rb)n-NRi-CO-; n = 0, 1, 2, or 3; (A1) = -CH(Z)-(1-4C)alkyl-(5-14C)aryl-, -CH(Z)-(5-14C)aryl-, (1-4C)alkyl-(5-14C)aryl-, or (5-14C)aryl-, the aryl groups being optionally substituted by R2 or R'2; Z = H, tetrazole, NRcR'c, NHCORc, CONHRc, NHCHNHRc, NHSORc, or NHSO2Rc; A2 = -PO(ORd)(ORe), -OPO(ORd)(ORe), -B(ORd)(ORe), -CRfRg-PO-(ORd)(ORe), -O-CRfRg-COORd, -N(CRfRg-COORd)2, -COORd, -CRfRg-CH2-COORd, -CRfRgSO3H, -O-CRfRgSO3H, -SO3H, -SO2NH2, -NHCO-PO(ORd)(ORe), or -CO-PO-(ORd)(ORe); R3, R4, Ra, Rb, Rc, Rd, Re, and Ri = H, 1-8C alkyl, 3-18C cycloalkyl, 3-18C cycloalkyl 1-8C alkyl, 5-14C aryl, or 5-14C aryl-1-4C alkyl, these groups being optionally substituted by R2; or RaRb together with the C to which they are attached = 3-6C cycloalkyl group; Rf and Rg = H, halogen, ORc, NHRc, -COORd, -CH2COORd, SO3H, PO(ORd)(ORe), or tetrazole; Y = CO, CS, C(=NH), or SO2; R1 = OH, ORc, -NRcR'c, 1-4C alkyl, or halogen; R2 = 1-8C alkyl or alkoxy, 1-3C alkylene dioxy, 5-14C aryl or aryloxy, 5-14C aryl-1-4C alkyl, 5-14C aryl-1-4C alkoxy, halogen, trihalomethyl, OH, NO2, formyl, CN, COOH, CONH2, 1-8C alkoxy carbonyl, NH2, mono or di-1-4C alkyl, -NHCO 1-4C alkyl, -NHCO-5-14C aryl, -CONH 1-4C alkyl, -CONH-5-14C aryl, -CO-1-4C alkyl or -CO-5-14C aryl; R'2 = a group selected from those of A2 ; or optionally A2 and R'2 = a 5-membered bridge of formula (i) or (ii). (R'c used but not defined)

Description

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 The present invention relates to novel imidazole derivatives, process for their preparation and intermediates thereof, their use as medicaments and pharmaceutical compositions containing them.

dans laquelle [Ao] , [A1], A2, V, Y ,R1 et R4 ont les significations indiquées plus bas, leurs sels physiologiquement acceptables et leurs promédicaments. Les composés de formule (I) sont des composés ayant une activité pharmacologique et sont donc utilisables à titre de médicaments. Ce sont notamment des antagonistes du domaine Src SH2 et ils inhibent la résorption osseuse médiée par les ostéoclastes. Ils sont donc utiles pour le traitement thérapeutique ou prophylactique de maladies qui sont causées au moins en partie par une augmentation non désirée de la résorption osseuse, par exemple l'ostéoporose. L'invention de plus a pour objet les procédés de préparation des composés de formule (I), les intermédiaires de ce procédé, leur application, en particulier à titre de médicament et les compositions pharmaceutiques les renfermant. The subject of the invention is an imidazole derivative of formula (I)

wherein [Ao], [A1], A2, V, Y, R1 and R4 have the meanings given below, their physiologically acceptable salts and their prodrugs. The compounds of formula (I) are compounds having a pharmacological activity and can therefore be used as medicaments. In particular, they are antagonists of the Src SH2 domain and they inhibit bone resorption mediated by osteoclasts. They are therefore useful for the therapeutic or prophylactic treatment of diseases that are caused at least in part by an unwanted increase in bone resorption, for example osteoporosis. The invention further relates to the processes for preparing the compounds of formula (I), the intermediates of this process, their application, in particular as a medicament and the pharmaceutical compositions containing them.

Field of the invention a) Tyrosine kinase catalytic activity
The tyrosine kinase catalytic activity is associated either with receptors possessing transmembrane domains (EDF, DPGF, c-fms, etc.) or with intracellular proteins (T.

Hunter, Biochem Soc. Trans; 24, 307-327 (1996). Intracellular tyrosine kinases ("non-receptor") are divided into 8 subfamilies mainly according to the sequence similarity of their catalytic domain and have been named after their most known member (Src, Csk, Btk, Abl, Fak, Syk , Jak, Fsp). Inside this class of tyrosines

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Intracellular kynases, the Src family contains 9 members sharing 70% sequence homology (Src, Fyn, Yes, Frg, Lyn, Hck, Lck, Blk, Yrd in vertebrates). b) - Proteins of the Src family
Proteins of the Src family share a common structure that is characterized by the following elements: a small N-terminal fragment involved in membrane anchoring (sometimes also called SH4), a single, poorly conserved domain (40-70 residues) , an SH3 domain that binds to proline-rich sequences (50 residues), an SH2 domain involved in phosphorylated specific peptide sequence recognition (100 residues), a catalytic domain (tyrosine kinase, 250 residues) and finally a short domain C-terminal involved in regulation. c) - Function of tyrosine kinase proteins of the c-Src family
The protein tyrosine kinases of the c-Src family have multiple and overlapping roles in signal transduction involved in a variety of different biological situations, including cell growth and differentiation, cell cycle control, the shape and adhesion of cells as well as the regulation of ion channels and neurotransmitter receptors.

While the expression of most members of the Src family is limited to the hematopoietic system, the Src, Fyn and Yes proteins are expressed in a large number of tissues and cell types. The c-Src gene in particular is very widely expressed in neurons, platelets and osteoclasts. d) bone resorption and c-Src
The biological functions of many of these proteins have finally begun to be better understood with the realization of knock out experiments. Thus Soriano et al (Cell 64, 693-702) recently generated a transgenic mouse line whose c-Src gene was not functional.

The observation of the phenotype of the homozygous mice for this mutation revealed several extremely interesting facts: they did not have a patent abnormality

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 at the level of neurons or platelets, however, these mice all had very poor bone resorption which gives rise to abnormalities of the skeleton (S.N.

 Popoff et al; Bone 17 (5) 437-445.It was then shown that these mice had osteoclasts in normal numbers, but that they did not have a brush border and were not capable of normal resorption in the pit test ( BF Boyce et al J. Clin Invest 90, 1622-27 (1992).

So, only osteoclasts seem to be affected by the mutation. The hypothesis is as follows: in neurons, platelets and other cells in which Src exerts a function, this function could be supported by a member very close to the family (fyn, lyn or yes); however, this functional substitution would not occur in osteoclasts. e) - Inhibition of Src Protein
Since this protein appears mainly in bone resorption processes and does not appear vital for other functions, the Applicant proposes to find new compounds inhibiting it to stop bone resorption.

This inhibition can be carried out either at the level of the SH2 domain, at the level of the SH3 domain (involved in the recognition and the interaction with other proteins), or at the level of the catalytic domain (tyrosine kinase).

STATE OF THE ART The following patent applications disclose compounds that inhibit the binding of SH2 domain-containing proteins to a phosphorylated protein.

WO 98/40093 discloses bicyclic heterocyclic derivatives, WO97 / 12903 discloses phenyl derivatives, WO97 / 30079 and WO96 / 23813 disclose peptide derivatives, 95/25118 discloses benzodiazepine derivatives, EP 727211 and WO 96/24343 disclose use of certain compounds specific to the SH2 domain to treat bone resorption as well as autoimmune diseases.

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 Other investigations made it possible to show that the 5-membered heterocycle derivatives of formula (I) exhibit a high activity as an antagonist of the human Src SH2 domain and bone resorption mediated via osteoclasts.

dans laquelle, - V représente un groupement R3, OR3 ou SR3, - [Ao] représente un groupement choisi parmi -(C(Ra)(Rb))n-CO-NRi- ou - (C (Ra) (Rb) ) n-NRi-CO-, n étant égal à 0,1,2 ou 3, - [A1] représente un groupement choisi parmi -CH (Z) - (C1-C4) -alkyle- (C5-C14) -aryle-,

-CH (Z) - (C5-C14) -aryle-, - (CI-C4) -alkyle- (C,-Cl4) -aryle-, et -(C5-C14)-aryle-, dans lesquels Z est un atome d'hydrogène, un tétrazole,
NRcR'c, NHCORc, CONHRc, NHC02Rc, NHCONHRc, NHSORc ou NHS02Rc; les dits radicaux aryles étant substitués ou non substitués par R2 ou par R'2; - A2 représente un groupement choisi parmi -PO (ORd) (ORe) , -OPO(ORd)(ORe), -B (ORd) (ORe) , -CRfRgPO(ORd)(ORe), -0-CRfRgPO(ORd)(ORe) , -CRfRg-C02Rd, -0-CRfRg-C02Rd, -N(CRfRg-CO2Rd)2, -C02Rd, -CRfRg-CH2-
C02Rd, -CRfRgS03H, -0-CRfRgS03H, -S03H , -S02NH2, -NHCO- PO (ORd) (ORe) et -CO-PO (ORd) (ORe) ; - R3, R4, Ra, Rb, Rc, Rd, Re ou Ri, indépendants les uns des autres, identiques ou différents, représentant un atome d'hydrogène, un radical (C1-C8)-alkyle-, (C3-CIS) -

cycloalkyle-, (C3-Cl,) - (cycloalkyl) - (CI-CS) -alkyle-, (CsC14) -aryle- ou (C5-C14) -aryl- (C1-C4) -alkyle- , les dits radicaux étant substitués ou non substitués par R2; - Rf et Rg identiques ou différents représentant un atome The subject of the invention is a compound of formula (I)

in which - V represents a group R3, OR3 or SR3, - [Ao] represents a group selected from - (C (Ra) (Rb)) n-CO-NRi- or - (C (Ra) (Rb)) n -NR 1 -CO-, n being equal to 0,1,2 or 3, - [A1] represents a group chosen from -CH (Z) - (C1-C4) -alkyl- (C5-C14) -aryl- ,

-CH (Z) - (C 5 -C 14) -aryl-, - (C 1 -C 4) -alkyl- (C 1 -C 4) -aryl-, and - (C 5 -C 14) -aryl-, wherein Z is a hydrogen atom, a tetrazole,
NRcR'c, NHCORc, CONHRc, NHC02Rc, NHCONHRc, NHSORc or NHSO2Rc; said aryl radicals being substituted or unsubstituted by R2 or R'2; A2 represents a group chosen from -PO (ORd) (ORe), -OPO (ORd) (ORe), -B (ORd) (ORe), -CRfRgPO (ORd) (ORe), -O-CRfRgPO (ORd) (ORe), -CRfRg-CO2Rd, -O-CRfRg-CO2Rd, -N (CRfRg-CO2Rd) 2, -CO2Rd, -CRfRg-CH2-
CO2Rd, -CRfRgSO3H, -O-CRfRgSO3H, -SO3H, -SO2NH2, -NHCO- PO (ORd) (ORe) and -CO-PO (ORd) (ORe); - R3, R4, Ra, Rb, Rc, Rd, Re or Ri, independent of each other, identical or different, representing a hydrogen atom, a radical (C1-C8) -alkyl-, (C3-CIS) -

cycloalkyl-, (C3-Cl,) - (cycloalkyl) - (C1-CS) -alkyl-, (CsC14) -aryl- or (C5-C14) -aryl- (C1-C4) -alkyl-, so-called radicals being substituted or unsubstituted by R2; - Rf and Rg identical or different representing an atom

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- R2 représente un groupement (C1-C8) -alkyle-, (C1-Ce) -alkoxy-, hydroxy- (Cl-C.) -alkyle-, (Cl-C8) -alkoxy- (CI-CS) -alkyle-, (CIC3) -alkylènedioxy-, (CS-C14) -aryle-, (C5-Cl4) -aryloxy-, (C5- C14) -aryl- (Cl-C4) -alkyle-, (C5-C14) -aryl- (C1-C4) -alkyloxy-, halogène, trihalogénométhyle-, hydroxyle, nitro, formyle,

cyano, carboxy, -CONH2, (C1-Ce)-alkyloxycarbonyle-, amino, NH- CI-C4) -alkyle) , -N ( (Cl-C4) alkyle) 2, -NHCO- (CI-C4) -alkyle, -NHCO- (CS-C,4) -aryle, -CONH- (CI -C4) -alkyle, -CONH- (CS-C14) - aryle, -CO- (C1-C4) -alkyle ou -CO- (CS-C14) -aryle ; - R'2 a les mêmes valeurs que A2; - éventuellement A2 et R2 forment ensemble avec l'aryle qui les porte, l'un des cycles à 5 chaînons suivants :

lesdits composés de formule (I) étant sous toutes leurs formes isomères possibles, seuls ou en mélange dans un rapport quelconque, ainsi que leurs sels physiologiquement acceptables et leurs promédicaments (prodrugs). hydrogen, a halogen, ORc, NHRc, a CO2Rd radical,
CH2CO2Rd, SO3H, PO (ORd) (ORe) or tetrazole; - optionally Ra and Rb form together with the carbon atom which carries them, a cycloalkyl group containing from 3 to 6 carbons, - Y represents a C = O atom, C = S, C = NH or SO 2; R1 represents a group -OH, -ORc, -NRcR 'c, (C1-C4) alkyl- or halogen;

R2 represents a (C1-C8) -alkyl- (C1-C6) -alkoxy-, hydroxy- (C1-C4) -alkyl-, (C1-C8) -alkoxy- (C1-CS) -alkyl group; -, (CIC3) -alkylenedioxy-, (CS-C14) -aryl-, (C5-C14) -aryloxy-, (C5-C14) -aryl- (C1-C4) -alkyl-, (C5-C14) - aryl- (C1-C4) -alkyloxy-, halogen, trihalomethyl-, hydroxyl, nitro, formyl,

cyano, carboxy, -CONH 2, (C 1 -C 6) alkyloxycarbonyl, amino, NH-C 1 -C 4) alkyl, N ((C 1 -C 4) alkyl) 2, -NHCO- (C 1 -C 4) -alkyl , -NHCO- (CS-C, 4) -aryl, -CONH- (C -C -C) -alkyl, -CONH- (CS-C14) -aryl, -CO- (C1-C4) -alkyl or -CO- (CS-C14) -aryl; - R'2 has the same values as A2; - optionally A2 and R2 together with the aryl which carries them, one of the following 5-membered rings:

said compounds of formula (I) being in all their possible isomeric forms, alone or in mixture in any ratio, as well as their physiologically acceptable salts and their prodrugs.

 All the radicals which can be found several times in the compounds of formula (I), for example the radical R2. are independent of each other and may be the same or different.

 The alkyl radicals can be linear or branched, saturated or mono- or poly-unsaturated. This also applies

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 when they carry a substituent or when they are included in groups such as for example alkoxy, alkoxycarbonyl or aralkyl.

 (C1-C8) -alkyl means methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, the n-isomers of these radicals, isopropyl, isobutyl, isopentyl, neopentyl, isohexyl, 3-methylpentyl, 2,3,4-trimethylhexyl, sec-butyl, tert-butyl, tert-pentyl. Among the preferred radicals, mention may be made of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl.

 The bivalent alkylene radicals corresponding to the monovalent radicals mentioned above are, for example, the methylene, ethylene, 1,3-propylene, 1,2-propylene (= 1-methylethylene) and 2,3-butylene (= 1,2-dimethylethylene) radicals. ), 1,4-butylene, or 1,6-hexylene.

 The unsaturated alkyl radicals are, for example, alkenyl radicals such as vinyl, 1-propenyl, allyl, butenyl, 3-methyl-2-butenyl or alkynyl radicals such as ethynyl, 1-propynyl or propargyl.

Unsaturated bivalent alkylene radicals are understood to mean the alkenylene and alkynylene radicals which may also be linear or branched. These are, for example, vinylene, propenylene, ethynylene or propynylene radicals.

 The cycloalkyl radicals can be monocyclic, bicyclic or tricyclic. These are, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, cyclotetradecyl or cyclooctadecyl radicals which may optionally be substituted, for example, with an alkyl containing from 1 to 4 carbon atoms. carbon. Substituted cycloalkyl radicals include 4-methylcyclohexyl and 2,3-dimethylcyclohexyl.

 The bicycloalkyl and tricycloalkyl radicals may be unsubstituted or substituted in any position, for example by one or more oxo groups and / or 1 or more identical or different alkyl groups such as methyl or isopropyl and preferably methyl. The junction link

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 bi or tricyclic radical may be in any position of the molecule. The bond may be at the bridged carbon atom or one of the other carbon atoms. This connection can also present any position from the point of view of stereochemistry, for example exo or endo. Examples of bicycloalkyl or tricycloalkyl radicals include camphanyl, bornyl, adamantyl such as 1-adamantyl or 2-adamantyl, caranyl, episobornyl, epibornyl, norbornyl or norpinanyl.

 By halogen is meant fluorine, chlorine, bromine or iodine.

When Rf and Rg represent a halogen, it is preferably fluorine.

 By the term (C5-C14) -aryl is meant - either the heterocyclic (C5-C14) -aryl radicals (= (CS-C14) - heteroaryl), in which the carbon atoms of the ring are replaced by a heteroatom such as nitrogen, oxygen or sulfur, or carbocyclic (C6-C14) -aryl radicals.

 Among the carbocyclic (C6-C14) -aryl radicals, mention may be made of phenyl, naphthyl, biphenylyl, anthryl or fluorenyl and especially 1-naphthyl, 2-naphthyl and phenyl. It is preferably phenyl.

aminocarbonyle, (C1-C4)-alkoxycarbonyle, phényle, phénoxy, benzyle et benzyloxy. En général, au plus 2 groupes nitro peuvent être utilisés dans les composés de formule (I) selon l'invention. Unless otherwise indicated, aryl radicals, in particular phenyl radicals, may be unsubstituted or substituted by one or more identical or different radicals chosen from (C 1 -C 8) alkyl, in particular (C 1 -C 4) alkyl, (C 1 -C 8) -alkoxy, formyl, halogen such as fluorine, chlorine and bromine, nitro, amino, trifluoromethyl, hydroxyl, -CH2OH, methylenedioxy, cyano, hydroxycarbonyl,

aminocarbonyl, (C1-C4) -alkoxycarbonyl, phenyl, phenoxy, benzyl and benzyloxy. In general, at most 2 nitro groups can be used in the compounds of formula (I) according to the invention.

 In the case of monosubstituted phenyl, the substituent may be in the 2,3 or 4 position, and preferably in

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 position 3 or 4. In the case where the phenyl is disubstituted, the substituents may be in the 2,3 or 2,4 or 2,5 or 2,6 or 3,4 or 3,5 position. Preferably, in the disubstituted phenyls, the two substituents are in position 3,4.

When this phenyl is tri-substituted the positions are as follows: 2,3,4 or 2,3,5 or 2,3,6 or 2,4,5 or 2,4,6 or 3,4,5. Similarly, the naphthyl radicals or other aryl radicals can be substituted in any position, for example the 1-naphthyl radical at the 2-, 3-, 4-, 5-, 6-, 7-, and 8-position. and the 2-naphthyl radical at the 1-, 3-, 4-, 5-, 6-, and 7-position.

 The (CS-C14) -aryl group may also represent a monocyclic or polycyclic aromatic system in which 1,2,3,4 or 5 carbon atoms of the ring are replaced by heteroatoms, in particular those which are identical or different from the group consisting of nitrogen, oxygen and sulfur. Among the (C 5 -C 14) -aryl heterocyclic groups (= (CS-C 14) -heteroaryl), mention may be made of 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl and isoxazolyl groups. thiazolyl, isothiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, isoindolyl, indazolyl, phthalazinyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, cinnolinyl, β-carbolinyl, or benzocondensed, cyclopenta-, cyclohexa- or cyclohepto-condensed derivatives of these radicals. The heterocyclic system may be substituted by the same substituents mentioned above for the carbocyclic system.

 Among the heteroaryl radicals, are preferred monocyclic or bicyclic aromatic systems having 1,2 or 3 heteroatoms, in particular 1 or 2 heteroatoms, chosen from N, O or S, and which are unsubstituted or substituted by groups such as (C1 -C6) -alkyl, (C1-C6) -alkoxy, fluorine, chlorine, nitro, amino, trifluoromethyl, hydroxyl, formyl, (C1-C4) -alkoxycarbonyl, phenyl, phenoxy, benzyloxy, and benzyl.

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 Most particularly, mention may be made of 5 to 10-membered monocyclic or bicyclic aromatic systems containing from 1 to 3 heteroatoms, in particular 1 or 2 heteroatoms, chosen from N, O and S and which may be substituted with 1 or 2 substituents such as (C1-C4) -alkyl, (C1-C4) -alkoxy, formyl, phenyl, phenoxy, benzyl and benzyloxy.

 The optically active carbon atoms contained in the compounds of formula (I) may independently of each other have the R configuration or the S configuration.

 The compounds of formula (I) may be in the form of pure enantiomers or of pure diastereoisomers or in the form of a mixture of enantiomers, for example in the form of racemates or mixtures of diastereoisomers.

 The present invention therefore relates to pure enantiomers, mixtures of these enantiomers, pure diastereoisomers and mixtures of these diastereoisomers.

 The invention comprises mixtures of two or more stereoisomers of formula (I) and all ratios of these stereoisomers within said mixtures.

 The compounds of formula (I) may optionally be present in the form of E isomers or Z isomers. The subject of the invention is therefore pure E isomers, pure Z isomers and E / Z mixtures in a ratio any.

Finally, the invention comprises the different regioisomers linked to the ortho, para or meta position of A2. Preferably A2 is in the para position and R2 is in the meta position.

 The diastereoisomers, including the E / Z isomers, can be separated into individual isomers, for example by chromatography. Racemates can be separated into two enantiomers by common methods such as chiral phase chromatography or by resolution methods.

 The physiologically acceptable salts of the compounds of formula (I) are in particular pharmaceutically usable or non-toxic or physiologically usable salts.

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 When the compounds of formula (I) contain an acidic group such as the carboxylic acid, they are, for example, alkali metal or alkaline earth metal salts such as the sodium, potassium, magnesium and calcium salts, and also the salts formed with physiologically acceptable quaternary ammonium ions and the addition salts with acids such as ammonia and physiologically acceptable organic amines such as for example triethylamine, ethanolamine or tris (2-hydroxyethyl) amine.

 When the compounds of formula (I) contain a basic group, they can form an addition salt with acids, for example with inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid or with organic carboxylic acids such as acetic acid, trifluoroacetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, methanesulfonic acid or para toluene sulfonic acid.

 Compounds of formula (I) which have a basic group and an acid group may be present as Zwiterions (betaines), which are also included in the present invention.

 The salts of the compounds of formula (I) can be obtained by the ordinary methods known to those skilled in the art, for example by combining a compound of formula (I) with an organic or inorganic acid or a base in a solvent or dispersant or from another salt by exchange of cation or anion.

 The invention also includes all the salts of the compounds of formula (I) which, because of their low physiological acceptability, are not directly usable as a medicament, but can be used as intermediates for carrying out subsequent chemical modifications at the level of compounds of formula (I) or as starting materials for the preparation of physiologically acceptable salts.

 The present invention also includes all the solvates of the compounds of formula (I), for example the hydrates, the solvates formed with the alcohols, and all the derivatives of the compounds of formula (I), for example the esters, prodrugs and

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 other physiologically acceptable derivatives, as well as the metabolites of the compounds of formula (I).

 The invention more particularly relates to prodrugs compounds of formula (I) which can be converted into compounds of formula (I) in vivo under physiological conditions. The prodrugs of the compounds of formula (I), namely the chemically modified derivatives of the compounds of formula (I) in order to obtain properties improved in a desired manner, are known to those skilled in the art.

 For more information on the type of prodrug contemplated in the present invention, the following can be cited: Fleicher et al., Advanced Drug Delivery Review 19 (1996) 115-130; of prodrugs, H. Bundgaard, Ed., Elsevier, 1985; H. Bungaard, Drugs of the Future 16 (1991) 443; et al. Bioorg. Med. Chem. Lett. 4 (1994) 1985; Safadi et al. Pharmaceutical Res. 10 (1993) 1350.

(C5-C14))-aryle-(Ci-C8) alkyle, dans lequel 1 à 5 atomes de carbone dans la partie aryle peuvent être remplacés par des Among the suitable prodrugs of the compounds of formula (I), mention may be made preferably of: - the ester-form prodrugs of the phosphate or phosphonate group; - the ester-form prodrugs of the carboxylic groups, in particular the COOH group; acyl and carbamate prodrugs for groups containing acylatable nitrogen such as amino groups. In acylated or carbamated products, one or more times, for example twice, a hydrogen atom on the nitrogen atom is replaced by an acyl or carbamate group. Among the preferred acyl or carbamate groups, mention may be made of the groups R10CO-, R11OCO-, in which R10 is a hydrogen or a (C1-C18) alkyl, (C3-C14) -cycloalkyl or (C3-C18) -cycloalkyl radical - (C1-C8) alkyl, (C5-C14) -aryl, in which 1 to 5 carbon atoms may be replaced by heteroatoms such as N, O, S or

(C5-C14)) - aryl- (C1-C8) alkyl, wherein 1 to 5 carbon atoms in the aryl part can be replaced by

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 heteroatoms such as N, O, S and R11 at the same values as R10 with the exception of hydrogen.

 Among the preferred embodiments, the invention more particularly relates to the compounds of formula (I) in which - [Ao] - represents the group - (CHRa) -NH-CO in which Ra is an alkyl radical containing from 1 to 4 carbon atoms.

CH(Z) - (CI-C4) -alkyl- (CS-C14) -aryle- ou (C5-C14) -aryle- éventuellement substitué en méta par un groupement R2. The invention also more particularly relates to the compounds of formula (I) in which - [A1] - represents -

CH (Z) - (C1-C4) -alkyl- (CS-C14) -aryl- or (C5-C14) -aryl- optionally substituted in meta by a R2 group.

préférence -0-P03Hz, -CFz-P03Hz ou -CH(CO,H), et est en position para. The invention also more particularly relates to the compounds of formula (I) in which -A 2 represents

preferably -0-P03Hz, -CFz-P03Hz or -CH (CO, H), and is in the para position.

 The invention also more particularly relates to the compounds of formula (I) in which Z preferably represents NHCORc, NHCO2Rc, in which Rc represents an alkyl radical containing from 1 to 6 carbon atoms.

cycloalkyl- (Ci-C6) -alkyle-. The invention also more particularly relates to the compounds of formula (I) in which V preferably represents OR3 or SR3 in which R3 represents a (C1-C6) -alkyl- (C3-C12) -cycloalkyl- or ( C3-C12) -

cycloalkyl- (C1-C6) -alkyl-.

 The invention also more particularly relates to compounds of formula (I) in which R 4 is preferably an alkyl group containing from 1 to 6 carbon atoms.

 The invention also more particularly relates to the compounds of formula (I) in which Y is a group C = O and R1 is OH, NH2 or an alkyloxy group containing from 1 to 6 carbon atoms.

 Preferred compounds of formula (I) are compounds in which one or more radicals have the preferred meanings mentioned above.

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-[ail] - représente -CH(Z)-(CI-C4)-alkyl-phényle- ou -phényle- éventuellement substitué en méta par un groupement R2, - A2 représente -O-PO3H2, -CF2-P03H2 ou -CH(CO2H) et est en position para, - Z représente NHCORc, NHC02Rc, dans lesquels Rc représente un radical alkyle renfermant de 1 à 6 atomes de carbone, - V représente un radical SR3 dans lequel R3 représente un groupement (C3-C12) -cycloalkyl- (C1-C6) -alkyle-, - R4 est un groupement méthyle, - Y est un groupement C=O, et - R1 est un groupement hydroxy, NH2, ou un groupement alkyloxy renfermant de 1 à 6 atomes de carbone, lesdits composés de formule (I) étant sous toutes leurs formes isomères possibles, seuls ou en mélange dans un rapport quelconque, ainsi que leurs sels physiologiquement acceptables et leurs promédicaments (prodrugs). The subject of the invention is particularly the compounds of formulas (I) as defined above in which - [Ao] - represents the group - (CHCH3) -NHCO-

- [garlic] - represents -CH (Z) - (C 1 -C 4) -alkyl-phenyl- or -phenyl- optionally substituted in meta by a group R2, - A2 represents -O-PO3H2, -CF2-P03H2 or -CH (CO2H) and is in the para position, - Z represents NHCORc, NHC02Rc, in which Rc represents an alkyl radical containing from 1 to 6 carbon atoms, - V represents an SR3 radical in which R3 represents a (C3-C12) - cycloalkyl- (C1-C6) -alkyl-, -R4 is a methyl group, - Y is a group C = O, and - R1 is a hydroxyl group, NH2, or an alkyloxy group containing from 1 to 6 carbon atoms, said compounds of formula (I) being in all their possible isomeric forms, alone or in mixture in any ratio, as well as their physiologically acceptable salts and their prodrugs.

. 2- [1- [ [2 (S) - (acetylamino) -1-oxo-3- [4- (phosphonooxy) phenyl] - 1-propyl] amino] ethyl] -5- [ (cyclohexylmethyl) thio] -3-methyl-1H- imidazole-4-carboxylate d'éthyle; . N-2-acetyl-N-[1-[5-(aminocarbonyl)-4- [(cyclohexylmethyl)thio]-1-methyl-1H-imidazol-2-yl]-ethyl]-4- (phosphonooxy)-L-phenylalaninamide; . Acide [[4-[2(S)-(acetylamino)-3-[[1-[4(aminocarbonyl)-

5[(cyclohexylmethyl)thio]-3-methyl-1H-imidazol-2- yl]ethyl]amino]-3-oxo-propyl]phenyl]difluoromethyl]- phosphonique ; ainsi que leurs sels physiologiquement acceptables et leurs promédicaments (prodrugs). The subject of the invention is also the compounds of formula (I) whose names follow:

. 2- [1- [[2 (S) - (acetylamino) -1-oxo-3- [4- (phosphonooxy) phenyl] -1-propyl] amino] ethyl] -5 - [(cyclohexylmethyl) thio] -3 ethyl-1H-imidazole-4-carboxylic acid ethyl ester; . N-2-acetyl-N- [1- [5- (aminocarbonyl) -4 - [(cyclohexylmethyl) thio] -1-methyl-1H-imidazol-2-yl] -ethyl] -4- (phosphonooxy) -L -phenylalaninamide; . Acid [[4- [2 (S) - (acetylamino) -3 - [[1- [4 (aminocarbonyl)] -

[(Cyclohexylmethyl) thio] -3-methyl-1H-imidazol-2-yl] ethyl] amino] -3-oxo-propyl] phenyl] difluoromethyl] phosphonic acid; as well as their physiologically acceptable salts and their prodrugs.

 The present invention also relates to a process for preparing the compounds of formula (I). The compounds can generally be prepared, for example during

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dans laquelle Ra, Rb, Y, V, n, R1 et R4 sont tels que définis plus haut pour la formule (I) et où, le cas échéant, les groupes fonctionnels sont sous forme de précurseurs ou sous forme protégée, avec un acide ou un dérivé d'acide de formule (III)
X-C(=O)-[A1] -A'2 dans laquelle [A1] est tel que défini plus haut dans la formule (I) et A'2 représentant, outre les valeurs de A2, le radical hydroxy, X est un groupe substituable par un nucléophile et où, le cas échéant, les groupes fonctionnels sont sous forme de précurseurs ou sous forme protégée, lesdits groupes fonctionnels éventuellement présents sous forme de précurseur ou sous forme protégée, étant par la of a convergent synthesis by coupling of two or more fragments which can be derived by retrosynthesis of the compounds of formula (I). In order to avoid that the functional groups can lead to undesirable or secondary reactions during each synthesis step, it may be advantageous or necessary during the synthesis of the compounds of formula (I), to introduce the functional groups under form of precursors which are subsequently converted into desired functional groups or to temporarily block these functional groups by implementing a synthesis group protecting strategy which is known to those skilled in the art (Greene, Wuts protective Group in Organic Synthesis, Wiley 1991)
Thus the compounds of formula (I) can be prepared, for example, by coupling an amine of formula (II)

in which Ra, Rb, Y, V, n, R1 and R4 are as defined above for formula (I) and where, if appropriate, the functional groups are in the form of precursors or in protected form, with an acid or an acid derivative of formula (III)
XC (= O) - [A1] -A'2 wherein [A1] is as defined above in formula (I) and A'2 representing, besides the values of A2, the hydroxyl radical, X is a group substitutable by a nucleophile and where, where appropriate, the functional groups are in the form of precursors or in protected form, said functional groups optionally present in precursor form or in protected form, being by the

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 subsequently converted into groups present in the compounds of formula (I).

 Some compounds of formula (I) may if desired or necessary, undergo one or more of the following reactions in an appropriate sequence: - action of a monodebenzylating agent when [A'2] represents OPO (OBn) 2, - action of a total deprotecting agent, - HP (O) (ORd) (ORe) action when A'2 is OH, - obtaining the different values of Z (NHCORc, NHSORc, NHC02Rc, NHSO2Rc) from the corresponding amine ( Z = NH2) - salification.

 When [A'2] represents OH, the phosphorylation reaction is carried out with HP (O) (ORd) (ORe) in the presence of N'N-disopropylethylamine (DIPEA) and N, N-dimethylaminopyridine (DMAP) in acetonitrile in the presence of carbon tetrachloride.

 The functionalization reactions when Z = NH 2 in order to obtain the different values of Z, objects of the invention are carried out according to the conventional methods of organic synthesis known to those skilled in the art and are illustrated in the examples described below.

peut être également par exemple (Cl- C4) -alkyle -0- CO-0- ou tolylsulfonyloxy et le dérivé d'acide activé peut être un anhydride mixte. The COX group in formula (III) is preferably the carboxylic acid group or an activated derivative of the carboxylic acid. X, for example is hydroxyl or halogen, in particular chlorine or bromine, alkoxy, preferably methoxy or ethoxy, aryloxy, for example phenoxy, pentafluorophenyloxy, phenylthio, methylthio, 2-pyridylthio or a nitrogen heterocycle bonded via a hydrogen atom , in particular a nitrogen such as for example 1-imidazolyl. X

may also be for example (C 1 -C 4) -alkyl -O-CO-O- or tolylsulfonyloxy and the activated acid derivative may be a mixed anhydride.

(DCCI) ou avec le O-((cyano(éthoxycarbonyl)-métylène)amino)- If X is a hydroxyl, then if the amine of formula (II) reacts with a carboxylic acid of formula (III), then the carboxylic acid is first activated. Activation can be carried out for example with dicyclohexylcarbodiimide

(DCCI) or with O - ((cyano (ethoxycarbonyl) -metylene) amino) -

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 1,1,3,3-tetramethyluronium tetrafluoroborate (TOTU, Konig et al., Proc., 21st Europ.Peptide Symp., 1990 (Eds Giralt, Andreu), Escom, Leiden 1991, p.243) or other common activating agents. peptide synthesis.

 In addition to the free amines of formula (II), the amine salts can also be used in the reaction with the compounds of formula (III), the free amines being formed in situ or in a separate step by means of a base.

 The reaction of an activated carboxylic acid derivative of formula (III) with the amine (or derivative) of formula (II) is preferably carried out in a manner known per se in a protic or aprotic organic solvent, but inert . In this case, solvents such as methanol, isopropanol, tert-butanol, dimethylformamide or tetrahydrofuran are used at temperatures ranging from 0 ° C. to the reflux temperature of these solvents, in particular during the reaction of the methyl esters. or ethyl (X is methoxy or ethoxy) with the amines.

 The reactions of the acids of formula (III) (COX = CO 2 H) with free amines are advantageously carried out in an inert aprotic solvent such as dimethylformamide, tetrahydrofuran, dimethoxyethane or dioxane, if appropriate by adding a base such as, for example, potassium tert-butoxide, sodium methoxide or an organic base such as N-methylmorpholine. However, water can also be used as a solvent in the reactions of the compounds of formula (II) with the amines of formula (III), for example using a base such as sodium hydroxide.

 If X is chlorine, the reaction will preferably be carried out by addition of an acid scavenger, for example a base or an excess of amine (or derivative). The reaction mixture is then treated and if desired the reaction product is purified according to methods known to those skilled in the art.

 The acylation reaction using the compound of formula (III) [A'2] - [A1] -COOH is carried out in particular in the presence of EDC (1- (3-dimethylaminopropyl) hydrochloride).

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 ethyl carbodiimide) and HOBt (1-hydroxybenzotriazole hydrate) in an aprotic dipolar solvent such as dimethylformamide.

 The protecting groups optionally present in the compounds obtained from the compounds of formulas (II) and (III) are then removed by conventional methods; for example, the tert-butyl ester groups are converted to the carboxylic acid by treatment with trifluoroacetic acid, the benzyl groups are removed by hydrogenation or the fluorenylmethoxycarbonyl groups are removed in the presence of secondary amine and other reactions are implemented by standard methods, for example by acylation reactions. If necessary, the conversion to physiologically acceptable salts is carried out by methods known to those skilled in the art.

 When the amine is protected (NHC02Rb), it is particularly protected by a Boc group. The return to the free amine can be carried out by the action of trifluoroacetic acid.

When this amine is protected by CO 2 CH 2 Ph, the deprotection is preferably carried out in the presence of Pd (OH) 2, MgO in cyclohexadiene under reflux.

To obtain monodebenzylation ([A2] = OP (O) (OH) (OBn)), sodium iodide is used in particular and the reaction is carried out under reflux of acetone, or DABCO (1). , 4diazabicyclo [2.2.2] octane) in toluene.

To obtain total deprotection ([AZ] = OP (O) (OH) 2), a conventional hydrogenation is preferably carried out in the presence of 10% Pd / C or trifluoroacetic acid in dichloromethane is used.

formule (III) est choisi parmi N-Boc-Tyr-O-(POjBn2), N-AcTyr-0- (po3Bn2) , N-Boc-Tyr-CF2- (PO3Et,) et N-Ac-Tyr-CF2- (PO3Et2) . The invention more particularly relates to a method as described above in which the compound of

Formula (III) is selected from N-Boc-Tyr-O- (POjBn2), N-AcTyr-O- (po3Bn2), N-Boc-Tyr-CF2- (PO3Et), and N-Ac-Tyr-CF2- (PO3Et2).

 The subject of the invention is also a process for preparing compounds of formula (II), characterized in that a compound of formula (IIa) is subjected to

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à l'action d'un agent réducteur tel que NaBH4 et d'un réactif organométallique tel que RaMgBr, afin d'obtenir le composé de formule (II)

que l'on soumet à l'action du diphenylphosphorylazide, afin d'obtenir le composé de formule (IIc)

que l'on hydrogène, afin d'obtenir l'amine correspondante de formule (II).

to the action of a reducing agent such as NaBH4 and an organometallic reagent such as RaMgBr, in order to obtain the compound of formula (II)

that is subjected to the action of diphenylphosphorylazide, in order to obtain the compound of formula (IIc)

that is hydrogenated, in order to obtain the corresponding amine of formula (II).

 The conversion reaction of the alcohol to azide is carried out in particular in the presence of diphenylphosphorylazide (DPPA) in toluene in basic medium.

 The reduction of the azide to amine is carried out in particular by catalytic hydrogenation.

 When V represents a thiomethyl group, the conversion to thioalkyl is preferably carried out according to the following process: a) passage with sulfoxide, b) reaction of pummerer, c) hydrolysis and d) alkylation of the thiol.

The subject of the invention is therefore the processes described above and the new intermediate compounds of formulas (II), (IIa), (IIb) and (IIc).

 The starting compounds of formula (III) which are subsequently bound with the compounds of formula (II) to give the compounds of formula (I) are commercial, can be prepared according to methods described in the literature or

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dimethyléthoxy) carbonyl] -L-tyrosine . (N-Boc-Tyr-O- (P03Bn2) , origine : Penissula Laboratories, Inc - Le N-acétyl-O-[bis-(diphenylmethoxy)phosphinyl]-L-tyrosine
N-Ac-Tyr-O- (P03Bn2) - Le N- [ (1, 1-dimethyléthoxy) carbonyl] -4- [bis- ethoxyphosphinyl)difluoromethyl]-L-phenylalanine : N-BocTyr-CF2- (P03Et2) - Le N-acétyl-4-[bis-ethoxyphosphinyl)difluoromethyl]-L- phenylalanine : N-Ac-Tyr-CF2- (P03Et2)
Les composés de formule (lia) dans laquelle Y-R1 représente un groupement C02Et sont préparés de façon similaire aux composés imidazole décrit dans les demandes de brevet W095 23791 ou W095 23792 en 6 étapes à partir de l'éthylcyanoglyoxolate-2-oxyme et du chlorure d'acétyldiéthylthioacétale. still are accessible by analogy. By way of example, the following products of formula (III) are preferably used: 0- [bis (phenylmethoxy) phosphinyl] -N- [(1, 1-

dimethylethoxy) carbonyl] -L-tyrosine. (N-Boc-Tyr-O- (P03Bn2), Origin: Penissula Laboratories, Inc - N-acetyl-O- [bis- (diphenylmethoxy) phosphinyl] -L-tyrosine
N-Ac-Tyr-O- (P03Bn2) N- [(1,1-dimethylethoxy) carbonyl] -4- [bis-ethoxyphosphinyl) difluoromethyl] -L-phenylalanine: N-BocTyr-CF2- (P03Et2) - N-Acetyl-4- [bis-ethoxyphosphinyl) difluoromethyl] -L-phenylalanine: N-Ac-Tyr-CF2- (P03Et2)
The compounds of formula (IIa) in which Y-R 1 represents a CO 2 Et group are prepared in a manner similar to the imidazole compounds described in patent applications WO95 23791 or WO95 23792 in 6 steps from ethylcyanoglyoxolate-2-oxyme and acetyldiethylthioacetal chloride.

 The preparation of the compounds of formula (II) is illustrated in the examples described below, it being understood that the present invention is not restricted to these syntheses or these starting materials. There is no major difficulty for those skilled in the art to provide for modifications of the syntheses described in our application for the preparation of other compounds of formula (IIa), (II) or (III) according to the invention.

 The compounds of formula (I) can be used to inhibit binding of a Src protein to a similar phosphorylated protein.

 This inhibition can be carried out either at the level of the SH2 domain, at the level of the SH3 domain (involved in the recognition and the interaction with other proteins), or at the level of the catalytic domain (tyrosine kinase).

The compounds according to the invention have a particular affinity with respect to the SH2 domain of the Src protein.

 The compounds of formula (I) can therefore be used to inhibit the binding of a Src protein containing the SH2 domain to a phosphorylated analog protein, the method

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 comprising administering to the patient whose treatment requires inhibition of the SH2 domain, an inhibitory amount of the compound according to the invention.

 The action of the compounds of formula (I) can be demonstrated for example in an assay in which the inhibition of the binding of the radiolabelled EPQpYEEIPIYL ligand to the SH2 protein is determined by Scintillation proximity assay (SPA). Details on this test are given below. As antagonists of the Src SH2 domain, the compounds of formula (I) and their physiologically acceptable salts and their prodrugs are generally suitable for the treatment or the prevention of diseases related to the interactions between SH2 domain and their ligands or which can be influenced by the inhibition of such interactions, to relieve or heal when inhibition of such interactions is desired. As was explained at the beginning, such an interaction plays an important role in bone resorption.

 The compounds of formula (I) are very particularly antagonists of the human Src SH2 receptor and are thus capable, for example, of inhibiting the adhesion of osteoclasts to the bone surface and thus bone resorption by osteoclasts.

 The diseases of the bone whose treatment or prevention require the use of the compounds of formula (I) or their prodrugs, are in particular osteoporosis, hypercalcemia, osteopenia, for example caused by bone metastases, dental disorders such as periodontitis, hyperparathyroidism, periarticular erosions in rheumatoid arthritis, Paget's disease, osteopenia induced by immobilization. In addition, the compounds of formula (I) can be used to relieve, prevent or treat bone disorders caused by treatments, by glucocorticoids, steroid or corticosteroid-related therapies or by deficiencies. of male or female sex hormones.

All these disorders are characterized by bone loss, which is based on a lack of balance between bone formation and bone destruction and which can be favorably influenced by the inhibition of bone resorption by

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 osteoclasts.

 The compounds according to the invention, by their affinity with the Src-SH2 domain, can also be used in other therapeutic applications. For example, it is known that platelets and neurons are tissues that express Src-SH2 as well. In addition several proteins of this family being mainly expressed in the haemopoietic system, many applications in the treatment of immunity, infection, allergy and autoimmune diseases are possible.

 Finally, the compounds of formula (I) can also be used to inhibit the binding of a protein containing the SH2 domain, other than Src, to a phosphorylated analog protein, the method of administering to the patient whose treatment requires treatment. inhibition of the SH2 domain, an inhibitory amount of the compound according to the invention.

 Proteins containing SH2 domain other than Src are selected from Fyn, Lck, Yes, Blk, Lyn, Fgr, Hck, Yrk, Abl and Zap 70.

 The compounds according to the invention can thus be used in the treatment of diseases such as proliferative diseases, cancer, restenosis, inflammation; allergies or cardiovascular diseases.

 Among the medicaments of the invention, mention may be made particularly of the compounds described in the experimental part.

 Among these products, the invention more particularly relates, as medicaments, the compounds of formula (I) listed above.

 The subject of the present invention is therefore a compound of formula (I), and / or its physiologically acceptable salts and / or its prodrugs, as a medicament.

 The present invention more particularly relates to a compound of formula (I), and / or its physiologically acceptable salts and / or its prodrugs, as a drug having a Src SH2 receptor antagonist activity.

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 The present invention more particularly relates to a compound of formula (I), and / or its physiologically acceptable salts and / or its prodrugs, as a drug having an inhibitory activity for bone resorption or for the treatment or prevention of osteoporosis.

 The present invention more particularly relates to a compound of formula (I), and / or its physiologically acceptable salts and / or its prodrugs, as a medicament for the treatment or the prevention of immunity, of infection, of allergy, and autoimmune diseases.

 The present invention more particularly relates to a compound of formula (I), and / or its physiologically acceptable salts and / or its prodrugs, as a medicament for the treatment or prevention of diseases such as proliferative diseases, cancer, restenosis, inflammation, allergies or cardiovascular disease.

 The subject of the present invention is also the use of the compounds of formula (I) and / or their physiologically acceptable salts and / or their prodrugs for the preparation of medicaments intended for the prevention or treatment of osteoporosis.

 The subject of the present invention is also the use of the compounds of formula (I) and / or their physiologically acceptable salts and / or their prodrugs for the preparation of medicaments intended for the treatment or the prevention of immunity, of infection , allergy, and autoimmune diseases.

 The subject of the present invention is also the use of the compounds of formula (I) and / or their physiologically acceptable salts and / or their prodrugs for the preparation of medicaments intended for the treatment or prevention of diseases such as proliferative diseases, cancer, restenosis, inflammation, allergies or cardiovascular diseases.

 The compounds of formula (I) as well as their physiologically acceptable salts and their prodrugs can be administered to animals, preferably to mammals and

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 particularly to human beings as medicaments for therapeutic or prophylactic purposes.

 They can be administered as such or in admixture with one or more other compounds of formula (I) or in the form of a pharmaceutical preparation (pharmaceutical composition) which allows enteral or parenteral administration and which contains as active compound a effective dose of at least one compound of formula (I) and / or its physiologically acceptable salts and / or prodrugs as well as common and pharmaceutically inert excipients and / or additives.

 The medicaments may be administered orally, for example in the form of a pill, tablets, coated tablets, film-coated tablets, granules, capsules and soft capsules, solutions, syrups, emulsions, suspensions or mixtures thereof. aerosol.

 The administration may, however, be carried out rectally, for example in the form of suppository or parenterally, for example in the form of injectable solutions or infusions, microcapsules or implants, or percutaneously, for example under the form of ointment, solutions, pigments or dyes, transdermally (patches) or by other routes such as in the form of aerosol or nasal spray.

 The pharmaceutical compositions according to the invention are prepared according to methods known per se, organic or inorganic, pharmaceutically inert carriers being added to the compounds of formula (I) and / or their physiologically acceptable salts and / or their prodrugs.

 For the production of pill, tablets, coated tablets and hard gelatin capsule, it is possible to use, for example, lactose, cornstarch or its derivatives, talc, stearic acid or its salts, etc.

Suitable carriers for soft gelatin capsules or for suppositories are, for example, fats, waxes, semi-solid or liquid polyols, natural or modified oils etc. Suitable vehicles for the preparation of solutions, for example injectable solutions, emulsions or syrups, are, for example, water,

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 alcohols, glycerol, polyols, sucrose, invert sugars, glucose, vegetable oils, etc. Suitable carriers for microcapsules or implants are, for example, copolymers of glyoxilic acid and lactic acid. The pharmaceutical preparations normally contain from 0.5% to 90% by weight of compounds of formula (I) and / or their physiologically acceptable salts.

 In addition to the active ingredients and excipients, the pharmaceutical preparations may contain additives such as, for example, diluents, disintegrants, binders, lubricants, wetting agents, stabilizers, emulsifiers, preservatives, sweetening agents, dyes of flavoring agents or flavoring agents, thickeners, buffering agents, and also solvents or solubilizers or agents for obtaining a retarding effect and also salts for modifying osmotic pressure, coating agents or antioxidants.

 They may also contain two or more compounds of formula (I) and / or their physiologically acceptable salts and / or their prodrugs. In addition, in addition to at least one or more compounds of formula (I) and / or their physiologically acceptable salts and / or their prodrugs, they may contain at least one or more other active ingredients that can be used therapeutically or prophylactically.

 The subject of the present invention is therefore pharmaceutical compositions which allow enteral or parenteral administration and which contain, as active compound, an effective dose of at least one compound of formula (I) and / or its physiologically acceptable salts and / or its prodrugs and one or more pharmaceutically acceptable excipients, and optionally one or more customary additives.

 When the compounds of formula (I) are used, the doses may vary within wide limits and must be set according to the person to be treated. This depends, for example, on the compound used or the nature and severity of the disease to be treated and whether in severe or chronic conditions or if prophylactic treatment is used.

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 The pharmaceutical preparations (pharmaceutical compositions) normally contain from 0.2 to 500 mg, and preferably from 1 to 200 mg of compound of formula (I) and / or their physiologically acceptable salts and / or their prodrugs.

 In the case of oral administration, the daily dose generally varies from 0.01 to 100 mg / kg and preferably from 0.1 to 50 mg / kg, in particular from 0.1 to 5 mg / kg. For example, for an adult weighing 75 kg, a daily dose ranging from 0.3 to 0.5 mg / kg can be considered.

 In the case of intravenous administration, the daily dose ranges from approximately 0.01 to 100 mg / kg and preferably from 0.05 to 10 mg / kg.

The daily dose can be divided, especially in the case of administration of a large amount of active ingredient, in several, for example 2.3 or 4 parts. If necessary, depending on the individual behavior, it may be necessary to administer the different doses increasing or decreasing. Apart from the use of the compounds of formula (I) as medicaments, it is also possible to envisage their use as a vehicle or carrier of active compounds in order to transport these active compounds in a specific manner to an action site (Drug targeting, see Targeted Drug Delivery, RC Juliano, Handbook of Experimental Pharmacology, Vol 100, Ed Born, GVR et al, Springer Verlag). The active compounds that can be transported are in particular those used for the treatment or prevention of the diseases mentioned above.

 The compounds of formula (I) and their salts can also be used as a diagnostic agent, for example for in vitro methods or as auxiliary in biochemical studies in which it is desired to antagonize the human SRC SH2 domain. They can also be used as intermediates for the preparation of other compounds, in particular other active agents, which are accessible from the compounds of formula (I), for example by modifying or introducing radicals or functional groups.

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Examples
The products were identified by mass spectrum (MS), infrared (IR), NMR spectrum and / or their Rf.

Abbreviations / chemical names.

AcOEt: ethyl acetate; EDC: 1- (3-dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride; DMF: dimethylformamide; HOBt: 1-hydroxybenzotriazole hydrate MeOH: methanol; TEA: triethylamine; TFA: trifluoroacetic acid; THF: tetrahydrofuran; MCPBA: meta-chloroperoxybenzoic acid; DBU: 1,8-diazabicyclo [5.4.0] undec-7-ene; DPPA: diphenylphosphorylazide; DMSO: dimethyl sulfoxide; Pd / C Palladium on charcoal; Boc: terbutoxycarbonyl; CBz: benzyloxycarbonyl; DCC 1,3dicyclohexylcarbodiimide; TMSBr: bromotrimethylsilane; TMSI: trimethylsilane iodide.

IR: Infrared; NMR: Nuclear Magnetic Resonance; MS: Mass Spectrum; ep. : Shoulder; F: strong; s: singlet; d: doublet; t: triplet; quad: quadruplet; quintuplet; 1: wide; m: multiplet or massive; J: coupling constant; Rf: retention factor (chromatography).

2- (1-aminoéthyl) -3-méthyl-5- [ (cyclohexylméthyl) thio] -lIi- imidazole-4-carboxylate d'éthyle

Stade A

2-(l-hydroxyêthyl)-3-mêthyl-5-(mêthylthio)-lH-imidazole-4- carboxylate d'éthyle A une solution de 4,5g de 2-formyl-3-methyl-5-(méthylthio)- 1H-imidazole-4-carboxylate d'éthyle (préparé de façon Preparation Pl

Ethyl 2- (1-aminoethyl) -3-methyl-5 - [(cyclohexylmethyl) thio] -1-imidazole-4-carboxylate

Stage A

Ethyl 2- (1-hydroxyethyl) -3-methyl-5- (methylthio) -1H-imidazole-4-carboxylate To a solution of 4.5 g of 2-formyl-3-methyl-5- (methylthio) - Ethyl 1H-imidazole-4-carboxylate (prepared so

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l'éthylcyanoglyoxolate-2-oxyme (HO-N=(CN) (Co2Et))et du chlorure d'acétyldiéthylthioacétal (EtS)2CHCOCl), la dernière étape de déprotection du groupement dithioacétal s'effectue avec de l'acide glyoxylique dans l'acide acétique et conduit à l'imidazole 2-aldéhyde attendu) dans 25 ml de THF, on ajoute, à 0 C, 1,5 équivalent d'une solution de Bromure de méthyle magnésium (1M) dans l'éther diéthylique, agite 15 minutes puis hydrolyse en ajoutant une solution de chlorure d'ammonium. On extrait avec de l'acétate d'éthyle, lave la phase organique, sèche sur sulfate de magnésium et évapore sous pression réduite. On purifie par chromatographie sur silice le produit brut en éluant avec un mélange acétate d'éthyle/hexane 50/50 pour obtenir 2,2 de l'alcool attendu. similar to the imidazole compounds described in patent applications WO95 23791 or WO95 23792 in 6 steps starting from

ethylcyanoglyoxolate-2-oxyme (HO-N = (CN) (Co2Et)) and acetyldiethylthioacetal chloride (EtS) 2CHCOCl), the last step of deprotection of the dithioacetal group is carried out with glyoxylic acid in the Acetic acid and led to the imidazole 2-aldehyde expected) in 25 ml of THF, is added at 0 C, 1.5 equivalents of a solution of methyl bromide magnesium (1M) in diethyl ether, stirred 15 minutes and then hydrolyzed by adding a solution of ammonium chloride. Extracted with ethyl acetate, the organic phase washed, dried over magnesium sulfate and evaporated under reduced pressure. The crude product is purified by chromatography on silica, eluting with a 50/50 ethyl acetate / hexane mixture to obtain 2.2 of the expected alcohol.

MH+ = 245, MH-Hz0 = 227' ; MH'-EtOH = 199+ ; 199±H20 = 181+ RMN (1H, CDC13, 250MHz) 1,35 (t, 3H, C02Et) ; 1,60 (d, 3H, CH3) ; 2,4 (s,3H, SMe) ; 3,75 (s, 3H, NMe) ; (q, 2H, C02Et) ; 4,4 (q,lH, CH-OH) Stade B

2-(l-azidoêthyl)-3-methyl-5-(mêthylthio)-lH-imidazole-4- carboxylate d'éthyle A une solution de 1,4 g d'alcool préparé au stade A dans 15 ml de toluène à 0 C, on ajoute 1 ml de DBU puis 1,2 équivalent de DPPA. La solution est agitée 24 heures à température ambiante et le solvant est évaporé. Le produit brut est purifié par chromatographie sur silice en éluant avec un mélange acétate d'éthyle/hexane 50/50 pour donner 1,2 g de produit attendu. SM (Electrospray)

MH + = 245, MH-Hz O = 227 ';MH'-EtOH = 199+; 199 ± H20 = 181+ NMR (1H, CDCl3, 250MHz) 1.35 (t, 3H, CO2Et); 1.60 (d, 3H, CH 3); 2.4 (s, 3H, SMe); 3.75 (s, 3H, NMe); (q, 2H, CO2Et); 4.4 (q, 1H, CH-OH) Stage B

Ethyl 2- (1-azidoethyl) -3-methyl-5- (methylthio) -1H-imidazole-4-carboxylate To a solution of 1.4 g of alcohol prepared in Step A in 15 ml of toluene at 0.degree. 1 ml of DBU is added, followed by 1.2 equivalents of DPPA. The solution is stirred for 24 hours at room temperature and the solvent is evaporated. The crude product is purified by chromatography on silica eluting with a 50/50 ethyl acetate / hexane mixture to give 1.2 g of the expected product.

2-(1-azidoéthyl)-3-méthyl-5-(méthylsulfoxide)-1H-imidazole-4- carboxylate d'éthyle NMR (1H, CDCl3, 250MHz) 1.25 (t, 3H) COOEt; 1.6 (d, 3H) CH3; 2.4 (s, 3H) SMe; (s, 3H) NMe; (q, 2H) COOEt; 4.4 (q, 1H) CHN3 Stage C

Ethyl 2- (1-azidoethyl) -3-methyl-5- (methylsulfoxide) -1H-imidazole-4-carboxylate

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 To a solution of 1.5 g of the product prepared in the preceding stage in 30 ml of dichloromethane at 0 ° C., 1.2 g of metachloroperbenzoic acid (MCPBA) is added, the mixture is stirred for 30 minutes and then a solution of NaHCO 3 is added, the organic phase is washed. with water, the solvent is evaporated off and the crude product is purified by chromatography on silica eluting with 50/50 ethyl acetate / cyclohexane and then with 5/95 dichloromethane / methanol to give 1.2 g of the expected product under form of a mixture of diastereoisomers.

2-(1-azidoéthyl)-3-méthyl-5-[(cyclohexylméthyl)thio]-1H- imidazole-4-carboxylate d'éthyle A 1,2 g du produit obtenu au stade précédent dans 10 ml de dichlorométhane, on ajoute 1,4 ml d'anhydride trifluoro acétique , agite 15 minutes, évapore le solvant puis traite le mélange réactionnel avec une solution préalablement dégazée de 20 ml de méthanol et 2,5 ml de TEA. Après 10 minutes, le thiol est transformé en sulfure par ajout de 1,5g de iodure de cyclohexylméthyle dans 2 ml de méthanol. La solution est agitée 12 heures et évaporée. Le produit brut obtenu est purifié par chromatographie sur silice en éluant avec le mélange acétate d'éthyle/cyclohexane 50/50 pour obtenir 1,2g du produit attendu. NMR (1H, CDCl3, 250MHz) 1.35 (t, 3H) COOEt; 1.81 and 1.83 (d, 3H) CH 3; and 2.92 (s, 3H) SOMe; 3.97 and 3.99 (s, 3H) N-Me; (q, 2H) COOEt; 4.6 and 4.75 (q, 1H) CH-N3 Stage D

Ethyl 2- (1-azidoethyl) -3-methyl-5 - [(cyclohexylmethyl) thio] -1H-imidazole-4-carboxylate To 1.2 g of the product obtained in the preceding stage in 10 ml of dichloromethane is added 1.4 ml of trifluoroacetic anhydride, stirred for 15 minutes, evaporated the solvent and then treated the reaction mixture with a previously degassed solution of 20 ml of methanol and 2.5 ml of TEA. After 10 minutes, the thiol is converted into sulfide by adding 1.5 g of cyclohexylmethyl iodide in 2 ml of methanol. The solution is stirred for 12 hours and evaporated. The crude product obtained is purified by chromatography on silica eluting with 50/50 ethyl acetate / cyclohexane to give 1.2 g of the expected product.

2-(1-aminoéthyl)-3-methyl-5-[(cyclohexylméthyl)thio]-1H- imidazole-4-carboxylate d'éthyle MS (Electrospray +) [M + Na] + = 374+ [M + Na + CH3CN] + = 415+ NMR (1H, CDCl3, 250 MHz) 0.8 to 1.7 (m, 11H) Cyclohexyl; (t, 3H) COOEt; 1.55 (d, 3H) CH3; 2. (m, 2H) SCH2; 3.6 (s, 3H) N-CH3; 4.10 (q, 2H) COOEt; 4.2 (m, 1H) CHN3 Stage E

Ethyl 2- (1-aminoethyl) -3-methyl-5 - [(cyclohexylmethyl) thio] -1H-imidazole-4-carboxylate

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 150 mg of azidoimidazole prepared in the preceding stage are dissolved in 5 ml of ethyl acetate and hydrogenated under hydrogen pressure in the presence of a catalytic amount of Pd / C. After 3 hours at room temperature, the solution is filtered and the solvent is evaporated to give the expected amine (mixture of both R and S isomers) in quantitative yield.

2-(1-aminoéthyl)-3-méthyl-5-[(cyclohexylmethyl)thio]-1H- imidazole-4-carboxamide

Stade A : hydrolyse de l'ester

Acide 2-(1-azidoéthyl)-3-méthyl-5-[(cyclohexylméthyl)thio]- 1H-imidazole-4-carboxylique A 550 mg de l'ester préparé au stade d de la préparation 1 dans 5 ml d'éthanol, on ajoute 5 équivalent d'une solution de soude. La solution est agitée 12 heures et puis on évapore le solvant. La phase aqueuse est ensuite acidifiée avec une solution d'acide chlorhydrique 1N jusqu'à obtention d'un pH égal à 3 puis on extrait avec de l'acétate d'éthyle. La phase MS (Positive mode electrospray) [M + H] + = 326 + [MH + - NH3] = 309 213+ = 309+ -CH2-Cyclohexyl 167+ = 213+ - 1H NMR (CDCl3, 250 MHz) 0.8 at 1.7 (m, 11H) Cyclohexyl; 1.25 (t, 3H) COOEt; 1.30 (d, 3H) CH3; 2.95 (m, 2H) SCH2; 3.75 (s, 3H) N-CH3; 4.35 (q, 2H) COOEt; 4.0 (m, 1H) CHNH2 Preparation 2

2- (1-aminoethyl) -3-methyl-5 - [(cyclohexylmethyl) thio] -1H-imidazole-4-carboxamide

Stage A: hydrolysis of the ester

2- (1-Azidoethyl) -3-methyl-5 - [(cyclohexylmethyl) thio] -1H-imidazole-4-carboxylic acid A 550 mg of the ester prepared in Step d of Preparation 1 in 5 ml of ethanol 5 equivalents of a sodium hydroxide solution are added. The solution is stirred for 12 hours and then the solvent is evaporated. The aqueous phase is then acidified with 1N hydrochloric acid solution until a pH of 3 is obtained and then extracted with ethyl acetate. The sentence

<Desc / Clms Page number 30>

 The organic material is then dried over magnesium sulphate and finally evaporated to give 500 mg of expected acid.

2-(1-azidoéthyl)-3-méthyl-5-[(cyclohexylméthyl)thio]-1H- imidazole-4-carboxamide A une solution de 350mg d'acide carboxylique préparé au stade A dans 4 ml de THF, on ajoute 307mg d'EDC, 215mg de HOBt et 150g de N-méthylmorpholine. Après 1 heure, on ajoute une solution d'hydroxyde d'ammonium à 30% et agite 3 heures. La solution est ensuite acidifiée avec de l'acide chlorhydrique 1N jusqu'à obtention d'un pH égal à 3, puis on extrait à l'acétate d'éthyle, lave la phase organique avec une solution de NaHC03, sèche sur sulfate de magnésium et évapore le solvant pour obtenir 200 g d'amide, après filtration sur silice (éluant AcOEt) . MS [M + H] + = 324 '; 280+ = MH '- COOH; 645- - [2M-H] -; 322- - [M-H] -; 279- - 322- - N3; NMR (1H, CDCl3, 250MHz) 0.8 to 1.7 (m, 11H, cyclohexyl); (d, 3H) CH3; 2.85 (m, 2H, SCH 2); 3.6 sec, 3H, NMe); (q, 1H, CHN3) Stage B formation of amide

2- (1-Azidoethyl) -3-methyl-5 - [(cyclohexylmethyl) thio] -1H-imidazole-4-carboxamide To a solution of 350 mg of carboxylic acid prepared in Step A in 4 ml of THF, 307 mg is added. EDC, 215mg of HOBt and 150g of N-methylmorpholine. After 1 hour, 30% ammonium hydroxide solution is added and the mixture is stirred for 3 hours. The solution is then acidified with 1N hydrochloric acid until a pH of 3 is obtained, then the mixture is extracted with ethyl acetate, the organic phase is washed with a solution of NaHCO 3 and dried over magnesium sulphate. and evaporating the solvent to obtain 200 g of amide, after filtration on silica (eluent AcOEt).

2-(1-aminoethyl)-3-methyl-5-[(cyclohexylmethyl)thio]-1H- imidazole-4-carboxamide On opère comme au stade E de la préparation 1 pour obtenir l'amine attendue sous la forme d'un mélange d'isomères R et S avec un rendement de 80%. MS [M + H] + = 323+; 245 '= [M + Na']; 280+ = MH ± N3; NMR (1H, CDCl3, 250MHz) 0.8 to 1.7 (m, 11H, cyclohexyl); 1.6 (d, 3H, CH3); 2.75 (m, 2H, SCH,); 3.75 s, 3H, NMe); Stage C Hydrogenation

2- (1-aminoethyl) -3-methyl-5 - [(cyclohexylmethyl) thio] -1H-imidazole-4-carboxamide The procedure is as in Step E of Preparation 1 to obtain the expected amine in the form of a mixture of R and S isomers with a yield of 80%.

NMR (1H, CDCl3, 250MHz) 0.8 to 1.7 (m, 11H, cyclohexyl); 1.55 (d, 3H, CH3); 2.8 (m, 2H, SCH 2); 3.75 (s, 3H, NMe); 4.5 (ql, 1H, CH-NH2)

<Desc / Clms Page number 31>

- 2- [1- [ [2 (S) - (acëetylamino) -1-oxo-3- [4- (phosphonooxy) phényl] -1-propyl] amino] éthyl] -5- [ (cyclohexylméthyl) thio] -3- méthyl-lH-imidazole-4-carboxylate d'éthyle,

Stade A

2- [1- [ [2 (S) - (acétylamino) -1-oxo-3- [4- [bis (phénylméthoxy) phosphinyl) phényl] -1-propyl] amino] ethyl] -5- [ (cyclohexyl méthyl) thio]-3-methyl-lH-imidazole-4-carboxylate d'éthyle A une solution de 240mg de N-Ac-Tyr-O- (PO3Bn2) (série L) , on ajoute 96mg d'EDC et 68mg de HOBt et agite 10 mn. On ajoute ensuite une solution de 110mg du produit préparé au stade E de la préparation 1, dans 1 ml de dichlorométhane. Le mélange est agité 3 heures puis traité avec une solution de 5 ml de NaHC03 aqueux. La phase organique est lavée avec successivement de l'eau, une solution d'acide citrique, de chlorure de sodium, puis de l'eau, séchée sur sulfate de magnésium et évaporée. Le produit brut est purifié par chromatographie sur silice en éluant avec le mélange acétate d'éthyle/cyclohexane 75/25 pour mener à 260 mg de produit attendu. Example 1

2- [1- [[2 (S) - (acetylamino) -1-oxo-3- [4- (phosphonooxy) phenyl] -1-propyl] amino] ethyl] -5 - [(cyclohexylmethyl) thio] - Ethyl 3-methyl-1H-imidazole-4-carboxylate,

Stage A

2- [1- [[2 (S) - (Acetylamino) -1-oxo-3- [4- [bis (phenylmethoxy) phosphinyl) phenyl] -1-propyl] amino] ethyl] -5 - [(cyclohexyl methyl) ethyl thio] -3-methyl-1H-imidazole-4-carboxylate To a solution of 240mg of N-Ac-Tyr-O- (PO3Bn2) (L series), 96mg of EDC and 68mg of HOBt are added. and stirred for 10 minutes. A solution of 110 mg of the product prepared in Stage E of Preparation 1 in 1 ml of dichloromethane is then added. The mixture is stirred for 3 hours and then treated with a solution of 5 ml of aqueous NaHCO 3. The organic phase is washed successively with water, a solution of citric acid, sodium chloride and then water, dried over magnesium sulfate and evaporated. The crude product is purified by chromatography on silica eluting with 75/25 ethyl acetate / cyclohexane to yield 260 mg of expected product.

NMR (1H, DMSO) 1.3 (t, 3H) COOEt; 0.8 to 1.8 (m, 13H) cyclohexyl; (m, 3H) CH3; 1.89 and 1.90 (s, 3H) NHCOCH 3; 2.9 (m, 2H) SCH2; 3.6 (s, 3H) NMe; 4.2 (q, 2H) COOEt; 4.50 (m, 1H) COCH-N; 5.1 (m, 5H) CH, PO (OBn) 2; 5.9 and 6.0 (d, 1H) NH; 6.4 and 6.6 (d, 1H) NH; at 7.3 (m, 14H) aromatic;

<Desc / Clms Page number 32>

2- [1- [ [2 (S) - (acétylamino) -1-oxo-3- [4- (phosphonooxy) phényl] -1propyl] amino] éthyl] -5- [ (cyclohexylméthyl) thio] -3-mëthyl-lH- imidazole-4-carboxylate d'éthyle 100 mg du dibenzylphosphateester est dissous dans 5 ml de méthanol et hydrogéné 5 heures sous atmosphère d'hydrogène en présence de Pd/C. Après filtration sur célite, le mélange réactionnel est purifié par chromatographie en phase inverse en éluant avec un mélange MeOH/H20 65/35 pour donner, après lyophilisation, 50mg d'un mélange de deux diastéréoisomères (RS + SS) correspondant au produit attendu. Stage B

2- [1- [[2 (S) - (Acetylamino) -1-oxo-3- [4- (phosphonooxy) phenyl] -1-propyl] amino] ethyl] -5 - [(cyclohexylmethyl) thio] -3-methyl Ethyl imidazole-4-carboxylate 100 mg of the dibenzylphosphate ester is dissolved in 5 ml of methanol and hydrogenated for 5 hours under an atmosphere of hydrogen in the presence of Pd / C. After filtration on celite, the reaction mixture is purified by reverse phase chromatography eluting with a 65/35 MeOH / H 2 O mixture to give, after lyophilization, 50 mg of a mixture of two diastereoisomers (RS + SS) corresponding to the expected product.

NMR (1H, DMSO) 1.28 (t, 3H) COOEt; 0.85 to 1.85 (m, 11H) cyclohexyl; and 1.44 (d, 3H) CH3; 1.74 and 1.76 (s, 3H) COCH3; 2.80-3.15 (m, 4H) SCH2 and PhCH2; 4, 24 (q, 2H) COOEt; 3.66 and 3.67 (s, 3H) N-CH3; 4.35 to 4.50 (m, 1H) COCH-N; 5.08 (m, 1H) C-CH-NH; at 7.18 (m, 4H) aromatic; 8.03 and 8.1 (d, 1H) NH; and 8.6 (d, 1H) NH.

MS (EI) 611+ = M + H +; 633+ = 610 '+ Na'; 530 '= 610 ± P03H2 + H; 512+ = 610+ - OP03H2 - H Example 2 N-2-acetyl-N- [1- [5- (aminocarbonyl) -4 - [(cyclohexylmethyl) thio] -1-methyl-1H-imidazol-2-yl] ethyl-4- (phosphonooxy) -L-phenylalaninamide,

<Desc / Clms Page number 33>

 The procedure is as in Example 1, Steps A and B, but starting from the amide prepared in Stage C of Preparation 2. A mixture of distoisteromers (RS + SS) is obtained.

5[(cyclohexylmêthyl)thio]-3-methyl-lH-imidazol-2-yl]éthyl] amino] -3-oxo-propyl] phényl] difluorométhyl] -phosphonique

Stade A diéthyl ester de l'acide [ [4- [2 (S) - (acétylamino) -3- [ [1-

[4(aminocarbonyl)-5[(cyclohexylméthyl)thio]-3-méthyl-1H- imidazol-2-yl] ethyl] amino] -3-oxo-propyl] phényl] difluoro méthyl] phosphonique On opère de la même façon qu'au stade A de l'exemple 2 mais en utilisant le N-Ac-Tyr-CF2- (P03Et2) (série L) . NMR (H1, DMSO) 0.8 to 1.7 (m, 11H) cyclohexyl; and 1.43 (d, 3H) CH3-CH; 1.75 and 1.79 (s, 3H) CH3-C =; 2.85 (m, 2H) Ph-CH 2; 3.65 and 3.66 (s, 3H) CH3-N; 4.39 (m, 1H) CH; 5.08 (m, 1H) CH; 7.0 to 7.2 (m, 4H) aromatic; 7.9 to 8.2 (m, 1.5H) NH; (m, 0.5H) NH Example 3 - [[4- [2 (S) - (acetylamino) -3 - [[1- [4 (aminocarbonyl)] - acid

[(Cyclohexylmethyl) thio] -3-methyl-1H-imidazol-2-yl] ethyl] amino] -3-oxo-propyl] phenyl] difluoromethyl] phosphonic

Stage A diethyl ester of [[4- [2 (S) - (acetylamino) -3- [1-

[4 (aminocarbonyl) -5 [(cyclohexylmethyl) thio] -3-methyl-1H-imidazol-2-yl] ethyl] amino] -3-oxo-propyl] phenyl] difluoromethyl] phosphonic The procedure is as follows: in Step A of Example 2 but using N-Ac-Tyr-CF2- (PO3Et2) (L series).

NMR (1H, CDCl3, 250MHz) 0.8 to 1.8 (m, 13H) cyclohexyl + CH2; 1.2 (m, 6H) and; 1.70 (m, 3H) CH 3; 1, 99 and 2 (s, 3H) NHCOMe; 3.0 (m, 2H) SCH 2; 3.9 (s, 3H) CH3-N; 4.1 (m, 4H) and; 4.6 (m, 1H) CH; 5.2 (m, 1H) CH; and 6.2 (d, 1H) NH; 6.65 and 6.9 (d, 1H) NH; (d, 1H) 7.25 (d, 1H) 7.40 (d, 1H) 7.5 (d, 1H) H aromatic.

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[(cyclohexylméthyl)thio]-3-methyl-1H-imidazol-2-yl]éthy1] amino]-3-oxo-propyl]phényl]difluorométhyl]-phosphonique A 35 mg du phosphonate préparé au stade précédent dans du dichlorométhane, on ajoute 1101 de TMSBr et porte au reflux pendant 3 heures. On ajoute ensuite du méthanol, évapore le solvant et purifie le mélange réactionnel par chromatographie sur phase inverse en éluant avec le mélange méthanol/Eau 65/35. On obtient un mélange de 2 diastéréoisomères (RS + SS :50/50) . MS 670- - [M-H] 694+ = [M + Na] Step B [[4- [2 (S) - (acetylamino) -3 - [[1- [4 (aminocarbonyl) -5-] acid

[(cyclohexylmethyl) thio] -3-methyl-1H-imidazol-2-yl] ethyl] amino] -3-oxo-propyl] phenyl] difluoromethyl] phosphonic acid To 35 mg of the phosphonate prepared in the preceding stage in dichloromethane, add 1101 TMSBr and reflux for 3 hours. Methanol is then added, the solvent is evaporated and the reaction mixture is purified by reverse phase chromatography, eluting with a methanol / water 65/35 mixture. A mixture of 2 diastereoisomers (RS + SS: 50/50) is obtained.

NMR (1H, DMSO) 0.8 to 1.8 (m, 11H) cyclohexyl; and 1.45 (d, 3H) CH3-CH: 1.74 and 1.75 (s, 3H) CH3-C =; 2.80 to 3.20 (m, 4H) 2 x CH 2; 3.65 and 3.67 (s, 3H) CH3-N; 4.50 (m, 1H) CH; 5.08 (m, 1H) CH; 7.3 to 7.45 (m, 4H) aromatic; 8, 10 and 8.17 (d, 1H) NH; 8.57 and 8.61 (d, 1H) NH MS (SIMS) 638 = M + Na + 616 = MH + Pharmacological study of the products of the invention: IC50 measurement by scintillation proximity test (SPA).

The ability of the molecules to bind to the SrcSH2 protein is assessed by competition (ICso measurement) in a test called Scintillation proximity assay (SPA). This test uses PVT beads (Amersham) that contain scintillating. These beads coated with streptavidin are incubated in MOPS buffer in 99-well plates with 50nM of pre-biotinylated SH2 protein and then with 125I-labeled EPQpYEEIPIYL ligand. By binding to the protein fixed on the ball the active ligand the scintillator that emits light measured in a Wallac micropeta scintillation counter. The value obtained in the absence of any competitor corresponds to the maximum binding of the ligand on the protein. This method does not require separating the free ligand from the bound.

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The test molecules are diluted in MOPS buffer containing 2% DMSO and added at different concentrations from 0.1nM to 100M in the wells containing the ligand, before the addition of the Src-SH2 coated beads. After 1 hour of incubation, a measurement of the binding is carried out on the scintillation counter. Inhibition of the binding of the radiolabeled ligand by the different competitor concentrations makes it possible to evaluate the IC50s of the molecules tested.

Result SPA Results: Reference Peptide
PYEEI ~ 0.2-0.4 mol

<Tb>
<tb> EXAMPLES <SEP> N <SEP> IC50 <SEP> (Mol)
<tb> 1 <SEP> 6.88 <SEP>
<tb> 2 <SEP> 8.65 <SEP>
<tb> 3 - l <SEP> 5.32
<Tb>

Claims (23)

C14) -aryl- or (C5-C14) -aryl- (C1-C4) -alkyl-, said radicals being substituted or unsubstituted by R2; - Rf and Rg identical or different representing a hydrogen atom, a halogen, ORc, NHRc, a CO2Rd radical,  of hydrogen, a (C1-C8) -alkyl-, (C3-C18) -cycloalkyl-, (C3-C18) - (cycloalkyl) - (C1-C8) -alkyl-, (C5-

NRcR'c, NHCORc, CONHRc, NHC02Rc, NHCONHRc, NHSORc or NHSO2Rc; said aryl radicals being substituted or unsubstituted by R2 or R'2; A2 represents a group chosen from -PO (ORd) (ORe), -OPO (ORd) (ORe), -B (ORd) (ORe), -CRfRgPO (ORd) (ORe), -O-CRfRgPO (ORd) (ORe), -CRfRg-CO2Rd, -O-CRfRg-CO2Rd, -N (CRfRg-CO2Rd) 2, -CO2Rd, -CRfRg-CH2-CO2Rd, -CRfRgSO3H, -O-CRfRgSO3H, -SO3H, -SO2NH2, - NHCO-PO (ORd) (ORe) and -CO-PO (ORd) (ORe); - R3, R4, Ra, Rb, Rc, Rd, Re or Ri, independent of each other, identical or different, representing an atom  -CH (Z) - (CS-C14) -aryl-, - (C1-C4) -alkyl- (C8-C14) -aryl-, and - (C5-C14) -aryl-, wherein Z is an atom hydrogen, a tetrazole,

 - (C (Ra) (Rb)) n -CO-NRi- or - (C (Ra) (Rb)) n-NRi-CO-, n being equal to 0,1,2 or 3, - [A1] represents a group selected from -CH (Z) - (C1-C4) -alkyl- (C5-C14) -aryl-,

 in which - V represents a group R3, OR3 or SR3, - [A0] represents a group chosen from

 1) A compound of formula (I) <Desc / Clms Page number 37>  said compounds of formula (I) being in all their possible isomeric forms, alone or in mixture in any ratio, as well as their physiologically acceptable salts and their prodrugs.

 cyano, carboxy, -CONH2, (C1-C8) alkyloxycarbonyl, amino, NH- ((C1-C4) alkyl), -N ((C1-C4) alkyl) 2 '-NHCO- (C1-C4) -alkyl, -NHCO- (CS-C14) -aryl, -CONH- (C1-C4) -alkyl, -CONH- (C5-C14) aryl, -CO- (C1-C4) -alkyl or -CO- ( CS-C14) -aryl; - R'2 has the same values as A2; - optionally A2 and R2 together with the aryl which carries them, one of the following 5-membered rings:

 R2 represents (C1-C8) -alkyl- (C1-C8) -alkoxy-, (C1-C3) -alkylenedioxy-, (CS-C14) -aryl-, (CS-C14) -aryloxy-, (CsCi) -aryl- (C1-C4) -alkyl-, (CS-C14) -aryl- (C1-C4) -alkyloxy-, halogen, trihalomethyl-, hydroxyl, nitro, formyl,

 CH2CO2Rd, SO3H, PO (ORd) (ORe) or tetrazole; - optionally Ra and Rb form together with the carbon atom which carries them, a cycloalkyl group containing from 3 to 6 carbons, - Y represents a C = O atom, C = S, C = NH or SO 2; R1 represents a group -OH, -ORc, -NRcR'c, (C1-C4) -alkyl- or halogen; 2) A compound of formula (I) as defined in claim 1 wherein -A2 represents -O-PO3H2, -CF2P03H2 or -CH (CO2H) 2 and is in the para position. 3) A compound of formula (I) as defined in claim 1 wherein - [A1] - represents -CH (Z) - (C1C4) -alkyl- (C5-C14) -aryl- or (C5-C14) - aryl-, optionally substituted in meta by a group R2, R2 and Z being as defined in claim 1. <Desc / Clms Page number 38> 4) Compound of formula (I) as defined in claim 1 wherein [Ao] represents-CHRa-NHCO in which Ra represents an alkyl radical containing from 1 to 4 carbon atoms 5) A compound of formula (I) as defined in claim 1 wherein V represents an OR3 or SR3 radical in which R3 represents a (C1-C6) -alkyl, (C3-C12) -cycloalkyl or (C3-C12) ) -cycloalkyl- (C1-C6) -alkyl. 6) compound of formula (I), as defined in claim 1, wherein R4 is an alkyl group containing from 1 to 6 carbon atoms. 7) Compound of formula (I) as defined in claim 1 wherein Y is a group C = O and R1 is OH, NH2 or an alkyloxy group containing 1 to 6 carbon atoms. 8) A compound of formula (I) as defined in any one of claims 1 to 7 wherein - [Ao] - represents the group - (CHCH3) -NHCO-

 - [garlic] - represents -CH (Z) - (Cx-C4) -alkyl-phenyl- or phenyl optionally substituted in meta by an R2 group.  (C3-C12) -cycloalkyl- (C1-C6) -alkyl group; - R4 is a methyl group; Y is a C = O group; R1 is a hydroxy group, NH2 group, or an alkyloxy group containing from 1 to 6 atoms carbon, said compounds of formula (I) being in all their possible isomeric forms, alone or in mixture in any ratio, as well as their physiologically acceptable salts and their prodrugs.

 A2 represents -O-po3H2. -CF, -po3H2 or -CH (Co2H) 2 and is in the para position; -V represents a radical SR3 in which R3 represents a

Z represents NHCORc, NHC02Rc, in which Rc represents an alkyl radical containing from 1 to 6 carbon atoms; 9) the compounds of formula (I) whose names follow: <Desc / Clms Page number 39>  . [[4- [2 (S) - (α-acetylamino) -3 - [[1- [4 (aminocarbonyl) - [(cyclohexylmethyl) thio] -3-methyl-1H-imidazol-2-yl] ethyl] amino acid] 3-oxo-propyl] phenyl] difluoromethyl] phosphonic acid; as well as their physiologically acceptable salts and their prodrugs.

 . 2- [1- [2- (S) - (acetylamino) -1-oxo-3- [4- (phosphonooxy) phenyl] -1-propyl] amino] ethyl] -5 - [(cyclohexylmethyl) thio] -3 ethyl-1H-imidazole-4-carboxylic acid ethyl ester; . N-2-acetyl-N- [1- [S- (aminocarbonyl) -4 - [(cyclohexylmethyl) thio] -1-methyl-1H-imidazol-2-yl] -ethyl] -4- (phosphonooxy) -L phenylalaninamide;

10) A process for the preparation of the compounds of formula (I) as defined in any one of claims 1 to 3, which comprises the coupling of two or more fragments which can be derived by retrosynthesis of the compounds of formula (I). 11) A process according to claim 10 wherein an amine of formula (II) is reacted

 in which Ra, Rb, Y, V, n, R1 and R4 are as defined in claim 1 and wherein, if appropriate, the functional groups are in precursor form or in protected form, with an acid or a derivative of acid of formula (III) XC (= O) - [A1] -A'2 wherein [A1] is as defined in claim 1 in formula (I) and A'2 representing, in addition to the values of [ A2] according to claim 1, the hydroxy radical, X is a nucleophilic substitutable group and where, if appropriate, the functional groups are in the form of precursors or <Desc / Clms Page number 40>  in protected form, said functional groups optionally present in precursor or protected form, being subsequently converted into groups present in the compounds of formula (I). 12) Process according to claim 11, characterized in that the compound of formula (III) is chosen from: N-Boc-Tyr-O- (PO3Bn2), N-Ac-Tyr-O- (PO3Bn2), N-Boc- Tyr-CF 2

 (po3Et,), N-Ac-Tyr-CF, - (PO3E t,). 13) Process for the preparation of the compounds of formula (II) as defined in claim 11, characterized in that a compound of formula (IIa) is subjected

 to the action of a reducing agent such as NaBH4 and an organometallic reagent such as RaMgBr, in order to obtain the compound of formula (IIb)

 that is subjected to the action of diphenylphosphorylazide, in order to obtain the compound of formula (IIc)

 which is hydrogenated, in order to obtain the corresponding amine of formula (II) in which Rb is a hydrogen atom and n is equal to 1. 14) As a medicament, a compound of formula (I) and / or its physiologically acceptable salts and / or its prodrugs as defined in any one of claims 1 to 9. <Desc / Clms Page number 41> 15) A pharmaceutical composition comprising at least one compound of formula (I) as defined in any one of claims 1 to 9 and / or its physiologically acceptable salts and / or its prodrugs and one or more pharmaceutically inert carriers and / or one or more additives. 16) As a medicament having a SRC SH2 receptor antagonist activity, a compound of formula (I) and / or its physiologically acceptable salts and / or its prodrugs as defined in any one of claims 1 to 9. 17) As a medicament having a bone resorption inhibiting activity or for the treatment or prevention of osteoporosis, a compound of formula (I) and / or its physiologically acceptable salts and / or its prodrugs as defined in FIG. any one of claims 1 to 9. 18) As a medicament for the treatment or prevention of immunity, infection, allergy, and autoimmune diseases, a compound of formula (I) and / or its physiologically acceptable salts and / or prodrugs as defined in any one of claims 1 to 9. 19) As a medicament for the treatment or prevention of diseases such as proliferative diseases, cancer, restenosis, inflammation, allergies or cardiovascular diseases, a compound of formula (I) and / or its salts physiologically and / or its prodrugs as defined in any one of claims 1 to 9. 20) Use of the compounds of formula (I) and / or their physiologically acceptable salts and / or their prodrugs as defined in any one of claims 1 to 9 for the preparation of medicaments intended for the prevention or treatment of osteoporosis. 21) Use of the compounds of formula (I) and / or their physiologically acceptable salts and / or their prodrugs as defined in any one of claims 1 to 9 for the preparation of medicaments intended for the treatment or prevention of immunity, infection, allergy, and autoimmune diseases. <Desc / Clms Page number 42> 22) Use of the compounds of formula (I) and / or their physiologically acceptable salts and / or their prodrugs as defined in any one of claims 1 to 9 for the preparation of medicaments for the treatment or prevention of diseases such as proliferative diseases, cancer, restenosis, inflammation, allergies or cardiovascular diseases. 23) Intermediates of formulas (II), (IIa), (IIb) and (IIc) as defined in claim 11 or 13.