FR2782997A1 - NOVEL BENZODIAZEPINONE DERIVATIVES, PREPARATION METHOD AND INTERMEDIATES THEREOF, MEDICAMENT APPLICATION AND PHARMACEUTICAL COMPOSITIONS COMPRISING THE SAME - Google Patents

Abstract

The invention concerns benzodiazepinone derivatives of formula (I) wherein: R1, R2 [A1] and [A2] are as defined in the description, their preparation method and intermediates therefor, their use as medicines, in particular as anti-absorption agent and pharmaceutical compositions containing them.

Description

<Desc / Clms Page number 1>

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

dans laquelle - R1 représente un atome d'hydrogène, un groupement

choisi parmi - (CH2) m-Alk, - (CH2)m-Ar/ - (CH2)m-Het/ - (CHRa) - co - (CH2) m - Al k / (CHRa) -C0- (CH2)m-Ar, - (CHRa) -C0- (CH2)m-Het, - (CHRa) -CONRi- (CH2)m-Alk/ - ( CHRa ) - CONRi - ( CH2 ) m-Ar , - ( CHRa ) - CONRi - ( CH2 ) m-Het , - (CHRa) -C02- (CH2)m-Alk, et - (CHRa) -C02- (CHJm-Ar/ m étant égal à 0, 1, 2,3 ou 4 ; - R2 représente un atome d'hydrogène ou un groupement choisi parmi C02Rb, CONHRb, NHRb, NHCORb, NHSORb, CONHS02Rb, NHC02Rb,CH20H, alkyle, alkényle, alkynyle et cycloalkyle, les dits groupements étant substitués ou non subtitués; - [A1] représente un groupement choisi parmi CH(Z)-CH2-

(Arl) , (CH2) 1- (Ar 1) , CH (Z) -CH2- (Hetl) , (CH2) 1- (Hetl) dans lesquels Z est un atome d'hydrogène, un tétrazole, NH2, NHCORc, NHC02Rc, NHSORc ouNHS02Rc et 1 est un entier égal à 0, 1 ou 2; - [A2] représente un groupement choisi parmi OPO(ORd)(Ore), B(ORd)(ORe), CRfRgPO(ORd) (ORe) ,

CH [ PO ( ORd ) ( ORe ) ] 2, CRf RgC02Rd, CH ( C02Rd ) ( CO2Re ) , OCH ( S03Rd ) (CO2Rc) et CH(CH2Co2Rd)(CH2Co2Re); The subject of the invention is the compounds of formula (I)

in which - R1 represents a hydrogen atom, a grouping

selected from - (CH2) m-Alk, - (CH2) m -Ar / - (CH2) m -Het / - (CHRa) - co - (CH2) m - Alk / (CHRa) -C0- (CH2) m -Ar, - (CHR?)? O- (CH 2) m -Het, - (CHR?) -CONR? (CH 2) m-Alk / - (CHR?) - CONR? - (CH 2) m -Ar, - (CHR?) - CONRi - (CH2) m -Het, - (CHRa) -CO2- (CH2) m-Alk, and - (CHRa) -CO2- (CHJm-Ar / m being equal to 0, 1, 2,3 or 4 R2 represents a hydrogen atom or a group chosen from CO2Rb, CONHRb, NHRb, NHCORb, NHSORb, CONHSO2Rb, NHC02Rb, CH20H, alkyl, alkenyl, alkynyl and cycloalkyl, the said groups being substituted or unsubstituted; ] represents a group selected from CH (Z) -CH2-

(Ar 1), (CH 2) 1- (Ar 1), CH (Z) -CH 2 - (Het 1), (CH 2) 1 - (Het 1) in which Z is a hydrogen atom, a tetrazole, NH 2, NHCORc, NHC02Rc, NHSORc or NHHS02Rc and 1 is an integer of 0, 1 or 2; [A2] represents a group chosen from OPO (ORd) (Ore), B (ORd) (ORe), CRfRgPO (ORd) (ORe),

CH [PO (ORd) (ORe)] 2, CRf RgCO2Rd, CH (CO2Rd) (CO2Re), OCH (SO3Rd) (CO2Rc) and CH (CH2Co2Rd) (CH2Co2Re);

<Desc / Clms Page number 2>

 Alk represents an alkyl, alkenyl or alkynyl radical containing from 1 to 6 carbon atoms, or cycloalkyl containing from 3 to 12 carbon atoms, said radicals being substituted or unsubstituted; Ar representing a substituted or unsubstituted aryl, Het representing a substituted or unsubstituted heterocycle; Ra, Rb, Rc, Rd, Re or Ri, identical or different, representing a hydrogen atom, an alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl) alkyl, aryl or aralkyl radical, said radicals being substituted or unsubstituted ; (Arl) representing a substituted or unsubstituted bivalent aryl and (Hetl) representing a substituted or unsubstituted bivalent heterocycle; Rf and Rg identical or different representing a hydrogen atom, a halogen, a CO2Rd radical, SO3Rd, PO (ORd) (ORe) or tetrazole; said compounds of formula (I) being in all their possible stereoisomeric forms, isolated or in mixtures and their addition salts with pharmaceutically acceptable acids and bases.

 By alkyl, alkenyl or alkynyl radical containing from 1 to 6 carbon atoms means alkyl radicals such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, 2-methylpentyl, 2,3-dimethylbutyl, alkenyl radicals such as vinyl, propenyl, isopropenyl, allyl, 2-methylallyl, butenyl or isobutenyl, and alkynyl radicals such as ethynyl, propynyl, propargyl, butynyl or isobutynyl.

By cycloalkyl containing from 3 to 12 carbon atoms is meant the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl or adamantyl radicals.
By (cycloalkyl) alkyl is meant for example (cyclopentyl) methyl, (cyclohexyl) methyl, (cyclohexyl) ethyl or (cyclohexyl) propyl.

 By aryl is meant a radical derived from an aromatic cyclic hydrocarbon containing from 6 to 18 carbon atoms, such as the phenyl, naphthyl or phenanthrenyl radical, or a radical derived from a bicyclic or tricyclic condensed hydrocarbon comprising a benzene ring such as indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl or fluorenyl, the junction taking place at the benzene ring. he

<Desc / Clms Page number 3>

 it is preferably phenyl or naphthyl.

 Heterocycle is understood to mean a saturated or unsaturated aromatic (heteroaryl) or nonaromatic heterocycle comprising from 1 to 9 carbon atoms and from 1 to 5 heteroatoms chosen from oxygen, nitrogen and sulfur atoms. Mention may be made of: heterocyclic monocyclic radicals, for example thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyridazinyl, thiazolyl, oxazolyl, furazanyl, pyrrolinyl, imidazolinyl, pyrazolinyl, thiazolinyl or triazolyl radicals , tetrazolyl, heterocyclic fused rings, for example benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, naphtho [2,3-b] thienyl, thianthrenyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl radicals , indazolyl, purinyl, quinolizinyl, isoquinolyl, quinolyl, hydroquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, betacarbolnyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, indolinyl, isoindolinyl, imidazopyridyl, imidazopyrimidinyl, or the polycylic systems condensed constituent s monocyclic heterocyclic as defined above such as furo [2,3-b] pyrrole or thieno [2,3-b] furan, - or saturated heterocycles such as pyrrolidine, piperidine or morpholine.

 Aralkyl is preferably benzyl.

-CH (Z) -CH2- (Arl) - ou (CHz) 1- (Arl) -, (Arl) représente un radical bivalent aryle tel que défini plus haut et notamment un groupement phényle ou naphtyle éventuellement substitué. When - [A1] - represents a group of formula

-CH (Z) -CH 2 - (Ar 1) - or (CH 2) 1 - (Ar 1) -, (Ar 1) represents a divalent aryl radical as defined above and in particular an optionally substituted phenyl or naphthyl group.

When - [A1] - represents a group of formula --CH (Z) -CH2- (Hetl) - or - (CH2) 1- (Hetl) -, (Hetl) represents a heterocyclic divalent radical as defined above and in particular a heteroaryl radical such as the radical indolyl, 2-pyridinyl, quinolyl or hydroquinolyl
When [A1] contains a divalent phenyl radical, the

<Desc / Clms Page number 4>

 grouping [A2] may be ortho, meta or para. It is preferably in the para position.

 Halogen is preferably chlorine or bromine.

The optional substituents - alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl or heterocycle radicals - or bivalent groups (Arl) and (Hetl), may be chosen from the following radicals: halogen: fluorine, chlorine, bromine, iodine alkyl, alkenyl, alkynyl containing from 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, vinyl or allenyl. These radicals themselves being optionally substituted with one or more halogen atoms, for example fluorine such as trifluoromethyl.

cyclo (C 3 -C 12) alkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or adamantyl.

- oxo, cyano, nitro, formyl, carboxy, carboxamide, alkyloxycarbonyl containing 1 to 6 carbon atoms such as Co2Me or CO 2 tBu, - alkoxy containing 1 to 6 carbon atoms such as methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy or - O- (CH 2) -O- (methylenedioxy), aryloxy such as phenyloxy, arylthio such as phenylthio, alkylthio having 1 to 6 carbon atoms such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, acylthio containing from 2 to 6 carbon atoms such as acetylthio, amino, alkylamino containing from 1 to 6 carbon atoms such as methylamino or ethylamino, dialkylamino containing from 2 to 12 carbon atoms such as dimethylamino, diethylamino, methylethylamino, each of these dialkylamino radicals being optionally in oxidized form, - C = N-NH-CO-NH2-aminoalkyl containing from 1 to 6 carbon atoms such as aminomethyl or aminoethyl, dialkylaminoalkyl containing from 3 to 18 carbon atoms such that dimethylamino methyl or ethyl,

<Desc / Clms Page number 5>

 dialkylaminoalkyloxy containing from 3 to 18 carbon atoms such as dimethylaminoethyloxy, hydroxyl optionally acylated containing 1 to 6 carbon atoms, for example acetoxy, acyl containing 1 to 6 carbon atoms, such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, succinyl, pivaloyl or benzoyl, optionally substituted for example by a chlorine, iodine or fluorine atom. Mention may be made of chloroacetyl, dichloroacetyl, trichloroacetyl, bromoacetyl or trifluoroacetyl, aryl or heteroaryl radicals such as phenyl, furyl, thienyl, pyrydinyl or aralkyl radicals such as benzyl radicals, the aryl heteroaryl, aralkyl or aryloxy radicals being themselves optionally substituted with radicals indicated above among which may be mentioned halogen, alkyl, alkenyl, alkynyl, alkoxy, methylenedioxy, alkylthio, aminoalkyl, dialkylamino, carboxy or alkyloxycarbonyl.

(C3-C12)alkyle, nitro, formyle, carboxy, alkoxycarbonyle, (C2-C6) alkoxy, méthylenedioxy, amino, (C1-C6) alkylamino, (CZ-Cl2) dialkylamino éventuellement sous forme oxydée, hydroxyle éventuellement acylé, (C2-C6) acyle, aryle ou aryloxy éventuellement substitués par les radicaux ci-dessus. Of course, one or more substituents, identical or different, may be present. In the case of heterocycles, the substituents may be at the level of nitrogen or carbon. Among the preferred substituents which are subjects of the invention, mention may be made of one or more of the following radicals: halogen, (C 1 -C 6) alkyl optionally substituted with one or more halogen atoms, cyclo

(C3-C12) alkyl, nitro, formyl, carboxy, alkoxycarbonyl, (C2-C6) alkoxy, methylenedioxy, amino, (C1-C6) alkylamino, (CZ-C12) dialkylamino optionally in oxidized form, optionally acylated hydroxyl, (C2 -C6) acyl, aryl or aryloxy optionally substituted with the radicals above.

Rl=CH2CONH- (CHZ) m-Ar avec Ar=phényle), ou par un hydroxy (cas où Z représente NHCORc avec Rc = benzyle). When the phenyl is substituted, it is in particular a phenyl, phenyloxy or methylenedioxy group (where

R1 = CH2CONH- (CHZ) m -Ar with Ar = phenyl), or with a hydroxy (where Z is NHCORc with Rc = benzyl).

 When Z = NHCORc with Rc = alkyl, this alkyl group may be especially substituted with a carboxy group.

 When R 1 = CH 2 CONH-Alk, where m is 0, this alkyl group may be substituted in the amine by a carboxy or methyloxycarbonyl group.

<Desc / Clms Page number 6>

@
The invention naturally extends to the salts of the compounds of formula (I), for example to the salts formed, when the compounds of formula (I) contain an amino function, with hydrochloric, hydrobromic, nitric, sulfuric, phosphoric and acetic acids. , trifluoroacetic, formic, propionic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, alkanesulfonic, such as methanes or ethanesulphonic acids, arylsulphonic acids, such as benzene or paratoluenesulphonic and arylcarboxylic acids, or salts formed with alkali or alkaline earth metals, amines or optionally substituted ammoniums.

dans laquelle R1 et R2 sont tels que définis précédemment; Rd représente un hydrogène ou un benzyle, et Z représente NHCORc, NHC02Rc ou NH2, Rc étant tel que défini précédemment. The subject of the invention is more particularly the compounds of formula (I) as described above, corresponding to general formula (Ia):

wherein R1 and R2 are as previously defined; Rd represents a hydrogen or a benzyl, and Z represents NHCORc, NHC02Rc or NH2, Rc being as defined above.

 The invention also more particularly relates to the compounds of formula (I) as described above corresponding to the general formula (Ib):

<Desc / Clms Page number 7>

dans laquelle 1, R1 et R2 sont tels que définis précédemment, et Rd représente un hydrogène ou un benzyle.

wherein 1, R 1 and R 2 are as previously defined, and Rd is hydrogen or benzyl.

 The subject of the invention is particularly the compounds of formulas (I), (Ia) or (Ib) in which R1 represents a hydrogen atom or a group chosen from CH2CONH- (CH2) m -Ar, CH2CONH- (CH2) m-Het, (CH2) m-Alk and (CH2) m-cycloalkyl, m, Alk, Ar and Het being as defined above.

 The subject of the invention is particularly those compounds of formulas (I), (Ia) or (Ib) in which Ar represents a Napht-1-yl, Napht-2-yl, phenyl or 1,3-benzodioxole-5 group. -yl, biphenyl, m- (phenyloxy) phenyl or p- (phenyloxy) phenyl, and Het represents an indolyl group.

 The subject of the invention is particularly the compounds of formulas (I), (Ia) or (Ib) in which R 2 is a hydrogen atom.

 The subject of the invention is particularly those compounds of formulas (I), (Ia) or (Ib) in which R2 represents CO2Rb.

 The subject of the invention is particularly those compounds of formulas (I), (Ia) or (Ib) in which R2 represents NHC02Rb or NHSO2Rb.

 The subject of the invention is also the compounds of formula (I) whose names follow:

<Desc / Clms Page number 8>

méthyl] -2- [ [2, 3-dihydro-1- [2- [ (4-phénoxyphényl) amino] -2oxoéthyl]-2-oxo-5-phényl-1H-1,4-benzodiazépin-3-yl]amino]-2- oxoéthyl]-carbamate de 1,1-diméthyléthyle, - [1- [ [4- [ [bis (phénylméthoxy) phosphinyl] oxy] phényl] méthyl] -

2-[[2,3-dihydro-l-[2-[[(l-naphthalênyl)mêthyl]amino]-2oxoéthyl]-2-oxo-5-phényl-1H-1,4-Benzodiazépin-3-yl]amino]-2- oxoéthyl]-Carbamate de 1,1-diméthyléthyle, - [1- [ [4 [ [hydroxy (phénylméthoxy) phosphinyl] oxy] phényl]

méthyl]-2-[[2,3-dihydro-1-[2-[[(1,3-benzodioxolan-5-yl) méthyl]amino]-2-oxoéthyl]-2-oxo-5-phényl-1H-1,4- Benzodiazépin-3-yl]amino]-2-oxoéthyl]-Carbamate de 1,1diméthyléthyle, - [1- [ [4- [ [hydroxy (phénylméthoxy) phosphinyl] oxy] phényl]

méthyl] -2- [ [2,3-dihydro-1- [2- [ [ (2-naphthalényl)méthyl] amino]-2-oxoéthyl]-2-oxo-5-phényl-1H-1,4-Benzodiazépin-3- yl]amino]-2-oxoéthyl]-Carbamate de 1,1-diméthyléthyle, - [1- [ [4- [ [hydroxy (phénylméthoxy) phosphinyl] oxy] phényl]

méthyl] -2- [ [2, 3-dihydro-1- [2- [ [1H-indol-5-yl] amino] -2oxoéthyl]-2-oxo-5-phényl-lH-1,4-Benzodiazépin-3-yl]amino]-2- oxoéthyl]-Carbamate de 1,1-diméthyléthyle, - [1- [ [4- [ [hydroxy (phénylméthoxy) phosphinyl] oxy] phényl]

méthyl]-2-[[2,3-dihydro-1-[2-[(9-éthyl-9H-carbazol-3-yl) amino]-2-oxoéthyl]-2-oxo-5-phényl-1H-1,4-Benzodiazépin-3- yl]amino]-2-oxoéthyl]-Carbamate de 1,1-diméthyléthyle, - [1- [ [4- [ [hydroxy (phénylméthoxy) phosphinyl] oxy] phényl]

méthyl] -2- [ [2, 3-dihydro-1- [2- [ (3-phénoxyphényl) amino] -2oxoéthyl]-2-oxo-5-phényl-1H-1,4-Benzodiazépin-3-yl]amino]-2- oxoéthyl]-Carbamate de 1,1-diméthyléthyle, - [1- [ [4- [ [hydroxy (phénylméthoxy) phosphinyl] oxy] phényl]

méthyl] -2- [ [2, 3-dihydro-1- [2- [ [2- (1-naphthalényl) éthyl]amino]-2-oxoéthyl]-2-oxo-5-phényl-1H-1,4-Benzodiazépin- 3-yl]amino]-2-oxoéthyl]-Carbamate de 1,1-diméthyléthyle, - [1- [ [4- [ (dihydroxy) phosphinyl] oxy] phényl] méthyl] -2- [ [2, 3dihydro-1- [2- [ [2- (1-naphthalényl) éthyl] amino] -2-oxoéthyl] -2oxo-5-phényl-1H-1,4-Benzodiazépin-3-yl]amino]-2-oxoéthyl]- Carbamate de 1,1-diméthyléthyle, - [1- [ [4- [ [hydroxy (phénylméthoxy) phosphinyl] oxy] phényl]

méthyl] -2- [[2,3-dihydro-l-[2-[[[ (1,l'-biphényl] -4- - [1 - [[4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl]

methyl] -2- [[2,3-dihydro-1- [2- [(4-phenoxyphenyl) amino] -2-oxoethyl] -2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl] 1,1-dimethylethyl amino] -2-oxoethyl] -carbamate, - [1- [[4- [[bis (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -

2 - [[2,3-dihydro-l- [2 - [[(l-naphthalenyl) methyl] amino] -2oxoéthyl] -2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl] amino] -2-oxoethyl] -1,1-dimethylethyl carbamate, - [1 - [[4 [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl]

methyl] -2 - [[2,3-dihydro-1- [2 - [[(1,3-benzodioxolan-5-yl) methyl] amino] -2-oxoethyl] -2-oxo-5-phenyl-1H 1,1-Dimethylethyl -1,4-Benzodiazepin-3-yl] amino] -2-oxoethyl] carbamate, - [1 - [[4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl]

methyl] -2- [[2,3-dihydro-1- [2- [[(2-naphthalenyl) methyl] amino] -2-oxoethyl] -2-oxo-5-phenyl-1H-1,4-benzodiazepine 1,1-Dimethylethyl] - [1 - [[4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] -3-yl] amino] -2-oxoethyl] carbamate

methyl] -2- [[2,3-dihydro-1- [2- [[1H-indol-5-yl] amino] -2-oxoethyl] -2-oxo-5-phenyl-1H-1,4-benzodiazepine 1,1-Dimethylethyl 3-yl] amino] -2-oxoethyl] carbamate, - [1 - [[4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl]

methyl] -2 - [[2,3-dihydro-1- [2 - [(9-ethyl-9H-carbazol-3-yl) amino] -2-oxoethyl] -2-oxo-5-phenyl-1H- 1,1-Dimethylethyl 1,4-Benzodiazepin-3-yl] amino] -2-oxoethyl] carbamate; [1- [[4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl]

methyl] -2- [[2,3-dihydro-1- [2- [(3-phenoxyphenyl) amino] -2-oxoethyl] -2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl] amino] -2-oxoethyl] -1,1-dimethylethyl carbamate, - [1 - [[4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl]

methyl] -2- [[2,3-dihydro-1- [2- [[2- (1-naphthalenyl) ethyl] amino] -2-oxoethyl] -2-oxo-5-phenyl-1H-1,4 1,1-Dimethylethyl -benzodiazepin-3-yl] amino] -2-oxoethyl] carbamate, [1- [[4- [(dihydroxy) phosphinyl] oxy] phenyl] methyl] -2- [[2], 3dihydro-1- [2- [[2- (1-naphthalenyl) ethyl] amino] -2-oxoethyl] -2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl] amino] -2-oxoethyl ] - 1,1-Dimethylethyl carbamate, - [1- [[4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl]

methyl] -2- [[2,3-dihydro-1 - [2 - [[[1, 1'-biphenyl] -4-

<Desc / Clms Page number 9>

yl]méthyl]amino]-2-oxoéthyl]-2-oxo-5-phényl-1H-1,4- Benzodiazépin-3-yl]amino]-2-oxoéthyl]-Carbamate de 1,1diméthyléthyle, - [1- [ [4- [ [hydroxy (phénylméthoxy) phosphinyl] oxy] phényl]

méthyl]-2-[[2,3-dihydro-1-[2-[[(4-phénoxyphénylméthyl]amino]- 2-oxoéthyl]-2-oxo-5-phényl-1H-1,4-Benzodiazépin-3-yl]amino]- 2-oxoéthyl]-Carbamate de 1,1-diméthyléthyle, - 2- [1- [ [4- [ [hydroxy (phénylméthoxy) phosphinyl] oxy] phényl] -

méthyl] -2- [ [2,3-dihydro-1- [2- [ (2 cyclohexyléthyl) méthylamino]-2-oxoéthyl]-2-oxo-5-phényl-1H-1,4-Benzodiazépin- 3-yl]amino]-2-oxoéthyl]-Carbamate de 1,1-diméthyléthyle, - 2- [1- [ [4- [ [dihydroxyphosphinyl] oxy] phényl] méthyl] -2- [ [2, 3-

dihydro-1- [2- [ (2-cyclohexyléthyl) méthylamino] -2-oxoéthyl] -2oxo-5-phényl-1H-1,4-Benzodiazépin-3-yl]amino]-2-oxoéthyl]- Carbamate de 1,1-diméthyléthyle, - [1- [ [4- [ [hydroxy (phénylméthoxy) phosphinyl] oxy] phényl] méthyl]-2-[[2,3-dihydro-1-(3-cyclohexylpropyl)-2-oxo-5-

phényl-1H-1,4-Benzodiazépin-3-yl]amino]-2-oxoéthyl]-Carbamate 1,1-diméthyléthyle, - [1- [ [4- [ [dihydroxyphosphinyl] oxy] phényl] méthyl] -2- [ [2, 3- dihydro-1-(3-cyclohexylpropyl)-2-oxo-5-phényl-1H-1,4- Benzodiazépin-3-yl]amino]-2-oxoéthyl]-Carbamate de 1,1diméthyléthyle, - 3- [ [3- [4- [ [hydroxy (phénylméthoxy) phosphinyl] oxy] phényl] -1-

oxo-propyl] -amino] - 2, 3-dihydro-N- [2- (1-naphthalényl) éthyl] - 2-oxo-5-phényl-1H-1,4-benzodiazépine-1-acétamide, - 3- [ [2- [4- [ [hydroxy (phénylméthoxy) phosphinyl] oxy. ] phényl] - l-oxoéthyl]-amino]- 2,3-dihydro-N-(lH-indol-5-yl)-2-oxo-5phényl-1H-1,4-benzodiazépine-1-acétamide, - Acide 4- [ [1- [4- [ [hydroxy (phénylméthoxy) phosphinyl]

oxy] phényl] méthyl] -2- [ [2, 3-dihydro-1- [2- [ [2- (1-naphthalényl) éthyl]amino]2-oxoéthyl]-2-oxo-5-phényl-1H-1,4-benzodiazépin- 3-yl] amino] -2-oxoéthyl] amino] -4-oxo-Butanoïque, - 3- [ [3- [4- [ [hydroxy (phénylméthoxy) phosphinyl] oxy] phényl] -2- [2- (3-hydroxyphényl) -1-oxoéthyl] -1-oxo-propyl] -amino] -N- [2-

(1-naphthalényl)éthyl]- 2,3-dihydro-2-oxo-5-phényl-lH-l,4benzodiazépine-1-acétamide, - 4- [2, 3-dihydro-1- [2- [ (4-phénoxyphényl) amino] -2-oxoéthyl] - 3- [ [1-oxo-2- [ [ (1, 1-diméthyléthoxy) carbonyl] amino] -3- [4-

1,1-Dimethylethyl [1-methyl] amino] -2-oxoethyl] -2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl] amino] -2-oxoethyl] carbamate; [[4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl]

methyl] -2 - [[2,3-dihydro-1- [2 - [[(4-phenoxyphenylmethyl] amino] -2-oxoethyl] -2-oxo-5-phenyl-1H-1,4-benzodiazepine-3 1,1-Dimethylethyl] -2- [1 - [[4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] -yl] amino] -2-oxoethyl] carbamate

methyl] -2- [[2,3-dihydro-1- [2- [(2-cyclohexylethyl) methylamino] -2-oxoethyl] -2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl ] amino] -2-oxoethyl] -1,1-dimethylethyl carbamate, 2- [1- [[4- [[dihydroxyphosphinyl] oxy] phenyl] methyl] -2- [[2,3-dimethyl] -2-oxoethyl] carbamate;

dihydro-1- [2- [(2-cyclohexylethyl) methylamino] -2-oxoethyl] -2oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl] amino] -2-oxoethyl] carbamate 1 , 1-dimethylethyl, - [1 - [[4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2 - [[2,3-dihydro-1- (3-cyclohexylpropyl) -2-oxo] 5-

phenyl-1H-1,4-benzodiazepin-3-yl] amino] -2-oxoethyl] carbamate 1,1-dimethylethyl, - [1 - [[4- [[dihydroxyphosphinyl] oxy] phenyl] methyl] -2- 1,1-Dimethylethyl [[2,3-dihydro-1- (3-cyclohexylpropyl) -2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl] amino] -2-oxoethyl] carbamate, 3- [[3- [4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] -1-

oxo-propyl] amino] -2,3-dihydro-N- [2- (1-naphthalenyl) ethyl] -2-oxo-5-phenyl-1H-1,4-benzodiazepine-1-acetamide; [[2- [4- [[hydroxy (phenylmethoxy) phosphinyl] oxy. ] phenyl] -1-oxoethyl] amino] -2,3-dihydro-N- (1H-indol-5-yl) -2-oxo-5-phenyl-1H-1,4-benzodiazepine-1-acetamide, - Acid 4- [[1- [4- [[hydroxy (phenylmethoxy) phosphinyl]

oxy] phenyl] methyl] -2- [[2,3-dihydro-1- [2- [[2- (1-naphthalenyl) ethyl] amino] -2-oxoethyl] -2-oxo-5-phenyl-1H- 1,4-benzodiazepin-3-yl] amino] -2-oxoethyl] amino] -4-oxo-butanoic acid, - 3 - [[3- [4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] -2 - [2- (3-hydroxyphenyl) -1-oxoethyl] -1-oxo-propyl] -amino] -N- [2-

(1-Naphthalenyl) ethyl] -2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-1-acetamide, 4- [2,3-dihydro-1- [2- [4 phenoxyphenyl) amino] -2-oxoethyl] - 3 - [[1-oxo-2 - [[(1,1-dimethylethoxy) carbonyl] amino] -3- [4-

<Desc / Clms Page number 10>

amino]-2-oxo-1H-1,4-Benzodiazépin-5-yl]-Benzoate de 1,1- diméthyléthyle, - 4-[2,3-dihydro-3-[[2-[[(l,l-diméthyléthoxy)carbonyl]amino] -3- [4- [ [hydroxy (phénylméthoxy) phosphinyl] oxy] phényl] -1- oxopropyl]amino]-2-oxo-1H-1,4-Benzodiazépin-5-yl]-Benzoate de 1,1-diméthyléthyle,

- 4-[2,3-dihydro-3-[[2-[[(1,1-diméthyléthoxy)carbonyl]amino] -3- [4- [ [hydroxy (phénylméthoxy) phosphinyl] oxy] phényl] -1- oxopropyl]amino]-2-oxo-1,4-Benzodiazépin-5-yl]-Benzoate de cyclohexylméthyle, - [1- [ [4- [ [hydroxy (phénylméthoxy) phosphinyl] oxy] phényl]

méthyl] -2- [ [2, 3-dihydro-1- [2- [ (4-phénoxyphényl) amino] -2oxoéthyl] -2-oxo-5- [4- [ [ (méthylsulfonyl) amino] carbonyl] phényl] -1H-1,4-Benzodiazépin-3-yl]amino]-2-oxoéthyl)-Carbamate de 1,1-diméthyléthyle, - [1- [ [4- [ (dihydroxyphosphinyl) oxy] phényl] méthyl] -2- [ [2, 3dihydro-1-[2-[(4-phénoxyphényl) amino]-2-oxoéthyl]-2-oxo-5- [4-[[(méthylsulfonyl)amino]carbonyl]phényl]-lH-l,4- Benzodiazépin-3-yl]amino]-2-oxoéthyl]-Carbamate de 1,1diméthyléthyle,. [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] propyl]

1,1-Dimethylethyl amino-2-oxo-1H-1,4-benzodiazepin-5-yl] -benzoate, - 4- [2,3-dihydro-3 - [[2 - [[(1, 1 dimethylethoxycarbonyl] amino] -3- [4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] -1-oxopropyl] amino] -2-oxo-1H-1,4-benzodiazepin-5-yl] 1,1-dimethylethyl benzoate

4- [2,3-Dihydro-3 - [[2 - [[(1,1-dimethylethoxy) carbonyl] amino] -3- [4 - [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] -1- cyclohexylmethyl oxopropyl] amino] -2-oxo-1,4-benzodiazepin-5-yl] benzoate, - [1 - [[4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl]

methyl] -2- [[2,3-dihydro-1- [2- [(4-phenoxyphenyl) amino] -2-oxoethyl] -2-oxo-5- [4- [[(methylsulfonyl) amino] carbonyl] phenyl] 1,1-Dimethylethyl -1H-1,4-benzodiazepin-3-yl] amino] -2-oxoethyl) carbamate, - [1 - [[4- [(dihydroxyphosphinyl) oxy] phenyl] methyl] -2- [[2,3-dihydro-1- [2 - [(4-phenoxyphenyl) amino] -2-oxoethyl] -2-oxo-5- [4 - [[(methylsulfonyl) amino] carbonyl] phenyl] -1H-1, 4-Benzodiazepin-3-yl] amino] -2-oxoethyl] -1,4-dimethylethyl carbamate.

méthyl] -2- [ [2, 3-dihydro-1- [2- [ (4-phénoxyphényl) amino] -2oxoéthyl]-2-oxo-5-[4-(aminocarbonyl)phényl]-1H-1,4- Benzodiazépin-3-yl]amino]-2-oxoéthyl]-Carbamate de 1,1diméthyléthyle,

- 4- [2, 3-dihydro-1- [2- [ (4-phénoxyphényl) amino] -2-oxoéthyl] 3- [ [1-oxo-2- [2- [4- [hydroxy (phénylméthoxy) -phosphinyl] oxy] phényl] éthyl] amino] -2-oxo-1H-1, 4-Benzodiazépin-5-yl] phényl-Carbamate de 1,1-diméthyléthyle, - 4- [2, 3-dihydro-1- [2- [ (4-phénoxyphényl) amino] -2-oxoéthyl] 3- [ [1-oxo-2- [2- [4- (dihydroxyphosphinyl) oxy] phényl] éthyl] amino] - 2-oxo-1H-1,4-Benzodiazépin-5-yl]-phényl-Carbamate de 1,1diméthyléthyle, - 3- [ [2- [4- [ [hydroxy (phénylméthoxy) phosphinyl] oxy] phényl] -1- oxoéthyl]-amino]- 2,3-dihydro-N-(4-phénoxyphényl)-2-oxo-5-(4- aminophényl)-lH-1,4-benzodiazépine-1-acétamide, - 3- [ [2- [4- [ (dihydroxyphosphinyl) oxy] phényl] -1-oxoéthyl] - amino]- 2,3-dihydro-N-(4-phénoxyphényl)-2-oxo-5-(4- - [1 - [[4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl]

methyl] -2- [[2,3-dihydro-1- [2- [(4-phenoxyphenyl) amino] -2oxoethyl] -2-oxo-5- [4- (aminocarbonyl) phenyl] -1H-1,4 1,1-Dimethylethyl carbamazepepin-3-yl] amino] -2-oxoethyl] carbamate

4- [2,3-Dihydro-1- [2 - [(4-phenoxyphenyl) amino] -2-oxoethyl] 3 - [[1-oxo-2- [2- [4- [hydroxy (phenylmethoxy)] - Phosphinyl] oxy] phenyl] ethyl] amino] -2-oxo-1H-1,4-benzodiazepin-5-yl] phenyl-1,1-dimethylethyl carbamate, 4- [2,3-dihydro-1- 2- [(4-Phenoxyphenyl) amino] -2-oxoethyl] -3 - [[1-oxo-2- [2- [4- (dihydroxyphosphinyl) oxy] phenyl] ethyl] amino] -2-oxo-1H-1 1,1-Dimethylethyl 4-Benzodiazepin-5-yl] -phenyl-carbamate, 3- [[2- [4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] -1-oxoethyl] amino] -2 3-Dihydro-N- (4-phenoxyphenyl) -2-oxo-5- (4-aminophenyl) -1H-1,4-benzodiazepine-1-acetamide, - 3 - [[2- [4- [(dihydroxyphosphinyl)] ) oxy] phenyl] -1-oxoethyl] amino] -2,3-dihydro-N- (4-phenoxyphenyl) -2-oxo-5- (4-

<Desc / Clms Page number 11>

aminophényl)-1H-1,4-benzodiazépine-1-acétamide, - [1- [ [4- [ [hydroxy (phénylméthoxy) phosphinyl] oxy] phényl] méthyl]-2-[[2,3-dihydro-2-oxo-5-[4-[(cyclohexylméthylamino)

méthyl]phényl]-1H-1,4-Benzodiazépin-3-yl]amino]-2-oxoéthyl]Carbamate de 1,1-diméthyléthyle, - 4- [2, 3-dihydro-1- [2- [ (3-phénoxyphényl) amino] -2-oxoéthyl] - 3- [ [1-oxo-2- [ [ (1, 1-diméthyléthoxy) carbonyl] amino] -3- [4- [ [hydroxy (phénylméthoxy) phosphinyl] oxy] phényl] propyl] amino] - 2-oxo-1H-1,4-benzodiazépin-5-yl]-benzoate de méthyle, - Acide-4- [2, 3-dihydro-1- [2- [ (3-phénoxyphényl) amino] -2oxoéthyl]-3-[[l-oxo-2-[[(1,1-dimêthyléthoxy)carbonyl]amino]- 2-oxo-1H-1,4-benzodiazépin-5-yl]-benzoique, - Acide-4- [2, 3-dihydro-1- [2- [ (4-phénoxyphényl) amino] -2oxoéthyl] -3- [ [1-oxo-2- (amino) -3- [4- [ [ (dihydroxy) phosphinyl] - oxy]phényl]propyl]amino]-2-oxo-lH-l,4-benzodiazépin-5-yl]- benzoique,

- 4-[2,3-dihydro-l-[2-[(3-phênoxyphényl)amino]-2-oxoéthyl]- 3- [ [1-oxo-2- [amino] -3- [4 [ [hydroxy (phénylméthoxy) phosphinyl] oxy] phényl] propyl] amino] -2-oxo-lH-1,4-benzodiazépin-5-yl] benzoate de 1,1-diméthyléthyle, - 4- [2, 3-dihydro-1- [2- [ (3-phénoxyphényl) amino] -2-oxoéthyl] 3- [[l-oxo-2-[2-[4-(hydroxy(phénylméthoxy)phosphinyl) oxylphénylléthyllaminol-2-oxo-lH-1,4-benzodiazépin-5-yllphényl-Carbamate de 1,1-diméthyléthyle, - Acide 4- [2, 3-dihydro-1- [2- [ (3-phénoxyphényl) amino] -2oxoéthyl]3-[[1-oxo-2-[[(1,1-diméthyléthoxy)carbonyl]amino]-3- [4-[[dihydroxy(phosphinyl]oxy]phényl]propyl]amino]-2-oxo-lHl,4-benzodiazépin-5-yl]-benzoique,

- 4- [2, 3-dihydro-1- [2- [ [2- (1-naphtalényl) éthyl] amino] -2oxoéthyl]-3-[[l-oxo-2-[[(1,1-dimêthyléthoxy)carbonyl]amino]- 3- [4- [ [hydroxy (phénylméthoxy) phosphinyl] oxy] phényl]propyl]amino]-2-oxo-1H-1,4-Benzodiazépin-5-yl]- Benzoate de 1,1-diméthyléthyle. -L -L

aminophenyl) -1H-1,4-benzodiazepine-1-acetamide, [1- [[4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2 - [[2,3-dihydro-2- oxo-5- [4 - [(cyclohexylmethylamino)

Methyl] phenyl] -1H-1,4-benzodiazepin-3-yl] amino] -2-oxoethyl] 1,1-Dimethylethyl carbamate, 4- [2,3-dihydro-1- [2- [(3 phenoxyphenyl) amino] -2-oxoethyl] -3- [[1-oxo-2 - [[(1,1-dimethylethoxy) carbonyl] amino] -3- [4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] Methyl phenyl] propyl] amino] -2-oxo-1H-1,4-benzodiazepin-5-yl] benzoate, - 4- [2,3-Dihydro-1- [2 - [(3-phenoxyphenyl) -acid] ) amino] -2-oxoethyl] -3 - [[1-oxo-2 - [[(1,1-dimethylethoxy) carbonyl] amino] -2-oxo-1H-1,4-benzodiazepin-5-yl] benzoic acid, - 4- [2,3-Dihydro-1- [2- [(4-phenoxyphenyl) amino] -2-oxoethyl] -3 - [[1-oxo-2- (amino) -3- [4- (Dihydroxy) phosphinyl] oxy] phenyl] propyl] amino] -2-oxo-1H-1,4-benzodiazepin-5-yl] benzoic acid,

4- [2,3-Dihydro-1- [2 - [(3-phenoxyphenyl) amino] -2-oxoethyl] -3 - [[1-oxo-2-amino] -3- [4 - [[hydroxy (1,1-Dimethylethyl) phenylmethoxy) phosphinyl] oxy] phenyl] propyl] amino] -2-oxo-1H-1,4-benzodiazepin-5-yl] benzoate, - 4- [2,3-dihydro-1- [2 - [(3-Phenoxyphenyl) amino] -2-oxoethyl] -3 - [[1-oxo-2- [2- [4- (hydroxy (phenylmethoxy) phosphinyl) oxylphenyl] ethyl] amino-2-oxo-1H-1,4 1,1-Dimethylethylbenzodiazepin-5-yllphenylcarbamate, 4- [2,3-Dihydro-1- [2- [(3-phenoxyphenyl) amino] -2-oxoethyl] 3 - [[1-oxo] -benzoate] 2 - [[(1,1-dimethylethoxy) carbonyl] amino] -3- [4 - [[dihydroxy (phosphinyl] oxy] phenyl] propyl] amino] -2-oxo-1H, 4-benzodiazepin-5-yl] benzoic acid,

4- [2,3-Dihydro-1- [2- [[2- (1-naphthalenyl) ethyl] amino] -2-oxoethyl] -3 - [[1-oxo-2 - [[(1,1-dimethylethoxy)] ) carbonyl] amino] - 3- [4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] propyl] amino] -2-oxo-1H-1,4-benzodiazepin-5-yl] benzoate 1,1 dimethylethyl.

 The subject of the invention is also a method for preparing compounds of formula (I) as defined above, characterized in that it comprises the following steps: a) a compound of formula (II) is subjected to:

<Desc / Clms Page number 12>

dans laquelle R2 est tel que défini précédemment à l'action d'un acide de formule (III)

Rb étant tel que défini précédemment, afin d'obtenir le composé de formule (IV) :

b) on soumet le composé de formule (IV) à l'action de l'ammoniac afin d'obtenir le composé de formule (V) :

in which R2 is as defined above for the action of an acid of formula (III)

Rb being as defined above, in order to obtain the compound of formula (IV):

b) subjecting the compound of formula (IV) to the action of ammonia in order to obtain the compound of formula (V):

<Desc / Clms Page number 13>

c) on cyclise le composé de formule (V) en milieu acide afin d'obtenir le composé de formule (VI) :

d) on soumet le composé de formule (VI) i) suit le cas échéant, à l'action de R'1X en présence d'une

base, R' représentant outre les valeurs de Rl, -(CHRa)-CO,Rc, et X représentant un halogène, afin d'obtenir un composé de formule (VI')

c) the compound of formula (V) is cyclized in an acid medium in order to obtain the compound of formula (VI):

d) subjecting the compound of formula (VI) i) if appropriate, to the action of R'1X in the presence of a

base, R 'representing the values of R1, - (CHRa) -CO, Rc, and X being halogen, to give a compound of formula (VI')

<Desc / Clms Page number 14>

puis à l'action, après retour à l'amine libre, de

[A' 2] - [Al] -C02H, [Al] étant tel que défini précédemment et [A'2] représentant, outre les valeurs de [A2], le radical hydroxy, ii) soit, après retour à l'amine libre, à l'action de

[A' 2] - [Al] -C02H afin d'obtenir le composé de formule (VI 1 1)

puis à l'action, le cas échéant de R'1X en présence d'une base afin d'obtenir dans les deux cas (i, ii) un composé de formule (I') :

then to action, after returning to the free amine, to

[A '2] - [Al] -CO 2 H, [Al] being as defined above and [A'2] representing, in addition to the values of [A2], the hydroxyl radical, ii) after returning to the amine free, to the action of

[A '2] - [Al] -CO 2 H in order to obtain the compound of formula (VI 1 1)

then to the action, where appropriate of R'1X in the presence of a base in order to obtain in both cases (i, ii) a compound of formula (I '):

<Desc / Clms Page number 15>

correspondant à certains composés de formule (I), les composés de formule (VI), (VI'), (VI'') ou (Il) pouvant si désiré ou si nécessaire, subir une ou plusieurs des réactions suivantes dans un ordre approprié : - action d'un agent de monodébenzylation lorsque [A'2] représente OPO (OBn) 2, - action d'un agent de déprotection totale, - action de NHRi- (CH2) m-Alk, NHRi- (CH2) m-Ar ou NHRi- (CH2) m-Het, en présence d'un agent couplant lorsque R'1 représente le groupement -CHRa-CO2H, - action de P(O) (H) (ORd) (ORe) lorsque [A'2] représente OH, - obtention des différentes valeurs de R2 à partir de l'acide carboxylique (R2=CO2H) correspondant, - obtention des différentes valeurs de Z (NHCORc, NHSORc, NHC02Rc, NHSO2Rc) à partir de l'amine (Z=NH2) correspondante , - salification.

corresponding to certain compounds of formula (I), the compounds of formula (VI), (VI '), (VI'') or (II) being able, if desired or if necessary, to undergo one or more of the following reactions in an appropriate order : - action of a monodebenzylation agent when [A'2] represents OPO (OBn) 2, - action of a total deprotection agent, - action of NHRi- (CH2) m-Alk, NHRi- (CH2) m -Ar or NHRi- (CH2) m -Het, in the presence of a coupling agent when R'1 represents the group -CHRa-CO2H, - action of P (O) (H) (ORd) (ORe) when [A '2' represents OH, - obtaining the different values of R2 from the corresponding carboxylic acid (R2 = CO2H), - obtaining the different values of Z (NHCORc, NHSORc, NHC02Rc, NHSO2Rc) from the amine ( Z = NH2), - salification.

 The action of the compounds of formula (III) on the amine of formula (II) is carried out in particular in the presence of isobutyl chloroformate and N-methyl-morpholine.

The cyclization reaction is carried out in particular in the presence of ammonium acetate and acetic acid.

 The alkylation reaction using R'1X is carried out according to the usual methods known to those skilled in the art, especially in the presence of a base such as sodium hydride in an aprotic dipolar solvent such as dimethylformamide.

<Desc / Clms Page number 16>

 The acylation reaction using the compound of formula [A'2] - [A1] -COOH is carried out according to the conventional acylation methods known to those skilled in the art and in particular in the presence of EDC (hydrochloride 1- (3dimethylaminopropyl) -3-ethyl-carbodiimide) and HOBt (1hydroxybenzotriazole hydrate) in an aprotic dipolar solvent such as dimethylformamide.

 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 CO2CH2Ph, 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 achieve total deprotection ([A2] = OP (O) (OH) 2), conventional hydrogenation is preferably carried out in the presence of 10% Pd / C or trifluoroacetic acid is used.

The action of the amines NHRi - (CH2) m - Alk, NHRi - (CH2) --Ar or NHRi - (CHz) m - Het on the acid function (Rl = CHRa - CO2H) is carried out in the presence of EDC. and HOBt.

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

 The salification reactions can be carried out according to the usual conditions.

 The functionalization reactions when R2 = CO2H and Z = NH2 in order to obtain the different values of Z and R2, 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 FIG. the examples described below.

 The compounds of formula (I) and their pharmaceutically acceptable addition salts have interesting pharmacological properties which are exposed

<Desc / Clms Page number 17>

below. 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). Within this class of intracellular tyrosine kynase, 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 cSrc 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

<Desc / Clms Page number 18>

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 show any obvious abnormality in the neurons or platelets, but these mice all had very weak bone resorption which gives rise to abnormalities of the skeleton (SN

 Popoff et al; Bone 17 (5) These mice were then shown to have osteoclasts in normal numbers, but 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); on the other hand, this functional substitution would not take place 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).

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

<Desc / Clms Page number 19>

 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 consisting in the administration to the patient whose treatment requires inhibition of the SH2 domain an inhibitory amount of the compound according to the invention.

 The invention therefore firstly relates generally to the compounds of formula (I) and their pharmaceutically acceptable salts and esters as medicaments.

More particularly, the compounds of the invention as anti-resorbents may be useful in the prevention or treatment of diseases caused by the loss of bone matrix, in particular, osteoporosis, hypercalculia of malignancy, osteopenia due to bone metastases, paradontitis, hyperparathyroidism, periarticular erosions in rheumatoid arthritis, Paget's disease, immobilization-induced osteopenia, glucocorticoid therapy, or male or female sex hormone deficiencies .

 The invention therefore particularly relates to the compounds of formula (I) and their pharmaceutically acceptable salts and esters as medicaments for the prevention or treatment of osteoporosis.

 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-SHc as well. In addition, several proteins of this family being mainly expressed in the hemopoietic system, many applications in the treatment of immunity, infection, allergy and antoimune 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.

<Desc / Clms Page number 20>

Proteins containing SH2 domain other than Src are selected from Fyn, Lck, Yes, Blk, Lyj, 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 dosage varies according to the condition to be treated and the route of administration: it may vary for example from 1 mg to 2000 mg per day in the adult orally.

 The invention extends to pharmaceutical compositions containing as active ingredient at least one drug as defined above.

 The compounds of formula (I) are used digestive, parenteral or local, for example percutaneously. They can be prescribed in the form of simple or coated tablets, capsules, granules, suppositories, ovules, injectables, ointments, creams, gels, microspheres, nanospheres, implants, patches which are prepared according to the usual methods.

 The active ingredient (s) can be incorporated into excipients usually employed in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vesicles. fatty substances of animal or vegetable origin, paraffinic derivatives, glycols, various wetting agents, dispersants or emulsifiers, preservatives.

- The compounds of formula (II) with R = H are known (Néosystem) - the compounds of formula (II) with R2 different from H are

<Desc / Clms Page number 21>

à l'action du bromoaryle de formule (IIb)

Rb étant tel que défini précédemment, en présence d'une base telle que le n-butyllithium afin d'obtenir le composé de formule (II) avec R2=CO2Rb

prepared according to the method described below (where R2 = CO2Rb)
The subject of the invention is therefore also a process for the preparation of the compounds of formula (II) with R2 = CO2Rb as defined previously in which the amide of formula (IIa) is subjected

to the action of bromoaryl of formula (IIb)

Rb being as defined above, in the presence of a base such as n-butyllithium in order to obtain the compound of formula (II) with R2 = CO2Rb

The compound of formula (IIa) is prepared by the action of NO-dimethylhydroxylamine, in the presence of a base such as triethylamine, on isatoic acid.

The compounds of formula (II), (IV), (V), (VI), when R2 is different from the hydrogen atom, (VI '), (VI' ') and (II) are intermediate products novel and the invention therefore also relates to these compounds, especially as intermediates for carrying out the process of the invention. The following examples illustrate the invention without limiting it.

Preparation P1

<Desc / Clms Page number 22>

(2,3-dihydro-2-oxo-5-phényl-1H-1,4-Benzodiazépin-3-yl)- Carbamate de phénylméthyle.

(2,3-Dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl) -phenylmethyl carbamate.

Phenylmethyl (2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl) carbamate is commercially available (Neosystem) or is prepared from (2-aminophenyl) phenylmethanone according to preparation 2, stages c, d and e.

carbonyllaminol-lH-1,4-benzodiazépin-5-yll-Benzoate de 1,1- diméthyléthyle. stade a : 2-amino-N-méthoxy-N-méthyl-benzamide
A une solution d'éthanol à 90% (100 ml) est ajouté le chlorhydrate de N-O-diméthyl hydroxylamine (23,8 g, 24 ml) et la triéthylamine (24,6 g, 33,4 ml). L'ensemble est agité 10 mn à température ambiante puis est ajouté par portion, 26,2 g d'acide isatoique. L'ensemble est porté au reflux pendant 1,5 h puis refroidi et versé dans l'eau glacée. L'éthanol est évaporé et la phase aqueuse obtenue est extraite avec de l'acétate d'éthyle. Après lavage à l'eau salée puis à l'eau, la phase organique est séchée et évaporée pour donner, après chromatographie sur colonne de silice (éluant : Et20/hexane 1/1), 25 g de produit attendu. Preparation P2: 4- [2,3-Dihydro-2-oxo-3 - [[(phenylmethoxy)

1,1-Dimethylethyl carbonyllaminol-1H-1,4-benzodiazepin-5-yl-benzoate. Step a: 2-amino-N-methoxy-N-methyl-benzamide
To a solution of 90% ethanol (100 ml) was added NO-dimethyl hydroxylamine hydrochloride (23.8 g, 24 ml) and triethylamine (24.6 g, 33.4 ml). The whole is stirred for 10 minutes at room temperature and is then added portionwise, 26.2 g of isatoic acid. The whole is refluxed for 1.5 h and then cooled and poured into ice water. The ethanol is evaporated and the aqueous phase obtained is extracted with ethyl acetate. After washing with salt water and then with water, the organic phase is dried and evaporated to give, after chromatography on a silica column (eluent: Et 2 O / hexane 1/1), 25 g of the expected product.

NMR (1H, CDCl3) 3.3 (s, 3H); 3.6 (s, 3H); 4.6 (s, 2H); 6.7 (m, 2H); 7.2 (t, 1H); 7.4 (d, 1H) b- (4- (2-Aminobenzoyl) -benzoate 1,1-dimethylethyl.

 1 g of amide prepared in step a and 1 g of 4-bromobenzoate 1,1-dimethylethyl are mixed under argon. The whole is cooled to -100 ° C. and n-Butyllithium (1.6N, 6.95 ml, at a flow rate of 0.6 ml / min) is added. After 12 minutes of introduction, the solution is brought to -70 ° C. for 10 minutes and a solution of 1N HCl (50 ml) is then introduced. After addition of ethyl acetate, the solution is extracted and the organic phase is washed and then chromatographed on silica (AcOEt / cyclohexane 1/1). 850 mg (52%) of the expected product is isolated.

NMR (1H, CDCl3) 1.4 (s, 9H); 6.0 (s, 2H); 6.4 (t, 1H); 6.6 (d, 1H); 7.3 (t, 2H); 7.5 (d, 2H); 8.0 (d, 2H)

<Desc / Clms Page number 23>

stade c : 4- [2- [ (1-méthyléthyl) thio] -1-oxo-2- [ [ (phényl- méthoxy) carbonyl] amino] -éthyl] amino] benzoyl] -benzoate de 1,1- diméthyléthyle.

Step c: 4- [2- [(1-Methylethyl) thio] -1-oxo-2- [[(phenylmethoxy) carbonyl] amino] ethyl] amino] benzoyl] benzoate 1,1-dimethylethyl.

13.6 g of 2 - [(1-methylethyl) thio] -2 - [[(phenylmethoxy) carbonyl] amino] -acetic acid, prepared from glyoxylic acid according to procedures described in the literature, (Tetrahedron Vol 31, p 863) are dissolved in 550 ml of dichloromethane. 5.28 ml of N-methylmorpholine and 6.2 ml of isobutylchloroformate are added at 0 ° C.

The mixture is stirred for 15 minutes at 0 ° C. It is then refluxed and a solution of 14.2 g of dissolved amine prepared in the preceding stage in 120 ml of dichloromethane is added dropwise. After 30 minutes of reflux and 18 hours at room temperature, the solution is taken up twice in 100 ml of 10% citric acid and then twice in 100 ml of NaHCO 3 and finally twice in salt water. The 30 grams of crude product are chromatographed on a silica column (70 cyclohexane / 30 ethyl acetate) to give 25 g of the expected product.

NMR (1H, CDCl3) 1.2 (d, 6H); 1.6 (s, 9H); 3.1 (m, 1H); 5.0 (s, 2H); 5.5 (d, 1H); 5.9 (d, 1H); 7.0 (t, 1H); 7.3 (m, 4H); 7.4 (m, 2H); 7.5 (d, 2H); 8.0 (d, 2H); 8.5 (d, 1H) Step d: 4- [2-Amino-1-oxo-2 - [[phenylmethoxy) carbonyl] amino] ethyl] amino] benzoyl] benzoate 1,1-dimethylethyl.

4 g (7.1 ml) of the compound obtained in the preceding stage are cooled to 0 ° C. in 50 ml of anhydrous THF. This solution is saturated for 1 hour with ammonia gas and is then added at once 2.12 g of mercury chloride HgCl 2. Ammonia bubbling is continued for 4 hours. The mercury salts are then filtered. After evaporation and chromatography (AcOEt / cyclohexane 75/25 then 50/50), 2.4 g of expected compound is recovered (yield = 75%).

Stage e: 4- [2,3-Dihydro-2-oxo-3 - [[(phenylmethoxy) carbonyl] amino] -1H-1,4-benzodiazepin-5-yl] benzoate 1,1-dimethylethyl .

 The preceding compound (2.4 g, 4.8 mol) is dissolved in 40 ml of acetic acid in the presence of 1.9 g of ammonium acetate. After a night of temperature stirring

<Desc / Clms Page number 24>

 In the room, the acetic acid is evaporated and 5 ml of 1N NaOH and 25 ml of ethyl acetate are added. After 30 minutes, the precipitate formed (1.1 g) is filtered and the solution is concentrated under reduced pressure. A new crystallization of the mother liquors makes it possible to recover another 500 mg of the expected compound (68% yield) NMR (1H, CDCl3) 1.6 (s, 9H), 5.2 (s, 2H), 5.4 (d, 1H), 6.7 (d, 1H) 7.3 (m, 9H), 7.6 (m, 9H), 7.6 (d, 2H), 8.0 (d, 2H), 9.0 (s, 1H) Preparation P3: 4 - [[bis (phenylmethoxy) phosphinyl] oxy] benzenepropanoic acid. a) Preparation of methyl ester 4 - [[bis (phenylmethoxy) phosphinyl] oxy] benzenepropanoate.

0.95 of methyl 3- (4-hydroxyphenyl) -propanoate in 31 ml of acetonitrile are mixed at -10 ° C. under a nitrogen atmosphere with 2.56 ml of carbon tetrachloride and 2 ml of diisopropylethylamine. ml of dibenzylphosphite (HPO (OBn) 2) and stirred for 1 hour at this temperature. After adding a solution of 0.5M KH2PO4 and 100ml of ethyl acetate, the organic phase is washed, dried and evaporated.

3.1 g of crude product is obtained which is purified by chromatography eluting with a cyclohexane / ethyl acetate mixture 5/5. 2.1 g of expected product are obtained IR (CHCl 3) C = O 1733 cm -1, aromatic 1608.1509, 1495 cm -1 b) Saponification 4 - [[(bis (phenylmethoxy) phosphinyl] oxy] - benzenepro panoic acid .

20 mg of lithium hydroxide monohydrate (LiOH) are added to 0.2 g of the ester obtained in the preceding stage in 7 ml of THF and 3.5 ml of water, the mixture is stirred for 4 hours at 0 ° C., adds 5 mg LiOH and stirred an additional hour at room temperature. Acidified to pH = 2, extracted with ethyl acetate, dried and evaporated under reduced pressure the organic phase and 0.10 g of expected product is obtained.

 IR (CHC13) General OH / NH absorption

<Desc / Clms Page number 25>

Préparation P4 : Acide 4-[[bis(phénylméthoxy)phosphinyl] oxy]-Benzèneacétique On opère comme à la préparation P3 mais à partir de 2-(4hydroxyphényl)-acétate de méthyle IR (CHC13) C=O : 1713 cm-1 (Max) Aromatique 1606,1509 et 1499 cm-1 Préparation P5 : 4-[3-amino-2,3-dihydro-2-oxo-lH-l,4-benzo-

diazépin-S-y1]-Benzoate de cyclohexylméthyle. C = O: 1728 cm -1 Aromatic 1605, 1589, 1508 and 1500 cm -1

Preparation P4: 4 - [[bis (phenylmethoxy) phosphinyl] oxy] benzeneacetic acid The procedure is as in Preparation P3 but starting from methyl 2- (4hydroxyphenyl) acetate IR (CHCl3) C = O: 1713 cm-1 (Max) Aromatic 1606,1509 and 1499 cm-1 Preparation P5: 4- [3-amino-2,3-dihydro-2-oxo-1H-1,4-benzoate

cyclohexylmethyl diazepin-S-yl] benzoate.

Stage a: hydrolysis of t-butyl ester 450 mg of compound P2 are dissolved in 3 ml of CH2Cl2 and 3 ml of trifluoroacetic acid are added. The solution is stirred for 2 hours at room temperature and then evaporated to dryness.

Stage b: Esterification The preceding product is taken up in solution with 226 mg of EDC, 159 mg of HOBt in 10 ml of dichloromethane and 1 ml of DMF for 15 minutes. 143 μl of cyclohexylcarbinol are then added and left overnight at room temperature. After evaporation of the dichloromethane, dissolution in 20 ml of AcOEt, then successive washings with 0.1N HCl, H2O, NaHCO3 and H2O, 256 mg of expected product is recovered.

[1- [ [4- [ [hydroxy (phénylméthoxy) phosphinyl] oxy] phényl] méthyl] - 2-[[2,3-dihydro-l-[2-[(4-phénoxyphênyl)amino]-2-oxoêthyl]-2oxo-5-phényl-1H-1,4-benzodiazépin-3-yl]amino]-2-oxoéthyl]- carbamate de 1,1-diméthyléthyle. MS MH + = 526 +; MNa + = 548 + (MH) - = 524- (M-CH2Cyclohexyl-H) - = 428RMN (1H, CDCl3) 0.9-1.2 (m, 5H); 1.5-1.7 (m, 6H); 3.4 (d, 2H); 5.1 (s, 2H); 5.35 (d, 1H); 6.65 (d, 1H); 7.2-7.5 (m, 9H); 7.7 (d, 2H); 8.0 (d, 1H); 8, 2 (d, 2H) EXAMPLE 1

[1 - [[4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2 - [[2,3-dihydro-1 - [2 - [(4-phenoxyphenyl) amino] -2-oxoethyl] 2 -oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl] amino] -2-oxoethyl] carbamate 1,1-dimethylethyl.

-1H-1,4-Benzodiazépin-1-acétate d'éthyle. Stage a: N-alkylation 2,3-dihydro-2-oxo-5-phenyl-3 [[(phenylmethoxy) carbonyl] amino]

-1H-1,4-Benzodiazepin-1-ethyl acetate.

<Desc / Clms Page number 26>

On mélange 5,8 g de (2,3-dihydro-2-oxo-5-phényl-1H-1,4- Benzodiazépin-3-yl) Carbamate de phénylméthyle (P1) dans 50 ml de diméthylformamide refroidi à 0 C, ajoute 0,65 g d'hydrure de sodium (à 50% dans l'huile) et 1,9 ml de bromoacétate d'éthyle, agite 1 heure trente à 0 C puis une nuit en laissant remonter à température ambiante. On verse sur l'eau, extrait à l'acétate d'éthyle, sèche et évapore sous pression réduite. On obtient 8,4 g de produit brut sous forme d'huile qu'on engage tel quel au stade b.

5.8 g of (2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl) phenylmethyl carbamate (P1) are mixed in 50 ml of dimethylformamide cooled to 0 ° C., 0.65 g of sodium hydride (at 50% in oil) and 1.9 ml of ethyl bromoacetate are added, the mixture is stirred for 1 hour at 0 ° C. and then left overnight at room temperature. It is poured into water, extracted with ethyl acetate, dried and evaporated under reduced pressure. 8.4 g of crude product are obtained in the form of an oil which is used as such in stage b.

1,5 (m,3H, C02CH2CH3) 4,1 (m,2H C02CH2CHI) 4,5 (s,2H NCH2) 5,0 (s,2H, C02CH2Ph) 5,2 (d,lH NHCH) ; 6,6 (d, lH, NH) ; 7,2 à 8 (14H aromatique) IR (CHCl3) 3425 cm-1 (=C-NH) ; 1747,1727,1688 cm-1 (C=0) ; 1606,1578, 1572,1506,1489 cm-1 (système conjugué + aromatiques + amide II). NMR (1H, CDCl3):

1.5 (m, 3H, CO 2 CH 2 CH 3) 4.1 (m, 2H CO 2 CH 2 CHI) 4.5 (s, 2H NCH 2) 5.0 (s, 2H, CO 2 CH 2 Ph) 5.2 (d, 1H NHCH); 6.6 (d, 1H, NH); 7.2 to 8 (aromatic 14H) IR (CHCl 3) 3425 cm -1 (= C-NH); 1747, 1727, 1688 cm -1 (C = O); 1606,1578, 1572,1506,1489 cm-1 (conjugated system + aromatics + amide II).

Stage b Saponification 2,3-Dihydro-2-oxo-5-phenyl-3 - [[(phenylmethoxy) carbonyl] amino] -1H-1,4-benzodiazepin-1-acetic acid.

The mixture consisting of the ester obtained in stage a, 25 ml of dioxane, 25 ml of water and 7.5 ml of 2N NaOH is stirred overnight at ambient temperature, the basic aqueous phase is washed with ether and acidified. (pH = 2) this aqueous phase with 4N hydrochloric acid, extracted with dichloromethane, dried and evaporated under reduced pressure. 6.7 g of the expected product are obtained.

IR (CHCl3) 3425 cm-1 (= C-NH); 1766, 1728 and 1691 cm-1 (C = O); 1606,1578, 1568,1506, 1489 cm-1 (conjugated system and aromatics + amide II).

2,3-dihydro-1H-1,4-Benzodiazépin-3-yl]-Carbamate de phénylméthyle. Stage c: Amidification [1- [2- [(4-Phenoxyphenyl) amino]] -2-oxo-ethyl] -2-oxo-5-phenyl-

Phenylmethyl 2,3-dihydro-1H-1,4-benzodiazepin-3-yl] carbamate.

To 0.36 g of the acid prepared in stage b in 10 ml of dichloromethane is added 0.180 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodimide hydrochloride (EDC) 0.131 g of hydrate of 1 -hydroxy benzotriazole (HOBt) then 0.18 g of 4

<Desc / Clms Page number 27>

 phenoxyaniline, stirred overnight at 20-25 C, extracted with ethyl acetate, washed, dried and evaporated under reduced pressure.

The dry extract crystallizes, and the crystals are dewatered, washed and dried. 0.435 g of purified product is obtained.

IR (CHCl 3) 3420 cm -1 (= C-NH), 1720, 1689, 1667 cm -1 (C = O), 1604, 1590, 1579, 1570, 1542, 1525, 1507 and 1489 cm -1 (aromatic + C = N + amide II).

3-amino-2,3-dihydro-2-oxo-5-phényl-N-(4-phénoxyphényl)-1H- 1,4-Benzodiazépine-1-acétamide On mélange 0,43 g du produit obtenu au stade c dans 30 ml de méthanol avec 0,05 ml d'acide formique, O,lg de Pd/C à 10% et fait passer un courant d'hydrogène pendant 5 heures sous une pression de 1,8 bar. Après filtration du milieu réactionnel, lavage avec du méthanol, on évapore sous pression réduite le méthanol, reprend l'extrait sec avec du dichlorométhane, lave, sèche, évapore sous pression réduite et purifie par chromatographie l'extrait sec obtenu en éluant avec le mélange CH2C12/MeOH(95/5). On obtient 0,19 g de produit pur attendu. Stage d: hydrogenolysis

3-amino-2,3-dihydro-2-oxo-5-phenyl-N- (4-phenoxyphenyl) -1H-1,4-benzodiazepine-1-acetamide 0.43 g of the product obtained in stage c are mixed in 30 ml of methanol with 0.05 ml of formic acid, 0.1 g of 10% Pd / C and a stream of hydrogen for 5 hours under a pressure of 1.8 bar. After filtration of the reaction medium, washing with methanol, the mixture is evaporated under reduced pressure, the dry extract is taken up with dichloromethane, washed, dried, evaporated under reduced pressure and the dry extract obtained by eluting with the mixture is purified by chromatography. CH2C12 / MeOH (95/5). 0.19 g of expected pure product is obtained.

[ [2, 3-dihydro-1- [2- [ (4-phénoxyphényl) amino] -2-oxoéthyl] -2- oxo-5-phényl-1H-1,4-benzodiazépin-3-yl]amino]-2-oxoéthyl]- carbamate de 1,1-diméthyléthyle. IR (Nujol) 3370.3266 cm-1 (OH / NH absorption); 1661 cm-1 (C = O) 1607.1,600, 1585,1532, 1505,1485 cm-1 (C = N + aromatic + amide II + NH2) Step e: Coupling between amine and phosphotyrosine [1- [ [4- [bis (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2-

[[2,3-dihydro-1- [2- [(4-phenoxyphenyl) amino] -2-oxoethyl] -2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl] amino] - 2-oxoethyl] - 1,1-dimethylethyl carbamate.

(N-Boc-Tyr-0(P03Bn2)), 30 ml de CH2C12, 4 ml de DMF, 73 mg de chlorydrate de 1-Ethyl-3-(3-diméthylamino-propyl)carbodiimide, 51 mg d'hydrate de 1-hydroxybenzotriazole et 0,18 g de l'amine préparée au stade d dans 5 ml de DMF, dilue par 50 ml d'acétate d'éthyle et verse dans une solution aqueuse à 10% d'acide citrique. La phase organique est lavée, The mixture consisting of 0.205 g of O- [bis (phenylmethoxy) phosphinyl] -N - [(1,1-dimethylethoxy) carbonyl] -Tyrosine is stirred for one hour at 0 ° C. and then for one hour at room temperature.

(N-Boc-Tyr-O (PO3Bn2)), 30 ml of CH2Cl2, 4 ml of DMF, 73 mg of 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, 51 mg of hydrate of 1 -hydroxybenzotriazole and 0.18 g of the amine prepared in stage d in 5 ml of DMF, diluted with 50 ml of ethyl acetate and poured into a 10% aqueous solution of citric acid. The organic phase is washed,

<Desc / Clms Page number 28>

dried, evaporated under reduced pressure, and the crude product obtained is purified by chromatography eluting 95/5 CH2Cl2 / MeOH mixture. 0.25 g of expected pure product is obtained.

EMM (1H, CDCl3) 1.40 1.42 (CO 2 C (CH 3) 3) 3.70 (m, Ph-CH 2 -CH); 4.43 (dd) 4.78 (m) Ph-NH-CH 2 -CO; 4.53 (m, N-CH 2-Co); 5.09 (m, Ph-CH 2 -O-P); 5.59 CO-CH (N) -N =; 6.90 (m) phenyls, 7.05 to 7.78 - 8.23 (sl) - 8.29 (si) aromatics and (= C-NH).

2- [ [2, 3-dihydro-1- [2- [ (4-phénoxyphényl) amino] -2-oxoéthyl] -2- oxo-5-phényl-1H-1,4-benzodiazépin-3-yl]amino]-2-oxoéthyl]- carbamate de 1,1-diméthyléthyle. Stage f: Partial deprotection [1- [[4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -

2- [[2,3-Dihydro-1- [2- [(4-phenoxyphenyl) amino] -2-oxoethyl] -2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl] amino ] -2-oxoethyl] - 1,1-dimethylethyl carbamate.

RMN ( 1H, CDC13 ) 1,35 (s) l,39(s) CO2C(CH3)3 ; 2, 70 à 3, 15 (m 1,5H) ; 4,30 à 5,75 (m large, 7,5H) ; 6,70à 7,90 (m complexe, 30,5H aromatiques) ; 9,24 (m) 9,68 (m) H mobiles. The mixture consisting of 0.25 g of product obtained in stage e, 20 ml of toluene and 70 mg of triethylene of amine (DABCO) diluted with 20 ml of ethyl acetate and refluxed for two hours, is refluxed for two hours. product crystallize. After filtration, washing and drying, 0.2 g of crude product is obtained. The crystals are taken up in 20 ml of CH 2 Cl 2 and the organic phase is then washed, dried and then evaporated under reduced pressure. 0.136 g of expected product is obtained

NMR (1H, CDCl3) 1.35 (s) 1.39 (s) CO2C (CH3) 3; 2.70-3.15 (m 1.5H); 4.30 to 5.75 (m, 7.5H); 6.70 to 7.90 (m complex, 30.5H aromatics); 9.24 (m) 9.68 (m) H mobile.

[1-[[4-[[bis (phénylméthoxy)phosphinylloxylphényllméthyll-2- [ [2, 3-dihydro-1- [2- [ [ (1-naphthalényl)méthyl] amino] -2oxoéthyl]-2-oxo-5-phényl-1H-1,4-Benzodiazépin-3-yl]amino]-2oxoéthy1]-Carbamate de 1,1-diméthyléthyle. EXAMPLE 2

[1 - [[4 - [[bis (phenylmethoxy) phosphinyl] phenyl] methyl] -2 - [[2,3-dihydro-1- [2- [[(1-naphthalenyl) methyl] amino] -2-oxoethyl] -2-oxo-5 1,1-Dimethylethyl phenyl-1H-1,4-benzodiazepin-3-yl] amino] -2oxoethyl] carbamate.

The operation is carried out as in Example 1, stages a to f, it being understood that the amidation step (stage c) is carried out with NMR 1 Naphthalenemethanamine (1H, DMSO) 1, 29 (s) 1, 30 (s) CO2C (CH3); 2.74 (m, 1H); 2.95-3.15 (m> 2H) Ph-CH2-CH; 4.33 (m, 1H); 4.50 to 4.82 (m, 6H CH2NCO, Ph-CH2-O-P and CH2-CH-NHCO) 5.38 (s, split H3); 7.00 to 7.67 (m, 22 to 23H); 7.81 (t, 1H) 7.91 (m, 1H) 7.97 (m, 1H)

<Desc / Clms Page number 29>

[1- [ [4- [ [hydroxy (phénylméthoxy) phosphinyl] oxy] phényl] méthyl] - 2-[[2,3-dihydro-l-[2-[[(l,3-benzodioxolan-5-yl)mêthyl]amino]- 2-oxoéthyll-2-oxo-5-phényl-lH-1,4-Benzodiazépin-3-yllaminol- 2-oxoéthyll-Carbamate de 1,1-diméthyléthyle. aromatics. EXAMPLE 3

[1 - [[4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2 - [[2,3-dihydro-1 - [2 - [[(1,3-benzodioxolan-5-yl)] Methyl] amino] -2-oxoethyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yllaminol-2-oxoethyl-1,1-dimethylethyl carbamate.

4,84 (1, Ph-N-CH2-C= ) ; 5,11 à 5,42 =N-CH-N-C= ; 5,90 à 5,98 Ph-CH2-O-P ; 6, 60 à 7,75 - 8,64 (m) -9, 09 (d) - 9,17 (d) aromatique et =C-NH EXEMPLE 4

[1- [ [4- [ [hydroxy (phénylméthoxy) phosphinyl] oxy] phényl] méthyl] - 2-[[2,3-dihydro-l-[2-[[(2-naphthalényl)méthyllaminol-2oxoéthyll-2-oxo-5-phényl-lH-1,4-Benzodiazépin-3-yllaminol-2- oxoéthyl]-Carbamate de 1,1-diméthyléthyle. The operation is carried out as in Example 1, step a to f, it being understood that the amidation step (stage c) is carried out with 1,3-benzodioxol-5-methanamine NMR (1H, DMSO) 1.30 (sl, CO2C (CH3) 3); 2.60-3.12 Ph-CH2-CH; 3.95-4, 28 Ph-CH2-OP 4.34 (1, = C-CH-NC =); 4.45 to 4.70 = CN-CH2-Ph;

4.84 (1, Ph-N-CH 2 -C =); 5.11 to 5.42 = N-CH-NC =; 5.90 to 5.98 Ph-CH2-OP; 6.60-7.75-8.64 (m) -9.09 (d) -9.17 (d) aromatic and = C-NH EXAMPLE 4

[1 - [[4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2 - [[2,3-dihydro-1 - [2 - [[(2-naphthalenyl) methyl] amino] -2-oxoethyl-2-yl 1,1-dimethylethylated oxo-5-phenyl-1H-1,4-benzodiazepin-3-yllaminol-2-oxoethyl] carbamate.

The operation is carried out as in Example 1, stages a to f with the proviso that the amidation step (stage c) is carried out with NMR 2Naphthalenemethanamine (1H, DMSO) 1, 30 (1, CO2C (CH 3) 3); 2.60 to 2.80 - 2.97 to 3.12 Ph-CH2-CH; 4.30 to 4.50 (m) = C-CH-NH-C =; 4.59 (m) - 4.70 (si) = C-NH-CH 2 Ph; 4.82 (ss, Ph-CH 2 OP) 5.40 (m, = N-CH-NH-C =); 6.50 to 7.90 aromatics; 8.89 (m) 9.12 (d) 9.23 (d) H mobile.

[1- [ [4- [ [hydroxy (phénylméthoxy) phosphinyl] oxy] phényl] méthyl] - 2-[[2,3-dihydro-l-[2-[[lH-indol-5-yl]amino]-2-oxoêthyl]-2oxo-5-phên.yl-lH-l,4-Benzodiazêpin.-3-yl]amino]-2-oxoêthyl]- Carbamate de 1,1-diméthyléthyle. EXAMPLE 5

[1 - [[4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2- [[2,3-dihydro-1 - [2 - [[1H-indol-5-yl] amino] - 2-Oxoethyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl] amino] -2-oxoethyl] -1,4-dimethylethyl carbamate.

The procedure is as in Example 1, stages a to f, it being understood that the amidation step (stage c) is carried out with 1H-

<Desc / Clms Page number 30>

 Indol-5-amine.

[1- [ [4- [ [hydroxy(phénylméthoxy)phosphinyl] oxy] phënyl]méthyl] - 2-[[2,3-dihydro-l-[2-[(9-éthyl-9H-carbazol-3-yl) amino] -2oxoéthyll-2-oxo-5-phényl-lH-1,4-Benzodiazépin-3-yllaminol-2oxoéthy1]-Carbamate de 1,1-diméthyléthyle. On opère comme à l'exemple 1 stades a à f étant entendu que l'étape d'amification (stade c) s'effectue avec le 9-éthyl- 9H-Carbazol-3-amine RMN (1H, DMSO) 1,30 (m,12H,Boc) ; 4,33 (m,lH, CO-CH (CH2) -NHCO) ; 4, 41 (m,2H,N-CH2) 4, 74 (d, Ph-CH2-O-P) ;

4,80 (m,Ph-N-CH2-CONH) ; 5,44 (dd,lH, =N-CH-NH-CO) ; 2,73 (m,lH) ; 3,00 (masqué Ph-CH2-CH) ; 6,90 à 7,57 (33H), 8,05 (m,lH) ; 8,38 (d,lH) ; 9,13 (d,lH) ; 9,19 (d,lH) ; 10,38 (d,lH). MS: 857+: MH +; 879+. MNa +; 895+: MK + EXAMPLE 6

[1 - [[4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2 - [[2,3-dihydro-1 - [2 - [(9-ethyl-9H-carbazol-3-yl] ) amino] -2oxoethyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yllaminol-2oxoethyl] -carbamate 1,1-dimethylethyl. The procedure is as in Example 1, steps a to f, provided that the amination step (stage c) is carried out with 9-ethyl-9H-carbazol-3-amine NMR (1H, DMSO) 1.30 (m, 12H, Boc); 4.33 (m, 1H, CO-CH (CH 2) -NHCO); 4.41 (m, 2H, N-CH 2) 4.74 (d, Ph-CH 2 -OP);

4.80 (m, Ph-N-CH 2 -CONH); 5.44 (dd, 1H, = N-CH-NH-CO); 2.73 (m, 1H); 3.00 (masked Ph-CH2-CH); 6.90 to 7.57 (33H), 8.05 (m, 1H); 8.38 (d, 1H); 9.13 (d, 1H); 9.19 (d, 1H); 10.38 (d, 1H).

2-[[2,3-dihydro-l-[2-[(3-phénoxyphényl)aminol-2-oxoéthyll-2oxo-5-phényl-1H-1,4-Benzodiazépin-3-yl]amino]-2-oxoéthyl]- Carbamate de 1,1-diméthyléthyle. EXAMPLE 7 [1- [[4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] methyl]

2 - [[2,3-dihydro-l- [2 - [(3-phenoxyphenyl) amino-2-oxoéthyll-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl] amino] -2- oxoethyl] - 1,1-dimethylethyl carbamate.

1,28 (s) 1, 29 (s) C02C {CH3) 3 2,73 (m, 1H) 3, 02 (m,lH, Ph-Cli.- CH-NHCO) ; 4,32 (m,lH, PhCH2-CH-NHCO) ; 4,6 à 4,85 (m,4H) 2CH2 ; 5,39 (d dédoublé) CO-CH-NHCO ; 6,70 (m, 1H) - 6,93 à 7,75 (m,33H aromatiques) ; 9,08 (d) 9,19 (d) CONHCH mobile ; 10,40 (sl, 1H) mobile. The procedure is as in Example 1, stages a to f, with the proviso that the amination step (stage c) is carried out with 3-phenoxybenzenamine NMR (1H, DMSO)

1.28 (s) 1, 29 (s) CO 2 C (CH 3) 3 2.73 (m, 1H) 3. 02 (m, 1H, Ph-Cl-CH-NHCO); 4.32 (m, 1H, PhCH 2 -CH-NHCO); 4.6 to 4.85 (m, 4H) 2 CH 2; 5.39 (d split) CO-CH-NHCO; 6.70 (m, 1H) - 6.93 to 7.75 (m, 33H aromatics); 9.08 (d) 9.19 (d) CONHCH mobile; 10.40 (sl, 1H) mobile.

The compound of Example 7, like all the compounds of this application, consists in fact of a mixture of 2 RS and SS diastereoisomers. In this example, the two compounds could be obtained separately (after separation on chiral column of the two enantiomers obtained in stage c of the

<Desc / Clms Page number 31>

 synthesis, the stages d, e and f being conducted separately on each of the two intermediates) to lead to the final products 7a and 7b.

[1- [ [4- [ [hydroxy (phénylméthoxy) phosphinyl] oxy] phényl] méthyl] - 2-[[2,3-dihydro-l-[2-[[2-(1-naphtha1ény1) éthyl] amino] -2oxoéthyll-2-oxo-5-phényl-IH-1,4-Benzodiazépin-3-yllaminol-2oxoéthy1]-Carbamate de 1,1-diméthyléthyle. On opère comme à l'exemple 1 stades a à f étant entendu que l'étape d'amidification (stade c) s'effectue avec le 1Naphthalèneéthanamine RMN (1H, DMSO)

1,27 (s, C02C (CH3) 3) 2,72 (m, 1H) - 3,04 (m,lH) Ph-CI12-CH 3,15 masqué - 3,31 masqué Ph-CH2 - CH2-NHCO ; 4,33 (m, CO-CH-NHCO) ; 4,49 Ph-CH2-OP ; 5,39 (m, =N-CH-NHCO) ; 7,00 à 8,45 aromatiques ; 9,10 (d) 9,14 (d)CO-NH-CH ; 4,80 (2H, H peu mobiles) EXEMPLE 9

[1- [ [4- [ (dihydroxy) phosphinyl] oxy] phényl] méthyl] -2- [ [2, 3dihydro-1- [2- [ [2- (1-naphthalényl) éthyl] amino] -2-oxoéthyl] -2oxo-5-phényl-lH-1,4-Benzodiazépin-3-yllaminol-2-oxoéthyll- Carbamate de 1,1-diméthyléthyle. EXAMPLE 8

[1 - [[4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2 - [[2,3-dihydro-1 - [2 - [[2- (1-naphthalenyl) ethyl] amino] 1,1-Dimethylethyl 2-oxoethyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yllaminol-2oxoethyl] carbamate. The operation is carried out as in Example 1, stages a to f, with the proviso that the amidation step (stage c) is carried out with NMR 1 Naphthaleneethanamine (1H, DMSO).

1.27 (s, CO 2 C (CH 3) 3) 2.72 (m, 1H) - 3.04 (m, 1H) Ph-Cl 2 -CH 3.15 masked - 3.31 masked Ph-CH 2 - CH 2 -NHCO ; 4.33 (m, CO-CH-NHCO); 4.49 Ph-CH2-OP; 5.39 (m, = N-CH-NHCO); 7.00 to 8.45 aromatics; 9.10 (d) 9.14 (d) CO-NH-CH; 4.80 (2H, slightly moving) EXAMPLE 9

[1 - [[4- [[Dihydroxy) phosphinyl] oxy] phenyl] methyl] -2 - [[2,3] dihydro-1- [2- [[2- (1-naphthalenyl) ethyl] amino] -2-oxoethyl] ] -2oxo-5-phenyl-1H-1,4-benzodiazepin-3-yllaminol-2-oxoethyl-1,1-dimethylethyl carbamate.

To a solution of 0.090 g of the dibenzyl compound prepared in Example 8 (before the step of partial deprotection with DABCO) in 9 ml of methanol is added 20 mg of 10% palladium on carbon (Pd / C). 10%) and placed under a pressure of 1.7 bar of hydrogen. After 4 hours of reaction, the solution is filtered and then evaporated under reduced pressure. 68 mg of crude product are obtained which is purified by chromatography, eluting with a 70/30 mixture of MeOH / H 2 O). 24 mg of expected pure product is obtained.

NMR (1H, DMSO) 1.32 (s, CO2C (CH 3) 3); 2.70-3, Ph-CH2-OP; 4.31 (m) 4.43 to 4.58 (m) = C-NH-CH 2 -CO and CO-NH-CH 2 5.30 (d, split = N-CH-NHCO); 7.03 (m) 7.15 (m) CH 2 Ph-0.77 (m) -7.70; ~ 7.80 (m); ~ 7.92 (m); ~ 8.12; 8.2, -9.10 aromatics and NHCO; 6.92 (d = C-NH-CH)

<Desc / Clms Page number 32>

[1- [ [4- [ [hydroxy (phénylméthoxy) phosphinyl] oxy] phényl] méthyl] - 2- [ [2, 3-dihydro-1- [2- [ [ [ (1,1' -biphényl] -4-yl] méthyl] amino] -2oxoêthyl]-2-oxo-5-phênyl-lH-l,4-Benzodiazêpin-3-yl]amino]-2- oxoéthyl]-Carbamate de 1,1-diméthyléthyle. EXAMPLE 10

[1 - [[4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2- [[2,3-dihydro-1- [2- [[[1,1 '-biphenyl] -4] 1-Dimethylethyl -yl] methyl] amino] -2-oxoethyl] -2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl] amino] -2-oxoethyl] carbamate.

[1- [ [4- [ [hydroxy (phénylméthoxy) phosphinyl] oxy] phényl] méthyl] - 2-[[2,3-dihydro-l-[2-[[(4-phênoxyphênylmêthyl]amino]-2oxoéthyll-2-oxo-5-phényl-lH-1,4-Benzodiazépin-3-yllaminol-2- oxoéthyl]-Carbamate de 1,1-diméthyléthyle. The procedure is as in Example 1, stages a to f with the proviso that the amidation step (stage C) is carried out with (1,1'-biphenyl) -4-methanamine NMR (1H, DMSO) 1.29 (s, CO2C (CH3) 3) 2.73 (m) 3.03 (m) PhCH2-OP: 4.32 (m, = N-CH2-CO CO-CH-NHCO) 4.55 (dd) 4.64 (dl) CONHCH2Ph, 5.42 (m, = N-CH-NHCO, 7.00 to 7.75 aromatics, 8.76 (d), 9.11 (d), 9.21 (d), H mobile, 7.13 C-Ph-O, 7.42 to 8.42 other aromatics and NH EXAMPLE 11

[1 - [[4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2 - [[2,3-dihydro-1 - [2 - [[(4-phenoxyphenylmethyl] amino] -2-oxoethyl] -2 1,1-Dimethylethyl 5-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yllaminol-2-oxoethyl] carbamate.

4,24 (AB) CO-N-Cli2-Co ; 4,35 (m) CO-CE(NHCO)-CH2 ; 4,54 dd) 4,65 (dd) CONH-CH2-Ph 8,69 (t dédoublé, mobile) CONH-CH2PH ; 4,84 (d) Ph-CH20P 5,40 (d dédoublé) COCH-NHCO ; 6,85 à 7,76 (m) H aromatiques ; 9,10 (d) 9,16 (d) CO-NH-CH. EXEMPLE 12

2- [1- [ [4- [ [hydroxy(phénylméthoxy)phosphinyl] oxy]phényl] méthyll-2-[[2,3-dihydro-l-[2-[(2 cyclohexyléthyl) mêthylamino]-2-oxoêthyl]-2-oxo-5-phênyl-lH-l,4-Benzodiazêpin- 3-yl]amino]-2-oxoéthyl]-Carbamate de 1,1-diméthyléthyle. The operation is carried out as in Example 1, stages a to f, it being understood that the amidification stage is carried out with 4-phenoxy-benzenemethanamine NMR (1H, DMSO) 1.30 (s, resolved CO2C (CH 3) 3); 2.75 (m) 3.03 (m) Ph-CH2-CH

4.24 (AB) CO-N-Cli 2-Co; 4.35 (m) CO-CE (NHCO) -CH 2; 4.54 dd) 4.65 (dd) CONH-CH2-Ph 8.69 (t split, mobile) CONH-CH2PH; 4.84 (d) Ph-CH 2 O 5.40 (d split) COCH-NHCO; 6.85 to 7.76 (m) aromatic H; 9.10 (d) 9.16 (d) CO-NH-CH. EXAMPLE 12

2- [1- [[4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] methyl-2 - [[2,3-dihydro-1- [2 - [(2-cyclohexylethyl) methylamino] -2-oxoethyl] 1-Dimethylethyl 2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl] amino] -2-oxoethyl] carbamate.

The procedure is as in Example 1, stages a to f, with the proviso that the amidification stage is carried out with N-methyl-cyclohexane-ethanamine.

<Desc / Clms Page number 33>

l, 30 (s) 1,31 (s) COZC (CH3) 3 0,7 à 1,80 C-CH2 , C-CH ; 2, 95 (s) 2, 96 (s) (<3H) =C-N-CH3 ; 2, 60 à 3, 10 =C-N-CH2 ; 4,31 (étalé, =C-CH-N-C=) ; 4,74 (d, Ph-CH2-O-P) ; 4,81 (sl, =N-CH-C=) ; 6,83 à 7, 65 ; 9,04 (d) 9,14 (t) aromatiques et/ou =C-NH EXEMPLE 13 Déprotection totale

2-[l-[[4-[[dihydroxyphosphinyl]oxy]phênyl]mêthyl]-2-[[2,3dihydro-1- [2- [ (2-cyclohexyléthyl)méthylamino] -2-oxoéthyl] -2oxo-5-phênyl-lH-l,4-Benzodiazêpin-3-yl]amino]-2-oxoêthyl]- Carbamate de 1,1-diméthyléthyle. NMR (1H, DMSO)

1.30 (s) 1.31 (s) COZC (CH 3) 3 0.7 to 1.80 C-CH 2, C-CH; 2.95 (s) 2, 96 (s) (<3H) = CN-CH3; 2.60-3, 10 = CN-CH2; 4.31 (spread, = C-CH-NC =); 4.74 (d, Ph-CH 2 -OP); 4.81 (s, = N-CH-C =); 6.83 to 7, 65; 9.04 (d) 9.14 (t) aromatic and / or = C-NH EXAMPLE 13 Total deprotection

2- [1 - [[4 - [[Dihydroxyphosphinyl] oxy] phenyl] methyl] -2 - [[2,3dihydro-1- [2- [(2-cyclohexylethyl) methylamino] -2-oxoethyl] -2oxo-5 1,1-Dimethylethyl-phenyl-1H-1,4-benzodiazepin-3-yl] amino] -2-oxoethyl] carbamate.

[1- [ [4- [ [hydroxy (phénylméthoxy) phosphinyl] oxy] phényl] méthyl] - 2-[[2,3-dihydro-1-(3-cyclohexylpropyl)-2-oxo-5-phényl-1H-1,4Benzodiazépin-3-yl]amino]-2-oxoéthyl]-Carbamate 1,1- diméthyléthyle. on opère comme à l'exemple 1, les étapes a, b et c étant remplacées par une alkylation directe mettant en oeuvre le l-bromo-4-cyclohexylbutyle SM [M-H]' = 807- 847+ = MK+ EXEMPLE 15

[l-[[4-[[dihydroxyphosphinyl]oxy]phênyl]mêthyl]-2-[[2,3dihydro-l- (3-cyclohexylpropyl) -2-oxo-5-phënyl-lH-l,4Benzodiazépin-3-yl]amino]-2-oxoéthyl]-Carbamate de 1,1- diméthyléthyle. The procedure is as in Example 9 starting from the dibenzylated compound obtained in Example 12 MS: (MH) - = 774EXAMPLE 14

[1 - [[4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2- [[2,3-dihydro-1- (3-cyclohexylpropyl) -2-oxo-5-phenyl] -1H- 1,4-Benzodiazepin-3-yl] amino] -2-oxoethyl] carbamate 1,1-dimethylethyl. the procedure is as in Example 1, steps a, b and c being replaced by a direct alkylation using 1-bromo-4-cyclohexylbutyl SM [MH] '= 807- 847+ = MK + EXAMPLE 15

[1 - [[4 - [[Dihydroxyphosphinyl] oxy] phenyl] methyl] -2 - [[2,3dihydro-1- (3-cyclohexylpropyl) -2-oxo-5-phenyl-1H-1,4-benzodiazepin-3- 1,1-dimethylethyl] -benzyl] -2-oxoethyl] carbamate.

The procedure is as in Example 9 (total deprotection) from the dibenzylated compound obtained in Example 14.

NMR (1H, DMSO) 1.31 (s) 1.33 (s) CO2C (CH3) 3; 0, 49 (m) 0.66 to 1.7 (m) CH2 and CH aliphatic; 2.7 (masked) 3.02 (m) Ph-CH2-CH;

<Desc / Clms Page number 34>

 3.78 (m, CO-N-CH 2 -CH 2); 5.30 (d split, CO-CH-NHCO); 6.85 to 7.80 (m) aromatics and NHCO; 9.09 (d) - 9.19 (d) CONHCH.

3- [ [3- [4- [ [hydroxy (phénylméthoxy) phosphinyl] oxy] phényl] -1oxo-propyl] -amino] - 2, 3-dihydro-N- [2- (1-naphthalényl) éthyl] - 2-oxo-5-phényl-1H-1,4-benzodiazépine-1-acétamide On opère comme à l'exemple 8 mais en utilisant au cours de l'étape de couplage (stade e) l'acide 4-[[bis(phénylméthoxy)phosphinyl]oxy]-Benzènepropanoïque (P3) au lieu du N-Boc-Tyr-O (PO3Bn2) RMN (1H, DMSO)

2, 58 (m, CH2-C=) ; 2,76 (m, CH2-C=) ; 3, 08 (t, Ar-CHz-CHz-NHCO) ; 3,27 (m, t après échange, Ph-CH2-CH2-NHCO) ;

7,71 (t mobile, Ph CHz-CHZ-NI3-CO) ; 4, 26 (AB CO-N-CH,-CO) 4,66 (d, Ph-CH2-OP) ; 5,11 (d,s après échange, CO-CH-NHCO) ; 8,40 (d, mobile COCH-NH-CO) ; 6,57 et 6,65 (AA'BB'phényle) ; 6,72 à 6,83 (m, 8H) - 6,86 à 7,03 (m, 10H) - 7,10 (dt, 1H) ; 7,22 (d, 1H) - 7,30 (m, 1H) 7,51 (m, 1H) H aromatiques. EXAMPLE 16

3 - [[3- [4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] -1-oxopropyl] amino] -2,3-dihydro-N- [2- (1-naphthalenyl) ethyl] -2 -oxo-5-phenyl-1H-1,4-benzodiazepine-1-acetamide The procedure is as in Example 8 but using during the coupling step (step e) 4 - [[bis ( phenylmethoxy) phosphinyl] oxy] benzenepropanoic acid (P3) instead of N-Boc-Tyr-O (PO3Bn2) NMR (1H, DMSO)

2. 58 (m, CH 2 -C =); 2.76 (m, CH 2 -C =); 3.08 (t, Ar-CH2-CH2-NHCO); 3.27 (m, t after exchange, Ph-CH2-CH2-NHCO);

7.71 (t mobile, Ph CHz-CHZ-NI3-CO); 4.26 (AB CO-N-CH, -CO) 4.66 (d, Ph-CH 2 -OP); 5.11 (d, s after exchange, CO-CH-NHCO); 8.40 (d, mobile COCH-NH-CO); 6.57 and 6.65 (AA'BB'phenyl); 6.72 to 6.83 (m, 8H) - 6.86 to 7.03 (m, 10H) - 7.10 (dt, 1H); 7.22 (d, 1H) - 7.30 (m, 1H) 7.51 (m, 1H) H aromatics.

3-[[2-[4-[[hydroxy(phênylmêthoxy)phosphinyl]oxy.]phênyl]-loxoéthy1]-amino]- 2,3-dihydro-N-(lH-indol-5-yl)-2-oxo-5phényl-1H-1,4-benzodiazépine-1-acétamide On opère comme à l'exemple 5 mais en utilisant au cours de l'étape de couplage (stade e) l'acide 4-[[bis(phénylméthoxy)phosphinyl]oxy]-Benzèneacétique (P4) au lieu du N-Boc-Tyr-O (PO3Bn2) SM (M-H)' = 726EXEMPLE 18

Acide 4- [ [1- [4- [ [hydroxy (phénylméthoxy) phosphinyl] oxy]phényl]méthyl] -2- [ [2,3-dihydro-1- [2- [ [2- (1-naphthalényl) éthy1]amino]2-oxoéthy1]-2-oxo-5-phény1-lH-l,4-benzodiazépin- 3-yl]amino]-2-oxoéthyl]amino]-4-oxo-Butanoïque. EXAMPLE 17

3 - [[2- [4 - [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] -loxoethyl] amino] -2,3-dihydro-N- (1H-indol-5-yl) -2-oxo -5-phenyl-1H-1,4-benzodiazepine-1-acetamide The procedure is as in Example 5 but using during the coupling step (step e) 4 - [[bis (phenylmethoxy) phosphinyl] oxy] -Benzeneacetic acid (P4) instead of N-Boc-Tyr-O (PO3Bn2) MS (MH) = 726SAMPLE 18

4- [[1- [4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2 - [[2,3-dihydro-1- [2- [[2- (1-naphthalenyl) ethyl] acid ] amino] -2-oxoethyl] -2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl] amino] -2-oxoethyl] amino] -4-oxo-butanoic acid.

The dibenzyl compound protected at the nitrogen level by a -CO2tBu group prepared in Example 8,

<Desc / Clms Page number 35>

[ [4- [ [bis (phénylméthoxy) phosphinyl] oxy] phényl] méthyl] -2- [[2,3-dihydro-l-[2-[[2-(l-naphtalényl)éthyllaminol-2oxoéthyl]-2-oxo-5-phényl-1H-1,4-Benzodiazépin-3-yl]amino]-2- oxoéthyl]-Carbamate de 1,1-diméthyléthyle), est d'abord déprotégé pour obtenir l'amine correspondante, par action d'acide trifluoroacétique dans le dichlorométhane (4 heures à température ambiante, Rdt = 55%). On fait ensuite agir de l'acide succinique en présence de diméthylaminopyridine (DMAP) dans la pyridine (2 heures à température ambiante, Rdt
72%), puis on débenzyle par action de DABCO dans le toluène (2 heures au reflux). On obtient le produit attendu (Rdt = 67%) .

[[4- [[bis (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2 - [[2,3-dihydro-1 - [2 - [[2- (1-naphthalenyl) ethyl] aminol-2-oxoethyl] -2- 1-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl] amino] -2-oxoethyl] -carbamate 1,1-dimethylethyl) is first deprotected to obtain the corresponding amine, by trifluoroacetic acid in dichloromethane (4 hours at room temperature, yield = 55%). Succinic acid is then reacted in the presence of dimethylaminopyridine (DMAP) in pyridine (2 hours at room temperature).
72%), then debenzyl by action of DABCO in toluene (2 hours at reflux). The expected product is obtained (yield = 67%).

NMR (1H, DMSO) 5.39 (dd, CO-CH (NHCO) -CH 2); 1.90 to 2.25 (m, CH 2 -C =) 2.60 to 3.40 (m) = C-CH 2 and CH 2 -N; 4.49 (m, 3-4H including CO-N-CH 2) 4.66 (m, 1H); 4.78 (dl, P-O-CH 2 -Ph); 7, 02 and 7.15 (AA 'BB', Ph-O); 7.18 to 7.70 (m); 7.79 (dl, 1H); 7.90 (m, 1H); 8.12 (m, 1H) excess aromatic H; 8.46 (m) 9.08 (m) 2H mobile.

EXAMPLE 19 3 - [[3- [4 - [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] -2- [2- (3-hydroxyphenyl) -1-oxoethyl] -1-oxo-propyl] -amino] N- [2- (1-naphthalenyl) ethyl] -2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-1-acetamide The procedure is as in Example 18 but 3-hydroxyphenyl-acetic acid in the presence of EDC and HOBt instead of succinic acid in pyridine.

NMR (1H, DMSO) ~ 2.73 (masked) 3.05 (m) Ph-CH 2 -CH; 3. 10 to 3.40 (m) = C-CH 2 -CH 2 -NHCO; ~ 3.30 (masked = C-CH2-C =); 4.48 (m, CO-N-CH 2 -C =); 4.77 (m, CO-CH-CH 2); 4.86 (d, PO-CH2-Ph); 5.40 (split and split after exchange, CO-CH-NHCO); 7.05 and 7.16 (AA 'BB', Ph-O); 6.41 (sl, 1H); 6.49 (m, 2H) - 6.49 (m, 2H); 6.97 (m, 1H); 7.20 to 7.58 (m, 20); 7.66 (m, 1H) 7.78 (m, 1H); 7.92 (m, 1H); 8.12 (m, 1H) aromatics; 8.00 (m) 8.37 (m) 9.30 (m) 9.84 (m) H mobile.

4-[2,3-dihydro-l-[2-[(4-phênoxyphênyl)amino]-2-oxoêthyl]-3- EXAMPLE 20

4- [2,3-dihydro-l- [2 - [(4-phenoxyphenyl) amino] -2-oxoethyl] -3-

<Desc / Clms Page number 36>

[[1-oxo-2-[[(1,1-diméthyléthoxy)carbonyl]amino]-3-[4- [[hydroxy(phénylméthoxy)phosphinyl]oxy]phényl]propyl] amino]-2-oxo-lH-l,4-Benzodiazêpin-5-yl]-Benzoate de 1,1- diméthyléthyle On opère comme à l'exemple 1 mais à partir de P2 RMN (1H, DMSO)

1,31 (s,NHC02C(CH3)3) ; 1,55 (s, PhC02C (CH3) 3) 2,73 (masqué) 3,03 (m large) PhCH2-CH ; 4,73 (d,PhCH20-P) 6,90 à 8,10 26H aromatiques ; 9,20 (m) - 10,31 (s) H mobiles.

[[1-Oxo-2 - [[(1,1-dimethylethoxy) carbonyl] amino] -3- [4 - [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] propyl] amino] -2-oxo-1H- 1,1-Dimethylethyl 1,4-Benzodiazepin-5-yl] -benzoate The procedure is as in Example 1 but starting with P2 NMR (1H, DMSO)

1.31 (s, NHC02C (CH3) 3); 1.55 (s, PhCO 2 C (CH 3) 3) 2.73 (masked) 3.03 (br m) PhCH 2 CH; 4.73 (d, PhCH20-P) 6.90 to 8.10 26H aromatics; 9.20 (m) - 10.31 (s) H mobile.

4- [2, 3-dihydro-3- [ [2- [ [ (1,1-diméthyléthoxy) carbonyl] amino] -3- [4- [ [hydroxy (phénylméthoxy) phosphinyl] oxy] phényl] -1oxopropyl]amino]-2-oxo-lH-l,4-Benzodiazépin-5-yl]-Benzoate de 1,1-diméthyléthyle On opère comme à l'exemple 1 mais à partir de P2 sans procéder à une alkylation de l'azote de la benzodiazépine. EXAMPLE 21

4- [2,3-Dihydro-3 - [[2 - [[(1,1-dimethylethoxy) carbonyl] amino] -3- [4 - [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] -1-oxopropyl] amino ] 2-oxo-1H-1,4-Benzodiazepin-5-yl] -benzoate 1,1-dimethylethyl The procedure is as in Example 1 but from P2 without alkylation of the nitrogen of the benzodiazepine.

NMR (DMSO) 1.31 (s) 1.32 (s) NHCO2C (CH3) 3; 1.56 (s split, PhCO2C (CH3) 3); 2.50 (masked) 3.05 (m) Ph-CH 2 -CH; 4.30 (m, 1H) 5.26 (m, 1H) 2CH 2; 4.75 (d, J = 6, PhCH 2 O-P) 9.12 (d) 9.24 (d, 1H) CONHCH; 6.91 (m, 1H), 7.07 (m, 2H); 7.15 to 7.36 (m, 10H); 7.55 to 7.69 (m, H) 7.98 (m, 2H) aromatic H and NHCO.

4- [2, 3-dihydro-3- [ [2- [ [ (1,1-diméthyléthoxy) carbonyl] amino] -3- [4- [ [hydroxy (phénylméthoxy) phosphinyl] oxy] phényl] -1oxopropyl]amino]-2-oxo-1,4-Benzodiazépin-5-yl]-Benzoate de cyclohexylméthyle On opère comme à l'exemple 1, mais à partir de P5 (19 mg) sans procéder à l'alkylation au niveau de l'azote de la benzodiazépine. EXAMPLE 22

4- [2,3-Dihydro-3 - [[2 - [[(1,1-dimethylethoxy) carbonyl] amino] -3- [4 - [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] -1-oxopropyl] amino Cyclohexylmethyl-2-oxo-1,4-benzodiazepin-5-yl] -benzoate The procedure is as in Example 1, but starting from P5 (19 mg) without carrying out the alkylation at the nitrogen level. benzodiazepine.

 MS: Negative Electrospray: MH: 823 EXAMPLE 23 [1- [[4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2- [[2,3-dihydro-1 - [2 - [(4- phenoxyphenyl) amino] -2-oxoethyl] -2-

<Desc / Clms Page number 37>

oxo-5- [4- [ [ (méthylsulfonyl) amino] carbonyl] phényl] - 1H-1,4-Benzodiazépin-3-yllaminol-2-oxoéthyll-Carbamate de 1,1-diméthyléthyle.

1,1-Dimethylethyl oxo-5- [4- [[(methylsulfonyl) amino] carbonyl] phenyl] -1H-1,4-benzodiazepin-3-yllaminol-2-oxoethyl-carbamate.

This compound is prepared from P2 by successively carrying out the following operations: a) - action of the brominated derivative, 2-bromo-N- (4-phenoxyphenyl) acetamide (Ph-O-Ph-NHCOCH 2 Br) in the presence of NaH in DMF (12 hours at room temperature, quantitative yield). b) - hydrolysis of the terbutyl ester in the presence of trifluoroacetic acid in dichloromethane (3 hours at room temperature, yield = 88%). c) - action of methanesulfonamide (CH3SO2NH2) in the presence of EDC and HOBt (3 hours at room temperature, 75%). d) - Deprotection of the amine by action of palladium dihydroxide in the presence of magnesium oxide and cyclohexadiene (7 hours at reflux, quantitative yield); e) Coupling of the amine and phosphotyrosine as in Example 1 stage E (EDC, HOBt 1 hour at 0 C then 30 minutes at room temperature, yield = 37%). f) - Partial denzylation by the action of DABCO in refluxing toluene (2 hours, yield = 51.5%).

1097,2 Da = (M-2H) Na3+ ; 1075,5 Da (M-H)Na2+ ; 1053,3 Da = MNa+ 997,2 Da MNa±tbu + H. EXEMPLE 24

[l-[[4-[(dihydroxyphosphinyl)oxy]phênyl]mêthyl]-2-[[2,3- dihydro-1- [2- [ (4-phénoxyphényl) amino] -2-oxoéthyl] -2-oxo-5- [4- [ [ (méthylsulfonyl) amino] carbonyl] phényl] -1H-1, 4-

Benzodiazépin-3-yllaminol-2-oxoéthyll-Carbamate de 1,1- diméthyléthyle. SM:

1097.2 Da = (M-2H) Na3 +; 1075.5 Da (MH) Na2 +; 1053.3 Da = MNa + 997.2 Da MNa ± tbu + H. EXAMPLE 24

[1 - [[4 - [(Dihydroxyphosphinyl) oxy] phenyl] methyl] -2 - [[2,3-dihydro-1- [2- [(4-phenoxyphenyl) amino] -2-oxoethyl] -2-oxo -5- [4- [[(methylsulfonyl) amino] carbonyl] phenyl] -1H-l, 4-

Benzodiazepin-3-yllaminol-2-oxoethyl-1,1-dimethylethyl carbamate.

The procedure is as in Example 9 (H2-Pd / C-MeOH, 4 hours, quantitative yield) from the dibenzyl compound prepared in Example 23.

1,32 (s) 1,33 (s) C02C(CH,), ; 2,87 (s, CH3S02) ; 3, 00 Ph-CH2-CH ; 3,99 (m) 4,30 (m) CO-CH-NHCO ; 4,76 (m,CO-N-CH2CO ; 5,41 (d dédoublé, CO-CH-NHCO) ; 6,90 à 8,05 (m) 26H NMR (1H, DMSO)

1.32 (s) 1.33 (s) C02C (CH3),; 2.87 (s, CH3SO2); 3.00 Ph-CH 2 -CH; 3.99 (m) 4.30 (m) CO-CH-NHCO; 4.76 (m, CO-N-CH 2 CO, 5.41 (d split, CO-CH-NHCO), 6.90 to 8.05 (m) 26H

<Desc / Clms Page number 38>

[1- [ [4- [ [hydroxy (phénylméthoxy) phosphinyl] oxy] phényl] méthyl] - 2-[[2,3-dihydro-l-[2-[(4-phénoxyphényl) aminol-2-oxoéthyll-2oxo-5-[4-(aminocarbonyl)phényl]-1H-1,4-Benzodiazépin-3yl]amino]-2-oxoéthyll-Carbamate de 1,1-diméthyléthyle. aromatic; 9.07 (d) 9.19 (d) CO-NH-CH; 10.36 (if) CONH. EXAMPLE 25

[1 - [[4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2 - [[2,3-dihydro-1 - [2 - [(4-phenoxyphenyl) amino] -2-oxoethyl] -2-oxo] 1,1-Dimethylethyl-5- [4- (aminocarbonyl) phenyl] -1H-1,4-benzodiazepin-3-yl] amino] -2-oxoethyl-carbamate.

The procedure is as in Example 23, except in step c during which the formation of the amide is carried out by the action of SOC12 (toluene, 2 hours at reflux) and then by the action of ammonium hydroxide ( yield = 70%).

4-[2,3-dihydro-l-[2-[(4-phénoxyphényl)aminol-2-oxogthyl]3- [ [1-oxo-2- [2- [4- [hydroxy (phénylméthoxy) -phosphinyl] oxy] phényl] éthyl] amino] -2-oxo-1H-l, 4-Benzodiazépin-5-yl] - phényl-Carbamate de 1,1-diméthyléthyle On opère comme à l'exemple 23, mis à part l'étape c où on met en oeuvre le diphénylphosphorylazide (DPPA) en présence de triéthylamine dans la terbutanol 3 heures à température ambiante puis 1 heure à reflux pour obtenir l'amine protégée par le t-butyloxycarbonyl correspondant (CO2H -> NHBoc, réaction de curtius). De plus la réaction de couplage s'effectue à l'aide de P4 au lieu de N-Boc-Tyr-O(PO3Bn2). MS (MH) = 951 EXAMPLE 26

4- [2,3-Dihydro-1- [2 - [(4-phenoxyphenyl) amino-2-oxo-thyl] -3 - [[1-oxo-2- [2- [4- [hydroxy (phenylmethoxy) -phosphinyl] oxy] phenyl] ethyl] amino] -2-oxo-1H-1,4-benzodiazepin-5-yl] phenyl-1,1-dimethylethyl carbamate The procedure is as in Example 23, except for the step c where diphenylphosphorylazide (DPPA) is used in the presence of triethylamine in terbutanol for 3 hours at room temperature and then 1 hour under reflux to obtain the amine protected by the corresponding t-butyloxycarbonyl (CO2H → NHBoc, curtius reaction) . In addition, the coupling reaction is carried out using P4 instead of N-Boc-Tyr-O (PO3Bn2).

NMR (1H, CDCl3) 1.49 (si, Boc); 3.57 ([AB] = C-CH-C = O); 4.66 (d) 4.77 (d) Ph-NCH 2 -CO; 4.88 (d) 5.37 (d) = N-CH-NH-C = O; 6.95 (AA 'BB', C-Ph-O); 7.07 7.20 (AA'BB 'O-Ph-N); 7.06 (m) 7.20 to 7.70 other aromatics; 9.20 (d, = C-NH-CH), 9.60 (s) 10.26 (s) other = CNH.

4-[2,3-dihydro-l-[2-[(4-phénoxyphény1)amino]-2-oxoéthy1]3- [ [1-oxo-2- [2- [4- (dihydroxyphosphinyl) oxy] phényl] éthyl] amino] - 2-oxo-lH-1,4-Benzodiazépin-5-yll-phényl-Carbamate de 1,1- diméthyléthyle On opère comme à l'exemple 9 (H2-Pd/C, Rdt=73,4%) à partir du EXAMPLE 27

4- [2,3-Dihydro-1- [2 - [(4-phenoxyphenyl) amino] -2-oxoethyl] -3 - [[1-oxo-2- [2- [4- (dihydroxyphosphinyl) oxy] phenyl] Ethyl] amino] -2-oxo-1H-1,4-benzodiazepin-5-yll-phenyl-1,1-dimethylethyl carbamate The procedure is as in Example 9 (H 2 Pd / C, Yt = 73.4). %) from the

<Desc / Clms Page number 39>

 dibenzyl compound formed in Example 26.

3- [ [2- [4- [ [hydroxy (phénylméthoxy) phosphinyl] oxy] phényl] -1oxoéthy1]-amino]- 2,3-dihydro-N-(4-phénoxyphényl)-2-oxo-5-(4aminophényl)-1H-1,4-benzodiazépine-1-acétamide On opère comme à l'exemple 26 en ajoutant une étape de déprotection de l'amine en para du phényle, par action, avant l'étape de débenzylation, d'acide trifluoroacétique dans le dichlorométhane 1 heure 30 à température ambiante (rdt = 78%) . MS 804- = [MH] EXAMPLE 28

3- [[2- [4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] -1-oxoethyl] amino] -2,3-dihydro-N- (4-phenoxyphenyl) -2-oxo-5- (4-aminophenyl) -1H-1,4-benzodiazepine-1-acetamide The procedure is as in Example 26 by adding a deprotection step of the amine para phenyl, by action, prior to the debenzylation stage, of trifluoroacetic acid in dichloromethane 1 hour 30 at room temperature (rdt = 78%).

3- [ [2- [4- [ (dihydroxyphosphinyl) oxy] phényl] -1-oxoéthyl] amino]- 2,3-dihydro-N-(4-phénoxyphényl)-2-oxo-5-(4aminophényl)-1H-1,4-benzodiazépine-1-acétamide. MS 818Da = MNa +; 796 Da = MH + EXAMPLE 29

3- [[2- [4- [(dihydroxyphosphinyl) oxy] phenyl] -1-oxoethyl] amino] -2,3-dihydro-N- (4-phenoxyphenyl) -2-oxo-5- (4-aminophenyl) -1H -1,4-benzodiazepine-1-acetamide.

The monobenzyl compound obtained in Example 28 is completely deprotected by the action of hydrogen in the presence of Pd / C in methanol (4 hours, rdt = 90%).

NMR (1H, DMSO) 4.69 (s, CO-N-CH 2 -CO); 3.52 (s, = C-CH2-C =); 5.30 (d, s after exchange, CO-CH-NH-CO); 9.09 (d, mobile, CO-CH (N) -NHCO); 5.69 (s, broad, 2H mobile); 6.58 (dl, 2H); 6.96 (m, 5H); 7.02 to 7.15 (m, 6H); 7.20 to 7.40 (m, 8H); 7.60 (m, 5 to 6H); 10.46 (s, H mobile).

[1- [ [4- [ [hydroxy (phénylméthoxy) phosphinyl] oxy] phényl] méthyl] - 2-[[2,3-dihydro-2-oxo-5-[4-[(cyclohexylméthylamino) méthy1]phény1]-lH-l,4-Benzodiazépin-3-y1]amino]-2-oxoéthy1]- Carbamate de 1,1-diméthyléthyle. EXAMPLE 30

[1 - [[4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2 - [[2,3-dihydro-2-oxo-5- [4 - [(cyclohexylmethylamino) methyl] phenyl]] 1H-1,4-Benzodiazepin-3-yl] amino] -2-oxoethyl] -1,6-dimethylethyl carbamate.

This compound is prepared from P2 by successively carrying out the following operations: a) Deprotection of compound P2 by the action of Pd (OH) 2, MgO in the presence of cyclohexadiene in refluxing methanol (4)

<Desc / Clms Page number 40>

 hours, quantitative quantity). b) Reprotection by action of Fmoc succinimide in the presence of TEA in the mixture CH2Cl2 / DMF (24 hours at room temperature, rdt = 58%). c) Hydrolysis of the terbutyl ester in para phenyl, by action of trifluoroacetic acid in CH2Cl2 50/50 (1 hour at room temperature, rdt = 83%). d) reduction of the acid by action, firstly ethyl chloroformate and TEA in THF (1 hour at 0 ° C.), then sodium borohydride (1 hour at room temperature, yield = 87%). e) Activation of the alcohol by the action of mesyl chloride in the presence of N-ethyldiisopropylamine 1 hour at 0 ° C and (cyclohexyl methylamine) (12 hours at room temperature, rdt = 73%). f) Coupling of amine and phosphotyrosine as in Example 1 step e (EDC, HOBT in CH2Cl2, rdt = 47%) g) Partial dbenzylation by the action of DABCO in toluene at reflux for 2 hours.

4- [2, 3-dihydro-1- [2- [ (3-phénoxyphényl) amino] -2-oxoéthyl] -3- [ [1-oxo-2- [ [ (1, 1-diméthyléthoxy) carbonyl] amino] -3- [4- [ [hydroxy (phénylméthoxy) phosphinyl] oxy] phényl] propyl] amino] - 2-oxo-1H-1,4-benzodiazépin-5-yl]-benzoate de méthyle Ce composé est préparé à partir de P2 en effectuant les opérations suivantes : a) alkylation de l'azote de la benzodiazépine, par action du bromoacétate d'éthyle, saponification de l'ester et amidification par action de 3-phénoxy-benzénamine selon les stades a, b et c de l'exemple 1. b) Hydrolyse de l'ester terbutylique par action d'acide trifluoroacitique. c) Estérification (formation de l'ester méthylique) par action de CH2N2 dans le CH2C12. d) hydrogénolyse, couplage de l'amine et de la phosphotyrosine et déprotection selon les méthodes décrites aux stades d, e, et f de l'exemple 1. MS 808- = [MH] '; 810+ = MH +; 832+ = MNa + EXAMPLE 31

4- [2,3-Dihydro-1- [2- [(3-phenoxyphenyl) amino] -2-oxoethyl] -3 - [[1-oxo-2 - [[(1,1-dimethylethoxy) carbonyl] amino Methyl 3- [4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] propyl] amino] -2-oxo-1H-1,4-benzodiazepin-5-yl] benzoate This compound is prepared from of P2 by carrying out the following operations: a) alkylation of the nitrogen of the benzodiazepine, by the action of ethyl bromoacetate, saponification of the ester and amidification by the action of 3-phenoxy-benzenamine according to stages a, b and c of Example 1. b) Hydrolysis of the terbutyl ester by the action of trifluoroacitic acid. c) Esterification (formation of the methyl ester) by the action of CH2N2 in CH2Cl2. d) hydrogenolysis, coupling of amine and phosphotyrosine and deprotection according to the methods described in stages d, e and f of example 1.

<Desc / Clms Page number 41>

NMR (1H, DMSO) 1.30 (s split Boc); 2.60 to 3.08 (m, 2H); 4.01 and 4.33 (m, 1H); 3.89 (s split, C02Me); 4.01 and 4.33 (m, 1H); 4.60 to 4.90 (m, 4H); 5.43 (m, 1H); 7.02 (AA 'BB' 4H); 6.48 (m, 1H); 7.10 to 7.50 (m, 15H); 7.68 (m, 4H); 8, 03 (d split, 2H); 9.13 (sl); 9.21 (sl); 10.30 (sl).

Acide-4-[2,3-dihydro-l-[2-[(3-phénoxyphény1)amino]-2oxoéthyl] -3- [ [1-oxo-2- [ [ (1,1-diméthyléthoxy) carbonyl] amino] - 2-oxo-lH-l,4-benzodiazêpin-5-yl]-benzoique Ce composé est préparé à partir de P2 en effectuant les opérations suivantes : a) Alkylation de l'azote de la benzodiazépinone par action du bromoacétate d'éthyle, saponification de l'ester et amidification, par action de 3-phénoxy-benzénamine selon les stades a, b, et c de l'exemple 1. b) Hydrolyse de l'ester terbutylique par action d'acide trifluoroacétique. c) Hydrogénolyse, couplage de l'amine avec la phosphotyrosine et déprotection selon la méthode décrite aux stades d, e et f à l'exemple 1. EXAMPLE 32

4- [2,3-Dihydro-1- [2 - [(3-phenoxyphenyl) amino] -2-oxoethyl] -3 - [[1-oxo-2 - [[(1,1-dimethylethoxy) carbonyl] amino acid ] - 2-oxo-1H-1,4-benzodiazepin-5-yl] benzoic acid This compound is prepared from P2 by carrying out the following operations: a) Alkylation of the nitrogen of the benzodiazepinone by the action of the bromoacetate of ethyl, saponification of the ester and amidification, by the action of 3-phenoxy-benzenamine according to stages a, b and c of Example 1. b) Hydrolysis of the terbutyl ester by the action of trifluoroacetic acid. c) Hydrogenolysis, coupling of the amine with phosphotyrosine and deprotection according to the method described in stages d, e and f in Example 1.

NMR (DMSO) 1.31 (s, split); 2.75 to 3.00 (m, 2H); 3.79 (m); 4.28 (m); 4.62 to 4.84 (m); 5.38 (d); 6.65 to 8.08 (aromatics); 9, 04 (d); 9, 13 (d); 10.40 (if).

Acide-4-[2,3-dihydro-l-[2-[(3-phénoxyphény1)amino]-2oxoëthyl] -3- [ [l-oxo-2- (amino) -3- [4- [ [ (dihydroxy)phosphinyl] oxy] phényl] propyl] amino] -2-oxo-lH-l,4-benzodiazépin-5-yl] - benzoique Ce composé est préparé à partir de P2 en effectuant les opérations suivantes : a) Alkylation de l'azote de la benzodiazépinone par action du bromoacétate d'éthyle, saponification de l'ester et amidification, par action de 3-phénoxy-benzénamine selon les stades a, b, et c de l'exemple 1. b) Hydrolyse de l'ester terbutylique par action d'acide EXAMPLE 33

4- [2,3-Dihydro-1 - [2 - [(3-phenoxyphenyl) amino] -2-oxoethyl] -3 - [[1-oxo-2- (amino) -3- [4- [[(-) - dihydroxy) phosphinyl] oxy] phenyl] propyl] amino] -2-oxo-1H-1,4-benzodiazepin-5-yl] benzoic acid This compound is prepared from P2 by carrying out the following operations: a) Alkylation of the nitrogen of the benzodiazepinone by the action of ethyl bromoacetate, saponification of the ester and amidification, by the action of 3-phenoxy-benzenamine according to stages a, b and c of Example 1. b) Hydrolysis of the Terbutyl ester by action of acid

<Desc / Clms Page number 42>

 trifluoroacetic. c) Hydrogenolysis and coupling of the amine with phosphotyrosine according to the method described in Steps d and e of Example 1. d) Action of trifluoroacetic acid in dichloromethane to obtain the expected product (total deprotection).

 NMR (1H, DMSO) 2.85 to 3.20 (m); 4.26 (sl); 4.65 to 4.81 (m); 5.4 (d); 6.73 (m, 1H) 7.00 (dl); 7.07 to 7.80 (m); 8.05 (dd, 2H) 8.45 (dt); 9, 90-10, 40 (NH).

4-[2,3-dihydro-l-[2-[(3-phênoxyphênyl)amino]-2-oxoêthyl]-3- [ [1-oxo-2- [amino] -3- [4 [ [hydroxy(phénylméthoxy)phosphinyl] oxy]phény1]propy1]amino]-2-oxo-lH-l,4-benzodiazépin-5-y1]- benzoate de 1,1-diméthyléthyle On opère comme à l'exemple 7 (stades A à F) mais à partir de P2 au lieu de Pl RMN (DMSO) 1,29 (s, Boc) 1,57 (s, Boc) ; 2,40 à 2,75 (m) ; 4,31 (m) 4,45 (d) 4,83 (d) ; 4,73 (d) ; 5,41 (dd) ; 6, 70 (m) ; 6,94 (m) 7,01 (m) ; 7,10 à 7,75 (m, H aromatiques) ; 7,65, 7,98 (m) 9,13 ; 9,22 ; 10,36 EXEMPLE 35

4-[2,3-dihydro-l-[2-[(3-phénoxyphényl)aminol-2-oxoéthyl]3- [ [1-oxo-2- [2- [4- (hydroxy(phénylméthoxy)phosphinyl) oxylphénylléthyllaminol-2-oxo-lH-1,4-benzodiazépin-5-yll- phényl-Carbamate de 1,1-diméthyléthyle Ce composé est préparé à partir de P2 en effectuant les opérations suivantes : a) Alkylation de l'azote de la benzodiazépine par action du bromoacétate d'éthyle, saponification de l'ester et amidification par action de 3-phénoxy-benzénamine selon les stades a, b, et c de l'exemple 1, b) Hydrolyse de l'ester butylique par action d'acide trifluoroacétique, c) Réaction de Curtius selon la méthode décrite à l'exemple EXAMPLE 34

4- [2,3-Dihydro-1- [2 - [(3-phenoxyphenyl) amino] -2-oxoethyl] -3 - [[1-oxo-2- [amino] -3- [4 [[hydroxy] ( 1,1-Dimethylethyl phenylmethoxy) phosphinyl] oxy] phenyl] propyl] amino] -2-oxo-1H-1,4-benzodiazepin-5-yl] benzoate The procedure is as in Example 7 (Steps A to F). ) but from P2 instead of 1M (DMSO) 1.29 (s, Boc) 1.57 (s, Boc); 2.40 to 2.75 (m); 4.31 (m) 4.45 (d) 4.83 (d); 4.73 (d); 5.41 (dd); 6, 70 (m); 6.94 (m) 7.01 (m); 7.10 to 7.75 (m, aromatic H); 7.65, 7.98 (m) 9.13; 9.22; 10.36 EXAMPLE 35

4- [2,3-Dihydro-1- [2 - [(3-phenoxyphenyl) aminol-2-oxoethyl] -3 - [[1-oxo-2- [2- [4- (hydroxyphenylmethoxy) phosphinyl) oxylphenyl] ethyl) aminolaminol 2-oxo-1H-1,4-benzodiazepin-5-yll-phenyl-1,1-dimethylethyl carbamate This compound is prepared from P2 by carrying out the following operations: a) Alkylation of the nitrogen of the benzodiazepine by action of ethyl bromoacetate, saponification of the ester and amidification by the action of 3-phenoxy-benzenamine according to stages a, b and c of Example 1; b) hydrolysis of the butyl ester by the action of trifluoroacetic acid, c) Curtius reaction according to the method described in the example

<Desc / Clms Page number 43>

 26 (DPPA / TEA / tBuOH), d) Hydrogenolysis, amine coupling and phosphotyrosine and deprotection according to the method described in Steps d, e, and f of Example 1.

NMR (1H, DMSO) 1.31 (s, 9H); 2.60 to 3.2 (m, 2H); 4.0 to 4.7 (m, 3H): 4.78 (dl, 2H); 5.38 (m, 1H); 6.71 (t, 1H); 7.0 (d, 1H); 7.1 (m, aromatics); 7.2 to 7.9 (m, aromatics); 9.20 (d, NH); 9.33 (d, NH); 9.65 (sl, NH); 10.38 (sl, NH).

Acide 4- [2, 3-dihydro-1- (2- [ (3-phénoxyphényl) amino] -2oxoéthyl] 3- [ [1-oxo-2- [ [ (1,1-diméthyléthoxy) carbonyl] amino] -3- [4- [ [dihydroxy(phosphinyl] oxy] phényl] propyl] amino] -2-oxo-1H- 1,4-benzodiazépin-5-yl]-benzoïque On opère comme à l'exemple 33, la dernière étape de déprotection s'effectuant ici avec de l'hydrogène en présence de Pd/C (cf exemple 9). EXAMPLE 36

4- [2,3-Dihydro-1- (2 - [(3-phenoxyphenyl) amino] -2-oxoethyl] 3 - [[1-oxo-2 - [[(1,1-dimethylethoxy) carbonyl] amino] - 3- [4- [[Dihydroxy (phosphinyl] oxy] phenyl] propyl] amino] -2-oxo-1H-1,4-benzodiazepin-5-yl] benzoic The procedure is as in Example 33, the last step deprotection taking place here with hydrogen in the presence of Pd / C (see Example 9).

 NMR (1H, DMSO) 1.30 and 1.32 (s, Boc); 2.70 to 3.10 (m, 2H); 3.95 (m); 4.19 (m); 4.60 to 4.85 (m); 5.37 (d); 6.67 (m, 1H); 6.9 to 7.4 (m, 14H); 7.59 (m, 4H); 8.01 (m, 2H); 9.14 (m); 10.48 (brs).

4- [2, 3-dihydro-1- [2- [ [2- (1-naphtalényl) éthyl] amino] -2oxoéthyl]-3-[I1-oxo-2-[[(1,1-diméthyléthoxy)carbonyl]amino]- 3- [4- [ [hydroxy(phénylméthoxy)phosphinyl] oxy] phênyl]propyl]amino]-2-oxo-lH-l,4-Benzodiazêpin-5-yl]- Benzoate de 1,1-diméthyléthyle On opère comme à l'exemple 32 mais en mettant en oeuvre le 1Naphtalèneméthanamide. EXAMPLE 37

4- [2,3-Dihydro-1- [2- [[2- (1-naphthalenyl) ethyl] amino] -2-oxoethyl] -3- [I1-oxo-2 - [[(1,1-dimethylethoxy) carbonyl] ] amino] - 3- [4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] propyl] amino] -2-oxo-1H-1,4-benzodiazepin-5-yl] -benzoate 1,1-dimethylethyl The procedure is as in Example 32 but using 1Naphthalenemethanamide.

NMR (1H, DMSO) 1.33-1.37 (s, 9H, Boc); 2.70 to 3.10 (m); 4.30 to 4.85 (m, 6H); 5.35 (m, 1H); 6.92 to 8.11 (m, aromatics); 8.77 (tl, 1H); 9.07 (m, 1H).

Pharmacological study of the products of the invention: IC50 measurement by scintillation proximity test (SPA).

The ability of molecules to bind to the SrcSH2 protein is

<Desc / Clms Page number 44>

 evaluated 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 plates and then with 50nM of pre-biotinylated SH2 protein and then with the ligand EPQpYEEIPIYL labeled with iodine 125. By binding to the protein fixed on the ball the ligand activates 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.

The test molecules are diluted in MOPS buffer containing 2% DMSO and added at different concentrations of 0.1M to 100M in the wells containing the ligand, prior to the addition of 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> 7 <SEP> 20 <SEP>
<tb> 7a <SEP> 25 <SEP>
<tb> 7b <SEP> 7 <SEP>
<tb> 22 <SEP> 38 <SEP>
<tb> 27 <SEP> 14 <SEP>
<tb> 29 <SEP> 18 <SEP>
<tb> 32 <SEP> 15 <SEP>
<tb> 33 <SEP> 30 <SEP>
<Tb>

Claims (17)

 OCH (SO3Rd) (CO2Rc) and CH (CH2CO2Rd) (CH2CO2Re);

 selected from - (CH2) m-Alk, - - (CH2) m -Ar, (CH2) m -Het, - (CHRa) -CO- (CH2) m-Alk, - (CHRa) -CO- (CH2) m-Ar, - (CHRα) -CO- (CH 2) m -Het, - (CHR a) -CONR 1 - (CH 2) m-Alk, - (CHR a) - CONR 1 - (CH 2) m - Ar, - (CHR a) - CONRi - (CH2) m - He t, - (CHRa) -CO2- (CH2) m-Alk, and - (CHRa) CO2- (CH2) m -Ar, m being equal to 0.1, 2.3 or 4; R2 represents a hydrogen atom or a group chosen from CO2Rb, CONHRb, NHRb, NHCORb, NHSORb, CONHS02Rb, NHC02Rb, CH20H, alkyl, alkenyl, alkynyl and cycloalkyl, said groups being substituted or unsubstituted; - [A1] represents a group chosen from CH (Z) -CH2- (Arl), [CH2) 1- (Arl), CH (Z) -CH2- (Hetl), (CH2) 1- (Hetl) in which Z is hydrogen, tetrazole, NH2, NHCORc, NHCO2Rc, NHSORc or NHSO2Rc and 1 is an integer of 0.1 or 2; [A2] represents a group chosen from OPO (ORd) (Ore), B (ORd) (ORe), CRfRgPO (ORd) (ORe), CH [PO (ORd) (ORe)] 2, CRfRgC02Rd, CH (CO2Rd ) (C02Re),

 in which - R1 represents a hydrogen atom, a grouping

 Claims 1) Compounds of formula (I) <Desc / Clms Page number 46>  Alk represents an alkyl, alkenyl or alkynyl radical containing from 1 to 6 carbon atoms, or cycloalkyl containing from 3 to 12 carbon atoms, said radicals being substituted or unsubstituted; Ar representing a substituted or unsubstituted aryl, Het representing a substituted or unsubstituted heterocycle; Ra, Rb, Rc, Rd, Re or Ri, identical or different, representing a hydrogen atom, an alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl) alkyl, aryl or aralkyl radical, said radicals being substituted or unsubstituted ; (Arl) representing a substituted or unsubstituted bivalent aryl and (Hetl) representing a substituted or unsubstituted bivalent heterocycle; Rf and Rg identical or different representing a hydrogen atom, a halogen, a CO2Rd radical, SO3Rd, PO (ORd) (ORe) or tetrazole; the said compounds of formula (I) being in all their possible stereoisomeric forms, isolated or in mixtures and their addition salts with pharmaceutically acceptable acids and bases. 2) Compounds according to claim 1 having the general formula (la)

 wherein R1 and R2 are as defined in claim 1, Rd is hydrogen or benzyl, and Z is NHCORc, NHC02Rc or NH2, wherein Rc is as defined in claim 1. <Desc / Clms Page number 47>  3) Compounds according to claim 1 having the general formula (Ib)

 wherein 1, R 1 and R 2 are as defined in claim 1, and Rd is hydrogen or benzyl. 4) Compounds of formula (I), (la) or (Ib) according to any one of claims 1 to 3 wherein R1 represents a hydrogen atom or a group selected from

 -CH 2 CONH- (CH 2) m -Ar, -CH 2 CONH- (CH 2) m -Het, - (CH 2) m-Alk and - (CH 2) m -cycloalkyl, m, Alk, Ar and Het being as defined in claim 1. 5) Compounds according to claim 4 characterized in that Ar represents a group Napht-1-yl, Napht-2-yl, phenyl, 1,3-benzodioxol-5-yl, biphenyl, m- (phenyloxy) phenyl or p- (phenyloxy) phenyl, and Het represents an indolyl group. 6) Compounds of formulas (I), (la) or (Ib) according to any one of claims 1 to 5 wherein R2 is a hydrogen atom. 7) Compounds of formulas (I), (la) or (Ib) according to any one of claims 1 to 5 wherein R2 represents CO2Rb, Rb being as defined in claim 1. 8) Compounds of formulas (I), (Ia) or (Ib) according to any one of claims 1 to 5 in which R2 <Desc / Clms Page number 48>  represents NHC02Rb or NHSO2Rb being as defined in claim 1. 9) Compounds of formulas (I), (Ia) or (Ib) as defined in one of claims 1 to 8 in which the optional substituents, - alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl or heterocycle radicals or bivalent groups (Arl) and (Het) may be chosen from one or more of the following radicals: halogen, (C 1 -C 6) alkyl optionally substituted by one or more halogen atoms, cyclo (C 3 -C 12) alkyl nitro formyl, carboxy, alkoxycarbonyl, (C 2 -C 6) alkoxy,

 methylenedioxy, amino, (C 1 -C 6) alkylamino, (C 2 -C 12) dialkylamino optionally in oxidized form, hydroxyl optionally acylated, (C 2 -C 6) -acyl, aryl or aryloxy optionally substituted with the radicals above. 10) Compounds of formulas (I) according to claim 1 whose names follow: - [1- [[4 [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl]

 methyl] -2- [[2,3-dihydro-1- [2- [(4-phenoxyphenyl) amino] -2-oxoethyl] -2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl] 1,1-dimethylethyl amino] -2-oxoethyl] -carbamate, - [1- [[4- [[bis (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -

 2- [[2,3-Dihydro-1- [2- [[(1-naphthalenyl) methyl] amino] -2-oxoethyl] -2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl] amino] -2-oxoethyl] -1,1-dimethylethyl carbamate, - [1 - [[4 [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl]

 methyl] -2 - [[2,3-dihydro-1- [2 - [[(1,3-benzodioxolan-5-yl) methyl] amino] -2-oxoethyl] -2-oxo-5-phenyl-1H 1,1-Dimethylethyl -1,4-Benzodiazepin-3-yl] amino] -2-oxoethyl] carbamate, - [1 - [[4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl]

 methyl] -2- [[2,3-dihydro-1- [2- [[(2-naphthalenyl) methyl] amino] -2-oxoethyl] -2-oxo-5-phenyl-1H-1,4-benzodiazepine 1,1-Dimethylethyl] - [1 - [[4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] -3-yl] amino] -2-oxoethyl] carbamate

 methyl] -2- [[2,3-dihydro-1- [2- [[1H-indol-5-yl] amino] -2-oxoethyl] -2-oxo-5-phenyl-1H-1,4-benzodiazepine 1,1-dimethylethyl 3-yl] amino] -2-oxoethyl] carbamate <Desc / Clms Page number 49>  - [1 - [[4- [[Dihydroxyphosphinyl] oxy] phenyl] methyl] -2 - [[2,3-dihydro-1- (3-cyclohexylpropyl) -2-oxo-5-phenyl] -1H-1,4-

 methyl] -2 - [[2,3-dihydro-1- (3-cyclohexylpropyl) -2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl] amino] -2-oxoethyl] carbamate 1,1-dimethylethyl,

 dihydro-1- [2- [(2-cyclohexylethyl) methylamino] -2-oxoethyl] -2oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl] amino] -2-oxoethyl] carbamate 1 , 1-dimethylethyl, - [1 - [[4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl]

 methyl] -2 - [[2,3-dihydro-1- [2 - [(2-cyclohexylethyl) methylamino] -2-oxoethyl] -2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl ] amino] -2-oxoethyl] -1,1-dimethylethyl carbamate, 2- [1- [[4- [[dihydroxyphosphinyl] oxy] phenyl] methyl] -2- [[2,3-dimethyl] -2-oxoethyl] carbamate;

 - [1 - [[4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2 - [[2,3-dihydro-1- [2- [[(4-phenoxyphenylmethyl] amino] -2- 1-Dimethylethyl 2-oxoethyl] -2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl] amino] -2-oxoethyl] carbamate; [hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl]

 methyl] -2- [[2,3-dihydro-1- [2- [[[(1,1'-biphenyl] -4-yl] methyl] amino] -2-oxoethyl] -2-oxo-5-phenyl- 1,1-1,4-Benzodiazepin-3-yl] amino] -2-oxoethyl] -1,1-dimethylethyl carbamate,

 methyl] -2- [[2,3-dihydro-1- [2- [[2- (1-naphthalenyl) ethyl] amino] -2-oxoethyl] -2-oxo-5-phenyl-1H-1,4 1,1-Dimethylethyl -benzodiazepin-3-yl] amino] -2-oxoethyl-carbamate, - [1- [[4- [(dihydroxy) phosphinyl] oxy] phenyl] methyl] -2- [[2,3-dihydro] 1- [2- [[2- (1-Naphthenyl) ethyl] amino] -2-oxoethyl] -2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl] amino] -2-oxoethyl] 1,1-Dimethylethyl carbamate, [1- [[4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl]

 1,1-Dimethylethyl [oxoethyl] -2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl] amino] -2-oxoethyl] carbamate, - [1- [[4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl]

 methyl] -2 - [[2,3-dihydro-1- [2 - [(9-ethyl-9H-carbazol-3-yl) amino] -2-oxoethyl] -2-oxo-5-phenyl-1H- 1,1-Dimethylethyl 1,4-Benzodiazepin-3-yl] amino] -2-oxoethyl] carbamate; [1- [[4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2- [ [2,3-dihydro-l- [2 - [(3-phenoxyphenyl) amino] -2-

 - [1 - [[4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] <Desc / Clms Page number 50>  - [1 - [[4- [(dihydroxyphosphinyl) oxy] phenyl] methyl] -2 - [[2,3-dihydro-1 - [2 - [(4-phenoxyphenyl) amino] -2-oxoethyl] -2-oxo] 1- [4 - [[(methylsulfonyl) amino] carbonyl] phenyl] -1H-1,4-benzodiazepin-3-yl] amino] -2-oxoethyl] -1,4-dimethylethyl carbamate;

 methyl] -2- [[2,3-dihydro-1- [2- [(4-phenoxyphenyl) amino] -2-oxoethyl] -2-oxo-5- [4- [[(methylsulfonyl) amino] carbonyl] phenyl] 1,1-Dimethylethyl 1H-1,4-Benzodiazepin-3-yl] amino] -2-oxoethyl] carbamate

 cyclohexylmethyl oxopropyl] amino] -2-oxo-1,4-benzodiazepin-5-yl] benzoate, - [1 - [[4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl]

 1,1-Dimethylethyl-oxo [propyl] amino] -2-oxo-1H-1,4-benzodiazepin-5-yl] -benzoate, - 4- [2,3-dihydro-3- [[2- [[(1 1-dimethylethoxy) carbonyl] amino] -3- [4 - [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] -1-

 (1-naphthalenyl) ethyl] -2,3-dihydro-2-oxo-5-phenyl-1H-1,4benzodiazepine-1-acetamide, 4- [2,3-dihydro-1 - [2 - [(4 phenoxyphenyl) amino] -2-oxoethyl] -3- [[1-oxo-2 - [[(1,1-dimethylethoxy) carbonyl] amino] -3- [4 - [[hydroxy (phenylmethoxy) phosphinyl] oxy] 1,1-Dimethylethyl phenyl] propyl] amino] -2-oxo-1H-1,4-benzodiazepin-5-yl] benzoate, - 4- [2,3-dihydro-3- [[2- [[ (1,1-dimethylethoxy) carbonyl] amino] -3- [4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] -1-

 phenyl-1H-1,4-benzodiazepine-1-acetamide, - 4 - [[1- [4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2- [[2,3-dihydro]] acid; 1- [2- [[2- (1-naphthalenyl) ethyl] amino] -2-oxoethyl] -2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl] amino] -2-oxoethyl] amino] -4-oxo-butanoic acid - 3 - [[3- [4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] -2- [2- (3-hydroxyphenyl) -1-oxoethyl] -1- oxo-propyl] -amino] -N- [2-

 3 - [[3- [4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] -1-oxopropyl] amino] -2,3-dihydro-N- [2- (1-naphthalenyl) ethyl] - 2-oxo-5-phenyl-1H-1,4-benzodiazepine-1-acetamide; 3-[[2- [4 - [[hydroxy (phenylmethoxy) phosphinyl] oxy. ] phenyl] -1-oxoethyl] amino] -2,3-dihydro-N- (1H-indol-5-yl) -2-oxo-5-

 1,1-Dimethylethyl benzodiazepin-3-yl] amino] -2-oxoethyl] carbamate <Desc / Clms Page number 51>  methyl] phenyl] -1H-1,4-benzodiazepin-3-yl] amino] -2-oxoethyl] 1,1-Dimethylethyl carbamate, 4- [2,3-dihydro-1- [2- [(3 phenoxyphenyl) amino] -2-oxoethyl] -3- [[1-oxo-2 - [[(1,1-dimethylethoxy) carbonyl] amino] -3- [4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] Methyl phenyl] propyl] amino] -2-oxo-1H-1,4-benzodiazepin-5-yl] benzoate, - 4- [2,3-Dihydro-1- [2 - [(3-phenoxyphenyl) -acid] ) amino] -2-oxoethyl] -3 - [[1-oxo-2 - [[(1,1-dimethylethoxy) carbonyl] amino] -2-oxo-1H-1,4-benzodiazepin-5-yl] benzoic acid, - 4- [2,3-Dihydro-1- [2- [(4-phenoxyphenyl) amino] -2-oxoethyl] -3 - [[1-oxo-2- (amino) -3- [4- (Dihydroxy) phosphinyl] oxy] phenyl] propyl] amino] -2-oxo-1H-1,4-benzodiazepin-5-yl] benzoic acid, 4- [2,3-dihydro-1- [2- [(3 phenoxyphenyl) amino] -2-oxoethyl] -3- [[1-oxo-2- [amino] -3- [4 [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] propyl] amino] -2-oxo] 1,1-Dimethylethyl-1H-1,4-benzodiazepin-5-yl] benzoate, - 4- [2,3-dihydro-1 - [2- [(3-Phenoxyphenyl) amino] -2-oxoethyl] 3

 aminophenyl) -1H-1,4-benzodiazepine-1-acetamide, [1- [[4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2 - [[2,3-dihydro-2- oxo-5- [4 - [(cyclohexylmethylamino)

 aminophenyl) -1H-1,4-benzodiazepine-1-acetamide, 3-[[2- [4- [(dihydroxyphosphinyl) oxy] phenyl] -1-oxoethyl] amino] -2,3-dihydro-N- (4-phenoxyphenyl) -2-oxo-5- (4-

 4- [2,3-Dihydro-1- [2 - [(4-phenoxyphenyl) amino] -2-oxoethyl] 3 - [[1-oxo-2- [2- [4- [hydroxy (phenylmethoxy)] - Phosphinyl] oxy] phenyl] ethyl] amino] -2-oxo-1H-1,4-benzodiazepin-5-yl] phenyl-1,1-dimethylethyl carbamate, - 4- [2,3-dihydro-1 - [ 2- [(4-Phenoxyphenyl) amino] -2-oxoethyl] -3 - [[1-oxo-2- [2- [4- (dihydroxyphosphinyl) oxy] phenyl] ethyl] amino] -2-oxo-1H-1 1,1-Dimethylethyl 4-Benzodiazepin-5-yl] -phenyl-carbamate, 3- [[2- [4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] -1-oxoethyl] amino] 2,3-Dihydro-N- (4-phenoxyphenyl) -2-oxo-5- (4-

 - [1 - [[4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2 - [[2,3-dihydro-1- [2- [(4-phenoxyphenyl) amino] -2-oxoethyl] -2- 1,1-Dimethylethyloxo-5- [4- (aminocarbonyl) phenyl-1H-1,4-benzodiazepin-3-yl] amino] -2-oxoethyl] carbamate

<Desc / Clms Page number 52>  [[1-Oxo-2- [2- [4- (hydroxy (phenylmethoxy) phosphinyl) oxy] phenyl] ethyl] amino] -2-oxo-1H-1,4-benzodiazepin-5-yl] phenylcarbamate 1,1-Dimethylethyl, 4- [2,3-dihydro-1- [2- [(3-phenoxyphenyl) amino] -2oxoethyl] 3 - [[1-oxo-2- [[(1, 1 dimethylethoxy) carbonyl] amino] -3- [4 - [[dihydroxy (phosphinyl] oxy] phenyl] propyl] amino] -2-oxo-1H-1,4-benzodiazepin-5-yl] benzoic acid, 4- [ 2,3-Dihydro-1- [2- [[2- (1-naphthalenyl) ethyl] amino] -2-oxoethyl] -3 - [[1-oxo-2 - [[(1,1-dimethylethoxy) carbonyl] amino] ] - - [Methyl] - [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] propyl] amino] -2-oxo-1H-1,4-benzodiazepin-5-yl] -benzoate 1,1-dimethylethyl.

11) Process for the preparation of the compounds of formulas (I) as defined in claim 1, characterized in that it comprises the following steps: a) a compound of formula (II) is subjected

 wherein R2 is as defined in claim 1 to the action of the acid of formula (III)

 Rb being as defined in claim 1, to obtain the compound of formula (IV) <Desc / Clms Page number 53>  c) the compound of formula (V) is cyclized in an acid medium in order to obtain the compound of formula (VI)

 b) subjecting the compound of formula (IV) to the action of ammonia in order to obtain the compound of formula (V)

<Desc / Clms Page number 54>  [Al 2] - [Al] -CO 2 H, [Al] being as defined in claim 1 and [A'2] representing in addition to the values of [A2], the hydroxy radical, ii) is, after returning to the free amine, with the action of [A '2] - [A1] -CO 2 H in order to obtain the compound of formula (VI' ')

 then to action, after returning to the free amine, to

 d) subjecting the compound of formula (VI) i) if appropriate, to the action of R'1X in the presence of a base, R'1représentant in addition to the values of Rl, (CHRa) -CO2Rc, and X representing a halogen to obtain a compound of formula (VI ')

<Desc / Clms Page number 55>  the action of NHRi- (CH2) m-Alk, NHRi- (CH2) m -Ar or NHRi- (CH2) m -Het, in the presence of a coupling agent, when R'1 represents the

 corresponding to certain compounds of formulas (I), the compounds of formulas (VI), (VI '), (VI' ') or (II) being able, if desired or if necessary, to undergo one or more of the following reactions in an appropriate order : - action of a monodebenzylation agent when [A'2] represents OPO (OBn) 2, - action of a total deprotection agent,

 then to the action, where appropriate of R'1X in the presence of a base in order to obtain in both cases (i, ii) a compound of formula (II).

<Desc / Clms Page number 56>  group -CHRa-CO2H, - action of P (O) (H) (ORd) (ORe) when [A'2] represents OH, - obtaining different values of R2 from the carboxylic acid (R2 = CO2H) corresponding, - obtaining the different values of Z (NHCORc, NHSORc, NHC02Rc, NHSO2Rc) from the corresponding amine (Z = NH2), - salification. 12) Process for the preparation of the compounds of formulas (II) with R2 = CO2Rb as defined in claim 11 in which the amide of formula (IIa) is subjected

 to the action of bromoaryl of formula (IIb)

 Rb being as defined in claim 1, in the presence of a base such as n-butyllithium to obtain the compound of formula (II) with R2 = CO2Rb

 13) As medicaments, the compounds of formulas (I), (Ia), (Ib) and their pharmaceutically acceptable addition salts, as defined in any one of claims 1 to 9. <Desc / Clms Page number 57> 14) As medicaments, the compounds of formulas (I) and their pharmaceutically acceptable addition salts as defined in claim 10. 15) Medicaments for the prevention or treatment of osteoporosis as defined in claims 13 or 14. 16) Pharmaceutical compositions containing as active ingredient at least one of the medicaments as defined in claims 13 to 15. 17) As intermediate compounds, the compounds of general formulas (II), (IV), (V), (VI), (VIa), (VIb), (II) as defined in claim 11, being understood that the compounds of formulas (II), (IV), (V) and (VI) with R2 representing a hydrogen atom are excluded