FR2781483A1 - Thioazepinone derivatives having Src domain SH2 inhibiting and osteoclast-mediated calcium resorption from bone inhibiting activity, for treatment of osteoporosis - Google Patents

Abstract

Thioazepinone derivatives (I) their isomers, salts, and prodrugs are new. (I) are of formula (Q): R1 and R2 = either H, or they are the same or different and are 1-8C alkyl, OH, 1-8C alkoxy, -COORa, CONRaRb, amino, 1-8C alkylamino, di-1-8C alkylamino, 5 - 14C aryl, or saturated or unsaturated heterocycle, the aryl, alkyl and heterocyclyl groups being optionally substituted by R6, or together R1 and R2 form the residue of an aromatic or heteroaromatic ring which may be substituted by R6; R5 = R'5, R5, or R'5; R'5 = alkyl, alkenyl, alkynyl, aryl, aryl alkyl, aryl alkenyl, aryl alkynyl, cycloalkyl, cycloalkyl alkyl, cycloalkyl alkenyl, cycloalkyl or alkynyl, the alkyl, alkenyl and alkynyl groups have up to 8C, aryl groups have 5 - 14C, and cycloalkyl groups have 3 - 18C, all of these being optionally substituted by R6; R5 = -CHRh-COR'5, or -CHRh-CONHR'5; R5 = H; -(A1)- = -CH(Z)-(1-4C alkylene)-(5-14C aryl)-, -C(Z)=CH-(5-14C aryl)-, -C(Z)=CH-(1-2C alkylene)-(5-14C aryl)-, -CH(Z)-(5-14C aryl), -(1-4C alkylene)-(5-14C aryl)-, -(5-14C aryl)-, )-(1-4C alkylene)-NHCO-(5-14C aryl)-, or -NH-(5-14C aryl)-, these radicals being optionally substituted by R6; Z = H, tetrazole, NRbRc, NHCORb, CONHRb, NHCOCOORb, NHCONHRb, or NHSO2Rb; A2 = -PO(ORd) (ORe), -OPO(Rd) Re), -B(ORd) (ORe), -CRfRgPO(ORd) (ORe), -O-CRfRgPO(ORd) (ORe), -CRfRgCOORd, -CRf(COORd)2, -OCRfRgCOORd, -OCRf(COORd)2, -N(CRfRgCOORd)2, -COORd, -CRfRgCH2-COORd, -CRfRgSO3H, -OCRfRgSO3H, -OSO3H, -OSO2NH2, -NHCO-PO(ORd)(ORe), -OH, or -O-CORd; R3, R4, Ra, Rb, Rc, Rd, Re, Rh, and Ri = 1-8C alkyl, 3-18C cycloalkyl, cycloalkyl alkyl, 5-14C aryl or arylalkyl, these groups being optionally substituted by R6, or R3-C- R4 may form a 3-6 membered cycloalkyl group; Rf and Rg = H, halogen, ORc, NHRc, COORc, CH2COORc, SO3H, PO(ORd)(ORe), or tetrazole; R6 = alkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, 1-3C alkylene dioxy, aryl, heterocyclyl, aryloxy, arylalkyl, aryl alkoxy, halogen, trihalomethyl, trihalomethoxy, trihalomethyl carbonyloxy alkyl, OH, NO2, CHO, -C=N-NH-CONH2, CN, COOH, -CONH2, alkoxycarbonyl, alkyl carbonyloxy, NH2, alkylamino, dialkylamino, alkyl carbonylamino, aryl carbonylamino, alkylamino carbonyl, arylamino carbonyl, alkyl carbonyl, aryl carbonyl, alkyl sulfonyl, aryl sulfonyl, arylsulfonyl alkyl, alkyl amino sulfonyl, aryl amino sulfonyl, cycloalkylamino sulfonyl, cycloalkyl alkyl aminosulfonyl, or heterocyclyl sulfonyl, in which alkyl and alkoxy have 1 - 4 C, aryl has 5-14C, and heterocyclyl is saturated with 5 or 6 members and may have a second O, N, or S hetero atom, or R6 and A2 together may form a 5-membered ring of formulae (a) and (b); R'6 = has the same meanings as A2; U = CO, CS, SO, SO2, or 1-4C alkylene that may be unsaturated, and the dotted line = an optional double bond. Independent claim covers intermediates of formula (III') and (III):

Description

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 The subject of the present invention is thioazepinone derivatives, process for their preparation and the intermediates of this process, their application as medicaments and the pharmaceutical compositions containing them.

dans laquelle soit R1 et R2, identiques ou différents, représentent un atome d'hydrogène, un radical alkyle, alkényle, alkynyle, hydroxy, alkoxy, amino, alkylamino, dialkylamino, un aryle, un hétérocycle ou un groupement C(O)Y dans lequel Y représente un radical hydroxy, alkoxy, amino, alkylamino ou dialkylamino, soit R1 et R2 forment ensemble le reste d'un cycle aromatique ou d'un hétéroaryle, R3 et R4, identiques ou différents représentent un atome d'hydrogène, un radical alkyle, alkényle, alkynyle, un aryle ou un hétérocycle, R5 représente un atome d'hydrogène, un radical alkyle, alkényle, alkynyle, arylalkyle, cycloalkyle, (cycloalkyle)alkyle, (cycloalkyl)alkényle ou (cycloalkyl)alkynyle, un groupement (CHR6)-CO-(CH2)m-Ar, (CHR6)-CO-(CH2)m-Het, (CHR6)-CONH- (CH2)m-Ar,(CHR6)-CONH-(CH2)m-Het, dans lequel les termes Ar et Het représentent respectivement un aryle ou un hétérocycle, R6 représente un atome d'hydrogène, un radical alkyle, alkényle, alkynyle, un aryle ou un hétérocycle, X représente un atome d'oxygène, de soufre ou NH, [Al] représente l'un des groupements divalents suivants -CH(Z)-CH2-(Ari)-, -(CH2)1-(Arl)-, -CH(Z)-CH2-(Hetl)-, The subject of the present invention is the compounds of formula (I)

in which either R1 and R2, which may be identical or different, represent a hydrogen atom, an alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, alkylamino or dialkylamino radical, an aryl, a heterocycle or a C (O) Y group in Y represents a hydroxyl, alkoxy, amino, alkylamino or dialkylamino radical, or R1 and R2 together form the residue of an aromatic ring or of a heteroaryl, R3 and R4, which are identical or different, represent a hydrogen atom, a radical alkyl, alkenyl, alkynyl, an aryl or a heterocycle, R5 represents a hydrogen atom, an alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, (cycloalkyl) alkyl, (cycloalkyl) alkenyl or (cycloalkyl) alkynyl radical, a group ( CHR6) -CO- (CH2) m -Ar, (CHR6) -CO- (CH2) m -Het, (CHR6) -CONH- (CH2) m -Ar, (CHR6) -CONH- (CH2) m -Het in which the terms Ar and Het respectively represent an aryl or a heterocycle, R6 represents a hydrogen atom, an alkyl, alkenyl, alkynyl, an aryl radical, ye or a heterocycle, X represents an oxygen, sulfur or NH atom, [Al] represents one of the following divalent groups -CH (Z) -CH2- (Ari) -, - (CH2) 1- (Arl ) -, -CH (Z) -CH2- (Hetl) -,

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CR1QR11PO(OR8) (0R9), CH[PO(OR8)(OR9)]2, COOR8, CR10R11-COORa' CH(COORB)(COOR9), CH(S03R8)(COOR9), O-CR1R11-COORB, OCH(COOR8)(COOR9), O-CH(S03R8)(COOR9) ou CH(CH2COOR8)(CH2COOR9), dans lesquels R8 et Rg, identiques ou différents, représentent un atome d'hydrogène, un radical alkyle ou un radical arylalkyle, R10 et R11 identiques ou différents représentent un atome d'hydrogène, un halogène, un radical COORg, S03R8, PO(OR8)(OR9) ou tétrazole, lesdits alkyle, alkényle ou alkynyle, renferment de 1 à 6 atomes de carbone et sont substitués ou non substitués, lesdits aryles et hétérocycles sont substitués ou non substitués, le radical cycloalkyle renferme de 3 à 12 atomes de carbone, 1 et m sont égals à 0,1, 2 ou 3, les traits en pointillés indiquent la présence d'une double liaison éventuelle, lesdits composés de formule (I) étant sous toutes leurs formes stéréoisomères possibles, isolés ou en mélanges, ainsi que leurs sels d'addition avec les acides et les bases pharmaceutiquement acceptables et les esters de ces composés. - (CH2) 1- (Hetl) -, -CH2NHCO- (Arl) -, CH2NHCO- (Hetl) -, - NH- (Arl) - or -NH- (Hetl) - in which, (Arl) is an aryl bivalent, (Hetl) is a divalent heterocycle, and Z is a hydrogen atom, an NH2 or NHP radical, P being a protective group of the amine or a group C (O) R7, R7 representing an alkyl radical, alkenyl , alkynyl, aryl, heterocycle, alkyloxy, alkenyloxy, alkynyloxy, aryloxy or arylalkyloxy, [A2] represents OPO (OR8) (OR9), B (OR8) (OR9),

CR1QR11PO (OR8) (OR9), CH [PO (OR8) (OR9)] 2, COOR8, CR10R11-COORa 'CH (COORB) (COOR9), CH (SO3R8) (COOR9), O-CR1R11-COORB, OCH ( COOR8) (COOR9), O-CH (SO3R8) (COOR9) or CH (CH2COOR8) (CH2COOR9), in which R8 and Rg, which may be identical or different, represent a hydrogen atom, an alkyl radical or an arylalkyl radical, R10 and R 11, which may be identical or different, represent a hydrogen atom, a halogen, a COORg, SO 3 R 8, PO (OR 8) (OR 9) or tetrazole radical, said alkyl, alkenyl or alkynyl radicals contain from 1 to 6 carbon atoms and are substituted or unsubstituted, said aryl and heterocycle are substituted or unsubstituted, the cycloalkyl radical contains from 3 to 12 carbon atoms, 1 and m are equal to 0.1, 2 or 3, the dotted lines indicate the presence of a double possible bond, said compounds of formula (I) being in all their possible stereoisomeric forms, isolated or in mixtures, as well as their addition salts with acids and bases pharmaceutically acceptable salts and the esters of these compounds.

 By alkyl or alkenyl 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-methyl pentyl, 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 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

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 a radical derived from a fused bicyclic or tricyclic hydrocarbon having a benzene ring such as indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl or fluorenyl, the joining occurring in the benzene ring. It is preferably phenyl or naphthyl.

 Heterocycle is understood to mean a saturated or unsaturated aromatic (or 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, thiazolyl, oxazolyl, furazanyl, pyrrolinyl, imidazolinyl, pyrazolinyl, thiazolinyl and triazolyl radicals, tetrazolyl, - heterocyclic fused rings, eg benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, naphtho [2,3-b] thienyl, thianthrenyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl , carbazolyl, beta-carbolinyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, indolinyl, isoindolinyl, imidazopyridyl, imidazopyrimidinyl, still the condensed polycyclic systems consisting of monocyclic heterocyclic as defined above such as for example furo [2,3-b] pyrrole or thieno [2,3-b] furan, - or saturated heterocycles such as pyrrolidine, piperidine or morpholine.

 When R 1 and R 2 together form the remainder of an aromatic ring or a heteroaryl, these may be the radicals mentioned above. R 1 and R 2 together together form a phenyl, which corresponds to the compounds of formula (I ') described below, namely the benzothioazepinone derivatives.

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 When R5 represents a radical (CHR6) -CO- (CH2) m -Ar, (CHR6) -CO- (CH2) m -Het, (CHR6) -CONH- (CH2) m -Ar, (CHR6) -CONH- (CH 2) m -Het, the term Ar represents an aryl radical as defined above and in particular a substituted or unsubstituted phenyl or naphthyl radical and the term Het represents a heterocycle as defined above substituted or unsubstituted.

 When R 5 represents a cycloalkyl, (cycloalkyl) alkyl, (cycloalkyl) alkenyl or (cycloalkyl) alkynyl radical, these are in particular the following cycloalkyls: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

 By arylalkyl radical is preferably meant benzyl or phenylethyl.

 When - [Al] - represents a group of formula CH (Z) -CH2- (Ar1) -, - (CH2) 1- (Ar1) - or -CH2NHCO- (Ar1) -, (Ar1) represents a divalent aryl radical as defined above and in particular an optionally substituted phenyl or naphthyl group.

 When - [Al] - represents a group of formula -CH (Z) -CH2- (Hetl) -, - (CH2) n- (Hetl) - or CH2NHCO- (Hetl) -, (Hetl) represents a heterocyclic divalent radical as defined above and in particular the optionally substituted indolyl or 2-pyridinyl radical.

 Among the protective groups of the amine, mention may be made of the tBoc, FMoc and acetyl groups. The present invention includes protecting groups known to those skilled in the art and in particular by reference to the work of Philip J. Kociensky Protecting Groups Ed. Georg. Thieme Verlog Stuttgart New York 1994.

 When [Al] contains a divalent phenyl radical, the [A2] group may be in the ortho, meta or para position of this phenyl. It is preferably in the para position.

 Possible substituents - alkyl, alkenyl, alkynyl, aryl, arylalkyl or heterocycle radicals that can represent R1, R2, R3, R4, R5, R6, R7, R8 or Rg, - of the ring that can be formed together R1 and R2, - or bivalent groups (Arl) and (Hetl), may be

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 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 by one or more halogen atoms, for example fluorine such as trifluoromethyl.

-cyclo (C3-C12) alkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or adamantyl.

- oxo, cyano, nitro, formyl, carboxy, alkyloxycarbonyl containing from 2 to 7 carbon atoms such as CO2Me or CO 2tBu, carboxamide, - alkoxy containing from 1 to 6 carbon atoms such as methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, aryloxy such as phenyloxy, arylthio, alkylthio containing from 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 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 optionally being in oxidized form, -C = N-NH-CO- NH 2, - aminoalkyl containing from 1 to 6 carbon atoms such as aminomethyl or aminoethyl, - dialkylaminoalkyl containing from 3 to 18 carbon atoms such as dimethylamino methyl or ethyl, - dialkylaminoalkyloxy r containing from 3 to 18 carbon atoms such as dimethylaminoethyloxy, - optionally acylated hydroxyl containing from 1 to 6 carbon atoms, for example acetoxy, - acyl containing from 1 to 6 carbon atoms such as formyl, acetyl, propionyl, butyryl, isobutyryl , valeryl, isovaleryl, succinyl, pivaloyl benzoyl optionally substituted for example by a chlorine, iodine or

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 fluorine. Mention may be made of chloroacetyl, dichloroacetyl, trichloroacetyl, bromoacetyl or trifluoroacetyl, aryl or heteroaryl radicals such as phenyl, furyl, thienyl, pyridinyl or aralkyl radicals such as benzyl, the aryl, heteroaryl, aralkyl or aryloxy radicals being themselves optionally substituted. by radicals indicated above among which may be mentioned halogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, aminoalkyl, dialkylamino, carboxy or alkyloxycarbonyl.

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 the nitrogen group or the carbon atom. Among the preferred substituents which are subjects of the invention, mention may be made in particular of the following radicals: halogen, (C 1 -C 6) alkyl optionally substituted with one or more halogen atoms, cyclo (C 3 -C 12) alkyl, nitro, formyl , C = N-NH-CONH2, carboxy, (C2-C7) alkyloxycarbonyl, (C1-C6) alkoxy, amino, (C1-C6) alkylamino, (C2-C12) dialkylamino, optionally in oxidized form, hydroxyl optionally acylated, (C2-C6) acyl, aryl or aryloxy themselves optionally substituted by the radicals indicated above,
When R 3 is phenyl, it is preferably substituted by alkyloxy such as methoxy;
When R 5 is alkyl, it is preferably substituted by a cycloalkyl group;
When R5 is a -CH2CONHPh group, the phenyl is preferably substituted by phenyl, phenyloxy or methoxy;
When R 5 is a phenylalkyl group, it is preferably substituted by a phenyl group itself optionally substituted by an alkyloxycarbonyl group.

 When [Al] is (CH2) n- (Ar1) -, (Ar1) is preferably phenyl substituted with CHO or C = N-NH-CO-NH2.

 When R 8 or R 8 represent an aralkyl group, it is preferably benzyl.

 The invention naturally extends to the salts of the compounds

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 of formula (I), for example the salts formed, when the compounds of formula (I) contain an amino or amino guanidine function, with hydrochloric, hydrobromic, nitric, sulfuric, phosphoric, acetic, trifluoroacetic, formic and propionic acids, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, alkanesulphonic acids such as methane or ethanesulfonic acids, arenesulphonic acids, such as benzene or paratoluenesulphonic and arylcarboxylic acids, or when the compounds of formula (I) comprise an acid function, with salts of alkali or alkaline earth metals or optionally substituted ammonium.

 The invention also extends to the esters (carboxylates and phosphates) known to those skilled in the art, which may in particular be used as a prodrug. For example, the esters formed with carboxylic acids such as acetic acid, benzoic acid, isopropionic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, oxalic acid, succinic acid, pivalic acid, undecanoic acid or esters formed with the known amino acids of skilled person. It is preferably methyl and ethyl esters.

dans laquelle R5, [Al] et [A2] sont tels que définis précédemment et R3 représente un atome d'hydrogène ou un groupement méthoxyphényle. The subject of the invention is more particularly the compounds of formula (I) as described above corresponding to formula (II)

in which R5, [A1] and [A2] are as defined above and R3 represents a hydrogen atom or a methoxyphenyl group.

 The subject of the invention is more particularly the compounds of formula (I) in which R1 and R2 are

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 hydrogen atoms and the dotted line does not represent a double bond.

 The invention also more particularly relates to compounds of formula (I) wherein R1 and R2 are hydrogen atoms and the dashed line represents a double bond.

le phényl étant substitué ou non substitué, 1 et Z étant tels que définis précédemment. The subject of the invention is particularly the compounds of formula (I) or (II) as defined previously in which [Al] represents a group chosen from

the phenyl being substituted or unsubstituted, 1 and Z being as defined above.

 Among the compounds of formulas (I) or (II) as defined above, Z preferably represents an NH-P group with P as protecting group for the amine chosen from CO 2 tBu and acetyl, and the phenyl is preferably substituted by CHO. .

 The invention more particularly relates to the compounds of formula (I) or (II) in which R5 is a (cyclohexyl) propyl, (cyclohexyl) butyl radical or a -CH2CONHAr group, Ar being a substituted or unsubstituted aryl radical. The subject of the invention is more particularly the compound of formula (I) or (II) in which [A2] is an OPO (OH) (OBn), CF2PO (OH) 2 or OPO (OH) 2 radical.

 The subject of the invention is particularly

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 compounds of formula (II) in which: [Al] represents a group -CH (Z) -CH2-Ph- with Z = NHC02tBu or NHAc [A2] represents a group OPO (OH) 2, OPO (OH) (OBn) or CF 2 PO (OH) 2, R 5 represents a group -CH 2 CONHA, Ar being a substituted or unsubstituted aryl radical, or a (cyclohexyl) alkyl group, the term alkyl containing 3 or 4 carbon atoms.

[A2] représente un groupement -OPO(OH)2,-OPO(OH)(OBn), ou CF2PO(OH)2' R5 représente un groupement -CH2CONHAr, Ar étant un radical aryle substitué ou non substitué, ou un groupement (cyclohexyl) alkyle le terme alkyle renfermant 3 ou 4 atomes de carbone. The subject of the invention is also particularly those compounds of formula (I ') as described above in which [Al] represents the radicals chosen from

[A2] represents a group -OPO (OH) 2, -OPO (OH) (OBn), or CF2PO (OH) 2 'R5 represents a group -CH2CONHAr, Ar being a substituted or unsubstituted aryl radical, or a group ( cyclohexyl) alkyl the term alkyl containing 3 or 4 carbon atoms.

- [2S-[3(S*),2a,3a]]-[1-[[4-[[hydroxy (phénylméthoxy) phosphinyl] oxy] phényl] méthyl]-2-[[2-(4-méthoxyphényl)-5- [2-[(1-naphtalényl) amino]-2-oxoéthyl]-4-oxo-2,3,4,5-tétra- hydro-1,5-benzothiazépin-3-yl] amino]-2-oxoéthyl]-carbamate de 1,1-diméthyléthyle, - [2R-[3(S*),2a,3a]]-[1-[[4-[[hydroxy (phénylméthoxy) phosphinyl] oxy] phényl] méthyl]-2-[[2-(4-méthoxyphényl)-5- [2-[(1-naphtalényl) amino]-2-oxoéthyl]-4-oxo-2,3,4,5-tétra- The subject of the invention is particularly the compounds of formula (I) whose names follow:

- [2S- [3 (S *), 2a, 3a]] - [1 - [[4 - [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2 - [[2- (4-methoxyphenyl)] -5- [2 - [(1-naphthalenyl) amino] -2-oxoethyl] -4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] amino] -2 1,1-Dimethylethyl carboxamethyl] -carbamate, [2R- [3 (S *), 2a, 3a]] - [1 - [[4 - [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] 2 - [[2- (4-methoxyphenyl) -5- [2 - [(1-naphthalenyl) amino] -2-oxoethyl] -4-oxo-2,3,4,5-tetrasulfonyl

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- [2S-[3(S*),2a,3a]]-1-[[4-[[bis(phénylméthoxy) phosphinyl] oxy] phényl] méthyl]-2-[[2-(4-méthoxyphényl)-5-[2-[(1naphtalényl) amino]-2-oxo-1-phényléthyl]-4-oxo-2,3,4,5-tétra- hydro-1,5-benzothiazépin-3-yl] amino]-2-oxoéthyl]-carbamate de 1,1-diméthyléthyle,

- [2S-[3(S*),2a,3Q]]-[1-[[4-[[hydroxy (phénylméthoxy) phosphinyl] oxy] phényl] méthyl]-2-[[2-(4-méthoxyphényl)-5- [2-[(4-phénoxyphényl) amino]-2-oxoéthyl]-4-oxo-2,3,4,5-tétra- hydro-1,5-benzothiazépin-3-yl] amino]-2-oxoéthyl]-carbamate de 1,1-diméthyléthyle,

- [2S-[3(S*),2a,3a]]-4'-[[3-[[2-[[[(1,1-diméthyl) éthoxy] carbonyl] amino]-3-[[4-[[hydroxy (phénylméthoxy) phosphinyl] oxy] phényl]-l-oxopropyl] amino]-2-(4-méthoxyphényl)-4-oxo- 2,3-dihydro-1,5-benzothiazépin-5(4H)-yl] méthyl]-[1,1'-biphényl] -2-carboxylate de 1,1-diméthyléthyle, - [S-[R[trans()]]]-[1-[[4-[[hydroxy (phénylméthoxy) phosphi- 1,1-Dimethylethyl-1,5-benzothiazepin-3-yl] amino] -2-oxoethyl] carbamate, - [2S- [3 (S *), 2a, 3]] - [1 - [[ 4 - [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2 - [[2- (4-methoxyphenyl) -5- [2 - [[4-methoxy - [(1,1'-biphenyl)] - 1,1-Dimethylethyl 3-yl] amino] -2-oxoethyl] -4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] amino] -2-oxoethyl] -carbamate, [ 2S- [3 (S *), 2a, 3]] - [1 - [[4 - [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2 - [[2- (4-methoxyphenyl) -5 - [2- [2- (3-Phenoxyphenyl) amino] -2-oxoethyl] -4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] amino] -2-oxoethyl] carbamate 1,1-dimethylethyl, - [2R- [3 (S *), 2a, 3a]] - [1 - [[4 - [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2 - [ 2- (4-Methoxyphenyl) -5- [2 - [(1-naphthalenyl) amino] -2-oxoethyl] -4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3 1 - [2S- [3 (S *), 2a, 3a]] - [1 - [[4 - [[hydroxy (phenylmethoxy) phosphinyl] -yl] amino] -2-oxoethyl] -carbamate 1,1-dimethylethylcarbamate ] oxy] phenyl] methyl] -2 - [[2- (4-methoxyphenyl) -5- [2 - [(1-naphthalenyl) amino] -2-oxoethyl] -4-oxo-2,3,4,5-tetrahydro-1, 1,1-Dimethylethyl 5-benzothiazepin-3-yl] amino] -2-oxoethyl] carbamate,

- [2S- [3 (S *), 2a, 3a]] - 1 - [[4 - [[bis (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2 - [[2- (4-methoxyphenyl)] - 5- [2 - [(1naphthalenyl) amino] -2-oxo-1-phenylethyl] -4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] amino] - 1,1-dimethylethyl 2-oxoethyl] carbamate,

- [2S- [3 (S *), 2a, 3Q]] - [1 - [[4 - [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2 - [[2- (4-methoxyphenyl)] -5- [2 - [(4-phenoxyphenyl) amino] -2-oxoethyl] -4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] amino] -2 -oxoethyl] -carbamate 1,1-dimethylethyl,

- [2S- [3 (S *), 2a, 3a]] - 4 '- [[3 - [[2 - [[[(1,1-dimethyl) ethoxy] carbonyl] amino] -3 - [[4 - [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] -1-oxopropyl] amino] -2- (4-methoxyphenyl) -4-oxo-2,3-dihydro-1,5-benzothiazepin-5 (4H) - 1,1-Dimethylethyl] [1,1'-biphenyl] -2-carboxylate, [S- [R [trans ()]]] - [1 - [[4 - [[hydroxy (phenylmethoxy)] ) phosphine

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tétrahydro-1 , 5-benzothiazépin-3-yl amino)-1-[[4-hydroxy (phénylméthoxy) phosphinyl] oxy] phényl] méthyl]-2-oxoéthyl]carbamate de 1,1-diméthyléthyle, - [S-[R*(3R*)]]-[2-[[5-(3-cyclohexylpropyl)-2,3,4,5-tétra- hydro-4-oxo-1,5-benzothiazépin-3-yl] amino]-2-oxo-l-[[4- phosphonooxyphényl] méthyl] éthyl]-carbamate de 1,1-diméthyl- éthyle, - trans()-2,3-dihydro-3-[[3-[4-[[hydroxy (phénylméthoxy) phosphinyl] oxy] phényl]-l-oxopropyl] amino]-2- (4-méthoxy-

phényl)-N-(1-naphtylméthyl)-4-oxo-1,5-benzothiazépine-5(4H)- acétamide, - trans()-2,3-dihydro-3-[[[6-[[hydroxy (phénylméthoxy) phosphinyl] oxy]-2-naphtalényl] carbonyl] amino]-2-(4-

méthoxyphényl)-N-(1-naphtylméthyl)-4-oxo-1,5-benzothiazépine- 5(4H)-acétamide, - trans()-2,3-dihydro-3-[[[5-[[hydroxy (phénylméthoxy) phosphinyl] oxy]-lH-indol-2-yl] carbonyl] amino]-2-(4- méthoxyphényl)-N-(1-naphtylméthyl)-4-oxo-1,5-benzothiazépine 5(4H)-acétamide, - trans()-3-[[(4-boronophényl) carbonyl] amino]-2,3-dihydro- 2-(4-méthoxyphényl)-N-(1-naphtylméthyl)-4-oxo-1,5-benzothia- zépine-5(4H)-acétamide, - trans()-3-[[2-[[(4-boronophényl) carbonyl] amino]-l-oxo- éthyl] amino]-2,3-dihydro-2-(4-méthoxyphényl)-N-(1-naphtyl- méthyl)-4-oxo-1,5-benzothiazépine-5(4H)-acétamide, - (R)-N-[5-(3-cyclohexylpropyl)-4-oxo-2,3,4,5-tétrahydro-1,5- Nyl] oxy] phenyl] methyl] -2 - [[5- (3-cyclohexylpropyl) -2- (4-methoxyphenyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] amino 1,1-dimethylethyl-2-oxoethyl] carbamate, [S- [R * (3S *)]] - [2 - [[5- (3-cyclohexylpropyl) -4-oxo-2,3, 4,5-tetrahydro-1,5-benzothiazepin-3-yl] amino] -1 - [[4 - [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2-oxoethyl] carbamate 1,1- dimethylethyl, - [S- [R * (3S *)]] - [2 - [[5- (3-cyclohexylpropyl) -2,3,4,5-tetrahydro-4-oxo-1,5-benzothiazepine 3-yl] amino] -2-oxo-1 - [[4-phosphonooxyphenyl] methyl] ethyl] -carbamate 1,1-dimethylethyl, - [S- [R * (3R *)]] - [ 2 - [[5- (3-cyclohexylpropyl) -4-oxo-2,3,4,5

1,1-Dimethylethyl tetrahydro-1,5-benzothiazepin-3-yl amino) -1 - [[4-hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2-oxoethyl] carbamate, - [S- [ R * (3R *)]] - [2 - [[5- (3-cyclohexylpropyl) -2,3,4,5-tetrahydro-4-oxo-1,5-benzothiazepin-3-yl] amino] 1,1-Dimethylethyl-trans () -2,3-dihydro-3 - [[3- [4 - [[2-oxo-1 - [[4-phosphonooxyphenyl] methyl] ethyl] carbamate hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] -1-oxopropyl] amino] -2- (4-methoxy)

phenyl) -N- (1-naphthylmethyl) -4-oxo-1,5-benzothiazepine-5 (4H) -acetamide, - trans () - 2,3-dihydro-3 - [[[6 - [[hydroxy] ( phenylmethoxy) phosphinyl] oxy] -2-naphthalenyl] carbonyl] amino] -2- (4-

methoxyphenyl) -N- (1-naphthylmethyl) -4-oxo-1,5-benzothiazepine-5 (4H) -acetamide, -trans () -2,3-dihydro-3 - [[[5 - [[hydroxy) ( phenylmethoxy) phosphinyl] oxy] -1H-indol-2-yl] carbonyl] amino] -2- (4-methoxyphenyl) -N- (1-naphthylmethyl) -4-oxo-1,5-benzothiazepine (4H) - acetamide, - trans () - 3 - [[(4-boronophenyl) carbonyl] amino] -2,3-dihydro-2- (4-methoxyphenyl) -N- (1-naphthylmethyl) -4-oxo-1,5 benzothiazepine-5 (4H) -acetamide, trans () - 3 - [[2 - [[(4-boronophenyl) carbonyl] amino] -1-oxoethyl] amino] -2,3-dihydro- 2- (4-Methoxyphenyl) -N- (1-naphthylmethyl) -4-oxo-1,5-benzothiazepine-5 (4H) -acetamide, - (R) -N- [5- (3-cyclohexylpropyl) -4-oxo-2,3,4,5-tetrahydro-1,5-

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 benzothiazepin-3-yl] -3-formyl-4- (phosphonooxy) -benzamide, - (R) -N- [5- (3-cyclohexylpropyl) -4-oxo-2,3,4,5-tetrahydro-1 5-Benzothiazepin-3-yl] -4- (phosphonooxy) -benzamide, - (R) - [4 - [[5- (3-cyclohexylpropyl) -4-oxo-2,3,4,5-tetrahydro- 1,5-Benzothiazepin-3-yl] amino] carbonyl] -2-formylphenoxy] -acetic acid, - (R) -N- [5- (3-cyclohexylpropyl) -4-oxo-2,3,4,5- 1,5-tetrahydro-benzothiazepin-3-yl] -4- (diphosphonomethyl) -benzamide, - [3R- [3R * (S *)] - - (acetylamino) -N- [5- (3-cyclohexylpropyl) - 2,3,4,5-tetrahydro-4-oxo-1,5-benzothiazepin-3-yl] -4- (difluorophosphonomethyl) -benzenepropanamide, - (R) -N- [5- (4-cyclohexylbutyl) 4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] -N '- [4- (phosphonooxy) phenyl] urea, - cis () - N- [5- (3-Cyclohexylpropyl) -2- (4-methoxyphenyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] -4 - [[hydroxy (phenylmethoxy) phosphinyl] oxy ] -benzeneacetamide, - cis () - N- [5- (3-cyclohexylpropyl) -2- (4-methoxyphenyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3- yl] -4- (Phosphonooxy) benzeneacetamide, - [S- [R * (6S *)]] - [2 - [[4- (3-cyclohexylpropyl) -hexahydro-5-oxo-1,4-thiazepin-6-yl] amino] 1,1-Dimethylethyl-2-oxo-1 - [[4- (phosphonooxy) phenyl] methyl] ethyl] carbamate, - (R) -3 - [[(aminocarbonyl) hydrazono] methyl] -4- (phosphono) oxy) -N- [5- (3-cyclohexylpropyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] benzamide, - [S- [R * 6R *)]] - N-acetyl- [4- (3-cyclohexylpropyl) -5-oxo-4,5,6,7-tetrahydro-1,4-thiazepin-6-yl] -4- (phosphono) - (difluoro) methyl] -L-phenylalaninamide, - (R) -5- (phosphonooxy) -N- [5- (3-cyclohexylpropyl) -4-oxo-2,3,4,5-tetrahydro-1,5- benzothiazepin-3-yl] -2-pyridine carboxamide, - (R) -4 - [(phosphono) fluoromethyl] -N- [5- (3-cyclohexylpropyl) -4-oxo-2,3,4,5-tetrahydro- -1,5-benzothiazepin-3-yl] -benzamide.

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

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dans laquelle R1,R2,R3,R4 et X sont tels que définis précédemment et l'amine est le cas échéant protégée, a)soit d'abord à l'action d'un composé de formule [A2]-[A1]COOH ou [A2]-[A1]-NCO, après avoir, le cas échéant, déprotégé l'amine, afin d'obtenir un composé de formule (III')

[Al] et [A2] étant tels que définis précédemment, puis à l'action de R5-hal, R5 étant tel que défini précédemment et Hal étant de préférence un chlore ou un brome, b) soit d'abord à l'action d'un composé de formule R5-Hal, en présence d'une base afin d'obtenir le composé de formule (III")

in which R1, R2, R3, R4 and X are as defined above and the amine is optionally protected, a) either initially to the action of a compound of formula [A2] - [A1] COOH or [A2] - [A1] -NCO, after having, if necessary, deprotecting the amine, in order to obtain a compound of formula (III ')

[Al] and [A2] being as defined above, then to the action of R5-hal, R5 being as defined above and Hal preferably being chlorine or bromine, b) first to the action a compound of formula R5-Hal in the presence of a base to obtain the compound of formula (III ")

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 in which R5 is as defined above, then to the action of [A2] - [A1] -COOH or [A2] - [A1] -NCO, after having deprotected the amine if necessary, in order to obtain in both cases the compound of formula (I) expected, which if appropriate is salified by the action of an acid or a base or esterified.

 The acylation reaction using the compound of formula [A2] - [A1] -COOH is carried out according to conventional acylation methods known to those skilled in the art and in particular in the presence of EDC [1- 3-dimethylaminopropyl) -3-ethylcarbodiimide HCl and HOBt (1-hydroxybenzotriazole hydrate) in an aprotic dipolar solvent such as dimethylformamide.

 The alkylation reaction using R5-Hal 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.

 When the amine is protected, it is particularly protected by a Boc group. This can be deprotected by the action of hydrochloric acid gas at 110 C.

 The salification and esterification reactions can be carried out under customary conditions.

 The subject of the invention is also a process as defined above in which the compounds of formula (I), in which [A2] represents a group OP (O) (OBn) 2, are subjected to the action of a monodebenzylation agent or a total deprotection agent, in order to obtain respectively the compounds of formula (I) in which [A2] represents a group 0-PO (OH) (OBn) or O-PO (OH) 2 .

 In order to obtain monodebenzylation, sodium iodide is used in particular and the reaction is carried out under reflux. Triethylaminediamine (DABCO) can also be used in refluxing toluene. In order to obtain a didebenzylation, a conventional hydrogenation is preferably carried out in the presence of 10% Pd / C or the trifluoroacetic anhydride will be used.

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qui sont par la suite phosphorylés par action de HO-P(O)-

(OR8)(OR9) ou étherifié par action de Hal-CR1R11 C02-Alkyle ou de Hal-CH(C02-Alkyle)2 suivie d'une saponification de l'ester, afin d'obtenir les composés de formules (III') et (I) tels que définis précédemment. The subject of the invention is also a process as defined above in which the compound [A2] - [A1] -COOH is used, [A2] being a hydroxyl, in order to obtain the compounds of formula (III'a ) or (the ')

which are subsequently phosphorylated by the action of HO-P (O) -

(OR8) (OR9) or etherified by the action of Hal-CR1R11CO2-Alkyl or Hal-CH (CO2-Alkyl) 2 followed by saponification of the ester, to obtain the compounds of formulas (III ') and (I) as defined above.

 The phosphorylation reaction is carried out in the presence of N, N-diisopropylethylamine (DIPEA) and N, N-dimethylaminopyridine (DMAP) in acetonitrile and carbon tetrachloride.

 The etherification reaction is carried out in the presence of a base such as potassium carbonate in refluxing acetone.

 The saponification reaction is carried out according to conventional conditions such as in the presence of sodium hydroxide in methanol.

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The compounds of formula (I) and their pharmaceutically acceptable addition salts have interesting pharmacological properties which are set out below. a) Tyrosine kinase catalytic activity
The tyrosine kinase catalytic activity is associated with either receptors possessing transmembrane domains (EGF, DPGF, c-fms ..) or 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, Yrk in vertebrates). . b) Proteines 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 Cterminal involved in regulation. c) Function of tyrosine kinase proteins of the cSrc family
The tyrosine kinase proteins 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

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

 The observation of the phenotype of mice homozygous for this mutation has revealed several extremely interesting facts: they did not have any obvious abnormality in neurons or platelets, but these mice all had severe osteopetrosis, a pathology characterized by a very diminished bone resorption which gives rise to abnormalities of the skeleton (SN

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

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

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This inhibition can occur either at the level of the SH2 domain, or at the level of the SH3 domain (involved in the recognition and the interaction with other proteins), or at the level of the catalytic domain (tyrosine kinase)
The compounds according to the invention have a particular affinity with respect to the SH2 domain of the src protein.

The compounds of formula (I) can therefore be used to inhibit the binding of a Src protein containing the SH2 domain to a phosphorylated analog protein, the method 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 ant resorbents may be useful in the treatment of diseases caused by the loss of bone matrix, in particular, osteoporosis, hypercalcemia of malignancy, osteopenia due to bone metastases. , periodontitis, hyperparathyroidism, periarticular erosions in rheumatoid arthritis, paget's disease, immobilization-induced osteopenia, glucocorticoid treatment, or male or female sex hormone deficiencies.

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

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

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

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

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

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

 The dosage varies depending on 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 may be prescribed in the form of single or coated tablets, capsules, granules, suppositories, ova, 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 vehicles. fatty substances of animal or vegetable origin, paraffinic derivatives, glycols, various wetting agents, dispersants or emulsifiers,

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 conservatives.

 The compounds of formula (II) are known or readily accessible to those skilled in the art.

 By way of example, the benzothiazepines of formula (II) in which R 1 and R 2 together form an adjacent phenyl, R 3 is an optionally substituted phenyl group or a hydrogen atom, R 4 is a hydrogen atom and X is a hydrogen atom. Oxygen are known in particular in the patent application JP 60139682. Furthermore, the compounds of formula (II) in which R1 and R2 form an adjacent phenyl, R3 and R4 are hydrogen and X is an oxygen atom, are described in J. Med. Chem (1985), 1517-1521 (J. Slade et al).

l'amine étant éventuellement protégée, avec un composé de formule (V)

dans laquelle R1 et R2 sont tels que définis précédemment, Hal représente un chlore ou un brome, et (D) représente NH2 ou N02, en présence d'une base afin d'obtenir le composé de formule (VI) The compounds of formula (II) are also accessible by the action of L or D-cysteine of formula (IV)

the amine being optionally protected, with a compound of formula (V)

wherein R1 and R2 are as previously defined, Hal represents chlorine or bromine, and (D) represents NH2 or NO2, in the presence of a base to obtain the compound of formula (VI)

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qui par la suite est cyclisé en présence d'EDC, après le cas échéant protection de l'amine et réduction du groupe nitro que peut représenter D, afin d'obtenir le composé de formule (II) attendu.

which is subsequently cyclized in the presence of EDC, optionally after protection of the amine and reduction of the nitro group that can be D, in order to obtain the expected compound of formula (II).

 The compounds of formula (II) with R1 and R2 representing hydrogen atoms and the dashed lines representing a double bond are obtained by the action of the compound of formula (IV) whose acidic function is amidated and the amine is protected with the compound Hal-CH (CO 2 Et) 2 followed by a cyclization and elimination reaction.

 The compounds of formula [A2] - [A1] -COOH are commercially available or easily accessible, for example 0- [bis (phenylmethoxy) phosphinyl] -N - [(1,1-dimethylethoxy) carbonyl] -L-tyrosine; [L-Boc-Tyr-O- (P03Bn2)]. The compounds of formula R5-X are commercially available (for example 1-bromo-3-cyclohexylpropyl) or easily accessible.

 The compounds of formulas (IV), (V) and (VI) are also commercially available or readily available.

 The invention also relates to the intermediate compounds of formula (III '), (III "), (III'a) and (a), the following examples illustrate the invention without, however, limiting it.

Abbreviations: AcOEt: Ethyl acetate; CH2Cl2. dichloromethane; DMF dimethylformamide: EDC: 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide HCl; HOBt: 1-hydroxybenzothiazole hydrate; MeOH: methanol; TFA: trifluoroacetic anhydride.

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Préparation 1 : (8)-[1-[[4-[[bis(phénylm6thoxy) phosphinyl] oxy) phényl] méthyl]-2-[[2,3,4,5-tétrahydro-2-(4-méthoxyphényl) 4-oxo-l,5-benzothiazépin-3-yl] amino]-2-oxoéthyl]carbamate de 1,1-diméthyléthyle.

Preparation 1: (8) - [1 - [[4 - [[bis (phenylmethoxy) phosphinyl] oxy) phenyl] methyl] -2 - [[2,3,4,5-tetrahydro-2- (4-methoxyphenyl)] 1,1-Dimethylethyl 4-oxo-1,5-benzothiazepin-3-yl] amino] -2-oxoethyl] carbamate.

FG (III '): R1, R2 = Ph; R3 = Ph-OMe, R4 = H, X = O, [Al] = -CH (NH2) -CH2-Ph-; [A2] = OPO (OBn) 2 Preparation la: trans isomer 1 Preparation ib: trans isomer 2 Preparation the: cis isomer 1 Preparation id: cis isomer 2 The mixture consisting of 384.4 is mixed for 15 minutes at 0 ° C. under argon mg of O- [bis (phenylmethoxy) phosphinyl] -N - [(1,1-dimethylethoxy) carbonyl] -L-tyrosine, 123.4 mg of [1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride] ( EDC) and 86.9 mg of (1-hydroxybenzothiazole hydrate) (HOBt) in 425 l of dimethylformamide (DMF) and 1.3 ml of dichloromethane (CH 2 Cl 2) and added a solution of 161 mg of 2,3,4,5 tetrahydro-3-amino-2- (4-methoxyphenyl) -4-oxo-1,5-benzothiazepine (d, 1 trans + 10% d, 1 cis) in 6 ml of dry CH 2 Cl 2 and cooled to 0 ° C. The mixture is stirred at ambient temperature for 3 hours, then is diluted in 15 ml of ethyl acetate and after washing and drying, the organic phase is evaporated under reduced pressure to obtain 443 mg of crude product which is purified by chromatography. e on silica eluting with a dichloromethane / ethyl acetate mixture 7/3. 4 fractions are thus isolated P1c = 10.9 mg Rf CH2Cl2 / AcOEt: 0.41 isomer Cis 1 Pld = 10.4 mg Rf CH2Cl2 / AcOEt: 0.30 isomer Cis 2 Pla = 118.5 mg Rf CH2Cl2 / AcOEt: 0.24 Trans Isomer 1 Plb = 20 mg Rf CH2Cl2 / AcOEt: 0.14 Trans Isomer 2 Preparation on: [28- [3 (8 *), 2a, 3a]] - [1 - [[4 - [[bis (Phenylmethoxy) phosphinyl] oxy) phenyl] methyl] -2 - [[2- (4-methoxyphenyl) -4-oxo 2,3,4,5-tetrahydro-1,5-benzothiazepin-3- 1,1-dimethylethyl] -amino] -2-oxoethyl] carbamate.

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NMR (CDCl3) Isomer C18 1.41 (s) C (CH3) 3; 2.66 (dd) 2.97 (dd) CH (NHBoc) -CH 2 Ph; 3.78 (s) CH30; 4.04 (m) CH (NHBoc) -CH2-Ph; 5.10 to 5.25 (m) (5H) S-CH-Ph (H 2 of the ring) and NH-CO; (t, J = 7)) CO-CH-N (H3 of the ring); 4.94 Ph-CH2-OP; 6.79,7.00 and 7.25 (AABB); 7.17 to 7.45 (m) aromatic 12H.

Preparation id: [2R- [3 (8 *), 2a, 3a]] - [1 - [[4 - [[bis (phenylmethoxy) phosphinyl] oxy) phenyl] methyl] -2 - [[2- ( 1,1-Dimethylethyl 4-methoxyphenyl) -4-oxo-1,2,3,4-l, 5-benzothiazepin-3-yl] amino] -2oxoethyl] carbamate.

Préparation la : [28-[3(8*),2a,3(3]]-[1-[[4-[[bis(phénylméthoxy) phosphinyl] oxy) phényl] méthyl]-2-[[2-(4méthoxyphënyl)-4-oxo-2,3,4,5-tétrahydro-1,5-benzothiazépin-3- yl] amino]-2-oxoéthyl]-carbamate de 1,1-diméthyléthyle. NMR (CDCl3) C18 Isomer 2 1.28 (s) C (CH3) 3, 2.72 (d, J = 5) CH (N) -CH2-Ph; 3.76 (s) CH30; 4.43 (m) CH (N) -CH 2 Ph; 5.07 to 5.20 (m) (5H) S-CH-Ph (ring) and Ph-CH2-OP; 4.86 (t, J = 7) CO-CH-N (ring); 6.83,7.00 and 7.30 2 (AA'BB '); 7.10 to 7.42 (m) 12H and 7.69 (dd) aromatics; (m wide) and 8.30 (s wide) 2NHCO

Preparation 1a: [28- [3 (8 *), 2a, 3 (3]] - [1 - [[4 - [[bis (phenylmethoxy) phosphinyl] oxy) phenyl] methyl] -2 - [[2- ( 1,1-Dimethylethyl 4-methoxyphenyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] amino] -2-oxoethyl] carbamate.

NMR (CDCl3) Trans 1 Isomer 1.42 (s) (CH3) 3; 2.50 (dd) 2.95 (m) H (N) -CH2-Ph; 3.78 (s) CH30; CH (N) -CH 2 Ph; 3.93 (m) -CH-Ph (ring); , 37 t, J = 7)) CO-CH-N (ring), 4.70 to 5.34 (m) Ph-CH 2 -OP; 6.35 to 7.46 (m) (24H), aromatic 7.67 (m) (1H).

Preparation 1b: [2R- [3 (8 *), 2a, 3 (3]] - [1 - [[4 - [[bis (phenylmethoxy) phosphinyl] oxy) phenyl] methyl] -2 - [[2 1,1-Dimethylethyl (1- (4-methoxyphenyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] amino] -2-oxoethyl] carbamate.

NMR (CDCl3) Trans 2 Isomer 1.33 (s) C (CH3) 3; 2.57 (br m)) 2.79 (broad dd) CH (N) -CH 2 Ph; 3.75 (s) CH30; 4.59 (m, broad) CH (N) -CH2-Ph; 5.02 (dd, J = 11.5 and 8) S-CH-Ph (ring); 4.35 (d, J = 11.5) COCH-N (ring); 5.09 (m) Ph-CH2-O-P; 6.78 to 7.45 (m) (24H), 7.65 (dl) (1H) (aromatic); 4.88 (dl) 1H mobile; 8.58 (s)

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 broad 1H mobile) Preparation 2: Phenylmethyl 2 ((R) - (4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl) carbamate.

FG (II): R1, R2 = Ph; R3, R4 = H, X = O, (protected NH2: NHC02Bn) Step A: S- (2-nitrophenyl) -L-cysteine.

To a solution of 8.52 g of L cysteine in 35.6 water is added, under argon, a solution of 1-fluro-2-nitro-benzene in 118 ml of ethanol and stirred at reflux for 4 hours.

After filtration and concentration of the filtrate, it is diluted with water, extracted with ether and acidified to pH 1 with 12N hydrochloric acid. 12.06 g of expected crude product are obtained.

Stage B amine protection. S- (2-nitrophenyl) -N - [[(phenyl) methoxy] carbonyl] -L-cysteine.

6 g of the product obtained in the preceding stage are dissolved in 12 ml of 2N sodium hydroxide at 0-5 ° C. under argon, 6 ml of 4N sodium hydroxide and 4.2 g of benzylchloroformate are added and the mixture is stirred for 20 hours at room temperature. After extraction with ether and acidification with 12N hydrochloric acid, 17.9 g of crude product (oil) are obtained.

Stage C Reduction of the nitro group: S- (2-aminophenyl) -N- [[(phenyl) methoxy] carbonyl] -L-cysteine.

The mixture consisting of 150 mg of the product obtained in the preceding stage, 440 mg of ammonium chloride, 7.5 ml of methanol and 3.5 mg of activated Zn powder is stirred for 5 hours under reflux and then overnight at room temperature. . After treatment 90 mg of expected crude product is obtained.

Stage D Cyclization: Phenylmethyl (R) - (4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl) carbamate.

4.01 g of the product obtained in the preceding stage are dissolved in 50 ml of DMF, 2.22 mg of EDC are added, the mixture is stirred for 4 hours under argon at room temperature and the reaction mixture is diluted in 100 ml of ethyl acetate. After treatment, 2 mg of crude product (Rf CH2Cl2 / AcOEt 90/10 = 0.32) are obtained. Preparation 3: (8) - (2,3,4,5-tetrahydro-4-oxo-1,5-benzothiazole)

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 phenylmethyl carbin-3-yl) carbamate.

FG (II): R1, R2 = Ph; R3, R4 = H, X = O, (protected NH2 NHCO2Bn) The procedure is as described in Preparation 2, Steps A to D, but starting with 1.9 g of D-cysteine. 433 mg of expected pure product are obtained.

tétrahydro-N-[(naphtalényl) méthyl]-4-oxo-l,5-benzothiazépine -5(2H)-acétamide. Preparation 4: trans () - 3-amino-2- (4-methoxyphenyl) -2,3,4,5-

Tetrahydro-N - [(naphthalenyl) methyl] -4-oxo-1,5-benzothiazepine -5 (2H) -acetamide.

FG (III "): R1, R2 = Ph; R3 = PhOMe; R4 = H; X = O, R5 = CH2CONHCH2Napht N-alkylation To a solution of 3.7 g of trans () - [2- (4-methoxyphenyl) ) (4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl) carbamoyl phenylmethyl in 50 ml of DMF, at a temperature of 0 C, 613 mg of hydride of 50% sodium and 2.84 g of N- (1-naphthylmethyl) -bromoacetamide, stirred for 3 hours, allowing the temperature to return to about 20 ° C., then pouring into ice water and filtering to obtain 5.85 g of amine. protected.

Deprotection Gaseous hydrochloric acid is bubbled into a suspension of 5.85 g of the product obtained in the preceding stage in 85 ml of acetic acid, with stirring at 110 ° C. and this temperature is maintained for 19 hours. It is then evaporated under reduced pressure, dichloromethane is added, the mixture is washed with sodium bicarbonate and the aqueous phase is extracted with dichloromethane. After evaporation under reduced pressure, 4.4 g of crude product are obtained, which is purified by chromatography, eluting with 99/1 dichloromethane / methanol then 98/2 and then 95/5 to obtain 3.5 g of product. expected.

NMR (CDCl3) Trans Isomer 1 3.59 (d, J = 11) H3 (trans / H2); 4.14 (m) 2H N-CH 2 -C =; 4.80 (m) (3H) = C-N-CH 2 -C =; 6.83 7.80 (AA'BB ') C-Ph-O; 7.31 (dt) 1H, 7.45 to 7.58 (7H), 7.86 (m) 1H, 7.96,8.05 Aromatic and = CNH; 8.53 (t) = C-NH-CH 2.

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Préparation 5 : (R)-3-amino-5-(3-cyclohexylpropyl)-2,3-dihydro-1,5-benzothiazépin-4(SH)-one.

Preparation 5: (R) -3-amino-5- (3-cyclohexylpropyl) -2,3-dihydro-1,5-benzothiazepin-4 (SH) -one.

FG (III "): RIIR2 = Ph; R3, R1 = H; X = O, R1 = (CH2) 3-cyclohexyl N-alkylation A solution of 500 mg of P2 in dimethylformamide at 0 ° C. under an inert atmosphere 90 mg of 60% sodium hydroxide are added and then 454 mg of 1-iodo-3-cyclohexylpropyl is stirred at 0 ° C. for 15 minutes and at room temperature for 2 hours, is poured into ice water, extracted with the ethyl acetate is dried and evaporated under reduced pressure until 733 mg of crude product is obtained, which is then added directly to the following step. Deprotection A solution of 733 mg of the product obtained in the preceding stage in 10 1 ml of acetic acid, gaseous hydrochloric acid is bubbled with stirring at 110 ° C. and stirred at this temperature for 12 hours, then evaporated under reduced pressure, dichloromethane is added, the mixture is washed with sodium bicarbonate and The aqueous phase is extracted with dichloromethane and, after evaporation under reduced pressure, 520 mg of crude product expected that is purified by chromatography eluting with 90/10 then 80/20 dichloromethane / ethyl acetate then 90/10 dichloromethane / methanol to obtain 114 mg + 137 mg of crude product.

Préparation 6 : (R)-3-amino-5-(4-cyclohexylbutyl)-2,3- dihydro-1,5-benzothiazépin-4(5H)-one.

FG (III") : R1,R2 = Ph; R3,R4=H;X=O, R5=(CH2) 4-cyclohexyle Alkylation A une solution de 403,4 mg de l'amine protégée P2 Dans 6 ml de DMF, à une température de 0 C, on ajoute 74 mg de d'hydrure NMR (CDCl3) 0.82 (m) 1.00 to 1.30 (m) 1.40 to 1.80 (m) 18H Mobile alkyl chain + 2H; 4.83 (t, J = 10) 1H 3.32 to 3.60 (m) CH2 at 2 and H3; 3.22 to 3.60 (masked) 1H 4.23 (m) 1H CO-N-CH 2 -CH 2; 7.15 to 7.30 (m) 2H, 7.43 (m) 1H, 7.65 (dd) 1H aromatics

Preparation 6: (R) -3-amino-5- (4-cyclohexylbutyl) -2,3-dihydro-1,5-benzothiazepin-4 (5H) -one.

FG (III "): R1, R2 = Ph; R3, R4 = H; X = O, R5 = (CH2) 4-cyclohexyl Alkylation To a solution of 403.4 mg of protected amine P2 in 6 ml of DMF at a temperature of 0 ° C., 74 mg of hydride are added

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 of 50% sodium and 393 mg of 1-iodo-4-cyclohexylbutyl, stirred for 3 hours, allowing the temperature to return to about 20 ° C., then pouring into ice water and filtering. 818 mg of expected product is obtained.

Deprotection To a solution of 818 mg of the product obtained in the preceding stage in 10 ml of acetic acid, gaseous hydrochloric acid is bubbled with stirring at 110 ° C. and stirred at this temperature for 4 hours. It is then evaporated under reduced pressure, dichloromethane is added, the mixture is washed with sodium bicarbonate and the aqueous phase is extracted with dichloromethane. After evaporation under reduced pressure, 413 mg of crude product are obtained, which is purified by chromatography, eluting with a dichloromethane / methanol 99 / 1.98.5 / 1.5 and then 98/2 mixture to obtain 130.2 mg of expected product.

Préparation 7 : cis()-3-amino-S-(3-cyclohexylpropyl)-2,3- dihydro-2-(4-méthoxyphényl)-1,5-benzothiazépin-4(5H)-one. NMR (CDCl3) 0.81 (m) 1.00 to 1.75 (m) 20H Alkyl chain; 4.82 (m) 1H 3.38 to 3.56 (m) 2H CH2 at 2 and H3; 3.38 to 3.56 (concealed) 1H 4.32 (m) 1H CO-N-CH 2 -CH 2; 7.21 (dt) 7.43 (dt) H7 H8 7.28 (dd) (dd) H6 H9

Preparation 7: cis () - 3-amino-5- (3-cyclohexylpropyl) -2,3-dihydro-2- (4-methoxyphenyl) -1,5-benzothiazepin-4 (5H) -one.

FG (III "): R1, R2 = Ph; R3 = PhOMe; R4 = H; X = O, R5 = (CH2) 3cyclohexyl cis d, l Alkylation To a solution of 1.01 g of cis () - [( Phenylmethyl 2- (4-methoxyphenyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] carbamate in 10 ml of DMF at a temperature of 0.degree. 140 mg of 50% sodium hydride and 705 mg of iodo-3-cyclohexylpropyl are added, the mixture is stirred for 3 hours, the temperature is allowed to return to about 20 ° C., then it is poured into ice water and filtered. 52 g of expected product.

Deprotection Gaseous hydrochloric acid is bubbled with stirring at 110 ° C. in a solution of 1.5 mg of the product obtained under

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 previous stage in 15 ml of acetic acid, and stirred at this temperature for 4 hours. It is then evaporated under reduced pressure, dichloromethane is added, the mixture is washed with sodium bicarbonate and the aqueous phase is extracted with dichloromethane. After evaporation under reduced pressure, 413 mg of crude product are obtained, which is purified by chromatography, eluting with a dichloromethane / methanol 99 / 1.98.5 / 1.5 and then 98/2 to obtain 747 mg of expected product. .

NMR (CDCl3) 0.84 (m) 2H 1.02 to 1.35 (m) 6H 1.65 (m) 7H (cycloalkyl) alkyl; 1.33 (m wide) mobile 2H, 3.50 (m) 4.43 (m) CO-N-CH 2 -CH 2; 3.82 (s) Ph-OMe; (d, J = 7) H3, 4.77 (d, J = 7) H2, 6.90 and 7.41 (AA'BB '); 7.25 (dt) 7.45 (dt) H7 H8 7.32 (dd) 7.70 (dd) H6 H9.

Preparation 8: (R) -6-amino-tetrahydro-1,4-thiazepin-5 (2H) -one.

FG (II): R1, R2, R3, R4 = H, the dotted line does not represent a double bond, X = 0 To a solution of 2g of L-cysteine methyl ester hydrochloride in 20 ml of methanol, 9.9 ml of triethylamine and 2 g of 1-amino-2-chloroethyl hydrochloride are added and refluxed for 16 hours. After treatment and purification by chromatography eluting with a CH 2 Cl 2 / MeOH mixture ranging from 99/1 to 90/10, 250 mg of pure product in the form of hydrochloric acid salt are obtained.

IR (CHCl 3) Absorption OH / NH region: 3181 cm -1 absorption NH 3 + region, C = O 1662 cm -1, NH 3 + 1601 cm -1, 1564 cm -1.

Preparation 9: (R) -6-Amino 4- (3-cyclohexylpropyl) -6,7-dihydro-1,4-thiazepin-5 (2H) -one.

FG (III "): R1, R2, R3, R4 = H, the dotted line represents a double bond, X = O, R5 = (cyclophexyl) propyl,

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dihydro-1,5-benzothiazépin-4(5H)-one. a) Protection of 5.0 g of L-cysteine methyl ester hydrochloride by the action of 6.54 g of (Boc) 2 in the presence of 4.15 ml of TEA in 60 ml of CH 2 Cl 2. b) Alkylation of the thiol (1 g) by the action of 1 g of 2-bromo-1,1-di-ethoxyethane in 10 ml of DMF in the presence of 245 mg of sodium hydride. c) Saponification of the ester (350 mg) by action of 50 mg of lithium hydroxide in THF at room temperature. d) Amidification of the acid (200 mg) by the action of 150 mg of 20% ammonium hydroxide in 5 ml of THF in the presence of 121 mg of HOBt, 171 mg of EDC, and 90 mg of N-methyl. e) Cyclization by heating the amide (135 mg) obtained in the previous stage in 5 ml of refluxing toluene with a DeanStark to remove the ethanol formed. f) alkylation of the amine obtained in the preceding stage (72 mg) by the action of 76 mg of 1-iodo-3- (cyclohexyl) propyl in the presence of sodium hydride in DMF g) Deprotection of 100 mg of the amine obtained in the preceding stage in order to obtain the free amine by the action of 2 ml of trifluoroacetic anhydride in 2 ml of CH 2 Cl 2. 158 mg of expected product is obtained (Rf CH2Cl2 / MeOH 95/5 = 0.25) Preparation 10: (S) -3-amino-5- (3-cyclohexylpropyl) -2,3-

dihydro-1,5-benzothiazepin-4 (5H) -one.

FG (III "): R1, R2 = Ph, R3, R4 = H, R = O, R5 = (CH2) 3-ayalohexyl The procedure is as in Preparation 5, but starting from 483 mg of product obtained in Preparation 3 (S- (2,3,4,5-tetrahydro-4-oxo-1,5-benzothiazepin-3-yl) -carbamate phenylmethyl) and 483 mg of 1-iodo-3- (cyclohexyl) propyl and then deprotected by action Hydrochloric acid gas for 6 hours at 110 C.

After isolation and purification by chromatography, eluting with dichloromethane / ethyl acetate 90/10 then 80/20 then dichloromethane / methanol 98/2, 50 mg of expected product is obtained.

Rf (CH2Cl2 / AcOEt): 98/2

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Exemple 1 : [2s-[3(s*),2a,3]]-[1-[[4-[[hydroxy (phénylméthoxy) phospninyl] oxy] phényl] méthyl]-2-[[2-(4méthoxyphényl)-5-[2-[(1-naphtalényl) amino]-2-oxoéthyl]-4oxo-2,3,4,5-tétrahydro-1,5-benzothiazipin-3-yl] amino]-2oxoéthyl]-carbamate de 1,1-diméthyléthyle (isomère trans 1).

Example 1: [2s- [3 (s *), 2a, 3]] - [1 - [[4 - [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2 - [[2- (4-methoxyphenyl)] N- [2- [(1-naphthalenyl) amino] -2-oxoethyl] -4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazipin-3-yl] amino] -2oxoethyl] carbamate 1,1-dimethylethyl (trans isomer 1).

oxy] phényl] méthyl]-2-[[2-(4-méthoxyphényl)-5-[2-[(1naphtalényl) amino]-2-oxoéthyl]-4-oxo-2,3,4,5-tétrahydro-1,5- benzothiazépin-3-yl] amino]-2-oxoéthyl]-carbamate de 1,1diméthyléthyle (isomère trans 1). FG (I ') R3 = PhOMe; R, = CH 2 CONH-Napht .; [A1] = - CH (NHC02tBu) -CH2-Ph-; [A2] = OPO (OBn) (OH) (trans 1) Step A: N-alkylation [2S- [3 (S *), 2a, 3a]] - [1 - [[4 - [[bis (phenylmethoxy) phospninyl]

oxy] phenyl] methyl] -2 - [[2- (4-methoxyphenyl) -5- [2 - [(1-naphthalenyl) amino] -2-oxoethyl] -4-oxo-2,3,4,5-tetrahydro- 1,1-Dimethylethyl 1,5-benzothiazepin-3-yl] amino] -2-oxoethyl] carbamate (trans-isomer 1).

To a solution of 106.4 mg of Pla (trans isomer 1) in 1.5 ml of dry DMF at 0 ° C. under argon, 7.4 mg of NaH is added, the mixture is stirred at about 0 ° C. and then added. 4 mg of N-1-naphthyl-bromoacetamide and then stirred at room temperature.

After 3 hours, 20 ml of distilled water are added. After extraction with ethyl acetate, dichloromethane and ethyl ether, drying of the organic phases and evaporation under reduced pressure, 105.8 mg of crude product is obtained which is purified by chromatography eluting with water / methanol mixture 20/80. After evaporation of the methanol and extraction of the aqueous phase with 80 ml of ethyl acetate, the organic phase is dried and then evaporated under reduced pressure until 30.4 mg of expected product is obtained.

Rf methanol / water 90/10 = 0.23 Step B: Monodebenzylation To a solution of 24.4 mg of the product obtained in the preceding stage in 3 ml of acetone is added 7.9 mg of NaI (sodium iodide) and the mixture is refluxed for 1h30. An additional 3.9 mg of NaI is added, then after 2 hr still 8 mg. After 40 minutes of stirring at reflux, the mixture is evaporated under reduced pressure until a dry extract is obtained which is washed with ethyl acetate and which is dissolved in 3 ml of methanol and a few drops. NaHSO 3 at 10%. After evaporation under reduced pressure, 17.3 mg of

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 crude product which is purified by chromatography eluting with a 80/20 dichloromethane / methanol mixture. 6.8 mg of expected product is obtained.

Rf CH2Cl2 / methanol 80/20 = 0.29 IR (Nujol) Absorption OH / NH C = O 1669 cm -1 Aromatic + amide II 1609.1584, 1533.1510, 1503 cm-1 NMR (DMSO) 1.21 ( s), 1.23 (s) C (CH 3) 3; 2.30 to 2.60 (m) CH (N) -CH 2 Ph; 3.67 (s) CH30; 3.86 CH (N) -CH2-Ph; 4.56 (dl, J = 11.4) S-CHPh (ring); 4.86 (dd) -CO-CH-N (ring); 4.76 (dl) Ph-CH 2 -O-P; 4.64 (dl) 5.00 (dl) N-CH 2 -CO-N; 6.37 (d) NH-CO; 6.85 (dl), 6.93 (dl), 7.04 (dl) aromatic Ph-OH; (m) aromatic 5H; 7.35 to 8.40 aromatic 11H naphthyl; masked, 8,29 (s) 8,31 (s), 10,15 (si) 3H mobile.

oxo-2,3,4,5-t6trahydro-1,5-benzothiazépin-3-yl] amino]-2- oxoéthyl]-carbamate de 1,1-diméthyléthyle. Example 2: [2R- [3 (8 *), 2a, 3a]] - [1 - [[4 - [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2 - [[2- ( 4-methoxyphenyl) -5- [2 - [(1-naphthalenyl) amino] -2-oxoethyl] -4-

1,1-dimethylethyl oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] amino] -2-oxoethyl] carbamate.

FG (I ') R3 = PhOMe; R5 = CH 2 CONH-Napht .; [Al] = - CH (NHC02tBu) -CH2-Ph-; [A2] = OPO (OBn) (OH) (trans 2) Step A: N-alkylation - [2R- [3 (S *), 2a, 3]] - [1 - [[4 - [[bis (phenylmethoxy ) phosphinyl] oxy] phenyl] methyl] -2 - [[2- (4-methoxyphenyl) -5- [2 - [(1-naphthalenyl) amino] -2-oxoethyl] -4-oxo-2,3 1,1-Dimethylethyl 4,5-tetrahydro-1,5-benzothiazepin-3-yl] amino] -2-oxoethyl] carbamate.

To a solution of 185.5 mg of Plb (trans isomer 2) in 3 ml of dry DMF at 0 ° C. under an inert atmosphere, 13.2 mg of NaH are added, the mixture is stirred at about 0 ° C., then 59 is added, 5 mg of N-1-naphthyl-bromoacetamide and then stirred at room temperature. After 3 hours, 12.2 mg of N-1-naphthylbromoacetamide are added and then, after 2 hours, 20 ml of distilled water.

After extraction with ethyl acetate and dichloromethane, drying of the organic phases and evaporation under

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 reduced pressure, 260.6 mg of crude product is obtained which is purified by chromatography eluting with a 25/75 water / methanol mixture. After evaporation of the methanol and extraction of the aqueous phase with 200 ml of ethyl acetate, the organic phase is dried and then evaporated under reduced pressure until 80.3 mg of expected product is obtained.

Rf methanol / water 90/10 = 0.41 Step B: Monodebenzylation To a solution of 24.4 mg of the product obtained in the preceding stage in 4 ml of acetone, 24.4 mg of NaI are added and the mixture is brought to room temperature. reflux for 1.6 hours. 14.6 mg of NaI are added again and then after 2.7 hours 20 mg. After stirring for 30 minutes under reflux, the mixture is evaporated under reduced pressure until a dry extract is obtained, to which 3 ml of methanol and a few drops of 10% NaHSO 3 are added. After evaporation under reduced pressure, 42.5 mg of crude product are obtained which is purified by chromatography, eluting with a 85/15 CH 2 Cl 2 / MeOH mixture. 29.5 mg of expected product are obtained.

Exemple 3 : [28-[3(8*),2a,3/3]]-[1-[[4-[[hydroxy (phénylméthoxy) phosphinyl] oxy] phényl] méthyl]-2-[[2-(4-méthoxyphényl)-5-[2-[[4-méthoxy-[(1,11-biphényl)-3-yll amino]-2- oxoéthyl]-4-oxo-2,3,4,5-tétrahydro-1,5-benzothiazépin-3-yl] amino]-2-oxoéthyl]-carbamate de 1,1-diméthyléthyle.

FG(I') R3=PhOMe; RS=CH2CONH-Ph(o-OMe)(m-Ph).; [Ai]=-CH(NHC02tBu)-CH2-Ph-; [A2]=OPO(OBn)(OH) Rf CH 2 Cl 2 / MeOH 80/20 = 0.44 IR (Nujol) Absorption OH / NH C = O 1668 cm -1 Aromatic + amide II 1508 cm -1 NMR (DMSO) 1.22 (s) C (CH 3) 3; 1.85 to 2.05 CH (N) -CH2-Ph; 3.62 CH30; 3,95CH (N) -CH 2 Ph; 4.54 (d, J = 11) S-CH-Ph H2 ring); 4.66 (dd) CO-CH (N) (H3 cycle); 4.75 (dl) Ph-CH 2 -O-P; 4.90-5.00 N-CH 2 -CO-N; 6.48 (d) NH-Boc; 6.82,6.93, 7.04 Ph-0; 7.43 to 8.06 naphthyl; (d) H mobile.

Example 3: [28- [3 (8 *), 2a, 3/3]] - [1 - [[4 - [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2 - [[2- ( 4-methoxyphenyl) -5- [2 - [[4-methoxy - [(1,11-biphenyl) -3-yl amino] -2-oxoethyl] -4-oxo-2,3,4,5-tetrahydro- 1,1-Dimethylethyl 1,5-benzothiazepin-3-yl] amino] -2-oxoethyl] carbamate.

FG (I ') R3 = PhOMe; RS = CH 2 CONH-Ph (o-OMe) (m-Ph) .; [Ai] = - CH (NHC02tBu) -CH2-Ph-; [A2] = OPO (OBn) (OH)

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- [2S-[3(S*) ,2a,3j3]]-[l-[ [4-[ [bis (phénylméthoxy) phosphinyl] oxy] phényl] méthyl]-2-[[2-(4-méthoxyphényl)-5-[2-[[4méthoxy-[(1,1'-biphényl)-3-yl] amino]-2-oxoéthyl]-4-oxo- 2,3,4,5-tétrahydro-1,5-benzothiazépin-3-yl] amino]-2oxoéthyl] -carbamate de 1,1-diméthyléthyle. Stage A: N-alkylation

- [2S- [3 (S *), 2a, 3d]] - [1 - [[4- [[bis (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2 - [[2- (4-methoxyphenyl)] -5- [2 - [[4methoxy - [(1,1'-biphenyl) -3-yl] amino] -2-oxoethyl] -4-oxo-2,3,4,5-tetrahydro-1,5- 1,1-dimethylethyl benzothiazepin-3-yl] amino] -2oxoethyl] carbamate.

The procedure is as in Example 1, stage A, starting from 159.3 mg of Pla, with 2-bromo-N- (4-methoxy) - [1,1'-biphenyl] -3-yl as alkylating agent. acetamide. 165.1 mg of expected pure product are obtained.

Rf methanol / water 80/20 = 0.07 Step B: Debenzylation The procedure is as in Example 1, stage B, starting from 155.8 mg of the product obtained in the preceding stage. 32.5 mg of expected pure product are obtained.

Rf Dichloromethane / methanol 80/20 = 0.58 IR (Mujol) Absorption OH / NH C = O 1670 cm-1 Aromatic + amide II: 1607.1 1592 (f), 1582 (f), 1573 (f), 1532, 1510 cm -1 NMR (DMSO) 1.21 (s) C (CH 3) 3; 2.2 to 2.6 CH (N) -CH2-Ph; 3.88 (s) CH30 as para phenyl; 3.68 (s) CH30 as para biphenyl; 3.85 (m) CH (N) -CH 2 Ph; 4.57 (d, J = 11.5) S-CH-Ph H2 trans; 4.85 COCH (N) H3 trans; 4.76 (d) Ph-CH 2 -O-P; 4.58 (d) -4.92 (d) NCH2-CO-N; 6.60 (d) 8.26 (d) NH-CO; 6.80, 6, 85, 6.38, 7.07 Ph-O; 7.00 to 7.75 other aromatics; (d) H mobile.

2,3,4,5-tétrahydro-1,5-benzothiazépin-3-yl] amino]-2- oxoéthyl]-carbamate de 1,1-diméthyléthyle. Example 4: [2S- [3 (S *), 2a, 3p]] - [1 - [[4 - [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2 - [[2- (4- methoxyphenyl) -5- [2- [2- (3-phenoxyphenyl) amino] -2-oxoethyl] -4-oxo

1,1-Dimethylethyl 2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] amino] -2-oxoethyl] carbamate.

FG (I ') R3 = PhOMe; RS = CH 2 CONH-Ph (m-OPh) .; [A1] = - CH (NHCO2tBu) - CH2-Ph-; [A2] = OPO (OBn) (OH) Step A: - [2S- [3 (S *), 2a, 3]] - [[2 - [[2- (4-methoxyphenyl) 5- [2- ( 3-

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

The procedure is as in Example 1, Stage A, starting from 200 mg of Pla with, as alkylation agent, 2-bromo-N- (3-phenoxyphenyl) -acetamide. 191.2 mg of expected pure product are obtained.

Rf methanol / water 90/10 = 0.36 Step B: Debenzylation The procedure is as in Example 1 Step B starting from 181.8 mg of the product obtained in the preceding stage. 104.7 mg of expected pure product are obtained.

Rf Dichloromethane / methanol 80/20 = 0.66 IR fNiO l) Absorption OH / NH C = O 1662 cm -1 Aromatic + amide II: 1609.1587 (f), 1538 (f), 1510 (f), 1487 (ep cm -1 NMR (DMSO) 1.22 (s) C (CH 3) 3; 2.27-2.3 CH (N) -CH2-Ph; 3.68 (s) CH30 para phenyl; 3.85 (m) CH (N) -CH 2 Ph; 4.44 to 4.60 S-CH-Ph CO-CH (N) (2H ring); 4.70 to 4.85 Ph-CH 2 -O-P N-CH 2 -CO-N (4H); 8.20 (d) NH-CO; 6.50 to 7.65 aromatic H (32H).

Example 5: [2R- [3 (s *), 2a, 3a]] - [1 - [[1 - [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2 - [[2- (4- Methoxyphenanthyl) -S- [2 - [(1-naphthalenyl) amino] -2-oxoethyl] -4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] amino] -2-oxoethyl ] 1,1-dimethylethylcarbamate.

FG (I ') R3 = PhOMe; R, = CH2CONX-Napht .; [Al] = - CH (NNCO2tBu) -CH2-Ph-; [A2] = OPO (OBn) (OH) (Cis 2) Step A: N-alkylation - [2R- [3 (S *), 2a, 3a]] - [1 - [[4 - [[bis (phenylmethoxy ) phosphinyl] oxy] phenyl] methyl] -2 - [[2- (4-methoxyphenyl) -5- [2 - [(1-naphthalenyl) amino] -2-oxoethyl] -4-oxo-2,3 1,1-Dimethylethyl 4,5-tetrahydro-1,5-benzothiazepin-3-yl] amino] -2-oxoethyl] carbamate.

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The procedure is as in Example 1 Step A from 200 mg of Pld (cis isomer 2) with N-1-naphthyl-bromoacetamide as alkylating agent. 102.3 mg of expected pure product are obtained.

Rf dichloromethane / 50/50 water = 0.42 Step B: Debenzylation The procedure is as in Example 1, Stage B, starting from 95.3 mg of the product obtained in the preceding stage. 23.3 mg of expected pure product are obtained.

Rf 90/10 dichloromethane / methanol = 0.16 IR (Nuiol) Absorption OH / NH region C = O 1684 cm-1 Aromatic + amide II 1609 (tf), 1582 (tf), 1505, cm-1 NMR (DMSO) 1.19 (s) C (CH3) 3; 2.50 (m) CH (N) -CH2-Ph; 3.71 (s) CH30; 4.07 (m) CH (N) -CH2-Ph; 4.68 (d) 5.07 (d) Napht-NH-CO-CH 2 -N; 5.00 (d, J = 7) -S-CH-Ph (H 2 C) H Cis; (t, J = 7.5)) -COCH (N) (H 3 ring) H Cis; NH-Boc; 6.97 (AA'BB '); 6.82 to 7.82 (m), 7.94 (m), 8.13 (m) aromatics; 10.28 (s) 1H mobile.

Example 6: [28- [3 (S *), 2a, 3a]] - [1 - [[4 - [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2 - [[2- ( 4-methoxyphenyl) -5- [2 - [(1-naphthalenyl) amino] -2-oxoethyl] -4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] amino] -2 1,1-dimethylethyl carboxamethylcarbamate.

FG (I ') R3 = PhOMe; R5 = CH 2 CONH-Napht .; [A1] = - CH (NHCO2tBu) -CH2Ph-; [A2] = OPO (OBn) (OH) (Cis 1) Step A: The procedure is as in Example 1 Step A starting from 220 mg of P1c (cis isomer 1) with N-1 naphthyl as alkylating agent -bromoacétamide. 67 mg of expected pure product are obtained.

Rf methanol / water 90/10 = 0.34 Step B: Debenzylation The procedure is as in Example 1 Step B starting from 65.5 mg of the product obtained in the preceding stage. We obtain 19.1 mg of

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 pure product expected.

Rf Dichloromethane / methanol 80/20 = 0.45 IR (Nujol) Absorption OH / NH C = O 1668 cm-1 Aromatic + amide II 1608.1505 cm-1 NMR (DMSO) 1.18 (s) C (CH3) 3; 2.35 to 2.75 (m) CH (N) -CH2-Ph; 3.76 (s) CH30; 3.95 (m) CH (N) -CH 2 Ph; 5.00 (d, J = 7) -S-CH-Ph (H2 cycle) Cis; 4,70-CO-CH (N) (H3 ring) Cis; 4.72 (m) Ph-CH 2 -O-P; 4.60 to 4.75 5.08 (d) N-CH 2 -CO-N; 6.48 (d) NH-Boc; 6.80 to 7.80 (m) (24H) 7.91 (m) (1H) 8.15 (m) (1H) H aromatics; 10.33 (s) 1H mobile.

2,3,1,5-tétrahydro-1,5-benzothiazépin-3-yl] amino]-2- oxoéthyl]-carbamate de 1,1-diméthyléthyle. Example 7: [28- [3 (8 *), 2a, 3]] - 1 - [[4 - [[bis (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2 - [[2- (4-methoxyphenyl)] ) -5- [2 - [(1-naphthalenyl) amino] -2-oxo-1-phenylethyl] -4-oxo

1,1-Dimethylethyl 2,3,1,5-tetrahydro-1,5-benzothiazepin-3-yl] amino] -2-oxoethyl] carbamate.

FG (I ') R3 = PhOMe; R5 = CH (Ph) CONH-Napht .; [A1] = - CH (NHCO2tBu) CH 2 Ph; [A2] = OPO (OBn) (OBn) (Trans 1) The procedure is as in Example 1, stage A, starting from 220.1 mg of Pla (Trans 1 isomer) with alpha-bromo as alkylating agent. -N- (l-naphtylalényl) benzeneacetamide. 113.7 mg of expected pure product are obtained.

Rf methanol / water 90/10 = 0.50 IR (Nujol) C-NH 3416 cm -1 C = O 1684 cm -1 Aromatic amide 11: 1610, 1599, 1584, 1523 ep., 1513, 1508, cm -1 1 NMR (DMSO) 1.28 (si) OC (CH 3) 3; 2.73 (d) CH (N) -CH 2 Ph; 3.74 (s) CH30; 4.98; CH (N) -CH 2 Ph; 4.07 (d, J = 11.5): -S-CH-Ph (H 2 H) H Trans; (d, J = 11.5): -CO-CH-N (H 3 ring) H Trans; 5.13 (d) (2H) and 5.24 (m) (2H): Ph-CH 2 -O-P; 6.63 (d) Napht-NH-CO-; 6.76 (d) (2H), 6.94 (d) (5H), aromatic H; 7.20 to 7.88 (m) 9.20 (sl) Other aromatics and NH.

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Exemple 8 : [28-[3(8*),2a,3(3]]-[1-[[!-[[hydroxy (phényl- méthoxy) phosphinyl] oxy] phényl] méthyl]-2-[[2-(4-méthoxyphényl)-5-[2-[(4-phénoxyphényl) amino]-2-oxoéthyl]-4-oxo-

2,3,4,5-tétrahydro-l,5-benzothiazépin-3-yl] amino]-2oxoéthyl]-carbamate de 1,1-diméthyléthyle.

Example 8: [28- [3 (8 *), 2a, 3 (3]] - [1 - [[1 - [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2 - [[2 - (4-Methoxyphenyl) -5- [2 - [(4-phenoxyphenyl) amino] -2-oxoethyl] -4-oxo

1,1-Dimethylethyl 2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] amino] -2oxoethyl] carbamate.

- [2S-[3(S*),2a,3(3]]-[1-[[4-[[bis(phénylméthoxy) phosphinyl] oxy] phényl] méthyl]-2-[[2-(4-méthoxyphényl)-5-[2-[(4-phénoxyphényl) amino]-2-oxoéthyl]-4-oxo-2,3,4,5-tétrahydro-1,5benzothiazépin-3-yl] amino]-2-oxoéthyl]-carbamate de 1,1diméthyléthyle. FG (I ') R = PhOMe; R5 = CH2CONH-Ph (p-OPh) .i [Al] = -CH (NBCO2tBU) -CH2-Ph-; [A2] = OPO (OBn) (OH) (Trans 1) Step A: N-alkylation

- [2S- [3 (S *), 2a, 3 (3]] - [1 - [[4 - [[bis (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2 - [[2- (4- Methoxyphenyl) -5- [2 - [(4-phenoxyphenyl) amino] -2-oxoethyl] -4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] amino] -2-oxoethyl ] 1,1-dimethylethylcarbamate.

The procedure is as in Example 1, stage A, starting from 200 mg of Pla (trans-isomer 1) with the alkylation agent as 2bromo-N- (4-phenoxyphenyl) -acetamide. 117.9 mg of expected pure product are obtained.

Rf methanol / water 90/10 = 0.32 Step B: Debenzylation The procedure is as in Example 1, stage B, starting from 112.4 mg of the product obtained in the preceding stage. 31 mg of expected pure product is obtained.

Rf Dichloromethane / methanol 80/20 = 0.52 IR (Nujol) Absorption OH / NH C = O 1662 cm-1 Aromatic + amide II 1609,1585,1737,1507,1488 cm-1 NMR (DMSO) 0.99 ( s), 1.22 (s) C (CH3) 3; 2.22 to 2.50 CH (N) -CH2-Ph; 3.66 (s) CH30; 3.84 (m) CH (N) -CH2-Ph; 4.50 to 4.85 (m) -S-CH-PhCO-CH (N); 4.50 to 4.85 (m) Ph-CH 2 -O-P-N-CH 2 -CO-N; Aromatic 6,50 to 7,70 (m) (28H); 8.20 (d) -NH-CO-; 8.26 (dl) 10.20 (si) other NH-CO.

phënyl)-4-oxo-2,3-dihydro-1,5-benzothiazépin-5(4H)-yl] Example 9: [28- [3 (8 *), 2a, 3/3]] - 4 '- [[3 - [[2 - [[[(1,1-dimethyl) ethoxy] carbonyl] amino] -3 - [[4 - [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] -1-oxopropyl] amino] -2- (4-methoxy)

phenyl) -4-oxo-2,3-dihydro-1,5-benzothiazepin-5 (4H) -yl]

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1,1-dimethylethyl methyl] - [1,1'-biphenyl] -2-carboxylate.

FG (I ') R3 = phome; R5 = CH2CONH-Ph-Ph (m -CO2tBU); [Al] = - CH (Nxco2tBu) -CH2-Ph-; [A2] = OPO (OBn) (OH) (Trans 1) Step A: N-alkylation - [2S- [3 (S *), 2a, 3 (3]] - 4 '- [[3 - [[3- [4 - [[bis (phenylmethoxy) phosphinyl] oxy] phenyl] 2 - [[[( 1,1-dimethyl) ethoxycarbonyl] amino] 1-oxopropyl] amino] -2- (4-methoxyphenyl) -4-oxo-2,3-dihydro-1,5-benzothiazepin-5 (4H) -yl] methyl ] - [1,1'-biphenyl] -2-carboxylate 1,1-dimethylethyl.

The procedure is as in Example 1, Stage A, starting from 200 mg of Pla (Trans 1 isomer), with 4 '- (bromomethyl) - [1,1'-biphenyl] -2-carboxylate as the alkylating agent. 1-dimethylethyl. 161.6 mg of expected pure product are obtained.

Rf dichloromethane / water 90/10 = 0.32 Step B: Monodebenzylation The procedure is as in Example 1 Step B starting from 150.3 mg of the product obtained in the preceding stage. 80.2 mg of expected pure product are obtained.

Rf Dichloromethane / methanol 80/20 = 0.57 IR (Nuiol) Absorption OH / NH C = O 1704 (ep), 1664 (max) cm-1 Aromatic + amide II 1609,1584,1512 cm-1 NMR (DMSO) 1.26 (si) C (CH3) 3; 2.40 CH (N) -CH2-Ph; 3.69 (s) CH30; 3.84 (m) CH (N) -CH2-Ph; 4.66 (d, J = 12) -S-CH-Ph H2 Trans; -COCH-N H3 Trans; 4.75 (si) 2H Ph-CH2-OP; 5.04 (d, J = 16) N-CH 2 -biphenyl; 6.80 to 7.10 (m) Ph-O; 7.10 to 7.75 6.62 (d) 8.79 (si) other aromatics and NH.

Example 10: [S - [R [trans ()]]] - [i - [[4 - [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2 - [[5- (3-cyclohexylpropyl) -2- 1,1-Dimethylethyl (4-methoxyphenyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] amino] -2-oxoethyl] carbamate.

FG (I ') R3 = PhOMe; R5 = (CH2), - cyclohexyl; [Al] = - CH (NHC02tBu) - CH2-Ph-; [A2] = OPO (OBn) (OH) (Trans 1)

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 Step A: N-alkylation - [S- [R [trans ()]]] - [1 - [[4 - [[bis (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2 - [[5- (3) 1-Cyclohexylpropyl) -2- (4-methoxyphenyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] amino] -2-oxoethyl] carbamate 1,1- dimethylethyl.

As in Example 1, step A is carried out starting from 258.4 mg of a mixture of trans-diastereoisomer with 1-iodo-3-cyclohexylpropyl as the alkylating agent. 179 mg of expected product is obtained.

Stage B: Monodebenzylation The procedure is as in Example 1, Stage B, starting from 76 mg of the product obtained in the preceding stage. 51 mg of expected pure product are obtained.

Rf Dichloromethane / methanol 80/20 = 0.50 IR (Nuiol) NH 3414.3294 cm -1 C = O 1694.1659 cm -1 Aromatic + amide II 1610.1585.11513 cm -1 NMR (DMSO) 0.7 at 1.65 (m) 18 to 19H (alkyl chain); 1.26 (s) C (CH3) 3; 3.68 (s) CH30; 3.55 (m), 3.84 (m) CO-N-CH 2; 4.18 (m) CH (N) CH2-Ph; 4.33 and 4.50 CH (N) -CH 2-Ph; 4.55 (d, J = 11.5) H2 Trans; 4.70 (dd) H3 Trans; (d1) Ph-CH2-O-P; 6.62 (d, mobile), 8.20 (d, somewhat mobile) NH; 6.80 to 7.70 (m) 19H aromatic.

Example 11: [8- [R * (38 *)]] - [2 - [[5- (3-cyclohexylpropyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazipin-3 1,1-Dimethylethyl [1 - [[4 - [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2oxoethyl] carbamate.

 FG (I ') R3 = H, R5 = (CH2) 3-cyclohexyl; [A1] = - CH (NHCO2tBu) -CH2Ph-; [A2] = OPO (OBn) (OH) Step A: N-acylation - [S- [R * (3S *)]] - [1 - [[bis (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] - [ 1,1-Dimethylethyl 2 - [[5- (3-cyclohexylpropyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] amino] -2-oxoethyl] carbamate .

To a 250 mg solution of the amine obtained according to

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 Preparation 5 in 2 ml of dichloromethane at 0 ° C. under an inert atmosphere, a solution prepared beforehand comprising 512 mg of O- [bis (phenylmethoxy) phosphinyl] -N- [(1,1-dimethylethoxy) carbonyl] -L-tyrosine ( L-Boc-Tyr-OP03Bn2, 182 mg of EDC, 128 mg HOBt, 2 ml of dichloromethane and 0.5 ml of dimethylformamide and stirred for 2 hours at room temperature, after dilution with ethyl acetate, washing with citric acid 5% of sodium bicarbonate and then of sodium chloride, dried and then evaporated under reduced pressure to obtain 661 mg of crude product which is purified by chromatography eluting with a dichloromethane / methanol mixture 99/1 498 mg of expected pure product are obtained.

Stage B: Monodebenzylation The procedure is as in Stage B of Example 1 starting from 115 mg of the product obtained in the preceding stage. 87 mg of expected pure product are obtained.

Rf dichloromethane / methanol 80/20 = 0.46 IR (Nuiol) Absorption OH / NH C = O 1701, 1656 (max) cm-1 Aromatic + amide II 1609,1585,1570,1509,1500 cm-1 NMR (DMSO 0.70 to 1.60 C-CH 2, C-CH; 1.27 (si) C (CH3) 3; 2.60 (m) CH (N) -CH2-Ph; 2.88 (dd) -S-CH2-Ph (H2 cycle); 3.01 (t) 3.46 (m) 4.06 = CN-CH 2 -C; 4.20 (m) (1H) 4.36-CO-CH (N) (H 3 ring); 4.80 to 5.10 (2H) Ph-CH2-OP; 6.44 (d) 6.88 (d) = CNH-CH; 7.09 (si) (4H) C-Ph-O; 7.25 (1) (5H) C-Ph-O; 7.32 (m) (1H) 7.57 (m) (2H) 7.67 (d) (1H) phenyl adjacent to the heterocycle; 8.32 (d) Other = C-NH-CH.

oxo-l-[[4-phosphonooxyphényl] méthyl] éthyl]-carbamate de 1,1-diméthyléthyle. Example 12: [8- [R * (38 *)]] - [2 - [[5- (3-cyalohexylpropyl) -2,3,4,5-tetrahydro-4-oxo-1,5-benzothiazepin-3 -yl] amino] -2-

1,1-Dimethylethyl oxo-1 - [[4-phosphonooxyphenyl] methyl] ethyl] carbamate.

FG (I ') R3 = H, R5 = (CH2) 3-cyclohexyl; [A1] = - CH (NHCO2tBu) -CH2Ph-; [A2] = OPO (OH) 2 to 207 mg of the product obtained in Step A of Example 11 in

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 5 ml of methanol is added 26 mg of 9.5% palladium on carbon and saturates the atmosphere with hydrogen. After filtration, rinsed with methanol and evaporated under reduced pressure to obtain 156 mg of expected product.

Rf dichloromethane / methanol 80/20 = 0.10 IR (Nuiol) Absorption OH / NH 3416.3296 cm-1 C = O 1700, 1696 (max) cm-1 Aromatic + amide II 1608.1585,1572.1508 cm -1 1 NMR (DMSO) 0.70 to 1.60 C-CH 2, C-CH; 1.27 (si) C (CH3) 3; 2.60 (m) (1H) CH (N) -CH2-Ph; 2.88 (dl) (1H) -S-CH 2 -CH (N); 3.00 (t) (1H) 3.46 (m) (2H) 4.08 (m) (1H) = CN-CH 2 -; 4.19 (m) (1H) 4.24-COCH (N) -; 6.91 (d) 8.23 = C-NH-; 7.04 C-Ph-O; 7.17 (AA'BB ') Ph-O; 7.33 (m) 7.17 (m) 7.69 (d) phenyl adjacent to the heterocycle.

Example 13: [8- [R * (3R *)]] - [2 - [[5- (3-cyclohexylpropyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3 1,1-Dimethylethyl] -yl] amino] -1 - [[4-hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2oxoethyl] carbamate.

 FG (I ') R3 = H, R5 = (CH2) 3-cyclohexyl; [A1] = - CH (NHCO2tBu) -CH2Ph-; [A2] = OPO (OBn) (OH) The procedure is as in Example 11 stages A and B but from 483 mg of the product obtained in Preparation 10. 20 mg of the expected monobenzylated product is obtained.

Rf dichloromethane / methanol 80/20 = 0.50 IR (Nuiol) Absorption OH / NH C = O 1700, 1696 (max) cm-1 Aromatic + amide II 1608.1555,1572.1508 cm-1 NMR (DMSO) 0 70 to 1.60: C-CH 2, C-CH; 2.70 to 2.85 = -S-CH 2; 4.12 (m) - 4.20: = C-N-CH 2; 4.35 (m), 4.20 (m): CO-N-CH-CO; 4.80 (dl): Ph-CH20P; 7.07 (m): -C-Ph-O; 7.28 (m): Ph-C; 6.82 (d): -C-NH-CH; 7.55 (m) (2H), 7.45 (d) (1H), 8.30 (d) (1H): phenyl adjacent to the heterocycle; (s), 1.30 (s): Boc.

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2#3,4p5-tétrahydro-4-oxo-1,5-benzothiazépin-3-yl] amino]-2- oxo-l-[[4-phosphonooxyphényl] méthyl] éthyl] -carbamate de
1,1-diméthyléthyle. Example 14: [8- [R * (3R *)]] - [2 - [[5- (3-cyclohexylpropyl)]

2 # 3,4p5-tetrahydro-4-oxo-1,5-benzothiazepin-3-yl] amino] -2-oxo-1 - [[4-phosphonooxyphenyl] methyl] ethyl] carbamate
1,1-dimethylethyl.

FG (I ') R3 = H, R5 = (CH2) 3-cyclohexyl; [A1] = - CH (NHCO2tBu) -CH2-
Ph; [A2] = OPO (OH) 2
The procedure is as in Example 12 from 55 mg of dibenzylated product obtained in Step A of Example 13. 37 mg of the expected monobenzylated product is obtained.

Rf dichloromethane / methanol 80/20 = 0.27
NMR (DMSO)
1.00 to 1.60: C-CH 2, -C-CH; 2.50 to 3.50; 4.11 (m): -CH 2 -CH, -SCH 2, = CN-CH 2; 4.22 (m), 4.35 (m): CO-CH-NCO; 6.89-7.08: C-Ph-O; 7.31 (1H), 7.54 (2H), 7.06 (1H): Phenyl adjacent to the heterocycle; 8.34 (d): = C-NH-CH; 1.29 (si): Boc.

i 2-(4-méthoxyphényl)-N-(1-naphtylméthyl) 4-oxo-1,5-benzo- thiazépine-5(4H)-acétamide. Example 15: trans () - 2,3-dihydro-3 - [[3- [4 - [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] -1-oxopropyl] amino]

2- (4-Methoxyphenyl) -N- (1-naphthylmethyl) -4-oxo-1,5-benzothiazepine-5 (4H) -acetamide.

FG (I ') R3 = H; R5 = (CH2) -CO-NH-CH2-Napht .; [A1] = - (CH2) -Ph-; [A2] = OPO (OBn) (OH) step A: trans () - 2,3-dihydro-3 - [[3- (4-hydroxyphenyl) -1-oxopropyl] amino] -2- (4-methoxyphenyl) N- (1-Naphthylmethyl) -4-oxo-1,5-benzothiazepine-5 (4H) -acetamide,
256.5 mg of amine P4 (preparation) is added at 0 ° C., under argon.
4) in 2 ml of dichloromethane to a solution of 103 mg of 3- (p-hydroxyphenyl) -propionic acid, 120 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) and 84 ml of 1-hydroxybenzotriazole hydrate (HOBT) in 1.4 ml of CH 2 Cl 2 and 0.4 ml of DMF. After treatment and purification by chromatography eluting with a CH 2 Cl 2 / MeOH 98/2 mixture, 258 mg of expected product is obtained.

 Step B: trans () 3 - [[3- [4 - [[bis (phenylmethoxy) phosphinyl] oxy] phenyl] -1-oxopropyl] amino] -2,3-dihydro-2- (4-methoxyphenyl) -N- (1-naphthylmethyl) -4-oxo-1,5-benzothiazepine-5 (4H) -

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 acetamide.

148.5 mg of the product obtained in the preceding stage are added in 4 ml of acetonitrile, 1 ml of carbon tetrachloride, 125 mg of N, N diisopropylethylamine, 6 mg of N, N-dimethylaminopyridine and 181 mg of the dibenzyl ester of the phosphonic acid. After treatment and purification on a silica column, eluting with the CH 2 Cl 2 / MeOH 98/2 mixture, 79 mg of expected product is obtained.

Stage C: Debenzylation To a solution of 85.2 mg of the product obtained in the preceding stage in 5 ml of acetone, 31 mg of sodium iodide, refluxed for 2 hours, then added 15 mg and maintained reflux for 45 hours. additional mn. After concentration under reduced pressure and washing with ethyl acetate and acetone, 64.9 mg of expected product.

Rf CH 2 Cl 2 / MeOH 80/20: 0.30 IR (Nujol) Absorption OH / NH C = O 1671, 1628 (max) cm -1 Aromatic + amide II 1610, 1600, 1585, 1555, 1539, 1511 cm -1 NMR (DMSO) 2.10 (m, 2H), 2.32 (m, 2H): CO-CH2-CH2-Ph-; 4.29 (d, 1H), 4.78 (4H): -CN-CH2-CO, CO-NH-CH2-Ph-; 4.46 (d, J = 11.5): Trans, H2 H3; 4.70 (d, 2H): Ph-CH20P; 6.78 (m, 4H), 6.96 (m, 4H): C-Ph-O; 7.30-7.62.7.85 (m, 1H), 7.95 (m, 1H), 8.03 (m, 1H): naphthyl and phenyl adjacent to the heterocycle; 8.44 (t): -C-NH-CH 2; 8.57 (d): -C-NH-CH; 3.70 (s): Ph-one.

Example 16 Trans () - 2,3-dihydro-3 - [[[6 - [[hydroxy (phenylmethoxy) phosphinyl] oxy] -2-naphthalenyl] carbonyl] amino] -2- (4-methoxyphenyl) -N- (1-Naphthylmethyl) -4-oxo-1,5-benzothiazepine-5 (4H) -acetamide.

 FG (I ') R3 = H; R5 = (CH2) -CO-NH-CH2-Napht .; [Al] = - naphth; [A2] = OP (O) (OBn) (OH) The procedure is as in Example 15, stages A, B and C, but starting from 252.8 mg of P4 and 115 mg of 6-hydroxy-acid. naphthoic. 108 mg of expected pure product is obtained.

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Rf CH2Cl2 / MeOH 80/20: 0.43 IR (Nuiol) Absorption OH / NH C = O 1693 (max) cm-1 Aromatic + amide II 1609,1582,1537,1512,1498 cm-1 NMR (DMSO) 3 , 65 (s) Ph-OCH3; 4.31 (d, J = 16.5), 4.80 (masked) N-CH 2 -CO-; 4.80 (masked) H2; 5.01 (dd, J = 8.5 and 11.5) H3; 4.80 (m) 4H-P-O-CH 2 -PH and CONH-CH 2 -Ar; 6.80 and 7.11 (AA'BB ') Ph; 8.48 (t) CO-NH-CH 2, -NH-CO-Ar; 7.15 to 7.82 (m) 20H; 7.93 (m) 1H; 8.04 (m) 1H; 8.13 (si) 1H aromatics.

(4-méthoxyphényl)-N-(1-naphtylméthyl)-4-oxo-1,5-benzothiazé- pine-5(4H)-acétamide. Example 17 Trans () - 2,3-dihydro-3 - [[[5- [[hydroxy (phenylmethoxy) phosphinyl] oxy] -1H-indol-2-yl] carbonyl] amino] -2-

(4-Methoxyphenyl) -N- (1-naphthylmethyl) -4-oxo-1,5-benzothiazepine-5 (4H) -acetamide.

PG (I ') R3 = H; R5 = (CH2) -CO-NH-CH2-Napht .; [Al] = - indolyl; [A2] = OPO (OBn) (OH) The procedure is as in Example 15, stages A, B and C, but starting with 258 mg of P4 and 110 mg of 5-hydroxy-1H-indolecarboxylic acid. . 104 mg of expected pure product are obtained.

2,3-dihydro-2-(4-méthoxyphényl)-N-(i-naphtylméthyl)-4-oxo- 1,5-benzothiazépine-5(4H)-acétamide. 80/20 Rf CH2Cl2 / MeOH: 0.49 IR (Nujol) Absorption OH / NH C = O 1658 (max) cm-1 Aromatic + amide II 1609,1584,1546,1513 cm-1 NMR (DMSO) 3.64 (s) Ph-OCH3; 4.29 (d, J = 16.5), 4.71 to 4.85 (7H), 5.01 (dd) N-CH 2 -CO-, H 2, H 3, -P-O-CH 2 -P and CONH-CH2-Ar; 6.80 and 7.11 (AA'BB ') Ph, 6.74 (d), 7.10 (d) Ph-O; 7.03 to 8.03 aromatics; 8.49 (t), 8.89 (d), 11.20 H mobile Example 18: trans () - 3 - [[(4-boronophenyl) carbonyl] amino]

2,3-Dihydro-2- (4-methoxyphenyl) -N- (1-naphthylmethyl) -4-oxo-1,5-benzothiazepine-5 (4H) -acetamide.

FG (I ') R3 = H; R5 = -CH2-CO-NH-CH2-Napht .; [Al] = - Ph; [A2] = B (OH) 2 The procedure is as in Example 15, stage A, but starting from

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 156.6 mg of P4 and 63 mg of 4-boronobenzoic acid. 135 mg of expected pure product is obtained.

Rf CH2Cl2 / MeOH 95/5: 0.42 IR (Nujol) Absorption OH / NH C = O 1653 (max) cm-1 Aromatic + amide II 1609,1584,1558,1528,1512 cm-1 NMR (DMSO) 3 , 66 (s) Ph-OCH3; 4.29 (d, J = 16.5), 4.76 N-CH 2 -CO-; 4.78 (m) H 2 and CONH-CH 2 -Ar, 4.96 (dd, J = 11.5 and 8.5) H 3; 6.78 and 7.07 (AA'BB ') Ph-O; 7.58 and 7.75 (AA'BB ') CO-Ph, 7.40 (m) 3H, 7.50 to 8.05 8H aromatics; 8.20 (s) 2H mobile, 8.42 (t, mobile) CO-NH-CH 2, 8.96 (t, mobile) CO-NH-CH.

aminO]-1-0xoéthyl] aMino]-2.3-dihydro-2-(4-méthoxyphényl)-N- (1-naphtylméthyl)-4-oxo-1,5-benzothiazépine-5(4H)-acétamide. Example 19: trans () - 3 - [[2 - [[(4-boronophenyl) carbonyl]

aminO] -1-oxoethyl] amino] -2,3-dihydro-2- (4-methoxyphenyl) -N- (1-naphthylmethyl) -4-oxo-1,5-benzothiazepine-5 (4H) -acetamide.

FG (I ') R3 = H; R5 = CH2-Co-NH-CH2-Napht .; [AI] = - CH2-NHCO-Ph-; [A2] = B (OH) 2 The procedure is as in Example 15, stage A, but starting from 51 mg of P4 and 27 mg of N- (4-boronobenzoyl) -glycine. 28 mg of expected pure product are obtained.

Rf CH2Cl2 / MeOH 90/10: 0.45 IR (Nuiol) Absorption OH / NH C = O 1669 (max), 1653 (ep) cm-1 Aromatic + amide II 1609,1584,1558,1528,1512 cm-1 NMR (DMSO) 3.53 (dd, d = exchange), 3.77 (dd, d = exchange) ArCH2-NHCO; 3.70 (s) Ph-OCH3; 4.29 (dl, J = 16.5), 4.75 concealed CON-CH 2 -CO-; 4.48 (d, J = 11.5) H2, 4.70 to 4.80 (m) H3 + CO-NCH2-CO-; 6.76 and 7.01 (AA'BB ') Ph-O; 7.76 (AA'BB ') CO-Ph; Aromatic 7,30 to 8,02 (m) 11H; 8.17 (s, broad) 2H mobile, 8.41 (t wide) 8.50 (t wide) CO-NH-CH2, 8.59 (d, mobile) CONH-CH.

Example 20: (R) -N- [5- (3-cyclohexylpropyl) -4-oxo-2,3,1,5-tetrahydro-1,5-benzothiazepin-3-yl] -3-formyl-4- ( phosphonooxy) benzamide.

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FG (I ') R3 = H; R5 = (CH2) 3-cyclohexyl; [Al] = - Ph (m-CHO) -; [A2] = OPO (OBn) (OH) Step A: (R) -N- [5- (3-cyclohexylpropyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl ] -4-hydroxy-3-formylbenzamide.

The procedure is as in Example 15, stage A, but starting from 318.1 mg of P5 and 199 mg of 3-formyl-4-hydroxy-benzoic acid. 226 mg of expected pure product are obtained.

Stages B and C: The procedure is as in Example 15, stages B and C, but starting from 100.7 mg of the product obtained in the preceding stage. 26.9 mg of expected product is obtained.

IR (Nujol) Absorption OH / NH C = O 1689 (m), 1639 (F) cm -1 Aromatic + amide II: 1605.1555.1550.1482 cm -1 NMR (DMSO) 0.80-1.65 CH2 and CH (cycle and chain); 3.30 to 3.60 (s) SCH2-CH (N) (cycle); 4.27 CO-N-CH 2 -; 4.59 (m) S-CH 2 -CH (N), 6.95-8.35.9.09 (d) aromatics; 10.37 (if) Ph-CHO.

Example 21: (R) -N- [5- (3-Cyclohexylpropyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] -4- (phosphonooxy) benzamide .

FG (I ') R3 = H; R5 = (CH2) 3-cyclohexyl; [Al] = - Ph; [A2] = -OPO (OH) (OH) The procedure is as in Example 15, stage A, B and C, but starting from 106.2 mg of P5 and 55 mg of 4-hydroxybenzoic acid. At the end of these three stages, after purification, 69 mg of expected pure product are obtained.

Rf CH2Cl2 / MeOH 90/10: 0.59 IR (Nuiol) Absorption OH / NH Max 3304 cm -1 C = O 1647 cm -1 Aromatic + amide II: 1605.1555.1548.1501 cm -1 NMR (DMSO) 0.77 (m) 2H, 1.10 (m) 6H, 1.30 to 1.65 (m) 6 to 7H, Aliphatic chain; 3.47 (m), 4.24 (m) CO-N-CH 2 -; 3.30 (t) 3.47 (m)

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 S-CH2-CH (N); 4.55 (m) H3, 7.10 to 7.80 to 8H aromatics; 8.63 (d) CH-NH-CO.

Example 22: (R) - [4 - [[[5- (3-Cyclohexylpropyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] amino] carbonyl] 2-formylphenoxy] -acetic acid.

FG (I ') R3 = H; R5 = (CH2) 3-cyclohexyl; [Al] = - Ph (m-CHO) -; [A2] = -OCH2COOH Step A: Alkylation - (R) - [4 - [[[5- (3-cyclohexylpropyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3 [α] -yl] amino] carbonyl] 2-formylphenoxy] ethyl acetate. To 43.4 mg of the product obtained in Step A of Example 20 in 5 ml of acetone is added 26 mg of potassium carbonate and 16 mg of ethyl bromoacetate and refluxed for 3 hours. After treatment, 52 mg of expected crude product are obtained.

Stage B: Saponification 52 mg of ester obtained in the preceding stage are stirred at room temperature in 5 ml of methanol with 0.094 ml of 2N sodium hydroxide solution. We obtain 37 mg of crude product which is purified by chromatography eluting with the mixture CH 2 Cl 2 / MeOH 90/10 then 85/15. 29 mg of expected pure product are obtained.

IR (Nujoll Absorption OH / NH 3414 (ep) 3310 (Max) C = O 1740 (ep), 1704 (ep), 1687.11645 cm -1 Aromatic + amide II: 1609.1585, 1547.1491 cm -1 MS (electrospray ionization, negative mode): mm = 524 / ... compatible with the expected structure.

tétrahydro-1,5-benzothiazépin-3-yl]-4-(diphosphonométhyl)- benzamide. Example 23: (R) -N- [5- (3-cyclohexylpropyl) -4-oxo-2,3,4,5-

tetrahydro-1,5-benzothiazepin-3-yl] -4- (diphosphonomethyl) benzamide.

 FG (I ') R3 = H; R5 = (CH2) 3-cyclohexyl; [Al] = - Ph; [A2] = -CH [PO (OH) 2] 2.

Step A: (R) -N- [5- (3-Cyclohexylpropyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] -4- (bis (diethoxy) -2-

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 phosphenyl) methyl] benzamide.

123 mg of 4- [bis (diethoxyphosphinyl) methyl] benzoic acid, 60 mg of EDC, 42 mg of HOBt, 2 ml of dichloromethane and 1 ml of DMF are stirred at room temperature at room temperature for 10 minutes. C. and then poured this mixture into the mixture consisting of 80 mg of P5 in 2 ml of dichloromethane at 0 ° C. under argon.

The medium is stirred overnight at room temperature. After treatment and purification by chromatography on silica eluting with a mixture of CH 2 Cl 2 / MeOH 98/2, 127 mg of expected pure product is obtained.

Stage B: Reduction 40 mg of trimethylsilane bromide are added dropwise to the mixture consisting of 29 mg of the product obtained in the preceding stage and 1.5 ml of dichloromethane and refluxed for 24 hours. then poured into methanol, evaporated under reduced pressure and recrystallized in ether cold.

17.5 mg of expected pure product are obtained.

Rf CH2Cl2 / MeOH 80/20 = 0.16 IR (Nuiol) Absorption OH / NH NH 3410 cm-1 C = O 1649 cm -1 Aromatic + amide II: 1611.1585, 1571.1549, 1523.1491 cm -1 NMR (DMSO) 0.70 to 1.60 CH 2 and CH (ring and chain); 3.26 to 3.98 (s) S-CH 2 -CH (N) (ring); 4.23 CO-N-CH 2 -; 4.56 (m): S-CH 2 -CH (N), 7.34 (m), 7.61 (m), 7.68 (m), 7.74) aromatics; (d) CH-NH-CO.

Example 24: [3R- [3R * (S *)]] - p- (acetylamino) -N- [5- (3-cyclohexylpropyl) -2,3,4,5-tetrahydro-4-oxo-1 5-Benzothiazepin-3-yl] -4- (difluorophosphonomethyl) benzenepropanamide.

FG (I ') R3 = H; R5 = (CH2) 3-cyclohexyl; [Al] = - CH (NHAC) -CH2-Ph-; [A2] = CF 2 PO (OH) (OH) The procedure is as in Example 23, Steps A and B, but starting from 121.5 mg of the amine P5 and 180 mg of N-acetyl-4 - [[(diethoxyphosphinyl) difluoro] methyl] -L-phenylalamine. Pure expected product is obtained.

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Rf CH 2 Cl 2 / MeOH 80/20 = 0.63 IR (NH) 3) NH 3421 (Max), 3393 (ep) cm -1 C = O 1677 (ep), 1656 (Max) cm -1 Aromatics + amide II: 1615, 1600, 1583, 1569, 1501 cm -1 NMR (DMSO) 1.10 to 1.70 CH 2 and CH (ring and chain); 1.97 (s) NHCOCH3; 1.31 (m) 4.18 (ml) β-EO; 2.72 (t) (1H), 3.35 (m) (1H), 3.04 (m) (2H) S-CH 2 -CH (N) (ring) and Ph-CH 2 -CH (N) - CO; 3.74 (m) (1H) 4.30 (m) (1H) CO-N-CH 2 -; 4.35 (m) (1H) 4.66 (q) H3, 5.92 (d), 6.82 (d) CH-NH-CO; 7.21 7.51 AA'BB 'Phenyl; 7.21 (1H), 7.29 (m) (1H), 7.46 (m) 1H, 7.65 (dd) (1H), benzothioazepinone phenyl.

tétrahydro-1,5-benzothiazépin-3-yl]-N'-[4-(phosphonooxy) phényl]-urée. Example 25: (R) -N- [5- (4-cyclohexylbutyl) -4-oxo-2,3,4,5-

tetrahydro-1,5-benzothiazepin-3-yl] -N '- [4- (phosphonooxy) phenyl] urea.

FG (I ') R3 = H; R5 = (CH2) 4-cyclohexyl; [A1] = - NH-PH; [A2] - = OP (O) (OH) 2 Stage A: formation of urea - (R) -N- [5- (4-cyclohexylbutyl) -4-oxo-2,3,4,5-tetrahydro -1,5-Benzothiazepin-3-yl] -N '- (4-methoxyphenyl) -urea.

To a mixture consisting of 14 mg of 4-methoxyisocyanate in 1 ml of toluene is added under argon 26.2 mg of P6 in 0.5 ml of toluene, stirred at room temperature for 3 hours and concentrated under reduced pressure. 44.1 mg of crude product are obtained which is purified by chromatography on silica eluting with CH 2 Cl 2 and then with the mixture CH 2 Cl 2 / MeOH 99.5 / 0.5. 31 mg of expected pure product is obtained.

Stage B: Cleavage of Methoxy- (R) -N- [5- (4-cyclohexylbutyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] -N'- (4-hydroxyphenyl) -urea.

To a solution of 29 mg of the product obtained in the preceding stage, in 2 ml of CH 2 Cl 2, 22 mg of ethanethiol and 48 mg of aluminum chloride are added under argon, the mixture is stirred for 3 hours at room temperature and then 2.2 ml of THF, 0.6 ml 0.5M hydrochloric acid and 2.2 ml water. After extraction with ethyl acetate, drying and evaporation under reduced pressure,

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 30 mg of the expected product is obtained.

Stage C: - (R) -N- [5- (4-Cyclohexylbutyl) -4-oxo-2,3,4,5-tetrahydro-1,5benzothiazepin-3-yl] -N '- [4- [phophorylation] [bis (phenylmethoxy) phosphinyl] oxy] phenyl] urea.

To 23.5 mg of the product obtained in the preceding stage in 2 ml of acetonitrile, 0.2 ml of carbon tetrachloride, 27 mg of N, N diisopropylethylamine, 1.2 mg of N, N-dimethylaminopyridine and 39 mg of the dibenzyl ester of phosphonic acid.

After treatment and purification on a silica column, eluting with a mixture of CH 2 Cl 2 / MeOH 99/1 then 98/2, 24 mg of expected product is obtained.

Stage D: Total Debenzylation A solution of 23.1 mg of the product obtained in the preceding stage is saturated with 3 ml of MeOH, stirred for 3 hours at room temperature and evaporated under reduced pressure until 17 mg of expected pure product is obtained.

Rf methanol / water 80/20 = 0.60 IR (Nuiol) Absorption OH / NH C = O 1652 cm-1 (ep) 1636 cm-1 (Max) Aromatic + amide II: 1608.1352.1554.1508 cm-1 NMR (DMSO) 2.9 (t) at 3.5 (m) S-CH 2 -CH (N) (ring); 4.30 H3; 6.96 7.06 (AA'BB ') phenyl, 7.32 (m), 7.55 (m) phenyl benzothioazepinone.

Example 26: cis () - N- [5- (3-cyalohexylpropyl) -2- (4-methoxyphenyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3- yl] -4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] benzeneacetamide.

FG (I ') R3 = PhOMe; R5 = (CH2) 3-cyclohexyl; [Al] = -CH2-Ph-; [A2] = - OPO (OBn) (OH) (cis) Step A: cis () 4 - [[bis (phenylmethoxy) phosphinyl] oxy] N- [5- (3-cyclohexylpropyl) -2- (4-methoxyphenyl) 4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] benzeneacetamide.

A solution under argon at 0 C consisting of 140 mg of 4 - [[bis (phenylmethoxy) phosphinyl] oxy] benzene acetic acid, 65 mg of EDC and 45 mg of HOBt in 1 ml of CH 2 Cl 2 is prepared.

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 and 0.25 ml of DMF, and poured into the mixture consisting of 0.499 g of cis-1 amine (Preparation 7) and 1 ml of CH 2 Cl 2.

After 6 hours at room temperature, it is diluted with ethyl acetate, washed, dried and concentrated. 233 mg of crude product is obtained which is purified by chromatography, eluting with a 98.5 / 1.5 CH 2 Cl 2 / MeOH mixture to obtain 211 mg of expected product. Step B: The solution of refluxing is heated for 1 hour 30 minutes. 71.8 mg of the product obtained in the preceding stage in 5 ml of acetone to which 44 mg of sodium iodide have been added, the acetone is concentrated under reduced pressure, diluted with ethyl acetate, washed, dried and concentrated under reduced pressure until 32.3 mg of expected product.

Exemple 27 : cis()-N-[5-(3-cyclohexylpropyl)-2-(4-méthoxy- phényl)-4-oxo-2,3,4,5-tétrahydro-1,5-benzothiazépin-3-yl]-4- (phosphonooxy)-benzèneacétamide. Rf CH2Cl2 / MeOH = 0.61 IR (Nujol) NH 3408 cm-1 C = O 1652 cm-1 (Max, complex) cm-1 Aromatic + amide II: 1609.1585.11513.1499 cm-1 NMR (DMSO) 0.83 (m) (2H) 1.15 (m) (8H) 1.63 (m) (7H) (ring and chain); 3.25 (s) Ph-CH2-CO, 3.80 (s) OCH3, 3.44 (m) 4.36 (m) N-CH2, 5.04 (d, J = 4.5) H2 Cis , 4.70 (d, J = 4.5) H3 Cis, 7.29 (masked) 7.71 (dd) H5 and H8.7, 29 (masked) 7.46 (t) H7 and H6 (phenyl) benzothioazépinone); 6.99 (d, J = 8.5) ortho CH of 0.6.85 (d, J = 8.5) CH in meta of 0; 7.18 (d, J = 8.5) 6.79 (d, J = 8.5) aromatic (Ph-OMe); 5.10 (s) 5.12 (s) 0-CH2-Ph, 7.34 (s) (benzyl phenyl)

Example 27: cis () - N- [5- (3-cyclohexylpropyl) -2- (4-methoxyphenyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3- yl] -4- (phosphonooxy) -benzeneacetamide.

FG (I ') R3 = PhOMe; R5 = (CH2) 3-cyclohexyl; [Al] = -CH2-Ph-; [A2] = -OPO (OH) 2 (cis) A solution of 134 mg of the product obtained in Step 2 in 2 ml of methanol, to which 18 mg of 95% palladium on carbon has been added, is saturated with hydrogen. hours at room temperature and evaporates under pressure

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 reduced to 94 mg of expected pure product.

Rf methanol / water 80/20 = 0.50 IR (Nuiol) Absorption OH / NH C = O 1650 cm-1 (Max) Aromatic + amide II: 1608.1 582.1510 cm-1 NMR (DMSO) 0.81 ( m) (2H) 1.10 to 1.30 (m) (7 to 8H) 1.44 to 1.70 (m) (8H) (ring and chain); 3.29 (AB, J = 14) Ph-CH2-CO; 3.52 (m) (1H) 4.37 (m) (1H) N-CH 2; 3.78 (s) 3H Ph-OMe; (t, J = 7) H3; 6.80 to 7.02 (m) 6H, 7.16 (dl) (2H), 7.37 (m) 2H, 7.58 (m) (2H), 7.72 (d) 1H aromatics Example 28 : [8- [R * (68 *)]] - [2 - [[4- (3-cyclohexylpropyl) hexahydro-5-oxo-1,4-thiazepin-6-yl] amino] -2-oxo 1,1-Dimethylethyl 1 - [[4- (phophenoxy) phenyl] methyl] ethyl] carbamate.

* FG (I ') R1, R2, R3, R4 = H, the dashed line does not represent a double bond; R5 = (CH2) 3-cyclohexyl; [A1] = -CH (NHCO2tBu) -CH2-Ph-; [A2] = OP (O) (OH) 2 Step A: Acylation - [S- [R * (6S *)]] - [1 - [[4 - [[bis (phenylmethoxy) phosphinyl] oxy] phenyl] methyl ] -2 - [[hexahydro-5-oxo-1,4-thiazepin-6-yl] amino] -2-oxoethyl] -carbamate 1,1-dimethylethyl.

The mixture consisting of 455 mg of L-Boc-tyr-O- (PO 3 Bn 2), 158 mg of [1- (3-dimethylaminopropyl) -3-ethylcarbodiimide HCl] (EDC) and 111 mg is mixed for 15 minutes at 0 ° C. under argon. (1-hydroxybenzothiazole hydrate) (HOBt) in 600 μl of dimethylformamide (DMF) and 1.9 ml of dichloromethane (CH 2 Cl 2) and added a solution of 162 mg of P 8 in 2 ml of CH 2 Cl 2 and 235 l of Hunig base. The mixture is stirred at ambient temperature for 5 hours, then is diluted in 30 ml of ethyl acetate, then after washing and drying, the organic phase is evaporated under reduced pressure to obtain 442 mg of crude product.

Rf: CH2Cl2 / MeOH 90/10 0.4 Step B: Alkylation - [S- [R * (6S *)]] - [1 - [[4 - [[bis (phenylmethoxy) phosphinyl] oxy]

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 phenyl] methyl] -2- [[4- (3-cyclohexylpropyl) hexahydro-5-oxo-1,4-thiazepin-6-yl] amino] -2-oxoethyl] carbamate 1,1-dimethylethyl.

To a solution of 222 mg of the product obtained in the previous stage in 3 ml of DMF at 0 ° C., under argon, 24 mg of sodium hydride and 116 mg of 1-iodo-3-cyclohexylpropyl in 1 ml of DMF are added and stirred. 15 minutes at 0 C then 3 hours at room temperature. It is diluted with 20 ml of water, extracted with ethyl acetate and evaporated under reduced pressure until 197 mg of expected crude product is obtained.

Rf: CH 2 Cl 2 / MeOH 98/2 0.2 Step C: Debenzylation A solution of 50 mg of the product obtained in the above Step in 2 ml of MeOH to which 7.7 mg of 95% palladium on carbon has been added is hydrogenated to hydrogen. %, stirred overnight at room temperature and evaporated under reduced pressure to obtain 36 mg of expected pure product.

Rf methanol / water 80/20 = 0.20 IR (Nuiol) Absorption OH / NH C = O 1707.1667 (ep), 1646 (Max) cm -1 Aromatic + amide II: 1609.1508 cm -1 NMR ( DMSO) 0.50 to 1.70 (ring and chain); 2.50 to 3.95 S-CH 2 -CH (N), CON-CH 2, Ph-CH 2, 4.04 (1) 4.87 (1) CH (NHBoc); 7.00 7.10 aromatic, 8.05 (d) CH-NHCO.

Example 29: (R) -3 - [[(aminocarbonyl) hydrazono] methyl] -4- (phosphonooxy) -N- [5- (3-cyclohexylpropyl) -4-oxo-2,3,4,5-tetrahydro- l, 5-benzothiazepin-3-yl] -benzamide.

 FG (I ') R3 = H, R5 = (CH2) 3-cyclohexyl; [Al] = -Ph (o-C = N-NH-CONH 2) -; [A2] = OPO (OH) 2 The procedure is as for example 15 stages A and B but from 322 mg of P5 and 270 mg of 3 - [[(aminocarbonyl) hydrazono] methyl] -4-hydroxybenzoic acid. At the end of these two stages, 1.18 g of crude product is obtained which is purified by chromatography and one of the fractions (78.7 mg) is engaged in the total debenzylation reaction by reaction.

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 of trifluoroacetic anhydride in CH2Cl2. 32 mg of expected product is obtained.

IR (Nujol) Absorption OH / NH: 3480.3310 cm-1 C = O complex 1649 (Max) cm-1 conjugated system, Aromatic + Amide II: 1616, 1584, 1486 cm-1 NMR (DMSO) 0.76 ( m) 1.10 (m) 1.30 to 1.70 (m) (cycle and chain); 3.50 (masked) 4.25 (m) CO-N-CH 2, 3.30 (m) 3.50 (m) S-CH 2 -CH (N), 4.57 (m) CO-CH-NH 7.00 to 7.90 aromatic, 8.05 (d) CH-NHCO, 6.48 (m), 8.10 to 8.90 (m), 10.50 (m).

5-oxo-4,5,6,7-tétrahydro-1,4-thiazépin-6-yl]-4-[(phosphono) (difluoro) méthyl]-L-phénylalaninamide. Example 30: [S- [R * (6R *)]] - N-acetyl- [4- (3-cyclohexylpropyl)]

5-oxo-4,5,6,7-tetrahydro-1,4-thiazepin-6-yl] -4 - [(phosphono) (difluoro) methyl] -L-phenylalaninamide.

FG (I) R1, R2, R3, R4 = H; the dotted line represents a double bond, R 5 = (CH 2) 3 -cyclohexyl; [A1] = -CH (NHAc) -CH2Ph-; [A2] = CF2P (O) (OH) 2 Step A: [S- [R * (6R *)]] - N-acetyl- [4- (3-cyclohexylpropyl) -5-oxo-4,5,6 7-Tetrahydro-1,4-thiazepin-6-yl] -4 - [(diethoxyphosphinyl) (difluoro) methyl] -L-phenylalaninamide.

80 mg of product P9 (preparation 9: (R) 3-amino-5- (3-cyclohexylpropyl) -2,3-dihydro-1,5-benzothiazepin-4 (5H) -one) are mixed for 5 hours at room temperature, with 140 mg of N-acetyl 4 - [[(diethoxyphosphinyl) difluoro] methyl] L-phenylalanine, 48 mg of HOBt, 68 mg of EDC, 4 ml of CH2Cl2 and 0.5 ml of DMF, run in ethyl acetate The mixture is dried and evaporated under reduced pressure until 108 mg of crude product is obtained which is purified by chromatography to give 60 mg of expected pure product.

Stage B: Deprotection 50 mg of the product obtained in the preceding stage is reacted with reflux for 5 hours with 1031 of TMSBr in 5 ml of dichloromethane then poured into methanol, evaporated under reduced pressure and purified by chromatography. 16 mg of expected product is obtained.

<Desc / Clms Page number 55>

IR (Nuiol) Absorption OH / NH: 3480.3310 cm-1 C = O 1707 cm-1, C = O complex, region C = C 1646 (Max) cm-1 Aromatic + Amide II: 1538 cm-1 NMR: 0.80 to 1.90.2.30 to 3.80.4.45 to 4.90.5.60 to 6.05, 5.7 (d) - 7.44 (m): Ph-; 8.49 (d) -8.56 (d): 2NHCH.

4-oxo-2,3,4,5-tétrahydro-1,5-benzothiazépin-3-yl]-2-pyridine carboxamide. Example 31: (R) -5- (Phosphonooxy) -N- [5- (3-cyclohexylpropyl)

4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] -2-pyridine carboxamide.

FG (I ') R3 = H, R5 = (CH2) 3-cyclohexyl; [Al] = 2-pyridinyl; [A2] = - OPO (OH) 2 Step A: Amidification (R) 5- (hydroxy) N- [5- (3-cyclohexylpropyl) -4-oxo 2,3,4,5tetrahydro 1,5-benzothiazepin-3 -yl] -2-pyridine carboxamide.

To a solution of 62 mg of 5-hydroxy-2-pyridine carboxylic acid, 103 mg of EDC, HCl, 73 mg of HOBt in 2 ml of DMF and 4 ml of CH 2 Cl 2, 412 mg are added at room temperature. of P5 in 4 ml of CH2Cl2 and stirred for 3 hours 30 minutes at this temperature. After washing, drying and evaporation under reduced pressure, 200 mg of crude product are obtained which is purified by chromatography eluting with CH2Cl2-AcOEt 70-30 to obtain 118 mg of purified product.

Stage B: Phosphorylation (R) 5 - [[(diethoxy) phosphinyl] oxy] N- [5- (3-cyclohexylpropyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine -3-yl] 2-pyridinecarboxamide.

90 mg of the product obtained in the preceding stage in 3 ml of acetonitrile are added at a temperature of -10 ° C., 0.125 ml of carbon tetrachloride, 2.5 mg of DMAP, 0.07 ml of diisopropylethylamine and 0.068 ml. of dibenzylphosphite and stirred for 1 hour 30 minutes at this temperature. After washing and drying, evaporated under reduced pressure and 150 mg of crude product which is purified by chromatography eluting with CH2Cl2-AcOEt 85-15 mixture. We obtain 110 mg of purified product expected.

Rf = CH2Cl2-AcOEt 70-30: 0.68.

<Desc / Clms Page number 56>

Stage C: Total debenzylation.

105 mg of the product obtained in the preceding stage in 6 ml of CH 2 Cl 2 are mixed with 3 ml of trifluoroacetic anhydride and stirred overnight at room temperature. After treatment, 36 mg of expected product is obtained.

NMR 0.77 (m): 2H; 1.00 to 1.28 (m) - 7H; at 1.68 (m) - 8H alkyl chain; 3.28 (t, J = 11.5), 3.57 (dd, J = 11.5) S-CH 2; 3.48 (m), 4.23 (m): CO-N-CH 2; 4.52 (m, dd after exchange): CO-CH-NH; 8.79 (d, mobile): CH-NH-CO; 8.48 (d, J = 2): H, 6 pyridinyl; 7.35 (m): 1H; 7.59 (m): 2H; 7.70 to 7.80 (m): 2H; 7.97 (d): 1H, aromatic H.

hexylpropyl)-4-oxo-2,3,4,5-tétrahydro-1,5-benzothiazépin-3- yl]-benzamide. Example 32: (R) -4 - [(Phosphono) fluoromethyl] -N- [5- (3-cyclohexyl) -N-

hexylpropyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] benzamide.

FG (I ') R3 = H, R5 = (CH2) 3-cyclohexyl; [Al] = Ph; [A2] = - CHFP (O) (OH) 2 The procedure is as for example 30 stages A and B but from 54 mg of P5 and 85 mg of 4- [bis (diethoxyphosphinyl) fluoromethyl] benzoic acid. 17.5 mg of expected product are obtained.

IR (Nuiol) Absorption OH / NH: 3405 cm -1 C = O 1649 (Max) cm -1 Aromatic + Amide II: 1616, 1605, 1585, 1571, 1545, 1501 cm -1 NMR (DMSO) 0.80- 1.70 (m) (ring and chain), 3.11 (ml) 3.47 (ml) S-CH 2 CH (N) 3.73 (ml) 4.30 CO-N-CH 2, 5.48 (ml) ) 5.62 NH, 7.30 to 7.70 aromatic.

Pharmacological study of the products of the invention IC50 measurement by sintillation proximity test (SPA)
The ability of molecules to bind to the SrcSH2 protein is evaluated by competition (IC50 measurement) in a test called Scintillation proximity assay (SPA). This test uses PVT beads (Amersham) that contain scintillating. These beads coated with streptavidin are

<Desc / Clms Page number 57>

 incubated in MOPS buffer in 9-well plates with 50nM pre-biotinylated SH2 protein and then with 125I-labeled EPQpYEEIPIYL ligand. By binding to the ball-bound protein the ligand activates the scintillant which emits measured light in a Wallac microeta 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 from 0.1μM to 100M in the wells containing the ligand, before 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

<Tb>
<tb> Example <SEP> IC50 <SEP> 2% <SEP> DMSO <SEP> (M)
<tb> 24 <SEP> 5.3
<tb> 28 <SEP> 1,4
<tb> 20 <SEP> 1.5
<tb> 21 <SEP> 7.7
<tb> 12 <SEP> 3,5
<tb> 16 <SEP> 40
<tb> 14 <SEP> 18
<tb> 3212
<Tb>

Claims (18)

1. Compounds of formula (I) in which either R1 and R2, which may be identical or different, represent a hydrogen atom, an alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, alkylamino or dialkylamino radical, an aryl or a heterocycle. or a group C (O) Y in which Y is hydroxy, alkoxy, amino, alkylamino or dialkylamino, or R1 and R2 together form the remainder of an aromatic ring or a heteroaryl, R3 and R4, the same or different represent a hydrogen atom, an alkyl, alkenyl, alkynyl, an aryl or a heterocycle, R5 represents a hydrogen atom, an alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, (cycloalkyl) alkyl, (cycloalkyl) alkenyl radical; or (cycloalkyl) alkynyl, a group (CHR6) -CO- (CH2) m -Ar, (CHR6) -CO- (CH2) m -Het, (CHR6) -CONH- (CH2) m -Ar, (CHR6) -CONH- (CH2) m -Het, in which the terms Ar and Het represent respectively an aryl or a heterocycle, R6 represents a hydrogen atom, a alkyl radical, alkenyl alkynyl, an aryl or a heterocycle, X represents an oxygen, sulfur or NH atom, [Al] represents one of the following divalent groups -CH (Z) -CH2- (Ari) -, - (CH2) 1- (Ar1) -, -CH (Z) -CH2- (Hetl) -, - (CH2) 1- (Hetl) -, -CH2NHCO- (Arl) -, -CH2NHCO- (Hetl) -, -NH- (Arl) -, NH- (Hetl) - wherein (Arl) is a divalent aryl, (Hetl) is a divalent heterocycle, and Z is a hydrogen atom, an NH 2 or NHP radical, where P is a protective group for the amine or a C (O) R 7 group, R 7 is an alkyl, alkenyl, alkynyl, aryl, heterocycle, alkyloxy, alkenyloxy or alkynyloxy, aryloxy or arylalkyloxy radical, [A2 ] represents the groups OPO (OR8) (OR9), B (OR8) (OR9), CR10R11PO (OR8) (ORg), CH [PO (OR8) (OR9)] 2 'COOR8, CR10R11-COOR8' CH (COOR) ) (COOR9), CH (SO3R6) (COOR9), O-CR10R1, L-COOR8, OCH (COOR6) (COOR9), O-CH (SO3R8) (COOR9) or CH (CH2COOR8) (CH2COOR9), in which R8 and R9, identical or different, represent an atom hydrogen, an alkyl radical or an arylalkyl radical, R10 and R11, which may be identical or different, represent a hydrogen atom, a halogen, a COOR8, SO3R8, PO (OR8) (OR9) or tetrazole radical, said alkyl, alkenyl or alkynyl radicals; , contain from 1 to 6 carbon atoms and are substituted or unsubstituted, and said aryl and heterocycle are substituted or unsubstituted, the cycloalkyl radical contains from 3 to 12 carbon atoms, 1 and m are equal to 0.1, 2 or 3, the dotted lines indicate the presence of a possible double bond, said compounds of formula (I) being in all their possible stereoisomeric forms, isolated or in mixtures, as well as their addition salts with acids and bases pharmaceutically acceptable salts and the esters of these compounds. 2. - Compounds of formula (I) according to claim 1 corresponding to formula (II):

 wherein R5, [A1] and [A2] are as defined in claim 1 and R3 represents a hydrogen atom or a <Desc / Clms Page number 60>  methoxyphenyl group. 3. - Compounds of formula (I) as defined in claim 1 wherein R1 and R2 are hydrogen atoms and the dashed line does not represent a double bond. 4. - Compounds of formula (I) as defined in claim 1 wherein R1 and R2 are hydrogen atoms and the dotted line represents a double bond 5. - Compounds of formula (I) or (II) such as defined in any one of claims 1 to 4 wherein the optional substituents - alkyl, aryl, aralkyl or heterocycle radicals - of the ring which can be formed together R1 and R2, - or bivalent groups (Arl) and (Hetl) may be chosen from one or more of the following radicals: halogen, (C1-C6) alkyl optionally substituted with one or more halogen atom, cyclo (C3-C12) alkyl, nitro, formyl, C = N-NH-CONH2 , carboxy, (C2-C7) alkyloxycarbonyl, (C1-C6) alkoxy, amino, (C1-C6) alkylamino, (C2-C12) dialkylamino, optionally in oxidized form, hydroxyl optionally acylated, (C2-C6) acyl, aryl or aryloxy themselves optionally substituted by the radicals indicated above, 6. - Compounds of formula (I) or (II) as defined in any one of claims 1 to 5 wherein [Al] represents a group selected from

 the phenyl being substituted or unsubstituted by the radicals as defined in claim 5, 1 and Z being as defined in claim 1. <Desc / Clms Page number 61> 7. Compounds according to claim 6, characterized in that Z represents an NH-P group with P representing a protective group of the amine chosen from CO 2 TBu and acetyl. 8. - Compounds according to claim 6 characterized in that the phenyl is substituted with a CHO group. 9. - Compounds of formula (I) or (II) as defined in any one of claims 1 to 5 wherein R5 is a (cyclohexyl) propyl, (cyclohexyl) butyl radical or a CH2CONH-Ar group, Ar being aryl substituted or unsubstituted by the radicals as defined in claim 5. 10. - Compounds of formula (I) or (II) as defined in any one of claims 1 to 5 wherein [A2] is a radical -OPO (OH) (OBn), CF2PO (OH) 2 or - OP (O) (OH) 2. 11. Compounds of formula (II) as defined in claim 2 wherein [Al] represents a group -CH (Z) -CH2-Ph- with Z = NHC02tBu or NHAc, [A2] represents an OP (O) group. ) (OH) 2, OP (O) (OH) (OBn) or CF 2 PO (OH) 2, R 5 represents a group -CH 2 CONHA R, Ar being an aryl radical, substituted or unsubstituted, by the radicals as defined in claim 5, or a (cyclohexyl) alkyl group, the term alkyl containing 3 or 4 carbon atoms. 12. - Compounds of formula (II) as defined in claim 2 wherein [Al] represents the radicals chosen from

 [A2] represents a group -OP (O) (OH) 2, -OP (O) (OH) (OBn) or <Desc / Clms Page number 62>  -CF2PO (OH) 2 'R5 represents a group -CH2CONHAr, Ar being an aryl radical substituted or not substituted by the radicals as defined in claim 5, or a (cyclohexyl) alkyl group the term alkyl containing 3 or 4 carbon atoms. carbon. 13. - The compounds according to any one of claims 1 to 12 whose names follow:

 - [2S- [3 (S *), 2a, 3]] - [1 - [[4 - [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2 - [[2- (4-methoxyphenyl)] -5- [2 - [(1-naphthalenyl) amino] -2-oxoethyl] -4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] amino] -2 -oxoethyl] -carbamate 1,1-dimethylethyl,

 - [2R- [3 (S *), 2a, 3]] - [1 - [[4 - [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2 - [[2- (4-methoxyphenyl)] -5- [2 - [(1-naphthalenyl) amino] -2-oxoethyl] -4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] amino] -2-oxoethyl ] 1,1-Dimethylethylcarbamate, - [2S- [3 (S *), 2a, 3a]] - [1 - [[4 - [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2 - [[2- (4-methoxyphenyl) -5- [2 - [[4-methoxy - [(1,1'-biphenyl) -3-yl] amino] -2-oxoethyl] -4oxo-2,3, 1,1-Dimethylethyl 4,5-tetrahydro-1,5-benzothiazepin-3-yl] amino] -2-oxoethyl] carbamate, - [2S- [3 (S *), 2a, 3a]] - [1- [[4 - [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2 - [[2- (4-methoxyphenyl) -5- [2- [2- (3-phenoxyphenyl) amino] -2-oxoethyl 1,4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] amino] -2-oxoethyl] carbamate 1,1-dimethylethyl, - [2R- [3 (S *), 2a, 3a]] - [1 - [[4 - [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2 - [[2- (4-methoxyphenyl) -5- [2 - [(1-naphthalenyl) ) amino] -2-oxoethyl] -4-oxo-2,3,4,5-t 1,1-Dimethylethyl trahydro-1,5-benzothiazepin-3-yl] amino] -2-oxoethyl] carbamate, - [2S- [3 (S *), 2a, 3a]] - [1 - [[ 4 - [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2 - [[2- (4-methoxyphenyl) -5- [2 - [(1-naphthalenyl) amino] -2-oxoethyl] -4- 1,1-dimethylethyl oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] amino] -2-oxoethyl] carbamate,

 - [2S- [3 (S *), 2a, 3a]] - 1 - [[4 - [[bis (phenylmethoxy) phosphinyl] <Desc / Clms Page number 63>  oxy] phenyl] methyl] -2 - [[2- (4-methoxyphenyl) -5- [2 - [(1naphthalenyl) amino] -2-oxo-1-phenylethyl] -4-oxo-2,3,4, 1,1-Dimethylethyl 5-tetrahydro-1,5-benzothiazepin-3-yl] amino] -2-oxoethyl] carbamate,

 - [2S- [3 (S *), 2a, 3Q]] - [1 - [[4 - [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2 - [[2- (4-methoxyphenyl)] -5- [2 - [(4-phenoxyphenyl) amino] -2-oxoethyl] -4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] amino] -2-oxoethyl ] 1,1-dimethylethyl carbamate,

 - [2S- [3 (S *), 2a, 30]] - 4 '- [[3 - [[2- [[[(1, 1-dimethyl) ethoxy] carbonyl] amino] -3 - [[4 - [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] -1-oxopropyl] amino] -2- (4-methoxyphenyl) -4-oxo-2,3-dihydro-1,5-benzothiazepin-5 (4H) - 1,1-Dimethylethyl [1 - [1,1'-biphenyl] -2-carboxylate] - [S - [R [trans ()]]] - [1 - [[4 - [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2 - [[5- (3-cyclohexylpropyl) -2- (4-

 Methoxyphenyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] amino] -2-oxoethyl] -carbamate 1,1-dimethylethyl, - [S- [R] (3S *)]] - [2 - [[5- (3-Cyclohexylpropyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] amino] -1- [ 1,1-Dimethylethyl [4 - [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2-oxoethyl] carbamate, - [S- [R * (3S *)] - [2 - [[5 (3-Cyclohexylpropyl) -2,3,4,5-tetrahydro-4-oxo-1,5-benzothiazepin-3-yl] amino] -2-oxo-1 - [[4-phosphonooxyphenyl] methyl] ethyl] 1,1-dimethylethylcarbamate, [S- [R * (3R *)]] - [2 - [[5- (3-cyclohexylpropyl) -4-oxo-2,3,4,5-tetrahydro] 1,1-Dimethylethyl 1,5-benzothiazepin-3-yl] amino] -1 - [[4-hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2-oxoethyl] carbamate, - [S- [R] * (3R *)]] - [2 - [[5- (3-cyclohexylpropyl) -2,3,4,5-tetrahydro-4-oxo-1,5-benzothiazepin-3-yl] amino] -2- 1,1-Dimethylethyl, - trans () - 2,3-dihydro-3 - [[3- [4 - [[hydroxyphenylmethoxy] oxo-1 - [[4-phosphonooxyphenyl] methyl] ethyl] carbamate y) Phosphinyl] oxy] phenyl] -1-oxopropyl] amino] -2- (4-methoxyphenyl) -N- (1-naphthylmethyl) -4-oxo-1,5-benzothiazepine-5 (4H) -acetamide , <Desc / Clms Page number 64>  trans () - 2,3-dihydro-3 - [[[6 - [[hydroxy (phenylmethoxy) phosphinyl] oxy] -2-naphthalenyl] carbonyl] amino] -2- (4-

 methoxyphenyl) -N- (1-naphthylmethyl) -4-oxo-1,5-benzothiazepine-5 (4H) -acetamide, -trans () -2,3-dihydro-3 - [[[5 - [[hydroxy) ( phenylmethoxy) phosphinyl] oxy] -1H-indol-2-yl] carbonyl] amino] -2- (4-

 methoxyphenyl) -N- (1-naphthylmethyl) -4-oxo-1,5-benzothiazepine (4H) -acetamide, - trans () - 3 - [[(4-boronophenyl) carbonyl] amino] -2,3- dihydro

 2- (4-methoxyphenyl) -N- (1-naphthylmethyl) -4-oxo-1,5-benzothiazepine-5 (4H) -acetamide, - trans () - 3 - [[2 - [[(4 -boronophenyl) carbonyl] amino] -1-oxoethyl] amino] -2,3-dihydro-2- (4-methoxyphenyl) -N- (1-naphthylmethyl) -4-oxo-1,5-benzothiazepine-5 (4H) -acetamide, - (R) -N- [5- (3-cyclohexylpropyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] -3-formyl 4- (Phosphonooxy) -benzamide, - (R) -N- [5- (3-cyclohexylpropyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] - 4- (Phosphonooxy) -benzamide; - (R) - [4 - [[[5- (3-Cyclohexylpropyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine- 3-yl] amino] carbonyl] -2-formylphenoxy] -acetic acid, - (R) -N- [5- (3-cyclohexylpropyl) -4-oxo-2,3,4,5-tetrahydro-1,5- benzothiazepin-3-yl] -4- (diphosphonomethyl) -benzamide, - [3R- [3R * (S *)] - - (acetylamino) -N- [5- (3-cyclohexylpropyl) -2,3- 4,5-tetrahydro-4-oxo-1,5-benzothiazepin-3-yl] -4- (difluorophosphonomethyl) -benzenepropanamide, - (R) -N- [5- (4-cyclohexylbutyl) -4-oxo -2,3,4,5-tetrahydro-1,5-benzothiazole pin-3-yl] -N '- [4- (phosphonooxy) phenyl] urea, - cis () - N- [5- (3-cyclohexylpropyl) -2- (4-methoxyphenyl) -4-oxo] 3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] -4 - [[hydroxy (phenylmethoxy) phosphinyl] oxy] benzeneacetamide, - cis () - N- [5- (3-cyclohexylpropyl)] 2- (4-Methoxyphenyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] -4- (phosphonooxy) benzeneacetamide, - [S- [R * (6S *)]] - [2 - [[4- (3-Cyclohexylpropyl) -hexahydro-5-oxo-1,4-thiazepin-6-yl] amino] -2-oxo-1 - [[4- (phosphonooxy)] 1,1-Dimethylethyl phenyl] methyl] ethyl] carbamate, - (R) -3 - [[(aminocarbonyl) hydrazono] methyl] -4- (phosphonyl) <Desc / Clms Page number 65>  oxy) -N- [5- (3-cyclohexylpropyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] benzamide, - [S- [R * (6R) *)]] - N-acetyl- [4- (3-cyclohexylpropyl) -5-oxo-4,5,6,7-tetrahydro-1,4-thiazepin-6-yl] -4- (phosphono) - ( difluoro) methyl] -L-phenylalaninamide, - (R) -5- (phosphonooxy) -N- [5- (3-cyclohexylpropyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine 3-yl] -2-pyridine carboxamide, - (R) -4 - [(phosphono) fluoromethyl] -N- [5- (3-cyclohexylpropyl) -4-oxo-2,3,4,5-tetrahydro- 1,5-benzothiazepin-3-yl] -benzamide. 14. - Process for the preparation of the compounds of formula (I) as defined in claim 1, characterized in that a compound of formula (II) is subjected

 in which R1, R2, R3, R4 and X are as defined in claim 1 and the amine is optionally protected, a) either first to the action of a compound of formula [A2] - [ A1] - COOH or [A2] - [A1] -NCO, if necessary deprotecting the amine, in order to obtain a compound of formula (III ')

 [Al] and [A2] being as defined in claim 1, followed by the action of R5-hal, wherein R5 is as defined at <Desc / Clms Page number 66>  claim 1 and Hal preferably being chlorine or bromine, b) firstly to the action of a compound of formula R 5-Hal in the presence of a base in order to obtain the compound of formula (III )

 in which R5 is as defined above, then to the action of [A2] - [A1] -COOH or [A2] - [A1] -NCO, after having deprotected the amine if necessary, in order to obtain in both cases the compound of formula (I) expected, which if appropriate is salified by the action of an acid or a base or esterified. 15. The process as claimed in claim 14, in which the compounds of formula (I) in which [A2] represents an OP (O) (OBn) 2 group are subjected to the action of a monodebenzylation agent or of a total deprotection agent, in order to obtain respectively the compounds of formula (I) in which [A2] represents a group OP (O) (OH) (OBn) or OP (O) (OH) 2. 16. - Process according to claim 14 wherein the compound [A2] - [A1] -COOH, [A2] is a hydroxyl, in order to obtain the compounds of formula (III'a) or (la ') <Desc / Clms Page number 67>

 which are subsequently phosphorylated by the action of HO-P (O) -

 (OR8) (OR9) or etherified by the action of Hal-CR10R11-CO2-Alkyl or Hal-CH (CO2-Alkyl) 2 followed by saponification of the ester, to obtain the compounds of formulas (III ' ) and (I) as defined in claims 1 and 15. 17. - As medicaments the compounds of formula (I) as defined in claim 1. 18. - As medicaments the compounds of formula (I) or (II) as defined in claims 2 to 12. 19. - As medicaments the compounds as defined in claim 13. 20. - The pharmaceutical compositions containing one or more drugs according to any one of claims 17 to 19. 21. The compounds of formulas (III '), (III "), (III'a) and (a) as defined in claims 14 and 16.