WO2000005246A1 - Thioazepinone derivatives, preparation method and intermediates therefor, use as medicines and pharmaceutical compositions containing same - Google Patents

Thioazepinone derivatives, preparation method and intermediates therefor, use as medicines and pharmaceutical compositions containing same Download PDF

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Publication number
WO2000005246A1
WO2000005246A1 PCT/FR1999/001770 FR9901770W WO0005246A1 WO 2000005246 A1 WO2000005246 A1 WO 2000005246A1 FR 9901770 W FR9901770 W FR 9901770W WO 0005246 A1 WO0005246 A1 WO 0005246A1
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oxo
phenyl
amino
thiazepin
hexahydro
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PCT/FR1999/001770
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French (fr)
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Didier Benard
Pierre Deprez
Dominique Lesuisse
Eliane Mandine
Antonio Ugolini
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Hoechst Marion Roussel
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Priority to AU49133/99A priority Critical patent/AU4913399A/en
Publication of WO2000005246A1 publication Critical patent/WO2000005246A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D281/02—Seven-membered rings
    • C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D281/10—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6536—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and sulfur atoms with or without oxygen atoms, as the only ring hetero atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0821—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0827—Tripeptides containing heteroatoms different from O, S, or N
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • Thioazepinone derivatives process for their preparation and intermediates, application as medicaments and pharmaceutical compositions containing them.
  • the subject of the invention is a thiazepinone derivative of formula (I)
  • the compounds of formula (I) are compounds having pharmacological activity and are therefore usable as medicaments. They are in particular inhibitors of the Src SH2 domain and they inhibit bone resorption mediated by osteoclasts. They are therefore useful for the therapeutic or prophylactic treatment of diseases which are caused at least in part by an unwanted increase in bone resorption, for example osteoporosis.
  • the invention further relates to the processes for preparing the compounds of formula (I), the intermediates of this process, their application, in particular as a medicament and the pharmaceutical compositions containing them.
  • the catalytic activity tyrosine kinase is associated either with receptors having transmembrane domains (EDF, DPGF, c-fms ..) or with intracellular proteins (T. Hunter, Biochem Soc. Trans; 24, 307-327 (1996).
  • Intracellular tyrosine kinases (“no receptor ”) are divided into 8 subfamilies mainly according to the sequence similarity of their catalytic domain and were named after their best known member (Src, Csk, Btk, Abl, Fak, Syk, Jak, Fsp).
  • the Src family contains 9 members sharing 70% of sequence homology between them (Src, Fyn, Yes, Frg, Lyn, Hck, Lck, Blk, Yrd in vertebrates).
  • Src family proteins share a common structure which is characterized by the following elements: a small N-terminal fragment involved in anchoring to the membrane (sometimes also called SH4), a unique domain poorly conserved (40-70 residues), an SH3 domain which binds to proline-rich sequences (50 residues), an SH2 domain involved in the recognition of specific phosphorylated peptide sequences (100 residues), a catalytic domain (tyrosine kinase, 250 residues) and finally a short C-terminal domain involved in regulation.
  • the protein tyrosine kinases of the c-Src family have multiple roles and overlap in signal transduction involved in a variety of different biological situations, including cell growth and differentiation, cell cycle control, cell shape and adhesion as well as the regulation of ion channels and neurotransmitter receptors. While the expression of most members of the Src family is limited to the hematopoietic system, the proteins Src, Fyn and Yes 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 several of these proteins finally began to be better understood with the carrying out of the knockout experiments.
  • This inhibition can be carried out either at the level of the SH2 domain, or at the level of the SH3 domain (involved in recognition and interaction with other proteins), or at the level of the catalytic domain (tyrosine kinase).
  • the subject of the invention is a thioazepinone derivative of formula (I)
  • R 5 is or R ' 5 , representing the following groups (C ⁇ -C ⁇ ) -al yle-, (C 2 -C 8 ) -alkenyl-, (C 2 -C 8 ) -alkynyl-, (C 5 - C ⁇ 4 ) -aryl -, (C5-C14) -aryl- (C ⁇ -C 8 ) -alkyle-, (C5-C14) -aryl- (C 2 - C 8 ) -alkenyl-, (C 5 -C ⁇ 4 ) -aryl- ( C 2 -C 8 ) -alkynyl-, (C 3 -C ⁇ 8 ) - cycloalkyle-, (C 3 -C 18 ) -cycloalkyl- (C ⁇ -C 8 ) -alkyle-, (C 3 -C ⁇ 8 ) - cycloalkyl - (C 2 -C 8 ) -
  • - A 2 represents a group chosen from -PO (ORd) (ORe), -OPO (ORd) (ORe), -B (ORd) (ORe), -CRfRgPO (ORd) (ORe), -O-CRfRgPO (ORd ) (ORe), -CRfRg-C0 2 Rd, - CRf (C0 2 Rd) 2 , -0-CRfRg-C0 2 Rd, -O-CRf (C0 2 Rd) 2 , -N (CRfRg-C0 2 Rd) 2 , -C0 2 Rd, -CRfRg-CH 2 -C0 2 Rd, -CRfRgS0 3 H, -0-CRfRgS0 3 H, -OSO 3 H, - OS0 2 NH 2 , -S0 2 NH 2 , -NHCO-PO (ORd) (ORe), -CO-PO (ORd) (ORe
  • R 6 -C 4 ) -alkyle-, said radicals being substituted or unsubstituted by R 6 ; - Rf and Rg identical or different representing a hydrogen atom, a halogen, ORe, NHRc, a radical C0 2 Rc, CH 2 C0 2 Rc, S0 3 H, PO (ORd) (ORe) or tetrazole;
  • R 3 and R 4 form together with the carbon atom which carries them, a cycloalkyl group containing 3 to 6 carbon atoms,
  • R 6 represents a group chosen from (C ⁇ -C 4 ) -alkyle-
  • - U represents a group chosen from CO, CS, SO, SO 2 and a saturated or unsaturated alkylene group containing from 1 to 4 carbon atoms, the dotted line indicates the presence of a possible double bond, said compounds of formula ( I) being in all their possible isomeric forms, alone or as a mixture in any ratio, as well as their physiologically acceptable salts and their prodrugs (prodrugs).
  • radicals which can be found several times in the compounds of formula (I), for example the radical R 6 are independent of each other and can be identical or different.
  • the alkyl radicals can be linear or branched, saturated or mono- or polyunsaturated. This also applies when they have a substituent or when they are included in groups such as, for example, alkoxy, alkoxycarbonyl or aralkyl.
  • (C ⁇ ⁇ C 8 ) -alkyl therefore means in particular
  • - saturated alkyl radicals such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, the n-isomers of these radicals, isopropyl, isobutyl, isopentyl, neopentyl, isohexyl, 3-methylpentyl, 2,3,4 - trimethylhexyle, sec-butyle, tert-butyle, tert-pentyle.
  • the preferred radicals mention may be made of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl.
  • (C 2 -C 8 ) -alkenyl radicals such as vinyl, 1-propenyl, allyl, butenyl, 3-methyl-2-butenyl or (C 2 -C 8 ) -alkynyl radicals such as ethynyl, 1-propynyl or propargyl.
  • (C 1 -C 4 ) -alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, vinyl, 1-propenyl, allyl, butenyl, ethynyl, 1-propynyl or propargyle
  • Cycloalkyl radicals can be monocyclic, bicyclic or tricyclic. These are, for example, the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, cyclotetradecyl or cyclooctadecyl radicals which, if appropriate, can be substituted, for example, by an alkyl containing 1 to 4 atoms. carbon.
  • cycloalkyl radicals As substituted cycloalkyl radicals, mention may be made of 4 methylcyclohexyl and 2,3-dimethylcyclohexyl.
  • the bicycloalkyl and tricycloalkyl radicals can be unsubstituted or substituted in any position, for example by one or more oxo groups and / or 1 or more identical or different alkyl groups such as methyl or isopropyl and preferably methyl.
  • the junction bond of the bi or tricyclic radical can be located in any position of the molecule. The bond can be located at the bridged carbon atom or at one of the other carbon atoms. This connection can also have any position from the point of view of stereochemistry, for example exo or endo.
  • bicycloalkyl or tricycloalkyl radicals mention may be made of camphanyl, bornyl, adamantyl such as 1-adamantyl or 2-adamantyl, caranyl, epiisobornyl, 1 epibornyl, norbornyl or norpinanyl.
  • Halogen means fluorine, chlorine, bromine or iodine.
  • Rf and Rg represent a halogen, it is preferably fluorine.
  • (C 5 -C 14 ) -aryl is meant
  • carbocyclic (C 6 -C ⁇ 4 ) -aryl radicals mention may be made of phenyl, naphthyl, biphenyl, anthryl or fluorenyl and very particularly 1-naphthyl, 2-naphthyl and phenyl. It is preferably phenyle.
  • the aryl radicals in particular phenyl, aryloxy, aralkyls or the saturated or unsaturated heterocycles can be unsubstituted or substituted by one or more identical or different radicals chosen from (C ⁇ -C 8 ) -alkyl, in particular (C ⁇ ⁇ C 4 ) -alkyl, (C ⁇ -C 8 ) -alkoxy, formyl, halogen such as fluorine, chlorine and bromine, nitro, amin ⁇ , trifluoromethyl, hydroxyl, - CH 2 OH, methylenedioxy, cyano, hydroxycarbonyl, aminocarbonyl, (C 1 -C 4 ) -alkoxycarbonyl, phenyl, phenoxy, benzyl and benzyloxy.
  • at most 2 nitro groups can be used in the compounds of formula (I) according to the invention.
  • the substituent can be located in position 2,3 or 4, and preferably in position 3 or 4.
  • the substituents can be in position 2,3 or 2, 4 or 2.5 or 2.6 or 3.4 or 3.5.
  • the two substituents are in position 3,4.
  • the positions are as follows: 2,3,4 or 2,3,5 or 2,3,6 or 2,4,5 or 2,4,6 or
  • naphthyl radicals or other aryl radicals can be substituted in any position, for example the 1-naphthyl radical in position 2-, 3-, 4-, 5-, 6-, 7-, and 8 and the 2-naphthyl radical in positions 1-, 3-, 4-, 5-, 6-, and 7.
  • the (C 5 -C 4 ) -aryl group can also represent a monocyclic or polycyclic aromatic system in which 1,2,3,4 or 5 ring carbon atoms are replaced by heteroatoms, in particular identical or different from the group formed nitrogen, oxygen and sulfur.
  • heteroaryl radicals are preferred the monocyclic or bicyclic aromatic systems having 1,2 or 3 heteroatoms, in particular 1 or 2 heteroatoms, chosen from N, O or S, and which are unsubstituted or substituted by groups such as (C ⁇ -C 6 ) -alkyl, (Cx-Cg) - alkoxy, fluorine, chlorine, nitro, amino, trifluoromethyl, hydroxyl, formyl, (C 1 -C 4 ) -alkoxycarbonyl, phenyl, phenoxy, benzyloxy, and benzyl.
  • groups such as (C ⁇ -C 6 ) -alkyl, (Cx-Cg) - alkoxy, fluorine, chlorine, nitro, amino, trifluoromethyl, hydroxyl, formyl, (C 1 -C 4 ) -alkoxycarbonyl, phenyl, phenoxy, benzyloxy, and benzyl.
  • heterocycles there may be mentioned the following heterocycles: piperidine, piperazine, morpholine or pyrrolidine.
  • the optically active carbon atoms contained in the compounds of formula (I) may independently of each other have the R configuration or the S configuration.
  • the compounds of formula (I) may be in the form of pure enantiomers or of pure diastereoisomers or in the form of a mixture of enantiomers, for example in the form of racemates or mixtures of diastereoisomers.
  • the present invention therefore relates to pure enantiomers, mixtures of these enantiomers, pure diastereoisomers and mixtures of these diastereoisomers.
  • the invention includes mixtures of two or more of two stereoisomers of formula (I) and all of the ratios of these stereoisomers within said mixtures.
  • the compounds of formula (I) can optionally be present in the form of E isomers or Z isomers.
  • the subject of the invention is therefore pure E isomers, pure Z isomers and E / Z mixtures in a ratio any.
  • the invention includes the different regioisomers linked to the ortho, para or meta position of A 2 .
  • a 2 is in the para position and R 6 is in the meta position.
  • the diastereoisomers including the E / Z isomers can be separated into individual isomers, for example by chromatography. Racemates can be separated into two enantiomers by standard methods such as chiral chromatography or by resolution methods.
  • the physiologically acceptable salts of the compounds of formula (I) are in particular pharmaceutically usable or non-toxic or physiologically usable salts.
  • the compounds of formula (I) contain an acid group such as the carboxylic acid, they are, for example, alkali or alkaline earth metal salts such as the sodium, potassium, magnesium, calcium salts, and equal- the salts formed with physiologically acceptable quaternary ammonium ions such as ammonia and physiologically acceptable organic amines such as for example triethylamine, ethanolamine or tris- (2-hydroxyethyl) amine.
  • alkali or alkaline earth metal salts such as the sodium, potassium, magnesium, calcium salts
  • physiologically acceptable quaternary ammonium ions such as ammonia
  • physiologically acceptable organic amines such as for example triethylamine, ethanolamine or tris- (2-hydroxyethyl) amine.
  • the compounds of formula (I) when they contain a basic group, they can form an addition salt with the acids, for example with inorganic acids such as hydrochloric, sulfuric, phosphoric acid or with organic carboxylic acids such as acetic, trifluoroacetic, citric, benzoic, maleic, fumaric, tartaric, methanesulfonic or para toluene sulfonic acid.
  • inorganic acids such as hydrochloric, sulfuric, phosphoric acid
  • organic carboxylic acids such as acetic, trifluoroacetic, citric, benzoic, maleic, fumaric, tartaric, methanesulfonic or para toluene sulfonic acid.
  • the compounds of formula (I) which have a basic group and an acid group can be present in the form of Zwiterions (betaines), which are also included in the present invention.
  • the salts of the compounds of formula (I) can be obtained by the ordinary methods known to those skilled in the art, for example by combining a compound of formula (I) with an organic or inorganic acid or a base in a solvent or a dispersant or from another salt by cation or anion exchange.
  • the invention also includes all the salts of the compounds of formula (I) which, because of their poor physiological acceptability, are not directly usable as a medicament, but are usable as intermediates for carrying out subsequent chemical modifications at the level of compounds of formula (I) or as starting materials for the preparation of physiologically acceptable salts.
  • the present invention also includes all the solvates of the compounds of formula (I), for example hydrates, the solvates formed with alcohols, and all the derivatives of the compounds of formula (I), for example esters, prodrugs and other physiologically acceptable derivatives. , as well as the metabolites of the compounds of formula (I).
  • a more particular subject of the invention is the prodrugs of the compounds of formula (I) which can be transformed into compounds of formula (I) in vivo under physiological conditions.
  • the prodrugs of the compounds of formula (I) namely the chemically modified derivatives of the compounds of formula (I) in order to obtain desired improved properties, are known to those skilled in the art.
  • acylated or carbamate prodrugs in the form of acyl and carbamate for groups containing an acylable nitrogen such as amino groups.
  • acylated or carbamate prodrugs one or more times, for example twice, a hydrogen atom located on the nitrogen atom is replaced by an acyl or carbamate group.
  • R 10 CO-, RnOCO- in which Rio is a hydrogen or a radical (C ⁇ ⁇ C ⁇ 8 ) - alkyl-, (C 3 -C ⁇ 8 ) -cycloalkyle- , (C 3 -C ⁇ 8 ) -cycloalkyl- (C-Cg) - alkyl-, (C 5 -C ⁇ 4 ) -aryl-, in which 1 to 5 carbon atoms can be replaced by heteroatoms such as N, 0 , S or (C 5 -C ⁇ 4 ) -aryl- (C ⁇ -C 8 ) alkyl-, in which 1 to 5 carbon atoms in the aryl part can be replaced by heteroatoms such as N, 0, S and Ru have the same values as Rio except for hydrogen.
  • a more particular subject of the invention is the benzothioazepinone derivatives of formula (I) corresponding to formula (I '):
  • R 5 , [Ai], and A 2 are as defined above and R 3 represents a hydrogen atom or a phenyl group optionally substituted by R 6 , as well as their physiologically acceptable salts and their prodrugs (prodrugs).
  • a more particular subject of the invention is the thioazepinone derivatives of formula (I) in which Ri, R 2 ,
  • R 3 and R 4 are hydrogen atoms and the dotted line does not represent a double bond corresponding to the formula d ")
  • a more particular subject of the invention is the compounds of formula (I) in which Ri, R 2 , R 3 and R 4 are hydrogen atoms and the dotted line represents a double bond corresponding to the formula (I "' )
  • a more particular subject of the invention is the compounds of formulas (I '), (I' ') and (I' ') as defined above corresponding respectively to the compounds of formulas (I'R), (I “R) and (I “'R) below:
  • the invention particularly relates to the compounds of formulas (I), (I '), (I ") and (I"') as defined above in which [Ai] represents a group chosen from
  • the invention more particularly relates to a compound of formulas (I), (I '), (I ") or (I"') as defined above, characterized in that the phenyle is substituted by R 6 representing a group chosen from CHO,
  • Z preferably represents NHCOCH 3 or NHC0 2 tBu and the carbon which carries this group Z has the configuration (S).
  • a more particular subject of the invention is the compounds of formulas (I), (I '), (I ") and (I" 1 ) in which
  • R5 is a (cyclohexyl) methyl-, (cyclohexyl) ethyl-, (cyclohexyl) propyl-, (cyclohexyl) butyl-, (phenyl) methyl- radical,
  • a more particular subject of the invention is the compounds of formulas (I), (I '), (I ") and (I"') as defined above in which A 2 is a radical - OPO (OH) (OBn) , -OPO (OH) 2 , -PO (OH) 2 , -CF 2 P0 (0H) 2 , -C0 2 H, - CH 2 C0 2 H, -OCH 2 C0 2 H, -CH (C0 2 H) 2 , -CF (C0 2 H) 2 -N (CH 2 C0 2 H) 2 or
  • the invention particularly relates to the compounds of formulas (I'S), (I "S) or (I" 'S) in which:
  • OPO (OH) (OBn) radical - OPO (OH) 2 , -PO (OH) 2 , -CF 2 PO (OH) 2 , -C0 2 H, -CH 2 C0 2 H, -OCH 2 C0 2 H, - CH (C0 2 H) 2 , -CF (C0 2 H) 2 -N (CH 2 C0 2 H) 2 or NHCOPO (OH) 2 ,
  • R 5 is a (cyclohexyl) methyl-, (cyclohexyl) ethyl-, (cyclohexyl) propyl-, (cyclohexyl) butyl-, (phenyl) methyl- radical
  • the invention particularly relates to the compounds of formulas (I'S), (I "S) or (I" 'S) in which: - [Ai] represents the radicals chosen from
  • OPO (OH) (OBn) radical - OPO (OH) 2 , -PO (OH) 2 , -CF 2 PO (OH) 2 , -C0 2 H, -CH 2 C0 2 H, -OCH 2 C0 2 H, - CH (C0 2 H) 2 , -CF (C0 2 H) 2 -N (CH 2 C0 2 H) 2 or NHCOPO (OH) 2 ,
  • R 5 is a (cyclohexyl) methyl-, (cyclohexyl) ethyl-, (cyclohexyl) propyl-, (cyclohexyl) butyl-, (phenyl) methyl- radical
  • a subject of the invention is also the compounds of formula (I), (I '), (I'') or (I''') the names of which follow: [2S- [3 (S *), 2 ⁇ , 3 ⁇ ]] - [l- [[4- [[hydroxy (phenylmethoxy) phosp inyl] oxy] phenyl] methyl] -2- [[2- (4-methoxyphenyl) -5- [2- [(1-naphthalenyl) amino] -2-oxoethyl] -4-oxo-2,3,4,5-tetra-hydro-1,5-benzothiazepin-3-yl] amino] -2 1,1-dimethylethyl-oxoethyl] -carbamate.
  • Acid 1,1-dioxide [[4- [(2S) -2- (acetylamino) -4- [[(6R) - 4- (3-cyclohexylpropyl) -hexahydro-5-thioxo-l, -thiazepin -6- yl] amino] -3-oxopropyl] phenyl] difluoromethyl] - Phosphonic
  • the present invention also relates to a process for the preparation of the compounds of formula (I).
  • the compounds can generally be prepared, for example during a convergent synthesis by coupling two or more fragments which can be derived by retrosynthesis of the compounds of formula (I).
  • R 5 being as defined above and Hal being preferably a chlorine or a bromine b) or, first of all, 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 ")
  • the group UX 'in X'-U- [A ⁇ ] -A 2 is preferably the carboxylic acid group or an activated derivative of the carboxylic acid.
  • X ' for example is hydroxyl or halogen, in particular, chlorine or bromine, alkoxy or phenyloxy, preferably methoxy, ethoxy, phenoxy, pentafluorophenyloxy, alkylthio or arylthio, preferably phenylthio, methylthio, 2-pyridylthio or a nitrogen heterocycle linked in in particular via a nitrogen such as for example 1-imidazolyl.
  • X ′ may also be, for example, a (C 1 -C 4 ) -alkyl-O-CO-O- or tolylsulfonyloxy group and the activated acid derivative may be a mixed anhydride.
  • the amine salts can also be used in the reaction with the compounds of formula X '-U- [A x ] -A 2 , the free amines being formed in situ. or by a separate step using a base.
  • reaction of an activated carboxylic acid derivative of formula HOOC- [Ai] -A 2 with the amine (or derivative) of formula (II) is preferably carried out in a manner known per se in a protic organic solvent or aprotic, but inert.
  • solvents such as methanol are used,
  • X ' is chlorine
  • the reaction will preferably be carried out by adding an acid scavenger, for example a base or an excess of amine (or derivative).
  • an acid scavenger for example a base or an excess of amine (or derivative).
  • the reaction mixture is then treated and if desired the reaction product is purified according to methods known to those skilled in the art.
  • the acylation reaction using the compound of formula HOOC- [Ai] -A 2 is preferably carried out in the presence of EDC (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride) and HOBt (1-hydroxybenzotriazole hydrate) in an aprotic dipolar solvent such as dimethylformamide.
  • EDC 3- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride
  • HOBt 1-hydroxybenzotriazole hydrate
  • This reaction can be carried out in solution as in solid phase as shown in the examples below.
  • the alkylation reaction using R 5 -Hal is carried out according to the usual methods known to those skilled in the art, in particular in the presence of a base such as sodium hydride in an aprotic dipolar solvent such as dimethylformamide .
  • the protective groups optionally present in the compounds of formulas (III 1 ), (III ") or (I) are then removed by conventional methods; for example, the tert-butyl ester groups are converted to the carboxylic acid by treatment with trifluoroacetic acid, the benzyl groups are eliminated by hydrogenation or the fluorenylmethoxycarbonyl groups are eliminated in the presence of secondary amine.
  • amine When the amine is protected (NHC0 2 Rb or NHCORb), it is in particular protected by a Boc or acetyl group.
  • the return to the free amine can be carried out by the action of trifluoroacetic acid.
  • the deprotection is preferably carried out in the presence of Pd (OH) 2 , MgO in cyclohexadiene at reflux.
  • a 2 OP (O) (OH) (OBn)
  • sodium iodide is used in particular and the reaction is carried out at reflux of acetone, or DABCO (1, 4-diazabicyclo [2.2.2] octane) in toluene.
  • the phosphorylation reaction is carried out with HP (O) (ORd) (ORe) in the presence of N'N-diisopropylethylamine (DIPEA) and of N, N-dimethylaminopyridine (DMAP) in acetonitrile in presence of carbon tetrachloride.
  • DIPEA N'N-diisopropylethylamine
  • DMAP N, N-dimethylaminopyridine
  • the subject of the invention is more particularly a process as described above in which the compound of formula (III) is chosen from the following phosphate tyrosines: N-Boc-Tyr-0- (P0 3 Bn 2 ), N-Ac -Tyr-O- (P0 3 Bn 2 ), N-Boc-Tyr-CF 2 - (P0 3 Et 2 ), N-Ac-Tyr-CF 2 - (P0 3 Et 2 ) or benzoic derivatives (Illa, IIIc)) or benzene (Illb, (Illd)) following:
  • R "f represents a hydrogen, fluorine or C0 2 Rd atom
  • R" g represents a hydrogen or fluorine atom
  • Z represents NHCORb or NHC0 2 Rb
  • R 6 is as defined previously, the compound of formula (IIIb) having an E or Z configuration.
  • benzothiazepinones of formula (II) in which Ri and R 2 together form an adjacent phenyl, X is an oxygen atom, R 3 is an optionally substituted phenyl group and R 4 is a hydrogen atom are known in particular in patent application JP 60139682 .
  • the compounds of formula (II) in which, X is an oxygen atom, Ri and R 2 together form an adjacent phenyle, R 3 and R 4 are hydrogen atoms are described in J. Med. Chem (1985) 1517-1521 (J. Slade et al).
  • the starting compounds of formula (III) are commercial, can be prepared according to methods described in the literature or are accessible by analogy.
  • the following products of formula (III) are preferably used:
  • R "f and R” g represent a fluorine atom in the compounds of formula (Illb). If it is desired to obtain only esters of formula (B), the decarboxylation reaction can be carried out in the presence of APTS, TFA or PPTS. Compounds of formula (IIIb) are obtained having an E or Z configuration or as an E / Z mixture depending on the nature of the substituents.
  • malonic acids from the corresponding terbutyl esters can be carried out with formic acid.
  • Catalytic hydrogenation provides the corresponding reduced compounds. It is also possible to envisage the formation of the corresponding reduced compounds by zinc coupling of an iodoserine with the iodized malonic ester of formula (A) according to the methods known to those skilled in the art.
  • the compounds of formula (III) can also be prepared in the solid phase.
  • the solid phase is prepared according to a publication by Mjalli et al (Tetrahedron letter, 1996, 6073).
  • the resin is reacted with either a phenol in the presence of CCI 4 and DMAP, or with a base such as DBU and an isocyanate to generate the phosphate and the amidophosphonate respectively.
  • a cleavage with the TFA makes it possible to regenerate the product (diagram 4).
  • the compounds of formula R 5 -X ' are known, can be prepared according to methods described in the literature or are accessible by analogy. Preferably halogen derivatives are used.
  • the compounds of formula (I) can be used to inhibit the binding of an Src protein to an analogous phosphorylee protein.
  • This inhibition can be carried out either at the level of the SH2 domain, or at the level of the SH3 domain (involved in recognition and interaction with other proteins), or at the level of the catalytic domain (tyrosine kinase).
  • the compounds according to the invention most particularly have an affinity for the SH2 domain of the Src protein.
  • the compounds of formula (I) can therefore be used to inhibit the binding of an Src protein containing the SH2 domain to an analogous phosphorylated protein, the method consisting in the administration to the patient whose treatment requires the inhibition of the SH2 domain , an inhibitory amount of the compound according to the invention.
  • the action of the compounds of formula (I) can be demonstrated for example in a test in which the inhibition of the Binding of the radiolabelled EPQpYEEIPIYL ligand to the SH2 protein is determined by Scintillation proximity assay (SPA). Details on this test are given below.
  • the compounds of formula (I) and their physiologically acceptable salts and their prodrugs are generally suitable for the treatment or prevention of diseases linked to interactions between the SH2 domain and their ligands or which can be influenced by inhibition of such interactions, to relieve or cure when inhibition of such interactions is desired. As explained at the beginning, such an interaction plays an important role in bone resorption.
  • the compounds of formula (I) are most particularly antagonists of the human receptor Src SH2 and are thus able for example to inhibit the adhesion of osteoclasts to the surface of the bone and thus the bone resorption by the osteoclasts.
  • Bone diseases whose treatment or prevention require the use of the compounds of formula (I) or their prodrugs, are in particular osteoporosis, hypercalcemia,
  • Osteopenia for example caused by bone metastases, dental disorders for example periodontitis, hyperparathyroidism, periarticular erosions in rheumatoid arthritis, Paget's disease, osteopenia induced by immobilization.
  • the compounds of formula (I) can be used to relieve, prevent or treat bone disorders which are caused by treatments, by glucocorticoids, therapies linked to the taking of steroids or corticosteroids or by deficiencies. male or female sex hormones.
  • All these disorders are characterized by bone loss, which is based on a lack of balance between bone formation and bone destruction and which can be favorably influenced by the inhibition of bone resorption by osteoclasts.
  • the compounds according to the invention by their affinity with the Src-SH2 domain can also be used in other therapeutic applications.
  • platelets and neurons are tissues that also express Src-SH2.
  • proteins of this family being predominantly expressed in the hemetopoietic system, numerous applications in the treatment of immunity, infection, allergy and autoimmune diseases are conceivable.
  • the compounds of formula (I) can also be used to inhibit the binding of a protein containing the SH2 domain, other than Src, to an analogous phosphorylated protein, the method consisting in 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 chosen 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 disease.
  • the invention more particularly relates, as medicaments, to the compounds of formula (I) listed above.
  • the present invention therefore relates to a compound of formula (I), and / or its physiologically acceptable salts and / or its prodrugs, as a medicament.
  • the present invention more particularly relates to a compound of formula (I), and / or its physiologically acceptable salts and / or its prodrugs, as a medicament having an inhibitory activity on the Src SH2 receptor.
  • the present invention more particularly relates to a compound of formula (I), and / or its physiologically acceptable salts and / or its prodrugs, as a medicament having an activity inhibiting bone resorption or for the treatment or prevention of 1 ′ osteoporosis.
  • the present invention more particularly relates to a compound of formula (I), and / or its physiologically acceptable salts and / or its prodrugs, as a medicament for the treatment or prevention of immunity, infection, l , and autoimmune diseases.
  • the present invention more particularly relates to a compound of formula (I), and / or its physiologically acceptable salts and / or its prodrugs, as a medicament for the treatment or prevention of diseases such as proliferative diseases, cancer, restenosis, inflammation, allergies or cardiovascular disease.
  • the present invention also relates to the use of the compounds of formula (I) and / or their physiologically acceptable salts and / or their prodrugs for the preparation of medicaments intended for the prevention or treatment of osteoporosis.
  • Another subject of the present invention is the use of the compounds of formula (I) and / or their physiologically acceptable salts and / or their prodrugs for the preparation of medicaments intended for the treatment or prevention of immunity, of infection , allergy, and autoimmune diseases.
  • a subject of the present invention is also the use of the compounds of formula (I) and / or their physiologically acceptable salts and / or their prodrugs for the preparation of medicaments intended for the treatment or prevention of diseases such as proliferative diseases, cancer, restenosis, inflammation, allergies or cardiovascular disease.
  • the compounds of formula (I) and their salts physiologically acceptable and their prodrugs can be administered to animals, preferably to mammals and in particular to humans as medicaments for therapeutic or prophylactic purposes. They can be administered as such or in admixture with one or more other compounds of formula (I) or alternatively in the form of a pharmaceutical preparation (pharmaceutical composition) which allows enteral or parenteral administration and which contains, as active compound, a effective dose of at least one compound of formula (I) and / or its physiologically acceptable salts and / or its prodrugs as well as one or more pharmaceutically acceptable excipients and optionally one or more additives.
  • a pharmaceutical preparation pharmaceutical composition
  • the drugs can be administered orally, for example, as a pill, tablet, coated tablet, film, granule, soft capsule or capsule, solution, syrup, emulsion, suspension, or mixture of aerosol.
  • Administration can however be carried out rectally, for example in the form of a suppository or parenterally, for example in the form of injectable solutions or infusions, of microcapsules or implants, or by percutaneous route, for example under the form of ointment, solutions, pigments or dyes, transdermally (patches) or by other routes such as in the form of aerosol or nasal spray.
  • compositions according to the invention are prepared according to methods known per se, pharmaceutically inert organic or inorganic supports being added to the compounds of formula (I) and / or their physiologically acceptable salts and / or their prodrugs.
  • Suitable supports for soft gelatin capsules or for suppositories are, for example, fats, waxes, semi-solid or liquid polyols, bound or modified natural oils, etc.
  • the vehicles suitable for the preparation of solutions for example injectable solutions, emulsions or syrups are for example water, alcohols, glycerol, polyols, sucrose, invert sugars, glucose, vegetable oils, etc.
  • Suitable supports for microcapsules or implants are, for example, copolymers of glyoxilic acid and lactic acid. Pharmaceutical preparations normally contain from 0.5% to 90% by weight of compounds of formula (I) and / or their physiologically acceptable salts.
  • pharmaceutical preparations can contain additives such as, for example, diluents, disintegrants, binders, lubricants, wetting agents, stabilizers, emulsifiers, preservatives, sweetening agents, coloring agents for flavoring agents or flavoring agents, thickeners, buffering agents, and also solvents or solubilizers or agents for obtaining a delayed effect and also salts for modifying the osmotic pressure, coating agents or antioxidants. They can also contain two or more compounds of formula (I) and / or their physiologically acceptable salts and / or their prodrugs. In addition, in addition to at least one or more compounds of formula (I) and / or their physiologically acceptable salts and / or their prodrugs, they may contain at least one or more other active ingredients which can be used therapeutically or prophylactically.
  • additives such as, for example, diluents, disintegrants, binders, lubricants, wetting agents, stabilizers, emulsifiers, pre
  • the present invention therefore relates to pharmaceutical compositions which allow enteral or parenteral administration and which contain, as active compound, an effective dose of at least one compound of formula (I) and / or its physiologically acceptable salts and / or his prodrugs as well that one or more pharmaceutically acceptable excipients, and optionally one or more usual additives.
  • the doses may vary within wide limits and must be fixed according to the person to be treated. This depends, for example, on the compound used or on the nature and severity of the disease to be treated and whether one is in severe or chronic conditions or whether one is implementing a prophylactic treatment.
  • Pharmaceutical preparations normally contain from 0.2 to 500 mg, and preferably from 1 to 200 mg of compound of formula (I) and / or their physiologically acceptable salts and / or their prodrugs.
  • the daily dose generally varies from 0.01 to 100 mg / kg and preferably from 0.1 to 50 mg / kg, in particular from 0.1 to 5 mg / kg.
  • a daily dose varying from 0.3 to 0.5 mg / kg could be considered.
  • the daily dose varies approximately from 0.01 to 100 mg / kg and preferably from 0.05 to 10 mg / kg.
  • the daily dose can be divided, in particular in the case of the administration of large amount of active ingredient, into several, for example 2,3 or 4 parts. If necessary, depending on individual behavior, it may be necessary to administer the different doses in an increasing or decreasing manner.
  • the compounds of formula (I) as medicaments, one can also envisage their use as vehicle or support for active compounds in order to transport these active compounds in a specific way towards a site of action (Drug targeting, see Targeted Drug Delivery, RC Juliano, Handbook of Experimental Pharmacology, Vol 100, Ed. Born, GVR et al, Springer Verlag). Active compounds that can be transported are in particular those used for the treatment or prevention of the diseases mentioned above.
  • the compounds of formula (I) and their salts can also be used as a diagnostic agent, for example for in vitro methods or as an aid in biochemical studies in which it is desired to inhibit the human SRC SH 2 domain. They can also be used as intermediates for the preparation of other compounds, in particular other active agents, which are accessible from the compounds of formula (I), for example by modification or introduction of radicals or functional groups.
  • IR Infrared
  • NMR Nuclear Magnetic Resonance
  • SM Mass spectrum
  • ESP Electrospray positive mode
  • ep. Shoulder
  • F strong
  • s singlet
  • d doublet
  • t triplet
  • quad quadruplet
  • quint quintuplet
  • 1 wide
  • m multiplet or massive
  • J coupling constant
  • Rf retention factor (chromatography).
  • Stage A S- (2-nitrophenyl) -L-cysteine.
  • the mixture consisting of 150 mg of 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 at reflux and then 1 night at room temperature. . After treatment, 90 mg of expected crude product is obtained.
  • Gaseous hydrochloric acid is "bubbled" in 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, added to dichloromethane, washed with sodium bicarbonate and the aqueous phase is extracted with dichloromethane. After evaporation under reduced pressure, 4.4 g of expected crude product are obtained, which product is purified by chromatography, eluting with a dichloromethane / methanol mixture 99/1 then 98/2 then 95/5 to obtain 3.5 g of product. expected.
  • N-alkylation To a solution of 500 mg of P2 in dimethylformamide at 0 ° C under an inert atmosphere is added 90 mg of sodium hydroxide at 60% then 454 mg of l-iodo-3-cyclohexylpropyl stirred at 0 ° C for 15 min and at room temperature for 2 hours. Poured into ice water, extracted with ethyl acetate 1, dried and evaporated under reduced pressure until 733 mg of expected crude product is used directly in the following step Deprotection To a solution of 733 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 left stirring at this temperature for 12 hours.
  • Gaseous hydrochloric acid is "bubbled" with stirring at 110 ° C. in a solution of 1.5 mg of the product obtained in the preceding stage in 15 ml of acetic acid, and left stirring at this temperature for 4 hours. It is then evaporated under reduced pressure, added to dichloromethane, washed with sodium bicarbonate and the aqueous phase is extracted with dichloromethane. After evaporation under reduced pressure, 413 mg of expected crude product is obtained which is purified by chromatography, eluting with a dichloromethane / methanol mixture 99/1, 98.5 / 1.5 and then 98/2 to obtain 747 mg of expected product.
  • Example 1 [2S- [3 (S *), 2 ⁇ , 3 ⁇ ]] - [1- [[4- [[hydroxy (phenylmethoxy) phospninyl] 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 oxoethyl] -carbamate (trans isomer 1).
  • Example 2 [2R- [3 (S *), 2 ⁇ , 3 ⁇ ]] - [1- [[4- [[hydroxy (phenylmethoxy) phospninyl] 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 oxoethyl] -carbamate.
  • Example 3 [2S- [3 (S *), 2 ⁇ , 3 ⁇ ]] - [1- [[4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2- [[2- (4- methoxy-phenyl) -5- [2- [[4-methoxy- [(1,1 '-biphenyl) -3-yl] amino] -2-oxoethyl] -4-oxo-2, 3,4, 5- 1,1-dimethylethyl tetrahydro-1,5-benzothiazepin-3-yl] amino] -2-oxoethyl] -carbamate.
  • Example 1 stage B The procedure is as in Example 1 stage B from 181.8 mg of the product obtained in the previous stage. 104.7 mg of expected pure product are obtained.
  • Example 5 [2R- [3 (S *), 2 ⁇ , 3 ⁇ ]] - [1- [[4- [[hydroxy (phenymethoxy) 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 of 1, 1-dimethylethyl.
  • Example 1 stage B The procedure is as in Example 1 stage B from 95.3 mg of the product obtained in the previous stage. 23.3 mg of expected pure product are obtained.
  • Example 6 [2S- [3 (S *), 2 ⁇ , 3 ⁇ ]] - [1- [[4- [[hydroxy (phenylmethoxy) phospninyl] 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 oxoethyl] -carbamate.
  • Example 1 stage B The procedure is as in Example 1 stage B from 65.5 mg of the product obtained in the previous stage. 19.1 mg of expected pure product are obtained.
  • Example 7 [2S- [3 (S *), 2 ⁇ , 3 ⁇ ]] -1- [[4- [[bis (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2- [[2- (4-methoxyphenyl ) -5- [2- [(1-naphthalenyl) amino] -2-oxo-1-phenylethyl] -4-oxo 2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] amino ] -2-oxoethyl] -carbamate of 1, 1-dimethylethyl.
  • Aromatic + amide 11 1610, 1599, 1584, 1523 ep., 1513, 1508, ccmm
  • Example 1 stage B The procedure is as in Example 1 stage B from 112.4 mg of the product obtained in the previous stage. 31 mg of expected pure product are obtained.
  • Example 9 [2S- [3 (S *), 2 ⁇ , 3 ⁇ ]] -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) -yl] methyl] - [1,1 '-biphenyl] -2-1,1-dimethylethyl carboxylate.
  • Example 10 [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-1,5,5-benzothiazepin-3-yl] amino] -2-oxoethyl] - 1,1-dimethylethyl carbamate.
  • Stage A N-alkylation - [S- [R [trans ( ⁇ )]]]] - [1- [[4- [[bis (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 of 1,1-dimethylethyl.
  • the procedure is as in Example 1, Stage A, starting from 258.4 mg of a mixture of trans diastereoisomer with the alkylating agent 1-iodo-3-cyclohexylpropyl. 179 mg of expected product are obtained.
  • Stage B Monodebenzylation The operation is carried out as in Example 1, Stage B from 76 mg of the product obtained in the preceding stage. 51 mg of expected pure product are obtained.
  • Example 12 [S- [R * (3S *)]] - [2- [[5- (3-cyclohexylpropyl) - 2,3,4,5-tetrahydro-4-oxo-1,5,5-benzothiazepin-3 -yl] amino] -2- oxo-1- [[4-phosphonooxyphenyl] methyl] ethyl]-1,1-dimethylethylcarbamate.
  • [Ai] -CH (NHC0 2 tBu) - CH 2 -Ph-;
  • a 2 OPO (OH) 2
  • Example 13 [S- [R * (3R *)]] - [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 of 1,1-dimethylethyl.
  • Example 14 [S- [R * (3R *)]] - [2- [[5- (3-cyclohexylpropyl) - 2,3,4,5-tetrahydro-4-oxo-1,5-benzothiazepin-3 -yl] amino] -2- oxo-1- [[4-phosphonooxyphenyl] methyl] ethyl] -carbamate of 1,1-dimethylethyl.
  • Example 12 The procedure is as in Example 12 from 55 mg of dibenzylated product obtained in stage A of Example 13. 37 mg of the expected monobenzylated product are obtained.
  • Ph-CH 2 -CH, Ph-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):
  • 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.
  • amine P4 (preparation 4) in 2 ml of dichloromethane are added at argon under 256 mg to a solution consisting 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 C1 2 and 0.4 ml of DMF.
  • EDC 1- (3-dimethylaminopropyl) -3 ethylcarbodiimide hydrochloride
  • HOBT 1-hydroxybenzotriazole hydrate
  • Stage 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) - acetamide.
  • 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.
  • 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-benzothiazepin-5 (4H) -acetamide.
  • Example 15 stage A The procedure is as in Example 15 stage A but from 156.6 mg of P4 and 63 mg of 4-boronobenzoic acid. 135 mg of expected pure product are obtained.
  • Stage A (R) -N- [5- (3-cyclohexylpropyl) -4-oxo-2, 3, 4, 5-tetrahydro-1, 5-benzothiazepin-3-yl] -4-hydroxy 3-formyl- benzamide.
  • Aromatic + amide II 1605,1585,1550,1482 cm "1
  • Example 15 stage A, B and C The procedure is as in Example 15 stage A, B and C but from 106.2 mg of P5 and 55 mg of 4-hydroxy-benzoic acid. At the end of these three stages and after purification, 69 mg of expected pure product are obtained.
  • Example 22 acid (R) - [4- [[[5- (3-cyclohexylpropyl) -4-oxo- 2, 3, 4, 5-tetrahydro-1,5, benzothiazepin-3-yl] amino] carbonyl] 2-formylphenoxy] -acetic.
  • Example 23 (R) -N- [5- (3-cyclohexylpropyl) -4-oxo-2, 3,4,5-tetrahydro-1,5,5-benzothiazepin-3-yl] -4- (diphosphonomethyl) - benzamide .
  • a 2 -CH [PO (OH) 2 ] 2.
  • Aromatic + amide II 1611,1585,1571,1549,1523,1491 cm "1 NMR (DMSO)
  • Example 25 (R) -N- [5- (4-cyclohexylbutyl) -4-oxo-2, 3,4,5-tetrahydro-1,5,5-benzothiazepin-3-yl] -N '- [4- ( phosphonooxy) phenyl] -urea.
  • Stage A formation of urea - (R) -N- [5- (4-cyclohexylbutyl) -4-oxo-2,3,4,5-tetrahydro-1,5,5-benzothiazepin-3-yl] -N '- (4-methoxyphenyl) -urea.
  • 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.
  • Stage C phophorylation - (R) -N- [5- (4-cyclohexylbutyl) -4-oxo-2,3,4,5-tetrahydro-1,5,5-benzothiazepin-3-yl] -N '- [4 - [[bis (phenylmethoxy) phosphinyl] oxy] phenyl] urea.
  • Stage D Total Debenzylation A solution of 23.1 mg of the product obtained in the preceding stage is saturated in 3 ml of MeOH, with hydrogen, stirred for 3 hours at room temperature and evaporated under reduced pressure until 17 mg is obtained. expected pure product.
  • Aromatic + amide II 1608,1582,1554,1508 cm "1
  • Example 26 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] -benzeneeacetamide.
  • Stage 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] -benzeneeacetamide.
  • a solution is prepared under argon at 0 ° C.
  • Example 27 cis ( ⁇ ) -N- [5- (3-cyclohexylpropyl) -2- (4-methoxyphenyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3 -yl] -4- (phosphonooxy) -benzeneeacetamide.
  • Aromatic + amide II 1608.1582.1515 cm "1 NMR (DMSO) 0.81 (m) (2H) 1.10 to 1.30 (m) (7 to 8H) 1.44 to 1.70 (m ) (8H)
  • Example 29 (R) -3- [[(aminocarbonyl) hydrazono] methyl] -4- (phosphonooxy) -N- [5- (3-cyclohexylpropyl) -4-oxo-2, 3,4,5- tetrahydro- 1, 5-benzothiazepin-3-yl] -benzamide.
  • Stage B Deprotection The reaction is carried out with reflux for 5 hours 50 mg of the product obtained in the previous stage with 103 ⁇ l of TMSBr in 5 ml of dichloromethane then flows into methanol, evaporates under reduced pressure and purifies by chromatography. 16 mg of expected product is obtained.
  • Example 31 (R) -5- (phosphonooxy) -N- [5- (3-cyclohexylpropyl) 4-oxo-2, 3,4,5-tetrahydro-1, 5-benzothiazepin-3-yl] -2- pyridine carboxamide.
  • Stage B Phosphorylation (R) 5- [[(diethoxy) phosphinyl] oxy] N- [5- (3-cyclohexylpropyl) -4-oxo-2,3,4,4-tetrahydro-1,5-benzothiazepin -3- yl] 2-pyridinecarboxamide.
  • Aromatic + Amide II 1616,1605,1585, 1571,1545, 1501 cm "1
  • the coupling reaction is carried out in this case in solid phase.
  • 200 mg of Wang H0 2 resin C- [CH (NHAc) -CH 2 -Ar-0-PO (OtBu) (OCH 2 -Wang) (Pli) are added, add 50 mg of amine prepared to the preparation P8 previously alkylated with an Rs ⁇ Br group according to the method described for (P5), 1 ml of dichloromethane, 1 ml of HOBt in DMF and 1 ml of DIC in DMF, stirred overnight at room temperature and washed thoroughly with d first DMF, then a DMF / CH 2 C1 2 mixture then CH 2 C1 2 .
  • Example 21 the para hydroxy benzoic acid is coupled with the amine P8 previously alkylated with an appropriate halide R 5 -Hal, followed by a phosphorylation reaction according to Example 15 with the dibenzylphosphite and then a deprotection reaction according to the methods indicated above, in particular by action of TFA.
  • Compounds of formula (I '') are then obtained with [A ⁇ ] -A 2 representing -Ar-OP0 3 H 2
  • Procedure D The operation is carried out using compounds of formula (IIIc) prepared according to scheme 3.
  • the coupling is carried out according to Example 28 on an amine P8 previously alkylated with an appropriate alkyl halide R 5 -Hal.
  • Deprotection is generally carried out with TMSBr or TMSI in dichloromethane.
  • Compounds of formula (I '') are then obtained with [A ⁇ ] -A 2 representing Ar-CF 2 P0 3 H.
  • Procedure F We operate with the resin P13 according to procedure A 'We then obtain compounds of formula (I'') with [A ⁇ ] -A 2 representing -Ar-NHCOP0 3 H 2 Procedure G
  • the operation is carried out from the following diacids of formula (III) (p-C0 2 Me) -Ar-CH 2 -CH (NHAc) -C0 2 H.
  • the coupling is carried out according to Example 35 on an amine P8 previously alkylated by a suitable alkyl halide R 5 -Hal.
  • Stage b Coupling To a solution of 362 mg of product prepared in stage a in dichloromethane is added 3 ml of TFA, stirred for one hour at room temperature, evaporates, dilutes with dichloromethane and then adds 0.5 ml of DIPEA. To a solution of 159 mg of parahydroxybenzoic acid in a dichloromethane / DMF mixture (4/1 by volume) is added 220 mg of HOBt and 255 mg of EDC at 0 ° C. After 15 minutes of stirring at room temperature, the medium is transferred to a 0 ° C flask containing the free amine solution.
  • a 2 -CF 2 -P (0) (OH) 2
  • a 2 -CF 2 P (0) (OH) 2 and the sulfur of thioazepinone is oxidized
  • a and R ⁇ form together with the phenyle which carries them a group -C (OH) -0-CO- (Procedure G; Ar represents a phenyl substituted in meta by a CHO group in the form of a cyclic dithioacetal.
  • the cyclization is carried out by the action of aqueous NaOH in THF after deproteging the formyl (Hg (C10 4 ) 2 ))
  • a 2 and R 6 form together with the phenyle which carries them a group -C (OEt) -O-CO-
  • Aromatic + amides II 1540 cm "1
  • Example 46 4- [(2S) -2- (acetylamino) -3- [[(6R) -4- (3- cyclohexylpropyl) -hexahydro-5-oxo-1,4-thiazepin-6-yl] amino acid] -
  • PhCH 2 N 4.59 (m, 1H, CH); 4.71 (dd, 1H, PhCH 2 N); 5.01 (m, 1H, CH); 6.87 (dl, 1H, Ph); 6.95 (si, 1H, Ph); 7.06 (d,
  • Aromatic 1505, 1510 cm "1
  • Ar representing a tetrahydro-5, 5, 8, 8-tetramethyl-2-naphthalene group.

Abstract

The invention concerns a thioazepinone derivative of formula (I) wherein: R1, R2, R3, R4, R5, X, [A1], A2 and U have the meanings given in the description, their salts and their pro-drugs. The invention further concerns methods for preparing compounds of formula (I), intermediates for said method, their use as medicines, in particular as Src domain SH2 inhibitors and inhibitors of osteoclast-mediated calcium resorption from bone, and pharmaceutical compositions containing them.

Description

Dérivés de thioazepinone, procédé de préparation et intermédiaires de ce procédé, application comme médicaments et compositions pharmaceutiques les contenant. Thioazepinone derivatives, process for their preparation and intermediates, application as medicaments and pharmaceutical compositions containing them.
L'invention a pour objet un dérivé de thiazépinone de formule (I)The subject of the invention is a thiazepinone derivative of formula (I)
Figure imgf000003_0001
dans laquelle Ri, R2, R3, R4, R5 U, X, [Ai] et A2 ont les significations indiquées plus bas, leurs sels physiologiquement acceptables et leurs promédicaments. Les composés de formule (I) sont des composés ayant une activité pharmacologique et sont donc utilisables à titre de médicaments. Ce sont notamment des inhibiteurs du domaine Src SH2 et ils inhibent la résorption osseuse médiée par les ostéoclastes . Ils sont donc utiles pour le traitement thérapeutique ou prophylactique de maladies qui sont causées au moins en partie par une augmentation non désirée de la résorption osseuse, par exemple 1 ' osteoporose. L'invention de plus a pour objet les procédés de préparation des composés de formule (I), les intermédiaires de ce procédé, leur application, en particulier à titre de médicament et les compositions pharmaceutiques les renfermant. Domaine de 1 ' invention a) L' activité catalytique Tyrosine kinase L'activité catalytique tyrosine kinase est associée soit à des récepteurs possédant des domaines transmembranaires (EDF, DPGF, c-fms .. ) soit à des protéines intracellulaires (T. Hunter, Biochem Soc. Trans; 24, 307-327 (1996). Les tyrosines kinases intracellulaires ("non récepteur") sont réparties en 8 sous familles principalement selon la similarité de séquence de leur domaine catalytique et ont été appelées du nom de leur membre le plus connu (Src, Csk, Btk, Abl, Fak, Syk, Jak, Fsp) . A l'intérieur de cette classe de tyrosines kynases intracellulaires, la famille Src contient 9 membres partageant entre eux 70% d'homologie de séquence (Src, Fyn, Yes, Frg, Lyn, Hck, Lck, Blk, Yrd chez les vertébrés) . b) - Protéines de la famille Src Les protéines de la famille Src partagent une structure commune qui est caractérisée par les éléments suivants : un petit fragment N-terminal impliqué dans l'ancrage à la membrane (appelé parfois aussi SH4), un domaine unique peu conservé (40-70 résidus), un domaine SH3 qui se lie à des séquences riches en prolines (50 résidus) , un domaine SH2 impliqué dans la reconnaissance de séquence peptidique spécifiques phosphorylées (100 résidus), un domaine catalytique (tyrosine kinase, 250 résidus) et enfin un court domaine C-terminal impliqué dans la régulation. c)- Fonction des protéines tyrosines kinases de la famille c-Src
Figure imgf000003_0001
in which Ri, R 2 , R 3 , R 4 , R 5 U, X, [Ai] and A 2 have the meanings indicated below, their physiologically acceptable salts and their prodrugs. The compounds of formula (I) are compounds having pharmacological activity and are therefore usable as medicaments. They are in particular inhibitors of the Src SH2 domain and they inhibit bone resorption mediated by osteoclasts. They are therefore useful for the therapeutic or prophylactic treatment of diseases which are caused at least in part by an unwanted increase in bone resorption, for example osteoporosis. The invention further relates to the processes for preparing the compounds of formula (I), the intermediates of this process, their application, in particular as a medicament and the pharmaceutical compositions containing them. FIELD OF THE INVENTION a) The catalytic activity Tyrosine kinase The catalytic activity tyrosine kinase is associated either with receptors having transmembrane domains (EDF, DPGF, c-fms ..) or with intracellular proteins (T. Hunter, Biochem Soc. Trans; 24, 307-327 (1996). Intracellular tyrosine kinases ("no receptor ") are divided into 8 subfamilies mainly according to the sequence similarity of their catalytic domain and were named after their best known member (Src, Csk, Btk, Abl, Fak, Syk, Jak, Fsp). Within this class of intracellular tyrosine kynases, the Src family contains 9 members sharing 70% of sequence homology between them (Src, Fyn, Yes, Frg, Lyn, Hck, Lck, Blk, Yrd in vertebrates). b) - Src family proteins Src family proteins share a common structure which is characterized by the following elements: a small N-terminal fragment involved in anchoring to the membrane (sometimes also called SH4), a unique domain poorly conserved (40-70 residues), an SH3 domain which binds to proline-rich sequences (50 residues), an SH2 domain involved in the recognition of specific phosphorylated peptide sequences (100 residues), a catalytic domain (tyrosine kinase, 250 residues) and finally a short C-terminal domain involved in regulation. c) - Function of the protein tyrosine kinases of the c-Src family
Les protéines tyrosine kinases de la famille c-Src ont des rôles multiples et se chevauchent au niveau de la transduction des signaux impliqués dans toute une série de situations biologiques différentes, notamment, la croissance et la différentiation cellulaire, le contrôle du cycle cellulaire, de la forme et de l'adhésion des cellules ainsi que la régulation des canaux ioniques et des récepteurs neurotransmetteurs . Tandis que l'expression de la plupart des membres de la famille de Src est limitée au système hématopoïétique, les protéines Src, Fyn et Yes sont exprimées dans un grand nombre de tissus et type cellulaires. Le gène c-Src en particulier est très largement exprimé dans les neurones, les plaquettes et les ostéoclastes . d) Résorption osseuse et c-Src Les fonctions biologiques de plusieurs de ces protéines ont finalement commencé à être mieux comprises avec la réalisation des expériences de knock out. Ainsi Soriano et al (Cell 64, 693-702 (1991)) ont récemment généré une lignée de souris transgénique dont le gène de c-Src n'était pas fonctionnel. L'observation du phénotype des souris homozygotes pour cette mutation a fait apparaître plusieurs faits extrêmement intéressants : elles ne présentaient pas d'anormalité patente au niveau des neurones ou des plaquettes, par contre ces souris étaient toutes atteintes d'une résorption osseuse très diminuée qui donne lieu à des anormalités du squelette (S.N. Popoff et al; Bone 17(5) 437- 445 (1995) ) . Il a ensuite été démontré que ces souris possédaient des ostéoclastes en nombre normal, mais que ces derniers ne possédaient pas de bordure en brosse et n' étaient pas capables de résorption normale dans le test du pit (B.F. Boyce et al. J. Clin. Invest. 90, 1622-27 (1992)). Donc, seuls les ostéoclastes semblent affectés par la mutation. L'hypothèse est la suivante : dans les neurones, plaquettes et autres cellules dans lesquelles Src exerce une fonction, cette fonction pourrait être prise en charge par un membre très proche de la famille (fyn, lyn ou yes) ; en revanche, cette substitution fonctionnelle n'aurait pas lieu dans les ostéoclastes. e)- Inhibition de la protéine SrcThe protein tyrosine kinases of the c-Src family have multiple roles and overlap in signal transduction involved in a variety of different biological situations, including cell growth and differentiation, cell cycle control, cell shape and adhesion as well as the regulation of ion channels and neurotransmitter receptors. While the expression of most members of the Src family is limited to the hematopoietic system, the proteins Src, Fyn and Yes 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 several of these proteins finally began to be better understood with the carrying out of the knockout experiments. Thus Soriano et al (Cell 64, 693-702 (1991)) recently generated a line of transgenic mice whose gene for c-Src was not functional. The observation of the phenotype of homozygous mice for this mutation revealed several extremely interesting facts: they did not exhibit any obvious abnormality in neurons or platelets, on the other hand these mice were all suffering from very reduced bone resorption which gives rise to skeletal abnormalities (SN Popoff et al; Bone 17 (5) 437-445 (1995)). It was then shown that these mice possessed osteoclasts in normal number, but that the latter 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)). Therefore, only the osteoclasts seem to be affected by the mutation. The hypothesis is as follows: in neurons, platelets and other cells in which Src performs a function, this function could be taken over 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 protein Src
Dès lors que cette protéine semble essentiellement dans les processus de résorption osseuse et n'apparaît pas vitale pour d'autres fonctions, la demanderesse se propose de trouver de nouveaux composés l'inhibant pour enrayer la résorption osseuse.As soon as this protein appears essentially in the processes of bone resorption and does not appear to be vital for other functions, the applicant proposes to find new compounds inhibiting it to halt bone resorption.
Cette inhibition peut s'effectuer soit au niveau du domaine SH2, soit au niveau du domaine SH3 (impliqué dans la reconnaissance et l'interaction avec d'autres protéines), soit au niveau du domaine catalytique (tyrosine kinase) . Etat de la techniqueThis inhibition can be carried out either at the level of the SH2 domain, or at the level of the SH3 domain (involved in recognition and interaction with other proteins), or at the level of the catalytic domain (tyrosine kinase). State of the art
Les demandes de brevets suivantes décrivent des composés inhibant la liaison de protéines contenant un domaine SH2 avec une protéine phosphorylée. WO 98/40093 décrit des dérivés hétérocycliques bicycliques, WO97/12903 décrit des dérivés du phényle, WO97/30079 et W096/23813 décrivent des dérivés peptidiques, 95/25118 décrit des dérivés de benzodiazépine, EP 727211 et WO 96/24343 décrivent l'utilisation de certains composés spécifiques du domaine SH2 pour traiter la résorption osseuse ainsi que les maladies autoimmunes.The following patent applications describe compounds that inhibit the binding of proteins containing an SH2 domain with a phosphorylated protein. WO 98/40093 describes bicyclic heterocyclic derivatives, WO97 / 12903 describes phenyl derivatives, WO97 / 30079 and WO96 / 23813 describe peptide derivatives, 95/25118 describes benzodiazepine derivatives, EP 727211 and WO 96/24343 describe it use of certain compounds specific to the SH2 domain to treat bone resorption as well as autoimmune diseases.
D'autres investigations ont permis de montrer que les dérivés de thioazepinones de formule (I) présentent une forte activité comme inhibiteurs du domaine humain Src SH2 et de la résorption osseuse médiée via les ostéoclastes.Other investigations have made it possible to show that the thioazepinone derivatives of formula (I) exhibit a strong activity as inhibitors of the human domain Src SH2 and of bone resorption mediated via osteoclasts.
L'invention a pour objet un dérivé de thioazepinone de formule (I)The subject of the invention is a thioazepinone derivative of formula (I)
Figure imgf000006_0001
dans laquelle, Ri et R2
Figure imgf000006_0001
in which, Ri and R 2
- soit représentent chacun un atome d'hydrogène,- either each represent a hydrogen atom,
- soit, identiques ou différents, représentent un radical (Cι-C8) -alkyle-, hydroxy, (Cι-C8) -alkoxy-, C02Ra, CONRaRb, amino, (Ci-Ce) alkylamino-, di (Ci-Ce) -alkylamino-, (C5-- either, identical or different, represent a (Cι-C 8 ) -alkyl-, hydroxy, (Cι-C 8 ) -alkoxy-, C0 2 Ra, CONRaRb, amino, (Ci-Ce) alkylamino-, di ( Ci-Ce) -alkylamino-, (C5-
Cι4)aryle- ou un hétérocycle saturé ou insaturé, les dits alkyles, aryles ou hétérocycles étant non substitués ou substitués par R6;Cι 4 ) aryle- or a saturated or unsaturated heterocycle, the said alkyls, aryls or heterocycles being unsubstituted or substituted by R 6 ;
- soit forment ensemble le reste d'un cycle aromatique ou d'un hétéroaryle, accolé en position 2 et 3 à la thioazepinone, non substitué ou substitué par R6 - or together form the remainder of an aromatic ring or a heteroaryl, attached in position 2 and 3 to thioazepinone, unsubstituted or substituted by R 6
- R5 est soit R'5, représentant les groupements suivants (Cι-Cβ)-al yle- , (C2-C8) -alkényle-, (C2-C8) -alkynyle- , (C5- Cι4)-aryle-, (C5-C14) -aryl- (Cι-C8) -alkyle- , (C5-C14) -aryl- (C2- C8) -alkényle- , (C5-Cι4) -aryl- (C2-C8) -alkynyle- , (C3-Cι8)- cycloalkyle-, (C3-C18) -cycloalkyl- (Cι-C8) -alkyle- , (C3-Cι8)- cycloalkyl- (C2-C8) -alkényle- ou (C3-Cι8) -cycloalkyl- (C2-C8) - alkynyle-, les dits groupements alkyles, alkényles, alkynyles, aryles et cycloalkyles étant non substitués ou substitués par un ou plusieurs radicaux R6, soit R"5, représentant les groupements suivants- R 5 is or R ' 5 , representing the following groups (Cι-Cβ) -al yle-, (C 2 -C 8 ) -alkenyl-, (C 2 -C 8 ) -alkynyl-, (C 5 - Cι 4 ) -aryl -, (C5-C14) -aryl- (Cι-C 8 ) -alkyle-, (C5-C14) -aryl- (C 2 - C 8 ) -alkenyl-, (C 5 -Cι 4 ) -aryl- ( C 2 -C 8 ) -alkynyl-, (C 3 -Cι 8 ) - cycloalkyle-, (C 3 -C 18 ) -cycloalkyl- (Cι-C 8 ) -alkyle-, (C 3 -Cι 8 ) - cycloalkyl - (C 2 -C 8 ) -alkenyl- or (C 3 -Cι 8 ) -cycloalkyl- (C 2 -C 8 ) - alkynyle-, the said alkyl, alkenyl, alkynyl, aryl and cycloalkyl groups being unsubstituted or substituted by one or more radicals R 6 , ie R " 5 , representing the following groups
-CHRh-CO-R'5 , -CHRh-CONH-R'5 , R'5 étant tel que défini plus haut ; soit R" ' 5 représentant un atome d'hydrogène-CHRh-CO-R ' 5 , -CHRh-CONH-R' 5 , R ' 5 being as defined above; either R "' 5 representing a hydrogen atom
- -[Aι]- représente un groupement choisi parmi -CH(Z)-(Cι-C4)-alkylène-(C5-Cι4)-aryle-, -C (Z)=CH- (C5-C14) - aryle-, -C (Z) =CH- (Cι-C2) -alkylène- (C5-C14) -aryle- , -CH(Z)-(C5- C14) -aryle-, - (C1-C4) -alkylène- (C5-C14) -aryle-, - (C5-C14) -aryle- , -(Cι-C4)-alkylène-NHCO-(C5-Cι4) -aryle-, -NH- (C5-C14) -aryle- dans lesquels Z est un atome d'hydrogène, un tétrazole, NRbRc, NHCORb, CONHRb, NHC02Rb, NHCOC02Rb, NHCONHRb ou- - [Aι] - represents a group chosen from -CH (Z) - (Cι-C 4 ) -alkylene- (C 5 -Cι 4 ) -aryl-, -C (Z) = CH- (C5-C14) - aryle-, -C (Z) = CH- (Cι-C 2 ) -alkylene- (C5-C14) -aryle-, -CH (Z) - (C 5 - C 14 ) -aryle-, - (C1 -C4) -alkylene- (C5-C14) -aryl-, - (C 5 -C14) -aryl-, - (Cι-C 4 ) -alkylene-NHCO- (C 5 -Cι 4 ) -aryl-, - NH- (C 5 -C14) -aryl- in which Z is a hydrogen atom, a tetrazole, NRbRc, NHCORb, CONHRb, NHC0 2 Rb, NHCOC0 2 Rb, NHCONHRb or
NHS02Rb; les dits radicaux aryles étant substitués ou non substitués par un ou plusieurs radicaux R6 ou R'ε/NHS0 2 Rb; the said aryl radicals being substituted or unsubstituted by one or more radicals R 6 or R'ε /
- A2 représente un groupement choisi parmi -PO(ORd) (ORe) , -OPO (ORd) (ORe) , -B (ORd) (ORe) , -CRfRgPO(ORd) (ORe) , -O-CRfRgPO (ORd) (ORe) , -CRfRg-C02Rd, - CRf(C02Rd)2, -0-CRfRg-C02Rd, -O-CRf (C02Rd) 2, -N (CRfRg-C02Rd) 2, -C02Rd, -CRfRg-CH2-C02Rd, -CRfRgS03H, -0-CRfRgS03H, -OSO3H , - OS02NH2, -S02NH2, -NHCO-PO(ORd) (ORe) , -CO-PO (ORd) (ORe) , -OH et -O-CORd; - R3, R4, Ra, Rb, Rc, Rd, Re, Rh ou Ri, indépendants les uns des autres, identiques ou différents, représentant un atome d'hydrogène, un radical (Cι-C8) -alkyle-, (C3-Cι8)- cycloalkyle-, (C3-Cι8) - (cycloalkyl) - (Cι~C8) -alkyle-, (C5- C14) -aryle- ou (C5-C14) -aryl- (C!-C4) -alkyle-, les dits radicaux étant substitués ou non substitués par R6; - Rf et Rg identiques ou différents représentant un atome d'hydrogène, un halogène, ORe, NHRc, un radical C02Rc, CH2C02Rc, S03H, PO (ORd) (ORe) ou tétrazole;- A 2 represents a group chosen from -PO (ORd) (ORe), -OPO (ORd) (ORe), -B (ORd) (ORe), -CRfRgPO (ORd) (ORe), -O-CRfRgPO (ORd ) (ORe), -CRfRg-C0 2 Rd, - CRf (C0 2 Rd) 2 , -0-CRfRg-C0 2 Rd, -O-CRf (C0 2 Rd) 2 , -N (CRfRg-C0 2 Rd) 2 , -C0 2 Rd, -CRfRg-CH 2 -C0 2 Rd, -CRfRgS0 3 H, -0-CRfRgS0 3 H, -OSO 3 H, - OS0 2 NH 2 , -S0 2 NH 2 , -NHCO-PO (ORd) (ORe), -CO-PO (ORd) (ORe), -OH and -O-CORd; - R 3 , R 4 , Ra, Rb, Rc, Rd, Re, Rh or Ri, independent of each other, identical or different, representing a hydrogen atom, a (Cι-C 8 ) -alkyl- radical, (C 3 -Cι 8 ) - cycloalkyle-, (C 3 -Cι 8 ) - (cycloalkyl) - (Cι ~ C 8 ) -alkyle-, (C 5 - C 14 ) -aryl- or (C 5 -C 14 ) -aryl- (C ! -C 4 ) -alkyle-, said radicals being substituted or unsubstituted by R 6 ; - Rf and Rg identical or different representing a hydrogen atom, a halogen, ORe, NHRc, a radical C0 2 Rc, CH 2 C0 2 Rc, S0 3 H, PO (ORd) (ORe) or tetrazole;
- éventuellement R3 et R4 forment ensemble avec l'atome de carbone qui les porte, un groupement cycloalkyle renfermant de 3 à 6 atomes de carbone,optionally R 3 and R 4 form together with the carbon atom which carries them, a cycloalkyl group containing 3 to 6 carbon atoms,
- R6 représente un groupement choisi parmi (Cχ-C4) -alkyle-- R 6 represents a group chosen from (Cχ-C 4 ) -alkyle-
, (C!-C4) -alkoxy-, hydroxy- (C1-C4) -alkyle-, (Cι-C4) -alkoxy- (Cι~ C4) -alkyle-, (C1-C3) -alkylènedioxy-, (C5-C14) -aryle-, Het, (C5- Cι4)-aryloxy-, (C5-C14) -aryl- (Cι~C4) -alkyle-, (C5-C14) -aryl- (d- C4) -alkyloxy-, halogène, trihalogénométhyle-, trihalogénométhyloxy-, , trihalogénomethylcarbonyloxy- (Ci- C4) -alkyle-, hydroxyle, nitro, formyle, -C=N-NH-CONH , cyano, carboxy, -CONH2, (C1-C4) -alkyloxycarbonyle-, (C1-C4)- alkylcarbonyloxy-, amino, (C1-C4) -alkylamino-, di-(Cχ-, (C ! -C 4 ) -alkoxy-, hydroxy- (C 1 -C 4 ) -alkyle-, (Cι-C 4 ) -alkoxy- (Cι ~ C 4 ) -alkyle-, (C 1 -C 3 ) -alkylenedioxy-, (C 5 -C 14 ) -aryl-, Het, (C 5 - Cι 4 ) -aryloxy-, (C 5 -C 14 ) -aryl- (Cι ~ C 4 ) -alkyl-, ( C 5 -C 14 ) -aryl- (d- C 4 ) -alkyloxy-, halogen, trihalomethylethyl-, trihalogenethyloxy-,, trihalogenethylcarbonyloxy- (Ci- C 4 ) -alkyl-, hydroxyl, nitro, formyl, -C = N -NH-CONH, cyano, carboxy, -CONH 2 , (C 1 -C 4 ) -alkyloxycarbonyle-, (C 1 -C 4 ) - alkylcarbonyloxy-, amino, (C 1 -C 4 ) -alkylamino-, di- (Cχ-
C4) alkylamino-, (C1-C4) -alkyl-carbonylamino-, (C5-C14) -aryl- carbonylamino-, (C1-C4) -alkyl-aminocarbonyle-, (C5-C14) -aryl- aminocarbonyle-, (C1-C4) -alkyl-carbonyle-, (C5-C14) -aryl- carbonyle-, (C1-C4) -alkyl-sulfonyle-, (C5-C14) -aryl-sulfonyle-, (C5-Cι4)-aryl-sulfonyl-(Cι-C4) -alkyle-, (C1-C4) -alkyl- aminosulfonyle-, di (C1-C4) -alkyl-aminosulfonyle-, (C5-C14)- aryl-aminosulfonyle-, (C3-C8) -cycloalkyl-aminosulfonyle-, ( (C3- C8) -cycloalkyl) ( (C1-C4) -alkyl) aminosulfonyle- et Het- sulfonyle-, Het représentant un hétérocycle saturé à 5 ou 6 chainons renfermant éventuellement un deuxième hétéroatome O, N ou S;C 4 ) alkylamino-, (C 1 -C 4 ) -alkyl-carbonylamino-, (C 5 -C14) -aryl- carbonylamino-, (C 1 -C 4 ) -alkyl-aminocarbonyl-, (C 5 -C14) -aryl- aminocarbonyl-, (C 1 -C 4 ) -alkyl-carbonyl-, (C 5 -C 14 ) -aryl- carbonyl-, (C 1 -C 4 ) -alkyl-sulfonyl-, (C 5 -C 14 ) -aryl-sulfonyl-, (C 5 -Cι 4 ) -aryl-sulfonyl- (Cι-C 4 ) -alkyle-, (C1-C4) -alkyl- aminosulfonyle-, di (C 1 -C 4 ) - alkyl-aminosulfonyle-, (C 5 -C 14 ) - aryl-aminosulfonyle-, (C 3 -C 8 ) -cycloalkyl-aminosulfonyle-, ((C 3 - C 8 ) -cycloalkyl) ((C 1 -C 4 ) -alkyl) aminosulfonyl- and Het-sulfonyl-, Het representing a saturated heterocycle with 5 or 6 links optionally containing a second heteroatom O, N or S;
- R'6 a les mêmes valeurs que A2;- R ' 6 has the same values as A 2 ;
- éventuellement A2 et Rζ forment ensemble avec 1 ' aryle qui les porte, l'un des cycles à 5 chaînons suivants :- optionally A 2 and Rζ together with the aryl which carries them, one of the following 5-membered rings:
Figure imgf000008_0001
- U représente un groupement choisi parmi CO, CS, SO, S02 et un groupement alkylène saturé ou insaturé renfermant de 1 à 4 atomes de carbone, le trait en pointillé indique la présence d'une double liaison éventuelle, lesdits composés de formule (I) étant sous toutes leurs formes isomères possibles, seuls ou en mélange dans un rapport quelconque, ainsi que leurs sels physiologiquement acceptables et leurs promédicaments (prodrugs) .
Figure imgf000008_0001
- U represents a group chosen from CO, CS, SO, SO 2 and a saturated or unsaturated alkylene group containing from 1 to 4 carbon atoms, the dotted line indicates the presence of a possible double bond, said compounds of formula ( I) being in all their possible isomeric forms, alone or as a mixture in any ratio, as well as their physiologically acceptable salts and their prodrugs (prodrugs).
Tous les radicaux qui peuvent se retrouver plusieurs fois dans les composés de formule (I), par exemple le radical R6, sont indépendants les uns des autres et peuvent être identiques ou différents. D'une manière générale, les radicaux alkyles peuvent être linéaires ou ramifiés, saturés ou mono- ou poly- insaturés. Ceci s'applique également lorsqu'ils portent un substituant ou lorsqu'ils sont inclus dans des groupements tels que par exemple alkoxy, alkoxycarbonyle ou aralkyle. Par (Cι~C8) -alkyle on entend donc notammentAll the radicals which can be found several times in the compounds of formula (I), for example the radical R 6 , are independent of each other and can be identical or different. In general, the alkyl radicals can be linear or branched, saturated or mono- or polyunsaturated. This also applies when they have a substituent or when they are included in groups such as, for example, alkoxy, alkoxycarbonyl or aralkyl. By (Cι ~ C 8 ) -alkyl therefore means in particular
- les radicaux alkyles saturés tels que méthyle, éthyle, propyle, butyle, pentyle, hexyle, heptyle, octyle, les n- isomères de ces radicaux, isopropyle, isobutyle, isopentyle, néopentyle, isohexyle, 3-méthylpentyle, 2,3,4- trimethylhexyle, sec-butyle, tert-butyle, tert-pentyle. Parmi les radicaux préférés on peut citer méthyle, éthyle, n- propyle, isopropyle, n-butyle, isobutyle, et tert-butyle.- saturated alkyl radicals such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, the n-isomers of these radicals, isopropyl, isobutyl, isopentyl, neopentyl, isohexyl, 3-methylpentyl, 2,3,4 - trimethylhexyle, sec-butyle, tert-butyle, tert-pentyle. Among the preferred radicals, mention may be made of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl.
- les radicaux alkyles insaturés à savoir les radicaux (C2- C8) -alkényles tels que vinyle, 1-propényle, allyle, butényle, 3-méthyl-2-butényle ou les radicaux (C2-C8) -alkynyles tels que éthynyle, 1-propynyle ou propargyle.- unsaturated alkyl radicals, namely (C 2 -C 8 ) -alkenyl radicals such as vinyl, 1-propenyl, allyl, butenyl, 3-methyl-2-butenyl or (C 2 -C 8 ) -alkynyl radicals such as ethynyl, 1-propynyl or propargyl.
Le terme (C1-C4) -alkyle, comprend les radicaux méthyle, éthyle, n-propyle, isopropyle, n-butyle, isobutyle, tert- butyle, vinyle, 1-propényle, allyle, butényle, éthynyle, 1- propynyle ou propargyle Les radicaux alkylènes, correspondant aux radicaux monovalents cités plus haut, sont par exemple les radicaux alkylène bivalents saturés tels que méthylène, éthylène, 1,3- propylène, 1, 2-propylène (=l-méthyléthylène) , 2,3-butylène (=l,2-diméthyléthylène) , 1, -butylène, ou 1, 6-hexylène, ou encore les radicaux alkylène bivalents insaturés tels que les radicaux alkénylène et alkynylène qui peuvent également être linéaires ou ramifiés. Il s'agit par exemple des radicaux vinylène, propénylène, éthynylène ou propynylène. Les radicaux cycloalkyles peuvent être monocycliques, bicycliques ou tricycliques . Il s'agit par exemple des radicaux cyclopropyle, cyclobutyle, cyclopentyle, cyclohexyle, cycloheptyle, cyclooctyle, cyclononyle, cyclodécyle, cycloundécyle, cyclododécyle, cyclotétradécyle ou cyclooctadecyle qui le cas échéant peuvent être substitués par exemple par un alkyle renfermant de 1 à 4 atomes de carbone. Comme radicaux cycloalkyles substitués, on peut citer le 4 méthylcyclohexyle et le 2, 3-diméthylcyclohexyle. Les radicaux bicycloalkyles et tricycloalkyles peuvent être non substitués ou substitués en toute position, par exemple par un ou plusieurs groupes oxo et/ou 1 ou plusieurs groupes alkyles identiques ou différents tels que méthyle ou isopropyle et de préférence méthyle. La liaison de jonction du radical bi ou tricyclique peut se situer en toutes positions de la molécule. La liaison peut se situer au niveau de l'atome de carbone ponté ou d'un des autres atomes de carbone. Cette liaison peut présenter également toutes positions du point de vue de la stéréochimie, par exemple exo ou endo. Comme exemple de radicaux bicycloalkyles ou tricycloalkyles, on peut citer le camphanyle, le bornyle, l'adamantyle tel que le 1-adamantyle ou le 2-adamantyle, le caranyle, 1 ' épiisobornyle, 1 ' épibornyle, le norbornyle ou le norpinanyle.The term (C 1 -C 4 ) -alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, vinyl, 1-propenyl, allyl, butenyl, ethynyl, 1-propynyl or propargyle The alkylene radicals, corresponding to the monovalent radicals mentioned above, are for example the saturated bivalent alkylene radicals such as methylene, ethylene, 1,3-propylene, 1,2-propylene (= 1-methylethylene), 2,3-butylene ( = 1, 2-dimethylethylene), 1, -butylene, or 1, 6-hexylene, or alternatively unsaturated bivalent alkylene radicals such as the alkenylene and alkynylene radicals which can also be linear or branched. These are, for example, vinylene, propenylene, ethynylene or propynylene radicals. Cycloalkyl radicals can be monocyclic, bicyclic or tricyclic. These are, for example, the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, cyclotetradecyl or cyclooctadecyl radicals which, if appropriate, can be substituted, for example, by an alkyl containing 1 to 4 atoms. carbon. As substituted cycloalkyl radicals, mention may be made of 4 methylcyclohexyl and 2,3-dimethylcyclohexyl. The bicycloalkyl and tricycloalkyl radicals can be unsubstituted or substituted in any position, for example by one or more oxo groups and / or 1 or more identical or different alkyl groups such as methyl or isopropyl and preferably methyl. The junction bond of the bi or tricyclic radical can be located in any position of the molecule. The bond can be located at the bridged carbon atom or at one of the other carbon atoms. This connection can also have any position from the point of view of stereochemistry, for example exo or endo. As an example of bicycloalkyl or tricycloalkyl radicals, mention may be made of camphanyl, bornyl, adamantyl such as 1-adamantyl or 2-adamantyl, caranyl, epiisobornyl, 1 epibornyl, norbornyl or norpinanyl.
Par halogène on entend fluor, chlore, brome ou iode. Lorsque Rf et Rg représentent un halogène, il s'agit de préférence de fluor. Par le terme (C5-C14) -aryle on entendHalogen means fluorine, chlorine, bromine or iodine. When Rf and Rg represent a halogen, it is preferably fluorine. By the term (C 5 -C 14 ) -aryl is meant
- soit les radicaux (C5-C14) -aryle hétérocycliques (= (C5- C14) -hétéroaryle) , dans lesquels les atomes de carbone du cycle sont remplacés par un hétéroatome tel que azote, oxygène ou soufre,- or the (C 5 -C 14 ) -aryl heterocyclic (= (C 5 - C 14 ) -heteroaryl) radicals, in which the ring carbon atoms are replaced by a heteroatom such as nitrogen, oxygen or sulfur,
- soit les radicaux (C6-C14) -aryle carbocyclique.- or the (C 6 -C 14 ) -aryl carbocyclic radicals.
Parmi les radicaux (C6-Cι4) -aryle carbocycliques, on peut citer le phenyle, le naphtyle, le biphényle, 1 ' anthryle ou le fluorényle et tout particulièrement le 1-naphtyle, le 2- naphtyle et le phenyle. Il s'agit de préférence du phenyle. Sauf indication contraire, les radicaux aryles, en particulier phenyle, aryloxy, aralkyles ou les hétérocycles saturés ou insaturés peuvent être non substitués ou substitués par un ou plusieurs radicaux identiques ou différents choisis parmi (Cχ-C8) -alkyle, en particulier (Cι~ C4) -alkyle, (Cχ-C8) -alkoxy, formyle, halogène tel que fluor, chlore et brome, nitro, aminό, trifluorométhyle, hydroxyle, - CH2OH, méthylènedioxy, cyano, hydroxycarbonyle, aminocarbonyle, (C1-C4) -alkoxycarbonyle, phenyle, phénoxy, benzyle et benzyloxy. En général, au plus 2 groupes nitro peuvent être utilisés dans les composés de formule (I) selon 1 ' invention.Among the carbocyclic (C 6 -Cι 4 ) -aryl radicals, mention may be made of phenyl, naphthyl, biphenyl, anthryl or fluorenyl and very particularly 1-naphthyl, 2-naphthyl and phenyl. It is preferably phenyle. Unless otherwise indicated, the aryl radicals, in particular phenyl, aryloxy, aralkyls or the saturated or unsaturated heterocycles can be unsubstituted or substituted by one or more identical or different radicals chosen from (Cχ-C 8 ) -alkyl, in particular (Cι ~ C 4 ) -alkyl, (Cχ-C 8 ) -alkoxy, formyl, halogen such as fluorine, chlorine and bromine, nitro, aminό, trifluoromethyl, hydroxyl, - CH 2 OH, methylenedioxy, cyano, hydroxycarbonyl, aminocarbonyl, (C 1 -C 4 ) -alkoxycarbonyl, phenyl, phenoxy, benzyl and benzyloxy. In general, at most 2 nitro groups can be used in the compounds of formula (I) according to the invention.
Dans le cas du phenyle monosubstitué, le substituant peut être situé en position 2,3 ou 4, et de préférence en position 3 ou 4. Dans le cas où le phenyle est disubstitue, les substituants peuvent être en position 2,3 ou 2,4 ou 2,5 ou 2,6 ou 3,4 ou 3,5. De préférence, dans les phényles di- substitués, les deux substituants sont en position 3,4. Lorsque ce phenyle est trisubstitué les positions sont les suivantes : 2,3,4 ou 2,3,5 ou 2,3,6 ou 2,4,5 ou 2,4,6 ouIn the case of monosubstituted phenyle, the substituent can be located in position 2,3 or 4, and preferably in position 3 or 4. In the case where the phenyle is disubstituted, the substituents can be in position 2,3 or 2, 4 or 2.5 or 2.6 or 3.4 or 3.5. Preferably, in the di-substituted phenyls, the two substituents are in position 3,4. When this phenyle is trisubstituted the positions are as follows: 2,3,4 or 2,3,5 or 2,3,6 or 2,4,5 or 2,4,6 or
3,4,5. De la même manière, les radicaux naphtyles ou d'autres radicaux aryles peuvent être substitués en toute position, par exemple le radical 1-naphtyle en position 2-, 3-, 4-, 5-, 6-, 7-, et 8 et le radical 2-naphtyle en position 1-, 3-, 4-, 5-, 6-, et 7. Le groupement (C5-C4) -aryle peut représenter également un système aromatique monocyclique ou polycyclique dans lequel 1,2,3,4 ou 5 atomes de carbone du cycle sont remplacés par des heteroatomes, en particulier identiques ou différents du groupe constitué de l'azote, l'oxygène et le soufre. Parmi les groupements (C5-C14) -aryle hétérocycliques (= (C5-C14)- hétéroaryle) on peut citer les groupements 2-pyridyle, 3- pyridyle, 4-pyridyle, pyrrolyle, furyle, thiényle, imidazo- lyle, pyrazolyle, oxazolyle, isoxazolyle, thiazolyle, isothiazolyle, tétrazolyle, pyridyle, pyrazinyle, pyrimi- dinyle, indolyle, isoindolyle, indazolyle, phtalazinyle, quinolyle, isoquinolyle, quinoxalinyle, quinazolinyle, cinnolinyle, β-carbolinyle, ou encore des dérivés benzo- condensés, cyclopenta-, cyclohexa-, ou cyclohepta- condensés de ces radicaux. Le système hétérocyclique peut être substitué par les mêmes substituants cités plus haut pour le système carbocyclique .3,4,5. Similarly, naphthyl radicals or other aryl radicals can be substituted in any position, for example the 1-naphthyl radical in position 2-, 3-, 4-, 5-, 6-, 7-, and 8 and the 2-naphthyl radical in positions 1-, 3-, 4-, 5-, 6-, and 7. The (C 5 -C 4 ) -aryl group can also represent a monocyclic or polycyclic aromatic system in which 1,2,3,4 or 5 ring carbon atoms are replaced by heteroatoms, in particular identical or different from the group formed nitrogen, oxygen and sulfur. Among the heterocyclic (C 5 -C 14 ) -aryl (= (C 5 -C 14 ) - heteroaryl) groups, mention may be made of 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, furyl, thienyl, imidazo- lyle, pyrazolyle, oxazolyle, isoxazolyle, thiazolyle, isothiazolyle, tétrazolyle, pyridyle, pyrazinyle, pyrimidinyle, indolyle, isoindolyle, indazolyle, phtalazinyle, quinolyle, isoquinolyle, quinoxalinyle, quinazolinyle, quinnolinyl, cinnolinyl condensed, cyclopenta-, cyclohexa-, or cyclohepta- condensed from these radicals. The heterocyclic system can be substituted by the same substituents mentioned above for the carbocyclic system.
Parmi les radicaux hétéroaryles, sont préférés les systèmes aromatiques monocycliques ou bicycliques ayant 1,2 ou 3 heteroatomes, en particulier 1 ou 2 heteroatomes, choisis parmi N, O ou S, et qui sont non substitués ou substitués par les groupes tels que (Cι-C6) -alkyle, (Cx-Cg) - alkoxy, fluor, chlore, nitro, amino, trifluorométhyle, hydroxyle, formyle, (C1-C4) -alkoxycarbonyle, phenyle, phénoxy, benzyloxy, et benzyle.Among the heteroaryl radicals, are preferred the monocyclic or bicyclic aromatic systems having 1,2 or 3 heteroatoms, in particular 1 or 2 heteroatoms, chosen from N, O or S, and which are unsubstituted or substituted by groups such as (Cι -C 6 ) -alkyl, (Cx-Cg) - alkoxy, fluorine, chlorine, nitro, amino, trifluoromethyl, hydroxyl, formyl, (C 1 -C 4 ) -alkoxycarbonyl, phenyl, phenoxy, benzyloxy, and benzyl.
Tout particulièrement, on peut citer les systèmes aromatiques monocycliques ou bicyclique de 5 à 10 chaînons renfermant de 1 à 3 heteroatomes, en particulier 1 ou 2 heteroatomes, choisis parmi N, O et S et qui peuvent être non substitués ou substitués par 1 ou 2 substituants tels que (Cι_-C ) -alkyle, (C1-C4) -alkoxy, formyle, phenyle, phénoxy, benzyle et benzyloxy.Most particularly, mention may be made of 5 to 10-membered monocyclic or bicyclic aromatic systems containing from 1 to 3 heteroatoms, in particular 1 or 2 heteroatoms, chosen from N, O and S and which may be unsubstituted or substituted by 1 or 2 substituents such as (Cι_-C) -alkyl, (C 1 -C 4 ) -alkoxy, formyl, phenyl, phenoxy, benzyl and benzyloxy.
Parmi les hétérocycles saturés (Het) on peut citer les hétérocycles suivants : piperidine, piperazine, morpholine ou pyrrolidine. Les atomes de carbone optiquement actifs contenus dans les composés de formule (I) peuvent indépendamment les uns des autres présenter la configuration R ou la configuration S. Les composés de formule (I) peuvent être sous la forme d' enantiomeres purs ou de diastereoisomeres purs ou sous la forme d'un mélange d' enantiomeres, par exemple sous forme de racémates ou de mélanges de diastereoisomeres.Among the saturated heterocycles (Het) there may be mentioned the following heterocycles: piperidine, piperazine, morpholine or pyrrolidine. The optically active carbon atoms contained in the compounds of formula (I) may independently of each other have the R configuration or the S configuration. The compounds of formula (I) may be in the form of pure enantiomers or of pure diastereoisomers or in the form of a mixture of enantiomers, for example in the form of racemates or mixtures of diastereoisomers.
La présente invention a donc pour objet les enantiomeres purs, les mélanges de ces enantiomeres, les diastereoisomeres purs et les mélanges de ces diastereoisomeres.The present invention therefore relates to pure enantiomers, mixtures of these enantiomers, pure diastereoisomers and mixtures of these diastereoisomers.
L'invention comprend les mélanges de deux ou plus de deux stéréoisomères de formule (I) et tous les rapports de ces stéréoisomères au sein des dits mélanges. Les composés de formule (I) peuvent le cas échéant être présent sous forme d'isomères E ou d'isomères Z. L'invention a donc pour objet les isomères E purs, les isomères Z purs et les mélanges E/Z selon un rapport quelconque.The invention includes mixtures of two or more of two stereoisomers of formula (I) and all of the ratios of these stereoisomers within said mixtures. The compounds of formula (I) can optionally be present in the form of E isomers or Z isomers. The subject of the invention is therefore pure E isomers, pure Z isomers and E / Z mixtures in a ratio any.
Enfin l'invention comprend les différents régioisomères liés à la position ortho, para ou meta de A2.Finally, the invention includes the different regioisomers linked to the ortho, para or meta position of A 2 .
De préférence, lorsque [Ai] comprend un groupement phenyle (Aryle = phenyle) , A2 est en position para et R6 est en position meta.Preferably, when [Ai] comprises a phenyl group (Aryl = phenyl), A 2 is in the para position and R 6 is in the meta position.
Les diastereoisomeres, incluant les isomères E/Z peuvent être séparés en isomères individuels, par exemple par chromatographie. Les racémates peuvent être séparés en deux enantiomeres par des méthodes courantes telles que la chromatographie en phase chirale ou par des méthodes de résolution. Les sels physiologiquement acceptables des composés de formule (I) sont en particulier des sels pharmaceutiquement utilisables ou non toxiques ou physiologiquement utilisables. Lorsque les composés de formule (I) renferment un groupe acide tel que l'acide carboxylique, il s'agit par exemple des sels de métaux alcalins ou alcalino terreux tels que les sels de sodium, de potassium, de magnésium, de calcium, et égale- ment les sels formés avec des ions ammonium quaternaires physiologiquement acceptables tel que l'ammoniac et des aminés organiques physiologiquement acceptables telles que par exemple la triéthylamine, l' éthanolamine ou le tris- (2- hydroxyéthyl) aminé.The diastereoisomers, including the E / Z isomers can be separated into individual isomers, for example by chromatography. Racemates can be separated into two enantiomers by standard methods such as chiral chromatography or by resolution methods. The physiologically acceptable salts of the compounds of formula (I) are in particular pharmaceutically usable or non-toxic or physiologically usable salts. When the compounds of formula (I) contain an acid group such as the carboxylic acid, they are, for example, alkali or alkaline earth metal salts such as the sodium, potassium, magnesium, calcium salts, and equal- the salts formed with physiologically acceptable quaternary ammonium ions such as ammonia and physiologically acceptable organic amines such as for example triethylamine, ethanolamine or tris- (2-hydroxyethyl) amine.
Lorsque les composés de formule (I) contiennent un groupe basique, ils peuvent former un sel d'addition avec les acides par exemple avec les acides inorganiques tels que l'acide chlorhydrique, sulfurique, phosphorique ou avec les acides organiques carboxyliques tels que l'acide acétique, trifluoroacétique, citrique, benzoique, maléique, fumarique, tartrique, methanesulfonique ou para toluène sulfonique.When the compounds of formula (I) contain a basic group, they can form an addition salt with the acids, for example with inorganic acids such as hydrochloric, sulfuric, phosphoric acid or with organic carboxylic acids such as acetic, trifluoroacetic, citric, benzoic, maleic, fumaric, tartaric, methanesulfonic or para toluene sulfonic acid.
Les composés de formule (I) qui comportent un groupe basique et un groupe acide peuvent être présents sous forme de Zwiterions (bétaînes) , qui sont également inclus dans la présente invention.The compounds of formula (I) which have a basic group and an acid group can be present in the form of Zwiterions (betaines), which are also included in the present invention.
Les sels des composés de formule (I) peuvent être obtenus par les méthodes ordinaires connues de l'homme du métier, par exemple en combinant un composé de formule (I) avec un acide organique ou inorganique ou une base dans un solvant ou un dispersant ou à partir d'un autre sel par échange de cation ou d'anion.The salts of the compounds of formula (I) can be obtained by the ordinary methods known to those skilled in the art, for example by combining a compound of formula (I) with an organic or inorganic acid or a base in a solvent or a dispersant or from another salt by cation or anion exchange.
L'invention inclut également tous les sels des composés de formule (I) qui, à cause de leur faible acceptabilité physiologique, ne sont pas directement utilisable comme médicament, mais sont utilisables comme produits intermédiaires pour mettre en oeuvre des modifications chimiques ultérieures au niveau des composés de formule (I) ou comme produits de départ pour la préparation de sels physiologiquement acceptables.The invention also includes all the salts of the compounds of formula (I) which, because of their poor physiological acceptability, are not directly usable as a medicament, but are usable as intermediates for carrying out subsequent chemical modifications at the level of compounds of formula (I) or as starting materials for the preparation of physiologically acceptable salts.
La présente invention inclut également tous les solvates des composés de formule (I) par exemples les hydrates, les solvates formés avec les alcools, et tous les dérivés des composés de formule (I), par exemple les esters, prodrugs et autres dérivés physiologiquement acceptables, ainsi que les métabolites des composés de formule (I). L'invention a plus particulièrement pour objet les prodrugs des composés de formule (I) qui peuvent être transformées en composés de formule (I) in vivo dans les conditions physiologiques. Les prodrugs des composés de formule (I), à savoir les dérivés chimiquement modifiés des composés de formule (I) afin d'obtenir des propriétés améliorées de manière désirée, sont connus de l'homme du métier.The present invention also includes all the solvates of the compounds of formula (I), for example hydrates, the solvates formed with alcohols, and all the derivatives of the compounds of formula (I), for example esters, prodrugs and other physiologically acceptable derivatives. , as well as the metabolites of the compounds of formula (I). A more particular subject of the invention is the prodrugs of the compounds of formula (I) which can be transformed into compounds of formula (I) in vivo under physiological conditions. The prodrugs of the compounds of formula (I), namely the chemically modified derivatives of the compounds of formula (I) in order to obtain desired improved properties, are known to those skilled in the art.
Pour avoir plus d'information sur le type de prodrug envisagé dans la présente invention, on peut citer les ouvrages suivants : Fleicher et al., Advanced Drug Delivery Review 19 (1996) 115-130; Design of prodrugs, H. Bundgaard, Ed., Elsevier, 1985; H. Bungaard, Drugs of the Future 16 (1991) 443; Saulnier et al. Bioorg. Med. Chem. Lett. 4 (1994) 1985; Safadi et al. Pharmaceutical Res . 10 (1993) 1350.For more information on the type of prodrug envisaged in the present invention, the following works may be cited: Fleicher et al., Advanced Drug Delivery Review 19 (1996) 115-130; Design of prodrugs, H. Bundgaard, Ed., Elsevier, 1985; H. Bungaard, Drugs of the Future 16 (1991) 443; Saulnier et al. Bioorg. Med. Chem. Lett. 4 (1994) 1985; Safadi et al. Pharmaceutical Res. 10 (1993) 1350.
Parmi les prodrugs appropriées des composés de formule (I) on peut citer de préférence :Among the suitable prodrugs of the compounds of formula (I), there may preferably be mentioned:
- les prodrugs sous forme d'esters du groupement phosphate ou phosphonate, - les prodrugs sous forme d'esters des groupes carboxyliques, en particulier du groupe COOH,- the prodrugs in the form of esters of the phosphate or phosphonate group, - the prodrugs in the form of esters of the carboxylic groups, in particular of the COOH group,
- les prodrugs sous forme d'acyle et de carbamate pour les groupes contenant un azote acylable tel que les groupes amino . Dans les prodrugs acylées ou sous forme de carbamate, une ou plusieurs fois, par exemple deux fois, un atome d'hydrogène situé sur l'atome d'azote est remplacé par un groupe acyle ou carbamate. Parmi les groupes acyles ou carbamates préférés, on peut citer les groupes R10CO-, RnOCO- , dans lesquels Rio est un hydrogène ou un radical (Cι~Cι8)- alkyle-, (C3-Cι8) -cycloalkyle-, (C3-Cι8) -cycloalkyl- (C-Cg) - alkyle-, (C5-Cι4) -aryle-, dans lequel 1 à 5 atomes de carbone peuvent être remplacés par des heteroatomes tels que N,0,S ou (C5-Cι4) -aryl- (Cι-C8) alkyle-, dans lequel 1 à 5 atomes de carbone dans la partie aryle peuvent être remplacés par des heteroatomes tels que N,0,S et Ru à les mêmes valeurs que Rio à l'exception d'hydrogène.- prodrugs in the form of acyl and carbamate for groups containing an acylable nitrogen such as amino groups. In acylated or carbamate prodrugs, one or more times, for example twice, a hydrogen atom located on the nitrogen atom is replaced by an acyl or carbamate group. Among the preferred acyl or carbamate groups, there may be mentioned the groups R 10 CO-, RnOCO-, in which Rio is a hydrogen or a radical (Cι ~ Cι 8 ) - alkyl-, (C 3 -Cι 8 ) -cycloalkyle- , (C 3 -Cι 8 ) -cycloalkyl- (C-Cg) - alkyl-, (C 5 -Cι 4 ) -aryl-, in which 1 to 5 carbon atoms can be replaced by heteroatoms such as N, 0 , S or (C 5 -Cι 4 ) -aryl- (Cι-C 8 ) alkyl-, in which 1 to 5 carbon atoms in the aryl part can be replaced by heteroatoms such as N, 0, S and Ru have the same values as Rio except for hydrogen.
L'invention a plus particulièrement pour objet, les dérivés benzothioazépinone de formule (I) répondant à la formule (I ' ) :A more particular subject of the invention is the benzothioazepinone derivatives of formula (I) corresponding to formula (I '):
Figure imgf000016_0001
dans laquelle R5, [Ai] , et A2 sont tels que définis précédemment et R3 représente un atome d'hydrogène ou un groupement phenyle éventuellement substitué par R6, ainsi que leurs sels physiologiquement acceptables et leurs promédicaments (prodrugs) .
Figure imgf000016_0001
in which R 5 , [Ai], and A 2 are as defined above and R 3 represents a hydrogen atom or a phenyl group optionally substituted by R 6 , as well as their physiologically acceptable salts and their prodrugs (prodrugs).
L'invention a plus particulièrement pour objet les dérivés de thioazepinone de formule (I) dans laquelle Ri, R2,A more particular subject of the invention is the thioazepinone derivatives of formula (I) in which Ri, R 2 ,
R3 et R4 sont des atomes d'hydrogène et le trait en pointillé ne représente pas une double liaison répondant à la formule d")R 3 and R 4 are hydrogen atoms and the dotted line does not represent a double bond corresponding to the formula d ")
Figure imgf000016_0002
Figure imgf000016_0002
ainsi que leurs sels physiologiquement acceptables et leurs promédicaments (prodrugs) .as well as their physiologically acceptable salts and their prodrugs.
L'invention a plus particulièrement pour objet les composés de formule (I) dans laquelle Ri, R2, R3 et R4 sont des atomes d'hydrogène et le trait en pointillé représente une double liaison répondant à la formule (I"')
Figure imgf000017_0001
A more particular subject of the invention is the compounds of formula (I) in which Ri, R 2 , R 3 and R 4 are hydrogen atoms and the dotted line represents a double bond corresponding to the formula (I "' )
Figure imgf000017_0001
ainsi que leurs sels physiologiquement acceptables et leurs promédicaments (prodrugs) . L'invention a plus particulièrement pour objet les composés de formules (I'), (I'') et (I''') tels que définis précédemment correspondant respectivement aux composés de formules (I'R), (I"R) et (I"'R) suivants :as well as their physiologically acceptable salts and their prodrugs. A more particular subject of the invention is the compounds of formulas (I '), (I' ') and (I' '') as defined above corresponding respectively to the compounds of formulas (I'R), (I "R) and (I "'R) below:
Figure imgf000017_0002
Figure imgf000017_0002
Figure imgf000017_0003
Figure imgf000017_0003
Figure imgf000017_0004
Figure imgf000017_0004
L'invention a tout particulièrement pour objet les composés de formules (I), (I'), (I") et (I"') telles que définies précédemment dans lesquelles [Ai] représente un groupement choisi parmi
Figure imgf000018_0001
The invention particularly relates to the compounds of formulas (I), (I '), (I ") and (I"') as defined above in which [Ai] represents a group chosen from
Figure imgf000018_0001
Figure imgf000018_0002
Figure imgf000018_0002
Figure imgf000018_0003
Figure imgf000018_0003
le phenyle étant substitué ou non substitué par un ou plusieurs groupement R tel que défini plus haut, 1 étant égal à 0, 1, 2 ou 3 et Z étant tel que défini précédemment. L'invention a plus particulièrement pour objet un composé de formules (I), (I'), (I") ou (I"') telles que définies plus haut caractérisé en ce que le phenyle est substitué par R6 représentant un groupement choisi parmi CHO,the phenyle being substituted or unsubstituted by one or more group R as defined above, 1 being equal to 0, 1, 2 or 3 and Z being as defined above. The invention more particularly relates to a compound of formulas (I), (I '), (I ") or (I"') as defined above, characterized in that the phenyle is substituted by R 6 representing a group chosen from CHO,
C02H et CH2OH, notamment en position meta, et A2 est en position para.C0 2 H and CH 2 OH, in particular in the meta position, and A 2 is in the para position.
Parmi les composés de formule (I), (I'), (I") ou (I"') tels que définis précédemment, Z représente de préférence NHCOCH3 ou NHC02tBu et le carbone qui porte ce groupement Z présente la configuration (S) .Among the compounds of formula (I), (I '), (I ") or (I"') as defined above, Z preferably represents NHCOCH 3 or NHC0 2 tBu and the carbon which carries this group Z has the configuration (S).
L'invention a plus particulièrement pour objet les composés de formules (I), (I'), (I") et (I"1) dans lesquellesA more particular subject of the invention is the compounds of formulas (I), (I '), (I ") and (I" 1 ) in which
R5 est un radical (cyclohexyl) méthyle-, (cyclohexyl) éthyle-, (cyclohexyl) propyle-, (cyclohexyl) butyle-, (phényl) méthyle-,R5 is a (cyclohexyl) methyl-, (cyclohexyl) ethyl-, (cyclohexyl) propyl-, (cyclohexyl) butyl-, (phenyl) methyl- radical,
(phényl) éthyle-, (phényl) propyle- , (phényl) butyle-,(phenyl) ethyl-, (phenyl) propyl-, (phenyl) butyl-,
(phényl) prop-2-ènyle-, (phényl) aminocarbonylméthyle-,(phenyl) prop-2-enyl-, (phenyl) aminocarbonylmethyl-,
(naphtyl)méthylaminocarbonylméthyle- et(naphthyl) methylaminocarbonylmethyl- and
(naphtyl) aminocarbonylméthyle-, lesdits phényles et naphtyles étant substitués ou non substitués par R6. L'invention a plus particulièrement pour objet les composés de formules (I), (I'), (I") et (I"') telles que définies précédemment dans lesquelles A2 est un radical - OPO(OH) (OBn) , -OPO(OH)2, -PO(OH)2, -CF2P0(0H)2, -C02H, - CH2C02H, -OCH2C02H, -CH(C02H)2, -CF(C02H)2 -N(CH2C02H)2 ou(naphthyl) aminocarbonylmethyl-, said phenyls and naphthyls being substituted or unsubstituted by R 6 . A more particular subject of the invention is the compounds of formulas (I), (I '), (I ") and (I"') as defined above in which A 2 is a radical - OPO (OH) (OBn) , -OPO (OH) 2 , -PO (OH) 2 , -CF 2 P0 (0H) 2 , -C0 2 H, - CH 2 C0 2 H, -OCH 2 C0 2 H, -CH (C0 2 H) 2 , -CF (C0 2 H) 2 -N (CH 2 C0 2 H) 2 or
NHCOPO(OH)2.NHCOPO (OH) 2 .
L'invention a tout particulièrement pour objet les composés de formules (I'S), (I"S) ou (I"'S) dans lesquelles :The invention particularly relates to the compounds of formulas (I'S), (I "S) or (I" 'S) in which:
- [Ai] représente un groupement -CH (Z) -CH2-Ph- ou C(Z)=CH-Ph- avec Z représentant NHCOCH3 ou NHC02tBu,- [Ai] represents a group -CH (Z) -CH 2 -Ph- or C (Z) = CH-Ph- with Z representing NHCOCH 3 or NHC0 2 tBu,
- A2, en position para représente un radical OPO(OH) (OBn), - OPO(OH)2, -PO (OH) 2, -CF2PO(OH)2, -C02H, -CH2C02H, -OCH2C02H, - CH(C02H)2, -CF(C02H)2 -N(CH2C02H)2 ou NHCOPO(OH)2,- At 2 , in the para position represents an OPO (OH) (OBn) radical, - OPO (OH) 2 , -PO (OH) 2 , -CF 2 PO (OH) 2 , -C0 2 H, -CH 2 C0 2 H, -OCH 2 C0 2 H, - CH (C0 2 H) 2 , -CF (C0 2 H) 2 -N (CH 2 C0 2 H) 2 or NHCOPO (OH) 2 ,
- R5 est un radical (cyclohexyl)méthyle-, (cyclohexyl) éthyle- , (cyclohexyl) propyle-, (cyclohexyl) butyle-, (phényl )méthyle-- R 5 is a (cyclohexyl) methyl-, (cyclohexyl) ethyl-, (cyclohexyl) propyl-, (cyclohexyl) butyl-, (phenyl) methyl- radical
, (phényl) éthyle-, (phényl) propyle- , (phényl) butyle-,, (phenyl) ethyl-, (phenyl) propyl-, (phenyl) butyl-,
(phényl) prop-2-ènyle-, (phényl) aminocarbonylméthyle-,(phenyl) prop-2-enyl-, (phenyl) aminocarbonylmethyl-,
(naphtyl)méthylaminocarbonylméthyle- et(naphthyl) methylaminocarbonylmethyl- and
(naphtyl) aminocarbonylméthyle-, lesdits phényles et naphtyles étant substitués ou non substitués par Rç, ainsi que leurs sels physiologiquement acceptables et leurs promédicaments(naphthyl) aminocarbonylmethyl-, said phenyls and naphthyls being substituted or unsubstituted by Rc, as well as their physiologically acceptable salts and their prodrugs
(prodrugs) .(prodrugs).
L'invention a tout particulièrement pour objet les composés de formules (I'S), (I"S) ou (I"'S) dans lesquelles : - [Ai] représente les radicaux choisis parmiThe invention particularly relates to the compounds of formulas (I'S), (I "S) or (I" 'S) in which: - [Ai] represents the radicals chosen from
Figure imgf000019_0001
- A2, en position para représente un radical OPO(OH) (OBn), - OPO(OH)2, -PO (OH) 2, -CF2PO(OH)2, -C02H, -CH2C02H, -OCH2C02H, - CH(C02H)2, -CF(C02H)2 -N(CH2C02H)2 ou NHCOPO(OH)2,
Figure imgf000019_0001
- At 2 , in the para position represents an OPO (OH) (OBn) radical, - OPO (OH) 2 , -PO (OH) 2 , -CF 2 PO (OH) 2 , -C0 2 H, -CH 2 C0 2 H, -OCH 2 C0 2 H, - CH (C0 2 H) 2 , -CF (C0 2 H) 2 -N (CH 2 C0 2 H) 2 or NHCOPO (OH) 2 ,
- R5 est un radical (cyclohexyl) méthyle-, (cyclohexyl) éthyle- , (cyclohexyl) propyle-, (cyclohexyl) butyle-, (phényl)méthyle-- R 5 is a (cyclohexyl) methyl-, (cyclohexyl) ethyl-, (cyclohexyl) propyl-, (cyclohexyl) butyl-, (phenyl) methyl- radical
, (phényl) éthyle-, (phényl) propyle , (phényl) butyle, (phényl) prop-2-ènyle-, (phényl) aminocarbonylméthyle-, (naphtyl) méthylaminocarbonylméthyle- et (naphtyl) aminocarbonylyméthyle-, lesdits phényles et naphtyles étant substitués ou non substitués par R^, ainsi que leurs sels physiologiquement acceptables et leurs promédicaments (prodrugs) ., (phenyl) ethyl-, (phenyl) propyl, (phenyl) butyl, (phenyl) prop-2-enyl-, (phenyl) aminocarbonylmethyl-, (naphthyl) methylaminocarbonylmethyl- and (naphthyl) aminocarbonylymethyl-, said phenyls and naphthyls being substituted or unsubstituted by R ^, as well as their physiologically acceptable salts and their prodrugs (prodrugs).
L'invention a également pour objet les composés de formule (I), (I' ),(I'') ou (I''') dont les noms suivent : . [2S-[3(S*) ,2α,3β] ]-[l-[ [4-[ [hydroxy (phénylméthoxy) phosp inyl] 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*) ,2α,3β] ]-[l-[ [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, . [2S-[3(S*) ,2α, 3β] ]-[l-[ [4-[ [hydroxy (phénylméthoxy) phosphinyl] oxy] phényl] méthyl] -2- [ [2- (4-méthoxyphényl) -5- [2- [ [4-méthoxy- [ (1,1' -biphényl) -3-yl] amino] -2-oxoéthyl] -4- oxo-2, 3, 4, 5-tétrahydro-l, 5-benzothiazépin-3-yl] amino] -2- xoéthyl] -carbamate de 1, 1-diméthyléthyle, . [2S-[3(S*) ,2α,3β] ]-[l-[ [4-[ [hydroxy (phénylméthoxy) phosphinyl] oxy] phényl] méthyl] -2- [ [2- (4-méthoxyphényl) -5- [2- [2- (3-phénoxyphényl) amino] -2-oxoéthyl] -4-oxo-2, 3,4,5- tétrahydro-1, 5-benzothiazépin-3-yl] amino] -2-oxoéthyl] - carbamate de 1, 1-diméthyléthyle, . [2R-[3(S*) ,2α,3α] ]-[l-[ [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,A subject of the invention is also the compounds of formula (I), (I '), (I'') or (I''') the names of which follow: [2S- [3 (S *), 2α, 3β]] - [l- [[4- [[hydroxy (phenylmethoxy) phosp inyl] oxy] phenyl] methyl] -2- [[2- (4-methoxyphenyl) -5- [2- [(1-naphthalenyl) amino] -2-oxoethyl] -4-oxo-2,3,4,5-tetra-hydro-1,5-benzothiazepin-3-yl] amino] -2 1,1-dimethylethyl-oxoethyl] -carbamate. [2R- [3 (S *), 2α, 3β]] - [l- [[4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2- [[2- (4-methoxyphenyl) - 5- [2- [(1-naphthalenyl) amino] -2-oxoethyl] -4-oxo-2, 3, 4, 5-tetra-hydro-1, 5-benzothiazepin-3-yl] amino] -2- 1,1-dimethylethyl oxoethyl] -carbamate. [2S- [3 (S *), 2α, 3β]] - [l- [[4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2- [[2- (4-methoxyphenyl) - 5- [2- [[4-methoxy- [(1,1 '-biphenyl) -3-yl] amino] -2-oxoethyl] -4- oxo-2, 3, 4, 5-tetrahydro-1,5 -benzothiazepin-3-yl] amino] -2-xoethyl] -carbamate of 1, 1-dimethylethyl,. [2S- [3 (S *), 2α, 3β]] - [l- [[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-1,5,5-benzothiazepin-3-yl] amino] -2- oxoethyl] - 1, 1-dimethylethyl carbamate, . [2R- [3 (S *), 2α, 3α]] - [l- [[4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2- [[2- (4-methoxyphenyl) - 5- [2- [(1-naphthalenyl) amino] -2-oxoethyl] -4-oxo-2, 3, 4, 5-tetra-hydro-1, 5-benzothiazepin-3-yl] amino] -2- 1,1-dimethylethyl oxoethyl] -carbamate,
. [2S-[3(S*) ,2α,3α] ]-[l-[ [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,. [2S- [3 (S *), 2α, 3α]] - [l- [[4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2- [[2- (4-methoxyphenyl) - 5- [2- [(1-naphthalenyl) amino] -2-oxoethyl] -4-oxo-2, 3, 4, 5-tetra-hydro-1, 5-benzothiazepin-3-yl] amino] -2- 1,1-dimethylethyl oxoethyl] -carbamate,
. [2S- [3 (S*) ,2α,3β] ]-l-[ [4- [ [bis (phénylméthoxy) phosphinyl] oxy] phényl] méthyl] -2- [ [2- (4-méthoxyphényl) -5- [2- [ (1- naphtalényl) amino] -2-oxo-l-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 *), 2α, 3β]] -l- [[4- [[bis (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2- [[2- (4-methoxyphenyl) -5 - [2- [(1- naphthalenyl) amino] -2-oxo-1-phenylethyl] -4-oxo-2, 3, 4, 5-tetra-hydro-1, 5-benzothiazepin-3-yl] amino] -2-oxoethyl] -carbamate of 1, 1-dimethylethyl,
. [2S-[3(S*) ,2α,3β] ]-[l-[ [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 *), 2α, 3β]] - [l- [[4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2- [[2- (4-methoxyphenyl) - 5- [2- [(4-phenoxyphenyl) amino] -2-oxoethyl] -4-oxo-2, 3, 4, 5-tetra-hydro-1, 5-benzothiazepin-3-yl] amino] -2- 1,1-dimethylethyl oxoethyl] -carbamate,
. [2S-[3(S*) ,2α,3β] ]-4'-[ [3-[ [2-[ [ [ (1, 1-diméthyl) éthoxy] carbonyl] amino] -3- [ [4- [ [hydroxy (phénylméthoxy) phosphinyl] oxy] phényl] -1-oxopropyl] amino] -2- (4-méthoxyphényl) -4-oxo- 2, 3-dihydro-l, 5-benzothiazépin-5 (4H) -yl] méthyl] -[1,1' -biphé- nyl] -2-carboxylate de 1, 1-diméthyléthyle,. [2S- [3 (S *), 2α, 3β]] -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) -yl ] methyl] - [1,1 '-biphenyl] -2-carboxylate of 1,1-dimethylethyl,
. [S- [R [trans (±) ]] ]-[l-[ [4- [ [hydroxy (phénylméthoxy) phosphinyl] oxy] phényl] méthyl] -2- [ [5- (3-cyclohexylpropyl) - 2- (4-méthoxyphényl) -4-oxo-2, 3,4, 5-tétrahydro-l, 5- benzothiazépin-3-yl] amino] -2-oxoéthyl] -carbamate de 1,1- diméthyléthyle,. [S- [R [trans (±)]]]] - [l- [[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]-1,1-dimethylethylcarbamate,
. [S-[R* (3S*) ] ]-[2-[ [5- (3-cyclohexylpropyl) -4-oxo-2,3, 4,5- tétrahydro-1, 5-benzothiazépin-3-yl] amino] -1- [ [4- [ [hydroxy (phénylméthoxy) phosphinyl] oxy] phényl] méthyl] -2-oxoéthyl] carbamate de 1, 1-diméthyléthyle, . [S- [R* (3S*) ] ] - [2- [ [5- (3-cyclohexylpropyl) -2, 3, 4, 5-tétra- hydro-4-oxo-l, 5-benzothiazépin-3-yl] amino] -2-oxo-l- [ [4- phosphonooxyphényl] méthyl] éthyl] -carbamate de 1, 1-diméthyléthyle, . [S-[R* (3R*) ] ]-[2-[ [5- (3-cyclohexylpropyl) -4-oxo-2, 3, 4 , 5- tétrahydro-1, 5-benzothiazépin-3-yl] amino] -1- [ [4-hydroxy (phénylméthoxy) phosphinyl] oxy] phényl] méthyl] -2-oxoéthyl] - carbamate de 1, 1-diméthyléthyle,. [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] 1,1-dimethylethyl carbamate, . [S- [R * (3S *)]] - [2- [[5- (3-cyclohexylpropyl) -2, 3, 4, 5-tetra-hydro-4-oxo-1,5, benzothiazepin-3- yl] amino] -2-oxo-l- [[4-phosphonooxyphenyl] methyl] ethyl] -carbamate of 1,1-dimethylethyl,. [S- [R * (3R *)]] - [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] - 1,1-dimethylethyl carbamate,
. [S- [R* (3R*) ] ] - [2- [ [5- (3-cyclohexylpropyl) -2, 3, 4, 5-tétra- hydro-4-oxo-l, 5-benzothiazépin-3-yl] amino] -2-oxo-l- [ [4- phosphonooxyphényl] méthyl] éthyl] -carbamate de 1, 1-diméthyléthyle,. [S- [R * (3R *)]] - [2- [[5- (3-cyclohexylpropyl) -2, 3, 4, 5-tetra-hydro-4-oxo-1,5, benzothiazepin-3- yl] amino] -2-oxo-l- [[4-phosphonooxyphenyl] methyl] ethyl] -carbamate of 1,1-dimethylethyl,
. trans (±) -2, 3-dihydro-3- [ [3- [4- [ [hydroxy (phénylméthoxy) phosphinyl] oxy] phényl] -1-oxopropyl] amino] -2- (4-méthoxy- phényl) -N- (1-naphtylméthyl) -4-oxo-l, 5-benzothiazépine-5 (4H) - acétamide,. 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,
. trans (±) -2, 3-dihydro-3- [[ [6- [ [hydroxy (phénylméthoxy) phosphinyl] oxy] -2-naphtalényl] carbonyl] amino] -2- (4- méthoxyphényl) -N- (1-naphtylméthyl) -4-oxo-l, 5-benzothiazépine- 5 (4H) -acétamide,. 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 (phénylméthoxy) phosphinyl] oxy] -lH-indol-2-yl] carbonyl] amino] -2- (4- méthoxyphényl) -N- (1-naphtylméthyl) -4-oxo-l, 5-benzothiazépine 5 (4H) -acétamide, . trans (±) -3- [ [ (4-boronophényl) carbonyl] amino] -2,3- dihydro-2- (4-methoxyphényl) -N- (1-naphtylméthyl) -4-oxo-l, 5- benzothiazépine-5 (4H) -acétamide,. trans (±) -2, 3-dihydro-3- [[[5- [[hydroxy (phenylmethoxy) phosphinyl] oxy] -lH-indol-2-yl] carbonyl] amino] -2- (4-methoxyphenyl) - N- (1-naphthylmethyl) -4-oxo-1,5,5-benzothiazepine 5 (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-boronophényl) carbonyl] amino] -1-oxo- éthyl] amino] -2, 3-dihydro-2- (4-methoxyphényl) -N- (1-naphtyl- méthyl) -4-oxo-l, 5-benzothiazépine-5 (4H) -acétamide,. trans (±) -3- [[2- [[(4-boronophenyl) carbonyl] amino] -1-oxoethyl] amino] -2, 3-dihydro-2- (4-methoxyphenyl) -N- (1 -naphthyl-methyl) -4-oxo-1,5-benzothiazepine-5 (4H) -acetamide,
. (R) -N- [5- (3-cyclohexylpropyl) -4-oxo-2, 3,4, 5-tétrahydro- 1, 5-benzothiazépin-3-yl] -3-formyl-4- (phosphonooxy) -benzamide,. (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-tétrahydro- 1, 5-benzothiazépin-3-yl] -4- (phosphonooxy) -benzamide, . acide (R) - [4- [ [ [5- (3-cyclohexylpropyl) -4-oxo-2, 3, 4, 5- tétrahydro-1, 5-benzothiazépin-3-yl] amino] carbonyl] -2- formylphénoxy] -acétique,. (R) -N- [5- (3-cyclohexylpropyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] -4- (phosphonooxy) -benzamide, . acid (R) - [4- [[[5- (3-cyclohexylpropyl) -4-oxo-2, 3, 4, 5-tetrahydro-1, 5-benzothiazepin-3-yl] amino] carbonyl] -2- formylphenoxy] -acetic,
. (R) -N- [5- (3-cyclohexylpropyl) -4-oxo-2, 3,4, 5-tétrahydro- 1, 5-benzothiazépin-3-yl] -4- (diphosphonométhyl) -benzamide,. (R) -N- [5- (3-cyclohexylpropyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] -4- (diphosphonomethyl) -benzamide,
. [3R- [3R* (S*) ] ] -β- (acétylamino) -N- [5- (3-cyclohexylpropyl) 2,3,4, 5-tétra-hydro-4-oxo-l, 5-benzothiazépin-3-yl] -4- (difluorophosphonométhyl) -benzènepropanamide,. [3R- [3R * (S *)]] -β- (acetylamino) -N- [5- (3-cyclohexylpropyl) 2,3,4,5-tetra-hydro-4-oxo-1,5-benzothiazepin -3-yl] -4- (difluorophosphonomethyl) -benzenepropanamide,
. (R) -N- [5- (4-cyclohexylbutyl) -4-oxo-2, 3, 4, 5-tétrahydro- 1, 5-benzothiazépin-3-yl] -N' - [4- (phosphonooxy) phényl] -urée,. (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-methoxyphényl) -4- oxo-2, 3,4, 5-tétrahydro-l, 5-benzothiazépin-3-yl] -4- [ [hydroxy (phénylméthoxy) phosphinyl] oxy] -benzèneacétamide,. 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] -benzeneeacetamide,
. cis (±) -N- [5- (3-cyclohexylpropyl) -2- (4-methoxyphényl) -4- oxo-2, 3, 4, 5-tétrahydro-l, 5-benzothiazépin-3-yl] -4- (phosphonooxy) benzèneacétamide,. 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-thiazépin-6-yl] amino] -2-oxo-l- [ [4- (phosphonooxy) phényl] méthyl] éthyl] -carbamate de 1, 1-diméthyléthyle, . (R) -3- [ [ (aminocarbonyl) hydrazono] méthyl] -4- (phosphonooxy) -N- [5- (3-cyclohexylpropyl) -4-oxo-2, 3, 4, 5-tétrahydro-l, 5- benzothiazépin-3-yl] -benzamide,. [S- [R * (6S *)]] - [2- [[4- (3-cyclohexylpropyl) -hexahydro-5-oxo-1, 4-thiazepin-6-yl] amino] -2-oxo-l - [1 - 1-dimethylethyl [[4- (phosphonooxy) phenyl] methyl] ethyl] -carbamate,. (R) -3- [[(aminocarbonyl) hydrazono] methyl] -4- (phosphonooxy) -N- [5- (3-cyclohexylpropyl) -4-oxo-2, 3, 4, 5-tetrahydro-1,5 - benzothiazepin-3-yl] -benzamide,
. [S- [R* (6R*) ] ] -N-acétyl- [4- (3-cyclohexylpropyl) -5-oxo- 4,5,6, 7-tétrahydro-l, 4-thiazépin-6-yl] -4- (phosphono) - (difluoro) méthyl] -L-phénylalaninamide,. [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-tétrahydro-l, 5-benzothiazépin-3-yl] -2-pyridine carboxamide,. (R) -5- (phosphonooxy) -N- [5- (3-cyclohexylpropyl) -4-oxo- 2,3,4,5-tetrahydro-1,5,5-benzothiazepin-3-yl] -2-pyridine carboxamide ,
. (R) -4- [ (phosphono) fluorométhyl] -N- [5- (3-cyclo- hexylpropyl) -4-oxo-2, 3, 4, 5-tétrahydro-l, 5-benzothiazépin-3- yl] -benzamide ;. (R) -4- [(phosphono) fluoromethyl] -N- [5- (3-cyclohexylpropyl) -4-oxo-2, 3, 4, 5-tetrahydro-1,5-benzothiazepin-3-yl] -benzamide;
. N- [ (6R) -4- (3-cyclohexylpropyl) -hexahydro-5-oxo-l, 4- thiazepin-6-yl] -4- (phosphonooxy) -Benzamide ;. N- [(6R) -4- (3-cyclohexylpropyl) -hexahydro-5-oxo-1,4-thiazepin-6-yl] -4- (phosphonooxy) -Benzamide;
. Acide [ [4-[ (2S) -2- (acétylamino) -4- [ [ (6R)-4-(3- cyclohexylpropyl) -hexahydro-5-thioxo-l, 4-thiazepin-6- yl] amino] -3-oxopropyl] phényl] difluorométhyl] - Phosphonique ;. Acid [[4- [(2S) -2- (acetylamino) -4- [[(6R) -4- (3- cyclohexylpropyl) -hexahydro-5-thioxo-1,4-thiazepin-6- yl] amino] -3-oxopropyl] phenyl] difluoromethyl] - Phosphonic;
. N- [ ( 6R) -hexahydro-5-oxo-4- (3-phenyl-2-propenyl) -1, 4- thiazepin-6-yl] -4- (phosphonooxy) -Benzamide ;. N- [(6R) -hexahydro-5-oxo-4- (3-phenyl-2-propenyl) -1, 4-thiazepin-6-yl] -4- (phosphonooxy) -Benzamide;
. Acide [ [4- [ (2S) -2- (acétylamino) -4- [ [ (6R) -4- (3- cyclohexylpropyl) -hexahydro-5-oxo-l, 4-thiazepin-6-yl] amino] - 3-oxopropyl] phényl] difluorométhyl] - Phosphonique ;. Acid [[4- [(2S) -2- (acetylamino) -4- [[(6R) -4- (3-cyclohexylpropyl) -hexahydro-5-oxo-1,4-thiazepin-6-yl] amino] - 3-oxopropyl] phenyl] difluoromethyl] - Phosphonic;
. Acide [ [4- [ [ [ (6R) -4- (3-cyclohexylpropyl) -hexahydro-5-oxo- 1, 4-thiazepin-6-yl] amino] carbonyl] phényl] difluorométhyl] - Phosphonique ; . N2-acetyl-N- [ (6R) -4- (3-cyclohexylpropyl) -hexahydro-5-oxo- 1, 4-thiazepin-6-yl] -3-formyl-4- (phosphonooxy) -L- Phenylalaninamide ;. Acid [[4- [[[(6R) -4- (3-cyclohexylpropyl) -hexahydro-5-oxo-1, 4-thiazepin-6-yl] amino] carbonyl] phenyl] difluoromethyl] - Phosphonic; . N2-acetyl-N- [(6R) -4- (3-cyclohexylpropyl) -hexahydro-5-oxo- 1, 4-thiazepin-6-yl] -3-formyl-4- (phosphonooxy) -L- Phenylalaninamide;
. N- [ ( 6R) -4- (3-cyclohexylpropyl) -hexahydro-5-oxo-l, 4- thiazepin-6-yl] -3-formyl-4- (phosphonooxy) -Benzamide ; . Acide [ [4-[ (2S) -2- (acétylamino) -4- [ [ (6R) -4- [3- (3- methoxyphenyl) propyl) -hexahydro-5-oxo-l, 4-thiazepin-6- yl] amino] -3-oxopropyl] phényl] difluorométhyl] - Phosphonique ;. N- [(6R) -4- (3-cyclohexylpropyl) -hexahydro-5-oxo-1,4-thiazepin-6-yl] -3-formyl-4- (phosphonooxy) -Benzamide; . Acid [[4- [(2S) -2- (acetylamino) -4- [[(6R) -4- [3- (3- methoxyphenyl) propyl) -hexahydro-5-oxo-1,4-thiazepin-6 - yl] amino] -3-oxopropyl] phenyl] difluoromethyl] - Phosphonic;
. 1,1-dioxyde de 1 ' acide [ [4- [ (2S) -2- (acétylamino) -4- [[ (6R) - 4- (3-cyclohexylpropyl) -hexahydro-5-thioxo-l, -thiazepin-6- yl] amino] -3-oxopropyl] phényl] difluorométhyl] - Phosphonique. Acid 1,1-dioxide [[4- [(2S) -2- (acetylamino) -4- [[(6R) - 4- (3-cyclohexylpropyl) -hexahydro-5-thioxo-l, -thiazepin -6- yl] amino] -3-oxopropyl] phenyl] difluoromethyl] - Phosphonic
. N2-acetyl-N- [ (3R) -5- (3-cyclohexylpropyl) -4-oxo-2, 3, 4, 5- tetrahydro-1, 5-benzothiazepin-3-yl] - 3- [8- (phosphonooxy) -quinolin-5-yl] - Alaninamide ;. N2-acetyl-N- [(3R) -5- (3-cyclohexylpropyl) -4-oxo-2, 3, 4, 5- tetrahydro-1, 5-benzothiazepin-3-yl] - 3- [8- ( phosphonooxy) -quinolin-5-yl] - Alaninamide;
. Acide [ [4- [ (2S) -2- (acétylamino) -4- [ [ (6R) -4- [3- (3- hydroxyphenyl) propyl) -hexahydro-5-oxo-l, 4-thiazepin-6- yl] amino] -3-oxopropyl] phényl] difluorométhyl] - Phosphonique ;. Acid [[4- [(2S) -2- (acetylamino) -4- [[(6R) -4- [3- (3-hydroxyphenyl) propyl) -hexahydro-5-oxo-1,4-thiazepin-6 - yl] amino] -3-oxopropyl] phenyl] difluoromethyl] - Phosphonic;
. N2-acetyl-N- [ (6R) -4- (3-cyclohexylpropyl) -hexahydro-5-oxo- 1, 4-thiazepin-6-yl] -3- (1, 3-dihydro-3-hydroxy-l-oxo-5- isobenzofuranyl] -L-Alaninamide ; . N2-acetyl-N- [ (6R) -4- (3-cyclohexylpropyl) -hexahydro-5-oxo- 1, 4-thiazepin-6-yl] -3- (1, 3-dihydro-3-ethoxy-l-oxo-5- isobenzofuranyl] -L-Alaninamide ;. N2-acetyl-N- [(6R) -4- (3-cyclohexylpropyl) -hexahydro-5-oxo- 1, 4-thiazepin-6-yl] -3- (1, 3-dihydro-3-hydroxy-1 -oxo-5-isobenzofuranyl] -L-Alaninamide;. N2-acetyl-N- [(6R) -4- (3-cyclohexylpropyl) -hexahydro-5-oxo- 1, 4-thiazepin-6-yl] -3 - (1, 3-dihydro-3-ethoxy-1-oxo-5-isobenzofuranyl] -L-Alaninamide;
. Acide 4-[ (2S) -2- (acétylamino) -3- [ [ (6R)-4-(3- cyclohexylpropyl) -hexahydro-5-oxo-l, 4-thiazepin-6-yl] amino] - 3-oxo-propyl] -1, 2-Benzenedicarboxylique ; . Acide [ [4- [ (2S) -2- (acétylamino) -3- [ [ (6R) -hexahydro-4- [ (3- methoxyphenyl) méthyl] -5-oxo-l, 4-thiazepin-6-yl] amino] -3- oxopropyl] phényl] difluorométhyl] - Phosphonique;. Acid 4- [(2S) -2- (acetylamino) -3- [[(6R) -4- (3- cyclohexylpropyl) -hexahydro-5-oxo-1,4, thiazepin-6-yl] amino] - 3 -oxo-propyl] -1,2-Benzenedicarboxylic; . Acid [[4- [(2S) -2- (acetylamino) -3- [[(6R) -hexahydro-4- [(3-methoxyphenyl) methyl] -5-oxo-1,4-thiazepin-6-yl ] amino] -3- oxopropyl] phenyl] difluoromethyl] - Phosphonic;
. Acide [ [4-[ (2S) -2- (acétylamino) -4- [ [ (6R) -hexahydro-4- [ (2- naphthalenyl) méthyl] -5-oxo-l, 4-thiazepin-6-yl] amino] -3- oxopropyl] phényl] difluorométhyl] - Phosphonique;. Acid [[4- [(2S) -2- (acetylamino) -4- [[(6R) -hexahydro-4- [(2- naphthalenyl) methyl] -5-oxo-1,4-thiazepin-6-yl ] amino] -3- oxopropyl] phenyl] difluoromethyl] - Phosphonic;
. Acide [ [4-[ (2S) -2- (acétylamino) -4- [ [ (6R)-4-[2- (trifluorométhyl) phényl] -hexahydro-5-oxo-l, 4-thiazepin-6- yl] amino] -3-oxopropyl] phényl] difluorométhyl] - Phosphonique ; . Acide [ [4- [ (2S) -2- (acétylamino) -4- [[ (6R) -hexahydro-5-oxo- 4- [ [4- (trifluoromethoxy) phényl]méthyl] -1, 4-thiazepin-6- yl] amino] -3-oxopropyl] phényl] difluorométhyl] -Phosphonique;. Acid [[4- [(2S) -2- (acetylamino) -4- [[(6R) -4- [2- (trifluoromethyl) phenyl] -hexahydro-5-oxo-1,4-thiazepin-6- yl ] amino] -3-oxopropyl] phenyl] difluoromethyl] - Phosphonic; . Acid [[4- [(2S) -2- (acetylamino) -4- [[(6R) -hexahydro-5-oxo- 4- [[4- (trifluoromethoxy) phenyl] methyl] -1, 4-thiazepin- 6-yl] amino] -3-oxopropyl] phenyl] difluoromethyl] -Phosphonic;
. Acide [ [4-[ (2S) -2- (acétylamino) -4- [ [ ( 6R) -4- [2- (4- fluorophenoxy) phényl] méthyl] -hexahydro-5-oxo-l, 4-thiazepin-6- yl] amino] -3-oxopropyl] -phényl] difluorométhyl] - Phosphonique; . Acide [ [4- [ (2S) -2- (acétylamino) -4- [[ (6R) -hexahydro-4- [ [3- (phenylcarbonyl) phényl] méthyl] -5-oxo-l, 4-thiazepin-6- yl] amino] -3-oxopropyl] -phényl] difluorométhyl] - Phosphonique ; . Acide [ [4-[ (2S) -2- (acétylamino) -4- [ [ (6R) -4- (3-cyclohexyl- 2-oxo-propyl) -hexahydro-5-oxo-l, -thiazepin-6-yl] amino] -3- oxopropyl] -phényl] difluorométhyl] - Phosphonique ;. Acid [[4- [(2S) -2- (acetylamino) -4- [[(6R) -4- [2- (4-fluorophenoxy) phenyl] methyl] -hexahydro-5-oxo-1,4-thiazepin -6- yl] amino] -3-oxopropyl] -phenyl] difluoromethyl] - Phosphonic; . [[4- [(2S) -2- (acetylamino) -4- [[(6R) -hexahydro-4- [[3- (phenylcarbonyl) phenyl] methyl] -5-oxo-1,4-thiazepin- acid 6- yl] amino] -3-oxopropyl] -phenyl] difluoromethyl] - Phosphonic; . Acid [[4- [(2S) -2- (acetylamino) -4- [[(6R) -4- (3-cyclohexyl- 2-oxo-propyl) -hexahydro-5-oxo-l, -thiazepin-6 -yl] amino] -3- oxopropyl] -phenyl] difluoromethyl] - Phosphonic;
. Acide [ [4- [ [ [ (6R) -4- (3-cyclohexylpropyl) -hexahydro-5-oxo- 1, 4-thiazepin-6-yl] amino] carbonyl] -2-formyl- phenyl] difluorométhyl] -Phosphonique ; . N2-acetyl-N-[ (3R) -5- (3-cyclohexylpropyl) -4-oxo-2,3, ,5- tetrahydro-1, 5-benzothiazepin-3-yl] -3- [8- (phosphonooxy) - 1,2,3, 4-tetrahydro-quinolin-5-yl] - L-Alaninamide;. Acid [[4- [[[(6R) -4- (3-cyclohexylpropyl) -hexahydro-5-oxo-1, 4-thiazepin-6-yl] amino] carbonyl] -2-formyl-phenyl] difluoromethyl] - Phosphonic; . N2-acetyl-N- [(3R) -5- (3-cyclohexylpropyl) -4-oxo-2,3,, 5-tetrahydro-1, 5-benzothiazepin-3-yl] -3- [8- (phosphonooxy ) - 1,2,3,4-tetrahydro-quinolin-5-yl] - L-Alaninamide;
. Acide [ [4- [ (2S) -2- (acétylamino) -4- [ [ (6R) -4- (3-phenyl-2- propenyl) -hexahydro-5-oxo-l, 4-thiazepin-6-yl] amino] -3- oxopropyl] -phényl] difluorométhyl] - Phosphonique ; . N- [ ( 6R) -hexahydro-5-oxo-l, 4-thiazepin-6-yl] -4- (phosphonooxy) -Benzamide;. Acid [[4- [(2S) -2- (acetylamino) -4- [[(6R) -4- (3-phenyl-2-propenyl) -hexahydro-5-oxo-1,4-thiazepin-6- yl] amino] -3-oxopropyl] -phenyl] difluoromethyl] - Phosphonic; . N- [(6R) -hexahydro-5-oxo-1,4-thiazepin-6-yl] -4- (phosphonooxy) -Benzamide;
. Acide [ [4- [ [ [ (6R) -hexahydro-4- [ (3-methoxyphenyl)méthyl] - 5-oxo-l, 4-thiazepin-6- yl] amino] carbonyl] phényl] difluorométhyl] -Phosphonique; . Acide [ [4- [ [ [ (6R) -hexahydro-4- [ (2-naphthalenyl) éthyl] -5- oxo-1, 4-thiazepin-6-yl] amino] carbonyl] phényl] difluorométhyl] - Phosphonique;. [[4- [[[(6R) -hexahydro-4- [(3-methoxyphenyl) methyl] - 5-oxo-1,4-thiazepin-6-yl] amino] carbonyl] phenyl] difluoromethyl] -Phosphonic acid; . Acid [[4- [[[(6R) -hexahydro-4- [(2-naphthalenyl) ethyl] -5- oxo-1, 4-thiazepin-6-yl] amino] carbonyl] phenyl] difluoromethyl] - Phosphonic;
. Acide [ [4- [ [ [ (6R) -hexahydro-5-oxo-4- [ [4- (trifluoromethoxy) phényl]méthyl] -1, 4-thiazepin-6- yl] amino] carbonyl] phényl] difluorométhyl] -Phosphonique ;. Acid [[4- [[[(6R) -hexahydro-5-oxo-4- [[4- (trifluoromethoxy) phenyl] methyl] -1,4-thiazepin-6- yl] amino] carbonyl] phenyl] difluoromethyl] -Phosphonic;
. Acide [ [4-[ [[ (6R)-hexahydro-5-oxo-4-[2-oxo-2-(5, 6,7,8- tetrahydro-5, 5,8, 8-tetramethyl-2-naphthalenyl) ethyl] 1, 4-thiazepin-6-yl] amino] carbonyl] phényl] difluorométhyl] - Phosphonique ;. Acid [[4- [[[(6R) -hexahydro-5-oxo-4- [2-oxo-2- (5, 6,7,8- tetrahydro-5, 5,8, 8-tetramethyl-2- naphthalenyl) ethyl] 1,4-thiazepin-6-yl] amino] carbonyl] phenyl] difluoromethyl] - Phosphonic;
. Acide [ [4-[ [ [ (6R)-hexahydro-5-oxo-4-[ [3- (trifluorométhyl) phényl] méthyl] -1, 4-thiazepin-6- yl] amino] carbonyl] phényl] difluorométhyl] Phosphonique ;. Acid [[4- [[[(6R) -hexahydro-5-oxo-4- [[3- (trifluoromethyl) phenyl] methyl] -1,4-thiazepin-6-yl] amino] carbonyl] phenyl] difluoromethyl] Phosphonic;
• [ [4- [ [ [ (6R) -hexahydro-4- [ (3-methoxyphenyl) méthyl] -5-oxo- 1, 4-thiazepin-6-yl] amino] carbonyl] phényl] difluorométhyl] - Phosphonate d' éthyle ;• [[4- [[[(6R) -hexahydro-4- [(3-methoxyphenyl) methyl] -5-oxo- 1, 4-thiazepin-6-yl] amino] carbonyl] phenyl] difluoromethyl] - Phosphonate d 'ethyl;
. 4- [2- (acétylamino) -3-oxo-3- [ [ ( 6R) -5-oxo-hexahydro-4- [ [4- (trifluoromethoxy) phényl]méthyl] -1, 4-thiazepin-6-yl] amino] -1- propenyl] -2-carboxy-phenyl-Propanedioate de bis (1,1- dimethylethyle) ;. 4- [2- (acetylamino) -3-oxo-3- [[(6R) -5-oxo-hexahydro-4- [[4- (trifluoromethoxy) phenyl] methyl] -1, 4-thiazepin-6-yl ] amino] -1-propenyl] -2-carboxy-phenyl-propanedioate bis (1,1-dimethylethyl);
. Acide 4- [ (2S) -2- (acétylamino) -3-OXO-3- [[ (6R) -hexahydro-5- oxo-4- [ [4- (trifluoromethoxy) phényl] méthyl] -1, 4-thiazepin-6- yl] amino] propyl] -2-formyl- Benzeneacetique ;. Acid 4- [(2S) -2- (acetylamino) -3-OXO-3- [[(6R) -hexahydro-5- oxo-4- [[4- (trifluoromethoxy) phenyl] methyl] -1, 4- thiazepin-6-yl] amino] propyl] -2-formyl-benzeneacetic;
. Acide 4- [2- (acétylamino) -3-oxo-3- [[ (6R) -hexahydro-5-oxo- 4- [ [4- (trifluoromethoxy) phényl]méthyl] -1, 4-thiazepin-6- yl] amino] -1-propenyl] -2- (methoxycarbonyl) -Benzeneacetique ;. 4- [2- (acetylamino) -3-oxo-3- [[(6R) -hexahydro-5-oxo 4-- [[4- (trifluoromethoxy) phenyl] methyl] -1,4-thiazepin-6- acid yl] amino] -1-propenyl] -2- (methoxycarbonyl) -Benzeneacetic;
. Acide 2-carboxy-4- [ (2S) -2- (acétylamino) -3-OXO-3- [[ (6R) - hexahydro-5-oxo-4- [ [4- (trifluoromethoxy) phényl] méthyl] -1,4- thiazepin-6-yl] amino] -1-propenyl] -Benzeneacetique ; . N2-acetyl-N-[ (6R)-4-[ [4- (dimethylamino) phenyl]methyl] - hexahydro-5-oxo-l, 4-thiazepin-6-yl] -4- (phosphonooxy) L-Phenylalaninamide ;. 2-carboxy-4- [(2S) -2- (acetylamino) -3-OXO-3- [[(6R) - hexahydro-5-oxo-4- [[4- (trifluoromethoxy) phenyl] methyl] acid - 1,4-thiazepin-6-yl] amino] -1-propenyl] -Benzeneacetic; . N2-acetyl-N- [(6R) -4- [[4- (dimethylamino) phenyl] methyl] - hexahydro-5-oxo-l, 4-thiazepin-6-yl] -4- (phosphonooxy) L-Phenylalaninamide ;
. N- [ ( 6R) -hexahydro-5-oxo-4- (3-phenyl-2-propenyl) -1, 4- thiazepin-6-yl] -4- (phosphonooxy) -Benzamide sel di (trihydroxymethyl)methanamine ; . N- [ (6R) -hexahydro-5-oxo-4- (3-phenyl-2-propenyl) -1, 4- thiazepin-6-yl] -4- (phosphonooxy) -Benzamide sel de disodium ;. N- [(6R) -hexahydro-5-oxo-4- (3-phenyl-2-propenyl) -1,4-thiazepin-6-yl] -4- (phosphonooxy) -Benzamide di (trihydroxymethyl) methanamine salt; . N- [(6R) -hexahydro-5-oxo-4- (3-phenyl-2-propenyl) -1,4-thiazepin-6-yl] -4- (phosphonooxy) -Benzamide disodium salt;
. N- [ (6R) -hexahydro-5-oxo-4- (3-phenyl-2-propenyl) -1, 4- thiazepin-6-yl] -2-methyl-4- (phosphonooxy) -Benzamide ; . N- [ (6R) -hexahydro-5-oxo-4- (3-phenyl-2-propenyl) -1, 4- thiazepin-6-yl] -4-hydroxy-Benzamide ;. N- [(6R) -hexahydro-5-oxo-4- (3-phenyl-2-propenyl) -1,4-thiazepin-6-yl] -2-methyl-4- (phosphonooxy) -Benzamide; . N- [(6R) -hexahydro-5-oxo-4- (3-phenyl-2-propenyl) -1,4-thiazepin-6-yl] -4-hydroxy-Benzamide;
. 4- [ [ ( 6R) - [ [4- [4- (phosphonooxy) phényl] carbonyl] amino] -5- oxo-hexahydro-1, 4-thiazepin-4-yl]methyl] -Benzoate de méthyle ; . N-[ (6R) -hexahydro-5-oxo-4-[ [3,5bis-. Methyl 4- [[(6R) - [[4- [4- (4- phosphonooxy) phenyl] carbonyl] amino] -5- oxo-hexahydro-1, 4-thiazepin-4-yl] methyl] -Benzoate; . N- [(6R) -hexahydro-5-oxo-4- [[3,5bis-
(trifluorométhyl) phényl] méthyl] -1, 4-thiazepin-6-yl] -4- (phosphonooxy) -Benzamide ;(trifluoromethyl) phenyl] methyl] -1,4-thiazepin-6-yl] -4- (phosphonooxy) -Benzamide;
. acide [ [ [4- [ [ [ (6R) -hexahydro-5-oxo-4- [ [3, 5bis- (trifluorométhyl) phényl] méthyl] -1, 4-thiazepin-6- yl] amino] carbonyl] phényl] amino] carbonyl] -Phosphonique ;. acid [[[4- [[[(6R) -hexahydro-5-oxo-4- [[3,5bis- (trifluoromethyl) phenyl] methyl]] -1,4-thiazepin-6- yl] amino] carbonyl] phenyl ] amino] carbonyl] -Phosphonic;
. N- [ (6R) -4 [ [ (l,l'-biphenyl)-4yl]methyl]-hexahydro-5-oxo- 1, 4-thiazepin-6-yl] -4- (phosphonooxy) -Benzamide ;. N- [(6R) -4 [[(l, l'-biphenyl) -4yl] methyl] -hexahydro-5-oxo-1, 4-thiazepin-6-yl] -4- (phosphonooxy) -Benzamide;
. 4- (aminosulfonyl) -N- [ ( 6R) -hexahydro-5-oxo-4- (3-phenyl-2- propen-1-yl) -1, 4-thiazepin-6-yl] -Benzenecarboxamide ; . Acide [4- [ [3- [ ( 6R) -hexahydro-5-oxo-4- (3-phenyl-2-propen- 1-yl) -1, 4-thiazepin-6-yl] amino] carbonyl] phényl] - Boronique ;. 4- (aminosulfonyl) -N- [(6R) -hexahydro-5-oxo-4- (3-phenyl-2-propen-1-yl) -1, 4-thiazepin-6-yl] -Benzenecarboxamide; . [4- [[3- [(6R) -hexahydro-5-oxo-4- (3-phenyl-2-propen- 1-yl) -1,4-thiazepin-6-yl] amino] carbonyl] phenyl acid ] - Boronique;
. Acide [ [4- [ [ [ (6R) -hexahydro-4- [ ( 4-bromophenyl) méthyl] -5- oxo-1, 4-thiazepin-6- yl] amino] carbonyl] phényl] hydroxymethyl] Phosphonique ;. Acid [[4- [[[(6R) -hexahydro-4- [(4-bromophenyl) methyl] -5- oxo-1, 4-thiazepin-6- yl] amino] carbonyl] phenyl] hydroxymethyl] Phosphonic;
. Acide [ [ [4- [ [ [ ( 6R) -4- [ (3-cyanophenyl)methyl] -hexahydro-5- oxo-1, 4-thiazepin-6-yl] amino] carbonyl] phényl] amino] carbonyl] - Phosphonique ;. Acid [[[4- [[[(6R) -4- [(3-cyanophenyl) methyl] -hexahydro-5-oxo-1, 4-thiazepin-6-yl] amino] carbonyl] phenyl] amino] carbonyl] - Phosphonic;
. Acide 4- [2- (acétylamino) -3-oxo-3- [[ (6R) -hexahydro-5-oxo- 4- [ [4- (trifluoromethoxy) phényl] méthyl] -1, 4-thiazepin-6- yl] amino] -1-propen-l-yl] -2-formyl-Benzeneacetique. 4- [2- (acetylamino) -3-oxo-3- [[(6R) -hexahydro-5-oxo 4-- [[4- (trifluoromethoxy) phenyl] methyl] -1,4-thiazepin-6- acid yl] amino] -1-propen-l-yl] -2-formyl-benzeneacetique
. N- [ (6R) -hexahydro-5-oxo-4- (3-phenyl-2-propenyl) -1,4- thiazepin-6-yl] -4- (sulfonooxy) -Benzamide sel de sodium ;. N- [(6R) -hexahydro-5-oxo-4- (3-phenyl-2-propenyl) -1,4-thiazepin-6-yl] -4- (sulfonooxy) -Benzamide sodium salt;
. N- [ (6R) -4- [ (2-fluoro-3-methylphenyl) méthyl] -hexahydro-5- oxo-1, 4-thiazepin-6yl] -4- (phosphonooxy) -Benzamide ;. N- [(6R) -4- [(2-fluoro-3-methylphenyl) methyl] -hexahydro-5-oxo-1, 4-thiazepin-6yl] -4- (phosphonooxy) -Benzamide;
. N- [ (6R) -4- [ (4-bromophenyl) méthyl] -hexahydro-5-oxo-l, 4- thiazepin-6-yl] -4- (phosphonooxy) -Benzamide ;. N- [(6R) -4- [(4-bromophenyl) methyl] -hexahydro-5-oxo-l, 4- thiazepin-6-yl] -4- (phosphonooxy) -Benzamide;
. 4- (phosphonooxy) -N- [ (6R) -hexahydro-5-oxo- [ [2- [ (phenylsulfonyl)methyl]phenyl] -1, 4-thiazepin-6-yl] - Benzamide ; . Acide 4- [2- (acétylamino) -3-oxo-3- [[( 6R) -hexahydro-5-oxo- 4- [ [4- (trifluoromethoxy) phényl]méthyl] -1, 4-thiazepin-6- yl] amino] -1-propen-l-yl] -alpha-fluoro-2-formyl- Benzeneacetique ;. 4- (phosphonooxy) -N- [(6R) -hexahydro-5-oxo- [[2- [(phenylsulfonyl) methyl] phenyl] -1, 4-thiazepin-6-yl] - Benzamide; . 4- [2- (acetylamino) -3-oxo-3- [[(6R) -hexahydro-5-oxo 4-- [[4- (trifluoromethoxy) phenyl] methyl] -1,4-thiazepin-6- acid yl] amino] -1-propen-1-yl] -alpha-fluoro-2-formyl-benzeneacetic;
. sulfamate de 4- [ [ [ (6R) -hexahydro-5-oxo-4- (3-phenyl-2- propenyl) -1, 4-thiazepin-6-yl] amino] carbonyl] phenyle ;. 4- [[[((6R) -hexahydro-5-oxo-4- (3-phenyl-2-propenyl) -1,4-thiazepin-6-yl] amino] carbonyl] phenyl sulfamate;
. Acide [4-[3-[[ ( 6R) -hexahydro-5-oxo-4- (3-phenyl-2-propen- 1-yl) -1, -thiazepin-6-yl] amino] 3-oxo-l-propenyl] phényl] - Boronique ;. [4- [3 - [[(6R) -hexahydro-5-oxo-4- (3-phenyl-2-propen- 1-yl) -1, -thiazepin-6-yl] amino] 3-oxo- acid l-propenyl] phenyl] - Boronic;
. N- [ ( 6R) -hexahydro-4- [ (4-nitrophenyl) méthyl] -5-oxo-l, 4- thiazepin-6yl] -4- (phosphonooxy) -Benzamide ;. N- [(6R) -hexahydro-4- [(4-nitrophenyl) methyl] -5-oxo-1,4-thiazepin-6yl] -4- (phosphonooxy) -Benzamide;
. N- [ (6R) -hexahydro-5-oxo-4- [3- [ (4-phenylpiperazin-l- yl) suifonyl] propyl] -1, 4-thiazepin-6yl] -4- (phosphonooxy) - Benzamide ;. N- [(6R) -hexahydro-5-oxo-4- [3- [(4-phenylpiperazin-1-yl) suifonyl] propyl] -1, 4-thiazepin-6yl] -4- (phosphonooxy) - Benzamide;
. 4- (phosphonooxy) -N- [ (6R) -4- [3- [ (4- thiomorpholinyl) suifonyl] propyl] -hexahydro-5-oxo-l, 4- thiazepin-6-yl] -Benzamide ;. 4- (phosphonooxy) -N- [(6R) -4- [3- [(4-thiomorpholinyl) suifonyl] propyl] -hexahydro-5-oxo-1,4,5 thiazepin-6-yl] -Benzamide;
. N- [ ( 6R) -4- [3- [ (butylmethylamino) suifonyl] propyl] - hexahydro-5-oxo-l, 4-thiazepin-6-yl] -4- (phosphonooxy) - Benzamide ; . Acide 4- [2- (acétylamino) -3- [ [ ( 6R) -hexahydro-5-oxo-4- [ [4- (trifluoromethoxy) phényl] méthyl] -1, 4-thiazepin-6-yl] amino] -3- oxo-1-propenyl] -2- [ [ (aminocarbonyl) hydrazono]méthyl] -alpha- fluoro-Benzeneacetique ;. N- [(6R) -4- [3- [(butylmethylamino) suifonyl] propyl] - hexahydro-5-oxo-1,4-thiazepin-6-yl] -4- (phosphonooxy) - Benzamide; . 4- [2- (acetylamino) -3- [[(6R) -hexahydro-5-oxo-4- [[4- (trifluoromethoxy) phenyl] methyl] -1,4-thiazepin-6-yl] amino acid] -3- oxo-1-propenyl] -2- [[(aminocarbonyl) hydrazono] methyl] -alphafluoro-benzeneacetic;
. N- [ (6R) -4- [3- [ (cyclohexylmethylamino) suifonyl] propyl] - hexahydro-5-oxo-l, 4-thiazepin-6-yl] -4- (phosphonooxy) - Benzamide ;. N- [(6R) -4- [3- [(cyclohexylmethylamino) suifonyl] propyl] - hexahydro-5-oxo-1,4, thiazepin-6-yl] -4- (phosphonooxy) - Benzamide;
. l-[[3-[(6R)-[[[4- (phosphonooxy) phényl] carbonyl] amino] -5- oxo-hexahydro-1, 4-thiazepin-4-yl] propyl] suifonyl] - tetrahydro-lH-pyrrole-2-carboxylate de méthyle ; . acide [ [ [4- [ [ [ ( 6R) -4- [ ( 6-chloro-l, 3-benzodioxolan-5- yl ) méthyl ] -hexahydro-5-oxo-l , 4-thiazepin-6- yl] amino] carbonyl] phényl] amino] carbonyl] -Phosphonique ;. l - [[3 - [(6R) - [[[4- (phosphonooxy) phenyl] carbonyl] amino] -5- oxo-hexahydro-1, 4-thiazepin-4-yl] propyl] sulfonyl] - tetrahydro-1H -pyrrole-2-methyl carboxylate; . acid [[[4- [[[(6R) -4- [(6-chloro-1,3-benzodioxolan-5- yl) methyl] -hexahydro-5-oxo-1,4-thiazepin-6- yl] amino] carbonyl] phenyl] amino] carbonyl] -Phosphonic;
. N2-acetyl-N-[ (6R)-4-[ [2 ' -cyano- (1, 1 ' -biphenyl) -4- yl]methyl] -hexahydro-5-oxo-l, 4-thiazepin-6-yl] -4- (phosphonooxy) Phenylalaninamide ;. N2-acetyl-N- [(6R) -4- [[2 '-cyano- (1, 1' -biphenyl) -4- yl] methyl] -hexahydro-5-oxo-l, 4-thiazepin-6- yl] -4- (phosphonooxy) Phenylalaninamide;
. acide [[ [4- [[[ (6R) -4- [[ (1, 1 ' -biphenyl) -4-yl]methyl] - hexahydro-5-oxo-l, 4-thiazepin-6- yl] amino] carbonyl] phényl] amino] carbonyl] -Phosphonique ; . acide [ [ [4- [ [ [ (6R) -hexahydro-5-oxo-4- [ [4- (trifluoromethoxy) phényl] méthyl] -1, 4-thiazepin-6- yl] amino] carbonyl] phényl] amino] carbonyl] -Phosphonique ;. acid [[[4- [[[(6R) -4- [[(1, 1 '-biphenyl) -4-yl] methyl] - hexahydro-5-oxo-1,4, thiazepin-6- yl] amino ] carbonyl] phenyl] amino] carbonyl] -Phosphonic; . acid [[[4- [[[(6R) -hexahydro-5-oxo-4- [[4- (trifluoromethoxy) phenyl] methyl] -1,4-thiazepin-6-yl] amino] carbonyl] phenyl] amino ] carbonyl] -Phosphonic;
. acide [ [ [4- [ [ [ (6R) -hexahydro-5-oxo-4- [ [4- (trifluorométhyl) phényl] méthyl] -1, 4-thiazepin-6- yl] amino] carbonyl] phényl] amino] carbonyl] -Phosphonique ; . 4, 5-dihydroxy-N- [ (6R) -hexahydro-5-oxo-4- (3-phenyl-2- propenyl) -1, 4-thiazepin-6-yl] -Benzamide ;. acid [[[4- [[[(6R) -hexahydro-5-oxo-4- [[4- (trifluoromethyl) phenyl] methyl] -1,4-thiazepin-6-yl] amino] carbonyl] phenyl] amino ] carbonyl] -Phosphonic; . 4,5-dihydroxy-N- [(6R) -hexahydro-5-oxo-4- (3-phenyl-2-propenyl) -1,4-thiazepin-6-yl] -Benzamide;
. N- [ (6R) -hexahydro-5-oxo-4- (3-phenyl-2-propenyl) -1, 4- thiazepin-6-yl] -4- (phosphonooxy) -Benzamide sel (trihydroxymethyl)methanamine ; . N2-acetyl-N-[ (6R)-hexahydro-5-oxo-4-[3-[ (4- phenylpiperazin-1-yl) suifonyl] propyl] -1, 4-thiazepin-6-yl] -4- (phosphonooxy) Phenylalaninamide ;. N- [(6R) -hexahydro-5-oxo-4- (3-phenyl-2-propenyl) -1, 4-thiazepin-6-yl] -4- (phosphonooxy) -Benzamide salt (trihydroxymethyl) methanamine; . N2-acetyl-N- [(6R) -hexahydro-5-oxo-4- [3- [(4- phenylpiperazin-1-yl) suifonyl] propyl] -1, 4-thiazepin-6-yl] -4- (phosphonooxy) Phenylalaninamide;
. N2-acetyl-N-[ (6R)-4-[3- [ (butylmethylamino) suifonyl] propyl] -hexahydro-5-oxo-l, 4- thiazepin-6-yl] -4- (phosphonooxy) Phenylalaninamide ;. N2-acetyl-N- [(6R) -4- [3- [(butylmethylamino) suifonyl] propyl] -hexahydro-5-oxo-1,4-thiazepin-6-yl] -4- (phosphonooxy) Phenylalaninamide;
. acide [ [ [4- [ [ [ (6R) -4- [ (4-bromophenyl) méthyl] -hexahydro-5- oxo-1, 4-thiazepin-6-yl] amino] carbonyl] phényl] amino] carbonyl] - Phosphonique ;. acid [[[4- [[[(6R) -4- [(4-bromophenyl) methyl] -hexahydro-5-oxo-1, 4-thiazepin-6-yl] amino] carbonyl] phenyl] amino] carbonyl] - Phosphonic;
. 4- (phosphonooxy) -N- [ ( 6R) -hexahydro-5-oxo-4- [ ( 6-chloro- 1, 3-benzodioxolan-5-yl) méthyl] -1, 4-thiazepin-6-yl] - Benzamide ;. 4- (phosphonooxy) -N- [(6R) -hexahydro-5-oxo-4- [(6-chloro- 1, 3-benzodioxolan-5-yl) methyl] -1, 4-thiazepin-6-yl] - Benzamide;
. N- [ ( 6R) -hexahydro-5-oxo-4- [ [ 4- (phenylcarbonyl) phényl] méthyl] -1, 4-thiazepin-6-yl] -4- (phosphonooxy) - Benzamide ; . N- [ (6R) -4- [ (3-chlorophenyl) méthyl] -hexahydro-5-oxo-l, 4- thiazepin-6-yl] -4- (phosphonooxy) - Benzamide ;. N- [(6R) -hexahydro-5-oxo-4- [[4- (phenylcarbonyl) phenyl] methyl] -1,4-thiazepin-6-yl] -4- (phosphonooxy) - Benzamide; . N- [(6R) -4- [(3-chlorophenyl) methyl] -hexahydro-5-oxo-l, 4- thiazepin-6-yl] -4- (phosphonooxy) - Benzamide;
. N- [ (6R) -hexahydro-5-oxo-4 [ [ (4- trifluoromethoxy) phényl] méthyl] -4- (phosphonooxy) - Benzamide ; . 4-[ [ (6R)-6-[ [ (3S) -2- (acétylamino) -l-oxo-3- [4-. N- [(6R) -hexahydro-5-oxo-4 [[((4-trifluoromethoxy) phenyl] methyl] -4- (phosphonooxy) - Benzamide; . 4- [[(6R) -6- [[(3S) -2- (acetylamino) -1-oxo-3- [4-
(phosphonooxy) phényl] -1-propyl] amino] -hexahydro-5-oxo-l, 4- thiazepin-4-yl]methyl] -Benzoate de méthyle ;(phosphonooxy) phenyl] -1-propyl] amino] -hexahydro-5-oxo-l, 4-thiazepin-4-yl] methyl] -Methyl benzoate;
. (6R)-4-(3-phenyl-2-propenyl)-6-[ [ [4- (phosphonooxy) phényl] méthyl] amino] -1, 4-thiazepin-5 (2H) -one ; . (6R)-4-(3-phenylpropyl)-6-[ [ [4-. (6R) -4- (3-phenyl-2-propenyl) -6- [[[4- (phosphonooxy) phenyl] methyl] amino] -1, 4-thiazepin-5 (2H) -one; . (6R) -4- (3-phenylpropyl) -6- [[[4-
(phosphonooxy) phényl] méthyl] amino] -1, 4-thiazepin-5 (2H) -one ;(phosphonooxy) phenyl] methyl] amino] -1,4-thiazepin-5 (2H) -one;
. N2-acetyl-N- [ (6R) -4- [ (5-chloro-l, 3-benzodioxolan-6- yl)methyl] -hexahydro—5-oxo-l, 4-thiazepin-6-yl] -4- (phosphonooxy) -L-Phenylalaninamide ; . N2-acétyl-N-[ (6R)-4-[ [- (1, 1 ' -biphényle) -4-yl) méthyl] - hexahydro-5-oxo-l, 4-thiazepin-6-yl] -4- (phosphonooxy) -L- Phenylalaninamide ;. N2-acetyl-N- [(6R) -4- [(5-chloro-1,3-benzodioxolan-6- yl) methyl] -hexahydro — 5-oxo-1,4-thiazepin-6-yl] -4 - (phosphonooxy) -L-Phenylalaninamide; . N2-acetyl-N- [(6R) -4- [[- (1,1 '-biphenyl) -4-yl) methyl] - hexahydro-5-oxo-1,4,4-thiazepin-6-yl] -4 - (phosphonooxy) -L- Phenylalaninamide;
. N2-acétyl-N- [ (6R) -hexahydro-5-oxo-4- [ [4- (phenylecarbonyl) phényl) méthyl] -1, 4-thiazepin-6-yl] -4- (phosphonooxy) -L-Phenylalaninamide ;. N2-acetyl-N- [(6R) -hexahydro-5-oxo-4- [[4- (phenylecarbonyl) phenyl) methyl] -1, 4-thiazepin-6-yl] -4- (phosphonooxy) -L- Phenylalaninamide;
. 4- (acetyloxy) -N- [ (6R) -hexahydro-4- (3-phenyl-2-propenyl) -5- oxo-1, 4-thiazepin-6-yl] Benzamide ;. 4- (acetyloxy) -N- [(6R) -hexahydro-4- (3-phenyl-2-propenyl) -5-oxo-1, 4-thiazepin-6-yl] Benzamide;
. N- [4- [ [ [ (6R)hexahydro-5-oxo-4- (3-phenyl-2-propenyl) -1, 4- thiazepin-6-yl] amino] carbonyl] phényl] -N- (2-hydroxy-2-oxo- ethyl) -Glycine ;. N- [4- [[[(6R) hexahydro-5-oxo-4- (3-phenyl-2-propenyl) -1, 4 thiazepin-6-yl] amino] carbonyl] phenyl] -N- (2 -hydroxy-2-oxoethyl) -Glycine;
. 3, 5-bis (acetyloxy) -N- [ ( 6R) -hexahydro-4- (3-phenyl-2- propenyl) -5-oxo-l, 4-thiazepin-6-yl] Benzamide ;. 3,5-bis (acetyloxy) -N- [(6R) -hexahydro-4- (3-phenyl-2-propenyl) -5-oxo-1,4-thiazepin-6-yl] Benzamide;
. 2- [3- [ [ [ (6R) -hexahydro-5-oxo-4- (3-phenyl-2-propenyl) -1, - thiazepin-6-yl] amino] carbonyl] phénoxy] - acétate de méthyle ;. 2- [3- [[[(6R) -hexahydro-5-oxo-4- (3-phenyl-2-propenyl) -1, - thiazepin-6-yl] amino] carbonyl] phenoxy] - methyl acetate;
. acide 2- [3- [ [ [ (6R) -hexahydro-5-oxo-4- (3-phenyl-2- propenyl) -1, 4-thiazepin-6-yl] amino] carbonyl] phénoxy] - acétique ; ainsi que leurs sels physiologiquement acceptables et leurs promédicaments (prodrugs) . La présente invention a également pour objet un procédé de préparation des composés de formule (I) . Les composés peuvent généralement être préparés, par exemple au cours d'une synthèse convergente par couplage de deux ou plusieurs fragments qui peuvent être dérivées par rétrosynthèse des composés de formule (I) . Afin d'éviter que les groupes fonctionnels puissent mener à des réactions indésirables ou secondaires au cours de chaque étape de synthèse, il peut être avantageux ou nécessaire au cours de la synthèse des composés de formule (I), d'introduire les groupes fonctionnels sous forme de précurseurs qui sont par la suite convertis en groupes fonctionnels désirés ou de bloquer temporairement ces groupes fonctionnels en mettant en oeuvre une stratégie de groupe protecteur appropriée à la synthèse qui est connue par l'homme de l'art (Greene, Wuts protective Group in Organic Synthesis, Wiley 1991). 2- [3- [[[(6R) -hexahydro-5-oxo-4- (3-phenyl-2-propenyl) -1,4-thiazepin-6-yl] amino] carbonyl] phenoxy] - acetic acid; as well as their physiologically acceptable salts and their prodrugs. The present invention also relates to a process for the preparation of the compounds of formula (I). The compounds can generally be prepared, for example during a convergent synthesis by coupling two or more fragments which can be derived by retrosynthesis of the compounds of formula (I). In order to avoid that the functional groups can lead to undesirable or secondary reactions during each synthesis step, it may be advantageous or necessary during the synthesis of the compounds of formula (I) to introduce the functional groups under form of precursors which are subsequently converted to desired functional groups or to temporarily block these functional groups by implementing a protective group strategy suitable for synthesis which is known to those skilled in the art (Greene, Wuts protective Group in Organic Synthesis, Wiley 1991)
Ainsi les composés de formule (I) peuvent être préparés, par exemple, en couplant une aminé de formule (II)Thus the compounds of formula (I) can be prepared, for example, by coupling an amine of formula (II)
Figure imgf000031_0001
dans laquelle Ri, R2, X, R3 et R4 sont tels que définis plus haut pour la formule (I) et où, le cas échéant, les groupes fonctionnels sont sous forme de précurseurs ou sous forme protégée, a) soit d'abord à l'action d'un acide ou un dérivé d'acide de formule (III)
Figure imgf000031_0001
in which Ri, R 2 , X, R 3 and R 4 are as defined above for formula (I) and where, where appropriate, the functional groups are in the form of precursors or in protected form, a) either d first to the action of an acid or an acid derivative of formula (III)
X'-U-[Aι]-A2 X'-U- [Aι] -A 2
dans laquelle [Ai] , A2 et U sont tels que définis plus haut dans la formule (I), X' est un groupe substituable par un nucléophile et où, le cas échéant, les groupes fonctionnels sont sous forme de précurseurs ou sous forme protégée, , afin d'obtenir un composé de formule (III1)in which [Ai], A 2 and U are as defined above in formula (I), X 'is a group substitutable by a nucleophile and where, where appropriate, the functional groups are in the form of precursors or in protected form, in order to obtain a compound of formula (III 1 )
Figure imgf000032_0001
Figure imgf000032_0001
puis à l'action de R5-Hal en présence d'une base, 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")then to the action of R 5 -Hal in the presence of a base, R 5 being as defined above and Hal being preferably a chlorine or a bromine b) or, first of all, 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 ")
Figure imgf000032_0002
Figure imgf000032_0002
puis à l'action d'un dérivé de formule (III]then to the action of a derivative of formula (III]
X'-U-[Aι]-A2 X'-U- [Aι] -A 2
lesdits groupes fonctionnels éventuellement présents sous forme de précurseur ou sous forme protégée, étant par la suite convertis en groupes présents dans les composés de formule (I)said functional groups optionally present in the form of a precursor or in protected form, being subsequently converted into groups present in the compounds of formula (I)
Certains composés de formule (I) peuvent si désiré ou si nécessaire, subir une ou plusieurs des réactions suivantes dans un ordre approprié :Certain compounds of formula (I) can, if desired or if necessary, undergo one or more of the following reactions in an appropriate order:
- action d'un agent de déprotection partielle, - action d'un agent de déprotection totale,- action of a partial deprotection agent, - action of a total deprotection agent,
- action de H-P(O) (ORd) (ORe) lorsque A2 représente OH, - saponification puis décarboxylation du dérivé malonique,- action of HP (O) (ORd) (ORe) when A 2 represents OH, - saponification then decarboxylation of the malonic derivative,
- réduction de la double liaison que peut renfermer [Ai]- reduction of the double bond that may contain [Ai]
- séparation des enantiomeres ou des diastereoisomeres- separation of enantiomeres or diastereoisomeres
- saufication. Le groupement U-X' dans X'-U-[Aι]-A2 est de préférence le groupe acide carboxylique ou un dérivé activé de l'acide carboxylique. X', par exemple est hydroxyle ou halogène, en particulier, chlore ou brome, alkoxy ou phényloxy, de préférence méthoxy, éthoxy, phénoxy, pentafluorophényloxy, alkylthio ou arylthio, de préférence phenylthio, methylthio, 2-pyridylthio ou un hétérocycle azoté lié en particulier via un azote tel que par exemple 1-imidazolyle. X' peut être également par exemple un groupement (C!-C4) -alkyle-O-CO-O- ou tolylsulfonyloxy et le dérivé d'acide activé peut être un anhydride mixte.- exceptication. The group UX 'in X'-U- [Aι] -A 2 is preferably the carboxylic acid group or an activated derivative of the carboxylic acid. X ', for example is hydroxyl or halogen, in particular, chlorine or bromine, alkoxy or phenyloxy, preferably methoxy, ethoxy, phenoxy, pentafluorophenyloxy, alkylthio or arylthio, preferably phenylthio, methylthio, 2-pyridylthio or a nitrogen heterocycle linked in in particular via a nitrogen such as for example 1-imidazolyl. X ′ may also be, for example, a (C 1 -C 4 ) -alkyl-O-CO-O- or tolylsulfonyloxy group and the activated acid derivative may be a mixed anhydride.
Si U est CO et X' est un hydroxyle, donc si l'aminé de formule (II) réagit avec un acide carboxylique de formule HOOC- [Ai] -A2, alors l'acide carboxylique est d'abord activé. L'activation peut être effectuée par exemple avec le dicyclohexylcarbodiimide (DCCI) ou avec le 0-If U is CO and X 'is a hydroxyl, therefore if the amine of formula (II) reacts with a carboxylic acid of formula HOOC- [Ai] -A 2 , then the carboxylic acid is first activated. Activation can be done for example with dicyclohexylcarbodiimide (DCCI) or with 0-
( (cyano (éthoxycarbonyl) -métylène) amino) -1,1,3,3- tétraméthyluronium tétrafluoroborate (TOTU; Kônig et al, Proc. 21st Europ. Peptide Symp. 1990 (Eds Giralt, Andreu) , Escom, Leiden 1991, p.243) ou d'autres agents activants courants en synthèse peptidique.((cyano (ethoxycarbonyl) -metylene) amino) -1,1,3,3- tetramethyluronium tetrafluoroborate (TOTU; Kônig et al, Proc. 21st Europ. Peptide Symp. 1990 (Eds Giralt, Andreu), Escom, Leiden 1991, p.243) or other activating agents common in peptide synthesis.
Outre les aminés libres de formule (II), les sels d'aminés peuvent également être mis en oeuvre dans la réaction avec les composés de formule X' -U- [Ax] -A2, les aminés libres étant formés in-situ ou par une étape séparée au moyen d'une base.In addition to the free amines of formula (II), the amine salts can also be used in the reaction with the compounds of formula X '-U- [A x ] -A 2 , the free amines being formed in situ. or by a separate step using a base.
La réaction d'un dérivé activé d'acide carboxylique de formule HOOC- [Ai] -A2 avec l'aminé (ou dérivé) de formule (II) est de préférence effectuée d'une manière connue en soi dans un solvant organique protique ou aprotique, mais inerte. Dans ce cas on utilise des solvants tels que le méthanol,The reaction of an activated carboxylic acid derivative of formula HOOC- [Ai] -A 2 with the amine (or derivative) of formula (II) is preferably carried out in a manner known per se in a protic organic solvent or aprotic, but inert. In this case, solvents such as methanol are used,
1 ' isopropanol, le tert-butanol, le diméthylformamide ou le tétrahydrofurane à des températures allant de 0°C à la température de reflux de ces solvants, notamment lors de la réaction des esters méthyliques ou éthyliques (X est un méthoxy ou un éthoxy) avec les aminés. Les réactions des acides de formule HOOC- [Ai] -A2 avec les aminés libres sont avantageusement mises en oeuvre dans un solvant aprotique inerte tel que le diméthylformamide, le tétrahydrofurane, le diméthoxyéthane, ou le dioxane, le cas échéant en additionnant une base telle que par exemple le tert-butoxide de potassium, le methoxide de sodium ou une base organique telle que la N-méthylmorpholine . Cependant, l'eau peut également être utilisée comme solvant dans les réactions des composés de formule (II) avec les acides de formule HOOC- [Ai] -A2, par exemple en utilisant une base telle que 1 ' hydroxyde de sodium.1 isopropanol, tert-butanol, dimethylformamide or tetrahydrofuran at temperatures ranging from 0 ° C. to the reflux temperature of these solvents, in particular during the reaction of methyl or ethyl esters (X is a methoxy or an ethoxy) with the amines. The reactions of the acids of formula HOOC- [Ai] -A 2 with the free amines are advantageously carried out in an inert aprotic solvent such as dimethylformamide, tetrahydrofuran, dimethoxyethane, or dioxane, if necessary by adding a base. such as for example potassium tert-butoxide, sodium methoxide or an organic base such as N-methylmorpholine. However, water can also be used as a solvent in the reactions of the compounds of formula (II) with the acids of formula HOOC- [Ai] -A 2 , for example using a base such as sodium hydroxide.
Si X' est le chlore, la réaction sera de préférence menée par addition d'un piégeur d'acide, par exemple d'une base ou d'un excès d'aminé (ou dérivé). Le mélange réactionnel est ensuite traité et si désiré le produit réactionnel est purifié selon les méthodes connues de l'homme du métier.If X 'is chlorine, the reaction will preferably be carried out by adding an acid scavenger, for example a base or an excess of amine (or derivative). The reaction mixture is then treated and if desired the reaction product is purified according to methods known to those skilled in the art.
La réaction d' acylation mettant en oeuvre le composé de formule HOOC- [Ai] -A2, s'effectue de préférence en présence d'EDC (chlorhydrate de 1- (3-diméthylaminopropyl) -3-éthyl- carbodiimide) et de HOBt (1-hydroxybenzotriazole hydrate) dans un solvant dipolaire aprotique tel que le diméthylformamide. Cette réaction peut s'effectuer en solution comme en phase solide comme le montrent les exemples plus bas. La réaction d'alkylation mettant en œuvre R5-Hal s'effectue selon les méthodes usuelles connues de l'homme du métier, notamment en présence d'une base telle que l'hydrure de sodium dans un solvant dipolaire aprotique tel que le diméthylformamide . Les groupes protecteurs éventuellement présents dans les composés de formules (III1), (III") ou (I) sont ensuite éliminés par des procédés classiques ; par exemple, les groupes tertbutyl ester sont convertis en acide carboxylique par traitement avec de l'acide trifluoroacetique, les groupes benzyles sont éliminés par hydrogénation ou encore les groupes fluorenylmethoxycarbonyle sont éliminés en présence d'aminé secondaire.The acylation reaction using the compound of formula HOOC- [Ai] -A 2 , is preferably carried out in the presence of EDC (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride) and HOBt (1-hydroxybenzotriazole hydrate) in an aprotic dipolar solvent such as dimethylformamide. This reaction can be carried out in solution as in solid phase as shown in the examples below. The alkylation reaction using R 5 -Hal is carried out according to the usual methods known to those skilled in the art, in particular in the presence of a base such as sodium hydride in an aprotic dipolar solvent such as dimethylformamide . The protective groups optionally present in the compounds of formulas (III 1 ), (III ") or (I) are then removed by conventional methods; for example, the tert-butyl ester groups are converted to the carboxylic acid by treatment with trifluoroacetic acid, the benzyl groups are eliminated by hydrogenation or the fluorenylmethoxycarbonyl groups are eliminated in the presence of secondary amine.
Lorsque l'aminé est protégée (NHC02Rb ou NHCORb), elle l'est notamment par un groupement Boc ou acétyle. Le retour à l'aminé libre peut s'effectuer par action d'acide trifluoroacetique.When the amine is protected (NHC0 2 Rb or NHCORb), it is in particular protected by a Boc or acetyl group. The return to the free amine can be carried out by the action of trifluoroacetic acid.
Lorsque cette aminé est protégée par C02CH2Ph, la déprotection s'effectue de préférence en présence Pd(OH)2, MgO dans le cyclohexadiene au reflux.When this amine is protected by C0 2 CH 2 Ph, the deprotection is preferably carried out in the presence of Pd (OH) 2 , MgO in cyclohexadiene at reflux.
Pour obtenir une monodébenzylation (A2 = OP(O) (OH) (OBn)), on met en oeuvre en particulier l'iodure de sodium et la réaction s'effectue au reflux de l'acétone, ou le DABCO (1,4- diazabicyclo [2.2.2] octane) dans le toluène.To obtain a monodebenzylation (A 2 = OP (O) (OH) (OBn)), sodium iodide is used in particular and the reaction is carried out at reflux of acetone, or DABCO (1, 4-diazabicyclo [2.2.2] octane) in toluene.
Pour obtenir une déprotection totale (A2 = OP(O) (OH)2), on effectue de préférence une hydrogénation classique en présence de Pd/C à 10% ou on utilisera l'acide trifluoroacetique dans le dichlorométhane.To obtain total deprotection (A 2 = OP (O) (OH) 2 ), a conventional hydrogenation is preferably carried out in the presence of Pd / C at 10% or trifluoroacetic acid will be used in dichloromethane.
Lorsque A2 représente OH, la réaction de phosphorylation s'effectue avec HP(O) (ORd) (ORe) en présence de N'N- diisopropyléthylamine (DIPEA) et de N,N-diméthylaminopyridine (DMAP) dans l' acétonitrile en présence de tétrachlorure de carbone .When A 2 represents OH, the phosphorylation reaction is carried out with HP (O) (ORd) (ORe) in the presence of N'N-diisopropylethylamine (DIPEA) and of N, N-dimethylaminopyridine (DMAP) in acetonitrile in presence of carbon tetrachloride.
Les réactions de saponification, de décarboxylation, de réduction de la double liaison et de séparation des enantiomeres et diastereoisomeres et si nécessaire, la conversion en des sels physiologiquement acceptables s'effectuent par des procédés connus de l'homme du métier.The saponification, decarboxylation, reduction of the double bond and separation of the enantiomers and diastereoisomers reactions and, if necessary, the conversion to physiologically acceptable salts are carried out by methods known to those skilled in the art.
A titre de variante lorsqu'on désire obtenir un composé de formule (I) dans laquelle U représente CO, et [Ai] représente un groupement NH- (C5-C14) -aryle, on utilise un dérivé d'ester isocyanique de formule OCN-[Aι]-A2 A titre de variante, lorqu'on désire obtenir un composé de formule (I) dans laquelle U représente un groupement alkylène et notamment méthylène, on fait réagir l'aminé avec un dérivé HCO-[Aχ]-A2 en présence d'un agent de réduction tel que NaBH3CN dans un solvant tel que le méthanol.As a variant when it is desired to obtain a compound of formula (I) in which U represents CO, and [Ai] represents an NH- (C 5 -C14) -aryl group, an isocyanic ester derivative of formula is used OCN- [Aι] -A 2 As a variant, when it is desired to obtain a compound of formula (I) in which U represents an alkylene group and in particular methylene, the amine is reacted with an HCO- [Aχ] -A 2 derivative in the presence of a reducing agent such as NaBH 3 CN in a solvent such as methanol.
L'invention a plus particulièrement pour objet un procédé tel que décrit plus haut dans lequel le composé de formule (III) est choisi parmi les tyrosines phosphatées suivantes :N-Boc-Tyr-0- (P03Bn2) , N-Ac-Tyr-O- (P03Bn2) , N-Boc-Tyr-CF2- (P03Et2) , N-Ac-Tyr-CF2- (P03Et2) ou les dérivés benzoiques (Illa, IIIc) ) ou benzénique (Illb, (Illd)) suivants :The subject of the invention is more particularly a process as described above in which the compound of formula (III) is chosen from the following phosphate tyrosines: N-Boc-Tyr-0- (P0 3 Bn 2 ), N-Ac -Tyr-O- (P0 3 Bn 2 ), N-Boc-Tyr-CF 2 - (P0 3 Et 2 ), N-Ac-Tyr-CF 2 - (P0 3 Et 2 ) or benzoic derivatives (Illa, IIIc)) or benzene (Illb, (Illd)) following:
Figure imgf000036_0001
Figure imgf000036_0001
(IIIc)(IIIc)
Figure imgf000036_0002
Figure imgf000036_0002
(Illd) dans lesquels R"f représente un atome d'hydrogène, de fluor ou C02Rd, R"g représente un atome d'hydrogène ou de fluor et Z" représente NHCORb ou NHC02Rb, R6 est tel que défini précédemment, le composé de formule (Illb) présentant une configuration E ou Z .(Illd) in which R "f represents a hydrogen, fluorine or C0 2 Rd atom, R" g represents a hydrogen or fluorine atom and Z "represents NHCORb or NHC0 2 Rb, R 6 is as defined previously, the compound of formula (IIIb) having an E or Z configuration.
L'invention a donc pour objet les procédés décrits plus haut et les nouveaux composés intermédiaires de formules (III'), (III").The subject of the invention is therefore the processes described above and the new intermediate compounds of formulas (III ′), (III ″).
La préparation des composés de formules (II) et (III) est illustrée dans les exemples décrits plus bas, étant entendu que la présente invention n'est pas restreinte à ces synthèses ou ces produits de départ. Il n'y a pas de difficulté majeure pour l'homme du métier de prévoir des modifications des synthèses décrites dans notre demande pour la préparation d'autres composés de formule (II) ou (III) selon l'invention.The preparation of the compounds of formulas (II) and (III) is illustrated in the examples described below, it being understood that the present invention is not limited to these syntheses or these starting products. There is no major difficulty for those skilled in the art to provide for modifications to the syntheses described in our application for the preparation of other compounds of formula (II) or (III) according to the invention.
A titre d'exemple les benzothiazepinones de formule (II) dans laquelle Ri et R2 forment ensemble un phenyle adjacent, X est un atome d'oxygène, R3 est un groupement phenyle éventuellement substitué et R4 est un atome d'hydrogène, sont connus notamment dans la demande de brevet JP 60139682.. Par ailleurs, les composés de formule (II) dans laquelle, X est un atome d'oxygène, Ri et R2 forment ensemble un phenyle adjacent, R3 et R4 sont des atomes d'hydrogène sont décrits dans J. Med. Chem (1985) 1517-1521 (J. Slade et al) .By way of example, the benzothiazepinones of formula (II) in which Ri and R 2 together form an adjacent phenyl, X is an oxygen atom, R 3 is an optionally substituted phenyl group and R 4 is a hydrogen atom, are known in particular in patent application JP 60139682 .. Furthermore, the compounds of formula (II) in which, X is an oxygen atom, Ri and R 2 together form an adjacent phenyle, R 3 and R 4 are hydrogen atoms are described in J. Med. Chem (1985) 1517-1521 (J. Slade et al).
La préparation des composés de formule (II) notamment avec Ri, R2, R3 et R4 représentant chacun un atome d'hydrogène, est illustrée dans le schéma ci-dessous (schéma 1)The preparation of the compounds of formula (II) in particular with Ri, R 2 , R 3 and R 4 each representing a hydrogen atom, is illustrated in the diagram below (diagram 1)
Figure imgf000037_0001
Figure imgf000037_0001
EDCEDC
Figure imgf000037_0002
L'action de la L ou D cystéine de formule (IV) éventuellement protégée au niveau de l'aminé avec un composé de formule (V) dans laquelle Hal représente un chlore ou un brome et (D) représente NH2 ou N02, s'effectue en présence d'une base telle que la triéthylamine . Le compsé de formule (VI) est ensuite cyclisé, notamment en présence d'EDC, après le cas échéant protection de l'aminé et réduction du groupe nitro que peut représenter (D) afin d'obtenir le composé de formule (II).
Figure imgf000037_0002
The action of the L or D cysteine of formula (IV) possibly protected at the level of the amine with a compound of formula (V) in which Hal represents a chlorine or a bromine and (D) represents NH 2 or N0 2 , is carried out in the presence of a base such as triethylamine. The compound of formula (VI) is then cyclized, in particular in the presence of EDC, after protection of the amine if necessary and reduction of the nitro group which may represent (D) in order to obtain the compound of formula (II).
Les composés de formule (II) avec Ri, R2, R3 et R4 représentant chacun un atome d'hydrogène et le trait en pointillé représente une double liaison, sont obtenus par action du composé de formule (IV) dont la fonction acide est amidifiée et l'aminé est protégée avec un dérivé malonique de formule Hal-CH (C02Et ) 2 suivie d'une réaction de cyclisation et d' élimination.The compounds of formula (II) with Ri, R 2 , R 3 and R 4 each representing a hydrogen atom and the dotted line represents a double bond, are obtained by action of the compound of formula (IV) whose acid function is amidified and the amine is protected with a malonic derivative of formula Hal-CH (C0 2 Et) 2 followed by a cyclization and elimination reaction.
Les composés de départ de formule (III) sont commerciaux, peuvent être préparés selon des procédés décrits dans la littérature ou encore sont accessibles par analogie. A titre d'exemple on utilise de préférence, les produits de formule (III) suivants:The starting compounds of formula (III) are commercial, can be prepared according to methods described in the literature or are accessible by analogy. By way of example, the following products of formula (III) are preferably used:
- le 0- [bis (phénylméthoxy) phosphinyl] -N- [ (1, 1- dimethyléthoxy) carbonyl] -L-tyrosine : (N-Boc-Tyr-O- (P03Bn2) , origine : Penissula Laboratories, Inc- 0- [bis (phenylmethoxy) phosphinyl] -N- [(1, 1-dimethylethoxy) carbonyl] -L-tyrosine: (N-Boc-Tyr-O- (P0 3 Bn 2 ), origin: Penissula Laboratories, Inc
- Le N-acétyl-O- [bis- (diphenylmethoxy) phosphinyl] -L-tyrosine : N-Ac-Tyr-O- (P03Bn2)- N-acetyl-O- [bis- (diphenylmethoxy) phosphinyl] -L-tyrosine: N-Ac-Tyr-O- (P0 3 Bn 2 )
- Le N- [ (1, 1-dimethyléthoxy) carbonyl] -4- [bis- ethoxyphosphinyl) difluorométhyl] -L-phenylalanine : N-Boc- Tyr-CF2-(P03Et2)- N- [(1, 1-dimethylethoxy) carbonyl] -4- [bis- ethoxyphosphinyl) difluoromethyl] -L-phenylalanine: N-Boc- Tyr-CF 2 - (P0 3 Et 2 )
- Le N-acétyl-4- [bis-ethoxyphosphinyl) difluorométhyl] -L- phenylalanine : N-Ac-Tyr-CF2- (P03Et2)- N-acetyl-4- [bis-ethoxyphosphinyl) difluoromethyl] -L- phenylalanine: N-Ac-Tyr-CF 2 - (P0 3 Et 2 )
La préparation des composés de formule (III) dans laquelle -[Ai]- représente un groupement -C (Z) =CH- (C5-Cι4) - aryle- (composés de formule (Illb) est illustrée dans le schéma décrit plus bas (schéma 2) :The preparation of the compounds of formula (III) in which - [Ai] - represents a group -C (Z) = CH- (C 5 -Cι 4 ) - aryle- (compounds of formula (IIIb) is illustrated in the diagram described below (diagram 2):
Figure imgf000039_0001
Figure imgf000039_0001
Lorsqu'on fait réagir le N-fluorobenzène sulfoniimide (NFSI) ou le mélange Potassium hexaméthyldisilizane (KHMDS) / N- fluorobenzène sulfoniimide (NFSI) préalablement à la réaction de Heck, R"f et R"g représentent un atome de fluor dans les composés de formule (Illb). Si l'on veut obtenir uniquement des esters de formule (B) , la réaction de décarboxylation peut s'effectuer en présence d'APTS, de TFA ou de PPTS. On obtient des composés de formule (Illb) ayant une configuration E ou Z ou en mélange E/Z selon la nature des substituants. La formation des acides maloniques à partir des ester terbutyliques correspondant peut s'effectuer avec l'acide formique. Une hydrogénation catalytique permet d'obtenir les composés réduits correspondants. On peut également envisager la formation des composés réduits correspondant par couplage zincique d'une iodosérine avec l'ester malonique iodé de formule (A) selon les méthodes connues de l'homme du métier.When the N-fluorobenzene sulfoniimide (NFSI) or the potassium hexamethyldisilizane (KHMDS) / N-fluorobenzene sulfoniimide (NFSI) mixture is reacted before the Heck reaction, R "f and R" g represent a fluorine atom in the compounds of formula (Illb). If it is desired to obtain only esters of formula (B), the decarboxylation reaction can be carried out in the presence of APTS, TFA or PPTS. Compounds of formula (IIIb) are obtained having an E or Z configuration or as an E / Z mixture depending on the nature of the substituents. The formation of malonic acids from the corresponding terbutyl esters can be carried out with formic acid. Catalytic hydrogenation provides the corresponding reduced compounds. It is also possible to envisage the formation of the corresponding reduced compounds by zinc coupling of an iodoserine with the iodized malonic ester of formula (A) according to the methods known to those skilled in the art.
La préparation des composés de formules (III) dans laquelle -[Ai]- représente un groupement -phenyle- et A2 représente un groupement -CF2PO(OEt) (composés de formule (IIIc) ) est illustrée dans le schéma décrit plus bas (schéma 3) :The preparation of the compounds of formulas (III) in which - [Ai] - represents a group -phenyl- and A 2 represents a group -CF 2 PO (OEt) (compounds of formula (IIIc)) is illustrated in the diagram described more bottom (diagram 3):
Figure imgf000040_0001
DMF
Figure imgf000040_0001
DMF
Figure imgf000040_0002
Figure imgf000040_0002
Les composés de formule (III) peuvent également être préparés en phase solide. La phase solide est préparée selon une publication de Mjalli et al (Tetrahedron letter, 1996, 6073) . La résine est mise en réaction avec soit un phénol en présence de CCI4 et de DMAP, soit avec une base telle que le DBU et un isocyanate pour générer respectivement le phosphate et 1 ' amidophosphonate. Une fois le couplage avec les composés de formule (II) effectué, toujours en phase solide, une coupure avec le TFA permet de régénérer le produit (schéma 4) .
Figure imgf000041_0001
The compounds of formula (III) can also be prepared in the solid phase. The solid phase is prepared according to a publication by Mjalli et al (Tetrahedron letter, 1996, 6073). The resin is reacted with either a phenol in the presence of CCI 4 and DMAP, or with a base such as DBU and an isocyanate to generate the phosphate and the amidophosphonate respectively. Once the coupling with the compounds of formula (II) has been carried out, still in the solid phase, a cleavage with the TFA makes it possible to regenerate the product (diagram 4).
Figure imgf000041_0001
Les composés de formule R5-X' sont connus, peuvent être préparés selon des procédés décrits dans la littérature ou encore sont accessibles par analogie. On utilise de préférence les dérivés halogènes. Les composés de formule (I) peuvent être utilisés pour inhiber la liaison d'une protéine Src à une protéine phosphorylee analogue.The compounds of formula R 5 -X 'are known, can be prepared according to methods described in the literature or are accessible by analogy. Preferably halogen derivatives are used. The compounds of formula (I) can be used to inhibit the binding of an Src protein to an analogous phosphorylee protein.
Cette inhibition peut s'effectuer soit au niveau du domaine SH2, soit au niveau du domaine SH3 (impliqué dans la reconnaissance et l'interaction avec d'autres protéines), soit au niveau du domaine catalytique (tyrosine kinase) . Les composés selon l'invention ont tout particulièrement une affinité vis-à-vis du domaine SH2 de la protéine Src.This inhibition can be carried out either at the level of the SH2 domain, or at the level of the SH3 domain (involved in recognition and interaction with other proteins), or at the level of the catalytic domain (tyrosine kinase). The compounds according to the invention most particularly have an affinity for the SH2 domain of the Src protein.
Les composés de formule (I) peuvent donc être utilisés pour inhiber la liaison d'une protéine Src contenant le domaine SH2, à une protéine phosphorylee analogue, la méthode consistant en l'administration au patient dont le traitement requiert l'inhibition du domaine SH2, une quantité inhibitrice du composé selon l'invention. L'action des composés de formule (I) peut être démontrée par exemple dans un test dans lequel l'inhibition de la liaison du ligand EPQpYEEIPIYL radiomarqué à la protéine SH2 est déterminée par Scintillation proximity assay (SPA) . Des précisions sur ce test sont données plus bas. Comme antagonistes du domaine Src SH2, les composés de formule (I) et leurs sels physiologiquement acceptables et leurs prodrugs conviennent en général pour le traitement ou la prévention de maladies liées aux interactions entre domaine SH2 et leur ligands ou qui peuvent être influencés par l'inhibition des interactions de ce type, pour soulager ou guérir lorsqu'une inhibition des interactions de ce type est désirée. Comme on l'a expliqué au début, une telle interaction joue un rôle important dans la résorption osseuse.The compounds of formula (I) can therefore be used to inhibit the binding of an Src protein containing the SH2 domain to an analogous phosphorylated protein, the method consisting in the administration to the patient whose treatment requires the inhibition of the SH2 domain , an inhibitory amount of the compound according to the invention. The action of the compounds of formula (I) can be demonstrated for example in a test in which the inhibition of the Binding of the radiolabelled EPQpYEEIPIYL ligand to the SH2 protein is determined by Scintillation proximity assay (SPA). Details on this test are given below. As antagonists of the Src SH2 domain, the compounds of formula (I) and their physiologically acceptable salts and their prodrugs are generally suitable for the treatment or prevention of diseases linked to interactions between the SH2 domain and their ligands or which can be influenced by inhibition of such interactions, to relieve or cure when inhibition of such interactions is desired. As explained at the beginning, such an interaction plays an important role in bone resorption.
Les composés de formule (I) sont tout particulièrement des antagonistes du récepteur humain Src SH2 et sont capables ainsi par exemple d'inhiber l'adhésion des ostéoclastes sur la surface de l'os et ainsi la résorption osseuse par les ostéoclastes .The compounds of formula (I) are most particularly antagonists of the human receptor Src SH2 and are thus able for example to inhibit the adhesion of osteoclasts to the surface of the bone and thus the bone resorption by the osteoclasts.
Les maladies de l'os dont le traitement ou la prévention nécessitent l'emploi des composés de formule (I) ou de leurs prodrugs, sont notamment 1 ' osteoporose, l'hypercalcémie,Bone diseases whose treatment or prevention require the use of the compounds of formula (I) or their prodrugs, are in particular osteoporosis, hypercalcemia,
1 ' ostéopénie, par exemple causée par les métastases osseuses, les désordres dentaires par exemple les parodontites, 1 ' hyperparathyroidisme, les érosions périarticulaires dans l'arthrite rhumatoïde, la maladie de Paget, l' ostéopénie induite par l'immobilisation. En outre les composés de formule (I) peuvent être utilisés pour soulager, empêcher ou traiter les désordres de l'os qui sont causés par les traitements, par les glucocorticoides, les thérapies liées à la prise de stéroides ou de corticostéroïdes ou par les déficiences d'hormones sexuelles mâles ou femelles.Osteopenia, for example caused by bone metastases, dental disorders for example periodontitis, hyperparathyroidism, periarticular erosions in rheumatoid arthritis, Paget's disease, osteopenia induced by immobilization. In addition, the compounds of formula (I) can be used to relieve, prevent or treat bone disorders which are caused by treatments, by glucocorticoids, therapies linked to the taking of steroids or corticosteroids or by deficiencies. male or female sex hormones.
Tous ces désordres sont caractérisés par une perte osseuse, qui est basée par un défaut d'équilibre entre la formation osseuse et la destruction osseuse et qui peut être influencé favorablement par l'inhibition de la résorption osseuse par les ostéoclastes.All these disorders are characterized by bone loss, which is based on a lack of balance between bone formation and bone destruction and which can be favorably influenced by the inhibition of bone resorption by osteoclasts.
Les composés selon l'invention, par leur affinité avec le domaine Src-SH2, peuvent également être utilisés dans d'autres applications thérapeutiques. Par exemple on sait que les plaquettes et les neurones sont des tissus qui expriment Src-SH2 également. En outre plusieurs protéines de cette famille étant majoritairement exprimées dans le système hémétopoiétique, de nombreuses applications dans le traitement de l'immunité, de l'infection, de l'allergie et des maladies autoimmunes sont envisageables.The compounds according to the invention, by their affinity with the Src-SH2 domain can also be used in other therapeutic applications. For example, we know that platelets and neurons are tissues that also express Src-SH2. In addition, several proteins of this family being predominantly expressed in the hemetopoietic system, numerous applications in the treatment of immunity, infection, allergy and autoimmune diseases are conceivable.
Enfin, les composés de formule (I) peuvent également être utilisés pour inhiber la liaison d'une protéine contenant le domaine SH2, autre que Src, à une protéine phosphorylee analogue, la méthode consistant en l'administration au patient dont le traitement requiert l'inhibition du domaine SH2, une quantité inhibitrice du composé selon l'invention.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 an analogous phosphorylated protein, the method consisting in administration to the patient whose treatment requires inhibition of the SH2 domain, an inhibitory amount of the compound according to the invention.
Les protéines contenant le domaine SH2 autres que Src sont choisies parmi Fyn, Lck, Yes, Blk, Lyn, Fgr, Hck, Yrk,Abl et Zap 70.Proteins containing the SH2 domain other than Src are chosen from Fyn, Lck, Yes, Blk, Lyn, Fgr, Hck, Yrk, Abl and Zap 70.
Les composés selon l'invention peuvent ainsi être utilisés dans le traitement de maladies telles que les maladies prolifératives, le cancer, la resténose, l'inflammation; les allergies ou les maladies cardiovasculaires .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 disease.
Parmi les médicaments de l'invention, on peut citer particulièrement les composés décrits dans la partie expérimentale .Among the medicaments of the invention, mention may be made in particular of the compounds described in the experimental part.
Parmi ces produits, l'invention a plus particulièrement pour objet, à titre de médicaments, les composés de formule (I) listés précédemment. La présente invention a donc pour objet un composé de formule (I), et/ou ses sels physiologiquement acceptables et/ou ses prodrugs, à titre de médicament.Among these products, the invention more particularly relates, as medicaments, to the compounds of formula (I) listed above. The present invention therefore relates to a compound of formula (I), and / or its physiologically acceptable salts and / or its prodrugs, as a medicament.
La présente invention plus particulièrement pour objet un composé de formule (I), et/ou ses sels physiologiquement acceptables et/ou ses prodrugs, à titre de médicament ayant une activité inhibitrice du récepteur Src SH2. La présente invention plus particulièrement pour objet un composé de formule (I), et/ou ses sels physiologiquement acceptables et/ou ses prodrugs, à titre de médicament ayant une activité inhibitrice de la résorption osseuse ou pour le traitement ou la prévention de 1 ' osteoporose.The present invention more particularly relates to a compound of formula (I), and / or its physiologically acceptable salts and / or its prodrugs, as a medicament having an inhibitory activity on the Src SH2 receptor. The present invention more particularly relates to a compound of formula (I), and / or its physiologically acceptable salts and / or its prodrugs, as a medicament having an activity inhibiting bone resorption or for the treatment or prevention of 1 ′ osteoporosis.
La présente invention plus particulièrement pour objet un composé de formule (I), et/ou ses sels physiologiquement acceptables et/ou ses prodrugs, à titre de médicament pour le traitement ou la prévention de l'immunité, de l'infection, de l'allergie, et des maladies autoimmunes.The present invention more particularly relates to a compound of formula (I), and / or its physiologically acceptable salts and / or its prodrugs, as a medicament for the treatment or prevention of immunity, infection, l , and autoimmune diseases.
La présente invention plus particulièrement pour objet un composé de formule (I), et/ou ses sels physiologiquement acceptables et/ou ses prodrugs, à titre de médicament pour le traitement ou la prévention de maladies telles que les maladies prolifératives, le cancer, la resténose, l'inflammation, les allergies ou les maladies cardiovasculaires .The present invention more particularly relates to a compound of formula (I), and / or its physiologically acceptable salts and / or its prodrugs, as a medicament for the treatment or prevention of diseases such as proliferative diseases, cancer, restenosis, inflammation, allergies or cardiovascular disease.
La présente invention a également pour objet l'utilisation des composés de formule (I) et/ou leurs sels physiologiquement acceptables et/ou leurs prodrugs pour la préparation de médicaments destinés à la prévention ou au traitement de 1 'osteoporose.The present invention also relates to the use of the compounds of formula (I) and / or their physiologically acceptable salts and / or their prodrugs for the preparation of medicaments intended for the prevention or treatment of osteoporosis.
La présente invention a également pour objet l'utilisation des composés de formule (I) et/ou leurs sels physiologiquement acceptables et/ou leurs prodrugs pour la préparation de médicaments destinés au traitement ou à la prévention de l'immunité, de l'infection, de l'allergie, et des maladies autoimmunes.Another subject of the present invention is the use of the compounds of formula (I) and / or their physiologically acceptable salts and / or their prodrugs for the preparation of medicaments intended for the treatment or prevention of immunity, of infection , allergy, and autoimmune diseases.
La présente invention a également pour objet l'utilisation des composés de formule (I) et/ou leurs sels physiologiquement acceptables et/ou leurs prodrugs pour la préparation de médicaments destinés au traitement ou à la prévention de maladies telles que les maladies prolifératives, le cancer, la resténose, l'inflammation, les allergies ou les maladies cardiovasculaires.A subject of the present invention is also the use of the compounds of formula (I) and / or their physiologically acceptable salts and / or their prodrugs for the preparation of medicaments intended for the treatment or prevention of diseases such as proliferative diseases, cancer, restenosis, inflammation, allergies or cardiovascular disease.
Les composés de formule (I) ainsi que leurs sels physiologiquement acceptables et leurs prodrugs peuvent être administrés aux animaux, de préférence aux mammifères et en particulier aux êtres humains comme médicaments à titre thérapeutique ou prophylactique. Ils peuvent être administrés tels quels ou en mélange avec un ou plusieurs autres composés de formule (I) ou encore sous la forme d'une préparation pharmaceutique (composition pharmaceutique) qui permet une administration entérale ou parentérale et qui renferme à titre de composé actif une dose efficace d'au moins un composé de formule (I) et/ou ses sels physiologiquement acceptables et/ou ses prodrugs ainsi qu'un ou plusieurs excipients pharmaceutiquements acceptables et éventuellement un ou plusieurs additifs.The compounds of formula (I) and their salts physiologically acceptable and their prodrugs can be administered to animals, preferably to mammals and in particular to humans as medicaments for therapeutic or prophylactic purposes. They can be administered as such or in admixture with one or more other compounds of formula (I) or alternatively in the form of a pharmaceutical preparation (pharmaceutical composition) which allows enteral or parenteral administration and which contains, as active compound, a effective dose of at least one compound of formula (I) and / or its physiologically acceptable salts and / or its prodrugs as well as one or more pharmaceutically acceptable excipients and optionally one or more additives.
Les médicaments peuvent être administrés oralement, par exemple sous forme de pilule, de comprimés, de comprimés enrobés, de pellicules, de granules, de gélules et capsules molles, de solutions, de sirops, d'émulsion, de suspension ou de mélange d'aérosol.The drugs can be administered orally, for example, as a pill, tablet, coated tablet, film, granule, soft capsule or capsule, solution, syrup, emulsion, suspension, or mixture of aerosol.
L'administration peut cependant être effectuée par voie rectale, par exemple sous forme de suppositoire ou par voie parentérale, par exemple sous forme de solutions injectables ou d'infusions, de microcapsules ou d'implants, ou par voie percutanée, par exemple sous la forme de pommade, de solutions, de pigments ou de colorants, par voie transdermique (patches) ou par d'autres voies telles que sous la forme d'aérosol ou de spray nasal.Administration can however be carried out rectally, for example in the form of a suppository or parenterally, for example in the form of injectable solutions or infusions, of microcapsules or implants, or by percutaneous route, for example under the form of ointment, solutions, pigments or dyes, transdermally (patches) or by other routes such as in the form of aerosol or nasal spray.
Les compositions pharmaceutiques selon l'invention sont préparées selon des méthodes connues en soi, des supports organiques ou inorganiques, pharmaceutiquement inertes étant additionnés aux composés de formule (I) et/ou leurs sels physiologiquement acceptables et/ou leurs prodrugs.The pharmaceutical compositions according to the invention are prepared according to methods known per se, pharmaceutically inert organic or inorganic supports being added to the compounds of formula (I) and / or their physiologically acceptable salts and / or their prodrugs.
Pour la production de pilule, de comprimés, de comprimés enrobés et de capsule en gélatine dure, il est possible d'utiliser par exemple, du lactose, de l'amidon de maïs ou ses dérivés, du talc, de l'acide stéarique ou ses sels, etc. Les supports convenables pour des capsules en gélatine molle ou pour les suppositoires sont par exemple les graisses, les cires les polyols semi-solides ou liquides, les huiles natu relies ou modifiées etc. Les véhicules appropriés pour la préparation de solutions, par exemple les solutions injectables, les émulsions ou les sirops sont par exemple l'eau, les alcools, le glycérol, les polyols, le sucrose, les sucres invertis, le glucose, les huiles végétales, etc. Les supports convenables pour les microcapsules ou les implants sont par exemple les copolymères d'acide glyoxilique et d'acide lactique. Les préparations pharmaceutiques contiennent normalement de 0,5% à 90% en poids de composés de formule (I) et/ou leurs sels physiologiquement acceptables.For the production of pills, tablets, coated tablets and hard gelatin capsules, it is possible to use, for example, lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc. The suitable supports for soft gelatin capsules or for suppositories are, for example, fats, waxes, semi-solid or liquid polyols, bound or modified natural oils, etc. The vehicles suitable for the preparation of solutions, for example injectable solutions, emulsions or syrups are for example water, alcohols, glycerol, polyols, sucrose, invert sugars, glucose, vegetable oils, etc. Suitable supports for microcapsules or implants are, for example, copolymers of glyoxilic acid and lactic acid. Pharmaceutical preparations normally contain from 0.5% to 90% by weight of compounds of formula (I) and / or their physiologically acceptable salts.
En plus des principes actifs et des excipients, les préparations pharmaceutiques peuvent contenir des additifs tels que par exemple des diluants, des désintégrants, des liants, des lubrifiants, des agents mouillant, des stabilisants, des émulsifiants, des préservateurs, des agents sucrant, des colorants des agents de flaveurs ou des aromatisants, des épaississants, des agents tampons, et aussi des solvants ou des solubilisants ou des agents pour obtenir un effet retard et également des sels pour modifier la pression osmotique, des agents d'enrobage ou des antioxydants. Elles peuvent également contenir deux ou plusieurs composés de formule (I) et/ou leurs sels physiologiquement acceptables et/ou leurs prodrugs. En outre, en plus d'au moins un ou plusieurs composés de formule (I) et/ou leurs sels physiologiquement acceptables et/ou leurs prodrugs, ils peuvent contenir au moins un ou plusieurs autres principes actifs utilisables à titre thérapeutique ou prophylactique.In addition to the active ingredients and excipients, pharmaceutical preparations can contain additives such as, for example, diluents, disintegrants, binders, lubricants, wetting agents, stabilizers, emulsifiers, preservatives, sweetening agents, coloring agents for flavoring agents or flavoring agents, thickeners, buffering agents, and also solvents or solubilizers or agents for obtaining a delayed effect and also salts for modifying the osmotic pressure, coating agents or antioxidants. They can also contain two or more compounds of formula (I) and / or their physiologically acceptable salts and / or their prodrugs. In addition, in addition to at least one or more compounds of formula (I) and / or their physiologically acceptable salts and / or their prodrugs, they may contain at least one or more other active ingredients which can be used therapeutically or prophylactically.
La présente invention a donc pour objet les compositions pharmaceutiques qui permettent une administration entérale ou parentérale et qui, renferment à titre de composé actif une dose efficace d'au moins un composé de formule (I) et/ou ses sels physiologiquement acceptables et/ou ses prodrugs ainsi qu'un ou plusieurs excipients pharmaceutiquement acceptables, et éventuellement un ou plusieurs additifs usuels.The present invention therefore relates to pharmaceutical compositions which allow enteral or parenteral administration and which contain, as active compound, an effective dose of at least one compound of formula (I) and / or its physiologically acceptable salts and / or his prodrugs as well that one or more pharmaceutically acceptable excipients, and optionally one or more usual additives.
Lorsqu'on utilise les composés de formule (I), les doses peuvent varier à l'intérieur de limites larges et doivent être fixées en fonction de la personne à traiter. Ceci dépend par exemple du composé employé ou de la nature et de la sévérité de la maladie à traiter et si on se trouve dans des conditions graves ou chronique ou si on met en oeuvre un traitement prophylactique. Les préparations pharmaceutiques (compositions pharmaceutiques) renferment normalement de 0,2 à 500mg, et de préférence de 1 à 200 mg de composé de formule (I) et/ou leurs sels physiologiquement acceptables et/ou leurs prodrugs . Dans le cas d'une administration par voie orale, la dose quotidienne varie en général de 0,01 à lOOmg/kg et de préférence de 0,1 à 50 mg/kg, en particulier de 0,1 à 5 mg/kg. Par exemple pour un adulte de 75kg on pourra envisager une dose quotidienne variant de 0,3 à 0,5 mg/kg. Dans le cas d'une administration par voie intraveineuse, la dose quotidienne varie approximativement de 0,01 à 100 mg/kg et de préférence de 0,05 à 10 mg/kg.When the compounds of formula (I) are used, the doses may vary within wide limits and must be fixed according to the person to be treated. This depends, for example, on the compound used or on the nature and severity of the disease to be treated and whether one is in severe or chronic conditions or whether one is implementing a prophylactic treatment. Pharmaceutical preparations (pharmaceutical compositions) normally contain from 0.2 to 500 mg, and preferably from 1 to 200 mg of compound of formula (I) and / or their physiologically acceptable salts and / or their prodrugs. In the case of oral administration, the daily dose generally varies from 0.01 to 100 mg / kg and preferably from 0.1 to 50 mg / kg, in particular from 0.1 to 5 mg / kg. For example, for an adult weighing 75 kg, a daily dose varying from 0.3 to 0.5 mg / kg could be considered. In the case of intravenous administration, the daily dose varies approximately from 0.01 to 100 mg / kg and preferably from 0.05 to 10 mg / kg.
La dose quotidienne peut être divisée, en particulier dans le cas de l'administration de grande quantité de principe actif, en plusieurs, par exemple 2,3 ou 4 parts. Le cas échéant, en fonction du comportement individuel, il peut être nécessaire d'administrer les différentes doses de manière croissante ou décroissante. Mise à part l'utilisation des composés de formule (I) comme médicaments, on peut également envisager leur utilisation comme véhicule ou support de composés actifs afin de transporter ces composés actifs de manière spécifique vers un site d'action (Drug targeting, voir Targeted Drug Delivery, R.C. Juliano, Handbook of Expérimental Pharmacology, Vol 100, Ed. Born, G.V.R. et al , Springer Verlag) . Les composés actifs qui peuvent être transportés sont en particulier ceux utilisés pour le traitement ou la prévention des maladies citées plus haut.The daily dose can be divided, in particular in the case of the administration of large amount of active ingredient, into several, for example 2,3 or 4 parts. If necessary, depending on individual behavior, it may be necessary to administer the different doses in an increasing or decreasing manner. Apart from the use of the compounds of formula (I) as medicaments, one can also envisage their use as vehicle or support for active compounds in order to transport these active compounds in a specific way towards a site of action (Drug targeting, see Targeted Drug Delivery, RC Juliano, Handbook of Experimental Pharmacology, Vol 100, Ed. Born, GVR et al, Springer Verlag). Active compounds that can be transported are in particular those used for the treatment or prevention of the diseases mentioned above.
Les composés de formule (I) et leurs sels peuvent également être employés comme agent de diagnostique, par exemple pour des méthodes in vitro ou comme auxiliaire dans des études biochimiques dans lesquelles on désire inhiber le domaine SRC SH2 humain. Ils peuvent en outre être utilisés comme intermédiaires pour la préparation d'autres composés, en particulier d'autres agents actifs, qui sont accessibles à partir des composés de formule (I) , par exemple par modification ou introduction de radicaux ou de groupes fonctionnels.The compounds of formula (I) and their salts can also be used as a diagnostic agent, for example for in vitro methods or as an aid in biochemical studies in which it is desired to inhibit the human SRC SH 2 domain. They can also be used as intermediates for the preparation of other compounds, in particular other active agents, which are accessible from the compounds of formula (I), for example by modification or introduction of radicals or functional groups.
Exemples Les produits ont été identifiés par spectre de masse (SM) , infrarouge (IR) , spectre RMN et / ou leur Rf .Examples The products have been identified by mass spectrum (MS), infrared (IR), NMR spectrum and / or their Rf.
Les composés qui ont été purifiés par chromatographie en utilisant un éluant qui contient par exemple de l'acide acétique ou trifuoroacétique et qui ensuite sont séchés ou dans lesquels lors de la dernière étape de synthèse, par exemple de l'acide trifluoroacetique a été utilisé pour éliminer un groupe protecteur tert-butyle, contiennent parfois, en fonction de la manière dont le produit a été séché, l'acide provenant de 1 ' éluant ou de la dernière étape de synthèse et donc se trouvent partiellement ou complètement sous la fortme du sel de l'acide utilisé, par exemple sous la forme d'un sel d'acide acétique ou trifluoroacetique . Ils peuvent également être plus ou moins hydratés.Compounds which have been purified by chromatography using an eluent which contains for example acetic or trifuoroacetic acid and which are then dried or in which during the last synthesis step, for example trifluoroacetic acid was used for remove a tert-butyl protecting group, sometimes contain, depending on how the product has been dried, the acid from the eluent or the last synthesis step and therefore are found partially or completely in the form of the salt of the acid used, for example in the form of a salt of acetic or trifluoroacetic acid. They can also be more or less hydrated.
Abbrévations/noms chimiques éventuellement employés :Abbreviations / chemical names possibly used:
AcOEt : acétate d' éthyle ; EDC : chlorhydrate de l-(3- diméthylaminopropyl) -3-éthyl-carbodiimide ; DMF : diméthylformamide ; DIC : diisopropylcarbodiimide ; HOBt : 1- hydroxybenzotriazole hydrate ; MeOH : méthanol ; TEA : triéthylamine ; TFA : acide trifluoroacetique ; THF : tétrahydrofurane ; MCPBA : acide méta-chloroperoxybenzoique ; DBU : 1, 8-diazabicyclo [5.4.0] undec-7-ene; DPPA : diphenylphosphorylazide; PPTS : acide Pyridinium paratoluène sulfonique ; DMSO : diméthylsulfoxyde ; Pd/C Palladium sur charbon ; Boc : terbutoxycarbonyl ; CBz : benzyloxycarbonyl ; DCC 1, 3-dicyclohexylcarbodiimide ; TMSBr : bromotriméthylsilane; TMSI : iodure de triméthylsilane. IR : Infrarouge ; RMN : Résonnance Magnétique Nucléaire ; SM : Spectre de Masse ; ESP : Electrospray mode positif ; ep. : Épaulement ; F : fort ; s : singulet ; d : doublet ; t :triplet ; quad : quadruplet ; quint : quintuplet ; 1: large ; m : multiplet ou massif; J : constante de couplage ; Rf : facteur de rétention (chromatographie) .AcOEt: ethyl acetate; EDC: 1- (3-dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride; DMF: dimethylformamide; DIC: diisopropylcarbodiimide; HOBt: 1- hydroxybenzotriazole hydrate; MeOH: methanol; TEA: triethylamine; TFA: trifluoroacetic acid; THF: tetrahydrofuran; MCPBA: meta-chloroperoxybenzoic acid; DBU: 1, 8-diazabicyclo [5.4.0] undec-7-ene; DPPA: diphenylphosphorylazide; PPTS: Pyridinium paratoluene sulfonic acid; DMSO: dimethyl sulfoxide; Pd / C Palladium on carbon; Boc: terbutoxycarbonyl; CBz: benzyloxycarbonyl; DCC 1, 3-dicyclohexylcarbodiimide; TMSBr: bromotrimethylsilane; TMSI: trimethylsilane iodide. IR: Infrared; NMR: Nuclear Magnetic Resonance; SM: Mass spectrum; ESP: Electrospray positive mode; ep. : Shoulder; F: strong; s: singlet; d: doublet; t: triplet; quad: quadruplet; quint: quintuplet; 1: wide; m: multiplet or massive; J: coupling constant; Rf: retention factor (chromatography).
Préparation 1 : (S) - [1- [ [4- [ [bis (phénylméthoxy) phosphinyl] oxy) phényl] méthyl] -2-[[2,3,4, 5-tétrahydro-2- (4-methoxyphényl) 4-oxo-l , 5-benzothiazépin-3-yl] amino] -2-oxoéthyl] - carbamate de 1, 1-diméthyléthyle.Preparation 1: (S) - [1- [[4- [[bis (phenylmethoxy) phosphinyl] oxy) phenyl] methyl] -2 - [[2,3,4,5-tetrahydro-2- (4-methoxyphenyl) 4-oxo-1,5-benzothiazepin-3-yl] amino] -2-oxoethyl] - 1,1-dimethylethyl carbamate.
FG (III'): Ri et R2 forment ensemble un Phenyle; R3 = Ph-OMe, R4 = H, X = O, [Ai] = -CH(Z)-CH2-Ph-; A2= OPO(OBn)2 FG (III '): Ri and R 2 together form a Phenyle; R 3 = Ph-OMe, R 4 = H, X = O, [Ai] = -CH (Z) -CH 2 -Ph-; A 2 = OPO (OBn) 2
Préparation la : isomère trans 1Preparation la: trans isomer 1
Préparation lb : isomère trans 2Preparation lb: trans isomer 2
Préparation le : isomère cis 1 Préparation ld : isomère cis 2Preparation le: cis isomer 1 Preparation ld: cis isomer 2
On mélange pendant 15 minutes à 0°C sous argon le mélange constitué de 384,4 mg de O- [bis (phénylméthoxy) phosphinyl] -N- [ (1, 1-diméthyléthoxy) carbonyl] -L-tyrosine, 123,4 mg de chlorhydrate de [1- (3-diméthylaminopropyl) -3-éthyl- carbodiimide] (EDC) et 86,9 mg de (1-hydroxybenzothiazole hydrate) (HOBt) dans 425μl de diméthylformamide (DMF) et 1,3 ml de dichlorométhane (CH2C12) et ajoute une solution de 161 mg de 2, 3, 4, 5-tetrahydro-3-amino-2- (4-methoxyphényl) -4-oxo- 1, 5-benzothiazépine (d,l trans + 10% d, 1 cis) dans 6 ml de CH2C12 sec et refroidit à 0°C. Le mélange est agité à température ambiante pendant 3 heures, puis est dilué dans 15 ml d'acétate d' éthyle puis après lavage, et séchage, la phase organique est évaporée sous pression réduite pour obtenir 443mg de produit brut que l'on purifie par chromatographie sur silice en éluant avec un mélange dichlorométhane/acétate d' éthyle 7/3. On isole ainsi 4 fractionsThe mixture consisting of 384.4 mg of O- [bis (phenylmethoxy) phosphinyl] -N- [(1,1-dimethylethoxy) carbonyl] -L-tyrosine, 123.4 is mixed for 15 minutes at 0 ° C. under argon. mg of [1- (3-dimethylaminopropyl) -3-ethyl-carbodiimide] hydrochloride (EDC) and 86.9 mg of (1-hydroxybenzothiazole hydrate) (HOBt) in 425 μl of dimethylformamide (DMF) and 1.3 ml of dichloromethane (CH 2 C1 2 ) and adds a solution of 161 mg of 2, 3, 4, 5-tetrahydro-3-amino-2- (4-methoxyphenyl) -4-oxo 1, 5-benzothiazepine (d, l trans + 10% d, 1 cis) in 6 ml of CH 2 C1 2 sec and cools to 0 ° C. The mixture is stirred at room temperature for 3 hours, then is diluted in 15 ml of ethyl acetate then after washing, and drying, the organic phase is evaporated under reduced pressure to obtain 443 mg of crude product which is purified by chromatography on silica, eluting with a dichloromethane / ethyl acetate mixture 7/3. We thus isolate 4 fractions
Pic = = 10, 9 mg Rf CH2Cl2/AcOEt 0,41 Isomère Cis 1Peak = = 10.9 mg Rf CH 2 Cl 2 / AcOEt 0.41 Cis Isomer 1
Pld = = 10,4 mg Rf CH2Cl2/AcOEt 0,30 Isomère Cis 2 Pla = = 118,5 mg Rf CH2Cl2/AcOEt 0,24 Isomère Trans 1Pld = = 10.4 mg Rf CH 2 Cl 2 / AcOEt 0.30 Cis 2 Isomer Pla = = 118.5 mg Rf CH 2 Cl 2 / AcOEt 0.24 Trans 1 Isomer
Plb = = 20 mg Rf CH2Cl2/AcOEt 0,14 Isomère Trans 2Plb = = 20 mg Rf CH 2 Cl 2 / AcOEt 0.14 Trans 2 isomer
Préparation le : [2S- [3 (S*) ,2α,3α] ]- [1- [ [4- [ [bis (phénylméthoxy) phosphinyl] oxy) phényl] méthyl] -2- [ [-2- (4-méthoxy- phényl) -4-oxo 2,3,4, 5-tétrahydro-l , 5-benzothiazépin-3-yl] amino] -2-oxoéthyl] -carbamate de 1 , 1-diméthyléthyle .Preparation on: [2S- [3 (S *), 2α, 3α]] - [1- [[4- [[bis (phenylmethoxy) phosphinyl] oxy) phenyl] methyl] -2- [[-2- (4 -methoxyphenyl) -4-oxo 2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] amino] -2-oxoethyl] -carbamate of 1,1-dimethylethyl.
RMN (CDC13) Isomère Cis 1NMR (CDC1 3 ) Cis 1 Isomer
1,41 (s) C(CH3)3; 2,66 (dd) 2,97 (dd) CH (NHBoc) -CH2-Ph; 3,78 (s) CH3O; 4,04 (m) CH (NHBoc) -CH2-Ph; 5,10 à 5,25 (m) (5H) S- CH-Ph (H2 du cycle) et NH-CO; 4,60 (t, J=7)) CO-CH-N (H3 du cycle); 4,94 Ph-CH2-0-P; 6,79, 7,00 et 7,25 (AA'BB'); 7,17 à 7,45 (m) 12H aromatiques.1.41 (s) C (CH 3 ) 3 ; 2.66 (dd) 2.97 (dd) CH (NHBoc) -CH 2 -Ph; 3.78 (s) CH 3 O; 4.04 (m) CH (NHBoc) -CH 2 -Ph; 5.10 to 5.25 (m) (5H) S-CH-Ph (cycle H2) and NH-CO; 4.60 (t, J = 7)) CO-CH-N (H3 of the ring); 4.94 Ph-CH 2 -0-P; 6.79, 7.00 and 7.25 (AA'BB '); 7.17 to 7.45 (m) 12H aromatic.
Préparation ld : [2R- [3 (S*) ,2α,3α] ] - [1- [ [4- [ [bis (phényl- méthoxy) phosphinyl] oxy) phényl] méthyl] -2- [ [2- (4-méthoxy- phényl) -4-oxo 1,2 ,3, 4-l,5-benzothiazépin-3-yl] amino] -2- oxoéthyl] carbamate de 1, 1-diméthyléthyle.Preparation ld: [2R- [3 (S *), 2α, 3α]] - [1- [[4- [[bis (phenyl-methoxy) phosphinyl] oxy) phenyl] methyl] -2- [[2- ( 4-methoxyphenyl) -4-oxo 1,2,3,4-1,5-benzothiazepin-3-yl] amino] -2-oxoethyl] 1,1-dimethylethyl carbamate.
RMN (CDCI3) Isomère Cis 2NMR (CDCI 3 ) Cis 2 Isomer
1,28 (s) C(CH3)3, 2,72 (d, J=5) CH (N) -CH2-Ph; 3,76 (s) CH30; 4,43 (m) CH (N) -CH2-Ph; 5,07 à 5,20 (m) (5H) S-CH-Ph (cycle) et Ph-CH2-0-P; 4,86(t, J=7) CO-CH-N (cycle); 6,83, 7,00 et 7,30 2 (AA'BB') ; 7,10 à 7,42 (m) 12H et 7,69 (dd) aromatiques; 6,35 (m large) et 8,30 (s large) 2NHCO Préparation la : [2S- [3 (S*) ,2α,3β] ]- [1- [ [4- [ [bis (phénylméthoxy) phosphinyl] oxy) phényl] méthyl] -2- [ [2- (4- méthoxyphényl) -4-oxo-2 ,3,4, 5-tétrahydro-l , 5-benzothiazépin-3- yl] amino] -2-oxoéthyl] -carbamate de 1, 1-diméthyléthyle.1.28 (s) C (CH 3 ) 3 , 2.72 (d, J = 5) CH (N) -CH 2 -Ph; 3.76 (s) CH 3 0; 4.43 (m) CH (N) -CH 2 -Ph; 5.07 to 5.20 (m) (5H) S-CH-Ph (cycle) and Ph-CH 2 -0-P; 4.86 (t, J = 7) CO-CH-N (cycle); 6.83, 7.00 and 7.30 2 (AA'BB '); 7.10 to 7.42 (m) 12H and 7.69 (dd) aromatics; 6.35 (m wide) and 8.30 (s wide) 2NHCO Preparation la: [2S- [3 (S *), 2α, 3β]] - [1- [[4- [[bis (phenylmethoxy) phosphinyl] oxy) phenyl] methyl] -2- [[2- (4- methoxyphenyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] amino] -2-oxoethyl] -carbamate of 1,1-dimethylethyl.
RMN (CDC13) Isomère Trans 1NMR (CDC1 3 ) Trans 1 isomer
1,42 (s) (CH3)3;2,50 (dd) 2,95 (m) H(N)-CH2-Ph; 3,78 (s)CH30; CH(N)-CH2-Ph; 3,93 (m) -CH-Ph (cycle); ,37 t, J=7))-C0-CH- N(cycle) ;4,70 à 5,34 (m) Ph-CH2-0-P; 6,35 à 7,46 (m) (24H) , 7,67 (m) (1H) aromatique.1.42 (s) (CH 3 ) 3 ; 2.50 (dd) 2.95 (m) H (N) -CH 2 -Ph; 3.78 (s) CH 3 0; CH (N) -CH 2 -Ph; 3.93 (m) -CH-Ph (cycle); , 37 t, J = 7)) - C0-CH- N (cycle); 4.70 to 5.34 (m) Ph-CH 2 -0-P; 6.35 to 7.46 (m) (24H), 7.67 (m) (1H) aromatic.
Préparation lb : [2R- [3 (S*) ,2α,3β] ]- [1- [ [4- [ [bis (phénylméthoxy) phosphinyl] oxy) phényl] méthyl] -2- [ [2- (4- méthoxyphényl) -4-oxo-2 ,3,4 , 5-tétrahydro-l , 5-benzothiazépin-3- yl] amino] -2-oxoéthyl] -carbamate de 1 , 1-diméthyléthyle. RMN (CDCI3) Isomère Trans 2Preparation lb: [2R- [3 (S *), 2α, 3β]] - [1- [[4- [[bis (phenylmethoxy) phosphinyl] oxy) phenyl] methyl] -2- [[2- (4- methoxyphenyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] amino] -2-oxoethyl] -carbamate of 1,1-dimethylethyl. NMR (CDCI 3 ) Trans 2 isomer
1,33 (s) C(CH3)3; 2,57 (m large)) 2,79 (dd large) CH(N)-CH2- Ph; 3,75 (s) CH30;4,59 (m, large) CH (N) -CH2-Ph; 5,02 (dd, J=ll,5 et 8) S-CH-Ph (cycle) ; 4,35 (d, J=ll, 5) CO-CH-N (cycle); 5,09 (m) Ph-CH2-0-P; 6,78 à 7,45 (m) (24H) , 7,65 (dl) (1H) (aromatique) ; 4,88 (dl) 1H mobile; 8,58 (s large 1H mobile)1.33 (s) C (CH 3 ) 3 ; 2.57 (m wide)) 2.79 (dd wide) CH (N) -CH 2 - Ph; 3.75 (s) CH 3 0; 4.59 (m, broad) CH (N) -CH 2 -Ph; 5.02 (dd, J = 11.5 and 8) S-CH-Ph (cycle); 4.35 (d, J = 11.5) CO-CH-N (ring); 5.09 (m) Ph-CH 2 -0-P; 6.78 to 7.45 (m) (24H), 7.65 (dl) (1H) (aromatic); 4.88 (dl) 1H mobile; 8.58 (s large 1H mobile)
Préparation 2 : (R) - (4-oxo-2 ,3,4,5-tétrahydro-l ,5-benzothia- zépin-3-yl) -carbamate de phénylméthyle (P2)Preparation 2: (R) - (4-oxo-2,3,4,5-tetrahydro-1,5-benzothia-zepin-3-yl) -phenylmethylcarbamate (P2)
FG (II) : Ri et R2 forment ensemble un Phenyle; R3 = R4 = H, X = O, (NH2 protégé :NHC02Bn)FG (II): Ri and R 2 together form a Phenyle; R 3 = R 4 = H, X = O, (NH 2 protected: NHC0 2 Bn)
Stade A : S- (2-nitrophényl) -L-cystéine .Stage A: S- (2-nitrophenyl) -L-cysteine.
A une solution de 8,52 g de L cystéine dans 35,6 l'eau on ajoute, sous argon, une solution de 1-fluoro-2-nitro-benzène dans 118ml d'éthanol et agite au reflux pendant 4 heures. Après filtration et concentration du filtrat, on dilue avec de l'eau, extrait avec de 1 ' ether et acidifie à pH 1 avec de l'acide chlorhydrique 12N. On obtient 12,06 g de produit brut attendu. Stade B protection de l'aminé : S- (2-nitrophényl) -N- [[ (phényl) méthoxy] carbonyl] -L-cystéine.To a solution of 8.52 g of L cysteine in 35.6 water is added, under argon, a solution of 1-fluoro-2-nitro-benzene in 118 ml of ethanol and stirred at reflux for 4 hours. After filtration and concentration of the filtrate, diluted with water, extracted with ether and acidified to pH 1 with 12N hydrochloric acid. 12.06 g of expected crude product are obtained. Amine protection stage B: S- (2-nitrophenyl) -N- [[(phenyl) methoxy] carbonyl] -L-cysteine.
On dissout 6g du produit obtenu au stade précédent dans 12 ml de soude 2N à 0-5 °C sous argon, ajoute 6 ml de soude 4N ainsi que 4,2g de benzylchloroformate et agite 20 heures à température ambiante. Après extraction avec de l'ether et acidification avec de l'acide chlorhydrique 12N, on obtient 17,9 g de produit brut (huile) attendu. Stade C Réduction du groupe nitro : S- (2-aminophényl) -N- [[(phényl) méthoxy] carbonyl] -L-cystéine .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 are added, as well as 4.2 g of benzylchloroformate 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 expected crude product (oil) are obtained. Stage C Reduction of the nitro group: S- (2-aminophenyl) -N- [[(phenyl) methoxy] carbonyl] -L-cysteine.
On agite pendant 5 heures au reflux puis 1 nuit à température ambiante le mélange constitué de 150 mg de produit obtenu au stade précédent, 440 mg de chlorure d'ammonium, 7,5 ml de méthanol et 3,5 mg de poudre de Zn activé. On obtient après traitement 90 mg de produit brut attendu.The mixture consisting of 150 mg of 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 at reflux and then 1 night at room temperature. . After treatment, 90 mg of expected crude product is obtained.
Stade D Cyclisation : (R) - (4-oxo-2, 3, 4, 5-tétrahydro-l, 5- benzothiazépin-3-yl) -carbamate de phénylméthyle . On dissout 4,01 g de produit obtenu au stade précédent dans 50 ml de DMF, ajoute 2,22 mg d'EDC, agite 4 heures sous argon à température ambiante et dilue le mélange réactionnel dans 100 ml d'acétate d' éthyle. Après traitement on obtient 2 mg de produit brut (Rf CH2Cl2/AcOEt 90/10 = 0,32)Stage D Cyclization: (R) - (4-oxo-2, 3, 4, 5-tetrahydro-1,5,5-benzothiazepin-3-yl) -phenylmethylcarbamate. 4.01 g of product obtained in the preceding stage is dissolved in 50 ml of DMF, 2.22 mg of EDC is 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 are obtained (Rf CH 2 Cl 2 / AcOEt 90/10 = 0.32)
Préparation 3 : (S) - (2 ,3,4,5-tétrahydro-4-oxo-l,5-benzothia- zépin-3-yl) -carbamate de phénylméthyle (P3)Preparation 3: (S) - (2, 3,4,5-tetrahydro-4-oxo-1,5, benzothia-zepin-3-yl) -phenylmethylcarbamate (P3)
FG (II) : Ri et R2 forment ensemble un Phenyle; R3 = R4 = H, X = O, (NH2 protégé :NHC02Bn)FG (II): Ri and R 2 together form a Phenyle; R 3 = R 4 = H, X = O, (NH 2 protected: NHC0 2 Bn)
On opère comme décrit à la préparation 2 stades A à D mais à partir de 1,9 g de D-cystéine. On obtient 433 mg de produit pur attendu.The procedure is as described in the preparation 2 stages A to D but from 1.9 g of D-cysteine. 433 mg of expected pure product is obtained.
Préparation 4 : trans (±) -3-amino-2- (4-methoxyphényl) -2,3,4,5- tétrahydro-N- [ (naphtalenyl) méthyl] -4-oxo-l , 5-benzothiazépine -5 (2H) -acétamide (P4) FG (III") : Ri et R2 forment ensemble un Phenyle; R3 = -Ph- OMe; R4 = H; X = O, R5 = -CH2CONHCH2-NaphtylePreparation 4: trans (±) -3-amino-2- (4-methoxyphenyl) -2,3,4,5- tetrahydro-N- [(naphthalenyl) methyl] -4-oxo-1,5-benzothiazepine -5 (2H) -acetamide (P4) FG (III "): Ri and R 2 together form a Phenyle; R 3 = -Ph- OMe; R 4 = H; X = O, R 5 = -CH 2 CONHCH 2 -Naphthyle
N-alkylation A une solution de 3,7 g de trans (±) - [2- (4-méthoxyphényl) -4- oxo-2, 3, 4, 5-tétrahydro-l, 5-benzothiazépin-3-yl] -carbamate de phénylméthyle dans 50 ml de DMF, à une température de 0°C, on ajoute 613 mg de d'hydrure de sodium à 50% et 2,84 g de N-(l- naphtylmethyl) -bromoacétamide, agite 3 heures en laissant la température revenir à environ 20°C, puis coule dans de l'eau glacée et filtre. On obtient 5,85g d'aminé protégée. DéprotectionN-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] -phenylmethyl carbamate in 50 ml of DMF, at a temperature of 0 ° C., 613 mg of 50% sodium hydride and 2.84 g of N- (1-naphthylmethyl) -bromoacetamide are added, stirred for 3 hours letting the temperature return to around 20 ° C, then run into ice water and filter. 5.85 g of protected amine are obtained. Protection
On "fait buller" de l'acide chlorhydrique gazeux dans une suspension de 5,85 g du produit obtenu au stade précédent dans 85 ml d'acide acétique, sous agitation à 110°C et maintient cette température 19 heures. On évapore ensuite sous pression réduite, ajoute du dichlorométhane, lave avec du bicarbonate de sodium et extrait la phase aqueuse avec du dichlorométhane. Après évaporation sous pression réduite on obtient 4,4 g de produit brut attendu que l'on purifie par chromatographie en éluant avec le mélange dichlorométhane- /méthanol 99/1 puis 98/2 puis 95/5 pour obtenir 3,5 g de produit attendu. RMN (CDC13) Isomère Trans 1 3,59 (d,J=ll) H3 (trans/H2); 4,14 (m) 2H N-CH2-C=; 4,80 (m) (3H) =C-N-CH2-C=; 6,83 7,80 (AA'BB') C-Ph-O; 7,31 (dt) 1H, 7,45 à 7,58 (7H) , 7,86 (m) 1H, 7,96, 8,05 Aromatiques et =C- NH; 8,53 (t) =C-NH-CH2. Préparation 5 : (R) -3-amino-5- (3-cyclohexylpropyl) -2 ,3-dihy- dro-l,5-benzothiazépin-4 (5H) -one (P5)Gaseous hydrochloric acid is "bubbled" in 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, added to dichloromethane, washed with sodium bicarbonate and the aqueous phase is extracted with dichloromethane. After evaporation under reduced pressure, 4.4 g of expected crude product are obtained, which product is purified by chromatography, eluting with a dichloromethane / methanol mixture 99/1 then 98/2 then 95/5 to obtain 3.5 g of product. expected. NMR (CDC1 3 ) Trans 1 isomer 3.59 (d, J = 11) H3 (trans / H2); 4.14 (m) 2H N-CH 2 -C =; 4.80 (m) (3H) = CN-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 Aromatics and = C-NH; 8.53 (t) = C-NH-CH 2 . Preparation 5: (R) -3-amino-5- (3-cyclohexylpropyl) -2, 3-dihy- dro-1,5, benzothiazepin-4 (5H) -one (P5)
FG (III") : Ri et R2 forment ensemble un Phenyle; R3= R4 = H;X = 0, R5 = - (CH2) 3-cyclohexyleFG (III "): Ri and R 2 together form a Phenyl; R 3 = R 4 = H; X = 0, R 5 = - (CH 2 ) 3 -cyclohexyl
N-alkylation A une solution de 500 mg de P2 dans le diméthylformamide à 0°C sous atmosphère inerte on ajoute 90 mg d'hydroxyde de sodium à 60% puis 454 mg de l-iodo-3-cyclohexylpropyle agite à 0°C pendant 15 mn et à température ambiante pendant 2 heures. On coule dans de l'eau glacée, extrait avec de l'acétate d1 éthyle, sèche et évapore sous pression réduite jusqu'à obtention de 733 mg de produit brut attendu que l'on engage directement dans l'étape suivant Déprotection A une solution de 733 mg du produit obtenu au stade précédent dans 10 ml d'acide acétique, on "fait buller" de l'acide chlorhydrique gazeux sous agitation à 110°C et laisse sous agitation à cette température 12 heures. On évapore ensuite sous pression réduite, ajoute du dichlorométhane, lave avec du bicarbonate de sodium et extrait la phase aqueuse avec du dichlorométhane. Après évaporation sous pression réduite on obtient 520 mg de produit brut attendu que l'on purifie par chromatographie en éluant avec le mélange dic- hlorométhane/acétate d' éthyle 90/10 puis 80/20 puis dichloro- méthane/méthanol 90/10 pour obtenir 114 mg + 137 mg de produit brut. RMN (CDC13)N-alkylation To a solution of 500 mg of P2 in dimethylformamide at 0 ° C under an inert atmosphere is added 90 mg of sodium hydroxide at 60% then 454 mg of l-iodo-3-cyclohexylpropyl stirred at 0 ° C for 15 min and at room temperature for 2 hours. Poured into ice water, extracted with ethyl acetate 1, dried and evaporated under reduced pressure until 733 mg of expected crude product is used directly in the following step Deprotection To a solution of 733 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 left stirring at this temperature for 12 hours. It is then evaporated under reduced pressure, added to dichloromethane, washed with sodium bicarbonate and the aqueous phase is extracted with dichloromethane. After evaporation under reduced pressure, 520 mg of expected crude product is obtained which is purified by chromatography, eluting with a dichloromethane / ethyl acetate mixture 90/10 then 80/20 then dichloromethane / methanol 90/10 for obtain 114 mg + 137 mg of crude product. NMR (CDC1 3 )
0,82 (m) 1,00 à 1,30 (m) 1,40 à 1,80 (m) 18H Chaîne alkyle + 2H mobiles; 4,83 (t,J=10) IH 3,32 à 3,60 (m) CH2 en 2 et H3; 3,22 à 3,60 (masqué) IH 4,23 (m) IH CO-N-CH2-CH2; 7,15 à 7,30 (m) 2H, 7,43 (m) IH, 7,65 (dd) IH H aromatiques0.82 (m) 1.00 to 1.30 (m) 1.40 to 1.80 (m) 18H Movable alkyl chain + 2H; 4.83 (t, J = 10) 1H 3.32 to 3.60 (m) CH 2 in 2 and H3; 3.22-3.60 (masked) 1H 4.23 (m) 1H CO-N-CH 2 -CH 2 ; 7.15 to 7.30 (m) 2H, 7.43 (m) IH, 7.65 (dd) IH H aromatic
Préparation 6 : (R) -3-amino-5- (4-cyclohexylbutyl) -2 ,3- dihydro-1 , 5-benzothiazépin-4 (5H) -one . (P6)Preparation 6: (R) -3-amino-5- (4-cyclohexylbutyl) -2, 3-dihydro-1, 5-benzothiazepin-4 (5H) -one. (P6)
FG (III" ) : Ri et R2 forment ensemble un Phenyle ; R3 = R4 = H ;X = O , R5 = - (CH2) 4-cyclohexyleFG (III "): Ri and R 2 together form a Phenyle; R 3 = R 4 = H; X = O, R 5 = - (CH 2 ) 4 -cyclohexyl
AlkylationAlkylation
A une solution de 403,4 mg de l'aminé protégée P2 Dans 6 ml de DMF, à une température de 0°C, on ajoute 74 mg de d'hydrure de sodium à 50% et 393 mg de l-iodo-4- cyclohexylbutyle, agite 3 heures en laissant la température revenir à environ 20°C, puis coule dans de l'eau glacée et filtre. On obtient 818 mg de produit attendu. DéprotectionTo a solution of 403.4 mg of the protected amine P2 In 6 ml of DMF, at a temperature of 0 ° C., 74 mg of 50% sodium hydride and 393 mg of l-iodo-4-cyclohexylbutyl, stir for 3 hours, allowing the temperature to return to about 20 ° C, then pour into ice water and filter. 818 mg of expected product is obtained. Protection
A une solution de 818 mg du produit obtenu au stade précédent dans 10 ml d'acide acétique, on "fait buller" de l'acide chlorhydrique gazeux sous agitation à 110°C et laisse sous agitation à cette température 4 heures. On évapore ensuite sous pression réduite, ajoute du dichlorométhane, lave avec du bicarbonate de sodium et extrait la phase aqueuse avec du dichlorométhane. Après évaporation sous pression réduite on obtient 413 mg de produit brut attendu que l'on purifie par chromatographie en éluant avec le mélange dichlorométhane/mé- thanol 99/1, 98,5/1,5 puis 98/2 pour obtenir 130,2 mg de produit attendu. RMN (CDC13)A solution of 818 mg of the product obtained in the preceding stage in 10 ml of acetic acid is "bubbled" with gaseous hydrochloric acid with stirring at 110 ° C and allowed to stir at this temperature for 4 hours. It is then evaporated under reduced pressure, added to dichloromethane, washed with sodium bicarbonate and the aqueous phase is extracted with dichloromethane. After evaporation under reduced pressure, 413 mg of expected crude product is obtained which is purified by chromatography, eluting with a dichloromethane / methanol mixture 99/1, 98.5 / 1.5 and then 98/2 to obtain 130.2 mg of expected product. NMR (CDC1 3 )
0,81 (m) 1,00 à 1,75 (m) 20H Chaîne alkyle; 4,82 (m) IH 3,38 à 3,56 (m) 2H CH2 en 2 et H3; 3,38 à 3,56 (masqué) IH 4,32 (m) IH CO-N-CH2-CH2; 7,21 (dt) 7,43 (dt) H7 H8 7,28 (dd) 7,64 (dd) H6 H90.81 (m) 1.00 to 1.75 (m) 20H Alkyl chain; 4.82 (m) IH 3.38 to 3.56 (m) 2H CH 2 in 2 and H3; 3.38 to 3.56 (masked) 1H 4.32 (m) 1H CO-N-CH 2 -CH 2 ; 7.21 (dt) 7.43 (dt) H7 H8 7.28 (dd) 7.64 (dd) H6 H9
Préparation 7 : cis (±) -3-amino-5- (3-cyclohexylpropyl) -2 , 3- dihydro-2- (4 -methoxyphényl) -l , 5-benzothiazépin-4 (5H) -one . (P7)Preparation 7: cis (±) -3-amino-5- (3-cyclohexylpropyl) -2, 3- dihydro-2- (4-methoxyphenyl) -1,5-benzothiazepin-4 (5H) -one. (P7)
FG (III") : Ri et R2 forment ensemble un Phenyle; R3 = PhOMe;FG (III "): Ri and R 2 together form a Phenyle; R 3 = PhOMe;
R4 = H; X = O, R5 = -(CH2)3-cyclohexyle (cis d,l)R 4 = H; X = O, R 5 = - (CH 2 ) 3 -cyclohexyl (cis d, l)
AlkylationAlkylation
A une solution de 1,01 g de cis (±) - [ (2- (4-methoxyphényl) -4- oxo-2, 3, 4, 5-tétrahydro-l, 5-benzothiazépin-3-yl] -carbamate de phénylméthyle dans 10 ml de DMF, à une température de 0°C, on ajoute 140 mg de d'hydrure de sodium à 50% et 705 mg de 1- iodo-3-cyclohexylpropyle, agite 3 heures en laissant la température revenir à environ 20°C, puis coule dans de l'eau glacée et filtre. On obtient 1,52 g de produit attendu. DéprotectionTo a solution of 1.01 g of cis (±) - [(2- (4-methoxyphenyl) -4- oxo-2, 3, 4, 5-tetrahydro-1,5, benzothiazepin-3-yl] -carbamate of phenylmethyl in 10 ml of DMF, at a temperature of 0 ° C., 140 mg of 50% sodium hydride and 705 mg of 1-iodo-3-cyclohexylpropyl are added, stirred for 3 hours while allowing the temperature to return to about 20 ° C, then run into ice water and filter to obtain 1.52 g of the expected product. Protection
On "fait buller" de l'acide chlorhydrique gazeux sous agitation à 110°C dans une solution de 1,5 mg du produit obtenu au stade précédent dans 15 ml d'acide acétique, et laisse sous agitation à cette température 4 heures. On évapore ensuite sous pression réduite, ajoute du dichlorométhane, lave avec du bicarbonate de sodium et extrait la phase aqueuse avec du dichlorométhane. Après évaporation sous pression réduite on obtient 413 mg de produit brut attendu que l'on purifie par chromatographie en éluant avec le mélange dichloro- méthane/méthanol 99/1, 98,5/1,5 puis 98/2 pour obtenir 747 mg de produit attendu.Gaseous hydrochloric acid is "bubbled" with stirring at 110 ° C. in a solution of 1.5 mg of the product obtained in the preceding stage in 15 ml of acetic acid, and left stirring at this temperature for 4 hours. It is then evaporated under reduced pressure, added to dichloromethane, washed with sodium bicarbonate and the aqueous phase is extracted with dichloromethane. After evaporation under reduced pressure, 413 mg of expected crude product is obtained which is purified by chromatography, eluting with a dichloromethane / methanol mixture 99/1, 98.5 / 1.5 and then 98/2 to obtain 747 mg of expected product.
RMN (CDC13)NMR (CDC1 3 )
0,84 (m) 2H 1,02 à 1,35 (m) 6H 1,65 (m) 7H (cycloalkyl) alkyle; 1,33 (m large) 2H mobiles, 3,50 (m) 4,43 (m) CO-N-CH2-CH2; 3,82 (s) Ph-OMe; 3,70 (d,J=7) H3, 4,77 (d,J=7) H2, 6,90 et 7,41 (AA'BB'); 7,25 (dt) 7,45 (dt) H7 H8 7,32(dd) 7,70 (dd) H6 H9.0.84 (m) 2H 1.02 to 1.35 (m) 6H 1.65 (m) 7H (cycloalkyl) alkyl; 1.33 (m wide) 2H mobile, 3.50 (m) 4.43 (m) CO-N-CH 2 -CH 2 ; 3.82 (s) Ph-OMe; 3.70 (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.
Préparation 8 : (R) -6-amino-tétrahydro-l,4-thiazépin-5 (2H) - one (P8)Preparation 8: (R) -6-amino-tetrahydro-1,4-thiazepin-5 (2H) - one (P8)
FG (II) :Rι=R2=R3=R4=H, le trait en pointillé ne représente pas une double liaison, X = O A une solution de 2g de chlorhydrate de l'ester methylique de la L-cystéine dans 20 ml de méthanol, on ajoute 9,9 ml de triéthylamine et 2g de chlorhydrate du l-amino-2-chloroéthyle et chauffe au reflux pendant 16 heures. Après traitement et purification par chromatographie en éluant avec un mélange CH2Cl2/MeOH variant de 99/1 à 90/10 on obtient 250 mg de produit pur sous forme de sel d'acide chlorhydrique. IR (CHCI3)FG (II): Rι = R 2 = R 3 = R 4 = H, the dotted line does not represent a double bond, X = OA a solution of 2g of hydrochloride of the methyl ester of L-cysteine in 20 ml of methanol, 9.9 ml of triethylamine and 2 g of 1-amino-2-chloroethyl hydrochloride are added and the mixture is heated at reflux for 16 hours. After treatment and purification by chromatography, eluting with a CH 2 Cl 2 / MeOH mixture varying from 99/1 to 90/10, 250 mg of pure product are obtained in the form of the hydrochloric acid salt. IR (CHCI3)
Absorption région OH/NH : 3181 cm-1 C=0 1662 cm-1, NH3 + 1601 cm"1, 1564 cm-1. L'aminé P8 sous forme protégée (NHBoc), est préparée par action préalable de (Boc)20 sur la L-cyctéine (ester methylique) dans le CH2C12 en présence de TEA. Préparation 9 : (R) -6-amino 4- (3-cyclohexylpropyl) -6,7- dihydro-l,4-thiazépin-5(2H)-one (P9)OH / NH region absorption: 3181 cm -1 C = 0 1662 cm -1 , NH 3 + 1601 cm "1 , 1564 cm -1 . The amine P8 in protected form (NHBoc) is prepared by the prior action of (Boc) 2 0 on L-cycteine (methyl ester) in CH 2 C1 2 in the presence of TEA. Preparation 9: (R) -6-amino 4- (3-cyclohexylpropyl) -6,7- dihydro-1,4-thiazepin-5 (2H) -one (P9)
FG (III") :Rι=R2=R3=R4 = H, le trait en pointillé représente une double liaison, X=0, R5 = (cyclophexyl) propyle- a) Protection de 5,0 g de chlorhydrate de l'ester methylique de la L-cystéine par action de 6,54 g de (Boc)2 en présence de 4,15 ml de TEA dans 60ml CH2C12. b) Alkylation du thiol (lg) par action de lg de 2-bromo 1,1- diéthoxyéthane dans 10 ml de DMF en présence de 245 mg d'hydrure de sodium. c) Saponification de l'ester (350 mg) par action de 50 mg d'hydroxyde de lithium dans le THF à température ambiante. d) Amidification de l'acide (200 mg) par action de 150 mg d'hydroxyde d'ammonium à 20% dans 5 ml de THF en présence de 121 mg d'HOBt, 171 mg d'EDC, et de 90 mg de N- méthylmorpholine. e) Cyclisation par chauffage de 1 ' amide (135 mg) obtenue au stade précédent dans 5 ml de toluène au reflux avec un Dean- Stark pour éliminer l'éthanol formé. f) alkylation de l'aminé obtenue au stade précédent (72 mg) par action de 76 mg de l-iodo-3- (cyclohexyl) propyle en présence d'hydrure de sodium dans le DMF g) Déprotection de 100 mg de l'aminé obtenue au stade précédent afin d'obtenir l'aminé libre par action de 2 ml de d'anhydride trifluoroacetique dans 2 ml de CH2C12. On obtient 158 mg de produit attendu (Rf CH2Cl2/MeOH 95/5 = 0,25)FG (III "): Rι = R 2 = R 3 = R 4 = H, the dotted line represents a double bond, X = 0, R 5 = (cyclophexyl) propyl- a) Protection of 5.0 g of hydrochloride of the methyl ester of L-cysteine by the action of 6.54 g of (Boc) 2 in the presence of 4.15 ml of TEA in 60 ml CH 2 C1 2. b) Alkylation of thiol (lg) by action of lg of 2-bromo 1,1-diethoxyethane 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 to room temperature d) Amidation 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-methylmorpholine e) Cyclization by heating of the amide (135 mg) obtained in the preceding stage in 5 ml of toluene at reflux with a Dean-Stark to remove the ethanol formed f) alkylation of the amine obtained in the previous stage (72 mg) per action of 76 mg of l-iodo-3- (cycl ohexyl) 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 C1 2 . 158 mg of expected product are obtained (Rf CH 2 Cl 2 / MeOH 95/5 = 0.25)
Préparation 10 : (S) -3-amino-5- (3-cyclohexylpropyl) -2 ,3- dihydro-1 , 5-benzothiazépin-4 (5H) -one . (P10) FG (III") : Ri et R2 forment ensemble un Phenyle; R3=R4=H; X = O, R5 = - (CH2) 3-cyclohexylePreparation 10: (S) -3-amino-5- (3-cyclohexylpropyl) -2, 3-dihydro-1, 5-benzothiazepin-4 (5H) -one. (P10) FG (III "): Ri and R 2 together form a Phenyl; R 3 = R 4 = H; X = O, R 5 = - (CH 2 ) 3 -cyclohexyl
On opère comme à la préparation 5 mais à partir de 483 mg de produit obtenu à la préparation 3 (S- (2, 3, 4, 5-tétrahydro-4- oxo-1, 5-benzothiazépin-3-yl) -carbamate de phénylméthyle) et 483 mg de l-iodo-3- (cyclohexyl) propyle puis on déprotège par action d'acide chlorhydrique gazeux pendant 6 heures à 110°C. Après isolement et purification par chromatographie en éluant avec le mélange dichlorométhane/acétate d' éthyle 90/10 puis 80/20 puis dichlorométhane/méthanol 98/2, on obtient 50 mg de produit attendu. Rf (CH2Cl2/AcOEt) : 98/2The procedure is as in preparation 5 but 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 l-iodo-3- (cyclohexyl) propyl then deprotected by the action of gaseous hydrochloric acid for 6 hours at 110 ° C. After isolation and purification by chromatography, eluting with a dichloromethane / ethyl acetate mixture 90/10 then 80/20 then dichloromethane / methanol 98/2, 50 mg of expected product is obtained. Rf (CH 2 Cl 2 / AcOEt): 98/2
Préparation de résines de Wang comportant le composé de formule (III) :Preparation of Wang resins comprising the compound of formula (III):
Résine PliFold Resin
N-acetyl-O- [ [ (1 , 1-dimethyl) ethoxy]methoxyphosphinyl] -N-acetyl-O- [[(1, 1-dimethyl) ethoxy] methoxyphosphinyl] -
L-Tyrosine supportée sur une résine Wang (Pli) .L-Tyrosine supported on a Wang resin (Pli).
Stade a) N-acetyl-O- [ [ (1 , 1-dimethyl) ethoxy]methoxyphosphinyl] -L-Stage a) N-acetyl-O- [[(1, 1-dimethyl) ethoxy] methoxyphosphinyl] -L-
Tyrosinate de 2-propenyle supportée sur une résine Wang2-propenyl tyrosinate supported on a Wang resin
(Res-CH2-OPO (OtBu) -0-Ph-CH2-CH (NHAc) -C02-CH2-CH=CH2) al) On mélange 2g de sel de Triéthylammonium methoxyphosphinyl sur une résine de Wang (Res-CH2-0-PO (H) (0~. N+Et3) décrit par A. M. Mjalli, Tet Lett, 1996, 37(34) 6073) et 20 ml d'une solution de 5ml de tert-butanol et 45ml d1 acétonitrile, agite 10 minutes par bullage d'azote et filtre. a2 ) On mélange ensuite cette résine avec 10 ml d'une solution de 5ml de tert-butanol et 45 ml d' acétonitrile puis 10 ml d'une solution de 2,4ml de tBuCOCl, 10ml d' acétonitrile et 10 ml de pyridine, agite 15 minutes, filtre et lave avec de(Res-CH 2 -OPO (OtBu) -0-Ph-CH 2 -CH (NHAc) -C0 2 -CH 2 -CH = CH 2 ) al) 2g of Triethylammonium methoxyphosphinyl salt are mixed on a Wang resin ( Res-CH 2 -0-PO (H) (0 ~ . N + Et 3 ) described by AM Mjalli, Tet Lett, 1996, 37 (34) 6073) and 20 ml of a 5 ml solution of tert-butanol and 45ml of 1 acetonitrile, stirred for 10 minutes with nitrogen bubbling and filter. a2) This resin is then mixed with 10 ml of a solution of 5 ml of tert-butanol and 45 ml of acetonitrile then 10 ml of a solution of 2.4 ml of tBuCOCl, 10 ml of acetonitrile and 10 ml of pyridine, stir for 15 minutes, filter and wash with
1 ' acétonitrile . a3) On reprend la résine avec 20ml d' acétonitrile et on ajoute une solution de 1,4 ml de CC1 , 2,5 ml de diisopropylamine, 2,5 ml de L-Tyrosinate de 2-propenyle (OH- Ph-CH2-CH(NHAc)-C02-CH2-CH=CH2) , 200 mg de DMAP et 15 ml d' acétonitrile, agite 45 minutes, filtre, lave avec de 1 ' acétonitrile puis avec du dichlorométhane. Stade b) Déprotection de la fonction acide1 acetonitrile. a3) The resin is taken up with 20 ml of acetonitrile and a solution of 1.4 ml of CC1, 2.5 ml of diisopropylamine, 2.5 ml of 2-propenyl L-Tyrosinate (OH-Ph-CH 2 -CH (NHAc) -C0 2 -CH 2 -CH = CH 2 ), 200 mg of DMAP and 15 ml of acetonitrile, stir 45 minutes, filter, wash with acetonitrile and then with dichloromethane. Stage b) Deprotection of the acid function
N-acetyl-O- [ [ (1 , 1-dimethyl) ethoxy]methoxyphosphinyl] - L-Tyrosine supportée sur une résine wangN-acetyl-O- [[(1, 1-dimethyl) ethoxy] methoxyphosphinyl] - L-Tyrosine supported on wang resin
Dans une colonne avec fritte, on place lg de résine préparée précédemment, 12,5 ml d'une solution de 27ml de DMF, 3ml d'acide acétique et 0,3ml de N-methylmorpholine et agite 15 minutes par bullage d'argon. On ajoute ensuite sous bullage d'argon 100 mg de Pd(PPh3) , agite 1 heure 30 minutes sous barbotage d'argon, rajoute 40 mg de Pd(PPh3) et agite 30 minutes sous barbotage d'argon. Après filtration et lavage (DMF, DMF/CHCI3 puis DMF) , on obtient la résine contenant la tyrosine phosphatée de formule (III) attendu. Résine P12In a column with frit, place 1 g of resin prepared above, 12.5 ml of a solution of 27 ml of DMF, 3 ml of acetic acid and 0.3 ml of N-methylmorpholine and stirred for 15 minutes by bubbling with argon. Then added under bubbling of argon 100 mg of Pd (PPh 3 ), stirred for 1 hour 30 minutes under bubbling with argon, added 40 mg of Pd (PPh 3 ) and stirred for 30 minutes under bubbling with argon. After filtration and washing (DMF, DMF / CHCl 3 then DMF), the resin containing the phosphate tyrosine of formula (III) expected is obtained. P12 resin
Acide 4- [ [ (1 , 1-dimethyl) ethoxy]methoxyphosphinyloxy] - benzoique supportée sur une résine Wang (P12) . On opère comme au stade a et b de la préparation 11 mais à partir de 4-hydroxybenzoate de 2-propenyle (OH-Ph-C02-CH2- CH=CH2) Résine P13 Acide 4- [[(1,1- dimethyl) ethoxy]methoxyphosphinylcarbonylamino] - benzoique supportée sur une résine Wang (P13) . On opère comme au stade al et a2 de la préparation 11. Puis on reprend la résine avec de l' acétonitrile et ajoute une solution de DBU (5eq) dans l' acétonitrile. On laisse 10 mn, filtre puis ajoute une solution de 4-isocyano-benzoate de 2- propenyle (OCN-Ph-C02-CH2-CH=CH2) dans l' actéonitrile. On laisse 30 mn à température ambiante puis on filtre.. La déprotection de la fonction acide s'effectue selon le stade b de Pli. Pour chaque exemple, on trouvera la correspondance avec les formules générales décrites plus haut. Sauf indications contraires, le groupement A2 est en position para de l' aryle. Exemple 1 : [2S- [3 (S*) ,2α,3β] ] - [1- [ [4- [ [hydroxy (phénylméthoxy) phospninyl] oxy] phényl] méthyl] -2- [ [2- (4- méthoxyphényl) -5- [2- [ (1-naphtalenyl) amino] -2-oxoéthyl] -4- oxo-2 ,3,4, 5-tétrahydro-l , 5-benzothiazépin-3-yl] amino] -2- oxoéthyl] -carbamate de 1 , 1-diméthyléthyle (isomère trans 1).4- [[(1, 1-dimethyl) ethoxy] methoxyphosphinyloxy] - benzoic acid supported on a Wang resin (P12). The procedure is carried out as in stage a and b of preparation 11 but starting from 2-propenyl 4-hydroxybenzoate (OH-Ph-C0 2 -CH 2 - CH = CH 2 ) Resin P13 Acid 4- [[(1,1 - dimethyl) ethoxy] methoxyphosphinylcarbonylamino] - benzoic supported on a Wang resin (P13). The procedure is carried out as in stages a1 and a2 of preparation 11. Then the resin is taken up with acetonitrile and a solution of DBU (5eq) in acetonitrile is added. It is left for 10 min, filtered and then a solution of 2-propenyl 4-isocyano-benzoate (OCN-Ph-C0 2 -CH 2 -CH = CH 2 ) in acteonitrile is added. It is left for 30 min at room temperature and then filtered. The deprotection of the acid function is carried out according to stage b of Pli. For each example, we will find the correspondence with the general formulas described above. Unless otherwise indicated, the group A 2 is in the para position of the aryl. Example 1: [2S- [3 (S *), 2α, 3β]] - [1- [[4- [[hydroxy (phenylmethoxy) phospninyl] 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 oxoethyl] -carbamate (trans isomer 1).
FG(I') R3=PhOMe; R5=CH2CONH-Napht. ; [Aι]=-CH (NHC02tBu) -CH2-Ph-; A2 = OPO(OBn) (OH) (trans 1) Stade A : N-alkylationFG (I ') R 3 = PhOMe; R 5 = CH 2 CONH-Napht. ; [Aι] = - CH (NHC0 2 tBu) -CH 2 -Ph-; A 2 = OPO (OBn) (OH) (trans 1) Stage A: N-alkylation
[2S-[3 (S*) ,2α,3β] ]-[l-[ [4-[ [bis (phénylméthoxy) phospninyl] oxy] phényl] méthyl] -2- [ [2- (4-methoxyphényl) -5- [2- [ (1- naphtalenyl) amino] -2-oxoéthyl] -4-oxo-2, 3,4, 5-tétrahydro-l, 5- benzothiazépin-3-yl] amino] -2-oxoéthyl] -carbamate de 1,1- diméthyléthyle (isomère trans 1) .[2S- [3 (S *), 2α, 3β]] - [l- [[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-1,5, benzothiazepin-3-yl] amino] -2-oxoethyl] 1,1-dimethylethyl carbamate (trans isomer 1).
A une solution de 106,4 mg de Pla (isomère trans 1) dans 1,5 ml de DMF sec à 0°C sous argon, on ajoute 7,4 mg de NaH, laisse agiter 15' à environ 0°C, puis ajoute 35,4 mg de de N- 1-naphtyl-bromoacétamide, puis agite à température ambiante. Après 3 heures, on ajoute 20 ml d'eau distillée. Après extraction avec de l'acétate d' éthyle, du dichlorométhane et de 1 ' ether éthylique, séchage des phases organiques et évaporation sous pression réduite, on obtient 105,8 mg de produit brut que l'on purifie par chromatographie en éluant avec un mélange eau/méthanol 20/80. Après évaporation du méthanol et extraction de la phase aqueuse avec 80 ml d'acétate d' éthyle, on sèche puis évapore sous pression réduite la phase organique jusqu'à obtention 30,4 mg de produit attendu. Rf méthanol/eau 90/10 = 0,23 Stade B : Monodébenzylation A une solution de 24,4 mg du produit obtenu au stade précé- dent dans 3 ml d'acétone, on ajoute 7,9 mg de Nal (iodure de sodium) et le mélange est porté au reflux pendant lh30. On rajoute encore 3,9 mg de Nal puis au bout de 2hl5 encore 8 mg. Après 40 minutes d'agitation au reflux on évapore sous pression réduite jusqu'à l'obtention d'un extrait sec que l'on lave avec de l'acétate d' éthyle et que l'on dissout dans 3ml de méthanol et quelques gouttes de NaHS03 à 10%. Après évaporation sous pression réduite on obtient 17,3 mg de produit brut que l'on purifie par chromatographie en éluant avec un mélange dichlorométhane/méthanol 80/20. On obtient 6,8 mg de produit attendu.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, left to stir for 15 'at approximately 0 ° C, then add 35.4 mg of N-1-naphthyl-bromoacetamide, then stir 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 a 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 Stage B: Monodebenzylation To a solution of 24.4 mg of the product obtained in the preceding stage in 3 ml of acetone, 7.9 mg of Nal (iodide of sodium) and the mixture is brought to reflux for 1 h 30 min. Another 3.9 mg of Nal is added, and then after 2.5 hours, another 8 mg. After 40 minutes of stirring at reflux, it 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. NaHS0 3 at 10%. After evaporation under reduced pressure, 17.3 mg of crude product is obtained which is purified by chromatography, eluting with a dichloromethane / methanol 80/20 mixture. 6.8 mg of expected product is obtained.
Rf CH2Cl2/méthanol 80/20 = 0,29 IR (Nujol) Absorption OH/NH C=0 1669 cm-1 Aromatique + amide II 1609, 1584, 1533, 1510, 1503 cm"1 RMN (DMSO)Rf CH 2 Cl 2 / methanol 80/20 = 0.29 IR (Nujol) OH / NH absorption C = 0 1669 cm -1 Aromatic + amide II 1609, 1584, 1533, 1510, 1503 cm "1 NMR (DMSO)
1,21 (s), 1,23 (s) C(CH3)3; 2,30 à 2,60 (m) CH (N) -CH2-Ph; 3,67 (s) CH30; 3,86 CH(N)-CH2-Ph; 4,56 (dl, J=ll, 4) S-CH-Ph (cycle) ; 4,86 (dd) -CO-CH-N (cycle); 4,76 (dl) Ph-CH2-0-P; 4,64 (dl) 5,00 (dl) N-CH2-CO-N; 6,37 (d) NH-CO; 6,79(dl), 6,85(dl), 6,93(dl), 7,04(dl) Ph-0 H aromatiques; 7,26 (m) 5H aromatiques; 7,35 à 8,40 naphtyl 11H aromatiques; 6,89 masqué, 8,29 (s) 8,31 (s), 10,15 (si) 3H mobile. Exemple 2 : [2R- [3 (S*) ,2α,3β] ] - [1- [ [4- [ [hydroxy (phénylméthoxy) phospninyl] oxy] phényl] méthyl] -2- [ [2- (4- méthoxyphényl) -5- [2- [ (1-naphtalenyl) amino] -2-oxoéthyl] -4- oxo-2 ,3,4, 5-tétrahydro-l , 5-benzothiazépin-3-yl] amino] -2- oxoéthyl] -carbamate de 1 , 1-diméthyléthyle.1.21 (s), 1.23 (s) C (CH 3 ) 3 ; 2.30 to 2.60 (m) CH (N) -CH 2 -Ph; 3.67 (s) CH 3 0; 3.86 CH (N) -CH 2 -Ph; 4.56 (dl, J = 11.4) S-CH-Ph (cycle); 4.86 (dd) -CO-CH-N (ring); 4.76 (dl) Ph-CH 2 -0-P; 4.64 (dl) 5.00 (dl) N-CH 2 -CO-N; 6.37 (d) NH-CO; 6.79 (dl), 6.85 (dl), 6.93 (dl), 7.04 (dl) aromatic Ph-0 H; 7.26 (m) 5H aromatic; 7.35 to 8.40 11H naphthyl aromatics; 6.89 masked, 8.29 (s) 8.31 (s), 10.15 (if) 3H mobile. Example 2: [2R- [3 (S *), 2α, 3β]] - [1- [[4- [[hydroxy (phenylmethoxy) phospninyl] 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 oxoethyl] -carbamate.
FG(I') R3=PhOMe; R5=CH2CONH-Napht. ; [AιJ=-CH (NHC02tBu) -CH2-Ph-;FG (I ') R 3 = PhOMe; R 5 = CH 2 CONH-Napht. ; [AιJ = -CH (NHC0 2 tBu) -CH 2 -Ph-;
A2=OPO(OBn) (OH) (trans 2)A 2 = OPO (OBn) (OH) (trans 2)
Stade A : N-alkylationStage A: N-alkylation
- [2R- [3 (S*) ,2α,3β] ]-[l-[ [4- [ [bis (phénylméthoxy) phosphinyl] oxy] phényl] méthyl] -2- [ [2- (4-methoxyphényl) -5- [2- [ (1-naphta- lényl) amino] -2-oxoéthyl] -4-oxo-2, 3, 4, 5-tétrahydro-l, 5- benzothiazépin-3-yl] amino] 2-oxoéthyl] -carbamate de 1,1- diméthyléthyle .- [2R- [3 (S *), 2α, 3β]] - [l- [[4- [[bis (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2- [[2- (4-methoxyphenyl) -5- [2- [(1-naphthalenyl) amino] -2-oxoethyl] -4-oxo-2, 3, 4, 5-tetrahydro-l, 5- 1,1-Dimethylethyl benzothiazepin-3-yl] amino] 2-oxoethyl] -carbamate.
A une solution de 185,5 mg de Plb (isomère trans 2) dans 3 ml de DMF sec à 0°C sous atmosphère inerte, on ajoute 13,2 mg de NaH, laisse agiter 15' à environ 0°C, puis ajoute 59,5 mg de de N-1-naphtyl-bromoacétamide, puis agite à température ambiante. Après 3 heures, on rajoute 12,2 mg de N-1-naphtyl- bromoacétamide puis après 2 heures, 20 ml d'eau distillée. Après extraction avec de l'acétate d' éthyle et du dichloro- méthane, séchage des phases organique et évaporation sous pression réduite, on obtient 260,6 mg de produit brut que l'on purifie par chromatographie en éluant avec un mélange eau/méthanol 25/75. Après évaporation du méthanol et extraction de la phase aqueuse avec 200ml d'acétate d' éthyle, on sèche puis évapore sous pression réduite la phase organique jusqu'à obtention 80,3mg de produit attendu. Rf méthanol/eau 90/10 = 0,41 Stade B : Monodébenzylation A une solution de 24,4 mg du produit obtenu au stade précé- dent dans 4 ml d'acétone, on ajoute 24,4 mg de Nal et le mélange est porté au reflux pendant 1,6 heures. On rajoute encore 14,6 mg de Nal puis au bout de 2,7 heures 20 mg. Après 30 minutes d'agitation au reflux on évapore sous pression réduite jusqu'à l'obtention d'un extrait sec auquel on ajoute 3 ml de méthanol et quelques gouttes de NaHSθ3 à 10%. Après évaporation sous pression réduite on obtient 42,5 mg de produit brut que l'on purifie par chromatographie en éluant avec un mélange CH2Cl2/MeOH 85/15. On obtient 29,5 mg de produit attendu. Rf CH2Cl2/MeOH 80/20 = 0,44 IR (Nu-jol) Absorption OH/NH C=0 1668 cm"1 Aromatique + amide II 1508 cm-1 RMN (DMSO) 1,22 (s) C(CH3)3; 1,85 à 2,05 CH (N) -CH2-Ph; 3,62 CH30; 3,95CH(N)-CH2-Ph; 4,54 (d,J=ll) S-CH-Ph H2 cycle); 4,66 (dd) CO-CH(N) (H3 cycle); 4,75 (dl) Ph-CH2-0-P; 4,90-5,00 N-CH2- CO-N; 6,48 (d) NH-Boc; 6,78, 6,82, 6,93, 7,04 Ph-0 ; 7,43 à 8,06 naphtyl; 8,77 (d) H mobile.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 is added, the mixture is stirred for 15 'at approximately 0 ° C, then added 59.5 mg of N-1-naphthyl-bromoacetamide, then stirred at room temperature. After 3 hours, 12.2 mg of N-1-naphthylbromoacetamide are added, then after 2 hours, 20 ml of distilled water. After extraction with ethyl acetate and dichloromethane, drying of the organic phases and evaporation under reduced pressure, 260.6 mg of crude product is obtained which is purified by chromatography eluting with a water / methanol mixture 25/75. 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 the expected product is obtained. Rf methanol / water 90/10 = 0.41 Stage 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 reflux for 1.6 hours. Another 14.6 mg of Nal is added, then 20 mg after 2.7 hours. After 30 minutes of stirring at reflux, it is evaporated under reduced pressure until a dry extract is obtained to which 3 ml of methanol and a few drops of 10% NaHSθ 3 are added . After evaporation under reduced pressure, 42.5 mg of crude product is obtained which is purified by chromatography, eluting with a CH 2 Cl 2 / MeOH 85/15 mixture. 29.5 mg of expected product is obtained. Rf CH 2 Cl 2 / MeOH 80/20 = 0.44 IR (Nu-jol) OH / NH absorption C = 0 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) -CH 2 -Ph; 3.62 CH 3 0; 3.95 CH (N) -CH 2 -Ph; 4.54 (d, J = 11) S-CH-Ph H2 cycle); 4.66 (dd) CO-CH (N) (H3 cycle); 4.75 (dl) Ph-CH 2 -0-P; 4.90-5.00 N-CH 2 - CO-N; 6.48 (d) NH-Boc; 6.78, 6.82, 6.93, 7.04 Ph-0; 7.43 to 8.06 naphthyl; 8.77 (d) H mobile.
Exemple 3 : [2S- [3 (S*) ,2α,3β] ] - [1- [ [4- [ [hydroxy (phénylméthoxy) phosphinyl] oxy] phényl] méthyl] -2- [ [2- (4- méthoxy-phényl) -5- [2- [ [4-méthoxy- [(1,1' -biphenyl) -3-yl] amino] -2-oxoéthyl] -4-oxo-2 ,3,4, 5-tétrahydro-l , 5- benzothiazépin-3-yl] amino] -2-oxoethyl] -carbamate de 1,1- diméthyléthyle .Example 3: [2S- [3 (S *), 2α, 3β]] - [1- [[4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2- [[2- (4- methoxy-phenyl) -5- [2- [[4-methoxy- [(1,1 '-biphenyl) -3-yl] amino] -2-oxoethyl] -4-oxo-2, 3,4, 5- 1,1-dimethylethyl tetrahydro-1,5-benzothiazepin-3-yl] amino] -2-oxoethyl] -carbamate.
FG(I') R3=PhOMe; R5=CH2CONH-Ph (o-OMe) (m-Ph) . ; [Al] =-CH (NHC02tBu) -CH2-Ph- ; [A2] =OPO (OBn) (OH) Stade A : N-alkylationFG (I ') R 3 = PhOMe; R 5 = CH 2 CONH-Ph (o-OMe) (m-Ph). ; [Al] = -CH (NHC0 2 tBu) -CH 2 -Ph-; [A2] = OPO (OBn) (OH) Stage A: N-alkylation
- [2S- [3 (S*) ,2α,3β] ]-[!-[ [4- [ [bis (phénylméthoxy) phosphinyl] oxy] phényl] méthyl] -2- [ [2- (4-methoxyphényl) -5- [2- [ [4- méthoxy- [(1,1' -biphenyl) -3-yl] amino] -2-oxoéthyl] -4-oxo- 2,3,4, 5-tétrahydro-l, 5-benzothiazépin-3-yl] amino] -2- oxoethyl] -carbamate de 1, 1-diméthyléthyle .- [2S- [3 (S *), 2α, 3β]] - [! - [[4- [[bis (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2- [[2- (4-methoxyphenyl) -5- [2- [[4- methoxy- [(1,1 '-biphenyl) -3-yl] amino] -2-oxoethyl] -4-oxo 2,3,4,5-tetrahydro-1, 5-benzothiazepin-3-yl] amino] -2-oxoethyl] -carbamate of 1,1-dimethylethyl.
On opère comme à l'exemple 1 stade A à partir de 159,3 mg de Pla avec comme agent d' alkylation le 2-bromo-N- (4-méthoxy) - [1, 1 ' -biphenyl] -3-yl-acétamide. On obtient 165,1 mg de produit pur attendu. Rf méthanol/eau 80/20 = 0,07 Stade B : DébenzylationThe procedure is as in Example 1 stage A from 159.3 mg of Pla with the alkylating agent 2-bromo-N- (4-methoxy) - [1,1 '-biphenyl] -3-yl -acetamide. 165.1 mg of expected pure product are obtained. Methanol / water Rf 80/20 = 0.07 Stage B: Debenzylation
On opère comme à l'exemple 1 stade B à partir de 155,8 mg du produit obtenu au stade précédent. On obtient 32,5 mg de produit pur attendu. Rf Dichlorométhane/methanol 80/20 = 0,58 IR (Nujol) Absorption OH/NH C=0 1670 cm"1 Aromatique + amide II : 1607 , 1592 (f) , 1582 (f), 1573 (f), 1532, 1510 cm"1 RMN (DMSO)The procedure is as in Example 1 stage B from 155.8 mg of the product obtained in the previous stage. 32.5 mg of expected pure product are obtained. Rf Dichloromethane / methanol 80/20 = 0.58 IR (Nujol) Absorption OH / NH C = 0 1670 cm "1 Aromatic + amide II: 1607, 1592 (f), 1582 (f), 1573 (f), 1532, 1510 cm "1 NMR (DMSO)
1,21 (s) C(CH3)3; 2,2 à 2,6 CH (N) -CH2-Ph; 3,88 (s) CH30 en para du phényl; 3,68 (s) CH30 en para du biphenyl; 3,85 (m)CH(N)-CH2-Ph; 4,57 (d,J=ll,5) S-CH-Ph H2 trans; 4,85 CO- CH(N) H3 trans; 4,76 (d) Ph-CH2-0-P; 4 , 58 (d) -4, 92 (d) N-CH2-CO- N; 6,60(d) 8,26(d) NH-CO; 6,80, 6,85, 6,38, 7,07 Ph-O;1.21 (s) C (CH 3 ) 3 ; 2.2 to 2.6 CH (N) -CH 2 -Ph; 3.88 (s) CH 3 para para phenyl; 3.68 (s) CH 3 para para biphenyl; 3.85 (m) CH (N) -CH 2 -Ph; 4.57 (d, J = 11.5) S-CH-Ph H2 trans; 4.85 CO-CH (N) H3 trans; 4.76 (d) Ph-CH 2 -0-P; 4,58 (d) -4,92 (d) N-CH 2 -CO- N; 6.60 (d) 8.26 (d) NH-CO; 6.80, 6.85, 6.38, 7.07 Ph-O;
7,00 à 7,75 autres aromatiques; 8,77 (d) H mobile. Exemple 4 : [2S- [3 (S*) ,2α,3β] ] - [1- [ [4- [ [hydroxy (phénylméthoxy) phosphinyl] oxy] phényl] méthyl] -2- [ [2- (4- méthoxy-phényl) -5- [2- [2- (3-phénoxyphényl) amino] -2 -oxoethyl ] - 4-oxo-2 ,3, 4,5-tétrahydro-l,5-benzothiazépin-3-yl] amino] -2- oxoéthyl] -carbamate de 1 , 1-diméthyléthyle.7.00 to 7.75 other aromatics; 8.77 (d) H mobile. Example 4: [2S- [3 (S *), 2α, 3β]] - [1- [[4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2- [[2- (4- methoxy-phenyl) -5- [2- [2- (3-phenoxyphenyl) amino] -2-oxoethyl] - 4-oxo-2, 3, 4,5-tetrahydro-1,5-benzothiazepin-3-yl] 1,1-dimethylethyl amino] -2-oxoethyl] -carbamate.
FG (I ' ) R3=PhOMe ; R5=CH2CONH-Ph (m-OPh) . ; [Ai] =-CH (NHC02tBu) -CH2- Ph-; A2=OPO(OBn) (OH)FG (I ') R 3 = PhOMe; R 5 = CH 2 CONH-Ph (m-OPh). ; [Ai] = -CH (NHC0 2 tBu) -CH 2 - Ph-; A2 = OPO (OBn) (OH)
Stade A : N-alkylationStage A: N-alkylation
- [2S-[3(S*) ,2α, 3β]]-[[2-[[2-(4-méthoxyphényl) 5- [2- (3- phénoxyphényl) amino] -2-oxoéthyl] -4-oxo-2, 3, 4, 5-tétrahydro- 1, 5-benzothiazépin-3-yl] amino] -1- [ [4- [ [bis (phénylméthoxy) phosphinyl] oxy] phényl] méthyl] -2-oxoéthyl] -carbamate de 1, 1-diméthyléthyle.- [2S- [3 (S *), 2α, 3β]] - [[2 - [[2- (4-methoxyphenyl) 5- [2- (3- 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] -1,1-dimethylethyl carbamate.
On opère comme à l'exemple 1 stade A à partir de 200 mg de Pla avec comme agent l' alkylation le 2-bromo-N- (3-phénoxy- phényl) -acétamide . On obtient 191,2 mg de produit pur attendu.The procedure is as in Example 1 stage A from 200 mg of Pla with the alkylating agent 2-bromo-N- (3-phenoxyphenyl) -acetamide. 191.2 mg of expected pure product are obtained.
Rf méthanol/eau 90/10 = 0,36Methanol / water Rf 90/10 = 0.36
Stade B : DébenzylationStage B: Debenzylation
On opère comme à l'exemple 1 stade B à partir de 181,8 mg du produit obtenu au stade précédent. On obtient 104,7 mg de produit pur attendu.The procedure is as in Example 1 stage B from 181.8 mg of the product obtained in the previous stage. 104.7 mg of expected pure product are obtained.
Rf Dichloro éthane/méthanol 80/20 = 0,66 IR (Nujol) Absorption OH/NH C=0 1662 cm"1 Aromatique + amide II : 1609, 1587 (f) , 1538 (f) , 1510 (f), 1487 (ep) cm"1 RMN (DMSO)Rf Dichloro ethane / methanol 80/20 = 0.66 IR (Nujol) OH / NH absorption C = 0 1662 cm "1 Aromatic + amide II: 1609, 1587 (f), 1538 (f), 1510 (f), 1487 (ep) cm "1 NMR (DMSO)
1,22 (s) C(CH3)3; 2,27 à 2,3 CH (N) -CH2-Ph; 3,68 (s) CH30 en para du phényl; 3,85 (m) CH (N) -CH2-Ph; 4,44 à 4,60 S-CH-Ph CO-CH(N) (2H cycle); 4,70 à 4,85 Ph-CH2-0-P N-CH2-CO-N (4H) ; 8,20(d) NH-CO; 6,50 à 7,65 H aromatiques (32H) . Exemple 5 : [2R- [3 (S*) ,2α,3α] ] - [1- [ [4- [ [hydroxy (phényméthoxy) phosphinyl] oxy] phényl] méthyl] -2- [ [2- (4- méthoxy-phényl) -5- [2- [ (1-naphtalenyl) amino] -2-oxoéthyl] -4- oxo-2 ,3,4, 5-tétrahydro-l , 5-benzothiazépin-3-yl] amino] -2- oxoéthyl] -carbamate de 1 , 1-diméthyléthyle.1.22 (s) C (CH 3 ) 3 ; 2.27 to 2.3 CH (N) -CH 2 -Ph; 3.68 (s) CH 3 para para phenyl; 3.85 (m) CH (N) -CH 2 -Ph; 4.44 to 4.60 S-CH-Ph CO-CH (N) (2H cycle); 4.70 to 4.85 Ph-CH 2 -0-P N-CH 2 -CO-N (4H); 8.20 (d) NH-CO; 6.50 to 7.65 H aromatic (32H). Example 5: [2R- [3 (S *), 2α, 3α]] - [1- [[4- [[hydroxy (phenymethoxy) 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 of 1, 1-dimethylethyl.
FG (I ' ) R3=PhOMe; R5=CH2CONH-Napht. ; [Ai] =-CH (NHC02tBu) -CH2-Ph- ; A2=OPO(OBn) (OH) (Cis 2)FG (I ') R 3 = PhOMe; R 5 = CH 2 CONH-Napht. ; [Ai] = -CH (NHC0 2 tBu) -CH 2 -Ph-; A2 = OPO (OBn) (OH) (Cis 2)
Stade A : N-alkylationStage A: N-alkylation
- [2R- [3 (S*) ,2α,3α] ]-[l-[ [4- [ [bis (phénylméthoxy) phosphinyl] oxy] phényl] méthyl] -2- [ [2- ( -methoxyphényl) -5- [2- [ (1-naphta- lényl) amino] -2-oxoethyl] -4-oxo-2, 3,4, 5-tétrahydro-l, 5- benzothiazépin-3-yl] amino] -2-oxoéthyl] -carbamate de 1,1- diméthyléthyle .- [2R- [3 (S *), 2α, 3α]] - [l- [[4- [[bis (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2- [[2- (-methoxyphenyl) - 5- [2- [(1-naphthalenyl) amino] -2-oxoethyl] -4-oxo-2, 3,4, 5-tetrahydro-l, 5-benzothiazepin-3-yl] amino] -2- 1,1-dimethylethyl oxoethyl] -carbamate.
On opère comme à l'exemple 1 stade A à partir de 200 mg deThe procedure is as in Example 1 stage A from 200 mg of
Pld (isomère cis 2) avec comme agent d' alkylation le N-l- naphtyl-bromoacétamide. On obtient 102,3 mg de produit pur attendu.Pld (cis isomer 2) with N-1-naphthyl-bromoacetamide as the alkylating agent. 102.3 mg of expected pure product are obtained.
Rf dichloromethane/eau 50/50 = 0,42Rf dichloromethane / water 50/50 = 0.42
Stade B : DébenzylationStage B: Debenzylation
On opère comme à l'exemple 1 stade B à partir de 95,3 mg du produit obtenu au stade précédent. On obtient 23,3 mg de produit pur attendu.The procedure is as in Example 1 stage B from 95.3 mg of the product obtained in the previous stage. 23.3 mg of expected pure product are obtained.
Rf Dichlorométhane/methanol 90/10 = 0,16Rf Dichloromethane / methanol 90/10 = 0.16
IR (Nujol)IR (Nujol)
Absorption région OH/NHOH / NH region absorption
C=0 1684 cm"1 Aromatique + amide II 1609 (tf) , 1582 (tf) , 1505, cm"1 RMN ( DMSO )C = 0 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-CH2-N; 5,00(d, J=7) -S-CH-Ph (H2 cycle) H Cis; 4,90 (t, J=7,5)) -CO- CH(N) (H3 cycle) H Cis; 6,48 (d) NH-Boc; 6,97 (AA'BB'); 6,82 à 7,82 (m), 7,94 (m), 8,13 (m) aromatiques; 10,28 (s) IH mobile.1.19 (s) C (CH 3 ) 3 ; 2.50 (m) CH (N) -CH 2 -Ph; 3.71 (s) CH 3 0; 4.07 (m) CH (N) -CH 2 -Ph; 4.68 (d) 5.07 (d) Napht-NH-CO-CH 2 -N; 5.00 (d, J = 7) -S-CH-Ph (H2 cycle) H Cis; 4.90 (t, J = 7.5)) -CO- CH (N) (H3 cycle) H Cis; 6.48 (d) NH-Boc; 6.97 (AA'BB '); 6.82 to 7.82 (m), 7.94 (m), 8.13 (m) aromatics; 10.28 (s) IH mobile.
Exemple 6 : [2S- [3 (S*) ,2α,3α] ] - [1- [ [4- [ [hydroxy (phénylméthoxy) phospninyl] oxy] phényl] méthyl] -2- [ [2- (4- methoxyphényl) -5- [2- [ (1-naphtalenyl) amino] -2-oxoéthyl] -4- oxo-2 ,3,4, 5-tétrahydro-l , 5-benzothiazépin-3-yl] amino] -2- oxoéthyl] -carbamate de 1, 1-diméthyléthyle.Example 6: [2S- [3 (S *), 2α, 3α]] - [1- [[4- [[hydroxy (phenylmethoxy) phospninyl] 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 oxoethyl] -carbamate.
FG (I ' ) R3=PhOMe ; R5=CH2CONH-Napht. ; [Ai] =-CH (NHC02tBu) -CH2-Ph- ; A2=OPO(OBn) (OH) (Cis 1)FG (I ') R 3 = PhOMe; R 5 = CH 2 CONH-Napht. ; [Ai] = -CH (NHC0 2 tBu) -CH 2 -Ph-; A 2 = OPO (OBn) (OH) (Cis 1)
Stade A : N-alkylationStage A: N-alkylation
On opère comme à l'exemple 1 stade A à partir de 220 mg deThe procedure is as in Example 1 stage A from 220 mg of
Pic (isomère cis 1) avec comme agent d1 alkylation le N-l- naphtyl-bromoacétamide. On obtient 67 mg de produit pur attendu.Pic (cis isomer 1) as with the alkylating agent 1 NL- naphthyl-bromoacetamide. 67 mg of expected pure product are obtained.
Rf méthanol/eau 90/10 = 0,34Methanol / water Rf 90/10 = 0.34
Stade B : DébenzylationStage B: Debenzylation
On opère comme à l'exemple 1 stade B à partir de 65,5 mg du produit obtenu au stade précédent. On obtient 19,1 mg de produit pur attendu.The procedure is as in Example 1 stage B from 65.5 mg of the product obtained in the previous stage. 19.1 mg of expected pure product are obtained.
Rf Dichlorométhane/methanol 80/20 = 0,45Rf Dichloromethane / methanol 80/20 = 0.45
IR (Nujol)IR (Nujol)
Absorption OH/NHOH / NH absorption
C=0 1668 cm"1 Aromatique + amide II 1608, 1505 cm"1 C = 0 1668 cm "1 Aromatic + amide II 1608, 1505 cm " 1
RMN (DMSO)NMR (DMSO)
1,18 (s) C(CH3)3; 2,35 à 2,75 (m) CH (N) -CH2-Ph; 3,76 (s) CH30;1.18 (s) C (CH 3 ) 3 ; 2.35 to 2.75 (m) CH (N) -CH 2 -Ph; 3.76 (s) CH 3 0;
3,95 (m) CH(N)-CH2-Ph; 5,00 (d, J=7 ) -S-CH-Ph (H2 cycle) Cis;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 cycle) Cis; 4, 72 (m) Ph-CH2-0-P ; 4,60 à 4,75 5,08 (d) N-CH2-CO-N; 6,48(d) NH-Boc; 6,80 à 7,80 (m) (24H) 7,91 (m) (IH) 8,15 (m) (IH) H aromatiques; 10,33 (s) IH mobile .4.70 -CO-CH (N) (H3 ring) Cis; 4.72 (m) Ph-CH 2 -0-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) Aromatic H; 10.33 IH mobile.
Exemple 7 : [2S- [3 (S*) ,2α,3β] ] -1- [ [4- [ [bis (phénylméthoxy) phosphinyl] oxy] phényl] méthyl] -2- [ [2- (4-methoxyphényl) -5- [2- [ (1-naphtalenyl) amino] -2-oxo-l-phényléthyl] -4-oxo- 2,3,4, 5-tétrahydro-l , 5-benzothiazépin-3-yl] amino] -2- oxoéthyl] -carbamate de 1 , 1-diméthyléthyle.Example 7: [2S- [3 (S *), 2α, 3β]] -1- [[4- [[bis (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2- [[2- (4-methoxyphenyl ) -5- [2- [(1-naphthalenyl) amino] -2-oxo-1-phenylethyl] -4-oxo 2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] amino ] -2-oxoethyl] -carbamate of 1, 1-dimethylethyl.
FG (I ' ) R3=PhOMe; R5=CH (Ph) CONH-Napht . ; [Ai] =-CH (NHC02tBu) -CH2- Ph-; A2 = OPO (OBn) (OBn) (Trans 1)FG (I ') R 3 = PhOMe; R 5 = CH (Ph) CONH-Napht. ; [Ai] = -CH (NHC0 2 tBu) -CH 2 - Ph-; A 2 = OPO (OBn) (OBn) (Trans 1)
On opère comme à l'exemple 1 stade A à partir de 220,1 mg de Pla (isomère Trans 1) avec comme agent d' alkylation l'alpha- bromo-N- (1-naphtylalényl) -benzèneacétamide . On obtient 113,7 mg de produit pur attendu. Rf méthanol/eau 90/10 = 0,50 IR (Nujol) C-NH 3416 cm"1 C=0 1684 cm"1 The procedure is as in Example 1 stage A from 220.1 mg of Pla (Trans isomer 1) with alpha-bromo-N- (1-naphthylalenyl) -benzeneacetamide as alkylating agent. 113.7 mg of expected pure product are obtained. Rf methanol / water 90/10 = 0.50 IR (Nujol) C-NH 3416 cm "1 C = 0 1684 cm " 1
Aromatique + amide 11:1610, 1599, 1584, 1523 ep., 1513, 1508, ccmmAromatic + amide 11: 1610, 1599, 1584, 1523 ep., 1513, 1508, ccmm
RMN (DMSO)NMR (DMSO)
1,28 (si) 0-C(CH3)3; 2,73 (d) CH (N) -CH2-Ph; 3,74 (s) CH30;1.28 (si) 0-C (CH 3 ) 3 ; 2.73 (d) CH (N) -CH 2 -Ph; 3.74 (s) CH 3 0;
4,98; CH(N)-CH2-Ph; 4,07 (d, J=ll,5) : -S-CH-Ph (H2 cycle) H4.98; CH (N) -CH 2 -Ph; 4.07 (d, J = ll, 5): -S-CH-Ph (H2 cycle) H
Trans; 4,25 (d, J=ll,5) : -CO-CH-N (H3 cycle) H Trans; 5,13(d) (2H) et 5,24 (m) (2H) : Ph-CH2-0-P; 6,63 (d) Napht-Trans; 4.25 (d, J = 11.5): -CO-CH-N (H3 ring) H Trans; 5.13 (d) (2H) and 5.24 (m) (2H): Ph-CH 2 -0-P; 6.63 (d) Napht-
NH-CO-; 6,76 (d) (2H) , 6,94 (d) (5H),H aromatiques; 7,20 àNH-CO-; 6.76 (d) (2H), 6.94 (d) (5H), Aromatic H; 7.20 to
7,88 (m) 9,20 (si) Autres aromatiques et NH.7.88 (m) 9.20 (si) Other aromatics and NH.
Exemple 8 : [2S- [3 (S*) ,2α,3β] ] - [1- [ [4- [ [hydroxyExample 8: [2S- [3 (S *), 2α, 3β]] - [1- [[4- [[hydroxy
(phényméthoxy) phosphinyl] oxy] phényl] méthyl] -2- [ [2- (4- méthoxy-phényl) -5- [2- [ (4-phénoxyphényl) amino] -2-oxoéthyl] -4- oxo-2 ,3,4, 5-tétrahydro-l , 5-benzothiazépin-3-yl] amino] -2- oxoéthyl] -carbamate de 1, 1-diméthyléthyle.(phenymethoxy) phosphinyl] oxy] phenyl] methyl] -2- [[2- (4-methoxy-phenyl) -5- [2- [(4-phenoxyphenyl) amino] -2-oxoethyl] -4- oxo-2 , 3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] amino] -2-oxoethyl] -carbamate of 1,1-dimethylethyl.
FG(I') R3=PhOMe; R5=CH2CONH-Ph (p-OPh) . ; [A ≈-CH (NHC02tBu) -CH2- Ph-; A2 = OPO (OBn) (OH) (Trans 1) Stade A : N-alkylationFG (I ') R 3 = PhOMe; R 5 = CH 2 CONH-Ph (p-OPh). ; [A ≈-CH (NHC0 2 tBu) -CH 2 - Ph-; A 2 = OPO (OBn) (OH) (Trans 1) Stage A: N-alkylation
- [2S- [3 (S*) ,2α,3β] ]-[l-[ [4- [ [bis (phénylméthoxy) phosphinyl] oxy] phényl] méthyl] -2- [ [2- (4-methoxyphényl) -5- [2- [ (4-phé- noxyphényl) amino] -2-oxoethyl] -4-oxo-2, 3,4, 5-tétrahydro-l, 5- benzothiazépin-3-yl] amino] -2-oxoéthyl] -carbamate de 1,1- diméthyléthyle .- [2S- [3 (S *), 2α, 3β]] - [l- [[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-1,5,5-benzothiazepin-3-yl] amino] -2 1,1-dimethylethyl-oxoethyl] -carbamate.
On opère comme à l'exemple 1 stade A à partir de 200 mg de Pla (isomère Trans 1) avec comme agent l' alkylation le 2- bromo-N- ( -phenoxyphenyl) -acétamide. On obtient 117,9 mg de produit pur attendu.The procedure is as in Example 1 stage A from 200 mg of Pla (Trans isomer 1) with the alkylating agent 2-bromo-N- (-phenoxyphenyl) -acetamide. 117.9 mg of expected pure product are obtained.
Rf méthanol/eau 90/10 = 0,32Methanol / water Rf 90/10 = 0.32
Stade B : DébenzylationStage B: Debenzylation
On opère comme à l'exemple 1 stade B à partir de 112,4 mg du produit obtenu au stade précédent. On obtient 31 mg de pro- duit pur attendu.The procedure is as in Example 1 stage B from 112.4 mg of the product obtained in the previous stage. 31 mg of expected pure product are obtained.
Rf Dichlorométhane/méthanol 80/20 = 0,52 IR (Nujol) Absorption OH/NH C=0 1662 cm"1 Aromatique + amide II 1609,1585,1737,1507,1488 cm"1 RMN (DMSO)Rf Dichloromethane / methanol 80/20 = 0.52 IR (Nujol) OH / NH absorption C = 0 1662 cm "1 Aromatic + amide II 1609.1585.173737.1507.1448 cm " 1 NMR (DMSO)
0,99 (s), 1,22 (s) C(CH3)3; 2,22 à 2,50 CH (N) -CH2-Ph; 3,66 (s)CH30; 3,84 (m) CH (N) -CH2-Ph; 4,50 à 4,85 (m) -S-CH-Ph-CO- CH(N) ; 4,50 à 4,85 (m) Ph-CH2-0-P -N-CH2-CO-N; 6,50 à 7,70 (m) (28H) aromatiques; 8,20 (d) -NH-CO-; 8,26 (dl) 10,20 (si) autres NH-CO.0.99 (s), 1.22 (s) C (CH 3 ) 3 ; 2.22 to 2.50 CH (N) -CH 2 -Ph; 3.66 (s) CH 3 0; 3.84 (m) CH (N) -CH 2 -Ph; 4.50 to 4.85 (m) -S-CH-Ph-CO- CH (N); 4.50 to 4.85 (m) Ph-CH 2 -0-P -N-CH 2 -CO-N; 6.50 to 7.70 (m) (28H) aromatic; 8.20 (d) -NH-CO-; 8.26 (dl) 10.20 (si) other NH-CO.
Exemple 9 : [2S- [3 (S*) ,2α,3β] ] -4 ' - [ [3- [ [2- [ [ [ (1,1-diméthyl) ethoxy] carbonyl] amino] -3- [ [4- [ [hydroxy (phénylméthoxy) phosphinyl] oxy] phényl] -1-oxopropyl] amino] -2- (4-méthoxy- phényl) -4-oxo-2 , 3-dihydro-l,5-benzothiazépin-5 (4H) -yl] méthyl] - [1 , 1 ' -biphenyl] -2-carboxylate de 1,1-diméthyléthyle .Example 9: [2S- [3 (S *), 2α, 3β]] -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) -yl] methyl] - [1,1 '-biphenyl] -2-1,1-dimethylethyl carboxylate.
FG(I') R3 = PhOMe; R5 = -CH2CONH-Ph-Ph (m-C02tBu) ) . ; [Aι]=-CH(NHC02tBu)-CH2-Ph-; A2 = OPO (OBn) (OH) (Trans 1) Stade A : N-alkylation - [2S-[3(S*) ,2α, 3β] ]-4'-[ [3-[ [3-[4-[ [bis (phénylméthoxy) phosphinyl] oxy] phényl] 2- [ [ [ (1, 1-diméthyl) ethoxy] carbonyl] amino] 1-oxopropyl] amino] -2- (4-methoxyphényl) 4- oxo-2, 3-dihydro-l, 5-benzothiazépin-5 (4H) -yl] méthyl] -[1,1'- biphenyl] -2-carboxylate de 1, 1-diméthyléthyle.FG (I ') R 3 = PhOMe; R 5 = -CH 2 CONH-Ph-Ph (m-C0 2 tBu)). ; [Aι] = - CH (NHC0 2 tBu) -CH 2 -Ph-; A 2 = OPO (OBn) (OH) (Trans 1) Stage A: N-alkylation - [2S- [3 (S *), 2α, 3β]] -4 '- [[3- [[3- [4- [[bis (phenylmethoxy) phosphinyl] oxy] phenyl) 2- [[[(1 , 1-dimethyl) ethoxy] carbonyl] amino] 1-oxopropyl] amino] -2- (4-methoxyphenyl) 4-oxo-2,3-dihydro-1,5-benzothiazepin-5 (4H) -yl] methyl] - [1,1'- biphenyl] -2-carboxylate of 1, 1-dimethylethyl.
On opère comme à l'exemple 1 stade A à partir de 200 mg de Pla (isomère Trans 1) avec comme agent l' alkylation le 4'- (bromométhyl) - [1, 1 ' -biphenyl] -2-carboxylate de 1, 1-diméthyléthyle. On obtient 161,6 mg de produit pur attendu. Rf dichlorométhane/eau 90/10 = 0,32 Stade B : MonodébenzylationThe procedure is as in Example 1 stage A from 200 mg of Pla (Trans isomer 1) with the alkylating agent 4'- (bromomethyl) - [1,1 '-biphenyl] -2-carboxylate of 1 , 1-dimethylethyl. 161.6 mg of expected pure product are obtained. R dichloromethane / water 90/10 = 0.32 Stage B: Monodebenzylation
On opère comme à l'exemple 1 stade B à partir de 150,3 mg du produit obtenu au stade précédent. On obtient 80,2 mg de produit pur attendu. Rf Dichlorométhane/méthanol 80/20 = 0,57 IR (Nujol) Absorption OH/NH C=0 1704 (ep), 1664 (max) cm"1 Aromatique + amide II 1609,1584,1512 cm"1 RMN (DMSO)The procedure is as in Example 1 stage B from 150.3 mg of the product obtained in the previous stage. 80.2 mg of expected pure product are obtained. Rf Dichloromethane / methanol 80/20 = 0.57 IR (Nujol) OH / NH absorption C = 0 1704 (ep), 1664 (max) cm "1 Aromatic + amide II 1609.1584.151512 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; 4,60 -CO- CH-N H3 Trans; 4,75 (si) 2H Ph-CH2-0-P; 5,04 (d,J=16) N-CH2- biphényl; 6,80 à 7,10 (m) Ph-O; 7,10 à 7,75 6,62 (d) 8,79 (si) autres aromatiques et NH.1.26 (si) C (CH 3 ) 3 ; 2.40 CH (N) -CH 2 -Ph; 3.69 (s) CH 3 0; 3.84 (m) CH (N) -CH 2 -Ph; 4.66 (d, J = 12) -S-CH-Ph H2 Trans; 4.60 -CO- CH-N H3 Trans; 4.75 (si) 2H Ph-CH 2 -0-P; 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 (if) other aromatics and NH.
Exemple 10 : [S- [R[trans (±) ]]]- [1- [ [4- [ [hydroxy (phénylméthoxy) phosphinyl] oxy] phényl] méthyl] -2- [ [5- (3- cyclohexylpropyl) -2- (4-methoxyphényl) -4-oxo-2 ,3,4,5- tétrahydro-1 , 5-benzothiazépin-3-yl] amino] -2-oxoéthyl] - carbamate de 1 , 1-diméthyléthyle.Example 10: [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-1,5,5-benzothiazepin-3-yl] amino] -2-oxoethyl] - 1,1-dimethylethyl carbamate.
FG(I') R3=PhOMe; R5= (CH2) 4-cyclohexyle. ; [Aι]=-CH (NHC02tBu) - CH2-Ph-; A2=OPO(OBn) (OH) (Trans 1)FG (I ') R 3 = PhOMe; R 5 = (CH 2 ) 4 -cyclohexyl. ; [Aι] = - CH (NHC0 2 tBu) - CH 2 -Ph-; A 2 = OPO (OBn) (OH) (Trans 1)
Stade A : N-alkylation - [S- [R [trans (±) ]]]- [1- [ [4- [ [bis (phénylméthoxy) phosphinyl] oxy] phényl] méthyl] -2- [ [5- (3-cyclohexylpropyl) -2- (4- méthoxyphényl) -4-oxo-2, 3,4, 5-tétrahydro-l, 5-benzothiazépin-3- yl] amino] -2-oxoéthyl] -carbamate de 1, 1-diméthyléthyle. On opère comme à l'exemple 1 stade A à partir de 258,4 mg d'un mélange de diastéréoisomère trans avec comme agent l' alkylation le l-iodo-3-cyclohexylpropyle . On obtient 179 mg de produit attendu.Stage A: N-alkylation - [S- [R [trans (±)]]]] - [1- [[4- [[bis (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 of 1,1-dimethylethyl. The procedure is as in Example 1, Stage A, starting from 258.4 mg of a mixture of trans diastereoisomer with the alkylating agent 1-iodo-3-cyclohexylpropyl. 179 mg of expected product are obtained.
Stade B : Monodébenzylation On opère comme à l'exemple 1 stade B à partir de 76 mg du produit obtenu au stade précédent. On obtient 51 mg de produit pur attendu.Stage B: Monodebenzylation The operation is carried out as in Example 1, Stage B from 76 mg of the product obtained in the preceding stage. 51 mg of expected pure product are obtained.
Rf= 0,50 (Dichlorométhane/méthanol: 80/20)Rf = 0.50 (Dichloromethane / methanol: 80/20)
IR (Nujol) NH 3414, 3294 cm"1 IR (Nujol) NH 3414, 3294 cm "1
C=0 1694,1659 cm"1 C = 0 1694.1659 cm "1
Aromatique + amide II 1610,1585,1513 cm"1 Aromatic + amide II 1610,1585,1513 cm "1
RMN (DMSO)NMR (DMSO)
0,7 à 1,65 (m, 18 à 19H, chaîne alkyle); 1,26 (s, C(CH3)3 ); 3,68 (s, OCH3) ; 3,55 3,84 (m, CO-N-CH2) ; 4,18 (m, CH(N)-CH2-0.7 to 1.65 (m, 18 to 19H, alkyl chain); 1.26 (s, C (CH 3 ) 3 ); 3.68 (s, OCH 3 ); 3.55 3.84 (m, CO-N-CH 2 ); 4.18 (m, CH (N) -CH 2 -
Ph) ; 4,33 et 4,50 (CH (N) -CH2-Ph) ; 4,55 (d,J=ll,5, H2 Trans);Ph); 4.33 and 4.50 (CH (N) -CH 2 -Ph); 4.55 (d, J = 11.5, H2 Trans);
4,70 (dd, H3 Trans); 4,81 (dl, Ph-CH2-0-P) ; 6,62 8,20 (d, peu mobile, NH) ; 6,80 à 7,70 (m, 19H aromatique).4.70 (dd, H3 Trans); 4.81 (dl, Ph-CH 2 -0-P); 6.62 8.20 (d, poorly mobile, NH); 6.80 to 7.70 (m, 19H aromatic).
Exemple 11 : [S- [R* (3S*) ] ] - [2- [ [5- (3-cyclohexylpropyl) -4-oxo- 2 ,3,4 ,5-tétrahydro-l,5-benzothiazépin-3-yl] amino] -1- [ [4-Example 11: [S- [R * (3S *)]] - [2- [[5- (3-cyclohexylpropyl) -4-oxo- 2,3,4,5-tetrahydro-1,5-benzothiazepin-3 -yl] amino] -1- [[4-
[ [hydroxy (phénylméthoxy) phosphinyl] oxy] phényl] méthyl] -2- oxoéthyl] -carbamate de 1, 1-diméthyléthyle.[[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2-oxoethyl] -carbamate of 1, 1-dimethylethyl.
FG (I ' ) R3=H , R5= - (CH2) 3-cyclohexyle . ; [Ai] = -CH (NHC02tBu) - CHz-Ph- ; A2 = -OPO (OBn) (OH)FG (I ') R 3 = H, R 5 = - (CH 2 ) 3 -cyclohexyl. ; [Ai] = -CH (NHC0 2 tBu) - CHz-Ph-; A 2 = -OPO (OBn) (OH)
Stade A : N-acylationStage A: N-acylation
- [S- [R* (3S*) ]]- [1- [ [bis (phénylméthoxy) phosphinyl] oxy] phényl] méthyl] - [2- [ [5- (3-cyclohexylpropyl) -4-oxo-2, 3,4,5- tétrahydro-1, 5-benzothiazépin-3-yl] amino] -2-oxoéthyl] - carbamate de 1, 1-diméthyléthyle . A une solution de 250 mg de l'aminé obtenue selon la préparation 5 dans 2ml de dichlorométhane à 0°C sous atmosphère inerte, on ajoute une solution préparée préalablement comprenant 512 mg de O- [bis (phénylméthoxy) phosphinyl] -N- [ (1, 1-diméthyléthoxy) carbonyl] -L-tyrosine (L-Boc-Tyr-- [S- [R * (3S *)]] - [1- [[bis (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] - [2- [[5- (3-cyclohexylpropyl) -4-oxo-2 , 3,4,5-tetrahydro-1,5,5-benzothiazepin-3-yl] amino] -2-oxoethyl] - 1,1-dimethylethyl carbamate. To a solution of 250 mg of the amine obtained according to preparation 5 in 2 ml of dichloromethane at 0 ° C. under an inert atmosphere, a solution previously prepared comprising 512 mg of O- [bis (phenylmethoxy) phosphinyl] -N- [ (1, 1-dimethylethoxy) carbonyl] -L-tyrosine (L-Boc-Tyr-
OP03Bn2, 182 mg d'EDC, 128 mg HOBt, 2 ml de dichlorométhane et 0,5 ml de diméthylformamide et agite pendant 2 heures à température ambiante. Après dilution avec de l'acétate d' éthyle, lavage avec de l'acide citrique 5% du bicarbonate de sodium puis du chlorure de sodium, on sèche puis évapore sous pression réduite jusqu'à obtention de 661 mg de produit brut que l'on purifie par chromatographie en éluant avec un mélange dichlorométhane/méthanol 99/1. On obtient 498 mg de produit pur attendu. Stade B : MonodébenzylationOP0 3 Bn 2 , 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 5% citric acid of sodium bicarbonate and then sodium chloride, drying and then evaporating under reduced pressure until 661 mg of crude product is obtained. purified by chromatography, eluting with a 99/1 dichloromethane / methanol mixture. 498 mg of expected pure product are obtained. Stage B: Monodebenzylation
On opère comme au stade B de l'exemple 1 à partir de 115 mg du produit obtenu au stade précédent. On obtient 87 mg de produit pur attendu. Rf= 0,46 (dichlorométhane/méthanol : 80/20) IR (Nujol)The procedure is carried out as in stage B of Example 1 from 115 mg of the product obtained in the preceding stage. 87 mg of expected pure product are obtained. Rf = 0.46 (dichloromethane / methanol: 80/20) IR (Nujol)
Absorption OH/NHOH / NH absorption
C=0 1701, 1656 (max) cm"1 C = 0 1701, 1656 (max) cm "1
Aromatique + amide II 1609,1585,1570,1509,1500 cm"1 Aromatic + amide II 1609.1585.1570.1509.1500 cm "1
RMN (DMSO) 0,70 à 1,60 (C-CH2, C-CH) ; 1,27 (si, C(CH3)3); 2,60 (m,NMR (DMSO) 0.70 to 1.60 (C-CH 2 , C-CH); 1.27 (si, C (CH 3 ) 3 ); 2.60 (m,
CH(N)-CH2-Ph; 2,88 (dd, -S-CH2-Ph (H2 cycle)); 3,01 (t) 3,46 (m) 4,06 (=C-N-CH2-C) ; 4,20 4,36 (m, IH, -CO-CH(N) (H3 cycle)); 4,80 à 5,10 (2H, Ph-CH2-0-P) ; 6,44 (d) 6,88 (d) =C- NH-CH; 7,09 (si, 4H C-Ph-O) ; 7,25 (1, 5H, C-Ph-O) ; 7,32 (m, IH) 7,57 (m, 2H) 7,67 (d, IH) phényl adjacent à l'hétérocycle; 8,32 (d, Autre =C-NH-CH) .CH (N) -CH 2 -Ph; 2.88 (dd, -S-CH 2 -Ph (H2 cycle)); 3.01 (t) 3.46 (m) 4.06 (= CN-CH 2 -C); 4.20 4.36 (m, 1H, -CO-CH (N) (H3 cycle)); 4.80 to 5.10 (2H, Ph-CH 2 -0-P); 6.44 (d) 6.88 (d) = C-NH-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).
Exemple 12 : [S- [R* (3S*) ] ] - [2- [ [5- (3-cyclohexylpropyl) - 2,3,4, 5-tétrahydro-4-oxo-l , 5-benzothiazépin-3-yl] amino] -2- oxo-1- [ [4-phosphonooxyphényl] méthyl] éthyl] -carbamate de 1,1-diméthyléthyle . FG (I ' ) R3 = H , R5 = - (CH2) 3-cyclohexyle . ; [Ai] = -CH (NHC02tBu) - CH2-Ph- ; A2 = OPO (OH) 2 Example 12: [S- [R * (3S *)]] - [2- [[5- (3-cyclohexylpropyl) - 2,3,4,5-tetrahydro-4-oxo-1,5,5-benzothiazepin-3 -yl] amino] -2- oxo-1- [[4-phosphonooxyphenyl] methyl] ethyl]-1,1-dimethylethylcarbamate. FG (I ') R 3 = H, R 5 = - (CH 2 ) 3 -cyclohexyl. ; [Ai] = -CH (NHC0 2 tBu) - CH 2 -Ph-; A 2 = OPO (OH) 2
A 207 mg du produit obtenu au stade A de l'exemple 11 dans 5 ml de méthanol, on ajoute 26 mg de palladium sur carbone à 9,5% et sature l'atmosphère avec de l'hydrogène. Après fil- tration, on rince avec du méthanol et évapore sous pression réduite jusqu'à obtention de 156 mg de produit attendu.To 207 mg of the product obtained in Stage A of Example 11 in 5 ml of methanol, 26 mg of 9.5% palladium on carbon is added and the atmosphere is saturated with hydrogen. After filtration, rinsing with methanol and evaporating under reduced pressure until 156 mg of expected product is obtained.
Rf= 0,10 (dichlorométhane/méthanol : 80/20)Rf = 0.10 (dichloromethane / methanol: 80/20)
IR (Nujol) Absorption OH/NH 3416, 3296 cm"1 IR (Nujol) Absorption OH / NH 3416, 3296 cm "1
C=0 1700, 1696 (max) cm"1 C = 0 1700, 1696 (max) cm "1
Aromatique + amide II 1608,1585,1572,1508 cm"1 Aromatic + amide II 1608,1585,1572,1508 cm "1
RMN (DMSO)NMR (DMSO)
0,70 à 1,60 (C-CH2, C-CH) ; 1,27 (si, C (CH3) 3) ; 2,60 (m, IH CH(N)-CH2-Ph) ; 2,88 (dl, IH, -S-CH2-CH (N) ) ; 3,00 (t, IH) 3,460.70 to 1.60 (C-CH 2 , C-CH); 1.27 (si, C (CH 3 ) 3 ); 2.60 (m, 1H CH (N) -CH 2 -Ph); 2.88 (dl, 1H, -S-CH 2 -CH (N)); 3.00 (t, IH) 3.46
(m, 2H) 4, 08 (m, IH) =C-N-CH2-; 4,19 4,24 (m, IH, -CO-CH(N)-(m, 2H) 4.08 (m, 1H) = CN-CH 2 -; 4.19 4.24 (m, 1H, -CO-CH (N) -
); 6,91 (d) 8,23 =C-NH-; 7,04 (C-Ph-O); 7,17 (AA'BB') Ph-O;); 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) phényl adjacent à 1 ' hétérocycle .7.33 (m) 7.17 (m) 7.69 (d) phenyl adjacent to the heterocycle.
Exemple 13 : [S- [R* (3R*) ] ] - [2- [ [5- (3-cyclohexylpropyl) -4-oxo- 2 ,3, 4,5-tétrahydro-l ,5-benzothiazépin-3-yl] amino] -1- [ [4- hydroxy (phénylméthoxy) phosphinyl] oxy] phényl] méthyl] -2- oxoéthyl] -carbamate de 1, 1-diméthyléthyle.Example 13: [S- [R * (3R *)]] - [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 of 1,1-dimethylethyl.
FG(I') R3 = H, R5 = -(CH2)3-cyclohexyle. ; [Ai] = -CH (NHC02tBu) - CH2-Ph-; A2 = OPO (OBn) (OH)FG (I ') R 3 = H, R 5 = - (CH 2 ) 3 -cyclohexyl. ; [Ai] = -CH (NHC0 2 tBu) - CH 2 -Ph-; A 2 = OPO (OBn) (OH)
On opère comme à l'exemple 11 stades A et B mais à partir de 483 mg du produit obtenu à la préparation 10. On obtient 20 mg du produit monobenzylé attendu. Rf = 0,50 (dichlorométhane/méthanol 80/20) IR (Nujol)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 are obtained. Rf = 0.50 (dichloromethane / methanol 80/20) IR (Nujol)
Absorption OH/NHOH / NH absorption
C=0 1700, 1696 (max) cm-1 C = 0 1700, 1696 (max) cm -1
Aromatique + amide II 1608,1585,1572,1508 cm"1 Aromatic + amide II 1608,1585,1572,1508 cm "1
RMN (DMSO) 0,70 à 1,60 (C-CH2, C-CH) ; 2,70 à 2,85 (-S-CH2) ; 4,12 -4,20 (m, =C-N-CH2) ; 4,35 4,20 (m, CO-N-CH-CO) ; 4,80 (dl, Ph- CH2OP) ; 7,07 (m, -C-Ph-O) ; 7,28 (m, Ph-C) ; 6,82 (d, -C- NH-CH) ; 7,55 (m, 2H) 7,45 (d, IH) 8,30 (d, IH) : phényl adjacent à 1 ' hétérocycle ; 1,24 1,30 (s, Boc) .NMR (DMSO) 0.70 to 1.60 (C-CH 2 , C-CH); 2.70 to 2.85 (-S-CH 2 ); 4.12 -4.20 (m, = CN-CH 2) ; 4.35 4.20 (m, CO-N-CH-CO); 4.80 (dl, Ph-CH 2 OP); 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; 1.24 1.30 (s, Boc).
Exemple 14 : [S- [R* (3R*) ] ] - [2- [ [5- (3-cyclohexylpropyl) - 2,3,4, 5-tétrahydro-4-oxo-l , 5-benzothiazépin-3-yl] amino] -2- oxo-1- [ [4-phosphonooxyphényl] méthyl] éthyl] -carbamate de 1 , 1-diméthyléthyle .Example 14: [S- [R * (3R *)]] - [2- [[5- (3-cyclohexylpropyl) - 2,3,4,5-tetrahydro-4-oxo-1,5-benzothiazepin-3 -yl] amino] -2- oxo-1- [[4-phosphonooxyphenyl] methyl] ethyl] -carbamate of 1,1-dimethylethyl.
FG (I ' ) R3 = H , R5 = (CH2) 3-cyclohexyle . ; [Ai] = -CH (NHC02tBu) - CH2-Ph- ; A2 = OPO (OH) 2 FG (I ') R 3 = H, R 5 = (CH 2 ) 3 -cyclohexyl. ; [Ai] = -CH (NHC0 2 tBu) - CH 2 -Ph-; A 2 = OPO (OH) 2
On opère comme à l'exemple 12 à partir de 55 mg de produit dibenzylé obtenu au stade A de l'exemple 13 . On obtient 37 mg du produit monobenzylé attendu.The procedure is as in Example 12 from 55 mg of dibenzylated product obtained in stage A of Example 13. 37 mg of the expected monobenzylated product are obtained.
Rf= 0,27 (dichlorométhane/méthanol : 80/20)Rf = 0.27 (dichloromethane / methanol: 80/20)
RMN (DMSO)NMR (DMSO)
1,00 à 1,60 : C-CH2, -C-CH ; 2,50 à 3,50 ; 4,11 (m) :1.00 to 1.60: C-CH 2 , -C-CH; 2.50 to 3.50; 4.11 (m):
Ph-CH2-CH, Ph-SCH2, =C-N-CH2 ; 4,22 (m), 4,35 (m) : CO-CH-NCO ; 6,89-7,08 : C-Ph-O ; 7,31 (IH), 7,54 (2H) , 7,06 (IH) :Ph-CH 2 -CH, Ph-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):
Phenyle adjacent à 1 ' hétérocycle ; 8,34 (d) : =C-NH-CH ; 1,29 (si) : Boc.Phenyl adjacent to the heterocycle; 8.34 (d): = C-NH-CH; 1.29 (if): Boc.
Exemple 15 : trans (±) -2 ,3-dihydro 3- [ [3- [4- [ [hydroxy (phénylméthoxy) phosphinyl] oxy] phényl] -1-oxopropyl] amino] - 2- (4-methoxyphényl) -N- (1-naphtylméthyl) 4-oxo-l , 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. ; [Aι]=- (CH2)-Ph-; A2 = OPO (OBn) (OH) Stade A : trans (±) -2, 3-dihydro 3- [ [3- (4-hydroxyphényl) -1- oxopropyl] amino] -2- (4-methoxyphényl) N- (1-naphtylméthyl) -4- oxo-1, 5-benzothiazépine-5 (4H) -acétamide,FG (I ') R 3 = H; R 5 = - (CH 2 ) -CO-NH-CH 2 -Napht. ; [Aι] = - (CH 2) -Ph-; A 2 = OPO (OBn) (OH) Stage 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,
On ajoute à 0°C, sous argon, 256,5 mg d'aminé P4 (préparation 4) dans 2 ml de dichlorométhane à une solution constituée de 103 mg d'acide 3- (p-hydroxyphényl) -propionique, 120 mg de chlorhydrate de 1- (3-diméthylaminopropyl) -3 ethylcarbodiimide (EDC) et 84 ml d'hydrate de 1-hydroxybenzotriazole (HOBT) dans 1,4ml de CH2C12 et 0,4 ml de DMF. Après traitement et purification par chromatographie en éluant avec un mélange CH2Cl2/MeOH 98/2 on obtient 258mg de produit attendu.256.5 mg of amine P4 (preparation 4) in 2 ml of dichloromethane are added at argon under 256 mg to a solution consisting 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 C1 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.
Stade B : trans (±) 3- [ [3- [4- [ [bis (phénylméthoxy) phosphinyl] oxy] phényl] -1-oxopropyl] amino] -2, 3-dihydro-2- (4-méthoxy- phényl) -N- (1-naphtylméthyl) -4-oxo-l, 5-benzothiazépine-5 (4H) - acétamide. On ajoute à 148,5 mg de produit obtenu au stade précédent dans 4 ml d' acétonitrile, 1 ml de tétrachlorure de carbone, 125mg de N,N diisopropylethylamine, 6 mg de N,N-diméthyl- aminopyridine et 181 mg de dibenzylphosphite (HPO(OBn)2). Après traitement et purification sur colonne de silice en éluant avec le mélange CH2Cl2/MeOH 98/2 on obtient 79 mg de produit attendu. Stade C : DébenzylationStage 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) - acetamide. 148.5 mg of product obtained in the preceding stage are added to 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 dibenzylphosphite ( HPO (OBn) 2 ). 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
A une solution de 85,2 mg du produit obtenu au stade précédent dans 5 ml d'acétone, on ajoute 31 mg de iodure de sodium porte au reflux pendant 2 heures, puis rajoute 15 mg et maintient le reflux pendant 45 mn supplémentaires. Après concentration sous pression réduite et lavages avec de l'acétate d' éthyle puis de l'acétone, obtient 64,9 mg de produit attendu. Rf = 0,30 (CH2Cl2/MeOH : 80/20) IR (Nujol) Absorption OH/NH C=0 1671, 1628 (max) cm"1 Aromatique + amide II 1610,1600,1585,1555,1539,1511 cm"1 RMN (DMSO)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 brought to reflux for 2 hours are added, then 15 mg is added and the reflux is maintained for an additional 45 min. After concentration under reduced pressure and washes with ethyl acetate and then acetone, 64.9 mg of expected product is obtained. Rf = 0.30 (CH 2 Cl 2 / MeOH: 80/20) IR (Nujol) Absorption OH / NH C = 0 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, IH) , 4,78 (4H) : -C-N-CH2-CO, CO-NH-CH2-Ph- ; 4,46 (d,J=ll,5) : H2 trans, H3 ; 4,70 (d, 2H) : Ph-CH2OP ; 6,78 (m, 4H) , 6,96 (m, 4H) : C-Ph-O ; 7,30 à 7,62, 7,85 (m, IH) , 7,95 (m, IH) , 8,03 (m, IH) : naphtyl et phenyle adjacent à 1 ' hétérocycle ; 8,44 (t) : -C-NH-CH2 ; 8,57 (d) : -C-NH-CH ; 3,70 (s) : Ph-OMe . Exemple 16 : trans (±) -2 ,3-dihydro-3- [[ [6- [ [hydroxy (phénylméthoxy) phosphinyl] oxy] -2-naphtalenyl] carbonyl] amino] -2- (4-methoxyphényl) -N- (1-naphtylméthyl) -4-oxo-l , 5-benzo- thiazépine-5 (4H) -acétamide .2.10 (m, 2H), 2.32 (m, 2H): CO-CH 2 -CH 2 -Ph-; 4.29 (d, 1H), 4.78 (4H): -CN-CH 2 -CO, CO-NH-CH 2 -Ph-; 4.46 (d, J = 11.5): H 2 trans, H 3 ; 4.70 (d, 2H): Ph-CH 2 OP; 6.78 (m, 4H), 6.96 (m, 4H): C-Ph-O; 7.30 to 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-OMe. 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. ; [Ai] = -Napht-; A2 = OP (O) (OBn) (OH)FG (I ') R 3 = H; R 5 = -CH 2 -CO-NH-CH 2 -Napht. ; [Ai] = -Napht-; A 2 = OP (O) (OBn) (OH)
On opère comme à l'exemple 15 stades A, B et C mais à partir de 252,8 mg de P4 et de 115 mg d1 acide-6-hydroxy- naphtanoique . On obtient 108 mg de produit pur attendu. Rf= 0,43 (CH2Cl2/MeOH : 80/20) IR (Nujol) Absorption OH/NH C=0 1693 (max) cm"1 Aromatique + amide II 1609,1582,1537,1512,1498 cm"1 RMN (DMSO)One operates as in Example 15 Steps A, B and C, but starting with 252.8 mg of P4 and 115 mg of acid 1-hydroxy-6-naphthoic. 108 mg of expected pure product are obtained. Rf = 0.43 (CH 2 Cl 2 / MeOH: 80/20) IR (Nujol) Absorption OH / NH C = 0 1693 (max) cm "1 Aromatic + amide II 1609.1582.151537.1512.14498 cm " 1 NMR (DMSO)
3,65 (s) Ph-OCH3; 4,31 (d,J=16,5), 4,80 (masqué) N-CH2-CO-; 4,80 (masqué) H2; 5,01 (dd, J=8,5 et 11,5) H3; 4,80 (m) 4H- P-0-CH2-Ph et C0NH-CH2-Ar; 6,80 et 7,11 (AA'BB') Ph; 8,48 (t)CO-NH-CH2, -NH-CO-Ar; 7,15 à 7, 82 (m) 20H ; 7,93 (m) IH ; 8,04 (m) 1H;8,13 (si) IH aromatiques.3.65 (s) Ph-OCH 3 ; 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 aromatic.
Exemple 17 : trans (±) -2 ,3-dihydro-3- [[ [5- [ [hydroxy (phénylméthoxy) phosphinyl] oxy] -lH-indol-2-yl] carbonyl] amino] -2- (4-methoxyphényl) -N- (1-naphtylméthyl) -4-oxo-l , 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-benzothiazepin-5 (4H) -acetamide.
FG(I') R3 = H; R5 = - (CH2) -CO-NH-CH2-Napht. ; [Ai] = -indolyl-; A2 = OPO (OBn) (OH)FG (I ') R 3 = H; R 5 = - (CH 2 ) -CO-NH-CH 2 -Napht. ; [Ai] = -indolyl-; A 2 = OPO (OBn) (OH)
On opère comme à l'exemple 15 stades A, B et C mais à partir de 258 mg de P4 et de 110 mg d' acide-5-hydroxy-lH-indole- carboxylique. On obtient 104 mg de produit pur attendu.The procedure is as in Example 15 stages A, B and C but starting from 258 mg of P4 and 110 mg of 5-hydroxy-1H-indole-carboxylic acid. 104 mg of expected pure product are obtained.
Rf= 0,49 (CH2Cl2/MeOH : 80/20)Rf = 0.49 (CH 2 Cl 2 / MeOH: 80/20)
IR (Nujol)IR (Nujol)
Absorption OH/NH C=0 1658 (max) cm"1 Aromatique + amide II 1609,1584,1546,1513 cm"1 OH / NH absorption C = 0 1658 (max) cm "1 Aromatic + amide II 1609,1584,1546,1513 cm "1
RMN (DMSO)NMR (DMSO)
3,64 (s) Ph-OCH3; 4,29 (d,J=16,5), 4,71 à 4,85 (7H) , 5,013.64 (s) Ph-OCH 3 ; 4.29 (d, J = 16.5), 4.71 to 4.85 (7H), 5.01
( dd) N-CH2-CO- , H2 , H3 , -P-0-CH2-Ph et CONH-CH2-Ar ; 6 , 80 et 7 , 11 (AA ' BB ' ) Ph, 6 , 74 ( d) , 7 , 10 ( d) Ph-O ; 7 , 03 à 8 , 03 aromatiques; 8,49 (t) , 8,89 (d) , 11,20 H mobiles(dd) N-CH 2 -CO-, H2, H3, -P-0-CH 2 -Ph and CONH-CH 2 -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 moving
Exemple 18 : trans (±) -3- [ [ (4-boronophényl) carbonyl] amino]Example 18: trans (±) -3- [[((4-boronophenyl) carbonyl] amino]]
2 , 3-dihydro-2- (4-methoxyphényl) -N- (1-naphtylméthyl) -4-oxo-2, 3-dihydro-2- (4-methoxyphenyl) -N- (1-naphthylmethyl) -4-oxo-
1 , 5-benzothiazépine-5 (4H) -acétamide .1,5-benzothiazepine-5 (4H) -acetamide.
FG(I') R3= H; R5 = -CH2-CO-NH-CH2-Napht. ; [Ai] = -Ph-; A2 =FG (I ') R 3 = H; R 5 = -CH 2 -CO-NH-CH 2 -Napht. ; [Ai] = -Ph-; A 2 =
B (OH) 2 B (OH) 2
On opère comme à l'exemple 15 stade A mais à partir de 156,6 mg de P4 et 63 mg d'acide 4-boronobenzoïque . On obtient 135 mg de produit pur attendu.The procedure is as in Example 15 stage A but from 156.6 mg of P4 and 63 mg of 4-boronobenzoic acid. 135 mg of expected pure product are obtained.
Rf= 0,42 (CH2Cl2/MeOH : 95/5)Rf = 0.42 (CH 2 Cl 2 / MeOH: 95/5)
IR (Nujol)IR (Nujol)
Absorption OH/NHOH / NH absorption
C=0 1653 (max) cm"1 Aromatique + amide II 1609,1584,1558,1528,1512 cm"1 C = 0 1653 (max) cm "1 Aromatic + amide II 1609,1584,1558,1528,1512 cm " 1
RMN (DMSO)NMR (DMSO)
3,66 (s) Ph-OCH3; 4,29 (d,J=16,5), 4,76 N-CH2-CO-; 4,78 (m)3.66 (s) Ph-OCH 3 ; 4.29 (d, J = 16.5), 4.76 N-CH 2 -CO-; 4.78 (m)
H2 et CONH-CH2-Ar, 4,96 (dd,J=ll,5 et 8,5) H3; 6,78 et 7,07H2 and CONH-CH 2 -Ar, 4.96 (dd, J = 11.5 and 8.5) H3; 6.78 and 7.07
(AA'BB') Ph-O; 7,58 et 7,75 (AA'BB') CO-Ph, 7,40 (m) 3H, 7,50 à 8,05 8H aromatiques; 8,20 (s) 2H mobile, 8,42 (t, mobile)(AA'BB ') Ph-O; 7.58 and 7.75 (AA'BB ') CO-Ph, 7.40 (m) 3H, 7.50 to 8.05 8H aromatic; 8.20 (s) 2H mobile, 8.42 (t, mobile)
CO-NH-CH2, 8,96 (t, mobile) CO-NH-CH.CO-NH-CH 2 , 8.96 (t, mobile) CO-NH-CH.
Exemple 19 : trans (±) -3- [ [2- [ [ (4-boronophényl) carbonyl] amino] -1-oxoéthyl] amino] -2 , 3-dihydro-2- (4-methoxyphényl) -N-Example 19: trans (±) -3- [[2- [[((4-boronophenyl) carbonyl] amino] -1 -1-oxoethyl] amino] -2,3-dihydro-2- (4-methoxyphenyl) -N-
(1-naphtylméthyl) -4-oxo-l , 5-benzothiazépine-5 (4H) -acétamide .(1-naphthylmethyl) -4-oxo-1,5-benzothiazepine-5 (4H) -acetamide.
FG(I') R3 = H; R5 = -CH2-CO-NH-CH2-Napht. ; [Ax] = -CH2-NHCO-Ph-FG (I ') R 3 = H; R 5 = -CH 2 -CO-NH-CH 2 -Napht. ; [A x ] = -CH 2 -NHCO-Ph-
; A2 = B (OH) 2 ; A 2 = B (OH) 2
On opère comme à l'exemple 15 stade A mais à partir de 51 mg de P4 et 27 mg de N- (4-boronobenzoyl) -glycine. On obtient 28 mg de produit pur attendu. Rf = 0,45 (CH2Cl2/MeOH : 90/10)The procedure is as in Example 15 stage A but from 51 mg of P4 and 27 mg of N- (4-boronobenzoyl) -glycine. 28 mg of expected pure product are obtained. Rf = 0.45 (CH 2 Cl 2 / MeOH: 90/10)
IR (Nujol)IR (Nujol)
Absorption OH/NHOH / NH absorption
C=0 1669 (max), 1653 (ep) cm"1 Aromatique + amide II 1609,1584,1558,1528,1512 cm"1 C = 0 1669 (max), 1653 (ep) cm "1 Aromatic + amide II 1609,1584,1558,1528,1512 cm " 1
RMN (DMSO)NMR (DMSO)
3,53 (dd, d après échange), 3,77 (dd, d après échange) Ar-3.53 (dd, after exchange), 3.77 (dd, after exchange) Ar-
CH2-NHCO; 3,70 (s) Ph-OCH3; 4,29 (dl,J=16,5), 4,75 masqué CO-CH 2 -NHCO; 3.70 (s) Ph-OCH 3 ; 4.29 (dl, J = 16.5), 4.75 masked CO-
N-CHz-CO-; 4,48 (d, J=ll,5) H2, 4,70 à 4,80 (m) H3 + CO-N- CH2-CO- ; 6,76 et 7,01 (AA'BB') Ph-O; 7,76 (AA'BB') CO-Ph;N-CHz-CO-; 4.48 (d, J = 11.5) H2, 4.70 to 4.80 (m) H3 + CO-N- CH 2 -CO-; 6.76 and 7.01 (AA'BB ') Ph-O; 7.76 (AA'BB ') CO-Ph;
7,30 à 8,02 (m) 11H aromatiques; 8,17 (s, large) 2H mobiles,7.30 to 8.02 (m) 11H aromatic; 8.17 (s, large) 2H mobile,
8,41 (t large) 8,50 (t large) CO-NH-CH2, 8,59 (d, mobile) CO-8.41 (wide t) 8.50 (wide t) CO-NH-CH 2 , 8.59 (d, mobile) CO-
NH-CH.NH-CH.
Exemple 20 : (R) -N- [5- (3 -cyclohexylpropyl) -4-oxo-2 , 3 , 4 , 5- tétrahydro-l , 5-benzothiazépin-3-yl] -3-formyl-4-Example 20: (R) -N- [5- (3-cyclohexylpropyl) -4-oxo-2, 3, 4, 5-tetrahydro-1,5-benzothiazepin-3-yl] -3-formyl-4-
(phosphonooxy) benzamide .(phosphonooxy) benzamide.
FG (I ' ) R3 = H ; R5 = - (CH2) 3-cyclohexyle . ; [Ai] = -Ph (m-CHO) - ;FG (I ') R 3 = H; R 5 = - (CH 2 ) 3 -cyclohexyl. ; [Ai] = -Ph (m-CHO) -;
A2 = OPO (OBn) (OH)A 2 = OPO (OBn) (OH)
Stade A : (R) -N- [5- (3-cyclohexylpropyl) -4-oxo-2, 3, 4, 5- tétrahydro-1, 5-benzothiazépin-3-yl] -4-hydroxy 3-formyl- benzamide .Stage A: (R) -N- [5- (3-cyclohexylpropyl) -4-oxo-2, 3, 4, 5-tetrahydro-1, 5-benzothiazepin-3-yl] -4-hydroxy 3-formyl- benzamide.
On opère comme à l'exemple 15 stade A, mais à partir de 318,1 mg de P5 et 199 mg d' acide-3-formyl-4-hydroxy-benzoique . On obtient 226 mg de produit pur attendu. Stades B et C :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 is obtained. Stage B and C:
On opère comme à l'exemple 15 stades B et C mais à partir deWe operate as in example 15 stages B and C but starting from
100,7 mg du produit obtenu au stade précédent. On obtient100.7 mg of the product obtained in the previous stage. We obtain
26,9 mg de produit attendu.26.9 mg of expected product.
IR (Nujol) Absorption OH/NHIR (Nujol) OH / NH absorption
C=0 1689 (m), 1639 (F) cm"1 C = 0 1689 (m), 1639 (F) cm "1
Aromatique + amide II : 1605,1585,1550,1482 cm"1 Aromatic + amide II: 1605,1585,1550,1482 cm "1
RMN (DMSO)NMR (DMSO)
0,80 à 1,65 CH2 et CH (cycle et chaîne); 3,30 à 3,60 (s) S- CH2-CH(N) (cycle); 4,27 CO-N-CH2-; 4,59 (m) S-CH2-CH(N),0.80 to 1.65 CH 2 and CH (cycle and chain); 3.30 to 3.60 (s) S-CH 2 -CH (N) (cycle); 4.27 CO-N-CH 2 -; 4.59 (m) S-CH 2 -CH (N),
6,95 à 8,35, 9,09 (d) aromatiques; 10,37 (si) Ph-CHO. Exemple 21 : (R) -N- [5- (3-cyclohexylpropyl) -4-oxo-2, 3,4,5- tétrahydro-1 , 5-benzothiazépin-3-yl] -4- (phosphonooxy) - benzamide .6.95 to 8.35, 9.09 (d) aromatics; 10.37 (si) Ph-CHO. Example 21: (R) -N- [5- (3-cyclohexylpropyl) -4-oxo-2, 3,4,5- tetrahydro-1,5,5-benzothiazepin-3-yl] -4- (phosphonooxy) - benzamide .
FG (I ' ) R3 = H ; R5 = (CH2) 3-cyclohexyle ; [Aι] =-Ph- ; A2 = -OPO (OH) (OH)FG (I ') R 3 = H; R 5 = (CH 2 ) 3 -cyclohexyl; [Aι] = -Ph-; A 2 = -OPO (OH) (OH)
On opère comme à l'exemple 15 stade A, B et C mais à partir de 106,2 mg de P5 et 55 mg d' acide-4-hydroxy-benzoique. On obtient au bout de ces trois stades et après purification 69 mg de produit pur attendu.The procedure is as in Example 15 stage A, B and C but from 106.2 mg of P5 and 55 mg of 4-hydroxy-benzoic acid. At the end of these three stages and after purification, 69 mg of expected pure product are obtained.
Rf= 0,59 (CH2Cl2/MeOH : 90/10) IR (Nujol)Rf = 0.59 (CH 2 Cl 2 / MeOH: 90/10) IR (Nujol)
Absorption OH/NH Max 3304 cm"1 C=0 1647 cm"1 Aromatique + amide II : 1605,1585,1548,1501 cm"1 RMN (DMSO)Absorption OH / NH Max 3304 cm "1 C = 0 1647 cm " 1 Aromatic + amide II: 1605,1585,1548,1501 cm "1 NMR (DMSO)
0,77 (m) 2H, 1,10 (m) 6H, 1,30 à 1,65 (m) 6 à 7H, Chaîne aliphatique; 3,47 (m), 4,24 (m) CO-N-CH2-; 3,30 (t) 3,47 (m) S-CH2-CH(N); 4,55 (m) H3, 7,10 à 7,80 7 à 8H aromatiques; 8,63 (d) CH-NH-CO.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) S-CH 2 -CH (N); 4.55 (m) H3, 7.10 to 7.80 7 to 8H aromatic; 8.63 (d) CH-NH-CO.
Exemple 22 : acide (R) - [4- [ [ [5- (3-cyclohexylpropyl) -4-oxo- 2 ,3, 4 ,5-tétrahydro-l,5-benzothiazépin-3-yl] amino] carbonyl] 2-formylphénoxy] -acétique.Example 22: acid (R) - [4- [[[5- (3-cyclohexylpropyl) -4-oxo- 2, 3, 4, 5-tetrahydro-1,5, benzothiazepin-3-yl] amino] carbonyl] 2-formylphenoxy] -acetic.
FG (I ' ) R3 = H ; R5 = - (CH2) 3-cyclohexyle ; [Ai] = -Ph (m-CHO) - ; A2 = -OCH2COOHFG (I ') R 3 = H; R 5 = - (CH 2 ) 3 -cyclohexyl; [Ai] = -Ph (m-CHO) -; A 2 = -OCH 2 COOH
Stade A : AlkylationStage A: Alkylation
- (R)-[4-[[[5- (3-cyclohexylpropyl) -4-oxo-2, 3,4, 5-tétrahydro-- (R) - [4 - [[[5- (3-cyclohexylpropyl) -4-oxo-2, 3,4, 5-tetrahydro-
1, 5-benzothiazépin-3-yl] amino] carbonyl] 2-formylphénoxy] acétate d' éthyle,1,5-benzothiazepin-3-yl] amino] carbonyl] 2-formylphenoxy] ethyl acetate,
A 43,4 mg du produit obtenu au stade A de l'exemple 20 dans 5 ml d'acétone on ajoute 26 mg de carbonate de potassium et 16 mg de bromoacétate d' éthyle et on chauffe au reflux pendant 3 heures. Après traitement on obtient 52 mg de produit brut attendu. Stade B : SaponificationTo 43.4 mg of the product obtained in stage A of Example 20 in 5 ml of acetone is added 26 mg of potassium carbonate and 16 mg of ethyl bromoacetate and the mixture is heated at reflux for 3 hours. After treatment, 52 mg of expected crude product is obtained. Stage B: Saponification
On agite à température ambiante 52 mg d'ester obtenu au stade précédent dans 5 ml de méthanol avec 0,094ml de soude 2N. On obtient 37 mg de produit brut que l'on purifie par chromato- graphie en éluant avec le mélange CH2Cl2/MeOH 90/10 puis 85/15. On obtient 29 mg de produit pur attendu. IR (Nujol)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. 37 mg of crude product are obtained, which product is purified by chromatography, eluting with a CH 2 Cl 2 / MeOH 90/10 then 85/15 mixture. 29 mg of expected pure product are obtained. IR (Nujol)
Absorption OH/NH 3414 (ep.) 3310 cm"1 (Max) C=0 1740 (ep) , 1704 (ep) , 1687, 1645 cm"1 Aromatique + amide II : 1609,1585,1547,1491 cm"1 Absorption OH / NH 3414 (ep.) 3310 cm "1 (Max) C = 0 1740 (ep), 1704 (ep), 1687, 1645 cm " 1 Aromatic + amide II: 1609,1585,1547,1491 cm "1
SM (ionisation Electrospray, mode négatif) : MM = 524/... compatible avec la structure attendue.SM (Electrospray ionization, negative mode): MM = 524 / ... compatible with the expected structure.
Exemple 23 : (R) -N- [5- (3-cyclohexylpropyl) -4-oxo-2 ,3,4,5- tétrahydro-1 , 5-benzothiazépin-3-yl] -4- (diphosphonométhyl) - benzamide .Example 23: (R) -N- [5- (3-cyclohexylpropyl) -4-oxo-2, 3,4,5-tetrahydro-1,5,5-benzothiazepin-3-yl] -4- (diphosphonomethyl) - benzamide .
FG(I') R3 = H; R5= - (CH2) 3-cyclohexyle; [Aι]=-Ph-;FG (I ') R 3 = H; R 5 = - (CH 2 ) 3 -cyclohexyl; [Aι] = - Ph-;
A2 = -CH[PO(OH)2]2. Stade A : (R) -N- [5- (3-cyclohexylpropyl) -4-oxo-2, 3, 4, 5- tétrahydro-1, 5-benzothiazépin-3-yl] -4- (bis (diéthoxy- phosphényl) méthyl] -benzamide.A 2 = -CH [PO (OH) 2 ] 2. Stage A: (R) -N- [5- (3-cyclohexylpropyl) -4-oxo-2, 3, 4, 5-tetrahydro-1, 5-benzothiazepin-3-yl] -4- (bis (diethoxy- phosphenyl) methyl] -benzamide.
On mélange à température ambiante 123 mg d'acide Acide 4- [bis (diéthoxyphosphinyl) méthyl] benzoique., 60 mg d'EDC, 42 mg d'HOBt, 2 ml de dichlorométhane, et 1 ml de DMF, agite 10 minutes à 0°C puis verse ce mélange dans le mélange constitué de 80 mg de P5 dans 2 ml de dichlorométhane à 0°C sous argon. Le milieu est agité une nuit à température ambiante. Après traitement et purification par chromatographie sur silice en éluant avec un mélange CH2Cl2/MeOH 98/2, on obtient 127 mg de produit pur attendu. Stade B : Réduction123 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 mixed at ambient temperature for 123 minutes. 0 ° C then pour 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 CH 2 Cl 2 / MeOH 98/2 mixture, 127 mg of expected pure product are obtained. Stage B: Reduction
On ajoute goutte à goutte 40 mg de bromure de trimethylsilane au mélange constitué de 29 mg du produit obtenu au stade précédent et 1,5 ml de dichlorométhane et porte au reflux pendant 24 heures, on coule ensuite dans le méthanol, évapore sous pression réduite et recristallise dans l'ether à froid.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 brought to reflux for 24 hours, it is then poured into methanol, evaporated under reduced pressure and recrystallized from cold ether.
On obtient 17,5 mg de produit pur attendu.17.5 mg of expected pure product are obtained.
Rf = 0,16 (CH2Cl2/MeOH : 80/20) IR (Nujol)Rf = 0.16 (CH 2 Cl 2 / MeOH: 80/20) IR (Nujol)
Absorption OH/NHOH / NH absorption
NH 3410 cm"1 NH 3410 cm "1
C=0 1649 cm"1 C = 0 1649 cm "1
Aromatique + amide II : 1611,1585,1571,1549,1523,1491 cm"1 RMN (DMSO)Aromatic + amide II: 1611,1585,1571,1549,1523,1491 cm "1 NMR (DMSO)
0,70 à 1,60 CH2 et CH (cycle et chaîne); 3,26 à 3,98 (s) S-0.70 to 1.60 CH 2 and CH (cycle and chain); 3.26 to 3.98 (s) S-
CH2-CH(N) (cycle); 4,23 CO-N-CH2-; 4,56 (m) : S-CH2-CH(N),CH 2 -CH (N) (cycle); 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) aromatiques; 8,74 (d)7.34 (m), 7.61 (m), 7.68 (m), 7.74) aromatic; 8.74 (d)
CH-NH-CO. Exemple 24 : [3R- [3R* (S*) ]] -β- (acétylamino) -N- [5- (3-cyclo- hexylpropyl) -2,3,4, 5-tétrahydro-4-oxo-l , 5-benzothiazépin-3- yl] -4- (di luorophosphonométhyl) -benzènepropanamide .CH-NH-CO. Example 24: [3R- [3R * (S *)]] -β- (acetylamino) -N- [5- (3-cyclohexylpropyl) -2,3,4,5-tetrahydro-4-oxo-1 , 5-benzothiazepin-3-yl] -4- (di luorophosphonomethyl) -benzenepropanamide.
FG (I ' ) R3 = H ; R5 = - (CH2) 3-cyclohexyle ; [Ai] = -CH (NHAc) -CH2-Ph- ; A2 ≈ -CF2PO (OH) 2 FG (I ') R 3 = H; R 5 = - (CH 2 ) 3 -cyclohexyl; [Ai] = -CH (NHAc) -CH 2 -Ph-; A 2 ≈ -CF 2 PO (OH) 2
On opère comme à l'exemple 23 stades A et B mais à partir de 121,5 mg de l'aminé P5 et 180 mg de N-acétyl-4- [ [ (diéthoxy- phosphinyl) difluoro] méthyl] -L-phénylalamine . On obtient de produit pur attendu. Rf CH2Cl2/MeOH 80/20 = 0,63 IR (Nujol)The procedure is as in Example 23 stages A and B but starting with 121.5 mg of the amine P5 and 180 mg of N-acetyl-4- [[(diethoxyphosphinyl) difluoro] methyl] -L-phenylalamine . Obtained pure product expected. Rf CH 2 Cl 2 / MeOH 80/20 = 0.63 IR (Nujol)
NH 3421 (Max.), 3393 (ep.) cm"1 C=0 1677 (ép.), 1656 (Max) cm"1 Aromatique + amide II : 1615,1600,1583,1569,1501 cm"1 RMN (DMSO)NH 3421 (Max.), 3393 (th.) Cm "1 C = 0 1677 (th.), 1656 (Max) cm " 1 Aromatic + amide II: 1615,1600,1583,1569,1501 cm "1 NMR ( DMSO)
1,10 à 1,70 CH2 et CH (cycle et chaîne); 1,97 (s) NHCOCH3; 1,31 (m) 4,18 (ml) les P-OEt; 2,72 (t) (IH) , 3,35 (m) (IH) , 3,04 (m) (2H) S-CH2-CH(N) (cycle) et Ph-CH2-CH (N) -CO; 3,74 (m) (IH) 4,30 (m) (IH) CO-N-CH2-; 4,35 (m) (IH) 4,66 (q) H3, 5,92 (d) , 6,82 (d) CH-NH-CO; 7,21 7,51 AA'BB' Phényl; 7,21 (IH), 7,29(m) (IH), 7,46 (m) IH, 7,65 (dd) (IH), phényl du benzothioazépinone .1.10 to 1.70 CH 2 and CH (cycle and chain); 1.97 NHCOCH 3 ; 1.31 (m) 4.18 (ml) P-OEt; 2.72 (t) (IH), 3.35 (m) (IH), 3.04 (m) (2H) S-CH 2 -CH (N) (cycle) 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), phenothenzothioazepinone.
Exemple 25 : (R) -N- [5- (4-cyclohexylbutyl) -4-oxo-2 ,3,4,5- 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-1,5,5-benzothiazepin-3-yl] -N '- [4- ( phosphonooxy) phenyl] -urea.
FG(I') R3 = H; R5 = - (CH2) 4-cyclohexyle; [Ai] = -NH-Ph-; A2 = OP(O) (OH) 2 FG (I ') R 3 = H; R 5 = - (CH 2 ) 4 -cyclohexyl; [Ai] = -NH-Ph-; A 2 = OP (O) (OH) 2
Stade A : formation de l'urée - (R)-N-[5-(4-cyclohexylbutyl)-4-oxo-2,3,4,5-tétrahydro-l,5- benzothiazépin-3-yl] -N' - (4-methoxyphényl) -urée. A un mélange consitué de 14 mg de 4-methoxyisocyanate dans 1 ml de toluène, on ajoute sous argon 26,2mg de P6 dans 0,5 ml de toluène, agite à température ambiante pendant 3 heures et concentre sous pression réduite. On obtient 44,1 mg de produit brut que l'on purifie par chromatographie sur silice en éluant avec du CH2C12 puis avec le mélange CH2Cl2/MeOH 99,5/0,5. On obtient 31mg de produit pur attendu. Stade B : clivage du méthoxy - (R)-N-[5- (4-cyclohexylbutyl) -4-oxo-2,3, 4, 5-tétrahydro-l, 5- benzothiazépin-3-yl] -N ' - (4-hydroxyphényl) -urée . A une solution de 29 mg du produit obtenu au stade précédent, dans 2 ml de CH2C12, on ajoute sous argon 22 mg d' ethanethiol et 48 mg de chlorure d'aluminium, agite 3 heures à tempéra- ture ambiante puis ajoute 2,2 ml de THF, 0,6 ml d'acide chlorhydrique 0,5M et 2,2 ml d'eau. Après extraction à l'acétate d' éthyle, séchage et évaporation sous pression réduite, on obtient 30 mg du produit attendu. Stade C :phophorylation - (R)-N-[5-(4-cyclohexylbutyl)-4-oxo-2,3,4,5-tétrahydro-l,5- benzothiazépin-3-yl] -N ' - [4- [ [bis (phénylméthoxy) phosphinyl] oxy] phényl] urée.Stage A: formation of urea - (R) -N- [5- (4-cyclohexylbutyl) -4-oxo-2,3,4,5-tetrahydro-1,5,5-benzothiazepin-3-yl] -N '- (4-methoxyphenyl) -urea. To a mixture of 14 mg of 4-methoxyisocyanate in 1 ml of toluene, 26.2 mg of P6 in 0.5 ml of toluene are added under argon, the mixture is stirred at room temperature for 3 hours and concentrated under reduced pressure. 44.1 mg of crude product is obtained which is purified by chromatography on silica eluting with CH 2 C1 2 then with the CH 2 Cl 2 / MeOH 99.5 / 0.5 mixture. 31 mg of expected pure product are 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 C1 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 added 2.2 ml of THF, 0.6 ml of 0.5M hydrochloric acid and 2.2 ml of water. After extraction with ethyl acetate, drying and evaporation under reduced pressure, 30 mg of the expected product are obtained. Stage C: phophorylation - (R) -N- [5- (4-cyclohexylbutyl) -4-oxo-2,3,4,5-tetrahydro-1,5,5-benzothiazepin-3-yl] -N '- [4 - [[bis (phenylmethoxy) phosphinyl] oxy] phenyl] urea.
On ajoute à 23,5mg de produit obtenu au stade précédent dans 2 ml d' acétonitrile 0,2ml de tétrachlorure de carbone, 27 mg de N,N diisopropylethylamine, 1,2 mg de N, N-diméthylaminopy- ridine et 39 mg du dibenzylphosphite . Après traitement et purification sur colonne de silice en éluant avec le mélangeTo 23.5 mg of product obtained in the preceding stage is added to 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 dibenzylphosphite. After treatment and purification on a silica column, eluting with the mixture
CH2Cl2/MeOH 99/1 puis 98/2 on obtient 24 mg de produit attendu.CH 2 Cl 2 / MeOH 99/1 then 98/2 to obtain 24 mg of the expected product.
Stade D : Débenzylation totale On sature une solution de 23,1 mg du produit obtenu au stade précédent dans 3 ml de MeOH, avec de l'hydrogène, agite 3 heures à température ambiante et évapore sous pression réduite jusqu'à obtention de 17 mg de produit pur attendu.Stage D: Total Debenzylation A solution of 23.1 mg of the product obtained in the preceding stage is saturated in 3 ml of MeOH, with hydrogen, stirred for 3 hours at room temperature and evaporated under reduced pressure until 17 mg is obtained. expected pure product.
Rf= 0,60 (Methanol/Eau : 80/20) IR (Nujol)Rf = 0.60 (Methanol / Water: 80/20) IR (Nujol)
Absorption OH/NHOH / NH absorption
C=0 1652 cm"1 (ép.) 1636 cm"1 (Max.)C = 0 1652 cm "1 (th.) 1636 cm " 1 (Max.)
Aromatique + amide II : 1608,1582,1554,1508 cm"1 Aromatic + amide II: 1608,1582,1554,1508 cm "1
RMN (DMSO) 2,9 (t) à 3,5 (m) S-CH2-CH(N) (cycle); 4,30 H3; 6,96 7,06NMR (DMSO) 2.9 (t) to 3.5 (m) S-CH 2 -CH (N) (cycle); 4.30 H3; 6.96 7.06
(AA'BB') phényl, 7,32 (m), 7,55 (m) phényl du benzothioazépinone .(AA'BB ') phenyl, 7.32 (m), 7.55 (m) phenyl of benzothioazepinone.
Exemple 26 : cis (±) -N- [5- (3-cyclohexylpropyl) -2- (4-méthoxy- phényl) -4-oxo-2 ,3,4,5-tétrahydro-l , 5-benzothiazépin-3-yl] -4- [[hydroxy (phénylméthoxy) phosphinyl] oxy] -benzèneacétamide .Example 26: 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] -benzeneeacetamide.
FG(I') R3 = -PhOMe; R5 = - (CH2) 3-cyclohexyle; [Ai] = -CH2-Ph-; A2 = -OPO (OBn) (OH) (cis)FG (I ') R 3 = -PhOMe; R 5 = - (CH 2 ) 3 -cyclohexyl; [Ai] = -CH 2 -Ph-; A 2 = -OPO (OBn) (OH) (cis)
Stade A : cis (±) 4- [ [bis (phénylméthoxy) phosphinyl] oxy] N- [5- (3-cyclohexylpropyl) -2- (4-methoxyphényl) -4-oxo-2, 3,4,5- tétrahydro-1, 5-benzothiazépin-3-yl] -benzèneacétamide . On prépare une solution sous argon à 0°C constituée de 140 mg d'acide 4- [ [bis (phénylméthoxy) phosphinyl] oxy] benzène acétique, de 65 mg d'EDC et de 45 mg d'HOBt dans 1 ml de CH2C12 et 0,25 ml de DMF, et verse dans le mélange constitué de 0,499g d'aminé cis d, 1 (Préparation 7) et 1 ml de CH2C12. Après 6 heures à température ambiante, on dilue à l'acétate d' éthyle, lave, sèche et concentre. On obtient 233 mg de produit brut que l'on purifie par chromatographie en éluant avec un mélange CH2Cl2/MeOH 98,5/1,5 pour obtenir 211 mg de produit attendu Stade B :Stage 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] -benzeneeacetamide. A solution is prepared 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 C1 2 and 0.25 ml of DMF, and pour into the mixture consisting of 0.499g of amine cis d, 1 (Preparation 7) and 1 ml of CH 2 C1 2 . After 6 hours at room temperature, diluted with ethyl acetate, washed, dried and concentrated. 233 mg of crude product is obtained which is purified by chromatography eluting with a CH 2 Cl 2 / MeOH 98.5 / 1.5 mixture to obtain 211 mg of the expected product Stage B:
On chauffe au reflux pendant 1 heure 30 la solution de 71,8 mg du produit obtenu au stade précédent dans 5 ml d'acétone à laquelle on a ajouté 44 mg de iodure de sodium, concentre l'acétone sous pression réduite, dilue avec l'acétate d' éthyle, lave, sèche et concentre sous pression réduite jusqu'à obtention de 32,3 mg de produit attendu. Rf CH2Cl2/MeOH = 0,61 IR (Nujol) NH 3408 cm"1 The solution of 71.8 mg of the product obtained in the preceding stage in 5 ml of acetone is heated to reflux for 1 hour 30 minutes to which 44 mg of sodium iodide are added, the acetone is concentrated under reduced pressure, diluted with 1 'ethyl acetate, washed, dried and concentrated under reduced pressure until 32.3 mg of expected product is obtained. Rf CH 2 Cl 2 / MeOH = 0.61 IR (Nujol) NH 3408 cm "1
C=0 1652 cm"1 (Max, complexe) cm"1 Aromatique + amide II : 1609,1585,1513,1499 cm"1 RMN (DMSO)C = 0 1652 cm "1 (Max, complex) cm " 1 Aromatic + amide II: 1609,1585,1513,1499 cm "1 NMR (DMSO)
0,83 (m) (2H) 1,15 (m) (8H) 1,63 (m) (7H) (cycle et chaîne); 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 (masqué) 7,71 (dd) H5 et H8, 7,29 (masqué) 7,46 (t) H7 et H6 (phényl du benzothioazépinone) ; 6,99 (d, J=8,5) CH en ortho de O, 6,85 (d, J=8,5) CH en meta de O; 7,18 (d, J=8,5) 6,790.83 (m) (2H) 1.15 (m) (8H) 1.63 (m) (7H) (cycle and chain); 3.25 (s) Ph-CH 2 -CO, 3.80 (s) OCH 3 , 3.44 (m) 4.36 (m) N-CH 2 , 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 (benzothioazepinone phenyl); 6.99 (d, J = 8.5) CH in ortho of O, 6.85 (d, J = 8.5) CH in meta of O; 7.18 (d, J = 8.5) 6.79
(d, J=8,5) aromatiques (Ph-OMe) ; 5,10 (s) 5,12 (s) 0-CH2-Ph,(d, J = 8.5) aromatics (Ph-OMe); 5.10 (s) 5.12 (s) 0-CH 2 -Ph,
7,34 (s) (phenyle du benzyle)7.34 (s) (benzyl phenyl)
Exemple 27 : cis (±) -N- [5- (3-cyclohexylpropyl) -2- (4-méthoxy- phényl) -4-oxo-2 ,3,4 ,5-tétrahydro-l ,5-benzothiazépin-3-yl] -4- (phosphonooxy) -benzèneacétamide .Example 27: cis (±) -N- [5- (3-cyclohexylpropyl) -2- (4-methoxyphenyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3 -yl] -4- (phosphonooxy) -benzeneeacetamide.
FG(I') R3= -PhOMe; R5= - (CH2) 3-cyclohexyle; [A ≈ -CH2-Ph-; A2 = -OPO (OH) 2 (cis) On sature en hydrogène une solution de 134 mg du produit obtenu au stade précédent dans 2 ml de méthanol à laquelle on a ajouté 18 mg de palladium sur carbone à 95%, agite 3 heures à température ambiante et évapore sous pression réduite jusqu'à obtention de 94 mg de produit pur attendu. Rf= 0,50 (Methanol/Eau : 80/20) IR (Nujol) Absorption OH/NH C=0 1650 cm"1 (Max)FG (I ') R 3 = -PhOMe; R 5 = - (CH 2 ) 3 -cyclohexyl; [A ≈ -CH 2 -Ph-; A 2 = -OPO (OH) 2 (cis) A 134 mg solution of the product obtained in the preceding stage is saturated with hydrogen in 2 ml of methanol to which 18 mg of 95% palladium on carbon is added, the mixture is stirred for 3 hours at room temperature and evaporated under reduced pressure until 94 mg of expected pure product is obtained. Rf = 0.50 (Methanol / Water: 80/20) IR (Nujol) OH / NH absorption C = 0 1650 cm "1 (Max)
Aromatique + amide II : 1608,1582,1510 cm"1 RMN (DMSO) 0,81 (m) (2H) 1,10 à 1,30 (m) (7 à 8H) 1,44 à 1,70 (m) (8H)Aromatic + amide II: 1608.1582.1515 cm "1 NMR (DMSO) 0.81 (m) (2H) 1.10 to 1.30 (m) (7 to 8H) 1.44 to 1.70 (m ) (8H)
(cycle et chaîne); 3,29 (AB, J=14) Ph-CH2-CO; 3,52 (m) (IH) 4,37 (m) (IH) N-CH2; 3,78 (s) 3H Ph-OMe; 4,62 (t, J=7) H3;(cycle and chain); 3.29 (AB, J = 14) Ph-CH 2 -CO; 3.52 (m) (1H) 4.37 (m) (1H) N-CH 2 ; 3.78 (s) 3H Ph-OMe; 4.62 (t, J = 7) H3;
6,80 à 7,02 (m) 6H, 7,16 (dl) (2H) , 7,37 (m) 2H, 7,58 (m)6.80 to 7.02 (m) 6H, 7.16 (dl) (2H), 7.37 (m) 2H, 7.58 (m)
(2H) , 7,72 (d) IH aromatiques Exemple 28 : [S- [R* (6S*) ] ] - [2- [ [4- (3-cyclohexylpropyl) hexahydro-5-oxo-l , 4-thiazépin-6-yl] -amino] -2-oxo-l- [ [4- (phosphonooxy) phényl] méthyl] éthyl] -carbamate de 1, 1-diméthyléthyle .(2H), 7.72 (d) IH aromatic Example 28: [S- [R * (6S *)]] - [2- [[4- (3-cyclohexylpropyl) hexahydro-5-oxo-l, 4- thiazepin-6-yl] -amino] -2-oxo-l- [[4- (phosphonooxy) phenyl] methyl] ethyl] -carbamate of 1,1-dimethylethyl.
FG (I ' ' ) ; R5= - (CH2) 3-cyclohexyle ; [A ≈ -CH (NHC02tBu) -CH2-Ph- ; A2 = -OP (O) (OH) 2 FG (I ''); R 5 = - (CH 2 ) 3 -cyclohexyl; [A ≈ -CH (NHC0 2 tBu) -CH 2 -Ph-; A 2 = -OP (O) (OH) 2
Stade A : AcylationStage A: Acylation
- [S- [R* (6S*) ]]- [1- [ [4- [ [bis (phénylméthoxy) phosphinyl] oxy] phényl] méthyl] -2- [ [hexahydro-5-oxo-l, 4-thiazépin-6-yl] amino] -2-oxoéthyl] -carbamate de 1, 1-diméthyléthyle .- [S- [R * (6S *)]] - [1- [[4- [[bis (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2- [[hexahydro-5-oxo-l, 4- 1,1-dimethylethyl thiazepin-6-yl] amino] -2-oxoethyl] -carbamate.
On mélange pendant 15 minutes à 0°C sous argon le mélange constitué de 455 mg de L-Boc-tyr-O- (P03Bn2) , 158 mg de [l-(3- diméthylaminopropyl) -3-ethylcarbodiimide HC1] (EDC) et 111 mg de (1-hydroxybenzothiazole hydrate) (HOBt) dans 600μl de diméthylformamide (DMF) et 1,9 ml de dichlorométhane (CH2C12) et ajoute une solution de 162 mg de P8 dans 2ml de CH2C12 et 235 μl de base de Hunig. Le mélange est agité à température ambiante pendant 5 heures, puis est dilué dans 30 ml d'acétate d' éthyle, puis après lavage et séchage, la phase organique est évaporé sous pression réduite pour obtenir 442 mg de produit brut . Rf = 0,4 (CH2Cl2/MeOH 90/10) Stade B : AlkylationThe mixture consisting of 455 mg of L-Boc-tyr-O- (P0 3 Bn 2 ), 158 mg of [1- (3-dimethylaminopropyl) -3-ethylcarbodiimide HC1] is mixed for 15 minutes at 0 ° C. under argon. (EDC) and 111 mg of (1-hydroxybenzothiazole hydrate) (HOBt) in 600 μl of dimethylformamide (DMF) and 1.9 ml of dichloromethane (CH 2 C1 2 ) and add a solution of 162 mg of P8 in 2 ml of CH 2 C1 2 and 235 μl of Hunig base. The mixture is stirred at room 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 = 0.4 (CH 2 Cl 2 / MeOH 90/10) Stage B: Alkylation
- [S-[R* (6S*) ]]- [l-[ [4- [ [bis (phénylméthoxy) phosphinyl] oxy] phényl] méthyl] -2- [ [4- (3-cyclohexylpropyl) hexahydro-5-oxo- 1, 4-thiazépin-6-yl] amino] 2-oxoéthyl] carbamate de 1,1- diméthyléthyle .- [S- [R * (6S *)]] - [l- [[4- [[bis (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2- [[4- (3-cyclohexylpropyl) hexahydro-5 -oxo- 1,4-thiazepin-6-yl] amino] 2-oxoethyl] 1,1-dimethylethyl carbamate.
A une solution de 222 mg du produit obtenu au stade précédent dans 3 ml de DMF à 0°C, sous argon, on ajoute 24 mg d'hydrure de sodium et 116 mg de l-iodo-3-cyclohexylpropyle dans 1 ml de DMF et agite 15 minutes à 0°C puis 3 heures à température ambiante. On dilue avec 20 ml d'eau, extrait à l'acétate d' éthyle et évapore sous pression réduite jusqu'à obtention de 197 mg de produit brut attendu. Rf = 0,2 (CH2Cl2/MeOH 98/2) Stade C : DébenzylationTo a solution of 222 mg of the product obtained in the preceding 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 for 15 minutes at 0 ° C then 3 hours at room temperature. 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 = 0.2 (CH 2 Cl 2 / MeOH 98/2) Stage C: Debenzylation
On sature en hydrogène une solution de 50 mg du produit obtenu au stade précédent dans 2 ml de MeOH à laquelle on a ajouté 7,7 mg de palladium sur carbone à 95%, agite 1 nuit à température ambiante et évapore sous pression réduite jusqu'à obtention de 36 mg de produit pur attendu. Rf = 0,20 (méthanol/Eau 80/20) IR (Nujol) Absorption OH/NH C=0 1707, 1667 (ep.), 1646 (Max) cm"1 Aromatique + amide II : 1609,1508 cm"1 RMN (DMSO)A 50 mg solution of the product obtained in the preceding stage in 2 ml of MeOH is saturated with hydrogen, to which 7.7 mg of 95% palladium on carbon is added, the mixture is stirred overnight at room temperature and evaporated under reduced pressure until to obtain 36 mg of expected pure product. Rf = 0.20 (methanol / Water 80/20) IR (Nujol) Absorption OH / NH C = 0 1707, 1667 (ep.), 1646 (Max) cm "1 Aromatic + amide II: 1609.1508 cm " 1 NMR (DMSO)
0,50 à 1,70 (cycle et chaîne); 2,50 à 3,95 S-CH2-CH(N), CO- N-CH2, Ph-CH2, 4,04 (1) 4,87 (1) CH (NHBoc); 7,00 7,10 aromatique, 8,05 (d) CH-NHCO.0.50 to 1.70 (cycle and chain); 2.50 to 3.95 S-CH 2 -CH (N), CO-N-CH 2 , Ph-CH 2 , 4.04 (1) 4.87 (1) CH (NHBoc); 7.00 7.10 aromatic, 8.05 (d) CH-NHCO.
Exemple 29 : (R) -3- [[ (aminocarbonyl) hydrazono] méthyl] -4- (phosphonooxy) -N- [5- (3-cyclohexylpropyl) -4-oxo-2 ,3,4,5- tétrahydro-1 , 5-benzothiazépin-3-yl] -benzamide .Example 29: (R) -3- [[(aminocarbonyl) hydrazono] methyl] -4- (phosphonooxy) -N- [5- (3-cyclohexylpropyl) -4-oxo-2, 3,4,5- tetrahydro- 1, 5-benzothiazepin-3-yl] -benzamide.
FG(I') R3 = H, R5 = - (CH2) 3-cyclohexyle; [A ≈ -Ph substitué en meta par -C=N-NH-CO-NH2 ; A2 = -OPO (OH) 2 FG (I ') R 3 = H, R 5 = - (CH 2 ) 3 -cyclohexyl; [A ≈ -Ph substituted in meta by -C = N-NH-CO-NH 2 ; A 2 = -OPO (OH) 2
On opère comme à l'exemple 15 stades A et B mais à partir de 322mg de P5 et 270 mg d'acide 3- [[ (aminocarbonyl) hydrazono] méthyl] -4-hydroxybenzoïque. On obtient au bout de ces deux stades 1,18 g de produit brut qui est purifié par chroma- tographie et dont l'une des fractions (78,7mg) est engagé dans la réaction de débenzylation totale par action d'acide trifluoroacetique dans le CH2C12. On obtient 32 mg de produit attendu. IR (Nujol)The procedure is as in Example 15 stages A and B but starting with 322 mg of P5 and 270 mg of 3- [[(aminocarbonyl) hydrazono] methyl] -4-hydroxybenzoic acid. 1.18 g of crude product is obtained at the end of these two stages, which is purified by chroma- tography and one of the fractions (78.7 mg) of which is involved in the total debenzylation reaction by the action of trifluoroacetic acid in CH 2 C1 2 . 32 mg of expected product are obtained. IR (Nujol)
Absorption OH/NH : 3480, 3310 cm-1OH / NH absorption: 3480, 3310 cm-1
C=0 complexe 1649 (Max) cm-1 C = 0 complex 1649 (Max) cm -1
Système conjugué, Aromatique + Amide II : 1616,1584,1486 cm"1 Conjugated system, Aromatic + Amide II: 1616,1584,1486 cm "1
RMN (DMSO) 0,76 (m) 1,10 (m) 1,30 à 1,70 (m) (cycle et chaîne); 3,50NMR (DMSO) 0.76 (m) 1.10 (m) 1.30 to 1.70 (m) (cycle and chain); 3.50
(masqué) 4,25 (m) CO-N-CH2, 3,30 (m) 3,50 (m) S-CH2-CH(N),(hidden) 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 à 7,90 aromatique, 8,05 (d) CH-NHCO,4.57 (m) CO-CH-NH 7.00 to 7.90 aromatic, 8.05 (d) CH-NHCO,
6,48 (m), 8,10 à 8,90 (m), 10,50 (m).6.48 (m), 8.10 to 8.90 (m), 10.50 (m).
Exemple 30 : [S- [R* (6R*) ] ] -N-acétyl- [4- (3-cyclohexylpropyl) - 5-oxo-4,5, 6, 7-tétrahydro-l, 4-thiazépin-6-yl] -4- [ (phosphono)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) méthyl] -L-phénylalaninamide .(difluoro) methyl] -L-phenylalaninamide.
FG (I" ' ) , R5 = - (CH2) 3-cyclohexyle ; [A ≈ -CH (NHAc) -CH2-Ph- ; A2 = -CF2P (0) (OH) 2 Stade A :FG (I "'), R 5 = - (CH 2 ) 3 -cyclohexyl; [A ≈ -CH (NHAc) -CH 2 -Ph-; A 2 = -CF 2 P (0) (OH) 2 Stage A :
[S-[R* (6R*) ] ] -N-acétyl- [4- (3-cyclohexylpropyl) -5-oxo-4,5, 6,7- tétrahydro-1, 4-thiazépin-6-yl] -4- [ (diéthoxyphosphinyl) (difluoro) méthyl] -L-phénylalaninamide . On mélange pendant 5 heures à température ambiante 80 mg de produit P9 (préparation 9 : (R) 3-amino 5- (3-cyclohexyl- propyl) 2,3-dihydro 1, 5-benzothiazépin-4 (5H) -one, avec 140 mg de N-acétyl 4- [[ (diéthoxyphosphinyl) difluoro] méthyl] L- phénylalanine, 48 mg d'HOBt, 68 mg d'EDC, 4 ml de CH2C12 et 0,5 ml de DMF, coule dans l'acétate d' éthyle, lave sèche et évapore sous pression réduite jusqu'à obtention de 108 mg de produit brut que l'on purifie par chromatographie. On obtient 60 mg de produit pur attendu. Stade B : Déprotection On fait réagir au reflux pendant 5 heures 50 mg du produit obtenu au stade précédent avec 103μl de TMSBr dans 5 ml de dichlorométhane puis coule dans le méthanol, évapore sous pression réduite et purifie par chromatographie. On obtient 16 mg de produit attendu.[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 is mixed for 5 hours at room temperature (preparation 9: (R) 3-amino 5- (3-cyclohexylpropyl) 2,3-dihydro 1, 5-benzothiazepin-4 (5H) -one, with 140 mg of N-acetyl 4- [[(diethoxyphosphinyl) difluoro] methyl] L-phenylalanine, 48 mg of HOBt, 68 mg of EDC, 4 ml of CH 2 C1 2 and 0.5 ml of DMF, flows in ethyl acetate, wash dry and evaporate under reduced pressure until 108 mg of crude product is obtained which is purified by chromatography. 60 mg of expected pure product is obtained Stage B: Deprotection The reaction is carried out with reflux for 5 hours 50 mg of the product obtained in the previous stage with 103 μl of TMSBr in 5 ml of dichloromethane then flows into methanol, evaporates under reduced pressure and purifies by chromatography. 16 mg of expected product is obtained.
IR (Nujol)IR (Nujol)
Absorption OH/NH : 3480, 3310 cm-1OH / NH absorption: 3480, 3310 cm-1
C=0 1707 cm-1, C=0 complexe, région C=C 1646 (Max) cm"1 C = 0 1707 cm-1, C = 0 complex, region C = C 1646 (Max) cm "1
Aromatique + Amide II : 1538 cm"1 Aromatic + Amide II: 1538 cm "1
RMN : 0,80 à 1,90, 2,30 à 3,80, 4,45 à 4,90, 5,60 à 6,05, 7,30 (d)- 7, 44 (m) : Ph- ; 8,49 (d)-8,56 (d) : 2NHCH.NMR: 0.80 to 1.90, 2.30 to 3.80, 4.45 to 4.90, 5.60 to 6.05, 7.30 (d) - 7.44 (m): Ph- ; 8.49 (d) -8.56 (d): 2NHCH.
Exemple 31 : (R) -5- (phosphonooxy) -N- [5- (3-cyclohexylpropyl) 4-oxo-2 ,3,4,5-tetrahydro-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-cyclohexyle ; [Ai] = 2-pyridinyl ;FG (I ') R 3 = H, R 5 = - (CH 2 ) 3 -cyclohexyl; [Ai] = 2-pyridinyl;
A2 = -OPO (OH) 2 A 2 = -OPO (OH) 2
Stade A : AmidificationStage A: Amidification
(R) 5- (hydroxy) N- [5- (3-cyclohexylpropyl) -4-oxo 2,3,4,5- tetrahydro 1, 5-benzothiazépin-3-yl] -2-pyridine carboxamide. A une solution de 62 mg d'acide 5-hydroxy 2-pyridine carboxylique, 103 mg d'EDC,HCl, 73 mg d'HOBt dans 2 ml de DMF et 4 ml de CH2C12, on ajoute, à température ambiante, 412 mg de P5 dans 4 ml de CH2C12 et agite 3 heures 30 minutes à cette température. Après lavage, séchage et évaporation sous pression réduite, on obtient 200 mg de produit brut que l'on purifie par chromatographie en éluant avec le mélange CH2Cl2/AcOEt 70/30 pour obtenir 118 mg de produit purifié. Stade B : Phosphorylation (R) 5- [ [ (diéthoxy) phosphinyl] oxy] N- [5- (3-cyclo- hexylpropyl) -4-oxo-2, 3, 4, 5-tétrahydro-l, 5-benzothiazépin-3- yl] 2-pyridinecarboxamide.(R) 5- (hydroxy) N- [5- (3-cyclohexylpropyl) -4-oxo 2,3,4,5-tetrahydro 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 C1 2 , the following are added at room temperature , 412 mg of P5 in 4 ml of CH 2 C1 2 and stirred for 3 hours 30 minutes at this temperature. After washing, drying and evaporation under reduced pressure, 200 mg of crude product is obtained which is purified by chromatography eluting with the CH 2 Cl 2 / AcOEt 70/30 mixture to obtain 118 mg of purified product. Stage B: Phosphorylation (R) 5- [[(diethoxy) phosphinyl] oxy] N- [5- (3-cyclohexylpropyl) -4-oxo-2,3,4,4-tetrahydro-1,5-benzothiazepin -3- yl] 2-pyridinecarboxamide.
A 90 mg du produit obtenu au stade précédent dans 3 ml d' acétonitrile, on ajoute à une température de -10°C, 0,125 ml de tétrachlorure de carbone, 2,5 mg de DMAP, 0,07 ml de diisopropylethylamine ainsi que 0,068 ml de dibenzylphosphite et agite 1 heure 30 minutes à cette température. Après lavage et séchage, on évapore sous pression réduite et obtient 150 mg de produit brut que l'on purifie par chromatographie en éluant avec le mélange CH2Cl2-AcOEt 85-15. On obtient 110 mg de produit purifié attendu.To 90 mg of the product obtained in the preceding stage in 3 ml of acetonitrile, 0.125 ml of carbon tetrachloride, 2.5 mg of DMAP, 0.07 ml of carbon dioxide are added at a temperature of -10 ° C. diisopropylethylamine and 0.068 ml of dibenzylphosphite and stirred for 1 hour 30 minutes at this temperature. After washing and drying, the mixture is evaporated under reduced pressure and 150 mg of crude product is obtained which is purified by chromatography eluting with the CH 2 Cl 2 -AcOEt 85-15 mixture. 110 mg of expected purified product are obtained.
Rf = 0,68 (CH2Cl2/AcOEt: 70/30)Rf = 0.68 (CH 2 Cl 2 / AcOEt: 70/30)
Stade C : Débenzylation totale.Stage C: Total debenzylation.
On mélange 105 mg du produit obtenu au stade précédent dans 6 ml de CH2C12, avec 3 ml d'acide trifluoroacetique et agite 1 nuit à température ambiante. Après traitement, on obtient 36 mg de produit attendu.105 mg of the product obtained in the preceding stage are mixed in 6 ml of CH 2 C1 2 with 3 ml of trifluoroacetic acid and the mixture is stirred overnight at room temperature. After treatment, 36 mg of expected product is obtained.
RMNNMR
0,77 (m) : 2H ; 1,00 à 1,28 (m) ~ 7H ; 1,35 à 1,68 (m) ~ 8H chaîne alkyle ; 3,28 (t,J = 11,5), 3,57 (dd,J=ll,5) S-CH2 ;0.77 (m): 2H; 1.00 to 1.28 (m) ~ 7H; 1.35 to 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-CH2 ; 4,52 (m, dd après échange) :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) : IH ; 7,59 (m) : 2H ; 7,70 à 7,80 (m) :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) : IH, H aromatique. Exemple 32 : (R) -4- [ (phosphono) fluorométhyl] -N- [5- (3-cyclo- hexylpropyl) -4-oxo-2 ,3,4,5-tétrahydro-l , 5-benzothiazépin-3- yl] -benzamide .2H; 7.97 (d): 1H, aromatic H. Example 32: (R) -4- [(phosphono) fluoromethyl] -N- [5- (3-cyclohexylpropyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3 - yl] -benzamide.
FG(I') R3 = H,R5 = (CH2)3-cyclohexyle; [Ai] = Ph; A2 = -CHFP(O) (OH) 2 FG (I ') R 3 = H, R 5 = (CH 2 ) 3 -cyclohexyl; [Ai] = Ph; A 2 = -CHFP (O) (OH) 2
On opère comme à l'exemple 30 stades A et B mais à partir de 54 mg de P5 et 85 mg d'acide 4- [bis (diéthoxyphosphinyl) fluorométhyl] -benzoique. On obtient 17,5 mg de produit attendu. IR (Nujol)The procedure is as in 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 is obtained. IR (Nujol)
Absorption OH/NH : 3405 cm"1 OH / NH absorption: 3405 cm "1
C=0 1649 (Max) cm"1 C = 0 1649 (Max) cm "1
Aromatique + Amide II : 1616,1605,1585, 1571,1545, 1501 cm"1 Aromatic + Amide II: 1616,1605,1585, 1571,1545, 1501 cm "1
RMN (DMSO) 0,80 à 1,70 (m) (cycle et chaîne); 3, 11 (ml) 3,47 (ml) S-CH2- CH(N) 3,73 (ml) 4,30 CO-N-CH2, 5,48 (ml) 5,62 NH, 7,30 à 7,70 aromatique.NMR (DMSO) 0.80 to 1.70 (m) (cycle 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.
Les exemples ci-dessous décrivent des composés de formule (I") préparés par couplage de l'aminé P8, préalablement alkylée avec R5-Hal au niveau de l'atome d'azote du cycle, avec un acide de formule (III) suivi le cas échéant d'une déprotection. Le cas échéant, la réaction d'alkylation des composés de formule (I'') s'effectue après le couplage avec (III) . Différents modes opératoires sont envisageables en fonction de l'acide de formule (III) employé .The examples below describe compounds of formula (I ") prepared by coupling the amine P8, previously alkylated with R 5 -Hal at the level of the ring nitrogen atom, with an acid of formula (III) possibly followed by deprotection. If necessary, the alkylation reaction of the compounds of formula (I '') is carried out after coupling with (III). Different procedures can be envisaged depending on the acid of formula (III) used.
Mode opératoire A Selon l'exemple 28, on effectue le couplage de L-N-Ac- Tyr-O- (P03Bn) 2 avec une aminé P8, préalablement alkylée avec un halogénure d' alkyle Rs-Hal approprié, puis une réaction de déprotection selon les méthodes indiquées plus haut, notamment par action de TFA. On obtient alors des composés de formule (I") avec [Aι]-A2 représentant -CH (NHAc) -CH2-Ph- OP03H2.Procedure A According to Example 28, LN-Ac- Tyr-O- (P0 3 Bn) 2 is coupled with an amine P8, previously alkylated with an appropriate Rs-Hal alkyl halide, then a reaction of deprotection according to the methods indicated above, in particular by action of TFA. Compounds of formula (I ") are then obtained with [Aι] -A 2 representing -CH (NHAc) -CH 2 -Ph- OP0 3 H 2 .
Mode opératoire A'Procedure A '
Ce couplage a également été effectuée sur support solide en mettant en œuvre le cas échéant un acide Pli avec une aminé P8 notamment selon la méthode suivante : a) CouplageThis coupling was also carried out on a solid support using, where appropriate, a Pli acid with an amine P8, in particular according to the following method: a) Coupling
La réaction de couplage s'effectue dans ce cas en phase solide. Dans chaque tube, on dispose 200mg de résine de Wang H02C- [CH (NHAc) -CH2-Ar-0-PO (OtBu) (OCH2-Wang) (Pli), ajoute 50mg d'amine préparée à la préparation P8 préalablement alkylée par un groupement Rs~Br selon la méthode décrite pour (P5), 1 ml de dichlorométhane, 1ml d'HOBt dans le DMF et 1ml de DIC dans le DMF, agite une nuit à température ambiante et lave abondamment avec d'abord du DMF, puis un mélange DMF/CH2C12 puis du CH2C12. b) Déprotection et déblocage A la résine obtenue plus haut, on ajoute 3ml de TFA à 15% dans le CH2C12 et laisse sous agitation 1 heure. Après filtration et évaporation sous pression réduite, on récupère le produit brut attendu éventuellement purifié par chromatographie. On obtient alors des composés de formule (I") avec [A -A2 représentant -CH (NHAc) -CH2-Ph-OP03H2 Mode opératoire BThe coupling reaction is carried out in this case in solid phase. In each tube, 200 mg of Wang H0 2 resin C- [CH (NHAc) -CH 2 -Ar-0-PO (OtBu) (OCH 2 -Wang) (Pli) are added, add 50 mg of amine prepared to the preparation P8 previously alkylated with an Rs ~ Br group according to the method described for (P5), 1 ml of dichloromethane, 1 ml of HOBt in DMF and 1 ml of DIC in DMF, stirred overnight at room temperature and washed thoroughly with d first DMF, then a DMF / CH 2 C1 2 mixture then CH 2 C1 2 . b) Deprotection and unlocking To the resin obtained above, 3 ml of 15% TFA in CH 2 C1 2 are added and the mixture is left stirring for 1 hour. After filtration and evaporation under reduced pressure, the expected crude product is recovered, optionally purified by chromatography. Compounds of formula (I ") are then obtained with [A -A 2 representing -CH (NHAc) -CH 2 -Ph-OP0 3 H 2 Procedure B
Selon l'exemple 21, on effectue le couplage de l'acide para hydroxy benzoique avec l'aminé P8 préalablement alkylée avec un halogénure R5-Hal approprié, suivi d'une réaction de phosphorylation selon l'exemple 15 avec le dibenzylphosphite puis une réaction de déprotection selon les méthodes indiquées plus haut, notamment par action de TFA. On obtient alors des composés de formule (I'') avec [Aι]-A2 représentant -Ar-OP03H2 According to Example 21, the para hydroxy benzoic acid is coupled with the amine P8 previously alkylated with an appropriate halide R 5 -Hal, followed by a phosphorylation reaction according to Example 15 with the dibenzylphosphite and then a deprotection reaction according to the methods indicated above, in particular by action of TFA. Compounds of formula (I '') are then obtained with [Aι] -A 2 representing -Ar-OP0 3 H 2
Mode opératoire B'Procedure B '
On opère avec la résine P12 selon le mode opératoire A' On obtient alors des composés de formule (I'') avec [Aι]-A2 représentant -Ar-OPθ3H2. Mode opératoire CThe operation is carried out with the resin P12 according to the procedure A '. We then obtain compounds of formula (I'') with [Aι] -A 2 representing -Ar-OPθ 3 H 2 . Procedure C
On opère à partir de composés de formule (III) préparés selon le schéma 2. Le couplage s'effectue selon l'exemple 28 sur une aminé P8 préalablement alkylée par un halogénure d' alkyle approprié R5-Hal. Le cas échéant une hydrogénation catalytique est effectuée pour obtenir une chaine saturée. On obtient alors des composés de formule (I'') avec [Aι]-A représentant -Ar-CH (C02H) 2, -Ar-CH2C02H, -Ar-CF2C02H ou Ar- CF(C02H)2.The operation is carried out from compounds of formula (III) prepared according to scheme 2. The coupling is carried out according to Example 28 on an amine P8 previously alkylated with an appropriate alkyl halide R 5 -Hal. If necessary, a catalytic hydrogenation is carried out to obtain a saturated chain. We then obtain compounds of formula (I '') with [Aι] -A representing -Ar-CH (C0 2 H) 2 , -Ar-CH 2 C0 2 H, -Ar-CF 2 C0 2 H or Ar- CF (C0 2 H) 2 .
Mode opératoire D On opère à partir de composés de formule (IIIc) préparés selon le schéma 3. Le couplage s'effectue selon l'exemple 28 sur une aminé P8 préalablement alkylée par un halogénure d' alkyle approprié R5-Hal. La déprotection s'effectue en général avec le TMSBr ou le TMSI dans le dichlorométhane. On obtient alors des composés de formule (I'') avec [Aι]-A2 représentant Ar-CF2P03H. Mode opératoire EProcedure D The operation is carried out using compounds of formula (IIIc) prepared according to scheme 3. The coupling is carried out according to Example 28 on an amine P8 previously alkylated with an appropriate alkyl halide R 5 -Hal. Deprotection is generally carried out with TMSBr or TMSI in dichloromethane. Compounds of formula (I '') are then obtained with [Aι] -A 2 representing Ar-CF 2 P0 3 H. Procedure E
On opère à partir de composés de formule (III) décrits à l'exemple 24. Le couplage s'effectue selon l'exemple 28 sur une aminé P8 préalablement alkylée par un halogénure d' alkyle approprié Rs-Hal. La déprotection s'effectue en général avec le TMSBr ou le TFA. On obtient alors des composés de formule (I") avec [Aι]-A2 représentant -CH (NHAc) -CH2-Ar-CF2P03H.The operation is carried out from compounds of formula (III) described in Example 24. The coupling is carried out according to Example 28 on an amine P8 previously alkylated with an appropriate alkyl halide Rs-Hal. Deprotection is generally carried out with TMSBr or TFA. Compounds of formula (I ") are then obtained with [Aι] -A 2 representing -CH (NHAc) -CH 2 -Ar-CF 2 P0 3 H.
Mode opératoire F On opère avec la résine P13 selon le mode opératoire A' On obtient alors des composés de formule (I'') avec [Aι]-A2 représentant -Ar-NHCOP03H2 Mode opératoire GProcedure F We operate with the resin P13 according to procedure A 'We then obtain compounds of formula (I'') with [Aι] -A 2 representing -Ar-NHCOP0 3 H 2 Procedure G
On opère à partir de diacides de formule (III) suivants (p-C02Me) -Ar-CH2-CH(NHAc) -C02H. Le couplage s'effectue selon l'exemple 35 sur une aminé P8 préalablement alkylée par un halogénure d' alkyle approprié R5-Hal .The operation is carried out from the following diacids of formula (III) (p-C0 2 Me) -Ar-CH 2 -CH (NHAc) -C0 2 H. The coupling is carried out according to Example 35 on an amine P8 previously alkylated by a suitable alkyl halide R 5 -Hal.
On obtient alors des composés de formule (I'') avec -[Aι]-A2 représentant -CH (NHAc) -CH2-Ar-C02H . Exemple 33 N- [ (6R) -4- (3-cyclohexylpropyl) -hexahydro-5-oxo-l , 4-thiazepin- 6-yl] -4- (phosphonooxy) -BenzamideCompounds of formula (I '') are then obtained with - [Aι] -A 2 representing -CH (NHAc) -CH 2 -Ar-C0 2 H. Example 33 N- [(6R) -4- (3-cyclohexylpropyl) -hexahydro-5-oxo-1,4,4-thiazepin- 6-yl] -4- (phosphonooxy) -Benzamide
FG(I''); R5= -(CH2)3-cyclohexyle; [A ≈ -Ph-; A2 = -OP(0)(OH)2 (Préparation selon le mode opératoire B) SM (ESP) : 469" = [M-H]" ; 389" = [MH - P03H2]" RMN (CDC13)FG (I ''); R 5 = - (CH 2 ) 3 -cyclohexyl; [A ≈ -Ph-; A 2 = -OP (0) (OH) 2 (Preparation according to procedure B) SM (ESP): 469 " = [MH] " ; 389 " = [MH - P0 3 H 2 ] " NMR (CDC1 3 )
0,84 (m, 2H, aliphatique) ; 1,15 (m, 7H, aliphatique) ; 1,53 (m, 6H, aliphatique) ; 2,71 (m, 4H, 2 SCH2) ; 3,25 (m, IH, NCH2) ; 3,38 (m, IH, NCH2) ; 3,74 (m, IH, NCH2) ; 3,85 (m, IH, NCH2) ; 5,11 (m, IH, CH) ; 7,21 (m, 2H, Ph) ; 7,75 (d, 2H, Ph) ; 8,29 (m, IH, NHCO) Exemple 340.84 (m, 2H, aliphatic); 1.15 (m, 7H, aliphatic); 1.53 (m, 6H, aliphatic); 2.71 (m, 4H, 2 SCH 2 ); 3.25 (m, 1H, NCH 2 ); 3.38 (m, 1H, NCH 2 ); 3.74 (m, 1H, NCH 2 ); 3.85 (m, 1H, NCH 2 ); 5.11 (m, 1H, CH); 7.21 (m, 2H, Ph); 7.75 (d, 2H, Ph); 8.29 (m, 1H, NHCO) Example 34
Acide [ [4- [ (2S) -2- (acétylamino) -4- [ [ (6R)-4-(3- cyclohexylpropyl) -hexahydro-5-thioxo-l , 4-thiazepin-6- yl] amino] -3-oxopropyl]phényl] difluorométhyl] - Phosphonique FG(I''); R5= - (CH2) 3-cyclohexyle; [Aι]= -CH (NHAc) -CH2-Ph-; A2 = -CF2-P(0) (OH) 2 et 5-thio au lieu de 5 oxo (Préparation selon le mode opératoire E) Rf = 0,43 (MeOH/eau : 90/10)Acid [[4- [(2S) -2- (acetylamino) -4- [[(6R) -4- (3- cyclohexylpropyl) -hexahydro-5-thioxo-1,4-thiazepin-6- yl] amino] -3-oxopropyl] phenyl] difluoromethyl] - Phosphonic FG (I ''); R 5 = - (CH 2 ) 3 -cyclohexyl; [Aι] = -CH (NHAc) -CH 2 -Ph-; A 2 = -CF 2 -P (0) (OH) 2 and 5-thio instead of 5 oxo (Preparation according to procedure E) Rf = 0.43 (MeOH / water: 90/10)
SM (ESP) : 604" = [M-H]" ; 606+ = [M+H]+ ; 628+ = [M+Na]+ ; RMN (CDC13)MS (ESP): 604 " = [MH] " ; 606 + = [M + H] + ; 628 + = [M + Na] + ; NMR (CDC1 3 )
0,85 (m, 2H, aliphatique) ; 1,16 (m, 2H, aliphatique ; 1,65 (m, 6H, aliphatique) ; 1,80 (s, 3H, Ac) ; 2,35-4,30 (m, 12H, 2 SCH2, 2 NCH2, PhCH2) ; 2,80-3,10 (m, 2H, CH2Ph) ; 3,64-3,83 (m, 5H, NCH2 OMe) ; 4,48 (m, IH, CH) ; 5,13 (m, IH, CH) ; 7,34 (d, 2H, Ph) ; 7,43 (d, 2H, Ph) ; 8,35 (d, IH, NHCO) ; 8,48-8,65 (m, IH, NHCO)0.85 (m, 2H, aliphatic); 1.16 (m, 2H, aliphatic; 1.65 (m, 6H, aliphatic); 1.80 (s, 3H, Ac); 2.35-4.30 (m, 12H, 2 SCH 2 , 2 NCH 2 , PhCH 2 ); 2.80-3.10 (m, 2H, CH 2 Ph); 3.64-3.83 (m, 5H, NCH 2 OMe); 4.48 (m, 1H, CH) ; 5.13 (m, 1H, CH); 7.34 (d, 2H, Ph); 7.43 (d, 2H, Ph); 8.35 (d, 1H, NHCO); 8.48-8 , 65 (m, 1H, NHCO)
Exemple 35Example 35
N- [ (6R) -hexahydro-5-oxo-4- (3-phenyl-2-propenyl) -1 , 4- thiazepin-6-yl] -4- (phosphonooxy) -BenzamideN- [(6R) -hexahydro-5-oxo-4- (3-phenyl-2-propenyl) -1, 4- thiazepin-6-yl] -4- (phosphonooxy) -Benzamide
FG ( I ' ' ) ; R5= -CH2-CH=CH-Ph ; [Aι ] = -Ph- ; A2 = -OP ( 0) ( OH) 2 FG (I ''); R 5 = -CH 2 -CH = CH-Ph; [Aι] = -Ph-; A 2 = -OP (0) (OH) 2
(Préparation selon le mode opératoire B)(Preparation according to procedure B)
Stade a : alkylation de P8Stage a: P8 alkylation
A une solution de 4g d'amine P8 dans le DMF on ajoute à 0°C sous argon 780 mg de NaH (suspension dans l'huile à 50%) . Après 15 minutes d'agitation à 0°C, on additionne 3,20g de bromure de 3-phényl-2-propènyle (Br-CH2-CH=CH-Ph) dissout dans le DMF. Le milieu réactionnel est agité 3 heures à température ambiante et 5,27g de produit brut sont purifiés par chromatographie flash (CH2Cl2/AcOEt 98/2) . On obtient 4,7g de produit alkyle attendu. Rf = 0,49 (CH2Cl2/MeOH : 98/2) Stade b : Couplage A une solution de 362 mg de produit préparé au stade a dans le dichlorométhane on ajoute 3 ml de TFA, agite une heure à température ambiante, évapore, dilue avec le dichlorométhane puis ajoute 0,5 ml de DIPEA. A une solution de 159 mg d'acide parahydroxybenzoique dans un mélange dichlorométhane/DMF (4/1 en volume) on ajoute 220 mg d'HOBt et 255 mg d'EDC à 0°C. Après 15 minutes d'agitation à température ambiante, le milieu est transféré dans un ballon à 0°C contenant la solution d'amine libre. Le milieu réactionnel est agité 3 heures à température ambiante, dilué à l'acétate d' éthyle, lavé avec une solution d'acide citrique à 5%, avec une solution aqueuse saturée de NaHC03, avec une solution aqueuse saturée de NaCl, séché sur MgS04 et évaporé. On obtient 306 mg de produit brut que l'on purifie par chromatographie flash (CH2Cl2/MeOH) On obtient 144 mg de produit pur attendu. Rf = 0,24 (CH2Cl2/AcOEt: 8/2) Stade c : Phosphorylation A une solution de 144 mg de produit préparé au stade b dans 5 ml d' acétonitrile, sont ajoutés à 0°C sous argon 0,5 ml de CC14, 0,271 ml de DIPEA et 9,2 mg de DMAP. La solution est agitée pendant 10 minutes à -10°C puis 0,252 ml d'HPO(OBn)2 sont ajoutés. Le milieu réactionnel est agité 2 heures à - 10°C puis 20 ml de KH2P04 sont ajoutés. Le milieu réactionnel est agité 15 mn à température ambiante puis extrait à l'acétate d' éthyle, séché sur MgS04 et évaporé. 444 mg de produit brut sont purifiés sur silice 60H (CH2Cl2/AcOEt : 90/10) . On obtient 112 mg de produit pur Rf = 0,27 (CH2Cl2/AcOEt: 90/10) Stade d : DéprotectionTo a solution of 4 g of amine P8 in DMF is added at 0 ° C under argon 780 mg of NaH (suspension in oil at 50%). After 15 minutes of stirring at 0 ° C., 3.20 g of 3-phenyl-2-propenyl bromide (Br-CH 2 -CH = CH-Ph) dissolved in DMF are added. The reaction medium is stirred for 3 hours at room temperature and 5.27 g of crude product are purified by flash chromatography (CH 2 Cl 2 / AcOEt 98/2). 4.7 g of expected alkyl product are obtained. Rf = 0.49 (CH 2 Cl 2 / MeOH: 98/2) Stage b: Coupling To a solution of 362 mg of product prepared in stage a in dichloromethane is added 3 ml of TFA, stirred for one hour at room temperature, evaporates, dilutes with dichloromethane and then adds 0.5 ml of DIPEA. To a solution of 159 mg of parahydroxybenzoic acid in a dichloromethane / DMF mixture (4/1 by volume) is added 220 mg of HOBt and 255 mg of EDC at 0 ° C. After 15 minutes of stirring at room temperature, the medium is transferred to a 0 ° C flask containing the free amine solution. The reaction medium is stirred for 3 hours at room temperature, diluted with ethyl acetate, washed with a 5% citric acid solution, with a saturated aqueous solution of NaHCO 3 , with a saturated aqueous solution of NaCl, dried on MgS0 4 and evaporated. 306 mg of crude product are obtained which is purified by flash chromatography (CH 2 Cl 2 / MeOH). 144 mg of expected pure product is obtained. Rf = 0.24 (CH 2 Cl 2 / AcOEt: 8/2) Stage c: Phosphorylation To a solution of 144 mg of product prepared in stage b in 5 ml of acetonitrile, are added at 0 ° C. under argon 0, 5 ml CC14, 0.271 ml DIPEA and 9.2 mg DMAP. The solution is stirred for 10 minutes at -10 ° C and then 0.252 ml of HPO (OBn) 2 is added. The reaction medium is stirred for 2 hours at −10 ° C. then 20 ml of KH 2 P0 4 are added. The reaction medium is stirred for 15 min at ambient temperature then extracted with ethyl acetate, dried over MgSO 4 and evaporated. 444 mg of crude product are purified on 60H silica (CH 2 Cl 2 / AcOEt: 90/10). 112 mg of pure product are obtained Rf = 0.27 (CH 2 Cl 2 / AcOEt: 90/10) Stage d: Deprotection
A une solution de 112 mg de produit préparé au stade c dans 3 ml de dichlorométhane, 3 ml de TFA sont ajoutés à 0°C. La solution est agitée pendant 20 heures à température ambiante, évaporée puis diluée au dichlorométhane et évaporée à nouveau. 74 mg de produit brut sont recristallisés dans l'acétate d' éthyle. On obtient 41 mg de produit pur attendu. Rf = 0,35 (Acétone/Acétate d'éthyle/Eau 50/40/1) RMN (CHC13) 2,74 (si, 2H, SCH2) ; 2,82 (m, 2H, SCH2) ; 4,40-5,70 (m, 4H, 2 NCH2) ; 5,22 (m, IH, CH) ; 6,25 (dt, IH, CH) ; 6,58 (d, J=16, IH, CH) ; ; 7,25 (d, 2H, aromatique) ; 7,40 (m, 5H, Ph) ; 7,85 (d, 2H, aromatique) ; 8,44 (d, IH, NH) IR 1632 cm"1 (C=0) ; 1600, 1575 cm"1 (aromatique, absorption générale OH/NH) SM (ESP) 461" = (M-H)" Exemple 36To a solution of 112 mg of product prepared in stage c in 3 ml of dichloromethane, 3 ml of TFA are added at 0 ° C. The solution is stirred for 20 hours at room temperature, evaporated then diluted with dichloromethane and evaporated again. 74 mg of crude product are recrystallized from ethyl acetate. 41 mg of expected pure product are obtained. Rf = 0.35 (Acetone / Ethyl acetate / Water 50/40/1) NMR (CHC1 3 ) 2.74 (si, 2H, SCH 2 ); 2.82 (m, 2H, SCH 2 ); 4.40-5.70 (m, 4H, 2 NCH 2 ); 5.22 (m, 1H, CH); 6.25 (dt, 1H, CH); 6.58 (d, J = 16, 1H, CH); ; 7.25 (d, 2H, aromatic); 7.40 (m, 5H, Ph); 7.85 (d, 2H, aromatic); 8.44 (d, IH, NH) IR 1632 cm "1 (C = 0); 1600, 1575 cm " 1 (aromatic, general absorption OH / NH) SM (ESP) 461 " = (MH) " Example 36
Acide [ [4- [ (2S) -2- (acétylamino) -4- [ [ (6R) -4- (3- cyclohexylpropyl) -hexahydro-5-oxo-l , 4-thiazepin-6-yl] amino] - 3-oxopropyl]phényl] difluorométhyl] - PhosphoniqueAcid [[4- [(2S) -2- (acetylamino) -4- [[(6R) -4- (3- cyclohexylpropyl) -hexahydro-5-oxo-1,4-thiazepin-6-yl] amino] - 3-oxopropyl] phenyl] difluoromethyl] - Phosphonic
FG(I''); R5= -(CH2)3-cyclohexyle; [Aι]= -CH (NHC0CH3) -CH2-Ph-; A2 = -CF2-P(0) (OH) 2 (Mode opératoire E) Rf = 0,46 Méthanol/Eau 70/3 SM (ESP) (M-H)" = 588" FG (I ''); R 5 = - (CH 2 ) 3 -cyclohexyl; [Aι] = -CH (NHC0CH 3 ) -CH 2 -Ph-; A 2 = -CF 2 -P (0) (OH) 2 (Procedure E) Rf = 0.46 Methanol / Water 70/3 SM (ESP) (MH) " = 588 "
Exemple 37Example 37
Acide [ [4- [ [ [ (6R) -4- (3-cyclohexylpropyl) -hexahydro-5-oxo- 1 , 4-thiazepin-6-yl] amino] carbonyl]phényl] difluorométhyl] - PhosphoniqueAcid [[4- [[[(6R) -4- (3-cyclohexylpropyl) -hexahydro-5-oxo-1, 4-thiazepin-6-yl] amino] carbonyl] phenyl] difluoromethyl] - Phosphonic
FG(I"); R= -(CH2)3-cyclohexyle; [Aι]= -Ph-; A2 = -CF2-FG (I "); R = - (CH 2 ) 3 -cyclohexyl; [Aι] = -Ph-; A 2 = -CF 2 -
P(O) (OH) 2 P (O) (OH) 2
(Mode opératoire D)(Procedure D)
Rf = 0,20 CH2Cl2/Méthanol 80/20 SM (ESP) MNa+ = 527Da ; MH+ = 505DaRf = 0.20 CH 2 Cl 2 / Methanol 80/20 SM (ESP) MNa + = 527Da; MH + = 505Da
Exemple 38Example 38
N2-acetyl-N- [ (6R) -4- (3-cyclohexylpropyl) -hexahydro-5-oxo-l , 4- thiazepin-6-yl] -3-formyl-4- (phosphonooxy) -L-PhenylalaninamideN2-acetyl-N- [(6R) -4- (3-cyclohexylpropyl) -hexahydro-5-oxo-1,4-thiazepin-6-yl] -3-formyl-4- (phosphonooxy) -L-Phenylalaninamide
FG(I") ; Rs= -(CH2)3-cyclohexyle; [Aι]= -CH (NHC0CH3) -CH2- (m- CHO)-Ph-; A2 = -OP(0) (OH)2 FG (I "); Rs = - (CH 2 ) 3 -cyclohexyl; [Aι] = -CH (NHC0CH 3 ) -CH 2 - (m- CHO) -Ph-; A 2 = -OP (0) (OH ) 2
(Mode opératoire A)(Procedure A)
Rf = 0,50 Méthanol/Eau 80/20Rf = 0.50 Methanol / Water 80/20
SM (ESP) [M + Na]+ = 606+ ; [M + H]+ = 584+ ; [M-H]" = 582" MS (ESP) [M + Na] + = 606 + ; [M + H] + = 584 +; [MH] " = 582 "
IR (Nujol) C=0 1681, 1634 cm"1 ; Amide II + aromatique 1535, 1490 cm"1 IR (Nujol) C = 0 1681, 1634 cm "1 ; Amide II + aromatic 1535, 1490 cm " 1
Exemple 39Example 39
N- [ (6R) -4- (3 -cyclohexylpropyl) -hexahydro-5-oxo-l , 4-thiazepin-N- [(6R) -4- (3 -cyclohexylpropyl) -hexahydro-5-oxo-1,4-thiazepin-
6-yl] -3-formyl-4- (phosphonooxy) -Benzamide6-yl] -3-formyl-4- (phosphonooxy) -Benzamide
FG(I' ') ; R5= - (CH2)3-cyclohexyle; [Aι]= - (m-CHO) -Ph-; A2 = - OP(0) (OH) 2 (Mode opératoire B)FG (I ''); R 5 = - (CH 2 ) 3 -cyclohexyl; [Aι] = - (m-CHO) -Ph-; A 2 = - OP (0) (OH) 2 (Procedure B)
Rf = 0,60 Méthanol/Eau 80/20Rf = 0.60 Methanol / Water 80/20
SM (ESP) [M + H]+ = 499+ ;MS (ESP) [M + H] + = 499 + ;
IR (Nujol) C=0 : 1688, 1627 cm"1 ; Aromatique + amides II : 1602, 1555 cm"1 IR (Nujol) C = 0: 1688, 1627 cm "1 ; Aromatic + amides II: 1602, 1555 cm " 1
Exemple 40Example 40
Acide [ [4- [ (2S) -2- (acétylamino) -4- [ [ (6R) -4- [3- (3- methoxyphenyl)propyl) -hexahydro-5-oxo-l , 4-thiazepin-6- yl] amino] -3-oxopropyl]phényl] difluorométhyl] - PhosphoniqueAcid [[4- [(2S) -2- (acetylamino) -4- [[(6R) -4- [3- (3- methoxyphenyl) propyl) -hexahydro-5-oxo-1,4-thiazepin-6 - yl] amino] -3-oxopropyl] phenyl] difluoromethyl] - Phosphonic
FG(I''); R5 = -(CH2)3-(m-OMe)-Ph; [Aι]= -CH (NHC0CH3) -CH2-Ph-;FG (I ''); R 5 = - (CH 2 ) 3 - (m-OMe) -Ph; [Aι] = -CH (NHC0CH 3 ) -CH 2 -Ph-;
A2 = -CF2-P(0) (OH) 2 A 2 = -CF 2 -P (0) (OH) 2
(Mode opératoire E)(Procedure E)
Rf = 0,43 (MeOH/eau 90/10) SM (ESP) : 612" = [M-H]" Rf = 0.43 (MeOH / water 90/10) SM (ESP): 612 " = [MH] "
RMN (CDCI3)NMR (CDCI3)
1,78 (m, 5H, Ac + aliphatique) ; 2,50-2,75 (m, 6H, 2 SCH2 +1.78 (m, 5H, Ac + aliphatic); 2.50-2.75 (m, 6H, 2 SCH 2 +
CH2Ph) ; 2,80, 3,06, 3,11 (dd, 2H, CH2Ph) ; 3,27, 3,50 (m,CH 2 Ph); 2.80, 3.06, 3.11 (dd, 2H, CH 2 Ph); 3.27, 3.50 (m,
2H, NCH2) ; 3,65-3,90 (m, 2H, NCH2) ; 3,73 (s, 3H, Ph) ; 4,55, 4,62 (m, IH, CH) ; 4,89 (m, IH, CH) ; 6,70-6,80 (m, 3H,2H, NCH 2 ); 3.65-3.90 (m, 2H, NCH 2 ); 3.73 (s, 3H, Ph); 4.55, 4.62 (m, 1H, CH); 4.89 (m, 1H, CH); 6.70 - 6.80 (m, 3H,
Ph) ; 7,18 (t, IH, Ph) ; 7,38 (d, 2H, Ph) ; 7,43 (d, 2H, Ph) ;Ph); 7.18 (t, 1H, Ph); 7.38 (d, 2H, Ph); 7.43 (d, 2H, Ph);
8,19 (d, IH, NHCO) ; 8,24 (dd, 2H, NHCO)8.19 (d, 1H, NHCO); 8.24 (dd, 2H, NHCO)
Exemple 41Example 41
1,1-dioxyde de 1 ' acide [ [4- [ (2S) -2- (acétylamino) -4- [[ (6R) -4- (3-cyclohexylpropyl) -hexahydro-5-thioxo-l , 4-thiazepin-6- yl] amino] -3-oxopropyl]phényl] difluorométhyl] - PhosphoniqueAcid 1,1-dioxide [[4- [(2S) -2- (acetylamino) -4- [[(6R) -4- (3-cyclohexylpropyl) -hexahydro-5-thioxo-l, 4- thiazepin-6- yl] amino] -3-oxopropyl] phenyl] difluoromethyl] - Phosphonic
FG(I''); R5= -(CH2)3-cyclohexyle; [Aι]= -CH (NHCOCH3) -CH2-Ph-;FG (I ''); R 5 = - (CH 2 ) 3 -cyclohexyl; [Aι] = -CH (NHCOCH 3 ) -CH 2 -Ph-;
A2 = -CF2P(0) (OH) 2 et le soufre de la thioazepinone est oxydéA 2 = -CF 2 P (0) (OH) 2 and the sulfur of thioazepinone is oxidized
(S02) (Mode opératoire E ; L' oxydation est effectuée sur le composé de l'exemple 40 avec le mCPBA)(SO 2 ) (Procedure E; Oxidation is carried out on the compound of Example 40 with mCPBA)
Rf = 0,16 Méthanol/Eau 80/20Rf = 0.16 Methanol / Water 80/20
SM (ESP) [M - H]" = 620" ;SM (ESP) [M - H] " = 620 " ;
IR (Nujol) C=0 : 1666, 1650 cm"1 ; Aromatique + amides II : 1532, 1515 cm"1 IR (Nujol) C = 0: 1666, 1650 cm "1 ; Aromatic + amides II: 1532, 1515 cm "1
Exemple 42Example 42
N2-acetyl-N- [ (3R) -5- (3-cyclohexylpropyl) -4-oxo-2 ,3,4,5- tetrahydro-1 , 5-benzothiazepin-3-yl] - 3- [8- (phosphonooxy) -1,2 ,3, 4-tetrahydro-quinolin-5-yl] -N2-acetyl-N- [(3R) -5- (3-cyclohexylpropyl) -4-oxo-2, 3,4,5- tetrahydro-1, 5-benzothiazepin-3-yl] - 3- [8- ( phosphonooxy) -1,2,3,4-tetrahydro-quinolin-5-yl] -
AlaninamideAlaninamide
FG (I1) : R5= -(CH2)3-cyclohexyle; [A1] = -CH (NHC0CH3) -CH2-Ar-;FG (I 1 ): R 5 = - (CH 2 ) 3 -cyclohexyl; [A 1 ] = -CH (NHC0CH 3 ) -CH 2 -Ar-;
A2 = -0P(0) (OH) 2 avec Ar : quinolineA 2 = -0P (0) (OH) 2 with Ar: quinoline
On opère comme à l'exemple 35 avec comme acide le (8-méthoxy- quinolin-5-yl) alaninamide que l'on déméthyle avec du BBr3 avant phosphorylation.The procedure is as in Example 35 with the acid (8-methoxy-quinolin-5-yl) alaninamide which is demethylated with BBr 3 before phosphorylation.
SM (ESP) MNa+ = 677Da ; MH+ = 655Da ; MH+ - [NHCOCH3] = 597DaMS (ESP) MNa + = 677Da; MH + = 655Da; MH + - [NHCOCH 3 ] = 597Da
Exemple 43Example 43
Acide [ [4- [ (2S) -2- (acétylamino) -4- [ [ (6R) -4- [3- (3- hydroxyphenyl)propyl) -hexahydro-5-oxo-l , 4-thiazepin-6- yl] amino] -3-oxopropyl]phényl] difluorométhyl] - PhosphoniqueAcid [[4- [(2S) -2- (acetylamino) -4- [[(6R) -4- [3- (3-hydroxyphenyl) propyl) -hexahydro-5-oxo-1,4-thiazepin-6 - yl] amino] -3-oxopropyl] phenyl] difluoromethyl] - Phosphonic
FG(I''); R5= -(CH2)3-(m-OH)-Ph; [Aχ]= -CH (NHCOCH3) -CH2-Ph-; A2 FG (I ''); R 5 = - (CH 2 ) 3 - (m-OH) -Ph; [Aχ] = -CH (NHCOCH 3 ) -CH 2 -Ph-; A 2
= -CF2P(0) (OH) 2 = -CF 2 P (0) (OH) 2
(Mode opératoire E, La déméthylation du composé de l'exemple 40 s'effectue avec le BBr3 dans le dichlorométhane (-15°C,lh)(Procedure E, Demethylation of the compound of Example 40 is carried out with BBr 3 in dichloromethane (-15 ° C, 1 h)
Rf = 0,71 (MeOH/eau 70/30)Rf = 0.71 (MeOH / water 70/30)
SM ( ESP ) : 490+ = [M+Na ] + ; 468+ = [M+H ] + : 451+ = [M-OH] + MS (ESP): 490 + = [M + Na] + ; 468 + = [M + H] + : 451 + = [M-OH] +
RMN ( CDCI3 )NMR (CDCI 3 )
1,77 (m, 5H, Ac + aliphatique) ; 2,44-2,90 (m, 6H, 2 SCH2 + CH2Ph) ; 3,05-3,90 (m, 6H, 2CH2N et MeO) ; 4,60 (m, IH, CH) ;1.77 (m, 5H, Ac + aliphatic); 2.44-2.90 (m, 6H, 2 SCH 2 + CH 2 Ph); 3.05-3.90 (m, 6H, 2CH 2 N and MeO); 4.60 (m, 1H, CH);
4,88 (m, IH, CH) ; 6,60 (m, 4H, Ph) ; 7,05 (m, IH, Ph) ;4.88 (m, 1H, CH); 6.60 (m, 4H, Ph); 7.05 (m, 1H, Ph);
7,40-7,50 (m, 3H, Ph) ; 8,10 (d, IH, NHCO) ; 8,30 (d, IH,7.40-7.50 (m, 3H, Ph); 8.10 (d, 1H, NHCO); 8.30 (d, 1H,
NHCO)NHCO)
Exemple 44 N2-acetyl-N- [ (6R) -4- (3-cyclohexylpropyl) -hexahydro-5-oxo-l , 4- thiazepin-6-yl] -3- (1 , 3-dihydro-3-hydroxy-l-oxo-5- isobenzofuranyl] -L-AlaninamideExample 44 N2-acetyl-N- [(6R) -4- (3-cyclohexylpropyl) -hexahydro-5-oxo-1,4-thiazepin-6-yl] -3- (1, 3-dihydro-3-hydroxy -l-oxo-5- isobenzofuranyl] -L-Alaninamide
FG(I''); R5= -(CH2)3-cyclohexyle; [Aι]= -CH (NHCOCH3) -CH2-Ph-;FG (I ''); R 5 = - (CH 2 ) 3 -cyclohexyl; [Aι] = -CH (NHCOCH 3 ) -CH 2 -Ph-;
A et Rβ forment ensemble avec le phenyle qui les porte un groupement -C(OH)-0-CO- (Mode opératoire G ; Ar représente un phenyle substitué en meta par un groupement CHO sous forme de dithioacétal cyclique. La cyclisation s'effectue par action de NaOH aqueux dans le THF après avoir déprotegé le formyle (Hg(C104)2)) Rf = 0,32 CH2Cl2/Méthanol 90/10 SM (ESP) [M + H]+ = 499+ IR (CHC1 )A and Rβ form together with the phenyle which carries them a group -C (OH) -0-CO- (Procedure G; Ar represents a phenyl substituted in meta by a CHO group in the form of a cyclic dithioacetal. The cyclization is carried out by the action of aqueous NaOH in THF after deproteging the formyl (Hg (C10 4 ) 2 )) Rf = 0.32 CH 2 Cl 2 / Methanol 90/10 SM (ESP) [M + H] + = 499 + IR (CHC1)
Absorption OH/NH : 3419, 3368 cm'1 C=0 : 1769,1662, 1636 cm"1 ; Aromatique + amides II : 1484 cm"1 OH / NH absorption: 3419, 3368 cm '1 C = 0: 1769.1662, 1636 cm "1 ; Aromatic + amides II: 1484 cm " 1
Exemple 45Example 45
N2-acetyl-N- [ (6R) -4- (3-cyclohexylpropyl) -hexahydro-5-oxo-l , 4- thiazepin-6-yl] -3- (1 , 3-dihydro-3-ethoxy-l-oxo-5- isobenzofuranyl] -L-AlaninamideN2-acetyl-N- [(6R) -4- (3-cyclohexylpropyl) -hexahydro-5-oxo-l, 4-thiazepin-6-yl] -3- (1, 3-dihydro-3-ethoxy-l -oxo-5- isobenzofuranyl] -L-Alaninamide
FG(I''); R5= -(CH2)3-cyclohexyle; [A1] = -CH (NHCOCH3) -CH2-Ph-;FG (I ''); R 5 = - (CH 2 ) 3 -cyclohexyl; [A 1 ] = -CH (NHCOCH 3 ) -CH 2 -Ph-;
A2 et R6 forment ensemble avec le phenyle qui les porte un groupement -C (OEt ) -O-CO-A 2 and R 6 form together with the phenyle which carries them a group -C (OEt) -O-CO-
(Mode opératoire G ; A partir du composé de l'exemple 44, on effectue la O-alkylation par action d' éthanol en présence de(Procedure G; From the compound of Example 44, O-alkylation is carried out by the action of ethanol in the presence of
PPTS)PPTS)
Rf = 0,58 CH2Cl2/Méthanol 90/10Rf = 0.58 CH 2 Cl 2 / Methanol 90/10
SM (ESP) [M + Na]+ = 482+ ; [2M + Na]+ = 1141+ ; [M-H]" = 558";MS (ESP) [M + Na] + = 482 + ; [2M + Na] + = 1141 + ; [MH] " = 558 " ;
(MH" - Et) = 530" ; (MH" - NHAc) = 499" IR (Nujol)(MH " - Et) = 530 " ; (MH " - NHAc) = 499 " IR (Nujol)
Absorption OH/NHOH / NH absorption
C=0 : 1773, 1635 cm"1 ;C = 0: 1773, 1635 cm "1 ;
Aromatique + amides II : 1540 cm"1 Aromatic + amides II: 1540 cm "1
Exemple 46 Acide 4- [ (2S) -2- (acétylamino) -3- [ [ (6R) -4- (3- cyclohexylpropyl) -hexahydro-5-oxo-l , 4-thiazepin-6-yl] amino] -Example 46 4- [(2S) -2- (acetylamino) -3- [[(6R) -4- (3- cyclohexylpropyl) -hexahydro-5-oxo-1,4-thiazepin-6-yl] amino acid] -
3-oxo-propyl] -1 , 2-Benzenedicarboxylique3-oxo-propyl] -1, 2-Benzenedicarboxylic
FG(I''); R5= -(CH2)3-cyclohexyle; [Aι]= -CH (NHCOCH3) -CH2- (m-FG (I ''); R 5 = - (CH 2 ) 3 -cyclohexyl; [Aι] = -CH (NHCOCH 3 ) -CH 2 - (m-
C02H)-Ph-; A2 = C02H (Mode opératoire G ; A partir du composé de l'exemple 44, on effectue une oxydation avec le réactif de Jones)C0 2 H) -Ph-; A 2 = C0 2 H (Procedure G; From the compound of Example 44, we performs oxidation with Jones' reagent)
Rf = 0,50 CH2Cl2/Méthanol 80/20Rf = 0.50 CH 2 Cl 2 / Methanol 80/20
SM (ESP) [M + Na]+ = 480+ ; [M-H]" = 546"; (MH" - H20) = 528" MS (ESP) [M + Na] + = 480 + ; [MH] " = 546 " ; (MH " - H 2 0) = 528 "
IR (Nujol) Absorption OH/NHIR (Nujol) OH / NH absorption
C=0 : 1763 cm"1 ;C = 0: 1763 cm "1 ;
CO + CO2 " + aromatiques tamide II : 1644 cm-1 (F, complexe) et 1525 cm-1 (ép.)CO + CO 2 " + aromatic tamide II: 1644 cm-1 (F, complex) and 1525 cm- 1 (th.)
Exemple 47 Acide [ [4- [ (2S) -2- (acétylamino) -3- [ [ (6R) -hexahydro-4- [ (3- methoxyphenyl)méthyl] -5-oxo-l , 4-thiazepin-6-yl] amino] -3- oxopropyl]phényl] difluorométhyl] - PhosphoniqueExample 47 Acid [[4- [(2S) -2- (acetylamino) -3- [[(6R) -hexahydro-4- [(3- methoxyphenyl) methyl] -5-oxo-1,4-thiazepin-6 -yl] amino] -3- oxopropyl] phenyl] difluoromethyl] - Phosphonic
FG(I''); R5= -CH2-Ph-OMe; [A = -CH (NHC0CH3) -CH2-Ph-; A2 = -FG (I ''); R 5 = -CH 2 -Ph-OMe; [A = -CH (NHC0CH 3 ) -CH 2 -Ph-; A 2 = -
CF2P(0) (OH) 2 (Mode opératoire E)CF 2 P (0) (OH) 2 (Procedure E)
Rf = 0,72 (MeOH/eau : 70/30)Rf = 0.72 (MeOH / water: 70/30)
SM (ESP) : 584" = [M-H]" ; 608+ = [M+Na]+ ; 630+ = M-H+2Na]+ MS (ESP): 584 " = [MH] " ; 608 + = [M + Na] + ; 630 + = M-H + 2Na] +
RMN (CDCI3)NMR (CDCI3)
1,78 (s, 3H, Ac) ; 2,44-2,58 (m, 4H, SCH2) ; 2,80-3,10 (m, 2H, CH2Ph) ; 3,64-3,83 (m, 5H, NCH2 OMe) ; 4,37 (dd, IH,1.78 (s, 3H, Ac); 2.44-2.58 (m, 4H, SCH 2 ); 2.80-3.10 (m, 2H, CH 2 Ph); 3.64-3.83 (m, 5H, NCH 2 OMe); 4.37 (dd, 1H,
PhCH2N) ; 4,58 (m, IH, CH) ; 4,74 (d, IH, PhCH2N) ; 5,00 (m,PhCH 2 N); 4.58 (m, 1H, CH); 4.74 (d, 1H, PhCH 2 N); 5.00 (m,
IH, CH) ; 6,86 (m, 3H, Ph) ; 7,26 (t, IH, Ph) ; 7,41 (m, 4H,1H, CH); 6.86 (m, 3H, Ph); 7.26 (t, 1H, Ph); 7.41 (m, 4H,
Ph) ; 8,27 (dd, 2H, NHCO)Ph); 8.27 (dd, 2H, NHCO)
Exemple 48 Acide [ [4- [ (2S) -2- (acétylamino) -4- [ [ (6R) -hexahydro-4- [ (2- naphthalenyl)méthyl] -5-oxo-l , 4-thiazepin-6-yl] amino] -3- oxopropyl]phényl] difluorométhyl] - PhosphoniqueExample 48 Acid [[4- [(2S) -2- (acetylamino) -4- [[(6R) -hexahydro-4- [(2- naphthalenyl) methyl] -5-oxo-1,4-thiazepin-6 -yl] amino] -3- oxopropyl] phenyl] difluoromethyl] - Phosphonic
FG(I''); R5= -CH2-Naphtyl; [Aι]= -CH (NHCOCH3) -CH2-Ph-; A2 = -FG (I ''); R 5 = -CH 2 -Naphthyl; [Aι] = -CH (NHCOCH 3 ) -CH 2 -Ph-; A 2 = -
CF2-P(0) (OH) 2 (Mode opératoire E)CF 2 -P (0) (OH) 2 (Procedure E)
Rf = 0,63 (MeOH/eau 70/30)Rf = 0.63 (MeOH / water 70/30)
SM (ESP) : 604" = [M-H]" ; 606+ = [M+H]+ ; 628+ = [M+Na]+ ;MS (ESP): 604 " = [MH] " ; 606 + = [M + H] + ; 628 + = [M + Na] + ;
1233+ = [2M+Na]+ 1233 + = [2M + Na] +
RMN (CDCI3) 1,79 (sd, 3H, Ac) ; 2,40-2,80 (m, 4H, SCH2) ; 2,81-3,11 (m, 2H, CH2Ph) ; 3 , 71-3 , 91 (m, 2H, NCH2 ) ; 4 , 58 (dd, IH, PhCH2N ) ;NMR (CDCI 3 ) 1.79 (nd, 3H, Ac); 2.40-2.80 (m, 4H, SCH 2 ); 2.81-3.11 (m, 2H, CH 2 Ph); 3, 71-3, 91 (m, 2H, NCH 2 ); 4.58 (dd, 1H, PhCH 2 N);
4 , 67 (m, IH, CH ) ; 4 , 95 ( dd, IH, PhCH2N ) ; 5 , 06 (m, IH, CH ) ;4.67 (m, 1H, CH); 4.95 (dd, 1H, PhCH 2 N); 5.06 (m, 1H, CH);
7 , 41 (m, 5H , Ph) ; 7 , 51 (m, 2H, Ph ) ; 7 , 82 ( si , IH , Ph ) ;7.41 (m, 5H, Ph); 7.51 (m, 2H, Ph); 7.82 (si, 1H, Ph);
7,90 (m, 3H, Ph) ; 8,28 (dd, IH, NHCO) ; 8,33 (dd, IH, NHCO) Exemple 497.90 (m, 3H, Ph); 8.28 (dd, 1H, NHCO); 8.33 (dd, IH, NHCO) Example 49
Acide [ [4- [ (2S) -2- (acétylamino) -4- [ [ (6R) -4- [2-Acid [[4- [(2S) -2- (acetylamino) -4- [[(6R) -4- [2-
(trifluorométhyl)phényl] -hexahydro-5-oxo-l , 4-thiazepin-6- yl] amino] -3-oxopropyl]phényl] difluorométhyl] - Phosphonique(trifluoromethyl) phenyl] -hexahydro-5-oxo-1,4-thiazepin-6-yl] amino] -3-oxopropyl] phenyl] difluoromethyl] - Phosphonic
FG(I''); R5= -CH2-Ph-(m-CF3) ; [Aι]= -CH (NHCOCH3) -CH2-Ph-; A2 = -CF2-P(0) (OH) 2 FG (I ''); R 5 = -CH 2 -Ph- (m-CF 3 ); [Aι] = -CH (NHCOCH 3 ) -CH 2 -Ph-; A 2 = -CF 2 -P (0) (OH) 2
(Mode opératoire E)(Procedure E)
Rf = 0,67 (MeOH/eau : 70/30)Rf = 0.67 (MeOH / water: 70/30)
SM (ESP) : 622" = [M-H]" ; 624+ = [M+H]+ ; 646+ = [M+Na]+ ;MS (ESP): 622 " = [MH] " ; 624 + = [M + H] + ; 646 + = [M + Na] + ;
1269+ = [2M+Na]+ RMN (CDC13)1269 + = [2M + Na] + NMR (CDC1 3 )
1.77 (sd, 3H, Ac) ; 2,42-2,80 (m, 4H, SCH2) ; 2,80-3,10 (m, 2H, CH2Ph) ; 3,69-3,91 (m, 2H, NCH2) ; 4,48 (dd, IH, PhCH2N) ; 4,52-4,70 (m, IH, CH) ; 4,87 (dd, IH, PhCH2N) ; 5,06 (m, IH, CH) ; 7,41 (m, 4H, Ph) ; 7,55-7,70 (m, 4H, Ph) ; 8,25 (dd, IH, NHCO) ; 8,33 (dd, IH, NHCO)1.77 (nd, 3H, Ac); 2.42-2.80 (m, 4H, SCH 2 ); 2.80-3.10 (m, 2H, CH 2 Ph); 3.69-3.91 (m, 2H, NCH 2 ); 4.48 (dd, 1H, PhCH 2 N); 4.52-4.70 (m, 1H, CH); 4.87 (dd, 1H, PhCH 2 N); 5.06 (m, 1H, CH); 7.41 (m, 4H, Ph); 7.55-7.70 (m, 4H, Ph); 8.25 (dd, 1H, NHCO); 8.33 (dd, IH, NHCO)
Exemple 50Example 50
Acide [ [4- [ (2S) -2- (acétylamino) -4- [ [ (6R) -hexahydro-5-oxo-4-Acid [[4- [(2S) -2- (acetylamino) -4- [[(6R) -hexahydro-5-oxo-4-
[ [4- (trifluoromethoxy)phényl]méthyl] -1 , 4-thiazepin-6- yl] amino] -3-oxopropyl]phényl] difluorométhyl] - Phosphonique FG(I''): R5= -CH2-Ph-OCF3; [Aι]= -CH (NHCOCH3) -CH2-Ph-; A2 = -[[4- (trifluoromethoxy) phenyl] methyl] -1, 4-thiazepin-6- yl] amino] -3-oxopropyl] phenyl] difluoromethyl] - Phosphonic FG (I ''): R 5 = -CH 2 -Ph -OCF 3 ; [Aι] = -CH (NHCOCH 3 ) -CH 2 -Ph-; A 2 = -
CF2-P(0) (OH) 2 CF 2 -P (0) (OH) 2
(Mode opératoire E)(Procedure E)
Rf = 0,63 (MeOH/eau : 70/30)Rf = 0.63 (MeOH / water: 70/30)
SM (ESP) : 638" = [M-H]" ; 640+ = [M+H]+ ; 608+ = [M+Na]+ ; RMN (CDCI3)MS (ESP): 638 " = [MH] " ; 640 + = [M + H] + ; 608 + = [M + Na] + ; NMR (CDCI 3 )
1.78 (s, 3H, Ac) ; 2,40-2,80 (m, 4H, SCH2) ; 2,80-3,10 (m, 2H, CH2Ph) ; 3,66-3,88 (m, 2H, NCH2) ; 4,38 (dd, IH, PhCH2N) ; 4,58-4,65 (m, IH, CH) ; 4,83 (dd, IH, PhCH2N) ; 5,03 (m, IH, CH) ; 7,30-7,50 (m, 8H, Ph) ; 8,20 (dd, 2H, NHCO) ; 8,35 (dd, IH, NHCO) Exemple 511.78 (s, 3H, Ac); 2.40-2.80 (m, 4H, SCH 2 ); 2.80-3.10 (m, 2H, CH 2 Ph); 3.66-3.88 (m, 2H, NCH 2 ); 4.38 (dd, 1H, PhCH 2 N); 4.58-4.65 (m, 1H, CH); 4.83 (dd, 1H, PhCH 2 N); 5.03 (m, 1H, CH); 7.30-7.50 (m, 8H, Ph); 8.20 (dd, 2H, NHCO); 8.35 (dd, IH, NHCO) Example 51
Acide [ [4- [ (2S) -2- (acétylamino) -4- [ [ (6R) -4- [2- (4- fluorophenoxy)phényl]méthyl] -hexahydro-5-oxo-l , 4-thiazepin-6- yl] amino] -3-oxopropyl]phényl] difluorométhyl] -Phosphonique FG(I''); R5= -CH2-Ph- (m-O-Ph-F) ; [Aι]= -CH (NHC0CH3) -CH2-Ph-; A2 Acid [[4- [(2S) -2- (acetylamino) -4- [[(6R) -4- [2- (4-fluorophenoxy) phenyl] methyl] -hexahydro-5-oxo-1,4-thiazepin -6- yl] amino] -3-oxopropyl] phenyl] difluoromethyl] -Phosphonique FG (I ''); R 5 = -CH 2 -Ph- (mO-Ph-F); [Aι] = -CH (NHC0CH 3 ) -CH 2 -Ph-; A 2
= -CF2-P(0) (OH) 2 = -CF 2 -P (0) (OH) 2
(Mode opératoire E)(Procedure E)
Rf = 0,54 (MeOH/eau : 70/30)Rf = 0.54 (MeOH / water: 70/30)
SM (ESP) : 664" = [M-H]" ; 666+ = [M+H]+ ; 688+ = [M+Na]+ ; 710+ = [M-H + 2Na]+ MS (ESP): 664 " = [MH] " ; 666 + = [M + H] + ; 688 + = [M + Na] + ; 710 + = [MH + 2Na] +
RMN (CDCI3)NMR (CDCI 3 )
1,77 (s, 3H, Ac) ; 2,40-2,75 (m, 4H, SCH2) ; 2,79-3,09 (m,1.77 (s, 3H, Ac); 2.40-2.75 (m, 4H, SCH 2 ); 2.79-3.09 (m,
2H, CH2Ph) ; 3,69-3,86 (m, 2H, NCH2 OMe) ; 4,42 (dd, IH,2H, CH 2 Ph); 3.69-3.86 (m, 2H, NCH 2 OMe); 4.42 (dd, 1H,
PhCH2N) ; 4,59 (m, IH, CH) ; 4,71 (dd, IH, PhCH2N) ; 5,01 (m, IH, CH) ; 6,87 (dl, IH, Ph) ; 6,95 (si, IH, Ph) ; 7,06 (d,PhCH 2 N); 4.59 (m, 1H, CH); 4.71 (dd, 1H, PhCH 2 N); 5.01 (m, 1H, CH); 6.87 (dl, 1H, Ph); 6.95 (si, 1H, Ph); 7.06 (d,
2H, Ph) ; 7,06 (IH, Ph) ; 7,22 (d, 2H, Ph) ; 7,34 (t, IH, Ph)2H, Ph); 7.06 (1H, Ph); 7.22 (d, 2H, Ph); 7.34 (t, 1H, Ph)
; 7,41 (m, 4H, Ph) ; 8,20 - 8,31 (dd, 2H, NHCO); 7.41 (m, 4H, Ph); 8.20 - 8.31 (dd, 2H, NHCO)
Exemple 52Example 52
Acide [ [4- [ (2S) -2- (acétylamino) -4- [ [ (6R) -hexahydro-4- [ [3- (phenylcarbonyl)phényl]méthyl] -5-oxo-l , 4-thiazepin-6- yl] amino] -3-oxopropyl]phényl] difluorométhyl] - PhosphoniqueAcid [[4- [(2S) -2- (acetylamino) -4- [[(6R) -hexahydro-4- [[3- (phenylcarbonyl) phenyl] methyl] -5-oxo-1,4-thiazepin- 6- yl] amino] -3-oxopropyl] phenyl] difluoromethyl] - Phosphonic
FG(I''); R5= -CH2-Ph-CO-Ph; [Aχ]= -CH (NHCOCH3) -CH2-Ph-; A2 = -FG (I ''); R 5 = -CH 2 -Ph-CO-Ph; [Aχ] = -CH (NHCOCH 3 ) -CH 2 -Ph-; A 2 = -
CF2-P(0) (OH) 2 CF 2 -P (0) (OH) 2
(Mode opératoire E) Rf = 0,63 (MeOH/eau)(Procedure E) Rf = 0.63 (MeOH / water)
SM (ESP) : 658" = [M-H]" ; 710+ = [M+Na]+ MS (ESP): 658 " = [MH] " ; 710 + = [M + Na] +
RMN (CDC13)NMR (CDC1 3 )
1,76 (s, 3H, Ac) ; 2,40-2,80 (m, 4H, SCH2) ; 2,80-3,09 (m,1.76 (s, 3H, Ac); 2.40-2.80 (m, 4H, SCH 2 ); 2.80-3.09 (m,
2H, CH2Ph) ; 3,74 (m, IH, NCH2 OMe) ; 3,90 (m, IH, NCH2) ; 4,55 (dd, IH, PhCH2N) ; 4,58-4,70 (m, IH, CH) ; 4,82 (d, IH,2H, CH 2 Ph); 3.74 (m, 1H, NCH 2 OMe); 3.90 (m, 1H, NCH 2 ); 4.55 (dd, 1H, PhCH 2 N); 4.58-4.70 (m, 1H, CH); 4.82 (d, 1H,
PhCH2N) ; 5,03 (m, IH, CH) ; 7,30-7,80 (m, 13H, Ph) ; 8,25PhCH 2 N); 5.03 (m, 1H, CH); 7.30-7.80 (m, 13H, Ph); 8.25
(m, IH, NHCO) ; 8,31 (m, IH, NHCO)(m, 1H, NHCO); 8.31 (m, 1H, NHCO)
Exemple 53Example 53
Acide [ [4- [ (2S) -2- (acétylamino) -4- [ [ (6R) -4- (3-cyclohexyl-2- oxo-propyl) -hexahydro-5-oxo-l , 4-thiazepin-6-yl] amino] -3- oxopropyl]phényl] difluorométhyl] - PhosphoniqueAcid [[4- [(2S) -2- (acetylamino) -4- [[(6R) -4- (3-cyclohexyl-2-oxo-propyl) -hexahydro-5-oxo-1,4-thiazepin- 6-yl] amino] -3- oxopropyl] phenyl] difluoromethyl] - Phosphonic
FG(I''); R5= -CH2-CO-CH2-cyclohexyle; [Aχ]= -CH (NHC0CH3) -CH2-FG (I ''); R 5 = -CH 2 -CO-CH 2 -cyclohexyl; [Aχ] = -CH (NHC0CH 3 ) -CH 2 -
Ph-; A2 = -CF2-P(0) (OH) 2 Ph-; A 2 = -CF 2 -P (0) (OH) 2
(Mode opératoire E) Rf = 0,48 (MeOH/eau : 70/30)(Procedure E) Rf = 0.48 (MeOH / water: 70/30)
SM (ESP) : 604+ = [M+H]+ ; 626+ = [M+Na]+ ; 1229+ = [2M+Na]+ MS (ESP): 604 + = [M + H] + ; 626 + = [M + Na] + ; 1229 + = [2M + Na] +
RMN (CDCI3)NMR (CDCI3)
0,91 (m, 2H, aliphatique) ; 1,00-1,30 (m, 8H, aliphatique) ;0.91 (m, 2H, aliphatic); 1.00-1.30 (m, 8H, aliphatic);
1,87 (m, IH, aliphatique) ; 1,76 (s, 3H, Ac) ; 2,27 (d, 2H, CO-CH2) ; 2,41-2,80 (m, 4H, SCH2) ; 3,06 (dd, 2H, CH2Ph) ;1.87 (m, 1H, aliphatic); 1.76 (s, 3H, Ac); 2.27 (d, 2H, CO-CH2); 2.41-2.80 (m, 4H, SCH 2 ); 3.06 (dd, 2H, CH 2 Ph);
3,64-3,90 (m, 4H, 2 NCH2) ; 4,80 (m, IH, CH) ; 4,98 (m, IH,3.64-3.90 (m, 4H, 2 NCH 2 ); 4.80 (m, 1H, CH); 4.98 (m, 1H,
CH) ; 7,40 (m, 4H, Ph) ; 8,23 (dd, 2H, NHCO)CH); 7.40 (m, 4H, Ph); 8.23 (dd, 2H, NHCO)
Exemple 54Example 54
Acide [ [4- [ [ [ (6R) -4- (3-cyclohexylpropyl) -hexahydro-5-oxo- 1 , 4-thiazepin-6-yl] amino] carbonyl] -2-formyl- phenyl] difluorométhyl] -PhosphoniqueAcid [[4- [[[(6R) -4- (3-cyclohexylpropyl) -hexahydro-5-oxo-1, 4-thiazepin-6-yl] amino] carbonyl] -2-formyl-phenyl] difluoromethyl] - Phosphonic
FG(I'') : R5= - (CH2)3-cyclohexyle; [Ax]= -(m-CHO)-Ph- ; A2 = -FG (I ''): R 5 = - (CH 2 ) 3 -cyclohexyl; [A x ] = - (m-CHO) -Ph-; A 2 = -
CF2-P(0) (OH)2 CF 2 -P (0) (OH) 2
(Mode opératoire D) Rf = 0,20 CH2Cl2/Méthanol 90/10(Procedure D) Rf = 0.20 CH 2 Cl 2 / Methanol 90/10
SM (ESP) [M + Na]+ = 482+ ; [2M + Na]+ = 1141+ ; [M-H]" = 558";MS (ESP) [M + Na] + = 482 + ; [2M + Na] + = 1141 + ; [MH] " = 558 " ;
(MH" - Et) = 530" ; (MH~ - NHAc) = 499" (MH " - Et) = 530 " ; (MH ~ - NHAc) = 499 "
IR (CHCI3)IR (CHCI3)
Absorption OH/NH ~ 3384 cm"1 C=0 : 1730, 1692, 1641 cm"1 ;OH / NH absorption ~ 3384 cm "1 C = 0: 1730, 1692, 1641 cm "1;
Aromatique: 1505, 1510 cm"1 Aromatic: 1505, 1510 cm "1
Exemple 55Example 55
N2-acetyl-N- [ (3R) -5- (3-cyclohexylpropyl) -4-oxo-2 ,3,4,5- tetrahydro-1 , 5-benzothiazepin-3-yl] -3- [8- (phosphonooxy) - 1,2,3, 4-tetrahydro-quinolin-5-yl] - L-AlaninamideN2-acetyl-N- [(3R) -5- (3-cyclohexylpropyl) -4-oxo-2, 3,4,5- tetrahydro-1, 5-benzothiazepin-3-yl] -3- [8- ( phosphonooxy) - 1,2,3,4-tetrahydro-quinolin-5-yl] - L-Alaninamide
FG (I') : R5= - (CH2)3-cyclohexyle; [Ax ] = -CH (NHCOCH3) -CH2-Ar-;FG (I '): R 5 = - (CH 2 ) 3 -cyclohexyl; [A x ] = -CH (NHCOCH 3 ) -CH 2 -Ar-;
A2 = -OP (O) (OH)2 avec Ar : , 2, 3, 4-tetrahydro-quinolyneA 2 = -OP (O) (OH) 2 with Ar:, 2, 3, 4-tetrahydro-quinolyne
(On opère comme à l'exemple 42, mais on effectue une déprotection avec H2 Pd/C au lieu de TFA) SM (ESP) [M-H]" = 657"; Exemple 56(The procedure is as in Example 42, but deprotection is carried out with H 2 Pd / C instead of TFA) SM (ESP) [MH] " = 657 " ; Example 56
Acide [ [4- [ (2S) -2- (acétylamino) -4- [ [ (6R) -4- (3-phenyl-2- propenyl) -hexahydro-5-oxo-l , 4-thiazepin-6-yl] amino] -3- oxopropyl]phényl] difluorométhyl] - Phosphonique FG (I") : R5 = -CH2-CH=CH-Ph; [Ax]= -CH (NHC0CH3) -CH2-Ph-; A2 =Acid [[4- [(2S) -2- (acetylamino) -4- [[(6R) -4- (3-phenyl-2-propenyl) -hexahydro-5-oxo-1,4-thiazepin-6- yl] amino] -3- oxopropyl] phenyl] difluoromethyl] - Phosphonic FG (I "): R 5 = -CH 2 -CH = CH-Ph; [A x ] = -CH (NHC0CH 3 ) -CH 2 -Ph -; A 2 =
-CF2-P(0) (OH) 2 -CF 2 -P (0) (OH) 2
(Mode opératoire E)(Procedure E)
Rf = 0,58 (MeOH/eau 70/30)Rf = 0.58 (MeOH / water 70/30)
SM (ESP) : 580" = [M-H]" ; 582+ = [M+H]+ RMN (CDC13)MS (ESP): 580 " = [MH] " ; 582 + = [M + H] + NMR (CDC1 3 )
1,76 (m, 3H, Ac) ; 2,54-2,69 (m, 4H, 2 SCH2) ; 2,80-3,09 (dd,1.76 (m, 3H, Ac); 2.54-2.69 (m, 4H, 2 SCH 2 ); 2.80-3.09 (dd,
2H, CH2Ph) ; 3,76-3,85 (m, 2H, NCH2) ; 4,04-4,30 (m, 2H, NCH2)2H, CH 2 Ph); 3.76-3.85 (m, 2H, NCH 2 ); 4.04-4.30 (m, 2H, NCH 2 )
; 4,56 (m, IH, CH) ; 4,98 (m, IH, CH) ; 6,23 (dt, IH, CH) ;; 4.56 (m, 1H, CH); 4.98 (m, 1H, CH); 6.23 (dt, 1H, CH);
6,58 (dl, IH, CH) ; 7,20-7,50 (m, 9H, Ph) ; 8,25 (m, 2H, NHCO)6.58 (dl, 1H, CH); 7.20-7.50 (m, 9H, Ph); 8.25 (m, 2H, NHCO)
Exemple 57Example 57
N- [ (6R) -hexahydro-5-oxo-l , 4-thiazepin-6-yl] -4- (phosphonooxy) -N- [(6R) -hexahydro-5-oxo-1,4, thiazepin-6-yl] -4- (phosphonooxy) -
BenzamideBenzamide
FG (I") : R5= H; [Ax]= - Ph-; A2 = -O-P(O) (OH)2 (Mode opératoire B' ; sans l'étape d'alkylation)FG (I "): R 5 = H; [A x ] = - Ph-; A 2 = -OP (O) (OH) 2 (Procedure B '; without the alkylation step)
SM (ESP) 345" = [M-H]" ; 265" = MH" - (PO(OH)2)SM (ESP) 345 " = [MH] " ; 265 " = MH " - (PO (OH) 2 )
Exemple 58Example 58
Acide [ [4- [ [ [ (6R) -hexahydro-4- [ (3-methoxyphényl)méthyl] -5- oxo-1 , 4-thiazepin-6-yl] amino] carbonyl]phényl] difluorométhyl] - PhosphoniqueAcid [[4- [[[(6R) -hexahydro-4- [(3-methoxyphenyl) methyl] -5- oxo-1, 4-thiazepin-6-yl] amino] carbonyl] phenyl] difluoromethyl] - Phosphonic
FG (I") : R5= -CH2-Ph-OMe; [Aι]= -Ph-; A2 = -CF2-P(0) (OH)2 FG (I "): R 5 = -CH 2 -Ph-OMe; [Aι] = -Ph-; A 2 = -CF 2 -P (0) (OH) 2
(Mode opératoire D)(Procedure D)
SM (ESP) 499" = [M-H]" SM (ESP) 499 " = [MH] "
Exemple 59 Acide [ [4- [ [ [ (6R) -hexahydro-4- [ (2-naphthalenyl)méthyl] -5-oxo-Example 59 Acid [[4- [[[((6R) -hexahydro-4- [(2-naphthalenyl) methyl] -5-oxo-
1 , 4-thiazepin-6-yl] amino] carbonyl]phényl] difluorométhyl] -1, 4-thiazepin-6-yl] amino] carbonyl] phenyl] difluoromethyl] -
PhosphoniquePhosphonic
FG (I") : R5= -CH2-Naphtyle; [Aι]= -Ph-; A2 = -CF2-P(0) (OH)2 FG (I "): R 5 = -CH 2 -Naphthyle; [Aι] = -Ph-; A 2 = -CF 2 -P (0) (OH) 2
(Mode opératoire D) SM (ESP) 519" = [M-H]" Exemple 60(Operating mode D) SM (ESP) 519 " = [MH] " Example 60
Acide [ [4- [ [ [ (6R) -hexahydro-5-oxo-4- [ [4- (trifluoromethoxy)phényl]méthyl] -1 , 4-thiazepin-6- yl] amino] carbonyl]phényl] difluorométhyl] -Phosphonique FG (I") : R5= -CH2-Ph-OCF3; [Ax]= -Ph-; A2 = -CF2-P(0) (0H)2 Acid [[4- [[[(6R) -hexahydro-5-oxo-4- [[4- (trifluoromethoxy) phenyl] methyl] -1,4-thiazepin-6- yl] amino] carbonyl] phenyl] difluoromethyl] -Phosphonic FG (I "): R 5 = -CH 2 -Ph-OCF 3 ; [A x ] = -Ph-; A 2 = -CF 2 -P (0) (0H) 2
(Mode opératoire D)(Procedure D)
SM (ESP) 553" = [M-H]" SM (ESP) 553 " = [MH] "
Exemple 61Example 61
Acide [ [4-[ [ [ (6R) -hexahydro-5-oxo-4- [2-oxo-2- (5, 6,7 ,8- tetrahydro-5 ,5,8, 8-tetramethyl-2-naphthalenyl) ethyl]Acid [[4- [[[(6R) -hexahydro-5-oxo-4- [2-oxo-2- (5, 6,7, 8- tetrahydro-5, 5,8, 8-tetramethyl-2- naphthalenyl) ethyl]
1 , 4-thiazepin-6-yl] amino] carbonyl]phényl] difluorométhyl] -1, 4-thiazepin-6-yl] amino] carbonyl] phenyl] difluoromethyl] -
PhosphoniquePhosphonic
FG (I") : R= -CH2-C0-Ar; [Aι]= -Ph-; A2 = -CF2-P (0) (OH) 2 avecFG (I "): R = -CH 2 -C0-Ar; [Aι] = -Ph-; A 2 = -CF 2 -P (0) (OH) 2 with
Ar représentant un groupement tetrahydro-5, 5, 8 , 8-tetramethyl- 2-naphtalène .Ar representing a tetrahydro-5, 5, 8, 8-tetramethyl-2-naphthalene group.
(Mode opératoire D)(Procedure D)
SM (ESP) 607" = [M-H]" SM (ESP) 607 " = [MH] "
Exemple 62Example 62
Acide [ [4- [ [ [ (6R) -hexahydro-5-oxo-4- [ [3- (trifluorométhyl)phényl]méthyl] -1 , 4-thiazepin-6- yl] amino] carbonyl]phényl] difluorométhyl] PhosphoniqueAcid [[4- [[[(6R) -hexahydro-5-oxo-4- [[3- (trifluoromethyl) phenyl] methyl] -1,4-thiazepin-6-yl] amino] carbonyl] phenyl] difluoromethyl] Phosphonic
FG (I") : R5= -CH2-Ph-(m-CF3) ; [Aι]= -Ph-; A2 = -CF2-P (0) (OH) 2 FG (I "): R 5 = -CH 2 -Ph- (m-CF 3 ); [Aι] = -Ph-; A 2 = -CF 2 -P (0) (OH) 2
(Mode opératoire D)(Procedure D)
SM (ESP) 537" = [M-H]" Exemple 63SM (ESP) 537 " = [MH] " Example 63
[ [4- [ [ [ (6R) -hexahydro-4- [ (3-methoxyphényl)méthyl] -5-oxo-[[4- [[[(6R) -hexahydro-4- [(3-methoxyphenyl) methyl] -5-oxo-
1 , 4-thiazepin-6-yl] amino] carbonyl]phényl] difluorométhyl] -1, 4-thiazepin-6-yl] amino] carbonyl] phenyl] difluoromethyl] -
Phosphonate d' éthyleEthyl phosphonate
FG (I") : R5= -CH2-Ph-(m-0Me) ; [Ax] = -Ph-; A2 = -CF2- P(0) (OH) (OEt)FG (I "): R 5 = -CH 2 -Ph- (m-0Me); [A x ] = -Ph-; A 2 = -CF 2 - P (0) (OH) (OEt)
(Mode opératoire D)(Procedure D)
SM (ESP) 527" = [M-H]" SM (ESP) 527 " = [MH] "
Exemple 64Example 64
4- [2- (acétylamino) -3-oxo-3- [ [ (6R) -5-oxo-hexahydro-4- [ [4- (trifluoromethoxy) phényl]méthyl] -1, 4-thiazepin-6-yl] amino] -1- propenyl] -2-carboxy-phenyl-Propanedioate de bis (1 , 1- dime thy le thy le )4- [2- (acetylamino) -3-oxo-3- [[(6R) -5-oxo-hexahydro-4- [[4- (trifluoromethoxy) phenyl] methyl] -1, 4-thiazepin-6-yl ] amino] -1- propenyl] -2-carboxy-phenyl-propanedioate bis (1, 1- dime thy le thy le)
FG ( I " ) : R5 = -CH2-Ph- (m-OCF3 ) ; [Aχ ] = -C (NHCOCH3 ) =CH- (m-FG (I "): R 5 = -CH 2 -Ph- (m-OCF 3 ); [Aχ] = -C (NHCOCH 3 ) = CH- (m-
C02H)Ph-; A2 = -CH(C02tBu)2 (Mode opératoire C)C0 2 H) Ph-; A 2 = -CH (C0 2 tBu) 2 (Operating mode C)
Rf = 0,22 (CH2Cl2/Méthanol/AcOH : 96/2/2)Rf = 0.22 (CH 2 Cl 2 / Methanol / AcOH: 96/2/2)
SM (ESP) 764" = [M-H]" ; 690- = MH" -(OtBu) ; 664- = MH" -MS (ESP) 764 " = [MH] " ; 690- = MH " - (OtBu); 664- = MH " -
(C02tBu)(C0 2 tBu)
RMN (CDCI3) 1,44 (s, 9H) ; 1,49 (s, 9H) ; 2,17 (s, 3H) ; 2,53 (m, 2H) ;NMR (CDCI3) 1.44 (s, 9H); 1.49 (s, 9H); 2.17 (s, 3H); 2.53 (m, 2H);
2,76 (dd, IH) ; 2,99 (dd, IH) ; 3,65 (m, IH) ; 3,91 (m, IH) ;2.76 (dd, 1H); 2.99 (dd, 1H); 3.65 (m, 1H); 3.91 (m, 1H);
4,45 (dl, IH) ; 4,88 (dl, IH) ; 5,18 (m, IH) ; 5,51 (s, IH) ;4.45 (dl, 1H); 4.88 (dl, 1H); 5.18 (m, 1H); 5.51 (s, 1H);
6,98 (si, IH) ; 7,20 à 7,30 (m, 4H) ; 7,40 à 8,10 (ml, 4H) ;6.98 (si, 1H); 7.20 to 7.30 (m, 4H); 7.40-8.10 (ml, 4H);
7,10 à 7,30 (m, IH) . Exemple 657.10 to 7.30 (m, 1H). Example 65
Acide 4- [ (2S) -2- (acétylamino) -3-oxo-3- [ [ (6R) -hexahydro-5-oxo-Acid 4- [(2S) -2- (acetylamino) -3-oxo-3- [[(6R) -hexahydro-5-oxo-
4- [ [4- (trifluoromethoxy) phényl]méthyl] -1 , 4-thiazepin-6- yl] amino]propyl] -2-formyl- Benzeneacetique4- [[4- (trifluoromethoxy) phenyl] methyl] -1, 4-thiazepin-6- yl] amino] propyl] -2-formyl- Benzeneacetique
FG (I") : R5= -CH2-Ph-0CF3; [Ax]= -CH (NHCOCH3) -CH2- (m-CHO) Ph-; A2 = -CH2-C02HFG (I "): R 5 = -CH 2 -Ph-0CF 3 ; [A x ] = -CH (NHCOCH 3 ) -CH 2 - (m-CHO) Ph-; A 2 = -CH 2 -C0 2 H
(Mode opératoire C, en utilisant un composé de formule (Illb) saturé préparé par couplage zincique d'une iodosérine avec le 4-iodo 2-formyl-phenyl-propanedioate de bis (1,1'- dimethylethyle) . Le formyle est alors protégé sous forme de dioxolane.(Procedure C, using a saturated compound of formula (IIIb) prepared by zinc coupling of an iodoserine with bis (1,1'-dimethylethyl) bis-1,1-formyl-phenyl-phenyl-propanedioate. The formyl is then protected in the form of dioxolane.
Rf = 0,35 (CH2Cl2/Méthanol/AcOH : 90/10/1)Rf = 0.35 (CH 2 Cl 2 / Methanol / AcOH: 90/10/1)
Exemple 66Example 66
Acide 4- [2- (acétylamino) -3-oxo-3- [ [ (6R) -hexahydro-5-oxo-Acid 4- [2- (acetylamino) -3-oxo-3- [[((6R) -hexahydro-5-oxo-
4- [ [4- (trifluoromethoxy) phényl]méthyl] -1 , 4-thiazepin-6- yl] amino] -1-propenyl] -2- (methoxycarbonyl) -Benzeneacetique4- [[4- (trifluoromethoxy) phenyl] methyl] -1, 4-thiazepin-6- yl] amino] -1-propenyl] -2- (methoxycarbonyl) -Benzeneacetique
FG (I") : R5= -CH2-Ph-OCF3; [Aι]= -CH (NHCOCH3) =CH- (m-C02Me) Ph-;FG (I "): R 5 = -CH 2 -Ph-OCF 3 ; [Aι] = -CH (NHCOCH 3 ) = CH- (m-C0 2 Me) Ph-;
A2 = -CH2-C02HA 2 = -CH 2 -C0 2 H
(Mode opératoire C)(Procedure C)
Rf = 0,22 Méthanol/H20 70/30 SM (ESP) [M-H]" = 641" RMN (DMSO)Rf = 0.22 Methanol / H 2 0 70/30 SM (ESP) [MH] " = 641 " NMR (DMSO)
2,04 (s, 3H) ; 2,50 à 2,82 (m, 2H) ; 3,68 (dl, IH) ; 3,932.04 (s, 3H); 2.50 to 2.82 (m, 2H); 3.68 (dl, 1H); 3.93
(dl, IH) ; 3,80 (s, 3H) ; 3,93 (s, 2H) ; 4,40 (d, IH) ; 4,82(dl, 1H); 3.80 (s, 3H); 3.93 (s, 2H); 4.40 (d, 1H); 4.82
(d, IH) ; 5,10 (m, IH) ; 7,19 (s, IH) ; 7,35 à 7,42 (m, 4H) ; 7,37 (m, IH) ; 8,04 (d, IH) .(d, 1H); 5.10 (m, 1H); 7.19 (s, 1H); 7.35 to 7.42 (m, 4H); 7.37 (m, 1H); 8.04 (d, 1H).
Exemple 67Example 67
Acide 2-carboxy-4- [ (2S) -2- (acétylamino) -3-oxo-3- [ [ (6R) - hexahydro-5-oxo-4- [ [4- (trifluoromethoxy)phényl] éthyl] -1 , 4- thiazepin-6-yl] amino] -1-propenyl] -Benzeneacetique FG (I") : R5= -CH2-Ph-OCF3; [Aι]= -CH (NHCOCH3) =CH- (m-C02H) Ph-;2-carboxy-4- [(2S) -2- (acetylamino) -3-oxo-3- [[(6R) - hexahydro-5-oxo-4- [[4- (trifluoromethoxy) phenyl] ethyl] acid] - 1,4-thiazepin-6-yl] amino] -1-propenyl] -Benzeneacetic FG (I "): R 5 = -CH 2 -Ph-OCF 3 ; [Aι] = -CH (NHCOCH 3 ) = CH- (m-C0 2 H) Ph-;
A2 = -CH2-C02HA 2 = -CH 2 -C0 2 H
(Mode opératoire C)(Procedure C)
Rf = 0,30 (CH2Cl2/Méthanol : 95/5)Rf = 0.30 (CH 2 Cl 2 / Methanol: 95/5)
SM (ESP) 608" = [M-H]" ; 564- = MH" - C02H RMN (DMSO)SM (ESP) 608 " = [MH] " ; 564- = MH " - C0 2 H NMR (DMSO)
2,03 (s, 3H) ; 2,53 (m, IH) ; 2,62 (m, IH) ; 2,69 (m, IH) ;2.03 (s, 3H); 2.53 (m, 1H); 2.62 (m, 1H); 2.69 (m, 1H);
2,79 (m, IH) ; 3,68 (m, IH) ; 3,95 (m, IH) ; 3,96 (s, 2H) ;2.79 (m, 1H); 3.68 (m, 1H); 3.95 (m, 1H); 3.96 (s, 2H);
4,42 (d, IH) ; 4,82 (d, IH) ; 5,10 (m, IH) ; 7,20 (s, IH) ;4.42 (d, 1H); 4.82 (d, 1H); 5.10 (m, 1H); 7.20 (s, 1H);
7,33 à 7,43 (m, 4H) ; 8,12 (d, IH) ; 12,20 (si, IH) ; 12,96 (si, IH)7.33 to 7.43 (m, 4H); 8.12 (d, 1H); 12.20 (si, 1H); 12.96 (si, IH)
Exemple 68Example 68
N2-acetyl-N- [ (6R) -4- [ [4- (dimethylamino) phényl]méthyl] - hexahydro-5-oxo-l , 4-thiazepin-6-yl] -4- (phosphonooxy)N2-acetyl-N- [(6R) -4- [[4- (dimethylamino) phenyl] methyl] - hexahydro-5-oxo-l, 4-thiazepin-6-yl] -4- (phosphonooxy)
L-Phenylalaninamide FG (I") : R5= -CH2-CO-Ph-NMe2; [Aχ]= -CH (NHCOCH3) -CH2-Ph-; A2 =L-Phenylalaninamide FG (I "): R 5 = -CH 2 -CO-Ph-NMe 2 ; [Aχ] = -CH (NHCOCH 3 ) -CH 2 -Ph-; A 2 =
-0-PO(OH)2 -0-PO (OH) 2
(Mode opératoire A' )(Procedure A ')
SM (ESP) [M-H]" = 591" SM (ESP) [MH] " = 591 "
RMN (DMSO) 1,75 (s, dédoublé) N-COCH3 ; 2,40 à 3,00 CH2 en position 2, 7 et CH2Ph ; 3,03 N(Me)2 ; 3,73 4,02 CH2 en position 6 ; 4,50 àNMR (DMSO) 1.75 (s, split) N-COCH 3; 2.40 to 3.00 CH 2 in position 2, 7 and CH 2 Ph; 3.03 N (Me) 2 ; 3.73 4.02 CH 2 in position 6; 4.50 to
5,00 NCH2CO ; 5,02 CO-CH2-NH ; 8,13 (m) CO-CH2-NH ;6,74 et5.00 NCH 2 CO; 5.02 CO-CH 2 -NH; 8.13 (m) CO-CH 2 -NH; 6.74 and
7,82 H aromatique (N-Ph-CO) ; 7,04 et 7,22 H aromatiques (Ph-7.82 H aromatic (N-Ph-CO); 7.04 and 7.22 H aromatic (Ph-
O-P) . Exemple 69 N- [ ( 6R) -hexahydro-5-oxo-4- (3-phenyl-2-propenyl) -1 , 4- thiazepin-6-yl] -4- (phosphonooxy) -OP). Example 69 N- [(6R) -hexahydro-5-oxo-4- (3-phenyl-2-propenyl) -1, 4- thiazepin-6-yl] -4- (phosphonooxy) -
Benzamide sel di (trihydroxymethyl)methanamineBenzamide salt di (trihydroxymethyl) methanamine
FG (I") : R5= -CH2-CH=CH-Ph; [Aι]= -Ph-; A2 = -OPO (OH) 2 sel Tris : TrihydroxymethylamineFG (I "): R 5 = -CH 2 -CH = CH-Ph; [Aι] = -Ph-; A 2 = -OPO (OH) 2 Tris salt: Trihydroxymethylamine
(Mode opératoire B)(Procedure B)
RMN (DMSO)NMR (DMSO)
2,73 (m) -S-CH2-CH2-N- ; 3,74 (m) 3,89 (m) -S-CH2-CH2-N-; 2,812.73 (m) -S-CH 2 -CH 2 -N-; 3.74 (m) 3.89 (m) -S-CH 2 -CH 2 -N-; 2.81
S-CH2-CH-NH ; 5,20 S-CH2-CH-NH ; 8,33 S-CH2-CH-NH ; 4,04 (dd) 4,31 (dd) NCH2-CH= ; 6,25 (dt, J=16 et 6,5) 6,60 (d, J= 16) éthylénique ; 7,24 7,76 H aromatiques (O-Ph-CO) ; 7,24 H en para 7,33 H en meta 7,44 H en ortho (Ph) ; 3,33 16H C-CH2-0.S-CH 2 -CH-NH; 5.20 S-CH 2 -CH-NH; 8.33 S-CH 2 -CH-NH; 4.04 (dd) 4.31 (dd) NCH 2 -CH =; 6.25 (dt, J = 16 and 6.5) 6.60 (d, J = 16) ethylenic; 7.24 7.76 H aromatics (O-Ph-CO); 7.24 H in para 7.33 H in meta 7.44 H in ortho (Ph); 3.33 16H C-CH 2 -0.
Exemple 70Example 70
N- [ (6R) -hexahydro-5-oxo-4- (3-phenyl-2-propenyl) -1 , 4- thiazepin-6-yl] -4- (phosphonooxy) -Benzamide sel de disodiumN- [(6R) -hexahydro-5-oxo-4- (3-phenyl-2-propenyl) -1, 4- thiazepin-6-yl] -4- (phosphonooxy) -Benzamide disodium salt
FG (I") : R5= -CH2-CH=CH-Ph; [Ax]= -Ph-; A2 = -OPO (OH) 2 sel de disodiumFG (I "): R 5 = -CH 2 -CH = CH-Ph; [A x ] = -Ph-; A 2 = -OPO (OH) 2 disodium salt
(Mode opératoire B)(Procedure B)
RMN (DMSO) 2,67 -S-CH2-CH2-N- ; 3,72 3,85 -S-CH2-CH2-N-; 2,76 S-CH2-CH-NHNMR (DMSO) 2.67 -S-CH 2 -CH 2 -N-; 3.72 3.85 -S-CH 2 -CH 2 -N-; 2.76 S-CH 2 -CH-NH
; 5,13 S-CH2-CH-NH ; 8,03 S-CH2-CH-NH ; 4,03 4,27 NCH2-CH= ;; 5.13 S-CH 2 -CH-NH; 8.03 S-CH 2 -CH-NH; 4.03 4.27 NCH 2 -CH =;
6,18 (dt) 6,54 (d, J= 15,5) éthylénique ; 7,10 à 7,45 (9H)6.18 (dt) 6.54 (d, J = 15.5) ethylenic; 7.10 to 7.45 (9H)
7,60 (m) 2H : aromatiques.7.60 (m) 2H: aromatic.
Exemple 71 N- [ (6R) -hexahydro-5-oxo-4- (3-phenyl-2-propenyl) -1 , 4- thiazepin-6-yl] -2-methyl-4- (phosphonooxy) -BenzamideExample 71 N- [(6R) -hexahydro-5-oxo-4- (3-phenyl-2-propenyl) -1, 4- thiazepin-6-yl] -2-methyl-4- (phosphonooxy) -Benzamide
FG ( I " ) : R5= -CH2-CH=CH-Ph ; [Aι ] = - ( o-Me ) Ph- ; A2 = -OPO (OH ) 2 FG (I "): R 5 = -CH 2 -CH = CH-Ph; [Aι] = - (o-Me) Ph-; A 2 = -OPO (OH) 2
(Mode opératoire B )(Procedure B)
Rf = 0 , 17 ( H20/MeOH : 40 / 60 ) Exemple 72Rf = 0.17 (H 2 0 / MeOH: 40/60) Example 72
N- [ ( 6R) -hexahydro-5-oxo-4- (3-phenyl-2-propenyl) -1 , 4- thiazepin-6-yl] -4-hydroxy-BenzamideN- [(6R) -hexahydro-5-oxo-4- (3-phenyl-2-propenyl) -1, 4- thiazepin-6-yl] -4-hydroxy-Benzamide
FG ( I " ) : R5= -CH2-CH=CH-Ph ; [Ax ] = -Ph- ; A2 = -OHFG (I "): R 5 = -CH 2 -CH = CH-Ph; [A x ] = -Ph-; A 2 = -OH
On opère selon l'exemple 35 stades a et b Rf = 0,34 CH2Cl2/iPrOH 95/5 Exemple 73We operate according to example 35 stages a and b Rf = 0.34 CH 2 Cl 2 / iPrOH 95/5 Example 73
4- [ [ (6R) -[[4-[4- (phosphonooxy) phényl] carbonyl] amino] -5-oxo- hexahydro-l,4-thiazepin-4-yl] méthyl] -Benzoate de méthyle4- [[(6R) - [[4- [4- (phosphonooxy) phenyl] carbonyl] amino] -5-oxohexahydro-1,4-thiazepin-4-yl] methyl] -Methyl benzoate
FG (I") : R5= -CH2-Ph-C02Me; [Aχ]= -Ph-; A2 = -0P0(0H)2 (Mode opératoire B' )FG (I "): R 5 = -CH 2 -Ph-C0 2 Me; [Aχ] = -Ph-; A 2 = -0P0 (0H) 2 (Operating mode B ')
SM (ESP) [M-H]" = 493" SM (ESP) [MH] " = 493 "
RMN (DMSO)NMR (DMSO)
2,57 -S-CH2-CH2-N- ; 3,69 3,92 -S-CH2-CH2-N-; 2,80 (dd) 2,892.57 -S-CH 2 -CH 2 -N-; 3.69 3.92 -S-CH 2 -CH 2 -N-; 2.80 (dd) 2.89
(dd) S-CH2-CH-NH ; 5,26 (m) S-CH2-CH-NH ; 8,53 (s) S-CH2-CH-NH ; 3,85 (s) C02Me ; 7,25 7,90 H aromatiques O-Ph-CO ; 7,44(dd) S-CH 2 -CH-NH; 5.26 (m) S-CH 2 -CH-NH; 8.53 (s) S-CH 2 -CH-NH; 3.85 (s) C0 2 Me; 7.25 7.90 H aromatic O-Ph-CO; 7.44
7,93 H aromatiques Ph-CO.7.93 H aromatic Ph-CO.
Exemple 74Example 74
N-[ (6R)-hexahydro-5-oxo-4-[ [3,5bis-N- [(6R) -hexahydro-5-oxo-4- [[3,5bis-
( trif luorométhyl) phényl] méthyl] -1 , 4-thiazepin-6-yl] -4- (phosphonooxy) -Benzamide(trifluoromethyl) phenyl] methyl] -1,4-thiazepin-6-yl] -4- (phosphonooxy) -Benzamide
FG (I") : R5= -CH2-(Di-3,5-CF3)Ph; [Aι]= -Ph-; A2 = -OPO(OH)2 FG (I "): R 5 = -CH 2 - (Di-3,5-CF 3 ) Ph; [Aι] = -Ph-; A 2 = -OPO (OH) 2
(Mode opératoire B' )(Procedure B ')
SM(ESP) [M-H]" = 571" ; (MH" - PO(OH)2) = 491" SM (ESP) [MH] " = 571 " ; (MH " - PO (OH) 2 ) = 491 "
Exemple 75 acide [ [ [4- [ [ [ (6R) -hexahydro-5-oxo-4- [ [3,5bis-Example 75 acid [[[4- [[[((6R) -hexahydro-5-oxo-4- [[3,5bis-
(trifluorométhyl)phényl]méthyl] -1 , 4-thiazepin-6- yl] amino] carbonyl]phényl] amino] carbonyl] -Phosphonique(trifluoromethyl) phenyl] methyl] -1, 4-thiazepin-6- yl] amino] carbonyl] phenyl] amino] carbonyl] -Phosphonic
FG (I") : R5= -CH2-(Di-3,5-CF3)Ph; [Aι]= -Ph-; A2 = -FG (I "): R 5 = -CH 2 - (Di-3,5-CF 3 ) Ph; [Aι] = -Ph-; A 2 = -
NHCOPO(OH)2 (Mode opératoire F)NHCOPO (OH) 2 (Procedure F)
SM (ESP) [M-H]" = 598" SM (ESP) [MH] " = 598 "
Exemple 76Example 76
N- [ (6R) -4 [ [ (1 , 1 ' -biphenyl) -4yl]methyl] -hexahydro-5-oxo-l , 4- thiazepin-6-yl] -4- (phosphonooxy) -Benzamide FG (I") : R5= -CH2-Ph-Ph; [Aι]= -Ph-; A2 = -OPO (OH) 2 N- [(6R) -4 [[(1, 1 '-biphenyl) -4yl] methyl] -hexahydro-5-oxo-l, 4-thiazepin-6-yl] -4- (phosphonooxy) -Benzamide FG ( I "): R 5 = -CH 2 -Ph-Ph; [Aι] = -Ph-; A 2 = -OPO (OH) 2
(Mode opératoire B' )(Procedure B ')
Exemple 77Example 77
4- (aminosulfonyl) -N- [ (6R) -hexahydro-5-oxo-4- (3-phenyl-2- propen-1-yl) -1 , 4-thiazepin-6-yl] -Benzenecarboxamide FG (I") : R5= -CH2-CH=CH-Ph; [Aι]≈ -Ph-; A2 = S02NH2 On opère comme à l'exemple 35 stades a et b mais en utilisant comme acide de formule (III) l'acide 4- (aminosulfonyl) - benzoique .4- (aminosulfonyl) -N- [(6R) -hexahydro-5-oxo-4- (3-phenyl-2-propen-1-yl) -1, 4-thiazepin-6-yl] -Benzenecarboxamide FG (I "): R 5 = -CH 2 -CH = CH-Ph; [Aι] ≈ -Ph-; A 2 = S0 2 NH 2 The procedure is as in Example 35 stages a and b but using as acid of formula (III) 4- (aminosulfonyl) benzoic acid.
Rf = 0,39 (heptane/Acétate d' éthyle/i-prOH : 30/70/5) Exemple 78Rf = 0.39 (heptane / Ethyl acetate / i-prOH: 30/70/5) Example 78
Acide [4-[[3-[ (6R) -hexahydro-5-oxo-4- (3-phenyl-2-propen-l- yl) -1 , 4-thiazepin-6-yl] amino] carbonyl]phényl] - Boronique[4 - [[3- [(6R) -hexahydro-5-oxo-4- (3-phenyl-2-propen-1-yl) -1,4-thiazepin-6-yl] amino] carbonyl] phenyl acid ] - Boronique
FG (I") : R5= -CH2-CH=CH-Ph; [Aχ]= -Ph-; A2 = B(OH)2 On opère comme à l'exemple 35 stades a et b mais en utilisant comme acide de formule (III) l'acide 4-boronobenzoique. Rf = 0,30 (heptane/Acétate d' éthyle/i-prOH 30/70/5)FG (I "): R 5 = -CH 2 -CH = CH-Ph; [Aχ] = -Ph-; A 2 = B (OH) 2 The procedure is as in Example 35 stages a and b but using as the acid of formula (III) 4-boronobenzoic acid. Rf = 0.30 (heptane / ethyl acetate / i-prOH 30/70/5)
Exemple 79 Acide [ [4- [ [ [ (6R) -hexahydro-4- [ ( -bromophenyl)méthyl] -5-oxo- 1 , 4-thiazepin-6- yl] amino] carbonyl]phényl] hydroxymethyl] PhosphoniqueExample 79 Acid [[4- [[[(6R) -hexahydro-4- [(-bromophenyl) methyl] -5-oxo-1,4-thiazepin-6-yl] amino] carbonyl] phenyl] hydroxymethyl] Phosphonic
FG (I") : R5= -CH2-Ph-Br; [A = -Ph-; A2 = -CH (OH) -PO (OH) 2 FG (I "): R 5 = -CH 2 -Ph-Br; [A = -Ph-; A 2 = -CH (OH) -PO (OH) 2
On opère selon le mode opératoire F mais en utilisant une résine P14 (Acide 4- [[(1,1- dimethylethoxy] methoxyphosphinylhydroxymethyl ] -benzoique préparée comme pour P13 mais à partir de 4-formyle benzoate de 2 propenyle..The procedure is carried out according to procedure F but using a P14 resin (4- [[(1,1-dimethylethoxy] methoxyphosphinylhydroxymethyl] -benzoic acid) prepared as for P13 but from 4-formyl benzoate of 2 propenyl.
SM (ESP) MH+ = 529-531Da Exemple 80 acide [ [ [4- [ [ [ (6R) -4- [ (3-cyanophenyl)méthyl] -hexahydro-5-oxo-MS (ESP) MH + = 529-531Da Example 80 acid [[[4- [[[(6R) -4- [(3-cyanophenyl) methyl] -hexahydro-5-oxo-
1 , 4-thiazepin-6-yl] amino] carbonyl]phényl] amino] carbonyl] -1, 4-thiazepin-6-yl] amino] carbonyl] phenyl] amino] carbonyl] -
PhosphoniquePhosphonic
FG (I") : R5= -CH2-Ph-CN; [Aλ] = -Ph-; A2 = -NHCO-PO (OH) 2 (Mode opératoire F)FG (I "): R 5 = -CH 2 -Ph-CN; [A λ ] = -Ph-; A 2 = -NHCO-PO (OH) 2 (Procedure F)
SM (ESP) [M+H]+ = 489DaSM (ESP) [M + H] + = 489Da
Exemple 81Example 81
Acide 4- [2- (acétylamino) -3-oxo-3- [ [ (6R) -hexahydro-5-oxo-4-Acid 4- [2- (acetylamino) -3-oxo-3- [[((6R) -hexahydro-5-oxo-4-
[ [4- (trifluoromethoxy) phényl]méthyl] -1 ,4-thiazepin-6- yl] amino] -1-propen-l-yl] -2-formyl-Benzeneacetique FG ( I " ) : R5= -CH2-Ph-OCF3 ; [Ax ] = -C (NHCOCH3 ) =CH- ( -CHO ) Ph- ; A2 [[4- (trifluoromethoxy) phenyl] methyl] -1, 4-thiazepin-6- yl] amino] -1-propen-l-yl] -2-formyl-Benzeneacetique FG (I "): R 5 = -CH 2 -Ph-OCF 3 ; [A x ] = -C (NHCOCH 3 ) = CH- (-CHO) Ph-; A 2
= -CH2-C02H= -CH 2 -C0 2 H
(Mode opératoire C)(Procedure C)
Rf = 0,31 CH2Cl2/MeOH/AcOH 90/10/1 SM (ESP) 616+ = [M + Na]+ ; 594+ = [M + H]+ ; 592" = [M-H]" Rf = 0.31 CH 2 Cl 2 / MeOH / AcOH 90/10/1 MS (ESP) 616 + = [M + Na] + ; 594 + = [M + H] + ; 592 " = [MH] "
RMN (CDC13)NMR (CDC1 3 )
2,40 à 3,00 (m, 4H) ; 3,40 à 4,10 (m, 4H) ; 4,44 et 4,89 (d,2.40 to 3.00 (m, 4H); 3.40 to 4.10 (m, 4H); 4.44 and 4.89 (d,
2H) ; 5,22 (si, IH) ; 6,90 (si, IH) ; 7,20 à 7,30 (m, 4H) ;2H); 5.22 (si, 1H); 6.90 (si, 1H); 7.20 to 7.30 (m, 4H);
7,50 à 8,12 (m, 3H) ; 7,91 (d, IH) ; 9,75 (si, IH) Exemple 827.50 to 8.12 (m, 3H); 7.91 (d, 1H); 9.75 (si, IH) Example 82
N- [ (6R) -hexahydro-5-oxo-4- (3-phenyl-2-propenyl) -1 , 4- thiazepin-6-yl] -4- (suifonooxy) -Benzamide sel de sodiumN- [(6R) -hexahydro-5-oxo-4- (3-phenyl-2-propenyl) -1, 4- thiazepin-6-yl] -4- (suifonooxy) -Benzamide sodium salt
FG (I") : R5= -CH2-CH=CH-Ph; [Aι]= -Ph-; A2 = -OSO3H sel de sodium On opère comme à l'exemple 35 stades a et b puis on effectue une réaction de sulfatation sur le phénol avec S03 dans la pyridine. L'obtention du sel de sodium s'effectue par passage sur une résine écangeuse d'ions.FG (I "): R 5 = -CH 2 -CH = CH-Ph; [Aι] = -Ph-; A 2 = -OSO 3 H sodium salt The procedure is as in Example 35 stages a and b then a sulfation reaction is carried out on the phenol with SO 3 in pyridine The sodium salt is obtained by passing over an ion-exchange resin.
Rf = 0,14 CH2Cl2/MeOH 90/10 SM (ESP) [M + Na]+ = 507+ ; 548+ = MNa+ + CH3CN ; 991+ = [2M +Rf = 0.14 CH 2 Cl 2 / MeOH 90/10 MS (ESP) [M + Na] + = 507 + ; 548 + = MNa + + CH 3 CN; 991 + = [2M +
Na]+ ; 1475+ = [3M + Na]+ Na] + ; 1475 + = [3M + Na] +
(ESM) Electrospray mode négatif(ESM) Electrospray negative mode
M" = 461" ; M" - (OS03 ") = 381" M " = 461 " ; M " - (OS0 3 " ) = 381 "
Exemple 83 N- [ (6R) -4- [ (2-fluoro-3-methylphenyl)méthyl] -hexahydro-5-oxo-Example 83 N- [(6R) -4- [(2-fluoro-3-methylphenyl) methyl] -hexahydro-5-oxo-
1 , 4-thiazepin-6yl] -4- (phosphonooxy) -Benzamide1,4-thiazepin-6yl] -4- (phosphonooxy) -Benzamide
FG (I") : R5= -CH2-(m-Me) (o-F) Ph; [Aι]= -Ph-; A2 = -OPO(OH)2 FG (I "): R 5 = -CH 2 - (m-Me) (oF) Ph; [Aι] = -Ph-; A 2 = -OPO (OH) 2
(Mode opératoire B' )(Procedure B ')
RMN (DMSO) 2,23 (d) CH3 ; 2,50 à 2,89 (m) CH2 en position 2 et 7 ; 3,68NMR (DMSO) 2.23 (d) CH 3 ; 2.50 to 2.89 (m) CH2 in positions 2 and 7; 3.68
(m) 3,94 (m) CH2 en position 6 ; 4,43 (d) 4,81 (d) N-CH2-Ph ;(m) 3.94 (m) CH2 in position 6; 4.43 (d) 4.81 (d) N-CH 2 -Ph;
5,26 (m) CO-CH-X ; 7,88 7,25 (AA'BB') CO-Ph-0 ; 7,07 (m) 7,165.26 (m) CO-CH-X; 7.88 7.25 (AA'BB ') CO-Ph-0; 7.07 (m) 7.16
(m) H aromatique ; 8,53 (d) NH.(m) H aromatic; 8.53 (d) NH.
SM (ESP) [M+H]+ = 469Da Exemple 84 N- [ (6R) -4- [ (4-bromophenyl)méthyl] -hexahydro-5-oxo-l , 4- thiazepin-6-yl] -4- (phosphonooxy) -BenzamideSM (ESP) [M + H] + = 469Da Example 84 N- [(6R) -4- [(4-bromophenyl) methyl] -hexahydro-5-oxo-1,4,4 thiazepin-6-yl] -4- (phosphonooxy) -Benzamide
FG (I") : R5= -CH2-Ph-Br; [Aι]= -Ph-; A2 = -0P0(0H)2 (Mode opératoire B' ) [M+H]+ = 515-517Da Exemple 85FG (I "): R 5 = -CH 2 -Ph-Br; [Aι] = -Ph-; A 2 = -0P0 (0H) 2 (Operating mode B ') [M + H] + = 515-517Da Example 85
4- (phosphonooxy) -N- [ (6R) -hexahydro-5-oxo- [ [2- [ (phenylsulfonyl)méthyl]phényl] -1 , 4-thiazepin-6-yl] - Benzamide FG (I") : R5= -CH2-Ph- (m-CH2-S02-Ph) ; [Aι]= -Ph-; A2 = -4- (phosphonooxy) -N- [(6R) -hexahydro-5-oxo- [[2- [(phenylsulfonyl) methyl] phenyl] -1, 4-thiazepin-6-yl] - Benzamide FG (I "): R 5 = -CH 2 -Ph- (m-CH 2 -S0 2 -Ph); [Aι] = -Ph-; A 2 = -
OPO (OH) 2 OPO (OH) 2
(Mode opératoire B' )(Procedure B ')
SMSM
MH+ = 591Da ; 2MH+ = 1181Da ; [M-H]" = 589" ; MH" - (PO(OH)2) = 509" MH + = 591Da; 2MH + = 1181Da; [MH] " = 589 " ; MH " - (PO (OH) 2 ) = 509 "
Exemple 86Example 86
Acide 4- [2- (acétylamino) -3-oxo-3- [ [ (6R) -hexahydro-5-oxo-4-Acid 4- [2- (acetylamino) -3-oxo-3- [[((6R) -hexahydro-5-oxo-4-
[ [4- (trifluoromethoxy)phényl]méthyl] -1 , 4-thiazepin-6- yl] amino] -1-propen-l-yl] -alpha-fluoro-2-formyl- Benzeneacetique[[4- (trifluoromethoxy) phenyl] methyl] -1, 4-thiazepin-6- yl] amino] -1-propen-l-yl] -alpha-fluoro-2-formyl- Benzeneacetique
FG (I") : R5= -CH2-Ph-OCF3; [Ax]= -C (NHC0CH3) =CH- (m-CHO) Ph-; A2 FG (I "): R 5 = -CH 2 -Ph-OCF 3 ; [A x ] = -C (NHC0CH 3 ) = CH- (m-CHO) Ph-; A 2
= -CHF-C02H= -CHF-C0 2 H
(Mode opératoire C)(Procedure C)
Rf = 0,10 CH2Cl2/MeOH/AcOH 87,5/12,5/3,0 SM : 610 = [M-H]" ; 566" = MH" - C02HRf = 0.10 CH 2 Cl 2 / MeOH / AcOH 87.5 / 12.5 / 3.0 SM: 610 = [MH] " ; 566 " = MH " - C0 2 H
RMN (DMSO)NMR (DMSO)
2,04 (s, 3H) ; 2,52 et 2,63 (m, 2H) ; 3,69 et 3,90 (m, 2H) ;2.04 (s, 3H); 2.52 and 2.63 (m, 2H); 3.69 and 3.90 (m, 2H);
2,70 et 2,79 (m, 2H) ; 4,40 (d, IH) ; 4,81 (d, IH) ; 5,102.70 and 2.79 (m, 2H); 4.40 (d, 1H); 4.81 (d, 1H); 5.10
(si, IH) ; 6,53 (dl, IH) ; 7,18 (s, IH) ; 7,32 à 7,42 (m, 4H) ; 7,60 (si, IH) ; 7,81 (si, IH) ; 8,05 (m, 2H) ; 10,3 (si,(if, 1H); 6.53 (dl, 1H); 7.18 (s, 1H); 7.32 to 7.42 (m, 4H); 7.60 (si, 1H); 7.81 (si, 1H); 8.05 (m, 2H); 10.3 (if,
IH)IH)
Exemple 87Example 87
Sulfamate de 4- [ [ [ (6R) -hexahydro-5-oxo-4- (3-phenyl-2- propenyl) -1 , 4-thiazepin-6-yl] amino] carbonyl] phenyle FG (I") : R5= -CH2-CH=CH-Ph; [Aι] = -Ph-; A2 = -OS02NH2 On opère comme à l'exemple 35 stades a et b puis on fait réagir le chlorosulfonamide dans le dichloroéthane.4- [[((6R) -hexahydro-5-oxo-4- (3-phenyl-2-propenyl) -1,4-thiazepin-6-yl] amino] carbonyl] phenyl FG (I ") sulfamate: R 5 = -CH 2 -CH = CH-Ph; [Aι] = -Ph-; A 2 = -OS0 2 NH 2 The operation is carried out as in Example 35 stages a and b and then the chlorosulfonamide is reacted in dichloroethane.
Rf 0,33 (CH2Cl2/Acétone : 90/10)Rf 0.33 (CH 2 Cl 2 / Acetone: 90/10)
Exemple 88 Acide [4-[3-[[ (6R) -hexahydro-5-oxo-4- (3-phenyl-2-propen-l- yl) -1 , 4-thiazepin-6-yl] amino] 3-oxo-1-propenyl]phényl] -Example 88 Acid [4- [3 - [[(6R) -hexahydro-5-oxo-4- (3-phenyl-2-propen-1-yl) -1, 4-thiazepin-6-yl] amino] 3 -oxo-1-propenyl] phenyl] -
BoroniqueBoronic
FG (I") : R5= -CH2-CH=CH-Ph; [Ai] = -CH=CH-Ph-; A2 = -B(OH)2 FG (I "): R 5 = -CH 2 -CH = CH-Ph; [Ai] = -CH = CH-Ph-; A 2 = -B (OH) 2
On opère comme à l'exemple 35 stades a et b en utilisant comme acide de formule (III) le H02C-CH=CH-Ph-B (OH) 2.The procedure is as in Example 35 stages a and b using as the acid of formula (III) H0 2 C-CH = CH-Ph-B (OH) 2 .
Rf = 0,45 (CH2Cl2/MeOH 95/5)Rf = 0.45 (CH 2 Cl 2 / MeOH 95/5)
Exemple 89Example 89
N- [ (6R) -hexahydro-4- [ (4-nitrophenyl)méthyl] -5-oxo-l , 4- thiazepin-6yl] -4- (phosphonooxy) -Benzamide FG (I") : R5= -CH2-Ph-N02; [Aι]= -Ph-; A2 = -OPO (OH) 2 N- [(6R) -hexahydro-4- [(4-nitrophenyl) methyl] -5-oxo-1,4-thiazepin-6yl] -4- (phosphonooxy) -Benzamide FG (I "): R 5 = - CH 2 -Ph-N0 2 ; [Aι] = -Ph-; A 2 = -OPO (OH) 2
(Mode opératoire B' )(Procedure B ')
SM (ESP) : MH+ = 482DaSM (ESP): MH + = 482Da
Exemple 90Example 90
N- [ (6R) -hexahydro-5-oxo-4- [3- [ (4-phenylpiperazin-l- yl) suifonyl]propyl] -1 , 4-thiazepin-6yl] -4- (phosphonooxy) -N- [(6R) -hexahydro-5-oxo-4- [3- [(4-phenylpiperazin-l- yl) suifonyl] propyl] -1, 4-thiazepin-6yl] -4- (phosphonooxy) -
BenzamideBenzamide
FG (I") : R5= -(CH2)3-S02_Het; [Aι]= -Ph-; A2 = -OPO (OH) 2, avecFG (I "): R 5 = - (CH 2 ) 3 -S0 2 _Het; [Aι] = -Ph-; A 2 = -OPO (OH) 2 , with
Het représentant un groupement 4-phenylpiperazineHet representing a 4-phenylpiperazine group
(Mode opératoire B' ) SM (ESP) : MH+ = 613Da ; [M-H]" = 611" (Procedure B ') SM (ESP): MH + = 613Da; [MH] " = 611 "
Exemple 91Example 91
4- (phosphonooxy) -N- [ (6R) -4- [3- [ (4- thiomorpholinyl) suifonyl]propyl] -hexahydro-5-oxo-l , 4- thiazepin-6-yl] -Benzamide FG (I") : R5= - (CH2) 3-S02-Het ; [Aι]= -Ph-; A2 = -OPO(OH)2, avec4- (phosphonooxy) -N- [(6R) -4- [3- [(4-thiomorpholinyl) suifonyl] propyl] -hexahydro-5-oxo-l, 4-thiazepin-6-yl] -Benzamide FG (I "): R 5 = - (CH 2 ) 3 -S0 2 -Het; [Aι] = -Ph-; A 2 = -OPO (OH) 2 , with
Het représentant un groupement thiomorpholineHet representing a thiomorpholine group
(Mode opératoire B' )(Procedure B ')
SM (ESP) : 571Da = [M + H20]+ ; 554Da = MH+ MS (ESP): 571Da = [M + H 2 0] + ; 554Da = MH +
Exemple 92 N- [ (6R) -4- [3- [ (butylmethylamino) suifonyl]propyl] -hexahydro-5- oxo-1 , 4-thiazepin-6-yl] -4- (phosphonooxy) -BenzamideExample 92 N- [(6R) -4- [3- [(butylmethylamino) suifonyl] propyl] -hexahydro-5- oxo-1, 4-thiazepin-6-yl] -4- (phosphonooxy) -Benzamide
FG ( I " ) : R5= - ( CH2 ) 3-S02-N (Me ) ( n-Bu) ; [Aχ ] = -Ph- ; A2 = -FG (I "): R 5 = - (CH 2 ) 3 -S0 2 -N (Me) (n-Bu); [Aχ] = -Ph-; A 2 = -
OPO (OH ) 2 ,OPO (OH) 2 ,
(Mode opératoire B' ) SM (ESP) : 555Da = [M + H20]+ ; 538Da = MH+ (Procedure B ') SM (ESP): 555Da = [M + H 2 0] + ; 538Da = MH +
Exemple 93Example 93
Acide 4- [2- (acétylamino) -3- [ [ (6R) -hexahydro-5-oxo-4- [ [4-Acid 4- [2- (acetylamino) -3- [[(6R) -hexahydro-5-oxo-4- [[4-
(trifluoromethoxy)phényl]méthyl] -1 , 4-thiazepin-6-yl] amino] -3- oxo-1-propenyl] -2- [ [ (aminocarbonyl) hydrazono]méthyl] -alpha- fluoro-Benzeneacetique(trifluoromethoxy) phenyl] methyl] -1,4-thiazepin-6-yl] amino] -3- oxo-1-propenyl] -2- [[(aminocarbonyl) hydrazono] methyl] -alpha- fluoro-benzeneacetic
FG (I") : R5= -CH2-Ph-OCF3; [Ax]= -C (NHCOCH3) =CH- (m-C=N-FG (I "): R 5 = -CH 2 -Ph-OCF 3 ; [A x ] = -C (NHCOCH 3 ) = CH- (mC = N-
NHCONH2)Ph-; A2 = -CHF-C02HNHCONH 2 ) Ph-; A 2 = -CHF-C0 2 H
(Mode opératoire C, le dérivé aminocarbonylhydrazine est préparé à partir du composé de l'esemple 86) Rf = 0,28 CH2Cl2/MeOH 60/40(Procedure C, the aminocarbonylhydrazine derivative is prepared from the compound of Example 86) Rf = 0.28 CH 2 Cl 2 / MeOH 60/40
SM : 667 = [M - H]" ; 625 = MH" - C02HMS: 667 = [M - H] " ; 625 = MH " - C0 2 H
RMN (DMSO)NMR (DMSO)
2,02 (s, 3H) ; 2,40 à 2,80 (m, 2H) ; 3,68 (d, IH) ; 3,92 (d,2.02 (s, 3H); 2.40 to 2.80 (m, 2H); 3.68 (d, 1H); 3.92 (d,
IH) ; 4,42 (d, IH) ; 4,83 (d, IH) ; 5,10 (m, IH) ; 5,65 (d, IH) ; 7,24 (s, IH) ; 7,33 à 7,43 (m, 4H) ; 8,00 (d, IH) ;IH); 4.42 (d, 1H); 4.83 (d, 1H); 5.10 (m, 1H); 5.65 (d, 1H); 7.24 (s, 1H); 7.33 to 7.43 (m, 4H); 8.00 (d, 1H);
8,18 (s, IH) ; 7,46 (d, 2H) ; 8,38 (s, IH) ; 9,73 (s, IH) ;8.18 (s, 1H); 7.46 (d, 2H); 8.38 (s, 1H); 9.73 (s, 1H);
10,31 (s, IH)10.31 (s, 1H)
Exemple 94Example 94
N- [ (6R) -4- [3- [ (cyclohexylmethylamino) suifonyl]propyl] - hexahydro-5-oxo-1 , 4-thiazepin-6-yl] -4- (phosphonooxy) -N- [(6R) -4- [3- [(cyclohexylmethylamino) suifonyl] propyl] - hexahydro-5-oxo-1, 4-thiazepin-6-yl] -4- (phosphonooxy) -
BenzamideBenzamide
FG (I") : R5= -(CH2)3-S02-N(Me) (cyclohexyle) ; [Aχ] = -Ph-; A2 =FG (I "): R 5 = - (CH 2 ) 3 -S0 2 -N (Me) (cyclohexyl); [Aχ] = -Ph-; A 2 =
-OPO (OH) 2 -OPO (OH) 2
(Mode opératoire B) SM (ESP) : 58lDa = [M + H20]+ ; 564Da = MH+ (Procedure B) SM (ESP): 58lDa = [M + H 2 0] + ; 564Da = MH +
Exemple 95Example 95
1~ t [3- [ (6R) - [ [ [4- (phosphonooxy)phényl] carbonyl] amino] -5-oxo- hexahydro-1 , 4-thiazepin-4-yl]propyl] suifonyl] - tetrahydro-lH-pyrrole-2-carboxylate de méthyle FG (I") : R5= - (CH2) 3-S02-Het ; [Ax] = -Ph-; A2 = -OPO (OH) 2, avec Het représentant un groupement pyrrole substitué en 2 par un carboxylate de méthyle.1 ~ t [3- [(6R) - [[[4- (phosphonooxy) phenyl] carbonyl] amino] -5-oxo hexahydro-1, 4-thiazepin-4-yl] propyl] suifonyl] - tetrahydro-1H -pyrrole-2-methyl carboxylate FG (I "): R 5 = - (CH 2 ) 3 -S0 2 -Het; [A x ] = -Ph-; A 2 = -OPO (OH) 2 , with Het representing a pyrrole group substituted in 2 with a methyl carboxylate.
(Mode opératoire B' )(Procedure B ')
SM (ESP) : 618Da = MK+ ; 602Da = MNa+ ; 580Da = MH+ Exemple 96MS (ESP): 618Da = MK + ; 602Da = MNa + ; 580Da = MH + Example 96
Acide [ [ [4-[ [ [ (6R) -4-[ (6-chloro-l,3-benzodioxolan-5- yl)méthyl] -hexahydro-5-oxo-l , 4-thiazepin-6- yl] amino] carbonyl]phényl] amino] carbonyl] -PhosphoniqueAcid [[[4- [[[(6R) -4- [(6-chloro-1,3-benzodioxolan-5-yl) methyl] -hexahydro-5-oxo-1,4-thiazepin-6- yl] amino] carbonyl] phenyl] amino] carbonyl] -Phosphonic
FG (I") : R5= -CH2-Ar; [Aι]= -Ph-; A2 = -NHCO-PO (OH) 2, avec Ar représentant un groupement phenyle substitué en 2 par un chlore et substitué en 4 et 5 par un groupement méthylènedioxy .FG (I "): R 5 = -CH 2 -Ar; [Aι] = -Ph-; A 2 = -NHCO-PO (OH) 2 , with Ar representing a phenyl group substituted in 2 with chlorine and substituted in 4 and 5 by a methylenedioxy group.
(Mode opératoire F)(Procedure F)
SM (ESP) : MH+ = 542Da Exemple 97SM (ESP): MH + = 542Da Example 97
N2-acetyl-N- [ (6R) -4- [ [2 ' -cyano- (1,1' -biphenyl) -4-yl]methyl] - hexahydro-5-oxo-l , 4-thiazepin-6-yl] -4- (phosphonooxy)N2-acetyl-N- [(6R) -4- [[2 '-cyano- (1,1' -biphenyl) -4-yl] methyl] - hexahydro-5-oxo-l, 4-thiazepin-6- yl] -4- (phosphonooxy)
PhenylalaninamidePhenylalaninamide
FG (I") : R5= -CH2-Ph-(o-CN)Ph-; [Ai] = -CH (NHCOCH3) -CH2-Ph-; A2 = -OPO (OH) 2 FG (I "): R 5 = -CH 2 -Ph- (o-CN) Ph-; [Ai] = -CH (NHCOCH 3 ) -CH 2 -Ph-; A 2 = -OPO (OH) 2
(Mode opératoire A' )(Procedure A ')
SM (ESP) : 645Da = MNa+ ; 623Da = MH+ MS (ESP): 645Da = MNa + ; 623Da = MH +
Exemple 98Example 98
Acide [ [ [4- [ [ [ (6R) -4- [ [ (1,1 ' -biphenyl) -4-yl]methyl] - hexahydro-5-oxo-l , 4-thiazepin-6- yl] amino] carbonyl]phényl] amino] carbonyl] -PhosphoniqueAcid [[[4- [[[(6R) -4- [[(1,1 '-biphenyl) -4-yl] methyl] - hexahydro-5-oxo-1,4-thiazepin-6- yl] amino ] carbonyl] phenyl] amino] carbonyl] -Phosphonic
FG (I") : R5= -CH2-Ph-Ph; [Aι]= -Ph-; A2 = -NHCOPO(OH)2 FG (I "): R 5 = -CH 2 -Ph-Ph; [Aι] = -Ph-; A 2 = -NHCOPO (OH) 2
(Mode opératoire F)(Procedure F)
SM (ESP) : MH+ = 540Da Exemple 99SM (ESP): MH + = 540Da Example 99
Acide [ [ [4- [ [ [ (6R) -hexahydro-5-oxo-4- [ [4-Acid [[[4- [[[(6R) -hexahydro-5-oxo-4- [[4-
(trifluoromethoxy)phényl]méthyl] -1 , 4-thiazepin-6- yl] amino] carbonyl]phényl] amino] carbonyl] -Phosphonique(trifluoromethoxy) phenyl] methyl] -1, 4-thiazepin-6- yl] amino] carbonyl] phenyl] amino] carbonyl] -Phosphonic
FG (I") : R5= -CH2-Ph-OCF3; [Ax ] = -Ph-; A2 = -NHCOPO(OH)2 (Mode opératoire F) SM : MH+ = 548DaFG (I "): R 5 = -CH 2 -Ph-OCF 3 ; [A x ] = -Ph-; A 2 = -NHCOPO (OH) 2 (Procedure F) SM: MH + = 548Da
Exemple 100Example 100
Acide [ [ [4- [ [ [ (6R) -hexahydro-5-oxo-4- [ [4-Acid [[[4- [[[(6R) -hexahydro-5-oxo-4- [[4-
(trifluorométhyl) phényl]méthyl] -1 , 4-thiazepin-6- yl] amino] carbonyl]phényl] amino] carbonyl] -Phosphonique(trifluoromethyl) phenyl] methyl] -1, 4-thiazepin-6- yl] amino] carbonyl] phenyl] amino] carbonyl] -Phosphonic
FG (I") : R5= -CH2-Ph-CF3; [A = -Ph-; A2 = -NHC0P0(0H)2 FG (I "): R 5 = -CH 2 -Ph-CF 3 ; [A = -Ph-; A 2 = -NHC0P0 (0H) 2
(Mode opératoire F)(Procedure F)
SM : MH+ = 532DaSM: MH + = 532Da
Exemple 101 4 , 5-dihydroxy-N- [ ( 6R) -hexahydro-5-oxo-4- (3-phenyl-2- propenyl) -1 , 4-thiazepin-6-yl] -BenzamideExample 101 4, 5-dihydroxy-N- [(6R) -hexahydro-5-oxo-4- (3-phenyl-2-propenyl) -1, 4-thiazepin-6-yl] -Benzamide
FG ( I " ) : R5= -CH2-CH=CH-Ph ; [Aι ] = - (m-OH) Ph- ; A2 = OHFG (I "): R 5 = -CH 2 -CH = CH-Ph; [Aι] = - (m-OH) Ph-; A 2 = OH
On opère comme à l'exemple 35 stades a et b, avec l'acideThe procedure is as in Example 35 stages a and b, with the acid
3, 4-dihydroxy benzoique. Rf = 0,32 (CH2Cl2/MeOH/AcOH : 98/2.0/0.5)3,4-benzoic dihydroxy. Rf = 0.32 (CH 2 Cl 2 / MeOH / AcOH: 98 / 2.0 / 0.5)
SM (ESP) 399+ = [M+H]+ ; 397" = [M-H]" ; 795" = [2M-H]" MS (ESP) 399 + = [M + H] + ; 397 " = [MH] " ; 795 " = [2M-H] "
Exemple 102Example 102
N- [ (6R) -hexahydro-5-oxo-4- (3-phenyl-2-propenyl) -1 , 4- thiazepin-6-yl] -4- (phosphonooxy) -Benzamide sel (trihydroxymethyl) methanamineN- [(6R) -hexahydro-5-oxo-4- (3-phenyl-2-propenyl) -1, 4- thiazepin-6-yl] -4- (phosphonooxy) -Benzamide salt (trihydroxymethyl) methanamine
FG ( I " ) : R5= -CH2-CH=CH-Ph ; [Aχ ] = -Ph- ; A2 = -OPO (OH ) 2 Sel de trihydroxyméthylamine (Tris)FG (I "): R 5 = -CH 2 -CH = CH-Ph; [Aχ] = -Ph-; A 2 = -OPO (OH) 2 Trihydroxymethylamine salt (Tris)
(Mode opératoire B, on obtient ici le mono-sel de Tris)(Procedure B, here we obtain the Tris mono-salt)
RMN (DMSO) 2,67 (m) -S-CH2-CH2-N- ; 3,88 3,73 -S-CH2-CH2-N-; 2,86 (m) S-NMR (DMSO) 2.67 (m) -S-CH 2 -CH 2 -N-; 3.88 3.73 -S-CH 2 -CH 2 -N-; 2.86 (m) S-
CH2-CH-NH ; 5,22 (m) S-CH2-CH-NH ; 8,03 S-CH2-CH-NH ; 4,07CH 2 -CH-NH; 5.22 (m) S-CH 2 -CH-NH; 8.03 S-CH 2 -CH-NH; 4.07
4,22 NCH2-CH= ; 6,18 (dt) 6,55 (d, J= 16) éthylénique ; 7,29 à 7,79 H aromatiques (O-Ph-CO) ; 7,20 à 7,40 H aromatiques4.22 NCH 2 -CH =; 6.18 (dt) 6.55 (d, J = 16) ethylenic; 7.29 to 7.79 H aromatic (O-Ph-CO); 7.20 to 7.40 H aromatic
(phenyle) ; 3,73 (s) 8H C-CH2-OH Exemple 103(phenyle); 3.73 (s) 8H C-CH 2 -OH Example 103
N2-acetyl-N- [ (6R) -hexahydro-5-oxo-4- [3- [ (4-phenylpiperazin-l- yl) sulfonyl]propyl] -1 , 4-thiazepin-6-yl] -4- (phosphonooxy)N2-acetyl-N- [(6R) -hexahydro-5-oxo-4- [3- [(4-phenylpiperazin-1- yl) sulfonyl] propyl] -1, 4-thiazepin-6-yl] -4- (phosphonooxy)
PhenylalaninamidePhenylalaninamide
FG (I") : R5= - (CH2)3-S02-Het; [Ai] = -CH (NHCOCH3) -CH2-Ph-; A2 = -OPO (OH) 2 avec Het représentant un groupement phényl- pipérarinyle .FG (I "): R 5 = - (CH 2 ) 3 -S0 2 -Het; [Ai] = -CH (NHCOCH 3 ) -CH 2 -Ph-; A 2 = -OPO (OH) 2 with Het representing a phenyl group piperarinyl.
(Mode opératoire A)(Procedure A)
SM (ESP) : MH+ = 697, 9DaSM (ESP): MH + = 697.9Da
Exemple 104 N2-acetyl-N- [ (6R) -4- [3- [ (butylmethylamino) sulfonyl]propyl] - hexahydro-5-oxo-l , 4-thiazepin-6-yl] -4- (phosphonooxy)Example 104 N2-acetyl-N- [(6R) -4- [3- [(butylmethylamino) sulfonyl] propyl] - hexahydro-5-oxo-1,4, thiazepin-6-yl] -4- (phosphonooxy)
PhenylalaninamidePhenylalaninamide
FG (I") : R= -(CH2)3-S02-N(Me) (nBu) ; [Ax] = -CH (NHC0CH3) -CH2-FG (I "): R = - (CH 2 ) 3 -S0 2 -N (Me) (nBu); [A x ] = -CH (NHC0CH 3 ) -CH 2 -
Ph-; A2 = -OPO (OH) 2 (Mode opératoire A' )Ph-; A 2 = -OPO (OH) 2 (Procedure A ')
SM (ESP) : MH+ = 623, IDaSM (ESP): MH + = 623, IDa
Exemple 105Example 105
Acide [ [ [4- [ [ [ (6R) -4- [ (4-bromophenyl)méthyl] -hexahydro-5-oxo-Acid [[[4- [[[(6R) -4- [(4-bromophenyl) methyl] -hexahydro-5-oxo-
1 , 4-thiazepin-6-yl] amino] carbonyl]phényl] amino] carbonyl] - Phosphonique1, 4-thiazepin-6-yl] amino] carbonyl] phenyl] amino] carbonyl] - Phosphonic
FG (I") : R5= -CH2-Ph-Br ; [Ai] = -Ph-; A2 = -NHC0P0(0H)2 FG (I "): R 5 = -CH 2 -Ph-Br; [Ai] = -Ph-; A 2 = -NHC0P0 (0H) 2
(Mode opératoire F)(Procedure F)
Rf = 0,37 H20/MeOH 50/50Rf = 0.37 H 2 0 / MeOH 50/50
MH+ = 542Da Exemple 106MH + = 542Da Example 106
4- (phosphonooxy) -N- [ (6R) -hexahydro-5-oxo-4- [ (6-chloro-l , 3- benzodioxolan-5-yl)méthyl] -1 , 4-thiazepin-6-yl] -4- (phosphonooxy) -N- [(6R) -hexahydro-5-oxo-4- [(6-chloro-1,3-benzodioxolan-5-yl) methyl] -1,4-thiazepin-6-yl] -
BenzamideBenzamide
FG (I") : R= -CH2-Ar; [Aχ] = -Ph-; A2 = -OPO (OH) 2, avec Ar représentant un groupement phenyle subsitué en 2 par un chlore et substitué en 4 et 5 par un groupement méthylènedioxy .FG (I "): R = -CH 2 -Ar; [Aχ] = -Ph-; A 2 = -OPO (OH) 2 , with Ar representing a phenyl group substituted in 2 by chlorine and substituted in 4 and 5 by a methylenedioxy group.
(Mode opératoire B' )(Procedure B ')
SM MH+ = 515DaSM MH + = 515Da
[M-H]" = 513" [MH] " = 513 "
Exemple 107Example 107
N- [ (6R) -hexahydro-5-oxo-4- [ [4- (phenylcarbonyl)phényl]méthyl] -N- [(6R) -hexahydro-5-oxo-4- [[4- (phenylcarbonyl) phenyl] methyl] -
1 , 4-thiazepin-6-yl] -4- (phosphonooxy) - Benzamide FG (I") : R5= -CH2-Ph-C0-Ph; [Aι]= -Ph-; A2 = -OPO (OH) 2, (Mode opératoire B' )1, 4-thiazepin-6-yl] -4- (phosphonooxy) - Benzamide FG (I "): R 5 = -CH 2 -Ph-C0-Ph; [Aι] = -Ph-; A 2 = -OPO (OH) 2 , (Procedure B ')
SM (ESP) : MH+ = 541DaSM (ESP): MH + = 541Da
Exemple 108Example 108
N- [ (6R) -4- [ (3-chlorophenyl)méthyl] -hexahydro-5-oxo-l , 4- thiazepin-6-yl] -4- (phosphonooxy) - BenzamideN- [(6R) -4- [(3-chlorophenyl) methyl] -hexahydro-5-oxo-1,4,4 thiazepin-6-yl] -4- (phosphonooxy) - Benzamide
FG (I") : R5= -CH2-(m-Cl)Ph; [Aι]= -Ph-; A2 = -OPO(OH)2 FG (I "): R 5 = -CH 2 - (m-Cl) Ph; [Aι] = -Ph-; A 2 = -OPO (OH) 2
(Mode opératoire B' )(Procedure B ')
SM (ESP) : MH+ = 471DaSM (ESP): MH + = 471Da
Exemple 109 N-[ (6R)-hexahydro-5-oxo-4[[ (4- trifluoromethoxy) phényl]méthyl] -4- (phosphonooxy) -Example 109 N- [(6R) -hexahydro-5-oxo-4 [[((4-trifluoromethoxy) phenyl] methyl] -4- (phosphonooxy) -
BenzamideBenzamide
FG (I") : R5= -CH2-Ph-OCF3; [Ai] = -Ph-; A2 = -OPO (OH) 2 FG (I "): R 5 = -CH 2 -Ph-OCF 3 ; [Ai] = -Ph-; A 2 = -OPO (OH) 2
(Mode opératoire B' ) SM (ESP) MH+ = 521Da(Operating mode B ') SM (ESP) MH + = 521Da
Exemple 110Example 110
4- [ [ (6R) -6- [ [ (3S) -2- (acétylamino) -l-oxo-3- [4-4- [[(6R) -6- [[(3S) -2- (acetylamino) -1-oxo-3- [4-
(phosphonooxy)phényl] -1-propyl] amino] -hexahydro-5-oxo-l , 4- thiazepin-4-yl]méthyl] -Benzoate de méthyle FG (I") : R5= -CH2-Ph-C02Me; [Ai] = -CH (NHC0CH3) -CH2-Ph-; A2 =(phosphonooxy) phenyl] -1-propyl] amino] -hexahydro-5-oxo-1,4-thiazepin-4-yl] methyl] -Methyl benzoate FG (I "): R 5 = -CH 2 -Ph- C0 2 Me; [Ai] = -CH (NHC0CH 3 ) -CH 2 -Ph-; A 2 =
-OPO (OH) 2 -OPO (OH) 2
(Mode opératoire A' )(Procedure A ')
SM (ESP) : MH+ = 580DaSM (ESP): MH + = 580Da
Exemple 111 (6R) -4- (3-phenyl-2-propenyl) -6- [ [ [4-Example 111 (6R) -4- (3-phenyl-2-propenyl) -6- [[[4-
(phosphonooxy) phényl]méthyl] amino] -(phosphonooxy) phenyl] methyl] amino] -
1 , 4-thiazepin-5 (2H) -one1, 4-thiazepin-5 (2H) -one
FG (I) : Rι=R2=R3=R4=H ; ϋ = CH2 ; R5 = -CH2-CH=CH-Ph; [Ai] = -FG (I): Rι = R 2 = R 3 = R 4 = H; ϋ = CH 2 ; R 5 = -CH 2 -CH = CH-Ph; [Ai] = -
Ph-; A2 = -OPO (OH) 2 On opère comme à l'exemple 35 mais en effectuant une réaction de couplage de l'amine avec le parahydroxybenzaldehyde en présence de NaBHsCN dans le méthanol.Ph-; A 2 = -OPO (OH) 2 The procedure is as in Example 35 but by carrying out a coupling reaction of the amine with the parahydroxybenzaldehyde in the presence of NaBHsCN in methanol.
SM (ESP) : MH+ = 449+ ; MNa+ = 471+ ; MH+ + CH3CN = 490+ ; MNa+ MS (ESP): MH + = 449 + ; MNa + = 471 + ; MH + + CH 3 CN = 490 + ; MNa +
+ CH3CN = 512+ ; [M-H]" = 447" Exemple 112 (6R) -4- (3-phenylpropyl) -6- [ [ [4-+ CH 3 CN = 512 + ; [MH] " = 447 " Example 112 (6R) -4- (3-phenylpropyl) -6- [[[4-
(phosphonooxy) phényl] méthyl] amino] -1 , 4-thiazepin-5 (2H) -one(phosphonooxy) phenyl] methyl] amino] -1,4-thiazepin-5 (2H) -one
FG ( I ) : R!=R2=R3=R4=H ; U = CH2 ; R5= - ( CH2 ) 3-Ph ; [Ai ] = -Ph- ;FG (I): R ! = R 2 = R 3 = R 4 = H; U = CH 2 ; R 5 = - (CH 2 ) 3 -Ph; [Ai] = -Ph-;
A2 = -OPO (OH) 2 On opère comme à l'exemple 112 mais à partir d'une aminé de formule (III'') avec R5 représentant (CH2)3-Ph.A 2 = -OPO (OH) 2 The procedure is as in Example 112 but starting from an amine of formula (III '') with R 5 representing (CH 2 ) 3 -Ph.
SM (ESP) MH+ = 451+ ; MNa+ = 473+ ; 2MH+ = 901+ ; [M-H]" = 449" MS (ESP) MH + = 451 + ; MNa + = 473 + ; 2MH + = 901 + ; [MH] " = 449 "
Exemple 113Example 113
N2-acetyl-N- [ (6R) -4- [ (5-chloro-l,3-benzodioxolan-6- yl)methyl] -hexahydro—5-oxo-l, 4-thiazepin-6-yl] -4-N2-acetyl-N- [(6R) -4- [(5-chloro-1,3-benzodioxolan-6- yl) methyl] -hexahydro — 5-oxo-1,4-thiazepin-6-yl] -4 -
(phosphonooxy) -L-Phenylalaninamide(phosphonooxy) -L-Phenylalaninamide
FG (I") : R5= -CH2-Ar; [Ai] = -CH (NHCOCH3) -CH2-Ph-; A2 = -FG (I "): R 5 = -CH 2 -Ar; [Ai] = -CH (NHCOCH 3 ) -CH 2 -Ph-; A 2 = -
OPO (OH) 2 avec Ar représentant un groupement phenyle substitué en 2 par un chlore et substitué en 4 et 5 par un groupement méthylènedioxy .OPO (OH) 2 with Ar representing a phenyl group substituted in 2 by chlorine and substituted in 4 and 5 by a methylenedioxy group.
(Mode opératoire A' )(Procedure A ')
SM (ESP) : MH+ = 600DaSM (ESP): MH + = 600Da
Exemple 114Example 114
N2-acétyl-N- [ (6R) -4- [[-(1,1' -biphényle) -4-yl)méthyl] - hexahydro-5-oxo-1 , 4-thiazepin-6-yl] -4- (phosphonooxy) -L-N2-acetyl-N- [(6R) -4- [[- (1,1 '-biphenyl) -4-yl) methyl] - hexahydro-5-oxo-1, 4-thiazepin-6-yl] -4 - (phosphonooxy) -L-
PhenylalaninamidePhenylalaninamide
FG (I") : R5= -CH2-Ph-Ph; [Ai] = -CH (NHCOCH3) -CH2-Ph-; A2 = -FG (I "): R 5 = -CH 2 -Ph-Ph; [Ai] = -CH (NHCOCH 3 ) -CH 2 -Ph-; A 2 = -
OPO (OH) 2 OPO (OH) 2
(Mode opératoire A' ) SM (ESP) : MH+ = 598Da(Operating mode A ') SM (ESP): MH + = 598Da
Exemple 115Example 115
N2-acétyl-N- [ (6R) -hexahydro-5-oxo-4- [ [4-N2-acetyl-N- [(6R) -hexahydro-5-oxo-4- [[4-
(phenylecarbonyl)phényl)méthyl] -1 , 4-thiazepin-6-yl] -4-(phenylecarbonyl) phenyl) methyl] -1, 4-thiazepin-6-yl] -4-
(phosphonooxy) -L-Phenylalaninamide FG (I") : R5= -CH2-Ph-CO-Ph; [Ai] = -CH (NHCOCH3) -CH2-Ph-; A2 =(phosphonooxy) -L-Phenylalaninamide FG (I "): R 5 = -CH 2 -Ph-CO-Ph; [Ai] = -CH (NHCOCH 3 ) -CH 2 -Ph-; A 2 =
-OPO (OH) 2 -OPO (OH) 2
(Mode opératoire A' )(Procedure A ')
SM (ESP) MH+ = 626Da ; MNa+ = 648Da Exemple 116 4- (acetyloxy) -N- [ (6R) -hexahydro-4- (3-phenyl-2-propenyl) -5- oxo-l , 4-thiazepin-6-yl] Benzamide FG (I" ) : R5= -CH2-CH=CH- Ph ; [Ai] = -Ph- ; A2 = -OCOCH3 MS (ESP) MH + = 626Da; MNa + = 648Da Example 116 4- (acetyloxy) -N- [(6R) -hexahydro-4- (3-phenyl-2-propenyl) -5- oxo-1,4-thiazepin-6-yl] Benzamide FG (I "): R 5 = -CH 2 -CH = CH- Ph; [Ai] = -Ph-; A 2 = -OCOCH 3
On opère comme à l'exemple 35 stades a et b, puis on effectue une acylation du phénol. Rf = 0,90 (CH2Cl2/acétate d' éthyle = 80/20)The procedure is as in Example 35 stages a and b, then an acylation of the phenol is carried out. Rf = 0.90 (CH 2 Cl 2 / ethyl acetate = 80/20)
Exemple 117Example 117
N- [4- [ [ [ (6R) hexahydro-5-oxo-4- (3-phenyl-2-propenyl) -1 , 4- thiazepin-6-yl] amino] carbonyl] phényl] -N- (2-hydroxy-2-oxo- ethyl) -Glycine FG ( I " ) : R5= -CH2-CH=CH-Ph; [Ai ] = -Ph- ; A2 = N ( CH2C02H) 2 N- [4- [[[(6R) hexahydro-5-oxo-4- (3-phenyl-2-propenyl) -1, 4 thiazepin-6-yl] amino] carbonyl] phenyl] -N- (2 -hydroxy-2-oxoethyl) -Glycine FG (I "): R 5 = -CH 2 -CH = CH-Ph; [Ai] = -Ph-; A 2 = N (CH 2 C0 2 H) 2
On opère comme à l'exemple 35 stades a et b mais en utilisant comme acide de formule (III) l'acide 4-bis (2-methoxy-2-oxo- ethyl) amino benzoique.The procedure is as in Example 35 stages a and b but using as acid of formula (III) 4-bis (2-methoxy-2-oxoethyl) amino benzoic acid.
Rf = 0,18 acétone/acétate d'éthyle/eau = 40/50/10 Exemple 118Rf = 0.18 acetone / ethyl acetate / water = 40/50/10 Example 118
3 , 5-bis (acetyloxy) -N- [ (6R) -hexahydro-4- (3-phenyl-2-propenyl) -3,5-bis (acetyloxy) -N- [(6R) -hexahydro-4- (3-phenyl-2-propenyl) -
5-oxo-l , 4-thiazepin-6-yl] Benzamide5-oxo-1,4-thiazepin-6-yl] Benzamide
FG (I") : R5= -CH2-CH=CH-Ph; [Ai] ≈ - (m-OCOCH3) Ph-; A2 = OCOCH3 en position meta On opère comme à l'exemple 35 stades a et b, mais en utilisant comme acide de formule (III) l'acide 2,4 acétoxy benzoique, puis on effectue une acylation du diphénol .FG (I "): R 5 = -CH 2 -CH = CH-Ph; [Ai] ≈ - (m-OCOCH 3 ) Ph-; A 2 = OCOCH 3 in meta position We operate as in example 35 stages a and b, but using as acid of formula (III) 2,4 acetoxy benzoic acid, then an acylation of the diphenol is carried out.
Rf = 0,18 (acétone/acétate d'éthyle/eau = 40/50/10)Rf = 0.18 (acetone / ethyl acetate / water = 40/50/10)
Exemple 119 2- [3- [ [ [ (6R) -hexahydro-5-oxo-4- (3-phenyl-2-propenyl) -1 , 4- thiazepin-6-yl] amino] carbonyl]phénoxy] -acétate de méthyleExample 119 2- [3- [[[(6R) -hexahydro-5-oxo-4- (3-phenyl-2-propenyl) -1, 4- thiazepin-6-yl] amino] carbonyl] phenoxy] -acetate methyl
FG (I") : R5= -CH2-CH=CH-Ph; [Ai] = -Ph-; A2 = -OCH2C02CH3 en position metaFG (I "): R 5 = -CH 2 -CH = CH-Ph; [Ai] = -Ph-; A 2 = -OCH 2 C0 2 CH 3 in meta position
On opère comme à l'exemple 35 stades a et b, avec comme acide l'acide 3-hydroxybenzoique puis on additionne le bromoacetate de méthyle en présence de carbonate de potassium selon l'exemple 22.The operation is carried out as in Example 35 stages a and b, with 3-hydroxybenzoic acid as the acid, then methyl bromoacetate is added in the presence of potassium carbonate according to Example 22.
Rf = 0,23 (Hexane/acétate d'éthyle/eau) = 50/50Rf = 0.23 (Hexane / ethyl acetate / water) = 50/50
Exemple 120 Acide 2- [3- [ [ [ (6R) -hexahydro-5-oxo-4- (3-phenyl-2-propenyl) - 1 , 4-thiazepin-6-yl] amino] carbonyl]phénoxy] - acétiqueExample 120 Acid 2- [3- [[[((6R) -hexahydro-5-oxo-4- (3-phenyl-2-propenyl) - 1, 4-thiazepin-6-yl] amino] carbonyl] phenoxy] - acetic
FG (I") : R5= -CH2-CH=CH-Ph; [Ax] = -Ph-; A2 = -OCH2C02H en position meta On opère comme à l'exemple 35 stades a et b avec comme acide l'acide 3-hydroxybenzoique, puis on additionne le bromoacetate d' éthyle en présence de carbonate de potassium puis saponifie en présence de soude selon l'exemple 22. Rf = 0,38 (Acétone/acétate d'éthyle/eau) = 40/50/10FG (I "): R 5 = -CH 2 -CH = CH-Ph; [A x ] = -Ph-; A 2 = -OCH 2 C0 2 H in meta position We operate as in example 35 stages a and b with 3-hydroxybenzoic acid as the acid, then ethyl bromoacetate is added in the presence of potassium carbonate and then saponified in the presence of sodium hydroxide according to Example 22. Rf = 0.38 (Acetone / ethyl acetate / water) = 40/50/10
Etude pharmacologique des produits de l'invention : Mesure des IC50 par scintillation proximity essay (SPA) . La capacité des molécules à se lier à la protéine SrcSH2 est évaluée par compétition (mesure de l'IC50) dans un test appelé Scintillation proximity assay (SPA) . Ce test utilise des billes PVT (Amersham) qui contiennent le scintillant. Ces billes coatées avec de la streptavidine sont incubées dans un tampon MOPS dans des plaques 99 puits avec 50nM de protéine SH2 préalablement biotinylée puis avec le ligand EPQpYEEIPIYL marqué à l'iode 125. En se liant à la protéine fixée sur la bille le ligand active le scintillant qui émet une lumière mesurée dans un compteur à scintillation allac microβeta. La valeur obtenue en absence de tout compétiteur correspond à la liaison maximale du ligand sur la protéine. Cette méthode ne nécessite pas de séparer le ligand libre du lié.Pharmacological study of the products of the invention: IC50 measurement by scintillation proximity essay (SPA). The ability of molecules to bind to the SrcSH2 protein is evaluated by competition (measurement of IC 50 ) in a test called Scintillation proximity assay (SPA). This test uses PVT (Amersham) beads which contain the scintillant. These beads coated with streptavidin are incubated in MOPS buffer in 99-well plates with 50 nM of SH2 protein previously biotinylated and then with the ligand EPQpYEEIPIYL labeled with iodine 125. By binding to the protein fixed on the bead, the active ligand the scintillant which emits a light measured in an allac microβeta 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 linked.
Les molécules à tester sont diluées dans le tampon MOPS contenant 2% DMSO et ajoutées à différentes concentrations deThe molecules to be tested are diluted in the MOPS buffer containing 2% DMSO and added to different concentrations of
0,lnM à lOOμM dans les puits contenant le ligand, avant l'addition des billes coatées avec Src-SH2. Après 1 heure d' incubation une mesure de la liaison est effectuée au compteur à scintillation. L'inhibition de la liaison du ligand radiomarqué par les différentes concentrations de compétiteur permet d'évaluer les IC50 des molécules testées. Résultat : Résultats SPA : Peptide de référence PYEEI .. 0,2-0,4 μmol
Figure imgf000120_0001
0.1 lnM to 100 μM in the wells containing the ligand, before the addition of the beads coated with Src-SH2. After 1 hour of incubation a measurement of the binding is carried out with the scintillation counter. The inhibition of the binding of the radiolabelled ligand by the different concentrations of competitor makes it possible to evaluate the IC 50 of the molecules tested. Result: SPA results: PYEEI reference peptide. 0.2-0.4 μmol
Figure imgf000120_0001

Claims

REVENDICATIONS
1) un dérivé de thioazepinone de formule (I)1) a thioazepinone derivative of formula (I)
Figure imgf000121_0001
dans laquelle,
Figure imgf000121_0001
in which,
Ri et R2 Ri and R 2
- soit représentent chacun un atome d'hydrogène,- either each represent a hydrogen atom,
- soit, identiques ou différents, représentent un radical (Cι-C8) -alkyle-, hydroxy, (Cι-C8) -alkoxy-, C02Ra, CONRaRb, amino, (Cι-C8) alkylamino-, di (Cι-C8) -alkylamino-, (C5- Cι ) aryle- ou un hétérocycle saturé ou insaturé, les dits alkyles, aryles ou hétérocycles étant non substitués ou substitués par Rβ; - soit forment ensemble le reste d'un cycle aromatique ou d'un hétéroaryle accolé en position 2 et 3 à la thioazepinone; non substitué ou substitué par Rζ- either, identical or different, represent a (Cι-C 8 ) -alkyl-, hydroxy, (Cι-C 8 ) -alkoxy-, C0 2 Ra, CONRaRb, amino, (Cι-C 8 ) alkylamino-, di (Cι-C 8 ) -alkylamino-, (C 5 - Cι) aryl- or a saturated or unsaturated heterocycle, the said alkyls, aryls or heterocycles being unsubstituted or substituted by Rβ; - or together form the remainder of an aromatic cycle or of a heteroaryl attached in position 2 and 3 to thioazepinone; unsubstituted or substituted by Rζ
- R5 est soit R'5, représentant les groupements suivants (Cι-C8) -alkyle- , (C2-C8) -alkényle-, (C2-C8) -alkynyle- , (C5- Cι4) -aryle-, (C5-C14) -aryl- (Cι-C8) -alkyle- , (C5-C14) -aryl- (C2- C8) -alkényle- , (C5-C14) -aryl- (C2-C8) -alkynyle- , (C3-Cι8)- cycloalkyle-, (C3-Cι8) -cycloalkyl- (Cι-C8) -alkyle- , (C3-Cι8)- cycloalkyl- (C2-C8) -alkényle- ou (C3-Cι8) -cycloalkyl- (C2-C8) - alkynyle-, les dits groupements alkyles, alkényles, alkynyles, aryles et cycloalkyles étant non substitués ou substitués par un ou plusieurs radicaux R6, soit R"s, représentant les groupements suivants -CHRh-CO-R'5 , -CHRh-CONH-R'5 , R'5 étant tel que défini plus haut; soit R" ' 5 représentant un atome d'hydrogène- R 5 is either R ' 5 , representing the following groups (Cι-C 8 ) -alkyle-, (C 2 -C 8 ) -alkenyl-, (C 2 -C 8 ) -alkynyle-, (C 5 - Cι 4 ) -aryl-, (C5-C14) -aryl- (Cι-C 8 ) -alkyle-, (C5-C14) -aryl- (C 2 - C 8 ) -alkenyl-, (C5-C14) -aryl - (C 2 -C 8 ) -alkynyle-, (C 3 -Cι 8 ) - cycloalkyle-, (C 3 -Cι 8 ) -cycloalkyl- (Cι-C 8 ) -alkyle-, (C 3 -Cι 8 ) - cycloalkyl- (C 2 -C 8 ) -alkenyl- or (C 3 -Cι 8 ) -cycloalkyl- (C 2 -C 8 ) - alkynyle-, the said alkyl, alkenyl, alkynyl, aryl and cycloalkyl groups being unsubstituted or substituted by one or more radicals R 6 , either R "s, representing the following groups -CHRh-CO-R ' 5 , -CHRh-CONH-R' 5 , R ' 5 being as defined above; or R"' 5 representing a hydrogen atom
- ~[Aι]- représente un groupement choisi parmi -CH (Z) - (C1-C4) -alkylène- (C5-C14) -aryle-, -C (Z) =CH- (C5-C14) - aryle-, -C (Z)=CH- (Cι-C2) -alkylène- (C5-C14) -aryle- , -CH(Z)-(C5- C14) -aryle-, - (C1-C4) -alkylène- (C5-C14) -aryle-, - (C5-C14) -aryle- , - (C1-C4) -alkylène-NHCO- (C5-Cι4) -aryle-, -NH- (C5-C14) -aryle- dans lesquels Z est un atome d'hydrogène, un tétrazole, NRbRc, NHCORb, CONHRb, NHC02Rb, NHCOC02Rb, NHCONHRb ou NHS02Rb; les dits radicaux aryles étant substitués ou non substitués par un ou plusieurs radicaux Rε ou R'β,"- ~ [Aι] - represents a group chosen from -CH (Z) - (C1-C4) -alkylene- (C5-C14) -aryl-, -C (Z) = CH- (C5-C14) - aryl-, -C (Z) = CH- (Cι -C 2 ) -alkylene- (C5-C14) -aryl-, -CH (Z) - (C 5 - C 14 ) -aryl-, - (C 1 -C 4 ) -alkylene- (C 5 -C 14 ) -aryl-, - (C 5 -C 14 ) -aryl-, - (C 1 -C4) -alkylene-NHCO- (C 5 -Cι 4 ) -aryl-, -NH- (C 5 -C 14 ) -aryl- in which Z is a hydrogen atom, a tetrazole, NRbRc, NHCORb, CONHRb, NHC0 2 Rb, NHCOC0 2 Rb, NHCONHRb or NHS0 2 Rb; the said aryl radicals being substituted or unsubstituted by one or more radicals Rε or R'β, "
- A2 représente un groupement choisi parmi -PO (ORd) (ORe) , -OPO (ORd) (ORe) , -B (ORd) (ORe) ,- A 2 represents a group chosen from -PO (ORd) (ORe), -OPO (ORd) (ORe), -B (ORd) (ORe),
-CRfRgPO(ORd) (ORe) , -O-CRfRgPO (ORd) (ORe) , -CRfRg-C02Rd, - CRf(C02Rd)2, -0-CRfRg-C02Rd, -O-CRf (C02Rd) 2, -N (CRfRg-C02Rd) 2, -C02Rd, -CRfRg-CH2-C02Rd, -CRfRgS03H, -O-CRfRgS03H, -OSO3H , - OSO2NH2, -SO2NH2, -NHCO-PO(ORd) (ORe) , -CO-PO (ORd) (ORe) , -OH et -O-CORd;-CRfRgPO (ORd) (ORe), -O-CRfRgPO (ORd) (ORe), -CRfRg-C0 2 Rd, - CRf (C0 2 Rd) 2 , -0-CRfRg-C0 2 Rd, -O-CRf ( C0 2 Rd) 2 , -N (CRfRg-C0 2 Rd) 2 , -C0 2 Rd, -CRfRg-CH 2 -C0 2 Rd, -CRfRgS0 3 H, -O-CRfRgS0 3 H, -OSO 3 H, - OSO2NH2, -SO2NH2, -NHCO-PO (ORd) (ORe), -CO-PO (ORd) (ORe), -OH and -O-CORd;
- R3, R4, Ra, Rb, Rc, Rd, Re, Rh ou Ri, indépendants les uns des autres, identiques ou différents, représentant un atome d'hydrogène, un radical (Cι~C8) -alkyle-, (C3-Cι8)- cycloalkyle-, (C3-Cι8) - (cycloalkyl) - (Cι-C8) -alkyle-, (C5- Ci4) -aryle- ou (C5-C14) -aryl- (C1-C4) -alkyle-, les dits radicaux étant substitués ou non substitués par Rç;- R 3 , R 4 , Ra, Rb, Rc, Rd, Re, Rh or Ri, independent of each other, identical or different, representing a hydrogen atom, a radical (Cι ~ C 8 ) -alkyl-, (C 3 -Cι 8) - cycloalkyl-, (C 3 -Cι 8) - (cycloalkyl) - (Cι-C 8) -alkyl-, (C 5 - C i4) -aryl- or (C 5 -C 14 ) -aryl- (C 1 -C 4 ) -alkyl-, the said radicals being substituted or unsubstituted by Rc;
- Rf et Rg identiques ou différents représentant un atome d'hydrogène, un halogène, ORe, NHRc, un radical CO2RC, CH2C02Rc, SO3H, PO (ORd) (ORe) ou tétrazole; - éventuellement R3 et R4 forment ensemble avec l'atome de carbone qui les porte, un groupement cycloalkyle renfermant de 3 à 6 atomes de carbone,- Rf and Rg identical or different representing a hydrogen atom, a halogen, ORe, NHRc, a radical CO 2 RC, CH 2 C0 2 Rc, SO 3 H, PO (ORd) (ORe) or tetrazole; optionally R 3 and R 4 form together with the carbon atom which carries them, a cycloalkyl group containing 3 to 6 carbon atoms,
- Rβ représente un groupement choisi parmi (C1-C4) -alkyle-- Rβ represents a group chosen from (C 1 -C 4 ) -alkyl-
, (C!-C4) -alkoxy-, hydroxy- (Cχ-C4) -alkyle-, (Cχ-C ) -alkoxy- (Cι~ C4) -alkyle-, (C1-C3) -alkylènedioxy-, (C5-C14) -aryle-, Het, (C5- C14) -aryloxy-, (C5-C14) -aryl- (C1-C4) -alkyle-, (C5-C14) -aryl- (Cι~ C4) -alkyloxy-, halogène, trihalogénométhyle-, trihalogénométhyloxy-, , trihalogénomethylcarbonyloxy- (Cι~ C4) -alkyle-, hydroxyle, nitro, formyle, -C=N-NH-CONH2, cyano, carboxy, -CONH2, (C1-C4) -alkyloxycarbonyle-, (C1-C4)- alkylcarbonyloxy-, amino, (C1-C4) -alkylamino-, di- (Cx- C4) alkylamino-, (C1-C4) -alkyl-carbonylamino-, (C5-C14) -aryl- carbonylamino-, (Cι~C4) -alkyl-aminocarbonyle-, (C5-C14) -aryl- aminocarbonyle-, (C1-C4) -alkyl-carbonyle-, (C5-C14) -aryl- carbonyle-, (C1-C4) -alkyl-sulfonyle-, (C5-C14) -aryl-sulfonyle-, (C5-C14) -aryl-sulfonyl- (C1-C4) -alkyle-, (C1-C4) -alkyl- aminosulfonyle-, di (C1-C4) -alkyl-aminosulfonyle-, (C5-C14)- aryl-aminosulfonyle-, (C3-C8) -cycloalkyl-aminosulfonyle-, ( (C3- C8) -cycloalkyl) ( (C1-C4) -alkyl) aminosulfonyle- et Het- sulfonyle-, Het représentant un hétérocycle saturé à 5 ou 6 chaînons renfermant éventuellement un deuxième hétéroatome O, N ou S;, (C ! -C 4 ) -alkoxy-, hydroxy- (Cχ-C 4 ) -alkyle-, (Cχ-C) -alkoxy- (Cι ~ C 4 ) -alkyle-, (C 1 -C 3 ) - alkylenedioxy-, (C 5 -C 14 ) -aryl-, Het, (C 5 - C 14 ) -aryloxy-, (C 5 -C 14 ) -aryl- (C 1 -C 4 ) -alkyl-, (C 5 -C 14 ) -aryl- (Cι ~ C 4 ) -alkyloxy-, halogen, trihalomethylethyl-, trihalogenomethyloxy-,, trihalomethylethylcarbonyloxy- (Cι ~ C4) -alkyl-, hydroxyl, nitro, formyl, -C = N-NH -CONH 2 , cyano, carboxy, -CONH 2 , (C 1 -C 4 ) -alkyloxycarbonyle-, (C 1 -C 4 ) - alkylcarbonyloxy-, amino, (C 1 -C 4 ) -alkylamino-, di- (C x - C 4 ) alkylamino-, (C 1 -C 4 ) -alkyl-carbonylamino-, (C 5 -C 14 ) -aryl - carbonylamino-, (Cι ~ C 4 ) -alkyl-aminocarbonyle-, (C 5 -C 14 ) -aryl- aminocarbonyle-, (C 1 -C 4 ) -alkyl-carbonyl-, (C 5 -C 14 ) - aryl- carbonyl-, (C1-C4) -alkyl-sulfonyl-, (C5-C 14 ) -aryl-sulfonyl-, (C5-C14) -aryl-sulfonyl- (C1-C4) -alkyl-, (C1- C4) -alkyl- aminosulfonyl-, di (C1-C4) -alkyl-aminosulfonyl-, (C 5 -C 14 ) - aryl-aminosulfonyl-, (C 3 -C 8 ) -cycloalkyl-aminosulfonyl-, ((C 3 - C 8 ) -cycloalkyl) ((C1-C4) -alkyl) aminosulfonyl- and Het-sulfonyl-, Het representing a saturated heterocycle with 5 or 6 members optionally containing a second heteroatom O, N or S;
- R'6 a les mêmes valeurs que A2;- R ' 6 has the same values as A 2 ;
- éventuellement A2 et Rβ forment ensemble avec 1 ' aryle qui les porte, l'un des cycles à 5 chaînons suivants :- optionally A 2 and Rβ together with the aryl which carries them, form one of the following 5-membered rings:
Figure imgf000123_0001
Figure imgf000123_0001
- U représente un groupement choisi parmi CO, CS, SO, S0 et un groupement alkylène saturé ou insaturé renfermant de 1 à 4 atomes de carbone, le trait en pointillé indique la présence d'une double liaison éventuelle, lesdits composés de formule (I) étant sous toutes leurs formes isomères possibles, seuls ou en mélange dans un rapport quelconque, ainsi que leurs sels physiologiquement acceptables et leurs promédicaments (prodrugs) .- U represents a group chosen from CO, CS, SO, S0 and a saturated or unsaturated alkylene group containing from 1 to 4 carbon atoms, the dotted line indicates the presence of a possible double bond, said compounds of formula (I ) being in all their possible isomeric forms, alone or as a mixture in any ratio, as well as their physiologically acceptable salts and their prodrugs (prodrugs).
2) dérivés de thioazepinone de formule (I) telle que définie à la revendication 1 répondant à la formule (I') :
Figure imgf000124_0001
dans laquelle R5, [Ax] , et A2 sont tels que définis précédemment et R3 représente un atome d'hydrogène ou un groupement phenyle substitué ou non substitué par R6 tel que défini à la revendication 1, ainsi que leurs sels physiologiquement acceptables et leurs promédicaments (prodrugs)2) thioazepinone derivatives of formula (I) as defined in claim 1 corresponding to formula (I '):
Figure imgf000124_0001
in which R 5 , [A x ], and A 2 are as defined above and R 3 represents a hydrogen atom or a phenyl group substituted or unsubstituted by R 6 as defined in claim 1, as well as their salts physiologically acceptable and their prodrugs (prodrugs)
3) Dérivés de thioazepinone de formule (I) telle que définie à la revendication 1, dans laquelle Ri, R2 R3 et R4 sont des atomes d'hydrogène et le trait en pointillé ne représente pas une double liaison répondant à la formule (I")3) Thioazepinone derivatives of formula (I) as defined in claim 1, in which Ri, R 2 R 3 and R 4 are hydrogen atoms and the dotted line does not represent a double bond corresponding to the formula (I ")
Figure imgf000124_0002
ainsi que leurs sels physiologiquement acceptables et leurs promédicaments (prodrugs) .
Figure imgf000124_0002
as well as their physiologically acceptable salts and their prodrugs.
4) Dérivés de thioazepinone de formule (I), telle que définie à la revendication 1, dans laquelle Ri, R2, R3 et R4 sont des atomes d'hydrogène et le trait en pointillé représente une double liaison répondant à la formule (I"1)4) Thioazepinone derivatives of formula (I), as defined in claim 1, in which Ri, R 2 , R 3 and R 4 are hydrogen atoms and the dotted line represents a double bond corresponding to the formula (I " 1 )
Figure imgf000124_0003
ainsi que leurs sels physiologiquement acceptables et leurs promédicaments (prodrugs). 5) Dérivés de thioazepinone de formules formules (I'),
Figure imgf000124_0003
as well as their physiologically acceptable salts and their prodrugs. 5) Thioazepinone derivatives of formulas formulas (I '),
(I'') et (I''') tels que définis aux revendications 2, 3 et 4 correspondant respectivement aux composés de formules (I'R), (I"R) et (I"'R) suivants :(I '') and (I '' ') as defined in claims 2, 3 and 4 corresponding respectively to the compounds of formulas (I'R), (I "R) and (I"' R):
Figure imgf000125_0001
Figure imgf000125_0001
Figure imgf000125_0002
Figure imgf000125_0002
Figure imgf000125_0003
Figure imgf000125_0003
R5, [Ai] et A2 étant tels que définis à la revendication 1. 6) Dérivés de thioazepinone de formules (I), (I'), (I") et (I"') telles que définies à l'une quelconque des revendications 1 à 5 dans lesquelles [A ] représente un groupement choisi parmi
Figure imgf000126_0001
R 5 , [Ai] and A 2 being as defined in claim 1. 6) Thioazepinone derivatives of formulas (I), (I '), (I ") and (I"') as defined in any one of claims 1 to 5 in which [A] represents a group chosen from
Figure imgf000126_0001
Figure imgf000126_0002
Figure imgf000126_0002
Figure imgf000126_0003
Figure imgf000126_0003
le phenyle étant substitué ou non substitué par un ou plusieurs groupement Rβ tel que défini à la revendication 1, 1 étant égal à 0, 1, 2 ou 3 et Z est tel que défini à la revendication 1.the phenyle being substituted or unsubstituted by one or more Rβ group as defined in claim 1, 1 being equal to 0, 1, 2 or 3 and Z is as defined in claim 1.
7) Dérivés de thioazepinone selon la revendication 6 caractérisé en ce que R6 représente un groupement choisi parmi CHO, C02H et CH2OH, notamment en position meta, et A2 est en position para.7) Thioazepinone derivatives according to claim 6 characterized in that R 6 represents a group chosen from CHO, C0 2 H and CH 2 OH, in particular in the meta position, and A 2 is in the para position.
8) Dérivés de thioazepinone de formules (I), (I'), (I") ou (I"') telles que définies à l'une quelconque des revendications 1 à 7 dans lesquels, Z représente de préférence NHCOCH3 ou NHC02tBu et le carbone qui porte ce groupement Z présente la configuration (S) .8) Thioazepinone derivatives of formulas (I), (I '), (I ") or (I"') as defined in any one of claims 1 to 7 in which, Z preferably represents NHCOCH 3 or NHC0 2 tBu and the carbon which carries this group Z presents the configuration (S).
9) Dérivés de thioazepinone de formules (I), (I1), (I") et (I"') telles que définies à l'une quelconque des revendications 1 à 8 dans lesquelles R5 est un radical (cyclohexyl)méthyle-, (cyclohexyl) éthyle-,9) Thioazepinone derivatives of formulas (I), (I 1 ), (I ") and (I"') as defined in any one of claims 1 to 8 in which R 5 is a (cyclohexyl) methyl radical -, (cyclohexyl) ethyl-,
(cyclohexyl) propyle-, (cyclohexyl) butyle-, (phényl)méthyle-, (phényl) éthyle-, (phényl) propyle- , (phényl) butyle-, (phényl) prop-2-ènyle-, (phényl) aminocarbonylméthyle-, (naphtyl) méthylaminocarbonylyméthyle- et (naphtyl) aminocarbonylméthyle-, lesdits phényles et naphtyles étant substitués ou non substitués par R6 tel que défini à la revendication 1.(cyclohexyl) propyle-, (cyclohexyl) butyl-, (phenyl) methyl-, (phenyl) ethyl-, (phenyl) propyl-, (phenyl) butyl-, (phenyl) prop-2-enyl-, (phenyl) aminocarbonylmethyl -, (naphthyl) methylaminocarbonylymethyl- and (naphthyl) aminocarbonylmethyl-, said phenyls and naphthyls being substituted or unsubstituted by R 6 as defined in claim 1.
10) Dérivés de thioazepinone de formules (I), (I'), (I") et (I"') telles que définies à l'une quelconque des revendications 1 à 9 dans lesquelles A2 est un radical - OPO (OH) (OBn) , -OPO (OH) 2, -PO(OH)2, -CF2PO(OH)2, -C02H, - CH2C02H, -OCH2C02H, -CH(C02H)2, -CF(C02H)2 -N(CH2C02H)2 ou NHCOPO(OH)2.10) Thioazepinone derivatives of formulas (I), (I '), (I ") and (I"') as defined in any one of claims 1 to 9 in which A 2 is a radical - OPO (OH ) (OBn), -OPO (OH) 2 , -PO (OH) 2 , -CF 2 PO (OH) 2 , -C0 2 H, - CH 2 C0 2 H, -OCH 2 C0 2 H, -CH ( C0 2 H) 2 , -CF (C0 2 H) 2 -N (CH 2 C0 2 H) 2 or NHCOPO (OH) 2 .
11) Dérivés de thioazepinone de formules (I'S), (I"S) ou (I"'S) telles que définies à l'une quelconque des revendications 5 à 10 dans lesquelles :11) Thioazepinone derivatives of formulas (I'S), (I "S) or (I" 'S) as defined in any one of claims 5 to 10 in which:
- [Ai] représente un groupement -CH (Z) -CH2-Ph- ou C(Z)=CH-Ph- avec Z représentant NHCOCH3 ou NHC02tBu,- [Ai] represents a group -CH (Z) -CH 2 -Ph- or C (Z) = CH-Ph- with Z representing NHCOCH 3 or NHC0 2 tBu,
- A2, en position para représente un radical OPO (OH) (OBn), - OPO (OH) 2, -PO (OH) 2, -CF2PO(OH)2, -C02H, -CH2C02H, -OCH2C02H, -- At 2 , in the para position represents an OPO (OH) (OBn) radical, - OPO (OH) 2 , -PO (OH) 2 , -CF 2 PO (OH) 2 , -C0 2 H, -CH 2 C0 2 H, -OCH 2 C0 2 H, -
CH(C02H)2, -CF(C02H)2 -N(CH2C02H)2 ou NHCOPO(OH)2,CH (C0 2 H) 2 , -CF (C0 2 H) 2 -N (CH 2 C0 2 H) 2 or NHCOPO (OH) 2 ,
- R5 est un radical (cyclohexyl) méthyle-, (cyclohexyl) éthyle- , (cyclohexyl) propyle-, (cyclohexyl) butyle-, (phényl )méthyle- , (phényl) éthyle-, (phényl) propyle- , (phényl) butyle-, (phényl) prop-2-ènyle-, (phényl) aminocarbonylméthyle-, (naphtyl) méthylaminocarbonylméthyle- et- R 5 is a (cyclohexyl) methyl-, (cyclohexyl) ethyl-, (cyclohexyl) propyl-, (cyclohexyl) butyl-, (phenyl) methyl-, (phenyl) ethyl-, (phenyl) propyl-, (phenyl) radical ) butyl-, (phenyl) prop-2-enyl-, (phenyl) aminocarbonylmethyl-, (naphthyl) methylaminocarbonylmethyl- and
(naphtyl) aminocarbonylméthyle-, lesdits phényles et naphtyles étant substitués ou non substitués par R6 tel que défini à la revendication 1, ainsi que leurs sels physiologiquement acceptables et leurs promédicaments (prodrugs) .(naphthyl) aminocarbonylmethyl-, said phenyls and naphthyls being substituted or unsubstituted by R 6 as defined in claim 1, as well as their physiologically acceptable salts and their prodrugs (prodrugs).
12) Dérivés de thioazepinone de formules (I'S), (I"S) ou (I"'S) telles que définies dans les revendications 5 à 10 dans lesquelles :12) Thioazepinone derivatives of formulas (I'S), (I "S) or (I" 'S) as defined in claims 5 to 10 in which:
[Ai] représente les radicaux choisis parmi[Ai] represents the radicals chosen from
Figure imgf000127_0001
- A2, en position para représente un radical OPO (OH) (OBn), - OPO (OH) 2, -PO (OH) 2, -CF2PO(OH)2, -C02H, -CH2C02H, -OCH2C02H, -
Figure imgf000127_0001
- At 2 , in the para position represents an OPO (OH) (OBn) radical, - OPO (OH) 2 , -PO (OH) 2 , -CF 2 PO (OH) 2 , -C0 2 H, -CH 2 C0 2 H, -OCH 2 C0 2 H, -
CH(C02H)2, -CF(C02H)2 -N(CH2C02H)2 ou NHCOPO(OH)2,CH (C0 2 H) 2 , -CF (C0 2 H) 2 -N (CH 2 C0 2 H) 2 or NHCOPO (OH) 2 ,
- R5 est un radical (cyclohexyl) méthyle-, (cyclohexyl) éthyle- , (cyclohexyl) propyle-, (cyclohexyl) butyle-, (phényl )méthyle- , (phényl) éthyle-, (phényl) propyle , (phényl) butyle, (phényl) prop-2-ènyle-, (phényl) aminocarbonylméthyle-, (naphtyl) méthylaminocarbonylméthyle- et (naphtyl) aminocarbonylyméthyle-, lesdits phényles et naphtyles étant substitués ou non substitués par R6 tel que défini à la revendication 1, ainsi que leurs sels physiologiquement acceptables et leurs promédicaments (prodrugs) .- R 5 is a (cyclohexyl) methyl-, (cyclohexyl) ethyl-, (cyclohexyl) propyl-, (cyclohexyl) butyl-, (phenyl) methyl-, (phenyl) ethyl-, (phenyl) propyl, (phenyl) radical butyl, (phenyl) prop-2-enyl-, (phenyl) aminocarbonylmethyl-, (naphthyl) methylaminocarbonylmethyl- and (naphthyl) aminocarbonylymethyl-, said phenyls and naphthyls being substituted or unsubstituted by R 6 as defined in claim 1, as well as their physiologically acceptable salts and their prodrugs.
13) Dérivés de thioazepinone de formules (I), (I' ) (I") ou13) Thioazepinone derivatives of formulas (I), (I ') (I ") or
(I"') dont les noms suivent :(I "') whose names follow:
. [2S-[3(S*) ,2α,3β] ]-[l-[ [4-[ [hydroxy (phénylméthoxy) phosphinyl] oxy] phényl] méthyl] -2- [ [2- (4-methoxyphényl) -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 ;. [2S- [3 (S *), 2α, 3β]] - [l- [[4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2- [[2- (4-methoxyphenyl) - 5- [2- [(1-naphthalenyl) amino] -2-oxoethyl] -4-oxo-2, 3, 4, 5-tetra-hydro-1, 5-benzothiazepin-3-yl] amino] -2- 1,1-dimethylethyl oxoethyl] -carbamate;
. [2R-[3(S*) ,2α,3β] ]-[l-[ [4-[ [hydroxy (phénylméthoxy) phosphinyl] oxy] phényl] méthyl] -2- [ [2- (4-methoxyphényl) -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 *), 2α, 3β]] - [l- [[4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2- [[2- (4-methoxyphenyl) - 5- [2- [(1-naphthalenyl) amino] -2-oxoethyl] -4-oxo-2, 3, 4, 5-tetra-hydro-1, 5-benzothiazepin-3-yl] amino] -2- 1,1-dimethylethyl oxoethyl] -carbamate;
. [2S-[3(S*) ,2α,3β] ]-[l-[ [4-[ [hydroxy (phénylméthoxy) phosphinyl] oxy] phényl] méthyl] -2- [ [2- (4-methoxyphényl) -5- [2-[ [4-méthoxy-[ (1, 1 ' -biphenyl) -3-yl] amino] -2-oxoéthyl] -4- oxo-2, 3, 4, 5-tétrahydro-l, 5-benzothiazépin-3-yl] amino] -2- xoéthyl] -carbamate de 1, 1-diméthyléthyle ;. [2S- [3 (S *), 2α, 3β]] - [l- [[4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2- [[2- (4-methoxyphenyl) - 5- [2- [[4-methoxy- [(1, 1 '-biphenyl) -3-yl] amino] -2-oxoethyl] -4- oxo-2, 3, 4, 5-tetrahydro-1,5 -benzothiazepin-3-yl] amino] -2-xoethyl] -carbamate of 1,1-dimethylethyl;
. [2S-[3(S*) ,2α,3β] ]-[l-[ [4-[ [hydroxy (phénylméthoxy) phosphinyl] oxy] phényl] méthyl] -2- [ [2- (4-methoxyphényl) -5- [2- [2- (3-phénoxyphényl) amino] -2-oxoéthyl] -4-oxo-2, 3,4,5- tétrahydro-1, 5-benzothiazépin-3-yl] amino] -2-oxoéthyl] - carbamate de 1, 1-diméthyléthyle ;. [2S- [3 (S *), 2α, 3β]] - [l- [[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] - 1,1-dimethylethyl carbamate;
. [2R-[3(S*) ,2α, 3α] ]-[l-[ [4-[ [hydroxy (phénylméthoxy) phosphinyl] oxy] phényl] méthyl] -2- [ [2- (4-methoxyphényl) -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 *), 2α, 3α]] - [l- [[4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2- [[2- (4-methoxyphenyl) - 5- [2- [(1-naphthalenyl) amino] -2-oxoethyl] -4-oxo-2, 3, 4, 5-tetra-hydro-1, 5-benzothiazepin-3-yl] amino] -2- 1,1-dimethylethyl oxoethyl] -carbamate;
. [2S-[3(S*) ,2α,3α] ]-[l-[ [4-[ [hydroxy (phénylméthoxy) phosphinyl] oxy] phényl] méthyl] -2- [ [2- (4-methoxyphényl) -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 ;. [2S- [3 (S *), 2α, 3α]] - [l- [[4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2- [[2- (4-methoxyphenyl) - 5- [2- [(1-naphthalenyl) amino] -2-oxoethyl] -4-oxo-2, 3, 4, 5-tetra-hydro-1, 5-benzothiazepin-3-yl] amino] -2- 1,1-dimethylethyl oxoethyl] -carbamate;
. [2S- [3 (S*) ,2α,3β] ]-l-[ [4- [ [bis (phénylméthoxy) phosphinyl] oxy] phényl] méthyl] -2- [ [2- (4-methoxyphényl) -5- [2- [ (1- naphtalenyl) amino] -2-oxo-l-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 *), 2α, 3β]] -l- [[4- [[bis (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2- [[2- (4-methoxyphenyl) -5 - [2- [(1- naphthalenyl) amino] -2-oxo-1-phenylethyl] -4-oxo-2, 3,4, 5-tetra-hydro-1, 5-benzothiazepin-3-yl] amino] -1, 1-dimethylethyl -2-oxoethyl] -carbamate;
. [2S-[3(S*) ,2α,3β] ]-[l-[ [4-[ [hydroxy (phénylméthoxy) phosphinyl] oxy] phényl] méthyl] -2- [ [2- (4-methoxyphényl) -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 *), 2α, 3β]] - [l- [[4- [[hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2- [[2- (4-methoxyphenyl) - 5- [2- [(4-phenoxyphenyl) amino] -2-oxoethyl] -4-oxo-2, 3, 4, 5-tetra-hydro-1, 5-benzothiazepin-3-yl] amino] -2- 1,1-dimethylethyl oxoethyl] -carbamate;
. [2S-[3(S*) ,2α,3β] ]-4'-[ [3-[ [2-[ [ [ (1, 1-diméthyl) ethoxy] carbonyl] amino] -3- [ [4- [ [hydroxy (phénylméthoxy) phosphinyl] oxy] phényl] -1-oxopropyl] amino] -2- (4-methoxyphényl) -4-oxo- 2, 3-dihydro-l, 5-benzothiazépin-5 (4H) -yl] méthyl] -[1,1' -biphenyl] -2-carboxylate de 1, 1-diméthyléthyle ;. [2S- [3 (S *), 2α, 3β]] -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) -yl ] methyl] - [1,1 '-biphenyl] -2-carboxylate of 1,1-dimethylethyl;
. [S- [R [trans (±) ]] ]-[l-[ [4- [ [hydroxy (phénylméthoxy) phosphinyl] oxy] phényl] méthyl] -2- [ [5- (3-cyclohexylpropyl) - 2- (4-methoxyphényl) -4-oxo-2, 3, 4, 5-tétrahydro-l, 5- benzothiazépin-3-yl] amino] -2-oxoéthyl] -carbamate de 1,1- diméthyléthyle ;. [S- [R [trans (±)]]]] - [l- [[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]-1,1-dimethylethylcarbamate;
. [S- [R* (3S*) ] ] - [2- [ [5- (3-cyclohexylpropyl) -4-OXO-2, 3, 4, 5- tétrahydro-1, 5-benzothiazépin-3-yl] amino] -1- [ [4- [ [hydroxy (phénylméthoxy) phosphinyl] oxy] phényl] méthyl] -2-oxoéthyl] carbamate de 1, 1-diméthyléthyle ;. [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 of 1,1-dimethylethyl;
. [S-[R*(3S*) ] ]-[2-[ [5-(3-cyclohexylpropyl)-2,3,4,5-tétra- hydro-4-oxo-l, 5-benzothiazépin-3-yl] amino] -2-oxo-l- [ [4- phosphonooxyphényl] méthyl] éthyl] -carbamate de 1, 1-diméthyléthyle ;. [S- [R * (3S *)]] - [2- [[5- (3-cyclohexylpropyl) -2,3,4,5-tetra-hydro-4-oxo-1,5,5-benzothiazepin-3- yl] amino] -2-oxo-l- [[4-phosphonooxyphenyl] methyl] ethyl] -carbamate of 1,1-dimethylethyl;
. [S-[R*(3R*) ] ]-[2-[ [5- (3-cyclohexylpropyl) -4-oxo-2,3, 4,5- 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) -4-oxo-2,3, 4,5-tetrahydro-1, 5-benzothiazepin-3-yl] amino] -1- [[4-hydroxy (phenylmethoxy) phosphinyl] oxy] phenyl] methyl] -2-oxoethyl] - 1,1-dimethylethyl carbamate;
. [S- [R* (3R*) ] ] - [2- [ [5- (3-cyclohexylpropyl) -2, 3, 4, 5-tétra- hydro-4-oxo-l, 5-benzothiazépin-3-yl] amino] -2-oxo-l- [ [4- phosphonooxyphényl] méthyl] éthyl] -carbamate de 1, 1-diméthyléthyle ; . trans (±) -2, 3-dihydro-3- [ [3- [4- [ [hydroxy (phénylméthoxy) phosphinyl] oxy] phényl] -1-oxopropyl] amino] -2- (4-methoxyphényl) -N- (1-naphtylméthyl) -4-oxo-l, 5-benzothiazépine-5 (4H) - acétamide ;. [S- [R * (3R *)]] - [2- [[5- (3-cyclohexylpropyl) -2, 3, 4, 5-tetra-hydro-4-oxo-1,5, benzothiazepin-3- yl] amino] -2-oxo-l- [[4-phosphonooxyphenyl] methyl] ethyl] -carbamate of 1,1-dimethylethyl; . 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;
. trans (±) -2, 3-dihydro-3- [[ [6- [ [hydroxy (phénylméthoxy) phosphinyl] oxy] -2-naphtalényl] carbonyl] amino] -2- (4- méthoxyphényl) -N- (1-naphtylméthyl) -4-oxo-l, 5-benzothiazépine- 5 (4H) -acétamide ;. 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 (phénylméthoxy) phosphinyl] oxy] -lH-indol-2-yl] carbonyl] amino] -2- (4- methoxyphényl) -N- (1-naphtylméthyl) -4-oxo-l, 5-benzothiazépine 5 (4H) -acétamide ;. trans (±) -2, 3-dihydro-3- [[[5- [[hydroxy (phenylmethoxy) phosphinyl] oxy] -lH-indol-2-yl] carbonyl] amino] -2- (4- methoxyphenyl) - N- (1-naphthylmethyl) -4-oxo-1,5-benzothiazepine 5 (4H) -acetamide;
. trans (±) -3- [ [ (4-boronophényl) carbonyl] amino] -2,3- dihydro-2- (4-methoxyphényl) -N- (1-naphtylméthyl) -4-oxo-l, 5- benzothiazépine-5 (4H) -acétamide ; . trans (±) -3- [ [2- [ [ (4-boronophényl) carbonyl] amino] -1-oxo- éthyl] amino] -2, 3-dihydro-2- (4-methoxyphényl) -N- (1-naphtyl- méthyl) -4-oxo-l, 5-benzothiazépine-5 (4H) -acétamide ;. 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-tétrahydro- 1, 5-benzothiazépin-3-yl] -3-formyl-4- (phosphonooxy) -benzamide, . (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-tétrahydro- 1, 5-benzothiazépin-3-yl] -4- (phosphonooxy) -benzamide ;. (R) -N- [5- (3-cyclohexylpropyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] -4- (phosphonooxy) -benzamide;
. acide (R) - [4- [ [ [5- (3-cyclohexylpropyl) -4-oxo-2, 3, 4, 5- tétrahydro-1, 5-benzothiazépin-3-yl] amino] carbonyl] -2- formylphénoxy] -acétique ;. acid (R) - [4- [[[5- (3-cyclohexylpropyl) -4-oxo-2, 3, 4, 5-tetrahydro-1, 5-benzothiazepin-3-yl] amino] carbonyl] -2- formylphenoxy] -acetic;
. (R) -N- [5- (3-cyclohexylpropyl) -4-oxo-2, 3,4, 5-tétrahydro- 1, 5-benzothiazépin-3-yl] -4- (diphosphonométhyl) -benzamide,. (R) -N- [5- (3-cyclohexylpropyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] -4- (diphosphonomethyl) -benzamide,
. [3R- [3R* (S*) ] ] -β- (acétylamino) -N- [5- (3-cyclohexylpropyl) - 2,3,4, 5-tétra-hydro-4-oxo-l, 5-benzothiazépin-3-yl] -4- (difluorophosphonométhyl) -benzènepropanamide ;. [3R- [3R * (S *)]] -β- (acetylamino) -N- [5- (3-cyclohexylpropyl) - 2,3,4,5-tetra-hydro-4-oxo-1,5- benzothiazepin-3-yl] -4- (difluorophosphonomethyl) -benzenepropanamide;
. (R) -N- [5- (4-cyclohexylbutyl) -4-oxo-2, 3, 4, 5-tétrahydro- 1, 5-benzothiazépin-3-yl] -N ' - [4- (phosphonooxy) phényl] -urée, . cis (±) -N- [5- (3-cyclohexylpropyl) -2- (4-methoxyphényl) -4- oxo-2, 3,4, 5-tétrahydro-l, 5-benzothiazépin-3-yl] -4- [ [hydroxy (phénylméthoxy) phosphinyl] oxy] -benzèneacétamide ;. (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] -benzeneeacetamide;
. cis (±) -N- [5- (3-cyclohexylpropyl) -2- (4-methoxyphényl) -4- oxo-2, 3,4, 5-tétrahydro-l, 5-benzothiazépin-3-yl] -4- (phosphonooxy) benzèneacétamide ;. 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-thiazépin-6-yl] amino] -2-oxo-l- [ [4- (phosphonooxy) phényl] méthyl] éthyl] -carbamate de 1, 1-diméthyléthyle,. [S- [R * (6S *)]] - [2- [[4- (3-cyclohexylpropyl) -hexahydro-5-oxo-1, 4-thiazepin-6-yl] amino] -2-oxo-l - [1 - 1-dimethylethyl [[4- (phosphonooxy) phenyl] methyl] ethyl] -carbamate,
. (R) -3- [[ (aminocarbonyl) hydrazono] méthyl] -4- (phosphonooxy) -N- [5- (3-cyclohexylpropyl) -4-oxo-2, 3, 4, 5-tétrahydro-l, 5- benzothiazépin-3-yl] -benzamide; . [S- [R* (6R*) ]] -N-acétyl- [4- (3-cyclohexylpropyl) -5-oxo- 4,5,6, 7-tétrahydro-l, 4-thiazépin-6-yl] -4- (phosphono) - (difluoro) méthyl] -L-phénylalaninamide ;. (R) -3- [[(aminocarbonyl) hydrazono] methyl] -4- (phosphonooxy) -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-tétrahydro-l, 5-benzothiazépin-3-yl] -2-pyridine carboxamide ;. (R) -5- (phosphonooxy) -N- [5- (3-cyclohexylpropyl) -4-oxo- 2,3,4,5-tetrahydro-1,5,5-benzothiazepin-3-yl] -2-pyridine carboxamide ;
. (R) -4- [ (phosphono) fluorométhyl] -N- [5- (3-cyclo- hexylpropyl) -4-oxo-2, 3,4, 5-tétrahydro-l, 5-benzothiazépin-3- yl] -benzamide ;. (R) -4- [(phosphono) fluoromethyl] -N- [5- (3-cyclohexylpropyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] -benzamide;
. N- [ (6R) -4- (3-cyclohexylpropyl) -hexahydro-5-oxo-l, 4- thiazepin-6-yl] -4- (phosphonooxy) -Benzamide ; . N- [(6R) -4- (3-cyclohexylpropyl) -hexahydro-5-oxo-1,4-thiazepin-6-yl] -4- (phosphonooxy) -Benzamide;
. Acide [ [4- [ (2S) -2- (acétylamino) -4- [ [ (6R) -4- (3- cyclohexylpropyl) -hexahydro-5-thioxo-l, 4-thiazepin-6- yl] amino] -3-oxopropyl] phényl] difluorométhyl] - Phosphonique ; . N- [ ( 6R) -hexahydro-5-oxo-4- (3-phenyl-2-propenyl) -1, 4- thiazepin-6-yl] -4- (phosphonooxy) -Benzamide ;. Acid [[4- [(2S) -2- (acetylamino) -4- [[(6R) -4- (3- cyclohexylpropyl) -hexahydro-5-thioxo-1,4-thiazepin-6- yl] amino] -3-oxopropyl] phenyl] difluoromethyl] - Phosphonic; . N- [(6R) -hexahydro-5-oxo-4- (3-phenyl-2-propenyl) -1, 4-thiazepin-6-yl] -4- (phosphonooxy) -Benzamide;
. Acide [ [4- [ (2S) -2- (acétylamino) -4- [ [ (6R) -4- (3- cyclohexylpropyl) -hexahydro-5-oxo-l, 4-thiazepin-6-yl] amino] - 3-oxopropyl] phényl] ifluorométhyl] - Phosphonique ;. Acid [[4- [(2S) -2- (acetylamino) -4- [[(6R) -4- (3-cyclohexylpropyl) -hexahydro-5-oxo-1,4-thiazepin-6-yl] amino] - 3-oxopropyl] phenyl] ifluoromethyl] - Phosphonic;
. Acide [ [4- [ [ [ (6R) -4- (3-cyclohexylpropyl) -hexahydro-5-oxo- 1, 4-thiazepin-6-yl] amino] carbonyl] phényl] difluorométhyl] - Phosphonique ;. Acid [[4- [[[(6R) -4- (3-cyclohexylpropyl) -hexahydro-5-oxo-1, 4-thiazepin-6-yl] amino] carbonyl] phenyl] difluoromethyl] - Phosphonic;
. N2-acetyl-N- [ (6R) -4- (3-cyclohexylpropyl) -hexahydro-5-oxo- 1, 4-thiazepin-6-yl] -3-formyl-4- (phosphonooxy) -L- Phenylalaninamide ; . N- [ (6R) -4- (3-cyclohexylpropyl) -hexahydro-5-oxo-l, 4- thiazepin-6-yl] -3-formyl-4- (phosphonooxy) - Benzamide ;. N2-acetyl-N- [(6R) -4- (3-cyclohexylpropyl) -hexahydro-5-oxo- 1, 4-thiazepin-6-yl] -3-formyl-4- (phosphonooxy) -L- Phenylalaninamide; . N- [(6R) -4- (3-cyclohexylpropyl) -hexahydro-5-oxo-1,4-thiazepin-6-yl] -3-formyl-4- (phosphonooxy) - Benzamide;
. Acide [ [4- [ (2S) -2- (acétylamino) -4- [ [ (6R) -4- [3- (3- methoxyphenyl) propyl) -hexahydro-5-oxo-l, 4-thiazepin-6- yl] amino] -3-oxopropyl] phényl] difluorométhyl] - Phosphonique ; . 1,1-dioxyde de 1 ' acide [ [4- [ (2S) -2- (acétylamino) -4- [[ (6R) - 4- (3-cyclohexylpropyl) -hexahydro-5-thioxo-l, 4-thiazepin-6- yl] amino] -3-oxopropyl] phényl] difluorométhyl] - Phosphonique . N2-acetyl-N- [ (3R) -5- (3-cyclohexylpropyl) -4-oxo-2, 3, 4 , 5- tetrahydro-1, 5-benzothiazepin-3-yl] -. Acid [[4- [(2S) -2- (acetylamino) -4- [[(6R) -4- [3- (3- methoxyphenyl) propyl) -hexahydro-5-oxo-1,4-thiazepin-6 - yl] amino] -3-oxopropyl] phenyl] difluoromethyl] - Phosphonic; . Acid 1,1-dioxide [[4- [(2S) -2- (acetylamino) -4- [[(6R) - 4- (3-cyclohexylpropyl) -hexahydro-5-thioxo-l, 4- thiazepin-6-yl] amino] -3-oxopropyl] phenyl] difluoromethyl] - Phosphonic. N2-acetyl-N- [(3R) -5- (3-cyclohexylpropyl) -4-oxo-2, 3, 4, 5-tetrahydro-1, 5-benzothiazepin-3-yl] -
3- [8- (phosphonooxy) -quinolin-5-yl] - Alaninamide ;3- [8- (phosphonooxy) -quinolin-5-yl] - Alaninamide;
. Acide [ [4-[ (2S) -2- (acétylamino) -4- [ [ ( 6R) -4- [3- (3- hydroxyphenyl) propyl) -hexahydro-5-oxo-l, 4-thiazepin-6- yl] amino] -3-oxopropyl] phényl] difluorométhyl] - Phosphonique ; . N2-acetyl-N- [ (6R) -4- (3-cyclohexylpropyl) -hexahydro-5-oxo- 1, -thiazepin-6-yl] -3- (1, 3-dihydro-3-hydroxy-l-oxo-5- isobenzofuranyl] -L-Alaninamide ;. Acid [[4- [(2S) -2- (acetylamino) -4- [[(6R) -4- [3- (3-hydroxyphenyl) propyl) -hexahydro-5-oxo-1,4-thiazepin-6 - yl] amino] -3-oxopropyl] phenyl] difluoromethyl] - Phosphonic; . N2-acetyl-N- [(6R) -4- (3-cyclohexylpropyl) -hexahydro-5-oxo- 1, -thiazepin-6-yl] -3- (1, 3-dihydro-3-hydroxy-l- oxo-5-isobenzofuranyl] -L-Alaninamide;
. N2-acetyl-N- [ ( 6R) -4- (3-cyclohexylpropyl) -hexahydro-5-oxo- 1, 4-thiazepin-6-yl] -3- (1, 3-dihydro-3-ethoxy-l-oxo-5- isobenzofuranyl] -L-Alaninamide ; . N2-acetyl-N- [(6R) -4- (3-cyclohexylpropyl) -hexahydro-5-oxo- 1, 4-thiazepin-6-yl] -3- (1, 3-dihydro-3-ethoxy-l -oxo-5-isobenzofuranyl] -L-Alaninamide;
. Acide 4-[ (2S) -2- (acétylamino) -3- [ [ (6R)-4-(3- cyclohexylpropyl) -hexahydro-5-oxo-l, 4-thiazepin-6-yl] amino] - 3-oxo-propyl ] -1 , 2-Benzenedicarboxylique ;. Acid 4- [(2S) -2- (acetylamino) -3- [[(6R) -4- (3-cyclohexylpropyl) -hexahydro-5-oxo-1,4, thiazepin-6-yl] amino] - 3 -oxo-propyl] -1,2-Benzenedicarboxylic;
. Acide [ [4-[ (2S) -2- (acétylamino) -3- [ [ (6R) -hexahydro-4- [ (3- methoxyphényl) méthyl] -5-oxo-l, 4-thiazepin-6-yl] amino] -3- oxopropyl ] phényl] difluorométhyl] - Phosphonique ;. Acid [[4- [(2S) -2- (acetylamino) -3- [[(6R) -hexahydro-4- [(3-methoxyphenyl) methyl] -5-oxo-1,4-thiazepin-6-yl ] amino] -3- oxopropyl] phenyl] difluoromethyl] - Phosphonic;
. Acide [ [4-[ (2S) -2- (acétylamino) -4- [ [ ( 6R) -hexahydro-4- [ (2- naphthalenyl) méthyl] -5-oxo-l, 4-thiazepin-6-yl] amino] -3- oxopropyl ] phényl] difluorométhyl ] - Phosphonique; . Acide [ [4-[ (2S) -2- (acétylamino) -4- [ [ (6R)-4-[2-. Acid [[4- [(2S) -2- (acetylamino) -4- [[(6R) -hexahydro-4- [(2- naphthalenyl) methyl] -5-oxo-1,4-thiazepin-6-yl ] amino] -3- oxopropyl] phenyl] difluoromethyl] - Phosphonic; . Acid [[4- [(2S) -2- (acetylamino) -4- [[(6R) -4- [2-
(trifluorométhyl) phényl] -hexahydro-5-oxo-l, 4-thiazepin-6- yl] amino] -3-oxopropyl] phényl] difluorométhyl] - Phosphonique ;(trifluoromethyl) phenyl] -hexahydro-5-oxo-1,4-thiazepin-6-yl] amino] -3-oxopropyl] phenyl] difluoromethyl] - Phosphonic;
. Acide [ [4- [ (2S) -2- (acétylamino) -4- [[ (6R) -hexahydro-5-oxo- 4- [ [4- (trifluoromethoxy) phényl] méthyl] -1, 4-thiazepin-6- yl] amino] -3-oxopropyl] phényl] difluorométhyl] -Phosphonique; . Acide [ [4-[ (2S) -2- (acétylamino) -4- [ [ ( 6R) -4- [2- (4- fluorophenoxy) phényl] méthyl] -hexahydro-5-oxo-l, 4-thiazepin-6- yl] amino] -3-oxopropyl] -phényl] difluorométhyl] - Phosphonique; . Acide [ [4- [ (2S) -2- (acétylamino) -4- [[ (6R) -hexahydro-4- [ [3- (phenylcarbonyl) phényl] méthyl] -5-oxo-l, 4-thiazepin-6- yl] amino] -3-oxopropyl] -phényl] difluorométhyl] - Phosphonique ; . Acide [ [4-[ (2S) -2- (acétylamino) -4- [ [ ( 6R) -4- (3-cyclohexyl- 2-oxo-propyl) -hexahydro-5-oxo-l, -thiazepin-6-yl] amino] -3- oxopropyl] -phényl] difluorométhyl] - Phosphonique ; . Acide [ [4- [ [ [ (6R) -4- (3-cyclohexylpropyl) -hexahydro-5-oxo- 1, 4-thiazepin-6-yl] amino] carbonyl] -2-formyl- phenyl ] difluorométhyl ] -Phosphonique ;. Acid [[4- [(2S) -2- (acetylamino) -4- [[(6R) -hexahydro-5-oxo- 4- [[4- (trifluoromethoxy) phenyl] methyl] -1, 4-thiazepin- 6-yl] amino] -3-oxopropyl] phenyl] difluoromethyl] -Phosphonic; . Acid [[4- [(2S) -2- (acetylamino) -4- [[(6R) -4- [2- (4-fluorophenoxy) phenyl] methyl] -hexahydro-5-oxo-1,4-thiazepin -6- yl] amino] -3-oxopropyl] -phenyl] difluoromethyl] - Phosphonic; . [[4- [(2S) -2- (acetylamino) -4- [[(6R) -hexahydro-4- [[3- (phenylcarbonyl) phenyl] methyl] -5-oxo-1,4-thiazepin- acid 6- yl] amino] -3-oxopropyl] -phenyl] difluoromethyl] - Phosphonic; . Acid [[4- [(2S) -2- (acetylamino) -4- [[(6R) -4- (3-cyclohexyl- 2-oxo-propyl) -hexahydro-5-oxo-l, -thiazepin-6 -yl] amino] -3- oxopropyl] -phenyl] difluoromethyl] - Phosphonic; . Acid [[4- [[[(6R) -4- (3-cyclohexylpropyl) -hexahydro-5-oxo-1, 4-thiazepin-6-yl] amino] carbonyl] -2-formyl-phenyl] difluoromethyl] - Phosphonic;
. N2-acetyl-N- [ (3R) -5- (3-cyclohexylpropyl) -4-oxo-2, 3, 4, 5- tetrahydro-1, 5-benzothiazepin-3-yl] -3- [8- (phosphonooxy) - 1, 2, 3, 4-tetrahydro-quinolin-5-yl] - L-Alaninamide;. N2-acetyl-N- [(3R) -5- (3-cyclohexylpropyl) -4-oxo-2, 3, 4, 5- tetrahydro-1, 5-benzothiazepin-3-yl] -3- [8- ( phosphonooxy) - 1, 2, 3, 4-tetrahydro-quinolin-5-yl] - L-Alaninamide;
. Acide [ [4- [ (2S) -2- (acétylamino) -4- [ [ (6R) -4- (3-phenyl-2- propenyl) -hexahydro-5-oxo-l, 4-thiazepin-6-yl] amino] -3- oxopropyl] -phényl] difluorométhyl] - Phosphonique ; . N- [ ( 6R) -hexahydro-5-oxo-1, 4-thiazepin-6-yl] -4- (phosphonooxy) -Benzamide; . Acid [[4- [(2S) -2- (acetylamino) -4- [[(6R) -4- (3-phenyl-2-propenyl) -hexahydro-5-oxo-1,4-thiazepin-6- yl] amino] -3-oxopropyl] -phenyl] difluoromethyl] - Phosphonic; . N- [(6R) -hexahydro-5-oxo-1, 4-thiazepin-6-yl] -4- (phosphonooxy) -Benzamide;
. Acide [ [4- [ [ [ (6R) -hexahydro-4- [ (3-methoxyphenyl) méthyl] - 5-oxo-l, 4-thiazepin-6- yl] amino] carbonyl] phényl] difluorométhyl] -Phosphonique;. [[4- [[[(6R) -hexahydro-4- [(3-methoxyphenyl) methyl] - 5-oxo-1,4-thiazepin-6-yl] amino] carbonyl] phenyl] difluoromethyl] -Phosphonic acid;
. Acide [ [4- [ [ [ (6R) -hexahydro-4- [ (2-naphthalenyl)methyl] -5- oxo-1, 4-thiazepin-6-yl] amino] carbonyl] phényl] difluorométhyl] - Phosphonique;. Acid [[4- [[[(6R) -hexahydro-4- [(2-naphthalenyl) methyl] -5- oxo-1, 4-thiazepin-6-yl] amino] carbonyl] phenyl] difluoromethyl] - Phosphonic;
. Acide [ [4-[ [ [ (6R) -hexahydro-5-oxo-4- [ [4- (trifluoromethoxy) phényl] méthyl] -1, 4-thiazepin-6- yl] amino] carbonyl] phényl] difluorométhyl] -Phosphonique ; . Acide [ [4- [ [ [ ( 6R) -hexahydro-5-oxo-4- [2-oxo-2- (5, 6, 7, 8- tetrahydro-5, 5,8, 8-tetramethyl-2-naphthalenyl) ethyl] 1, 4-thiazepin-6-yl] amino] carbonyl] phényl] difluorométhyl] - Phosphonique ;. Acid [[4- [[[(6R) -hexahydro-5-oxo-4- [[4- (trifluoromethoxy) phenyl] methyl] -1,4-thiazepin-6- yl] amino] carbonyl] phenyl] difluoromethyl] -Phosphonic; . Acid [[4- [[[(6R) -hexahydro-5-oxo-4- [2-oxo-2- (5, 6, 7, 8- tetrahydro-5, 5,8, 8-tetramethyl-2- naphthalenyl) ethyl] 1,4-thiazepin-6-yl] amino] carbonyl] phenyl] difluoromethyl] - Phosphonic;
. Acide [ [4-[ [ [ (6R)-hexahydro-5-oxo-4-[ [3- (trifluorométhyl) phényl] méthyl] -1, 4-thiazepin-6- yl] amino] carbonyl] phényl] difluorométhyl] Phosphonique ;. Acid [[4- [[[(6R) -hexahydro-5-oxo-4- [[3- (trifluoromethyl) phenyl] methyl] -1,4-thiazepin-6-yl] amino] carbonyl] phenyl] difluoromethyl] Phosphonic;
• [ [4- [ [ [ (6R) -hexahydro-4- [ (3-methoxyphenyl) méthyl] -5-oxo- 1, 4-thiazepin-6-yl] amino] carbonyl] phényl] difluorométhyl] - Phosphonate d' éthyle ; . 4- [2- (acétylamino) -3-OXO-3- [[ (6R) -5-oxo-hexahydro-4- [ [4- (trifluoromethoxy) phényl] méthyl] -1, 4-thiazepin-6-yl] amino] -1- propenyl] -2-carboxy-phenyl-Propanedioate de bis (1,1- dimethylethyle) ;• [[4- [[[(6R) -hexahydro-4- [(3-methoxyphenyl) methyl] -5-oxo- 1, 4-thiazepin-6-yl] amino] carbonyl] phenyl] difluoromethyl] - Phosphonate d 'ethyl; . 4- [2- (acetylamino) -3-OXO-3- [[(6R) -5-oxo-hexahydro-4- [[4- (trifluoromethoxy) phenyl] methyl] -1, 4-thiazepin-6-yl ] amino] -1-propenyl] -2-carboxy-phenyl-propanedioate bis (1,1-dimethylethyl);
. Acide 4- [ (2S) -2- (acétylamino) -3-OXO-3- [[ (6R) -hexahydro-5- oxo-4- [ [4- (trifluoromethoxy) phényl] méthyl] -1, -thiazepin-6- yl] amino] propyl] -2-formyl- Benzeneacetique ;. Acid 4- [(2S) -2- (acetylamino) -3-OXO-3- [[(6R) -hexahydro-5- oxo-4- [[4- (trifluoromethoxy) phenyl] methyl] -1, -thiazepin -6- yl] amino] propyl] -2-formyl-benzeneacetic;
. Acide 4- [2- (acétylamino) -3-OXO-3- [[ (6R) -hexahydro-5-oxo- 4- [ [4- (trifluoromethoxy) phényl] méthyl] -1, 4-thiazepin-6- yl] amino] -1-propenyl] -2- (methoxycarbonyl) -Benzeneacetique ; . Acide 2-carboxy-4- [ (2S) -2- (acétylamino) -3-oxo-3- [[( 6R) - hexahydro-5-oxo-4- [ [4- (trifluoromethoxy) phényl] méthyl] -1,4- thiazepin-6-yl] amino] -1-propenyl] -Benzeneacetique ;. 4- [2- (acetylamino) -3-OXO-3- [[(6R) -hexahydro-5-oxo 4- [[4- (trifluoromethoxy) phenyl] methyl] -1,4-thiazepin-6- acid yl] amino] -1-propenyl] -2- (methoxycarbonyl) -Benzeneacetic; . 2-carboxy-4- [(2S) -2- (acetylamino) -3-oxo-3- [[(6R) - hexahydro-5-oxo-4- [[4- (trifluoromethoxy) phenyl] methyl] acid] - 1,4-thiazepin-6-yl] amino] -1-propenyl] -Benzeneacetic;
. N2-acetyl-N- [ (6R) -4- [ [4- (dimethylamino) phényl] méthyl] - hexahydro-5-oxo-l, 4-thiazepin-6-yl] -4- (phosphonooxy) L-Phenylalaninamide ; . N2-acetyl-N- [(6R) -4- [[4- (dimethylamino) phenyl] methyl] - hexahydro-5-oxo-l, 4-thiazepin-6-yl] -4- (phosphonooxy) L-Phenylalaninamide ;
. N- [ ( 6R) -hexahydro-5-oxo-4- (3-phenyl-2-propenyl) -1, 4- thiazepin-6-yl] -4- (phosphonooxy) -Benzamide sel di (trihydroxymethyl)methanamine ;. N- [(6R) -hexahydro-5-oxo-4- (3-phenyl-2-propenyl) -1,4-thiazepin-6-yl] -4- (phosphonooxy) -Benzamide di (trihydroxymethyl) methanamine salt;
. N- [ (6R) -hexahydro-5-oxo-4- (3-phenyl-2-propenyl) -1,4- thiazepin-6-yl] -4- (phosphonooxy) -Benzamide sel de disodium ;. N- [(6R) -hexahydro-5-oxo-4- (3-phenyl-2-propenyl) -1,4-thiazepin-6-yl] -4- (phosphonooxy) -Benzamide disodium salt;
. N- [ (6R) -hexahydro-5-oxo-4- (3-phenyl-2-propenyl) -1, 4- thiazepin-6-yl] -2-methyl-4- (phosphonooxy) -Benzamide ;. N- [(6R) -hexahydro-5-oxo-4- (3-phenyl-2-propenyl) -1,4-thiazepin-6-yl] -2-methyl-4- (phosphonooxy) -Benzamide;
. N- [ (6R) -hexahydro-5-oxo-4- (3-phenyl-2-propenyl) -1, 4- thiazepin-6-yl] -4-hydroxy-Benzamide ; . 4- [[ (6R) -[ [4- [4- (phosphonooxy) phényl] carbonyl] amino] -5- oxo-hexahydro-1, 4-thiazepin-4-yl]methyl] -Benzoate de méthyle ;. N- [(6R) -hexahydro-5-oxo-4- (3-phenyl-2-propenyl) -1,4-thiazepin-6-yl] -4-hydroxy-Benzamide; . Methyl 4- [[(6R) - [[4- [4- (4- phosphonooxy) phenyl] carbonyl] amino] -5- oxo-hexahydro-1, 4-thiazepin-4-yl] methyl] -Benzoate;
. N- [ (6R) -hexahydro-5-oxo-4- [ [3, 5bis- (trifluorométhyl) phényl] méthyl] -1, 4-thiazepin-6-yl] -4- (phosphonooxy) -Benzamide ;. N- [(6R) -hexahydro-5-oxo-4- [[3,5bis- (trifluoromethyl) phenyl] methyl] -1,4-thiazepin-6-yl] -4- (phosphonooxy) -Benzamide;
. acide [ [ [4- [ [ [ (6R) -hexahydro-5-oxo-4- [ [3, 5bis- (trifluorométhyl) phényl] méthyl] -1, 4-thiazepin-6- yl] amino] carbonyl] phényl] amino] carbonyl] -Phosphonique ;. acid [[[4- [[[(6R) -hexahydro-5-oxo-4- [[3,5bis- (trifluoromethyl) phenyl] methyl]] -1,4-thiazepin-6- yl] amino] carbonyl] phenyl ] amino] carbonyl] -Phosphonic;
. N- [ (6R) -4 [ [ (1, l' -biphenyl) -4yl]méthyl] -hexahydro-5-oxo- 1, 4-thiazepin-6-yl] -4- (phosphonooxy) -Benzamide ;. N- [(6R) -4 [[(1, l -biphenyl) -4yl] methyl] -hexahydro-5-oxo 1, 4-thiazepin-6-yl] -4- (phosphonooxy) -Benzamide;
. 4- (aminosulfonyl) -N- [ ( 6R) -hexahydro-5-oxo-4- (3-phenyl-2- propen-1-yl) -1, 4-thiazepin-6-yl] -Benzenecarboxamide ;. 4- (aminosulfonyl) -N- [(6R) -hexahydro-5-oxo-4- (3-phenyl-2-propen-1-yl) -1, 4-thiazepin-6-yl] -Benzenecarboxamide;
. Acide [4-[[3-[ ( 6R) -hexahydro-5-oxo-4- (3-phenyl-2-propen- 1-yl) -1, 4-thiazepin-6-yl] amino] carbonyl] phényl] - Boronique ;. [4 - [[3- [(6R) -hexahydro-5-oxo-4- (3-phenyl-2-propen- 1-yl) -1,4-thiazepin-6-yl] amino] carbonyl] phenyl acid ] - Boronique;
. Acide [ [4- [ [ [ (6R) -hexahydro-4- [ (4-bromophenyl) méthyl] -5- oxo-1, -thiazepin-6- yl] amino] carbonyl] phényl] hydroxymethyl] Phosphonique ;. Acid [[4- [[[(6R) -hexahydro-4- [(4-bromophenyl) methyl] -5- oxo-1, -thiazepin-6- yl] amino] carbonyl] phenyl] hydroxymethyl] Phosphonic;
. Acide [ [ [4- [ [ [ (6R) -4- [ (3-cyanophenyl)methyl] -hexahydro-5- oxo-1, 4-thiazepin-6-yl] amino] carbonyl] phényl] amino] carbonyl] - Phosphonique ;. Acid [[[4- [[[(6R) -4- [(3-cyanophenyl) methyl] -hexahydro-5-oxo-1, 4-thiazepin-6-yl] amino] carbonyl] phenyl] amino] carbonyl] - Phosphonic;
. Acide 4- [2- (acétylamino) -3-oxo-3- [[ (6R) -hexahydro-5-oxo- 4- [ [4- (trifluoromethoxy) phényl]méthyl] -1, 4-thiazepin-6- yl] amino] -1-propen-l-yl] -2-formyl-Benzeneacetique . N- [ (6R) -hexahydro-5-oxo-4- (3-phenyl-2-propenyl) -1, 4- thiazepin-6-yl] -4- (sulfonooxy) -Benzamide sel de sodium ; . 4- [2- (acetylamino) -3-oxo-3- [[(6R) -hexahydro-5-oxo 4-- [[4- (trifluoromethoxy) phenyl] methyl] -1,4-thiazepin-6- acid yl] amino] -1-propen-1-yl] -2-formyl-benzeneacetic. N- [(6R) -hexahydro-5-oxo-4- (3-phenyl-2-propenyl) -1,4-thiazepin-6-yl] -4- (sulfonooxy) -Benzamide sodium salt;
. N- [ (6R) -4- [ (2-fluoro-3-methylphenyl) méthyl] -hexahydro-5- oxo-1, 4-thiazepin-6yl] -4- (phosphonooxy) -Benzamide ;. N- [(6R) -4- [(2-fluoro-3-methylphenyl) methyl] -hexahydro-5-oxo-1, 4-thiazepin-6yl] -4- (phosphonooxy) -Benzamide;
. N- [ (6R) -4- [ (4-bromophenyl) méthyl] -hexahydro-5-oxo-l, 4- thiazepin-6-yl] -4- (phosphonooxy) -Benzamide ; . 4- (phosphonooxy) -N- [ (6R) -hexahydro-5-oxo- [ [2- [ (phenylsulfonyl) méthyl] phényl] -1, 4-thiazepin-6-yl] - Benzamide ;. N- [(6R) -4- [(4-bromophenyl) methyl] -hexahydro-5-oxo-1,4,4 thiazepin-6-yl] -4- (phosphonooxy) -Benzamide; . 4- (phosphonooxy) -N- [(6R) -hexahydro-5-oxo- [[2- [(phenylsulfonyl) methyl] phenyl] -1, 4-thiazepin-6-yl] - Benzamide;
. Acide 4- [2- (acétylamino) -3-oxo-3- [[ (6R) -hexahydro-5-oxo- 4- [ [4- (trifluoromethoxy) phényl] méthyl] -1, 4-thiazepin-6- yl] amino] -1-propen-l-yl] -alpha-fluoro-2-formyl- Benzeneacetique ;. 4- [2- (acetylamino) -3-oxo-3- [[(6R) -hexahydro-5-oxo 4-- [[4- (trifluoromethoxy) phenyl] methyl] -1,4-thiazepin-6- acid yl] amino] -1-propen-1-yl] -alpha-fluoro-2-formyl-benzeneacetic;
. sulfamate de 4- [ [ [ ( 6R) -hexahydro-5-oxo-4- (3-phenyl-2- propenyl) -1, 4-thiazepin-6-yl] amino] carbonyl] phenyle ;. 4- [[[((6R) -hexahydro-5-oxo-4- (3-phenyl-2-propenyl) -1,4-thiazepin-6-yl] amino] carbonyl] phenyl sulfamate;
. Acide [4-[3-[[ (6R) -hexahydro-5-oxo-4- (3-phenyl-2-propen- 1-yl) -1, 4-thiazepin-6-yl] amino] 3-oxo-l-propenyl] phényl] - Boronique ;. [4- [3 - [[(6R) -hexahydro-5-oxo-4- (3-phenyl-2-propen- 1-yl) -1,4-thiazepin-6-yl] amino] 3-oxo acid -l-propenyl] phenyl] - Boronic;
. N- [ (6R) -hexahydro-4- [ (4-nitrophenyl) méthyl] -5-oxo-l, 4- thiazepin-6yl] -4- (phosphonooxy) -Benzamide ;. N- [(6R) -hexahydro-4- [(4-nitrophenyl) methyl] -5-oxo-1,4-thiazepin-6yl] -4- (phosphonooxy) -Benzamide;
. N- [ (6R) -hexahydro-5-oxo-4- [3- [ (4-phenylpiperazin-l- yl) sulfonyl] propyl] -1, 4-thiazepin-6yl] -4- (phosphonooxy) - Benzamide ;. N- [(6R) -hexahydro-5-oxo-4- [3- [(4-phenylpiperazin-1-yl) sulfonyl] propyl] -1, 4-thiazepin-6yl] -4- (phosphonooxy) - Benzamide;
. 4- (phosphonooxy) -N- [ (6R)-4-[3-[ (4- thiomorpholinyl) sulfonyl] propyl] -hexahydro-5-oxo-l, 4- thiazepin-6-yl] -Benzamide ; . N- [ (6R) -4- [3- [ (butylmethylamino) suifonyl] propyl] - hexahydro-5-oxo-l, 4-thiazepin-6-yl] -4- (phosphonooxy) - Benzamide ;. 4- (phosphonooxy) -N- [(6R) -4- [3- [(4-thiomorpholinyl) sulfonyl] propyl] -hexahydro-5-oxo-1,4-thiazepin-6-yl] -Benzamide; . N- [(6R) -4- [3- [(butylmethylamino) suifonyl] propyl] - hexahydro-5-oxo-1,4-thiazepin-6-yl] -4- (phosphonooxy) - Benzamide;
. Acide 4- [2- (acétylamino) -3- [ [ (6R) -hexahydro-5-oxo-4- [ [4- (trifluoromethoxy) phényl] méthyl] -1, 4-thiazepin-6-yl] amino] -3- oxo-1-propenyl] -2- [ [ (aminocarbonyl) hydrazono]méthyl] -alpha- fluoro-Benzeneacetique ;. 4- [2- (acetylamino) -3- [[(6R) -hexahydro-5-oxo-4- [[4- (trifluoromethoxy) phenyl] methyl] -1,4-thiazepin-6-yl] amino acid] -3- oxo-1-propenyl] -2- [[(aminocarbonyl) hydrazono] methyl] -alphafluoro-benzeneacetic;
. N- [ ( 6R) -4- [3- [ (cyclohexylmethylamino) suifonyl] propyl] - hexahydro-5-oxo-l, 4-thiazepin-6-yl] -4- (phosphonooxy) - Benzamide ; . 1- [ [3- [ (6R) -[[ [4- (phosphonooxy) phényl] carbonyl] amino] -5- oxo-hexahydro-1, 4-thiazepin-4-yl] propyl] sulfonyl] - tetrahydro-lH-pyrrole-2-carboxylate de méthyle ;. N- [(6R) -4- [3- [(cyclohexylmethylamino) suifonyl] propyl] - hexahydro-5-oxo-1,4, thiazepin-6-yl] -4- (phosphonooxy) - Benzamide; . 1- [[3- [(6R) - [[[4- (phosphonooxy) phenyl] carbonyl] amino] -5- methyl oxo-hexahydro-1,4-thiazepin-4-yl] propyl] sulfonyl] - methyl tetrahydro-1H-pyrrole-2-carboxylate;
. acide [ [ [4- [ [ [ (6R) -4- [ (6-chloro-l, 3-benzodioxolan-5- yl) méthyl] -hexahydro-5-oxo-l, -thiazepin-6- yl] amino] carbonyl] phényl] amino] carbonyl] -Phosphonique ; . N2-acetyl-N-[ (6R)-4-[ [2 ' -cyano- (1, 1 ' -biphenyl) -4- yl]methyl] -hexahydro-5-oxo-l, 4-thiazepin-6-yl] -4- (phosphonooxy) Phenylalaninamide ;. acid [[[4- [[[(6R) -4- [(6-chloro-1,3-benzodioxolan-5-yl) methyl] -hexahydro-5-oxo-l, -thiazepin-6- yl] amino ] carbonyl] phenyl] amino] carbonyl] -Phosphonic; . N2-acetyl-N- [(6R) -4- [[2 '-cyano- (1, 1' -biphenyl) -4- yl] methyl] -hexahydro-5-oxo-l, 4-thiazepin-6- yl] -4- (phosphonooxy) Phenylalaninamide;
. acide [[ [4- [[[ (6R) -4- [[ (1, 1 ' -biphenyl) -4-yl] méthyl] - hexahydro-5-oxo-l, 4-thiazepin-6- yl] amino] carbonyl] phényl] amino] carbonyl] -Phosphonique ;. acid [[[4- [[[(6R) -4- [[(1,1 '-biphenyl) -4-yl] methyl] - hexahydro-5-oxo-1,4-thiazepin-6- yl] amino ] carbonyl] phenyl] amino] carbonyl] -Phosphonic;
. acide [ [ [4- [ [ [ ( 6R) -hexahydro-5-oxo-4- [ [4- (trifluoromethoxy) phényl]méthyl] -1, 4-thiazepin-6- yl] amino] carbonyl] phényl] amino] carbonyl] -Phosphonique ; . acide [ [ [4- [ [ [ ( 6R) -hexahydro-5-oxo-4- [ [4-. acid [[[4- [[[(6R) -hexahydro-5-oxo-4- [[4- (trifluoromethoxy) phenyl] methyl] -1,4-thiazepin-6-yl] amino] carbonyl] phenyl] amino ] carbonyl] -Phosphonic; . acid [[[4- [[[(6R) -hexahydro-5-oxo-4- [[4-
(trifluorométhyl) phényl] méthyl] -1, 4-thiazepin-6- yl] amino] carbonyl] phényl] amino] carbonyl] -Phosphonique ;(trifluoromethyl) phenyl] methyl] -1, 4-thiazepin-6-yl] amino] carbonyl] phenyl] amino] carbonyl] -Phosphonic;
. 4, 5-dihydroxy-N- [ (6R) -hexahydro-5-oxo-4- (3-phenyl-2- propenyl) -1, 4-thiazepin-6-yl] -Benzamide ; . N- [ (6R) -hexahydro-5-oxo-4- (3-phenyl-2-propenyl) -1, 4- thiazepin-6-yl] -4- (phosphonooxy) - Benzamide sel (trihydroxymethyl) methanamine ;. 4,5-dihydroxy-N- [(6R) -hexahydro-5-oxo-4- (3-phenyl-2-propenyl) -1,4-thiazepin-6-yl] -Benzamide; . N- [(6R) -hexahydro-5-oxo-4- (3-phenyl-2-propenyl) -1,4-thiazepin-6-yl] -4- (phosphonooxy) - Benzamide salt (trihydroxymethyl) methanamine;
. N2-acetyl-N- [ (6R) -hexahydro-5-oxo-4- [3- [ (4- phenylpiperazin-1-yl) sulfonyl] propyl] -1, 4-thiazepin-6-yl] -4- (phosphonooxy) Phenylalaninamide ; . N2-acetyl-N-[ (6R)-4-[3- [ (butylmethylamino) sulfonyl] propyl] -hexahydro-5-oxo-l, 4- thiazepin-6-yl] -4- (phosphonooxy) Phenylalaninamide ;. N2-acetyl-N- [(6R) -hexahydro-5-oxo-4- [3- [(4- phenylpiperazin-1-yl) sulfonyl] propyl] -1, 4-thiazepin-6-yl] -4- (phosphonooxy) Phenylalaninamide; . N2-acetyl-N- [(6R) -4- [3- [(butylmethylamino) sulfonyl] propyl] -hexahydro-5-oxo-1,4-thiazepin-6-yl] -4- (phosphonooxy) Phenylalaninamide;
. acide [ [ [4- [ [ [ (6R) -4- [ (4-bromophenyl) méthyl] -hexahydro-5- oxo-1, 4-thiazepin-6-yl] amino] carbonyl] phényl] amino] carbonyl] - Phosphonique ;. acid [[[4- [[[(6R) -4- [(4-bromophenyl) methyl] -hexahydro-5-oxo-1, 4-thiazepin-6-yl] amino] carbonyl] phenyl] amino] carbonyl] - Phosphonic;
. 4- (phosphonooxy) -N- [ (6R) -hexahydro-5-oxo-4- [ (6-chloro- 1, 3-benzodioxolan-5-yl) méthyl] -1, 4-thiazepin-6-yl] - Benzamide ; . N-[ (6R)-hexahydro-5-oxo-4-[ [4- (phenylcarbonyl) phényl] méthyl] -1, 4-thiazepin-6-yl] -4- (phosphonooxy) - Benzamide ;. 4- (phosphonooxy) -N- [(6R) -hexahydro-5-oxo-4- [(6-chloro- 1,3-benzodioxolan-5-yl) methyl] -1,4-thiazepin-6-yl] - Benzamide; . N- [(6R) -hexahydro-5-oxo-4- [[4- (phenylcarbonyl) phenyl] methyl] -1,4-thiazepin-6-yl] -4- (phosphonooxy) - Benzamide;
. N- [ (6R) -4- [ (3-chlorophenyl)methyl] -hexahydro-5-oxo-l, 4- thiazepin-6-yl] -4- (phosphonooxy) - Benzamide ; . N-[ (6R)-hexahydro-5-oxo-4 [ [ (4- trifluoromethoxy) phényl] méthyl] -4- (phosphonooxy) - Benzamide ;. N- [(6R) -4- [(3-chlorophenyl) methyl] -hexahydro-5-oxo-1,4-thiazepin-6-yl] -4- (phosphonooxy) - Benzamide; . N- [(6R) -hexahydro-5-oxo-4 [[((4-trifluoromethoxy) phenyl] methyl] -4- (phosphonooxy) - Benzamide;
. 4-[ [ (6R)-6-[ [ (3S) -2- (acétylamino) -l-oxo-3- [4- (phosphonooxy) phényl] -1-propyl] amino] -hexahydro-5-oxo-l, 4- thiazepin-4-yl]methyl] -Benzoate de méthyle ;. 4- [[(6R) -6- [[(3S) -2- (acetylamino) -1-oxo-3- [4- (phosphonooxy) phenyl] -1-propyl] amino] -hexahydro-5-oxo- 1,4-thiazepin-4-yl] methyl] -Methyl benzoate;
. (6R)-4-(3-phenyl-2-propenyl)-6-[ [ [4- (phosphonooxy) phényl] méthyl] amino] -1, 4-thiazepin-5 (2H) -one ;. (6R) -4- (3-phenyl-2-propenyl) -6- [[[4- (phosphonooxy) phenyl] methyl] amino] -1, 4-thiazepin-5 (2H) -one;
. (6R)-4-(3-phenylpropyl)-6-[ [ [4- (phosphonooxy) phényl] méthyl] amino] -1, 4-thiazepin-5 (2H) -one ; . N2-acetyl-N-[ (6R)-4-[ (5-chloro-l, 3-benzodioxolan-6- yl)methyl] -hexahydro—5-oxo-l, 4-thiazepin-6-yl] -4- (phosphonooxy) -L-Phenylalaninamide ;. (6R) -4- (3-phenylpropyl) -6- [[[4- (phosphonooxy) phenyl] methyl] amino] -1,4-thiazepin-5 (2H) -one; . N2-acetyl-N- [(6R) -4- [(5-chloro-1,3-benzodioxolan-6- yl) methyl] -hexahydro — 5-oxo-1,4-thiazepin-6-yl] -4 - (phosphonooxy) -L-Phenylalaninamide;
. N2-acétyl-N-[ (6R)-4-[ [- (1, 1 ' -biphényle) -4-yl)methyl] - hexahydro-5-oxo-l, 4-thiazepin-6-yl] -4- (phosphonooxy) -L- Phenylalaninamide ;. N2-acetyl-N- [(6R) -4- [[- (1,1 '-biphenyl) -4-yl) methyl] - hexahydro-5-oxo-1,4, thiazepin-6-yl] -4 - (phosphonooxy) -L- Phenylalaninamide;
. N2-acétyl-N-[ ( 6R) -hexahydro-5-oxo-4- [ [4- (phenylecarbonyl) phényl) méthyl] -1, 4-thiazepin-6-yl] -4- (phosphonooxy) -L-Phenylalaninamide ;. N2-acetyl-N- [(6R) -hexahydro-5-oxo-4- [[4- (phenylecarbonyl) phenyl) methyl] -1, 4-thiazepin-6-yl] -4- (phosphonooxy) -L- Phenylalaninamide;
. 4- (acetyloxy) -N- [ (6R) -hexahydro-4- (3-phenyl-2-propenyl) -5- oxo-1, 4-thiazepin-6-yl] Benzamide ;. 4- (acetyloxy) -N- [(6R) -hexahydro-4- (3-phenyl-2-propenyl) -5-oxo-1, 4-thiazepin-6-yl] Benzamide;
. N- [4- [ [ [ (6R) hexahydro-5-oxo-4- (3-phenyl-2-propenyl) -1, 4- thiazepin-6-yl] amino] carbonyl] phényl] -N- (2-hydroxy-2-oxo- ethyl) -Glycine ;. N- [4- [[[(6R) hexahydro-5-oxo-4- (3-phenyl-2-propenyl) -1, 4 thiazepin-6-yl] amino] carbonyl] phenyl] -N- (2 -hydroxy-2-oxoethyl) -Glycine;
. 3, 5-bis (acetyloxy) -N- [ ( 6R) -hexahydro-4- (3-phenyl-2- propenyl) -5-oxo-l, 4-thiazepin-6-yl] Benzamide ;. 3,5-bis (acetyloxy) -N- [(6R) -hexahydro-4- (3-phenyl-2-propenyl) -5-oxo-1,4-thiazepin-6-yl] Benzamide;
. 2- [3- [ [ [ (6R) -hexahydro-5-oxo-4- (3-phenyl-2-propenyl) -1,4- thiazepin-6-yl] amino] carbonyl] phénoxy] - acétate de méthyle ;. 2- [3- [[[(6R) -hexahydro-5-oxo-4- (3-phenyl-2-propenyl) -1,4- thiazepin-6-yl] amino] carbonyl] phenoxy] - methyl acetate ;
. acide 2- [3- [ [ [ (6R) -hexahydro-5-oxo-4- (3-phenyl-2- propenyl) -1, 4-thiazepin-6-yl] amino] carbonyl] phénoxy] - acétique ; ainsi que leurs sels physiologiquement acceptables et leurs promédicaments (prodrugs). acid 2- [3- [[[(6R) -hexahydro-5-oxo-4- (3-phenyl-2-propenyl) -1, 4-thiazepin-6-yl] amino] carbonyl] phenoxy] - acetic; as well as their physiologically acceptable salts and their prodrugs (prodrugs)
14) Un procédé de préparation des composés de formule (I) tels que définis à l'une quelconque des revendications 1 à 13, qui comprend le couplage de deux ou plusieurs fragments qui peuvent être dérivés par rétrosynthèse des composés de formule (I) .14) A process for preparing the compounds of formula (I) as defined in any one of claims 1 to 13, which comprises the coupling of two or more fragments which can be derived by retrosynthesis of the compounds of formula (I).
15) Procédé de préparation des composés de formule (I) caractérisé en ce que on soumet une aminé de formule (II]15) Process for preparing the compounds of formula (I) characterized in that an amine of formula (II) is subjected
Figure imgf000139_0001
Figure imgf000139_0001
dans laquelle Ri, R2, X, R3 et R4 sont tels que définis à la revendication 1 pour la formule (I) et où, le cas échéant, les groupes fonctionnels sont sous forme de précurseurs ou sous forme protégée, a) soit d'abord à l'action d'un acide ou un dérivé d'acide de formule (III)in which Ri, R 2 , X, R 3 and R 4 are as defined in claim 1 for formula (I) and where, where appropriate, the functional groups are in the form of precursors or in protected form, a) either first to the action of an acid or an acid derivative of formula (III)
X'-U-[Aι]-A2 X'-U- [Aι] -A 2
dans laquelle [Ai] , A2 et U sont tels que définis à la revendication 1 dans la formule (I) et X ' est un groupe substituable par un nucleophile et où, le cas échéant, les groupes fonctionnels sont sous forme de précurseurs ou sous forme protégée, , afin d'obtenir un composé de formule (III1)in which [Ai], A 2 and U are as defined in claim 1 in formula (I) and X 'is a group substitutable by a nucleophile and where, where appropriate, the functional groups are in the form of precursors or in protected form,, in order to obtain a compound of formula (III 1 )
Figure imgf000139_0002
puis à l'action de R5-Hal en présence d'une base, R5 étant tel que défini à la revendication 1 et Hal étant de préférence un chlore ou un brome b) soit, d'abord à l'action d'un composé de formule Rs-Hal, en présence d'une base afin d'obtenir le composé de formule (III")
Figure imgf000139_0002
then to the action of R 5 -Hal in the presence of a base, R5 being as defined in claim 1 and Hal being preferably a chlorine or a bromine b) either, first of all to the action of a compound of formula Rs-Hal, in the presence of a base in order to obtain the compound of formula (III ")
Figure imgf000140_0001
Figure imgf000140_0001
puis à l'action d'un dérivé de formule (III)then to the action of a derivative of formula (III)
X'-U-[Aι]-A2 X'-U- [Aι] -A 2
lesdits groupes fonctionnels éventuellement présents sous forme de précurseur ou sous forme protégée, étant par la suite convertis en groupes présents dans les composés de formule (I), certains composés de formule (I) pouvant si désiré ou si nécessaire, subir une ou plusieurs des réactions suivantes dans un ordre approprié :said functional groups possibly present in the form of a precursor or in protected form, being subsequently converted into groups present in the compounds of formula (I), certain compounds of formula (I) being able, if desired or if necessary, to undergo one or more of the following reactions in an appropriate order:
- action d'un agent de déprotection partielle, - action d'un agent de déprotection totale,- action of a partial deprotection agent, - action of a total deprotection agent,
- action de H-P(O) (ORd) (ORe) lorsque A2 représente OH,- action of HP (O) (ORd) (ORe) when A 2 represents OH,
- saponification puis décarboxylation du dérivé malonique,- saponification then decarboxylation of the malonic derivative,
- réduction de la double liaison que peut renfermer [Ai]- reduction of the double bond that may contain [Ai]
- séparation des enantiomeres ou des diastereoisomeres - saufication. 16) Procédé tel que décrit plus haut dans lequel le composé de formule (III) est choisi parmi les tyrosines phosphatées suivantes :- separation of enantiomeres or diastereoisomeres - exceptication. 16) Process as described above in which the compound of formula (III) is chosen from the following phosphate tyrosines:
N-Boc-Tyr-O- ( P03Bn2 ) , N-Ac-Tyr-O- ( P03Bn2 ) ,N-Boc-Tyr-O- (P0 3 Bn 2 ), N-Ac-Tyr-O- (P0 3 Bn 2 ),
N-Boc-Tyr-CF2- ( P03Et2 ) , N-Ac-Tyr-CF2- ( P03Et2 ) ou les dérivés benzoiques (Illa, IIIc) ou benzénique (Illb,N-Boc-Tyr-CF 2 - (P0 3 Et 2 ), N-Ac-Tyr-CF 2 - (P0 3 Et 2 ) or the benzoic derivatives (Illa, IIIc) or benzene (Illb,
Illd) suivants :Illd) following:
Figure imgf000141_0001
Figure imgf000141_0001
(IIIc)(IIIc)
Figure imgf000141_0002
Figure imgf000141_0002
(Illd)(Illd)
dans lesquels R"f représente un atome d'hydrogène, de fluor ou C02Rd, R"g représente un atome d'hydrogène ou de fluor et Z" représente NHCORb ou NHC02Rb, R6 est tel que défini à la revendication 1, le composé de formule (Illb) présentant une configuration E ou Z . 17) A titre de médicament, un composé de formule (I) et/ou ses sels physiologiquement acceptables et/ou ses prodrugs tel que défini à l'une quelconque des revendications 1 à 13.in which R "f represents a hydrogen, fluorine or C0 2 Rd atom, R" g represents a hydrogen or fluorine atom and Z "represents NHCORb or NHC0 2 Rb, R 6 is as defined in claim 1, the compound of formula (IIIb) having an E or Z configuration. 17) As a medicament, a compound of formula (I) and / or its physiologically acceptable salts and / or its prodrugs as defined in any one of claims 1 to 13.
18) Une composition pharmaceutique comprenant au moins un composé de formule (I) tel que défini à l'une quelconque des revendications 1 à 13 et/ou ses sels physiologiquement acceptables et/ou ses prodrugs ainsi qu'un ou plusieurs excipients pharmaceutiquement acceptables et éventuellement un ou plusieurs additifs.18) A pharmaceutical composition comprising at least one compound of formula (I) as defined in any one of claims 1 to 13 and / or its physiologically acceptable salts and / or its prodrugs as well as one or more pharmaceutically acceptable excipients and possibly one or more additives.
19) A titre de médicament selon la revendication 17 un composé de formule (I) et/ou ses sels physiologiquement acceptables et/ou ses prodrugs tel que défini à l'une quelconque des revendications 1 à 13 ayant une activité inhibitrice du récepteur Src SH2.19) As a medicament according to claim 17, a compound of formula (I) and / or its physiologically acceptable salts and / or its prodrugs as defined in any one of claims 1 to 13 having an inhibitory activity on the Src SH2 receptor .
20) A titre de médicament selon la revendication 17, un composé de formule (I) et/ou ses sels physiologiquement acceptables et/ou ses prodrugs tel que défini à l'une quelconque des revendications 1 à 13 ayant une activité inhibitrice de la résorption osseuse ou pour le traitement ou la prévention de 1 ' osteoporose .20) As a medicament according to claim 17, a compound of formula (I) and / or its physiologically acceptable salts and / or its prodrugs as defined in any one of claims 1 to 13 having a resorption inhibiting activity bone or for the treatment or prevention of osteoporosis.
21) A titre de médicament selon la revendication 17 un composé de formule (I) et/ou ses sels physiologiquement acceptables et/ou ses prodrugs tel que défini à l'une quelconque des revendications 1 à 13 pour le traitement ou la prévention de l'immunité, de l'infection, de l'allergie, et des maladies autoimmunes, .21) As a medicament according to claim 17, a compound of formula (I) and / or its physiologically acceptable salts and / or its prodrugs as defined in any one of claims 1 to 13 for the treatment or prevention of immunity, infection, allergy, and autoimmune diseases,.
22) A titre de médicament selon la revendication 17 un composé de formule (I) et/ou ses sels physiologiquement acceptables et/ou ses prodrugs tel que défini à l'une quel- conque des revendications 1 à 13 pour le traitement ou la prévention de maladies telles que les maladies prolifératives, le cancer, la resténose, l'inflammation, les allergies ou les maladies cardiovasculaires.22) As a medicament according to claim 17, a compound of formula (I) and / or its physiologically acceptable salts and / or its prodrugs as defined in any one of claims 1 to 13 for treatment or prevention of diseases such as diseases proliferative, cancer, restenosis, inflammation, allergies or cardiovascular disease.
23) Utilisation des composés de formule (I) et/ou leurs sels physiologiquement acceptables et/ou leurs prodrugs tels que définis à l'une quelconque des revendications 1 à 13 pour la préparation de médicaments destinés à la prévention ou au traitement de 1 ' osteoporose.23) Use of the compounds of formula (I) and / or their physiologically acceptable salts and / or their prodrugs as defined in any one of claims 1 to 13 for the preparation of medicaments intended for the prevention or treatment of 1 ' osteoporosis.
24) Utilisation des composés de formule (I) et/ou leurs sels physiologiquement acceptables et/ou leurs prodrugs tels que définis à l'une quelconque des revendications 1 à 13 pour la préparation de médicaments destinés au traitement ou à la prévention de l'immunité, de l'infection, de l'allergie, et des maladies autoimmunes.24) Use of the compounds of formula (I) and / or their physiologically acceptable salts and / or their prodrugs as defined in any one of claims 1 to 13 for the preparation of medicaments intended for the treatment or prevention of immunity, infection, allergy, and autoimmune diseases.
25) Utilisation des composés de formule (I) et/ou leurs sels physiologiquement acceptables et/ou leurs prodrugs tels que définis à l'une quelconque des revendications 1 à 13 pour la préparation de médicaments destinés au traitement ou à la prévention de maladies telles que les maladies prolifératives, le cancer, la resténose, l'inflammation, les allergies ou les maladies cardiovasculaires.25) Use of the compounds of formula (I) and / or their physiologically acceptable salts and / or their prodrugs as defined in any one of claims 1 to 13 for the preparation of medicaments intended for the treatment or prevention of diseases such as proliferative diseases, cancer, restenosis, inflammation, allergies or cardiovascular disease.
26) Intermédiaires de formules (III') et (III") tels que définis à la revendications 15. 26) Intermediaries of formulas (III ') and (III ") as defined in claims 15.
PCT/FR1999/001770 1998-07-21 1999-07-20 Thioazepinone derivatives, preparation method and intermediates therefor, use as medicines and pharmaceutical compositions containing same WO2000005246A1 (en)

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FR9809258A FR2781483A1 (en) 1998-07-21 1998-07-21 Thioazepinone derivatives having Src domain SH2 inhibiting and osteoclast-mediated calcium resorption from bone inhibiting activity, for treatment of osteoporosis
FR98/09258 1998-07-21

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FR2796381A1 (en) * 1999-07-12 2001-01-19 Hoechst Marion Roussel Inc Thiazepin and caprolactam bicyclic derivatives, useful in the treatment of e.g. osteoporosis and other bone disorders, infections, allergies or cancers
WO2005114197A2 (en) * 2004-04-15 2005-12-01 Albert Einstein College Of Medicine Of Yeshiva University Activity-based probes for protein tyrosine phosphatases
US7229983B2 (en) 2003-04-28 2007-06-12 Wyeth Holdings Corporation 4-substituted or unsubstituted-7-hydro-1,4-thiazepine-7-[bicyclic or tricyclic heteroaryl] substituted-3,6-dicarboxylic acid derivatives as β-lactamase inhibitors
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CN103232373A (en) * 2013-05-15 2013-08-07 武汉大学 Chiral sulfur-containing compound with hexafluoroisopropyl ester based structure as well as synthetic method and application of compound
US9815850B2 (en) 2016-02-05 2017-11-14 Denali Therapeutics Inc. Compounds, compositions and methods
JP2018150372A (en) * 2013-02-15 2018-09-27 グラクソスミスクライン、インテレクチュアル、プロパティー、ディベロップメント、リミテッドＧｌａｘｏｓｍｉｔｈｋｌｉｎｅ Ｉｎｔｅｌｌｅｃｔｕａｌ Ｐｒｏｐｅｒｔｙ Ｄｅｖｅｌｏｐｍｅｎｔ Ｌｉｍｉｔｅｄ Heterocyclic amides as kinase inhibitors
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CN103232373B (en) * 2013-05-15 2014-09-03 武汉大学 Chiral sulfur-containing compound with hexafluoroisopropyl ester based structure as well as synthetic method and application of compound
US9815850B2 (en) 2016-02-05 2017-11-14 Denali Therapeutics Inc. Compounds, compositions and methods
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US11072618B2 (en) 2016-12-09 2021-07-27 Denali Therapeutics Inc. Compounds, compositions and methods

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