Patent EA-005072-B1 (EA)
Title: Purine derivatives, preparation method and pharmaceutical compositions containing same
Inventor: HAESSLEIN JEAN-LUC
IPC: A61K31/52
Filed: 2000-05-18
Abstract: 1. A compound of formula (I) wherein: Z represents a bivalent -CH2-, -SO2-, -CO-, -COO-, -CONH- or -(CH2)2-NR3-; n represents 0 or 1; R1 is selected from hydrogen, aryl, -CH2-aryl, -SO2-aryl, -CO-aryl, heterocyclic, -CH2- heterocyclic, alkyl and -SO2-alkyl; R2 represents optionally substituted linear or branched alkyl, containing up to 10 carbon atoms, cycloalkyl or saturated or unsaturated heterocycle formed by not more than 6 rings of which one or a plurality of rings are represented by an oxygen atom, a sulphur atom or NR3; Y represents an oxygen atom, a sulphur atom or NR3; D1 and D2 either, identical or different, are selected among a hydrogen atom, hydroxyl, linear or branched alkyl and alkoxy containing up to 6 carbon atoms and NHR5, or together form =O, or =N-OR4; R3 represents a hydrogen atom, alkyl or cycloalkyl; R4 represents a hydrogen atom, alkyl, cycloalkyl or aryl; R5 represents a hydrogen atom, alkyl, cycloalkyl or -COO-t-bu; R6 represents a hydrogen atom, a halogen atom, hydroxyl, alkyl, alkoxy, linear or branched, containing up to 6 carbon atoms or NHR3; all the defined above cycloalkyls contain up to 6 carbon atoms; all the defined above alkyls, being linear or branched, contain up to 6 carbon atoms; all the defined above cycloalkyl, alkyl, aryl and heterocycle may be substituted by one or a plurality of radicals selected from halogen atoms, hydroxyl, cyano, nitro, aryl, trifluoromethyl, trifluoromethoxy, alkoxy, containing up to 6 carbon atoms, -NHR4, -COR4, -COOR4 and -CONHR4, in which R4 as defined above, and radicals with acid functions or acid isoster representing free, converted in salt or esterified carboxy radical, free, converted in salt tetrazolylradical or radicals: -SO3H, -PO(OH)2, NH-SO2-CF3, -NH-SO2-NH-V, -NH-SO2-NH-CO-V, -NH-CO-V, -NH-CO-NH-V, NH-CO-NH-SO2-V, -SO2-NH-V, -SO2-NH-CO-V, SO2-NH-CO-NH-V, -CO-NH-V, -CO-NH-OH, -CO-NH-SO2-V, in which V represents a hydrogen atom, linear or branched alkyl or alkenyl containing up to 6 carbon atoms, phenyl or thiazolyl, wherein representing V alkyl, alkenyl and phenyl may be substituted by substituents defined above for alkyl and aryl radicals, all defined above aryl and heterocyclic radicals may be also substituted by one or a plurality of alkyl radicals containing up to 6 carbon atoms and, optionally substituted by a CN radical or a COOR4 radical, in which R4 as defined above; all defined above aryl radicals may be also substituted by a dioxol radical, -S-alkyl radical, containing up to 6 carbon atoms, or aryl radical or cycloalkyl, containing up to 6 carbon atoms interrupted by one or a plurality of heteroatoms, selected from oxygen, nitrogen and sulfur atoms; wherein the heterocyclic radical represents a saturated or unsaturated carbocyclic radical, formed not more than 6 rings interrupted by one or a plurality of different heteroatoms selected from oxygen, nitrogen and sulfur atoms; provided that if Z represents -CH2-, n represents 0 or 1, R1represents aryl, -CH2-aryl, heterocyclic radical, -CH2-heterocyclic radical or alkyl, Y represents NR3, and R2, R3, R4 and R5 as defined above, then either D1 and D2 form together (O radical or (N-OR4, or one of D1, D2 and R6 differs a hydrogen atom, halogen, alkyl or alkoxyl, wherein the compounds of formula I exist in all possible isomeric forms: racemic, enantomeric, and diastereoisomeric as well as in the form of salt an additive product with mineral and organic acids or inorganic and organic bases of said compounds of formula I. 2. A compound of formula (I) defined in claim 1, corresponding to formula Ia: wherein: Za represents a bivalent -CH2-, -SO2-, -CO- or -(CH2)2-NR3a-; n represents 0 or 1; R1a is selected from a hydrogen atom and phenyl radicals, CH2-phenyl, -CO-phenyl, -SO2-phenyl, pyridyl, -CH2-pyridyl, alkyl, and SO2-alkyl; R2a represents an alkyl radical, cycloalkyl or saturated or unsaturated heterocyclic radical, formed by 5 rings of which one or a plurality of rings are represented by an oxygen atom, a sulphur atom or NR3; Ya represents an oxygen atom, a sulphur atom or NR3a; D1a and D2a either, identical or different, are selected among a hydrogen atom, hydroxyl, linear or branched alkyl and alkoxy containing up to 6 carbon atoms and NHR5, or together form =O, or =N-OR4a; R3a represents a hydrogen atom, alkyl radical or cycloalkyl; R4a represents a hydrogen atom, alkyl radical, cycloalkyl or phenyl; R5a represents a hydrogen atom, alkyl radical, cycloalkyl or -COO-t-bu; R6a represents a hydrogen atom, a halogen atom, hydroxyl, alkyl, alkoxy, linear or branched, containing up to 6 carbon atoms or NHR3a; all the defined above cycloalkyls contain up to 6 carbon atoms; all the defined above alkyls, being linear or branched, contain up to 6 carbon atoms; all the defined above cycloalkyl, alkyl and phenyl may be substituted by one or a plurality of radicals selected from halogen atoms, hydroxyl, cyano, nitro, aryl, trifluoromethyl, trifluoromethoxy, alkoxy, containing up to 6 carbon atoms, -NHR4a, -COR4a, -COOR4a and -CONHR4a, in which R4a as defined above, and radicals: -SO3H, -PO(OH)2, NH-SO2-CF3, -NH-SO2-NH-V, -SO2-NH-V and -NH-SO2-NH-CO-V, in which V represents a hydrogen atom, phenyl, thiazolyl, alkyl or alkenyl of which alkyl or alkenyl are linear or branched containing up to 6 carbon atoms a -S-alkyl radical, containing up to 6 carbon atoms, or aryl radical or cycloalkyl, containing up to 6 carbon atoms interrupted by one or a plurality of heteroatoms, selected from oxygen, nitrogen and sulfur atoms, and a dioxol radical; wherein the compounds of formula Ia exist in all possible isomeric forms: racemic, enantomeric, and diastereoisomeric as well as in the form of salt an additive product with mineral and organic acids or inorganic and organic bases of said compounds of formula Ia. 3. A compound of formula (I) defined in claim 1, corresponding to formula Ib: wherein: Zb represents a bivalent -CH2-, -SO2-, -CO-, or -(CH2)2-NR3b-; n represents 0 or 1; R1b is selected from a hydrogen atom and phenyl radicals, CH2-phenyl, -CO-phenyl, -SO2-phenyl, pyridyl, -CH2-pyridyl, alkyl, and SO2-alkyl, in which alkyl radical contains up to 4 carbon atoms and alkyl and phenyl may be substituted as defined below; R2b represents linear or branched alkyl radical containing up to 6 carbon atoms, cycloalkyl radical containing up to 6 carbon atoms, tetrahydrofuryl radical tetrahydrothienyl, pyrrolinyl or pyrrolidinyl; Ya represents an oxygen atom or NR3b; D1b and D2b either, identical or different, are selected among a hydrogen atom, hydroxyl, linear or branched alkyl and alkoxy containing up to 4 carbon atoms and NHR5, or together form =O, or =N-OR4b; R3b represents a hydrogen atom, alkyl radical containing up to 4 carbon atoms, cycloalkyl containing up to 6 carbon atoms or -CH2-phenyl; R4b represents a hydrogen atom, alkyl radical containing up to 4 carbon atoms, phenyl, -CH2-phenyl or cycloalkyl radical containing up to 6 carbon atoms, optionally substituted by - NR3b; R5b represents a hydrogen atom, alkyl radical, cycloalkyl containing up to 6 carbon atoms or -COO-t-bu; all the defined above cycloalkyl, alkyl and phenyl may be substituted by one or a plurality of radicals selected from halogen atoms, hydroxyl radicals, cyano, nitro, phenyl, trifluoromethyl, trifluoromethoxy, alkoxy, containing up to 4 carbon atoms, carboxy-free, in the form of a salt or esterified, -NHR4b, -COR4b- and -CONHR4b, in which R4b as defined above, and radicals:-SO3H, -PO(OH)2, NH-SO2-CF3 and -SO2-NH-thiazolyl; all the defined above phenyl radicals may be also substituted by one or a plurality of radicals selected from alkyl radicals containing up to 4 carbon atoms and optionally substituted by a CN radical or COOR4b, in which R4b as defined above, a -S-alkyl radical, containing up to 4 carbon atoms, a tetrazolyl radical, a cycloalkyl radical, which may include in the cycle one or a plurality of atoms selected from oxygen and nitrogen atoms, and a dioxol radical; wherein the compounds of formula Ib exist in all possible isomeric forms: racemic, enantomeric, and diastereoisomeric as well as in the form of salt an additive product with mineral and organic acids or inorganic and organic bases of said compounds of formula Ib. 4. A compound of formula (I) defined in claim 1, corresponding to formula Ic: Zc represents a bivalent -CH2-, -SO2-, -CO-, -(CH2)2-NH-, or -(CH2)2-N-alkyl, -(CH2)2-CH2-phenyl, in which a phenyl radical may be substituted by a halogen atom, a hydroxyl radical, trifluoromethyl, alkoxy containing up to 4 carbon atoms, carboxy-free, in the form of a salt or esterified, n represents 0 or 1; R1c is selected from a hydrogen atom and phenyl radicals, CH2-phenyl, -CO-phenyl, pyridyl, alkyl, and SO2-alkyl, in which alkyl radical contains up to 4 carbon atoms and or may be substituted by a carboxy-radical-free in the form of a salt or esterified, and all phenyl radicals may be substituted by one or a plurality of radicals selected from halogen atoms, hydroxyl radicals, cyano, nitro, phenyl, trifluoromethyl, trifluoromethoxy, thioalkyl and alkoxy, containing up to 4 carbon atoms, alkyl containing up to 4 carbon atoms and optionally substituted by a cyano radical, -COOH or COOalk, phenyl radicals tetrazolyl, cycloalkyl, the cycle of which may include one or a plurality of oxygen or nitrogen atoms, -SO2NH2 radical and SO2-NH-thiazolyl, dioxol radicals, carboxy-free, esterified or in the form of a salt and -NHR4c and -CONHR4c radicals, in which R4c represents a hydrogen atom, an alkyl radical containing up to 4 carbon atoms, or a cyclohexyl radical, which may be substituted by a NH2 radical; R2c represents linear or branched alkyl radical containing up to 6 carbon atoms, cycloalkyl radical containing up to 6 carbon atoms, cyclopentyl radicals, tetrahydrofuryl or a tetrahydrothienyl radical; Yc represents an oxygen atom or a -NH radical or -N-alkyl, in which linear or branched alkyl radical contains up to 4 carbon