Patent EA-004649-B1 (EA)
Title: Pharmaceutical compositions containing 3-amino-azeitidine derivatives, novel derivatives and preparation thereof
Inventor: ACHARD DANIEL
IPC: A61K31/4025
Filed: 2001-03-01
Abstract: 1. A pharmaceutical compositions containing as active ingredient a compound of formula (I): wherein: R1 represents a -NHCOR4 or -N(R5)-Y-R6 radical; Y is CO or SO2; R2 and R3, identical or different, represent either an aromatic radical selected from phenyl, naphtyl and indenyl, these aromatic radicals being unsubstituted or substituted with one or more substituents: halogen, alkyl, alcoxy, formyl, hydroxy, trifluoromethyl, trifluoromethoxy, -CO-alk, cyano, -COOH, -COOalk, -CONR7R8, -CO-NH-NR9R10, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, hydroxyalkyl, or -alk-NR7R8; or a heteroaromatic radical selected from cycles: benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromannyl, 2, 3-dihydrobenzofuryl, 2, 3-dihydrobenzothienyl, pyrimidinyl, furyl, imidazolyl, isochromannyl, isoquinolyl, pyrrolyl, pyridyl, quinolyl, 1, 2, 3,4-tetrahydroisoquinolyl, thiazolyl and thienyl, it being possible for these heteroaromatic radicals to be unsubstituted or substituted with halogen, alkyl, alcoxy, hydroxy, trifluoromethyl, trifluoromethoxy, cyano, -COOH, -COOalk, -CO-NH-NR9R10, -CONR7R8, -alk-NR9R10, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl or hydroxyalkyl; R4 represents a radical -alk-SO2-R11-alk-SO2-CH=CH-R11, Het substituted with -SO2-R11 or phenyl substituted with -SO2-R11 or -alk-SO2-R11, R5 represents a hydrogen atom or an alkyl radical; R6 represents a phenylalkyl radical, Het or Ar; R7 and R8, which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively R7 and R8 together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated mono- or bicyclic heterocycle, optionally further having another heteroatom selected from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl radicals; R9 and R10, which are identical or different, represent a hydrogen atom or an alkyl, -COOalk, cycloalkyl, alkylcycloalkyl, -alk-O-alk or hydroxyalkyl radical or alternatively R9 and R10 together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated or unsaturated mono- or bicyclic heterocycle, optionally further having another heteroatom selected from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl, -COalk, -COOalk, -CO-NHalk, -CS-NHalk, oxo, hydroxyalkyl, -alk-O-alk or -CO-NH2 radicals; R11 represents an alkyl, Ar or Het radical; Ar represents a phenyl, naphthyl or indenyl radical, these radicals being optionally substituted with one or more halogen atoms or alkyl, alkoxy, cyano, -CO-alk, -COOH, -COOalk, -CONR12R13, -CO-NH-NR14R15, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, -alk-NR14R15, -NR14R15, alkylthioalkyl, formyl, hydroxyl, hydroxyalkyl, Het, -O-alk-NH-cycloalkyl, OCF3, CF3, -NH-CO-alk, -SO2NH2, -NH-COCH3, -NH-COOalk or Het radicals or alternatively, a fused ring containing a 3-10 membered Het radical is formed on 2 adjacent carbon atoms, with a dioxymethylene, Het being an unsaturated or saturated mono- or bicyclic heterocycle having one or more heteroatoms selected from oxygen, sulfur and nitrogen optionally substituted with one or more halogen atoms or alkyl, alkoxy, vinyl, alkoxycarbonyl, oxo, hydroxyl, OCF3 or CF3 radicals, the nitrogen-containing heterocycles being optionally in their N-oxidized form; R12 and R13, which are identical or different, represent a hydrogen atom or an alkyl radical or, alternatively, R12 and R13 together with the nitrogen atom to which they are attached form a 3- to 10-membered saturated mono- or bicyclic heterocycle, optionally further having another heteroatom selected from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl radicals; R14 and R15, which are identical or different, represent a hydrogen atom or an alkyl, -COOalk, cycloalkyl, alkylcycloalkyl, -alk-O-alk or hydroxyalkyl radical or alternatively R14 and R15 together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated or unsaturated mono- or bicyclic heterocycle, optionally further having another heteroatom selected from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl, -COalk, -COOalk, -CO-NHalk, -CS-NHalk, oxo, hydroxyalkyl, -alk-O-alk or -CO-NH2 radicals; alk represents an alkyl or alkylene radical; the alkyl and alkylene radicals and portions and the alkoxy radicals and portions are in the form of a straight or branched chain having 1 to 6 carbon atoms and the cycloalkyl radicals have 3 to 10 carbon atoms; or the optical isomers thereof or pharmaceutically acceptable salts thereof. 2. The composition of claim 1 wherein, in the compound of formula (I), Het is selected from benzimidazole, benzoxazole, benzothiazole, benzothiophene, cinnoline, thiophene, quinazoline, quinoxaline, quinoline, pyrazole, pyrrole, pyridine, imidazole, indole, isoquinoline, pyrimidine, thiazole, thiadiazole, piperidine, piperazine, pyrrolidine, triazole, furan, tetrahydroisoquinoline, tetrahydroquinoline, these heterocycles being optionally substituted with one or more substituents selected from halogen, alkyl, alkoxy, vinyl, alkoxycarbonyl, oxo, hydroxyl, OCF3 and CF3 radicals. 3. A pharmaceutical composition of claim 1 containing as active ingredient at least a compound of formula (I) in which: R1 represents a radical -N(R5)-Y-R6; Y is SO2; R2 represents either a phenyl which is unsubstituted or substituted with one or more halogen atoms or alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, cyano, -CONR7R8 hydroxyalkyl or -alk-NR7R8 radicals; or a heteroaromatic radical selected from pyridyl, pyrimidyl, thiazolyl and thienyl rings, it being possible for these heteroaromatic radicals to be unsubstituted or substituted with a substituent selected from halogen, alkyl, alkoxy, hydroxyl, trifluoromethyl, trifluoromethoxy, -CONR7R8, -alk-NR9R10, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl and hydroxyalkyl radicals; R3 represents either a phenyl which is unsubstituted or substituted with one or more substituents selected from halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, cyano, -CONR7R8, hydroxyalkyl and -alk-NR7R8 radicals; or a heteroaromatic radical selected from pyridyl, pyrimidyl, thiazolyl and thienyl rings, it being possible for these heteroaromatic radicals to be unsubstituted or substituted with a substituent selected from halogen, alkyl, alkoxy, hydroxyl, trifluoromethyl, trifluoromethoxy, -CONR7R8, -alk-NR9R10, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl and hydroxyalkyl radical; R5 represents a hydrogen atom or an alkyl radical; R6 represents a naphthyl, phenylalkyl, Het or phenyl radical optionally substituted with one or more substituents selected from halogen, alkyl, alkoxy, cyano, -CO-alk, COOalk, -CONR12R13, -alk-NR14R15, -NR14R15, hydroxyl, hydroxyalkyl, Het, OCF3, CF3, -NH-CO-alk, -SO2NH2 and -NH-COOalk radicals, or alternatively, a fused ring containing a 3-10 membered Het radical is formed on 2 adjacent carbon atoms of said phenyl radical, with dioxymethylene; R7 and R8, which are identical or different, represent a hydrogen atom or an alkyl radical or, alternatively, R7 and R8 together with the nitrogen atom to which they are attached form a 3- to 10-membered saturated mono- or bicyclic heterocycle, optionally further having another heteroatom selected from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl radicals; R9 and R10, which are identical or different, represent a hydrogen atom or an alkyl, cycloalkyl, alkylcycloalkyl or hydroxyalkyl radical or, alternatively, R9 and R10 together with the nitrogen atom to which they are attached form a 3- to 10-membered saturated or unsaturated mono- or bicyclic heterocycle, optionally further having another heteroatom selected from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl, oxo or -CO-NH2 radicals; R12 and R13, which are identical or different, represent a hydrogen atom or an alkyl radical or, alternatively, R12 and R13 together with the nitrogen atom to which they are attached form a 3- to 10-membered saturated mono- or bicyclic heterocycle, optionally further having another heteroatom selected from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl radicals; R14 and R15, which are identical or different, represent a hydrogen atom or an alkyl, cycloalkyl, alkylcycloalkyl or hydroxyalkyl radical or, alternatively, R14 and R15 together with the nitrogen atom to which they are attached form a 3- to 10-membered saturated or unsaturated mono- or bicyclic heterocycle, optionally further having another heteroatom selected from oxygen, sulfur and nitrogen and being optionally substituted with one or more substituents selected from alkyl, oxo, hydroxyalkyl and -CO-NH2 radicals; Het represents a 3- to 10-membered unsaturated or saturated mono- or bicyclic heterocycle containing one or more heteroatoms selected from oxygen, sulfur and nitrogen optionally substituted with one or more substituents selected from halogen, alkyl, alkoxy, vinyl, alkoxycarbonyl, oxo and hydroxyl radicals, the nitrogen-containing heterocycles being optionally in their N-oxidized form, and, preferably, Het represents a heterocycle selected from benzimidazole, benzoxazole, benzothiazole, benzothiophene, thiophene, quinazoline, quinoxaline, quinoline, pyrrole, pyridine, imidazole, indole, isoquinoline, pyrimidine, thiazole, thiadiazole, furan, tetrahydroisoquinoline and tetrahydroquinoline, these heterocycles being optionally substituted with one or more substituents selected from halogen, alkyl, alkoxy, vinyl, oxo, hydroxyl, OCF3 and CF3 radicals, an optical isomer thereof or a pharmaceutically acceptable salt thereof. 4. The pharmaceutical composition of claim 1, containing as active ingredient at least a compound of formula (I)