Patent CA-2105072-C (CA)
Title: Morphinan derivative and its pharmaceutical applications
Inventor: NAGASE HIROSHI
IPC: C07D401/12
Filed: 1993-01-22
Granted: 1998-07-28
Abstract: There is disclosed morphinan derivative represented by the general formula (I) or its pharmacologically acceptable acid addition salt:     (see fig. I) ~  represents a single or double bond.   R1 represents an alkyl group having 1-5 carbon atoms, a cycloalkylalkyl group having 4-7 carbon atoms, a cycloalkenylalkyl group having 5-7 carbon atoms,  an aryl group having 6-12 carbon atoms,  an aralkyl group having 7-13 carbon atoms, an alkenyl group having 4-7 carbon atoms,  an allyl group,  a furan-2-ylalkyl group having 1-5 carbon atoms, or a thiophen-2-ylalkyl group having 1-5 carbon atoms.  R2 represents a hydrogen atom, a hydroxy group, a nitro group, an alkanoyloxy group having 1-5 carbon atoms, an alkoxy group having 1-5 carbon atoms, an alkyl group having 1-5 carbon atoms or -NR9R10.  R9 represents a hydrogen atom or an alkyl group having 1-5 carbon atoms.  R10 represents a hydrogen atom, an alkyl group having 1-5 carbon atoms or -C(=0)R11.  R11 represents a hydrogen atom, a phenyl group or an alkyl group having 1-5 carbon atoms, R3 represents a hydrogen atom, a hydroxy group, an alkanoyloxy group having 1-5 carbon atoms or an alkoxy group having 1-5 carbon atoms.  A represents -XC(=Y)-, -XC(=Y)Z-, -X-, -XSO2- or -OC(OR4)R4- where, X, Y and Z each independently represent NR4, S or 0, R4 represents a hydrogen atom, a straight-chain or branched alkyl group having 1-5 carbon atoms or an aryl group having 6-12 carbon atoms, and wherein R4 may be identical or different.   B represents a valence bond,  a straight-chain or branched alkylene group having 1-14 carbon atoms (which may be substituted with one or more types of substituent groups selected from the group consisting of an alkoxy group having 1-5 carbon atoms,  an alkanoyloxy group having 1-5 carbon atoms, a hydroxy group, fluorine, chlorine, bromine, iodine, an amino group, a nitro group, a cyano group, a trifluoromethyl group and a phenoxy group, and wherein from 1 to 3 methylene groups may be replaced with carbonyl groups with proviso that adjacent methylene groups are not replaced with carbonyl groups), a straight chain or branched acyclic unsaturated hydrocarbon containing 1 to 3 double bonds and/or triple bonds and having 2-14 carbon atoms (which may be substituted with one or more substituent groups selected from the group consisting of an alkoxy group having 1-5 carbon atoms, an alkanoyloxy group having 1-5 carbon atoms, a hydroxy group, fluorine, chlorine, bromine, iodine, an amino group, a nitro group, a cyano group, a trifluoromethyl group and a phenoxy group, and wherein 1 to 3 methylene groups may be replaced with carbonyl groups),  or a straight-chain or branched saturated or unsaturated hydrocarbon containing from 1 to 5 thioether, ether and/or amino bonds and having 1-14 carbon atoms (wherein hetero atoms are not bonded directly to A).  R5 represents a hydrogen atom or an organic group having the basic skeleton (which may be substituted with one or more substituent groups selected from the group consisting of an alkyl group having 1-5 carbon atoms, an alkoxy group having 1-5 carbon atoms, an alkanoyloxy group having 1-5 carbon atoms, a hydroxy group, fluorine, chlorine, bromine, iodine, an amino group, a nitro group, a cyano group, an isothiocyanate group, a trifluoromethyl group and a methylenedioxy group).                                     Organic Group Represented by R5 R6 represents a hydrogen atom, R7 represents a hydrogen atom, a hydroxy group, an alkoxy group having 1-5 carbon atoms, an alkanoyloxy  group having  1-5  carbon  atoms,  or  R6  and  R7 together represent -O-, -CH2- or -S-.  R8 represents a hydrogen atom, an alkyl group having 1-5 carbon atoms or an alkanoyl group having 1-5 carbon atoms, and general formula (I) includes the  (+)  form,  (-)  form  and  (~)  form.    With  the  above definitions, there is the proviso that 1) R5 is not a hydrogen atom and B is not a valence bond, when R4 is a hydrogen atom; 2) R5 is not a hydrogen atom and B is not a valence bond, when A is -SC(=0)-, -OC(=0)-, or -OSO2-; and 3) R5 is not a hydrogen atom and B is not a valence bond, when A is -X-.