Claims
- 1. A method of protecting brain nerve cells against cytotoxic damage caused by ischemic brain disorder, the method comprising administering to a patient in need thereof an effective brain cell protecting amount of a brain cell protective agent of formula (I) or pharmacologically acceptable acid addition salt thereof: ##STR71## wherein, the dashed line "- - - - " represents an optional double bond; R.sup.1 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, or an allyl group;
- R.sup.2 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, a straight chain alkyl group having 1-5 carbon atoms or --NR.sup.9 R.sup.10, wherein, R.sup.9 represents a hydrogen atom or an alkyl group having 1-5 carbon atoms, and R.sup.10 represents a hydrogen atom, an alkyl group having 1-5 carbon atoms or --C(.dbd.O)R.sup.11 (wherein R.sup.11 represents a hydrogen atom, phenyl group or alkyl group having 1-5 carbon atoms);
- R.sup.3 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(.dbd.Y)--, --XC(.dbd.Y)Z--, --X-- or --XSO.sub.2 --, where, X represents NR.sub.4, and Y and Z respectively and independently represent NR.sup.4, S or O, R.sup.4 represents a hydrogen atom, a straight chain alkyl group having 1-14 carbon atoms or a branched chain alkyl group having 3 to 14 carbon atoms (which may be substituted with at least one substituent selected from the group consisting of an alkoxy group having 1-5 carbon atoms, an alkanoyloxy group having 1-5 carbon atoms, fluorine, chlorine, bromine, iodine, a nitro group and a cyano group), a cycloalkylalkyl group having 4 to 15 carbon atoms (which may be substituted with at least one substituent selected from the group consisting of an alkyl group having 1-5 carbon atoms, an aryl group having 6-12 carbon atoms, an alkoxy group having 1-5 carbon atoms, an alkanoyloxy group having 1-5 carbon atoms, fluorine, chlorine, bromine, iodine, a nitro group, a cyano group and a trifluoromethyl group), an aralkyl group having 7-15 carbon atoms (which may be substituted with at least one substituent selected from the group consisting of an alkyl group having 1-5 carbon atoms, an aryl group having 6-12 carbon atoms, an alkoxy group having 1-5 carbon atoms, an alkanoyloxy group having 1-5 carbon atoms, fluorine, chlorine, bromine, iodine, a nitro group, a cyano group and a trifluoromethyl group), or an aryl group having 6-12 carbon atoms (which may be substituted with at least one substituent selected from the group consisting of an alkyl group having 1-5 carbon atoms, an aryl group having 6-12 carbon atoms, an alkoxy group having 1-5 carbon atoms, an alkanoyloxy group having 1-5 carbon atoms, fluorine, chlorine, bromine, iodine, a nitro group, a cyano group and a trifluoromethyl group), and wherein said R.sup.4 groups may be identical or different;
- B represents a valence bond, a straight chain alkylene group having 1-14 carbon atoms or a branched chain alkylene group having 3-14 carbon atoms (which may be substituted with at least one substituent 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 that are not adjacent may be replaced with carbonyl groups), a straight chain, acyclic, unsaturated hydrocarbon having 2-14 carbon atoms or a branched chain, acyclic, unsaturated hydrocarbon having 3 to 14 carbon atoms, and having from 1 to 3 double and/or triple bonds (which may be substituted with at least one substituent 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 that are not adjacent may be replaced with carbonyl groups), or a straight chain, saturated hydrocarbon having 1-14 carbon atoms, a straight chain unsaturated hydrocarbon having 2-14 carbon atoms, or a branched chain saturated or unsaturated hydrocarbon having 3 to 14 carbon atoms, having from 1 to 5 thioether, ether and/or amino bonds (wherein hetero atoms are not bonded directly to A);
- R represents a hydrogen atom or an organic group having a structure as shown below: ##STR72## wherein Q is N, O or S, 1 is 2 or 3, m and n are greater than or equal to 0, and m+n is less than or equal to 5,
- and which organic group may be substituted with one or two same or different substituents selected from the group consisting of C.sub.1-5 alkyl, C.sub.1-5 alkoxy, C.sub.1-5 alkanoyloxy, hydroxy, fluoro, chloro, bromo, iodo, amino, nitro, cyano, isothiocyanate, and trifluoromethyl;
- R.sup.6 and R.sup.7 collectively represent --O--;
- R.sup.8 represents a hydrogen atom, a straight chain alkyl group having 1-5 carbon atoms or an alkanoyl group having 1-5 carbon atoms.
- 2. The method as recited in claim 1 wherein, in the formula (I), A is --NR.sup.4 C(.dbd.O)--, --NR.sup.4 C(.dbd.O)O--, --NR.sup.4 C(.dbd.O)NR.sup.4 --, --NR.sup.4 C(.dbd.S)NR.sup.4 --, --NR.sup.4 -- or --NR.sup.4 SO.sub.2 -- (wherein R.sup.4 is the same as previously defined).
- 3. The method as recited in claim 1 wherein, in the formula (I), A is --NR.sup.4 C(.dbd.O)--, --NR.sup.4 C(.dbd.O)O--, --NR.sup.4 C(.dbd.O)NR.sup.4 --, --NR.sup.4 C(.dbd.S)NR.sup.4 -- or --NR.sup.4 -- (where R.sup.4 is the same as previously defined).
- 4. The method as recited in claim 1 wherein, in the formula (I), A is --NR.sup.4 C(.dbd.O)-- or --NR.sup.4 -- (where R.sup.4 is the same as previously defined).
- 5. The method as recited in claim 2 wherein, in the formula (I), A is --NR.sup.4 C(.dbd.O)--, .dbd.NR.sup.4 C(.dbd.O)O--, --NR.sup.4 C(.dbd.O)NR.sup.4 --, --NR.sup.4 C(.dbd.S)NR.sup.4 -- or --NR.sup.4 -- (where R.sup.4 is the same as previously defined).
- 6. The method as recited in claim 2 wherein, in the formula (I), A is --NR.sup.4 C(O.dbd.)-- or --NR.sup.4 -- (where R.sup.4 is the same as previously defined).
- 7. The method as recited in claim 3, wherein, in the formula (I), A is --NR.sup.4 C(.dbd.O)-- or --NR.sup.4 -- (where NR.sup.4 is the same as previously defined).
- 8. A method of protecting brain nerve cells against cytotoxic damage caused by ischemic brain disorder, the method comprising administering to a patient in need thereof an effective brain cell protecting amount of a brain cell protective agent of formula (I') or a pharmacologically acceptable acid addition salt thereof: ##STR73## wherein, R.sup.1 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, or an allyl group;
- R.sup.2 represents a hydrogen atom, hydroxy group, alkanoyloxy group having 1-5 carbon atoms or alkoxy group having 1-5 carbon atoms;
- R.sup.3 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' represent --NR.sup.4' C(.dbd.O)-- or --NR.sup.4' --, where R.sup.4' represents a straight chain or branched chain alkyl group having 6-14 carbon atoms (which may be substituted with at least one substituent selected from the group consisting of an alkoxy group having 1-5 carbon atoms, an alkanoyloxy group having 1-5 carbon atoms, fluorine, chlorine, bromine, iodine, a nitro group and a cyano group), a straight chain alkyl group having 1-5 carbon atoms or a branched chain alkyl group having 3-5 carbon atoms (which is substituted with at least one substituent selected from the group consisting of an alkoxy group having 1-5 carbon atoms, an alkanoyloxy group having 1-5 carbon atoms, fluorine, chlorine, bromine, iodine, a nitro group and a cyano group), a cycloalkylalkyl group having 4 to 15 carbon atoms (which may be substituted with at least one substituent selected from the group consisting of an alkyl group having 1-5 carbon atoms, an aryl group having 6-12 carbon atoms, an alkoxy group having 1-5 carbon atoms, an alkanoyloxy group having 1-5 carbon atoms, fluorine, chlorine, bromine, iodine, a nitro group, a cyano group and a trifluoromethyl group), an aralkyl group having 7-15 carbon atoms (which may be substituted with at least one substituent selected from the group consisting of an alkyl group having 1-5 carbon atoms, an aryl group having 6-12 carbon atoms, an alkoxy group having 1-5 carbon atoms, an alkanoyloxy group having 1-5 carbon atoms, fluorine, chlorine, bromine, iodine, a nitro group, a cyano group and a trifluoromethyl group), or an aryl group having 6-12 carbon atoms (which is substituted with at least one substituent group selected from the group consisting of an alkyl group having 1-5 carbon atoms, an aryl group having 6-12 carbon atoms, an alkoxy group having 1-5 carbon atoms, an alkanoyloxy group having 1-5 carbon atoms, fluorine, chlorine, bromine, iodine, a nitro group, a cyano group and a trifluoromethyl group;
- B represents a valence bond, a straight chain alkylene group having 1-14 carbon atoms or a branched chain alkylene group having 3-14 carbon atoms (which may be substituted with at least one substituent 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 that are not adjacent may be replaced with carbonyl groups), a straight chain, acyclic, unsaturated hydrocarbon having 2-14 carbon atoms or a branched chain, acyclic, unsaturated hydrocarbon having 3 to 14 carbon atoms, and having from 1 to 3 double and/or triple bonds (which may be substituted with at least one substituent 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 that are not adjacent may be replaced with carbonyl groups), or a straight chain, saturated hydrocarbon having 1-14 carbon atoms, a straight chain unsaturated hydrocarbon having 2-14 carbon atoms, or a branched chain saturated or unsaturated hydrocarbon having 3 to 14 carbon atoms, having from 1 to 5 thioether, ether and/or amino bonds (wherein hetero atoms are not bonded directly to A);
- R.sup.5 represents a hydrogen atom or an organic group having a structure as shown below: ##STR74## wherein Q is N, O, or S, 1 is 2 or 3, m and n are greater than or equal to 0, and m+n is less than or equal to 5,
- and which organic group may be substituted with one or two same or different substituents selected from the group consisting of C.sub.1-5 alkyl, C.sub.1-5 alkoxy, C.sub.1-5 alkanoyloxy, hydroxy, fluoro, chloro, bromo, iodo, amino, nitro, cyano, isothiocyanate, and trifluoromethyl.
- 9. The method as recited in claim 1, wherein said formula (I) compound is 17-cyclopropylmethyl-3,14.beta.-dihydroxy-4,5.alpha.-epoxy-6.beta.-(N-methyl-3-trifluoromethylcinnamamido) morphinan, or a pharmaceutically acceptable salt thereof.
- 10. A method of protecting brain nerve cells against cytotoxic damage caused by glutamate, the method comprising administering to a patient in need thereof an effective brain cell protecting amount of a brain cell protective agent of formula (I) or pharmacologically acceptable acid addition salt thereof: ##STR75## wherein, the dashed line "- - - - " represents an optional double bond; R.sup.1 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, or an allyl group;
- R.sup.2 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, a straight chain alkyl group having 1-5 carbon atoms or --NR.sup.9 R.sup.10, wherein, R.sup.9 represents a hydrogen atom or an alkyl group having 1-5 carbon atoms, and R.sup.10 represents a hydrogen atom, an alkyl group having 1-5 carbon atoms or --C(.dbd.O)R.sup.11 (wherein R.sup.11 represents a hydrogen atom, phenyl group or alkyl group having 1-5 carbon atoms);
- R.sup.3 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(.dbd.Y)--, --XC(.dbd.Y)Z--, --X-- or --XSO.sub.2 --, where, X represents NR.sub.4, and Y and Z respectively and independently represent NR.sup.4, S or O, R.sup.4 represents a hydrogen atom, a straight chain alkyl group having 1-14 carbon atoms or a branched chain alkyl group having 3 to 14 carbon atoms (which may be substituted with at least one substituent selected from the group consisting of an alkoxy group having 1-5 carbon atoms, an alkanoyloxy group having 1-5 carbon atoms, fluorine, chlorine, bromine, iodine, a nitro group and a cyano group), a cycloalkylalkyl group having 4 to 15 carbon atoms (which may be substituted with at least one substituent selected from the group consisting of an alkyl group having 1-5 carbon atoms, an aryl group having 6-12 carbon atoms, an alkoxy group having 1-5 carbon atoms, an alkanoyloxy group having 1-5 carbon atoms, fluorine, chlorine, bromine, iodine, a nitro group, a cyano group and a trifluoromethyl group), an aralkyl group having 7-15 carbon atoms (which may be substituted with at least one substituent selected from the group consisting of an alkyl group having 1-5 carbon atoms, an aryl group having 6-12 carbon atoms, an alkoxy group having 1-5 carbon atoms, an alkanoyloxy group having 1-5 carbon atoms, fluorine, chlorine, bromine, iodine, a nitro group, a cyano group and a trifluoromethyl group), or an aryl group having 6-12 carbon atoms (which may be substituted with at least one substituent selected from the group consisting of an alkyl group having 1-5 carbon atoms, an aryl group having 6-12 carbon atoms, an alkoxy group having 1-5 carbon atoms, an alkanoyloxy group having 1-5 carbon atoms, fluorine, chlorine, bromine, iodine, a nitro group, a cyano group and a trifluoromethyl group), and wherein said R.sup.4 groups may be identical or different;
- B represents a valence bond, a straight chain alkylene group having 1-14 carbon atoms or a branched chain alkylene group having 3-14 carbon atoms (which may be substituted with at least one substituent 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 that are not adjacent may be replaced with carbonyl groups), a straight chain, acyclic, unsaturated hydrocarbon having 2-14 carbon atoms or a branched chain, acyclic, unsaturated hydrocarbon having 3 to 14 carbon atoms, and having from 1 to 3 double and/or triple bonds (which may be substituted with at least one substituent 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 that are not adjacent may be replaced with carbonyl groups), or a straight chain, saturated hydrocarbon having 1-14 carbon atoms, a straight chain unsaturated hydrocarbon having 2-14 carbon atoms, or a branched chain saturated or unsaturated hydrocarbon having 3 to 14 carbon atoms, having from 1 to 5 thioether, ether and/or amino bonds (wherein hetero atoms are not bonded directly to A);
- R.sup.5 represents a hydrogen atom or an organic group having a structure as shown below: ##STR76## wherein Q is N, O or S, 1 is 2 or 3, m and n are greater than or equal to 0, and m+n is less than or equal to 5,
- and which organic group may be substituted with one or two same or different substituents selected from the group consisting of C.sub.1-5 alkyl, C.sub.1-5 alkoxy, C.sub.1-5 alkanoyloxy, hydroxy, fluoro, chloro, bromo, iodo, amino, nitro, cyano, isothiocyanate, and trifluoromethyl;
- R.sup.6 and R.sup.7 collectively represent --O--;
- R.sup.8 represents a hydrogen atom, a straight chain alkyl group having 1-5 carbon atoms or an alkanoyl group having 1-5 carbon atoms.
- 11. A method of protecting brain nerve cells against cytotoxic damage caused by glutamate, the method comprising administering to a patient in need thereof an effective brain cell protecting amount of a brain cell protective agent of formula (I') or a pharmacologically acceptable acid addition salt thereof: ##STR77## wherein, R.sup.1 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, or an allyl group;
- R.sup.2 represents a hydrogen atom, hydroxy group, alkanoyloxy group having 1-5 carbon atoms or alkoxy group having 1-5 carbon atoms;
- R.sup.3 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' represent --NR.sup.4' C(.dbd.O)-- or --NR.sup.4' --, where R.sup.4' represents a straight chain or branched chain alkyl group having 6-14 carbon atoms (which may be substituted with at least one substituent selected from the group consisting of an alkoxy group having 1-5 carbon atoms, an alkanoyloxy group having 1-5 carbon atoms, fluorine, chlorine, bromine, iodine, a nitro group and a cyano group), a straight chain alkyl group having 1-5 carbon atoms or a branched chain alkyl group having 3-5 carbon atoms (which is substituted with at least one substituent selected from the group consisting of an alkoxy group having 1-5 carbon atoms, an alkanoyloxy group having 1-5 carbon atoms, fluorine, chlorine, bromine, iodine, a nitro group and a cyano group), a cycloalkylalkyl group having 4 to 15 carbon atoms (which may be substituted with at least one substituent selected from the group consisting of an alkyl group having 1-5 carbon atoms, an aryl group having 6-12 carbon atoms, an alkoxy group having 1-5 carbon atoms, an alkanoyloxy group having 1-5 carbon atoms, fluorine, chlorine, bromine, iodine, a nitro group, a cyano group and a trifluoromethyl group), an aralkyl group having 7-15 carbon atoms (which may be substituted with at least one substituent selected from the group consisting of an alkyl group having 1-5 carbon atoms, an aryl group having 6-12 carbon atoms, an alkoxy group having 1-5 carbon atoms, an alkanoyloxy group having 1-5 carbon atoms, fluorine, chlorine, bromine, iodine, a nitro group, a cyano group and a trifluoromethyl group), or an aryl group having 6-12 carbon atoms (which is substituted with at least one substituent group selected from the group consisting of an alkyl group having 1-5 carbon atoms, an aryl group having 6-12 carbon atoms, an alkoxy group having 1-5 carbon atoms, an alkanoyloxy group having 1-5 carbon atoms, fluorine, chlorine, bromine, iodine, a nitro group, a cyano group and a trifluoromethyl group;
- B represents a valence bond, a straight chain alkylene group having 1-14 carbon atoms or a branched chain alkylene group having 3-14 carbon atoms (which may be substituted with at least one substituent 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 that are not adjacent may be replaced with carbonyl groups), a straight chain, acyclic, unsaturated hydrocarbon having 2-14 carbon atoms or a branched chain, acyclic, unsaturated hydrocarbon having 3 to 14 carbon atoms, and having from 1 to 3 double and/or triple bonds (which may be substituted with at least one substituent 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 that are not adjacent may be replaced with carbonyl groups), or a straight chain, saturated hydrocarbon having 1-14 carbon atoms, a straight chain unsaturated hydrocarbon having 2-14 carbon atoms, or a branched chain saturated or unsaturated hydrocarbon having 3 to 14 carbon atoms, having from 1 to 5 thioether, ether and/or amino bonds (wherein hetero atoms are not bonded directly to A);
- R.sup.5 represents a hydrogen atom or an organic group having a structure as shown below: ##STR78## wherein Q is N, O, or S, 1 is 2 or 3, m and n are greater than or equal to 0, and m+n is less than or equal to 5,
- and which organic group may be substituted with one or two same or different substituents selected from the group consisting of C.sub.1-5 alkyl, C.sub.1-5 alkoxy, C.sub.1-5 alkanoyloxy, hydroxy, fluoro, chloro, bromo, iodo, amino, nitro, cyano, isothiocyanate, and trifluoromethyl.
Priority Claims (1)
| Number |
Date |
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Kind |
| 5-177963 |
Jul 1993 |
JPX |
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Parent Case Info
This application is a divisional of application Ser. No. 08/403,759, filed on Mar. 17, 1995, abandoned, which is a national stage entry of PCT/JP94/01 filed Jul. 19, 1994, the entire contents of which are hereby incorporated by reference.
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Divisions (1)
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| Parent |
403759 |
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Patent Grant
5972953
