Atisane compounds and use thereof
The present invention provides a novel compound exhibiting an excellent suppressing effect to cell injury caused by radicals and neurotoxicity induced by excitatory nuerotransmitters such as glutamate. Specifically, it provides a compound represented by the following formula, a salt thereof or a hydrate of them. Wherein Z represents a bivalent organic group and the like of from 2 to 3 carbon atom(s) which may have a substituent; and R 3 represents a carboxyl group and the like.
1. A compound represented by the following formula, or a salt thereof or a hydrate thereof:
wherein Z is a group represented by the formula:
wherein Q 1 is
wherein A 1 represents an optionally substituted C 1-6 alkylene group or a single bond;
X 1 represents a halogen atom or a cyano group;
X 2 represents the formula —S(O) m —, an oxygen atom, a carbonyl group or a single bond, wherein m of —S(O) m — is an integer of 0, 1 or 2;
R 4a represents a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 2-6 alkynyl group, an optionally substituted C 6-14 aromatic hydrocarbon cyclic group, an optionally substituted from 5- to 14-membered aromatic heterocyclic group, an optionally substituted C 1-6 alkoxy group or a hydroxyl group; and
R 4b and R 4c are independent of each other and each represents a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 2-6 alkynyl group, an optionally substituted C 6-14 aromatic hydrocarbon cyclic group, an optionally substituted from 5- to 14-membered aromatic heterocyclic group, an optionally substituted C 2-7 acyl group or an optionally substituted C 1-6 alkylsulfonyl group;
Q 2a represents a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 2-6 alkynyl group, an optionally substituted C 1-6 alkoxy group, a hydroxyl group or a group represented by the formula —NR 6a R 6b , wherein R 6a and R 6b are independent of each other and each represents a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 2-6 alkynyl group, an optionally substituted C 2-7 acyl group or an optionally substituted C 1-6 alkylsulfonyl group:
R 3a represents a carbonyl group, a methylene group or a single bond; and
R 3b represents a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 2-6 alkynyl group, an optionally substituted C 1-6 alkoxy group, a hydroxyl group, a cyano group or a group represented by the formula —NR 5a R 5b ,
wherein R 5a and R 5b are independent of each other and each represents a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 2-6 alkynyl group, an optionally substituted C 6-14 aromatic hydrocarbon cyclic group, an optionally substituted from 5- to 14-membered aromatic heterocyclic group, an optionally substituted C 2-7 acyl group or an optionally substituted C 1-6 alkylsulfonyl group, provided that the following cases (1) to (3) are excluded:
(1) Z represents a 1,2-dicarboxyethane-1,2-yl group or a 1,2-dimethoxycarbonylethane-1,2-yl group, and the formula —R 3a –R 3b represents a hydroxymethyl group or an acetoxymethyl group;
(2) Z represents a 1-i-propylethane-1,2-yl group and the formula —R 3a –R 3b represents a hydrogen atom; and
(3) the formula —R 3a –R 3b represents a methyl group, and Z represents the formula:
wherein R 11 represents a hydrogen atom or a methyl group, and R 12 represents a hydroxyl group, a methyl group or a tetrahydropyran-2H-pyran-2-yl-oxy group.
2. The compound, according to claim 1 , a salt thereof or a hydrate thereof, wherein said compound of formula (I) is a compound of formula (Ia):
wherein Z, R 3a and R 3b respectively represent those defined for the above Z, R 3a and R 3b in claim 1 , provided that the following cases (1) to (3) are excluded:
(1) Z represents a 1,2-dicarboxyethane-1,2-yl group or a 1,2-dimethoxycarbonylethane-1,2-yl group, and the formula —R 3a –R 3b represents a hydroxymethyl group or an acetoxymethyl group;
(2) Z represents a 1-i-propylethane-1,2-yl group and the formula —R 3a –R 3b represents a hydrogen atom; and
(3) the formula —R 3a –R 3b represents a methyl group, and Z represents the formula:
wherein R 11 represents a hydrogen atom or a methyl group, and R 12 represents a hydroxyl group, a methyl group or a tetrahydropyran-2H-pyran-2-yl-oxy group.
3. The compound according to claim 1 , a salt thereof or a hydrate thereof,
wherein Q 1 is
wherein A 1 , X 2 and R 4a respectively represent those defined for A 1 , X 1 and R 4a in claim 1 .
4. The compound according to claim 1 , a salt thereof or a hydrate thereof, wherein Z is a group represented by the formula:
wherein Q 1 and Q 2a respectively represent those defined for Q 1 and Q 2a in claim 1 .
5. The compound according to claim 1 , a salt thereof or a hydrate thereof,
wherein Q 1 is
wherein A 1 , X 2 , R 4b and R 4c respectively represent those defined for A 1 , X 2 , R 4b and R 4c in claim 1 .
6. The compound according to claim 1 , a salt thereof or a hydrate thereof, wherein R 3a is a carbonyl group.
7. A compound represented by the following formula, or a salt thereof or a hydrate thereof:
wherein Z represents a bivalent organic group of from 2 to 3 carbon atoms, provided that Z may have one or two group(s) selected from the group consisting of those represented by the following formula:
wherein A 1 represents an optionally substituted C 1-6 alkylene group or a single bond;
X 1 represents a halogen atom or a cyano group;
X 2 represents the formula —S(O) m —, an oxygen atom a carbonyl group or a single bond, wherein m of —S(O) m — is an integer of 0, 1 or 2;
R 4a represents a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 2-6 alkynyl group, an optionally substituted C 6-14 aromatic hydrocarbon cyclic group, an optionally substituted from 5- to 14-membered aromatic heterocyclic group, an optionally substituted C 1-6 alkoxy group or a hydroxyl group; and
R 4b and R 4c are independent of each other and each represents a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 2-6 alkynyl group, an optionally substituted C 6-14 aromatic hydrocarbon cyclic group, an optionally substituted from 5- to 14-membered aromatic heterocyclic group, an optionally substituted C 2-7 acyl group or an optionally substituted C 1-6 alkylsulfonyl group;
wherein in the case where Z is a 1,2-ethylene group not having a substituent or a 1,2-vinylene group not having a substituent is excluded;
R 3a represents a carbonyl group, a methylene group or a single bond; and
wherein R 3b is a hydroxyl group.
8. The compound according to claim 1 , a salt thereof or a hydrate thereof, wherein Q 2a is a hydroxyl group.
9. A compound represented by the following formula, or a salt thereof or a hydrate thereof:
wherein Z is a group represented by the formula:
wherein Q 1 is a group represented by the formula -A 1 -S(O) m —R 4a , wherein A 1 represents an optionally substituted C 1-6 alkylene group or a single bond, m is an integer of 0, 1 or 2, and R 4a represents a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 2-6 alkynyl group, an optionally substituted C 6-14 aromatic hydrocarbon cyclic group, an optionally substituted from 5- to 14-membered aromatic heterocyclic group, an optionally substituted C 1-6 alkoxy group or a hydroxyl group;
wherein Q 2 represents a group represented by the formula:
wherein A 1 represents an optionally substituted C 1-6 alkylene group or a single bond;
X 1 represents a halogen atom or a cyano group;
X 2 represents the formula —S(O) m —, an oxygen atom, a carbonyl group or a single bond, wherein m of —S(O) m — is an integer of 0, 1 or 2;
R 4a represents a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 2-6 alkynyl group, an optionally substituted C 6-14 aromatic hydrocarbon cyclic group, an optionally substituted from 5- to 14-membered aromatic heterocyclic group, an optionally substituted C 1-6 alkoxy group or a hydroxyl group; and
R 4b and R 4c are independent of each other and each represents a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 2-6 alkynyl group, an optionally substituted C 6-14 aromatic hydrocarbon cyclic group, an optionally substituted from 5- to 14-membered aromatic heterocyclic group, an optionally substituted C 2-7 acyl group or an optionally substituted C 1-6 alkylsulfonyl group;
wherein in the case where Z is a 1,2-ethylene group not having a substituent or a 1,2-vinylene group not having a substituent is excluded;
R 3a represents a carbonyl group, a methylene group or a single bond; and
R 3b represents a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 2-6 alkynyl group, an optionally substituted C 1-6 alkoxy group, a hydroxyl group, a cyano group or a group represented by the formula —NR 5a R 5b ,
wherein R 5a and R 5b are independent of each other and each represents a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 2-6 alkynyl group, an optionally substituted C 6-14 aromatic hydrocarbon cyclic group, an optionally substituted from 5- to 14-membered aromatic heterocyclic group, an optionally substituted C 2-7 acyl group or an optionally substituted C 1-6 alkylsulfonyl group,
provided that the following cases (1) to (3) are excluded:
(1) Z represents a 1,2-dicarboxyethane-1,2-yl group or a 1,2-dimethoxycarbonylethane-1,2-yl group, and the formula —R 3a –R 3b represents a hydroxymethyl group or an acetoxymethyl group;
(2) Z represents a 1-i-propylethane-1,2-yl group and the formula —R 3a –R 3b represents a hydrogen atom; and
(3) the formula —R 3a –R 3b represents a methyl group, and Z represents the formula:
wherein R 11 represents a hydrogen atom or a methyl group, and R 12 represents a hydroxyl group, a methyl group or a tetrahydropyran-2H-pyran-2-yl-oxy group.
10. The compound according to claim 1 , a salt thereof or a hydrate thereof, wherein R 4a is an optionally substituted methyl group, an optionally substituted ethyl group, an optionally substituted n-propyl group or an optionally substituted i-propyl group.
11. The compound according to claim 1 , a salt thereof or a hydrate thereof, wherein A 1 is a methylene group.
12. A compound represented by the following formula, or a salt thereof or a hydrate thereof:
wherein Z represents a bivalent organic group of from 2 to 3 carbon atoms, provided that Z may have one or two group(s) selected from the group consisting of those represented by the following formula:
wherein A 1 represents an optionally substituted C 1-6 alkylene group or a single bond;
X 1 represents a halogen atom or a cyano group;
X 2 represents the formula —S(O) m —, wherein m is 1;
R 4a represents a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 1-6 alkenyl group, an optionally substituted C 2-6 alkynyl group, an optionally substituted C 6-14 aromatic hydrocarbon cyclic group, an optionally substituted from 5- to 14-membered aromatic heterocyclic group, an optionally substituted C 1-6 alkoxy group or a hydroxyl group; and
R 4b and R 4c are independent of each other and each represents a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 2-6 alkynyl group, an optionally substituted C 6-14 aromatic hydrocarbon cyclic group, an optionally substituted from 5- to 14-membered aromatic heterocyclic group, an optionally substituted C 2-7 acyl group or an optionally substituted C 1-6 alkylsulfonyl group;
wherein in the case where Z is a 1,2-ethylene group not having a substituent or a 1,2-vinylene group not having a substituent is excluded;
R 3a represents a carbonyl group, a methylene group or a single bond; and
R 3b represents a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 2-6 alkynyl group, an optionally substituted C 1-6 alkoxy group, a hydroxyl group, a cyano group or a group represented by the formula —NR 5a R 5b ,
wherein R 5a and R 5b are independent of each other and each represents a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 2-6 alkynyl group, an optionally substituted C 6-14 aromatic hydrocarbon cyclic group, an optionally substituted from 5- to 14-membered aromatic heterocyclic group, an optionally substituted C 2-7 acyl group or an optionally substituted C 1-6 alkylsulfonyl group,
provided that the following cases (1) to (3) are excluded:
(1) Z represents a 1,2-dicarboxyethane-1,2-yl group or a 1,2-dimethoxycarbonylethane-1,2-yl group, and the formula —R 3a –R 3b represents a hydroxymethyl group or an acetoxymethyl group;
(2) Z represents a 1-i-propylethane-1,2-yl group and the formula —R 3a –R 3b represents a hydrogen atom; and
(3) the formula —R 3a –R 3b represents a methyl group, and Z represents the formula:
wherein R 11 represents a hydrogen atom or a methyl group, and R 12 represents a hydroxyl group, a methyl group or a tetrahydropyran-2H-pyran-2-yl-oxy group.
13. The compound according to claim 1 , a salt thereof or a hydrate thereof, wherein A 1 represents a C 1-6 alkylene group or a single bond; R 4a represents a hydrogen atom, a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a C 6-14 aromatic hydrocarbon cyclic group, a 5- to 14-membered aromatic heterocyclic group, a C 1-6 alkoxy group or a hydroxyl group; R 4b and R 4c are independent of each other and each represents a hydrogen atom, a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a C 6-14 aromatic hydrocarbon cyclic group, a 5- to 14-membered aromatic heterocyclic group, a C 2-7 acyl group or a C 1-6 alkylsulfonyl group; and R 3b represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a C 1-6 alkoxy group, a hydroxyl group, a cyano group or a group represented by the formula —NR 5a R 5b wherein R 5a and R 5b are independent of each other and each represents a hydrogen atom, a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a C 6-14 aromatic hydrocarbon cyclic group, a 5- to 14-membered aromatic heterocyclic group, a C 2-7 acyl group or a C 1-6 alkylsulfonyl group.
14. The compound according to claim 1 , a salt thereof or a hydrate thereof, wherein Q 2a represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a C 1-6 alkoxy group, a hydroxyl group or a group represented by the formula —NR 6a R 6b , wherein R 6a and R 6b are independent of each other and each represents a hydrogen atom, a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a C 2-7 acyl group or a C 1-6 alkylsulfonyl group.
15. A pharmaceutical composition comprising the compound according to claim 1 , a salt thereof or a hydrate thereof; and
a pharmaceutically acceptable carrier.
16. A pharmaceutical composition comprising the compound according to claim 7 , a salt thereof or a hydrate thereof; and
a pharmaceutically acceptable carrier.
17. A pharmaceutical composition comprising the compound according to claim 9 , a salt thereof or a hydrate thereof; and
a pharmaceutically acceptable carrier.
18. A pharmaceutical composition comprising the compound according to claim 12 , a salt thereof or a hydrate thereof; and
a pharmaceutically acceptable carrier.
19. A method for treating a disease or condition selected from the group consisting of glaucoma, retinopathy of prematurity, diabetic retinopathy, macular degeneration, hearing disorder, atopic dermatitis, contact dermatitis or hyperesthesia, said method comprising:
administering a pharmacologically effective amount of the compound according to claim 1 , a salt thereof or a hydrate thereof to a patient with said disease or condition.
20. A method for treating a disease or condition selected from the group consisting of glaucoma, retinopathy of prematurity, diabetic retinopathy, macular degeneration, hearing disorder, atopic dermatitis, contact dermatitis or hyperesthesia, said method comprising:
administering a pharmacologically effective amount of the compound according to claim 7 , a salt thereof or a hydrate thereof to a patient with said disease or condition.
21. A method for treating a disease or condition selected from the group consisting of glaucoma, retinopathy of prematurity, diabetic retinopathy, macular degeneration, hearing disorder, atopic dermatitis, contact dermatitis or hyperesthesia, said method comprising:
administering a pharmacologically effective amount of the compound according to claim 9 , a salt thereof or a hydrate of them to a patient with said disease or condition.
22. A method for treating a disease or condition selected from the group consisting of glaucoma, retinopathy of prematurity, diabetic retinopathy, macular degeneration, hearing disorder, atopic dermatitis, contact dermatitis or hyperesthesia, said method comprising:
administering a pharmacologically effective amount of the compound according to claim 12 , a salt thereof or a hydrate thereof to a patient with said disease or condition.