HDAC inhibitor
View Patent ↗A compound having the following formula (I): wherein R 1 is N-containing heterocyclic ring optionally substituted with one or more suitable substituent(s), R 2 is hydroxyamino, R 3 is hydrogen or a suitable substituent, L 1 is —(CH 2 ) n — (wherein n is an integer of 0 to 6) optionally substituted with one or more suitable substituent(s), wherein one or more methylene(s) may be replaced with suitable heteroatom(s), and L 2 is lower alkenylene, or a salt thereof. The compound is useful as a histone deacetylase inhibitor.
1. A compound having the following formula (I):
wherein
R 1 is N-containing heterocyclic ring represented by the following formula:
wherein
R 4 is hydrogen or a group selected from the group consisting of:
(1) lower alkyl optionally substituted with di(lower)alkylamino or hydroxy,
(2) lower alkoxy,
(3) aryl optionally substituted with the substituent selected from the group consisting of halogen, lower alkanoyl, lower alkylsulfonyl, lower alkoxy and di(lower)alkylamino,
(4) lower alkanoyl,
(5) lower alkoxy-carbonyl,
(6) arylcarbonyl,
(7) aryl(lower)alkoxy,
(8) amino optionally mono- or di-substitited with substituent(s) selected from the group consisting of lower alkyl, lower alkanoyl and cycloalkyl,
(9) halo(lower)alkyl,
(10) aryloxy,
(11) aryl(lower)alkyl optionally substituted with hydroxy,
(12) carboxyl,
(13) nitro,
(14) cyano,
(15) halogen,
(16) heteroaryl,
(17) non-aromatic heterocycle optionally substituted with lower alkyl,
(18) hydroxy,
(19) (lower)alkylsulfonylcarbamoyl and
(20) non-aromatic heterocycle carbonyl;
R 5 is hydrogen or a group selected from the group consisting of lower alkyl and aryl(lower)alkyl, and
R 6 , R 7 and R 8 are each hydrogen or lower alkyl,
R 9 is hydrogen or a group selected from the group consisting of:
(1) lower alkyl optionally substituted with di(lower)alkylamino,
(2) aryl optionally substituted with lower alkoxy,
(3) (lower)alkoxy-carbonyl,
(4) cyano,
(5) carbamoyl optionally mono- or di-substituted with (lower)alkyl,
(6) halogen,
(7) (lower)alkyl-carbonyl,
(8) arylcarbonyl and
(9) cyclo(lower)alkyl,
R 10 is hydrogen or a group selected from the group consisting of:
(1) (lower)alkylcarbamoyl,
(2) di(lower)alkylcarbamoyl,
(3) aryl optionally substituted with halogen,
(4) (lower)alkoxy-carbonyl,
(5) carboxy,
(6) non-aromatic heterocycle carbonyl,
(7) halogen,
(8) (lower)alkyl optionally substituted with hydroxy, (lower)alkoxy, non-aromatic heterocycle, aryl, di(lower)alkylamino or halogen, and
(9) adamantyl;
R 11 is hydrogen or aryl(lower)alkyl in which the aryl portion is substituted with lower alkoxy,
R 12 is hydrogen or a group selected from the group consisting of lower alkyl and aryl optionally substituted with halogen,
R 13 is hydrogen or a group selected from the group consisting of lower alkyl and aryl,
R 14 is hydrogen or lower alkyl,
R 2 is hydroxyamino,
R 3 is hydrogen or lower alkoxy,
L 1 is —(CH 2 ) n — (wherein n is 1 to 5) optionally substituted with one or more substituent(s) selected from the group consisting of lower alkyl(s) and aryl(lower)alkyl, and wherein one methylene may be replaced with an oxygen atom, and
L 2 is vinylene;
or a salt thereof.
2. The compound of claim 1 , wherein
R 1 is an N-containing condensed heterocyclic ring represented by the following formula:
wherein R 4 and R 5 are each as defined in claim 1 .
3. The compound of claim 2 , wherein
R 4 and R 5 are each hydrogen,
R 2 is hydroxyamino,
R 3 is hydrogen,
L 1 is —CH 2 —, and
L 2 is vinylene;
or a salt thereof.
4. The compound of claim 1 , wherein
R 1 is an N-containing heterocyclic ring represented by the following formula:
wherein R 9 , R 10 and R 11 are each as defined in claim 1 .
5. The compound of claim 4 , wherein
R 9 is hydrogen or aryl optionally substituted with lower alkoxy,
R 10 is hydrogen or aryl optionally substituted with halogen, and
R 11 is hydrogen,
R 2 is hydroxyamino,
R 3 is hydrogen,
L 1 is —CH 2 —, and
L 2 is vinylene;
or a salt thereof.
6. A compound of the following formula
or a salt thereof.
7. A compound having the following formula (I′):
wherein
R 1 is N-containing condensed heterocyclic ring represented by the following formula:
wherein
R 4 is hydrogen or a group selected from the group consisting of
(1) lower alkyl,
(2) lower alkoxy,
(3) aryl optionally substituted with the substituent selected from the group consisting of halogen, lower alkanoyl, lower alkylsulfonyl, lower alkoxy and di(lower)alkylamino,
(4) lower alkanoyl,
(5) lower alkoxy-carbonyl,
(6) arylcarbonyl,
(7) aryl(lower)alkoxy,
(8) amino optionally mono- or di-substitited with substituent(s) selected from the group consisting of lower alkyl, lower alkanoyl and cycloalkyl,
(9) halo(lower)alkyl,
(10) aryloxy,
(11) aryl(lower)alkyl optionally substituted with hydroxy,
(12) carboxyl,
(13) nitro,
(14) cyano,
(15) halogen,
(16) heteroaryl and
(17) non-aromatic heterocycle optionally substituted with lower alkyl,
R 5 is hydrogen or a group selected from the group consisting of lower alkyl and aryl(lower)alkyl, and
R 6 , R 7 and R 8 are each hydrogen or lower alkyl,
R 2 is hydroxyamino,
R 3 is hydrogen or lower alkoxy,
L 1 is —(CH 2 ) n — (wherein n is 1 or 2) optionally substituted with one or more substituent(s) selected from the group consisting of lower alkyl(s) and aryl(lower)alkyl, and wherein one methylene may be replaced with an oxygen atom, and
L 2 is vinylene;
or a salt thereof.
8. A compound having the following formula (I″):
wherein
R 1 is an N-containing condensed heterocyclic ring represented by the following formula:
wherein
R 4 is hydrogen or a group selected from the group consisting of lower alkyl and aryl, and
R 5 is hydrogen or a group selected from the group consisting of lower alkyl and aryl(lower)alkyl,
R 2 is hydroxyamino,
L 1 is —(CH 2 ) n — (wherein n is 1 or 2) optionally substituted with aryl(lower)alkyl, and
L 2 is vinylene;
or a salt thereof.
9. A composition comprising: the compound of claim 1 in an amount sufficient to inhibit histone deacetylase, and a pharmaceutically acceptable carrier or excipient.
10. A pharmaceutical composition comprising the compound of claim 1 which composition is in a solid form.
11. A pharmaceutical composition comprising: the compound of claim 1 which composition is in a liquid form.
12. The composition of claim 11 in a form suitable for intravenous or intramuscular administration.
13. A method for treating a disease or disorder caused by abnormal gene expression benefited by inhibiting histone deacetylase, comprising administering an amount of the compound of claim 1 effective to inhibit histone deacetylase to a mammal in need thereof.
14. A method for treating a disease or disorder associated with histone deacetylase selected from the group consisting of an inflammation, diabetes, diabetic complications, homozygous thalassemia, fibrosis, cirrhosis, acute promyelocytic leukaemia (APL), organ transplant rejection, and a protozoal infection, which comprises administering an effective amount of the compound of claim 1 to a mammal in need thereof.
15. A commercial package comprising: the pharmaceutical composition of claim 10 and a written matter associated therewith.
16. A composition comprising: the compound of claim 6 in an amount sufficient to inhibit histone deacetylase and a pharmaceutically acceptable carrier or excipient.
17. A pharmaceutical composition comprising an amount of the compound of claim 6 which composition is in a solid form.
18. A pharmaceutical composition comprising: the compound of claim 6 which composition is in a liquid form.
19. The composition of claim 17 in a form suitable for intravenous or intramuscular administration.
20. A method for treating a disease or disorder caused by abnormal gene expression benefited by inhibiting histone deacetylase, comprising administering an amount of the compound of claim 6 effective to inhibit histone deacetylase to a mammal in need thereof.
21. A method for treating a disease or disorder associated with histone deacetylase selected from the group consisting of an inflammation, diabetes, diabetic complications, homozygous thalassemia, fibrosis, cirrhosis, acute promyelocytic leukaemia (APL), organ transplant rejection, and a protozoal infection, which comprises administering an effective amount of the compound of claim 6 to a mammal in need thereof.
22. A commercial package comprising:
the pharmaceutical composition of claim 17 , and a written matter associated therewith.
23. A composition comprising the compound of claim 7 in an amount sufficient to inhibit histone deacetylase, and a pharmaceutically acceptable carrier or excipient.
24. A pharmaceutical composition comprising the compound of claim 7 which composition is in a solid form.
25. A pharmaceutical composition comprising: the compound of claim 7 which composition is in a liquid form.
26. The composition of claim 24 in a form suitable for intravenous or intramuscular administration.
27. A method for treating a disease or disorder caused by abnormal gene expression benefited by inhibiting histone deacetylase, comprising administering an amount of the compound of claim 7 effective to inhibit histone deacetylase to a mammal in need thereof.
28. A method for treating an inflammation, diabetes, diabetic complications, homozygous thalassemia, fibrosis, cirrhosis, acute promyelocytic leukaemia (APL), organ transplant rejection, and a protozoal infection, which comprises administering an effective amount of the compound of claim 7 to a mammal in need thereof.
29. A commercial package comprising: the pharmaceutical composition of claim 24 and a written matter associated therewith.
30. A composition comprising the compound of claim 8 in an amount sufficient to inhibit histone deacetylase, and a pharmaceutically acceptable carrier or excipient.
31. A pharmaceutical composition comprising the compound of claim 8 which composition is in a solid form.
32. A pharmaceutical composition comprising: the compound of claim 8 which composition is in a liquid form.
33. The composition of claim 30 in a form suitable for intravenous or intramuscular administration.
34. A method for treating a disease or disorder associated with histone deacetylase, comprising administering an amount of the compound of claim 8 effective to inhibit histone deacetylase to a mammal in need thereof.
35. A method for treating a disease or a disorder associated with histone deacetylase selected from the group consisting of an inflammation, diabetes, diabetic complications, homozygous thalassemia, fibrosis, cirrhosis, acute promyelocytic leukaemia (APL), organ transplant rejection, and a protozoal infection, which comprises administering an effective amount of the compound of claim 8 to a mammal.
36. A commercial package comprising: the pharmaceutical composition of claim 31 , and a written matter associated therewith.