1,3-benzodioxole derivative
The present invention provides a compound having a particular chemical structure or a pharmacologically acceptable salt thereof which has an excellent inhibitory effect on EZH1 and/or EZH2 activity. The present invention provides a compound having a 1, 3-benzodioxole structure represented by the general formula (I) or a pharmacologically acceptable salt thereof, or a pharmaceutical composition comprising the compound (wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and V in the formula (I) are each as defined in the present specification).
1. A method of treating lymphoma in a subject in need thereof, comprising administering to a subject with a lymphoma in which enhancer of zeste homolog 2 (EZH2) is overexpressed or hyperactive a compound represented by the formula (I) or a pharmacologically acceptable salt thereof:
wherein
R 1 represents a hydrogen atom, a halogen atom, a C 1 -C 6 alkyl group optionally having 1 to 3 halogen atoms,
V represents a single bond,
R 2 represents a hydrogen atom, a C 1 -C 6 alkyl group, or a C 3 -C 6 cycloalkyl group wherein the C 1 -C 6 alkyl group, or a C 3 -C 6 cycloalkyl group optionally has a substituent group of —NR 20 R 21 , wherein R 20 and R 21 each independently represent a hydrogen atom, a formyl group, or a C 1 -C 6 alkyl group,
R 3 represents a C 1 -C 6 alkyl group,
R 4 represents a halogen atom or a C 1 -C 6 alkyl group optionally having 1 to 3 halogen atoms,
R 5 represents a C 1 -C 6 alkyl group or a C 1 -C 6 alkoxy group,
R 6 represents a C 1 -C 6 alkyl group.
2. The method of claim 1 , wherein the cancer overexpresses EZH2.
3. The method of claim 1 , wherein the cancer has a somatic mutation in EZH2.
4. The method of claim 1 further comprising administering an additional antitumor agent.
5. The method of claim 4 , wherein the additional antitumor agent is selected from the group consisting of an alkylating agent, an antimetabolite, an antitumor antibiotic, an antitumor plane component, a biological response modifier (BRM), a hormone, a vitamin, an antitumor antibody, cisplatin, carboplatin, oxaliplatin, tamoxifen, camptothecin, ifosfamide, cyclophosphamide, melphalan, L-asparaginase, aceglatone, sizofiran, picibanil, procarbazine, pipobroman, neocarzinostatin, hydroxyurea, ubenimex, and krestin.
6. The method of claim 1 , wherein the compound is administered orally.
7. The method of claim 1 , wherein R 1 represents a halogen atom.
8. The method of claim 1 , wherein R 1 represents a chloro group.
9. The method of claim 1 , wherein R 2 represents a C 3 -C 6 cycloalkyl group and the C 3 -C 6 cycloalkyl group has a substituent group of —NR 20 R 21 , wherein R 20 and R 21 each independently represent a hydrogen atom, a formyl group, or a C 1 -C 6 alkyl group.
10. The method of claim 1 , wherein R 3 represents a methyl group.
11. The method of claim 1 , wherein the compound is (2R)-7-chloro-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide or a pharmacologically acceptable salt thereof.
12. The method of claim 1 , wherein the compound is (2R)-7-chloro-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide p-toluenesulfonate.
13. A method of treating lymphoma in a subject in need thereof, comprising administering to a subject with lymphoma in which enhancer of zeste homolog 2 (EZH2) is overexpressed or hyperactive any one compound selected from the following group or a pharmacologically acceptable salt thereof:
7-bromo-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide;
(2R)-7-bromo-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide;
7-chloro-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide;
(2R)-7-chloro-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide;
2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4,7-trimethyl-1,3-benzodioxole-5-carboxamide;
(2S)-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4,7-trimethyl-1,3-benzodioxole-5-carboxamide;
4,7-dichloro-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2-methyl-1,3-benzodioxole-5-carboxamide;
2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide; or
2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-7-ethyl-2,4-dimethyl-1,3-benzodioxole-5-carboxamide.
14. The method of claim 13 , wherein the cancer overexpresses EZH2.
15. The method of claim 13 , wherein the cancer has a somatic mutation in EZH2.
16. The method of claim 13 further comprising administering an additional antitumor agent.
17. The method of claim 16 , wherein the additional antitumor agent is selected from the group consisting of an alkylating agent, an antimetabolite, an antitumor antibiotic, an antitumor plane component, a biological response modifier (BRM), a hormone, a vitamin, an antitumor antibody, cisplatin, carboplatin, oxaliplatin, tamoxifen, camptothecin, ifosfamide, cyclophosphamide, melphalan, L-asparaginase, aceglatone, sizofiran, picibanil, procarbazine, pipobroman, neocarzinostatin, hydroxyurea, ubenimex, and krestin.
18. The method of claim 13 , wherein the compound is administered orally.
19. A method of inhibiting enhancer of zeste homolog 2 (EZH2), comprising contacting EZH2 with a compound represented by the formula (I) or a pharmacologically acceptable salt thereof:
wherein
R 1 represents a hydrogen atom, a halogen atom, or a C 1 -C 6 alkyl group optionally having 1 to 3 halogen atoms,
V represents a single bond,
R 2 represents a hydrogen atom, a C 1 -C 6 alkyl group, or a C 3 -C 6 cycloalkyl group wherein the C 1 -C 6 alkyl group, or a C 3 -C 6 cycloalkyl group optionally has a substituent group of —NR 20 R 21 , wherein R 20 and R 21 each independently represent a hydrogen atom, a formyl group, or a C 1 -C 6 alkyl group,
R 3 represents a C 1 -C 6 alkyl group,
R 4 represents a halogen atom or a C 1 -C 6 alkyl group optionally having 1 to 3 halogen atoms,
R 5 represents a C 1 -C 6 alkyl group or a C 1 -C 6 alkoxy group,
R 6 represents a C 1 -C 6 alkyl group.
20. The method of claim 19 , wherein R 1 represents a halogen atom.
21. The method of claim 19 , wherein R 1 represents a chloro group.
22. The method of claim 19 , wherein R 2 represents a C 3 -C 6 cycloalkyl group and the C 3 -C 6 cycloalkyl group has a substituent group of —NR 20 R 21 , wherein R 20 and R 21 each independently represent a hydrogen atom, a formyl group, or a C 1 -C 6 alkyl group.
23. The method of claim 19 , wherein R 3 represents a methyl group.
24. The method of claim 19 , wherein the compound is (2R)-7-chloro-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide or a pharmacologically acceptable salt thereof.
25. The method of claim 19 , wherein the compound is (2R)-7-chloro-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide p-toluenesulfonate.
26. The method of claim 19 , wherein the compound is selected from the group consisting of:
7-bromo-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide;
(2R)-7-bromo-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide;
7-chloro-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide;
(2R)-7-chloro-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide;
2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4,7-trimethyl-1,3-benzodioxole-5-carboxamide;
(2S)-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4,7-trimethyl-1,3-benzodioxole-5-carboxamide;
4,7-dichloro-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2-methyl-1,3-benzodioxole-5-carboxamide;
2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide; or
2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-7-ethyl-2,4-dimethyl-1,3-benzodioxole-5-carboxamide.
27. The method of claim 3 , wherein the somatic mutation is a substitution mutation at tyrosine 641, alanine 677, or alanine 687.
28. The method of claim 27 , wherein the somatic mutation is selected from the group consisting of Y641F, Y641N, Y641S, Y641H, Y641C, A677G, and A687V.
29. The method of claim 15 , wherein the somatic mutation is a substitution mutation at tyrosine 641, alanine 677, or alanine 687.
30. The method of claim 29 , wherein the somatic mutation is selected from the group consisting of Y641F, Y641N, Y641S, Y641H, Y641C, A677G, and A687V.