5, 6, or 7-substituted-3-(hetero)arylisoquinolinamine derivatives and therapeutic use thereof
The present invention relates to 5, 6, or 7-substituted-3-(hetero)arylisoquinolinamine derivatives represented by general formula D, their pharmacologically acceptable salts thereof, and compositions containing such compounds. Methods for treating hyperproliferative disorders by administering the compounds are also included.
1. A compound according to formula D
wherein n is 1;
X is C; R 1 , R 2 and R 3 are independently H, NH 2 , NHR 5 , or N(R 5 ) 2 ;
R 4 is one or two substituents independently selected from H, 3,4-methylendioxide, halogen, —O—R 5 , and C 1 -C 6 alkyl optionally substituted with —O—R 5 ;
R 5 is C 1 -C 6 alkyl; and
when there is more than one group R 5 , each of the R 5 groups may be the same or different or a pharmaceutically acceptable salt thereof;
with the proviso that the compound is not a compound having R 1 ═R 2 ═R 3 ═H.
2. The compound of claim 1 or salt thereof, selected from the group having:
(a)
n=1, X═C, R 1 ═dimethylamino, R 2 ═R 3 ═H, and R 4 selected from hydrogen, 2-methyl, 3,4-dimethoxy and 2,6-dimethyl;
(b) n=1, X═C, R 1 ═R 3 ═H, R 2 =dimethylamino, and R 4 =3-methoxy; and
(c) n=1, X═C, R 1 ═R 2 ═H, R 3 =dimethylamino, and R 4 selected from 3-methoxy, 3-methyl, 3,4-dimethoxy and 3,5-dimethoxy.
3. The compound of claim 1 or salt thereof, selected from the group having:
(a) n=1, X═C, R 1 ═R 3 ═H, R 2 =dimathylamino, and R 4 ═3-methoxy; and
(b) n=1, X═C, R 1 ═R 2 ═H, R 3 =dimethylamino, and R 4 selected from 3-methoxy, 3-methyl, 3,4-dimethoxy and 3,5-dimethoxy.
4. The compound of claim 1 or a salt thereof, selected from the group having:
(a) n=1, X═C, R 1 ═R 3 ═H, R 2 =dimethylamino, and R 4 ═3-methoxy; and
(b) n=1, X═C, R 1 ═R 2 ═H, R 3 =dimethylamino, and R 4 selected from 3-methoxy, 3-methyl and 3,5-dimethoxy.
5. The compound of claim 1 or a salt thereof, selected from the group having n=1, X═C, R 1 ═R 2 ═H, R 3 =dimethylamino, and R 4 selected from 3-methoxy and 3-methyl.
6. The compound of claim 1 or salt thereof having an IC 50 of not greater than 0.2 μM with respect to at least one cell line for a tumor selected from breast tumors, prostate tumors, colon tumors, ovary tumors, kidney tumors, pancreas tumors, glioblastoma and melanoma.
7. The compound or salt of claim 6 , wherein the cell line is selected from human MDA-MB-231, PC3, HCT116, HCT-15, OVCAR-3, Caki-1, PANC-1, SNB-19 and SK-MEL-28.
8. The compound of claim 1 or salt thereof having an IC 50 of not greater than 0.1 μM with respect to at least one cell line for a tumor selected from breast tumors, prostate tumors, colon tumors, ovary tumors, kidney tumors, pancreas tumors, glioblastoma and melanoma.
9. The compound or salt of claim 8 , wherein the cell line is selected from human MDA-MB-231, PC3, HCT116, HCT-15, OVCAR-3, Caki-1, PANC-1, SNB-19 and SK-MEL-28.
10. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
11. A method-for treating a hyperproliferative disorder comprising administering a composition comprising a compound according to formula D
wherein n is 1;
X is C; R 1 , R 2 and R 3 are independently H, NH 2 , NHR 5 , or N(R 5 ) 2 ;
R 4 is one or two substituents independently selected from H, 3,4-methylendioxide, halogen, —O—Rand C 1 -C 6 alkyl optionally substituted with —O—R 5 ;
R 5 is C 1 -C 6 alkyl; and
when there is more than one group R 5 , each of the R 5 groups may be the same or different or a pharmaceutically acceptable salt thereof;
with the proviso that the compound is not a compound having R 1 =R 2 =R 3 ═H.
12. The method of claim 11 wherein the compound or salt thereof is selected from the group having:
(a)
n=1, X═C, R 1 =dimethylamino, R 2 ═R 3 ═H, and R 4 selected from hydrogen, 2-methyl, 3,4-dimethoxy and 2,6-dimethyl;
(b) n=1, X═C, R 1 ═R 3 ═H, R 2 =dimethylamino, and R 4 =3-methoxy; and
(c) n=1, X═C, R 1 ═R 2 ═H, R 3 =dimethylamino, and R 4 selected from 3-methoxy, 3-methyl, 3,4-dimethoxy and 3,5-dimethoxy.
13. The method of claim 11 , wherein the compound or salt thereof is selected from the group having:
(a) n=1, X═C, R 1 ═R 3 ═H, R 2 =dimethylamino, and R 4 =3-methoxy; and
(b) n=1, X═C, R 1 ═R 2 ═H, R 3 =dimethylamino, and R 4 selected from 3-methoxy, 3-methyl, 3,4-dimethoxy and 3,5-dimethoxy.
14. The method of claim 11 wherein the compound or salt thereof is selected from the group having:
(a) n=1, X═C, R 1 ═R 3 ═H, R 2 =dimethylamino, and R 4 =3-methoxy; and
(b) n=1, X═C, R 1 ═R 2 ═H, R 3 =dimethylamino, and R 4 selected from 3-methoxy, 3-methyl and 3,5-dimethoxy.
15. The method of claim 11 wherein the compound or salt thereof is selected from the group having n=1, X═C, R 1 ═R 2 ═H, R 3 =dimethylamino, and R 4 selected from 3-methoxy and 3-methyl.
16. The method of claim 11 , wherein said hyperproliferative disorder comprises a tumor.
17. The method of claim 16 , wherein the tumor is selected from breast tumors, prostate tumors, colon tumors, ovary tumors, kidney tumors, pancreas tumors, glioblastoma and melanoma.
18. The method of claim 11 , wherein the compound or salt thereof is conjugated to a targeting moiety, optionally through a linking agent.