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;
either:
(1) R 2 is H, halogen, NH 2 , NHR 5 , N(R 5 ) 2 , —O—R 5 or C 1 -C 6 alkyl optionally substituted with —OR 5 ;
R 1 is H, halogen, NH 2 , NHR 5 , N(R 5 ) 2 , and —O—R 5;
R 3 is H, halogen, NH 2 , NHR 5 , N(R 5 ) 2 , or C 1 -C 6 alkyl optionally substituted with —O—R 5 ;
R 4 is one or two substituents independently selected from 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; or
(2) R 1 is H, R 2 and R 3 are —O—CH 3 , and R 4 is selected from the group consisting of H, 3-methoxy, 2,6-dimethyl, 3-methyl, 3,5-dimethoxy and 2-methyl; or
(3) R 1 and R 3 are H, R 2 is —O—CH 3 , and R 4 is H; 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 (a) R 1 =R 2 =R 3 =H or (b) R 1 =R 3 =H, R 2 =methyl, n =1, X =C and R 4 =H, 2-methyl or 3-methyl.
2. The compound of claim 1 or salt thereof, selected from the group having:
(a) n =1, X =C, R 1 =R 2 =H, R 3 =chloro, and R 4 =5-chloro-2-methyl;
(b) n =1, X =C, R 1 =R 3 =H, R 2 =methoxy, and R 4 =3,4-dimethoxy;
(c) n =1, X =C, R 1 =R 3 =H, R 2 =methyl, and R 4 selected from 4-methyl, 2-methoxy, 3-methoxy, 4-methoxy, 3,4-dimethoxy, 3,4-methylenedioxide, 4-ethoxy, 3,5-dimethoxy, 4methoxy-2-methyl, 3,4,5-trimethoxy, 2-fluoro and 2,6-dimethyl;
(d) n =1, X =C, R 1 =R 2 =H, R 3 =methyl, and R 4 selected from 2-methyl, 3-methyl, 2-methoxy, 3-methoxy, 4-methoxy, 4-ethoxy, 2-fluoro, 4-methoxy-2-methyl, 5-methoxy-2- methyl, 2,6-dimethyl, 3,4-dimethoxy, 3,4-methylenedioxide, 3,5-dimethoxy and 3,4,5- trimethoxy;
(e) 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;
(f) n =1, X =C, R 1 =R 3 =H, R 2 =dimethylamino, and R 4 =3-methoxy;
(g) n =1, X =C, R 1 =H, R 2 =R 3 =methoxy, and R 4 =hydrogen, 2-methyl, 3-methyl, 2,6-dimethyl, 3-methoxy or 3,5-dimethoxy; and
(h) 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 1 =R 2 =H, R 3 =chloro, and R 4 =5-chloro-2-methyl;
(b) n =1, X =C, R 1 =R 3 =H, R 2 =methyl, and R 4 selected from 4-methyl, 3-methoxy, 4-methoxy-2-methyl, 2,6-dimethyl and 3,4-methylenedioxide;
(c) n =1, X =C, R 1 =R 3 =H, R 2 =dimethylamino, and R 4 =3-methoxy;
(d) n =1, X =C, R 1 =H, R 2 =R 3 =methoxy, and R 4 =3-methoxy;
(e) 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; and
(f) n =1, X =C, R 1 =R 2 =H, R 3 =methyl, and R 4 selected from 2-methyl, 4-methoxy-2-methyl, 5-methoxy-2-methyl, 2,6-dimethyl and 3,4-methylenedioxide.
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;
(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; and
(c) n =1, X =C, R 1 =R 2 =H, R 3 =methyl, and R 4 selected from 2-methyl, 4-methoxy-2-methyl, 5-methoxy-2-methyl and 2,6-dimethyl.
5. 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.
6. The compound or salt of claim 5 , 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.
7. 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.
8. The compound or salt of claim 7 , 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.
9. 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.
10. 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;
either:
(1) R 2 and R 3 are independently H, halogen, NH 2 , NHR 5 , N(R 5 ) 2 , —O—R 5 or C 1 -C 6 alkyl optionally substituted with —O—R 5 ;
R 1 is H, halogen, NH 2 , NHR 5 , N(R 5 ) 2 , and —O—R 5;
R 4 is one or two substituents independently selected from 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; or
(2) R 1 is H, R 2 and R 3 are —O—CH 3 , and R 4 is H;
(3) R 1 and R 3 are H, R 2 is —O—CH 3 , and R 4 is H; 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 (a) R 1 =R 2 =R 3 =H or (b) R 1 =R 3 =H, R 2 =methyl, n =1, X =C and R 4 =H, 2-methyl or 3-methyl.
11. The method of claim 10 , wherein the compound or salt thereof is selected from the group having:
(a) n =1, X =C, R 1 =R 2 =H, R 3 =chloro, and R 4 =5-chloro-2-methyl;
(b) n =1, X =C, R 1 =R 3 =H, R 2 =methoxy, and R 4 =3,4-dimethoxy;
(c) n =1, X =C, R 1 =R 3 =H, R 2 =methyl, and R 4 selected from 4-methyl, 2-methoxy, 3-methoxy, 4-methoxy, 3,4-dimethoxy, 3,4-methylenedioxide, 4-ethoxy, 3,5-dimethoxy, 4-methoxy-2-methyl, 3,4,5-trimethoxy, 2-fluoro and 2,6-dimethyl;
(d) n =1, X =C, R 1 =R 2 =H, R 3 =methyl, and R 4 selected from 2-methyl, 3-methyl, 2-methoxy, 3-methoxy, 4-methoxy, 4-ethoxy, 2-fluoro, 4-methoxy-2-methyl, 5-methoxy-2-methyl, 2,6-dimethyl, 3,4-dimethoxy, 3,4-methylenedioxide, 3,5-dimethoxy and 3,4,5-trimethoxy;
(e) 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;
(f) n =1, X =C, R 1 =R 3 =H, R 2 =dimethylamino, and R 4 =3-methoxy;
(g) n =1, X =C, R 1 =H, R 2 =R 3 =methoxy, and R 4 =hydrogen, 2-methyl, 3-methyl, 2,6-dimethyl, 3-methoxy or 3,5-dimethoxy; and
(h) 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.
12. The method of claim 10 , wherein the compound or salt thereof is selected from the group having:
(a) n =1, X =C, R 1 =R 1 =R 2 =H, R 3 =chloro, and R 4 =5-chloro-2-methyl;
(b) n =1, X =C, R 1 =R 3 =H, R 2 =methyl, and R 4 selected from 4-methyl, 3-methoxy, 4-methoxy-2-methyl, 2,6-dimethyl and 3,4-methylenedioxide;
(c) n =1, X =C, R 1 =R 3 =H, R 2 =dimethylamino, and R 4 =3-methoxy;
(d) n =1, X =C, R 1 =H, R 2 =R 3 =methoxy, and R 4 =3-methoxy;
(e) 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; and
(f) n =1, X =C, R 1 =R 2 =H, R 3 =methyl, and R 4 selected from 2-methyl, 4-methoxy-2-methyl, 5-methoxy-2-methyl, 2,6-dimethyl and 3,4-methylenedioxide.
13. The method of claim 10 , 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;
(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; and
(c) n =1, X =C, R 1 =R 2 =H, R 3 =methyl, and R 4 selected from 2-methyl, 4-methoxy-2-methyl, 5-methoxy-2-methyl and 2,6-dimethyl.
14. The method of claim 10 , wherein said hyperproliferative disorder is a tumor.
15. The method of claim 14 , wherein the tumor is selected from breast tumors, prostate tumors, colon tumors, ovary tumors, kidney tumors, pancreas tumors, glioblastoma and melanoma.
16. The method of claim 10 , wherein the compound or salt thereof is conjugated to a targeting moiety, optionally through a linking agent.