Methyltransferase inhibitors for treating cancer
Compounds having methyltransferase inhibitory activity are disclosed. The compounds have the structure and are useful in the treatment of cancer and similar diseases associated with inappropriate methyltransferase activity.
1. A compound of formula I or II
wherein:
X 1 is N or CH;
Q is NH or 0;
A is chosen from direct bond, (C 1 -C 20 )hydrocarbon, (C 1 -C 20 )oxaalkyl and (C 1 -C 20 )azaalkyl;
R 1 is chosen from —C(═NH)NH 2 , —C(═NH)NH(C 1 -C 10 )hydrocarbon, fluoro(C 1 -C 6 )hydrocarbon, and —CH(NH 2 )COOH, with the provisos that,
(1) when A is a direct bond, R 1 cannot be H;
(2) when QR 3 is OH, R 1 cannot be fluoro(C 2 -C 6 )hydrocarbon; or
the combination R 1 A is chosen from ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, cyclic hydrocarbon groups of from 3 to 8 carbon atoms, benzyl, phenethyl, cyclohexylmethyl, adamantyl, camphoryl and naphthylethyl;
R 2 is chosen from hydrogen, —C(═NH)NH 2 , —C(═NH)NH(C 1 -C 10 )hydrocarbon and —CH(NH 2 )COOH;
R 3 is chosen from H and (C 1 -C 20 ) hydrocarbon; and
n is 1 or 2.
2. A compound according to claim 1 wherein R 3 is chosen from H, methyl and ethyl.
3. A compound according to claim 1 wherein n is 2.
4. A compound according to claim 3 wherein QR 3 is OH.
5. A compound according to claim 1 of formula Ia or IIa
wherein:
X 1 is N or CH;
A is chosen from direct bond, (C 1 -C 20 )hydrocarbon, (C 1 -C 20 )oxaalkyl and (C 1 -C 20 )azaalkyl;
R 1 is chosen from —C(═NH)NH 2 , —C(═NH)NH(C 1 -C 10 )hydrocarbon, CF 3 and —CH(NH 2 )COOH, with the proviso that, when A is a direct bond, R 1 cannot be H; or
the combination R 1 A is chosen from ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, cyclic hydrocarbon groups of from 3 to 8 carbon atoms, benzyl, phenethyl, cyclohexylmethyl, adamantyl, camphoryl and naphthylethyl;
R 2 is chosen from hydrogen, —C(═NH)NH 2 , —C(═NH)NH(C 1 -C 10 )hydrocarbon and —CH(NH 2 )COOH.
6. A compound according to claim 1 of formula I or Ia wherein R 1 -A is chosen from ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, cyclic hydrocarbon groups of from 3 to 8 carbon atoms, benzyl and (C 3 -C 6 )oxaalkyl.
7. A compound according to claim 1 of formula I or Ia wherein R 1 -A is chosen from amino(C 1 -C 6 )alkyl, benzylamino(C 1 -C 6 )alkyl and guanidino(C 1 -C 6 )alkyl.
8. A compound according to claim 1 of formula I or Ia wherein R 1 -A is chosen from HOOC(NH 2 )CH-azaalkyl and NH 2 (NH═)C-azaalkyl.
9. A compound according to claim 1 of formula II or IIa wherein R 2 -A is chosen from hydrogen, (C 1 -C 6 )alkyl, benzyl and —C(═NH)NH 2 .
10. A compound according to claim 1 wherein X 1 is N.
11. A compound according to claim 1 wherein X 1 is CH.
12. A method for inhibiting the activity of a G9a, GLP1, SET7/9, SET8, SETD2, PRMT1, PRMT3, SUV39H2, CARM1, or SMYD2-FL methyltransferase enzyme comprising bringing said methyltransferase enzyme into contact with a compound according to claim 1 .
13. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to claim 1 .