Stereoisomerically enriched 3-aminocarbonyl bicycloheptene pyrimidinediamine compounds and their uses
View Patent ↗The present invention provides stereoisomers and stereoisomeric mixtures of 3-aminocarbonyl-bicycloheptene-2,4-pyrimidinediamine compounds having antiproliferative activity, compositions comprising the compounds and methods of using the compounds to inhibit cellular proliferation and to treat proliferate diseases such as tumorigenic cancers.
1. A compound according to structural formula (I):
or a salt, or N-oxide thereof, that is enriched in the corresponding diastereomer of structural formula (Ia):
wherein:
each R 1 is independently selected from the group consisting of hydrogen, lower alkyl, —(CH 2 ) n —OH, —OR a , —O(CH 2 ) n —R a , —O(CH 2 ) n —R b , —C(O)OR a , halo, —CF 3 and —OCF 3 ;
each R 2 is independently selected from the group consisting of hydrogen, lower alkyl, —OR a , —O(CH 2 ) n —R a , —O(CH 2 ) n —R b , —NHC(O)R a , halo, —CF 3 , —OCF 3 ,
each R 3 is independently selected from the group consisting of hydrogen, lower alkyl, —(CH 2 ) n —OH, —OR a , —O(CH 2 ) n —R a , —O(CH 2 ) n —R b , halo, —CF 3 , —OCF 3 ,
each R 4 is independently selected from the group consisting of hydrogen, lower alkyl, arylalkyl, —OR a , —NR c R c , —C(O)R a , —C(O)OR a and —C(O)NR c R c ;
R 5 is hydrogen, halo, fluoro, —CN, —NO 2 , CO 2 R a , or —CF 3 ;
each n is independently an integer from 1 to 3;
each R a is independently selected from the group consisting of hydrogen, lower alkyl and lower cycloalkyl;
each R b is independently selected from the group consisting of —OR a , —CF 3 , —OCF 3 , —NR c R c , —C(O)R a , —C(O)OR a , —C(O)NR c R c and —C(O)NR a R d ;
each R c is independently selected from the group consisting of hydrogen and lower alkyl, or, alternatively, two R c substituents may be taken together with the nitrogen atom to which they are bonded to form a 5-7 membered saturated ring which optionally includes 1-2 additional heteroatomic groups selected from O, NR a , NR a —C(O)R a , NR a —C(O)OR a and NR a —C(O)NR a ; and
each R d is independently lower mono-hydroxyalkyl or lower di-hydroxyalkyl.
2. The compound of claim 1 in which the compound according to structural formula (I) is a (2-exo-3-exo) cis racemate.
3. The compound of claim 1 which contains about 60% or more of the diastereomer of structural formula (Ia).
4. The compound of claim 1 which contains about 90% or more of the diastereomer of structural formula (Ia).
5. The compound of claim 1 which contains about 99% or more of the diastereomer of structural formula (Ia).
6. The compound of claim 1 in which R 5 is fluoro.
7. The compound of claim 6 in which R 1 is hydrogen; R 2 is
and R 3 is other than
8. The compound of claim 7 in which R 3 is hydrogen, methyl, methoxy, trifluoromethyl or chloro.
9. The compounds of claim 7 in which R 4 is methyl, —C(O)CH 3 , —C(O)OCH 3 or —C(O)OCH 2 CH 3 .
10. The compound of claim 6 in which R 1 is hydrogen; R 2 is other than
and R 3 is
11. The compound of claim 10 in which R 2 is hydrogen, methyl, methoxy, trifluoromethyl or chloro.
12. The compound of claim 10 in which R 4 is methyl, —C(O)CH 3 , —C(O)OCH 3 or —C(O)CH 2 CH 3 .
13. The compound of claim 6 in which R 2 is other than
and R 3 is other than
14. The compound of claim 13 in which R 1 and R 2 are each hydrogen and R 3 is —OCH 2 NHR a .
15. The compound of claim 13 in which R 1 , R 2 and R 3 are each, independently selected from the group consisting of hydrogen, methyl, methoxy, trifluoromethyl and chloro, with the proviso that at least two of R 1 , R 2 and R 3 are other than hydrogen.
16. The compound of claim 6 in which R 1 is hydrogen; R 2 is selected from the group consisting of hydrogen,
and R 3 is selected from the group consisting of hydrogen, lower alkyl, halo, —CF 3 ,
17. The compound of claim 16 in which R 3 is selected from the group consisting of hydrogen, methyl, chloro, —CF 3 ,
and R 4 is methyl, —COR a or —CO(O)R a where R a is methyl or ethyl.
18. The compound of claim 16 in which R 2 is selected from the group consisting of hydrogen,
and R 3 is selected from the group consisting of hydrogen, lower alkyl, halo, —CF 3 ,
19. The compound of claim 18 in which R 3 is selected from the group consisting of hydrogen, methyl, chloro, —CF 3 ,
and R 4 is methyl, —COR a or —CO(O)R a wherein R a is methyl or ethyl.
20. The compound of claim 19 in which R 2 is
R 4 is —COR a wherein R a is methyl; and R 3 is hydrogen.
21. The compound of claim 19 in which R 2 is
R 4 is —CO(O)R a wherein R a is ethyl; and R 3 is hydrogen.
22. The compound of claim 19 in which R 2 is
and R 3 is hydrogen.
23. The compound of claim 19 in which R 2 is hydrogen; R 3 is
and R 4 is methyl, —COR a or —CO(O)R a where R a is methyl or ethyl.
24. The compound of claim 19 in which R 2 is
R 4 is methyl; and R 3 is selected from the group consisting of hydrogen, methyl, chloro and —CF 3 .
25. The compound of claim 24 in which R 3 is hydrogen, chloro, or —CF 3 .
26. A composition comprising a compound according to claim 1 and a carrier, excipient, and/or diluent.
27. The composition of claim 26 in which the carrier, excipient, and/or diluent is acceptable for pharmaceutical uses.