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 pharmaceutically acceptable salt of a compound according to structural formula (I):
or an N-oxide thereof, that is enriched in the 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
wherein the pharmaceutically acceptable salt is an acid addition salt.
2. The pharmaceutically acceptable salt of claim 1 in which the compound according to structural formula (I) is a (2-exo-3-exo) cis racemate.
3. The pharmaceutically acceptable salt of claim 1 which contains about 60% or more of the diastereomer of structural formula (Ia).
4. The pharmaceutically acceptable salt of claim 1 which contains about 90% or more of the diastereomer of structural formula (Ia).
5. The pharmaceutically acceptable salt of claim 1 which contains about 99% or more of the diastereomer of structural formula (Ia).
6. The pharmaceutically acceptable salt of claim 1 in which R 5 is fluoro.
7. The pharmaceutically acceptable salt 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 ,
8. The pharmaceutically acceptable salt of claim 7 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.
9. The pharmaceutically acceptable salt of claim 7 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 ,
10. The pharmaceutically acceptable salt of claim 9 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.
11. The pharmaceutically acceptable salt of claim 10 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 .
12. The pharmaceutically acceptable salt of claim 11 in which R 3 is methyl.
13. A composition comprising a pharmaceutically acceptable salt according to claim 1 and a pharmaceutically acceptable carrier, excipient and/or diluent.
14. The pharmaceutically acceptable salt of claim 1 , wherein the pharmaceutically acceptable salt is an organic acid salt.
15. A composition comprising a pharmaceutically acceptable salt according to claim 14 and a pharmaceutically acceptable carrier, excipient and/or diluent.
16. The pharmaceutically acceptable salt of claim 7 , wherein the pharmaceutically acceptable salt is an acid addition salt of acetic acid, hydrochloric acid, hydrobromic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, oxalic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, palmitic acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, or muconic acid.
17. The pharmaceutically acceptable salt of claim 16 , wherein the pharmaceutically acceptable salt is an acid addition salt of benzoic acid.
18. A composition comprising a pharmaceutically acceptable salt according to claim 16 and a pharmaceutically acceptable carrier, excipient and/or diluent.
19. A composition comprising a pharmaceutically acceptable salt according to claim 17 and a pharmaceutically acceptable carrier, excipient and/or diluent.
20. The pharmaceutically acceptable salt of claim 11 , wherein the pharmaceutically acceptable salt is an acid addition salt of acetic acid, hydrochloric acid, hydrobromic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, oxalic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, palmitic acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, or muconic acid.
21. The pharmaceutically acceptable salt of claim 20 , wherein the pharmaceutically acceptable salt is an acid addition salt of benzoic acid.
22. A composition comprising a pharmaceutically acceptable salt according to claim 20 and a pharmaceutically acceptable carrier, excipient and/or diluent.
23. A composition comprising a pharmaceutically acceptable salt according to claim 21 and a pharmaceutically acceptable carrier, excipient and/or diluent.
24. The pharmaceutically acceptable salt of claim 12 , wherein the pharmaceutically acceptable salt is an acid addition salt of acetic acid, hydrochloric acid, hydrobromic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, oxalic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, palmitic acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, or muconic acid.
25. The pharmaceutically acceptable salt of claim 24 , wherein the pharmaceutically acceptable salt is an acid salt of benzoic acid.
26. A composition comprising a pharmaceutically acceptable salt according to claim 24 and a pharmaceutically acceptable carrier, excipient and/or diluent.
27. A composition comprising a pharmaceutically acceptable salt according to claim 25 and a pharmaceutically acceptable carrier, excipient and/or diluent.