Rosuvastatin and atorvastatin derivatives
This invention relates to the discovery of novel rosuvastatin and atorvastatin analogues.
1. A compound of Formula I and pharmaceutically acceptable salts thereof:
wherein:
A is
wherein R 1a is i-propyl, R 2a is —S(O) 2 Me, R 3a is methyl and R 4a 4-fluorophenyl;
R 5 and R 6 are independently selected and R 5 is selected from the group consisting of: hydrogen, C 1-6 haloalkyl, C 2-6 alkenyl, C 3-6 cycloalkyl, aryl, C 1-6 alkyl aryl, C 1-6 alkanoyl aryl, heteroaryl, C 1-6 alkanoyl heteroaryl and C 1-6 alkyl heteroaryl; and R 6 is selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 3-6 cycloalkyl, aryl, C 1-6 alkanoyl aryl, heteroaryl, C 1-6 alkanoyl heteroaryl and C 1-6 alkyl heteroaryl; provided always that R 5 is not benzyl or H when R 6 is methyl;
R 7 and R 8 are independently selected from the group consisting of: C 1-4 alkyl and halo;
X is —(CR a R b ) m (CR a ═CR b ) n (CR a R b ) o — where R a and R b are independently selected from the group consisting of: H, methyl, ethyl and halo and m, n, and o are independently 0, 1, 2, or 3 provided that m+n+o is not more than 3; and wherein
each of the above R groups may, where chemically possible, be independently optionally substituted by from 1 to 5 groups chosen independently at each occurrence from the group consisting of: halo, C 1-3 alkyl, halo C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, hydroxy, and cyano.
2. The compound of claim 1 , wherein R 5 is selected from the group consisting of: hydrogen, aryl, C 1-6 alkyl aryl, C 1-6 alkanoyl aryl, heteroaryl, C 1-6 alkanoyl heteroaryl and C 1-6 alkyl heteroaryl.
3. The compound of claim 2 , wherein R 5 is hydrogen.
4. The compound of claim 2 , wherein R 5 is selected from the group consisting of: —C 1 alkyl-Ph, —C 2 alkyl-Ph, —C 3 alkyl-Ph, and —C 4 alkyl-Ph.
5. The compound of claim 4 , wherein R 5 is benzyl.
6. The compound of claim 5 , wherein R 5 is C 1-6 alkanoyl pyridine.
7. The compound of claim 6 , wherein R 5 is 3-methanoyl pyridine.
8. The compound of claim 1 , wherein R 6 is selected from the group consisting of: C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 3-6 cycloalkyl, aryl, heteroaryl and C 1-6 alkyl heteroaryl.
9. The compound of claim 8 , wherein R 6 is selected from the group consisting of: C 1-6 alkyl, C 1-6 haloalkyl and C 2-6 alkenyl.
10. The compound of claim 9 wherein R 6 is selected from the group consisting of: methyl, ethyl, propyl, butyl, chloromethyl, chloroethyl, chloropropyl, chlorobutyl and propylene.
11. The compound of claim 8 , wherein R 6 is optionally substituted aryl.
12. The compound of claim 11 , wherein R 6 is selected from the group consisting of: C 1-6 alkoxy substituted phenyl and halo substituted phenyl.
13. The compound of claim 11 , wherein R 6 is selected from the group consisting of: 2,4,6-trifluorophenyl and 2,4-dimethoxyphenyl.
14. The compound of claim 8 , wherein R 6 is selected from the group consisting of: C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl and aryl.
15. The compound of claim 14 wherein R 6 is selected from the group consisting of: methyl, ethyl, propyl, butyl, cyclohexyl and allyl.
16. The compound of claim 1 , wherein R 5 is hydrogen and R 6 is an optionally substituted aryl group.
17. The compound of claim 1 , wherein R 5 is an optionally substituted benzyl and R 6 is an optionally substituted C 1-6 alkyl, an optionally substituted C 2-6 alkenyl or a C 1-6 haloalkyl, or wherein R 5 is a C 1-6 alkanoyl heteroaryl and R 6 is an optionally substituted C 1-6 alkyl, or wherein R 5 is hydrogen and R 6 is an C 1-6 alkyl, C 3-6 cycloalkyl or an optionally substituted aryl.
18. The compound of claim 1 , wherein R 7 is H and R 8 is H.
19. The compound of claim 1 , wherein R a is H, R b is H and m=0, n=1 and o=0.
20. The compound of claim 1 , wherein each R a is H, each R b is H and m=2, n=0 and o=0.
21. The compound of claim 1 which has a structure selected from:
22. A compound of Formula I and pharmaceutically acceptable salts thereof:
wherein:
A is
wherein R 1a is i-propyl, R 2a is —S(O) 2 Me, R 3a is methyl and R 4a 4-fluorophenyl;
R 5 and R 6 are independently selected and R 5 is selected from the group consisting of: hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 3-6 cycloalkyl, aryl, C 1-6 alkyl aryl, C 1-6 alkanoyl aryl, heteroaryl, C 1-6 alkanoyl heteroaryl and C 1-6 alkyl heteroaryl; and R 6 is selected from the group consisting of C 2-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl, aryl, heteroaryl and C 1-6 alkyl heteroaryl;
R 7 and R 8 are independently selected from the group consisting of: H, C 1-4 alkyl and halo;
X is —(CR a R b ) m (CR a ═CR b ) m (CR a R b ) o — where R a and R b are independently selected from the group comprising: H, methyl, ethyl and halo and m, n, and o are independently 0, 1, 2, or 3 provided that m+n+o is not more than 3; and wherein
each of the above R groups may, where chemically possible, be independently optionally substituted by from 1 to 5 groups chosen independently at each occurrence from the group consisting of: halo, C 1-3 alkyl, halo C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, hydroxy, and cyano.