Use of rosuvastatin lactols as medicaments
This invention relates to the discovery of novel rosuvastatin analogs. More specifically, the invention relates to novel rosuvastatin analogs which have utility in treating conditions treatable by the inhibition of HMG-CoA reductase.
1. A method of treating a condition comprising: administering an effective amount of a compound of Formula I
or pharmaceutically acceptable salts or solvates thereof to inhibit the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase),
wherein the condition is selected from the group consisting of: hypercholesterolemia, atherosclerosis, hyperlipidemia, coronary heart disease, myocardial infarction, stroke, and peripheral artery disease,
further wherein:
R 1 and R 4 are independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl, aryl, C 1-4 alkyl aryl, heterocyclyl, and C 1-4 alkyl heteroaryl;
R 2 is —S(O) 2 R 9 wherein R 9 is C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkyl aryl or aryl;
R 3 is hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl or aryl;
R 5 and R 6 are independently 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; provided always that both R 5 and R 6 are not hydrogen;
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 ) 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 groups R 1 to R 9 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 method of claim 1 wherein the condition is selected from the group consisting of: hypercholesterolemia, atherosclerosis, hyperlipidemia, coronary heart disease, myocardial infarction, and peripheral artery disease.
3. The method of claim 1 wherein the condition is selected from the group consisting of: hypercholesterolemia, atherosclerosis and hyperlipidemia.
4. The method of claim 1 , wherein R 1 is C 1-6 alkyl.
5. The method of claim 1 , wherein R 9 is C 1-6 alkyl.
6. The method of claim 1 , wherein R 3 is hydrogen or C 1-6 alkyl.
7. The method of claim 1 , wherein R 4 is optionally substituted aryl.
8. The method of claim 1 , wherein R 1 is i-propyl, R 2 is —S(O) 2 Me, R 3 is methyl and R 4 is 4-fluorophenyl.
9. The method of claim 1 , wherein R 5 is selected from the group consisting of: hydrogen, C 1-6 alkyl, aryl, C 1-6 alkyl aryl, C 1-6 alkanoyl aryl, heteroaryl, C 1-6 alkanoyl heteroaryl and C 1-6 alkyl heteroaryl.
10. The method of claim 9 , wherein R 5 is hydrogen.
11. The method of claim 9 , 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.
12. The method of claim 11 , wherein R 5 is benzyl.
13. The method of claim 9 , wherein R 5 is C 1-6 alkanoyl pyridine.
14. The method of claim 13 , wherein R 5 is 3-methanoyl pyridine.
15. The method claim 1 , wherein R 6 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, heteroaryl and C 1-6 alkyl heteroaryl.
16. The method of claim 15 , wherein R 6 is selected from the group consisting of: C 1-6 alkyl, C 1-6 halo alkyl and C 2-6 alkenyl.
17. The method of claim 16 wherein R 6 is selected from the group consisting of: methyl, ethyl, propyl, butyl, chloromethyl, chloroethyl, chloropropyl, chlorobutyl and propylene.
18. The method of claim 15 , wherein R 6 is optionally substituted aryl.
19. The method of claim 18 , wherein R 6 is selected from the group consisting of: C 1-6 alkoxy substituted phenyl and halo substituted phenyl.
20. The method of claim 19 , wherein R 6 is selected from the group consisting of: 2,4,6-trifluorophenyl and 2,4-dimethoxyphenyl.
21. The method of claim 1 , wherein R 5 is hydrogen and R 6 is an optionally substituted aryl group.
22. The method 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.
23. The method of claim 1 , wherein R 5 is a C 1-6 alkanoyl heteroaryl and R 6 is an optionally substituted C 1-6 alkyl.
24. The method of claim 1 , wherein R 7 is H and R 8 is H.
25. The method of claim 1 , wherein R a is H, R b is H and m=0, n=1 and o=0.
26. The method of claim 1 wherein in the step of administering the compound has a structure selected from: