Use of Rosuvastatin Lactols as Medicaments
This invention relates to the discovery of novel rosuvastatin analogues. More specifically, the invention relates to novel rosuvastatin analogues which have utility in treating conditions treatable by the inhibition of HMG-CoA reductase.
1 . A compound of Formula I and pharmaceutically acceptable salts and solvates thereof:
for use in treating a condition treatable by the inhibition of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase), wherein condition treatable by the inhibition of HMG-CoA reductase is selected from the group consisting of: hypercholesterolemia, atherosclerosis, hyperlipidemia, cardiovascular disease, coronary heart disease, myocardial infarction, stroke, peripheral artery disease, inflammation, dementia, cancer, nuclear cataracts, diabetes and hypertension, 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 groups comprising: halo, C 1-3 alkyl, halo C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, hydroxy, and cyano.
2 . A compound of claim 1 , wherein R 1 is C 1-6 alkyl.
3 . A compound of claim 1 , wherein R 2 —S(O) 2 R 9 wherein R 9 is C 1-6 alkyl.
4 . A compound of claim 1 , wherein R 3 is hydrogen or C 1-6 alkyl.
5 . A compound of claim 1 , wherein R 4 is optionally substituted aryl.
6 . A compound of claim 1 , wherein R 1 is i-propyl, R 2 is —S(O) 2 Me, R 3 is methyl and R 4 4-fluorophenyl.
7 . A compound 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.
8 . A compound of claim 7 , wherein R 5 is hydrogen.
9 . A compound of claim 7 , 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.
10 . A compound of claim 9 , wherein R 5 is benzyl.
11 . A compound of claim 7 , wherein R 5 is C 1-6 alkanoyl pyridine.
12 . A compound of claim 11 , wherein R 5 is 3-methanoyl pyridine.
13 . A compound of 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.
14 . A compound of claim 13 , wherein R 6 is selected from the group consisting of: C 1-6 alkyl, C 1-6 haloalkyl and C 2-6 alkenyl.
15 . A compound of claim 14 wherein R 6 is selected from the group consisting of: methyl, ethyl, propyl, butyl, chloromethyl, chloroethyl, chloropropyl, chlorobutyl and propylene.
16 . A compound of claim 13 , wherein R 6 is optionally substituted aryl.
17 . A compound of claim 16 , wherein R 6 is selected from the group consisting of: C 1-6 alkoxy substituted phenyl and halo substituted phenyl.
18 . A compound of claim 16 , wherein R 6 is selected from the group consisting of: 2,4,6-trifluorophenyl and 2,4-dimethoxyphenyl.
19 . A compound of claim 1 , wherein R 5 is hydrogen and R 6 is an optionally substituted aromatic group.
20 . A 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.
21 . A compound of claim 1 , wherein R 5 is a C 1-6 alkanoyl heteroaryl and R 6 is an optionally substituted C 1-6 alkyl.
22 . A compound of claim 1 , wherein R 7 is H and R 8 is H.
23 . A compound of claim 1 , wherein R a is H, R b is H and m=0, n=1 and o=0.
24 . A compound of claim 1 which has a structure selected from:
25 - 27 . (canceled)