BIPHENYLAZETIDINONE CHOLESTEROL ABSORPTION INHIBITORS
The invention relates to a chemical genus of 4-biphenyl-1-phenylazetidin-2-ones useful in the treatment of hypercholesterolemia and other disorders. The compounds have the general formula I: Pharmaceutical compositions and methods for treating cholesterol- and lipid-associated diseases are also disclosed.
1 . A compound of formula I
wherein
R 1 and R 2 are selected independently from the group consisting of hydrogen, halogen, —OH, and lower alkoxy;
R 4 is selected from the group consisting of hydrogen, —OH, and a glucuronide;
R 5 is selected from the group consisting of —OH, —PO 3 H 2 , —SO 3 H, a sugar, a polyol, a glucuronide and a sugar carbamate; and
U is (C 2 -C 6 )-alkylene in which one or more individual —CH 2 — is replaced by a radical chosen from —S—, —S(═O)—, —SO 2 —, —O—, —C(═O)—, —CH(glucuronide)-, and —CH(OH)—, or a pharmaceutically acceptable salt thereof, in any stereoisomeric form, or a mixture of any such compounds in any ratio.
2 . A compound according to claim 1 of formula Ia
3 . A compound according to claim 1 , wherein U is (C 2 -C 4 )-alkylene in which one or more individual —CH 2 — is replaced.
4 . A compound according to claim 3 , wherein one or more individual —CH 2 — is replaced by —CH(OH)—.
5 . A compound according to claim 3 , wherein one or more individual —CH 2 — is replaced by —CH(glucuronide)-, —SCH 2 CH(OH)—, —S(═O)CH 2 CH(OH)—, —SO 2 CH 2 CH(OH)—, —SCH 2 C(═O)—, —S(═O)CH 2 C(═O)—, —SO 2 CH 2 C(═O)— —OCH 2 CH(OH)—, —OCH 2 C(═O)—, —CH(OH)CH 2 O—, —C(═O)CH 2 O—, —CH(OH)CH 2 S—, —C(═O)CH 2 S—, —CH 2 CH(OH)—, —CH 2 CH 2 CH 2 CH(OH)—, —OCH 2 CH 2 C(═O)—, SCH 2 CH 2 CH(OH)—, —SCH 2 CH 2 C(═O)—, —S(═O)CH 2 CH 2 CH(OH)—, —S(═O)CH 2 CH 2 C(═O)—, —SO 2 CH 2 CH 2 CH(OH)—, —SO 2 CH 2 CH 2 C(═O)—, —CH(OH)CH 2 CH(OH)—, or —OCH 2 CH 2 CH(OH)—.
6 - 28 . (canceled)
29 . A compound according to claim 4 , wherein one or more —CH(OH)— is replaced with —CH(glucuronide)-.
30 . A compound according to claim 1 , wherein the 3-position of the azetidinone ring is of the (S)-configuration, and the 4-position of the azetidinone ring is of the (R)-configuration.
31 . A compound according to claim 1 , wherein the 3-position of the azetidinone ring is of the (R)-configuration, and the 4-position of the azetidinone ring is of the (S)-configuration.
32 . A compound according to claim 1 , wherein U is (C 2 -C 4 )-alkylene wherein at least one —CH 2 — is replaced by —CH(OH)— or by —CH(glucuronide)-, and wherein each carbon bearing an (OH) or (glucuronide) substituent is of the (S)-configuration.
33 . A compound according to claim 1 , wherein U is (C 2 -C 4 )-alkylene wherein at least one —CH 2 — is replaced by —CH(OH)— or by —CH(glucuronide)-, and wherein each carbon bearing an (OH) or (glucuronide) substituent is of the (R)-configuration.
34 . A compound according to claim 1 , wherein R 4 is —OH.
35 . A compound according to claim 1 , wherein R 4 is a glucuronide.
36 . A compound according to claim 1 , wherein R 4 is in the ortho position relative to the azetidinone ring.
37 . A compound according to claim 1 , wherein R 2 is fluorine.
38 . A compound according to claim 37 , wherein R 2 is in the para position.
39 . A compound according to claim 1 , wherein R 1 is hydrogen.
40 . A compound according to claim 1 , wherein R 5 is in the para position.
41 . A compound according to claim 1 , wherein R 5 is in the meta position.
42 . A pharmaceutical formulation comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.
43 . A method for treating hypercholesterolemia comprising administering to a mammal a therapeutically effective amount of a compound according to claim 1 .