Prodrugs of oxazolidinone CETP inhibitors
View Patent ↗The compounds of Formula I are pro-drugs of CETP inhibitors having a central oxazolidinone ring. The compounds cyclize by the elimination of HX to form an oxazolidinone ring after administration to a patient.
1. A compound of formula I, or a pharmaceutically acceptable salt thereof:
wherein R 1 is selected from H and C 1-4 alkyl, which is optionally substituted with 1-5 F groups;
Each R 2 is independently selected from the group consisting of halogen, —CN, C 1-4 alkyl, and —OC 1-4 alkyl, wherein C 1-4 alkyl and —OC 1-4 alkyl are optionally substituted with 1-5 halogens;
R 3 is selected from the group consisting of H, halogen, C 1-4 alkyl, and —OC 1-4 alkyl, wherein C 1-4 alkyl and —OC 1-4 alkyl are optionally substituted with 1-5 halogens;
R 4 and R 5 are each independently selected from the group consisting of halogen, C 1-4 alkyl, and —OC 1-4 alkyl, wherein C 1-4 alkyl and —OC 1-4 alkyl are optionally substituted with 1-5 halogens;
R 6 is selected from H and C 1 -C 5 alkyl optionally substituted with 1-5 halogens and optionally substituted with 1-2 phenyl groups, wherein phenyl is optionally substituted with 1-3 groups independently selected from halogen, C 1 -C 3 alkyl, —OC 1 -C 3 alkyl, CF 3 , and —OCF 3 ;
R 7 is selected from H and C 1 -C 3 alkyl optionally substituted with 1-3 F;
X is selected from —OZ and —SZ, wherein Z is selected from:
(a) C 1 -C 5 alkyl which optionally includes an —O— atom between 2 adjacent carbon atoms, wherein C 1 -C 5 alkyl is optionally substituted with 1-5 halogens and is optionally substituted with 1-2 substituent groups independently selected from phenyl, —C(═O)OR 6 , —OP(═O)(OR 7 ) 2 , and —P(═O)(OR 7 ) 2 , wherein phenyl is optionally substituted with 1-3 groups independently selected from halogen, —C(═O)OR 7 , and C 1 -C 3 alkyl optionally substituted with 1-3 halogens; and
(b) phenyl, wherein phenyl is optionally substituted with 1-3 groups independently selected from halogen; C 1 -C 5 alkyl; —OC 1 -C 5 alkyl; —C(═O)OR 7 ; and C 5 -C 7 cycloalkyl optionally substituted with 1-2 groups independently selected from halogen, C 1 -C 3 alkyl, —OC 1 -C 3 alkyl, CF 3 , and —OCF 3 ; wherein C 1 -C 5 alkyl and —OC 1 -C 5 alkyl are optionally substituted with 1-5 F and are optionally substituted with 1-2 groups independently selected from —C(═O)OR 7 , —N(R 7 ) 2 , —OP(═O)(OR 7 ) 2 , and —P(═O)(OR 7 ) 2 ;
a and b are integers independently selected from 0-4; and
c is an integer from 0-2.
2. The compound of claim 1 , wherein
Z is selected from
(a) C 1 -C 5 alkyl which optionally includes an —O— atom between 2 adjacent carbon atoms, wherein C 1 -C 5 alkyl is optionally substituted with 1-3 F and is optionally substituted with 1-2 substituent groups independently selected from phenyl, —C(═O)OR 6 , —OP(═O)(OR 7 ) 2 , and —P(═O)(OR 7 ) 2 , wherein phenyl is optionally substituted with 1-3 groups independently selected from halogen, C 1 -C 3 alkyl, CF 3 , and —C(═O)OR 7 ; and
(b) Phenyl, wherein phenyl is optionally substituted with 1-3 groups independently selected from halogen; C 1 -C 5 alkyl; CF 3 ; —OC 1 -C 3 alkyl; —OCF 3 ; —C(═O)OR 7 ; and C 5 -C 6 cycloalkyl which is optionally substituted with 1-2 groups independently selected from halogen, CH 3 , and —OCH 3 ; wherein C 1 -C 5 alkyl and —OC 1 -C 3 alkyl are optionally substituted with 1-2 groups independently selected from —C(═O)OR 7 , —N(R 7 ) 2 , —OP(═O)(OR 7 ) 2 ; and —P(═O)(OR 7 ) 2 .
3. The compound of claim 2 , wherein
R 1 is C 1-2 alkyl, optionally substituted with 1-3 F;
Each R 2 is independently selected from —CN, C 1-3 alkyl, CF 3 , —OCH 3 , —OCF 3 , and F;
R 3 is selected from C 1-3 alkyl, —OC 1-3 alkyl , and F, wherein C 1-3 alkyl and OC 1-3 alkyl are optionally substituted with 1-5 F;
R 4 and R 5 are each independently selected from C 1-3 alkyl, CF 3 , —OCH 3 , —OCF 3 , and F;
R 6 is selected from H and C 1 -C 2 alkyl, wherein C 1 -C 2 alkyl is optionally substituted with one phenyl group, said phenyl being optionally substituted with 1-3 groups independently selected from halogen, CH 3 , CF 3 , —OCH 3 , and —OCF 3 ;
R 7 is selected from H and C 1 -C 3 alkyl optionally substituted with 1-3 F;
a is 1 or 2;
b is an integer from 1-3; and
c is 0 or 1.
4. The compound of claim 3 , wherein
X is selected from —SC 1 -C 2 alkyl and —OZ;
Z is selected from the group consisting of
(a) —(CH 2 CH 2 O—) n C 1 -C 3 alkyl, wherein C 1 -C 3 alkyl is optionally substituted with 1-2 substituent groups independently selected from phenyl, —C(═O)OR 6 , —OP(═O)(OR 7 ) 2 , and —P(═O)(OR 7 ) 2 , wherein phenyl is optionally substituted with one group —C(═O)OR 7 ; and
(b) phenyl, which is optionally substituted with 1-3 substituents independently selected from C 1 -C 4 alkyl, —OC 1 -C 3 alkyl, —C(═O)OR 7 , and cyclohexyl, wherein C 1 -C 4 alkyl and —OC 1 -C 3 alkyl are optionally substituted with 1-2 groups independently selected from —N(R 7 ) 2 , —C(═O)OR 7 , and —OP(═O)(OR 7 ) 2 ; and
n is an integer selected from 0 and 1.
5. The compound of claim 4 , wherein
R 1 is C 1-2 alkyl;
R 2 is CF 3 ;
R 3 is selected from CH 3 , CF 3 and F;
Each R 4 is independently selected from C 1-3 alkyl, —OCH 3 , and F;
R 6 is selected from H, C 1 -C 2 alkyl, and —CH 2 phenyl;
R 7 is selected from H and C 1 -C 2 alkyl;
a is 2;
b is 2 or 3; and
c is 0.
6. The compound of claim 5 , wherein
R 1 is CH 3 ; and
b is 3.
7. The compound of claim 1 having formula IV, or a pharmaceutically acceptable salt thereof:
8. The compound of claim 7 , wherein Z is selected from the group consisting of:
(a) C 1 -C 5 alkyl which optionally includes an —O— atom between 2 adjacent carbon atoms, wherein C 1 -C 5 alkyl is optionally substituted with 1-3 F and is optionally substituted with 1-2 substituent groups independently selected from phenyl, —C(═O)OR 6 , —OP(═O)(OR 7 ) 2 , and —P(═O)(OR 7 ) 2 , wherein phenyl is optionally substituted with 1-3 groups independently selected from halogen, C 1 -C 3 alkyl, CF 3 , and —C(═O)OR 7 ; and
(b) Phenyl, wherein phenyl is optionally substituted with 1-3groups independently selected from halogen; C 1 -C 5 alkyl; CF 3 ; —OC 1 -C 3 alkyl; —OCF 3 ; —C(═O)OR 7 , and C 5 -C 6 cycloalkyl which is optionally substituted with 1-2 groups independently selected from halogen, CH 3 , and —OCH 3 ; wherein C 1 -C 5 alkyl and —OC 1 -C 3 alkyl are optionally substituted with 1-2 groups independently selected from —C(═O)OR 7 , —N(R 7 ) 2 , —OP(═O)(OR 7 ) 2 , and —P(═O)(OR 7 ) 2 .
9. The compound of claim 8 , wherein
X is selected from —SC 1 -C 2 alkyl and —OZ;
Z is selected from the group consisting of
(a) —(CH 2 CH 2 O—) n C 1 -C 3 alkyl, wherein C 1 -C 3 alkyl is optionally substituted with 1-2 substituent groups independently selected from phenyl, —C(═O)OR 6 , —OP(═O)(OR 7 ) 2 , and —P(═O)(OR 7 ) 2 , wherein phenyl is optionally substituted with one group —C(═O)OR 7 ; and
(b) phenyl, which is optionally substituted with 1-3 substituents independently selected from C 1 -C 4 alkyl, —OC 1 -C 3 alkyl, —C(═O)OR 7 , and cyclohexyl, wherein C 1 -C 4 alkyl and —OC 1 -C 3 alkyl are optionally substituted with 1-2 groups independently selected from —N(R 7 ) 2 , —C(═O)OR 7 , and —OP(═O)(OR 7 ) 2 ;
n is an integer selected from 0 and 1; and
R 6 is selected from the group consisting of H and C 1 -C 2 alkyl which is optionally substituted with one phenyl group, said phenyl being optionally substituted with 1-3 groups independently selected from halogen, CH 3 , CF 3 , —OCH 3 , and —OCF 3 .
10. The compound of claim 9 , wherein
X is selected from —SC 1 -C 2 alkyl and —OZ;
Z is selected from the group consisting of:
(a) —(CH 2 CH 2 O—) n C 1 -C 3 alkyl, wherein C 1 -C 3 alkyl is optionally substituted with 1-2 substituent groups independently selected from phenyl, —C(═O)OR 6 , —OP(═O)(OR 7 ) 2 , and —P(═O)(OR 7 ) 2 , wherein phenyl is optionally substituted with one group —C(═O)OR 7 ; and
(b) phenyl, which is substituted with 1-3 substituents independently selected from C 1 -C 4 alkyl, —OC 1 -C 3 alkyl, —C(═O)OR 7 , and cyclohexyl, wherein C 1 -C 4 alkyl and —OC 1 -C 3 alkyl are optionally substituted with 1-2 groups independently selected from —N(R 7 ) 2 , —C(═O)OR 7 , and —OP(═O)(OR 7 ) 2 ;
R 6 is selected from H, C 1 -C 2 alkyl, and —CH 2 phenyl; and
R 7 is selected from H and C 1 -C 2 alkyl.
11. The compound of claim 10 , wherein X is —OZ.
12. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
13. The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein the compound has a structure which is selected from the group consisting of the following structures:
14. The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein the compound has a structure which is selected from the group consisting of the following structures:
R
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15. A method of raising HDL-cholesterol in a patient in need of treatment, comprising the administration of the compound of claim 1 , or a pharmaceutically acceptable salt thereof to the patient.
16. A method of lowering LDL-cholesterol in a patient in need of treatment, comprising the administration of the compound of claim 1 , or a pharmaceutially acceptable salt thereof to the patient.
17. A method of treating hypercholesterolemia in a patient in need of treatment, comprising the administration of the compound of claim 1 , or a pharmaceutially acceptable salt thereof to the patient.