Niacin receptor agonists, compositions containing such compounds and methods of treatment
View Patent ↗The present invention encompasses compounds of Formula (I): as well as pharmaceutically acceptable salts and hydrates thereof, that are useful for treating atherosclerosis, dyslipidemias and the like. Pharmaceutical compositions and methods of use are also included.
1. A compound represented by formula I:
or a pharmaceutically acceptable salt thereof is disclosed wherein:
X represents CH 2 ,
R 6 represents C 1-3 alkyl optionally substituted with 1-3 groups, 0-3 of which are halo, and 0-1 of which are selected from the group consisting of: OC 1-3 alkyl, OH, NH 2 , NHC 1-3 alkyl, N(C 1-3 alkyl) 2 , CN, Hetcy, Aryl and HAR,
said Aryl and HAR being further optionally substituted with 1-3 groups, 1-3 of which are halo, and 0-1 of which are selected from the group consisting of: OH, NH 2 , C 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkyl and haloC 1-3 alkoxy groups;
a and b are each integers 1 or 2, such that the sum of a and b is 3;
ring A is selected from the group consisting of: phenyl; naphthyl; HAR which represents a member selected from the group consisting of: pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benzopyrazolyl, benzotriazolyl, furo(2,3-b)pyridyl, benzoxazinyl, tetrahydrohydroquinolinyl, tetrahydroisoquinolinyl, quinolyl, isoquinolyl, indolyl, dihydroindolyl, quinoxalinyl, quinazolinyl, naphthyridinyl, pteridinyl, 2,3-dihydrofuro(2,3-b)pyridyl indolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, or a member selected from the group consisting of:
each R 2 and R 3 is independently H, C 1-3 alkyl, haloC 1-3 alkyl, OC 1-3 alkyl, haloC 1-3 alkoxy, OH or F;
n represents an integer of from 1 to 5;
each R 4 is H or is independently selected from halo and R 6 ;
R 5 represents —CO 2 H,
or —C(O)NHSO 2 R e wherein R e represents C 1-4 alkyl or phenyl, said C 1-4 alkyl and phenyl each being optionally substituted with 1-3 groups, 1-3 of which are selected from halo and C 1-3 alkyl, and 1-2 of which are selected from the group consisting of: OC 1-3 alkyl, haloC 1-3 alkyl, haloC 1-3 alkoxy, OH, NH 2 and NHC 1-3 alkyl;
and each R 1 is H or is independently selected from the group consisting of:
a) halo, OH,
f) phenyl or a 5-6 membered heteroaryl, said heteroaryl is pyridinyl, pyrazolyl, triazolyl, or dihydrobenzofuranyl, attached at any available ring atom and each being optionally substituted with 1-3 groups, 1-3 of which are selected from halo, OH; NH 2 .
2. A compound in accordance with claim 1 wherein ring A is selected from the group consisting of: phenyl; naphthyl; and
HAR which is a member selected from the group consisting of: isoxazolyl, pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, triazolyl, thienyl, benzothiazolyl, and a member selected from the group consisting of:
3. A compound in accordance with claim 1 wherein R 2 and R 3 are independently H, C 1-3 alkyl, OH or haloC 1-3 alkyl.
4. A compound in accordance with claim 3 wherein R 2 and R 3 are independently H or methyl.
5. A compound in accordance with claim 1 wherein n represents an integer of from 2 to 4.
6. A compound in accordance with claim 5 wherein n is 2.
7. A compound in accordance with claim 1 wherein each R 4 is H or is independently selected from the group consisting of: halo, C 1-3 alkyl optionally substituted with 1-3 halo groups or 0-1 OC 1-3 alkyl groups.
8. A compound in accordance with claim 1 wherein R 5 represents —CO 2 H.
9. A compound in accordance with claim 1 wherein:
ring A is selected from the group consisting of: phenyl; naphthyl; HAR which represents a member selected from the group consisting of: pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benzopyrazolyl, benzotriazolyl, furo(2,3-b)pyridyl, benzoxazinyl, tetrahydrohydroquinolinyl, tetrahydroisoquinolinyl, quinolyl, isoquinolyl, indolyl, dihydroindolyl, quinoxalinyl, quinazolinyl, naphthyridinyl, pteridinyl, 2,3-dihydrofuro(2,3-b)pyridyl indolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, or a member selected from the group consisting of:
a and b are 1 or 2 such that the sum of a and b is 2 or 3;
X represents O or CH 2 ;
R 2 and R 3 are independently H, OH, C 1-3 alkyl or haloC 1-3 alkyl;
n represents 2;
R 4 is H or is independently selected from the group consisting of: halo, C 1-3 alkyl optionally substituted with 1-3 halo groups or 0-1 OC 1-3 alkyl groups; and
R 5 represents —CO 2 H.
10. A compound in accordance with claim 1 wherein:
ring A is selected from the group consisting of:
each R 1 is independently H, CH 3 , phenyl, 4-hydroxy-phenyl, OH, 2-hydroxy-phenyl, 3-hydroxy-phenyl, 3-amino-phenyl, 2,3-dihydro-benzofuran-6-yl, 2-chloro-4-hydroxy-phenyl, 1H-pyrazol-4-yl, 5-hydroxy-pyridin-2-yl, 4-hydroxy-pyrazol-1-yl, 1H-[1,2,3]triazol-4-yl, or 5-fluoro-pyridin-2-yl;
a and b are 1 or 2 such that the sum of a and b is 2 or 3;
X represents CH 2 ;
each R 2 and R 3 is independently H, OH or CH 3 ;
n represents 2;
R 4 is H, CH 3 , CH 2 CH 3 , CF 3 or CH 2 OCH 3 ; and
R 5 represents —CO 2 H.
11. A compound in accordance with claim 1 selected from the following table:
TABLE 1
Compound 2
Compound 3
Compound 4
Compound 5
Compound 7
Compound 8
Compound 9
Compound 10
Compound 11
Compound 12
Compound 13
Compound 15
Compound 17
Compound 19
Compound 21
Compound 22
Compound 23
Compound 24
Compound 25
Compound 26
Compound 27
Compound 28
Compound 29
Compound 30
Compound 31
Compound 32
Compound 33
Compound 34
Compound 35
Compound 36
Compound 37
Compound 38
Compound 39
and
Compound 41
or a pharmaceutically acceptable salt thereof.
12. A pharmaceutical composition comprising a compound in accordance with claim 1 in combination with a pharmaceutically acceptable carrier.
13. The compound of claim 11
or a pharmaceutically acceptable salt thereof.
14. The compound, according to claim 13 , of formula
or a pharmaceutically acceptable salt thereof.
15. The compound, according to claim 13 , of formula
or a pharmaceutically acceptable salt thereof.
16. The compound, according to claim 13 , of formula
or a pharmaceutically acceptable salt thereof.
17. The compound, according to claim 13 , of formula
or a pharmaceutically acceptable salt thereof.
18. The compound, according to claim 13 , of formula
or a pharmaceutically acceptable salt thereof.
19. The compound, according to claim 13 , of formula
or a pharmaceutically acceptable salt thereof.
20. A pharmaceutical composition comprising a compound in accordance with claim 13 or a pharmaceutically acceptable salt thereof and DP receptor antagonist of formula:
in combination with a pharmaceutically acceptable carrier.