Niacin Receptor Agonists, Compositions Containing Such Compounds and Methods of Treatment
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 or solvate thereof is disclosed wherein:
X represents a carbon or nitrogen atom;
Z represents Aryl and Heteroaryl, said Aryl and Heteroaryl being 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;
R 4 is H, fluoro, or 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 and Hetcy;
a and b are each integers 1 or 2, such that the sum of a and b is 3;
ring A represents a 6-10 membered Aryl, or a 5-13 membered Heteroaryl group, said Heteroaryl group containing at least one heteroatom selected from O, S, S(O), S(O) 2 and N, and optionally containing 1 other heteroatom selected from O and S, and optionally containing 1-3 additional N atoms, with up to 5 heteroatoms being present;
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 2 to 4;
R 5 represents —CO 2 H,
—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, CO 2 H, CN, NH 2 , S(O) 0-2 R e , C(O)R e , OC(O)R e and CO 2 R e , wherein R e is as previously defined;
b) C 1-6 alkyl and OC 1-6 alkyl, said C 1-6 alkyl and alkyl portion of OC 1-6 alkyl being optionally substituted with 1-3 groups, 1-3 of which are halo and 1-2 of which are selected from: OH, CO 2 H, CO 2 C 1-4 alkyl, CO 2 C 1-4 haloalkyl, OCO 2 C 1-4 alkyl, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , Hetcy and CN;
c) NHC 1-4 alkyl and N(C 1-4 alkyl) 2 , the alkyl portions of which are optionally substituted as set forth in (b) above;
d) C(O)NH 2 , C(O)NHC 1-4 alkyl, C(O)N(C 1-4 alkyl) 2 , C(O)Hetcy, C(O)NHOC 1-4 alkyl and C(O)N(C 1-4 alkyl)(OC 1-4 alkyl), the alkyl portions of which are optionally substituted as set forth in (b) above;
e) NR′C(O)R″, NR′SO 2 R″, NR′CO 2 R″ and NR′C(O)NR″R′″ wherein:
R′ represents H, C 1-3 alkyl or haloC 1-3 alkyl,
R″ represents (a) C 1-8 alkyl optionally substituted with 1-4 groups, 0-4 of which are halo, and 0-1 of which are selected from the group consisting of: OC 1-6 alkyl, OH, CO 2 H, CO 2 C 1-4 alkyl, CO 2 C 1-4 haloalkyl, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , CN, Hetcy, Aryl and HAR,
said Hetcy, Aryl and HAR being further optionally substituted with 1-3 halo, C 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkyl or haloC 1-4 alkoxy groups;
(b) Hetcy, Aryl or HAR, each being optionally substituted with 1-3 members selected from the group consisting of: halo, C 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkyl and haloC 1-4 alkoxy groups;
and R′″ representing H or R″;
f) phenyl or a 5-6 membered Heteroaryl or a Hetcy group attached at any available ring atom and each being optionally substituted with 1-3 groups, 1-3 of which are selected from halo, C 1-3 alkyl and haloC 1-3 alkyl groups, and 1-2 of which are selected from OC 1-3 alkyl and haloOC 1-3 alkyl groups, and 0-1 of which is selected from the group consisting of:
i) OH; CO 2 H; CN; NH 2 and S(O) 0-2 R e wherein R e is as described above;
ii) NHC 1-4 alkyl and N(C 1-4 alkyl) 2 , the alkyl portions of which are optionally substituted with 1-3 groups, 1-3 of which are halo and 1-2 of which are selected from: OH, CO 2 H, CO 2 C 1-4 alkyl, CO 2 C 1-4 haloalkyl, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 and CN;
iii) C(O)NH 2 , C(O)NHC 1-4 alkyl, C(O)N(C 1-4 alkyl) 2 , C(O)NHOC 1-4 alkyl and C(O)N(C 1-4 alkyl)(OC 1-4 alkyl), the alkyl portions of which are optionally substituted as set forth in b) above; and
iv) NR′C(O)R″, NR′SO 2 R″, NR′CO 2 R″ and NR′C(O)NR″R′″ wherein R′, R″ and R′″ are as described above.
2 . A compound in accordance with claim 1 wherein ring A represents an Aryl group, a 5-6 membered monocyclic Heteroaryl group or a 9-13 membered bicyclic or tricyclic Heteroaryl group.
3 . A compound in accordance with claim 2 wherein: ring A is selected from the group consisting of:
a) Aryl selected from phenyl and naphthyl;
b) HAR 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:
4 . A compound in accordance with claim 3 wherein ring A is selected from the group consisting of: phenyl, naphthyl, pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, furanyl, and thienyl.
5 . A compound in accordance with claim 4 wherein ring A is selected from the group consisting of: phenyl, naphthyl, oxadiazolyl, pyrazolyl and thiazolyl.
6 . A compound in accordance with claim 1 wherein each R 1 is H or is independently selected from the group consisting of:
a) halo, OH, CO 2 H, CN, NH 2 , S(O) 0-2 R e , C(O)R e , OC(O)R e and CO 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;
b) C 1-6 alkyl and OC 1-6 alkyl, said C 1-6 alkyl and alkyl portion of OC 1-6 alkyl being optionally substituted with 1-3 groups, 1-3 of which are halo and 1-2 of which are selected from: OH, CO 2 H, CO 2 C 1-4 alkyl, CO 2 C 1-4 haloalkyl, OCO 2 C 1-4 alkyl, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , Hetcy and CN;
c) phenyl or a 5-6 membered Heteroaryl or a Hetcy group attached at any available ring atom and each being optionally substituted with 1-3 groups, 1-3 of which are selected from halo, C 1-3 alkyl and haloC 1-3 alkyl groups, and 1-2 of which are selected from OC 1-3 alkyl and haloOC 1-3 alkyl groups, and 0-1 of which is selected from the group consisting of:
i) OH; CO 2 H; CN; NH 2 and S(O) 0-2 R e wherein R e is as described above;
ii) NHC 1-4 alkyl and N(C 1-4 alkyl) 2 , the alkyl portions of which are optionally substituted with 1-3 groups, 1-3 of which are halo and 1-2 of which are selected from: OH, CO 2 H, CO 2 C 1-4 alkyl, CO 2 C 1-4 haloalkyl, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 and CN;
iii) C(O)NH 2 , C(O)NHC 1-4 alkyl, C(O)N(C 1-4 alkyl) 2 , C(O)NHOC 1-4 alkyl and C(O)N(C 1-4 alkyl)(OC 1-4 alkyl), the alkyl portions of which are optionally substituted as set forth in b) above; and
iv) NR′C(O)R″, NR′SO 2 R″, NR′CO 2 R″ and NR′C(O)NR″R′″;
R′ represents H, C 1-3 alkyl or haloC 1-3 alkyl,
R″ represents (a) C 1-8 alkyl optionally substituted with 1-4 groups, 0-4 of which are halo, and 0-1 of which are selected from the group consisting of: OC 1-6 alkyl, OH, CO 2 H, CO 2 C 1-4 alkyl, CO 2 C 1-4 haloalkyl, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , CN, Hetcy, Aryl and HAR,
said Hetcy, Aryl and HAR being further optionally substituted with 1-3 halo, C 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkyl or haloC 1-4 alkoxy groups;
(b) Hetcy, Aryl or HAR, each being optionally substituted with 1-3 members selected from the group consisting of: halo, C 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkyl and haloC 1-4 alkoxy groups;
and R′″ representing H or R″.
7 . A compound in accordance with claim 6 wherein each R 1 is H or is independently selected from the group consisting of:
a) halo, OH, CO 2 H, CN, NH 2 , S(O) 0-2 R e , C(O)R e , OC(O)R e and CO 2 R e , and
b) phenyl or a 5-6 membered Heteroaryl or a Hetcy group attached at any available ring atom and each being optionally substituted with 1-3 groups, 1-3 of which are selected from halo, C 1-3 alkyl and haloC 1-3 alkyl groups, and 1-2 of which are selected from OC 1-3 alkyl and haloOC 1-3 alkyl groups, and 0-1 of which is selected from the group consisting of:
i) OH; CO 2 H; CN; NH 2 and S(O) 0-2 R e wherein R e is as described above;
ii) NHC 1-4 alkyl and N(C 1-4 alkyl) 2 , the alkyl portions of which are optionally substituted with 1-3 groups, 1-3 of which are halo and 1-2 of which are selected from: OH, CO 2 H, CO 2 C 1-4 alkyl, CO 2 —C 1-4 haloalkyl, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 and CN;
iii) C(O)NH 2 , C(O)NHC 1-4 alkyl, C(O)N(C 1-4 alkyl) 2 , C(O)NHOC 1-4 alkyl and C(O)N(C 1-4 alkyl)(OC 1-4 alkyl), the alkyl portions of which are optionally substituted as set forth in b) above; and
iv) NR′C(O)R″, NR′SO 2 R″, NR′CO 2 R″ and NR′C(O)NR″R′″.
8 . A compound in accordance with claim 7 wherein each R 1 is H or is independently selected from the group consisting of:
a) halo, OH, CN, NH 2 , and
b) phenyl or a 5-6 membered Heteroaryl or a Hetcy group attached at any available ring atom and each being optionally substituted with 1-3 groups, 1-3 of which are selected from halo, C 1-3 alkyl and haloC 1-3 alkyl groups, and 1-2 of which are selected from OC 1-3 alkyl and haloOC 1-3 alkyl groups, and 0-1 of which is selected from the group consisting of:
i) OH; CN; NH 2 ;
ii) NHC 1-4 alkyl and N(C 1-4 alkyl) 2 , the alkyl portions of which are optionally substituted with 1-3 groups, 1-3 of which are halo and 1-2 of which are selected from: OH, CO 2 H, CO 2 C 1-4 alkyl, CO 2 C 1-4 haloalkyl, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 and CN; and
iii) NR′C(O)R″, NR′SO 2 R″, NR′CO 2 R″ and NR′C(O)NR″R′″.
9 . A compound in accordance with claim 1 wherein X represents a carbon atom.
10 . A compound in accordance with claim 1 wherein X represents a nitrogen atom.
11 . A compound in accordance with claim 1 wherein R 2 and R 3 are independently H, C 1-3 alkyl or haloC 1-3 alkyl.
12 . A compound in accordance with claim 11 wherein R 2 and R 3 are independently H or methyl.
13 . A compound in accordance with claim 1 wherein n is 2.
14 . A compound in accordance with claim 1 wherein Z is Aryl optionally substituted with 1-3 halo groups and 0-1 groups selected from C 1-3 alkyl and haloC 1-3 alkyl.
15 . A compound in accordance with claim 1 wherein Z is Heteroaryl optionally substituted with 1-3 halo groups and 0-1 groups selected from C 1-3 alkyl and haloC 1-3 alkyl.
16 . A compound in accordance with claim 1 wherein R 4 is H, fluoro or methyl optionally substituted with 1-3 halo groups.
17 . A compound in accordance with claim 1 wherein R 5 represents —CO 2 H.
18 . A compound in accordance with claim 1 wherein:
ring A is selected from the group consisting of: phenyl, naphthyl, oxadiazolyl, pyrazolyl and thiazolyl;
each R 1 is H or is independently selected from the group consisting of:
a) halo, OH, CN, NH 2 , and
b) phenyl or a 5-6 membered Heteroaryl or a Hetcy group attached at any available ring atom and each being optionally substituted with 1-3 groups, 1-3 of which are selected from halo, C 1-3 alkyl and haloC 1-3 alkyl groups, and 1-2 of which are selected from OC 1-3 alkyl and haloOC 1-3 alkyl groups, and 0-1 of which is selected from the group consisting of:
i) OH; CN; NH 2 ;
ii) NHC 1-4 alkyl and N(C 1-4 alkyl) 2 , the alkyl portions of which are optionally substituted with 1-3 groups, 1-3 of which are halo and 1-2 of which are selected from: OH, CO 2 H, CO 2 C 1-4 alkyl, CO 2 C 1-4 haloalkyl, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 and CN; and
iii) NR′C(O)R″, NR′SO 2 R″, NR′CO 2 R″ and NR′C(O)NR″R′″ wherein
R′ represents H, C 1-3 alkyl or haloC 1-3 alkyl,
R″ represents (a) C 1-8 alkyl optionally substituted with 1-4 groups, 0-4 of which are halo, and 0-1 of which are selected from the group consisting of: OC 1-6 alkyl, OH, CO 2 H, CO 2 C 1-4 alkyl, CO 2 C-haloalkyl, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , CN, Hetcy, Aryl and HAR,
said Hetcy, Aryl and HAR being further optionally substituted with 1-3 halo, C 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkyl or haloC 4 alkoxy groups;
(b) Hetcy, Aryl or HAR, each being optionally substituted with 1-3 members selected from the group consisting of: halo, C 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkyl and haloC 1-4 alkoxy groups;
and R′″ representing H or R″;
R 2 and R 3 are independently H or methyl;
n is 2;
Z is Aryl or Heteroaryl optionally substituted with 1-3 halo groups and 0-1 groups selected from C 1-3 alkyl and haloC 1-3 alkyl;
R 4 is H, fluoro or methyl optionally substituted with 1-3 halo groups, and
R 5 represents —CO 2 H.
19 . A compound in accordance with claim 1 selected from the following table:
TABLE 1
or a pharmaceutically acceptable salt or solvate thereof.
20 . A pharmaceutical composition comprising a compound in accordance with claim 1 in combination with a pharmaceutically acceptable carrier.
21 . A method of treating atherosclerosis in a human patient in need of such treatment comprising administering to the patient a compound of claim 1 in an amount that is effective for treating atherosclerosis.
22 . A method of treating dyslipidemia in a human patient in need of such treatment comprising administering to the patient a compound of claim 1 in an amount that is effective for treating dyslipidemias.
23 . A method of treating diabetes in a human patient in need of such treatment comprising administering to the patient a compound of claim 1 in an amount that is effective for treating diabetes.
24 . A method of treating metabolic syndrome in a human patient in need of such treatment comprising administering to the patient a compound of claim 1 in an amount that is effective for treating metabolic syndrome.
25 . A method of treating atherosclerosis, dyslipidemias, diabetes, metabolic syndrome or a related condition in a human patient in need of such treatment, comprising administering to the patient a compound of claim 1 and a DP receptor antagonist, said compounds being administered in an amount that is effective to treat atherosclerosis, dyslipidemia, diabetes or a related condition in the absence of substantial flushing.
26 . A method of treatment in accordance with claim 25 wherein the DP receptor antagonist selected from the group consisting of compounds A through AJ:
or a pharmaceutically acceptable salt or solvate thereof