US2012178750A1PendingUtilityA1
Niacin Receptor Agonists, Compositions Containing Such Compounds and Methods of Treatment
Est. expiryJun 28, 2025(expired)· nominal 20-yr term from priority
Inventors:Subharekha RaghavanSteven L. CollettiFa-Xiang DingHong ShenJames R. TataAshley Rouse LinsAbigail Lee SmentonWeichun ChenDarby SchmidtGeorge Scott Tria
A61P 9/10A61P 3/06A61P 3/10A61P 3/00C07D 307/79C07C 2601/10C07D 257/04C07C 233/55C07D 271/06C07D 401/04C07C 233/52C07D 249/06C07D 309/14C07D 513/04C07C 237/20C07D 309/28C07D 277/30C07C 2601/16C07D 261/20C07D 413/04C07D 417/04C07D 231/12C07C 235/36C07D 249/08C07C 233/45C07C 233/46A61K 31/196
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Claims
Abstract
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.
Claims
exact text as granted — not AI-modified1 - 28 . (canceled)
29 . 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 therapeutically effective amount of a compound represented by formula I:
or a pharmaceutically acceptable salt or solvate thereof is disclosed wherein:
X represents CH 2 , O, S, S(O), SO 2 or NH, such that when X represents NH, the nitrogen atom may be optionally substituted with R 6 , C(O)R 6 , or SO 2 R 6 , wherein:
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, 2 or 3, such that the sum of a and b is 2, 3 or 4;
ring A represents a 6-10 membered aryl, a 5-13 membered heteroaryl or a partially aromatic heterocyclic group, said heteroaryl and partially aromatic heterocyclic 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 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, 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; or
(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.
30 . The method of claim 29 , comprising administering to the patient a compound of Formula I in an amount that is effective for treating atherosclerosis.
31 . The method of claim 29 , comprising administering to the patient a compound of Formula I in an amount that is effective for treating dyslipidemias.
32 . The method of claim 29 , comprising administering to the patient a compound of Formula I in an amount that is effective for treating diabetes.
33 . The method of claim 29 , comprising administering to the patient a compound of Formula I in an amount that is effective for treating metabolic syndrome.
34 . The method of treating atherosclerosis, dyslipidemias, diabetes, metabolic syndrome or a related condition, in accordance with claim 29 , in a human patient in need of such treatment, comprising administering to the patient a compound of Formula I 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.
35 . The method in accordance with claim 34 wherein the DP receptor antagonist selected from the group consisting of compounds A through AJ:
or a pharmaceutically acceptable salt or solvate thereof.
36 . 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 therapeutically effective amount of a compound selected from:
TABLE 1
Compound 1
Compound 2
Compound 3
Compound 4
Compound 5
Compound 6
Compound 7
Compound 8
Compound 9
Compound 10
Compound 11
Compound 12
Compound 13
Compound 14
Compound 15
Compound 16
Compound 17
Compound 18
Compound 19
Compound 20
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
Compound 40
Compound 41
or a pharmaceutically acceptable salt or solvate thereof.
37 . The method of claim 36 , wherein the compound is selected from:
or a pharmaceutically acceptable salt thereof.Cited by (0)
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