US2008167310A1PendingUtilityA1
Modulators of peroxisome proliferator activated receptors (ppar)
Est. expiryJun 7, 2021(expired)· nominal 20-yr term from priority
Inventors:Lynn Stacy GossettJonathan Edward GreenJames Robert HenryWinton D. JonesDonald P. MatthewsQuanrong ShenDaryl Lynn SmithJennifer Ann VanceAlan M. WarshawskyMaria Rosario Gonzalez-Garcia
A61P 43/00A61P 9/12A61P 9/04A61P 9/00A61P 3/10A61P 9/10A61P 3/06C07D 277/28C07D 231/12C07C 233/63C07D 333/28C07D 417/14A61P 25/00C07D 413/14C07D 413/12C07D 417/04C07D 409/12C07D 413/04C07D 263/32C07C 2601/14C07D 213/81C07D 417/12C07D 277/42A61P 3/04C07C 233/87C07D 495/04A61P 3/02C07D 401/06C07D 209/48C07D 239/28C07D 413/06C07C 271/22C07C 271/24C07C 255/57C07D 307/79C07C 2601/04
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Claims
Abstract
The present invention is directed to a compound of formula I, and pharmaceutically acceptable salts, solvates, hydrates or stereoisomer thereof, which are useful in treating Syndrome X, Type II diabetes, hyperglycemia, hyperlipidemia, obesity, coagaulopathy, hypertension, arteriosclerosis, and other disorders related to Syndrome X as well as cardiovascular diseases.
Claims
exact text as granted — not AI-modified1 . A compound of formula I,
and pharmaceutically acceptable salts, solvates, hydrates or stereoisomers thereof, wherein:
n 1 is 2, 3, 4 or 5;
V is a bond or O;
X is CH 2 or O;
p is 0 or 1;
m is 1-4;
Y 1 is:
wherein,
is: 1-3-thiazolyl,
wherein 1-3-thiazolyl are optionally substituted with one or more groups independently selected from the group consisting of:
hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo, haloalkyl and haloalkyloxy;
Y 1a is: hydrogen,
(C 0 -C 3 )alkyl-aryl,
C(O)-aryl,
heteroaryl,
cycloalkyl,
heterocycloalkyl,
aryloxy,
NR 5 (CH 2 ) m OR 5 ,
aryl-Z-aryl,
aryl-Z-heteroaryl,
aryl-Z-cycloalkyl,
aryl-Z-heterocycloalkyl,
heteroaryl-Z-aryl,
heteroaryl-Z-heterocycloalkyl or
heterocycloalkyl-Z-aryl,
wherein aryl, cycloalkyl, aryloxy, heteroaryl, and heterocycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of:
halo,
hydroxyl,
nitro,
cyano,
C 1 -C 6 alkyl,
C 1 -C 6 alkoxy optionally substituted with N(R 5 ) 2 ,
haloalkyl,
N(R 5 ) 2 ,
N[C(O)R 5 ] 2 ,
N[S(O) 2 R 5 ] 2 ,
NR 5 S(O) 2 R 5 ,
NR 5 C(O)R 5 ,
NR 5 C(O)OR 5 ,
C(O)N(R 5 ) 2 ,
C(O)OR 5 and
C(O)R;
Z is: a bond,
-oxygen-
—C(O)NR 5 —
—NR 5 C(O)—,
—NR 5 C(O)O—,
—C(O)—,
—NR 5 —,
—[O] p (CH 2 ) m —,
—(CH 2 ) m [O] p —,
—NR 5 (CH 2 ) m — or
—(CH 2 ) m NR 5 —;
Y 2 and Y 3 are each independently:
hydrogen,
C 1 -C 6 alkyl or
C 1 -C 6 alkoxy;
Y 4 is: (C 1 -C 3 )alkyl-NR 5 C(O)—(C 0 -C 5 )alkyl-Y 7 ,
(C 1 -C 3 )alkyl-NR 5 C(O)—(C 2 -C 5 )alkenyl-Y 7 ,
(C 1 -C 3 )alkyl-NR 5 C(O)—(C 2 -C 5 )alkynyl-Y 7 ;
(C 1 -C 3 )alkyl-NR 5 C(O)O—(C 0 -C 5 )alkyl-Y 7 ,
(C 1 -C 3 )alkyl-NR 5 C(O)NR 5 —(C 0 -C 5 )alkyl-Y 7 ,
(C 1 -C 3 )alkyl-NR 5 C(S)NR 5 —(C 0 -C 5 )alkyl-Y 7 ,
(C 0 -C 3 )alkyl-C(O)NR 5 —(C 0 -C 5 )alkyl-Y 7 ,
(C 1 -C 3 )alkyl-OC(O)NY 10 Y 11 ,
(C 1 -C 3 )alkyl-NY 10 Y 11 ,
(C 1 -C 3 )alkyl-O—(C 0 -C5)alkyl-Y 7 ,
(C 1 -C 3 )alkyl-S—(C 0 -C5)alkyl-Y 7 or
CN;
Y 7 is: hydrogen,
aryl,
heteroaryl,
C 1 -C 12 alkyl,
C 1 -C 6 alkoxy,
cycloalkyl,
heterocycloalkyl,
aryloxy,
C(O)-heteroaryl or
SR 6 ,
wherein alkyl, aryl, aryloxy, alkoxy, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more groups independently selected from R 7 :
Y 10 and Y 11 are each independently:
hydrogen,
aryl,
heteroaryl,
C 1 -C 10 alkyl,
cycloalkyl,
SO 2 (R 6 ); or
Y 10 and Y 11 together are a 5- to 10-membered heterocycloalkyl ring or heterocycloalkyl ring fused with aryl, and the heterocycloalkyl ring optionally containing one or more heteroatoms selected from N, O or S; and wherein, aryl, heteroaryl, heterocycloalkyl and alkyl are optionally substituted with one or more substituents independently selected from R 7 ;
R 5 is: hydrogen or C 1 -C 6 alkyl;
R 6 is: hydrogen,
C 1 -C 10 alkyl,
cycloalkyl,
aryl, or
heteroaryl,
wherein alkyl, cycloalkyl, aryl and heteroaryl are optionally substituted with one or more substituents independently selected from R 7 ;
R 7 is: halo,
nitro,
oxo,
cyano,
hydroxyl,
benzyl,
phenyl,
phenoxy,
heteroaryl,
C(O)R 6 ,
C 1 -C 10 alkyl,
C 1 -C 6 alkoxy,
C 1 -C 6 haloalkyl,
C 1 -C 6 haloalkyloxy,
O(CH 2 ) m -phenyl,
(CH 2 ) m OC(O)-aryl,
C(O)OR 5 ,
S(O) 2 R 5 ,
S(O) 2 N(R 5 ) 2 ,
SR 5 or
N(R 5 ) 2 ,
wherein phenyl and phenoxy are optionally substituted with one or more groups independently selected from halo or trifluoromethyl.
2 . The compound of claim 1 , wherein Y 1a is selected from the group consisting of: aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aryloxy,
3 . The compound of claim 1 , wherein the compound is represented by the following structural formula,
wherein E is S.
4 . The compound of claim 3 , wherein the compound is represented by the following structural formula,
wherein q is 1 or 2; and each R 5 is independently hydrogen or methyl.
5 . The compound of claim 3 , wherein the compound is represented by the following structural formula.
wherein q is 1 or 2; and each R 5 is independently hydrogen or methyl.
6 . The compound of claim 3 , wherein the compound is represented by the following structural formula,
wherein q is 1 or 2; and each R 5 is independently hydrogen or methyl.
7 . The compound of claim 3 , wherein the compound is represented by the following structural formula,
wherein q is 0 or 1; and each R 5 is independently hydrogen or methyl.
8 . The compound of claim 3 , wherein the compound is represented by the following structural formula,
wherein q is 1 or 2; and each R 5 is independently hydrogen or methyl.
9 . The compound of claim 3 , wherein the compound is represented by the following structural formula,
wherein q is 1 or 2; and each R 5 is independently hydrogen or methyl.
10 . The compound of claim 3 , wherein the compound is represented by the following structural formula,
wherein q is 1 or 2; and each R 5 is independently hydrogen or methyl.
11 . The compound of claim 3 , wherein the compound is represented by the following structural Formula,
wherein q is 1 or 2; and each R 5 , Y 2 and Y 3 are independently hydrogen or methyl.
12 . (canceled)
13 . (canceled)
14 . The compound of claim 3 , represented by the following structural formula,
wherein Y 1a is optionally substituted aryl, heteroaryl, heterocycloalkyl, heteroaryl-Z-heterocycloalkyl or heteroaryl-Z-aryl.
15 . (canceled)
16 . (canceled)
17 . The compound of claim 1 represented by the following structural formula,
wherein,
Y 1a is hydrogen, aryl, heteroaryl, or aryloxy; q is 1 or 2; and n 1 is 2, 3, or 4.
18 . The compound of claim 1 represented by the following structural formula,
wherein,
Y 1a is hydrogen, aryl, heteroaryl or aryloxy; q is 1 or 2; and n 1 is 2, 3, or 4.
19 . The compound of claim 1 represented by a following structural formula,
20 . (canceled)
21 . A compound selected from the group consisting of:
No.
Compound
Name
10
3-{2-(Isopropoxycarbonyl-aminomethyl)-4-[2-(5-methyl-2-morpholin-4-ylthiazol-4-yl)ethoxy]phenyl} propionic acid
20
3-(2-(Isopropoxycarbonyl-aminomethyl)-4-{2-[5-methyl-2-(6-phenylpyridin-3-yl)thiazol-4-yl]ethoxy}phenyl) propionicacid
33
3-(4-{2-[5-Methyl-2-(6-phenylpyridin-3-yl)thiazol-4-yl]ethoxy}-2-{[(pyridine-2-carbonyl)amino]methyl}phenyl)propionic acid HCl salt
43
3-{2-(Cyclopropylmethoxy-carbonylaminomethyl)-4-[2-(5-methyl-2-morpholin-4-ylthiazol-4-yl)ethoxy]phenyl} propionicacid HCl salt
45
3-{2-(Cyclobutoxycarbonyl-aminomethyl)-4-[2-(5-methyl-2-morpholin-4-ylthiazol-4-yl)ethoxy]phenyl} propionic acidHCl salt
54
3-{2-(Isobutoxycarbonyl-aminomethyl)-4-[2-(5-methyl-2-morpholin-4-ylthiazol-4-yl)ethoxy]phenyl} propionic acid
22 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof.
23 . (canceled)
24 . A method of modulating a peroxisome proliferator activated receptor (PPAR), comprising the step of contacting the receptor with a compound of claim 1 , or a pharmaceutically acceptable salt, solvate or hydrate thereof.
25 . (canceled)
26 . (canceled)
27 . (canceled)
28 . A method for lowering blood-glucose comprising the step of administering an effective amount of a compound of claim 1 .
29 . (canceled)
30 . A method of treating or preventing diabetes mellitus in a mammal comprising the step of administering to a mammal a therapeutically effective amount of a compound of claim 1 .
31 . A method of treating or preventing cardiovascular disease in a mammal comprising the step of administering to a mammal a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof.
32 . A method of treating or preventing syndrome X in a mammal, comprising the step of administering to the mammal a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof.
33 . (canceled)
34 . (canceled)
35 . The compound of claim 5 represented by the following structural formula,
or pharmaceutically acceptable salts, solvates, hydrates or stereoisomers thereof.
36 . (canceled)Join the waitlist — get patent alerts
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