CHEMICAL COMPOUNDS
The present disclosure describes novel compounds, or their pharmaceutically acceptable salts, pharmaceutical compositions containing them, and their medical uses. The compounds of the disclosure have activity as prostaglandin EP4 receptor antagonists, and are useful in the treatment or alleviation of pain and inflammation and other inflammation-associated disorders, such as arthritis, treating or preventing disorders or medical conditions selected from pain, inflammatory diseases and the like. Also described herein are methods of treating pain by administering the compounds of the disclosure, which are EP4 receptor antagonists.
1 . A method for treating inflammation comprising:
administering to a subject in need thereof an effective amount of a compound of Formula (II), or a veterinary, or pharmaceutically acceptable salt thereof:
wherein
X is N or CR 1 , where each R 1 individually is hydrogen, halogen, CN, C 1-3 alkyl, or C 1-3 haloalkyl;
R 2 is hydrogen, halogen, C 1-3 alkyl, C 1-3 haloalky, CN, aryl, or heteroaryl;
R 3 is hydrogen, halogen, C 1-3 alkyl, C 1-3 haloalkyl or CN;
R 4 is hydrogen, C 1-3 alkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, heterocyclyl, heteroaryl, or aryl;
Z is phenyl or C 6-7 cycloalkyl, each substituted with one or more R 5 , where R 5 is hydrogen, halogen, CN, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 haloalkoxy, or C 1-3 alkoxy;
Ar is phenyl, pyridyl, or thiophenyl, each optionally substituted with one or more halogen, CN, NO 2 , NH 2 , N(C 1-3 alkyl) 2 , OH, C 1-3 alkoxy, C 1-3 alkyl, or C 1-3 haloalkyl;
L is —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, or —OCH 2 CH 2 —; and
n is 0 or 1.
2 . The method of claim 1 , further comprising the step of administering at least one COX-2 selective NSAID, COX-1 selective NSAID, non-selective NSAID, opioid, anticonvulsant, antidepressant, local anesthetic, disease-modifying anti-rheumatoid drug, or steroid in conjunction with the compound of Formula (II).
3 . The method of claim 2 , wherein the COX-2 selective NSAID is selected from the group consisting of nimesulide, celecoxib, rofecoxib, firocoxib and valdecoxib.
4 . The method of claim 1 , wherein the inflammation is associated with an inflammation-associated disorder selected from the group consisting of rheumatoid arthritis, pain, common cold, osteoarthritis, neuropathic pain, brain tumor, and diuresis.
5 . The method of claim 1 , wherein the compound of Formula (II) is administered at an initial dosage of about 0.1 mg/kg to about 100 mg/kg per an interval selected from the group consisting of daily, weekly, monthly, quarterly, semi-annually, and annually.
6 . The method of claim 1 , wherein the compound of Formula (II) is formulated as a capsule, tablet or lozenge.
7 . The method of claim 1 , wherein the compound of Formula (II) is administered by contacting skin, fur, or feathers of a subject animal.
8 . The method of claim 1 , wherein the compound of Formula (II) is administered by feeding or injecting a subject animal.
9 . The method of claim 1 , wherein the compound of Formula (II) is administered indirectly by application to the subject dwelling.
10 . The method of claim 1 , wherein the subject is an animal selected from the group consisting of a dog, cat, horse, livestock, and fowl.
11 . The method of claim 1 , wherein:
Ar is phenyl and the group L is arranged para to the depicted imidazopyridine/pyrazine core;
Ar is pyridyl and the group L is arranged para to the depicted imidazopyridine/pyrazine core; or
Ar is thiophene and the group L is arranged 2,4, 2,5, or 3,5 to the depicted imidazopyridine/pyrazine core.
12 . The method of claim 1 , wherein L is —CH 2 CH 2 —.
13 . The method of claim 1 , wherein X is N.
14 . The method of claim 1 , wherein R 2 is C 1-3 alkyl.
15 . The method of claim 1 , wherein R 3 is C 1-3 alkyl.
16 . The method of claim 1 , wherein R 4 is C 1-3 alkyl or C 1-3 haloalkyl.
17 . The method of claim 1 , wherein R 5 is C 1-3 alkyl or halogen.
18 . The method of claim 1 , wherein Ar is phenyl or 1,4-phenyl and unsubstituted or substituted at one or more of 2 and 3 positions.
19 . A method for treating inflammation comprising:
administering to a subject in need thereof an effective amount of a compound selected from:
a) 1-(4-chlorophenyl)sulfonyl-3-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]urea;
b) 1-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(o-tolylsulfonyl)urea;
c) 1-(benzenesulfonyl)-3-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]urea;
d) 1-cyclopentylsulfonyl-3-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]urea;
e) 1-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-[4-(trifluoromethoxy)phenyl]sulfonyl-urea;
f) 1-[2-[5-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)-2-pyridyl]ethyl]-3-(p-tolylsulfonyl)urea;
g) 1-[2-[5-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)-2-thienyl]ethyl]-3-(p-tolylsulfonyl)urea;
h) 1-[2-[4-(6,8-dichloro-2-ethyl-imidazo[1,2-a]pyridin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;
i) 1-[2-[4-(6-cyano-2-ethyl-8-methyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;
j) 1-[2-[4-(2-ethyl-8-methyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;
k) 1-[2-[4-(2-ethyl-8-methyl-6-phenyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;
l) 1-[2-[4-[2-ethyl-8-methyl-6-(3-pyridyl)imidazo[1,2-a]pyrazin-3-yl]phenyl]ethyl]-3-(p-tolylsulfonyl)urea;
m) 1-[2-[4-[2-ethyl-8-methyl-6-(4-pyridyl)imidazo[1,2-a]pyrazin-3-yl]phenyl]ethyl]-3-(p-tolylsulfonyl)urea;
n) 1-[2-[4-(6,8-dimethyl-2-phenyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;
o) 1-[2-[4-(2-isoxazol-3-yl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;
p) 1-[2-[4-(6,8-dimethyl-2-tetrahydrofuran-3-yl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;
q) 1-[2-[4-(2-ethyl-6,8-difluoro-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea; and
r) 1-[2-[4-[6,8-dimethyl-2-(1-methylsulfonyl-4-piperidyl)imidazo[1,2-a]pyrazin-3-yl]phenyl]ethyl]-3-(p-tolylsulfonyl)urea,
or a veterinary, or pharmaceutically acceptable salt thereof.
20 . A method for treating one or more of rheumatoid arthritis or osteoarthritis comprising:
administering to a subject in need thereof an effective amount of a compound of Formula (II), or a veterinary, or pharmaceutically acceptable salt thereof:
wherein
X is N or CR 1 , where each R 1 individually is hydrogen, halogen, CN, C 1-3 alkyl, or C 1-3 haloalkyl;
R 2 is hydrogen, halogen, C 1-3 alkyl, C 1-3 haloalky, CN, aryl, or heteroaryl;
R 3 is hydrogen, halogen, C 1-3 alkyl, C 1-3 haloalkyl or CN;
R 4 is hydrogen, C 1-3 alkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, heterocyclyl, heteroaryl, or aryl;
Z is phenyl or C 6-7 cycloalkyl, each substituted with one or more R 5 , where R 5 is hydrogen, halogen, CN, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 haloalkoxy, or C 1-3 alkoxy;
Ar is phenyl, pyridyl, or thiophenyl, each optionally substituted with one or more halogen, CN, NO 2 , NH 2 , N(C 1-3 alkyl) 2 , OH, C 1-3 alkoxy, C 1-3 alkyl, or C 1-3 haloalkyl;
L is —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, or —OCH 2 CH 2 —; and
n is 0 or 1.