Small molecule prostagladin transport inhibitors
The disclosure provides compounds of Formula 1, and the pharmaceutically acceptable salts thereof. The variables in Formula 1, e.g. X 1 -X 5 , A 1 , A 2 , and R 1 -R 4 are described herein. Such compounds are useful as prostaglandin transport (PGT) inhibitors. The disclosure further includes pharmaceutical compositions comprising a compound of Formula 1 or salt thereof and methods of using compounds of Formula 1 and salts thereof to treat diseases and disorders mediated, at least in part, by prostaglandin levels or cyclooxygenase activity. Such diseases and disorders include painful and inflammatory conditions.
1 . A compound of Formula 1:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 and R 2 are independently chosen from C 1 -C 6 alkyl, (C 1 -C 4 alkoxy) (C 1 -C 4 alkyl), (C 3 -C 7 cycloalkyl)C 0 -C 2 alkyl, —CO 2 C 1 -C 6 alkyl, and —CO 2 C 0 -C 2 alkyl(C 3 -C 7 cycloalkyl), or
R 1 and R 2 together may be a 3-6 membered carbocyclic ring or a 4-6-membered heterocycloalkyl ring containing one heteroatom or substituted heteroatom chosen from NH, N—C 1 -C 6 alkyl, NCO—C 1 -C 6 -alkyl, NCO 2 —C 1 -C 6 -alkyl, NSO 2 —C 1 -C 6 -alkyl, O, S and SO 2 ;
R 3 and R 4 are independently chosen from hydrogen, fluoro, and methyl or R 3 and R 4 can be taken together to form a C 3 -C 5 saturated or partially unsaturated carbocyclic ring or an oxetanyl ring which is optionally 2,2 or 3,3 disubstituted with halogen or C 1 -C 2 alkyl;
A 1 is a pyrazinyl or pyrimidinyl heteroarylene group optionally substituted with one or more substituents independently chosen from halogen, hydroxyl, cyano, C 1 -C 6 -alkyl, C 1 -C 6 alkoxy, (C 3 -C 7 -cycloalkyl) C 0 -C 2 alkyl, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy;
A 2 is —CO 2 H;
X 1 , X 2 , X 3 , X 4 , and X 5 are aromatic ring atoms chosen from N and C, where up to 3 of X 1 , X 2 , X 3 , X 4 , and X 5 are N ring atoms and each C ring atom is optionally substituted with R 6 where each R 6 is independently chosen from halogen, hydroxyl, cyano, amino, —CONH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, mono- or di-(C 1 -C 6 alkylamino) C 0 -C 2 alkyl, (C 3 -C 7 cycloalkyl) C 0 -C 2 alkyl, (C 3 -C 7 cycloalkyl) C 0 -C 2 alkoxy, (C 1 -C 6 alkylSO 2 ) C 0 -C 2 alkyl, C 1 -C 6 alkylNHCO—, and (C 1 -C 6 alkyl) 2 NCO—; and
Q is absent or is —CH 2 —, or —CH 2 CH 2 —.
2 . The compound or salt of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 and R 2 are independently chosen from C 1 -C 6 alkyl, and —CO 2 —C 1 -C 6 alkyl;
R 3 and R 4 are independently chosen from hydrogen, fluoro, and methyl;
X 1 , X 2 , X 3 , X 4 , and X 5 are aromatic ring atoms chosen from N and C, where up to 3 of X 1 , X 2 , X 3 , X 4 , and X 5 are N ring atoms and each C ring atom is optionally substituted with R 6 where each R 6 is independently chosen from halogen, hydroxyl, cyano, amino, —CONH 2 , C 1 -C 6 alkyl, C 1 -C 6 -alkoxy, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, C 3 -C 7 -cycloalkyl, and C 3 -C 7 -cycloalkyl-O—.
3 . The compound or salt of claim 1 , wherein
R 1 is —CO 2 —C 1 -C 6 alkyl or C 1 -C 6 alkyl and R 2 is C 1 -C 6 alkyl;
R 3 and R 4 are hydrogen or methyl;
A 1 is a pyrimidyl or pyrazinyl heteroarylene, group, each of which is optionally substituted with one or more substituents independently chosen from halogen, hydroxyl, cyano, C 1 -C 2 alkyl, C 1 -C 2 alkoxy, trifluoromethyl, and trifluoromethoxy;
X 1 , X 2 , X 3 , X 4 , and X 5 are aromatic ring atoms chosen from N and C, where 0 or 1 of X 1 , X 2 , X 3 , X 4 , and X 5 are N ring atoms and each C ring atom is optionally substituted with R 6 where each Re is independently chosen from fluoro, chloro, hydroxyl, cyano, —CONH 2 , C 1 -C 2 alkyl, C 1 -C 2 alkoxy, trifluoromethyl, trifluoromethoxy, C 1 -C 2 alkylSO 2 —, C 1 -C 2 alkylNHCO—, and (C 1 -C 2 alkyl) 2 NCO—; and
Q is —CH 2 —.
4 . The compound or salt of claim 1 of the Formula 1B, or 1C;
where R is absent or is one or more substituents independently chosen from halogen, cyano, and C 1 -C 2 alkyl, or C 1 -C 2 alkoxy.
5 . The compound or salt of claim 4 , where the X 1 -X 5 containing ring is a phenyl or pyridyl and is optionally substituted with 1, 2, or 3 substituents independently chosen from fluoro, chloro, bromo, hydroxyl, cyano, CH 3 SO 2 -C 1 -C 3 alkyl, C 1 -C 3 alkoxy, trifluormethyl, and trifluromethoxy.
6 . The compound or salt of claim 4 , where the X 1 -X 5 containing ring is a phenyl or 2-pyridyl and is optionally substituted with 1, 2, or 3 substituents independently chosen from fluoro, chloro, hydroxyl, methyl, methoxy, and CH 3 SO 2 —.
7 . The compound or salt of claim 5 , where
R 1 is ethyl, —CO 2 -ethyl, or —CO 2 -t-butyl; and R 2 is ethyl.
8 . The compound or salt of claim 5 , where Q is —CH 2 — and R 3 and R 4 are both hydrogen.
9 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof
4-ethoxycarbonyl-4-[6-(4-methylanilino)pyrazin-2-yl]hexanoic acid;
4-[6-(2,4-difluoroanilino)pyrazin-2-yl]-4-ethoxycarbonyl-hexanoic acid;
(4R)-4-[6-(2,4-difluoroanilino)pyrazin-2-yl]-4-ethoxycarbonyl-hexanoic acid;
(4S)-4-[6-(2,4-difluoroanilino)pyrazin-2-yl]-4-ethoxycarbonyl-hexanoic acid;
4-ethoxycarbonyl-4-[2-(4-methylanilino)pyrimidin-4-yl]hexanoic acid;
4-tert-butoxycarbonyl-4-[6-(4-methylanilino)pyrazin-2-yl]hexanoic acid;
4-ethoxycarbonyl-4-[6-(2-methoxyanilino)pyrazin-2-yl]hexanoic acid;
4-[6-(2,4-difluoroanilino)pyrazin-2-yl]-4-ethyl-hexanoic acid;
4-[6-(2,4-difluoroanilino)-3-ethyl-pyrazin-2-yl]-4-ethyl-hexanoic acid;
4-[6-(2,5-difluoroanilino)pyrazin-2-yl]-4-ethoxycarbonyl-hexanoic acid;
4-[6-[(3,5-difluoro-2-pyridyl)amino]pyrazin-2-yl]-4-ethyl-hexanoic acid;
4-[6-(2-chloroanilino)pyrazin-2-yl]-4-ethyl-hexanoic acid;
4-ethyl-4-[6-(2,4,5-trifluoroanilino)pyrazin-2-yl]hexanoic acid;
4-(isobutoxycarbonyl)-4-(6-(p-tolylamino)pyrazin-2-yl) hexanoic acid;
4-(cyclopropylmethyl)-5-ethoxy-5-oxo-4-(6-(p-tolylamino)pyrazin-2-yl)pentanoic acid;
4-(ethoxycarbonyl)-4-(6-((3-fluoro-4-hydroxyphenyl)amino)pyrazin-2-yl) hexanoic acid;
4-(6-((2,4-difluorophenyl)amino)pyrazin-2-yl)-4-(methoxymethyl)hexanoic acid; or
4-(6-((2,4-difluorophenyl)amino)pyrazin-2-yl)-4-((1-methylcyclopropoxy)carbonyl)hexanoic acid.
10 . A pharmaceutical composition comprising a compound of claim 4 and a pharmaceutically acceptable carrier.
11 . A method of treating obesity, pulmonary arterial hypertension, or non-alcoholic steatohepatitis (NASH) in a subject, comprising administering a therapeutically effective amount of a compound of salt of claim 4 to the subject.
12 . A method of preventing or delaying the onset of pulmonary arterial hypertension in a subject at risk for pulmonary arterial hypertension comprising administering an effective amount of a compound or salt claim 4 to the subject.
13 . A method of treating pain or inflammation in a subject, comprising administering a therapeutically effective amount of a compound of salt of claim 4 to the subject.
14 . A method of treating or preventing cisplatin nephrotoxicity in a patient, comprising administering a therapeutically effective amount of a compound or salt of claim 4 to the patient prior to cisplatin administration, concurrently with cisplatin administration, or following cisplatin administration.
15 . A method of treating ARDS or hyperinflammation associated with SARS-CoV-2 infection in a subject comprising administering an effective amount of a compound or salt of claim 4 in a subject.