US2021106587A1PendingUtilityA1
Compositions and methods of modulating short-chain dehydrogenase activity
Est. expiryOct 15, 2033(~7.3 yrs left)· nominal 20-yr term from priority
Inventors:Sanford MarkowitzJames K.V. WillsonBruce PosnerJoseph M. ReadyMonika AntczakYongyou ZhangAmar DesaiStanton GersonWilliam J. GreenleeSung Yeun YangKibeom Bae
A61P 35/02A61P 17/02A61K 31/4365A61P 9/00A61P 21/00A61P 35/04A61P 1/02A61P 13/12A61P 15/10A61P 9/08A61P 17/00A61K 31/496A61P 19/10A61P 7/02A61K 31/437A61K 31/5377A61K 31/519A61P 29/00A61P 39/02A61P 3/06A61P 19/00A61P 25/00A61P 9/12A61P 17/14A61P 13/02A61K 31/444A61P 43/00A61P 9/10A61P 19/08A61P 37/02A61P 1/16A61P 31/00A61P 7/06C07D 495/04A61P 35/00A61P 37/06A61P 19/02A61P 1/04A61P 7/00
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Claims
Abstract
Compounds and methods of modulating 15-PGDH activity, modulating tissue prostaglandin levels, treating disease, diseases disorders, or conditions in which it is desired to modulate 15-PGDH activity and/or prostaglandin levels include 15-PGDH inhibitors described herein.
Claims
exact text as granted — not AI-modified1 - 79 . (canceled)
80 : A compound having the formula (V):
or a pharmaceutically acceptable salt thereof;
wherein n=1;
R 1 is
R 3 is H, alkyl, —CO 2 H, —CO 2 alkyl, —CONH 2 , —CONH(alkyl), —CON(alkyl) 2 ,
R 2 is N or CH;
R 4 is H or NH 2 ;
R 5 is a branched or linear alkyl or
wherein n 2 =0-6 and X is CF 3 , CHF 2 , CH 2 F, CCl 3 , CHCl 2 , CH 2 Cl, OH, OAc, OMe, CN, or
wherein n 3 =0-5 and m=1-5;
each R 6 is the same or different and is independently one or more substituent selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, C 3 -C 20 aryl, heterocycloalkenyl containing from 5-6 ring atoms, heteroaryl or heterocyclyl containing from 5-14 ring atoms, C 6 -C 24 alkaryl, C 6 -C 24 aralkyl, halo, silyl, hydroxyl, sulfhydryl, C 1 -C 24 alkoxy, C 2 -C 24 alkenyloxy, C 2 -C 24 alkynyloxy, C 5 -C 20 aryloxy, acyl, acyloxy, C 2 -C 24 alkoxycarbonyl, C 6 -C 20 aryloxycarbonyl, C 2 -C 24 alkylcarbonato, C 6 -C 20 arylcarbonato, carboxy, carboxylato, carbamoyl, C 1 -C 24 alkyl-carbamoyl, arylcarbamoyl, thiocarbamoyl, carbamido, cyano(—CN), isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl, thioformyl, amino, C 1 -C 24 alkyl amino, C 1 -C 24 alkyl amino substituted with hydroxyl, C 5 -C 20 aryl amino, C 2 -C 24 alkylamido, C 6 -C 20 arylamido, sulfanamido, imino, alkylimino, arylimino, nitro, nitroso, sulfo, sulfonato, C 1 -C 24 alkylsulfanyl, arylsulfanyl, C 1 -C 24 alkylsulfinyl, C 5 -C 20 arylsulfinyl, C 1 -C 24 alkylsulfonyl, C 5 -C 20 arylsulfonyl, sulfonamide, phosphono, phosphonato, phosphinato, phospho, phosphino, polyalkyl ethers, phosphates, phosphate ester, and combinations thereof;
provided that R 3 is not hydrogen if R 1 is an unsubstituted thiophene or an unsubstituted thiazole and R 5 is butyl;
provided that R 3 is not an unsubstituted phenyl if R 1 is
an unsubstituted thiophene, or an unsubstituted thiazole; and R 5 is (CH 2 )n 5 (CH 3 ), wherein n 5 =0-7; and
provided that R 3 is not —CF 3 if R 1 is an unsubstituted thiophene.
81 : The compound of claim 80 , wherein R1 is a heterocyclyl containing 5-6 ring atoms.
82 : The compound of claim 80 , wherein R 1 is a substituted or unsubstituted thiazole, oxazole, imidazole, pyrimidine or pyridine.
83 : The compound of claim 80 , wherein R 2 is CH.
84 : The compound of claim 80 , wherein R 3 is H, substituted or unsubstituted aryl, cycloalkyl, heterocyclyl, alkyl, —CO 2 H, —CO 2 alkyl, —CONH 2 , —CONH(alkyl), and —CON(alkyl) 2 ,
85 : The compound of claim 80 , wherein R 3 is
86 : The compound of claim 80 , wherein R 6 is independently selected from hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, amino, substituted or unsubstituted C 1 -C 24 alkyl amino, or C 1 -C 24 alkyl amino substituted with hydroxyl.
87 : The compound of claim 80 , wherein R 4 is NH 2 .
88 : The compound of claim 80 , wherein R 5 is branched or linear C 1 -C 6 alkyl;
wherein n 2 =2-6 and X is CF 3 , CHF 2 , CH 2 F, CCl 3 , CHCl 2 , CH 2 Cl, OH, OAc, OMe, or CN; or
wherein n 3 =0-5 and m=1-5.
89 : The compound of claim 80 , wherein R5 is branched or linear C 2 -C 6 alkyl or
wherein n 3 =0 and m=1-5.
90 : The compound of claim 80 , wherein the compound has formula (V 1 )
or a pharmaceutically acceptable salt thereof;
wherein n=1;
R 3 is selected from the group consisting of H, alkyl, —CO 2 H, —CO 2 alkyl, —CONH 2 , —CONH(alkyl), —CON(alkyl) 2 ,
R 2 is N or CH;
R 4 is selected from the group consisting of H and NH 2 ;
R 5 is a branched or linear alkyl or
wherein n 2 =0-6 and X is any of the following: CF y H z (y+z=3), CCl y H z (y+z=3), OH, OAc, OMe, CN, or
(n 3 =0-5, m=1-5);
each R 6 is the same or different and is independently one or more substituent selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, C 3 -C 20 aryl, heterocycloalkenyl containing from 5-6 ring atoms, heteroaryl or heterocyclyl containing from 5-14 ring atoms, C 6 -C 24 alkaryl, C 6 -C 24 aralkyl, halo, silyl, hydroxyl, sulfhydryl, C 1 -C 24 alkoxy, C 2 -C 24 alkenyloxy, C 2 -C 24 alkynyloxy, C 5 -C 20 aryloxy, acyl, acyloxy, C 2 -C 24 alkoxycarbonyl, C 6 -C 20 aryloxycarbonyl, C 2 -C 24 alkylcarbonato, C 6 -C 20 arylcarbonato, carboxy, carboxylato, carbamoyl, C 1 -C 24 alkyl-carbamoyl, arylcarbamoyl, thiocarbamoyl, carbamido, cyano(—CN), isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl, thioformyl, amino, C 1 -C 24 alkyl amino, C 5 -C 20 aryl amino, C 2 -C 24 alkylamido, C 6 -C 20 arylamido, sulfanamido, imino, alkylimino, arylimino, nitro, nitroso, sulfo, sulfonato, C 1 -C 24 alkylsulfanyl, arylsulfanyl, C 1 -C 24 alkylsulfinyl, C 5 -C 20 arylsulfinyl, C 1 -C 24 alkylsulfonyl, C 5 -C 20 arylsulfonyl, sulfonamide, phosphono, phosphonato, phosphinato, phospho, phosphino, polyalkyl ethers, phosphates, phosphate ester, and combinations thereof;
R 3 is not hydrogen if R 5 is butyl; or R 3 is not an unsubstituted phenyl if R 5 is (CH 2 )n 5 (CH 3 )(n 5 =0-5).
91 : The compound of claim 90 , wherein R3 is selected from the group consisting of H, substituted or unsubstituted aryl, cycloalkyl, heterocyclyl, alkyl, —CO 2 H, —CO 2 alkyl, —CONH 2 , —CONH(alkyl), and —CON(alkyl) 2 .
92 : The compound of claim 80 , the compound inhibiting the activity of a 15-PGDH enzyme.
93 : The compound of claim 80 , wherein the compound inhibits the enzymatic activity of recombinant 15-PGDH at an IC 50 of less than 250 nM.
94 : The compound of claim 80 , wherein the compound inhibits the enzymatic activity of recombinant 15-PGDH at an IC 50 of less than 50 nM.
95 : The compound of claim 80 , wherein the compound inhibits the enzymatic activity of recombinant 15-PGDH at an IC 50 of less than 10 nM.
96 : The compound of claim 80 , wherein the compound inhibits the enzymatic activity of recombinant 15-PGDH at an IC 50 of less than 5 nM.
97 : The compound of claim 80 , wherein the compound inhibits the enzymatic activity of recombinant 15-PGDH at an IC 50 of less than 1 PM.
98 : A compound selected from:
or a pharmaceutically acceptable salt thereof.Cited by (0)
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