N-acylethanolamine hydrolyzing acid amidase (NAAA) inhibitors and their use thereof

Patent metadata

Field	Value
Publication number	US-10640494-B2
Application number	US-201815942345-A
Country	US
Kind code	B2
Filing date	Mar 30, 2018
Priority date	May 19, 2014
Publication date	May 5, 2020
Grant date	May 5, 2020

Abstract

A compound is represented as Formula I, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

Compounds of Formula I are inhibitors of N-acylethanolamine hydrolyzing acid amidase (NAAA).

First claim

What is claimed is:

1. A compound of Formula I, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

wherein:
M is CR, wherein R is H or alkyl;
Z is NCS;
W is (CH 2 ) n , and n is 0, 1, 2, or 3;
D is a substituted or unsubstituted cycloalkyl;
Y is (CH 2 ) n , O(CH 2 ) n , NR 3 (CH 2 ) n , (CH 2 ) n O, (CH 2 ) n NR 3 , where n is 0, 1, or 2, and R 3 is H or C 1 -C 4 alkyl;
X is (CH 2 ) n , where n is 0, 1, or 2;
V is absent or O;
B is a substituted or unsubstituted aryl or heteroaryl; and
A is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, wherein
A, B and D, when substituted, are each independently substituted with one or more substituent groups selected from halogen, hydroxyl, alkoxy, alkenoxy, aryloxy, aralkyloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkoxy, carbonyl, carboxylate, ester, urethane, oxime, hydroxylamine, alkoxyamine, aralkoxyamine, thiol, sulfide, sulfoxide, sulfone, sulfonyl, pentafluorosulfanyl, sulfonamide, amine, N-oxide, hydrazine, hydrazide, hydrazone, azide, amide, urea, amidine, guanidine, enamine, imide, isocyanate, isothiocyanate, cyanate, thiocyanate, imine, nitro, nitrile or alkyl optionally substituted one or more times with halo, hydroxy, thio, amino, alkylamino, dialkylamino, alkoxy or carboxy.

2. A compound selected from the group consisting of:
4-(((1R,3R)-3-isothiocyanatocyclobutoxy)methyl)-4′-methyl-1,1′-biphenyl;
4-(((1S,3S)-3-isothiocyanatocyclobutoxy)methyl)-4′-methyl-1,1′-biphenyl;
4-(((1R,3R)-3-isothiocyanatocyclobutoxy)methyl)-1,1′-biphenyl;
4-(((1S,3S)-3-isothiocyanatocyclobutoxy)methyl)-1,1′-biphenyl;
3,4′-difluoro-4-(((1 S, 3S)-3-isothiocyanatocyclobutoxy)methyl)-1,1′-biphenyl;
3,3′-difluoro-4-(((1 S, 3S)-3-isothiocyanatocyclobutoxy)methyl)-4′-methoxy-1,1′-biphenyl;
4′-(((1R,3R)-3-isothiocyanatocyclobutoxy)methyl)-3-methoxy-1,1′-biphenyl;
4′-(((1S,3S)-3-isothiocyanatocyclobutoxy)methyl)-3-methoxy-1,1′-biphenyl;
4-ethoxy-3,3′-difluoro-4′-(((1S,3S)-3-isothiocyanatocyclobutoxy)methyl)-1,1′-biphenyl;
3,3′-difluoro-4-isopropoxy-4′-(((1S,3S)-3-isothiocyanatocyclobutoxy)methyl)-1,1′-biphenyl;
6-(3-fluoro-4-(((1S,3S)-3-isothiocyanatocyclobutoxy)methyl)phenyl)-2,3-dihydrobenzo[b][1,4]dioxine;
5-(3-fluoro-4-(((1S,3S)-3-isothiocyanatocyclobutoxy)methyl)phenyl)benzo[d][1,3]dioxole;
3-fluoro-4-(((1S,3S)-3-isothiocyanatocyclobutoxy)methyl)-3′,4′-dimethoxy-1,1′-biphenyl;
3-(3-fluoro-4-(((1R,3R)-3-isothiocyanatocyclobutoxy)methyl)phenyl)-2-methoxypyridine;
5-(3-fluoro-4-methoxyphenyl)-2-(((1R,3R)-3-isothiocyanatocyclobutoxy)methyl)pyridine;
3,4′-difluoro-3′-(((1 S, 3S)-3-isothiocyanatocyclobutoxy)methyl)-4-methoxy-1,1′-biphenyl;
4-(3-fluoro-4-(((1R,3R)-3-isothiocyanatocyclobutoxy)methyl)phenyl)-3,5-dimethylisoxazole;
4-(3-fluoro-4-(((1R,3R)-3-isothiocyanatocyclobutoxy)methyl)phenyl)-1-methyl-1h-pyrazole;
3-fluoro-4-(((1R,3R)-3-isothiocyanatocyclobutoxy)methyl)-3′-(trifluoromethyl)-1,1′-biphenyl;
3′-(benzyloxy)-3-fluoro-4-(((1R,3R)-3-isothiocyanatocyclobutoxy)methyl)-1,1′-biphenyl;
3-fluoro-4′-((1R,3R)-3-isothiocyanatocyclobutoxy)-4-methoxy-1,1′-biphenyl; and
3-fluoro-4′-((1S,3S)-3-isothiocyanatocyclobutoxy)-4-methoxy-1,1′-biphenyl;
or
a tautomer thereof;
a stereoisomer thereof; or
a pharmaceutically acceptable salt thereof.

3. A composition comprising a compound of claim 1 , a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

4. A method for inhibiting N-acylethanolamine hydrolyzing acid amidase, the method comprising contacting the N-acylethanolamine hydrolyzing acid amidase with a compound of claim 1 , or a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

5. A method of treating an inflammatory gastrointestinal motility disorder, irritable bowel syndrome, or an inflammatory bowel disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 1 , or a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

6. A method for the treatment of ulcerative colitis in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the compound of claim 1 , or a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

7. A method for the treatment of Crohn's disease in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the compound of claim 1 , or a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

8. A method for modulating the activity of N-acylethanolamine hydrolyzing acid amidase, the method comprising contacting a receptor thereof with an effective amount of the compound of claim 1 , or a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

9. A compound of the following structural formula:

or an N-oxide thereof, or a pharmaceutically acceptable salt of either of the foregoing.

10. A composition comprising a compound of claim 9 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

11. A method of treating an inflammatory gastrointestinal motility disorder, irritable bowel syndrome, or an inflammatory bowel disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 9 , or a pharmaceutically acceptable salt thereof.

12. A method for the treatment of ulcerative colitis in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the compound of claim 9 , or a pharmaceutically acceptable salt thereof.

13. A method for the treatment of Crohn's disease in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the compound of claim 9 , or a pharmaceutically acceptable salt thereof.

Assignees

• Univ Northeastern

Inventors

• Malamas Michael
• Makriyannis Alexandros
• Subramanian Kumara Vadivel
• Whitten Kyle M
• Zvonok Nikolai M
• West Jay Matthew
• Mccormack Michael
• Pavlopoulos Spiro

Classifications

• C07D211/10

  with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms · CPC title

• C07D295/135

  with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings · CPC title

• C07C2601/08

  the ring being saturated · CPC title

• C07D413/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D239/26

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms · CPC title