OX2R compounds

Patent metadata

Field	Value
Publication number	US-11472813-B2
Application number	US-202017033879-A
Country	US
Kind code	B2
Filing date	Sep 27, 2020
Priority date	Mar 27, 2018
Publication date	Oct 18, 2022
Grant date	Oct 18, 2022

Abstract

Methods and compositions for agonizing a type-2 orexin receptor (OX2R) in a cell determined to be in need thereof, including the general method of (a) administering to a subject a cyclic guanidinyl OX2R agonist and (b) detecting a resultant enhanced wakefulness or increased resistance to diet-induced accumulation of body fat, or abbreviated recovery from general anesthesia or jet lag.

First claim

What is claimed is:

1. A method of treating a subject suffering from or diagnosed with a disease, disorder, or medical condition mediated by orexin receptor activity, wherein the disease, disorder, or medical condition is a disorder of the sleep-wake cycle, insomnia, restless legs syndrome, jet-lag, disturbed sleep, a sleep disorder secondary to neurological disorders, mania, depression, manic depression, schizophrenia, a pain syndromes, fibromyalgia, neuropathic pain, catatonia, Parkinson's disease, Tourette's syndrome, anxiety, delirium, dementia, overweight, obesity or a condition related to overweight or obesity, insulin resistance, type II diabetes, hyperlipidemia, gallstones, angina, hypertension, breathlessness, tachycardia, infertility, sleep apnea, back and joint pain, varicose veins, osteoarthritis, arrhythmias, angina pectoris, acute heart failure, ulcers, irritable bowel syndrome, diarrhea, gastroesophageal reflux, post-traumatic stress disorder, panic disorders, attention deficit disorders, cognitive deficiencies, or substance abuse, the method comprising administering to the subject in need thereof an effective amount of a compound of formula (A):

or a pharmaceutically acceptable salt thereof, wherein:
Y 1 , Y 2 , Y 3 , and Y 4 , are each independently N or CR 6 , wherein no more than two of Y 1 , Y 2 , Y 3 , and Y 4 are N, wherein one of Y 1 and Y 2 is N and the other is CH or CR 6 ;
W 1 and W 2 are each independently selected from aryl, heterocyclyl, or heteroaryl, which are each optionally substituted with one or more R 10 ;
L 1 is C 1 -C 6 alkylene or C 2 -C 6 alkenylene, optionally substituted with one or more R 7 ;
L 2 is C 1 -C 6 alkylene or C 2 -C 6 alkenylene, optionally substituted with one or more R 8 ;
R 2 is NH, or NR 11 ;
R 6 is hydrogen, halogen, —CN, —NO 2 , —SC 1 -C 6 alkyl, —COR g , —C 1 -C 6 alkyl, —C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or —C 1 -C 6 haloalkoxy,
R 7 is halogen, —OH, —NR a R b , —CN, —C 1 -C 6 alkyl, —C 1 -C 3 alkylene-OH, —C 1 -C 3 alkylene-CN, —CH(OH)CH 2 CN, —C 1 -C 3 alkylene-(C 1 -C 6 alkoxy), —C 1 -C 3 alkylene-(C 1 -C 6 haloalkoxy), —C 1 -C 3 alkylene-OCO(optionally substituted heterocyclyl), —C 1 -C 3 alkylene-OCOR 9 , —C 1 -C 3 alkylene-OCOOR g , —C 1 -C 3 alkylene-NR a R b , —C 1 -C 3 alkylene-NR a COR 9 , —C 1 -C 3 alkylene-NR a CO (optionally substituted heterocyclyl), —C 1 -C 3 alkylene-NR a COOR g , —C 1 -C 3 alkylene-NR a CONR a R b , —C 1 -C 3 alkylene-CONR a R b , —C 1 -C 3 alkylene-CONR c R d , —CONR a R b , —CONR c R d , —(C 1 -C 3 alkylene)-O—(C 1 -C 3 alkylene)-OH, —(C 1 -C 3 alkylene)-O—(C 1 -C 3 alkylene)-CN, —(C 1 -C 3 alkylene)-O—(C 1 -C 3 alkylene)-O—(C 1 -C 4 alkyl), —(C 1 -C 3 alkylene)-O—(C 1 -C 3 alkylene)-O—(C 1 -C 4 haloalkyl), —(C 1 -C 3 alkylene)-O—(C 1 -C 3 alkylene)-S—(C 1 -C 3 alkyl), —C 1 -C 3 alkylene-S(C 1 -C 6 alkyl), —C 1 -C 3 alkylene-SO(C 1 -C 6 alkyl), —C 1 -C 3 alkylene-SO 2 (C 1 -C 6 alkyl), —C 1 -C 3 alkylene-SO 2 R 12 , or hetercyclyl optionally substituted with R 10 ;
R 8 is —OH, —CN, —NO 2 , —COR g , oxo, —C 1 -C 6 alkyl, C 1 -C 6 alkylene-OH, —C 1 -C 6 haloalkyl, or —C 3 -C 6 cycloalkyl;
R a and R b are each independently H, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —CHO, —COOH, —CO(C 1 -C 3 alkyl), —CO(C 1 -C 3 haloalkyl), —CO(C 3 -C 8 cycloalkyl), —CO(C 2 -C 4 alkenyl), —CO(C 1 -C 6 alkylene)-OH, —CO(C 1 -C 6 alkylene)-(C 1 -C 6 alkoxy), —CONR e R f , —CO(C 1 -C 3 alkylene)-NR e R f , —CO(C 1 -C 3 alkylene)-NR e SR f , —CO(C 1 -C 3 alkylene)-NR e SOR g , —CO(C 1 -C 3 alkylene)-NR e SO 2 R f , —CO(C 2 -C 3 alkenyl), —CO(C 1 -C 3 haloalkyl), —CO(CH 2 ) n (cycloalkyl), —CO(CH 2 ) n (optionally substituted aryl), —CO(CH 2 ) n (optionally substituted heterocyclyl), or —CO(CH 2 ) n (optionally substituted heteroaryl);
R c and R d together with the nitrogen atom to which it is attached to form an optionally substituted ring, which can be monocyclic, fused bicyclic, or spiral bicyclic, wherein the ring can contain up to 3 heteroatoms selected from N, O, or S;
R e and R f are each independently H, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, or —C 1 -C 6 alkylene-OH;
R g is H, —C 1 -C 6 alkyl, —C 3 -C 6 cycloalkyl, —C 1 -C 6 haloalkyl, phenyl, or benzyl;
R 9 is —C 1 -C 3 alkylene-OH, —C 1 -C 3 alkylene-CN, —C 1 -C 3 alkylene-(C 1 -C 3 alkoxy), —C 1 -C 3 alkylene-NR a R b , —C1-C4 alkyl or —C1-C4 fluoroalkyl;
R 10 is halogen, —CN, oxo, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 alkoxy, —C 1 -C 6 haloalkoxy, —S—S—(C 1 -C 6 alkyl), or optionally substituted phenyl;
R 11 is —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 alkoxy, —C 1 -C 3 alkylene-OH, —C 1 -C 3 alkylene-(C 1 -C 3 alkoxy), or —COO(C 1 -C 6 alkyl);
alternatively, R 11 and R 7 together form a 5- to 7-membered ring, which is optionally substituted with R 10 ;
R 12 is —OH, —C 1 -C 6 alkyl, —C 3 -C 6 cycloalkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 alkoxy, phenyl, benzyl, —NR a R b , —CONR a R b , or —NR a COR g ; and
n is 0, 1, or 2.

2. The method of claim 1 , wherein R 2 is NH.

3. The method of claim 1 , wherein Y 3 and Y 4 , are each independently CH or CR 6 .

4. The method of claim 1 , wherein R 6 is halogen, methyl, —CH 2 F, —CHF 2 , or —CF 3 .

5. The method of claim 1 , wherein R 10 is halogen, methyl, —CH 2 F, —CHF 2 , or —CF 3 .

6. The method of claim 1 , wherein L 2 is C 1 alkylene or C 4 alkenylene, optionally substituted with one R 8 .

7. The method of claim 1 , wherein L 2 is C 1 alkylene, optionally substituted with one R 8 .

8. The method of claim 1 , wherein R 8 is methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, —CH 2 F, —CHF 2 , or —CF 3 .

9. The method of claim 1 , wherein L 1 is C 2 alkylene optionally substituted with one R 7 .

10. The method of claim 1 , wherein -L 1 -W 1 is —CHR 7 CH 2 —W 1 .

11. The method of claim 1 , wherein W 1 is phenyl optionally substituted with R 10 .

12. The method of claim 1 , wherein W 2 is phenyl optionally substituted with R 10 .

13. The method of claim 1 , wherein R 7 is —C 1 -C 3 alkylene-OH, —C 1 -C 3 alkylene-CN, —C 1 -C 3 alkylene-(C 1 -C 6 alkoxy), —C 1 -C 3 alkylene-NR a R b , —C 1 -C 3 alkylene-OCO(optionally substituted heterocyclyl), —C 1 -C 3 alkylene-OCOR 9 , —C 1 -C 3 alkylene-NR a COR 9 , —C 1 -C 3 alkylene-NR a CO(optionally substituted heterocyclyl), —C 1 -C 3 alkylene-NR a CONR a R b , —CONR c R d , —(C 1 -C 3 alkylene)-O—(C 1 -C 3 alkylene)-OH, —(C 1 -C 3 alkylene)-O—(C 1 -C 3 alkylene)-CN, —(C 1 -C 3 alkylene)-O—(C 1 -C 3 alkylene)-O—(C 1 -C 3 alkyl), —C 1 -C 3 alkylene-S(C 1 -C 6 alkyl), —C 1 -C 3 alkylene-SO(C 1 -C 6 alkyl), or —C 1 -C 3 alkylene-SO 2 (C 1 -C 6 alkyl).

14. The method of claim 1 , wherein R 7 is —CH 2 OH, —CH 2 NH 2 , —CH(CH 3 )OH, —CH 2 CN, —CH 2 (C 1 -C 3 alkoxy), —CH 2 OCO(optionally substituted heterocyclyl), —CH 2 OCOR 9 , —CH 2 NR a COR 9 , —CH 2 NR a CO(optionally substituted heterocyclyl), —CH 2 NR a CONR a R b , —CONR c R d , —CH 2 O—(C 1 -C 3 alkylene)-OH, —CH 2 O—(C 1 -C 3 alkylene)-CN, —CH 2 O—(C 1 -C 3 alkylene)-O—(C 1 -C 3 alkyl), —CH 2 S(C 1 -C 6 alkyl), —CH 2 SO(C 1 -C 6 alkyl), or —CH 2 SO 2 (C 1 -C 6 alkyl).

15. The method of claim 1 , wherein R 7 is —CH 2 OH, —CH 2 NH 2 , —CH(CH 3 )OH, —CH 2 CN, —CH 2 OCH 3 , —CH 2 OCO(optionally s

Assignees

• Univ Texas

Inventors

• Brabander Jef De
• Rosenbaum Daniel
• Liang Qiren
• Wang Wentian

Classifications

• C07D487/10

  Spiro-condensed systems · CPC title

• A61K31/4355

  the heterocyclic ring system containing a five-membered ring having oxygen as a ring hetero atom · CPC title

• C07D403/12

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

• A61K31/4184

  condensed with carbocyclic rings, e.g. benzimidazoles · CPC title

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title