Small molecule antagonist to PACAP receptor and uses thereof

Patent metadata

Field	Value
Publication number	US-12453716-B2
Application number	US-202017429843-A
Country	US
Kind code	B2
Filing date	Feb 13, 2020
Priority date	Feb 13, 2019
Publication date	Oct 28, 2025
Grant date	Oct 28, 2025

Abstract

The invention relates to compounds that demonstrate efficacy in blocking PACAP receptors (e.g. PAC1) and associated methods of treating neurological diseases or disorders using the disclosed compounds. The neurological diseases or disorders include, but are not limited to, stress-related diseases (e.g. chronic stress, post-traumatic stress disorder (PTSD), anxiety, or general anxiety disorder), pain-related diseases (e.g. chronic pain, primary headache disorders, or migraines), or addiction (e.g. addiction to a substance (e.g. addiction to cocaine, amphetamines, methamphetamine, methylphenidate, nicotine, alcohol, prescription medication, marijuana, tobacco, or an opioid selected from heroin, fentanyl, codeine, hydrocodone, morphine, oxycodone, hydromorphone, and methadone)).

First claim

What is claimed is:

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
each R 1 is fluorine;
R 2 is halogen or —NO 2 ;
X 1 is C—H; and
X 2 is C—H or N.

2. The compound of claim 1 , wherein X 2 is C—H.

3. The compound of claim 1 , wherein R 2 is —NO 2 .

4. A compound of Formula (III):

or a pharmaceutically acceptable salt, wherein:
R 3 is hydrogen, halogen, —CF 3 , —CN, —NO 2 , —C(═O)OR c , wherein each R c is independently optionally substituted C 1-6 alkyl;
R 4 and R 5 are independently halogen, —CF 3 , —CN, —NO 2 , or —C(═O)OR b , wherein R b is optionally substituted C 1-6 alkyl;
R 6 is optionally substituted aryl, optionally substituted C 1-6 alkyl, or optionally substituted C 1-8 heteroalkyl; and
X is C—H or N.

5. The compound of claim 4 , of the formula:

or a salt thereof.

6. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient.

7. A method of treating a subject suffering from an anxiety-related disorder, stress-related disease or disorder, addiction, or panic disorder, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 1 .

8. A method of treating a subject identified as in need of treatment for an anxiety-related disorder, stress-related disorder, panic disorder, or addiction, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 1 or
a salt, or composition thereof.

9. The method of claim 7 , further comprising administering an additional pharmaceutical agent to the subject.

10. The method of claim 9 , wherein the additional pharmaceutical agent is a compound of claim 1 , or a compound of the formula:

or a salt, or composition thereof.

11. The method of claim 9 , wherein the additional pharmaceutical agent is the compound I-20, of the formula:

or a salt thereof.

12. A kit comprising:
a compound of claim 1
or a pharmaceutically acceptable salt, or composition thereof; and
instructions for administering to a subject or contacting a biological sample with the compound, or composition.

13. A method of treating a subject suffering from an anxiety-related disorder, the method comprising administering to the subject a therapeutically effective amount of a compound of the formula:

or a salt, or composition thereof.

14. A compound of Formulae

or a salt, or composition thereof.

Assignees

• Univ Of Vermont And State Agricultural College

Inventors

• May Victor
• Brewer Matthias
• Li Jianing

Classifications

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D209/10

  with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring · CPC title

• C07C251/80

  the carbon skeleton containing rings · CPC title

• A61K31/437

  the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline · CPC title

• A61K31/166

  having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol · CPC title