Allosteric activators of the ALPHA1A-adrenergic receptor

Patent metadata

Field	Value
Publication number	US-12384751-B2
Application number	US-202017605801-A
Country	US
Kind code	B2
Filing date	Apr 23, 2020
Priority date	Apr 23, 2019
Publication date	Aug 12, 2025
Grant date	Aug 12, 2025

Abstract

The present invention relates to compounds that are activators of the Alpha 1A -Adrenergic Receptor (α 1A -AR) and methods of using such compounds: for treating neurological conditions, for cardio-protection, and for treating other conditions. In certain embodiments, the α 1A -AR activator compound is a compound of Formula I. In certain embodiments, the neurological condition is Alzheimer's disease, benign prostatic hyperplasia, memory loss, depression, or Parkinson's disease.

First claim

We claim:

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is a 5-membered heterocyclyl ring having 1, 2, or 3 nitrogen atoms;
R 2 is —X—(CH 2 ) m —, wherein X is selected from —O—, —NH—, —S—, and —CH 2 —, and wherein m is 0, 1, or 2;
R 3 is selected from C 2 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 hydroxyalkyl, C 2 -C 6 haloalkyl, C 2 -C 6 hydroxyhaloalkyl, C 3 -C 6 cycloalkyl, aryl, halo, a hydrophobic amino acid moiety, and —(CHR a ) n —R 6 , wherein:
R a is selected from hydrogen and hydroxy;
n is 1 or 2; and
R 6 is selected from aryl, C 3 -C 6 cycloalkyl, a 3- to 6-membered heterocyclic ring having 1, 2, or 3 heteroatoms selected from O, N, and S;

R 4 is selected from —NR b —SO 2 —R 7 , —(CR c R d )—SO 2 —R 7 , and —(CR e R f ) p —R 8 , wherein:
R b is selected from hydrogen, C 1 -C 3 alkyl and C 1 -C 3 haloalkyl;
R c and R d are each independently selected from hydrogen and methyl, or R e and R d are taken together with the carbon atom to which they are attached to form a C 3 -C 4 cycloalkyl group;
R e and R f are each independently selected from hydrogen and halo;
p is 0 or 1;
R 7 is selected from hydrogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, and C 3 -C 6 cycloalkyl; and
R 8 is selected from C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, hydroxy, —COOH, —CONH 2 , and a 5-membered heteroaryl having 1, 2, or 3 nitrogen atoms; and

R 5 is selected from hydrogen, halo, and any of the groups indicated for R 3 and R 4 ;
wherein each aryl, heteroaryl, cycloalkyl, and heterocyclyl can be independently unsubstituted or substituted with 1, 2, or 3 substituents independently selected from hydroxy, halo, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, and oxo.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from imidazolinyl and imidazolidinyl.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is 4,5-dihydroimidazol-2-yl.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is O.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound has formula (Ia):

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from C 2 -C 6 alkyl, C 2 -C 6 hydroxyalkyl, C 2 -C 6 haloalkyl, C 2 -C 6 hydroxyhaloalkyl, halo, and —(CHR a ) n —R 6 .

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is isobutyl.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is —NR b —SO 2 —R 7 or —(CR c R d )—SO 2 —R 7 .

9. The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein R 4 is —NR b —SO 2 —R 7 , R b is C 1 -C 3 alkyl, and R 7 is hydrogen or C 1 -C 3 alkyl.

10. The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein R 4 is —N(CH 3 )—SO 2 —CH 3 .

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from hydrogen and halo.

12. The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein R 5 is hydrogen.

13. The compound of claim 1 , wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.

14. The compound of claim 1 , wherein the compound is not in a salt form.

15. The compound of claim 1 , wherein the compound is in the form of a pharmaceutically acceptable salt.

16. The compound of claim 15 , wherein the compound is in the form of a hydrochloride salt.

17. A method of treating a disorder in a subject, comprising: treating the subject with a compound of claim 1 , wherein the disorder is selected from the group consisting of: benign prostatic hyperplasia, Alzheimer's disease, memory loss, cognitive decline, depression, depressed mood, diabetes, seizures, neurodegeneration, Parkinson's disease, autonomic failure, Multiple System Atrophy, amyotrophic lateral sclerosis (ALS), Huntington's disease, heart failure, cardiovascular disease, and Multiple Sclerosis.

18. The method of claim 17 , wherein said treating causes at least one of the following: improved memory, reduced depression, increased mood, increased metabolism, prolonged lifespan, arousal, satiety, and reduced seizures.

19. The method of claim 17 , wherein said subject has Alzheimer's disease.

20. A method of treating loss of bladder control in a subject, comprising treating the subject with a compound of claim 1 .

Assignees

• Cleveland Clinic Found

Inventors

• Perez Dianne M
• Stauffer Shaun R
• Macdonald Jonathan

Classifications

• G01N33/57555

  of the prostate · CPC title

• C07D233/06

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

• C07D231/12

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

• A61K45/06 Primary

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K31/4192

  1,2,3-Triazoles · CPC title