Use of ZT-1A and analogs thereof to prevent and/or treat neurodegenerative and neurocognitive disorders

Patent metadata

Field	Value
Publication number	US-11925611-B2
Application number	US-202217704789-A
Country	US
Kind code	B2
Filing date	Mar 25, 2022
Priority date	Mar 26, 2021
Publication date	Mar 12, 2024
Grant date	Mar 12, 2024

Abstract

The present disclosure is concerned with substituted N-(5-chloro-4-((4-chlorophenyl)(cyano)methyl)-2-methylphenyl)benzamide compounds, and methods of treating and/or preventing neurodegenerative or neurocognitive disorders including, but not limited to, Alzheimer's disease, cerebral autosomal dominant arteriopathy with sub-cortical infarcts and leukoencephalopathy (CADASIL), Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS/Lou Gehrig's disease), Multiple Sclerosis, spinal muscular atrophy, spinal and bulbar muscular atrophy, familial spastic paraparesis, Machado Joseph disease, Friedreich's ataxia, Lewy body disease, and dementia (e.g., vascular dementia, Lewy body dementia, frontotemporal dementia, mixed dementia, dementia induced by Alzheimer's disease or Parkinson's disease). This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

First claim

What is claimed is:

1. A method for treating and/or preventing a neurodegenerative disease or a neurocognitive disease in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula:

wherein each of X 1 and X 2 is independently halogen;
wherein R 1 is selected from —OH, —SR 10 , and —NR 11a R 11b ;
wherein each of R 10 , R 11a ,and R 11b , when present, is independently selected from hydrogen and C1-C4 alkyl;

wherein each of R 2a , R 2b , R 2c , and R 2d is independently selected from hydrogen, halogen, —NO 2 , —CN, —OH, —SH, —NH 2 , C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino;
wherein each of R 3a , R 3b , R 3c , and R 3d is independently selected from hydrogen, halogen, —NO 2 , —CN, —OH, —SH, —NH 2 , C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino;
wherein R 4 is selected from hydrogen and C1-C4 alkyl; and
wherein R 5 is C1-C4 alkyl, provided that the compound is not:

or a pharmaceutically acceptable salt thereof,
wherein the subject has not been diagnosed as having had an ischemic stroke prior to the administering step, and
wherein the neurodegenerative disease is selected from Alzheimer's disease, cerebral autosomal dominant arteriopathy with sub-cortical infarcts and leukoencephalopathy (CADASIL), Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS/Lou Gehrig's disease), Multiple Sclerosis, spinal muscular atrophy, spinal and bulbar muscular atrophy, familial spastic paraparesis, Machado Joseph disease, Friedreich's ataxia, and Lewy body disease.

2. The method of claim 1 , wherein the compound has a structure represented by a formula:

wherein R 1 is selected from —OH, —SR 10 , and —NR 11a R 11b ;
wherein each of R 10 , R 11a , and R 11b , when present, is independently selected from hydrogen and C1-C4 alkyl;

wherein each of R 2a , R 2b , R 2c , and R 2d is independently selected from hydrogen, halogen, —NO 2 , —CN, —OH, —SH, —NH 2 , C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and
wherein each of R 3a , R 3b , R 3c , and R 3d is independently selected from hydrogen, halogen, —NO 2 , —CN, —OH, —SH, —NH 2 , C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.

3. The method of claim 1 , wherein R 1 is —OH.

4. The method of claim 1 , wherein R 1 is —SH.

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

6. The method of claim 1 , wherein each of R 2a , R 2b , R 2c , and R 2d is independently selected from hydrogen, —F, —Cl, —NO 2 , —CN, —OH, —SH, —NH 2 , C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.

7. The method of claim 1 , wherein each of R 2a , R 2b , R 2c , and R 2d is hydrogen.

8. The method of claim 1 , wherein at least one of R 2a , R 2b , R 2c , and R 2d is halogen.

9. The method of claim 1 , wherein each of R 2a , R 2b , R 2c , and R 2d is independently selected from hydrogen, —F, and —Cl.

10. The method of claim 1 , wherein the compound has a structure represented by a formula:

wherein R 1 is selected from —OH, —SR 10 , and —NR 11a R 11b ;
wherein each of R 10 , R 11a , and R 11b , when present, is independently selected from hydrogen and C1-C4 alkyl; and

wherein each of R 2a , R 2b , R 2c , and R 2d is independently selected from hydrogen, halogen, —NO 2 , —CN, —OH, —SH, —NH 2 , C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.

11. The method of claim 1 , wherein the compound has a structure represented by a formula:

wherein each of R 2a , R 2b , R 2c ,and R 2d is independently selected from hydrogen, halogen, —NO 2 , —CN, —OH, —SH, —NH 2 , C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.

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

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

14. The method of claim 1 , wherein the method does not comprise administering an inhibitor of COX-1, COX-2, or lipoxygenase to the subject.

15. The method of claim 1 , wherein the method treats or prevents a neurocognitive disease, and wherein the neurocognitive disease is dementia.

16. The method of claim 15 , wherein the dementia is vascular dementia, frontotemporal dementia, Lewy body dementia, or mixed dementia.

17. The method of claim 15 , wherein the dementia is induced by Alzheimer's disease or Parkinson's disease.

18. A method of treating and/or preventing dementia in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula:

or a pharmaceutically acceptable salt thereof,
wherein the subject has not been diagnosed as having had an ischemic stroke prior to the administering step.

Assignees

• Us Gov Veterans Affairs
• Univ Of Pittsburgh—Of The Commonwealth Of Higher Education
• Univ Of Pittsburgh Of The Commonwealth Of Higher Education

Inventors

• Sun Dandan
• Bhuiyan Mohammad Iqbal Hossain

Classifications

• A61K31/167 Primary

  having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol · CPC title

• A61P25/28 Primary

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title