IP Library › Granted Patent US 12,291,535
Granted Patent B2
US 12,291,535 · App. 17/850,144 · Granted May 6, 2025

Benzodiazepine derivatives, compositions, and methods for treating cognitive impairment

Inventors: Belew Mekonnen (Gilbertsville, PA); John A. Butera (Clarksburg, NJ); Jianxing Huang (Bethlehem, PA); Hemantbhai Patel (Piscataway, NJ); Qin Jiang (Latham, NY); Robert Jason Herr (Voorheesville, NY); Emily Elizabeth Freeman (Voorheesville, NY); Nicholas James Mayhew (Niskayuna, NY)
Assignee: AGENEBIO, INC.
C07D487/14A61P25/16A61P25/18A61P25/28
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Quick Facts
Patent No.
US 12,291,535
App. No.
17/850,144
Granted
May 6, 2025
Kind
B2
Abstract

This invention relates to benzodiazepine derivatives, compositions comprising therapeutically effective amounts of those derivatives and methods of using those derivatives or compositions in treating cognitive impairment associated with CNS disorders. It also relates to the use of an α5-containing GABA A receptor agonist (e.g., an α5-containing GABA A receptor positive allosteric modulator) in treating cognitive impairment associated with CNS disorders in a subject in need or at risk thereof, including age-related cognitive impairment, Mild Cognitive Impairment (MCI), amnestic MCI, Age-Associated Memory Impairment, Age Related Cognitive Decline, dementia, Alzheimer's Disease (AD), prodromal AD, PTSD, schizophrenia, bipolar disorder, ALS, cancer-therapy-related cognitive impairment, mental retardation, Parkinson's disease, autism spectrum disorders, fragile X disorder, Rett syndrome, compulsive behavior, and substance addiction. It also relates to the use of an α5-containing GABA A receptor agonist (e.g., an α5-containing GABA A receptor positive allosteric modulator) in treating brain cancers (including brain tumors, e.g., medulloblastomas), and cognitive impairment associated therewith.

Claims (68)

1. A compound of formula X:

or a pharmaceutically acceptable salt, hydrate, isomer, or combination thereof, wherein:

m is an integer selected from 0-4;

each R 1 is independently selected from: -halogen, —(C6-C10) aryl, —OMe, —CN, —C≡C—R 8 , —CHF 2 , —CF 3 , —OCF 3 , —OCHF 2 , —(C1-C6) alkyl, —(C1-C6) alkyl-(C6-C10) aryl, −5-10 membered heteroaryl, —(C1-C6) alkyl-5-10 membered heteroaryl, or —(C3-C6) cycloalkyl;

R 2 is —H, —CH 2 R 8 , —CH 3 , or —CH 2 —OR 8 ;

wherein each occurrence of R 8 is independently-H, —(C1-C6) alkyl, —(C6-C10)-aryl, 5- to 10-membered heteroaryl-, 5-10 membered heteroaryl-(C1-C6) alkyl-, —(C3-C6) cycloalkyl, —(C1-C6) alkyl-(C6-C10) aryl, or —(C1-C6) alkyl-(C3-C6) cycloalkyl;

wherein each R 8 excluding-H and-(C1-C6) alkyl is independently substituted with 0-5 of —halogen, —(C1-C6) alkyl, —CF 3 , —OCF 3 , or —O—(C1-C6) alkyl;

R 3 is selected from: —C≡CR 9 or —(C1-C6) alkyl-C≡C—R 10 ;

wherein R 9 is selected from -5-10 membered heteroaryl, —(C1-C6) alkyl-5-10 membered heteroaryl, or 5-10 membered heterocycle;

wherein each R 9 is independently substituted with 0-5 R 11 ;

wherein each occurrence of R 11 is independently selected from -halogen, —CF 3 , —OCF 3 , —OMe, —(C6-C10) aryl, —(C1-C6) alkyl, or −5 to 10 membered heteroaryl,

wherein R 10 is selected from —H, -halogen, —(C1-C6) alkyl, —(C6-C10) aryl, −5-10 membered heteroaryl, —(C3-C6) cycloalkyl, —CH 2 —(C3-C6) cycloalkyl, —CH 2 —(C6-C10) aryl, or —CH 2 -5-10-membered heteroaryl;

wherein each R 10 is independently substituted with 0-5 R′;

wherein each occurrence of R′ is independently selected from —Cl, —F, —(C1-C6) alkyl, —OMe, or —(C6-C10) aryl; and

each of R 4 , R 5 , and R 6 is independently-H or —(C1-C6) alkyl.

2. The compound according to claim 1 , or a pharmaceutically acceptable salt, hydrate, isomer, or combination thereof, wherein R 9 is selected from

and

wherein each R 9 is independently substituted with 0-5 R 11 .

3. The compound according to claim 1 , or a pharmaceutically acceptable salt, hydrate, isomer, or combination thereof, wherein R 9 is selected from

and

wherein each R 9 is independently substituted with 0-5 R 11 .

4. The compound according to claim 1 , or a pharmaceutically acceptable salt, hydrate, isomer, or combination thereof, wherein R 9 is selected from

and

wherein each R 9 is independently substituted with 0-5 R 11 .

5. The compound according to claim 1 , or a pharmaceutically acceptable salt, hydrate, isomer, or combination thereof, wherein:

each R 1 is independently selected from: —Cl, —Br, —(C6-C10) aryl, —OMe, —CF 3 , or —OCHF 2 ;

R 2 is —H, —CH 2 R 8 , or —CH 3 , wherein each occurrence of R 8 is independently-H, —(C1-C6) alkyl, or (C6-C10)-aryl;

wherein each R 8 excluding-H and-(C1-C6) alkyl is independently substituted with 0-5—halogen;

R 3 is —C≡CR 9 ;

wherein R 9 is -5-10 membered heteroaryl;

wherein each R 9 is independently substituted with 0-5 R 11 ;

wherein each occurrence of R 11 is independently selected from —CF 3 or —OMe; and

each of R 4 , R 5 , and R 6 is —H.

6. The compound according to claim 5 , or a pharmaceutically acceptable salt, hydrate, isomer, or combination thereof,

wherein R 9 is selected from

7. The compound according to claim 1 , wherein the compound is selected from:

or a pharmaceutically acceptable salt, hydrate, isomer, or combination thereof.

8. The compound according to claim 1 , wherein the compound is selected from:

or a pharmaceutically acceptable salt, hydrate, isomer, or combination thereof.

9. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt, hydrate, isomer, or combination thereof, in a therapeutically effective amount; and an acceptable carrier, adjuvant or vehicle.

10. The pharmaceutical composition according to claim 9 , wherein said composition further comprises a second agent selected from a) an antipsychotic, selected from aripiprazole, olanzapine and ziprasidone, or a pharmaceutically acceptable salt, or hydrate thereof, b) memantine or a pharmaceutically acceptable salt, or hydrate thereof, and c) an acetylcholine esterase inhibitor (AChE-I) selected from Donepezil, Galantamine, and Rivastigmine, or a pharmaceutically acceptable salt, or hydrate thereof.

11. The pharmaceutical composition according to claim 10 , wherein the second agent is an antipsychotic selected from aripiprazole, olanzapine and ziprasidone, or a pharmaceutically acceptable salt, or hydrate thereof.

12. The pharmaceutical composition according to claim 10 , wherein the second agent is memantine or a pharmaceutically acceptable salt, or hydrate thereof.

13. The pharmaceutical composition according to claim 10 , wherein the second agent is an AChE-I selected from Donepezil, Galantamine, and Rivastigmine, or a pharmaceutically acceptable salt, or hydrate thereof.

14. A method of treating cognitive impairment associated with a central nervous system (CNS) disorder in a subject in need thereof, comprising the step of administering a compound according to claim 1 , or a pharmaceutically acceptable salt, hydrate, isomer, or combination thereof.

15. The method of claim 14 , wherein the CNS disorder is age-related cognitive impairment.

16. The method of claim 14 , wherein the CNS disorder is Mild Cognitive Impairment (MCI).

17. The method of claim 16 , wherein the Mild Cognitive Impairment is amnestic Mild Cognitive Impairment (aMCI).

18. The method according to claim 14 , wherein the CNS disorder is dementia.

19. The method of claim 14 , wherein the CNS disorder is Alzheimer's disease.

20. The method of claim 14 , wherein the CNS disorder is schizophrenia, amyotrophic lateral sclerosis (ALS), post-traumatic stress disorder (PTSD), mental retardation, Parkinson's disease (PD), autism, compulsive behavior, substance addiction, bipolar disorder, or a disorder associated with cancer therapy.

21. A method of treating a brain cancer in a subject in need thereof, comprising the step of administering a compound according to claim 1 , or a pharmaceutically acceptable salt, hydrate, isomer or combination thereof.

22. A method of treating cognitive impairment associated with a brain cancer in a subject in need thereof, comprising the step of administering a compound according to claim 1 , or a pharmaceutically acceptable salt, hydrate, isomer, or combination thereof.

23. The method of claim 21 , wherein said brain cancer is medulloblastoma.

24. The method of claim 22 , wherein said brain cancer is medulloblastoma.

25. A method of treating Parkinson's disease psychosis in a patient in need thereof, comprising the step of administering a compound according to claim 1 , or a pharmaceutically acceptable salt, hydrate, isomer, or combination thereof.

26. A method of treating cognitive impairment associated with a central nervous system (CNS) disorder in a subject in need thereof, comprising the step of administering a pharmaceutical composition according to claim 13 .

27. The method of claim 26 , wherein the CNS disorder is age-related cognitive impairment.

28. The method of claim 26 , wherein the CNS disorder is Mild Cognitive Impairment (MCI).

29. The method of claim 28 , wherein the Mild Cognitive Impairment is amnestic Mild Cognitive Impairment (aMCI).

30. The method according to claim 26 , wherein the CNS disorder is dementia.

31. The method of claim 26 , wherein the CNS disorder is Alzheimer's disease.

32. The method of claim 26 , wherein the CNS disorder is schizophrenia, amyotrophic lateral sclerosis (ALS), post-traumatic stress disorder (PTSD), mental retardation, Parkinson's disease (PD), autism, compulsive behavior, substance addiction, bipolar disorder, or a disorder associated with cancer therapy.

33. A method of treating a brain cancer in a subject in need thereof, comprising the step of administering a pharmaceutical composition according to claim 13 .

34. A method of treating cognitive impairment associated with a brain cancer in a subject in need thereof, comprising the step of administering a pharmaceutical composition according to claim 13 .

35. The method of claim 33 , wherein said brain cancer is medulloblastoma.

36. The method of claim 34 , wherein said brain cancer is medulloblastoma.

37. A method of treating Parkinson's disease psychosis in a patient in need thereof, comprising the step of administering a pharmaceutical composition according to claim 9 .

Assignments (5)
CONFIRMATORY LICENSE Recorded Jan 17, 2024
From: AGENEBIO, INC.
To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT
Reel/Frame 066340/0329 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 27, 2022
From: JIANG, QIN; HERR, ROBERT JASON; FREEMAN, EMILY ELIZABETH; MAYHEW, NICHOLAS JAMES
To: ALBANY MOLECULAR RESEARCH, INC.
Reel/Frame 060323/0537 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 27, 2022
From: ALBANY MOLECULAR RESEARCH, INC.
To: AGENEBIO, INC.
Reel/Frame 060323/0582 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 27, 2022
From: MEKONNEN, BELEW; BUTERA, JOHN A.; HUANG, JIANXING; PATEL, HEMANTBHAI
To: HAGER BIOSCIENCES
Reel/Frame 060323/0591 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 27, 2022
From: HAGER BIOSCIENCES
To: AGENEBIO, INC.
Reel/Frame 060323/0626 →
Continuity (3)
Division 16445854 · Jun 19, 2019
Provisional Application 62687195 · Jun 19, 2018
Related Publication 20230107032A1 · Apr 6, 2023
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