Isoindoline compositions and methods for treating neurodegenerative disease

• US 10,207,991 B2
• Filed: 09/11/2017
• Issued: 02/19/2019
• Est. Priority Date: 01/31/2014
• Status: Active Grant

• Current Assignee: Cognition Therapeutics, Inc.
• Original Assignee: Cognition Therapeutics, Inc.
• Inventors: Rishton, Gilbert M., Catalano, Susan M., Look, Gary C.
• Primary Examiner(s): Anderson, Rebecca L
• Assistant Examiner(s): Cheng, Karen
• Application Number:
  US15/700,923
• Publication Number:
  US 20180086703A1
• Time in Patent Office: 526 Days
• CPC Class Codes: A61K 31/4035 Isoindoles, e.g. phthalimide
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: C07D 209/44 Iso-indoles; Hydrogenated iso-indoles
• CPC Class Codes: C07D 209/62 Naphtho [c] pyrroles; Hydrogenated naphtho [c] pyrroles
• CPC Class Codes: C07D 403/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 491/048 the oxygen-containing ring being five-membered
• CPC Class Codes: C07D 491/056 with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring

Abstract

Isoindoline sigma-2 receptor antagonist compounds, pharmaceutical compositions comprising such compounds, and methods for inhibiting Abeta-associated synapse loss or synaptic dysfunction in neuronal cells, modulating an Abeta-associated membrane trafficking change in neuronal cells, and treating cognitive decline associated with Abeta pathology are provided.

Claims

1. A compound of Formula I:

2. The compound of claim 1 wherein

each R₃, R₄, R₅, and R₆ is independently selected from the group consisting of H, OCH₂CH₂OH, O(C₁-C₆ alkyl)OH, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxyC₁-C₆ alkyl, aryl, heteroaryl, heterocycloalkyl, alkylaryl, heteroaryl, CO₂R′

, C(O)R′

, N(C₁-C₄ alkyl)₂, NH(C₃-C₇ cycloalkyl), NHC(O)(C₁-C₄ alkyl), CONR′

₂, NC(O)R′

, NS(O)_nR′

, S(O)_nNR′

₂, S(O)_nR′

, C(O)O(C₁-C₄ alkyl), OC(O)N(R′

)₂, C(O)(C₁-C₄ alkyl), and C(O)NH(C₁-C₄ alkyl);

each n is independently 0, 1, or 2;

each R′

is independently selected from the group consisting of H, CH₃, CH₂CH₃, C₃-C₆ alkyl, C₁-C₆ haloalkyl, or optionally substituted aryl, alkylaryl, piperazin-1-yl, piperidin-1-yl, morpholinyl, heterocycloalkyl, heteroaryl, C₁-C₆ alkoxy, NH(C₁-C₄ alkyl), and N(C₁-C₄ alkyl)₂, wherein the optionally substituted group is selected from C₁-C₆ alkyl or C₂-C₇ acyl.

3. The compound of claim 1 wherein each of R₃, R₄, R₅, and R₆ is independently selected from the group consisting of H, CO₂R′

, C(O)R′

, CONR′

₂, and S(O)_nR′

;

each n is independently 0, 1, or 2; and

each R′

if present in R₃, R₄, R₅, and R₆ is independently selected from the group consisting of H, CH₃, CH₂CH₃, C₃-C₆ alkyl, C₁-C₆ haloalkyl, or optionally substituted aryl, alkylaryl, piperazin-1-yl, piperidin-1-yl, morpholinyl, heterocycloalkyl, heteroaryl, C₁-C₆ alkoxy, NH(C₁-C₄ alkyl), and N(C₁-C₄ alkyl)₂, wherein the optionally substituted group is selected from C₁-C₆ alkyl or C₂-C₇ acyl.

4. The compound of claim 1 wherein at least one of R₃, R₄, R₅, and R₆ is S(O)_nR′

; and

n is 2.

5. The compound of claim 1 of Formula II

8. A composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

9. A method for inhibiting amyloid beta effect on a neuronal cell comprising administering to a subject in need thereof an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

10. The method of claim 9, wherein the amyloid beta effect is associated with cognitive decline and the subject exhibits or is at risk of exhibiting cognitive decline.

11. The method of claim 10, wherein the amyloid beta effect is associated with cognitive impairment in Alzheimer'"'"'s disease.

12. A method of treating Alzheimer'"'"'s disease comprising administering to a subject having said disease an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

21. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:

each of R₁ and R₂ is independently selected from H or C₁-C₆ alkyl;

each of R₃, R₄, R₅, and R₆ is independently selected from the group consisting of H, OCH₃, OCH(CH₃)₂, OCH₂CH(CH₃)₂, OC(CH₃)₃, O(C₁-C₆ alkyl), OCH₂CH₂OH, O(C₁-C₆ alkyl)OH, O(C₁-C₆ haloalkyl), F, Cl, Br, I, CF₃, CN, NO₂, NH₂, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy C₁-C₆alkyl, aryl, heteroaryl, C₃-C₇ cycloalkyl, heterocycloalkyl, alkylaryl, CO₂R′

, C(O)R′

, NH(C₁-C₄ alkyl), N(C₁-C₄ alkyl)₂, NH(C₃-C₇ cycloalkyl), NHC(O)(C₁-C₄ alkyl), CONR′

₂, NC(O)R′

, NS(O)_nR′

, S(O)_nNR′

₂, S(O)_nR′

, C(O)O(C₁-C₄ alkyl), OC(O)N(R′

)₂, C(O)(C₁-C₄ alkyl), and C(O)NH(C₁-C₄ alkyl);

wherein each R′

if present in R₃, R₄, R₅, and R₆ is independently selected from the group consisting of H, CH₃, CH₂CH₃, C₃-C₆ alkyl, C₁-C₆ haloalkyl, or optionally substituted aryl, alkylaryl, piperazin-1-yl, piperidin-1-yl, morpholinyl, heterocycloalkyl, heteroaryl, C₁-C₆ alkoxy, NH(C₁-C₄ alkyl), and N(C₁-C₄ alkyl)₂, wherein the optionally substituted group is selected from C₁-C₆ alkyl or C₂-C₇ acyl;

each of R₇, R₈, R₉, R₁₀, and R₁₁ is independently selected from the group consisting of H, C₁-C₆ alkyl, OH, OCH₃, OCH(CH₃)₂, OCH₂CH(CH₃)₂, OC(CH₃)₃, O(C₁-C₆ alkyl), OCF₃, OCH₂CH₂OH, O(C₁-C₆ alkyl)OH, O(C₁-C₆ haloalkyl), O(CO)R′

, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy C₁-C₆ alkyl, aryl, heteroaryl, C₃-C₇ cycloalkyl, heterocycloalkyl, alkylaryl, heteroaryl, CO₂R′

, C(O)R′

, NH(C₁-C₄ alkyl), N(C₁-C₄ alkyl)₂, NH(C₃-C₇ cycloalkyl), NHC(O)(C₁-C₄ alkyl), CONR′

₂, NC(O)R′

, NS(O)_nR′

, S(O)_nNR′

₂, S(O)_nR′

, C(O)O(C₁-C₄ alkyl), OC(O)N(R′

)₂, C(O)(C₁-C₄ alkyl), and C(O)NH(C₁-C₄ alkyl);

wherein each R′

if present in R₇, R₈, R₉, R₁₀, and R_u is independently selected from the group consisting of H, CH₃, CH₂CH₃, C₃-C₆ alkyl, C₁-C₆ haloalkyl, aryl, alkylaryl, piperazin-1-yl, piperidin-1-yl, morpholinyl, heterocycloalkyl, heteroaryl, C₁-C₆ alkoxy, NH(C₁-C₄ alkyl), and N(C₁-C₄ alkyl)₂;

each n is independently 0, 1, or 2;

with the proviso that R₇, R₈, R₉, R₁₀, and R_u are not all H; and

with the proviso that the following compounds, or pharmaceutically acceptable salts thereof are excluded;

22. The compound of claim 1 wherein R₁ and R₂ are each methyl or wherein one of R₁ or R₂ is methyl, and the other is H.

6. A compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of

13. A composition comprising a compound of claim 6 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

14. A method for inhibiting amyloid beta effect on a neuronal cell comprising administering to a subject in need thereof an effective amount of a compound of claim 6 or a pharmaceutically acceptable salt thereof.

15. The method of claim 14, wherein the amyloid beta effect is associated with cognitive decline and the subject exhibits or is at risk of exhibiting cognitive decline.

16. The method of claim 15, wherein the amyloid beta effect is associated with cognitive impairment in Alzheimer'"'"'s disease.

17. A method of treating Alzheimer'"'"'s disease comprising administering to a subject having said disease an effective amount of a compound of claim 6 or a pharmaceutically acceptable salt thereof.

7. A compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of

18. A composition comprising a compound of claim 7 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

19. A method for inhibiting amyloid beta effect on a neuronal cell comprising administering to a subject in need thereof an effective amount of a compound of claim 7 or a pharmaceutically acceptable salt thereof.

20. A method of treating Alzheimer'"'"'s disease comprising administering to a subject having said disease an effective amount of a compound of claim 7 or a pharmaceutically acceptable salt thereof.