Tricyclic compounds useful as neurogenic and neuroprotective agents

• US 9,187,439 B2
• Filed: 09/19/2012
• Issued: 11/17/2015
• Est. Priority Date: 09/21/2011
• Status: Expired due to Fees

• Current Assignee: Inception Orion, Inc.
• Original Assignee: Inception Orion, Inc.
• Inventors: Chen, Austin Chih-Yu, Baccei, Jill Melissa, Stearns, Brian Andrew, Stock, Nicholas Simon, Truong, Yen Pham
• Primary Examiner(s): Habte, Kahsay
• Application Number:
  US14/345,914
• Publication Number:
  US 20140243313A1
• Time in Patent Office: 1,154 Days
• Field of Search: 514/210.21, 514/225.2, 544/46
• US Class Current: 1/1
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: C07D 279/28 with other substituents attached to the ring system
• CPC Class Codes: C07D 487/10 Spiro-condensed systems
• CPC Class Codes: C07D 491/107 with only one oxygen atom as ring hetero atom in the oxygen-containing ring

Abstract

The invention disclosed herein is direct to compounds of Formula I and pharmaceutically acceptable salts thereof, which are useful in treating neurodegenerative diseases and promoting the generation or survival of neurons in the mammalian brain. The invention also comprises pharmaceutical compositions comprising a therapeutically effective amount of compound of Formula I or a pharmaceutically acceptable salt thereof. The invention disclosed herein is also directed to a method of promoting the generation or survival of neurons in a patient in need thereof in neurodegenerative and related diseases.

Claims

1. A compound of Formula I

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R₉ and R₁₀ joined together with the atoms connecting R₉ and R₁₀ form a C_3-6cycloalkyl, or a 4, 5 or 6 membered saturated or unsaturated monocyclic heterocycloalkyl ring or a 6 to 12 membered saturated or unsaturated bicyclic heterocycloalkyl ring, said monocyclic or bicyclic ring having 1 or 2 heteroatoms selected from N, S(O)_n and O, and said C_3-6cycloalkyl, monocyclic or bicyclic heterocycloalkyl ring is optionally mono or di-substituted with substituents independently selected from the group consisting of

(a) halogen,

(b) optionally substituted C_1-6alkyl,

(c) optionally substituted C_1-6alkoxy,

(d) —

NR₁₂R₁₃,

(e) optionally substituted —

S(O)_nC_1-6alkyl,

(f) optionally substituted —

S(O)_naryl,

(g) optionally substituted —

S(O)_nheteroaryl,

(h) optionally substituted heteroaryl,

(i) —

N(R₁₂)C(O)R₁₃,

(j) —

N(R₁₂)C(O)OR₁₃,

(k) —

N(R₁₄)C(O)NR₁₂R₁₃,

(l) —

C(O)NR₁₂R₁₃,

(m) —

C(O)R₁₂, and

(n) —

C(O)OR₁₂.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the group

4. The compound according to claim 1, wherein the compound of Formula I has the structure of Formula Ia:

5. The compound according to claim 4, or a pharmaceutically acceptable salt thereof, wherein:

(a) R₁ is CF₃,

(b) R₆ is hydroxyl, and

(c) R₁₁ is hydrogen.

6. The compound according to claim 5, or a pharmaceutically acceptable salt thereof, wherein R₉ and R₁₀ joined together with the atoms connecting R₉ and R₁₀ form a C_3-6cycloalkyl, or a 4, 5 or 6 membered saturated or unsaturated monocyclic heterocycloalkyl ring or a 6 to 12 membered saturated or unsaturated bicyclic heterocycloalkyl ring, said monocyclic or bicyclic heterocycloalkyl rings having 1 or 2 heteroatoms selected from N, S(O)_n and O, and said C_3-6cycloalkyl, monocyclic or bicyclic heterocycloalkyl ring is optionally mono or di-substituted with substituents are independently selected from the group consisting of

(a) halogen,

(b) optionally substituted C_1-6alkyl,

(c) optionally substituted C_1-6alkoxy,

(d) —

NR₁₂R₁₃,

(e) optionally substituted —

S(O)_nC_1-6alkyl,

(f) optionally substituted —

S(O)_naryl,

(g) optionally substituted —

S(O)_nheteroaryl,

(h) optionally substituted heteroaryl,

(i) —

N(R₁₂)C(O)R₁₃,

(j) —

N(R₁₂)C(O)OR₁₃,

(k) —

N(R₁₄)C(O)NR₁₂R₁₃,

(l) —

C(O)NR₁₂R₁₃,

(m) —

C(O)R₁₂, and

(n) —

C(O)OR₁₂.

7. The compound according to claim 1 selected from 1-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-3-(2-(trifluoromethyl)-10H-phenothiazin-10-yl)propan-2-ol, 1-(2,6-diazaspiro[3.3]heptan-2-yl)-3-(2-(trifluoromethyl)-10H-phenothiazin-10-yl)propan-2-ol, 10-(3-(2,6-diazaspiro[3.3]heptan-2-yl)propyl)-2-(trifluoromethyl)-10H-phenothiazine, 1-(2-(ethylthio)-10H-phenothiazin-10-yl)-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)propan-2-ol, 1-(2-methoxy-10H-phenothiazin-10-yl)-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)propan-2-ol, 1-(2-chloro-10H-phenothiazin-10-yl)-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)propan-2-ol, and

8. A pharmaceutical composition comprising a compound according to claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.