Triple reuptake inhibitors and methods of their use

Patent metadata

Field	Value
Publication number	US-9850204-B2
Application number	US-201514850338-A
Country	US
Kind code	B2
Filing date	Sep 10, 2015
Priority date	Dec 16, 2008
Publication date	Dec 26, 2017
Grant date	Dec 26, 2017

Abstract

Provided herein are bicyclic compounds and methods of synthesis thereof. The compounds provided herein are useful for the treatment, prevention, and/or management of various neurological disorders. Compounds provided herein inhibit reuptake of endogenous monoamines, such as dopamine, serotonin and norepinephrine (e.g., from the synaptic cleft) and modulate one or more monoamine transporter. Pharmaceutical formulations containing the compounds are also provided.

First claim

What is claimed is:

1. A compound of formula (I)

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein:
m is 0;
n is 0, 1, or 2;
X is hydrogen, (C 3 -C 10 )cycloalkyl, (C 3 -C 10 )cycloalkyl-(C 1 -C 10 )alkyl, (C 1 -C 10 )alkenyl, (C 1 -C 10 )alkynyl, (C 1 -C 10 )alkoxy, 6 to 10 membered aryl, (6 to 10 membered aryl)-(C 1 -C 10 )alkyl, —OR 1 , heteroalkyl, heteroalkenyl, or heteroalkynyl,
Y and Z are each independently halogen, —CF 3 , —CN, —NH 2 , —NO 2 , dioxolano, (C 1 -C 10 )alkyl, (C 3 -C 10 )cycloalkyl, (C 1 -C 10 )alkenyl, (C 1 -C 10 )alkynyl, (C 1 -C 10 )alkoxy, (C 3 -C 10 )cycloalkoxy, or —OR 2 ; or
Y and Z, taken together, may form 5, 6 or 7 membered cycloalkyl; and
R 1 and R 2 are each independently hydrogen, (C 1 -C 10 )alkyl, (C 1 -C 10 )alkenyl, (C 1 -C 10 )alkynyl, (C 3 -C 10 )cycloalkyl, (C 3 -C 10 )cycloalkyl-(C 1 -C 10 )alkyl, (C 1 -C 10 )alkoxy, 6 to 10 membered aryl, 6 to 10 membered heteroaryl, (6 to 10 membered aryl)-(C 1 -C 10 )alkyl, —SO 2 (C 1 -C 10 )alkyl, or —SO 2 -(6 to 10 membered aryl).

2. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein X is hydrogen.

3. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Y and Z are both halogen.

4. The compound of claim 3 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Y and Z are both chloride.

5. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is stereomerically pure.

6. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

7. The pharmaceutical composition of claim 6 , which further comprises one or more additional active agents.

8. A method of inhibiting binding of a monoamine transporter ligand to monoamine transporter, said method comprising contacting said monoamine transporter and a compound of claim 1 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

9. A method of inhibiting the activity of at least one monoamine transporter, said method comprising contacting said monoamine transporter and a compound of claim 1 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

10. The method of claim 8 or 9 , wherein said monoamine transporter is a serotonin transporter (SERT), a dopamine transporter (DAT), a norepinephrine transporter (NET), or a combination thereof.

11. The method of claim 9 , wherein said compound inhibits the activity of at least two different monoamine transporters.

12. A method of inhibiting uptake of at least one monoamine by a cell, said method comprising contacting said cell and a compound of claim 1 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

13. The method of claim 12 , wherein said monoamine is serotonin, dopamine, norepinephrine, or a combination thereof.

14. The method of claim 12 , wherein said compound or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof inhibits uptake of at least two different monoamines.

15. A method of treating depression comprising administering to a patient a compound of claim 1 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

16. The method of claim 15 , wherein the patient is human.

17. A method of treating a central nervous system disorder comprising administering to a patient a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

18. The method of claim 17 , wherein the patient is human.

19. The method of claim 17 , wherein said central nervous system disorder is depression, cognitive deficit, fibromyalgia, pain, sleep disorder, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), restless leg syndrome, schizophrenia, anxiety, obsessive compulsive disorder, posttraumatic stress disorder, premenstrual dysphoria, or a neurodegenerative disease.

20. The method of claim 19 , wherein the depression is major depressive disorder (MDD), unipolar depression, bipolar disorder, seasonal affective disorder (SAD) or dysthymia.

21. The method of claim 19 , wherein the neurodegenerative disease is Parkinson's disease.

22. The method of claim 19 , wherein the sleep disorder is sleep apnea.

23. The method of claim 19 , wherein the pain is neuropathic pain.

Assignees

• Sunovion Pharmaceuticals Inc

Inventors

• Shao Liming
• Wang Fengjiang
• Malcolm Scott C
• Hewitt Michael C

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P25/16

  Anti-Parkinson drugs · CPC title

• A61P25/28

  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

• A61P25/04

  Centrally acting analgesics, e.g. opioids · CPC title

• A61P25/20

  Hypnotics; Sedatives · CPC title