Muscarinic agonists

• US 7,238,713 B2
• Filed: 07/17/2003
• Issued: 07/03/2007
• Est. Priority Date: 04/28/2000
• Status: Expired due to Fees

• Current Assignee: Acadia Pharmaceuticals Inc.
• Original Assignee: Acadia Pharmaceuticals Inc.
• Inventors: Skjaerbaek, Niels, Uldam, Allan K., Anderson, Carl-Magnus A., Friberg, Bo Lennart M., Spalding, Tracy A.
• Primary Examiner(s): CHANG, CELIA C
• Application Number:
  US10/623,119
• Publication Number:
  US 20050113357A1
• Time in Patent Office: 1,447 Days
• Field of Search: 514/321, 514/324, 546/198, 546/202
• US Class Current: 514/324
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/28 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 Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/06 Antiglaucoma agents or miotics
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 405/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 409/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 413/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 473/00 Heterocyclic compounds containing purine ring systems
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems

Abstract

Compounds and methods are provided for the treatment of disease conditions in which modification of cholinergic, especially muscarinic m1, m4, or both m1 and m4, receptor activity has a beneficial effect. In the method, an effective amount of a compound is administered to a patient in need of such treatment.

Claims

1. A compound of formula (I):

2. The compound of claim 1, wherein each t is 2.

3. The compound of claim 2, wherein R₁₀ is n-butyl.

4. The compound of claim 2, wherein each R₁, R₂, R₃, and R₄, independently, is H, hydroxyl, halo, methoxymethyl, ethoxymethyl, proproxymethyl, CF₃, —

NO₂, or straight- or branched-chain C_1-6 alkyl, or R₁ and R₂ together form —

NH—

N═

N—

or R₃ and R₄ together form —

NH—

N═

N—

.

5. The compound of claim 2, wherein Y is absent or O, p is 0, 1, 2 or 3, and R₈ and R₉ are H.

6. The compound of claim 5, wherein Z is absent, Y is absent and p is 3.

7. The compound of claim 6, wherein R₁₀ is n-butyl.

8. The compound of claim 1, wherein the compound is:

1-benzo [b]thiophen-2-yl-4-(4-butylpiperidin-1-yl)-butan-1-one

4-(4-butylpiperidin-1-yl)-1-(5-fluoro-3-methyl-benzo[b]thiophen-2-yl)-butan-1-one;

1-(3-bromo-benzo[b]thiophen-2-yl)-4-(4-butylpiperidin-1-yl)-butan-1-one

1-(3-benzo[b]thiophen-2-yl-propyl)-4-butylpiperidine;

4-butyl-1-[3-(5-fluoro-3-methyl-benzo[b]thiophen-2-yl)-propyl]-piperidine;

1-(3-benzo[b]thiophen-2-yl-propyl)-4-methylpiperidine

1-(3-benzo[b]thiophen-2-yl-propyl)-4-benzylpiperidine;

or

3-[3-(4-butyl-piperidin-1-yl)-propyl]-benzo[d]isothiazole.

9. A pharmaceutical composition comprising an effective amount of a compound of formula (I):

10. A pharmaceutical composition of claim 9, wherein each t is 2.

11. A pharmaceutical composition of claim 10, wherein R₁₀ is n-butyl.

12. A pharmaceutical composition of claim 10, wherein each R₁, R₂, R₃, and R₄, independently, is H, hydroxyl, halo, methoxymethyl, ethoxymethyl, proproxymethyl, CF₃, —

NO₂, or straight- or branched-chain C_1-6 alkyl, or R₁ and R₂ together form —

NH—

N═

N—

or R₃ and R₄ together form —

NH—

N═

N—

.

13. A pharmaceutical composition of claim 10, wherein Y is absent or O, p is 0, 1, 2 or 3, and R₈ and R₉ are H.

14. A pharmaceutical composition of claim 13, wherein Z is absent, Y is absent and p is 3.

15. A pharmaceutical composition of claim 14, wherein R₁₀ is n-butyl.

16. A pharmaceutical composition of claim 10, wherein the compound is:

1-benzo[b]thiophen-2-yl-4-(4-butylpiperidin-1-yl)-butan-1-one

4-(4-butylpiperidin-1-yl)-1-(5-fluoro-3-methyl-benzo[b]thiophen-2-yl)-butan-1-one;

1-(3-bromo-benzo[b]thiophen-2-yl)-4-(4-butylpiperidin-1-yl)-butan-1-one

1-(3-benzo[b]thiophen-2-yl-propyl)-4-butylpiperidine;

4-butyl-1-[3-(5-fluoro-3-methyl-benzo[b]thiophen-2-yl)-propyl]-piperidine;

1-(3-benzo[b]thiophen-2-yl-propyl)-4-methylpiperidine

1-(3-benzo[b]thiophen-2-yl-propyl)-4-benzylpiperidine;

or

3-[3-(4-butyl-piperidin-1-yl)-propyl]-benzo[d]isothiazole.