Modulators of central nervous system neurotransmitters

• US 8,168,635 B2
• Filed: 06/20/2005
• Issued: 05/01/2012
• Est. Priority Date: 06/19/2004
• Status: Active Grant

• Current Assignee: Human Biomolecular Research Institute
• Original Assignee: Human Biomolecular Research Institute
• Inventors: Cashman, John
• Primary Examiner(s): Solola, Taofiq A
• Application Number:
  US11/629,797
• Publication Number:
  US 20080261967A1
• Time in Patent Office: 2,507 Days
• Field of Search: 514/248, 544/237
• US Class Current: 514/248
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: C07D 237/32 with oxygen atoms directly attached to carbon atoms of the nitrogen-containing ring
• CPC Class Codes: C07D 307/14 Radicals substituted by nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/06 linked by a carbon chain containing only aliphatic carbon atoms

Abstract

Disclosed are agents having pharmacological activity against cellular receptors and intracellular signaling, particularly receptors and signaling pathways of central nervous system (CNS) neurotransmitters. Also disclosed are related methods and compositions for the treatment or prevention of diseases or disorders using the agents.

Claims

1. A compound of Formula XIV:

2. The compound of claim 1, selected from the group consisting of:

4-(3,4-Dimethoxy-phenyl)-2-{5-[3-phenyl-3-(4-trifluoromethyl-phenoxy)-propylamino]-pentyl}-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one, and

4-(3-Cyclopentyloxy-4-methoxy-phenyl)-1-{5-[3-phenyl-3-(4-trifluoromethyl-phenoxy)-propylamino]-pentyl}-pyrrolidin-2-one.

3. The compound of claim 1, wherein said compound is a dual inhibitor of serotonin reuptake and phosphodiesterase 4 (PDE4) enzyme activity.

4. A pharmaceutical composition comprising:

a compound of claim 1; and

a pharmaceutically acceptable carrier.

5. A method for treating a central nervous system (CNS) disease or disorder in a subject, the method comprising:

administering to a subject an effective amount of a compound of claim 1, wherein said subject is suffering from a CNS disease or disorder amenable to treatment or prevention by inhibition of at least one of serotonin reuptake and phosphodiesterase 4 (PDE4) activity wherein the disease or disorder is selected from the group consisting of depression, a drug addiction, anxiety, attention-deficit disorder, schizophrenia, bipolar disorder and neurodegenerative disease or disorder.

6. The method of claim 5, wherein the compound is a dual inhibitor of serotonin reuptake and phosphodiesterase 4 (PDE4) enzyme activity.

7. The method of claim 5, wherein the neurodegenerative disease is Parkinson'"'"'s Disease or Alzheimer'"'"'s Disease.

8. The compound of claim 1, wherein D is 4-trifluoromethyl-phenyl.

9. The compound of claim 1, wherein b is 2.

10. The compound of claim 1, wherein c is 5.

11. The compound of claim 1, wherein E is 4a,5,8,8a-tetrahydro-2H-phthalazin-1-one, connected to (CH₂)_c at position 2 and to G at position 4.

12. The compound of claim 1, wherein E is pyrrolidin-2-one, connected to (CH₂)_c at position 1 and to G at position 4.

13. The compound of claim 1, wherein G is 3,4-dimethoxy-phenyl or 3-cyclopentyloxy-4-methoxy-phenyl.