Selective serotonin 2A/2C receptor inverse agonists as therapeutics for neurodegenerative diseases

• US 20060264466A1
• Filed: 05/03/2006
• Published: 11/23/2006
• Est. Priority Date: 01/16/2003
• Status: Active Grant

• Current Assignee: Acadia Pharmaceuticals Inc.
• Original Assignee: Acadia Pharmaceuticals Inc.
• Inventors: Davis, Robert E., Brann, Mark R., Weiner, David M.
• Granted Patent: US 7,659,285 B2
• Time in Patent Office: Days
• US Class Current: 514/317
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/194 having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
• CPC Class Codes: A61K 31/4468 having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/20 Pills, tablets, discs, rods A61K9/0004, A61K9/0007, A61K9/0056, A61K9/0065 take precedence; for reconstitution of a drink A61K9/0095
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/06 Antimigraine agents
• 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 25/22 Anxiolytics
• 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 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07C 59/255 : Tartaric acid
• CPC Class Codes: C07D 211/58 : attached in position 4
• CPC Class Codes: C12Q 2600/106 : Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
• CPC Class Codes: C12Q 2600/156 : Polymorphic or mutational markers

Abstract

Behavioral pharmacological data with the compound of formula (I), a novel and selective 5HT2A/2C receptor inverse agonist, demonstrate in vivo efficacy in models of psychosis and dyskinesias. This includes activity in reversing MK-801 induced locomotor behaviors, suggesting that this compound may be an efficacious anti-psychotic, and activity in an MPTP primate model of dyskinesias, suggesting efficacy as an anti-dyskinesia agent. These data support the hypothesis that 5HT2A/2C receptor inverse agonism may confer antipsychotic and anti-dyskinetic efficacy in humans, and indicate a use of the compound of formula (I) and related agents as novel therapeutics for Parkinson'"'"'s Disease, related human neurodegenerative diseases, and psychosis.

Claims

1. A method of making a compound of formula (I):

2. The method of claim 1, wherein the isobutyl halide is isobutyl bromide.

3. The method of claim 1, wherein the first base is a carbonate.

4. The method of claim 3, wherein the first base is potassium carbonate.

5. The method of claim 1, wherein the second base is a hydroxide.

6. The method of claim 5, wherein the second base is potassium hydroxide.

7. The method of claim 1, wherein reaction step (a) is performed in dimethyl formamide.

8. The method of claim 1, wherein reaction step (b) is performed in methanol/water.

9. The method of claim 1, wherein reaction step (c) is performed in tetrahydrofuran.

10. The method of claim 1, wherein reaction step (d) is performed in methylene chloride.

11. The method of claim 1, wherein reaction step (c) is performed in the presence of a proton sponge.

12. The method of claim 1, further comprising mixing the compound of formula (I) with tartaric acid to produce a tartrate salt of the compound of formula (I).

13. A method of making a tartrate salt of the compound of formula (I):

14. The method of claim 13, wherein the tartaric acid is L-(+)-tartaric acid.

15. The method of claim 13, wherein the solvent is ethanol.

16. A tartrate salt of the compound of formula (I):

17. An L-(+) tartrate salt of the compound of formula (I):

18. A pharmaceutical composition comprising a tartrate salt of the compound of formula (I):