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

• US 9,211,289 B2
• Filed: 11/10/2014
• Issued: 12/15/2015
• Est. Priority Date: 01/16/2003
• Status: Expired due to Term

• Current Assignee: Acadia Pharmaceuticals Inc.
• Original Assignee: Acadia Pharmaceuticals Inc.
• Inventors: Weiner, David M., Davis, Robert E., Brann, Mark R., Andersson, Carl-Magnus A., Uldam, Allan K.
• Primary Examiner(s): Kim, Jennifer M
• Application Number:
  US14/537,793
• Publication Number:
  US 20150202194A1
• Time in Patent Office: 400 Days
• Field of Search: 514/310, 514/317
• US Class Current: 1/1
• 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 for treating side-effects caused or exacerbated by a dopaminergenic agent-associated therapy comprising administering an therapeutically effective amount of a serotonin 2A or 2C receptor inverse agonist to a patient on a dopaminergenic agent, wherein the serotonin 2A or 2C receptor inverse agonist is a compound of Formula (I) or a salt thereof:

2. The method of claim 1, wherein the serotonin 2A or 2C receptor inverse agonist is a tartrate salt of the compound of Formula (I).

3. The method of claim 2, wherein the therapeutically effective amount of the tartrate salt of the compound of Formula (I) is from 10 mg to 50 mg.

4. The method of claim 2, wherein the therapeutically effective amount of the tartrate salt of the compound of Formula (I) is 10 mg.

5. The method of claim 2, wherein the therapeutically effective amount of the tartrate salt of the compound of Formula (I) is 25 mg.

6. The method of claim 2, wherein the therapeutically effective amount of the tartrate salt of the compound of Formula (I) is 50 mg.

7. The method of claim 1, wherein the salt of the compound of formula (I) is administered daily.

8. The method of claim 1, wherein the salt of compound of formula (I) is administered once daily.

9. The method of claim 1, wherein the salt of compound of formula (I) is formulated for oral administration as a unit dose.

10. The method of claim 9, wherein the unit dose is a tablet.

11. The method of claim 1, wherein the dopaminergenic agent is selected from the group consisting of levodopa, bromocriptine, pergolide, ephedrine sulfate, pemoline, mazindol, d,l-α

-methylphenethylamine, methylphenidate, pramipexole, modafinil, and ropinirole.

12. The method of claim 1, wherein the therapeutically effective amount of serototonin 2A or 2C receptor inverse agonist is from 0.01 μ

g/kg of body weight per day to 1.0 g/kg of body weight per day.

13. The method of claim 1, wherein the therapeutically effective amount of serototonin 2A or 2C receptor inverse agonist is from 0.01 mg/kg of body weight per day to 100 mg/kg of body weight per day.