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

• US 7,732,462 B2
• Filed: 05/03/2006
• Issued: 06/08/2010
• 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., Uldam, Allan K., Andersson, Carl-Magnus A.
• Primary Examiner(s): Kim; Jennifer M
• Application Number:
  US11/416,527
• Publication Number:
  US 20060264465A1
• Time in Patent Office: 1,497 Days
• Field of Search: 514/310, 514/317
• US Class Current: 514/310
• 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 treating schizophrenia in a patient, comprising administering to a patient having schizophrenia a therapeutically effective amount of (a) N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′

-(4-(2-methylpropyloxy)phenylmethyl)carbamide or a pharmaceutically acceptable salt thereof, and (b) risperidone.

4. The method of claim 1, wherein the tartrate salt of N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′

-(4-(2-methylpropyloxy)phenylmethyl)carbamide is administered.

7. The method of claim 1, wherein about 0.01 mg/kg of body weight to about 2 mg/kg body weight of N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′

-(4-(2-methylpropyloxy)phenylmethyl)carbamide or a pharmaceutically acceptable salt thereof is administered.

10. The method of claim 1, wherein about 10 mg to about 50 mg of N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′

-(4-(2-methylpropyloxy)phenylmethyl)carbamide, or a pharmaceutically acceptable salt thereof, is administered.

13. The method of claim 10, wherein about 10 mg of N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′

-(4-(2-methylpropyloxy)phenylmethyl)carbamide, or a pharmaceutically acceptable salt thereof, is administered.

14. The method of claim 10, wherein about 25 mg of N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′

-(4-(2-methylpropyloxy)phenylmethyl)carbamide, or a pharmaceutically acceptable salt thereof, is administered.

15. The method of claim 10, wherein about 50 mg of N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′

-(4-(2-methylpropyloxy)phenylmethyl)carbamide, or a pharmaceutically acceptable salt thereof, is administered.

22. The method of claim 1, wherein the hydrochloride salt of N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′

-(4-(2-methylpropyloxy)phenylmethyl)carbamide is administered.

2. A method of treating schizophrenia in a patient, comprising administering to the patient having schizophrenia a therapeutically effective amount of (a) N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′

-(4-(2-methylpropyloxy)phenylmethyl)carbamide or a pharmaceutically acceptable salt thereof, and (b) haloperidol.

5. The method of claim 2, wherein the tartrate salt of N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′

-(4-(2-methylpropyloxy)phenylmethyl)carbamide is administered.

8. The method of claim 2, wherein about 0.01 mg/kg of body weight to about 2 mg/kg body weight of N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′

-(4-(2-methylpropyloxy)phenylmethyl)carbamide or a pharmaceutically acceptable salt thereof is administered.

11. The method of claim 2, wherein about 10 mg to about 50 mg of N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′

-(4-(2-methylpropyloxy)phenylmethyl)carbamide, or a pharmaceutically acceptable salt thereof, is administered.

16. The method of claim 11, wherein about 10 mg of N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′

-(4-(2-methylpropyloxy)phenylmethyl)carbamide, or a pharmaceutically acceptable salt thereof, is administered.

17. The method of claim 11, wherein about 25 mg of N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′

-(4-(2-methylpropyloxy)phenylmethyl)carbamide, or a pharmaceutically acceptable salt thereof, is administered.

18. The method of claim 11, wherein about 50 mg of N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′

-(4-(2-methylpropyloxy)phenylmethyl)carbamide, or a pharmaceutically acceptable salt thereof, is administered.

23. The method of claim 2, wherein the hydrochloride salt of N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′

-(4-(2-methylpropyloxy)phenylmethyl)carbamide is administered.

3. A method for reducing an amount of haloperidol or risperidone effective to treat psychosis in a schizophrenic patient, the method comprising administering a therapeutically effective amount of N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′

-(4-(2-methylpropyloxy)phenylmethyl)carbamide, or a pharmaceutically acceptable salt thereof, to the schizophrenic patient with psychosis being treated with haloperidol or risperidone.

6. The method of claim 3, wherein the tartrate salt of N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′

-(4-(2-methylpropyloxy)phenylmethyl)carbamide is administered.

9. The method of claim 3, wherein about 0.01 mg/kg of body weight to about 2 mg/kg body weight of N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′

-(4-(2-methylpropyloxy)phenylmethyl)carbamide or a pharmaceutically acceptable salt thereof is administered.

12. The method of claim 3, wherein about 10 mg to about 50 mg of N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′

-(4-(2-methylpropyloxy)phenylmethyl)carbamide, or a pharmaceutically acceptable salt thereof, is administered.

19. The method of claim 12, wherein about 10 mg of N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′

-(4-(2-methylpropyloxy)phenylmethyl)carbamide, or a pharmaceutically acceptable salt thereof, is administered.

20. The method of claim 12, wherein about 25 mg of N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′

-(4-(2-methylpropyloxy)phenylmethyl)carbamide, or a pharmaceutically acceptable salt thereof, is administered.

21. The method of claim 12, wherein about 50 mg of N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′

-(4-(2-methylpropyloxy)phenylmethyl)carbamide, or a pharmaceutically acceptable salt thereof, is administered.

24. The method of claim 3, wherein the hydrochloride salt of N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′

-(4-(2-methylpropyloxy)phenylmethyl)carbamide is administered.