4-(5-(2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethylpropanamido)-4-(o-tolyl)pyridin-2-yl)-1-methyl-1-((phosphonooxy)methyl)piperazin-1-ium as a neurokinin receptor modulator

Patent metadata

Field	Value
Publication number	US-9403772-B2
Application number	US-201214360991-A
Country	US
Kind code	B2
Filing date	Nov 28, 2012
Priority date	Nov 29, 2011
Publication date	Aug 2, 2016
Grant date	Aug 2, 2016

Abstract

Compounds and methods for the prevention and/or treatment of diseases which are pathophysiologically mediated by the neurokinin (NK 1 ) receptor, based on 4-(5-(2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethylpropanamido)-4-(o-tolyl)3yridine-2-yl)-1-methyl-1-((phosphonooxy)methyl)piperazin-1-ium and pharmaceutically acceptable salts thereof.

First claim

What is claimed is:

1. A pharmaceutically acceptable salt of a compound of formula GA1:

2. A method of treating emesis, bladder dysfunction, depression or anxiety in a patient, comprising administering to said patient in need thereof a therapeutically effective amount of a compound of formula GA1:

or a pharmaceutically acceptable salt thereof.

3. The method of claim 2 , wherein the patient is a human.

4. The method of claim 2 , wherein said compound, or pharmaceutically acceptable salt thereof, is intravenously administered at a dosage of from 10 mg to 200 mg.

5. The method of claim 2 , wherein said emesis comprises chemotherapy induced nausea and vomiting, radiation therapy induced nausea and vomiting, or post-operative nausea and vomiting.

6. The method of claim 2 , wherein said emesis is induced by moderately or highly emetogenic chemotherapy.

7. The method of claim 2 , wherein said emesis is acute and delayed emesis induced by moderately or highly emetogenic chemotherapy.

8. The method of claim 2 , wherein said emesis is acute and delayed emesis induced by moderately or highly emetogenic chemotherapy, further comprising administering ondansetron, palonosetron, granisetron or tropisetron, or a pharmaceutically acceptable salt thereof and a corticosteroid.

9. A method for making a compound of formula GA1:

comprising
(a) reacting 2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethyl-N-(6-(4-methylpiperazin-1-yl)-4-(o-tolyl)pyridin-3-yl)propanamide with chloromethyl di-tert-butyl phosphate in the presence of a polar aprotic solvent; and
(b) isolating the compound of formula GA1.

10. The method of claim 9 , wherein step (a) is carried out in the presence of an iodide salt and in the absence of a proton scavenger.

11. The method of claim 9 , wherein step (a) is carried out in the absence of air and oxygen.

12. A method for stabilizing a compound of formula GA1:

comprising contacting the compound with two equivalents of hydrochloric acid.

13. The method of claim 12 , wherein the hydrochloric acid is 4M hydrochloric acid.

14. A compound having the following formula:

Assignees

• Helsinn Healthcare Sa

Inventors

• Fadini Luca
• Manini Peter
• Pietra Claudio
• Giuliano Claudio
• Lovati Emanuela
• Cannella Roberta
• Venturini Alessio
• Stella Valentino J

Classifications

• C07D213/72

  Nitrogen atoms (nitro radicals C07D213/61) · CPC title

• C07D213/74

  Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals · CPC title

• C07D213/89 Primary

  with hetero atoms directly attached to the ring nitrogen atom · CPC title

• C07D213/76

  to which a second hetero atom is attached (nitro radicals C07D213/61) · CPC title

• C07D401/04

  directly linked by a ring-member-to-ring-member bond · CPC title