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
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.
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: