Process for the Synthesis of Quaternary Amine Compounds
AssigneeAlkermes, Inc.
InventorScott Duncan
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Abstract
The invention relates to a process for the synthesis of quaternized compounds of formula:
Claims43
A process for the synthesis of a compound of Formula IA by quaternization of a compound of Formula I:
- wherein, Each RA, RB and RC is independently is selected from aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, —C(O)R20, —C(O)OR20, —C(O)NR20R21, or —N(R20)C(O)R21;
- or alternatively RA, RB, and/or RC, together with the nitrogen they are attached to form one, two or three optionally substituted ring(s);
- wherein each R20 and R21 is independently selected from absent, hydrogen, halogen, —OH, —SH, —NH2, —CF3, —CN, —NO2, —N3, —C(O)OH, —C(O)NH2, acyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, aliphatic, substituted aliphatic, aryl or substituted aryl;
- Q is aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl or substituted heterocyclyl;
- and,
- Y— is a counterion;
- wherein the quaternization process comprises the step of reacting a compound of Formula I with Q-LG in the presence of a base and a solvent, wherein LG is a leaving group;
- wherein said solvent is a biphasic solvent, or at least said compound of Formula IA is insoluble in said solvent.
A method of treating opioid induced constipation in a patient comprising the step of administering a composition comprising a compound of Formula IIA and a compound of Formula II wherein the molar ratio of Formula IIA to Formula II is more than 100:1.
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A method of treating opioid induced constipation in a patient comprising the step of administering a composition comprising a compound of Formula IIA wherein said composition is essentially free of a compound of Formula II.
A unit dosage form of a compound of Formula IIA comprising about 10 to about 100 mg of a compound of a compound Formula IIA and about 0 to about 0.25 mg of a compound of a compound Formula II.
A method of treating a disease or disorder selected from a group consisting of constipation, post-operative ileus, immune suppression, inhibition of gastrointestinal motility, inhibition of gastric emptying, nausea, emesis, incomplete evacuation, bloating, abdominal distension, increased gastroesophageal reflux, hypotension, bradycardia, gastrointestinal dysfunction, pruritus, dysphoria, or urinary retention in a patient comprising the step of administering a composition comprising a compound of Formula IIA and a compound of Formula II wherein the molar ratio of Formula IIA to Formula II is more than 100:1.
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Dependencies are inferred from the claim text.