Methods of manufacturing treprostinil and treprostinil derivative prodrugs

Patent metadata

Field	Value
Publication number	US-10343979-B2
Application number	US-201515527811-A
Country	US
Kind code	B2
Filing date	Nov 18, 2015
Priority date	Nov 18, 2014
Publication date	Jul 9, 2019
Grant date	Jul 9, 2019

Abstract

Methods for making prodrugs of trepreostinil and treprostinil derivatives are provided. Specifically, methods are provided herein for producing prostacyclin compounds comprising treprostinil covalently linked to a linear C5-C18 alkyl, branched C5-C18 alkyl, linear C2-C18 alkenyl, branched C3-C18 alkenyl, aryl, aryl-C1-C18 alkyl or an amino acid or a peptide (e.g., dipeptide, tripeptide, tetrapeptide). The linkage, in one embodiment, is via an amide or ester bond. Prostacyclin compounds provided herein can also include at least one hydrogen atom substituted with at least one deuterium atom. The compounds provided herein can be used to treat pulmonary hypertension (e.g., pulmonary arterial hypertension) and portopulmonary hypertension.

First claim

The invention claimed is:

1. A method for making a treprostinil prodrug having the following formula:

comprising,
mixing, in the presence of an acid catalyst, treprostinil with an alcohol of the formula R 2 —OH, wherein R 2 is a linear or branched C 5 -C 18 alkyl, a linear C 2 -C 18 alkenyl or a branched C 3 -C 18 alkenyl, aryl, aryl-C 1 -C 18 alkyl, an amino acid or a peptide,
incubating the mixture for a sufficient period of time to form the compound of Formula (A).

2. The method of claim 1 , wherein treprostinil is dissolved in a solvent prior to mixing with the acid catalyst.

3. The method of claim 2 , wherein the solvent comprises dioxane.

4. The method of claim 2 , wherein the solvent comprises acetonitrile (MeCN), N,N′-dimethylformamide (DMF), dichloromethane (DCM), or a combination thereof.

5. The method of claim 2 , wherein the solvent comprises 2 mL of dioxane per 100 μmol of treprostinil, 1 mL of dioxane per 100 μmol of treprostinil, DMF, DCM, MeCN, 1:1 dioxane:MeCN, DMF/DCM, 10% DMF/DCM, or 20% DMF/DCM.

6. The method of claim 1 , wherein the acid catalyst is a solid.

7. The method of claim 6 , wherein the solid is a solid resin.

8. The method of claim 1 , wherein the acid catalyst comprises sulfuric acid, sulfonic acid, hydrofluoric acid, phosphoric acid, toluenesulfonic acid, polystyrene solfonate, hyeteropoly acid, zeolites, metal oxides, graphene oxygene or a combination thereof.

Assignees

• Insmed Inc

Inventors

• Malinin Vladimir
• Perkins Walter
• Leifer Franziska
• Konicek Donna M
• Li Zhili
• Plaunt Adam

Classifications

• C07C231/02 Primary

  from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines · CPC title

• C07C67/08

  by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds · CPC title

• C07C2602/24

  the ring system containing nine carbon atoms, e.g. perhydroindane · CPC title

• C07C2601/18

  with a ring being at least seven-membered · CPC title

• C07C235/12

  having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups · CPC title