Methods of manufacturing treprostinil and treprostinil derivative prodrugs

Patent metadata

Field	Value
Publication number	US-2023250051-A1
Application number	US-202318302682-A
Country	US
Kind code	A1
Filing date	Apr 18, 2023
Priority date	Nov 18, 2014
Publication date	Aug 10, 2023
Grant date	—

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-C18alkenyl, branched C3-C18alkenyl, 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

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

comprising,
mixing, in the presence of a coupling reagent, a compound of Formula (B) with an a compound of the formula R 1 —NH 2 , wherein R 1 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 (B).

2 . The method of claim 1 , wherein the coupling reagent is 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU).

3 . The method of claim 1 , wherein the coupling reagent is benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP).

4 . The method of claim 1 , wherein the coupling reagent is N,N′-Disuccinimidyl carbonate (DSC).

5 . The method of claim 1 , wherein the coupling reagent is N,N′-Dicyclohexylcarbodiimide (DCC), DIC=N,N′-Diisopropylcarbodiimide (DIC) or N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC).

6 . The method of any one of claims 1 - 5 , wherein the compound of the formula R 2 —NH 2 is added to the compound of Formula (B) and the coupling reagent after the of the compound of Formula (B) and the coupling reagent are mixed for a period of time.

7 . The method of claim 6 , wherein the period of time is from about 30 minutes to about 96 hours, from about 30 minutes to about 72 hours, from about 30 minutes to about 48 hours, from about 30 minutes to about 24 hours or from about 30 minutes to about 150 minutes.

8 . The method of claim 7 , wherein the period of time is about 30 minutes.

9 . The method of claim 7 , wherein the period of time is about 24 hr.

10 . The method of claim 7 , wherein the period of time is about 48 hr.

11 . The method of claim 7 , wherein the period of time is about 68 hr.

12 . The method of claim 7 , wherein the period of time is about 91 hr.

13 . The method of any one of claims 1 - 12 , wherein the compound of Formula (B) is dissolved in a solvent.

14 . The method of claim 13 , wherein the solvent comprises dioxane.

15 . The method of claim 13 , wherein the solvent comprises acetonitrile (MeCN), N,N′-dimethylformamide (DMF), dichloromethane (DCM), or a combination thereof.

16 . The method of claim 13 , wherein the solvent comprises Dioxane (2 mL/100 μmol TRP), Dioxane (1 mL/100 μmol TRP), DMF, DCM, MeCN, 1:1 dioxane:MeCN, DMF/DCM, 10% DMF/DCM, or 20% DMF/DCM.

17 . The method of any one of claims 1 - 8 , wherein R 2 is a linear C 5 -C 18 alkyl.

18 . The method of any one of claims 1 - 8 , wherein R 2 is a linear C 6 -C 18 alkyl.

19 . The method of any one of claims 1 - 8 , wherein R 2 is a linear C 7 -C 18 alkyl.

20 . The method of any one of claims 1 - 8 , wherein R 2 is a linear C 8 -C 18 alkyl.

21 . The method of any one of claims 1 - 8 , wherein R 2 is a linear C 9 -C 18 alkyl.

22 . The method of any one of claims 1 - 8 , wherein R 2 is a linear C 10 -C 18 alkyl.

23 . The method of any one of claims 1 - 8 , wherein R 2 is a linear C 11 -C 18 alkyl.

24 . The method of any one of claims 1 - 8 , wherein R 2 is a linear C 12 -C 18 alkyl.

25 . The method of any one of claims 1 - 8 , wherein R 2 is a linear C 13 -C 18 alkyl.

26 . The method of any one of claims 1 - 8 , wherein R 2 is a linear C 14 -C 18 alkyl.

27 . The method of any one of claims 1 - 8 , wherein R 2 is a linear C 5 -C 10 alkyl.

28 . The method of any one of claims 1 - 8 , wherein R 2 is a linear C 5 -C 9 alkyl.

29 . The method of any one of claims 1 - 8 , wherein R 2 is a linear C 5 -C 8 alkyl.

30 . The method of any one of claims 1 - 8 , wherein R 2 is a linear C 5 -C 7 alkyl.

31 . The method of any one of claims 1 - 8 , wherein R 2 is an amino acid.

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

comprising,
mixing, in the presence of an acid catalyst, a compound of Formula (A) 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).

33 . The method of claim 32 , wherein the compound of Formula (A) is dissolved in a solvent prior to mixing with the acid catalyst.

34 . The method of claim 33 , wherein the solvent comprises dioxane.

35 . The method of claim 33 , wherein the solvent comprises acetonitrile (MeCN), N,N′-dimethylformamide (DMF), dichloromethane (DCM), or a combination thereof.

36 . The method of claim 33 , wherein the solvent comprises Dioxane (2 mL/100 TRP), Dioxane (1 mL/100 μmol TRP), DMF, DCM, MeCN, 1:1 dioxane:MeCN, DMF/DCM, 10% DMF/DCM, or 20% DMF/DCM.

37 . The method of any one of claims 32 - 36 , wherein the acid catalyst is a solid.

38 . The method of claim 37 , wherein the solid is a solid resin.

39 . The method of any one of claims 32 - 38 , 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.

40 . The method of any one of claims 32 - 39 , wherein R 2 is a linear C 5 -C 18 alkyl.

41 . The method of any one of claims 32 - 39 , wherein R 2 is a linear C 6 -C 18 alkyl.

42 . The method of any one of claims 32 - 39 , wherein R 2 is a linear C 7 -C 18 alkyl.

43 . The method of any one of claims 32 - 39 , wherein R 2 is a linear C 8 -C 18 alkyl.

44 . The method of any one of claims 32 - 39 , wherein R 2 is a linear C 9 -C 18 alkyl.

45 . The method of any one of claims 32 - 39 , wherein R 2 is a linear C 10 -C 18 alkyl.

46 . The method of any one of claims 32 - 39 , wherein R 2 is a linear C 11 -C 18 alkyl.

47 . The method of any one of claims 32 - 39 , wherein R 2 is a linear C 12 -C 18 alkyl.

48 . The method of any one of claims 32 - 39 , wherein R 2 is a linear C 13 -C 18 alkyl.

49 . The method of any one of claims 32 - 39 , wherein R 2 is a linear C 14 -C 18 alkyl.

50 . The method of any one of claims 32 - 39 , wherein R 2 is a linear C 5 -C 10 alkyl.

51 . The method of any one of claims 32 - 39 , wherein R 2 is a linear C 5 -C 9 alkyl.

52 . The method of any one of claims 32 - 39 , wherein R 2 is a linear C 5 -C 8 alkyl.

53 . The method of any one of claims 32 - 39 , wherein R 2 is a linear C 5 -C 7 alkyl.

Assignees

• Insmed Inc

Inventors

• Malinin Vladimir
• Perkins Walter
• Leifer Fraziska
• 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