Method for large-scale production of di(uridine 5')-tetraphosphate and salts thereof
AssigneeInspire Pharmaceuticals, Inc.
InventorsBenjamin R. Yerxa, William Pendergast
Life of this patent
Estimating the term…
Abstract
The present invention provides new methods for the synthesis of the therapeutic dinucleotide, P1,P4-di(uridine 5′-tetraphosphate), and demonstrates applicability to the production of large quantities. The methods of the present invention substantially reduce the time period required to synthesize diuridine tetraphosphate, preferably to three days or less. The novel tetrammonium and tetrasodium salts of P1,P4-di(uridine 5′-tetraphosphate) (Formula I) prepared by these methods are stable, soluble, nontoxic, and easy to handle during manufacture. 1 wherein: X is Na, NH4 or H, provided that all X groups are not H.
Claims25
The compounds of Formula I:
- 14
- wherein:
- X is selected from the group consisting of:
- Na, NH4 and H, provided that all X groups are not H.
P1,P4-di(uridine 5′-tetraphosphate), tetrasodium salt.
P1,P4-di(uridine 5′-tetraphosphate), tetrammonium salt.
A process for the synthesis of compounds of Formula I, and pharmaceutically acceptable salts thereof, said process comprising:
- a) dissolving uridine or uridine nucleotide compounds of Formulas IIa-d in a polar, aprotic organic solvent and a hydrophobic amine;
- b) phosphorylating with a phosphorylating agent of Formulas IVa-b and/or activating with an activating agent of Formulas IIIa-c;
- and
- c) purification by chromatography of the compounds of Formula I, and pharmaceutically acceptable salts thereof;
- 15
- wherein:
- X is selected from the group consisting of:
- Na, NH4 and H, provided that all X groups are not H;
- 16 17
- and salts thereof;
- 18
- and salts thereof;
- 19
- and salts thereof;
- 20
- wherein R1 and R2 are independently selected from the group consisting of:
- C1-C8 alkyl, C1-C8 cycloalkyl, C1-C8 optionally substituted alkyl, C1-C8 optionally substituted cycloalkyl substituted with hydroxy and amino groups, aryl, and optionally substituted aryl substituted with hydroxy and amino groups;
- 21
- wherein X is independently selected from the group consisting of:
- imidazole, tetrazole and halogen;
- 22
- wherein X is halogen and R1 and R2 are each independently selected from the group consisting of:
- C1-C8 alkyl, C1-C8 cycloalkyl, C1-C8 optionally substituted alkyl substituted with hydroxy and amino groups, C1-C8 optionally substituted alkoxy substituted with hydroxy and amino groups, C1-C8 optionally substituted cycloalkyl substitued with hydroxy and amino groups, aryl, alkoxy, optionally substituted aryl substituted with hydroxy or amino groups, optionally substituted alkoxy substituted with hydroxy and amino groups, and halogen;
- 23
- wherein X is halogen;
- 24
- wherein X is selected from the group consisting of:
- oxygen, hydroxy, halogen, and salts thereof.
Dependencies are inferred from the claim text.