Novel phosphorus-containing prodrugs

a phosphorus-containing, prodrug technology, applied in the field of new phosphorus-containing prodrugs, can solve the problems of poor oral bioavailability, poor cell penetration and limited tissue distribution, poor drug effect, etc., to reduce the production of enzymes, reduce the activity of phosphorylating enzymes, and improve the effect of drug

Inactive Publication Date: 2007-10-25
METABASIS THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0134] The term “pharmacodynamic half-life” refers to the time after administration of the drug or prodrug to observe a diminution of one half of the measured pharmacological response. Pharmacodynamic half-life is enhanced when the half-life is increased by preferably at least 50%.
[0146] The term “decreased activity of the phosphorylating enzyme” includes decreased production of the enzyme, mutations that lead to decreased efficiency (lower Km or Vmax), or enhanced production of endogenous inhibitors of the enzyme.

Problems solved by technology

Free phosphorus and phosphonic acids and their salts are highly charged at physiological pH and therefore frequently exhibit poor oral bioavailability, poor cell penetration and limited tissue distribution (e.g. CNS).
Phosphates have an additional limitation in that they are not stable in plasma as well as most tissues since they undergo rapid hydrolysis via the action of phosphatases (e.g. alkaline phosphatase, nucleotidases).
The cyclic 2′,2′-difluoro-1′,3′-propane ester is reported to be hydrolytically unstable with rapid generation of the ring-opened monoester.
In addition, acrolein produces other toxicities such as the dose-limiting bladder toxicity commonly observed with cyclophosphamide therapy.
The lack of activity was postulated to arise from the steric hindrance of the phenyl and therefore limited oxidation of the prodrug.
Numerous phosphorus-containing compounds are known to exhibit pharmacological activity but remain far from optimal due to one or more of the above-described limitations.
Nevertheless, many of the nucleoside-based drugs are associated with significant non-hepatic toxicity.
In other cases, the efficacy and / or therapeutic index of nucleosides is compromised by poor phosphorylation efficiencies and therefore low levels of the biologically active triphosphate (e.g. Yamanaka et al., Antimicrob.
Monophosphates and phosphonic acids, however, are difficult to deliver to virally-infected cells after oral administration due to their high charge and in the case of the monophosphate instability in plasma.
In addition, these compounds often have short half-lives (e.g. PMEA, Adefovir) due in most cases to high renal clearance.
In some cases, the high renal clearance can lead to nephrotoxicities or be a major limitation in diseases such as diabetes where renal function is often compromised.
Liver cancer is poorly treated with current therapies.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

General Procedure for Phosphoramidate Prodrugs of Phosphonic Acid Containing Drugs

[0674] A suspension of 5-Isobutyl-2-methyl-4-(2-(5-phosphono)furanyl)thiazole (200 mg, 0.6 mmol) in 2.5 mL of thionyl chloride was heated at reflux temperature for 4 h. The reaction mixture was cooled and evaporated to dryness followed by azeotroping with toluene. To the solution of the resulting residue in 4 ml of methylene chloride was added a solution of amino alcohol (82 mg, 0.54 mmol) and pyridine (0.5 ml, 6 mmol) in 1 mL of methylene chloride.

[0675] After stirring at 25° C. for 4 h the reaction was evaporated and coevaporated with toluene. The crude product was chromatographed by eluting with 10% methanol-dichloromethane to give 52 mg (20.8%) of a less polar isomer and 48 mg (19.2%) of a more polar isomer.

[0676] The following compounds were prepared in this manner:

[0677] 1.1: 5-Isobutyl-2-methyl-4-{2-[5-(1-phenyl-1,3-propyl)phosphorimido]furanyl}thiazole, less polar isomer. Rf=0.76 in 10% MeO...

example 2

Step A:

[0688] A solution of 3-amino-3-phenyl-1-propanol (1 g, 6.6 mmol) and triethylamine (3 ml, 21.8 mmol) in tetrahydrofuran (60 ml) was added dropwise over 20 minutes into a solution of 4-nitrophenyl phosphorodichloridate in tetrahydrofuran at 0° C. A white precipitate quickly forms. The yellow heterogeneous mixture was stirred at 0° C. for 1 hour then warmed slowly to rt. After stirring at rt for 60 hours, the precipitate was dissolved with water (40 ml). The clear yellow solution was concentrated to ca 40 ml. The resulting mixture was diluted with a saturated aqueous solution of sodium bicarbonate and extracted twice with ethyl acetate. The combined organic extracts were washed with a saturated aqueous solution of sodium bicarbonate and brine. The aqueous washes were back extracted and the organic extracts combined. The combined organic extracts were dried over sodium sulfate, concentrated and purified by column chromatography (silica gel, hexanes / ethyl acetate) to give fast ...

example 3

Step A:

[0692] Same as step A of example 2.

Step B:

[0693] Lithium hydride (15 mg, 1.52 mmol) was added to a solution of 9-β-D-arabinofuranosyl-adenine (100 mg, 0.37 mmol) and fast eluting (4-nitrophenoxy)-4-phenyl-1,3,2-oxazaphosphorinan-2-one (250 mg, 0.74 mmol) in dimethylformamide at room temperature. After 6 hours the yellow heterogeneous mixture was neutralized with acetic acid. The clear yellow solution was concentrated and the residue was purified by column chromatography (silica gel, methanol / dichloromethane). The isolated product was further purified by preparative TLC and re crystallized from ethanol to give the prodrug: 18 mg (11% yield);

[0694] The following compound is prepared in this manner:

[0695] 3.1 5′-O-(2-oxo-4-Phenyl-1,3,2-oxazaphosphorin-2-yl)-9-β-D-arabinofuranosyl-adenine. mp>250. Rf=0.25 (silica gel, 2 / 8 methanol / dichloromethane). Anal. cald. for C19H23N6O6P: C: 49.35; H: 5.01; N: 18.17. Found: C: 49.22; H: 4.89; N: 18.03.

[0696] The following compounds ar...

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Abstract

Novel cyclic phosphoramidate prodrugs of drugs of formula I their use in delivery of drugs to the liver, their use in enhancing oral bioavailability, and their method of preparation are described.

Description

RELATED APPLICATION [0001] This application is a continuation-in-part of Provisional Application Ser. No. 60 / 153,127, filed Sep. 8, 1999, and Provisional Application Ser. No. 60 / 123,013, filed Mar. 5, 1999, and they are incorporated by reference in their entirety.FIELD OF THE INVENTION [0002] The present invention is directed towards novel prodrugs that generate phosph(on)ate compounds which are biologically active or are further phosphorylated to produce biologically active compounds, to their preparation, to their synthetic intermediates, and to their uses. More specifically, the invention relates to the area of substituted cyclic 1,3-propanyl esters wherein the cyclic moiety contains at least one amino attached to the phosphorus. BACKGROUND OF THE INVENTION [0003] The following description of the background of the invention is provided to aid in understanding the invention, but is not admitted to be, or to describe, prior art to the invention. All cited publications are incorpora...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07F9/576A61K31/661A61K31/665A61K31/675A61K47/06A61K47/08A61P31/12A61P35/00C07F9/09
CPCC07F9/65846C07H19/20C07H19/10C07F9/65848A61P3/04A61P3/06A61P3/10A61P31/12A61P33/00A61P35/00
Inventor ERION, MARKREDDY, K.BOYER, SERGE
Owner METABASIS THERAPEUTICS INC
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