Thiophosphonate inhibitors of phosphatase enzymes and metallophosphatases

• US 6,943,267 B1
• Filed: 01/16/2003
• Issued: 09/13/2005
• Est. Priority Date: 08/24/2001
• Status: Expired due to Fees

• Current Assignee: Utah State University
• Original Assignee: Utah State University
• Inventors: Swierczek, Krzysztof Jerzy, Hengge, Alvan Carl
• Primary Examiner(s): Weddington, Kevin E.
• Application Number:
  US10/346,672
• Time in Patent Office: 971 Days
• Field of Search: 562/9, 558/179, 558/8
• US Class Current: 562/9
• CPC Class Codes: C07C 211/63 having quaternised nitrogen atoms bound to acyclic carbon atoms
• CPC Class Codes: C07C 211/64 having quaternised nitrogen atoms bound to carbon atoms of six-membered aromatic rings
• CPC Class Codes: C07F 9/3808 Acyclic saturated acids which can have further substituents on alkyl
• CPC Class Codes: C07F 9/3882 Arylalkanephosphonic acids C07F9/3839 takes precedence

Abstract

Compounds of the general formula
wherein R is selected from the group consisting essentially of hydrogen, methyl, ethyl, phenyl, a carboxyl, or naphthyl substituted or a carbonyl substituted, alkyl of from 3 to 20 carbon atoms, a mono, bi or tri cyclic aryl or substituted aryl for the inhibition of phosphatase enzymes, including metallophosphatases; and, novel methods for synthesizing such compounds. The methods of use include the administration of an effective amount of the compound to provide effective phosphatase inhibition and therapeutic use to treat or prevent certain diseases, which utilize specific phosphatase enzymes.

Claims

1. A method for the preparation of the mono-protonated thiophosphonate salts of the general formula

wherein R is selected from the group consisting essentially of hydrogen, methyl, ethyl, phenyl, a carboxyl, or naphthyl substituted or a carbonyl substituted, alkyl of from 3 to 20 carbon atoms, a mono cyclic, bicyclic or polycyclic aryl or substituted aryl comprising the steps of:

(a) heating a mixture of dimethyl phosphite and Lawesson'"'"'s reagent in the presence of suitable organic solvent to produce a thiophosphite ester;

(b) performing an Michaelis-Becker alkylation reaction by contacting a halide of the general formula R—

CH₂—

X, wherein X is a halide, in the presence of a base and a phase transfer catalyst with said thiophosphite ester to produce the corresponding R substituted O,O-dimethyl ester;

(c) producing the corresponding O-methylphosphonothioic acid, tetramethylammonium salt by addition of an excess of trimethylamine;

(d) heating the O-methylphosphonothioic acid, tetramethylammonium salt in the presence of a solvent with a stoicheiometric amount of methyl iodide to yield the corresponding O-S-dimethyl ester;

(e) contacting the cooled O—

S-dimethyl ester with iodotrimethylsilane to produce the corresponding disilyl ester;

(f) hydrolyzing the corresponding disilyl ester; and

,

(g) precipitating the corresponding thiophosphonate salt from the corresponding disilyl ester in the presence of a base.

2. The method of claim 1 further comprising removing said suitable organic solvent under reduced pressure and vacuum distillation of the residue prior to performing said Michaelis-Becker alkylation reaction.

3. The method of claim 1 wherein said corresponding R substituted O,O-dimethyl ester is extracted from the Michaelis-Becker alkylation reaction mixture by first washing the reaction mixture with water followed by drying the residual non-aqueous layer and evaporating the remaining solvent.

4. The method of claim 1 wherein said excess of trimethylamine is added in the presence of a solvent, and filtering the precipitated product.

5. The method of claim 1 further comprising:

washing the post reaction mixture from step (d) with water followed by drying the residual non-aqueous layer and evaporating the remaining solvent.

6. The method of claim 1 wherein said R is selected from the group consisting of imidazole, indole, pyrrole, morpholine, isoxazole, pyrazole, amino acid, or a polypeptide.

7. The method of claim 1 wherein X is bromine.

8. The method of claim 1, wherein R is selected from the group consisting of propyl, benzyl, 6-hexanyl-carboxylic acid, 7-1 methanylnaphthalene-carboxylic acid, 6-hexanyl carboxylic acid methyl ester.

9. The method of claim 1, wherein the base added to the thiophosphite ester is selected from the group consisting of sodium hydroxide, and anhydrous potassium carbonate or DBU, or an amine.