Phosphoramidates and methods therefor

• US 20050171060A1
• Filed: 02/08/2005
• Published: 08/04/2005
• Est. Priority Date: 03/31/2000
• Status: Active Grant

• Current Assignee: Hugo Garrido-Hernandez, Richard F. Borch, Sandra C. Tobias
• Original Assignee: Hugo Garrido-Hernandez, Richard F. Borch, Sandra C. Tobias
• Inventors: Tobias, Sandra C., Garrido-Hernandez, Hugo, Borch, Richard F.
• Granted Patent: US 7,173,020 B2
• Time in Patent Office: Days
• US Class Current: 514/79
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07F 9/2458 of aliphatic amines
• CPC Class Codes: C07F 9/26 containing P-halide groups
• CPC Class Codes: C07F 9/65515 the oxygen atom being part of a five-membered ring
• CPC Class Codes: C07F 9/655345 the sulfur atom being part of a five-membered ring
• CPC Class Codes: C07H 19/10 with the saccharide radical esterified by phosphoric or polyphosphoric acids

Abstract

Novel phosphoramidate derivatives of hydroxy functional or amino functional compounds, including amino acids, peptides, peptidomimetics and nucleotide analogs, are described. The compounds enable enhanced intracellular delivery of drugs as their corresponding phosphate esters or amides. Described phosphoramidate compounds exhibit antiproliferative activity. Pharmaceutical formulations are provided for treatment of cancers.

Claims

1. A compound of the formula

R_rCH₂OP(halo)NR(CH₂)_nX

wherein

R is C₁-C₄ alkyl or —

(CH₂)_nX;

n is 4 or 5;

X is an electrophilic group capable of being nucleophilically displaced from its bonded carbon atom;

halo is chloro, bromo, or iodo; and

R_rCH₂—

is a biologically labile ester forming group.

2. The compound of claim 1 wherein n is 4.

3. The compound of claim 1 wherein n is 5.

4. The compound of claim 1 wherein R is methyl.

5. The compound of claim 1 wherein halo is chloro.

6. The compound of claim 1 wherein X is chloro or bromo.

7. A method for preparing a phosphoramidate prodrug for enhanced intracellular delivery of a drug as a phosphate ester or amide, said method comprising the steps of reacting a hydroxy functional or amino functional drug compound of the formula

Drug-ZH

with a compound of the formula

R_rCH₂OP(halo)NR(CH₂)_nX

to form an intermediate compound of the formula

R_rCH₂OP(Z-Drug)NR(CH₂)_nX

and oxidizing the intermediate compound to form the phosphoramidate prodrug of the formula

R_rCH₂OP(O)(Z-Drug)NR(CH₂)_nX

wherein in each of said formulas

R is C₁-C₄ alkyl or —

(CH₂)_nX;

n is 4 or 5;

Z is oxygen or nitrogen;

X is an electrophilic group capable of being nucleophilically displaced from its bonded carbon atom;

halo is chloro, bromo, or iodo; and

R_rCH₂—

is a biologically labile ester forming group.

8. The method of claim 7 wherein Drug-ZH is an amino acid, or a biologically active peptide or peptidomimetic.

9. The method of claim 8 wherein Drug-ZH is a peptidomimetic of the formula

10. The method of claim 7 wherein Drug-ZH is a biologically active nucleotide analog.

11. A method for preparing a compound of the formula

R_rCH₂OP(O)_m(halo)NR(CH₂)_nX

comprising the steps of reacting a compound of the formula

P(O)_m(halo)₃

with 1) an alcohol of the formula R_rCH₂OH and 2) an amine of the formula HNR(CH₂)_nX, each in the presence of an acid scavenger, wherein in each of said formulas

m is 0 or 1;

R is C₁-C₄ alkyl or —

(CH₂)_nX;

n is 4 or 5;

X is an electrophilic group capable of being nucleophilically displaced from its bonded carbon atom;

halo is chloro, bromo, or iodo; and

R_rCH₂—

is a biologically labile ester forming group.

12. A method for preparing a phosphoramidate prodrug of the formula

R_rCH₂OP(O)(Z-Drug)NR(CH₂)_nX

for enhanced intracellular delivery of a compound of the general formula

Drug-Z(PO₃)²⁻

said method comprising the steps of reacting a hydroxy functional or amino functional drug compound of the formula Drug-ZH with a compound of the formula

R_rCH₂OP(O)(halo)NR(CH₂)_nX

to form the prodrug;

wherein in each of said formulas

R is C₁-C alkyl or —

(CH₂)_nX;

n is 4 or 5;

Z is oxygen or nitrogen;

X is an electrophilic group capable of being nucleophilically displaced from its bonded carbon atom;

halo is chloro, bromo, or iodo; and

R_rCH₂—

is a biologically labile ester forming group.