US 8,076,310 B2 · Phosphonate nucleosides useful as active ingredients in pharmaceutical compositions for the treatment of viral infections, and intermediates for their production

Abstract

Disclosed herein are novel phosphonate nucleosides and thiophosphonate nucleosides comprising a phosphonalkoxy-substituted or phosphonothioalkyl-substituted five-membered, saturated or unsaturated, oxygen-containing or sulfur-containing ring coupled to a heterocyclic nucleobase such as a pyrimidine or purine base. The invention further relates to compounds having HIV (Human Immunodeficiency Virus) replication inhibiting properties and to compounds having antiviral activities with respect to other viruses. The invention also relates to methods for preparation of all such compounds and pharmaceutical compositions comprising them. The invention further relates to the use of said compounds as a medicine and in the manufacture of a medicament useful for the treatment of subjects suffering from HIV infection, as well as for treatment of other viral, retroviral or lentiviral infections and to the treatment of animals suffering from FIV, viral, retroviral or lentiviral infections.

A compound represented by one of the general formulae (II) and (XIX):

wherein:
X1, X2, X3, X4 and X5 are each a divalent moiety independently selected from the group consisting of —O— and —S—,
B is a heterocyclic moiety selected from the group consisting of pyrimidine and purine base moieties,
R1 and R2 are each independently selected from the group consisting of hydrogen;
(—PO3R16)m—PO3R17R18;
alkyl;
alkenyl;
alkynyl;
cycloalkyl;
cycloalkenyl;
cycloalkynyl;
aryl;
arylalkyl;
acyloxyalkyl;
acyloxyalkenyl;
acyloxyalkynyl;
acyloxyaryl;
acyloxyarylalkyl;
acyloxyarylalkenyl;
acyloxyarylalkynyl;
dialkylcarbonato;
alkylarylcarbonato;
alkylalkenylcarbonato;
alkylalkynylcarbonato;
alkenylarylcarbonato;
alkynylarylcarbonato;
and alkenyl-alkynylcarbonato;
wherein said alkyl, alkenyl and alkynyl optionally contains one or more heteroatomic moieties in the hydrocarbon chain, said heteroatomic moieties being independently selected from the group consisting of oxygen and sulfur and NH;
and wherein said dialkylcarbonato group has the structure alkyl-OC(O)O-alkylenyl wherein the alkylenyl moiety is further coupled to X4 or X5;
R4, R5 and R6 are each independently selected from the group consisting of hydrogen, azido, halogen, cyano, alkyl, alkenyl, alkynyl, SR14 and OR14;
R3, R7 and R8 are each hydrogen;
R14 is selected from the group consisting of hydrogen;
alkyl;
alkenyl;
alkynyl;
cycloalkyl;
cycloalkenyl;
cycloalkynyl;
aryl;
arylalkyl;
and acyloxyalkyl;
wherein said alkyl, alkenyl and alkynyl optionally contain one or more heteroatomic moieties in the hydrocarbon chain, said heteroatomic moieties being independently selected from the group consisting of oxygen and sulfur;
R16, R17 and R18 are independently selected from the group consisting of hydrogen;
alkyl;
alkenyl;
alkynyl;
cycloalkyl;
cycloalkenyl;
cycloalkynyl;
aryl;
arylalkyl;
and acyloxyalkyl;
wherein said alkyl, alkenyl and alkynyl optionally contain one or more heteroatomic moieties in the hydrocarbon chain, said heteroatomic moieties being independently selected from the group consisting of oxygen and sulfur;
R9 is selected from the group consisting of hydrogen, alkyl, aryl, alkenyl, alkynyl, alkenylaryl, alkynylaryl and alkylaryl, wherein each of said alkyl, alkenyl, alkynyl and aryl groups is optionally substituted with one or more atoms or groups selected from the group consisting of halo, cyano, azido, nitro and OR14;
R10 is selected from the group consisting of hydrogen, alkyl, aryl, alkenyl, alkynyl, alkenylaryl, alkynylaryl and alkylaryl, wherein each of said alkyl, alkenyl, alkynyl and aryl groups is optionally substituted with one or more atoms or groups selected from the group consisting of halo, cyano, azido, nitro, OR14 and NR11R12;
R11 and R12 are each independently selected from the group consisting of hydrogen and alkyl, provided that at least one of R11 and R12 is not hydrogen;
n is an integer representing the number of methylene groups between X2 and P, each of said methylene groups being optionally and independently substituted with one or two substituents selected from the group consisting of halogen, hydroxyl, sulhydryl and C1-4 alkyl, and n being selected from 1, 2, 3, 4, 5 and 6;
and
m is 0 or 1,
or a pharmaceutically acceptable salt or a stereoisomer thereof.

57 more elements

Facts

Application

10/598,535Filed 4 Mar 2005 · us provisional application

Priority

GB 0404891.44 Mar 2004

Published

US 2007/0185062 A19 Aug 2007

Granted

13 Dec 2011

Term ends

Not estimatedThe source records don’t support an estimate.

Classification17 codes

C07H 19/20
Purine radicals: with the saccharide radical esterified by phosphoric or polyphosphoric acids
A61P 31/12
Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics: antivirals
A61P 31/14
Antivirals: for RNA viruses
A61P 31/18
For RNA viruses: for HIV

Phosphonate nucleosides useful as active ingredients in pharmaceutical compositions for the treatment of viral infections, and intermediates for their production

Life of this patent

Phosphonate nucleosides useful as active ingredients in pharmaceutical compositions for the treatment of viral infections, and intermediates for their production

Life of this patent

Abstract

Claims15