Process for preparing antiviral 2-phosponate nucleotide analogs

Details Process for preparing antiviral 2-phosponate nucleotide analogs Process for preparing antiviral 2-phosponate nucleotide analogs

1999-10-04

2001-02-27

Shah, Mukund J. (Department: 1611)

Organic compounds -- part of the class 532-570 series

Organic compounds

Four or more ring nitrogens in the bicyclo ring system

C544S214000, C544S232000, C544S243000, C544S244000, C546S023000, C546S024000, C548S112000, C548S113000

Reexamination Certificate

active

06194576

ABSTRACT:

The present invention relates to new nucleotide analogues. Particularly, it is concerned with the use of 2-phosphonate-nucleotide analogues in the treatment of viral infections.
Cytomegalovirus (CMV) is recognized as an important pathogen in patients with AIDS. The virus often contributes to the immunosuppression observed in such patients and may cause disseminated disease involving the lungs, gastrointestinal tract, central nervous system, or eyes. CMV retinitis is recognized as an important cause of blindness in patients with AIDS. Also, human cytomegalovirus (HCMV) infection is a major cause of death in AIDS patients. Currently, there are only two approved drugs, ganciclovir and foscarnet, for its treatment. Ganciclovir has exhibited bone marrow suppression as a serious side effect and resistant strains have also been isolated. Foscarnet presents side effects that are associated with its administration such as reversible renal dysfunction, thrombophlebitis at the infusion site, headaches and anemia. Also, foscarnet is not orally bioavailable, limiting its utility in clinical treatment. It is poorly soluble, and large doses are required because of its relatively low potency. Therefore, the development of a potent and non-toxic anti-CMV agents is highly desired.
All human herpesviruses have a worldwide distribution and are amongst the most difficult human pathogens to control. Currently, considerable efforts are being directed towards the development of vaccines and antiviral agents that will be active against herpesviruses, particularly Herpes Simplex viruses HSV-1 and HSV-2. A number of nucleoside and nucleotide derivatives are active against primary and recurrent HSV infection; of these, acyclovir is the most used drug. However, among patients with AIDS, acyclovir-resistant HSV-2 may lead to chronic progressive infections. There is therefore a need for development of a potent and non-toxic agent against HSV-1 and HSV-2.
Since their discovery in 1986, the acyclic phosphonate nucleotide analogs have generated considerable attention as broad spectrum antiviral agents. The guanine analogues HPMPG and PMEG, the adenine analogues HPMPA, and the cytosine analogue HPMPC have been shown to exhibit good anti-HCMV activity and HSV activity. PMEA has also demonstrated in vitro activity against retroviruses such as the human immunodeficiency virus (HIV), as well as DNA viruses such as herpes simplex virus (HSV), and in vivo activity against murine cytomegalovirus (CMV).
Unfortunately, in general these compounds present problems in cytotoxicity, particularly, PMEG is very cytotoxic.
SUMMARY OF THE INVENTION
We have designed a novel class of 2-phosphonate-nucleotide analogues having the general formula (I), salts or esters thereof, and pharmaceutically acceptable derivatives. Members of this series of analogues possess anti-viral activity.
wherein n is 0 or an integer;
X is O or S, CH
2
, CH-halogen, CH—N
3
, or C═CH
2
;
Q and U are independently selected from: O, S, and CH(R
a
) wherein R
a
is hydrogen, OH, halogen, N
3
,NH
2
SH, carboxyl, C
1-6
alkyl or R
a
is CH
2
(R
b
) wherein R
b
is hydrogen, OH, SH, NH
2
, C
1-6
alkyl or carboxyl; or both Q and U are CH when Q and U are linked by a double bond;
Z is selected from: O, a C
1-6
alkoxy, a C
1-6
thioalkyl, a C
1-6
aminoalkyl, (CH
2
)
m
wherein m is 0 or an integer, and N(R
c
)
2
wherein both R
c
are independently hydrogen or a C
1-6
alkyl,; and
R2 is a purine or pyrimidine base or an analogue or derivative thereof.
Also included within the scope of the invention are compounds of formula (I) when X, Q, or U is S, further oxidized to form SO or SO
2
.
It will be appreciated by those of skill in the art that the compounds of formula (I) may contain several chiral centers and thus, amongst other forms, exist in the form of pairs of optical isomers (i.e. enantiomers) and mixtures thereof including racemic mixtures. Thus the compounds of formula (I) may be either cis isomers, as represented by formula (IA), or trans isomers, as represented by formula (IB), or mixtures thereof. Each of the cis and trans isomers can exist as one of two enantiomers or as mixtures thereof including racemic mixtures. All such isomers and mixtures thereof including racemic mixtures are included within the scope of the invention.
By purine or pyrimidine base or an analogue thereof is meant a purine or pyrimidine base found in a nucleotide or an analogue thereof which mimics such bases in that their structures (the kinds of atoms and their arrangement) are similar to the normal bases but may possess additional or lack certain of the functional properties of the normal bases. Such analogues include imidazopyrimidines, iso-imidazopyrimidines, or those derived by replacement of a CH moiety by a nitrogen atom (for example, 5-azapyrimidines such as 5-azacytosine) or vice versa (for example 7-deazapurines, such as 7-deazadenosine or 7-deazaguanosine) or both (e.g. 7-deaza, 8-azapurines). By derivatives of such bases or analogues are meant those compounds wherein ring substituents are either incorporated, removed or modified by conventional substituents known in the art e.g. halogen, hydroxyl, amino, C
1-6
alkyl. Such purine or pyrimidine base, analogues and derivatives will be well known to those skilled in the art.
Conveniently, the group R2 is preferably selected from:
wherein:
x is oxygen or sulfur;
y is oxygen or sulfur;
R
3
and R
4
are independently selected from the group consisting of hydrogen, hydroxyl, amino, C
1-6
alkyl or C
1-6
alkenyl, C
1-6
alkynyl, C
1-10
acyl, aryl or carboxyl;
R
5
, R
6
, R
11
, and R
12
are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, amino, cyano, carboxy, carbamoyl, alkoxycarbonyl, hydroxymethyl, trifluoromethyl, thioaryl, C
1-6
alkyl, C
1-6
alkenyl substituted or unsubstituted with halogen or azido, C
1-6
alkynyl, C
1-10
acyloxy, thiocarboxy, thiocarbamoyl, carbamate, ureido, amidino, or aryloxy; and
wherein:
R
7
, R
8
, R
9
, and R
10
are each independently selected from the group consisting of hydrogen, hydroxy, alkoxy, thiol, thioalkyl, amino, substituted amino, halogen, azido, cyano, carboxy, alkoxycarbonyl, carbamoyl, C
1-6
alkyl, C
1-6
alkenyl, or C
1-6
alkynyl, C
1-10
acyloxy, aryl, aryloxy, thiocarboxy, thiocarbamoyl, carbamate, ureido, amidino, and aryloxy.
The purine or pyrimidine base R2 is linked through the linker “Z” at any position on the base, but preferably at N9- for the purines, or N1- or N3-position for the pyrimidines.
Preferred compounds of formula (I) are in the cis configuration.
Preferably, n is 0 to 4.
Preferably, X is O, S, CH
2
, CH-halo, or CH—N
3
.
Preferably, Q and U are independently O, S, CH
2
, CHOH, CH-halogen, CH—N
3
or both are CH and linked by a double bond.
Preferably, Z is a C
1-6
alkoxy or (CH
2
)
m
wherein m is preferably from 0 to 6.
Preferred R2 include: A), B), C), D), E), F), G), H), L) and M), N), O), P), Q), R), S), T), U).
More preferably, n is 0 to 2.
More preferably, X is O, S, or CH
2
.
More preferably, Q and U are independently O, S, CH
2
, CHOH, CH-halo, or CH—N
3
.
More preferably, Z is (CH
2
)
m
wherein m is preferably 0 to 4. More preferably, R2 is A), F) or M).
Most preferably, n is 0 or 1.
Most preferably, X is O or S.
Most preferably, Q is O, S, CH
2
or CHOH.
Most preferably, U is CH
2
or S.
Most preferably, Z is (CH
2
)
m
wherein m is preferably from 0 or 1.
Most preferably, R2 is cytosine, adenine, guanine, uracil, thymine, 2-amino-6-chloropurine, 6-chloropurine, or 2,6-diaminopurine.
In a further or alternative aspect of the invention, there is provided a method for the treatment of a viral infection comprising the step of administering an antivirally effective dose of a compound of formula (I) as defined hereinabove or a pharmaceutically acceptable derivative thereof.
As will be appreciated by those skilled in the art, references herein to treatment extends to prophylaxis as well as to the treatment of established infections of symptoms.
By the term “pharmaceutically acceptable deriva

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