Antiviral phosphonate nucleotides

Details Antiviral phosphonate nucleotides Antiviral phosphonate nucleotides

2000-03-24

2002-09-03

Ford, John M. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Phosphorus containing other than solely as part of an...

C514S086000, C514S088000, C544S243000, C544S244000

Reexamination Certificate

active

06444656

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to new nucleotide analogues. Particularly, it is concerned with the novel substituted nucleotide compounds having pharmacological activity in the treatment of viral infections in mammals.
BACKGROUND OF THE INVENTION
Infections from retroviruses and related viruses are a serious cause of disease, most notably, the acquired immunodeficiency syndrome (AIDS) and Hepatitis B virus infections. The human immunodeficiency virus (HIV) has been recognized as the etiologic agent of AIDS. Compounds having an inhibitory effect on viral multiplication or are otherwise effective in the therapy of retroviral infections are being actively sought.
HBV, while classified as a hepadnavirus rather than a retrovirus, is related to retroviruses. HBV uses a reverse transcriptase enzyme for replication, like retroviruses.
Nucleoside analogues and derivatives are an important class of therapeutic agents. For example, a number of nucleoside analogues have shown antiviral activity against retroviruses (and related viruses) such as human immunodeficiency virus (HIV), hepatitis B virus (HBV) and human T-lymphotropic virus (HTLV) (PCT publication WO 89/04662 and European Patent publication 0349242 A2). Among the nucleoside analogues shown to have antiviral activity are 3′-azido-3′-deoxythymidine (AZT), 2′,3′-dideoxy-cytidine (ddC) and 2′-deoxy-3′-thiacytidine [(−)2-hydroxymethyl-5-(cytosin-1′-yl)-1,3-oxathiolane (3TC)], (European Patent publication 0382526 A2).
It is known that before nucleoside analogues can be incorporated into viral DNA, these analogues first undergo a phosphorylation step to form the triphosphorylated molecule (Jones, R. J. and Bischofbergern, N. (1995) Antiviral Res. 27:1). This is accomplished by the cell which subjects the analogue to three phosphorylations steps, the first step being rate limiting. Therefore, it is believed that, in many cases, a monophosphorylated nucleotide analogue will be incorporated with greater ease than the corresponding non-phosphorylated analogue.
Since their discovery in 1986, acyclic phosphonate nucleotide analogs have generated considerable attention as broad spectrum antiviral agents. The guanine analogues HPMPG and PMEG, the adenine analogue HPMPA, and the cytosine analogue HPMPC have been shown to exhibit good activity against human cytomegalovirus (HCMV) and herpes simplex virus (HSV). The adenine analogue PMEA has also demonstrated in vitro activity against retroviruses such as the human immunodeficiency virus (HIV), as well as DNA viruses such as HSV, and in vivo activity against murine cytomegalovirus (CMV).
Unfortunately, these compounds present problems due to their cytotoxicity, particularly, PMEG is very cytotoxic. Cyclic phosphonate nucleotides related to HPMPA have been synthesized but exhibited little or no antiviral activity (Collect. Chez. Chem. Commun. (1993) 58: 2159-2191).: These compounds have been reported to exhibit little or no activity against some DNA viruses and no activity against retroviruses and RNA viruses.
In order to facilitate the uptake of the phosphorylated nucleotide analogues and increase their bioavailability, several neutral monophosphorylated nucleotide prodrugs have been developed. These neutral nucleotides are more lipophilic due to the masking of the negative charge of the phosphate group with enzyme or pH labile neutral substitutes. This allows the prodrug to penetrate the cell membrane much more readily than their corresponding 5′-monophosphate dianion counterpart. Once inside the cell, the prodrug decomposes to generate the original monophosphorylated nucleotide analogue which can then be further phophorylated and incorporated into the viral DNA. To achieve this result several substituents have been developed for use in the preparation of monophosphorylated nucleotide prodrugs. Examples of these substituents include S-acyl-2-thioethyls (SATE) (J. Med. Chem. (1995) 38:3941-3950, Antiviral Chem. Chemother. (1998) 9(1):41-52.) such as methyl (SATE), isopropyl(SATE), t-butyl(SATE) and phenyl(SATE), or carboxyloxymethyl such as pivaloyloxymethyl (POM) (Antiviral Chem. Chemother (1994) 5:91-98) and di-S-[(2-hydroxyethyl)sulfidyl]-2-thioethyl. Additionally, substituents such as alkyl methyl carbonates, for example isopropyl methyl carbonate (POC), have also been used to form alkylmethyl carbamate prodrugs (Antiviral Chem. Chemother. (1997) 8: 557-564). Recently, an alternative approach has been developed by the synthesis of phenyl and benzylphosphotriesters analogues (Bioorg. Med. Chem. Lett. (1997) 7: 99-104) and phophostriesters analogues (WO98/17281) of nucleotides have been prepared exhibiting antiviral activity.
SUMMARY OF THE INVENTION
The present invention relates to novel nucleotide analogues having the general formula (I):
and pharmaceutically acceptable derivatives thereof, for example, pharmaceutically acceptable salts, esters, or salts of such esters, wherein
n is 0 or 1;
X is O, S, CH
2
, CH-halogen, CH—N
3
, or C═CH
2
;
Q and U are independently selected from S, O, CF
2
, C═CH
2
. CH(R
a
) or U and Q are both CH and Q and U are linked by a double bond;
R
a
is hydrogen, OH, CN, halogen, N
3
, NH
2
, SH, C
1-6
alkyl, C
1-6
alkoxy, C
2-6
alkenyl, C
2-6
alkynyl, C(O)R
b
, NHR
b
, or SR
b
;
R
b
is hydrogen, OH, CN, halogen, N
3
, NH
2
, SH, C
1-6
alkyl, C
1-6
acyl, or C(O)OR
c
;
R
c
is C
1-6
alkyl or C
1-6
acyl;
Z is (CH
2
)
m
wherein m is 1;
R1 and R1′ are independently selected from H, C
1-6
alkyl, C
2-6
alkenyl, C
6-10
aryl, C
7-11
arylmethyl, C
2-7
acyloxymethyl, C
3-8
alkoxycarbonyloxymethyl, C
7-11
aryloyloxymethyl, C
3-8
S-acyl-2-thioethyl, phosphate or diphosphate;
R
2
is a purine or pyrimidine base or a derivative thereof, provided that when R
2
is adenine, R
a
is CN, halogen, N
3
, NH
2
, SH, C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, C(O)R
b
, NHR
b
, SR
b
wherein R
b
is hydrogen, OH, CN, halogen, N
3
, NH
2
, SH, C
1-6
alkyl.
The present invention also includes methods and compositions for the treatment of viral infections in mammals. Particularly, methods and compositions for the treatment of infections by retroviruses and related viruses. Of special interest are methods and compositions for the treatment of acquired immunodeficiency syndrome (AIDS) and/or Hepatitis B virus infections in mammals.
The present inventions also includes compositions which contains mixtures of compounds of the present invention active against viral infections as well as combinations of compounds of the present invention active against viral infections and other therapeutic agents.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a novel nucleotide analogue having the general formula (I):
and pharmaceutically acceptable derivatives thereof, for example, pharmaceutically acceptable salts, esters, or salts of such esters, wherein
n is 0 or 1;
X is O, S, CH
2
, CH-halogen, CH—N
3
, or C═CH
2
;
Q and U are independently selected from S, O, CF
2
, C═CH
2
. CH(R
a
) or U and Q are both CH and Q and U are linked by a double bond;
R
a
is hydrogen, OH, CN, halogen, N
3
, NH
2
, SH, C
1-6
alkyl, C
1-6
alkoxy, C
2-6
alkenyl, C
2-6
alkynyl, C(O)R
b
, NHR
b
, or SR
b
;
R
b
is hydrogen, OH, CN, halogen, N
3
, NH
2
, SH, C
1-6
alkyl, C
1-6
acyl, or C(O)OR
c
;
R
c
is C
1-6
alkyl or C
1-6
acyl;
Z is (CH
2
)
m
wherein m is 1;
R1 and R1′ are independently selected from the group H, C
1-6
alkyl, C
2-6
alkenyl, C
6-10
aryl, C
7-11
arylmethyl, C
2-7
acyloxymethyl, C
3-8
alkoxycarbonyloxymethyl, C
7-11
aryloyloxymethyl, C
3-8
S-acyl-2-thioethyl, phosphate or diphosphate;
R
2
is a purine or pyrimidine base or derivative thereof, provided that when R
2
is adenine, R
a
is CN, halogen, N
3
, NH
2
, SH, C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, C(O)R
b
, NHR
b
, SR
b
wherein R
b
is hydrogen, OH, CN, halogen, N
3
, NH
2
, SH, C
1-6
alkyl.
The compounds of the present invention may be in the form of single

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