Pyrrolo[2,3-d] pyrimidines as antiviral agents

Details Pyrrolo[2,3-d] pyrimidines as antiviral agents Pyrrolo[2,3-d] pyrimidines as antiviral agents

1999-01-11

2002-01-29

Shah, Mukund J. (Department: 1611)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C544S280000

Reexamination Certificate

active

06342501

ABSTRACT:

TECHNICAL FIELD
The present invention relates to new non-phosphorylatable, non-nucleoside pyrrolo[2,3-d]pyrimidines and their use in the treatment of viral infections.
BACKGROUND OF THE INVENTION
Broad spectrum antiviral activity of pyrrolo[2,3-d]pyrimidine nucleosides such as tubercidin, sangivamycin and toyocamycin and some substituted derivatives previously has been reported. Activity of those compounds against specific viruses, such as RNA rhinovirus and DNA herpes simplex virus type 1 and type 2 also has been reported. See, for example, Bergstrom, D. E. et al.,
J. Med. Chem.
27:285-292 (1984); and DeClercq, E. et al.,
Antimicrob. Agents Chemother.,
29:482-487 (1986).
Pyrrolo[2,3-d]pyrimidine nucleosides are particularly attractive as potential antiviral agents because of their stability toward the action of two major enzymes of bioactive purine nucleoside inactivation, deamination by adenosine deaminase and glycosidic bond cleavage by purine nucleoside phosphorylases. Unfortunately, many of the pyrrolo[2,3-d]pyrimidine nucleosides which have been previously described as having potential antiviral activity also exhibit unacceptable levels of cytotoxicity, thereby diminishing their usefulness in treatment of viral infections.
A number of pyrrolo[2,3-d]pyrimidine nucleoside derivatives which exhibit improved antiviral activity and more acceptable levels of cytotoxicity than tubercidin, sangivamycin, toyocamycin and thiosangivamycin have been reported. These prior art pyrrolo[2,3-d]pyrimidine nucleoside derivatives are described below.
Townsend et al. (U.S. Pat. No. 4,892,865) disclose the use of, inter alia, several 4-amino-pyrrolo[2,3-d]pyrimidine-5-carbonitriles and 4-aminopyrrolo[2,3-d]pyrimidine-5-thiocarboxamides substituted at the 7-position with 2′,3′-dideoxy-2′,3′-didehydro-&bgr;-D-ribofuranose and 2′,3′-dideoxyribofuranose as antiviral agents.
Renau et al. (
Bioorg.
&
Med. Chem. Lett.,
2:1755-1760, 1992) disclose the use of, inter alia, 4-amino-pyrrolo[2,3-d]pyrimidine -5-thiocarboxamides and 4-amino-pyrrolo[2,3-d]pyrimidine-5-carbonitriles substituted at the 7-position with &bgr;-D-ribofuranose as antiviral agents.
A number of pyrrolo[2,3-d]pyrimidine non-nucleoside derivatives which exhibit improved antiviral activity and more acceptable levels of cytotoxicity than tubercidin, sangivamycin, toyocamycin and thiosangivamycin as well as the nucleoside derivatives described above have been reported. These prior art pyrrolo[2,3-d]pyrimidine non-nucleoside derivatives are described below.
Townsend et al. (U.S. Pat. Nos. 4,927,830 and 4,968,686) disclose the use of, inter alia, several 4-amino-pyrrolo[2,3-d]pyrimidine-5-thiocarboxamides and 4,6-diamino-pyrrolo[2,3-d]pyrimidine-5-thiocarboxamides variously substituted at the 7-position with —CH
2
OCH(CH
2
OH)
2
, —CH
2
OCH
2
CH
2
OH and —CH(CH
2
OH)(OCH(CH
2
OH)
2
) as antiviral agents.
Gupta et al. (
J. Med. Chem.,
32: 402-408, 1989) disclose the use of, inter alia, several 4-amino-pyrrolo[2,3-d]pyrimidine-5-thiocarboxamides and 4-amino-pyrrolo[2,3-d]pyrimidine-5-carbonitriles variously substituted at the 7-position by —CH
2
OCH(CH
2
OH)
2
and —CH(CH
2
OH)(OCH(CH
2
OH)
2
) as antiviral agents.
Gupta et al. (J. Med. Chem., 32:1420-1425, 1989) disclose the use of, inter alia, several 4-amino.-pyrrolo[2,3-d]pyrimidine-5-thiocarboxamides and 4-amino-pyrrolo[2,3-d]pyrimidine-5-carbonitriles substituted at the 7-position by —CH
2
OCH
2
CH
2
OH as antiviral agents.
Renau et al. (
Antiviral Res.,
19:15-28, 1992) disclose the use of 4-amino-pyrrolo[2,3-d]pyrimidine-5-thiocarboxamide and 4-aminopyrrolo[2,3-d]pyrimidine-5-carbonitrile substituted at the 7-position by —CH
2
—OCH
2
—CH
2
—OH as antiviral agents.
Swayze et al. (
Nucleosides and Nucleosides,
11:1507-1527, 1992) disclose the use of, inter alia, 4,6-diamino-pyrrolo[2,3-d]pyrimidine -5-thiocarboxamides and 4,6-diamino-pyrrolo[2,3-d]pyrimidine-5carbonitriles variously substituted at the 7-position by —CH
2
—OCH
2
—CH
2
—OH and —CH
2
—OCH(CH
2
—OH)
2
as antiviral agents.
A limited number of pyrrolo[2,3-d]pyrimidine non-nucleoside, non-phosphorylatable derivatives which exhibit improved antiviral activity and more acceptable levels of cytotoxicity than tubercidin, sangivamycin, toyocamycin and thiosangivamycin as well as the nucleoside derivatives described above have been reported.
For example, Renau et al. (
Bioorg
&
Med Chem. Lett.,
2:1755-1760, 1992) disclose the use of, inter alia, several 4-amino-pyrrolo[2,3-d]pyrimidine-5-thiocarboxamides and 4-amino-pyrrolo[2,3-d]pyrimidine-5-carbonitriles variously substituted at the 7-position with —CH
2
—OCH
2
—CH
2
—OH, —CH
2
—OCH(CH
2
—OH)
2
, CH
3
, —CH
2
—CH═CH
2
, and —CH
2
—CH
2
—CH
3
as antiviral agents.


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