Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-09-22
2003-06-24
Wilson, James O. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S262100, C514S269000
Reexamination Certificate
active
06583149
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a method for the treatment or prevention of viral infection using nucleoside analogues.
BACKGROUND OF THE INVENTION
The herpes group of viruses which include cytomegalovirus (CMV), a member of Epstein-Barr virus (EBV), Varicella Zoster virus (VZV), herpes simplex viruses (HSV-1, HSV-2) and human herpes viruses HHV6, HHV7, and HHV8, 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 a major 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, an acyclic guanine nucleoside, 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. Thus, the development of potent and non-toxic anti-CMV agents is therefore highly desirable.
Since their discovery in 1986, the acyclic phoaphonate 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 ask herpes simplex virus (HSV), and in vivo activity against murine cytomegalovirus (CMV).
Unfortunately, in general these compounds present problems in cytotoxicity, particularly, PMEG which is very cytotoxic.
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, and Varicella Zoster virus (VZV). 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 potent and non-toxic agents against Herpes viruses.
SUMMARY OF THE INVENTION
The present invention provides a method for treating or preventing a viral infection selected from the group consisting of herpes simplex virus (HSV), varicella zoster virus (VZV), respiratory syncytial virus (RSV) and cytomegalovirus (CMV) in a host comprising administering a therapeutically effective amount of a compound having the formula I:
wherein
Y is N or C—X;
X is selected from the group consisting of H, halogen, C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, CN, CF
3
, N
3
, NO
2
, C
6-10
aryl, C
6-10
heteroaryl and CORb wherein Rb is selected from the group consisting of H, OH, SH, C
1-6
alkyl, C
1-6
aminoalkyl, C
1-6
alkoxy and C
1-6
thioalkyl;
and Ra is selected from the group consisting of H, C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, C
6-10
aryl, monophosphate, diphosphate, triphosphate, carbonyl substituted with a C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, C
6-10
aryl, and
wherein each Rc are independently selected from the group comprising H, C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl and an hydroxy protecting group,
R1 is selected is selected from the group consisting of H, a C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, C
6-10
aryl, and carbonyl substituted with a C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, C
6-10
aryl,
wherein said compound is in the form of a single enantiomer or a mixture thereof including racemic mixtures.
The present invention provides a method for treating or preventing a viral infection selected from the group consisting of herpes simplex virus (HSV), varicella zoster virus (VZV) and cytomegalovirus (CMV) in a host comprising administering a therapeutically effective amount of a compound having the formula I:
wherein
Y is N or C—X;
X is selected from the group consisting of H, halogen, C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, CN, CF
3
, N
3
, NO
2
, C
6-10
aryl, C
6-10
heteroaryl and CORb wherein Rb is selected from the group consisting of H, OH, SH, C
1-6
alkyl, C
1-6
aminoalkyl, C
1-6
alkoxy and C
1-6
thioalkyl;
and Ra is selected from the group consisting of H, monophosphate, diphosphate, triphosphate, carbonyl substituted with a C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alknyl, C
6-10
aryl, and
wherein each Rc are independently selected from the group comprising H, C
1-6
alkyl; C
2-6
alkenyl, C
2-6
alkynyl and an hydroxy protecting group,
wherein said compound is in the form of a single enantiomer or a mixture thereof including racemic mixtures.
In another embodiment, there is provided a method for treating or preventing a viral infection selected from the group consisting of herpes simplex virus, varicella zoster virus and cytomegalovirus in a host comprising administering to the host a therapeutically effective amount of at least one compound according to formula I and at least one further antiviral agent.
Still another embodiment, there is provided a pharmaceutical composition for treating or preventing a viral infection selected from the group consisting of herpes simplex virus, varicella zoster virus and cytomegalovirus comprising at least one compound according to formula I together with at least one pharmaceutically acceptable carrier or excipient.
In another embodiment, there is provided a pharmaceutical composition for treating or preventing a viral infection selected from the group consisting of herpes simplex virus, varicella zoster virus and cytomegalovirus comprising at least one compound according to formula I and at least one further antiviral agent.
In another embodiment of the invention is the use of a compound according to formula I for the manufacture of a medicament for treating or preventing a viral infection selected from the group consisting of herpes simplex virus, varicella zoster virus and cytomegalovirus in a host.
In another embodiment, there is provided a method for treating or preventing respiratory syncytial virus in a host comprising administering to the host a therapeutically effective amount of at least one compound according to formula I and at least one further antiviral agent.
Still another embodiment, there is provided a pharmaceutical composition for treating or preventing respiratory syncytial virus comprising at least one compound according to formula I together with at least one pharmaceutically acceptable carrier or excipient.
In another embodiment, there is provided a pharmaceutical composition for treating or preventing respiratory syncytial virus comprising at least one compound according to formula I and at least one further antiviral agent.
In another embodiment of the invention is the use of a compound according to formula I for the manufacture of a medicament for treating or preventing respiratory syncytial virus in a host.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a for treating or preventing a viral infection selected from the group consisting of herpes simplex virus, varicella zoster virus respiratory syncytial virus and cytomegalovirus in a host comprising administering a therapeutically effective amount of a compound having the formula I as defined above.
In one embodiment of the invention, Ra is selected from the group comprising H, monophosphate, diphosphate, and tr
Bedard Jean
Giles Francis J.
Rando Robert F.
Bio-Chem Pharma Inc.
McIntosh Traviss
Millen White Zelano & Branigan P.C.
Wilson James O.
LandOfFree
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