Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1998-12-15
2002-10-01
Low, Christopher S. F. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S002600, C530S329000, C424S093100, C424S093600
Reexamination Certificate
active
06458766
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates generally to the fields of biochemistry and medicine, and more specifically to compounds useful as antiviral and antimicrobial agents.
2. Background Information
Viral infections have long been and continue to be a major cause of human suffering. The large variety of viruses combined with the diverse types of afflictions continue to challenge endeavors to find and make available agents capable of treating or mitigating the effects viral infections.
One family of viruses that is particularly troublesome is the Herpes simplex viruses (HSV). HSV is a relatively common human pathogen which can cause fatal disease in the young or immunocompromised. HSV includes two closely related variants designated type 1 (“HSV-1”) and type 2 (“HSV-2”). These types cross react strongly, but can be distinguished by neutralization titrations. HSV-1 and HSV-2 are responsible for a variety of human diseases, such as skin infection, fever blisters, genital herpes, viral encephalitis, and the like. Both HSV-1 and HSV-2 have been shown to be capable of causing neonatal infections. HSV-2 genital infections has been linked with the development of cervical cancer.
Cytomegalovirus (CMV) is another member of the HSV family. CMV infection is the leading cause of congenital viral infections with an incidence averaging 1% of all live births. An additional 5% to 10% of infants acquire CMV perinatally as a result of mother-to-infant transmission. Although the virus is widely distributed in the population about 40% of women enter pregnancy without antibodies and thus are susceptable to infection. CMV infections of the eye have resulted in the loss of sight to immunocomprised individuals afficted with AIDS. CMV infection is also a major concern organ transplant recipients, especially, kidney and liver transplants.
A major avenue for HSV transmission is through skin to skin contact with an infected area, such as genital to genital contact, and contact to the eye with the hands. It is therefore desirable to administer a potent antiviral, particularly, anti-HSV or anti-CMV agent topically prior to potential viral introduction into an individual.
Because of these disease conditions, there is a continuing effort made by individual academic investigators, and by small and large pharmaceutical companies to identify new and useful antiviral agents. Various drug discovery strategies have been developed. In some instances, derivatives of known effective drugs are prepared and examined for improved or different, but useful, characteristics. Another approach is to develop or acquire large libraries of randomly synthesized drugs candidates, and screen these compounds for potential efficacy as antiviral agents. Both of these methods have resulted in the identification of potentially useful antiviral agents. Yet another approach has been to identify potentially useful drugs that are produced naturally by living organisms. For example, paclitaxel is a chemical that is produced by the yew tree and, when purified, is effective in treating cancers such as ovarian carcinoma. Applying a similar discovery strategy, naturally occurring agents with antiviral activity are being sought and screened for antiviral activity.
A naturally occurring compound has been recently discovered, which surprisingly possesses antiviral activity, and fulfills the needs of the requirements for an antiviral agent.
SUMMARY OF THE INVENTION
The present invention provides a compound having the structure:
wherein,
R
1a
and R
1b
are independently selected from the group consisting of —H, alkyl, lower-alkyl, substituted alkyl and substituted lower-alkyl;
R
2a
and R
2b
are independently selected from the group consisting of —H, lower-alkyl, and substituted lower-alkyl;
R
3
is —H, lower-alkyl, substituted lower-alkyl and where R
3
and R
4
are attached together by a lower-alkyl or a substituted lower-alkyl moiety;
R
4
is —H, lower-alkyl, substituted lower-alkyl and where R
3
and R
4
are attached together form a lower-alkyl or substituted lower-alkyl bridge;
R
5
, R
7
, R
9
and R
11
are independently selected from the group consisting of —H, lower-alkyl, and substituted lower-alkyl;
R
6
is —H, lower-alkyl and substituted lower-alkyl;
R
8
is —H, lower-alkyl and substituted lower-alkyl;
R
10
is —H, lower-alkyl and substituted lower-alkyl;
R
12
is —H, lower-alkyl and substituted lower-alkyl; and
A is —C(O)—R
13
, wherein R
13
is —H, —OH, alkyl, lower-alkyl, substituted lower-alkyl or —O(lower-alkyl); —CH
2
—OR
14
wherein R
14
is —H, —C(O)CH
3
, alkyl, lower-alkyl or substituted lower-alkyl; or —CH
2
—NR
15
R
16
, where R
15
and R
16
are independently selected from —H, lower-alkyl, alkyl, substituted lower-alkyl or substituted alkyl;
a pharmaceutically acceptable salt or derivatives thereof, useful for preventing and treating viral and microbial infections.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides method for treating viral infections, in particular, herpes simplex type I and II viral infections and cytomegalovirus.
The present invention provides a compound having the structure:
wherein,
R
1a
and R
1b
are independently selected from the group consisting of —H, alkyl, lower-alkyl, substituted alkyl and substituted lower-alkyl;
R
2a
and R
2b
are independently selected from the group consisting of —H, lower-alkyl, and substituted lower-alkyl;
R
3
is —H, lower-alkyl, substituted lower-alkyl and where R
3
and R
4
are attached together by a lower-alkyl or a substituted lower-alkyl moiety;
R
4
is —H, lower-alkyl, substituted lower-alkyl and where R
3
and R
4
are attached together form a lower-alkyl or substituted lower-alkyl bridge;
R
5
, R
7
, R
9
and R
11
are independently selected from the group consisting of —H, lower-alkyl, and substituted lower-alkyl;
R
6
is —H, lower-alkyl and substituted lower-alkyl;
R
8
is —H, lower-alkyl and substituted lower-alkyl;
R
10
is —H, lower-alkyl and substituted lower-alkyl;
R
12
is —H, lower-alkyl and substituted lower-alkyl; and
A is —C(O)—R
13
, wherein R
13
is —H, —OH, alkyl, lower-alkyl, substituted lower-alkyl or —O(lower-alkyl); —CH
2
—OR
14
wherein R
14
is —H, —C(O)CH
3
, alkyl, lower-alkyl or substituted lower-alkyl; or —CH
2
—NR
15
R
16
, where R
15
and R
16
are independently selected from —H, lower-alkyl, alkyl, substituted lower-alkyl or substituted alkyl;
a pharmaceutically acceptable salt or derivatives thereof, useful for preventing and treating viral and microbial infections.
The invention provides a method for preventing and treating viral infections, such as, HSV-1, HSV-2 and CMV.
In addition, the invention provides a method for preventing and treating microbial infections.
Further, the invention provides a method of treating viral infections in combination with antiviral agents, such as, acyclovir, penciclovir, valaciclovir, famciclovir, ganciclovir and foscarnet.
Still further, the invention provides a method of preventing and treating,viral infection in combination with antiviral topical agents, such as, nonoxynol.
Definitions
As used herein the term “alkyl” refers to a branched or straight chain monovalent saturated aliphatic hydrocarbon radical of seven to twenty carbon atoms. This term is further exemplified by such radicals as n-heptyl, n-decyl, n-tridecyl and the like.
As used herein, the term “lower-alkyl” refers to a branched or straight chain monovalent alkyl radical of one to six carbon atoms. This term is further exemplified by such radicals as methyl, ethyl, propyl, isopropyl, butyl (for example, isobutyl, t-butyl, or n-butyl), pentyl (for example, 2-methylbutyl, 3-methylbutyl), and hexyl (for example, 2-methylpentyl, 2,2-dimethylbutyl and 2,3-dimethylbutyl).
As used herein, the term “substituted alkyl” refers to an alkyl moiety optionally substituted with hydroxy, carbonyl, carboxy, halide, amidyl, guanidyl, thio and carboxyamide. Example of substituted alkyl moieties, include but are not limited by, tetradecanoyl, nonylcarbonyl, and 1-chloropentylcarbonyl.
As used
Fenical William
Jensen Paul R.
Rowley David C.
Brown Martin Haller & McClain LLP
Low Christopher S. F.
Mohamed Abdel A.
The Regents of the University of California
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