Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2000-07-07
2003-04-29
Horlick, Kenneth R. (Department: 1637)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S456000
Reexamination Certificate
active
06555523
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention is directed to the use of flavones, flavanones and related compounds, to treat infectious conditions such as viral or parasite infections.
The common cold and other respiratory infections are often associated with or caused by infection by a number of viruses that can infect the respiratory system (“respiratory viruses”), such as rhinoviruses, paramyxoviruses such as respiratory syncytial virus (RSV), enteroviruses and coronaviruses. Methods to treat such infections are usually limited to treating symptoms and not the infectious agent.
RSV is a virus classified in the genus Pneumovirus of the Paramyxovirus family. This virus can cause lower respiratory tract infections such as bronchiolitis or pneumonia in, e.g., infants, young children, elderly persons or immunosuppressed patients. RSV can progress to cause serious or fatal symptoms in some cases (see e.g., Englund et al.,
Ann. Int. Med
. 1988 1:203). Ribavirin aerosol has been used to treat RSV infections, but its toxicity limits its systemic use (se e.g., Gladu et al.,
J. Toxic Env. Health
1989 28:1). A vaccine of inactivated RSV has been developed, but significant side effects are associated with it and additional therapies are needed.
Otitis media, middle ear inflammation, is another common early childhood infection. Agents responsible for otitis media typically are respiratory syncytial viruses, rhinoviruses, influenza A viruses or adenoviruses (Henderson et al.,
New Eng. J. Med
. 1982 1377; Ruuskanin et al.,
Pedr. Infect. Dis. J
. 1989 94). Prevention of respiratory virus infections decreases the incidence of otitis media (Heikkinen et al.,
AJDC
1991 445). Agents that treat or prevent such infections are needed.
Influenza viruses are members of the Orthomyxovirus family. Seasonal outbreaks occur almost yearly and occasional worldwide pandemics also arise. Treatment with vaccines are usually effective at preventing the disease, but the vaccine is needed each year, due to the variation of the flu viruses that arise each year. Amantadine has been used for treatment of ongoing infection, but it has some CNS toxicity. Influenza virus infection can progress to a primary influenza viral pneumonia, which can not be treated with amantadine or rimantidine. Additional agents to treat or prevent such infections are needed.
Herpesviruses such as herpes simplex viruses and related viruses (e.g., HSV-1, HSV-2, EBV, CMV, HHV-6, HHV-8) are members of the Herpesviridae family. Transmission of the viruses can arise from direct contact, e.g., HSV-1 through the oral cavity and HSV-2 through the genital tract. A number of therapeutic agents are available, e.g., acyclovir, trifluridine and vidarabine. These agents are not uniformly effective to treat the spectrum of infections that are associated with these viruses and additional agents to treat these infections are needed.
Retroviruses are associated with a number of infections, notably AIDS, and some cancers. The human immunodeficiency virus, HIV, (HIV-1, HIV-2, HTLV-III, LAV) is believed to be responsible for causing immune deficiency conditions in humans. Related viruses can lead to similar conditions in animals, e.g., SIV or SHIV in primates or FIV in cats. Loss of cell-mediated immunity and development of eventually fatal opportunistic infections frequently occurs in HIV infections. Most available treatment options have one or more limitations, such as toxicities or unwanted side effects and complicated dosing regimens. Large-scale efforts to identify additional treatment options for retrovirus infections are underway.
Hepatitis viruses such as human hepatitis A virus (“HAV”), human hepatitis B virus (“HBV”), and human hepatitis C virus (“HCV”), can lead to significant symptoms and mortality. For example, HCV infection is common, with estimates of worldwide prevalence of chronic hepatitis ranging from 90 million up to over 200 million. There is no vaccine or candidate vaccine for pre-exposure prophylaxis and no effective globulin for post-exposure prophylaxis. Related viruses of the Togaviridae, Hepadnaviridae, Flaviviridae and Picornaviridae families, including alphaviruses (also known as arboviruses, group A), flaviviruses (also known as arboviruses, group B)(such as yellow fever, as well as hepatitis C and hepatitis G), Rubiviruses (also known as rubella viruses)(such as rubella) and pestiviruses (also known as mucosal disease viruses, such as bovine virus diarrhea virus (BVDV)) are also significant causes of disease and mortality. Therapies for some of these infections exist, e.g., interferon treatment for HCV infection, but the treatments are not always effective and can have serious unwanted side effects. Considerable efforts are underway to identify additional therapeutic agents to use in treating these infections.
The protozoan parasite
Toxoplasma gondii
is the etiologic agent of toxoplasmosis. The organism is a sporozoan that lives as an intracellular parasite in macrophages. It has evolved mechanisms to avoid killing by host cell defenses such as oxygen radicals and lysosomal enzymes. The parasite synthesizes molecules that appear to prevent lysosomes in infected macrophages from fusing with phagosomes that contain the parasite.
A number of flavonoids, coumarins and related compounds, methods to obtain them and their uses have been described. See, e.g., J. A. Manthey and B. S. Buslig, editors,
Flavonoids in the living system, Advances in experimental medicine and biology
, volume 439, Plenum Press, New York, 1998, chapter 15 (pages 191-225), chapter 16 (pages 227-235) and chapter 17 (pages 237-247), C. N. Alves et al.,
Theochem
. 1999 491:123-131, J-H. Lee et al.,
Saengyak Hakhoechi
1999, 30:34-39, S. J. Semple et al.,
J. Ethnopharmacology
1999 68:283-288, E. Z. Baum et al.,
Biochemistry
1996 35:5847-5855, J. W. Critchfield et al.,
AIDS Res. Hum. Retroviruses
1996 12:39-46, H. K. Wang et al.,
J. Med. Chem
. 1996 39:1975-1980, T. Nagai et al.,
Antiviral Res
. 1995 26:11-25, T. Nagai et al.,
Biol. Pharm. Bull
. 1995 18:295-299, N. Mahmood et al.,
Antiviral Res
. 1993 22:189-99, J. A. Beutler et al.,
J. Nat. Prod
. 1992 55:207-213, R. I. Brinkworth et al.,
Biochem. Biophys. Res. Commun
. 1992 188:631-637, M. S. Chapman et al.,
J. Mol. Biol
. 1991 217:455-463, I. T. Kusumoto et al.,
Shoyakugaku Zassi
1991 45:240-54, T. Konoshima et al.,
Shoyakugaku Zassi
1989 42:135-141, R. Vrijsen et al.,
Antiviral Res
. 1987 7:35-42, J. L Castrillo et al.,
Virology
1986 152:219-227, T. Horie et al.,
J. Med. Chem
. 1986 29:2256-2262, T. N. Kaul et al.,
J. Med. Virol
. 1985 15:71-79, T. Yoshinori et al.,
Chem. Pharm. Bull
. 1985 33:3881-3886, P. G. Higgins et al.,
British. Soc. Antimicrobial Chemother
1984 403-409, Y. Graziani et al.,
Eur. J. Biochem
. 1983 135:583-589 and U.S. Pat. Nos. 6,063,809, 5,955,256, 5,877,208, 5,869,701, 5,830,894, 5,510,375, 5,489,585 and 4,238,483.
The present invention provides compounds for use in these infectious conditions to treat or prevent them, or to ameliorate one or more symptoms associated with such infections. Also provided are compounds and compositions suitable for use in the methods.
SUMMARY OF THE INVENTION
In accordance with the present invention, a method is provided to treat or prevent a virus or a parasite infection comprising administering to a subject having the virus or parasite infection an effective amount of a compound having the formula 1 or 2
wherein a double or a single bond is present at the dotted line and, when a double bond is present, (i) the optionally substituted phenyl ring at the 2- or 3-position is present and the R
8
that is bonded to that position is absent, and (ii) one R
8
at the adjacent 2- or 3-position is absent;
X
1
is —O— or —C(R
8
)
2
—;
X
2
is —C(O)— or —C(R
11
)
2
—;
each R
8
independently is —H, —OH, —SH, halogen, C
1-6
alkly, C
1-6
alkoxy, glucuronide, a moiety that can hydrolyze to hydroxyl, a protecting group, a C
1-25
fatty acid, the residue of a formula 1 or 2 compound where a hydrogen atom is removed to form the fo
Callahan Heather L.
Horlick Kenneth R.
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