Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
1994-01-18
2001-06-19
Jarvis, William R. A. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C514S554000, C514S555000, C514S576000
Reexamination Certificate
active
06248782
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to a method of treating diseases in mammals caused by retroviruses. This invention also provides methods for treating diseases in mammals caused by a DNA virus. The term “DNA virus” is defined as being a virus with a DNA genome and the term “retrovirus” is defined as being a RNA virus having a reverse transcriptase (RNA-dependent DNA polymerase) within the virion, according to the
TEXTBOOK OF HUMAN VIROLOGY
, 2nd ed. R. B. Belshe Ed., (Mosby, St. Louis 1991). Replication of the viral RNA involves a DNA provirus that is integrated into host cellular DNA. Among mammalian diseases caused by DNA viruses which can be treated by the therapeutic processes of this invention are included the Paroviruses which can infect both rodents (Kilham's virus, Aleutian mink disease) and humans (Parovirus strain B19 and RA-1 virus), the Papovaviruses which include the Papilloma viruses which can infect rabbits (Shope papillomavirus), and the Polyomaviruses which infect primates (vacuolating virus of Rhesus monkeys and JC and BK viruses of man). JC virus is associated with progressive multifocal leukoencephalopathy (PML). Other diseases caused by DNA viruses which can be treated by the processes of this invention are those caused by the Adenoviruses which cause acute respiratory diseases, febrile catarrhs, pharyngitis and conjunctivitis of man, the Herpes viruses which cause both latent and persistent infection in man including Epstein-Barr herpes virus (Lymphocryptovirus) associated with human Burkitt's lymphoma, nasopharyngeal carcinoma and causes infectious mononucleosis in man;
Herpes simplex
which causes both fever blisters and genital herpes among other human diseases, Simian B virus, often fatal to man;
Herpes zoster
(Varicellovirus) which causes infectious mononucleosis and shingles in man; Betaherpes viruses which are associated with cytomegalic inclusion disease and infection of T and B cell leukocytes; the Hepadnaviruses which, upon infection in man are associated with hepatitis, hepatocellular carcinoma and immune complex-mediated extrahepatic injury including hepatitis B and three similar viruses are found in wood ducks, ground squirrels and domestic ducks.
Retroviral diseases in mammals which are treatable by the therapeutic processes of this invention include those caused by the RNA tumor viruses (oncoviruses) and the slow viruses (lentiviruses). Specific oncovirus caused diseases include, in man, T-cell leukemia induced by human T-cell lymphotropic viruses (HTLV-I and II). In addition, there are oncovirus caused diseases other than human which include sarcoma and leukemic diseases of cats, birds, hamsters and primates. Among the lentiviruses caused diseases, HIV which causes AIDS in man is the most prominent. Lentiviruses which cause diseases in mice include murine C-type retroviruses which cause leukemias, such as Friend leukemia, Rauscher, Abelson, Gross and Moloney viruses. Murine lentiviruses causing sarcomas include Kirsten, Harvey, Moloney, Balb and FBJ.
Ideally, virus suppression in an infected mammal by one or more drugs would be the treatment of choice; that is to say, to find a drug which can kill the infecting virus on contact. However, no such drug is currently available, and a more attainable goal would involve discovering a drug which can prevent viral reproduction. One of the major problems in developing such a treatment method for persons infected with one or more DNA or retroviruses is the occurrence of an asymptomatic viremia in mammals lasting from several weeks to several years or, in the case of
Herpes simplex
infections, of recurrent episodes after periods of dormancy while the human subject still harbors the virus. Thus, a useful method of treating a retroviral disease would be to use a drug that can destroy all cells harboring latent virus, rather than simply finding a drug which is only useful after an initial exposure and acts by preventing implanting of the virus or provirus into host chromosomal cells or by inhibiting other early steps in the viral replication cycle. Another therapeutic approach would be to find a drug capable, in the case of HIV-I or II infections, of stimulating the immune system of the host. AZT, the first drug currently approved for the treatment of AIDS, is targeted against reverse transcriptase, an enzyme with a critical function in the early part of the retroviral life cycle. Unfortunately, AZT can cause anemia after prolonged administration.
A second major problem which has hindered the search for effective anti-AIDS drugs has been the lack of an animal model. Ruprecht et al CANCER RESEARCH (SUPPL.) 50 5618a Sept. 1, 1990 describe and evaluate the various models then available for evaluating antiretroviral therapy. Johnson et al ibid 5682 have described a useful murine model which utilizes the retrovirus, Friend leukemia virus, in what is described as a Friend Virus-induced ErythroLeukemia Model. This system for the first time enables investigators to evaluate various anti-retroviral treatment methods and drugs useful in such methods as candidates for the therapy of AIDS and other retroviral diseases.
To date, there has been no publication demonstrating a relationship between ribonucleotide reductase inhibitors and antiretroviral activity, particularly against HIV except for a recent publication Gao et al, Proc. Natl. Acad. Sci. USA, 90:8925-8928 (1993).
SUMMARY OF THE INVENTION
This invention provides a therapeutic process for the treatment of diseases caused by retroviruses in mammals which therapeutic process comprises administering to a mammal suffering from one or more of said viral diseases and in need of treatment, an effective amount of a ribonucleotide reductase inhibitor sufficient to-treat said viral disease in said mammal. Among the ribonucleotide reductase inhibitors which are useful in the therapeutic processes of this invention, we particularly prefer derivatives of polyhydroxy-substituted benzamides and phenylacetamides derivatives of the following formula:
wherein n is 2-5, m is 0 or 1, R is NH
2
, NHOH, OC
1-3
alkyl or O-phenyl, R′ is 0, NH or NOH and R″ is H or OH. Also included are the pharmaceutically-acceptable salts of compounds according to the above formula where chemically feasible. Also included within the scope of this invention are the phenolic acetyl derivatives of compounds according to the above formula. Such acetyl derivatives act as “pro-drugs” in that they are converted by the mammalian body to the corresponding compound having entirely unesterified phenolic hydroxyls, which are the therapeutically active drugs.
Illustrative of the polyhydroxy-substituted phenyl ring in the above formula are included 2,3-dihydroxyphenyl, 3,4-dihydroxyphenyl, 2,5-dihydroxyphenyl, 2,6-dihydroxyphenyl, 2,3,4-trihydroxyphenyl, 2,3,5-trihydroxyphenyl, 3,4,5-trihydroxyphenyl, 2,4,5-trihydroxyphenyl, 2,3,4,5-tetrahydroxyphenyl, pentahydroxyphenyl and the like groups.
In the above formula, when m is 1 and R″ is H, a phenylacetic acid derivative is denominated. When m is 1 and R″ is OH, a mandelic acid derivative is represented. When m is O, R is NHOH and R′ is O, an N-hydroxybenzamide (formerly, a benzohydroxamic acid) is represented; when R is NH
2
and R′ is NH, a benzimidamide (formerly a benzamidine) is represented; when R is NHOH and R′ is NH, an N-hydroxy benzimidamide (formerly a benzamidoxime) is shown; when R is NHOH and R′ is NOH, an N,N′-dihydroxy benzimidamicle (formerly, an hydroxyamidoxime) is represented; and when R is O-alkyl or O-phenyl and R′ is NH, the resulting compounds are benzimidates (rather than benzamidates as previously). In the above formula, when R is OC
1-3
alkyl, the alkyl groups represented include methyl, ethyl, isopropyl and n-propyl.
Compounds represented by the above formula are fully illustrated in U.S. Pat. Nos. 4,253,322, 4,623,659, 2,848,430 and 3,629,443. Methods for their preparation are also fully disclosed in those patents as well as in the many re
Elford Howard L.
van't Riet Bartholomeus
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