5′-amino acid esters of ribavirin and the use of same...

Details 5′-amino acid esters of ribavirin and the use of same... 5′-amino acid esters of ribavirin and the use of same...

1999-07-07

2001-08-21

Wilson, James O. (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S002600, C514S021800, C514S894000, C424S085400, C424S085700, C530S351000

Reexamination Certificate

active

06277830

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to 5′-amino acid esters of ribavirin represented by formula I:
pharmaceutical compositions containing them as well as methods of treating patients having susceptible viral infections, e.g., chronic hepatitis C infections by administering a therapeutically effective amount of an amino acid ester of ribavirin represented by formula I, alone, or in combination with a therapeutically effective amount of interferon-alpha.
Chronic infection with hepatitis C virus (“HCV”) is an insidious and slow-progressing disease having a significant impact on the quality of life. It can eventually result in cirrhosis of the liver, decompensated liver disease and/or hepatocelluar carcinoma.
Combination treatment with interferon alfa-
2
b
and ribavirin of patients with chronic hepatitis C is disclosed by Reichard et al.(The Lancet 1998; 351;83-87; and T. Poynard et al.( The Lancet, 1998, Vol. 352, Oct. 31, p 1426-1432). See also J. G. McHutchinson et al. (N. Engl. J. Med.,1998, 339:1485-1492); and G. L. Davis et al. (N. Engl. J. Med., 1998, 339:1493-1499). However, this combination therapy is not always effective due to side effects associated ribavirin such as ribavirin-related hemolysis, and anemia.
There is a definite need for more potent, safer ribavirin derivatives having fewer side effects for use as monotherapy or in combination with antiviral agents, e.g., interferon-alpha, to treat patients having susceptible viral infections, e.g., chronic hepatitis C infections, in a long-term, effective manner.
SUMMARY OF THE INVENTION
The present invention provides a compound represented by the formula I:
wherein R is CH
3
CH(NH
2
)—CO—, CH
3
CH
2
(CH
3
)CHCH(NH
2
)—CO—or H
2
N(CH
2
)
4
CH(NH
2
)—CO—;
or a pharmaceutically acceptable salt thereof.
The present invention also provides pharmaceutical compositions for treating susceptible viral infections comprising a compound of formula I and at least one pharmaceutically acceptable carrier.
The present invention also provides a method of treating a patient with a susceptible viral infection which comprises administering to said patient an effective amount of a compound of formula I.
The present invention also provides a method of treating a patient infected with chronic hepatitis C which comprises administering to said patient an effective amount of a compound of formula I in association with an effective amount of an interferon alfa for a time sufficient to eradicate detectable HCV-RNA levels, wherein the compound represented by the formula I:
wherein R is CH
3
CH(NH
2
)—CO—, CH
3
,CH
2
(CH
3
)CHCH(NH
2
)—CO—or
H
2
N(CH
2
)
4
CH(NH
2
)p—CO—; or a pharmaceutically acceptable salt thereof.
The present invention also provides a method of treating a patient infected with chronic hepatitis C which comprises administering to said patient an effective amount of a compound of formula II:
or a pharmaceutically acceptable salt thereof, in association with an effective amount of an interferon alfa for a time sufficient to eradicate detectable HCV-RNA levels.
DETAILED DESCRIPTION
The compounds of formula I metabolize in vivo into ribavirin and are useful for treating susceptible viral infections treatable with ribavirin, alone, or in combination with other ant-viral therapies eg., interferon-alfa, and so-called Highly Active Antiretroviral Therapy (“HAART”. A-M. Vandamme et al.,
Antiviral Chemistry
&
Chemotherapy,
9:187-203 (1998) disclose current clinical treatments of HIV-1 infections in man including at least triple drug combinations or so-called Highly Active Antiretroviral Therapy (“HAART”) ; HAART involves various combinations of nucleoside reverse transcriptase inhibitors (“NRTl”), non-nucleoside reverse transcriptase inhibitors (“NNRTI”) and HIV protease inhibitors (“PI”). The treating of patients having chronic hepatitis C with the compounds of formula I is performed as part of a combination therapy with interferon-alfa, including interferon alfa-
2
a,
interferon alfa-
2
b,
consensus interferon especially interferon alfa-
2
b
as well as pegylatyed interferon alfa-
2
a
and pegylatyed interferon alfa-
2
b.
The present invention provides methods and pharmaceutical compositions containing a compound of formula I for treating susceptible viral infections, especially hepatitis C viral infections.
The term “susceptible viral infections” as used herein means viral infections caused by a wide range of RNA and DNA viruses, including, but not limited to, orthomyxoviruses, paramyxoviruses, arenaviruses, bunyaviruses, herpes viruses, adenoviruses, poxviruses, and retroviruses.
Typical suitable “susceptible viral infections” include influenza A and B viral infections; parainfluenza viral infections, respiratory syncytial virus(“RSV”) infections such as RSV bronchiolitis and RSV pneumonia especially such RSV infections in children and infants as well as RSV pneumonia in patients with preexisting cardiopulmonary disease, measles viral infections, Lassa fever viral infections, Korean Haemorrhagic fever infections, hepatitis B viral (HBV) infections, Crimean-Congo-Haemorrhagic and HCV infections and HIV-1 infections as well as viral infections found in immunocompromised patients. Other susceptible viral infections are disclosed in U.S. Pat. No. 4,211,771 at column 2, line 21 to column 3 line 37; doses and dose regimens and formulations are disclosed at column 3, line 4 to column 9, line 5; see also Canadian Patent No. 1,261, 265. Sidwell, R. W., et al. Pharmacol. Ther., 1979, Vol 6 pp 123-146 discloses that the in vivo antiviral experiments conducted with ribavirin generally confirm one broad-spectrum antiviral activity seen in vitro and states that the efficacy of ribavirin is quite dependent upon the site of infection; the manner of treatment; the age of the animal and the virus dosage utilized. Tables 4 and 5 on page 127 list the RNA and DNA virus infections significantly inhibited in vivo by ribavirin.
The in vitro inhibitory concentrations of ribavirin are disclosed in Goodman & Gilman's “
The Pharmacological Basis of Therapeutics”,
Ninth Edition, (1996) McGraw Hill, NY, at pages 1214-1215. The Virazole product information discloses a dose of 20 mg/mL of Virazole aerosol for 18 hours exposure in the 1999 Physicians Desk Reference at pages 1382-1384.
Ribavirin dosage and dosage regimens are also disclosed by Sidwell, R. W., et al. Pharmacol. Ther 1979 Vol 6. pp23-146 in section 2.2 pp 126-130. Fernandes, H., et al., Eur. J. Epidemiol., 1986, Vol 2(1) pp1-14 at pages 4-9 disclose dosage and dosage regimens for oral, parenteral and aerosol administration of ribavirin in various preclinical and clinical studies.
The term “patients having hepatitis C infections” as used herein means any patient-including a pediatric patient- having hepatitis C and includes treatment-naive patients having hepatitis C infections and treatment-experienced patients having hepatitis C infections as well as those pediatric, treatment-naive and treatment-experienced patients having chronic hepatitis C infections.
These patients having hepatitis C include those who are infected with multiple HCV genotypes including type 1 as well as those infected with, e.g., HCV genotypes 2, 3, 4, 5 and/or 6 and other possible HCV genotypes.
The term “treatment-naive patients having hepatitis C infections” as used herein means patients with hepatitis C who have never been treated with ribavirin or any interferon, including but not limited to interferon-alfa, or pegylated interferon alfa.
The term “treatment-experienced patients having hepatitis C infections” as used herein means patients with hepatitis C who have been treated with ribavirin or any interferon, including but not limited to interferon-alfa, or pegylated interferon alfa, including relapsers and non-responder.
The term “relapsers” as used herein means treatment-experienced patients with hepatitis C who have relapsed after initial response to previous treatment with interferon alone, or in combination with ribavirin.
The term “non-responders” as used herein means treatm

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