Antiviral methods using [1,8]naphthyridine...

Details Antiviral methods using [1,8]naphthyridine... Antiviral methods using [1,8]naphthyridine...

2000-02-22

2002-01-22

Dentz, Bernard (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

Reexamination Certificate

active

06340690

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to heterocyclic compounds, more specifically derivatives of [1,8] naphthyridine, useful for the inhibition of viral infections.
BACKGROUND OF THE INVENTION
Hepatitis is a disease occurring throughout the world. It is generally or viral nature, although there are other causes known. Viral hepatitis is by far the most common form of hepatitis. Nearly 750,000 Americans are affected by hepatitis each year, and out of those, more than 150,000 are infected with the hepatitis C virus (“HCV”).
HCV is a positive-stranded RNA virus belonging to the Flaviviridae family and has closest relationship to the pestiviruses that include hog cholera virus and bovine viral diarrhea virus (BVDV). HCV is believed to replicate through the production of a complementary negative-strand RNA template. Due to the lack of efficient culture replication system for the virus, HCV particles were isolated from pooled human plasma and shown, by electron microscopy, to have a diameter of about 50-60 nm. The HCV genome is a single-stranded, positive-sense RNA of about 9,600 bp coding for a polyprotein of 3009-3030 amino-acids, which is cleaved co and post-translationally by cellular and two viral proteinases into mature viral proteins (core, E1, E2, p7, NS2, NS3, NS4A, NS4B, NS5A, NS5B). It is believed that structural proteins, E1 and E2, the major glycoproteins are embedded into a viral lipid envelope and form stable heterodimers. The structural core protein interacts with the viral RNA genome to form the nucleocapsid. The nonstructural proteins designated NS2 to NS5 code for proteins with enzymatic functions involved in virus replication and protein processing including a polymerase, protease and helicase.
The main sources of contamination with HCV is blood. The magnitude of the HCV infection as a health problem is illustrated by the prevalence among high-risk groups. For example, 60% to 90% of hemophiliacs and more than 80% of intravenous drug abusers in western countries are chronically infected with HCV. For intravenous drug abusers, the prevalence varies from about 28% to 70% depending on the population studied. The proportion of new HCV infections associated with post-transfusion has been markedly reduced lately due to advances in diagnostic tools used to screen blood donors.
The only treatment currently available for HCV infection is interferon-&agr; (IFN-&agr;), either as monotherapy and in combination with ribavirin. However, according to different clinical studies, only 70% of treated patients normalize alanine aminotransferase (ALT) levels in the serum and after discontinuation of IFN, 35% to 45% of these responders relapse. In general, only 40% of patients have long-term responses to IFN/ribavirin combination therapy. On the other hand, pilot studies suggest that combination treatment with IFN plus Ribavirin (RIBA) results in sustained response in the majority of patients. Different genotypes of HCV respond differently to IFN therapy, genotype 1b is more resistant to IFN therapy then type 2 and 3.
In spite of advances in the knowledge of HCV replication and transmission, it therefore appears that to this date, no effective universal treatment of HCV is available. This is due in great part to the fact that only humans and chimpanzees can be infected with the virus. Consequently, there are no in vivo animal models for testing potential therapeutic agents and thus, no vaccine available for hepatitis C. Another factor preventing the development of in vivo assays is that human liver tissue is difficult to obtain and is expensive, thereby preventing its use in large scale screening where large quantities of tissue would be needed. Combined with the prohibitive cost and availability of chimpanzees, in vivo models are presently not amenable for screening purposes.
Jin et al. described [1,6] naphthyridine derivatives useful as inhibitors of human cytomegalovirus (HCMV). A [1,8] naphthyridine derivative was also identified as having such inhibiting activity, though to lesser extent, i.e. [1,8] naphthyridine-2-carboxylic acid 2-methoxybenzyl-amine. However, no other use is suggested for this particular compound. There is therefore a great need for the development of a hepatitis virus inhibitor, and particularly HCV.
The herpes group of viruses which includes Epstein-Barr virus (EBV), Varicella Zoster virus (VZV), Herpes Simplex viruses (HSV-1, HSV-2) and Human Herpes virus (HHV6) is recognized as an important pathogen in patients with AIDS. These viruses often contribute to the immunosuppression observed in such patients and may cause disseminated disease involving the lungs, gastrointestinal tract, central nervous system, or eyes.
All human Herpes viruses 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 Herpes viruses, particularly Herpes Simplex viruses HSV-1 and HSV-2, and Varicella Zoster virus (VZV). A number of nucleosides and nucleotides 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 and hepatitis viruses.
SUMMARY OF THE INVENTION
In accordance with the present invention, there is provided a method for the inhibition of a viral infection in a mammal, the method comprising administering to the mammal an antiviral amount of a [1,8] naphthyridine derivative of Formula I or a pharmaceutically acceptable salt thereof;
wherein
Z
1
, Z′
1
, Z″
1
, and Z
2
are independently H, halogen, carboxyl, amino, amidino, guanidino, nitro, OH, SH, CN, C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, C
1-6
alkoxy or C
1-6
heteroalkyl;
A is
X is O, NH, or S;
Y is O, S, (CH
2
)
n
, O(CH
2
)
n
, or S(CH
2
)
n
; with n is 0 to 6;
R
1
and R
2
are independently H or C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl; or R
1
and R
2
together form a saturated or unsaturated 5 or 6 member heterocycle; and
W is C
6-12
aryl, C
6-12
heteroaryl, or C
3-12
heterocycle
In accordance with the present invention, there is also provided a [1,8] naphthyridine derivative of Formula I or pharmaceutically acceptable salts thereof;
wherein;
A, Z
1
, Z′
1
, Z″
1
, and Z
2
are as defined above; with the provisos that:
1) when; Y is CH
2
, X is O, R
1
, Z
1
, Z
1
′, Z
1
″ and Z
2
are H, and A is
then W is not 2-methoxyphenyl or 3-trifluoromethylphenyl; and
2) when Y is (CH
2
)
0
, X is O, R
1
, Z
1
, Z
1
′, Z
1
″ and Z
2
are H, and A is
then W is not phenyl, 3-trifluoromethylphenyl or 3-pyridinyl.
DETAILED DESCRIPTION OF THE INVENTION
As used in this application, the term “alkyl” represents an unsubstituted or substituted (by a halogen, nitro, aminoamidino, amidino, guanido, CONH
2
, COOH, O—C
1-6
alkyl, O—C
2-6
alkenyl, O—C
2-6
alkynyl, amino, hydroxyl or COOQ, wherein Q is C
1-6
alkyl, C
2-6
alkenyl, a C
2-6
alkynyl) straight chain, branched chain, or cyclic hydrocarbon moiety (e.g. isopropyl, ethyl, flurohexyl or cyclopropyl). The term alkyl is also meant to include alkyls in which one or more hydrogen atoms is replaced by an halogen, more preferably, the halogen is fluoro (e.g., CF
3
—, or CF
3
CH
2
—).
The terms “alkenyl” and “alkynyl” represent an alkyl containing at least one unsaturated group (e.g., allyl).
The term “heteroalkyl” represents an alkyl, alkenyl, or alkynyl in which a C atom which is part of the straight chain, branched chain or cyclic hydrocarbon moiety is replaced by one or more heteroatom such as oxygen, sulfur and nitrogen (e.g., ether, thiohexanoyl, thiomorpholino, isothiazole, imidazole, triazole, ethylmethylsulfone or ethylthio).
The term “heterocycle” represents a cyclic heteroalkyl (imidazole, isothiazole, or tr

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