8-hydroxy-7-substituted quinolines as anti-viral agents

Details 8-hydroxy-7-substituted quinolines as anti-viral agents 8-hydroxy-7-substituted quinolines as anti-viral agents

1997-09-05

2001-10-30

Bernhardt, Emily (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S153000, C546S159000, C546S161000, C546S169000, C546S014000, C546S177000, C544S128000, C514S307000, C514S311000, C514S314000

Reexamination Certificate

active

06310211

ABSTRACT:

FIELD OF THE INVENTION
The present invention provides for 8-hydroxy-7-substituted quinoline compounds and pharmaceutically acceptable salts thereof which are useful as antiviral agents. The invention also relates to a pharmaceutical composition containing such compound in combination with a suitable excipient, the composition being useful in combating viral infections. The invention also relates to a method for selectively combating viral infections in animals, including man. Specifically, these compounds have anti-viral activity against the herpes virus, cytomegalovirus (CMV). Many of these compounds are also active against other herpes viruses, such as the varicella zoster virus, the Epstein-Barr virus, the herpes simplex virus, and the human herpes virus type 8 (HHV-8).
BACKGROUND OF THE INVENTION
The herpesviruses comprise a large family of double stranded DNA viruses. The herpesvirus family can be divided into three subfamilies (&agr;, &bgr;, &ggr;) based upon a number of biological properties such as host range and tropism, viral life cycle, and viral persistence and latency. Eight of the herpesviruses, herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), varicella zoster virus (VZV), human cytomegalovirus (HCMV), Epstein-Barr virus (EBV), and human herpes viruses 6, 7, and 8 (HHV-6, HHV-7, and HHV-8), have been shown to infect humans.
HSV-1 and HSV-2 are the prototypic &agr;-herpesviruses. These two serotypes share approximately 50% nucleotide homology. Both are neurotropic viruses, but their primary sites of replication are different. HSV-1 typically infects the oral mucosa resulting in ulcerations commonly referred to as cold sores. HSV-2 infects and causes ulcerations of the genital mucosa. HSV infection can also result in disseminated disease and encephalitis, especially in immunocompromised patients. D. O. White and F. J. Fenner, In Medical Virology, D. O. White and F. J. Fenner, eds., Academic Press, p. 318-347 (1994).
VZV is also an &agr;-herpesvirus and is the causitive agent of chicken pox. VZV establishes a latent infection in the dorsal root ganglia of the peripheral nervous system. From its latent site, VZV can cause recurrent disease commonly referred to as shingles or zoster. The probability of shingles increases with age and frequently occurs in immunocompromised patients. A. M. Arvin, In Virology, B. N. Field, D. M. Knipe, and P. M. Howley, ed., Lippincott-Raven Press, New York, p. 2547-2586 (1996).
Human cytomegalovirus (HCMV), a &bgr;-herpesvirus, is an ubiquitous agent producing infection in individuals of all age groups. Infection rates of 60-100%, depending on geographic area and socioeconomic status have been reported. R. J. Whitley, S. Goldsmith and J. Gnann, In Society for General Microbiology. 45th Symposium: Control of Virus Diseases, Mimmock, N.J.; P. D. Griffiths and C. R. Madely, eds., Cambridge University Press, Cambridge, p. 315 (1990). The majority of infections are asymptomatic. However infections occuring in the immunocompromised patient, including organ transplant recipients and individuals with AIDS may be severe and include HCMV induced pneumonia, colitis, and retinitis. L. W. Drew, Clin. Infect. Dis. 14:608-615 (1992). HCMV is the leading cause of blindness in AIDS patients. T. C. Merigan and S. Resta, Rev. Infect. Dis.12: S693 (1990). HCMV also establishes lifelong latency in the host.
HCMV DNA polymerase (HCMV pol) is an enzyme essential for viral replication. D. H. Spector, K. M. Klucher, D. K. Rabert and D. A. Wright, In Herpesvirus Transcription and Its Regulation, E. K. Wagner, ed., CRC Press, Boca Raton, Fla., p. 261 (1991). The current therapies for HCMV; Ganciclovir, Foscarnet and Vistide act by inhibition of HCMV pol. A. K. Field and K. K. Biron, Clin. Micro. Reviews 7:(1) 1-13 (1994). See also U.S. Pat. Nos. 4,199,574; 4,215,113; 4,355,032; and E. DeClercq et al., Antiviral Research, Vol 8, pages 261-272 (1987). Ganciclovir and Foscarnet display significant toxicity and induction therapy is restricted to an intravenous route of administration. D. Faulds and R. C. Heel, Drugs, 39:597 (1990). Maintenance therapy with Ganciclovir and Foscarnet will likely contribute to drug resistant virus. A. K. Field and K. K. Biron, Clin. Micro. Reviews 7:(1) 1-13 (1994). Clearly less toxic, orally bioavailable alternatives are needed.
EBV is a &ggr;-herpesvirus which replicates in the epithelial cells of the nasopharynx and salivary glands and resides latently in B-cells. Childhood infections of EBV are normally asymptomatic. However, EBV infection is associated with several diseases in adults such as infectious mononucleosis, Burkitt's lymphoma, nasopharyngeal carcinoma, and Hodgkins disease. A. B. Rickinson and E. Kieff, In Virology, B. N. Fields, D. M. Knipe, and P. M. Howley, eds., Lippincott-Raven Press, New York, p. 2397-2446 (1996).
HHV-6 is a &bgr;-herpesvirus which causes roseola (exanthem subitum) in children. P. Lusso, Antivir. Res. 31:1-21 (1996). HHV-7 shares 50-60% nucleotide sequence homology with HHV-6. It's disease association is unclear, but it may be involved in some cases of roseola. N. Frenkel and E. Roffman, In Virology, B. N. Fields, D. M. Knipe, P. M. Howley, eds., Lippincott-Raven Press, New York, p. 2609-2622 (1996). HHV-8, also known as Kaposi's sarcoma associated herpesvirus (KSHV), is a &ggr;-herpesvirus which has recently been associated with Kaposi's sarcoma in AIDS patients and multiple myeloma. M. B. Rettig et al., Science, 276:1851-1854 (1997).
INFORMATION DISCLOSURE
Published Japanese patent application H1-136152 published May 29, 1989 discloses a silver halide photographic light-sensitive material comprising a support, and thereon, at least 1 silver halide emulsion layer containing a cyan dye-forming coupler represented by a broad generic formula. This broad generic formula includes 8-hydroxy-quinoline derivatives substituted by a wide variety of substituents, e.g., substituted carboxamide groups at the 7-position. None of the specific compounds disclosed in this reference are structurally similar to the compounds of the present invention. Also, the compounds of the present invention are useful as pharmaceutical agents, specifically HCMV inhibitors, whereas the reference compounds are useful in color photography.
Published Japanese patent application HEI 3-73949 published Mar. 28, 1991 discloses a thermally developable color light-sensitive material comprising at least a light-sensitive silver halide, a reducing agent, a binder, and a coupler represented by a first generic formula and/or a second generic formula on a support. These broad generic formulas include 8-hydroxy-quinoline derivatives substituted by a wide variety of substituents, e.g., substituted carboxamide groups at the 7-position. As noted for the previous Japanese reference, none of the specific compounds disclosed in this reference are structurally similar to the compounds of the present invention. Also, the compounds of the present invention are useful as pharmaceutical agents, specifically HCMV inhibitors, whereas the reference compounds are useful in color photography.
Published Japanese patent application 02152966 A2 discloses 4-hydroxy-carbostyryl derivatives as anti-allergy and antiinflammatory agents. The compounds of the present invention are 1-(N-unsubstituted)-8-hydroxy-7-quinolinecarboxamides.
U.S. Pat. No. 4,959,363 discloses 1-(N-substituted)-1,4-dihydro-4-oxo-6- and/or -7-substituted-3-quinolinecarboxamides as antiviral agents. The compounds of the present invention are 1-(N-unsubstituted)-8-hydroxy-7-quinolinecarboxamides.
U.S. Pat. Nos. 5,459,146 and 5,506,236 disclose 4-substituted-3-alkyl-pyrazolo[3,4-b]quinoline compounds as antiviral agents. Basically, these compounds are the tricyclic version of compounds such as those disclosed in the '363 patent above, and are structurally very different from the compounds of the present invention.
U.S. Pat. No. 5,378,694 discloses compounds such as 1-(N-substituted)-3-substituted-4-hydroxy-2-quinolinones, and generically, 3-substituted-4-hydro

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