Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-12-27
2004-11-23
Lambkin, Deborah C. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S101000
Reexamination Certificate
active
06821969
ABSTRACT:
FIELD OF THE INVENTION
The present invention provides thioxazinoquinolone derivatives having a ring connecting position 4 (N-4) and position 11 (C-11), and more specifically, provides compounds of formula (I) described herein below. These compounds are useful as antiviral agents, in particular, as agents against viruses of the herpes family.
BACKGROUND OF THE INVENTION
The herpesviruses comprise a large family of double stranded DNA viruses. They are also a source of the most common viral illnesses in man. Eight of the herpes viruses, 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 cause herpetic lesions on the lips and genitals, respectively. They also occasionally cause infections of the eye and encephalitis. HCMV causes birth defects in infants and a variety of diseases in immunocompromised patients such as retinitis, pneumonia, and gastrointestinal disease. VZV is the causative agent of chicken pox and shingles. EBV causes infectious mononucleosis. It can also cause lymphomas in immunocompromised patients and has been associated with Burkitt's lymphoma, nasopharyngeal carcinoma, and Hodgkin's disease. HHV-6 is the causative agent of roseola and may be associated with multiple sclerosis and chronic fatigue syndrome. HHV-7 disease association is unclear, but it may be involved in some cases of roseola. HHV-8 has been associated with Karposi's sarcoma, body cavity based lymphomas, and multiple myeloma.
Due to the unique position of the chloro substitutent on the N-phenylmethyl of formula I described herein below, compounds of the present invention demonstrate unexpected activity against the above reference herpesviral infections, particularly, human cytomegaloviral infection.
INFORMATION DISCLOSURE
U.S. Pat. No. 5,792,774 discloses oxazino 1,4-dihydro-4-oxoquinolines useful for the treatment of a large number of diseases modulated by tissue necrosis factor (TNF) or phosphodiesterase IV, including cytomegalovirus (CMV) infections.
U.S. Pat. No. 4,847,373 discloses 1,8-bridged 4-quinoline-3-carboxylic acids useful as antibacterial agents.
U.S. Pat. No. 5,583,135 discloses heterotricyclic derivatives having a strong immunomodulating activity, anti-inflammatory activity and anti-cancer activity.
The abstract of Japanese Patent JP 10324631-A discloses IgE antibody production inhibitor comprise a pyrido(1,2,3-de 1, 4-benzoxazine or a pyrido (1,2,3,-de)-1,4-benzothiazine derivative.
PCT patent application, PCT/US00/21985 discloses oxazinoquinolones useful for the treatment of viral infections.
SUMMARY OF THE INVENTION
The present invention provides a compound of formula I,
wherein R
1
is C
1-6
alkyl, optionally substituted with —OH, —OC
1-4
alkyl or het;
wherein C
1-6
alkyl is optionally partially unsaturated;
wherein het is a radical of a five- or six-membered heterocyclic ring having one or two heteroatoms selected from the group consisting of oxygen, sulfur and N; or a pharmaceutically acceptable salt, racemate, solvate, tautomer, optical isomer or prodrug derivative thereof.
In another aspect, the present invention also provides:
a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier (the composition preferably comprises an effective antiviral amount of the compound or salt),
a method of treating or preventing a herpesviral infection, comprising administering to a mammal (e.g. a human) in need of such treatment, a compound of formula (I) or a pharmaceutically acceptable salt thereof,
a method for inhibiting a viral DNA polymerase, comprising contacting the polymerase with an effective inhibitory amount of a compound of claim
1
, or a pharmaceutically acceptable salt thereof,
a compound of formula I or a pharmaceutically acceptable salt thereof for use in medical treatment or prevention of a herpesviral infection in a mammal.
The invention also provides novel intermediates and processes disclosed herein that are useful for preparing compounds of formula I.
The invention also provides novel intermediates of formula II,
wherein X is O or S; and R
2
is optionally partially unsaturated C
1-6
alkyl substituted with O-TIPS.
The invention further provides processes disclosed herein that are useful for preparing compounds of formula I.
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Wentland et al, “3-Quinolinecarboxamides. A Series of Novel Orally-Active Antiherpetic Agents,” Journal of Medicinal Chemistry, American Chemical Society, Washington, DC, vol. 36, No. 11, 1993, pp. 1580-1596.
Vaillancourt, VA et al, “Naphthalene Carboxamides as Inhibitors of Human Cytomegalovirus DNA Polymerase,” Bioorganic & Medicinal Chemistry Letters 10 (2000), pp. 2079-2081.
Lambkin Deborah C.
Pharmacia & UpJohn Company
Richardson Peter C.
Yang Lucy
Zielinski Bryan C.
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