Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-03-26
1997-09-23
Carr, Deborah D.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514885, A01N 4342
Patent
active
056705204
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to a method for inhibiting nucleoside and nucleobase transport in mammalian cells, as well as to a method for inhibition of virus replication, and augmenting phosphorylation of nucleoside analogues, wherein each method uses, as the active agent, a carbostyril derivative.
BACKGROUND OF THE INVENTION
I. Carbostyrils
Carbostyril derivatives represented by the following general formula (1), and salts thereof: ##STR1## wherein R is a benzoyl group which may optionally have lower alkoxy groups on the phenyl ring as substituents and the carbon-carbon bond in the 3 and 4 positions of the carbostyril skeleton is a single bond or double bond, by reference herein in its entirety).
These carbostyrils have been found to be an oral inotropic agent that augments myocardial contractility in model systems, with little effect on the heart rate or myocardial oxygen consumption (Feldman et al, N. Engl. J. Med., 329:149-155 (1993)), and are useful for treatment of patients with congestive heart failure (U.S. Pat. No. 4,415,572; and Hori et al, Jpn Circ. J., 50:659-666 (1986)). Several studies have demonstrated that the above carbostyrils improve hemodynamic indexes, and exercise capacity in congestive heart failure patients (Inoue et al, Heart Vessels, 2:166-171 (1986); Sasayama et al, Heart Vessels, 2:23-28 (1986); and Feldman et al, Am. Heart J., 116:771-777 (1988)). In addition, multi-center randomized placebo-controlled trials both in Japan and in the United States have demonstrated that these carbostyrils improve both quality of life and reduced the risk of death in patients with congestive heart failure (OPC-8212 Multicenter Research Group, Cardiovasc. Drugs Ther., 4:419-425 (1990); Feldman et al, Am. J. Cardiol., 68:1203-1210 (1991); and Feldman et al, N. Engl. J. Med., 329:149-155 (1993)).
The mechanisms of action associated with the inotropic properties of these carbostyrils include a decrease in potassium current (Iijima et al, J. Pharmacol. Exp. Ther., 240:657-662 (1987)), a mild inhibition of phosphodiesterase, and an increase in the inward calcium current (Yatani et al, J. Cardiovasc. Pharmacol., 13:812-819 (1989); and Taira et al, Arzneimittelforschung, 34:347-355 (1984)). However, the dose of the carbostyrils which was most effective in reducing mortality (60 mg daily) showed no or little hemodynamic effect, implying that the drug may reduce mortality through another mechanism, rather than its positive inotropic effect (Feldman et al, N. Eng. J. Med., 329:149-155 (1993); and Packer, N. Engl. J. Med., 329:201-202 (1993)).
The above carbostyrils are also known to inhibit the production of various cytokines, including TNF-.alpha. and IL-6, by lipopolysaccharide-stimulated peripheral blood mononuclear cells (PBMC) in a dose-dependent manner (Maruyama et al, Biochem. Biophys. Res. Commu., 195:1264-1271 (1993); and Matsumori et al, Circul., 89:955-958 (1994)).
Moreover, they can induce a reversible neutropenia associated with a decrease in CFU-C (Feldman et al, Am. Heart J., 116:771-777 (1988); OPC-8212 Multicenter Research Group, Cardiovasc. Drugs, Ther., 4:419-425 (1990); Feldman et al, Am. J. Cardiol., 68:1203-1210 (1991); and Feldman et al, N. Engl. J. Med., 329:149-155 (1993)).
Additionally, the above carbostyrils have been found to be useful in regulating apoptosis (programmed cell, death), and in the treatment of cancer, inhibition of tumor metastasis and inhibition of RNA virus replication (U.S. patent application Ser. No. 07/989,028, filed Apr. 30, 1993, which corresponds to European Patent Publication 0552373, each of which is incorporated by reference herein in their entirety; Nakai et al, Jpn. J. Cancer Res., Abstract, and Proc. Jpn. Cancer Assoc., page 581 (1993); and Maruyama et al, Biochem. Biophys. Res. Comm., 195:1264-1271 (1993)).
It has been surprising to find in the present invention that these carbostyrils, particularly the species (hereinafter "vesnarinone"), inhibit nucleoside and nucleobase transport in mammalian cells, as the structur
REFERENCES:
patent: 4415572 (1983-11-01), Tominaga et al.
Matsumori et al, "Vesnarinone, a New Inotropic Agent, Inhibits Cytokine Production by Stimulated, Human Blood From Patients With Heart Failure", Circulation, 89(3):955-958 (1994).
Shioi et al, "Inhibition of Cytokine Production by a New Inotropic Agent, Vesnarinone, In Human Lymphocytes, T Cell Line, and Monocytic Cell line", Life Sciences, 54:11-16 (1994).
Meyerhans et al, "Restriction and Enhancement of Human Immunodeficiency Virus Type 1 Replication by Modulation of Intracellular Deoxynucleoside Triphosphate Pools", J. Virol., 68(1):535-540 (1994).
O'Brien et al, "Kinetics of Human Immunodeficiency Virus Type 1 Reverse Transcription in Blood Mononuclear Phagocytes are Slowed by Limitations of Nucleotide Precursors", J. Virol., 68(2):1258-1263 (1994).
Gao et al, "Low levels of Deoxynucleotides in Peripheral Blood Lymphocytes: A Strategy to Inhibit Human Immunodeficiency Virus Type 1 Replication", Proc. Natl. Acad. Sci. USA, 90:8925-8928 (1993).
Maruyama et al, "Vesnarinone Inhibits Production of HIV-1 in Cultured Cells", Biochemical and Biophysical Research Communications, 195(3):1264-1271 (1993).
Datta et al, "Acyclovir Inhibition of Epstein-Barr Virus Replication", Proc. Natl. Acad. Sci. USA, 77(9):5163-5166 (1980).
Sasayama et al, "Acute Hemodynamic Effects of a New Inotropic Agent, OPC-8212, On Severe Congestive Heart Failure", Heart and Vessels, 2(1):23-28 (1986).
Lueprasitsukul et al, "Effect of the Cardiac Inotropic Drug, OPC 8212, on Pituitary-Thyroid Function in the Rat", Endocrinology, 128(6):2709-2714 (1991).
Berkow, Editor-in-Chief, "The Merck Manual of Diagnosis and Therapy", 15th Edition, Merck Sharp & Dohme Research Laboratories, Rahway, N.J., pp. 1043-1050 (1987).
Bush et al, "Effect of OPC-8212, A New Positive Intropic Agent, on the Hemopoietic System In Vitro", Experimental Hematology, 19(6):490 (1991).
Nakai et al, "Differentiation-Inducing Activity of (vesnarinone) Against Tumor Leukemia and Solid Tumor Cells," Biomedicine & Pharmacotherapy, 46(5-7):308 (1992).
Miller, "Epstein-Barr Virus: Biology, Pathogenesis, and Medical Aspects", Virology, 2nd Edition, Chaptter 68, pp. 1921-1958 (1990).
International Search Report.
Gelfand Erwin W.
Terada Naohiro
Carr Deborah D.
Otsuka Pharmaceutical Co. Ltd.
LandOfFree
Method for inhibiting virus replication in mammalian cells using does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Method for inhibiting virus replication in mammalian cells using, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Method for inhibiting virus replication in mammalian cells using will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-1938779