Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Patent
1996-07-26
1999-03-09
Rotman, Alan L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
514571, 5253276, 5253277, C08F 2206, C08F 2216, A61K 31195, A61K 3119
Patent
active
058801545
DESCRIPTION:
BRIEF SUMMARY
CROSS-REFERENCE
This application is a .sctn.371 of PCT/US94/00138 filed Feb. 1, 1994.
BACKGROUND OF THE INVENTION
formula: ##STR1## As can be seen from the structure, each of the carbon atoms is a member of at least two of the four-ring systems, all of which are equivalent. Consequently this structure is exceptionally rigid and allows virtually no movement of the individual atoms. This feature and the symmetry of the molecule are responsible for a great extent of unusual physical and chemical properties exhibited by adamantane.
First uses of this compound included modifications with an amino group !decan-1-amine). Amantadine was shown to have utility as an anti-viral agent against certain strains of influenza A virus. Other amino-substituted derivatives have included amantadine hydrochloride(1-adamantanamine hydrochloride) inhibitors of influenza virus replication in cell culture and influenza infection in humans (Hay, A. G. et al (1985) Molecular basis of the specific anti influenza action of amantadine. EMBO J4:3021-3024. Other related derivatives of amantadine have also been developed. See generally U.S. Pat. No. 4,661,512, adamantanamine derivatives, processes for the preparation and drugs in which they are present. These amino-substituted derivatives have generally been touted for use as anti-viral agents against various strains of influenza A virus.
To date very little has been investigated for the base compound, non-amine substituted adamantane, as an antiviral agent. There is always a need for development of antiviral substances which may be administered safely without toxic side effects. With the advent of the viral disease Acquired Immune Deficiency Syndrome (AIDS) the need only increases further.
It is an object of the present invention to provide novel polymeric adamantane analogues which have been shown to have potent anti-viral activity against Human Immunodeficiency Virus-1 (HIV-1), processes for their preparation and drugs in which they are present.
SUMMARY OF THE INVENTION
This invention relates to new adamantane analogues and to polymeric adamantane analogues modified to specifically direct the compound to the plasma membrane of host cells, comprising a non-toxic water soluble anionogenic polymer carrier and an adamantane derivative chemically linked to the carrier by use of a spacer group. The compounds of the present invention were shown to inhibit HIV 1 infection in lymphoblastoid cells. Methods for synthesis are also disclosed.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a graph demonstrating inhibition of HIV-1 replication in MT4 cells by AS342 measured by optical density of samples in ELISA. HIV-1 infected cells were treated just after infection with increasing concentrations of AS342. Forty-eight hours after infection, p24 antigen production was measured in supernatents by a p24 capture assay.
FIG. 2 is a graph demonstrating Inhibition of HIV-1 as in FIG. 1, as measured by percent of virus inhibition by increasing concentrations of the drug.
FIG. 3 is a photograph demonstrating the effect of the drugs on viral replication as revealed by immunoblotting. The cells were treated with either AS342, AS343 or the drug carrier just after virus adsorption. Forty-eight hours after infection, cell lysates were obtained by ultrasonic treatment of the cells. The proteins were resolved by 10% SDS-polyacrylamide gel electrophoresis and detected by immunoblotting using seropositive sera and monoclonal antibody against p24 (7-9).
3. lanes 1,4,7--untreated cells; lanes 2,3,5,6--cells treated with 200 (lanes 2,5) and 400 .mu.g ml.sup.-1 (lanes 3,6) of 342 and 343, respectively; lanes 8,9--cells treated with 200 and 400 .mu.g ml.sup.-1 of 342, respectively.
FIG. 4 is a photograph demonstrating the antiviral effect after cell pretreatment with drugs. The cells were pretreated with compounds 342, 337 and 336, adamantane component or the carrier two hours before virus adsorption. Forty-eight hours after infection, the proteins in cell lysates were detected by immunoblotting using seropositive s
REFERENCES:
patent: 2937211 (1960-05-01), Ludwig
patent: 3152180 (1964-10-01), Haaf
patent: 3974128 (1976-08-01), Block et al.
patent: 4309413 (1982-01-01), Fields et al.
patent: 4661512 (1987-04-01), Laurelle et al.
patent: 4980371 (1990-12-01), Parker et al.
patent: 4992427 (1991-02-01), Nair
Chemical Abstracts, vol. 113(12),abst.No. 106, 502g,published Sep. 17, 1990.
Chemical Abstracts, vol. 113(14),abst.No. 117, 183e,published Oct. 1, 1990.
Chemical Abstracts, vol. 114,(60abst.No. 52,635c, published Feb. 11, 1991.
Rytik, P., 1991, Susceptibility of Primary Human Glial Fibrillary Acidic Protein-Positive Brain Cells To Human Immunodeficiency Virus Infection in vitro: Anti-HIV Activity of Memantine, Aids Research and Human Retroviruses, 7(1):89-95, Mary Ann Liebert, Inc., Publishers.
Alymova Irina V.
Bogdan Olga P.
Boukrinskaia Alissa G.
Klimochkin Yurii N.
Serbin Alexander V.
Rotman Alan L.
The Board of Regents of the University of Nebraska
LandOfFree
Polymeric adamantane analogues does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Polymeric adamantane analogues, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Polymeric adamantane analogues will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-1321558