Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1994-08-29
1996-11-05
Kunz, Gary L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
536 255, A61K 3170, C07H 19167
Patent
active
055717993
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
Novel (2'-5')oligoadenylate analogues have been synthesized by the phosphotriester method, specifically adenylyl (2'-5')adenylyl (2'-5')-9-(2,3-anhydro-.beta.-D-lyxofuranosyl)adenine disodium salts [(2'-5')A.sub.2 A.sup.l-epoxy ], and adenylyl (2'-5')adenylyl (2'-5')-9-(2,3-anhydro-.beta.-D-ribofuranosyl)adenine disodium salts [(2'-5')A.sub.2 A.sub.r-epoxy ]. Their action is directed to the modulation of both the helper and killer T-lymphocyte cells of the immune system. Unlike the commonly used cyclosporine, inhibitory action of (2'-5')oligoadenylate analogues does not suppress the anti-bacterial and anti-viral defense mechanism of the host. This compensatory effect on the immune system is accompanied by the appearance of increased amounts of .alpha.-interferon and .gamma.-interferon in the lymphocytes, an elevated level of phagocytosis along with a decrease of .alpha.-interferon in blood plasma and a decrease of interleukin-II in lymphocytes. The invention is useful in appropriate concentrations to suppress the division of T-helper and T-killer cells and is useful to treat diseases connected with the disturbance of T-cellular immunity, e.g., autoimmune diseases, viral diseases, lymphocytic tumor and organ transplant rejection.
STATE OF THE PRIOR ART
In connection with the dissemination and recognition of autoimmune diseases and the introduction of organ and tissue transplantation a dire need arose for novel, non-toxic, immunosuppressive drugs.
Presently, various cyclopeptides, steroids and antimetabolites are used as immunosuppressants, primary among them being cyclosporine.
The goal when using any immunosuppressive drug in organ and tissue transplantation is to achieve an effective prevention of the acute and chronic transplant rejection (host-vs.-graft rejection), while keeping infections and other side effects to a minimum. The latter result from the high toxicity of the three types of immunosuppressors mentioned above.
The (2'-5')oligoadenylate [(2'-5']A.sub.3 ], proposed by Kimchi et al., 1983, U.S. Pat. No. 4,378,352, as an immunesuppressor, inhibits the in vitro blast-transformation of T-lymphocytes, but when applied in vivo, it did not suppress the number of T-helper and T-killer cells, the principal targets of the post-transplantation immunosuppressors.
The rapid hydrolysis of 2'-5'A.sub.3 by phosphodiesterase may explain the absence of its in vivo immunosuppressive action.
Analogues of (2'-5')oligoadenylate modified in 2' and 3' positions of the ribose fragment, which are key positions for the recognition necessary for the phosphodiesterase splitting, do not break down in vivo and thus are capable of manifesting their immunosuppressive property to the fullest.
In vitro administration of analogues of (2'-5')oligoadenylates have been shown to suppress the biosynthesis of DNA, RNA, and proteins (Kerr et al., G. B. No. 2,002,773, 3/1979, Johnston, Torrence, 1984).sup.1, show antiviral activity (Suhadolnik et al., U.S. Pat. No. 4,464,359, 8/1984, Montefiori, Sobol, Wu et al , 1989).sup.2, affect the natural killer activity (Black, Henderson, Pfleiderer et al., 1984), act as antimitogens (Eppstein, Schryver, Marsh, et al., 1983).sup.3 and as mediators of the action of interferon (Imbach J. et al., U.S. Pat. No. 4,476,301 10/1984). proteins, double-stranded RNA and (2'-5')oligoadenylate in the interferon-mediated inhibition of viral translation. Interferon; Mechanisms of production and action. Ed. R. M. Friedman--Amsterdam: Elsevier Scientific Publ. Co.-1984.-3.-p.189-298. core (2'-5')oligoadenylate exerts its antimitogenic effect through mechanisms different from the (2'-5') A-dependent endonuclease. J. Interferon Res.-1983, N 3.-p. 305-311. of human immunodeficiency virus type 1 reverse transcriptase and infection in vitro. Proc. Nat. Acad. Sci. USA.-1989.86, N 18.-C., p. 7191-7194.
SUMMARY OF THE INVENTION
One of the biochemical reactions initiated by interferon is the induction of (2'-5')oligoadenylate synthetase, which, due to the presence of double helical RNA polym
REFERENCES:
patent: 4378352 (1983-03-01), Kimchi et al.
patent: 4464359 (1984-08-01), Suhadolnik et al.
patent: 4515781 (1985-05-01), Torrence et al.
patent: 4539313 (1985-09-01), Suhadolnik et al.
patent: 4708935 (1987-11-01), Suhadolnik et al.
patent: 4859768 (1989-08-01), Suhadolnik et al.
patent: 4924624 (1990-05-01), Suhadolnik et al.
patent: 4990498 (1991-02-01), Suhadolnik
Kvasyuk Eugeny
Matsuka Gennady
Mikhailopulo Igor
Tkachuk Zenovy
Basco, Ltd.
Kunz Gary L.
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