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WO1993003733A1 - Synthese, composition pharmaceutique et procede d'application d'analogues de (2'-5') oligoadenylate - Google Patents

Synthese, composition pharmaceutique et procede d'application d'analogues de (2'-5') oligoadenylate Download PDF

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Publication number
WO1993003733A1
WO1993003733A1 PCT/US1991/005734 US9105734W WO9303733A1 WO 1993003733 A1 WO1993003733 A1 WO 1993003733A1 US 9105734 W US9105734 W US 9105734W WO 9303733 A1 WO9303733 A1 WO 9303733A1
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treatment
mammal
need
effective amount
administering
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PCT/US1991/005734
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English (en)
Inventor
Zenovy Tkachuk
Eugeny Kvasyuk
Gennady Matsuka
Igor Mikhailopulo
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Basco, Ltd.
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Application filed by Basco, Ltd. filed Critical Basco, Ltd.
Priority to US08/185,795 priority Critical patent/US5571799A/en
Priority to PCT/US1991/005734 priority patent/WO1993003733A1/fr
Publication of WO1993003733A1 publication Critical patent/WO1993003733A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids

Definitions

  • Novel (2'-5')oligoadenylate analogues have been synthesized by the phosphotriester method, specifically adenylyl (2' -5' Jadenyl (2' -5' )-9-(2,3-anhydro- ⁇ -D-lyxoribofuranosyl adenine disodium salts (2'-5' lyxoA3), and adenylyl(2'-5')adenyl (2'-5')-9-(2,3-anhydro- ⁇ -D-epoxyribofuranosyl adenine disodium) salts (2'-5' epoxyA3) .
  • Their action is directed to the modulation of both the helper and killer T-lymphocyte cells of the immune system.
  • 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 ⁇ - interferon and 7-interferon in the lymphocytes, an elevated level of phagocytosis along with a decrease of ⁇ -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.
  • 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'A3) proposed byKimchi et al., 1983, U.S.Patent No. 4,378,352, as an immunosuppressor, 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.
  • 2'-5'A converts to 5'- diphosphorylated "core" (2'-5')oligonucleotides (2'-5'An) .
  • These compounds exhibit a wide spectrum of biological effects: they inhibit the biosynthesis of DNA, RNA, and proteins (Johnston, Torrence, 1984) 4 , they exhibit antimitogenic effect (Eppstein, Schryver, Marsh, et al., 1984) 5 and affect the activity of natural killer cells (Black, Henderson, Pfleiderer et al., 1984) 6 .
  • 2'-5'A3 analogues which include well- known antimetabolites 9-( ⁇ -D-xylofuranosyl) adenine (2'-5' xyloA3) and 3'-desoxyadenosine (2'-5'-3'dA3) in their structure, it has shown that they are active against the Type I and II herpes virus. Under the influence of cellular phosphodiesterase, the trimers are hydrolyzed to the respective nucleoside-5'- monophosphates and nucleosides with their characteristic activity (Eppstein, Marsh, Schryver, 1983) 8 .
  • (2'-5')oligoadenylate analogues relates to their biological activity. They break down slowly under the influence of phosphodiesterase and maintain a long duration of activity in respect to T-lymphocytes (about 2 weeks) . They are easily synthesized in large quantities using readily available synthetic chemical technique 12 .
  • This activity relates particularly to the treatment of diseases related to disturbance of T-cellular immunity: the autoimmune disorders, viral diseases, lymphocytic tumors and post-transplantation patients.
  • Figure 1 is a schematic diagram for the synthesis of 2'-5' epoxyA3.
  • Figure 2 is a schemtaic diagram for the wynthesis of 2'-5' lyxoA3.
  • the 2'-5'A3 analogues act highly specifically.
  • the data obtained allow the assumption that one of the analogues, (2'-5') oligoepoxyribo- furanosyladenylate (2'-5' epoxyA3) , suppresses selectively the proliferation of activated T-lymphocytes evoked by interleukin- II.
  • Suppressing production of interleukin-II with T-helper lymphocytes, 2'-5' epoxyA3 suppresses formation of T-killer cells.
  • the 2'-5' epoxyA3 stimulates somewhat the number of T-suppressors which assures the tolerance of the host immune system towards the allotransplant.
  • 2'-5' epoxyA3 does not suppress the production of 7-interferon.
  • 2'-5' epoxyA3 supports high anti-viral and anti ⁇ microbial status of the patients after transplantation.
  • 2'-5' epoxyA3 stimulates, in a compensatory fashion, the antiviral and antimicrobial functional mechanisms of the immune system protecting the weakened organism from infection during the post- transplantation period.
  • 2'-5'A3 did not show that (2'-5')A3 at concentrations proposed by Kimchi et al., 1980, showed no immunosuppressive activity; in fact it stimulated the number of T-killers and T-helpers in monkeys by 50% after IV injection for four days.
  • the optimal concentration of 2'-5' epoxyA3 is in the range of 5-50 ⁇ g/kg body weight of the experimental animal. Depending on the administration frequency, this value may range from 0.01 to 1000 ⁇ g/kg body weight.
  • the best criterion for the selection of the dose and administration schedule should be based on clinical indices: first of all the number of T-killer and T-helper cells which should not rise and could fall only within 50% of the normal level during the first 2-3 post-transplantation weeks, while staying at the lower limit of the normal reading during the post-transplantation period.
  • 2'-5' epoxyA3 is recommended as an immunosuppressor for transplantation of kidneys, heart, lungs, bone marrow and other organs. 2'-5' epoxyA3 may be used in rescue treatment of transplant rejection. It could also be used for prophylaxis of transplant rejection after bone marrow transplantation and in treatment of the graft vs. host disease.
  • a mixture of 80 g (3.21 mM) of nucleoside I* (see Table I) in 12 mf of hexamethyldisilazane (HMDS) and 10 mg of ammonium chloride is boiled for 2 hours until complete dissolution of the compound.
  • the reaction mixture is evaporated, the residue is dissolved in 5 mu of pyridine, the solution is cooled to 0°C and 0.78 ml? (0.95 g; 6.74 mM) of benzoyl chloride is added to it. Twenty hours later, 5 m£ of 10% aqueous ammonia solution is added to the reaction mixture and 7 minutes later the solution is evaporated.
  • trimer VII The total yield of trimer VII, calculating on the basis of adenosine, used for obtaining the anhydro derivative II, is equal to 50.5%. Moreover, the presence of only one benzoyl group in 6-N-position of the compound II has a positive effect on its stability, which leads, ultimately, to higher yield of the end product.
  • 0.40 ir? (3.17mM) of trimethylchlorosilane was added to the solution of 0.10 g (0.40 mM) of nucleoside l in 2.8 ml of pyridine and the reaction mixture was stirred for 4 hours. Then the mixture was cooled to 0°C, 0.11 g (0.09 mf; 0.80 mM) of benzoyl chloride was added, and the reaction mixture was allowed to warm to room temperature with stirring for 40 minutes, after which it was cooled to 0°C, 0.6 ml of water was added, followed 5 minutes later by 0.8 ml of 25% aqueous ammonia solution.
  • Trinucleoside diphosphate VI was obtained by condensation of 79 mg (0.076 mM) of dimmer V and 114 mg (0.106 mM) of diether III in the presence of 64 mg (0.212 mM) of triisopropylbenzene chlorosulfide and of 45 mg (0.636 mM) of tetrazole followed by treatment of the reaction mixture, as it was described for obtaining the compound IV.
  • Trinucleoside diphosphate VI was dissolved in 8.5 ml of 2% p-TsOH solution in 7:3 mixture of methylene chloride-methanol.
  • UV-spectrum in water ⁇ max. , nm (lg E) : 260 (4.54).
  • the spot corresponding to the initial trimer, was cut out, the substance was extracted with 2 ml of 0.5% solution of the dodecylsulfate sodium salt solution for 2 hours, and the optical density of the solution was determined at 260 nm. The time during which the optical density of the solution of the initial compound decreased by 50% was determined.
  • T% for 2'-5'A3 was shown to be 27 minutes, for 2'-5' lyxoA3 it was 10.5 hours and for 2'-5' epoxyA3 it was 16.0 hours.
  • the experiments have shown that 2'-5'A3 was extremely sensitive to the action of phosphodiesterase while its analogues 2'-5' epoxyA3 and 2'-5' lyxoA3 were significantly more resistant towards hydrolysis by phosphodiesterase. This demonstrates that these analogues are more resistant to metabolism within an organism wherein phosphodiesterase is present.
  • lymphocytes The immune reactions in an organism begins with the division of lymphocytes.
  • lymphocyte blast-transformation reaction under the influence of mitogens makes it possible to use this model system to select chemically synthesized 2'-5'A3 analogues which suppress division of lymphocytes.
  • Concanavalin A and lipopolysaccharide as mitogens, the effect of analogues on the division of T- and ⁇ - lymphocytes may be investigated.
  • a suspension of mouse splenocytes were obtained by gently teasing spleens with forceps.
  • Lymphocytes cultivated in flat-bottomed 96-well plates (Linbro) in RPMI-1640 medium (Flow Lab.) were supplemented with 2 mM 1-glutamine, 10 ⁇ g/ml gentamicin, 10 "5 M 2-mercaptoethanol and 10% heat inactivated fetal calf serum (Flow Lab) .
  • Cultures were maintained in 5% C0 2 at 37°C.
  • One ⁇ Ci of 3 H-thymidine (Isotop ® ) was added to each well 4 hours before the end of the incubation period. Incorporation of 3 H-thymidine into cellular DNA was determined by liquid scintillation counting using standard techniques. Oligoadenylate was added to the medium at the beginning of culturing to achieve the final concentration.
  • Con A Con A
  • LPS lipopolysaccharide
  • Tables 3, 4, and 5 show the different actions of the three investigated preparations.
  • the parent 2'-5'A3 suppresses the division of ⁇ -lymphocytes more effectively, while the 2'-5' epoxyA3 suppresses the T-lymphocyte division to a greater extent, but shows a weaker effect of the division of ⁇ - lymphocytes.
  • the reaction shows a concentration dependence
  • Immunosuppressive activity of the prototype 2'-5'A3 and two analogues 2'-5' epoxyA3 and 2'-5' lyxoA3 were investigated in monkeys. The experiments were performed on 4 year-old Macaque Rh. monkeys. The levels of the principal subpopulations of T-lymphocytes, IgA, IgG, IgM and the amount of ⁇ - and ⁇ - interferon and interleukin II after administration (2'-5')olygoadenylate and its analogues at the concentration of 50 and 25 ⁇ g/kg of the body weight was investigated.
  • Serum levels of IgG, IgA, IgM were determined by radial immunodiffusion using antisera against human immunoglobulin A, M, G.
  • the amount of interferon and interleukine-Il were determined by the method of Lopez-Botet M. et al., 1982.
  • T-helpers 22 20.5 18.4 (%)
  • T-killers 12 12 (%) The results show that 2'-5'A3 is different from 2'-5' epoxyA3 in its action on T-cell immunity. It is shown that a single intravenous injection of 2'-5'A3 increases in about 50% the quantity of the subpopulation of T-helpers and T-killers, which contribute to the rejection transplant organs.
  • Kidney allotransplantations were performed using chinchilla rabbits of the same sex, weighing 5.0-6.5 kg. In the series of 10 rabbits, allogenic kidneys were transplanted on the neck vessels, rabbit ureter was taken outside for performing ureterocutaneostoma. Anastomosis was performed on the donor kidney vessels according to the "end-into-end" pattern, with the external carotid artery and the jugular vein joined by means of their preliminary cannulation and fixation by the cannulae with the recipient vessels.
  • the recipient rabbits had combined anesthesia: intravenous introduction of hexenal at a rate of 10 mg per 1.0 kg body weight was supplemented by local anesthesia with 0.25 - 0.5% novocaine solution up to 15.0 ml.
  • An intact rabbit served as a kidney donor, whose kidneys were exposed by means of transperitoneal access and perfused with 500 ml of Eurocollins solution, in situ .
  • kidney vessels and ureters were utilized, the latter being cut at the level of iliac vessels. Having performed perfusion without extracting a kidney from the donor, kidney vessels were cannulated from the aorta and vena cava, the canulae were fixed with separate ligatures and the vessels were released. After this, the kidney was extracted.
  • the organs were preserved at the temperature of melting ice. Then we proceeded directly to kidney transplantation. The preservation lasted for about 2.5-3.0 hours and thermal ischemia (secondary) duration was 30-40 minutes.
  • Immunosuppression was performed by IV injection of 2'-5' epoxyA3 at a dose of 5 ⁇ g per 1.0 kg body weight at 0.1 ml of the physiologic solution daily until the conclusion of the experiment. During the first two weeks of the post-operative period, blood was taken for immunological analysis; BTR with PHA and Concanavalin A were tested.
  • results of the experiments were evaluated clinically, by the presence or absence of urination from the ureterocutaneostoma and by the behavior of the experimental animals. Overall, the results may be divided into four groups.
  • the fourth group also a single rabbit, showed negative results, postoperative wound suppuration, sepsis and death within the first week after transplantation.
  • the experiments were performed on 4 year-old Macaque Rh. monkeys. Each cohort consisted of 3 animals. The animals were observed for a period of 3 consecutive months. The results of the experiments were evaluated clinically: by the presence or absence of urination from the ureterocutaneostoma.
  • the monkeys were narcotized by means of the intravenous anesthesia with Ketalar ® and subjected to medial laparotomy from the xiphoid down to the pubic joint. Access to the left kidney was made extraperitoneally. The kidney was teased from the surrounding tissues. A clamp was put on the vessel limb; the artery, the vein and the ureter were dressed separately; the kidney was cut and transferred for hypothermal conservation in Collins' solution.
  • the internal iliac artery and the external iliac vein were extracted extra-peritoneally, immobilized and prepared for anastomosis.
  • the donor kidney was transferred to the recipient.
  • Vessel anastomosis was performed: the graft arteries were anastomosed with the internal iliac artery according to the end-to-end method and the graft veins were anastomosed with the external iliac vein according to the end-to-side method.
  • Ureterocutaneostomy was performed.
  • the abdominal cavity was lavaged with the solution of disodium carbenicillin. Layer-upon-layer sutures on the wound were applied.
  • Aseptic dressing was performed.
  • the administration schedule of 2'-5' epoxyA3 was modified slightly for the second group of monkeys.
  • the preparation was injected two days before the operation and every other day at a concentration of 50 ⁇ g/kg during the entire post- transplantation period. It was found that the normal function of the kidney was reinstituted in the transplanted monkeys within 10 hours. Immunological analyses showed that 7 days after surgery, the quantity of T-suppressors increased from 44% (presurgical level) to 49%. The number of T-helpers dropped correspondingly from 37% to 7%. Analogous suppression effect was shown for the T-killers. During the entire postoperative period, this activity tendency continues.

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Abstract

Production d'analogues de sel disodique d'adényle (2'-5') adénylyle (2'-5')-9-(2,3-anhydro-β-D-ribofuranosyle) adénine par le procédé de phosphotriester. La composition pharmaceutique préparée selon la présente invention module la réponse immunitaire de mammifères, y compris des humains, et peut être utilisée pour l'immuno-suppression, après une transplantation d'organes, pour le traitement de maladies autoimmunes, virales, de tumeurs lymphocytaires et d'autre maladies pour lesquelles l'immunomodulation est cliniquement bénéfique.
PCT/US1991/005734 1991-08-12 1991-08-12 Synthese, composition pharmaceutique et procede d'application d'analogues de (2'-5') oligoadenylate WO1993003733A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US08/185,795 US5571799A (en) 1991-08-12 1991-08-12 (2'-5') oligoadenylate analogues useful as inhibitors of host-v5.-graft response
PCT/US1991/005734 WO1993003733A1 (fr) 1991-08-12 1991-08-12 Synthese, composition pharmaceutique et procede d'application d'analogues de (2'-5') oligoadenylate

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PCT/US1991/005734 WO1993003733A1 (fr) 1991-08-12 1991-08-12 Synthese, composition pharmaceutique et procede d'application d'analogues de (2'-5') oligoadenylate

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5559101A (en) * 1994-10-24 1996-09-24 Genencor International, Inc. L-ribofuranosyl nucleosides
US5885972A (en) * 1994-10-24 1999-03-23 Genencor International, Inc. L-pyranosyl nucleosides

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4378352A (en) * 1979-10-09 1983-03-29 Yeda Research & Development Co. Ltd. (2'-5')Oligo-isoadenylate pharmaceutical compositions and method of use
US4464359A (en) * 1981-04-10 1984-08-07 Research Corporation (2'-5')-Oligo (3'-deoxyadenylate) and derivatives thereof
US4515781A (en) * 1983-02-23 1985-05-07 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services 2',5'-Riboadenylate-morpholinoadenylate nucleotides
US4539313A (en) * 1981-04-10 1985-09-03 Research Corporation (2'-5')-Oligo (3'-deoxyandenylate) and derivatives thereof
US4708935A (en) * 1981-04-10 1987-11-24 Research Corporation (2-5')-Oligo (3'-deoxyadenylate) and derivatives thereof
US4859768A (en) * 1984-07-11 1989-08-22 Temple University Of The Commonwealth System Of Higher Education Derivatives of 2', 5'-oligoadenylate and antiviral uses thereof
US4924624A (en) * 1987-10-22 1990-05-15 Temple University-Of The Commonwealth System Of Higher Education 2,',5'-phosphorothioate oligoadenylates and plant antiviral uses thereof
US4990498A (en) * 1988-04-26 1991-02-05 Temple University-Of The Commonwealth System Of Higher Education 2- and 8-azido(2'-5')oligoadenylates and antiviral uses thereof

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4378352A (en) * 1979-10-09 1983-03-29 Yeda Research & Development Co. Ltd. (2'-5')Oligo-isoadenylate pharmaceutical compositions and method of use
US4464359A (en) * 1981-04-10 1984-08-07 Research Corporation (2'-5')-Oligo (3'-deoxyadenylate) and derivatives thereof
US4539313A (en) * 1981-04-10 1985-09-03 Research Corporation (2'-5')-Oligo (3'-deoxyandenylate) and derivatives thereof
US4708935A (en) * 1981-04-10 1987-11-24 Research Corporation (2-5')-Oligo (3'-deoxyadenylate) and derivatives thereof
US4515781A (en) * 1983-02-23 1985-05-07 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services 2',5'-Riboadenylate-morpholinoadenylate nucleotides
US4859768A (en) * 1984-07-11 1989-08-22 Temple University Of The Commonwealth System Of Higher Education Derivatives of 2', 5'-oligoadenylate and antiviral uses thereof
US4924624A (en) * 1987-10-22 1990-05-15 Temple University-Of The Commonwealth System Of Higher Education 2,',5'-phosphorothioate oligoadenylates and plant antiviral uses thereof
US4990498A (en) * 1988-04-26 1991-02-05 Temple University-Of The Commonwealth System Of Higher Education 2- and 8-azido(2'-5')oligoadenylates and antiviral uses thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
J. MED. CHEM., Volume 31, issued 1988, HERDEWIJN et al., "Synthesis and Anti-HIV Activity of Different Sugar-Modified. Pyrimidine and Purine Nucleosides", pages 2040-2048. *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5559101A (en) * 1994-10-24 1996-09-24 Genencor International, Inc. L-ribofuranosyl nucleosides
US5885972A (en) * 1994-10-24 1999-03-23 Genencor International, Inc. L-pyranosyl nucleosides

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