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WO1988003804A2 - Procede pour traiter des infections virales chez des humains, et compositions a cet effet - Google Patents

Procede pour traiter des infections virales chez des humains, et compositions a cet effet Download PDF

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Publication number
WO1988003804A2
WO1988003804A2 PCT/EP1987/000719 EP8700719W WO8803804A2 WO 1988003804 A2 WO1988003804 A2 WO 1988003804A2 EP 8700719 W EP8700719 W EP 8700719W WO 8803804 A2 WO8803804 A2 WO 8803804A2
Authority
WO
WIPO (PCT)
Prior art keywords
compound
azido
hypoxanthine
guanine
purine
Prior art date
Application number
PCT/EP1987/000719
Other languages
English (en)
Other versions
WO1988003804A3 (fr
Inventor
Fritz Eckstein
Gerhard Hunsmann
Heinz Hartmann
Original Assignee
Max-Planck-Gesellschaft Zur Förderung Der Wissensc
Deutsches Primatenzentrum Gmbh
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from DE19863639780 external-priority patent/DE3639780A1/de
Priority claimed from DE19873708849 external-priority patent/DE3708849A1/de
Priority claimed from US07/041,147 external-priority patent/US4880782A/en
Application filed by Max-Planck-Gesellschaft Zur Förderung Der Wissensc, Deutsches Primatenzentrum Gmbh filed Critical Max-Planck-Gesellschaft Zur Förderung Der Wissensc
Priority to DE1987907426 priority Critical patent/DE332626T1/de
Publication of WO1988003804A2 publication Critical patent/WO1988003804A2/fr
Publication of WO1988003804A3 publication Critical patent/WO1988003804A3/fr
Priority to FI892451A priority patent/FI892451A0/fi

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • 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

Definitions

  • This invention relates to a method of treating humans with diseases brought about by viruses which are characterized by RNA-dependent DNA polymerase.
  • viruses which are characterized by RNA-dependent DNA polymerase.
  • retrovirus infections especially those caused by Human Immunodeficiency Virus (HIV), which is the cause of Acquired Immune Deficiency Syndrome (AIDS).
  • HIV Human Immunodeficiency Virus
  • AIDS acquired immune deficiency syndrome
  • AIDS infection has been characterized as an epidemic in some parts of the world, and it is expected that other parts of the world will soon characterize the infection as such.
  • HTLV human T-cell leukemia virus
  • These viruses are characterized by pronounced tropism for T4 cells, reverse transcriptase with high molecular weight (100 kd), and with preference for Mg 2+ for optimal enzymatic activity.
  • the work ot Barre-Sinussi, et al., Science 220:868-871 (May 20, 1983) agreed with the Gallo hypothesis, and differed only in its calling the virus lymphadenopathy AIDS associated virus (LAV).
  • LAV virus lymphadenopathy AIDS associated virus
  • AZT azido thymidine
  • AZT in severely limited trials, has been shown to interfere with viral replication, which results in some remission of the infection.
  • a method of treating humans infected with viruses characterized by RNA dependent polymerases comprising administering to an infected individual an effective amount of at least one compound of the formula
  • compositions are also prepared which comprise at least one compound as described supra, taken with conventional pharmaceutical carriers and diluents.
  • Figure 1 shows graphically the pathogencity of HIV on MT 4 cells.
  • Figure 2 shows results of in vitro viability studies when 3'-azido-2',3'-dideoxyguanosine was added to HIV infected cells.
  • Figure 3 shows results of in vitro viability studies when 3 '-fluoro-3'-deoxythymidine was added to HIV infected cells.
  • Figure 4 shows results of in vitro viability studies when 3'-fluoro-2',-3'-dideoxyguanosine was added to HIV infected cells.
  • Figure 5 shows results of in vitro viability studies when 3'-azido-2',-3'-dideoxyinosine was added to HIV infected cells.
  • the active materials described supra will be seen to be 9-(beta-D-deoxyribofuranosyl) nucleosides of the thymidine uridine guanosine cytidine purinnucleoside or inosine series.
  • Of particular interest are the specific compounds 3'-azido-2',3'-dideoxy guanosine, 3'-azido-2',2'-dideoxyinosine, 3'-fluoro,2',3'-dideoxy guanosine and 3'-fluoro-3'- deoxythymidine.
  • the first compound is prepared according to the process described in Imazawa, et. al., J. Org. Chem. 43: 3044-3048 (1978), the disclosure of which is incorporated by reference herein.
  • hypoxanthine compound is obtained in an analogous manner by the use of the corresponding palmitoyl-hypoxanthine.
  • these guanine and hypoxanthine compounds may be obtained by the reaction of 1-O-methyl-5-0-(4-methylbenzoyl)-3-azido-2,3-dideoxy-D- ribofuranose, obtained according to the procedure of N.D. Dyatkina and A.V. Azhayev described in Synthesis, 1984, p. 961, with silylated guanine or hypoxanthine with the help of a catalyst, for example trimethylsilyl-trifluoromethane- sulphonate, according to the procedure of H. Vorbruggen, K.
  • a catalyst for example trimethylsilyl-trifluoromethane- sulphonate
  • 3'-fluoro-3'-deoxythymidine and its preparation is known from G. Etzold, R. Hintsche, G. Kowollik and P. Langen, Tetrahedron 27 (1971) pp. 2463-2472.
  • the preparation is achieved in principle by the reaction of cyclothymidine in diethylene glycol with potassium hydrogen difluoride.
  • the reaction products are separated on a kieselgel column with a mixture of CHCl 3 and methanol.
  • a second purification step was done by chromatography on a LiChroprep RP-18 column with a mixture of 50 mM triethyl- ammoniumcarbonate/5% acetonitrile.
  • 3 '-fluoro-3'-deoxythymidine can also be prepared by reacting the cyclothymidine, prepared by the method of G. Kowollik, G. Etzold, M. von Janta, Lipinski, K. Gartner, B. Langen in J. Prakt. Chem. (1973) 315, p. 895, with hydrofluoric acid and aluminum trifluoride.
  • the cyclothymidine can be reacted with potassium fluoride in the presence the crown ether 18-crown-6 in dimethyl formamide or dioxane.
  • hypoxanthine compositions may be obtained from the corresponding adenine compositions, which are in part known from the literature cited above, by deamination with nitric acid or nitrosyl chloride.
  • T-cells The in vitro pathogeneity of the so cultured HIV was determined with the use of MT 4 -cells, a T 4 -cell line for which HIV is cytopathic.
  • the MT 4 -cell line is described in Science, 229 (1985) pp. 563-566.
  • the cytopathological effect was thereby monitored by measurement of the incorporation of thymidine into the cells. If the active materials according to the present invention, especially 3'-azido-2',3'-dideoxyguanosine was added to the MT 4 -cells inocculated with HIV, then, even with nanomolar concentrations of the active materials it was possible to protect against the cytopathological effects brought about by the virus.
  • the toxicity determination also took place in the same system.
  • MT 4 -cells were exposed to the nucleoside analogue contained in the pharmaceutical composition according to the present invention as active materials in the absence of HIV and again the toxicity was determined on the basis of the incorporation of thymidine. From the so determined concentration for the achievement of an antiviral effect in comparison with the amount of active material necessary for a toxic effect, there was determined an in vitro therapeutic index.
  • this therapeutic index in the case of the human cell line used, was equal or greater than 10 3 , for
  • Fig. 1 there is graphically illustrated the influence of different dilutions of the HIV virus-containing supernatant of the virus producing cell line (differing virus concentration) on the thymidine incorporation into MT 4 -cells.
  • the incorporation curve shows that up to a dilution of 1:30 the pathogeneity of HIV viruses leads to a very low thymidine uptake increase correspondingly and does achieve the highest value at a dilution of the virus-containing supernatant of 1:10000.
  • Fig. 1 shows, in the case of a dilution of the cultured supernatant of 1:40, an almost maximum pathogeneity of the HIV on the MT 4 -cells is still present.
  • the investigations of the effectiveness of the active materials to the pharmaceutical compositions according to the present invention took place in the case of this virus dilution in that a premixed solution of virus dilution and of the active material to be investigated was added to the cell line sample and the thymidine incorporation again determined.
  • the results of these experiments with the preferred compound 3'-azido-2',3'-dideoxyguanosine are shown in Fig. 2 of the accompanying drawing.
  • Fig. 2 shows graphically the relationship between the amount of active material added in ⁇ g .
  • Fig. 3 depicts the connection between the amount of 3'-fluoro-3'-deoxythymidine added in ⁇ g./ml. and the thymidine incorporation in cpm (counts per minute) in analogy as explained for Fig. 2. It shows that at a concentration of less than 0,002 ⁇ g./ml. the active compound protects the cells already with half maximal action against the pathogenic effect of a 1:40 dilution of the HIV parent liquid.
  • FIG. 4 shows the in vitro antiviral activity of 3'-fluoro-2',3'-dideoxyguanosine. The realization and interpretation was done according to the explanation for Fig. 2.
  • This active material at a concentration of less than 1.5 ⁇ g./ml. protects the cells already with half maximal action against the pathogenic effect of the 1:40 dilution of HIV patent liquid.
  • the amount of HIV present following administration of the drug was determined by radioimmunoassay for the component of HIV known as "p24".
  • the radioimmunoassay used has a sensitivity of 20-0.625 ⁇ g / ml tested. It was essential when running this test to determine the viability of the PBLS as well. This was done via incorporation of radioactive thymidine, as set forth in Example I, supra.
  • AZT azido-thymidine
  • ADG 3'-azido-2',3'-dideoxy guanosine
  • + positive controls
  • - negative controls
  • Assays were run at 4, 7, 11, and 14 days of culture. At each point, the culture medium was replaced by fresh medium.
  • ADG at a concentration of 3 ug, was slightly more effective than AZT. Both AZT and ADG began to lose e fficacy at their lowest concentrations at about the same time. The drugs do not show toxicity against the PBL either, as the "counts" resulting from thymidine indicate that cell viability remained good.
  • Table 2 presents this data in term of a RIA adjusted for 10 6 cells/ml.
  • EXAMPLE III The Experiment as described in Example II was repeated for 3'-fluoro-2'-3'-dideoxyguanosine.
  • 3'-fluoro-2'-3'- dideoxyguanosine was synthesized in analogy to the synthesis of 3'-azido-2',3'-dideoxyguanosine (Imazawa and Eckstein, J. Org. Chem. 43: 3044) (1978) by transgiycosidation of 3'-fluoro-3'-deoxythymidine (synthesized according to G.
  • compositions according to the present invention can contain the active material in free form or in the form of physiologically acceptable salts, namely in the form of a compound or a mixture of compounds of the above given general formula.
  • pharmaceutical composition can contain pharmaceutical additives and diluents usual for the intended form of administration.
  • Administration can be oral, parenteral, intrathecal, or intravenous, with oral administration being preferred.
  • Preferred dosages range from about 1 to about 20g per day per 70 kilograms of body weight when administered to a human subject.
  • Optimum dosage and mode of administration will vary from subject to subject.
  • a method of treating viral diseases in a human subject involves applying effective amounts of the co pound (I), wherein X is an azido group, a methoxy radical or a fluorine atom and B is thymine, uracil, guanine, cytosi purine or hypoxanthine if X is methoxy or fluorine, and B is guanine, purine or hypoxanthine if X is azido or a phar ceutically acceptable salt thereof. Also disclosed are compositions and compounds useful in the method.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Molecular Biology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Virology (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Communicable Diseases (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • Genetics & Genomics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Un procédé pour traiter des maladies virales chez un sujet humain consiste à appliquer des quantités efficaces du composé (I) où X est un groupe azido, un radical méthoxy ou un atome de fluor et B est thymine, uracil, guanine, cytosine, purine ou hypoxanthine si X est méthoxy ou fluor, et B est guanine, purine ou hypoxanthine si X est azido ou un sel pharmaceutiquement acceptable de ce dernier. Sont également décrits des compositions et des composés utiles dans ce procédé.
PCT/EP1987/000719 1986-11-21 1987-11-19 Procede pour traiter des infections virales chez des humains, et compositions a cet effet WO1988003804A2 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
DE1987907426 DE332626T1 (de) 1986-11-21 1987-11-19 Verfahren zur behandlung viraler infektionen bei menschen und zubereitungen dazu.
FI892451A FI892451A0 (fi) 1986-11-21 1989-05-19 Foerfarande med vilket virusinfektioner i maenniskor kan skoetas och kompositioner anvaenda daeri.

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
DE19863639780 DE3639780A1 (de) 1986-11-21 1986-11-21 Arzneimittel zur behandlung von viruserkrankungen
DEP3639780.6 1986-11-21
DE19873708849 DE3708849A1 (de) 1987-03-18 1987-03-18 Arzneimittel zur behandlung von viruserkrankungen
DEP3708849.1 1987-03-18
US041,147 1987-04-22
US07/041,147 US4880782A (en) 1986-11-21 1987-04-22 Method of treating viral infections in humans and compositions therefor

Publications (2)

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WO1988003804A2 true WO1988003804A2 (fr) 1988-06-02
WO1988003804A3 WO1988003804A3 (fr) 1988-10-06

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PCT/EP1987/000719 WO1988003804A2 (fr) 1986-11-21 1987-11-19 Procede pour traiter des infections virales chez des humains, et compositions a cet effet

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EP (1) EP0332626A1 (fr)
JP (1) JPH02500364A (fr)
CA (1) CA1296330C (fr)
FI (1) FI892451A0 (fr)
IL (1) IL84550A (fr)
WO (1) WO1988003804A2 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0305117A2 (fr) * 1987-08-22 1989-03-01 The Wellcome Foundation Limited 2',3'-Didéoxy-3'-fluorothymidine et composés apparentés pour le traitement des infections à l'adénovirus
EP0375471A2 (fr) * 1988-12-19 1990-06-27 Ste Civile De Recherche Newpharm Utilisation de 1,2,3,4-tétrahydro-acridines pour le traitement du SIDA, et composés
US8569478B2 (en) 2005-09-26 2013-10-29 Gilead Pharmasset Llc Modified 4′-nucleosides as antiviral agents

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DD209197A1 (de) * 1981-07-21 1984-04-25 Akad Wissenschaften Ddr Verfahren zur herstellung von 3'-fluor-2',3'-didesoxyguanosin
SU1053474A1 (ru) * 1982-02-08 1985-08-07 Институт биоорганической химии АН БССР 3-Фтор-2,3-дидезоксигуанозин,про вл ющий цитостатическую активность
EP0196185A2 (fr) * 1985-03-16 1986-10-01 The Wellcome Foundation Limited Nucléosides antiviraux
EP0199451A2 (fr) * 1985-03-16 1986-10-29 The Wellcome Foundation Limited Nucléosides thérapeutiques
EP0217580A2 (fr) * 1985-09-17 1987-04-08 The Wellcome Foundation Limited Nucléosides thérapeutiques

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DD279407A1 (de) * 1986-07-24 1990-06-06 Akad Wissenschaften Ddr Verfahren zur herstellung eines mittels gegen aids

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DD209197A1 (de) * 1981-07-21 1984-04-25 Akad Wissenschaften Ddr Verfahren zur herstellung von 3'-fluor-2',3'-didesoxyguanosin
SU1053474A1 (ru) * 1982-02-08 1985-08-07 Институт биоорганической химии АН БССР 3-Фтор-2,3-дидезоксигуанозин,про вл ющий цитостатическую активность
EP0196185A2 (fr) * 1985-03-16 1986-10-01 The Wellcome Foundation Limited Nucléosides antiviraux
EP0199451A2 (fr) * 1985-03-16 1986-10-29 The Wellcome Foundation Limited Nucléosides thérapeutiques
EP0217580A2 (fr) * 1985-09-17 1987-04-08 The Wellcome Foundation Limited Nucléosides thérapeutiques

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
Biochem. Biophys. Res. Commun., Vol. 148, No. 1, October 14, 1987, pages 78-85; Acad. Press, Inc., US, E. MATTHES et al.: "Inhibition of HIV-associated reverse transcriptase by sugar-modified derivatives of thymidine 5'-triphosphate in comparison to cellular DNA polymerases alpha and beta", Abstract. *
Biochem. Pharm., Vol. 29, No. 12, 1980, pages 1849-1851, E. DE CLERCQ et al.: "Antiviral, antimetabolic and antineoplastic activities of 2'- of 3'-amino or -azido-substituted deoxyribonucleosides", whole document. *
Biomed. Biochim. Acta, Vol. 44, No. 10, 1985, pages K63-K73, E. MATTHES et al.: "3'-Deoxy-3'-fluorothymidinetriphosphate: Inhibitor and terminator of DNA synthesis catalysed by DNA polymerase beta, terminal deoxynucleotidyltransferase and DNA polymerase I", Abstract. *
CHEMICAL ABSTRACTS, Vol. 101, No. 19, November 5, 1984, page 740, Ref. No. 171660y; Columbus Ohio, US; & DD-A1-209197 (AKADEMIE DER WISSENSCHAFTEN DER DDR) 25-04-1984, Abstract. *
CHEMICAL ABSTRACTS, Vol. 105, No. 19, November 10, 1986, page 74, Ref. No. 165001a; Columbus, Ohio, US; & SU-A1-1053474 (INST. OF BIOORG. CHEM. AC. OF SCIENCES; BELORUSSIAN SSR), Abstract. *
Dialog Information Services, file 155: Medline 66-68; Accession No. 06296673, M. BABA et al.: "Selective inhibition of human immunodeficiency virus (HIV) by 3'-azido-2',3'-dideoxyguanosine in vitro", & Biochem. Biophys. Res. Commun, June 30, 1987, 145(3), p. 1080-6, whole document. *
J. Biol. Chem., Vol. 262, No. 5, February 1987, pages 2187-2189, Am. Soc. of Biol. Chem. Inc., US, Y. CHENG et al.: "Human immunodeficiency virus reverse transcriptase", whole document. *
J. Med. Chem., Vol. 30, No. 8, August 1987, pages 1270-1278, Am. Chem. Soc., US, P. HERDEWIJN et al.: "3'-Substituted 2',3'-dideoxynucleoside analogues as potential anti-HIV (HTLV-III/LAV) agents", whole document. *
The Lancet, Vol. I, No. 8523, January 3, 1987, pages 40-41, London, GB, H. HARTMANN et al.: "Inhibition of HIV-induced cytopathogenicity in vitro by 3'-azido-2',3'-dideoxyguanosine", whole document. *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0305117A2 (fr) * 1987-08-22 1989-03-01 The Wellcome Foundation Limited 2',3'-Didéoxy-3'-fluorothymidine et composés apparentés pour le traitement des infections à l'adénovirus
EP0305117A3 (en) * 1987-08-22 1989-12-27 The Wellcome Foundation Limited 2',3'-dideoxy-3'-fluorothymidine and related compounds for the treatment of adenovirus infections
EP0479336A1 (fr) * 1987-08-22 1992-04-08 The Wellcome Foundation Limited Composés antiviraux
US5376644A (en) * 1987-08-22 1994-12-27 Burroughs Wellcome Co. Treatment of adenovical infections with 3'-fluoro-5-halo uracil compounds
EP0375471A2 (fr) * 1988-12-19 1990-06-27 Ste Civile De Recherche Newpharm Utilisation de 1,2,3,4-tétrahydro-acridines pour le traitement du SIDA, et composés
EP0375471A3 (fr) * 1988-12-19 1992-07-08 Ste Civile De Recherche Newpharm Utilisation de 1,2,3,4-tétrahydro-acridines pour le traitement du SIDA, et composés
US8569478B2 (en) 2005-09-26 2013-10-29 Gilead Pharmasset Llc Modified 4′-nucleosides as antiviral agents

Also Published As

Publication number Publication date
FI892451L (fi) 1989-05-19
CA1296330C (fr) 1992-02-25
EP0332626A1 (fr) 1989-09-20
JPH02500364A (ja) 1990-02-08
IL84550A (en) 1993-07-08
WO1988003804A3 (fr) 1988-10-06
FI892451A0 (fi) 1989-05-19

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