WO1994014981A1 - Traitement des infections virales - Google Patents

Traitement des infections virales Download PDF

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Publication number
WO1994014981A1
WO1994014981A1 PCT/US1993/012592 US9312592W WO9414981A1 WO 1994014981 A1 WO1994014981 A1 WO 1994014981A1 US 9312592 W US9312592 W US 9312592W WO 9414981 A1 WO9414981 A1 WO 9414981A1
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WIPO (PCT)
Prior art keywords
compounds mentioned
effective amount
administered
salt
aqueous
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Application number
PCT/US1993/012592
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English (en)
Inventor
Rolland Chen
Tin-Wa Maung
Original Assignee
Rolland Chen
Maung Tin Wa
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.)
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Publication date
Application filed by Rolland Chen, Maung Tin Wa filed Critical Rolland Chen
Priority to AU59608/94A priority Critical patent/AU5960894A/en
Publication of WO1994014981A1 publication Critical patent/WO1994014981A1/fr

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    • 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

Definitions

  • This invention relates to novel compositions and preparation of matter which possess activity for the potential treatment for viral infections, especially potent anti-AIDS activity.
  • HIV human immunodeficiency virus
  • AIDS acquired immunodeficiency syndrome
  • T-cells t-lymphocytes
  • helper T-cells are invaded by the virus and the T- cells becomes an HIV virus producer.
  • the helper T-cells are quickly destroyed and their number is depleted to such an extent that the body's B-cells as well as other T-cells normally stimulated by helper T-cells no longer function normally or produce sufficient lymphokines and antibodies to destroy the invading virus or other invading microbes, etc.
  • the HIV virus will gradually erode the ability of the human's immune system to resist various pathogens, that the human falls prey to various other diseases (secondary infections or unusual tumors) such as herpes, cytomegalovirus, Kaposi's sarcoma and Epstein-Barr virus related lymphomas among others . These secondary infections are conventionally treated separately using other medications.
  • secondary infections are conventionally treated separately using other medications.
  • AIDS virus commonly referred to as AIDS virus and which is meant herein to include mutants thereof
  • the infected persons seem to live on with little or no symptoms, but appear to have persistent infections.
  • Another group of humans suffers mild immune system depression showing various symptoms of weight loss, malaise, fever, swollen lymph nodes etc.
  • PDL persistent generalized lymphadenopathy syndrome
  • ARC AIDS related complex
  • Azidothymidine was the first clinically useful drug against AIDS with significant decrease in mortality and frequency of opportunistic infections.
  • severe toxicity, in particular, the bone marrow suppression (anemia, leukopenia) was associated with long term administration of AZT.
  • the initial immunologic improvement, i.e. , increase in CD4 + cells there was further decline of immunologic conditions, despite the continued AZT treatment.
  • Other effective inhibitors of HIV replication include (a) a variety of 2', 3'- dideoxynucleosides , ⁇ such as 2', 3'-dideoxycytidine (ddC), 2', 3'- dideoxyasenosine (ddA), 2', 3'-dideoxyguanosine (ddG), 2', 3,- dideoxyinosine (ddl) ⁇ , (b) 2', 3'-didehydro-2', 3'-dideoxynucleosides ⁇ i.e., 2', 3'-didehydro 2', 3'-dideoxycytidine (d4C), 2', 3'-didehydro-2', 3'-dideoxythymidine (d4T) ⁇ , (c) 3'-fluoro-2', 3'-dideoxynucleosides ⁇ i.e., 3'-fluoro-2 ⁇ 3'-dideoxythymidine (Fd
  • ddC ddC
  • ddl d4T
  • ddC usefulness is hmited by painful peripheral neuropathy. Such neuropathy may also occur following administration of d4T; on the other hand , the use of ddl may in some instances be complicated by acute pancreatitis.
  • HIV human immunodeficiency virus
  • FIG . 1 is a compositiion wherein Y differs as follows :
  • G . 2 is a composition wherein B , n , X , Y and Z differ as follows :
  • FIG . 3 is a compound wherein B , n , X , Y and Z differ as follows :
  • Thymidylyl (3' — >5' )-azido-3'-deoxythymidine having the Formula I is the Thymidylyl (3' — >5' )-azido-3'-deoxythymidine having the Formula I.
  • NSC-D-631744 the No. of (NSC-D-631744) . It is found to be active. Testing performed under the National Cancer Institute's protocol for AIDS antiviral screening (See O .W . Weislow, et. al. , J. National Cancer Inst. 81 ,577-586 (1989) showed Formula I with a therapeutic index of 19.8 X 10 3 compared to 1.2 X 10 J that was indicated for AZT under the same AIDS antiviral screening protocol. Higher levels of protection than AZT provided at different concentrations also suggest an additional advantage. Other compounds of similar design are also disclosed in this invention.
  • the compound of Formula I may be administered per se or in the form of a pharmaceutically acceptable salt , e. g . an alkali metal salt such as sodium or potassium, or an alkaline earth salt or an ammonium salt (all of which are hereinafter referred to as a pharmaceutically acceptable base salt) .
  • a pharmaceutically acceptable salt e. g . an alkali metal salt such as sodium or potassium, or an alkaline earth salt or an ammonium salt (all of which are hereinafter referred to as a pharmaceutically acceptable base salt) .
  • the mono- , di- and triphosphates of the Thymidylyl (3' — >5 ) - azido-3'-deoxythymidine are of the Formulas II, III and IV respectively.
  • the present invention also discloses compounds of Formula I, II, III, IV and their appropriate salts for use in the treatment of the conditions refered to above, as well as the use of such compounds in the preparation of pharmaceutical formulations for the treatment of such conditions.
  • the above mentioned pharmaceutically acceptable salts may be prepared in a conventional manner, e. g. , treatment of the compound with an appropriate base.
  • antisense oligodeoxynucleotides in the development of anti-HIV agents has expanded the knowledge of oligonucleotide analog chemistry .
  • Anti-HIV and other biological activities found for oligonucleotides suggest that sequence-specific and sequence-nonspecific mechanisms of action can be found. Areas in which these compounds are considered to be very limited included all the biological areas, such as cellular uptake, toxicology and pharmacokinetics .
  • improved and cheaper methods of large scale synthesis are vital to the question of cost relative to effective dose . See J.S. Cohen, Antisense oligonucleotides as an approach towards Anti- AIDS therapy; Design of Anti-AIDS Drugs . ED . by E . De Clerq Elsevier Science Publishers 1990, page 195-224.
  • Formula I is found to have potent antiviral activity and better therapeutic index than the corresponding nucleoside when tested at the National Cancer Insitiute performed under their protocol for AIDS antiviral screening .
  • Formula I (Thymidylyl 3' — >5' )-azido-3'- deoxythymidine) has a therapeutic index of 19.8 X 10 compared to 1.2 X 10 "" that was indicated for AZT under the same AIDS antiviral screening protocol. Higher levels of protection than AZT provided at different concentrations also suggest an additional advantage. Moreover, they are simpler and much less expensive for large scale synthesis than the longer chain oligonucleotides .
  • this invention discloses methods and compositions of other compounds useful in treating viral infections, including AIDS virus or human and/or animals carrying or infected with the AIDS virus or having antibodies to the AIDS virus.
  • These compounds include the shorter isomeric and nonisomeric nucleotide type compounds, such as dinucleotides , trinucleotides , etc . i.e.
  • nucleosides linked by the (3' — >5' ) linkages to the chain terminating nucleosides or other chain terminating chemical moieties such as AZT , ddl, ddC , ddG , ddA, d4T , d4C ,FddT , FddCIU , AzddU , AzddCIU, AzddDAPR , Carbovir, iso-ddA, cyclobut-A, cyclobut-G and others.
  • the present invention also discloses above mentioned compounds and their appropriate salts for use in the treatment of the conditions refered to above, as well as the use of such compounds in the preparation of pharmaceutical formulations for the treatment of such conditions.
  • the above mentioned pharmaceutically acceptable salts may be prepared in a conventional manner , e. g . , by the treatment of the compound with an appropriate base.
  • a suitable effective dose of the Formula I, Thymidylyl (3* — >5' )-azido-3'-deoxythymidine) and other shorter sequence nucleotides mentioned above and their mono- , di and triphosphates or their pharmaceutically acceptable basic salts (all of which are herein after referred to as the administered ingredient) will be administered as prescribed.
  • the desired dose is preferably as two, three, four or more sub-doses administered at appropriate intervals throughout the day. These sub-doses may be administered as unit dosage forms .
  • the dosages will be changed according to new clinical data and procedures for administering the compounds as appropriate.
  • Administration may be by any suitable route including oral, rectal, nasal, topical (including buccal and sublingual, vaginal, and parenteral
  • other medicaments such as 9-[ [2-hydroxy-l-(hydroxymethyl) ethoxy] methyl] guanine, 9-(2-hydroxylethoxymethyl) guanine (acyclovir) , 2-amino-9- (2 hydroxye
  • the formulations of the present invention comprise at least one administered ingredient, as above defined, together with one or more acceptable carriers thereof and optionally other therapeutic ingredients.
  • the carrier( s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof .
  • the formulations of this invention include those suitable for oral, rectal, nasal, topical (including buccal and sublingual) , vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration.
  • the formulations may conveniently be presented in unit dosage form, e. g . , tablets and sustained release capsules, and/or may be prepared by any methods well known in the art of pharmacy.
  • Such preparation methods include the step of bringing into association the to be administered ingredients, with the carrier, which constitutes one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in a aqueous liquid or a non- aqueous liquid; or as an oil- in water liquid emulsion or a water-in-oil liquid emulsion and as a bolu, etc.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface-active or dispersing agent.
  • Molded tablets may be made by loading in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.
  • Formulations suitable for topical administration include lozenges, comprising the ingredients in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin , or sucrose and acacia; and mouth washes comprising the ingredient to be administered in a suitable liquid carrier.
  • Formulations suitable for topical administration to the skin may be presented as ointments, creams, gels and pastes comprising the ingredient to be administered and a pharmaceutically acceptable carrier.
  • a preferred topical delivery system is a transdermal patch containing the ingredient to be administered.
  • Formulations for rectal administration may be presented as a suppository with a suitable base comprising , for example, cocoa butter or a salicylate .
  • Formulations suitable for nasal administration wherein the carrier is a solid, include a coarse powder having a particle size, for example, in the range 20 to 500 microns which is administered in the manner in which snuff is taken , i.e. , by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • Suitable formulations, wherein the carrier is a liquid, for administration, as for example, a nasal spray or as nasal drops include aqueous or oily solutions of the active ingredient .
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons , creams, gels, pastes, foams, or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants , buffers, bacteriostats and solutes which render the formulations isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents .
  • the formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, water for injections , immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • Preferred unit dosage formulations are those containing a daily dose or unit, daily sub-dose, as herein above recited , or an appropriate fraction thereof , of the administered ingredient.
  • formulations of this invention may included other agents conventional in the art, giving due regard to the type of formulation in question, for example, those suitable for oral administration may include flavoring agents .
  • Thymidine (7.26g, 30m mole) was stirred with p-anisyl chloro diphenyl methane (9.26g, 30m mole) in a mixture of dimethyl formamide (60 ml) and pyridine ( 60 ml) for 20 hours at room temperature to give a clear greenish solution.
  • This method is disclosed by F . Puegh et. al. J. Med. Chem. 1988, 31 , 1897.
  • the clear greenish solution was poured into ice water (500 ml) .
  • the gummy precipitate was collected .
  • the greenish gum was purified by chromatography on a silica gel column ( 65 g) by eluting with a gradient of chloroform and methanol mixtures.
  • a pure product ( 1.1 g) of 5-0-(4- monomethoyx trityl ) -thymidine was obtained from the chloroform: methanol (9.1 ) fraction. It has Rf value of 0.66 on a thin layer chromatography ( TLC ) system of silica gel and chloroform-methanol (9.1 ) in contrast to thymidine Rf value of 0.29.
  • the white foam was dissolved in 4 ml of dry pyridine . To this solution was added ( l-mesitylene-2 sulfonyl-3-nitro-l , 2 , 4-triazole) (MSNT , 370 mg , 1.25 m mole) and the mixture stirred at room temperature for 1 hour.
  • Fraction 4 was eluted with methylene dichloride: methanol (8 :2 ) was found to be the major fraction with an Rf value of 0.53 in the TLC system of Silica gel G and butanol: glacial acetic acid: water ( 18: 1 : 1 ) .
  • Fraction 4 was evaporated to dryness and was taken in 14 ml of 80% acetic acid . The clear solution was allowed to stand at room temperature overnight. The solution was diluted with water (30 ml) and extracted with methylene dichloride ( 3 X 10 ml ) . The aqueous solution was evaporated to a gummy residue which was triturated with acetone, followed by either to give a white powder (0.2 g) of Formula I .
  • Novel compositions and methods of preparing compounds comprising the shorter sequence isomeric and non-isomeric nucleotide-type compounds , such as dinucleotides , trinucleotides , etc . , i.e. , one , two , or more nucleosides linked by the (3' — >5' ) linages to the chain terminating nucleosides, some examples of which are shown in Figures 1 - 3.
  • Formula I (Thymidylyl (3' — >5' )-3'-deoxythymidine) has a therapeutic index of 19.8 X 10" compared to 1.2 X 10 3 that was indicated for AZT under the same AIDS antiviral screening protocol. Higher levels of protection than AZT provided at different concentrations also suggests an additional advantage . Moreover, they are simpler and much less expensive for the large scale synthesis than the longer chain oligonucleotides.
  • chain termination nucleosides can be replaced by other chain terminating chemical moieties, such as phosphonylmethoxyalkyl derivatives (i.e. , PMEA and PMEDAP type compounds) , acyclic uridine analogs (i.e . , HEPT like compounds) , benzodiazepine derivatives, etc .
  • chain terminating chemical moieties such as phosphonylmethoxyalkyl derivatives (i.e. , PMEA and PMEDAP type compounds) , acyclic uridine analogs (i.e . , HEPT like compounds) , benzodiazepine derivatives, etc .

Abstract

Cette invention concerne de nouvelles compositions et de nouveaux procédés de traitement des infections virales, y compris du SIDA, ou d'hommes et/ou d'animaux porteurs du virus du SIDA ou contaminés par ce virus ou encore ayant des anticorps contre ce virus. Un composition représentative est illustrée par la formule (1).
PCT/US1993/012592 1992-12-29 1993-12-28 Traitement des infections virales WO1994014981A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU59608/94A AU5960894A (en) 1992-12-29 1993-12-28 Treatment of viral infections

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US99707992A 1992-12-29 1992-12-29
US07/997,079 1992-12-29

Publications (1)

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WO1994014981A1 true WO1994014981A1 (fr) 1994-07-07

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PCT/US1993/012592 WO1994014981A1 (fr) 1992-12-29 1993-12-28 Traitement des infections virales

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AU (1) AU5960894A (fr)
MX (1) MX9400210A (fr)
WO (1) WO1994014981A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4724232A (en) * 1985-03-16 1988-02-09 Burroughs Wellcome Co. Treatment of human viral infections

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4724232A (en) * 1985-03-16 1988-02-09 Burroughs Wellcome Co. Treatment of human viral infections

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
J.S. COHEN et al., "Oligodeoxynucleotides: Antisense inhibitors of Gene Expression", published 1989, by CRC PRESS (BOCA RATON, FLORIDA), pages 62-67, 90-91, 94-95, 108-109, 112-113, 233, 240-241. *
JOURNAL OF MEDICINAL CHEMISTRY, Vol. 31, No. 10, issued 1988, F. PUECH et al., "Synthesis and Biological Evaluation of Isomeric Dinucleoside Monophosphates and Monomethylphosphonates of 9-B-D-Arabinafuranosyladenine and Related Analogues", pages 1897-1907. *
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, Vol. 84, issued November 1987, MATSUKURA et al., "Phosphorothioate Analogs of Oligodeoxynucleotides: Inhibitors of Replication and Cytopathic Effects of Human Immunodeficiency Virus", pages 7706-7710. *
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, Vol. 85, issued August 1988, GOODCHILD et al., "Inhibition of Human Immunodeficiency Virus Replication Antisense Oligonucleotides", pages 5507-5511. *
Z. CHEM., Vol. 23, No. 50, issued 1983, A. ROSENTHAL et al., "Chemische Synthese von Oligodesoxyribonucleotiden mit Abgewandelter Desoxyribose am 3'-Ende nach der Triester-Methode", pages 178-179. *

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MX9400210A (es) 1994-07-29
AU5960894A (en) 1994-07-19

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