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
• • 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
  • A61P31/14—Antivirals for RNA viruses
  • A61P31/18—Antivirals for RNA viruses for HIV
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
  • C07H15/20—Carbocyclic rings
  • C07H15/22—Cyclohexane rings, substituted by nitrogen atoms
  • C07H15/222—Cyclohexane rings substituted by at least two nitrogen atoms
  • C07H15/226—Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings
  • C07H15/228—Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings attached to adjacent ring-carbon atoms of the cyclohexane rings
  • C07H15/232—Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings attached to adjacent ring-carbon atoms of the cyclohexane rings with at least three saccharide radicals in the molecule, e.g. lividomycin, neomycin, paromomycin

Definitions

• Hexa-N-(o-hy ⁇ roxybenzyl )Neomyci B for inhibiting human retroviruses and for the treatment of AIDS
• This invention relates to N-poly-(o-hydroxybenzyl) Neomycin B or salts and/or hydrates thereof, as a drug to treat a human cell system, including a human patient, possibly infected with a human retrovirus (HRV) to prevent or retard the further replication of the HRV in that human system or patient.
• HRV human retrovirus
• AZT zidovudine
• U.S. Patent 4,724,232 claims a method of treating humans having acquired immunodeficiency syndrome utilizing 3'-azido-3'-deoxy-thymidine (azidothymidine, AZT).
• European Patent Application 88306456.0 Publication No. 0 0300 687; 25.01.89 Bulletin
• 89/04 describes a method of inhibiting human immunodeficiency virus utilizing a therapeutically effective amount of an antiviral agent to attack the first splice acceptor site of tat m gene of HIV.
• OMPs Oligodeoxyyribonucleosidemethylphosphonates
• This invention is a method for treating a human infected with one or more than one strain of a human immunodeficiency virus which comprises administering an effective amount of a N- poly-(o-hydroxybenzyl) Neomycin B, or salts and/or hydrates thereof, to the infected human.
• a N- poly-(o-hydroxybenzyl) Neomycin B or salts and/or hydrates thereof
• alkali metal salt forms of N-poly-(o-hydroxybenzyl) Neomycin B include the sodium, potassium and lithium salts thereof.
• human retrovirus includes human immunodeficiency virus type I, human immunodeficiency virus type II, or strains thereof, as well as human T cell leukemia virus 1 and
• HTLV-1 and HTLV-2 strains apparent to one skilled in the art, which belong to the same viral families and which create similar physiological effects in humans as various human retroviruses
• Patients to be treated would be those individuals: 1) infected with one or more than on strain of a human retrovirus as determined by the presence of either measurable viral antibody antigen in the serum and 2) having either a symptomatic AIDS defining infection such as disseminated histoplasmosis, ii) isopsoriasis, iii) bronchial and pulmonary candidiasis includin pneumocystic pneumonia iv) non-Hodgkin's lymphoma or v) Kaposi's sarcoma and being less tha
• Treatment would consist of maintaining an inhibitory level of the compound use according to this invention in the patient at all times and would continue until the occurrence o a second symptomatic AIDS defining infection indicates alternate therapy is needed.
• N-poly-(o-hydroxybenzyI) Neomycin B is illustrated in Chart I where R is -(2-hydroxy)phenyl.
• th dosage forms include oral formulations, such as tablets or capsules, or parenteral formulations, such as sterile solutions.
• an effective amount is from about 1 to 100 mg per kg per day.
• a typical unit dose for a 70 kg human would be from about 50 mg to 1000 mg, preferably 200 mg to 1000 mg taken one to four times per day.
• Either solid or fluid dosage forms can be prepared for oral administration.
• Solid compositions are prepared by mixing the compounds used to practice the method claimed in this invention with conventional ingredients such as talc, magnesium stearate, dicalcium phosphate, magnesium aluminum silicate, calcium sulfate, starch, lactose, acacia, methyl cellulose, or functionally similar pharmaceutics diluents and carriers.
• Capsules are prepared by mixing the compounds used to practice the method claimed in this invention with an inert pharmaceutical diluent and placing the mixture into an appropriately sized hard gelatin capsule.
• Soft gelatin capsules are prepared by machine encapsulation of a slurry of the compounds used to practice the method claimed in this invention with an acceptable inert oil such as vegetable oil or light liquid petrolatum.
• Syrups are prepared by dissolving the compounds used to practice the method claimed in this invention in an aqueous vehicle and adding sugar, aromatic flavoring agents and preserva- tives.
• Elixirs are prepared using a hydroalcoholic vehicle such as ethanol, suitable sweeteners such as sugar or saccharin and an aromatic flavoring agent.
• Suspensions are prepared with an aqueous vehicle and a suspending agent such as acacia, tragacanth, or methyl cellulose.
• parenteral solutions are prepared by dissolving the compounds used to practice the method claimed in this invention in water and filter sterilizing the solution before placing in a suitable sealable vial or ampule.
• Parenteral suspensions are prepared in substantially the same way except a sterile suspension vehicle is used and the compounds used to practice the method claimed in this invention are sterilized with ethylene oxide or suitable gas before it is suspended in the vehicle.
• Patients to be treated would be those individuals: 1) infected with one or more than one strain of a human immunodeficiency virus as determined by the presence of either measurable viral antibody or antigen in the serum and 2) having either a symptomatic AIDS defining infection such as i) disseminated histoplasmosis, ii) isoporiasis, iii) bronchial and pulmonary candidiasis including pneumocystis pneumonia, iv) non-Hodgkin's lymphoma, or v) Kaposi's sarcoma and being less than sixty years old; or having an absolute CD4 lymphocyte count of less than 200/mm 3 in the peripheral blood.
• Treatment would consist of maintaining an inhibitory level of the compounds of this invention in the patient at all times and would continue until the occurrence of a second symptomatic AIDS defining infection indicates alternate therapy is needed.
• Preparation 1 Preparation of N-poly-(o-hydroxybenzyl) Neomycin B Part A:
• Neomycin B free base 12.33 g. (20mM) of Neomycin B free base is dissolved in 25 ml. of water. The solution is diluted with 50 ml of methanol. The resulting solution is mixed with an aqueous methanol solution of salicylaldehyde (SAL; salicylic aldehyde; 2-hydroxybenzaldehyde) consisting of 17.1 g. (140 mM) of the SAL, 100 ml methanol and 200 ml water). The resulting solution is heated to boiling, then allowed to stand at room temperature for SAL, SAL, 100 ml methanol and 200 ml water). The resulting solution is heated to boiling, then allowed to stand at room temperature for
• the product of Part A is dissolved in 200 ml methanol and hydrogenated at roo temperature at 50 psi initial pressure for 24 hours with 1.0 g of PtO 2 (Adams' catalyst). T pressure drop is 7.0 psi per 100 mM.
• the product is filtered through diatomaceous earth (Celit and the filtrate concentrated jn vacuo to about 50 ml and resulting concentrate added slowly to 30 ml of ether.
• the resulting mixture is refrigerated overnight, filtered/decanted and the solid produ - dried initially at room temperature in vacuo for several days and finally overnight at 50° C. in vacuum oven to yield 9.5 g of N-poly-(o-hydroxybenzyl) Neomycin B.
• N-poly-(o-hydroxybenzyl) Neomycin B 50 gm
• N-poly-(o-hydroxybenzyl) Neomycin B 50 mg
• N-poly-(o-hydroxybenzyl) Neomycin B is sterilized, added to the sterile water, filled into sterile containers and sealed.
• N-poly-(o-hydroxybenzyl) Neomycin B to practice the method claimed in this invention to inhibit HIV-1 tat mediated transactivation, enzyme essential for human immunodeficiency virus replication.
• HIV contains various genes, including "tat” which encodes a trans-activator (TAT) that functions in the infected cell by increasing the levels of steady-state viral mRNA as well as the translational utilization of this mRNA. TAT is both essential for HIV replication and not structurally related to any normal cellular protein.
• TAT trans-activator
• "A Rapid, Quantitative Bioassay Based on the Human Immunodeficiency Virus Trans-Activator” is described in AIDS RESEARCH AND HUMAN RETROVIRUSES, Vol. 5, Number 5, 1989, pp 507-516. The results (% Inhibition in sCD4 levels) in Table I.
• the anti-HIV utility of this invention is further demonstrated by determining the levels of HIV p24 and HIV RNA in culture supematants of human peripheral blood lymphocytes (PBLs) 3 and 4 days after HIV infection.
• the HIV infectivity experiments were conducted in primary cultures of (PBLs) with HTLV-IIIB. Cultures were infected in triplicate with HIV, Compound 1 added, and 3 to 4 days after infection the levels of HIV p24 synthesized and released were quantified by an enzyme-linked immunosorbent assay (ELISA) [R. Maiolini and R. Masseyeff, J. Immunol.

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• Organic Chemistry (AREA)
• Animal Behavior & Ethology (AREA)
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• Molecular Biology (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Oncology (AREA)
• Communicable Diseases (AREA)
• Genetics & Genomics (AREA)
• Biotechnology (AREA)
• Biochemistry (AREA)
• Engineering & Computer Science (AREA)
• Epidemiology (AREA)
• AIDS & HIV (AREA)
• Tropical Medicine & Parasitology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

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• 1991
  • 1991-07-16 EP EP91913197A patent/EP0541597A1/de not_active Ceased
  • 1991-07-16 AU AU82300/91A patent/AU640511B2/en not_active Ceased
  • 1991-07-16 WO PCT/US1991/004849 patent/WO1992002530A1/en not_active Application Discontinuation
  • 1991-07-16 CA CA002085367A patent/CA2085367A1/en not_active Abandoned
  • 1991-07-16 JP JP3512462A patent/JPH05509306A/ja active Pending

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