WO2000032177A2 - Utilisation de composes 17-cetosteroides et de leurs derives, metabolites et precurseurs pour le traitement du virus de l'hepatite c ou autres togavirus - Google Patents

Utilisation de composes 17-cetosteroides et de leurs derives, metabolites et precurseurs pour le traitement du virus de l'hepatite c ou autres togavirus Download PDF

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WO2000032177A2
WO2000032177A2 PCT/US1999/028082 US9928082W WO0032177A2 WO 2000032177 A2 WO2000032177 A2 WO 2000032177A2 US 9928082 W US9928082 W US 9928082W WO 0032177 A2 WO0032177 A2 WO 0032177A2
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Prior art keywords
compound
formula
alkyl
virus
optionally substituted
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WO2000032177A3 (fr
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Clarence Nathaniel Ahlem
James Martin Frincke
Patrick T. Prendergast
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Colthurst Ltd
Harbor Biosciences Inc
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Colthurst Ltd
Hollis Eden Pharmaceuticals Inc
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Priority to KR1020017006525A priority Critical patent/KR20010101074A/ko
Priority to IL14294299A priority patent/IL142942A0/xx
Priority to BR9915644-0A priority patent/BR9915644A/pt
Priority to AU31052/00A priority patent/AU775614B2/en
Priority to EP99965050A priority patent/EP1133287A2/fr
Priority to HK02102267.0A priority patent/HK1042426A1/zh
Priority to JP2000584873A priority patent/JP2002531397A/ja
Priority to NZ511721A priority patent/NZ511721A/en
Application filed by Colthurst Ltd, Hollis Eden Pharmaceuticals Inc filed Critical Colthurst Ltd
Priority to APAP/P/2001/002181A priority patent/AP2001002181A0/en
Priority to CA002352205A priority patent/CA2352205A1/fr
Publication of WO2000032177A2 publication Critical patent/WO2000032177A2/fr
Publication of WO2000032177A3 publication Critical patent/WO2000032177A3/fr
Priority to IL142942A priority patent/IL142942A/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
    • A61K31/5685—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone having an oxo group in position 17, e.g. androsterone
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/06—Antimalarials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/08—Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • C07J1/0003—Androstane derivatives
    • C07J1/0011—Androstane derivatives substituted in position 17 by a keto group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J3/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by one carbon atom
    • C07J3/005—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by one carbon atom the carbon atom being part of a carboxylic function
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to steroid compositions and methods to use them to treat flavivirus and togavirus infections, such as human hepatitis C virus (“HCN”) infections.
  • flavivirus and togavirus infections such as human hepatitis C virus (“HCN”) infections.
  • HTN human hepatitis C virus
  • the present invention is directed to the use of 17-ketosteroid compounds, as well as derivatives, metabolites and precursors of such compounds, and pharmaceutically acceptable salts of any of these compounds, collectively defined herein as the "compounds of the present invention", optionally together with one or more additional chemical agents and/or treatment methods (as described below) in the treatment of hepatitis C type virus and/or hepatitis G type virus in patients in need of such treatment.
  • the present invention is directed to methods of treatment of togaviruses, including alphaviruses (also known as arboviruses, group A), flaviviruses (also known as arboviruses, group 13)(such as yellow fever, as well as hepatitis C and hepatitis G), rubiviruses (also known as rubella viruses)(such as rubella) and pestiviruses (also known as mucosal disease viruses)(such as bovine virus diarrhea virus (BVDN)).
  • alphaviruses also known as arboviruses, group A
  • flaviviruses also known as arboviruses, group 13
  • rubiviruses also known as rubella viruses
  • pestiviruses also known as mucosal disease viruses
  • BVDN bovine virus diarrhea virus
  • Hepatitis C virus infection is extremely common, with estimates of worldwide prevalence of chronic hepatitis ranging from 90 million up to over 200 million (2 % to 4 %). There is no vaccine or candidate vaccine for pre-exposure prophylaxis and no effective globulin for post- exposure prophylaxis.
  • the major liability of HCV infection is the propensity to develop chronic hepatitis in at least 75 % of the cases; virtually all infected patients may be chronically infected. It is theorized that HCN-related liver injury is directly or indirectly related to cytotoxic Tlymphocytes (CTL) directed at viral peptides expressed on the hepatocyte membrane.
  • CTL cytotoxic Tlymphocytes
  • CTL CTL are localized within the liver, are present in small numbers, and are probably only transiently effective since the virus is so heterogeneous and mutates at such a rapid rate.
  • purely antiviral compounds such as nucleoside analogues or enzyme inhibitors, are likely to be virostatic but unlikely to eliminate infection.
  • immune directed therapies such as antibody preparations or cellular immune stimulants are likely to be transiently effective due to changes or mutations in the virus.
  • Chronic hepatitis C is insidiously progressive. In general, infection progresses to chronic hepatitis, cirrhosis, liver failure, and hepatocellular carcinoma over a period of decades, not months or years.
  • a reliable and effective cell culture for HCV does not exist. In addition, no nonprimate animal model exists. As a result, few agents have been tested against HCV. It is known that acyclovir, ribavirin, and corticosteroids are ineffective, and that corticosteroids increase the level of HCV replication.
  • Interferons have been used in the treatment of chronic hepatitis C.
  • Interferons are natural glycoproteins produced by cells in response to infection by viruses.
  • Interferons inhibit the replication of a wide spectrum of RNA and DNA viruses, including hepatitis viruses. This occurs via a variety of mechanisms including inhibition of virus attachment and uncoating, induction of intracellular proteins and ribonucleases which convey antiviral properties to the cell, and amplification of both specific (cytotoxic T- lymphocyte) and nonspecific (natural killer cell) immune response to viral proteins.
  • the specific mechanism of interferon activity in chronic hepatitis C infection is not known.
  • interferon was evaluated as a potential treatment for patients with non-A, non-B hepatitis before the hepatitis C virus was even identified.
  • Several reports indicate that a response during interferon therapy can be expected in about 40 % of chronic hepatitis C patients, and this response generally occurs quickly.
  • HCV RNA levels fall dramatically and become undetectable within 4 - 8 weeks in the majority of patients who subsequently normalize their serum aminotransferases.
  • interferon can intensify an immune-mediated hepatocullular inflammation (see Shindo et al, "Acute exacerbation of liver disease during interferon alfa therapy for chronic hepatitis C" Gastroenterology 1992: 102: 1406- 1408).
  • Interferon can transform chronic viral hepatitis into an autoimmune hepatitis (Silva et al, "Interferon- induced chronic active hepatitis?" Gastroenterology 1991: 101: 840-8-42).
  • Administering interferon can also induce production of a variety of autoantibodies of uncertain clinical significance (Mayet et al, "Treatment of chronic type B hepatitis with recombinant alpha- interferon induces autoantibodies, not specific for autoimmune chronic hepatitis," Hepatology
  • Interferon causes an increase in HLA display on membrane surfaces, impairs suppressor T cell function, enhances autoantibody production, stimulates natural killer cell function, affects cytokine release, and activates macrophages, making it capable of worsening an immune-mediated disease (Baron et al., "The interferons: ⁇ mechanisms of action and clinical applications," JAMA 1991; 266:1375-1383, which is incorporated herein by reference).
  • the advantages of therapy are unproved and doubtful.
  • interferon has a number of well- known side effects, including fever, chills, flu like syndrome, fatigue, anorexia, worsening in performance status, nausea and vomiting, weight loss, leukopenia, anemia, neurological symptoms, psychological symptoms and dyspnea. See, e.g., Tsavaris, N. et al, "Treatment of renal cell carcinoma with escalating doses of alpha-interferon," Chemotherapy, 1993 Sep-Oct; 39 (5): 361-6.
  • interferon has been linked with the development of thyroid disease in HCV patients. Lisker-Melman M, et al., "Development of thyroid disease during therapy of chronic viral hepatitis with interferon alfa". Gastroenterology 1992 Jun;102(6):2155-60.
  • Ribavarin is a compound which is reported to have a broad spectrum of in vitro activity against both RNA and DNA viruses, including flaviviridae related to hepatitis C. Pilot studies reported reduction of both serum ALT and HCV RNA levels in patients with chronic HCV infection, but in a subsequent randomized controlled trial, the antiviral effect of ribavirin alone . could not be confirmed. Several subsequent small studies appear to demonstrate a synergistic effect of ribavirin and interferon in patients with hepatitis C infection, however, the risks and side effects of interferon monotherapy remain as important drawbacks.
  • Hepatitis G virus (HGV; also called hepatitis GB virus C or HGBV-C) was fully characterized in early 1996. HGV is a flavivirus and a distant relative of HCV. At this time, HGV infection can be identified only through PCR testing, which indicates current infection. Such testing is not readily available or standardized.
  • HGV RNA is usually no longer present. Transmission of HGV through blood transfusion has been documented (the only Canadian study indicated that infection may occur in 1 in 1500 transfusion recipients and account for 9% of post-transfusion hepatitis), and from mother to child in the perinatal period. There is an increased prevalence of HGV RNA among groups with frequent exposure to blood or blood products (e.g., persons with hemophilia or thalassemia, patients on hemodialysis and injection drug users). Other modes of transmission (e.g., sexual) are possible but have not been well documented.
  • HGV steroid compound
  • a principal embodiment of the invention provides a method to treat or prevent a togavirus infection comprising administering to a subject an effective amount of a compound(s) of formula 1,
  • Q is -C(R,) 2 - or -C(0)-;
  • Q 2 is -C(R,) 2 -, -C(R,)(Y)-, -C(Y)- or -CH 2 -CH 2 -;
  • Q 3 is -H or -C(R ⁇ ) 3 -;
  • Qs is -C ⁇ - or -QO)-
  • R 2 is -H, -OH, -F, -Cl, -Br, -I, C 1-6 alkyl, Ci-e alkoxy, -OR 3 , an ester (e.g., -0-C(0)-R, or - C(0)-0-R,), a thioester (e.g., -0-C(S)-R 4 or -C(S)-0-R 4 ), a thioacetal (e.g., -S-C ⁇ -R,, or -C(0)-S- R 4 ), a sulfate ester (e.g., -0-S(0)(0)-0-R ), a sulfonate ester (e.g., -0-S(0)-0-R 4 ) or a carbamate (e.g., -0-C(0)-NH-R 4 or -NH-C(0)-0-R 4 ) or R 2 , together with the R ⁇ that is bonded to the same carbon
  • R 3 is -S(0)(0)-OM, -S(0)(0)-0-CH 2 -CH(0-C(0)-R 0 )-CH 2 -0-C(0)-R 6 , -P(0)(0)-0-CH 2 -CH(0-C(0)-R 7 )-CH2-0-C(0)-R 7 , a glucuronide group of structure (A)
  • R 3 is C1. 1 8 alkyl, Qj-is alkenyl, C 2 - ⁇ s alkynyl, a C MS ester or a C MS thioester, where any of the. foregoing C MS or C 2 - 1 8 moieties are optionally substituted at one or more hydrogen atoms with one or more independently selected -OR PR , (including -OH), -NHR PR , (including -NH 2 ) or -SR PR , (including -SH) groups, or R 3 is a C MS fatty acid, C 2 . 1 0 alkynyl, (J) n -phenyl-C ⁇ . 5 -alkyl, (J) n -phenyl- C 2 - 5 -alkenyl;
  • R-t is -H, a protecting group, optionally substituted C S alkyl, optionally substituted C
  • Another invention embodiment comprises a method to treat or prevent a togavirus infection comprising administering to a subject a compound of the invention simultaneously or sequentially with a compound of formula 2A or 2B wherein a double or a single bond is present at the dotted line and, when a double bond is present, (i) the optionally substituted phenyl ring at the 2- or 3-position is present and the Rg that is bonded to the carbon is absent, and (ii) one R 8 at the adjacent 2- or 3-position is absent;
  • X is ' -0- or -C(Rs) 2 -;
  • Rio is C ⁇ _ 6 alkyl, alkoxy, neohesperidoside, apioglucoside, rutinoside, glucoside, galactoside, rhamnoside, arabinoside, or a stereoisomer, hydrate, analog, derivative or metabolite of any of these moieties, any of which are optionally independently substituted at one or more hydrogen atoms with -OH, halogen, C ⁇ alkyl, C
  • Another embodiment of the invention is a method to treat or prevent a togavirus infection, including one or more infections with alphaviruses, flaviviruses, rubiviruses or pestiviruses, comprising administering to a subject a compound of the invention ( a formula 1 compound) and a macrophage stimulating factor and optionally also administering a formula 2A or 2B compound.
  • a further invention embodiment is a method to treat or prevent a togavirus infection, including one or more infections with alphaviruses, flaviviruses, rubiviruses or pestiviruses, comprising administering to a subject a compound of formula 1 and (1) administering an oxidation agent or (2) using oxygen ventilation and optionally also administering a macrophage stimulating factor(s) and or a formula 2A or 2B compound.
  • Another invention embodiment is a method to treat or prevent a togavirus infection, including one or more infections with alphaviruses, flaviviruses, rubiviruses or pestiviruses, comprising administering to a subject a compound of formula 1 and ribavirin and/or ⁇ lFN and optionally also using one or more of a formula 2A or 2B compound, a macrophage stimulating factor, an oxidation agent or oxygen ventilation.
  • a "patient” or “subject” means a human or animal. Usually the animal is a vertebrate such as a primate, rodent, domestic animal or game animal. Primates include chimpanzees, cynomologous monkeys, spider monkeys, and macaques, e.g., Rhesus. Rodents include mice, rats, woodchucks, ferrets, rabbits and hamsters.
  • Domestic and game animals include cows, horses, pigs, deer, bison, buffalo, felines, e.g., domestic cat, canines, e.g., dog, avians, e.g., chicken, emu, ostrich, and fish, e.g., trout, catfish and salmon.
  • felines e.g., domestic cat
  • canines e.g., dog
  • avians e.g., chicken, emu, ostrich
  • fish e.g., trout, catfish and salmon.
  • Patient or subject includes any subset of the foregoing, e.g., all of the above, but excluding one or more groups or species such as humans, primates or rodents.
  • Alkyl as used herein, unless stated to the contrary, is a C1-C18 hydrocarbon containing 1,
  • Halogen or "halo” means fluorine (-F), chlorine (-C1), bromine (-Br) or iodine (-1) and if more than one halogen is referred to (e.g., two or more variable groups may be a halogen), each halogen is independently selected.
  • Step nucleus means 4 fused rings having the formula 1 structure.
  • PEG means an ethylene glycol polymer that contains about 20 to about 2000000 linked monomers, typically about 50-1000 linked monomers, usually about 100-300.
  • Polyethylene glycols include PEGs containing various numbers of linked monomers, e.g., PEG20, PEG30, PEG40, PEG60, PEG80, PEGIOO, PEGl 15, PEG 200, PEG 300, PEG400, PEG500, PEG600, PEG 1000, PEG 1500, PEG2000, PEG 3350, PEG4000, PEG4600, PEG5000, PEG6000, PEG8000, PEGl 1000, PEG 12000, PEG2000000 and any mixtures thereof.
  • excipient or a “carrier” means a component or an ingredient that is acceptable in the sense of being compatible with the other ingredients of compositions or formulations as disclosed herein and not overly deleterious to the patient or animal to which the formulation is to be administered.
  • excipients and carriers include liquids, including benzyl benzoate, cottonseed oil, N,N-dimethylacetamide, a C 2 - ⁇ 2 alcohol (e.g., ethanol), glycerol, peanut oil, a PEG, vitamin E, poppyseed oil, propylene glycol, safflower oil, sesame oil, soybean oil and vegetable oil.
  • Excipients may exclude solvents such as olive oil, chloroform, dioxane or DMSO.
  • Excipients comprise one or more components typically used in the pharmaceutical formulation arts, e.g., fillers, binders, disintegrants and lubricants.
  • compositions or methods e.g., methods to treat a togavirus infection as disclosed herein, where one or more than one formula 1 or formula 2A or 2B compound is present, typically 1, 2, 3 or 4, usually 1.
  • Alcohol as used herein, includes excipients, means an alcohol that comprises a C 2 alkyl moiety substituted at one or more hydrogen atoms with one or more hydroxyl groups, usually one, two or three. Alcohols include, e.g., ethanol, n-propanol, i-propanol, w-butanol, /-butanol, s- butanol, t-butanol, «-pentanol, z ' -pentanol, «-hexanol, cyclohexanol, w-heptanol, w-octanol, n- nonanol, «-decanol and benzyl alcohol.
  • the carbon atoms in alcohols can be straight, branched or cyclic. Alcohol includes any subset of the foregoing, e.g., C 2 . alcohols (alcohols having 2, 3 or 4 carbon atoms).
  • esters means a moiety that comprises a -C(0)-0- structure.
  • esters as used here comprise an organic moiety containing about 1-50 carbon atoms (e.g., about 2-12 carbon atoms) and 0 to about 10 independently selected heteroatoms (e.g., O, S, N, P, Si), where the organic moiety is bonded to a formula 1 steroid nucleus at R 2 through the -C(0)-0- structure, e.g., organic moiety-C(Q)-0-steroid or organic moiety-0-C(0)-steroid.
  • the organic moiety usually comprises one or more of any of the organic groups described above, e.g., C 1 . 2 0 alkyl moieties, C 2 .
  • alkenyl moieties C 2 - 2 0 alkynyl moieties, aryl moieties, C 2 .9 heterocycles or substituted derivatives of any of these, e.g., comprising 1, 2, 3, 4 or more substituents, where each substituent is independently chosen.
  • the organic moiety includes compounds defined by the R variable.
  • the organic moieties exclude obviously unstable moieties, e.g., -O-O-, except where such unstable moieties are transient species that one can use to make a compound with sufficient chemical stability for the one or more of the uses described herein.
  • Thioester means a moiety that comprises a -C(S)-0- structure.
  • thioesters as used here comprise an organic moiety containing about 1-50 carbon atoms (e.g., about 2-12 carbon atoms) and 0 to about 10 heteroatoms (e.g., O, S, N, P, Si), where the organic moiety is bonded to a formula 1 steroid nucleus at R 2 through the -C(S)-0- structure, e.g., organic moiety-C(S)-0-steroid or organic moiety-0-C(S)-steroid.
  • the organic moiety usually comprises one or more of any of the organic groups described above, e.g., Cuo alkyl moieties, C 2 .
  • the organic moiety includes compounds defined by the R 4 variable.
  • the organic moieties exclude obviously unstable moieties, e.g., -O-O-, except where such unstable moieties are transient species that one can use to make a compound with sufficient chemical stability for the one or more of the uses described hqfein.
  • substitutions listed above are typically substituents that one can use to replace one or more carbon atoms, e.g., -O- or -C(O)-, or one or more hydrogen atom, e.g., halogen, -NH 2 or -OH.
  • Thioacetal means a moiety that comprises a -C(0)-S- structure.
  • thioacetals as used here comprise an organic moiety containing about 1-50 carbon atoms (e.g., about 2-12 carbon atoms) and 0 to about 10 heteroatoms (e.g., O, S, N, P, Si), where the organic moiety is bonded to a formula 1 steroid nucleus at R 2 through the -C(0)-S- structure, e.g., organic moiety-C(0)-S-steroid or organic moiety-S-C(0)-steroid.
  • the organic moiety is as described above for thioesters.
  • “Carbamate” means an organic moiety as described for ester that comprises 1, 2, 3, 4 or more -0-C(O)NR PR - structures where R PR is -H, a protecting group or an organic moiety as described for ester.
  • carbamate groups as used here comprise an organic moiety containing about 1-50 carbon atoms (e.g., about 2-12 carbon atoms) and 0 to about 10 heteroatoms (e.g., O, S, N, P, Si), where the organic moiety is bonded to a formula 1 steroid nucleus at R 2 through the -0-C(0)-NR PR - structure, e.g., organic moiety-NR PR -C(0)-0-steroid or organic moiety- 0-C(0)-NR PR -steroid.
  • sulfate ester means a moiety that comprises a -0-S(0)(0)-0- structure.
  • sulfate esters as used here comprise an organic moiety containing about 1-50 carbon atoms (e.g., about 2-12 carbon atoms) and 0 to about 10 heteroatoms (e.g., O, S, N, P, Si), where the organic moiety is bonded to a formula 1 steroid nucleus at R 2 through the -0-S(0)(0)-0- structure, e.g., organic moiety-0-S(0)(0)-0-steroid.
  • the organic moiety is as described above for thioesters.
  • “Sulfite ester” means a moiety that comprises a -0-S(0)-0- structure.
  • sulfite esters as used here comprise an organic moiety containing about 1-50 carbon atoms (e.g., about 2- 12 carbon atoms) and 0 to about 10 heteroatoms (e.g., O, S, N, P, Si), where the organic moiety is bonded to a formula 1 steroid nucleus at R 2 through the -0-S(0)-0- structure, e.g., organic moiety- 0-S(0)-0-steroid.
  • the organic moiety is as described above for thioesters.
  • compositions disclosed herein optionally comprise salts of the formula 1 and 2 compounds that comprise an ionizable moiety or a polar moiety.
  • salts include complexes that comprise moieties of opposite charge. Ionizable moieties include -0-S(0)(0)-OH or an -NH 2 group at R 2 and polar moieties include -OH.
  • Salts include pharmaceutically acceptable salts that comprise, for example, an uncharged moiety or a monovalent anion moiety or a monovalent cation moiety. Salts include compounds derived by combination of appropriate anions such as inorganic acids. Suitable acids include those having sufficient acidity to form a stable salt, preferably acids of low toxicity.
  • certain organic acids e.g., organic sulfonic acids, organic carboxylic acids in the same manner.
  • Exemplary organic sulfonic acids include C6-16 aryl sulfonic acids, C6-16 heteroaryl sulfonic acids and Ci-16 alkyl sulfonic acids such as phenyl, ⁇ -naphthyl, ⁇ -naphthyl, (5)-camphor, methyl, ethyl, w-propyl, z ' -propyl, n- butyl, 5-butyl, /-butyl, t-butyl, pentyl and hexyl sulfonic acids.
  • Exemplary organic carboxylic acids include C ⁇ . ⁇ alkyl, C6-16 aryl carboxylic acids and C4.I6 heteroaryl carboxylic acids such as acetic, glycolic, lactic, pyruvic, malonic, glutaric, tartaric, citric, fumaric, succinic, malic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic and 2-phenoxybenzoic. Salts also include the invention compound salts with one or more amino acids.
  • amino acids are suitable, especially the naturally occurring amino acids found as protein components, although the amino acid typically is one bearing a side chain with a basic or acidic group, e.g., lysine, arginine or glutamic acid, or a neutral group such as glycine, serine, threonine, alanine, isoleucine, or leucine.
  • Salts are usually biologically compatible or pharmaceutically acceptable or non-toxic, particularly for mammalian cells. Salts that are biologically toxic are generally used as synthetic intermediates for making other invention compounds.
  • neohespcridoside, rutinosidc and glucoside groups have the structures
  • Heterocycle or “heterocyclic” includes by way of example and not limitation these heterocycles described in Paquette, Leo A.; “Principles of Modern Heterocyclic Chemistry” (W. A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds, A series of Monographs” (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. 1960, 82:5566; and U.S. patent 5763483, all of which are incorporated herein by reference.
  • heterocycles include by way of example and not limitation pyridyl, thiazolyl, tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, azocinyl, triazinyl
  • carbon bonded heterocycles are bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline.
  • carbon bonded heterocycles include 2-pyridyl, 3- pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.
  • nitrogen bonded heterocycles are bonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, lH-indazole, position 2 of a isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or ⁇ -carboline.
  • nitrogen bonded heterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1 -piperidinyl.
  • Heteroaryl means an aromatic ring or two or more fused rings that contain one or more aromatic rings where the ring or fused rings comprise 1, 2, 3 or more heteroatoms, usually oxygen (-0-), nitrogen (-NX-) or sulfur (-S-) where X is -H, a protecting group or C ⁇ _ 5 alkyl, usually -H. Examples are as described for heterocycle.
  • Various groups that the formula 1, 2 A or 2B compounds may comprise include, e.g., substituted alkyl groups, substituted alkenyl groups, esters or substituted heterocycles, which can contain one or more reactive moieties such as hydroxyl, or thiol.
  • Intermediates used to make formula 1 or formula 2A or 2B compounds may be protected as is apparent in the art. Noncyclic and cyclic protecting groups and corresponding cleavage reactions are described in "Protective Groups in Organic Chemistry", Theodora W. Greene (John Wiley & Sons, Inc., New York, 1991, ISBN 0-471-62301-6) (hereafter “Greene”).
  • these protecting groups are groups that can be removed from the molecule of the invention without irreversibly changing the covalent bond structure or oxidation/reduction state of the remainder of the molecule.
  • the protecting group, -X that is bonded to a -OX or -NHX group can be removed to form -OH or -NH 2 , respectively, without affecting other covalent bonds in the molecule.
  • more than one protecting group can be removed at a time, or they can be removed sequentially.
  • the protecting groups are the same or different.
  • Protecting groups are intended to be removed by known procedures, although it will be understood that the protected intermediates fall within the scope of this invention.
  • protecting group may be arduous or straightforward, depending upon the economics and nature of the conversions involved.
  • a protecting group with exocyclic amines or with carboxyl groups during synthesis of a formula 1 compound.
  • a ine groups should be deprotected.
  • Protecting groups commonly are employed to protect against covalent modification of a sensitive group in reactions such as alkylation or acylation.
  • protecting groups are removed by, e.g. hydrolysis, elimination or aminolysis.
  • Suitable protecting groups and criteria for their selection are described in T.W. Greene and P.G.M.
  • a group is a protecting group if when, based on mole ratio, 90% of that protecting group has been removed by a deprotection reaction, no more than 50%, preferably 25%, more preferably 10%, of the deprotected product molecules of the invention have undergone changes to their covalent bond structure or oxidation/reduction state other than those occasioned by the removal of the protecting group.
  • the mole ratios are determined when all of the groups of that type are removed.
  • each type of protecting group is treated (and the mole ratios are determined) independently or together with others depending on whether the deprotection reaction conditions pertinent to one type are also pertinent to the other types present.
  • a group is a protecting group if when, based on mole ratio determined by conventional techniques, 90% of that protecting group has been removed by a conventional deprotection reaction, no more than 50%, preferably 25%, more preferably 10%, of the deprotected product molecules of the invention have undergone irreversible changes to their covalent bond structure or oxidation/reduction state other than those occasioned by the removal of the protecting group. Irreversible changes require chemical reactions (beyond those resulting from aqueous hydrolysis, acid/base neutralization or conventional separation, isolation or purification) to restore the covalent bond structure or oxidation/reduction state of the deprotected molecule of the invention.
  • Methyl Substituted Methyl Ethers (Methoxymethyl, Methylthiomethyl, t-Butylthiomethyl, (Phenyldimethylsilyl)methoxymethyl, Benzyloxymethyl, p-Methoxybenzyloxymethyl, (4- Methoxyphenoxy)methyl, Guaiacolmethyl, t-Butoxymethyl, 4-Pentenyloxymethyl, Siloxymethyl, 2-Methoxyethoxymethyl, 2,2,2-Trichloroethoxymethyl, Bis(2-chloroethoxy)methyl, 2- (Trimethylsilyl)ethoxymethyl, Tetrahydropyranyl, 3-Bromotetrahydropyranyl, Tetrahydropthiopyranyl, 1-Methoxycyclohexyl, 4-methoxytetrahydropyranyl, 4- Methoxytetrahydrothiopyranyl, 4-Methoxytetrahydropthiopyranyl S,S-Dioxid
  • hydroxy protecting groups include subtituted methyl ethers, substituted benzyl ethers, silyl ethers, and esters including sulfonic acid esters, still more typically, trialkylsilyl ethers, tosylates and acetates.
  • 1,2- and 1,3-diol protecting groups include epoxides and acetonides.
  • Typical amino protecting groups are described in Greene at pages 315-385 and include Carbamates (Methyl and Ethyl, 9-Fluorenylmethyl, 9(2-Sulfo)fluoroenylmethyl, 9-(2,7- Dibromo)fluorenylmethyl, 2,7-Di-t-buthy 1- [9-( 10, 10-dioxo- 10,10,10,10- tetrahydrothioxanthyl)]rnethyl, 4-Methoxyphenacyl); Substituted Ethyl (2,2,2-Trichoroethyl, 2-
  • Trimethylbenzyl Trimethylbenzyl
  • Amides N-Formyl, N-Acetyl, N-Choroacetyl, N-Trichoroacetyl, N- Trifluoroacetyl, N-Phenylacetyl, N-3-Phenylpropionyl, N-Picolinoyl, N-3-Pyridylcarboxamide, N- Benzoylphenylalanyl Derivative, N-Benzoyl, N-p-Phenylbenzoyl); Amides With Assisted Cleavage (N-o-Nitrophenylacetyl, N-o-Nitrophenoxyacetyl, N-Acetoacetyl, (N'- Dithiobenzyloxycarbonylamino)acetyl, N-3-(p-Hydroxyphenyl)propionyl, N-3-(o- Nitrophenyl)propionyl, N-2-Methyl-2-(
  • amino protecting groups include carbamates and amides, still more typically, N-acetyl groups.
  • the formula 1 and formula 2A or 2B compounds include enriched or resolved optical isomers at any or all asymmetric atoms as are apparent from the depictions. Both racemic and diasteromeric mixtures, as well as the individual optical isomers can be isolated or synthesized so as to be substantially free of their enantiomeric or diastereomeric partners, and these are all within the scope of the invention. Chiral centers may be found in invention compounds at, for example, R* , R ⁇ or R ⁇ .
  • One or more of the following methods are used to prepare the enantiomerically enriched or pure isomers herein.
  • the methods are listed in approximately their order of preference, i.e.; one ordinarily should employ stereospecific synthesis from chiral precursors before chromatographic resolution before spontaneous crystallization.
  • Stereospecific synthesis is described in the examples. Methods of this type conveniently are used when the appropriate chiral starting material is available and reaction steps are chosen that do not result in undesired racemization at chiral sites.
  • One advantage of stereospecific synthesis is that it does not produce undesired enantiomers that must be removed from the final product, thereby lowering overall synthetic yield. In general, those skilled in the art would understand what starting materials and reaction conditions should be used to obtain the desired enantiomerically enriched or pure isomers by stereospecific synthesis.
  • Enzymatic resolution is another method of potential value.
  • one prepares covalent derivatives of the enantiomers in the racemic mixture, generally lower alkyl esters, and then exposes the derivative to enzymatic cleavage, generally hydrolysis.
  • an enzyme must be chosen that is capable of stereospecific cleavage, so it is frequently necessary to routinely screen several enzymes. If esters are to be cleaved, then one selects a group of esterases, phosphatases, and lipases and determines their activity on the derivative. Typical esterases are from liver, pancreas or other animal organs, and include porcine liver esterase.
  • the enantiomeric mixture separates from solution or a melt as a conglomerate, i.e., a . mixture of enantiomerically pure crystals, then the crystals can be mechanically separated, thereby producing the enantiomerically enriched preparation.
  • This method is not practical for large-scale preparations and is of limited value for true racemic compounds.
  • Asymmetric synthesis is another technique for achieving enantiomeric enrichment. For example, a chiral protecting group is reacted with the group to be protected and the reaction mixture allowed to equilibrate. If the reaction is enantiomerically specific then the product will be enriched in that enantiomer.
  • Embodiments include compositions that transiently occur when a method step or operation is performed.
  • a formula 1 compound is contacted with an excipient, e.g., water, a cyclodextrin, a PEG, an alcohol, propylene glycol, benzyl alcohol or benzyl benzoate
  • the composition before addition of one ingredient with another is a non-homogenous mixture.
  • the mixture's homogeneity increases and the proportion of ingredients relative to each other approaches a desired value.
  • compositions as disclosed herein optionally contain less than about 3% w/w water, e.g., less than 0.5% w/w water, can comprise about 0.0001 -99% w/w of a formula 1 compound such as 16 ⁇ -bromoepiandrosterone and one or more excipients.
  • formula 1 compound such as 16 ⁇ -bromoepiandrosterone
  • excipients are intermediates that necessarily arise when one makes an invention composition or formulation and they are included in invention embodiments to the extent that they are patentable.
  • Togaviruses as used herein includes the Togaviridae family, including the Alphavirus and Rubivirus genera, as well as the flavivirus family (Flaviviridae) and the Flavivirus and Pestivirus genera. A review of virus taxonomy and the biology of these viruses may be found at, e.g., B.N.
  • the R moiety bonded to the steroid ring is generally in the ⁇ configuration
  • two Ri are bonded to Q 2
  • one of the Ri bonded to Q 2 is hydrogen in the ⁇ configuration
  • the other Ri bonded to Q 2 is hydrogen or a halogen, usually bromine, in the ⁇ configuration and a double bond is present at the 5-6 positions.
  • Such preferred compounds include dehydroepiandrosterone ("DHEA”) and 16 ⁇ - bromodehydroepiandrosterone (“Br-DHEA").
  • Other preferred compounds include compound having the structures 20-43
  • Q 3 and Q 6 are each -C(R ⁇ ) 3 wherein each R x is independently selected;
  • is independently selected and has the definition given above; and R has the definition given above.
  • the formula 1 compound has the structure 20-43 and 2, 3, 4, 5 or 6 Ri groups independently are -OH, halogen or alkoxy, and the remaining R are all hydrogen;
  • X is -OH or -0-C(0)-R 5 , or X, together with the R
  • at the 17-position comprises 0; and
  • Q 3 and Q 6 independently are -CH 3 or -CH 2 OH.
  • Such embodiments include structure 20-43 compounds where two -OH are present at the 3-position, the 16-position or at the 17-position.
  • Preferred invention embodiments include compounds having the formula 44
  • Y is hydrogen or bromine
  • R 4 is -H, -S(0)(0)-OH, -S(0)(0)-ONa, -S(0)(0)-0-CH 2 - CH(0-C(0)-R «)-CH 2 -0-C(0)-R 6 , -P(0)(0)-0-CH 2 -CH(0-C(0)-R 7 )-CH 2 -0-C(0)-R 7 or a glucuronide group of structure (A).
  • Y and R ⁇ in formula 44 are both hydrogen.
  • An especially preferred compound is dehydroepiandrosterone (Y and R ⁇ in formula 44 are both hydrogen and the double bond at the 5-6 position is present).
  • the compound is epiandrosterone (Y and R 44 in formula 44 are both hydrogen and the double bond at the 5-6 position is absent).
  • a 16-haloepiandrosterone with a F, Cl, Br or I at the 16 position can also be used as an antiviral agent, e.g., 16 ⁇ -bromoepiandrosterone.
  • Other preferred compounds are (i) 16 ⁇ -bromodehydroepiandrosterone, (ii) dehydroepiandrosterone-3-sulfate (Y is - H and R 44 is -S(0)(0)-OM in formula 44 are both hydrogen and the double bond at the 5-6 position is present) and (iii) 5 ⁇ -androstan-3 ⁇ -ol-17-one.
  • Related embodiments comprise compounds related to formula 44 compounds comprise the formula 44 compounds wherein 1, 2, 3, 4, 5 or 6 hydrogen atoms that are bonded to the steroid nucleus are substituted with independently selected -OH, -Br, - Cl, -F, -I, -OCH 3 or -OC 2 H 5 atoms or groups.
  • the 17-ketosteroids of formula 1 are dehydro-epiandrosterone where R 44 in formula 44 is a -S(0)(0)-0-CH 2 -CH(0-C(0)-R 6 )-CH 2 -0-C(0)-R 5 , -P(0)(0)-0-CH 2 -CH(0- C(0)-R 7 )-CH 2 -0-C(0)-R 7 or a glucuronide group of structure (A), Y is hydrogen and the 5-6 double bond is present.
  • formula 44 compounds include conjugates of dehydroepiandrosterone wherein Y is hydrogen, a double bond is present at the 5-6 position and R 4 is hexyl sulfate, dodecyl sulfate, octadecyl sulfate, octadecanoyl sulfate, O-dihexadecylglycerol sulfate, hexadecane sulfonate, dioctadecanoylglycerol phosphate or O-hexadecylglycerol phosphate.
  • the steroid of formula 1 is a compound of formula 45
  • Related embodiments comprise compounds related to formula 45 compounds wherein 1, 2, 3, 4, 5 or 6 hydrogen atoms that are bonded to the steroid nucleus are substituted with independently selected -OH, -Br, -Cl, -F, -I, -OCH 3 or -OC 2 H 5 atoms or groups.
  • the formula 1 compounds have the formula 1 B or 1 C
  • R 2 is -H, -OH, a halogen, C,.
  • Q 3 and Q 6 are usually both in the ⁇ -configuration, typically they are -CH 3
  • Related embodiments comprise compounds related to formula I B and 1C compounds wherein 1, 2, 3, 4, 5 or 6 hydrogen atoms that are bonded to the steroid nucleus are substituted with independently selected -OH, -Br, -Cl, -F, -I, -OCH 3 or -OC 2 H 5 atoms or groups.
  • the formula 1 compounds can exist in a crystalline or polymo ⁇ hic form. Metabolites. Also falling within the scope of this invention are the in vivo metabolites of the compounds of the invention, to the extent such products are novel and unobvious over the prior art.
  • the invention includes novel and unobvious compounds produced by a process comprising contacting a compound of this invention with a subject, e.g., a human, rodent or a primate, for a period of time sufficient to yield a metabolic product thereof.
  • a subject e.g., a human, rodent or a primate
  • Such products typically are identified by preparing a radiolabelled (e.g. C 14 or H 3 ) compound of the invention, administering it parenterally or orally in a detectable dose (e.g.
  • metabolite structures are determined in conventional fashion, e.g. by HPLC, MS or NMR analysis. In general, analysis of metabolites is done in the same way as conventional drug metabolism studies well-known to those skilled in the art.
  • the conversion products so long as they are not otherwise found in vivo, are useful in diagnostic assays for therapeutic dosing of the compounds of the invention even if they possess no therapeutic activity of their own.
  • R 2 is in the 3 ⁇ -position and hydrogen fills the remaining valence or R 2 is double bonded to the 3 carbon
  • R,A is an R x group at the 7 ⁇ -position or RiA is an Ri group double bonded to the 7 carbon
  • Y is in the l ⁇ -position and hydrogen fills the remaining valence or R 2 is double bonded to the 16 carbon
  • X is in the 17 ⁇ - position and hydrogen fills the remaining valence or X is double bonded to the 17 carbon.
  • 9.3.8.7, 9.3.8.8. 9.3.8.9, 9.3.8.10. 9.3.9.1 , 9.3.9.2. 9.3.9.3. 9.3.9.4, 9.3.9.5, 9.3.9.6, 9.3.9.7, 9.3.9.8, 9.3.9.9, 9.3.9.10, 9.3.10.1 , 9.3.10.2, 9.3.10.3, 9.3.10.4, 9.3.10.5, 9.3.10.6, 9.3.10.7, 9.3.10.8, 9.3.10.9, 9.3.10.10, 9.4.1.1, 9.4.1.2, 9.4.1.3, 9.4.1.4, 9.4.1.5, 9.4.1.6, 9.4.1.7, 9.4.1.8, 9.4.1.9, 9.4.1.10, 9.4.2.1, 9.4.2.2, 9.4.2.3, 9.4.2.4, 9.4.2.5, 9.4.2.6, 9.4.2.7, 9.4.2.8, 9.4.2.9, 9.4.2.10, 9.4.3.1, 9.4.3.2, 9.4.3.3, 9.4.3.4, 9.4.3.5, 9.4.3.6, 9.4.3.7, 9.4.3.8, 9.4.3.9, 9.4.3.10, 9.4.4.1, 9.4.4.2, 9.4.4.3, 9.4.4.4, 9.4.4.5, 9.4.4.6, 9.
  • Additional exemplary formula 1 compound groups include the following groups as disclosed below.
  • Group 2 compounds are as named in Table B, i.e., R 2 , R,A, Y and X substituents are as defined in Table A, but they are bonded to the steroid nucleus shown in formula 5, which is the same as the formula 4 steroid nucleus, except that the 5-6 double bond is absent and hydrogen is present at the 5 -position in the ⁇ -configuration
  • Group 3 compounds are as named in Table B, i.e., R 2 , RiA, Y and X substituents are as defined in Table A, but they are bonded to the steroid nucleus shown in formula 6, which is the same as the formula 4 steroid nucleus, except that the 5-6 double bond is absent and hydrogen is present at the 5-position in the ⁇ -configuration
  • Group 4 compounds are as named in Table B, i.e., R , RiA, Y and X substituents are as defined in Table A, but they are bonded to the steroid nucleus shown in formula 7, which is the same as the formula 4 steroid nucleus, except that Q 3 is -CH 2 OH
  • the group 4 compound named 1.2.1.1 has the structure
  • Group 5 compounds are as named in Table B, i.e., R 2 , RiA, Y and X substituents are as defined in Table A, but they are bonded to the steroid nucleus shown in formula 8, which is the same as the formula 4 steroid nucleus, except that the 5-6 double bond is absent and hydrogen is present at the 5-position in the ⁇ -configuration and Q 3 is -CH 2 OH
  • Group 6 compounds are as named in groups 1-5, except that Q 6 in formulas 4-8 is -CII 2 OH instead of methyl.
  • group 6 there arc 5 subgroups of group 6 compounds.
  • the first subgroup, subgroup 6-1 has the same steroid nucleus with the substituents as defined for group 1 compounds while the second, subgroup 6-2, has the same steroid nucleus with the substituents as defined for group 2 compounds.
  • Subgroups 6-3 through 6-5 have the same steroid nucleus with the substituents as defined for group 3 through 5 respectively.
  • the subgroup 6-1 compound named 1.2.1.1 has the structure
  • Group 7 compounds are as named in groups 1-5, except that the Y moiety in formulas 4-8 is in the ⁇ -configuration instead of in the ⁇ -configuration.
  • Group 7 comprises 5 subgroups, wherein the compounds are named essentially as described for group 6 compounds, except that the Y group is in the ⁇ -configuration.
  • Group 8 compounds are as named in groups 1-5, except that the X moiety in formulas 4-8 is in the ⁇ -configuration instead of in the ⁇ -configuration.
  • Group 8 comprises 5 subgroups, wherein the compounds are named essentially as described for group 6 compounds, except that the X group is in the ⁇ -configuration.
  • Group 9 compounds are as named in groups 1-5, except that the R 2 moiety in formulas 4-8 is in the ⁇ -conf ⁇ guration instead of in the ⁇ -configuration.
  • Group 9 comprises 5 subgroups, wherein the compounds are named essentially as described for group 6 compounds, except that the R 2 group is in the ⁇ -configuration.
  • Group 10 compounds are as named in groups 1-9, except that R moieties 1 through 10 in Table A are replaced with the following moieties.
  • Group 10 comprises 25 subgroups of compounds.
  • the first, subgroup 10-1 has the same steroid nucleus with substituents as defined for group 1 , except that the R 2 moieties or groups listed replace those in Table A above.
  • the subgroup 10-1 compound named 1.2.1.1 has the structure
  • Group 11 1 compounds are as named in groups 1-9, except that R 2 moieties 1 through 10 in Table A are replaced with the following moieties. 1 -S-C(0)-CH 2 CH2-0-CH 2 CH3
  • Group 1 1 comprises 25 subgroups, wherein the compounds are named essentially as described for group 10 compounds, except that the R 2 group is given above.
  • Group 12 compounds are as named in groups 1-9, except that R 2 moieties 1 through 10 in Table A are replaced with the following moieties. 1 -S-C(0)-CH 2 CH 2 -0-CH 2 C(0)OH 2 -S-C(0)-CH 2 -C 6 H 4 F
  • Group 13 compounds are as named in groups 1-9, except that R 2 moieties 1 through 10 in Table ⁇ are replaced with the following moieties. 1 -S-C(0)-CH 2 CH 2 -0-CH 2 CH 2 OH 2 -S-C(0)-CH 2 -C 6 H 4 CH 3
  • Group 14 compounds are as named in groups 1-9, except that R 2 moieties 1 through 10 in Table A are replaced with the following moieties.
  • Group 15 compounds are as named in groups 1-9, except that R 2 moieties 1 through 10 in Table A are replaced with the following moieties. 1 -S-C(0)-CH 2 CH 2 -0-CH 2 CH 2 NHR PR 2 -S-C(0)-CH 2 -C 6 H 3 (OR PR ) 2
  • Group 16 compounds are as named in groups 1-9, except that R moieties 1. through 10 in Table A are replaced with the following moieties.
  • Group 17 compounds are as named in groups 1-9, except that R moieties 1 through 10 in Table A arc replaced with the following moieties.
  • Group 18 compounds are as named in groups 1-9, except that R 2 moieties 1 through 10 in Table A are replaced with the following moieties.
  • Group 19 compounds are as named in groups 1-9, except that R 2 moieties 1 through 10 in Table A are replaced with the following moieties. 1 -0-CH 2 CH 2 -(0-CH 2 CH 2 ) ⁇ -5 o-H
  • Group 20 Group 20 compounds are as named in groups 1-9, except that R 2 moieties 1 through 10 in Table A are replaced with the following moieties. 1 -C(0)-0-CH 2 CH 2 -(0-CH 2 CH 2 )i -5 o-H
  • Group 21 10 -C(0)-0-CH 2 -C 6 H 4 F Group 21.
  • Group 21 compounds are as named in groups 1-9, except that R 2 moieties 1 through 10 in Table A are replaced with the following moieties.
  • the group 21 - 1 compound named 1.2.1.1 has the structure while the group 21-2 compound named 1.2.1.1 has the structure
  • alkyl C 2-8 alkenyl, C -g alkynyl, CM alkyl-aryl (e.g., benzyl), aryl (e.g. phenyl) or C alky1-C 2 .Q heterocycle.
  • Embodiments also include formula 1 compounds (e.g., formula 4 compounds) wherein R 4 is optionally substituted C ⁇ -8 alkyl, optionally substituted C 2 . 8 alkenyl, optionally substituted C 2-8 alkynyl, optionally substituted aryl, optionally substituted heterocycle, optionally substituted C ⁇ -8 alkyl-aryl, optionally substituted C ⁇ -8 alkyl-heterocycle or optionally substituted -CH 2 -C ⁇ .
  • R 4 is optionally substituted C ⁇ -8 alkyl, optionally substituted C 2 . 8 alkenyl, optionally substituted C 2-8 alkynyl, optionally substituted aryl, optionally substituted heterocycle, optionally substituted C ⁇ -8 alkyl-aryl, optionally substituted C ⁇ -8 alkyl-heterocycle or optionally substituted -CH 2 -C ⁇ .
  • R 4 moieties include -CH 2 -C ⁇ optionally substituted alkyl, -CH 2 -C 2 . 6 optionally substituted alkenyl, -CH 2 -C ⁇ . 6 - optionally substituted aryl and -CH 2 -C 2 -9 optionally substituted heterocycle.
  • Plasma concentration-enhancing compounds comprises administering an effective amount of a plasma concentration-enhancing compound, e.g., a compound of formula 2A or 2B compound with a formula 1 compound to facilitate preventing or treating one or more togavirus infections (including flavivirus, alphavirus, pestivirus or rubivirus) in a subject.
  • a plasma concentration-enhancing compound e.g., a compound of formula 2A or 2B compound with a formula 1 compound to facilitate preventing or treating one or more togavirus infections (including flavivirus, alphavirus, pestivirus or rubivirus) in a subject.
  • the plasma concentration-enhancing compounds include bavachinin ⁇ , didymin (isosakurnnctin-7-rutinosidc or neoponcirin), flavanomarein (isookanine-7-glucoside), flavanone azine, flavanone diacetylhydrazone, flavanone hydrazone, silybin, which has the structure
  • silandrin which has the structure
  • the formula 2A and 2B compounds encompass a number of natural and synthetic flavonoids, including certain flavones, flavans, and their iso analogs.
  • the presence of a formula 2A or 2B compound in compositions comprising a formula 1 compound has been found to enhance the systemic bioavailability of formulations that comprise a formula 1 compound.
  • the presence of a formula 2A or 2B compound, e.g., naringin or naringenin results in enhanced plasma concentrations of the formula 1 compound.
  • the formula 2A or 2B compound need not be present in a formulation that contains a formula 1 compound.
  • the formula 2A or 2B compound can also be administered, e.g., about 1-4 hours, before or after, preferably before, the formula 1 compound is administered. In these embodiments, one will administer an oral or parenteral formulation that contains a formula 1 compound and a formula 2A or 2B compound.
  • the plasma concentration-enhancing compounds include compounds of formulas 50-65
  • . & alkoxy, glucuronide, a C]. 2 s fatty acid or -CH 2 -CH C(CH 3 ) 2 ; and
  • Rio (i) is -OH or -F, -Cl, -Br, -I, C ⁇ . 6 alkyl, C . 6 alkoxy, neohesperidoside, apioglucoside, rutinoside, glucoside, galactoside, rhamnoside, arabinoside, or a stereoisomer, hydrate, analog, derivative or metabolite of any of these moieties, any of which are optionally independently substituted at one or more hydrogen atoms with -OH, -F, -Cl, -Br, -I, C ⁇ -6 alkyl, C w alkoxy, glucuronide or a C ⁇ .
  • Rio is the radical of bavachinin A, didymin, flavanomarein, flavanone azine, flavanone diacetylhydrazone, flavanone hydrazone, silybin, silychristin, isosilybin, silandrin, a moiety of structure (E) or a stereoisomer, hydrate, analog, derivative or metabolite of any of these moieties.
  • a method of treatment of one or more of the conditions described above, e.g., togavirus infections comprising administering a combination therapy including one or more of the compounds of the present invention administered simultaneously or sequentially with one or more macrophage stimulating factor (and optionally further co-
  • Macrophage stimulating factors are well known to those of skill in the art, examples including GM-CSF (see, e.g., Callard et al., The Cytokine Facts Book, Academic Press, 1994, p. 139, which is incorporated herein by reference) and Interleukin-4 (sold by Immunex as "Leukine” and by Schering Plough as "Prokine”).
  • the compounds of the present invention can be co-administered with one or more oxidation agent (optionally further together with a plasma concentration-enhancing compound and/or a macrophage stimulating factor), or the patient may be given oxygen ventilation to increase oxidative steroids in the plasma.
  • the present invention is further directed to a combination therapy for the treatment of patients suffering from hepatitis C and/or hepatitis G, comprising administering to the patient, simultaneously or sequentially, one or more of the compounds of the present invention together with ribavirin and/or alpha interferon, and optionally further together with one or more plasma concentration-enhancing compound, one or more macrophage stimulating factor, one or more oxidation agent, and/or oxygen ventilation.
  • the present invention is further directed to a combination therapy as discussed above in this paragraph for the treatment of patients suffering from or susceptible to any type of togavirus infection.
  • the invention also includes the use of combinations of compounds as disclosed herein in the manufacture of a medicament for use in the treatment of a togavirus or a flavivirus, in particular, HCV.
  • any of the combination therapies disclosed herein can be administered simultaneously (in a combination formulation), essentially simultaneously (e.g., administration of each compound a few minutes or a few hours apart), or they can be administered sequentially, e.g., several days apart, or more than a week apart.
  • a compound of the present invention and a plasma-concentration-enhancing compound (and/or a macrophage stimulating factor) can be administered together, or essentially simultaneously, e.g., administration of each compound a few minutes or a 1 few hours apart, or can be administered sequentially, e.g., several days apart, or more than a week apart (optionally together with simultaneous or sequential administration of oxidizing agent or oxygen ventilation). All such variations in administration of the combination therapy are encompassed within the scope of the invention.
  • the invention also includes pharmaceutical formulations containing any combination that is described herein.
  • the present invention is also directed to the use of compounds of the present invention in the manufacture of a medicament for therapeutic treatments as described herein, e.g., for treatment of a togavirus infection such as HCV.
  • the present invention is also directed to administering compounds of the present invention (optionally together with one or more combination compounds) to provide a prophylactic treatment of a patient to prevent, e.g., togavirus infections.
  • Articles of manufacture also provides articles of manufacture comprising, for example, packaging material, at least one unit-dosage of a compound according to the present invention (optionally together with one or more unit-dosage of a compound which can be administered in a combination therapy) and a label or package insert indicating that the compound can be used in a method disclosed herein.
  • an article of manufacture comprises packaging material, at least one unit dose of a 17-ketosteroid compound (a formula 1 compound) and a label or package insert indicating that the 17-ketosteroid compound (a formula 1 compound) can be used in a method as described herein.
  • the packaging material can be made from one or more generally known materials, e.g., foam, cardboard, fiberboard, polystyrene and polypropylene, and is of a size suitable to contain the compound(s) accompanying the packaging material.
  • a label or package insert can be a tag or label secured to the packaging material, a label printed on the packaging material or a label inserted within the packaging material.
  • the label indicates that the 17-ketosteroid can be used in a therapy as disclosed herein, e.g., in combination with a plasma concentration-enhancing compound, a macrophage stimulating factor, ribavirin and/or alpha interferon.
  • the label can also indicate that the compound(s) have received approval from an official agency, for example, the U.S.
  • the label may also indicate suitable administration routes, dosage regimen, and the like.
  • the article may contain additional components such as at least one unit dose of a plasma concentration-enhancing compound, macrophage stimulating factor, ribavirin and/or alpha interferon.
  • The, dosage of a formula 1 , 2A or 2B compound for a particular patient will vary depending on factors such as the overall health of the patient, the method, route and dose of administration and the severity of side effects (if any). Determination of the appropriate dose is made by the clinician using parameters known in the art. Generally, the -dose begins with an amount somewhat less than the optimum dose and it is increased by small increments thereafter until the desired or optimum effect is achieved.
  • the dosage of the compounds of the invention is suitably determined depending on the individual cases taking symptoms, age and sex of the subject and the like into consideration. With respect to the duration of treatment, it is typical for skilled clinicians to monitor patients in order to determine when inhibition is providing therapeutic benefit, and to determine whether to increase dosage, decrease dosage, discontinue therapy, resume therapy or alter therapy.
  • the therapeutically effective dosage of any specific compound of the invention will vary somewhat from compound to compound and patient to patient. As a general proposition, a dosage in the range of from about 0.1 to about 500 mg/kg will have therapeutic efficacy. Typically, a dosage in the range of from about 0.5 mg/kg to about 500 mg/kg will be employed.
  • a daily dosage of a formula 1 compound will typically comprise about 10 to about 750 mg, usually about 20 to about 400 mg, which may be administered as a single dose or as two or more subdoses. Such doses or subdoses may be administered at one or more sites or by one or more than one route of administration. The duration for the treatment is usually once per day for a sufficient length of time for the patient to become asymptomatic, or for symptoms to abate noticeably.
  • the dosages used in accordance with the invention are suitably determined depending on the individual cases, taking symptoms, age and sex of the subject and the like into consideration. In addition, it is well known that it is within the skill of ordinary artisans to determine suitable dosages based on the above and other factors.
  • a compound of the present invention may be administered orally, intramuscularly (IM); intravenously (IV), or subcutaneously (SC), with intravenous administration being especially preferred.
  • IM intramuscularly
  • IV intravenously
  • SC subcutaneously
  • intravenous administration is especially preferred.
  • other routes of administration can be used, it has been found that intravenous administration provides surprising effectiveness.
  • a plasma concentrationenhancing compound may be of great importance.
  • a formula 1 compound or salt may also be administered intravenously or intramuscularly as a liposomal suspension.
  • Such administration may comprise a cyclodextrin formulation (given orally, SC, IV or IM).
  • Compounds of the invention and their pharmaceutically or physiologically, acceptable salts are thus administered by any route suitable to the condition to be treated, including oral, rectal, nasal, topical (including ocular, buccal or sublingual), vaginal, parenteral (including subcutaneous, intramuscular, intravenous, intraperitoneal, intradermal, intrathecal, intradural and epidural) and pulmonary by aerosol.
  • the compounds of the invention arp administered parenterally, orally or topically. If an embodiment is not sufficiently orally bioavailable it can be administered by the other routes noted above.
  • Embodiments include formulations that comprise a liposome or lipid complex that comprises a formula 1 compound. Such formulations are prepared according to known methods, e.g., U.S. patents 4427649, 5043165, 5714163, 5744158, 5783211, 5795589, 5795987, 5798348, 5811118, 5820848, 5834016 and 5882678, all of which are incorporated herein by reference.
  • the liposomes may optionally comprise an additional therapeutic or other agent(s), e.g., a compound of formula 2A or 2B.
  • the liposomes can be delivered to a subject by any standard route, e.g., oral, aerosol or parenteral (e.g., SC, IV, IM).
  • the pharmaceutical compositions useful in the present invention will comprise a compound of formula 1, or a pharmaceutically acceptable salt thereof, in any pharmaceutically acceptable carrier.
  • water is the carrier of choice with respect to water- soluble compounds or salts.
  • an organic vehicle such as glycerol, ethanol, propylene glycol, polyethylene glycol, DMSO, DMS0 2 , vegetable or mineral oils, ethanol, benzyl benzoate, or mixtures thereof, may be suitable.
  • the solutions in any instance should be sterilized in a suitable manner, preferably by filtration through a 0.22 micron filter.
  • the compositions useful in the practice of the present invention may be provided in the form of vials, ampoules, and the like.
  • the formula 1 compound that is present in the compositions or that is used in the methods disclosed herein is completely dissolved in non-aqueous excipients.
  • the formula 1 compound is partially dissolved while the remaining portion is present as a solid, which can be a suspension or a colloid.
  • the formula 1 compound is incompletely dissolved and is present as a suspension or gel.
  • the pharmaceutical compositions may contain other additives, such as pi I adjusting additives, in particular, agents such as acids, bases, or buffers, including sodium lactate, sodium acetate, and sodium gluconate.
  • additives such as pi I adjusting additives, in particular, agents such as acids, bases, or buffers, including sodium lactate, sodium acetate, and sodium gluconate.
  • such compositions may contain microbial preservatives, such as methylparaben, propylparaben, benzyl alcohol and benzyl benzoate. If a multiple use vial is supplied, the pharmaceutical composition should likewise include such a microbial preservative.
  • the formulations may be lyophilized, using techniques well known in the art.
  • the formulations include those suitable for the foregoing administration routes.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques, excipients and formulations generally are found in, e.g., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA 1985, 17 th edition, Nema et al., PDA J. Pharm. Sci. Tech. 1997 51:166-171, both of which are inco ⁇ orated herein by reference.
  • Methods to make invention formulations include the step of bringing into association a formula 1 compound with one or more excipients or carriers. In general, the formulations are prepared by uniformly and intimately bringing into association the formula 1 compound with liquid excipients or finely divided solid excipients or both, and then, if appropriate, 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 formula 1 or formula 2A or 2B compound; as a powder or granules; as solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the formula 1 or formula 2A or 2B compound may also be presented as a bolus, electuary or paste.
  • a tablet may be made by compression or molding, optionally with one or more excipients.
  • Compressed tablets may be prepared by compressing in a suitable machine the formula 1 or formula 2A or 2B compound 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 moulding 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 formula 1 or formula 2A or 2B compound therein.
  • the oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner.
  • the phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil.
  • a hydrophilic emulsifier is included together with a lipophilic emulsifier, which acts as a stabilizer. It is also preferred to include both an oil and a fat.
  • the emulsifier(s) with or without stabilizer(s) make up the emulsifying wax, and the wax together with the oil and fat make up the emulsifying ointment base which forms the oily dispersed phase of the cream formulations.
  • Emulgents and emulsion stabilizers suitable for use in formulations comprising a formula 1 or a formula 2A or 2B compound include Tween® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl sulfate.
  • Formulations suitable for buccal administration include lozenges comprising a formula 1 or formula 2 ⁇ or 2B compound in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the formula 1 or formula 2A or 2B compound in an inert basis such as gelatin and glycerin, or sucrose and acacia.
  • 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 intrapulmonary or nasal administration will have a particle size for example in the range of 0.01 to 200 microns (including particle sizes in a range between 0.01 and 500 mi ⁇ rons in increments of 0.1 microns such as 0.1, 0.2, 0.3, 0.4, 0.5, 1, 2, 5, 30 microns, 35 microns, etc.), which is administered by inhalation through the nasal passage or by inhalation through the mouth so as to reach the various bronchi or alveolar sacs.
  • Formulations suitable for aerosol or dry powder administration may be prepared according to conventional methods and may be delivered with other therapeutic agents such as compounds heretofore used in the treatment or prophylaxis of togavirus, flavivirus or retrovirus other infections. Inhalation therapy is readily administered by metered dose inhalers.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the formula 1 compound such carriers or excipients as are known in the art to be appropriate.
  • Formulations suitable for parenteral administration are sterile and include aqueous and nonaqueous injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation 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 ampoules and vials with elastomeric stoppers, 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. Unit dosage formulations will typically contain a daily dose or unit daily sub-dose, as recited above, or an appropriate fraction thereof, of a formula 1 or formula 2A or 2B compound.
  • the formula 1 compounds will be administered on an intermittent basis.
  • the formula 1 compound e.g., a dose that comprises about 5-500 mg of a formula 1 compound (typically about 25-400 mg, or about 50-350 mg), is administered to a subject for at least one day, followed by no dosing for at least one day (at least 24 hours), optionally followed by at least one more daily dose of, e.g., about 50-500 mg.
  • Intermittent dosing methods may comprise dosing (1, 2, 3 or 4 doses per week) based on a weekly schedule, e.g., dosing on Monday, Wednesday and Friday, or on Tuesday, Thursday Saturday for about 1, 2, 3, 4, 6, 8 or more weeks, followed by periods of about 2, 3, 4, 5, 30, 45, 60, 90 or more days with no dosing, optionally followed by dosing again on Monday, Wednesday and Friday for about 1, 2, 3, 4, 6, 8 or more weeks.
  • Weekly dosing methods may comprise administration of the formula 1 compound to a subject 1, 2, 3, 4 or 5 times per week for 1, 2, 3, 4, or more weeks..
  • dosing may be administered to a subject daily for 2, 3, 4, 5, 6, 7 or more days, followed by a period of about 1, 2, 3, 4, 5, 7, 14, 30, 45 60, 90 or more days, optionally followed by another course of daily dosing.
  • These embodiments may further comprise treatment with a formula 2A or 2B compound or another treatment as described herein.
  • compositions disclosed herein will typically comprise one or more compounds of formula 1, and, the methods disclosed herein will utilize such compositions, which will contain one, two or more of such compounds, usually one. While it is possible for the compounds of the invention to be administered as pure compounds it is preferable to present them as pharmaceutical formulations.
  • the formulations of the present invention comprise at least one formula 1 compound together with one or more acceptable carriers or excipients and optionally other therapeutic agents, e.g., a formula 2A or 2B compound(s), ⁇ lFN, ribavirin, a macrophage stimulating factor(s) and/or an oxidation agent(s).
  • the one or more carriers or excipients must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the patient.
  • Togavirus and flavivirus infections that can be treated with the formula 1 compounds include HCV, California encephalitis virus, St. Louis encephalitis virus, western equine encephalitis virus, eastern equine encephalitis virus, Colorado tick fever virus, LaCrosse encephalitis virus, Japanese encephalitis virus, yellow fever virus, Venezuelan equine encephalitis virus, Murray valley fever virus, tick-borne encephalitis viruses, GB virus A, GB virus B, GB virus C, Dengue virus 1 , Dengue virus 2, Dengue virus 3, Dengue virus 4, Semliki Forest virus and Sindbis virus.
  • the rubiviruses include human rubella virus. Pestiviruses include mucosal disease viruses such as bovine virus diarrhea virus, hog cholera virus and sheep border disease virus.
  • the formula 1 compounds are also useful to treat hepatitis G virus. In addition to preventing or treating togaviral infections, the some of the formula 1 compounds can be used to treat subjects who are coinfected with a togavirus and another virus, such as a retrovirus or a second togavirus.
  • Retroviruses such as a human immunodeficiency virus, e.g., HIVl or HIV2, a simian immunodeficiency virus, a recombinant human-simian immunodeficiency virus (SHIV), a feline immunodeficiency virus or a feline or murine leukemia or sarcoma virus can be treated with formula 1 compounds.
  • a human immunodeficiency virus e.g., HIVl or HIV2
  • a simian immunodeficiency virus e.g., a recombinant human-simian immunodeficiency virus (SHIV)
  • a feline immunodeficiency virus or a feline or murine leukemia or sarcoma virus can be treated with formula 1 compounds.
  • Coinfections with hepatitis viruses may be treated using the compounds of the invention, e.g., a HCV and HIV coinfection.
  • the subject will typically be one who has been tested to determine that (i) one or more togavirus infections is present (HCV, etc.) and (ii) a second virus infection is present (e.g., human herpes simplex virus 1, human herpes simplex virus 2, or a retrovirus such as HIVl, HJN2, etc.).
  • a second virus infection e.g., human herpes simplex virus 1, human herpes simplex virus 2, or a retrovirus such as HIVl, HJN2, etc.
  • a dosing regimen for a formula 1 compound will comprise the use of a relatively high induction dose, e.g., about 150-750 mg per day or about 150-750 mg per day using an intermittent dosing schedule (such as described herein), followed by lower maintenance dosing, e.g., about 50-250 mg per day or about 50-250 mg per day on an intermittent dosing schedule.
  • a relatively high induction dose e.g., about 150-750 mg per day or about 150-750 mg per day using an intermittent dosing schedule (such as described herein)
  • lower maintenance dosing e.g., about 50-250 mg per day or about 50-250 mg per day on an intermittent dosing schedule.
  • These embqdiments may further comprise treatment with a formula 2A or 2B compound or another treatment as described herein.
  • Parenteral formulations may comprise a cyclodextrin, e.g., an ⁇ -cyclodextrin, a ⁇ - cyclodextrin (e.g., ⁇ -hydroxypropylcyclodextrin) or a ⁇ -cyclodextrin, which are typically employed in aqueous formulations, which optionally comprise one or more of a buffer, a salt ( ⁇ aCl, etc.) to, e.g., render the solution isotonic, a bacteriostat or other excipients as known in the art and a formula 1 compound at a concentration of, e.g., about 5-25 mg/mL, typically about 10-20 mg/mL.
  • a cyclodextrin e.g., an ⁇ -cyclodextrin, a ⁇ - cyclodextrin (e.g., ⁇ -hydroxypropylcyclodextrin) or a ⁇ -cyclodextr
  • Parenteral formulations that comprise a formula 1 compound and one or more excipients may be diluted into, e.g., sterile saline and infused into a subject.
  • Parenteral formulations are typically administered by, e.g., intravenous, topical or oral delivery to a subject such as a human.
  • one or more solvents such as propylene glycol, a PEG, e.g., PEG 300 or PEG 400, ethanol, and benzyl benzoate may be employed.
  • Typical aqueous and non-aqueous formulations will contain about 5 to about 400 mg/mL of a formula 1 compound, usually about 10 to about 200 mg/mL.
  • compositions that comprise a formula 1 compound (and optionally one or more excipients) may be delivered orally, or by intramuscular, intravenous or subcutaneous injection.
  • a formula 1 compound such as 16 ⁇ -bromoepiandrosterone, to obtain an average particle size (or diameter) of about 0.5-25 ⁇ M or about 1-10 ⁇ M (e.g., about 2, 5 or 10 ⁇ M average particle size or diameter) before contacting the milled formula 1 compound with a liquid or solid excipient.
  • Milled formula 1 compound is useful to facilitate dissolution or suspension of the formula 1 compound in one or more liquid excipients (e.g., a PEG such as PEG 300, propylene glycol or benzyl benzoate) or to facilitate uniformly distributing drug substance when the milled compound is contacted with one or more solid excipients (e.g., a filler, a binder or a lubricant).
  • liquid excipients e.g., a PEG such as PEG 300, propylene glycol or benzyl benzoate
  • solid excipients e.g., a filler, a binder or a lubricant
  • compositions and formulations disclosed herein are useful in the treatment of, or ameliorate one or more symptoms associated with, the conditions or infections disclosed herein. These compositions and formulations may also be used to treat, or ameliorate one or more symptoms associated with, a retroviral infection such as a HIVl or HIV2 infection in humans, or Malaria in humans.
  • a retroviral infection such as a HIVl or HIV2 infection in humans, or Malaria in humans.
  • phrases such as "amelioration of one or more symptoms associated with” means that such compounds or formulations may be used to reduce replication of an infectious agent or to reduce the number of infectious agents that are present in a subject or to ameliorate one or more symptoms associated with, or caused by, the condition or infection (e.g., reduced fever, a shortened duration or degree of pain, or a noticeable reduction of or elimination of diarrhea or fatigue).
  • formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, ' for example those suitable for oral administration may include flavoring or coloring agents.
  • the present invention further provides veterinary compositions comprising at least one formula 1 or formula 2A or 2B compound together with a veterinary carrier therefor.
  • the formula 1 compound may be present in the animal's feed or water.
  • Excipients for veterinary applications may include compounds, e.g., small amounts of chloroform, that may not be generally suitable for human use.
  • Veterinary carriers are materials useful for the purpose of administering the composition to cats, dogs, horses, mice, rats, hamsters, rabbits and other animals and may be solid, liquid or gaseous materials that are otherwise inert or acceptable in the veterinary art and are compatible with the formula 1 or formula 2A or 2B compound. These veterinary compositions may be administered orally, parenterally or by any other desired route, e.g., as described herein.
  • human patients infected with HCV are given an aqueous isotonic ⁇ -cyclodextrin or ⁇ -cyclodextrin (e.g., ⁇ -hydroxypropyl cyclodextrin) formulation containing about 5-30 mg/mL of dehydroepiandrosterone or 16 ⁇ -bromoepiandrosterone, e.g., about 10-20 mg/mL.
  • the formulation is delivered intravenously in a single daily dose or two subdoses per day.
  • the patients are dosed with 1 to 10 mg/kg/day for 4 to 10 days, followed by no dosing for 5 to 30 days, followed by dosing again with the cyclodextrin formulation for 4 to 10 days.
  • the dosing regimen is repeated one, two or more times.
  • Clinical markers for HCV infection are followed during treatment, e.g., viral nucleic acid in the blood or plasma, liver enzyme levels in the blood or plasma (aminotransferase).
  • a standard anti-HCV treatment(s) e.g., interferon and/or ribavirin
  • a formula 1 compound(s) is administered daily continuously as a component in an oral or parenteral composition or formulation, e.g., for a formula 1 compound(s) that is a new compound per se.
  • the dehydroepiandrosterone or 16 ⁇ -bromoepiandrosterone is optionally also administered systemically using, e.g., the formulation of example 1 to deliver 1-5 mg/kg/day every other day for about 1 to 4 months, or an oral formulation to deliver about 5-40 mg/kg/day every other day for about 1 to 4 months.
  • Embodiments of formula 1 compounds include or exclude any subset of compounds within the definition of formula 1, provided that at least one compound remains.
  • a subset of formula 1 compounds that are generally preferred and are usually included for example are aqueous or nonaqueous formulations comprising 16 ⁇ -bromoepiandrosterone.
  • a subset compounds or applications for compounds that are optionally excluded from formula 1 compounds or their uses in any embodiment or claim herein comprises, e.g., the use of one or more compounds (or their use) that are disclosed in one or more prior art references or publications, to the extent that the disclosed compounds or uses renders any claim or embodiment unpatentable for novelty, obviousness and/or inventive sl ip reasons.
  • Another subset of the formula 1 compounds excludes one or more formula
  • Q 6 is -CH 3 or -CH OH
  • Q is -CH 3
  • the remaining positions (Ri) comprise, e.g., -H and 0, 1 or 2 hydroxyl groups.
  • a formula 1 compound may be linked to an oligonucleotide or an oligonucleotide analog to facilitate delivery of the oligonucleotide or analog into cells.
  • the formula 1 compound will be linked to the steroid nucleus through a terminal hydroxyl group at a 5', 3' or 2' position of the oligonucleotide.
  • Oligonucleotides and analogs of oligonucleotides are known and have been described, e.g., U.S.
  • a method of treating hepatitis virus C in a patient in need of such treatment comprising administering to said patient an effective amount of at least one compound selected from the group consisting of the compounds of the present invention.
  • a method as recited in embodiment 2, wherein said plasma concentration- enhancing compound is naringin or naringenin. 14. A method of reducing at least one aminotransferase level in a patient suffering from hepatitis virus C in a patient in need of such treatment, comprising administering to said patient an effective amount of at least one compound selected from the group consisting of the compounds of the present invention.
  • a method of treating a togavirus in a patient in need of such treatment comprising administering to said patient an effective amount of at least one compound selected from the group consisting of the compounds of to the present invention.
  • 28. A method as recited in embodiment 27, further comprising administering to said patient at least one plasma concentration-enhancing compound.
  • 34 A method as recited in any one of embodiments 27 - 33, wherein said patient is a mammal.
  • a method according to embodiment 46, wherein said pestivirus is bovine virus diarrhea virus (BVDV).
  • BVDV bovine virus diarrhea virus
  • a composition comprising 16 ⁇ -bromoepiandrosterone, and 2, 3, 4 or 5 excipients selected from polyethylene glycol, dehydrated ethanol, benzyl benzoate, benzyl alcohol and propylene glycol, wherein the composition comprises less than about 3% v/v, or less than about 1% v/v, or less than about 0.5% v/v of water, or less than about 0.1% v/v of water.
  • composition of embodiment 50 wherein the composition comprises (i) 16 ⁇ - bromoepiandrosterone at a concentration of about 45-55 mg/mL, (ii) 20-30% v/v polyethylene glycol 300, polyethylene glycol 400 or a mixture of polyethylene glycol 300 and 400, (iii) 10-15% v/v dehydrated ethyl alcohol, 2.5-7.5% v/v benzyl benzoate, and (iv) 55-60% v/v propylene glycol.
  • composition of embodiment 51 wherein the composition comprises 16 ⁇ - bromoepiandrosterone at a concentration of about 50 mg/mL, about 25% v/v polyethylene glycol 300, about 12.5% v/v dehydrated ethyl alcohol, about 5% v/v benzyl benzoate, about 57.5% v/v propylene glycol and less than about 0.5% v/v water.
  • composition of embodiment 50 wherein the composition comprises 16 ⁇ - bromoepiandrosterone at a concentration of about 50-105 mg/mL, about 27-33% w/w benzyl benzoate, about 27-33% w/w polyethylene glycol 300, about 25-30% w/w propylene glycol and about 1-3% w/w benzyl alcohol. 54.
  • composition of embodiment 53 wherein the composition comprises 16 ⁇ - bromoepiandrosterone at a concentration of about 100 mg/mL (about 10% w/w), about 30.4% w/w benzyl benzoate, about 30.7% w/w polyethylene glycol 300, about 28% w/w propylene glycol and benzyl alcohol about 1.9% w/w.
  • a method to enhance the oral bioavailability of a therapeutic agent comprising administering to a subject an effective amount of a compound of formula 2A or 2B.
  • the therapeutic agent is a steroid, a steroid analog an antibiotic, an antiviral agent (e.g., a nucleoside, nucleoside analog, nucleotide analog, protease inhibitor or a polymerase inhibitor) or an antifungal agent (e.g., amphotericin B).
  • a method comprising administering an effective amount of a composition of any of embodiments 50-54 to a subject having, or susceptible to, a togavirus infection (e.g., HCV).
  • a togavirus infection e.g., HCV
  • 63 The method of embodiment 62 wherein the subject is a human and the human is optionally coinfcctcd with a retrovirus (e.g., HIVl or I IIV2).
  • a retrovirus e.g., HIVl or I IIV2.
  • 64. A method to ameliorate or reduce one or more symptoms associated with a togavirus infection in a subject, or to reduce replication of a togavirus in a subject infected with a togavirus, comprising administering to the subject an effective amount of a compound of formula 1.
  • a composition comprising a formula 1 compound wherein the formula 1 compound is a compound or within a genus of compounds as disclosed herein, e.g., a compound or genus named in compound groups 1-21 or in the claims as originally filed, and at least one excipient and a local anesthetic, wherein the local anaesthetic is optionally selected from procaine, benzocaine and lidocaine.
  • a method comprising administering an effective amount of the composition of embodiment 66 or the product of embodiments 67 or 68 to a subject having an infection or condition described herein, e.g., HCV, whereby the infection or condition, or a symptom thereof, is eliminated, reduced, treated, improved or ameliorated.
  • an infection or condition described herein e.g., HCV
  • Example 1 16 ⁇ -Bromocpiandrostcronc formulation 1. Two lots of a non-aqueous formulation was made at a 16 ⁇ -bromoepiandrosterone ("BrEA") concentration of 50 mg/mL in 25% polyethylene glycol 300, 12.5% dehydrated ethyl alcohol, 5% benzyl benzoate, and 57.5% propylene glycol, hereafter "formulation 1", as follows. BrEA was obtained from Procyte, Inc. The remaining excipients are shown below.
  • BrEA 16 ⁇ -bromoepiandrosterone
  • the formulation was prepared by suspending BrEA in polyethylene glycol 300, and sequentially adding propylene glycol, benzyl benzoate, and dehydrated ethyl alcohol to form a solution, which was diluted to the final desired volume with additional propylene glycol. The procedure is described below.
  • the calculated amount of polyethylene glycol 300 was added to a compounding vessel. Then, while mixing, the calculated amount of BrEA was added to the vessel, and mixed for at least 5 minutes to form a smooth, creamy liquid. Propylene glycol was added to the vessel, and mixed for a minimum of 5 minutes to form a uniform suspension. The calculated amount of benzyl benzoate is added to the vessel, and mixed for approximately 5 minutes to form a translucent liquid suspension. Dehydrated alcohol was added to the vessel, and mixed for approximately 5 minutes to form a clear, colorless solution. Propylene glycol was then added to achieve the desired final formulation, and mixed for approximately 5 minutes. The drug solution was transferred to a volume-dispensing device set to deliver 1.2 mL per vial.
  • the solution was filtered through two 0.2 ⁇ m polyvinylidene fluoride filters in series before dispensing into 2 cc amber galss vials.
  • the vials were capped with Teflon-coated, butyl-rubber stoppers and crimp sealed.
  • Example 2 BrEA formulation 2. A formulation containing 100 mg/mL of BrEA, 10% w/w, in benzyl benzoate (USP) 30.4% w/w, polyethylene glycol 300 (NF) 30.7% w/w, propylene glycol (USP), qs, about 28% w/w and benzyl alcohol (NF) 1.9% w/w, hereafter "formulation 2", was prepared as follows. A desired amount of BrEA (1.0 kg) was suspended in PEG 300 (about 3.0 L) in a compounding vessel and mixed for at least 5 minutes at room temperature to form a smooth creamy liquid. The needed amount of propylene glycol (about 1.5 L) was then added and mixing was continued for at least 5 minutes to form a uniform suspension.
  • Benzyl benzoate (about 3.0 L) was then added and the vessel contents were mixed for about 5minutes to form a translucent suspension.
  • Benzyl alcohol (about 200 mL) was then added and the mixing was continued for about 5 minutes to form a clear, colorless solution.
  • Propylene glycol was then added to achieve the desired finafformulation volume (about 1.5 L) and mixing was continued for about 5 minutes.
  • the drug solution was transferred to a volume-dispensing device, which was set to deliver 1.2 mL per vial (2 mL, glass, type 1 amber vials).
  • the formulation was filtered under nitrogen pressure (about 3 atm) through two 0.2 ⁇ m polyvinylidine fluoride filters in series.
  • the vials were capped using Teflon-coated, butyl rubber stoppers and then crimp sealed essentially as described in example 1.
  • the vials were stored in the dark at reduced temperature (about 2-8 C).
  • Example 3 Human clinical trial.
  • a clinical trial protocol that incorporates about 15-20 patients is designed.
  • the patients are mildly infected with one or more togaviruses, e.g., HCV and they are mildly to moderately symptomatic.
  • the patients are administered treatment for 1, 2 or 3 weeks.
  • dose groups e.g., 25, 50 or 100 mg/day of 16 ⁇ -bromoepiandrosterone (BrEA), or an ester thereof, is administered parenterally, e.g., by intramuscular or intravenous injection, on 3, 4 or 5 days of the weeks when dosing occurs.
  • BrEA 16 ⁇ -bromoepiandrosterone
  • Dosing is on consecutive days or on an intermittent schedule, e.g., 2, 3 or 4 doses with one dose administered every other day.
  • the formulation containing BrEA is as described herein, e.g., the formulation of example 1 or 2, preferably the formulation of example 2.
  • blood samples are taken periodically for evaluation of the infection or its symptoms, pharmacokinetics, plasma cytokines (e.g., IL-2, IL-4, IL-10, IGFl, ⁇ lFN, GM-CSF), and intracellular cytokines (e.g., IL-2, IL-4, IL-10, IGFl, ⁇ lFN, GM- CSF).
  • the patients are optionally treated again at about 2 to 12 weeks after the initial dosing, using the same or a similar protocol as that used in the initial dosing protocol.

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Abstract

L'invention concerne l'utilisation de composés 17-cétostéroïdes, ainsi que des dérivés, des métabolites et des précurseurs desdits composés, et des sels pharmaceutiquement acceptables de l'un quelconque de ces composés (ci-après appelés collectivement 'composés de l'invention') pour le traitement ou la prévention du virus de l'hépatite C et/ou du virus de l'hépatite G chez des patients nécessitant un tel traitement. L'invention concerne en outre des méthodes de traitement ou de prévention d'infections à togavirus, notamment l'infection à un ou plusieurs alphavirus, flavivirus tels que le virus de la fièvre jaune, le virus de l'hépatite C et le virus de l'hépatite G, les virus de la rubéole, les pestivirus tels que le virus de la diarrhée virale des bovins. L'invention concerne enfin des thérapies combinées qui consistent en l'administration d'un ou plusieurs composés de l'invention, tels que définis plus haut, et l'administration d'un ou plusieurs composés choisis parmi des composés facilitant la concentration de plasma, un facteur d'activation des macrophages, des agents d'oxydation, la ribavirine et l'interféron alpha, et/ou la ventilation à l'oxygène. Les composés de l'invention peuvent être également utilisés pour améliorer ou diminuer un ou plusieurs symptômes associés à l'infection à togavirus.
PCT/US1999/028082 1998-11-24 1999-11-24 Utilisation de composes 17-cetosteroides et de leurs derives, metabolites et precurseurs pour le traitement du virus de l'hepatite c ou autres togavirus Ceased WO2000032177A2 (fr)

Priority Applications (11)

Application Number Priority Date Filing Date Title
JP2000584873A JP2002531397A (ja) 1998-11-24 1999-11-24 Ｃ型肝炎ウイルスおよび他のトガウイルスの処置における１７−ケトステロイド化合物ならびにそれらの誘導体、代謝物および前駆体の使用
BR9915644-0A BR9915644A (pt) 1998-11-24 1999-11-24 Uso de compostos de 17-cetoesteróides e seus derivados, metabolitos e precursores no tratamento de vìrus de hepatite c e outros togavìrus
AU31052/00A AU775614B2 (en) 1998-11-24 1999-11-24 Use of 17-ketosteroid compounds and derivatives, metabolites and precursors thereof in the treatment of hepatitis C virus and other togaviruses
EP99965050A EP1133287A2 (fr) 1998-11-24 1999-11-24 Utilisation de composes 17-cetosteroides et de leurs derives, metabolites et precurseurs pour le traitement du virus de l'hepatite c ou autres togavirus
HK02102267.0A HK1042426A1 (zh) 1998-11-24 1999-11-24 17-酮甾类化合物及其衍生物、代谢产物和前体在治疗丙型肝炎病毒和其他披膜病毒中的应用
NZ511721A NZ511721A (en) 1998-11-24 1999-11-24 Use of 17-ketosteroid compounds and derivatives, metabolites and precursors thereof in the treatment of hepatitis C virus and other togaviruses
APAP/P/2001/002181A AP2001002181A0 (en) 1998-11-24 1999-11-24 Use of 17-ketosteroid compounds and derivatives, metabolites and precursors thereof in the treatment of hepatitis C virus and other toga viruses.
KR1020017006525A KR20010101074A (ko) 1998-11-24 1999-11-24 17-케토스테로이드 화합물 및 그의 유도체, 대사산물 및전구체의 간염 ｃ 바이러스 및 기타 토가바이러스 치료용용도
IL14294299A IL142942A0 (en) 1998-11-24 1999-11-24 Use of 17-ketosteroid compounds and derivatives, metabolites and precursors thereof in the treatment of hepatitis c virus and other toga viruses
CA002352205A CA2352205A1 (fr) 1998-11-24 1999-11-24 Utilisation de composes 17-cetosteroides et de leurs derives, metabolites et precurseurs pour le traitement du virus de l'hepatite c ou autres togavirus
IL142942A IL142942A (en) 1998-11-24 2001-05-03 Use of compounds 17 - ketosteroid and their derivatives, metabolites and stimulants for the preparation of drugs for the treatment of hepatitis C virus and other toga viruses

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US10992498P 1998-11-24 1998-11-24
US60/109,924 1998-11-24
US12408799P 1999-03-11 1999-03-11
US60/124,087 1999-03-11
US12605699P 1999-03-23 1999-03-23
US60/126,056 1999-03-23

Publications (2)

Publication Number Publication Date
WO2000032177A2 true WO2000032177A2 (fr) 2000-06-08
WO2000032177A3 WO2000032177A3 (fr) 2001-03-22

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PCT/US1999/028082 Ceased WO2000032177A2 (fr) 1998-11-24 1999-11-24 Utilisation de composes 17-cetosteroides et de leurs derives, metabolites et precurseurs pour le traitement du virus de l'hepatite c ou autres togavirus

Country Status (14)

Country Link
EP (1) EP1133287A2 (fr)
JP (1) JP2002531397A (fr)
KR (1) KR20010101074A (fr)
CN (1) CN1328463A (fr)
AP (1) AP2001002181A0 (fr)
AU (1) AU775614B2 (fr)
BR (1) BR9915644A (fr)
CA (1) CA2352205A1 (fr)
HK (1) HK1042426A1 (fr)
ID (1) ID29864A (fr)
IL (2) IL142942A0 (fr)
NZ (1) NZ511721A (fr)
OA (1) OA11716A (fr)
WO (1) WO2000032177A2 (fr)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001003681A3 (fr) * 1999-07-08 2002-05-10 Patrick T Prendergast Utilisation de flavones, de coumarines et de composes associes dans le traitement d'infections
EP1534299A4 (fr) * 2002-07-02 2007-04-11 Corcept Therapeutics Inc Methodes de traitement de la psychose associee a une therapie aux interferon alpha
US7396827B2 (en) 2000-03-16 2008-07-08 Hollis-Eden Pharmaceuticals, Inc. Pharmaceutical compositions and treatment methods
US7691835B2 (en) 1999-09-30 2010-04-06 Hollis-Eden Pharmaceuticals, Inc. Formulations
EP2298315A1 (fr) * 2002-08-28 2011-03-23 Harbor BioSciences, Inc. Procédés de traitement thérapeutique
EP2392326A1 (fr) * 2007-11-15 2011-12-07 Madaus GmbH Composant de la Silibinine pour le traitement de l'hépatite
CN102993148A (zh) * 2011-09-13 2013-03-27 复旦大学 槲皮素衍生物或其类似物及其应用
WO2013178782A1 (fr) * 2012-05-30 2013-12-05 Universidad De Zaragoza Inhibiteurs allostériques de la protéase ns3 du virus de l'hépatite c virus
WO2022066600A1 (fr) * 2020-09-22 2022-03-31 Micronization Technologies And Therapeutics Group Llc Nébuliseur et agents antiviraux nébulisés

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108003212A (zh) * 2017-12-24 2018-05-08 扬州工业职业技术学院 一种去氢表雄酮-6-葡萄糖苷衍生物及其作为抗丙型肝炎病毒药物的应用
CN110452280B (zh) * 2019-07-25 2020-11-17 中国人民解放军第二军医大学 一类四环三萜酸衍生物及其制备方法与应用

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL194728C (nl) * 1987-04-16 2003-01-07 Hollis Eden Pharmaceuticals Farmaceutisch preparaat geschikt voor de profylaxe of therapie van een retrovirale infectie of een complicatie of gevolg daarvan.
US5837269A (en) * 1989-09-25 1998-11-17 University Of Utah Research Foundation Vaccine compositions and method for enhancing an immune response
EP0901375A1 (fr) * 1996-04-17 1999-03-17 Patrick Thomas Prendergast Therapie associee reposant sur l'utilisation de la dehydroepiandrosterone (dhea)
WO1998047516A1 (fr) * 1997-04-17 1998-10-29 Prendergast Patrick T Therapie combinee mettant en application des 17-cetosteroides et des inhibiteurs d'interleukine, ou interleukine-10 eventuellement avec des inhibiteurs d'interleukine

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7723532B2 (en) 1999-03-23 2010-05-25 Harbor Biosciences, Inc. Pharmaceutical compositions 3
US6555523B1 (en) 1999-07-08 2003-04-29 Patrick T. Prendergast Use of cirsiliol and derivatives to treat infections
WO2001003681A3 (fr) * 1999-07-08 2002-05-10 Patrick T Prendergast Utilisation de flavones, de coumarines et de composes associes dans le traitement d'infections
US7691835B2 (en) 1999-09-30 2010-04-06 Hollis-Eden Pharmaceuticals, Inc. Formulations
US7396827B2 (en) 2000-03-16 2008-07-08 Hollis-Eden Pharmaceuticals, Inc. Pharmaceutical compositions and treatment methods
US8476254B2 (en) 2002-07-02 2013-07-02 Corcept Therapeutics, Inc. Methods for treating psychosis associated with interferson-α therapy
EP1534299A4 (fr) * 2002-07-02 2007-04-11 Corcept Therapeutics Inc Methodes de traitement de la psychose associee a une therapie aux interferon alpha
EP2298315A1 (fr) * 2002-08-28 2011-03-23 Harbor BioSciences, Inc. Procédés de traitement thérapeutique
EP2298316A1 (fr) * 2002-08-28 2011-03-23 Harbor BioSciences, Inc. Procedes de traitement therapeutique
EP2392326A1 (fr) * 2007-11-15 2011-12-07 Madaus GmbH Composant de la Silibinine pour le traitement de l'hépatite
US9248115B2 (en) 2007-11-15 2016-02-02 Madaus Gmbh Silibinin component for the treatment of hepatitis
CN102993148A (zh) * 2011-09-13 2013-03-27 复旦大学 槲皮素衍生物或其类似物及其应用
WO2013178782A1 (fr) * 2012-05-30 2013-12-05 Universidad De Zaragoza Inhibiteurs allostériques de la protéase ns3 du virus de l'hépatite c virus
WO2022066600A1 (fr) * 2020-09-22 2022-03-31 Micronization Technologies And Therapeutics Group Llc Nébuliseur et agents antiviraux nébulisés

Also Published As

Publication number Publication date
IL142942A (en) 2006-08-20
EP1133287A2 (fr) 2001-09-19
OA11716A (en) 2005-01-25
CN1328463A (zh) 2001-12-26
ID29864A (id) 2001-10-18
AU3105200A (en) 2000-06-19
IL142942A0 (en) 2002-04-21
WO2000032177A3 (fr) 2001-03-22
BR9915644A (pt) 2001-08-07
AU775614B2 (en) 2004-08-05
JP2002531397A (ja) 2002-09-24
AP2001002181A0 (en) 2001-05-24
NZ511721A (en) 2004-07-30
HK1042426A1 (zh) 2002-08-16
KR20010101074A (ko) 2001-11-14
CA2352205A1 (fr) 2000-06-08

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