CN1328463A - Use of 17-ketosteroid compounds, as well as derivatives, metabolites and precursors for treatment of hapatitis C type virus and other togavirus infections - Google Patents

Use of 17-ketosteroid compounds, as well as derivatives, metabolites and precursors for treatment of hapatitis C type virus and other togavirus infections Download PDF

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CN1328463A
CN1328463A CN99813658A CN99813658A CN1328463A CN 1328463 A CN1328463 A CN 1328463A CN 99813658 A CN99813658 A CN 99813658A CN 99813658 A CN99813658 A CN 99813658A CN 1328463 A CN1328463 A CN 1328463A
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chemical compound
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virus
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克拉伦斯·纳撒尼尔·阿勒姆
詹姆斯·马丁·弗林克
帕特里克·T·普伦德加斯特
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Harbor Biosciences Inc
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Hollis Eden Pharmaceuticals Inc
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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

Abstract

The invention provides 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', in the treatment of prevention of hepatitis C type virus and/or hepatitis G type virus in patients in need of such treatment. In addition, the invention provides methods to treat or prevent togavirus infections, including infections by one or more alphaviruses, flaviviruses, such as yellow fever virus, hepatitis C virus and hepatitis G virus, rubella viruses, or pestiviruses, such as bovine virus diarrhea virus. In addition, the invention provides combination therapies including administration of one or more compound of the present invention, as defined herein, and administration of one or more compound selected from plasma concentration-enhancing compounds, macrophage stimulating factor, oxidation agents, ribavirin and alpha interferon, and/or oxygen ventilation. The compounds of the present invention may also be used to ameliorate or reduce one or more symptoms associated with a togavirus infection.

Description

The application in treatment hepatitis C virus and other togavirus of 17-ketosteroid chemical compound and derivant thereof, metabolite and precursor
Background of invention
The present invention relates to their treatment banzi virus of steroid based composition and application and togavirus and infect the method that infects as hepatitis C virus (" HCV ").
The present invention relates to derivant, metabolite and the precursor of 17-ketosteroid chemical compound and this compounds and any officinal salt (being generically and collectively referred to as " chemical compound of the present invention ") thereof one or more other chemical agents of optional associating and/or Therapeutic Method (as described below) and need the intravital hepatitis C virus of patient of this treatment and/or the application in the hepatitis G virus in treatment.In addition, the present invention relates to treat the method for togavirus, described togavirus comprises alphavirus (being also referred to as arbovirus A group), Flavivirus (being also referred to as arbovirus B group) (for example yellow fever, hepatitis C and hepatitis G), rubella virus genus (as rubella) and pestivirus (being also referred to as bovine diarrhoea virus) (as bovine viral diarrhea virus (BVDV)).
All the time exist further demand for the hepatitis C virus Therapeutic Method, these methods should be than known therapies safety and/or more effective.Said as preceding U.S. medical officer C.Everett Koop: " we are in the grave edge that threatens public health ... it affects people's all one's life in each state, each country.Unless we take action at once, will kill more people otherwise compare it with AIDS ", Koop, hepatitis C-proprietary epidemic diseases.As Maddrey, W.C. wait people " surmount monotherapy: the therapy of new generation of chronic hepatitis C " described, unfortunately, it is invalid to provide the unique therapy to the control hepatitis C in (in March, 1997 open) to be proved for considerable patient by the U.S.'s state-run health research joint development meeting (U.S.National Institutes of HealthConsensus Development Statement)---and not only the patient of significant proportion does not produce response to this treatment, and considerable patient is in addition recurred or produced limited response.Owing to be not that the patient who all suffers from the chronic hepatitis infection produces response to the standard care of adopting interferon-alpha (" IFN α "), so need new therapeutic scheme, DiBisceglie, A.M., " the emerging therapy of chronic hepatitis C ".
Hepatitis C is very general, and whole world chronic hepatitis patient has 9,000 ten thousand to surpassing 200,000,000 (2% to 4%) according to estimates.But be not used in the vaccine or the candidate vaccine that prevent before the contact, also be not used in effective globulin of contact back prevention.
The main tendency that HCV infects is to be easy to make progress into chronic hepatitis at least 75% case; In fact all infected patients can be by chronic infection.Theoretically, HCV dependency hepar damnification directly or indirectly relates to the cytotoxic T lymphocyte (CTL) at the viral peptide of expressing on liver plasma membrane.These CTL are positioned in the liver, and exist with minority, and they may only be effectively temporary transient, because viral species difference like this and sudden change are so fast.Therefore, simple antiviral compound such as nucleoside analog or enzyme inhibitor can suppress virus but can't eliminate infection.In addition, immune-related treatment such as antibody preparation or cellular immunization stimulant may be effectively temporary transient, because virus can change or suddenly change.
Chronic hepatitis C is making progress unconsciously.Usually, this infection progress is a many decades for the time of chronic hepatitis, liver cirrhosis, liver failure and hepatocarcinoma, rather than several months or several years.
There is not reliable and effective HCV cell culture.In addition, there is not the non-human primate animal model.So, almost do not test out the medicine of anti-HCV so far.Known acycloguanosine, virazole and corticosteroid are invalid, and corticosteroid can increase the level that HCV duplicates.
Interferon has been used to treat chronic hepatitis C.Interferon is the natural sugar albumen that is produced by the cell to the viral infection response.Interferon suppresses duplicating of wide spectrum RNA and DNA viruses (comprising hepatitis virus).This suppresses to take place by different mechanism, comprises suppressing viral adhesion and shelling, inducing cell internal protein and ribonuclease (they make cell have ntiviral characteristic) and amplification specificity (cytotoxic T lymphocyte) and non-specific (natural killer cell) immunne response to virus protein.The active specific mechanisms of interferon in chronic hepatitis C is still unknown.
According to the known ntiviral characteristic of interferon and its experience in its alloytype viral hepatitis treatment, before identifying hepatitis C virus, interferon is considered to treat the patient who suffers from non-first type, non-hepatitis B.Some reports are pointed out, can produce among the chronic hepatitis C patient about 40% in the response during the interferon therapy.This response occurs rapidly usually.In Most patients, the rna level of HCV sharply descends and becomes in week and can't detect at 4-8, and these patients' transaminase is with postnormalize.
Though in the response patient, produce rapidly antiviral and biochemistry response and can't detected remaining HCV in liver and serum, only in the small number of patients of 8-35%, can keep in normally biochemical and the serum and can survey not existing of viremia at treatment.After interrupting interferon therapy, it is the recurrence of feature that 50-90% can be occurred with Serum ALT bounce-back overrun by the patient of " success " treatment.
At least the half chronic hepatitis C patient that accepts interferon therapy does not produce response.Some were confirmed already by the patient that Serum ALT levels normalization demonstrates the interferon response at first that although continue to use interferon therapy, its Serum ALT levels still raise gradually.
Checked multiple factor and the patient relation between whether interferon is responded already, these factors comprise whether genotype, fibre modification or the liver cirrhosis of HCV-RNA reduces in HCV-RNA level before age, sex, body weight, processing, the treatment beginning process degree, virus exist, the iron content of ferritin content regulating liver-QI in the dosage of interferon, serum, but these factors none can be accurately and self-consistentency forecast which HCV patient and will have response interference.
In addition, in some diseases, use the interferon therapy hepatitis C as if harmful to the patient, very harmful to the patient sometimes separately.For example, interferon autoimmunity account for use among the leading patient can aggravate immune-mediated hepatocyte inflammation (referring to people such as Shindo, " hepatopathy sharply increases the weight of during with interferon-alpha treatment chronic hepatitis C " (" Acute exacerbation ofLiver desease during interferon alfa therapy for chronic hepatitis C ") gastroenterology (Gestroenterology) 1992; 102:1406-1408).Interferon can make chronic viral hepatitis be converted into autoimmune hepatitis (people such as Silva, " chronic active hepatitis that interferon brings out? " (" Interferon-induced chronic actire hepatitis? ") gastroenterology 1991; 101:840-842).Interferon use the generation (people such as Mayet that also can bring out the uncertain autoantibody of various clinical effectiveness, " recombinant alpha interferon brings out autoantibody to the treatment of hepatitis B; this is not specific for the autoimmune chronic hepatitis " (" Treatment of chronic typeB hepatitis with recombinant alpha-interferon induces auto antibodies, notspecific for auto immune chronic hepatitis ") hepatology (Hepatology) 1989; 10:24-28), all are hereby incorporated by.Interferon causes function, the release that influences cytokine and the activated macrophage of the increase that HLA shows on the film surface, the function that weakens suppressor T lymphocyte, the generation that strengthens autoantibody, stimulation natural killer cell, this make interferon can cause immune-mediated disease deterioration (people such as Baron., " interferon: the mechanism of action and clinical practice " (" The interferons:mechanism of action and clinicalapplications ") JAMA 1991; 266:1375-1383, they are hereby incorporated by).In other patients, for example in the patient with normal serum ALT level or Metabolic disorder disease, the superiority of this therapy is examined and is open to suspicion.
In addition, learn according to the research that interferon is used in other treatment, interferon has the multiple side effect of knowing, and comprises heating, shiver with cold, influenza-like symptom, fatigue, anorexia, behavior state deterioration, nausea and vomiting, loses weight, leukopenia, anemia, nervous symptoms, mental symptom and dyspnea.Referring to for example Tsavaris, N. wait people's " with the interferon-alpha treatment renal cell carcinoma of cumulative dosage " (" Treatment of renal cell carcinoma with escalatingdoses of alpha-interferon ") chemotherapy (chem otherapy), the 1993 9-10 months; 39 (5): 361-6.In addition, the progress of the thyroid disease among interferon and the HCV patient is relevant.People such as Lisker-Melman M, 1992 June of " progress of thyroid disease during with interferon-alpha treatment chronic viral hepatitis " (" Development ofthyroid disease during therapy of chronicviral hepatitis with interferon alfa ") gastroenterology; 102 (6): 2155-60.
Virazole is virazole have been reported in the Compound P ilot research that RNA and DNA viruses have (comprising the flaviviridae relevant with hepatitis C) a broad-spectrum external activity can reduce the patient's who suffers from chronic HCV infection Serum ALT and HCV rna level according to reports, but in random controlled experiment subsequently, can't confirm the antivirus action that the virazole list is used.As if some follow-up small-scale researchs have confirmed virazole and the synergism of interferon in the hepatitis C infection patient, yet the danger of interferon monotherapy and side effect remain fatal shortcoming.
Some medicines or strategy (comprising ursodesoxycholic acid, indometacin, acetaminophen-cysteine, silymarin, certain plants goods and venesection) can effectively have been assisted the treatment of interferon already by report, but wherein none can be shown as in controlled experiment effectively all the time.
Hepatitis G virus (HGV; Be also referred to as third type GB hepatitis virus or the HGBV-C) just characterized fully in early days in 1996.HGV is a kind of banzi virus and is the distant relative of HCV.At this moment, have only by the PCR experiment and just can identify the HGV infection, this experiment indicates current infection.This experiment is not easy to implement or standardization.Antibody experiment at HGV is developed, and when it can utilize, will the popularity that HGV infects more fully be described than HGV RNA experiment.In a single day as if find antibody, HGV RNA is general just no longer have been existed.
Have reported in literature HGV by blood transfusion propagate (only Canadian research points out to have 1 among per 1500 blood transfusion receivers and infect, this infection account for post-transfusion hepatitis 9%), and can infect to child by mother in perinatal stage.The popularity of HGV RNA increases in crowd's (for example user of the patient of hemophilia or thalassemia, the patient who carries out hemodialysis and injectivity medicine) of normal contact blood or blood product.Other communication modes (as sexual intercourse) are possible but are not proved.As if HBV, HCV or the two coinfection are very common and showed similar communication mode.In the acquired acute viral hepatitis case of 0.3% colony, HGV is unique virus that is identified.
Many steroids and application thereof were open already.Referring to for example United States Patent (USP) 4956355,5859000,4268441,4666898,5837269,5827841,5811418,5824313,5686438,5635496,5587369,5583126,5562910,5532230,5518725,5736537,5843932,5837700,5824671,5807849,5798347,5780460,5776923,5728688,5610150,5593981,5372996,5110810,5807848,5707983,5641766,5585371,5506223,5424463,5296481,5292730,5776921,5641768,5559107,5478566,5461042,5407684,5387583,5277907,5206008,5077284,5162198,5660835,5527789,5756482,5709878,5804576,5744462,5714481,5700793,5696106,5656621,5175154,5157031,5028631,5001119,4898694,5824668,5710143,5795880,5527788,5591736,5861390 and the open WO98/05338 of PCT, WO95/21617, WO98/50040, WO98/50041 and WO97/48367, all these are hereby incorporated by.
Many flavone compounds, its preparation method and application were open already.Referring to for example J.A.Manthey and B.S.Buslig edit " flavone compound in the biosystem; experimental medicine and biology progress " the 439th volume, Plenum Press, New York, 1998, the 15th chapter (191-225 page or leaf), the 16th chapter (227-235) and the 17th chapter (237-247 page or leaf), they are hereby incorporated by.
Summary of the invention
The method that main embodiment of the present invention provides treatment or prevention togavirus to infect comprises to individuality and uses chemical compound shown in the formula 1 of effective dose Q wherein 1Be-C (R 1) 2-or-C (O)-; Q 2Be-C (R 1) 2-,-C (R 1) (Y)-,-C (Y)-or-CH 2-CH 2-;
Q 3Be-H or-C (R 1) 3-;
Q 4Be-C (R 1) 2-,-C (O)-, hydroxyl ethenylidene (CH (CH=CHOH)-) or methyl methylene (CH (CH 3)-);
Q 5Be-C (R 1) 2-or-C (O)-;
X and Y be independently-OH ,-H, low alkyl group be (as C 1-6Alkyl) ,-O-C (O)-R 5,-C (O)-OR 5, halogen (promptly-F ,-Cl ,-Br or-I) or=O;
Each R 1Be independently-H ,-F ,-Cl ,-Br ,-I ,-OH, C 1-6Alkoxyl or C 1-6Alkyl;
R 2Be-H ,-OH ,-F ,-Cl ,-Br ,-I, C 1-6Alkyl, C 1-6Alkoxyl ,-OR 3, ester is (as-O-C (O)-R 4Or-C (O)-O-R 4), thioesters is (as-O-C (S)-R 4Or-C (S)-O-R 4), mercaptal is (as-S-C (O)-R 4Or-C (O)-S-R 4), sulfuric ester (as-O-S (O) (O)-O-R 4), sulphonic acid ester is (as-O-S (O)-O-R 4) or carbamate (as-O-C (O)-NH-R 4Or-NH-C (O)-O-R 4), or R 2With the R that is bonded on the same carbon atom 1Be combined into=O;
R 3Be-S (O) (O)-OM ,-S (O) (O)-O-CH 2-CH (O-C (O)-R 6)-CH 2-O-C (O)-R 6,-P (O) (O)-O-CH 2-CH (O-C (O)-R 7)-CH 2-O-C (O)-R 7, the glucuronyl-shown in the structure (A):
Figure A9981365800221
Or R 3Be C 1-18Alkyl, C 2-18Alkenyl, C 2-18Alkynyl, C 1-18Ester or C 1-18Thioesters, wherein above-mentioned any C 1-18Or C 2-18Part is optional at one or more hydrogen atoms place to be replaced by one or more following radicals of independently being selected :-OR PR(comprise-OH) ,-NHR PR(comprise-NH 2) or-SR PR(comprise-SH); Or R 3Be C 1-18Fatty acid, C 2-10Alkynyl, (J) n-phenyl-C 1-5-alkyl, (J) n-phenyl-C 2-5-alkenyl;
R 4Be-H, protecting group, the optional C that replaces 1-18Alkyl, the optional C that replaces 1-18Alkenyl, the optional C that replaces 1-18Alkynyl, the optional aryl that replaces, the optional aryl-C that replaces 1-6Alkyl, the optional aryl-C that replaces 2-6Alkenyl, the optional aryl-C that replaces 2-6Alkynyl, the optional heterocycle-C that replaces 1-6Alkyl, the optional C that replaces 2-6Alkenyl-heterocycle, the optional C that replaces 2-6Alkynyl-heterocycle or the optional heterocycle that replaces, wherein any above-mentioned part is 1,2,3,4,5 or a plurality of carbon or hydrogen atom position are optional independently is selected from following group or atom replaces by one or more :-O-,-S-,-NR PR-(comprise-NH-) ,-NH-C (O)-,-OR PR(comprise-OH) ,-NHR PR(comprise-NH 2) ,-SR PR(comprise-SH) ,=O ,=S ,=N-OH ,-CN ,-NO 2,-F ,-Cl ,-Br or-I;
Each R 5Be straight or branched C independently 1-14Alkyl;
Each R 6Be straight or branched C independently 1-14Alkyl;
Each R 7Be straight or branched C independently 1-14Glucuronyl-shown in alkyl or the structure (A);
Each R PRBe independently-H or the independent protecting group of selecting;
N is 0,1,2 or 3;
Each J is independently-F ,-Cl ,-Br ,-I, C 1-4Alkyl, C 2-4Alkenyl, C 1-4Alkoxyl, carboxyl, nitro, sulphuric acid, sulfonyl, C 1-6Carboxylate or C 1-6Sulfuric ester;
M be hydrogen, sodium ,-S (O) (O)-O-CH 2-CH (O-C (O)-R 6)-CH 2-O-C (O)-R 6,-P (O) (O)-O-CH 2-CH (O-C (O)-R 7)-CH 2-O-C (O)-R 7Or the glucuronyl-shown in the structure (A);
Dotted line in the formula 1 is represented an arbitrarily two key, and condition is all not to be two keys at 4-5 and 5-6 position, and when two keys exist, 0 or 1 R 1Being bonded in and making these carbon atoms on 1,2,4,5,6 or 17 the carbon atom is tetravalence; With their salt, stereoisomer, position isomer, metabolite, analog, precursor, hydrate, tautomer, ionization form and solvate.The chemical compound of formula 1 is generically and collectively referred to as " chemical compound of the present invention " at this.
Another embodiment of the present invention comprises the method that a kind of treatment or prevention togavirus infect, and this method comprises to individuality uses chemical compound of the present invention and formula 2A or 2B chemical compound simultaneously or sequentially
Figure A9981365800241
Wherein the dotted line place exists two keys or singly-bound, and when two keys exist, and (i) has the phenyl ring of optional replacement in 2-or 3-position and does not have R with bond with carbon 8, (ii) do not have a R at adjacent 2-or 3-position 8
X 1Be-O-or-C (R 8) 2-;
X 2Be-C (O)-or-C (R 11) 2-;
Each R 8Be independently-H ,-OH, halogen, C 1-6Alkyl, C 1-6Alkoxyl, glucosiduronic acid, C 1-25Fatty acid, formula 2A or 2B chemical compound residue (remove a hydrogen atom therein and form formula 2A or 2B chemical compound free radical) ,-CH 2CH=C (CH 3) 2, glucoside, have structure (B) or group (C),
R 10Be C 1-6Alkyl, C 1-6Alkoxyl, neohesperidoside, Herba Apii graveolentis glucosides (apioglucoside), rutinoside, glucoside, galactoside, rhamnoside, arabinose glucosides, or stereoisomer, hydrate, analog, derivant or the metabolite of any of these part, they are optional independently by-OH, halogen, C on one or more hydrogen atoms 1-6Alkyl, C 1-6Alkoxyl, glucosiduronic acid or C 1-25Fatty acid replaces, or R 10Be-H ,-OH or halogen;
Each R 11Be independently-H ,-OH, halogen, C 1-6Alkyl, C 1-6Alkoxyl, glucosiduronic acid or C 1-25Fatty acid, or two R 11Be combined into=O; With their salt, stereoisomer, position isomer, metabolite, analog, precursor, hydrate, tautomer, ionization form and solvate.
Another embodiment of the present invention is the method that a kind of treatment or prevention togavirus infect, described togavirus infects and comprises that the infection that one or more are caused by Alphavirus, banzi virus, rubella virus or Pestivirus, this method comprise to individuality and use The compounds of this invention (chemical compound shown in the formula 1) and macrophage stimulation factor and choose wantonly and use formula 2A or 2B chemical compound.
Another embodiment of the present invention is the method that a kind of treatment or prevention togavirus infect, described togavirus infects and comprises the infection that one or more are caused by Alphavirus, banzi virus, rubella virus or Pestivirus, and this method comprises: to individuality use chemical compound shown in the formula 1 also (1) use oxidant or (2) adopt oxygen supply and optional macrophage stimulation factor and/or formula 2A or the 2B chemical compound also used.
Another embodiment of the present invention is the method that a kind of treatment or prevention togavirus infect, described togavirus infects and comprises that the infection that one or more are caused by Alphavirus, banzi virus, rubella virus or Pestivirus, this method comprise to individuality and use chemical compound shown in the formula 1 and virazole and/or α TFN and optionally also use one or more formulas 2A or 2B chemical compound, macrophage stimulation factor, oxidant or oxygen supply.Detailed Description Of The Invention
Has implication at this used term, unless otherwise noted or hint as giving a definition.
" patient " or " individuality " is meant the human or animal.Usually animal is a vertebrates, as primate, rodent, domestic animal or wild animal.Primate comprises chimpanzee, machin, Ateles and macaque such as Rhesus Macacus.Rodent comprises mice, rat, marmot, ferret, rabbit and hamster.Domestic animal and wild animal comprise cattle, horse, pig, deer, wild ox, Babalus bubalis L., cat family (for example family keeps a cat), Canidae (as Canis familiaris L.), birds (as chicken, Dromaius novaehollandiae, Ostriches) and Fish (as Squaliobarbus ourriculus, Silurus asotus fish and salmon).Patient or individuality comprise any above-mentioned subgroup, for example whole above-mentioned patients or individuality, but except one or more populations or species, as people, primates or rodent.
Unless make opposite explanation, be meant C at this used " alkyl " 1-C 18Hydrocarbon, its contain form for just, 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17 or 18 carbon atom of the second month in a season, uncle, ring-type or mixed structure.Example is-CH 3,-CH 2CH 3,-CH 2CH 2CH 3, CH (CH 3) 2,-CH 2CH 2CH 2CH 3,-CH 2CH (CH 3) 2,-CH (CH 3) CH 2CH 3,-C (CH 3) 3,-CH 2CH 2CH 2CH 2CH 3,-CH (CH 3) CH 2CH 2CH 3,-CH (CH 2CH 3) 2,-C (CH 3) 2CH 2CH 3,-CH (CH 3) CH (CH 3) 2,-CH 2CH 2CH (CH 3) 2,-CH 2CH (CH 3) CH 2CH 3,-CH 2C (CH 3) 3,-CH 2CH 2CH 2CH 2CH 2CH 3,-CH (CH 3) CH 2CH 2CH 2CH 3,-CH (CH 2CH 3) (CH 2CH 2CH 3) ,-C (CH 3) 2CH 2CH 2CH 3,-CH (CH 3) CH (CH 3) CH 2CH 3,-CH (CH 3) CH 2CH (CH 3) 2,-C (CH 3) (CH 2CH 3) 2,-CH (CH 2CH 3) CH (CH 3) 2,-C (CH 3) 2CH (CH 3) 2,-CH (CH 3) C (CH 3) 3, cyclopropyl, cyclobutyl, cyclopropyl methyl, cyclopenta, cyclobutylmethyl, 1-cyclopropyl-1-ethyl, 2-cyclopropyl-1-ethyl, cyclohexyl, cyclopentyl-methyl, 1-cyclobutyl-1-ethyl, 2-cyclobutyl-1-ethyl, 1-cyclopropyl-1-propyl group, 2-cyclopropyl-1-propyl group, 3-cyclopropyl-1-propyl group, 2-cyclopropyl-2-propyl group and 1-cyclopropyl-2-propyl group.
Unless do opposite explanation, this used " alkenyl " be meant contain form for just, 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17 or 18 carbon atom of the second month in a season, uncle, ring-type or mixed structure and between adjacent carbon atom, have 1,2,3 or the C of a plurality of pairs of keys 2-18Hydrocarbon.Example is-CH=CH 2,-CH=CHCH 3,-CH 2CH=CH 2,-C (=CH 2) (CH 3) ,-CH=CHCH 2CH 3,-CH 2CH=CHCH 3,-CH 2CH 2CH=CH 2,-CH=C (CH 3) 2,-CH 2C (=CH 2) (CH 3) ,-C (=CH 2) CH 2CH 3,-C (CH 3)=CHCH 3,-CH (CH 3) CH=CH 2,-C=CHCH 2CH 2CH 3,-CHCH=CHCH 2CH 3,-CHCH 2CH=CHCH 3,-CHCH 2CH 2CH=CH 2,-C (=CH 2) CHxCH 2CH 3,-C (CH 3)=CH 2CH 2CH 3,-CH (CH 3) CH=CHCH 3,-CH (CH 3) CH 2CH=CH 2,-CH 2CH=C (CH 3) 2, 1-ring penta-1-thiazolinyl, 1-ring penta-2-thiazolinyl, 1-ring penta-3-thiazolinyl, 1-hexamethylene-1-thiazolinyl, 1-hexamethylene-2-thiazolinyl and 1-hexamethylene-3-thiazolinyl.
Unless do opposite explanation, this used " alkynyl " be meant contain form for just, 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17 or 18 carbon atom of the second month in a season, uncle, ring-type or mixed structure and between adjacent carbon atom, have 1,2,3 or the C of a plurality of three keys 2-18Hydrocarbon.Example is-CCH ,-CCCH 3,-CH 2CCH ,-CCCH 2CH 3,-CH 2CCCH 3,-CH 2CH 2CCH ,-CH (CH 3) CCH ,-CCCH 2CH 2CH 3,-CH 2CCCH 2CH 3,-CH 2CH 2CCCH 3With-CH 2CH 2CH 2CCH.
" halogen " or " halo " be meant fluorine (F), chlorine (Cl), bromine (Br) or iodine (I), and if relate to more than one halogen (for example two or more variable groups can be halogens), each halogen is selected independently.
" steroid nucleus " is meant 4 fused rings with formula 1 structure.
" PEG " is meant that containing the 20-that has an appointment about 2000000 connects monomeric ethylene glycol polymer, contains about 50-1000 usually and connects monomer, more common about 100-300.Polyethylene Glycol comprises that containing different numbers connects monomeric PEG compounds, as PEG20, PEG30, PEG40, PEG60, PEG80, PEG100, PEG115, PEG200, PEG300, PEG400, PEG500, PEG600, PEG1000, PEG1500, PEG2000, PEG3350, PEG4000, PEG4600, PEG5000, PEG6000, PEG8000, PEG11000, PEG12000, PEG2000000 and any mixture thereof.
" excipient " or " carrier " is meant acceptable composition or component, just produces excessively infringement with other component compatibility of disclosed compositions of the application or preparation and the patient who preparation is not used or animal.At this, excipient and carrier comprise liquid, and it comprises benzyl benzoate, Oleum Gossypii semen, N,N-dimethylacetamide, C 2-12Alcohol (as ethanol), glycerol, Oleum Arachidis hypogaeae semen, PEG, vitamin E, poppy seed oil, propylene glycol, safflower oil, Oleum sesami, Oleum Glycines and vegetable oil.Can not comprise solvent at this used excipient, as chloroform, dioxane or DMSO.Excipient comprises the composition that one or more are habitual in field of pharmaceutical preparations, as filler, binding agent, disintegrating agent and lubricant.
Unless otherwise indicated, phrase " chemical compound shown in the formula 1 ", " chemical compound of the present invention ", " chemical compound of formula 2A or 2B ", " increasing the chemical compound of plasma concentration " etc. are meant compositions or method, the method that treatment togavirus for example disclosed herein infects, the chemical compound that wherein has one or more formulas 1 or formula 2A or 2B, common 1,2,3 or 4 kind, more normal is a kind.
Comprise at this used " alcohol " that excipient is meant and contain the C that on one or more hydrogen atoms, is replaced by one or more hydroxyls (being generally 1,2 or 3 hydroxyl) 1-12The alcohol of moieties.Alcohol comprises, for example ethanol, normal propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutanol, sec-butyl alcohol, the tert-butyl alcohol, n-amyl alcohol, isoamyl alcohol, hexanol, Hexalin, n-heptanol, n-octyl alcohol, n-nonyl alcohol, Decanol and benzylalcohol.Carbon atom in the alcohol can be straight chain, side chain or ring-type.Alcohol comprises any subclass of above-mentioned alcohol, as C 2-4Alcohol (alcohol) with 2,3 or 4 carbon atoms.
" ester " is meant to have-part of C (O)-O-structure.Usually, comprise the organic moiety that contains about 10 the independent hetero atoms of selecting (as O, S, N, P, Si) of 1-50 the carbon atom of having an appointment (2-12 carbon atom according to appointment) and 0-at this used ester, wherein this organic moiety is combined in the R of formula 1 steroid nucleus by-C (O)-O-structure 2Position, for example organic moiety-C (O)-O-steroid class or organic moiety-O-C (O)-steroid class.This organic moiety contains one or more above-mentioned organic groups usually, as C 1-20Moieties, C 2-20Alkenyl part, C 2-20Alkynyl part, aryl moiety, C 2-9The substitutive derivative of heterocycle or these parts for example has 1,2,3,4 or a plurality of substituent group, and wherein each substituent group is selected independently.In these organic groups for the typical substituent group of hydrogen or carbon atom comprise 1,2,3,4 or a plurality of (common 1,2 or 3)-O-,-S-,-NR PR-(comprise-NH-) ,-C (O)-,=O ,=S ,-N (R PR) 2(comprise-NH 2) ,-C (O) OR PR(comprising-C (O) OH) ,-OC (O) R PR(comprise-O-C (O)-H) ,-OR PR(comprise-OH) ,-SR PR(comprise-SH) ,-NO 2,-CN ,-NHC (O)-,-C (O) NH-,-OC (O)-,-C (O) O-,-O-A8 ,-S-A8 ,-C (O)-A8 ,-OC (O)-A8 ,-C (O) O-A8 ,=N-,-N=,=N-OH ,-OPO 3(R PR) 2,-OSO 3H 2Perhaps halogen part or atom, wherein each R PRThe protecting group that is-H, independently selects, or two R PRBe combined into protecting group, A8 is C 1-8Alkyl, C 2-8Alkenyl, C 2-8Alkynyl, C 1-4Alkyl-aryl (as benzyl), aryl (as phenyl) or C 0-4Alkyl-C 2-9Heterocycle.Substituent group is selected independently.This organic moiety comprises R 4Change the chemical compound that is limited.This organic moiety has obviously been got rid of l fraction, as-O-O-, be a kind of transition material unless work as this type of l fraction, it has enough chemical stabilities can be used for preparing the chemical compound that is fit to described one or more purposes of the application.Above-mentioned substituent group is the typical substituent group that can be used for replacing one or more carbon atoms, as-O-or-C (O)-, or replace the typical substituent group of one or more hydrogen atoms, as halogen ,-NH 2,-OH or=O.
" thioesters " is meant to have-part of C (S)-O-structure.Usually, comprise the organic moiety that contains 1-50 carbon atom of having an appointment (as 2-12 carbon atom) and about 10 hetero atoms of 0-(as O, S, N, P, Si) at this used thioesters, wherein this organic moiety is combined in formula 1 steroid nucleus R by-C (S)-O-structure 2Position, for example organic moiety-C (S)-O-steroid class or organic moiety-O-C (S)-steroid class.This organic moiety contains one or more above-mentioned organic groups usually, as C 1-20Moieties, C 2-20Alkenyl part, C 2-20Alkynyl part, aryl moiety, C 2-9The substitutive derivative of heterocycle or these parts, as contain 1,2,3,4 or a plurality of substituent group, wherein each substituent group is selected independently.In these organic groups for the typical substituent group of hydrogen or carbon atom comprise 1,2,3,4 or a plurality of (common 1,2 or 3)-O-,-S-,-NR PR-(comprise-NH-) ,-C (O)-,=O ,=S ,-N (R PR) 2(comprise-NH 2) ,-C (O) OR PR(comprising-C (O) OH) ,-OC (O) R PR(comprise-O-C (O)-H) ,-OR PR(comprise-OH) ,-SR PR(comprise-SH) ,-NO 2,-CN ,-NHC (O)-,-C (O) NH-,-OC (O)-,-C (O) O-,-O-A8 ,-S-A8 ,-C (O)-A8 ,-OC (O)-A8 ,-C (O) O-A8 ,=N-,-N=,=N-OH ,-OPO 3(R PR) 2,-OSO 3H 2Perhaps halogen part or atom, wherein each R PRThe protecting group that is-H, independently selects, or two R PRBe combined into protecting group, and A8 is C 1-8Alkyl, C 1-8Alkenyl, C 1-8Alkynyl, C 1-4Alkyl-aryl (as benzyl), aryl (as phenyl) or C 0-4Alkyl-C 2-9Heterocycle.Substituent group is selected independently.This organic moiety comprises R 4Change the chemical compound that is limited.This organic moiety has obviously been got rid of l fraction, as-O-O-, be a kind of transition material unless work as this type of l fraction, it has enough chemical stabilities can be used for preparing the chemical compound that is fit to described one or more purposes of the application.Above-mentioned substituent group is the typical substituent group that can be used for replacing one or more carbon atoms, as-O-or-C (O)-, or replace the typical substituent group of one or more hydrogen atoms, as halogen ,-NH 2Or-OH.
" mercaptal " is meant to have-part of C (O)-S-structure.Usually, comprise the organic moiety that contains 1-50 carbon atom of having an appointment (as 2-12 carbon atom) and about 10 hetero atoms of 0-(as O, S, N, P, Si) at this used mercaptal, wherein this organic moiety is combined in the R of formula 1 steroid nucleus by-C (O)-S-structure 2Position, for example organic moiety-C (O)-S-steroid class or organic moiety-S-C (O)-steroid class.As described in described organic moiety defines as thioesters.
" carbamate " is meant as the definition ester is described and contains 1,2,3,4 or a plurality of-O-C (O) NR PRThe organic moiety of-structure, wherein R RPFor-H, protecting group or as the organic moiety of ester definition.Usually, comprise the organic moiety that contains 1-50 carbon atom of having an appointment (as 2-12 carbon atom) and about 10 hetero atoms of 0-(as O, S, N, P, Si) at this used carbamate groups, wherein this organic moiety is passed through-O-C (O)-NR PR-structure is combined in formula 1 steroid nucleus R 2Position, for example organic moiety-NR PR-C (O)-O-steroid class or organic moiety-O-C (O)-NR PR-steroid class.As described in described organic moiety defines as thioesters.
" sulfuric ester " be meant have-O-S (O) (O)-part of O-structure.Usually, comprise the organic moiety that contains 1-50 carbon atom of having an appointment (as 2-12 carbon atom) and about 10 hetero atoms of 0-(as O, S, N, P, Si) at this used sulfuric ester, wherein this organic moiety by-O-S (O) (O)-the O-structure is combined in formula 1 steroid nucleus R 2The position, for example organic moiety-O-S (O) (O)-O-steroid class.As described in described organic moiety defines as thioesters.
" sulfite " is meant to have-part of O-S (O)-O-structure.Usually, comprise the organic moiety that contains 1-50 carbon atom of having an appointment (as 2-12 carbon atom) and about 10 hetero atoms of 0-(as O, S, N, P, Si) at this used sulfite, wherein this organic moiety is combined in formula 1 steroid nucleus R by-O-S (O)-O-structure 2Position, for example organic moiety-O-S (O)-O-steroid class.As described in described organic moiety defines as thioesters.
Compositions disclosed herein wherein has ionization part or the formula 1 of polarity part and the salt of 2 chemical compounds optional comprising.The complex that comprises the part that contains opposite charges at this used " salt ".Ionizable part comprises and is positioned at R 2The position-O-S (O) (O)-OH or-NH 2, and polarity partly comprises-OH.Salt comprises officinal salt, comprising for example uncharged part or univalent anion part or monovalent cation part.Salt comprises by in conjunction with suitable anion such as mineral acid and derived compounds.The salt that is suitable for comprises that those have the chemical compound of the acidity that is enough to form sta-salt, preferred hypotoxic acid.For example, can be from some mineral acid such as HF, HCI, HBr, HI, H 2SO 4, H 3PO 4The sour addition at alcaliotropism center forms salt of the present invention, and basic center is amine normally, and it is present in formula 1,2A or the 2B chemical compound.Perhaps, can adopt some organic acid chemical compound in the same manner, for example, organic sulfonic acid class, organic carboxyl acid class.The example of organic sulfonic acid class comprises C 6-16Aryl sulfonic acid, C 6-16Heteroaryl sulfonic acid and C 1-16Alkyl sulfonic acid is as phenyl, Alpha-Naphthyl, betanaphthyl, (S)-Camphora, methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, sec-butyl, isobutyl group, the tert-butyl group, amyl group and hexyl sulfonic compound.The example of organic carboxyl acid comprises C 1-16Alkyl, C 6-16Aryl carboxylic acid, C 4-16Heteroaryl carboxylic acid is as acetic acid, glycolic, lactic acid, acetone acid, malonic acid, 1,3-propanedicarboxylic acid, tartaric acid, citric acid, fumaric acid, succinic acid, malic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxy benzoic acid, phenylacetic acid, cinnamic acid, salicylic acid and 2-phenoxy benzoic acid.Salt also can comprise The compounds of this invention and one or more amino acids formed salt.Several amino acids is applicable to the present invention, the aminoacid as the protein composition of especially natural discovery, and aminoacid has the side chain with alkalescence or acidic-group usually, for example lysine, arginine or glutamic acid, or have side chain with neutral group, as glycine, serine, threonine, alanine, isoleucine or leucine.Salt is generally biocompatible or pharmaceutically acceptable or avirulence, particularly for mammalian cell.Biologically deleterious salt generally is used to prepare other The compounds of this invention as synthetic intermediate.
Neohesperidoside, rutinoside and glucoside group have following structure respectively:
Figure A9981365800311
Wherein one or more hydrogen atoms are optional independently by hydroxyl, halogen, C 1-6Alkyl, C 1-6Alkoxyl, glucosiduronic acid or C 1-25Fatty acid replaces.
Heterocycle " heterocycle " comprises, such as but not limited to Paquette, and the described heterocycle of Leo A.; " contemporary heterocyclic chemistry principle " (" Principle of Madern Heterocyclic Chemistry ") (W.A.Benjamin, New York, 1968), particularly 1,3,4,6,7 and 9 chapters; " chemistry of heterocyclic compound, one group of monograph " (" The Chemistry of HeterocyclicCompounds, A series of Monographs ") (John Wiley﹠amp; Sons, New York, 1950 so far), particularly the 13rd, 14,16,19 and 28 roll up; And JACS (J.Am.Chem.Soc.) 1960,82:5566; With United States Patent (USP) 5763483, all these are hereby incorporated by.
Heterocyclic example comprises and for example is not limited to pyridine radicals, thiazolyl, the tetrahydrochysene thiophenyl, by thio-oxidizing tetrahydrochysene thiophenyl, pyrimidine radicals, furyl, thienyl, pyrrole radicals, pyrazolyl, imidazole radicals, tetrazole radical, benzofuranyl, the thiophene naphthyl, indyl, indolinyl, quinolyl, isoquinolyl, benzimidazolyl, piperidyl, the 4-piperidone base, pyrrolidinyl, the 2-Pyrrolidone base, pyrrolinyl, tetrahydrofuran base, tetrahydric quinoline group, tetrahydro isoquinolyl, decahydroquinolyl, the octahydro isoquinolyl, the azocine base, triazine radical, 6H-1,2,5-thiadiazine base, 2H, 6H-1,5,2-dithiazine base, thienyl, thianthrene group, pyranose, isobenzofuran-base, chromenyl, xanthyl Fen Evil thia cyclohexadienyl (phenoxathiinyl), the 2H-pyrrole radicals, isothiazolyl isoxazolyl, pyrazinyl, pyridazinyl, the indolizine base, isoindolyl, the 3H-indyl, the IH-indazolyl, purine radicals, the 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolyl, the cinnolines base, pteridyl, the 4aH-carbazyl, carbazyl, the B-carboline base, phenanthridinyl, acridinyl, pyrimidine radicals, phenanthroline, phenazinyl, phenothiazinyl, furazan base phenoxazine, the isochroman base, chromanyl, the imidazoles thiazolinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, iso-dihydro-indole-group, quinine pyridine base, morpholinyl oxazolinyl, the benzotriazole base, the benzoisoxazole base, hydroxyindole base; benzoxazole quinoline base and isatin acidic group (isatinoyl).
Such as but not limited to, the heterocycle of bonded carbon is to be bonded in 2,3,4,5 or 6 of pyridine, 3,4,5 or 6 of pyridazine, 2,4,5 or 6 of pyrimidine, 2,3,5 or 6 of pyrazine, 2,4 or 5 isoxazoles of 2,3,4 or 5 oxazoles, imidazoles or thiazoles of furan, oxolane, thio-furan, thiophene, pyrroles or nafoxidine, pyrazoles, isothiazole 3,4 or 5,2 or 3 of aziridine, 2,3 or 4 of azetidine, 2,3,4,5,6,7 or 8 of quinoline, or 1,3,4,5,6,7 or 8 of isoquinolin.More typically, the heterocycle of bonded carbon comprises 2-pyridine radicals, 3-pyridine radicals, 4-pyridine radicals, 5-pyridine radicals, 6-pyridine radicals, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidine radicals, 4-pyrimidine radicals, 5-pyrimidine radicals, 6-pyrimidine radicals, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl or 5-thiazolyl.
Such as but not limited to, the heterocycle of bonding nitrogen is to be bonded in aziridine, azetidine, pyrroles, pyrrolidine, 2-pyrrolin, 3-pyrrolin, imidazoles, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazoles, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidines, piperazine, indole, indoline, 1H-indazole 1, iso-indoles or isoindoline 2,4 and carbazole or B-carboline 9 of morpholine.Typically, the heterocycle of bonding nitrogen comprises 1-azacyclo-propyl group, 1-azelidinyl, 1-pyrrole radicals, 1-imidazole radicals, 1-pyrazolyl and piperidino.
" heteroaryl " is meant aromatic ring or two or more fused rings that contains one or more aromatic rings, and wherein aromatic ring or fused rings contain 1,2,3 or a plurality of hetero atom, be generally (O-), nitrogen (NX-) or sulfur (S-), wherein X is-H, protecting group or C 1-6Alkyl is generally-H.As described in example defines as heterocycle.
Protecting group. the multiple group of formula 1,2A or 2B chemical compound can contain, for example substituted alkyl, substituted alkenyl base, ester or substituted heterocycle, they can contain one or more reactive parts as hydroxyl or sulfydryl.The intermediate that is used for preparation formula 1 or formula 2A or 2B chemical compound can be protected, and this is conspicuous in affiliated field.Non-annularity or ring protection base and corresponding cleavage reaction thereof are disclosed in " protecting group in the organic chemistry " (" Protective Groups inOrganic Chemistry "), Theodora W.Greene (John Wiley﹠amp; Sons, Inc., New York, 1991, ISBN 0-471-62301-6) (after this being called " Greene ").In this article, these protecting groups are can remove from molecule of the present invention and can reversibly change the covalent bond structure of molecule remainder or oxidation/go back ortho states.For example, bonding for the protecting group-X of-OX or NHX group can be removed respectively generation-OH or-NH 2, do not influence other covalent bond in the molecule simultaneously.Sometimes, if necessary, can remove more than one protecting group simultaneously, or can remove them in proper order.In containing the The compounds of this invention of a plurality of protecting groups, described protecting group can be identical or different.
Belong to protection scope of the present invention though should understand protected intermediate, protecting group can remove by known method.Removing of protecting group may be effort or simple, and this depends on the cost and the character of related transformation.Usually, people use amine or carboxyl outside the protecting group protection ring in the process of chemical compound shown in the synthesis type 1.Treat in the application in the overwhelming majority, amino is answered deprotection.Protecting group generally is used for protecting sensitive group in reacting as alkylation or acyl groupization covalent modification not to take place.Usually, can remove protecting group by for example hydrolysis, elimination or aminolysis.So simple functionalized consideration can be for specifying the selection reversible or irreversible protecting group on the site that guidance is provided at The compounds of this invention.Protecting group that is suitable for and choice criteria thereof are disclosed in " protecting group in the organic synthesis " (" Protective Groups in Organic Synthesis ") the 2nd edition that T.W.Greene and P.G.M.Wuts edit; Wiley Press; 10-142,143-174,175-223,224-276,277-308,309-405 and 406-454 page or leaf, the document is hereby incorporated by.
Judge in a usual manner whether a group is protecting group, for example, as Kocienski, Philip J.; " protecting group " (" Protecting Groups ") (Georg Thieme Verlag Stuttgart, New York, 1994) (after this being called " Kocienski "), 1.1 joints, page 2 and Greene the 1st chapter, 1-9 page or leaf; Described in United States Patent (USP) 5763483, these documents are hereby incorporated by.Particularly; based on molar ratio computing; if remove 90% protecting group by deprotection reaction; and; be no more than 50%, preferred 25%, more preferably 10% deprotection product molecule covalent bond structure of the present invention or oxidation/go back ortho states variation (except removing that protecting group causes) has taken place, then this group is a protecting group.When having a plurality of protecting group of same type in the molecule, can when sloughing all this type of protecting group, measure molar ratio.When having dissimilar a plurality of protecting groups in the molecule; can be independently or handle all kinds of protecting group (and measure molar ratio) each other together, this depends on whether the deprotection reaction condition that is fit to a kind of protecting group also is fit to the protecting group of other type of existing.In one embodiment of the invention; calculate based on the mol ratio of measuring with routine techniques; if remove 90% protecting group by habitual deprotection reaction; and except protecting group remove cause have and be no more than 50%, preferred 25%, more preferably 10% deprotection product molecule covalent bond structure of the present invention or oxidation/irreversible variation takes place to go back ortho states, then this group is a protecting group.Irreversible change needs the covalent bond structure of chemical reaction (except those are caused by hydrolysis, acid/alkali neutralization or conventional separation, fractionation or purification) recovery deprotection molecule of the present invention or oxidation/go back ortho states.
Protecting group also is disclosed in Kocienski, Philip J. in detail with the specific strategy of other general concept and its application; In " protecting group " (Georg Thieme Verlag Stuttgart, New York, 1994), it is incorporated herein by reference in full at this.Particularly, the 1st chapter, protecting group: summary, 1-20 page or leaf; The 2nd chapter, hydroxyl protecting group, 21-94 page or leaf; The 3rd chapter, glycerol protection base, 95-117 page or leaf; The 4th chapter, carboxyl-protecting group, 118-154 page or leaf; The 5th chapter, carbonyl-protection base, 155-184 page or leaf; The 6th chapter, amino protecting group, 185-243 page or leaf; The 7th chapter, postscript, 244-252 page or leaf; And index, the 253-260 page or leaf, its content is incorporated herein specially.More especially, 2.3 joint silyl ethers; 2.4 alkyl ether chemical compound; 2.5 alkoxyalkyl ether compound (acetal compound); 2.6 summary (hydroxyl and sulfhydryl protected base); 3.2 acetal compound; 3.3 silylene derivant; 3.4 1,1,3,3-tetra isopropyl two methylene silicon ether derivants, 3.5 comment (glycerol protection base); 4.2 ester; 4.32,6,7-trioxa bicyclo-[2.2.2] octane [OBO] and other ortho esters; 4.4 oxazoline compounds; 4.5 comment (carboxyl-protecting group); 5.2 O, the O-acetal compound; 5.3 S, the S-acetal compound; 5.4 O, the S-acetal compound; 5.5 comment in (carbonyl-protection base); 6.2 N-acyl derivative; 6.3 N-sulfonyl analog derivative; 6.4 N-sulfenyl derivant; 6.5 N-alkyl derivative; 6.6 N-silicyl derivant; 6.7 imines analog derivative and 6.8 is commented (amino protecting group), its content is incorporated herein specially, has wherein inquired into the protection/deprotection of necessary functional group.In addition, the form that occurs in preceding front cover and the facing pages " main protecting group index ", introduce in full at this respectively in " abbreviation " of xiv page or leaf and " reagent and the solvent " of xv page or leaf.
Typical hydroxyl protecting group is disclosed in the 14-118 page or leaf of Greene and comprises: ether (methyl ether); Substituent methyl ether (methoxy, the methyl sulfidomethyl, tert-butyl group sulfidomethyl, (phenyl dimetylsilyl) methoxy, benzyloxymethyl, to methoxyl group benzyloxy ylmethyl, (4-methoxyl group phenoxy group) methyl, the guaiacol methyl, the tert-butoxy methyl, 4-amylene oxygen ylmethyl, the siloxy methyl, 2-methoxy ethoxy methyl, 2,2,2-trichlorine ethoxyl methyl, two (2-chloroethoxy) methyl, 2-(trimethyl silyl) ethoxyl methyl, THP trtrahydropyranyl, 3-bromine THP trtrahydropyranyl, tetrahydro thiapyran base, 1-methoxyl group cyclohexyl, 4-methoxyl group THP trtrahydropyranyl, 4-methoxyl group tetrahydro thiapyran base, 4-methoxyl group tetrahydro thiapyran base, S, the S-bicyclic oxygen, 1-[(2-chloro-4-methyl) phenyl]-4-methoxyl group piperidin-4-yl, 1,4-diox-2-base, tetrahydrofuran base, tetrahydro-thienyl, 2,3,3a, 4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methylene benzo furan-2-yl); The ether class (1-ethoxyethyl group, 1-(2-chloroethoxy) ethyl, 1-methyl isophthalic acid-methoxy ethyl, 1-methyl isophthalic acid-benzyloxy ethyl, the 1-methyl isophthalic acid-benzyloxy-2-fluoro ethyl, 2 that replace, 2,2-three chloroethyls, 2-trimethyl silyl ethyl, 2-(phenyl selenyl) ethyl, the tert-butyl group, pi-allyl, rubigan, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl); The benzyl ethers that replaces is (to methoxy-benzyl, 3, the 4-dimethoxy-benzyl, adjacent nitrobenzyl, to nitrobenzyl, to halogeno-benzyl, 2, the 6-dichloro benzyl, to the cyano group benzyl, to phenylbenzyl, 2-and 4-picolyl, 3-methyl-2-picolyl N-epoxy radicals, diphenyl methyl, p, p '-dinitro benzhydryl, 5-dibenzo suberyl, trityl group, the Alpha-Naphthyl diphenyl methyl, the p-methoxyphenyl diphenyl methyl, two (p-methoxyphenyl) phenyl methyl, three (p-methoxyphenyl) methyl, 4-(4 '-bromobenzene formyl methoxyl group) the phenyl benzhydryl, 4,4 ', 4 " three (4; 5-hexichol diformazan acylimino phenyl) methyl; 4; 4 '; 4 "-three (levulinic acyl-oxygen base phenyl) methyl, 4,4 ', 4 " three (benzoyloxy phenyl) methyl; 3-(imidazoles-1-ylmethyl) two (4 '; 4 "-Dimethoxyphenyl) methyl, 1, two (the 4-methoxyphenyls)-1 of 1-'-the pyrenyl methyl, the 9-anthryl, 9-(9-phenyl) xanthyl, 9-(9-phenyl-10-oxo) anthryl, 1,3-benzo dithiolane-2-base, benzisothiazole base S, the S-dioxide); Silyl ether (trimethyl silyl, triethylsilyl, triisopropyl silicyl, dimethyl isopropyl silicyl, diethyl isopropyl silicyl, dimethyl hexyl silicyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, tribenzyl silicyl, three-xylol base silicyl, triphenyl silicyl, diphenyl methyl silicyl, tert-butyl group methoxyphenyl silicyl); Ester type compound (formic acid esters, the benzoyl formic acid esters, acetas, chloracetate, the dichloroacetic acid ester, trichloroacetic esters, trifluoro-acetate, the 2-Methoxyacetic acid ester, triphenyl 2-Methoxyacetic acid ester, the phenoxyacetic acid ester, the parachlorophen-oxyacetic acid ester, to poly--phenylacetic acid ester, 3-phenylpropionic acid ester, 4-oxopentanoie acid ester (levulinate), 4,4-(ethylene sulfo-) valerate, pivalate, adamantate (Adamantoate), crotonates, 4-methoxyl group crotonates, benzoate, to phenylbenzoate, 2,4,6-trimethylbenzoic acid ester (trimethylbenzene methyl ester); Carbonic ester (methyl, 9-fluorenyl methyl, ethyl, 2,2,2-three chloroethyls, 2-(trimethyl silyl) ethyl, 2-(phenyl sulfonyl) ethyl, 2-(triphenyl phosphorio) ethyl, isobutyl group, vinyl, pi-allyl, p-nitrophenyl, benzyl, to methoxy-benzyl, 3,4-dimethoxy-benzyl, adjacent nitrobenzyl, to nitrobenzyl, S-benzyl sulfocarbonate, 4-ethyoxyl-1-naphthyl, methyl dithiocarbonates); Assist cracked group (2-iodobenzoic acid ester, 4-azido butyrate, 4-nitro-4-methyl valerate, neighbour's (two bromomethyls) benzoate, 2-formoxyl benzene sulfonate, 2-(methyl sulfo-methoxyl group) ethyl carbonate ester, 4-(methyl sulfo-methoxyl group) butyrate, 2-(methyl sulfo-methoxy) benzoate); Various esters (2,6-two chloro-4-methylenedioxy phenoxy yl acetates, 2,6-two chloro-(1,1,3, the 3-tetramethyl butyl) phenoxyacetic acid ester, 2,4-two (1, the 1-dimethyl propyl) phenoxyacetic acid ester, the chlorodiphenyl yl acetate, isobutyrate, succinic acid one ester, (E)-2-methyl-2-butene acid esters (tiglate), adjacent (methoxycarbonyl) benzoate, the p-poly-phenyl formic acid esters, the α-Nai Jiasuan ester, nitrate, alkyl N, N, N ', N '-tetramethyl phosphoro diamides thing, the N-carbanilate, borate, the dimethyl disulfide phosphino-, 2,4-dinitrophenyl sulfenic acids ester); And sulphonic acid ester (sulfuric ester, methane sulfonate (methanesulfonates), benzyl sulphonic acid ester, tosylate).
More typical hydroxyl protecting group comprise replacement methyl ether compounds, replacement benzyl ethers compounds, silicyl ether compound and comprise the ester of sulphonic acid ester, especially be typically trialkylsilyl ethers, tosylate and acetas.
Typical 1,2-and 1,3-glycerol protection base is disclosed in the 118-142 page or leaf of Greene and comprises cyclic acetal and ketal (methylene, ethylidene, 1-tert-butyl group ethylidene, 1-phenyl ethylidene, (4-methoxyphenyl) ethylidene, 2,2,2-three chlorethylidenes, acetonide (isopropylidene), cyclopentylene, cyclohexylidene, inferior suberyl, benzal, to methoxyl group benzal, 2,4-dimethoxybenzylidenegroup group, 3,4-dimethoxybenzylidenegroup group, 2-nitro benzal); Cyclic ortho ester (methoxyl group methylene, ethyoxyl methylene, dimethoxy methylene, 1-methoxyl group ethylidene, 1-ethyoxyl ethylidene, 1,2-dimethoxy ethylidene, α-methoxyl group benzal, 1-(N, the N-dimethyl amido) ethidene derivant, α-(N, N-dimethyl amido) benzylidene derivatives, 2-oxa-cyclopentylene); With silicyl derivant (two-tert-butyl group silicylene, 1,3-(1,1,3,3-tetra isopropyl two inferior siloxy groups) derivant, four-tert-butoxy disiloxane-1,3-two ylidene derivatives, cyclic carbonate, ring-type borate, ethyl-boron dihydroxide ester, phenyl boronate).
More typically, 1,2-and 1,3-glycerol protection base comprises epoxide and acetonide.
Typical amino protecting group is disclosed in the 315-385 page or leaf of Greene, comprising carbamate (methyl and ethyl, 9-fluorenyl methyl, 9 (2-sulfo group) fluorenyl methyl, 9-(2, the 7-dibromo) fluorenyl methyl, 2,7-two-tert-butyl group-[9-(10,10-dioxy-10,10,10,10-tetrahydrochysene thioxanthene base)] methyl, 4-methoxybenzoyl methyl); The ethyl (2 that replaces, 2,2-three chloroethyls, 2-trimethyl silyl ethyl, the 2-phenethyl, 1-(1-adamantyl)-1-Methylethyl, 1,1-dimethyl-2-halogenated ethyl, 1,1-dimethyl-2,2-two bromoethyls, 1,1-dimethyl-2,2,2-three chloroethyls, 1-methyl isophthalic acid-(4-xenyl) ethyl, 1-(3,5-two-tert-butyl-phenyl)-the 1-Methylethyl, 2-(2 '-and 4 '-pyridine radicals) ethyl, 2-(N, N-dicyclohexyl formamido) ethyl, the tert-butyl group, the 1-adamantyl, vinyl, pi-allyl, 1-isopropyl pi-allyl, cinnamyl, 4-nitro cinnamyl, the 8-quinolyl, N-hydroxy piperidine base, the alkyl disulfide group, benzyl, to methoxy-benzyl, to nitrobenzyl, to bromobenzyl, right-the benzyl chloride base, 2, the 4-dichloro benzyl, 4-methylsulfinyl benzyl, 9-anthryl methyl, diphenyl methyl); Assist cracked group (2-methyl thio-ethyl, 2-methyl sulphonyl ethyl, 2-(p-toluenesulfonyl) ethyl, 2-(1,3-two sulfonyls) methyl, 4-methyl thio phenyl, 2,4-dimethyl disulfide phenyl, the phosphonio ethyl of 2-, the phosphonio isopropyl of 2-triphenyl, 1,1-dimethyl-2-cyanoethyl, m-chloro are to the acyloxy benzyl, to (dihydroxy boryl) benzyl, 5-benzoisoxazole ylmethyl, 2-(trifluoromethyl)-6-chromone ylmethyl); Group (m-nitro base, 3,5-dimethoxy-benzyl, adjacent nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, phenyl (ortho-nitrophenyl base) methyl) that can photodestruciton; Carbamide derivative (phenothiazinyl-(10)-carbonyl derivative, N '-p-toluenesulfonyl amino carbonyl, N '-phenyl amino thiocarbonyl); Various carbamate (tertiary pentyls, S-benzyl thiocarbamate, to the cyano group benzyl, cyclobutyl, cyclohexyl, cyclopenta, the cyclopropyl methyl, to oxy-benzyl in the last of the ten Heavenly stems, the diisopropyl methyl, 2,2-dimethoxy carbonyl ethenyl, adjacent (N, N-dimethylformamide base) benzyl, 1,1-dimethyl-3-(N, N-dimethylformamide base) propyl group, 1, the 1-alkynyl dimethyl, two (2-pyridine radicals) methyl, the 2-furyl methyl, 2-iodo ethyl, isobornyl, isobutyl group, the nicotimine base, to (p '-the methoxyphenyl azo) benzyl, 1-methyl cyclobutyl, the 1-methylcyclohexyl, 1-methyl isophthalic acid-cyclopropyl methyl, 1-methyl isophthalic acid-(3, the 5-Dimethoxyphenyl) ethyl, 1-methyl isophthalic acid-(to the phenylazo phenyl) ethyl, 1-methyl isophthalic acid-phenylethyl, 1-methyl isophthalic acid-(4-pyridine radicals) ethyl, phenyl, to (phenylazo) benzyl, 2,4,6-three (tert-butyl group) phenyl, 4-(trimethyl ammonium) benzyl, 2,4, the 6-trimethyl benzyl); Amides compound (N-formoxyl, N-acetyl group, N-chloracetyl, N-tribromo-acetyl base, N-TFA base, N-phenyl acetyl, N-3-phenyl propiono, N-pyridine formoxyl, N-3-pyridine radicals Methanamide, N-benzoyl phenyl alanyl derivant, N-benzoyl, N-are to the phenyl benzoyl); Assist cracked amides compound (N-ortho-nitrophenyl base acetyl group, N-ortho-nitrophenyl oxygen base acetyl group, the N-acetoacetyl, (N '-dithio benzyloxycarbonyl amino) acetyl group, N-3-(p-hydroxybenzene) propiono, N-3-(ortho-nitrophenyl base) propiono, N-2-methyl-2-(ortho-nitrophenyl oxygen base) propiono, N-2-methyl-2-(adjacent phenylazo phenoxy group) propiono, the N-4-chlorobutyryl, N-3-methyl-3-nitro bytyry, the adjacent nitro cinnamoyl of N-, N-acetyl methionine derivant, the N-o-nitrobenzoyl, N-neighbour's (benzoyloxy methyl) benzoyl, 4,5-diphenyl-3-oxazoline-2-ketone); Cyclic imide derivant (N phlhalimide base, N-dithia succinyl group, N-2,3-diphenyl maleoyl, N-2,5-dimethyl pyrrole, N-1,1,4,1 of 4-tetramethyl dimethyl silanyl aza-cyclopentane adduct, 5-replacement, 3-dimethyl-1,3,1 of 5-Trianacyclohexane-2-ketone, 5-replacement, 3-dibenzyl-1,3,3 of 5-Trianacyclohexane-2-ketone, 1-replacement, 5-dinitro-4-pyriconyl); N-alkyl and N-arylamine compounds (N-methyl, N-pi-allyl, N-[2-(trimethyl silyl) ethyoxyl] methyl, N-3-acetoxyl group propyl group, N-(1-isopropyl-4-nitro-2-oxygen-3-pyrrolidine-3-yl), quaternary ammonium salt, N-benzyl, N-two (4-methoxyphenyl) methyl, N-5-dibenzo suberyl, N-trityl group, N-(4-methoxyphenyl) diphenyl methyl, N-9-phenyl fluorenyl, N-2,7-two chloro-9-fluorenyl methylene, N-ferrocenyl methyl, N-2-picolyl amine N '-oxide); Imine derivative (N-1,1-dimethyl thio-methylene, N-benzal, N-are to methoxyl group benzal, N-diphenyl methylene, N-[(2-pyridine radicals) trimethylphenyl] methylene, N ', N '-dimethylamino methylene, N, N '-isopropylidene, N-are to nitro benzal, N-salicylidene, N-5-chlorine salicylidene, N-(5-chloro-2-hydroxy phenyl) phenylmethylene, N-cyclohexylidene); Enamine derivates (N-(5,5-dimethyl-3-oxygen-1-cyclohexenyl group)); The N-metal derivative (N-borane derivative, N-diphenyl boronic acid derivatives, N-[phenyl (pentacarbonyl chromium or tungsten)] Cabbeen, N-copper or N-chelates of zinc); N-N derivant (N-nitro, N-nitroso-group, N-oxide); N-P derivant (N-diphenyl phosphine acyl group, N-dimethyl disulfide are for phosphono, N-diphenyl sulfo-phosphono, N-dialkyl phosphoryl, N-dibenzyl phosphoryl, N-diphenylphosphine acyl group); The N-Si derivant; The N-S derivant; N-sulfinyl derivant (N-benzenesulfinyl, N-ortho-nitrophenyl sulfinyl, N-2,4-dinitro benzene sulfinyl, N-pentachloro-sulfinyl, N-2-nitro-4-methoxybenzene sulfinyl, N-trityl group sulfinyl, N-3-nitropyridine sulfinyl); N-sulfonyl-derivatives (N-p-toluenesulfonyl; the N-benzenesulfonyl; N-2; 3; 6-trimethyl-4-methoxybenzene sulfonyl; N-2; 4; 6-trimethoxy benzenesulfonyl; N-2; 6-dimethyl-4-methoxybenzene sulfonyl; N-pentamethylbenzene sulfonyl; N-2; 3; 5,6 ,-tetramethyl-4-methoxybenzene sulfonyl; N-4-methoxybenzene sulfonyl; N-2; 4; 6-trimethylbenzene sulfonyl; N-2,6-dimethoxy-4 '-Methyl benzenesulfonyl base; N-2,2; 5; 7,8-pentamethyl chromane-6-sulfonyl; the N-mesyl; N-β-trimethyl silyl ethane sulfonyl; N-9-anthracene sulfonyl; N-4-(4 ', 8 '-the dimethoxy naphthyl methyl) benzenesulfonyl; N-benzyl sulfonyl; the N-trifluoromethyl sulfonyl; N-phenacyl sulfonyl).
More typically, amino protecting group comprises carbamate and amide, in addition more typical be the N-acetyl group.
Stereoisomer.It is evident that according to description the chemical compound of formula 1 and formula 2A or 2B comprises by the optical isomer of isomery on arbitrary or whole chiral atom of enrichment or fractionation.Raceme and non-enantiomer mixture and single optical isomer can be separated or synthetic, thereby are substantially devoid of its enantiomerism or diastereo-isomerism counter pair, and these all belong in the scope of the present invention.In chemical compound of the present invention, can find chiral centre, for example R 1, R 2Or R 4
A kind of or several following methods can be used to prepare the enantiomer enrichment or purified isomer.These methods roughly are to list with its preferred order, should adopt successively in a kind of conventional method promptly that to carry out steroselectivity by chiral precursor synthetic, and chromatograph splits subsequently, spontaneous crystallization subsequently.
Stereospecific synthesis illustrates.When the reactions steps that can buy suitable chirality initiation material and selection can not cause in the chirality site non-required racemization taking place, adopt this type of conventional method.An advantage of stereospecific synthesis is that it can not produce non-required must being removed non-required enantiomer by end-product and can be reduced total synthesis yield by the enantiomer of removing in the end-product.Usually, it will be appreciated by those skilled in the art that and to adopt which kind of initiation material and reaction condition to obtain required enantiomer enrichment or purified isomer by stereospecific synthesis.
If can't rule of thumb design or utilize normal experiment to determine suitable stereospecific synthesis, one of ordinary skill in the art will change other method.A kind of method commonly used is that chromatograph splits enantiomer on the chiral chromatogram resin.These resins are filled in the chromatographic column, generally are called the Pirkle post, and can commerce buy.Chromatographic column contains chiral stationary phase.Raceme is placed solution and be seated on the chromatographic column, after this separate by HPLC.For example referring to, the international symposium (ProceedingsChromatographic Society-International Symposium on ChiralSeparations) of chromatograph society conference collection of thesis-relevant chiral separation, 1987.9.3-4, be hereby incorporated by.Can be used for the optimal separation technology and comprise Diacel Chriacel OD, Regis Pirkle CovalentD-phenylglycine, Regis Pirkle Type 1A, Astec Cyclobond II with the chromatographic column example that screens,, AstecCyclobond III, Serva Chiral D-DL=Daltosil 100, Bakerbond DNBLeu, Sumipax OA-1000, Merck primary cellulose acetate chromatographic column, Astec CyclobondI-Beta or Regis Pirkle Covalent D-naphthyl alanine.Not all these chromatographic columns are all effective to various racemic compounds.Yet one of ordinary skill in the art should understand, need the routine of some to screen and identify the most effective immobile phase.When using these chromatographic columns, wish to adopt the embodiment of The compounds of this invention, electric charge is not neutralized therein, for example wherein not esterified the or amidatioon of acidic functionality such as carboxyl.
Another kind method need be converted into diastereomer with the enantiomer in the mixture with the chirality adjuvant, utilizes common column chromatography separation coupling thing subsequently.This is well-adapted method, and particularly when containing free hydroxyl group in the embodiment, it can form salt or covalent bonding with the chirality adjuvant.The aminoacid of chiral purity, organic acid or organic sulfonic acid compounds all can be used as the chirality adjuvant, and they are that affiliated technical field is known.Can form salt with this type of adjuvant, or they can be bonded in the functional group by covalency (but reversibly).
It is the method that another kind has potential value that enzymatic splits.In these methods, a kind of method has prepared the covalence derivative of enantiomer in the racemic mixture, and normally lower alkyl esters makes this derivant generation enzymatic lysis, normally hydrolysis subsequently.For successfully using the method, must selection can carry out the cracked enzyme of Stereoselective, therefore usually need some kinds of enzymes of conventional screening.If the cracking ester then can be selected one group of esterase, phosphate, lipase and measure their activity to derivant.Typical esterase derives from liver, pancreas and other animal organ, and comprises the pig liver esterase.
If mixture of enantiomers is separated from solution or dissolved matter as assembling agglomerating form (being the crystalline mixture of enantiomer-pure), then can these crystallizations of mechanical separation, generate the goods of enantiomer enrichment thus.Yet this method is inapplicable for large-scale production, and is worth limited for real racemic compound.
Asymmetric synthesis is the another kind of technology that obtains the enantiomer enrichment.For example, chirality protecting group and protected radical reaction and make reactant mixture reach balance.If reaction is that enantiomer is selected, then product is with this enantiomer of enrichment.
Can find other guidance, such as but not limited at " enantiomer, raceme and fractionation " (" Enantiomers, Racemates; and Resolutions ") for the enantiomer separation mixture, Jean Jacques, Andre Collet and Samuel H.Wilen (Krieger PublishingCompany, Malabar, FL, 1991, ISBN 0-89464618-4): part 2, the fractionation of mixture of enantiomers, the 217-435 page or leaf; Particularly, the 4th joint, the direct crystallization Split Method, the 217-251 page or leaf, the 5th joint, the formation of diastereomer with separate 251-369 page or leaf, the 6th joint, the asymmetric conversion that crystallization causes, 369-378 page or leaf, the 7th joint, the test aspect and the skill of fractionation, 378-435 page or leaf; More especially, 5.1.4 joint, the fractionation of alcohol, alcohol is to the conversion that becomes salt derivative, the 263-266 page or leaf, 5.2.3 joint, alcohol, the covalence derivative of mercaptan and phenol, the 332-335 page or leaf, 5.1.1 joint, the fractionation of acid, the 257-259 page or leaf, 5.1.2 joint, the fractionation of alkali, the 259-260 page or leaf, 5.1.3 joint, amino acid whose fractionation, the 261-263 page or leaf, 5.2.1 joint, the covalence derivative of acid, 329 pages, 5.2.2 joint, the covalence derivative of aminated compounds, the 330-331 page or leaf, 5.2.4 joint, aldehyde, the covalence derivative of ketone and sulfoxide, 335-339 page or leaf and 5.2.7 joint, the chromatographic behavior of covalency diastereomer, the 348-354 page or leaf, foregoing is hereby incorporated by.
Embodiment is included in the compositions of carrying out step of one in the method or the temporary transient appearance of when processing.For example, when the chemical compound of formula 1 contacted with excipient such as water, cyclodextrin, PEG, alcohol, propylene glycol, benzylalcohol or benzyl benzoate, the compositions before a component is added another component was a heterogeneous mixture.When component is in contact with one another, improved uniformity of mixture, component ratio each other reaches desirable value, thus, the optional water that contains less than about 3% (w/w) of the disclosed compositions of some the application, for example less than the water of 0.5% (w/w), it can contain chemical compound shown in the formula 1 of the 0.0001-99% that has an appointment (w/w), as 16 alpha-brominated epiandrosterones and one or more excipient.When preparation compositions of the present invention or preparation, these transition combination things are the intermediate that certainly lead to, and they belong to embodiments of the present invention, reach patentable degree.
Chemical compound shown in the chemical compound formula 1 shown in the formula 1 or " chemical compound of the present invention " can effectively be treated the individuality that has one or more togavirus, or the prevention individuality is infected by one or more togavirus.Togavirus described herein comprises Togaviridae, comprising alphavirus and rubella virus genus; Also comprise flaviviridae, comprising Flavivirus and pestivirus." basic virology " (" Fundamental Virology ") that the viral taxonomy that these are viral and biology, summary can be edited referring to people such as for example B.N.Fields the 3rd edition, 1996, Lippencott-RavenPublishers, the 1st chapter (15-58 page or leaf) and the 17th chapter (523-540 page or leaf), it is hereby incorporated by.
For chemical compound shown in the preferred formula 1, be bonded in the R on the cyclopentanoperhydro-phenanthrene 2Part is generally beta configuration, is bonded in Q 2On two R 1For the oxygen of two bondings part (=O).Typically, be bonded in Q 2On a R 1Be the hydrogen of beta comfiguration, another is bonded in Q 2On R 1Be the hydrogen or halogen of α configuration, be generally bromine, and two key is present in the 5-6 position.This type of preferred compound comprises dehydroepiandrosterone (" DHEA ") and 16 α-bromine dehydroepiandrosterone (" Br-DHEA ").
Chemical compound comprises the 17-ketosteroid chemical compound of formula 1 shown in other preferred formula 1, and wherein two keys are present in the 5-6 position, and X is=O Q 2For-CH 2-or-CHBr-, R 2For-H ,-S (O) (O)-OH ,-S (O) (O)-ONa ,-S (O) (O)-O-CH 2-CH (O-C (O)-R 6)-CH 2-O-C (O)-R 6(R wherein 6Be C independently 1-14The straight or branched alkyl) ,-P (O) (O)-O-CH 2-CH (O-C (O) R 7)-CH 2-OC (O)-R 7(R wherein 7Be glucuronyl-or C independently 1-14The straight or branched alkyl) or R 2It is glucuronyl-.Other preferred compound comprises the chemical compound with structure 20-43:
Figure A9981365800441
Figure A9981365800461
Figure A9981365800471
Wherein for each structural formula 20-43
Q 3And Q 6Be respectively-C (R 1) 3, each R wherein 1Select independently;
X and Y be independently-OH ,-H, low alkyl group (C for example 1-6Alkyl) ,-C (O)-O-R 5,-O-C (O)-R 5, halogen, perhaps, X and Y independently with same position on R 1Be combined into ketone (=O);
Each R 1Select independently and have as above to define; With
R 2Has as above definition.
In some embodiments, the chemical compound of formula 1 has structure 20-43 and 2,3,4,5 or 6 R 1Group is independently-OH, halogen or alkoxyl, and all the other R 1Be hydrogen; R 2Be-OH, ester, thioesters or carbamate, R 2R with 3 1Be combined into=O; Y is-H ,-OH, halogen or-O-C (O)-R 5, or Y and 16 s' R 1Be combined into=O; X is-OH or-O-C (O)-R 5, or X and 17 s' R 1Be combined into=O; Q 3And Q 6Be independently-CH 3Or-CH 2OH.This type of embodiment is included in structure 20-43 chemical compound, and wherein two-OH is present in 3,16 or 17.
Preferred embodiment of the present invention comprises the chemical compound with formula 44: Wherein Y is hydrogen or bromine, R 44Be-H ,-S (O) (O)-OH ,-S (O) (O)-ONa ,-S (O) (O)-O-CH 2-CH (O-C (O)-R 6)-CH 2-O-C (O)-R 6,-P (O) (O)-O-CH 2-CH (O-C (O)-R 7)-CH 2-O-C (O)-R 7Or the glucuronyl-shown in the structure (A).In other preferred implementation, Y in the formula 44 and R 44Be hydrogen.Especially preferred chemical compound is dehydroepiandrosterone (Y in the formula 44 and R 44Be that hydrogen and 5-6 position exist two keys simultaneously).In other embodiments, chemical compound is epiandrosterone (Y in the formula 44 and R 44Be that hydrogen and 5-6 position do not exist two keys simultaneously).16 16-halo epiandrosterones that replaced by F, Cl, Br or I can be used as antiviral agent, for example 16 alpha-brominated epiandrosterones.Other preferred compound is (i) 16 alpha-brominated dehydroepiandrosterones, and (ii) (Y is-H and R dehydroepiandrosterone-3-sulfate in the formula 44 44Be-S (O) (O)-there are two keys in OM and 5-6 position) and (iii) 5-3 β-alcohol-17-ketone.About embodiment comprises the chemical compound relevant with formula 44, its be included in wherein 1,2,3,4,5 or 6 hydrogen atom that is bonded on the steroid nucleus be selected from independently-OH ,-Br ,-Cl ,-F ,-I ,-OCH 3Or-OC 2H 5Formula 44 chemical compounds that atom or group replaced.
In other embodiments, the 17-ketosteroid chemical compound of formula 1 is a dehydroepiandrosterone, the R in its Chinese style 44 44Be-S (O) (O)-O-CH 2-CH (O-C (O)-R 6)-CH 2-O-C (O)-R 5,-P (O) (O)-O-CH 2CH (O-C (O)-R 7)-CH 2-O-C (O)-R 7Or the glucuronyl-shown in the structure (A), Y is that hydrogen and 5-6 position exist two keys.Other formula 44 chemical compounds comprise the conjugate of dehydroepiandrosterone, and wherein Y is a hydrogen, and two keys are present in 5-6 position and R 44Be hexyl sulfate, lauryl sulfate, octadecyl sulfate, octadecanoyl sulfate, O-two (cetyl) glycerol sulfate, hexadecane sulfonate, two (octadecanoyl) glycerophosphate or O-cetyl glycerophosphate.
Of the present invention another preferred aspect, the steroid class of formula 1 is the chemical compound of formula 45,
Figure A9981365800491
R wherein 50For-H ,-OH or=O; R 51Be for-Br ,-Cl ,-F or-I; R 52Be-OH or=O; R 49Be-H ,-OH or-OR 53And R 53Be C 1-18Alkyl, C 2-18Alkenyl, C 2-18Alkynyl, C 1-18Ester, C 1-18Thioesters, wherein above-mentioned arbitrary C 1-18And C 2-18Group independently is selected from following group and replaces by one or more in one or more hydrogen atoms position :-O-,-S-,-OH ,-NH 2,-SH or=O, or R 53Be mercaptal, sulfuric ester, sulphonic acid ester, carbamate or thioesters.One preferred aspect, R 49Be-O-C (O)-CH 2-CH 2-CH (R 54)-CH (R 55)-CH 2R 56, R wherein 54Be-NH 2,-OH ,-SH ,-O-PO 3,-SO 3Or-OSO 3R 55Be-H ,-NH 2,-OH ,-SH ,-O-PO 3,-SO 3Or-OSO 3And R 56Be C 1-18Alkyl, C 2-18Alkenyl, C 2-18Alkynyl, C 1-18Ester, C 1-18Thioesters, wherein above-mentioned arbitrary C 1-18And C 2-18Group one or morely independently be selected from one or more hydrogen atoms position-OH ,-NH 2,-SH or=the O group replaces and their precursor, metabolite and analog.About embodiment has comprised and the relevant chemical compound of formula 45 chemical compounds, in described formula 45 chemical compounds 1,2,3,4,5 or 6 be bonded on the steroid nucleus hydrogen atom independently by-OH ,-Br ,-Cl ,-F ,-I ,-OCH 3Or-OC 2H 5Atom or group replace.
In other preferred implementation, the chemical compound of formula 1 has formula 1B or 1C:
Figure A9981365800501
Each R wherein 1Be independently-H ,-OH, halogen ,-CHCH 2,-CHCHCH 3,-CCH or-CCCH 3, perhaps, other part that is bonded on the identical carbon atoms does not exist and R 1Be=O; R 2Be-H ,-OH, halogen, C 1-8Alkoxyl ,-S-C (O)-(CH 2) m-R 4,-C (O)-S-(CH 2) m-R 4,-O-S (O) (O)-(CH 2) m-R 4,-O-S (O) (O)-O-(CH 2) m-R 4,-O-C (O)-NH-(CH 2) m-R 4,-NH-C (O)-O-(CH 2) m-R 4,-O-C (S)-(CH 2) m-R 4,-C (S)-O-(CH 2) m-R 4,-O-C (O)-(CH 2) m-R 4Or-C (O)-O-(CH 2) m-R 4R 4For-H ,-CH 3,-C 2H 5,-C 3H 7,-C 2H 4OH ,-C 3H 6OH ,-CH 2-CH 2-O-CH 3,-CH 2-CH 2-O-CH 2-CH 3,-CH 2-CH 2-O-CH 2-CH 2OH, C 3-6Alkenyl, C 3-6Alkynyl, benzyl or phenyl, wherein phenyl or benzyl are optional by 1,2 or 3 independent halogen, C that selects 1-4Alkoxyl ,-OH ,-SH ,-O-or-NH-part replaces; Q 3And Q 6Be independently-H ,-CH 3Or-CH 2OH; Q 2Be-C (R 1) 2-or-CH 2-CH 2-; And m is 0,1,2 or 3.In these embodiments, Q 3And Q 6Be beta comfiguration simultaneously usually, they generally are-CH 3, Q 2Usually be wherein Br, I or OH partly for the α configuration-CH 2-,-C (O)-,-CH (Br)-,-CH (I)-or-CH (OH)-, or Q 2For=O, and 7 R 1For-H ,-OH or=O.Relevant embodiment has comprised the chemical compound relevant with the 1C chemical compound with formula 1B, in described formula 1B and the 1C chemical compound 1,2,3,4,5 or 6 hydrogen atom that is bonded on the steroid nucleus independently selected-OH ,-Br ,-Cl ,-F ,-I ,-OCH 3Or-OC 2H 5Atom or group replace.
The chemical compound of formula 1 can exist with crystallization or pleomorphic type.
Metabolite belongs to the interior metabolism product that also has The compounds of this invention in the scope of the invention, because these products upgrade than prior art and be more non-apparent.This type of product can be by being passed through as acquisitions such as oxidation, reduction, hydrolysis, amidatioon, esterifications under enzymatic or chemical treatment by chemical compound shown in the formula 1 of administration.So, the present invention includes new and non-obvious chemical compound by the preparation of certain method, this method comprises chemical compound of the present invention is contacted the enough time of its metabolite of generation with individual as people, rodent or primate.This type of product generally is to identify by following process: preparation radio-labeled (C for example 14Or H 3) The compounds of this invention with radiolabeled The compounds of this invention can detect dosage (for example greater than about 0.5mg/kg) to animal such as rat, mice, Cavia porcellus, the non-intestinal of primate or oral administration, keep the time of enough metabolism generations (about 30 seconds to about 30 hours usually), by isolating its converted product in urine, blood or other biological specimen.These products are easy to separate, this be because they be labeled (other can by adopt can conjugated metabolite in the antibody of antigenic determinant separate).Measure the structure of metabolite in a usual manner, for example by HPLC, MS or NMR assay.Generally, the analysis of metabolite be with well-known to one skilled in the art conventional medicine metabolism research in identical mode carry out.As long as never find these converted products in vivo, they just can be used for the therapeutic dose of diagnostic analysis The compounds of this invention, even they itself do not have therapeutic activity.
The embodiment of chemical compound shown in the formula 1 is for example understood in following description.
The 1st group of embodiment that exemplifies is included in chemical compound shown in the formula of naming among the table B 1, and its name is based on the compound structure name that defines in the Table A.Each chemical compound of naming among the table B is represented as the chemical compound of formula 4: Q wherein 3And Q 6Be-CH 3, Q 4Be-CH 2-, R 2, R 1A, Y and X have the structure that defines in the Table A.Be called " the 1st group " chemical compound according to the chemical compound of naming among Table A and the B.
The chemical compound of naming among the table B is by regulation R 2, R 1The numeral of A, Y and X is specified according to the following compounds UNC, R 2, R 1A, Y and X adopt the chemical constitution of the Table A middle finger number of delimiting the organizational structure.As shown in Equation 4, R 2Be positioned at 3 β positions and hydrogen and fill up all the other valence links or R 2With 3 carbon Cheng Shuanjian, R 1A is the R of 7 β positions 1Group, or R 1A is the R with 7 carbon Cheng Shuanjian 1Group, Y are positioned at 16 α positions and hydrogen fills up all the other valence links or Y and 16 carbon Cheng Shuanjian, and X is positioned at 17 β positions and hydrogen fills up all the other valence links or X and 17 carbon Cheng Shuanjian.Work as R 2, R 1When A, Y or X are divalent moiety, for example be=during O, the hydrogen of relevant position does not exist.So the 1st group of chemical compound of called after 1.2.1.1 refers in particular to have and is bonded in 3-or 7-position carbon (is respectively variable radicals R 2And R 1β hydroxyl A), the α-bromine (variable group Y) that is bonded in carbon 16 and the two key oxygen on the carbon 17 (=O) formula 4 structures of (variable radicals X) promptly have following structure: Table A R2 R1A1-OH 1-H2=O 2-OH3-O-P (O) (O)-OH 3=O4-O-P (O) (O)-O-CH 2-CH (O-C (O)-CH 3)-CH 2-O-C (O) CH 34-CH 35-O-S (O) (O)-OH 5-OCH 36-O-S (O) (O)-ONa +6-OC 2H 57-O-S (O) (O)-OC 2H 57-OCH 2CH 2CH 38-O-S (O) (O)-O-CH 2-CH (O-C (O)-CH 3)-CH 2-O-C (O) CH 38-OCH (CH 3) CH 39-O-S (O) (O)-OCH 2CH 2CH 2CH 39-OCH 2CH 2CH 2CH 310-O-S (O) (O)-OC (CH 3) 310-OC (CH 3) 3Y X1-Br 1＝O2-Cl 2-OH3-I 3-H4-F 4-F5-H 5-Cl6-OH 6-Br7＝O 7-I8-O-C (O)-CH 38-O-C (O)-CH 39-O-C (O)-CH 2CH 39-O-C (O)-CH 2CH 310-O-C (O)-CH 2CH 2CH 310-O-C (O)-CH 2CH 2CH 3
Table B 1.1.1.1,1.1.1.2,1.1.1.3,1.1.1.4,1.1.1.5,1.1.1.6,1.1.1.7,1.1.1.8,1.1.1.9,1.1.1.10,1.1.2.1,1.1.2.2, 1.1.2.3,1.1.2.4,1.1.2.5,1.1.2.6,1.1.2.7,1.1.2.8,1.1.2.9,1.1.2.10,1.1.3.1,1.1.3.2,1.1.3.3,1.1.3.4, 1.1.3.5,1.1.3.6,1.1.3.7,1.1.3.8,1.1.3.9,1.1.3.10,1.1.4.1,1.1.4.2,1.1.4.3,1.1.4.4,1.1.4.5,1.1.4.6, 1.1.4.7,1.1.4.8,1.1.4.9,1.1.4.10,1.1.5.1,1.1.5.2,1.1.5.3,1.1.5.4,1.1.5.5,1.1.5.6,1.1.5.7,1.1.5.8, 1.1.5.9,1.1.5.10,1.1.6.1,1.1.6.2,1.1.6.3,1.1.6.4,1.1.6.5,1.1.6.6,1.1.6.7,1.1.6.8,1.1.6.9,1.1.6.10, 1.1.7.1,1.1.7.2,1.1.7.3,1.1.7.4,1.1.7.5,1.1.7.6,1.1.7.7,1.1.7.8,1.1.7.9,1.1.7.10,1.1.8.1,1.1.8.2, 1.1.8.3,1.1.8.4,1.1.8.5,1.1.8.6,1.1.8.7,1.1.8.8,1.1.8.9,1.1.8.10,1.1.9.1,1.1.9.2,1.1.9.3,1.1.9.4, 1.1.9.5,1.1.9.6,1.1.9.7,1.1.9.8,1.1.9.9,1.1.9.10,1.1.10.1,1.1.10.2,1.1.10.3,1.1.10.4,1.1.10.5, 1.1.10.6,1.1.10.7,1.1.10.8,1.1.10.9,1.1.10.10,1.2.1.1,1.2.1.2,1.2.1.3,1.2.1.4, 1.2.1.5,1.2.1.6, 1.2.1.7,1.2.1.8,1.2.1.9,1.2.1.10,1.2.2.1,1.2.2.2,1.2.2.3,1.2.2.4,1.2.2.5,1.2.2.6,1.2.2.7,1.2.2.8, 1.2.2.9,1.2.2.10,1.2.3.1,1.2.3.2,1.2.3.3,1.2.3.4,1.2.3.5,1.2.3.6,1.2.3.7,1.2.3.8,1.2.3.9,1.2.3.10, 1.2.4.1,1.2.4.2,1.2.4.3,1.2.4.4,1.2.4.5,1.2.4.6,1.2.4.7,1.2.4.8,1.2.4.9,1.2.4.10,1.2.5.1,1.2.5.2, 1.2.5.3,1.2.5.4,1.2.5.5,1.2.5.6,1.2.5.7,1.2.5.8,1.2.5.9,1.2.5.10,1.2.6.1,1.2.6.2,1.2.6.3,1.2.6.4, 1.2.6.5,1.2.6.6,1.2.6.7,1.2.6.8,1.2.6.9,1.2.6.10,1.2.7.1,1.2.7.2,1.2.7.3,1.2.7.4,1.2.7.5,1.2.7.6, 1.2.7.7,1.2.7.8,1.2.7.9,1.2.7.10,1.2.8.1,1.2.8.2,1.2.8.3,1.2.8.4,1.2.8.5,1.2.8.6,1.2.8.7,1.2.8.8, 1.2.8.9,1.2.8.10,1.2.9.1,1.2.9.2,1.2.9.3,1.2.9.4,1.2.9.5,1.2.9.6,1.2.9.7,1.2.9.8,1.2.9.9,1.2.9.10, 1.2.10.1,1.2.10.2,1.2.10.3,1.2.10.4,1.2.10.5,1.2.10.6,1.2.10.7,1.2.10.8,1.2.10.9,1.2.10.10, 1.3.1.1,1.3.1.2,1.3.1.3,1.3.1.4,1.3.1.5,1.3.1.6,1.3.1.7,1.3.1.8,1.3.1.9,1.3.1.10,1.3.2.1,1.3.2.2, 1.3.2.3,1.3.2.4,1.3.2.5,1.3.2.6,1.3.2.7,1.3.2.8,1.3.2.9,1.3.2.10,1.3.3.1,1.3.3.2,1.3.3.3,1.3.3.4, 1.3.3.5,1.3.3.6,1.3.3.7,1.3.3.8,1.3.3.9,1.3.3.10,1.3.4.1,1.3.4.2,1.3.4.3,1.3.4.4,1.3.4.5,1.3.4.6, 1.3.4.7,1.3.4.8,1.3.4.9,1.3.4.10,1.3.5.1,1.3.5.2,1.3.5.3,1.3.5.4,1.3.5.5,1.3.5.6,1.3.5.7,1.3.5.8, 1.3.5.9,1.3.5.10,1.3.6.1,1.3.6.2,1.3.6.3,1.3.6.4,1.3.6.5,1.3.6.6,1.3.6.7,1.3.6.8,1.3.6.9,1.3.6.10, 1.3.7.1,1.3.7.2,1.3.7.3,1.3.7.4,1.3.7.5,1.3.7.6,1.3.7.7,1.3.7.8,1.3.7.9,1.3.7.10,1.3.8.1,1.3.8.2, 1.3.8.3,1.3.8.4,1.3.8.5,1.3.8.6,1.3.8.7,1.3.8.8,1.3.8.9,1.3.8.10,1.3.9.1,1.3.9.2,1.3.9.3,1.3.9.4, 1.3.9.5,1.3.9.6,1.3.9.7,1.3.9.8,1.3.9.9,1.3.9.10,1.3.10.1,1.3.10.2,1.3.10.3,1.3.10.4,1.3.10.5, 1.3.10.16,1.3.10.7,13.10.8,1.3.10.9,1.3.10.10,1.4.1.1,1.4.1.2,1.4.1.3,1.4.1.4,1.4.1.5,1.4.1.6, 1.4.1.7,1.4.1.8,1.4.1.9,1.4.1.10,1.4.2.1,1.4.2.2,1.4.2.3,1.4.2.4,1.4.2.5,1.4.2.6,1.4.2.7,1.4.2.8, 1.4.2.9,1.4.2.10,1.4.3.1,1.4.3.2,1.4.3.3,1.4.3.4,1.4.3.5,1.4.3.6,1.4.3.7,1.4.3.8,1.4.3.9,1.4.3.10, 1.4.4.1,1.4.4.2,1.4.4.3,1.4.4.4,1.4.4.5,1.4.4.6,1.4.4.7,1.4.4.8,1.4.4.9,1.4.4.10,1.4.5.1,1.4.5.2, 1.4.5.3,1.4.5.4,1.4.5.5,1.4.5.6,1.4.5.7,1.4.5.8,1.4.5.9,1.4.5.10,1.4.6.1,1.4.6.2,1.4.6.3,1.4.6.4, 1.4.6.5,1.4.6.6,1.4.6.7,1.4.6.8,1.4.6.9,1.4.6.10,1.4.7.1,1.4.7.2,1.4.7.3,1.4.7.4,1.4.7.5,1.4.7.6, 1.4.7.7,1.4.7.8,1.4.7.9,1.4.7.10,1.4.8.1,1.4.8.2,1.4.8.3,1.4.8.4,1.4.8.5,1.4.8.6,1.4.8.7,1.4.8.8, 1.4.8.9,1.4.8.10,1.4.9.1,1.4.9.2,1.4.9.3,1.4.9.4,1.4.9.5,1.4.9.6,1.4.9.7,1.4.9.8,1.4.9.9,1.4.9.10, 1.4.10.1,1.4.10.2,1.4.10.3,1.4.10.4,1.4.10.5,1.4.10.6,1.4.10.7,1.4.10.8,1.4.10.9,1.4.10.10, 1.5.1.1,1.5.1.2,1.5.1.3,1.5.1.4,1.5.1.5,1.5.1.6,1.5.1.7,1.5.1.8,1.5.1.9,1.5.1.10,1.5.2.1,1.5.2.2, 1.5.2.3,1.5.2.4,1.5.2.5,1.5.2.6,1.5.2.7,1.5.2.8,1.5.2.9,1.5.2.10,1.5.3.1,1.5.3.2,1.5.3.3,1.5.3.4, 1.5.3.5,1.5.3.6,1.5.3.7,1.5.3.8,1.5.3.9,1.5.3.10,1.5.4.1,1.5.4.2,1.5.4.3,1.5.4.4,1.5.4.5,1.5.4.6, 1.5.4.7,1.5.4.8,1.5.4.9,1.5.4.10,1.5.5.1,1.5.5.2,1.5.5.3,1.5.5.4,1.5.5.5,1.5.5.6,1.5.5.7,1.5.5.8, 1.5.5.9,1.5.5.10,1.5.6.1,1.5.6.2,1.5.6.3,1.5.6.4,1.5.6.5,1.5.6.6,1.5.6.7,1.5.6.8,1.5.6.9,1.5.6.10, 1.5.7.1,1.5.7.2,1.5.7.3,1.5.7.4,1.5.7.5,1.5.7.6,1.5.7.7,1.5.7.8,1.5.7.9,1.5.7.10,1.5.8.1,1.5.8.2, 1.5.8.3,1.5.8.4,1.5.8.5,1.5.8.6,1.5.8.7,1.5.8.8,1.5.8,9,1.5.8.10,1.5.9.1,1.5.9.2,1.5.9.3,1.5.9.4, 1.5.9.5,1.5.9.6,1.5.9.7,1.5.9.8,1.5.9.9,1.5.9.10,1.5.10.1,1.5.10.2,1.5.10.3,1.5.10.4,1.5.10.5, 1.5.10.6,1.5.10.7,1.5.10.8,1.5.10.9,1.5.10.10,1.6.1.1,1.6.1.2,1.6.1.3,1.6.1.4,1.6.1.5,1.6.1.6, 1.6.1.7,1.6.1.8,1.6.1.9,1.6.1.10,1.6.2.1,1.6.2.2,1.6.2.3,1.6.2.4,1.6.2.5,1.6.2.6,1.6.2.7,1.6.2.8, 1.6.2.9,1.6.2.10,1.6.3.1,1.6.3.2,1.6.3.3,1.6.3.4,1.6.3.5,1.6.3.6,1.6.3.7,1.6.3.8,1.6.3.9,1.6.3.10, 1.6.4.1,1.6.4.2,1.6.4.3,1.6.4.4,1.6.4.5,1.6.4.6,1.6.4.7,1.6.4.8,1.6.4.9,1.6.4.10,1.6.5.1,1.6.5.2, 1.6.5.3,1.6.5.4,1.6.5.5,1.6.5.6,1.6.5.7,1.6.5.8,1.6.5.9,1.6.5.10,1.6.6.1,1.6.6.2,1.6.6.3,1.6.6.4, 1.6.6.5,1.6.6.6,1.6.6.7,1.6.6.8,1.6.6.9,1.6.6.10,1.6.7.1,1.6.7.2,1.6.7.3,1.6.7.4,1.6.7.5,1.6.7.6, 1.6.7.7,1.6.7.8,1.6.7.9,1.6.7.10,1.6.8.1,1.6.8.2,1.6.8.3,1.6.8.4,1.6.8.5,1.6.8.6,1.6.8.7,1.6.8.8, 1.6.8.9,1.6.8.10,1.6.9.1,1.6.9.2,1.6.9.3,1.6.9.4,1.6.9.5,1.6.9.6,1.6.9.7,1.6.9.8,1.6.9.9,1.6.9.10, 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2.8.5.6,2.8.5.7,2.8.5.8,2.8.5.9,2.8.5.10,2.8.6.1,2.8.6.2,2.8.6.3,2.8.6.4,2.8.6.5,2.8.6.6,2.8.6.7, 2.8.6.8,2.8.6.9,2.8.6.10,2.8.7.1,2.8.7.2,2.8.7.3,2.8.7.4,2.8.7.5,2.8.7.6,2.8.7.7,2.8.7.8,2.8.7.9, 2.8.7.10,2.8.8.1,2.8.8.2,2.8.8.3,2.8.8.4,2.8.8.5,2.8.8.6,2.8.8.7,2.8.8.8,2.8.8.9,2.8.8.10,2.8.9.1, 2.8.9.2,2.8.9.3,2.8.9.4,2.8.9.5,2.8.9.6,2.8.9.7,2.8.9.8,2.8.9.9,2.8.9.10,2.8.10.1,2.8.10.2, 2.8.10.3,2.8.10.4,2.8.10.5,2.8.10.6,2.8.10.7,2.8.10.8,2.8.10.9,2.8.10.10,2.9.1.1,2.9.1.2,2.9.1.3, 2.9.1.4,2.9.1.5,2.9.1.6,2.9.1.7,2.9.1.8,2.9.1.9,2.9.1.10,2.9.2.1,2.9.2.2,2.9.2.3,2.9.2.4,2.9.2.5, 2.9.2.6,2.9.2.7,2.9.2.8,2.9.2.9,2.9.2.10,2.9.3.1,2.9.3.2,2.9.3.3,2.9.3.4,2.9.3.5,2.9.3.6,2.9.3.7, 2.9.3.8,2.9.3.9,2.9.3.10,2.9.4.1,2.9.4.2,2.9.4.3,2.9.4.4,2.9.4.5,2.9.4.6,2.9.4.7,2.9.4.8,2.9.4.9, 2.9.4.10,2.9.5.1,2.9.5.2,2.9.5.3,2.9.5.4,2.9.5.5,2.9.5.6,2.9.5.7,2.9.5.8,2.9.5.9,2.9.5.10,2.9.6.1, 2.9.6.2,2.9.6.3,2.9.6.4,2.9.6.5,2.9.6.6,2.9.6.7,2.9.6.8,2.9.6.9,2.9.6.10,2.9.7.1,2.9.7.2,2.9.7.3, 2.9.7.4,2.9.7.5,2.9.7.6,2.9.7.7,2.9.7.8,2.9.7.9,2.9.7.10,2.9.8.1,2.9.8.2,2.9.8.3,2.9.8.4,2.9.8.5, 2.9.8.6,2.9.8.7,2.9.8.8,2.9.8.9,2.9.8.10,2.9.9.1,2.9.9.2,2.9.9.3,2.9.9.4,2.9.9.5,2.9.9.6,2.9.9.7, 2.9.9.8,2.9.9.9,2.9.9.10,2.9.10.1,2.9.10.2,2.9.10.3,2.9.10.4,2.9.10.5,2.9.10.6,2.9.10.7,2.9.10.8, 2.9.10.9,2.9.10.10,2.10.1.1,2.10.1.2,2.10.1.3,2.10.1.4,2.10.1.5,2.10.1.6,2.10.1.7,2.10.1.8, 2.10.1.9,2.10.1.10,2.10.2.1,2.10.2.2,2.10.2.3,2.10.2.4,2.10.2.5,2.10.2.6,2.10.2.7,2.10.2.8, 2.10.2.9,2.10.2.10,2.10.3.1,2.10.3.2,2.10.3.3,2.10.3.4,2.10.3.5,2.10.3.6,2.10.3.7,2.10.3.8, 2.10.3.9,2.10.3.10,2.10.4.1,2.10.4.2,2.10.4.3,2.10.4.4,2.10.4.5,2.10.4.6,2.10.4.7,2.10.4.8, 2.10.4.9,2.10.4.10,2.10.5.1,2.10.5.2,2.10.5.3,2.10.5.4,2.10.5.5,2.10.5.6,2.10.5.7,2.10.5.8, 2.10.5.9,2.10.5.10,2.10.6.1,2.10.6.2,2.10.6.3,2.10.6.4,2.10.6.5,2.10.6.6,2.10.6.7,2.10.6.8, 2.10.6.9,2.10.6.10,2.10.7.1,2.10.7.2,2.10.7.3,2.10.7.4,2.10.7.5,2.10.7.6,2.10.7.7,2.10.7.8, 2.10.7.9,2.10.7.10,2.10.8.1,2.10.8.2,2.10.8.3,2.10.8.4,2.10.8.5,2.10.8.6,2.10.8.7,2.10.8.8, 2.10.8.9,2.10.8.10,2.10.9.1,2.10.9.2,2.10.9.3,2.10.9.4,2.10.9.5,2.10.9.6,2.10.9.7,2.10.9.8, 2.10.9.9,2.10.9.10,2.10.10.1,2.10.10.2,2.10.10.3,2.10.10.4,2.10.10.5,2.10.10.6,2.10.10.7, 2.10.10.8,2.10.10.9,2.10.10.10,3.1.1.1,3.1.1.2,3.1.1.3,3.1.1.4,3.1.1.5,3.1.1.6,3.1.1.7,3.1.1.8, 3.1.1.9,3.1.1.10,3.1.2.1,3.1.2.2,3.1.2.3,3.1.2.4,3.1.2.5,3.1.2.6,3.1.2.7,3.1.2.8,3.1.2.9,3.1.2.10, 3.1.3.1,3.1.3.2,3.1.3.3,3.1.3.4,3.1.3.5, 3.1.3.6,3.1.3.7,3.1.3.8,3.1.3.9,3.1.3.10,3.1.4.1,3.1.4.2, 3.1.4.3,3.1.4.4,3.1.4.5,3.1.4.6,3.1.4.7, 3.1.4.8,3.1.4.9,3.1.4.10,3.1.5.1,3.1.5.2,3.1.5.3,3.1.5.4, 3.1.5.5,3.1.5.6,3.1.5.7,3.1.5.8,3.1.5.9, 3.1.5.10,3.1.6.1,3.1.6.2,3.1.6.3,3.1.6.4,3.1.6.5,3.1.6.6, 3.1.6.7,3.1.6.8,3.1.6.9,3.1.6.10,3.1.7.1, 3.1.7.2,3.1.7.3,3.1.7.4,3.1.7.5,3.1.7.6,3.1.7.7,3.1.7.8, 3.1.7.9,3.1.7.10,3.1.8.1,3.1.8.2,3.1.8.3, 3.1.8.4,3.1.8.5,3.1.8.6,3.1.8.7,3.1.8.8,3.1.8.9,3.1.8.10, 3.1.9.1,3.1.9.2,3.1.9.3,3.1.9.4,3.1.9.5, 3.1.9.6,3.1.9.7,3.1.9.8,3.1.9.9,3.1.9.10,3.1.10.1, 3.1.10.2,3.1.10.3,3.1.10.4,3.1.10.5,3.1.10.6,3.1.10.7,3.1.10.8,3.1.10.9,3.1.10.10,3.2.1.1, 3.2.1.2,3.2.1.3,3.2.1.4,3.2.1.5,3.2.1.6,3.2.1.7,3.2.1.8,3.2.1.9,3.2.1.10,3.2.2.1,3.2.2.2,3.2.2.3, 3.2.2.4,3.2.2.5,3.2.2.6,3.2.2.7,3.2.2.8,3.2.2.9,3.2.2.10,3.2.3.1,3.2.3.2,3.2.3.3,3.2.3.4,3.2.3.5, 3.2.3.6,3.2.3.7,3.2.3.8,3.2.3.9,3.2.3.10,3.2.4.1,3.2.4.2,3.2.4.3,3.2.4.4,3.2.4.5,3.2.4.6,3.2.4.7, 3.2.4.8,3.2.4.9,3.2.4.10,3.2.5.1,3.2.5.2,3.2.5.3,3.2.5.4,3.2.5.5,3.2.5.6,3.2.5.7,3.2.5.8,3.2.5.9, 3.2.5.10,3.2.6.1,3.2.6.2,3.2.6.3,3.2.6.4,3.2.6.5,3.2.6.6,3.2.6.7,3.2.6.8,3.2.6.9,3.2.6.10,3.2.7.1, 3.2.7.2,3.2.7.3,3.2.7.4,3.2.7.5,3.2.7.6,3.2.7.7,3.2.7.8,3.2.7.9,3.2.7.10,3.2.8.1,3.2.8.2,3.2.8.3, 3.2.8.4,3.2.8.5,3.2.8.6,3.2.8.7,3.2.8.8,3.2.8.9,3.2.8.10,3.2.9.1,3.2.9.2,3.2.9.3,3.2.9.4,3.2.9.5, 3.2.9.6,3.2.9.7,3.2.9.8,3.2.9.9,3.2.9.10,3.2.10.1,3.2.10.2,3.2.10.3,3.2.10.4,3.2.10.5,3.2.10.6, 3.2.10.7,3.2.10.8,3.2.10.9,3.2.10.10,3.3.1.1,3.3.1.2,3.3.1.3,3.3.1.4,3.3.1.5,3.3.1.6,3.3.1.7, 3.3.1.8,3.3.1.9,3.3.1.10,3.3.2.1,3.3.2.2,3.3.2.3,3.3.2.4,3.3.2.5,3.3.2.6,3.3.2.7,3.3.2.8,3.3.2.9, 3.3.2.10,3.3.3.1,3.3.3.2,3.3.3.3,3.3.3.4,3.3.3.5,3.3.3.6,3.3.3.7,3.3.3.8,3.3.3.9,3.3.3.10,3.3.4.1, 3.3.4.2,3.3.4.3,3.3.4.4,3.3.4.5,3.3.4.6,3.3.4.7,3.3.4.8,3,3.4.9,3.3.4.10,3.3.5.1,3.3.5.2,3.3.5.3, 3.3.5.4,3.3.5.5,3.3.5.6,3.3.5.7,3.3.5.8,3.3.5.9,3.3.5.10,3.3.6.1,3.3.6.2,3.3.6.3,3.3.6.4,3.3.6.5, 3.3.6.6,3.3.6.7,3.3.6.8,3.3.6.9,3.3.6.10,3.3.7.1,3.3.7.2,3.3.7.3,3.3.7.4,3.3.7.5,3.3.7.6,3.3.7.7, 3.3.7.8,3.3.7.9,3.3.7.10,3.3.8.1,3.3.8.2,3.3.8.3,3.3.8.4,3.3.8.5,3.3.8.6,3.3.8.7,3.3.8.8,3.3.8.9, 3.3.8.10,3.3.9.1,3.3.9.2,3.3.9.3,3.3.9.4,3.3.9.5,3.3.9.6,3.3.9.7,3.3.9.8,3.3.9.9,3.3.9.10, 3.3.10.1,3.3.10.2,3.3.10.3,3.3.10.4,3.3.10.5,3.3.10.6,3.3.10.7,3.3.10.8,3.3.10.9,3.3.10.10, 3.4.1.1,3.4.1.2,3.4.1.3,3.4.1.4,3.4.1.5,3.4.1.6,3.4.1.7,3.4.1.8,3.4.1.9,3.4.1.10,3.4.2.1,3.4.2.2, 3.4.2.3,3.4.2.4,3.4.2.5,3.4.2.6,3.4.2.7,3.4.2.8,3.4.2.9,3.4.2.10,3.4.3.1,3.4.3.2,3.4.3.3,3.4.3.4, 3.4.3.5,3.4.3.6,3.4.3.7,3.4.3.8,3.4.3.9,3.4.3.10,3.4.4.1,3.4.4.2,3.4.4.3,3.4.4.4,3.4.4.5,3.4.4.6, 3.4.4.7,3.4.4.8,3.4.4.9,3.4.4.10,3.4.5.1,3.4.5.2,3.4.5.3,3.4.5.4,3.4.5.5,3.4.5.6,3.4.5.7,3.4.5.8, 3.4.5.9,3.4.5.10,3.4.6.1,3.4.6.2,3.4.6.3,3.4.6.4,3.4.6.5,3.4.6.6,3.4.6.7,3.4.6.8,3.4.6.9,3.4.6.10, 3.4.7.1,3.4.7.2,3.4.7.3,3.4.7.4,3.4.7.5,3.4.7.6,3.4.7.7,3.4.7.8,3.4.7.9,3.4.7.10,3.4.8.1,3.4.8.2, 3.4.8.3,3.4.8.4,3.4.8.5,3.4.8.6,3.4.8.7,3.4.8.8,3.4.8.9,3.4.8.10,3.4.9.1,3.4.9.2,3.4.9.3,3.4.9.4, 3.4.9.5,3.4.9.6,3.4.9.7,3.4.9.8,3.4.9.9,3.4.9.10,3.4.10.1,3.4.10.2,3.4.10.3,3.4.10.4,3.4.10.5, 3.4.10.6,3.4.10.7,3.4.10.8,3.4.10.9,3.4.10.10,3.5.1.1,3.5.1.2,3.5.1.3,3.5.1.4,3.5.1.5,3.5.1.6, 3.5.1.7,3.5.1.8,3.5.1.9,3.5.1.10,3.5.2.1,3.5.2.2,3.5.2.3,3.5.2.4,3.5.2.5,3.5.2.6,3.5.2.7,3.5.2.8, 3.5.2.9,3.5.2.10,3.5.3.1,3.5.3.2,3.5.3.3,3.5.3.4,3.5.3.5,3.5.3.6,3.5.3.7,3.5.3.8,3.5.3.9,3.5.3.10, 3.5.4.1,3.5.4.2,3.5.4.3,3.5.4.4,3.5.4.5,3.5.4.6,3.5.4.7,3.5.4.8,3.5.4.9,3.5.4.10,3.5.5.1,3.5.5.2, 3.5.5.3,3.5.5.4,3.5.5.5,3.5.5.6,3.5.5.7,3.5.5.8,3.5.5.9,3.5.5.10,3.5.6.1,3.5.6.2,3.5.6.3,3.5.6.4, 3.5.6.5,3.5.6.6,3.5.6.7,3.5.6.8,3.5.6.9,3.5.6.10,3.5.7.1,3.5.7.2,3.5.7.3,3.5.7.4,3.5.7.5,3.5.7.6, 3.5.7.7,3.5.7.8,3.5.7.9,3.5.7.10,3.5.8.1,3.5.8.2,3.5.8.3,3.5.8.4,3.5.8.5,3.5.8.6,3.5.8.7,3.5.8.8, 3.5.8.9,3.5.18.10,3.5.9.1,3.5.9.2,3.5.9.3,3.5.9.4,3.5.9.5,3.5.9.6,3.5.9.7,3.5.9.8,3.5.9.9,3.5.9.10, 3.5.10.1,3.5.10.2,3.5.10.3,3.5.10.4,3.5.10.5,3.5.10.6,3.5.10.7,3.5.10.8,3.5.10.9,3.5.10.10, 3.6.1.1,3.6.1.2,3.6.1.3,3.6.1.4,3.6.1.5,3.6.1.6,3.6.1.7,3.6.1.8,3.6.1.9,3.6.1.10,3.6.2.1,3.6.2.2, 3.6.2.3,3.6.2.4,3.6.2.5,3.6.2.6,3.6.2.7,3.6.2.8,3.6.2.9,3.6.2.10,3.6.3.1,3.6.3.2,3.6.3.3,3.6.3.4, 3.6.3.5,3.6.3.6,3.6.3.7,3.6.3.8,3.6.3.9,3.6.3.10,3.6.4.1,3.6.4.2,3.6.4.3,3.6.4.4,3.6.4.5,3.6.4.6, 3.6.4.7,3.6.4.8,3.6.4.9,3.6.4.10,3.6.5.1,3.6.5.2,3.6.5.3,3.6.5.4,3.6.5.5,3.6.5.6,3.6.5.7,3.6.5.8, 3.6.5.9,3.6.5.10,3.6.6.1,3.6.6.2,3.6.6.3,3.6.6.4,3.6.6.5,3.6.6.6,3.6.6.7,3.6.6.8,3.6.6.9,3.6.6.10, 3.6.7.1,3.6.7.2,3.6.7.3,3.6.7.4,3.6.7.5,3.6.7.6,3.6.7.7,3.6.7.8,3.6.7.9,3.6.7.10,3.6.8.1,3.6.8.2, 3.6.8.3,3.6.8.4,3.6.8.5,3.6.8.6,3.6.8.7,3.6.8.8,3.6.8.9,3.6.8.10,3.6.9.1,3.6.9.2,3.6.9.3,3.6.9.4, 3.6.9.5,3.6.9.6,3.6.9.7,3.6.9.8,3.6.9.9,3.6.9.10,3.6.10.1,3.6.10.2,3.6.10.3,3.6.10.4,3.6.10.5, 3.6.10.6,3.6.10.7,3.6.10.8,3.6.10.9,3.6.10.10,3.7.1.1,3.7.1.2,3.7.1.3,3.7.1.4,3.7.1.5,3.7.1.6, 3.7.1.7,3.7.1.8,3.7.1.9,3.7.1.10,3.7.2.1,3.7.2.2,3.7.2.3,3.7.2.4,3.7.2.5,3.7.2.6,3.7.2.7,3.7.2.8, 3.7.2.9,3.7.2.10,3.7.3.1,3.7.3.2,3.7.3.3,3.7.3.4,3.7.3.5,3.7.3.6,3.7.3.7,3.7.3.8,3.7.3.9,3.7.3.10, 3.7.4.1,3.7.4.2,3.7.4.3,3.7.4.4,3.7.4.5,3.7.4.6,3.7.4.7,3.7.4.8,3.7.4.9,3.7.4.10,3.7.5.1,3.7.5.2, 3.7.5.3,3.7.5.4,3.7.5.5,3.7.5.6,3.7.5.7,3.7.5.8,3.7.5.9,3.7.5.10,3.7.6.1,3.7.6.2,3.7.6.3,3.7.6.4, 3.7.6.5,3.7.6.6,3.7.6.7,3.7.6.8,3.7.6.9,3.7.6.10,3.7.7.1,3.7.7.2,3.7.7.3,3.7.7.4,3.7.7.5,3.7.7.6, 3.7.7.7,3.7.7.8,3.7.7.9,3.7.7.10,3.7.8.1,3.7.8.2,3.7.8.3,3 .. 7.8.4,3.7.8.5,3.7.8.6,3.7.8.7,3.7.8.8 , 3.7.8.9,3.7.8.10,3.7.9.1,3.7.9.2,3.7.9.3,3.7.9.4,3.7.9.5,3.7.9.6,3.7.9.7,3.7.9.8,3.7.9.9,3.7.9.10, 3.7.10.1,3.7.10.2,3.7.10.3,3.7.10.4,3.7.10.5,3.7.10.6,3.7.10.7,3.7.10.8,3.7.10.9,3.7.10.10, 3.8.1.1,3.8.1.2,3.8.1.3,3.8.1.4,3.8.1.5,3.8.1.6,3.8.1.7,3.8.1.8,3.8.1.9,3.8.1.10,3.8.2.1,3.8.2.2, 3.8.2.3,3.8.2.4,3.8.2.5,3.8.2.6,3.8.2.7,3.8.2.8,3.8.2.9,3.8.2.10,3.8.3.1,3.8.3.2,3.8.3.3,3.8.3.4, 3.8.3.5,3.8.3.6,3.8.3.7,3.8.3.8,3.8.3.9,3.8.3.10,3.8.4.1,3.8.4.2,3.8.4.3,3.8.4.4,3.8.4.5,3.8.4.6, 3.8.4.7,3.8.4.8,3.8.4.9,3.8.4.10,3.8.5.1,3.8.5.2,3.8.5.3,3.8.5.4,3.8.5.5,3.8.5.6,3.8.5.7,3.8.5.8, 3.8.5.9,3.8.5.10,3.8.6.1,3.8.6.2,3.8.6.3,3.8.6.4,3.8.6.5,3.8.6.6,3.8.6.7,3.8.6.8,3.8.6.9,3.8.6.10, 3.8.7.1,3.8.7.2,3.8.7.3,3.8.7.4,3.8.7.5,3.8.7.6,3.8.7.7,3.8.7.8,3.8.7.9,3.8.7.10,3.8.8.1,3.8.8.2, 3.8.8.3,3.8.8.4,3.8.8.5,3.8.8.6,3.8.8.7,3.8.8.8,3.8.8.9,3.8.8.10,3.8.9.1,3.8.9.2,3.8.9.3,3.8.9.4, 3.8.9.5,3.8.9.6,3.8.9.7,3.8.9.8,3.8.9.9,3.8.9.10,3.8.10.1,3.8.10.2,3.8.10.3,3.8.10.4,3.8.10.5, 3.8.10.6,3.8.10.7,3.8.10.8,3.8.10.9,3.8.10.10,3.9.1.1,3.9.1.2,3.9.1.3,3.9.1.4,3.9.1.5,3.9.1.6, 3.9.1.7,3.9.1.8,3.9.1.9,3.9.1.10,3.9.2.1,3.9.2.2,3.9.2.3,3.9.2.4,3.9.2.5,3.9.2.6,3.9.2.7,3.9.2.8, 3.9.2.9,3.9.2.10,3.9.3.1,3.9.3.2,3.9.3.3,3.9.3.4,3.9.3.5,3.9.3.6,3.9.3.7,3.9.3.8,3.9.3.9,3.9.3.10, 3.9.4.1,3.9.4.2,3.9.4.3,3.9.4.4,3.9.4.5,3.9.4.6,3.9.4.7,3.9.4.8,3.9.4.9,3.9.4.10,3.9.5.1,2.9.5.2, 3.9.5.3,3.9.5.4,3.9.5.5,3.9.5.6,3.9.5.7,3.9.5.8,3.9.5.9,3.9.5.10,3.9.6.1,3.9.6.2,3.9.6.3,3.9.6.4, 3.9.6.5,3.9.6.6,3.9.6.7,3.9.6.8,3.9.6.9,3.9.6.10,3.9.7.1,3.9.7.2,3.9.7.3,3.9.7.4,3.9.7.5,3.9.7.6, 3.9.7.7,3.9.7.8,3.9.7.9,3.9.7.10,3.9.8.1,3.9.8.2,3.9.8.3,3.9.8.4,3.9.8.5,3.9.8.6,3.9.8.7,3.9.8.8, 3.9.8.9,3.9.8.10,3.9.9.1,3.9.9.2,3.9.9.3,3.9.9.4,3.9.9.5,3.9.9.6,3.9.9.7,3.9.9.8,3.9.9.9,3.9.9.10, 3.9.10.1,3.9.10.2,3.9.10.3,3.9.10.4,3.9.10.5,3.9.10.6,3.9.10.7,3.9.10.8,3.9.10.9,3.9.10.10, 3.10.1.1,3.10.1.2,3.10.1.3,3.10.1.4,3.10.1.5,3.10.1.6,3.10.1.7,3.10.1.8,3.10.1.9,3.10.1.10, 3.10.2.1,3.10.2.2,3.10.2.3,3.10.2.4,3.10.2.5,3.10.2.6,3.10.2.7,3.10.2.8,3.10.2.9,3.10.2.10, 3.10.3.1,3.10.3.2,3.10.3.3,3.10.3.4,3.10.3.5,3.10.3.6,3.10.3.7,3.10.3.8,3.10.3.9,3.10.3.10, 3.10.4.1,3.10.4.2,3.10.4.3,3.10.4.4,3.10.4.5,3.10.4.6,3.10.4.7,3.10.4.8,3.10.4.9,3.10.4.10, 3.10.5.1,3.10.5.2,3.10.5.3,3.10.5.4,3.10.5.5,3.10.5.6,3.10.5.7,3.10.5.8,3.10.5.9,3.10.5.10, 3.10.6.1,3.10.6.2,3.10.6.3,3.10.6.4,3.10.6.5,3.10.6.6,3.10.6.7,3.10.6.8,3.10.6.9,3.10.6.10, 3.10.7.1,3.10.7.2,3.10.7.3,3.10.7.4,3.10.7.5,3.10.7.6,3.10.7.7,3.10.7.8,3.10.7.9,3.10.7.10, 3.10.8.1,3.10.8.2,3.10.8.3,3.10.8.4,3.10.8.5,3.10.8.6,3.10.8.7,3.10.8.8,3.10.8.9,3.10.8.10,
Chemical compound comprises group as described below shown in other formula that exemplifies 1.
The 2nd group of the 2nd group of chemical compound such as among the table B name, promptly by the R that defines in the Table A 2, R 1A, Y and X substituent group are named, but they are bonded on as shown in Equation 5 the steroid nucleus, and the steroid nucleus of its steroid nucleus such as cotype 4 is not except the two keys in 5-6 position exist and 5 hydrogen is the α configuration.
Figure A9981365800781
So the 2nd group of chemical compound of called after 1.2.1.1 has structure:
Figure A9981365800782
The 2nd group, chemical compound 1.2.1.1
The 3rd group of the 2nd group of chemical compound such as among the table B name, promptly by the R that defines in the Table A 2, R 1A, Y and X substituent group are named, but they are bonded on as shown in Equation 6 the steroid nucleus, and the steroid nucleus of its steroid nucleus such as cotype 4 is not except the two keys in 5-6 position exist and 5 hydrogen is the beta comfiguration
So the 3rd group of chemical compound of called after 1.2.1.1 has structure
Figure A9981365800784
The 3rd group, chemical compound 1.2.1.1.
The 4th group of the 4th group of chemical compound such as among the table B name, promptly by the R that defines in the Table A 2, R 1A, Y and X substituent group are named, but they are bonded on as shown in Equation 7 the steroid nucleus, and the steroid nucleus of its steroid nucleus such as cotype 4 is except Q 3Be-CH 2Beyond the OH:
Figure A9981365800791
So the 4th group of chemical compound of called after 1.2.1.1 has structure The 4th group, chemical compound 1.2.1.1.
The 5th group of the 5th group of chemical compound such as among the table B name, promptly by R 2, R 1A, Y and X substituent group are named, but they are bonded on as shown in Equation 8 the steroid nucleus, and the steroid nucleus of its steroid nucleus such as cotype 4 is except the two keys of 5-6 do not exist, 5 hydrogen exist and Q with the α configuration 3Be-CH 2Beyond the OH:
Figure A9981365800793
So the 5th group of chemical compound of called after 1.2.1.1 has structure
Figure A9981365800801
The 5th group, chemical compound 1.2.1.1.
The 6th group of the 6th group of chemical compound named as group 1-5, except the Q of formula 4-8 6Be usefulness-CH 2OH has replaced methyl.In 6 groups, there are 5 subgroups in 6 groups of chemical compounds.First subgroup is that subgroup 6-1 has to be same as and definedly in the 1st group of chemical compound has substituent steroid nucleus, and the second subgroup substituent steroid nucleus that has that to be subgroup 6-2 have as 2 groups of chemical compounds definition.Subgroup 6-3 has respectively to subgroup 6-5 and has a substituent steroid nucleus as the 3rd group to the 5th group definition.So for example the subgroup 6-1 chemical compound of called after 1.2.1.1 has structure:
And the subgroup 6-2 chemical compound of called after 1.2.1.1 has structure:
The 7th group of the 7th group of chemical compound named as the 1-5 group, and the Y in formula 4-8 has replaced the α configuration with beta comfiguration.The 7th group contains 5 subgroups, and chemical compound name wherein is described as the 6th group chemical compound basically, except Y group is beta comfiguration.
The 8th group of the 8th group of chemical compound named as the 1-5 group, and the X in formula 4-8 has replaced the beta comfiguration with the α configuration.The 8th group contains 5 subgroups, and chemical compound name wherein is described as the 6th group chemical compound basically, except the X group is the α configuration.
The 9th group of the 9th group of chemical compound named as the 1-5 group, except the R among the formula 4-8 2Part is to have replaced beyond the beta comfiguration with the α configuration.The 9th group contains 5 subgroups, and chemical compound name wherein is described as the 6th group chemical compound basically, except R 2Group is beyond the α configuration.
The 10th group of the 10th group of chemical compound named as the 1-9 group, except R in the Table A 2Beyond part 1-10 is replaced by following part.
1-S-C(O)-CH 3
2-S-C(O)-CH 2-C 6H 5
3-O-S(O)-O-CH 3
4-O-S(O)-O-CH 2-C 6H 5
5-O-S(O)(O)-O-CH 3
6-O-S(O)(O)-O-CH 2-C 6H 5
7-O-C(O)-NH-CH 3
8-O-C(O)-NH-C 6H 5
9-O-C(S)-CH 3
10-O-C(S)-CH 2-C 6H 5
The 10th group of chemical compound that contains 25 subgroups.At first, subgroup 10-1 has the substituent identical steroid nucleus that has as the 1st group of definition, except using above-mentioned R 2Part or group replaced beyond those in the Table A.The chemical compound of the subgroup 10-1 of called after 1.2.1.1 has structure:
Figure A9981365800811
The chemical compound of the subgroup 10-2 of called after 1.2.1.1 has structure:
Figure A9981365800821
The chemical compound of the subgroup 10-6-1 of called after 1.2.1.1 has structure:
Figure A9981365800822
The chemical compound of the subgroup 10-6-2 of called after 1.2.1.1 has structure:
The 11st group of the 11st group of chemical compound named as the 1-9 group, except R in the Table A 2Beyond part 1-10 is replaced by following part.
1-S-C(O)-CH 2CH 2-O-CH 2CH 3
2-S-C(O)-CH 2-C 6H 4OCH 3
3-O-S(O)-O-CH 2CH 2-O-CH 2CH 3
4-O-S(O)-O-CH 2-C 6H 4OCH 3
5-O-S(O)(O)-O-CH 2CH 2-O-CH 2CH 3
6-O-S(O)(O)-O-CH 2-C 6H 4OCH 3
7-O-C(O)-NH-CH 2CH 2-O-CH 2CH 3
8-O-C(O)-NH-C 6H 4OCH 9
9-O-C(S)-CH 2CH 2-O-CH 2CH 3
10-O-C(S)-CH 2-C 6H 4OCH 3
The 11st group comprises 25 subgroups, and wherein chemical compound is named as the 10th group of chemical compound, except R 2By top given outside.
The 12nd group of the 12nd group of chemical compound named as the 1-9 group, except R in the Table A 2Beyond part 1-10 is replaced by following part.
1-S-C(O)-CH 2CH 2-O-CH 2C(O)OH
2-S-C(O)-CH 2-C 6H 4F
3-O-S(O)-O-CH 2CH 2-O-CH 2C(O)OH
4-O-S(O)-O-CH 2-C 6H 4F
5-O-S(O)(O)-O-CH 2CH 2-O-CH 2C(O)OH
6-O-S(O)(O)-O-CH 2-C 6H 4F
7-O-C(O)-NH-CH 2CH 2-O-CH 2C(O)OH
8-O-C(O)-NH-C 6H 4F
9-O-C(S)-CH 2CH 2-O-CH 2C(O)OH
10-O-C(S)-CH 2-C 6H 4F
The 13rd group of the 13rd group of chemical compound named as the 1-9 group, except R in the Table A 2Beyond part 1-10 is replaced by following part.
1-S-C(O)-CH 2CH 2-O-CH 2CH 2OH
2-S-C(O)-CH 2-C 6H 4CH 3
3-O-S(O)-O-CH 2CH 2-O-CH 2CH 2OH
4-O-S(O)-O-CH 2-C 6H 4CH 3
5-O-S(O)(O)-O-CH 2CH 2-O-CH 2CH 2OH
6-C-S(O)(O)-O-CH 2-C 6H 4CH 3
7-O-C(O)-NH-CH 2CH 2-O-CH 2CH 2OH
8-O-C(O)-NH-C 6H 4CH 3
9-O-C(S)-CH 2CH 2-O-CH 2CH 2OH
10-C-C(S)-CH 2-C 6H 4CH 3
The 14th group of the 14th group of chemical compound named as the 1-9 group, except R in the Table A 2Beyond part 1-10 is replaced by following part.
1-?S-C(O)-CH 2CH 2-O-CH 2CH 2OR PR
2-S-C(O)-CH 2-C 6H 4OR PR
3-O-S(O)-O-CH 2CH 2-O-CH 2CH 2OR PR
4-O-S(O)-O-CH 2-C 6H 4OR PR
5-O-S(O)(O)-O-CH 2CH 2-O-CH 2CH 2OR PR
6-O-S(O)(O)-O-CH 2-C 6H 4OR PR
7-O-C(O)-NH-CH 2CH 2-O-CH 2CH 2OR PR
8-O-C(O)-NH-C 6H 4OR PR
9-O-C(S)-CH 2CH 2-O-CH 2CH 2OR PR
10-O-C(S)-CH 2-C 6H 4OR PR
The 15th group of the 15th group of chemical compound named as the 1-9 group, except R in the Table A 2Beyond part 1-10 is replaced by following part.
1-S-C(O)-CH 2CH 2-O-CH 2CH 2NHR PR
2-S-C(O)-CH 2-C 6H 3(OR PR) 2
3-O-S(O)-O-CH 2CH 2-O-CH 2CH 2NHR PR
4-O-S(O)-O-CH 2-C 6H 3(OR PR) 2
5-O-S(O)(O)-O-CH 2CH 2-O-CH 2CH 2NHR PR
6-O-S(O)(O)-O-CH 2-C 6H 3(OR PR) 2
7-O-C(O)-NH-CH 2CH 2-O-CH 2CH 2NHR PR
8-O-C(O)-NH-C 6H 3(OR PR) 2
9-O-C(S)-CH 2CH 2-O-CH 2CH 2NHR PR
10-O-C(S)-CH 2-C 6H 3(OR PR) 2
The 16th group of the 16th group of chemical compound named as the 1-9 group, except R in the Table A 2Beyond part 1-10 is replaced by following part.
1-S-C(O)-(CH 2) 0-6-CH 3
2-S-C(O)-CH 2-C 6H 5
3-O-S(O)-O-(CH 2) 0-6-CH 3
4-O-S(O)-O-CH 2-C 6H 5
5-O-s(O)(O)-O-(CH 2) 0-6-CH 3
6-O-S(O)(O)-O-CH 2-C 6H 5
7-O-C(O)-NH-(CH 2) 0-6-CH 3
8-O-C(O)-NH-(CH 2) 0-6-C 6H 5
9-O-C(S)-(CH 2) 0-6-CH 3
10-O-C(S)-CH 2-C 6H 5
The 17th group of the 17th group of chemical compound named as the 1-9 group, except R in the Table A 2Beyond part 1-10 is replaced by following part.
1-S-C(O)-CH 2CH 2-(O-CH 2CH 2) 1-50-H
2-S-C(O)-CH 2-C 6H 4OCH 3
3-O-S(O)-O-CH 2CH 2-(O-CH 2CH 2) 1-50-H
4-O-S(O)-O-CH 2-C 6H 4OCH 3
5-O-S(O)(O)-O-CH 2CH 2-(O-CH 2CH 2) 1-50-H
6-O-S(O)(O)-O-CH 2-C 6H 4OCH 3
7-O-C(O)-NH-CH 2CH 2-(O-CH 2CH 2) 1-50-H
8-O-C(O)-NH-C 6H 4OCH 3
9O-C(S)-CH 2CH 2-(O-CH 2CH 2) 1-50-H
10-O-C(S)-CH 2-C 6H 4OCH 3
The 18th group of the 18th group of chemical compound named as the 1-9 group, except R in the Table A 2Beyond part 1-10 is replaced by following part.
1-O-C(O)-CH 2CH 2-(O-CH 2CH 2) 1-50-H
2-O-C(O)-CH 2-C 6H 4OCH 3
3-O-C(O)-(CH 2) 0-6-CH 3
4-O-C(O)-CH 2-C 6H 4NO 2
5-O-C(O)-CH 2CH 2-(O-CH 2CH 2) 1-50-H
6-O-C(O)-CH 2-C 6H 5
7-O-C(O)-CH 2CH 2-O-CH 2CH 3
8-O-C(O)-C 6H 5
9-O-C(O)-CH 2CH 2-S-CH 2CH 3
10-O-C (O)-CH 2-C 6H 4The 19th group of the 19th group of chemical compound of F named as the 1-9 group, except R in the Table A 2Beyond part 1-10 is replaced by following part.
The 20th group of the 20th group of chemical compound named as the 1-9 group, except R in the Table A 2Beyond part 1-10 is replaced by following part.
1-C(O)-O-CH 2CH 2-(O-CH 2CH 2) 1-50-H
2-C(O)-O-CH 2-C 6H 4OCH 3
3-C(O)-O-(CH 2) 0-6-CH 3
4-C(O)-O-CH 2-C 6-H 4NO 2
5-C(O)-O-CH 2CH 2-(O-CH 2CH 2) 1-50H
6-C(O)-O-CH 2-C 6H 5
7-C(O)-O-CH 2CH 2-O-CH 2CH 3
8-C(O)-O-C 6H 5
9-C(O)-O-CH 2CH 2-S-CH 2CH 3
10-C(O)-O-CH 2-C 6H 4F
The 21st group of the 21st group of chemical compound named as the 1-9 group, except R in the Table A 2Beyond part 1-10 is replaced by following part.
1-C(O)-O-G12
2-O-C(O)-G12
3-C(O)-S-G12
4-S-C(O)-G12
5-C(S)-O-G12
6-O-C(S)-G12
7-O-C(O)-NH-G12
8-NH-C(O)-O-G12
9-C(O)-O-CH 2-G12
10-O-C(O)-CH 2-G12
So the 21-1 group chemical compound of called after 1.2.1.1 has structure
And the 21-2 of called after 1.2.1.1 group chemical compound has structure
Figure A9981365800872
The 21-3 group chemical compound of called after 1.2.1.1 has structure
The 21-4 group chemical compound of called after 1.2.1.1 has structure
Figure A9981365800874
The 21-6-1 group chemical compound of called after 1.2.1.1 has structure
The 21-6-2 group chemical compound of called after 1.2.1.1 has structure
Figure A9981365800882
So the 21-6-3 group chemical compound of called after 1.2.1.1 has structure
G12 in the 21st group is the organic moiety that contains 1,2,3,4,5,6,7,8,9,10,11 or 12 carbon atom and 0,1,2,3,4,5,6,7 or 8 independent O, S, N, P or Si atom of selecting, if but Si or P exist, then can only have a Si or P, wherein this organic moiety is selected from C 1-12Alkyl, C 2-12Alkenyl, C 2-12Alkynyl, aryl, C 2-9Heterocycle or these groups contain 1,2,3,4 or a plurality of substituent substitutive derivative, and wherein each substituent group is selected independently and is selected from :-O-,-S-,-NR PR-(comprise-NH-) ,-C (O)-,=O ,=S ,-N (R PR) 2(comprise-NH 2) ,-C (O) OR PR(comprising-C (O) OH) ,-OC (O) R PR(comprise-O-C (O)-H) ,-OR PR(comprise-OH) ,-SR PR(comprise-SH) ,-NO 2,-CN ,-NHC (O)-,-C (O) NH-,-OC (O)-,-C (O) O-,-O-A8 ,-S-A8 ,-C (O)-A8 ,-OC (O)-A8 ,-C (O) O-A8 ,=N-,-N=,=N-OH ,-OPO 3(R PR) 2,-OSO 3H 2Perhaps halogen part or atom, wherein each R PRBe -H, the independent protecting group of selecting, or two R PRBe combined into protecting group, A8 is C 1-8Alkyl, C 2-8Alkenyl, C 2-8Alkynyl, C 1-4Alkyl-aryl (as benzyl), aryl (as phenyl) or C 1-4Alkyl-C 2-9Heterocycle.G12 partly comprises-CH 3,-C 2H 5,-C 3H 7,-C 4H 9,-C 6H 13,-CH 2-C 6H 5,-C 2H 4-C 6H 5,-C 3H 6-C 6H 5,-C 6H 5,-CH 2-heterocycle ,-CH 2-CH 2-heterocycle and heterocycle, and they by 1,2,3 or a plurality of independent select-O-,-S-,-F ,-Cl ,-Br ,-I ,-NH-,=O ,-CN ,-OCH 3,-OC 2H 5,-OC 4H 9,-NO 2,-NH 2,-COOH or-NH-C (O)-part replace.
Other embodiment comprises arbitrary formula 4 chemical compounds or formula 4 compounds named in above-mentioned arbitrary group is used for any treatment of the present invention or other purposes.This comprises the formula 4 of arbitrary name or this compounds is applied to these purposes, wherein (i) R 2Be the α configuration, (ii) Q4 be-CH (halogen)-, (iii) X is that α configuration and 17 existence-H are beta comfiguration, (iv) Y be beta comfiguration and 16-H is the α configuration, or (v) R 1A is that α configuration and 7-H are beta comfiguration.
Embodiment comprises chemical compound shown in the formula 1 (for example formula 4 chemical compounds), wherein R 4Be the C that is optionally substituted 1-8Alkyl, the optional C that replaces 2-8Alkenyl, the optional C that replaces 2-8Alkynyl, the optional aryl that replaces, the optional heterocycle that replaces, the optional C that replaces 1-8Alkyl-aryl, the optional C that replaces 1-8Alkyl-heterocycle or optional replacement-CH 2-C 1-8Organic moiety (wherein organic moiety as to the definition of ester as described in), wherein any above-mentioned group independently by 1,2,3,4,5,6 or a plurality of-O-,-S-,-NH-,-NH-C (O)-(promptly-NH-C (O)-or-C (O)-NH-) ,=O ,=NOH ,-NO 2,-F ,-Cl ,-Br ,-I ,-OH ,-SH or-NH 2Replace.This R 4Part does not comprise-CH 2-C 1-6The optional alkyl that replaces ,-CH 2-C 2-6The optional alkenyl that replaces ,-CH 2-C 1-6The optional aryl that replaces and-CH 2-C 2-9The optional heterocycle that replaces.
The chemical compound one aspect of the present invention that increases plasma concentration comprises that chemical compound that the plasma concentration of using effective dose increases chemical compound (for example chemical compound of formula 2A or 2B) and formula 1 is used for preventing or one or more togavirus for the treatment of individuality infect (comprising banzi virus, Alphavirus, Pestivirus or rubella virus).Except the chemical compound of formula 2A or 2B, plasma concentration increases chemical compound and comprises the plain A of methyl benefit bone ester first, monarda glycoside (Isosakuranetin-7-rutinoside or neoponcirin), flavanomarcin (different kokko element-7-glucoside), flavanone azine, flavanone diacetyl hydrazone, Flavanone hydrazone, silymarin (it has following structure)
Figure A9981365800901
Silychristin (it has following structure)
Figure A9981365800902
Silydianin (it has following structure)
Figure A9981365800903
Silicon androsin (silandrin) (it has following structure)
With chemical compound with structure (E)
Figure A9981365800912
In a word, the chemical compound of these chemical compounds and formula 2A and 2B is known as " chemical compound that increases plasma concentration ".
The chemical compound of formula 2A and 2B comprises multiple natural and synthetic flavone compound, comprises some flavone, flavane and isomery analog thereof.Discovery can improve the systemic bioavailability of the preparation that contains chemical compound shown in the formula 1 in the existence that contains compound compositions Chinese style 2A shown in the formula 1 or 2B chemical compound.Formula 2A or 2B chemical compound can improve the plasma concentration of chemical compound shown in the formula 1 as naringin or naringenin.Formula 2A or 2B chemical compound not necessarily will be present in the preparation that contains chemical compound shown in the formula 1.Formula 2A and 2B also can be before or after compound administration shown in the formula 1 administration about 1-4 hour the time, preferably administration about 1-4 hour time the before compound administration shown in the formula 1.In these embodiments, can use the oral or parenteral formulation that contains chemical compound shown in the formula 1 and formula 2A or 2B chemical compound.
The chemical compound that increases plasma concentration comprises the chemical compound of formula 50-65:
Figure A9981365800921
Figure A9981365800941
Wherein
6 R 8Be independently-H ,-OH ,-F ,-Cl ,-Br ,-I, C 1-6Alkyl, C 1-6Alkoxyl, glucosiduronic acid, C 1-25Fatty acid, glucoside ,-CH 2CH=C (CH 3) 2Or has the group of structure (B);
8 R 8Be independently-H ,-OH ,-F ,-Cl ,-Br ,-I, C 1-6Alkyl, C 1-6Alkoxyl, glucosiduronic acid, C 1-25Fatty acid, glucoside ,-CH 2CH=C (CH 3) 2Or the residue of formula 50-65 chemical compound (hydrogen atom is removed to form formula 50-65 chemical compound free radical therein);
R 8A is independently -H,-OH ,-F ,-Cl ,-Br ,-I, C 1-6Alkyl, C 1-6Alkoxyl, glucosiduronic acid, C 1-25Fatty acid, glucoside ,-CH 2CH=C (CH 3) 2Or has the group of structure (C);
Remaining R 8Be independently-H ,-OH ,-F ,-Cl ,-Br ,-I, C 1-6Alkyl, C 1-6Alkoxyl, glucosiduronic acid, C 1-25Fatty acid, glucoside ,-CH 2CH=C (CH 3) 2And
R 10Be (i)-OH or-F ,-Cl ,-Br ,-I, C 1-6Alkyl, C 1-6Any stereoisomer, hydrate, analog, derivant or metabolite in alkoxyl, neohesperidin, Herba Apii graveolentis glucosides (apioglucoside), rutinoside, glucoside, galactoside, rhamnoside, arabinose glycosides or these parts, in them any on one or more hydrogen atoms independently by-OH ,-F ,-Cl ,-Br ,-I, C 1-6Alkyl, C 1-6Alkoxyl, glucosiduronic acid, C 1-25Fatty acid replaces; Or (ii) R 10Be that methyl is mended the plain A of bone ester first, monarda glycoside, flavanomarcin, flavanone azine, flavanone diacetyl hydrazone, Flavanone hydrazone, silymarin, any one stereoisomer, hydrate, analog, derivant or metabolite in the part of Silychristin, silydianin, silicon androsin (silandrin), structure (E) or these parts.
Other treatment embodiment is according to another preferred aspect of the present invention, a kind of method for the treatment of one or more above-mentioned diseases such as togavirus infection is provided, comprise and use conjoint therapy, wherein contain one or more chemical compounds of the present invention and one or more macrophage stimulation factors (giving the chemical compound that one or more increase plasma concentration) administration simultaneously or sequentially with optional further the associating.Macrophage stimulation factor is known for one of ordinary skill in the art, for example comprise that GM-CSF is (referring to as people such as Callard, " cytokine application manual " (The Cytokine FactsBook), Academic Press, 1994,139 pages, it is hereby incorporated by) and interleukin-4 (sell as " Leukine " and sell as " Prokine " by Schering Plough by Immunex).
Of the present invention another preferred aspect, chemical compound of the present invention and one or more oxidants (optional further with chemical compound that increases plasma concentration and/or macrophage stimulation factor) administering drug combinations maybe can be to patient's oxygen supply to increase the oxidation steroid in the blood plasma.
In addition, the invention further relates to the conjoint therapy that is used for the treatment of hepatitis C and/or hepatitis G patient, comprise to this patient and use one or more chemical compounds of the present invention and virazole and/or interferon-alpha simultaneously or sequentially, and one or more increase chemical compound, one or more macrophage stimulation factors, one or more oxidants of plasma concentration to choose further associating wantonly, and/or oxygen supply.And, the invention further relates to the conjoint therapy described in this paragraph, this conjoint therapy can be used for treating the patient who suffers from or easily suffer from the infection of any kind togavirus.
The present invention also relates to combination of compounds of the present invention and be used for the treatment of application in the medicine of togavirus or banzi virus (particularly HCV) in preparation.
Any composition of conjoint therapy disclosed by the invention is (in combination preparation), (for example, the dosing interval number of each component minute or a few hours) administration basically simultaneously simultaneously, or can the order administration, for example is separated by some days, or is separated by and surpasses a week.For example, chemical compound of the present invention can with the chemical compound that increases plasma concentration (and/or macrophage stimulation factor) administration together, or administration simultaneously basically, be separated by several minutes or a few hours administration as each chemical compound, or administration in proper order, as it is some day to be separated by, or is separated by and surpasses all administrations (optional simultaneously or sequentially with oxidant or oxygen ventilation administering drug combinations).The variation pattern of all these administering drug combinations therapies all belongs in the scope of the present invention.
The present invention also relates to contain the pharmaceutical preparation of any combination of the present invention.
The invention still further relates to chemical compound of the present invention and be used for the application of the medicine of treatment of the present invention (infecting as HCV) in preparation as the treatment togavirus.
So that the patient is carried out prophylactic treatment, togavirus infects for example to prevent to the present invention also relates to use chemical compound of the present invention (optional one or more combination of compounds that adopt).
Industrial product the present invention also provides industrial product, comprising such as the The compounds of this invention of packaging material, at least one unit dose (optional and one or more unit dose can at the chemical compound of conjoint therapy administration) with instruct chemical compound to can be used for the label or the package insert of the inventive method.
In one embodiment, industrial product comprises the 17-ketosteroid chemical compound (chemical compound shown in the formula 1) of packaging material, at least one unit dose and instructs the label or the package insert that can use 17-ketosteroid chemical compound (chemical compound shown in the formula 1) in the method for the invention.Packaging material can be made by the known raw material of one or more glucose, for example made by foam, presspaper, fibre board, polystyrene and polypropylene, and the suitable dress of its size contain the described chemical compound that has packaging material.And label or package insert can be to be fixed on sign or label on the packaging material, to be printed on the label on the packaging material or to be inserted in label in the packaging material.Label has been indicated and can use 17-ketosteroid chemical compound in therapy of the present invention, for example unites use with the chemical compound that increases plasma concentration, macrophage stimulation factor, virazole and/or alpha-interferon.This label also can indicate described chemical compound and obtain official mission (such as U.S. food and drug administration) approval and be used for medical science or veterinary applications according to the method for the invention.This label also can be indicated the approach that is fit to administration, dosage regimen etc.If desired, goods can contain other composition, as the chemical compound that increases plasma concentration, macrophage stimulation factor, virazole and/or the alpha-interferon of at least one unit dose.
The method and formulation formula 1 of administration, 2A or 2B chemical compound for the dosage of particular patient should according to due to total health status, medication, approach and the dosage of factor such as patient and the order of severity (if existence) of side effect change.The clinicist utilizes the known parameter in this field can determine the dosage that is suitable for.Usually, begin administration, after this increase dosage until obtaining required or best effect by little increment with the dosage that is slightly less than optimal dose.The dosage of chemical compound of the present invention suitably waits and considers according to suffering from disease individual instances, individual age and sex.As for the treatment time-histories, monitor the patient by the treatment time-histories that experienced clinicist selects to be fit to, so that judge when inhibitory action provides therapeutic efficiency, and judge whether to need to increase dosage, minimizing dosage, therapy discontinued, continuation treatment or change treatment.
The treatment effective dose of any specific compound changes with chemical compound and the different of patient.As general recommendation, about dosage range of 0.1 to about 500mg/kg has therapeutic efficiency.Typically, can adopt about 0.5mg/kg to the interior dosage of about 500mg/kg scope.The daily dose of chemical compound shown in the formula 1 is generally about 10 to about 750mg, and more Chang Weiyue 20 is to about 400mg, and this dosage can be used as single dose or two or more sub-doses administration.Above-mentioned dosage or sub-doses can be administered to one or more sites by one or more route of administration.Normally administration every day 1 time and continue to be enough to make the time that the patient is asymptomatic or symptom obviously alleviates of the persistent period of treatment.According to the order of severity that infects in the individual patients, sustainable some days of treatment time, some weeks or longer time.
For the frequency and the persistent period of treatment, known the technical scope that this belongs to the gengral practitioner, they should observe patient's disease and make about interrupting, stop and continue the decision of treatment.
The used dosage of the present invention waits suitably according to the individual instances of suffering from disease, individual age and sex to be considered.In addition, known the technical scope that this belongs to one skilled in the art, they are based on dosage above-mentioned and that the other factors decision is suitable.
According to method of the present invention, chemical compound of the present invention can oral administration, intramuscular (IM), intravenous (IV) or subcutaneous (SC) administration, especially preferred intravenous administration.Though can adopt other administration route, have found that intravenous administration can provide effectiveness astoundingly.For oral administration, it may be very important using the chemical compound that increases plasma concentration.In addition, chemical compound or salt shown in the formula 1 also can be used as liposome turbid liquor through intravenous or intramuscular administration.Administration also can be taked cyclodextrin formulations (oral administration, SC, IV or IM administration).Therefore chemical compound of the present invention and pharmaceutically acceptable or physiological acceptable salt thereof can be fit to wait the administration of curing the disease disease by any, comprise through (comprise in subcutaneous, intramuscular, intravenous, intraperitoneal, intradermal, the sheath, in the dura mater and epidural) outside oral cavity, rectum, nose, part (comprising), vagina, the intestinal administration through eye, cheek or Sublingual and by aerosol through the lung administration.Usually, chemical compound of the present invention is through intestinal external administration, oral or topical.If the bioavailability of embodiment oral administration is not enough, then can pass through other above-mentioned administrations.
Embodiment comprises the preparation that contains liposome or liquid complex, contains chemical compound shown in the formula 1 in liposome or the liquid complex.These preparations are to prepare by known method, for example United States Patent (USP) 4427649,5043165,5714163,5744158,5783211,5795589,5795987,5798348,5811118,5820848,5834016 and 5882678, and they are hereby incorporated by.Liposome can be chosen wantonly and contain additional treatment agent or other reagent, for example chemical compound of formula 2A or 2B.Can (as SC, IV IM) be transported to liposome in the individual body by standard way such as oral, aerosol or the outer approach of intestinal.
In modal situation, be applicable to that pharmaceutical composition of the present invention contains compound or pharmaceutically acceptable salt thereof shown in the formula 1 in any pharmaceutically suitable carrier.Solution is then selected the carrier of water as water soluble compound or salt if desired.In other embodiments, organic carrier such as glycerol, ethanol, propylene glycol, Polyethylene Glycol, DMSO, DMSO 2, vegetable oil, mineral oil, benzyl benzoate or its mixture also be suitable for.Usually, in any situation, should be in a suitable manner with solution sterilization, preferably through 0.22 micron membrane filtration.Be applicable to that the compositions that the present invention puts into practice can provide with forms such as bottle, ampoules.
In some embodiments, be present in the compositions or be applicable to that chemical compound is dissolved in the non-water excipient fully shown in the formula 1 of the open method of the present invention.Yet in some embodiments, for example in transition combination thing or some preparation, chemical compound shown in the formula 1 is partly dissolved and remainder exists with solid, and it can be suspension or colloid.In relevant embodiment, chemical compound shown in the formula 1 not exclusively dissolves and exists as suspension or gel.
Except compound or its salt shown in the formula 1, pharmaceutical composition can also contain other additives, pH regulator additive for example, and particularly as the reagent of acid, alkali or buffer agent, buffer agent comprises sodium lactate, sodium acetate and gluconic acid sodium salt.In addition, described compositions can contain microbiological antiseptic, for example methyl parahydroxybenzoate, propyl p-hydroxybenzoate, benzylalcohol and benzyl benzoate.If adopt and repeatedly use bottle, pharmaceutical composition should contain microbiological antiseptic in addition.Obviously, can utilize the known technology in this field with described preparation lyophilization.
Described preparation comprises the preparation that those are applicable to above-mentioned route of administration.Preparation can provide with unit dosage forms easily and the method for using pharmaceutical field to know prepares.Technology, excipient and preparation usually can be referring to RemingtonShi pharmaceutical science (Remington ' s PharmaceuticalSciences), Mack Publishing Co., Easton, PA 1985, the 17 editions; People such as Nema, " PDA pharmaceutical science technical journal " (PDA J.Pharm.Sci.Tech.) 1997 51:166-171, both are hereby incorporated by.The method for preparing preparation of the present invention comprises chemical compound shown in the formula 1 and one or more excipient or carrier-bound step.Usually, closely chemical compound shown in the formula 1 and liquid excipient or solid excipient in small, broken bits or the two are combined,, can make described preparation if suitable subsequently product is shaped by all even.
Be suitable for oral preparation of the present invention and can be used as the discrete unit existence, as capsule, flat capsule or tablet, they contain formula 1 or the formula 2A or the 2B chemical compound of scheduled volume separately; As powder or granule; As solution in liquid, aqueous or the on-aqueous liquid or suspension; Or oil-in-water liquid emulsion or Water-In-Oil liquid emulsion.Formula 1 or formula 2A or 2B chemical compound also can be used as pill, electuary or paste and exist.
Tablet can be shaped with one or more excipient by compression or molded choosing wantonly.Can prepare compressed tablets by compression free-flowing form such as powder or particulate formula 1 or formula 2A or 2B chemical compound in suitable equipment, wherein optional binding agent, lubricant, inert diluent, antiseptic, surface activity or the dispersant of being mixed with.Molded tablet can make with the moistening powder compound of inert liquid diluent by molded in suitable equipment.Tablet can be chosen wantonly by coating or groove, and can prepare formula 1 or formula 2A or 2B chemical compound so that slow release or controlled release to be provided.
The oil phase of Emulsion of the present invention can be made of by known way known component.Though this can only contain emulsifying agent mutually, expect it contain at least a emulsifying agent and fat or oil or with fat and both mixture of oil.Preferably, hydrophilic emulsifier with lipophilic emulsifier with which, lipophilic emulsifier serves as stabilizing agent.Also preferably contain oil ﹠ fat.Simultaneously, the emulsifying agent that contains or do not contain stabilizing agent makes emulsifing wax, and this wax is formulated as the emulsifying ointment base with oil ﹠ fat, and this substrate forms the oiliness decentralized photo of cream.Be applicable to that emulsifying agent and emulsion stabilizer in the preparation that contains formula 1 or formula 2A or 2B chemical compound comprise tween _60, Span _80, cetostearyl alcohol, benzylalcohol, myristyl alcohol, monostearin and sodium lauryl sulphate.
The preparation that is fit to the buccal administration is included in the lozenge that contains formula 1 or formula 2A or 2B chemical compound in the flavoring substrate, and described substrate is generally sucrose and arabic gum or Tragacanth; The lozenge that in inert base (as gelatin and glycerol or sucrose and arabic gum), contains formula 1 or formula 2A or 2B chemical compound.
The preparation of rectally can be used as the suppository with suitable substrate and exists, and described substrate contains for example cocoa butter or Salicylate.
Be fit in the lung or the preparation of nose administration has 0.01-200 micron for example and (is included in increment in the 0.01-500 micrometer range and is 0.1 micron granularity, for example 0.1,0.2,0.3,0.4,0.5,1,2,5,30 micron, 35 microns etc.) granularity, it can be through the nasal meatus inhalation or through the oral cavity inhalation, to reach different bronchus or alveolar sac.The preparation that is fit to aerosol or dried powder administration can be according to conventional method preparation and can be with the other treatment agent chemical compound of treatment or prevention togavirus, banzi virus or other infection of retrovirus (as be used herein to) administration.Utilize the dose inhaler of metering to be easy to carry out anapnotherapy.
The preparation that is fit to vagina administration can be used as medicated vaginal suppository, tampon, cream, gel, foam or spray and exists, and these preparations also contain known suitable carrier in this field or excipient except containing the chemical compound shown in the formula 1.
The preparation that is fit to the intestinal external administration should be sterilized, and comprises moisture or non-water injection, wherein can contain antioxidant, buffer agent, antibacterial and make preparation and the isoosmotic solute of receiver's blood; Moisture and non-water sterilized suspension wherein can comprise suspending agent and thickening agent.Preparation may reside in the container of unit dose or multidose, Mi Feng ampoule and have the bottle of elastic plug for example, and can be deposited under lyophilizing (lyophilization) condition, this only need add the sterilized liquid carrier immediately before facing use, as water for injection.Extemporaneous injection and suspension can be prepared by above-mentioned sterile powder, granule and tablet.The preparation of unit dose contains daily dose or unit sub-doses every day or its suitable formula 1 or formula 2A or 2B chemical compound partly as mentioned above usually.
In some embodiments, chemical compound shown in the formula 1 is administration on intermittent basis.In these embodiments, chemical compound shown in the formula 1 is administered to individual at least one day with the dosage that for example contains the chemical compound shown in the 5-500mg formula 1 of having an appointment (about usually 25-400mg or about 50-350mg), after this not administration at least one day (at least 24 hours) is chosen wantonly and is given daily dose 50-500mg according to appointment after this.The batch (-type) dose regimen can comprise that the schedule based on 1 week carries out administration (administration is 1,2,3 or 4 times weekly), three and five administrations or for example on Monday, in Tuesday, four or six administrations, continue about 1,2,3,4,6,8 or more all, after this about 2,3,4,5,30,45,60,90 or period of more days in not administration, choose wantonly after this once more on Monday, three and five administrations 1,2,3,4,6,8 or week more how.Can comprise to individuality in the dose regimen in week and to use chemical compound shown in 1,2,3,4 or 5 formula 1 weekly and to continue 1,2,3,4 or week more how.In related embodiment, administration can be to individual administration every day and continue 2,3,4,5,6,7 or more days, after this about 1,2,3,4,5,7,14,30,45,60,90 or time of more days in not administration, and then carry out administration every day in another period.These embodiments may further include treatment or another treatment of the present invention of carrying out with formula 2A or 2B chemical compound.
For the scope of never pointing out, one skilled in the art it will be understood that any one mode in this description and the multiple specific embodiment of giving an example can improve further to comprise the disclosed in other embodiments feature of the present invention.
Treatment is used for treatment and is used, and compositions disclosed herein contains chemical compound shown in one or more formulas 1 usually, and method disclosed herein adopts these compositionss, wherein contains a kind of, two or more these compounds, is generally a kind of chemical compound.Though chemical compound of the present invention can be used as the pure compound administration, preferably they provide with pharmaceutical dosage forms.Preparation of the present invention contains the chemical compound of at least a formula 1 and one or more can accept carrier or excipient, and optionally contains the other treatment agent, suc as formula 2A or 2B chemical compound, α IFN, virazole, macrophage stimulation factor and/or oxidant.One or more carriers or excipient must be " can accept ", just with other component compatibility of preparation and harmless to the patient.
Chemical compound of the present invention can effectively treat or prevent one or more banzi virus or the togavirus among the human or animal to infect.Can comprise HCV with the togavirus and the flaviviridae infections of compounds for treating shown in the formula 1, california antigenic group viruses, Saint Louis type encephalitis, western equine encephalitis virus, Eastern equine encephalitis virus, colorado tick fever virus, LaCrosse's encephalitis, Japanese encephalitis virus, yellow fever virus, Venezuelan equine encephalitis virus, Murray Valley encephalitis virus Ticks biography property encephalitis, first type GB virus, B-mode GB virus, the third type GB virus, dengue virus 1, dengue virus 2, dengue virus 3, dengue virus heat 4, Semliki Forest virus and sindbis virus.Described rubella virus comprises the people rubella virus.Pestivirus comprises bovine diarrhoea virus, as bovine viral diarrhea virus, Canis familiaris L. cholera virus and sheep edge disease (border disease) virus.Chemical compound shown in the formula 1 also can effectively be treated hepatitis G virus.
Except prevention or the infection of treatment togavirus, chemical compound shown in some formulas 1 can be used for treatment by the individuality of togavirus and (for example retrovirus or the second kind of togavirus) coinfection of another kind of virus.Retrovirus can be with compounds for treating shown in the formula 1 as human immunodeficiency virus (as HIV2 or HIV2), ape immune deficiency virus, recombined human-ape immune deficiency virus (SHIV), feline immunodeficiency virus or cat or murine leukemia or sarcoma virus.The coinfection of hepatitis virus can be used compounds for treating of the present invention, as the coinfection of HCV and HIV.In these embodiments, individuality be verified usually (i) whether exist one or more togavirus infect (HCV etc.) and (ii) second viral infection whether have (as people I herpes simplex virus type, people II herpes simplex virus type or retrovirus such as HIV1, HIV2 etc.).
In other embodiments, the dosage regimen of chemical compound will comprise the inductive dose that application is high relatively shown in the formula 1,150-750mg/ days according to appointment, or adopted 150-750mg/ days based on batch (-type) administration schedule (schedule as described herein) approximately, after this adopt lower maintenance dose, 50-250mg/ days according to appointment, or based on batch (-type) administration schedule employing about 50-250mg/ days.These embodiments may further include the treatment or the another kind of therapy of the present invention of carrying out with formula 2A or 2B chemical compound.
The intestinal external preparation can contain cyclodextrin, for example alpha-cyclodextrin, beta-schardinger dextrin-(as β-hydroxypropyl cyclodextrin) or gamma-cyclodextrin, they generally are to use as aqueous compositions, wherein optionally contain one or more buffer agents, chemical compound shown in other excipient that salt (NaCl etc.), antibacterial or the affiliated field of solution isotonicity know and the formula 1 is provided, compound concentrations shown in the formula 1 is for example about 5-25mg/ml, about usually 10-20mg/ml.The intestinal external preparation that contains chemical compound shown in the formula 1 and one or more excipient can be diluted to as also injecting in the sterile saline individual.The intestinal external preparation normally through as intravenous, part or be administered orally to the individuality as the people.For non-water formulation, can adopt one or more solvents, as propylene glycol, PEG (as PEG 300 or PEG400), ethanol and benzyl benzoate.Typical moisture and non-water formulation will contain chemical compound shown in 5 to about 400mg/ml the formula 1 of having an appointment, the about 200mg/ml of about usually 10-.Such intestinal external preparation can oral administration or intramuscular, intravenous or subcutaneous injection carry.
In the preparation of compositions that contains chemical compound shown in the formula 1 (optional and one or more excipient), can grind this chemical compound or chemical compound is granulated with optional before or after one or more excipient contact at chemical compound shown in the formula 1, so that obtain desired particle size.For example, chemical compound is as 16 alpha-brominated epiandrosterones shown in can abrading type 1, obtain the particle mean size (or diameter) (for example about 2.5 or 10 μ M particle mean size or diameter) of about 0.5-25 μ M or about 1-10 μ M, subsequently chemical compound shown in the formula 1 of grinding is contacted with the liquid or solid excipient.Chemical compound makes chemical compound shown in the formula 1 be easy to be dissolved or suspended in one or more liquid excipients (as PEG (as PEG300), propylene glycol or benzyl benzoate) effectively shown in the formula 1 of grinding, and maybe promotes the uniform distribution of medicine when contacting when the chemical compound that grinds and one or more solid excipients (as filler, binding agent or lubricant).
One or more can effectively be treated or alleviate to compositions disclosed by the invention and preparation with described disease or infect relevant symptom.These compositionss and preparation also are applicable to treatment or alleviate one or more and the relevant symptom of retroviral infection (as people's HIV1 or HIV2 infection or people's malaria).Term of the present invention is meant as " alleviating one or more and ... relevant symptom ", described chemical compound or preparation can effectively reduce the quantity of duplicating or reduce the infective agent that exists in the individuality of infective agent, or alleviation and described disease or infect relevant or by its symptom that causes (for example bring down a fever, shorten pain time, the level that eases the pain or obviously reduce or eliminate diarrhoea or fatigue).
Except the above-mentioned component of mentioning especially, preparation of the present invention comprises that this field is usually used in other reagent in this type of preparation, and for example those of suitable oral administration can comprise correctives or coloring agent.
The present invention further provides veterinary composition, wherein contain at least a formula 1 or formula 2A or 2B chemical compound and carrier for animals.In addition, chemical compound shown in the formula 1 may reside in the feedstuff or water of animal.The veterinary can comprise the chemical compound that is not suitable for the mankind usually, for example minimum of chloroform with excipient.
Carrier for animals is to meet cat, Canis familiaris L., horse, mice, rat, hamster, rabbit or other animals administer purpose materials, and can be solid, liquid or gaseous matter, they are inertia in field for animals maybe can accept, and compatible with formula 1 or formula 2A or 2B chemical compound.These veterinary compositions can oral administration, intestinal external administration or by any other required administration, as by administration of the present invention.
In the embodiment that exemplifies, the human patient that is infected by HCV is given moisture grade and oozes alpha-cyclodextrin or beta-schardinger dextrin-(as β-hydroxypropyl cyclodextrin) preparation, said preparation contains dehydroepiandrosterone or 16 alpha-brominated epiandrosterone, the 10-20mg/ml according to appointment of the 5-30mg/ml that has an appointment.Said preparation with once-a-day or twice on the one through intravenous administration.To patient's administration is to amount to 4-10 days in 1-10mg/kg/ days, 5-30 days not administration subsequently, and after this rechallenge cyclodextrin formulations amounts to 4-10 days.This dosage regimen can repeat 1,2 or repeatedly.The clinical marker that monitoring HCV infects during treating, for example liver enzyme level (transaminase) in viral nucleic acid, blood or the blood plasma in blood or the blood plasma.For these patients, can choose approval beginning or the anti-HCB treatment of continuation standard (as interferon and/or virazole) that recommendation and this patient according to patient doctor obtain wantonly.In some such embodiments, chemical compound shown in the formula 1 is as continuous administration every day of the composition in oral or intestinal external administration compositions or the preparation, for example itself is chemical compound shown in the formula 1 of noval chemical compound.Also can choose wantonly dehydroepiandrosterone or 16 alpha-brominated epiandrosterone general administrations, for example wherein can utilize the preparation of embodiment 1 to amount to 1-4 month in every other day administration 1-5/mg/kg/ days, or utilize the administration every other day of a kind of oral formulations to amount to 1-4 in about 5-40mg/kg/ days individual month.
The embodiment of chemical compound shown in the formula 1 can comprise or not comprise any subclass of chemical compound shown in the formula 1, and condition is to keep at least a chemical compound.For example, usually effectively and a subclass of chemical compound shown in the formula 1 that usually comprises for example be the moisture or non-water formulation that contains 16 alpha-brominated epiandrosterones.Subclass chemical compound outside chemical compound shown in the optional formula of getting rid of in any embodiment of the present invention or claim 1 or its are used or chemical compound are used and comprised: such as disclosed already one or more chemical compounds (or its application) in one or more prior art lists of references or publication, its extent of disclosure causes chemical compound or purposes formula claim or embodiment to lose patentability on novelty, apparent property and/or creativeness.Another subclass of chemical compound shown in the formula 1 does not comprise that one or more have chemical compound shown in the active formula 1 of corticosteroid, chemical compound shown in one or more formulas 1 for example, wherein 3 are=O, the 4-5 position is two keys, a hydroxyl (OH) is bonded on 11-C (O)-CH 2OH and-H or-C (O)-CH 2OH and-OH or=O is bonded in 17, Q 6Be-CH 3Or-CH 2OH, Q 3Be-CH 3, all the other position (R 1) for for example-H and 0,1 or 2 hydroxyl.
In other embodiments, chemical compound shown in the formula 1 can be connected with oligonucleotide or oligonucleotide analogs so that make in this oligonucleotide or its analog transporte to cells.Usually, chemical compound shown in the formula 1 links to each other with steroid nucleus through oligonucleotide 5 ', 3 ' or 2 ' terminal hydroxyl.Oligonucleotide and oligonucleotide analogs known and for example be disclosed in United States Patent (USP) 4725677,4973679,4997927,4415732,4458066,5047524,4959463,5212295,5386023,, 5489677,5594121,5614622,5624621; With PCT open WO92/07864, WO96/29337, WO97/14706, WO97/14709, WO97/31009, WO98/04585 and WO98/04575, all these documents are hereby incorporated by.
Synthetic method is common, and the used chemical compound of the present invention can be synthetic in the known and understandable mode of one of ordinary skill in the art.Therefore, need not the used method of synthetic most these compounds is done to explain in detail.
At R 2Containing the known method that chemical compound is gone up substantially according to prior art shown in mercaptal part, sulfuric ester, sulfite, carbamate or the thioesters formula 1 partly on (3) prepares.Obviously will adopt the intermediate of due care.Referring to, for example United States Patent (USP) 5198432; Open EP576915 of European patent and EP576914; People such as C.Christiana " chemistry meeting will and chemical communication magazine " are 1991 the 22nd volumes (J.Chem.Soc.Chem.Commun.), people such as C.Christiana, " chemistry meeting will and chemical communication magazine " be 199119:1403-1405 (J.Chem.Soc.Chem.Commun.); People such as H.N.Abramson, " pharmaceutical science magazine " 1977 66:602-603; People such as E.J.Corey, " American Chemical Society's meeting will " is 1996 118:8765-8766 (J.Am.Chem.Soc.); People such as A.G.M.Barrett, " organic chemistry magazine " 1989 54:227; People such as D.H.R.Barton, " Englishize association magazine-Charles Bell study of the Chinese classic meeting collection of thesis 1 " (J.Chem.Soc.Perkin Trans.1) 1976 19:2112-2116; People such as D.H.R.Barton, people such as " Englishize association magazine-Charles Bell study of the Chinese classic meeting collection of thesis 1 " 1975 16:1574-1585 and W.T.Smith, Kansas State academy of science transactions (Trans.Kentucky Acad.Sci.) 1984 45:76-77, they all are incorporated herein by reference at this.
Exemplify embodiment aspect of the present invention and comprise the embodiment that hereinafter exemplifies, it further illustrates the present invention and preferred aspect or related subject.
1. a method for the treatment of the hepatitis C among the patient who needs this treatment comprises at least a chemical compound that is selected from The compounds of this invention of using effective dose to this patient.
2. one kind as enforcement mode 1 described method, further comprises to this patient and uses at least a chemical compound that increases plasma concentration.
3. one kind as enforcement mode 2 described methods, wherein at least a chemical compound of the present invention and at least a chemical compound administration simultaneously of increasing plasma concentration.
4. one kind as enforcement mode 2 described methods, and wherein at least a chemical compound of the present invention and at least a chemical compound of plasma concentration that increases are by the order administration.
5. one kind as the arbitrary described method of enforcement mode 1-4 wherein further comprise to this patient and use virazole and/or alpha-interferon.
6. one kind as the described method of the enforcement arbitrary mode of mode 1-5 further comprise to this patient and use at least a macrophage stimulation factor.
7. the described method of the arbitrary mode of embodiment 1-6 further comprises to this patient and uses one or more oxidants and/or oxygen supply.
8. one kind as implement the described method of the arbitrary mode of mode 1-7, wherein this patient is a mammal.
9. one kind as enforcement mode 8 described methods, and wherein this patient behaves.
10. described method of the arbitrary mode of embodiment 1-9, wherein administration is to be undertaken by injection.
11. one kind as the described method of the enforcement arbitrary mode of mode 1-9, wherein administration is to be undertaken by transfusion.
12. one kind as the described method of the enforcement arbitrary mode of mode 1-9, wherein administration is to be undertaken by intravenous injection.
13. one kind as enforcement mode 2 described methods, the wherein said chemical compound that increases plasma concentration is naringin or naringenin.
14. a method that reduces at least a transaminase level among the patient who carries hepatitis C virus who needs this treatment comprises at least a The compounds of this invention of using effective dose to this patient.
15. one kind as enforcement mode 14 described methods, wherein further comprise to this patient and use at least a chemical compound that increases plasma concentration.
16. one kind as enforcement mode 14 described methods, wherein at least a chemical compound of the present invention and at least a chemical compound administration simultaneously of increasing plasma concentration.
17. one kind as enforcement mode 15 described methods, wherein said at least a chemical compound of the present invention and the described at least a chemical compound of plasma concentration that increases are by the order administration.
18. one kind as the described method of enforcement mode 14-17 further comprise to this patient and use virazole and/or interferon-alpha.
19. one kind as the described method of the enforcement arbitrary mode of mode 14-18 further comprise to this patient and use at least a macrophage stimulation factor.
20. the described method of the arbitrary mode of embodiment 14-19 further comprises to this patient and uses one or more oxidants and/or oxygen ventilation.
21. one kind as the described method of the enforcement arbitrary mode of mode 14-20, wherein this patient is a mammal.
22. one kind as enforcement mode 21 described methods, wherein this patient behaves.
23. the described method of the arbitrary mode of embodiment 14-22, wherein administration is to be undertaken by injection.
24. one kind as the described method of the enforcement arbitrary mode of mode 14-22, wherein administration is to be undertaken by transfusion.
25. one kind as the described method of the enforcement arbitrary mode of mode 14-22, wherein administration is to be undertaken by intravenous injection.
26. one kind as enforcement mode 15 described methods, the wherein said chemical compound that increases plasma concentration is naringin or naringenin.
27. a method for the treatment of the togavirus among the patient who needs this treatment comprises at least a The compounds of this invention that gives this patient's effective dose.
28. one kind as enforcement mode 27 described methods, wherein further comprise to this patient and use at least a chemical compound that increases plasma concentration.
29. one kind as enforcement mode 28 described methods, wherein said at least a chemical compound of the present invention and described at least a chemical compound administration simultaneously of increasing plasma concentration.
30. one kind as enforcement mode 28 described methods, wherein said at least a chemical compound of the present invention and the described at least a chemical compound of plasma concentration that increases are by the order administration.
31. one kind as the described method of enforcement mode 27-30 further comprise to this patient and use virazole and/or interferon-alpha.
32. one kind as the described method of the enforcement arbitrary mode of mode 27-31 further comprise to this patient and use at least a macrophage stimulation factor.
33. the described method of the arbitrary mode of embodiment 27-32 further comprises to this patient and uses one or more oxidants and/or oxygen supply.
34. one kind as the described method of the enforcement arbitrary mode of mode 27-33, wherein this patient is a mammal.
35. one kind as enforcement mode 34 described methods, wherein this patient behaves.
36. the described method of the arbitrary mode of embodiment 27-35, wherein administration is to be undertaken by injection.
37. one kind as the described method of the enforcement arbitrary mode of mode 27-35, wherein administration is to be undertaken by transfusion.
38. one kind as the described method of the enforcement arbitrary mode of mode 27-35, wherein administration is to be undertaken by intravenous injection.
39. one kind as enforcement mode 28 described methods, the wherein said chemical compound that increases plasma concentration is naringin or naringenin.
40. one kind as enforcement mode 27 described methods, wherein said togavirus is an alphavirus.
41. one kind as enforcement mode 27 described methods, wherein said togavirus is a Flavivirus.
42. one kind as enforcement mode 41 described methods, wherein said banzi virus is a hepatitis G virus.
43. one kind as enforcement mode 41 described methods, wherein said banzi virus is a yellow fever virus.
44. one kind as enforcement mode 27 described methods, wherein said togavirus is a rubella virus genus.
45. one kind as enforcement mode 44 described methods, wherein said rubella virus genus is a rubella virus.
46. one kind as enforcement mode 27 described methods, wherein said togavirus is a Pestivirus.
47. one kind as enforcement mode 46 described methods, wherein said Pestivirus is bovine viral diarrhea virus (BVDV).
48. the method for any embodiment 1-47, wherein said chemical compound of the present invention are chemical compound shown in the formula 1 or its metabolite.
49. the method for embodiment 48, chemical compound shown in its Chinese style 1 are the chemical compounds in chemical compound group 1-21 name, or the present invention is open or any formula 1 of name shown in chemical compound (as any formula 4 chemical compounds) or this compounds, or its metabolite.
50. compositions, contain 16 alpha-brominated epiandrosterones and 2,3,4 or 5 kind of excipient that is selected from Polyethylene Glycol, dewatered ethanol, benzyl benzoate, benzylalcohol and propylene glycol, wherein said composition contains and is less than about 3%v/v or is less than about 1%v/v or is less than about 0.5%v/v or is less than the water of about 0.1%v/v.
51. the compositions of embodiment 50, wherein said composition contains the 16 alpha-brominated epiandrosterones that (i) concentration is about 45-55mg/mL, (ii) 20-30%v/v Liquid Macrogol, PEG400 or Liquid Macrogol and 400 mixture, (iii) 10-15%v/v dewatered ethanol, 2.5-7.5%v/v benzyl benzoate and (iv) 55-60%v/v propylene glycol.
52. the compositions of embodiment 51, wherein said composition contains 16 alpha-brominated epiandrosterones, about 25%v/v Liquid Macrogol, about 12.5%v/v dewatered ethanol, about 5%v/v benzyl benzoate, about 57.5%v/v propylene glycol that concentration is about 50mg/ml and the water that is less than about 0.5%v/v.
53. the compositions of embodiment 50, wherein said composition contains 16 alpha-brominated epiandrosterones, about 27-33%w/w benzyl benzoate, about 27-33%w/w Liquid Macrogol, about 25-30%w/w propylene glycol and the about 1-3%w/w benzylalcohol that concentration is about 50-105mg/ml.
54. the compositions of embodiment 53, wherein said composition contains the 16 alpha-brominated epiandrosterones that concentration is about 100mg/ml (about 10%w/w), about 30.4%w/w benzyl benzoate, about 30.7%w/w Liquid Macrogol, about 28%w/w propylene glycol and about 1.9%w/w benzylalcohol.
55. the product that this method that is contacted with liquid excipient by 16 alpha-brominated epiandrosterones prepares, wherein this product contains the water that is less than 3%w/w, and condition is that liquid excipient is not chloroform, dimethyl sulfoxide, olive oil or vegetable oil.
56. the product of embodiment 55, wherein liquid excipient is Polyethylene Glycol, dewatered ethanol, benzyl benzoate, benzylalcohol and propylene glycol, and wherein this product contains and is less than about 3%v/v or is less than about 1%v/v or is less than the water of about 0.5%v/v.
57. chemical compound shown in the formula 1 is used for the treatment of application in the medicine of the infection that is caused by one or more togavirus in preparation in individuality.
58. the application of embodiment 57, chemical compound shown in its Chinese style 1 are chemical compound or its metabolites of naming in chemical compound 1-21.
59. a method that improves the oral administration biaavailability of therapeutic agent comprises formula 2A or the 2B chemical compound of using effective dose to individuality.
60. the method for embodiment 59, wherein said therapeutic agent are steroid, steroid class analog, antibiotic, antiviral drugs (for example nucleoside, nucleoside analog, nucleotide analog, protease inhibitor or AG14361) or antifungal (as amphotericin B).
61. the method for embodiment 59, wherein said therapeutic agent are the chemical compounds of formula 1.
62. a method comprises to suffering from or easily suffer from the arbitrary described compositions of embodiment 50-54 that individuality that togavirus infects (as HCV) is used effective dose.
63. the method for embodiment 62, wherein this individuality is that optional being reversed of people and this people recorded virus (as HIV1 or HIV2) coinfection.
64. alleviate or alleviate in the individuality with togavirus and infect one or more relevant symptoms or reduce the method that togavirus duplicates in the individuality that is infected by togavirus for one kind, comprise to this individuality and use chemical compound shown in the formula 1 of effective dose.
65. the method for embodiment 64, chemical compound shown in its Chinese style 1 is a kind of or belongs to class chemical compound disclosed by the invention, for example in chemical compound group 1-21 or an a kind of or compounds of in initial claims of submitting to, naming, or chemical compound shown in the formula 1 is present in the compositions that contains one or more pharmaceutical excipients the preparation that for example any the present invention discloses or illustrates.
66. compositions that contains chemical compound shown in the formula 1 and at least a excipient and local anesthetic, chemical compound shown in its Chinese style 1 is a kind of or belongs to class chemical compound disclosed by the invention, for example in chemical compound group 1-21 or an a kind of or compounds of naming in initial claims of submitting to, wherein local anesthetic is selected from procaine, benzocaine and lignocaine.
67. product, its preparation method is to make any chemical compound of naming among chemical compound shown in the formula 1 such as the chemical compound group 1-21 contact with second excipient with first excipient, wherein this product is optional further contains local anesthetic, and wherein this local anesthetic is selected from procaine, benzocaine and lignocaine.
68. product, it makes each method is to make any chemical compound of naming among chemical compound shown in the formula 1 such as the chemical compound group 1-21 contact with the second on-aqueous liquid excipient with the first on-aqueous liquid excipient, wherein this product contains the water that is less than about 3%w/w, or be less than about 0.5%w/w, or be less than the water of about 0.1%w/w, and wherein first the or second on-aqueous liquid excipient is chosen wantonly and is got rid of dimethyl sulfoxide, chloroform, dioxane, one or more of vegetable oil and olive oil, and wherein this product is optional further contains local anesthetic, and wherein said local anesthetic is selected from procaine, benzocaine and lignocaine.
69. method, comprise to the individuality of suffering from above-mentioned infection or disease such as HCV and use the compositions of embodiment 66 of effective dose or the product of embodiment 67 or 68, eliminate thus, alleviate, treat, improve or alleviate described infection or disease or their symptom.
70. the method for embodiment 69, chemical compound shown in its Chinese style 1 are 16 alpha-halogen epiandrosterones or 16 alpha-halogen dehydroepiandrosterones.
Embodiment
The following example further illustrates the present invention and does not constitute limitation of the invention.
The non-water formulation that embodiment 1.16 alpha-brominated epiandrosterone preparation 1. preparations are two batches, wherein the concentration of 16 alpha-brominated epiandrosterones (" BrEA ") in 25% Liquid Macrogol, 12.5% dehydrated alcohol, 5% benzyl benzoate and 57.5% propylene glycol is 50mg/ml, and after this this is called " preparation 1 ".BrEA derives from Procyte, Inc..Remaining excipient is as follows:
Excipient specification supplier end-product concentration
Lot number
Propylene glycol USP Arco Chemical 57.5% (v: v)
HOC-61220-01104 Liquid Macrogol NF Union Carbide 25% (v: v)
695752
Absolute alcohol USP McCormick Distilling 12.5% (v: v)
(ethanol) 97K10 benzyl benzoate USP Spectrum 5% (v: v)
Parmaceuticals
MG025
Said preparation is to prepare by following steps: BrEA is suspended in the Liquid Macrogol, adds propylene glycol, benzyl benzoate and dehydrated alcohol subsequently to form solution, be diluted to predetermined final volume with other propylene glycol.Method is as described below.
The polypropylene glycol 300 of amount of calculation is added in the proportion container.Subsequently,, in this container, add the BrEA of amount of calculation, and mix at least and formed non-caking emulsion liquid in 5 minutes in the blended while.In container, add propylene glycol, mix forming uniform suspension in 5 minutes at least.In container, add the benzyl benzoate of amount of calculation, mix generating translucent suspension in about 5 minutes.In this container, add absolute alcohol, mix generating clear colorless solution in about 5 minutes.Add propylene glycol subsequently to obtain final required preparation, mixed about 5 minutes.This drug solution is transferred in the volume separate loading device, be set in and transmit the 1.2mL/ bottle.Under nitrogen pressure,, divide in the amber glass bottle of the 2cc that packs into then continuously through two 0.2 these solution of μ m polyvinylidene fluoride membrane filtration.With butyl rubber gag with poly tetrafluoroethylene coating on bottle and sealed.
Material used in the product bottle is as described below.Material source product coding explanation bottle Wheaton 2702-B51BA Tubing Vial, 2mL/13mm glass, the amber stopper Omniflex of 1 type V9239 FM257/2 13mm, politef coats, butyl rubber bung sealing West 4107 seamings, 13mm, the smoky gray bridge joint
2. 1 kinds of preparations of embodiment 2.BrEA preparation contain the BrEA (10%w/w) of 100mg/mL, it is present in 30.4%w/w benzyl benzoate (USP), 30.7%w/w Liquid Macrogol (NF), about 28%w/w propylene glycol (USP) and the 1.9%w/w benzylalcohol (NF), and this formulation preparation that after this is called " preparation 2 " is as follows.The BrEA (1.0kg) of scheduled volume is suspended among the PEG300 (about 3.0L) that is present in the proportion container, formed even emulsion liquid in 5 minutes in mixed at room temperature at least subsequently.After this add the propylene glycol (about 1.5L) and continuous the mixing at least 5 minutes of necessary amount, form uniform suspension.Add benzyl benzoate (about 3.0L), container contents was mixed about 5 minutes, generate a kind of translucent suspension.Add benzylalcohol (about 200ml), continue to mix about 5 minutes generation clear colorless solutions.Add propylene glycol subsequently to obtain final required dose volume (about 1.5L), mixed continuously about 5 minutes.This drug solution is transferred in the volume distribute type device, be set in and transmit 1.2mL/ bottle (2ml, glass, 1 type amber bottle).Under nitrogen pressure, before distributing continuously through two 0.2 these solution of μ m polyvinylidene fluoride membrane filtration.With butyl rubber gag with poly tetrafluoroethylene coating on bottle and basically according to embodiment 1 described sealed.Bottle is deposited under the lucifuge low temperature (about 2-8 ℃).
Embodiment 3. human clinical trials.Clinical trial protocol comprises the patient of about 15-20 name.In Phase I or I/II test, the patient is infected by one or more togavirus (as HCV) appropriateness and they symptom moderately occurs.The patient accepts the treatment in 1,2 or 3 weeks.In the patient takes medicine 3,4 or 5 days of week, outside intestinal (as intramuscular or intravenous injection) give two or more dosage groups, for example 25,50 or 100mg/ days 16 alpha-brominated epiandrosterone (BrEA) or its esters.Administration is to carry out in successive a couple of days or take the batch (-type) schedule to carry out, for example 2,3 or 4 dosage of administration and every administration in 1 day 1 time.The preparation that contains BrEA is a preparation described herein, for example embodiment 1 or 2 preparation, the preparation of preferred embodiment 2.Treatment when in week and after this 1,2,3 or more a plurality of week in, regularly get blood and be used for assessment infection or its symptom, pharmacokinetics, the blood cell factor (for example IL-2, IL-4, IL-10, IGF1, γ IFN, GM-CSF) and the cell within a cell factor (for example IL-2, IL-4, IL-10, IGF1, γ IFN, GM-CSF).About 2-12 chose wantonly once more and uses and the same or analogous scheme treatment of first administration scheme patient during week after first administration.

Claims (37)

  1. One kind in suffering from or easily suffer from the individuality that togavirus infects treatment or prevention togavirus infect or alleviate or alleviate the method for one or more symptoms that togavirus infects, this method comprise to described individuality use chemical compound shown in the formula 1 of effective dose and
    Their salt, stereoisomer, position isomer, metabolite, analog, precursor, hydrate, tautomer, ionization form and solvate
    Figure A9981365800021
    Wherein
    Q 1Be-C (R 1) 2-or-C (O)-;
    Q 2Be-C (R 1) 2-,-C (R 1) (Y)-,-C (Y)-or-CH 2-CH 2-;
    Q 3Be-H or-C (R 1) 3-;
    Q 4Be-C (R 1) 2-,-C (O)-, hydroxyl ethenylidene or methyl methylene;
    Q 5Be-C (R 1) 2-or-C (O)-;
    X and Y be independently-OH ,-H, low alkyl group ,-O-C (O)-R 5,-C (O)-OR 5, halogen or=O;
    Each R 1Be independently-H, halogen ,-OH, C 1-6Alkoxyl or C 1-6Alkyl;
    R 2Be-H ,-OH, halogen, C 1-6Alkyl, C 1-6Alkoxyl ,-OR 3, ester, thioesters, mercaptal, sulfuric ester, sulphonic acid ester or carbamate or R 2With the R that is bonded on the same carbon atom 1Be together=O;
    R 3Be-S (O) (O)-OM ,-S (O) (O)-O-CH 2-CH (O-C (O)-R 6)-CH 2-O-C (O)-R 6,-P (O) (O)-O-CH 2-CH (O-C (O)-R 7)-CH 2-O-C (O)-R 7, the glucuronyl-shown in the structure (A):
    Or R 3Be C 1-18Alkyl, C 2-18Alkenyl, C 2-18Alkynyl, C 1-18Ester or C 1-18Thioesters, wherein above-mentioned any C 1-18Or C 2-18Part at one or more hydrogen atoms place optional by one or more independent select-OR PR,-NHR PROr-SR PRGroup replaces; Or R 3Be C 1-18Fatty acid, C 2-10Alkynyl, (J) n-phenyl-C 1-5-alkyl, (J) n-phenyl-C 2-5-alkenyl;
    Each R 5Be straight or branched C independently 1-14Alkyl;
    Each R 6Be straight or branched C independently 1-14Alkyl;
    Each R 7Be straight or branched C independently 1-14Glucuronyl-shown in alkyl or the structure (A);
    Each R PRBe independently-H or the independent protecting group of selecting;
    N is 0,1,2 or 3;
    Each J is halogen, C independently 1-4Alkyl, C 2-4Alkenyl, C 1-4Alkoxyl, carboxyl, nitro, sulfate, sulfonyl, C 1-6Carboxylate or C 1-6Sulfuric ester;
    M be hydrogen, sodium ,-S (O) (O)-O-CH 2-CH (O-C (O)-R 6)-CH 2-O-C (O)-R 6,-P (O) (O)-O-CH 2-CH (O-C (O)-R 7)-CH 2-O-C (O)-R 7Or the glucuronyl-shown in the structure (A); With
    Dotted line represents that two keys of choosing wantonly, condition are not have two keys at 4-5 and 5-6 position, and condition is when pair keys exist, 0 or 1 R 1Be bonded on 1-, 2-, 4-, 5-, 6-or 17 s' the carbon atom so that these carbon atoms become tetravalence.
  2. 2. the process of claim 1 wherein that the togavirus infection is one or more during flaviviridae infections, pestivirus infection, rubella virus infection or Alphavirus infect.
  3. 3. the method for claim 2, chemical compound shown in its Chinese style 1 is one or more chemical compounds that are selected from chemical compound group 1-21.
  4. 4. it is by one or more infection of causing of influenza virus down that the method for claim 2, wherein said togavirus infect: hepatitis C virus, hepatitis G virus, california antigenic group viruses, Saint Louis type encephalitis, western equine encephalitis virus, Eastern equine encephalitis virus, colorado tick fever virus, LaCrosse's encephalitis, Japanese encephalitis virus, yellow fever virus, Venezuelan equine encephalitis virus, Murray Valley encephalitis, first type GB virus, B-mode GB virus, the third type GB virus, dengue virus 1, dengue virus 2, dengue virus 3, dengue virus 4, Semliki Forest virus, people rubella virus and bovine viral type diarrhea virus.
  5. 5. the method for claim 4, chemical compound shown in its Chinese style 1 is one or more chemical compounds that are selected from chemical compound group 1-21.
  6. 6. the method for claim 4, wherein to infect be the infection that is caused by HCV, HGV, yellow fever virus, rubella virus or bovine viral diarrhea virus to togavirus.
  7. 7. the method for claim 5, wherein said individuality is people or primate.
  8. 8. the method for claim 7, chemical compound shown in its Chinese style 1 is one or more chemical compounds that are selected from chemical compound group 1-21.
  9. 9. the method for claim 8, chemical compound shown in its Chinese style 1 is 16 alpha-brominated-3 beta-hydroxy-5 α-androstane-17-ketone or 16 alpha-brominated dehydroepiandrosterones.
  10. 10. the process of claim 1 wherein that described individuality is reversed the viral coinfection of record.
  11. 11. the method for claim 10, wherein said individuality are people and retrovirus is HIV1 or HIV2.
  12. 12. the process of claim 1 wherein that chemical compound has structural formula 1B or 1C shown in the formula 1:
    Figure A9981365800051
    Wherein
    Each R 1Be independently-H ,-OH, halogen ,-CHCH 2,-CHCHCH 3,-CCH ,-CCCH 3Or R 1Hydrogen atom on being bonded in identical carbon atoms constitutes=O;
    R 2Be-O-C (O)-R 4,-S-C (O)-R 4,-O-S (O) (O)-R 4,-O-S (O) (O)-OR 4,-O-C (O)-NHR 4Or-O-C (S)-R 4
    R 4Be-H, protecting group, the optional C that replaces 1-18Alkyl, the optional C that replaces 1-18Alkenyl, the optional C that replaces 1-18Alkynyl, the optional aryl that replaces, the optional aryl-C that replaces 1-6Alkyl, the optional aryl-C that replaces 2-6Alkenyl, the optional aryl-C that replaces 2-6Alkynyl, the optional heterocycle-C that replaces 1-6Alkyl, the optional C that replaces 2-6Alkenyl-heterocycle, the optional C that replaces 2-6Alkynyl-heterocycle or the optional heterocycle that replaces, wherein any above-mentioned part in one or more carbon or hydrogen atom position optional by one or more independent group or atoms of selecting :-O-,-S-,-NR PR,-OR PR,-NHR PR,-SR PR,=O ,=S ,=N-OH ,-CN ,-NO 2,-F ,-Cl ,-Br or-I replaces;
    Each R PRBe independently-H or the independent protecting group of selecting;
    Q 2Be-C (R 1) 2-; With
    Q 3And Q 6Be independently-H ,-CH 3Or-CH 2OH.
  13. 13. the method for claim 12, wherein Q 3And Q 6Be simultaneously beta comfiguration-CH 3With
    Q 2Be-CH 2-,-C (O)-,-CH (Br)-,-CH (I)-or-CH (OH)-, Br wherein, I or OH are the α configuration, or Q 2Contain-C (O)-or-CH 2-CH 2-; With
    7 R 1Be-H ,-OH or, when when being bonded in hydrogen atom on the identical carbon atoms and lumping together, R 1Be=O.
  14. 14. the process of claim 1 wherein that chemical compound has structural formula 1A shown in the formula 1
    Wherein:
    R 2Be-OH, halogen, C 1-6Alkoxyl ,-OR 3, C 1-18Fatty acid, C 1-10Alkynyl, (J) n-phenyl-C 1-5-alkyl, (J) n-phenyl-C 1-5-thiazolinyl is selected from-O-C (O)-(CH 2) m-R 4With-C (O)-O-(CH 2) m-R 4Ester, or R 2Be-S-C (O)-(CH 2) m-R 4,-C (O)-S-(CH 2) m-R 4,-O-S (O) (O)-(CH 2) m-R 4,-O-S (O) (O)-O-(CH 2) m-R 4,-O-C (O)-NH-(CH 2) m-R 4,-NH-C (O)-O-(CH 2) m-R 4,-O-C (S)-(CH 2) m-R 4,-C (S)-O-(CH 2) m-R 4,-O-C (O)-(CH 2) m-R 4Or-C (O)-O-(CH 2) m-R 4Or R 2With the R that is bonded on the identical carbon atoms 1Be together=O;
    R 4Be-H, protecting group, the optional C that replaces 1-18Alkyl, the optional C that replaces 2-18Alkenyl, the optional C that replaces 2-18Alkynyl, the optional aryl that replaces, the optional aryl-C that replaces 1-6Alkyl, the optional aryl-C that replaces 2-6Alkenyl, the optional aryl-C that replaces 2-6Alkynyl, the optional heterocycle-C that replaces 1-6Alkyl, the optional C that replaces 2-6Alkenyl-heterocycle, the optional C that replaces 2-6Alkynyl-heterocycle or the optional heterocycle that replaces, wherein any above-mentioned part 1,2,3,4,5 or more a plurality of carbon or the hydrogen atom position is optional is replaced by one or more independent following groups of selecting or atom :-O-,-S-,-NR PR,-OR PR,-NHR PR,-SR PR,=O ,=S ,-CN ,-NO 2,-F ,-Cl ,-Br or-I;
    Each R PRBe independently-H or the independent protecting group of selecting;
    M is 0,1,2 or 3; With
    Dotted line is optional two keys.
  15. 15. the process of claim 1 wherein that chemical compound has structural formula 45 shown in the formula 1
    Wherein
    R 50Be-H ,-OH or=O;
    R 51Be for-Br ,-Cl ,-F ,-I or-OH;
    R 52Be-OH or, R 52On being bonded in identical carbon atoms-H is=O;
    R 49Be-H ,-OH or-OR 53
    R 53Be C 1-18Alkyl, C 2-18Alkenyl, C 2-18Alkynyl, C 1-18Ester, C 1-18Thioesters, wherein above-mentioned arbitrary C 1-18And C 2-18Group is replaced by one or more independent following groups of selecting in one or more hydrogen atoms position :-O-,-S-,-OH ,-NH 2,-SH or=O, or R 53Be mercaptal, sulfuric ester, sulphonic acid ester, carbamate or sulfur ester; With
    Dotted line is two keys of choosing wantonly.
  16. 16. the method for claim 15, wherein R 49Be-O-C (O)-CH 2-CH 2-CH (R 54)-CH (R 55)-CH 2R 56, R wherein 54Be-NH 2,-OH ,-SH ,-O-PO 3, SO 3Or-OSO 3R 55Be-H ,-NH 2,-OH ,-SH ,-O-PO 3,-SO 3Or-OSO 3And R 56Be C 1-18Alkyl, C 2-18Alkenyl, C 2-18Alkynyl, C 1-18Ester or C 1-18Thioesters, wherein above-mentioned arbitrary C 1-18Group in one or more hydrogen atoms position by one or more independent select-OH ,-NH 2,-SH or=the O group replaces.
  17. 17. the process of claim 1 wherein that chemical compound has structural formula 44 shown in the formula 1
    Figure A9981365800072
    Wherein
    Y is a hydrogen or halogen;
    R 44For-H ,-S (O) (O)-OH ,-S (O) (O)-ONa ,-S (O) (O)-O-CH 2-CH (O-C (O)-R 6)-CH 2-O-C (O)-R 6,-P (O) (O)-O-CH 2-CH (O-C (O)-R 7)-CH 2-O-C (O)-R 7Or the glucuronyl-shown in the structure (A); With
    The optional two keys of dotted line representative.
  18. 18. the method for claim 17, wherein chemical compound shown in the structural formula 44 is dehydroepiandrosterone, epiandrosterone, 16 alpha-brominated epiandrosterones, 16 alpha-brominated dehydroepiandrosterones, dehydroepiandrosterone-3-sulfuric ester or 5-3 β-alcohol-17-ketone.
  19. 19. the method for claim 1; wherein this method further comprises simultaneously or the suitable chemical compound that increases plasma concentration of using effective dose, and the described chemical compound that increases plasma concentration is selected from the chemical compound that methyl is mended bone ester first plain A, monarda glycoside, flavanomarcin, flavanone azine, flavanone diacetyl hydrazone, Flavanone hydrazone, silicon androsin, silymarin, Silychristin, different silybum marianum, had structure (E):
    Figure A9981365800081
    With the chemical compound shown in structural formula 2A or the 2B:
    Figure A9981365800091
    Wherein have two keys or singly-bound at the dotted line place and when two keys exist (i) have the phenyl ring of optional replacement in 2-or 3-position and do not have R with described bond with carbon 8And (ii) there is not a R at adjacent 2-or 3-position 8
    X 1Be-O-or-C (R 8) 2-;
    X 2Be-C (O)-or-C (R 11) 2-;
    Each R 8Be independently-H ,-OH, halogen, C 1-6Alkyl, C 1-6Alkoxyl, glucosiduronic acid, C 1-25In fatty acid, formula 2A or the 2B chemical compound hydrogen atom be removed with the residue that forms formula 2A or 2B chemical compound free radical ,-CH 2CH=C (CH 3) 2, glucoside, have structural formula (B) or group (C),
    Figure A9981365800092
    R 9Be phenyl-(R 8) 5, one of them R 9Be bonded in 2-or 3-position, but two R 9Be not bonded in simultaneously on 2-position or the 3-position;
    R 10Be C 1-6Alkyl, C 1-6Alkoxyl, neohesperidoside, Herba Apii graveolentis glucosides, rutinoside, glucoside, galactoside, rhamnoside, arabinose glucosides, or stereoisomer, hydrate, analog, derivant or the metabolite of any of these part, any one in them be optional quilt-OH, halogen, C on one or more hydrogen atoms independently 1-6Alkyl, C 1-6Alkoxyl, glucosiduronic acid or C 1-25Fatty acid replaces or R 10Be-H ,-OH or halogen;
    Each R 11Be independently-H ,-OH, halogen, C 1-6Alkyl, C 1-6Glucuronyl-or C shown in alkoxyl, the structure (A) 1-25Fatty acid, or two R 11Be combined into=O; With
    Their salt, stereoisomer, position isomer, metabolite, analog, precursor, hydrate, tautomer, ionization form and solvate.
  20. 20. the method for claim 19, the chemical compound that wherein increases plasma concentration are naringin or naringenin.
  21. 21. the method for claim 20, wherein said individuality are people or primate.
  22. 22. the method for claim 21, chemical compound shown in its Chinese style 1 is administration simultaneously with the chemical compound that increases plasma concentration.
  23. 23. the method for claim 19 further comprises to individuality and using, or adopts one or more treatments in virazole, alpha-interferon, macrophage stimulation factor, oxidant and the oxygen supply individual.
  24. 24. the method for claim 23, the chemical compound that wherein increases plasma concentration are naringin or naringenin.
  25. 25. the method for claim 24, wherein individuality is people or primate.
  26. 26. the method for claim 25, chemical compound shown in its Chinese style 1 is administration simultaneously with the chemical compound that increases plasma concentration.
  27. 27. a method that improves the oral administration biaavailability of therapeutic agent is comprising using the chemical compound that increases plasma concentration of effective dose for described individuality.
  28. 28. the method for claim 27, the wherein said chemical compound that increases plasma concentration is naringin or naringenin, or have structure shown in formula 2A or the 2B the chemical compound that increases plasma concentration and
    Their salt, stereoisomer, position isomer, metabolite, analog, precursor, hydrate, tautomer, ionization form and solvate:
    Figure A9981365800111
    Wherein the dotted line place exists two keys or singly-bound, when two keys exist (i) exist in 2-or 3-position the optional phenyl ring that replaces and with the R of described bond with carbon 8Do not exist, and (ii) do not have a R at adjacent 2-or 3-position 8
    X 1Be-O-or-C (R 8) 2-;
    X 2Be-C (O)-or-C (R 11) 2-;
    Each R 8Be independently-H ,-OH, halogen, C 1-6Alkyl, C 1-6Alkoxyl, glucosiduronic acid, C 1-25Fatty acid, one of them hydrogen atom be removed the formula 2A of the free radical that forms formula 2A or 2B chemical compound or 2B chemical compound residue ,-CH 2CH=C (CH 3) 2, glucoside, have structural formula (B) or group (C),
    Figure A9981365800112
    R 9Be-phenyl-(R 8) 5, one of them R 9Be bonded in 2-or 3-position, but two R 9Be not bonded in 2-and 3-position simultaneously;
    R 10Be C 1-6Alkyl, C 1-6Stereoisomer, hydrate, analog, derivant or the metabolite of alkoxyl, neohesperidoside, Herba Apii graveolentis glucosides, rutinoside, glucoside, galactoside, rhamnoside, arabinose glucosides or any of these part, any one in them are optional independently by-OH, halogen, C on one or more hydrogen atoms 1-6Alkyl, C 1-6Alkoxyl, glucosiduronic acid or C 1-25Fatty acid replaces, or R 10Be-H ,-OH or halogen;
    Each R 11Be independently-H ,-OH, halogen, C 1-6Alkyl, C 1-6Glucuronyl-or C shown in alkoxyl, the structure (A) 1-25Fatty acid, or two R 11Be combined into=O.
  29. 29. the method for claim 27, wherein therapeutic agent is steroid, steroid class analog, antibiotic, antiviral agent or antifungal.
  30. 30. the method for claim 27, wherein therapeutic agent be chemical compound shown in the formula 1 and
    Their salt, stereoisomer, position isomer, metabolite, analog, precursor, hydrate, tautomer, ionization form and solvate:
    Figure A9981365800121
    Wherein
    Q 1Be-C (R 1) 2-or-C (O)-;
    Q 2Be-C (R 1) 2-,-C (R 1) (Y)-,-C (Y)-or-CH 2-CH 2-;
    Q 3Be-H or-C (R 1) 3-;
    Q 4Be-C (R 1) 2-,-C (O)-, hydroxyl ethenylidene or methyl methylene;
    Q 5Be-C (R 1) 2-or-C (O)-;
    X and Y be independently-OH ,-H, low alkyl group ,-O-C (O)-R 5,-C (O)-OR 5, halogen or=O;
    Each R 1Be independently-H, halogen ,-OH, C 1-6Alkoxyl or C 1-6Alkyl;
    R 2Be-H ,-OH, halogen, C 1-6Alkyl, C 1-6Alkoxyl ,-OR 3, C 1-8Fatty acid, C 1-10Alkynyl, (J) n-phenyl-C 1-5-alkyl, (J) n-phenyl-C 1-5-alkenyl, ester, thioesters, mercaptal, sulfuric ester, sulphonic acid ester or carbamate or R 2With the R that is bonded on the same carbon atom 1Be together=O;
    R 3Be-S (O) (O)-OM ,-S (O) (O)-O-CH 2-CH (O-C (O)-R 6)-CH 2-O-C (O)-R 6,-P (O) (O)-O-CH 2-CH (O-C (O)-R 7)-CH 2-O-C (O)-R 7, the glucuronyl-shown in the structure (A):
    Figure A9981365800131
    Or R 3Be C 1-18Alkyl, C 1-18Alkenyl, C 1-18Alkynyl, C 1-18Ester or C 1-18Thioesters, wherein above-mentioned any C 1-18Part at one or more hydrogen atoms place optional by one or more independent select-OH ,-NH 2Or-replacement of SH group;
    Each R 5Be straight or branched C independently 1-14Alkyl;
    Each R 6Be straight or branched C independently 1-14Alkyl;
    Each R 7Be straight or branched C independently 1-14Glucuronyl-shown in alkyl or the structure (A);
    N is 0,1,2 or 3;
    Each J is halogen, C independently 1-4Alkyl, C 1-4Alkenyl, C 1-4Alkoxyl, carboxyl, nitro, sulfate, sulfonyl, C 1-6Carboxylate or C 1-6Sulfuric ester;
    M be hydrogen, sodium ,-S (O) (O)-O-CH 2-CH (O-C (O)-R 6)-CH 2-O-C (O)-R 6,-P (O) (O)-O-CH 2-CH (O-C (O)-R 7)-CH 2-O-C (O)-R 7Or the glucuronyl-shown in the structure (A); With
    Dotted line represents that two keys of choosing wantonly, condition are not have two keys at 4-5 and 5-6 position, and condition is when pair keys exist, 0 or 1 R 1Be bonded on 1-, 2-, 4-, 5-, 6-or 17 s' the carbon atom so that these carbon atoms become tetravalence.
  31. 31. treatment or prevention treatment or prevention togavirus in suffering from or easily suffer from the individuality that togavirus infects infect, or alleviate or alleviate the method that infects one or more relevant symptoms with togavirus, this method comprises the compositions of using effective dose to described individuality, said composition contains 16 alpha-brominated epiandrosterones and 2,3,4 or 5 kind be selected from Polyethylene Glycol, dewatered ethanol, benzyl benzoate, the excipient of benzylalcohol and propylene glycol, wherein said composition is chosen wantonly to contain and is less than about 3%v/v, or be less than about 1%v/v, or be less than about 0.5%v/v, or be less than the water of about 0.1%v/v.
  32. 32. the method for claim 31, wherein said compositions contains the 16 alpha-brominated epiandrosterones that concentration is about 45-55mg/mL, 20-30%v/v Liquid Macrogol, PEG400 or Liquid Macrogol and 400 mixture, 10-15%v/v dewatered ethanol, 2.5-7.5%v/v benzyl benzoate and 55-60%v/v propylene glycol.
  33. 33. the method for claim 32, wherein said compositions contain 16 alpha-brominated epiandrosterones, about 25%v/v Liquid Macrogol, about 12.5%v/v dewatered ethanol, about 5%v/v benzyl benzoate, about 57.5%v/v propylene glycol that concentration is about 50mg/ml and the water that is less than about 0.5%v/v.
  34. 34. the method for claim 31, wherein said compositions contain 16 alpha-brominated epiandrosterones, about 27-33%w/w benzyl benzoate, about 27-33%w/w Liquid Macrogol, about 25-30%w/w propylene glycol and about 1-3%w/w benzylalcohol that concentration is about 85-105mg/ml.
  35. 35. the compositions of claim 34, wherein said composition contains 16 alpha-brominated epiandrosterones, about 30.4%w/w benzyl benzoate, about 30.7%w/w Liquid Macrogol, about 28%w/w propylene glycol and the about 1.9%w/w benzylalcohol that concentration is about 100mg/ml.
  36. 36. the process of claim 1 wherein 2,3,4,5 or 6 R 1Not hydrogen.
  37. 37. the method for claim 27 wherein is not 2,3,4,5 or 6 R of hydrogen 1Be independently selected from-OH ,=O, halogen and C 2-4Alkoxyl.
CN99813658A 1998-11-24 1999-11-24 Use of 17-ketosteroid compounds, as well as derivatives, metabolites and precursors for treatment of hapatitis C type virus and other togavirus infections Pending CN1328463A (en)

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CN110452280A (en) * 2019-07-25 2019-11-15 中国人民解放军第二军医大学 A kind of tetracyclic triterpene acid derivative and the preparation method and application thereof

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CN108003212A (en) * 2017-12-24 2018-05-08 扬州工业职业技术学院 A kind of dehydroepiandros-sterone -6- glucoside derivatives and its application as anti hepatitis C virus drug
CN110452280A (en) * 2019-07-25 2019-11-15 中国人民解放军第二军医大学 A kind of tetracyclic triterpene acid derivative and the preparation method and application thereof

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