KR20010101074A - Use of 17-ketosteroid compounds and derivatives, metabolites and precursors thereof in the treatment of hepatitis c virus and other togaviruses - Google Patents

Abstract

The present invention relates to 17-ketosteroid compounds, as well as derivatives, metabolites and precursors of these compounds, and pharmaceutically acceptable salts of any of these compounds, for the treatment of hepatitis C type virus and / or hepatitis G type virus, Collectively, there is provided the use of a compound referred to herein as a “compound of the invention”. Additionally, the present invention provides a method for the treatment or prevention of toga virus infection, including one or more alphaviruses, praviviruses such as yellow fever virus, hepatitis C virus and hepatitis G virus, rubella virus, or bovine Viral diarrhea infections caused by pestiviruses, such as viruses. Additionally, the present invention relates to the administration of one or more of the compounds of the present invention and a plasma concentration-promoting compound as described herein, and to one or more compounds selected from macrophage stimulating factors, oxidants, ribavirin and alpha interferon and / or oxygen supply. Provided is a combination therapy comprising administration. The compounds of the present invention may also alleviate or reduce one or more symptoms associated with togavirus infection.

Description

Use of 17-KETOSTEROID COMPOUNDS AND DERIVATIVES, METABOLITES AND PRECURSORS THEREOF IN THE TREATMENT OF HEPATITIS C VIRUS AND OTHER TOGAVIRUSES

There is a continuing need for methods of treating hepatitis C virus that are more effective and / or stable than known methods of treatment. C. Evertt Koop, former chairman of US Surgeon, said, "Our public health is at the brink of a desperate treatment ... and its effects are killing people in all regions and countries. If you don't, you may lose a lot more people than AIDA, ”Koop, Hepatitis C -An Epidemic for Anyone, Maddrey, WC. Et al. In "Beyond Monotherapy: Next Gerneration Therapies for Chronic Hepatitis C", unfortunately, U.S. The therapies provided in the National Institutes of Health Consensus Development Statement on the Management of Hepatitis c, published in March, 1997 are not only effective for most patients, but many do not respond to these treatments, Had limited reactivity. Not all patients with chronic hepatitis C virus infection respond to standard therapies with interferon alpha (IFNα), so a new treatment strategy is needed. Di Bisceglie, A.M. "Emrging Therapies for Chronic Hepatitis C".

Hepatitis C virus infections are very common when statistics show that the worldwide prevalence of chronic hepatitis ranges from 90 million to 200 million (2% to 4%). There is no known vaccine or vaccine candidate for globulin and pre-exposure prophylaxis for post-exposure prophylaxis.

In most cases of HCV infection, more than 75% of cases tend to develop chronic hepatitis, and virtually all infected patients can become chronically infected. HCV-associated liver damage is known to be associated with cytotoxicity false positives (CTLs) on viral peptides expressed directly or indirectly on hepatosite medium. This CTL is located in the liver and is present in minority, and is usually only temporary because the virus is exogenous and matures at this rapid rate. In view of this, it is believed that purely antibiotic compounds, such as nucleoside cognates or enzyme inhibitors, are not likely to eliminate vitrostatic or infectious diseases. In addition, immune-related therapies such as antibody preparations or cellular immune stimulants are believed to have a temporary effect due to modifications or variations to the virus.

Chronic hepatitis C is potentially worse. In general, infections develop into chronic hepatitis, cirrhosis, liver failure and hepatocellular carcinoma over a period of decades rather than months or years.

There is no reliable and effective cell culture for HCV. In addition, there is no non-primate model. As a result, no drugs against HCV have been tested. Acyclovir, ribovarin and corticosteroids are invalid and it is known that corticosteroids increase HCV replication levels.

Interferon has been used to treat chronic hepatitis C. Interferon is a natural glycoprotein produced by cells in response to viral infections. Interferon inhibits the replication of a wide range of RNA and DNA viruses, including hepatitis viruses. This is the inhibition of viral attachment and de-envelopment, the induction of intracellular proteins and ribonucleases that carry antiviral activity to the cells, and specific (cytotoxic T-lymphocytes) and nonspecific (natural killer cells) for viral proteins. A) through mechanism changes, including amplification of the immune response. The specific mechanism of interferon activity in chronic hepatitis C is not known.

In view of the known antiviral properties and the experience of using interferon to treat other forms of viral hepatitis, interferon was evaluated as a potential therapeutic for non-A, non-B hepatitis patients even before hepatitis C virus was identified. Responses can be expected in about 40% of patients with chronic hepatitis C during interferon treatment, and several reports indicate that this reaction is usually rapid. HCV RNA levels drop dramatically and subsequently become undetectable within 4-8 weeks in the majority of patients whose serum aminotransferases are standardized.

Despite the inability to detect immediate antiviral and biochemical responses to treatment and HCV remaining in the liver or serum of responding patients, biochemical normalization and the absence of detectable viremia in the serum are 8-35. Only a few percent of patients are maintained. Recurrences in which serum ALT is outside the standard range and characterized by reverberation occur in 50-90% of patients treated “successfully” after stopping interferon treatment.

More than half of patients with chronic hepatitis C treated with interferon fail to respond. Some patients who initially exhibit a response to interferon by normalizing serum ALT levels will demonstrate a gradual increase in serum ALT levels despite sustaining interferon.

Regarding the patient's response to interferon, age, sex, weight, pre-treatment HCV-RNA level, HCV-RNA loss during treatment, viral genotype, presence of fibrosis and sclerosis, interferon dose, serum ferritin level and Various factors were investigated, including iron levels in the liver. However, none of these could accurately and consistently predict whether HCV patients would respond to interferon.

In addition, the administration of interferon alone in the treatment of hepatitis C has often been detrimental to the patient and sometimes very harmful to the patient. For example, the use of interferon in patients with predominant autoimmune properties may result in severe immune-mediated hepatocellular inflammation (Shindo et al., "Acute exacerbation of liver disease during interferon alfa therapy for chronic hepatitis C" Gastroenterology 1992; 102: 1406-17408). Interferon can transform chronic viral hepatitis into autoimmune hepatitis (Silva et al., "Interferon-induced chronic active hepatitis?" Gastroenterology 1991; 101: 840-8-42). Administration of interferon may also lead to the production of various clinically uncertain autoantibodies (Mayer et al., "Treatment of chronic type B hepatitis with recombinant alpha-interferon induces autoantibodies, not specific for autoimmune chronic hepatitis", Hepatology 1989; 10: 24-28). Everyone is here by reference. Interferon can exacerbate immune-mediated diseases, increase HLA alignment on the membrane surface, weaken expression-inhibiting T cell function, enhance autoantibody production, stimulate natural killer cell function and influence cytokine release And activate macrophages (Baron et al., "The interferons: mechanisms of action and clinical applications", JAMA 1991; 266: 1375-1383, hereby incorporated by reference). Still other patients, such as those with standard serum ALT levels or subject dysfunction, have not demonstrated and are suspect in their therapeutic effectiveness.

Moreover, from its use studies for other diseases, numerous side effects of interferon, such as fever, chills, flu symptoms, fatigue, loss of appetite, worsening of improvement, nausea and vomiting, weight loss, leukocyte reduction, anemia, neurotic symptoms, psychosis Symptoms Side effects such as shortness of breath are well known. Tsavaris, N. Et al., "Treatment of renal cell carcinoma with escalating doses of alpha-interferon", Chemotherapy , 1993 Sep-Oct; 39 (5): 361-6. In addition, interferon is associated with the development of thyroid disease in HCV patients. Lisker-Melman M et al., "Development of thyroid disease during therapy of chronic viral hepatitis with interferon alfa", Gastroenterology 1992 Jun; 102 (6): 2155-60.

Ribaraline is a compound that has a wide range of in vitro activity on both RNA and DNA, including the flaviviridae associated with hepatitis C. Reduction of both serum ALT and HCV RNA levels in patients with chronic HCV infection has been reported in pilot trials, but in subsequent randomized controlled trials, antiviral activity of ribovarin alone could not be established. Several subsequent subtests have demonstrated the synergistic effects of ribovarin and interferon in patients with hepatitis C infection, but the dignity and side effects of interferon alone treatment remain significant drawbacks.

Several agents and therapies, including ursodeoxycholic acid, indomethanesin, nacetylcysteine, silymarin, and some herbal preparations, are known to be useful excipients in interferon therapy, but none of these continue to be effective in control trials. It was.

Hepatitis G virus (HGV; Hepatitis GB Virus C or HGBV-C) was fully identified in early 1996. HGV is a flavivirus and is a slightly different virus from HCV. At this time, HGV aliases can be identified through PCR testing, indicating current infection. Such tests cannot be easily used or standardized. Antibody testing for HGV is under development and, when available, will reveal the epidemiological nature of HGV infection more fully than would be possible with HGV RNA testing. If only antibodies are found, HGV RNA will usually no longer be present.

Infection of HGV through transfusion has been reported (in Canada studies alone, it is known that infection occurs in only 1 out of 1500 recipients and accounts for 9% of post-transfusion hepatitis) and transmission of maternal inheritance during fetal periods. The spread of HGV RNA in groups frequently exposed to blood or blood products is increased (eg, hemophilia or anemia, hemodialysis patients and injectable drug users). Other routes of infection (eg sexual) are possible but have not been reported. Simultaneous infection of HBV, HCV, or both is common and probably has the same infection pathway. In 0.3% of the masses with acute viral hepatitis, HGV is the only identified agent.

Many steroidal compounds and uses thereof are disclosed. See, for example, US Patent Publications 4956355, 5859000, 4268441, 4666898, 5837269, 5827841, 5811418, 5824313, 5686438, 5635496, 5587369, 5583126, 5562910, 5532230, 5518725, 5736537,5843932, 5837700, 5824671, 5807849, 579877 , 5728688, 5610150, 5593981, 5372996, 5110810, 5807848, 5707983, 5641766, 5585371, 5506223, 5424463, 5296481, 5292730, 5776921, 5641768, 5559107, 5478566, 5471042, 5407684, 5387583, 5277907, 5206008, 5077284, 51621 , 5527789, 5756482, 5709878, 5804576, 5744462, 5714481, 5700793, 5696106, 5656621, 5175154, 5157031, 5028631, 5001119, 4898694, 5824668, 5710143, 5795880, 5527788, 5591736, 5861390 and PCT Patent Publication WO 98/05338, WO 95/21617, WO 98/50040, WO 98/50041 and WO 97/48367, all of which are incorporated herein by reference.

A number of flavonoids, methods of obtaining them and their use are disclosed. For example, J.A. Manthey and BSBuslig, editors, Flavonoids in the living system, Advances in experimental medicine and biology, volume 439, Plenum Press, New York, 1998, Chapter 15 (pp. 191-225), Chapter 16 (pp. 227-235) And Chapter 17 (pp. 237-247), all of which are incorporated herein by reference.

Summary of the Invention

According to a basic example of the present invention, the present invention provides a compound of formula (1) (or a pharmaceutically acceptable salt thereof) and salts, stereoisomers, regioisomers, metabolites, homologues, precursors, hydrates, tautomers thereof The present invention provides a method for treating or preventing togavirus infection by ionized form and solvates. .

In the formula,

Q ₁ is -C (R ₁ ) ₂ -or -C (O)-;

Q ₂ is —C (R ₁ ) ₂ —, —C (R ₁ ) (Y) —, —C (Y) — or —CH ₂ —CH ₂ —;

Q ₃ is -H or -C (R ₁ ) _3- ;

Q ₄ is -C (R ₁ ) _2- , -C (O)-, hydroxyvinylidene (-CH (CH = CHOH)-) or methyl methylene (-CH (CH ₃ )-);

Q ₅ is -C (R ₁ ) ₂ -or -C (O)-;

X and Y are -OH, -H, lower alkyl (e.g., C _1-6 alkyl), -OC (O) -R ₅ , -C (O) -OR ₅ , halogen (ie -F, -Cl) , -Br or -I) or = O;

Each R ₁ is independently —H, —F, —Cl, —Br, —I, —OH, C _1-6 alkoxy, or C _1-6 alkyl;

R ₂ is independently —H, —OH, —F, —Cl, —Br, —I, C _1-6 alkyl, C _1-6 alkoxy, —OR ₃ , ester (eg, —OC (O) —R ₄ or -C (O) -OR ₄ ), thioester (eg -OC (S) -R ₄ or -C (S) -OR ₄ ), thioacetal (eg -SC (O) -R ₄ or -C (O) -SR ₄ ), sulfate esters (eg -OS (O) (O) -OR ₄ ), sulfonate esters (eg -OS (O) -OR ₄ ) or carbamate (eg- OC (O) —NH—R ₄ or —NH—C (O) —OR ₄ ), or R ₂ is ═O with R ₁ bonded to the same carbon atom;

R ₃ is -S (O) (O) -OM, -S (O) (O) -O-CH ₂ -CH (OC (O) -R ₆ ) -CH ₂ -OC (O) -R ₆ , -P (O) (O) -O-CH ₂ -CH (OC (O) -R ₇ ) -CH ₂ -OC (O) -R ₇ , or a glucuronide group having the formula A:

R ₃ is C _1-18 alkyl, C _2-18 alkenyl, C _2-18 alkynyl, C _1-18 ester, or C _1-18 thioester, wherein said C _1-18 or C _2-18 substituent is Any one or more hydrogen atoms may be substituted with one or more selected from -OR ^PR (including -OH), -NHR ^PR (including -NH ₂ ) or -SR ^PR (including -SH), respectively, or R ₃ is C _1-18 fatty acids, C _2-10 alkynyl carbonyl, (J) _n - phenyl -C _1- 5- alkynyl carbonyl or (J) _n - phenyl -C _2-5 - Al kennil gt;

R ₄ is H, a protecting group, optionally substituted C _1-18 alkyl, optionally substituted C _1-18 alkenyl, optionally substituted C _1-18 alkynyl, optionally substituted aryl, optionally substituted aryl-C _1-6 Alkyl, optionally substituted aryl-C _2-6 alkenyl, optionally substituted aryl-C _2-6 alkynyl, optionally substituted heterocycle-C _1-6 alkyl, optionally substituted C _2-6 alkenyl-hetero cycle , Optionally substituted C _2-6 alkynyl-heterocycle or optionally substituted heterocycle, wherein any one of said substituents optionally has one, two, three, four, five or more carbon or hydrogen atoms —O—, —S—, NR ^PR -(With -NH-), -NH-C (O)-, -OR ^PR (with -OH), -NHR ^PR (with -NH ₂ ), -SR ^PR (with -SH), = O, = S , May be substituted with one or more selected from the groups — = N—OH, —CN, —NO, —F, —Cl, —Br, or —I, or an atom;

Each R ₅ is independently straight or branched C _1-14 alkyl;

Each R ₆ is independently straight or branched C _1-14 alkyl;

Each R ₇ is independently straight or branched C _1-14 alkyl or a glucuronide group of formula A above;

Each R ^PR is independently —H or each selected protecting group;

n is 0, 1, 2 or 3;

Each J is independently -F, -Cl, -Br, -I, C _1-4 alkyl, C _1-4 alkenyl, C _1-4 alkoxy, carboxy, nitro, sulfate, sulfonyl, C _1-6 Carboxy ester or C _1-6 sulphate ester;

M is hydrogen, sodium, -S (O) (O) -O-CH ₂ -CH (OC (O) -R ₆ ) -CH ₂ -OC (O) -R ₆ , -P (O) (O) -O-CH ₂ -CH (OC (O) -R ₇ ) -CH ₂ -OC (O) -R ₇ or a glucuronide group of Formula A;

In Chemical Formula 1, the dotted line represents an arbitrary double bond, provided that there is no double bond in both 4-5 and 5-6 positions, and in the case where a double bond exists, 1-, 2-, 4-, 5- , At the 6- or 17 position, one or more R ₁ groups bonded to the carbon atom are trivalent. Hereinafter, the compound of formula 1 is collectively referred to as "invented compound" or "compound of the present invention".

Another example of the invention relates to a subject to be treated with a compound of the formula 2A or 2B and salts, stereoisomers, regioisomers, metabolites, homologues, hydrates, tautomers, ionized forms, and solvates thereof. Methods of treating or inhibiting togavirus infection, which consist of simultaneous or sequential administration, include:

Wherein a double bond or a single bond is present in the dashed line, and when a double bond is present, (i) an optionally substituted phenyl ring is present at the 2- or 3-position and R ₈ bonded to this carbon atom is present And (ii) there is no one R ₈ in the adjacent 2- or 3- position;

X ₁ is —O— or —C (R ₈ ) ₂ —;

X ₂ is -CO- or -C (R ₁₁ ) _2- ;

Each R ₈ may independently form a substituent of —H, —OH, halogen, C _1-6 alkyl, C _1-6 alkoxy, glocuronide, C _1-25 fatty acid, or a compound of Formula 2A or 2B The residue of the compound of formula 2A or 2B wherein the hydrogen atom has been removed, -CH ₂ CH = C (CH ₃ ) ₂ , glucoside, a substituent having the structure of formula B or C:

R ₁₀ is C _1-6 alkyl, C _1-6 alkoxy, neohesperidoside, apiglucoside, lutinoside, glucoside, galactoside, rhamnoside, arabinoside, or the stereoisomer of any of these substituents , Hydrate, homologue, derivative, or metabolite, any of which optionally represents one or more hydrogen atoms each -OH, halogen, C _1-6 alkyl, C _1-6 alkoxy, glucuronide or C _1-25 fatty acid Or R ₁₀ is —H, —OH or halogen;

Each R ₁₁ is independently —H, —OH, halogen, C _1-6 alkyl, C _1-6 alkoxy, glucuronide, C _1-25 fatty acid, or both R ₁₁ together form ═O .

Another example of the present invention relates to an alphavirus, pravivirus, rubyvirus or pestivirus, which comprises administering a compound of the present invention (compound 1) and a macrophage stimulating factor to a patient, optionally administering a compound of formula 2A or 2B. It is a method of treating or preventing togavirus infection.

Yet another embodiment of the present invention is directed to administering a compound of Formula 1 of the present invention and (1) administering an oxidant or (2) using an oxygen supply, optionally also administering a macrophage stimulating factor and a compound of Formula 2A or 2B to a patient. It is a method for treating or preventing togavirus infections including alphaviruses, praviviruses, rubyviruses and pestiviruses.

Another example of the invention is an alphavirus, a pra, consisting of administering a compound of formula 1 and ribavirin and / or αIFN, optionally also to a patient using a macrophage stimulating factor and a compound of formula 2A or 2B, an oxidant or an oxygen supply It is a method for treating or preventing togavirus infections including non-viral, ruby-viruses, and pestiviruses.

The present invention relates to steroid compositions and methods of using them to treat flavivirus and togavirus infections, such as human hepatitis C virus ("HCV") infections.

The present invention relates to a 17-ketosteroid compound, and derivatives, metabolites thereof, in the treatment of hepatitis C hepatitis G type virus in a patient in need thereof, optionally in combination with one or more additional administration and / or treatments (as described below). And the use of precursors of these compounds and pharmaceutically acceptable salts of any of these compounds (hereinafter collectively referred to as "compounds of the present invention"). The invention further relates to alphaviruses (arboviruses, also known as group A), flaviviruses (arboviruses, also known as group 13) (yellow fever, and hepatitis C and hepatitis G, etc.), rubyviruses (rubella virus) It also relates to a method for the treatment of togaviruses, including (also known as Rubella) and pestivirus (also known as mucosal disease virus) (Bovine virus diarrhea virus: BVDV).

Unless otherwise stated in the context as used in the text, the following terms have the meanings as defined herein.

"Patient" or "treatment subject" means a human or animal. Usually animals are vertebrates such as primates, rodents, livestock or wildlife. Primates include chimpanzee cynomorgus monkeys, spider monkeys, and macaques, such as the rhesus monkey. Rodents include mice, rats, marmots, ferrets, rabbits and hamsters. Livestock and wildlife include cats such as cattle, horses, pigs, deer, bison, buffalo and breeding cats, canine animals such as dogs, birds such as chickens, emus and ostrich, fish such as trout, catfish and salmon do. The patient or subject to be treated includes any subset as described above, but excludes one or more species or groups, such as humans, primates or rodents.

"Alkyl" in the text refers to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 in the form of CH ₂ primary, secondary, tertiary, cyclic or mixed structure, unless otherwise specified. , C ₁ -C ₁₈ hydrocarbon containing 11, 12, 13, 14, 15, 16, 17 or 18 carbon atoms. Examples thereof include -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH (CH ₃ ) ₂ , -CH ₂ CH ₂ CH ₂ CH ₃ , -CH ₂ CH (CH ₃ ) ₂ , -CH (CH ₃ ) CH ₂ CH ₃ , -C (CH ₃ ) ₃ , -CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ , -CH (CH ₃ ) CH ₂ CH ₂ CH ₃ , -CH (CH ₂ CH ₃ ) ₂ , -C (CH ₃ ) ₂ CH ₂ CH ₃ , -CH (CH ₃ ) CH (CH ₃ ) ₂ , -CH ₂ CH ₂ CH (CH ₃ ) ₂ , -CH ₂ CH (CH ₃ ) CH ₂ CH ₃ , -CH ₂ C (CH ₃ ) ₃ , -CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ , -CH (CH ₃ ) CH ₂ CH ₂ CH ₂ CH ₃ , -CH (CH ₂ CH ₃ ) ( CH ₂ CH ₂ CH ₃ ), -C (CH ₃ ) ₂ CH ₂ CH ₂ CH ₃ , -CH (CH ₃ ) CH (CH ₃ ) CH ₂ CH ₃ , -CH (CH ₃ ) CH ₂ CH (CH ₃₎ ) ₂ , -C (CH ₃ ) (CH ₂ CH ₃ ) ₂ , -CH (CH ₂ CH ₃ ) CH (CH ₃ ) ₂ , -C (CH ₃ ) ₂ CH (CH ₃ ) ₂ , -CH (CH ₃ ) C (CH ₃ ) ₃ , cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclopentyl, cyclobutylmethyl, 1-cyclopropyl-1-ethyl, 2-cyclopropyl-1-ethyl, cyclohexyl, cyclopentylmethyl , 1-cyclobutyl-1-ethyl, 2-cyclobutyl-1-ethyl, 1-cyclopropyl-1-propyl, 2-cyclopropyl-1-propyl, 3-cyclopropyl-1-propyl , 2-cyclopropyl-2-propyl, and 1-cyclopropyl-2-propyl.

As used herein, "alkenyl", unless otherwise specified, in the form of primary, secondary, tertiary, cyclic or mixed structures 1, 2, 3, 4, 5, 6, 7, 8, 9, C ₂ -C ₁₈ hydrocarbons containing 10, 11, 12, 13, 14, 15, 16, 17 or 18 carbon atoms and containing 1, 2, 3 or more double bonds between adjacent carbon atoms. Examples thereof include -CH = CH ₂ , -CH = CHCH ₃ , -CH ₂ CH = CH ₂ , -C (= CH ₂ ) (CH ₃ ), -CH = CHCH ₂ CH ₃ , -CH ₂ CH = CHCH ₃ , -CH ₂ CH ₂ CH = CH ₂ , -CH = C (CH ₃ ) ₂ , -CH ₂ C (= CH ₂ ) (CH ₃ ), -C (= CH ₂ ) CH ₂ CH ₃ , -C ( CH ₃ ) = CHCH ₃ , -CH (CH ₃ ) CH = CH ₂ , -C = CHCH ₂ CH ₂ CH ₃ , -CHCH = CHCH ₂ CH ₃ , -CHCH ₂ CH = CHCH ₃ , -CHCH ₂ CH ₂ CH = CH ₂ , -C (= CH ₂ ) CH ₂ CH ₂ CH ₃ , -C (CH ₃ ) = CH ₂ CH ₂ CH ₃ , -CH (CH ₃ ) CH = CHCH ₃ , -CH (CH ₃ ) CH ₂ CH = CH ₂ , -CH ₂ CH = C (CH ₃ ) ₂ , 1-cycloprop-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, 1-cyclohex -1-enyl, 1-cyclohex-2-enyl, and 1-cyclohex-3-enyl are mentioned.

In the text, "alkynyl", unless otherwise specified, in the form of primary, secondary, tertiary, cyclic or mixed structures 1, 2, 3, 4, 5, 6, 7, 8, 9, C ₂ -C ₁₈ hydrocarbons containing 10, 11, 12, 13, 14, 15, 16, 17 or 18 carbon atoms and containing 1, 2, 3 or more triple bonds between adjacent carbon atoms. Examples thereof include -CCH, -CCCH ₃ , -CH ₂ CCH, -CCCH ₂ CH ₃ , -CH ₂ CCCH ₃ , -CH ₂ CH ₂ CCH, -CH (CH ₃ ) CCH, -CCCH ₂ CH ₂ CH ₃ , -CH ₂ CCCH ₂ CH ₃ , -CH ₂ CH ₂ CCCH ₃ , and -CH ₂ CH ₂ CH ₂ CCH.

"Halogen" or "halo" means fluorine (-F), chlorine (-Cl), bromine (-Br) or iodine (-I), where one or more halogens are mentioned (e.g. Halogen), and each halogen is independently selected.

"Steroid nucleus" means four fused rings having the structure of Formula 1.

"PEG" means an ethylene glycol polymer containing about 20 to about 2000000 linked monomers, typically about 50-1000, usually about 100-300 linked monomers. Polyethylene glycols include PEGs containing various numbers of linked monomers, such 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 mixtures thereof.

"Excipient" or "carrier" means an ingredient or element that is acceptable in view of being suitable for other compositions or combinations as described herein and that is not severely harmful to the patient or animal to which the combination is administered. Excipients and carriers in the body include benzyl benzoate, cottonseed oil, N, N-dimethylacetamide, C _1-12 alcohols (such as ethanol), glycerol, peanut oil, PEG, vitamin E, poppy seed oil, propylene glycol, safflower seed Liquids including oils, sesame oil, soybean oil, and vegetable oils. As excipients in the text, solvents such as chloroform, dioxane or DMSO may be excluded. Excipients typically include one or more components used in the field of pharmaceutical formulations, such as fillers, binders, disintegrants and lubricants.

Unless otherwise specified, the expressions referring to "compound (s) of Formula 1", "compound of the present invention", "Compound 2A or 2B", "plasma concentration increasing compound", etc. By a composition or method, typically 1, 2, 3, or 4, usually 1, where a compound of Formula 2A or 2B is present, such as a method of treating togavirus infection as described in the text.

By "alcohol" is meant herein an alcohol comprising an excipient and containing one or more hydrogen atoms as one or more hydroxyl groups, usually one, two or three substituted C _1-12 alkyl groups. Alcohols include, for example, ethanol, n-propanol, i-propanol, n-butanol, i-butanol, s-butanol, t-butanol, n-pentanol, i-pentanol, n-hexanol, cyclohexanol, n-heptanol, n-octanol, n-nonanol, n-decanol, and benzyl alcohol. The carbon atoms in the alcohols may be straight chain, branched or cyclic. Alcohols include any subset of bar as described above, such as C _2-4 alcohols (containing 2, 3 or 4 carbon atoms).

"Ester" means a substituent comprising a -C (O) -O- structure. Typically, esters in the text refer to organic substituents containing about 1-50 carbon atoms (eg, about 2-12 carbon atoms) and 0 to about 10 selected heteroatoms (eg, O, S, N, respectively). , P, Si), wherein the organic substituent is R ² of the steroid nucleus of the formula (1) through the structure -C (O) -O-, for example, the organic substituent -C (O) -O- steroid or organic Substituents -OC (O)-are bound together with steroids. These organic substituents are usually one or more of any of the organic functional groups as described above, such as C _1-20 alkyl groups, C _2-20 alkenyl groups, C _2-20 alkynyl groups, aryl groups, C _2-9 heterocycles, or And substituted derivatives of any of these, including one, two, three, four or more substituents, each substituent being selected independently. Typical substituents for hydrogen or carbon atoms in this organic functional group include one, two, three, four or more, usually one, two or three -O-, -S-, -NR ^PR- (including -NH-), -C (O)-, = O, = S, -N (R ^PR ) ₂ (with -NH ₂ ), C (O) OR ^PR (with -C (O) OH), -OC (O) R ^PR (With -OC (O) -H), -OR ^PR (with -OH), -SR ^PR (with -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 ₃ H ₂ or halogen substituents or atoms, wherein each R ^PR is -H, each selected protecting group Or two R ^PR together form a protecting group, and A8 is C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _1-4 alkyl-aryl (eg benzyl), aryl ( Phenyl) or a C _0-4 alkyl-C _2-9 heterocycle. Substituents are each independently selected. Organic substituents are defined by the R ₄ variable. Organic substituents explicitly exclude unstable substituents such as -OO- except that such unstable substituents are a type of retention step that can be used to prepare compounds having sufficient chemical stability for one or more uses as in the text. And exclude such unstable substituents. Substituents as described above are typically substituents that can be used to replace one or more carbon atoms, such as -O- or -C (O)-, or substituents that can be used to replace one or more hydrogen atoms, such as Halogen, -NH ₂ or -OH or = O and the like.

"Thioester" means a substituent comprising a -C (S) -O-structure. Typically, thioesters in the text refer to organic substituents containing about 1-50 carbon atoms (eg, about 2-12 carbon atoms) and 0 to about 10 selected heteroatoms (eg, O, S, N, P, Si), wherein the organic substituent is attached to R ² of the steroid nucleus of the formula (1) via a -C (S) -O- structure, for example, an organic substituent -C (S) -O- steroid or Organic substituent -OC (S)-is bound together with steroids. These organic substituents are usually one or more of any of the organic functional groups as described above, such as C _1-20 alkyl groups, C _2-20 alkenyl groups, C _2-20 alkynyl groups, aryl groups, C _2-9 heterocycles, or And substituted derivatives of any of these, including one, two, three, four or more substituents, each substituent being selected independently. Typical substituents for hydrogen or carbon atoms in this organic functional group include one, two, three, four or more, usually one, two or three -O-, -S-, -NR ^PR- (including -NH-), -C (O)-, = O, = S, -N (R ^PR ) ₂ (with -NH ₂ ), C (O) OR ^PR (with -C (O) OH), -OC (O) R ^PR (With -OC (O) -H), -OR ^PR (with -OH), -SR ^PR (with -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 ₃ H ₂ or halogen substituents or atoms, wherein each R ^PR is -H, each selected protecting group Or two R ^PR together form a protecting group, and A8 is C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _1-4 alkyl-aryl (eg benzyl), aryl ( Phenyl) or a C _0-4 alkyl-C _2-9 heterocycle. Substituents are each independently selected. Organic substituents are defined by the R ₄ variable. Organic substituents clearly exclude unstable substituents such as -OO-, except that such unstable substituents are a type of retention step that can be used to prepare compounds having sufficient chemical stability for one or more uses as in the text. And exclude such unstable substituents. Substituents as described above are typically substituents that can be used to replace one or more carbon atoms, such as -O- or -C (O)-, or substituents that can be used to replace one or more hydrogen atoms, such as Halogen, -NH ₂ or -OH and the like.

"Tioacetal" means a substituent comprising a -C (O) -S- structure. Typically, thioacetal herein refers to organic substituents containing about 1-50 carbon atoms (eg, about 2-12 carbon atoms) and 0 to about 10 selected heteroatoms (eg, O, S, N, P, Si), wherein the organic substituent is, for example, an organic substituent -C (O) -S steroid or an organic substituent to R ² of the steroid nucleus of the formula (1) through the structure -C (O) -S- Bound like SC (O) -steroids. This organic substituent is as having described in the part regarding thioester.

A "carbamate" refers to an ester, comprising a -C (O) -NR- structure, wherein each R ^PR is -H, an organic substituent as described in the section on the selected protecting group or ester, respectively. It means an organic substituent as described in. Typically, the term carbamate in the text refers to organic substituents containing about 1-50 carbon atoms (eg, about 2-12 carbon atoms) and 0 to about 10 selected heteroatoms (eg, O, S, N, P, Si), wherein the organic substituent is -OC (O) -NR ^PR -to the R ² of the steroid nucleus of Formula 1, for example, the organic substituent -NR ^PR -C (O)- O-steroids or organic substituents -OC (O) -NR ^PR -are bound together. This organic substituent is as having described in the part regarding thioester.

"Sulfate ester" means a substituent comprising a structure -OS (O) (O) -O-. Typically, the term sulfate ester in the text refers to organic substituents containing about 1-50 carbon atoms (eg, about 2-12 carbon atoms) and 0 to about 10 selected heteroatoms (eg, O, S, N, P, and Si), wherein the organic substituent is attached to R ² of the steroid nucleus of Formula 1 through the structure -OS (O) (O) -O-, for example, the organic substituent -OS (O) (O Combined with) -O-steroids. This organic substituent is as having described in the part regarding thioester.

"Sulfite ester" means a substituent comprising a -OS (O) -O- structure. Typically, sulfite esters in the text refer to organic substituents containing about 1-50 carbon atoms (eg, about 2-12 carbon atoms) and 0 to about 10 selected heteroatoms each (eg, O, S). , N, P, Si), wherein the organic substituent is attached to R ² of the steroid nucleus of the general formula (I) through -OS (O) -O- structure, for example, the organic substituent -OS (O) -O-steroid Combined as This organic substituent is as having described in the part regarding thioester.

Compositions herein include salts of compounds of Formulas 1 and 2 above, including optionally non-ionizable substituents or polar substituents. As used herein, the term "salt" includes complexes containing substituents of relative charge. Ionizable substituents include NH ₂ and —OS (O) (O) —OH substituents in r, and polar substituents include —OH. Salts include, for example, pharmaceutically acceptable salts comprising uncharged substituents or monovalent cation substituents or monovalent anion substituents. Salts include compounds derived by combination of suitable anions such as inorganic acids. Suitable acids include those with sufficient acidity to form stable salts, preferably acids with low toxicity. As an example, an acid addition reaction in which a predetermined inorganic acid such as HF, HCl, HBr, HI, H ₂ SO ₄ , H ₃ PO ₄ is added to a basic center, typically amine, which may be present in the compound of Formula 1, 2A or 2B It is also possible to form the salts of the present invention from. Alternatively, certain organic acids such as organic sulfonic acids and organic carboxylic acids may be used in the same manner. Examples of organic sulfonic acids are C _6-16 aryl sulfonic acids, C _6-16 heteroaryl sulfonic acids and C _1-16 alkyl sulfonic acids such as phenyl, α-naphthyl, β-naphthyl, (S) -camphor , Methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, pentyl and hexyl sulfonic acid and the like. Examples of organic carboxylic acids include C _1-16 alkyl, C _6-16 aryl carboxylic acid and C _4-16 heteroaryl carboxylic acid, such as acetic acid, glycolic acid, lactic acid pyruvic acid malonic acid, glutaric acid, tartaric acid, Citric acid, fumaric acid, succinic acid, malic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid and phenoxybenzoic acid. Salts also include salts of one or more amino acids and compounds of the invention. Although amino acids typically include a basic or acidic group such as lysine, argin, or glutamic acid, or a side chain having a neutral group such as glycine, serine, threonine, alanine, isoleucine, or leucine, Amino acids are suitable, in particular natural amino acids found as protein components. Salts are usually biologically compatible or pharmaceutically acceptable, nontoxic, and especially those having mammalian cells. Biologically toxic salts are generally used as synthetic intermediates for preparing other inventive compounds.

Neohesperidoside, rutinoside and glucoside groups each have the following structure:

Wherein one or more hydrogen atoms are each optionally substituted with a hydroxy group, halogen, C _1-6 alkyl C _1-6 alkoxy, glucuronide or C _1-25 fatty acid.

Heterocycle . "Heterocycle" or "heterocyclic" includes, but is not limited to, a heterocycle as disclosed in Paquette, Leo A .: "Principles of Modern Heterocyclic Chemistry" (WA Benjamin, New York, 1968), in particular Chapters 1, 3, 4, 6, 7, and 9; "The Chemistry of Heterocyclic Compounds, A series of Monographs" (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19 and 28; And J. Am. Chem. Soc. 1960, 82: 5566; And US Patent 5763483, all of which are incorporated herein by reference.

Examples of heterocycles include pyridyl, thiazoyl, tetrahydrothiophenyl, sulfur oxygen substituted tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofu Ranil, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benziindazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidoneyl, pyrrolinyl , Tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, azosinyl, triazinyl, 6H-1,2,5-thiadiazinyl , 2H, 6H-1,5,2-dithiazinyl, thienyl, thiaandrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxatiinyl, 2H-pyrrolyl, isothiazolyl , Isoxazolyl, pyrazinyl, pyridazinyl, indolinyl, isoindoli, 3H-indolyl, 1H-indazolyl, purinyl, 4H -Quinolinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnaolinyl, putridinyl, 4aH-carbazolyl, carbazolyl, b-carbolinyl, phenandrodinyl, arc Lidinyl, pyrimidinyl, phenadolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromenyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinin, pyra Zolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl, benzisooxazolyl, oxindolinyl, benzoxazolinyl, and istinoyl But it is not limited thereto.

The carbon-bonded heterocycle is at position 2, 3, 4, 5 or 6 of pyridine, at position 3, 4, 5, or 6 of pyridazine, at position 2, 4, 5 or 6 of pyrimidine, In position 2, 3, 4, or 5 of furan, tetrahydrofuran, thiofuran, thiophene, pyrrole, or tetrahydropyrrole, in position 2, 4 or 5 of oxazole, imidazole or thiazole At position 3, 4 or 5 of oxazole, pyrazole or isothiazole, at position 2 or 3 of aziridine, at position 2, 3 or 4 of azetidine, 2, 3, 4, 5 of quinoline , 6, 7, or 8 position, is coupled to the 1, 3, 4, 5, 6, 7 or 8 position of isoquinoline, but is not limited thereto.

Nitrogen conjugation heterocycles include aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrrolidine, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyra At position 1 of sol, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indolin, 1H-indazole, at position 2 of isoindole or isoindolin, For example, the binding to carbazole or 9-position of β-carboline at position 4 of the polyline is not limited thereto. Typically, nitrogen-bonded heterocycles include 1-aziridyl, 1-azededyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl.

"Heteroaryl" means one, two, three or more heteroatoms, usually oxygen (-O-), nitrogen (-NX-) or sulfur (-S-), where X is -H, a protecting group or C _{1 -6} alkyl, which is usually -H, and means an aromatic ring or two or more fused rings comprising one or more aromatic rings. Examples include those described in the section on heterocycles.

Protector . Examples of the various substituents that the compounds of Formula 1, 2A or 2B may include include substituted alkyl groups, substituted alkenyl groups, esters or substituted heterocycles, and the like, and these may include one or more reactors such as hydroxy groups or thiols. It may include. Intermediates used to prepare the compounds of Formula 1 or Formula 2A or 2B may be substituted with protecting groups as is well known in the art. Bicyclic and cyclic protecting groups and their deprotecting reactions are described in "Protective Groups in Organic Chemistry", Theodora W. Greene (Jphn Wiley & Sons, Inc., New York, 191, ISBM 0-471-62301-6) Greene ". In the context of the present invention, these protecting groups are substituents that can be removed from the molecule of the present invention without non-thermally changing the oxidation / reduction index or covalent structure of the rest of the molecule of the present invention. For example, a protecting group bound to a -OX or -NHX group, -X, can be eliminated without affecting other covalent bonds in the molecule and forming -OH or -NH ₂ , respectively. At this time, if necessary, one or more protecting groups can be removed simultaneously or continuously. In the compounds of the present invention comprising one or more protecting groups, the protecting groups may be the same or different.

Although protecting group substituted intermediates are also included within the scope of the present invention, protecting groups are intended to be removed by known methods. Removal of protecting groups can be easy or rough depending on the deterioration characteristics and economics involved. Generally, during the synthesis of Formula 1, a protecting group will be used as an out-of-cyclic amino group or carboxyl group. In most therapeutic uses, the amine groups must be deprotected. Protecting groups are typically used to prevent covalent modification of functional groups sensitive to reactions such as alkylation or acylation reactions. In general, protecting groups are removed by, for example, hydrolysis, removal reactions or amine decomposition reactions. Thus, simple functional considerations will be sufficient as a guide to selecting reversible or irreversible protecting groups at a given position on the compounds of the present invention. Appropriate protectors and the criteria for selecting them are listed in T.W. Greene and P.G.M. Wuts, Eds. "Protective Groups in Organic Synthesis" 2nd edition, pps. Of Wiley Press. 10-142, 143-174, 175-223, 224-276, 277-308, 309-405, and 406-454, which are incorporated herein by reference.

Determination of whether a functional group is a protecting group is carried out in conventional manner, eg, in Kocienski, Philip J .; "Portecting Groups" (Georg thieme Verlag Shuttgart, New York, 1994) (hereinafter referred to as "Kocienski"), Section 1.1, page 2 and Greene Chapter 1, pages 1-9; And US Patent Publication 5763483, which are incorporated herein by reference. In particular, 90% of the protecting groups are removed in the deprotection reaction based on the molar ratio, and changes carried out to the covalent structure or oxidation / reduction state other than that produced by removal of the protecting groups result in the deprotected production of the present invention. If it is 50%, preferably 25%, more preferably 10% or less of the molecule, the functional group is a protecting group. If multiple protecting groups of the same type are present in the molecule, the molar ratio when all functional groups of that type are removed is calculated. If different types of multiple protecting groups are present in the molecule, each type of protecting group is treated with each or the other, depending on which one is also associated with another type containing deprotection reaction conditions for one type. (By measuring the molar ratio). In one example of the invention, based on the molar ratio measured by conventional techniques, 90% of the protecting groups are removed by conventional deprotection reactions and covalently bonded structures or oxidation other than those produced by removal of the protecting groups The functional group becomes a protecting group when an irreversible change to the / reduced state is carried out at 50%, preferably 25%, more preferably 10% or less of the deprotecting product of the invention. Irreversible changes are other than those caused by chemical reactions (aqueous hydrolysis, acid / base neutralization or conventional separation, identification or purification methods) to regenerate the covalent bond structure or oxidation / reduction state of the deprotected molecules of the invention. Need).

Protectors are also described in general conceptual terms and in strategic terms for each use, Kocienski, Phili J .; Expected in detail in the "Protecting Group" (Georg Thieme Verlag Stuttgart, New York, 1994), which is a reference of the present invention. In particular, Chapter 1, protecting groups; Overview, pp. 1-20, Chapter 2, Hydroxy protecting groups, pages 21-94, Chapter 3 Diol protecting groups, pages 95-117, Chapter 4, Carboxyl protecting groups, pages 118-154, Chapter 5, Carbonyl protecting groups , 155-184, Chapter 6, amino protecting groups, pages 185-243, Chapter 7, Epilogue, pages 244-252 and the index, pages 253-260, are specifically incorporated by reference. More specifically, section 2.3 silyl ether, 2.4 alkyl ether, 2.5 alkoxyalkyl ether (acetal), 2.6 reviews (hydroxy and thiol protecting groups), 3.2 acetal, 3.3 silylene derivatives, 3.4 1,1,3,3-tetraiso Propyldisiloxanenilidene derivatives, 3.5 reviews (diol protecting groups), 4.2 esters, 4.3 2,6,7-trioxabicyclo [2.2.2] octane [OBO] and other ortho esters, 4.4 oxazolines, 4.5 reviews ( Carboxyl protecting group), 5.2 O, O-acetal, 5.3 S, S-acetal, 5.4 O, S-acetal, 5.5 reviews (carbonyl protecting group), 6.2 N-acyl derivatives, 6.3 N-sulfonyl derivatives, 6.4 N- Sulphenyl derivatives, 6.5 N-alkyl derivatives, 6.6 N-silyl derivatives, 6.7 imine derivatives, and 6.8 reviews (amino protecting groups) are described in detail in which the protecting group substitution reaction / deprotection group substitution reaction of the required functional groups is discussed. It becomes the literature. In addition, the tables of "Index for Major Protectors" on the inside and opposite sides of the front cover, "abbreviations" on page xiv, and "reagents and solvents" on page xv, respectively, are incorporated herein by reference in their entirety. It becomes the literature.

Typical hydroxy protecting groups are described on pages 14-118 of Greene, ether (methyl); Substituted methyl ether (methoxymethyl, methylthiomethyl, t-butylthiomethyl, (phenyldimethylsilyl) methoxymethyl, benzyloxymethyl, p-methoxybenzyloxymethyl, (4-methoxyphenoxy) methyl, Guoacolmethyl, t-butoxymethyl, 4-pentenyloxymethyl, siloxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, bis (2-chloroethoxy) Methyl, 2- (trimethylsilyl) ethoxymethyl, tetrahydropyranyl, 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl, 4- Methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiothioranil, S, S-dioxido, 1-[(2-chloro-4-methyl) phenyl] -4-methoxypiperidine-4- 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a, 4,5,6,7,7a-octahydro-7,8,8-trimethyl -4,7-methanobenzofuran-2-yl); Substituted ethyl ether (1-ethoxyethyl, 1- (2-chloroethoxy) ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy 2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2- (phenylselenyl) ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2 , 4-dinitrophenyl, benzyl); Chihoned benzyl ethers (p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p- Phenylbenzyl, 2- and 4-picolyl, 3-methyl-2-picolyl N-oxido, diphenylmethyl, p, p'-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, Alpha-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di (p-methoxyphenyl) phenylmethyl, tri (p-methoxyphenyl) methyl, 4- (4'-bromophenacyloxy) phenyldi Phenylmethyl, 4,4 ', 4 "-tris (levulinoyloxyphenyl) methyl, 4,4', 4" -tris (benzoyloxyphenyl) methyl, 3- (imidazol-1-ylmethyl) bis ( 4 ', 4 "-dimethoxyphenyl) methyl, 1,1-bis (4-methoxyphenyl) -1'-phenylmethyl, 9-anthryl, 9- (9-phenyl) xanthenyl, 9- ( 9-vslf-10-oxo) anthryl, 1,3-benzodithiolan-2-yl, benzisothiazolyl, S, S-dioxido); silyl ether (trimethylsilyl, triethylsilyl, triisopropyl Silyl, dimethylisopropyl Reyl, diethylisopropylsilyl, dimethyltexylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl, t-butyldiyl Phenylsilyl, tribenzylsilyl, tri-p-) xylylsilyl, triphenylsilyl, diphenylmethylsilyl, t-butylmethoxyphenylsilyl); ester (formate, benzoylformate, acetate, chloroacetate, dichloroacetate , Trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, p-poly-phenylacetate, 3-phenylpropionate, 4-oxopentano Ate (levulinate), 4,4- (ethylenedithio) pentanoate, pivaloate, adamantatoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesh Toate)); carbonate (methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2- (trimethylsilyl) ethyl, 2- (phenylsulfonyl) ethyl, 2- ( Phenylsulfonyl) ethyl, 2- (triphenylphosphonio) ethyl, isobutyl, vinyl, allyl, p-nitrophenyl, benzyl, p-methoxybenzyl, 3.4-dimethoxybenzyl, o-nitrobenzyl, p- Nitrobenzyl, S-benzyl thiocarbonate, 4-ethoxy-1-naphthyl, methyl dithiocarbonate); Functional groups with assisted cleavage (2-iodobenzoate, 4-azidobutylate, 4-nitro-4-methylpentanoate, o- (dibromomethyl) benzoate, 2-formylbenzene Sulfonate, 2- (methylthiomethoxy) ethyl carbonate, 4- (methylthiomethoxy) butyrate, 2- (methylthiomethoxymethyl) benzoate); Miscellaneous esters (2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4- (1,1,3,3-tetramethylbutyl) phenoxyacetate, 2,4- Bis (1,1-dimethylpropyl) phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E) -2-methyl-2-butenenoate (tigloate), o- (methoxy Carbonyl) benzoate, p-poly-benzoate, α-naphtholate, nitrate, alkyl N, N, N ', N'-tetramethylphosphorodiamidate, N-phenylcarbamate, borate, dimethyl Phosphinothioyl, 2,4-dinitrophenylsulfenate); And sulfonates (sulfates, methanesulfonates (mesylate), benzylsulfonates, tosylate).

More typically, hydroxy protecting groups include substituted methyl ethers, substituted benzyl ethers, silyl ethers, and esters including sulfonic acid esters, and even more typically, trialkylsilyl ethers, tosylates and acetates.

Typical 1,2- and 1, -diol protecting groups are described on pages 118-142 of Greene and include cyclic acetals and ketals (methylene, ethylene, 1-t-butylethylidene, 1-phenylethylidene, (4 -Methoxyphenyl) ethylidene, 2,2,2-trichloroethylidene, acetonide (isopropylidene), cyclopentylidene, cyclohexylidene, cycloheptylidene, benzylidene, p-methoxy Benzylidene, 2,4-dimethoxybenzylidene, 3,4-dimethoxybenzylidene, 2-nitrobenzylidene); Cyclo ortho esters (methoxymethylene, ethoxymethylene, dimethoxymethylene, 1-methoxyethylidene, 1-ethoxyethylidene, 1,2-dimethoxyethylidene, alpha-methoxybenzylidene, 1- (N, N-dimethylamino) ethylidene derivative, alpha- (N, N-dimethylamino) benzylidene derivative, 2-oxacyclopentylidene); And silyl derivatives (di-t-butylsilyl group, 1,3- (1,1,3,3-tetraisopropyldisiloxanylidene) derivative, tetra-t-butoxydisiloxane-1,3-diyl Den derivatives, cyclic carbonates, cyclic boronates, ethyl boronates, phenyl boronates).

More typically, 1,2- and 1,3-diol protecting groups include epoxides and acetonides.

Typical amine protecting groups are disclosed on pages 315-385 of Greene, carbamate (methyl and ethyl, 9-fluorenylmethyl, 9 (2-sulfo) fluoroenylmethyl, 9- (2,7-dibromo) ) Fluorenylmethyl, 2,7-di-t-butyl- [9- (10,10-dioxo-10,10,10,10-tethahydrothiooxanthyl)]-methyl, 4-methoxy Phenacyl); Substituted ethyl (2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-phenylethyl, 2- (1-adamantyl) -1-methylethyl, 1,1-methyl-2-haloethyl , 1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl, 1-methyl-1- (4-biphenylyl) ethyl, 1- ( 3,5-di-t-butylphenyl) -1-methylethyl, 2- (2'- and 4'-pyridyl) ethyl, 2- (N, N-dicyclohexylcarboxamido) ethyl, t- Butyl, 1-adamantyl, vinyl, allyl, 1-isopropylallyl, cinnamil, 4-nitrocinnamil, 8-quinolyl, N-hydroxypiperidinyl, alkyldithio, benzyl, p-meth Oxybenzyl, p-nitrobenzyl, p-nitrobenzyl, p-bromobenzyl, p-chlorobenzyl, 2,4-dichlorobenzyl, 4-methylsulfinylbenzyl, 9-anthrylmethyl, diphenylmethyl); Functional groups having secondary cleavage (2-methylthioethyl, 2-methylsulfonylethyl, 2- (p-toluenesulfonyl) ethyl, [2- (1,3-dithiayl)] methyl, 4-methylthiophenyl, 2,4-dimethylthiophenyl, 2-phosphonioethyl, 2-triphenylphosphonioisopropyl, 1,1-dimethyl-2-cyanoethyl, m-chloro-p-acyloxybenzyl, p- (di Hydroxyboryl) benzyl, 5-benzisooxazolylmethyl, 2- (trifluoromethyl) -6-chromonylmethyl); Functional groups capable of photolytic decomposition (m-nitrophenyl, 3,5-dimethoxybenzyl, o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, phenyl (o-nitrophenyl) methyl); Urea-type derivatives (phenothiazinyl- (10) -carbonyl derivatives, N'-p-toluenesulfonylaminocarbonyl, N'-phenylaminothiocarbonyl); Mixed carbamate (t-amyl, S-benzyl thiocarbamate, p-cyanobenzyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropylmethyl, p-decyloxybenzyl, diisopropylmethyl, 2,2 Dimethoxycarbonylvinyl, o- (N, N-dimethylcarboxamido) benzyl, 1, -dimethyl-3- (N, N-dimethylcarboxamido) propyl, 1,1-dimethylpropynyl, di ( 2-pyridyl) methyl, 2-furanylmethyl, 2-iodineethyl, isobornyl, isobutyl, isonicotyl, p- (p'-methoxyphenylazo) benzyl, 1-methylcyclobutyl, 1- Methylcyclohexyl, 1-methyl-1-cyclopropylmethyl, 1-methyl-1- (3,5-dimethoxyphenyl) ethyl, 1-methyl-1- (p-phenylazophenyl) ethyl, 1-methyl -1-phenylethyl, 1-methyl-1- (4-pyridyl) ethyl, phenyl, p- (phenylazo) benzyl, 2,4,6-tri-t-butylphenyl, 4- (trimethylammonium) benzyl , 2,4,6-trimethylbenzyl); Amides (N-formyl, N-acetyl, N-chloroacetyl, N-trichloroacetyl, N-trofluoroacetyl, N-phenylacetyl, N-3-phenylpropionyl, N-picorynoyl, N-3 -Pyridylcarboxamide, N-qswhdlfvpslfdkffkslf derivative, N-benzoyl, Np-phenylbenzoyl); Amides with secondary cleavage (No-nitrophenylacetyl, No-nitrophenoxyacetyl, N-acetoacetyl, (N'-dithiobenzyloxycarbonylamino) acetyl, N-3- (p-hydroxyphenyl) propy O'Neill, N-3- (o-nitrophenyl) propionyl, N-2-methyl-2- (o-nitrophenoxy) propionyl, N-2-methyl-2- (o-phenylazophenoxy) Propionyl, N-4-chlorobutyryl, N-3-methyl-3-nitrobutyl, No-nitrocinnamoyl, N-acetylmethionine derivative, No-nitrobenzoyl, No- (benzoyloxymethyl) benzoyl, 4 , 5-diphenyl-3-oxazolin-2-one); Cyclic imide derivatives (N-phthalilicin, N-dithiasuccinoyl, N-2,3-diphenylmaleoyl, N-2,5-dimethylpyrrolyl, N-1,1,4,4- Tetramethyldisilylazacyclopentane adduct, 5-substituted 1,3-dimethyl-1,35-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5 Triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridonyl); N-alkyl and N-aryl amines (N-methyl, N-allyl, N- [2- (trimethylsilyl) ethoxy] methyl, N-3-acetoxypropyl, N- (1-isopropyl-4-nitro -2-oxo-3-pyrrolin-3-yl), quaternary ammonium salts, N-benzyl, N-di (4-methoxyphenyl) methyl, N-5-dibenzosubbeli, N-triphenylmethyl, N- (4-methoxyphenyl) diphenylmethyl, N-9-phenylfluorenyl, N-2,7-dichloro-9-fluorenylmethylene, N-ferrocenylmethyl, N-2-phycoylamine N'-oxide); Imine derivatives (N-1,1-dimethylthiomethylene, N-benzylidene, Np-methoxybenzylidene, N-diphenylmethylene, N-[(2-pyridyl) mesityl] methylene, N, (N ' , N'-dimethylaminomethylene, N, N'-isopropylidene, Np-nitrobenzylidene, N-salicylidene, N-5-chlorosalicylidene, N- (5-chloro-2-hydroxy Phenyl) phenylmethylene, N-cyclohexylidene); enamine derivatives (N- (5,5-dimethyl-3-oxo-1-cyclohexenyl); N-metal derivatives (N-borane derivatives, N-di Phenylboronic acid derivatives, N- [phenyl (pentacarbonylchrome- or -tungsten)] carbenyl, N-copper or N-zinc chelate), NN derivatives (N-nitro, N-nitroso, N-oxide); NP-derivatives (N-diphenylphosphinyl, N-dimethylthiophosphinyl, N-diphenylthiophosphinyl, N-dialkyl phosphoryl, N-dibenzyl phosphoryl, N-diphenyl phosphoryl); Si derivatives; NS derivatives; N-sulphenyl derivatives (N-benzenesulphenyl, No-nitrobenzenesulphenyl, N-2,4-dinitrobenzenesulphenyl, N-pen Tachlorobenzenesulfenyl, N-2-nitro-4-methoxybenzenesulphenyl, N-triphenylmethylsulphenyl, N-3-nitropyridinesulphenyl) and N-sulfonyl derivatives (Np-toluenesulfonyl , N-benzenesulfonyl, N-2,3,6-trimethyl-4-methoxybenzenesulfonyl, N-2,4,6-trimethoxybenzenesulfonyl, N-2,6-dimethyl-4- Methoxybenzenesulfonyl, N-pentamethylbenzenesulfonyl, N-2,3,5,6-tetramethyl-4-methoxybenzenesulfonyl, N-4-methoxybenzenesulfonyl, N-2,4 , 6-trimethylbenzenesulfonyl, N-2,6-dimethoxy-4-methylbenzenesulfonyl, N-2,2,5,7,8-pentamethylchroman-6-sulfonyl, N-methanesulphur Ponyl, N-beta-trimethylsilylethanesulfonyl, N-9-anthracenesulfonyl, N-4- (4 ', 8'-dimethoxynaphthylmethyl) benzenesulfonyl, N-benzylsulfonyl, N-tri Fluoromethylsulfonyl, N-peacylsulfonyl).

More typically, amino protecting groups include carbamates and amides, and even more typically include n-acetyl groups.

Stereoisomer . Formula 1 and Formula 2A or 2B compounds include predominant or purified optical isomers at any or all asymmetric atoms as can be seen from the structural formula. Both racemic and diastereomeric mixtures, and individual optical isomers, can be synthesized or purified to be substantially free of enantiomeric or diastereomeric partners, all of which are included within the scope of the present invention. Chiral centers can be found, for example, in R ¹ , R ² or R ⁴ in the compounds of the invention.

In the text, one or more of the following methods may be used to prepare predominant or pure isomers of enantiomers. This method is described in roughly its preferred order, that is, generally, using stereospecific synthesis from chiral precursors followed by chromatographic separation and spontaneous crystallization.

Stereospecific synthesis is as described in the Examples. These types of methods are conveniently used where appropriate chiral starting materials are available and the reaction steps are chosen so as not to cause undesirable racemization reactions at the chiral site. One advantage of steric specific synthesis is that it does not produce undesirable enantiomers that must be removed from the final product, thereby lowering the overall synthesis yield. In general, one skilled in the art will know by certain synthesis which starting materials and reaction conditions should be used to obtain the preferred or pure isomer of the preferred enantiomer.

If a suitable stereospecific synthesis method is not empirically designed or determined through routine experimentation, one skilled in the art will be able to switch to another method. One commonly used method is the chromatographic separation of enantiomers on chiral chromatography resins. This resin is commonly referred to as a Pirkle column and packed in a commercially available column. This column contains a chiral rectified phase. The racemics were placed in solution and loaded on a column and then separated by HPLC. See, eg, Proceedings Chromatogrphic Society-International Symposium on Chiral Separations, Sept. 3-4, 1987, which is incorporated herein by reference. Examples of chiral columns that can be used for blocking for appropriate separation techniques include Diacel Chriacel OD, Regis Pirkle Covalent D-phenylglycine, Regis Pirkle Type 1A, Astec Cyclobond II, Astec Cyclobond III, Serva Chiral D-DL = Daltosil 100, Bakerbond DNBLeu, Sumipax OA-1000, Merck cellulose triacetate column, Astec Cyclobond I-Beta, or Regis Pirkle Covalent D-Naphthylalanine. Not all of these columns are effective for all racemic mixtures. However, one skilled in the art will appreciate that some amount of conventional screening may be required to select the most effective rectified phase. When using such a column, it is preferable to use an example of the compound of the present invention where the charge is not neutralized, for example, acidic functionalities such as carboxyl groups are not esterified or amidated.

Another method includes converting the enantiomer in the mixture to a diastereomer with a chiral assistant, followed by separation of this conjugate by normal column chromatography. This method is particularly well suited when the example comprises free hydroxy groups which can form salts or covalently bond with chiral auxiliaries. Chirally pure amino acids, organic acids or organic sulfonic acids are all worth investigating as chiral auxiliaries, all of which are well known in the art. Salts with these auxiliaries may be formed or they may be covalently (irreversibly) functional groups.

Enzyme separation is another method of significant value. In these methods, after preparing covalent derivatives of enantiomers, generally lower alkyl esters, in a racemic mixture, these derivatives are subjected to enzymatic degradation reactions, generally hydrolysis reactions. For this method to be successful, enzymes must be screened for steric-specific degradation reactions, and therefore usually several enzymes need to be routinely screened. If the ester is to be degraded, it is selected from the group consisting of esterases, phosphatases, and lipases, and the activity for this derivative is detected. Typical esterases are obtained from liver, pancreas or other animal organs and include pig liver esterases.

If the enantiomeric mixture is to be separated from the melt or solution as agglomerates, ie a mixture of pure enantiomeric crystals, the crystals can be physically separated, thereby producing an enantiomericly superior preparation. However, this method is not practically available in high volume formulations and has limited value for pure racemic compounds.

Asymmetric synthesis is another technique for achieving the preponderance of enantiomers. For example, the chiral protecting group reacts with the functional group to be substituted for the protecting group and the reaction mixture is in equilibrium. If this reaction is enantiomeric specific, the product will be ethanomeric predominant.

Further instructions in the separation of enantiomer mixtures are described, for example, in "Enatiomers, Racemates, and resilutions", Jean Jacques, Andre Collet, and Samuel H. Wilen (Krieger Publishing Company, Malabar, FL, 1991, ISBN 0-89464-618- 4): Part 2, Separation of Enantiomer Mixture, pp. 217-435; More specifically, section 4, Separation by Direct Crystallization, pp. 217-251, Section 5, Formation and Separation of Diastereomers, pp. 251-369, Section 6, Crystallization-Induced Asymmetric Rice, pp. 369-378, And Section 7, Laboratory Aspects and Techniques of Separation, pp. 378-435, more specifically, Section 5.1.4, Separation of Alcohols, Conversion of Alcohols to Salt-Forming Derivatives, pp. 263-266, Section 5.2.3 , Covalent derivatives of alcohols, thiols and phenols, pp. 332-335, section 5.1.1, acid separation, p. 257-259, section 5.1.2, base separation p. 259-260, section 5.1.3, amino acid separation 261- Page 263, section 5.2.1, covalent derivatives of acids, page 329, section 5.2.2, covalent derivatives of amines, pages 330-331, section 5.2.4, covalent derivatives of aldehydes, ketones and sulfoxides, pages 335-339 , Section 5.2.7, Chromatographic Aspects of Covalent Diastereomers, pages 348-354, but are not limited to, all of which Reference is this literature.

Specific examples include compositions that are produced temporarily when performing a method step or operation. For example, when contacting a compound of Formula 1 with an excipient such as water, cyclodextrin, PEG, alcohol, propylene glycol, benzyl alcohol or benzyl benzoate, the composition may be added before adding one component with another Non-uniform mixtures. As the components contact, the uniformity of the mixture increases and the ratio of components to each other approaches the desired value. Thus, some compositions as disclosed herein optionally contain less than about 3% w / w water, such as less than 0.5% w / w, and include such as 16a-bromoepiandrosterone and one or more excipients. It may contain about 0.0001-99% w / w of the compound of formula (1). These temporary compositions are intermediates that may arise in the process of preparing the present qkfaudd compositions or combinations, which are included in the examples of the present invention to the patentable scope.

Compound of Formula 1 . The compound of formula (I) or “inventive compound” may include one or more togaviruses, togaviruses, togavirus groups as used in the text, such as alphaviruses and rubyvirus genera, and fluvoviruses Lida) and viruses, including the flubbivirus and peptivirus genera, are useful for preventing and treating patients with infectious diseases. Review of virus classification and the biological properties of these viruses are disclosed, for example, in BN Fields, editors, Fundamental Virology, 3rd edition, 1996, Lippencott-Raven Publishers, chapter 1 (pages 15-58) and chapter 17 (pages 523-540). This document is a reference in the text.

Preferred compounds of formula (1) have R ₂ groups bonded to the steroid ring generally having a β-array structure, two R ₁ are bonded to Q ₂ , and X is a double bond oxygen group (═O). Typically, one R ₁ bonded to Q ₂ is hydrogen of β-configuration, the remaining R ₁ bonded to Q ₂ is hydrogen or halogen of the α-configuration, usually bromine, and the double bond is 5-6 times Exists at the location. Such preferred compounds include dehydroepiandrosterone ("DHEA") and 16α-bromodehydroepiandrosterone ("Br-DHEA").

In another preferred compound of Formula 1, a double bond is present at positions 5-6, X is = O, Q ₂ is -CH ₂ -or -CHBr-, and R ₂ is -H-, -S (O) ( O) -OH, -S (O) (O) -ONa, -S (O) (O) -O-CH ₂ -CH (OC (O) -R ₆ ) -CH ₂ -OC (O) -R ₆ (wherein R ₆ is each C _1-14 linear or branched alkyl), -P (O) (O) -O-CH ₂ -CH (OC (O) R ₇ ) -CH ₂ -OC ( O) -R ₇ , wherein R ₇ is a glucuronide group or a C _1-14 linear or branched alkyl, respectively, or a 17-ketosteroid of Formula 1 wherein R ₂ is a glucuronide group do. As another preferable compound, the compound which has following General formula 20-43 is mentioned.

In the formula of each general structure 20-43,

Q ₃ and Q ₆ are each —C (R ₁ ) ₃ —, wherein each R ₁ is independently selected;

X and Y are each -OH, -H, lower alkyl (eg, C _1-6 alkyl), -OC (O) -R ₅ , -C (O) -OR ₅ , halogen, or X and Y are the same Together with R _{1 at the} position independently form a ketone (═O);

Each R ₁ is independently selected and as described above;

R ₂ and R ₅ are as described above.

In some examples, the compound of Formula 1 has a structure of Formula 20-43, wherein the R ₁ groups of 2, 3, 4, 5, or 6 are each -OH, halogen, or alkoxy, and the remaining R ₁ are all hydrogen; R ₂ is —OH, ester, thioester or carbamate, or R ₂ together with R ₁ in the 3-position form ═O; Y is -H, -OH, halogen or -OC (O) -R ₅ , or Y forms = O with R ₁ at the 16-position; X is —OH or —OC (O) —R ₅ , or X together with R ₁ at the 17-position forms ═O and Q and Q are —CH ₃ or —CH ₂ OH, respectively. Examples of this include compounds of the general formula 20-43 wherein two OHs are present at 3-, 16- or 17- dentures.

Preferred examples of the present invention include compounds having the formula

Wherein Y is hydrogen or bromine, R ₄₄ is -H, -S (O) (O) -OH, -S (O) (O) -ONa, -S (O) (O) -O-CH ₂ -CH (OC (O) -R ₆ ) -CH ₂ -OC (O) -R ₆ , -P (O) (O) -O-CH ₂ -CH (OC (O) -R ₇ ) -CH ₂ -OC (O) -R ₇ , or a glucuronide group of the formula (A). In another preferred embodiment, both of Y and R ₄₄ in Formula 44 are hydrogen. Particularly preferred compounds are dehydroepiandrosterone (Y and R ₄₄ in formula ₄₄ are both hydrogen and have a double bond in positions 5-6). In another example, the compound is epiandrosterone (Y and R ₄₄ in formula ₄₄ are hydrogen and there are no double bonds in positions 5-6). 16-haloepiandrosterones having F, Cl, Br or I at the 16 position, such as 16α-bromoepiandrosterone, may also be used as antiviral agents. Other preferred compounds are (i) 16a-bromodehydroepiandrosterone, (ii) dehydroepiandrosterone-3-sulfate (wherein Y is -H and R ₄₄ is -S (O) (O) -OM And both are hydrogen and the double complex is at position 5-6) (iii) 5β-androstan-3β-ol-17one. Relevant examples consisting of compounds associated with compounds of Formula 44 include -OH, -Br, -Cl, -F, -I, wherein 1, 2, 3, 4, 5 or 6 hydrogen atoms each attached to the steroid nucleus are selected. It consists of a compound of formula 44 substituted with -OCH ₃ or -OC ₂ H ₅ atom or atom group.

In another embodiment, the 17-ketosteroid of Chemical Formula 1 may be represented by: in Formula 44, R ₄₄ is -S (O) (O) -O-CH ₂ -CH (OC (O) -R ₆ ) -CH ₂ -OC (O) —R ₆ , —P (O) (O) —O—CH ₂ —CH (OC (O) —R ₇ ) —CH ₂ —OC (O) —R ₇ , or a glucuronide group of Formula A And Y is hydrogen and dehydro-epiandrosterone with 5-6 double bonds present. In other compounds of formula 44, Y is hydrogen, double bond is present at 5-6 and R ₄₄ is hexyl sulfate, dodecyl sulfate, octadecyl sulfate, octadecyl sulfate, O-dihexadecylglycerol sulfate, hexadecane sulfonate di Conjugates of dehydroepiandrosterone, which is an octadecanenoylglycerol phosphate or O-hexadecylglycerol phosphate.

In another preferred embodiment of the present invention, the steroid of Formula 1 is a compound of Formula 45:

Wherein R ₅₀ is -H, -OH or = O; R ₅₁ is -Br, -Cl, -F or -I; R ₅₂ is -OH or = O; R ₄₉ is -H, -OH or -OR ₅₃ ; R ₅₃ is C _1-18 alkyl, C _2-18 alkenyl, C _2-18 alkynyl, C _1-18 ester, C _1-18 thioester, wherein the C _1-18 or C _2-18 substituent Any one of at least one hydrogen atom may be substituted with at least one selected from the group —O—, —S—, —OH, —NH ₂ , —SH═O), or R ₅₃ is thioacetal, sulfate ester, Sulfonate esters, carbamates or thioesters. In a preferred embodiment, R ₄₉ is —OC (O) —CH ₂ —CH ₂ —CH (R ₅₄ ) —CH (R ₅₅ ) —CH ₂ R ₅₆ , wherein R ₅₄ is —NH, —OH, —SH , -O-PO ₃ , -SO ₃ or -OSO ₃ ; R ₅₅ is —H, —NH ₂ , —OH, —SH, —O—PO ₃ , —SO ₃ or —OSO ₃ ; R ₅₆ is C _1-18 alkyl, C _2-18 alkenyl, C _2-18 alkynyl, C _1-18 ester, C _1-18 thioester, wherein the C _1-18 or C _2-18 substituent In any of these, one or more hydrogen atoms can be substituted with one or more selected from -OH, -NH ₂ , or -SH groups, respectively, and become precursors, metabolites and homologues thereof. Relevant examples of compounds of formula 44 include -OH, -Br, -Cl, -F, -I, -OCH ₃ or-each selected from 1, 2, 3, 4, 5 or 6 hydrogen atoms attached to the steroid nucleus, respectively. It consists of a compound of formula 45 substituted with an OC ₂ H ₅ atom or atom group.

In another preferred embodiment, Formula 1 compound has Formula 1B or 1C:

Wherein R ₁ is —H, —OH, halogen, —CHCH ₂ , —CHCHCH ₃ , —CCH, —CCCH ₃ , or there are no other substituents attached to the same carbon atom, and R ₁ is ═O; R ₂ is —H, —OH, halogen, C _1-18 alkoxy, —SC (O) — (CH ₂ ) _m -R ₄ , -C (O) -S- (CH ₂ ) _m -R ₄ ,- OS (O) (O)-(CH ₂ ) _m -R ₄ , -OS (O) (O) -O- (CH ₂ ) _m -R ₄ , -OC (O) -NH- (CH ₂ ) _m -R ₄ , -NH-C (O) -O- (CH ₂ ) _m -R ₄ , -OC (S)-(CH ₂ ) _m -R ₄ , -C (S) -O- (CH ₂ ) _m- R ₄ , -OC (O)-(CH ₂ ) _m -R ₄ , or -C (S) -O- (CH ₂ ) _m -R ₄ ; R ₄ is —H, —CH ₃ , —C ₂ H ₅ , —C ₃ H ₇ , —C ₂ H ₄ OH, —C ₃ H ₅ OH, —CH ₂ —CH ₂ —O—CH ₃ , —CH ₂ -CH ₂ -O-CH ₂ -CH ₃ , -CH ₂ -CH ₂ -O-CH ₂ -CH ₂ OH, C _3-6 alkenyl group, C _3-6 alkynyl group, benzyl or phenyl, wherein Phenyl or benzyl groups may be optionally substituted with 1, 2, or 4 selected halogen, C _1-4 alkoxy, —OH, —SH, —O— or —NH— groups; Q ₃ and Q ₆ are each -H, -CH ₃ or -CH ₂ OH; Q ₂ is —C (R ₁ ) ₂ — or —CH ₂ —CH ₂ —. In this example, Q ₃ and Q ₆ usually all have a β-array structure, typically —CH ₃ , and Q ₂ is usually a-array structure with —CH ₂ —, —C (with a Br, I or OH group). O)-, -CH (Br)-, -CH (I)-, or -CH (OH)-, or Q ₂ consists of = O, and in the 7-position R ₁ is -H,- OH or = O. A related example consisting of the above formula 44 and related compounds is selected from -OH, -Br, -Cl, -F, -I, -OCH ₃ or 1, 2, 3, 4, 5 or 6 hydrogen atoms respectively attached to the steroid nucleus or -OC ₂ H ₅ consisting of compounds of Formula 1A or 1B substituted with atoms or groups of atoms.

The compound of Formula 1 may be derived in crystalline or polymorphic form.

Metabolites . In vivo metabolites of the compounds of the present invention are also included within the scope of the present invention to the extent that such products are novel and not obvious from the prior art. Such products can be derived, for example, from oxidation, reduction, hydrolysis, amidation, esterification, etc. of the compound of formula 1 administered. Accordingly, the present invention includes novel non-magnetic compounds produced by the method comprising contacting a compound of the invention with a subject, such as a human, rodent or primate, for a period sufficient to produce a product of its acid. Such products are typically identified by making radiolabeled (eg, C ¹⁴ or H ³ ) compounds of the compounds of the present invention, which are detectable doses (eg, about 0.5 mg / mg) in rats, mice, guinea pigs, primates or humans. parenteral or oral administration of at least kg) allow sufficient time for metabolism to occur (typically from about 30 seconds to about 30 hours) to identify its conversion product from urine, blood or other biological sample. These products are labeled and easily identified (the rest are identified using antibodies capable of binding epitopes that live in metabolites). This metabolite structure is measured by conversion and is determined by HPLC, MS or NMR analysis. In general, the analysis of metabolites is performed in the same manner as metabolic studies of conventional drugs well known to those skilled in the art. The conversion product is useful for diagnostic assessment of therapeutic administration of a compound of the invention, even if it does not have therapeutic activity on its own, unless otherwise found in vivo.

Specific examples of the compound of Formula 1 are as follows.

Group 1 . Illustrative examples include compounds of Formula 1 referred to in Table B based on the designation of compound structures as defined in Table A below. Each compound referred to in Table B below is depicted as a compound of Formula 4 below.

In the formula, both Q ₃ and Q ₆ are —CH ₃ , Q ₄ is —CH ₂ —, and R ₂ , R ₁ A, and Y and X have a structure as shown in the following Table A. Compounds defined according to Tables A and B are referred to as "Group 1" compounds.

Compounds defined in Table B are formulated using the following chemical formulas as indicated in Table A, using the following compound name arrangements, R ₂ . R ₁ AYXR _{2. According} to R ₁ A and the numbers assigned to Y and X. As shown in Formula 4, R ₂ is in the 3β-position and hydrogen fills the rest of the valence, or R ₂ is a double bond to 16 carbons, R ₁ A is an R ₁ group in the 7b-position, or R ₁ A is a R ₁ group double bonded to 7 carbons, Y is at 16α-position, hydrogen fills the rest of the valence, or R ₂ is double bond to 16 carbons, X is at 17β-position, and hydrogen is remaining To fill the valence, or X double bonds to 17 carbons. When R ₂ , R ₁ A, Y or X are divalent substituents such as ═O, there is no hydrogen at that position. Thus, Group 1 compounds defined as 1.2.1.1. Have β-hydroxy groups bonded to carbon in 3- and 7-positions (variable substituents R ₂ and R ₁ A, respectively) and α-bromine bonded to carbon 16 (Variable substituent y) and the structure of the formula (4) having oxygen (= O) (variable substituent X) double-bonded at the position 17, and has the following structural formula.

Further examples of compounds of Formula 1 include groups as described below.

Group 2. Group 2 compounds are as defined in Table B above, ie, R ₂ , R ₁ A, Y and X substituents are as defined in Table A above, but without 5-6 double bonds and in the 5-position It is bonded to the steroid nucleus as shown in the following formula (5), which is identical to formula (4) except that hydrogen is present in the α-array structure.

Therefore, the group 2 compound defined as 1.2.1.1 has the following structural formula.

Group 3. Group 3 compounds are as defined in Table B above, ie, R ₂ , R ₁ A, Y and X substituents are as defined in Table A above, but without 5-6 double bonds and in the 5-position It is bonded to the steroid nucleus as shown in the following formula (6), except that hydrogen is present in the β-array structure.

Thus, Group 3 compounds defined as 1.2.1.1 have the following structural formula.

Group 4. Group 4 compounds are as defined in Table B above, that is, except that R ₂ , R ₁ A, Y and X substituents are as defined in Table A above, but Q ₃ is -CH ₂ OH. Is bound to the steroid nucleus as shown in the following formula (7), the same as in formula (4).

Thus, Group 4 compounds defined as 1.2.1.1 have the following structural formula.

Group 5. Group 5 compounds are as defined in Table B above, that is, while the R ₂ , R ₁ A, Y and X substituents are as defined in Table A above, there are no 5-6 double bonds and the 5-position It is bonded to the steroid nucleus as shown in the following formula (8), which is identical to formula (4) except that hydrogen is present in the α-array structure and Q ₃ is —CH ₂ OH.

Therefore, the group 5 compound defined as 1.2.1.1 has the following structural formula.

Group 6. Group 6 compounds are as defined in Groups 1-5, except that Q in Formulas 4-8 is -CH ₂ OH instead of methyl. In group 6, there are five subgroups of group 6 compounds. The first subgroup, subgroup 6-1, has the same steroid nucleus with substituents as defined in group 1 compounds above, and the second subgroup, subgroup 6-2, as defined in group 2 compounds above Have the same steroid nucleus with substituents. Subgroups 6-3 to 6-5 each have the same steroid nucleus with substituents as defined in groups 3 to 5 above. Thus, for example, a subgroup 6-1 compound defined as 1.2.1.1. Has the structure

The compound of subgroup 6-2, defined as 1.2.1.1., Has the following structural formula:

Group 7. Group 7 compounds are as defined in Groups 1-5 except that the Y group of Formula 4-8 has a β-array structure in place of the α-array structure. Group 7 consists of five subgroups, and these compounds are basically as described for the Group 6 compounds except that the Y group has a β-configuration.

Group 8. Group 8 compounds are as defined in Groups 1-5, except that the X group of Formula 4-8 has an α-array structure instead of the β-array structure. Group 7 consists of five subgroups, and these compounds are basically as described for the above Group 6 compounds except that the X group has an α-array structure.

Group 9. Group 9 compounds are as defined in Groups 1-5, except that the R ₂ groups of Formula 4-8 have an α-configuration structure instead of the β-configuration structure. Group 7 consists of five subgroups, and these compounds are basically as described for the Group 6 compounds except that the R ₂ groups have an α-configuration.

Group 10. Group 10 compounds are as defined in Groups 1-9, except that R ₂ substituents 1-10 in Table A above are replaced with the following substituents.

Group 10 consists of compounds of 25 subgroups. The first subgroup 10-1 has the same steroid nucleus with substituents as defined in Group 1 above, except that the R ₂ substituents or atom groups as described above replaced those in Table A above. Subgroup 10-1 compound, defined as 1.2.1.1, has the structure

The subgroup 10-2 compound, defined as 1.2.1.1, has the structure

Subgroup 10-6-1 compound, defined as 1.2.1.1, has the structure

The subgroup 10-6-2 compound defined as 1.2.1.1 has the following structure.

Group 11. Group 11 compounds are as defined in Groups 1-9, except that R ₂ substituents 1-10 in Table A above are replaced with the following substituents.

Group 12. Group 12 compounds are as defined in Groups 1-9, except that R ₂ substituents 1 to 10 in Table A above were replaced with the following substituents.

Group 13. Group 13 compounds are as defined in Groups 1-9, except that R ₂ substituents 1 to 10 in Table A above were replaced with the following substituents.

Group 14. Group 14 compounds are as defined in Groups 1-9, except that R ₂ substituents 1 to 10 in Table A above were replaced with the following substituents.

Group 15. Group 15 compounds are as defined in Groups 1-9, except that R ₂ substituents 1 to 10 in Table A above were replaced with the following substituents.

Group 16. Group 16 compounds are as defined in Groups 1-9, except that R ₂ substituents 1 to 10 in Table A above were replaced with the following substituents.

Group 17. Group 17 compounds are as defined in Groups 1-9, except that R ₂ substituents 1 to 10 in Table A above were replaced with the following substituents.

Group 18. Group 18 compounds are as defined in Groups 1-9, except that R ₂ substituents 1 to 10 in Table A above were replaced with the following substituents.

Group 19. Group 19 compounds are as defined in Groups 1-9, except that R ₂ substituents 1 to 10 in Table A above were replaced with the following substituents.

Group 20. Group 20 compounds are as defined in Groups 1-9, except that R ₂ substituents 1-10 in Table A were replaced with the following substituents.

Group 21. Group 21 compounds are as defined in Groups 1-9, except that R ₂ substituents 1-10 in Table A were replaced with the following substituents.

Accordingly, the group 21-1 compound defined as 1.2.1.1 has the structure

A group 21-2 compound defined as 1.2.1.1 has the structure

A group 21-3 compound defined as 1.2.1.1 has the structure

Subgroup 21-4 compound, defined as 1.2.1.1, has the structure

A group 21-6-1 compound defined as 1.2.1.1 has the structure

A group 21-6-2 compound defined as 1.2.1.1 has the structure

The subgroup 21-6-3 compound, defined as 1.2.1.1, has the structure

G12 in group 21 contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms, each having an selected O, S, N, P or Si atom Substituent, provided that only one Si or P is present if Si or P warmer is present, wherein the organic substituent is optionally C _1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl, aryl , A C _2-9 heterocycle or a substituted derivative of any of these, including 1, 2, 3, 4 or more substituents, wherein each substituent is independently selected and is selected from -O-, -S-, NR ^PR- (With -NH-), -C (O)-, = O, = S, -N (R ^PR ) ₂ (with -NH ₂ ), -C (O) OR ^PR (with -C (O) OH) , -OC (O) R ^PR (with -OC (O) -H), -OR ^PR (with -OH), -SR ^PR (with -SH), -NO ₂ , -CN, -NHC (O)- , -C (O) NH-, -OC (O)-, -C (O) O-, -O-A8, -S-A8, -C (O) -A8, -C (O) O-A8 , = N-, -N =, = N-OH, -OPO ₃ (R ^PR ) ₂ , -OSO ₃ H ₂ and halogen substituents or atoms, each R ^PR is -H, each selected protecting group, Or two R ^PR together form a protecting group and A 8 is C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _1-4 alkyl-aryl (eg benzyl), aryl (eg , Phenyl) or a C _1-4 alkyl-C _2-9 heterocycle. G12 substituents include -CH ₃ , -C ₂ H ₅ , -C ₃ H ₇ , -C ₄ H ₉ , -C ₆ H ₁₃ , -CH ₂ -C ₆ H ₆ , -C ₂ H ₄ -C ₆ H ₅ , -C ₃ H ₆ -C ₆ H ₅ , -C ₆ H ₅ , -CH ₂ -heterocycle, -CH ₂ -CH ₂ -heterocycle and heterocycle, these include -O-, -S-, -F, -Cl, -Br, -I, -NH-, = O, -CN, -OCH ₃ , -OC ₂ H ₅ , -OC ₄ H ₉ , -NO ₂ , -NH ₂ , -COOH or- It may be substituted with one, two, three or more each selected from the group NH-C (O)-.

Other examples include the use of any of the above Formula 4 compound classes defined as any of the above Formula 4 compounds, or any of the groups as described above, for any therapeutic use or other use as described herein. Where (i) R ₂ has an α-configuration, (ii) Q ₄ is —CH (halogen) —, (iii) X has an α-configuration, and —H at 17 position is β -Has an array structure, (iv) Y has a β-array structure, -H at the 16-position has an α-array structure, or (v) R ₁ A has an α-array structure and 7- The use of the compound of formula (4) or the like in any definition for any of these applications, where -H in position has a β-array structure, is included.

Specific examples include compounds of Formula 1 (eg, Formula 4), wherein R ₄ is optionally substituted C _1-8 alkyl, optionally substituted C _2-8 alkenyl, optionally substituted C _2-8 alkynyl , Optionally substituted aryl, optionally substituted heterocycle, optionally substituted C _1-8 alkyl-aryl, optionally substituted C _1-8 alkyl-heterocycle or optionally substituted -CH ₂ -C _1-8 organic substituent, wherein , Organic substituents as described in the section on esters), any of which is independently 1, 2, 3, 4, 5, or 6 or more -O-,-S-, -NH-, -NH-C (O)-(ie -NH-C (O)-or -C (O) -NH-), = O, = NOH, -NO ₂ , -CN, -F, -Cl,- It may be substituted with Br, -I, -OH, -SH, or -NH ₂ . Such R ₄ substituents include -CH ₂ -C _1-6 optionally substituted alkyl, -CH ₂ -C _2-6 optionally substituted alkenyl, -CH ₂ -C _1-6 optionally substituted aryl, and -CH ₂ -C _2-9 optionally substituted phenerocycles are included.

Plasma concentration-increasing compounds . In one aspect of the invention, an effective amount of a plasma concentration-increasing compound, such as the compound of formula 2A or 2B, is administered in combination with a compound of formula 1, thereby treating one or more togavirus infections (fravivirus, alphavirus, pesti) Virus or ruby virus). In addition to the above formula (2A) or (2B), plasma concentration-increasing compounds include barbakinin A, didiamine (isosacuranetin-7-rutinoside or neophonyrine), flavanomarine (isoocyanin-7- Glucoside), flavanone azine, flavanone diacetylhydrazone, flavanone hydrazone, silybin having the structure

Silylcristine having the following structure,

Isosilyl bean having the structure

Silanelin having the following structure, and

Compounds having the following formula E are included.

Collectively, these compounds and the above formulas 2A and 2B are referred to as "plasma senescence-increasing compounds".

The compounds of Formulas 2A and 2B include a number of natural and synthetic flavonoids, including any flavones, flavans, and iso analogs thereof. It is known that the systematic biocompatibility of formulations containing a compound of Formula 1 is enhanced by including the compounds of Formula 2A and 2B in a composition containing the compound of Formula 1. Increased plasma concentrations of the compound of formula 1 can be obtained by containing the compound of formula 2A or 2b, such as naringin or naringinin. The above Formula 2A or 2B compound does not necessarily have to be included in the formulation containing the above Formula 1 compound. Formula 2A or 2B may also be administered, for example, about 1-4 hours before, preferably, before, or after the compound of Formula 1 is administered. In such instances, an oral or parenteral combination containing the Formula 1 compound and Formula 2A or 2B compound will be administered.

Plasma concentration-promoting compounds include compounds of the general formula

In the formula,

R ₈ at the 6-position is -H, -OH, -F, -Cl, -Br, -I, -C _1-6 alkyl, -C _1-6 alkoxy, glucuronide, C _1-25 fatty acid , Glucoside, —CH ₂ CH═C (CH ₃ ) ₂ or a substituent having Formula B above;

R ₈ in the 8-position is -H, -OH, -F, -Cl, -Br, -I, -C _1-6 alkyl, -C _1-6 alkoxy, glucuronide, C _1-25 fatty acid , A glucoside, —CH ₂ CH═C (CH ₃ ) ₂ or a residue of the above formula 50-65 compound which removes hydrogen to form the above formula 50-65 substituent;

R ₈ A is -H, -OH, -F, -Cl, -Br, -I, -C _1-6 alkyl, -C _1-6 alkoxy, glucuronide, C _1-25 fatty acid, glucoside, -CH ₂ CH = C (CH ₃ ) ₂ or a substituent having the formula (C) above;

R ₈ at the 6-position is -H, -OH, -F, -Cl, -Br, -I, -C _1-6 alkyl, -C _1-6 alkoxy, glucuronide, C _1-25 fatty acid , Glucoside, —CH ₂ CH═C (CH ₃ ) ₂ or a substituent having Formula B above;

The other R ₈ is —H, —OH, —F, —Cl, —Br, —I, —C _1-6 alkyl, —C _1-6 alkoxy, glucuronide, C _1-25 fatty acid, or — CH ₂ CH═C (CH ₃ ) ₂ ;

R ₁₀ is (i) —OH or —F, —Cl, —Br, —I, —C _1-6 alkyl, —C _1-6 alkoxy, neoesperidoside, apioglucoside, lutinoside, glucoside , Galactoside, rhamnoside, arabinoside or a stereoisomer, hydrate, homologue, derivative or metabolite of any of these substituents, wherein any one or more of the hydrogen atoms is optionally -OH, -F, -Cl, May be substituted with —Br, —I, —C _1-6 alkyl, —C _1-6 alkoxy, glucuronide, C _1-25 fatty acid, and (ii) R ₁₀ is barbaminamine A, didamine, flava Nomarane, flavanone azine, flavanone diacetylhydrazone, flavanone hydrazone, silylbin, silylcristine, isosilylbin, siladrin, stereoisomers, hydrates of the compounds of formula E or any of these substituents , Homologues, derivatives or metabolites.

Additional therapeutic example. According to another preferred aspect of the present invention, a combination therapy comprising at least one compound of the present invention is administered simultaneously or consecutively with one or more macrophage stimulating factors (optionally additional co-administered one or more plasma concentration increasing compounds). A method of treating one or more symptoms as described above, such as togavirus infection and the like, is provided. Macrophage stimulating factors are well known to those skilled in the art and include GM-CSF (see, eg, Callad et al., The Cytokine Facts Book, Academic Press, 1994, p. 139, which is incorporated herein by reference) and inter Examples include leukin-4 (available as "Leukine" by Immunex and "Prokine" by Schering Plow).

In another preferred aspect of the invention, a compound of the invention is administered in combination with one or more oxidizing agents (optionally together with the addition of a plasma concentration enhancing compound and / or macrophage stimulating factor) or oxygenated to the patient in plasma Increases oxidative steroids.

In addition, the present invention further provides one or more compounds of the present invention with ribanirin and / or alpha interferon, optionally further, a plasma concentration-enhancing compound, one or more macrophage stimulating factors, one or more oxidants, and / or It also relates to a combination therapy for the treatment of patients with hepatitis C and / or hepatitis G, which consists of administering to the patient simultaneously or sequentially with an oxidative supply. In addition, the present invention further relates to a combination therapy as described in the text for the treatment of patients susceptible to or suffering from any type of togavirus infection.

The present invention also relates to the combined use of a compound as described herein in the manufacture of a drug for the treatment of togaviruses or flaviviruses, in particular HCV.

The components of any of the above combination treatments in the body may be administered simultaneously (in complex combinations), substantially simultaneously (eg, at intervals of minutes or hours of administration of each compound) or continuously, eg, several days It may be administered at intervals or at least one week apart. For example, the compound of the present invention and the plasma concentration enhancing compound (and / or macrophage stimulating factor) may be administered together or substantially simultaneously, eg, each compound may be administered at intervals of several minutes or hours, or continuously, for example, It may be administered at intervals of several days or more than a week (optionally or in combination with oxidant or oxygen supply). All such modifications in the administration of combination therapy are included within the scope of the present invention.

The present invention also encompasses pharmaceutical combinations comprising any combination as described herein.

The invention also relates to the use of a compound of the invention as described herein in the manufacture of a medicament for use in therapeutic treatment as described in the text, such as for the treatment of togavirus infections such as HCV.

The present invention also relates to administering a compound of the present invention (optionally in combination with one or more combination compounds) to provide a prophylactic treatment of Chinese characters, for example, to prevent togavirus and the like.

Article of manufacture . The invention also relates to articles of manufacture, such as packing materials, at least one or more unit-dosers of a compound of the invention (along with one or more unit-dosers of a compound that can optionally be administered in a combination therapy) and the compounds are described herein. An article of manufacture consisting of a label or package insert indicating that it can be used in such a manner is provided.

In one example, the article of manufacture indicates that a packing material, 17-ketosteroid compound (Formula 1 compound) and 17-ketosteroid compound (Formula 1 compound) of at least one or more unit dosage forms can be used in the manner as described herein. It consists of a label or package insert. The packing material may be prepared from one or more common known materials, such as foams, cardboard, fiberboard, polystyrene, and polypropylene, and has a suitable size to include the compounds involved in the packing material. The label or package insert may be a tag or label affixed to the packing material, or a label printed on the packing material, or a label contained within the packing material. This label will specify that 17-ketosteroids can be used in therapy as described in the text, eg, in combination with plasma concentration-increasing compounds and / or macrophage-stimulating factors. The label may also specify that the compound has been approved for medicinal or veterinary use in accordance with this method by a secretariat such as the US Food and Drug Administration (FDA). This label may also include additional components such as plasma concentration increasing compounds or macrophage stimulating factors, ribavirin and / or alpha interferon in at least one or more unit doses.

Formulation and Administration Method . Dosages for individual patients will depend on factors such as the patient's overall health, dosage and route and method, and the severity of the side effects, if any. Appropriate dosages are determined by the clinician using factors as are well known in the art. In general, administration begins with an amount that is less than the proper dosage and then incrementally increases until a desired or proper effect is achieved. The dosage of the compound of the present invention is appropriately determined depending on the individual case in consideration of the degree of symptoms, the age and sex of the patient, and the like. In the treatment period, the clinician decides whether to increase the dose, decrease the dose, stop the treatment, start the treatment or change the treatment, and determine the point of inhibition that provides the therapeutic benefit. The patient should be observed

The therapeutically effective dosage of a particular compound will vary slightly from compound to compound and from patient to patient. As a general suggestion, dosages in the range of about 0.1 to 500 mg / kg will have therapeutic efficacy. Typically dosages in the range of about 0.5 mg / kg to about 500 mg / kg will be used. The compound of formula 1 will typically comprise about 10 to 750 mg, usually about 20 to about 400 mg, in a single dose, E may be administered in two or more subdoses. Such dosages or subdoses may be administered to one or more sites or by one or more routes of administration. The duration of treatment is usually once a day for a period of time sufficient for the patient to feel no symptoms or to significantly reduce symptoms. Depending on the severity of the infection of the individual patient, it lasts for days, weeks or more.

In the frequency and duration of treatment, the average physician will be able to observe the patient's symptoms and make adequate decisions about stopping, pausing and resuming treatment.

The dosage used in the present invention is appropriately determined depending on the individual case in consideration of the sex, age, symptoms, etc. of the patient. In addition, it is known to the clinician in this field that it is within the knowledge category to determine the appropriate dosage based on the above and other factors.

According to the method of the invention, the compounds of the invention can be administered orally, intramuscularly (IM), intravenously (IV), subcutaneously (SC), and intravenous administration is particularly desirable. Although other routes of administration may be used, it has been found that intravenous administration provides surprising efficacy. For oral administration, the use of plasma concentration-enhancing compounds may become very important. The compounds or salts of the invention may also be administered intravenously or intramuscularly as liposome suspensions. Administration may also consist of a cyclodextrin combination (provided by oral, SC, IN or IM). Thus, the compounds of the present invention and their pharmaceutically or physiologically acceptable salts can be administered by any suitable route depending on the condition to be treated, such as oral, rectal, intranasal, topical (eye drops, mouthwashes, sublingual agents). Vaginal administration, parenteral (including subcutaneous, intramuscular, intravenous, intraperitoneal, transdermal, intramedullary, epidural injections) and aerosol by respiratory system. In general, the compounds of the present invention may be parenterally administered, orally administered or topically administered. If oral administration does not provide sufficient bioavailability, it may be administered by other routes as described above.

Specific examples include combinations of liposomes or lipid complexes containing a compound of formula (I). Such formulations are prepared according to known methods, for example, according to US Pat. Nos. 4427649, 5043165, 5714163, 5744158, 5783211, 5795589, 5795987, 5798348, 5811118, 5820848, 5834016 and 5882678, all of which are incorporated by reference herein. do. Liposomes may optionally contain additional therapeutic or other agent (s), such as a compound of Formula 2A or 2B. Liposomes can be delivered to the patient via any standard route, such as oral, aerosol or parenteral (eg SC, IV, IM).

Most generally, pharmaceutical compositions useful in the present invention will contain a compound of formula 1, a pharmaceutically acceptable salt thereof, in any pharmaceutically acceptable carrier. If a solution is desired, water is selected as the carrier for the water-soluble compound or salt. In another example, organic excipients such as glycerol, ethanol, propylene glycol, polyethylene glycol, DMSO, DMSO ₂ , vegetable oils, mineral oils, ethanol, benzyl benzoate or mixtures thereof may be suitable. In general, any solution should be sterilized in a suitable manner, preferably filtration through a 0.22 micron filter. Compositions useful for practicing the present invention may be provided in the form of vials, ampoules, and the like.

In some examples, the compound of Formula 1 present in the composition or used in the methods as described herein is completely dissolved in the non-aqueous excipient. However, in some examples, for example, in a temporary composition or in some combinations, the compound of formula 1 may be partially dissolved and the remainder present as a solid to form a colloid or suspension. In a related example, the compound of formula 1 is incompletely dissolved and exists as a suspension or gel.

In addition to the compounds of formula (1), or salts thereof, the pharmaceutical composition may contain other additives such as Ph modulating additives, in particular agents such as acids, bases, buffers, including sodium lactate, sodium acetate and sodium gluconate. It may be. In addition such compositions may contain microbiological preservatives such as methylparaben, propylparaben, benzyl alcohol and benzyl benzoate. If a multi-use vial is provided, the pharmaceutical composition must also contain such microbial preservatives. Of course, this formulation may be lyophilized using known techniques in the art.

This combination includes those suitable for the route of administration as described above. This combination may conveniently be presented in unit dosage form or may be prepared by any method well known in the art of pharmacy. Techniques, excipients and combinations are generally described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA 185, 17 edition, Nema et al., PDA J. Pharm. Sci. Tech. 197 51: 166-171, both of which are incorporated herein by reference. Methods of preparing the inventive combinations include mixing a compound of Formula 1 with one or more excipients or carriers. Generally, the formulation is prepared by uniformly and intimately mixing the compound of formula 1 with a liquid excipient or a finely divided solid excipient, followed by molding the product as the case may be.

Formulations of the present invention suitable for oral administration are in discrete form, such as capsules, cachets, or tablets, each containing an amount of Formula 1 or Formula 2A or 2B, as a powder or granules; As a solution or suspension of an aqueous or non-aqueous solution; Or as a liquid emulsion of oily water phase or a water-based emulsion of a water layer in oil. The compound of formula 1 or formula 2A or 2B may also be provided as a pill, soft or paste.

Tablets may be made by compression or molding, optionally with one or more excipients. Compressed tablets may be prepared by compressing the above formula (1) or (2A) or (2B) compound in a fluidless form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant or dispersant and then compressed in a suitable apparatus. Can be. Molded tablets may be prepared by molding in a suitable apparatus a mixture of the powdered compounds moistened with an inert liquid diluent. Tablets may be optionally coated or graduated and may be formulated to control or delay the release of contained Formula 1 or Formula 2A or 2B compounds.

The oil phase of the emulsion of the invention can be prepared from known ingredients by the known art. Although this oil phase may contain only emulsifiers (otherwise known as emulsifiers), it is preferred to contain at least one emulsifier and a mixture of fats or oils or both fats and oils. Preferably, a hydrophilic emulsifier can be included with the hydrophobic emulsifier to act as a stabilizer. It is also desirable to contain both oils and fats. In addition, the emulsifier (s), with or without stabilizer, constitutes an emulsifying wax, and together with oils and fats, the wax constitutes an emulsifying ointment base material that forms an oil phase dispersed phase of the cream formulation. . Suitable emulsifiers and emulsion stabilizers for use in formulations containing Formula 1 or Formula 2A or 2B compounds include Tween ^® 60, Span ^® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium Lauryl sulfate.

Formulations suitable for oral administration include tablets (lozenges) containing a compound of Formula 1 or Formula 2A or 2B in an aromatic base, generally in sucrose and acacia or tragacanth; Pastllers containing a compound of Formula 1 or Formula 2A or 2B in an inert base such as gelatin and glycerin, or sucrose and acacia.

Formulations for rectal administration may be provided as suppositories of suitable bases such as cocoa butter or salicylate.

Formulations suitable for inhalation or intranasal administration can have particle sizes on the order of, for example, 0.01 to 200 microns (0.1, 0.2, 0.3, 0.4, 0.5, 1, 2, 5, 30 microns, 35 microns, etc.). Increasing to include various particle sizes in the range between 0.01 and 500 microns), by inhalation through the nasal route, or through inhalation through the mouth to various bronchial or alveolar cysts. Formulations suitable for aerosol or dry powder administration may be prepared according to conventional methods and may be delivered together with other therapeutic agents such as compounds used to treat or prevent togaviruses, praviviruses or retroviruses and other infectious diseases. have. Inhalation therapy is easily administered with a metered dose inhaler.

Formulations suitable for intravaginal administration may be provided as pessaries, tampons, creams, gels, pastes, foams, spray formulations containing excipients or carriers such as those well known in the art, in addition to compounds of formula (I).

Formulations suitable for parenteral administration are sterile and comprise aqueous and non-aqueous injectable solutions comprising antioxidants, buffers, bacteriostatic agents and solute components providing the isotonic formulation with the blood of treatment; Water-soluble and non-aqueous sterile suspensions, which may include suspending agents and concentration increasing agents. This formulation may be provided in unit dose or multi-dose containers, eg in ampoules and vials sealed with a rubber stopper, and freeze-drying (freeze-drying) which requires only a sterile liquid carrier, such as water for injection, immediately prior to use. It can also be stored in a closed state. Instant injection water and suspensions may also be prepared from sterile powders, granules and tablets as described above. The unit dosage combination will typically contain the compound of Formula 1 or Formula 2A or 2B above in a daily dosage or unit daily sub-dose, or appropriate fraction thereof, as described above.

In some embodiments, the compound of Formula 1 will be administered according to intermittent criteria. In this example, after a dose containing about 5-500 mg (typically 25-400 mg or about 50-350 mg) of said Formula 1 compound, such as said Formula 1 compound, is administered for at least one day, at least After no administration for more than one day (more than 24 hours), optionally a daily administration of, for example, about 50-500 mg may be administered at least once. Intermittent dosing regimens may be administered on a weekly basis (1, 2, 3 or 4 daily), for example, Monday, Wednesday and Friday for at least about 1, 2, 3, 4, 6, 8 weeks or more. , Or after administration on Tuesday, Thursday, and Saturday, without administration for a period of at least about 2, 3, 4, 5, 30, 45, 60, 90 days, and then optionally about 1, 2, 3, 4, 6 It may be administered on Mondays, Wednesdays and Fridays for more than eight weeks. The weekly administration method consists of administering a compound of Formula 1 to a patient 1, 2, 3, 4 or 5 times weekly for at least 1, 2, 3, 4 weeks. In a related example, the administration consists of administering to the patient daily for at least 2, 3, 4, 5, 6, 7 days, followed by about 1, 2, 3, 4, 5, 7, 14, 30, 45 After having spent at least 60, 90 days, optionally another route may be administered daily. These examples may further include treatment with a compound of Formula 2A or 2B or another therapy as described herein.

To the extent not yet indicated, those skilled in the art will appreciate that any of the various specific examples described and illustrated in the text may further be modified to incorporate the features indicated in any of the other examples described herein. There will be.

Treatment regimen . In therapeutic applications, a composition as described herein will typically contain one or more compounds of Formula 1 and will utilize such compositions in a manner as described herein, with one or two or more such compounds, usually one something to do. Although the compounds of the present invention may be administered as pure compounds, they are preferably provided as a pharmaceutical combination. Formulations of the present invention may comprise at least one compound of Formula 1 and one or more acceptable carriers or excipients, and any other therapeutic agents, such as Formula 2A or 2B compound (s), αIFN, ribavirin, macrophage stimulating factor (s) and / or Or oxidant (s). One or more carriers or excipients are not harmful to the patient and must be "acceptable" in the sense of being suitable for other formulation ingredients.

The compounds of the present invention are useful for the prevention and treatment of one or more flavivirus or togavirus infections in humans or animals. Togaviruses and flavivirus infections that can be treated with Formula 1 include HCV, California encephalitis virus, St. Louis encephalitis virus, Western encephalitis virus, Eastern encephalitis virus, Colorado tick fever virus, Lacrosse encephalitis virus, Japanese encephalitis virus Yellow fever virus, Venezuelan encephalitis virus, Murray valley fever virus GB virus A, GB virus B, GB virus C, dengue virus 1, dengue virus 2, dengue virus 3, dengue virus 4, Semiki forest virus, and sin Vis virus can be mentioned. The ruby virus includes human rubella virus. Pestiviruses include mucosal disease viruses such as bovine viral diarrhea virus, Hog cholera virus Schiff border disease virus. The compound of formula 1 is also useful for the treatment of hepatitis G virus.

In addition to treating or preventing togavirus infections, some of the compounds of Formula 1 may also be used to treat concurrently infected patients such as togaviruses and other viruses such as retroviruses or secondary togaviruses. HIV1 or HIV2, Simian immunodeficiency virus, recombinant human-Simian immunodeficiency virus (SHIV), or Pelin or Murine Leukemia or Sarcoma virus, such as human immunodeficiency virus, can be treated with Formula 1 compound have. Co-infection with hepatitis virus, such as HCV and HIV, can be treated with a compound of the invention. In this example, the patient typically has (i) one or more togavirus infections (such as HCV), and (ii) whether secondary viral infections are present (eg, human herpes simplex virus 1, human herpes simplex virus). , Or retroviruses such as HIV1, HIV2, etc.).

In another example, the dosage form of the compound of Formula 1 may be administered at a relatively high introductory dose, such as about 150-750 mg per day or about 150-750 mg per day using an intermittent dosing cycle, followed by a lower maintenance dose, such as , About 50-250 mg per day or about 50-250 mg per day on an intermittent dosing cycle. In these examples it may further include a treatment with a compound of Formula 2A or 2B or another treatment as described in the text.

Parenteral formulations may contain cyclodextrins such as α-cyclodextrin, α, β-cyclodextrin (eg β-hydroxypropylcyclodextrin) or C1-6-cyclodextrin and are typically used as water soluble formulations. May optionally include one or more buffers, salts (NaCl, etc.), such as to provide an isotonic solution, and may include bacteriostatic agents or other excipients known in the art. For example, a concentration of about 5-25 mg / mL, typically about 10-20 mg / mL. Parenteral formulations containing the compound of Formula 1 and one or more excipients may be administered to a patient, eg, diluted with sterile saline. Parenteral formulations are typically administered to patients, such as humans, eg, by intravenous, topical or oral route. For non-aqueous formulations, one or more solvents may be used, such as propylene glycol, PEG such as PEG 300 or PEG 400, ethanol and benzyl benzoate. Typical water soluble and non-aqueous formulations will contain about 5 to 400 mg / mL of Formula 1, usually about 10 to 200 mg / mL. Such parenteral combinations may be delivered orally or via intramuscular, intravenous or subcutaneous injection.

In preparing a composition containing the compound of Formula 1, the compound of Formula 1 may be optionally ground or granulated before or after contacting the compound of Formula 1 with one or more excipients to produce a desired particle size. For example, a compound of formula 1, such as 16α-bromoepiandrosterone, may be ground to obtain an average particle size (or about 0.5-25 uM or about 1-10 uM (eg, about 2,5 or 10 uM average particle size or diameter) (or Diameter) can be contacted with the ground compound of Formula 1 and liquid or solid excipients. The ground compound of Formula 1 may dissolve or suspend the compound of Formula 1 in one or more liquid excipients (eg, PEG, propylene glycol, or benzyl benzoate, such as PEG 300), or the ground compound in one or more solid excipients. (E.g., fillers, binders or lubricants) is useful for uniformly dispersing the medicinal material.

Compositions and combinations in the body are useful for treating or alleviating one or more of the symptoms associated with an infection or infection as described herein. The compositions and combinations may also be used to treat one or more symptoms associated with retroviral infections or malaria, such as HIV1 or HIV2 infections in humans. As described herein, "reduction of one or more related symptoms" refers to the reduction of the number of infectious agents or the copying of an infectious agent in the subject or combination of these compounds or combinations, It can be used to alleviate one or more of the symptoms caused by or associated with (eg, decreased fever, decreased duration or level of pain, or significantly reduced or eliminated lethargy or fatigue).

In addition to the components specifically mentioned above, the inventive formulations may include other agents customary in the art, which are relevant to the type of the formulation, for example, those suitable for oral administration may include perfumes or pigments. have.

The present invention further provides a veterinary composition containing at least one compound of Formula 1 or Formula 2A or 2B and at least one veterinary carrier. In addition, the compound of Formula 1 may be included in animal feed or water. Excipients for veterinary use include, for example, small amounts of compounds such as chloroform, which are generally not suitable for human use.

Veterinary carriers are substances useful for the purpose of administering the composition to cats, dogs, horses, mice, rats, hamsters, rabbits, and other animals, and are inert or acceptable in the veterinary arts, Suitable solid, liquid or gaseous materials for 2B. These veterinary compositions can be administered by oral administration, parenteral administration or any other desired route, such as those described in the text.

In an illustrative example, a patient infected with HCV may be provided in a water soluble isotonic α-cyclodextrin or β-cyclodextrin (β-hydroxypropyl cyclodextrin) combination. This formulation contains 5-50 mg / mL of 16-α-cyclodextrin, such as about 10-20 mg / mL. This combination is injected intravenously in a single dose every day or as twice as many subdoses per day. The patient may be administered 1 to 10 mg / kg / day for 4 to 10 days, then not for 5 to 30 days, and then again for 4 to 10 days. This mode of administration is repeated once, two or more times. Clinical markers for HCV infection may be followed during treatment, such as viral nucleic acids in blood or plasma, liver enzyme levels (aminotransferases) in blood or plasma. For this patient, standard anti-HCV therapies, such as interferon and / or lipvirin, are initiated or sustained according to the patient's clinical instructions, optionally by suggesting the patient's information. In some of these examples, the compound of formula 1 may be administered continuously daily, eg as a combination of a compound of formula 1 that is itself a new compound or as a component of an oral or parenteral composition. Dehydroepiandrosterone or 16α-broboepiandrosterone may optionally also be used, for example, using the formulation of Example 1 for about 1-4 mg / kg / day for about 1 to 4 months or 5-oral combination 40 mg / kg / day may be administered periodically for about 1 to 4 months on the day of sale.

Specific examples of the compound of Formula 1 include or exclude a subset of compounds within the definition of Formula 1, provided that at least one compound remains. For example, a subset of the general formula (1) compounds that are generally preferred and usually included are, for example, water-soluble or water-insoluble formulations containing 16α-bromoepiandrosterone. A subset compound or usage that is optionally excluded from the compound of Formula 1 or its use in the claims or any specific example of the text, includes, for example, the use of one or more compounds described in one or more prior art references or publications. To the extent that the disclosed compounds or uses provide claims or examples that cannot be patented for reasons of novelty, self-evident, and / or progression. In another example of Formula 1 compounds, at the 3-position = O, 4-5 A double bond at the position, a hydroxy group (-OH) bonded at the 11-position, -C (O) -CH ₂ OH, -H or -C (O) -CH ₂ OH and -OH or = O at the 17-position; Corticosteroid, wherein Q ₆ is -CH ₃ or -CH ₂ OH, Q ₃ is -CH ₃ , and (R ₁ ) in the remaining position comprises, for example, -H and 0,1, or 2 hydroxy groups. At least one formula having activity Other than a compound of formula I with water, for example one or more.

In another example, the compound of Formula 1 may be combined with an oligonucleotide or oligonucleotide analog to be used to deliver an oligonucleotide or analog to a cell. Typically the compound of Formula 1 will bind to the steroid nucleus via terminal hydroxyl groups at the 5 ', 3' or 2 'position of the oligonucleotide. Oligonucleotides and homologues of oligonucleotides are known and described, for example, in US Patent Publications 4725677, 4973679, 4997927, 4415732, 4458066, 5047524, 4959463, 5212295, 5386023, 5489677, 5594121, 5614622, 5624621; And PCT patent publications WO 92/07864, WO 96/29337, WO 97/14706, WO 97/14709. WO 97/31009. WO 98/04585 and WO 98/04575, all of which are incorporated herein by reference.

Synthesis method . In general, the compounds used in the present invention can be synthesized in a manner well known to those skilled in the art. Thus, the methods used for the synthesis of most of these compounds need not be described in great detail.

Formula 1 compounds containing thioacetal groups, sulfate esters, sulfite esters, carbamate or thioester groups in R ₂ (3-position) were prepared substantially according to methods known in the art. Suitable protecting group substituted intermediates can be used as specified. See, eg, US Patent Publication 5198432; European Patent Publication EP 576915; C. Chrostoana et al., J. Chem. Soc. Che. Coommun. 1991 vol 22, C. Christiana et al., J. Chem. Soc., Chem. Commun. 1991 19 : 1403-1405, hN Abramson et al., J. Pharm. Sci. 1977 66: 602-603, EJ Corey et al., J. Am. Chem. Soc. 1996 118: 8765-8766, AGM Barrett et al., J. Org. Chem. 1989 54: 227, DHR Barton et al., J. Chem. Soc. Perkin Trans. I 1976 19: 2112-2116, DHR Barton et al., J. Chem. Soc. Perkin Trans. I 1975 16: 1574-1585, and WT Smith et al., Trans. Kentucky Acad. Sci. 1984 45: 76-77, all of which are incorporated herein by reference.

Examples listed . One aspect of the invention includes the examples listed below, which further illustrate the invention and its preferred aspects or related subject matter.

1. A method of treating hepatitis C virus in a patient in need thereof, comprising administering to a patient in need thereof an effective amount of at least one compound selected from the group consisting of the compounds of the invention.

2. The method of example 1, further comprising administering at least one plasma concentration-enhancing compound to said patient.

3. In a second example, a method of simultaneously administering at least one of the compounds of the present invention and at least one of said plasma concentration enhancing compounds.

4. In a second example, a method of continuously administering at least one compound of the invention and at least one plasma concentration enhancing compound.

5. The method of any one of items 1-4, further comprising administering ribavirin and / or alpha interferon to the patient.

6. The method of any one of 1-5, further comprising administering at least one macrophage stimulating factor to said patient.

7. The method of any one of paragraphs 1-6, further comprising performing at least one oxidant administration and / or oxygenation to said patient.

8. The method of any one of paragraphs 1-7, wherein the patient is a mammal.

9. The method of example 8, wherein the patient is a human.

10. The method of any one of paragraphs 1-9, wherein said administration is via injection.

11. The method of any one of paragraphs 1-9, wherein said administration is via infusion.

12. The method of any one of 1-9, wherein the administration is via intravenous injection.

13. The method of example 2, wherein at least one or more of said plasma concentration enhancing compound inargin or naringenin.

14. At least one aminotransferase level of a patient with hepatitis virus C in a patient in need of such treatment, comprising administering to a patient in need thereof an effective amount of at least one compound selected from the group of compounds of the invention. How to reduce.

15. The method of example 14, further comprising administering at least one or more plasma concentration-enhancing compounds to said patient.

16. The method of example 14, wherein at least one of the compounds of the present invention and at least one of the plasma concentration enhancing compounds are administered simultaneously.

17. The method of embodiment 15, wherein continuously administering at least one of the compounds of the present invention and at least one of the plasma concentration enhancing compounds.

18. The method of any one of paragraphs 14-17, further comprising administering ribavirin and / or alpha interferon to the patient.

19. The method of any one of paragraphs 14-18, further comprising administering at least one macrophage stimulating factor to the patient.

20. The method of any one of clauses 14-19, further comprising performing at least one oxidant administration and / or oxygenation to said patient.

21. The method of any one of paragraphs 14-20, wherein the patient is a mammal.

22. The method of example 21, wherein the patient is a human.

23. The method of any one of 14-22, wherein said administering is via injection.

24. The method of any one of paragraphs 14-22, wherein said administration is via infusion.

25. The method of any one of 14-22, wherein the administration is via intravenous injection.

26. The method of example 15, wherein at least one of said plasma concentration enhancing compounds is naringin or naringenin.

27. A method of treating a togavirus in a patient in need thereof comprising administering to a patient in need thereof an effective amount of at least one compound selected from the group consisting of the compounds of the invention.

28. The method of example 27, further comprising administering at least one or more plasma concentration-enhancing compounds to said patient.

29. The method of example 28, wherein at least one of the compounds of the present invention and at least one of the plasma concentration enhancing compounds are administered simultaneously.

30. The method of example 28, wherein continuously administering at least one of the compounds of the present invention and at least one of the plasma concentration enhancing compounds.

31. The method of any one of paragraphs 27-30, further comprising administering ribavirin and / or alpha interferon to the patient.

32. The method of any one of items 27-31, further comprising administering at least one macrophage stimulating factor to the patient.

33. The method of any one of paragraphs 27-32, further comprising performing at least one oxidant administration and / or oxygenation to said patient.

34. The method of any one of paragraphs 27-33, wherein the patient is a mammal.

35. The method of example 34, wherein the patient is a human.

36. The method of any one of paragraphs 27-35, wherein said administration is via injection.

37. The method of any one of paragraphs 21-35, wherein said administration is via infusion.

38. The method of any one of items 27-35, wherein said administering is via intravenous injection.

39. The method of example 28, wherein at least one of said plasma concentration enhancing compounds is naringin or naringinin.

40. The method of example 27, wherein the togavirus is an alphavirus.

41. The method of example 27, wherein the togavirus is a flavivirus.

42. The method of example 41, wherein the flavivirus is an alphavirus.

43. The method of example 41, wherein the flavivirus is a yellow fever virus.

44. The method of example 27, wherein the togavirus is a ruby virus.

45. The method of example 44, wherein the ruby virus is a Rubella virus.

46. The method of example 27, wherein the togavirus is a pestivirus.

47. The method of example 46, wherein the pestivirus is bovine virus diarrhea virus (BVDV).

48. The method of embodiment 1-47, wherein the compound of the present invention is the compound of Formula 1 or a metabolite thereof.

49. The method of example 48, wherein the compound of formula 1 is a compound defined by compound group 1-21, or any compound of formula 1 (eg, formula 4) or the kind described or referred to herein, or a metabolite thereof.

50. A composition containing 16α-bromoepiandrosterone and 2, 3, 4 or 5 excipients selected from polyethylene glycol, dehydrated ethanol, benzyl benzoate, benzyl alcohol, and propylene glycol, wherein about 3% v / v A composition containing less than, or less than about 1% v / v, or less than about 0.5% v / v or less than about 0.1% v / v.

51. In an example 50, the composition comprises (i) 16α-bromoepiandrosterone at a concentration of about 45-55 mg / mL, (ii) 20-30% v / v polyethylene glycol 300, polyethylene glycol 400 or polyethylene glycol A composition containing 300 and 400, (iii) 10-15% v / v dehydrated ethyl alcohol, 2.5-7.5% v / v benzyl benzoate, and (iv) 55-60% v / v propylene glycol.

52. In an example 51, wherein the composition has a concentration of 50α / bromoepiandrosterone, about 25% v / v polyethylene glycol 300, about 12.5% v / v dehydrated ethyl alcohol, about 5% v / v A composition containing benzyl benzoate, about 57.5% v / v propylene glycol and less than about 0.5% v / v water.

53. In an example 50, the composition comprises 16α-bromoepiandrosterone at a concentration of 50-105 mg / mL, about 27-33% w / w benzyl benzoate, about 27-33% w / w polyethylene glycol 300, A composition containing about 25-30% w / w propylene glycol and about 1-3% w / w benzyl alcohol.

54. In an example 53, the composition comprises 16α-bromoepiandrosterone at a concentration of 100 mg / mL, about 30.4% w / w benzyl benzoate, about 30.7% w / w polyethylene glycol 300, about 28% w / w A composition containing propylene glycol and about 1.9% w / w benzyl alcohol.

55. A product produced by the process of contacting 16α-bromoepiandrosterone with a liquid excipient, wherein the product contains less than about 3% v / v of water and the liquid excipient optionally contains one or more dimethylsulfoxide, chloroform, vegetable Product excluding oil and olive oil.

56. In an example 55, wherein the liquid excipient is polyethylene glycol, dehydrated ethanol, benzyl benzoate, benzyl alcohol and propylene glycol and the product is less than about 3% v / v, or less than about 1% v / v, or about Product containing less than 0.5% v / v of water.

57. Use of said compound of formula 1 for the manufacture of a medicament for the treatment of an infection caused by one or more togaviruses in a treatment subject.

58. The use of embodiment 57, wherein the compound of formula 1 is a compound defined as compound group 1-21 or a metabolite thereof.

59. A method for enhancing biocompatibility of a therapeutic agent comprising administering to the subject a therapeutically effective amount of a compound of Formula 2A or 2B.

60. In an example 59, wherein the therapeutic agent is a steroid, steroid analog, antibacterial agent, antibiotic (eg nucleoside, nucleoside analog, nucleotide homologue, protease inhibitor or polymerase inhibitor) or antifungal agent (eg cancer cell) Tersin B).

61. The method of example 59, wherein the therapeutic agent is a compound of formula 1.

62. A method comprising administering an effective amount of a composition according to any one of items 50-54 to a subject that is susceptible to or infected with a togavirus infection (eg, HCV).

63. The method of example 62, wherein the subject is a human and the human is optionally co-infected with a retrovirus (eg, HIV1 or HIV2).

64. An effective amount of the compound of Formula 1 to the subject to be treated, wherein at least one of the togavirus infections in the subject is reduced or reduced replication of the togavirus. How to reduce or alleviate symptoms.

65. In an example 64, the compound of formula 1 is a compound as defined herein in the text, such as a compound as defined in the claims or compounds group 1-21 as originally filed or a compound of this kind, or a compound within this class range, Or the compound of Formula 1 is present in a composition containing one or more pharmaceutical excipients, such as in any combination as described or disclosed herein.

66. A compound of formula 1 above and at least one of which is a compound as defined herein or a compound within this class, such as a compound as defined in the claims or compound groups 1-21 as originally filed or a compound of this kind At least one excipient and a local anesthetic, wherein said local anesthetic is optionally selected from procaine, benzocaine and lidocaine.

67. A product produced by a process of contacting a compound of Formula 1, such as, for example, any compound defined by compound group 1-21 and a first excipient with a second excipient, wherein the product optionally further contains a local anesthetic; The local anesthetic is optionally a product selected from procaine, benzocaine and lidocaine.

68. A product produced by a process of contacting a compound of Formula 1, such as any compound defined by compound group 1-21 and a first non-aqueous liquid excipient, with a second non-aqueous liquid excipient, wherein the product is about 3% v optionally containing less than / v, or less than about 1% v / v, or less than about 0.5% v / v or less than about 0.1% v / v, wherein said first or second water-insoluble liquid excipient The above dimethyl sulfoxide, chloroform, dioxane, vegetable oil and olive oil are excluded, the product optionally further contains a local anesthetic, and the local anesthetic is optionally selected from procaine, benzocaine and lidocaine.

69. An effective amount of the composition of Example 66 or the product of Example 67 or 68 is administered to a patient having an abnormal disease or infectious disease, such as HCV, as described herein, thereby providing the infectious disease or abnormal disease, or How to alleviate, eliminate, treat, enhance or alleviate symptoms.

70. The method of embodiment 69, wherein the compound of formula 1 is 16α-haloepiandrosterone or 16α-halidehydroepiandrosterone.

The following examples further illustrate the invention and should not be construed as limiting the reaction thereto.

Example 1.16 α-bromoepiandrosterone Formulation 1.

Two non-aqueous formulations were prepared with 50 mg / mL concentration of 16a-bromoepiandrosterone ("BrEA") in 25% polyethylene glycol 300, 12.5% dehydrated ethyl alcohol, 5% benzyl benzoate, and 57.5% propylene glycol as follows: It was prepared as, hereinafter referred to as "compound 1". BrEA was purchased from Procyte, Inc. The remaining excipients are:

Excipient Detail Supplier's Lot No. Final product concentration Propylene glycol USP Arco ChemicalHOC-61220-01104 57.5% (v: v) Polyethylene Glycol 300 NF Union carbide695752 25% (v: v) Dehydrated Alcohol (ethanol) USP McComickDistilling97K10 12.5% (v: v) Benzyl benzoate USP Spectrum Pharmaceuticals MG025 5% (v: v)

After suspending BrEA in polyethylene glycol 300, propylene glycol, benzyl benzoate and dehydrating alcohol are added to form a solution to prepare a formulation which is diluted with further propylene glycol to the final desired volume. This process is as follows.

A predetermined amount of polyethylene glycol 300 was added to the compounding vessel. Thereafter, a mixture was added, and a predetermined amount of BrEA was added to this vessel and mixed for at least 5 minutes to form a soft creamy liquid. Porphylene glycol was added to this vessel and at least 5 minutes were mixed to produce a homogeneous suspension. An amount of benzyl benzoate was added to this vessel and mixed for approximately 5 minutes to form a clear liquid suspension. Dehydrated alcohol was added to this vessel and mixed for approximately 5 minutes to yield a clear colorless solution. Propylene glycol was then added to produce the desired final blend and mixed for about 5 minutes. The drug solution was transferred in succession to the concentration-dilution device through two 0.2 μm polyvinylidene fluoride filters prior to dilution in 2 cc brown glass vials. The vials were crimp sealed after capping with Teflon-coated, butyl-rubber stoppers.

The substances used in this potion bottle are:

matter Source Product code Detailed mention Vials Wheaton 2702-B51BA Tubing vial, 2 mL / 13 mm, glass, type 1 brown bottle Stopper omniflex V9239 FM257 / 2 13 mm, teflon coated, butyl rubber stopper Sealant West 4107 Flip sealant, 13 mmm, mist gray bridge

Example 2. BrEA Blend 2.

Benzyl Benzoate (USP) 30.4 $ w / w, Polyethylene Glycol 300 (NF) 30.7% w / w, Propylene Glycol (USP), qs, about 28% w / w and Benzyl Alcohol (NF) 1.9% w / A formulation containing 100 mg / mL of BrEA, 10% w / w in w was prepared as follows, hereinafter referred to as "Formulation 2". A predetermined amount of BrEA (1.0 kg) was suspended in a mixing vessel with PEG 300 (about 3.0 L) and mixed for at least about 5 minutes at room temperature to produce a soft creamy liquid. Thereafter, the required amount of propylene glycol (about 1.5 L) was added and mixing continued for at least 5 minutes to produce a homogeneous suspension. Thereafter, benzyl benzoate (about 3.0 L) was added and the material in the container was mixed for about 5 minutes to prepare a clear suspension. Thereafter, benzyl alcohol (about 200 mL) was added and mixing continued for about 5 minutes to yield a clear colorless solution. Thereafter, propylene glycol was added to achieve the final desired compounding volume (about 1.5 L) and mixing continued for about 5 minutes. This drug solution was transferred to a concentration-dilution device and divided into 1.2 mL per vial (2 mL, glass, type 1 brown vial). This blend was filtered under nitrogen pressurization (about 3 atm) continuously through two 0.2 μm polyvinylidene fluoride filters. These vials were capped using a Teflon-coated butyl rubber stopper, followed by crimp sealing essentially as in Example 1 above. This vial was stored in a low temperature dark room (about 2-8 ° C.).

Example 3. Clinical Study of the Human Body.

A clinical trial protocol was devised that performed with about 15-20 patients. For state I or I / II trials, patients were mildly infected with one or more togaviruses, such as HCV, and they became mildly symptomatic. Patients received 1, 2, or 3 weeks of treatment. In two or more administration groups, for example, 25, 50 or 100 mg / day of 16α-bromoepiandrosterone (BrEA) or its esters, 3, 4, wherein administration of parenteral administration such as intramuscular injection and intravenous injection started Or 5 days. Administration can be 2, 3 or 4 administrations in a single dose administered daily, continuously or at intermittent intervals, eg every other day. Formulations containing BrEA are as described above and are, for example, blends of Examples 1 or 2 above, preferably blends of Example 2 above. During the treatment week, and for more than one, two, three or more weeks thereafter, blood samples are taken at regular intervals to determine infectious diseases or their symptoms, pharmacokinetics, plasma cytokines (eg, IL-2, IL-4, IL-10, IGF1). , γIFN, GM-CSF), and intracellular cytokines (eg, IL-2, IL-4, IL-10, IGF1, γIFN, GM-CSF) were evaluated. Patients are optionally retreated using the same or similar protocol as used in the initial dosing protocol about 2-12 weeks after the start of dosing.

Claims (37)

Togavirus infection comprising the administration of an effective amount of a compound having the formula (1) and salts, stereoisomers, regioisomers, metabolites, homologues, precursors, hydrates, tautomers, ionized forms and solvates thereof to the subject of treatment To alleviate one or more of the symptoms of togavirus infection, or to treat or prevent togavirus infection in a patient susceptible to or suffering from: [Formula 1] In the formula, Q ₁ is -C (R ₁ ) ₂ -or -C (O)-; Q ₂ is —C (R ₁ ) ₂ —, —C (R ₁ ) (Y) —, —C (Y) — or —CH ₂ —CH ₂ —; Q ₃ is -H or -C (R ₁ ) _3- ; Q ₄ is -C (R ₁ ) _2- , -C (O)-, hydroxyvinylidene or methyl methylene; Q ₅ is -C (R ₁ ) ₂ -or -C (O)-; X and Y are -OH, -H, lower alkyl, -OC (O) -R ₅ , -C (O) -OR ₅ , halogen or = 0; Each R ₁ is independently —H, —F, —Cl, —Br, —I, —OH, C _1-6 alkoxy, or C _1-6 alkyl; R ₂ is independently —H, —OH, —F, —Cl, —Br, —I, C _1-6 alkyl, C _1-6 alkoxy, —OR ₃ , ester, thioester, thioacetal, sulfate ester, Sulfonate ester or carbamate, or R ₂ together with R ₁ bonded to the same carbon atom form ═O; R ₃ is -S (O) (O) -OM, -S (O) (O) -O-CH ₂ -CH (OC (O) -R ₆ ) -CH ₂ -OC (O) -R ₆ , -P (O) (O) -O-CH ₂ -CH (OC (O) -R ₇ ) -CH ₂ -OC (O) -R ₇ , or a glucuronide group having the formula A: [Formula A] Or R ₃ is C _1-18 alkyl, C _2-18 alkenyl, C _2-18 alkynyl, C _1-18 ester, or C _1-18 thioester, and C _1-18 or C _2-18 At least one of the substituents may be substituted with one or more hydrogen atoms each selected from -OR ^PR , -NHR ^PR or -SR ^PR , or R ₃ is C _1-18 fatty acid, C _2-10 alkynyl, ( J) _n -phenyl-C _1-5 -alkynyl or (J) _n -phenyl-C _2-5 -alkenyl; Each R ₅ is independently straight or branched C _1-14 alkyl; Each R ₆ is independently C _1-14 straight or branched alkyl; Each R ₇ is independently C _1-14 straight or branched alkyl or a glucuronide group of formula A; Each R ^PR is independently —H or each selected protecting group; n is 0, 1, 2 or 3; Each J is independently halogen, C _1-4 alkyl, C _2-4 alkenyl, C _1-4 alkoxy, carboxy, nitro, sulfate, sulfonyl, C _1-6 carboxy ester or C _1-6 sulfate ester ; M is hydrogen, sodium, -S (O) (O) -O-CH ₂ -CH (OC (O) -R ₆ ) -CH ₂ -OC (O) -R ₆ , -P (O) (O) -O-CH ₂ -CH (OC (O) -R ₇ ) -CH ₂ -OC (O) -R ₇ or a glucuronide group of Formula A; The dashed line represents any double bond, provided there are no double bonds at both positions 4-5 and 5-6, and if double bonds are present 1-, 2-, 4-, 5-, 6- or At position 17 one or more R ₁ groups bonded to the carbon atom become trivalent. The method of claim 1, wherein the togavirus infection is one or more of flavivirus infection pestivirus infection, rubyvirus infection, or alphavirus infection. The method of claim 2, wherein the compound of formula 1 is at least one compound selected from compound group 1-21. The method according to claim 2, wherein the togavirus infection is at least one hepatitis C virus, hepatitis G virus, California encephalitis virus, St. Louis encephalitis virus, western encephalitis virus, encephalitis virus, Colorado tick fever virus, lacrosse encephalitis virus, Japanese encephalitis virus, yellow fever virus, Venezuelan encephalitis virus, Murray valley fever virus GB virus A, GB virus B, GB virus C, dengue virus 1, dengue virus 2, dengue virus 3, dengue virus 4, Semiki forest virus, And at least one of human Rubella virus and Bovine viral diarrhea virus. The method of claim 4, wherein the compound of formula 1 is at least one compound selected from compound group 1-21. 5. The method of claim 4, wherein the togavirus infection is HCV, HGV, yellow fever virus, rubella virus or bovine virus diarrhea virus prasmodium bergei or tropic pyrophage infection. 6. The method of claim 5, wherein said subject is a human or a primate. 8. The method of claim 7, wherein said compound of formula 1 is at least one compound selected from compound groups 1-21. The method of claim 8, wherein the compound of Formula 1 is 16α-bromo-3β-hydroxy-5α-androstan-17-one or 16α-bromodehydroepiandrosterone. The method of claim 1, wherein said subject is co-infected with a retrovirus. The method of claim 10, wherein said subject is a human and said retrovirus is HIV1 or HIV2. The method of claim 1, wherein the compound of Formula 1 has the following Formula 1B or 1C: [Formula 1B] [Formula 1C] Wherein R ₁ is -H, -OH, halogen, -CHCH ₂ , -CHCHCH ₃ , -CCH, -CCCH ₃ , or there are no other substituents attached to the same carbon atom, and R ₁ is = O; R ₂ is -0-C (O) -R ₄ , -SC (O) -R ₄ , -OS (O) (O) -R ₄ , -OS (O) (O) -OR ₄ , -OC ( O) -NHR ₄ , or -OC (S) -R ₄ ; R ₄ is —H, a protecting group, optionally substituted C _1-18 alkyl, optionally substituted C _1-18 alkenyl, optionally substituted C _1-18 alkynyl, optionally substituted aryl, optionally substituted aryl-C _{1- 6} alkyl, optionally substituted aryl-C _2-6 alkenyl, optionally substituted aryl-C _2-6 alkynyl, optionally substituted heterocycle-C _1-6 alkyl, optionally substituted C _2-6 alkenyl-hetero Cycle, optionally substituted C _2-6 alkynyl-heterocycle, or optionally substituted heterocycle, wherein the substituents optionally represent one, two, three, four, or five or more carbon or hydrogen atoms. -, -NR ^PR- , -OR ^PR , -NHR ^PR , -SR ^PR , = O, = S, -CN, -NO ₂ , -F, -Cl, -Br or -I group selected from May be substituted; Each R ^PR is independently —H or an independently selected protecting group; Q ₂ is -C (R ₁ ) _2- ; Q ₃ and Q ₆ are —H, —CH ₃ or —CH ₂ OH, respectively. 13. The method of claim 12, wherein Q ₃ and Q ₆ are both -CH ₃ of β-configuration; Q ₂ is -CH _2- , -C (O)-, -CH (Br)-, CH (I)-, or -CH (OH)-having Br, I, OH in an α-array structure, or Q ₂ together with a hydrogen atom bonded to the same carbon atom forms —C (O) — or —CH ₂ —CH ₂ —; R ₁ at the 7-position is —H or —OH, or when taken with a hydrogen atom bonded to the same carbon atom, R ₁ is ═O. The method of claim 1, wherein the compound of formula 1 has the formula [Formula 1A] In the formula, R ₂ is —OH, halogen, C _1-6 alkoxy, —OR ₃ , C _1-18 fatty acid, C _1-10 alkynyl, (J) _n -phenyl-C _1-5 -alkyl, (J) _n − Phenyl-C _1-5 -alkenyl, or -OC (O)-(CH ₂ ) _m -R ₄ and -C (O) -O- (CH ₂ ) _m -R ₄ ), or R ₂ is -SC (O)-(CH ₂ ) _m -R ₄ or -C (O) -S- (CH ₂ ) _m -R ₄ , -OS (O) (O)-(CH ₂ ) _m- R ₄ , -OS (O) (O) -O- (CH ₂ ) _m -R ₄ , -OC (O) -NH- (CH ₂ ) _m -R ₄ , -NH-C (O) -O- (CH ₂ ) _m -R ₄ , -OC (S)-(CH ₂ ) _m -R ₄ or -C (S) -O- (CH ₂ ) _m -R ₄ , -OC (O)-(CH ₂ ) _m -R ₄ , or -C (O) -O- (CH ₂ ) _m -R ₄ , or R ₂ together with R ₁ bonded to the same carbon atom form ═O; R ₄ is H, a protecting group, optionally substituted C _1-18 alkyl, optionally substituted C _2-18 alkenyl, optionally substituted C _2-18 alkynyl, optionally substituted aryl, optionally substituted aryl-C _1-6 Alkyl, optionally substituted aryl-C _2-6 alkenyl, optionally substituted aryl-C _2-6 alkynyl, optionally substituted heterocycle-C _1-6 alkyl, optionally substituted C _2-6 alkenyl-hetero cycle , Optionally substituted C _2-6 alkynyl-heterocycle or optionally substituted heterocycle, wherein any one of said substituents optionally has one, two, three, four, five or more carbon or hydrogen atoms —O—, —S—, NR ^PR Can be substituted with one or more selected from-, -OR ^PR , -NHR ^PR , -SR ^PR , = O, = S, -CN, -NO ₂ , -F, -Cl, -Br or -I substituent or atom, respectively And; Each R ^PR is independently —H or each selected protecting group; m is 0, 1, 2 or 3; Dotted line is any double bond. The method of claim 1, wherein the compound of Formula 1 has the formula [Formula 45] Wherein R ₅₀ is -H, -OH or = O; R ₅₁ is -Br, -Cl, -F or -I; R ₅₂ is -OH, or R ₅₂ forms -O with -H bonded at the same position; R ₄₉ is -H, -OH or -OR ₅₃ ; R ₅₃ is C _1-18 alkyl, C _2-18 alkenyl, C _2-18 alkynyl, C _1-18 ester, C _1-18 thioester, wherein the C _1-18 or C _2-18 substituent Any one of the at least one hydrogen atom may be substituted with at least one selected from the group -O-, -S-, -OH, -NH ₂ , -SH = O, or R ₅₃ is thioacetal, sulfate ester, sulfo Nate esters, carbamates or thioesters; Dotted line is any double bond. The compound of claim 15, wherein R ₄₉ is —OC (O) —CH ₂ —CH ₂ —CH (R ₅₄ ) —CH (R ₅₅ ) —CH ₂ R ₅₆ , wherein R ₅₄ is —NH, —OH, -SH, -O-PO ₃ , -SO ₃ or -OSO ₃ ; R ₅₅ is —H, —NH ₂ , —OH, —SH, —O—PO ₃ , —SO ₃ or —OSO ₃ ; R ₅₆ is C _1-18 alkyl, C _2-18 alkenyl, C _2-18 alkynyl, C _1-18 ester, C _1-18 thioester, wherein the C _1-18 or C _2-18 substituent Wherein any one or more hydrogen atoms may be substituted with one or more selected from among —OH, —NH ₂ , or —SH groups, respectively. The method of claim 1, wherein the compound of Formula 1 has the formula [Formula 44] Wherein Y is hydrogen or bromine, R ₄₄ is -H, -S (O) (O) -OH, -S (O) (O) -ONa, -S (O) (O) -O-CH ₂ -CH (OC (O) -R ₆ ) -CH ₂ -OC (O) -R ₆ , -P (O) (O) -O-CH ₂ -CH (OC (O) -R ₇ ) -CH ₂ -OC (O) -R ₇ , Or a glucuronide group of Formula A; Dotted line is any double bond. The compound according to claim 17, wherein the compound of Formula 44 is dehydroepiandrosterone, epiandrosterone, 16α-bromodehydroepiandrosterone, dehydroepiandrosterone-3-sulfate or 5β-androsterone-3β-ol-17 How to be on. The method of claim 1, wherein the method further comprises bevacinin A, didamine, flavanomarei, flavanone azine, flavanone diacetylhydrazone, flavanone hydrazone, sillandrin, silibine, silicistine, Plasma concentrations selected from isosilbin, a compound of formula E and a compound of formula 2A or 2B, and salts, stereoisomers, regioisomers, metabolites, homologues, precursors, hydrates, tautomers, ionized forms and solvates thereof A method comprising administering an effective amount of an enhancing compound simultaneously or sequentially: [Formula E] [Formula 2A] [Formula 2B] Wherein a double bond or a single bond is present in the dashed line, and when a double bond is present, (i) an optionally substituted phenyl ring is present at the 2- or 3-position and R ₈ bonded to this carbon atom is not present; And (ii) there is no one R ₈ in the adjacent 2- or 3- position; X ₁ is —O— or —C (R ₈ ) ₂ —; X ₂ is -CO- or -C (R ₁₁ ) _2- ; Each R ₈ may independently form a substituent of —H, —OH, halogen, C _1-6 alkyl, C _1-6 alkoxy, glocuronide, C _1-25 fatty acid, or a compound of Formula 2A or 2B The residue of the compound of formula 2A or 2B wherein the hydrogen atom has been removed, -CH ₂ CH = C (CH ₃ ) ₂ , glucoside, a substituent having the structure of formula B or C: [Formula B] [Formula C] R ₁₀ is C _1-6 alkyl, C _1-6 alkoxy, neohesperidoside, apiglucoside, lutinoside, glucoside, galactoside, rhamnoside, arabinoside, or the stereoisomer of any of these substituents , Hydrate, homologue, derivative, or metabolite, any of which optionally represents one or more hydrogen atoms each -OH, halogen, C _1-6 alkyl, C _1-6 alkoxy, glucuronide or C _1-25 fatty acid Or R ₁₀ is —H, —OH or halogen; Each R ₁₁ is independently —H, —OH, halogen, C _1-6 alkyl, C _1-6 alkoxy, glucuronide, C _1-25 fatty acid, or both R ₁₁ together form ═O . 20. The method of claim 19, wherein said plasma concentration-enhancing compound is naringin or naringenin. The method of claim 20, wherein said subject is a human or a primate. The method of claim 21, wherein Formula 1 and the plasma concentration-promoting compound are administered simultaneously. 20. The method of claim 19, further comprising administering to or treating the subject with one or more of ribavirin, alpha interferon, macrophage stimulating factor, oxidant, and oxygen supply. The method of claim 23, wherein said plasma concentration-enhancing compound is naringin or naringinin. The method of claim 24, wherein said subject is a human or a primate. The method of claim 25, wherein the compound of Formula 1 and the plasma concentration-promoting compound are administered simultaneously. A method of enhancing the biocompatibility of a therapeutic agent, which comprises administering an effective amount of a plasma concentration-enhancing compound to a therapeutic subject. The method of claim 27, wherein the plasma concentration-enhancing compound is naringin or naringenin, or the plasma concentration-enhancing compound has the formula (2A) or 2B, and salts, stereoisomers, regioisomers, metabolites, Methods are homologues, precursors, hydrates, tautomers, ionized forms and solvates: [Formula 2A] [Formula 2B] Wherein a double bond or a single bond is present in the dashed line, and when a double bond is present, (i) an optionally substituted phenyl ring is present at the 2- or 3-position and R ₈ bonded to this carbon atom is not present; And (ii) there is no one R ₈ in the adjacent 2- or 3- position; X ₁ is —O— or —C (R ₈ ) ₂ —; X ₂ is -CO- or -C (R ₁₁ ) _2- ; Each R ₈ may independently form a substituent of —H, —OH, halogen, C _1-6 alkyl, C _1-6 alkoxy, glocuronide, C _1-25 fatty acid, or a compound of Formula 2A or 2B The residue of the compound of formula 2A or 2B wherein the hydrogen atom has been removed, -CH ₂ CH = C (CH ₃ ) ₂ , glucoside, a substituent having the structure of formula B or C: [Formula B] [Formula C] R ₁₀ is C _1-6 alkyl, C _1-6 alkoxy, neohesperidoside, apiglucoside, lutinoside, glucoside, galactoside, rhamnoside, arabinoside, or the stereoisomer of any of these substituents , Hydrate, homologue, derivative, or metabolite, any of which optionally represents one or more hydrogen atoms each -OH, halogen, C _1-6 alkyl, C _1-6 alkoxy, glucuronide or C _1-25 fatty acid Or R ₁₀ is —H, —OH or halogen; Each R ₁₁ is independently —H, —OH, halogen, C _1-6 alkyl, C _1-6 alkoxy, glucuronide, C _1-25 fatty acid, or both R ₁₁ together form ═O . 28. The method of claim 27, wherein said therapeutic agent is a steroid, a steroid homologue, an antibacterial agent, an antibiotic or an antifungal agent. The method of claim 27, wherein the therapeutic agent is a compound having Formula 1 and salts, stereoisomers, regioisomers, metabolites, homologues, precursors, hydrates, tautomers, ionized forms and solvates thereof. [Formula 1] In the formula, Q ₁ is -C (R ₁ ) ₂ -or -C (O)-; Q ₂ is —C (R ₁ ) ₂ —, —C (R ₁ ) (Y) —, —C (Y) — or —CH ₂ —CH ₂ —; Q ₃ is -H or -C (R ₁ ) _3- ; Q ₄ is -C (R ₁ ) _2- , -C (O)-, hydroxyvinylidene or methyl methylene; Q ₅ is -C (R ₁ ) ₂ -or -C (O)-; X and Y are -OH, -H, lower alkyl, -OC (O) -R ₅ , -C (O) -OR ₅ , halogen or = 0; Each R ₁ is independently —H, —F, —Cl, —Br, —I, —OH, C _1-6 alkoxy, or C _1-6 alkyl; R ₂ is independently —H, —OH, —F, —Cl, —Br, —I, C _1-6 alkyl, C _1-6 alkoxy, —OR ₃ , ester, thioester, thioacetal, sulfate ester, Sulfonate ester or carbamate, or R ₂ together with R ₁ bonded to the same carbon atom form ═O; R ₃ is -S (O) (O) -OM, -S (O) (O) -O-CH ₂ -CH (OC (O) -R ₆ ) -CH ₂ -OC (O) -R ₆ , -P (O) (O) -O-CH ₂ -CH (OC (O) -R ₇ ) -CH ₂ -OC (O) -R ₇ , or a glucuronide group having the formula A: [Formula A] Or R ₃ is C _1-18 alkyl, C _2-18 alkenyl, C _2-18 alkynyl, C _1-18 ester, or C _1-18 thioester, and C _1-18 or C _2-18 Any one or more of the substituents may be substituted with one or more hydrogen atoms selected from -OR ^PR , -NHR ^PR or -SR ^PR , respectively, or R ₃ is C _1-18 fatty acid, C _2-10 alkynyl, ( J) _n -phenyl-C _1-5 -alkynyl or (J) _n -phenyl-C _2-5 -alkenyl; Each R ₅ is independently straight or branched C _1-14 alkyl; Each R ₆ is independently C _1-14 straight or branched alkyl; Each R ₇ is independently C _1-14 straight or branched alkyl or a glucuronide group of formula A; Each R ^PR is independently —H or each selected protecting group; n is 0, 1, 2 or 3; Each J is independently halogen, C _1-4 alkyl, C _2-4 alkenyl, C _1-4 alkoxy, carboxy, nitro, sulfate, sulfonyl, C _1-6 carboxy ester or C _1-6 sulfate ester ; M is hydrogen, sodium, -S (O) (O) -O-CH ₂ -CH (OC (O) -R ₆ ) -CH ₂ -OC (O) -R ₆ , -P (O) (O) -O-CH ₂ -CH (OC (O) -R ₇ ) -CH ₂ -OC (O) -R ₇ or a glucuronide group of Formula A; The dashed line represents any double bond, provided there are no double bonds at both positions 4-5 and 5-6, and if double bonds are present 1-, 2-, 4-, 5-, 6- or At position 17 one or more R ₁ groups bonded to the carbon atom become trivalent. An effective amount of a composition containing 16α-bromoepiandrosterone and polyethylene glycol, dehydrated ethanol, benzyl benzoate, benzyl alcohol, and propylene glycol is administered to the subject to be treated, wherein the composition is optionally about 3% v / Subjects suffering from or suffering from togavirus infection, consisting of less than v, less than about 1% v / v, or less than about 0.5% v / v or less than about 0.1% v / v of water A method of treating, alleviating one or more symptoms associated with togavirus infection, or treating or preventing togavirus infection. 32. The composition of claim 31 wherein the composition contains 16α-bromoepiandrosterone at a concentration of about 15-55 mg / mL and comprises 20-30% v / v polyethylene glycol 300, polyethylene glycol 400 or polyethylene glycol 300 and 400 A mixture containing 10-15% v / v dehydrated ethyl alcohol, 2.5-7.5% v / v benzyl benzoate, and 55-60% v / v propylene glycol. 33. The composition of claim 32, wherein the composition contains 16α-bromoepiandrosterone at a concentration of about 50 mg / mL, 25% v / v polyethylene glycol 300, polyethylene glycol 400 or a mixture of polyethylene glycol 300 and 400, 12.5 % v / v dehydrated ethyl alcohol, 5% v / v benzyl benzoate, and 57.5% v / v propylene glycol and 0.5% v / v water. 32. The composition of claim 31, wherein the composition contains 16α-bromoepiandrosterone at a concentration of about 85-105 mg / mL, about 27-33% w / w benzyl benzoate, about 27-33% w / w Polyethylene glycol 300, about 25-30% w / w propylene glycol and 1-3% w / w benzyl alcohol. The composition of claim 34, wherein the composition contains 16α-bromoepiandrosterone at a concentration of about 100 mg / mL, about 30.4% w / w benzyl benzoate, about 30.7% w / w polyethylene glycol 300, about 28 a process comprising% w / w propylene glycol and 1.9% w / w benzyl alcohol. The method of claim 1, wherein R ₁ of 2, 3, 4, 5 or 6 is not hydrogen. 28. The method of claim 27, wherein R ₁ of 2, 3, 4, 5 or 6 which is not hydrogen is each selected from -OH, halogen and C _2-4 alkoxy.