CN101287744A

CN101287744A - Antiviral compounds

Info

Publication number: CN101287744A
Application number: CNA2006800221718A
Authority: CN
Inventors: E·阿然兹普拉泽; K·M·耶格; D·A·格里什; M·B·安德森; I·C·金; D·V·库玛
Original assignee: Myriad Pharmaceuticals Inc
Current assignee: Myrexis Inc
Priority date: 2005-06-22
Filing date: 2006-06-22
Publication date: 2008-10-15

Abstract

The present invention relates to compounds, pharmaceutical compositions and methods useful for treating viral infection.

Description

Antiviral compounds

Cross reference to related U.S. applications

Priority is claimed for U.S. provisional application No. 60/692,826 filed on 22/6/2005 and U.S. provisional application No. 60/765,790 filed on 7/2/2006, the contents of each of which are incorporated herein by reference in their entirety.

Technical Field

The present invention relates generally to methods, compounds and pharmaceutical compositions for treating (and delaying the onset of) viral infections. The compositions and methods of the present invention are useful for treating viral infections caused by viruses such as HIV, hepatitis B virus, hepatitis C virus, herpes simplex virus type 1, herpes simplex virus type 2, herpes simplex virus type 4 (Epstein-Barr virus), influenza virus, smallpox virus, coronavirus (i.e., SARS-associated virus), and West Nile virus.

Background

Viral infection in humans is a major health problem, and viral infection in domesticated animals is a major economic problem. Combating viral infections has proven to be highly effective in certain situations, such as smallpox, where the disease is essentially eradicated with the advent of vaccinia vaccination. Although smallpox has been essentially eradicated by about 1980, there are many concerns about the resurgence of smallpox due to the existence of this viral source and the fact that bioterrorism is far from being possible and practical. Other viral infections have been more difficult to combat. Hepatitis b and c, Human Immunodeficiency Virus (HIV), herpes simplex virus, and influenza are just a few prominent members of a range of viruses that pose significant health threats worldwide. In addition, the emerging viral infections continue to threaten the world with human epidemics, such as the recent outbreak of Severe Acute Respiratory Syndrome (SARS), now associated with coronavirus infection. Current treatments that are effective against many viral infections often have deleterious side effects. Furthermore, antiviral treatments directed against specific viral gene products often have the effect of leading to the selection of viruses that are resistant to such treatments, and viral strains that are resistant to current treatment methods are an increasing problem. Thus, there is a clear and ongoing need for new antiviral treatments.

Disclosure of Invention

The present invention relates generally to compounds and methods for treating viral infections. Furthermore, the invention also relates to the treatment of symptoms caused by viral infections and/or to the delay of the onset of such symptoms. The present invention provides compounds of formula I', including compounds of formula I-IV, and pharmaceutical compositions comprising one or more compounds of formula I-IV and one or more pharmaceutically acceptable excipients. The compounds of formula I' and formula I-IV include the following and pharmaceutically acceptable salts and stereoisomers thereof:

wherein:

q is (CH)₂)_1-2；

L is an alkyl group having 0 to 10 carbon atoms which may be saturated or partially saturated; one or more carbon atoms of the alkyl group L may be replaced by-O-, -S-, -N-, -C (═ O) -, -NC (═ O) -, -C (═ O) N-, -SO-, -C ═ O) -, and₂、-NSO₂、-SO₂n-, cycloalkyl and-NC (═ O) N-substitutions; l may be substituted with one or more substituents selected from: hydroxy, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, -N (C)_1-3Alkyl radical)₂、-NH(C_1-3Alkyl), -C (═ O) OH, -C (═ O) O (C)_1-3Alkyl), -C (═ O) NH₂、-C(＝O)NH(C_1-3Alkyl), -C (═ O) N (C)_1-3Alkyl radical)₂、-S(＝O)₂(C_1-3Alkyl), -S (═ O)₂NH₂、-S(＝O)₂N(C_1-3Alkyl radical)₂、-S(＝O)₂NH(C_1-3Alkyl), -CHF₂、-OCF₃、-OCHF₂、-SCF₃、-CF₃、-CN、-NH₂and-NO₂；

R1 is selected from hydrogen, -C (═ O) - (CH)₂)_m-CH₃、-C(＝O)-(CH₂)_m-C(CH₃)₂-COOH；

R2 is selected from cycloalkyl, aryl, heterocycle and heteroaryl, which may be optionally substituted with one or more substituents selected from: hydrogen, hydroxy, halogen, alkyl, alkoxy, alkylthio, arylthio, thiocarbonyl, O-carboxy, C-carboxy, O-carbamoyl, O-thiocarbamoyl, N-carbamoyl, N-thiocarbamoyl, ester, haloalkyl, haloalkoxy, cycloalkyl, aryl, heteroaryl, heterocycle, -C (═ O) OH, -CH (CH)₃)C(＝O)OH；-CH₂C(＝O)OH、-C(CH₃)₂C(＝O)OH、-C(CH₃)(CH₂CH₃)C(＝O)OH、-CH(CH₂CH₃)C(＝O)OH、-CH＝C(CH₃)C(＝O)OH、-C(CH₂CH₃)₂C(＝O)OH、-N(C_1-3Alkyl radical)₂、-NH(C_1-3Alkyl), -C (═ O) NH₂、-C(＝O)NH(C_1-3Alkyl), -C (═ O) N (C)_1-3Alkyl radical)₂、-S(＝O)₂(C_1-3Alkyl), -S (═ O)₂NH₂、-S(＝O)₂N(C_1-3Alkyl radical)₂、-S(＝O)₂NH(C_1-3Alkyl), -CHF₂、-OCF₃、-OCHF₂、-SCF₃、-CF₃、-CN、-NH₂and-NO₂；

m is an integer selected from 0 to 10; and is

R3 and R4 are independently selected from-H, -CH₃、-(CH₃)₂、-CH(CH₃)₂and-C (═ CH)₂)CH₃。

Accordingly, the present invention provides, in a related aspect, methods of treating a viral infection by administering to a patient in need of treatment for a viral infection a pharmaceutical composition or medicament containing a therapeutically (or prophylactically) effective amount of a compound of formulae I-IV.

In another aspect, the invention also provides methods of inhibiting viral maturation by administering to a patient in need of such treatment a pharmaceutical composition or medicament containing a compound of formulae I-IV in an amount sufficient to inhibit viral maturation from human or animal cells. In a particular aspect of this embodiment of the invention, the method of inhibiting viral maturation comprises treating a human infected with a virus with a compound of formulae I-IV.

In addition, the present invention provides methods of delaying the onset of symptoms of a viral infection comprising administering to an individual infected with or at risk of being infected with the virus or at risk of developing symptoms of a viral infection a pharmaceutical composition or medicament comprising a prophylactically effective amount of a compound of formulae I-IV. In a particular aspect of this embodiment of the invention, the method of inhibiting or delaying the onset of symptoms of a viral infection comprises treating a human infected with the virus with a compound of formulae I-IV.

In one aspect of the invention, a method is provided for treating a human who is a carrier of any HIV family retrovirus, i.e., infected with HIV but has not yet developed AIDS (AIDS is defined as the more severe AIDS-defining disease and/or the number of circulating CD4 cells drops below a level that is tolerated by effective immune function). The method comprises identifying such an individual in need of treatment and administering to the individual a pharmaceutical composition or medicament containing a therapeutically effective amount of a compound of formulae I-IV. The method is therefore useful for treating acute primary HIV infection syndrome (which may be asymptomatic or associated with influenza-like disease with fever, malaise, diarrhea and neurological symptoms such as headache) or asymptomatic infection (asymptomatic infection is a long incubation period with a gradual decrease in the number of circulating CD4T cells).

In another aspect, the invention provides a method of treating a human actively infected with Hepatitis B Virus (HBV), Hepatitis C Virus (HCV), or a carrier of such a virus that has not developed symptoms of such a viral infection (the symptoms being defined as liver damage) or has experienced a reduction in such symptoms, or has recently been exposed to such a virus. The method comprises identifying such a subject in need of treatment and administering to the subject a pharmaceutical composition or medicament comprising a therapeutically effective amount or a prophylactically effective amount of a compound of formulae I-IV.

In another aspect of the invention, a method is provided for treating a human actively infected with herpes simplex virus type 1, herpes simplex virus type 2, or herpes simplex virus type 4 (also known as epstein-barr virus), or a carrier of such a virus that has not developed symptoms of such a virus infection or has experienced a reduction in such symptoms, or has recently been exposed to such a virus. The method comprises identifying such a subject in need of treatment and administering to the subject a pharmaceutical composition or medicament comprising a therapeutically effective amount or a prophylactically effective amount of a compound of formulae I-IV.

In another aspect of the invention, a method is provided for treating a human actively infected with influenza a, b or c virus, or a carrier of such a virus that has not developed symptoms of such a viral infection or has experienced a reduction in such symptoms, or has recently been exposed to such a virus. The method comprises identifying such a subject in need of treatment and administering to the subject a pharmaceutical composition or medicament comprising a therapeutically effective amount or a prophylactically effective amount of a compound of formulae I-IV.

In another aspect of the invention, a method is provided for treating a human actively infected with any one of the viruses of the poxvirus family, i.e., a smallpox virus, or a carrier of such a virus that has not yet developed symptoms of such a viral infection (the symptoms being defined as more severe smallpox-defining disease) or has experienced a reduction in such symptoms, or has recently been exposed to such a virus. The method comprises identifying such a subject in need of treatment and administering to the subject a pharmaceutical composition or medicament comprising a therapeutically effective amount or a prophylactically effective amount of a compound of formulae I-IV.

In another aspect of the invention, a method is provided for treating a human infected with any one of the viral activities of the coronavirus family, i.e., with a SARS-associated coronavirus activity, or a carrier of such a virus that has not developed symptoms of such viral infection (which symptoms are defined as more severe SARS-defined disease) or has experienced a reduction in such symptoms, or has recently been exposed to such a virus. The method comprises identifying such a subject in need of treatment and administering to the subject a pharmaceutical composition or medicament containing a prophylactically effective amount of a compound of formulae I-IV.

In another aspect of the invention, a method is provided for treating a human or animal actively infected with West Nile Virus, or a carrier of West Nile Virus that has not developed symptoms of such viral infection or has experienced a reduction in such symptoms, or has recently been exposed to West Nile Virus. The method comprises identifying such a subject in need of treatment and administering to the subject a pharmaceutical composition or medicament containing a prophylactically effective amount of a compound of formulae I-IV.

The compounds of formulae I-IV used in the present invention may be provided as a pharmaceutical composition containing one or more salts, carriers or excipients. Some of the compounds used in the present invention have chiral centers and therefore the present invention includes the use of all stereoisomers, enantiomers, diastereomers and mixtures thereof of said compounds.

The invention also provides pharmaceutical compositions or medicaments for use in the combined treatment of viral infections. The composition contains a therapeutically effective amount of a first compound of formulas I-IV and a therapeutically effective amount of a second antiviral compound, the second compound being different from the first compound. Examples of antiviral compounds include, but are not limited to, protease inhibitors, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, integrase inhibitors, fusion inhibitors, maturation inhibitors, immunomodulators and vaccines.

The compounds of the invention are useful for treating a variety of other diseases or conditions, such as hypertension, cancer (including cancer metastasis), immune system related diseases, autoimmune diseases, bacterial infections (e.g., in the digestive tract), retinopathy, and neurological disorders.

The foregoing and other advantages and features of the invention and the manner of attaining them will become more apparent upon consideration of the following detailed description of the invention, along with the accompanying examples which illustrate preferred and exemplary embodiments.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

Other features and advantages of the invention will become apparent from the following detailed description, and from the claims.

Detailed Description

The present invention provides compounds of formula I', including compounds of formulae I-IV, which are useful for treating viral infections and symptoms thereof. The compounds of formula I' and formula I-IV include the following compounds and pharmaceutically acceptable salts and stereoisomers thereof:

wherein:

q is (CH)₂)_1-2；

R2 is selected from cycloalkyl, aryl, heterocycle and heteroaryl, which may be optionally substituted with one or more substituents selected from: H. hydroxy, halogen, alkyl, alkoxy, alkylthio, arylthio, thiocarbonyl, O-carboxy, C-carboxy, O-carbamoyl, O-thiocarbamoyl, N-carbamoyl, N-thiocarbamoyl, ester, haloalkyl, haloalkoxy, cycloalkyl, aryl, heteroaryl, heterocycle, -C (═ O) OH, -CH (CH)₃)C(＝O)OH；-CH₂C(＝O)OH、-C(CH₃)₂C(＝O)OH、-C(CH₃)(CH₂CH₃)C(＝O)OH、-CH(CH₂CH₃)C(＝O)OH、-CH＝C(CH₃)C(＝O)OH、-C(CH₂CH₃)₂C(＝O)OH、-N(C_1-3Alkyl radical)₂、-NH(C_1-3Alkyl), -C (═ O) NH₂、-C(＝O)NH(C_1-3Alkyl), -C (═ O) N (C)_1-3Alkyl radical)₂、-S(＝O)₂(C_1-3Alkyl), -S (═ O)₂NH₂、-S(＝O)₂N(C_1-3Alkyl radical)₂、-S(＝O)₂NH(C_1-3Alkyl), -CHF₂、-OCF₃、-OCHF₂、-SCF₃、-CF₃、-CN、-NH₂and-NO₂；

m is an integer selected from 0 to 10; and is

In one of the formulae I to IVIn some embodiments, R1 is-C (═ O) - (CH)₂)_m-CH₃And m is an integer selected from 0 to 10. In some embodiments of formulas I-IV, R1 is-C (═ O) - (CH)₂)_m-C(CH₃)₂-COOH, and m is an integer selected from 0 to 10. In particular embodiments of formulae I-IV, L is an alkyl group having 0, 1, 2, 3, 4, or 5 carbon atoms, which alkyl group may be saturated or partially saturated; and the carbon atom may be substituted and/or substituted as described above for L.

In some embodiments, L may have one or more substituents selected from halogen, alkyl, haloalkyl, -C (═ O) OH, -C (═ O) O (C)_1-3Alkyl), -C (═ O) NH₂、-C(＝O)NH(C_1-3Alkyl), -C (═ O) N (C)_1-3Alkyl radical)₂、-CHF₂、-CF₃And a substituent of-CN. In some embodiments, L may have one or more substituents selected from hydroxy, alkoxy, haloalkoxy, -S (═ O)₂(C_1-3Alkyl), -S (═ O)₂NH₂、-S(＝O)₂N(C_1-3Alkyl radical)₂、-S(＝O)₂NH(C_1-3Alkyl), -OCF₃、-OCHF₂and-SCF₃A substituent of (1). In certain embodiments, L may have one or more groups selected from-N (C)_1-3Alkyl radical)₂、-NH(C_1-3Alkyl), -NH₂and-NO₂A substituent of (1).

In some embodiments, R2 is substituted with one or more substituents selected from halogen, alkyl, C-carboxy, haloalkyl, -C (═ O) OH, -CH (CH)₃)C(＝O)OH；-CH₂C(＝O)OH、-C(CH₃)₂C(＝O)OH、-C(CH₃)(CH₂CH₃)C(＝O)OH、-CH(CH₂CH₃)C(＝O)OH、-CH＝C(CH₃)C(＝O)OH、-C(CH₂CH₃)₂C(＝O)OH、-C(＝O)NH₂、-C(＝O)NH(C_1-3Alkyl), -C (═ O) N (C)_1-3Alkyl radical)₂、-CHF₂、-CF₃And a phenyl group substituted with a substituent of-CN.

In some embodiments, R2 is substituted with one or more substituents selected from the group consisting of hydroxy, alkoxy, alkylthio, arylthio, thiocarbonyl, O-carboxy, O-carbamoyl, O-thiocarbamoyl, ester, haloalkoxy, -S (═ O)₂(C_1-3Alkyl), -S (═ O)₂NH₂、-S(＝O)₂N(C_1-3Alkyl radical)₂、-S(＝O)₂NH(C_1-3Alkyl), -OCF₃、-OCHF₂and-SCF₃A phenyl group substituted with the substituent(s) of (1).

In some embodiments, R2 is substituted with one or more groups selected from N-carbamoyl, N-thiocarbamoyl, -N (C)_1-3Alkyl radical)₂、-NH(C_1-3Alkyl), -NH₂and-NO₂A phenyl group substituted with the substituent(s) of (1). In certain embodiments, R2 is a phenyl group substituted with one or more substituents selected from the group consisting of cycloalkyl, aryl, heteroaryl, and heterocycle.

In one embodiment, the present invention provides compounds of formula i (a) -iv (a):

wherein:

r1 is-C (═ O) -CH₂-C(CH₃)₂-COOH；

R2 is selected from the group consisting of cycloalkyl, aryl, heterocyclic and heteroaryl rings, which are optionally substituted with one or more substituents selected from the group consisting of: hydrogen, hydroxy, halogen, alkyl, alkoxy, alkylthio, arylthio, thiocarbonyl, O-carboxy, C-carboxyO-carbamoyl, O-thiocarbamoyl, N-carbamoyl, N-thiocarbamoyl, ester, haloalkyl, haloalkoxy, cycloalkyl, aryl, heteroaryl, heterocycle, -C (═ O) OH, -CH (CH)₃)C(＝O)OH；-CH₂C(＝O)OH、-C(CH₃)₂C(＝O)OH、-C(CH₃)(CH₂CH₃)C(＝O)OH、-CH(CH₂CH₃)C(＝O)OH、-CH＝C(CH₃)C(＝O)OH、-C(CH₂CH₃)₂C(＝O)OH、-N(C_1-3Alkyl radical)₂、-NH(C_1-3Alkyl), -C (═ O) NH₂、-C(＝O)NH(C_1-3Alkyl), -C (═ O) N (C)_1-3Alkyl radical)₂、-C(＝O)NH(C_1-3Alkyl) NHC (═ O) (C)_1-3Alkyl), -S (═ O)₂(C_1-3Alkyl), -S (═ O)₂NH₂、-S(＝O)₂N(C_1-3Alkyl radical)₂、-S(＝O)₂NH(C_1-3Alkyl), -CHF₂、-OCF₃、-OCHF₂、-SCF₃、-CF₃、-CN、-NH₂and-NO₂；

n is an integer selected from 0, 1, 2 and 3.

In one embodiment, the present invention provides compounds of formula i (a) -iv (a) wherein R1 is-C (═ O) -CH, and pharmaceutical compositions comprising the compounds and one or more pharmaceutically acceptable excipients₂-C(CH₃)₂-COOH; r2 is a phenyl group optionally substituted with one or more substituents selected from the group consisting of: hydroxy, halogen, alkyl, alkoxy, alkylthio, arylthio, thiocarbonyl, O-carboxy, C-carboxy, O-carbamoyl, O-thiocarbamoyl, N-carbamoyl, N-thiocarbamoyl, ester, haloalkyl, haloalkoxy, cycloalkyl, aryl, heteroaryl, heterocycle, -C (═ O) OH, -CH (CH)₃)C(＝O)OH；-CH₂C(＝O)OH、-C(CH₃)₂C(＝O)OH、-C(CH₃)(CH₂CH₃)C(＝O)OH、-CH(CH₂CH₃)C(＝O)OH、-CH＝C(CH₃)C(＝O)OH、-C(CH₂CH₃)₂C(＝O)OH、-N(C_1-3Alkyl radical)₂、-NH(C_1-3Alkyl), -C (═ O) NH₂、-C(＝O)NH(C_1-3Alkyl), -C (═ O) N (C)_1-3Alkyl radical)₂、-S(＝O)₂(C_1-3Alkyl), -S (═ O)₂NH₂、-S(＝O)₂N(C_1-3Alkyl radical)₂、-S(＝O)₂NH(C_1-3Alkyl), -CHF₂、-OCF₃、-OCHF₂、-SCF₃、-CF₃、-CN、-NH₂and-NO₂(ii) a And n is an integer selected from 0, 1, 2 and 3.

In one embodiment, the stereochemistry of the betulin core moiety is preserved. For example, a compound of the invention may have the stereochemistry of formula i (b):

wherein L, R1 and R2 are as defined above for formula I.

One pharmaceutically acceptable salt of the compounds of the present invention is exemplified by the following salts: a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like; and salts with an organic acid such as acetic acid, propionic acid, succinic acid, maleic acid, fumaric acid, benzoic acid, citric acid, malic acid, methanesulfonic acid, benzenesulfonic acid, and the like. Hydrates (1 hydrate, 2 hydrate, 3 hydrate, 1/2 hydrate, 3/2 hydrate, 1/4 hydrate, 4/5 hydrate, 1/5 hydrate, 3/4 hydrate, 1/3 hydrate, 5/3 hydrate, 5/4 hydrate, etc.), solvates, and the like thereof are also included in the compound of the present invention. In addition, N-oxides are also included in the compounds of the present invention.

In addition, pharmaceutically acceptable salts include acid salts of inorganic bases, such as salts containing alkali metal cations (e.g., Li +, Na +, or K +), alkaline earth metal cations (e.g., Mg + +, Ca + +, or Ba + +), ammonium cations, and acid salts of organic bases, including aliphatic and aromatic substituted ammonium and quaternary ammonium cations, such as substituted ammonium and quaternary ammonium cations resulting from the protonation of the peralkylation of triethylamine, N-diethylamine, N-dicyclohexylamine, pyridine, N-Dimethylaminopyridine (DMAP), 1, 4-diazabicyclo [2.2.2] octane (DABCO), 1, 5-diazabicyclo [4.3.0] non-5-ene (DBN), and 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU).

Furthermore, the compounds of the formulae I to IV may comprise asymmetric carbon atoms and can therefore exist in racemic and optically active forms. Thus, optical isomers or enantiomers, racemates and diastereomers are also included in the compounds of formulae I-IV. The process of the present invention includes the use of all such isomers and mixtures thereof. Methods for separating enantiomeric and diastereomeric mixtures are well known to those skilled in the art. The present invention includes any isolated racemic or optically active form of the compounds of formulae I-IV, or any mixture thereof, which has antiviral activity.

In one embodiment of the invention, the stereochemistry of the compounds of formulae I-IV is equivalent to the stereochemistry of the natural product from which the compound is derived (e.g., betulinic acid).

Unless otherwise indicated or indicated by a single bond symbol (dash or double dash), the point of attachment of a given group will be to the far right of the group in question. Thus, for example, a hydroxyalkyl group is attached to the primary structure through an alkyl group, and the hydroxyl group is a substituent on the alkyl group.

The term "alkyl" as used herein refers to saturated aliphatic hydrocarbons including straight and branched chain radicals. Preferably, the alkyl group has 1-20 carbon atoms (whenever it appears herein, a numerical range such as "1-20" refers to each integer in the given range; e.g., "1-20 carbon atoms" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms). More preferably it is a medium size alkyl group having 1 to 10 carbon atoms. Still more preferably, it is a lower alkyl group having 1 to 6 carbon atoms, and still more preferably 1 to 4 carbon atoms. The alkyl group may be substituted or unsubstituted. When it is substituted, the substituent or substituents are preferably one or more groups each selected from the group consisting of cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-amido, C-carboxy, O-carboxy, cyanato, isocyanato, thiocyanato, isothiocyanato, nitro, silyl and amino.

The term "halogen" as used herein refers to chlorine, fluorine, bromine and iodine.

The term "hydrogen" as used herein refers to a hydrogen atom (-H group).

The term "hydroxy" as used herein refers to an-OH group.

The term "alkoxy" as used herein refers to both one-O-alkyl and one-O-cycloalkyl group as described herein. Lower alkoxy means-O-lower alkyl.

The term "aryloxy" as used herein refers to both one-O-aryl and one-O-heteroaryl as described herein.

The term "mercapto" as used herein refers to an-SH group.

The term "alkylthio" as used herein refers to both one-S alkyl and one-S-cycloalkyl as described herein.

The term "arylthio" as used herein refers to both one-S aryl and one-S-heteroaryl as described herein.

The term "carbonyl" as used herein refers to a group — C (═ O) R ", where R" is selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon), and heterocyclic (bonded through a ring carbon) as described herein.

The term "aldehyde group" as used herein refers to a carbonyl group, wherein R "is hydrogen.

The term "cyclic ketone" as used herein refers to a cycloalkyl group wherein one of the carbon atoms forming the ring is bonded to an "═ O"; i.e. one of the ring carbon atoms is a-C (═ O) group.

The term "thiocarbonyl" as used herein refers to a group-C (═ S) R ", R" being as defined herein.

The term "O-carboxy" as used herein refers to an R "C (═ O) O-group, R" being as defined herein.

The term "C-carboxy" as used herein refers to a group-C (═ O) OR ", R" being as defined herein.

The term "ester" as used herein is a C-carboxy group as defined herein, wherein R "is any one of the groups listed except hydrogen (e.g., methyl, ethyl, lower alkyl).

The term "C-carboxy salt" as used herein refers to a-C (═ O) O^-M⁺In which M is⁺Selected from the group consisting of lithium, sodium, magnesium, calcium, potassium, barium, iron, zinc, and quaternary ammonium.

The term "acetyl" as used herein refers to a group-C (═ O) CH₃And (4) a base.

The term "carboxyalkyl" as used herein refers to- (CH)₂)_rC (═ O) OR ", where R is 1 to 6 and R" is as defined above.

The term "carboxyalkyl salt" as used herein refers to a- (CH)₂)_rC(＝O)O^-M⁺Wherein M is⁺Selected from the group consisting of lithium, sodium, potassium, calcium, magnesium, barium, iron, zinc, and quaternary ammonium.

The term "carboxylic acid" as used herein refers to a C-carboxyl group, wherein R "is hydrogen.

The term "haloalkyl" as used herein refers to an alkyl group substituted with 1-6 halogen groups, preferably the haloalkyl is one-CX₃Wherein X is a halogen group. The halogen groups may be independently selected.

The term "trihalomethylsulfonyl" as used herein refers to an X₃CS(＝O)₂-a radical, X being as defined above.

The term "cyano" as used herein refers to a-C.ident.N group.

The term "cyanato" as used herein refers to a-CNO group.

The term "isocyanato" as used herein refers to one-NCO group.

The term "thiocyanato" as used herein refers to a-CNS group.

The term "isothiocyanato" as used herein refers to a-NCS group.

The term "sulfinyl" as used herein refers to a group-S (═ O) R ", R" being as defined herein.

The term "sulfonyl" as used herein refers to a group-S (═ O)₂R 'group, R' is as defined herein.

The term "sulfonamido" as used herein refers to a group-S (═ O)₂NR¹⁷R¹⁸，R¹⁷And R¹⁸As defined herein.

The term "trihalomethylsulphonamido" as used herein refers to an X₃CS(＝O)₂NR¹⁷-radical, X and R¹⁷As defined herein.

The term "O-carbamoyl" as used herein refers to an-OC (═ O) NR¹⁷R¹⁸Radical, R¹⁷And R¹⁸As defined herein.

The term "N-carbamoyl" as used herein refers to an R¹⁸OC(＝O)NR¹⁷Radical R¹⁷And R¹⁸As defined herein.

The term "O-thiocarbamoyl" as used herein refers to an — OC (═ S) NR¹⁷R¹⁸Radical, R¹⁷And R¹⁸As defined herein.

The term "N-thiocarbamoyl" as used herein refers to an R¹⁷OC(＝S)NR¹⁸Radical R¹⁷And R¹⁸As defined herein.

The term "amino" as used herein refers to a-NR group¹⁷R¹⁸Radical, R¹⁷And R¹⁸Both are hydrogen.

The term "C-amido" as used herein refers to a-C (═ O) NR¹⁷R¹⁸Radical, R¹⁷And R¹⁸As defined herein. An "N-acylamino" refers to an R¹⁷C(＝O)NR¹⁸Radical R¹⁷And R¹⁸As defined herein.

The term "nitro" as used herein refers to a-NO group₂And (4) a base.

The term "quaternary ammonium" as used herein refers to an-⁺NR¹⁷R¹⁸R¹⁹Wherein R is¹⁷、R¹⁸And R¹⁹Independently selected from hydrogen and unsubstituted lower alkyl.

The term "methylenedioxy" as used herein refers to an-OCH₂An O-group in which an oxygen atom is bonded to an adjacent ring carbon atom.

The term "ethylenedioxy" as used herein refers to an-OCH₂CH₂An O-group in which an oxygen atom is bonded to an adjacent ring carbon atom.

As used herein, "heterocycle" refers to a monocyclic or bicyclic ring containing 4 to 12 atoms, at least one of which is selected from nitrogen, sulfur or oxygen, one of which-CH₂The-group may optionally be replaced by one-C (═ O) -and one ring sulfur atom may optionally be oxidized to one or more S-oxides. Examples of "heterocycle" or "heterocyclic" rings include, but are not limited to, morpholino, piperidinyl, piperazinyl, pyrrolidinyl, thiomorpholino, homopiperazinyl, imidazolyl, imidazolidinyl, pyrazolidinyl, dioxacyclohexyl, and dioxolanyl. When the pi-electron system of the heterocycle is fully conjugated, the "heterocycle" may include heteroaryl.

As used herein, "heteroaryl" refers to a monocyclic or fused ring (i.e., several rings that share a pair of adjacent atoms) group having one or more atoms selected from nitrogen, oxygen, and sulfur in the ring and also having a fully conjugated pi-electron system. Examples of heteroaryl groups are, but are not limited to, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, isoquinoline, quinazoline, purine, and carbazole.

As used herein, "aryl" refers to an all-carbon monocyclic or fused-ring polycyclic (i.e., several rings which share adjacent pairs of carbon atoms) groups having one fully conjugated pi-electron system. Examples of aryl groups are, but not limited to, phenyl, naphthyl, and anthracenyl.

As used herein, "cycloalkyl" refers to an all-carbon monocyclic or fused ring group (i.e., several rings that share an adjacent pair of carbon atoms), one or more of which does not have a fully conjugated pi-electron system. Examples of cycloalkyl groups are, but not limited to, cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, adamantane, cyclohexadiene, cycloheptane, and cycloheptatriene.

Methods of treating viral infections

The present invention provides methods for treating viral infections by administering to a patient (human or other animal) who is a viral carrier a pharmaceutical composition or medicament containing a therapeutically effective amount of a compound of formulae I-IV. For example, virus carriers can be identified by routine diagnostic techniques known in the art, as described above. The identified carrier is administered with a compound of formulae I-IV, preferably in a pharmaceutical composition with a pharmaceutically acceptable carrier.

Another aspect of the invention provides methods for treating active viral infections by administering a pharmaceutical composition or medicament containing a therapeutically effective amount of a compound of formulae I-IV to a patient (human or other animal) exhibiting symptoms characteristic of viral infections. Alternatively, the presence of a viral infection can be detected or determined directly by any suitable method in the art. The infected subject thus identified is administered with a compound of formulae I-IV, preferably in a pharmaceutical composition with a pharmaceutically acceptable carrier.

Thus, the methods of the invention are useful for treating or preventing diseases or disorders associated with viral infection in animals in general, and humans in particular. Such viral infections may be caused by viruses including, but not limited to, lentiviruses, such as human immunodeficiency virus type 1 and type 2 (HIV), human T cell lymphotrophic virus type 1 and type 2 (HTLV-I and HTLV-II), SIV, EIAV (equine infectious anemia Virus), BIV, FIV, CAEV, VMV, and MMLV (Moloney murine leukemia Virus). The above viral infections may also be caused by the following viruses: hepatitis a virus, hepatitis b virus, hepatitis c virus, hepatitis d virus, hepatitis e virus, hepatitis g virus, human foamy virus, or human herpes virus (e.g., herpes simplex virus 1, herpes simplex virus 2, herpes simplex virus 3 (also called varicella-zoster virus), herpes simplex virus 4 (also called epstein-barr virus or EBV), herpes simplex virus 5, herpes simplex virus 7). The above viral infections may also be caused by the following viruses: influenza virus (type A, type B or type C), human parainfluenza virus, respiratory syncytial virus, smallpox virus (smallpox virus), monkeypox virus, vaccinia virus, human papilloma virus, human parainfluenza virus 2(human parechovirus 2), mumps virus, measles virus, rubella virus, semliki forest virus, West Nile virus, Colorado tick fever virus, foot and mouth disease virus, Ebola virus, Marburg virus, polyoma virus, TT virus, lassa virus, lymphocytic choriomeningitis virus, vesicular stomatitis virus, rotavirus, varicella virus, parvovirus, cytomegalovirus, encephalitis virus, adenovirus, echovirus group, rhinovirus, filovirus, coxsackievirus (coxsackievirus), coronavirus (e.g., SARS-associated coronavirus), dengue virus, yellow fever virus, hantavirus, hemorrhagic fever virus, localized virus, Molluscum viruses, poliovirus, rabies virus, and the like. In some embodiments, the method is for treating or preventing an infection caused by an enveloped virus. In particular embodiments, specific viruses known to infect humans and cause disease are treated with the methods of the invention, as described below.

HIV

The term "HIV infection" as used herein generally includes infection of a host animal, particularly a human host, by the Human Immunodeficiency Virus (HIV) family of retroviruses, including, but not limited to, HIVI (also known as HTLV-III), HIV II (also known as LAV-1), HIV III (also known as LAV-2), and the like. "HIV" is used herein to refer to any strain, form, subtype, clade or variant of the HIV family. Thus, treatment of an HIV infection would include treatment of carriers of any of the HIV families of retroviruses or persons diagnosed with active AIDS, as well as treatment or prevention of AIDS-related symptoms in such patients. An HIV carrier can be identified by any method known in the art. For example, a human anti-HIV antibody positive or HIV positive or having symptoms of AIDS can be used to determine that it is an HIV carrier. I.e. "treating an HIV infection" should be understood as treating a patient at any one of several stages of the progression of an HIV infection, including, for example, acute primary infection syndrome (which may be asymptomatic or accompanied by fever, malaise, diarrhea and neurological symptoms such as headache) asymptomatic infection (asymptomatic infection with long latency and with a gradual decrease in the number of circulating CD4T cells) and AIDS (AIDS is defined as a more severe AIDS-defining disease and/or a decrease in the number of circulating CD4 cells below a level that is tolerated by effective immune function).

The term "delay of onset of HIV infection" as used herein means the treatment of an individual who is (1) at risk of being infected by HIV, or (2) suspected of being infected by or exposed to HIV, or (3) suspected of having been exposed to HIV in the past, to delay the onset of acute primary infection syndrome by at least three months. As is known in the art, clinical manifestations typically associated with acute primary infection syndrome include influenza-like diseases with fever, malaise, nausea/vomiting/diarrhea, pharyngitis, lymphadenopathy, myalgia, and neurological symptoms such as headache, encephalitis, and the like. An individual at risk may be a person performing any of the following acts: contact with HIV-contaminated blood, blood transfusions, fluid exchanges, "unsafe" sexual intercourse with infected persons, accidental needle sticks, drug injections with contaminated needles or syringes, tattoo or needle sticks with contaminated instruments or the transmission of viruses from mother to baby during pregnancy, childbirth or shortly thereafter. The term "delaying the onset of HIV infection" may also include treating a person who has not been diagnosed as infected with HIV but who is believed to be at risk of being infected with HIV or who has been exposed to HIV through contaminated blood or the like.

Furthermore, the term "delaying the onset of AIDS" means delaying the onset of AIDS (which is characterized by a more severe AIDS-defining disease and/or a reduction in the number of circulating CD4 cells below a level tolerable for effective immune function, i.e., below about 200 μ Ι) and/or AIDS-related symptoms for at least six months by treating individuals (1) at risk of or suspected of being infected with HIV, or (2) infected with HIV but not developing AIDS. Individuals at risk of being infected by HIV may be those suspected of having been exposed to HIV in the past, or believed to be at risk of being exposed to HIV now or in the future, by, for example, exposure to HIV-contaminated blood, blood transfusion, transplantation, exchange of body fluids, "unsafe" sexual intercourse with an infected person, accidental needle stick injury, tattoo or needle stick with a contaminated instrument, or viral transmission from mother to baby during pregnancy, childbirth, or shortly thereafter.

The term "treating AIDS" means treating patients who exhibit a more severe AIDS-defining disease and/or a reduction in the number of circulating CD4 cells below levels tolerable for effective immune function (typically below about 200/μ l). The term "treating AIDS" also includes treating AIDS-related conditions, which means disorders and diseases associated with or associated with AIDS or HIV infection, such as AIDS-related syndrome (ARC), Progressive Generalized Lymphadenopathy (PGL), anti-HIV antibody positive conditions and HIV positive conditions, AIDS-related neurological conditions (e.g., dementia or tropical paraparesis), kaposi's sarcoma, thrombocytopenic purpura and related opportunistic infections, such as pneumocystis, mycobacterium tuberculosis, esophageal candidiasis, encephalotoxoplasmosis, CMV retinitis, HIV-related encephalopathy, HIV-related wasting syndrome, and the like.

HBV

The term "HBV infection" as used herein generally includes infection of humans with any strain or serotype of hepatitis b virus, including acute hepatitis b infection and chronic hepatitis b infection. Thus, treating an HBV infection means treating a carrier of any strain or serotype of hepatitis b virus or a person diagnosed with active hepatitis b to reduce the amount of HBV viral load in that patient or to alleviate one or more symptoms associated with HBV infection and/or hepatitis b, including, for example, nausea and vomiting, loss of appetite, fatigue, muscle and joint pain, elevated blood levels of transaminases, increased prothrombin time, jaundice (yellowing of the eyes and body), and deep urine color. The carrier of HBV can be identified by any method known in the art. For example, a human anti-HBV antibody can be determined to be a HBV carrier by being positive for it (e.g., by a hepatitis b core antibody or a hepatitis b surface antibody) or by being positive for HBV (e.g., by a hepatitis b surface antigen (HBeAg or HbsAg) or HBV RNA or DNA) or having symptoms of hepatitis b infection or hepatitis b. Thus, "treating HBV infection" should be understood as treatment of a patient at any one of several stages of progression of HBV infection. Furthermore, the term "treating HBV infection" may also include treatment of an individual suspected of being infected with HBV after being suspected of having been exposed to HBV, such as exposure to HBV-contaminated blood, blood transfusion, exchange of body fluids, "unsafe" sexual intercourse with an infected person, accidental needle stick injury, tattooing or needle stick with contaminated instruments or pregnancy, viral transmission from mother to baby during delivery or shortly thereafter. The term "treating HBV infection" also includes treatment of a patient who is not infected with HBV but is considered at risk for HBV infection.

In another aspect, methods are provided for treating HBV infection in a patient co-infected with HBV and HIV by administering to the patient a therapeutically effective amount of a compound of formulae I-IV. In particular, HIV infection is associated with an approximately three-fold increase in the progression of persistent hepatitis b. The compounds of formulae I-IV are particularly suitable for patients co-infected with HIV and HBV. The current marketed drug interferon alpha is not effective in treating patients co-infected with HBV and HIV. Lamivudine and some other reverse transcriptase inhibitors are useful for treating the above-mentioned coinfects, but lamivudine is particularly toxic and causes liver damage, thus exacerbating hepatitis B. Furthermore, the above reverse transcriptase inhibitors often have to be used in cocktails. In contrast, the compounds of the present invention are much less toxic and have less of a potential to cause development of viral resistance. Thus, according to the present invention, a compound of formulae I-IV can be administered to a mammal, especially a human, co-infected with both HBV and HIV, either alone or in combination with another anti-HIV or anti-HBV agent, in a therapeutically effective amount. The method may include the step of identifying a patient co-infected with HBV and HIV using techniques well known in the art. For example, PCR assays can be used to detect HBV DNA or RNA and HIV RNA in a blood sample obtained from a subject. Alternatively, virus-specific antibodies or antigens may also be used to detect HBV and HIV infection.

The term "preventing hepatitis b" as used herein means preventing the development of hepatitis b (hepatitis b is characterized by more severe hepatitis defining symptoms), cirrhosis or hepatocellular carcinoma in a patient having, suspected of having, or at risk of HBV infection.

HCV

The term "HCV infection" as used herein generally includes infection of a human with any type or subtype of hepatitis C virus, including acute hepatitis C infection and chronic hepatitis C infection. Thus, treating an HCV infection means treating a carrier of any type or subtype of hepatitis c virus or a patient diagnosed as having active hepatitis c to reduce the HCV viral load of the patient or to alleviate one or more symptoms associated with HCV infection and/or hepatitis c. Carriers of HCV can be identified by any method known in the art. For example, a human can be identified as a carrier of HCV by being positive for anti-HCV antibodies or positive for HCV (e.g., by HCV RNA or DNA) or having hepatitis c infection or symptoms of hepatitis c (e.g., elevated serum transaminases). Thus, "treating an HCV infection" should be understood as treating a patient at any one of several stages of the HCV infection process. Furthermore, the term "treating HCV infection" also includes treating an individual suspected of being infected with HCV after being suspected of having been exposed to HCV in the past, for example, by: contact with HCV-contaminated blood, blood transfusions, fluid exchanges, "unsafe" sexual intercourse with infected patients, accidental needle sticks, tattoos or needle sticks with contaminated instruments or viral transmission from mother to infant during or shortly after pregnancy, childbirth. The term "treating HCV infection" also includes treating a human that is not infected with HCV but is considered at risk of infection with HCV. The term "preventing HCV" as used herein means preventing the development of hepatitis c (hepatitis c is characterized by more severe hepatitis-defining symptoms), cirrhosis, or hepatocellular carcinoma in a patient having, or suspected of having, or at risk of having, HCV infection.

Importantly, about one quarter of all people infected with HIV in the United states, i.e., an estimated 200,000 people, are infected with both HCV and HIV (see webpage http:// www.cdc.gov/HIV/pubs/facts/HIV-HCV _ Coolnfection. htm report National Center for HIV, STD and TB preservation and Thomas, D.L. Hepatology 36: S201-S209 (2002)). Liver disease has become a significant, and in some cases leading, cause of morbidity and mortality due to the extended life span of HIV-infected patients through the use of highly active antiretroviral therapy. HIV infection appears to have a deleterious effect on all stages of HCV infection. In particular, HIV infection is associated with a significant increase in the progression to persistent hepatitis c, higher HCV titers, a more rapid progression to HCV-related liver disease, and an increased risk of HCV-related cirrhosis (scarring). Furthermore, HCV can affect the treatment of HIV infection, increasing the incidence of hepatotoxicity caused by antiretroviral drugs. (Heatology 36: S201-S209, Thomas, D.L., (2002) and the report National Center for HIV, STD and TB preservation on the webpage http:// www.cdc.gov/HIV/pubs/features/HIV-HCV _ Cooffection. htm)

In the united states, two different therapeutic approaches have been approved for the treatment of chronic hepatitis c: monotherapy with interferon alpha and combination therapy with interferon alpha and ribavirin (ribavirin). In HIV-negative chronic hepatitis c patients, combination therapy consistently produces a higher rate (30% -40%) of sustained response than monotherapy (10% -20%). Combination therapy is more effective against viral gene types 1 and 2 and requires shorter treatment periods; however, viral genotype 1 is most common among patients in the united states. Combination therapy has more side effects than monotherapy, but in most cases combination therapy is preferred. Interferon monotherapy is currently prescribed for patients with contraindications to ribavirin. (see http:// www.cdc.gov/HIV/pubs/features/HIV-HCV _ Coinfection. htm)

Thus, in another aspect of the invention, there is provided a method of treating HCV infection in a patient co-infected with HCV and HIV by administering to the patient a therapeutically effective amount of a compound of formulae I-IV. The compounds of formulae I-IV are particularly useful in patients co-infected with HCV and HIV. In particular, the compounds are particularly effective in inhibiting HCV infection and/or efflux from a host cell. Furthermore, the compounds are also effective in inhibiting the entry and/or exit of HIV into and/or out of host cells. Compared to the above combination therapies, the compounds of the present invention have much less toxicity and less potential to cause viral resistance. Thus, according to the present invention, a therapeutically effective amount of a compound of formulae I-IV is administered to a mammal, especially a human, co-infected with both HCV and HIV, either alone or in combination with another anti-HIV or anti-HCV agent. The method may include the step of identifying a patient co-infected with HCV and HIV using techniques well known in the art. For example, PCR assays can be used to detect HCV DNA or RNA and HIV RNA in a blood sample obtained from a subject. Alternatively, virus-specific antibodies or antigens may also be used to detect HCV and HIV infection.

Herpes virus

Herpes viruses are one of the most common human pathogens. Members of the herpes virus family include herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2), varicella-zoster virus (herpes simplex virus type 3 or HSV-3; also known as varicella) and Epstein-Barr virus (herpes simplex virus type 4 or HSV-4). HSV-1 commonly causes cold sores (also known as oral herpes, cold sores, fever blisters) which are open sores of high infectivity that form scabs before healing. HSV-1 can also cause eye and brain infections. HSV-2 commonly causes genital herpes. HSV-1 also causes genital herpes, but with a much lower frequency than HSV-2. After an initial infection period, HSV-1 and HSV-2 typically form a life-long latent infection in sensory neurons close to the site of infection. These latent infections do not manifest any signs or symptoms of infection or disease and exist until some event reactivates the virus. Reactivation usually results in recurrent lesions at a site close to or at the same site as the initial infection. Reactivation appears to occur during periods of emotional stress or reduced immune system function.

Apart from oral and genital herpes, HSV-1 and HSV-2 cause other diseases. Examples of such diseases include herpes simplex encephalitis, a rare but potentially fatal herpetic infection of the brain; neonatal herpes-a rare but possibly severe HSV infection in newborns (resulting from viral transmission from the mother to the infant during delivery); herpetic whitlow-an HSV infection of the fingers (resulting from transfer of the infection from another part of the body or direct contact with another party infected with HSCV); and herpetic keratitis (herpes keratitis) — an HSV infection of the seed eye (the most common cause of blindness). Thus, herpes simplex virus infection in humans is an important health problem.

Genital herpes is treated primarily with inhibitory and episodic therapy (epidotrophic therapy). Inhibitory therapy is used for their treatment prior to onset, whereas episodic therapy is used for their treatment at onset. Treatment with hci valacyclovir (valacyclovir), acyclovir (acyclovir) and famciclovir (famciclovir) can be used in both inhibitory and episodic therapy.

There is currently no known therapy for HSV-1 infection. Available antiviral therapies are not completely effective and may render the virus resistant to treatment. Thus, there is a clear need for improved methods and compositions for treating HSV-1.

Epstein-Barr virus (herpes simplex virus type 4), hereinafter referred to as "EBV", exists worldwide. In fact, most people are infected with EBV during their lives. A large percentage of adults in the united states have become infected. Infants are susceptible to EBV as long as the protective effect of maternal antibodies is lost at birth. Many children are infected with EBV, and these infections usually do not cause symptoms. The symptoms of EBV infection in children are difficult to distinguish from other typical childhood disease symptoms. Children are at risk of contracting infections in early adolescence or adulthood, which often leads to infectious mononucleosis (mononucleosis). Symptoms of infectious mononucleosis include fever, sore throat and swollen lymph glands, with the possible formation of an infrequent accompanying swelling of the spleen or liver. Cardiac problems or problems involving the central nervous system occur less frequently. Infectious mononucleosis is almost never fatal. Symptoms of infectious mononucleosis usually resolve within 1 or 2 months, but EBV remains dormant or latent in some cells of the throat and blood during the next lifetime of an infected patient. The virus can be reactivated periodically and is commonly found in the saliva of infected patients. Reactivation usually occurs without disease symptoms.

EBV is thought to be associated with a number of other diseases including burkitt's lymphoma, nasopharyngeal carcinoma, and hodgkin's disease. Diseases caused by EBV are particularly common in persons with reduced immunity. EBV is associated with a tumor commonly found in organ transplant patients, which is known as post-transplant lymphoproliferative disorder. The immune system of such patients is often artificially suppressed using drug therapy to help prevent the body from rejecting new organs. Individuals infected with HIV and suffering from AIDS also have reduced immunity and often suffer from oral hairy white spots, a condition with considerable EBV replication in cells along the margin of the tongue. It is also believed that in countries where burkitt's lymphoma is prevalent, the high incidence of malaria may play a role in the lymphoma disease by suppressing the body's immune system.

Scientists find it difficult to explain why the virus causes relatively mild diseases such as glandular fever in some people and malignant tumors in others. Genetic factors may play a role. In any event, treatment is required to combat EBV.

The term "herpes simplex virus" or HSV as used herein refers to herpes simplex virus of any strain, including but not limited to HSV-1, HSV-2, HSV-3 (varicella-zoster virus or varicella) and HSV-4 (or EBV). Thus, "treating an HSV infection" would include treating a patient infected actively with any of the HSV family of herpes viruses, or carriers of latent infection with any of the HSV family of herpes viruses.

The term "HSV infection" as used herein generally includes infection of a human by herpes simplex virus of any strain, and includes both active and latent infections. Thus, "treating HSV infection" means treating carriers of HSV of any strain. For example, a human anti-HSV antibody can be identified as a carrier of HSV by being positive for or having symptoms of HSV infection. Thus, "treating an HSV infection" should be understood as treating a patient at any one of several stages of the course of an HSV infection. Furthermore, the term "treating an HSV infection" shall also include treating an individual suspected of having an HSV infection following contact with HSV, for example by contact with HSV contaminated blood, blood transfusion, fluid exchange, "unsafe" sexual intercourse with an infected person, accidental needle stick injury, tattooing or needle stick with contaminated instruments or pregnancy, viral transmission from mother to baby during delivery or shortly thereafter. The term "treating an HSV infection" shall also include treating a person who is not infected with HSV but who is deemed to be at risk of infection with HSV.

In another aspect of the invention, methods of treating HSV infection in a patient co-infected with HSV and HIV are provided by administering to the patient a therapeutically effective amount of a compound of formulae I-IV. In particular, HIV infection is associated with an increase in active infection by HSV, presumably due to the immunocompromised state created by HIV infection. The compounds of formulae I-IV are particularly suitable for patients co-infected with HIV and HSV. The currently marketed drug interferon alpha is not effective in treating HBV and HIV co-infection. Lamivudine and some other reverse transcriptase inhibitors are useful for treating the above-mentioned coinfects, but lamivudine is particularly toxic and causes liver damage, which can exacerbate hepatitis b. Furthermore, the above reverse transcriptase inhibitors often have to be used in cocktails. In contrast, the compounds of the present invention are much less toxic and less likely to cause viral resistance. Thus, according to the present invention, a therapeutically effective amount of a compound of formulae I-IV can be administered alone or in combination with another anti-HIV or anti-HSV agent to a mammal, especially a human, co-infected with both HSV and HIV. The method may include the step of identifying a patient co-infected with HSV and HIV using techniques well known in the art. For example, PCR assays can be used to detect HSV DNA or RNA and HIV RNA in a blood sample obtained from a subject. Alternatively, antibodies or antigens specific to the virus may be used to detect HSV and HIV infection.

The term "delaying the onset of HSV-associated symptoms" as used herein means preventing the development of an oral herpes, genital herpes, varicella or shingles, or chronic EBV infection in a patient having, suspected of having, or at risk of contacting, an HSV infection.

Influenza

Influenza is accompanied by an average of 36,000 deaths and 114,000 hospitalizations each year in the united states alone. Although there are three recognized influenza virus types, influenza a, influenza b and influenza c, influenza a and influenza b are responsible for the annual winter flu epidemics. Influenza a, in addition to infecting humans, infects many different animal species, including ducks, chickens, pigs, whales, horses, and seals. Influenza b usually only infects humans.

All three influenza virus types have a genome consisting of eight distinct RNA helices that encode a single gene and are linked by nucleoproteins that determine the virus type: type A, type B or type C. In fact, the influenza genome consists of eight isolated nucleic acid segments that aggregate to form a virus with a novel combination of viral genes when cells are co-infected with more than one virus type. Two of these RNA helices encode important viral surface proteins: hemagglutinin and neuraminidase, which are embedded in the lipid bilayer of the mature viral particle.

Changes in viral hemagglutinin and neuraminidase determine the viral subtype. Hemagglutinin is responsible for the entry of the virus into the host cell, while neuraminidase plays an important role in releasing the newly formed virus from the infected cell. Hemagglutinin antibodies are capable of neutralizing viruses and are a major determinant of immunity. Neuraminidase antibodies do not neutralize the virus but limit the viral replication and infection process. Host antibodies to specific types of hemagglutinin and neuraminidase prevent and generally improve future infection by the same virus species. However, because the genetic makeup of virus varieties is dynamic and constantly changing, immunity to the successful resistance of a virus obtained during the next year following infection may not be effective against a new, recombinant variant variety for the next year.

Influenza epidemics are thought to arise when virus species change over time through antigenic drift processes. Antigenic drift (caused by mutations in major viral antigen genes, particularly the hemagglutinin or neuraminidase genes) results in minor changes in surface antigens and occurs essentially continuously. When these changes occur at the appropriate positions in the gene, they render the new antigen unrecognizable by antibodies raised against other influenza virus species from the previous infection.

The occurrence of an influenza pandemic (or a pandemic worldwide) is the result of an "antigenic drift". Antigenic drift is a sudden major change in influenza a virus resulting from a new hemagglutinin and/or a new hemagglutinin and neuraminidase protein appearing in influenza a virus species. The drift is generally thought to occur when a new combination of viral genomic RNA is produced, which may be in a non-human species, and is passed to humans. When such an antigenic drift occurs, most people have little or no resistance to the virus, and the infection proves to be fatal.

Influenza pandemics have led to a number of deaths in human history. 1918-1919 influenza pandemics caused death of about 2 to 4 million people. In support of the above antigenic drift hypothesis, recent molecular analyses have demonstrated that the influenza virus responsible for the pandemic of 1918-19 is associated with a swine influenza virus belonging to the same family as influenza viruses that are still causing human influenza today.

Two types of therapeutic/prophylactic strategies are available for treatment of influenza infection: vaccination with "influenza vaccine" and administration of antiviral drugs. Influenza vaccines include vaccines containing inactivated or inactivated influenza virus. Antiviral drugs that can be used to treat influenza infection include amantadine, rimantadine, zanamivir (zanamivir), and cretinidazole (ostamivir). Amantadine and rimantadine are used to treat and prevent influenza a infections, zanamivir is used to treat influenza a and b infections, and kirilowii is used to treat and prevent influenza a and b infections.

Despite the existence of numerous drugs and vaccinations, there is a need for improved methods and compositions for the treatment and prevention of influenza infection.

The terms "influenza" and "influenza virus" as used herein refer to any type or subtype of influenza, including types a, b and c and all subtypes thereof. Thus, the term "influenza infection" includes infection by any breed of influenza virus, and the term "treating influenza infection" is understood to mean treating animals, particularly humans, infected by any breed of influenza virus. Furthermore, the term "treating an influenza infection" shall also include treating an individual suspected of having an influenza infection after suspected of having been exposed to influenza. The term "treating influenza infection" will also include treating a person who is not superficially infected with influenza but who is considered at risk of being infected with influenza.

Jaundice virus

The term "variola virus" as used herein refers to variola virus of any species, including variola major and variola minor (also known as variola-like). Examples of such human smallpox isolates are well known and the complete genomic nucleotide sequence of a single strain has been determined (see, e.g., Harrison, 15 th edition Principles of Internalmedicine, Braunwald et al EDS. McGraw-Hill, United States, and accession number NC-001611 in the Genbank database). The skilled artisan is able to diagnose individuals infected or suspected to be infected with smallpox. The term "treating smallpox" or "treating smallpox virus" refers to both treating the symptoms of the disease and reducing the amount of virus carried, infectivity, and/or replication of the virus. As used herein, the term "delaying the onset of symptoms associated with smallpox infection" means treating a patient who is not infected with smallpox, or treating a patient who is considered at risk of being infected with smallpox, or treating a patient who is infected with smallpox, such that the onset of one or more symptoms associated with smallpox infection is delayed by at least three months. The term "treating smallpox" also includes treating such persons: persons suffering from, or suspected of having, or at risk of developing smallpox infection from a smallpox viral infection to smallpox (smallpox is characterized by more severe smallpox-defining symptoms such as macula, fever, alveolar lesions, and pustular lesions).

Outbreaks of monkeypox occurred first in the united states in 6 months of 2003. The pathogen is simian pox virus, which belongs to a class of viruses that includes smallpox virus (smallpox), virus used in smallpox vaccines (vaccinia) and vaccinia virus. In humans, monkeypox, unlike smallpox, does not cause lymph node swelling, but signs and symptoms of monkeypox are similar to, but generally lighter than, smallpox. In africa where most monkeypox cases are known to occur, infection results in the death of 1% to 10% of infected individuals. The term "treating monkeypox" or "treating monkeypox virus" as used herein refers to both the treatment of symptoms of the disease and the reduction in the amount carried by, infectivity of and/or replication of the virus. The term "preventing monkeypox infection" as used herein means preventing infection in a patient who is not infected with monkeypox but who is considered at risk of infection with monkeypox. As used herein, the term "delaying the onset of symptoms associated with monkeypox infection" means treating a patient who is not infected, or is considered at risk of, or has been infected with monkeypox to delay the onset of one or more symptoms associated with monkeypox infection for at least three months.

Coronavirus (CPV)

As used herein, the term "SARS-CoV", "SARS" or "SARS-associated coronavirus" refers to any of the various types of coronavirus that are associated with severe acute respiratory symptoms. Examples of such human coronavirus isolates are the known HCoV-OC43 and HCoV-229E (see, e.g., Marra et al science 300: 1399(2003) and Rota et al science 300: 1394(2003) (accession No. AY278741 in the Genbank database)). The skilled artisan is able to diagnose individuals infected with or suspected of being infected with a SARS-associated coronavirus. The terms "treating SARS" or "treating SARS-associated coronavirus" refer to both the treatment of the symptoms of the disease and the reduction of the replication of the infectious and/or SARS-associated coronavirus. The term "treating SARS" also includes treating a person who is not infected with SARS-CoV but who is considered at risk of infection with SARS-CoV. The term "preventing SARS" as used herein means preventing the development of SARS in a person having or suspected of having or at risk of a SARS-CoV infection (SARS is characterized by more severe SARS-CoV defining symptoms such as severe respiratory disease, fever, dry cough without phlegm, shortness of breath and atypical pneumonia).

West Nile virus

West Nile (WN) virus has emerged in temperate regions of europe and north america in recent years, presenting a threat to the health of the public, horses, and animals. The most serious manifestations of WN virus infection are fatal encephalitis (brain inflammation) in humans and horses, and lethality in certain poultry and wild birds. WN virus infection is a growing problem in north america. In 2002 there were 4,156 documented cases of human WN virus infection and 284 deaths in the United states alone. The terms "treating west nile virus" and "treating west nile disease" as used herein refer to treating the symptoms of the disease in both cases known to be infected with WN virus and cases suspected of being infected with WN.

In one embodiment, the method of treatment is generally for treating an individual experiencing an acute or chronic active viral infection caused by any of the above viruses. In another embodiment, the method of treatment is generally for treating a carrier of any of the above viruses that is not experiencing an active viral outbreak. In another embodiment, the method is generally used to treat an individual known to have been exposed or suspected of having been exposed to any of the above viruses. In another embodiment, the method is generally used for prophylactic treatment of an individual who may have been exposed to or at risk of exposure to any of the above viruses, thereby preventing infection or alleviating a symptom thereof.

In a particular embodiment, the method is used to treat HIV carriers diagnosed as not having developed AIDS (AIDS is characterized by a more severe AIDS-defining disease and/or a reduction in the number of circulating CD4 cells below a level tolerable for effective immune function, i.e., below about 200/μ l). For example, the method may be used to treat patients at any stage of HIV infection prior to being diagnosed with AIDS, including treatment of acute HIV symptoms (or acute primary HIV infection symptoms) and asymptomatic infection (asymptomatic infection with long latency with a gradual decrease in the number of circulating CD4T cells).

In one aspect, the invention provides a method of treating a viral infection at any stage, and caused by any of the above viruses, particularly HIV, in a patient who has been used or is being treated with one or more established accepted antiviral drugs. Examples of such other antiviral compounds include, but are not limited to, protease inhibitors, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, integrase inhibitors, fusion inhibitors, and combinations thereof. The compounds of formulae I-IV may be administered to patients who are not responding well to other antiviral drugs (e.g., do not respond or develop viral tolerance) or who relapse after treatment with one or more other antiviral drugs or medications. As used herein, a "non-responsive patient" or a patient "who is not responsive to other antiviral drugs" means the professional observation or judgment of a physician under relevant medical standards or in routine practice in the field of treatment of antiviral infections. For example, in the case of HIV, a patient is characterized as non-responsive or non-responsive if the patient's plasma HIV rna level (or its equivalent parameter) does not substantially decrease after a sufficient period of treatment with one or more other anti-HIV drugs, or if the plasma HIV rna level (or its equivalent parameter) decreases by an amount that is less than 10-fold the amount of decrease after 4 weeks of initial treatment. Other indications of non-responsive patients may include, for example, a sustained decrease in the number of CD4T cells, adverse drug reactions or drug toxicity, and clinical exacerbations. Thus, the methods of the present invention include the steps of identifying such a patient and then administering to the patient a pharmaceutical composition or medicament having a therapeutically effective amount of a compound of formulae I-IV.

In another embodiment, a compound of formulae I-IV is administered to a patient who has undergone one or more drug treatments targeting a viral protein such as a viral protease, reverse transcriptase, integrase, envelope protein (e.g., anti-fusogenic gp120 and gp41 or homologs thereof) and has not responded well to the treatment. The compounds of the present invention belong to a new class of antiviral drugs which are believed to target one or certain host cell proteins. They act in a different way than other antiviral drugs. Thus, they are particularly effective in treating patients who are infected with a virus and who have failed to respond to or have relapsed after treatment with one or more other classes of antiviral drugs.

In addition, the present invention provides methods of delaying the onset of acute infection comprising administering to an individual having or at risk of developing an acute viral infection or at risk of developing a symptomatic infection, a pharmaceutical composition or medicament having a prophylactically effective amount of a compound of formulae I-IV. For example, in delaying the onset of a symptomatic infection, an individual infected with a virus or at risk of infection with a virus may be identified and administered a prophylactically effective amount of a compound of formulae I-IV, i.e., an amount sufficient to delay the onset of the acute viral infection by at least 6 months. Preferably in a sufficient amount to delay the onset of the acute viral infection by at least 12 months, 18 months or 24 months.

In addition, the invention also provides a method of delaying the onset of a symptomatic viral infection, the method comprising identifying an individual who (1) is at risk of being infected by a virus, or (2) is suspected of being infected by a virus or of being exposed to a virus, or (3) is suspected of having been exposed to a virus in the past, and administering to the individual a pharmaceutical composition or medicament having a prophylactically effective amount of a compound of formulae I-IV.

To prevent viral infections, treat asymptomatic viral infections, delay the onset of symptomatic viral infections or treat symptomatic viral infections, a compound of the invention may be used in combination with one or more other antiviral compounds, preferably with other antiviral compounds that act by different mechanisms of action. Examples of such other antiviral compounds include, but are not limited to, protease inhibitors, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, integrase inhibitors, fusion inhibitors, and combinations thereof. By "co-administration" is meant that several active agents are administered together as part of the same treatment or medical regimen. The active agents may be administered separately at different times of the day or at the same time. In addition, the present invention also provides a pharmaceutical composition having a compound of formula I and a compound selected from the group consisting of protease inhibitors, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, integrase inhibitors, fusion inhibitors, maturation inhibitors, immunomodulators, vaccines and combinations thereof. However, it should be understood that the other antiviral compounds described above should not interfere with or adversely affect the desired effect of the active compounds of the present invention. Co-administration of a therapeutically effective amount of a compound of formulae I-IV and one or more other antiviral compounds to a subject in need of treatment is a method provided in this aspect of the invention.

Accordingly, the present invention also provides pharmaceutical compositions and medicaments useful for the above-mentioned therapeutic and prophylactic purposes, which compositions and medicaments have a therapeutically effective amount of a compound of formula I and one or more other antiviral compounds. Preferably the other antiviral compounds mentioned above have a different mode of action than the compounds of the formulae I to IV. More preferably the other antiviral compounds mentioned above are targeted to one viral protein. Examples of such compounds include, but are not limited to, protease inhibitors, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, integrase inhibitors, fusion inhibitors, and combinations thereof.

The invention also provides a product comprising a pharmaceutical composition or medicament having a therapeutically or prophylactically effective amount of a compound of formulae I-IV. The pharmaceutical composition or medicament may be placed in a container such as a bottle, gel capsule, vial or syringe. The product may also include instructions for use of the pharmaceutical composition or medicament in the various antiviral applications set forth above. The instructions may be printed on paper or in the form of a booklet or book. Preferably, the products of the invention also contain one or more other antiviral compounds as described above in a therapeutically or prophylactically effective amount.

Generally, the compounds of formulas I-IV are effective in amounts of about 0.01 μ g/kg to about 100mg/kg per day based on total weight. The active ingredient may be administered at one time, or may be divided into smaller doses to be administered at predetermined time intervals. A suitable dosage unit for each administration may be, for example, from about 1. mu.g to about 2000mg, preferably from about 5. mu.g to about 1000 mg. In the case of combination therapy, a therapeutically effective amount of one or more other antiviral compounds may be administered by separate pharmaceutical compositions, or may be included in a pharmaceutical composition of the invention containing one of the compounds of formulae I-IV. The pharmacology and toxicology of many of the other antiviral compounds described above are well known in the art. See, e.g., physics Desk Reference, Medical Economics, Montvale, NJ; and The Merck Index, Merck & Co., Rahway, NJ. Therapeutically effective amounts of the compounds and suitable unit dosage ranges for use in the art are also equally applicable to the present invention.

It should be understood that the above dosage ranges are exemplary only and are not intended to limit the scope of the invention. The therapeutically effective amount of each active compound will vary depending upon a variety of factors including, but not limited to, the activity of the compound employed, the stability of the active compound in the patient, the severity of the symptoms to be alleviated, the total weight of the patient treated, the route of administration, the ease of absorption, distribution and excretion of the active compound in the body, the age and sensitivity of the patient to be treated, and the like, as will be apparent to those skilled in the art. The amount administered can be adjusted according to the change over time of various factors.

In the pharmaceutical composition, the active agent may be in the form of any pharmaceutically acceptable salt. The term "pharmaceutically acceptable salt" as used herein refers to a relatively non-toxic organic or inorganic salt of the active compound, including inorganic or organic acid addition salts of the compound. Examples of salts of basic active ingredient compounds include, but are not limited to, hydrochloride, hydrobromide, sulfate, bisulfate, nitrate, acetate, phosphate, oxalate, valerate, oleate, borate, benzoate, laurate, stearate, palmitate, lactate, tosylate, citrate, maleate, succinate, tartrate, naphthenate, fumarate, mesylate, laurylsulfonate, glucoheptonate, and the like. See, e.g., Berge, et al.j.pharm.sci., 66: 1-19(1997). Examples of salts of acidic active ingredient compounds include, for example, alkali metal salts, alkaline earth salts, and ammonium salts. Suitable salts are therefore aluminum, calcium, lithium, magnesium, potassium, sodium and zinc salts. In addition, organic salts may also be used, including, for example, salts of lysine, N' -dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), procaine, and tris.

For oral administration, the active compound may be incorporated into a formulation including a pharmaceutically acceptable carrier, such as binders (e.g., gelatin, cellulose, tragacanth), excipients (e.g., starch, lactose), lubricants (e.g., magnesium stearate, silicon dioxide), disintegrants (e.g., alginates, xanthan gum (primogel) and corn starch), and sweetening or flavoring agents (e.g., glucose, sucrose, saccharin, methyl salicylate and peppermint). Formulations in the form of gelatin capsules or compressed tablets may be administered orally. Capsules and tablets may be prepared by any conventional method. Capsules and tablets may also be coated with various coatings known in the art to improve the odor, taste, color and shape of the capsules and tablets. In addition, liquid carriers such as fatty oils may also be included in the capsules.

Suitable oral formulations may also be in the form of suspensions, syrups, chewing gums, wafers, elixirs and the like. Conventional agents for modifying the odor, taste, color and shape of particular forms may also be included in the formulation, if desired. In addition, for routine administration to patients unable to swallow via the enteral feeding tube, the active compound may be dissolved in an acceptable lipophilic vegetable oil carrier such as olive oil, corn oil and safflower oil.

The active compounds may also be administered parenterally in the form of solutions or suspensions or in lyophilized form which can be converted into a solution or suspension prior to use. In such formulations, a diluent or a pharmaceutically acceptable carrier such as sterile water and physiological saline buffer may be used. Other conventional solvents, pH buffers, stabilizers, antimicrobials, surfactants, and antioxidants can all be included in the formulation. For example, useful ingredients include sodium chloride, acetate, citrate or phosphate buffers, glycerol, glucose, nonvolatile oils, methylparaben, polyethylene glycol, propylene glycol, sodium bisulfate, benzyl alcohol, ascorbic acid, and the like. The parenteral formulations may be stored in any conventional container such as vials and ampoules.

Routes of topical administration include nasal, buccal, mucosal, rectal or vaginal administration. For topical administration, the active compounds can be formulated as lotions, creams, ointments, gels, powders, pastes, sprays, suspensions, drops and aerosols. Thus, one or more thickening agents, humectants, and stabilizers may be included in the formulation. Examples of such agents include, but are not limited to, polyethylene glycol, sorbitol, xanthan gum, petrolatum, beeswax or mineral oil, lanolin, squalene, and the like. One particular form of topical administration is delivery by a transdermal patch. Methods of making transdermal patches are disclosed in, for example, Brown, et al, Annual Review of Medicine, 39: 221-229(1988), the contents of which are incorporated herein by reference.

Subcutaneous implantation for sustained release of the active compound may also serve as a suitable route of administration. A surgical procedure is required to implant one of the active compounds in any suitable dosage form into the subcutaneous space, e.g., under the anterior abdominal wall. See, e.g., Wilson et al, j.clin.psych.45: 242-247(1984). Hydrogels can be used as carriers for sustained release of active compounds. Hydrogels are well known in the art. They are typically prepared by cross-linking high molecular weight biocompatible polymers into a network which swells in water to form a gel-like mass. Preferably the hydrogel is biodegradable or bioabsorbable. Hydrogels made from polyethylene glycol, collagen, or poly (glycolic acid-co-L-lactic acid) may be useful for the present invention. See, e.g., Phillips et al, j.pharmaceut.sci., 73: 1718-1720(1984).

The active compound may also be conjugated to a water-soluble, non-immunogenic, non-peptide, high molecular weight polymer to form a polymeric conjugate. For example, an active compound is covalently linked to polyethylene glycol to form a conjugate. Generally, such conjugates exhibit improved solubility, stability, and reduced toxicity and immunogenicity. Thus, the active compounds in the conjugates may have a longer half-life in vivo and exhibit better therapeutic efficacy when administered to a patient. See generally Burnham, am.j.hosp.pharm., 15: 210-218(1994). Pegylated proteins are currently used in protein replacement therapy and as other therapies. For example, pegylated interferon (PEG-INTRON)

) Can be used for treating hepatitis B in clinic. Pegylated adenosine deaminase (A)

) Can be used for treating Severe Combined Immunodeficiency Disease (SCIDS). Pegylated L-asparaginase () Can be used for treating Acute Lymphocytic Leukemia (ALL). Preferably, the covalent bond between the polymer and the active compound as well as the polymer itself is hydrolytically degradable under physiological conditions. The above conjugates, known as "prodrugs", readily release the active compound in vivo. Controlled release of the active compound can also be achieved by incorporating the active ingredient in microcapsules, nanocapsules or hydrogels as is well known in the art.

Liposomes can also be used as carriers for the active compounds of the invention. Liposomes are micelles composed of various lipids, such as cholesterol, phospholipids, fatty acids, and derivatives thereof. Various modified lipids may also be used. Liposomes can reduce the toxicity of the active compounds and increase their stability. Methods for preparing liposomal suspensions, including active ingredients, are generally known in the art. See, for example, U.S. Pat. Nos. 4,522,811; prescript, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976).

The active compound may also be administered in combination with another active agent, provided that the other active agent does not interfere with or adversely affect the effect of the active compound of the invention, and the other active agent synergistically treats or prevents the same condition or is effective in treating another disease or condition in the patient being treated. Such other active agents include, but are not limited to, anti-inflammatory agents, antiviral agents, antibiotics, antifungal agents, antithrombotic agents, cardiovascular agents, cholesterol lowering agents, anticancer agents, hypertension agents, and the like. In this combination therapy, the two different pharmaceutically active compounds may be administered separately or in the same pharmaceutical composition.

Examples of antiviral compounds suitable for use in combination therapy with the compounds of the present invention include, but are not limited to, HIV protease inhibitors, nucleoside HIV reverse transcriptase inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV fusion inhibitors, HIV maturation inhibitors, immunomodulators and vaccines.

Examples of nucleoside HIV reverse transcriptase inhibitors include 3 '-azido-3' deoxythymidine (Zidovudine), also known as AZT and RETROVIR

)2 ', 3' -didehydro-3 '-deoxythymidine (Stavudine), also known as 2', 3 '-didehydro-3' -deoxythymidine, d4T and ZERIT

) (2R-cis) -4-amino-1-, [ 2R-cis ] -22- (hydroxymethyl) -1, 3-oxathiolan-5-yl]-2(1H) -pyrimidinones (Lamivudine), also known as 3TC and EPIVIR

)2 ', 3' -dideoxyinosine (ddI), and 9- [ (R) -2- [ [ bis [ [ isopropoxycarbonyl ] carbonyl]Oxy radical]Methoxy radical]Phosphinyl radical]Methoxy radical]Propyl radical]Adenine fumarate (tenofovir disoproxil fumarate, also known as VireadTM).

Examples of non-nucleoside HIV reverse transcriptase inhibitors include (-) -6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1, 4-dihydro-2H-3, 1-benzoxazin-2-one (efavirenz), also known as DMP-266 or SUSTIVA) (see U.S. Pat. No.5,519,021), 1- [3- [ (1-methylethyl) amino group]-2-pyridyl]-4- [ [5- [ (methylsulfonyl) amino ] amino]-1H-indol-2-yl]Carbonyl radical]Piperazine (Delavirdine (see PCT International patent application No. WO 91/09849), and (1S, 4R) -cis-4- [ 2-amino-6- (cyclopropylamino) -9H-purin-9-yl]-2-cyclopentene-1-methanol (Abacavir)).

Examples of protease inhibitors include [5S- (5R)^*，8R^*，10R^*，11R^*)]-10-hydroxy-2-methyl-5- (1-methylethyl) -1- [2- (1-methylethyl) -4-thiazolyl]5-Thiazolylmethyl (Ritonavir), NORVIR from Abbott, 3, 6-dioxo-8, 11-bis (phenylmethyl) -2, 4, 7, 12-tetraazatridecane-13-oate

Sold under the trademark, [3S- [2 (2S) ]^*，3S^*)，3a，4ab，8ab]]-N- (1, 1-dimethylethyl) decahydro-2- [ 2-hydroxy-3- [ (3-hydroxy-2-methylbenzoyl) amino]-4- (phenylthio) butyl]-3-Isoquinolinecarboxylic acid ethanediamide monomethanesulfonate (Nefinavir (Neifinavir), prepared by Agouron as VIRACEPT

Sold under the trademark N- (2(R) -hydroxy-1 (S) -indanyl-2 (R) -phenylmethyl-4- (S) -hydroxy-5- (1- (4- (2-benzo [ b ]))]Furylmethyl) -2(S) -N '(tert-butylcarboxamido) -piperazinyl)) pentanamide (see U.S. Pat. No.5,646,148), N- (2(R) -hydroxy-1 (S) -indanyl) 2(R) -phenylmethyl-4- (S) -hydroxy-5- (1- (4- (3-pyridylmethyl) -2(S) -N' - (tert-butylcarboxamido) -piperazinyl)) -pentanamide (indonavir (Indinavir) by Merck as CRXIVAN

Sold under the trademark) 4-amino-N- ((2syn, 3S) -2-hydroxy-4-phenyl-3- ((S) -tetrahydrofuran-3-yloxycarbonylamino) -butyl) -N-isobutyl-benzenesulfonamide (amprenavir (see U.S. Pat. No.5,585,397), and N-tert-butyl-decahydro-2- [2(R) -hydroxy-4-phenyl-3 (S) - [ [ N- (2-quinolinylcarbonyl)]-L-asparaginyl group]Amino group]Butyl radical](4aS, 8aS) -isoquinoline-3 (S) -carboxamide (Saquinavir), by Roche laboratories aS INVIRASE

Sold under the trademark trade).

Examples of suitable HIV integrase inhibitors are disclosed in us patent 6,110,716; 6,124,327 and 6,245,806, the contents of which are incorporated herein by reference.

A variety of other antiviral agents may also be used in combination therapy with the compounds of the present invention, including, but not limited to, 9- (2-hydroxyethoxymethyl) guanine (acyclovir), 2-amino-9- (2-hydroxyethoxymethyl) purine, suramin (suramin), ribavirin, antimony tungstate (antimitostat) (HPA-23), interferon, interleukin-II, and phosphonoformate (Foscarnet). In addition, other agents such as levamisole or thymosin which stimulate lymphocyte growth and/or function may also be used.

Examples of HIV fusion inhibitors include antibodies against HIV envelope proteins (e.g., gp120, gp41) and peptides derived from HIV envelope proteins. For example, phase III clinical trials have shown that a peptide derived from gp41 (Trimeris, Inc., Durham, NC), designated T-20, is effective in treating HIV infection.

Any suitable pharmaceutically acceptable derivative of the above compounds, including pharmaceutically acceptable salts and esters thereof, may also be used.

Examples

The synthesis of the compounds of formulae I-IV can be accomplished according to the following general synthetic routes. See tables 1-3 for representative structures and associated characterization data.

The above scheme summarizes the synthetic routes for the compounds in tables 1-3, wherein the reagents/conditions are: ac₂O, DMAP, Py,. DELTA.. Oxalyl chloride (2M), CH₂Cl₂。iii.NHR₁R₂、TEA、CH₂Cl₂. NaOH (4M), THF/MeOH. v.2, 2-dimethylsuccinic anhydride, DMAP, Py,. DELTA.. PtO₂、H₂(15psi)、AcOH。

In general, the compounds of the invention are synthesized according to the following steps:

(i) adding a protecting group to a selected position of the starting material (i.e. C of betulinic acid)₃Bits);

(ii) (ii) formation of an acid chloride (i.e. C) at any desired position of the compound synthesized in step (i)₂₈Bits);

(iii) (iii) reacting the acid chloride formed in step (ii) with the appropriate desired moiety (e.g.NH as in the above scheme₂-R group) is reacted;

(iv) (ii) removing the protecting group added in step (i); and optionally

(v) (iv) addition of any moiety to the deprotected site of the compound formed in step (iv) (i.e. addition of dimethylsuccinyl to C)₃Bits, as shown in the above scheme).

Optionally reducing the unsaturated bond to form the compounds of the present invention. The compounds of the invention can also be synthesized by the following steps:

(i) activating selected sites of the starting material (i.e. C of betulinic acid)₂₈Bits);

(ii) (ii) reacting the compound formed in step (i) with a suitable desired moiety (e.g. NH as in the above scheme)₂-R group) is reacted; and is

(iii) Adding either moiety to the other desired position of the material formed in step (ii) (i.e., adding dimethylsuccinyl to C)₃Bits, as shown in the above scheme);

a protecting group refers to a moiety that protects a chemical group from undesirable reactions. For example, protecting groups include those known to those skilled in the art, such as those described in protective groups in Organic Synthesis, Greene, T., John Wiley & Sons, New York, N.Y. (first edition, 1981), where the protecting groups can be added or removed using the procedures described herein. Examples of protected hydroxy groups include, but are not limited to, silyl ethers such as those obtained by the reaction of one hydroxy group with a reagent such as, but not limited to, tert-butyldimethylchlorosilane, trimethylchlorosilane, triisopropylchlorosilane, triethylchlorosilane; substituted methyl and ethyl ethers such as, but not limited to, methoxymethyl ether, methylthiomethyl ether, benzyloxymethyl ether, t-butoxymethyl ether, 2-methoxyethoxymethyl ether, tetrahydropyranyl ether, 1-ethoxyethyl ether, allyl ether, benzyl ether; esters such as, but not limited to, benzoyl formate, acetate, trichloroacetate and trifluoroacetate. Examples of protected amine groups include, but are not limited to, amides such as formamide, acetamide, trifluoroacetamide, and benzamide; diimides such as phthalimide and dithiosuccinimide; and others. Examples of protected mercapto groups include, but are not limited to, thioethers such as S-benzyl sulfide and S-4-pyridylmethyl sulfide; substituted S-methyl derivatives such as thiohemiacetals, dithioacetals, and aminothioacetals; and others. Examples of protecting groups for protein synthesis include, but are not limited to, BOC, FMOC, and CBZ (i.e., t-butyloxycarbonyl, 9-fluorenylmethoxycarbonyl, and benzyloxycarbonyl, respectively).

Groups may be added or removed during synthesis using methods known in the art. For example, the protecting group may be added by adding an activated acid (e.g., acetic anhydride) and an organic base (e.g., triethylamine or pyridine) and heating the resulting mixture. The position of the compound may be activated by reaction with an activating agent known in the art, such as dicyclohexylcarbodiimide, EDCI, HATU or PyBOP. Acid chlorides can be formed by reacting a carboxylic acid with a chlorinating agent, such as thionyl chloride, oxalyl chloride, phosphoryl chloride, and cyanuric chloride. Acid chlorides can be reacted with suitable moieties such as primary and secondary amines to form desired groups such as amide groups.

The protecting group can be removed by methods known to those skilled in the art. For example, removal of an acetate protecting group can be achieved by contacting the material with a base such as aqueous sodium hydroxide. Other moieties may be added at desired locations of the material, for example by reacting the material with dimethyl succinic anhydride in the presence of a base such as pyridine, thereby adding a dimethyl succinyl group to the C3 position.

The compounds of formulae II and III can also be synthesized according to the general synthetic route described above by replacing betulinic acid with the appropriate starting materials. For example, compounds of formula II can be synthesized according to the general synthetic route described above by replacing betulinic acid with caryophyllin; the compound of formula III can be synthesized by using ursolic acid instead of betulinic acid.

General procedure for HPLC purification: the samples were dissolved in DMSO (. about.50 mg/ml) and then subjected to HPLC column (250X 21.2mm, 10. mu. sphere diameter, 80. mu. sphere diameter) on Phenomenex Synergi Hydro-RP (00G-4376-P0)

Pore size), solvent system 50-90% acetonitrile in water (0.01% trifluoroacetic acid), run isocratic elution for up to 25 minutes. Fractions were collected based on absorbance at 203 λ.

(3 beta) -3- (acetoxy) lup-20 (29) -en-28-oic acid (1)

With Ac under nitrogen₂O (0.26ml, 2.8mmol) and DMAP (0.14g, 1.1mmol) were treated with a solution of betulinic acid (0.50g, 1.1mmol) in dry pyridine (10ml) and the mixture was refluxed for 1 h. Reaction mixture with CHCl₃Diluted and washed with water. With MgSO₄The organic layer was dried and concentrated under reduced pressure to give 1(0.42g, 76%).

¹H NMR(DMSO-d₆，400MHz)δ0.79(s，6H，CH₃)，0.80(s，3H，CH₃)，0.87(s，3H，CH₃)，0.94(s，3H，CH₃)，1.25-1.62(m，18H，CH₂)，1.65(s，3H，CH₃)，1.75-1.85(m，2H，CH₂)，1.99(s，3H，CH₃CO)，2.08-2.14(m，1H)，2.18-2.27(m，1H)，2.90-3.00(m，1H)，4.36(dd，1H，J＝11.24Hz，J＝4.8Hz，H-3)，4.56(m，1H，CH＝)，4.69(d，1H，J＝2.15Hz，CH＝)，12.10(bs，1H，CO₂H)。

Preparation of acid chloride 3(3 β) -3- (acetoxy) lup-20 (29) -en-28-oic acid (2)

Oxalyl chloride solution (2M in CH)₂Cl₂Of 4ml) was added to 3-0-acetyl-betulinic acid (0.1g, 0.2mmol) and stirred for 2 h. The mixture was concentrated to dryness under reduced pressure. Anhydrous CH for residue₂Cl₂(3X 1ml) diluted under reduced pressureConcentrated to dryness and then used without further purification.

General procedure for the Synthesis of Compound (3-34)

To an acid chloride 2(0.2mmol) in anhydrous CH under a nitrogen atmosphere₂Cl₂To the solution (5ml) was added the appropriate amine (0.26mmol) and TEA (0.44mmol, 0.061 ml). The reaction mixture was stirred at room temperature overnight with CH₂Cl₂Diluting and then using H₂O washing CH₂Cl₂And (3) a layer. With MgSO₄The organic layer was dried and concentrated under reduced pressure to give an amide compound. In some cases, the product was sufficiently pure to be used directly in the next step, while some of the product was purified by HPLC.

TABLE 1

Note: arom: the aromatic compound is aromatic and the aromatic compound is aromatic,

and: and (c).

General procedure for the Synthesis of Compounds (35-68)

A solution of the appropriate amide (0.21mmol) in THF (1.6ml) and methanol (1ml) was treated with NaOH (4M, 0.27 ml). The mixture was stirred at room temperature overnight and then the solvent was evaporated off under reduced pressure. The residue is substituted by CH₂Cl₂Diluted and washed with HCl solution (0.5N). With MgSO₄The organic layer was dried and concentrated under reduced pressure to give amide compounds 35-68.

TABLE 2

and: and (c).

General procedure for the Synthesis of Compounds (69-121)

A solution of the appropriate amide 35-68(0.17mmol) in dry pyridine (4ml) was treated with 2, 2-dimethylsuccinic anhydride (0.109g, 0.85mmol) and DMAP (0.021g, 0.17mmol) under nitrogen and the mixture refluxed overnight. By CH₂Cl₂Dilute the reaction mixture and use H₂And O washing. With MgSO₄The organic layer was dried and concentrated under reduced pressure to give the carboxylic acid product. The crude product was purified by HPLC.

TABLE 3

amide: the acid amide,

and: and (c).

General procedure for the Synthesis of Compound (122)

Compound 73(0.112g, 0.15mmol) was suspended in glacial acetic acid (10ml) and purged with nitrogen. A catalytic amount of platinum (IV) oxide (0.012g) was added. The reaction was placed under 15psi hydrogen overnight. The mixture was filtered through a pad of celite and the solvent was evaporated under reduced pressure. The resulting crude compound 122 was purified by HPLC.

The synthesis of compounds 123 and 124 is similar to compound 122.

TABLE 4

Note: arom: and (4) aromatic.

General procedure for the Synthesis of Compound (125)

The synthesis of compound 125 was similar to the synthesis scheme for the compounds in tables 1-3 above, with ursolic acid instead of the starting material betulinic acid.

Example 2: determination of antiviral Activity

The compounds of the present invention can be tested in the following assays to test for antiviral activity and general toxicity.

Detection of MT-4 cytoprotective Effect

HTLV-1 transformed T cell line, MT-4, is highly susceptible to HIV-1 infection. The ability of anti-HIV-1 agents to protect cells from HIV-induced cytopathic effects was evaluated in this target cell line. In this assay, viability of both HIV-1 cells and mock-infected cells was assessed in a colorimetric assay that monitors the ability of metabolically active cells to deplete tetrazolium salt WST-1. A positive result of increased WST-1 division indicates cytoprotective effects of the antiviral compound.

Briefly, exponentially growing MT-4 cells were mock-infected or batch-infected with a multiplicity of infection of 0.0005 with the laboratory strain NL4-3 of HIV-1. After two hours of infection, the cells were washed to remove unbound virus and plates with increasing concentrations of compound were accessed. After four days of culture, the WST-1 assay was used to analyze cytoprotective effects in infected cells and to mimic compound toxicity in infected cells.

PBMC drug sensitivity assay

Human Peripheral Blood Mononuclear Cells (PBMC) were used to test compounds for antiviral activity as an indicator of clinical efficacy. PBMCs were isolated from both donors using a Ficoll-Hypaque density gradient, pooled and stimulated with PHA-L for three days. After stimulation, the cells were washed and maintained in IL-2 containing medium. Followed by HIV-1_IIIBThe virus strain mock-infected or batch-infected the stimulated cells for one hour at a multiplicity of infection of 0.01. Cells (unwashed) were then plated in the presence of increasing concentrations of compound and incubated for seven days. The result of viral replication in these media is the concentration of HIV-1p24 in the supernatant, since PBMCs are generally unaffected by HIV-induced cytopathic effects. Toxicity of the compounds in mock-infected cells was analyzed using the WST-1 assay.

Based on these assays, the compounds of the present invention were found to have antiviral activity. Compound 71 had an EC50 of about 126 nanomolar (concentration of compound that reduced virus-induced cytopathic effects by 50% (MT-4) (antiviral activity assay)) and a TC50 of about 7.7 micromolar (TC50 is the concentration of compound that caused 50% mortality of the host cells (toxicity measurement)). Compound 73 has an EC50 of about 8.1 nanomolar and a TC50 of about 6.3 micromolar. Compound 70 has an EC50 of about 2.9 nanomolar and a TC50 of greater than 10 micromolar. Compound 76 has an EC50 of about 11 nanomolar and a TC50 of greater than 10 micromolar. Compound 46 has an EC50 of about 8.6 micromolar and a TC50 of greater than 10 micromolar. Representative compounds of the invention include those having an EC50 of less than about 100 nanomolar, such as compounds 69, 70, 73-84, 87, 88, 91-95, 97, 99-106, 108-.

All publications and patent applications mentioned in this specification are indicative of the level of skill of those skilled in the art to which this invention pertains. All publications and patent applications are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. The mere mentioning of publications and patent applications does not necessarily indicate that they are prior art to the present application.

Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be apparent that certain changes and modifications may be practiced within the scope of the appended claims.

Claims

1. A compound having the structure:

and pharmaceutically acceptable salts and stereoisomers thereof,

wherein,

q is (CH)₂)_1-2；

L is an alkyl group having 0 to 10 carbon atoms which may be saturated or partially saturated; and is

One or more carbon atoms of the alkyl group L may be replaced with-O-, -S-, -N-, -C (═ O) -, -NC (═ O) -, -C (═ O) N-, -SO-, -C ═ O) -, and₂、-NSO₂、-SO₂n-, cycloalkyl and-NC (═ O) N-substitutions; and is

L may be substituted with one or more substituents selected from: hydroxy, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, -N (C)_1-3Alkyl radical)₂、-NH(C_1-3Alkyl), -C (═ O) OH, -C (═ O) O (C)_1-3Alkyl), -C (═ O) NH₂、-C(＝O)NH(C_1-3Alkyl), -C (═ O) N (C)_1-3Alkyl radical)₂、-S(＝O)₂(C_1-3Alkyl), -S (═ O)₂NH₂、-S(＝O)₂N(C_1-3Alkyl radical)₂、-S(＝O)₂NH(C_1-3Alkyl), -CHF₂、-OCF₃、-OCHF₂、-SCF₃、-CF₃、-CN、-NH₂and-NO₂；

R1 is-C (═ O) - (CH)₂)_m-C(CH₃)₂-COOH；

R2 is selected from the group consisting of hydrogen, hydroxy, halogen, alkyl, alkoxy, alkylthio, arylthio, thiocarbonyl, O-carboxy, C-carboxy, O-carbamoyl, O-thiocarbamoyl, N-carbamoyl, N-thiocarbamoyl, ester, haloalkyl, haloalkoxy, cycloalkyl, aryl, heteroaryl, heterocycle, -C (═ O) OH, -CH (CH) OH₃)C(＝O)OH；-CH₂C(＝O)OH、-C(CH₃)₂C(＝O)OH、-C(CH₃)(CH₂CH₃)C(＝O)OH、-CH(CH₂CH₃)C(＝O)OH、-CH＝C(CH₃)C(＝O)OH、-C(CH₂CH₃)₂C(＝O)OH、-N(C_1-3Alkyl radical)₂、-NH(C_1-3Alkyl), -C (═ O) NH₂、-C(＝O)NH(C_1-3Alkyl), -C (═ O) N (C)_1-3Alkyl radical)₂、-S(＝O)₂(C_1-3Alkyl), -S (═ O)₂NH₂、-S(＝O)₂N(C_1-3Alkyl radical)₂、-S(＝O)₂NH(C_1-3Alkyl), -CHF₂、-OCF₃、-OCHF₂、-SCF₃、-CF₃、-CN、-NH₂and-NO₂Cycloalkyl, aryl, heterocycle and heteroaryl optionally substituted with the substituents of (a);

r3 and R4 are independently selected from-H, -CH₃、-(CH₃)₂、-CH(CH₃)₂and-C (═ CH)₂)CH₃(ii) a And is

m is an integer selected from 0 to 10.

2. The compound of claim 1, having the structure:

and pharmaceutically acceptable salts and stereoisomers thereof,

wherein,

R1 is-C (═ O) - (CH)₂)_m-C(CH₃)₂-COOH；

R2 is selected from the group consisting of optionally one or more hydrogen, hydroxy, halogen, alkyl, alkoxy, alkylthio, arylthio, thiocarbonyl, O-carboxy, C-carboxy, O-carbamoyl, O-thiocarbamoyl, N-carbamoyl, N-thiocarbamoyl, ester, haloalkyl, haloalkoxy, cycloalkyl, aryl, heteroaryl, heterocycle, -C (═ O) OH, -CH (CH)₃)C(＝O)OH；-CH₂C(＝O)OH、-C(CH₃)₂C(＝O)OH、-C(CH₃)(CH₂CH₃)C(＝O)OH、-CH(CH₂CH₃)C(＝O)OH、-CH＝C(CH₃)C(＝O)OH、-C(CH₂CH₃)₂C(＝O)OH、-N(C_1-3Alkyl radical)₂、-NH(C_1-3Alkyl), -C (═ O) NH₂、-C(＝O)NH(C_1-3Alkyl), -C (═ O) N (C)_1-3Alkyl radical)₂、-S(＝O)₂(C_1-3Alkyl), -S (═ O)₂NH₂、-S(＝O)₂N(C_1-3Alkyl radical)₂、-S(＝O)₂NH(C_1-3Alkyl), -CHF₂、-OCF₃、-OCHF₂、-SCF₃、-CF₃、-CN、-NH₂and-NO₂Cycloalkyl, aryl, heterocycle and heteroaryl optionally substituted with the substituents of (a); and is

m is an integer selected from 0 to 10.

3. The compound of claim 1, wherein L is an alkyl group having 0, 1, 2, 3, 4, or 5 carbon atoms, which alkyl group may be saturated or partially saturated; and is

L may be substituted with one or more substituents selected from: hydroxy, halogen, alkyl, alkoxy, haloalkyl,Haloalkoxy, -N (C)_1-3Alkyl radical)₂、-NH(C_1-3Alkyl), -C (═ O) OH, -C (═ O) O (C)_1-3Alkyl), -C (═ O) NH₂、-C(＝O)NH(C_1-3Alkyl), -C (═ O) N (C)_1-3Alkyl radical)₂、-S(＝O)₂(C_1-3Alkyl), -S (═ O)₂NH₂、-S(＝O)₂N(C_1-3Alkyl radical)₂、-S(＝O)₂NH(C_1-3Alkyl), -CHF₂、-OCF₃、-OCHF₂、-SCF₃、-CF₃、-CN、-NH₂and-NO₂。

4. The compound of claim 1, having the structure:

and pharmaceutically acceptable salts and stereoisomers thereof,

wherein,

r1 is-C (═ O) -CH₂-C(CH₃)₂-COOH；

R2 is selected from the group consisting of hydrogen, hydroxy, halogen, alkyl, alkoxy, alkylthio, arylthio, thiocarbonyl, O-carboxy, C-carboxy, O-carbamoyl, O-thiocarbamoyl, N-carbamoyl, N-thiocarbamoyl, ester, haloalkyl, haloalkoxy, cycloalkyl, aryl, heteroaryl, heterocycle, -C (═ O) OH, -CH (CH) OH₃)C(＝O)OH；-CH₂C(＝O)OH、-C(CH₃)₂C(＝O)OH、-C(CH₃)(CH₂CH₃)C(＝O)OH、-CH(CH₂CH₃)C(＝O)OH、-CH＝C(CH₃)C(＝O)OH、-C(CH₂CH₃)₂C(＝O)OH、-N(C_1-3Alkyl radical)₂、-NH(C_1-3Alkyl), -C (═ O) NH₂、-C(＝O)NH(C_1-3Alkyl), -C (═ O) N (C)_1-3Alkyl radical)₂、-S(＝O)₂(C_1-3Alkyl), -S (═ O)₂NH₂、-S(＝O)₂N(C_1-3Alkyl radical)₂、-S(＝O)₂NH(C_1-3Alkyl), -CHF₂、-OCF₃、-OCHF₂、-SCF₃、-CF₃、-CN、-NH₂and-NO₂One cycloalkyl, aryl, heterocycle and heteroaryl ring optionally substituted with the substituent of (a); and is

n is an integer selected from 0, 1, 2 and 3.

5. The compound of claim 4, wherein R2 is substituted with one or more substituents selected from the group consisting of hydroxy, halogen, alkyl, alkoxy, alkylthio, arylthio, thiocarbonyl, O-carboxy, C-carboxy, O-carbamoyl, O-thiocarbamoyl, N-carbamoyl, N-thiocarbamoyl, ester, haloalkyl, haloalkoxy, cycloalkyl, aryl, heteroaryl, heterocycle, -C (═ O) OH, -CH (CH) OH₃)C(＝O)OH；-CH₂C(＝O)OH、-C(CH₃)₂C(＝O)OH、-C(CH₃)(CH₂CH₃)C(＝O)OH、-CH(CH₂CH₃)C(＝O)OH、-CH＝C(CH₃)C(＝O)OH、-C(CH₂CH₃)₂C(＝O)OH、-N(C_1-3Alkyl radical)₂、-NH(C_1-3Alkyl), -C (═ O) NH₂、-C(＝O)NH(C_1-3Alkyl), -C (═ O) N (C)_1-3Alkyl radical)₂、-S(＝O)₂(C_1-3Alkyl), -S (═ O)₂NH₂、-S(＝O)₂N(C_1-3Alkyl radical)₂、-S(＝O)₂NH(C_1-3Alkyl), -CHF₂、-OCF₃、-OCHF₂、-SCF₃、-CF₃、-CN、-NH₂and-NO₂A phenyl group optionally substituted with the substituent(s) of (a); and is

n is an integer selected from 0, 1, 2 and 3.

6. The compound of claim 5, wherein n is 0 or 1.

7. The compound of claim 5, wherein n is 2 or 3.

8. The compound of claim 5, wherein R2 is substituted with one or more substituents selected from the group consisting of halogen, alkyl, C-carboxy, haloalkyl, -C (═ O) OH, -CH (CH)₃)C(＝O)OH；-CH₂C(＝O)OH、-C(CH₃)₂C(＝O)OH、-C(CH₃)(CH₂CH₃)C(＝O)OH、-CH(CH₂CH₃)C(＝O)OH、-CH＝C(CH₃)C(＝O)OH、-C(CH₂CH₃)₂C(＝O)OH、-C(＝O)NH₂、-C(＝O)NH(C_1-3Alkyl), -C (═ O) N (C)_1-3Alkyl radical)₂、-CHF₂、-CF₃And a phenyl group substituted with a substituent of-CN.

9. The compound of claim 5, wherein R2 is substituted with one or more groups selected from hydroxy, alkoxy, alkylthio, arylthio, thiocarbonyl, O-carboxy, O-carbamoyl, O-thiocarbamoyl, ester, haloalkoxy, -S (═ O)₂(C_1-3Alkyl), -S (═ O)₂NH₂、-S(＝O)₂N(C_1-3Alkyl radical)₂、-S(＝O)₂NH(C_1-3Alkyl), -OCF₃、-OCHF₂and-SCF₃A phenyl group substituted with the substituent(s) of (1).

10. The compound of claim 5, wherein R2 is substituted with one or more groups selected from N-carbamoyl, N-thiocarbamoyl, -N (C)_1-3Alkyl radical)₂、-NH(C_1-3Alkyl), -NH₂and-NO₂A phenyl group substituted with the substituent(s) of (1).

11. The compound of claim 5, wherein R2 is a phenyl group substituted with one or more substituents selected from the group consisting of cycloalkyl, aryl, heteroaryl, and heterocycle.

12. The compound of claim 5, having the structure

13. The compound of claim 5, having the structure

14. The compound of claim 5, having the structure

15. The compound of claim 5, having the structure

16. The compound of claim 5, having the structure

17. The compound of claim 5, having one of the following structures:

18. the compound of claim 5, having one of the following structures:

19. the compound of claim 1, having the following stereochemistry:

20. a pharmaceutical composition comprising a compound according to any one of claims 1 to 19 and one or more pharmaceutically acceptable excipients.

21. Use of a compound according to any one of claims 1 to 19 for the manufacture of a medicament useful in the treatment of diseases and disorders.

22. The use of claim 21, wherein the disease or disorder is a viral infection.

23. A process for the production of a compound according to any one of claims 1 to 19, comprising:

(i) adding a protecting group to a selected position of the starting material;

(ii) (ii) forming an acid chloride at the desired position of the compound formed in step (i);

(iii) (iii) reacting the acid chloride formed in step (ii) with a suitable desired moiety;

(iv) (ii) removing the protecting group added in step (i); and optionally

(v) (iv) adding a moiety to the deprotected site of the compound formed in step (iv).