EP1150665A2 - M thodes pour traiter des infections virales - Google Patents

M thodes pour traiter des infections virales

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Publication number
EP1150665A2
EP1150665A2 EP00908609A EP00908609A EP1150665A2 EP 1150665 A2 EP1150665 A2 EP 1150665A2 EP 00908609 A EP00908609 A EP 00908609A EP 00908609 A EP00908609 A EP 00908609A EP 1150665 A2 EP1150665 A2 EP 1150665A2
Authority
EP
European Patent Office
Prior art keywords
statin
compound
virus
compounds
hepatitis
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP00908609A
Other languages
German (de)
English (en)
Inventor
Patrick T. Prendergast
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Harbor Biosciences Inc
Original Assignee
Hollis Eden Pharmaceuticals Inc
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Filing date
Publication date
Application filed by Hollis Eden Pharmaceuticals Inc filed Critical Hollis Eden Pharmaceuticals Inc
Publication of EP1150665A2 publication Critical patent/EP1150665A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to the field of medicine generally, and particularly relates to the treatment of viral infections, and more particularly relates to the use of statin compounds such as mevastatin and other statin-like compounds in the treatment of viral infections.
  • U.S. Patents Nos. 4,346,227 and 4,448,979 disclose that certain members of the disclosed class of compounds (a class that includes pravastatin) are capable of inhibiting biosynthesis of cholesterol and are thus useful in the treatment of hypercholesteraemia.
  • U.S. Patent No. 4,739,073 discloses that certain members of the class of compounds defined therein may be used to inhibit cholesterol biosynthesis and to lower the blood cholesterol level and, therefore, are useful in the treatment of hyperlipoproteinemia and atherosclerosis.
  • U.S. Patent No. 5,273,995 discloses that compounds defined therein provide surprising inhibition of the biosynthesis of cholesterol, and may be used to treat mammals, including humans, suffering from hypercholesterolemia, or may be useful as hypolipidemic or hypocholesterolemic agents.
  • U.S. Patents Nos. 5.169,857, 5,006,530 and 5,401 ,746 disclose that certain members of the class of compounds described therein are useful in treating hyperproteinaemia, lipoproteinaemia, and arteriosclerosis, and exhibit inhibitory action on HMG-CoA reductase (3-hydroxy-3-methyl-glutaryl coenzyme A reductase) and are consequently inhibitors of cholesterol biosynthesis, and additionally cause a lowering of cholesterol content in the blood.
  • HMG-CoA reductase 3-hydroxy-3-methyl-glutaryl coenzyme A reductase
  • certain compounds known in the art including but not limited to mevastatin, lovastatin, pravastatin and simvastatin, are effective in treating a vertebrate, particularly a mammal and more particularly murine or human patient, suffering from one or more viral infections viral infection, treating viral infection, such viral infections include but are not limited to HIV, or hepatitis, including but not limited to hepatitis C, hepatitis A, hepatitis B, hepatitis G, and hepatitis H
  • the present invention relates to methods of treating viral infection by administering to patients suffering from one or more viral infection at least one compound selected from the group consisting of mevastatin, lovastatin, pravastatin and simvastatin, and all analogues, metabolites, and precursors thereof, and all physiologically acceptable salts and pro-drug esters thereof
  • the present invention relates to methods of treating a vertebrate afflicted with a viral infection by administering to said vertebrate suffering from one or more viral infection at least one compound (or physiologically acceptable salt or pro-drug ester thereof) selected from the groups of compounds (and all analogues, metabolites, precursors thereof) disclosed in any of the follow U S patents U S Patents Nos 4,346,227,
  • pro-drug ester refers to a chemical derivative of the compound that is rapidly transformed in vivo to yield the compound, for example, by hydrolysis in blood
  • pro-drug ester 1 refers to derivatives of the compound of the present invention formed by the addition of any of several ester-forming groups that are hydrolyzed under physiological conditions
  • pro-drug ester groups include pivoyloxymethyl, acetoxymethyl, phthalidyl, indanyl and methoxymethyl, as well as other such groups known in the art, including a (5-R-2-oxo-1 ,3-d ⁇ oxolen-4-yl)methyl group
  • pro-drug ester groups can be found in for example T Higuchi and V Stella in "Pro-drugs as Novel Delivery Systems", Vol 14, A C S Symposium Series, American Chemical Society (1975), and "Bioreversible Carriers
  • pharmaceutically acceptable salt refers to any pharmaceutically acceptable salts of a compound, and preferably refers to an acid addition salt of a compound
  • pharmaceutically acceptable salt are the alkali metal salts (sodium or potassium), the alkaline earth metal salts (calcium or magnesium), or ammonium salts derived from ammonia or from pharmaceutically acceptable organic amines, for example C C 7 alkylamine, cyclohexylamine, tnethanolamine, ethylenediamine or tr ⁇ s-(hydroxymethyl)- ammomethane
  • the preferred examples of pharmaceutically acceptable salts are acid addition salts of pharmaceutically acceptable inorganic or organic acids, for example, hydrohahc, sulfunc, phosphoric acid or aliphatic or aromatic carboxylic or sulfonic acid, for example acetic,
  • compositions of the present invention include pharmaceutically acceptable salts and pro-drug esters of the anti-viral statin and statin-like compounds disclosed herein Accordingly, if the manufacture of pharmaceutical formulations involves intimate mixing of the pharmaceutical excipients and the active ingredient in its salt form, then it is preferred to use pharmaceutical excipients which are non-basic, that is, either acidic or neutral excipients
  • antiviral statin and statin-like compounds refers to the group of compounds (including any possible stereoisomers in any ratios, including isolated or substantially isolated stereoisomers) consisting of mevastatin, lovastatin, pravastatin and simvastatin, and therein derivatives, compounds disclosed in any of U S Patents Nos 4,346,227, 4,448,979, 4,739,073, 5,273,995, 5,169,857, 5,006,530, and 5,401 ,746 as being useful in the particular treatments described in any of those patents, and all analogues, metabolites and precursors of mevastatin, lovastatin, pravastatin, simvastatin and the compounds disclosed in U S Patents Nos 4,346,227, 4,448,979, 4,739,073,
  • Mevastatin [1 S-[1 alpha (R * ), 7 beta (2S * ,4S * ),5A beta]]-2- methylbutanoic acid 1 ,2,3,7,8,8A-hexahydro-7-methyl-8-[2-tetrahydro-4- hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1 - naphthalenyl ester) has the formula:
  • Pravastatin [1 S-[1 alpha (beta S * . delta S * ), 2 alpha 6 alpha 8 beta - (R * ), 8 alpha)]1 ,2,6,7,8,8A-hexahydro-beta, delta, 6-trihydroxy-2-methyl-8- (2-methyl-1-oxo butoxy)-1-naphthaleneheptanoic acid) has the formula
  • Lovastatin [1 S-[1 alpha (R * ), 3 alpha, 7 beta, 8 beta (2S*,4S*),-8A beta)]-2-Methylbutanoicacid1 ,2,3,7,8,8A-hexahydro-3,7-dimethyl-8-[2-
  • Simvastatin [1S-[1 alpha, 3 alpha, 7 beta, 8 beta (2S*,4S')-8A beta]]-2,-2- dimethylbutanoic acid 1 ,2,3,7,8,8A-hexahydro-3,7,-dimethyl- 8-[2-(tetrahydro-4-hydroxy-6- oxo-2H-pyran-2-yl)ethyl]-1-naphthalenyl ester) has the formula:
  • anti-viral statin or statin-like compounds disclosed in U.S. Patent Nos. 5,401 ,746, 5,169,857, and 5,006,530 include substituted pyridines having the following general structures:
  • A— stands for heteroaryl which can be monosubstituted, disubstituted or trisubstituted by identical or different halogen, alkyl, alkoxy, alkylthio, alkylsulphonyl, aryl, aryloxy, arylthio, arylsulphonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl or by a group of the formula --N R R 2 ,
  • R 1 and R 2 are identical or different and denote alkyl, aryl, aralkyl, acyl, alkylsulphonyl or arylsulphonyl, or stands for aryl which can be mono-substituted to penta-substituted by identical or different alkyl groups which can be optionally substituted by hydroxyl or alkoxy, by alkoxy, alkylthio, alkylsulphonyl, aryl, aryloxy, arylthio, arylsulphonyl, aralkyl, aralkoxy, aralkylthio, aralkylsulphonyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl, sulphamoyl, dialkylsulphamoyl, carbamoyl, dialkylcarbamoyl or by a group of the formula
  • R 1 and R 2 have the abovementioned meaning and denote straight chain or branched alkyl
  • B - stands for cycloalkyl, or stands for alkyl which can be substituted by halogen, cyano, alkoxy, alkylthio, alkylsulphonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphonyl, alkoxycarbonyl, acyl or by a group of the formula --N R and R 2 ,
  • R 1 and R 2 are identical or different and denote alkyl, aryl, aralkyl, acyl, alkylsulphonyl or arylsulphonyl, or by carbamoyl, dialkyl carbamoyl, sulphamoyl, dialkylsulphamoyl, heteroaryl, aryl, aryloxy, arylthio, arylsulphonyl, aralkoxy, aralkylthio or aralkylsulphonyl, where the heteroaryl and aryl radicals of the last mentioned substituents can be mono substituted, disubstituted or trisubstituted by different halogen, cyano, trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, alkylthio or alkylsulphonyl,
  • D and E are identical or different and stand for hydrogen, or stand for CN or N0 2 , or stand for cycloalkyl, or stand for straight-chain or branched alkyl which can be substituted by azido, halogen, hydroxy, cyano, alkoxy, alkylthio, alkylsulphonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, t ⁇ fluoromethylsulphonyl, alkoxycarbonyl, acyl or by a group of the formula -N R 1 R 2 , wherein R and R 2 have the abovementioned meaning, or by carbamoyl, dialkylcarbamoyl, sulphamoyl, dialkylsulphamoyl, heteroaryl, aryl, aryloxy, arylthio, arylsulphonyl, aralkoxy, aralkylthio or aralkylsulphonyl, where the hetero
  • R 6 stands for hydrogen, or stands for a group --NHR 8 , or stands for alkoxy, or stands for alkyl, aryl, aryloxy, aralkyl, aralkoxy or heteroaryl, where the radicals mentioned can be monosubstituted, disubstituted or trisubstituted by identical or different alkyl, alkoxy, alkylthio, halogen, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, ammo, alkylamino or dialkylamino, RAstands for cycloalkyl, or stands for alkyl which can be substituted by cyano, halogen, trifluoromethyl, trifluoromethoxy or alkoxycarbonyl, or stands for aryl, aralkyl or heteroaryl, where the radicals mentioned can be monosubstituted, disubstituted or trisubstituted by identical or different alkyl, alkoxy
  • N-alkyl N-aryl, N-aralkyl, N-carbamoyl or N-alkoxycarbonyl,
  • R15 denotes hydrogen, or denotes a group -NR18 R19, or denotes alkyl or alkoxy, or denotes aryl, aryloxy, aralkyl, aralkoxy or heteroaryl, where the radicals mentioned can be monosubstituted, disubstituted or trisubstituted by identical or different alkyl, alkoxy, alkylthio, halogen, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, amino, alkylamino or dialkylamino,
  • R1 and R2 have the abovementioned meaning, or by carbamoyl, dialkylcarbamoyl, sulphamoyl, dialkylsulphamoyl, heteroaryl, aryl, aryloxy, arylthio, arylsulphonyl, aralkoxy, aralkylthio or aralkylsulphonyl, where the heteroaryl and aryl radicals can be monosubstituted, disubstituted or trisubstituted by identical or different halogen, cyano, trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, alkylthio or alkylsulphonyl, or stands for heteroaryl which can be monosubstituted disubstituted or trisubstituted by identical or different halogen, alkyl, alkoxy, alkylthio, alkylsulphonyl, aryl, aryloxy, ary
  • R1 and R2 have the abovementioned meaning, or stands for aryl which can be monosubstituted to pentasubstituted by identical or different alkyl, alkoxy, alkylthio, alkylsulphonyl, aryl, aryloxy, arylthio, arylsulphonyl, aralkyl, aralkoxy, aralkylthio, aralkylsulphonyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl, sulphamoyl, dialkylsulphamoyl, carbamoyl or dialkylcarbamoyl, or by a group of the formula -NR1 R2, wherein
  • R1 and R2 have the abovementioned meaning, or stands for 2,5-d ⁇ oxo-tetrahydropyrryl, stands for tetrahydropyranyl, or stands for t ⁇ alkylsilyl , or denotes a group COR16, where R16 has the abovementioned meaning, and R18 and R19 are identical or different and denote hydrogen, or denote cycloalkyl, or denote alkyl which is optionally substituted by cyano, halogen, trifluoromethyl or trifluoromethoxy, or denote aryl, aralkyl or heteroaryl, where the radicals mentioned can be monosubstituted, disubstituted or trisubstituted by identical or different alkyl, alkoxy, alkylthio, halogen, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, ammo, alkylamino or dialkylamino, or D and E together
  • cycloalkyl in general stands for a cyclic hydrocarbon radical having 3 to 8 carbon atoms
  • the cyclopropyl, cyclopentyl and cyclohexyl ring is preferred Example's which may be mentioned are cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl
  • alkyl in general stands for a straight-chain or branched hydrocarbon radical having 1 to 12 carbon atoms Lower alkyl having 1 to about 6 carbon atoms is preferred Examples which may be mentioned are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, isoheptyl, octyl and isooctyl
  • alkoxy in general stands for a straight-chain or branched hydrocarbon radical having 1 to 12 carbon atoms which is bonded via an oxygen atom
  • Lower alkoxy having 1 to about 6 carbon atoms is preferred
  • An alkoxy radical having 1 to 4 carbon atoms is particularly preferred Examples which may be mentioned are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, isopentoxy, hexoxy, isohexyloxy, heptoxy, isoheptoxy, octoxy and isooctoxy.
  • alkylthio in general stands for a straight-chain or branched hydrocarbon radical having 1 to 12 carbon atoms which is bonded via a sulphur atom. Lower alkylthio having 1 to about 6 carbon atoms is preferred. An alkylthio radical having 1 to 4 carbon atoms is particularly preferred.
  • alkylsulphonyl in general stands for a straight-chain or branched hydrocarbon radical having 1 to 12 carbon atoms which is bonded via an S0 2 group.
  • Lower alkylsulphonyl having 1 to about 6 carbon atoms is preferred. Examples which may be mentioned are: methylsulphonyl, ethylsulphonyl, propylsulphonyl, isopropylsulphonyl, butylsulphonyl, isobutylsulphonyl, pentylsulphonyl, isopentylsulphonyl, hexylsulphonyl and isohexylsulphonyl.
  • sulphamoyl (aminosulphonyl) stands for the group -S02 -NH2.
  • aryl in general stands for an aromatic radical having 6 to about 12 carbon atoms.
  • Preferred aryl radicals are phenyl, naphthyl and biphenyl.
  • aryloxy in general stands for an aromatic radical having 6 to about 12 carbon atoms which is bonded via an oxygen atom.
  • Preferred aryloxy radicals are phenoxy and naphthyloxy.
  • arylthio in general stands for an aromatic radical having 6 to about 12 carbon atoms which is bonded via a sulphur atom.
  • Preferred arylthio radicals are phenylthio and naphthylthio.
  • arylsulphonyl in general stands for an aromatic radical having 6 to about 12 carbon atoms which is bonded via an S02 group. Examples which may be mentioned are phenylsulphonyl, naphthylsulphonyl and biphenylsulphonyl.
  • aralkyl in general stands for an aryl radical having 7 to 14 carbon atoms which s bonded via an alkylene chain.
  • Aralkyl radicals having 1 to 6 carbon atoms in the aliphatic moiety and 6 to 12 carbon atoms in the aromatic moiety are preferred. Examples which maybe mentioned are the following alkyl radicals' benzyl, naphthylmethyl, phenethyl and phenylpropyl
  • Aralkoxy in general stands for an aralkyl radical having 7 to 14 carbon atoms, the alkylene chain being bonded via an oxygen atom.
  • Aralkoxy radicals having 1 to 6 carbon atoms in the aliphatic moiety and 6 to 12 carbon atoms in the aromatic moiety are preferred. Examples which may be mentioned are the following aralkoxy radicals: benzyloxy, naphthylmethoxy, phenethoxy and phenylpropoxy.
  • aralkylthio in general stands for an aralkyl radical having 7 to about 14 carbon atoms, the alkyl chain being bonded via a sulphur atom.
  • Aralkylthio radicals having 1 to 6 carbon atoms in the aliphatic moiety and 6 to 12 carbon atoms in the aromatic moiety are preferred. Examples which may be mentioned are the following aralkylthio radicals: benzylthio, naphthylmethylthio, phenethylthio and phenylpropylthio.
  • aralkylsulphonyl in general stands for an aralkyl radical having 7 to about 14 carbon atoms, the alkyl radical being bonded via an SO2 link.
  • Aralkylsulphonyl radicals having 1 to 6 carbon atoms in the aliphatic moiety and 6 to 12 carbon atoms in the aromatic moiety are preferred. Examples which may be mentioned are the following aralkylsulphonyl radicals: benzylsulphonyl, naphthylmethylsulphonyl, phenethylsulphonyl and phenylpropylsulphonyl.
  • alkoxycarbonyl can be represented, for example, by the formula CO-O-alkyl.
  • alkyl stands for a straight-chain or branched hydrocarbon radical having 1 to 12 carbon atoms. Lower alkoxycarbonyl having 1 to about 6 carbon atoms in the alkyl moiety is preferred. An alkoxycarbonyl having 1 to 4 carbon atoms in the alkyl moiety is particularly preferred. Examples which may be mentioned are the following alkoxycarbonyl radicals: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl and isobutoxycarbonyl.
  • acyl in general stands for phenyl or straight-chain or branched lower alkyl having 1 to about 6 carbon atoms which are bonded via a carbonyl group. Phenyl and alkyl radicals having up to 4 carbon atoms are preferred. Examples which may be mentioned are benzoyl, acetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl and isobutylcarbonyl.
  • Halogen in general stands for fluorine, chlorine, bromine or iodine, preferably for fluorine, chlorine or bromine. Particularly preferably, halogen stands for fluorine or chlorine.
  • heteroaryl in general stands for a 5- to 6-membered aromatic ring which can contain oxygen, sulphur and/or nitrogen as hetero atoms and onto which can be fused further aromatic rings.
  • 5- and 6- membered aromatic rings which contain one oxygen, one sulphur and/or up to 2 nitrogen atoms and which are optionally fused to benzene are preferred.
  • Heteroaryl radicals which may be mentioned as particularly preferred are thienyl, furyl, pyrolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, quinazolyl, quinoxalyl, phthalazinyl, cinnolyl, thiazolyl, benzothiazolyl, isothiazolyl, oxazolyl, benzoxazolyl, isoxazolyl, imidazolyl, benzimidazolyl, pyrazolyl, indolyl and isoindolyl.
  • R22 stands for an ester radical
  • a physiologically tolerable ester radical is preferably meant by this, which is easily hydrolyzed in vivo to a freecarboxyl group and a corresponding physiologically tolerable alcohol.
  • alkyl esters include, for example, alkyl esters
  • esters C1 to C4 and aralkyl esters (C7 to C10), preferably lower alkyl esters and benzyl esters.
  • ester radicals may be mentioned: methyl esters, ethylesters, propyl esters and benzyl esters.
  • R 22 stands for a cation then a physiologically tolerable metal cation or ammonium cation is preferably meant.
  • alkali metalcations or alkaline earth metal cations such as, for example, sodium cations, potassium cations, magnesium cations or calcium cations, and alsoaluminum cations or ammonium cations, and also non-toxic substituted ammonium cations from amines such as dilower alkylamines, triloweralkylamines, procain, dibenzylamine, N,N'-dibenzylethylenediamine, N-benzyl-.beta.-phenylethylamine, N- methylmorpholine or N-ethylmorpholine, 1-ephenamine, dihydroabietylamine, N,N'-bis- dihydroabietylethylenediamine, N-lower alkylpiper
  • antiviral statin or statin-like compounds disclosed in U.S. Patent Nos. 5,401 ,746, 5,169,857, and 5,006,530 also include substituted pyridines having the following, more specific, general structure:
  • A represents phenyl or phenyl which is monosubstituted or disubstituted by a substituent selected from the group consisting of methyl, hydroxymethyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, methoxy, ethoxy, propoxy, isopropoxy, phenoxy, benzyloxy, fluorine, chlorine or trifluoromethyl;
  • B represents cyclopropyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert.-butyl
  • E represents methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, pentyl, isopentyl, hexyl or isohexyl
  • R 22 represents hydrogen, lower alkyl, phenyl, benzyl or a physiologically tolerable metal or ammonium cation. These compounds may be synthesized or isolated from natural sources according to methods and techniques well known in the art.
  • 4,739,073 include compounds having the following structure:
  • R and R 0 is an unsubstituted, mono-substituted, bi-substituted, or trisubstituted aromatic ring, preferably a benzyl ring and the other is primary or secondary CL6 alkyl not containing an asymmetric carbon atom, C 3 . 6 cycloalkyl or phenyl(CH 2 ) m --•
  • CL6 alkyl not containing an asymmetric carbon atom, C 3 . 6 cycloalkyl or phenyl(CH 2 ) m --
  • the anti-viral statin or statin-like compounds disclosed in U S Patent Nos 4,448,979 and 4,346,227 include compounds having the following general structure wherein
  • R represents a hydrogen atom or a C1 -C5 alkyl group and one of the two X's represents a hydroxyl group and the other represents, preferably, a hydrogen or a C1-C5 alkyl, and pharmaceutically acceptable salts and pro-drug esters thereof and the corresponding lactone in which the Ri moiety is lost
  • dosage and duration of treatment it is recognized that the ability of an artisan skilled in pharmaceutical administration of drugs to determine suitable dosages depending on many inter-related factors is well-known, and skilled artisans are readily able to monitor patients to determine whether treatment should be started, continued, discontinued or resumed at any given time.
  • dosages of the compounds are suitably determined depending on the Individual cases taking symptoms, age and sex of the subject and the like into consideration.
  • the amount of a compound to be incorporated into the pharmaceutical composition of the invention varies with the dosage form, solubility and chemical properties of the compound, administration route, administration scheme and the like.
  • An effective amount for a particular patient may vary depending on factors such as the condition being treated, the overall health of the patient, the method route and dose of administration and the severity of side effects.
  • Dosages should be varied according to side effects (if any) and blood cell counts which should be monitored frequently, preferably every several days. Determination of the appropriate dose is made by the clinician using parameters known in the art. Generally, the dose begins with an amount somewhat less than the optimum dose and it is increased by small increments thereafter until the desired or optimum effect is achieved. Suitable dosages can be determined by further taking into account relevant disclosure known in the art (e.g., with regard to use of mevastatin, lovastatin, pravastatin and simvastatin, by reference to any of the large amount of information known in the art concerning administration of the particular compound or compounds to patients; with regard to use of one or more compound disclosed in any of U.S. Patents Nos.
  • the compounds for use in accordance with the present invention can be obtained readily by those skilled in the art.
  • compounds can be obtained in accordance with relevant disclosure known in the art (e.g., with regard to mevastatin, lovastatin, pravastatin and simvastatin. by reference to any of the large amount of information known in the art concerning methods of obtaining the particular compound or compounds; with regard to one or more compound disclosed in any of U.S. Patents Nos.
  • the compounds disclosed herein as having antiviral properties may be administered alone or in combination with one or more other anti-viral drug, and/or one or more other drug administered to counteract any condition caused by one or more viral infection and/or by a therapy given to combat one or more viral infection.
  • Such drugs e.g.,
  • AZT AZT
  • ribavirin etc.
  • any of the combination therapies disclosed herein can be administered simultaneously (in a combination formulation), essentially simultaneously (e.g., administration of each compound a few minutes or a few hours apart), or can be administered sequentially, e.g., several days apart, or more than a week apart.
  • a compound according to the invention and a second anti-viral agent can be administered together, or essentially simultaneously, e.g., administration of each compound a few minutes or a few hours apart, or can be administered sequentially, e.g., several days apart, or more than a week apart. All such variations in administration of the combination therapy are encompassed within the scope of the invention.
  • a dosage in the range of from about 0.1 to about 50 mg/kg/day will have therapeutic, anti-viral efficacy within the meaning of the present invention.
  • a dosage in the range of from about 0.5 mg/kg/day to about 10 mg/kg/day will be employed.
  • a daily dosage of a statin compound will typically comprise about 10 to about 1000 mg, usually about 20 to about 500 mg, which may be administered as a single dose or as two or more subdoses. Such doses or subdoses may be administered at one or more sites or by one or more than one route of administration.
  • the duration for the treatment is usually once per day for a sufficient length of time, typically about 1-4 weeks, for the patient to become asymptomatic, or for one or more symptoms to abate noticeably.
  • a compound of the present invention may be administered orally, topically in creams, aerosol for nasal inhibition of, for example, Rhinovirus infections, intramuscularly (IM), intravenously (IV), or subcutaneously (SC).
  • Preferred embodiments include IV administration using a statin compound that is micronized to an average particle diameter of about 0.1-10 ⁇ M, generally about 0.5-5 ⁇ M.
  • a statin such as mevastatin or lovastatin is micronized to a size of about 5 ⁇ M or less and the micronized compound is suspended in sterile saline or buffer, which is administered by an IV route
  • Compounds of the invention and their pharmaceutically or physiologically acceptable salts are thus administered by any route suitable to the condition to be treated, including oral, rectal, nasal, topical (including ocular, buccal or sublmgual), vaginal, parenteral (including subcutaneous, intramuscular, intravenous, intrape ⁇ toneal, intradermal, mtrathecal, intradural and epidural) and pulmonary by aerosol
  • Suitable formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy Techniques, excipients and formulations generally are found in, e g , Remington's Pharmaceutical
  • compositions suitable for use in the present invention include the step of bringing into association a statin compound with one or more excipients or carriers
  • formulations are prepared by uniformly and intimately bringing into association a statin compound with liquid excipients or finely divided solid excipients or both, and then, if appropriate, shaping the product
  • Formulations suitable for oral administration in the present invention may be presented as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of statin compound, as a powder or granules, as solution or a suspension in an aqueous liquid or a non-aqueous liquid, or as an oil-m-water liquid emulsion or a water-in-oil liquid emulsion
  • the statin compound may also be presented as a bolus, electuary or paste
  • a tablet may be made by compression or molding, optionally with one or more excipients
  • Compressed tablets may be prepared by compressing in a suitable machine the statin compound in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent Molded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the statin compound therein
  • Formulations suitable for buccal administration include lozenges comprising a statin compound in a flavored basis, usually sucrose and acacia or tragacanth
  • Formulations suitable for parenteral administration are usually sterile and include aqueous and non-aqueous injection solutions which may contain anti-oxidants, buffers, bactenostats and solutes which render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents
  • the formulations may be presented in unit- dose or multi-dose containers, for example sealed ampoules and vials with elastomenc stoppers, and may be stored in a freeze-dned (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections immediately prior to use
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described Unit dosage formulations will typically contain a daily dose or unit daily sub-dose, as recited above, or an appropriate fraction thereof
  • compositions disclosed herein will typically comprise one or more anti-viral statin or statin-like compounds, and, the methods disclosed herein will utilize such compositions, which will contain one, two or more of such compounds, usually one While it is possible for the compounds of the invention to be administered as pure compounds it is preferable to present them as pharmaceutical formulations
  • the formulations of the present invention comprise at least one statin compound together with one or more acceptable carriers or excipients and optionally other therapeutic agents, e.g , ⁇ -IFN, ribavirm, a nucleoside analog or a protease inhibitor
  • the one or more carriers or excipients must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the patient
  • the compounds of this invention are useful in the treatment or prophylaxis of one or more flaviviral or togavirai infections in man or animals
  • Togavirus and flavivirus infections that can be treated with statin compounds include human hepatitis C virus
  • HCV California encephalitis virus
  • St Louis encephalitis virus California encephalitis virus
  • western equine encephalitis virus eastern equine encephalitis virus, Colorado tick fever virus
  • LaCrosse encephalitis virus Japanese encephalitis virus
  • yellow fever virus Venezuelan equine encephalitis virus
  • Murray valley fever virus tick-borne encephalitis viruses
  • GB virus A GB virus B
  • GB virus C Dengue virus 1 , Dengue virus 2
  • Dengue virus 4 Dengue virus 4
  • the rubiviruses include human rubella virus Pestiviruses include mucosal disease viruses such as bovine virus diarrhea virus, hog cholera virus and sheep border disease virus
  • the statin compounds can be used to treat vertebrate subjects (humans, animals or mammals) who are co fected with a togavirus and another virus, such as a retrovirus or a second togavirus Retroviruses such as a human immunodeficiency virus, e g , HIV1 or HIV2, a simian immunodeficiency virus, a recombmant human-simian immunodeficiency virus (e g , SHIV 229 ), a feline immunodeficiency virus or a feline or murine leukemia or sarcoma virus can be treated as described herein
  • Coinfections with hepatitis viruses may be treated using the compounds of the invention, e g , a HCV and HIV co fection
  • the subject will typically be one who has been tested to determine that (1) one or more togavirus infections is present (HCV, etc ) and (11) a second virus infection is present, e.
  • compositions and formulations may also be used to treat, or ameliorate one or more symptoms associated with, a retroviral infection such as a HIV1 or HIV2 infection in humans
  • phrases such as "amelioration of one or more symptoms associated with” means that such compounds or formulations may be used to reduce replication of an infectious agent or to reduce the number of infectious agents that are present in a subject or to ameliorate one or more symptoms associated with, or caused by, the condition or infection (e g , reduced fever, a shortened duration or degree of pain, or a noticeable reduction of or elimination of diarrhea or fatigue)
  • formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring or coloring agents
  • the present invention further provides veterinary compositions comprising one or more anti-viral statin or statin-like compound together with a veterinary carrier therefor
  • Veterinary carriers are materials useful for the purpose of administering the composition to cats, dogs, horses, mice, rats, hamsters, rabbits and other animals and may be solid, liquid or gaseous materials that are otherwise inert or acceptable in the veterinary art and are compatible with a statin compound
  • These veterinary compositions may be administered orally, parenterally (e g , IV) or by any other desired route, e g , as described herein
  • Example 1 was an in vitro test in which simvastatin was tested in MDBK cells against bovine virus diarrhea virus (BVDV)
  • BVDV bovine virus diarrhea virus
  • Example 2 was a comparative in vitro test in which ⁇ bavi ⁇ n was tested (as a standard) in MDBK cells against BVDV The parameters of the test, and the test results are shown in Tables 2-1 through 2-3 (which may be graphed by depicting % of control cell viability and % reduction in viral CPE as a fuction of drug concentration), below
  • Example 3 was an in vitro test in which simvastatin was tested in MDBK cells against BVDV The parameters of the test, and the test results are shown in Tables 3-1 through 3-3 (which may be graphed by depicting % of control cell viability and % reduction in viral CPE as a fuction of drug concentration), below
  • H tox cell toxicit
  • cc cell control
  • Example 4 was an in vitro test in which pravastatin was tested in MDBK cells against BVDV The parameters of the test, and the test results are shown in Tables 4-1 through 4-3 (which may be graphed by depicting % of control cell viability and % reduction in viral CPE as a fuction of drug concentration), below
  • Example 5 was an in vitro test in which lovastatin was tested in MDBK cells against BVDV The parameters of the test, and the test results are shown in Tables 5-1 through
  • Example 6 was a test in which mevastatin was tested in PBMCs against the ROJO strain of the HIV virus.
  • the parameters of the test, and the test results are shown in Table
  • Example 11 was a test in which lovastatin was tested in macropharge against the
  • Example 14 was a test in which pravastatin was tested in PBMC against ROJO.
  • Example 15 was a test in which simvastatin was tested in PBMC against ROJO.

Abstract

La présente invention concerne des méthodes pour traiter un vertébré, en particulier un mammifère, et plus spécifiquement un patient murin ou humain atteint d'une ou plusieurs infections virales, ou une lignée cellulaire infectée par une ou plusieurs infections virales. Ces infections virales sont par exemple des infections des virus suivants, sans toutefois se limiter à celles-ci: hépatite C, VIH, hépatite A, hépatite B, hépatite G ou hépatite H. Les méthodes de cette invention consistent notamment à administrer au patient infecté par au moins un des virus susmentionnés une statine ou un composé apparenté à la statine présentant une activité antivirale, cette statine ou ce composé apparenté à la statine pouvant être choisis dans le groupe constitué par: la mévastatine, la lovastatine, la pravastine, la simvastatine, et les composés décrits dans les brevets américains nos. 4,346,227, 4,448,979, 4,739,073, 5,273,995, 5,169,857, 5,006,530, et 5,401,746.
EP00908609A 1999-02-11 2000-02-11 M thodes pour traiter des infections virales Withdrawn EP1150665A2 (fr)

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US11962999P 1999-02-11 1999-02-11
US119629P 1999-02-11
PCT/US2000/003634 WO2000047196A2 (fr) 1999-02-11 2000-02-11 Méthodes pour traiter des infections virales

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JP (1) JP2002536405A (fr)
AU (1) AU2991700A (fr)
CA (1) CA2363088A1 (fr)
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ZA (1) ZA200106406B (fr)

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WO2003103640A1 (fr) * 2002-06-10 2003-12-18 Elan Pharma International, Ltd Formulations nanoparticulaires comprenant des derives d'un inhibiteur de la hmg coa-reductase (≤statines≥), nouvelles combinaisons associees et production de ces compositions pharmaceutiques
CA2522089A1 (fr) * 2003-04-30 2004-11-11 Consejo Superior De Investigaciones Cientificas Prevention d'une infection par le virus hiv-1 a travers l'inhibition de la reorganisation et/ou de l'alteration des domaines a reservoir de la membrane cellulaire induites par rho
US7223787B2 (en) * 2003-10-21 2007-05-29 Board Of Regents, The University Of Texas System Prenylation inhibitors reduce host cell permissiveness to viral replication
US8765704B1 (en) * 2008-02-28 2014-07-01 Novartis Ag Modified small interfering RNA molecules and methods of use
WO2006039656A2 (fr) * 2004-10-01 2006-04-13 Novartis Vaccines And Diagnostics Inc. Molecules de petits arn interferants modifiees et methodes d'utilisation de celles-ci
WO2006038797A1 (fr) * 2004-10-06 2006-04-13 Primagen Holding B.V. Utilisation d'une statine ou d'un precurseur de celle-ci pour le traitement des infections par le vih
EP1658845A1 (fr) * 2004-10-06 2006-05-24 PrimaGen Holding B.V. Utilisation des statines et de leurs precurseurs pour le traitement des infections virales
CA2650980A1 (fr) * 2006-05-04 2007-11-15 Patrick T. Prendergast Procede de traitement et de prophylaxie des infections de grippe virale
KR20100005063A (ko) * 2006-09-18 2010-01-13 패트릭 티. 프렌더게스트 바이러스 감염을 치료하기 위한 스타틴 및 카페인을 포함하는 조성물
EP2241561A1 (fr) * 2009-04-16 2010-10-20 Neuron Biopharma, S.A. Composé neuroprotecteur, hypocholestérolémiant et antiépileptique
FR3041529A1 (fr) * 2015-09-24 2017-03-31 Inst De Rech Pour Le Dev (Ird) Compositions utiles pour le traitement des arboviroses
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AU2991700A (en) 2000-08-29
WO2000047196A3 (fr) 2001-03-15
WO2000047196A2 (fr) 2000-08-17
CA2363088A1 (fr) 2000-08-17
JP2002536405A (ja) 2002-10-29

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