Classifications

• • 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
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
• • 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
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• • 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
  • A61P31/14—Antivirals for RNA viruses

Definitions

• HCV Hepatitis C virus
• HCV Di Bisceglie, A.M., ( 1 997) Hepatology 26(3 Suppl. 1 ) : 345-385). HCV belongs
• Flaviviridae which consists of three genera: flaviviruses,
• BVDV bovine viral diarrhea virus
• analogue 1 ,5-Dideoxy-1 ,5-imino-D-galactitol also called
• DGJ deoxygalactonojirimycin
• DNJ derivatives are antiviral inhibitors at least partially because they
• Calnexin interaction is crucial for the proper folding of many host and
• virus encoded glycoproteins including the envelope glycoproteins of BVDV and
• envelope glycoproteins may lead to an impaired secretion of virions from
• N-DNJ alkylchain derivative N-nonyl-DNJ
• N-butyl-DNJ N-butyl-DNJ
• amphiphilic, alkylated iminosugar derivatives as the structurally similar
• n-octyl glucoside n-OG
• n-nonyl glucoside n-nonyl glucoside
• glycoproteins and alters the membrane glycoprotein composition of secreted
• BVDV virions but does not influence either viral RNA replication or protein
• DEV DENV
• JEV Japanese Encephalitis virus
• pestiviruses Unlike the closer related pesti- and hepaciviruses, flaviviruses do
• DNJ- and DGJ- derivatives may inhibit viral replication by inhibiting p7 or
• the HCV positive stranded RNA genome encodes a single polyprotein
• the polyprotein is co-reacted
• HCV replication information about HCV replication is derived by using a BVDV cell culture
• infectious viral particles can be generated by complementing
• the HCV p7 protein is a 63 amino acid peptide which has been
• the p7 protein has been shown to include two transmembrane domains.
• the N- terminal transmembrane domain includes amino acids from about position 1 0
• transmembrane domains (typically greater than about 70%), are members of a
• hydrophobic group characterized as F, I, W, Y, L, V, M, P, C, and A.
• LPQRAYA (SEQ ID NO. : 1 ) .
• HCV p7 has been
• viroporins which mediate cation permeability across membranes and are
• transmembrane domain has been shown to be sufficient to form membrane
• One embodiment relates to a method of treating HCV infection by
• HCV p7 protein in a subject in need thereof, particular a human.
• the compounds are represented by the following Formula I or II :
• R 31 ' , R 32 , R 32' , R 33 , R 33' , R 34 , and R 34' is selected, independently from each other,
• dialkylamino linear or branched Ci 6 alkyl, C 2 -6 alkenyl and alkynyl; aralkyl;
• alkyDthio (Ci e alkyl)sulfonamide; arylsulfonamide; -NHNH 2 ; -NHOH; aryl; and
• heteroaryl wherein each of the substituents may be the same or different.
• R 2 and R 4 are substituents selected independently of each other from
• alkyl C 2 - ⁇ s alkenyl and alkynyl, and aralkyl.
• Each linear C7-18 alkyl, branched C3- is alkyl, C 2 - ⁇ s alkenyl and alkynyl, and aralkyl optionally may be substituted, and
• substituted C1-18 alkyl is substituted with one or more substituents
• alkyl- and dialkylamino linear or branched C1-6 alkyl, C 2 -e alkenyl and alkynyl;
• aralkyl linear or branched Ci e alkoxy, aryloxy; aralkoxy; -CN; -NO 2 ; -COOH; -
• alkyDsulfonyl arylsulfonyl; sulfamoyl, (C1-6 alkyDsulfamoyl; (C1-6 alkyDthio; (C1-6
• alkyDsulfonamide arylsulfonamide; -NHNH 2 ; and -NHOH, wherein selected
• N-DNJ N-nonyldeoxynojirimycin
• oxaundecyl-1 ,6-dideoxygalactonojirimycin i.e. , N-1 0-oxaundecyl-6-
• One or more of the compounds may be packaged as a kit for treating
• the kit may include instructions for treating HCV infection as
• Another embodiment relates to a method of screening compounds for
• FIGURE 1 A shows the growth curves of E. co/i Rosetta gami(DE3)pLacl
• FIGURE 1 B shows the release of [ 3 H]-uridine by non-transformed E. co/i Rosetta
• FIGURE 2 shows a Tris-tricine gel electrophoresis analysis of synthetic
• the gel was silver-stained (left panel) or transferred to a membrane
• FIGURE 3A shows channel recordings of synthetic HCV p7
• FIGURE 3B is reconstituted into a BLM. Straight lines denote the closed state.
• FIGURE 3B is reconstituted into a BLM. Straight lines denote the closed state.
• FIGURE 3C shows a current histogram of the trace recorded at
• FIGURE 4 shows the effect of the short ( ⁇ B-DNJ, NB-DGJ) and long
• iminosugar derivatives were added to a final concentration as indicated.
• FIGURE 5 shows the effect of N7-oxanonyl-6-deoxy-DGJ (alternatively
• N7-oxanonyl-methyl-DGJ N7-oxanonyl-methyl-DGJ
• FIGURE 6 shows a graphical representation of the normalized
• the data represent the average of three representative trace slices of 4
• Ka PP 1 1 0.4 ( ⁇ 1 9.9) ⁇ M; and for N7-oxanonyl-6-deoxy-DGJ, Ka PP
• FIGURE 7 shows the effect of SP240 (i.e. , N-1 0-oxaundecyl-1 ,6-
• atoms and includes, for example, methyl, ethyl, butyl, and nonyl.
• aryl refers to a monocyclic aromatic group
• phenyl such as phenyl or a benzo-fused aromatic group such as indanyl, naphthyl, or
• heteroaryl refers to aromatic compounds containing one
• hetero atoms examples include pyridyl, furyl, and thienyl or a
• benzofused aromatic containing one or more heteroatoms such as indolyl or
• heteroatom refers to non-carbon atoms
• cycloalkyl refers to a carbocyclic ring
• alkenyl refers to a straight or branched-
• chain alkyl containing one or more double bonds such as ethenyl and propenyl.
• aralkyl refers to an alkyl substituted with
• an aryl such as benzyl and phenethyl.
• alkynyl refers to a straight or branched-
• aryloxy refers to a substituent created by
• replacing the hydrogen atom in an -OH group with an aryl group includes,
• alkoxy refers to an alkoxy group
• alkylamino refers to an amino group
• alkyl group such as methylamino (-NHCH3) and
• dialkylamino refers to an amino group
• DNG means 1 ,5-Dideoxy-1 ,5-imino-D-
• DGJ means 1 ,5-Dideoxy-1 ,5-imino-D-
• BLM black lipid membranes
• the method contemplates administering compounds of
• R 1 1 , R 1 1 ' , R 12 , R 12' , R 13 , R 13' , R 14 , R 14' , R 15 , and R 15' is
• alkenyl and alkynyl aralkyl; linear or branched Ci e alkoxy; aryloxy; aralkoxy; -
• alkyl -C(O)NH(aryl); sulfonyl; (C1-6 alkyDsulfonyl; arylsulfonyl; sulfamoyl, (C1-6
• alkyDsulfamoyl (Ci-e alkyDthio; (C1-6 alkyDsulfonamide; arylsulfonamide; -
• R 14 , R 14' , R 15 , and R 15' is a hydroxymethyl group (-CH 2 OH).
• R 1 1 , R 1 V , R 12 , R 12' , R 13 , R 13' , R 14 , R 14' , R 15 , and R 15' is a hydroxy
• R 1 1 , R 1 1 ' , R 12 , R 12' , R 13 , R 13' , R 14 , R 14' , R 15 , and R 15' being selected from -CHs, -
• R 2 is a substituent selected from linear C7- ⁇ s alkyl, substituted CM S
• alkyl is alkyl, branched C 3 - ⁇ s alkyl, C 2 - ⁇ alkenyl and alkynyl, and aralkyl optionally
• dialkylamino linear or branched C1-6 alkyl, C 2 -6 alkenyl and alkynyl; aralkyl;
• alkyDsulfonyl arylsulfonyl; sulfamoyl, (C1-6 alkyDsulfamoyl; (C1-6 alkyDthio; (C1-6
• alkyDsulfonamide arylsulfonamide; -NHNH 2 ; and -NHOH.
• R 2 is a linear C7-18 alkyl, branched C3-18 alkyl, or
• R 2 is a linear C7-11 alkyl
• R 2 that are linear C7-11 alkyl
• substituents include heptyl, octyl, and nonyl.
• R 2 being a
• substituted alkyl group is 7-oxanonyl (-CH 2 (CH 2 )5-O-CH 2 CH 3 ).
• -CH 2 (CH 2 )5-O-CH 2 CH 3 7-oxanonyl
• R 2 is n-nonyl, 7-oxanonyl, or 1 0-oxaundecyl.
• the compound may be represented as one of the following formulas:
• the compound has one of the formulas as set forth in Table I:
• the compound has one of the formulas:
• R 2 is nonyl, 7-oxanonyl, or 10-oxaundecyl
• N-DNJ N-nonyldeoxynojirimycin
• oxaundecyl-1 ,6-dideoxygalactonojirimycin i.e. , N-10-oxaundecyl-6-
• Another aspect of the disclosed method contemplates administering
• R 31 , R 31 ' , R 32 , R 32' , R 33 , R 33' , R 34 , and R 34' is
• alkenyl and alkynyl aralkyl; linear or branched C1-6 alkoxy; aryloxy; aralkoxy; -
• alkyl -C(0)NH(aryl); sulfonyl; (Ci-e alkyDsulfonyl; arylsulfonyl; sulfamoyl, (Ci-e
• alkyDsulfamoyl (Ci - ⁇ alkyDthio; (C1-6 alkyDsulfonamide; arylsulfonamide; -
• R 34 , and R 34" is a hydroxymethyl group (-CH 2 OH).
• R 1 1 , R 1 1 ' , R 12 , R 12' , R 13 , R 13' , R 14 , R 14' , R 15 , and R 15' is a hydroxy group (-OH) .
• the most preferred embodiment contemplates at least two of R 11 , R 1 1 , R 12 ,
• R 12' , R 13 , R 13' , R 14 , R 14' , R 15 , and R 15' being selected from -CH 3 , -CH 2 OH, and -
• R 4 is a substituent selected from linear C7- ⁇ alkyl
• aralkyl Each linear C7- ⁇ s alkyl, branched C3-18 alkyl, C 2 - ⁇ 8 alkenyl and alkynyl,
• aralkyl linear or branched C1-6 alkoxy, aryloxy; aralkoxy; -CN; - NO 2 ; -COOH; -COO(alkyl); -COO(aryl); -C(O)NH(C ⁇ -e alkyl); -C(O)NH(aryl);
• alkyDthio (Ci-e alkyDsulfonamide; arylsulfonamide; -NHNH 2 ; and -NHOH.
• R 4 is a linear C7-18 alkyl, branched C3-18 alkyl, or
• R 4 is a linear C7-11 alkyl
• R 4 that are linear C7-11 alkyl
• substituents include heptyl, octyl, and nonyl.
• R 4 being a
• substituted alkyl group is 7-oxanonyl (-CH 2 (CH 2 )5-O-CH 2 CH 3 ).
• -CH 2 (CH 2 )5-O-CH 2 CH 3 7-oxanonyl
• R 4 is A?-nonyl, 7-oxanonyl, or 1 0-undecyl.
• a membrane that includes the p7 protein with one or more compounds that
• particular compounds can inhibit the ability of p7 to permeabilize membranes.
• the selected compound may inhibit one or more activities of the p7
• the compound may prevent p7 from forming
• channels, or the compound may block the channel after it has formed, (i.e. , as
• the compound may inhibit the p7 protein by
• the compound may inhibit the capability of p7 to
• method comprises incorporating p7 or a variant of p7 into a membrane system
• Black lipid membranes may be used in the method, but other organic solvents (e.g., but other organic solvents (e.g., organic solvents (OLED), organic solvents (OLED), organic solvents (OLED), organic solvents (OLED), organic solvents (OLED), organic solvents (OLED), organic solvents (OLED), organic solvents (OLED), organic solvents (OLED), organic solvents (OLED), organic solvents (OLED), organic solvent, but other organic solvent, but other organic solvent, but other organic solvent, but other organic solvents (OLED).
• BLM are commonly used to study membrane permeability, e.g. , as mediated by channel-forming proteins.
• p7 may be incorporated into the membranes to form p7-containing
• the p7 protein may be selected from any HCV strain where the
• p7 protein can be shown to increase the permeability of a selected membrane.
• the p7 protein from the HCV-H strain may be selected (i.e. ,
• LPQRAYA SEQ ID NO.: 1
• p7 protein from another strain may be any suitable p7 protein from another strain.
• a p7 protein from a particular HCV clade, (e.g. , clade 1 ).
• the variant may be shown to permeabilize a chosen membrane
• Possible variants include fusions,
• deletions, and/or mutations or substitutions may be desirable.
• p7 that can be shown to permeabilize a chosen membrane (e.g. , a selected
• p7 protein or variant may demonstrate a conductance level in a BLM of no less
• a "hydrophobic amino acid” may be
• the chosen p7 protein or variant may be synthesized artificially or
• a suitable biological system such as bacterial or eukaryotic cells.
• the permeability of the membranes may be measured to determine whether the
• protein demonstrates activity (e.g. , causing an increase in permeability or a
• Test compounds may be contacted with the protein
• test compounds may be contacted with p7 and/or the components of the p7-
• test compounds in the screening method.
• N-1 0- oxaundecyl-1 ,6-dideoxygalactonojirimycin i.e. , N-1 0-oxaundecyl-6-
• membrane components as test compounds in the method e.g. , compounds
• amantadine is a known channel blocker of influenza A virus M2 channels. (See
• an inducible bacterial system may be utilized to generate a plurality of cells.
• membranes may lead to an arrest in cell growth.
• p7 or a variant thereof may be expressed from an inducible promoter in a suitable bacteria
• radioactive molecule such as [ 3 H]-uridine prior to induction of p7 expression.
• Test compounds may be any organic compound having the release of [ 3 H]-uridine into the media.
• Test compounds may be any organic compound having the release of [ 3 H]-uridine into the media.
• the present compounds can be prepared by synthetic
• the medicaments may be adapted for administration by any means.
• Such a composition may be prepared
• bitartrate bromide, calcium edetate, camsylate, carbonate, citrate, edetate,
• estolate estolate
• esylate fumarate
• gluceptate gluconate
• glutamate glutamate
• glycollylarsanilate hexylresorcinate, hydrabamine, hydrobromide
• salicylate stearate, subacetate, succinate, sulfate, tannate, tartrate, or
• Preferred pharmaceutically acceptable salts include, for example,
• hydrochloride maleate, mesylate, napsylate, pamoate (embonate), phosphate,
• the compounds and agents may be formulated in
• aqueous solutions preferably in physiologically compatible buffers such as
• penetrants are generally known
• compositions suitable for use in the present methods are provided.
• compositions wherein the active ingredients are contained in an
• compositions may contain suitable pharmaceutically acceptable carriers
• preparations formulated for oral administration may be in the form of tablets,
• methods provided herein may include one or more of the following: preserving
• sweeteners colorants, odorants, salts, buffers, coating agents or antioxidants.
• oral use can be obtained by combining the active compounds with solid
• Suitable excipients are, in particular, fillers such as sugars,
• cellulose preparations for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum
• tragacanth methyl cellulose, hydroxypropylmethyl-cellulose, sodium
• CMC carboxymethyl-cellulose
• PVP polyvinylpyrrolidone
• disintegrating agents may be added, such as the cross-linked
• polyvinylpyrrolidone agar, or alginic acid or a salt thereof such as sodium
• compositions which can be used orally include push-fit
• capsules made of gelatin as well as soft, sealed capsules made of gelatin, and
• the push-fit capsules can contain the following plasticizer, such as glycerol or sorbitol.
• a plasticizer such as glycerol or sorbitol.
• the push-fit capsules can contain the following plasticizer, such as glycerol or sorbitol.
• starches, and/or lubricants such as talc or magnesium stearate and, optionally,
• the active compounds may be dissolved or
• liquids such as fatty oils, liquid paraffin, or liquid
• PEGs polyethylene glycols
• stabilizers may be added.
• Medicaments adapted for oral administration may be provided as
• capsules or tablets as powders or granules; as solutions, syrups or
• suspensions in aqueous or non-aqueous liquids); as edible foams or whips; or
• Tablets or hard gelatin capsules may comprise lactose, maize starch
• Soft gelatin capsules may comprise vegetable oils, waxes, fats, semi-
• Solutions and syrups may comprise water, polyols and sugars.
• suspensions oils e.g. , vegetable oils
• Medicaments adapted for transdermal administration may be provided
• ingredient may be delivered from the patch by iontophoresis (Iontophoresis is
• Medicaments adapted for topical administration may be provided as
• a topical ointment or cream is preferably used.
• a topical ointment or cream is preferably used.
• the active ingredient may be employed with either a paraffinic or
• the active ingredient may be any suitable ointment base.
• the active ingredient may be any suitable ointment base.
• the active ingredient may be any suitable ointment base.
• the active ingredient may be any suitable ointment base.
• the active ingredient may be any suitable ointment base.
• the active ingredient may be any suitable ointment base.
• Medicaments adapted for topical administration to the eye include
• the active ingredient can be dissolved or suspended in a
• Suitable carrier e.g. , in an aqueous solvent.
• Medicaments adapted for topical administration in the mouth include
• Medicaments adapted for rectal administration may be provided as
• carriers include a coarse powder (e.g. , having a particle size in the range of 20
• compositions adopted for nasal administration which use liquid
• nasal sprays or nasal drops include nasal sprays or nasal drops. These may comprise aqueous or
• Medicaments adapted for administration by inhalation include fine particles
• particle dusts or mists which may be generated by means of various types of
• apparatus e.g. , pressurized aerosols, nebulizers or insufflators.
• apparatus can be constructed so as to provide predetermined dosages of the
• Medicaments adapted for parenteral administration include aqueous
• compositions substantially isotonic with the blood of an intended recipient.
• compositions include water,
• compositions for example, alcohols, polyols, glycerine and vegetable oils, for example.
• adapted for parenteral administration may be presented in unit-dose or multi-
• dose containers for example sealed ampoules and vials, and may be stored in
• liquid carrier e.g. , sterile water for injections, immediately prior to use.
• active agent 0.1 mg to 5 g of active agent, and may be in the range of from
• the dosage may be administered in a single
• EXAMPLE 1 Inducible p7 expression in bacteria.
• p7 expression effects a release in radioactively labeled uridine.
• Example 1 .1 Materials and Methods.
• the coding region of HCV p7 was amplified by polymerase
• PCR chain reaction
• HCV 1 a strain cDNA (AF009606), kindly provided by J. Dubuisson. PCR
• AAGCGCCCATGGCTTTGGAGAACCTCGTAATAC (SEQ ID NO. : 2) and 2,
• the ligation mixture was used to transform competent E. coli R. garni
• plasmid was amplified in 50 ⁇ g/ml carbenicillin (Sigma) containing medium.
• pTriEx1 .1 p7 isolated p7-containing plasmid was designated pTriEx1 .1 p7.
• IPTG isopropylthiogalactopyranoside
• Rosetta garni (DE3)pLacl cells carry a
• Example 2.1 Materials and Methods.
• LPQRAYA (SEQ ID NO.: 4)
• MALDI-MS spectrometry
• the source, extraction, and focusing voltages were 20000,
• Tricine sample buffer was applied in Tricine sample buffer to a gel (8 x 1 0 cm 2 ) consisting of
• the gel was washed for 1 0 min in 50% methanol and for 10
• portion of the loaded protein contained the full-length, biotinylated p7 protein.
• This broad band may
• POPC oleoyl-srj-glycero-3-phosphocholine
• the BLM was formed by raising the
• NB-DNJ (Sigma) and NB-DGJ were added on either the cis or trans side.
• the channels had a conductance level of up to 2 nS at - 1 00 mV ( Figure 3A). The smallest mean conductance level detected was around
• Table 1 Conductance levels of p7. Data are derived from the recordings in
• Fig. 3A and presented as the mean value ⁇ the standard error of the mean, as shown in brackets.
• the mean was calculated from 1 second slices of the recordings.
• recording may indicate the presence of sub-conductance states.
• TMD I transmembrane domain I
• TMD II transmembrane domain II
• N-octylglucoside up to 3.0 mM, had no effect on channel activity.
• alkylchain derivatives NN-DGJ, NN-DNJ and N7-oxanonyl-6-deoxy-DGJ led to a
• Ka PP 1 1 0.4 ( ⁇ 1 9.9) ⁇ M for NN-DGJ, Ka PP

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