EP1244356A1 - Compositions et procedes relatives a des nucleosides-l, a des nucleotides-l ainsi qu'a leurs analogues - Google Patents

Compositions et procedes relatives a des nucleosides-l, a des nucleotides-l ainsi qu'a leurs analogues

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Publication number
EP1244356A1
EP1244356A1 EP00988189A EP00988189A EP1244356A1 EP 1244356 A1 EP1244356 A1 EP 1244356A1 EP 00988189 A EP00988189 A EP 00988189A EP 00988189 A EP00988189 A EP 00988189A EP 1244356 A1 EP1244356 A1 EP 1244356A1
Authority
EP
European Patent Office
Prior art keywords
compound
contemplated
type
antiviral
response
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Withdrawn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
EP00988189A
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German (de)
English (en)
Other versions
EP1244356A4 (fr
Inventor
Johnson Lau
Zhi Hong
Robert Tam
Kanda Ramasamy
Chin-Chung Lin
Füsûn ZEYTIN
Ljubisa Rakic
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.)
Valeant Pharmaceuticals International Inc USA
Original Assignee
ICN Pharmaceuticals Inc
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Filing date
Publication date
Application filed by ICN Pharmaceuticals Inc filed Critical ICN Pharmaceuticals Inc
Publication of EP1244356A1 publication Critical patent/EP1244356A1/fr
Publication of EP1244356A4 publication Critical patent/EP1244356A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/12—Triazine radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/056—Triazole or tetrazole radicals
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • HCV hepatitis C virus
  • dnect antiviral drugs block the reverse transciiptase Reveise transc ⁇ ptase (RT) inhibitors are typically nucleoside analogs such as AZT, 3TC, or ddl Alternati ⁇ ely, non-nucleoside RT inhibitois, including quercetm may be used
  • RT inhibitors aie typically potent antiviral drugs
  • v ⁇ o and especially during a period of relatively high rate of viral replication, the generation of RT inhibitor resistant virus mutants aie pi oblematic
  • Other direct antiviral drugs block or mterfeie with the virus protem
  • the immune response to a viral challenge may be modulated
  • immunosuppressive drugs may be employed to reduce the inflammatory condition associated with the ⁇ iral infection
  • cyclosporm A is known as a potent immunosuppressor and is frequently used to repress tissue rejection after organ transplantation
  • the use of cyclosporm A tends to be problematic due to its general immunosuppressing effect, making the patient more prone to new infectious diseases
  • long-term administration of cyclosporm A is frequently associated with severe side effects, including hirsutism and gmgival hyperplasia
  • the bioavailabihty of cyclosporm A is at least in part dependent on bile, which may pose additional problems in a hepatitis infection
  • Tacrohmus may be employed as an immunosuppressing drug
  • Tacrohmus has found recognition in the treatment of facial atopic dermatitis
  • Topical administration of the m muno suppressant resulted m significant improvement m 95% of all treated patients [Alaiti, S et al Tacrohmus (FK506) ointment for atopic dermatitis A phase I study m adults and childien J Am Acad Dei matol 1998, 38(1) 69-76]
  • Tacrohmus appeared not to permeate through the skm ba ⁇ ier, thereby eliminating problems associated with systemic administration
  • Treatment with Tacrohmus without generally compiomismg immunity is limited to topical administration When systemically administered o ⁇ er piolonged periods, Taciolimus frequently leads to lymphopio ferative disorders and cardiomyopathy
  • Many known immunosuppressive drugs provide some relief for inflammatory conditions.
  • the window of a usable concentration of immunosuppressive drugs is defined by the maximum concentration that will not entirely compromise a patient's immune system, and the minimum concentration that will provide at least some desirable effect.
  • the present invention is directed to methods and compositions in which a nucleoside and/or nucleotide drug or its analog is administered to a subject in a concentration or dosage effective to achieve a desired pharmacological or physiological effect.
  • contemplated compounds have a structure according to formula I, wherein R is H, a P0 3 2" , (PO 3 ) 2 3 ⁇ , or (PO ) 3 4" group.
  • Contemplated compounds are optionally further modified with a modifying group that is covalently coupled to the carbonyl atom, and it is further contemplated that compounds according to the inventive subject matter are in a D- or L-configuration.
  • contemplated compounds are employed to treat a viral infection, and may further be co-administered with a cytokine, preferably IFN-alpha-2b, an antibody, or Ribavirin (l- ⁇ -D-ribofuranosyl-l,2,4-triazole-3-carboxamide).
  • a cytokine preferably IFN-alpha-2b, an antibody, or Ribavirin (l- ⁇ -D-ribofuranosyl-l,2,4-triazole-3-carboxamide).
  • the selectivity of contemplated compounds with respect to a pharmacological effect m a target cell is increased by modifying the compounds with a modifying group, wherem the modifying group is covalently attached to the drug via a mtiogen atom, and wherein the modifying group is enzymatically removed from the drug m the target cell
  • a method of treating a disease characterized by inflammation of an organ m a patient has a step in which contemplated compounds are administered to a patient at a dosage that causes systemic immunomodulation and not systemic immunosuppression of Type I and Type II responses This causes lmmuno- suppression of Type I and Type II responses m the organ of the patient due to selective accumulation of contemplated compounds m the organ
  • a method of stimulating neuronal growth has a step m which it is recognized that contemplated compounds are effective to stimulate growth of neurons withm a given concentration range
  • the compounds are provided to the neurons within the given concentration range
  • Figures 1A-1C are exemplary compounds according to the inventive subject matter
  • Figure 2 is an exemplary synthetic scheme for the synthesis of 1- ⁇ -L- ⁇ bofuranosyl- 1,2,4- t ⁇ azole-3-carboxam ⁇ de
  • Figure 3 is an alternah . e exemplaiy synthetic scheme for the synthesis of 1- ⁇ -L- ⁇ bofuranosyl-l,2,4-tr ⁇ azole-3-carboxam ⁇ de
  • Figure 4 is another exemplaiy synthetic scheme for the synthesis of 1- ⁇ -L- ⁇ bofuranosyl- 1 2,4-t ⁇ azole-3-carboxam ⁇ de
  • Figure 5 is a flow diagram depicting an exemplary method of organ-targeted immuno- suppression according to the inventive subject matter.
  • Figure 6 is a flow diagram depicting an exemplary method of stimulating cell growth according to the inventive subject matter.
  • nucleotides, nucleosides, and their corresponding analogs are suitable for use in conjunction with the teachings presented herein, wherein all of the contemplated compounds may be in their respective L-configuration or D-configuration.
  • particularly preferred compounds include phosphorylated and unphosphorylated LevovirinTM (l- ⁇ -L-ribofuranosyl-l,2,4-triazole-3-carboxamide, Structure 1), in which R may be hydrogen, or a phosphorous or sulfur-containing group.
  • R is a phosphorous containing group
  • R is especially preferred that R is a monophosphate, a diphosphate, or a triphosphate as depicted in Figures 1A-1C.
  • the phosphate groups may be in their corresponding mono-, di-, tri-, and tetra-protonated forms, and it should also be appreciated that when the phosphate groups are partially or completely deprotonated, salts may be formed with one or more mono- or multivalent cations.
  • Especially contemplated cations are alkaline metal ions and alkaline earth metal ions such as Mg 2 ⁇ , Cs 2+ , Na + , etc.
  • R may also be a P0 3 ⁇ " , (PO 3 ) 2 " ⁇ or (P0 3 ) 3 4" group in which one or more than one oxygen is replaced with a sulfur atom.
  • phosphate groups are generally preferred substitutents for R, other chemical groups may also be employed, and particulaily contemplated gioups mclude mono-, or polyaniomc groups, preferably with a tetragonal geometry
  • contemplated compounds especially include modified and unmodified phosphor lated LevovirmTM
  • contemplated compounds may also have a sugar moiety m the D-configuration, and an especially contemplated compound with a sugai m D-configuration is Ribavirm (1- ⁇ -D- ribofurai_osyl-l,2,4-tnazole-3-carboxamide)
  • contemplated compounds exhibit a direct antiviral effect (i e contemplated compounds immediately inhibit viral propagation) Since most organisms possess phosphatases m various compartments, it is contemplated that the compounds according to the mventn e subject matter may be gradually dephosphorylated, and one or more than one phosphate group may be removed at a time For example, a t ⁇ phosphorylated compound may be converted into a diphosphorylated, or monophosphorylated compound, or a diphosphorylated compound may be converted mto LevovirmTM in a single reaction
  • the mode of anti . iral action shifts from a direct antiviral effect to an indirect antiviral effect
  • the shift from a direct antiviral response to an indirect antiviral response is particularly advantageous, because even though the contemplated compounds are metabolized they retain anti-viral action over an extended period
  • the mode of action of contemplated compounds, and particularly phosphorylated LevovirmTM is actually at least bimodal - comprising a direct antiviral effect portion and an indirect antiviral effect portion
  • phosphorylated Levo ⁇ innTM is dephosphorylated at a considerably slower rate than phosphorylated Ribavirm, an effect that is contemplated to be due to the L-configuration of the ribose in LevovirmTM
  • dephosphorylation preferably takes place m the In er, however, other organs and compartments, including kidney, neuronal cells, and blood sitesam are also contemplated
  • suitable prodrugs include prodrugs formed by addition of a nitrogen-containing group to the carboxamide moiety of LevovirmTM, which may be especially advantageous where contemplated compounds are preferentially directed to the liver.
  • the inventors have discovered (unpublished results) that the specificity of LevovirinTM with respect to its pharmacological effect in hepatocytes can be improved by modifying LevovirinTM with a nitrogen-containing modifying group that is selectively removed in hepatocytes.
  • Structure 2 below shows LevovirinTM
  • Structure 3 shows LevovirinTM modified at the carboxamide group to form a carboxamidine group.
  • a modification of LevovirinTM with a (preferably nitrogen- containing) modifying group that can be selectively removed in a target cell will (1) increase the selectivity of LevovirinTM with respect to the target cell, thereby (2) reducing the overall dosage to achieve a desired effective concentration, and (3) reduce potential toxicity in non-target cells.
  • the modifying group is covalently bound to the carbonyl atom of the carboxamide group.
  • alternative modifying groups are enzymatically removable from Le ⁇ ovi ⁇ nTM, and particularly contemplated enzymes include ammohydrolases such as liver deammases (e g , adenosme or cytosme deammase), hvei deamidases (e g , aryl deamidase) and liver transammases (glutamate-pyruvate transaminase)
  • ammohydrolases such as liver deammases (e g , adenosme or cytosme deammase), hvei deamidases (e g , aryl deamidase) and liver transammases (glutamate-pyruvate transaminase)
  • the modifying group may inactivate LevovirmTM, or prevent subsequent activation once the modified LevovirmTM is presented to a non-target cell
  • the nitrogen- containing modifying group may also prevent metabolic activation of the modified LevovirmTM
  • the modification may comprise an organo-synthetic modification, an enzymatic modification, or a de-novo synthesis to produce the modified LevovirmTM
  • Enzymatic removal may include enzymes from various classes, including hydrolases, transferases, lyases, and oxidoreductases, and particularly preferred subclasses are adenosme and cytosme deammases, arginases, transammases, and arylamidases
  • contemplated enzymes for the enzymatic removal of the modification group may exclusively be expressed m the target cells, however, in alternative aspects of the inventive subject matter appropriate enzymes may also be expressed in cells other than the target cells, so long as the enzyme is not ubiquitously expressed m all cells m a cell containing system
  • contemplated enzymes are preferably natively expressed (/ e , are non-recombinant) in the respective target cells under normal and/or pathological conditions Foi example, it is known that glut
  • a mixture of methyl-l,2,4-triazole-3-carboxylate (25.4g, 200mmol), 1,2,3,5-tetra-O- acetyl- ⁇ -L-ribofuranose (63,66g, 200mmo_) and bis(p-nitrophenyl)phosphate (lg) were placed in an RB flask (500ml).
  • the flask was placed in a preheated oil bath at 165-175°C under water aspirator vacuum with stirring for 25min.
  • the acetic acid displaced was collected in an ice-cold trap that was placed between the aspirator and the RB flask.
  • the flask was removed from the oil bath and allowed to cool.
  • the volume of the EtOH solution was reduced to 150ml by heating and stirring on a hot plate.
  • the hot EtOH solution on cooling provided colorless crystals, which were filtered, washed with acetone, and dried under vacuum. Further concentration of the filtrate gave additional material.
  • the total yield was 35g (89%).
  • the synthesis of LevovirinTM may also employ one or more enzymatic conversions.
  • the acetylation of L-ribose may be performed with a suitable acetyl-transferase (e.g., EC 2.3.1.xx).
  • the formation of the carboxamide group from the corresponding methylester may be facilitated by a single or dual-enzyme system involving an esterase (e. g. , EC 3.1.1.xx) and/or aminotransferase (e.g., EC 2.6.1.xx).
  • LevovirinTM may be enzymatically converted into the corresponding mono-, di-, or triphosphate (e.g., EC 3.1.3.xx or EC 3. L4.xx).
  • catalysts other than bis(p-itrophenyl)phosphate in quantities other than lg may be utilized. Changing the amount (i.e., the molar fraction) of the catalyst may advantageously increase the selectivity of the reaction towards a higher yield of the desired Ni isomer (L-ribose coupled to the Ni atom of the triazole ring) over the N 2 ison er.
  • appropriate amounts of bis(p-nitrophenyl)phosphate include amounts between 3-30mmol. and more. Alternatively, where appropriate, amounts lower than 3mmol (0.3mmol - 2.99mmol) may be included.
  • the catalyst need not be limited to bis(p-nitrophenyl)phosphate, and alternative catalysts include p-toluenesulfonic acid, trichloro acetic acid, and p-nitrobenzoic acid.
  • reaction temperature it is particularly contemplated that lower temperatures may further increase the selectivity of the reaction towards a higher yield of the desired N] isomer over the N 2 isomer. Therefore, it is contemplated that appropriate temperatures for the coupling reaction between the triazole moiety and the ribose moiety include temperatures between about 155-165°C. more preferably between 145-165°C, and most preferably between 130-165"C.
  • the selectivity of the reaction towards a higher yield of the desired Ni isomer over the N? isomer may also be favorably influenced by a chemical modification of the methyl- l ,2,4-triazole-3- carboxylate.
  • Chemical modifications include formation of a complexmg structure that involves the N 2 atom, ste ⁇ c hindrance, and direct chemical modifications of the N 2 -atom For example, the free electron pair m the N?
  • the carboxylate group in the methyl- 1, 2.4-t ⁇ azole-3-carboxylate may be modified with a relatively bulky group that preferentially and ste ⁇ cally blocks or reduces leactions occurring at the N 2 atom
  • the N 2 atom may be directly modified by a protecting group, and suitable protecting groups include t-Boc, and benzyl.
  • a higher yield of the desired Ni isomer over the N 2 isomer may also be achieved using enzymatic synthesis in which the ribose moiety (or an L- ⁇ bonucleotide) and a modified or non-modified methyl- l,2,4-t ⁇ azole-3-carboxylate serve as a substrate for a ⁇ bosyltransferase (e g , EC 2.4.2.5 or EC 2 4.2 6).
  • a ⁇ bosyltransferase e g , EC 2.4.2.5 or EC 2 4.2 6
  • LevovirmTM may be synthesized via coupling of a protected L- ⁇ bose to a l,2,4-t ⁇ azole-3-nit ⁇ le, with subsequent conversion of the nit ⁇ le group to the carboxamide as shown m Figure 3.
  • the coupling of the triazole moiety with the ribose moiety may also be achieved in a reaction m which a (e g , benzyl protected) ribose has an -NHNH 2 group coupled to the Ci atom, that is reacted with the Ni atom of the triazole carboxylate, wherein the triazole carboxylate is subsequently converted to the carboxamidme as depicted in Figure 4
  • L-nucleotides, L-nucleosides and their lespective analogs are phosphorylated it is contemplated that all manners of incorporating a phosphate group into a nucleotide, nucleoside or their lespective analogs are suitable Conveision of contemplated nucleosides to their corresponding phosphorylated forms can be achie ⁇ ed synthetically (Hughes B G et al, (1983), 2', 5'-ohgoadenylated and related 2', 5-ol ⁇ gonucleot ⁇ de analogues 1 Substrate specificity of the mterferon-mduced murme 2',5'-ohgoadenylate synthetase and enzymatic synthesis of ohgomers Biochemistry, 22 21 16-2126) However, various alternati .
  • e methods are also contemplated and include enzymatic phosphoiylation (see e g , Van Rompay. A R , et al (2000). Phosphoiylation of nucleosides and nucleoside analogs by mammalian nucleoside monophosphate kinases, Pharmacol Ther 87(2-3) 189-198), and organochemical phosphoiylation m aqueous media (Schwartz, A and Ponnamperuma, C (1968), Phosphorylation of adenosme with linear polyphosphate salts in aqueous solution (Nature 218, 443)
  • contemplated compounds may be employed in any treatment or therapy of a system that positively responds to administration of contemplated compounds
  • contemplated compounds may be employed in antiviral treatments (as a direct antiviral compound and/or as an indirect antiviral compound), m treatments to modulate the immune system, and in treatments to stimulate cellulai growth
  • antiviral treatments as a direct antiviral compound and/or as an indirect antiviral compound
  • m treatments to modulate the immune system and in treatments to stimulate cellulai growth
  • particularly contemplated uses include administration of contemplated compounds m antmeoplastic treatments
  • a method of treating a viral infection in a patient comprises a step m which composition is administered to the patient at a dosage effective to inhibit viral propagation (i e , a process involving a host cell in which one or more than one vnus causes the host cell to produce one or more copies of the virus, wherem the term "to pioduce” refers to nucleotide synthesis, protem piocessing, and protem assembly), wheiein the composition comprises at least one the contemplated compounds, and pieferably at least one of a compound according to Structures 1 and 3 Preferred dosages are m the range of bet v.
  • contemplated compounds are not restricted to a particular virus in a particular viral infection, especially contemplated viral infections are an HIV infection, an HCV infection, an HBV infection, a RSV infection, an influenza virus infection, and a parainfluenza virus infection
  • PBMCs Peripheral blood mononucleai cells
  • PMBCs are infected with the desired virus, and the cell lines are then studied for relevant information on how particular drugs interact with the PBMCs and how the infected PBMCs act over time or under different environmental conditions.
  • models can be generated that show the effects of particular pharmaceuticals, environments, and/or conditions on the PBMC-Virus infected cells
  • LevovirmTM shows a positive response against PBMC-HIN infected cells
  • LevovirmTM also shows a similar immunomodulatory profile against PBMC-HIV infected cells despite the body's lack of enzymes necessary to phosphorylate the LevovirmTM present in the patient. Based on the above observations, along with other related information and tests, it is contemplated that LevovirmTM, phosphorylated LevovirinTM, and modified LevovirmTM according to Structure 3 can be utilized in the treatment of HIV and related viruses
  • a method of organ-targeted immunosuppression 500 has a first step 510 m which a drug is provided that reduces both a Type 1 response and a Type 2 response when administered above an immunosuppressive concentration, and increases the Type 1 response relative to the Type 2 response when administered below the immunosuppressive concentration, wherem the drug accumulates preferentially m a target organ
  • the drug is administered to a patient m a dosage effective to accumulate the drug in the target oigan to the immunosuppiessive concentration Consequently, it is contemplated that a method of treating a disease characterized by liver inflammation in a patient may comprise one step in which a compound is provided, wherem the compound comprises Levovirm, phosphorylated LevovirmTM, a modified phosphoiylated LevovirinTM, or a modified Ribavirm (supra) In a further step, the compound is administered to the patient at a dosage that (a) causes systemic immunomodulation and not systemic immunos
  • Immunosuppression refeis to an event m which T and/or B cell clones of lymphocytes are depleted in size or suppressed in their reactivity, expansion or differentiation Immunosuppression may thereby arise from activation of specific or nonspecific T suppressor lymphocytes of either T or B clones, or by drugs that have generalized effects on most oi all T or B lymphocytes
  • Cyclosporm A and FK506 act relatively specifically on T cells, while alkylatmg agents such as cyclophosphamide are less specific in their action
  • cytokme refers to a group of soluble protems and peptides which act as humoral regulators at nano- to picomolar concentrations and which, either under normal or pathological conditions, modulate the functional activities of individual cells and tissues Cytokines also mediate interactions between cells directly and regulate processes taking place in the extra-cellular environment
  • Type 1 and Type 2 Type 1 cells produce mterleukm 2 (IL-2), tumor necrosis factor (TNF ) and interferon gamma (IFN ⁇ ), and are responsible pnmarily foi cell-mediated immunity such as delayed type hypersensitivity and antiviral immunity
  • Type 2 cells produce mterleukms, IL4, IL-5, IL-6, IL-9, IL-10, and IL-13, and aie primanly involved in assisting humoial immune lesponses such as those seen m response to allergens (e g IgE and IgG4 antibody isotype switching)
  • Type 1 and Type 2 "responses” are meant to include the entire range of effects resulting from induction of Type 1 and Type 2 lymphocytes, respectively Among other things, such responses include mei eased production of the corresponding cytokines, increased proliferation of the corresponding lymphocytes, and other effects associated with increased production of cytokines, including moti ty effects
  • a Type 1 response is generally characterized by an increase m IL-2, TNF- ⁇ , and IFN- ⁇
  • a Type 2 response is typically characterized by an increase in IL4, IL-5, IL-6, and IL-10
  • the term the drug "accumulates preferentially" m a target organ refers to a selective mechanism of a target organ resulting in an increased net uptake or retention of the drug mto the target organ relative to other tissue or organs The mechanism may thereby include active import via transporters, receptors, vesicles, etc, but may also be based on physicochemical principles, including pH dependent charge of the
  • the drug is Ribavirm, which is provided to a patient with an HCV (Hepatitis C Virus) infection, and Ribavirm is orally administered to the patient m a single dosage of 600mg/ day for a period of 180 days
  • a single dosage of 600mg/ day is generally below a systemic immunosuppressive concentration, however is effective to preferentially accumulate m the hvei
  • the concentration of Ribavirm m the target organ here the liver
  • will significantly increase and reach an immunosuppressive concentration in the liver Ribavirm is known to increase a Type 1 response relative to a Type 2 response, and to reduce the Type 1 and Type 2 response at relatively high concentrations Examples are set forth in International Patent Application Number PCT/US98/00634 filed on January 13, 1998, incorporated herein by reference
  • the drug need not necessa ⁇ ly be limited to Ribavirm
  • alternative drugs include contemplated compounds (supra), particularly modified and unmodified LevovirmTM and phosphorylated LevovirmTM
  • contemplated compounds so long as alternative compounds reduce both a Type 1 response and a Type 2 response at an lmmunosuppressn e concentration, and increase the Type 1 response relative to the Type 2 response below the immunosuppressive concentration
  • the target organ is not restricted to the liver, but may also include other organs such as the bram, the lung, the spleen, the thymus, the kidneys, etc
  • the disease that can be treated with the method according to the subject matter presented herein will depend on the drug's specific accumulation pattern (i e m which organ the drug prefeientially accumulates)
  • Foi example, Ribavirm and Levov innTM both pieferentialh accumulate in the liver, and reduce both the Type 1 and Type 2 lesponse above an immunosuppressive concentration Therefore, diseases in which suppression of an immune response in the liver is desirable are especially contemplated, and include hepatitis C, autoimmune/lupoid hepatitis, liver transplant recipients, etc
  • the method according to the inventive subject matter is not designed to provide a direct antiviral treatment, but is designed to at least partially suppress an immune response m an organ that is infected with a virus Organ targeted immune suppression is contemplated to be especially advantageous m hepatitis C, where the organ damage is not immediately attributable to the HCV virus, but rather to an infection-induced imbalance between a Type 1 response and a Type 2 response Therefore, a method of treatment with a drug that reduces specifically both the Type 1 and Type 2 response in the liver of a patient infected with HCV is contemplated to prevent hepatic damage prophylactically as well as in therapeutic approach Since Ribavirm and LevovirmTM both have excellent tolerabi ty in humans, long-term prophylaxis, and long-term treatment are particularly advantageous
  • Ribavirm or alternative contemplated compounds can be employed in a general health setting, as opposed to a clinical, therapeutic setting Consequently, it is contemplated that Ribavirm or alternative contemplated compounds may also be used to improv e digestion
  • one or more of the compounds may be taken by an individual suffenng from poor digestion - whether the poor digestion is due to liver conditions such as Hepatitis B or C infections, or indeed any other conditions characterized by liver inflammation
  • digestion can be improved by having the person take Ribavirm or a Ribavirm like compound below an amount normally producing systemic immunosuppression, but m an amount that accumulates in the liver to a concentration that produces immunosuppression in the person's liver
  • Ribavirm or alternative contemplated compounds as a means of lmpro ⁇ mg skin color
  • skin color can be improved by having the person take Ribavirm oi alternative contemplated compounds below an amount normally producing systemic immunosuppression, but m an amount that accumulates m the liver to a concentration that produces immunosuppiession m the person's liver
  • Ribavirm l-(5-Deoxy- ⁇ - D-r ⁇ bofuranosyl)-l,2,4-tnazole-3-carboxam ⁇ de
  • LevovirinTM l-(5-Deoxy- ⁇ -L- ⁇ bofuranosyl)- l,2,4-t ⁇ azole-3-carboxam ⁇ de
  • the amount taken or administered is preferably sufficient to produce
  • the term "stimulating neuronal growth” refers to any process m which cell growth and/or division is either initiated from a resting cell, or accelerated in a growing and/or dividing cell, wherein “neuronal” refers to all cells that are directly or indirectly involved in the propagation of cognitive, sensory or motoi signals
  • neurons are contemplated to be directly involved m signal propagation, while myelm sheath cells or glia cells are indirectly involved by virtue of their insulating function or structural/metabolic support to a neuron
  • receptors are also considered neuronal cells under the scope of this definition
  • cells forming the inner and outer layer of the dura are not considered nemonal cells. since they are not directly or indirectly involved the propagation of cognitive, sensory or motor signals
  • Ribavirm is effective to stimulate neuronal growth
  • the inventors further contemplate that the various phosphorylated analogs of Ribavirm may also be effective to stimulate such growth
  • LevovirmTM and its phosphorylated analogs may be effective in a similar manner
  • LevovirmTM is effective to stimulate growth of unipolar neuronal cells in viti o withm a concentration lange of 0 5 ⁇ M to 500 ⁇ M Consequently, addition of Levov innTM to a cultuie medium at a concentration of about 5 O ⁇ M can be employed to stimulate growth of unipolar neuronal cells
  • methods of stimulating neuronal growth need not be limited to unipolar neuronal cells, but may include various alternative cells, including bipolar and multipolar neuronal cells
  • m alternative aspects of methods of stimulating neuronal giowth individual cell types may be targeted m a population of
  • contemplated methods are not necessarily limited to stimulating neuronal growth in cell culture
  • cells may be stimulated m a tissue culture, and it is particularly contemplated that neuronal cells may be stimulated in vivo
  • In vivo stimulation of neuronal growth may advantageously be utilized as a prophylactic treatment, or a therapeutic treatment
  • contemplated methods according to the inventive subject matter may be utilized for prevention of demyelmating disorders or neurodegenerative diseases such as Alzheimei's disease or Parkinson's disease, or as a preventative treatment pnor to operative procedures in a patient
  • Contemplated therapeutic treatments include reversion or attenuation of asphyxial, traumatic, toxic, infectious, degenerative, metabolic, lschemic or hypoxic insults
  • a method 600 of improving coordination in a patient has a first step 610 m which it is recognized that phosphorylated oi unphosphorylated Ribavirm or LevovirmTM is effective to stimulate growth of neurons in vivo withm a given concentration range h a subsequent step 620, the patient takes an amount of phosphorylated or unphosphorylated Ribavirm or LevovirmTM that is effective to stimulate growth of at least some of the person's neurons Impiovement of eye-hand coordination is especially contemplated
  • Ribavirm is effective to stimulate giowth of neuronal cells in vivo withm a concentration lange of 0 5 ⁇ M to 500 ⁇ M, and Ribavirm is oially administered to a patient suffering from a traumatic injury to the nervus ischiadicus m a dosage of 1200mg/day
  • various conditions other than traumatic injury to the nervus ischiadicus aie also contemplated, including mechanical and chemical damage to a plurality of nerv e cells, infection of neuronal cells with bactena and/or viruses, and degenerative diseases Regaidless of the nature of the patient's condition, it is contemplated that the method according to the mventn e subject matter may stimulate a wide range of neuronal cells, and it is especially contemplated that the stimulated neurons communicate between the person's bram and voluntaiy muscles, or between the persons biam and skin sensors
  • Anothei class of contemplated methods includes improving tactile or other sensory sensitivity m a patient Still another class of contemplated methods includes improving gross and fine motor control
  • Levo ⁇ innTM or Ribavirm may effect a change m the Type 1 or Type 2 response m a patient which concomitantly may lead to a neuroprotective status, or a stimulation of neuronal growth Therefore, it is contemplated that compounds according to the inventive subject matter may be administered as part of a treatment of a disease m a patient in a dosage range effective to increase a Type 1 response and decrease a Type 2 response in the patient
  • in vivo administration route, dosage, schedule, term, etc
  • contemplated compounds according to the inventive subject matter may be employed as antineoplastic agent m treatment of a solid oi lymphatic tumor, and contemplated neoplasms include various carcinomas, sarcomas, and lymphomas, and particularl ⁇ include acute myeloid leukemia and chronic myeloid leukemia in blast crisis It should further be appreciated that administration of contemplated compounds in antiviral treatments will generalh follow a route, dosage, schedule and term as employed with known D-nucleotides, D-nucleosides. and then lespective analogs m antineoplastic treatments Administration of Contemplated Compounds
  • contemplated compounds may be admmisteied under any appropriate protocol in any appropriate pharmaceutical formulation It is generally preferred that contemplated compounds aie oially administered
  • va ous alternative admmistiations aie also suitable, and it should further be recognized that a particular administration will generally depend on chemical stability, bioavailabihty, dosage, formulation, and/or desired pharmacokinetic/pharmacodynamic properties of contemplated compounds
  • appropriate administrations will include topical delivery (e g , ointment, spray, cream, etc ), parenteral systemic delivery (e g , inhalation), and direct or indirect delivery to the blood stream (e g , l v o ⁇ ra injection, etc )
  • contemplated compounds may vary consideiably Foi example, wheie the drug or drug composition exhibits sufficient stability to pass through the gastro-mtestinal system without undesired chemical or enzymatic modification, oral formulations may mclude syrup, tablets, gel caps, powder, etc
  • suitable formulations especially include injectable solutions oi suspensions (e g , physiological salme solution buffered to a pH of about 7 2 to 7 5)
  • dosages aie suitable, and contemplated dosages typically are m the range of lmg to several lOOmg, and even moie
  • heie contemplated compounds are excieted oi metabolized at a lelatively low late, or wheie long-term tieatment is desired, dosages will typically be m the range between 5mg-200mg per day
  • dosages will typically be m the range betw een 100mg-2500mg per day
  • LevovirmTM appeals not to be phosphor, lated in ⁇ vo, at least not in hepatocytes and e ⁇ .hrocytes, and since the antivnal effect of Ribaviim appears to be dependent on phosphoiylation.
  • LevovirmTM surprisingly appears to be at a dosage of not moie than 200 mg per da), preferably in the 10 to 200 mg range, more preferably in the 50 to 200 mg range, and even more preferably in the 50 to 100 mg range. This is supported by experimental evidence demonstrating that a given dose of LevovirinTM results in a serum level five times that of an equivalent dose of Ribavirin.
  • Ribavirin is removed from serum by becoming phosphorylated in red blood cells (see, e.g., Homma, M. et al.; High-performance liquid chromatographic determination of ribavirin in whole blood to assess disposition in erythrocytes; Antimicrob. Agents Chemother. (1999), 43(11):2716-9).
  • Ribavirin cannot leave the cells. Consequently, red blood cells act as a Ribavirin sink, and higher doses of Ribavirin are needed to achieve a given serum level.
  • LevovirinTM is not phosphorylated, and therefore, tends not to accumulate in red blood cells. As a result, red blood cells do not act as a LevovirinTM sink, and lower doses of LevovirinTM are sufficient to achieve a desired serum level.
  • the schedule of administration may vary considerably, and contemplated schedules include a single dose over the entire course of treatment, multiple single daily doses over the entire course of treatment, multiple daily doses, and permanent dosing (e.g., permanent infusion, implanted osmotic pump, etc.) for at least part of the course of treatment. While it is generally preferred that suitable schedules sustain constant delivery of contemplated compounds, burst delivery (i.e., at least one administration at a first dose followed by at least one more administration at a dose lower than the first dose) is also appropriate. With respect to the term (i.e., duration) of treatment, it is contemplated that appropriate durations may vary between a single administration and several days, several weeks, several years, and even longer.
  • contemplated compounds are employed in a cell culture, a single administration, or relatively short administration may be sufficient.
  • appropriate treatment duration may be in the range between several days and several weeks.
  • extended administration over one or more years may be suitable.
  • contemplated compounds may be combined with additional phanriaceutically active substances to assist in the treatment of various diseases, and particularly viral infections. Additional pharmaceutically active substances may be administered separately or together, and when administered separately,
  • antiviral agents include protease inhibitors, nucleotide and/or nucleoside analogs (and especially Ribavirm), and immune modulator substances may include cytokines (e g , mterferon and ⁇ , IL2, IL4, IL6, IL8, IL10, and IL12)
  • cytokines e g , mterferon and ⁇ , IL2, IL4, IL6, IL8, IL10, and IL12
  • pharmacologically active agents include anti-fungal agents such as tolnaftate, FungizoneTM, LotnmmTM, MycelexTM, Nystatin and Amphoteracin, anti-parasitics such as MmtezolTM, NiclocideTM, VermoxTM, and FlagylTM, bowel agents such as ImmodmmTM, LomotilTM, and PhazymeTM, anti-tumor agents such as mterferon and ⁇ , AdnamycmTM, CytoxanTM, ImuranTM, Methotrexate, Mithrac TM, TiazofunnTM, TaxolTM, dermatologic agents such as AclovateTM, CyclocortTM, DenorexTM, FloroneTM, OxsoralenTM, coal tar and salicylic acid, migraine preparations such as ergotamme compounds, steroids and immunosuppresants not listed above, including cyclosporms, DiprosoneTM, hydrocortisone, FloronTM, LidexTM
  • LevovirmTM is typically not, or only to a significantly lesser extent than Ribavirm, phosphorylated in erythrocytes while still exhibiting antiviral and immunomodulatory activity Consequently, it is contemplated that the pharmacological action of mterferon, and especially in the treatment of hepatic diseases, can be potentiated by co-admmistration of Levovirm at significantly lower dosages as compared to Ribavirm
  • effective synergistic doses of LevovirmTM in combination with mterferon needed to treat HCV infection are projected to be in the 1-600 mg range, more preferably m the 10-400 mg range, still more preferably in the 50-300 mg range, and most preferably in the 100-300 mg range
  • the synergistic combination of LevovirmTM and mterferon will result m reduced toxicity relative to a combination of Ribavirm and inteiferon at equivalent effectiv e dosages, predominantly due to the lack of significant phosphorylation in eiythrocytes
  • the synergistic combination of Levovirm and mterferon specifically allows targeting of the liver due to the lack of phosphorylation of LevovirmTM in compartments other than the liver, especially erytlirocytes
  • Levovirm and mterferon With respect to co-admimstration of Levovirm and mterferon, it is contemplated that all suitable routes and protocols are appropriate, and it is especially prefened that Levovirm and mterferon are administered m a protocol similar to known administration protocols of Riba . inn and mterferon
  • LevovirmTM may be orally administered while Interferon may be subcutaneously injected
  • Levov innTM and mterferon may utilize schedules and routes independent from each other so long as both drugs are in the blood stream at measurable concentrations at the same time It is further contemplated that effective dosages of Levovirm can be projected from the effective concentiations of Ribavirm in the liver where Ribavirm was administered
  • LevovirmTM is particularly contemplated, chemical modifications including prodrug forms such as modified LevovirmTM (l-beta-L- ⁇ bofuranosyl-l,2,4-tr ⁇ azole-3- carboxamidme), mono- di- and tnphosphorylated LevovmnTM, and stereochemical variants (e g , enantiomers, isomers, etc ) are also appropnate Examples for suitable chemical modifications and prodiug forms are descnbed in U S Patent Application Number 09/594410, (supra) It is still further contemplated, that suitable drugs may also include drugs other than Levovirm and its variants, and particularly contemplated alternative drugs include In er specific prodrugs with an amine or amide group that can be enzymatically deaminated/ deamidated m the liver
  • co-administration of Levovirm need not be limited to IFN- ⁇ -2b, and co-administration may also mclude natural and synthetic fragments, isoforms, and consensus forms of mterferon-alpha
  • mterferons other than interfeion-alpha are also suitable, including mterferon-beta and its natural and synthetic fragments, isoforms, and consensus forms
  • cytokines other than mteifeion and chemokines are also appropriate, including IL-2, IL-12, and TNF
  • pegylated forms of contemplated mteiferons i e contemplated mterferons associated with pol ethylene glycol
  • aie also suitable for use in conjunction with the teachingshnented herein Combination of contemplated compounds with a second compound that binds a viral protein or
  • contemplated compounds with other pharmacologically active agents may comprise contemplated compounds with a direct and an indirect antiviral effect, and a second compound that increases the total antiviral effect (the total antiviral effect includes the direct antiviral effect and the indirect antiviral effect), wherein the second compound specifically binds a viral protein or a cytokine.
  • nucleoside analogs are prefened, and it is even more prefened that the nucleoside analog is Ribavirin (l-(5-Deoxy- ⁇ -D- ribofuranosyl)-l,2,4-triazole-3-carboxamide).
  • Ribavirin is known to have a direct antiviral effect by inhibiting RNA and DNA virus replication [Huffman et al, Antimicrob. Agents Chemother (1973), 3: 235; Sidwell et al, Science (1972), 177: 705] and an indirect antiviral effect by suppressing Type 2 mediated T cell responses and promoting Type 1 mediated T cell responses as described in U.S.
  • the first compound may have a more pronounced direct antiviral effect or a more pronounced indirect antiviral effect.
  • Contemplated direct antiviral effects include inhibition of viral replication, for example, an inhibition of a reverse transcriptase
  • contemplated indirect antiviral effects include a shift in a Type 1/Type 2 balance towards a Type 1 or Type 2 response as described in U.S. Patent Application Number 09/156,646.
  • an indirect antiviral effect may comprise a suppression of a Type 1 and Type 2 response, which is described in greater detail in U.S. Provisional Patent Application Number 60/172,097 (supra).
  • the shift of a Type 1/Type 2 balance towards a Type 1 or Type 2 response or suppression of the Type 1/Type 2 response may be advantageously controlled by the same first compound, wherein the dosage of the first compound determines the shift or suppression in a Type 1 or Type 2 response.
  • the second compound comprises an antibody (e.g., a monoclonal or polyclonal antibody).
  • an antibody e.g., a monoclonal or polyclonal antibody.
  • the antibody need not be restricted to a naturally occurring form of an antibody, but may also include a synthetic form of an antibody (e.g., mini antibodies obtained by phage panning, or other molecular evolution technology), or antibody fragments.
  • Antibody fragments are especially desirable, where such fragments are produced by a recombinant cell, or where the molecular weight of the second compound should be relatively low (i.e., below 75kDa).
  • Contemplated antibody fragments include an Fab, an F(ab) 2 , and an scFab.
  • a reporter group may include a radioisotope, or a metal that is detectable with in vivo scanning devices (e.g., magnetic resonance imaging).
  • Contemplated pharmacologically active molecules may include reverse transcriptase inhibitors, protease inhibitors, or cytotoxic agents. The production of recombinant and non-recombinant antibodies is well known in the art (e.g., see Current Protocols in Immunology; John Wiley & Sons (1999); Edited by: John E. Coligan, Ada M.
  • Antibodies are typically administered by injection (e.g., i.v. injection), and the actual dose will typically lie between O.Olmg and several l Omg, however, ⁇ vhere appropriate, lower dosages are also contemplated.
  • binding of the second compound to a viral protein or a cytokine is particularly advantageous where binding leads to an inactivation of a viral protein and/or a cytokine, and it is contemplated that inactivation may occur via various mechanisms.
  • inactivation of a virus may be achieved by antibody-mediated precipitation (i.e., formation of a molecular network between antibodies and viruses).
  • binding of the second compound may inactivate a virus by blocking or otherwise obstructing proteins or other viral surface structures that are essential to the infectivity or propagation of the virus.
  • binding of the second compound may occur with non-structural viral proteins, including viral polymerases and proteases.
  • contemplated binding targets include protems such as the gp 120/41 of a HIV virus, but also protems such as the reverse transcnptase of the HIV virus
  • HIV protems include protems from a HIV virus, a hepatitis virus, an influenza virus, and an RSV virus
  • inactivation may be achieved by sequestration of the cytokme from the pool of cytokines
  • the hapten for contemplated second compounds is a Type 1 cytokme
  • particularly contemplated cytokines include mterleukm-2, mterferon-gamma, and tumor necrosis factor-beta
  • hapten for the second compound is a Type 2 cytokine
  • particularly contemplated cytokines include ⁇ nterleuk ⁇ n-4, mterleukm-5, and ⁇ nterleukm-10
  • inactivation of a virus or a cytokine by the second compound may have a plurality of desirable effects, which may or may not exhibit an additive or synergistic effect in combination with the first compound
  • a second compound may even further reduce the virus titer by precipitating remaining viruses
  • the second compound may reduce the number of infectious virus particles by binding to viral components that are essential for mfectivity
  • the second compound may shift the Type 1/Type 2 balance towards a Type 1 response by sequestenng one or more Type 2 cytokines from the pool of cytokines, and thereby helping to restore cellular immunity while the virus load is already significantly reduced
  • the first compound has an indirect antiviral effect (also resulting m a significant reduction of virus tite
  • a combination of a first compound that has a direct and indirect antiviral effect with a second compound that specifically binds a virus and/or a cytokine will reduce a viral titer not only by a mechanistic (i e enzyme inhibition), but also by a systemic (i e , stimulation/modulation of immunity) action
  • prefened antiviral drug compositions include a first and second compound having a synergistic effect, which advantageously will help reduce the effective dosage of the first and second compound
  • appropriate antiviral drug compositions may also be employed in a prophylactic treatment
  • LevovmnTM co-administration of LevovmnTM with Ribavirm will reduce adverse side effects and improve tolerabi ty of Ribavirm and/or LevovirmTM With respect to the ratio of Ribavirin to LevovirmTM in the co-admmistration, it is prefened that Levov innTM is present in at least an equimolar amount of Ribavirm
  • vanous alternative ratios are also appropnate, and the particular ratio will predominantly depend on the desired effect and dosage/route of administration
  • LevovinnTM may be present in the co- admmistration in a range of about 5 lmol% to about 80mol%, or more
  • LevovinnTM may be present m the co-administration m a range of about 49mol% to about 20mol%, or less
  • co-administration of Ribavirm and LevovirmTM need not necessarily employ the same route of administration
  • co-admimstration refers to any form of administration of Ribavmn and LevovinnTM such that Ribavirm and Levov innTM are present in a measurable concentration in the system at the same time
  • contemplated co-admmistrations include protocols in which Ribavirin is administered in one route and LevovinnTM is administered m another route, wherem the co-admmistration may be performed simultaneously or at two different points in time
  • Ribavirm may be administered orally while LevovinnTM may be injected mtrav enously
  • Ribav inn may be administered orally BID
  • LevovirmTM may be administered orally QID
  • the administration or co-admimstration of Ribavirm and Levo ⁇ innTM will include a continuous release and/oi a reduced dosage at intervals that are moie frequent It is particularly contemplated that continuous release and/or reduced dosage at frequent intervals will reduce undesirable side effects and may increase the direct and/or indirect antiviral effect. While it is generally contemplated that compounds according to the inventive subject matter may be administered to any system, it is prefened that contemplated compounds are administered to a mammal, preferably a human, or to a cell or tissue culture.
  • LevovirinTM is metabolically inert when administered to a system, however, the inventors also contemplate that LevovirinTM may have metabolites, which are shown in Structures 4-8.
  • Structure 4 is a triazole carboxamide
  • Structure 5 is a triazole carboxylic acid
  • Structure 6 is a L-ribofuranosyl triazole carboxamide
  • Structure 7 is a 5'-acetyl L-ribofuranosyl triazole carboxamide
  • Structure 8 is an 5'-acetyl- ⁇ -L-ribofuranosyl triazole carboxamide.
  • Contemplated reaction products are typically degradation products of LevovirmTM, however, it should be recognized that metabolites may also mclude products formed by addition of chemical groups (e g , glycosylation or acetylation), and that such modified compounds may be subject to subsequent degradation m the same or different compartment While it is generally contemplated that the metabolites have a significantly reduced pharmacologically effect as compared to LevovirmTM, it should be appreciated that the metabolites may have a pharmacological effect similar to LevovirmTM
  • the triazole or ribose moiety may serve as an effector (e g , allostenc inhibitor)
  • LevovirmTM administered to a system, between 20% and 50%, preferably between 51% and 75%, more preferably between 76% and 99%, and most preferably 100% are excreted m an unmetabohzed form
  • the primary endpomt was defined as a reduction m ALT level
  • a complete ALT response was defined as normalization of the ALT level at the end of treatment
  • a partial ALT response was defined as either a 50% or greater reduction at the end of treatment from the patient's baseline value, or a 50% or greater reduction to a level not higher than 1 5 times the upper limit of normal
  • ALT response For the purposes of the integrated effectiveness analyses, the following definitions of ALT response were used:
  • Partial Response 50% or greater reduction from the patient's baseline level to within 1.5 times the upper limit of normal at the end of treatment.
  • responder Meets above definitions of either complete or partial response.
  • the definition of "responder” was determined by plotting the ALT values over time for the groups of patients fitting various definitions of response employed within each study. (The data were fitted with a cubic spline smoothing function Reinsch 1967). Three definitions of response were used:
  • Partial response (A) 50% or greater reduction from the patient's baseline level to within 1.5 times the upper limit of normal at the end of treatment.
  • Partial response (B) 50% or greater reduction from the patient's baseline level at the end of treatment.
  • the three curves for "complete response” demonstrated that this response was achieved after approximately one third of the treatment period and was maintained thereafter.
  • the three curves for "partial response (A)” demonstrated a similar pattern of response.
  • the three curves for' “partial response (B)” demonstrated distinctly more variability of ALT levels during the treatment periods.
  • the plots for Ribavirin-treated non-responders and the plots for placebo patients demonstrated, as expected, a dispersion of the data points which did not change in any recognizable pattern across the treatment and follow-up periods. It was decided that the "partial response (B)" definition was inappropriate for the purpose of the integrated effectiveness analyses.
  • Table 2 displays the results for each study and for the combined database, using the above definition of ALT response.
  • the proportions of responders in the two treatment groups were compared using either a Chi-square or Fisher's Exact test.
  • Table 3 summarizes the rates of sustained response in studies 92-001 and 91 -DK-178 and in these two studies combined.
  • the individual study, analysis plan definitions of sustained response are used.
  • a sustained responder is essentially a patient with either normalization of ALT or a partial response at the end of treatment, who still meets either of these criteria throughout the follow-up period. It was not possible to provide this same analysis for study CT00/002 because too few patients had complete ALT data throughout the follow-up period.
  • Study Ribavirin n/N (%) Placebo n/N (%)
  • the liver histology data was examined further by analysis of covariance, using the baseline Knodell score as covariate.
  • Regression analysis of the baseline Knodell scores versus the end of treatment scores for all Ribavirin-treated and placebo patients combined resulted in a slope of less than 1.0 but greater than zero. This indicated that the baseline Knodell score influenced the expectation of outcome of treatment, regardless of any difference between Ribavirin and placebo. Where the regression slope differs markedly from 1.0, analysis of covariance is a more appropriate test than analysis of variance (Fisher 1951).
  • the result of the analysis of covariance is displayed in Table 4.
  • the mean changes in the scores for Ribavirin- treated patients are only small, but due to small variances, the differences from placebo are statistically significant. It is of interest to note that the only Knodell sub-score that does not improve is fibrosis, and that there is less deterioration in the Ribavirin group than in the placebo group.
  • Ribavirin was significantly more effective than placebo in normalizing and reducing ALT levels (An elevated serum ALT level is a biochemical indicator of hepatic inflammation). There was also a conelation between response to Ribavirin therapy in terms of normalization or reduction of ALT level within individual patients, and by an improvement in liver histology as determined by Knodell scores. We found that there was indeed a consistent trend towards a positive relationship between ALT response and improvement in Knodell scores when both parameters are treated in a categorical manner.
  • CT00 002 Improved 11 42 3 12 48.0 0.171
  • ALT response and improvement in liver histology was studied further in order to quantify the improvement in liver histology in patients responding to Ribavirin, and to determine if there was a subgroup of patients who derive a more substantial clinical benefit from treatment with Ribavirin.
  • Ribavirin- treated ALT responders and non-responders were compared in terms of the mean changes in total Knodell scores over the course of treatment. This analysis, displayed in Table 8 thus quantifies the directional changes displayed in Table 5.
  • ALT normalization or reduction cone lates with improvement in liver histology in patients with hepatitis C treated with Ribavirin, and patients who achieve an ALT response are likely to derive a substantial clinical benefit.
  • patients treated with Ribavirin who do not achieve an ALT response there does not appear to be any clinical benefit in comparison to patients who received placebo.
  • ALT response was defined as normalization at the end of treatment or reduction of 50% or more from baseline to withm 1.5 times the upper limit of normal at the end of treatment Regression analysis
  • phase III program on Ribavirin in chronic hepatitis C consisted of three randomized, double blind, placebo-controlled, parallel group studies. 134 total patients were randomized to receive Ribavirin and 97 to receive placebo. Response to treatment was assessed using three parameters :

Abstract

Cette invention a trait à des composés nucléosidiques et nucléotidiques ainsi qu'à leurs analogues/promédicaments. Parmi les composés étudiés figure le 1-β-L-ribofuranosyl-1,2,4-triazole-3-carboxamide, pouvant avoir été modifié et/ou phosphorylé. Ces composés, peuvent, de plus, être combinés avec d'autre composés à usage pharmaceutique, notamment la Ribavirine, des anticorps et des cytokines. Parmi les utilisations préférées de ces composés, on note une utilisation antivirale, une utilisation anti-inflammatoire, une utilisation anti néoplasique et une utilisation visant à stimuler la croissance cellulaire.
EP00988189A 1999-12-23 2000-12-19 Compositions et procedes relatives a des nucleosides-l, a des nucleotides-l ainsi qu'a leurs analogues Withdrawn EP1244356A4 (fr)

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WO2005023826A2 (fr) 2003-09-11 2005-03-17 F.Hoffmann-La Roche Ag Composes nucleosides polymorphes
US20050182252A1 (en) 2004-02-13 2005-08-18 Reddy K. R. Novel 2'-C-methyl nucleoside derivatives
AU2007325551A1 (en) * 2006-09-11 2008-06-05 Arrowhead Center Inc. Azole nucleosides and use as inhibitors of RNA and DNA varial polymerases
CN102952104A (zh) * 2011-08-17 2013-03-06 黑龙江省松花江药业有限公司 一种呋喃类化合物
EP3623364A1 (fr) 2014-02-13 2020-03-18 Ligand Pharmaceuticals, Inc. Composés de promédicaments et leurs utilisations
JP2017520545A (ja) 2014-07-02 2017-07-27 リガンド・ファーマシューティカルズ・インコーポレイテッド プロドラッグ化合物およびそれらの使用
CN104387431A (zh) * 2014-10-24 2015-03-04 江南大学 一种高特异性的利巴韦林人工抗原的制备方法
EP3156050A1 (fr) * 2015-10-16 2017-04-19 Universitat Autònoma De Barcelona Nouvelles thérapies combinées pour le traitement de lésions neurologiques
CN109528638B (zh) * 2018-12-20 2021-07-06 江西润泽药业有限公司 利巴韦林衍生物制剂及其制备方法

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CA2384326A1 (fr) 2001-06-28
BR0016162A (pt) 2002-08-13
NO20022969L (no) 2002-06-20
HUP0300219A3 (en) 2005-07-28
NZ517634A (en) 2004-06-25
YU47802A (sh) 2006-03-03
AU2442201A (en) 2001-07-03
CN1420723A (zh) 2003-05-28
NO20022969D0 (no) 2002-06-20
SK8612002A3 (en) 2003-03-04
KR20030032908A (ko) 2003-04-26
MXPA02006251A (es) 2003-01-28
PL364927A1 (en) 2004-12-27
IL148514A0 (en) 2002-09-12
WO2001045509A1 (fr) 2001-06-28
HRP20020485A2 (en) 2005-10-31
CZ20022112A3 (cs) 2003-05-14
HUP0300219A2 (hu) 2003-06-28

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