WO2004083186A1 - Agent therapeutique pour hepatite virale, et agent carcinostatique - Google Patents

Agent therapeutique pour hepatite virale, et agent carcinostatique Download PDF

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Publication number
WO2004083186A1
WO2004083186A1 PCT/JP2004/003509 JP2004003509W WO2004083186A1 WO 2004083186 A1 WO2004083186 A1 WO 2004083186A1 JP 2004003509 W JP2004003509 W JP 2004003509W WO 2004083186 A1 WO2004083186 A1 WO 2004083186A1
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group
interferon
hydroxymethyl
cancer
agent according
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PCT/JP2004/003509
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English (en)
Japanese (ja)
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Kunitada Shimotohno
Naoki Tohdoh
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Sumitomo Pharmaceuticals Co. Ltd.
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Priority to JP2005503702A priority Critical patent/JPWO2004083186A1/ja
Publication of WO2004083186A1 publication Critical patent/WO2004083186A1/fr

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    • 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
    • C07H19/052—Imidazole radicals
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • 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
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • 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
    • A61P31/20—Antivirals for DNA viruses
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a combination therapy with interferon for viral hepatitis or cancer disease.
  • hepatitis for example, for chronic hepatitis C
  • treatment mainly for eliminating hepatitis C virus (HCV) and improving liver function is being promoted.
  • HCV hepatitis C virus
  • the treatment of chronic hepatitis C with interferon which has both HCV elimination and liver function improving effects, is regarded as the only treatment to eliminate the virus, but the complete elimination efficiency of HCV is 20 to 30.
  • interferon combination therapy with ribavirinilleradine has been promoted.
  • the effects of interferon are broadly classified into antiviral effects that act directly on infected cells and activation of host immunity.
  • the antiviral effect of interferon is caused by signal transduction via the interferon receptor, and promotes the degradation of HCV RA and the inhibition of translation by inducing the production of antiviral factors.
  • activation of immunity by interferon is involved in activation and maintenance of the antiviral state of a living body by activating cellular immunity and humoral immunity.
  • Interferon therapy for HCV has different therapeutic effects depending on patient characteristics such as HCV serotype, viral load, and histological progression. In particular, it is known that the improvement effect is low and the virus elimination rate is low in cases of ginotype I and hyperviremia. This low exclusion rate is thought to be related to viral factors and the patient's immunological background factors.
  • liver function has been attempted for patients who show resistance to interferon, but liver function is promptly improved after glycyrrhizin administration is completed.
  • immunomodulators such as glycyrrhizin and interphenic acid
  • Interferon is also being promoted as a treatment for cancer, but is administered interferon alone as chronic myelogenous leukemia, multiple myeloma, non-Hodgkin's malignant lymphoma, renal cell carcinoma, etc.
  • interferon alone as chronic myelogenous leukemia, multiple myeloma, non-Hodgkin's malignant lymphoma, renal cell carcinoma, etc.
  • In combination with is limited to limited cancers such as hepatocellular carcinoma, stomach cancer, spleen cancer, prostate cancer, esophageal cancer, superficial bladder cancer (Am. J. Surg. 2000; 179: 367-371 Prostate 1998; 35: 56-62, Am. J. Clin. Oncol. 2002; 25: 391-397).
  • the effect is thought to be due to the effects of interferon on cell growth suppression and the activation of cell-mediated immunity, but the therapeutic effect is not satisfactory.
  • cancer cells such as non-Hodgkin's malignant lymphoma, hepatocellular carcinoma, and stomach cancer
  • the present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, have found that the compound represented by the formula (1) enhances the antiviral effect when used in combination with interferon. Furthermore, the optimal concentration range of the anti-Wilz effect enhancing action is The present inventors have newly found that the concentration corresponds to the concentration range in which interferon- ⁇ production is induced (enhancement of production), and completed the present invention.
  • R 1 represents a hydrogen atom, a nitrogen atom protecting group or a nitrogen atom substituent
  • R 2 represents a hydrogen atom or a hydroxyl group protecting group.
  • a salt thereof as an active ingredient which is a combination drug with interferon which is effective and safe against viral hepatitis and cancer diseases.
  • the gist of the present invention resides in the following points (1) to (49).
  • R 1 and R 2 have the same meanings as described above
  • a salt thereof as an active ingredient, in combination with interferon for viral hepatitis or cancer disease
  • the substituent of the nitrogen atom of R 1 is a ribofuranosyl group, a 2-hydroxyethoxymethyl group, a 2-hydroxymethyl-1,3-oxathiolan-5-yl group, or a 4-hydroxymethyl-2-methylcyclopropyl Benzyl group, [2-hydroxy-11- (hydroxymethyl) ethoxy] methyl group, tetrahydroxy 2-furyl group, n-hexylcarbamoyl group, 3-hydroxymethyl-tetrahydro-2-furyl group, 3 —Hydroxyme Cyl-5-hydroxy-tetrahydro-2-furyl group, 3-hydroxymethyl-4,5-dihydroxy-1-tetrahydro-2-furyl group, 3-hydroxymethyl-4,5-dihydroxy-5-methinolatetetrahydro-2-
  • the combination therapy with interferon according to (1) which is a furyl group or a 3-hydroxymethyl-4-azidotetrahydro-2-furyl group.
  • the interferon is alpha-interferon ⁇ (1) to (4), the agent according to any of the above,
  • the interferon is Sumiferon, Intron II, Adpaferon, Equinintron or Egasis (1) to (4)
  • Interferon is 1/3 of interferon (1) to (4)
  • the agent is characterized in that it exhibits activity at a blood concentration of 10 ⁇ or less.
  • the viral hepatitis is chronic hepatitis C (1) to (14).
  • the cancer is chronic myelogenous leukemia, multiple myeloma, myelodysplastic syndrome, polycythemia vera, non-Hodgkin's malignant lymphoma, dry cell cancer, gastric cancer, superficial bladder cancer, knee cancer, renal cell cancer , Prostate cancer or esophageal cancer (1) to (14)
  • an anti-hepatitis virus agent comprising a salt thereof as an active ingredient, which is used in combination with interferon;
  • the substituent for the nitrogen atom of R 1 is a ribofuranosyl group, 2-hydroxyethoxymethyl group, 2-hydroxymethyl-1,3-oxathiolane-15-group, 4-hydroxymethyl-2-cyclopropenyl group , [2-hydroxy-1- (hydroxymethyl) ethoxy] methyl group, tetrahydroxy 2-furyl group, n-hexylcarbamoyl group, 3-hydroxymethyl-tetrahydroxy 2-furyl group, 3-hydroxy Doxymethyl-5-hydroxy-1-tetrahydro-2-furinole group, 3-hydroxymethynole-4,5-dihydroxy-1-tetrahydroxy 2-furyl group, 3-hydroxymethyl-14,5-dihydroxy-1-5-methyl-tetrahydro _ (2-) furyl or 3-hydroxymethyl-4-azidotetrahydro-12-furyl, (17) or (18) The agent according to the above,
  • interferon _] 3 (17)-(21) The agent described in the
  • the agent is characterized in that it exhibits activity at a blood concentration of 10 ⁇ or less.
  • the agent according to any one of (17) to (25), wherein the agent has an activity at a blood concentration of 1 ⁇ ⁇ to 8 ⁇ ;
  • a method for treating viral hepatitis which comprises administering interferon to a patient with viral hepatitis and using any one of the above-mentioned (17) to (31) anti-hepatitis virus agents in combination.
  • an immune activator comprising a compound represented by the formula (1) (wherein R 1 and R 2 are as defined above) or a salt thereof as an active ingredient:
  • the substituent of the nitrogen atom of R 1 is a lipofuranosyl group, a 2-hydroxyethoxymethinole group, a 2-hydroxymethyl-1,3-oxathiolan-1-yl group, or a 4-hydroxymethyl-2-cyclopropyl group.
  • the agent is characterized in that it exhibits activity at a blood concentration of 10 ⁇ or less.
  • a method for treating viral hepatitis which comprises administering the agent described in any one of (35) to (46) to a patient with viral hepatitis.
  • FIG. 1 shows that mizoribine induces interferon- ⁇ .
  • Splenocytes are prepared from naive mice and the culture supernatant contains sperm antigen
  • Staphylococcal enterotoxin B (SEB) was added at a concentration of 400 pg / ml. Stimulation was added by adding mizoribine to the culture solution, and after culturing for 48 hours, cytodynamics in the culture supernatant was measured by ELISA.
  • Figure 2 shows the pharmacokinetics when mizoribine was administered.
  • (A) shows the pharmacokinetics at the time of administration of 50 mg at a time, three times a day
  • (B) shows the pharmacokinetics at the time of administration of 100 mg at a time, three times daily.
  • FIG. 3 shows the results of measurement of RNA derived from HCV replicon by HLBI injection.
  • FIG. 4 shows the suppressive effect of replicon thighs by the combined use of Ribavirin (RBV) and natural interferon.
  • FIG. 5 shows the suppressive effect of replicon RA by the combined use of Mizoribine (MIZ) and natural interferon- ⁇ .
  • FIG. 6 shows the inhibitory effect of replicon RA by the combined use of SM-108 and natural interferon-1 ⁇ .
  • FIG. 7 shows the inhibitory effect of replicon RNA by the combined use of natural interferon- ⁇ .
  • the average value of the copy number measured twice by the real-time PCR method and the reduction (%) of the replicon RNA are shown.
  • Ribavirin and mizoribine show the results of two experiments, and SM-108 shows the results of one experiment.
  • FIG. 8 shows the effect of HLBI and ribavirin in combination to eliminate replicon RNA.
  • Samples from each lane were: 1; # 50-1 cells, 2-7; HLBI 3 IU / ml + ribavirin (2; 0 ⁇ , 3; 1 ⁇ , 4; 3 ⁇ , 5; 5 ⁇ , 6; 10 ⁇ , 7; 20 ⁇ ).
  • FIG. 1 is a diagram showing a migration pattern by 1% agarose gel electrophoresis.
  • ⁇ Northern hybridization using a probe that detects HCV thighs (arrow indicates replicon RNA).
  • C Northern hybridization using G3PDH mRNA detection probe. (The arrow indicates G3PDH mRNA).
  • FIG. 9 shows the elimination effect of replicon RNA by the combined use of HLBI and mizoribine.
  • Samples in each lane were: 1; # 50-1 cells, 2-7; HLBI 3 IU / ml + mizoribine (2; 0 ⁇ , 3; 1 ⁇ , 4; 3 ⁇ , 5; 5 ⁇ , 6; 10 ⁇ , 7; 20 ⁇ ).
  • A is a view showing a migration pattern by 1% agarose gel electrophoresis.
  • B The result of Northern hybridization using a probe for detecting HCV RNA (the arrow indicates that the replicon is awake).
  • C Northern hybridization using a probe for detecting GSPDH mRNA (arrows indicate G3PDH mRNA).
  • FIG. 10 shows the effect of HLBI and SM-108 in combination to eliminate replicon RNA.
  • Samples in each lane were NC; Huh-7 cells, 1; # 50-1 cells, 2-7; HLBI 3 IU / ral + SM-108 (2; 0 ⁇ , 3; 1 ⁇ ⁇ 4; 3 ⁇ , 5; 5 ⁇ , 6; 10 ⁇ , 7; 20 ⁇ ).
  • ( ⁇ ) is a diagram showing a migration pattern by 1% agarose gel electrophoresis.
  • ( ⁇ ) Northern hybridization results using a probe that detects HCV RA (arrows indicate replicon RNA).
  • C Northern hybridization using a probe for detecting G3PDH mRNA (arrows indicate GI3PDH mRNA).
  • FIG. 11 shows the disappearance effect of replicon RA by combined use of HLBI and ribavirin by Northern hybridization angle analysis. The ratio of replicon RNA to the amount of G3PDH gene expression at each amount of ribavirin added is shown.
  • FIG. 12 shows the elimination effect of replicon RA by the combined use of HLBI and mizoribine by Northern hybridization angle-harvesting.
  • FIG. 4 is a graph showing the ratio of replicon RA to the amount of G3PDH gene expression at each amount of mizoribine added.
  • FIG. 13 shows the effect of elimination of replicon RA by the combined use of HLBI and SM-108 by Northern hybridization analysis.
  • FIG. 3 is a view showing the ratio of replicon RNA to the amount of G3PDH gene expression in each amount of added SM-108.
  • Fig. 14 shows the anti-BVDV activity when sumiferon, mizoribine, and SM-108 were used alone or in combination (the vertical axis indicates the degree of cell proliferation, and the higher the value, the more effective the cell treatment with the drug. Indicating that they are growing).
  • FIG. 15 shows the anti-BVDV activity when Sumiferon, Adpaferon or Intron II was used in combination with Mizoribine or SM-108.
  • (A) is 1 IU / ml of sumeferon or adpaferon, 1.88 ⁇ of mizoribine
  • (B) shows the results obtained when using sumiferone or adpaferon at 10 IU / ml and mizoribine 1.88 ⁇ alone or in combination
  • (C) shows the results when using interferon- ⁇ with 10 IU / ml each of sumiferon, intron II or adpaferon, and 7.5 ⁇ of SM-108 alone or in combination.
  • a first aspect of the present invention is a combination therapy with interferon for the compound represented by the general formula (1) or a salt thereof.
  • R 1 represents a hydrogen atom, a nitrogen atom protecting group or a nitrogen atom substituent
  • R 2 represents a hydrogen atom or a hydroxyl group protecting group
  • Examples of the substituent represented by R 1 in the compound of the present invention include a hydrogen atom, a lipofuranosyl group, a 2-hydroxyethoxymethyl group, a 2-hydroxymethyl-1,3-oxathiolan-1-inole group, and a 4-hydroxymethylino.
  • a hydrogen atom and a ribofuranosyl group are preferable.
  • Examples of the protective group represented by R 1 in the compound of the present invention include a substituted or unsubstituted alkoxycanoleboninole group such as a methoxycarbonyl group, an ethoxycarbonyl group, a t-butoxycarbol group, etc., for example, p-etrobenzi ⁇ / reoxycanolevo And substituted or unsubstituted aryloxycarbonyl groups such as phenolic groups, benzylinoxycarbonyl groups, and p-methoxybenzyloxycarbonyl groups. Also, protecting groups that are deprotected in vivo It can be used and can be used depending on the situation.
  • Examples of the substituent represented by R 2 in the compound of the present invention include a protecting group for a hydrogen atom or a hydroxyl group.
  • the hydroxyl-protecting group includes, for example, those described in The Chemical Society of Japan, Experimental Chemistry Course (Maruzen), and refers to a protecting group that can be chemically or biologically cleaved to return to a hydroxyl group.
  • acetyl groups such as acetyl group and benzoyl group can be mentioned.
  • the compound having a carboxyl group may be an HCV RNA polymerase inhibitor such as JTK-003 or BILN-2061.
  • the salt examples include pharmaceutically acceptable salts, for example, a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid And the like.
  • a salt with an inorganic base include, for example, alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; and aluminum salt, ammonium salt and the like.
  • the salt with an organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, ethanolanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N′-dipentinoleethylene.
  • Preferable examples of the salt with an inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • Preferred examples of salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, : — Salts with tonoren sulfonic acid and the like.
  • Preferred examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, orditin and the like.
  • Preferred examples of the salt with an acidic amino acid include, for example, salts with aspartic acid, glutamic acid, etc. Are listed.
  • a compound in which the substituent represented by R in the above general formula (1) is a lipofuranosyl group is known as mizoribine
  • a compound in which the substituent is a hydrogen atom is known as SM-108.
  • Mizoribine is marketed as a drug for renal rejection and rheumatoid arthritis, but serious side effects such as hemolytic anemia have hardly appeared clinically.
  • Mizoribine is It has an antiproliferative effect on specific cancer cell cells (Cancer Res. 1975; 35: 1643-1648), has an antiviral effect (Exp. Opin. Invest. Drug 2000; 9: 221-235, Antiviral Chemi. Chemother. 1994; 5: 366-371; J Infect Dis 1993; 168: 641-64).
  • the stimulatory response of immunity is maintained in vitro (Transplant. Pro 1992; 24: 2845-2846, J. Clin.
  • SM-108 is a prodrug of the active form of mizoribine, a compound that is converted to mizoribine by adenine-phosphoribosyltransferase (Cancer Res. 1982; 42: 1098-1102). It has been shown to be clinically effective when administered as a single agent against hematopoietic tumors such as chronic myelogenous leukemia, myelodysplastic syndrome, and polycythemia vera and lung cancer, and is reported to be an extremely safe drug as an anticancer drug. (Cancer and Chemotherapy 1989; 16: 123-130; Cancer and Chemotherapy 1989; 16: 113-121).
  • Mizoribine and SM-108 have not been administered to chronic hepatitis C as to whether they have an antiviral effect on HCV or the ability to eliminate virus-infected cells, and their efficacy is unknown. Nor has it been studied in combination with interferon.
  • the viral hepatitis in the present invention refers to, for example, hepatitis due to viral infections such as hepatitis C virus (HCV) and hepatitis B virus ( ⁇ ), that is, hepatitis C, hepatitis B and the like.
  • the viral hepatitis may be acute hepatitis, fulminant hepatitis or chronic hepatitis, and chronic hepatitis may be associated with cirrhosis.
  • Viral hepatitis preferably includes chronic hepatitis C and chronic active hepatitis B, and more preferably chronic hepatitis C.
  • Hepatitis C virus includes, for example, the dienotypes la, lb, 2a, 2b, 3a, There are genotypes such as 3b, but are not limited to these HCV genotypes.
  • the cancer diseases according to the present invention include chronic myelogenous leukemia, multiple myeloma, myelodysplastic syndrome group, polycythemia vera, non-Hodgkin's malignant lymphoma, hairy cell leukemia, and hematopoietic tumors represented by cutaneous T lymphoma.
  • Solid cancers such as hepatocellular carcinoma, gastric carcinoma, superficial bladder carcinoma, renal carcinoma, renal cell carcinoma, prostate carcinoma, esophageal carcinoma, melanoma, and lipopositive sarcoma associated with AIDS can be mentioned.
  • the interferon (IFN) in the present invention is a natural IFN or a recombinant IFN.
  • the natural IFN may be derived from lymphoblasts, leukocytes, or the like.
  • IFN was screened by a DNA shuffling method, or the like, in which one or more amino acids in the amino acid sequence were substituted, deleted and / or modified, as long as they had substantially the same action as the natural IFN.
  • the modified product may be a modified product in which the sugar chain is substituted, deleted, Z- or added, or similarly, a sustained interferon agent such as PEGylated IFN or albumin-forced UIFN, tissue absorption or tissue transfer.
  • IFN may be a DDS formulation of IFN with enhanced properties.
  • Preferable examples include natural or recombinant IFN-a, natural or recombinant IFN-consensus IFN, and PEGylated IFN.
  • IFN a known commercially available IFN can be used.
  • Interferon-a includes, for example, natural IFN- ⁇ and recombinant IFN- ⁇ .
  • IFN-a 2a and recombinant IFN-a 2b and the like. Any subtype may be used as long as it is IFN- ⁇ .
  • IFN- ⁇ the natural forms of IFN-0 !, IFN- ⁇ , such as Sumiferon (Sumitomo Pharmaceutical), OIF (Otsuka Pharmaceutical) and IFN- ⁇ Mochida (Mochida Pharmaceutical), and Ito-Katari IFN-a2a Examples include, but are not limited to, certain canferon II (Takeda Pharmaceutical), mouth feron A (Chugai Pharmaceutical), and intron II (Schering-Plough), which is a recombinant IFN- ⁇ 2b.
  • canferon II Takeda Pharmaceutical
  • mouth feron A Chougai Pharmaceutical
  • intron II Schering-Plough
  • Interferon-1] includes, for example, natural IFN- ⁇ and recombinant IFN- ⁇ , and any type of IFN-i3 may be used.
  • IFN-i3 Mochida Mochida Pharmaceutical
  • Feron Toray
  • mm beta-feron (Nippon Schering), which is IFN-lb, can be mentioned, but is not limited thereto.
  • Consensus interferon is a newly developed IFN based on the consensus sequence theory and includes, but is not limited to, interferon-analfacon-1.
  • Adfaferon (Yamanouchi Pharmaceutical Co., Ltd.) is an example of the interface / refacon-1.
  • a long-acting interferon is an interferon formulation that uses PEG (polyethylene glycol), microparticles and nanoparticles, atelocollagen, silicon, and other sustained-release carriers to improve its sustainability.
  • IFN is PEG (polyethylene glycol) bound to an IFN protein molecule. What is a long-acting interferon?
  • PEGylated IFN- ⁇ 2a and PEGylated IFN-hi 2b can be mentioned.
  • the types of IFN are not limited to these. Specific examples include Vegasis (Roche), which is PEGylated IFN-hi 2a, and Peguintron (Schering'Brow), which is PEGylated IFN- ⁇ 2b.
  • Interferon DDS preparations with enhanced tissue absorption include, for example, pulmonary or nasal administration using microparticles, nanoparticles, or other fine particle carriers.
  • Interferon DDS preparations with enhanced tissue absorption may be used, and are not limited to these.
  • Interferon DDS preparations with improved tissue transport include, for example, interferon preparations that have improved affinity for the liver by modification, such as glycation of sugar chains, etc. It is sufficient if it is a DDS preparation of interferon, and it is not limited to these.
  • interferon in the present invention, preferably, Sumiferon, Intron A, Adpaferon, Pguintron and Pegasis, particularly preferably Sumiferon, Intron A and Adpaferon, more preferably Sumiferon are used.
  • the administration in the present invention includes, but is not limited to, oral administration, parenteral administration (including rectal administration, subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, etc.). No. Administration is more preferably oral administration.
  • the administration can be carried out by appropriately adjusting the dose and the number of administrations according to the administration form, age, weight, symptoms, side effects, etc. of the patient.
  • the single dose is not particularly limited as long as it is not more than an amount that causes side effects, but is, for example, 10 mg to 500 mg, preferably 10 mg to 300 mg, and more preferably 20 mg to: LOO mg. But not limited to this.
  • the number of administrations is, for example, 1 to 3 times a day, but is not limited thereto.
  • the administration may be once every other day or several days. It may be administered several times daily at the beginning of administration, and then continuously several times or once daily or once every several days.
  • the concentration in the present invention refers to the blood concentration of the agent after administration of the agent.
  • the blood concentration is the concentration of the agent in the blood in the body after administration of the agent, and is not particularly limited as long as it is lower than the concentration that causes side effects and is an effective concentration.
  • the blood concentration is, for example, 10 ⁇ or less, and preferably 1 ⁇ to 8 ⁇ .
  • the activity in the present invention is an activity of activating an antiviral action or immunity, and refers to an action of enhancing an antiviral action and an action of enhancing the ability to eliminate virus-infected cells when used in combination with interferon. .
  • a second aspect of the present invention is an immunoactivator comprising a compound represented by the general formula (1) or a salt thereof as an active ingredient.
  • the immunity activator in the present invention is an agent having an action of activating immunity
  • the cell immunity activator is an agent having an action of activating cell immunity.
  • Cell-mediated immunity is an immune mechanism in which the immune cells themselves attack and eliminate foreign substances, and are responsible for defense against intracellular parasitic microorganisms, such as killing against intracellular parasites, fungi, and protozoa. It is involved in the elimination of ruptures and rupture of tumor cells, and has natural immunity and acquired immunity.
  • a third aspect of the present invention is an interferon- ⁇ production inducer (production enhancer) comprising a compound represented by the general formula (1) or a salt thereof as an active ingredient.
  • the agent for inducing interferon- ⁇ production (enhancing production) in the present invention is an agent for increasing the concentration of interferon- ⁇ (IFN- ⁇ ) in blood or / and in living tissue.
  • IFN- ⁇ is an HLA protein involved in surface antigen presentation recognized by immune cells. Ras I antigen, HLA class II antigen,] 32_ Microglobulin, TAP, LMP, etc., induces antigen-specific activation of cytotoxic T lymphocytes (CTL), expression of immunoglobulin Fc receptor It has the effect of activating antigen-specific acquired immunity by effector cells by induction, activating NK cells, and activating macula phage. Therefore, this agent is effective as an agent showing a killing action against intracellular parasite microorganisms such as intracellular parasite bacteria, fungi and protozoa, and a destruction / elimination action of virus-infected cells and tumor cells.
  • CTL cytotoxic T lymphocytes
  • the compound represented by the formula (1) or a salt thereof according to the present invention has a short half-life in the body, does not accumulate in the body, and enhances the antiviral effect of interferon on HCV by combination with interferon. It is useful as a therapeutic agent for viral hepatitis or cancer disease in mammals. Furthermore, the compound represented by the formula (1) or a salt thereof according to the present invention has an action of enhancing an immune response, and thus is useful as an immunoactivating agent.
  • the compound represented by the general formula (1) or a salt thereof may be used as it is or as a pharmaceutically acceptable carrier known per se (including excipients, bulking agents, binders, lubricants, etc.), Pharmaceutical compositions or formulations (e.g., powders, granules, tablets, pills, capsules, powders, syrups, injections, drops, topical preparations, suppositories, emulsions, enxyls) Agent) can be used.
  • a pharmaceutically acceptable carrier known per se (including excipients, bulking agents, binders, lubricants, etc.)
  • Pharmaceutical compositions or formulations e.g., powders, granules, tablets, pills, capsules, powders, syrups, injections, drops, topical preparations, suppositories, emulsions, enxyls) Agent
  • Splenocytes were prepared from naive mice. The mouse spleen was removed, transferred to a 60-ml petri dish containing 5 ml of RPMI 1640 medium, crushed with the blasted part of a slide glass, and collected in a 50 ml centrifuge tube through a cell strainer (FALCON 70 ⁇ Nylon). .
  • ACK buffer for hemolysis in pellets of splenocytes (0. 15M NH 4 C1, ⁇ KHC0 3, 0. IraM EDTA, pH7 2 -. 7. 4) was added and after Shizu ⁇ room temperature, 5 minutes, 20 ml of the medium was added, and collected in a 50 ml centrifuge tube through a cell strainer.
  • Staphylococcal enterotoxin B (SEB; Toxin technology), a superantigen, was added to the culture supernatant at a concentration of 400 pg / ml. After adding 2.5 ral of PBS to 1 mg of SEB, the solution was sterilized by filtration using a 0.2 ⁇ filter to prepare a concentrated solution of 400 ng / ml. To 0.1 ml of this solution, 100 ml RPMI 1640 medium (1% L-glutaraine, 10% Penicil lin-Streptomycin, 10% FCS) was added, and the spleen-derived cell pellet was washed twice with 10 ml medium for 1,200 minutes.
  • SEB Staphylococcal enterotoxin B
  • the measurement was performed using an Immunoassay system mouse IFN- ⁇ kit.
  • the absorbance was measured at 450 nm by an endpoint method using a microplate reader (BioRad, model 3550 UV). Perform 4-parameter regression using SoftMax (Molecular Device) The concentration was calculated.
  • Fig. 1 shows the measurement results.
  • interferon-1 ⁇ /] 3 promotes differentiation of Th1 cells, induces proliferation of CD8 + T cells with antigen-specific cytotoxicity, promotes differentiation of NK cells, surface antigen presenting molecule It has various immunomodulatory activities, such as promotion of expression of.
  • the cell-mediated immunity-activating effect of mizoribine and SM-108 is not only effective for the treatment of chronic hepatitis C in combination with interferon- ⁇ /] 3, but also at the same dose to eliminate cancer cells. It was shown to be effective.
  • HCV replicon introduction into cultured cells (Huh-7), establishment of established cells (# 50-1), and cell culture were performed according to the literature (Biochem. Biophys. Res. Comm. 2002; 293: 993-999, J. Virol. 2001; 75: 1437-1449).
  • an oligonucleotide (DNA) consisting of bases 148 to 168 of the replicon RNA was labeled with TaqMan Kit (Kuchisha).
  • the primers and probes used were the base sequence shown in Seq. ID No. 1 for the forward primer, SEQ ID NO. 2 for the reverse primer, and SEQ ID NO. 3 for the Probe.
  • Ribavirin, mizoribine, SM- 108 dissolved each in PBS of, 0. 5, 1, 2, 5, 10 mM solution was prepared, 10 to 2 x l0 4 each Ueru cells / well and the 2 4 well plates ⁇ Drugs were added in increments of 0, 5, 10, 20, and 20 ⁇ l. HLBI was added so that the addition amount was 0, 3 IU / ml.
  • RNA loss rate was 18-35% with ribavirin, 53-61% with mizoribine, and 59% with SM-108.
  • the combination of interferon with mizoribine or SM-108 was higher than that with ribavirin.
  • RNA is transferred to a membrane filter, a probe is prepared using a DNA fragment obtained from a plasmid containing an HCV replicon and a DNA fragment of a Glyceraldehyde 3-phosphate dehydrogenase (G3PDH) gene, and hybridization is performed.
  • G3PDH Glyceraldehyde 3-phosphate dehydrogenase
  • the plasmid pNNRz2 DNA (Biochera. Biophys. Res. Comm. 2002; 293: 993-999) into which the HCV genome was integrated and digested with the restriction enzyme EcoT22I was used as a primer type XN7-
  • a single-stranded DNA probe (about 300 bp upstream of NS5B) can be prepared using 4R (SEQ ID NO: 4) and 32 P-dCTP. The probe used is shown in SEQ ID NO: 5.
  • a probe for detecting the G3PDH gene was prepared by using a PCR primer of about 250 bp amplified using primers GAPDH S (SEQ ID NO: 6) and GAPDH R (SEQ ID NO: 7) to 32 P- Label with dCTP.
  • GAPDH S SEQ ID NO: 6
  • GAPDH R SEQ ID NO: 7
  • ULTRAhyb solution containing one of the above probes, heat at -42 ° C, perform hybridization, wash the filter, and use the bio-imaging analyzer BAS-5000 (Fujifilm). The analysis was performed by.
  • Figure 8 shows the electrophoresis pattern of agarose gel when ribavirin, mizoribine and SM-108 were added in the presence of HLBI, and the results of hybridization using HCV and G3PDH as probes. 9, shown in Figure 10.
  • the intensity of the detected band was measured with a densitometer, and the remaining amount of replicon RNA was quantified based on the expression of the constantly expressed G3PDH gene.
  • Mizoribine is shown in Table 2 and Figure 12
  • SM-108 is shown in Table 3 and Figure 13. As shown in Table 2, Table 3, Figures 12 and 13, both low doses of mizoribine and SM-108 synergistically reduce replicon RNA in the presence of 3 IU / ml of interferon- ⁇ . This was confirmed.
  • the single dose may range from 50 tng to 100 mg, and the dose was consistent with the blood concentration (1-8 ⁇ ) at which immune activation was expected.
  • the blood concentration was 10 ⁇ or less, which was considered to enhance the antiviral effect of Sumiferon.
  • the blood concentration at which immunostimulation of SM-108, a prodrug of mizoribine monophosphate, is expected to increase. was determined to be 10 ⁇ or less.
  • the dose of mizoribine shown in this study is a dose that has been confirmed to have no clinically significant side effects, and does not cause the hemolytic anemia that is problematic with ribavirin administration It was considered.
  • SM-108 In the case of SM-108, the administration of 400 rag / ra 2 (about 520 rag) per day slightly reduced the hemoglobin level.
  • the dose at which the blood concentration of SM-108 is less than 10 ⁇ is considered to be approximately 20 mg / m 2 to 60 mg / ra 2 (clinical cancer: 1985; 31: 757-766). Since this corresponds to a single dose of approximately 26 to 78 mg, it was determined that hemolytic anemia would not occur.
  • the dose should also be considered to be influenced by factors such as the patient's age, gender, weight, and excretion rate.
  • factors such as the patient's age, gender, weight, and excretion rate.
  • SM-108 it has been shown that the blood concentration tends to be longer at higher doses (clinical cancer: 1985; 31: 757-766). It is expected that they will be eliminated from the blood one day later. Therefore, administration of high doses of SM-108 may maintain the concentration range in which synergistic effects can be produced in combination with interferon over a long period of time.
  • SM-108 used in combination with interferon is effective even at a high dose, and it is considered that high dose SM-108 can be administered once a day or every other day. It is thought that the same applies to mizoribine. Therefore, the dose may be any effective concentration that is lower than the concentration that induces side effects, and may be 100 mg or more.
  • BVDV Bovine Viral Diarrhea Virus
  • BVDV bovine viral diarrhea virus
  • 96-well plate in ⁇ Shi kidney cells (MDBK Madin-Darby Bovine Kidney cells, manufactured by Dainippon agents purchased from) were seeded at 8xl0 3 cells / Veil, 37 ° C, 5% C0 24 hours at 2 presence did . Except for the medium (Ham's F-12 medium containing 10% FBS (anti-BVDV antibody negative)), wash the cells with 0.1 ml / well of new medium, and then dilute the BVDV virus (BVDV KS-WS strain, inoculated with Sumitomo Pharma at preparation) was 0. 1 ml / well, incubated for 2 hours at 37 ° C, 5% C0 2 presence. Sumiphelon (Sumitomo Pharmaceutical, Lot.
  • the degree of cell growth of the test cells to which the drug and the BVDV virus were added was determined using the control cells without the BVDV virus as a control.
  • FIGS. 14 and 15 The experimental results are shown in FIGS. 14 and 15. As shown in Figure 14, at the concentration at which mizoribine or SM-108 shows only low anti-BVDV activity with the drug alone, when used in combination with sumiferon, the activity of anti-BVDV activity is more than doubled compared to the activity of sumiferone alone. Sumiferon was found to show a strong combination effect when combined with mizoribine or SM-108. In addition, as shown in FIG. 15, this combined effect was observed not only with Sumiferon, but also with other recombinant interferon- ⁇ , Intron A or Advbhaferon.
  • a concomitant drug with interferon for diarrhea hepatitis or cancer disease is provided.
  • This drug has no accumulation in the body, activates cell-mediated immunity, and has a synergistic effect when used in combination with interferon.
  • Hepatitis c chronic myelogenous leukemia, polymyeloma myeloma, myelodysplastic syndrome, polycythemia vera, non-Hodgkin's malignant lymphoma, hepatocellular carcinoma, gastric cancer, superficial bladder, for which interferon is effective It can be a very effective combination for cancer, knee, renal cell, prostate and esophageal cancer. Sequence listing free text
  • the base sequence described in SEQ ID NO: 1 is a forward primer.
  • the base sequence described in SEQ ID NO: 2 is Reverse priraer.
  • the nucleotide sequence set forth in SEQ ID NO: 3 is Probe.
  • the nucleotide sequence set forth in SEQ ID NO: 4 is primer XN7-4R.
  • the base sequence described in SEQ ID NO: 5 is Probe.
  • the nucleotide sequence set forth in SEQ ID NO: 6 is a primer GAPDH S c
  • the nucleotide sequence set forth in SEQ ID NO: 7 is a primer GAPDH R t

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Abstract

L'invention concerne un agent thérapeutique pour hépatite C chronique, caractérisé en ce qu'il contient, soit un composé représenté par la formule (1) (dans laquelle R1 désigne un hydrogène ou un ribofuranosyle ; et R2 désigne un hydrogène ou un groupe de protection hydroxy), soit un sel de ce composé. Cet agent est administré en combinaison avec l'interféron.
PCT/JP2004/003509 2003-03-18 2004-03-16 Agent therapeutique pour hepatite virale, et agent carcinostatique WO2004083186A1 (fr)

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JP2006321765A (ja) * 2005-05-20 2006-11-30 Mikiko Ueda 肝移植における拒絶反応の予防又は治療薬、或いは拒絶反応とは断定できない肝機能異常の治療薬
JP2009142262A (ja) * 2007-11-20 2009-07-02 Asahi Kasei Pharma Kk ミゾリビン及び／又はリバビリンの測定方法
WO2014112529A1 (fr) * 2013-01-15 2014-07-24 富士フイルム株式会社 Sulfate de 5-hydroxy-1h-imidazole-4-carboxamide

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JPS6089418A (ja) * 1983-10-20 1985-05-20 Sumitomo Chem Co Ltd 徐放性制癌剤
JPH04208224A (ja) * 1990-11-30 1992-07-29 Yakult Honsha Co Ltd 抗腫瘍剤

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JPS6089418A (ja) * 1983-10-20 1985-05-20 Sumitomo Chem Co Ltd 徐放性制癌剤
JPH04208224A (ja) * 1990-11-30 1992-07-29 Yakult Honsha Co Ltd 抗腫瘍剤

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KIYOJI KIMURA ET AL.: "Zoketsuki shuyo ni taisuru sm-108 (4-carbomoylimidazolium-5-olate) no phase II study", JAPANESE JOURNAL OF CANCER AND CHEMOTHERAPY, vol. 16, no. 1, 1989, pages 123 - 128,130, XP002982778 *
SHIN'ICHI OSHIA ET AL.: "Men'eki. Allergy nado kenkyu jigyo (zoki ishoku bumon) kenkyu hokokusho heisei 10 nendo", ISHOKU ZOKI NO SEICHAKURITSU KOJO NI KANSURU KENKYU - CHOKI ISHOKUJIN NO SEICHAKU KOJO NI KANSURU KENKYU, pages 82 - 87, XP002982780 *
TATSUYA TAKAYAMA ET AL.: "Seitai jin'ishoku no ato ni C-gata mansei kan'en ni taishite interferon-x o shiyo shita ichirei", BIOTHERAPY, vol. 8, no. 11, 1994, pages 1449 - 1452, XP002982779 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006321765A (ja) * 2005-05-20 2006-11-30 Mikiko Ueda 肝移植における拒絶反応の予防又は治療薬、或いは拒絶反応とは断定できない肝機能異常の治療薬
JP2009142262A (ja) * 2007-11-20 2009-07-02 Asahi Kasei Pharma Kk ミゾリビン及び／又はリバビリンの測定方法
WO2014112529A1 (fr) * 2013-01-15 2014-07-24 富士フイルム株式会社 Sulfate de 5-hydroxy-1h-imidazole-4-carboxamide
CN104903299A (zh) * 2013-01-15 2015-09-09 富士胶片株式会社 5-羟基-1h-咪唑-4-甲酰胺的硫酸盐
JP6001684B2 (ja) * 2013-01-15 2016-10-05 富士フイルム株式会社 ５−ヒドロキシ−１ｈ−イミダゾール−４−カルボキサミドの硫酸塩
US9475778B2 (en) 2013-01-15 2016-10-25 Fujifilm Corporation Sulfate of 5-hydroxy-1H-imidazole-4-carboxamide

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