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WO2001058877A1 - POTENTIALISATEURS DE PRODUCTION D'INTERFERON $g(Y) - Google Patents

POTENTIALISATEURS DE PRODUCTION D'INTERFERON $g(Y) Download PDF

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Publication number
WO2001058877A1
WO2001058877A1 PCT/JP2001/000999 JP0100999W WO0158877A1 WO 2001058877 A1 WO2001058877 A1 WO 2001058877A1 JP 0100999 W JP0100999 W JP 0100999W WO 0158877 A1 WO0158877 A1 WO 0158877A1
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Prior art keywords
group
hydrogen atom
ifn
production
coor
Prior art date
Application number
PCT/JP2001/000999
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English (en)
Japanese (ja)
Inventor
Kiyoshi Mizuguchi
Yutaka Kato
Tsutomu Satoh
Original Assignee
Mochida Pharmaceutical Co., Ltd.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Mochida Pharmaceutical Co., Ltd. filed Critical Mochida Pharmaceutical Co., Ltd.
Priority to AU2001232272A priority Critical patent/AU2001232272A1/en
Publication of WO2001058877A1 publication Critical patent/WO2001058877A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/08—Radicals containing only hydrogen and carbon atoms
    • 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
    • A61P35/00—Antineoplastic agents
    • 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

  • the present invention relates to a benzimidazole derivative, more specifically, 3- (2- (2-phenylethyl) benzimidazole-41-yl) -13-hydroxypropanoic acid and its esters, and the compound or its optical compound.
  • the present invention relates to an interferon alpha production enhancer containing an active form or a pharmaceutically acceptable salt thereof, and more particularly to an antitumor agent which is effective even in oral administration and which is based on the action of enhancing IFN-alpha production.
  • Interferon is a substance found as a protein with antiviral activity that is synthesized and secreted by virus-infected animal cells. It has been shown to have versatile activities such as a cell growth inhibitory effect, an antitumor effect, and an immune response regulating effect. IFN is roughly classified into ⁇ -type,] 3 type and ⁇ -type, and those produced from ⁇ cells and the like by stimulating mitogen or the like are called ⁇ -type (IFN- ⁇ ).
  • IFN- ⁇ The biological activity of IFN- ⁇ is known to be antiviral, antitumor, immunomodulatory, and suppresses cell proliferation.
  • IFN- ⁇ s are composed of native IFN- ⁇ produced by immune responder cells and a transformant produced by transforming DNA encoding IFN- ⁇ collected from immunocompetent cells into Escherichia coli. They are roughly classified into recombinant IFN-r, and any of them is administered parenterally in the form of injections as "foreign IFN-r".
  • IFN is originally a biological substance that plays a part in the defense mechanism against foreign substances of biological substances, and has extremely high selective toxicity and is highly safe for living organisms. Therefore, a substance that stimulates living cells to enhance the release of IFN- ⁇ has the potential to elicit the biological activity of IFN- ⁇ .
  • the natural IFN- ⁇ is usually obtained by culturing the immunocompetent cells in the culture in a culture medium containing mitogen, which induces IFN- ⁇ production, and purifying the culture.
  • mitogens show remarkable side effects when administered to a living body, and some substances show toxicity, and it is extremely difficult to administer to a living body to enhance the release of IFN- ⁇ .
  • IFN- Drugs and interleukin_2 (hereinafter abbreviated as IL_2)
  • IL_2 interleukin_2
  • a compound that has a production-promoting action promotes the production of IFN- ⁇ and IL-12 from human peripheral blood mononuclear cells, It is described in JP-A-4-208271 that it is useful as an agent.
  • these compounds have a different structure from the compound of the present invention, and there is a description of the action of stimulating the immunocompetent cells to promote the production of cytokines. There is no disclosure of the effect of acquiring the trait that enhances the basal production in the steady state.
  • Benzimidazole derivatives especially 3- (2- (2-phenylethyl) benzoimidazole-41-yl) — 3-hydroxypropanoic acid and its esters, suppress eosinophilia and increase eosinophilia. It is disclosed in WO 98Z01429 that it is useful as a prophylactic and / or therapeutic agent.
  • antigen stimulation such as concanapalin A or roundworm extract
  • An object of the present invention is to provide an orally effective and safe interferon monoester production enhancer, particularly IFN-7 "containing a compound having an action of enhancing IFN-alpha production by oral administration. It is to provide a production inhibitor, especially an antitumor agent.
  • the present inventor has proposed a benzimidazole derivative, particularly 3- (2- (2-phenylethyl) benzimidazole-4-1 ⁇ fur) -13-hydroxypropanoic acid and esters thereof, or optically active forms thereof.
  • a benzimidazole derivative particularly 3- (2- (2-phenylethyl) benzimidazole-4-1 ⁇ fur) -13-hydroxypropanoic acid and esters thereof, or optically active forms thereof.
  • R 2 represents a cyano group, a hydroxymethyl group, a 2_ (2-imidazolyl) ethenyl group, a group : _C ⁇ R : a phenyl group substituted by 1 or 2 with I , or a group: —COOR 3 or 1 CONR ′ 1 R 5 , wherein R 3 is a hydrogen atom or a straight chain having 1 to 4 carbon atoms.
  • R and R 5 are each a hydrogen atom, an alkyl group having 1 or 2 carbon atoms, or a group: one CH 2 COOR 6 or one CH (CH 2 Ph) COOR 6
  • R 4 and R 5 may be the same or different, and when any one of R 4 and R 5 is a group: one CH 2 C ⁇ R 6 or one CH (CH 2 Ph) COOR 6 the remaining one is a hydrogen atom
  • R 6 represents a linear or branched alkyl group having 1 to 4 carbon atoms
  • R 7 represents a hydrogen atom, a hydroxyl group, a halogen atom, or a carbon atom number.
  • R 8 represents a hydrogen atom or a Asechiru group
  • R 9 is a hydrogen atom, Asechiru group, Fuenirusuru Honiru group, or Represents a good Benzoiru group which may be monosubstituted by a methoxy group.
  • an pharmaceutically acceptable salt thereof which is an interferon alpha production enhancer, particularly for oral administration.
  • Preferred substituents or preferred combinations of the compounds represented by the above formula (I) are shown below, but the present invention is not limited thereto.
  • R 1 is preferably a hydrogen atom.
  • R 2 is a group: A COOR 3 in 1 or 2-substituted phenyl group or a group: one COOR 3 or - CONR4 It is preferred that R is 5, group: one COOR 3 1 or 2 substituted phenyl group or a group: and more preferably an COOR 3.
  • R 3 is preferably a linear or branched alkyl group having 1 to 4 carbon atoms.
  • A is preferably a group: —C ⁇ , one CH (OR 8 ) —, or one CH 2 O—.
  • W is preferably a group: 1 CH 2 —.
  • Q is unsubstituted phenyl It is preferably a group.
  • n is preferably 1 or 2, and more preferably 2.
  • R 7 is preferably a hydrogen atom, a halogen atom, or a linear or branched alkoxyl group having 1 to 4 carbon atoms, and more preferably a hydrogen atom.
  • R 1 is a hydrogen atom
  • W is a group: —CH 2 —
  • A is a group consisting of —CO—, —CH (OR 8 ) —, and one CH 2 it is any one selected from, and preferably at 1 Moshigu the R 2 guard C_ ⁇ _ ⁇ _R 3 or a C_ ⁇ _ ⁇ _R 3 is a 2-substituted phenyl group, in particular R 1, hydrogen An atom
  • W is a group: —CH 2 —
  • the combination of A and R 2 is a group: —CO— or —CH (OR 8 ) — and a group: —COOR 3
  • the combination is preferably a combination of a group: one CH 20 — and a group: a phenyl group substituted by 1 or 2 with one C ⁇ R 3 .
  • R represents a hydrogen atom or a lower alkyl group.
  • R represents a pharmaceutically acceptable salt thereof.
  • a second aspect of the present invention is to enhance the amount of IFN-produced by immunocompetent cells containing at least one of the compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof.
  • IFN- ⁇ production enhancer particularly for oral administration.
  • a third aspect of the present invention is an antitumor agent containing at least one compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof, particularly an antitumor agent for oral administration.
  • a fourth embodiment of the present invention provides a compound represented by the following formula (II)
  • R ′ represents a lower alkyl group, and * represents an asymmetric carbon atom.
  • R ′ represents a lower alkyl group, and * represents an asymmetric carbon atom.
  • a pharmaceutically acceptable salt thereof More preferably, it is (i) an isomer.
  • At least one of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof for the production of the above-mentioned agent for enhancing the production of insulin-feronone is provided.
  • a compound containing at least one of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof for the production of the above antitumor agent; and prevention of tumor 'A method of treatment, comprising administering to a mammal, including a human, a substance selected from the group consisting of a compound represented by the formula (I), or an optically active form thereof, and a pharmacologically acceptable salt thereof. are provided.
  • the compound used for the IFN-fer production enhancer of the present invention has the following formula (I)
  • R 1 represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms
  • R 2 represents a cyano group, a hydroxymethyl group, a 2- (2-imidazolyl) ethenyl group
  • R 3 is a hydrogen atom or a C 1 to C 4 Represents a linear or branched alkyl group
  • R ′ 1 and R 5 are each a hydrogen atom, an alkyl group having 1 or 2 carbon atoms, or a group: one CH 2 C ⁇ OR 6 or one CH (CH 2 P h) represents COOR 6
  • R ′ 1 and R 5 may be the same or different
  • one of R ′ 1 and R 5 is a group: one CH 2 C ⁇ R S or one CH ( When CH 2 P h)
  • R h represents a phenyl group.
  • R h represents a phenyl group.
  • the compounds of the present invention can form salts with inorganic or organic acids. Examples of these salts include salts with inorganic acids such as hydrochloride, hydrobromide, phosphate, sulfate, acetate, oxalate, citrate, tartrate, maleate, and alginic acid. Salts, salts with organic acids such as p-toluenesulfonate and salicylate, and salts with acidic amino acids such as glutamate and aspartate.
  • the compound of the present invention can form a salt with an inorganic base or an organic base depending on the type of the substituent.
  • salts examples include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, salts with inorganic bases such as ammonium salt, triethylamine salt, pyridine salt and the like. Salts with basic amino acids such as salts with organic bases, arginine salts, lysine salts, histidine salts and the like are included. Further, the compound of the present invention or a salt thereof can form a solvate with a solvent such as water, ethanol, and glycerol, and such a solvate is also included in the present invention.
  • a solvent such as water, ethanol, and glycerol
  • a racemic mixture of a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof and an optically active substance or a pharmaceutically acceptable salt thereof of the present invention are described in International Publication No. WO 98/0142429.
  • the definition of each substituent, and the definition of a preferable substituent and a combination thereof are also described in the publication. More preferably, the following formula (II) -a
  • R represents a hydrogen atom or a lower alkyl group.
  • R represents a hydrogen atom or a lower alkyl group.
  • “Lower” means, unless otherwise stated, a straight or branched carbon chain having any of 1 to 4 carbon atoms. Accordingly, the “lower alkyl group or alkyl group having 1 to 4 carbon atoms” represents, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group and the like. . When R is a lower alkyl group, it is preferably an ethyl group.
  • optically active forms include a compound having a negative optical rotation (hereinafter referred to as (1) isomer) and a compound having a positive optical rotation (hereinafter referred to as (+) isomer). Although present, racemic mixtures, and any optically active form are encompassed by the present invention.
  • optically active form of the present invention for example, the (1) isomer is substantially free of the corresponding (+) isomer.
  • the optically active isomers of the invention contain less than 10% of the corresponding opposite isomer. More preferably, it is less than 5%, and still more preferably, it is less than 1%.
  • Single optically active substance Qualitatively free refers to one of the individual enantiomers of a given compound.
  • any of a racemic mixture, a (+) isomer or a (1) isomer may be used as the IFN- ⁇ release enhancer of the present invention. More preferably, among the optically active substances of the present invention, (1) isomers are more preferable.
  • a racemic mixture of a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof and an optically active substance or a pharmaceutically acceptable salt thereof of the present invention are described in International Publication No. WO 98/0142429. It can be obtained by using the method described or a method analogous thereto.
  • the present specification refers to this publication and constitutes the content of the present invention.
  • methods for producing an optically active substance methods such as an asymmetric reduction method and an optical resolution method are disclosed. Examples of more specific methods include chiral pack AD TM and chiral cell ⁇ D TM ( Can be separated into optically active compounds by high performance liquid chromatography (HPLC) using an appropriate optically active column such as Daicel Chemical Industries.
  • a solvent to be used a mixed solvent of hexane and an alcohol such as ethyl alcohol and isopropyl alcohol, and a solvent to which several% of an amine such as diisopropylamine is added as necessary can be used.
  • a suitable asymmetric acid or base such as cisamine
  • separation by differences in physical properties such as solubility or separation by chromatography can be performed. Isolated induction
  • the body can obtain a pure optically active compound by dissociation of a salt.
  • FCS fetal calf serum
  • DMEM phosphate-buffered saline, pH 7.4
  • PBS phosphate-buffered saline, pH 7.4
  • the tumor volume was calculated as (minor axis) 2 X (major axis), and grouping was performed using this value and body weight as indices. Herd classification was carried out for mice on day 7 of the tumor was fully grown, the average tumor diameter of about 70mm 3, as the average weight is about 22 ⁇ 23 g, were used in the experiment.
  • the test compound was orally administered from the 7th to the 21st.
  • the solvent used was 0.5% HPMC (Hydroxypropylmethylcellulose), and the control group received only the solvent. Tumor diameter measurements were taken on days 7, 11, 14, 18, and 21. On Day 22, blood was collected from the fundus, followed by decapitation and excision of the thymus and spleen.
  • the spleen was homogenized with a glass homogenizer and adjusted to 5 x 10 6 ce 11 sZml. And cultured in S—C 1 one S F_B medium (Sanko Junyaku). Twenty-four hours later, the culture supernatant was collected and stored frozen at 180 ° C. The IFN- concentration (pg / mL) in the culture supernatant was measured by the EIA method (Enzyme Immu noassay). In addition, the measurement kit of ENDOGEN was used for the measurement. Table 1 shows the dose and IFN- ⁇ concentration of the test compound. Table 1 Test compound dose (mg / Kg / day) I FN— concentration (pg / ml)
  • control 40 As evident from the above results, the compound of the present invention was orally administered to tumor-bearing mice, and the spleen cells were cultured without immunostimulation (without stimulation). Then, the effect of enhancing the IFN_a production of the spleen cells was observed. Furthermore, the optically active isomer of the present invention was found to have the same level of IFN- ⁇ production enhancement activity for both the (+) isomer and the (1) isomer.
  • Example 2 Toxicity test The toxicity of the compound of the present invention was examined.
  • BALB / c male mice (body weight: about 25 g) were orally administered with the compounds of Examples Nos. 1 to 4 of the present invention suspended in 0.5% HPMC aqueous solution for 100 days at 100 mg ZKg daily for 4 days. place, no deaths, also in body weight and general symptoms abnormality was observed t
  • SD female rats were orally administered the compounds of Examples Nos. 3 and 4 of the present invention suspended in a 0.5% HPMC aqueous solution at a dose of 30 Omg / kg daily for 14 days.
  • the compound of the present invention (1) the heterologous living body is more excellent in safety.
  • the compound of the present invention when administered orally, has an effect of enhancing IFN- ⁇ production on the immunocompetent cells themselves. Further, the toxicity of the compound of the present invention is extremely low, and the compound is excellent in safety. More preferably, among the optically active substances of the present invention, (1) isomers are more preferable as pharmaceuticals.
  • an IFN-fer production enhancer containing the compound of the present invention By using an IFN-fer production enhancer containing the compound of the present invention, it is possible to obtain a trait that enhances the basal production of IFN-fa of the immunocompetent cell itself in a steady state. Therefore, stable IFN- ⁇ production can be expected without receiving any drug or irritation. In addition, higher IFN- ⁇ production can be expected with drugs and stimuli. Unlike direct administration of IFN-r or exertion of IFN-r production by stimulation, a safe drug with fewer side effects can be provided.
  • the IFN- ⁇ production enhancer of the present invention it is also possible to enhance the IFN-inducibility of a person whose IFN-inducibility is reduced.
  • the pharmaceutical composition of the present invention is useful for diseases in which IFN-producing ability enhancing effect is effective, for example, for example, tumors, viral diseases (eg, viral hepatitis (A, B, C or E, etc.), influenza, viral pneumonia, viral bronchitis, herpes infectious diseases (simple virus, EB virus (infectious) Suitable for the treatment or prevention of mononucleosis), shingles, polio, HIV infection, etc., and bacterial infections (eg, liver tumors, hepatic amoebiasis), but is particularly suitable for use as an antitumor agent
  • the types of organs and tissues that can be used are not limited, and include, for example, liver, kidney, spleen, kidney, brain, lung, digestive system (stomach, small intestine, duodenum, large intestine, rectum, etc.) ) Or blood, etc.
  • the pharmaceutical composition of the present invention can also be used prophylactically. For example, familial tumors and the like can be diagnosed quite accurately by genetic diagnosis in recent years. By administering to patients, it is possible to prevent the onset. In addition, by administering the compound of the present invention to a patient whose tumor has been removed by surgery after surgery, it can be used to prevent recurrence or metastasis of the tumor. In addition, the method of the present invention can be applied to patients with subclinical infection in which the virus infection is positive using a method for directly detecting a virus-specific virus-specific substance (antigen or nucleic acid) or a method for detecting an antibody against the virus. By administering the composition, it can be used to prevent the onset of viral infection.
  • the compound of the present invention or a salt thereof is usually orally administered to humans and other animals as a drug, but is administered parenterally (for example, intravenous administration, intramuscular administration, subcutaneous administration, rectal administration, transdermal absorption). Or transmucosal absorption, etc.), and oral administration is preferable.
  • the medicament of the present invention is administered in the form of a pharmaceutical composition.
  • the pharmaceutical composition of the present invention may contain at least one or more of the compounds represented by the formula (I) of the present invention, and is prepared in combination with a pharmaceutically acceptable carrier. More specifically, excipients (eg, lactose, sucrose, mannitol, microcrystalline cellulose, caic acid), binders (eg, microcrystalline cellulose, saccharides (mannitol, sucrose), dextrin, hydroxypropylcellulose (HPC), hydroxy Propylmethylcellulose (HPMC), polyvinylpyrrolidone (PVP), macrogol), lubricants (eg, magnesium stearate, calcium stearate, talc), coloring agents, flavoring agents, disintegrants (eg, corn starch, carboxymethyl cellulose) ), Preservatives, isotonic agents, stabilizers (eg, sugars, sugar alcohols), dispersants, antioxidants (eg, ascorbic acid, butylhydroxydisole (BHA), propyl gallate, d1 —
  • Examples of the dosage form include capsules, pills, tablets, granules, fine granules, powders, suspensions, emulsions, internal liquids such as limonade, elixirs, syrups, and inhalants Solutions, sprays, aerosols, topical solutions such as coatings, ophthalmic solutions, nasal solutions, patches, ointments, lotions, liniments, cataplasms, suppositories, aqueous or non-aqueous injections, emulsions Or suspending injection, or dissolution before use, emulsion or Include solid injections used in suspension.
  • the dose of the compound of the present invention as a drug is sufficient to treat the disease of interest, but the dosage form of the therapeutic agent, the method of administration, the number of doses per day, the degree of symptoms, Increase or decrease as appropriate according to weight, age, etc.
  • the dose of the compound of the present invention for an adult is 0.01 to 500 Omg per day, preferably 0.1 to 50 Omg, more preferably 0.1 to LO Omg per day. .
  • the daily dose for an adult in the case of oral administration is 0.01 to 5000 mg, preferably 0.1 to 30 Omg, more preferably 0.1 to: L0 Omg. Administration can be divided into one or two to six times daily.
  • the drug of the present invention can be used in combination with other drugs, for example, drugs for treating diseases such as anticancer drugs, antiviral drugs, antibiotics, and chemotherapeutic drugs, and nutritional supplements such as bismuth agents and sugar solutions. is there.
  • NMR NMR was measured with J EOL J NM-EX 270 or J NM-LA 300 (both manufactured by JEOL Ltd.) and expressed as ⁇ (ppm) using TMS (tetramethylsilane) as an internal standard.
  • the IR was measured using a HOR IBA FT-200 (manufactured by Horiba, Ltd.) tablets of potassium bromide and expressed in cm- 1 .
  • the melting point was measured using Mett 1er FP 80 or FP 90 (both manufactured by Metra Toledo).
  • Optical purity is determined by high performance liquid chromatography (LC-10, manufactured by Shimadzu Corporation), using Chiral Cell OD TM (Daicel Chemical Industries), eluent: Hexane / isopropanol Z Jethylamine (80Z20Z1), wavelength: 254 nm, temperature: 40 ° C And expressed in% ee.
  • the optical rotation was measured using JASCO DIP-1000 (manufactured by JASCO Corporation), and was expressed as specific rotation [Q!] D.
  • (+) — 3 to (2- (2-phenylethyl) benzimidida as the first fraction (Ethyl 4-yl) -3-ethyl hydroxypropanoate (Example 3) was obtained.
  • ⁇ -NMR CDCh ⁇ [ppm]: 9.60 (1H, brs), 7.7-7.5 (1H, m), 7.3-7.1 (6H, m), 7.0-6.9 (1H, m), 5.5-5.4 (lH, ra), 4.22 (2H, q, J-7Hz), 3.3-3.1 (4H, m), 2.9-2.7 (2H, m), 1.30 (3H, t, G7Hz)
  • (+)-3-(2-(2-phenylethyl) benzimidazole-41-)-3-hydroxypropanoic acid (Example 5)
  • Example 6 According to the method of Example 8 and Example 9 described in International Publication WO98 / 014929, the target compound (+) — 3-— (2- (2-phenylenyl) benzoimidazoyl 1) -Hydroxypropanoic acid (Example 5), (1) 13- (2- (2-phenylethyl) benzimidazole-41-yl) -3-hydroxypropanoic acid (Example 6) can get.
  • Magnesium stearate 15 After weighing the above components, the title compound, lactose, and potato starch were uniformly mixed. An aqueous solution of polyvinyl alcohol is added to this mixture, and the granules are prepared by a wet granulation method. The granules were dried, mixed with magnesium stearate, and compressed and compressed to produce tablets weighing 30 Omg.
  • Hydroxypropyl cellulose 50 After weighing each of the above components and mixing them uniformly, granules could be produced by a conventional method.
  • the use of the compound having a benzoimidazole skeleton of the present invention exerts an effect on the immunocompetent cell itself to enhance the production of IFN- ⁇ . Further, the toxicity of the compound having a benzimidazole skeleton of the present invention is extremely low and excellent in safety.
  • ⁇ production enhancement for which ⁇ production enhancement is effective, such as tumors, viral diseases (eg, viral hepatitis (A, B, C or E, etc.), influenza, viral pneumonia, viral bronchitis, herpes infectious disease ( Adapt to the treatment or prevention of simple viruses, Epstein-Barr virus (Infectious mononucleosis), shingles, polio, HIV infection, etc., bacterial infections (eg liver tumors, hepatic amoebiasis), especially It is expected to be suitably used as an antitumor agent.
  • viral diseases eg, viral hepatitis (A, B, C or E, etc.
  • influenza e.g, influenza, viral pneumonia, viral bronchitis, herpes infectious disease ( Adapt to the treatment or prevention of simple viruses, Epstein-Barr virus (Infectious mononucleosis), shingles, polio, HIV infection, etc.
  • bacterial infections eg liver tumors, hepatic amoebiasis
  • an IFN- ⁇ production enhancer containing the compound of the present invention When an IFN- ⁇ production enhancer containing the compound of the present invention is used, it is possible to obtain a trait that enhances the basal production of the IFN- ⁇ of the immunocompetent cell itself in a steady state. Therefore, stable production of IFN- ⁇ can be obtained without receiving any drug or irritation. In addition, with drugs and stimuli, it is possible to obtain even higher IFN-a production. Unlike the direct administration of IFN-r or the stimulation of IFN-r to exert its production effect, a safer drug with fewer side effects can be provided.
  • the medicament and the pharmaceutical composition of the present invention can achieve the purpose of preventing and / or treating a disease for which IFN a production enhancing effect is effective.
  • diseases for which IFN_a production enhancing effect is effective such as tumors, viral diseases (eg, viral meningitis (A, B, C or E type, etc.), influenza, viral pneumonia, Viral bronchitis, herpes infection (simple virus, Epstein-Barr virus (infectious mononucleosis), shingles, polio, HIV infection, etc.), bacterial infection (eg, liver tumor, hepatic amoebiasis) It is effective for these treatments, including prevention, prevention of onset, prevention of exacerbation of symptoms, improvement of symptoms, and treatment, and is particularly effective for use in the prevention or treatment of various tumors.

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Abstract

La présente invention concerne des potentialisateurs de production d'interféron Ω et des médicaments antitumoraux, lesquels présentent une grande innocuité même lorsqu'ils sont administrés par voie orale. Par ailleurs, cette invention concerne les composés de la formule générale (I), en particulier l'acide 3-(2-(2-phényléthyl)benzimidazol-4-yl)-3-hydroxypropanoïque et les esters de cet acide; et concerne également les potentialisateurs de production d'interféron Ω contenant chacun au moins un élément sélectionné parmi les composées précités, des isomères optiques de ceux-ci et des sels de ceux-ci acceptables sur le plan pharmaceutique. Dans cette formule, R1 représente hydrogène ou analogue; R2 représente cyano ou analogue; A représente-CO- ou analogue; W représente-CH¿2?- ou analogue; Q représente phényle ou analogue; n vaut 0 ou 2; et R?7¿ représente hydrogène ou analogue.
PCT/JP2001/000999 2000-02-14 2001-02-14 POTENTIALISATEURS DE PRODUCTION D'INTERFERON $g(Y) WO2001058877A1 (fr)

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JP2000035283 2000-02-14
JP2000-35283 2000-02-14

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007119889A1 (fr) 2006-04-18 2007-10-25 Japan Tobacco Inc. Nouveau compose de piperazine et son utilisation en tant qu'inhibiteur de la polymerase du vhc
US7659263B2 (en) 2004-11-12 2010-02-09 Japan Tobacco Inc. Thienopyrrole compound and use thereof as HCV polymerase inhibitor
EP2206715A1 (fr) 2004-02-24 2010-07-14 Japan Tobacco, Inc. Composé héterotétracycliques fusionnés et leur utilisation en tant qu'inhibiteurs de la polymérase du HCV
US7977331B1 (en) 2004-02-24 2011-07-12 Japan Tobacco Inc. Tetracyclic fused heterocyclic compound and use thereof as HCV polymerase inhibitor

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998001429A1 (fr) * 1996-07-05 1998-01-15 Mochida Pharmaceutical Co., Ltd. Nouveaux derives de benzimidazole
WO1998005327A1 (fr) * 1996-08-05 1998-02-12 Rhone-Poulenc Rorer Pharmaceuticals Inc. Composes aromatiques substitues
WO1998038986A2 (fr) * 1997-03-06 1998-09-11 Roche Diagnostics Gmbh Medicament pour la prevention et la therapie d'infections virales

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998001429A1 (fr) * 1996-07-05 1998-01-15 Mochida Pharmaceutical Co., Ltd. Nouveaux derives de benzimidazole
WO1998005327A1 (fr) * 1996-08-05 1998-02-12 Rhone-Poulenc Rorer Pharmaceuticals Inc. Composes aromatiques substitues
WO1998038986A2 (fr) * 1997-03-06 1998-09-11 Roche Diagnostics Gmbh Medicament pour la prevention et la therapie d'infections virales

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
THE JOURNAL OF IMMUNOLOGY, vol. 162, 1999, pages 7470 - 7479, XP002941451 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2206715A1 (fr) 2004-02-24 2010-07-14 Japan Tobacco, Inc. Composé héterotétracycliques fusionnés et leur utilisation en tant qu'inhibiteurs de la polymérase du HCV
US7977331B1 (en) 2004-02-24 2011-07-12 Japan Tobacco Inc. Tetracyclic fused heterocyclic compound and use thereof as HCV polymerase inhibitor
US7659263B2 (en) 2004-11-12 2010-02-09 Japan Tobacco Inc. Thienopyrrole compound and use thereof as HCV polymerase inhibitor
WO2007119889A1 (fr) 2006-04-18 2007-10-25 Japan Tobacco Inc. Nouveau compose de piperazine et son utilisation en tant qu'inhibiteur de la polymerase du vhc

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