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WO2011074608A1 - Agent prophylactique ou thérapeutique pour le traitement de l'hépatite c chronique - Google Patents

Agent prophylactique ou thérapeutique pour le traitement de l'hépatite c chronique Download PDF

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Publication number
WO2011074608A1
WO2011074608A1 PCT/JP2010/072565 JP2010072565W WO2011074608A1 WO 2011074608 A1 WO2011074608 A1 WO 2011074608A1 JP 2010072565 W JP2010072565 W JP 2010072565W WO 2011074608 A1 WO2011074608 A1 WO 2011074608A1
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group
hydrogen atom
formula
compound
chronic hepatitis
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Japanese (ja)
Inventor
誠 石川
重輝 鈴木
信 青木
宣人 箕輪
幸吉 鈴木
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Meiji Seika Kaisha Ltd
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Meiji Seika Kaisha Ltd
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    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/047—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates having two or more hydroxy groups, e.g. sorbitol
    • 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
    • A61K31/075—Ethers or acetals
    • A61K31/08—Ethers or acetals acyclic, e.g. paraformaldehyde
    • 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
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
    • C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids

Definitions

  • the present invention relates to a drug for the prevention or treatment of chronic hepatitis C, comprising administering a triterpene derivative or a pharmaceutically acceptable salt thereof as an active ingredient in an effective amount.
  • HCV hepatitis C virus
  • the patient who is the target of prevention or treatment of chronic hepatitis C is a patient infected with HCV.
  • HCV There are six types of HCV, mainly genotypes, from type 1 to type 6. Particularly, genotype 1 and genotype 2 are known to be widely distributed worldwide (see FIG. Non-Patent Documents 6 and 7).
  • genotype 1 and genotype 2 are known to be widely distributed worldwide (see FIG. Non-Patent Documents 6 and 7).
  • There are further subtypes in these genotype types. Differences in subtypes can be identified by the base sequence of a specific region of RNA constituting HCV, and the amount of HCV of each subtype can also be measured (see Non-Patent Document 8).
  • interferon In the prevention or treatment of chronic hepatitis C, interferon (IFN) is widely used for the purpose of removing HCV.
  • IFN is a physiologically active substance that is produced in the innate immune system during viral infection and has antiviral activity that inhibits viral replication.
  • IFN is a species-specific protein with high homology, and it is known that four classes of IFN exist in humans (see Non-Patent Document 9).
  • IFN ⁇ interferon ⁇
  • IFN ⁇ interferon ⁇
  • IFN ⁇ interferon ⁇
  • IFN ⁇ interferon ⁇
  • IFN ⁇ interferon ⁇
  • ribavirin in order to expect a high therapeutic effect, it is necessary to use ribavirin in combination, so the problem of side effects caused by ribavirin cannot be avoided. If a useful and highly safe drug is developed for intractable cases of chronic hepatitis C, these medical problems can be solved, and therapeutic agents such as HCV subtypes that are more difficult to treat in the future. Alternatively, it can be expected to be used as a therapeutic agent having a high therapeutic effect that can be used in combination with a combination of a drug that directly inhibits the growth of HCV in the development stage or an anti-HCV drug including a novel interferon preparation.
  • anti-HCV activity is not known for triterpene derivatives derived from Soyasapogenol B other than 22 ⁇ -methoxyolean-12-ene-3 ⁇ , 24-diol.
  • an object of the present invention is to provide a novel drug for the prevention or treatment of chronic hepatitis C, which comprises a triterpene derivative as an active ingredient.
  • an object of the present invention is to provide the above-mentioned drug comprising as an active ingredient a triterpene derivative that exhibits stronger antiviral activity than conventional triterpene derivatives against chronic hepatitis C.
  • an object of the present invention is to provide the above drug containing a triterpene derivative having good pharmacokinetics as an active ingredient.
  • the present inventor succeeded in synthesizing triterpene derivatives having various substituents.
  • the synthesized triterpene derivatives were examined for anti-HCV action, a plurality of compounds showed stronger anti-HCV action than the conventional 22 ⁇ -methoxyolean-12-ene-3 ⁇ , 24-diol. I found out.
  • some of these compounds also showed good pharmacokinetics. From such characteristics, the present inventors have found that the identified triterpene derivative can be an excellent preventive or therapeutic agent for chronic hepatitis C, and have completed the present invention.
  • a drug for the prevention or treatment of chronic hepatitis C comprising as an active ingredient a triterpene derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof.
  • R 1 represents hydrogen or a hydroxyl group
  • R 2 represents a C 1-6 alkyl group, —CH 2 OR 7 , or —CON (R 8 ) R 9
  • R 3 and R 4 represent Same or different, hydrogen atom, hydroxyl group, C 1-6 alkyl group, —OR 10 , —O— (CH 2 ) m—COOH, —OCON (R 11 ) R 12 , or —OCOCH 2 COOH, or R 3 and R 4 together represent an oxo group or a methylene group
  • 5 and R 6 represent the same or different hydrogen atom, hydroxyl group, or alkoxy group.
  • R 7 represents a hydrogen atom, a C 1-6 alkyl group, an acetyl group, or a benzyl group
  • R 8 and R 9 are the same or different and each represents a hydrogen atom, a C 1-6 alkyl group, or a benzyl group
  • R 10 represents a C 1-6 alkyl group, a C 2-6 alkenyl group, a benzyl group optionally substituted with a halogen atom, or a C 1-6 alkylcarbonyl group
  • R 11 and R 12 are the same or Represents a different hydrogen atom or phenyl group
  • M represents an integer of 1 to 3.
  • “-----” in the formula represents a single bond or a double bond, but when it represents a double bond, R 4 and R 6 do not exist.
  • a drug for the prevention or treatment of chronic hepatitis C comprising as an active ingredient a triterpene derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof.
  • R 1 represents hydrogen or a hydroxyl group
  • R 2 represents a hydroxymethyl group
  • R 3 and R 4 are the same or different and each represents a hydrogen atom, a hydroxyl group, —OR 13 , or —OCONHR 14
  • R 5 and R 6 represent different hydrogen atoms, hydroxyl groups, and methoxy groups.
  • R 13 represents a C 1-3 alkyl group, a C 3-5 alkenyl group, a benzyl group optionally substituted with a halogen atom, or a C 1-3 alkylcarbonyl group
  • R 14 represents a different hydrogen atom or Represents a phenyl group.
  • “-----” in the formula represents a single bond.
  • a drug for the prevention or treatment of chronic hepatitis C comprising as an active ingredient a triterpene derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof.
  • R 1 represents a hydroxyl group
  • R 2 represents a hydroxymethyl group
  • one of R 3 and R 4 represents a hydrogen atom
  • the other represents —OR 15 or —OCONH (R 16 ).
  • R 5 and R 6 each represent a hydrogen atom.
  • R 15 represents a methyl group, an ethyl group, an acetyl group, a propionyl group, an allyl group, a 3-methyl-2-butenyl group or a benzyl group
  • R 16 represents a hydrogen atom or a phenyl group.
  • a drug for the prevention or treatment of chronic hepatitis C comprising as an active ingredient a triterpene derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof.
  • R 1 represents a hydroxyl group
  • R 2 represents a hydroxymethyl group
  • one of R 3 and R 4 represents a hydrogen atom
  • the other represents a methoxy group
  • R 5 and R 6 represent one Represents a hydrogen atom, and the other represents a methoxy group.
  • a drug for the prevention or treatment of chronic hepatitis C comprising a triterpene derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • R 1 represents a hydroxyl group
  • R 2 represents a hydroxymethyl group
  • one of R 3 and R 4 represents a hydrogen atom
  • the other represents a hydroxyl group
  • one of R 5 and R 6 represents one A hydrogen atom and the other represents a methoxy group.
  • a drug for the prevention or treatment of chronic hepatitis C comprising as an active ingredient a triterpene derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof.
  • R 1 represents a hydroxyl group
  • R 2 represents a hydroxymethyl group
  • R 3 and R 4 each represent a hydrogen atom
  • R 5 and R 6 each represent one hydrogen atom and the other represents Represents a hydroxyl group.
  • a drug for the prevention or treatment of chronic hepatitis C comprising as an active ingredient a triterpene derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof.
  • R 1 represents a hydrogen atom
  • R 2 represents a hydroxymethyl group
  • one of R 3 and R 4 represents a hydrogen atom
  • the other represents a hydroxyl group
  • R 5 and R 6 are Represents a hydrogen atom.
  • a type C comprising administering a prophylactically or therapeutically effective amount of the drug according to any one of (1) to (10) to a patient in need of prevention or treatment of chronic hepatitis C How to prevent or treat chronic hepatitis.
  • the prophylactic or therapeutic agent of the present invention comprises a triterpene derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient. Since these triterpene derivatives can exhibit excellent anti-HCV activity and excellent pharmacokinetics when administered in an effective amount, a high prophylactic effect or therapeutic effect can be expected for chronic hepatitis C. Further, the preventive agent or therapeutic agent of the present invention can be expected to have a better preventive effect or therapeutic effect even in combination with clinically used IFN or ribavirin, or various anti-HCV agents to be clinically used in the future.
  • chronic hepatitis C refers to an inflammatory disease of the liver caused by continuous infection of the hepatitis C virus in the liver. means.
  • the triterpene derivative that is an active ingredient of the preventive or therapeutic agent of the present invention can exhibit excellent anti-HCV activity.
  • the anti-HCV activity here mainly indicates an activity that inhibits the growth of HCV, and the smaller the concentration at which HCV is inhibited by 50% (IC50 value), the stronger the anti-HCV activity.
  • IC50 value concentration at which HCV is inhibited by 50%
  • a compound having an IC50 value exceeding 20 ⁇ M cannot be said to have strong anti-HCV activity, and the antiviral effect of a single agent in the prevention or treatment of chronic hepatitis C is considered to be small.
  • the triterpene derivative as an active ingredient of the preventive or therapeutic agent of the present invention preferably has a strong anti-HCV activity, that is, an IC50 value of 20 ⁇ M or less (for example, 15 ⁇ M or less, 12 ⁇ M or less, 10 ⁇ M or less, 9 ⁇ M or less). 8 ⁇ M or less, 7 ⁇ M or less, 6 ⁇ M or less, 5 ⁇ M or less).
  • IC50 value of 10 ⁇ M or less include compounds 3, 15, 17, 18, 20, 21, 25 , 31, 34, 38.
  • the triterpene derivative as an active ingredient of the preventive or therapeutic agent of the present invention preferably has good pharmacokinetics, that is, AUC is 50 ⁇ g ⁇ hr / ml or more (for example, 60 ⁇ g ⁇ hr / ml or more, 70 ⁇ g).
  • Hr / ml or more 80 ⁇ g ⁇ hr / ml or more, 90 ⁇ g ⁇ hr / ml or more, 100 ⁇ g ⁇ hr / ml or more), or AUC of 30 to 50 ⁇ g ⁇ hr / ml and a half-life (t 1 / 2 ) is 10 hours or longer (for example, 12 hours or longer, 14 hours or longer, 16 hours or longer, 18 hours or longer, 20 hours or longer, 22 hours or longer, 24 hours or longer).
  • t 1 / 2 half-life
  • compounds 15 and 18 are exemplified as compounds having particularly strong anti-HCV activity and good pharmacokinetics.
  • Examples of the active ingredient in the prophylactic or therapeutic agent of the present invention include a triterpene derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof.
  • R 1 represents hydrogen or a hydroxyl group
  • R 2 represents a C 1-6 alkyl group, —CH 2 OR 7 , or —CON (R 8 ) R 9 .
  • R 3 and R 4 are the same or different, hydrogen atom, hydroxyl group, C 1-6 alkyl group, —OR 10 , —O— (CH 2 ) m—COOH, —OCON (R 11 ) R 12 , or —OCOCH 2 COOH or R 3 and R 4 together represent an oxo group or a methylene group, and R 5 and R 6 are the same or different and represent a hydrogen atom, a hydroxyl group or an alkoxy group.
  • 22 ⁇ -methoxyolean-12-ene-3 ⁇ , 24-diol is excluded from the formula (I).
  • R 7 represents a hydrogen atom, a C 1-6 alkyl group, an acetyl group or a benzyl group
  • R 8 and R 9 represent the same or different hydrogen atom, a C 1-6 alkyl group or a benzyl group
  • R 10 represents a C 1-6 alkyl group, a C 2-6 alkenyl group, a benzyl group optionally substituted with a halogen atom, or a C 1-6 alkylcarbonyl group
  • R 11 and R 12 are the same or different
  • M represents an integer of 1 to 3.
  • “-----” in the formula represents a single bond or a double bond, but when it represents a double bond, R 4 and R 6 do not exist.
  • the “C 1-6 alkyl group” represented by the above R 2 , R 3 , R 4 , R 7 , R 8 , R 9 , R 10 is a linear or branched C 1-6 , preferably An alkyl group having 1 to 4 carbon atoms is meant. Specific examples thereof include methyl group, ethyl group, propyl group, isopropyl group, n-propyl group, n-butyl group, isobutyl group, t-butyl group and the like.
  • C 1-6 alkyl group represented by R 2
  • R 3 or R 4 it is more preferably a methyl group
  • R 7 represents a “C 1-6 alkyl group”, more preferably a methyl group
  • R 8 or R 9 represents a “C 1-6 alkyl group”, more preferably a methyl group or
  • a “C 1-6 alkyl group” represented by R 10 which is an n-butyl group
  • a “C 1-3 alkyl group” is more preferred, and a methyl group or an ethyl group is still more preferred.
  • C 2-6 alkenyl group represented by R 10 means a linear or branched alkenyl group having 2 to 6, preferably 3 to 5 carbon atoms. Specific examples thereof include allyl group, 1-propenyl group, isopropenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 2-methyl-1-propenyl group, 2-methylallyl group, 1-methyl -1-propenyl group, 1-methylallyl group, 1,1-dimethylvinyl group, 1-pentenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 3-methyl-1-butenyl group, 3- And a methyl-2-butenyl group. Among these, an allyl group or a 3-methyl-2-butenyl group is preferable.
  • halogen atom represented by the above R 10 means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • C 1-6 alkylcarbonyl group represented by the above R 10 means a linear or branched alkylcarbonyl group having 1 to 6, preferably 1 to 4 carbon atoms.
  • Preferable specific examples include an acetyl group and a propionyl group.
  • Examples of the “alkoxy group” represented by R 5 and R 6 include a methoxy group and an ethoxy group. Of these, a methoxy group is preferable.
  • benzyl group optionally substituted with a halogen atom represented by the above R 10 include a benzyl group and an iodobenzyl group.
  • the triterpene derivative as an active ingredient in the prophylactic or therapeutic agent of the present invention preferably has a configuration represented by the following formula (I-1).
  • the definitions of R 1 , R 2 , R 3 , R 4 , R 5 and R 6 in formula (I-1) are the same as those in formula (I) above.
  • triterpene derivative of the formula (I) in the present invention include compounds having combinations of substituents shown in Table 1, but the present invention is not limited thereto.
  • Compound 3 and Compound 9 are the methods described in Chemical & Pharmaceutical Bulletin, 36, 153 (1988), Compound 5, Compound 8, Compound 31 and Compound 32 are the methods described in Bioorganic & Medicinal Chemistry, 13, 4900 (2005), Compound 20 is Bioorganic & Med The method described in Cinal Chemistry Letters, 7, 85 (1997), Compound 4, Compound 6, Compound 7, Compound 10, Compound 11, Compound 12, Compound 13, Compound 15, Compound 16, Compound 17, Compound 18 and Compound 19 Is the method described in the specification of Japanese Patent No. 3279574, Compound 14, Compound 21, Compound 22, Compound 23, Compound 24, Compound 25, Compound 26, Compound 27, Compound 28, Compound 29, and Compound 30 are disclosed in Japanese Patent No. 3727353. Can be obtained by the method described in the specification.
  • a preferred method for producing a compound whose production method has not been clarified is as follows. In the following production method, it is desirable that a functional group not involved in the reaction is protected, and a known protective group for protecting the functional group can be used. These facts will be apparent to those skilled in the art.
  • a compound of the formula (II) (synthesized by the method described in Chem. Pharm. Bull., 36.153 (1988)) and a compound R 10 Y of the formula (III) (where R 10 is as defined above, and Y is a halogen atom) in the presence of a base to produce a compound of formula (IV).
  • the reaction is carried out in a solvent that does not participate in the reaction (for example, chloroform, dichloromethane, diethyl ether, THF, benzene, toluene, DMF, DMSO or the like alone or in a mixed solvent) at a temperature in the range of ⁇ 78 ° C. to 100 ° C.
  • the base examples include pyridine, triethylamine, 4-dimethylaminopyridine, sodium hydride, potassium hydride, n-butyllithium, NaCH 2 SOCH 3 , tert-BuOK, tert-BuONa, and the like.
  • the base and the compound of the formula (III) are desirably used in the range of 1 to 10 equivalents relative to the compound of the formula (II).
  • the compound represented by the formula (V) can be produced by subjecting the compound represented by the formula (IV) to a hydrolysis reaction in the presence of an acid.
  • the solvent used in this reaction include methanol, ethanol, propanol, water, dichloromethane, chloroform, and THF alone or a mixed solvent.
  • the acid include mineral acids such as hydrochloric acid and sulfuric acid, or Lewis acids such as BF 3 ⁇ OEt 2 .
  • the reaction is carried out at a temperature ranging from 0 ° C to 100 ° C.
  • the compound of the formula (V) (the method described in Method (A), the specification of Japanese Patent No. 3279574, the specification of Japanese Patent No. 3727353, or Bioorganic & Medicinal Chemistry, 13, 4900 (2005) ) Can be converted to the compound of formula (VI) by oxidation.
  • Usable oxidizing agents are (1) pyridinium chloroformate, (2) pyridinium dichromate, (3) manganese dioxide, (4) tetra-n-propylammonium perruthenate and N-methylmorpholine-N-oxide.
  • DMSO oxidation reagents such as a combination of dimethyl sulfoxide (DMSO) and oxalyl chloride, and the like.
  • the oxidizing agent is preferably used in the range of 2-10 equivalents relative to the compound of formula (V).
  • the oxidation reaction can be carried out in a solvent that does not participate in the reaction (eg, dichloromethane, chloroform, diethyl ether, THF, etc.) at a temperature in the range of ⁇ 78 ° C. to 40 ° C.
  • PG 1 represents a protecting group for a carboxyl group.
  • Protective groups for this carboxyl group are those described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter GM Wuts, John Wiley & Sons, Inc.) and are known to those skilled in the art. It is well known. More preferably, PG 1 includes a methyl group, an ethyl group, a benzyl group, and the like.
  • Examples of the oxidizing agent that can be used for the oxidation reaction in the third step include pyridinium dichromate, Jones reagent, potassium permanganate, sodium chlorite, and the like, and 1 to 30 equivalents of the compound of formula (VI). It is preferably used in a range.
  • the oxidation reaction can be carried out in a solvent that does not participate in the reaction (for example, DMF, tert-butanol, acetone, water, etc.) at a temperature ranging from 0 ° C. to 60 ° C.
  • the conditions for protecting the carboxylic acid in the fourth step vary depending on the type of protecting group used.
  • PG 1 is a methyl, ethyl, or benzyl group
  • 1 to 10 equivalents of PG 1 Y is used with respect to formula (VI), and 1 equivalent to an excess amount.
  • a base eg, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydride, etc.
  • a solvent that does not participate in the reaction eg, toluene, benzene, THF, DMF, DMSO, etc.
  • the compound of the formula (VII) is reduced by a usual reduction reaction and converted into the compound of the formula (VIII).
  • the solvent used in the reduction reaction include methanol, ethanol, THF, chloroform, dichloromethane, and the like alone or a mixed solvent.
  • the reaction can be carried out at a temperature in the range of ⁇ 78 ° C. to 30 ° C.
  • the reducing agent include lithium aluminum hydride, sodium borohydride, lithium borohydride, diisobutylaluminum hydride, and the like.
  • the reducing agent may be used in the range of 1 to 10 equivalents relative to the compound of formula (VII). desirable.
  • PG 2 represents a hydroxyl-protecting group. “Hydroxyl protecting group” is described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter GM Wuts, John Wiley & Sons, Inc.) and is well known to those skilled in the art. . Preferable PG 2 in this reaction includes methoxymethyl, 1-ethoxyethyl, benzyloxymethyl group and the like.
  • the conditions for protecting the hydroxyl group in the fifth step vary depending on the type of protecting group used.
  • 1 to 10 equivalents of PG 2 Y (where Y is a halogen atom) with respect to formula (VIII) is used.
  • a base eg pyridine, triethylamine, 4-dimethylaminopyridine, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydride, etc.
  • Benzene, THF, DMF, DMSO, etc. at a temperature ranging from room temperature to 100 ° C.
  • the deprotection conditions for the protecting group of the carboxyl group in the sixth step vary depending on the type of protecting group used.
  • deprotection is performed by adding 1 equivalent to an excess amount of a base (for example, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, tert-BuOK, etc.).
  • a base for example, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, tert-BuOK, etc.
  • the reaction can be performed in a polar solvent (for example, methanol, ethanol, propanol, water, etc.) at a temperature in the range of 0 ° C to 100 ° C.
  • PG 1 When PG 1 is benzyl, it can be carried out by catalytic reduction using 0.1 to 0.5 equivalents of a catalyst (for example, palladium carbon, palladium black, palladium hydroxide, etc.).
  • a catalyst for example, palladium carbon, palladium black, palladium hydroxide, etc.
  • the reaction can be carried out in a solvent that does not participate in the reaction (for example, methanol, ethanol, THF, dioxane, dichloromethane, chloroform, water) at room temperature under a hydrogen atmosphere of usually 1 to 4 atm.
  • the seventh step after reacting the compound of formula (IX) with the compound of formula (X) (wherein R 8 and R 9 are as defined above) in the presence of a suitable condensing agent
  • the protecting group is removed under the deprotection conditions of the protecting group for the hydroxyl group, whereby the compound of the formula (XI) can be produced.
  • the solvent used in the reaction in the seventh step include dichloromethane, chloroform, benzene, toluene, THF, DMF and the like.
  • the condensing agent examples include dicyclohexylcarbodiimide (DCC), DCC-hydroxybenzobenzotriazole, benzotriazol-1-yl-oxytris (dimethylamino) phosphonium hexafluorophosphate (BOP reagent), diphenylphosphoryl azide, and the like.
  • the condensing agent is used in the range of 1 to 5 equivalents relative to the compound of formula (IX).
  • the reaction is usually carried out at a temperature ranging from 0 ° C to 80 ° C.
  • the deprotection conditions for removing the hydroxyl protecting group in the eighth step vary depending on the type of protecting group used.
  • Deprotection can be performed, for example, when PG 2 is methoxymethyl, 1-ethoxyethyl, benzyloxymethyl, in the presence of an acid (a mineral acid such as hydrochloric acid and sulfuric acid, or a Lewis acid such as BF 3 ⁇ OEt 2 ) in a solvent (for example, , Methanol, ethanol, propanol, water, dichloromethane, chloroform, or THF alone or in a mixed solvent, etc.) at a temperature in the range of 0 ° C. to 100 ° C.
  • an acid a mineral acid such as hydrochloric acid and sulfuric acid, or a Lewis acid such as BF 3 ⁇ OEt 2
  • a solvent for example, Methanol, ethanol, propanol, water, dichloromethane, chloroform, or THF alone or in a mixed solvent, etc.
  • the compound of the formula (XII) (wherein PG 2 is as defined above, and preferably PG 2 includes a benzyl group in this reaction) is converted into the first step of the method (B). And is converted to a compound of formula (XIII).
  • the compound of the formula (XII) can be synthesized by the method described in the specification of Japanese Patent No. 3279574, the specification of Japanese Patent No. 3727353, or Bioorganic & Medicinal Chemistry, 13, 4900 (2005).
  • the compound of formula (XIII) is oxidized and converted to the compound of formula (IX) by the method described in the second step of method (B).
  • the compound represented by the above (I) can exist as a salt.
  • the compound represented by (I) can be easily converted into a salt by allowing a pharmaceutically acceptable base to act on the compound according to an ordinary method.
  • a pharmaceutically acceptable base for example, an inorganic base such as sodium hydroxide, potassium hydroxide, aluminum hydroxide, sodium carbonate, potassium carbonate, or sodium bicarbonate, or an organic base such as piperazine, morpholine, piperidine, ethylamine, or trimethylamine should be used. Can do.
  • the prophylactic or therapeutic agent of the present invention can be orally administered as a dosage form such as a capsule, a microcapsule, a tablet, a granule, a fine granule, or a powder. It can also be administered parenterally (for example, intravenous injection, intramuscular injection, subcutaneous administration, intraperitoneal administration, rectal administration, transdermal administration) in the form of a conventional pharmaceutical preparation.
  • a pharmaceutically acceptable carrier can be added to the above dosage form.
  • Pharmaceutically acceptable carriers include, for example, excipients, extenders, binders, wetting agents, disintegrants, surfactants, lubricants, dispersants, buffers, preservatives, solubilizers, preservatives And pharmaceutical additives such as agents, flavoring agents, soothing agents, and stabilizers.
  • Each dosage form can be manufactured by a conventional method.
  • Specific additives include, for example, lactose, fructose, glucose, starch, gelatin, magnesium carbonate, synthetic magnesium silicate, talc, magnesium stearate, crystalline cellulose, methylcellulose, carboxymethylcellulose or a salt thereof, gum arabic, polyethylene glycol Syrup, petrolatum, glycerin, ethanol, propylene glycol, citric acid, sodium chloride, sodium sulfite, sodium phosphate and the like.
  • the dosage form, administration method, dosage, administration period, administration route, etc. of the preventive or therapeutic agent of the present invention can be appropriately set depending on, for example, the patient's weight, age, degree of symptoms, viral load in the patient, etc. .
  • the prophylactic or therapeutic agent of the present invention is administered orally or parenterally, for example, in an amount of 1 to 1000 mg per day in one or more divided doses.
  • the dose is preferably 5 to 500 mg per day.
  • the prophylactic or therapeutic agent of the present invention can be used in combination (that is, used in combination) with other drugs having an antiviral effect such as IFN or ribavirin in some cases.
  • the combination of the prophylactic or therapeutic agent of the present invention and another drug may be in the form of a single preparation, or may be a one-drug drug containing the active ingredients of both drugs.
  • each drug can be administered at the same time or with a time difference, and the number of administrations of each drug may be the same or different.
  • IFN ⁇ Natural type IFN ⁇ (Sumiferon: manufactured by Dainippon Sumitomo Pharma Co., Ltd.), IFN ⁇ -2a, IFN ⁇ -2b (Intron A: manufactured by Schering-Plough) ), Polyethylene glycol (PEG) natural IFN ⁇ , PEGylated IFN ⁇ -2a (Pegasys: Roche, Chugai Pharmaceutical), PEGylated IFN ⁇ -2b (Pegintron A: Schering-Plough), natural IFN ⁇ ( IFN ⁇ Mochida: Mochida Pharmaceutical Co., Ltd., Feron: Toray Industries, Inc.), PEGylated IFN ⁇ , natural IFN ⁇ , consensus IFN (Advaferon: manufactured by Astellas Pharma Inc.) or PEGylated consensus IFN, long-term IFN, etc. IFN derivatives that can be used, but are not limited thereto. Preferably, it is IFN ⁇ 2b or I
  • IFN is usually administered subcutaneously, intravenously, or intramuscularly.
  • parenteral methods eg, by nasal spray, transdermal, suppository, etc.
  • Oral administration is also conceivable when using IFN that is effective by an oral method, such as oral IFN.
  • the ratio of each active ingredient (use ratio or combination ratio) in the combination drug is not particularly limited as long as it is effective for the prevention or treatment of chronic hepatitis C cases.
  • the dose of the triterpene derivative of the present invention is appropriately determined from the range of 1 mg to 1000 mg per day for the effective dose of IFN.
  • the dose of the triterpene derivative of the present invention is preferably in the range of 5 mg to 500 mg per day. Appropriate doses and intervals in the combination of the prophylactic or therapeutic agent of the present invention and other drugs can be determined by controlled clinical trials.
  • the obtained compound was dissolved in a mixture of 2 ml of chloroform and 1 ml of methanol, 0.1 ml of 1N aqueous hydrochloric acid solution was added, and the mixture was stirred at room temperature for 10 minutes.
  • the reaction was quenched with saturated aqueous sodium hydrogen carbonate, and the reaction solution was diluted with chloroform and washed with saturated brine. After drying over anhydrous magnesium sulfate, the inorganic salt was filtered off and the solvent was concentrated under reduced pressure.
  • the obtained residue was dissolved in 8.5 ml of methylene chloride, 521 mg of molecular sieves, 408 mg of 4-methylmorpholine N-oxide, and 30 mg of tetra-N-propylammonium perruthenate were added and stirred at room temperature for 20 minutes.
  • Step 1 The title compound of Step 1 was prepared in the same manner as in Step 5 of Example 3 using 186 mg of 22 ⁇ -benzyloxy-3 ⁇ -methoxymethoxyolean-12-ene-24-euic acid and 0.41 ml of benzylamine. 148 mg (yield 69%) was obtained. 1 H-NMR (CDCl 3 ) ...
  • the mixture was further stirred at room temperature for 25 minutes. After extraction with methylene chloride, the mixture was concentrated under reduced pressure. The residue was dissolved in a mixed solution of 4 ml of ethanol and 2 ml of methylene chloride, 2 ml of 1N aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 4 hours and then at 50 ° C. for 18 hours and 40 minutes. Further, 1 ml of 1N sodium hydroxide was added and stirred at 75 ° C. for 3 hours and 30 minutes. Chloroform and water were added, and the mixture was acidified with 1N aqueous hydrochloric acid and extracted with chloroform.
  • a luciferase gene was introduced as a reporter gene in the HCV genomic gene sequence of Con1 strain. According to the method of Krieger et al. (J. Virol. 75: 4614 (2001)), the luciferase gene was introduced in the form of fusing with the neomycin resistance gene immediately after the IRES (Internal Ribosome Entry Site) of the HCV gene. The constructed RNA was introduced into Huh7 cells by electroporation and isolated as a G418 resistant clone.
  • HCV replicon cells containing a luciferase gene and a neomycin resistance gene are suspended in a culture solution [D-MEM (SIGMA, D6046) containing 10% fetal bovine serum (EQUITECH-BIO, INC.)] And 5000 to 8100 in a 96-well plate. Cells / well were seeded. Test compounds were added to various concentrations, and cultured for 3 days at 37 ° C. with 5% CO 2 . When the test compound was added, the test compound solution dissolved in dimethyl sulfoxide (DMSO) was used and diluted to the above-mentioned culture solution so as to have an appropriate concentration. The experiment was conducted such that the final concentration of DMSO used for dissolving the test compound in the replicon cell culture was 0.4%. DMSO was added to wells to which no test compound had been added to a final concentration of 0.4%.
  • DMSO dimethyl sulfoxide
  • the IC50 (50% growth inhibitory concentration) of the drug was calculated with the value of no drug added as 0% inhibition.
  • the IC50 value of compound 40 was> 20 ⁇ M, while the IC50 value of the compound of the present invention was as shown in Table 3 below.
  • mice Male, 7-8 weeks old were used (3 or more mice per group).
  • the test compound suspended in olive oil was collected from the jugular vein at 2, 6 and 24 hours after oral administration of 20 mg / kg or after 2, 4, 6, 8, 24 and 48 hours, and liquid chromatography / mass spectrometry was collected.
  • the drug concentration in plasma was measured using Mass spectrometry (LC-MS / MS). Further, pharmacokinetic parameters were determined from the obtained plasma concentration transition.
  • Table 4 shows the maximum plasma concentration (C max ), plasma half-life (t 1/2 ), and area under the plasma drug concentration-time curve (AUC) of each compound obtained in this study.
  • the prophylactic or therapeutic agent comprising the triterpene derivative active ingredient of the present invention can exhibit excellent anti-HCV activity and excellent pharmacokinetics when administered in an effective amount. High preventive effect or therapeutic effect can be expected. Therefore, the present invention can be used particularly in the medical field.

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Abstract

L'invention concerne un agent prophylactique ou thérapeutique de traitement de l'hépatite C chronique, qui contient un dérivé triterpénique représenté par la formule générale (I) ou un sel pharmaceutiquement acceptable de celui-ci comme ingrédient actif. (Dans la formule (I), R1 représente un atome d'hydrogène ou un groupe hydroxyle ; R2 représente un groupe alkyle en C1-6, -CH2OR7 ou -CON(R8)R9 ; R3 et R4 peuvent être identiques ou différents et représentent chacun un atome d'hydrogène, un groupe hydroxyle ou similaire ; et R5 et R6 peuvent être identiques ou différents et représentent chacun un atome d'hydrogène, un groupe hydroxyle ou un groupe alcoxy. À cet effet, R7 représente un atome d'hydrogène, un groupe alkyle en C1-6 ou similaire ; et R8 et R9 peuvent être identiques ou différents et représentent chacun un atome d'hydrogène, un groupe alkyle en C1-6 ou similaire. Également dans la formule (I), la ligne en pointillés (-----) représente une simple liaison ou une double liaison, et lorsque la ligne en pointillés représente une double liaison, R4 et R6 n'existent pas. À cet égard, le 22ß-méthoxyoléan-12-ène-3ß,24-diol est exclu des dérivés triterpéniques représentés par la formule (I)).
PCT/JP2010/072565 2009-12-15 2010-12-15 Agent prophylactique ou thérapeutique pour le traitement de l'hépatite c chronique Ceased WO2011074608A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102584930A (zh) * 2012-01-17 2012-07-18 北京大学 刺囊酸衍生物及其生物转化方法和用途

Citations (3)

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Publication number Priority date Publication date Assignee Title
WO1997003088A1 (fr) * 1995-07-07 1997-01-30 Meiji Seika Kabushiki Kaisha Derives triterpenes et medicament pour les maladies du foie
WO1997031014A1 (fr) * 1996-02-26 1997-08-28 Meiji Seika Kabushiki Kaisha Derives triterpeniques et remedes pour maladies hepatiques
WO2008004653A1 (fr) * 2006-07-07 2008-01-10 Meiji Seika Kaisha, Ltd. Agent prophylactique ou thérapeutique pour une maladie virale

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Publication number Priority date Publication date Assignee Title
WO1997003088A1 (fr) * 1995-07-07 1997-01-30 Meiji Seika Kabushiki Kaisha Derives triterpenes et medicament pour les maladies du foie
WO1997031014A1 (fr) * 1996-02-26 1997-08-28 Meiji Seika Kabushiki Kaisha Derives triterpeniques et remedes pour maladies hepatiques
WO2008004653A1 (fr) * 2006-07-07 2008-01-10 Meiji Seika Kaisha, Ltd. Agent prophylactique ou thérapeutique pour une maladie virale

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HIASA, Y.: "Hepatitis C Virus Replication Is Inhibited by 22p-methoxyolean-12-ene-3p, 24(4p)-diol (ME3738) Through Enhancing Interferon-P", HEPATOLOGY, vol. 48, no. 1, 2008, pages 59 - 69, XP002686099, DOI: doi:10.1002/hep.22289 *
NOBUTO MINOWA: "DEVELOPMENT OF THERAPEUTIC AGENT FOR CHRONIC HEPATITIS C USING SOYASAPOGENOL DERIVATIVE", JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN, vol. 126, no. SUPP.3, 2006, pages 24 - 27 *
SASAKI, K.: "Synthesis and hepatoprotective effects of soyasapogenol B derivatives", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 7, no. 1, 1997, pages 85 - 88, XP004135971, DOI: doi:10.1016/S0960-894X(96)00572-0 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102584930A (zh) * 2012-01-17 2012-07-18 北京大学 刺囊酸衍生物及其生物转化方法和用途

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