WO2010150739A1 - Dérivés de pyripyropène contenant un groupe hydroxyle manifestant une activité inhibitrice d'acat2 activity - Google Patents

Dérivés de pyripyropène contenant un groupe hydroxyle manifestant une activité inhibitrice d'acat2 activity Download PDF

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WO2010150739A1
WO2010150739A1 PCT/JP2010/060461 JP2010060461W WO2010150739A1 WO 2010150739 A1 WO2010150739 A1 WO 2010150739A1 JP 2010060461 W JP2010060461 W JP 2010060461W WO 2010150739 A1 WO2010150739 A1 WO 2010150739A1
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group
meoh
esi
compound
acat2
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洋 供田
亨 長光
大介 松田
太一 大城
正樹 大多和
智 大村
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学校法人北里研究所
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4433—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to a pyripyropene A derivative having extremely excellent cholesterol acyltransferase isozyme 2 (hereinafter abbreviated as ACAT2) inhibitory activity, and more particularly to a pyripyropene A derivative in which the 1-position or the 11-position is substituted with a hydroxyl group.
  • ACAT2 cholesterol acyltransferase isozyme 2
  • statins that specifically inhibit hydroxy-3-methylglutaryl coenzyme A (reduced to HMG-CoA) reductase Systemic drugs are mainly used.
  • Statin drugs are the most widely sold drugs in the world for seven consecutive years since 2001, and are widely used so that two products are included in the top 30 sales in FY2007.
  • statin drugs only 30-40% of statin drugs have an effect of suppressing the onset, and it has become clear that half of patients undergoing treatment do not suppress cardiovascular disease etc. Patent Document 1).
  • HMG-CoA reductase inhibitor a prophylactic / therapeutic agent for arteriosclerosis
  • onset mechanism of arteriosclerosis is complicated, and various factors such as heredity, diabetes, drugs, etc. It is thought that this is because there are many cases of overlapping. Therefore, it is necessary to diagnose and treat according to the patient's individual condition.
  • the mechanism of action differs from that of statin drugs, and there is an urgent need to develop a drug with a new mechanism of action that can be expected to suppress the onset of coronary arteries and regress coronary artery lesions.
  • statin drugs that replace statin drugs has hardly progressed.
  • Cholesterol acyltransferase (more precisely, acyl coenzyme A cholesterol acyltransferase, acyl-CoA-cholesterol acyltransferase, hereinafter abbreviated as ACAT) is an enzyme that introduces an acyl group into cholesterol and is a statin-resistant arteriosclerosis It is regarded as a drug target that is expected to develop into tailor-made medical treatment according to individual treatment and individual pathological conditions. This enzyme has been attracting attention as an important target molecule for arteriosclerosis preventive and therapeutic agents for many years, and many synthetic ACAT inhibitors have been developed, but no side effects or sufficient effects have been observed, and it has not yet been linked to clinical application. No (non-patent document 2).
  • ACAT has two types of isozymes, ACAT1 and ACAT2, which have different functions and localization in vivo (Non-patent Document 3).
  • ACAT1 is widely distributed in many cells and tissues in the living body, and is highly expressed particularly in macrophages and smooth muscle cells, and causes macrophage foaming that causes arteriosclerosis in the arterial wall.
  • ACAT2 is specifically expressed in the small intestine and liver, and is considered to be involved in the absorption of dietary cholesterol and the secretion of very low density lipoprotein in each tissue. Since the difference in function between ACAT1 and ACAT2 in vivo has been clarified, the importance of clarifying the selectivity of drug discovery targeting ACAT has been recognized again.
  • Synthetic agents that have been discontinued during development so far have the properties of selective inhibition of ACAT1 (eg Wu-V-23) or inhibition of both ACAT1 and ACAT2 isozymes (eg abashimibe and pakimimibe) Became clear (Non-Patent Document 4).
  • Non-Patent Document 5 Considering the results of the recently announced knockout mouse (Non-Patent Document 5), the possibility of drug discovery from an ACAT2-selective inhibitor is strongly expected.
  • pyripyropene A Non-patent document 6
  • Non-patent document 7 Only pyripyropene A (Non-patent document 6) has been reported as an ACAT2-selective inhibitor (Non-patent document 7), and no drug discovery research led by an ACAT2-selective inhibitor has been found to date.
  • a pyripyropene derivative inhibits ACAT2 (Non-patent Document 8).
  • a derivative in which 1-position or 11-position is substituted with a hydroxyl group selectively inhibits ACAT2. Is not disclosed or suggested.
  • An object of the present invention is to provide a drug effective for the prevention or treatment of arteriosclerosis having a mechanism of action different from that of statin drugs.
  • the present inventors have found that a novel pyripyropene A derivative has an extremely high inhibitory activity against ACAT2, which is attracting attention as a target for arteriosclerosis preventive and therapeutic agents, and has completed the present invention. .
  • the present invention provides the following general formula (I) or (II) or (III):
  • R 1 and R 2 are groups selected from a hydroxyl group, a lower acyloxy group, an arylcarbonyloxy group, and a heteroarylcarbonyloxy group.
  • R 1 and R 2 may be the same or different from each other, but at least one of them is not a hydroxyl group, and in general formula (II) at least one of R 1 and R 2 is not an acetoxy group
  • R 3 represents a group selected from a hydroxyl group, a lower alkoxy group, an arylalkoxy group, a heteroarylalkoxy group, a lower alkylamino group, an arylamino group, and a heteroarylamino group).
  • pharmaceutically acceptable salts, solvates and hydrates thereof are examples of pharmaceutically acceptable salts, solvates and hydrates thereof.
  • the position of the OH group at the 1-position or the 11-position and the position of the R 2 group are interchanged with each other.
  • the compound represented by the general formula (III) is a compound in which —R 2 is a (C ⁇ O) R 3 group in the compound represented by the general formula (I).
  • lower acyloxy group as a group or a part of the group means a linear, branched or cyclic acyloxy group having about 1 to 7 carbon atoms.
  • lower acyloxy include acetoxy, n-propionyloxy, i-propionyloxy, n-butyryloxy, i-butyryloxy, s-butyryloxy, t-butyryloxy, n-valeryloxy, neovaleryloxy, i-valeryloxy, Examples include t-valeryloxy, n-caproyloxy, i-caproyloxy, cyclohexylcarbonyloxy and the like.
  • the lower acyloxy group includes those in which a hydrogen atom is substituted with another functional group. Examples of functional groups that may be present in the lower acyloxy group include halogen, cyano group, lower alkoxy group and the like.
  • arylcarbonyloxy group as a group or a part of the group means a phenylcarbonyloxy group (benzoyloxy group), a naphthylcarbonyloxy group or the like, and one or two or more on an aromatic ring May be present.
  • substituents include lower alkyl groups, lower alkoxy groups, cyano, nitro, halogen, azide groups, optionally substituted amino groups, hydroxyl groups, optionally substituted aryl groups, lower alkylsulfonyls. Groups and the like.
  • the lower alkyl group and the lower alkoxy group mean a linear, branched or cyclic group having about 1 to 7 carbon atoms.
  • preferred arylcarbonyloxy groups include p-cyanobenzoyl group and p-nitrobenzoyl group.
  • heteroaryl as a group or part of a group refers to a 5- or 6-membered aromatic heterocycle having one or more heteroatoms selected from nitrogen, oxygen, and sulfur. Or a polycyclic heteroaromatic compound.
  • preferred heteroaryl include groups derived from furan, pyrrole, imidazole, thiazole, triazole, tetrazole, thiadiazole, pyridine, pyridazine, pyrimidine, indole, thianaphthene and the like.
  • the heteroaryl group may be substituted with one or more substituents (similar to those exemplified for the arylcarbonyloxy group).
  • lower alkoxy group as a group or a part of the group means a linear, branched or cyclic alkoxy group having about 1 to 7 carbon atoms.
  • lower alkoxy include methoxy, ethoxy, propyloxy and the like.
  • the lower alkoxy group includes those in which a hydrogen atom is substituted with another functional group.
  • functional groups that may be present in the lower alkoxy group include halogen, cyano, azide, lower alkoxy group, lower alkoxycarbonyl group, optionally substituted aryl group, optionally substituted heteroaryl group and the like.
  • lower alkylamino group as a group or part of a group means an amino group having a linear, branched, or cyclic alkyl group having about 1 to 7 carbon atoms, The number of lower alkyl groups bonded to the atom is 1 or 2.
  • Examples of “lower alkylamino group” include methylamino group, dimethylamino group, ethylamino group, diethylamino group, propylamino group, dipropylamino group and the like.
  • the lower alkylamino group includes those in which a hydrogen atom is substituted with another functional group.
  • Examples of functional groups that may be present in the lower alkylamino group include halogen, cyano, azide, lower alkoxy group, lower alkoxycarbonyl group, optionally substituted aryl group, optionally substituted heteroaryl group, and the like.
  • Examples of the “substituted lower alkylamino group” include methoxycarbonylmethyl group, ethoxycarbonylmethyl group, benzylamino group, 2,4-dimethoxyphenylmethyl group, and the like.
  • R 1 is an arylcarbonyloxy group (for example, p-cyanobenzoyl group, p-nitrobenzoyl group). Or a lower acyloxy group (eg, acetyl group), and R 2 is a lower acyloxy group or arylcarbonyloxy group, particularly an acetyl group, a propionyl group, an isobutyryl group, or a benzoyl group.
  • the compound according to the present invention has an excellent ACAT2 inhibitory activity and is a therapeutic or prophylactic agent for obesity, obesity, hyperlipidemia, hypercholesterolemia, dyslipidemia, arteriosclerosis, hypertension, etc. Useful as.
  • a pharmaceutical composition containing the compound of the present invention and a pharmacologically acceptable salt thereof, a pharmacologically acceptable ester thereof or another pharmacologically acceptable derivative thereof as an active ingredient is a prophylactic agent for arteriosclerotic diseases. Alternatively, it is useful as a therapeutic agent.
  • a compound in which R 1 is a lower alkyl or arylcarbonyloxy group and R 2 is an acetoxy group is a scheme shown below (hereinafter also referred to as a first scheme). ).
  • R 1 CO 2 H represents a carboxylic acid corresponding to the lower alkyl or arylcarbonyloxy group defined in the general formula (I).
  • the compound of the formula (a) in the above scheme can be synthesized by a conventional method (for example, Obata et al., J. Antibiot. 49, 1133-1148, 1996).
  • the conversion from compound (a) to compound (b) can be carried out by the following method. That is, in the presence of 1.2 equivalents of di-tert-butylsilylditrifluoromethanesulfonate or di-tert-butylsilyldichloride and 2.4 equivalents or an excess of an organic amine (preferably 2,6-lutidine) relative to (a).
  • (B) can be obtained by reacting in a dimethylformamide solvent at ice temperature for 1 hour and then subjecting it to ordinary post-treatment.
  • Conversion from compound (b) to compound (c) can be carried out by the following method. 1 equivalent or excess of the corresponding carboxylic acid R 1 CO 2 H relative to (b) and 1 equivalent or excess of condensing agent (preferably 1-ethyl-3- (3-dimethylaminopropyl) Carbodiimide hydrochloride or dicyclohexylcarbodiimide), and 0.5 equivalent or excess of an organic base (preferably dimethylaminopyridine) in dichloromethane, dimethylformamide, tetrahydrofuran, acetonitrile or the like or a mixed solvent thereof for 30 minutes to 2 at room temperature.
  • condensing agent preferably 1-ethyl-3- (3-dimethylaminopropyl) Carbodiimide hydrochloride or dicyclohexylcarbodiimide
  • an organic base preferably dimethylaminopyridine
  • the conversion from compound (c) to compound (d) can be carried out by the following method. That is, in the presence of 10 equivalents or an excess amount of ammonium fluoride relative to (c), in an alcohol solvent (preferably methanol, ethanol), tetrahydrofuran, acetonitrile or the like or a mixed solvent thereof at room temperature for 3 to 5 hours. After the reaction, (d) can be obtained as the main product by subjecting it to ordinary post-treatment.
  • the conversion from compound (d) to compound (e) can be performed by the following method. 1 equivalent or excess of acetic anhydride and 1.5 equivalent or excess of organic amine (preferably triethylamine, diisopropylethylamine) and 0.5 equivalent or excess of organic base (preferably dimethylaminopyridine relative to (d). ) In a dichloromethane, dimethylformamide, tetrahydrofuran, acetonitrile or the like or a mixed solvent thereof at 0 ° C. or room temperature for 30 minutes to 2 days, and then carrying out a usual post-treatment, Obtainable.
  • R 2 is an acetoxy group, but an acyloxy group other than an acetoxy group can be introduced by using a corresponding acid anhydride when converting the compound (d) to the compound (e). it can.
  • the conversion from compound (e) to compound (f) can be carried out by the following method. That is, tetrahydrofuran, an alcohol solvent (preferably methanol, ethanol), acetonitrile, in the presence of a fluorine reagent (preferably triethylamine hydrogen trifluoride, tetrabutylammonium fluoride, etc.) of 1 equivalent or excess with respect to (e).
  • a fluorine reagent preferably triethylamine hydrogen trifluoride, tetrabutylammonium fluoride, etc.
  • R 1 represents the same meaning as defined for general formula (I).
  • Compound (c) in the above scheme can be synthesized by the same method as described in the first scheme.
  • the conversion from compound (c) to compound (g) can be carried out by the following method. That is, 3 to 5 at room temperature in an alcohol solvent (preferably methanol, ethanol), tetrahydrofuran, acetonitrile, or a mixed solvent thereof in the presence of 10 equivalents or an excess amount of ammonium fluoride relative to (c).
  • (G) can be obtained as a by-product by carrying out normal post-treatment after reacting for a period of time.
  • R 2 is an acetoxy group, but an acyloxy group other than an acetoxy group can be introduced by using a corresponding acid anhydride when converting the compound (g) to (h). Can do.
  • a compound in which R 1 is an arylcarbonyloxy group and R 3 is a propylamino group is produced by the following scheme (hereinafter also referred to as the third scheme). be able to.
  • R 1 represents the same meaning as defined for general formula (III).
  • Compound (d) in the above scheme can be synthesized by the same method as described for the first scheme.
  • the conversion from compound (d) to compound (j) can be carried out by the following method. That is, the reaction is carried out in a water-containing acetone solvent (preferably 5% water-containing acetone) for 12 hours at room temperature in the presence of 2 equivalents or an excess amount of Jones reagent with respect to (d), followed by normal post-treatment. (J) can be obtained.
  • a water-containing acetone solvent preferably 5% water-containing acetone
  • conversion from compound (j) to compound (k) can be synthesized by a conventional method (for example, Nagamitsu et al., J. Org. Chem. 61, 882-886, 1996). Conversion from compound (k) to compound (l) can be carried out by the following method.
  • R 3 is a propylamino group, but an alkylamino group or an arylamino group other than the propylamino group can be obtained by using a corresponding amine in the conversion from the compound (k) to the compound (l). Alternatively, a heteroarylamino group can be introduced.
  • a compound having a methoxy group at R 3 can be synthesized by reacting compound (k) with diazomethane or trimethylsilyldiazomethane in an alcohol solvent (preferably methanol) and a benzene mixed solvent.
  • an alcohol solvent preferably methanol
  • a compound having an alkoxy group at R 3 can be synthesized by subjecting one equivalent or excess of the corresponding alcohol to (k) under the above-mentioned conditions.
  • a compound having a hydroxyl group at R 3 can be synthesized by removing the fluorodi-tert-butylsilyl group from compound (k) by the same method as described for the first scheme.
  • the present invention includes salts, solvates and hydrates of the compounds represented by formula (I) or (II) or (III).
  • salts include inorganic acids (eg, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.) or organic acids (eg, acetic acid, propionic acid, citric acid, tartaric acid, malonic acid, maleic acid, fumaric acid, Toluenesulfonic acid, succinic acid, etc.).
  • the compounds according to the invention have a high inhibitory activity against ACAT2.
  • the compounds according to the invention can be used for the prevention and treatment of arteriosclerosis in animals, including humans.
  • the present invention also provides an ACAT2 inhibitor comprising the above compound or a pharmaceutically acceptable salt, solvate or hydrate thereof as an active ingredient, and the above compound or a pharmaceutically acceptable salt, solvate or hydrate thereof.
  • a pharmaceutical composition for inhibiting ACAT2, comprising a product and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition of the present invention can be formulated by methods known to those skilled in the art.
  • the compound of the present invention can be added to a pharmaceutically acceptable carrier such as sterile water or saline, vegetable oil, emulsifier, suspension, surfactant, stabilizer, flavoring agent, excipient, vehicle, preservative. It can be formulated by mixing with one or two or more selected from binders and the like in a unit dose form generally required for pharmaceutical practice.
  • tablets, pills, dragees, capsules, liquids, gels, syrups, slurries are prepared by mixing a compound of the present invention or a salt thereof with a pharmaceutically acceptable carrier well known in the art.
  • a pharmaceutically acceptable carrier well known in the art.
  • excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid and the like.
  • Binders such as water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone; dry starch, sodium alginate, agar powder, laminaran powder, carbonic acid Disintegrating agents such as sodium hydride, calcium carbonate, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose; disintegrating inhibitors such as sucrose, stearic cocoa butter, hydrogenated oil; Absorption promoters such as sodium uryl sulfate; humectants such as glycerin and starch; adsorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid; abundance of purified talc, stearate, boric acid powder, polyethylene glycol, etc.
  • Binders such
  • the tablet can be a tablet coated with a normal coating, for example, a sugar-coated tablet, a gelatin-encapsulated tablet, an enteric-coated tablet, a film-coated tablet, a double tablet, or a multilayer tablet, if necessary.
  • a normal coating for example, a sugar-coated tablet, a gelatin-encapsulated tablet, an enteric-coated tablet, a film-coated tablet, a double tablet, or a multilayer tablet, if necessary.
  • the compounds of the invention or their salts can be formulated according to conventional pharmaceutical practice using pharmaceutically acceptable vehicles well known in the art as carriers.
  • water-soluble vehicles for injection include isotonic solutions containing, for example, physiological saline, glucose and other adjuvants (for example, water-soluble salts such as D-sorbitol, D-mannose, D-mannitol, sodium chloride).
  • a suitable solubilizing agent such as alcohol, specifically ethanol, polyalcohol such as propylene glycol, polyethylene glycol, nonionic surfactant such as polysorbate 80 TM , HCO-50.
  • Oily vehicles include sesame oil and soybean oil, which may be used in combination with benzyl benzoate or benzyl alcohol as a solubilizer. Further, a buffer such as phosphate buffer, sodium acetate buffer, soothing agent such as procaine hydrochloride, stabilizer such as benzyl alcohol, phenol and antioxidant may be added.
  • the prepared injection solution is usually filled in a suitable ampoule.
  • Suitable routes of administration of the pharmaceutical composition of the present invention include, but are not limited to, oral, rectal, radial mucosa, or enteral administration, or intramuscular, subcutaneous, intramedullary, intrathecal, direct intraventricular, intravenous, Intravitreal, intraperitoneal, intranasal, or intraocular injection is included.
  • the administration route can be appropriately selected in consideration of the age and medical condition of the patient, other drugs used in combination, and the like.
  • the dosage of the pharmaceutical composition of the present invention can be selected in the range of 0.001 to 10 mg / kg body weight per administration, or in the range of 0.1 to 100 mg per administration. It is not necessarily limited to the numerical value of. Administration may be carried out once or several times a day or once every several days.
  • the dose and administration method can be appropriately selected by the doctor in charge taking into account the patient's weight, age, symptoms, and other drugs used in combination.
  • 1,7,11-trideacetylpyripyropene A (also referred to as PRD165, obtained according to the method of Obata et al. (J. Antibiot. 49, 1149-1156, 1996) under an argon atmosphere.
  • 2,6-lutidine (103 ⁇ L, 0.88 mmol) and t Bu 2 Si (OTf) 2 (161 ⁇ L, 0.44 mmol) were added to a dry DMF (4 mL) solution of mg, 0.367 mmol) and stirred at 0 ° C. for 0.5 hour. . MeOH was added to stop the reaction.
  • Test Example 1 Analysis of metabolites of administered pyripyropene A and its derivatives C57BL6 / J mice (male, purchased from Japan SLC Co., Ltd.) under artificial light (day) -dark (night) cycle in a 12-hour cycle A standard diet (CE-2, manufactured by CLEA Japan, Inc.) was appropriately given and maintained. Before starting each drug test, they were fasted for 20 hours (water ad libitum). In these animals, pyripyropene A or PRD017 is dissolved in a 0.5% (w / v) carboxymethylcellulose physiological saline solution and orally administered to a 10-week-old mouse in a volume of 2.5 ml / kg to a concentration of 50 mg / kg. Administered.
  • 100 ⁇ L of blood was collected from the tail vein of test animals at 0.5, 6 and 12 hours after administration of pyripyropenes. Immediately before administration of pyripyropene, 100 ⁇ L of blood was collected, and this was defined as 0 hour. After 200 ⁇ L of ethyl acetate was added to these blood and mixed well, 150 ⁇ L of the ethyl acetate layer was collected in a 1.5 ⁇ ml tube tube (Catalog No. 3810, Eppendorf). After drying with a centrifugal evaporator (manufactured by Tokyo Science Instruments Co., Ltd.), it was redissolved in 100 ⁇ L of methanol.
  • feces excreted within 6 hours after administration of pyripyropene were collected.
  • the collected feces were heated at 55 ° C. for 24 hours, dried and then crushed.
  • 10 mg of crushed feces was collected in a glass vial, and 1 ml of ethyl acetate was added to dissolve excreted pyripyropenes and their metabolites.
  • the total amount of the ethyl acetate was filtered through a filter having a pore size of 0.22 ⁇ m, and the filtrate was collected in a 1.5 ml tube, dried to dryness with a centrifugal evaporator, and redissolved in 100 ⁇ L of methanol.
  • an ultrahigh performance liquid chromatography kit (system; Prominence, manufactured by Shimadzu Corp .: column; Shin-Pack XR-ODS, 2.0 ⁇ ⁇ 75 mm, 40 ° C., manufactured by Shimadzu Corp.) was used. Elution was started with 5% acetonitrile and 0.1% phosphoric acid aqueous solution, and after 6 minutes, elution was performed with a linear concentration gradient so as to become 95% acetonitrile and 0.1% phosphoric acid aqueous solution, and detection was performed at a wavelength of 320 nm.
  • the molecular weight is high performance liquid chromatography / mass spectrometry (Waters; column, PEGASIL ODS, 2.0 O X 50 mm, Senshu Scientific); mass detector, micromass ZQ 2000, Waters; moving bed, 10% acetonitrile Then, elution was started with 0.05% aqueous trifluoroacetic acid, and after 13 minutes, linear concentration gradient so that it became 100% acetonitrile and 0.05% aqueous trifluoroacetic acid; analysis software, MassLynx (Ver.4.0) was detected.
  • pyripyropene A Three types of pyripyropene A (PPA) -related substances were detected from samples extracted from the blood of mice administered with pyripyropene A, and they were named Peak B1 to Peak B3 in order from those with the latest elution time. From the sample extracted from feces, two types of pyripyropene A-related substances were detected, and were named Peak F1 and Peak F2 in order from the one with the latest elution time. Table 1 shows the elution times and molecular weights of the samples, peaks B1 to B3, and peaks F1 and F2.
  • PRD017-related substances Three types were detected from samples extracted from the blood of mice administered with PRD017, and were named as peak B1 ′ to peak B3 ′ in order from those with the latest elution time. Two types of PRD017-related substances were detected from the sample extracted from the feces, and were named as peak F1 ′ and peak F2 ′ in order from the one with the latest elution time. Table 2 shows the elution times and molecular weights of the samples and peaks B1 ′ to B3 ′ and peaks F1 ′ and F2 ′.
  • PRD017 (7? Op-cyanobenzoyl-pyripyropene A) administered and PRD148 (7-deacetylpyripyropene A) and PRD138 (7-Op-cyanobenzoyl-1,7,11-trideacetylpyri) used as comparative examples
  • PRD148 7-deacetylpyripyropene A
  • PRD138 7-Op-cyanobenzoyl-1,7,11-trideacetylpyri
  • peaks B1 to B3 were identified as PPA, PRD147, and PRD146, respectively. Peaks F1 and F2 were identified as PPA and PRD146, respectively. Further, as is clear from Table 2, peaks B1 ′ to B3 ′ were identified as PRD017, PRD118, and PRD138, respectively. Peaks F1 ′ and F2 ′ were identified as PRD017 and PRD138, respectively.
  • a metabolite detected from blood 30 minutes after administration of pyripyropene a metabolite in which the acetyl group at the 1-position was hydrolyzed and converted to a hydroxyl group, and two metabolites at the 1- and 11-positions
  • Two types of metabolites in which the acetyl group was hydrolyzed and converted to a hydroxyl group were identified.
  • Metabolites detected from feces excreted within 6 hours after administration of pyripyropene are metabolites in which the acetyl groups at the 1st and 11th positions are hydrolyzed and converted to hydroxyl groups.
  • Test Example 2 Measurement of ACAT2 inhibitory activity [Method for preparing enzyme source of ACAT2]
  • An enzyme source was prepared by partially modifying the method of Uelmen et al. (J. Biol. Chem. 270, 26192-26201, 1995).
  • the supernatant obtained by centrifuging this at 12000 ⁇ g was ultracentrifuged at 100,000 ⁇ g to obtain a microsomal fraction, and this fraction was prepared with buffer A so as to have a protein concentration of 5 mg / mL.
  • ACAT activity of the pyripyropene derivative prepared in each example was measured according to the method of Field et al. (Gastroenterology, 83, 873-880, 1982). It said enzyme source 200 ⁇ g protein amount, 200 mM bovine serum albumin, [1- 14 C] oleoyl coenzyme A (final concentration 170 ⁇ M, 0.090 ⁇ Ci) each pyripyropene derivative to be tested (1,0.1,0.01,0.001,0.0001,0.00001Mg 10 ⁇ L / mL methanol solution) was added to buffer A to make a total volume of 200 ⁇ L, followed by reaction at 37 ° C. for 5 minutes. As a control, 10 ⁇ L of methanol was added instead of the pyripyropene derivative.
  • the amount of [ 14 C] cholesteryl oleate produced was quantified with a BAS 2000 bioimage analyzer (manufactured by Fuji Film Co., Ltd.) and compared with the control, whereby the inhibitory activity of the test compound was calculated by the following formula.
  • the radioactivity of thin-layer chromatography in which nothing was spotted was used as the background.
  • Inhibition rate 100-[(radioactivity when test compound is added)-(background)] / [(radioactivity of control)-(background)] From these inhibition rate data, the concentration at which the enzyme activity was inhibited by 50% (IC 50 , inhibition activity) was calculated.
  • the compound according to the present invention exhibits extremely high inhibitory activity against ACAT2.
  • the ACAT2 inhibitory activity test is not limited to the above method, and for example, microsomes prepared from the small intestine or liver of animals such as rats and monkeys may be used as the ACAT2 enzyme source.
  • microsomes prepared from cultured cells (Caco-2 enterocytes, primary cultured hepatocytes, HePG2 hepatocytes, etc.) or cultured cells highly expressing ACAT2 can also be used as the ACAT2 enzyme source.

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Abstract

Cette invention concerne des composés efficaces pour prévenir ou traiter l'artériosclérose, qui ont un mécanisme d'action différent de celui des médicaments de type statine. Cette invention concerne les dérivés de pyripyropène représentés par la formule générale (I) ou (II) [dans les formules, R1 et R2 sont chacun un groupe choisi parmi un groupe hydroxyle, acyloxy inférieur, arylcarbonyloxy, et hétéroaryl-carbonyloxy ; ou ─R2 peut être (=O)R3, R3 étant un groupe hydroxyle, alcoxy inférieur, arylalcoxy, hétéroarylalcoxy, alkylamino inférieur, arylamino, ou hétéroarylamino] ; ainsi que leurs sels, solvates et hydrates pharmaceutiquement acceptables.
PCT/JP2010/060461 2009-06-23 2010-06-21 Dérivés de pyripyropène contenant un groupe hydroxyle manifestant une activité inhibitrice d'acat2 activity WO2010150739A1 (fr)

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WO2011122468A1 (fr) * 2010-03-31 2011-10-06 学校法人北里研究所 Dérivé de pyripyropène ayant une activité d'inhibition d'acat2 et stable vis-à-vis d'enzymes de métabolisation
EP2578084A1 (fr) * 2010-05-24 2013-04-10 Meiji Seika Pharma Co., Ltd. Agent de lutte contre les organismes nuisibles
JP2014144922A (ja) * 2013-01-28 2014-08-14 Kitasato Institute Ａｃａｔ２阻害活性を示すピリピロペンａ構造簡略型誘導体
WO2015198966A1 (fr) * 2014-06-24 2015-12-30 学校法人北里研究所 Nouveau composé pharmaceutique ayant une activité inhibant l'isozyme 2 de la cholestérol acyltransférase (acat2)

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WO2021153570A1 (fr) 2020-01-27 2021-08-05 学校法人北里研究所 Inhibiteur de proprotéine convertase subtilisine/kexine de type 9 (pcsk9) et son utilisation pharmaceutique

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011122468A1 (fr) * 2010-03-31 2011-10-06 学校法人北里研究所 Dérivé de pyripyropène ayant une activité d'inhibition d'acat2 et stable vis-à-vis d'enzymes de métabolisation
US9187492B2 (en) 2010-03-31 2015-11-17 School Juridical Person Kitasato Institute Pyripyropene derivative having ACAT2 inhibiting activity and stable to metabolizing enzymes
EP2578084A1 (fr) * 2010-05-24 2013-04-10 Meiji Seika Pharma Co., Ltd. Agent de lutte contre les organismes nuisibles
EP2578084A4 (fr) * 2010-05-24 2014-04-23 Meiji Seika Pharma Co Ltd Agent de lutte contre les organismes nuisibles
JP2014144922A (ja) * 2013-01-28 2014-08-14 Kitasato Institute Ａｃａｔ２阻害活性を示すピリピロペンａ構造簡略型誘導体
WO2015198966A1 (fr) * 2014-06-24 2015-12-30 学校法人北里研究所 Nouveau composé pharmaceutique ayant une activité inhibant l'isozyme 2 de la cholestérol acyltransférase (acat2)
JP2016008191A (ja) * 2014-06-24 2016-01-18 学校法人北里研究所 コレステロールアシル転移酵素アイソザイム２（ａｃａｔ２）阻害活性を有する新規医薬化合物
US9896456B2 (en) 2014-06-24 2018-02-20 School Juridical Person Kitasato Institute Pharmaceutical compound having inhibitory activity against cholesterol acyltransferase isozyme 2 (ACAT2)

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