WO2011122468A1 - Acat2阻害活性を示す代謝酵素に安定なピリピロペン誘導体 - Google Patents
Acat2阻害活性を示す代謝酵素に安定なピリピロペン誘導体 Download PDFInfo
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Classifications
-
- 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
- C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
- C07D493/14—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
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/453—Non condensed piperidines, e.g. piperocaine 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
-
- 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
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 specifically, to an acyloxy group in which one or both of the 1-position and the 11-position are not acetoxy groups.
- ACAT2 cholesterol acyltransferase isozyme 2
- the present invention relates to a substituted derivative, a derivative substituted at the 11-position with a carboxyl, alkoxycarbonyl, or arylcarbamoyl group, or a pyripyropene A derivative substituted at the 1,11-position with a cyclic acetal.
- statins that specifically inhibit hydroxy-3-methylglutaryl coenzyme A (hydroxy-3-methylglutaryl) Co-A) (hereinafter abbreviated as HMG-CoA) reductase Systemic drugs are mainly used.
- Statin drugs are the most widely sold drugs in the world for eight consecutive years since 2001, and are widely used so that two products are included in the top 30 sales in 2008.
- HMG-CoA hydroxy-3-methylglutaryl coenzyme A
- reductase Systemic drugs are the most widely sold drugs in the world for eight consecutive years since 2001, and are widely used so that two products are included in the top 30 sales in 2008.
- statin drugs only 30 to 40% of statin drugs have an onset suppression effect, and it has become clear that half of patients receiving treatment do not suppress cardiovascular disease or the like ( Non-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, diagnosis and treatment tailored to the patient's individual pathology are necessary.
- statin drugs 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.
- development of drugs that replace statin drugs has hardly progressed.
- ACAT Cholesterol acyltransferase
- 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.
- Synthetic ACAT inhibitors that have been discontinued in the past have properties of selective inhibition of ACAT1 (eg, Wu-V-23) or inhibition of both ACAT1 and ACAT2 isozymes (eg, abashimibe and pactimibe). (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. However, only Pyripyropene A (Non-Patent Document 6) having the structure shown in the following formula has been reported as an ACAT2-selective inhibitor (Non-Patent Document 7). There is no drug discovery research.
- pyripyropene derivative substituted at the 1-position, 7-position and / or 11-position of pyripyropene A inhibits ACAT2 (Patent Document 1), but it is not decomposed by metabolic enzymes. There is no disclosure or suggestion of inhibiting ACAT2.
- Patent Document 1 J. Am. Coll. Cardiol., Vol.46, pp.1225-1228, 2005 Meuwese et al., Curr. Opin. Lipidol., Vol.17, pp.426-431, 2006 Chang et al., Acta. Biochim. Biophys. Sin., Vol.38, pp.151-156, 2006 Farese, Arterioscler. Thromb. Vasc.
- An object of the present invention is to provide a compound that has a mechanism of action different from that of statin drugs and is an effective drug for the prevention or treatment of arteriosclerosis.
- Another object of the present invention is to provide a compound that can selectively inhibit ACAT2 and exhibits a high activity without being decomposed by metabolism, thereby being useful as a drug effective for the prevention or treatment of arteriosclerosis. It is to be.
- the present inventors show that a novel specific pyripyropene derivative is hardly subject to hydrolysis by metabolic enzymes, and has an extremely high inhibitory activity against ACAT2, which is attracting attention as a target for arteriosclerosis preventive and therapeutic agents. And the present invention was completed.
- the present invention relates to a compound represented by the following general formula (I) and pharmaceutically acceptable salts, solvates and hydrates thereof.
- R 1 represents an optionally substituted aliphatic, alicyclic or aromatic acyloxy group, or a group represented by the formula: —O—CH (R 7 ) —R 8 , wherein R 7 is a lower group.
- R 8 means an optionally substituted aryl group
- R 2 and R 3 are R 2 represents a carboxyl group, a lower alkoxycarbonyl group, an arylmethylcarbamoyl group which may be substituted on the aromatic ring, or a group represented by the formula: —CH 2 —R 4 , wherein R 4 is substituted
- R 3 means an aliphatic, alicyclic or aromatic acyloxy group which may be substituted, provided that R 4 and R 3 At least one of them is a group other than an acetoxy group, or R 2 and R 3 together represent a group represented by —O—CH (R 7 ) —R 8 , wherein R 7 is a lower group.
- the aliphatic acyloxy group is preferably a lower alkylcarbonyloxy group.
- “lower alkyl” means a linear or branched alkyl group having 1 to 6, preferably 1 to 4 carbon atoms.
- “lower alkoxy” means a linear or branched alkoxy group having 1 to 6, preferably 1 to 4 carbon atoms.
- lower alkylcarbonyloxy examples include acetoxy, n-propionyloxy, i-propionyloxy, n-butyryloxy, i-butyryloxy, s-butyryloxy, t-butyryloxy, n-valeryloxy, neovaleryloxy, i- Valeryloxy, t-valeryloxy, n-caproyloxy, i-caproyloxy and the like can be mentioned.
- the hydrogen atom of the lower alkylcarbonyloxy group may be substituted with a substituent. Examples of substituents include halogen (F, Cl, Br or I), nitro, cyano, amino (including mono- and di-lower alkylamino), lower alkoxy.
- An alicyclic acyloxy group means a cycloalkylcarbonyloxy group having 4 to 7 ring carbon atoms. Specific examples include cyclopentylcarbonyloxy and cyclohexylcarbonyloxy.
- the hydrogen atom on the carbocycle may be substituted with the above substituents.
- aromatic acyloxy group is an arylcarbonyloxy group.
- aryl include phenyl group and naphthyl group. Accordingly, examples of the aromatic acyloxy group include a benzoyloxy group and a naphthoyloxy group.
- Arylmethylcarbamoyl means a group —CONH—CH 2 -aryl, which may be a substituted aryl group, for example, a substituted phenyl group. “Aryl” may be a substituted aryl group having one or more substituents on the aromatic ring. Examples of substituents on the aromatic ring include lower alkyl, lower alkoxy, halogen (F, Cl, Br or I), nitro, cyano, amino (including mono- and di-lower alkylamino).
- R 5 is a substituted aryl group
- examples of the substituted aryl group when the aryl group in arylcarbonyloxy is substituted include p-cyanophenyl, p-nitrophenyl, p-fluorophenyl and the like.
- examples of the substituted aryl group in the case where the aryl group in arylmethylcarbamoyl is substituted include an o, p-dimethoxyphenyl group.
- the pyripyropene derivative according to the present invention is a novel compound that can be easily synthesized, can selectively inhibit ACAT2, and is hardly subject to hydrolysis by metabolic enzymes, so its inhibitory effect persists in the body. Therefore, these compounds are useful as drugs effective for the prevention or treatment of arteriosclerosis.
- the compounds represented by the above general formula (I) according to the present invention include compounds represented by the following general formulas (II), (III) and (IV).
- R 1 , R 3 and R 4 all represent a group selected from lower alkylcarbonyloxy, substituted or unsubstituted arylcarbonyloxy, preferably substituted or unsubstituted benzoyloxy, and cycloalkylcarbonyloxy.
- R 1 , R 3, and R 4 may be the same group, or R 3 and R 4 are not both an acyloxy group.
- R 6 represents a hydroxyl group (OH), a lower alkoxy group, or a benzylamino group which may be substituted on an aromatic ring, more generally an arylmethylamino group
- R 1 and R 3 May be the same or different and each represents a group selected from lower alkylcarbonyloxy, substituted or unsubstituted arylcarbonyloxy, and cycloalkylcarbonyloxy.
- R 5 represents an optionally substituted aryl group
- R 1 represents a group selected from lower alkylcarbonyloxy, substituted or unsubstituted arylcarbonyloxy, and cycloalkylcarbonyloxy, Or a group represented by the formula: —O—CH (R 7 ) —R 8 , wherein R 7 represents a lower alkoxy group, and R 8 represents an optionally substituted aryl group, preferably phenyl.
- R 8 is a substituted phenyl group include o-methylphenyl, p-methoxyphenyl, o, o-dimethylphenyl, o-fluorophenyl and the like.
- R 1 is an arylcarbonyloxy group (eg, benzoyloxy group)
- R 4 is an acetoxy group
- R 3 is a benzoyloxy group
- R * CO 2 H represents an aromatic carboxylic acid corresponding to the arylcarbonyloxy group R 1 , for example, benzoic acid.
- Compound (a) in the above scheme can be synthesized by a conventional method (for example, Obata et al., J. Antibiot., Vol. 49, pp. 1133-1148, 1996).
- the conversion from compound (a) to compound (b) can be carried out by the following method. That is, 1.2 equivalents of ditertiary butylsilyl ditrifluoromethanesulfonate or ditertiary butylsilyl dichloride with respect to compound (a) in the presence of 2.4 equivalents or an excess amount of an organic amine (preferably 2,6-lutidine).
- the compound (b) can be obtained by reacting in a formamide 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. That is, 1 equivalent or excess of the corresponding carboxylic acid R * CO 2 H and 1 equivalent or excess of condensing agent (preferably 1-ethyl-3- (3-dimethylaminopropyl) relative to compound (b). ) Carbodiimide hydrochloride or dicyclohexylcarbodiimide), and 0.5 equivalent or excess of an organic base (preferably dimethylaminopyridine) in one or more solvents such as dichloromethane, dimethylformamide, tetrahydrofuran, acetonitrile, After reacting at room temperature for 30 minutes to 2 days, compound (c) can be obtained by subjecting to normal post-treatment.
- condensing agent preferably 1-ethyl-3- (3-dimethylaminopropyl
- 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 with respect to compound (c), alcohol solvent (preferably methanol, ethanol) or tetrahydrofuran, acetonitrile or a mixed solvent thereof for 3 to 5 hours at room temperature. After the reaction, the compound (d) can be obtained as a main product by subjecting to ordinary post-treatment.
- the conversion from compound (d) to compound (e) can be performed by the following method. That is, 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 dimethylamino) relative to compound (d).
- Compound (e) is obtained by reacting in dichloromethane, dimethylformamide, tetrahydrofuran, acetonitrile or the like or a mixed solvent thereof in the presence of pyridine) at 0 ° C. or room temperature for 30 minutes to 2 days and then subjecting to usual post-treatment. be able to.
- the conversion from compound (e) to compound (f) can be carried out by the following method. That is, tetrahydrofuran or an alcohol solvent (preferably methanol, ethanol) in the presence of 1 equivalent or excess of a fluorine reagent (preferably triethylamine hydrogen trifluoride, tetrabutylammonium fluoride, etc.), relative to compound (e),
- a fluorine reagent preferably triethylamine hydrogen trifluoride, tetrabutylammonium fluoride, etc.
- the compound (f) can be obtained by reacting in acetonitrile or the like or a mixed solvent thereof at room temperature for 1 hour and then subjecting to usual post-treatment.
- the conversion from compound (f) to compound (g) can be carried out by the following method. That is, 1 equivalent or excess amount of benzoic acid and 1 equivalent or excess amount of condensing agent (preferably 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride or dicyclohexylcarbodiimide) with respect to compound (e). , And 0.5 equivalents or an excess amount of an organic base (preferably dimethylaminopyridine) in the presence of dichloromethane, dimethylformamide, tetrahydrofuran, acetonitrile or a mixed solvent thereof at room temperature for 30 minutes to 2 days.
- Compound (g) can be obtained by post-treatment.
- R 3 is a benzoyloxy group, but by using a corresponding arylcarboxylic acid (eg, substituted benzoic acid) corresponding to the conversion from compound (f) to compound (g), Arylcarbonyloxy groups other than benzoyl groups can be introduced into R 3 .
- R 1 is a lower alkylcarbonyloxy group such as an aliphatic acyloxy group, for example, an acetoxy group.
- a compound that is an alicyclic acyloxy group, such as a cycloalkylcarbonyloxy group can be synthesized.
- the compound in which R 6 is 2,4-dimethoxybenzylamino group and R 3 is an acetoxy group can be obtained from the compound (d) shown in the upper scheme. Starting from, it can be prepared according to the following scheme.
- the conversion from compound (d) to compound (h) can be performed by the following method. That is, after reacting for 12 hours at room temperature in a water-containing acetone solvent (preferably 5% water-containing acetone) in the presence of 2 equivalents or an excess amount of Jones reagent with respect to the compound (d), a normal post-treatment is performed.
- Compound (h) can be obtained by applying.
- Conversion from compound (h) to compound (i) can be synthesized by a conventional method (for example, Nagamitsu et al., J. Org. Chem., Vol. 61, pp. 882-886, 1996). Conversion from compound (i) to compound (j) can be carried out by the following method.
- R 6 is a 2,4-dimethoxybenzylamino group, but by using a corresponding amine in the conversion from compound (i) to compound (j), the substituent on the phenyl group can be changed.
- Different benzylamino groups eg, dimethyl, monomethyl, monomethoxy substituted benzylamino groups
- R 6 can be introduced into R 6 .
- R 3 is an acetoxy group, but an acyloxy group other than an acetoxy group is introduced into R 3 by using a corresponding acid anhydride in the conversion from compound (k) to compound (l). can do.
- R * CO 2 H represents a carboxylic acid corresponding to R 1 .
- the compound (m) in the above scheme can be synthesized by a conventional method (for example, Obata et al., J. Antibiot., Vol. 49, pp. 1149-1156, 1996).
- R 1 is a group represented by the formula: —O—CH (R 7 ) —R 8 (wherein R 7 represents a methoxy group, R 8 represents a p-methoxyphenyl group), and a compound in which R 5 is a phenyl group can be produced according to the following scheme.
- the compound of the formula (m) in the above scheme can be synthesized by a conventional method (for example, Obata et al., J. Antibiot., Vol. 49, pp. 1149-1156, 1996). Conversion from compound (m) to compound (o) can be carried out by the following method. That is, 10 equivalents or excess of p-methoxybenzaldehyde dimethyl acetal and a catalytic amount of an organic acid (preferably pyridinium p-toluenesulfonate) in the presence of 10 equivalents or more of compound (m) at room temperature in a dimethylformamide solvent.
- the compound (o) can be obtained by reacting for a period of time and then subjecting to usual post-treatment.
- R 8 is a p-methoxyphenyl group, but the dimethylacetal of the corresponding aldehyde is used for the conversion from the compound (p) to the compound (r), so that other than the p-methoxyphenyl group.
- An aryl group can be introduced into R 8 .
- 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.
- Disintegrating agents such as sodium hydrogen carbonate, calcium carbonate, poly
- 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 compound of the present invention or a salt thereof can be formulated according to normal pharmaceutical practice using a pharmaceutically acceptable vehicle well known in the art as a carrier.
- a pharmaceutically acceptable vehicle well known in the art as a carrier.
- 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). And may be used in combination with a suitable solubilizer such as alcohol, specifically ethanol, polyalcohol such as propylene glycol, polyethylene glycol, nonionic surfactants such as polysorbate 80 TM and HCO-50.
- a suitable solubilizer such as alcohol, specifically ethanol, polyalcohol such as propylene glycol, polyethylene glycol, nonionic surfactants such as polysorbate 80 TM and 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. Alternatively, the dose can be selected in the range of 0.1 to 100 mg per administration, but is not necessarily limited to these values. 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.
- 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.
- Example 1 7-Op-Cyanobenzoyl-1,7-dideacetyl-1-O-isobutyrylpyrpyropen A (PRD119) a) Synthesis of 1,11-O- (ditertiary butylsilylene) -1,7,11-trideacetylpyripyropene A (b)
- the obtained residue was purified by neutral flash silica gel column chromatography (1 ⁇ 4, MeOH in CH 2 Cl 2 0.5-1.5%), and the fraction containing the product was concentrated.
- the obtained residue was dissolved in THF (0.5 mL), TBAF (100 ⁇ L, 1.0 M sol. In THF, 0.100 mmol) and AcOH (5.7 ⁇ L, 0.100 mmol) were added, and the mixture was stirred at room temperature for 30 minutes.
- the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by neutral flash silica gel column chromatography (1 ⁇ 5, MeOH in CH 2 Cl 2 2-3%), and the fraction containing the product was concentrated. did.
- the obtained residue was roughly purified by neutral flash silica gel column chromatography (1 ⁇ 4, MeOH in CH 2 Cl 2 0-1.5%), and the fraction containing the product was concentrated.
- the obtained residue was dissolved in THF (0.5 mL), Et 3 N ⁇ 3HF (18.0 ⁇ L, 113 ⁇ mol) was added, and the mixture was stirred at room temperature for 30 min.
- the reaction mixture was concentrated under reduced pressure, and the resulting residue was roughly purified by neutral flash silica gel column chromatography (1 ⁇ 5 + 1, MeOH in CH 2 Cl 2 3-10%) to obtain a product-containing fraction. The minutes were concentrated.
- the obtained residue was dissolved in DMF (0.5 mL), isobutyric anhydride (11.0 ⁇ L, 67.8 ⁇ mol), Et 3 N (19.0 ⁇ L, 136 ⁇ mol), and a catalytic amount of DMAP were added, and the mixture was stirred at room temperature for 45 minutes. .
- MeOH was added to the reaction solution to stop the reaction, and further diluted with EtOAc, the organic layer was washed with water and dried over anhydrous sodium sulfate. After filtering the solution, the filtrate was concentrated under reduced pressure.
- the obtained residue was purified by neutral flash silica gel column chromatography (1 ⁇ 4, MeOH in CH 2 Cl 2 0-1.5%) to obtain white foam PRD074 (10.6 mg, 3 steps, 60%). It was.
- the obtained residue was roughly purified by neutral flash silica gel column chromatography (1 ⁇ 15, MeOH in CH 2 Cl 2 0-1.5%), and the fraction containing the product was concentrated.
- the obtained residue was dissolved in THF (1.0 mL), Et 3 N ⁇ 3HF (39.0 ⁇ L, 241 ⁇ mol) was added, and the mixture was stirred at room temperature for 30 min.
- the reaction mixture was concentrated under reduced pressure, and the resulting residue was roughly purified by neutral flash silica gel column chromatography (1 ⁇ 5 + 1, MeOH in CH 2 Cl 2 3-10%) to obtain a product-containing fraction. The minutes were concentrated.
- the obtained residue was dissolved in DMF (1.0 mL), isobutyric anhydride (40.0 ⁇ L, 241 ⁇ mol), Et 3 N (67.0 ⁇ L, 482 ⁇ mol), and a catalytic amount of DMAP were added, and the mixture was stirred at room temperature for 30 minutes. .
- MeOH was added to the reaction solution to stop the reaction, and further diluted with EtOAc, the organic layer was washed with water and dried over anhydrous sodium sulfate. After filtering the solution, the filtrate was concentrated under reduced pressure.
- the obtained residue was purified by neutral flash silica gel column chromatography (1.5 ⁇ 5, MeOH in CH 2 Cl 2 0-1.5%) to obtain white foam PRD079 (37.0 mg, 3 steps, 60%). It was.
- the obtained residue was dissolved in THF (0.6 mL), Et 3 N ⁇ 3HF (11.1 ⁇ L, 68.3 ⁇ mol) was added, and the mixture was stirred at room temperature for 30 minutes.
- the reaction solution was concentrated under reduced pressure and roughly purified by neutral flash silica gel column chromatography (1 ⁇ 4, MeOH in CH 2 Cl 2 0-3%), and the fraction containing the product was concentrated.
- the obtained residue was dissolved in CH 2 Cl 2 (0.5 mL), Ac 2 O (4.6 ⁇ L, 48.5 ⁇ mol), Et 3 N (7.4 ⁇ L, 52.8 ⁇ mol), and a catalytic amount of DMAP were added. Stir for hours.
- o-toluenealdehyde 48.8 ⁇ L, 0.410 mmol
- PPTS 0.4 mg, 1.36 ⁇ mol
- DMF 0.5 mL
- EtOAc was added to the reaction solution for dilution, and the organic layer was washed with water and dried over anhydrous sodium sulfate. After filtering the solution, the filtrate was concentrated under reduced pressure. The obtained residue was purified by neutral flash silica gel column chromatography (1 ⁇ 3, MeOH in CH 2 Cl 2 0-5%), and the fraction containing the product was concentrated.
- the obtained residue was dissolved in CH 2 Cl 2 (0.5 mL) solution, p-cyanobenzoic acid (5.3 mg, 35.8 ⁇ mol), EDCI (10.3 mg, 53.7 ⁇ mol) and a catalytic amount of DMAP were added, Stir for hours. MeOH was added to the reaction solution to stop the reaction, and further diluted with EtOAc, the organic layer was washed with water and dried over anhydrous sodium sulfate. After filtering the solution, the filtrate was concentrated under reduced pressure. The obtained residue was purified by neutral flash silica gel column chromatography (1 ⁇ 3, MeOH in CH 2 Cl 2 0-1.5%) to obtain white foam PRD125 (11.2 mg, 2 steps, 60%). It was.
- o-toluenealdehyde 48.8 ⁇ L, 0.410 mmol
- PPTS 0.4 mg, 1.36 ⁇ mol
- DMF 0.5 mL
- EtOAc was added to the reaction solution for dilution, and the organic layer was washed with water and dried over anhydrous sodium sulfate. After filtering the solution, the filtrate was concentrated under reduced pressure. The obtained residue was purified by neutral flash silica gel column chromatography (1 ⁇ 3, MeOH in CH 2 Cl 2 0-5%), and the fraction containing the product was concentrated.
- o-anisaldehyde (73.6 ⁇ L, 0.607 mmol) and a catalytic amount of PPTS were added to a solution of a (18.5 mg, 40.3 ⁇ mol) in DMF (0.5 mL), and the mixture was stirred at room temperature for 24 hours.
- EtOAc was added to the reaction solution for dilution, and the organic layer was washed with water and dried over anhydrous sodium sulfate. After filtering the solution, the filtrate was concentrated under reduced pressure. The obtained residue was purified by neutral flash silica gel column chromatography (1 ⁇ 3, MeOH in CH 2 Cl 2 0-5%), and the fraction containing the product was concentrated.
- o-anisaldehyde (59.7 ⁇ L, 0.492 mmol) and a catalytic amount of PPTS were added to a DMF (0.5 mL) solution of a (15.0 mg, 32.7 ⁇ mol), and the mixture was stirred at room temperature for 24 hours.
- EtOAc was added to the reaction solution for dilution, and the organic layer was washed with water and dried over anhydrous sodium sulfate. After filtering the solution, the filtrate was concentrated under reduced pressure. The obtained residue was purified by neutral flash silica gel column chromatography (1 ⁇ 3, MeOH in CH 2 Cl 2 0-5%), and the fraction containing the product was concentrated.
- o-fluoroaldehyde 85.5 ⁇ L, 0.820 mmol
- a catalytic amount of PPTS were added to a DMF (0.5 mL) solution of a (25.0 mg, 54.5 ⁇ mol), and the mixture was stirred at room temperature for 24 hours.
- EtOAc was added to the reaction solution for dilution, and the organic layer was washed with water and dried over anhydrous sodium sulfate. After filtering the solution, the filtrate was concentrated under reduced pressure. The obtained residue was purified by neutral flash silica gel column chromatography (1 ⁇ 3, MeOH in CH 2 Cl 2 0-5%), and the fraction containing the product was concentrated.
- o-fluoroaldehyde 85.5 ⁇ L, 0.820 mmol
- a catalytic amount of PPTS were added to a DMF (0.5 mL) solution of a (25.0 mg, 54.5 ⁇ mol), and the mixture was stirred at room temperature for 24 hours.
- EtOAc was added to the reaction solution for dilution, and the organic layer was washed with water and dried over anhydrous sodium sulfate. After filtering the solution, the filtrate was concentrated under reduced pressure. The obtained residue was purified by neutral flash silica gel column chromatography (1 ⁇ 3, MeOH in CH 2 Cl 2 0-5%), and the fraction containing the product was concentrated.
- the reaction solution was concentrated under reduced pressure, and the resulting residue was roughly purified by neutral flash silica gel column chromatography (2 ⁇ 5, MeOH in CH 2 Cl 2 2-5%), and the fraction containing the product was purified. Concentrated. Dissolve the resulting residue in CH 2 Cl 2 (3.0 mL), add Ac 2 O (17.0 ⁇ L, 180 ⁇ mol), Et 3 N (27.4 ⁇ L, 197 ⁇ mol), and a catalytic amount of DMAP at 0 ° C. Stir for 4 hours. MeOH was added to the reaction solution to stop the reaction, and further diluted with EtOAc, the organic layer was washed with water and dried over anhydrous sodium sulfate. After filtering the solution, the filtrate was concentrated under reduced pressure. The resulting residue was purified by neutral flash silica gel column chromatography (2 ⁇ 5, MeOH in CH 2 Cl 2 0-3%) to obtain white foam PRD069 (137 mg, 4 steps, 44%). It was.
- Test Example 1 Analysis of stability to liver metabolic enzymes Stability of pyripyropene derivatives against liver metabolic enzymes was performed according to the method of Ishigami et al. (Drug Metab. Dispos., 30, 904-910, 2002). . The enzyme source was liver microsomes (manufactured by XenoTech) prepared from female SD rats.
- an ultrahigh performance liquid chromatography kit (system; Prominence, manufactured by Shimadzu Corp .: column; Shin-Pack XR-ODS, 2.0 mm ⁇ mm ⁇ 75 mm mm, 40 ° C., manufactured by Shimadzu Corporation) 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 peak area of each pyripyropene derivative was calculated using analysis software LCMS “solution” (manufactured by Shimadzu Corporation). The residual amount of each pyripyropene derivative at each reaction time was calculated with the peak area immediately before the reaction as 100%.
- the known compounds PPA, PRD007, PRD009, PRD021, PRD024, PRD025 and PRD026 have a half-life of 1 hour
- the known compound PPA used for comparison was pyripyropene A, and the remaining PRD007, PRD009, PRD021, PRD024, PRD025, PRD026, PRD043, and PRD056 were each compounds represented by the following formulae.
- 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). As an enzyme source of ACAT2, a membrane fraction derived from mouse liver microsomes was used. The mouse liver was homogenized in a buffer A [50 mM Tris-HCl solution (pH 7.8), 1 mM ethylenediaminetetraacetic acid and 1 mM phenylmethanesulfonyl fluoride] using a potter type homogenizer (Tokyo-RIKO).
- a buffer A 50 mM Tris-HCl solution (pH 7.8), 1 mM ethylenediaminetetraacetic acid and 1 mM phenylmethanesulfonyl fluoride
- 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 obtain 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).
- 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 (1,0.1,0.01,0.001,0.0001,0.00001 mg 10 ⁇ L / mL methanol solution) was added to buffer A to make a total volume of 200 ⁇ L, and the mixture was reacted at 37 ° C. for 5 minutes.
- 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 at the time of addition of test compound)-(background)] / [(radioactivity of control)-(background)]
- concentration that inhibits this enzyme activity by 50% IC 50 , inhibitory activity
- specific activity of the test compound relative to the known compound PRD043 that inhibits ACAT2 was calculated by the following formula.
- the compounds according to the present invention exhibit extremely high inhibitory activity against ACAT2.
- the novel compound according to the present invention not only exhibits a high ACAT2 inhibitory activity compared to known compounds, but also has a long half-life due to liver metabolic enzymes and is difficult to metabolize in the liver. continue. Therefore, the novel compound according to the present invention is expected to be useful for treating arteriosclerosis as a highly active and long-lasting ACAT2-selective inhibitor.
- 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
Description
Libby, J. Am. Coll. Cardiol., Vol.46, pp.1225-1228, 2005 Meuwese et al., Curr. Opin. Lipidol., Vol.17, pp.426-431, 2006 Chang et al., Acta. Biochim. Biophys. Sin., Vol.38, pp.151-156, 2006年 Farese, Arterioscler. Thromb. Vasc. Biol., Vol.26, pp. 1684-1686, 2006 Bell et al., Arterioscler. Thromb. Vasc. Biol., Vol.27, pp.1396-1402, 2007, Tomoda et al.,J. Antibiot., Vol.47, pp.148-153, 1994 Lada et al., J. Lipid. Res., Vol.45, pp.378-386, 2004
本発明の別の目的は、ACAT2を選択的に阻害することができ、かつ代謝によって分解されずに高い活性を示すことにより、動脈硬化症の予防または治療に有効な薬剤として有用な化合物を提供することである。
R1は、置換されていてもよい脂肪族、脂環式もしくは芳香族アシロキシ基、または式:-O-CH(R7)-R8で示される基を意味し、ここでR7は低級アルコキシ基を意味し、R8は置換されていてもよいアリール基を意味し、
R2およびR3は、
R2がカルボキシル基、低級アルコキシカルボニル基、芳香環上で置換されていてもよいアリールメチルカルバモイル基、または式:-CH2-R4で示される基を意味し、ここでR4は置換されていてもよい脂肪族、脂環式もしくは芳香族アシロキシ基を意味し、R3が置換されていてもよい脂肪族、脂環式もしくは芳香族アシロキシ基を意味し、但し、R4とR3の少なくとも一方はアセトキシ基以外の基であるか、或いは
R2とR3とが一緒になって-O-CH(R5)-O-で示される基を意味し、R5は置換されていてもよいアリール基を意味する。
「アリール」は芳香環上に1または2以上の置換基を有している置換アリール基であってもよい。芳香環上の置換基の例としては、低級アルキル、低級アルコキシ、ハロゲン(F、Cl、BrまたはI)、ニトロ、シアノ、アミノ(モノ-およびジ-低級アルキルアミノを含む)が例示される。
上記スキーム中の化合物(a)は、常法(例えば、Obata et al., J. Antibiot., Vol.49, pp.1133-1148, 1996)により合成できる。
化合物(i)から化合物(j)への変換は以下の方法で行うことができる。即ち、化合物(i)に対して1当量または過剰量の対応するアミン、ならびに1当量または過剰量の縮合剤(好ましくは、ベンゾトリアゾール-1-イルオキシトリスジメチルアミノホスホニウムヘキサフルオロホスフェート/BOP)ならびに0.5当量または過剰量の有機塩基(好ましくはジメチルアミノピリジン)の存在下、ジクロロメタン、ジメチルホルムアミド、テトラヒドロフラン、アセトニトリル等またはそれらの混合溶媒中で、室温において30分から2日間反応させた後、通常の後処理にかけることにより化合物(j)を得ることができる。
尚、上記スキームではR3をアセトキシ基としているが、化合物(k)から化合物(l)への変換の際に対応する酸無水物を用いることで、アセトキシ基以外のアシロキシ基をR3に導入することができる。
上記スキーム中の化合物(m)は、常法(例えば、Obata et al., J. Antibiot., Vol.49, pp. 1149-1156, 1996)により合成できる。
本発明に係る一般式(IV)で示される化合物のうち、R1が式:-O-CH(R7)-R8で示される基(式中、R7はメトキシ基を意味し、R8はp-メトキシフェニル基を意味する)であって、R5がフェニル基である化合物は、以下のスキームに従って製造することができる。
化合物(m)から化合物(o)への変換は以下の方法で行うことができる。即ち、化合物(m)に対して10当量または過剰量のp-メトキシベンズアルデヒド・ジメチルアセタールならびに触媒量の有機酸(好ましくはp-トルエンスルホン酸ピリジニウム)存在下、ジメチルホルムアミド溶媒中で、室温において12時間反応させた後、通常の後処理にかけることにより、化合物(o)を得ることができる。
本発明はまた、上記化合物またはその医薬に許容される塩、溶媒和物もしくは水和物を有効成分とするACAT2阻害剤、ならびに上記化合物またはその医薬に許容される塩、溶媒和物もしくは水和物と医薬に許容される担体とを含むACAT2阻害用薬剤組成物も提供する。
実施例1
7-O-p-シアノベンゾイル-1,7-ジデアセチル-1-O-イソブチリルピリピロペンA (PRD119)
a) 1,11-O-(ジターシャリーブチルシリレン)-1,7,11-トリデアセチルピリピロペンA (b) の合成
FAB-LRMS m/z 727 (MH+); FAB-HRMS (m-NBA) calcd. for C41H50N2O8Si727.3415 (MH+), found 727.3428 (MH+)。
IR (KBr) 3456, 2942, 2890, 2862, 2235, 1716, 1643, 1579, 1475, 1274, 1112 cm-1;
1H NMR (CDCl3, 300 MHz) δ 8.97 (d, 1H, H-2", J = 2.4 Hz), 8.65 (dd, 1H, H-6", J = 1.8, 5.1 Hz), 8.21 (d, 2H, H-Ar, J = 8.7 Hz), 8.09-8.04 (m, 1H, H-4"), 7.78 (d, 2H, H-Ar, J = 8.7 Hz), 7.39-7.35 (m, 1H, H-5"), 6.45 (s, 1H, H-5'), 5.36 (dd, 1H, H-7, J = 4.8, 10.8 Hz), 5.03 (d, 1H, H-13, J = 3.0 Hz), 4.17 (dd, 1H, H-1, J = 7.8, 8.4 Hz), 3.60 (dd, 1H, H-11a, J = 3.6, 10.5 Hz), 3.31 (dd, 1H, H-11b, J = 3.6, 10.5 Hz), 3.03 (br s, 1H, OH-13), 2.17-1.09 (m, 8H, H-2, 3, 5, 8, 9), 1.85 (s, 3H, Me), 1.47 (s, 3H, Me), 1.07-1.05 (m, 18H, tBu x 2), 0.74 (s, 3H, Me);
13C NMR (CDCl3, 100 MHz) δ 164.05, 163.90, 162.11, 157.22, 151.42, 146.76, 134.00, 132.93, 132.28, 130.16, 127.11, 123.60, 117.82, 116.62, 103.12, 99.31, 83.46, 83.26, 79.91, 73.73, 63.91, 60.08, 54.70, 44.02, 43.28, 40.64, 37.75, 36.34, 29.01, 27.70, 27.17, 27.06, 26.29, 25.45, 20.66, 20.50, 20.28, 20.13, 17.51, 16.68, 12.72;
ESI-LRMS m/z 769 (M+Na+); ESI-HRMS (MeOH) calcd. for C41H51FN2NaO11Si769.3296 (M+Na+), found 769.3261 (M+Na+)。
ESI-LRMS m/z 651 (M+Na+); ESI-HRMS (MeOH) calcd. for C35H36N2NaO9 651.2319 (M+Na+), found 651.2231 (M+Na+)。
ESI-LRMS m/z 699 (MH+); ESI-HRMS (TFA-Na) calcd. for C39H43N2O10 699.2918 (MH+), found 699.2903 (MH+)。
7-O-p-シアノベンゾイル-1,7-ジデアセチル-1-O-ベンゾイルピリピロペンA (PRD121) の合成
ESI-LRMS m/z 755 (M+Na+); ESI-HRMS (MeOH) calcd. for C42H40N2NaO10 755.2581 (M+Na+), found 755.2587 (M+Na+)。
7-O-p-シアノベンゾイル-1,7-ジデアセチル-11-O-イソブチリルピリピロペンA (PRD081) の合成
ESI-LRMS m/z 699 (MH+); ESI-HRMS (TFA-Na) calcd. for C39H43N2O10 699.2918 (MH+), found 699.2914 (MH+)。
7-O-p-シアノベンゾイル-7,11-ジデアセチル-11-O-ベンゾイルピリピロペンA (PRD143) の合成
ESI-LRMS m/z 755 (M+Na+); ESI-HRMS (TFA-Na) calcd. for C42H40N2NaO10 755.2581 (M+Na+), found 755.2574 (M+Na+)。
7-O-シクロヘキサンカルボニル-1,11-O-ジイソブチリル-1,7,11-トリデアセチルピリピロペンAの合成 (PRD074)
ESI-LRMS m/z 730 (M+Na+); ESI-HRMS (TFA-Na) calcd. for C40H53NNaO10 730.3567 (M+Na+), found 730.3554 (M+Na+)。
7-O-p-ニトロベンゾイル-1,11-O-ジイソブチリル-1,7,11-トリデアセチルピリピロペンAの合成 (PRD079)
ESI-LRMS m/z 769 (M+Na+); ESI-HRMS (TFA-Na) calcd. for C40H46N2NaO12 769.2948 (M+Na+), found 769.2941 (M+Na+)。
7-O-p-シアノベンゾイル-1,11-O-ジベンゾイル-1,7,11-トリデアセチルピリピロペンA (PRD166) の合成
a) 7-O-p-シアノベンゾイル-1,7,11-トリデアセチルピリピロペンA (r) の合成
1H NMR (DMSO-d6, 300 MHz) δ 9.00 (dd, 1H, H-2", J = 0.6, 2.4 Hz), 8.62 (dd, 1H, H-6", J = 1.5, 4.5 Hz), 8.22-8.17 (m, 3H, H-4", Ar), 8.07-8.03 (m, 2H, H-Ar), 7.49-7.44 (m, 1H, H-5"), 6.84 (s, 1H, H-5'), 5.44 (d, 1H, OH-11, J = 4.5 Hz), 5.18 (dd, 1H, H-7, J = 4.8, 11.4 Hz), 4.80 (dd, 1H, H-13, J = 3.3, 5.4 Hz), 4.52 (t, 1H, OH-1, J = 1.5 Hz), 4.26 (d, 1H, OH-13, J = 2.1 Hz), 3.46 (dd, 1H, H-11a, J = 5.4, 10.8 Hz), 3.36-3.27 (m, 1H, H-1), 3.01 (dd, 1H, H-11b, J = 4.5, 10.8 Hz), 2.07-1.32 (m, 8H, H-2, 3, 5, 8, 9), 1.80 (s, 3H, Me), 1.34 (s, 3H, Me), 0.58 (s, 3H, Me);
FAB-LRMS m/z 587 (MH+)。
ESI-LRMS m/z 795 (MH+); ESI-HRMS (TFA-Na) calcd. for C47H43N2O10 795.2918 (MH+), found 795.2916 (MH+)。
7-O-p-シアノベンゾイル-1,11-O-ジヘキサノイル-1,7,11-トリデアセチルピリピロペンA (PRD167) の合成
ESI-LRMS m/z 805 (M+Na+); ESI-HRMS (TFA-Na) calcd. for C45H54N2NaO10 805.3676 (M+Na+), found 805.3672 (M+Na+)。
11-O-ベンゾイル-11-デアセチルピリピロペンA (PRD177) の合成
a) 1,11-O-(ジターシャリーブチルシリレン)-1,11-ジデアセチルピリピロペンA (s) の合成
ESI-LRMS m/z 662 (M+Na+); ESI-HRMS (MeOH) calcd. for C35H49NNaO8Si662.3125 (M+Na+), found 662.3136 (M+Na+)。
1H NMR (CDCl3, 300 MHz) δ 9.02 (br s, 1H, H-2"), 8.67 (br d, 1H, H-6", J = 4.5 Hz), 8.12-8.08 (m, 1H, H-4"), 7.40 (dd, 1H, H-5", J = 4.8, 7.8 Hz), 6.49 (s, 1H, H-5'), 5.07 (dd, 1H, H-7, J = 4.8, 7.5 Hz), 4.99 (d, 1H, H-13, J = 2.7 Hz), 4.16 (t, 1H, H-1, J = 7.8 Hz), 3.56 (d, 1H, H-11a, J = 10.8 Hz), 3.31 (d, 1H, H-11b, J = 10.8 Hz), 3.18 (br s, 1H, OH-13), 2.53 (br s, 1H, OH-13), 2.12-1.12 (m, 8H, H-2, 3, 5, 8, 9), 2.17 (s, 3H, Ac), 1.71 (s, 3H, Me), 1.42 (s, 3H, Me), 1.05-1.03 (m, 18H, tBu x 2), 0.71 (s, 3H, Me);
ESI-LRMS m/z 682 (M+Na+); ESI-HRMS (TFA-Na) calcd. for C35H50FNNaO8Si682.3187 (M+Na+), found 682.3192 (M+Na+)。
ESI-LRMS m/z 668 (M+Na+); ESI-HRMS (TFA-Na) calcd. for C36H39NNaO10 668.2472 (M+Na+), found 668.2456 (M+Na+)。
1,11-O-ジイソブチリル-1,11-デアセチルピリピロペンA (PRD187) の合成
ESI-LRMS m/z 662 (M+Na+); ESI-HRMS (TFA-Na) calcd. for C35H45NNaO10 662.2941 (M+Na+), found 662.2932 (M+Na+)。
1,11-O-ベンジリデン-7-O-シクロヘキサンカルボニル-1,7,11-トリデアセチルピリピロペンA (PRD080) の合成
ESI-LRMS m/z 678 (M+Na+); ESI-HRMS (TFA-Na) calcd. for C39H45NNaO8 678.3043 (M+Na+), found 678.3066 (M+Na+)。
1,11-O-ベンジリデン-7-O-ベンゾイル-1,7,11-トリデアセチルピリピロペンA (PRD122) の合成
ESI-LRMS m/z 672 (M+Na+); ESI-HRMS (TFA-Na) calcd. for C39H39NaNO8 672.2573 (M+Na+), found 675.2587 (M+Na+)。
1,11-O-ベンジリデン-1,11-ジデアセチルピリピロペンA (PRD186) の合成
ESI-LRMS m/z 610 (M+Na+); ESI-HRMS (TFA-Na) calcd. for C34H37NaNO8 610.2417 (M+Na+), found 610.2405 (M+Na+)。
1,11-O-p-ジメチルアミノベンジリデン-7-O-p-シアノベンゾイル-1,7,11-トリデアセチルピリピロペンA (PRD123) の合成
ESI-LRMS m/z 718 (MH+); ESI-HRMS (TFA-Na) calcd. for C42H44N3O8 718.3128 (MH+), found 718.3145 (M+Na+)。
1,11-O-o-メチルベンジリデン-7-O-p-シアノベンゾイル-1,7,11-トリデアセチルピリピロペンA (PRD125) の合成
ESI-LRMS m/z 689 (MH+); ESI-HRMS (TFA-Na) calcd. for C41H41N2O8 689.2863 (MH+), found 689.2885 (MH+)。
1,11-O-p-メチルベンジリデン-7-O-p-シアノベンゾイル-1,7,11-トリデアセチルピリピロペンA (PRD126) の合成
ESI-LRMS m/z 689 (MH+); ESI-HRMS (TFA-Na) calcd. for C41H41N2O8 689.2863 (MH+), found 689.2858 (MH+)。
1,11-O-o-メチルベンジリデン-7-O-p-フルオロベンゾイル-1,7,11-トリデアセチルピリピロペンA (PRD155) の合成
ESI-LRMS m/z 704 (M+Na+); ESI-HRMS (TFA-Na) calcd. for C40H40FNNaO8 704.2636 (M+Na+), found 704.2636 (M+Na+);
実施例18
1,11-O-p-メチルベンジリデン-7-O-p-フルオロベンゾイル-1,7,11-トリデアセチルピリピロペンA (PRD156) の合成
ESI-LRMS m/z 704 (M+Na+); ESI-HRMS (TFA-Na) calcd. for C40H40FNNaO8 704.2636 (M+Na+), found 704.2646 (M+Na+)。
1,11-O-m-メチルベンジリデン-7-O-p-シアノベンゾイル-1,7,11-トリデアセチルピリピロペンA (PRD157) の合成
ESI-LRMS m/z 689 (MH+); ESI-HRMS (TFA-Na) calcd. for C41H41N2O8 689.2863 (MH+), found 689.2864 (MH+)。
1,11-O-m-メチルベンジリデン-7-O-p-フルオロベンゾイル-1,7,11-トリデアセチルピリピロペンA (PRD158) の合成
ESI-LRMS m/z 704 (M+Na+); ESI-HRMS (TFA-Na) calcd. for C40H40FNNaO8 704.2636 (M+Na+), found 704.2636 (M+Na+)。
1,11-O-o,p-ジメチルベンジリデン-7-O-p-シアノベンゾイル-1,7,11-トリデアセチルピリピロペンA (PRD159) の合成
FAB-LRMS m/z 703 (MH+); FAB-HRMS (CHCl3) calcd. for C42H43N2O8 703.3019 (MH+), found 703.3039 (MH+)。
1,11-O-o,p-ジメチルベンジリデン-7-O-p-フルオロベンゾイル-1,7,11-トリデアセチルピリピロペンA (PRD160) の合成
ESI-LRMS m/z 718 (M+Na+); ESI-HRMS (TFA-Na) calcd. for C41H42FNNaO8 718.2792 (M+Na+), found 718.2798 (M+Na+)。
1,11-O-o-メトキシベンジリデン-7-O-p-シアノベンゾイル-1,7,11-トリデアセチルピリピロペンA (PRD161) の合成
ESI-LRMS m/z 727 (M+Na+); ESI-HRMS (TFA-Na) calcd. for C41H40N2NaO9 727.2632 (M+Na+), found 727.2634 (M+Na+)。
1,11-O-o-メトキシベンジリデン-7-O-p-フルオロベンゾイル-1,7,11-トリデアセチルピリピロペンA (PRD162) の合成
ESI-LRMS m/z 720 (M+Na+); ESI-HRMS (TFA-Na) calcd. for C40H40FNNaO9 720.2585 (M+Na+), found 720.2582 (M+Na+)。
1,11-O-o-フルオロベンジリデン-7-O-p-シアノベンゾイル-1,7,11-トリデアセチルピリピロペンA (PRD163) の合成
ESI-LRMS m/z 693 (MH+); ESI-HRMS (TFA-Na) calcd. for C40H38FN2O8 693.2612 (MH+), found 693.2607 (MH+)。
1,11-O-o-フルオロベンジリデン-7-O-p-フルオロベンゾイル-1,7,11-トリデアセチルピリピロペンA (PRD164) の合成
ESI-LRMS m/z 686 (MH+); ESI-HRMS (TFA-Na) calcd. for C39H38F2NO8 686.2565 (MH+), found 686.2544 (MH+)。
1,11-O-o-ナフチリデン-7-O-p-シアノベンゾイル-1,7,11-トリデアセチルピリピロペンA (PRD180) の合成
ESI-LRMS m/z 725 (MH+); ESI-HRMS (TFA-Na) calcd. for C44H41N2O8 725.2863 (MH+), found 725.2885 (MH+)。
1,11-O-o,o-ジメチルベンジリデン-7-O-p-シアノベンゾイル-1,7,11-トリデアセチルピリピロペンA (PRD181) の合成
ESI-LRMS m/z 703 (MH+); ESI-HRMS (TFA-Na) calcd. for C42H43N2O8 703.3019 (MH+), found 703.3035 (MH+)。
7-O-p-シアノベンゾイル-11-デアセトキシメチル-7-デアセチル-11-カルボキシルピリピロペンA (PRD069) の合成
ESI-LRMS m/z 643 (MH+); ESI-HRMS (TFA-Na) calcd. for C35H35N2O10 643.2292 (MH+), found 643.2285 (MH+)。
7-O-p-シアノベンゾイル-11-デアセトキシメチル-7-デアセチル-11-メトキシカルボニルピリピロペンA (PRD070) の合成
ESI-LRMS m/z 679 (M+Na+); ESI-HRMS (TFA-Na) calcd. for C36H36N2NaO10 679.2268 (M+Na+), found 679.2254 (M+Na+)。
7-O-p-シアノベンゾイル-11-デアセトキシメチル-7-デアセチル-11-(2,4-ジメトキシベンジルアミノ)カルボニルピリピロペンA (PRD071) の合成
ESI-LRMS m/z 814 (M+Na+); ESI-HRMS (TFA-Na) calcd. for C44H45N3NaO11 814.2972 (M+Na+), found 814.2954 (M+Na+)。
1,11-O-ベンジリデン-1,7,11-トリデアセチル-7-O-(1-メトキシ-1-p-メトキシフェニル)メチルピリピロペンA (PRD073) の合成
試験例1:肝臓の代謝酵素に対する安定性の解析
肝臓の代謝酵素に対するピリピロペン誘導体の安定性は、Ishigamiらの方法 (Drug Metab. Dispos.、30巻、904-910頁、2002年) に従って実施した。酵素源は雌性のSD系ラットより調製した肝ミクロソーム (XenoTech社製) を用いた。肝ミクロソーム180 pmol (P450)/mL、1 mMエチレンジアミンテトラ酢酸 (和光純薬社製)、グルコース6リン酸 (SIGMA社製)、1 mMニコチンアミドアデニンジヌクレオチドリン酸 (SIGMA社製)、1.5 unitグルコース6リン酸脱水素酵素 (SIGMA社製) と試験する各ピリピロペン誘導体 (6μg/mL) を100 mMのリン酸ナトリウム緩衝液 (pH 7.4) に加えて、全量を200μLとし、37℃で30、120、360、540分間反応させた。
[ACAT2の酵素源の調製方法]
Uelmenらの方法(J. Biol. Chem. 270巻、26192-26201頁、1995年)を一部改変して酵素源を調製した。ACAT2の酵素源としては、マウス肝臓ミクロソーム由来の膜画分を用いた。マウス肝臓は緩衝液A[50 mMトリス塩酸液(pH 7.8)、1 mMエチレンジアミン四酢酸及び1 mMフェニルメタンスルフォニルフルオリド]中でポッター型ホモジナイザー(Tokyo-RIKO社製)を用いてホモジナイズした。これを12000×gで遠心した上清を100000×gで超遠心した沈さをミクロソーム画分とし、この画分を5 mg/mLの蛋白質濃度となるように緩衝液Aで調製した。
各実施例で調製したピリピロペン誘導体のACAT活性の測定は、Fieldらの方法(Gastroenterology、83巻、873-880頁、1982年)に従って実施した。上記酵素源200μg蛋白量、200 mM牛血清アルブミン、[1-14C]オレオイルコエンザイムA(最終濃度 170μM、0.090μCi)と試験する各ピリピロペン誘導体(1、0.1、0.01、0.001、0.0001、0.00001 mg/mLのメタノール溶液を10μL)を緩衝液A中に加えて全量200μLとし、37℃で5分間反応させた。ピリピロペン誘導体の代わりにメタノール10μLを加えたものをコントロールとした。
本酵素活性を50%阻害する濃度(IC50、阻害活性)を算定した。さらに、ACAT2を阻害する既知化合物PRD043 (供田洋ら、ACAT2阻害活性を有するピリピロペン誘導体、WO 2009/081957) に対する試験化合物の比活性を以下の式により算定した。
阻害活性と比活性について、得られた結果を下記の表2に示した。表の符号の意味は次の通りである。
***:阻害活性<0.5 nM
**:0.5 nM≦阻害活性<1.0 nM
*:1.0 nM≦阻害活性<10.0 nM
(*):10.0 nM≦阻害活性
比活性:(試験化合物のIC50)/(PRD043のIC50)
++++:20<比活性
+++:10<比活性≦20
++:5<比活性≦10
+:1<比活性≦5
-:0.1≦比活性<1
--:0.01≦比活性<0.1
Claims (7)
- 下記一般式(I)で示される化合物ならびにその薬学上許容される塩、溶媒和物および水和物。
式中、
R1は、置換されていてもよい脂肪族、脂環式もしくは芳香族アシロキシ基、または式:-O-CH(R7)-R8で示される基を意味し、ここでR7は低級アルコキシ基を意味し、R8は置換されていてもよいアリール基を意味し、
R2およびR3は、
R2がカルボキシル基、低級アルコキシカルボニル基、芳香環上で置換されていてもよいアリールメチルカルバモイル基、または式:-CH2-R4で示される基を意味し、ここでR4は置換されていてもよい脂肪族、脂環式もしくは芳香族アシロキシ基を意味し、R3が置換されていてもよい脂肪族、脂環式もしくは芳香族アシロキシ基を意味し、但し、R4とR3の少なくとも一方はアセトキシ基以外の基であるか、或いは
R2とR3とが一緒になって-O-CH(R5)-O-で示される基を意味し、R5は置換されていてもよいアリール基を意味する。 - 請求項1~4のいずれかに記載の化合物またはその薬学上許容される塩、溶媒和物もしくは水和物を有効成分とするACAT2阻害剤。
- ACAT2阻害に有効な量の請求項1~4のいずれかに記載の化合物またはその薬学上許容される塩、溶媒和物もしくは水和物と医薬に許容される担体とを含むACAT2阻害用薬剤組成物。
- ACAT2阻害に有効な量の請求項1~4のいずれかに記載の化合物またはその薬学上許容される塩、溶媒和物もしくは水和物を、必要とする患者に投与することを含む、ACAT2が関与する疾患の予防又は治療方法。
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WO2015198966A1 (ja) * | 2014-06-24 | 2015-12-30 | 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 |
WO2020063663A1 (zh) * | 2018-09-27 | 2020-04-02 | 中国科学院上海药物研究所 | 一类三环类似物、其制备方法和用途 |
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WO2015198966A1 (ja) * | 2014-06-24 | 2015-12-30 | 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 |
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 |
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BR112012024816A2 (pt) | 2019-09-24 |
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CA2795064A1 (en) | 2011-10-06 |
JP5592482B2 (ja) | 2014-09-17 |
US20130085163A1 (en) | 2013-04-04 |
JPWO2011122468A1 (ja) | 2013-07-08 |
CN102947313A (zh) | 2013-02-27 |
US9187492B2 (en) | 2015-11-17 |
EP2554546B1 (en) | 2017-07-19 |
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