JPWO2010150739A1 - Acat2阻害活性を示す水酸基含有ピリピロペン誘導体 - Google Patents
Acat2阻害活性を示す水酸基含有ピリピロペン誘導体 Download PDFInfo
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- JPWO2010150739A1 JPWO2010150739A1 JP2011519884A JP2011519884A JPWO2010150739A1 JP WO2010150739 A1 JPWO2010150739 A1 JP WO2010150739A1 JP 2011519884 A JP2011519884 A JP 2011519884A JP 2011519884 A JP2011519884 A JP 2011519884A JP WO2010150739 A1 JPWO2010150739 A1 JP WO2010150739A1
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- 229920000609 methyl cellulose Polymers 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 230000003228 microsomal effect Effects 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N n-hexanoic acid Natural products CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 231100000957 no side effect Toxicity 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- XDUHQPOXLUAVEE-BPMMELMSSA-N oleoyl-CoA Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)CCCCCCC\C=C/CCCCCCCC)O[C@H]1N1C2=NC=NC(N)=C2N=C1 XDUHQPOXLUAVEE-BPMMELMSSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000001301 oxygen Chemical group 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 229940021222 peritoneal dialysis isotonic solution Drugs 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 229960001309 procaine hydrochloride Drugs 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- CAEWJEXPFKNBQL-UHFFFAOYSA-N prop-2-enyl carbonochloridate Chemical compound ClC(=O)OCC=C CAEWJEXPFKNBQL-UHFFFAOYSA-N 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 229940043274 prophylactic drug Drugs 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000020374 simple syrup Nutrition 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000007974 sodium acetate buffer Substances 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229960002920 sorbitol Drugs 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000000891 standard diet Nutrition 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 239000011593 sulfur Chemical group 0.000 description 1
- 229910052717 sulfur Chemical group 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- FKHIFSZMMVMEQY-UHFFFAOYSA-N talc Chemical compound [Mg+2].[O-][Si]([O-])=O FKHIFSZMMVMEQY-UHFFFAOYSA-N 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 238000001195 ultra high performance liquid chromatography Methods 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
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
- C07D493/02—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
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- 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
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- 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
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- 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
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
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- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
Description
本発明者らは、新規なピリピロペンA誘導体が、動脈硬化予防治療薬の標的として注目されているACAT2に対して極めて高い阻害活性を有していることを見いだし、本発明を完成するに至った。
「低級アシロキシ」の例としては、アセトキシ、n-プロピオニルオキシ、i-プロピオニルオキシ、n-ブチリルオキシ、i-ブチリルオキシ、s-ブチリルオキシ、t-ブチリルオキシ、n-バレリルオキシ、ネオバレリルオキシ、i-バレリルオキシ、t-バレリルオキシ、n-カプロイルオキシ、i-カプロイルオキシ、シクロヘキシルカルボニルオキシ等が挙げられる。低級アシロキシ基は、水素原子が他の官能基で置換されているものも包含する。低級アシロキシ基に存在しうる官能基の例としては、ハロゲン、シアノ基、低級アルコキシ基などが挙げられる。
上記スキーム中の式(a)の化合物は、常法(例えば、Obata等、J. Antibiot. 49巻、1133-1148頁、1996年)により合成できる。
上記スキーム中の化合物(c)は、第1スキームにおいて説明したのと同様の手法で合成できる。
上記スキーム中の化合物(d)は、第1スキームについて説明したのと同様の手法で合成できる。
化合物(k)から化合物(l)への変換は以下の方法で行うことができる。即ち、(k)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(l)を得ることができる。
尚、上記スキームではR3をプロピルアミノ基としているが、化合物(k)から化合物(l)への変換の際に対応するアミンを用いることで、プロピルアミノ基以外のアルキルアミノ基またはアリールアミノ基もしくはヘテロアリールアミノ基を導入することができる。
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-ジデアセチルピリピロペンA (PRD118) の合成
a) 1,11-O-(ジ-tert-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
ESI-LRMS m/z 620 (M+Na+); ESI-HRMS (MeOH) calcd. for C33H47NNaO7Si 620.3020 (M+Na+), found 620.2968 (M+Na+)。
FAB-LRMS m/z 727 (MH+); FAB-HRMS (m-NBA) calcd. for C41H51N2O8Si727.3415 (MH+), found 727.3428 (MH+)。
[α]24 D +101.07 (c 1.0, CHCl3);
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+)。
[α]24 D +85.04 (c 1.0, CHCl3);
IR (KBr) 3451, 2938, 2888, 2861, 2233, 1725, 1643, 1577, 1473, 1273, 1101 cm-1;
1H NMR (CDCl3, 400 MHz) δ 8.96 (dd, 1H, H-2", J = 0.4, 1.2 Hz), 8.66 (dd, 1H, H-6", J = 1.6, 4.8 Hz), 8.22 (d, 2H, H-Ar, J = 8.8 Hz), 8.08-8.05 (m, 1H, H-4"), 7.80 (d, 2H, H-Ar, J = 8.8 Hz), 7.40-7.36 (m, 1H, H-5"), 6.40 (s, 1H, H-5'), 5.31 (dd, 1H, H-7, J = 5.2, 12.0 Hz), 5.04 (br s, 1H, H-13), 3.90 (d, 1H, H-11a, J = 10.4 Hz), 3.78 (dd, 1H, H-1, J = 7.6, 8.8 Hz), 3.56 (d, 1H, H-11b, J = 10.4 Hz), 3.21 (br s, 1H, OH-13), 2.34 (br s, 1H, OH-1), 2.21-1.26 (m, 8H, H-2, 3, 5, 8, 9), 1.85 (s, 3H, Me), 1.48 (s, 3H, Me), 1.09-1.08 (m, 18H, tBu x 2), 0.81 (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 C41H51FN2NaO11Si 769.3296 (M+Na+), found 769.3265 (M+Na+)。
ESI-LRMS m/z 651 (M+Na+); ESI-HRMS (MeOH) calcd. for C35H36N2NaO9 651.2319 (M+Na+), found 651.2231 (M+Na+)。
11-イソブチリル-7-O-p-シアノベンゾイル-1,7-ジデアセチルピリピロペンA (PRD171) の合成
ESI-LRMS m/z 657 (MH+); ESI-HRMS (MeOH) calcd. for C37H41N2O9 657.2812 (MH+), found 657.2803 (MH+)。
7-O-p-シアノベンゾイル-1,7-ジデアセチル-11-ヘキサノイルピリピロペンA (PRD173) の合成
ESI-LRMS m/z 685 (MH+); ESI-HRMS (MeOH) calcd. for C39H45N2O9 685.3125 (MH+), found 685.3087 (MH+)。
7-O-p-シアノベンゾイル-1,7-ジデアセチル-11-ベンゾイルピリピロペンA (PRD172) の合成
ESI-LRMS m/z 691 (MH+); ESI-HRMS (MeOH) calcd. for C40H39N2O9 691.2656 (MH+), found 691.2622 (MH+)。
7-O-p-シアノベンゾイル-7,11-ジデアセチルピリピロペンA (PRD136)の合成
1H NMR (CDCl3, 400 MHz) δ 8.96 (d, 1H, H-2", J = 2.0 Hz), 8.63 (dd, 1H, H-6", J = 1.6, 4.8 Hz), 8.20 (d, 2H, H-Ar, J = 8.4 Hz), 8.07-8.04 (m, 1H, H-4"), 7.79 (d, 2H, H-Ar, J = 8.4 Hz), 7.39-7.36 (m, 1H, H-5"), 6.41 (s, 1H, H-5'), 5.40 (dd, 1H, H-7, J = 5.2, 11.6 Hz), 4.95 (dd, 1H, H-1, J = 4.4, 11.6 Hz), 5.02 (d, 1H, H-13, J = 2.8 Hz), 3.29 (d, 1H, H-11a, J = 12.0 Hz), 3.02-3.00 (m, 2H, H-11b, OH-13), 2.73 (br s, 1H, OH-1), 2.24-1.17 (m, 8H, H-2, 3, 5, 8, 9), 2.10 (s, 3H, Ac), 1.85 (s, 3H, Me), 1.48 (s, 3H, Me), 0.81 (s, 3H, Me);
ESI-LRMS m/z 651 (M+Na+); ESI-HRMS (MeOH) calcd. for C35H36N2NaO9 651.2319 (M+Na+), found 651.2331 (M+Na+)。
1-デアセチルピリピロペンA (PRD147) の合成
a) 1,11-O-(ジ-tert-ブチルシリレン)-1,11-ジデアセチルピリピロペンA (p) の合成
ESI-LRMS m/z 662 (M+Na+); ESI-HRMS (MeOH) calcd. for C35H49NNaO8Si 662.3125 (M+Na+), found 662.3136 (M+Na+)。
(q)のデータ (11-OH)
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 (MeOH) calcd. for C35H50FNNaO8Si 682.3187 (M+Na+), found 682.3192 (M+Na+)。
1H NMR (CDCl3, 300 MHz) δ 9.02 (br s, 1H, H-2"), 8.68 (br s, 1H, H-6"), 8.12-8.08 (m, 1H, H-4"), 7.40 (dd, 1H, H-5", J = 5.1, 8.1 Hz), 6.47 (s, 1H, H-5'), 5.06-5.00 (m, 2H, H-7, 13), 3.88 (d, 1H, H-11a, J = 10.2 Hz), 3.74 (t, 1H, H-1, J = 7.5 Hz), 3.55 (d, 1H, H-11b, J = 10.2 Hz), 2.98 (br s, 1H, OH-13), 2.14-1.25 (m, 8H, H-2, 3, 5, 8, 9), 2.16 (s, 3H, Ac), 1.70 (s, 3H, Me), 1.41 (s, 3H, Me), 1.07-1.06 (m, 18H, tBu x 2), 0.80 (s, 3H, Me);
ESI-LRMS m/z 682 (M+Na+); ESI-HRMS (MeOH) calcd. for C35H50FNNaO8Si 682.3187 (M+Na+), found 682.3207 (M+Na+)。
1H NMR (CDCl3, 400 MHz) δ 9.01 (br s, 1H, H-2"), 8.68 (br d, 1H, H-6", J = 2.0 Hz), 8.12-8.09 (m, 1H, H-4"), 7.42-7.39 (m, 1H, H-5"), 6.45 (s, 1H, H-5'), 5.03-4.99 (m, 2H, H-7, 13), 3.73-3.40 (m, 2H, H-1, 11a), 3.41 (d, 1H, H-11b, J = 10.8 Hz), 2.85 (br s, 1H, OH-13), 2.19-1.13 (m, 8H, H-2, 3, 5, 8, 9), 2.17 (s, 3H, Ac), 1.42 (s, 3H, Me), 1.25 (s, 3H, Me), 0.89 (s, 3H, Me);
ESI-LRMS m/z 522 (M+Na+); ESI-HRMS (MeOH) calcd. for C27H33NNaO8 522.2104 (M+Na+), found 522.2071 (M+Na+)。
1H NMR (CDCl3, 400 MHz)δ 9.02 (dd, 1H, H-2"), 8.68 (dd, 1H, H-6", J = 1.6, 4.8 Hz), 8.11-8.08 (m, 1H, H-4"), 7.42-7.39 (m, 1H, H-5"), 6.45 (s, 1H, H-5'), 5.06-5.00 (m, 2H, H-7, 13), 4.24 (d, 1H, H-11a, J = 11.6 Hz), 3.70 (d, 1H, H-11b, J = 11.6 Hz), 3.46 (dd, 1H, H-1, J = 6.0, 10.0 Hz), 3.01 (br s, 1H, OH-13), 2.33 (br s, 1H, OH-1), 2.16-1.25 (m, 8H, H-2, 3, 5, 8, 9), 2.17 (s, 3H, Ac), 2.11 (s, 3H, Ac), 1.70 (s, 3H, Me), 1.42 (s, 3H, Me), 0.82 (s, 3H, Me);
ESI-LRMS m/z 564 (M+Na+); ESI-HRMS (MeOH) calcd. for C29H35NNaO9 564.2210 (M+Na+), found 564.2160 (M+Na+)。
1,11-ジデアセチル-11-イソブチリルピリピロペンA (PRD174) の合成
1H NMR (CDCl3, 270 MHz) δ 8.99 (s, 1H, H-2"), 8.67 (d, 1H, H-6", J = 3.3 Hz), 8.08 (d, 1H, H-4", J = 7.9 Hz), 7.39 (dd, 1H, H-5", J = 4.9, 7.9 Hz), 6.44 (s, 1H, H-5’), 5.00 (br s, 2H, H-7, 13), 4.24 (d, 1H, H-11a, J = 11.9 Hz), 3.67 (d, 1H, H-11b, J = 11.9 Hz), 3.43 (dd, 1H, H-1, J = 6.6, 8.2 Hz), 3.00 (br s, 1H, OH-13), 2.65-2.54 (m, 1H, CHMe2), 2.31-0.73 (m, 8H, H-2, 3, 5, 8, 9), 2.15 (s, 3H, Ac), 1.69 (s, 3H, Me), 1.41 (s, 3H, Me), 1,21-1.18 (m, 6H, CHMe 2 ), 0.81 (s, 3H, Me);
ESI-LRMS m/z 592 (M+Na+); ESI-HRMS (MeOH) calcd. for C31H39NNaO9 592.2523 (M+Na+), found 592.2568 (M+Na+)。
11-ベンゾイル-1,11-ジデアセチル-ピリピロペンA (PRD175) の合成
1H NMR (CDCl3, 270 MHz) δ 8.98 (br s, 1H, H-2"), 8.66 (br s, 1H, H-6"), 8.09-8.03 (m, 3H, H-4", Ar x 2), 7.58-7.36 (m, 4H, H-5", Ar x 3), 6.44 (s, 1H, H-5’), 5.07-4.96 (m, 2H, H-7, 13), 4.64 (d, 1H, H-11a, J = 11.9 Hz), 3.85 (d, 1H, H-11b, J = 11.9 Hz), 3.48-3.44 (br s, 1H, H-1), 3.02 (br s, 1H, OH-13), 2.70 (br s, 1H, OH-1), 2.09-1.24 (m, 8H, H-2, 3, 5, 8, 9), 2.17 (s, 3H, Ac), 1.70 (s, 3H, Me), 1.43 (s, 3H, Me), 0.89 (s, 3H, Me);
ESI-LRMS m/z 626 (M+Na+); ESI-HRMS (MeOH) calcd. for C34H37NNaO9 626.2366 (M+Na+), found 626.2342 (M+Na+)。
11-デアセチルピリピロペンA (PRD149)の合成
1H NMR (CDCl3, 400 MHz) δ 9.01 (dd, 1H, H-2", J = 0.8, 2.4 Hz), 8.69-8.68 (m, 1H, H-6"), 8.11-8.08 (m, 1H, H-4"), 7.42-7.38 (m, 1H, H-5"), 6.46 (s, 1H, H-5'), 5.12 (dd, 1H, H-7, J = 5.2, 11.6 Hz), 4.98 (d, 1H, H-13, J = 2.0 Hz), 4.93 (dd, 1H, H-1, J = 4.4, 12.0 Hz), 3.29 (d, 1H, H-11a, J = 12.8 Hz), 2.98 (d, 1H, H-11b, J = 12.8 Hz), 2.93 (br s, 1H, OH-13), 2.61 (br s, 1H, OH-11), 2.19-1.12 (m, 8H, H-2, 3, 5, 8, 9), 2.16 (s, 3H, Ac), 2.09 (s, 3H, Ac), 1.69 (s, 3H, Me), 1.43 (s, 3H, Me), 0.93 (s, 3H, Me);
ESI-LRMS m/z 564 (M+Na+); ESI-HRMS (MeOH) calcd. for C29H35NNaO9 564.2210 (M+Na+), found 564.2160 (M+Na+)。
1,7-ジデアセチルピリピロペンA (PRD150)の合成
a) 7-O-アリルオキシカルボニル-1,11-O-(ジ-tert-ブチルシリレン)-1,7,11-トリデアセチルピリピロペンA (s) の合成
ESI-LRMS m/z 704 (M+Na+); ESI-HRMS (MeOH) calcd. for C37H51NNaO9Si 704.3231 (M+Na+), found 704.3239 (M+Na+)。
(t)のデータ (11-OH)
1H NMR (CDCl3, 400 MHz)δ 9.03 (dd, 1H, H-2", J = 0.8, 1.5 Hz), 8.66 (d, 1H, H-6", J = 4.4 Hz), 8.14-8.11 (m, 1H, H-4"), 7.42-7.39 (m, 1H, H-5"), 6.62 (s, 1H, H-5'), 6.04-5.96 (m, 1H, OCH2 CHCH2), 5.41 (dd, 1H, 1/2 OCH2CHCH 2 (trans), J = 1.2, 16.0 Hz), 5.31 (dd, 1H, 1/2 OCH2CHCH 2 (cis), J = 1.2, 10.4 Hz), 5.00-4.98 (m, 1H, H-13), 4.95-4.92 (m, 1H, H-7), 4.72-4.70 (m, 2H, OCH 2 CHCH2), 4.16 (t, 1H, H-1, J = 8.0 Hz), 3.59 (d, 1H, H-11a, J = 10.8 Hz), 3.33 (d, 1H, H-11b, J = 10.8 Hz), 3.00 (br s, 1H, OH-13), 2.46 (br s, 1H, OH-11), 2.12-1.25 (m, 8H, H-2, 3, 5, 8, 9), 1.72 (s, 3H, Me), 1.41 (s, 3H, Me), 1.06-1.04 (m, 18H, tBu×2), 0.73 (s, 3H, Me);
ESI-LRMS m/z 724 (M+Na+); ESI-HRMS (MeOH) calcd. for C37H52FNNaO9Si 724.3293 (M+Na+), found 724.3351 (M+Na+)。
1H NMR (CDCl3, 400 MHz) δ 9.00 (dd, 1H, H-2", J = 0.8, 2.0 Hz), 8.68 (dd, 1H, H-6", J = 1.6, 4.8 Hz), 8.11-8.08 (m, 1H, H-4"), 7.42-7.39 (m, 1H, H-5"), 6.47 (s, 1H, H-5'), 6.03-5.95 (m, 1H, OCH2 CHCH2), 5.42 (dd, 1H, 1/2 OCH2CHCH 2 (trans), J = 1.2, 16.0 Hz), 5.31 (dd, 1H, 1/2 OCH2CHCH 2 (cis), J = 1.2, 10.4 Hz), 5.01-4.99 (m, 1H, H-13), 4.88 (dd, 1H, H-7, J = 5.6, 12.0 Hz), 4.72-4.68 (m, 2H, OCH 2 CHCH2), 3.89 (d, 1H, H-11a, J = 10.4 Hz), 3.74 (t, 1H, H-1, J = 8.0 Hz), 3.56 (d, 1H, H-11b, J = 10.4 Hz), 2.91 (br s, 1H, OH-13), 2.17-1.23 (m, 8H, H-2, 3, 5, 8, 9), 1.71 (s, 3H, Me), 1.41 (s, 3H, Me), 1.08-1.07 (m, 18H, tBu×2), 0.80 (s, 3H, Me);
ESI-LRMS m/z 724 (M+Na+); ESI-HRMS (MeOH) calcd. for C37H52FNNaO9Si 724.3293 (M+Na+), found 724.3367 (M+Na+)。
ESI-LRMS m/z 522 (M+Na+); ESI-HRMS (MeOH) calcd. for C27H33NNaO8 522.2104 (M+Na+), found 522.2056 (M+Na+)。
11,7-ジデアセチルピリピロペンA (PRD151)の合成
1H NMR (CDCl3, 400 MHz) δ 9.01 (dd, 1H, H-2", J = 0.8, 2.4 Hz), 8.68 (dd, 1H, H-6", 1.2, 4.8 Hz), 8.12-8.09 (m, 1H, H-4"), 7.43-7.40 (m, 1H, H-5"), 6.54 (s, 1H, H-5'), 4.98-4.97 (m, 1H, H-13), 4.90 (dd, 1H, H-1, J = 4.8, 12.0 Hz), 3.91 (dd, 1H, H-7, J = 4.8, 7.2 Hz), 3.35 (d, 1H, H-11a, J = 12.0 Hz), 2.96 (d, 1H, H-11b, J = 12.0 Hz), 2.89 (br s, 1H, OH-13), 2.81 (br s, 1H, OH-7), 2.41 (br s, 1H, OH-1), 2.20-1.25 (m, 8H, H-2, 3, 5, 8, 9), 2.11 (s, 3H, Ac), 1.65 (s, 3H, Me), 1.41 (s, 3H, Me), 0.74 (s, 3H, Me);
ESI-LRMS m/z 522 (M+Na+); ESI-HRMS (MeOH) calcd. for C27H33NNaO8 522.2104 (M+Na+), found 522.2075 (M+Na+)。
7-O-p-シアノベンゾイル-10-デアセトキシメチル-10-プロピルカルバモイル-1,7-ジデアセチルピリピロペンA (PRD189) の合成
a) 10-カルボキシル-7-O-p-シアノベンゾイル-10-デアセトキシメチル-1-O-ジターシャリーブチルフルオロシリルオキシ-13-ケト-1,7-ジデアセチルピリピロペンA (v)の合成
ESI-LRMS m/z 759 (MH+); ESI-HRMS (MeOH) calcd. for C41H48FN2O9Si 759.3113 (MH+), found 759.3066 (MH+)。
ESI-LRMS m/z 761 (MH+); ESI-HRMS (MeOH) calcd. for C41H50FN2O9Si 761.3270 (MH+), found 761.3231 (MH+)。
ESI-LRMS m/z 664 (M+Na+); ESI-HRMS (MeOH) calcd. for C36H39N3NaO8 664.2635 (M+Na+), found 664.2668 (M+Na+)。
7-O-p-シアノベンゾイル-10-デアセトキシメチル-10-(3-ヒドロキシプロピル)カルバモイル-1,7-ジデアセチルピリピロペンA (PRD190) の合成
ESI-LRMS m/z 680 (M+Na+); ESI-HRMS (MeOH) calcd. for C36H39N3NaO9 680.2584 (M+Na+), found 680.2595 (M+Na+)。
10-ベンジルカルバモイル-7-O-p-シアノベンゾイル-10-デアセトキシメチル-1,7-ジデアセチルピリピロペンA (PRD191) の合成
ESI-LRMS m/z 712 (M+Na+); ESI-HRMS (MeOH) calcd. for C40H39N3NaO8 712.2635 (M+Na+), found 712.2639 (M+Na+)。
7-O-p-シアノベンゾイル-10-デアセトキシメチル-10-(4-メトキシベンジル)カルバモイル-1,7-ジデアセチルピリピロペンA (PRD192) の合成
ESI-LRMS m/z 742 (M+Na+); ESI-HRMS (MeOH) calcd. for C41H41N3NaO9 742.2741 (M+Na+), found 742.2805 (M+Na+)。
7-O-p-シアノベンゾイル-10-デアセトキシメチル-10-[(R)-3-メトキシ-3-オキソ-1-フェニルプロピルカルバモイル]-1,7-ジデアセチルピリピロペンA (PRD193) の合成
ESI-LRMS m/z 784 (M+Na+); ESI-HRMS (MeOH) calcd. for C43H43N3NaO10 784.2846 (M+Na+), found 784.2837 (M+Na+)。
C57BL6/Jマウス (雄性、日本SLC株式会社より購入) を12時間周期での人工光 (昼)−暗黒 (夜) サイクルのもと、標準的な食餌 (CE-2、日本クレア社製) を適宜与えて維持した。各薬剤の試験を開始する前に、20時間絶食(水は自由摂取)させた。これら動物に、ピリピロペンAまたはPRD017を0.5% (w/v) カルボキシメチルセルロースの生理食塩水溶液に溶解し、50 mg/kgの濃度になるように2.5 ml/kgの量で10週齢のマウスに経口で投与した。
[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)、1mMエチレンジアミン四酢酸及び1mM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5mg/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、0.00001mg/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。
これらの阻害率のデータから、本酵素活性を50%阻害する濃度(IC50、阻害活性)を算定した。
阻害活性:ACAT2を50%阻害する濃度(=IC50)
+++++:阻害活性<0.5μM
++++:0.5μM≦阻害活性<1.0μM
+++:1.0μM≦阻害活性<5.0μM
++:5.0μM≦阻害活性<10.0μM
+:10.0μM≦阻害活性
Claims (4)
- 下記一般式(I)または(II)または(III):
(式中、R1およびR2は、ヒドロキシル基、低級アシロキシ基、アリールカルボニルオキシ基、およびヘテロアリールカルボニルオキシ基から選ばれた基を意味し、一般式(I)および(II)においてR1とR2は互いに同一でも異なっていてもよいが、少なくとも一方はヒドロキシル基ではなく、かつ一般式(II)においてR1とR2の少なくとも一方はアセトキシ基ではなく、R3はヒドロキシル基、低級アルコキシ基、アリールアルコキシ基、ヘテロアリールアルコキシ基、低級アルキルアミノ基、アリールアミノ基、およびヘテロアリールアミノ基から選ばれた基を意味する)で示されるピリピロペンA誘導体、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。 - R1がヒドロキシル基、アリールカルボニルオキシ基、または低級アシロキシ基であり、R2が低級アシロキシ基またはアリールカルボニルオキシ基である、請求項1に記載の化合物。
- 請求項1に記載のピリピロペン誘導体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。
- 請求項1に記載のピリピロペン誘導体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。
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