JP2016008191A - 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 - Google Patents
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 Download PDFInfo
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- JP2016008191A JP2016008191A JP2014129126A JP2014129126A JP2016008191A JP 2016008191 A JP2016008191 A JP 2016008191A JP 2014129126 A JP2014129126 A JP 2014129126A JP 2014129126 A JP2014129126 A JP 2014129126A JP 2016008191 A JP2016008191 A JP 2016008191A
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Classifications
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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
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
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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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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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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- 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
- A61P9/12—Antihypertensives
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
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Abstract
Description
(1) 式(I):
R1は、置換若しくは非置換のシクロアルキル、置換若しくは非置換のアリール、置換若しくは非置換のヘテロシクロアルキル、又は置換若しくは非置換のヘテロアリールであり、
nは、0〜5の整数であり、
R2は、ハロゲン、シアノ、ニトロ、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換のシクロアルキル、置換若しくは非置換のシクロアルケニル、置換若しくは非置換のシクロアルキニル、置換若しくは非置換のヘテロシクロアルキル、置換若しくは非置換のアリール、置換若しくは非置換のアリールアルキル、置換若しくは非置換のアリールアルケニル、置換若しくは非置換のヘテロアリール、置換若しくは非置換のヘテロアリールアルキル、置換若しくは非置換のアルコキシ、置換若しくは非置換のシクロアルコキシ、置換若しくは非置換のヘテロシクロアルコキシ、置換若しくは非置換のアリールオキシ、置換若しくは非置換のアリールアルキルオキシ、置換若しくは非置換のアリールアルケニルオキシ、置換若しくは非置換のヘテロアリールオキシ、置換若しくは非置換のヘテロアリールアルキルオキシ、置換若しくは非置換のアシル、又は-NRN1RN2であり、但しnが2以上の場合、複数のR2は互いに同一又は異なっていてもよく、
RN1及びRN2は、互いに独立して、水素、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換のシクロアルキル、置換若しくは非置換のシクロアルケニル、置換若しくは非置換のシクロアルキニル、置換若しくは非置換のヘテロシクロアルキル、置換若しくは非置換のアリール、置換若しくは非置換のアリールアルキル、置換若しくは非置換のアリールアルケニル、置換若しくは非置換のヘテロアリール、置換若しくは非置換のヘテロアリールアルキル、置換若しくは非置換のアルコキシ、置換若しくは非置換のシクロアルコキシ、置換若しくは非置換のヘテロシクロアルコキシ、置換若しくは非置換のアリールオキシ、置換若しくは非置換のアリールアルキルオキシ、置換若しくは非置換のアリールアルケニルオキシ、置換若しくは非置換のヘテロアリールオキシ、置換若しくは非置換のヘテロアリールアルキルオキシ、及び置換若しくは非置換のアシルからなる群より選択される1価基であり、
R3及びR4は、互いに独立して、水素、ヒドロキシル、置換若しくは非置換のアルキルカルボニルオキシ、置換若しくは非置換のアリールカルボニルオキシ、又は置換若しくは非置換のアルコキシであるか、或いは、
R3及びR4は、一緒になって-O-CR7R8-O-を形成しており、
R5は、水素、ヒドロキシル、置換若しくは非置換のアルキルカルボニルオキシ、置換若しくは非置換のアリールカルボニルオキシ、又は置換若しくは非置換のアルコキシであり、
R6は、-C(CH3)2-又は-CH2-であり、
R7及びR8は、互いに独立して、水素、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換のシクロアルキル、置換若しくは非置換のシクロアルケニル、置換若しくは非置換のシクロアルキニル、置換若しくは非置換のヘテロシクロアルキル、置換若しくは非置換のアリール、置換若しくは非置換のアリールアルキル、置換若しくは非置換のアリールアルケニル、置換若しくは非置換のヘテロアリール、又は置換若しくは非置換のヘテロアリールアルキルである。]
で表される化合物若しくはその塩、又はそれらの溶媒和物。
R2が、ハロゲン、シアノ、ニトロ、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、又は置換若しくは非置換のアルキニルであり、
R7及びR8が、互いに独立して、水素、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、又は置換若しくは非置換のアリールである、前記(1)に記載の化合物。
式(II):
で表される化合物をエポキシ化して、式(III):
で表される化合物を得る、エポキシ化工程;
前記エポキシ化工程で得られる式(III)で表される化合物にアルデヒド基を導入して、式(IV):
R3、R4、R5及びR6は、前記と同義であり、
RP1は、ヒドロキシルの保護基である。]
で表される化合物を得る、アルデヒド基導入工程;
前記アルデヒド基導入工程で得られる式(IV)で表される化合物を増炭及び環化して、式(V):
R3、R4、R5、R6及びRP1は、前記と同義であり、
RP2は、カルボン酸の保護基である。]
で表される化合物を得る、C環導入工程;
C環導入工程で得られる式(V)で表される化合物を環化して、式(VII):
R1は、前記(1)〜(4)のいずれかに記載の定義と同義であり、
R3、R4、R5、R6及びRP1は、前記と同義である。]
で表される化合物を得る、D環導入工程;
D環導入工程で得られる式(VII)で表される化合物と、式(VIII):
R2及びnは、前記(1)〜(4)のいずれかに記載の定義と同義であり、
RL2は、カルボン酸の活性化基である。]
で表される化合物とを反応させて、式(IX):
で表される化合物を得る、ベンゾイル基導入工程;
ベンゾイル基導入工程で得られる式(IX)で表される化合物の10-位カルボニル基を還元して、式(I)で表される化合物を得る、還元工程;
を含む、前記方法。
本明細書において、「アルキル」は、特定の数の炭素原子を含む、直鎖又は分枝鎖の飽和脂肪族炭化水素基を意味する。例えば、「C1〜C5アルキル」は、少なくとも1個且つ多くても5個の炭素原子を含む、直鎖又は分枝鎖の飽和脂肪族炭化水素基を意味する。好適なアルキルは、限定するものではないが、例えばメチル、エチル、n-プロピル、イソプロピル、n-ブチル、sec-ブチル、イソブチル、tert-ブチル及びn-ペンチル等の直鎖又は分枝鎖のC1〜C5アルキルを挙げることができる。
(5aS,6S,8S,9aS,10R)-10-ヒドロキシ-8-イソプロピル-5a-メチル-1-オキソ-3-(ピリジン-3-イル)-1,5a,6,7,8,9,9a,10-オクタヒドロピラノ[4,3-b]クロメン-6-イル 4-シアノベンゾエート ((10R)-8), (PT005);
(5aS,6S,8S,9aS,10S)-10-ヒドロキシ-8-イソプロピル-5a-メチル-1-オキソ-3-(ピリジン-3-イル)-1,5a,6,7,8,9,9a,10-オクタヒドロピラノ[4,3-b]クロメン-6-イル 4-シアノベンゾエート ((10S)-8), (PT006);
(5aS,6S,8S,9aS,10R)-10-ヒドロキシ-8-イソプロピル-5a-メチル-1-オキソ-3-フェニル-1,5a,6,7,8,9,9a,10-オクタヒドロピラノ[4,3-b]クロメン-6-イル 4-シアノベンゾエート(34), (PT007);
(5aS,6S,8S,9aS,10R)-10-ヒドロキシ-8-イソプロピル-5a,9,9-トリメチル-1-オキソ-3-(ピリジン-3-イル)-1,5a,6,7,8,9,9a,10-オクタヒドロピラノ[4,3-b]クロメン-6-イル 4-シアノベンゾエート(15), (PT009);
(5aS,6S,8S,9aS,10R)-10-ヒドロキシ-5a,9,9-トリメチル-1-オキソ-3-(ピリジン-3-イル)-8-(2-(o-トルイル)-1,3-ジオキサン-5-イル)-1,5a,6,7,8,9,9a,10-オクタヒドロピラノ[4,3-b]クロメン-6-イル 4-シアノベンゾエート (PT017);及び
2-((5aS,6S,8S,9aS,10R)-6-((4-シアノベンゾイル)オキシ)-10-ヒドロキシ-5a,9,9-トリメチル-1-オキソ-3-(ピリジン-3-イル)-1,5a,6,7,8,9,9a,10-オクタヒドロピラノ[4,3-b] クロメン-8-イル)プロパン-1,3-ジイル ジアセテート (PT022)
からなる群より選択される。
本発明者らは、ピリピロペンAの全合成(非特許文献9)を参照することにより、本発明の式(I)で表される化合物を、天然物であるピリピロペンAを原料とすることなく、単純な2-シクロヘキセノン骨格を有する化合物を出発原料として合成できることを見出した。それ故、本発明はまた、本発明の式(I)で表される化合物を製造する方法に関する。
本発明の式(I)で表される化合物を製造する方法は、エポキシ化工程で得られる式(III)で表される化合物にアルデヒド基を導入して、式(IV):
本発明の式(I)で表される化合物を製造する方法は、アルデヒド基導入工程で得られる式(IV)で表される化合物を増炭及び環化して、式(V):
R1-CORL1 (VI)
で表される化合物と塩基存在下で反応させることにより、式(VII)で表される化合物を得ることができる。前記式(VI)において、R1は、前記と同義である。RL1は、カルボン酸の活性化基である。RL1は、ハロゲン(例えば、Cl、Br若しくはI)、又はベンゾトリアゾールであることが好ましい。前記塩基は、リチウムヘキサメチルジシラジド(LHMDS)又はリチウムジイソプロピルアミド(LDA)であることが好ましい。前記反応により、R1及びD環が導入された式(VII)で表される化合物を得ることができる。
本発明の式(I)で表される化合物を製造する方法は、D環導入工程で得られる式(VII)で表される化合物と、式(VIII):
本発明の式(I)で表される化合物を製造する方法は、ベンゾイル基導入工程で得られる式(IX)で表される化合物の10-位カルボニル基を還元して、式(I)で表される化合物を得る、還元工程を含む。
本発明の式(I)で表される化合物は、ピリピロペンAと同等又はそれ以上のACAT2阻害活性を有する。それ故、本発明は、本発明の式(I)で表される化合物若しくはその塩、又はそれらの溶媒和物を有効成分として含むACAT2阻害剤に関する。また、本発明の式(I)で表される化合物を対象に投与した場合、ACAT2阻害活性を介して、該対象の有する特定の疾患若しくは症状を予防又は治療し得る。それ故、本発明はまた、本発明の式(I)で表される化合物若しくはその塩、又はそれらの溶媒和物を有効成分として含む医薬に関する。
[実施例1]
(5aS,6S,8S,9aS,10R)-10-ヒドロキシ-8-イソプロピル-5a-メチル-1-オキソ-3-(ピリジン-3-イル)-1,5a,6,7,8,9,9a,10-オクタヒドロピラノ[4,3-b]クロメン-6-イル・アセテート (10R)-29, (PT001)の製造
1) (1S,4R,6S)-4-イソプロピル-1-メチル-7-オキサビシクロ[4.1.0]ヘプタン-2-オン(2)の合成
HRMS (EI) [M]+ 次式の計算値: C10H16O2168.1150, 実測値: 168.1148。
IR (KBr) 3020, 2401, 1665, 1423, 1216, 756, 670, 472, 445, 405 cm-1;
1H-NMR (400 MHz, CDCl3) δ 10.13 (s, 1H, C[H]O), 4.29-4.24 (m, 1H, C(CH3)C[H](OH)CH2), 2.39 (d, 1H, J=16.6 Hz, 1/2 C[H2]CCHO), 2.22-2.21 (m, 3H, C[H3]CCH(OH)), 2.18-2.12 (m, 1H, 1/2 C[H2]CH(OH), 1.76-1.67 (m, 1H, 1/2 C[H2]CCHO), 1.58-1.50 (m, 1H, (CH3)2C[H]CH), 1.40-1.30 (m, 1H, (CH3)2CHC[H]), 1.25-1.16 (m, 1H, 1/2 C[H2]CH(OH)), 0.89 (d, 6H, J=6.8 Hz, (C[H3])2CHCH);
13C-NMR (100 MHz, CDCl3) δ 192.6, 156.3, 134.5, 72.9, 38.3, 36.5, 32.5, 26.7, 19.9, 19.6, 13.2;
HRMS (EI) [M]+ 次式の計算値: C11H18O2182.1307, 実測値: 182.1311。
IR (KBr) 3054, 2959, 2934, 1710, 1680, 1423, 1265, 839, 732, 707 cm-1;
1H-NMR (400 MHz, CDCl3) δ 10.15 (s, 1H, C[H]O), 4.27 (br s, 1H, CH2C[H](OTBS)), 2.41-2.35 (m, 1H, 1/2 C[H2]CCHO), 2.14 (s, 3H, C=C(C[H3])), 2.04-1.96 (m, 1H, 1/2 C[H2]CH(OTBS), 1.78-1.68 (m, 1H, 1/2 C[H2]CCHO), 1.61-1.49 (m, 1H, (CH3)2C[H]CH), 1.33-1.24 (m, 1H, (CH3)2CHC[H]), 1.26 (dd, 1H, J=11.2, 10.0 Hz, 1/2 C[H2]CH(OTBS)), 0.92 (s, 9H, Si(CH3)2C(C[H3])3) 0.90 (dd, 6H, J=6.6, 1.8 Hz, (C[H3])2CHCH), 0.12 (d, 6H, J=4.2 Hz, Si(C[H3])2C(CH3)3);
13C-NMR (100 MHz, CDCl3) δ 192.5, 157.2, 134.3, 73.7, 38.2, 36.7, 32.5, 26.4, 26.1, 20.0, 19.5, 18.4, 13.7, -3.6, -4.6;
HRMS (FAB, PEG400) [M+Na]+ 次式の計算値: C17H32NaO2Si 319.2069, 実測値: 319.2064。
IR (KBr) 3054, 2958, 2933, 2859, 1736, 1617, 1417, 1265, 1218, 1079, 1041, 836, 741 cm-1;
1H-NMR (400 MHz, CDCl3) δ 4.23-4.14 (m, 3H, CH2C[H](OTBS), CO2C[H2]CH3), 3.57 (s, 2H, J=3.6 Hz, COC[H2]CO2Et), 2.21-2.15 (m, 1H, 1/2 C[H2]CCOCH2CO2Et), 2.02-1.85 (m, 2H, 1/2 C[H2]CH(OTBS), 1/2 C[H2]COCH2CO2Et), 1.82 (s, 3H, C=C(C[H3])), 1.59-1.48 (m, 1H, (CH)2C[H]CH), 1.47-1.41 (m, 1H, (CH3) 2CHC[H]), 1.27 (t, 3H, J=7.2 Hz, CO2CH2C[H3]), 1.27-1.21 (m, 1H, 1/2 C[H2]CH(OTBS)), 0.95-0.85 (m, 15H, Si(CH3) 2C(C[H3])3, (C[H3])2CHCH), 0.10 (s, 3H, Si(C[H3])2C(CH3)3), 0.08 (s, 3H, Si(C[H3])2C(CH3)3);
13C-NMR (100 MHz, CDCl3) δ 175.7, 168.0, 139.6, 129.1, 91.3, 73.1, 61.6, 49.1, 39.0, 36.6, 32.4, 31.6, 30.6, 26.2, 19.5, 18.5, 17.2, 16.7, 14.6, -3.7, -4.5;
HRMS (ESI, TFANa) [M+Na]+ 次式の計算値: C21H38NaO4Si 405.2437, 実測値: 405.2434。
IR (KBr) 3055, 2983, 2958, 2934, 1725, 1681, 1393, 1265, 1112, 835, 733, 706 cm-1;
1H-NMR (400 MHz, CDCl3) δ 4.23 (q, 2H, J=4.4 Hz, CO2C[H2]CH3), 3.83 (dd, 1H, J=11.2, 5.2 Hz, C[H]OTBS), 2.44 (dd, 1H, J=12.4, 4.0 Hz, CH2C[H]CO), 2.17 (s, 3H, C=CC[H3]), 2.07 (ddd, 1H, J=17.6, 9.2, 3.2 Hz, 1/2 COCHC[H2]), 1.74-1.66 (m, 1H, 1/2 C[H2]CH(OTBS)), 1.52-1.44 (m, 1H, (CH3)2C[H]CH), 1.43-1.38 (m, 1H, (CH3)2CHC[H]), 1.28 (t, 3H, J=7.2 Hz, CO2CH2C[H3]), 1.16 (s, 3H, C(C[H3])CH(OTBS)), 1.13 (dd, 1H, J=12.4, 1.6 Hz, 1/2 C[H2]CH(OTBS)), 0.91 (dd, 1H, J=14.0, 1.6 Hz, 1/2 C[H2]CHCO), 0.90 (s, 9H, Si(CH3)2C(C[H3])3), 0.87 (d, 6H, J=3.6 Hz, (C[H3])2CHCH), 0.09 (s, 3H, 1/2 Si(C[H3])2C(CH3)3), 0.07 (s, 3H, 1/2 Si(C[H3])2C(CH3)3);
13C-NMR (100 MHz, CDCl3) δ 189.7, 174.9, 165.9, 110.9, 87.2, 76.2, 60.9, 49.9, 40.5, 36.0, 32.2, 25.9, 24.0, 20.8, 20,1, 19.7, 18.3, 14.4, 10.2, -4.4;
HRMS (ESI, TFANa) [M+Na]+ 次式の計算値: C23H40NaO5Si 447.2543, 実測値: 447.253
3。
13C-NMR (100 MHz, CDCl3) δ 196.8, 175.4, 158.8, 138.5, 136.1, 109.8, 106.6, 73.0, 39.1, 36.7, 32.4, 31.3, 31.1, 26.2, 25.8, 25.7, 20.2, 19.9, 19.7, 18.5, 16.5, -3.7, -4.5;
HRMS (ESI, TFANa) [M+Na]+ 次式の計算値: C24H40NaO5Si, 459.2543, 実測値: 459.2526。
13C-NMR (100 MHz, CDCl3) δ 189.4, 175.3, 166.0, 110.3, 87.5, 76.3, 69.0, 52.2, 50.1, 40.6, 36.1, 32.4, 25.4, 23.6, 20.6, 19.7, 19.4, 17.9, 9.8, -4.8, -5.3;
HRMS (ESI, TFANa) [M+Na]+ 次式の計算値: C22H38NaO5Si, 433.2386, 実測値: 433.2403。
IR (KBr) 3055, 2982, 2307, 1758, 1429, 1265, 738 cm-1;
1H-NMR (400 MHz, CDCl3) δ 9.06 (d, 1H, J=2.4 Hz, Py), 8.75 (dd, 1H, J=4.8, 1.6 Hz, Py), 8.19 (dt, 1H, J=8.0, 2.0 Hz, Py), 7.46 (ddd, 1H, J=8.0, 4.8, 2.0 Hz, Py), 6.43 (s, 1H, PyC=C[H]), 3.97 (dd, 1H, J=11.2, 5.3 Hz, C[H](OTBS)), 2.63 (dd, 1H, J=12.0, 4.0 Hz, CH2C[H]CO), 2.20 (dd, 1H, J=14.0, 2.0 Hz, 1/2 C[H2]CHCO), 1.81 (dt, 1H, J=13.2, 2.4 Hz, 1/2 C[H2]CH(OTBS)), 1.56 (dd, 1H, J=12.4, 6.8 Hz, (CH3)2C[H]CH), 1.48-1.40 (m, 1H, (CH3)2CHC[H]), 1.30 (s, 3H, C(C[H3])CCH(OTBS)), 1.22-1.21 (m, 1H, 1/2 C[H2]CHOSi(CH3)2C(CH3)3), 1.11-1.05 (m, 1H, 1/2 C[H2]CH(OTBS)), 0.96 (s, 9H, Si(CH3)2C(C[H3])3), 0.92 (dd, 6H, J=6.8, 2.4 Hz, (C[H3])2CHCH), 0.19 (s, 3H, 1/2 Si(C[H3])2C(CH3)3), 0.15 (s, 3H, 1/2 Si(C[H3])2C(CH3)3);
13C-NMR (100 MHz, CDCl3) δ 188.0, 173.5, 162.7, 157.0, 152.8, 147.8, 134.1, 127.0, 134.1, 127.0, 124.1, 98.3, 89.9, 76.1, 51.6, 40.4, 36.0, 32.3, 30.0, 26.1, 24.3, 20.1, 19.0, 11.1, -4.1, -4.2;
HRMS (ESI, TFANa) [M+Na]+ 次式の計算値: C27H37NNaO5Si 506.2339, 実測値: 506.23
45。
(5aS,6S,8S,9aS)-6-(アセトキシ)-8-イソプロピル-5a-メチル-3-(フェニル)-5a,6,7,8,9,9a-ヘキサヒドロピラノ[4,3-b]クロメン-1,10-ジオン ((9aS)-28)の合成
[α]27 D +10.2 (c 1.0, CHCl3);
IR (KBr) 2930, 1757, 1628, 1536. 1431, 1262, 738 cm-1;
1H-NMR (300 MHz, CDCl3) δ 9.06 (dd, 1H, J=2.1, 0.6 Hz, Py), 8.74 (dd, 1H, J=4.8, 1.5 Hz, Py), 8.18 (ddd, 1H, J=8.4, 2.4, 1.8 Hz, Py), 7.44 (dd, 1H, J=8.1, 0.6 Hz, Py), 6.54 (s, 1H, PyC=C[H]), 5.26 (dd, 1H, J=11.7, 5.1 Hz, C[H](OAc)), 2.75 (dd, 1H, J=12.3, 3.6 Hz, CH2C[H]CO), 2.27 (ddd, 1H, J=14.4, 5.7, 3.9 Hz, 1/2 C[H2]CHCO), 2.19 (s, 3H, COCHC(C[H3])), 2.06-1.98 (m, 1H, 1/2 C[H2]CH(OAc)), 1.64-1.53 (m, 1H, (CH3)2C[H]CH), 1.39 (s, 3H, CH(OAc)C(C[H3])), 1.40-1.29 (m, 1H, (CH3)2CHC[H]), 1.18-1.05 (m, 1H, 1/2 C[H2]CHCO), 0.87-0.81 (m, 1H, 1/2 C[H2]CH(OAc)), 0.92 (d, 6H, J=6.3 Hz, (C[H3])2CHCH);
13C-NMR (100 MHz, CDCl3) δ 187.0, 173.2, 170.5, 162.9, 156.9, 153.0, 147.9, 134.1, 126.9, 124.1, 100.5, 98.5, 87.4, 76.1, 51.6, 40.4, 32.3, 32.0, 24.5, 21.6, 20.2, 20.0, 12.0;
HRMS (ESI, TFANa) [M+Na]+ 次式の計算値: C23H25NNaO6 434.1580, 実測値: 434.1565。
[α]27 D +63.5 (c 1.0, CHCl3);
IR (KBr) 2930, 1757, 1628, 1536, 1431, 1262, 737 cm-1;
1H-NMR (300 MHz, CDCl3) δ 9.08-9.06 (m, 1H, Py), 8.75-8.72 (m, 1H, Py), 8.22 (dd, 1H, J=7.2, 1.5 Hz, Py), 7.65 (dd, 1H, J=6.9, 5.1 Hz, Py), 6.41 (s, 1H, PyC=C[H]), 5.38 (dd, 1H, J=11.7, 5.1 Hz, C[H](OAc)), 2.94 (dd, 1H, J=4.2, 3.0 Hz, CH2C[H]CO), 2.67 (dd, 1H, J=13.2, 2.1 Hz, 1/2 C[H2]CHCO), 2.09 (s, 3H, COCHC(C[H3])), 1.91-1.85 (m, 1H, 1/2 CH2C[H]CO), 1.67 (s, 3H, CH(OAc)C(C[H3])), 1.54-1.35 (m, 2H, (CH3)2C[H]CH, (CH3)2CHC[H]), 1.35-1.09 (m, 2H, 1/2 C[H2]CHCO, 1/2 C[H2]CH(OAc)), 0.90 (d, 6H, J=5.1 Hz, (C[H3])2CHCH);
13C-NMR (75 MHz, CDCl3) δ 186.7, 173.6, 170.3, 162.8, 157.0, 152.4, 147.5, 134.6, 129.1, 124.3, 100.2, 98.7, 88.0, 70.0, 51.6, 37.7, 33.0, 32.4, 30.0, 25.7, 21.6, 21.4, 20.7;
HRMS (ESI, TFANa) [M+Na]+ 次式の計算値: C23H25NNaO6 434.1588, 実測値: 434.1565。
IR (KBr) 3055, 2929, 2309, 1708, 1428, 1264, 897, 735 cm-1;
1H-NMR (300 MHz, CDCl3) δ 9.03 (d, 1H, J=4.8 Hz, Py), 8.70 (d, 1H, J=4.5 Hz, Py), 8.15 (d, 1H, J=5.1 Hz, Py), 7.44 (dd, 1H, J=4.8, 3.0 Hz, Py), 6.50 (s, 1H, PyC=C[H]), 5.02 (dd, 1H, J=11.7, 4.8 Hz, C[H](OAc)), 4.64 (d, 1H, J=4.2 Hz, CHC[H](OH)), 2.21 (s, 3H, OCHC(C[H3])), 2.01-1.95 (m, 1H, 1/2 C[H2]CH(OAc)), 1.90-1.81 (m, 2H, 1/2 C[H2]CHCH(OH), CH2C[H]CH(OH)), 1.65-1.42 (m, 3H, 1/2 C[H2]CHCH(OH), (CH3)2C[H]CH, (CH3)2CHC[H]), 1.50 (s, 3H, CC(C[H3])O), 1.37-1.29 (m, 1H, 1/2 C[H2]CH(OAc)), 0.95 (d, 3H, J=4.5 Hz, (C[H3])2CHCH), 0.93 (d, 3H, J=4.5 Hz, (C[H3])2CHCH);
13C-NMR (75 MHz, CDCl3) δ 170.8, 164.4, 163.4, 157.7, 151.9, 147.2, 133.4, 103.6, 99.9, 83.0, 62.0, 43.7, 41.4, 32.6, 30.1, 27.8, 23.0, 21.7, 20.2, 20.1, 14.5, 13.0;
HRMS (ESI, TFANa) [M+Na]+ 次式の計算値: C23H27NNaO6 436.1736, 実測値: 436.1723。
(5aS,6S,8S,9aS,10S)-10-ヒドロキシ-8-イソプロピル-5a-メチル-1-オキソ-3-(ピリジン-3-イル)-1,5a,6,7,8,9,9a,10-オクタヒドロピラノ[4,3-b]クロメン-6-イル・アセテート ((10S)-29), (PT002)の製造
IR (KBr) 2928, 2859, 1715, 1261, 735 cm-1;
1H-NMR (400 MHz, CDCl3) δ 9.01 (d, 1H, J=2.0 Hz, Py), 8.69 (dd, 1H, J=4.8, 1.6 Hz, Py), 8.10 (ddd, 1H, J=8.0, 2.4, 1.6 Hz, Py), 7.40 (ddd, 1H, J=8.4, 5.2, 0.8 Hz, Py), 6.49 (s, 1H, PyC=C[H]), 5.06 (dd, 1H, J=12.0, 4.8 Hz, C[H](OAc)), 4.45 (d, 1H, J=10.0 Hz, CHC[H](OH)), 2.33-2.27 (m, 1H, 1/2 C[H2]CHCH(OH), 2.18 (s, 3H, C[H3]CO), 2.01-1.95 (m, 1H, 1/2 C[H2]CH(OAc)), 1.86 (ddd, 1H, J=12.4, 10.0, 3.6 Hz, CH2C[H]CH(OH)), 1.59-1.43 (m, 2H, (CH3)2C[H]CH, (CH3)2CHC[H]), 1.28 (s, 3H, CC(C[H3])O), 1.37-1.20 (m, 1H, 1/2 C[H2]CH(OAc)), 1.02-0.87 (m, 1H, 1/2 C[H2]CHCH(OH)), 0.93 (d, 3H, J=4.8 Hz, (C[H3])2CHCH), 0.91 (d, 3H, J=4.8 Hz, (C[H3])2CHCH);
13C-NMR (100 MHz, CDCl3) δ 170.6, 164.0, 163.4, 157.6, 151.2, 146.8, 133.7, 121.0, 100.0, 83.9, 64.5, 63.6, 45.0, 40.9, 32.4, 30.0, 28.9, 23.0, 21.7, 20.2, 20.1, 14.5, 12.3;
HRMS (ESI, TFANa) [M+Na]+ 次式の計算値: C23H27NNaO6 436.1736, 実測値: 436.1734。
(5aS,6S,8S,9aS,10R)-10-ヒドロキシ-8-イソプロピル-5a-メチル-1-オキソ-3-(ピリジン-3-イル)-1,5a,6,7,8,9,9a,10-オクタヒドロピラノ[4,3-b]クロメン-6-イル 4-シアノベンゾエート ((10R)-8), (PT005)の製造
IR (KBr) 3442, 3020, 2400, 2360, 1635, 1215, 1105, 784, 753, 669, 603, 468, 445, 421, 406 cm-1;
1H-NMR (300 MHz, CDCl3) δ 9.11 (s, 1H, Py), 8.76 (s, 1H, Py), 8.52 (s, 1H, Py), 8.21 (d, 2H, J=8.4 Hz, Ph), 7.80 (d, 3H, J=8.4 Hz, Ph, Py), 6.54 (s, 1H, PyC=C[H]), 5.31 (dd, 1H, J=11.1, 5.1 Hz, C[H]OC(O)PhCN), 4.69 (d, 1H, J=4.2 Hz, C[H](OH)CH), 2.12 (d, 1H, J=5.1 Hz, 1/2 C[H2]CHCH(OH), 1.95 (m, 1H, 1/2 CHC[H2]CHOC(O)PhCN), 1.88 (s, 1H, C[H]CH(OH)), 1.72-1.54 (m, 1H, C[H](CH3)2), 1.51-1.49 (m, 1H, C[H]CH(CH3)2), 1.31-1.22 (m, 2H, 1/2 CHC[H2]CHOC(O)PhCN, 1/2 C[H2]CHCH(OH), 1.25 (s, 9H, (C[H3])2CHCH, C[H3]COC=C);
13C-NMR (75 MHz, CDCl3) δ 164.3, 162.1, 134.0, 132.5, 130.4, 129.4, 118.0, 116.9, 105.7, 83.6, 77.9, 77.3, 61.4, 43.5, 41.3, 32.4, 32.1, 29.8, 29.7, 29.5, 22.8, 20.0, 19.9, 14.2, 13.2;
HRMS (ESI) [M+Na]+ 次式の計算値: C29H28N2NaO6523.1845, 実測値: 523.1843。
(5aS,6S,8S,9aS,10S)-10-ヒドロキシ-8-イソプロピル-5a-メチル-1-オキソ-3-(ピリジン-3-イル)-1,5a,6,7,8,9,9a,10-オクタヒドロピラノ[4,3-b]クロメン-6-イル 4-シアノベンゾエート ((10S)-8), (PT006)の製造
13C-NMR (150 MHz, CDCl3) δ 164.0, 163.4, 162.8, 156.9, 150.4, 145.7, 134.0, 132.3, 130.2, 127.5, 124.1, 117.8, 116.7, 103.1, 99.8, 83.6, 77.7, 63.1, 44.7, 40.6, 32.2, 29.7, 28.6, 19.8, 19.7, 12.3;
HRMS (ESI) [M+Na]+ 次式の計算値: C29H28N2NaO6523.1845, 実測値: 523.1847。
(5aS,6S,8S,9aS,10R)-10-ヒドロキシ-8-イソプロピル-5a-メチル-1-オキソ-3-フェニル-1,5a,6,7,8,9,9a,10-オクタヒドロピラノ[4,3-b]クロメン-6-イル・アセテート (10R)-33, (PT003)の製造
1) (5aS,6S,8S,9aR)-6-((tert-ブチルジメチルシリル)オキシ)-8-イソプロピル-5a-メチル-3-(フェニル)-5a,6,7,8,9,9a-ヘキサヒドロピラノ[4,3-b]クロメン-1,10-ジオン (31)の合成
IR (KBr) 3056, 2957, 1755, 1531, 1428, 1264, 739 cm-1;
1H-NMR (400 MHz, CDCl3) δ 7.85 (d, 2H, J=0.8 Hz, Ph), 7.54-7.46 (m, 3H, Ph), 6.38 (s, 1H, C=C[H](Ph)), 3.97 (dd, 1H, J=11.2, 5.2 Hz, C[H](OTBS)), 2.63 (dd, 1H, J=12.0, 3.6 Hz, CH2C[H]CO), 2.20 (dd, 1H, J=14.4, 2.0 Hz, 1/2 C[H2]CHCO), 1.83-1.78 (m, 1H, 1/2 C[H2]CH(OTBS)), 1.56 (dd, 1H, J=12.4, 6.8 Hz, (CH3)2C[H]CH), 1.49-1.40 (m, 1H, (CH3)2CHC[H]), 1.29 (s, 3H, C(C[H3])CH(OTBS)), 1.22-1.21 (m, 1H, 1/2 C[H2]CHOSi(CH3)2C(CH3)3), 1.11-1.01 (m, 1H, 1/2 C[H2]CH(OTBS)), 0.96 (s, 9H, Si(CH3)2C(C[H3])3), 0.92 (dd, 6H, J=6.8, 2.4 Hz, (C[H3])2CHCH), 0.20 (s, 3H, 1/2 Si(C[H3])2C(CH3)3), 0.15 (s, 3H, 1/2 Si(C[H3])2C(CH3)3);
13C-NMR (100 MHz, CDCl3) δ 188.1, 173.9, 165.2, 157.6, 132.8, 129.5, 126.8, 100.0, 97.2, 89.5, 76.2, 51.6, 40.5, 36.0, 32.3, 30.0, 26.1, 24.4, 20.1, 18.5, 11.2, -4.1, -4.5;
HRMS (ESI, TFANa) [M+Na]+ 次式の計算値: C28H38NaO5Si 505.2386, 実測値: 505.2367。
[α]27 D +27.0 (c 1.0, CHCl3);
IR (KBr) 3055, 2984, 2307, 1674, 1563, 1427, 1265, 745 cm-1;
1H-NMR (400 MHz, CDCl3) δ 7.81-7.79 (m, 2H, Ph), 7.48-7.44 (m, 3H, Ph), 6.48 (s, 1H, PhC=C[H]), 4.65 (d, 1H, J=4.0 Hz, CHC[H](OH)), 3.80 (dd, 1H, J=11.6, 4.8 Hz, CH2C[H](OH)), 2.00-1.95 (m, 1H, 1/2 C[H2]CH(OH)), 1.83-1.76 (m, 2H, 1/2 C[H2]CHCH(OH), CH2C[H]CH(OH)), 1.62-1.52 (m, 3H , 1/2 C[H2]CHCH(OH), (CH3)2C[H]CH, (CH3)2CHC[H]), 1.44 (s, 3H, CC(C[H3])O), 1.34-1.21 (m, 1H, 1/2 C[H2]CH(OH)), 0.96 (d, 3H, J=4.4 Hz, (C[H3])2CHCH), 0.93 (d, 3H, J=4.4 Hz, (C[H3])2CHCH);
13C-NMR (100 MHz, CDCl3) δ 164.9, 163.8, 160.4, 131.4, 129.3, 126.0, 103.0, 98.6, 84.9, 76.4, 62.1, 43.4, 41.6, 34.3, 32.6, 30.4, 28.1, 23.0, 20.4, 20.2, 14.5, 12.0;
HRMS (ESI, TFANa) [M+Na]+ 次式の計算値: C22H26NaO5 393.1678, 実測値: 393.1670。
[α]27 D +39.7 (c 1.0, CHCl3);
IR (KBr) 3054, 2369, 2342, 1693, 1265, 745 cm-1;
1H-NMR (400 MHz, CDCl3) δ 7.80-7.76 (m, 2H, Ph), 7.47-7.43 (m, 3H, Ph), 6.48 (s, 1H, PhC=C[H]), 4.46 (d, 1H, J=10.0 Hz, CHC[H](OH)), 3.85 (dd, 1H, J=11.6, 4.8 Hz, CH2C[H](OH)), 2.31-2.25 (m, 1H, 1/2 C[H2]CHCH(OH)), 2.00-1.95 (m, 1H, 1/2 C[H2]CH(OH)), 1.78 (ddd, 1H, J=14.0, 10.0, 4.0 Hz, CH2C[H]CH(OH)), 1.59-1.52 (m, 1H, (C[H3])2C[H]CH)), 1.42-1.36 (m, 1H, (CH3)2CHC[H])), 1.29-1.19 (m, 1H, 1/2 C[H2]CH(OH)), 1.23 (s, 3H, CC(C[H3])O), 1.01-0.95 (m, 1H, 1/2 C[H2]CHCH(OH)), 0.95 (d, 3H, J=3.6 Hz, (C[H3])2CHCH), 0.92 (d, 3H, J=3.6 Hz, (C[H3])2CHCH);
13C-NMR (100 MHz, CDCl3) δ 164.6, 164.0, 163.9, 131.5, 129.3, 126.0, 102.5, 98.6, 86.0, 75.9, 63.8, 44.7, 41.0, 34.2, 32.6, 30.0, 29.3, 23.0, 20.3, 20.2, 11.3;
HRMS (ESI, TFANa) [M+Na]+ 次式の計算値: C22H26NaO5 393.1678, 実測値: 393.1690。
IR (KBr) 2927, 1736, 1689, 1636, 1571, 1424, 1381, 1258, 733 cm-1;
1H-NMR (300 MHz, CDCl3) δ 7.81-7.79 (m, 2H, Ph), 7.47-7.43 (m, 3H, Ph), 6.43 (s, 1H, PhC=C[H]), 5.02 (dd, 1H, J=11.7, 4.8 Hz, C[H](OAc)), 4.64 (d, 1H, J=4.5 Hz, CHC[H](OH)), 2.21 (s, 3H, OCHC(C[H3])), 2.01-1.95 (m, 1H, 1/2 C[H2]CH(OAc)), 1.90-1.80 (m, 2H, 1/2 C[H2]CHCH(OH), CH2C[H]CH(OH)), 1.65-1.42 (m, 3H, 1/2 C[H2]CHCH(OH), (CH3)2C[H]CH, (CH3)2CHC[H]), 1.48 (s, 3H, CC(C[H3])O), 1.37-1.29 (m, 1H, 1/2 C[H2]CH(OAc)), 0.95 (d, 3H, J=4.5 Hz, (C[H3])2CHCH), 0.93 (d, 3H, J=4.5 Hz, (C[H3])2CHCH);
13C-NMR (75 MHz, CDCl3) δ 170.7, 164.5, 163.8, 160.3, 131.4, 129.3, 126.0, 102.8, 82.6, 62.1, 43.7, 41.5, 32.6, 32.5, 30.1, 27.8, 21.7, 20.2, 20.1, 13.0;
HRMS (ESI, TFANa) [M+Na]+ 次式の計算値: C24H28NaO6 435.1784, 実測値: 435.1773。
(5aS,6S,8S,9aS,10S)-10-ヒドロキシ-8-イソプロピル-5a-メチル-1-オキソ-3-フェニル-1,5a,6,7,8,9,9a,10-オクタヒドロピラノ[4,3-b]クロメン-6-イル・アセテート ((10S)-33), (PT004)の製造
IR (KBr) 2927, 1736, 1689, 1263, 740 cm-1;
1H-NMR (300 MHz, CDCl3) δ 7.81-7.77 (m, 2H, Ph), 7.47-7.26 (m, 3H, Ph), 6.42 (s, 1H, PhC=C[H]), 5.05 (dd, 1H, J =11.7, 4.8 Hz, C[H](OAc)), 4.45 (d, 1H, J=10.2 Hz, CHC[H](OH)), 2.34-2.23 (m, 1H, 1/2 C[H2]CHCH(OH), 2.18 (s, 3H, C[H3]CO2), 2.04-1.94 (m, 1H, 1/2 C[H2]CH(OAc)), 1.86 (ddd, 1H, J=12.3, 10.2, 3.6 Hz, CH2C[H]CH(OH)), 1.59-1.43 (m, 2H, (CH3)2C[H]CH, (CH3)2CHC[H]), 1.33-1.27 (m, 1H, 1/2 C[H2]CH(OAc)), 1.28 (s, 3H, CC(C[H3])O), 1.02-0.87 (m, 1H, 1/2 C[H2]CHCH(OH)), 0.93 (d, 3H, J=4.8 Hz, (C[H3])2CHCH), 0.91 (d, 3H, J=4.8 Hz, (C[H3])2CHCH);
13C-NMR (100 MHz, CDCl3) δ 170.7, 164.2, 163.5, 160.3, 131.4, 129.3, 126.0, 102.8, 83.2, 76.3, 63.3, 44.7, 41.5, 32.6, 32.5, 32.2, 30.1, 27.8, 21.7, 20.2, 20.1, 12.0;
HRMS (ESI, TFANa) [M+Na]+ 次式の計算値: C24H28NaO6 435.1784, 実測値: 435.1775。
(5aS,6S,8S,9aS,10R)-10-ヒドロキシ-8-イソプロピル-5a-メチル-1-オキソ-3-フェニル-1,5a,6,7,8,9,9a,10-オクタヒドロピラノ[4,3-b]クロメン-6-イル 4-シアノベンゾエート(34), (PT007)の製造
IR (KBr) 3436, 2958, 2230, 1723, 1637, 1575, 1415, 1269, 1209, 1100, 757, 472 cm-1;
1H-NMR (400 MHz, CDCl3) δ 8.24-8.21 (m, 1H, Ph), 8.16-8.13 (m, 1H, Ph), 7.83-7.80 (m, 2H, Ph), 7.78-7.73 (m, 3H, Ph, C(O)[Ph]CN), 7.46-7.40 (m, 2H, C(O)[Ph]CN), 6.39-6.34 (m, 1H, PhC=C[H]), 5.37-5.33 (m, 1H, C[H]OC(O)PhCN), 4.14-4.10 (m, 1H, CHC[H](OH)), 2.27-2.23 (m, 1H, 1/2 C[H2]CHCH(OH), 2.16-2.13 (m, 1H, 1/2 CHC[H2]CHOC(O)PhCN), 2.05 (s, 1H, C[H]CH(OH)), 1.71-1.74 (bs, 3H, C[H3]COC=C), 1.55-1.15 (m, 4H, C[H](CH3)2,C[H]CH(CH3)2, C[H2]CHCH(OH), 0.84 (m, 6H, (C[H3])2CHCH);
13C-NMR (150 MHz, CDCl3) δ 164.2, 163.5, 160.1, 131.1, 131.0, 129.0, 125.6, 102.1, 98.2, 85.6, 75.5, 65.7, 65.6, 63.4, 44.4, 40.7, 33.9, 32.2, 31.9, 29.7, 29.3, 29.0, 28.5, 25.8, 24.7, 22.7, 20.0, 19.8, 14.1, 10.9;
HRMS (ESI) [M+Na]+ 次式の計算値: C30H29NNaO6522.1893, 実測値: 522.1915。
(5aS,6S,8S,9aS,10R)-10-ヒドロキシ-8-イソプロピル-5a,9,9-トリメチル-1-オキソ-3-(ピリジン-3-イル)-1,5a,6,7,8,9,9a,10-オクタヒドロピラノ[4,3-b]クロメン-6-イル・アセテート(35), (PT008)の製造
1) (1S,4S,6S)-4-イソプロピル-1,3,3-トリメチル-7-オキサビシクロ[4.1.0]ヘプタン-2−オン(10)の合成
IR (KBr) 2855, 2363, 2343, 1075, 857, 773, 466 cm-1;
1H-NMR (400 MHz, CDCl3) δ 3.42 (d, 1H, J=4.8 Hz, C[H](O)C), 2.15 (dd, 1H, J=15.6, 10.4 Hz, 1/2 C[H2]CH(O)C), 2.02 (ddd, 1H, J=15.6, 6.4, 4.8 Hz, 1/2 C[H2]CH(O)C), 1.96-1.89 (m, 1H, C[H](CH3)2), 1.58-1.53 (m, 1H, C[H]CH(CH3)2), 1.38 (s, 3H, C[H3]COCH), 1.16 (s, 3H, C[H3]CCH3), 1.12 (s, 3H, CH3CC[H3]), 0.93 (d, 3H, J=6.8 Hz, CH(C[H3])2), 0.87 (d, 3H, J=7.2 Hz, CH(C[H3])2);
13C-NMR (100 MHz, CDCl3) δ 210.5, 63.3, 57.1, 49.9, 47.5, 27.6, 24.8, 24.4, 20.9, 20.8, 18.9, 16.7;
HRMS (EI) [M]+ 次式の計算値: C12H20O2196.1463, 実測値: 196.1451。
IR (KBr) 3474, 2957, 2858, 1744, 1656, 1545, 1468, 1377, 1346, 1253, 1198, 1088, 1050, 867, 836 cm-1;
1H-NMR (300 MHz, CDCl3) δ 4.18-4.13 (m, 1H, C[H]OTBS), 2.45 (s, 3H, C[H3]COC(CH3)2), 1.98-1.89 (m, 1H, C[H](CH3)2), 1.79-1.71 (m, 1H, C[H]CH(CH3)2), 1.70 (s, 3H, C[H3]COC=O), 1.69 (s, 3H, C[H3]COC=O), 1.60-1.55 (m, 2H, C[H2]CHOTBS), 1.55 (s, 3H, C[H3]CCHOTBS), 1.13 (s, 3H, C[H3]C(CH3)C), 0.95 (s, 3H, C[H3]CH(CH3)CH), 0.93 (d, 3H, J=6.9 Hz, C[H3]CH(CH3)CH), 0.89 (s, 9H, (C[H3])3CSi), 0.84 (d, 3H, J=6.9 Hz, C[H3]CH(CH3)CH), 0.10 (s, 3H, 1/2 (C[H3])2Si), 0.07 (s, 3H, 1/2 (C[H3])2Si);
13C-NMR (75 MHz, CDCl3) δ 197.6, 179.1, 158.2, 143.4, 132.4, 110.3, 105.8, 77.4, 72.6, 47.3, 39.5, 29.7, 26.0, 25.6, 25.3, 25.3, 25.2, 24.8, 24.6, 23.7, 21.8, 18.8, 18.3, 16.5, -3.8, -4.7;
HRMS (ESI, TFANa) [M+Na]+ 次式の計算値: C26H44NaO5Si 487.2856, 実測値: 487.2841。
IR (KBr) 2371, 2345, 1060, 773, 618, 476 cm-1;
1H-NMR (400 MHz, CDCl3) δ 3.82 (dd, 1H, J=11.6, 4.8 Hz, CHOTBS), 3.78 (s, 3H, C[H3]OC=O), 2.39 (s, 1H, C[H]C=O), 2.13 (s, 3H, C[H3]C=C), 2.02-1.97 (m, 1H, C[H](CH3)2), 1.52 (ddd, 1H, J=13.2, 4.8, 3.2 Hz, 1/2 C[H2]CHOTBS), 1.39-1.29 (m, 1H, 1/2 C[H2]CHOTBS), 1.31 (s, 3H, C[H3]CCHOTBS), 1.25 (s, 3H, C[H3]CCH3), 1.04-1.00 (m, 1H, C[H]CH(CH3)2), 1.03 (s, 3H, C[H3]CCH3), 0.90 (d, 3H, J=6.8 Hz, C[H3]CH(CH3)CH), 0.91 (s, 9H, (C[H3])3CSi), 0.79 (d, 3H, J=6.8 Hz, C[H3]CH(CH3)CH), 0.10 (s, 3H, 1/2 (C[H3])2Si), 0.10 (s, 3H, 1/2 (C[H3])2Si);
13C-NMR (100 MHz, CDCl3) δ 189.3, 174.0, 166.6, 111.5, 87.9, 77.2, 58.9, 52.0, 51.3, 37.8, 29.4, 28.9, 25.9, 25.2, 24.6, 20.6, 19.0, 18.3, 16.9, 13.5, -4.4, -4.4;
HRMS (ESI, TFANa) [M+Na]+ 次式の計算値: C24H42NaO5Si 461.2699, 実測値: 461.2697。
1H-NMR (400 MHz, CDCl3) δ 9.04 (br s, 1H, Py), 8.75 (br s, 1H, Py), 8.17 (d, 1H, J=8.0 Hz, Py), 7.47-7.46 (m, 1H, Py), 6.38 (s, 1H, C[H]=C), 3.94 (dd, 1H, J=11.6, 4.8 Hz, C[H]OTBS), 2.54 (s, 1H, C[H]C=O), 2.08-1.99 (m, 1H, C[H](CH3)2), 1.62-1.56 (m, 2H, C[H2]CHOTBS), 1.30 (s, 3H, C[H3]CCHOTBS), 1.24 (s, 3H, C[H3]CCH3), 1.11 (s, 3H, C[H3]CCH3), 1.11-1.06 (m, 1H, C[H]CH(CH3)2), 0.95 (s, 9H, (C[H3])3CSi), 0.93 (d, 3H, J=7.2 Hz, C[H3]CH(CH3)CH), 0.80 (d, 3H, J=6.4 Hz, C[H3]CH(CH3)CH), 0.18 (s, 3H, 1/2 (C[H3])2Si), 0.15 (s, 3H, 1/2 (C[H3])2Si);
13C-NMR (100 MHz, CDCl3) δ 187.5, 172.4, 161.9, 157.1, 151.9, 146.9, 134.5, 100.9, 98.1, 90.8, 90.5, 77.4, 76.9, 60.4, 51.1, 38.2, 29.8, 29.4, 28.8, 25.9, 25.2, 24.6, 22.8, 18.9, 18.3, 16.8, 14.2, -4.2, -4.3;
HRMS (ESI, TFANa) [M+Na]+ 次式の計算値: C29H41NNaO5 534.2652, 実測値: 534.2658。
IR (KBr) 3433, 2361, 1638, 1241, 1041, 804, 669, 535, 418 cm-1;
1H-NMR (400 MHz, CDCl3) δ 9.03 (br s, 1H, Py), 8.70 (br s, 1H, Py), 8.13 (d, 1H, J=8.4 Hz, Py), 7.44 (bs, 1H, Py), 6.47 (s, 1H, C[H]=C), 5.05 (d, 1H, J=4.0 Hz, C[H](OH)CH), 5.00 (dd, 1H, J=12.0, 4.8 Hz, C[H]OAc), 2.82 (bs, 1H, [H]OCH), 2.18 (s, 3H, C[H3]C(O)OCH), 2.06-1.99 (m, 1H, C[H](CH3)2), 1.79 (ddd, 1H, J=13.2, 4.8, 3.2 Hz, 1/2 C[H2]CHOAc), 1.67 (s, 3H, C[H3]CCHOAc), 1.54 (m, 2H, C[H]CH(OH), C[H]CH(CH3)2), 1.32 (m, 1H, 1/2 C[H2]CHOAc), 1.28 (s, 3H, C[H3]C(CH3)CH), 1.23 (s, 3H, C[H3]C(CH3)CH), 0.96 (d, 3H, J=6.8 Hz, C[H3]CHCH3), 0.85 (d, 3H, J=6.8 Hz, C[H3]CHCH3);
13C-NMR (75 MHz, CDCl3) δ 170.5, 161.7, 126.5, 105.0, 102.2, 84.3, 78.0, 77.4, 60.6, 53.0, 51.5, 39.8, 29.9, 27.8, 26.3, 25.6, 25.4, 21.6, 19.1, 19.1, 15.9, 15.8;
HRMS (ESI) [M+Na]+ 次式の計算値: C25H31NNaO6464.2049, 実測値: 464.2048。
(5aS,6S,8S,9aS,10R)-10-ヒドロキシ-8-イソプロピル-5a,9,9-トリメチル-1-オキソ-3-(ピリジン-3-イル)-1,5a,6,7,8,9,9a,10-オクタヒドロピラノ[4,3-b]クロメン-6-イル 4-シアノベンゾエート(15), (PT009)の製造
IR (KBr) 3433, 3020, 2360, 2341, 1637, 1216, 772, 669 cm-1;
1H-NMR (400 MHz, CDCl3) δ 8.99 (br s, 1H, Py), 8.68 (br s, 1H, Py), 8.23 (d, 2H, J=8.4 Hz, p-CN[Bz]), 8.14 (br s, 1H, Py), 7.80 (d, 2H, J=8.0 Hz, p-CN[Bz]), 7.45 (br s, 1H, Py), 6.41 (s, 1H, C[H]=C), 5.28 (dd, 1H, J=12.2, 5.0 Hz, C[H]Op-CNBz), 5.09 (d, 1H, J=3.6 Hz, C[H](OH)CH), 2.85 (br s, 1H, [H]OCH), 2.10-2.04 (m, 1H, C[H](CH3)2), 1.92 (ddd, 1H, J=13.0, 4.8, 3.2 Hz, 1/2 C[H2]CHOp-CNBz), 1.82 (s, 3H, C[H3]CCHOp-CNBz), 1.70 (m, 1H, C[H]CH(CH3)2), 1.62 (d, 1H, J=4.0 Hz, C[H]CH(OH)), 1.28 (s, 3H, C[H3]C(CH3)CH), 1.25 (m, 4H, C[H3]C(CH3)CH, C[H2]CHOp-CNBz), 0.98 (d, 3H, J=6.8 Hz, C[H3]CHCH3), 0.86 (d, 3H, J=6.4 Hz, C[H3]CHCH3);
HRMS (ESI,TFANa) [M+Na]+ 次式の計算値: C31H32N2NaO6 551.2158, 実測値: 511.2171。
2-((5aS,6S,8S,9aS,10R)-6-アセトキシ-10-ヒドロキシ-5a,9,9-トリメチル-1-オキソ-3-(ピリジン-2-イル)-1,5a,6,7,8,9,9a,10-オクタヒドロピラノ[4,3-b]クロメン-8-イル)プロパン-1,3-ジイル・ジアセテート(26), (PT010)の製造
1) (R)-5-(3-クロロプロプ-1-エン-2-イル)-2,6,6-トリメチルシクロヘキス-2-エンオン(17)の合成
HRMS (EI) [M]+ 次式の計算値: C12H17ClO 212.0968, 実測値: 212.0976。
HRMS (EI) [M]+ 次式の計算値: C12H18O2194.1307, 実測値: 194.1306。
HRMS (EI) [M]+ 次式の計算値: C12H18O3210.1256, 実測値: 210.1253。
HRMS (ESI, TFANa) [M+Na]+ 次式の計算値: C18H32NaO3Si 347.2018, 実測値: 347.2021。
HRMS (ESI, TFANa) [M+Na]+ 次式の計算値: C18H34NaO3Si 349.2175, 実測値: 349.2168。
HRMS (ESI, TFANa) [M+Na]+ 次式の計算値: C24H48NaO3Si2 463.3040, 実測値: 463.3061。
HRMS (ESI, TFANa) [M+Na]+ 次式の計算値: C24H48NaO4Si2 479.2989, 実測値: 479.2967。
HRMS (ESI, TFANa) [M+Na]+ 次式の計算値: C38H72NaO7Si3 747.4484, 実測値: 747.4481。
HRMS (ESI, TFANa) [M+Na]+ 次式の計算値: C36H70NaO7Si3 721.4327, 実測値: 721.4349。
HRMS (ESI, TFANa) [M+]+ 次式の計算値: C41H69NO7Si3772.4460, 実測値: 772.4446。
HRMS (ESI, TFANa) [M+Na]+ 次式の計算値: C29H35NNaO10 580.2159, 実測値: 580.2137。
(5aS,6S,8S,9aS,10R)-10-ヒドロキシ-5a,9,9-トリメチル-1-オキソ-3-(ピリジン-3-イル)-8-(2-(o-トルイル)-1,3-ジオキサン-5-イル)-1,5a,6,7,8,9,9a,10-オクタヒドロピラノ[4,3-b]クロメン-6-イル 4-シアノベンゾエート (PT017)の製造
13C-NMR (100 MHz, CDCl3) δ171.1, 171.0, 164.0, 163.8, 161.8, 157.4, 151.5, 146.7, 133.9, 133.1, 132.4, 130.2, 117.9, 116.8, 103.2, 99.1, 82.8, 78.9, 65.6, 62.4, 60.5, 52.5, 46.1, 39.1, 34.9, 27.1, 26.7, 20.9, 18.5, 15.9;
ESI-HRMS (TFA-Na) 次式の計算値: C35H36N2NaO10 666.2268 (M+Na+), 実測値: 666.2293 (M+Na+)。
2-((5aS,6S,8S,9aS,10R)-6-((4-シアノベンゾイル)オキシ)-10-ヒドロキシ-5a,9,9-トリメチル-1-オキソ-3-(ピリジン-3-イル)-1,5a,6,7,8,9,9a,10-オクタヒドロピラノ[4,3-b] クロメン-8-イル)プロパン-1,3-ジイル ジアセテート (PT022)の製造
13C-NMR (100 MHz, CDCl3) δ164.3, 163.6, 161.7, 135.9, 135.7, 133.9, 132.6, 130.5, 130.4, 129.0, 126.1, 125.7, 117.9, 117.0, 103.8, 100.0, 82.9, 79.0, 72.0, 70.7, 60.5, 52.6, 45.7, 39.4, 32.8, 32.0, 29.8, 29.7, 29.5, 27.3, 27.2, 22.8, 19.0, 18.8, 16.0, 14.2;
ESI-HRMS (TFA-Na) 次式の計算値: C39H39N2O8 663.2706 (MH+), 実測値: 663.2713 (MH+)。
〔試験例1:ACAT2阻害活性試験〕
前記の手順で製造された化合物について、下記の手順でACAT2阻害活性を調査した。
ACAT2酵素タンパク質の調製は、Uelmenらの方法(Uelmenら, J. Biol. Chem., 第270巻, 26192-26210頁, 1995年)を一部改変して行った。ACAT2酵素タンパク質の抽出源としては、マウス肝臓ミクロソーム由来の膜画分を用いた。マウス肝臓を、緩衝液A[50 mMトリス塩酸緩衝溶液(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、その上清を、10000×gで超遠心した。得られた沈渣を、マウス肝臓ミクロソーム画分とした。この画分を、5 mg/mlのタンパク質濃度となるように緩衝液Aで調整して、ACAT2酵素タンパク質の酵素源を得た。
ACAT2活性の測定は、下記の手順で行った。200μgタンパク質量の前記酵素源、200 mM牛血清アルブミン及び[1-14C]オレオイルコエンザイムA(最終濃度170μM, 0.09μCi)と、所定量の各実施例化合物又は比較例化合物を含む試料とを緩衝液Aに加えて、全量を200μlに調整して、反応溶液を得た。前記反応溶液を、37℃で5分間インキュベートした。前記試料の代わりに、10μlのメタノールを加えて調製した反応溶液を、コントロールの反応溶液とした。
***:0.5μM≧阻害活性
** :10μM≧阻害活性>0.5μM
* :100μM≧阻害活性>10μM
阻害活性=ACAT2活性を50%阻害する濃度(IC50)
Claims (10)
- 式(I):
R1は、置換若しくは非置換のシクロアルキル、置換若しくは非置換のアリール、置換若しくは非置換のヘテロシクロアルキル、又は置換若しくは非置換のヘテロアリールであり、
nは、0〜5の整数であり、
R2は、ハロゲン、シアノ、ニトロ、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換のシクロアルキル、置換若しくは非置換のシクロアルケニル、置換若しくは非置換のシクロアルキニル、置換若しくは非置換のヘテロシクロアルキル、置換若しくは非置換のアリール、置換若しくは非置換のアリールアルキル、置換若しくは非置換のアリールアルケニル、置換若しくは非置換のヘテロアリール、置換若しくは非置換のヘテロアリールアルキル、置換若しくは非置換のアルコキシ、置換若しくは非置換のシクロアルコキシ、置換若しくは非置換のヘテロシクロアルコキシ、置換若しくは非置換のアリールオキシ、置換若しくは非置換のアリールアルキルオキシ、置換若しくは非置換のアリールアルケニルオキシ、置換若しくは非置換のヘテロアリールオキシ、置換若しくは非置換のヘテロアリールアルキルオキシ、置換若しくは非置換のアシル、又は-NRN1RN2であり、但しnが2以上の場合、複数のR2は互いに同一又は異なっていてもよく、
RN1及びRN2は、互いに独立して、水素、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換のシクロアルキル、置換若しくは非置換のシクロアルケニル、置換若しくは非置換のシクロアルキニル、置換若しくは非置換のヘテロシクロアルキル、置換若しくは非置換のアリール、置換若しくは非置換のアリールアルキル、置換若しくは非置換のアリールアルケニル、置換若しくは非置換のヘテロアリール、置換若しくは非置換のヘテロアリールアルキル、置換若しくは非置換のアルコキシ、置換若しくは非置換のシクロアルコキシ、置換若しくは非置換のヘテロシクロアルコキシ、置換若しくは非置換のアリールオキシ、置換若しくは非置換のアリールアルキルオキシ、置換若しくは非置換のアリールアルケニルオキシ、置換若しくは非置換のヘテロアリールオキシ、置換若しくは非置換のヘテロアリールアルキルオキシ、及び置換若しくは非置換のアシルからなる群より選択される1価基であり、
R3及びR4は、互いに独立して、水素、ヒドロキシル、置換若しくは非置換のアルキルカルボニルオキシ、置換若しくは非置換のアリールカルボニルオキシ、又は置換若しくは非置換のアルコキシであるか、或いは、
R3及びR4は、一緒になって-O-CR7R8-O-を形成しており、
R5は、水素、ヒドロキシル、置換若しくは非置換のアルキルカルボニルオキシ、置換若しくは非置換のアリールカルボニルオキシ、又は置換若しくは非置換のアルコキシであり、
R6は、-C(CH3)2-又は-CH2-であり、
R7及びR8は、互いに独立して、水素、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換のシクロアルキル、置換若しくは非置換のシクロアルケニル、置換若しくは非置換のシクロアルキニル、置換若しくは非置換のヘテロシクロアルキル、置換若しくは非置換のアリール、置換若しくは非置換のアリールアルキル、置換若しくは非置換のアリールアルケニル、置換若しくは非置換のヘテロアリール、又は置換若しくは非置換のヘテロアリールアルキルである。]
で表される化合物若しくはその塩、又はそれらの溶媒和物。 - R1が、置換若しくは非置換のアリール、又は置換若しくは非置換のヘテロアリールであり、
R2が、ハロゲン、シアノ、ニトロ、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、又は置換若しくは非置換のアルキニルであり、
R7及びR8が、互いに独立して、水素、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、又は置換若しくは非置換のアリールである、請求項1に記載の化合物。 - R2がシアノである、請求項1又は2に記載の化合物。
- nが1であり、且つR2が4-シアノである、請求項1〜3のいずれか1項に記載の化合物。
- 請求項1〜4のいずれか1項に記載の化合物を製造する方法であって、以下:
式(II):
で表される化合物をエポキシ化して、式(III):
で表される化合物を得る、エポキシ化工程;
前記エポキシ化工程で得られる式(III)で表される化合物にアルデヒド基を導入して、式(IV):
R3、R4、R5及びR6は、前記と同義であり、
RP1は、ヒドロキシルの保護基である。]
で表される化合物を得る、アルデヒド基導入工程;
前記アルデヒド基導入工程で得られる式(IV)で表される化合物を増炭及び環化して、式(V):
R3、R4、R5、R6及びRP1は、前記と同義であり、
RP2は、カルボン酸の保護基である。]
で表される化合物を得る、C環導入工程;
C環導入工程で得られる式(V)で表される化合物を環化して、式(VII):
R1は、請求項1〜4のいずれか1項に記載の定義と同義であり、
R3、R4、R5、R6及びRP1は、前記と同義である。]
で表される化合物を得る、D環導入工程;
D環導入工程で得られる式(VII)で表される化合物と、式(VIII):
R2及びnは、請求項1〜4のいずれか1項に記載の定義と同義であり、
RL2は、カルボン酸の活性化基である。]
で表される化合物とを反応させて、式(IX):
で表される化合物を得る、ベンゾイル基導入工程;
ベンゾイル基導入工程で得られる式(IX)で表される化合物の10-位カルボニル基を還元して、式(I)で表される化合物を得る、還元工程;
を含む、前記方法。 - 請求項1〜4のいずれか1項に記載の化合物若しくはその塩、又はそれらの溶媒和物を有効成分として含むACAT2阻害剤。
- 請求項1〜4のいずれか1項に記載の化合物若しくはその製薬上許容される塩、又はそれらの製薬上許容される溶媒和物を有効成分として含む医薬。
- 請求項1〜4のいずれか1項に記載の化合物若しくはその製薬上許容される塩、又はそれらの製薬上許容される溶媒和物と、1種以上の製薬上許容される担体とを含む医薬組成物。
- 脂質異常症、動脈硬化症、高血圧症、脂肪肝及び肥満症からなる群より選択される1種以上の疾患若しくは症状の予防又は治療に使用するための、請求項7に記載の医薬。
- 脂質異常症、動脈硬化症、高血圧症、脂肪肝及び肥満症からなる群より選択される1種以上の疾患若しくは症状の予防又は治療に使用するための、請求項8に記載の医薬組成物。
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EP15812239.0A EP3162805B1 (en) | 2014-06-24 | 2015-06-18 | Novel pharmaceutical compound having a cholesterol acyltransferase isozyme 2 (acat2) -inhibiting activity |
US15/320,834 US9896456B2 (en) | 2014-06-24 | 2015-06-18 | Pharmaceutical compound having inhibitory activity against cholesterol acyltransferase isozyme 2 (ACAT2) |
PCT/JP2015/067636 WO2015198966A1 (ja) | 2014-06-24 | 2015-06-18 | 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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JPH08291164A (ja) * | 1995-04-18 | 1996-11-05 | Kitasato Inst:The | ピリピロペン誘導体 |
US6916824B1 (en) * | 1999-11-12 | 2005-07-12 | Kansas State University Research Foundation | Methods of treating cataracts and diabetic retinopathy with tricyclic pyrones |
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