JP2019524686A - セスキテルペン誘導体の新規用途 - Google Patents
セスキテルペン誘導体の新規用途 Download PDFInfo
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- JP2019524686A JP2019524686A JP2018568856A JP2018568856A JP2019524686A JP 2019524686 A JP2019524686 A JP 2019524686A JP 2018568856 A JP2018568856 A JP 2018568856A JP 2018568856 A JP2018568856 A JP 2018568856A JP 2019524686 A JP2019524686 A JP 2019524686A
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Abstract
Description
i)3番炭素と4番炭素の結合及び5番炭素と6番炭素の結合が単一結合であるとき、R2bは存在せず、R2aはCH2である構造、
ii)3番炭素と4番炭素の結合が二重結合であるとき、5番炭素と6番炭素の結合は単一結合であり、R2bは存在せず、R2aはCH3である構造、及び
iii)5番炭素と6番炭素の結合が二重結合であるとともに、3番炭素と4番炭素の結合は単一結合であるとき、R2a及びR2bはCH3である構造からなる群から選択される一つの構造であって、R1はH又はCH3であって、R3は下記R3a〜R3dからなる群から選択されるいずれか一つの作用基であって、
i)R4及びR7がそれぞれOH又はOCH3であり、R5、R6及びR8はHである構造、又は
ii)R5がCOOCH3であり、R7はH又はOHであり、R8はOHであり、R4及びR6はHである構造であって、前記R3bは、R9がH、NH2、C1〜C8アルコキシ基及び下記のR9a〜R9jからなる群から選択されるいずれか一つの作用基であり、R10はH又はOHであって、
R11及びR12はそれぞれOH又はOCH3であり、R13はCH3である構造であって、前記R3dはR14がOCH3であり、R15及びR16はCH3である構造。
i)3番炭素と4番炭素の結合及び5番炭素と6番炭素の結合が単一結合であるとき、R2bは存在せず、R2aはCH2である構造;
ii)3番炭素と4番炭素の結合が二重結合であるとき、5番炭素と6番炭素の結合は単一結合であり、R2bは存在せず、R2aはCH3である構造;及び
iii)5番炭素と6番炭素の結合が二重結合であるとき、3番炭素と4番炭素の結合は単一結合であり、R2a及びR2bはCH3である構造からなる群から選択される一つの構造であって、R1はH又はCH3であって、R3は下記R3a〜R3dからなる群から選択されるいずれか一つの作用基であって、
i)R4及びR7がそれぞれOH又はOCH3であり、R5、R6及びR8はHである構造、又は
ii)R5がCOOCH3であり、R7はH又はOHであり、R8はOHであり、R4及びR6はHである構造であって、前記R3bはR9がH、NH2、C1〜C8アルコキシ基及び下記のR9a〜R9jからなる群から選択されるいずれか一つの作用基であり、R10はH又はOHであって、
R11及びR12はそれぞれOH又はOCH3であり、R13はCH3である構造であり、前記R3dはR14がOCH3であり、R15及びR16はCH3である構造であることを特徴とする。
i)3番炭素と4番炭素の結合及び5番炭素と6番炭素の結合が単一結合であるとき、R2bは存在せず、R2aはCH2である構造は下記化学式4で表示されるものであってもよく;
ii)3番炭素と4番炭素の結合が二重結合であるとき、5番炭素と6番炭素の結合は単一結合であり、R2bは存在せず、R2aはCH3である構造は下記化学式5で表示されるものであってもよく;
iii)5番炭素と6番炭素の結合が二重結合であるとき、3番炭素と4番炭素の結合は単一結合であり、R2a及びR2bはCH3である構造は下記化学式6で表示されるものであってもよい。
IR(film)3339、1680、1303cm−1、
UV(CH3OH)λmax 221(17440)、269(7460)、305nm(3341、sh);UV(CH3OH/NaOH)λmax 210(18520)、241(13176)、284(4310)、322nm(6950)、
1H NMR (600 MHz) δ 7.49 (1H, d, 1.5), 7.45 (1H, d, 1.5), 5.32 (1H, bs), 3.87 (3H, s), 2.84 (1H, d, 14) and 2.60 (1H, d, 14) AB system, 1.64 (3H, bs), 0.98 (3H, d, 6), 0.95 (3H, s), 0.90 (3H, s)、
13C−NMR(CDCl3、150.87MHz)データは下記[表5]参照。
m.p.>350、
SM m/e(%):191(40)、154(12)、135(44)、121(65)、109(56)、107(87)、95(100、
UV(EtOH)λmax nm(ε):214、286、
IR(KBr)υcm−l:3324、2940、1645、1535、
1H NMR (MeOD, 80 MHz) δ ppm: 5.71(1H, s), 4.76 (2H, br s), 2.40 (2H, br s), 1.01 (3H, s), 0.92 (3H, d, J=7 HZ), 0.78 (3H,s)、
13C NMR(δppm、CD3OD、20.115MHz)データは下記の[表6]参照。
m.p.:170−172;SM m/e(%):413(4)、3ll(8)、283(12)、223(100)、191(11)、167(22)、153(27)、149(15)、135(14)、121(16)、109(18)、107(12)、95(79)、
m/e191.179、calc.191.179 for Cl4H23;m/e223.119、calc.223.120 for C12H17NO3、
UV(EtOH)λmax nm(ε):204(27230).324(14070)、
IR(KBr)υcm−l:3417、3275、1640、1592;1H NMR (CDC1 3.200 MHz) δ ppm: 8.41 (1H exch., s), 6.41 (1H exch., t). 5.36 (lH, s), 4.43 (br s), 3.20 (2H. dt), 2.48 (d)-2.37 (d) (AB syst.). 2.31 (dt), 2.07 (2 H, m), 1.85 (lH, m), 1.80-1.05 (llH, m). 1.04 (3H. s). 0.95 (9H, 3d overlaped), 0.83 (3H, s), 0.78 (lH, dd)、
13C NMR(δppm、CDCl3、20.115MHz)データは下記[表6]参照。
SM m/e(%):399(5)、209(100)、191(17)、166(36)、152(18)、135(11)、121(15)、109(15)、107(12)、95(66)、
UV(EtOH)λmax nm(ε):210(14000)、329(20150);IR(KBr)υcm−l:3417、3275、1640、1592、
1H NMR (CDC1 3, 200 MHz) δ ppm: 6.53 (1H. s). 5.41 (1H. S), 4.45 (2H br s), 2.95 (2H, dt), 2.48 (lH, d), 2.45 (lH, d, J =13 Hz), 1.O3 (3H, s), 0.97 (9H. 3d overlaped), 0.82 (3H. s). 0.76 (lH, dd)。
C21H30O3N(HRESIMS m/z 344.2295、[M+H]+)、
UV(MeOH)λmax(logε)315(3.58)nm;IR(KBr)3835、3566、1624、1536cm−1;1H-NMR (400 MHz, CD 3OD) δ: 2.17/1.43 (2H, m H-1), 1.39 (2H,m, H-2), 1.50/1.38 (2H, m, H-3), 2.34/2.05 (2H, m, H-6), 1.23/1.82 (2H, m, H-7), 1.23 (1H, m, H-8), 0.82(1H, m, H-10), 4.44 (2H, s, H-11), 1.05 (3H, s, H-12), 0.98 (3H, d, J = 6.4 Hz H-13), 0.84 (3H, s, H-14), 2.47/2.40 (2H, dd, J = 13.7 Hz, H-15), 5.51 (1H, s, H-19)、
13C-NMR (100 MHz, CD 3OD) δ: 22.8 (t, C-1), 27.5 (t, C-2), 36.4 (t, C-3), 160.1 (s, C-4), 39.9 (s, C-5), 32.5 (t, C-6), 28.3 (t, C-7), 37.6 (d, C-8), 42.1 (s, C-9), 49.7 (d, C-10), 101.1 (t, C-11), 19.4 (q, C-12), 16.9 (q, C-13), 16.2 (q, C-14), 31.6 (t, C-15), 113.7 (s, C-16), 159.4 (s, C-17), 183.2 (s, C-18), 93.6 (d, C-19), 183.2 (s, C-21)。
[α]D+94.4(c0.018、MeOH)、
UV(PDA、CH3CN/H2O)λmax 218、311、494nm;IR(neat)νmax 3598、2936、2064、1657cm−1、
1H(300MHz)及び13C(75MHz)NMR(CD3OD)データは下記[表7]参照、
HRESIMS m/z 424.2104[M+Na]+(calcd for C23H31NO5Na、424.2094、Δ1.0mmu)。
[α]D+13(c0.06、MeOH)、
UV(PDA、CH3CN/H2O)λmax 233、314、494nm、
IR(neat)νmax 3410、2930、1686、1632、1567cm−1、
HRESIMS m/z 438.2264[M+Na]+(calcd for C24H33NO5Na、438.2251、Δ1.3mmu)、
1H NMR (CD 3OD, 300 MHz) δ 5.38 (1H, s, H-19), 4.40 (2H, s, H 2-11), 3.45 (2H, t, J = 6.8 Hz, H 2-23), 2.59 (2H, t, J = 6.8 Hz, H 2-24), 2.47 (1H, d, J = 13.6 Hz, H a-15), 2.38 (1H, d, J = 13.6 Hz, H b-15), 2.32 (1H, m, H a-3), 2.16 (1H, m, H a-1), 2.04 (1H, m, H b-3), 1.80 (1H, m, H a-2), 1.48 (1H, m, H a-6), 1.43 (1H, m, H b-1), 1.41 (1H, m, H a-7), 1.36 (1H, m, H b-6), 1.35 (1H, m, H b-7), 1.29 (1H, m, H b-2), 1.21 (1H, m, H-8), 1.04 (3H, s, H 3-12), 0.97 (3H, d, J = 6.4 Hz, H 3-13), 0.83 (3H, s, H 3-14), 0.81 (1H, m, H-10)、
13C NMR (CD 3OD, 75 MHz) δ 183.4 (C, C-21), 179.6(C, C-18), 176.0 (C, C-25), 162.9 (C, C-4), 161.1 (C, C-17), 152.0 (C, C-20), 115.5 (C, C-16), 103.3 (CH 2, C-11), 92.6 (CH, C-19), 51.1 (CH, C-10), 44.0 (C, C-9), 41.8 (C, C-5), 39.9 (CH 2, C-23), 39.0 (CH, C-8), 38.2 (CH 2, C-6), 34.5 (CH 2, C-24), 34.2 (CH 2, C-3), 33.4 (CH 2, C-15), 30.0 (CH 2, C-2), 29.4 (CH 2, C-7), 24.3 (CH 2, C-1), 21.4 (CH 3, C-12), 18.7 (CH 3, C-13), 18.1 (CH 3, C-14)。
[α]D−6.7(c0.075、MeOH)、
UV(PDA、CH3CN/H2O)λmax 236、297、323(sh)nm;IR(neat)νmax 3408、2927、1541cm−1、
1H(300MHz)及び13C(75MHz)NMR(CD3OD)データは下記[表8]参照、
HRESIMS m/z 378.2050[M+Na]+(calcd for C22H29NO3Na、378.2040、Δ1.0mmu)。
[α]D−170(c0.003、CHCl3)、
UV(PDA、CH3CN/H2O)λmax 233、278、284、300(sh)nm、
IR(neat)νmax 3488、2927、1775、1630、1458cm−1、
HRESIMS m/z 462.2250[M+Na]+(calcd for C26H33NO5Na、462.2251、Δ0.1mmu)、
1H NMR (CDCl 3, 300 MHz) δ 8.07 (1H, s, H-22), 7.54 (1H, s, H-19), 4.42 (1H, d, J = 1.6 Hz, H a-11), 4.38 (1H, d, J = 1.6 Hz, H b-11), 2.83 (1H, d, J = 14.2 Hz, H a-15), 2.76 (1H, d, J = 14.2 Hz, H b-15), 2.35 (1H, m, H a-3), 2.34 (s, a-OCOCH 3), 2.30 (s, b-OCOCH 3), 2.08 (1H, m, H b-3), 1.92 (1H, m, H a-2), 1.58 (1H, m, H a-1), 1.49 (1H, m, H a-6), 1.45 (1H, m, Hb-1),1.43 (1H, m, H-8), 1.42 (2H, m, H 2-7), 1.28 (1H, m, H b-6), 1.26 (1H, m, H b-2), 1.07 (3H, s, H 3-12), 0.97 (3H, d, J = 5.6 Hz, H 3-13), 0.94 (3H, s, H 3-14), 0.92 (1H, m, H-10)、
13C NMR (CDCl 3, 150 MHz) δ168.1 (C, a-OCOCH 3), 167.9 (C, b-OCOCH 3), 159.1 (C, C-4), 152.7 (CH, C-22), 147.9 (C, C-21), 140.4 (C, C-17), 137.4 (C, C-18), 136.6 (C, C-20), 118.3 (C, C-16), 111.9 (CH, C-19), 102.2 (CH 2, C-11), 50.1 (CH, C-10), 43.0 (C, C-9), 40.3 (C, C-5), 37.6 (CH, C-8), 36.2 (CH 2, C-6), 35.6 (CH 2, C-15), 32.6 (CH 2, C-3), 28.3 (CH 2, C-2), 27.7 (CH 2, C-7), 23.1 (CH 2, C-1), 20.1 (2 × CH 3, -OCOCH 3), 19.9 (CH 3, C-12), 18.1 (CH 3, C-13), 16.8 (CH 3, C-14)。
[α]20 579+64.4°(c0.27CHCl3)、
IR(film)3341、1652、1645、1609、1243cm−1、
UV(CH3OH)λmax 213(9600)、288nm(13485)、
UV(CH3OH/NaOH)λmax 210(12850)、290(8930)、526nm(1650)、
1H NMR(600MHz、CDCl3、δ、JinHz)データは下記[表9]参照、
13C NMR(150.87MHz、CDCl3)データは下記[表9]参照、
HREIMS m/z 358.2151 [M+](12、calcd for C22H30O4、358.2144)、191.1803(15、calcd for C14H23、191.1800)、168.0423(41、calcd for C8H8O4、168.0422)、121.1013(12、calcd for C9H13、121.1017)、107.0859(30、calcd for C8H11、107.0861)、95.0861(100、calcd for C7H11、95.0861)。
m.p. 108.5−109.5、
C22H3004(high resolution FABMS(M+358.2146、Δ0.2mmu、C22H3004;MH+359.2223、Δ0.1mmu、C22H3104))、
lH NMR (500 MHz, CDCl 3) δ: 0.73 (s, 3H), 0.90 (sh, lH), 0.92 (s, 3H), 0.96 (d, J=7 Hz, 3H), 0.99 (s, 3H), I.12 (ddd, J=13.5,13.5, 4.3 Hz, 1H), 1.33-1.45 (complex mult., 4H), 1.73 (mult, lH), 1.79 (br d, lH), 1.95 (ddd, J=18, 17.5, 4.5 Hz, 1H), 2.08 (br d, J=13 Hz, 1H), 2.45 (d, cJ=13.0 HZ, lH), 2.58 (d, J=13.0 Hz, lH), 3.84 (s, 3H), 5.35 (br s, lH), 5.84 (s, 1H), 7.45 (s, 1H)、
13C NMR (500 MHz, CDCl3), δ (mult., proton asignments): 16.0 (q, 0.73, C-14), 16.5 (q, 0.92, C-11), 22.7 (t, 1.40, 1.46, C-2), 27.9 (q, 0.96, C-13), 29.7 (q, 0.99, C-12). 30.6 (t, 0.90, 1.79, C-l), 31.5 (t, 1.73, 1.95, C-7), 32.7 (t, 2.45,2.58, C-15), 36.3 (s, C-4), 36.4 (d, 1.36, C-8), 40.9 (s, C-g), 41.2 (t, 1.13, 1.32, C-3), 41.7 (s, 2.08, C-10), 56.8 (q, 3.86, C-22), 102.0 (d, 5.85, C-19),114.8 (d, 5.35, C-6), 118.3 (s, C-16), 146.3 (s, C-5), 152.8 (s, -OH, C-17), 161.5 (s, C-20), 182.0 (s, C-21), 182.4 (s, C-18).
[α]23 D−14(c0.2、CHCl3)、
IR(film)νmax 3290、1730、1650、1590、1510、1460、1380、1360、1220cm−1、
UV(MeOH)λmax 336(log4.28)、507nm(2.84)、
1H NMR(CDCl3)データは下記[表10]参照、
13C NMR(CDCl3)データは下記[表10]参照、
EIMS m/z(%)447(M+、9)、257(100)、191(2)、166(20)、152(5)、105(10)、95(15);HREIMS m/z 447.2790[M]+(calcd for C29H37NO3、447.2773)。
[α]25 D+180(c0.1、CHCl3)、
IR(film)νmax 3270、1730、1640、1590、1510、1460、1380、1210cm−1、
UV(MeOH)λmax 335(log4.20)、502nm(2.74)、
1H NMR(CDCl3)データは下記[表11]参照、
13C NMR(CDCl3)データは下記[表11]参照、
EIMS m/z(%)447(M+、25)、257(100)、209(17)、191(18)、168(45)、166(48)、152(17)、119(42)、105(40)、
HREIMS m/z 447.2783[M]+(calcd for C29H37NO3、447.2773)。
[α]23 D+160(c0.1、CHCl3)、
IR(film)νmax 3270、1730、1640、1590、1510、1380、1210cm−1、
UV(MeOH)λmax 334(log4.29)、509nm(2.86)、
1H NMR(CDCl3)データは下記[表12]参照、
13C NMR(CDCl3)データは下記[表12]参照、
EIMS m/z(%)399(M+、8)、209(100)、191(3)、166(11)、152(9)、107(9)、95(22)、
HREIMS m/z 399.2790[M]+(calcd for C25H37NO3、399.2773)。
[α]21 D+136(c0.25、CHCl3)、
IR(film)νmax 3270、1680、1650、1590、1510、1450、1380、1210cm−1、」
UV(MeOH)λmax 336(log4.09)、505nm(2.67)、
1H NMR(CDCl3)データは下記[表13]参照、
13C NMR(CDCl3)データは下記[表13]参照、
HREIMS m/z 413.2940[M]+(calcd for C26H39NO3、413.2930)。
[α]21 D+124(c0.25、CHCl3)、
IR(film)νmax 3270、1680、1640、1590、1510、1380、1210cm−1、
UV(MeOH)λmax 336(log4.17)、515nm(2.55)、
1H NMR(CDCl3)データは下記[表14]参照、
13C NMR(CDCl3)データは下記[表14]参照、
EIMS m/z(%)413(M+、7)、223(100)、191(3)、166(8)、152(9)、107(8)、95(18)、
HREIMS m/z 413.2947[M]+(calcd for C26H39NO3、413.2930)。
[α]23 D−42(c0.25、CHCl3)、
IR(film)νmax 3290、1680、1650、1590、1520、1460、1390、1200cm−1、
UV(MeOH)λmax 338(log4.06)、511nm(2.63)、
1H NMR(CDCl3)データは下記[表15]参照、
13C NMR(CDCl3)データは下記[表15]参照、
EIMS m/z(%)413(M+、15)、223(100)、191(10)、168(15)、166(14)、152(16)、119(18)、
HREIMS m/z 413.2916[M]+(calcd for C26H39NO3、413.2930)。
[α]21 D−38(c0.2、CHCl3)、
IR(film)νmax 3270、1680、1650、1590、1510、1460、1380、1200cm−1、
UV(MeOH)λmax 338(log4.21)、515nm(2.63)、
1H NMR(CDCl3)データは下記[表16]参照、
13C NMR(CDCl3)データは下記[表16]参照、
EIMS m/z(%)413(M+、24)、223(100)、191(13)、166(20)、152(17)、119(20)、
HREIMS m/z 413.2947[M]+(calcd for C29H37NO3、413.2930)。
[α]22 D+33(c0.2、CHCl3)、
IR(film)νmax 3280、1640、1590、1510、1380、1200cm−1、
UV(MeOH)λmax 501(log2.88)、327(4.17)、243(3.86)、208nm(4.25)、
1H NMR(CDCl3)データは下記[表17]参照、
13C NMR(CDCl3)データは下記[表17]参照、
EIMS m/z(%)413(M+、15)、223(100)、191(3)、166(10)、152(10)、95(10)、
HREIMS m/z 413.2934[M]+(calcd for C26H39NO3、413.2930)。
[α]22 D+38(c0.2、MeOH)、
IR(KBr)νmax 3450、1640、1600、1530、1380、1210cm−1、
UV(MeOH)λmax 237(log2.8)、345(4.00)、513nm(2.47)、
1H NMR(DMSO−d6)データは下記[表18]参照、
13C NMR(DMSO−d6)データは下記[表18]参照、
ESIMS(neg)m/z 450[M−H]−、
HRESIMS(neg)m/z 450.1955[M−H]−(calcd for C23H32NO6S、450.1950)。
[α]27 D+17.3(c0.12、CHCl3)、
1H NMR (500 MHz, CDCl 3) δ: 7.77 (1H, s), 7.77-7.74 (1H, m), 6.77 (1H, d, J = 8.0 Hz), 6.01 (1H, s), 4.41 (1H, s), 4.36 (1H, s), 3.87 (3H, s), 2.68 (1H, d, J = 14.3 Hz), 2.64 (1H, d, J = 14.3 Hz), 2.33 (1H, td, J = 13.7, 5.2 Hz), 2.08 (2H, d, J = 13.7 Hz), 1.93-1.89 (1H, m), 1.61-1.56 (1H, m), 1.47 (1H, dt, J = 12.2, 3.2 Hz), 1.41-1.38 (3H, m), 1.31-1.27 (1H, m), 1.22-1.19 (1H, m), 1.06 (3H, s), 1.02 (3H, d, J = 6.9 Hz), 0.96 (1H, dd, J = 12.0, 1.7 Hz), 0.88 (3H, s)、
13C NMR (125 MHz, CDCl 3) δ: 167.6, 160.0, 159.2, 135.0, 129.3, 125.2, 121.6, 115.3, 102.8, 52.0, 48.0, 42.0, 40.2, 37.0, 36.5, 36.3, 33.0, 27.8, 27.7, 23.2, 20.5, 17.62, 17.59、
IR(KBr):3341、1686、1601、1426、1287cm−1、
MS(ESI−TOF)m/z:379[M+Na]+、
HRMS(ESI−TOF)m/z:379.2249(Calcd for C23H32O3Na;Found:379.2266)。
[α]26 D+10.4(c0.19、CHCl3)、
1H NMR (500 MHz, CDCl 3) δ: 7.49 (1H, d, J = 2.0 Hz), 7.40 (1H, d, J = 2.0 Hz), 5.90 (2H, S), 4.41 (1H, s), 4.37 (1H, s), 3.87 (3H, s), 2.68 (1H, d, J = 14.3 Hz), 2.65 (1H, d, J = 14.3 Hz), 2.34 (1H, td, J = 13.7, 5.0 Hz), 2.09 (2H, d, J = 14.3 Hz), 1.93-1.91 (1H, m), 1.60-1.55 (1H, m), 1.47 (1H, dt, J = 11.6, 2.7 Hz), 1.43-1.35 (3H, m), 1.33-1.19 (2H, m), 1.06 (3H, s), 1.03(3H, d, J = 6.3 Hz), 0.96 (1H, d, J = 11.5 Hz), 0.88 (3H, s)、
13C NMR(125 MHz, CDCl 3) δ: 167.7, 160.1, 148.7, 142.3, 127.4, 125.2,
120.3、114.0、102.8、52.1、48.0、42.1、40.2、37.0、36.5、36.3、33.0、
27.9、27.7、23.2、20.6、17.64、17.59、
IR(KBr):3341、1686、1601、1426、1287cm−1、
MS(ESI−TOF)m/z:395[M+Na]+、
HRMS(ESI−TOF)m/z:395.2198(Calcd for C23H32O4Na;Found:395.2214)。
mp 77−78、
シリカゲルTLC Rf0.70(15%EtOAc in hexanes);
1H NMR (CDCl 3) δ 0.86 (s, 3H), 1.01 (d, 3H, J=5.5 Hz), 1.07 (s, 3H), 1.15-1.65 (m, 7H), 1.70-1.95 (m, 2H), 2.05-2.15 (m, 2H), 2.20-2.45 (m,1H), 2.64 (AB q, 2H, J=14 Hz), 3.72 (s, 3H), 3.75 (s, 3H), 4.33-4.47 (m, 2H), 6.65-6.77 (m, 3H)、
Anal Calcd for C23H34O2:C、80.65;H、10.00.Found:C、80.82;H、10.04。
mp 63−68、
シリカゲルTLC Rf0.71(15%EtOAc in hexanes)、0.37(5%EtOAc in hexanes)、
1H NMR (CDCl 3) δ 0.75-1.15 (m, 4H), 0.87 (s, 3H), 1.01 (s, 3H), 1.24-1.65 (m, 9H), 2.0-2.15 (br m, 3H), 2.70 (br s, 2H), 3.72 (s, 3H), 3.75 (s, 3H), 5.15 (br s, 1H), 6.65-6.85 (m, 3H)、
マススペクトル(化学イオン化、陰イオン)、m/z341(M−1)−。
シリカゲルTLC Rf 0.55(15%EtOAc in hexanes);λmax(CH3OH)292nm、
1H NMR (CDCl 3) δ 0.80-2.15 (m, 5H), 0.85 (s, 3H), 0.93 (d, 3H, J=6.5 Hz), 1.00 (s, 3H), 1.53 (br s, 1H), 2.45-2.67 (AB q, 2H, J=13.5 Hz), 5.14 (br s, 1H), 6.51 (br s, 1H), 6.71 (m, 2H)、
マススペクトル(化学イオン化)m/z 312(M+1)+、
マススペクトル(電子衝撃)、m/z311.199(C21H27O2 requires 311.201)。
(−)−1:[α]25 D−19.5°(c1.0、CKCl3)、
mp 125−127.、
シリカゲルTLC Rf0.10(15%EtOAc in hexanes);λmax(DMSO)305nm、
1H NMR (CDCl 3) δ 0.86 (s, 3H), 0.99 (d, 3H, J=8 Hz), 1.02 (s, 3H), 1.51 (br s, 3H), 1.2-1.65 (m, 7H), 1.9-2.15 (m, 3H), 2.54-2.70 (AB q, 2H, J=14 HZ), 4.38 (br s, 1H), 4.41 (br s, 1H), 5.14 (br s, 1H) and 6.59 (m, 3H); mass spectrum (chemical ionization), m/z 315 (M+1) +、
マススペクトル(電子衝撃)、m/z 314.225(M)+(C21H30O2 requires 314.225)。
[α]20 D−71.7°(C1.0、MeOH)、
IR(KBr)Vmax 3300、1720、1640、1580、1370、1200cm−l、
UV(MeOH)λmax 317(ε11800)及び488nm(860)、
ELMS m/z(%)401(M+、1).385(l)、357(4)、343(3)、211(20)、191(25)及び95(100)、
FABMS(positive)m/z 404(M+2H+H)+;HRFABMS m/z 404.2461(M+2H+H)+、calcd for C23H34N05、404.2437、
1H NMR(CD3OD)データは下記[表19]参照、
13C NMR(CD3OD)データは下記[表19]参照。
[α]17 D−71°(c0.73、EtOH)、
IR(KBr)Vmax 3400、1670、1630、1590、1540、1380、1200cm−1、
UV(MeOH)λmax 321(ε12100)及び498nm(920);
FABMS(negative、diethanolamine matrix)m/z 432(M+2H−H)−、
HRFABMS m/z 432.2381(M+2H−H)−、calcd for C24H34NO6 432.2386、
1H NMR(DMSO−d6)データは下記[表20]参照、
13C NMR(DMSO−d6)データは下記[表20]参照。
[α]17 D−183°(c1.0、EtOH)、
IR(KBr)Vmax 3400、1670、1630、1590、1540、1380、1200cm−1、
UV(MeOH)λmax 317(ε12600)及び490nm(1000)、
FABMS(negative、diethanolamine matrix)m/z 446(M+2HH)−、
HRFABMS m/z 446.2524(M+2H−H)−、calcd for C25H36NO6、446.2906、
1H NMR(DMSO−d6)データは下記[表21]参照、
13C NMR(DMSO−d6)データは下記[表21]参照。
[α]25 D+21(c0.1、MeOH)、
UV(MeOH)λmax 297nm、
lH NMR(150MHz、CDCl3)データは下記[表22]参照、
13C NMR(150MHz、CDCl3)データは下記[表22]参照、
HRFABMS m/z 398.2696[M+H]+(calcd for C25H36NO3、398.2695)、420.2509[M+Na]+(calcd for C25H35NO3Na、420.2515)。
[α]25 D−29(c0.1、MeOH)、
UV(MeOH)λmax 295nm、
lH NMR(150MHz、CDCl3)データは下記[表23]参照、
13C NMR(150MHz、CDCl3)データは下記[表23]参照。
HRFABMS m/z 384.2540[M+H]+(calcd for C24H34NO3、384.2539)、
406.2357[M+Na]+(calcd for C24H33NO3Na、406.2358)。
mp. 168−170、
SM m/e(%):447(7)s257(64)、191(ll)、166(59)、152(25)、135(16)、121(23)、109(23)、107(20)、95(100);
m/e 166.0495.Calc.166.0504 for C8H8NO3;m/e 191.1795.calc.191.1799 for C14H23;m/e 257.104、calc.257.105 for C15H15NO3、
IR(KBr)υcm−l:3265、1600、1395、
1H NMR(CDCl 3, 250 MHz) δ ppm: 6.47 (1H exch., s), 5.41 (lH, s), 4.45 (2H, br s). 3.43 (2H, q), 2.87 (2H, t), 2.52-2.51 (dd, AB syst., J= 14 and 2 Hz), 1.05 (3H, s), 0.98 (3H, d, J = 7.5 Hz), 0.84 (3H, s), 0.79 (1H. dd, J = 11.2 and 2 Hz)、
13C NMR(ppm;CDCl3)データは下記[表24]参照。
C22H30O4、
分子量:358.47、
m.p. 72.5、
IT−TOF/MS:m/z 381.1972[M+Na]+、
1H-NMR (CDCl 3, 600 MHz) : 2.08, 1.42 (each 1H, m, H 2-1), 1.84, 1.16(each 1H, m, H 2-2), 2.29, 2.05 (each 1H, ddd, J = 13.7, 8.6, 5.4, H 2-3), 1.49,1.32 (each 1H, m, H 2-6), 1.37 (2H, m, H 2-7), 1.14 (1H, m, H-8), 0.74 (1H, d, J= 12.0, H-10), 4.43, 4.41 (each 1H, s, H 2-11), 1.02 (3H, s, H 3-12), 0.96 (3H,d, J = 6.4, H 3-13), 0.82 (3H, s, H 3-14), 2.51, 2.45 (each 1H, d, J = 13.7, H 2-15), 5.83 (1H, s, H-19), 3.84 (3H, s, H 3-22) 、
13C-NMR (CDCl 3, 150 MHz) : 23.34 (C-1), 28.11 (C-2), 33.13 (C-3), 160.69 (C-4), 40.63 (C-5), 36.82 (C-6), 28.80 (C-7), 38.25 (C-8), 43.50 (C-9), 50.30 (C-10), 102.66 (C-11), 20.73 (C-12), 18.01 (C-13), 17.52 (C-14),32.52 (C-15), 117.49 (C-16), 153.49 (C-17), 182.51 (C-18), 102.17 (C-19), 161.90 (C-20), 182.20 (C-21), 57.01 (C-22)。
C23H32O4、
分子量:372.5、
IT−TOF/MS:m/z 395.2146[M+Na]+、
1H-NMR (CDCl 3, 600 MHz) : 7.47 (1H, s), 5.83 (1H, s), 4.46, 4.44 (each 1H, s), 4.06 (2H, q, J = 7.2 Hz), 2.50 (2H, dd, J = 12, 6.0 Hz), 2.33 (1H, dt, J = 12, 6.0 Hz), 2.17-1.66 (4H, m), 1.49 (3H, t, J = 7.2 Hz), 1.46-1.09 (7H, m), 1.04 (3H, m), 0.98 (3H, d, J = 6 Hz), 0.84 (3H, s) 、
13C-NMR (CDCl 3, 150 MHz) : 182.68, 182.26, 161.19, 160.75, 153.35, 117.45, 102.63, 102.40, 66.10, 50.35, 43.45, 40.63, 38.29, 36.82, 33.14, 32.63, 28.79, 28.12, 23.32, 20.73, 18.46, 18.05, 13.97.
製造された化合物のうち、構造的に代表性を現す数種の化合物に対して、Wnt/β−カテニンを阻害するかを確認した。
HEK293(人間の胚腎臓細胞)及びWnt3a−分泌L細胞はATCC(American Type Culture Collection、USA)から入手し、10%FBS(ウシ胎仔血清)、120μg/mlペニシリン及び200μg/mlストレプトマイシンが含まれたDMEM(ダルベッコ変性イーグル培地(Dulbecco’s modified Eagle’s medium)))で培養した。
前記実施例<1−1>と同様な方法で製造例32の化合物のWnt/β−カテニン経路抑制活性を評価した。簡略に言えば、前記Wnt3a−CMと、製造例32の化合物を濃度別(それぞれ10又は20μM)で15時間HEK293細胞に処理し、前記細胞から細胞質タンパク質を抽出した後、Wnt/β−カテニン経路のCRT(β−カテニン応答転写)を調節する細胞内β−カテニン量をβ−カテニン抗体(BD Transduction Laboratories、USA)及びECLシステム(Santa Cruze Biotechnology)を用いたウェスタンブロットで確認し、これを図2に示した。
ARPE−19細胞(人間の網膜上皮細胞)とWnt3a−分泌L細胞はATCC(American Type Culture Collection、USA)から入手し、10%FBS、120μg/mlペニシリン及び200μg/mlストレプトマイシンが含まれた(ダルベッコ変性イーグル培地(DMEM;Dulbecco’s modified Eagle’s medium))で培養した。Wnt3a−CM(Wnt3a−conditioned medium)はWnt3a−分泌L細胞を10%[v/v]ウシ胎仔血清(FBS;fetal bovine serum)が含まれたDMEMで4日間培養した後、前記培養されたDMEM培地を回収し、0.22μmフィルターで滅菌して準備した。その後、細胞に新しいDMEM(10%[v/v]FBS含み)を添加して3日間追加培養した後、もう一度Wnt3a−CMを収得した。
<2−1>硝子体腔内投与
前記実施例1で良い活性を現した製造例33の化合物を対象として、黄斑浮腫を引き起こしたマウスモデルに対して黄斑変性又は黄斑浮腫の原因となる血管漏出に対する抑制作用があるかを確認した。レーザーを照射して10週齢のC57BL/6マウスに黄斑浮腫を引き起こした。ケタミン(ketamine、70mg/kg)とキシラジン(xylazine、30mg/kg)で痲酔し、1%トロピカマイド(tropicamide)で瞳孔を散大させた。ヒドロキシプロピルメチルセルロース(hydroxypropyl methycellulose)を目に点眼し、顕微鏡カバーガラス(microscope cover glass)をコンタクトレンズ(contact lens)として使った。その後、視神経乳頭周囲の血管間の空間に5個のレーザーバーン(laser burns)を作った(Zeiss 1149−630、laser power 180mW、duration 0.1s、spot size 50μm)。この状態で、蛍光眼底血管撮影(fluorescein angiography、FA)及び光干渉断層撮影(optical coherence tomography、OCT)で血管の大きさ及び透過性を確認した。レーザーを照射してから24時間後に、マウスの硝子体腔内に、対照群にはDMSO(dimethyl sulfoxide)0.5μlを、実験群にはDMSOに溶解した製造例33の化合物100ng/0.5μlを注射し、1週後にさらに蛍光眼底血管撮影及び光コヒーレンス断層撮影検査を遂行し、対照群と化合物処理群の写真を対照撮影して図4に示した。
C57BL/6マウスに黄斑浮腫を引き起こして製造例33の化合物を腹腔投与した後、網膜内血管漏出の有無を確認した。
Samtako Co.(Osan、Korea)から雄性ICRマウス(8週齢、30−35g)を購入した。購入した実験動物は1週間次のような条件で順応化(acclimatize)した:温度23±2℃、相対湿度55±10%、照度(illumination intensity)150−300lux、換気頻度15−20回/h及び照明周期(illumination cycle)12h(07:00−19:00)。全ての動物実験はAnimal Care and Use Committee of Kyungpook National University(Study No.2016−0043)の承認を受けた。
<4−1>急性毒性評価
製造例33の化合物を短期間に過量取ったとき、急性的(24時間以内)に動物体内に及ぶ毒性を調査し、致死率を決定するために、この実験を遂行した。一般的なマウスであるICRマウス系20匹を対照群と実験群にそれぞれ10匹ずつ割り当てた。対照群にはPEG−400:ツイン−80:エタノール(8:1:1、v:v:v)のみを投与し、実験群は製造例33の化合物を前記PEG−400:ツイン−80:エタノール(8:1:1、v:v:v)に溶かしてそれぞれ経口投与した。投与24時間後にそれぞれの致死率を調査した結果、対照群と2g/kg/day濃度の製造例33の化合物を投与した実験群の両方でマウスの生存が確認された。
長期毒性実験は製造例33の化合物を各濃度で8週間C57BL/6Jマウス(各群当たり10匹)に投与して実験した。動物の各臓器(組職)に及ぶ影響を調査するために、製造例33の化合物を投与した実験群とPEG−400:ツイン−80:エタノール(8:1:1、v:v:v)のみを投与した対照群の動物から8週後に血液を採取してGPT(glutamate−pyruvate transferase)及びBUN(blood urea nitrogen)の血液内濃度をSelect E(Vital Scientific NV、Netherland)機器で測定した。その結果、肝毒性に関係があると知られたGPTと腎臓毒性に関係があると知られたBUNの場合、対照群に比べて実験群は大きな差を現さなかった。また、各動物から肝臓と腎臓を切り取り、通常的な組職切片製作過程に従って光学顕微鏡で組職学的観察を施行したが、全ての組職で特異な異常が観察されなかった。
<製剤例1>錠剤の製造
本発明の化合物200gをラクトース175.9g、ジャガイモ澱粉180g及びコロイド性珪酸32gと混合した。この混合物に10%ゼラチン溶液を添加した後、粉砕して14メッシュ篩を通過させた。これを乾燥させ、これにジャガイモ澱粉160g、滑石50g及びステアリン酸マグネシウム5gを添加して得た混合物を錠剤とした。
本発明の化合物1g、塩化ナトリウム0.6g及びアスコルビン酸0.1gを蒸溜水に溶解させて100mlにした。この溶液を瓶に入れ、20℃で30分間加熱して滅菌させた。
Claims (13)
- 下記化学式1で表示される化合物又はその薬学的に許容可能な塩を有効成分として含む、黄斑変性又は黄斑浮腫の予防又は治療用薬学的組成物であって、
i)3番炭素と4番炭素の結合及び5番炭素と6番炭素の結合が単一結合であるとき、R2bは存在せず、R2aはCH2である構造、
ii)3番炭素と4番炭素の結合が二重結合であるとき、5番炭素と6番炭素の結合は単一結合であり、R2bは存在せず、R2aはCH3である構造、及び
iii)5番炭素と6番炭素の結合が二重結合であるとき、3番炭素と4番炭素の結合は単一結合であり、R2a及びR2bはCH3である構造からなる群から選択される一つの構造であり、
R1はH又はCH3であり、
R3は下記R3a〜R3dからなる群から選択されるいずれか一つの作用基であり、
i)R4及びR7がそれぞれOH又はOCH3であり、R5、R6及びR8はHである構造、又は
ii)R5がCOOCH3であり、R7はH又はOHであり、R8はOHであり、R4及びR6はHである構造であり、
前記R3bは、
R9がH、NH2、C1〜C8アルコキシ基及び下記のR9a〜R9jからなる群から選択されるいずれか一つの作用基であり、R10はH又はOHであり、
R11及びR12はそれぞれOH又はOAcであり、R13はHである構造、又は
R11及びR12はそれぞれOH又はOCH3であり、R13はCH3である構造であり、
前記R3dはR14がOCH3であり、R15及びR16はCH3である構造の組成物。 - 前記化学式1の化合物は、3番炭素と4番炭素の結合及び5番炭素と6番炭素の結合が単一結合であるとき、R2bは存在せず、R2aはCH2である構造であり、R3は前記R3b〜R3dからなる群から選択されるいずれか一つの作用基であることを特徴とする、請求項1に記載の薬学的組成物。
- 前記化学式1の化合物において、前記R3b〜R3dからなる群から選択されるいずれか一つの前記作用基は、
R3bはR9がエトキシ基、メトキシ基及びR9aからなる群から選択されたいずれか一つであり、
R3cはR11がOHであり、R12がOCH3であり、R13がCH3であり、又は
R3dはR14がOCH3であり、R15及びR16がCH3であることを特徴とする、請求項2に記載の薬学的組成物。 - 前記化学式1の化合物は、
3−[[(1R,2S,4aS,8aS)−1,2,4a−トリメチル−5−メチリデン−3,4,6,7,8,8a−ヘキサヒドロ−2H−ナフタリン−1−イル]メチル]−4−ヒドロキシ−5−(2−フェニルエチルアミノ)シクロヘキサ−3,5−ジエン−1,2−ジオン、
3−[[(1R,2S,4aS,8aS)−1,2,4a−トリメチル−5−メチリデン−3,4,6,7,8,8a−ヘキサヒドロ−2H−ナフタリン−1−イル]メチル]−2−ヒドロキシ−5−メトキシシクロヘキサ−2,5−ジエン−1,4−ジオン、
3−[[(1S,2R,4aR,8aR)−1,2,4a−トリメチル−5−メチリデン−3,4,6,7,8,8a−ヘキサヒドロ−2H−ナフタリン−1−イル]メチル]−5−エトキシ−2−ヒドロキシシクロヘキサ−2,5−ジエン−1,4−ジオン、
18−メトキシ−22−メチル−16−[{(5S,8S,9R,10S)−5,8,9−トリメチル−4−メチレンデカヒドロナフタリン−9−イル}メチル]ベンゾ[d]−オキサゾール−17−オル、及び
18−メトキシ−22,22−ジメチル−16−[{(5R,8S,9R,10S)−5,8,9−トリメチル−4−メチレンデカヒドロナフタリン−9−イル}メチル]ベンゾ[d]−オキサゾール−17(2H)−オン、からなる群から選択されるいずれか1種の化合物であることを特徴とする、請求項3に記載の薬学的組成物。 - 前記組成物は、経口剤、注射剤、点眼剤及び軟膏剤からなる群から選択されるいずれか一つの形態に製造されることを特徴とする、請求項1に記載の薬学的組成物。
- 化学式1で表示される化合物又はその薬学的に許容可能な塩を有効成分として含む、眼球内血管漏出抑制用薬学的組成物であって、
i)3番炭素と4番炭素の結合及び5番炭素と6番炭素の結合が単一結合であるとき、R2bは存在せず、R2aはCH2である構造、
ii)3番炭素と4番炭素の結合が二重結合であるとき、5番炭素と6番炭素の結合は単一結合であり、R2bは存在せず、R2aはCH3である構造、及び
iii)5番炭素と6番炭素の結合が二重結合であるとき、3番炭素と4番炭素の結合は単一結合であるとき、R2a及びR2bはCH3である構造からなる群から選択される一つの構造であり、
R1はH又はCH3であり、
R3は下記R3a〜R3dからなる群から選択されるいずれか一つの作用基であり、
i)R4及びR7がそれぞれOH又はOCH3であり、R5、R6及びR8はHである構造、又は
ii)R5がCOOCH3であり、R7はH又はOHであり、R8はOHであり、R4及びR6はHである構造であり、
前記R3bは、
R9がH、NH2、C1〜C8アルコキシ基及び下記のR9a〜R9jからなる群から選択されるいずれか一つの作用基であり、R10はH又はOHであり、
R11及びR12はそれぞれOH又はOAcであり、R13はHである構造、又は
R11及びR12はそれぞれOH又はOCH3であり、R13はCH3である構造であり、
前記R3dはR14がOCH3であり、R15及びR16はCH3である構造の組成物。 - 前記化学式1の化合物は、3番炭素と4番炭素の結合及び5番炭素と6番炭素の結合が単一結合であるとき、R2bは存在せず、R2aはCH2である構造であり、R3は前記R3b〜R3dからなる群から選択されるいずれか一つの作用基であることを特徴とする、請求項6に記載の薬学的組成物。
- 前記化学式1の化合物において、前記R3b〜R3dからなる群から選択されるいずれか一つの作用基は、
R3bはR9がエトキシ基、メトキシ基及びR9aからなる群から選択されたいずれか一つであり、
R3cはR11がOHであり、R12がOCH3であり、R13がCH3であり、又は
R3dはR14がOCH3であり、R15及びR16がCH3であることを特徴とする、請求項7に記載の薬学的組成物。 - 前記化学式1の化合物は、
3−[[(1R,2S,4aS,8aS)−1,2,4a−トリメチル−5−メチリデン−3,4,6,7,8,8a−ヘキサヒドロ−2H−ナフタリン−1−イル]メチル]−4−ヒドロキシ−5−(2−フェニルエチルアミノ)シクロヘキサ−3,5−ジエン−1,2−ジオン、
3−[[(1R,2S,4aS,8aS)−1,2,4a−トリメチル−5−メチリデン−3,4,6,7,8,8a−ヘキサヒドロ−2H−ナフタリン−1−イル]メチル]−2−ヒドロキシ−5−メトキシシクロヘキサ−2,5−ジエン−1,4−ジオン、
3−[[(1S,2R,4aR,8aR)−1,2,4a−トリメチル−5−メチリデン−3,4,6,7,8,8a−ヘキサヒドロ−2H−ナフタリン−1−イル]メチル]−5−エトキシ−2−ヒドロキシシクロヘキサ−2,5−ジエン−1,4−ジオン、
18−メトキシ−22−メチル−16−[{(5S,8S,9R,10S)−5,8,9−トリメチル−4−メチレンデカヒドロナフタリン−9−イル}メチル]ベンゾ[d]−オキサゾール−17−オル、及び
18−メトキシ−22,22−ジメチル−16−[{(5R,8S,9R,10S)−5,8,9−トリメチル−4−メチレンデカヒドロナフタリン−9−イル}メチル]ベンゾ[d]−オキサゾール−17(2H)−オン、からなる群から選択されるいずれか1種の化合物であることを特徴とする、請求項3に記載の薬学的組成物。 - 化学式1で表示される化合物又はその薬学的に許容可能な塩を有効成分として含む、黄斑変性又は黄斑浮腫の予防又は改善用食品組成物であって、
i)3番炭素と4番炭素の結合及び5番炭素と6番炭素の結合が単一結合であるとき、R2bは存在せず、R2aはCH2である構造、
ii)3番炭素と4番炭素の結合が二重結合であるとき、5番炭素と6番炭素の結合は単一結合であり、R2bは存在せず、R2aはCH3である構造、及び
iii)5番炭素と6番炭素の結合が二重結合であるとともに、3番炭素と4番炭素の結合は単一結合であるとき、R2a及びR2bはCH3である構造からなる群から選択される一つの構造であり、
R1はH又はCH3であり、
R3は下記R3a〜R3dからなる群から選択されるいずれか一つの作用基であり、
i)R4及びR7がそれぞれOH又はOCH3であり、R5、R6及びR8はHである構造、又は
ii)R5がCOOCH3であり、R7はH又はOHであり、R8はOHであり、R4及びR6はHである構造であり、
前記R3bは、
R9がH、NH2、C1〜C8アルコキシ基及び下記のR9a〜R9jからなる群から選択されるいずれか一つの作用基であり、R10はH又はOHであり、
R11及びR12はそれぞれOH又はOAcであり、R13はHである構造、又は
R11及びR12はそれぞれOH又はOCH3であり、R13はCH3である構造であり、
前記R3dはR14がOCH3であり、R15及びR16はCH3である構造の組成物。 - 前記化学式1の化合物は、3番炭素と4番炭素の結合及び5番炭素と6番炭素の結合が単一結合であるとき、R2bは存在せず、R2aはCH2である構造であり、R3は前記R3b〜R3dからなる群から選択されるいずれか一つの作用基であることを特徴とする、請求項10に記載の食品組成物。
- 前記化学式1の化合物において、前記R3b〜R3dからなる群から選択されるいずれか一つの作用基は、
R3bはR9がエトキシ基、メトキシ基及びR9aからなる群から選択されたいずれか一つであり、
R3cはR11がOHであり、R12がOCH3であり、R13がCH3であり、又は
R3dはR14がOCH3であり、R15及びR16がCH3であることを特徴とする、請求項11に記載の食品組成物。 - 前記化学式1の化合物は、
3−[[(1R,2S,4aS,8aS)−1,2,4a−トリメチル−5−メチリデン−3,4,6,7,8,8a−ヘキサヒドロ−2H−ナフタリン−1−イル]メチル]−4−ヒドロキシ−5−(2−フェニルエチルアミノ)シクロヘキサ−3,5−ジエン−1,2−ジオン、
3−[[(1R,2S,4aS,8aS)−1,2,4a−トリメチル−5−メチリデン−3,4,6,7,8,8a−ヘキサヒドロ−2H−ナフタリン−1−イル]メチル]−2−ヒドロキシ−5−メトキシシクロヘキサ−2,5−ジエン−1,4−ジオン、
3−[[(1S,2R,4aR,8aR)−1,2,4a−トリメチル−5−メチリデン−3,4,6,7,8,8a−ヘキサヒドロ−2H−ナフタリン−1−イル]メチル]−5−エトキシ−2−ヒドロキシシクロヘキサ−2,5−ジエン−1,4−ジオン、
18−メトキシ−22−メチル−16−[{(5S,8S,9R,10S)−5,8,9−トリメチル−4−メチレンデカヒドロナフタリン−9−イル}メチル]ベンゾ[d]−オキサゾール−17−オル、及び
18−メトキシ−22,22−ジメチル−16−[{(5R,8S,9R,10S)−5,8,9−トリメチル−4−メチレンデカヒドロナフタリン−9−イル}メチル]ベンゾ[d]−オキサゾール−17(2H)−オン、からなる群から選択されるいずれか1種の化合物であることを特徴とする、請求項12に記載の食品組成物。
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