CN105968072A - Preparation method of lasiokaurin derivative and new application of antibacterial activity thereof - Google Patents

Preparation method of lasiokaurin derivative and new application of antibacterial activity thereof Download PDF

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CN105968072A
CN105968072A CN201610330460.XA CN201610330460A CN105968072A CN 105968072 A CN105968072 A CN 105968072A CN 201610330460 A CN201610330460 A CN 201610330460A CN 105968072 A CN105968072 A CN 105968072A
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carbon atom
lasiokaurin
aryl
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李达翃
徐进宜
华会明
徐盛涛
李占林
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Shenyang Pharmaceutical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
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    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

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Abstract

The invention relates to the field of natural medicines and medicinal chemistry and particularly relates to a series of lasiokaurin derivatives. The structural general formula of the lasiokaurin derivatives and pharmaceutically acceptable salt thereof is shown in the specification, wherein R is alkyl with 1-16 carbon atoms, substituted alkyl with 1-16 carbon atoms (the substituent is halogen, aryl with 5-12 carbon atoms, halogen substituted aryl with 5-12 carbon atoms and heterocyclic aryl with 1-3 N, O or S atoms and 5-12 carbon atoms), cycloalkyl with 3-8 carbon atoms, aromatic ring or halogenated aromatic ring with 5-12 carbon atoms or aromatic heterocyclic ring or halogenated aromatic heterocyclic ring with 5-12 carbon atoms, wherein the aromatic heterocyclic ring contains 1-3 N, O or S heteroatoms. The lasiokaurin derivatives provided by the invention have perfect antibacterial effects and can be further used for preparing antibacterial medicines.

Description

The preparation method of lasiokaurin derivant and the new application of antibacterial activity thereof
Technical field
The present invention relates to natural drug and medicinal chemistry art, be specifically related to a series of lasiokaurin derivant.The present invention Disclose preparation method and the antibacterial activity of these compounds.
Background technology
Lasiokaurin is one of main active of Rabdosia rubescens, and its structure is complicated, containing mulitiple chiral centers in molecule. As far back as the 60 to 70's of last century, lasiokaurin just be it is found that together with rubescensine A.Then, to rubescensine A And the research of derivant is the most, the report about lasiokaurin is the most rare.And to its bioactivity research master Antitumor direction to be concentrated on, other association areas are almost without report.
The present invention has designed and synthesized the derivant of a series of lasiokaurin, and tests synthesized derivant antibacterial side The biological activity in face.
Summary of the invention
Invention to solve the technical problem that being to find the good lasiokaurin derivant of antibacterial activity and pharmaceutically acceptable Salt, and further provide for a kind of pharmaceutical composition.
For solving above-mentioned technical problem, the present invention provides following technical scheme:
Lasiokaurin derivant of the present invention and pharmaceutically acceptable salt thereof have a following structure formula:
Wherein, R is the alkyl containing 1-16 carbon atom, replacement alkyl (the wherein substituent group containing 1-16 carbon atom The aryl of 5-12 carbon atom is contained, containing 1-3 N, O or S for halogen, the aryl containing 5-12 carbon atom, halogen substiuted The heterocyclic aryl containing 5-12 carbon atom of atom), the cycloalkyl of 3-8 carbon atom, containing the fragrance of 5-12 carbon atom Ring or halogenated aromatic ring, 5-12 carbon atom aryl heterocycle or halo heteroaromatic, comprise 1-3 N, O or S in described heteroaromatic Hetero atom.
Preferably, R is the alkyl containing 1-16 carbon atom, and the replacement alkyl containing 1-16 carbon atom (wherein replaces Base be halogen, the aryl containing 5-12 carbon atom, halogen substiuted contain 5-12 carbon atom aryl, containing 1-3 N, O or The heterocyclic aryl containing 5-12 carbon atom of S atom), the cycloalkyl of 3-8 carbon atom, containing the aromatic rings of 6 carbon atoms Or halogenated aromatic ring, 5-12 carbon atom aryl heterocycle or halo heteroaromatic, described heteroaromatic comprises 1-3 atom N.
It is highly preferred that R be cyclopenta, cyclohexyl, n-heptyl, Pentadecane base, 4-trifluoromethyl, 4-fluorophenyl, 3-fluorophenyl, 2-fluorophenyl, 2,3,4,5-tetrafluoro phenyl, 2-(4-fluorophenyl)-vinyl, 1H-indole-3-methyl or 2-quinoline Base.
The invention further particularly discloses structure lasiokaurin derivant as follows and pharmaceutically acceptable salt thereof:
Involved compound name is:
Ent-1 α-O-acetyl group-6 β, 7 beta-dihydroxy-14 β-O-ring valeryl-15-oxo-7,20-oxygen bridge-16-shell China fir alkene (5a)
Ent-1 α-O-acetyl group-6 β, 7 beta-dihydroxy-14 β-O-ring caproyl-15-oxo-7,20-oxygen bridge-16-shell China fir alkene (5b)
Ent-1 α-O-acetyl group-6 β, 7 beta-dihydroxy-14 β-O-positive caprylyl-15-oxo-7,20-oxygen bridge-16-shell China fir alkene (5c)
Ent-1 α-O-acetyl group-6 β, 7 beta-dihydroxy-14 β-O-positive hexadecanoyl group-15-oxo-7,20-oxygen bridge-16-shellfish Shell China fir alkene (5d)
Ent-1 α-O-acetyl group-6 β, 7 beta-dihydroxy-14 β-O-(4-TRIFLUOROMETHYLBENZOYL)-15-oxo-7,20- Oxygen bridge-16-kaurene (5e)
Ent-1 α-O-acetyl group-6 β, 7 beta-dihydroxy-14 β-O-(4-fluoro benzoyl)-15-oxo-7,20-oxygen bridges- 16-kaurene (5f)
Ent-1 α-O-acetyl group-6 β, 7 beta-dihydroxy-14 β-O-(3-fluoro benzoyl)-15-oxo-7,20-oxygen bridges- 16-kaurene (5g)
Ent-1 α-O-acetyl group-6 β, 7 beta-dihydroxy-14 β-O-(2-fluoro benzoyl)-15-oxo-7,20-oxygen bridges- 16-kaurene (5h)
Ent-1 α-O-acetyl group-6 β, 7 beta-dihydroxy-14 β-O-(2,3,4,5-phenyl tetrafluoride formoxyl)-15-oxo-7, 20-oxygen bridge-16-kaurene (5i)
Ent-1 α-O-acetyl group-6 β, 7 beta-dihydroxy-14 β-O-(4-fluorine cinnamoyl)-15-oxo-7,20-oxygen bridge- 16-kaurene (5j)
Ent-1 α-O-acetyl group-6 β, 7 beta-dihydroxy-14 β-O-(3-1H-indole acetyl group)-15-oxo-7,20-oxygen Bridge-16-kaurene (5k)
Ent-1 α-O-acetyl group-6 β, 7 beta-dihydroxy-14 β-O-(2-quinoline formyl base)-15-oxo-7,20-oxygen bridge- 16-kaurene (5l)
The derivant of the present invention can prepare by following method:
Wherein, wherein, R is the alkyl containing 1-16 carbon atom, and the replacement alkyl containing 1-16 carbon atom (wherein takes Dai Jiwei halogen, the aryl containing 5-12 carbon atom, halogen substiuted contain the aryl of 5-12 carbon atom, containing 1-3 N, O Or the heterocyclic aryl containing 5-12 carbon atom of S atom), the cycloalkyl of 3-8 carbon atom, containing the virtue of 5-12 carbon atom Fragrant ring or halogenated aromatic ring, 5-12 carbon atom aryl heterocycle or halo heteroaromatic, comprise 1-3 N, O or S in described heteroaromatic Hetero atom.
Preferably, R is the alkyl containing 1-16 carbon atom, and the replacement alkyl containing 1-16 carbon atom (wherein replaces Base be halogen, the aryl containing 5-12 carbon atom, halogen substiuted contain 5-12 carbon atom aryl, containing 1-3 N, O or The heterocyclic aryl containing 5-12 carbon atom of S atom), the cycloalkyl of 3-8 carbon atom, containing the aromatic rings of 6 carbon atoms Or halogenated aromatic ring, 5-12 carbon atom aryl heterocycle or halo heteroaromatic, described heteroaromatic comprises 1-3 atom N.
It is highly preferred that R be cyclopenta, cyclohexyl, n-heptyl, Pentadecane base, 4-trifluoromethyl, 4-fluorophenyl, 3-fluorophenyl, 2-fluorophenyl, 2,3,4,5-tetrafluoro phenyl, 2-(4-fluorophenyl)-vinyl, 1H-indole-3-methyl or 2-quinoline Base.
By rubescensine A (1), through 7,14-position acetonylidene protection (2), 1-position acetylation (3), then take off acetonylidene Protection, obtains the i.e. lasiokaurin of 1-O-acetyl group rubescensine A (4), and crude product requires no column chromatography and can be directly used for next Step derivative reaction.By lasiokaurin (4) from different acid under DMAP, EDCI effect, reaction generate lasiokaurin derivant 5a-l。
Described acid is: cyclopenta formic acid, hexahydrobenzoid acid, caprylic acid, n-hexadecanoic, 4-(Trifluoromethyl)benzoic acid., 4- Fluobenzoic acid, 3-fluobenzoic acid, 2-fluobenzoic acid, 2,3,4,5 tetra fluoro benzoic acid, 4-fluoro cinnamic acid, 1H-heteroauxing or 2- Quinolinecarboxylic acid.
Pharmacological testing proves, the lasiokaurin derivant of the present invention has good antibacterial action, may be used for further Preparation antibacterials.
Detailed description of the invention:
Embodiment 1
Ent-1 α-O-acetyl group-6 β, 7 beta-dihydroxy-14 β-O-ring valeryl-15-oxo-7,20-oxygen bridge-16-shell China fir alkene (5a)
100mg rubescensine A 1 (0.27mmol) is dissolved in 3ml anhydrous propanone, adds the 2 of 0.4ml, 2-dimethoxy Propane and the p-methyl benzenesulfonic acid of catalytic amount, under nitrogen protective condition, back flow reaction about 1h, after reactant liquor is cooled to room temperature, Add the saturated NaHCO of 10ml3Solution, extracts three times with dichloromethane, each 10ml, merges organic facies, washes with saturated common salt Twice, anhydrous sodium sulfate is dried, and filters, concentrates, silica gel column chromatography (petroleum ether acetone=3 1), obtains 2.By 80mg compound 2 (0.20mmol) it is dissolved in about 10ml anhydrous methylene chloride, adds and stir under 0.3ml acetic anhydride and the DMAP of catalytic amount, room temperature condition Mixing reaction 1h, TLC and monitor reaction, question response is complete, stopped reaction.Wash with saturated common salt, separatory, organic facies anhydrous slufuric acid Sodium is dried, and filters, concentrates, and obtains crude product 3 and is directly used in next step reaction.80mg compound 3 (0.2mmol) is dissolved in 15ml tetra- In hydrogen furan, add 10% aqueous hydrochloric acid solution of 15ml, 1h is stirred at room temperature.Oxolane is evaporated off, extracts three times with dichloromethane, About 10ml every time, merges organic facies, and saturated common salt washing organic facies twice, anhydrous sodium sulfate is dried, and filters, concentrates, silicagel column Chromatography (petroleum ether: acetone=2 1), obtains white solid lasiokaurin 4.72mg 4 (0.2mmol) is dissolved in the anhydrous dichloro of 10ml In methane, add corresponding acid (0.3mmol), EDCI (93mg, 0.6mmol), the DMAP of catalytic amount, 6-48h is stirred at room temperature. TLC monitors reaction, when question response is complete or does not goes on, and stopped reaction.Separatory after washing, organic facies saturated aqueous common salt Wash, then be dried with anhydrous sodium sulfate, filter, concentrate, silica gel column chromatography (dichloromethane: methanol=500:1 to 100:1), obtain Target compound 5.White powdery solids, productivity 31%:mp.196-198 DEG C；IR(KBr)υmax 3365,2954,2869, 1723,1647,1246,1169,950,933,912,820,640cm-1；1H NMR(CDCl3,300MHz),δ(ppm):6.14 (1H,s,17-CH2), 6.13 (1H, d, J=10.3Hz, 6-OH), 5.75 (1H, s, 14-CH), 5.49 (1H, s, 17-CH2), 4.63(1H,m,1-CH),4.46(1H,s,7-OH),4.26,4.19(each 1H,dd,JA=JB=10.4Hz, 20-CH2), 3.81 (1H, m, 6-CH), 3.17 (1H, d, J=9.5Hz, 13-CH)；MS ESI m/z:503.2[M+H]+；HR-MS(ESI,M+ NH4)m/z:calcd for C28H42NO8:520.2905,found 520.2913。
Embodiment 2
Ent-1 α-O-acetyl group-6 β, 7 beta-dihydroxy-14 β-O-ring caproyl-15-oxo-7,20-oxygen bridge-16-shell China fir alkene (5b)
Colorless oil, productivity 41%:IR (KBr) υmax 3362,2924,2851,1733,1646,1452,1133, 1079,1062,950,913,750cm-1；1H NMR(CDCl3, 300MHz), δ (ppm): 6.21 (1H, d, J=10.3Hz, 6- OH),6.15(1H,s,17-CH2),5.76(1H,s,14-CH),5.48(1H,s,17-CH2),4.63(1H,m,1-CH),4.51 (1H,s,7-OH),4.26,4.19(each 1H,dd,JA=JB=10.4Hz, 20-CH2),3.81(1H,m,6-CH),3.17 (1H, d, J=9.5Hz, 13-CH)；MS ESI m/z:517.4[M+H]+；HR-MS(ESI,M+NH4)m/z:calcd for C29H44NO8:534.3061,found 534.3057。
Embodiment 3
Ent-1 α-O-acetyl group-6 β, 7 beta-dihydroxy-14 β-O-positive caprylyl-15-oxo-7,20-oxygen bridge-16-shell China fir alkene (5c)
Colorless oil, productivity 26%:IR (KBr) υmax 3381,2925,1854,1739,1653,1461,1079, 1063,910,764,750cm-1；1H NMR(CDCl3, 300MHz), δ (ppm): 6.23 (1H, d, J=9.9Hz, 6-OH), 6.15 (1H,s,17-CH2),5.80(1H,s,14-CH),5.50(1H,s,17-CH2),4.43(1H,s,1-OH),4.63,4.19 (each 1H,dd,JA=JB=10.2Hz, 20-CH2), 3.83 (1H, m, 6-CH), 3.19 (1H, d, J=9.6Hz, 13-CH)； MS ESI m/z:533.3[M+H]+；HR-MS(ESI,M+NH4)m/z:calcd for C30H48NO8:550.3374,found 550.3368。
Embodiment 4
Ent-1 α-O-acetyl group-6 β, 7 beta-dihydroxy-14 β-O-positive hexadecanoyl group-15-oxo-7,20-oxygen bridge-16-shellfish Shell China fir alkene (5d)
Colorless oil, productivity 39%:IR (KBr) υmax 3373,2920,2850,1738,1645,1463,1079, 1063,951,912,767,759,743cm-1；1H NMR(CDCl3, 300MHz), δ (ppm): 6.31 (1H, d, J=9.9Hz, 6- OH),6.01(1H,s,17-CH2),5.79(1H,s,14-CH),5.50(1H,s,17-CH2),4.63(1H,m,1-OH),4.27, 4.19(each 1H,dd,JA=JB=10.5Hz, 20-CH2), 3.81 (1H, m, 6-CH), 3.18 (1H, d, J=9.6Hz, 13- CH)；MS ESI m/z:645.4[M+H]+；HR-MS(ESI,M+NH4)m/z:calcd for C38H64NO8:662.4626, found 662.4637。
Embodiment 5
Ent-1 α-O-acetyl group-6 β, 7 beta-dihydroxy-14 β-O-(4-TRIFLUOROMETHYLBENZOYL)-15-oxo-7,20- Oxygen bridge-16-kaurene (5e)
White powdery solids, productivity 27%:mp.56-60 DEG C；IR(KBr)υmax 3377,2922,2852,1742, 1641,1065,1017,964,950,773,703,632,608cm-1；1H NMR(CDCl3,300MHz),δ(ppm):8.07 (2H,m,Ar-H),7.71(2H,m,Ar-H),6.24(1H,s,17-CH2), 6.16 (1H, s, 14-CH), 6.09 (1H, d, J= 11.1Hz,6-OH),5.54(1H,s,17-CH2),4.80(1H,s,14-CH),4.68(1H,m,1-CH),4.38,4.23 (each 1H,dd,JA=JB=10.5Hz, 20-CH2), 3.77 (1H, m, 6-CH), 3.28 (1H, d, J=10.2Hz, 13-CH)； MS ESI m/z:579.1[M+H]+,601.1[M+Na]+；HR-MS(ESI,M+NH4)m/z:calcd for C30H37F3NO8: 596.2466,found 596.2471。
Embodiment 6
Ent-1 α-O-acetyl group-6 β, 7 beta-dihydroxy-14 β-O-(4-fluoro benzoyl)-15-oxo-7,20-oxygen bridges- 16-kaurene (5f)
White powdery solids, productivity 29%:mp.90-92 DEG C；IR(KBr)υmax 3357,2952,2360,2341, 1715,1646,1121,1062,963,950,912,817cm-1；1H NMR(CDCl3,300MHz),δ(ppm):7.96(2H,m, Ar-H), 7.07 (2H, t, J=10.5Hz, Ar-H), 6.20 (1H, s, 17-CH2), 6.17 (1H, d, J=11.0Hz, 6-OH), 6.07(1H,s,14-CH),5.53(1H,s,17-CH2),4.65(1H,m,1-CH),4.33,4.19(each 1H,dd,JA=JB =10.5Hz, 20-CH2), 4.09 (1H, s, 7-OH), 3.77 (1H, m, 6-CH), 3.27 (1H, d, J=10.0Hz, 13-CH)； MS ESI m/z:529.2[M+H]+,551.2[M+Na]+,567.2[M+K]+；HR-MS(ESI,M+NH4)m/z:calcd for C29H37FNO8:546.2498,found 546.2503。
Embodiment 7
Ent-1 α-O-acetyl group-6 β, 7 beta-dihydroxy-14 β-O-(3-fluoro benzoyl)-15-oxo-7,20-oxygen bridges- 16-kaurene (5g)
White powdery solids, productivity 35%:mp.142-144 DEG C；IR(KBr)υmax 3388,2954,2360,1715, 1645,1098,1062,950,912,813,753cm-1；1H NMR(CDCl3,300MHz),δ(ppm):7.71(1H,m,Ar- H), 7.63 (2H, d, J=8.7Hz, Ar-H), 7.38 (1H, m, Ar-H), 7.22 (1H, m, Ar-H), 6.21 (1H, s, 17- CH2), 6.14 (1H, d, J=10.8Hz, 6-OH), 6.09 (1H, s, 14-CH), 5.54 (1H, s, 17-CH2),4.66(1H,m,1- CH),4.34,4.21(each 1H,dd,JA=JB=10.8Hz, 20-CH2),3.89(1H,s,7-OH),3.77(1H,m,6- CH), 3.28 (1H, d, J=10.0Hz, 13-CH)；MS ESI m/z:529.2[M+H]+；HR-MS(ESI,M+NH4)m/z: calcd for C29H37FNO8:546.2498,found 546.2498。
Embodiment 8
Ent-1 α-O-acetyl group-6 β, 7 beta-dihydroxy-14 β-O-(2-fluoro benzoyl)-15-oxo-7,20-oxygen bridges- 16-kaurene (5h)
White powdery solids, productivity 31%:mp.186-188 DEG C；IR(KBr)υmax 3567,3381,2953,1716, 1644,1173,1084,1062,951,911,758cm-1；1H NMR(CDCl3,300MHz),δ(ppm):7.91(1H,m,Ar- H),7.54(1H,m,Ar-H),7.11(2H,m,Ar-H),6.18(1H,s,17-CH2),6.14(1H,s,6-OH),6.04(1H, s,14-CH),5.50(1H,s,17-CH2),4.67(1H,m,1-CH),4.52(1H,s,7-OH),4.33,4.22(each 1H, dd,JA=JB=10.8Hz, 20-CH2), 3.81 (1H, m, 6-CH), 3.37 (1H, d, J=9.6Hz, 13-CH)；MS ESI m/ z:529.2[M+H]+；HR-MS(ESI,M+NH4)m/z:calcd for C29H37FNO8:546.2498,found 546.2490。
Embodiment 9
Ent-1 α-O-acetyl group-6 β, 7 beta-dihydroxy-14 β-O-(2,3,4,5-phenyl tetrafluoride formoxyl)-15-oxo-7, 20-oxygen bridge-16-kaurene (5i)
White powdery solids, productivity 10%:mp.218-220 DEG C；IR(KBr)υmax 3367,2925,1739,1646, 1172,1098,1037,771,699cm-1；1H NMR(CDCl3,300MHz),δ(ppm):7.61(1H,m,Ar-H),6.21 (1H,s,17-CH2), 6.13 (1H, s, 14-CH), 6.04 (1H, d, J=11.1Hz, 6-OH), 5.56 (1H, s, 17-CH2), 4.69(1H,m,1-CH),4.34,4.21(each 1H,dd,JA=JB=10.5Hz, 20-CH2),3.85(1H,s,7-OH), 3.70(1H,m,6-CH),3.56(2H,s,-CH2-), 3.25 (1H, d, J=9.6Hz, 13-CH)；MS ESI m/z:583.2[M +H]+；HR-MS(ESI,M+NH4)m/z:calcd for C29H34F4NO8:600.2215,found 600.2217。
Embodiment 10
Ent-1 α-O-acetyl group-6 β, 7 beta-dihydroxy-14 β-O-(4-fluorine cinnamoyl)-15-oxo-7,20-oxygen bridge- 16-kaurene (5j)
White powdery solids, productivity 32%:mp.140-142 DEG C；IR(KBr)υmax 3547,3380,2954,1716, 1161,1062,984,951,833cm-1；1H NMR(CDCl3, 300MHz), δ (ppm): 7.59 (1H, d, J=9.0Hz ,-COCH =), 7.49 (2H, m, Ar-H), 7.07 (2H, t, J=8.2Hz, Ar-H), 6.27 (1H, d, J=15.9Hz ,-CH=), 6.18 (1H,s,17-CH2), 6.14 (1H, d, J=10.5Hz, 6-OH), 5.94 (1H, s, 14-CH), 5.52 (1H, s, 17-CH2), 4.66(1H,m,1-CH),4.31,4.21(each 1H,dd,JA=JB=10.5Hz, 20-CH2),3.81(1H,m,6-CH), 3.26 (1H, d, J=9.6Hz, 13-CH)；MS ESI m/z:555.2[M+H]+；HR-MS(ESI,M+NH4)m/z:calcd for C31H39FNO8:572.2654,found 572.2661。
Embodiment 11
Ent-1 α-O-acetyl group-6 β, 7 beta-dihydroxy-14 β-O-(3-1H-indole acetyl group)-15-oxo-7,20-oxygen Bridge-16-kaurene (5k)
White powdery solids, productivity 39%:mp.129-131 DEG C；IR(KBr)υmax 3384,2924,2853,1716, 1643,1174,1062,951,912,742cm-1；1H NMR(CDCl3,300MHz),δ(ppm):8.12(1H,s,NH),7.46 (1H, d, J=7.8Hz, Ar-H), 7.32 (1H, d, J=8.1Hz, Ar-H), 7.15 (2H, m, Ar-H), 7.06 (1H, s, Ar- H),5.93(1H,s,17-CH2),5.76(1H,s,14-CH),5.21(1H,s,17-CH2),4.60,4.22(each 1H,dd, JA=JB=10.2Hz, 20-CH2),4.09(1H,s,1-OH),3.83(2H,s,CH2),3.77(1H,m,6-CH),3.12(1H, D, J=10.0Hz, 13-CH)；MS ESI m/z:564.2[M+H]+,562.3[M-H]-；HR-MS(ESI,M+NH4)m/z: calcd for C32H41N2O8:581.2857,found 581.2864。
Embodiment 12
Ent-1 α-O-acetyl group-6 β, 7 beta-dihydroxy-14 β-O-(2-quinoline formyl base)-15-oxo-7,20-oxygen bridge- 16-kaurene (5l)
Pale yellow powder shape solid, productivity 39%:mp.128-130 DEG C；IR(KBr)υmax 3472,3124,2922, 2848,1738,1642,1131,951,777cm-1；1H NMR(CDCl3, 300MHz), δ (ppm): 8.31 (2H, d, J= 8.2Hz, Ar-H), 8.26 (2H, d, J=8.6Hz, Ar-H), 7.75 (2H, m, Ar-H), 6.41 (1H, d, J=9.3Hz, 6- OH),6.15(1H,s,17-CH2),5.92(1H,s,14-CH),5.49(1H,s,17-CH2),4.70(1H,m,1-H),4.29, 4.21(each 1H,dd,JA=JB=10.2Hz, 20-CH2), 3.93 (1H, m, 6-CH), 3.58 (1H, d, J=9.3Hz, 13- CH)；MS ESI m/z:562.2[M+H]+；HR-MS(ESI,M+NH4)m/z:calcd for C32H39N2O8:579.2701, found 579.2696。
Embodiment 13:
The pharmacological results of of the present invention part of compounds be presented herein below:
Experimental facilities and reagent
Instrument superclean bench (safe and sound company of Su Jing group)
Autoclave (the Amada Co., Ltd. Pingshan Mountain makes institute)
Constant incubator (Thermo electron Corporation)
Constant temperature culture oscillator (Shanghai ZHICHENG Anaiytical Instrument Manufacturing Co., Ltd.)
Magnetic stirring apparatus (Beijing Xin Weier)
Reagent is all purchased in king Yu and Lai Bo Reagent Company
Strains B. subtilis Bacillus subtilis (CMCC 63501), golden yellow
Staphylococcus Staphylococcus aureus (ATCC 29213)
Experimental technique
In Vitro Bacteriostatic experimental technique
Preparation bacillus subtilis and the bacteria suspension of staphylococcus aureus, first actication of culture Secondary Culture are to F2 respectively In generation, dilute bacteria suspension respectively to 1 × 10 by sterile purified water and culture medium7CFU/mL, standby.Chloromycetin is used as positive control Medicine, is each configured to 1mg/mL concentration by testing compound and positive control drug, under aseptic condition, variable concentrations medicine and bacterium is hanged Liquid is sequentially added in 96 orifice plates, sets up positive controls and solvent blank group simultaneously, rearmounted 37 DEG C of incubators in cultivate 18-24h, observes with or without colony growth, with have no bacterial growth lowest concentration of drug as minimum inhibitory concentration (MIC).
Experimental result
Table 1 embodiment MIC value (μ g/ml) to 2 kinds of bacterial strain inhibitory activity

Claims (10)

1. lead to the lasiokaurin derivant shown in formula (I) and pharmaceutically acceptable salt thereof:
Wherein, R is the alkyl containing 1-16 carbon atom or replaces alkyl, and the cycloalkyl of 3-8 carbon atom, containing 5-12 carbon The aromatic rings of atom or halogenated aromatic ring, 5-12 carbon atom aryl heterocycle or halo heteroaromatic, comprise 1-3 in described heteroaromatic The hetero atom of individual N, O or S, it is individual that described substituent group is halogen, the aryl containing 5-12 carbon atom, halogen substiuted contains 5-12 The aryl of carbon atom, the heterocyclic aryl containing 5-12 carbon atom containing 1-3 N, O or S atom.
2. the lasiokaurin derivant described in claim 1 and pharmaceutically acceptable salt thereof:
R is the alkyl containing 1-16 carbon atom or replaces alkyl, and the cycloalkyl of 3-8 carbon atom, containing the virtue of 6 carbon atoms Fragrant ring or halogenated aromatic ring, 5-12 carbon atom aryl heterocycle or halo heteroaromatic, comprise 1-3 atom N in described heteroaromatic, Described substituent group be halogen, the aryl containing 5-12 carbon atom, halogen substiuted contain 5-12 carbon atom aryl, containing 1- 3 N, O or the heterocyclic aryl containing 5-12 carbon atom of S atom.
3. the lasiokaurin derivant described in claim 1 or 2 and pharmaceutically acceptable salt thereof, wherein R is cyclopenta, hexamethylene Base, n-heptyl, Pentadecane base, 4-trifluoromethyl, 4-fluorophenyl, 3-fluorophenyl, 2-fluorophenyl, 2,3,4,5-phenyl tetrafluoride Base, 2-(4-fluorophenyl)-vinyl, 1H-indole-3-methyl or 2-quinolyl.
4. the lasiokaurin derivant described in claim 1-3 any one and pharmaceutically acceptable salt thereof, is selected from:
5. a pharmaceutical composition, described in the claim 1-4 any one containing therapeutically effective amount derivant and medicine Acceptable salt and pharmaceutically acceptable carrier on.
6. a pharmaceutical preparation, comprise the derivant described in claim 1-4 any one and pharmaceutically acceptable salt thereof or Pharmaceutical composition described in claim 5.
7. the derivant described in claim 1-4 any one and pharmaceutically acceptable salt answering in preparation antibacterials thereof With.
8. the application in preparation antibacterials of the pharmaceutical composition described in claim 5.
9. the application in preparation antibacterials of the pharmaceutical preparation described in claim 6.
10. the application as described in claim 7-9 any one, it is characterised in that the bacterium in described antibacterials is hay bud Spore bacillus or staphylococcus aureus.
CN201610330460.XA 2016-05-18 2016-05-18 Preparation method of lasiokaurin derivative and new application of antibacterial activity thereof Pending CN105968072A (en)

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