WO1996020176A1 - Derives d'huperzine a, leur preparation et leur emploi - Google Patents

Derives d'huperzine a, leur preparation et leur emploi Download PDF

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Publication number
WO1996020176A1
WO1996020176A1 PCT/CN1995/000100 CN9500100W WO9620176A1 WO 1996020176 A1 WO1996020176 A1 WO 1996020176A1 CN 9500100 W CN9500100 W CN 9500100W WO 9620176 A1 WO9620176 A1 WO 9620176A1
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Prior art keywords
group
substituted
huperzine
hydrogen
low
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PCT/CN1995/000100
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English (en)
French (fr)
Inventor
Dayuan Zhu
Xican Tang
Jinlai Lin
Cheng Zhu
Jingkang Shen
Guansong Wu
Shanhao Jiang
Takuji Yamaguchi
Kazuhiro Tanaka
Takeshi Wakanatsu
Hiroaki Nishimura
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Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences
Tsumura & Co.
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Application filed by Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences, Tsumura & Co. filed Critical Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences
Priority to DK95941572T priority Critical patent/DK0806416T3/da
Priority to AU42966/96A priority patent/AU4296696A/en
Priority to AT95941572T priority patent/ATE239708T1/de
Priority to EP95941572A priority patent/EP0806416B1/en
Priority to JP52010296A priority patent/JP3545416B2/ja
Priority to US08/860,524 priority patent/US5929084A/en
Priority to DE69530706T priority patent/DE69530706T2/de
Priority to US09/799,127 priority patent/USRE38460E1/en
Publication of WO1996020176A1 publication Critical patent/WO1996020176A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/22—Bridged ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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

Definitions

  • the present invention relates to the semi-synthesis of natural products, in particular to alkaloids and their analogs.
  • Guo Xibu has used choline esters and preparations to improve the function of the cholinergic system in the brain to treat early dementia. Although gratifying research results have been obtained, there are many shortcomings. At the same time, the treatment effect appears There is a severe toxic reaction, and the duration of action is short.
  • the present invention utilizes the resource advantages of Chinese herbal medicine to design a semi-synthesis starting from Huperzine A. It is hoped to find compounds with better therapeutic effect and lower toxicity than existing Huperzine A from many Huperzine A derivatives .
  • the invention implements the following steps:
  • Alcohols such as ethanol are used as extraction solvents from the Melaleuca tower plants.
  • the concentrated residue is treated with an inorganic acid (such as hydrochloric acid), and the aqueous layer is neutralized with an alkali.
  • alkalization such as ammonia, NaOH
  • an organic solvent such as Chloroform
  • G group is phenyl, furanyl, carboxyl, ester; and dialkyl or tetrahydropyridyl substituted with lower alkyl on nitrogen;
  • R ' is hydrogen, C 5 lower alkyl, pyridyl, C 5 lower alkoxy substituted benzyl;
  • R " is f ⁇ CC 5 lower alkyl.
  • R ' is hydrogen, ⁇ " ⁇ : 5 's lower fluorenyl, pyridyl, -Cs lower fluorenyl substituted benzoyl;
  • R " is 3 ⁇ 43 ⁇ 4-(: 5 lower alkyl.
  • Y is X and hydrogen
  • No. 1 C 0 H00C-CH 2 CH 2 -HH
  • the invention uses the El lman 3 ⁇ 4 colorimetric method to determine the inhibitory effect of drugs on enzyme activity.
  • the total capacity of the enzyme activity reaction solution is 4ml, which contains thioacetylcholine iodide 0.3ramol / L (acetylcholinesterase substrate), or 0.mmol / L (butyrylcholinesterase) Substrate) 1ml of pH 7.4 phosphate 25mmol / L buffer, make up to 4ml with water (including enzyme solution and test solution), incubate at 37'C for 5 minutes, and then add enzyme solution (rat erythrocyte membrane) Or rat serum) 0.1-0.2 ml or 0.1-0.3 ml with the same B bB test solution, incubate for 8 minutes and add 1 ml of 3% sodium dodecyl sulfate to stop the reaction, ftjg plus 1 ml 0.2 23 ⁇ 4 5, 5'-disulfide-2, 2'-nitro-benzo
  • mice The acute toxicity test of mice showed that the LD 50 of the derivatives No. 18 and No. 19 was less than the compound (1) and only 1/3 of the latter (see Table 5).
  • Table i Xi body hit huperzine A derivative with a choline ester (colorimetric assay) inhibition of enzyme activity concentration 50 (IC 50, ⁇ ⁇ ) IC 50 Ratio
  • AChE was taken from rat red blood cell membrane. BuChE is taken from the big jL Qing. Table 2. Use of Huperzine A Derivatives
  • mice AChE from rat cortical homogenate BuChE from rat serum Table 3. Huperzine A derivatives improve scopolamine J93 ⁇ 4 escaping operation in memory-damaged groups. Number of mice
  • mice were administered immediately after training and tested 24 hours later.
  • Rats Eight-arm maze test. Rats were trained to meet the standards (less than 1 error per day for 3 consecutive days) and used for testing. Rat's first arm without feeding material is reference memory. The arm with feeding material is working memory.
  • IR ⁇ -3280, 1660 (s), 1620 (s), 1550 '1450, 1350, 1300,
  • IR ⁇ MX 3450, 2900, 1660 (s), 1615 (s), 1530 (s), 1460,
  • Derivatives No. 12, 14 can be prepared in the same way.
  • Example 3 Preparation of Derivative No. 19 Weigh out compound (I) (0.5mmole) and put it in a 50ml H ⁇ flask, add anhydrous ethanol, add 4,6-dimethoxy-2-light benzaldehyde (0.51mmole), and heat it to reflux slightly, continuously through the water separator Evaporate part of the ethanol, and replenish the solvent in the reaction at any time. After several hours of reaction and analyze the reaction status at any time by analysis, after completion, remove the ethanol under reduced pressure to obtain a solid. Recrystallize the mixed solvent of petroleum jelly and petroleum ether to obtain Product, yield 92.
  • IR "m. X 3480 (m), 2960 (s), 2930 (s), 2870 (s), 1670 (s), 1620 (s), 1540 (s), 1450 (s), 1330 (s) , 1300 (s), 1218 (sh), 1186 (m), 1155 (s), 1110 (s), 1080 (m), 1050 (m), 1000 (ra), 930 (m), 840 (s) , 730 (m), 670 (m), 610 (m), 520 (s) cnT 1 , Derivative No. 20
  • IR ⁇ MX 3420, 2900, 1660, 1620, 1580, 1560, 1500, 1460, 1420, 1380, 1350,
  • IR ⁇ MX 2940, 1660 (s), 1590, 1560, 1500, 1565, 1420, 1370, 1330, 1300 1230, 1190, 1130c s), 1005, 960, 930, 840, 770, 735, 725, 660, 605, 540, 530 cm—
  • Derivatives No. 45 and 46 can be prepared by the same method, and the yields are (84%, 82%)

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  • Physical Education & Sports Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Description

石杉械甲衍生物， 其制备方法和用途 本发明涉及天然产物半合成，具体涉及生物碱及它的类似物。
近 10年来国夕卜应用胆碱酯,制剂提高脑内胆碱能系统功能措施治疗早 ¾¾痴 呆症进行大量研究， 虽然取得了可喜的研究结果， ίΜ¾存在不少缺点， 在出现治疗 作用的同时， 有较严重的毒付反应， 且作用持续时间较短。
近年来中国从中草药千层塔中分离得到新的生物碱石杉碱甲 ( 5R， 9R， HE) -5 一氨基一11一亚乙基一 5， 6， 9 , 10—四氢一 7—甲基一5， 9一甲撑环辛錄 W 吡 啶一 2( 1H)—酮化合物（ I )
Figure imgf000003_0001
(I)
经药理研究证明它有强效的可逆的抗胆碱酯酶 ¾tt，对脑内乙酰胆碱酯酶有选择性 抑制作用 [美国专利 5177082]， 国夕卜对石杉碱甲进行^ ί¾»合成石杉碱甲类似 物， 希1人中发现 抗胆碱酯酶 ¾¾的化合物 [ J. Org Qiem 56 199K 4636 - 4645) ]和寻找全合成石杉碱甲的力 美国专利 4929731] 但尚未发现良好的方法， 找到更 ^的类似物。
本发明利用中国中草药的资源优势设计了从石杉碱甲出发进行半合成， 希望从 诸多的石杉碱甲衍生物中寻找出比现有石杉碱甲治疗效果更佳且毒性较低的化合物。
本发明 下列步骤实施：
1.从千层塔植物中经乙醇等醇类作为提取溶剂， 浓缩所得残渣经无机酸（ 如盐 酸)处理,水层用碱中和， 碱化 (如氨水， NaOH)后用有机溶剂 (如氯仿)提取总生物碱， 经处理、 层析分离得到化合物（ I ) o
2.化合物（ I )经与相应取代醛或与相应取代酰氣或酸野在无水溶剂中进 合 得通式（ Π )
Figure imgf000004_0001
Y为- C或- R", Y为 =CH
II
0
R为 Cs的低垸基；
Figure imgf000004_0002
, λΌ· ,n=0,l，X为氢， d
- c5的低烷基， cs的低 氧基， 硝基， 卤素 基， 酯基， 羟甲基， 羟基， 二
Figure imgf000004_0003
"G基， G为苯基， 呋喃基， 羧基， 酯基； 及氮上 低烷基取代的二氢或四氢吡啶 基；
R'为氢、 C5的低烷基， 吡啶酰基， C5低烷氧基取代的苯甲醜基；
R"为 f^C C5低烷基。
当 Y为 C=0时，！！为^"^的低'烷基， - (CH2)n~ ^基， η=0，1,Χ为氢， d_C 5的 低烷氧基， 羧基， 酯基， '吡啶基， 氮上 CfCs低垸基取代的二氢或四氢吡啶基， - (CH2)mCOOZ基， m=0-5, Z为氢或 d-Cs的低垸基； - CH=CH- G基， G为苯基， 呋喃基， 羧基， 酯基''
R'为氢， ^"<：5的低垸基， 吡啶酰基， -Cs低焼基取代的苯甲酰基；
R"为 ¾¾ -(：5低烷基。 当 R"， Y为 X为氢，
Figure imgf000005_0001
的低烷基， ^"Cs的低垸氧基， 硝基， 卤素， 羟基， 羟甲基， ="^- 5低烷 基取代的氨基； ~CH=CH"G¾， 6为¾¾，呋喃基；
R'为氢及 CrCs低垸基。 石杉碱甲衍生物 --
No Y R R' R'
No. 1 C = 0 H00C-CH2CH2- H H
No. 2 C = 0 C6H5CH2- H
Figure imgf000005_0002
Figure imgf000005_0003
Figure imgf000005_0004
No. 7 C = 0 4-CH30CeH4- H H
No. 8 C = 0 2, 3, 4-( CH30) 3C6H2- H H
Figure imgf000006_0001
Figure imgf000006_0002
Figure imgf000006_0003
Figure imgf000006_0004
-H HD¾XXX)H-s J
H H -"H9D-DOOH-Z 0 = 3 SI '0M
H d-f 0 = 3 n "ON
Figure imgf000006_0005
H H
H H H9D 0=3 IT "ON
H H -HDZ (eHD ) 0 = 0 OT -°N
Figure imgf000006_0006
'Z'Z 0 = 3 6*°NI00/S6ND/JLDd 9110296 ΟΛλ
Figure imgf000007_0001
HO、 OCH,
No. 22 CH H
Figure imgf000007_0002
Figure imgf000007_0003
Figure imgf000007_0004
Figure imgf000007_0005
Figure imgf000007_0006
No. 28 CH H
Figure imgf000007_0007
Figure imgf000008_0001
Figure imgf000008_0002
Figure imgf000008_0003
Figure imgf000008_0004
Figure imgf000008_0005
9LI0U96 O/A
OOI00/S6N /1DJ
Figure imgf000009_0001
Figure imgf000009_0002
Figure imgf000009_0003
Figure imgf000009_0004
Figure imgf000009_0005
Figure imgf000010_0001
Figure imgf000010_0002
Figure imgf000010_0003
石杉碱甲衍生物的药理作用 ··
本发明应用 El lman¾¾的比色法测定药物对酶活力的抑制作用。酶活力反应液 总容量为 4ml ,内含碘化硫代乙酰胆碱 0. 3ramol/L(乙酰胆碱酯酶底物）， 或碘化硫代 丁酰胆碱 0. mmol/L(丁酰胆碱酯酶底物) PH7. 4磷酸盐 25mmol/L的缓冲液 lml， 最后 加水补足到 4ml (包括后加酶液量及测试药液）， 37'C保温 5分钟后， 加入酶液（ 大鼠 红细胞膜或大鼠血清） 0. 1—0. 2ml或同 B bB测试药液 0. 1— 0. 3ml， 再保温 8分钟加 入 lml 3%十二烷基硫酸钠终止反应， ftjg加 lml 0. 2¾ 5， 5'—联硫一 2， 2' ― 硝基一苯甲酸溶液显色， 用 "721"分光光度计于 440nm测定光密度。 以不加抑制药 物的酶活力 (为 1003 对照， 以剩余酶活力的百分数对药物克分子浓度作图， 求得抑 制酶活力 50%时的药物剂量即 IC5。。 试验结果表明：所有衍生物均有乙酰胆碱酯酶抑 制作用，衍生物 Nol， Nol7 , Nol8 , Nol9对乙酰胆碱酯酶有明显的抑制作用，稍弱于 石杉碱甲， 但明显强于毒扁豆碱及加兰他敏。 它们对丁酰胆碱酯酶 (假性酶)的抑制 作用弱于石杉碱甲，衍生物 Nol及 Nol7对乙酰胆碱酯酶的选 抑制大于石杉碱甲（ 见表 1、 2、 6)酶动力学研究表明，衍生物 Nol7， Nol8及 Nol9与乙酰胆碱酯酶的结合 是可逆的。
用小鼠被动逃避操作 (跳台法)及大 A臂迷宫空间辨别操作二种记忆模型测试 表明,衍生物 Nol8，Nol9均有很强的改 己忆障碍作用 ( iW3， 4) , 它们的作用强度 与化合物（ I )相似。
小鼠的急性毒性试验表明， 衍生物 No. 18及 No. 19的 LD50小于化合物（ 1 )， 仅为 后者的 1/3(见表 5) 表 i， 石杉碱甲衍生物的体夕 hit胆碱酯 用（比色法测定) 抑制 50酶活力浓度 ( IC50, μ Μ) IC50比率
BuQiE 乙酰胆碱酯酶 丁酰胆碱酯酶 AChE ( ACHE) ( BUCHE)
1 0. 348 380. . 19 1092. . 5
2 9. 05 〉346. , 7
3 3. 63 〉331. , 1
4 〉12. 88 58. 9
5 〉10· 96 〉275. 4
6 > 12. 3 〉309. 1
17 0. 172 199. 5 1159. 9
18 0. 151 107. 2 709. 9
19 0. 145 104. 7 722. 1
10 > 15. 85 109. 6
11 > 14. 45 363 化合物（ I ) 0. 06309 63. 09 1000 毒扁豆喊 0. 251 1. 259 5. 02 加兰他敏 1. 995 12. 59 6. 3
AChE取自大鼠红细胞膜。 BuChE取自大 jL清。 表 2，石杉碱甲衍生物的体夕 ι¾胆碱酯 用
IC50( μ Μ) ic50比率 化 奸量
No. 乙酰胆碱酯酶 丁酰胆碱酯酶
( ACHE) ( BUCHE)
Figure imgf000012_0001
石杉碱甲 242 0. 0977 100. 0 1023. 3
1 342 0. 3475 380. 2 1094. 1
12 376 0. 1259 251. 2 1995. 2
15 390 0. 6310 502. 0 795. 6
17 428 0. 1718 199. 5 1161. 2
18 376 0. 1514 107. 2 708. 2
19 406 0. 1445 104. 7 724. 6
20 346 0. 1778 125. 9 708. 1
21 420 0. 1413 158. 5 1121. 3
22 406 0. 1259 125. 9 1000. 0
23 362 0. 2512 199. 5 794. 2
24 362 0. 1000 158. 5 1585. 0
25 378 0. 1585 251. 2 1584. 9
27 356 0. 1259 100. 0 794. 3
AChE取自大鼠皮层匀浆 BuChE取自大鼠血清 表 3，石杉碱甲衍生物改善东茛菪碱 J9¾¾动逃避操作的记忆损害 组 别 剂 量 小鼠数 下台潜伏期
(mg/kg ip+po) (只） （秒士 SEM)
理盐 7l +半理盐 7l — + — 20 71.9士 12.9
¾^碱+生珲盐水 2+ ― 20 29.5士 2.7 东 碱 +衍生物 No.18 2+0.2 20 67.7±11.7**
2 + 0.3 20 64.0士 9.8*
2 + 0.4 20 48.7士 6.9
生珲盐水 +牛珲盐水 → — 18 81.7士 19.0 东茛菪碱 +生珲盐水 2+ ― 23 32.3士 8.2 东^碱 +衍生物 No.19 2 + 0.1 11 48.9士 12.6
2 + 0.2 16 71.6土 14.5
2 + 0.3 21 99.8±16.4**
2 + 0.4 18 92, 2土 15.5*
Δ:小鼠先经训练后立即给药， 24小时后测验。
与生理盐水组比较 P<0.01 **与东^组比较 * P<0.05, " P<0.01 表 4， 石杉碱衍生物改善东 «¾空间辨别操作记忆损害
达标 作 次数 组 别 剂 量 小鼠数
(mg/kg) (只） 记忆 工作记忆 ip+po (X+SEM)
生 生珲盐水 —+― 24 0.42士 0.1 0.08±0.01 东 碱 +生珲盐水 0.2+ ― 6 1.67土 0.21 2.33土 0.42 东 碱 +衍生物 Nol9 0.2 + 0.1 6 1.33±0.21 1.33士 0.49**
0.2土 0.3 6 0.33±0.2Γ * 0.17土 0.17*
生 生珲盐水 一 +― 24 0.33±0.13 0.08士 0.06
^^碱 +生珲盐水 0.125 +— 6 2.0土 0.45 2.0士 0.52 东^碱 +衍生物 Nol8 0.125 + 0.2 6 0.67土 0.33* " 0.33士 0.13*
生¾&7 +生 Sbd →- 14 0.21土 0.11 0.07士 0.07 东茛菪碱 +生珲盐水 0.15+— 7 2.14土 0.14 2.57士 0.29 东 碱 +石杉碱甲 0.15 + 0.25 10 0.57土 0.30* ' 0.86士 0.14*
厶:八臂迷宫测试。大鼠经训练达标 (每天错误次数 1次以下， 连 续 3天)后， 用于测验。 大鼠第一 未置放食料的臂为参考记忆 大 ¾入置放食料的臂为工作记忆 。
与生 ¾&i组比较 P<0.01
"与东 组比较 P<0.01e 表 5， 石杉碱甲衍生物对小鼠的急性毒性 (Bliss法) mg/kg p.o. (95可信限)
LDe 60 化合物（ I ) 3.1(3.5 - 3.8) 4.6(4.2 一 5.1) 衍生物 Nol8 9.6(7.3 -12.5) 14.4(12.8 -16.4) 衍生物 Nol9 11.1(9.6 -12.9) 14.1(15.5 -20.5)
*小鼠 10只一组， 早$各半。 各药测试用 4—5剂量组。
观察 7天内的死亡率。 表 6， 石杉碱甲衍生物的体夕(¾胆碱酯酶作用
抑制活性
化合物 AChE BuChE BuChE/ > A 5QiE No. o o
Figure imgf000015_0001
(18) 90.2 8.4X10—8 0 >500 (20) 83.7 9.4X10一 8 0 〉500 (21) 84.9 l.oxio-7 0 >500 (22) 68.7 0
(23) 34.4 0
(15) 60.8 0
(24) 78.3 2.8X10—7 0 〉100 (25) 62.0 0
(27) 84.0 l.lXlO-7 3.3
Figure imgf000015_0002
E-2020 86.2 6.6X10-8 2.9 >500 石杉碱甲 88.3 1.2X10—7 0 >500 ±^5S研究结果表明衍生物 Nol7 ,Nol8, Nol9是 3S¾乙酰胆戚酯酶选择 ft抑制 剂， 其急性毒性低于化合物（ 1)， 因此， 推论它们具有临床应用开发前景。 用于治 疗缓解 无力 中枢胆碱能系统功能衰竭导致的记忆功能障碍。
实施例 1， 衍生物 No.2的制备
称取化合物（ I )(0.50mmole)于 50mlH¾瓶中，加入 20ml¾吡啶，使（ I ) 化合 物溶解，冰^ ¾下,滴入苯乙酰氣 (0.55mmOle)， 滴加毕后， 室温 »过夜（ 25'C) 析表明原料基本消失， 停止反应， 水泵减压蒸去吡啶， 用硅 析分离以二 氣甲烷：丙酮：甲醇 =50： 45： 5洗脱得粗产品， 丙酮、 石油醚混合溶剂重结晶得产 品， 收率 75。
UV λ X=229nm (e =17360)
λ一 =316nm (ε =9320)
[a ]gsic=29.430
1HNMR: [CDC13]
3H 6.31(lH,d, J=9.9Hz)
4H 7.20( lH.d, J=9.9Hz)
10H 2.89( 2H m)
9H 3.52( lH,m)
8H 5.38( lH,d,J=5.0Hz)
14- H 1.62( 3H d, J=6.7Hz)
13-H 5.08( 1H q, J=6.7Hz)
6-H 2.15,2. 5( 2H,m)
12-H 1.50(3H，s)
2' ,4'-H 7.36( 2H,m)
3' ,5'-H 7.29(2H，ra)
6'- H 7.24( lH,m)
7'-H 3.59( s)
MS(m/z) 360(M+) 345 269 252 227 224 210( 100¾) 91
mp: 171— 173*C
IR: υ 一 3280, 1660(s)，1620(s)，1550' 1450， 1350, 1300，
1175,1130,840,620 cm"1
同法可制;^生物， No.3, No.5， No.6, No.7, No.8, No.9' No.10， No. 11， No.13。
实施例 2， 衍生物 No4的制备
称取化合物（ I )(0.5mmole)于 50mlH¾瓶中， 加入 20ml¾ |i比淀， 使 解， 在冰浴 ^i下， 先加入 DBU( 0.6mmole)， 再加入 0.55mmole的盐酸吡啶- 2-甲酰氣， 室温 夜， 用薄 析测定表明反应已基本完全， 用水泵减压蒸去吡啶， 用 ¾^析分离， 展开剂为二氯甲烷：丙酮：甲醇 =50： 45： 5洗脱， 得粗产品， 用丙 酮、 石油醚混合溶剂重结晶得产品，收率 74%。
UV λ ^=226^ (ε =1.35Χ104)
Figure imgf000017_0001
λ =315nm (ε =5730)
[α ]D=77.85°
1HNM :[CDC13]
3- Η 6.36( 1Η, J=9.2Hz)
4- Η 7.44( 1Η， J=9.2Hz)
10-Η 3.05( 2H,m)
9-Η 3.74( lH，m)
8-Η 5.42( lH,d,J=4.7Hz)
14- Η 1.65( 3H,d,J=6.6Hz)
13-Η 5.35( lH,q=6.6HZ)
6-Η 2.42( 2H,s)
12- Η 1.55( 3H,s)
2'-Η 8.58( lH,m)
4'-Η 7.85( lH,m)
Figure imgf000017_0002
6'-Η' 8.15( lH,m)
MS(m/z) 347( Μ+) 241( 100%) 169， 149， 106,95,79,71,55
mp: 170— 171 'C
IR: υ ΜΧ 3450, 2900，1660( s)，1615( s)，1530( s)， 1460,
1300， 1180,1140, 1000,830,750, era"1
同法可制衍生物 No.12， 14。
实施例 3， 衍生物 No.19的制备 称取化合物（ I )(0.5mmole〉放于 50mlH ^烧瓶中， 加入无水乙醇， 加入 4,6― 二甲氧基 2—轻基苯甲醛 ( 0.51mmole)微微加热回流， 经分水器不断蒸出部分乙醇， 并随时补充反应中的溶剂，反应数小时并随时用 析测定其反应状况，待完全 后， 减压除去乙醇，得固体， ffiJ^品刚、 石油醚混合溶剂重结晶，得产品， 产率 92 。
同法可制衍生物 Nol7, 18, 20, 21, 22,23， 24,25,26， 27, 28， 29， 30, 31，32, 33， 34, 35， 36, 37, 38, 39, 0, 1, 42, 43„
衍生物 No.19
m.p. 207〜210'C
MS:m/z 406(M+)
391(M+—CH3), 351(M+—C4H7)
(CDC13)
1-H 13.12C lH.br. s)
3-H 6.41(lH,d,J=9. 1HZ)
4-H 7.25( lH,d J=9. 1HZ)
6-H 2.85( 2H,s)
8-H 3.45( lH,d,J=4. 7HZ)
9-H 3.6K lH.ra)
10-H 2.85( 2H,m)
I2-H3 1.60(3H，s)
13-H 5.22( lH,q,J=7. 7Hz)
14-H3 1.25( 3H,d,J=7.7Hz)
2' -OH 14.58( lH.br. s)
3'-H 5.57( lH,s)
4'-0CH3 3.79(3H,s)
5' - H 5.85( lH,s)
6'-0CH3 3.70( 3H,s)
7'-H 8.15( lH,s)
IR:" m.x 3480( m) , 2960(s), 2930( s) , 2870(s)， 1670( s) , 1620(s)， 1540( s) , 1450(s) , 1330( s) , 1300( s) , 1218( sh)， 1186( m) , 1155( s) , 1110(s)， 1080(m)， 1050(m) , 1000( ra) , 930(m)， 840( s) , 730( m) , 670( m) , 610(m) , 520( s) cnT1, 衍生物 No.20
XH NMR (CDCI3)：
1- -H 12.72(lH,br,s)
3- -H 6.34(lH，d J=9.4Hz)
4- -H 7.11(lH,d,J=9.4Hz)
6. »-H 2.79( lH,d,J=16.0Hz)
6, 2.75( lH,d,J=16.0Hz)
8- -H 5.4K lH,d,J=5.0Hz)
9- -H 3.63( lH,m)
10.-H 2.95( lH,dd,J=16.6, 4 9Hz)
10b-H 2.27( lH,d,J=16.6Hz)
12- H 1.57( 3H,s)
13- H 5.07( lH,q,J=6.8Hz)
14- H 1.55( 3H，d， J=6.8Hz)
2' -OH 13.77( lH.br. s)
3'-H 6.94( lH,d,J=8.4H2)
4'-H 7.30( 1H， t with small splitts, J=8.4Hz)
5'-H 6.85( lH,t with small splitts, J=7.4Hz)
6'-H 7.22( lH，dd，J=7.4，1.6Hz)
7'-H 8.3K lH.s)
346(M+)， 331,317， 303,291,253, 239, 226, 210， 197， 184, 167, 128
121, 97。
IR: υ ΜΧ 3420, 2900, 1660, 1620， 1580, 1560,1500, 1460， 1420， 1380， 1350，
1280, 1205, 1150， 1120， 1080, 1010,970,910, 840, 790, 755( s)， 650, 630,
610, 520 cm—1
衍生物 No.21
Figure imgf000019_0001
1-H 12.87( lH.br. s)
3- H 6.32( lH,d,J=9.4Hz)
4- H 7.07( lH,d,J=9.4Hz)
6 -H 2.79( lH,d,J=16.0Hz) 6to-H 2.75( lH,d,J=16.0Hz)
8- H 5.43( lH,d,J=5.0Hz)
9- H 3.63( lH,m)
10.-H 2.97( lH,dd,J=16.0, 4.0Hz)
I0b-H 2.18( lH,d,J=16.0Hz)
12- H 1.58( 3H,s)
13- H 5.14(lH,q,J=6.8Hz)
14- H 1.57(3H,d,J=6.8Hz)
2'6'-2H 7.04(2H,s)
7'-H 8.25( lH.s)
3'5'-2(0CH3) 3.87C 6H,s)
4'-0Οί3 3.84( 3H,s)
MS-- 420(M+)， 405(M+"CH3), 391, 365， 351, 313, 284， 239,226, 210， 196， 181， 140, 124。
IR: υ MX 2940, 1660(s), 1590, 1560, 1500, 1565, 1420,1370, 1330, 1300 1230， 1190, 1130c s), 1005, 960， 930, 840, 770， 735, 725， 660, 605, 540， 530 cm—
衍生物 No.22
XH NMR(CDC13)：
1-H 13.03( lH.br. s)
3- H 6.34( lH,d, J=9.4Hz)
4- H 7.14( lH,d,J=9.4Hz)
6-H2 2.73( 2H,s)
8- H 5.39( lH,d,J=4.7Hz)
9- H 3.61(lH,m)
10a-H 2.94( lH，dd，J=16.8， 4.9Hz)
lO^-H 2.27( lH,d,J=16.8Hz)
12- H 1.55( 3H,s)
13- H 5.09( lH,q,J=6.8Hz)
14- H 1.54(3H,d, J=6.8Hz)
2' -OH 14.39( lH.br. s) — —
'OS 'OWOSSI' ("S09I ' (s)929l ' (s )9991 ' 〉008Z- OOSS xm> Λ:ΗΙ
° εΓΖ9ΐ ' 6T 'οιζ '9ζζ ζη 'zos '6ΐε 'm '(+w)z9s ： sw
(S'HI Lf2 H-.Z
(ZH^ g=f ' Ήΐ )IS'Z H-.9
^m "8=f 'sunds TTBOIS mj 'p'HT )0S'9 H-.9
Figure imgf000021_0001
(s'HT )81 '9 H-.S
(s-iq'HI )0 H HO-^
Figure imgf000021_0002
(s'HS )6S'T H-Zl
(ZHS'9I=f 'P'HI ) Z'Z H-q0l
(ZH0 'g"9l=r'PP'HT )ZZ"2 H-e0I
(αι'Ηΐ )99 '2 H-6
(ZH ^=f 'ΡΉΙ )8^ '9 H-8
(ΖΗΖ'9ΐ=Γ 'Ρ'Ηΐ )6 'Z H- 9
(ZHZ'9T=f 'P'HT H-"9
(ZH^'6=f 'ΡΉΐ )10' 1 H-t'
(ZH^"6=f 'P'HT )SI '9 H - S
Figure imgf000021_0003
·■ (OSWa-9P〉丽 Ητ
'0 9 'SZ9 '969 'S8Z '988 '0£6 ΌΖ6Ό901 '(s)OIII 'ΟΙΖΙ ' (s)O ZT Ό62Ι ΐίΊ '59^1*01 1 'SSSl ' (s )0291 ' (s )0991 ' (ω )0ί-62 (^Q )0388-09^ ^ Λ ： HI ΐθΐ '6ST 'Ζ9Τ'28ΐ 'Ζ6Τ 'TSS '(SHD~+W)I6S ' (+W〉90 :SW
(s'HI ) •8 H- .L
(ΖΗ '8=Γ'Ρ'ΗΙ)Ι6 •9 H- .9
(ZHZ •8=f 'Ρ'Ηΐ ,9 H- ,S
(s'HS )S8 S eHDO-
(s'HS 2 '2 eHDO-
00I00/S6ND/XOd 9.I0Z/96 OA 。A1XDdS6KD/ 00/
Figure imgf000022_0001
οr - *
os olis/dslDW/。\.I96Λ
Figure imgf000023_0001
4'-H 7.06( lH,m)
7'-H 6.99( lH,d,J=15.9Hz)
9'-H 8.06(lH,d,J=8.1Hz)
MS: 356(M+)， 341(M+~CH3)， 327， 301, 265, 237， 226, 210,197, 167, 131, 115, 91， 77。
IR: υ一: 3600〜3400(br), 2950〜2850( br)， 1660( s)， 1632, 1620, 1550， 1465, 1445， 1300( m) , 1175， 1115， 975, 825, 750(s)， 690(s)， 630, 620,520cra_1 o 衍生物 No.28
1HNMR(CDC13)：
1-H 12.76( lH.br, s)
3- H 6.38(lH,d J=9.3Hz)
4- H 7.12(lH,d,J=9.3Hz)
6e-H 2.81(lH,d,J=16.0Hz)
6„-H 2.78( lH,d,J=16.0Hz)
8- H 5.46( lH.br, s)
9- H 3.67( lH,m)
10.-H 3.00( lH.dd, J=16.4, 4.5Hz)
I0b-H 2.3K lH,d,J=16.4Hz)
12- H 1.62(3H，s)
13- H 5.07( lH,q,J=6.6Hz)
14- H 1.60( 3H,d, J=6.6Hz)
2' -OH 13.76( lH.br.s)
3'-H 6.94( lH,d,J=8.7Hz)
4'-H 7.29(lH,dd,J=8.7,2.3Hz)
5'，6' ,7'，8'-4H 7.25( 4H,m)
1Γ-Η 8.30(lH，s)
MS(ra/z): 396(M+, 3% ) , 381( M + -CH3， 1)， 226( 2) , 172( 4) , 144( 2) , 127( 1) ， 115(5)， 85(13), 71(22)， 57( 100)。
IR (KBr) : 3408,1660, 1626， 1479， 1280cm- 1衍生物 No.30
2ΗΝΜΚ(ΟΧ:ΐ3):
1-H 10.92( lH.br, s) 3- H 6.42( lH,d J=9.3Hz)
4- H 7.15( lH,d,J=9.3Hz)
6«-H 2.82( lH,d,J=17.2Hz)
6b-H 2.76( lH,d,J=17.2Hz)
8- H 5.47(lH,br,s)
9- H 3.69( lH,m)
10e-H 2.99(lH,dd,J=16.0, 3.7Hz)
Figure imgf000025_0001
12- H 1.63( 3H,s)
13- H 5.07( lH.q, J=6.8Hz)
14- H 1.61(3H,d,J=6.8Hz)
3'-H 6.89( lH,d,J=6.8Hz)
4' ,6'-2H 7.42( 2H,m)
7'-H 8.30( lH,s)
MS( m/z)： 426( +2, 3% ) , 424( , 43) , 411[ ( M+ +2) ~CH3， 42]，409(M+ 45)， 369( 11), 289(5)， 253( 18) ,239( 33) , 226( 100) ,210( 54) , 197(47), (31), 128(31)， 115(46) , 91(32)， 77( 59) ,57(81) 0
IR(KBr): 3400, 1660, 1630， 1475, 1280， 823cm"1
衍生物 No.32
1HNMR(CDC13)：
1-H 12.70( lH.br, s)
3- H 6.39( lH.d J=9.4Hz)
4- H 7. IK lH,d, J=9.4Hz)
6a-H 2.8K lH,d,J=16.2Hz)
6b-H 2.77( lH,d,J=16.2H2)
8- H 5.45( lH.br, s)
9- H 3.67( lH.m)
10a- H 2.99( lH,dd,J=16.7, 4.9Hz)
10b-H 2.3K lH,d,J=16.7Hz)
12- H 1.62( 3H,s)
13— H 5.06( lH,q,J=6.8Hz) —
,,,,,, 31)431124RKBr66263312135124275cm I(59：
。，，， 1，5) 221 239(60) 212281)(00(25) 19)3( 67(
,，/%3， 2,，,881428))z) 39145) 381(B(( 66) 41) 356( MmM 376C((H M：I++
, 718.24)H(SH-、
,, 6 l 7.6H4(Hd87.Z)JH=I、
,, 56l)H.77t8(H7.Z VH-、
49).ZH
Figure imgf000026_0001
-,,,,)4831911616133633 IR(RB6605491cmr：
。，，2) 8 1018391((53) 500)(
3，%,，,， 1253)/，,28)260)24<)916(32+1)145)376G M8SZ(139(H(MMM(：I+++
, 72)H 8.9Hs-、
6、
,,, 44 l824.2(dd.7.Z)H 7HJH=—、
3、
., 28010 Ib3.(H s)HrI、 ,, 1413dH.60(H6.8)JHZ=- — sz—
(s'Hg )39 'ΐ -Zl
(ΖΗΖ"9Ι=Γ'Ρ'Ηΐ )ZZ Z H-^OT
Figure imgf000027_0001
(ω'Ηΐ )Z9'S H-6
(s'aq'Hl H-8
Figure imgf000027_0002
(ZHg'6=f ' 'HDSr H -
(ZHg*6=f Ρ'Ηΐ )8S'9 H-S
Figure imgf000027_0003
= (eT3CD)¾WNHx
'U '8191 '0991 'ΖΖβΖ'
°(00I)S8 ' (2)912
( "ΐ )6S2' (SO'eHD-÷W)96S ' ·ΐ ' +W )01 ' ( %S'0 'Ζ-l· ^Vi)ZU :(z/m)sw
(s'HI )ZZ'2 H--Z
( 'ΗΖ)98·9 Η2-,9'
(S'HS )06 S eHDO-,S
Figure imgf000027_0004
(ZH '9=f ' 'HS )6 'ΐ H - (ZHZ*9=f 'b'HT )60 '9 H-S I
(s'HS )Ζ9Ί H-ZT
Figure imgf000027_0005
(ZH6 'g-9T=f 'PP'HT )00 "S H-"0I
( 'ΗΙ"9·ε H-6
Figure imgf000027_0006
(s'HZ )2L Z zH-9
(ZH9 '6=f 'Ρ'Ηΐ )£ΓΖ H-
Figure imgf000027_0007
S ΌΝ<¾^¾
OOIOO/S6M3/JOd 9LI01/96 OA! 13- H 5.08( lH,q,J=6.8Hz)
14- H 1.59( 3H,d,J=6.8Hz)
2' -OH 14.45( lH,br,s)
Figure imgf000028_0001
4' ,6'-2H 7.00( 2H,m)
7'-H 8.21(lH,s)
MS(m/z):456(M+2 79 454(M+ 7a) 441[ (M++2)~CH3 40] 439(M^-CH3, 42) ,401(7) ,399(8) , 285( 14) , 239(24) , 226( 100) 210( 33) , 197(37 83(84 IR( Br): 3431,1660, 1624, 1471, 1252cm—1
实施例 4衍生物 No.15制备
称取化合物（ I )(0.5mmOle)于 50 1三颈瓶中， 加入 20ral无水吡啶 '使其溶解， 在冰浴冷却下， 加入邻苯二甲酸肝， 室温搅拌过夜。 用薄 ¾ 析测定表明反应基本 完全后， 用水泵减压蒸去吡啶， 硅 J^ 析分离， 展开剂为二氯甲垸： 甲醇 =3 : 1得 粗品， 重结晶后得 No.15白色粉末，收率 78%
同法可制衍生物 No.1.16
XH d6-DMS0)
3-H 6.09( lH,d, J=9.4Hz)
Figure imgf000028_0002
8- H 5.44( lH,d,J=4.8Hz)
9- H 3.56( lH,m)
10a- H 2.66( lH,dd,J=16.8, 4.6Hz)
10b- H 2.09( lH,d,J=16.8Hz)
Figure imgf000028_0003
13- H 5.60(lH,q,J=6.8Hz)
14- H3 1.62( 3H,d,J=6.8Hz)
3'4'5'and4-H 7.51(4H,m)
6'-H 7.73(lH,d,J=7.5Hz)
Figure imgf000028_0004
COO-H 8.46(lH,br.s)
IR: υ MX 3650-2400 1710 1655 1605 1546 1450, 1300 cm—1
MS m/z: 372(M+),357 343 329 242, 227 187 147 104(100 实施例 5衍生物 No.44的制备
氩气流下石杉碱甲 150mg(0.620mmole)， ^筛 200mg， 混悬于 4ml苯中，加入 P比啶- 3-甲醛 76μ l(0.86mmol)对甲苯磺酸单水化合物 20 mg, 回流 3小时， 放冷后用 三乙胺中和， 反应液 celi te, i ,浓缩后， 残渣经赚 tt 析 (甲醇： 二氯甲垸 =1： 20)棚， ¾生物^.44,无色面体(18311«， 收率 89%)。
同法可制备衍生物 No.45，46， 收率分别为 (84% ,82%)
衍生物 No.44
NMR(CDCL3) 1.64(3H， d, J=7.0Hz) , 1.65(3H,s)
2.25( lH.d, J=16.0Hz) , 2.82( lH.d, J=17. OHz)
2.86( lH.d, J=16.0Hz),
3.07( lH,dd,J=5.0， 17. OHz)，8.65-3.75( lH.m)
5.14( lH.q, J=7. OHz), 5.50( lH,d, J=5. OHz)
6.34( lH.d, J=8.5Hz) , 7.09( lH,d, J=9.5Hz)
7.40( lH,dd, J=5.0,8.0Hz) ,
8.28( lH.dt, J=2.0,8.0Hz) , 8.47( lH,s)
8.70-8.72( 1H， m)， 8.94-8.96( lH.m) ,
MS: 331(M÷) , 316( base) ,226
HR S计箅值： ^H式 C22H21N2( M+ )：331.16846
实验值： 331.16888
衍生物 No.45
NMR( CDCL3) 1.64(3H, d， J=7.0Hz) , 1.65(3H，s)
2.25( lH,d, J=16.0Hz) , 2.82( lH,d, J=16.5Hz)
2.86(lH,d, J=16.0Hz) ,
3.07( lH,dd, J=5.0,16.5Hz) ,3.61-3.70( ΙΗ,ιη)
5.10( lH,q, J=7.0Hz) , 5.50( lH,d, J=4. OHz)
6.39(lH，d, J=9.5Hz) , 7.05( lH.d, J=9.5Hz)
7.11-7.73( 2H,m) , 8.4K lH.s) ,
8.73-8.79( 2H，m)，
MS: 33 M+), 316( base) ,226
HRMS计算值： ^H1式 C22H21N3C M+ )：331.16846
实验值： 331.18836 衍生物 No.46
NMR(CDCL3) 1.64( 3H, d, J=6.5Hz) , 1.65( 3H,s)
2.24( lH.d, J=16.0Hz) , 2.82( lH，d， J=16.5Hz) 2.85(lH,d， J=16.0Hz) ,
3.07( lH,dd,J=5.0, 16.5Hz) ,3.67-3.70( lH,m) 3.96(6H,s), 5.22( lH.q, J=6.5HZ) , 5.30( lH,s) 5.47-5.49(lH,m)， 6.39( lH.d, J=9.5Hz) , 7.12( lH.s), 7.15( lH,d, J=9.5Hz) , 8.29( lH.s) MS: 406( M", ase) ,391,228,167
HRMS计箅值：
Figure imgf000030_0001
M+ )： 406.18926
实验值： 406.18949

Claims

权利要求
1.一种结构式如下的石杉碱甲衍生物
Figure imgf000031_0001
其中 Y^C-或 -R"， (Π)
Y=CH
0
&为^"€5的低垸基； -(CH2)„-g
Figure imgf000031_0002
π=0,1,
Figure imgf000031_0003
的低垸基， （^" 的低垸氧基， 硝基， 卤素,羧基， 酯基， 羟甲基， 羟基， 二" ^"Cs低焼基取代的氨基; -(CH2)mC00Z基， ra=0-5, Z为氢或 d ~CS低垸基； -CH=CH-G¾, G为錢， 呋喃基， 羧基， 酯基； 及氮上 : 5低垸基取 代的二氢或四氢吡啶基；
R'为氢、 "Cs的低垸基， 吡啶酰基， C5低垸氧基取代的苯甲酰基；
R"为 低垸基。
2、 根据权利要求 1J¾的化^ I， 其特征在于， 当 Y为 C=0时,！^为 - C 5的低烷 基，- (012)„^基， π=0,1, X为氢， C Cs的低垸氧基， 羧基， 酯基， 吡啶基 ， 氮上 -(：5低垸基取代的二氢或四氢吡啶基， - (CH2)mCOOZ基， m=0-5, Z为氢或 C广 C 5的低垸基； "Oi=CH"G基， G为 ^S， 呋喃基， 幾基， 酷基；
R'为氢， ^~€5的低焼基， 吡啶酰基， "Cs低烷基取代的苯甲酷基；
R"为氢及 低^ ¾。
3、根据权利要求 1 的化合物，其特征在于，当 R"，Y为 =CH时， R为
Figure imgf000031_0004
， X为
氢， :5的低垸基， d"C5的低烷氧基， 硝基， 卤素， 羟基， 羟甲基， 二" d"Cs低 垸基取代的氨基， -CH=CH-G¾, G为^ S，呋喃基； R'为氢及 C5低垸基.
4、根据权利要求 l ¾的化合物， 其特征在于它的制备方法为：
ω当 γ为 c时， 石杉碱甲与相应取代酰氣或酸酐在 ¾τΚ溶剂中
II
0
进御合，
(2〉当 R" , Υ为 =CH时， 则石杉碱甲与相应取代的醛在无水溶剂中进行缩合。
5.根据权利要求 lj^的石杉碱甲衍生物， 其特征在于它是胆碱酯 W制剂。
摘 要 石杉碱甲衍生物系海克林碱与取代酰氣、 酸酑、 取代醛在无水溶剂中縮合而成 的新衍生物。经药理 ¾ME明它是一类强效的胆碱酯酶抑制剂，毒性较低且有临床 应用开发前景的化合物。
PCT/CN1995/000100 1994-12-28 1995-12-26 Derives d'huperzine a, leur preparation et leur emploi WO1996020176A1 (fr)

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DK95941572T DK0806416T3 (da) 1994-12-28 1995-12-26 Huperzinderivater, deres fremstilling og anvendelse
AU42966/96A AU4296696A (en) 1994-12-28 1995-12-26 Huperzine a derivatives, their preparation and their use
AT95941572T ATE239708T1 (de) 1994-12-28 1995-12-26 Huperzin-derivate, ihre herstellung und ihre verwendung
EP95941572A EP0806416B1 (en) 1994-12-28 1995-12-26 Huperzine a derivatives, their preparation and their use
JP52010296A JP3545416B2 (ja) 1994-12-28 1995-12-26 フペルジンａ誘導体、その製造およびその使用
US08/860,524 US5929084A (en) 1994-12-28 1995-12-26 Huperzine A derivatives, their preparation and their use
DE69530706T DE69530706T2 (de) 1994-12-28 1995-12-26 Huperzin-derivate, ihre herstellung und ihre verwendung
US09/799,127 USRE38460E1 (en) 1994-12-28 1995-12-26 Huperzine A derivatives, their preparation and their use

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CN94114057A CN1125725A (zh) 1994-12-28 1994-12-28 一类海克林碱衍生物及它的用途
CN94114057.1 1994-12-28

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JP2002518337A (ja) * 1998-06-18 2002-06-25 ゼノバイオシス 抽出方法、薬剤成分および美容成分
KR100390777B1 (ko) * 2000-12-19 2003-07-10 한국화학연구원 피리돈 유도체의 제조방법
WO2008006286A1 (fr) * 2006-07-05 2008-01-17 Tianjin Hemay Bio-Tech Co. Ltd Dérivés analgésiques 5,9 - méthanocyclo-octa (b) pyridine - 2 (1h) - one, leur procédé de préparation et leur utilisation
US8097726B2 (en) * 2006-05-17 2012-01-17 Industrial Technology Research Institute Huperzine a compound for treatment of alzheimer's disease
DE10144041B4 (de) * 2001-09-07 2012-04-19 Leica Mikrosysteme Gmbh Gerät und Verfahren zum selbsttätigen Zuführen von Objektträgern zu einem Eindeckautomaten
TWI404531B (zh) * 2007-05-17 2013-08-11 Ind Tech Res Inst 石杉鹼甲化合物及包含此化合物之醫藥組合物

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US6159986A (en) * 1999-11-02 2000-12-12 Altman; David A. Compounds and therapy for resisting memory loss in humans
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CN1308312C (zh) * 2003-11-13 2007-04-04 中国科学院上海药物研究所 石杉碱乙双分子和双功能团衍生物、制备方法及它的用途
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Publication number Priority date Publication date Assignee Title
JP2002518337A (ja) * 1998-06-18 2002-06-25 ゼノバイオシス 抽出方法、薬剤成分および美容成分
KR100390777B1 (ko) * 2000-12-19 2003-07-10 한국화학연구원 피리돈 유도체의 제조방법
DE10144041B4 (de) * 2001-09-07 2012-04-19 Leica Mikrosysteme Gmbh Gerät und Verfahren zum selbsttätigen Zuführen von Objektträgern zu einem Eindeckautomaten
DE10144041B9 (de) * 2001-09-07 2012-07-26 Leica Mikrosysteme Gmbh Gerät zum selbsttätigen Zuführen von Objektträgern zu einem Eindeckautomaten
US8097726B2 (en) * 2006-05-17 2012-01-17 Industrial Technology Research Institute Huperzine a compound for treatment of alzheimer's disease
WO2008006286A1 (fr) * 2006-07-05 2008-01-17 Tianjin Hemay Bio-Tech Co. Ltd Dérivés analgésiques 5,9 - méthanocyclo-octa (b) pyridine - 2 (1h) - one, leur procédé de préparation et leur utilisation
TWI404531B (zh) * 2007-05-17 2013-08-11 Ind Tech Res Inst 石杉鹼甲化合物及包含此化合物之醫藥組合物

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