WO2015070713A1 - 柠檬苦素肟醚衍生物、其制法以及医药用途 - Google Patents

柠檬苦素肟醚衍生物、其制法以及医药用途 Download PDF

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WO2015070713A1
WO2015070713A1 PCT/CN2014/090148 CN2014090148W WO2015070713A1 WO 2015070713 A1 WO2015070713 A1 WO 2015070713A1 CN 2014090148 W CN2014090148 W CN 2014090148W WO 2015070713 A1 WO2015070713 A1 WO 2015070713A1
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acid
preparation
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徐云根
何广卫
朱启华
杨芸
龚国清
储昭兴
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HEFEI INDUSTRIAL PHARMACEUTICAL INSTITUTE Co Ltd
China Pharmaceutical University
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HEFEI INDUSTRIAL PHARMACEUTICAL INSTITUTE Co Ltd
China Pharmaceutical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J73/00—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms
    • C07J73/008—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by two hetero atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

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  • the invention relates to the field of medicinal chemistry, in particular to a kind of water-soluble limonin and deoxy limonoid oxime ether derivatives, a preparation method thereof, and an analgesic, anti-inflammatory and therapeutic effect on rheumatoid arthritis.
  • RA Rheumatoid arthritis
  • RA Rheumatoid arthritis
  • non-steroidal anti-inflammatory drugs are more commonly used to relieve symptoms, but the efficacy is weak, and the gastrointestinal side effects are large; the immunosuppressive agents such as methotrexate have clear effects.
  • the immunosuppressive agents such as methotrexate have clear effects.
  • it is currently the gold standard for the treatment of rheumatoid arthritis, but its slow onset, high toxicity, many adverse reactions and difficult to tolerate, long-term blood concentration monitoring; biological agents such as adalimumab have clear efficacy, but It is expensive and difficult to popularize; small molecule-targeted drugs such as tofacitini have been approved for marketing in 2012.
  • Limonoid analogues are highly oxidized tetracyclic triterpenoids of the family Rutaceae and Polygonaceae, which are widely found in citrus plants. To date, more than 300 limonoid analogs have been isolated, and limonin is representative of such compounds. Limonin is easily soluble in fat-soluble organic solvents, and has a high solubility in methanol and ethanol, but it is almost insoluble in water, and its oral bioavailability is extremely low, which limits its clinical application.
  • the invention discloses a compound of the general formula I and II.
  • the pharmacological experiments show that the compound of the invention has good analgesic, anti-inflammatory activity and obvious curative effect of rheumatoid arthritis.
  • the compounds of the formula I, II according to the invention are clinically useful for relieving pain and have an anti-inflammatory effect, in particular for the treatment of rheumatoid arthritis.
  • R 1 , R 2 represents: CH 3 , C 2 H 5 , C 3 H 7 , CH(CH 3 ) 2 or C 4 H 9
  • n 1 or 2.
  • the compound of the formula I of the present invention can be produced by the following method:
  • the process for preparing compound IV by deuteration of compound III the reactant is hydroxylamine hydrochloride; the catalyst is pyridine, triethylamine or potassium carbonate; the solvent is ethanol or isopropanol.
  • the process for preparing compound I from compound IV the base used is sodium hydride, potassium t-butoxide, sodium methoxide, sodium ethoxide, sodium hydroxide or potassium hydroxide; the catalyst is tetrabutylammonium bromide (TBAB) or benzyl tri Ethyl ammonium chloride (TEBA); the activator is sodium iodide or potassium iodide; the solvent is N, N-dimethylformamide, tetrahydrofuran or a mixed solvent of the two.
  • TBAB tetrabutylammonium bromide
  • TEBA benzyl tri Ethyl ammonium chloride
  • the activator is sodium iodide or potassium iodide
  • the solvent is N, N-dimethylformamide, tetrahydrofuran or a mixed solvent of the two.
  • the reactant is a saturated hydrogen chloride solution in diethyl ether, a saturated hydrogen chloride solution in ethanol, a saturated hydrogen chloride solution in methanol or a saturated aqueous solution of hydrogen chloride in ethyl acetate;
  • the solvent is methanol, ethanol, and Methyl chloride or ethyl acetate.
  • the compound of the formula II of the present invention can be produced by the following method:
  • reaction reagent is hydroiodic acid
  • reaction solvent is acetic acid
  • the reactant is hydroxylamine hydrochloride
  • the catalyst is pyridine, triethylamine or potassium carbonate
  • the solvent is ethanol, acetonitrile or a mixed solvent of the two.
  • the process for preparing compound II from compound VII the base used is sodium hydride, potassium t-butoxide, sodium methoxide, sodium ethoxide, sodium hydroxide or potassium hydroxide; the catalyst is tetrabutylammonium bromide or benzyltriethyl chloride. Ammonium; the activator is sodium iodide or potassium iodide; the solvent is N, N-dimethylformamide, tetrahydrofuran or a mixed solvent of the two.
  • the reactant is a saturated hydrogen chloride solution in diethyl ether, a saturated hydrogen chloride solution in ethanol, a saturated hydrogen chloride solution in methanol or a saturated aqueous solution of hydrogen chloride in ethyl acetate;
  • the solvent is methanol, ethanol, and Methyl chloride or ethyl acetate.
  • the pharmaceutically acceptable salt of the compound of the present invention has the same activity as the compound, wherein the pharmaceutically acceptable salt is an acid addition salt of the compound of the formula (I) or (II) with the following acid: hydrochloric acid, hydrobromic acid, Sulfuric acid, carbonic acid, citric acid, succinic acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or ferulic acid.
  • the pharmaceutically acceptable salt is an acid addition salt of the compound of the formula (I) or (II) with the following acid: hydrochloric acid, hydrobromic acid, Sulfuric acid, carbonic acid, citric acid, succinic acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzenesul
  • the compound code I series (e.g., I-1) represents a derivative of the compound of formula I
  • the II series (e.g., II-1) represents a derivative of the compound of formula II.
  • mice 1. Compound acetic acid writhing test test of mice:
  • mice male and female, 18-22 g, were randomly divided into control group, aspirin group, limonin group, and compound group of the present invention, with 8 rats in each group. After 1 hour of intragastric administration, the mice were intraperitoneally injected with 0.7% acetic acid 0.1 ml/10 g. Immediately observe and record the number of writhing in each group of animals within 15 min, and then calculate the inhibition rate of the mouse writhing according to the following formula. See the result Table 1.
  • Inhibition rate (average number of writhing in negative control group - average number of writhing in experimental group) ⁇ average writhing number in negative control group ⁇ 100
  • mice acetic acid writhing test showed that intraperitoneal injection of 0.7% acetic acid 0.1ml/10g can cause abdominal pain in mice, and a writhing reaction occurs.
  • the compound of the present invention has obvious inhibitory effect on the writhing reaction of mice.
  • ICR male mice, 18-22 g were randomly divided into control group, aspirin group, limonin group, and compound group of the present invention, with 8 rats in each group.
  • 3 cm of the tip of the mouse tail was immersed in a constant temperature water bath at 48 ° C, and the tip of the mouse tail was immersed in a constant temperature water bath at 48 ° C, and twice before the administration (interval of 5 minutes), and the average value was taken.
  • the changes of the tail-end latency of the mice were measured 30 minutes, 60 minutes, 90 minutes, and 120 minutes after the intragastric administration.
  • the response was not more than 25 seconds, and the pain threshold was 25 seconds.
  • the cut-off time here is defined as 25 seconds to protect the mouse's tail skin from damage.
  • mice tail-squeezing experiment showed that the compounds of the present invention can greatly enhance the pain threshold in the tail-finishing reaction of mice, and exhibit strong analgesic activity.
  • ICR male mice 18-22 g were randomly divided into control group, ibuprofen group, limonin group, and compound group of the present invention, with 8 rats in each group.
  • each group was randomly divided into a model group and each test group, with 8 rats in each group.
  • 25 ul of xylene was applied to the right ear of the mice to cause inflammation.
  • the neck was sacrificed.
  • the ears were punched with an 8 mm punch and the ears were weighed to calculate the swelling rate (%). And swelling inhibition rate (%).
  • the results are shown in Table 2.
  • pKa ionization constant
  • log D 7.4 oil-water partition coefficient at pH 7.4
  • solid solubility was determined using a Gemini Profiler instrument (pION).
  • the instrument is based on Avdeef and Tsinman's 'goldstandard' Av-deef-Bucher potentiometric titration, which is in compliance with the US Food and Drug Administration (FDA) requirements for solubility and pKa.
  • FDA US Food and Drug Administration
  • the experimental results of the adjuvant arthritis model showed that the compound I-3 hydrochloride of the present invention has a significant inhibitory effect on CFA-induced adjuvant arthritis, and each dose group can reduce the swelling degree of the model joint and the swelling of the secondary joint. Improve the arthritis index score and inhibit the weight loss caused by arthritis.
  • the swelling degree, body mass index and arthritis index of I-3 hydrochloride 40mg/kg and 20mg/kg groups were significantly better than limonin 40mg/kg group, and 10mg/kg low dose group was more than limonin 40mg/kg.
  • the superiority of the group mainly occurred after 15 days of administration.
  • Figure 1 is the effect of limonoid derivative I-1 ⁇ 5 hydrochloride on tail contraction in mice
  • Figure 2 is the effect of limonoid derivative II-1 ⁇ 5 hydrochloride on tail contraction in mice
  • the residue was added to 100 ml of water, the pH was made acidic with 5% diluted hydrochloric acid, and the aqueous layer was extracted three times with 70 ml of dichloromethane, and the mixture was combined and washed three times with saturated brine and dried over anhydrous sodium sulfate. Filter and distill off the solvent under reduced pressure.
  • the compound I-2 was used as a starting material, and the preparation method of the same I-1 ⁇ HCl was carried out to obtain 0.15 g of a white solid of I-2 ⁇ HCl, yield 71%, and 200° C. (decomposition).
  • the compound I-5 was used as a starting material, and the preparation method of the same I-1 ⁇ HCl was carried out to obtain 0.18 g of a white solid of I-5 ⁇ HCl, yield 84%, and 98° C. (shrinkage).
  • the compound VII and 1-(2-chloroethyl)morpholine hydrochloride were used as the starting materials, and the same method as I-1 was carried out, and the crude product was subjected to column chromatography using dichloromethane:methanol (70:1) to obtain II-2 white.
  • the solid was 0.28 g, and the yield was 45%. 210 ° C (carbonization).
  • the compound VII and 2-chloroethyl dimethylamine hydrochloride were used as the starting materials, and the same method as that of I-1 was carried out.
  • the crude product was chromatographed with dichloromethane:methanol (25:1) to give a white solid. The yield was 26%. 210 ° C (carbonization).
  • Example 2 0.5 g of the compound obtained in Example 2, 2 g of starch, and 1 g of dextrin were mixed, and an appropriate amount of 30% ethanol was used as a wetting agent, granulated, and tableted.

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  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pain & Pain Management (AREA)
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Abstract

本发明涉及药物化学领域，具体涉及柠檬苦素肟醚衍生物（I）和（II）、其制法以及医药用途。药理实验证明，本发明化合物具有镇痛和抗炎作用，可用于临床缓解疼痛和炎症疾病。

Description

柠檬苦素肟醚衍生物、其制法以及医药用途 技术领域
本发明涉及药物化学领域，具体涉及一类水溶性柠檬苦素及脱氧柠檬苦素肟醚衍生物，它们的制备方法、以及镇痛、抗炎、治疗类风湿性关节炎的作用。
背景技术
类风湿性关节炎(RA)属于自身免疫性疾病，表现为外周关节的非特异性炎症，患病关节及其周围组织呈现进行性破坏，滑膜炎持久反复发作，可导致关节内软骨和骨的破坏，关节功能障碍，甚至残废。其患病率随着年龄的增长而逐渐增加，多数群体研究显示老年人(65岁以上)中的患病率最高，全球的发病率约为1.0％，其中美国为3.0％，日本为0.3％，中国为0.29％。女性易患本病，女性与男性罹患本病之比约2～3:1。
现有类风湿性关节炎的治疗药物中，非甾体抗炎药较为常用，可缓解症状，但药效较弱，胃肠道副作用大；免疫抑制剂如甲氨蝶呤药效明确，作用持久，是目前治疗类风湿性关节炎的金标准，但其起效缓慢，毒性大，不良反应多且难以耐受，需长期进行血药浓度监测；生物制剂如阿达木单抗疗效明确，但价格昂贵，难以普及；小分子靶向药如托法替尼2012年批准上市，上市初被认为是开启类风湿性关节炎治疗药物中疗效、成本和安全性均符合临床要求的新型作用机制药物，但随着临床应用的深入和范围扩大，众多安全性问题逐渐显现，产品标签亦有安全黑框警告，主要为增加肿瘤、感染风险。
由于现有药物难以满足临床需求，临床上对于新型类风湿性关节炎治疗药物的需求极大，进行相关新药研究开发具有重大意义。
柠檬苦素类似物是高度氧化的四环三萜类化合物芸香科和楝科植物家族，广泛存在于柑橘类植物中。迄今已分离得到大约300多种柠檬苦素类似物，柠檬苦素是这类化合物中的代表。柠檬苦素易溶于脂溶性有机溶剂，在甲醇、乙醇中溶解度较大，但其几乎不溶于水，口服生物利用度极低，限制了其临床应用。
Figure PCTCN2014090148-appb-000001
早期的研究主要是为了探寻引起柑桔果实和果汁苦味的化学物质。近年来人们主要集中在生物活性的研究上。目前，柠檬苦素类化合物已被证明具有广泛的生物活性。Matsuda等(Planta Medica,1998,64:339-342)从疏毛吴茱萸中分离的柠檬苦素具有明显的镇痛和抗炎作用。施英等(食品科学,2007,28:515-518)的研究证实了橘核中柠檬苦素类物质有显著的局部镇痛消炎作用。本发明的柠檬苦素类物质不仅被证明有显著的抗炎、镇痛活性，而且有明显的类风湿性关节炎的疗效。
发明内容
本发明公开了一类I、II通式的化合物，经药理实验显示，本发明的化合物具有较好的镇痛、抗炎活性和明显的类风湿性关节炎的疗效。因此，本发明的式I、II化合物临床可用于缓解疼痛并且具有消炎的作用，特别是治疗类风湿性关节炎的作用。
Figure PCTCN2014090148-appb-000002
R代表：
Figure PCTCN2014090148-appb-000003
R1,R2代表：CH3,C2H5,C3H7,CH(CH3)2或C4H9
m＝1或2；
n＝1或2。
本发明通式化合物I可用下列方法制备：
Figure PCTCN2014090148-appb-000004
Figure PCTCN2014090148-appb-000005
其中：
由化合物III经肟化制备化合物IV的过程，反应物为盐酸羟胺；催化剂为吡啶，三乙胺或碳酸钾；溶剂为乙醇或异丙醇。
由化合物IV经醚化制备化合物I的过程，反应物为RX，R代表：
Figure PCTCN2014090148-appb-000006
其中：R1,R2代表：CH3,C2H5,C3H7,CH(CH3)2或C4H9；m＝1或2；n＝1或2
由化合物IV制备化合物I的过程，所用的碱为氢化钠，叔丁醇钾，甲醇钠，乙醇钠，氢氧化钠或氢氧化钾；催化剂为四丁基溴化铵(TBAB)或苄基三乙基氯化铵(TEBA)；活化剂为碘化钠或碘化钾；溶剂为N,N-二甲基甲酰胺，四氢呋喃或两者的混合溶剂。
由化合物I经成盐制备化合物I·HCl的过程，反应物为饱和氯化氢的乙醚溶液、饱和氯化氢的乙醇溶液、饱和氯化氢的甲醇溶液或饱和氯化氢的乙酸乙酯溶液；溶剂为甲醇、乙醇、二氯甲烷或乙酸乙酯。
本发明通式化合物II可用下列方法制备：
Figure PCTCN2014090148-appb-000007
Figure PCTCN2014090148-appb-000008
其中：
由化合物III经脱氧成双键制备化合物VI的过程，反应试剂为氢碘酸；反应溶剂为乙酸。
由化合物VI经肟化制备化合物VII的过程，反应物为盐酸羟胺；催化剂为吡啶，三乙胺或碳酸钾；溶剂为乙醇、乙腈或两者的混合溶剂。
由化合物VII经醚化制备化合物II的过程，反应物为RX，R代表：
Figure PCTCN2014090148-appb-000009
其中：R1,R2代表：CH3,C2H5,C3H7,CH(CH3)2或C4H9；m＝1或2；n＝1或2
由化合物VII制备化合物II的过程，所用的碱为氢化钠，叔丁醇钾，甲醇钠，乙醇钠，氢氧化钠或氢氧化钾；催化剂为四丁基溴化铵或苄基三乙基氯化铵；活化剂为碘化钠或碘化钾；溶剂为N,N-二甲基甲酰胺、四氢呋喃或两者的混合溶剂。
由化合物II经成盐制备化合物II·HCl的过程，反应物为饱和氯化氢的乙醚溶液、饱和氯化氢的乙醇溶液、饱和氯化氢的甲醇溶液或饱和氯化氢的乙酸乙酯溶液；溶剂为甲醇、乙醇、二氯甲烷或乙酸乙酯。
本发明化合物药学上可接受的盐具有与化合物同样的活性，其中药学上可接受的盐为通式(I)或(II)化合物与下列酸形成的酸加成盐：盐酸、氢溴酸、硫酸、碳酸、柠檬酸、琥珀酸、酒石酸、磷酸、乳酸、丙酮酸、乙酸、马来酸、甲磺酸、苯磺酸、对甲苯磺酸或阿魏酸。
以下是本发明部分化合物的药理试验及结果。其中化合物代号I系列(如I-1)表示通式I化合物的衍生物，II系列(如II-1)表示通式II化合物的衍生物。
一、化合物的小鼠的醋酸扭体测试试验：
试验方法：
ICR小鼠，雌雄各半，18～22g，随机分成对照组、阿司匹林组、柠檬苦素组、本发明化合物组，每组8只。各组灌胃给药1h后，给小鼠腹腔注射0.7％醋酸0.1ml/10g，立即观察并记录各组动物在15min内的扭体次数，然后根据下列公式计算小鼠扭体的抑制率，结果见 表1。
抑制率＝(阴性对照组平均扭体次数－实验组平均扭体次数)÷阴性对照组平均扭体次数×100
表1 柠檬苦素衍生物对小鼠醋酸扭体次数的影响(
Figure PCTCN2014090148-appb-000010
n＝8)
Figure PCTCN2014090148-appb-000011
Figure PCTCN2014090148-appb-000012
Figure PCTCN2014090148-appb-000013
注：*P<0.05，**P<0.01vs.模型组。
小鼠醋酸扭体实验结果表明，腹腔注射0.7％醋酸0.1ml/10g后可引起小鼠的腹腔疼痛，出现扭体反应，本发明的化合物对小鼠扭体反应均具有明显的抑制作用。
二、化合物的小鼠缩尾实验测试试验：
实验方法：
ICR雄性小鼠，18～22g，随机分成对照组、阿司匹林组、柠檬苦素组、本发明化合物组，每组8只。将小鼠尾尖端3cm浸入48℃恒温水浴锅中，将小鼠尾尖端3cm浸入48℃的恒温水浴锅中，给药前测两次(间隔5分钟)，取其平均值。各给药组分别灌胃后，测定各组灌胃后30分钟，60分钟，90分钟，120分钟小鼠的缩尾潜伏期的变化，超过25秒无反应者，痛阈按25秒计。然后根据下列公式计算MPE(％)。结果见图1和图2。
MPE(最大可能效应的百分比)＝100×∣(给药后痛阈-基础痛阈)/(强制停止时间-基础痛阈)∣。此处的cut-off time定义为25秒，来保护小鼠尾部皮肤不受损伤。
小鼠缩尾实验结果显示本发明的化合物均能够大幅度的提升小鼠缩尾反应中的痛阈，表现出较强的镇痛活性。
三、化合物的小鼠耳肿胀实验：
实验方法：
ICR雄性小鼠，18～22g，随机分成对照组、布洛芬组、柠檬苦素组、本发明化合物组，每组8只。各组灌胃给药90分钟后，随机分为模型组和各受试药组，每组8只。各组灌胃给药90分钟后在小鼠右耳涂二甲苯25ul致炎，30分钟后拉颈处死，用8mm打孔器对双耳打孔，取耳称重，计算肿胀率(％)和肿胀抑制率(％)。结果见表2。
表2 柠檬苦素衍生物对小鼠耳肿胀的作用(
Figure PCTCN2014090148-appb-000014
n＝8)
Figure PCTCN2014090148-appb-000015
Figure PCTCN2014090148-appb-000016
注：*P<0.05，**P<0.01，***P<0.005vs.模型组；#P<0.05，##P<0.01，###P<0.005vs.柠檬苦素组。
小鼠扭体实验结果显示本发明的化合物对小耳肿胀具有明显的抑制作用。其中化合物I-3表现出最强活性。
四、化合物的理化性质：
理化性质包括pKa(电离常数)，log D7.4(pH 7.4时的油水分配系数)和固体溶解度是使用Gemini Profiler instrument(pION)进行测定的。该仪器是根据Avdeef和Tsinman的‘goldstandard’Av-deef-Bucher电位滴定法，该测量方法符合美国食品药品管理局(FDA)对溶解度和pKa的测试要求。
对化合物I-1～5和II-1～5(以盐酸盐形式测定)进行了理化性质的评价，结果见表3。由于柠檬苦素和脱氧柠檬苦素不在仪器的测量范围内，因此采用了经典的摇瓶法进行溶解度的测定。
表3 化合物I-1～5和II-1～5的理化性质数据
Figure PCTCN2014090148-appb-000017
Figure PCTCN2014090148-appb-000018
a—：未测定
五、化合物I-3盐酸盐的佐剂性关节炎模型实验：
实验方法：SD雄性大鼠70只，160～180g，适应性饲养3天后，随机分空白组、模型组、I-3盐酸盐10mg/kg组、I-3盐酸盐20mg/kg组、I-3盐酸盐40mg/kg组、柠檬苦素40mg/kg组，每组10只。造模前各组灌胃给药，空白组给予生理盐水，1小时后除空白组外其余组大鼠右后足足垫注射0.1ml完全弗氏佐剂(Complete freund adjuvant,CFA)致炎，以后每天给药1次，给药30天，造模期间于不同时间点(造模前、6h、12h、24h、48h、72h、7天、10天、15天、20天、25天、30天)检测大鼠急性炎症引起的足肿胀及继发性足肿胀、体重变化并进行关节炎评分，结果见表4～6。
Figure PCTCN2014090148-appb-000019
Figure PCTCN2014090148-appb-000020
根据关节炎指数评分表，每只动物最高分数16分，结果见表7。
表7 I-3盐酸盐对佐剂性关节炎大鼠模型关节指数评分(
Figure PCTCN2014090148-appb-000021
n＝10)
Figure PCTCN2014090148-appb-000022
注：*P<0.05,**P<0.01vs.模型组；#P<0.05，##P<0.01vs.柠檬苦素。
佐剂性关节炎模型实验结果显示本发明的化合物I-3盐酸盐对CFA诱导的佐剂性关节炎具有显著抑制作用，各剂量组均能降低造模关节肿胀度以及继发性关节肿胀，改善关节炎指数评分，抑制关节炎引起的体重下降。I-3盐酸盐40mg/kg、20mg/kg剂量组肿胀度、体重指标和关节炎指数指标均显著优于柠檬苦素40mg/kg组，10mg/kg低剂量组较柠檬苦素40mg/kg组的优效性主要出现在给药15天后。
附图说明
图1是柠檬苦素衍生物I-1～5盐酸盐对小鼠缩尾的作用
图2是柠檬苦素衍生物II-1～5盐酸盐对小鼠缩尾的作用
具体实施方式
实施例1
化合物IV的制备
在100ml茄形瓶中加入柠檬苦素(III)1.0g(0.002mol)，盐酸羟胺1.1g(0.016mol)，无水乙醇45ml，吡啶15ml，加热回流2.5h。薄层层析(TLC)检测，反应完全后将待反应液冷至室温，将其倒入事先配置好的5％稀盐酸125ml中，调其pH为酸性，冰水冷却。水层用50ml二氯甲烷萃取三次，合并萃取液，饱和食盐水洗三次，无水硫酸钠干燥。过滤，减压蒸除溶剂。粗品用二氯甲烷：甲醇(125:1)柱层析，得白色固体0.98g，收率95％。mp>250℃；1HNMR(CDCl3,500MHz),δ(ppm):7.70(1H,brs),7.39(2H,d,J＝1.7Hz),6.34 (1H,s),5.46(1H,s),4.68(1H,d,J＝13.0Hz),4.36(1H,d,J＝13.0Hz),3.99(1H,brs),3.81(1H,s),3.57(1H,d,J＝11.8Hz),2.96(1H,dd,J1＝3.8Hz,J2＝16.7Hz),2.69(1H,dd,J1＝1.5Hz,J2＝16.7Hz),2.42(1H,d,J＝10.2Hz),1.92-2.02(2H,m),1.74–1.88(3H,m),1.49–1.51(1H,m),1.32(3H,s),1.23(3H,s),1.19(3H,s),0.97(3H,s).
实施例2
化合物I-1的制备
在50ml的茄形瓶中将0.50g(0.001mol)IV完全溶解在25ml无水四氢呋喃中。此时加入60％氢化钠0.2g(0.005mol)，室温搅拌30min后加入1-(2-氯乙基)哌啶盐酸盐0.55g(0.003mol)、碘化钾0.17(0.001mol)及催化量的TBAB，继续室温搅拌1h后，升温至80℃反应12h。TLC检测至反应完全，冷却，减压蒸除溶剂。残留物加入100ml水，用5％稀盐酸调pH至酸性，水层用70ml二氯甲烷萃取三次，合并萃取液，饱和食盐水洗三次，无水硫酸钠干燥。过滤，减压蒸除溶剂。粗品用二氯甲烷：甲醇(75:1)柱层析，得I-1白色固体0.32g，收率54％。mp 195～198℃；IR(KBr,υcm-1):2932,1746,1561,1414,1021,810；1H NMR(CDCl3,500MHz),δ(ppm):7.40(2H,d,J＝1.6Hz),6.36(1H,s),5.47(1H,s),4.67(1H,d,J＝13.0Hz),4.33(1H,d,J＝13.0Hz),4.24(2H,brs),3.96(1H,s),3.79(1H,s),3.47(1H,dd,J1＝2.6Hz,J2＝13.1Hz),2.95(1H,dd,J1＝3.8Hz,J2＝16.8Hz),2.66(1H,d,J＝16.6Hz),2.52(4H,brs),2.39(1H,d,J＝11.3Hz),1.72-2.02(6H,m),1.47-1.57(8H,m),1.30(3H,s),1.25(3H,s),1.17(3H,s),0.95(3H,s)；13C NMR(CDCl3,300MHz),δ(ppm):205.83,169.38,166.87,158.21,143.18,141.01,120.23,109.74,80.39,79.29,78.28,72.33,65.81,64.78,60.68,57.67,54.99,54.29,49.97,46.18,46.03,37.99,35.86,33.14,30.28,25.92,24.15,21.60,21.36,19.78,19.61,18.01；HR-ESIMS m/z 597.3172[M+H]+(calcd for C33H45N2O8,597.3170).
在25ml的茄形瓶中将0.2g I-1完全溶解在4ml二氯甲烷中，室温搅拌下缓慢滴入HCl饱和的乙醚溶液10ml，有白色固体析出，搅拌5min后，过滤，用乙醚溶液洗涤，干燥得I-1·HCl白色固体0.13g，收率65％，110℃(分解)。
实施例3
化合物I-2的制备
以化合物IV和1-(2-氯乙基)吗啉盐酸盐为原料，操作同I-1的方法，粗品用二氯甲烷： 甲醇(75:1)柱层析，得I-2白色固体0.29g，收率48％。mp 138～141℃；IR(KBr,υcm-1):2963,1750,1025,807；1H NMR(CDCl3,500MHz),δ(ppm):7.41(2H,d,J＝4.6Hz),6.36(1H,s),5.49(1H,s),4.66(1H,d,J＝13.0Hz),4.33(1H,d,J＝13.0Hz),3.96(1H,brs),3.86(4H,brs),3.80(1H,s),3.45(1H,dd,J1＝2.9Hz,J2＝14.0Hz),2.95(1H,dd,J1＝3.8Hz,J2＝16.8Hz),2.67–2.93(4H,brs),2.66(1H,dd,J1＝1.9Hz,J2＝16.7Hz),2.39(1H,d,J＝11.6Hz),1.73-2.06(9H,m),1.49-1.53(2H,m),1.30(3H,s),1.25(3H,s),1.17(3H,s),0.97(3H,s)；13CNMR(CDCl3,300MHz),δ(ppm):169.37,166.96,158.44,143.20,140.98,120.14,109.69,80.35,79.27,78.28,71.86,66.88,65.76,64.73,60.65,57.38,54.27,54.04,49.95,46.14,46.03,37.99,35.84,33.09,30.27,21.59,21.34,19.78,19.57,17.99；HR-ESIMS m/z 599.2958[M+H]+(calcd for C32H43N2O9,599.2963).
以化合物I-2为起始原料，操作同I-1·HCl的制备方法，得I-2·HCl白色固体0.15g，收率71％，200℃(分解)。
实施例4
化合物I-3的制备
以化合物IV和N,N-二乙基氯乙胺盐酸盐为原料，操作同I-1的方法，粗品用二氯甲烷：甲醇(60:1)柱层析，得I-3白色固体0.25g，收率43％。mp 134～136℃；IR(KBr,υcm-1):2979,2623,1744,1036,809；1H NMR(CDCl3,500MHz),δ(ppm):7.40(2H,d,J＝1.6Hz),6.36(1H,s),5.47(1H,s),4.67(1H,d,J＝13.0Hz),4.33(1H,d,J＝13.0Hz),4.18(2H,m),3.96(1H,brs),3.80(1H,s),3.48(1H,dd,J1＝2.3Hz,J2＝13.8Hz),2.95(1H,dd,J1＝3.8Hz,J2＝16.7Hz),2.79(2H,brs),2.68(4H,s),2.65(1H,s),2.39(1H,d,J＝11.6Hz),1.72-2.50(4H,m),1.49-1.53(2H,m),1.30(3H,s),1.25(3H,s),1.17(3H,s),1.08(6H,brs),0.95(3H,s)；13C NMR(CDCl3,300MHz),δ(ppm):169.43,143.29,140.98,119.99,109.64,80.43,79.18,78.55,65.85,64.71,60.52,54.34,50.12,49.81,47.22,46.28,46.15,45.84,38.13,35.84,32.99,30.30,29.71,21.57,21.46,20.35,19.62,17.87,8.96,8.67；HR-ESIMS m/z 585.3165[M+H]+(calcd for C32H45N2O8,585.3170).
以化合物I-3为起始原料，操作同I-1·HCl的制备方法，得I-3·HCl白色固体0.11g，收率52％，78℃(收缩)，210℃(分解)。
实施例5
化合物I-4的制备
以化合物IV和N,N-二甲基-3-氯丙胺盐酸盐为原料，操作同I-1的方法，粗品用二氯甲烷：甲醇(50:1)柱层析，得I-4白色固体0.20g，收率34％。mp 178～180℃；IR(KBr,υcm-1):2961,1743,1025,810；1H NMR(CDCl3,500MHz),δ(ppm):7.41(1H,s),7.40(1H,s),6.36(1H,s),5.47(1H,s),4.68(1H,d,J＝13.1Hz),4.34(1H,d,J＝13.1Hz),4.08–4.11(2H,m),3.99(1H,brs),3.79(1H,s),3.40–3.48(2H,m),3.37–3.41(7H,m),2.93(1H,dd,J1＝3.6Hz,J2＝16.9Hz),2.67(1H,d,J＝16.9Hz),2.64–2.66(2H,m),2.42(1H,d,J＝11.3Hz),1.98-2.04(2H,m),1.79–1.90(2H,m),1.63–1.74(1H,m),1.43–1.55(1H,m),1.32(3H,s),1.26(6H,s),1.18(3H,s)；13C NMR(CDCl3,300MHz),δ(ppm):169.54,167.71,159.98,143.27,140.98,120.00,109.68,80.29,79.08,78.57,70.49,65.88,64.80,60.18,54.94,54.31,49.59,46.23,46.13,42.88,38.08,35.83,32.93,30.21,24.66,21.61,21.42,19.89,19.58,17.84,13.70；HR-ESIMS m/z 571.3012[M+H]+(calcd for C31H43N2O8,571.3014).
以化合物I-4为起始原料，操作同I-1·HCl的制备方法，得I-4·HCl白色固体0.16g，收率75％，218℃(分解)。
实施例6
化合物I-5的制备
以化合物IV和2-氯乙基二甲胺盐酸盐为原料，操作同I-1的方法，粗品用二氯甲烷：甲醇(40:1)柱层析，得I-5白色固体0.18g，收率31％。mp 137～140℃；IR(KBr,υcm-1):2962,1748,1030,810；1H NMR(CDCl3,500MHz),δ(ppm):7.42(1H,s),7.40(1H,t,J＝2.8Hz),6.36(1H,d,J＝1.5Hz),5.47(1H,s),4.67(1H,d,J＝21.7Hz),4.33(1H,d,J＝21.8Hz),4.17(2H,t,J＝9.5Hz),3.96(1H,brs),3.80(1H,s),3.44-3.51(1H,m),2.95(1H,dd,J1＝6.3Hz,J2＝27.9Hz),2.73–2.60(3H,m),2.40(1H,d,J1＝18.4Hz),2.32(6H,s),2.15–2.02(2H,m),1.97–1.82(1H,m),1.80–1.69(2H,m),1.42–1.56(1H,m),1.29(3H,s),1.25(6H,s),1.17(3H,s)；13C NMR(CDCl3,300MHz),δ(ppm):169.62,168.21,162.21,143.30,141.02,119.98,109.66,80.47,79.18,78.68,67.06,65.96,64.79,60.42,55.46,54.34,49.76,46.37,46.11,44.29,42.83,38.17,35.87,32.91,30.29,24.46,21.59,21.47,20.67,19.57,17.83,13.92；HR-ESIMS m/z 557.2845[M+H]+(calcd for C30H41N2O8,557.2857).
以化合物I-5为起始原料，操作同I-1·HCl的制备方法，得I-5·HCl白色固体0.18g，收率84％，98℃(收缩)。
实施例7
化合物VI的制备
在250ml的茄形瓶中将依次加入柠檬苦素4g(0.009mol)，70ml氢碘酸和70ml醋酸，在60℃反应。TLC跟踪至反应完全，待反应液冷却后缓慢倒入400ml饱和亚硫酸钠溶液中，用150ml二氯甲烷萃取三次，合并萃取液，分别用饱和碳酸氢钠溶液，饱和食盐水各洗二次，无水硫酸钠干燥。过滤，减压蒸除溶剂。粗品用乙腈和水重结晶，得白色或淡黄色晶体2.7g，收率70％。mp>250℃；1H NMR(CDCl3,500MHz),δ(ppm):7.50(1H,s),7.45(1H,s),6.85(1H,s),6.42(1H,d,J＝0.95Hz),5.01(1H,s),4.63(2H,dd,J1＝13.1Hz,J2＝56.0Hz),4.11(1H,brs),2.98(1H,dd,J1＝3.6Hz,J2＝16.9Hz),2.82(1H,t,J＝16.0Hz),2.65(1H,dd,J1＝1.95Hz,J2＝16.9Hz),2.61(1H,dd,J1＝3.8Hz,J2＝16.1Hz),2.54(1H,q,J＝7.4Hz),2.31(1H,dd,J1＝3.7Hz,J2＝15.8Hz),2.03-2.13(1H,m),1.81-1.91(1H,m),1.54–1.65(1H,m),1.42(3H,s),1.31(3H,s),1.26(3H,s),1.20(3H,s)；MS(ESI(-)70V,m/z):455.2([M+H]+)
实施例8
化合物VII的制备
在100ml茄形瓶中加入化合物VI 1.0g(0.002mol)，盐酸羟胺1.1g(0.016mol)，无水乙醇20ml，乙腈20ml，吡啶15ml，加热回流24h。TLC跟踪至反应完全，待反应液冷至室温，将其倒入事先配置好的5％稀盐酸125ml中，调pH为酸性，冰水冷却。水层用50ml二氯甲烷萃取三次，合并萃取液，并用饱和食盐水洗三次，无水硫酸钠干燥。过滤，减压蒸除溶剂。粗品用二氯甲烷：甲醇(125:1)柱层析，得白色固体0.60g，收率58％。248℃(碳化)。1H NMR(CDCl3,500MHz),δ(ppm):7.75(1H,brs),7.50(1H,s),7.43(1H,s),6.72(1H,s),6.41(1H,d,J＝1.05Hz),5.10(1H,s),4.47(2H,dd,J1＝13.0Hz,J2＝46.3Hz),4.06(1H,brs),3.33(1H,dd,J1＝4.8Hz,J2＝22.0Hz),2.93(1H,dd,J1＝3.6Hz,J2＝10.5Hz),2.63(1H,dd,J1＝2.3Hz,J2＝16.8Hz),2.41(1H,q,J＝5.7Hz),2.31(1H,dd,J1＝14.9Hz,J2＝17.1Hz),1.96-2.13(1H,m),1.78-1.86(1H,m),1.51–1.68(1H,m),1.47(3H,s),1.33(3H,s),1.28(3H,s),1.20(3H,s)；MS(ESI(-)70V,m/z):470.2([M+H]+)
实施例9
化合物II-1的制备
以化合物VII和1-(2-氯乙基)哌啶盐酸盐为原料，操作同I-1的方法，粗品用二氯甲烷：甲醇(100:1)柱层析，得II-1白色固体0.38g，收率62％。230℃(碳化)。IR(KBr,υcm-1):2937,1754,1721,1039,874；1H NMR(CDCl3,500MHz),δ(ppm):7.51(1H,s),7.44(1H,d,J＝1.5Hz),6.77(1H,s),6.42(1H,s),5.02(1H,s),4.45(2H,dd,J1＝12.9Hz,J2＝41.2Hz),4.33(2H,t,J＝5.9Hz),4.07(1H,s),3.20(1H,dd,J1＝5.0Hz,J2＝17.6Hz),2.93(1H,dd,J1＝3.5Hz,J2＝16.8),2.72(2H,brs),2.63(1H,dd,J1＝2.3Hz,J2＝16.8Hz),2.52(4H,brs),2.43(1H,dd,J1＝6.5Hz,J2＝13.1Hz),2.35(1H,dd,J1＝14.9Hz,J2＝17.5Hz),1.94–2.10(2H,m),1.82(1H,m),1.57–1.73(5H,m),1.43-1.56(3H,m),1.49(3H,s),1.31(3H,s),1.30(3H,s),1.20(3H,s)；13C NMR(CDCl3,300MHz),δ(ppm):169.68,168.92,165.21,158.74,143.14,141.47,119.98,116.89,109.98,93.97,82.31,81.17,78.17,72.32,64.73,57.84,57.67,55.06,46.14,45.81,45.56,38.79,35.68,30.73,29.02,26.57,25.86,24.12,22.13,21.99,21.85,21.53,19.01,18.19；HR-ESIMS m/z 581.3210[M+H]+(calcd for C33H45N2O7,581.3221).
以化合物II-1为起始原料，操作同I-1·HCl的方法，得II-1·HCl白色固体0.19g，收率90％，108℃(分解)。
实施例10
化合物II-2的制备
以化合物VII和1-(2-氯乙基)吗啉盐酸盐为原料，操作同I-1的方法，粗品用二氯甲烷：甲醇(70:1)柱层析，得II-2白色固体0.28g，收率45％。210℃(碳化)。IR(KBr,υcm-1):2961,1751,1719,1036,871；1H NMR(CDCl3,500MHz),δ(ppm):7.52(1H,s),7.45(1H,t,J＝1.6Hz),6.75(1H,s),6.43(1H,d,J＝1.0Hz),5.03(1H,s),4.46(2H,dd,J1＝12.9Hz,J2＝42.2Hz),4.34(2H,brs),4.07(1H,t,J＝2.7Hz),3.77(4H,brs),3.22(1H,dd,J1＝4.4Hz,J2＝17.3Hz),2.94(1H,dd,J1＝3.5Hz,J2＝16.9Hz),2.76(2H,brs),2.63(2H,dd,J1＝2.4Hz,J2＝16.9Hz),2.59(2H,brs),2.44(1H,dd,J1＝6.6Hz,J2＝13.0Hz),2.34(1H,dd,J1＝14.9Hz,J2＝17.4Hz),1.95–2.10(2H,m),1.77–1.88(1H,m),1.63–1.74(2H,m),1.51–1.61(1H,m),1.50(3H,s),1.31(3H,s),1.3(3H,s),1.20(3H,s)；13C NMR(CDCl3,300MHz), δ(ppm):169.56,168.75,165.16,143.12,141.43,119.90,117.02,109.93,82.29,81.07,78.17,71.75,66.74,65.85,64.70,57.70,57.55,53.96,46.09,45.81,45.62,38.75,35.62,30.69,28.89,26.55,22.07,21.86,21.40,18.15,15.28；HR-ESIMS m/z 583.3001[M+H]+(calcd for C32H43N2O8,583.3014).
以化合物II-2为起始原料，操作同I-1·HCl的方法，得II-2·HCl白色固体0.14g，收率66％，82℃(收缩)，158℃(分解)。
实施例11
化合物II-3的制备
以化合物VII和N，N-二乙基氯乙胺盐酸盐为原料，操作同I-1的方法，粗品用二氯甲烷：甲醇(50:1)柱层析，得II-3白色固体0.32g，收率53％。mp 176～178℃；IR(KBr,υcm-1):2969,1758,1721,1041,877；1H NMR(CDCl3,500MHz),δ(ppm):7.51(1H,s),7.44(1H,s),6.80(1H,s),6.42(1H,s),5.03(1H,s),4.44(2H,dd,J1＝12.9Hz,J2＝39.2Hz),4.26(2H,t,J＝6.0Hz),4.07(1H,s),3.21(1H,dd,J1＝4.9Hz,J2＝17.7Hz),2.93(1H,dd,J1＝3.3Hz,J2＝16.8Hz),2.75–2.86(2H,m),2.57–2.71(5H,m),2.44(1H,dd,J1＝6.5Hz,J2＝13.0Hz),2.30–2.40(1H,m),1.94–2.08(2H,m),1.75–1.87(2H,m),1.65–1.72(1H,m),1.49(3H,s),1.30(3H,s),1.30(3H,s),1.19(3H,s),1.08(6H,t,J＝7.1Hz)；13C NMR(CDCl3,300MHz),δ(ppm):169.61,168.92,165.14,158.48,143.05,141.39,119.90,116.72,109.90,82.22,81.11,78.09,73.06,64.62,57.50,51.45,47.91,46.06,45.68,45.41,38.72,35.60,30.65,29.05,26.46,22.06,21.94,21.49,18.11,11.85；HR-ESIMS m/z 569.3217[M+H]+(calcd for C32H45N2O7,569.3221).
以化合物II-3为起始原料，操作同I-1·HCl的方法，得II-3·HCl白色固体0.15g，收率71％，182℃(分解)。
实施例12
化合物II-4的制备
以化合物VII和N,N-二甲基-3-氯丙胺盐酸盐为原料，操作同I-1的方法，粗品用二氯甲烷：甲醇40:1柱层析，得II-4白色固体0.25g，收率42％。220℃(碳化)。IR(KBr,υcm-1):2927,1751,1718,1040,874；1H NMR(CDCl3,500MHz),δ(ppm):7.50(1H,s),7.43(1H,s),6.79(1H,s),6.41(1H,s),5.01(1H,s),4.44(2H,dd,J1＝12.8Hz,J2＝39.1Hz),4.29–4.14 (2H,m),4.06(1H,brs),3.18(1H,dd,J1＝5.0Hz,J2＝17.7Hz),2.92(1H,dd,J1＝3.4Hz,J2＝16.8Hz),2.62(1H,dd,J1＝2.0Hz,J2＝16.8Hz),2.30–2.52(4H,m),2.27(6H,s),1.99-2.02(2H,m),1.85–1.93(2H,m),1.75–1.84(1H,m),1.63–1.73(2H,m),1.48(3H,s),1.30(3H,s),1.28(3H,s),1.19(3H,s)；13C NMR(CDCl3,300MHz),δ(ppm):169.65,169.07,165.23,158.37,143.10,141.43,119.94,116.68,109.94,82.29,81.15,78.14,72.79,64.65,59.11,57.55,56.28,46.11,45.72,45.42,45.30,38.77,35.65,30.71,29.14,27.42,26.47,24.19,22.11,21.84,21.52,19.80,18.14,15.28,13.69；HR-ESIMS m/z 555.3056[M+H]+(calcd for C31H43N2O7,555.3065).
以化合物II-4为起始原料，操作同I-1·HCl的方法，得II-4·HCl白色固体0.12g，收率56％，200℃(分解)。
实施例13
化合物II-5的制备
以化合物VII和2-氯乙基二甲胺盐酸盐为原料，操作同I-1的方法，粗品用二氯甲烷：甲醇(25:1)柱层析，得II-5白色固体0.15g，收率26％。210℃(碳化)。IR(KBr,υcm-1):2966.1758,1720,1039,871；1H NMR(CDCl3,500MHz),δ(ppm):7.52(1H,s),7.44(1H,t,J＝1.6Hz),6.80(1H,s),6.42(1H,s),5.03(1H,s),4.45(2H,dd,J1＝12.9Hz,J2＝41.8Hz),4.29(2H,t,J＝5.7Hz),4.07(1H,s),3.23(1H,dd,J1＝5.0Hz,J2＝17.7Hz),2.93(1H,dd,J1＝3.5Hz,J2＝16.8Hz),2.70(2H,t,J＝5.3Hz),2.63(1H,dd,J1＝2.4Hz,J2＝16.8Hz),2.40–2.47(1H,m),2.37(1H,m),2.36(6H,s),1.95–2.07(2H,m),1.77–1.87(1H,m),1.70(2H,m),1.50(3H,s),1.30(3H,s),1.30(3H,s),1.19(3H,s)；13C NMR(CDCl3,300MHz),δ(ppm):169.64,168.95,165.17,158.73,143.06,141.39,119.91,116.74,109.91,82.24,81.13,78.08,72.29,64.65,59.26,58.33,57.51,46.06,45.85,45.69,45.47,38.72,35.62,30.65,29.02,26.47,24.30,22.10,21.99,21.48,19.78,18.11,13.69；HR-ESIMS m/z 541.2897[M+H]+(calcd for C30H41N2O7,541.2908).
以化合物II-5为起始原料，操作同I-1·HCl的方法，得II-5·HCl白色固体0.14g，收率66％，152℃(收缩)，201℃(分解)。
实施例14
化合物I-3.对甲苯磺酸的制备
在25ml的茄形瓶中将化合物I-3(200mg,0.34mmol)完全溶解在5ml乙酸乙酯中，室温搅拌下缓慢滴入对甲苯磺酸(65.6mg,0.38mmol)与2ml乙酸乙酯组成的溶液，有白色固体析出，5℃左右搅拌2小时，过滤，固体用乙醚洗涤，干燥得I-3.对甲苯磺酸白色固体0.22g，收率84.9％，m.p.142～144℃,HPLC:99.09％。
1H NMR(500MHz,CDCl3)δ10.75(s,1H),7.75(d,J＝7.9Hz,2H),7.41(s,2H),7.18(d,J＝7.8Hz,2H),6.35(s,1H),5.51(s,1H),4.57(d,J＝13.0Hz,1H),4.54–4.48(m,1H),4.28(dd,J1＝3.0Hz,J2＝7.5Hz,2H),3.94(s,1H),3.77(s,1H),3.72–3.57(m,1H),3.40(d,J＝12.0Hz,2H),3.33(dd,J1＝6.7Hz,J2＝4.9Hz,2H),3.27-3.18(m,2H),2.93(dd,J1＝16.8Hz,J2＝3.5Hz,1H),2.65(d,J＝16.6Hz,1H),2.36(s,3H),1.99(d,J＝14.4Hz,1H),1.95–1.69(m,6H),1.44(t,J＝7.2Hz,3H),1.38(t,J＝7.2Hz,3H),1.29(s,3H),1.23(s,3H),1.14(s,3H),0.90(s,3H).
实施例15
化合物I-3.D-樟脑磺酸的制备
在25ml的茄形瓶中将化合物I-3(200mg,0.34mmol)完全溶解在5ml乙酸乙酯中，室温搅拌下缓慢滴入D-樟脑磺酸(83.5mg,0.36mmol)与2ml乙酸乙酯组成的溶液，室温搅拌20分钟后，缓慢滴加10ml无水乙醚，搅拌过夜后，有固体析出，抽滤，固体用乙醚洗涤，干燥得I-3·D-樟脑磺酸白色固体0.25g，收率89.5％，m.p.>240℃，HPLC:99.34％。
1H NMR(500MHz,CDCl3)δ10.87(s,1H),7.42(s,2H),6.36(s,1H),5.51(s,1H),4.73(d,J＝13.0Hz,1H),4.65–4.55(m,1H),4.34(d,J＝18.5Hz,2H),3.97(s,1H),3.73(s,1H),3.59–3.49(m,1H),3.46(d,J＝14.8Hz,1H),3.37–3.26(m,5H),2.95(dd,J1＝16.8Hz,J2＝3.4Hz,1H),2.84(d,J＝14.6Hz,1H),2.68(t,J＝13.3Hz,2H),2.40(d,J＝11.4Hz,1H),2.32(d,J＝18.2Hz,1H),2.12(t,J＝14.7Hz,1H),2.04(d,J＝16.6Hz,2H),1.98(s,2H),1.94–1.70(m,6H),1.40(dd,J1＝11.9Hz,J2＝6.9Hz,6H),1.31(s,3H),1.24(s,3H),1.18(s,3H),1.10(s,3H),0.99(s,3H),0.84(s,3H).
实施例16
化合物I-3.L-(+)-酒石酸的制备
在25mL的茄形瓶中将化合物I-3(200mg,0.34mmol)完全溶解在5ml乙酸乙酯中， 室温搅拌下缓慢滴入L-(+)-酒石酸(54mg,0.36mmol)溶于1ml乙醇所得的溶液，有固体析出，室温搅拌20分钟后，抽滤，固体用乙酸乙酯洗涤，干燥得I-3·酒石酸白色固体0.24g，收率95.5％，m.p.124～126℃,HPLC:99.32％。
1H NMR(500MHz,MeOD)δ7.52(d,J＝14.9Hz,2H),6.45(s,1H),5.56(s,1H),4.89(d,J＝13.2Hz,1H),4.46(d,J＝13.1Hz,1H),4.39(s,2H),4.33(d,J＝8.6Hz,1H),4.16–4.06(m,2H),3.82(s,1H),3.55(d,J＝11.3Hz,1H),3.52–3.46(m,1H),3.42(d,J＝19.8Hz,2H),2.90(d,J＝16.5Hz,1H),2.80(d,J＝16.6Hz,1H),2.50(d,J＝10.3Hz,1H),2.33(t,J＝14.6Hz,1H),2.05(d,J＝14.9Hz,1H),2.01(s,1H),1.96–1.77(m,3H),1.52(dd,J1＝22.9Hz,J2＝9.4Hz,1H),1.34(t,J＝7.2Hz,6H),1.26(s,6H),1.23(d,J＝7.1Hz,1H),1.18(d,J＝7.0Hz,1H),1.16(s,3H),1.00(s,3H).
实施例17
化合物I-3.马来酸的制备
在25ml的茄形瓶中将化合物I-3(200mg,0.34mmol)完全溶解在5ml乙酸乙酯中，室温搅拌下缓慢滴入马来酸(42mg,0.36mmol)与2ml乙酸乙酯组成的溶液，室温搅拌2h后，无固体析出，缓慢滴加20ml无水乙醚，有固体洗出，继续搅拌30分钟，抽滤，固体用乙醚洗涤，干燥得I-3·马来酸白色固体0.22g，收率91.7％，m.p.66-68℃,HPLC:99.1％。1H NMR(500MHz,CDCl3)δ10.75(s,1H),7.75(d,J＝7.9Hz,2H),7.41(s,2H),7.18(d,J＝7.8Hz,2H),6.35(s,1H),5.51(s,1H),4.57(d,J＝13.0Hz,1H),4.54–4.48(m,1H),4.28(dd,J1＝13.0Hz,J2＝7.5Hz,2H),3.94(s,1H),3.77(s,1H),3.72–3.57(m,1H),3.40(d,J＝12.0Hz,2H),3.33(dd,J1＝6.7Hz,J2＝4.9Hz,2H),3.28-3.23(m,2H),2.93(dd,J1＝16.8Hz,J2＝3.5Hz,1H),2.65(d,J＝16.6Hz,1H),2.36(s,3H),1.99(d,J＝14.4Hz,1H),1.95–1.69(m,6H),1.44(t,J＝7.2Hz,3H),1.38(t,J＝7.2Hz,3H),1.29(s,3H),1.23(s,3H),1.14(s,3H),0.90(s,3H).
实施例18
化合物I-3.柠檬酸的制备
在25ml的茄形瓶中将化合物I-3(300mg,0.51mmol)完全溶解在5ml乙酸乙酯中，室温搅拌下缓慢滴入柠檬酸(113mg,0.59mmol)与2ml乙酸乙酯组成的溶液，有固体析出， 搅拌30分钟，抽滤，固体用乙酸乙酯洗涤，干燥得I-3·柠檬酸白色固体0.36g，收率90.3％，HPLC:99.49％。
1H NMR(500MHz,MeOD)δ7.52(d,J＝14.1Hz,2H),6.44(s,1H),5.57(s,1H),5.48(s,2H),4.49–4.25(m,3H),4.13(s,1H),3.81(s,1H),3.57(s,1H),3.43(d,J＝11.2Hz,2H),2.90(d,J＝16.5Hz,1H),2.82(d,J＝15.2Hz,3H),2.74(d,J＝15.5Hz,2H),2.62(s,1H),2.50(d,J＝10.6Hz,1H),2.33(t,J＝14.5Hz,1H),2.18(s,1H),2.05(d,J＝13.9Hz,1H),1.89(dd,J1＝26.1Hz,J2＝12.1Hz,4H),1.52(d,J＝13.6Hz,2H),1.35(t,J＝6.7Hz,6H),1.26(d,J＝8.7Hz,9H),1.16(s,3H),1.00(s,3H).
实施例19
片剂
取实施例2中所得化合物0.5g，淀粉2g,糊精1g混合,用适量30％乙醇作湿润剂,制粒，压片。

Claims (7)

  1. 通式(I)或(II)的化合物或其药学上可接受的盐：
    Figure PCTCN2014090148-appb-100001
    其中：R代表：
    Figure PCTCN2014090148-appb-100002
    R1、R2代表：CH3、C2H5、C3H7、CH(CH3)2或C4H9；
    m＝1或2；
    n＝1或2。
  2. 权利要求1中通式(I)化合物的制备方法，包括：
    Figure PCTCN2014090148-appb-100003
    其中R的定义同权利要求1。
  3. 权利要求1中通式(II)化合物的的制备方法，包括：
    Figure PCTCN2014090148-appb-100004
    其中R的定义同权利要求1。
  4. 权利要求1的化合物或其药学上可接受的盐，其中药学上可接受的盐为权利要求1的通式(I)或(II)化合物与下列酸形成的酸加成盐：盐酸、氢溴酸、硫酸、碳酸、柠檬酸、琥珀酸、酒石酸、磷酸、乳酸、丙酮酸、乙酸、马来酸、甲磺酸、苯磺酸、对甲苯磺酸或阿魏酸。
  5. 一种药物组合物，其中含有权利要求1的化合物或其药学上可接受的盐及药学上可接受的载体。
  6. 权利要求1的化合物或其药学上可接受的盐在制备镇痛药物中的用途。
  7. 权利要求1的化合物或其药学上可接受的盐在制备抗炎药物中的用途。
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Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
RUBERTO, G. ET AL.: "Citrus Limonoids and their Semisynthetic Derivatives as Antifeedant Agents against Spodopterafrugiperda Larvae. A Structure-activity Relationship Study", JOURNAL OF AGRICULTURE AND FOOD CHEMISTRY, vol. 50, no. 23, 9 October 2002 (2002-10-09), pages 6766 - 6774 *

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