CN106928311A - Limonin derivative, its preparation method and medical usage - Google Patents
Limonin derivative, its preparation method and medical usage Download PDFInfo
- Publication number
- CN106928311A CN106928311A CN201710182024.7A CN201710182024A CN106928311A CN 106928311 A CN106928311 A CN 106928311A CN 201710182024 A CN201710182024 A CN 201710182024A CN 106928311 A CN106928311 A CN 106928311A
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- CN
- China
- Prior art keywords
- acid
- compound
- hcl
- pharmaceutically acceptable
- acceptable salt
- Prior art date
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- Granted
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- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 150000002629 limonins Chemical class 0.000 title abstract description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 91
- 206010039073 rheumatoid arthritis Diseases 0.000 claims abstract description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 68
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 63
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 63
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 42
- 239000002253 acid Substances 0.000 claims description 17
- 150000003839 salts Chemical class 0.000 claims description 17
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 12
- 230000000202 analgesic effect Effects 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 9
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 8
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 8
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 7
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 claims description 6
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 5
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 4
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 4
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims description 4
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 4
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- 239000002260 anti-inflammatory agent Substances 0.000 claims 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 1
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims 1
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 120
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- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
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- 238000006243 chemical reaction Methods 0.000 description 15
- 150000002630 limonoids Chemical class 0.000 description 14
- 239000002904 solvent Substances 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- QUTATOGBENCRSS-JWLOEITESA-N (1R,2R,7S,10R,13R,18R,19R)-18-(furan-3-yl)-9,9,13,19-tetramethyl-4,8,17-trioxapentacyclo[11.8.0.02,7.02,10.014,19]henicos-14-ene-5,12,16-trione Chemical compound C=1([C@H]2[C@]3(C)CC[C@H]4[C@@](C3=CC(=O)O2)(C)C(=O)C[C@@H]2[C@]34COC(=O)C[C@@H]3OC2(C)C)C=COC=1 QUTATOGBENCRSS-JWLOEITESA-N 0.000 description 13
- 241000699666 Mus <mouse, genus> Species 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- VHLJDTBGULNCGF-UHFFFAOYSA-N Limonin Natural products CC1(C)OC2CC(=O)OCC23C4CCC5(C)C(CC(=O)C6OC56C4(C)C(=O)CC13)c7cocc7 VHLJDTBGULNCGF-UHFFFAOYSA-N 0.000 description 10
- KBDSLGBFQAGHBE-MSGMIQHVSA-N limonin Chemical compound C=1([C@H]2[C@]3(C)CC[C@H]4[C@@]([C@@]53O[C@@H]5C(=O)O2)(C)C(=O)C[C@@H]2[C@]34COC(=O)C[C@@H]3OC2(C)C)C=COC=1 KBDSLGBFQAGHBE-MSGMIQHVSA-N 0.000 description 10
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
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- 206010014025 Ear swelling Diseases 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 6
- 240000001307 Myosotis scorpioides Species 0.000 description 6
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- 230000005764 inhibitory process Effects 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
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- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 5
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- CDIIZULDSLKBKV-UHFFFAOYSA-N 4-chlorobutanoyl chloride Chemical compound ClCCCC(Cl)=O CDIIZULDSLKBKV-UHFFFAOYSA-N 0.000 description 4
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
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Classifications
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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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
技术领域technical field
本发明属于药物化学领域，具体涉及一类水溶性的柠檬苦素衍生物，它们的制备方法，以及含有这些化合物的药物组合物及其在治疗疼痛和炎症方面的用途。The invention belongs to the field of medicinal chemistry, and in particular relates to a class of water-soluble limonin derivatives, their preparation method, pharmaceutical composition containing these compounds and their application in treating pain and inflammation.
背景技术Background technique
疼痛已被现代医学列为继体温、脉搏、呼吸、血压之后的第五大生命体征。疼痛如不及时有效处理，将严重影响日常的生活质量和社会安定。尽管镇痛药的研究有了长足的进步，但无论是用于轻、中度疼痛的非甾体解热镇痛抗炎药，还是用于中、重度疼痛的止痛剂，都有着各自的副作用和局限性，有的还面临潜在的滥用问题。Pain has been listed as the fifth vital sign after body temperature, pulse, respiration and blood pressure by modern medicine. If the pain is not treated in time and effectively, it will seriously affect the daily quality of life and social stability. Although great progress has been made in the research of analgesics, both non-steroidal antipyretic analgesic and anti-inflammatory drugs for mild and moderate pain, and analgesics for moderate and severe pain all have their own side effects and limitations, and some face potential abuse issues.
类风湿关节炎是一种常见的关节炎症，发病原因还不是很明确，它是一种慢性病，是以炎性滑膜炎为主的系统性疾病。目前临床治疗类风湿性关节炎的主要药物包括非甾体抗炎药、免疫抑制剂、生物制剂和小分子靶向药。其中非甾体抗炎药可缓解症状，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，但起效缓慢，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，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。因此，寻找安全、有效、副作用小的镇痛和抗炎药物具有重大的现实意义和社会意义。Rheumatoid arthritis is a common joint inflammation. The cause of the disease is not very clear. It is a chronic disease and a systemic disease mainly based on inflammatory synovitis. At present, the main drugs for the clinical treatment of rheumatoid arthritis include non-steroidal anti-inflammatory drugs, immunosuppressants, biological agents and small molecule targeted drugs. Among them, non-steroidal anti-inflammatory drugs can relieve symptoms, but their efficacy is weak and their gastrointestinal side effects are large; immunosuppressants such as methotrexate have clear efficacy and long-lasting effects, but their onset is slow, their toxicity is high, and they have many adverse reactions. Difficult to tolerate, long-term monitoring of blood drug concentration is required; biological agents such as adalimumab have clear curative effects, but are expensive and difficult to popularize; small molecule targeted drugs such as tofacitinib were approved for marketing in 2012, but with the development of clinical application With the deepening and expansion of the scope, many safety problems have gradually emerged, and product labels also have safety black box warnings, mainly to increase the risk of tumors and infections. Therefore, it is of great practical and social significance to find analgesic and anti-inflammatory drugs that are safe, effective, and have little side effects.
柠檬苦素类似物是高度氧化的四环三萜类化合物，广泛存在于柑橘类等芸香科和楝科植物家族中。迄今已分离得到大约300多种柠檬苦素类似物，柠檬苦素(limonin)是这类化合物中的代表。研究发现柠檬苦素化合物在镇痛、抗炎、抗癌、抗菌等方面具有作用，但是由于其作用不够强，水溶性差，生物利用度低，影响了其临床应用。Limonoid analogues are highly oxidized tetracyclic triterpenoids widely found in citrus and other Rutaceae and Meliaceae plant families. So far, more than 300 kinds of limonin analogues have been isolated, and limonin is the representative of such compounds. Studies have found that limonin compounds have effects in analgesia, anti-inflammation, anti-cancer, antibacterial, etc., but their clinical application is affected due to their insufficient effects, poor water solubility, and low bioavailability.
发明内容Contents of the invention
本发明公开了通式I和II的化合物，经药理实验证明，本发明的化合物具有较好的镇痛、抗炎活性。因此，本发明的通式I和II的化合物可用于临床缓解疼痛和消除炎症的作用。The invention discloses compounds of the general formulas I and II. Pharmacological experiments prove that the compounds of the invention have better analgesic and anti-inflammatory activities. Therefore, the compounds of the general formulas I and II of the present invention can be used for clinical pain relief and inflammation elimination.
其中：in:
R代表 R is for
R1代表H、CH3、CH2CH3、CH2OH或OH。R 1 represents H, CH 3 , CH 2 CH 3 , CH 2 OH or OH.
X代表CH2、O、NH、N-CH3或N-COCH3。X represents CH 2 , O, NH, N-CH 3 or N-COCH 3 .
R2、R3各自独立地代表H或C1～C6的烷基。R 2 and R 3 each independently represent H or a C 1 -C 6 alkyl group.
R4代表H、CH3、F、Cl或Br。R 4 represents H, CH 3 , F, Cl or Br.
m＝1～5。m=1～5.
R优选代表R1优选代表H或CH3，X优选代表CH2、O、NH或N-CH3，m优选＝1～4。R is preferred to represent R 1 preferably represents H or CH 3 , X preferably represents CH 2 , O, NH or N-CH 3 , m preferably=1-4.
R还优选代表R2、R3优选各自独立地代表C1～C3的烷基，m＝1～4。R also preferably represents R 2 and R 3 preferably each independently represent a C 1 -C 3 alkyl group, and m=1-4.
通式I和II的化合物可与药学上可接受的酸形成酸加成盐，所述酸包括氯化氢、溴化氢、硫酸、磷酸、碳酸、草酸、柠檬酸、琥珀酸、酒石酸、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。Compounds of general formula I and II can form acid addition salts with pharmaceutically acceptable acids including hydrogen chloride, hydrogen bromide, sulfuric acid, phosphoric acid, carbonic acid, oxalic acid, citric acid, succinic acid, tartaric acid, lactic acid, acetone acid, acetic acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or ferulic acid.
本发明通式I的化合物及其药学上可接受的酸加成盐(I.A)可用下列方法制备：The compound of general formula I of the present invention and its pharmaceutically acceptable acid addition salt (I.A) can be prepared by the following methods:
其中：in:
由化合物III(柠檬苦素)经酰化制备化合物IV的过程，所用的酰化剂为氯乙酰氯、3-氯丙酰氯、4-氯丁酰氯、5-氯戊酰氯或6-氯己酰氯，酰化剂也可以是乙酸酐、丙酸酐、丁酸酐、戊酸酐或己酸酐；催化剂为三氯化铝或氯化锌；溶剂为二氯甲烷、三氯甲烷、1,2-二氯乙烷、氯苯、硝基苯。The process of preparing compound IV by acylation of compound III (limonin), the acylating agent used is chloroacetyl chloride, 3-chloropropionyl chloride, 4-chlorobutyryl chloride, 5-chloropentanoyl chloride or 6-chlorohexanoyl chloride , the acylating agent can also be acetic anhydride, propionic anhydride, butyric anhydride, valeric anhydride or hexanoic anhydride; the catalyst is aluminum trichloride or zinc chloride; the solvent is dichloromethane, chloroform, 1,2-dichloroethane alkanes, chlorobenzenes, nitrobenzenes.
由化合物IV经取代制备化合物I的过程，所用的胺为其中R1选自H、CH3、CH2CH3、CH2OH或OH，X选自CH2、O、NH、N-CH3或N-COCH3，R2、R3选自H或C1～C6的烷基，R4选自H、CH3、F、Cl或Br；缚酸剂为碳酸钾、碳酸钠、三乙胺或反应物胺本身；溶剂为四氢呋喃、乙腈、丙酮、乙酸乙酯，或任意两者的混合溶剂。The process of preparing compound I by substitution of compound IV, the amine used is Wherein R 1 is selected from H, CH 3 , CH 2 CH 3 , CH 2 OH or OH, X is selected from CH 2 , O, NH, N-CH 3 or N-COCH 3 , R 2 and R 3 are selected from H or C 1 ~ C 6 alkyl, R 4 is selected from H, CH 3 , F, Cl or Br; the acid-binding agent is potassium carbonate, sodium carbonate, triethylamine or the reactant amine itself; the solvent is THF, acetonitrile, acetone , ethyl acetate, or any mixed solvent of the two.
由化合物I与酸A成盐制备酸加成盐I·A的过程，所用的酸A为氯化氢、溴化氢、硫酸、磷酸、碳酸、草酸、柠檬酸、琥珀酸、酒石酸、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；溶剂为乙酸乙酯、丙酮、四氢呋喃、二氯甲烷、乙醇、甲醇或异丙醇，或任意两者的混合溶剂。The process of preparing acid addition salt I A from compound I and acid A, the acid A used is hydrogen chloride, hydrogen bromide, sulfuric acid, phosphoric acid, carbonic acid, oxalic acid, citric acid, succinic acid, tartaric acid, lactic acid, pyruvic acid , acetic acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or ferulic acid; the solvent is ethyl acetate, acetone, tetrahydrofuran, dichloromethane, ethanol, methanol, or isopropanol, or any two mixed solvents.
本发明通式II的化合物及其药学上可接受的酸加成盐(II.A)可用下列方法制备：The compound of general formula II of the present invention and its pharmaceutically acceptable acid addition salt (II.A) can be prepared by the following methods:
其中：in:
由化合物V(脱氧柠檬苦素，desoxylimonin)经酰化制备化合物VI的过程，所用的酰化剂为氯乙酰氯、3-氯丙酰氯、4-氯丁酰氯、5-氯戊酰氯或6-氯己酰氯，酰化剂也可以是乙酸酐、丙酸酐、丁酸酐、戊酸酐或己酸酐；催化剂为三氯化铝或氯化锌；溶剂为二氯甲烷、三氯甲烷、1,2-二氯乙烷、氯苯、硝基苯。The process of preparing compound VI by acylation of compound V (deoxylimonin, desoxylimonin), the acylating agent used is chloroacetyl chloride, 3-chloropropionyl chloride, 4-chlorobutyryl chloride, 5-chloropentanoyl chloride or 6- Chlorhexanoyl chloride, the acylating agent can also be acetic anhydride, propionic anhydride, butyric anhydride, valeric anhydride or hexanoic anhydride; the catalyst is aluminum trichloride or zinc chloride; the solvent is dichloromethane, chloroform, 1,2- Dichloroethane, chlorobenzene, nitrobenzene.
由化合物VI经取代制备化合物II的过程，所用的胺为其中R1选自H、CH3、CH2CH3、CH2OH或OH，X选自CH2、O、NH、N-CH3或N-COCH3，R2、R3选自H或C1～C6的烷基，R4选自H、CH3、F、Cl或Br；缚酸剂为碳酸钾、碳酸钠、三乙胺或反应物胺本身；溶剂为四氢呋喃、乙腈、丙酮、乙酸乙酯，或任意两者的混合溶剂。The process of preparing compound II by substitution of compound VI, the amine used is Wherein R 1 is selected from H, CH 3 , CH 2 CH 3 , CH 2 OH or OH, X is selected from CH 2 , O, NH, N-CH 3 or N-COCH 3 , R 2 and R 3 are selected from H or C 1 ~ C 6 alkyl, R 4 is selected from H, CH 3 , F, Cl or Br; the acid-binding agent is potassium carbonate, sodium carbonate, triethylamine or the reactant amine itself; the solvent is THF, acetonitrile, acetone , ethyl acetate, or any mixed solvent of the two.
由化合物II与酸A成盐制备酸加成盐II·A的过程，所用的酸A为氯化氢、溴化氢、硫酸、磷酸、碳酸、草酸、柠檬酸、琥珀酸、酒石酸、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；溶剂为乙酸乙酯、丙酮、四氢呋喃、二氯甲烷、乙醇、甲醇或异丙醇，或任意两者的混合溶剂。The process of preparing acid addition salt II·A from compound II and acid A, the acid A used is hydrogen chloride, hydrogen bromide, sulfuric acid, phosphoric acid, carbonic acid, oxalic acid, citric acid, succinic acid, tartaric acid, lactic acid, pyruvic acid , acetic acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or ferulic acid; the solvent is ethyl acetate, acetone, tetrahydrofuran, dichloromethane, ethanol, methanol, or isopropanol, or any two mixed solvents.
本发明在于提供一种药物组合物，其包括本发明的化合物I或II或其盐I·A或II·A和药学上可接受的载体。The present invention is to provide a pharmaceutical composition, which comprises the compound I or II of the present invention or its salt I·A or II·A and a pharmaceutically acceptable carrier.
本发明所述的化合物或其盐可以添加药学上可接受的载体制成常见的药用制剂，如片剂、胶囊、粉剂、糖浆、液剂、悬浮剂、冻干粉针、针剂，可以加入香料、甜味剂、液体或固体填料或稀释剂等常用药用辅料。The compound of the present invention or its salt can be made into common pharmaceutical preparations by adding pharmaceutically acceptable carriers, such as tablets, capsules, powders, syrups, liquids, suspensions, lyophilized powder injections, injections, and can be added Common pharmaceutical excipients such as flavourings, sweeteners, liquid or solid fillers or diluents.
本发明所述的化合物在临床上的给药方式可以采用口服、注射、外用等方式。The clinical administration of the compounds of the present invention can be oral administration, injection, external administration and the like.
本发明同时包括通式I或II的化合物的立体异构体、水合物、溶剂合物或结晶，它们与化合物具有同样的药理药效。在制备治疗疼痛或炎症药物中的应用。The present invention also includes stereoisomers, hydrates, solvates or crystals of the compound of general formula I or II, which have the same pharmacological effect as the compound. Application in preparation of medicine for treating pain or inflammation.
本发明部分化合物如下：Some compounds of the present invention are as follows:
下面是本发明部分化合物的药理实验及结果：Below are the pharmacological experiments and results of some compounds of the present invention:
为了给药方便，药理实验采用I和II类化合物的盐酸盐。For the convenience of administration, the hydrochloride salts of class I and class II compounds were used in pharmacological experiments.
药效学实验证明，本发明化合物具有抗炎和镇痛效果。下面是部分药效学试验及结果：(1)小鼠醋酸扭体实验Pharmacodynamic experiments prove that the compound of the present invention has anti-inflammatory and analgesic effects. The following are some pharmacodynamic tests and results: (1) Mouse acetic acid writhing experiment
试验方法：experiment method:
ICR小鼠，雌雄各半，18～22g，随机分为模型组、阿司匹林组、柠檬苦素组、脱氧柠檬苦素组、本发明化合物组，每组8只。各组灌胃给药1小时后腹腔注射0.7％乙酸0.1mL/10g，模型组腹腔注射0.7％乙酸0.1mL/10g，立即观察并记录15分钟内小鼠扭体次数。结果见表1和表2。ICR mice, half male and half male, weighing 18-22 g, were randomly divided into model group, aspirin group, limonin group, deoxylimonin group and compound group of the present invention, with 8 mice in each group. 0.1 mL/10 g of 0.7% acetic acid was injected intraperitoneally after 1 hour of intragastric administration in each group, and 0.1 mL/10 g of 0.7% acetic acid was injected intraperitoneally in the model group, and the number of writhing of mice within 15 minutes was immediately observed and recorded. The results are shown in Table 1 and Table 2.
扭体次数抑制率＝(模型组扭体次数均值-给药组扭体次数均值)/模型组扭体次数均值*100％Inhibition rate of writhing times=(mean value of writhing times of model group-mean value of writhing times of drug administration group)/mean value of writhing times of model group*100%
表1柠檬苦素衍生物对小鼠醋酸扭体次数的影响 Table 1 Effect of limonin derivatives on the number of writhing times in mice with acetic acid
注：*P<0.05，**P<0.01vs模型组。Note: * P<0.05, ** P<0.01 vs model group.
表2脱氧柠檬苦素衍生物对小鼠醋酸扭体次数的影响 Table 2 Effect of deoxylimonin derivatives on the number of acetic acid writhing in mice
注：*P<0.05，**P<0.01vs模型组。Note: * P<0.05, ** P<0.01 vs model group.
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，本发明部分化合物对小鼠的扭体反应具有明显抑制作用。改造后的化合物的镇痛活性较柠檬苦素或脱氧柠檬苦素均有所提高，总体是柠檬苦素系列衍生物活性高于脱氧柠檬苦素系列衍生物，且在柠檬苦素系列衍生物中碳链长的化合物活性优于碳链短的化合物，其中化合物I-5·HCl、I-6·HCl、I-7·HCl镇痛活性远高于柠檬苦素。The results of mouse acetic acid writhing test show that intraperitoneal injection of 0.7% acetic acid 0.1ml/10g can cause abdominal pain and writhing reaction in mice, and some compounds of the present invention have obvious inhibitory effect on the writhing reaction of mice. The analgesic activity of the modified compound is higher than that of limonin or deoxylimonin. Overall, the activity of limonin series derivatives is higher than that of deoxylimonin series derivatives, and among the limonin series derivatives Compounds with long carbon chains are more active than compounds with short carbon chains, and the analgesic activity of compounds I-5·HCl, I-6·HCl, and I-7·HCl is much higher than limonin.
(2)小鼠缩尾实验(2) Mouse tail retraction test
试验方法：experiment method:
ICR雄性小鼠，18～22g，随机分为模型组、阿司匹林组、柠檬苦素组、脱氧柠檬苦素组、本发明化合物各受试药组，每组8只。将小鼠尾尖端3cm浸入48℃恒温水浴锅中，以缩尾反射(鼠尾回缩出水面)为痛反应指标，记录鼠尾放入水浴至受热引起缩尾反射的时间(秒)作为痛反应阈值。给药前测两次缩尾反射时间取其平均值作为基础痛域。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。结果如图1、图2和图3。ICR male mice, weighing 18-22 g, were randomly divided into model group, aspirin group, limonin group, deoxylimonin group, and each test drug group of the compound of the present invention, with 8 mice in each group. Immerse the mouse tail tip 3cm into a constant temperature water bath at 48°C, take the tail retraction reflex (rat tail retracts out of the water) as the pain response index, and record the time (seconds) from putting the mouse tail in the water bath to the tail retraction reflex caused by heating as pain response threshold. The average value of the tail withdrawal reflex time was measured twice before administration as the basic pain domain. After each administration group is gavaged respectively, measure the change of the latent period of tail withdrawal of the mice in each group after gavage for 30 minutes, 60 minutes, 90 minutes, and 120 minutes. If there is no response for more than 25 seconds, the pain threshold is calculated by 25 seconds. The results are shown in Figure 1, Figure 2 and Figure 3.
小鼠缩尾实验结果显示在测试的时间点内本发明的部分化合物能提升小鼠缩尾反应中的痛域，表现出一定的镇痛活性。总体上柠檬苦素系列化合物的作用强于脱氧柠檬苦素系列，且化合物中碳链长度为4个碳时活性较高，与小鼠醋酸扭体实验中所得结论基本一致。The results of the mouse tail-winch test show that some compounds of the present invention can increase the pain range in the mouse tail-winch response within the tested time point, showing certain analgesic activity. In general, the effects of limonin series compounds are stronger than those of deoxylimonin series, and the activity is higher when the carbon chain length in the compounds is 4 carbons, which is basically consistent with the conclusions obtained in the mouse acetic acid writhing experiment.
(3)小鼠耳肿胀实验(3) Mouse ear swelling test
实验方法：experimental method:
ICR雄性小鼠，18～22g，随机分成模型组、萘普生组、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3和表4。ICR male mice, weighing 18-22 g, were randomly divided into a model group, a naproxen group, a limonin group, and a compound group of the present invention, with 8 mice in each group. After 90 minutes of intragastric administration, 25ul of xylene was applied to the right ear of the mouse to cause inflammation, and the neck was pulled to kill after 30 minutes, and both ears were punched with an 8mm puncher, and the ears were weighed to calculate the swelling rate (%) and swelling inhibition rate (%). The results are shown in Table 3 and Table 4.
肿胀率(％)＝(右耳重量-左耳重量)/左耳重量*100％Swelling rate (%) = (right ear weight - left ear weight) / left ear weight * 100%
肿胀抑制率(％)＝(模型组肿胀率-受试药组肿胀率)/模型组肿胀率*100％Swelling inhibition rate (%)=(the swelling rate of the model group-the swelling rate of the test drug group)/the swelling rate of the model group*100%
表3柠檬苦素衍生物对小鼠耳肿胀的影响 Table 3 Effect of limonin derivatives on mouse ear swelling
注：*P<0.05，**P<0.01vs模型组。Note: * P<0.05, ** P<0.01 vs model group.
表4脱氧柠檬苦素衍生物对小鼠耳肿胀的影响 The effect of table 4 deoxylimonin derivatives on mouse ear swelling
注：*P<0.05，**P<0.01vs模型组。Note: * P<0.05, ** P<0.01 vs model group.
小鼠耳肿胀实验结果显示本发明的化合物对小鼠耳肿胀具有显著的抑制作用。构效关系与小鼠醋酸扭体实验及小鼠热缩尾实验结果基本一致。其中化合物I-5·HCl、I-6·HCl表现出较强的抗炎活性，且高于阳性对照萘普生和柠檬苦素。The results of mouse ear swelling test show that the compound of the present invention has a significant inhibitory effect on mouse ear swelling. The structure-activity relationship is basically consistent with the results of the mouse acetic acid writhing test and the mouse heat tail shrinkage test. Among them, compounds I-5·HCl and I-6·HCl showed strong anti-inflammatory activity, which was higher than that of the positive controls naproxen and limonin.
(4)大鼠佐剂关节炎实验(4) Adjuvant arthritis experiment in rats
根据小鼠醋酸扭体实验，小鼠热水缩尾实验及小鼠耳肿胀实验结果，我们选择化合物I-5·HCl和I-6·HCl进行了大鼠佐剂关节炎实验，对化合物活性进行进一步验证与研究。According to the results of mouse acetic acid writhing test, mouse hot water tail shrinkage test and mouse ear swelling test, we selected compounds I-5·HCl and I-6·HCl to carry out the rat adjuvant arthritis experiment, and the compound activity Carry out further verification and research.
实验方法：experimental method:
雄性wistar大鼠90只，适应性饲养3天后，随机分为9组，每组10只，即空白组、模型组、I-5·HCl 200mg/kg组、I-5·HCl 100mg/kg组、I-5·HCl 50mg/kg组、I-6·HCl 200mg/kg组、I-6·HCl 100mg/kg组、I-6·HCl 50mg/kg组、托法替尼5mg/kg组。造模前，灭活卡介苗与不完全弗氏佐剂充分混合，配成含灭活卡介苗10mg/ml的完全弗氏佐剂(CFA)。除空白组外其余组各只大鼠右后足足趾注射0.1ml CFA致炎。造模第21天开始各组大鼠灌胃给药，连续给药14天。每隔一段时间，对各大鼠的右足踝测肿胀情况及体重变化，第15天各组大鼠眼眶采血，用于检测TNF-α和IL-6。结果如下：90 male wistar rats were fed adaptively for 3 days and randomly divided into 9 groups, 10 rats in each group, namely blank group, model group, I-5·HCl 200mg/kg group, I-5·HCl 100mg/kg group , I-5·HCl 50mg/kg group, I-6·HCl 200mg/kg group, I-6·HCl 100mg/kg group, I-6·HCl 50mg/kg group, tofacitinib 5mg/kg group. Before modeling, inactivated BCG and incomplete Freund's adjuvant were fully mixed to prepare complete Freund's adjuvant (CFA) containing inactivated BCG 10 mg/ml. Except the blank group, each rat in the right hind toe was injected with 0.1ml CFA to induce inflammation. On the 21st day after modeling, the rats in each group were administered orally, and the administration continued for 14 days. At regular intervals, the swelling and body weight changes of the right ankles of the rats were measured. On the 15th day, blood was collected from the orbits of the rats in each group for the detection of TNF-α and IL-6. The result is as follows:
①足趾肿胀抑制率①Suppression rate of toe swelling
各组大鼠给予受试化合物后每三天测量一次其右足踝肿胀情况，计算肿胀抑制率，结果见表5。After the rats in each group were given the test compound, the swelling of their right ankle was measured every three days, and the swelling inhibition rate was calculated. The results are shown in Table 5.
肿胀抑制百分率＝(给药前平均肿胀率-给药后平均肿胀率)/模型组平均肿胀率×100％Swelling inhibition percentage=(average swelling rate before administration-average swelling rate after administration)/average swelling rate of model group×100%
表5 I-5·HCl和I-6·HCl对大鼠原发侧足趾肿胀的影响(n＝8)Table 5 Effects of I-5·HCl and I-6·HCl on swelling of the primary toes of rats (n=8)
从足趾肿胀抑制率结果看出，两个化合物对大鼠原发侧足肿均具有抑制活性，且随剂量的升高，抑制活性也升高，表明其具有一定的剂量依赖性。从结果也可以看出化合物I-6·HCl的活性略高于化合物I-5·HCl。It can be seen from the results of the toe swelling inhibition rate that the two compounds have inhibitory activity on the primary lateral foot swelling in rats, and with the increase of the dose, the inhibitory activity also increases, indicating that it has a certain dose dependence. It can also be seen from the results that the activity of compound I-6·HCl is slightly higher than that of compound I-5·HCl.
②对大鼠体重的影响②Effect on the body weight of rats
给予受试化合物后每隔两天测量一次大鼠体重，观察大鼠体重的变化，结果如图4。After administration of the test compound, the body weight of the rats was measured every two days, and the changes in the body weight of the rats were observed. The results are shown in Figure 4.
从图中可以看出，大鼠在给药前期时体重变化较小，从第五天往后体重均呈上升趋势，说明在化合物起效后大鼠的身体状况好转，进一步验证了化合物具有缓解炎症疼痛的效果。It can be seen from the figure that the body weight of the rats changed little in the early stage of administration, and the body weight showed an upward trend from the fifth day onwards, indicating that the physical condition of the rats improved after the compound took effect, further verifying that the compound has the effect of relieving The effect of inflammation on pain.
③对大鼠临床评分的影响③ Effects on the clinical scores of rats
在本实验中化合物对大鼠临床评分影响主要是通过大鼠全身评分及大鼠关节炎指数来表现，评分或指数越高说明临床状态越差，结果如图5和图6。In this experiment, the effect of the compound on the clinical score of rats is mainly expressed by the rat systemic score and the rat arthritis index. The higher the score or index, the worse the clinical state. The results are shown in Figures 5 and 6.
图中显示在给予受试化合物后大鼠的全身评分及关节炎指数均有所下降，说明大鼠临床状态好转，进一步验证本发明化合物具有镇痛抗炎活性。The figure shows that after administration of the test compound, the systemic score and arthritis index of the rats all decreased, indicating that the clinical state of the rats improved, and further verified that the compound of the present invention has analgesic and anti-inflammatory activity.
④血清中TNF-α和IL-6含量测定④Determination of TNF-α and IL-6 content in serum
给予受试化合物第15天各组大鼠眼眶采血，检测TNF-α和IL-6，结果如表6。On the 15th day after administration of the test compound, blood was collected from the orbits of rats in each group, and TNF-α and IL-6 were detected. The results are shown in Table 6.
表6血清中TNF-α和IL-6含量测定 Determination of TNF-α and IL-6 content in table 6 serum
注：*p<0.05，**p<0.01，***p<0.001vs模型组，△p<0.05，△△p<0.01，△△△p<0.001vs空白组Note: * p<0.05, ** p<0.01, *** p<0.001vs model group, △ p<0.05, △△ p<0.01, △△△ p<0.001vs blank group
从结果中看出在给药后大鼠血清中的TNF-α和IL-6含量均有下降，提示这两个炎症因子可能是化合物发挥镇痛抗炎活性的重要介质。具体机制有待进一步研究。It can be seen from the results that the levels of TNF-α and IL-6 in rat serum decreased after administration, suggesting that these two inflammatory factors may be important mediators for the compound to exert analgesic and anti-inflammatory activities. The specific mechanism needs further study.
(5)小鼠热板实验(5) Mouse hot plate experiment
利用小鼠热板实验考察同种化合物以不同方式给药时镇痛活性的差异。The difference in analgesic activity of the same compound administered in different ways was investigated by mouse hot plate experiment.
实验方法：experimental method:
ICR雌性小鼠90只，将恒温水浴箱加热到55(±0.5)℃，将雌性小鼠置于热板上，以其足部接触热板到开始舔后足的时间为热板法痛阈(HPPT)，剔除HPPT大于30s或小于5s的动物，选择符合标准的70只雌性小鼠按体重随机分为7组，分别为模型对照组、柠檬苦素100mg/kg剂量组、I-5·HCl灌胃给药100mg/kg剂量组、I-5·HCl静脉给药10mg/kg剂量组、I-6·HCl灌胃给药100mg/kg剂量组、I-6·HCl静脉给药10mg/kg剂量组。以给药前三次热板法HPPT的平均值为基础痛阈，对超过60s无反应者则中止刺激，以60s痛反应计时，给药后30min开始记录痛阈时间。痛阈提高率(％)＝(给药后痛阈-基础痛阈)/基础痛阈×100％，结果如表7。90 ICR female mice, heated the constant temperature water bath to 55 (±0.5) ℃, placed the female mice on the hot plate, and the pain threshold of the hot plate method was defined as the time from when the feet touched the hot plate to when they started licking the hind feet (HPPT), remove the animal that HPPT is greater than 30s or less than 5s, select 70 female mice that meet the standard and be divided into 7 groups at random according to body weight, be respectively model control group, limonin 100mg/kg dosage group, I-5. HCl intragastric administration 100mg/kg dosage group, I-5·HCl intravenous administration 10mg/kg dosage group, I-6·HCl intragastric administration 100mg/kg dosage group, I-6·HCl intravenous administration 10mg/kg kg dose group. The pain threshold was based on the average value of the hot plate method HPPT three times before the administration. For those who did not respond for more than 60s, the stimulation was stopped, and the pain response was timed at 60s. The pain threshold time was recorded 30 minutes after the administration. Pain threshold improvement rate (%)=(pain threshold after administration-basic pain threshold)/basic pain threshold×100%. The results are shown in Table 7.
表7 I-5·HCl和I-6·HCl小鼠热板镇痛实验 Table 7 Hot plate analgesia experiment of I-5·HCl and I-6·HCl mice
注：*P<0.05，**P<0.01vs模型组，△P<0.05，△△P<0.01vs组内基础痛阈，◇P<0.05，◇◇P<0.01vs萘普生组Note: * P<0.05, ** P<0.01vs the model group, △ P<0.05, △△ P<0.01vs the basic pain threshold in the group, ◇ P<0.05, ◇◇ P<0.01vs the naproxen group
本实验中，我们采取了灌胃与静脉注射两种给药方式，从实验结果可以看出，静脉给药10mg/kg剂量的镇痛活性强于相应的口服100mg/kg剂量的镇痛活性。In this experiment, we adopted two methods of administration, intragastric administration and intravenous injection. It can be seen from the experimental results that the analgesic activity of intravenous administration of 10 mg/kg is stronger than that of the corresponding oral administration of 100 mg/kg.
柠檬苦素不溶水，而本发明的化合物加酸成盐后可溶于水中。Limonin is insoluble in water, but the compound of the present invention is soluble in water after being salted with acid.
附图说明Description of drawings
图1是本发明柠檬苦素衍生物I-1～I-6盐酸盐对小鼠缩尾的作用Fig. 1 is the effect of limonin derivatives I-1～I-6 hydrochloride of the present invention on mouse tail shrinkage
图2是本发明柠檬苦素衍生物I-7～I-9、I-12～I-13盐酸盐对小鼠的缩尾作用Fig. 2 is the tailing effect of limonin derivatives I-7～I-9, I-12～I-13 hydrochloride of the present invention on mice
图3是本发明脱氧柠檬苦素衍生物II-2～II-3、II-5～II-6盐酸盐对小鼠的缩尾作用Fig. 3 is the indentation effect of deoxylimonin derivatives II-2～II-3, II-5～II-6 hydrochloride of the present invention on mice
图4是本发明化合物I-5·HCl和I-6·HCl对大鼠体重的影响Fig. 4 is the impact of compound I-5 HCl and I-6 HCl of the present invention on rat body weight
图5是本发明化合物I-5·HCl和I-6·HCl对大鼠全身评分的影响Fig. 5 is the impact of compound I-5.HCl and I-6.HCl of the present invention on the whole body score of rats
图6是本发明化合物I-5·HCl和I-6·HCl对大鼠关节炎指数的影响Fig. 6 is the impact of compound I-5 HCl and I-6 HCl of the present invention on rat arthritis index
具体实施方式detailed description
实施例1Example 1
23-(2-(哌啶-1-基)乙酰基)柠檬苦素(I-1)的制备Preparation of 23-(2-(piperidin-1-yl)acetyl)limonoid (I-1)
23-氯乙酰基柠檬苦素(IV-1)23-Chloroacetyllimonoid (IV-1)
250mL三颈瓶中加入柠檬苦素(8g,17mmol)和二氯甲烷(125mL)，搅拌下降温至0℃，分批加入三氯化铝(10.2g,76.5mmol)，加毕，保温搅拌20分钟，滴加氯乙酰氯(2.2g,19.5mmol)与二氯甲烷(5mL)的混合溶液，滴毕，保持0～-5℃反应1小时，再于室温继续搅拌反应3小时，停止反应，将反应液慢慢倒入100mL冰水中，分取二氯甲烷层，水层用二氯甲烷萃取两次(100mL×2)，合并有机层，用1mol/L氢氧化钠水溶液洗三次(100mL×3)，饱和食盐水洗涤两次(100mL×2)，无水硫酸钠干燥，抽滤，减压蒸除溶剂。粗品用柱层析(二氯甲烷:甲醇＝180:1)纯化，得浅绿色固体(IV-1)2.8g，收率30.2％，m.p.>200℃。1H NMR(300MHz,CDCl3)δ7.62(s,1H),7.24(s,1H),5.50(s,1H),4.77(d,J＝13.1Hz,1H),4.55(s,2H),4.46(d,J＝13.0Hz,1H),4.03(s,2H),2.99(dd,J＝17.0,3.7Hz,1H),2.93–2.79(m,1H),2.68(d,J＝15.7Hz,1H),2.58–2.40(m,2H),2.22(d,J＝13.0Hz,1H),1.98–1.75(m,3H),1.59–1.51(m,1H),1.29(s,3H),1.18(s,3H),1.14(s,3H),1.08(s,3H).ESI-MS(m/z):569.2[M+Na]+ Add limonin (8g, 17mmol) and dichloromethane (125mL) into a 250mL three-necked bottle, stir and cool down to 0°C, add aluminum trichloride (10.2g, 76.5mmol) in batches, after the addition is complete, keep stirring for 20 Minutes, dropwise added a mixed solution of chloroacetyl chloride (2.2g, 19.5mmol) and dichloromethane (5mL), after dropping, kept at 0～-5°C for 1 hour, then continued stirring at room temperature for 3 hours, then stopped the reaction. Slowly pour the reaction solution into 100 mL of ice water, separate the dichloromethane layer, extract the water layer twice with dichloromethane (100 mL×2), combine the organic layers, and wash three times with 1 mol/L sodium hydroxide aqueous solution (100 mL×2). 3), washed twice with saturated brine (100 mL×2), dried over anhydrous sodium sulfate, filtered with suction, and evaporated to remove the solvent under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol=180:1) to obtain 2.8 g of light green solid (IV-1), yield 30.2%, mp>200°C. 1 H NMR (300MHz, CDCl 3 )δ7.62(s,1H),7.24(s,1H),5.50(s,1H),4.77(d,J＝13.1Hz,1H),4.55(s,2H) ,4.46(d,J=13.0Hz,1H),4.03(s,2H),2.99(dd,J=17.0,3.7Hz,1H),2.93–2.79(m,1H),2.68(d,J=15.7 Hz, 1H), 2.58–2.40(m, 2H), 2.22(d, J=13.0Hz, 1H), 1.98–1.75(m, 3H), 1.59–1.51(m, 1H), 1.29(s, 3H) ,1.18(s,3H),1.14(s,3H),1.08(s,3H).ESI-MS(m/z):569.2[M+Na] +
23-(2-(哌啶-1-基)乙酰基)柠檬苦素(I-1)23-(2-(piperidin-1-yl)acetyl)limonoid (I-1)
100mL三颈瓶中加入四氢呋喃(30mL)、碳酸钾(0.66g,4.78mmol)、碘化钾(0.03g,0.18mmol)、哌啶(0.92g,10.8mmol)，室温搅拌20分钟，滴加IV-1(1.97g,3.6mmol)溶于四氢呋喃(30mL)的溶液，滴毕，室温继续反应5小时，TLC检测(二氯甲烷:甲醇＝25:1)反应完全，减压蒸除溶剂。残留物加入20mL水，析出固体，抽滤，粗品用柱层析(二氯甲烷:甲醇＝80:1)纯化，得淡黄色固体(I-1)1.1g，收率51.3％,128℃(炭化)。1H NMR(300MHz,CDCl3)δ7.57(s,1H),7.31(s,1H),5.49(s,1H),4.78(d,J＝13.4Hz,1H),4.47(d,J＝13.2Hz,1H),4.03(s,2H),3.63(s,2H),2.99(dd,J＝16.8,3.5Hz,1H),2.94–2.82(m,1H),2.69(d,J＝16.4Hz,1H),2.63–2.36(m,6H),2.23(d,J＝13.0Hz,1H),1.94–1.78(m,3H),1.69–1.41(m,7H),1.30(s,3H),1.19(s,3H),1.16(s,3H),1.08(s,3H).ESI-MS(m/z):596.3[M+H]+ Add tetrahydrofuran (30mL), potassium carbonate (0.66g, 4.78mmol), potassium iodide (0.03g, 0.18mmol), piperidine (0.92g, 10.8mmol) into a 100mL three-necked flask, stir at room temperature for 20 minutes, add IV-1 dropwise (1.97g, 3.6mmol) dissolved in tetrahydrofuran (30mL), dropwise, continue to react at room temperature for 5 hours, TLC detection (dichloromethane:methanol=25:1) complete reaction, evaporate the solvent under reduced pressure. The residue was added with 20mL of water to precipitate a solid, which was filtered by suction, and the crude product was purified by column chromatography (dichloromethane:methanol=80:1) to obtain 1.1g of a light yellow solid (I-1), with a yield of 51.3%, 128°C ( charring). 1 H NMR (300MHz, CDCl 3 ) δ7.57(s, 1H), 7.31(s, 1H), 5.49(s, 1H), 4.78(d, J=13.4Hz, 1H), 4.47(d, J= 13.2Hz, 1H), 4.03(s, 2H), 3.63(s, 2H), 2.99(dd, J=16.8, 3.5Hz, 1H), 2.94–2.82(m, 1H), 2.69(d, J=16.4 Hz,1H),2.63–2.36(m,6H),2.23(d,J＝13.0Hz,1H),1.94–1.78(m,3H),1.69–1.41(m,7H),1.30(s,3H) ,1.19(s,3H),1.16(s,3H),1.08(s,3H).ESI-MS(m/z):596.3[M+H] +
将I-1(1.0g,1.68mmol)溶解在乙酸乙酯(40mL)中，冰浴搅拌下缓慢滴加饱和HCl的乙酸乙酯溶液至pH 2左右，析出淡黄色固体，继续搅拌1小时，抽滤，所得固体用20mL乙酸乙酯打浆，抽滤，干燥得淡黄色固体(I-1·HCl)0.9g，收率85％，m.p.>200℃。1H NMR(300MHz,DMSO)δ10.04(s,1H),8.20(s,1H),7.69(s,1H),5.58(s,1H),4.91(d,J＝12.9Hz,1H),4.74(s,2H),4.48(d,J＝13.1Hz,1H),4.16(s,1H),4.08(s,1H),3.43–3.29(m,4H),3.17–3.05(m,1H),2.75(d,J＝16.6Hz,1H),2.65–2.51(m,2H),2.45–2.38(m,1H),2.27(d,J＝12.1Hz,1H),1.99–1.57(m,9H),1.45–1.32(m,1H),1.17(s,3H),1.08(s,3H),1.00(s,6H).Dissolve I-1 (1.0g, 1.68mmol) in ethyl acetate (40mL), slowly add saturated HCl in ethyl acetate dropwise to about pH 2 under stirring in an ice bath, a pale yellow solid precipitates, and continue stirring for 1 hour. Suction filtration, the resulting solid was slurried with 20 mL of ethyl acetate, suction filtration, and drying to obtain 0.9 g of light yellow solid (I-1·HCl), yield 85%, mp>200°C. 1 H NMR (300MHz,DMSO)δ10.04(s,1H),8.20(s,1H),7.69(s,1H),5.58(s,1H),4.91(d,J=12.9Hz,1H), 4.74(s,2H),4.48(d,J＝13.1Hz,1H),4.16(s,1H),4.08(s,1H),3.43–3.29(m,4H),3.17–3.05(m,1H) ,2.75(d,J=16.6Hz,1H),2.65–2.51(m,2H),2.45–2.38(m,1H),2.27(d,J=12.1Hz,1H),1.99–1.57(m,9H ),1.45–1.32(m,1H),1.17(s,3H),1.08(s,3H),1.00(s,6H).
实施例2Example 2
23-(2-(吗啉-4-基)乙酰基)柠檬苦素(I-2)的制备Preparation of 23-(2-(morpholin-4-yl)acetyl)limonoid (I-2)
以化合物IV-1(2.0g,3.65mmol)和吗啉(0.95g,10.90mmol)为原料，操作过程同I-1，粗品用柱层析(二氯甲烷:甲醇＝90:1)纯化，得浅黄色固体(I-2)1.2g，收率54.9％，146℃(炭化)。1H NMR(300MHz,CDCl3)δ7.59(s,1H),7.26(s,1H),5.51(s,1H),4.79(d,J＝13.1Hz,1H),4.49(d,J＝13.2Hz,1H),4.06(s,2H),3.85–3.73(m,4H),3.70(s,2H),3.00(dd,J＝16.8,3.7Hz,1H),2.95–2.79(m,1H),2.78–2.57(m,5H),2.57–2.42(m,2H),2.24(dd,J＝15.8,3.1Hz,1H),1.91–1.78(m,3H),1.62–1.46(m,1H),1.32(s,3H),1.20(s,3H),1.17(s,3H),1.10(s,3H).ESI-MS(m/z):598.3[M+H]+ Using compound IV-1 (2.0g, 3.65mmol) and morpholine (0.95g, 10.90mmol) as raw materials, the operation process was the same as I-1, and the crude product was purified by column chromatography (dichloromethane:methanol=90:1), 1.2 g of light yellow solid (I-2) was obtained, yield 54.9%, 146° C. (charring). 1 H NMR (300MHz, CDCl 3 ) δ7.59(s, 1H), 7.26(s, 1H), 5.51(s, 1H), 4.79(d, J=13.1Hz, 1H), 4.49(d, J= 13.2Hz, 1H), 4.06(s, 2H), 3.85–3.73(m, 4H), 3.70(s, 2H), 3.00(dd, J＝16.8, 3.7Hz, 1H), 2.95–2.79(m, 1H ),2.78–2.57(m,5H),2.57–2.42(m,2H),2.24(dd,J＝15.8,3.1Hz,1H),1.91–1.78(m,3H),1.62–1.46(m,1H ),1.32(s,3H),1.20(s,3H),1.17(s,3H),1.10(s,3H).ESI-MS(m/z):598.3[M+H] +
以化合物I-2(1.0g,1.67mmol)为原料，操作过程同I-1·HCl，得浅黄色固体(I-2·HCl)0.87g，收率83％，m.p.>200℃。Using compound I-2 (1.0g, 1.67mmol) as raw material, the operation process was the same as I-1·HCl to obtain 0.87g of light yellow solid (I-2·HCl), yield 83%, m.p.>200℃.
实施例3Example 3
23-(2-(哌嗪-1-基)乙酰基)柠檬苦素(I-3)的制备Preparation of 23-(2-(piperazin-1-yl)acetyl)limonoid (I-3)
以化合物IV-1(2.0g,3.65mmol)和N-叔丁氧羰基哌嗪(2.73g,14.6mmol)为原料，操作过程同I-1，粗品用柱层析(二氯甲烷:甲醇＝150:1)纯化，得1.46g淡黄色中间体。将该中间体溶于甲醇(20mL)，冰浴搅拌下滴加饱和HCl的甲醇溶液(20mL)，滴毕，室温反应2小时，TLC检测(展开剂：二氯甲烷:甲醇＝25:1)反应完全，0～5℃放置1小时，抽滤得淡黄色固体(I-3)0.9g，两步合计收率41.2％，140℃(炭化)。1H NMR(300MHz,CDCl3)δ7.57(s,1H),7.25(s,1H),5.49(s,1H),4.77(d,J＝12.7Hz,1H),4.47(d,J＝13.4Hz,1H),4.03(s,2H),3.68(s,2H),3.06(s,4H),2.97(dd,J＝16.8,3.9Hz,1H),2.93–2.81(m,1H),2.78–2.62(m,4H),2.60–2.41(m,3H),2.23(d,J＝12.4Hz,1H),2.03–1.76(m,3H),1.62–1.45(m,1H),1.29(s,3H),1.18(s,3H),1.15(s,3H),1.08(s,3H),0.90–0.82(m,1H).ESI-MS(m/z):597.3[M+H]+ Using compound IV-1 (2.0g, 3.65mmol) and N-tert-butoxycarbonylpiperazine (2.73g, 14.6mmol) as raw materials, the operation process was the same as I-1, and the crude product was subjected to column chromatography (dichloromethane:methanol = 150:1) purification to obtain 1.46g light yellow intermediate. Dissolve the intermediate in methanol (20mL), add saturated HCl in methanol (20mL) dropwise with stirring in an ice bath, after the dropwise reaction, react at room temperature for 2 hours, and detect by TLC (developing solvent: dichloromethane:methanol=25:1) After the reaction was complete, it was placed at 0-5°C for 1 hour, and 0.9 g of a light yellow solid (I-3) was obtained by suction filtration. The total yield of the two steps was 41.2%. 1 H NMR (300MHz, CDCl 3 ) δ7.57(s, 1H), 7.25(s, 1H), 5.49(s, 1H), 4.77(d, J=12.7Hz, 1H), 4.47(d, J= 13.4Hz, 1H), 4.03(s, 2H), 3.68(s, 2H), 3.06(s, 4H), 2.97(dd, J=16.8, 3.9Hz, 1H), 2.93–2.81(m, 1H), 2.78–2.62(m,4H),2.60–2.41(m,3H),2.23(d,J＝12.4Hz,1H),2.03–1.76(m,3H),1.62–1.45(m,1H),1.29( s,3H),1.18(s,3H),1.15(s,3H),1.08(s,3H),0.90–0.82(m,1H).ESI-MS(m/z):597.3[M+H] +
以化合物I-3(0.8g,1.34mmol)为原料，操作过程同I-1·HCl，得浅黄色固体(I-3·HCl)0.69g，收率81.4％，m.p.>200℃。Using compound I-3 (0.8g, 1.34mmol) as raw material, the operation process was the same as that of I-1·HCl to obtain 0.69g of light yellow solid (I-3·HCl), yield 81.4%, m.p.>200°C.
实施例4Example 4
23-(2-(4-甲基哌嗪-1-基)乙酰基)柠檬苦素(I-4)的制备Preparation of 23-(2-(4-methylpiperazin-1-yl)acetyl)limonin (I-4)
以化合物IV-1(2.0g,3.65mmol)和N-甲基哌嗪(1.64g,16.42mmol)为原料，操作过程同I-1，粗品用柱层析(二氯甲烷:甲醇＝100:1)纯化，得黄色固体(I-4)0.85g，收率38.2％，180℃(炭化)。1H NMR(300MHz,CDCl3)δ7.56(s,1H),7.23(s,1H),5.48(s,1H),4.77(d,J＝12.9Hz,1H),4.46(d,J＝13.3Hz,1H),4.02(s,2H),3.67(s,2H),2.98(d,J＝16.0Hz,1H),2.92–2.80(m,1H),2.75–2.41(m,9H),2.32(s,3H),2.26–2.04(m,3H),1.97–1.75(m,3H),1.61–1.44(m,1H),1.29(s,3H),1.17(s,3H),1.14(s,3H),1.07(s,3H).ESI-MS(m/z):611.3[M+H]+ Using compound IV-1 (2.0g, 3.65mmol) and N-methylpiperazine (1.64g, 16.42mmol) as raw materials, the operation process was the same as I-1, and the crude product was subjected to column chromatography (dichloromethane:methanol=100: 1) Purification to obtain 0.85 g of yellow solid (I-4), yield 38.2%, 180° C. (charring). 1 H NMR (300MHz, CDCl 3 ) δ7.56(s, 1H), 7.23(s, 1H), 5.48(s, 1H), 4.77(d, J=12.9Hz, 1H), 4.46(d, J= 13.3Hz, 1H), 4.02(s, 2H), 3.67(s, 2H), 2.98(d, J=16.0Hz, 1H), 2.92–2.80(m, 1H), 2.75–2.41(m, 9H), 2.32(s,3H),2.26–2.04(m,3H),1.97–1.75(m,3H),1.61–1.44(m,1H),1.29(s,3H),1.17(s,3H),1.14( s,3H),1.07(s,3H).ESI-MS(m/z):611.3[M+H] +
以化合物I-4(0.8g,1.31mmol)为原料，操作过程同I-1·HCl，得浅黄色固体(I-4·HCl)0.68g，收率80.3％，m.p.>200℃。Using compound I-4 (0.8g, 1.31mmol) as raw material, the operation process was the same as I-1·HCl to obtain 0.68g of light yellow solid (I-4·HCl), yield 80.3%, m.p.>200℃.
实施例5Example 5
23-(4-(哌啶-1-基)丁酰基)柠檬苦素(I-5)的制备Preparation of 23-(4-(piperidin-1-yl)butyryl)limonoid (I-5)
23-(4-氯丁酰基)柠檬苦素(IV-2)23-(4-Chlorobutyryl)limonoid (IV-2)
1000ml三颈瓶中加入柠檬苦素(40.0g,85.01mmol)和二氯甲烷(500mL)，搅拌下降温至0℃，分批加入三氯化铝(51.0g,382.5mmol)，加毕，保温搅拌20min，滴加4-氯丁酰氯(14.4g,102.0mmol)与二氯甲烷(15mL)的混合溶液，滴毕，保持0～-5℃反应1小时，再于室温继续搅拌反应2小时，停止反应，将反应液慢慢倒入500mL冰水中，分取二氯甲烷层，水层用二氯甲烷萃取两次(300mL×2)，合并有机层，用1mol/L氢氧化钠水溶液洗三次(300mL×3)，饱和食盐水洗涤两次(300mL×2)，无水硫酸钠干燥，抽滤，减压蒸除溶剂。粗品用柱层析(二氯甲烷:甲醇＝160:1)纯化，得浅绿色固体(IV-2)20.5g，收率42％，m.p.160～163℃。1HNMR(300MHz,CDCl3)δ7.58(s,1H),7.13(s,1H),5.50(s,1H),4.78(d,J＝12.9Hz,1H),4.47(d,J＝13.1Hz,1H),4.03(s,2H),3.65(t,J＝6.2Hz,2H),3.03(t,J＝7.0Hz,2H),2.99–2.80(m,2H),2.68(d,J＝16.7Hz,1H),2.59–2.42(m,2H),2.30–2.11(m,3H),1.97–1.76(m,3H),1.54(s,1H),1.30(s,3H),1.19(s,3H),1.15(s,3H),1.08(s,3H).ESI-MS(m/z):597.2[M+Na]+ Add limonin (40.0g, 85.01mmol) and dichloromethane (500mL) into a 1000ml three-necked bottle, stir and cool down to 0°C, add aluminum trichloride (51.0g, 382.5mmol) in batches, complete the addition, and keep warm Stir for 20min, add dropwise a mixed solution of 4-chlorobutyryl chloride (14.4g, 102.0mmol) and dichloromethane (15mL), after dropping, keep at 0～-5°C for 1 hour, then continue stirring at room temperature for 2 hours, Stop the reaction, slowly pour the reaction solution into 500 mL of ice water, separate the dichloromethane layer, extract the water layer twice with dichloromethane (300 mL×2), combine the organic layers, and wash three times with 1 mol/L sodium hydroxide aqueous solution (300mL×3), washed twice with saturated brine (300mL×2), dried over anhydrous sodium sulfate, filtered with suction, and evaporated to remove the solvent under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol=160:1) to obtain 20.5 g of light green solid (IV-2), yield 42%, mp 160-163°C. 1 HNMR (300MHz, CDCl 3 ) δ7.58(s, 1H), 7.13(s, 1H), 5.50(s, 1H), 4.78(d, J=12.9Hz, 1H), 4.47(d, J=13.1 Hz, 1H), 4.03(s, 2H), 3.65(t, J＝6.2Hz, 2H), 3.03(t, J＝7.0Hz, 2H), 2.99–2.80(m, 2H), 2.68(d, J ＝16.7Hz,1H),2.59–2.42(m,2H),2.30–2.11(m,3H),1.97–1.76(m,3H),1.54(s,1H),1.30(s,3H),1.19( s,3H),1.15(s,3H),1.08(s,3H).ESI-MS(m/z):597.2[M+Na] +
23-(4-(哌啶-1-基)丁酰基)柠檬苦素(I-5)23-(4-(piperidin-1-yl)butyryl)limonoid (I-5)
100ml三颈瓶中加入IV-2(2g,3.48mmol)，乙腈(50mL)，哌啶(1.78g,20.88mmol)和碘化钾(0.1g,0.6mmol)，加热回流反应48h，TLC(二氯甲烷:甲醇＝25:1)检测反应完全，减压蒸除溶剂。残留物加入50mL水，析出黄色固体，抽滤，粗品用柱层析(二氯甲烷:甲醇＝60:1)纯化，得浅褐色固体(I-5)0.74g，收率34％，150℃(炭化)。1H NMR(300MHz,CDCl3)δ7.56(s,1H),7.13(s,1H),5.47(s,1H),4.76(d,J＝13.1Hz,1H),4.46(d,J＝13.1Hz,1H),4.03(d,J＝9.1Hz,2H),3.08–2.96(m,2H),2.95–2.80(m,3H),2.78–2.56(m,6H),2.52(d,J＝11.2Hz,1H),2.44(d,J＝14.5Hz,1H),2.22(d,J＝13.5Hz,1H),2.11–1.98(m,2H),1.96–1.76(m,3H),1.76–1.63(m,4H),1.61–1.42(m,3H),1.28(s,3H),1.16(s,3H),1.13(s,3H),1.06(s,3H).ESI-MS(m/z):624.3[M+H]+ Add IV-2 (2g, 3.48mmol), acetonitrile (50mL), piperidine (1.78g, 20.88mmol) and potassium iodide (0.1g, 0.6mmol) into 100ml three-necked flask, heat to reflux for 48h, TLC (dichloromethane :methanol=25:1) detection reaction was complete, and the solvent was distilled off under reduced pressure. The residue was added with 50 mL of water, and a yellow solid was precipitated, which was filtered by suction, and the crude product was purified by column chromatography (dichloromethane:methanol=60:1) to obtain 0.74 g of light brown solid (I-5), yield 34%, 150°C (carbonization). 1 H NMR (300MHz, CDCl 3 ) δ7.56(s, 1H), 7.13(s, 1H), 5.47(s, 1H), 4.76(d, J=13.1Hz, 1H), 4.46(d, J= 13.1Hz,1H),4.03(d,J＝9.1Hz,2H),3.08–2.96(m,2H),2.95–2.80(m,3H),2.78–2.56(m,6H),2.52(d,J =11.2Hz,1H),2.44(d,J=14.5Hz,1H),2.22(d,J=13.5Hz,1H),2.11–1.98(m,2H),1.96–1.76(m,3H),1.76 –1.63(m,4H),1.61–1.42(m,3H),1.28(s,3H),1.16(s,3H),1.13(s,3H),1.06(s,3H).ESI-MS(m /z):624.3[M+H] +
以化合物I-5(0.65g,1.04mmol)为原料，操作过程同I-1·HCl，得白色固体(I-5·HCl)0.51g，收率74％，m.p.190～193℃。1H NMR(300MHz,DMSO)δ9.94(s,1H),8.05(s,1H),7.49(s,1H),5.54(s,1H),4.92(d,J＝12.6Hz,1H),4.48(d,J＝13.1Hz,1H),4.14(s,1H),4.08(s,1H),3.38–3.30(m,2H),3.20–3.05(m,1H),3.05–2.91(m,4H),2.90–2.79(m,2H),2.76(d,J＝16.7Hz,1H),2.66–2.52(m,2H),2.45–2.39(m,1H),2.27(d,J＝14.4Hz,1H),2.04–1.91(m,2H),1.87–1.61(m,9H),1.43–1.32(m,1H),1.17(s,3H),1.09(s,3H),1.00(d,J＝3.3Hz,6H).Using compound I-5 (0.65g, 1.04mmol) as raw material, the operation process was the same as I-1·HCl to obtain 0.51g of white solid (I-5·HCl), yield 74%, mp 190～193°C. 1 H NMR(300MHz,DMSO)δ9.94(s,1H),8.05(s,1H),7.49(s,1H),5.54(s,1H),4.92(d,J=12.6Hz,1H), 4.48(d,J＝13.1Hz,1H),4.14(s,1H),4.08(s,1H),3.38–3.30(m,2H),3.20–3.05(m,1H),3.05–2.91(m, 4H), 2.90–2.79(m, 2H), 2.76(d, J＝16.7Hz, 1H), 2.66–2.52(m, 2H), 2.45–2.39(m, 1H), 2.27(d, J＝14.4Hz ,1H),2.04–1.91(m,2H),1.87–1.61(m,9H),1.43–1.32(m,1H),1.17(s,3H),1.09(s,3H),1.00(d,J =3.3Hz,6H).
实施例6Example 6
23-(4-(吗啉-4-基)丁酰基)柠檬苦素(I-6)的制备Preparation of 23-(4-(morpholin-4-yl)butyryl)limonoid (I-6)
以化合物IV-2(2.0g,3.48mmol)和吗啉(1.52g,17.4mmol)为原料，操作过程同I-5，粗品用柱层析(二氯甲烷:甲醇＝80:1)纯化，得浅褐色固体(I-6)1.43g，收率66％，144℃(炭化)。1H NMR(300MHz,CDCl3)δ7.55(s,1H),7.08(s,1H),5.49(s,1H),4.77(d,J＝13.0Hz,1H),4.46(d,J＝13.2Hz,1H),4.03(d,J＝7.7Hz,2H),3.68–3.52(m,4H),2.98(dd,J＝16.7,3.6Hz,1H),2.93–2.86(m,1H),2.82(t,J＝6.9Hz,2H),2.68(d,J＝17.2Hz,1H),2.57–2.47(m,2H),2.47–2.35(m,6H),2.26–2.18(m,1H),1.97–1.77(m,5H),1.58–1.48(m,1H),1.29(s,3H),1.18(s,3H),1.14(s,3H),1.07(s,3H).ESI-MS(m/z):626.3[M+H]+ Using compound IV-2 (2.0g, 3.48mmol) and morpholine (1.52g, 17.4mmol) as raw materials, the operation process was the same as I-5, and the crude product was purified by column chromatography (dichloromethane:methanol=80:1), 1.43 g of light brown solid (I-6) was obtained, yield 66%, 144° C. (charring). 1 H NMR (300MHz, CDCl 3 ) δ7.55(s, 1H), 7.08(s, 1H), 5.49(s, 1H), 4.77(d, J=13.0Hz, 1H), 4.46(d, J= 13.2Hz, 1H), 4.03(d, J=7.7Hz, 2H), 3.68–3.52(m, 4H), 2.98(dd, J=16.7, 3.6Hz, 1H), 2.93–2.86(m, 1H), 2.82(t, J＝6.9Hz, 2H), 2.68(d, J＝17.2Hz, 1H), 2.57–2.47(m, 2H), 2.47–2.35(m, 6H), 2.26–2.18(m, 1H) ,1.97–1.77(m,5H),1.58–1.48(m,1H),1.29(s,3H),1.18(s,3H),1.14(s,3H),1.07(s,3H).ESI-MS (m/z):626.3[M+H] +
以化合物I-6(1.3g,2.08mmol)为原料，操作过程同I-1·HCl，得白色固体(I-6·HCl)1.18g，收率86％，200℃(炭化)。1H NMR(300MHz,DMSO)δ10.71(s,1H),8.05(s,1H),7.49(s,1H),5.54(s,1H),4.92(d,J＝13.5Hz,1H),4.48(d,J＝12.9Hz,1H),4.14(s,1H),4.08(s,1H),3.98–3.88(m,2H),3.82–3.70(m,2H),3.49–3.40(m,2H),3.15–3.02(m,4H),3.01–2.92(m,3H),2.75(d,J＝16.5Hz,1H),2.65–2.52(m,2H),2.45–2.40(m,1H),2.27(d,J＝11.7Hz,1H),2.04–1.91(m,2H),1.85–1.63(m,3H),1.31–1.22(m,1H),1.17(s,3H),1.09(s,3H),1.00(d,J＝3.4Hz,6H).Using compound I-6 (1.3g, 2.08mmol) as raw material, the operation process was the same as I-1·HCl to obtain 1.18g of white solid (I-6·HCl), yield 86%, 200°C (charring). 1 H NMR (300MHz,DMSO)δ10.71(s,1H),8.05(s,1H),7.49(s,1H),5.54(s,1H),4.92(d,J=13.5Hz,1H), 4.48(d,J＝12.9Hz,1H),4.14(s,1H),4.08(s,1H),3.98–3.88(m,2H),3.82–3.70(m,2H),3.49–3.40(m, 2H),3.15–3.02(m,4H),3.01–2.92(m,3H),2.75(d,J＝16.5Hz,1H),2.65–2.52(m,2H),2.45–2.40(m,1H) ,2.27(d,J＝11.7Hz,1H),2.04–1.91(m,2H),1.85–1.63(m,3H),1.31–1.22(m,1H),1.17(s,3H),1.09(s ,3H),1.00(d,J=3.4Hz,6H).
实施例7Example 7
23-(4-(4-甲基哌嗪-1-基)丁酰基)柠檬苦素(I-7)的制备Preparation of 23-(4-(4-methylpiperazin-1-yl)butyryl)limonoid (I-7)
以化合物IV-2(2.0g,3.48mmol)和N-甲基哌嗪(1.74g,17.4mmol)为原料，操作过程同I-5，粗品用柱层析(二氯甲烷:甲醇＝80:1)纯化，得浅褐色固体(I-7)1.0g，收率45％，146℃(炭化)。1H NMR(300MHz,CDCl3)δ7.55(s,1H),7.08(s,1H),5.49(s,1H),4.77(d,J＝13.1Hz,1H),4.46(d,J＝13.0Hz,1H),4.03(d,J＝4.5Hz,2H),2.99(dd,J＝16.8,3.7Hz,1H),2.93–2.85(m,1H),2.82(t,J＝7.0Hz,2H),2.75–2.63(m,2H),2.62–2.35(m,10H),2.31(s,3H),2.27–2.16(m,2H),1.98–1.74(m,5H),1.60–1.47(m,1H),1.30(s,3H),1.18(s,3H),1.15(s,3H),1.07(s,3H).ESI-MS(m/z):639.3[M+H]+ Using compound IV-2 (2.0g, 3.48mmol) and N-methylpiperazine (1.74g, 17.4mmol) as raw materials, the operation process was the same as I-5, and the crude product was subjected to column chromatography (dichloromethane:methanol=80: 1) Purification to obtain 1.0 g of light brown solid (I-7), yield 45%, 146°C (charring). 1 H NMR (300MHz, CDCl 3 ) δ7.55(s, 1H), 7.08(s, 1H), 5.49(s, 1H), 4.77(d, J=13.1Hz, 1H), 4.46(d, J= 13.0Hz, 1H), 4.03(d, J=4.5Hz, 2H), 2.99(dd, J=16.8, 3.7Hz, 1H), 2.93–2.85(m, 1H), 2.82(t, J=7.0Hz, 2H),2.75–2.63(m,2H),2.62–2.35(m,10H),2.31(s,3H),2.27–2.16(m,2H),1.98–1.74(m,5H),1.60–1.47( m,1H),1.30(s,3H),1.18(s,3H),1.15(s,3H),1.07(s,3H).ESI-MS(m/z):639.3[M+H] +
以化合物I-7(0.9g,1.4mmol)为原料，操作过程同I-1·HCl，得白色固体(I-7·HCl)0.69g，收率73.1％，m.p.>200℃。Using compound I-7 (0.9g, 1.4mmol) as raw material, the operation process was the same as I-1·HCl to obtain 0.69g of white solid (I-7·HCl), yield 73.1%, m.p.>200℃.
实施例8Example 8
23-(4-(吡咯-1-基)丁酰基)柠檬苦素(I-8)的制备Preparation of 23-(4-(pyrrol-1-yl)butyryl)limonoid (I-8)
以化合物IV-2(2.0g,3.48mmol)和吡咯烷(1.24g,17.4mmol)为原料，操作过程同I-5，粗品用柱层析(二氯甲烷:甲醇＝60:1)纯化，得褐色固体(I-8)0.91g，收率42.9％，m.p.154～156℃。1H NMR(300MHz,CDCl3)δ7.59(s,1H),7.21(s,1H),5.49(s,1H),4.77(d,J＝13.1Hz,1H),4.46(d,J＝13.1Hz,1H),4.04(d,J＝9.2Hz,2H),3.11–2.78(m,10H),2.69(d,J＝16.0Hz,1H),2.56–2.42(m,2H),2.27–2.10(m,3H),2.06–1.96(m,4H),1.91–1.79(m,3H),1.61(s,1H),1.29(s,3H),1.18(s,3H),1.14(s,3H),1.06(s,3H).ESI-MS(m/z):610.4[M+H]+ Using compound IV-2 (2.0g, 3.48mmol) and pyrrolidine (1.24g, 17.4mmol) as raw materials, the operation process was the same as I-5, and the crude product was purified by column chromatography (dichloromethane:methanol=60:1), 0.91 g of brown solid (I-8) was obtained, yield 42.9%, mp 154-156°C. 1 H NMR (300MHz, CDCl 3 ) δ7.59(s, 1H), 7.21(s, 1H), 5.49(s, 1H), 4.77(d, J=13.1Hz, 1H), 4.46(d, J= 13.1Hz, 1H), 4.04(d, J=9.2Hz, 2H), 3.11–2.78(m, 10H), 2.69(d, J=16.0Hz, 1H), 2.56–2.42(m, 2H), 2.27– 2.10(m,3H),2.06–1.96(m,4H),1.91–1.79(m,3H),1.61(s,1H),1.29(s,3H),1.18(s,3H),1.14(s, 3H),1.06(s,3H).ESI-MS(m/z):610.4[M+H] +
以化合物I-8(0.8g,1.31mmol)为原料，操作过程同I-1·HCl，得浅黄色固体(I-8·HCl)0.55g，收率64.9％，190℃(炭化)。Using compound I-8 (0.8g, 1.31mmol) as raw material, the operation process was the same as I-1·HCl to obtain 0.55g of light yellow solid (I-8·HCl), yield 64.9%, 190°C (charring).
实施例9Example 9
23-(4-(哌嗪-1-基)丁酰基)柠檬苦素(I-9)的制备Preparation of 23-(4-(piperazin-1-yl)butyryl)limonoid (I-9)
以化合物IV-2(2g,3.48mmol)和N-叔丁氧羰基哌嗪(5.21g,27.86mmol)为原料，操作过程同I-5，粗品用柱层析(二氯甲烷:甲醇＝100:1)纯化，得黄色中间体0.92g。将该黄色中间体溶于甲醇(10mL)和二氯甲烷(10mL)的混合溶剂中，冰浴搅拌下滴加饱和HCl的甲醇溶液(10mL)，滴毕，室温反应5小时，TLC检测(二氯甲烷:甲醇＝20:1)反应完全，停止反应，调pH至中性，减压蒸除溶剂，用二氯甲烷(30mL)溶解残留物，加水(20mL)，分取二氯甲烷层，水层用二氯甲烷萃取两次(20mL×2)，合并有机层，饱和食盐水洗涤两次(20mL×2)，无水硫酸钠干燥，抽滤，减压蒸除溶剂。粗品用柱层析(二氯甲烷:甲醇＝60:1)纯化，得黄色固体(I-9)0.33g，两步合计收率15.2％，162℃(炭化)。1H NMR(300MHz,CDCl3)δ7.56(s,1H),7.08(s,1H),5.49(s,1H),4.77(d,J＝13.6Hz,1H),4.47(d,J＝11.6Hz,1H),4.07(d,J＝34.5Hz,2H),3.07–2.56(m,9H),2.55–2.30(m,8H),2.29–2.25(m,1H),2.01–1.79(m,5H),1.64–1.51(m,1H),1.30(s,3H),1.18(s,3H),1.15(s,3H),1.07(s,3H),0.88(brs,1H).ESI-MS(m/z):625.2[M+H]+ Using compound IV-2 (2g, 3.48mmol) and N-tert-butoxycarbonylpiperazine (5.21g, 27.86mmol) as raw materials, the operation process was the same as I-5, and the crude product was subjected to column chromatography (dichloromethane:methanol=100 : 1) purification to obtain 0.92g of yellow intermediate. The yellow intermediate was dissolved in a mixed solvent of methanol (10mL) and dichloromethane (10mL), and a saturated methanol solution of HCl (10mL) was added dropwise with stirring in an ice bath. Chloromethane:methanol=20:1) complete reaction, stop the reaction, adjust the pH to neutral, evaporate the solvent under reduced pressure, dissolve the residue with dichloromethane (30mL), add water (20mL), and separate the dichloromethane layer, The aqueous layer was extracted twice with dichloromethane (20 mL×2), the organic layers were combined, washed twice with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, filtered with suction, and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol=60:1) to obtain 0.33 g of yellow solid (I-9), the total yield of two steps was 15.2%, 162°C (charring). 1 H NMR (300MHz, CDCl 3 ) δ7.56(s, 1H), 7.08(s, 1H), 5.49(s, 1H), 4.77(d, J=13.6Hz, 1H), 4.47(d, J= 11.6Hz, 1H), 4.07(d, J＝34.5Hz, 2H), 3.07–2.56(m, 9H), 2.55–2.30(m, 8H), 2.29–2.25(m, 1H), 2.01–1.79(m ,5H),1.64–1.51(m,1H),1.30(s,3H),1.18(s,3H),1.15(s,3H),1.07(s,3H),0.88(brs,1H).ESI- MS(m/z):625.2[M+H] +
以化合物I-9(0.25g,0.4mmol)为原料，操作过程同I-1·HCl，得浅黄色固体(I-9·HCl)0.23g，收率87.1％，m.p.>200℃。Using compound I-9 (0.25g, 0.4mmol) as raw material, the operation process was the same as I-1·HCl to obtain 0.23g of light yellow solid (I-9·HCl), yield 87.1%, m.p.>200℃.
实施例10Example 10
23-(4-(二正丙氨基)丁酰基)柠檬苦素(I-12)的制备Preparation of 23-(4-(di-n-propylamino)butyryl)limonoid (I-12)
以化合物IV-2(2.0g,3.48mmol)和二正丙胺(2.11g,20.85mmol)为原料，操作过程同I-5，粗品用柱层析(二氯甲烷:甲醇＝40:1)纯化，得浅黄色固体(I-12)0.36g，收率16.2％，148℃(炭化)。1H NMR(300MHz,CDCl3)δ7.55(s,1H),7.10(s,1H),5.48(s,1H),4.77(d,J＝13.1Hz,1H),4.46(d,J＝13.1Hz,1H),4.03(s,2H),2.98(dd,J＝16.8,3.7Hz,1H),2.93–2.79(m,3H),2.68(d,J＝16.6Hz,1H),2.61–2.39(m,8H),2.26–2.18(m,1H),2.02–1.77(m,5H),1.58–1.41(m,5H),1.29(s,3H),1.17(s,3H),1.14(s,3H),1.07(s,3H),0.87(t,J＝7.3Hz,6H).ESI-MS(m/z):640.3[M+H]+ Using compound IV-2 (2.0g, 3.48mmol) and di-n-propylamine (2.11g, 20.85mmol) as raw materials, the operation process was the same as I-5, and the crude product was purified by column chromatography (dichloromethane:methanol=40:1) , 0.36 g of light yellow solid (I-12) was obtained, yield 16.2%, 148° C. (charring). 1 H NMR (300MHz, CDCl 3 ) δ7.55(s, 1H), 7.10(s, 1H), 5.48(s, 1H), 4.77(d, J=13.1Hz, 1H), 4.46(d, J= 13.1Hz, 1H), 4.03(s, 2H), 2.98(dd, J＝16.8, 3.7Hz, 1H), 2.93–2.79(m, 3H), 2.68(d, J＝16.6Hz, 1H), 2.61– 2.39(m,8H),2.26–2.18(m,1H),2.02–1.77(m,5H),1.58–1.41(m,5H),1.29(s,3H),1.17(s,3H),1.14( s,3H),1.07(s,3H),0.87(t,J＝7.3Hz,6H).ESI-MS(m/z):640.3[M+H] +
以化合物I-12(0.3g,0.47mmol)为原料，操作过程同I-1·HCl，得浅黄色固体(I-12·HCl)0.28g，收率88.5％，m.p.174～176℃。Using compound I-12 (0.3g, 0.47mmol) as raw material, the operation process was the same as I-1·HCl to obtain 0.28g of light yellow solid (I-12·HCl), yield 88.5%, m.p.174～176℃.
实施例11Example 11
23-(4-(咪唑-1-基)丁酰基)柠檬苦素(I-13)的制备Preparation of 23-(4-(imidazol-1-yl)butyryl)limonoid (I-13)
以化合物IV-2(2.0g,3.48mmol)和咪唑(1.18g,17.3mmol)为原料，操作过程同I-5，粗品用柱层析(二氯甲烷:甲醇＝50:1)纯化，得灰色固体(I-13)0.27g，收率12.8％，150℃(炭化)。1H NMR(300MHz,DMSO)δ8.02(s,1H),7.93(s,1H),7.44(s,1H),7.36(s,1H),6.97(s,1H),5.52(s,1H),4.91(d,J＝13.2Hz,1H),4.47(d,J＝12.4Hz,1H),4.11(s,2H),4.09–4.02(m,2H),3.19–3.05(m,1H),2.85–2.77(m,2H),2.76–2.70(m,1H),2.66–2.51(m,2H),2.45–2.39(m,1H),2.27(d,J＝11.7Hz,1H),2.09–1.95(m,2H),1.90–1.65(m,3H),1.28–1.22(m,1H),1.17(s,3H),1.08(s,3H),1.00(d,J＝4.3Hz,6H).ESI-MS(m/z):607.3[M+H]+ Using compound IV-2 (2.0g, 3.48mmol) and imidazole (1.18g, 17.3mmol) as raw materials, the operation process was the same as I-5, and the crude product was purified by column chromatography (dichloromethane:methanol=50:1) to obtain Gray solid (I-13) 0.27g, yield 12.8%, 150°C (charring). 1 H NMR (300MHz,DMSO)δ8.02(s,1H),7.93(s,1H),7.44(s,1H),7.36(s,1H),6.97(s,1H),5.52(s,1H ),4.91(d,J=13.2Hz,1H),4.47(d,J=12.4Hz,1H),4.11(s,2H),4.09–4.02(m,2H),3.19–3.05(m,1H) ,2.85–2.77(m,2H),2.76–2.70(m,1H),2.66–2.51(m,2H),2.45–2.39(m,1H),2.27(d,J＝11.7Hz,1H),2.09 –1.95(m,2H),1.90–1.65(m,3H),1.28–1.22(m,1H),1.17(s,3H),1.08(s,3H),1.00(d,J＝4.3Hz,6H ).ESI-MS(m/z):607.3[M+H] +
以化合物I-13(0.2g,0.33mmol)为原料，操作过程同I-1·HCl，得灰白色固体(I-13·HCl)0.18g，收率85.1％，196℃(炭化)。Using compound I-13 (0.2g, 0.33mmol) as raw material, the operation process was the same as I-1·HCl to obtain 0.18g of off-white solid (I-13·HCl), yield 85.1%, 196°C (charring).
实施例13Example 13
23-(4-(哌啶-1-基)丁酰基)脱氧柠檬苦素(II-2)的制备Preparation of 23-(4-(piperidin-1-yl)butyryl)deoxylimonin (II-2)
23-(4-氯丁酰基)脱氧柠檬苦素(VI)23-(4-Chlorobutyryl)deoxylimonoid (VI)
250ml茄形瓶中加入脱氧柠檬苦素V(10g,22.02mmol)和二氯甲烷(140mL)，Add deoxylimonin V (10g, 22.02mmol) and dichloromethane (140mL) into a 250ml eggplant-shaped bottle,
搅拌下降温至-5℃，分批加入三氯化铝(14.69g,110.1mmol)，加毕，保温搅拌30min，滴加4-氯丁酰氯(4.04g,28.65mmol)，滴毕，保持0～-5℃反应1小时，于室温继续搅拌反应12小时，停止反应，将反应液慢慢倒入150ml冰水中，分取二氯甲烷层，水层用二氯甲烷萃取两次(100mL×2)，合并有机层，用1mol/L氢氧化钠水溶液洗三次(100mL×3)，饱和食盐水洗涤两次(100mL×2)，无水硫酸钠干燥，抽滤，减压蒸除溶剂。粗品用柱层析(石油醚:乙酸乙酯＝1:1)纯化，得白色固体(VI)6.48g，收率52.7％，m.p.136-139℃。1H NMR(300MHz,CDCl3)δ7.65(s,1H),7.19(s,1H),6.86(s,1H),5.03(s,1H),4.68(d,J＝13.3Hz,1H),4.57(d,J＝13.3Hz,1H),4.11(s,1H),3.65(t,J＝6.2Hz,2H),3.04(t,J＝7.1Hz,2H),2.97(dd,J＝12.6,4.1Hz,1H),2.90–2.76(m,1H),2.67–2.49(m,3H),2.31(d,J＝15.6Hz,1H),2.25–2.15(m,2H),2.15–2.06(m,1H),1.92–1.80(m,1H),1.61–1.50(m,2H),1.41(s,3H),1.30(s,3H),1.22(s,3H),1.19(s,3H).ESI-MS m/z:557.2[M-H]- Stir and lower the temperature to -5°C, add aluminum trichloride (14.69g, 110.1mmol) in batches, after the addition is complete, keep stirring for 30min, add 4-chlorobutyryl chloride (4.04g, 28.65mmol) dropwise, and keep at 0 React at ~-5°C for 1 hour, continue to stir the reaction at room temperature for 12 hours, stop the reaction, slowly pour the reaction solution into 150ml of ice water, separate the dichloromethane layer, and extract the water layer twice with dichloromethane (100mL×2 ), combined organic layers, washed three times with 1mol/L sodium hydroxide aqueous solution (100mL×3), washed twice with saturated brine (100mL×2), dried over anhydrous sodium sulfate, filtered with suction, and evaporated the solvent under reduced pressure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain 6.48 g of white solid (VI), yield 52.7%, mp 136-139°C. 1 H NMR (300MHz, CDCl 3 )δ7.65(s,1H),7.19(s,1H),6.86(s,1H),5.03(s,1H),4.68(d,J＝13.3Hz,1H) ,4.57(d,J=13.3Hz,1H),4.11(s,1H),3.65(t,J=6.2Hz,2H),3.04(t,J=7.1Hz,2H),2.97(dd,J= 12.6, 4.1Hz, 1H), 2.90–2.76(m, 1H), 2.67–2.49(m, 3H), 2.31(d, J=15.6Hz, 1H), 2.25–2.15(m, 2H), 2.15–2.06 (m,1H),1.92–1.80(m,1H),1.61–1.50(m,2H),1.41(s,3H),1.30(s,3H),1.22(s,3H),1.19(s,3H ).ESI-MS m/z:557.2[MH] -
23-(4-(哌啶-1-基)丁酰基)脱氧柠檬苦素(II-2)23-(4-(piperidin-1-yl)butyryl)deoxylimonin (II-2)
以化合物VI(2.0g,3.58mmol)和哌啶(1.83g,21.5mmol)为原料，操作过程同I-5，粗品用柱层析(二氯甲烷:甲醇＝60:1)纯化，得黄色固体(II-2)0.88g，收率40.5％，m.p.139～142℃。1H NMR(300MHz,CDCl3)δ7.62(s,1H),7.13(s,1H),6.85(s,1H),5.02(s,1H),4.67(d,J＝13.4Hz,1H),4.56(d,J＝13.2Hz,1H),4.11(s,1H),2.95(d,J＝16.3Hz,1H),2.89–2.74(m,3H),2.70–2.46(m,3H),2.45–2.30(m,6H),2.30–2.19(m,1H),2.17–2.02(m,1H),1.99–1.90(m,2H),1.89–1.78(m,1H),1.72–1.55(m,2H),1.55–1.45(m,4H),1.40(s,5H),1.28(s,3H),1.20(s,3H),1.17(s,3H).ESI-MS m/z:608.4[M+H]+ Using compound VI (2.0g, 3.58mmol) and piperidine (1.83g, 21.5mmol) as raw materials, the operation process was the same as I-5, and the crude product was purified by column chromatography (dichloromethane:methanol=60:1) to obtain yellow Solid (II-2) 0.88g, yield 40.5%, mp 139-142°C. 1 H NMR (300MHz, CDCl 3 )δ7.62(s,1H),7.13(s,1H),6.85(s,1H),5.02(s,1H),4.67(d,J＝13.4Hz,1H) ,4.56(d,J=13.2Hz,1H),4.11(s,1H),2.95(d,J=16.3Hz,1H),2.89–2.74(m,3H),2.70–2.46(m,3H), 2.45–2.30(m,6H),2.30–2.19(m,1H),2.17–2.02(m,1H),1.99–1.90(m,2H),1.89–1.78(m,1H),1.72–1.55(m ,2H),1.55–1.45(m,4H),1.40(s,5H),1.28(s,3H),1.20(s,3H),1.17(s,3H).ESI-MS m/z:608.4[ M+H] +
以化合物II-2(0.8g,1.32mmol)为原料，操作过程同I-1·HCl，得浅黄色固体(II-2·HCl)0.64g，收率75.5％，178℃(炭化)。Using compound II-2 (0.8g, 1.32mmol) as raw material, the operation process was the same as I-1·HCl to obtain 0.64g of light yellow solid (II-2·HCl), yield 75.5%, 178°C (charring).
实施例14Example 14
23-(4-(吗啉-4-基)丁酰基)脱氧柠檬苦素(II-3)23-(4-(morpholin-4-yl)butyryl)deoxylimonoid (II-3)
以化合物VI(2.0g,3.58mmol)和吗啉(1.87g,21.5mmol)为原料，操作过程同I-5，粗品用柱层析(二氯甲烷:甲醇＝60:1)纯化，得浅黄色固体(II-3)0.8g，收率36.7％，m.p.141～144℃。1H NMR(300MHz,CDCl3)δ7.62(s,1H),7.13(s,1H),6.84(s,1H),5.02(s,1H),4.67(d,J＝13.3Hz,1H),4.56(d,J＝13.3Hz,1H),4.11(s,1H),3.58(s,4H),3.03–2.86(m,2H),2.86–2.76(m,2H),2.69–2.52(m,3H),2.52–2.35(m,6H),2.34–2.24(m,1H),2.17–2.02(m,1H),2.00–1.89(m,2H),1.88–1.78(m,1H),1.66–1.48(m,2H),1.39(s,3H),1.28(s,3H),1.20(s,3H),1.17(s,3H).ESI-MS m/z:632.3[M+Na]+ Using compound VI (2.0g, 3.58mmol) and morpholine (1.87g, 21.5mmol) as raw materials, the operation process was the same as I-5, and the crude product was purified by column chromatography (dichloromethane:methanol=60:1) to obtain shallow Yellow solid (II-3) 0.8g, yield 36.7%, mp 141-144°C. 1H NMR (300MHz, CDCl3) δ7.62(s,1H),7.13(s,1H),6.84(s,1H),5.02(s,1H),4.67(d,J=13.3Hz,1H),4.56 (d,J=13.3Hz,1H),4.11(s,1H),3.58(s,4H),3.03–2.86(m,2H),2.86–2.76(m,2H),2.69–2.52(m,3H ),2.52–2.35(m,6H),2.34–2.24(m,1H),2.17–2.02(m,1H),2.00–1.89(m,2H),1.88–1.78(m,1H),1.66–1.48 (m,2H),1.39(s,3H),1.28(s,3H),1.20(s,3H),1.17(s,3H).ESI-MS m/z:632.3[M+Na] +
以化合物II-3(0.7g,1.15mmol)为原料，操作过程同I-1·HCl，得浅黄色固体(II-3·HCl)0.62g，收率83.5％，198℃(炭化)。Using compound II-3 (0.7g, 1.15mmol) as raw material, the operation process was the same as I-1·HCl to obtain 0.62g of light yellow solid (II-3·HCl), yield 83.5%, 198°C (charring).
实施例15Example 15
23-(4-(二正丙氨基)丁酰基)脱氧柠檬苦素(II-5)的制备Preparation of 23-(4-(di-n-propylamino)butyryl)deoxylimonoid (II-5)
以化合物VI(2.0g,3.58mmol)和二正丙胺(2.17g,21.44mmol)为原料，操作过程同I-5，粗品用柱层析(二氯甲烷:甲醇＝60:1)纯化，得灰褐色固体(II-5)0.44g，收率19.7％，m.p.126～128℃。1H NMR(300MHz,CDCl3)δ7.64(s,1H),7.18(s,1H),6.84(s,1H),5.02(s,1H),4.67(d,J＝12.3Hz,1H),4.57(d,J＝12.4Hz,1H),4.11(s,1H),3.08–2.74(m,4H),2.72–2.41(m,9H),2.30(d,J＝15.2Hz,1H),2.20–2.06(m,1H),2.04–1.81(m,3H),1.71–1.46(m,6H),1.40(s,3H),1.28(s,3H),1.20(s,3H),1.17(s,3H),0.95–0.84(m,6H).ESI-MSm/z:624.4[M+H]+ Using compound VI (2.0g, 3.58mmol) and di-n-propylamine (2.17g, 21.44mmol) as raw materials, the operation process was the same as I-5, and the crude product was purified by column chromatography (dichloromethane:methanol=60:1) to obtain Gray brown solid (II-5) 0.44g, yield 19.7%, mp 126-128°C. 1 H NMR (300MHz, CDCl 3 )δ7.64(s,1H),7.18(s,1H),6.84(s,1H),5.02(s,1H),4.67(d,J＝12.3Hz,1H) ,4.57(d,J=12.4Hz,1H),4.11(s,1H),3.08–2.74(m,4H),2.72–2.41(m,9H),2.30(d,J=15.2Hz,1H), 2.20–2.06(m,1H),2.04–1.81(m,3H),1.71–1.46(m,6H),1.40(s,3H),1.28(s,3H),1.20(s,3H),1.17( s,3H),0.95–0.84(m,6H).ESI-MSm/z:624.4[M+H] +
以化合物II-5(0.35g,0.56mmol)为原料，操作过程同I-1·HCl，得灰色固体(II-5·HCl)0.27g，收率72.9％，172℃(炭化)。Using compound II-5 (0.35g, 0.56mmol) as the starting material, the procedure was the same as that of I-1·HCl to obtain 0.27g of gray solid (II-5·HCl), yield 72.9%, 172°C (carbonization).
实施例16Example 16
23-(4-(咪唑-1-基)丁酰基)脱氧柠檬苦素(II-6)的制备Preparation of 23-(4-(imidazol-1-yl)butyryl)deoxylimonin (II-6)
以化合物VI(2.0g,3.58mmol)和咪唑(1.22g,17.92mmol)为原料，操作过程同I-5，粗品用柱层析(二氯甲烷:甲醇＝60:1)纯化，得黄色固体(II-6)0.26g，收率12.3％，m.p.132～135℃。1H NMR(300MHz,DMSO)δ8.04(s,1H),7.62(s,1H),7.45(s,1H),7.18(s,1H),6.88(s,1H),6.63(s,1H),5.19(s,1H),4.82(d,J＝11.7Hz,1H),4.61(d,J＝11.7Hz,1H),4.11(s,1H),4.06–3.89(m,2H),3.22–3.06(m,1H),2.89–2.73(m,2H),2.71–2.52(m,3H),2.44–2.25(m,2H),2.22–1.90(m,3H),1.87–1.43(m,3H),1.28(s,3H),1.16(s,3H),1.13(s,3H),1.00(s,3H).ESI-MS m/z:591.3[M+H]+ Using compound VI (2.0g, 3.58mmol) and imidazole (1.22g, 17.92mmol) as raw materials, the operation process was the same as I-5, and the crude product was purified by column chromatography (dichloromethane:methanol=60:1) to obtain a yellow solid (II-6) 0.26g, yield 12.3%, mp 132-135°C. 1 H NMR (300MHz,DMSO)δ8.04(s,1H),7.62(s,1H),7.45(s,1H),7.18(s,1H),6.88(s,1H),6.63(s,1H ),5.19(s,1H),4.82(d,J=11.7Hz,1H),4.61(d,J=11.7Hz,1H),4.11(s,1H),4.06–3.89(m,2H),3.22 –3.06(m,1H),2.89–2.73(m,2H),2.71–2.52(m,3H),2.44–2.25(m,2H),2.22–1.90(m,3H),1.87–1.43(m, 3H),1.28(s,3H),1.16(s,3H),1.13(s,3H),1.00(s,3H).ESI-MS m/z:591.3[M+H] +
以化合物II-6(0.2g,0.34mmol)为原料，操作过程同I-1·HCl，得灰色固体(II-6·HCl)0.18g，收率84.8％，176℃(炭化)。Using compound II-6 (0.2g, 0.34mmol) as raw material, the operation process was the same as that of I-1·HCl to obtain 0.18g of gray solid (II-6·HCl), yield 84.8%, 176°C (charring).
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|---|---|---|---|---|
| CN111518111A (en) * | 2020-05-26 | 2020-08-11 | 中国药科大学 | Ring-opening amination derivative of deoxylimonin A or its pharmaceutically acceptable salt, preparation method and use |
| CN111574533A (en) * | 2020-05-26 | 2020-08-25 | 中国药科大学 | Limonin A ring-opening aminated derivative or pharmaceutically acceptable salt thereof, preparation method and application |
| CN111574533B (en) * | 2020-05-26 | 2021-06-01 | 中国药科大学 | Limonin A ring-opening aminated derivative or pharmaceutically acceptable salt thereof, preparation method and application |
| CN111518111B (en) * | 2020-05-26 | 2021-06-01 | 中国药科大学 | Deoxylimonin A ring-opening aminated derivative or pharmaceutically acceptable salt thereof, preparation method and application |
| CN113929730A (en) * | 2020-07-13 | 2022-01-14 | 衢州市展宏生物科技有限公司 | Limonin derivative and preparation method and application thereof |
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| Publication number | Publication date |
|---|---|
| CN106928311B (en) | 2019-06-04 |
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