CN101102761B - 木酚素类化合物用于治疗或预防炎症性疾病的用途 - Google Patents
木酚素类化合物用于治疗或预防炎症性疾病的用途 Download PDFInfo
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- CN101102761B CN101102761B CN2006800019887A CN200680001988A CN101102761B CN 101102761 B CN101102761 B CN 101102761B CN 2006800019887 A CN2006800019887 A CN 2006800019887A CN 200680001988 A CN200680001988 A CN 200680001988A CN 101102761 B CN101102761 B CN 101102761B
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Abstract
本发明涉及木酚素类化合物用于治疗或预防炎症性疾病的用途。更具体地说，本发明涉及含有由通式I表示的木酚素类化合物的用于治疗或预防炎症性疾病的药物组合物、利用该组合物的炎症性疾病的治疗方法及用途。本发明的木酚素类化合物，具有通过阻碍炎症介质因子NO、iNOS、PGE2、COX-2及TNF-α的生成或表达来抑制炎症反应的效果。因此，本发明的木酚素类化合物或肉豆蔻提取物能够极其有用地用于炎症性疾病的治疗或预防中。
Description
技术领域
本发明主张2005年1月7日申请的韩国专利申请号为10-2005-0001761的专利申请作为优先权。
本发明涉及木酚素类化合物用于治疗或预防炎症性疾病的用途。更具体地说，本发明涉及用于治疗或预防炎症性疾病的药物组合物、利用该组合物治疗炎症性疾病的治疗方法及用途，所述组合物含有通式I表示的木酚素类化合物。
背景技术
炎症反应是指在组织(细胞)损伤或受外部感染源感染时发生的，在局部血管与体液内显现出的酶活化、炎症介质物质分泌、体液浸润、细胞移动、组织破坏等的一系列综合的生理反应以及红斑、浮肿、发热、疼痛等的外部症状，其中涉及各种炎症介质因子及免疫细胞。进一步地，其结果会导致急性炎症与肉芽肿、以及诸如类风湿性关节炎、骨关节炎等的慢性炎症(Goodwin J.S.et al.，J.Clin.Immunol.，9：295-314，1989)。
在对血液凝固以及炎症产生重要影响的酶中，环氧化酶(以下称作“COX”)起到了重要的作用，COX生成前列腺素以及血栓素两种主要产物。前列腺素是具有极其多样的生理活性的不饱和脂肪酸，作为人体内的局部的荷尔蒙或细胞功能调节因子而起作用，例如炎症及疼痛传达、血管扩张、体温调节、胃液分泌促进等(Marnett，L.J.et al.，J.Biol.Chem.，274：22903-22906，1999)。COX-1通过维持诸如胃肠管保护、肾脏的血流调节及血小板凝集等正常生理反应，对细胞的正常维持起到重要的作用。另一方面，在受外部刺激而诱发的炎症的传导过程中，可诱导的同工酶COX-2暂时表达而在产生炎症的部位释放过量的前列腺素。前列腺素能引起作为炎症的主要症状的红斑、浮肿及疼痛，具有将作为内因性炎症介质物质的组胺等的作用增强的活性，因而抑制炎症部位中的前列腺素的生成在炎症治疗中有很大的作用。
现在，商业上使用的作为非甾体类抗炎药(NSAIDs)的阿司匹林(aspirin)、吲哚美辛(indomethacin)、萘普生(naproxen)、布洛芬(ibuprofen)等，是通过抑制COX-2酶的活性来阻碍前列腺素的生成，从而显示出抗炎效果(Meade E.A.et al.，J.Biol.Chem.，268：6610，1993)。但是，这些NSAID药物不仅抑制由于炎症刺激而暂时表达的COX-2，也抑制对胃肠管、肾脏血小板的正常功能的维持起重要作用的COX-1，因而有导致胃肠管出血、肾脏功能不全等的严重副作用的问题(Surh Y.J.et al.，Mutation Research 480-481：243-268，2001)。因此，从天然物中发掘使副作用最小化、同时提供抗炎症作用的物质，在产业上及其重要。
另一方面，木酚素(lignan)是n—苯基丙烷在n—丙基侧链的β位上结合而成的天然化合物的总称，广泛分布在自然界中。已针对木酚素的降血糖作用、抗癌作用、抗喘息作用、美白作用等的多种生理学活性进行了研究。例如，已报道了作为从芝麻分离出的木酚素的芝麻素(sesamin)、异芝麻素(episesamin)、芝麻素酚(sesaminol)、芝麻林素(sesamolin)及异芝麻素酚(episesaminol)具有抗炎症效果(韩国公开专利公报第1997-7001043号)；此外，还公开了从辛夷(白木莲)(Magnoliae flos)分离出的木酚素类化合物能够作为抗喘息剂使用(韩国注册专利第0263439号)。进一步地，已报道了肉豆蔻木酚素(macelignan)，其是从肉豆蔻(Myristica fragrans)中发现的代表性的木酚素类化合物(Tuchinda P.etal.，Phytochemistry，59：169-173，2002)，其具有对诱导细胞凋亡的caspase(天冬氨酸特异性半胱氨酸蛋白酶)-3的增强作用(Park B.Y.et al.，Biol.Pharm.Bull.，27(8)：1305-1307，2004)及抗氧化作用(Sadhu，S.K.et al.，Chem.Pharm.Bull.，51(9)：595-598，2003)。但是，对于包括上述肉豆蔻木酚素的木酚素类化合物的抗炎症活性，至今还没有报道过。
发明内容
发明要解决的课题
本发明人为了寻找具有抗炎症活性的来自天然物质的化合物，进行了长期的探索，其结果发现从肉豆蔻提取物中分离纯化的木酚素类化合物呈现出卓越的抗炎症活性，从而完成了本发明。
本发明的目的是，提供木酚素类化合物治疗或预防炎症性疾病的用途。
解决课题的方法
为了达到上述目的，本发明提供一种治疗或预防炎症性疾病的药物组合物，该药物组合物包含由下述通式I表示的木酚素类化合物或其药学上可接受的盐的有效成分。
通式I
式中，R1及R2独立地是C1-5烷氧基或羟基；R3是
或
进一步地，本发明提供一种通过施用有效量的由上述通式I表示的木酚素类化合物或其药学上可接受的盐而预防或治疗炎症性疾病的方法。
进一步地，本发明提供一种由上述通式I表示的木酚素类化合物用于制造预防或治疗炎症性疾病的药物组合物的用途。
本发明中，“有效量”是指本发明的木酚素类化合物能够有效地治疗作为使用对象的受试者体内的炎症性疾病的量。
进一步地，本发明中，“受试者(subject)”是指哺乳动物，特别是包括人类在内的动物。上述受试者也可以是需要治疗的患者。
下面，详细说明本发明。
本发明的特征在于提供从肉豆蔻提取物中分离纯化的木酚素类化合物的新用途。
本发明的木酚素类化合物由下述通式I表示：
通式I
其中，R1及R2独立地是C1-5烷氧基或羟基；R3是
优选本发明的木酚素类化合物可以为上述R1是甲氧基、R2是羟基、R3是
的由下述式1表示的肉豆蔻木酚素[(8R，8’S)-7-(3，4-亚甲基二氧苯基)-7’-(4-羟基-3-甲氧基苯基)-8，8’-二甲基丁烷)]：
本发明的木酚素类化合物，可以以盐的形式，优选为药学上可接受的盐的形式使用。上述盐优选为由药学上可接受的游离酸形成的酸加成盐。上述游离酸可使用有机酸及无机酸。所述有机酸包括柠檬酸、醋酸、乳酸、酒石酸、马来酸、富马酸、甲酸、丙酸、草酸、三氟醋酸、安息香酸、葡萄糖酸、甲磺酸、羟基乙酸、琥珀酸、对甲苯磺酸、谷氨酸及天门冬氨酸，但并不限制于此。另外，所述无机酸包括盐酸、溴酸、硫酸及磷酸，但并不限制于此。
本发明的木酚素类化合物，可利用通常的提取和分离物质的方法从植物或植物的一部分获得。对茎、根或叶进行适宜的脱水、浸渍，或仅仅脱水以获得所需的提取物，然后利用本发明所属技术领域的技术人员公知的纯化方法进行纯化。进一步地，对应于上述通式I表示的木酚素类化合物的合成化合物或它们的衍生物，一般为可商购的物质，或可利用公知的合成方法制造而得到。
上述由通式I表示的本发明的木酚素类化合物，可从肉豆蔻(Myristica fragnance Houtt.)中分离纯化而得到(Jung Yun Lee etal.，Kor.J.Pharmacogn.21(4)：270-273，1990；Masao Hattori et al.，Chem.Pharm.Bull.，34(9)：3885-3893，1986；Masao Hattori et al.，Chem Pharm.Bull.，35(2)：668-674，1987)。优选地，可从核仁(nutmeg)或假种皮(aril)中分离纯化而得到。上述核仁，是指肉豆蔻的成熟的果实或果实中的种子。进一步地，本发明的木酚素类化合物，可从压榨核仁而得到的油中分离纯化而得。进一步地，也可从肉豆蔻科的另一种植物长形肉豆蔻(Myristica argentea Warb)等中分离纯化而得(Filleur，F.et al.，Natural Product Letters，16：1-7，2002)。或，也可以从红楠(Machilus thunbergii)(Park B.Y.et al.，Biol.Pharm.Bull.，27(8)：1305-1307，2004)、蜂巢草(Leucas aspera)中分离纯化而得(Sadhu，S.K.et al.，Chem.Pharm.Bull.，51(9)：595-598，2003)。
用于分离本发明的木酚素类化合物的提取溶剂可以是水或C1-C6的有机溶剂。优选地，可单独使用或混合使用的提取溶剂包括纯化水、甲醇、乙醇、丙醇、异丙醇、丁醇、丙酮、乙醚、苯、氯仿、乙酸乙酯、二氯甲烷、己烷、环己烷、石油醚等。更优选地，可使用甲醇或己烷。从肉豆蔻提取物中分离纯化本发明的木酚素类化合物时，可单独或组合使用填充有硅胶或活性氧化铝等各种合成树脂的柱色谱及高效液相色谱(HPLC)等。但是，有效成分的提取及分离纯化方法，并不限制于使用上述方法。
如上所述，本发明的木酚素类化合物，可以以纯的分离纯化的化合物的形式使用，也可直接以含有该化合物的提取物的形式使用。例如，也可以以如上述记载的肉豆蔻的种子、果实或假种皮的提取物形式或压榨肉豆蔻的种子得到的油的形式使用。如上所述，上述提取物可用水或C1-C6有机溶剂对肉豆蔻进行提取而得到。优选地，也可以是肉豆蔻的种子，即核仁的提取物。
本发明的木酚素类化合物通过抑制作为炎症反应的介质的多种物质而具有抗炎症活性。
NO作为与神经传达、血管舒张及细胞介质性免疫反应有关的物质，通过NOS(一氧化氮合成酶)从L-精氨酸生成(Nathan and Xie，1994；Aldertonet al.，2001)。特别地，当巨噬细胞被IFN-γ或LPS(内毒素)刺激时，iNOS(诱导型一氧化氮合成酶)被表达，通过上述iNOS生成大量的NO。本发明的木酚素类化合物，能够浓度依赖性地抑制巨噬细胞内NO的生成及参与NO生成的iNOS的表达(参照图8及图9)。
进一步地，COX-2作为与体内的炎症反应有关的物质，产生致炎性PG。COX-2的表达通过细菌类分泌的内毒素LPS以及炎症性细胞活素类IL-1、TNF-α、IFN-γ等诱导。本发明的木酚素类化合物不仅抑制COX-2的表达，而且也浓度依赖性地抑制PG类之一的PGE2(前列腺素E2)的生成(参照图10及图11)。
肿瘤坏死因子TNF-α是革兰阴性菌与其它感染性微生物引发的急性炎症反应的主要的介质因子。被LPS刺激的巨噬细胞增强TNF-α的合成。TNF-α的生物学作用是在低浓度时作用于白细胞与内皮细胞而引发急性炎症；中等浓度时，其介导全身炎症反应；高浓度时，其由于导致败血症休克的病理学异常而引起死亡。进一步地，TNF-α增强PG的合成而产生热量，抑制凝血酶调节蛋白(trombomodulin)的表达，导致血管堵塞(Abbas andLichtman，″Cellular and Molecular Immunology″the fifth edition.pp.247-253，2003)。本发明的木酚素类化合物具有抑制巨噬细胞和人类单核细胞中TNF-α的生成的效果(参照图12及图13)。
进一步地，通过TPA(佛波酯(12-O-tetradecanoylphorbol-13-acetate))处理诱发浮肿的大鼠的耳朵局部涂布本发明的木酚素类化合物，其结果表明能够浓度依赖性地抑制浮肿生成率，比现在可商购获得的抗炎剂吲哚美辛呈现出更高的浮肿抑制率(参照表2)。进一步地，制造含有木酚素类化合物的乳膏，并将其局部涂敷在大鼠的耳朵上，其结果表明能够抑制浮肿生成率(参照表4)。
另一方面，本发明人等，在通过对TPA处理诱发浮肿的大鼠的耳朵局部涂布肉豆蔻提取物(甲醇及己烷粗提物)，其结果表明能够确认可浓度依赖性地抑制浮肿生成率(参照表5)。
如上所述的结果意味着本发明的木酚素类化合物不仅抑制COX-2，也抑制作为炎症反应介质的多种因子，呈现出卓越的抗炎症作用。进一步地，结果表明肉豆蔻提取物本身也能够得到相同的抗炎症效果。如上述的由通式I表示的本发明的木酚素类化合物及肉豆蔻提取物的抗炎症活性，是本发明首先发现的。
相对于现在产业上使用的非甾体类抗炎药大部分都是抑制了COX-2酶的活性而表现出抗炎症效果，能够确认本发明的木酚素类化合物可作为比以往的抗炎症剂具有更优异的效果的抗炎症剂来使用。
因此，本发明提供一种治疗或预防炎症性疾病的药物组合物，该药物组合物含有作为活性成分的由上述通式I表示的木酚素类化合物、其药学上可接受的盐。进一步地，本发明提供一种治疗或预防炎症性疾病的药物组合物，该药物组合物含有作为有效成分的肉豆蔻提取物。上述肉豆蔻提取物的制造如上所述。
进一步地，本发明提供一种治疗或预防炎症性疾病的方法，该方法将有效量的由通式I表示的木酚素类化合物或其药学上可接受的盐施用于所需受试者。
进一步地，本发明提供由通式I表示的木酚素类化合物在制造治疗或预防炎症性疾病的药物组合物中的用途。
本发明的木酚素类化合物或其药学上可接受的盐，在临床使用时，可以口服或胃肠外给药的形式使用，可以以一般的药物制剂的形式使用。以一般的药物制剂的形式进行制剂化时，可采用通常使用的填充剂、增稠剂、粘结剂、湿润剂、崩解剂、表面活性剂等稀释剂或赋形剂进行调制。用于口服的固体制剂包括片剂、丸剂、散剂、颗粒剂、胶囊等，如上所述的固体制剂，是在上述木酚素类化合物或肉豆蔻提取物中混合至少一种以上的赋形剂例如淀粉、炭酸钙、蔗糖或乳糖、凝胶等制成。进一步地，除单纯的赋形剂以外，也可以使用硬脂酸镁或滑石粉等润滑剂。用于口服的液体制剂，包括混悬剂、液体、乳剂、糖浆等。液体制剂除了广泛使用的单纯的稀释剂如水、液体石蜡以外还包括各种赋形剂，例如湿润剂、甜味剂、芳香剂、防腐剂等。用于胃肠外给药的药物制剂包括灭菌的水溶液、非水溶液、混悬剂、乳剂、冻干制剂、软膏、乳膏。非水溶液和混悬液可使用丙二醇、聚乙二醇、橄榄油等的植物油、油酸乙酯等的可注射酯等制备。
进一步地，本发明的木酚素类化合物或其药学上可接受的盐，可采用胃肠外给药途径给药，如可采用皮下注射、静脉注射、肌肉注射或腹内注射方式。制备胃肠外给药制剂时，将上述通式I的木酚素类化合物或肉豆蔻提取物与稳定剂或缓冲剂一起在水中混合制成溶液或混悬液，然后将其制成存在于安剖或小瓶中的单位剂型。剂量单位可含有，例如单独剂量的1、2、3或4倍，或1/2、1/3或1/4倍。单独剂量，优选含有有效药物的一次给药量，这相当于通常一天给药量的全部、1/2、1/3或1/4倍。
本发明的由通式I表示的木酚素类化合物或肉豆蔻提取物的有效剂量为0.1-50mg/kg，优选为1-10mg/kg，可一天服用1～3次。对特定患者的给药量基准，也可根据患者的体重、年龄、性别、健康状态、饮食、给药时间、给药方法、排泄率、疾病的严重程度等变化。
大鼠口服本发明的木酚素类化合物时的毒性实验的结果，显示了口服毒性试验的50％致死量(LD50)为2,000mg/kg以上。
特别是，含有本发明的木酚素类化合物或肉豆蔻提取物的药物组合物，能够制成皮肤涂布用剂型，即软膏、乳膏的形式，相对于制剂总重量，可根据剂型在0.001-10.0重量％，优选为0.005-5.0重量％的范围内适宜配制。当添加量低于0.005重量％时，抗炎症活性降低，当添加量超过10.0重量％时，只是添加量增多而抗炎症活性没有大的差别。
本发明中的炎症性疾病，是指因NO、iNOS、COX-2、PGE2、TNF-α等引起一系列炎症反应的多种刺激因素而诱发的炎症疾病。上述炎症性疾病包括，例如浮肿等一般性炎症症状、炎症性肠病、腹膜炎、骨髄炎、蜂巢炎、胰腺炎、创伤性休克、支气管哮喘、过敏性鼻炎、囊性纤维化、急性支气管炎、慢性支气管炎、急性细支气管炎、慢性细支气管炎、骨关节炎、痛风、脊柱关节病、强直性脊柱炎、赖特尔综合症、干癣性关节病变、与炎症性肠病相关的脊柱炎、幼年关节病、幼年强直性脊柱炎、反应性关节炎、感染性关节炎、感染后关节炎、淋菌性关节炎、结核性关节炎、病毒性关节炎、真菌性关节炎、梅毒性关节炎、莱姆病、与“血管炎综合症”相关的关节炎、结节性多动脉炎、过敏性血管炎、Luegenec’s肉芽肿症(Luegenec’sgranulomatosis)、风湿性多肌痛、关节细胞动脉炎、钙结晶沉积性关节病、假痛风、非关节性风湿症、滑囊炎、腱鞘炎、上髁炎(网球肘)、神经性关节病(neuropathic joint disease)、关节血肿(hemarthrosic)、过敏性紫癜(Henoch-Schonlein Purpura)、肥大性骨关节病、多中心网状组织细胞瘤、脊柱侧凸、血色病、血红蛋白病、高脂蛋白血症、低丙种球蛋白血症、家族性地中海热、白塞氏病(Behat’s disease)、系统性红斑狼疮、回归热、多发性硬化症、败血症、败血症性休克、急性呼吸窘迫综合症、多器官衰竭、慢性阻塞性肺疾病、类风湿性关节炎、急性肺损伤、支气管肺发育不良，但并不限制于此。进一步地，也包括急性和慢性湿疹、接触性皮炎、异位性皮炎、脂溢性皮炎、剥脱性皮炎、日光性皮炎、银屑病等炎症性皮肤病。
附图说明
图1是从肉豆蔻(Myristica fragrans)分离木酚素类化合物的流程图。
图2是本发明的木酚素类化合物的13C-NMR谱图。
图3是本发明的木酚素类化合物的1H-NMR谱图。
图4是本发明的木酚素类化合物的1H-1H COSY谱图。
图5是本发明的木酚素类化合物的1H-13C HMBC谱图。
图6是本发明的木酚素类化合物的EI-Mass谱图。
图7显示了本发明的木酚素类化合物的细胞毒性效果。
图8显示了本发明的木酚素类化合物抑制NO生成的效果。
图9显示了本发明的木酚素类化合物抑制iNOS表达的效果。
A：免疫印迹分析结果。
B：相对于LPS刺激的对照群的iNOS蛋白水平图。
图10显示了本发明的木酚素类化合物(A)及姜黄素(B)抑制PGE2生成的效果。
图11显示了本发明的木酚素类化合物抑制COX-2表达的效果。
A：免疫印迹分析结果。
B：相对于LPS刺激的对照群的COX-2蛋白水平图。
图12显示了本发明的木酚素类化合物(A)及姜黄素(B)抑制用LPS刺激的巨噬细胞生成TNF-α的效果。
图13显示了本发明的木酚素类化合物(A)及吲哚美辛(B)抑制痤疮丙酸杆菌(P.acnes)刺激的人类单核细胞U937细胞生成TNF-α的效果。
本发明的最佳实施方式
以下，通过实施例详细地说明本发明。
其中，下述实施例仅用于示例本发明，本发明的内容并不限于下述实施例。而且，在下述实施例及实验例中，百分含量没有特别表明是体积％的时候，则表示重量％。进一步地，所有的活性分析，都重复进行3次以上，其结果用平均值±标准偏差来表示。另外，统计分析是利用Students’s t-test来进行的，p<0.05时判定为具有统计学上的显著性。
实施例1
从肉豆蔻分离及纯化木酚素类化合物
<1-1>木酚素类化合物的分离及纯化
向干燥粉碎的核仁100g(干燥重量)中添加75体积％、400ml的甲醇，常温下放置2天。利用Whatman2号滤纸过滤上述溶液。重复2次上述过程。真空浓缩甲醇滤液，并冷冻干燥，制得核仁的甲醇粗提物(7g)。依次用乙酸乙酯、丁醇、水对甲醇粗提取物进行分级分离，得到乙酸乙酯分级物(4.2g)。利用硅胶柱色谱(Merck Kieselgel66；70-230目)，用己烷与乙酸乙酯以10:1(v/v)的比例混合成的溶剂洗脱乙酸乙酯分级物，得到分级物III(1.0g)。用真空旋转浓缩器，完全除去溶剂，制得核仁的粗提物。接下来，利用硅胶柱色谱(Merck Kieselgel66；70-230目)，用己烷与乙酸乙酯以20:1(v/v)的比例混合的溶剂洗脱分级物III，得到分级物III-B(0.52g)。利用Rp-18柱色谱(Merck LiChroprep；25-40μm)，用80％甲醇洗脱分级物III-B，得到单一物质分级物III-B-2(0.5g)。将如上所述的分离工序示于图1中。
<1-2>结构分析
为了确定上述分离的单一物质III-B-2的结构，分别于600MHz、150MHz(溶剂：DMSO)下测定了1H-NMR谱与13C-NMR谱。将其结果分别示于图2及图3中。为了确定基于13C-NMR谱与1H-NMR谱结果的1H-1H相互关系以及1H-13C相互关系，测定了1H-1H COSY谱与1H-13C HMBC谱。将其结果分别示于图4及图5中。对1H-NMR、13C-NMR、1H-1H COSY及1H-13C HMBC结果综合分析，并示于表1中。
表1
<1-3>质量分析
为了对上述分离的单一物质进行质量分析而测定的EI/MS的结果示于图6中。该化合物的EI/MS在m/z328时观察到[M]+，判断其分子量为328，分子式为C20H24O4。
将上述的1H-NMR、13C-NMR、1H-1H COSY、1H-13C HMBC及EI/MS的结果与已经发表的研究报告(Woo，W.S.et al.，Phytochemistry，26：1542-1543，1987)进行比较分析所鉴定的结果，可确认分离出的单一物质为用下述式1表示的肉豆蔻木酚素(macelignan)。
式1
实施例2
本发明的木酚素类化合物的细胞毒性效果的调查
<2-1>RAW264.7细胞系的培养
为了调查上述实施例1得到的肉豆蔻木酚素对炎症反应介质物质的生成产生的影响，使用了巨噬细胞RAW264.7细胞。巨噬细胞RAW264.7细胞是使用从American Tissue Culture Collection(ATCC TIB TIB-71，Rockville，MD，USA)购买的产品。在补充有热失活的10％FBS(胎牛血清，Gibco，USA)、100U/ml盘尼西林G及100μm/ml链霉素的DMEM(Dulbecco’s ModifiedEagle’s Medium，Gibco，USA)培养基上，在含有5％CO2的37℃的培养器中培养上述细胞系。
<2-2>细胞毒性的测定
为了调查本发明的肉豆蔻木酚素对RAW264.7细胞的存活率产生的影响，通过线粒体脱水素酶使MTT还原成紫色甲月替(formazan)生成物为基础进行分析(Hayon T.et al.，Leuk.Lymphoma.44(11)：1957-1962，2003)。将1×106细胞/ml的RAW264.7细胞接种到RPMI1640培养基，6小时后，用本发明的肉豆蔻木酚素以1～80μM/ml的浓度处理所述细胞。24小时后，利用MTT分析法，测定细胞存活率。
其结果是，如图7所示，本发明的肉豆蔻木酚素，在1-20μM的浓度时，对RAW264.7细胞的存活率没有大的影响。基于上述结果，接下来的炎症实验中，使用了1-20μM浓度的肉豆蔻木酚素。
实施例3
本发明的木酚素类化合物的NO抑制效果的调查
<3-1>NO生成的抑制
被IFN-γ或LPS刺激的巨噬细胞高表达iNOS，生成大量的作为炎症反应介质的物质NO(Miyasaka and Hirata.，Immunol.Today.，16：128-130，1995；Guzik et al.，J.Physiol.Pharmacol.，54(4)：469-487，2003)。因而，调查了本发明的肉豆蔻木酚素对通过LPS活化的RAW264.7细胞内NO的生成所产生的影响。
将RAW264.7细胞稀释至1×106细胞/ml的浓度后，接种至RPMI1640培养基。5小时后，添加1～20μM的各浓度的本发明的肉豆蔻木酚素，然后培养2个小时。接下来，用LPS(10μg/ml)处理培养基，并培养24小时。对照群仅用LPS处理。NO的生成量，是利用细胞培养液、通过测定NO的反应产物NO2-的方法进行定量(Han et al.，Life Sci.，75(6)：675-684，2004)。在96孔组织培养板上混合100μl培养液与相同体积的Greiss试剂(0.5％磺胺、0.05％N-(1-萘基)乙二胺二盐酸盐/2.5％H3PO4)，在常温阴暗处反应10分种。接下来，利用ELISA酶标仪，测定试样在550nm处的吸光度。NO2 -的浓度是利用NaNO3制作标准曲线，与其进行比较测定NO的生成量。所有的试验重复进行3次以上，利用student’s t-test，对其分别定量。
其结果是，如图8所示，仅通过LPS处理，NO的生成被大幅地增强，并确认了通过本发明的肉豆蔻木酚素的处理，能够浓度依赖性地抑制该增强。特别是，在1μM与5μM的低浓度下，也确认了抑制NO生成的效果优异(P<0.01)。另外，用20μM肉豆蔻木酚素处理时，其抑制NO生成的程度达到与未经任何处理群近乎相似的程度。
<3-2>iNOS表达的抑制
用LPS刺激巨噬细胞，iNOS被过量表达的同时生成大量的NO。因此，为了调查上述实施例<3-1>中确认的本发明的肉豆蔻木酚素对NO生成的抑制与iNOS的关系，测定了上述肉豆蔻木酚素对iNOS的表达产生的影响。
溶解用本发明的肉豆蔻木酚素及LPS处理的RAW264.7细胞，用考马斯亮兰(Bradford assay)方法定量蛋白质。用10％SDS-PAGE分离蛋白质10μg，然后利用转移溶液(转移溶液；20％甲醇，25mM Tris，192mM氨基乙酸，pH8.3)将上述分离的蛋白质移至硝化纤维素膜上(Hall，Methods Mol.Biol.，261：167-174，2004)。使SDS-聚丙烯酰胺凝胶与硝化纤维素膜紧密接触，并装入微型凝胶转移试剂盒中。接下来，将样品装载到试剂盒中，在100V下电泳移动1小时。接下来，用TBST(Tris缓冲生理盐水吐温20，trisbuffered saline tween-20)溶液洗涤膜1次，将上述膜移至干燥的滤纸上，在常温下进行干燥。为了除去非特异反应，用含有5％脱脂乳的TBST在4℃下充分振动24小时以上，然后放置。接下来，用TBST溶液洗涤膜3次，然后注入抗-iNOS抗体(1:2,000)(Calbiochem)，在室温下反应1小时。再次利用TBST溶液将膜洗涤3次，每次洗涤10分钟。注入结合有HRP(辣根过氧化物酶)的抗-兔IgG-HRP(1:2,000)(Calbiochem)，在震荡器上反应1小时。接下来，再次用TBST溶液洗涤上述膜3次后，浸泡在ECL(增强化学发光)溶液中，在振动1分钟的同时，使其全部被浸渍。上述ECL溶液的制造，是通过相同量地混合溶液A(含有发光氨与增强剂)与溶液B(含有过氧化氢)，振动1分钟而制造。从上述ECL溶液取出上述膜，除去水分，在暗室中用X射线胶片扫描。
其结果是，如图9所示，确认本发明的肉豆蔻木酚素能够浓度依赖性地抑制巨噬细胞中的iNOS的表达，从5μM开始抑制效果显著(P<0.01)。从上述结果能够确认本发明的肉豆蔻木酚素不仅抑制炎症诱发因子NO的生成，也抑制了生成该因子的iNOS的表达。
实施例4
本发明的木酚素类化合物的COX-2抑制效果的调查
<4-1>PEG2生成的抑制
类似于iNOS同炎症反应密切相关，COX-2是作为炎症反应介质的PG类生成中必须的酶，已知iNOS与COX的表达及活性相互关联(Surh et al.，Mutat.Res.，481：243-268，2001)。因此，调查了本发明的肉豆蔻木酚素对LPS活化的巨噬细胞的PGE2的生成产生的影响。
首先，将1×106细胞/ml的RAW264.7细胞接种至96孔组织培养板上，常温下放置5小时。接下来，分别添加1～20μM浓度的本发明的肉豆蔻木酚素，培养2小时。在阴性对照群中，不进行任何处理；阳性对照群中，进行已报道过的具有PGE2抑制活性的姜黄素(curcumin)(是从姜黄(Curcumalonga)分离的物质，Sigma社制造)处理。接下来，用1μg/ml的LPS处理细胞，并培养18小时。利用检测试剂盒(R&D System Inc，Minneopolis，USA)，用ELISA法定量巨噬细胞中的PGE2的生成量(Chen et al.，Biochem.Pharmacol.，68：1089-1100，2002)。
其结果是，如图10所示，通过LPS单独处理时PGE2被大量生成，能够确认通过本发明的肉豆蔻木酚素的处理，可浓度依赖性地抑制该生成。其抑制效果即使在5μM时也能表现出来。如上所述的本发明的肉豆蔻木酚素抑制PGE2生成的效果与用姜黄素处理的效果近乎相似，显示出与实施例3中确认的NO及iNOS的抑制效果的相同模式(P<0.05)。
<4-2>COX-2表达的抑制
本发明人利用免疫印迹分析，调查了对PGE2生成产生直接影响的COX-2的表达。除了作为一次抗体使用抗-COX-2抗体(1:2,000)(Calbiochem社制造)、作为二次抗体使用抗-山羊IgG-HRP(1:2,000)(Calbiochem社制造)以外，以与上述实施例<3-2>中记载的相同方法进行。
其结果是，如图11所示，确认了本发明的肉豆蔻木酚素能够浓度依赖性地抑制COX-2蛋白的表达。特别是，10-20μM的浓度时表达量明显地減少。
从上述结果能够确认本发明的肉豆蔻木酚素不仅抑制作为炎症诱发因子的PGE2的生成，也抑制生成它的COX-2的表达。
实施例5
本发明的木酚素类化合物的TNF-α抑制效果的调查
TNF-α是对炎症反应有重要作用的炎症细胞因子。因此，调查了本发明的肉豆蔻木酚素对TNF-α的生成的影响。
<5-1>巨噬细胞株中的TNF-α生成的抑制
首先，将1×106细胞/ml的RAW264.7细胞接种至96孔组织培养板上，常温下放置5小时。接下来，分别添加1～20μM浓度的本发明的肉豆蔻木酚素，培养2小时。对阴性对照群不施加任何处理，对阳性对照群用姜黄素(Sigma)处理(Araujo and Leon，Mem.Inst.Oswaldo.Cruz.，96(5)：723-728，2001；Chainani-Wu，J.Altern.Complement.，9(1)：161-168，2003)。接下来，用1μg/ml的LPS处理，培养18小时。利用检测试剂盒(R&DSystem Inc，Minneopolis，USA)，用ELISA法定量巨噬细胞中的TNF-α的生成量(Chen et al.，J.Dermatol.Sci.29：97-103，2002)。其结果是，如图12所示，用本发明的肉豆蔻木酚素处理时，从5μM开始显示出了TNF-α的生成有明显的减少(P<0.05)。
<5-2>人类单核细胞中的TNF-α生成的抑制
本发明人用与上述实施例<5-1>相同的方法测定了用痤疮丙酸杆菌(Propionibacterium acnes)活化的人类单核细胞(Human monocytic)U937细胞中的TNF-α的生成量。其中，阳性对照群使用吲哚美辛(Sigma)进行处理(Walch and Morris，Endocrinology.143(9)：3276-3283，2002)。
其结果是，如图13所示，能够确认本发明的肉豆蔻木酚素可浓度依赖性地減少人类单核细胞中的TNF-α的生成(P<0.01)。
从上述结果能够确认本发明的肉豆蔻木酚素抑制诱发和/或介导急性炎症及全身炎症反应的介质TNF-α的生成。
实施例6
利用动物实验对本发明的木酚素类化合物的抗炎症活性进行调查
通过动物实验确认上述实施例1中分离纯化的木酚素类化合物的抗炎活性。通过对大鼠的浮肿抑制实验，测定上述抗炎活性。实验动物采用5周龄的Wistar大鼠(DaeHan Biolink Co.，Ltd，韩国)。饲料供给标准鼠饲料(Cheiljedang Corporation，Korea)，并自由供给饲料与水。大鼠是在12小时的荧光灯日照、25±2℃及60±10％湿度的条件下进行饲养。作为炎症引发剂的TPA(佛波酯(12-O-tetradecanoylphorbol-13-acetate)；Sigma)，在丙酮中溶解达到200μg/mL。大鼠耳的浮肿，是通过在耳廓的外面与内面局部分别涂敷10μl/耳(4μg/耳)的TPA溶液而引发。将实施例1中生成的纯的肉豆蔻木酚素和作为对照物质的非甾体类抗炎药吲哚美辛溶解在丙酮中，且其使用量为20,200和2000μg/耳。将肉豆蔻木酚素与吲哚美辛分别局部涂布在用TPA处理30分钟后的大鼠耳上。对照群局部涂布丙酮。用各物质处理8小时后，利用卡尺(calliper)测定大鼠耳的厚度。样品处理群的耳厚度的增加，与未经样品处理群相比较，通过计算浮肿抑制百分率，测定炎症抑制效果。将其结果示于下述表2中。
表2
*p<0.01
实施例7
含有肉豆蔻木酚素的乳膏的制造及其抗炎症活性调查
<7-1>含有肉豆蔻木酚素的乳膏的制造
利用本发明的肉豆蔻木酚素，分别制造具有下述表3中记载的多种组成的膏霜剂。首先，在75-80℃下溶解下述表3中用B表示的物质。进一步，在相同温度下溶解下述表3中用C表示的物质中的十六醇与防腐剂。将上述C物质在上述B物质中乳化。接下来，分别以5.0、0.5、0.05、0.005％的浓度投入下述表3中用A表示的本发明的肉豆蔻木酚素，进行混合。最后，加入香料和余量的纯化水，制得乳膏。
表3
<7-2>抗炎症活性调查
通过对大鼠的浮肿抑制实验，测定上述实施例<7-1>中制造的含有肉豆蔻木酚素的乳膏的抗炎症活性。浮肿抑制实验以与实施例6相同的方法进行实施。将其结果示于下述表4中。
表4
| 试样 | 1 | 2 | 3 | 4 |
| 肉豆蔻木酚素的含量 | 0.005％ | 0.05％ | 0.5％ | 5％ |
| 浮肿抑制率(％) | 14.2 | 42.3 | 64.6 | 88.7 |
从上述表4的结果可知，含有本发明的肉豆蔻木酚素的乳膏以乳膏内含有的肉豆蔻木酚素的浓度依赖性地抑制TPA诱发的大鼠的浮肿。
实施例8
肉豆蔻提取物的抗炎症活性调查
<8-1>甲醇提取物的制备
往100g干燥粉碎的核仁(干燥重量)中添加95体积％、400ml的甲醇，在常温下放置2天。利用Whatman2号滤纸过滤上述溶液。重复两次上述过程。真空浓缩并冷冻干燥甲醇滤液，制得甲醇粗提物(16.2g)。
<8-2>己烷提取物的制备
往100g干燥粉碎的核仁(干燥重量)中添加100体积％、400ml的己烷，在常温下放置2天。利用Whatman2号滤纸过滤上述溶液。重复两次上述过程。真空浓缩并冷冻干燥己烷滤液，制得己烷粗提物(37.0g)。
<8-3>利用动物实验进行肉豆蔻提取物的抗炎症活性调查
通过动物实验，确认了上述实施例<8-1>及<8-2>制造的肉豆蔻提取物的抗炎活性。通过与上述实施例6相同的方法，利用对大鼠的浮肿抑制实验，测定了上述抗炎活性。其结果如下述表5所示。
表5
*p<0.01
如上述表5所示，能够确认本发明的肉豆蔻的甲醇粗提物与己烷粗提物，全都能够浓度依赖性地抑制TPA诱发的大鼠浮肿(统计学上的显著性p<0.01)。
制备例1
含有本发明的治疗或预防炎症性疾病的药物组合物的药剂的制备
<1-1>片剂的制造
将25mg本发明的木酚素类化合物或肉豆蔻提取物、26mg作为直接压片用赋形剂的乳糖、3.5mg Avicel(微晶纤维素)、1.5mg作为崩解辅助剂的葡萄糖酸淀粉钠、以及8mg作为粘结剂的直接压片用的L-HPC(低取代羟丙基纤维素)一起加入U型混合机中，混合20分钟。混合结束后，再添加1mg作为润滑剂的硬脂酸镁，混合3分钟。经过定量分析与湿度含量分析，压片、包膜，制成片剂。
<1-2>糖浆的制备
通过如下所述的方法，制备将本发明的肉豆蔻木酚素或其药学上可接受的盐作为2％(w/v)的有效成分而含有的糖浆。将2g本发明的肉豆蔻木酚素的酸加成盐、0.8g糖精及25.4g糖，溶解到80g温水中。冷却上述溶液后，往其中加入8.0g丙三醇、0.04g香料、4.0g乙醇、0.4g山梨酸及适量的蒸馏水加以混合。往上述混合物中添加水至100ml。
<1-3>胶囊的制备
混合50mg本发明的木酚素类化合物或肉豆蔻提取物、50mg乳糖、50mg淀粉、1mg滑石粉、及适量的硬脂酸镁，将其填充至硬明胶胶囊中，制成胶囊剂。
<1-4>注射液的制备
按照如下所述的方法，制造含有10mg有效成分的注射液：将1g本发明的肉豆蔻木酚素的盐酸盐、0.6g氯化钠及0.1g抗坏血酸溶解在蒸馏水中，制成100ml的溶液。将上述溶液装入瓶中，并在20℃下加热30分钟灭菌。
应用例1
胃炎消化性疾病
已知胃炎与多种外部原因及不规则的饮食习惯有关，但主要由受肠道细菌Helicobacter pylori影响。肠道细菌Helicobacter pylori，不仅能够引起胃溃疡、胃炎，甚至会引起胃癌。肠道细菌Helicobacter pylori增殖过程中，COX-2酶(环氧化酶-2)也同时增加(Nam N.T.et al.，Clin.CancerRes.10(23)：8105-8113，2004)。当被Helicobacter pylori感染时，胃的粘膜细胞会增殖成癌细胞，但确认了COX-2抑制剂能够阻止胃粘膜细胞生长增殖成癌细胞，并且抑制从正常组织演变成癌组织。已发现，使用COX-2抑制剂群与未使用群相比，在通过凋亡方法使癌组织死亡的效果方面非常优异(Nam N.T.et al.，Clin.Cancer Res.10(23)：8105-8113，2004)。因此，本发明的木酚素类化合物的COX-2抑制效果，能够在早期预防胃癌的胃炎治疗中起作用，从而具有充分的治疗效果。
应用例2
关节炎
关节炎由自身免疫异常引起，但在病情发展的同时，关节间的滑液腔上产生慢性炎症，诱使血管增生因而破坏软骨。关节炎包括感染性关节炎、退行性关节炎、类风湿性关节炎、股骨头缺血性坏死、强直性脊柱炎、先天性畸形引起的关节炎等多种。不管是何种原因，已知在病情发展的过程中，滑液腔上出现的慢性炎症诱使血管增生，并且具有新的毛细血管侵袭关节导致损伤软骨的特征(Kocb A.E.et al.，Arth.Rheum.，29：471-479，1986；Stupack D.G.et al.，J.Med.Biol.Rcs.，32：578-281，1999；Koch A.E.，Arthritis Rheum.，41：951-962，1998)。已有报道，根据疾病种类，炎症反应发生在几个步骤而破坏软骨，在疾病的发展过程中起到了重要的作用，并且关节内的新毛细血管的形成作为重要的病理机理而起作用(Colville-Nash，P.R.et al.，Ann.Rheum.Dis.，51，919-925，1992；Eisenstein，R.，Pharmacol.Ther.，49：1-19，1991)。关节炎的治疗，与根据原因来治疗相比，优选抑制疼痛和感染现象，最大限度地抑制关节或肌肉等的破坏速度、使功能消失最小化。因此，本发明的木酚素类化合物或肉豆蔻提取物，对防止与治疗关节炎的发展极为有效。
工业实用性
如上所述，本发明的木酚素类化合物，通过阻碍炎症介质因子NO、iNOS、PGE2、COX-2及TNF-α的生成或表达，有抑制炎症反应的效果。因此，本发明的木酚素类化合物或肉豆蔻提取物能够极其有效地用于炎症性疾病的治疗或预防中。
Claims (2)
1.通式I表示的木酚素类化合物在制造治疗或预防炎症性疾病的药物组合物中的用途：
其中，R1及R2独立地是C1-5烷氧基或羟基；R3是
2.根据权利要求1所述的用途，其特征在于，R1是甲氧基，R2是羟基，R3是
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| Application Number | Priority Date | Filing Date | Title |
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| KR10-2005-0001761 | 2005-01-07 | ||
| KR1020050001761 | 2005-01-07 | ||
| KR1020050001761A KR100579752B1 (ko) | 2004-09-07 | 2005-01-07 | 리그난계 화합물을 함유하는 염증성 질환의 치료 또는예방용 약학적 조성물 |
| PCT/KR2006/000065 WO2006073285A1 (en) | 2005-01-07 | 2006-01-06 | Use of lignan compounds for treating or preventing inflammatory disease |
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| CN101102761B true CN101102761B (zh) | 2010-09-29 |
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| JP (1) | JP4956440B2 (zh) |
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| US7902254B1 (en) * | 2005-06-27 | 2011-03-08 | Newtree Co., Ltd. | Method for treating conditions mediated by PPAR using macelignan |
| CN101827579B (zh) * | 2007-10-17 | 2013-01-23 | 生物关怀有限公司 | 木酚素系化合物或含有该化合物的肉豆蔻提取物或肉豆蔻假种皮提取物的新用途 |
| KR20100049272A (ko) * | 2008-11-03 | 2010-05-12 | 에스케이케미칼주식회사 | 과민성 장 증후군의 예방 및 치료용 조성물 |
| US20100160351A1 (en) * | 2008-12-19 | 2010-06-24 | Nuon Therapeutics, Inc. | Pharmaceutical compositions and methods for treating hyperuricemia and related disorders |
| WO2010071865A1 (en) | 2008-12-19 | 2010-06-24 | Nuon Therapeutics, Inc. | Pharmaceutical compositions and methods for treating hyperuricemia and related disorders |
| KR101062670B1 (ko) * | 2009-06-01 | 2011-09-06 | (주)아모레퍼시픽 | 2,5-비스-아릴-3,4-디메틸테트라하이드로퓨란 리그난을 유효성분으로 포함하는 에이엠피케이의 활성화에 의해 매개되는 비만 관련 질환의 예방 또는 치료용 조성물 |
| WO2011032175A1 (en) | 2009-09-14 | 2011-03-17 | Nuon Therapeutics, Inc. | Combination formulations of tranilast and allopurinol and methods related thereto |
| US9962326B2 (en) | 2010-08-19 | 2018-05-08 | Johnson & Johnson Consumer Inc. | Compositions comprising paulownia tomentosa wood extracts and uses thereof |
| US9168219B2 (en) | 2010-08-19 | 2015-10-27 | Johnson & Johnson Consumer Inc. | Compositions comprising Paulownia tomentosa wood extracts and uses thereof |
| US9161958B2 (en) | 2010-08-19 | 2015-10-20 | Johnson & Johnson Consumer Inc. | Methods of treating cellulite |
| US9168207B2 (en) | 2010-08-19 | 2015-10-27 | Johnson & Johnson Consumer Inc. | Compositions comprising Paulownia tomentosa wood extracts and uses thereof |
| US9387349B2 (en) | 2010-08-19 | 2016-07-12 | Johnson & Johnson Consumer Inc. | Compositions comprising Paulownia tomentosa wood extracts and uses thereof |
| US9168279B2 (en) | 2010-08-19 | 2015-10-27 | Johnson & Johnson Consumer Inc. | Compositions comprising paulownin and/or Paulownia extracts and uses thereof |
| US9173913B2 (en) | 2010-08-19 | 2015-11-03 | Johnson & Johnson Consumer Inc. | Compositions comprising Paulownia tomentosa wood extracts and uses thereof |
| WO2012024399A2 (en) * | 2010-08-19 | 2012-02-23 | Johnson & Johnson Consumer Companies, Inc. | Compositions comprising paulownin and/or paulownia extracts and uses thereof |
| CN103893226A (zh) * | 2012-12-28 | 2014-07-02 | 中国科学院上海生命科学研究院湖州营养与健康产业创新中心 | 肉豆蔻提取物的应用 |
| CN104706688A (zh) * | 2013-12-11 | 2015-06-17 | 中国科学院上海生命科学研究院湖州营养与健康产业创新中心 | 一种肉豆蔻总木脂素有效部位的制备方法 |
| KR101787458B1 (ko) * | 2016-04-15 | 2017-10-19 | 부산대학교 산학협력단 | 육두구 추출물을 포함하는 자궁내막증의 예방 또는 치료용 조성물 |
| KR20190093395A (ko) * | 2018-02-01 | 2019-08-09 | 한국기초과학지원연구원 | 육두구 추출물을 유효성분으로 포함하는 체력 또는 운동수행능력 향상용 조성물 |
| CN111773293A (zh) * | 2020-06-28 | 2020-10-16 | 和田地区维吾尔医医院 | 治疗类风湿性关节炎的药物组合物 |
| TW202320749A (zh) * | 2021-10-08 | 2023-06-01 | 學校法人神戶學院 | 腸炎抑制用組成物 |
| CN113956229B (zh) * | 2021-12-20 | 2022-03-08 | 江西中医药大学 | 一种紫丁香中的木脂类化合物及其制备方法与应用 |
| CN115054598A (zh) * | 2022-05-24 | 2022-09-16 | 核工业总医院 | 小分子化合物在制备治疗多发性骨髓瘤药物中的应用 |
| CN115624542A (zh) * | 2022-10-21 | 2023-01-20 | 苏州科技城医院 | 肉豆蔻木脂素在制备治疗骨性关节炎药物中的应用 |
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| KR100542323B1 (ko) * | 2002-12-27 | 2006-01-11 | 한국생명공학연구원 | 후박나무로부터 세포사멸 유도작용을 갖는 화합물을 분리하는 방법 |
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- 2006-01-06 CN CN2006800019887A patent/CN101102761B/zh active Active
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Also Published As
| Publication number | Publication date |
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| CN101102761A (zh) | 2008-01-09 |
| JP2008526834A (ja) | 2008-07-24 |
| WO2006073285A1 (en) | 2006-07-13 |
| US20080114058A1 (en) | 2008-05-15 |
| JP4956440B2 (ja) | 2012-06-20 |
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