CN116710105A - 肺纤维化治疗剂 - Google Patents
肺纤维化治疗剂 Download PDFInfo
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- CN116710105A CN116710105A CN202180079446.6A CN202180079446A CN116710105A CN 116710105 A CN116710105 A CN 116710105A CN 202180079446 A CN202180079446 A CN 202180079446A CN 116710105 A CN116710105 A CN 116710105A
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- pulmonary fibrosis
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- A61K31/66—Phosphorus compounds
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本发明的课题为提供治疗效果高的肺纤维化治疗剂。根据本发明,提供含有以下述式(1)表示的化合物作为有效成分的肺纤维化治疗剂。式中,R是碳原子数1~30的直链状或分支状烷基、碳原子数2~30的直链状或分支状烯基或者碳原子数2~30的直链状或分支状炔基,这些基团也可含有环烷烃环或芳环。X和Y各自独立地表示氧原子或亚甲基,但X和Y不同时为亚甲基。M是氢原子或碱金属原子。
Description
技术领域
本发明涉及以环状磷脂酸或卡巴环状磷脂酸(carbacyclic phosphatidic acid)或其结晶形式作为有效成分的肺纤维化治疗剂。
背景技术
肺纤维化是指肺组织因过剩的胶原和其它细胞外基质的蓄积而纤维化的症状。在肺纤维化中,特发性肺纤维化是中位生存期平均为3年,5年生存率为20~40%的预后不良的慢性难治性疾病。尽管特发性肺纤维化是预后差的疾病,但几乎不存在值得推荐的药物治疗。以往暂且使用类固醇或免疫抑制剂,但近年来累积了它们使预后恶化的证据,成为了不推荐的治疗。吡非尼酮、尼达尼布等抗纤维化药经过科学验证试验而被引入市场,开始作为新的治疗药使用,但需要开发更有效的治疗药。
本发明人发现特定的环状磷脂酸衍生物及其盐对类风湿性关节炎或变形性关节病等关节病(专利文献1)、特应性皮炎(专利文献2)以及抑制癌的转移和浸润(专利文献3)等具有优异的预防、治疗效果。
现有技术文献
专利文献
专利文献1:日本特许第5465815号公报,
专利文献2:日本特开2012-056853号公报,
专利文献3:日本特许第4163007号公报。
发明内容
发明所要解决的课题
如上所述,虽然已知特定的环状磷脂酸衍生物及其盐显示某些药理效果,但不知道环状磷脂酸衍生物及其盐对肺纤维化具有治疗效果。
本发明以提供治疗效果高的肺纤维化治疗剂为课题。
解决课题的手段
本发明人为了解决上述课题而进行了深入研究,结果发现,环状磷脂酸及其衍生物具有治疗肺纤维化的效果,从而完成了本发明。
根据本发明,提供以下发明。
<1>肺纤维化治疗剂,其含有以下述式(1)表示的化合物作为有效成分:
[化学式1]
式中,R是碳原子数1~30的直链状或分支状烷基、碳原子数2~30的直链状或分支状烯基或者碳原子数2~30的直链状或分支状炔基,这些基团也可含有环烷烃环或芳环;X和Y各自独立地表示氧原子或亚甲基,但X和Y不同时为亚甲基;M是氢原子或碱金属原子。
<2>根据<1>所述的肺纤维化治疗剂,其中在式(1)中,X或Y的其中一个为氧原子,另一个为亚甲基。
<3>根据<1>或<2>所述的肺纤维化治疗剂,其中以式(1)表示的化合物是1-油酰基环状磷脂酸或1-棕榈油酰基环状磷脂酸及其衍生物的卡巴环状磷脂酸。
根据本发明,进一步提供包括将以上述式(1)表示的化合物给药于肺纤维化的患者的肺纤维化的治疗方法。
根据本发明,进一步提供用于在肺纤维化的治疗中使用的以上述式(1)表示的化合物。
根据本发明,进一步提供用于制造肺纤维化治疗剂的以上述式(1)表示的化合物的用途。
发明效果
根据本发明,可提供治疗效果高的肺纤维化治疗剂。
附图说明
[图1]图1显示2ccPA对博来霉素诱发肺纤维化模型小鼠的右肺湿重的效果。
[图2]图2显示2ccPA对博来霉素诱发肺纤维化模型小鼠的右肺干重的效果。
[图3]图3显示2ccPA对博来霉素诱发肺纤维化模型小鼠的右肺羟基脯氨酸的效果。
具体实施方式
以下,对本发明更具体地进行说明。
本发明的肺纤维化治疗剂可用于肺纤维化的治疗。作为引起肺的纤维化的疾病,可列举出间质性肺炎、囊性纤维化、慢性阻塞性肺病(COPD:Chronic obstructivepulmonary disease)、急性呼吸窘迫综合征(ARDS:Acute respiratory distresssyndrome)、炎症性肺病、肺感染、放射性肺炎、药物性间质性肺炎、伴随胶原性疾病的间质性肺炎等,特别优选原因不明的特发性间质性肺炎中的特发性肺纤维化。在特发性间质性肺炎(IIP)中,作为临床病理学疾病,包含特发性肺纤维化(IPF)、非特异性间质性肺炎(NSIP)、特发性机化性肺炎(COP/BOOP)、急性间质性肺炎(AIP)、剥脱性间质性肺炎(DIP)、伴随呼吸性细支气管炎的间质性肺病(RB-ILD)、淋巴细胞间质性肺炎(LIP)等。
本发明的肺纤维化治疗剂含有环状磷脂酸或卡巴环状磷脂酸或其盐作为有效成分。作为环状磷脂酸或卡巴环状磷脂酸或其盐,只要是显示本发明的效果的物质,则没有特别限定,但优选可使用以下述式(I)表示的化合物。
[化学式2]
(式中,R是碳原子数1~30的直链状或分支状烷基、碳原子数2~30的直链状或分支状烯基或者碳原子数2~30的直链状或分支状炔基,这些基团也可含有环烷烃环或芳环。X和Y各自独立地表示氧原子或亚甲基,但X和Y不同时为亚甲基。M是氢原子或碱金属原子。)
在式(I)中,作为取代基R所示的碳原子数1~30的直链状或分支状烷基的具体实例,例如可列举出甲基、乙基、丙基、丁基、戊基、己基、庚基、辛基、壬基、癸基、十一烷基、十二烷基、十三烷基、十四烷基、十五烷基、十六烷基、十七烷基、十八烷基、十九烷基、二十烷基等。
作为取代基R所示的碳原子数2~30的直链状或分支状烯基的具体实例,例如可列举出烯丙基、丁烯基、辛烯基、癸烯基、十二碳二烯基、十六碳三烯基等,更具体而言,可列举出8-癸烯基、8-十一烯基、8-十二烯基、8-十三烯基、8-十四烯基、8-十五烯基、8-十六烯基、8-十七烯基、8-十八烯基、8-二十烯基、8-二十二烯基、十七碳-8,11-二烯基、十七碳-8,11,14-三烯基、十九碳-4,7,10,13-四烯基、十九碳-4,7,10,13,16-五烯基、二十一碳-3,6,9,12,15,18-六烯基等。
作为取代基R所示的碳原子数2~30的直链状或分支状炔基的具体实例,例如可列举出8-癸炔基、8-十一炔基、8-十二炔基、8-十三炔基、8-十四炔基、8-十五炔基、8-十六炔基、8-十七炔基、8-十八炔基、8-二十炔基、8-二十二炔基、十七碳-8,11-二炔基等。
作为上述烷基、烯基或炔基中可含有的环烷烃环的具体实例,例如可列举出环丙烷环、环丁烷环、环戊烷环、环己烷环、环辛烷环等。环烷烃环也可含有1个以上的杂原子,作为这样的实例,例如可列举出环氧乙烷环、氧杂环丁烷环、四氢呋喃环、N-甲基吡咯烷环等。
作为上述烷基、烯基或炔基中可含有的芳环的具体实例,例如可列举出苯环、萘环、吡啶环、呋喃环、噻吩环等。
因此,作为在取代基R是被环烷烃环取代的烷基的情况下的具体实例,例如可列举出环丙基甲基、环己基乙基、8,9-桥亚甲基十五烷基等。
作为在取代基R是被芳环取代的烷基的情况下的具体实例,可列举出苄基、苯乙基、对戊基苯基辛基等。
R优选为碳原子数9~17的直链状或分支状烷基、碳原子数9~17的直链状或分支状烯基或者碳原子数9~17的直链状或分支状炔基。R进一步优选为碳原子数9、11、13、15或17的直链状或分支状烷基,或者碳原子数9、11、13、15或17的直链状或分支状烯基。R特别优选为碳原子数9、11、13、15或17的直链状或分支状烯基。
以通式(1)表示的化合物中的X和Y各自独立地表示氧原子(-O-)或亚甲基(-CH2-),但X和Y不同时为亚甲基。即,X和Y的组合为以下3种。
(1)X为氧原子,Y为氧原子。
(2)X为氧原子,Y为亚甲基。
(3)X为亚甲基,Y为氧原子。
以式(I)表示的环状磷脂酸衍生物中的M是氢原子或碱金属原子。作为碱金属原子,例如可列举出锂、钠、钾等,特别优选为钠。
作为本发明中使用的以式(1)表示的化合物的具体实例,特别优选具有R是碳原子数17的烯基的油酰基(简写为C18:1)、R是碳原子数15的烯基的棕榈油酰基(简写为C16:1)作为1位酰基的环状磷脂酸及卡巴环状磷脂酸衍生物。
式(I)的化合物根据其取代基的种类,有时存在如位置异构体、几何异构体、互变异构体或光学异构体那样的异构体,所有可能的异构体以及以任意的比率含有2种以上的该异构体的混合物也在本发明的范围内。
另外,式(I)的化合物有时也以与水或各种溶剂的加成物(水合物或溶剂合物)的形式存在,这些加成物也在本发明范围内。此外,式(I)的化合物及其盐的任意结晶形式也在本发明的范围内。
作为以式(1)表示的化合物的结晶形式,例如可列举出日本特许第6736466号公报所记载的环状膦酸钠盐的结晶等。在日本特许第6736466号公报中,记载了通过以下来制造环状磷酸钠盐的结晶:使环状膦酸酯和卤化钠在有机溶剂中反应,得到2ccPA的工序;以及通过将在上述工序中得到的含有2ccPA的溶液在减压下浓缩,或将在上述工序中得到的含有2ccPA的溶液冷却,使结晶析出的工序。以式(1)表示的化合物的结晶形式可通过日本特许第6736466号公报所记载的方法制造,也可通过上述以外的方法制造。
以通式(1)表示的化合物中X和Y为氧原子的化合物例如可依据日本特开平5-230088号公报、日本特开平7-149772号公报、日本特开平7-258278号公报、日本特开平9-25235号公报所记载的方法等进行化学合成。
另外,以通式(1)表示的化合物中X和Y为氧原子的化合物也可依据日本特开2001-178489号公报所记载的方法,通过使磷酯酶D作用于溶血型磷脂来合成。这里所使用的溶血型磷脂只要是可作用磷酯酶D的溶血型磷脂,则没有特别限定。溶血型磷脂已知有很多种类,已知有脂肪酸种类不同的溶血型磷脂、具有醚键或乙烯基醚键的分子种类等,它们可作为市售品获取。作为磷酯酶D,来源于甘蓝或花生等高等植物的磷酯酶D或来源于色褐链霉菌(Streptomyces chromofuscus)、马杜拉放线菌属物种(Actinomadula sp.)等微生物的磷酯酶D可作为市售试剂获取,但由来源于马杜拉放线菌属物种(Actinomadula sp.)No.362的酶极其选择性地合成环状磷脂酸(日本特开平11-367032号说明书)。溶血型磷脂与磷酯酶D的反应只要是酶可表现活性的条件,则没有特别限定,例如通过在含有氯化钙的乙酸缓冲液(pH5~6左右)中从室温起在加热下(优选为37℃左右)反应1~5小时左右来进行。生成的环状磷脂酸衍生物可依据常规方法,通过提取、柱色谱法、薄层色谱法(TLC)等进行纯化。
另外,以通式(1)表示的化合物中X为氧原子、Y为亚甲基的化合物可依据文献记载的方法(Kobayashi,S.等人,Tetrahedron Letters 34,4047-4050(1993))进行合成,或可通过国际公开WO2002/094286号公报所记载的方法进行合成。具体的合成路径的一个实例如下所示。
[化学式3]
在上述中,首先,用BF3·Et2O活化市售的(R)-苄基缩水甘油醚(1),使n-BuLi作用于甲基膦酸二甲酯而得到的锂体反应,由此得到醇(2)。
在甲苯中使用过剩的对甲苯磺酸的吡啶盐使所得的醇在80℃下反应,由此得到环化体(3)。在氢气氛下使用20% Pd(OH)2-C将该环化体加氢分解,进行脱苄基化(4)。使用1-乙基-3-(3-二甲基氨基丙基)碳化二亚胺盐酸盐作为缩合剂,使其与脂肪酸反应,得到偶联体(5)。接着,使用溴三甲基硅烷作为亲核剂,仅将甲基位置选择性地除去,得到环状膦酸(6)。使用乙醚将其移入分液漏斗中,滴加少量的0.02N氢氧化钠水溶液,进行分液操作,提取、纯化作为钠盐(7)的目标化合物。
另外,以通式(1)表示的化合物中X为亚甲基、Y为氧原子的化合物可通过日本特开2004-010582号公报或国际公开WO03/104246号公报所记载的方法进行合成。
本发明的肺纤维化治疗剂优选以含有1种或2种以上的制剂学上可容许的制剂用添加剂和作为有效成分的以式(1)表示的化合物的药物组合物的形式提供。
本发明的肺纤维化治疗剂可以各种形式给药,作为优选的给药形式,可以是经口给药,也可以是非经口给药(例如向静脉内、肌肉内、皮下或皮内等的注射,直肠内给药,经粘膜给药等)。作为适合于经口给药的药物组合物,例如可列举出片剂、颗粒剂、胶囊剂、散剂、溶液剂、混悬剂、糖浆剂等,作为适合于非经口给药的药物组合物,例如可列举出注射剂、输液剂、栓剂、经皮吸收剂等,本发明的药剂的剂型不限于此。另外,本发明的肺纤维化治疗剂还可以是吸入剂。在吸入剂的情况下,给药途径可列举出经口给药或经鼻给药。此外,还可通过公知的技术制成持久性制剂。
用于制造本发明的肺纤维化治疗剂的制剂用添加剂的种类没有特别限定,本领域技术人员可适当选择。例如,可使用赋形剂、崩解剂或崩解助剂、粘合剂、润滑剂、包衣剂、基质、溶解剂或溶解助剂、分散剂、悬浮剂、乳化剂、缓冲剂、抗氧化剂、防腐剂、等渗剂、pH调节剂、溶解剂、稳定剂等,用于这些目的的各个具体成分是本领域技术人员众所周知的。
作为可用于调制经口给药用制剂的制剂用添加剂,例如可使用葡萄糖、乳糖、D-甘露醇、淀粉或结晶纤维素等赋形剂;羧甲基纤维素、淀粉或羧甲基纤维素钙等崩解剂或崩解助剂;羟丙基纤维素、羟丙基甲基纤维素、聚乙烯吡咯烷酮或明胶等粘合剂;硬脂酸镁或滑石粉等润滑剂;羟丙基甲基纤维素、白糖、聚乙二醇或氧化钛等包衣剂;凡士林、液体石蜡、聚乙二醇、明胶、高岭土、甘油、纯化水或固体脂肪等基质。
作为可用于调制注射或输液用制剂的制剂用添加剂,可使用注射用蒸馏水、生理盐水、丙二醇、表面活性剂等能够构成水性或用时溶解型注射剂的溶解剂或溶解助剂;葡萄糖、氯化钠、D-甘露醇、甘油等等渗剂;无机酸、有机酸、无机碱或有机碱等pH调节剂等制剂用添加剂。
本发明的肺纤维化治疗剂可给药于人等哺乳动物。
本发明的肺纤维化治疗剂的给药量应根据患者的年龄、性别、体重、症状和给药途径等条件适当增减,一般来说,作为成人每一日的有效成分的量,为约1μg/kg~1,000mg/kg左右的范围,优选为约10μg/kg~100mg/kg左右的范围。上述给药量的药剂可一天一次给药,也可分成数次(例如2~4次左右)给药。
通过以下的实施例来具体地说明本发明,但本发明不受实施例限定。
实施例
<材料及方法>
(1)受试物质及介质
(1-1)受试物质
2-卡巴环状磷脂酸(2ccPA):
[化学式4]
(1-2)介质
日本药局方生理盐水(生理盐水)
(2)试验系统
小鼠Crl:CD1(ICR),45只,雄性,从Charles River Laboratories Japan,Inc.购入(购入时11周龄)
(3)给药液的调制
受试物质在给药日前分成6mg×28支。给药液为用时调制的。向事先分取的1支(6mg)受试物质中添加6mL的生理盐水,翻转混合。实施加热(40℃左右)和超声处理,直至能够目视确认溶解(1mg/mL溶液)。分取0.5mL的1mg/mL溶液,添加4.5mL的生理盐水。翻转混合,确认溶解(0.1mg/mL溶液)。
(4)给药
给药途径为腹腔内给药。
为了适应给药,从第-7天(将博来霉素和受试物质的给药第一天作为第0天)起以1次/天的频率以10mL/kg的容量将介质腹腔内给药,合计7天。
以1次/天的频率给药28天。制作肺纤维化模型时(第0天~第4天)的给药为博来霉素给药之前。
使用1mL的注射器和注射针(TERUMO CORPORATION),腹腔内给药10mL/kg。
(5)试验组构成
[表1]
#:给药了介质。
(6)实验方法
(6-1)起算方法
将博来霉素溶液和生理盐水给药的第一天作为第0天。
(6-2)体重测定
第0天~第4天每天进行测定,第-7天~第-1天和第5天以后以3次/周(包括解剖检查时)的频率进行测定。
(6-3)肺纤维化模型的制作
将博来霉素溶液以5mL/kg的给药容量(博来霉素给药量:15mg/kg),以1次/天的频率在小鼠的尾静脉内给药5天。给药液量基于最新的体重计算,计算到0.01mL单位(将小数点后第3位四舍五入)。正常组以5mL/kg的容量给药生理盐水。
(6-4)采血
在最后给药的第二天(第28天)实施。对全部生存例实施采血。将动物在2%异氟烷麻醉下开腹,从腹部大静脉用添加有肝素的注射器和注射针进行全血采血。然后,通过切开腹主动脉而使其放血致死。将所采集的血液用离心条件设定为4℃、1800g、10分钟的离心分离机采集血浆。将血浆分装为约100μL×2支以及其余的分装至总计3支中,保存在超低温冰箱内(容许范围:-90~-65℃)。
(6-5)肺的采集、右肺重量测定及固定
放血致死后,结扎右支气管分支部,只摘出右肺。对所取出的右肺测定湿重。测定重量后,将右肺切碎。然后,将右肺在设定为72℃的干热灭菌器中干燥72小时左右,测定右肺的干重。测定干重后,保存在超低温冰箱(容许范围:-90~-65℃)中,直至测定羟脯氨酸量。左肺在气管内插入套管后结扎固定,通过套管在15cm H2O的压力下注入10%磷酸缓冲福尔马林溶液,将肺组织扩张固定。对实施了采血的动物实施肺的采集。固定的左肺正在实施病理组织学检查。
(6-6)右肺中羟脯氨酸(HYP)的测定
羟脯氨酸的测定样品的调制
对于(6-5)项中冷冻保存的右肺,测定羟脯氨酸含量。向干燥的右肺中加入2mL的水解用HCl,在约121℃下用高压釜水解30分钟。然后用2.5N NaOH中和(pH约6~7:使用pH试纸进行确认)。预先测定皮重,测定中和后的重量,由此计算中和后的样品量(g)。中和后的样品用注射用水适当稀释,将2mL的该溶液作为HYP含量测定用试样。
标准曲线的制作
向2mL的HYP标准溶液中添加1mL的氯胺T试剂,室温放置20分钟后,加入1mL的高氯酸试剂,室温放置5分钟。加入1mL的对二甲基氨基苯甲醛试剂,在60℃下加热20分钟后,将用过滤器过滤得到的上清液用分光光度计测定557nm的吸光度,制作标准曲线。
试样中的HYP含量测定
对于2mL的各HYP含量测定用试样,以与3.6.6.2项相同的操作测定吸光度,由该测定值基于3.6.6.2项中求得的标准曲线计算HYP含量(μg/mL)。将各HYP含量测定用试样稀释20倍来测定。测定为单次测定。
HYP量(μg/mL)×稀释倍数×中和后的样品量(g)=右肺中HYP量(μg/肺)
(7)统计学分析(USOP/STA/1001)
(7-1)处理项目
右肺湿重、右肺干重、右肺中HYP量、左肺病理组织学检查(在实施了的情况下)
(7-2)处理方法
通过以下的组合进行检验。
右肺湿重、右肺干重及右肺中HYP量
学生t检验:试验组编号1相对于2、试验组编号2相对于3、试验组编号2相对于4
Dunnett检验:试验组编号2相对于3、4
病理组织学检查(在实施了的情况下)
Wilcoxon检验:试验组编号1相对于2
Steel检验:试验组编号2相对于3、4
将显著水平设为5%,分别分成1和5%表示。
(7-3)分析软件
使用SAS 9.4[EXSUS Version 8.1.0,SAS Institute Japan株式会社(CAC CroitCorporation)]。
<结果>
右肺重量和羟脯氨酸量显示于图1~图3、表2中。
在图1~图3中,各值表示平均值±S.E.M.。
##:p<0.01,根据学生t检验与正常组有显著差异
**:p<0.01,根据学生t检验与对照组有显著差异
*:p<0.05,根据学生t检验与对照组有显著差异
[表2]
表2:2ccPA对博来霉素诱发肺纤维化模型小鼠的右肺湿重及干重以及羟基脯氨酸的效果
各值表示平均值±S.E.M.。
##:p<0.01,根据学生t检验与正常组有显著差异**:p<0.01,根据学生t检验与对照组有显著差异*:p<0.05,根据学生t检验与对照组有显著差异。
Claims (3)
1.肺纤维化治疗剂,其含有以下述式(1)表示的化合物作为有效成分:
[化学式1]
式中,R是碳原子数1~30的直链状或分支状烷基、碳原子数2~30的直链状或分支状烯基或者碳原子数2~30的直链状或分支状炔基,这些基团也可含有环烷烃环或芳环;X和Y各自独立地表示氧原子或亚甲基,但X和Y不同时为亚甲基;M是氢原子或碱金属原子。
2.根据权利要求1所述的肺纤维化治疗剂,其中在式(1)中,X或Y的其中一个为氧原子,另一个为亚甲基。
3.根据权利要求1或2所述的肺纤维化治疗剂,其中以式(1)表示的化合物是1-油酰基环状磷脂酸或1-棕榈油酰基环状磷脂酸及其衍生物的卡巴环状磷脂酸。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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JP2020195818 | 2020-11-26 | ||
PCT/JP2021/043186 WO2022114058A1 (ja) | 2020-11-26 | 2021-11-25 | 肺線維症治療剤 |
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JP3195833B2 (ja) | 1991-09-30 | 2001-08-06 | きみ子 室伏 | 新規生理活性物質及びその製造法 |
JPH07149772A (ja) | 1993-11-26 | 1995-06-13 | Sagami Chem Res Center | タンパク質リン酸化酵素cの活性促進剤 |
JPH07258278A (ja) | 1994-03-18 | 1995-10-09 | Sagami Chem Res Center | 1−O−アシルグリセロール−2,3−ホスフェート誘導体を有効成分とするDNAポリメラーゼαの阻害剤 |
JPH0925235A (ja) | 1995-07-13 | 1997-01-28 | Sagami Chem Res Center | 1−o−アシルグリセロール−2,3−ホスフェート誘導体を有効成分とするがん転移抑制剤 |
JP2001178489A (ja) | 1999-12-24 | 2001-07-03 | Kimiko Murofushi | 環状ホスファチジン酸の製造法 |
US20040214799A1 (en) | 2001-05-21 | 2004-10-28 | Mutsuko Mukai | Cancerous metastasis inhibitors containing carbacyclic phosphatidic acid derivatives |
JP4162927B2 (ja) | 2002-06-11 | 2008-10-08 | きみ子 室伏 | カルバ環状ホスファチジン酸誘導体 |
JP2008208058A (ja) * | 2007-02-26 | 2008-09-11 | Nof Corp | フォーカルアドヒージョン形成促進剤および、その用途 |
JP5737888B2 (ja) | 2010-09-06 | 2015-06-17 | Sansho株式会社 | アトピー性皮膚炎治療剤 |
CN103906519B (zh) | 2011-11-11 | 2017-10-10 | 山椒株式会社 | 关节病治疗剂 |
EP3483169B1 (en) | 2014-08-12 | 2021-05-26 | Otsuka Chemical Co., Ltd. | Crystal of cyclic phosphonic acid sodium salt and method for manufacturing same |
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