CN101337930B - 脲衍生物的制备方法 - Google Patents
脲衍生物的制备方法 Download PDFInfo
- Publication number
- CN101337930B CN101337930B CN200810128200XA CN200810128200A CN101337930B CN 101337930 B CN101337930 B CN 101337930B CN 200810128200X A CN200810128200X A CN 200810128200XA CN 200810128200 A CN200810128200 A CN 200810128200A CN 101337930 B CN101337930 B CN 101337930B
- Authority
- CN
- China
- Prior art keywords
- compound
- preparation
- salt
- alkali
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C275/32—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms
- C07C275/34—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms having nitrogen atoms of urea groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
Abstract
Description
本申请是申请日为2004年11月8日、申请号为200480033071.6(国际申请号为PCT/JP2004/016526)、发明名称为“脲衍生物及其制备方法”的申请的分案申请。
技术领域
本发明涉及有效预防或治疗伴随血管新生异常增殖的各种疾病的脲衍生物及其制备方法。
背景技术
已知以通式(C)表示的脲衍生物具有优异的血管新生抑制作用(专利文献1)。另外,还已知以通式(C)表示的脲衍生物具有强的c-Kit激酶抑制作用(专利文献2、非专利文献1)。
[式中,R1表示氢原子、C1-6烷基或C3-8环烷基;R2表示氢原子或甲氧基。]
专利文献1所述的制备方法作为脲衍生物的制备方法是有用的,但从总收率等方面考虑,还有进一步改善的余地。所以,期待开发出总收率更高的脲衍生物的工业化制法以及该制备方法中有用的中间体。
另外,在专利文献1中完全没有公开以本发明中所述通式(C)表示的脲化合物的有效制备方法以及以通式(A-1)及(A-2)表示的有用中间体。
专利文献1:国际公开第02/32872号说明书
专利文献2:国际公开第2004/080462号说明书
非专利文献1:95th Annual Meeting Proceedings,AACR(AmericanAssociation for Cancer Research),Volume 45,Page 1070-1071,2004
发明内容
本发明的目的是提供有效预防或治疗伴随血管新生异常增殖的各种疾病的脲衍生物的新制备中间体及其制备方法。
鉴于上述情况,本发明人等进行了深入研究,结果发现了有效预防或治疗伴随血管新生异常增殖的各种疾病的脲衍生物的新制备中间体及其制备方法,从而完成了本发明。即,本发明提供
[1]下式表示的化合物(A-1)或其盐或它们的水合物;
[式中,R1表示氢原子、C1-6烷基或C3-8环烷基。]
[2]如[1]所述的化合物或其盐或它们的水合物,其中,R1为氢原子、甲基、乙基、正丙基或环丙基;
[3]如[1]所述的化合物或其盐或它们的水合物,其中,R1为环丙基;
[4]下式表示的化合物(A-1)的制备方法,
[式中,R1表示与上述相同的含义。]
其特征在于,利用下式表示的化合物(A-3)和下式表示的化合物(A-4)反应生成下式表示的化合物(A-2),然后,使化合物(A-2)与式R1-NH2[式中,R1表示与上述相同的含义]表示的化合物反应;
[式中,Ar表示可以具有选自卤原子、甲基、甲氧基以及硝基中的1个或2个取代基的C6-10芳基。]
[式中,Ar表示与上述相同的含义。]
[5]如[4]所述的制备方法,其中,R1为氢原子、甲基、乙基、正丙基或环丙基;
[6]如[4]所述的制备方法,其中,R1为环丙基;
[7]如[4]~[6]任一项所述的制备方法,其中,Ar为苯基;
[8]下式表示的化合物(A-2)或其盐或它们的水合物;
[式中,Ar表示与上述相同的含义。]
[9]如[8]所述的化合物或其盐或它们的水合物,其中,Ar为苯基;
[10]下式表示的化合物(C)或其盐的制备方法,
[式中,R1和R2表示与上述相同的含义。]
其特征在于,使下式表示的化合物(A-1)和下式表示的化合物(B)反应;
[式中,R1表示与上述相同的含义。]
[式中,R2表示氢原子或甲氧基;L表示离去基团。]
[11]如[10]所述的制备方法,其特征在于,该方法使用碱;
[12]如[11]所述的制备方法,其中,碱是碱金属的碳酸盐或碱金属的醇盐;
[13]如[11]所述的制备方法,其中,碱是碳酸铯、碳酸钾或叔丁醇钾;
[14]如[10]~[13]任一项所述的制备方法,其中,R1为氢原子、甲基、乙基、正丙基或环丙基;
[15]如[10]~[13]任一项所述的制备方法,其中,R1为环丙基;
[16]如[10]~[15]任一项所述的制备方法,其中,R2为氢原子;
[17]如[10]~[16]任一项所述的制备方法,其中,L是氯原子。
具体实施方式
下面,对本说明书中记载的用语、符号等的含义进行说明,并对本发明进行详细说明。
本发明中的化合物或其盐是无水物、水合物、溶剂合物中的任一种。
本说明书中使用的“C1-6烷基”是作为从碳原子数为1~6的脂肪族烃中任意除去1个氢原子后衍生的一价基团的碳原子数为1~6的直链或支链烷基,具体可以举出甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、仲戊基、新戊基、1-甲基丁基、2-甲基丁基、1,1-二甲基丙基、1,2-二甲基丙基、正己基、异己基、1-甲基戊基、2-甲基戊基、3-甲基戊基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2,3-二甲基丁基、3,3-二甲基丁基、1-乙基丁基、2-乙基丁基、1,1,2-三甲基丙基、1,2,2-三甲基丙基、1-乙基-1-甲基丙基、1-乙基-2-甲基丙基等,优选为甲基、乙基、正丙基等。
本说明书中使用的“C3-8环烷基”表示碳原子数为3~8的环状脂肪族烃基,具体可以举出环丙基、环丁基、环戊基、环己基、环庚基、环辛基等,优选为环丙基。
本说明书中使用的“C6-10芳基”表示碳原子数为6~10的芳香族烃环基,具体可以举出苯基、1-萘基、2-萘基等,优选为苯基。
本说明书中使用“卤原子”是指氟原子、氯原子、溴原子或碘原子,优选氯原子。
本说明书中使用的“碱”表示有机碱(例如吡啶、2,6-二甲基吡啶、三甲基吡啶、三乙胺、二异丙基乙基胺、二氮杂双环[5.4.0]十一碳-7烯等)或无机碱(碱金属的碳酸盐(例如,碳酸铯、碳酸钾、碳酸钠等)、碱金属的醇盐(例如,叔丁醇钾、乙醇钠等)、碱金属的氢化物(例如,氢化钾、氢化钠等)、碱金属的氢氧化物(例如,氢氧化钾、氢氧化钠等))。作为使化合物(A-1)与化合物(B)作用得到化合物(C)的步骤中使用的碱,优选碱金属的碳酸盐或碱金属的醇盐,较优选碳酸铯、碳酸钾或叔丁醇钾。
本说明书中使用的“盐”,例如可以举出与无机酸成的盐、与有机酸成的盐、与无机碱成的盐、与有机碱成的盐、与酸性或碱性氨基酸成的盐等。
作为无机酸盐的优选例,例如可以举出与盐酸、氢溴酸、硫酸、硝酸、磷酸等成的盐;作为有机酸盐的优选例,例如可以举出与醋酸、琥珀酸、富马酸、马来酸、酒石酸、柠檬酸、乳酸、硬脂酸、安息香酸、甲磺酸、乙磺酸、对甲苯磺酸等成的盐。
作为与无机碱成盐的优选例,例如可以举出钠盐、钾盐等碱金属盐、钙盐、镁盐等碱土金属盐、铝盐、铵盐等。作为与有机碱成盐的优选例,例如可以举出与二乙基胺、二乙醇胺、甲葡胺(meglumine)、N,N-二苄基乙二胺等成的盐。
作为与酸性氨基酸成盐的优选例,例如可以举出与天冬氨酸、谷氨酸等成的盐,作为与碱性氨基酸成盐的优选例,例如可以举出与精氨酸、赖氨酸、鸟氨酸等成的盐。
本发明中使用的“离去基团”只要是在有机合成时通常作为离去基团的基团,可以是任意基团,没有特别限定,具体可以举出例如,氯原子、溴原子、碘原子等卤原子;例如,甲磺酰氧基、三氟甲磺酰氧基、乙磺酰氧基等烷基磺酰氧基;例如,苯磺酰氧基、对甲苯磺酰氧基等芳基磺酰氧基;例如,甲氧基、乙氧基等烷氧基;例如,甲硫基、乙硫基等烷硫基等。作为该“离去基团”,优选氯原子、溴原子、碘原子等卤原子,较优选氯原子。
下面详细说明本发明的制备方法。
制备方法1脲(A-1)的制备方法
[式中,各符号表示与上述相同的含义。]
[步骤1-1]
该步骤是使氯甲酸苯酯等氨基甲酸酯化试剂(A-3)与化合物(A-4)反应得到化合物(A-2)的步骤。作为反应溶剂,可以使用二甲基亚砜、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、四氢呋喃、乙酸乙酯等。反应中还可以使用吡啶等碱。相对化合物(A-4)可以使用1当量~2当量氨基甲酸酯试剂(A-3)。相对化合物(A-4)可以使用1当量~5当量碱。反应时间为10分钟~30小时。反应温度为0℃~加热回流温度,优选O℃~室温。
[步骤1-2]
该步骤是使胺衍生物R1-NH2与化合物(A-2)反应得到化合物(A-1)的步骤。作为反应溶剂,可以使用二甲基亚砜、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、四氢呋喃、乙酸乙酯、乙腈、甲苯、氯仿等。反应中还可以使用有机碱(例如,吡啶、三乙胺、二异丙基乙基胺等)或无机碱(碱金属的碳酸盐(例如,碳酸铯、碳酸钾、碳酸钠等)、碱金属的氢化物(例如,氢化钾、氢化钠等))。相对化合物(A-2)可以使用1当量~3当量胺衍生物。相对化合物(A-2)可以使用1当量~3当量碱。反应时间为10分钟~30小时。反应温度为0℃~加热回流温度,优选0℃~室温。
制备方法2化合物(C)的制备方法
[式中,各符号表示与上述相同的含义。]
[步骤2]
该步骤是使化合物(A-1)与化合物(B)反应得到化合物(C)的步骤。作为反应溶剂,可以使用1-甲基吡咯烷酮、二甲基亚砜、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、1,3-二甲基-2-咪唑啉酮、甲苯、氯苯等。作为适当的碱,可以添加有机碱(例如,吡啶、2,6-二甲基吡啶、三甲基吡啶、三乙胺、二异丙基乙基胺、二氮杂双环[5.4.0]十一碳-7-烯等)或无机碱(碱金属的碳酸盐(例如,碳酸铯、碳酸钾、碳酸钠等)、碱金属的醇盐(例如,叔丁醇钾、乙醇钠等)、碱金属的氢化物(例如,氢化钾、氢化钠等)、碱金属的氢氧化物(例如,氢氧化钾、氢氧化钠等))。作为该碱,优选碱金属的碳酸盐或碱金属的醇盐,较优选碳酸铯、碳酸钾或叔丁醇钾。相对化合物(B)使用1当量~2当量化合物(A-1)。相对化合物(B)使用1当量~2当量碱。反应时间为10分钟~48小时。反应温度为室温~加热回流温度,优选40℃~80℃。
上述反应结束后,根据要求,利用常规的处理方法进行精制,例如,可以利用使用硅胶或吸附树脂等的柱色谱或利用适当的溶剂重结晶。
实施例
为了更容易地理解本发明,列举以下实施例,但本发明并不限定于此。
(实施例1)N-(2-氯-4-羟基苯基)氨基甲酸苯酯
将4-氨基-3-氯苯酚(23.7g)悬浊在N,N-二甲基甲酰胺(100mL)中,在冰冷却下加入吡啶(23.4mL)后,于20℃或20℃以下滴入氯甲酸苯酯(23.2mL)。在室温下搅拌30分钟后,加入水(400mL)、乙酸乙酯(300mL)、6N-HCl(48mL),搅拌后分离有机层。用10%食盐水(200mL)洗涤2次有机层,然后用硫酸镁干燥。蒸馏除去溶剂,得到46g固体状标题化合物。
1H-NMR(CDCl3):5.12(1h,br s),6.75(1H,dd,J=9.2,2.8Hz),6.92(1H,d,J=2.8Hz),7.18-7.28(4H,m),7.37-7.43(2H,m),7.94(1H,br s)
(实施例2)1-(2-氯-4羟基苯基)-3-环丙基脲
将N-(2-氯-4-羟基苯基)氨基甲酸苯酯溶解于N,N-二甲基甲酰胺(100mL),在冰冷却下加入环丙基胺(22.7mL),于室温下搅拌过夜。加入水(400mL)、乙酸乙酯(300mL)、6N-HCl(55mL),搅拌后分离有机层。用10%食盐水(200mL)洗涤2次有机层,然后用硫酸镁干燥。用庚烷洗涤,过滤浓缩溶剂得到的棱晶,得到22.8g标题化合物。(从4-氨基-3-氯苯酚开始计算,收率为77%)
1H-NMR(CDCl3):0.72-0.77(2H,m),0.87-0.95(2H,m),2.60-2.65(1H,m),4.89(1H,br s),5.60(1H,br s),6.71(1H,dd,J=8.8,2.8Hz),6.88(1H,d,J=2.8Hz),7.24-7.30(1H,br s),7.90(1H,d,J=8.8H)
(实施例3)4-(3-氯-4-(环丙基氨基羰基)氨基苯氧基)-7-甲氧基-6-喹啉甲酰胺
在二甲基亚砜(20mL)中添加7-甲氧基-4-氯-喹啉-6-甲酰胺(0.983g)、1-(2-氯-4-羟基苯基)-3-环丙基脲(1.13g)以及碳酸铯(2.71g),于70℃下加热搅拌23小时。将反应液恢复至室温后,加入水(50mL),过滤生成的结晶,得到1.56g标题化合物。(收率88%)
1H-NMR(d6-DMSO):0.41(2H,m),0.66(2H,m),2.56(1H,m),4.01(3H,s),6.51(1H,d,J=5.6Hz),7.18(1H,d,J=2.8Hz),7.23(1H,dd,J=2.8,8.8Hz),7.48(1H,d,J=2.8Hz),7.50(1H,s),7.72(1H,s),7.84(1H,s),7.97(1H,s),8.25(1H,d,J=8.8Hz),8.64(1H,s),8.65(1H,d,J=5.6Hz)
(实施例4)4-(3-氯-4-(环丙基氨基羰基)氨基苯氧基)-7-甲氧基-6-喹啉甲酰胺
在氮气氛围中,向反应容器中依次加入7-甲氧基-4-氯-喹啉-6-甲酰胺(5.00kg、21.13mol)、二甲基亚砜(55.05kg)、1-(2-氯-4-羟基苯基)-3-环丙基脲(5.75kg、25.35mol)以及叔丁醇钾(2.85kg、25.35mol)。然后在20℃下搅拌30分钟,接下来,经2.5小时将温度升至65℃。在同温度下搅拌19小时后,经3.5小时滴入33%(v/v)丙酮水溶液(5.0L)以及水(10.0L)。滴完后,在60℃下搅拌2小时,然后在55℃或55℃以上经1小时滴入33%(v/v)丙酮水溶液(20.0L)以及水(40.0L)。在40℃下搅拌16小时后,利用氮气压式过滤器过滤析出的结晶,依次用33%(v/v)丙酮水溶液(33.3L)、水(66.7L)以及丙酮(50.0L)洗涤结晶。利用圆锥式减压干燥机,在60℃下将得到的结晶干燥22小时,得到7.78kg标题化合物。(收率96.3%)
利用本发明的脲衍生物的制备方法,能制备有效预防或治疗伴随血管新生异常增殖的各种疾病的脲衍生物,且该制备方法效率高、可工业化。另外,本发明的脲衍生物的中间体作为用于高效制备上述脲衍生物的中间体是有用的。
产业上的可利用性
利用本发明的脲衍生物的制备方法,能制备有效预防或治疗伴随血管新生异常增殖的各种疾病的脲衍生物,且该制备方法效率高、可工业化。另外,本发明的脲衍生物的中间体作为用于高效制备上述脲衍生物的中间体是有用的。
Claims (5)
2.如权利要求1所述的制备方法,其中,R1为氢原子、甲基、乙基、正丙基或环丙基。
3.如权利要求1所述的制备方法,其中,R1为环丙基。
4.如权利要求1~3任一项所述的制备方法,其中,R2为氢原子。
5.如权利要求1~3任一项所述的制备方法,其中,L是氯原子。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2003381249 | 2003-11-11 | ||
JP381249/2003 | 2003-11-11 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB2004800330716A Division CN100450998C (zh) | 2003-11-11 | 2004-11-08 | 脲衍生物的制备方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN101337930A CN101337930A (zh) | 2009-01-07 |
CN101337930B true CN101337930B (zh) | 2010-09-08 |
Family
ID=34567274
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB2004800330716A Active CN100450998C (zh) | 2003-11-11 | 2004-11-08 | 脲衍生物的制备方法 |
CN200810128200XA Active CN101337930B (zh) | 2003-11-11 | 2004-11-08 | 脲衍生物的制备方法 |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB2004800330716A Active CN100450998C (zh) | 2003-11-11 | 2004-11-08 | 脲衍生物的制备方法 |
Country Status (6)
Country | Link |
---|---|
US (2) | US7683172B2 (zh) |
EP (1) | EP1683785B1 (zh) |
JP (1) | JP4303726B2 (zh) |
CN (2) | CN100450998C (zh) |
IL (1) | IL175363A (zh) |
WO (1) | WO2005044788A1 (zh) |
Families Citing this family (38)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1506962B1 (en) * | 2000-10-20 | 2008-07-02 | Eisai R&D Management Co., Ltd. | Nitrogen-containing aromatic heterocycles |
EP1604665B1 (en) | 2003-03-10 | 2011-05-11 | Eisai R&D Management Co., Ltd. | C-kit kinase inhibitor |
CN100450998C (zh) | 2003-11-11 | 2009-01-14 | 卫材R&D管理有限公司 | 脲衍生物的制备方法 |
PT1698623E (pt) | 2003-12-25 | 2015-06-29 | Eisai R&D Man Co Ltd | Cristal de sal de 4-(3-cloro-4-(ciclopropilaminocarbonil)amino fenoxi)-7-metoxi-6-quinolinacarboxamida ou de seu solvato e rocesso para produção destes |
WO2006030826A1 (ja) | 2004-09-17 | 2006-03-23 | Eisai R & D Management Co., Ltd. | 医薬組成物 |
US7550483B2 (en) | 2005-06-23 | 2009-06-23 | Eisai R&D Management Co., Ltd. | Amorphous salt of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide and process for preparing the same |
US20100105031A1 (en) * | 2005-08-01 | 2010-04-29 | Esai R & D Management Co., Ltd. | Method for prediction of the efficacy of vascularization inhibitor |
WO2007015578A1 (ja) | 2005-08-02 | 2007-02-08 | Eisai R & D Management Co., Ltd. | 血管新生阻害物質の効果を検定する方法 |
AU2006285673B2 (en) * | 2005-09-01 | 2010-12-02 | Eisai R&D Management Co., Ltd. | Method for preparation of pharmaceutical composition having improved disintegratability |
JPWO2007052849A1 (ja) | 2005-11-07 | 2009-04-30 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | 血管新生阻害物質とc−kitキナーゼ阻害物質との併用 |
US20090247576A1 (en) * | 2005-11-22 | 2009-10-01 | Eisai R & D Management Co., Ltd. | Anti-tumor agent for multiple myeloma |
CN101443009A (zh) * | 2006-05-18 | 2009-05-27 | 卫材R&D管理有限公司 | 针对甲状腺癌的抗肿瘤剂 |
CN101511793B (zh) | 2006-08-28 | 2011-08-03 | 卫材R&D管理有限公司 | 针对未分化型胃癌的抗肿瘤剂 |
JP5319306B2 (ja) | 2007-01-29 | 2013-10-16 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | 未分化型胃癌治療用組成物 |
WO2009054004A2 (en) * | 2007-10-22 | 2009-04-30 | Natco Pharma Limited | Process for the preparation of sorafenib |
CN101848895B (zh) | 2007-11-09 | 2013-10-23 | 卫材R&D管理有限公司 | 血管新生抑制物质和抗肿瘤性铂络合物的组合使用 |
MX2010008187A (es) * | 2008-01-29 | 2010-08-10 | Eisai R&D Man Co Ltd | Uso combinado de inhibidor de angiogenesis y taxano. |
US9012458B2 (en) | 2010-06-25 | 2015-04-21 | Eisai R&D Management Co., Ltd. | Antitumor agent using compounds having kinase inhibitory effect in combination |
CA2828946C (en) | 2011-04-18 | 2016-06-21 | Eisai R&D Management Co., Ltd. | Therapeutic agent for tumor |
EP3444363B1 (en) | 2011-06-03 | 2020-11-25 | Eisai R&D Management Co., Ltd. | Biomarkers for prediciting and assessing responsiveness of thyroid and kidney cancer subjects to lenvatinib compounds |
CA2889866A1 (en) | 2012-12-21 | 2014-06-26 | Eisai R&D Management Co., Ltd. | Amorphous form of quinoline derivative, and method for producing same |
NZ714049A (en) | 2013-05-14 | 2020-05-29 | Eisai R&D Man Co Ltd | Biomarkers for predicting and assessing responsiveness of endometrial cancer subjects to lenvatinib compounds |
ES2705698T3 (es) | 2013-06-26 | 2019-03-26 | Eisai R&D Man Co Ltd | Terapia de combinación para el tratamiento del cáncer que comprende eribulina y lenvatinib |
CN106660964B (zh) | 2014-08-28 | 2021-09-03 | 卫材R&D管理有限公司 | 高纯度喹啉衍生物及其生产方法 |
US20180028662A1 (en) | 2015-02-25 | 2018-02-01 | Eisai R&D Management Co., Ltd. | Method for Suppressing Bitterness of Quinoline Derivative |
KR20170122809A (ko) | 2015-03-04 | 2017-11-06 | 머크 샤프 앤드 돔 코포레이션 | 암을 치료하기 위한 pd-1 길항제 및 vegfr/fgfr/ret 티로신 키나제 억제제의 조합 |
CN104876864B (zh) * | 2015-06-05 | 2017-03-08 | 北京康立生医药技术开发有限公司 | 一种乐伐替尼的制备方法 |
RU2729936C2 (ru) | 2015-06-16 | 2020-08-13 | Эйсай Ар Энд Ди Менеджмент Ко., Лтд. | Противораковое средство |
CN105801481A (zh) * | 2016-05-20 | 2016-07-27 | 湖南欧亚生物有限公司 | 一种乐伐替尼的合成方法 |
WO2017221215A1 (en) * | 2016-06-23 | 2017-12-28 | Sun Pharmaceutical Industries Limited | Salts of lenvatinib |
WO2017221214A1 (en) * | 2016-06-23 | 2017-12-28 | Sun Pharmaceutical Industries Limited | Crystalline forms of salts of lenvatinib |
CN106632033A (zh) * | 2016-10-28 | 2017-05-10 | 北京万全德众医药生物技术有限公司 | 乐伐替尼的一种制备方法 |
CN106854180B (zh) * | 2016-11-30 | 2018-08-31 | 济南轩德化工有限公司 | 一种4-氯-7-甲氧基喹啉-6-酰胺的制备方法 |
CN110590839B (zh) * | 2018-06-13 | 2022-04-05 | 四川海思科制药有限公司 | 一种乐伐替尼衍生物及制备方法和用途 |
SI3620452T1 (sl) | 2018-09-07 | 2021-08-31 | Indena S.P.A. | Postopek za pripravo lenvatiniba |
CN111484490A (zh) * | 2019-01-25 | 2020-08-04 | 百济神州有限公司 | 适合大规模生产b-raf激酶二聚体抑制剂的方法 |
WO2021217537A1 (zh) * | 2020-04-30 | 2021-11-04 | 天津睿创康泰生物技术有限公司 | 一种乐伐替尼游离碱晶型及其制备方法 |
CN115872906A (zh) * | 2023-01-09 | 2023-03-31 | 山东铂源药业股份有限公司 | 一种乐伐替尼杂质及其制备方法 |
Family Cites Families (159)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CU22545A1 (es) * | 1994-11-18 | 1999-03-31 | Centro Inmunologia Molecular | Obtención de un anticuerpo quimérico y humanizado contra el receptor del factor de crecimiento epidérmico para uso diagnóstico y terapéutico |
US4526988A (en) * | 1983-03-10 | 1985-07-02 | Eli Lilly And Company | Difluoro antivirals and intermediate therefor |
EP0154434B1 (en) * | 1984-02-17 | 1993-01-27 | Genentech, Inc. | Human transforming growth factor and precursor or fragment thereof, cells, dna, vectors and methods for their production, compositions and products containing them, and related antibodies and diagnostic methods |
CA1264738A (en) * | 1984-12-04 | 1990-01-23 | Eli Lilly And Company | Treatment of tumors in mammals |
JPS62168137A (ja) | 1985-12-20 | 1987-07-24 | Fuji Photo Film Co Ltd | ハロゲン化銀カラ−写真感光材料およびその処理方法 |
AU4128089A (en) * | 1988-09-15 | 1990-03-22 | Rorer International (Overseas) Inc. | Monoclonal antibodies specific to human epidermal growth factor receptor and therapeutic methods employing same |
US4983615A (en) | 1989-06-28 | 1991-01-08 | Hoechst-Roussel Pharmaceuticals Inc. | Heteroarylamino- and heteroaryloxypyridinamine compounds which are useful in treating skin disorders |
JPH0340486A (ja) | 1989-07-07 | 1991-02-21 | Asahi Chem Ind Co Ltd | 印刷配線基板 |
JP2980326B2 (ja) | 1989-08-31 | 1999-11-22 | 株式会社東芝 | ディスク制御装置 |
US5180818A (en) * | 1990-03-21 | 1993-01-19 | The University Of Colorado Foundation, Inc. | Site specific cleavage of single-stranded dna |
GB9105677D0 (en) | 1991-03-19 | 1991-05-01 | Ici Plc | Heterocyclic compounds |
US5367057A (en) * | 1991-04-02 | 1994-11-22 | The Trustees Of Princeton University | Tyrosine kinase receptor flk-2 and fragments thereof |
US5710158A (en) | 1991-05-10 | 1998-01-20 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Aryl and heteroaryl quinazoline compounds which inhibit EGF and/or PDGF receptor tyrosine kinase |
ES2108120T3 (es) | 1991-05-10 | 1997-12-16 | Rhone Poulenc Rorer Int | Compuestos bis arilicos y heteroarilicos mono- y biciclicos que inhiben tirosina quinasa receptora de egf y/o pdgf. |
US5721237A (en) | 1991-05-10 | 1998-02-24 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Protein tyrosine kinase aryl and heteroaryl quinazoline compounds having selective inhibition of HER-2 autophosphorylation properties |
US5750376A (en) * | 1991-07-08 | 1998-05-12 | Neurospheres Holdings Ltd. | In vitro growth and proliferation of genetically modified multipotent neural stem cells and their progeny |
JPH08501203A (ja) * | 1992-06-03 | 1996-02-13 | ケイス・ウエスタン・リザーブ・ユニバーシティー | 生理活性物質を連続的に適用するための包帯 |
GB9323290D0 (en) | 1992-12-10 | 1994-01-05 | Zeneca Ltd | Quinazoline derivatives |
JPH07176103A (ja) | 1993-12-20 | 1995-07-14 | Canon Inc | 光磁気記録再生システムならびにこれに用いる磁気ヘッド及び光磁気記録媒体 |
GB9326136D0 (en) | 1993-12-22 | 1994-02-23 | Erba Carlo Spa | Biologically active 3-substituted oxindole derivatives useful as anti-angiogenic agents |
IL112249A (en) | 1994-01-25 | 2001-11-25 | Warner Lambert Co | Pharmaceutical compositions containing di and tricyclic pyrimidine derivatives for inhibiting tyrosine kinases of the epidermal growth factor receptor family and some new such compounds |
US6811779B2 (en) * | 1994-02-10 | 2004-11-02 | Imclone Systems Incorporated | Methods for reducing tumor growth with VEGF receptor antibody combined with radiation and chemotherapy |
JP3660391B2 (ja) | 1994-05-27 | 2005-06-15 | 株式会社東芝 | 半導体装置の製造方法 |
JPH0848078A (ja) * | 1994-08-05 | 1996-02-20 | Nippon Paper Ind Co Ltd | 感熱記録体 |
GB9510757D0 (en) | 1994-09-19 | 1995-07-19 | Wellcome Found | Therapeuticaly active compounds |
US5656454A (en) * | 1994-10-04 | 1997-08-12 | President And Fellows Of Harvard College | Endothelial cell-specific enhancer |
IL115256A0 (en) * | 1994-11-14 | 1995-12-31 | Warner Lambert Co | 6-Aryl pyrido (2,3-d) pyrimidines and naphthyridines and their use |
JPH08176138A (ja) | 1994-12-19 | 1996-07-09 | Mercian Corp | イソクマリン誘導体 |
US5658374A (en) | 1995-02-28 | 1997-08-19 | Buckman Laboratories International, Inc. | Aqueous lecithin-based release aids and methods of using the same |
US5624937A (en) | 1995-03-02 | 1997-04-29 | Eli Lilly And Company | Chemical compounds as inhibitors of amyloid beta protein production |
DK0817775T3 (da) | 1995-03-30 | 2001-11-19 | Pfizer | Quinazolinderivater |
GB9508538D0 (en) | 1995-04-27 | 1995-06-14 | Zeneca Ltd | Quinazoline derivatives |
JP3290666B2 (ja) | 1995-06-07 | 2002-06-10 | ファイザー・インコーポレーテッド | 複素環式の縮合環ピリミジン誘導体 |
US5880141A (en) * | 1995-06-07 | 1999-03-09 | Sugen, Inc. | Benzylidene-Z-indoline compounds for the treatment of disease |
GB9514265D0 (en) | 1995-07-13 | 1995-09-13 | Wellcome Found | Hetrocyclic compounds |
AR004010A1 (es) | 1995-10-11 | 1998-09-30 | Glaxo Group Ltd | Compuestos heterociclicos |
GB9520822D0 (en) | 1995-10-11 | 1995-12-13 | Wellcome Found | Therapeutically active compounds |
US6346398B1 (en) * | 1995-10-26 | 2002-02-12 | Ribozyme Pharmaceuticals, Inc. | Method and reagent for the treatment of diseases or conditions related to levels of vascular endothelial growth factor receptor |
AU7340096A (en) | 1995-11-07 | 1997-05-29 | Kirin Beer Kabushiki Kaisha | Quinoline derivatives and quinazoline derivatives inhibiting autophosphorylation of growth factor receptor originating in platelet and pharmaceutical compositions containing the same |
US5849759A (en) | 1995-12-08 | 1998-12-15 | Berlex Laboratories, Inc. | Naphthyl-substituted benzimidazole derivatives as anti-coagulants |
GB9604361D0 (en) | 1996-02-29 | 1996-05-01 | Pharmacia Spa | 4-Substituted pyrrolopyrimidine compounds as tyrosine kinase inhibitors |
IL126610A0 (en) | 1996-04-17 | 1999-08-17 | Du Pont Pharm Co | N-(amidinophenyl)-n'-(subst.)-3h-2,4-benzodiazepin-3- one derivatives as factor xa inhibitors |
JP2000514061A (ja) * | 1996-06-28 | 2000-10-24 | メルク エンド カンパニー インコーポレーテッド | フィブリノーゲン受容体拮抗物質 |
PL331154A1 (en) | 1996-07-13 | 1999-06-21 | Glaxo Group Ltd | Bicyclic heteroaromatic compounds as inhibitors of proteinous tyrosine kinase |
US6391874B1 (en) | 1996-07-13 | 2002-05-21 | Smithkline Beecham Corporation | Fused heterocyclic compounds as protein tyrosine kinase inhibitors |
HRP970371A2 (en) | 1996-07-13 | 1998-08-31 | Kathryn Jane Smith | Heterocyclic compounds |
AU733551B2 (en) | 1996-09-25 | 2001-05-17 | Astrazeneca Ab | Qinoline derivatives inhibiting the effect of growth factors such as VEGF |
CA2268129C (en) | 1996-09-30 | 2003-03-11 | Nihon Nohyaku Co., Ltd. | 1,2,3-thiadiazole derivatives or salts thereof and agrohorticultural disease controller and method for using the same |
EP0837063A1 (en) | 1996-10-17 | 1998-04-22 | Pfizer Inc. | 4-Aminoquinazoline derivatives |
IL129825A0 (en) | 1996-11-27 | 2000-02-29 | Pfizer | Fused bicyclic pyrimidine derivatives |
EP1014971A1 (en) | 1997-01-29 | 2000-07-05 | Eli Lilly And Company | Treatment for premenstrual dysphoric disorder |
CO4950519A1 (es) | 1997-02-13 | 2000-09-01 | Novartis Ag | Ftalazinas, preparaciones farmaceuticas que las comprenden y proceso para su preparacion |
PL335235A1 (en) | 1997-02-19 | 2000-04-10 | Berlex Lab | N-heterocyclic derivatives as nos inhibitors |
US6090556A (en) | 1997-04-07 | 2000-07-18 | Japan Science & Technology Corporation | Method for quantitatively determining the expression of a gene |
WO1998050346A2 (en) | 1997-04-18 | 1998-11-12 | Smithkline Beecham Plc | Acetamide and urea derivatives, process for their preparation and their use in the treatment of cns disorders |
PT1019040E (pt) | 1997-05-23 | 2005-01-31 | Bayer Pharmaceuticals Corp | Inibicao da actividade de p38-quinase por meio de arilureias |
US6093742A (en) | 1997-06-27 | 2000-07-25 | Vertex Pharmaceuticals, Inc. | Inhibitors of p38 |
WO1999001738A2 (en) * | 1997-06-30 | 1999-01-14 | University Of Maryland, Baltimore | Heparin binding-epidermal growth factor in the diagnosis of interstitial cystitis |
JP3765918B2 (ja) | 1997-11-10 | 2006-04-12 | パイオニア株式会社 | 発光ディスプレイ及びその駆動方法 |
JP4194678B2 (ja) | 1997-11-28 | 2008-12-10 | キリンファーマ株式会社 | キノリン誘導体およびそれを含む医薬組成物 |
IL136738A0 (en) | 1997-12-22 | 2001-06-14 | Bayer Ag | Inhibition of p38 kinase activity using substituted heterocyclic ureas |
BR9814374B1 (pt) | 1997-12-22 | 2013-09-17 | "urÉias heterocÍclicas substituÍdas e composiÇÕes compreendendo as mesmas" | |
DE69836563T2 (de) | 1997-12-22 | 2007-05-16 | Bayer Pharmaceuticals Corp., West Haven | INHIBIERUNG DER p38 KINASE-AKTIVITÄT DURCH DIE VERWENDUNG VON ARYL- UND HETEROARYL-SUBSTITUIERTEN HARNSTOFFEN |
RU2247109C9 (ru) | 1997-12-22 | 2005-06-20 | Байер Копэрейшн | Симметричные и несимметричные производные дифенилмочевины (варианты), фармацевтическая композиция, способ подавления роста опухолевых клеток, опосредованного киназой raf |
RS49779B (sr) | 1998-01-12 | 2008-06-05 | Glaxo Group Limited, | Biciklična heteroaromatična jedinjenja kao inhibitori protein tirozin kinaze |
GB9800575D0 (en) | 1998-01-12 | 1998-03-11 | Glaxo Group Ltd | Heterocyclic compounds |
UA60365C2 (uk) | 1998-06-04 | 2003-10-15 | Пфайзер Продактс Інк. | Похідні ізотіазолу, спосіб їх одержання, фармацевтична композиція та спосіб лікування гіперпроліферативного захворювання у ссавця |
IL143089A0 (en) | 1998-11-19 | 2002-04-21 | Warner Lambert Co | N-[4-(3-chloro-4-fluoro-phenylamino)-7-(3-morpholin-4-yl-propoxy)-quinazolin-6-yl]-acrylamide, an irreversible inhibitor of tyrosine kinases |
WO2000042012A1 (en) | 1999-01-13 | 2000-07-20 | Bayer Corporation | φ-CARBOXYARYL SUBSTITUTED DIPHENYL UREAS AS RAF KINASE INHIBITORS |
UA73492C2 (en) | 1999-01-19 | 2005-08-15 | Aromatic heterocyclic compounds as antiinflammatory agents | |
CN1183114C (zh) | 1999-01-22 | 2005-01-05 | 麒麟麦酒株式会社 | 喹啉衍生物及喹唑啉衍生物 |
JP3270834B2 (ja) | 1999-01-27 | 2002-04-02 | ファイザー・プロダクツ・インク | 抗がん剤として有用なヘテロ芳香族二環式誘導体 |
UA71945C2 (en) | 1999-01-27 | 2005-01-17 | Pfizer Prod Inc | Substituted bicyclic derivatives being used as anticancer agents |
IL144745A0 (en) | 1999-02-10 | 2002-06-30 | Astrazeneca Ab | Quinazoline derivatives as angiogenesis inhibitors |
GB9904103D0 (en) | 1999-02-24 | 1999-04-14 | Zeneca Ltd | Quinoline derivatives |
JP2000328080A (ja) | 1999-03-12 | 2000-11-28 | Shin Etsu Chem Co Ltd | シートベルト用低摩擦化処理剤 |
RS49836B (sr) * | 1999-03-31 | 2008-08-07 | Pfizer Products Inc., | Postupci i intermedijeri za dobijanje anti-kancernih jedinjenja |
EP1185559A2 (en) * | 1999-04-28 | 2002-03-13 | Board Of Regents, The University Of Texas System | Compositions and methods for cancer treatment by selectively inhibiting vegf |
WO2000071097A1 (fr) | 1999-05-20 | 2000-11-30 | Takeda Chemical Industries, Ltd. | Composition contenant du sel d'acide ascorbique |
PE20010306A1 (es) | 1999-07-02 | 2001-03-29 | Agouron Pharma | Compuestos de indazol y composiciones farmaceuticas que los contienen utiles para la inhibicion de proteina kinasa |
AU6762400A (en) | 1999-08-12 | 2001-03-13 | Cor Therapeutics, Inc. | Inhibitors of factor xa |
DOP2000000070A (es) | 1999-09-28 | 2002-02-28 | Bayer Healthcare Llc | Piridinas y piridacinas sustituidas con actividad de inhibición de angiogénesis |
UA75054C2 (uk) | 1999-10-13 | 2006-03-15 | Бьорінгер Інгельхайм Фарма Гмбх & Ко. Кг | Заміщені в положенні 6 індолінони, їх одержання та їх застосування як лікарського засобу |
JP2001131071A (ja) | 1999-10-29 | 2001-05-15 | Meiji Seika Kaisha Ltd | 非晶質および非晶質を含有する医薬組成物 |
AU784338B2 (en) | 1999-11-01 | 2006-03-16 | Curagen Corporation | Differentially expressed genes involved in angiogenesis, the polypeptides encoded thereby, and methods of using the same |
WO2001036403A1 (en) | 1999-11-16 | 2001-05-25 | Boehringer Ingelheim Pharmaceuticals, Inc. | Urea derivatives as anti-inflammatory agents |
UA75055C2 (uk) | 1999-11-30 | 2006-03-15 | Пфайзер Продактс Інк. | Похідні бензоімідазолу, що використовуються як антипроліферативний засіб, фармацевтична композиція на їх основі |
MXPA02006263A (es) | 1999-12-22 | 2004-02-26 | Sugen Inc | Metodos de modulacion de la funcion de la cinasa de tirosina c-kit de la proteina con compuestos de indolinona. |
AU2223501A (en) | 1999-12-24 | 2001-07-09 | Kyowa Hakko Kogyo Co. Ltd. | Fused purine derivatives |
AU2223201A (en) * | 1999-12-24 | 2001-07-09 | Kirin Beer Kabushiki Kaisha | Quinoline and quinazoline derivatives and drugs containing the same |
AR034118A1 (es) * | 2000-02-15 | 2004-02-04 | Sugen Inc | Compuestos de 2-indolinonas sustituidas con pirroles inhibidoras de proteinquinasas; sus composiciones farmaceuticas e intermediarios de sintesis |
JP2004512023A (ja) * | 2000-06-09 | 2004-04-22 | コリクサ コーポレイション | 結腸癌の治療および診断のための組成物および方法 |
WO2002016348A1 (en) | 2000-08-09 | 2002-02-28 | Astrazeneca Ab | Antiangiogenic bicyclic derivatives |
EP1506962B1 (en) * | 2000-10-20 | 2008-07-02 | Eisai R&D Management Co., Ltd. | Nitrogen-containing aromatic heterocycles |
TWI283575B (en) * | 2000-10-31 | 2007-07-11 | Eisai Co Ltd | Medicinal compositions for concomitant use as anticancer agent |
PT1339458E (pt) * | 2000-11-22 | 2007-11-09 | Novartis Ag | Combinação compreendendo um agente para diminuir a actividade do vegf e um agente para diminuir a actividade do egf |
AU2002232439A1 (en) | 2000-11-29 | 2002-06-11 | Glaxo Group Limited | Benzimidazole derivatives useful as tie-2 and/or vegfr-2 inhibitors |
US6960580B2 (en) | 2001-03-08 | 2005-11-01 | Millennium Pharmaceuticals, Inc. | Nitrogenous heterocyclic substituted quinoline compounds |
SI1385551T1 (sl) | 2001-04-06 | 2008-12-31 | Wyeth Five Giralda Farms | Antineoplastiäśne kombinacije, ki vsebujejo cci-779 (derivat rapamicina) skupaj z gemcitabinom ali fluorouracilom |
US6821987B2 (en) | 2001-04-27 | 2004-11-23 | Kirin Beer Kabushiki Kaisha | Quinoline derivatives and quinazoline derivatives having azolyl group |
ATE359790T1 (de) | 2001-05-16 | 2007-05-15 | Novartis Pharma Gmbh | Kombination von n- 5- 4-(4-methyl-piperazino- methyl)-benzoylamido -2-methylphenyl -4-(3- pyridil)-2pyrimidine-amin mit einem biphosphonat |
KR100883731B1 (ko) | 2001-06-22 | 2009-02-12 | 기린 파마 가부시끼가이샤 | 간세포 증식 인자 수용체 자기 인산화를 저해하는 퀴놀린유도체 및 퀴나졸린 유도체 및 이들을 함유하는 의약 조성물 |
GB0117144D0 (en) | 2001-07-13 | 2001-09-05 | Glaxo Group Ltd | Process |
GB0119467D0 (en) | 2001-08-09 | 2001-10-03 | Smithkline Beecham Plc | Novel compound |
US7063946B2 (en) * | 2001-09-10 | 2006-06-20 | Meso Scale Technologies, Llc. | Methods, reagents, kits and apparatus for protein function analysis |
CA2461812C (en) | 2001-09-27 | 2011-09-20 | Allergan, Inc. | 3-(arylamino)methylene-1,3-dihydro-2h-indol-2-ones as kinase inhibitors |
US20040266779A1 (en) | 2001-09-27 | 2004-12-30 | Anderson Kenneth C. | Use of c-kit inhibitors for the treatment of myeloma |
US20040191254A1 (en) * | 2001-10-09 | 2004-09-30 | Fagin James Alexander | Method of treatment of thyroid cancer |
US7495104B2 (en) * | 2001-10-17 | 2009-02-24 | Kirin Beer Kabushiki Kaisha | Quinoline or quinazoline derivatives inhibiting auto-phosphorylation of fibroblast growth factor receptors |
US6821988B2 (en) | 2001-11-27 | 2004-11-23 | Wyeth Holdings Corporation | 3-cyanoquinolines as inhibitors of EGF-R and HER2 kinases |
EP1481678A4 (en) * | 2002-03-05 | 2009-12-30 | Eisai R&D Man Co Ltd | ANTITUMORAL AGENT CONTAINING A SULFONAMIDE-CONTAINING HETEROCYCLIC COMPOUND AND AN ANGIOGENESIS INHIBITOR |
EP1488239A2 (en) | 2002-03-20 | 2004-12-22 | Dana-Farber Cancer Institute, Inc. | Methods and compositions for the identification, assessment, and therapy of small cell lung cancer |
AU2003235838A1 (en) | 2002-05-01 | 2003-11-17 | Kirin Beer Kabushiki Kaisha | Quinoline derivatives and quinazoline derivatives inhibiting autophosphorylation of macrophage colony stimulating factor receptor |
UA77303C2 (en) * | 2002-06-14 | 2006-11-15 | Pfizer | Derivatives of thienopyridines substituted by benzocondensed heteroarylamide useful as therapeutic agents, pharmaceutical compositions and methods for their use |
WO2004006862A2 (en) | 2002-07-16 | 2004-01-22 | Children's Medical Center Corporation | A method for the modulation of angiogenesis |
US7169936B2 (en) * | 2002-07-23 | 2007-01-30 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Indolinone derivatives substituted in the 6-position, their preparation and their use as medicaments |
AU2003261807B9 (en) | 2002-08-30 | 2007-02-15 | Eisai R & D Management Co., Ltd. | Azaarene derivatives |
AU2003279923A1 (en) | 2002-10-09 | 2004-05-04 | Kosan Biosciences, Inc. | Epo D + 5-FU/GEMCITABINE |
GB0223380D0 (en) | 2002-10-09 | 2002-11-13 | Astrazeneca Ab | Combination therapy |
JP4749660B2 (ja) | 2002-10-16 | 2011-08-17 | 武田薬品工業株式会社 | 安定な固形製剤 |
AU2003273000A1 (en) * | 2002-10-16 | 2004-05-04 | Takeda Pharmaceutical Company Limited | Stable solid preparations |
JPWO2004039782A1 (ja) | 2002-10-29 | 2006-03-02 | 麒麟麦酒株式会社 | Flt3自己リン酸化を阻害するキノリン誘導体およびキナゾリン誘導体並びにそれらを含有する医薬組成物 |
WO2004039785A1 (en) | 2002-11-01 | 2004-05-13 | Pfizer Products Inc. | Process for the preparation of pyrrolidinyl ethylamine compounds via a copper-mediated aryl amination |
AU2003276453A1 (en) | 2002-11-06 | 2004-06-07 | Cyclacel Limited | Pharmaceutical composition comprising a cdk inhibitor and gemcitabine |
GB0226434D0 (en) | 2002-11-13 | 2002-12-18 | Astrazeneca Ab | Combination product |
AR042042A1 (es) | 2002-11-15 | 2005-06-08 | Sugen Inc | Administracion combinada de una indolinona con un agente quimioterapeutico para trastornos de proliferacion celular |
CA2511970C (en) | 2003-01-14 | 2012-06-26 | Cytokinetics, Inc. | Urea derivatives useful in the treatment of heart failure |
CN1780811A (zh) | 2003-03-05 | 2006-05-31 | 细胞基因公司 | 二苯基乙烯化合物及其用途 |
EP1604665B1 (en) | 2003-03-10 | 2011-05-11 | Eisai R&D Management Co., Ltd. | C-kit kinase inhibitor |
JP4736043B2 (ja) | 2003-03-14 | 2011-07-27 | 小野薬品工業株式会社 | 含窒素複素環誘導体およびそれらを有効成分とする薬剤 |
JPWO2004081047A1 (ja) * | 2003-03-14 | 2006-06-29 | 大正製薬株式会社 | モノクローナル抗体及びこれを産生するハイブリドーマ |
US20070117842A1 (en) * | 2003-04-22 | 2007-05-24 | Itaru Arimoto | Polymorph of 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6- quinolinecarboxamide and a process for the preparation of the same |
EP1653934B1 (en) * | 2003-08-15 | 2008-05-14 | AB Science | Use of c-kit inhibitors for treating type ii diabetes |
US7521448B2 (en) * | 2003-08-21 | 2009-04-21 | Osi Pharmaceuticals, Inc. | N-substituted benzimidazolyl c-Kit inhibitors |
EA200600495A1 (ru) | 2003-09-23 | 2006-10-27 | Новартис Аг | Комбинация ингибитора vegf рецептора с химиотерапевтическим агентом |
PL2210607T3 (pl) | 2003-09-26 | 2012-01-31 | Exelixis Inc | N-[3-fluoro-4-({6-(metyloksy)-7-[(3-morfolin-4-ylopropylo)oksy]chinolin-4-ylo} oxy)fenylo]-N'-(4-fluorofenylo)cyklopropano-1,1-dikarboksamid do leczenia raka |
CN100450998C (zh) * | 2003-11-11 | 2009-01-14 | 卫材R&D管理有限公司 | 脲衍生物的制备方法 |
US20080312192A1 (en) | 2003-11-28 | 2008-12-18 | Guido Bold | Diaryl Urea Derivatives in the Treatment of Protein Kinase Dependent Diseases |
SG149004A1 (en) | 2003-12-05 | 2009-01-29 | Bristol Myers Squibb Co | Inhibitors of type 2 vascular endothelial growth factor receptors |
PT1698623E (pt) | 2003-12-25 | 2015-06-29 | Eisai R&D Man Co Ltd | Cristal de sal de 4-(3-cloro-4-(ciclopropilaminocarbonil)amino fenoxi)-7-metoxi-6-quinolinacarboxamida ou de seu solvato e rocesso para produção destes |
KR100799535B1 (ko) * | 2004-02-27 | 2008-01-31 | 에자이 알앤드디 매니지먼트 가부시키가이샤 | 신규 피리딘 유도체 및 피리미딘 유도체(2) |
KR20050091462A (ko) | 2004-03-12 | 2005-09-15 | 한국과학기술연구원 | 푸로피리미딘 화합물 및 이를 포함하는 ddr2 티로신키나아제 활성 저해제 |
NZ551406A (en) * | 2004-06-03 | 2010-03-26 | Hoffmann La Roche | Treatment of non small cell lung cancer with gemcitabine and erlotinib (an egfr kinase inhibitor) |
US8772269B2 (en) * | 2004-09-13 | 2014-07-08 | Eisai R&D Management Co., Ltd. | Use of sulfonamide-including compounds in combination with angiogenesis inhibitors |
WO2006030947A1 (ja) | 2004-09-13 | 2006-03-23 | Eisai R & D Management Co., Ltd. | スルホンアミド含有化合物の血管新生阻害物質との併用 |
WO2006030826A1 (ja) * | 2004-09-17 | 2006-03-23 | Eisai R & D Management Co., Ltd. | 医薬組成物 |
EP1794137A4 (en) | 2004-09-27 | 2009-12-02 | Kosan Biosciences Inc | SPECIFIC KINASE INHIBITORS |
CA2586420A1 (en) | 2004-11-22 | 2007-04-12 | King Pharmaceuticals Research & Development, Inc. | Enhancing treatment of cancer and hif-1 mediated disoders with adenosine a3 receptor antagonists |
JP2008523072A (ja) | 2004-12-07 | 2008-07-03 | ルーカス ファーマシューティカルズ, インコーポレイテッド | タンパク質キナーゼの阻害剤 |
RS51821B (en) | 2005-02-28 | 2012-02-29 | Eisai R. &D. Management Co. Ltd. | NEW COMBINED USE OF SULFONAMIDE UNITS IN CANCER TREATMENT |
EP1859797A4 (en) | 2005-02-28 | 2011-04-13 | Eisai R&D Man Co Ltd | NEW SIMULTANEOUS USE OF A SULPHONAMIDE COMPOUND AND A MEDIUM AGAINST CANCER |
JP4733700B2 (ja) | 2005-06-23 | 2011-07-27 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | 4−(3−クロロ−4−(シクロプロピルアミノカルボニル)アミノフェノキシ)−7−メトキシ−6−キノリンカルボキサミドの塩のアモルファスおよびその製造方法 |
US7550483B2 (en) * | 2005-06-23 | 2009-06-23 | Eisai R&D Management Co., Ltd. | Amorphous salt of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide and process for preparing the same |
US20100105031A1 (en) * | 2005-08-01 | 2010-04-29 | Esai R & D Management Co., Ltd. | Method for prediction of the efficacy of vascularization inhibitor |
WO2007015578A1 (ja) | 2005-08-02 | 2007-02-08 | Eisai R & D Management Co., Ltd. | 血管新生阻害物質の効果を検定する方法 |
JPWO2007052849A1 (ja) | 2005-11-07 | 2009-04-30 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | 血管新生阻害物質とc−kitキナーゼ阻害物質との併用 |
US20090247576A1 (en) * | 2005-11-22 | 2009-10-01 | Eisai R & D Management Co., Ltd. | Anti-tumor agent for multiple myeloma |
CN101443009A (zh) * | 2006-05-18 | 2009-05-27 | 卫材R&D管理有限公司 | 针对甲状腺癌的抗肿瘤剂 |
JP5319306B2 (ja) | 2007-01-29 | 2013-10-16 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | 未分化型胃癌治療用組成物 |
-
2004
- 2004-11-08 CN CNB2004800330716A patent/CN100450998C/zh active Active
- 2004-11-08 CN CN200810128200XA patent/CN101337930B/zh active Active
- 2004-11-08 US US10/577,308 patent/US7683172B2/en not_active Expired - Fee Related
- 2004-11-08 WO PCT/JP2004/016526 patent/WO2005044788A1/ja active Application Filing
- 2004-11-08 EP EP04818213.3A patent/EP1683785B1/en active Active
- 2004-11-08 JP JP2005515330A patent/JP4303726B2/ja not_active Expired - Fee Related
-
2006
- 2006-05-01 IL IL175363A patent/IL175363A/en active IP Right Grant
-
2009
- 2009-03-09 US US12/400,562 patent/US8058474B2/en not_active Expired - Fee Related
Non-Patent Citations (2)
Title |
---|
David A. Nugiel,et al..Synthesis and Evaluation of Indenopyrazoles as Cyclin-Dependent Kinase Inhibitors. 2. Probing the Indeno Ring Substituent Pattern.J. Med. Chem..2002,45(24),5224-5232. * |
Gary Gardner,et al..In vitro activity of sorghum-selective.Pesticide Biochemistry and Physiology.1985,24(3),285-297. * |
Also Published As
Publication number | Publication date |
---|---|
CN101337930A (zh) | 2009-01-07 |
US7683172B2 (en) | 2010-03-23 |
JPWO2005044788A1 (ja) | 2007-11-29 |
IL175363A0 (en) | 2006-09-05 |
WO2005044788A1 (ja) | 2005-05-19 |
CN1878751A (zh) | 2006-12-13 |
CN100450998C (zh) | 2009-01-14 |
US20090171112A1 (en) | 2009-07-02 |
EP1683785B1 (en) | 2013-10-16 |
EP1683785A4 (en) | 2007-08-29 |
JP4303726B2 (ja) | 2009-07-29 |
US8058474B2 (en) | 2011-11-15 |
EP1683785A1 (en) | 2006-07-26 |
US20070037849A1 (en) | 2007-02-15 |
IL175363A (en) | 2013-10-31 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN101337930B (zh) | 脲衍生物的制备方法 | |
RU2419617C2 (ru) | Способ получения дигидрохиназолинов | |
JP5817079B2 (ja) | 6−(7−((1−アミノシクロプロピル)メトキシ)−6−メトキシキノリン−4−イルオキシ)−n−メチル−1−ナフトアミド、またはそれの薬学的に許容される塩を調製するための方法 | |
EP3658547B1 (en) | Process for preparing n-(5-(4-(4-formyl-3-phenyl-1h-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide | |
EP2066623B1 (en) | Process for producing 1-(3,4-dichlorobenzyl)-5-octylbiguanide or a salt thereof | |
Tang et al. | Synthesis of a water-soluble cationic chiral diamine ligand bearing a diguanidinium and application in asymmetric transfer hydrogenation | |
EP0990647B1 (en) | Process for producing quinolone derivatives | |
EP1619179A1 (en) | Production method of O-substituted tyrosine compound | |
ES2546487T3 (es) | Procedimiento para la preparación de derivados de ácido aril- y heteroarilacético | |
EP3620452A1 (en) | Process for the preparation of lenvatinib | |
EP3215489B1 (en) | Method for the preparation of 1-(2-halogen-ethyl)-4 piperidine-carboxylic acid ethyl esters | |
CN103339124A (zh) | 二(芳氨基)芳基化合物的制备方法及其合成中间体 | |
KR102212650B1 (ko) | 싸이오아우론계 화합물의 제조방법 | |
KR100968576B1 (ko) | 2-아실-3-아미노-2-알케노에이트의 제조방법 | |
WO2000029369A1 (fr) | Derives d'acide aminoacrylique et procede de production correspondant | |
CN117383994A (zh) | 一种不对称脲类化合物的制备方法及不对称脲类化合物 | |
CN117886718A (zh) | 一种高选择性的不对称脲类化合物的制备方法及不对称脲类化合物 | |
CN105712939B (zh) | 一种合成瑞舒伐他汀钙关键中间体的方法 | |
CN116239575A (zh) | 一种新型联萘咪唑啉三齿手性配体的制法及其应用 | |
JP2013221025A (ja) | ビフェニルアセトアミド誘導体の製造方法及びその中間体 | |
JP2009046401A (ja) | ヒドラジン化合物の製造方法およびその製造中間体 | |
CN105820040A (zh) | 一种异丙基苯酚衍生物及其制备方法 | |
JP2013100279A (ja) | マンデル酸アミド誘導体の製造方法及びその中間体 | |
CN105985311A (zh) | 一种制备瑞舒伐他汀钙的中间体及其制备瑞舒伐他汀钙的方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant |