CN1094036A - 新型非对称的可取代的双萘二甲酰亚胺 - Google Patents
新型非对称的可取代的双萘二甲酰亚胺 Download PDFInfo
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- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract
由化学式Ⅰ表示的非对称的可取代的双萘二甲
酰亚胺，式中，A、B、D、R1、R2、m和的含义已在说
明书中陈述，另外，用生理上可接受的酸制备其相应
的盐也已描述了。
这种新的化合物适用于医治某些疾病。
Description
本发明是关于新型非对称的可取代的双萘二甲酰亚胺（bisnaphthalimides）、其制备方法以及它们在控制疾病方面的应用。
US-A-4841052揭示了某些化合物，这些化合物是通过一个含有芳香族基的桥基，把两个萘二甲酰亚胺基连结在一起。这类化合物可被用作电子摄影有机调色剂的敏化剂。US-A-4874863描述了适于作为具有抑制癌作用的双萘二甲酰亚胺。US-A-5086059描述了某些类似的物质，只是在其萘基上还含有桥接的亚乙基。
本发明是有关用下述化学式Ⅰ的非对称可取代的双萘二甲酰亚胺以及它们与生理上可接受酸的生成盐。
式中，A、B和D可以相同或者不同，它们是直链或支链亚烷基、环亚烷基或亚苯基，
R1和R2可以相同或者不同，它们是氢原子或C1-C6烷基或芳基或苯甲基，这些也可被如下一些基团取代，如C1-C6烷基、卤素原子、CF3-、硝基、羟基、NR3 2、OR4、COOR5、CONR6 2、CONHR7、NHCOR8、SO2NHR9或SOmR10基团，还可以一起为-CH2-，-C2H4-或-C3H6-基团，
X、X′、Y和Y′可以相同或者不同，它们是氢或卤素原子，硝基、氨基、C1-C6烷基、CF3、羟基、NR3 2、OR4、COOR5、CHO、CONR6 2、CONHR7、NHCOR8、SO2NHR9、SOmR10、COR11、脲基、C1-C6烷脲基、N＝C＝S和N＝C＝O基团，
R3-R11可以是相同或不同，它们是C1-C6烷基，环烷基或芳基，
m表示数目0、1或2;
‖表示单键或双键;
在A、B和D中优选的亚烷基是具有1～8个碳原子、特别是1-4个碳原子。优选的环亚烷基是具有3～7个碳原子。
在R1-R8中特别提到的芳基是苯基，它可优先被所述1～2个基团取代。在R3-R11中优选的环烷基是那些具有3～7个碳原子的（环烷基）。X和Y最好是硝基、氨基或甲基或氯原子，而X′和Y′最好是氢。
这种新化合物可以按照下述的反应图解进行制备：
萘二甲酸酐Ⅱ与1当量的或是高达50%过量的多胺Ⅲ在20～150℃，在有机溶剂，例如，二噁烷、乙醇或二甲基甲酰胺中进行反应。由此得到的溶液被浓缩，残留物通过例如重结晶或色谱法进行纯化。然后将由此得到的单酰亚胺与上述反应图解中的酐Ⅴ进行反应，并按同样的方法进行纯化。
用上述方法制备化合物，如果有必要的话，可以用生理上可接受的酸将其转换成相应的盐。为此先将该碱溶解于，例如，乙醇、二氯甲烷或乙醚中，然后用酸使盐沉淀出来。合适的酸有：柠檬酸、酒石酸、乳酸、磷酸、链烷磺酸特别是甲磺酸、醋酸、甲酸、马来酸、富马酸、苹果酸、琥珀酸、丙二酸、硫酸、甲苯磺酸、L-谷氨酸、L-天冬氨酸、丙酮酸、半乳糖二酸、苯甲酸、葡糖醛酸、草酸、抗坏血酸以及特别是盐酸。
在五元环上带有单键的化学式Ⅴ原料，可以按照文献（J.Amer.Chem.Soc.93，737（1971））中揭示的方法制备。在五元环上带有双键的相应化合物可以由带有单键的化合物按“J.Amer.Chem.Soc.91，（1969）917”中用于吡环苯醌（pyracycloquinones）的方法制得。
多胺Ⅲ可以买到也可以用已知方法制备。
上述新的化合物能激活非特异性的免疫细胞，借此杀死肿瘤细胞，因此这些化合物能被用来医治某些癌症，例如直肠癌、肺癌、乳腺癌以及白血病，其用药的剂量按人的体重计算约为1-500mg/Kg。
这类新化合物具有很易溶于水的优点，因此，它们与已知的具有类似结构的化合物相比，使用起来更为方便。
以下给出的实施例将试图对本发明作进一步的解释。在这些实施例中，份数或百分数的数据是相对于重量而言的。
A.原料的制备
a.（3-氨丙基）[3-（1，8-萘二甲酰亚氨基）丙基]-甲胺
将2.2g（0.015mol）的双-（3-氨丙基）甲胺溶解在250ml的乙醇中，之后将2.4g（0.012mol）的萘-1，8-二羧酸酐在4小时期间缓慢地加入到溶液中。所得混合物在室温下搅拌1小时。然后，在减压下将有机溶剂除去。剩余油状物用快速色层法（CH2Cl2/MeOH/NH4OH＝4/6/1）进行纯化。所得产物的重量为1.7g（50%）[熔点为266℃（甲醇）]，它可直接用于下一步的反应。
下面是用类似于Aa方法制备的化合物：
b.N-（2-氨乙基）-N′-[2-（1，8-萘二甲酰亚氨基）乙基]-1，2-二氨基乙烷，产率30%，熔点137℃（乙酸乙酯）。
c.N-（2-氨乙基）-N′-[2-（4-氯-1，8-萘二甲酰亚氨基）乙基]-1，3-二氨基丙烷，产率53%，油状物[氢氯化物，熔点253℃]。
d.N-（3-氨丙基）-N′-[3-（3-羟基-1，8-萘二甲酰亚氨基）丙基]-1，4-二（乙氨基）丁烷，产率44%，油状物。
e.N-[3-（3-氨基-1，8-萘二甲酰亚氨基）丙基]（3-氨丙基）胺，产率33%，熔点190℃。
f.N-（2-氨乙基）[2-（4-氯-1，8-萘二甲酰亚氨基）乙基]胺，产率24%，m.p.280℃（甲醇）。
g.N-[3-（3-氨基-1，8-萘二甲酰亚氨基）丙基]-N′-（3-氨丙基）-1，4-二氨基丁烷，产率25%，m.p.260℃。
h.N-（3-氨丙基）[3-（4-氯-1，8-萘二甲酰亚氨基）-丙基]甲胺，产率37%，油状物。
i.N-[3-（3-氨基-1，8-萘二甲酰亚氨基）丙基]（3-氨丙基）甲胺，产率32%，m.p.330℃（分解）。
B.最终产物的制备
实施例1
N-[3-（3-氨基-1，8-萘二甲酰亚氨基）丙基]-N-[3-（5，6-二氢苊二甲酰亚氨基（5，6-acenaphthalimido）丙基]胺
将上述实施例Ae得到的N-[3-（3-氨基-1，8-萘二甲酰亚氨基）丙基]（3-氨丙基）胺0.7克（0.0021摩尔）和0.45g（0.002mol）5，6-二氢苊二羧酐在50ml乙醇中回流2小时。冷却后，将沉淀过滤出来，用乙醇洗涤并从二甲苯中进行重结晶。得到了纯产物0.4g（38%），m.p.205℃。
在下表中列出了用类似于实施例1的方法制得的物质：
表
制备的化学式Ⅰ所示的一些化合物（‖＝单键）
＊）化合物23在五元环中有一个双键（‖＝双键）
表（续）制备的化学式Ⅰ所示的一些化合物（‖＝单键）
＊）化合物23在五元环中有一个双键（‖＝双键）
Claims (3)
1、用化学式Ⅰ表示的一种不对称的可取代的双萘二甲酰亚胺以及它们与一些在生理上可接受的酸生成的盐。
式中，A、B和D可以相同或者不同，它们是直链或支链亚烷基、环亚烷基或亚苯基，
R1和R2可以相同或者不同，它们是氢原子或C1-C6烷基或芳基或苯甲基，这些也可被如下一些基团取代，如C1-C6烷基、卤素原子、CF3 -、硝基、羟基、NR3 2、OR4、COOR5、CONR6 2、CONHR7、NHCOR8、SO2NHR9或SOmR10基团，还可以一起为-CH2-，-C2H4-或-C3H6-基团，
X、X′、Y和Y′可以相同或者不同，它们是氢或卤素原子，硝基、氨基、C1-C6烷基、CF3、羟基、NR3 2、OR4、COOR5、CHO、CONR6 2、CONHR7、NHCOR8、SO2NHR9、SOmR10、COR11、脲基、C1-C6烷脲基、N=C=S和N=C=O基团，
R3-R11可以是相同或不同，它们是C1-C6烷基，环烷基或芳基，
m表示数目0、1或2；
2、根据权利要求1中化学式Ⅰ所示的化合物，其特征是用于医治某些疾病。
3、含有权利要求1中化学式Ⅰ所示化合物的一种药物。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP4232739.3 | 1992-09-30 | ||
| DE4232739A DE4232739A1 (de) | 1992-09-30 | 1992-09-30 | Neue asymmetrisch substituierte bis-Naphthalimide |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1094036A true CN1094036A (zh) | 1994-10-26 |
Family
ID=6469201
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN93114145A Pending CN1094036A (zh) | 1992-09-30 | 1993-09-30 | 新型非对称的可取代的双萘二甲酰亚胺 |
Country Status (9)
| Country | Link |
|---|---|
| US (1) | US5554622A (zh) |
| EP (1) | EP0662960A1 (zh) |
| JP (1) | JPH08502050A (zh) |
| CN (1) | CN1094036A (zh) |
| CA (1) | CA2145867A1 (zh) |
| DE (1) | DE4232739A1 (zh) |
| MX (1) | MX9306035A (zh) |
| TW (1) | TW272191B (zh) |
| WO (1) | WO1994007862A1 (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1039414C (zh) * | 1993-08-18 | 1998-08-05 | Basf公司 | 双萘二甲酰亚胺类化合物 |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5461176A (en) * | 1991-03-27 | 1995-10-24 | The Du Pont Merck Pharmaceutical Company | Processes for preparing bis-naphthalimides containing amino-acid derived linkers |
| US5359070A (en) * | 1993-02-11 | 1994-10-25 | The Du Pont Merck Pharmaceutical Company | Unsymmetrical bis-imides as anticancer agents |
| SG73418A1 (en) * | 1994-04-28 | 2000-06-20 | Knoll Ag | Novel dihydrodibenzoquinolinediones |
| US5703089A (en) * | 1994-04-28 | 1997-12-30 | Knoll Aktiengesellschaft | Dihydrodibenzisoquinolinediones |
| ES2257768T3 (es) * | 1996-10-21 | 2006-08-01 | Nps Allelix Corp. | Antagonistas de neurotropina para el tratamiento de epilepsia, enfermedad de alzheimer y el dolor. |
| US6468990B1 (en) | 1999-05-17 | 2002-10-22 | Queen's University At Kingston | Method of inhibiting binding of nerve growth factor to p75 NTR receptor |
| US6492380B1 (en) * | 1999-05-17 | 2002-12-10 | Queen's University At Kingston | Method of inhibiting neurotrophin-receptor binding |
| EP1742920A2 (en) * | 2004-05-05 | 2007-01-17 | Unibioscreen S.A. | Naphthalimide derivatives for the treatment of cancer |
| WO2006003670A1 (en) * | 2004-06-30 | 2006-01-12 | Council Of Scientific And Industrial Research | Pyrrolo[2,1-c][1,4]benzodiazepine-napthalimide conjugates linked through piperazine moiety and process for preparation thereof |
| US6979684B1 (en) | 2004-06-30 | 2005-12-27 | Council Of Scientific And Industrial Research | Pyrrolo[2,1-c][1,4]benzodiazepine-napthalimide conjugates linked through piperazine moiety and process for preparation thereof |
| JP2009507861A (ja) | 2005-09-15 | 2009-02-26 | ペインセプター ファーマ コーポレーション | ニューロトロフィン媒介性活性を調節する方法 |
| PT103503B (pt) | 2006-06-19 | 2009-05-18 | Univ Do Porto | Novos derivados do bisnaftalimidopropil, processo para a sua preparação, composições farmacêuticas que os contêm e sua utilização em doenças cancerígenas e parasitárias, nomeadamente leishmanioses, tripanossomíases e malária. |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3604827A1 (de) * | 1986-02-15 | 1987-08-20 | Bayer Ag | Elektrophotographische toner |
| DE3707651A1 (de) * | 1987-03-10 | 1988-09-22 | Knoll Ag | Bis-naphthalimide, ihre herstellung und verwendung |
| US5086059A (en) * | 1990-06-07 | 1992-02-04 | Du Pont Merck Pharmaceutical Company | Bis-naphthalimides as anticancer agents |
| US5359070A (en) * | 1993-02-11 | 1994-10-25 | The Du Pont Merck Pharmaceutical Company | Unsymmetrical bis-imides as anticancer agents |
-
1992
- 1992-09-30 DE DE4232739A patent/DE4232739A1/de not_active Withdrawn
-
1993
- 1993-09-23 US US08/397,259 patent/US5554622A/en not_active Expired - Fee Related
- 1993-09-23 WO PCT/EP1993/002581 patent/WO1994007862A1/de not_active Application Discontinuation
- 1993-09-23 CA CA002145867A patent/CA2145867A1/en not_active Abandoned
- 1993-09-23 JP JP6508664A patent/JPH08502050A/ja active Pending
- 1993-09-23 EP EP93920807A patent/EP0662960A1/de not_active Withdrawn
- 1993-09-24 TW TW82107878A patent/TW272191B/zh active
- 1993-09-29 MX MX9306035A patent/MX9306035A/es not_active IP Right Cessation
- 1993-09-30 CN CN93114145A patent/CN1094036A/zh active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1039414C (zh) * | 1993-08-18 | 1998-08-05 | Basf公司 | 双萘二甲酰亚胺类化合物 |
Also Published As
| Publication number | Publication date |
|---|---|
| TW272191B (en) | 1996-03-11 |
| MX9306035A (es) | 1994-05-31 |
| MX188885B (zh) | 1998-05-12 |
| EP0662960A1 (de) | 1995-07-19 |
| US5554622A (en) | 1996-09-10 |
| CA2145867A1 (en) | 1994-04-14 |
| WO1994007862A1 (de) | 1994-04-14 |
| JPH08502050A (ja) | 1996-03-05 |
| DE4232739A1 (de) | 1994-03-31 |
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