CN85104893A - 有关苯磺酰胺衍生物的改进 - Google Patents
有关苯磺酰胺衍生物的改进 Download PDFInfo
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- CN85104893A CN85104893A CN85104893.5A CN85104893A CN85104893A CN 85104893 A CN85104893 A CN 85104893A CN 85104893 A CN85104893 A CN 85104893A CN 85104893 A CN85104893 A CN 85104893A
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
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Abstract
本发明提供某种苯磺酰胺衍生物的用法,以治疗患敏感性肿瘤的哺乳动物。还提供某种新颖的苯磺酰胺衍生物以及它们的医药配方。
Description
虽然在药物疗法中,已经开发了许多化学药剂和先进的摄生法,但是人类癌症的发病率和死亡率仍在继续不断的增长。对治疗肿瘤和白血病虽已取得很大进展,特别是结合药物治疗方面,但仍然需要新的更有效的治疗方法。这对不宜动手术的或转移性实体瘤,如各种各样的肺癌尤为明显。
新的更有效化疗剂应该是活性范围宽,治疗指数高,并应是化学性质稳定,能与其它制剂相适应的。另外,为了使初期治疗和以后的维持治疗容易进行,而且不会给患者带来不便和痛苦,任何具有口服活性的新药剂都是特别有用的。
我们已经发现磺酰脲系列可用于治疗实体瘤。这些化合物是口服活性的,提供了显著治疗指数,并相对来说是无毒的。其中有些化合物和它们的配方是新的。
本发明所用的一些磺酰脲是现有技术中已知的。“化学文摘71:1157W(1969年),Holland等人J.Med,pham chem,3(1),99(1961),Gandhi等人,Arzneim-Forsch,21968(1971),Rajagopalan等人,J.Org,chem,30,3369(1965)和Petersen,chem,Ber,83,551(1950)已经指出象1-(4-氟代-,4-氯代-,4-溴代-,和4-甲基-苯基)-3-〔苯基-和(4-氯代-,4-溴代-,和4-甲基-苯基)磺酰〕脲这类化学物。通常指出这些化合物具有口服降血糖活性。另外,也提到一些抗真菌活性,这些化合物已按碳化二亚胺的衍生物来制备。尽管1-(3-三氟甲苯基)-3-(4-甲基-苯磺酰)脲缺少降血糖活性,Holland的参考文献还是叙述了该化合物的制备。Kurzor对这类结构的化合物作了综述(Chem.Rev.50,1(1952))。以上任何一篇参考文献均未揭示或提及这些化合物有抗肿瘤活性。
R1和R3可任意是氢,C1-C3烷基,卤代基,三氟甲基,或C1-C3烷氧基;
R2是卤代基,甲基,或三氟甲基;
R4是氢,卤代基,甲基,或三氟甲基。
根据本发明的第二种情况,提供了一种药剂配方,该配方包含作为活性成份的结构式(I)的化合物,其中:
(A)如果R1为氯代基,氢或甲基,R3为氢时;
(I)当R4是氢时,R2不能是卤代基;
(II)当R4是氢或甲基时,R2不能是甲基,
(B)如果R1为溴代基,R3为氢,则当R4为氢时,R2不能为甲基。
所提供的结构式(I)的化合物与一种或多种适合于制药的载体,稀释剂或赋形剂相结合。
根据本发明的第三种情况,提供了结构式(I)的化合物:其中,
(A)如果R1是氯代基,氢或甲基,R3是氢时
(I)当R4是氢时,R2不能是卤代基
(II)当R4是氯代基时,R2不能是氯代基
(III)当R4是氢或甲基时,R2不能是甲基
(B)如果R1是溴代基,R3是氢,则当R4是氢时,R2不能是甲基。这些化合物是新的。
另外,本发明也提供了新化合物N-(〔(4-氯苯基)氨基〕羰基)-3-甲基苯磺酰胺(化合物IIIa),该化合物是治疗敏感性肿瘤中活性最高的化合物之一(结构式I,R1=R4=氢;R3=甲基;R2=氯代基),而没有降血糖倾向性。
术语“卤代基”指的是氟代基,氯代基,溴代基和碘代基。术语“C1-C3烷基”指的是甲基,乙基,正丙基和异丙基。术语“C1-C3烷氧基”指的是甲氧基,乙氧基,丙氧基和异丙氧基。
本发明方法所用的较好的化合物是结构式(I)中的:
a)R3和R4任意为氯代基,氟代基,甲基或氢,
b)R1是氢,卤代基,特别是氯代基,C1-C3烷基,特别是甲基或乙基,或是C1-C3烷氧基,特别是甲氧基
C)R2是卤代基特别是氯代基或氟代基,或者是三氟甲基。
专门用于本发明的更好的化合物是结构式II和IIIa的那些化合物结构式I中R1是甲基或甲氧基的化合物也是很好的。最好的化合物是4-甲基-N-(〔(4-三氟甲基苯基)氨基〕羰基)苯磺酰胺4-甲氧基-N-(〔(4-三氟甲基苯基)氨基〕羰基)苯磺酰胺N-(〔(4-氯苯基)氨基〕羰基)-4-甲基苯磺酰胺,以及尤其是N-(〔(4-氯苯基)氨基〕羰基)-3-甲基苯磺酰胺(化合物IIIa)。
一般认为结构式(I)的化合物,如上段中所用的,是指N-(〔(取代苯基)-氨基〕羰基)苯磺酰胺的衍生物,而且也可以认为这些化合物是指1-(取代苯基)-3-(任意取代苯磺酰)脲类。
文献中已知的许多方法都可用来制备结构式(I)的化合物。Kulzer对这些方法作了综合性的概述(chem.Rem.501(1952)特别在4-19页上)。用化合物 与化合物进行反应,能够制备结构式(I)的化合物,其中X和Y是不同的,可以各代表-NH2或-NCO。
化合物IV与V进行反应,尽管也可用其它摩尔比,但通常采用等摩尔数。本反应最好是在不反应的非质子传递溶剂中进行,例如苯,甲苯,乙腈,醚,四氢呋喃,二噁烷或二氯甲烷。反应可以在0℃直至反应混合物的沸点温度范围内进行,典型的是小于100℃。在较适宜的20~30℃下,反应放出强热,通常在1小时内就完成了反应。所得到的产物可通过过滤回收,如果需要的话,可用本专业领域的技术人员已知的那些方法,如色谱法或结晶法提纯该产品。
另外,适当取代的磺酰胺VI:与结构式是VII:的异氰酸酯反应,生成结构式I化合物。反应通常在水溶性,不反应的有机溶剂如四氢呋喃或丙酮中进行。一般地采用等康尔数或使VII摩尔数稍微过量,但是,也可用其它摩尔比。另外,还要采用碱的水溶液,如氢氧化钠或氢氧化钾溶液。通常,所用碱的摩尔数近似等于VI的摩尔效,反应温度是约从0℃直至反应混合物的沸点,典型的温度不超过100℃,在最佳的反应温度范围20~30℃内,反应一般是在约三天内完成。
中间产物IV、V、VI和VII及任何为其它制备方法所需要的中间产物,或者属于可买到的已知产品,或者能够用现有技术中已知的方法加以制备。
下面的实施例进一步阐明本发明化合物的制备,这些实施例只是用于说明本发明,而绝不是对发明范围的限制。
实施例1
4-甲基-N-{〔(4-三氟甲基苯基)氨基〕羰基}苯磺酰胺。
把8克4-氨基苯并三氟化物在10毫升二氯甲烷中的液液加到9.85克对-甲苯磺酰异氰酸酯在75毫升二氯甲烷的溶液中,同时进行搅拌。混合物变热并形成大量白色沉淀。再加100毫升二氯甲烷。将反应混合物再搅拌15分钟,经过滤回收沉淀,制得15克白色固体标题化合物。把少量该物质用二乙醚结晶出熔点为194~197℃的4-甲基-N-{〔(4-三氟甲基苯基)氨基〕}苯磺酰胺。
分析C15H13F3N2SO3:
计算值:C,50.25;H,3.66;N,7.82;
实测值:C:50.02;H,3.63;N,7.79
实施例2~16
按着实施例1的基本操作步骤,由合适的苯磺酰异氰酸酯和苯胺衍生物制得以下化合物。产率以摩尔百分率表示。
2.N-{〔(4-氯苯基)氨基〕羰基}-4-甲基苯磺酰胺产率87%,熔点174~176℃。
分析C14H13ClN2O3S:
计算值 C:51.77;H:4.03;N:8.63
实测值 C:51.90;H:4.08;N:8.67
3. 4-甲氧基-N-{〔(4-三氟甲基苯基)氨基〕羰基}-苯磺酰胺,产率58.9%,熔点188~189℃
分析C16H13F3N2O4S:
计算值 C:48.13;H:3.50;N:7.48;
实测值 C:48.38;H:3.61;N:7.53
4. N-{〔(4-三氟甲基苯基)氨基〕羰基}苯磺酰胺,产率68.7%,熔点195~196℃
分析C14H11F3N2O3S
计算值 C:48.84;H:3.22;N:8.14;
实测值 C:49.09;H:3.28;N:8.22;
5. 4-甲基-N-{〔(4-甲基苯基)氨基〕羰基}苯磺酰胺,产率84.9,熔点148~149℃。
分析C15H16N2O3S:
计算值 C:59.19;H:5.30;N:9.20;
实测值 C:59.00;H:5.21;N:8.96;
6. 4-溴-N-{〔(4-溴苯基)氨基〕羰基}苯磺酰胺,产率68.0%,熔点213~215℃(分解的)。
计算值:C:35.97;H:2.32;N:6.45;
实测值:C:36.21;H:2.33;N:6.48;
7. N{〔(4-氟苯基)氨基〕羰基}-4-甲基苯磺酰胺,产率99%,熔点172~173℃。
分析C24H18FN2O3S·1/2CH3Cl3(用0.5摩尔氯甲烷溶化):
计算值 C:49.65;H:4.02;N:7.99;S:9.14;
实测值 C;49.84;H:3.97;N:8.26;S:8.97;
8. 1-(4-溴苯基)-3-(4-甲基苯磺酰)脲,产率88%,熔点188~189℃。
分析C14H13BrN2O3S:
计算值:C:45.54;H:3.55;N:7.59;S:8.68;
实测值:C:45.30;H:3.62;N:7.49;S:8.74。
9. N{〔(4-氯苯基)氨基〕羰基}-4-甲氧基苯磺酰胺产率72%,熔点163~165℃。
分析C14H13ClN2O4S:
计算值:C:49.34;H:3.85;N:8.22;S:9.14;Cl:10.40;
实测值:C:49.06;H:3.75;N:8.16;S:9.18;Cl:10.36。
10. N-{〔(4-氯苯基)氨基〕羰基}苯磺酰胺,产率76%,熔点180~181℃。
分析C15H11ClN2O3S
计算值:C,50.25;H,3.57;N,9.01;
S,10.32;Cl,11.41;
实测值:C,50.05;H,3.61;N,8.92;
S,10.13;Cl,11.21。
11. 1-(4-氯苯基)-3-(4-氯苯磺酰基)脲,产率41.3%,熔点180~183℃。
分析C18H10Cl2N2O3S:
计算值:C:45.23;H,2.92;N,8.12;
实测值:C,44.95;H:2.82;N,8.02。
12. N-{〔(4-碘苯基)氨基〕羰基}-4-甲基苯磺酰胺,产率87%,熔点197℃(分解的)
分析C14H12IN2O3S:
计算值:C,40.04;H,3.15;N,6.73;
S,7.70;I,30.49;
实测值:C,40.22;H,3.21;N,6.49;
S,7.47;I,30.70。
13. N-{〔(4-溴苯基)氨基〕羰基〕苯磺酰胺,产率77%,熔点191~192℃。
分析C13H11BrN2O3S:
计算值:C,43.96;H,3.12;N,7.89;S,9.03;
实测值:C,43.76;H,2.90;N,7.73;S,8.69。
14. 4-氯-N-{〔(4-三氟甲基苯基)氨基〕羰基}-苯磺酰胺,产率82.4%,熔点197~198.5℃。
分析C14H10ClF3N2O3S:
计算值:C,44.40;H,2.66;N,7.40;S,8.47;
实测值:C,44.23;H,2.47;N,7.28;S,8.31。
15. N-{〔(3,4-二氯苯基)氨基〕羰基}-4-甲基苯磺酰胺,产率88.4%,熔点199~200℃。
分析C14H12Cl2N2O3S:
计算值:C,46.81;H,3.37,N,7.80;S,8.93;
实测值:C,46.71;H,3.61;N,7.59;S,8.65。
16. 4-氯-N-{〔(4-氟苯基)氨基〕羰基}苯磺酰胺产率98%,熔点201~202℃。
分析C13H10ClFN2O3S:
计算值:C,47.50,H,3.07;N,8.52;
实测值:C,47.31;H,3.13;N,8.33。
实施例17
N-{〔(4-溴苯基)氨基〕羰基}-4-甲氧基苯磺酰胺。
把9.97克4-甲氧基苯磺酰胺在54毫升丙酮中的溶液加到54毫升IN氢氧化钠溶液中。随着搅拌,加进11.54克4-溴苯异氰酸酯在50毫升丙酮中的溶液。在室温下搅拌三天后,把反应混合物过滤并向过滤液中加55毫升(1N)盐酸,生成精细白色沉淀。加入200毫升水,用过滤法回收固体,生成18.85克所需要的标题化合物。
分析C14H13BrN2O4S:
计算值:C,43.65;H,3.40;N,7.27;S,8.32;
实测值:C,43.52;H,3.54;N,7.32;S,8.31。
实施例18~19
按着实施例17的操作步骤,由合适的磺酰胺与相应的异氰酸酯制备下列化合物。
18. 3,4-二氯-N-{〔(4-三氟甲基苯基)氨基)羰基}苯磺酰胺,产率86%。
分析C14H9Cl2F3N2O3S:
计算值:C,40.70;H,2.20;N,6.78;S,7.76;
实测值:C,40.70;H,2.36;N,6.61;S,7.62
19. 3-三氟甲基-N-{〔(4-三氟甲基苯基)氨基〕羰基}-苯磺酰胺,产率89.5%。
分析C15H10F6N2O3S:
计算值:C,43.70;H,2.44;N,6.79;S,7.78;
实测值:C,43.80;H,2.18;N,6.92;S,8.04
实施例20
N-(〔(3,4-二氯苯基)氨基〕羰基)苯磺酰胺
按实施例1的步骤,由苯磺酰异氰酸盐和3,4-二氯苯胺制备标题化合物,其产率为83.5%,熔点为194~195℃。
分析:C13H10Cl2N2O3S
计算值:C,45.23;H,2.92;N,8.12;S,9.29
实测值:C,45.04;H,3.07;N,7.82;S,9.34
实施例21~31
按实施例17的步骤,由适当的磺酰胺和相应的异氰酸盐制备下列化合物。
21. 3,4-二氯-N-{〔(4-氯苯基)氨基〕羰基}苯磺酰胺,其产率为82%,熔点为183~184℃。
分析:C13H9Cl2N2O3S
计算值:C,41.13;H,2.39;N,7.38;S,8.45;
实测值:C,40.85;H,2.52;H,7.14;S,8.56
22. 3-氯-N-{〔(4-氯苯基)氨基〕羰基}苯磺酰胺其产率为79%,熔点为135℃。
分析:C13H13Cl2N2O2S
计算值:C,45.23;H,2.92;N,8.12;S,9.29;
实测值:C,45.36;H,2.74;N,8.16;S,9.51。
23. N-{〔(4-氯苯基)氨基〕羰基)-3-甲基苯磺酰胺,其产率为92.4%,熔点为171~173℃。
分析:C14H13ClN2O3S
计算值:C,51.77;H,4.03;N,8.63;
实测值:C,51.53;H,4.15;N,8.63。
24. N-{〔(4-氯苯基)氨基〕羰基}-3-甲氧基苯磺酰胺,其产率为91%,熔点为152~154℃
分析:C14H13ClN2O4S
计算值:C,49.34;H,3.85;N,8.22;S,9.41;
实测值:C,49.49;H,3.97;N,8.06;S,9.22。
25. N-{〔(4-氯苯基)氨基〕羰基)-3,4-二甲基苯酰胺,其产率为82.9%,熔点为149~151℃。
分析:C15H15ClN2O3S
计值值:C,53.18;H,4.46;N,8.27;S,9.46;
实测值:C,53.44;H,4.33,N,8.03;S,9.24。
26. N-{〔(4-氯苯基)氨基〕羰基}-4-乙基苯磺酰胺其产率为85.4%,熔点为176~177℃。
分析:C15H15ClN2O3S
计算值:C,53.18;H,4.46;N,8.27;
实测值:C,53.04;H,4.56;N,8.13。
27. N-{〔(4-氯苯基)氨基〕羰基}-4-乙氧基苯磺酰胺,其产率为65%,熔点为172~174℃。
分析:C15H15ClN2O4S
计算值:C,50.78;H,4.26;N,7.90;S,9.04;
实测值:C,50.75;H,4.23;N,7.86;S,9.06。
28. N-{〔(4-氯苯基)氨基〕羰基}-4-氟-苯磺酰胺,其产率为67%。
分析:C13H10ClFN2O3S
计算值:C,47.50;H,3.07;N,8.52;Cl,10.78;F,5.78;
实测值:C,47.45;H,3.25;N,8.44;Cl,11.02;F,6.06。
29. (〔-(〔(4-氯苯基)氨基〕羰基)-3,4-二乙基苯磺酰胺,其产率为87%,熔点为108~111℃。
分析:C17H19ClN2O3S
计算值:C,55.66;H,5.22;N,7.64;S,8.74;
实测值:C,55.69;H,5.13;N,7.70;S,8.57。
30. N-{〔(4-氯苯基)氨基〕羰基}-4-丙基苯磺酰胺,其产率为79%,熔点为125℃。
分析:C16H17ClN2O3S
计算值:C,54.47;H,4.86;N,7.94;S,9.09;
实测值:C,54.71;H,5.00;N,7.66;S,9.34。
31. N-{〔(4-氯苯基)氨基〕羰基}-4-(1-甲基乙基)苯磺酰胺,其产率为89%,熔点175~178℃。
分析:C16H17ClN2O3S
计算值:C,54.47;H,4. 86;N,7.94;S,9.09;
实测值:C,54.23;H,4.75;N,7.86;S,8.85。
实施例32
4-氯-N-{〔(3,4-二氯苯基)氨基〕羰基}苯磺酰胺,
按实施例1的步骤,使5.04克4-氯苯磺酰异氰酸盐与3.85克3.4-二氯苯胺反应,生成8.06克所要求的标题化合物,其熔点为195~196℃。
实施例33
N-{〔(4-溴-3-甲苯基)氨基〕羰基}-4-甲基磺酰胺
在氮气气氛下,向含有5.91克对-甲苯磺酰异氰酸盐的50毫升甲苯和10毫升二氯甲烷溶液中,加入含5.58克4-溴-3-甲基苯胺的20毫升甲苯和5毫升的二氯甲烷溶液,该混合物搅拌一整夜后过滤,得到的9.19克标题产物,其熔点为178~180℃。
分析:C15H15BrN2O3S
计算值:C,47.01;H,3.95;N,7.31;S,8.37
实测值:C,46.92;H,4.04;N,7.39;S,8.54
结构式1的化合物表现出具有小鼠体内肿瘤的抗移植活性。当口服给药或通过腹膜内途径时,该化合物是有效的,在试验系统内,如果按照各种剂量计划表给药,该化合物是有效的。一般来说,连续8~10天,每天一次或两次给药,或在用适当的肿瘤接种后的第1、第5和第9天给药。在一些其它实验中,既使用瘤接种后几天不给药,该化合物仍起作用。
为了证明结构式I化合物的抗瘤活性,在患有6C3HED淋巴肉瘤的动物体内试验该化合物,该瘤也称为Gordmel淋巴肉瘤(GLS)。表1显示了患有这种瘤的小鼠内几个实验结果,表中第一项显示了化合物的实施例号,第二项为给药方式,第3项为用剂量或用剂量范围和服用这种式药剂量的天数,第4项为瘤生长抑制百分率,该结果汇集了一种或多种与适当的对照试验共同进行的试验情况。
表 1
结构式1的化合物抗6C3HED淋巴肉瘤的活性化合物的 给药途径 毫克/公斤×天数** 抑制百分率实施例号
1 IP(腹腔内) 100~200(天数1,5,9) 31~49
50~150×8~10 41~92
PO(径口) 6.25~50(每天二次)×8 28~84
25~200×8×10 28~100
2 PO(径口) 37.5~400×8 25~100
3 PO 100~200×8 86~100
4 PO 150×8 81~85
5 PO 150~600×8 31~100
6 PO 37.5~150×8 76~100
7 PO 100~1200×8 41~95
8 PO 37.5~200×8 59~100
9 PO 150×8 100
10 PO 100~200×8 82~100
11 PO 37.5~200×8 82~100
12 PO 150×8 76
13 PO 150×8 82
14 PO 150×8 94
15 PO 150~300×8 93~100
16 PO 150~300×8 34~74
17 PO 150×8 99
18 PO 150×8 85
19 PO 150×8 39
20 PO 50~150×8 84~100
21 PO 150~300×8 100
22 PO 150×8 98
23 PO 37.5~300×8 30~100
24 PO 15~300×8 94~100
25 PO 150~300×8 90~100
26 PO 37.5~200×8 48~100
27 PO 150~300×8 82~100
28 PO 150×8 79
29 PO 150~300×8 22~46
30 PO 150~300×8 40~70
31 PO 150~300×8 43~65
32 PO 150×8 85
33 PO 150~300×8 65~81*以雄性C3H小鼠实验**以乳化剂给药,接种当天就给,除另有注明外,每天给药一次。
此外,在其它试验系统中,也实验了结构式1化合物,这些包括皮下B-16黑素瘤(B16-SC),Yoshicla老鼠肉瘤(Yoshicla),X5563血浆细胞骨髓瘤(X5563),M-5卵巢癌(M-5)、C3H乳房癌(C3H),结肠癌-26(C6)、CA-755腺癌(CA755),P1534J淋巴血癌(P1534J),P388淋巴细胞血癌(P388)、和Lewis Lung癌(LL),这些实验结果的摘要列于表2。
表2
结构式I的化合物抗各种肿瘤型的活性化合物的 肿瘤 给药 毫克/公斤×天数* 抑制百分数实施例号 途径1 B16-SC 径口 50-150×10 24-57
C3H 经口 50-150×10 47-93
CA755 腹腔内 25-50(一天二次)
×10 85-90
经口 75-150×10 44-94
C6 腹腔内 50-100×10
(延迟5天) 42-82
经口 75-200×10 41-89
LL 经口 50-150×10 49-67
M-5 腹腔内 100-150×10
(延迟5天) 58-83
经口 50-100×10
(延迟5天) 79-93
P1534J 腹腔内 50-150×10 70-96
经口 6.25-50(一天二次)
×10 26-98
X5563 腹腔内 100×10 64
经口 100-150×10 62-77
P388 经口 25-100×10 37-85
腹腔内 50-150×10 15-47**
经口 75-150×10 27-61**2 M-5 经口 50-200×10
(延迟3天)
经口 50-200×10 47-99
(延迟3天) 60-93
CA755 经口 50-200×10 69-98
B16-SC 经口 50-200×10 40-74
Yoshida 经口 50-200×10 47-85
X5563 经口 50-100×10 78-91
P388 经口 100-200×10 19-23**
P1534J 经口 50-200×10 79-10023 CA755 经口 18.75-150
(一天二次)
LL 经口 ×10 22-100
75-150(一天二次)
C6 经口 ×10 22-56
37.5-75(一天二次)
经口 ×10 36-76
M-5 18.75-75(一天二次)
经口 ×10 49-90
*以乳化剂形式给药。除特别注明的以外,在接种当天给药。除特
别注明外,化合物按每天一剂给药。
**百分数随残存时间增加。
结构式I的化合物是抑制肿瘤剂。本发明提供了一种治疗受病痛折磨的哺乳动物的敏感性肿瘤和白血病的方法。该方法可以由各种途径给药,包括口服、直肠的、经皮的、皮下、静脉内、肌肉内,或鼻内途径,通常以药品组合物形式给药。这类化合物的特点是口服显效好。这类组合物是依据制药技术领域众所周知的方法制备的,其中至少含有一种活性化合物。所以除了结构式II的新型化合物以外,本发明还包括由活性配料,结构式II III,或IIIa的化合物和适宜的制药载体制成的药品。
在制备本发明组合物,以及含有结构式I的其它化合物的组合物时,活性成份通常与一种载体混合、或被一种载体稀释,或被一种载体包封,该包封载体可以做成胶囊、小香袋、纸状或其它包装器的形式,作稀释剂的载体可以是固体、半固体或液态料,它的作用是作活性成份的载体,赋形剂或介质。因而,该药品可做成药片、药丸、药粉、锭剂、小香袋、胶囊、配剂,悬胶液、乳浊剂、溶液、糖浆、气雾剂(作为固态或在一种液体介质中)、软膏(例如含活性化合物重量10%以下)、软的和硬的凝胶胶囊、栓剂、无菌注射溶液和无菌包装粉末。
适宜的载体、赋形剂、和稀释剂的例子有乳糖、葡萄糖、蔗糖、山梨糖、甘露糖醇,锭粉,阿拉伯树胶、磷酸钙、藻酸块、黄胶、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、水、糖浆、甲基纤维素、羟基苯甲酸的甲脂和丙脂、滑石、硬脂酸镁和矿物油。这些配方还可以包含润滑剂、润湿剂、乳化剂和悬浮剂、防腐剂、甜化剂或调味剂。按本技术领域已知的方法向病人给药以便使所配制的组合物能够迅速、持续或延迟地释放活性成份。
最好把组合物配制成单剂药量形式,每剂药量含有约25-500毫克,通常约为25-300毫克活性成份。术语“单剂药量形式”意指对人体和其它哺乳动物相适应的单剂药量的生物离散单元,每单剂药量含有预定量的活性物质以便达到期望的治疗效果,而且单剂药量要与适宜的药用载体混合。
该活性化合物在很宽的药剂量范围内都是有效的。例如,常规每天药量在0.5-1200毫克/公斤体重。在治疗成年人时,药量为1-50毫克/公斤一次或分二次给药为佳。然而,情况很明显,实际给药量要由内科医生按照具体情况来定,所说具体情况包括治疗情况给药化合物的选择、给药途径的选择、年令、体重、各个病人的反应和病人症状的严重程度。所以,上述药剂量范围绝不是对本发明范围的限制。
下述配方实例可以选用结构式II、III和IIIa中任一种作活性化合物。这些例子仅是本发明的具体化而绝不是对发明的范围的限制。
实例34
用下列配料配制硬凝胶胶囊:
组份(毫克/胶囊)
4-甲基-N{〔(4-三氟-甲基苯基)氨基〕
羰基)苯磺酸胺 250
干燥的淀粉 200
硬酯酸镁 10
混合上述配料组分并按每份460毫克装填胶囊中。
实例35
用以下配料组份配制药片:
组份(毫克/药片)
4-甲氧基-N(〔(4-三氟-
甲基苯基)氨基〕羰基)苯磺酸胺 250
微晶纤维素 400
烘制过的二氧化硅 10
硬脂酸 5
混合配料组份并压制成每份665毫克的药片。
实例36
配制一种含有下述组成的气雾剂溶液:
重量百分比%
4-氯-N-(〔(3-氯-4-
三氟甲基苯基)氨基〕羰基)苯
磺酸胺 0.25
乙醇 29.75
气雾剂基质22 70.00
(氯二氟代甲烷)
活性化合物与乙醇和一部分气雾剂基质22混合,冷却到-30℃,送入一个填充装置。随后按需要的量向不锈钢容器供料,同时用剩下的气雾剂基质稀释。随后关闭容器阀门。
实例37
按下述组成配制每片含有60毫克活性成份的药片:
N(〔(3,4-二氯苯基)氨基〕羰基)-
4-甲基苯磺酸胺 60毫克
淀粉 45毫克
微晶纤维素 35毫克
聚乙烯吡咯烷酮
(10%的水溶液) 4毫克
羧基甲基钠淀粉 4.5毫克
滑石 1毫克
合计 150毫克
活性成份、淀粉和纤维素需要通过45目筛(美国)完全混合。聚乙烯吡啶烷酮溶液与组合粉末混合,然后通过14目筛(美用)。所得到的颗粒在50℃-60℃干燥并通过18目筛(美国)。羰基甲基钠淀粉、硬脂酸镁和滑石先要通过60目筛(美国),然后加入到该颗粒中,把它们混合后在压片机上将其压制成每片150毫克的药片。
实例38
每个胶囊中含有80毫克药物,其组成如下:
正-(〔(4-三氟甲基苯基)-氨基〕
羰基)苯磺酰胺 80毫克
淀粉 59毫克
微晶纤维素 59毫克
硬脂酸镁 2毫克
总计 200毫克
将药的有效成份,微晶纤维素,淀粉和硬脂酸镁掺混,用美国45目筛过筛,然后按每份200毫克装填胶囊中。
实例39
每只栓剂内含有225毫克有效药成分,其组成如下:
4-氯-N-(〔(4-三氟甲基苯基〕
羰基)苯磺酰胶 225毫克
饱和脂肪酸甘油酯 加至2000毫克
先将有效成份用美国60目筛进行过筛,并使之悬浮在饱和脂肪酸甘油酯液中,该液可预先用微热融化。然后注入到正常含量为2克的栓剂模中,并使之冷却。
实例40
每5毫升剂量的悬浮液中含有50毫克药量,其组成如下:
4-甲基-N(〔(3,4-二氟苯基)
氨基〕羰基)-苯磺酰胺 50毫克
羧基甲基钠纤维素 50毫克
糖浆 1.25毫升
苯甲酸溶液 0.10毫升
香料 适量
色素 适量
净水 加至5毫升
先将药粉用美国45目筛进行过筛,然后与羧基甲钠纤维素,糖糖浆混合成均匀的糊状物,然后将苯甲酸溶液,香料和色素加水稀释后倒入糊状物中,并不停搅动,然后按所需量加入足够的水。
实例41
每只胶囊含有150毫克的药物,其组成如下:
N-(〔(4-氯苯基)氨基〕羰基)
-3-甲基苯磺酰胺 150毫克
淀粉 164毫克
微晶纤维素 164毫克
硬脂酸镁 22毫克
总计 500毫克
将药有效成分,纤维素,淀粉和硬脂酸镁掺混,并用美国45目筛过筛,按每只500毫克量填入硬胶囊中。
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CA2267852A1 (en) * | 1996-10-04 | 1998-04-09 | Eli Lilly And Company | Antitumor compositions and methods of treatment |
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DK1401806T3 (da) * | 2001-06-06 | 2006-11-27 | Lilly Co Eli | Benzoylsulfonamider og sulfonylbenzamidiner til anvendelse som antitumormidler |
AU2003224917A1 (en) * | 2002-04-11 | 2003-10-27 | Carbomer | Diabetes imaging probes |
WO2011009059A2 (en) * | 2009-07-17 | 2011-01-20 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Method of treating or preventing cancer |
CN114761379A (zh) * | 2019-11-28 | 2022-07-15 | 三菱化学株式会社 | 显色剂及热敏记录材料 |
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DE1144259B (de) * | 1956-05-29 | 1963-02-28 | Hoechst Ag | Verfahren zur Herstellung von Sulfonylharnstoffen |
US3097241A (en) * | 1956-08-10 | 1963-07-09 | Hoechst Ag | Nu-cyclohexane-sulphonyl-n'-(beta-phenylethyl)-urea |
DE1159937B (de) * | 1960-06-29 | 1963-12-27 | Heyden Chem Fab | Verfahren zur Herstellung von Hydrindensulfonylharnstoffen |
US3097242A (en) * | 1960-06-29 | 1963-07-09 | Olin Mathieson | Hydrindene sulfonylureas |
DE1240866B (de) * | 1961-06-29 | 1967-05-24 | Heyden Chem Fab | Verfahren zur Herstellung von Indolin-6-sulfonylharnstoffen |
US3849110A (en) * | 1963-01-07 | 1974-11-19 | Lilly Co Eli | Herbicidal method employing aryl-sulfonylureas or salts thereof |
US3736122A (en) * | 1969-04-10 | 1973-05-29 | C Tung | Method of controlling plant growth |
US4276290A (en) * | 1977-10-10 | 1981-06-30 | Rohm And Haas Company | Phosphonoureide and phosphonothioureide anthelmintics |
US4634465A (en) * | 1982-07-16 | 1987-01-06 | Ciba-Geigy Corporation | Fused N-phenylsulfonyl-N'-pyrimidinylureas and N-phenylsulfonyl-N'triazinylureas |
IT1161220B (it) * | 1983-04-21 | 1987-03-18 | Montedison Spa | Diidro-benzofurano derivati ad attivita' erbicida |
CA1208561A (en) * | 1984-01-19 | 1986-07-29 | Marius S. Brouwer | Pharmaceutical compositions containing benzoylurea compounds |
IL80032A (en) * | 1985-09-23 | 1992-07-15 | Lilly Co Eli | Anti-tumor phenyl-aminocarbonylsulfonamides,their preparation and pharmaceutical compositions containing them |
-
1985
- 1985-05-02 US US06/729,581 patent/US4845128A/en not_active Expired - Fee Related
- 1985-06-24 PH PH32448A patent/PH22825A/en unknown
- 1985-06-24 GR GR851538A patent/GR851538B/el unknown
- 1985-06-24 NZ NZ212521A patent/NZ212521A/xx unknown
- 1985-06-24 IL IL75616A patent/IL75616A0/xx not_active IP Right Cessation
- 1985-06-24 ZA ZA854744A patent/ZA854744B/xx unknown
- 1985-06-25 PT PT80708A patent/PT80708B/pt not_active IP Right Cessation
- 1985-06-25 AR AR300790A patent/AR240916A1/es active
- 1985-06-25 CA CA000485070A patent/CA1291163C/en not_active Expired - Lifetime
- 1985-06-25 ES ES544526A patent/ES8604128A1/es not_active Expired
- 1985-06-26 HU HU852508A patent/HU197298B/hu not_active IP Right Cessation
- 1985-06-26 JP JP60141458A patent/JPH0714881B2/ja not_active Expired - Lifetime
- 1985-06-26 EP EP85304574A patent/EP0166615B1/en not_active Expired - Lifetime
- 1985-06-26 AT AT85304574T patent/ATE89733T1/de not_active IP Right Cessation
- 1985-06-26 AU AU44192/85A patent/AU571706B2/en not_active Ceased
- 1985-06-26 DK DK288785A patent/DK288785A/da not_active Application Discontinuation
- 1985-06-26 KR KR1019850004552A patent/KR870000741B1/ko not_active IP Right Cessation
- 1985-06-26 DE DE85304574T patent/DE3587359T2/de not_active Expired - Fee Related
- 1985-06-26 CN CN85104893A patent/CN1006548B/zh not_active Expired
Also Published As
Publication number | Publication date |
---|---|
EP0166615A3 (en) | 1990-03-21 |
CA1291163C (en) | 1991-10-22 |
DK288785A (da) | 1985-12-28 |
CN1006548B (zh) | 1990-01-24 |
ZA854744B (en) | 1987-02-25 |
EP0166615A2 (en) | 1986-01-02 |
EP0166615B1 (en) | 1993-05-26 |
DK288785D0 (da) | 1985-06-26 |
PH22825A (en) | 1989-01-19 |
KR870000741B1 (ko) | 1987-04-13 |
PT80708A (en) | 1985-07-01 |
NZ212521A (en) | 1989-02-24 |
IL75616A0 (en) | 1985-10-31 |
HUT38093A (en) | 1986-04-28 |
PT80708B (pt) | 1987-10-20 |
ATE89733T1 (de) | 1993-06-15 |
KR860000253A (ko) | 1986-01-27 |
ES8604128A1 (es) | 1986-01-16 |
JPH0714881B2 (ja) | 1995-02-22 |
JPS6118754A (ja) | 1986-01-27 |
AU571706B2 (en) | 1988-04-21 |
AR240916A2 (es) | 1991-03-27 |
AR240916A1 (es) | 1991-03-27 |
US4845128A (en) | 1989-07-04 |
ES544526A0 (es) | 1986-01-16 |
AU4419285A (en) | 1986-01-02 |
DE3587359D1 (de) | 1993-07-01 |
HU197298B (en) | 1989-03-28 |
DE3587359T2 (de) | 1993-11-04 |
GR851538B (zh) | 1985-11-25 |
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