CN1274303C - 一种化合物及其衍生物在制备防治癌症药物中的应用 - Google Patents
一种化合物及其衍生物在制备防治癌症药物中的应用 Download PDFInfo
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- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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Abstract
本发明涉及一种化合物及其衍生物在制备预防和治疗癌症药物中的应用,属于预防和治疗癌症的药物技术领域。用G7874,G6850,G7612,G7852,Ro31-7549,Ro31-8425,Ro31-8220,Ro31-0432和NGIC-1及类似的化学化合物对癌症的化疗是对哺乳动物实施的癌症治疗。上述化合物是针对抑制PKC α的活性。试验证明上述化合物能有效的治疗肺癌,肝癌,消化道癌症包括胃癌和肠癌,乳腺癌,前列腺癌,宫颈癌,皮肤癌,胰腺癌,白血病,淋巴癌,脑癌,膀胱癌,口腔癌,还可作为通过预防细胞的癌变而作为预防癌变药。
Description
技术领域
本发明涉及一种化合物及其衍生物在制备防治癌症药物中的应用,属于预防和治疗癌症的药物技术领域。
背景技术
研究人员经过验证发现酶家族中的蛋白激酶C酶与很多癌相关联。此家族包括至少11个同工酶。此家族中的一个特殊成员被认知是蛋白激酶C阿尔发酶,即蛋白激酶Cα,以下简称PKCα。研究人员报道了PKCα的活性在人类乳腺肿瘤中增高(NG et al.,cience.283:2085-2089)和PKCα在前列腺癌中的高表达(Cornford et al.,Am.J.Pathol.154:137-144)。研究人员还报道了PKCα参与黑色素瘤的转移(Dennis et al.,Cancer Lett.128:65-70)和与脑癌的预后有关(Shen et al.,Mol.Pharmacol.55:396-402).
G6976的化学制剂是PKCα的抑制剂。本申请人曾经提出的美国专利,其专利号为6,310,989和6,696,478,以及中国专利99125118.0都公开了G6976可作为治癌和防癌试剂。上述发明公开了其它PKCα抑制剂也用作抗癌的化疗和预防试剂。
发明内容
本发明的目的是提出一种化合物及其衍生物在制备防治癌症药物中的应用,以用于对哺乳动物的癌症进行治疗和预防。
本发明提出的一种化合物及其衍生物在制备防治癌症药物中的应用,其中的化合物,具有如下两种不同结构:
其中的A、B、C、D、E、F、G、H、I、J、K、L、M、N、和O,可以分别,也可以同时为:
氢(hydrogen),氧(oxygen),甲基(methyl),乙基(ethyl),丙基(propyl),异
丙基(isopropyl),羧甲基(carboxymethyl),2-羧乙基(2-carboxyethyl),3-羧丙基(3-carboxypropyl),1~20碳原子直链或支链烷基(a straight or branched alky of from 1 to a number of carbonatoms),直链或支链叠氮烷基(straight or branched azidoalkyll),
羧基烷基(carboxyalkyl),脒基硫代烷基(amidinothioalkyl),脒基烷基(amidinoalkyl)。(2-硝基胍)烷基((2-nitroguanidino)alkyl,每个化学结构中含有1~20个碳原子),或者是-(CH2)2-CO-NX,其中X为氢或1~20碳的烷基(alkyl of from 1 to a number of carbon atoms),或苯基(benzyl)中的任何一种。
本发明提出的化学化合物可抑制PKCα的活性。试验显示具有这些分子结构式的化合物象G7874,G6850,G7612,G7852,Ro31-7549,Ro31-8425,Ro31-8220,Ro31-0432和NGIC-1,能有效的治疗肺癌,肝癌,消化道癌症如胃癌和肠癌,乳腺癌,前列腺癌,宫颈癌,皮肤癌,胰腺癌,白血病,淋巴癌,脑癌,膀胱癌,口腔癌。可用这些化合物和类似的化合物(衍生物)单独或与其他化疗药物或放疗联合使用来完成治疗。这些化合物还可阻止癌细胞形成,故可以用作癌症发生的预防药物。
本发明提出的针对PKCα的化学首选制剂分别是具有以下结构的化学制品:
1、商品名为:G7874,化学分子式为:C27H26N4O4·HCl,化学名称为:
5,7(6H)-二酮,13-[3-(二甲氨基)-2-羟丙基]-12,13-二氢-3-甲氧基-12-甲基-5H-吲哚[2,3-吡咯[3,4-咔脞,盐酸。
结构为:
2、商品名为:G6850,分子式为:C25H24N4O2.,化学名称为:二吲哚马来酰胺I,即:2-[1-(3-二甲氨丙基)-1H-3-吲哚]-3-(1H-3-吲哚)-马来酰胺。
结构式为:
3、商品名为:NGIC-I,分子式为:C23H16N4O,化学名称为:非糖苷吲哚咔唑I,即:12-丙腈,5,6,7,13-四氢-5-氧桥-12H-吲哚[2,3-a]吡咯[3,4-c]咔唑。结构式为:
4、商品名为:G7852,分子式为:C26H26N4O2,化学名称为:5-酮,12-[3-(二甲氨基)-2-羟丙基]-6,7,12,13-四氢-13-甲基-5H-吲哚[2,3-a]吡咯[3,4-c]咔唑。
结构式为:
5、商品名为:G7612,分子式为:C25H18N4O3,化学名称为:12-丙腈,5,6,7,13-四氢-9-甲氧基-13-甲基-5,7-二氧桥-12H-吲哚[2,3-a]吡咯[3,4-c]咔唑。
结构式为:
6、商品名为:Ro31-7549;分子式为:C24H22N4O2·C2H4O2,化学名称为:2-[1-3(氨基丙烷)-3-吲哚]-3(1-甲基-1H-3-吲哚)马来酰胺,醋酸盐,二吲哚马来酰胺VIII,醋酸盐。
结构式为:
7、商品名为:Ro31-8220,分子式为:C25H23N5O2S·CH4O3S,化学名称为:二吲哚马来酰胺IX,甲基磺酸盐,即:3-[1-[3-(脒基硫代)丙基-1H-3-吲哚]-3-(1-甲基-1H-3-吲哚)马来酰胺。
结构式为:
8、商品名为:Ro31-8425,分子式为:C26H24N4O2·HCl,化学名称为:二吲哚马来酰胺X,盐酸,即:2-[8-(氨甲基)-6,7,8,9-四氢吡啶[1,2-a]-3-吲哚]-3-(1-甲基-1H-3-吲哚)马来酰胺X,盐酸。
结构式为:
9、商品名为:Ro31-0432,分子式为:C28H28N4O2·HCl,化学名称为:二吲哚马来酰胺XI,HCl,即:2-{8-[(二甲氨基)甲基]-6,7,8,9-四氢吡啶[1,2-a]-3-吲哚}-3-(1-甲基-1H-3-吲哚)马来酰胺,盐酸。
化学结构式为:
本发明提出的化合物在制备防治癌症药物中的应用,有效杀死了癌细胞,降低了所试验的癌细胞的生长率,因此可有效地处理未试验的与PKCα相关的癌细胞,例如鼻咽癌,肾细胞癌,内分泌肿瘤如垂体瘤和甲状腺癌,食道癌和黑素瘤,也可作为癌症的治疗及预防癌变药物,尤其对特定癌症的高危人群。
具体实施方式
本发明实施例中所用的细胞培养如下:
以下肿瘤细胞株来源于美国ATCC(the American Type CultureCollection,Rockville,Md.)公司:
PC3人类前列腺癌细胞,HepG2人类肝癌细胞,AGS人类胃癌细胞,HT29人类结肠癌细胞,U251人类神经胶质瘤细胞,Hela人类子宫颈癌细胞,MNA-MB-468人类乳腺癌细胞,A431人类皮肤癌细胞,PANC-1人类胰腺癌细胞,Jurkat白血病细胞(人类急性T-细胞白血病细胞),KB口腔癌细胞,K562白血病细胞(人类慢性骨髓性白血病),H460人类肺癌细胞,NBT-II人类膀胱癌细胞,上述细胞在加入百分之十胎牛血清的Dulbecco修正培养液(DMEM)中培养。
细胞存活率试验:细胞接种后24小时,对它们用化合物进行处理或者不予处理。此后定期收集细胞并用台盘离排除方法对其存活率评估。
实施例1:G7874对癌细胞生长和存活的影响。
G7874对人类各种癌细胞的治疗结果归纳在表格1。用5微摩尔G7874处理培养的4×104细胞(除了PC3前列腺癌细胞用10微摩尔处理),第6天检查计算存活的细胞。如表格1所示,未处理细胞成倍增长,用G7874处理的癌细胞数量明显降低。PC3人类前列腺癌细胞,MDA-MB-468人类乳腺癌细胞,H460人类肺癌细胞,HT29人类结肠癌细胞,AGS人类胃癌细胞,HepG2人类肝癌细胞,PANC-1人类胰腺癌细胞,A431人类皮肤癌细胞,U251人类神经胶质瘤细胞,Hela人类子宫颈细胞,KB口腔癌细胞,和U-937淋巴瘤细胞在处理后都凋亡,Jurkat白血病细胞的存活比原接种时少三分之一。处理后AGS人类胃癌细胞的生长率得到了60%以上的抑制。
表格1 G7874对癌细胞生长和存活的影响
PC3 | MDA-MB-468MB468 | H460 | HT29 | AGS | HepG2 | |
未处理(细胞数) | 7.1×105+0.3×105 | 6.1×105±0.4×105 | 2.4×105±0.2×105 | 3.8×105±0.4×105 | 2.4×105±0.3×105 | 4.2×105±0.4×105 |
经处理(细胞数) | 0 | 0 | 0 | 0 | 0.8×105±0.05×104 | 0 |
PANC-1 | Jurkat | A431 | U251 | NBT-II | Hela | KB | |
未处理(细胞数) | 2.1×105±0.3×105 | 8.8×105±0.4×105 | 5.4×105±0.4×105 | 9.6×105±0.5×105 | 2.9×105±0.4×105 | 3.4×105±0.4×105 | 3.8×105±0.4×105 |
经处理(细胞数) | 0 | 0.1×105±0.05×104 | 0 | 0 | 0 | 0 | 0 |
根据3个独立的实验计算标准误差。
实施例2:G6850对癌细胞生长和存活的影响
培养的约4×104细胞经或未经10微摩尔G6850处理,对存活的细胞在第6天计数。如图表格2所示,经处理的Hela人类子宫颈癌细胞的数量明显降低,对照未经处理的癌细胞,经处理的癌细胞的生长显示了25-60%抑制。
表格2 G6850对癌细胞生长和存活的影响
PC3 | MDA-MB-468MB468 | H460 | HT29 | AGS | HepG2 | |
未经处理(细胞数) | 7.1×105±0.3×105 | 6.1×105±0.4×105 | 2.4×105±0.2×105 | 3.8×105±0.4×105 | 2.4×105±0.3×105 | 4.2×105±0.4×105 |
经处理(细胞数) | 2.8×105±0.2×105 | 4.6×105±0.2×105 | 1.6×105±0.1×105 | 2.4×105±0.2×105 | 1.5×105±0.2×105 | 2.4.×105±0.2×105 |
%抑制 | 60 | 25 | 31 | 22 | 34 | 41 |
PANC-1 | Jurkat | A431 | U251 | NBT-II | Hela | KB | |
未经处理(细胞数) | 2.1×105±0.3×105 | 8.8×105±0.4×105 | 5.4×105±0.4×105 | 9.6×105±0.5×105 | 2.9×105±0.4×105 | 3.4×105±0.4×105 | 3.8×105±0.4×105 |
经处理(细胞数) | 1.4×105±0.1×105 | 4.1×105±0.2×105 | 4.1×105±0.2×105 | 7.2×105±0.4×105 | 1.3×105±0.1×105 | 0.3×105±0.1×105 | 1.7×105±0.1×105 |
%抑制 | 30 | 53 | 24 | 23 | 57 | * | 55 |
*抑制剂使细胞明显的死亡,比原接种时细胞数减少。
实施例3 NGIC-I对癌细胞生长和存活的影响
培养的约4×104细胞经或未经10微摩尔NGIC-I处理,第6天对存活的细胞计数。如表格3所示,KB口腔癌细胞全部凋亡。Jurkat白血病细胞比原始细胞数降低三分之二,Hela人类子宫颈癌细胞比原始细胞数降低三分之一,而其他经处理的癌细胞与未经处理的比较显示了25-82%的生长抑制。
表格3 NGIC-I对癌细胞生长和存活的影响
PC3 | MDA-MB-468MB468 | H460 | HT29 | AGS | HepG2 | |
未经处理(细胞数) | 7.1×105±0.3×105 | 6.1×105±0.4×105 | 2.4×105±0.2×105 | 3.8×105±0.4×105 | 2.4×105±0.3×105 | 4.2×105±0.4×105 |
经处理(细胞数) | 3.7×105±0.1×105 | 1.3×105±0.2×105 | 1.6×105±0.1×105 | 3.2×105±0.1×105 | 1.7×105±0.1×105 | 0.9.×105±0.1×105 |
%抑制 | 48 | 78 | 32 | 15 | 30 | 78 |
PANC-1 | Jurkat | A431 | U251 | NBT-II | Hela | KB | |
未经处理(细胞数) | 2.1×105±0.3×105 | 8.8×105±0.4×105 | 5.4×105±0.4×105 | 9.6×105±0.5×105 | 2.9×105±0.4×105 | 3.4×105±0.4×105 | 3.8×105±0.4×105 |
经处理(细胞数) | 1.2×105±0.1×105 | 0.2×105±0.1×104 | 2.7×105±0.2×105 | 1.6×105±0.3×105 | 0.9×105±0.1×105 | 0.3×105±0.1×105 | 0 |
%抑制 | 44 | * | 49 | 82 | 73 | * | * |
*抑制剂使细胞明显的死亡,比原接种时细胞数减少。
实施例4 Ro31-7549对癌细胞生长和存活的影响
培养的约4×104细胞经或未经10微摩尔Ro31-7549处理,第6天对存活的细胞计数。如表格4所示,所有的HepG2人类肝癌细胞和KB人类口腔癌细胞和大量的MDA-MB-468人类乳腺癌细胞和Hela人类子宫颈癌细胞因处理而凋亡。所有其它经处理的癌细胞与未经处理的相比生长抑制达43-92%。
表格4 Ro31-7549对癌细胞生长和存活的影响
PC3 | MDA-MB-468MB468 | H460 | HT29 | AGS | HepG2 | |
未经处理(细胞数) | 7.1×105±0.3×105 | 6.1×105±0.4×105 | 2.4×105±0.2×105 | 3.8×105±0.4×105 | 2.4×105±0.3×105 | 4.2×105±0.4×105 |
经处理(细胞数) | 2.7×105±0.2×105 | 0.2×105±0.05×105 | 0.5×105±0.1×105 | 1.7×105±0.1×105 | 1.7×105±0.1×105 | 0 |
%抑制 | 62 | * | 81 | 63 | 30 | * |
PANC-1 | Jurkat | A431 | U251 | NBT-II | Hela | KB | |
未经处理(细胞数) | 2.1×105±0.3×105 | 8.8×105±0.4×105 | 5.4×105±0.4×105 | 9.6×105±0.5×105 | 2.9×105±0.4×105 | 3.4×105±0.4×105 | 3.8×105±0.4×105 |
经处理(细胞数) | 1.2×105±0.1×105 | 0.7×105±0.1×104 | 2.8×105±0.2×105 | 1.9×105±0.3×105 | 0.6×105±0.1×105 | 6×105±0.1×103 | 0 |
%抑制 | 43 | 92 | 48 | 80 | 80 | * | * |
*抑制剂使细胞明显的死亡,比原接种时细胞数减少。
实施例5 Ro31-8220对癌细胞生长和存活的影响
培养的约4×104细胞经或未经10微摩尔Ro31-8220处理,第6天对存活的细胞计数。如表格5所示,所有的AGS人类胃癌细胞,PANC-1人类胰腺癌细胞,NBT-II人类膀胱癌细胞,KB人类口腔癌细胞,和大量的MDA-MB-468人类乳腺癌细胞,及Hela人类子宫颈癌细胞因处理而凋亡。所有其它经处理的癌细胞与未经处理的相比显示生长抑制达60-94%。
表格5 Ro31-8220对癌细胞生长和存活的影响
PC3 | MDA-MB-468MB468 | H460 | HT29 | AGS | HepG2 | |
未经处理(细胞数) | 7.1×105±0.3×105 | 6.1×105±0.4×105 | 2.4×105±0.2×105 | 3.8×105±0.4×105 | 2.4×105±0.3×105 | 4.2×105±0.4×105 |
经处理(细胞数) | 2.7×105±0.2×105 | 0.2×105±0.05×105 | 0.4×105±0.1×105 | 0.6×105±0.1×105 | 0 | 0.4×105±0.1×105 |
%抑制 | 62 | * | 85 | 85 | * | 90 |
PANC-1 | Jurkat | A431 | U251 | NBT-II | Hela | KB | |
未经处理(细胞数) | 2.1×105±0.3×105 | 8.8×105±0.4×105 | 5.4×105±0.4×105 | 9.6×105±0.5×105 | 2.9×105±0.4×105 | 3.4×105±0.4×105 | 3.8×105±0.4×105 |
经处理(细胞数) | 0 | 0.5×105±0.2×104 | 2.1×105±0.2×105 | 1.4×105±0.1×105 | 0 | 6×103±0.1×103 | 0 |
%抑制 | * | 94 | 60 | 85 | * | * | * |
*抑制剂使细胞明显的死亡,比原接种时细胞数减少。
实施例6 Ro31-8425对癌细胞生长和存活的影响
培养的约4×104细胞经或未经10微摩尔Ro31-8425处理,第6天对存活的细胞计数。如表格6所示,所有的H460人类肺癌细胞,AGS人类胃癌细胞,PANC-1人类胰腺癌细胞,海拉人类子宫颈癌细胞,和KB人类口腔癌细胞,及大量的MDA-MB-468人类乳腺癌细胞,Jurkat人类白血病细胞和NBT-II人类膀胱癌细胞因处理而凋亡。所有其它经处理的癌细胞与未经处理的相比显示生长抑制达52-90%。
表格6 Ro31-8425对癌细胞生长和存活的影响
PC3 | MDA-MB-468MB468 | H460 | HT29 | AGS | HepG2 | |
未经处理(细胞数) | 7.1×105±0.3×105 | 6.1×105±0.4×105 | 2.4×105±0.2×105 | 3.8×105±0.4×105 | 2.4×105±0.3×105 | 4.2×105±0.4×105 |
经处理(细胞数) | 3×105±0.2×105 | 0.1×105±0.05×105 | 0 | 0.6×105±0.1×105 | 0 | 0.4×105±0.1×105 |
%抑制 | 53 | * | * | 85 | * | 90 |
PANC-1 | Jurkat | A431 | U251 | NBT-II | Hela | KB | |
未经处理(细胞数) | 2.1×105±0.3×105 | 8.8×105±0.4×105 | 5.4×105±0.4×105 | 9.6×105±0.5×105 | 2.9×105±0.4×105 | 3.4×105±0.4×105 | 3.8×105±0.4×105 |
经处理(细胞数) | 0 | 0.3×105±0.1×104 | 2.6×105±0.2×105 | 1.4×105±0.1×105 | 0.3×105±0.1×105 | 0 | 0 |
%抑制 | * | * | 52 | 85 | * | * | * |
*抑制剂使细胞明显的死亡和比原接种时细胞数减少。
实施例7 Ro31-0432对癌细胞生长和存活的影响
培养的约4×104细胞经或未经10微摩尔Ro31-0432处理,第6天对存活的细胞计数。如表格7所示,所有经处理的癌细胞与未经处理的相比显示生长抑制达10-60%。
表格7 Ro31-0432对癌细胞生长和存活的影响
PC3 | MDA-MB-468MB468 | H460 | HT29 | AGS | HepG2 | |
未经处理(细胞数) | 7.1×105±0.3×105 | 6.1×105±0.4×105 | 2.4×105±0.2×105 | 3.8×105±0.4×105 | 2.4×105±0.3×105 | 4.2×105±0.4×105 |
经处理(细胞数) | 6.0×105±0.1×105 | 4.3×105±0.2×105 | 1.3×105±0.2×105 | 3.0×105±0.3×105 | 1.7×105±0.1×105 | 2.4.×105±0.1×105 |
%抑制 | 15 | 30 | 48 | 19 | 30 | 43 |
PC3 | MDA-MB-468MB468 | H460 | HT29 | AGS | HepG2 | |
未经处理(细胞数) | 7.1×105±0.3×105 | 6.1×105±0.4×105 | 2.4×105±0.2×105 | 3.8×105±0.4×105 | 2.4×105±0.3×105 | 4.2×105±0.4×105 |
经处理(细胞数) | 6.0×105±0.1×105 | 4.3×105±0.2×105 | 1.3×105±0.2×105 | 3.0×105±0.3×105 | 1.7×105±0.1×105 | 2.4.×105±0.1×105 |
%抑制 | 15 | 30 | 48 | 19 | 30 | 43 |
PKCα抑制剂阻止细胞的癌变:1×103高表达表皮生长因子受体的3Y1大鼠纤维原细胞按100ng/ml表皮生长因子处理48小时后显示了癌变形态。1微摩尔G6976 or Ro31-8425与表皮生长因子一起处理部分阻止了表皮生长因子引起癌变形态而没有发现细胞凋亡。
人类和动物治疗:以上描述的试验清晰的表明G7874,G6850,G7612,G7852,Ro31-7549,Ro31-8425,Ro31-8220,Ro31-0432和NGIC-1及与其相似的化学化合物可导致人类多种癌细胞的凋亡以及影响抑制其它人类癌细胞的生长。基于PKCα抑制剂可阻止细胞的癌变,G7874,G6850,G7612,G7852,Ro31-7549,Ro31-8425,Ro31-8220,Ro31-0432和NGIC-1及相似的化学化合物能用作防止癌症发生的预防药物。可应用于对肿瘤化疗。例如,可直接注射至肿瘤,注射到血液或体腔或口腔或通过皮肤贴片。剂量的选择须足以达有效治疗,但不能太高以产生负作用。病人癌症和健康情形在治疗和治疗后的合理周期内须适宜的密切监察。
以上实例描述的G7874,G6850,G7612,G7852,Ro31-7549,Ro31-8425,Ro31-8220,Ro31-0432和NGIC-1及相似化合物对癌症作化疗不限于以上各种癌症。以上化学制品有效的杀死癌细胞和降低了所试验的癌细胞的生长率。因此它显然可有效的处理未试验的与PKCα相关的癌细胞,例如鼻咽癌,肾细胞癌,内分泌肿瘤,例如垂体瘤和甲状腺癌,食道癌和黑素瘤。G7874,G6850,G7612,G7852,Ro31-7549,Ro31-8425,Ro31-8220,Ro31-0432和NGIC-1的衍生物能有效的抑制PKCα,也可作为癌症的治疗。同样因为G7874,G6850,G7612,G7852,Ro31-7549,Ro31-8425,Ro31-8220,Ro31-0432和NGIC-1及及其衍生物可防治细胞的癌变,故可作为预防癌变药物,尤其对特定癌症的高危人群。
Claims (7)
1、一种化合物在制备预防和治疗癌症药物中的应用,其特征在于该化合物为G7874,其结构式为:
2、一种化合物在制备预防和治疗癌症药物中的应用,其特征在于该化合物为G6850,其结构式为:
3、一种化合物在制备预防和治疗癌症药物中的应用,其特征在于该化合物为NGIC-I,其结构为:
4、一种化合物在制备预防和治疗癌症药物中的应用,其特征在于该化合物为Ro31-7549,其结构式为:
7、一种化合物在制备预防和治疗癌症药物中的应用,其特征在于所说的化合物为Ro31-0432,其结构式为Ro31-0432:
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CNB2004100627688A CN1274303C (zh) | 2004-07-09 | 2004-07-09 | 一种化合物及其衍生物在制备防治癌症药物中的应用 |
US11/175,315 US20060009492A1 (en) | 2004-07-09 | 2005-07-07 | Cancer treatment with compounds inhibiting PKC alpha |
US11/902,334 US20080009511A1 (en) | 2004-07-09 | 2007-09-20 | Cancer treatment with compounds inhibiting PKC alpha |
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CNB2004100627688A CN1274303C (zh) | 2004-07-09 | 2004-07-09 | 一种化合物及其衍生物在制备防治癌症药物中的应用 |
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EP2047849A1 (en) * | 2007-10-08 | 2009-04-15 | KTB Tumorforschungsgesellschaft mbH | Use of indolocarbazole imides as protein kinase inhibitors for the treatment of hematologic and solid tumors |
US20120026995A1 (en) * | 2010-01-12 | 2012-02-02 | Autonet Mobile, Inc. | Mobile router with lan internet connectivity |
US9561245B2 (en) | 2012-09-06 | 2017-02-07 | The Board Of Regents Of The University Of Texas System | Combination treatments for melanoma |
WO2014090398A1 (en) * | 2012-12-10 | 2014-06-19 | Centogene Ag | Use of maleimide derivatives for preventing and treating leukemia |
US9572828B2 (en) | 2013-07-18 | 2017-02-21 | The Board Of Regents Of The University Of Texas System | Treatment for melanoma |
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US5882927A (en) * | 1992-03-16 | 1999-03-16 | Isis Pharmaceuticals, Inc. | Oligonucleotide inhibition of protein kinase C |
US5885970A (en) * | 1992-03-16 | 1999-03-23 | Isis Pharmaceuticals, Inc. | Antisense oligonucleotides against human protein kinase C |
US5723456A (en) * | 1993-12-07 | 1998-03-03 | Eli Lilly & Company | Therapeutic treatment for cardiovascular diseases |
US5843935A (en) * | 1993-12-07 | 1998-12-01 | Eli Lilly And Company | Protein kinase C inhibitors |
US5821072A (en) * | 1996-02-20 | 1998-10-13 | Sloan-Kettering Institute For Cancer Research | Combinations of PKC inhibitors and therapaeutic agents for treating cancers |
US5744460A (en) * | 1996-03-07 | 1998-04-28 | Novartis Corporation | Combination for treatment of proliferative diseases |
GB9620390D0 (en) * | 1996-09-30 | 1996-11-13 | Eisai London Res Lab Ltd | Substances and their uses |
US6284783B1 (en) * | 1999-06-09 | 2001-09-04 | The Uab Research Foundation | Use of bisindolylmaleimide compounds to induce Fas-mediated apoptosis |
US6303646B1 (en) * | 1999-08-09 | 2001-10-16 | Zhimin Lu | Cancer treatment with Gö 6976 |
US6696478B2 (en) * | 1999-08-09 | 2004-02-24 | Zhimin Lu | Cancer treatment with Gö6976 and its related compounds |
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US20080009511A1 (en) | 2008-01-10 |
US20060009492A1 (en) | 2006-01-12 |
CN1586476A (zh) | 2005-03-02 |
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