CN1038278A - 取代的苯衍生物和它们的制备方法及包含它们的抗癌组合物 - Google Patents
取代的苯衍生物和它们的制备方法及包含它们的抗癌组合物 Download PDFInfo
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- CN1038278A CN1038278A CN89101896A CN89101896A CN1038278A CN 1038278 A CN1038278 A CN 1038278A CN 89101896 A CN89101896 A CN 89101896A CN 89101896 A CN89101896 A CN 89101896A CN 1038278 A CN1038278 A CN 1038278A
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- Prior art keywords
- replacement
- alkyl
- group
- nitro
- halogen atom
- Prior art date
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- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 239000007935 oral tablet Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 239000001814 pectin Substances 0.000 description 1
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- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
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- 238000000746 purification Methods 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
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- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
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- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- RSIJVJUOQBWMIM-UHFFFAOYSA-L sodium sulfate decahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].[O-]S([O-])(=O)=O RSIJVJUOQBWMIM-UHFFFAOYSA-L 0.000 description 1
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- 238000002525 ultrasonication Methods 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 238000005550 wet granulation Methods 0.000 description 1
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- C07D213/62—Oxygen or sulfur atoms
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Abstract
一种由下述结构式表示的取代的苯衍生物:
式中A表示:
Description
本发明涉及包括苯甲酰脲类型化合物和苯亚氨基酸酯类型化合物的取代的苯衍生物,以及制备它们及其中间体的方法,涉及包括一种包含上述取代的苯衍生物作为治疗白血病(血癌)、黑色素瘤、肉瘤或癌的组合物以及治疗白血病(血癌)或上述提及的诸如此类的方法。
各种苯甲酰脲类型化合物以及苯亚氨基酸酯化合物在许多发行物上业已公知。例如,某些苯甲酰脲类型化合物已在美国专利号4,623,658 4,672,139、4,666,942、4,698,365以及日本未审查的专利申请号277664/88中已有揭示。某些苯亚氨基酸酯化合物已在美国专利号4,200,653,欧洲专利公开号109,211和138,772和比利时专利号892,042中揭示。然而,在这些发行物中所揭示的化合物在它们在化学结构上与本发明是不同的,本发明的取代的苯衍生物在构成苯甲酰脲或苯亚氨基酸酯中具有上述不同的取代基的苯基。另外,上述发行物并无应用本发明的化合物的启示。
进一步地,欧洲专利公开号193,249揭示某些苯甲酰脲类型化合物以及将该化合物用作抗肿瘤剂,然而,在发行物中揭示的化合物在化学结构上在氮原子连接到苯环上的取代基与本发明的取代的苯衍生物是不同的。
本发明的发明者对苯甲酰脲类型化合物和苯亚氨基酸酯类型化合物进行了广泛的研究并已发现一种在构成苯甲酰脲或苯亚氨基酸酯的苯基上具有硝基或取代的氨基以及在脲部分或亚胺部分上有特定的取代基,显示优异的抗肿瘤活性,并改进了已知化合物在有机溶剂中不良的溶解性。
本发明提供由下述结构式表示的取代的苯衍生物:
式中A表示:
其特征在于X的氢原子、卤原子或硝基;R1为X1Z1(X为氢原子或硫原子以及Z1为取代的或非取代的烷基、取代的或非取代的链烯基、取代的或非取代的链炔基、取代的或非取代的芳族基团,或取代的或非取代的杂环芳族基团),-COZ1基团(Z1如上述所规定的), 基团(Z1如上述所规定的,Z2为CO2Z3,式中Z3与Z1相同,或为-SO2Z3,式中Z3如上述所规定的以及n为0或1), (Z1和Z3如上述所规定的)或 X2,X3和X4分别为氧原子或硫原子以及Z4和Z5与Z1相同),以及R3为硝基或 (R4和R5分别为烷基,或者它们可以和相邻的氮原子一起形成杂环基团),或
式中X和R3如上述所规定的,以及R2为-X1Z1(X1和Z1如上述所规定的);Y为卤原子、取代的或非取代的烷基、取代的或非取代的烷氧基、取代的或非取代的烷硫基,硝基或 (R6和R7分别为取代的或非取代的烷基;R为
(R8与Y相同以及q为1至4的整数)
(R8如上述所规定的,以及γ为1至3的整数)或者
(R8和r如上述所规定的);以及m为1至4的整数,或其盐。
本发明同时提供制备这些产物及其中间体的方法,包含上述取代苯衍生物作为治疗哺乳动物的白血病、黑色素瘤、肉病或癌的组合物以及治疗白血病或上述提及的诸如此类的方法。
以下,本发明将通过较佳的具体实施例对本发明作详细说明。
在结构式Ⅰ中,包含在Z1、Z3至Z5、R8和Y中的取代的或非取代的烷基、取代的或非取代的烷氧基、取代的或非取代的烷硫基构成烷基部分,较佳地包括具有1至11个碳原子的烷基,诸如:甲基、乙基、丙基、丁基、戊基、己基、庚基、辛基、壬基、癸基和十一烷基。它们可以是直链的或支链的脂肪族结构的异构体。包含在R4至R7的取代的或非取代的烷基,较佳地包括具有1至6个碳原子的烷基,诸如:甲基、乙基、丙基、丁基、戊基或己基。同时它们包括结构上的如上述提及的异构体。
包含在Z1和Z3至Z5中的取代的或非取代的链烯基,较佳地包括2至6个碳原子的链烯基,诸如:乙烯基、丙烯基、丁烯基、戊烯基和己烯基。另外,取代的或非取代的链炔基,较佳地包括2至6个碳原子的链炔基,诸如:乙炔基、丙炔基、丁炔基、戊炔基和己炔基。它们包括结构上如上述提及的异构体。
包含在Z1和Z3至Z5的芳族基团包括苯基和萘基以及杂环芳基包括噻吩基、呋喃基、吡喃基、吡啶基、嘧啶基、喹啉基和喹喔啉基。
包含在R3的由R4和R5和相邻氮原子一起形成的杂环,包括吗啉基、吖丙啶基、吡咯烷基和哌啶子基。
包含在Z1和Z3至Z5的取代的烷基、取代的链烯基、取代的链炔基、取代的芳族基团或取代的杂环芳族基团的取代基包括卤原子、硝基、氰基、可以由卤原子取代的烷基、可以由卤原子取代的链烯基、可以由卤原子取代的链炔基、可以由卤原子取代的环烷基以及可以由卤原子取代的苯基。这些取代基的数目可以为1或大于1。包含在Y和R6至R8的取代的烷基取代的烷氧基,取代的烷硫基的取代基包括卤原子等。取代基数目可以为1或大于Ⅰ。
当包含在Z1和Z3至Z5中烷基作为取代的烷基、取代的链烯基、取代的链炔基、取代的芳族基团或取代的杂环芳族基团的取代基时,较佳地包括具有1至11个碳原子的烷基,以及较佳地包括分别具有2至6个碳原子的链烯基或链炔基。它们中的特定的例子是包含在Z1中的取代的或非取代的烷基、取代的或非取代的链烯基和取代的或非取代的链炔基是相同的。另外,环烷基较佳地包括3至6个碳原子和环烷基,诸如:环丙烷基、环戊烷基以及环己烷基。
进一步地,在结构式Ⅰ中Z3和Z5可以与Z1相同,以及R8可以与Y相同。然而,这并不意味着Z3至Z5和Z1或R8和Y经常地同时相同。它们相互间可以是相同或彼此不同的。
另外,当结构式Ⅰ中的(Y)m、(R8)q或(R8)r的整数m、q或r为2或更多时,Y和R8相互间可以是相同或不同的。
在结构式Ⅰ中的卤原子,作为例子,包括氟原子、氯原子、溴原子和碘原子。
在结构式Ⅰ中的-NH-部分的氮原子是酸性的,结构式Ⅰ的化合物可以和碱性物质诸如碱金属盐形成盐类。
结构Ⅰ的化合物中,以下为选择性地作为抗肿瘤组合物的活性成份:
(1)A化合物中X为氢原子。
(2)A化合物中R1为-SZ1或-COZ1。
(3)A化合物中R2为-OZ1
(4)A化合物中的R3为硝基
(5)A化合物中(Y)m的Y为可以由卤原子取代的烷基以及m为1,更佳地,Y为甲基以及m为1。
(6)A化合物中(Y)m(m为1)位于连结A位置的间位。
(7)A化合物中R为,
更佳地R8为卤原子。
(8)A化合物中-OR位于连结A位置的对位。
在结构式Ⅰ的化合物中,苯甲酰脲可以通过如下方法生产:
(A)
在上式中,X、R1、R3、Y、m和R为如上述所规定,A1为-NCO或-NH2以及A2为氢原子或-COCl,当A为氢原子时,A1为-NCO,或当A2为-COCl时,A1为-NH2。上述反应通常在从0℃至回流温度并在溶剂的存在下进行,以及反应时间通常为从0.1至70小时。溶剂包括苯、甲苯、二甲苯、氯苯、己烷、氯仿、二氯甲烷、二氯乙烷、二乙基醚、四氢呋喃、二噁烷、乙酸乙酯、二甲基甲酰胺、二甲基亚砜和六甲基磷酸三酰胺。另外,当A2为-COCl和A1为-NH2的情况下,该反应最好在碱存在下进行。碱包括:正丁基锂、三乙胺、氢氧化钠、氢氧化钾、碳酸钠、碳酸钾和氢化钠。
进一步地,苯亚氨基酸酯化合物可以通过如下方法生产:
(B)
上式中,X、R2、R3、Y、m和R如上述所规定。上述反应通常在0℃至回流温度,并在溶剂存在下进行,反应时间通常从1至24小时。所用的溶剂通常可以采用在方法(A)中的一种。
结构式Ⅰ的化合物也可以通过如下的另一个方法制备:
在上式中,X、R1、R2、R4、R5、Y、m和R如上述所规定,以及Hal为卤原子。
上述(C-1)和(C-2)反应通常在0℃至回流温度并在溶剂存在下进行,反应时间通常从1至24小时,作为溶剂,可以采用方法(A)中的一种以及可以采用水。
用于方法(A)中的结构式Ⅲ的化合物是一种新型化合物并可以通过例如以下的方法制备:
(a-1)
在上式中,R1、Y、m、Hal和R如上述所规定:用于上述反应(a-1)中的溶剂和碱可以同样用于方法(A)中的。
(a-2)
在上式中,R1、Y、m和R如上述所规定。
用于上述反应(a-2)中的溶剂和碱可以用于方法(a-1)中同样的溶剂。
用于上述方法(B)中的结构式Ⅳ的化合物也是一种新型的化合物并可以通过如下方法制备:
(b)
式中X和R3如上述所规定,以及X5为氧原子或硫原子它和卤化物诸如:甲基碘或苄基氯反应和硫酸化物诸如:硫酸二甲酯或硫酸二乙酯,强酸酯诸如:氟磺酸异丙基酯或三氟甲烷磺酸甲酯或三乙基氧(氟硼酸盐[(C2H5)3O+BF- 4]于-78℃至回流温度下并在溶剂存在下反应1至24小时,以在结构式Ⅳ的化合物上导入R2。溶剂包括:氯仿、二氯甲烷、二乙基醚和四氢呋喃。以下,将典型例子的结构式Ⅲ和Ⅳ中间体化合物示于表1和2中。
以下将说明结构式Ⅰ、Ⅲ和Ⅳ的化合物的具体的制备实施例。制备实施例1。
4-[4-(5-溴-2-嘧啶基氧)-3-氯苯基]-7-(2-硝基苯基)-2-辛基-5,7-二氧-3-硫-2,4,6-三氮庚烷酸甲酯(化合物No.31)的制备
(1)将3.0克4-[4-(5-溴-2-嘧啶基氧)-3-氯苯胺和3.04克N-氯硫基-N-正辛基氨基甲酸甲酯溶解在30毫升的二氯甲烷中,将1.52毫升三乙胺在3毫升二氯甲烷的溶液在冰的冷却下滴加入其中。该混合物在室温下反应3小时,反应完全后,二氯甲烷从反应产物中蒸出,反应产物通过硅胶色谱柱纯化,得到4.0克N-{[[4-(5-溴-2-嘧啶基氧)-3-氯苯基]氨基]硫}N-正-辛基氨基甲酸甲酯(中间体化合物No.31)
(2)将4.0克在步骤(1)中得到的中间体化合物No.31溶解在30毫升1,2-二氯乙烷中,并在其中加入1.77克2-硝基苯甲酰异氰酸酯。该混合物在室温反应1.5小时。反应完全后,从产物中蒸去1,2-二氯乙烷,反应产物通过硅胶柱色谱纯化,得到2.65克所需的化合物(熔点:51-54℃)呈非结晶形态。
制备实施例2.
N-[4-(5-溴-2-嘧啶基氧)-3-甲苯基]0.0-二乙基N-(2-硝基本甲酰氨基羰基)酰氨基硫磷酸酯的制备:(化合物No.52)
(1)向3.0克4(5-溴-2-嘧啶苯氧)-3-甲苯胺溶解在30毫升四氢呋喃的溶液于-78℃下,滴加0.70克丁基锂溶解在7.4毫升正己烷的溶液。滴加完毕后,该混合物搅拌15分钟,并在其中滴加入2.22克0.0-氯硫磷酸二乙酯溶解在3毫升四氢呋喃的溶液。混合物于室温反应2小时,反应完全后,反应产物倾入水中并用乙酸乙酯萃取。然后萃取液在Glauber′s盐(硫酸钠)上干燥并通过硅胶柱色谱纯化,得到1.48克N-[4-(5-溴-2-嘧啶基氧)-3-甲苯基]0.0-酰氨基硫磷酸二乙酯(中间体化合物No.44)为油状物质。
(2)将1.48克在上述步骤(1)中得到的中间体化合物No.44和1.32克2-硝基苯甲酰异氰酸酯溶解在20毫升四氢呋喃中。该混合物在回流下反应24小时并进一步在室温反应44小时。反应完全后,将反应产物倾入水中并用乙酸乙酯萃取,萃取液用硫酸钠干燥并通过硅胶柱色谱纯化得到1.40克所需的化合物(熔点:56-60℃)。
制备实施例3
N-[4-(5-溴-2-嘧啶基氧)-3-甲苯基]-N′-(2-硝基苯甲酰)-N-(2-硝基苯基硫)脲(化合物No.38)的制备
(1)将2.0克4-(5-氯-2-嘧啶基氧)-3-甲基苯胺和0.94克三乙胺溶解在20毫升甲苯中,于室温下滴加入1.61克2-硝基苯硫基氯溶解在5毫升甲苯中的溶液。该混合物于室温搅拌1小时。反应完全后,向反应产物加入乙酸乙酯,乙酸乙酯层用水洗涤,并用硫酸钠干燥,然后用柱色谱纯化得到2.76克N-[4-(5-氯-2-嘧啶基氧)-3-甲苯基]-2-硝基苯硫基胺(中间体化合物No.37)(熔点:74-85℃)为黄色非结晶形态。
(2)将2.0克在上述步骤(1)得到的中间体化合物No.37溶解在30毫升甲苯中,并加入1.48克2-硝基苯甲酰异氰酸酯。混合物于室温反应2小时。反应完全后,向反应产物加入20毫升正-己烷,将该混合物过滤。得到的晶体用甲醇洗涤,得到2.85克所需的化合物(熔点:171-174℃)为微黄色结晶。
制备实施例4.
N-[4-(5-氯-2-嘧啶基氧)-3-甲苯基]-N′-(2-硝基苯甲酰)-N-戊酰脲(化合物No.12):
(1)将2.0克4-(5-氯-2-嘧啶基氧)-3-甲苯胺和1.3毫升三乙胺溶解在20毫升四氢呋喃中,并在冰的冷却下加入1.12毫升戊酰氯。混合物于室温下搅拌40分钟。反应完全后,反应产物倾入水中并用乙酸乙酯萃取。萃取液层用硫酸钠干燥。然后蒸去乙酸乙酯,得到2.8克N-[4-(5-氯-2-嘧啶基氧)-3-甲苯基]戊酰胺(中间体化合物No.13)(熔点:146-150℃)
(2)将在上述步骤(Ⅰ)中得到的2.0克中间体化合物No.13和2.43克2-硝基苯甲酰异氰酸酯溶解在40毫升四氢呋喃中,该混合物于回流下反应2.5小时,反应完全后,反应产物在减压下蒸去四氢呋喃,反应产物通过硅胶柱色谱纯化得到1.65克所需的化合物(熔点:69-75℃)呈非结晶状态。
制备实施例5
N-[4-(5-溴-2-嘧啶基氧)-3-甲苯基]氨基甲酰基-甲丁基2-硝基苯亚氨酸酯(化合物No.71)的制备:
(1)将9克氟磺酸用干冰一丙酮冷却至-78℃,在搅拌下将30毫升1-戊烯逐渐滴入,滴加完全后,在相同的温度下继续搅15分钟,将予先冷却至-78℃的100毫升二氯乙烷滴入,然后立刻加入15克2-硝基苯甲酰胺。然后,当溶液温度回复到室温时,在搅拌下反应12小时。反应完全后,将反应溶液倾入250毫升1N的氢氧化钠和100毫升二氯甲烷的冷却至0℃的混合物中,然后混合物强烈搅拌10分钟。萃取反应溶液,萃取液用水洗涤,并用硫酸钠干燥。蒸去溶剂后残留物通过硅胶色谱纯化得到0.3克油状的1-甲丁基2-硝基苯亚氨基酸酯(中间体化合物No.63)
(2)将通过0.4克4-(5-溴-2-嘧啶基氧)-3-甲苯胺和0.4毫升氯甲酸三氯甲基酯反应得到的0.5克4-(5-溴-2-嘧啶基氧)-3-甲苯基异氰酸酯溶解在10毫升甲苯中,并向该溶液滴加入上述步骤(1)得到的0.3克中间体化合物No.63,然后,在相同的温度下搅拌1.5小时。反应完全后,在减压下从反应产物蒸去甲苯,残留物通过硅胶柱色谱纯化得到0.35克所需的化合物(熔点:54-58℃)
以下将典型的结构式Ⅰ的化合物的例子示于表3和表4中。
结构式Ⅰ化合物对抗试验动物即老鼠的癌症诸如P-388白血病、L-1210白血病、B-16黑色素瘤、N-5076肉瘤、克隆38(Colon38)、克隆26(Colon26)和鲁易斯肺癌是有效的。在另一方面,为了决定某些化合物可用作抗肿瘤药剂的适合性,某些在体内的试验系统已由国家癌症研究所(National Cancer Institute)开发。这些在“Cancer Chemotherapy Reports”第Ⅲ部,3卷No.2(1972),由Deran,Greenberg、MacDonald、Schumacher和Abott的著作中已作报导。这些工程方案通常按抗肿瘤剂的试验领域建立标准化的筛选试验。在这些系统中,本发明对P-388白血病具有特别重要的意义。这些肿瘤是在小鼠中发现的。在这些工程方案中用处理动物(T)与对照动物(C)的平均生存期的增加%表示优异的抗肿瘤活性,通常提示对人类抗白血病得出相同的结果。
以下将说明结构式Ⅰ的化合物的抗肿瘤活性剂量和给药方法。这些化合物显示优异的抗肿活性。
(1)抗肿瘤活性
试验实施例1(腹腔内移植一腹腔内施药)
将每只小鼠以1×106P-388白血病细胞通过腹腔移植至BDF小鼠。移植后1和8天腹腔内施以每一种制剂。
观察30天的死亡率。测定每一组增加的生命延长率,以生理食盐水施药的对照组的生存时间以0%为基础,求得增加的生命延长率(ILS)。其结果示于表5中。每一制剂为按下述的制剂实施例8制成的。
施验实施例2(腹腔内移植一口服施药)
将每只小鼠以1×106P-388白血病细胞腹腔内移植在BDF小鼠。移植后1至8天口服每一种制剂。观察30天的死亡率。用试验实施例1同样的方法测定增加的生命延长率,以生理食盐水施药的对照组的生存时间为0%作基准,求得增加的生命延第率(ILS)%。其结果示于表6中。化合物No.4至12、23、29、31、32、35和37的制剂是按下述制剂实施例9形成的,以及其它化合物的制剂是按制剂实施例8形成的。
试验实施例3(腹腔内移植一口服施药)
一种B-16黑色素瘤细胞悬浮液以0.5毫升/小鼠的数量在腹腔内移接种至BDF小鼠,接种后1天,8天和15天口服每一种制剂。观察60天的小鼠死亡率。每组增加的生命移长率(ILS)的测定,系以生理食盐水施药的对照组的生存时间为0%作基准,求得增加的生命延长率(ILS)。其结果示于表7中。每一制剂是按下述的配方实施例4形成的。将B-16黑素瘤细胞接连地皮下移植在C57BL/6小鼠在无菌条件下取出的黑色素瘤,然后将黑色素瘤通过不锈钢筛孔,并将1克黑色素瘤细胞分散在9毫升诸如:培养介质或生理食盐水的等渗压溶液中。制成B-16黑色素瘤细胞悬浮液。
结构式Ⅰ化合物无论在癌细胞的接种部位和制剂的施药部位相同或不同都显示高的抗肿瘤活性。其原因尚不清楚,然而,可能由于以下事实即本发明的化合物在消化道吸收性是好的,在血液中的药剂浓度以及至靶部位的传递性是优异的所致。
(2)剂量和施药方法
在动物的情况,施药的方法,可以通过诸如:腹腔内注射、静脉注射或局部施药或通过口服给药。在人类的情况,可以通过诸如:动脉或静脉注射或局部施药,通过口服或栓剂施药。施药的剂量视动物试验的结果以及各种状况,其总的数量不超过一定数量范围。药剂可以连续或间断施予。然而,该剂量可以选择性地随施药的方法、患者或被处理的动物的状况,诸如:年龄、体重、性别、敏感性、食物、施药时间、并用的药剂或患者或疾病的程度。合适的施药数量和次数,在一定的条件下,必须根据上述指导方针为基础,通过专门医生作出需要的合适数量的测定。
本发明的抗肿瘤剂可以是如在通常药剂中相同方式的配制剂剂。由活性成份和各种医药上可接受的各种辅助剂诸如:惰性稀释剂配成。该制剂经口服或静脉注射或以栓剂形式为最佳。
另外,本发明的抗肿瘤剂中的活性成份的含量根据各种条件的不同而不可能一概而定。该剂可以含有通常抗肿瘤剂的情况同样的活性成份。例如:它可以含有至少0.001%的活性成份。
结构式Ⅰ的化合物比通常的化合物容易溶解在有机溶剂中,并适用于各种制剂或方法的施药。例如:制剂,可以提到栓剂或胶囊,由通过直接混合化合物和聚乙二醇,或一种水质悬浮液组成。
当结构式Ⅰ的化合物配制成水质悬浮液时,它可以含有一种磷脂质。不含有磷脂质的水质悬浮液的制造方法,可以提到,例如的方法包括活性成份化合物予先形成细粉,加至含有表面活性剂的水质溶液,如果需要,加入消泡剂,然后将混合物湿法粉碎以得到颗粒尺寸不大于5μm,例如:颗粒的80%的颗粒尺寸不大于2μm,以及如果需要,可在其中加入增稠剂。表面活性剂包括例如:聚氧乙烯硬化的蓖麻油、聚氧乙烯山梨醇脂肪酸酯、蔗糖酯、聚氧乙烯一聚氧丙烯嵌段聚合物和氧乙基化的多芳基苯酚磷酸(盐)酯。消泡剂包括例如:二甲基聚硅氧烷、甲基苯基硅氧烷、山梨醇脂肪酸酯、聚氧乙烯聚氧丙烯十六烷基和聚硅氧烷。增稠剂包括例如:瓜耳胶、藻酸(alginicacid),阿拉伯胶、果胶、淀粉、苍耳烷胶和白明胶。另一方面,作为制造水质悬浮剂含有的磷脂质,可以提及例如:用大豆磷酯或卵磷酯代替用在上述方法中的表面活性剂,以及抗氧剂诸如:α-生育酚代替增稠剂。
另外,这些配方可以用在药剂领域中通常采用的方法形成片剂、胶囊、包复肠溶衣的片剂、粉剂、注射液或栓剂。
以下,将提及本发明的抗癌剂的具体制剂实施例。
制剂实施例1.
将70毫克结构式Ⅰ化合物的非结晶性粉末和30毫克乳糖充分混合,将混合物以100毫克每粒的数量充填入胶囊,得到用于口服的胶囊。
制剂实施例2.
将85份(重量)的结构式Ⅰ化合物的非结晶性粉末和1份(重量)的葡萄糖、10份(重量)的玉米淀粉和1.5份(重量)的5%玉米淀粉糊溶液均匀混合。该混合物通过湿法成粒、然后加入1份(重量)的硬脂酸镁,该混合物压片,得到用于口服的片剂。
制剂实施例3.
将5克结构式Ⅰ的化合物溶解在5毫升二甲基乙酰胺中,在其中加入25毫升椰子油、7克Pegnol HC-17(注册商标,由Tohokagaku生产的硬化的蓖麻油)和6克Pegnol HO-10M(注册商标,由Toho Kagaku生产的蔗糖酯)得到乳浊液。向该乳浊液加入等量的无菌蒸馏水,该混合物经过20至30秒钟超声波处理得到油质的悬浮液。
制剂实施例4.
将结构式Ⅰ的化合物予先经离心粉碎机粉碎成细粉。另一方面,将5份(重量)的聚氧乙烯(60)硬化蓖麻油、0.2份(重量)的硅氧烷和0.3份(重量)的聚氧乙烯-聚氧丙烯嵌段聚合物加至79.5份(重量)的生理食盐水中得到一种水溶液。向该水溶液中入10份(重量)的结构式Ⅰ化合物的细粉。该混合物通过砂磨机用玻璃珠湿法粉碎至80%的颗粒的颗粒尺寸在2μm以下,然后,加入5份(重量)的2%苍耳烷胶溶液得到水质悬浮剂。
制剂实施例5.
将40份(重量)的结构式Ⅰ的化合物加入至1.5份(重量)的乙氧基化的多芳基苯酚磷酸盐和0.2份(重量)的硅氧烷溶解在53.5份(重量)的生理食盐水的溶液中,该混合物通过砂磨机用玻璃珠湿法粉碎至90%的颗粒的颗粒尺寸在2μm以下,然后,加入5份(重量)的2%苍耳烷胶溶液得到水性悬浊液。
制剂实施例6.
将结构式Ⅰ的化合物予先经离心粉碎机粉碎成细粉。将5份(重量)的结构式Ⅰ的化合物的细粉加入至由2份(重量)的卵磷酯,0.001克(重量)的α-生育酚和92.999份(重量)的生量食盐水的通过分散和搅拌得到的水性溶液。该混合物用玻璃珠砂磨机粉碎至80%的颗粒的颗粒尺寸在2μm以下得到水质悬浊剂。
制剂实施例7.
将结构式Ⅰ的化合物通过离心粉碎机予先粉碎成细粉。另一方面,将5份(重量)的聚氧乙烯(60)硬化的蓖麻油加至60份(重量)的生理食盐水中得到水质溶液。向该水质溶液加入30份(重量)的结构式Ⅰ的化合物的细粉。该混合物通过砂磨机用玻璃珠湿法粉碎至80%颗粒的颗粒尺寸在2μm以下。然后在其中加入5份(重量)的2%苍耳烷胶溶液得到水质悬浮液。
制剂实施例8.
将10份(重量)的结构式Ⅰ的化合物加至包含1.5份(重量)的氧乙基化的多芳基磷酸盐、0.2份(重量)的硅氧烷和0.3份(重量)的聚氧乙烯-聚氧丙烯嵌段聚合物溶解在80份(重量)的生理食盐水的溶液中,该混合物通过砂磨机用玻璃珠湿法粉碎至90%颗粒的颗粒尺寸在2μm以下。然后,在其中加入7份(重量)的2%苍耳烷胶溶液,得到水性悬浊液。
制剂实施例9.
向1份(重量)的结构式1化合物,加入100份(重量)的聚乙二酯400#(分子量:380-420,由Nakarai Kagaku Yakuhin制造)并溶解得到均质的溶液。
表1(续)
表1(续)
表1(续)
中间体化合物No.56:
异丙基[[[4-5-硝基-2-吡啶基氧)-3-氯苯基]氨基]硫]-N-氨基甲酸甲酯油状物质
中间体化合物No.57:
异丙基[[[3-5-氯-2-嘧啶基氧)-4-甲苯基]氨基]硫]-N-氨基甲酸甲酯油状物质
中间体化合物No.58:
异丙基[[[4-(6-氯-3-吡啶基氧)-3-氯苯基]氨基]硫]-N-氨基甲酸甲酯 熔点:132-134℃
中间体化合物No.59:
N-[3-甲基-4-(4,5,6-三甲基-2-吡啶基氧]丙酰氨
表3(续)
化合物No.55:
4-[3-(5-氯-2-嘧啶基氧)-4-甲苯基]-7-(2-硝基苯基)-2-甲基-5,7-二氧-3-硫-2,4,6-三氮庚烷酸异丙酯
熔点:72-84℃(非结晶形态)
化合物No.56:
4-[4-(6-氯-3-哒嗪基氧)-3-氯苯基]-7-(2-硝基苯基)-2-甲基-5,7-二氧-3-硫-2,4,6-三氮庚烷酸异丙酯
熔点:96-105℃(非结晶形态)
化合物No.57:
4-[4-(5-硝基-2-吡啶基氧)-3-氯苯基]-7-(2-硝基苯基)-2-甲基-5,7-二氧-3-硫-2,4,6-三氮庚烷酸异丙酯
熔点:85-91℃(非结晶形态)
化合物58:
N-[3-甲基-4-(4,5,6-三甲基-2-吡啶基氧)苯基]-N′-(2-硝基苯甲酰)-N-丙炔基脲
表4(续)
化合物No.93:
N-[3-(5-溴-2-嘧啶基氧)-4-甲苯基]氨基甲酰基-1-甲丁基硝基苯亚氨酸酯
化合物No.94:
N-[4-(6-溴-3-哒嗪基氧)-3-甲苯基]氨基甲酰基-1-甲丁基硝基苯亚氨酸酯
化合物No.95:
N-[4-(5-溴-2-吡啶基氧)-3-甲苯基]氨基甲酰基-1-甲丁基硝基苯亚氨酸酯
表5
表5(续)
(注)*增加的生命延长期通过下式计算:
增加的生命延长期%(ILS)=( (试验组的生存时间)/(对照组动物的生存时间) ×100)-100
表6
Claims (20)
1、一种由下述结构式表示的取代的苯衍生物:
式中A表示:
其特征在于X为氢原子、卤原子或硝基;R1为-X1Z1(X为氧原子或硫原子以及Z1为取代的或非取代的烷基,取代的或非取代的链烯基,取代的或非取代的链炔基,取代的或非取代的芳族基团,或取代的或非取代的杂环芳族基团),-COZ1基团(Z如上述所确定的), 基团(Z1如上述所确定的Z2为-CO2Z3,式中Z3与Z1相同,或为-SO2Z3,式中Z3如上述所确定的以及n为0或1), (Z和Z如上述所确定的)或 X2、X3和X4分别为氧原子或硫原子以及Z4和Z5与Z1相同),以及R3为硝基或 (R4和R5分别为烷基,或者它们可以和相邻的氮原子一起形成杂环基团),或
式中X和R3如上述所确定的以及R2为-X1Z1(X1和Z1如上述所确定的);Y为卤原子,取代的或非取代的烷基,取代的或非取代的烷氧基,取代的或非取代的烷硫基,硝基或 (R6和R7分别为取代的或非取代的烷基);R为
(R8与Y相同,q为1至4的整数)、
(R8如上述所确定的,以及r为1至3的整数)或者
(R8和r如上述所确定的);以及m为1至4的整数,或其盐。
2、如权利要求1所述的取代的苯衍生物或其盐,其特征在于在A中限定的为取代的烷基、取代的链烯基、取代的链炔基、取代的芳基或取代的杂环基团中的取代基,至少选自包括卤原子、硝基、氰基、可以由卤原子取代的烷基、可以由卤原子取代的链烯基、可以由卤原子取代的链炔基、它可以由卤原子取代的环烷基或可以由卤原子取代的苯基的组,定义为R3的R4和R5与相邻氮原子一起形成的杂环基团为吗啉基、吖丙烷基、吡咯烷基或哌啶子基,以及定义为Y、R6、R7和R8中的取代的烷基、取代的烷氧基或取代的烷硫基中的取代基为卤原子。
4、如权利要求1所述的取代的苯衍生物或其盐,其特征在于A为
5、如权利要求4所述的取代的苯衍生物或其盐,其特征在于X为氢原子,R3为硝基以及R1为-SZ1或-COZ1。
7、如权利要求6所述的取代的苯衍生物或其盐,其特征在于X为氢原子,R3为硝基以及R2为-OZ1。
8、如权利要求1所述的取代的苯衍生物或其盐,其特征在于Y为可以由卤原子取代的烷基以及m为1。
9、如权利要求8所述的取代的苯衍生物或其盐,其特征在于可以由卤素取代的烷基为甲基。
10、如权利要求1所述的取代的苯衍生物或其盐,其特征在于R8为
11、如权利要求10所述的取代的苯衍生物或其盐,其特征在于R为卤原子。
12、如权利要求1所述的取代的苯衍生物或其盐,其特征在于该化合物为N-[4-(5-溴-2-嘧啶基氧)-3-甲苯基]-N′-(2-硝基苯甲酰基)-N-戊酰脲、N-[4-(5-溴-2-嘧啶基氧基)-3-甲苯基]-N′-(2-硝基苯甲酰基)-N′-十一烷酰脲、N-[4-(5-溴-2-嘧啶基氧)-3-甲苯基]-N-己酰-N′-(2-硝基苯甲酰)脲、N-[4-(5-氯-2-嘧啶基氧)-3-甲苯基]-N-己酰-N′-(2-硝基苯甲酰)脲、N-[4-(5-溴-2-嘧啶基氧)-3-甲苯基]-N-庚酰-N′-(2-硝基苯甲酰脲、N-丁酰-N-[4-(5-氯-2-嘧啶基氧)-3-甲苯基]-N′-(2-硝基苯甲酰)脲、N-[4-(5-溴-2-嘧啶基氧)-3-甲苯基]-N-丁酰-N′-(2-硝基苯甲酰)脲、N-[4-(5-氯-2-嘧啶基氧)-3-甲苯基]-N′-(2-硝基苯甲酰)-N-戊酰脲、N-[4-(5-氯-2-嘧啶基氧)-3-甲苯基]-N′-(2-硝基苯甲酰)-N-(2-硝基苯硫)脲、N-[4-(5-溴-2-嘧啶基氧)-3-氯苯基)-N-丁基硫-N′-(2-硝基苯甲酰)脲、N-[4-(5-溴-2-嘧啶基氧)-3-甲苯基]氨基甲酰基-1-甲丁基-2-硝基苯亚氨酸酯或N-[4-(5-溴-2-嘧啶基氧)-3-甲苯基)氨基甲酰基戊烷基]2-硝基亚氨酸酯。
13、一种制备如下结构式表示的化合物的方法:
式中X为氢原子、卤原子或硝基;R1为-X1Z1(X1为氧原子或硫原子以及Z1为取代的或非取代的烷基,取代的或非取代的链烯基、取代的或非取代的链炔基、取代的或非取代的芳族基团,或取代的或非取代的杂环芳族基团),-COZ1基团(Z1如上述所规定的), (Z1如上述所规定的,Z2为-CO2Z3式中Z3与Z1相同,或-SO2Z3式中Z3如上所述所规定的以及n为0或1), (Z1和Z3如上述所规定的)或 X2、X3和X4分别为氧原子或硫原子以及Z4和Z5与Z1相同);以及R3为硝基或 R4和R5分别为烷基、或者它们可以和相邻的氮原子一起形成杂环基团);Y为卤原子、取代的或非取代的烷基、取代的或非取代的烷氧基、取代的或非取代的烷硫基,硝基或 R6和R7分别为取代的或非取代的烷基);R为
(R8与Y相同以及q为1至4的整数)、
(R8如上述所规定以及r为1至3的整数)、或
(R8如上述所规定),m为1至4的整数,其特征在于包括反应如下结构式表示的化合物:
式中A1为-NCO或-NH2,以及X和R3如上述所规定的,与如下结构式表示的化合物:
式中A2为氢原子或-COCl,当A2为氢原子时,A1为-NCO,或者当A2为-COCl,A为NH2,R1、R、Y和m如上述所规定的。
14、一种制备如下结构式表示的化合物的方法:
式中X为氢原子、卤原子或硝基;R2为-X1Z1(X1为氧原子或硫原子以及Z1为取代的或非取代的烷基、取代的或非取代的链烯基、取代的或非取代的链炔基、取代的或非取代的芳族基团或者取代的或非取代的杂芳族基团);R3为硝基或 R4和R5分别为烷基,或者它们可以和相邻的氮原子一起形成杂环基团);Y为卤原子、取代的或非取代的烷基、取代的和非取代的烷氧基、取代的或非取代的烷硫基、硝基或 (R6和R7分别为取代的或非取代的烷基);R为
(R8为与Y相同以及q为1至4的整数);
(R8如上述所规定以及r为1至3的整数);以及m为1至4的整数,其特征在于将如下结构式的化合物:
式中X、R2和R3如上述所规定,和如下结构式表示的化合物反应:
式中R、Y和m如上述所规定的。
15、一种作为治疗哺乳动物白血病(血癌)、黑色素瘤、肉瘤或癌的组合物,其特征在于包括如权利要求1所述的取代的苯衍生物或其盐可控制对于抗白血病(血癌)、黑色素瘤、肉瘤或癌的有效活性的足够数量以及医学上可接受的辅助剂。
16、一种治疗哺乳动物白血病(血癌)黑色素瘤、肉瘤或癌的方法,其特征在于包括施以如权利要求1所述的取代的苯衍生物或其盐的足够数量,它具有控制活性以对抗白血病(血癌)、黑色素瘤、肉瘤或癌。
17、一种如下结构式表示的化合物:
其特征在于A2为氢原子或-COCl;R1为-X1Z1(X1为氧原子或硫原子以及Z1为取代的或非取代的烷基、取代的或非取代的链烯基、取代的或非取代的链炔基、取代的或非取代的芳族基团或取代的或非取代的杂芳族基团),-COZ1(Z1如上述所规定的), (Z1如上述所规定的,Z2为-CO2Z3式中Z3与Z1相同,或为-SO2Z3式中Z3如上述所规定以及n为0或1), (Z1和Z2如上述所规定)或 (X2、X3和X4分别为氧原子或硫原子以及Z4和Z5与Z1相同);Y为卤原子、取代的或非取代的烷基、取代的或非取代的烷氧基、取代的或非取代的烷硫基、硝基或 (R6和R7分别为取代的或非取代的烷基);R为
(R8为与Y相同以及q为1至4的整数),
(R8如上述所规定以及r为1至3的整数)或
(R8如上述所规定);以及m为1至4的整数。
18、如权利要求17所述的化合物,其特征在于A2为氢原子、R为-SZ1或-COZ1,Y为甲基,m为1,R为
以及R8为卤原子。
20、如权利要求19所述的化合物,其特征在于X为氢原子、R2为-OZ1以及R3为硝基。
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP79658/1988 | 1988-03-31 | ||
JP7965888 | 1988-03-31 | ||
JP79658/88 | 1988-03-31 | ||
JP1034487A JPH029855A (ja) | 1988-03-31 | 1989-02-14 | 置換ベンゼン誘導体、それらの製造方法及びそれらを含有する抗癌性組成物 |
JP34487/89 | 1989-02-14 | ||
JP34487/1989 | 1989-02-14 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1038278A true CN1038278A (zh) | 1989-12-27 |
CN1020097C CN1020097C (zh) | 1993-03-17 |
Family
ID=26373308
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Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN89101896A Expired - Fee Related CN1020097C (zh) | 1988-03-31 | 1989-03-27 | 取代的苯衍生物的制备方法 |
Country Status (4)
Country | Link |
---|---|
US (1) | US4987135A (zh) |
EP (1) | EP0335408A3 (zh) |
JP (1) | JPH029855A (zh) |
CN (1) | CN1020097C (zh) |
Cited By (1)
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CN102164893A (zh) * | 2008-09-29 | 2011-08-24 | 住友化学株式会社 | 1-取代-反-4-(取代氨基)哌啶-3-醇的制造方法 |
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NZ234551A (en) * | 1989-07-28 | 1991-10-25 | Ishihara Sangyo Kaisha | Benzoylurea derivatives and antitumour compositions |
JPH0810522A (ja) * | 1994-06-30 | 1996-01-16 | Fuji Filter Kogyo Kk | 高粘度流体用フィルター |
JP2008536932A (ja) * | 2005-04-18 | 2008-09-11 | サイード・アール・カーン | チューブリン重合阻害剤:ボンゾイルフェニル尿素(bpu)硫黄類似体の設計及び合成 |
DE102005044108A1 (de) | 2005-09-15 | 2007-03-29 | Bayer Cropscience Ag | Dioxazin- und Oxdiazin-substituierte Arylamide |
US20090099218A1 (en) * | 2007-09-17 | 2009-04-16 | Khan Saeed R | Synthesis of novel tubulin polymerization inhibitors: benzoylphenylurea (bpu) sulfur analogs |
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US4200653A (en) * | 1978-09-29 | 1980-04-29 | Imperial Chemical Industries Limited | Insecticidal compound and method of use |
BE892042A (fr) * | 1981-02-09 | 1982-08-05 | Upjohn Co | Phenylcarbamoylbenzimidates, leur preparation et leur utilisation |
EP0109211A1 (en) * | 1982-11-05 | 1984-05-23 | Imperial Chemical Industries Plc | Pyridine derivatives |
US4723015A (en) * | 1983-10-17 | 1988-02-02 | Ciba-Geigy Corporation | Certain insecticidal N-2-pyridyloxyphenylbenzimidates |
JPS60112764A (ja) * | 1983-11-22 | 1985-06-19 | Ishihara Sangyo Kaisha Ltd | Ν−ベンゾイル−ν′−ピリジルオキシフエニルウレア系化合物及びそれらを含有する殺虫剤 |
CA1339745C (en) * | 1984-04-10 | 1998-03-17 | Martin Anderson | Pesticidal benzoylurea compounds |
US4623658A (en) * | 1984-04-10 | 1986-11-18 | Shell Oil Company | Pesticidal benzoylurea compounds |
JPS6133176A (ja) * | 1984-07-24 | 1986-02-17 | Ishihara Sangyo Kaisha Ltd | N−ニトロベンゾイル−n’−ピリダジニルオキシフエニルウレア系化合物、それらの製造方法及びそれらを含有する抗癌剤 |
AU601145B2 (en) * | 1985-03-01 | 1990-09-06 | Duphar International Research B.V. | Benzoyl urea derivatives having anti-tumor activity |
AU594098B2 (en) * | 1985-12-11 | 1990-03-01 | Ishihara Sangyo Kaisha Ltd. | N-benzoyl urea compounds, antitumorous compositions containing them, and process for their preparation |
JPS63277664A (ja) * | 1987-05-09 | 1988-11-15 | Ishihara Sangyo Kaisha Ltd | N−フェニル−n′−ベンゾイルウレア系化合物及びそれらを含有する殺虫、殺ダニ剤 |
-
1989
- 1989-02-14 JP JP1034487A patent/JPH029855A/ja active Pending
- 1989-03-16 US US07/324,559 patent/US4987135A/en not_active Expired - Fee Related
- 1989-03-27 CN CN89101896A patent/CN1020097C/zh not_active Expired - Fee Related
- 1989-03-30 EP EP19890105670 patent/EP0335408A3/en not_active Withdrawn
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN102164893A (zh) * | 2008-09-29 | 2011-08-24 | 住友化学株式会社 | 1-取代-反-4-(取代氨基)哌啶-3-醇的制造方法 |
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Publication number | Publication date |
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US4987135A (en) | 1991-01-22 |
CN1020097C (zh) | 1993-03-17 |
EP0335408A2 (en) | 1989-10-04 |
EP0335408A3 (en) | 1990-11-14 |
JPH029855A (ja) | 1990-01-12 |
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