CN1258279A - 作为细胞增殖抑制剂的氰基胍 - Google Patents

作为细胞增殖抑制剂的氰基胍 Download PDF

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CN1258279A
CN1258279A CN98805595A CN98805595A CN1258279A CN 1258279 A CN1258279 A CN 1258279A CN 98805595 A CN98805595 A CN 98805595A CN 98805595 A CN98805595 A CN 98805595A CN 1258279 A CN1258279 A CN 1258279A
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C·S·汉尼克
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Abstract

本发明涉及式(Ⅰ)的迄今未知的化合物或它们的互变形式,与吡啶环的连接在3－或4－位,式中R代表一个或多个取代基,它们可以是相同的,也可以是不同的,选自:氢、卤素、三氟甲基、C1－C4烷基、烷氧基或烷氧羰基、硝基、氨基或氰基;Q代表C4－C20二价烃基,它们可以是直链的、支链的、饱和的或不饱和的;X代表羰基、羰基氨基、氨基羰基、氧基羰基氧基、氧基羰基、羰基氧基、氨基羰基氧基、氨基硫代羰基氧基、氧基羰基氨基或氧基硫代羰基氨基;Y代表亚苄基或亚苯基;R2代表一个或多个取代基,它们可以是相同的,也可以是不同的,选自:氢、C1－C4烷基、羟烷基或烷氧基、羟基、卤素、三氟甲基、氰基、甲酰氨基、磺酰氨基、硝基、氨基、羧基、烷氧羰基或苄氧基;本发明还涉及式(Ⅰ)化合物的药物上可接受的无毒盐及其N－氧化物。本化合物在人和兽医实践中具有价值。

Description

作为细胞增殖抑制剂的氰基胍
本发明涉及一类迄今未知的化合物，这些化合物在抑制剂例如皮肤细胞和癌细胞的不良的细胞增殖方面显示出强活性。本发明还涉及含有这些化合物的药物制剂，这类制剂的剂量单位，以及它们在治疗和预防以异常细胞分化和/或细胞增殖为特征的疾病如牛皮癣和癌症中的应用。
本发明的化合物由通式I表示
Figure A9880559500051
或它们的互变形式，与吡啶环的连接在3-或4-位，式中R1代表一个或多个取代基，它们可以是相同的，也可以是不同的，选自：氢、卤素、三氟甲基、C1-C4烷基、烷氧基或烷氧羰基、硝基、氨基或氰基；X代表C4-C20二价烃基，它们可以是直链的、支链的、饱和的或不饱和的；X代表羰基、羰基氨基、氨基羰基、氧基羰基氧基、氧基羰基、羰基氧基、氨基羰基氧基、氨基硫代羰基氧基、氧基羰基氨基或氧基硫代羰基氨基；Y代表亚苄基或亚苯基；R2代表一个或多个取代基，它们可以是相同的，也可以是不同的，选自：氢、C1-C4烷基、羟烷基或烷氧基、羟基、卤素、三氟甲基、氰基、甲酰氨基、磺酰氨基、硝基、氨基、羧基、烷氧羰基或苄氧基。
如果本发明的化合物含有一个或多个不对称碳原子，则这些化合物可形成光学异构体或非对映体。本发明也包括这样的异构体和它们的混合物。
本发明式I化合物的盐可以用药物上可接受的无机酸或有机酸形成，所说的酸例如为盐酸、氢溴酸和氢碘酸、磷酸、硫酸、硝酸、4-甲苯磺酸、甲磺酸、甲酸、乙酸、丙酸、柠檬酸、酒石酸、苯甲酸和马来酸。
本发明式I化合物的盐也可以用药物上可接受的无机碱或有机碱形成。与药物上可接受的无毒碱所形成的盐可以是碱金属盐和碱土金属盐，如锂盐、钠盐、钾盐、镁盐、钙盐，以及与氨和适宜的非毒性胺，如C1-C6烷基胺，例如三乙胺，C1-C6链烷醇胺，例如二乙醇胺或三乙醇胺，普鲁卡因，环烷基胺，例如二环己胺，苄胺，例如N-甲基-苄胺，N-乙基苄胺，N-苄基-2-苯乙胺，N，N’-二苄基亚乙基二胺或二苄基胺，和杂环胺，例如吗啉，N-乙基呱啶等等所形成的盐。
即使本发明的化合物在肠道给药后被完全吸收，在某些情况下制备本发明化合物的适宜的生物可逆性衍生物，即制备所谓的前体药物，优选衍生物，还是有利的，所说衍生物的物理化学性质可提高所述化合物在生理pH下的溶解性和/或吸收性和/或生物利用率。
例如这样的衍生物是本发明化合物的吡啶基N-氧化物衍生物，这类化合物是通过在惰性溶剂，例如二氯甲烷中，用适宜的氧化剂，例如用3-氯过苯甲酸氧化吡啶基N-氧化物来制备的。
用于改善有关化合物的理化性质和/或溶解度的其它适宜的方法也可以使用。
在英国专利1,489,879中描述的N-烷基-N’-氰基-N”-吡啶基胍是有效的钾通道活化剂，它们作为前毛细血管的血管舒张剂具有显著的作用，可降低动物和人的总外周阻力，因而可用作抗高血压剂。如1993年9月13日提交的，公开号为WO 94/06770的国际专利PCT/DK93/00291所述，向上述英国专利中的脂族基中引入含芳氧基的基团产生了与上述英国专利所包括的化合物的公认的作用相比对离体组织和细胞具有更特异的药理学作用，而对来自钾通道的86Rb-流出物没有影响或其影响可忽略不计的结构。
本发明的化合物在低于已知化合物的浓度下可抑制培养物中各种肿瘤细胞系的增殖，如下表1所示，因此使得它们可有效地用于抗肿瘤的化疗。
用不同类型的人癌症细胞系对肿瘤细胞增殖的抑制作用进行了研究。所研究的细胞系是小细胞肺癌(NYH)，非小细胞肺癌(NCI-H 460)和乳癌(MCF-7)，所用的方法是下列一般性方法：
在所研究的化合物存在下体外培养细胞24小时。通过掺加[3H]胸苷测定DNA合成，计算化合物的半数抑制浓度(IC50)。
表1在人乳癌(MCF-7)，人小细胞肺癌(NYH)
和人非小细胞肺癌(NCI-H460)细胞系中本发明
下列实施例的化合物对肿癌细胞在体外增殖的抑制作用
得自以下实施例的化合物     MCF-7       NYH         NCI-H460IC50(nm)   IC50(nm)   IC50(nm)
  实施例号2实施例号4     57            6.2          662.2           1.7          -
  现有技术A现有技术B     920           380          ＞1000250           45           67
A：N-氰基-N’-(4-苯氧丁基)-N”-4-吡啶基胍，PCT/DK 93/00291，实施例14。
B：N-氰基-N’-(4-苯氧戊基)-N”-4-吡啶基胍，PCT/DK 93/00291，实施例18。
结果表明本发明的化合物在与PCT/DK 93/00291的化合物A和B相同浓度下或低于化合物A和B的浓度下能抑制肿瘤细胞的体外增殖。
本发明的化合物可被完全耐受，无毒，能发挥所述的有益活性，对全身血压没有影响或影响很小。一般来说，它们可以口服、静脉内、皮内、鼻内或透皮途径给药。
本发明也涉及制备所需的通式I化合物的方法。式I的化合物可以用在现有技术中详述的标准方法方便地制备。下列反应流程概括了制备式I化合物的途径。A＝O，S或NHB＝-(C＝O)-或-(C＝O)-O-Q，R1，R2，X和Y如上所定义。a)BCCD，NH2CN，Et3N，CH3CN，2周(一般性方法1)。b)DMAP，Et3N，吡啶，55℃，3小时(一般性方法2)。c)吡啶，0-5℃(一般性方法3)。
预期将本发明的化合物用于药物组合物中，所说的药物组合物可用于治疗上述疾病。
当然，为达到治疗效果所需的式(I)化合物(以下称为有效成分)的量将随着特定的化合物，给药途径和接爱治疗的哺乳动物不同而改变。适于全身性治疗的式(1)化合物的剂量为0.1-400mg/kg体重，最优选的剂量为1.0-100mg/kg哺乳动物体重，例如5-20mg/kg；每天给药一次或多次。
每日剂量(成人)可达1mg-10000mg，优选的是70-5000mg，相应地在兽医实践中，每日剂量为0.1-400mg/kg体重。
尽管有效成分可作为原化学药品单独给药，但优选的是制成药物制剂。通常，有效成分占制剂的0.1-99％。制剂的剂量单位含有0.5mg-1g的有效成分。对于体表给药来说，有效成分优选的量占制剂的1％-20％，但有效成分可多达50％w/w。适合于鼻或口给药的制剂可含有0.1％-20w/w，例如大约2％w/w的有效成分。
术语“剂量单位”是指能够给患者服用，易于处理和包装的单位剂量，即单剂量，它可作为含有活性物质本身或活性物质与固体或液体药物稀释剂或载体的物理和化学稳定性单位剂量存在。
本发明的兽医用和人类医用制剂含有有效成分以及药物上可接受的载体和非必需性其它治疗性成分。载体在可与制剂中的其它成分相容且对其接受者无害的意义上说必须是“可接受的”。
制剂包括适合于口服、直肠、肠胃外(包括皮下、肌肉内、静脉内和皮内)给药形式的制剂。
这些制剂可方便地制成剂量单位形式，可用制药领域熟知的任何方法来制备。所有方法都包括使有效成分与构成一种或多种辅助成分的载体结合的步骤。一般来说，这些制剂是通过使有效成分与液体载体或细碎的固体载体或二者均匀而紧密地结合，然后，若需要，则将产品成型为所需的制剂来制备的。
适于口服的本发明的制剂可以为分立的单位形式如胶囊、药囊、片剂或锭剂，它们各自含有预定量的有效成分；粉末或颗粒形式；水或非水溶液或悬浮液形式；或水包油型乳液或油包水型乳液形式。有效成分也可以大丸剂，干药糖剂或糊状物形式给药。
适于直肠给药的制剂可以为含有有效成分和载体如可可脂的栓剂形式，或灌肠剂形式。
适于肠胃外给药的制剂一般为含有有效成分的无菌油性或水性制剂，优选的是该制剂与接受者的血液等渗。
除了上述成分以外，本发明的制剂还可包括一种或多种附加的成分，如稀释剂、缓冲剂、香味剂、粘合剂、表面活性剂、增稠剂、润滑剂、防腐剂，例如甲基羟基苯甲酸酯(包括抗氧化剂)、乳化剂等等。
这些组合物还可以含有通常用于治疗上述病症的其它治疗活性化合物，例如可对肿瘤细胞产生协同作用的抗肿瘤剂。
在下列一般性方法和实施例中将对本发明做进一步描述：
举例说明的化合物I列于表2中。
                      表2
化合物号 实施例号 R1 3-或4-吡啶基 Q X Y R2
    101     1     H     4   (CH2)5   CONH   苯基     H
    102     2     H     4   (CH2)6   NHCO   苯基     H
    103     3     H     4   (CH2)4   NH(CO)O   苄基     H
    104     4     H     4   (CH2)6   O(CO)   苯基   4-Cl
    105     5     H     4   (CH2)6   O(CO)O   苯基   4-Cl
    106     6     H     4   (CH2)5   (CO)O   苯基   4-Cl
    107     7     H     4   (CH2)6   O(CS)NH   苯基   4-Cl
    108     8     H     4   (CH2)6   NHCO   苯基   4-Cl
    109     9   6-OCH3     3   (CH2)6   NHCO   苯基   4-Cl
    110     10   2-CH3     4   (CH2)6   NHCO   苯基   4-Cl
    111     11     H     4   (CH2)5     CO   苯基   4-Cl
    112     12     H     4   (CH2)7     CO   苯基   4-Cl
    113     13     H     4   (CH2)6     CO   苯基   4-Cl
所有熔点都是未校正的。对于1H核磁共振(NMR)谱(300MHz)，给出了化学位移值(δ)。除另有规定外，该值是在氘代氯仿和六可代二甲基亚砜溶液中，以氯仿(1H NMR δ 7.25，13CNMR δ 76.81)或四甲基硅烷(δ 0.00)为内标测定的。如果不给出一个范围(s单峰，b宽峰)，则给出多重峰(m)的值，该值或者在中点附近限定(双重峰(d)，三重峰(t)，四重峰(q)或者未限定。在硅胶上进行色谱。使用下列缩写和式子：DCCD(N，N’-二环己基碳化二亚胺)，NH2CN(氨基氰)，Et3N(三乙胺)，CH3CN(乙腈)，DMAP(二甲基氨基吡啶)，MeOH(甲醇)，CH2Cl2(二氯甲烷)，NH3(氨)，CDCl3(氘代氯仿)和DMSO-d6(六氘代二甲基亚砜)。
一般性方法1：通式II的化合物转变为通式I的化合物
将通式II的化合物(5mmol)悬浮于乙腈(12ml)中，加入二环己基碳化二亚胺(10mmol)，氨基氰(10mmol)和三乙胺(0.07ml)。在室温下搅拌反应混合物2周。
将反应混合物过滤并用乙腈洗涤。用氯仿(20ml)研制含有产物和二环己基硫脲的白色固体过夜，过滤，得到通式I的产物，其为白色结晶。
一般性方法2：通式III的化合物与通式IV的化合物偶联生成通式I的化合物
将通式III的化合物(4mmol)，通式IV的化合物(5mmol)，三乙胺(0.12ml)和4-二甲基氨基吡啶(15mg)溶于吡啶(4ml)中。在55℃下搅拌反应混合物3小时，然后冷却至室温。
用乙醚使产物沉淀。过滤，得到纯的通式I的产物，其为白色结晶。
一般性方法3：通式V的化合物与通式VI的化合物偶联生成通式I的化合物
在具有三通旋塞和隔膜的双颈烧瓶中，将通式V的化合物(2.0mmol)悬浮于无水吡啶(4ml)中。通过三通旋塞使空气与氩气交换。在冰上冷却烧瓶并通过隔膜加入通式VI的化合物(3.0mmol)。将反应混合物在0℃下搅拌2小时，在5℃下搅拌5天。
用快速色谱法(洗脱剂1％NH3(含水的)和0-20％MeOH/CH2Cl2)纯化产物并用乙醚使产物结晶。
                        实施例1
N-氰基-N’-(5-苯基氨基羰基戊基)-N”-4-吡啶基胍(化合物101)
一般性方法1。
起始化合物II：N-(5-苯基氨基羰基戊基)-N’-4-吡啶基硫脲。
纯化：一般性方法。
1H NMR(DMSO-d6)δ：9.86(s，1H)，9.39(bs，1H)，8.37(d，2H)，7.85(bs，1H)，7.59(d，2H)，7.28(t，2H)，7.21(bd，2H)，7.01(t，1H)，3.28(bs，2H)，2.32(t，2H)，1.59(m，4H)，1.35(m，2H).
                          实施例2
N-(6-苯甲酰氨基己基)-N’-氰基-N”-4-吡啶基胍(化合物102)
一般性方法2。
起始化合物II：N-(6-苯甲酰氨基己基)-N’-4-吡啶基硫脲。
纯化：一般性方法。
1H NMR(DMSO-d6)δ：9.40(bs，1H)，8.43(t，1H)，8.38(d，2H)，7.83(m，3H)，7.47(m，3H)，7.20(m，2H)，3.25(q，4H)，1.54(m，4H)，1.33(m，4H).
                          实施例3
N-(4-苄氧羰基氨基丁基)-N’-氰基-N”-4-吡啶基胍(化合物103)
一般性方法2。
起始化合物III：S-甲基N-氰基-N’-4-吡啶基异硫脲。
起始化合物IV：4-苄氧羰基氨基丁胺。
纯化：快速色谱法(洗脱剂0.5％NH3(含水的)和0-20％MeOH/CH2Cl2)并用乙醚进行结晶。
13C NMR(DMSO-d6)δ：157.2，156.1，150.0，145.8，137.2，128.3，127.6，116.4，114.6，65.1，48.5，41.5，39.9，26.7，26.0.
                          实施例4
N-(6-(4-氯苯甲酰氧基)己基)-N’-氰基-N”-4-吡啶基胍(化合物104)
一般性方法3。
起始化合物V：N-氰基-N’-(6-羟基己基)-N”-4-吡啶基胍。
起始化合物VI：4-氯苯甲酰氯。
纯化：一般性方法。
13C NMR(DMSO-d6)δ：164.8，157.0，150.0，145.8，138.1，130.9，128.9，128.6，116.4，114.5，64.8，41.6，28.5，27.9，25.7，25.0.
                          实施例5
N-(6-(4-氯苯氧羰基氧基)己基)-N’-氰基-N”-4-吡啶基胍(化合物105)
一般性方法3。
起始化合物V：N-氰基-N’-(6-羟基己基)-N”-4-吡啶基胍。
起始化合物VI：氯甲酸4-氯苯基酯。
纯化：一般性方法。
13C NMR(CDCl3)δ：157.7，153.5，150.7，145.0，149.6，131.4，129.6，122.4，117.1，116.0，68.8，42.4，29.0，28.4，26.3，25.3.
                        实施例6
N-(6-(4-氯苯氧羰基)戊基)-N’-氰基-N”-4-吡啶基胍(化合物106)
将N-(5-羧基戊基)-N’-氰基-N”-4-吡啶基胍(2.0g)，4-氯苯酚(0.94g)，三乙胺(2.0ml)和六氟磷酸溴-三-吡咯烷基鏻(3.4g)和无水二氯甲烷(100ml)混合并在室温下搅拌过夜。加入更多的六氟磷酸溴-三-吡咯烷基鏻(0.68g)和三乙胺(0.2ml)并搅拌反应混合物过夜。
蒸发溶剂，用快速色谱法(洗脱剂0.5％NH3(含水的)和0-17％MeOH/CH2Cl2)纯化残余物。用乙醚进行结晶，得到含有产物和三乙基铵盐的白色结晶。经用水提取除去三乙基铵盐，得到纯的产物。
13C NMR(DMSO-d6)δ：171.5，157.1，150.1，149.1，145.7，129.8，129.3，123.7，116.4，114.6，41.5，33.2，28.2，25.5，23.8.
                         实施例7
N-(6-4-氯苯基氨基硫代羰基氧基)己基)-N’-氰基-N”-4-吡啶基胍(化合物107)
在具有三通旋塞和隔膜的双颈烧瓶中将N-氰基-N’-(6-羟基己基)-N”-4-吡啶基胍(0.5g)，异硫氰酸4-氯苯基酯(0.4g)和二异丙基乙胺(0.32ml)混合。通过三通旋塞使空气与氩气交换。通过隔膜加入无水吡啶(10ml)。在室温下搅拌反应混合物5天。
用快速色谱法(洗脱剂1％NH3(含水的)和0-10％ MeOH/CH2Cl2)纯化产物并用乙醚进行结晶。
1H NMR(DMSO-d6)δ：11.16(bs，1H)，9.37(bs，1H)，8.38(bd，2H)，7.84(bt，1H)，7.40(m，4H)，7.22(bd，2H)，4.46(m，2H)，3.26(q，2H)，1.72(m，2H)，1.54(m，2H)，1.36(m，4H).
实施例8
N-(6-(4-氯苯甲酰氨基)己基)-N’-氰基-N”-4-吡啶基胍(化合物108)
一般性方法2。
起始化合物III：S-甲基N-氰基-N’-4-吡啶基异硫脲。
起始化合物IV：4-氯苯甲酰氨基己胺。
纯化：快速色谱法(洗脱剂0.5％NH3(含水的)和0-13％MeOH/CH2Cl2)并用丙酮/乙醚进行结晶。
13C NMR(DMSO-d6)δ：164.9，157.1，150.0，145.8，135.7，133.3，129.0，128.2，116.4，114.5，41.7，39.1，28.9，28.5，26.0，25.9，
实施例9
N-(6-(4-氯苯甲酰氨基)己基)-N’-氰基-N”-(2-甲氧基-5-吡啶基)胍(化合物109)
一般性方法2。
起始化合物III：S-甲基N-氰基-N’-(2-甲氧基-5-吡啶基)异硫脲。
起始化合物IV：4-氯苯甲酰氨基己胺。
纯化：一般性方法。
13C NMR(DMSO-d6)δ：164.9，161.2，158.6，143.4，137.0，135.7，133.3，129.0，128.2，127.9，117.3，110.3，53.2，41.3，39.1，28.9，28.7，26.1，25.8。
                实施例10
N-(6-(4-氯苯甲酰氨基)己基)-N’-氰基-N”-(2-甲基-4-吡啶基)胍(化合物110)
一般性方法2。
起始化合物III：S-甲基N-氰基-N’-(2-甲基-4-吡啶基)异硫脲。
起始化合物IV：4-氯苯甲酰氨基己胺。
纯化：快速色谱法(洗脱剂1％NH3(含水的)和2-10％MeOH/CH2Cl2)。
13C NMR(DMSO-d6)δ：165.0，158.4，157.1，149.4，146.0，135.7，133.4，129.0，128.2，116.5，113.6，112.1，41.7，28.9，28.6，26.1，25.9，24.1.
                    实施例11
N-(5-(4-氯苯甲酰基)戊基)-N’-氰基-N”-4-吡啶基胍(化合物111)
一般性方法2。
起始化合物III：S-甲基N-氰基-N’-4-吡啶基异硫脲。
起始化合物IV：4-氯苯甲酰戊胺。
纯化：一般性方法。
13C NMR(DMSO-d6)δ：198.9，157.3，149.8，146.0，137.9，135.3，129.7，128.7，116.4，114.5，41.6，37.7，28.5，25.7，23.2.
                      实施例12
N-(7-(4-氯苯甲酰基)庚基)-N’-氰基-N”-4-吡啶基胍(化合物112)
一般性方法2。
起始化合物III：S-甲基N-氰基-N’-4-吡啶基异硫脲。
起始化合物IV：4-氯苯甲酰庚胺。
纯化：一般性方法。
13C NMR(DMSO-d6)δ：199.0，157.0，150.1，145.7，137.8，135.3，129.7，128.7，116.3，114.5，41.7，37.8，28.5，28.4，26.0，23.5
                         实施例13
N-(6-(4-氯苯甲酰基)己基)-N’-氰基-N”-4-吡啶基胍(化合物113)
一般性方法2。
起始化合物III：S-甲基N-氰基-N’-4-吡啶基异硫脲。
起始化合物IV：4-氯苯甲酰己胺。
纯化：一般性方法。
                           实施例14胶囊1粒胶囊含有：N-(6-(4-氯苯甲酰氧基)己基)-N’-氰基-N”-4-吡啶基胍(活性化合物)                      100mg聚乙二醇                                         962mg明胶胶囊00号明胶                                             122mg
                           实施例15片剂制造10,000片I N-(6-(4-氯苯甲酰氧基)己基)-N’-氰基-N”-4-吡啶基胍(活性化合物)                        10,000kg交联羧甲醚纤维素钠                                 0.300kgII羟丙基甲基纤维素，低粘度型                                           0.200kg吐温                                               0.010kg纯化水                                             适量III交联羧甲醚纤维素钠                              0.200kg胶体无水硅石                                       0.050kg硬脂酸镁                                           0.050kg
在高剪切混合器中将I充分混合，用II润温，粒化成湿团块。在进口空气温度为60℃的流化床干燥器中干燥湿颗粒，直到干燥颗粒的水活度为0.3-0.4(＝与30-40％R.H的空气平衡)。
使干燥颗粒通过网眼为850μm的筛网。
最后在锥形混合器中将筛分的颗粒与III混合。
将制成的颗粒压成质量为1071mg且具有足够硬度的片剂。

Claims (9)

1.式I的化合物
Figure A9880559500021
或它们的互变形式，与吡啶环的连接在3-或4-位，式中R代表一个或多个取代基，它们可以是相同的，也可以是不同的，选自：氢、卤素、三氟甲基、C1-C4烷基、烷氧基或烷氧羰基、硝基、氨基或氰基；Q代表C4-C20二价烃基，它们可以是直链的、支链的、饱和的或不饱和的；X代表羰基、羰基氨基、氨基羰基、氧基羰基氧基、氧基羰基、羰基氧基、氨基羰基氧基、氨基硫代羰基氧基、氧基羰基氨基或氧基硫代羰基氨基；Y代表亚苄基或亚苯基；R2代表一个或多个取代基，它们可以是相同的，也可以是不同的，选自：氢、C1-C4烷基、羟烷基或烷氧基、羟基、卤素、三氟甲基、氰基、甲酰氨基、磺酰氨基、硝基、氨基、羧基、烷氧羰基或苄氧基；其药物上可接受的无毒盐及其N-氧化物。
2.根据权利要求1的式I化合物，其中与吡啶环的连接在4-位，式中R1代表氢；Q代表C4-C12二价烃基，它们可以是直链的、支链的、饱和的或不饱和的；X代表羰基、羰基氨基、氨基羰基、氧基羰基氧基、氧基羰基、羰基氧基、氨基羰基氧基、氨基硫代羰基氧基、氧基羰基氨基或氧基硫代羰基氨基；Y代表亚苄基或亚苯基；R2代表一个或多个取代基，它们可以是相同的，也可以是不同的，选自：氢、C1-C4烷基、羟烷基或烷氧基、卤素、三氟甲基或氰基；其药物上可接受的无毒盐及其N-氧化物。
3.根据权利要求1的盐，其中盐选自与盐酸、氢溴酸、氢碘酸、磷酸、硫酸、硝酸、对甲苯磺酸、甲磺酸、甲酸、乙酸、丙酸、柠檬酸、酒石酸和马来酸所形成的盐，和锂盐、钠盐、钾盐、镁盐、钙盐，以及与氨、C1-C6烷基胺、C1-C6链烷醇胺、普鲁卡因、环烷基胺、苄基胺和杂环胺所形成的盐。
4.权利要求1的化合物，该化合物选自：
N-(6-苯甲酰氨基己基)-N’-氰基-N”-4-吡啶基胍；
N-(6-(4-氯苯甲酰氧基)己基)-N’-氰基-N”-4-吡啶基胍；
N-(5-(4-氯苯甲酰基)戊基)-N’-氰基-N”-4-吡啶基胍；
N-(7-(4-氯苯甲酰基)庚基)-N’-氰基-N”-4-吡啶基胍；
和它们的盐及纯的对映体形式。
5.一种药物制剂，含有根据权利要求1-4任一项的化合物本身或者还含有必要的辅助剂。
6.一种对患者进行治疗的方法，其特征在于给所说的患者服用有效量的一种或多种根据权利要求1-5任一项的化合物，如果需要，与一种或多种其它治疗上有效的组分一起或相伴服用。
7.根据权利要求6的治疗和预防疾病的方法，所说的疾病的特征是在皮肤细胞和癌细胞中发生的不良的细胞增殖。
8.生产根据权利要求1的式I化合物的方法，其中
a)在三乙胺或另一种叔胺的存在下，在乙腈或另一种惰性溶剂中，在室温或高于室温的温度下使通式II的化合物
Figure A9880559500031
其中R，Q，X，Y和R2定义如上，与二环己基碳化二亚胺和氨基氰反应；或者
b)在三乙胺或另一种叔胺和4-二甲基氨基吡啶的存在下，在吡啶或惰性溶剂中，在室温或高于室温的温度下使通式III的化合物其中R1如上所定义，与通式IV的化合物反应NH2-Q-X-Y-R2
     IV其中Q，X，Y和R2如上所定义；或者
c)在吡啶或惰性溶剂中，在0℃或高于0℃下，使通式V的化合物其中R1和Q如上所定义，A是被氢取代的氧、硫或氮，与通式VI的化合物反应CI-B-Y-R2
   VI其中Y和R2如上所定义，B是羰基或羰基氧基。
9.权利要求1的化合物在制备用于治疗和预防多种疾病的药物中的应用，所说的疾病的特征是在皮肤细胞和癌细胞中的不良的细胞增殖。
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HUP0002921A2 (hu) 2001-01-29
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JP2001526694A (ja) 2001-12-18
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DK0984938T3 (da) 2004-01-12
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CN1116283C (zh) 2003-07-30
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US6346541B1 (en) 2002-02-12
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