CN1258277A - 细胞增生抑制剂氰基胍 - Google Patents
细胞增生抑制剂氰基胍 Download PDFInfo
- Publication number
- CN1258277A CN1258277A CN98805591A CN98805591A CN1258277A CN 1258277 A CN1258277 A CN 1258277A CN 98805591 A CN98805591 A CN 98805591A CN 98805591 A CN98805591 A CN 98805591A CN 1258277 A CN1258277 A CN 1258277A
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- Prior art keywords
- compound
- pyridyl
- cyano group
- group
- acid
- Prior art date
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Links
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
本发明涉及迄今未知的式(Ⅰ)化合物或它们的互变异构形式,与吡啶环的连接是在3位或4位,其中式R代表一个或几个可以是相同或不同的取代基,选自由下列基团组成的组:氢、卤素、三氟甲基、羧基、C1-C4烷基、烷氧基或烷氧羰基、硝基、氨基或氰基,Q代表可以是直链、支链、环状、饱和或不饱和的C5-C14二价烃基,X代表羧基、C1-C4烷氧羰基、二(C1-C4烷氧基)膦酰氧基、氨基、C1-C4烷氧羰基氨基或四氢吡喃氧基;及其药学上可接受的无毒的盐和N氧化物。本化合物在人和兽医中具有应用价值。
Description
本发明涉及迄今未知的一类化合物,它们对例如皮肤细胞和癌细胞中的不良细胞增生显示出强烈的抑制活性,并涉及含有这些化合物的药物制剂,涉及该制剂的剂量单位,还涉及它们在疾病治疗和预防中的用途,这些疾病是以异常细胞分化和/或细胞增生为特征的,例如牛皮癣和癌。
本发明化合物是由通式I代表的:
或它们的互变异构形式,与吡啶环的连接是在3位或4位,其中式R代表一个或几个可以是相同或不同的取代基,选自由下列基团组成的组:氢、卤素、三氟甲基、羧基、C1-C4烷基、烷氧基或烷氧羰基、硝基、氨基或氰基,Q代表可以是直链支链、环状、饱和或不饱和的C5-C14二价烃基,X代表羧基、氨基、四氢吡喃氧基、C1-C4饱和或不饱和的烷氧羰基氨基、烷氧羰基或二(烷氧基)膦酰氧基(phosphinoyloxy)。
如果本化合物含有一个或几个不对称碳原子,这些化合物可以形成旋光异构体或非对映异构体。本发明也包含这些异构体及其混合物。
该式I化合物的盐可以是与药学上可接受的无机或有机酸所生成的,例如盐酸、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、琥珀酸、苯甲酸和马来酸。
该式I化合物的盐也可以是与药学上可接受的无机或有机碱所生成的。与药学上可接受的无毒的碱所生成的盐可以是碱金属盐和碱土金属盐,例如锂盐、钠盐、钾盐、镁盐、钙盐,以及与氨和适合的无毒的胺所生成的盐,胺例如C1-C6烷基胺、如三乙胺,C1-C6烷醇胺、如二乙醇胺、三乙醇胺,普鲁卡因,环烷基胺、如二环己胺,苄胺、如N-甲基苄胺、N-乙基苄胺、N-苄基-2-苯乙胺、N,N’-二苄基乙二胺或二苄胺,和杂环基胺、如吗啉、N-乙基哌啶等等。
即使本化合物在肠给药后被充分吸收,在某些情况下制备适当的本发明化合物生物可逆的衍生物也是有利的,即制备所谓的前体药物、优选为衍生物,其物理化学性质提高了所述化合物在生理pH下的溶解度和/或吸收和/或生物利用度。
这样的衍生物例如是本发明化合物的吡啶基N-氧化物,该化合物是通过用一种适当的氧化剂在一种惰性溶剂中氧化吡啶基N而制备的,氧化剂例如3-氯过苯甲酸,溶剂例如二氯甲烷。
也可以使用其他适当的方法,来提高所述化合物的物理化学性质和/或溶解度。
英国专利第1489879号所述的N-烷基-N’-氰基-N”-吡啶基胍是有效的钾通道活化剂,具有显著的前毛细血管舒张剂的作用,能降低动物和人的总外周阻力,因此可用作抗高血压药。正如申请日为1993年9月13日、公开号为WO 94/06770的国际专利第PCT/DK93/00291号所述,与上述英国专利所要求保护的化合物的既定作用相比,向来自上述英国专利的脂族基团中引入含芳氧基的原子团所产生的结构对离体组织和细胞显示出更为特异的药理作用,并对钾通道的86Rb-流出物没有作用或其作用可以忽略不计。
与已知化合物相比,更低浓度的本发明化合物即可抑制培养物中多种肿瘤细胞系的增生,见下表1,因此本发明化合物用在抗肿瘤化疗中是非常有效的。
使用不同类型的人癌细胞系研究了对肿瘤细胞增生的抑制作用。所研究的细胞系是小细胞肺癌(NYH)、非小细胞肺癌(NCI-H460)和乳腺癌(MCF-7),一般程序如下:
在所研究的化合物的存在下,将细胞进行体外培养24小时。通过[3H]胸苷的结合测量DNA合成,计算化合物的中位抑制浓度(IC50)。
表1:下列本发明实施例的化合物对人乳腺癌(MCF-7)、人小细胞肺癌(NYH)和人非小细胞肺癌(NCI-H460)的肿瘤细胞增生的体外抑制作用
化合物 | MCF-7 NYH NCI-H460IC50(nM) IC50(nM) IC50(nM) |
实施例1实施例7实施例8 | 3.6 0.62 454.2 0.51 4.61.7 0.48 6.0 |
现有技术A现有技术B | 920 380 >1000250 45 67 |
A:N-氰基-N’-(4-苯氧基丁基)-N”-4-吡啶基胍,PCT/DK93/00291的实施例14
B:N-氰基-N’-(5-苯氧基戊基)-N”-4-吡啶基胍,PCT/DK93/00291的实施例18
结果显示,本发明化合物能够抑制体外肿瘤细胞增生,抑制浓度低于来自PCT/DK93/00291的化合物A和B。
本发明化合物易于接受,并且无毒,在发挥出所述有益活性的同时,对全身血压没有作用,或者作用极小。一般来说,它们可以通过口服、静脉内、腹膜内、鼻内或经皮途径给药。
R、Q和X定义同上。
a)DCCD、NH2CN、Et3N、CH3CN,9天(通用程序1)
b)DMAP、Et3N、吡啶(通用程序2)
本化合物预期用在药物组合物中,可用于治疗上述疾病。
式I化合物(以下称之为活性成分)发挥治疗作用所需的量当然因具体化合物、给药途径和所治疗的哺乳动物而异。用于全身治疗的式I化合物的适当剂量为0.1至400mg每千克体重,最优选的剂量为1.0至100mg每kg哺乳动物体重,例如5至20mg/kg;每日给药一次或多次。
每日剂量(成人用)可以是1mg至10000mg,优选为70-5000mg,在兽医中,相应的每日剂量为0.1至400mg/kg体重。
对一种活性成分来说,尽管以原化学品的形式单独给药是可能的,也还是优选提供其药物制剂的形式。活性成分宜构成制剂的0.1至99重量%。制剂的剂量单位宜含有0.5mg至1g活性成分。对局部给药来说,活性成分优选构成制剂的1至20重量%,不过活性成分可以构成多达50%w/w。适合于鼻给药或口含给药的制剂可以包含0.1%至20%w/w的活性成分,例如约2%w/w。
术语“剂量单位”意为能够对患者给药的单元、即单一剂量,它易于操作和包装,同时保持有物理与化学稳定的单位剂量,其中包含活性物质本身,或者包含它与固体或液体药物稀释剂或载体的混合物。
兽用和人用的本发明制剂包含活性成分以及药学上可接受的载体,可选地包含其他治疗成分。载体必须是“可接受的”,也就是说它必须与制剂中其他成分相容,并对接受它的患者无害。
制剂包括适合于口服、直肠、胃肠外(包括皮下、肌内、静脉内和腹膜内)给药的剂型。
可以方便地提供制剂的剂量单位形式,并且制剂可以用药学领域熟知的任意方法制备。所有方法都包括将活性成分与载体结合的步骤,载体构成了一种或几种附属成分。一般来说,制剂的制备方法是将活性成分与液体载体或精细粉碎的固体载体均匀和密切结合,或两种载体兼而有之,然后,如果必要的话,使产物成形为所需制剂。
适合于口服给药的本发明制剂可以是分散单位的形式,即胶囊剂、扁囊剂、片剂或锭剂,各含有预定量的活性成分;可以是粉末或颗粒的形式;可以是在含水液体或不含水液体中的溶液或混悬液的形式;或者可以是水包油乳剂或油包水乳剂的形式。活性成分也可以以大丸剂、干药糖剂或糊剂的形式给药。
直肠给药制剂可以是栓剂的形式,其中含有活性成分和一种载体、例如椰子油,或者可以是灌肠剂的形式。
适合于胃肠外给药的制剂宜包含活性成分的无菌油状或含水制品,它优选与接受者的血液是等渗的。
除了上述成分以外,本发明制剂还可以包括一种或几种附加成分,例如稀释剂、缓冲剂、矫味剂、粘合剂、表面活性剂、增稠剂、润滑剂、防腐剂,如羟基苯甲酸甲酯(包括抗氧化剂),和乳化剂等。
组合物可以进一步含有其他常用于治疗上述病理学状态的治疗活性化合物,例如抗肿瘤剂,可以对肿瘤细胞产生协同作用。
在下列通用程序和实施例中将对本发明作进一步描述。
例证化合物列在表2中。表2化合物 实施例 R 3-或 Q X
4-序号 序号 吡啶基101 1 H 4 (CH2)12 NH(CO)O-叔丁基102 2 H 4 (CH2)5 NH(CO)O-叔丁基103 3 H 4 (CH2)12 NH2104 4 H 4 (CH2)10 COOH105 5 H 4 (CH2)7 COOH106 6 H 4 (CH2)5 COOH107 7 H 4 (CH2)11 O-2-四氢吡喃基108 8 H 4 (CH2)11 O(PO)(O-乙基)2109 9 H 4 (CH2)8 NH(CO)O-叔丁基110 10 H 4 (CH2)10 NH(CO)O-叔丁基111 11 2-CH3 4 (CH2)10 NH(CO)O-叔丁基112 12 6-OCH3 3 (CH2)10 NH(CO)O-叔丁基113 13 6-OCH3 3 (CH2)10 NH2114 14 H 4 (CH2)10 NH(CO)O-正丁基115 15 H 4 (CH2)6 O-2-四氢吡喃基116 16 H 4 (CH2)6 O(PO)(O-乙基)2117 17 H 4 (CH2)8 O-2-四氢吡喃基118 18 H 4 (CH2)9 O(PO)(O-乙基)2119 19 6-OCH3 3 (CH2)11 O-2-四氢吡喃基120 20 H 4 (CH2)10 NH(CO)O-烯丙基
所有熔点均未校正。除非另有说明,在1H和13C核磁共振(NMR)光谱(300MHz)中,所引用的化学位移值(δ)在氘代氯仿和六氘代二甲基亚砜溶液中测得,并且是相对于内部的氯仿(1H NMR δ7.25,13CNMR δ76.81)或四甲基硅烷(δ0.00)而言的。除非引用了一个范围(s为单峰,b为宽峰),多重峰的值(m)均在大约中点处给出,该值是定义过的(双峰(d)、三重峰(t)、四重峰(q))或者没有定义过。色谱法在硅胶上进行。使用下列缩写和化学式:DCCD(N,N’-二环己基碳二亚胺)、NH2CN(氨基氰)、Et3N(三乙胺)、CH3CN(乙腈)、DMAP(二甲氨基吡啶)、MeOH(甲醇)、CH2Cl2(二氯甲烷)、EtOAc(乙酸乙酯)、NH3(氨)、CDCl3(氘代氯仿)和DMSO-d6(六氘代二甲基亚砜)。
通用程序1:通式II化合物转化为通式I化合物
将通式II化合物(5mmol)悬浮在乙腈(12ml)中,加入二环己基碳二亚胺(10mmol)、氨基氰(10mmol)和三乙胺(0.07ml)。反应混合物在室温下搅拌9天。
将反应混合物过滤,用乙腈洗涤。粗产物用快速色谱法(洗脱剂:0-7%MeOH的CH2Cl2溶液)纯化,并从乙醚中结晶,得到通式I产物,为白色晶体。
通用程序2:通式III化合物与通式IV化合物偶合生成通式I化合物
将通式III化合物(4mmol)、通式IV化合物(5mmol)、三乙胺(0.12ml)和4-二甲氨基吡啶(15mg)溶于吡啶(4ml)。反应混合物在60℃下搅拌11小时,然后冷却至室温。
将产物用乙醚沉淀出来。过滤得到纯的通式I产物,为白色晶体。
实施例1
N-(12-叔丁氧羰基氨基十二烷基)-N’-氰基-N”-4-吡啶基胍(化合物101)
通用程序1。
原料化合物II:N-(12-叔丁氧羰基氨基十二烷基)-N-4-吡啶基硫脲
纯化:通用程序。
13C NMR(DMSO-d6)δ:157.1,155.5,150.0,145.9,116.4,114.5,
77.2,48.6,41.8,29.4,29.0,28.6,28.2,26.2,26.1.
实施例2
N-(5-叔丁氧羰基氨基戊基)-N’-氰基-N”-4-吡啶基胍(化合物102)
通用程序1。
原料化合物II:N-(5-叔丁氧羰基氨基戊基)-N-4-吡啶基硫脲
纯化:通用程序。
1H NMR(DMSO-d6)δ:9.37(bs,1H),8.38(d,2H),7.81(bs,1H),
7.21(bd,2H),6.77(t,1H),3.25(m,2H),2.91(q,2H),1.52(m,2H),1.45-
1.20(m,4H),1.37(s,9H).
实施例3
N-(12-氨基十二烷基)-N’-氰基-N”-4-吡啶基胍(化合物103)
通用程序2;反应时间:在室温下2天。
原料化合物III:S-甲基N-氰基-N’-4-吡啶基异硫脲
原料化合物IV:1,12-二氨基十二烷基
纯化:快速色谱法(洗脱剂:0-30%MeOH的CH2Cl2溶液)
1H NMR(DMSO-d6)δ:8.30(bs,2H),7.18(bs,2H),3.30(m,2H),
2.88(m,2H),1.60-1.00(m,22H).
实施例4
N-(10-羧基癸基)-N’-氰基-N”-4-吡啶基胍(化合物104)
通用程序2。
原料化合物III:S-甲基N-氰基-N’-4-吡啶基异硫脲
原料化合物IV:11-氨基十一烷酸
纯化:将残余的11-氨基十一烷酸用乙醚沉淀出来。过滤后将滤液浓缩,将残余物加入水搅拌。第二次过滤后,滤液中含有几乎纯的产物。在真空中蒸发,并从乙腈中结晶,得到纯产物。
1H NMR(DMSO-d6)δ:8.38(d,2H),8.03(bs,1H),7.21(bd,2H),
3.26(q,2H),2.17(t,2H),1.50(m,4H),1.25(bs,12H).
实施例5
N-(7-羧基庚基)-N’-氰基-N”-4-吡啶基胍(化合物105)
通用程序2。
原料化合物III:S-甲基N-氰基-N’-4-吡啶基异硫脲
原料化合物IV:8-氨基辛酸
纯化:快速色谱法(洗脱剂:0-100%MeOH的CH2Cl2溶液),并从乙腈中结晶。
13C NMR(DMSO-d6)δ:174.7,157.2,149.8,146.1,116.3,114.4,
41.7,33.8,28.6,28.4,28.3,26.0,24.5.
实施例6
N-(5-羧基戊基)-N’-氰基-N”-4-吡啶基胍(化合物106)
通用程序2;反应时间:在室温下14天。
原料化合物III:S-甲基N-氰基-N’-4-吡啶基异硫脲
原料化合物IV:6-氨基己酸
纯化:快速色谱法(洗脱剂:0-55%MeOH的CH2Cl2溶液),并从丙酮/水中结晶。
13C NMR(DMSO-d6)δ:175.0,157.2,149.8,146.1,116.4,114.5,
41.6,34.0,28.4,25.7,24.2.
实施例7
N-氰基-N’-4-吡啶基-N”-(11-四氢吡喃氧基十一烷基)胍(化合物107)
通用程序2;反应时间:在室温下14天。
原料化合物III:S-甲基N-氰基-N’-4-吡啶基异硫脲
原料化合物IV:11-四氢吡喃氧基十一烷胺
纯化:快速色谱法(洗脱剂:CH2Cl2/MeOH/NH3(水溶液)95∶5∶0.5),然后在乙醚中研制。
13C NMR(DMSO-d6)δ:157.5,150.9,144.8,117.0,115.9,99.1,
67.8,62.6,42.6,30.9,29.7,29.5,29.4,29.2,26.8,26.2,25.5,19.8.
实施例8
N-氰基-N’-(11-二乙基膦酰氧基十一烷基)-N”-4-吡啶基胍(化合物108)
通用程序2;反应时间:在室温下14天。
原料化合物III:S-甲基N-氰基-N’-4-吡啶基异硫脲
原料化合物IV:二乙基11-氨基十一烷基磷酸酯
纯化:快速色谱法(洗脱剂:EtOAc/MeOH/NH3(水溶液)100∶5∶0.2,然后是50∶5∶0.1)。所得化合物为黄色的油。
13C NMR(CDCl3)δ:157.4,150.5,145.3,116.9,115.3,67.9,67.9,
63.9,63.9,42.7,30.2,30.1,29.3,29.2,29.1,29.0,28.8,26.6,25.2,16.2,
16.1.
实施例9
N-(8-叔丁氧羰基氨基辛基)-N’-氰基-N”-4-吡啶基胍(化合物109)
通用程序2。
原料化合物III:S-甲基N-氰基-N’-4-吡啶基异硫脲
原料化合物IV:8-叔丁氧羰基氨基辛胺
纯化:通用程序。
13C NMR(CDCl3)δ:157.3,155.5,149.8,146.1,116.4,114.5,
77.2,41.7,29.4,28.6,28.6,28.2,26.1,26.0.
实施例10
N-(10-叔丁氧羰基氨基癸基)-N’-氰基-N”-4-吡啶基胍(化合物110)
通用程序2。
原料化合物III:S-甲基N-氰基-N’-4-吡啶基异硫脲
原料化合物IV:10-叔丁氧羰基氨基癸胺
纯化:通用程序。
13C NMR(CDCl3)δ:157.3,155.5,149.8,146.0,116.4,114.5,
77.2,41.7,29.4,28.8,28.8,28.6,28.5,28.2,26.2,26.1.
实施例11
N-(10-叔丁氧羰基氨基癸基)-N’-氰基-N”-(2-甲基-4-吡啶基)胍(化合物111)
通用程序2。
原料化合物III:S-甲基N-氰基-N’-(2-甲基-4-吡啶基)异硫脲
原料化合物IV:10-叔丁氧羰基氨基癸胺
纯化:快速色谱法(洗脱剂:1%NH3(水溶液)和0-10%MeOH的CH2Cl2溶液)。所得化合物为黄色的油。
13C NMR(CDCl3)δ:158.1,157.3,155.5,149.4,146.2,116.5,
113.5,112.0,77.2,41.7,29.4,28.9,28.8,28.6,28.6,28.6,28.2,26.2,
26.1,24.0.
实施例12
N-(10-叔丁氧羰基氨基癸基)-N’-氰基-N”-(2-甲氧基-5-吡啶基)胍(化合物112)
通用程序2。
原料化合物III:S-甲基N-氰基-N’-(2-甲氧基-5-吡啶基)异硫脲
原料化合物IV:10-叔丁氧羰基氨基癸胺
纯化:快速色谱法(洗脱剂:1%NH3(水溶液)和0-6%MeOH的CH2Cl2溶液),并从乙醚中结晶。
13C NMR(CDCl3)δ:161.2,158.6,155.5,143.3,137.0,127.9,
117.3,110.3,77.2,53.2,41.3,29.4,28.9,28.8,28.8,28.6,28.6,28.2,
26.2,26.1.
实施例13
N-(10-氨基癸基)-N’-氰基-N”-(2-甲氧基-5-吡啶基)胍(化合物113)
通用程序2。
原料化合物III:S-甲基N-氰基-N’-(2-甲氧基-5-吡啶基)异硫脲
原料化合物IV:1,10-二氨基癸烷
纯化:快速色谱法(洗脱剂:EtOAc/MeOH 6∶1,然后是EtOAc/MeOH/NH3(水溶液)6∶1∶1)。
13C NMR(CDCl3)δ:161.1,158.5,143.2,136.9,128.0,117.3,
110.3,53.2,41.3,41.0,32.0,28.9,28.8,28.8,28.6,26.2,26.0.
实施例14
N-(10-正丁氧羰基氨基癸基)-N’-氰基-N”-4-吡啶基胍(化合物114)
通用程序2。
原料化合物III:S-甲基N-氰基-N’-4-吡啶基异硫脲
原料化合物IV:10-正丁氧羰基氨基癸胺
纯化:快速色谱法(洗脱剂:5-100%EtOAc的石油醚溶液),并从乙醚中结晶。
13C NMR(CDCl3)δ:157.0,156.3,150.1,145.8,116.3,114.5,
63.1,41.7,30.7,29.3,28.8,28.8,28.6,28.5,26.1,26.1,18.5,13.5.
实施例15
N-氰基-N’-4-吡啶基-N”-(6-四氢吡喃氧基己基)胍(化合物115)
通用程序2;反应时间:60℃下4天。
原料化合物III:S-甲基N-氰基-N’-4-吡啶基异硫脲
原料化合物IV:6-四氢吡喃氧基己胺
纯化:快速色谱法(洗脱剂:CH2Cl2/MeOH/NH3(水溶液)98∶2∶0.2,然后是95∶5∶0.5),在石油醚中研制,然后从EtOAc中重结晶。
13C NMR(CDCl3)δ:157.3,149.8,146.0,116.4,114.5,97.9,66.4,
61.2,41.7,30.3,29.1,28.6,25.9,25.3,25.0,19.2.
实施例16
N-氰基-N’-(6-二乙基膦酰氧基氧基己基)-N”-4-吡啶基胍(化合物116)
通用程序2;反应时间:60℃下4天。
原料化合物III:S-甲基N-氰基-N’-4-吡啶基异硫脲
原料化合物IV:6-二乙基膦酰氧基己胺
纯化:快速色谱法(洗脱剂:CH2Cl2/MeOH/NH3(水溶液)98∶2∶0.2,然后是95∶5∶0.5)。
13C NMR(CDCl3)δ:157.1,150.0,116.4,114.5,66.7,63.0,41.6,
29.5,28.4,25.6,24.5,15.9.
实施例17
N-氰基-N’-4-吡啶基-N”-(8-四氢吡喃氧基辛基)胍(化合物117)
通用程序2;反应时间:60℃下4天。
原料化合物III:S-甲基N-氰基-N’-4-吡啶基异硫脲
原料化合物IV:8-四氢吡喃氧基辛胺
纯化:快速色谱法(洗脱剂:CH2Cl2/MeOH/NH3(水溶液)98∶2∶0.2),并从EtOAc中结晶。
13C NMR(CDCl3)δ:157.3,150.0,146.1,116.5,114.6,98.0,66.6,
61.3,41.8,30.4,29.2,28.8,28.7,28.7,26.2,25.7,25.1,19.3.
实施例18
N-氰基-N’-(9-二乙基膦酰氧基壬基)-N”-4-吡啶基胍(化合物118)
通用程序2;反应时间:60℃下4天。
原料化合物III:S-甲基N-氰基-N’-4-吡啶基异硫脲
原料化合物IV:9-二乙基膦酰氧基壬胺
纯化:快速色谱法(洗脱剂:EtOAc/EtOH/NH3(水溶液)30∶3∶0.2,然后是25∶5∶0.2)。
13C NMR(CDCl3)δ:157.2,149.9,146.0,116.4,114.5,66.8,63.0,
41.7,29.6,28.7,28.6,28.5,28.3,26.0,24.8,15.9.
实施例19
N-氰基-N’-(2-甲氧基-5-吡啶基)-N”-(11-四氢吡喃氧基十一烷基)胍(化合物119)
通用程序2;反应时间:60℃下4天。
原料化合物III:S-甲基N-氰基-N’-(2-甲氧基-5-吡啶基)异硫脲
原料化合物IV:11-四氢吡喃氧基十一烷胺
纯化:快速色谱法(洗脱剂:CH2Cl2/MeOH/NH3(水溶液)98∶2∶0.2)。
13C NMR(CDCl3)δ:163.5,159.4,145.4,137.6,125.3,117.8,
112.2,98.9,67.7,62.4,54.0,42.1,30.8,29.8,29.5,29.5,29.4,29.3,29.2,
26.7,26.2,25.5,19.8.
实施例20
N-(10-烯丙氧基羰基氨基癸基)-N’-氰基-N”-4-吡啶基胍(化合物120)
通用程序2。
原料化合物III:S-甲基N-氰基-N’-4-吡啶基异硫脲
原料化合物IV:10-烯丙氧基羰基氨基癸胺
纯化:快速色谱法(洗脱剂:0.5%NH3(水溶液)和0-13%MeOH的CH2Cl2溶液),并从丙酮/乙醚中结晶。
13C NMR(CDCl3)δ:157.08,155.81,150.06,145.77,133.83,
116.66,116.37,114.46,63.97,41.72,40.13,29.31,28.85,28.82,28.62,
28.61,28.56,26.13,26.08
实施例21:胶囊剂
1粒胶囊中含有:
N-(12-叔丁氧羰基氨基十二烷基)-N’-氰基-
N”-4-吡啶基胍(活性化合物) 100mg
聚乙二醇 962mg
00号明胶胶囊
明胶 122mg
实施例22:片剂
10000片的制备
I N-(12-叔丁氧羰基氨基十二烷基)-N’-氰基-
N”-4-吡啶基胍(活性化合物) 10.000kg
交联羧甲纤维素(Crosscarmellose)钠 0.300kg
II 羟丙甲基纤维素,低粘度型 0.200kg
吐温(Sorbimacrogol oleate) 0.010kg
纯净水 适量
III 交联羧甲纤维素(Crosscarmellose)钠 0.200kg
胶体无水二氧化硅 0.050kg
硬脂酸镁 0.050kg
将I在高剪切混合机中密切混合,用II润湿,并造粒制成湿材。将湿颗粒在入口气温为60℃的流化床干燥机中干燥,直到颗粒的水分活度为0.3-0.4(=与相对湿度为30-40%的空气平衡)时为止。
使干颗粒通过筛孔为850mm的筛。
过完筛的颗粒最后在锥形混合机中与III混合。
将最终的颗粒压制成片,片重1071mg,并具有足够的硬度。
Claims (9)
1.式I化合物
或它们的互变异构形式,与吡啶环的连接是在3位或4位,其中式R代表一个或几个可以是相同或不同的取代基,选自由下列基团组成的组:氢、卤素、三氟甲基、羧基、C1-C4烷基、烷氧基或烷氧羰基、硝基、氨基或氰基,Q代表可以是直链、支链、环状、饱和或不饱和的C5-C14二价烃基,X代表羧基、氨基、四氢吡喃氧基、C1-C4饱和或不饱和的烷氧羰基氨基、烷氧羰基或二(烷氧基)膦酰氧基;及其药学上可接受的无毒的盐和N-氧化物。
2.根据权利要求1式I的化合物,其中与吡啶环的连接是在4位的,其中式R代表氢,Q代表可以是直链、支链、饱和或不饱和的C5-C12二价烃基,X代表羧基、氨基、四氢吡喃氧基、C1-C4饱和或不饱和的烷氧羰基氨基、烷氧羰基或二(烷氧基)膦酰氧基;及其药学上可接受的无毒的盐和N-氧化物。
3.根据权利要求1的盐,其中的盐选自由下列盐组成的组:与盐酸、氢溴酸和氢碘酸、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烷醇胺、普鲁卡因、环烷基胺、苄胺、和杂环基胺所形成的盐。
4.权利要求1的化合物,选自由下列化合物组成的组:
N-(12-叔丁氧羰基氨基十二烷基)-N’-氰基-N”-4-吡啶基胍;
N-氰基-N’-4-吡啶基-N”-(11-四氢吡喃氧基十一烷基)胍;
N-氰基-N’-(11-二乙基膦酰氧基十一烷基)-N”-4-吡啶基胍;
N-(8-叔丁氧羰基氨基辛基)-N’-氰基-N”-4-吡啶基胍;
N-氰基-N’-4-吡啶基-N”-(8-四氢吡喃氧基辛基)胍;
N-氰基-N’-(9-二乙基膦酰氧基壬基)-N”-4-吡啶基胍;
和它们的盐和纯的对映异构形式。
5.药物制剂,含有单独的根据权利要求1-4任意一项的化合物或者还含有必要的助剂。
6.对需要治疗的患者的治疗方法,其特征在于将有效量的一种或几种根据权利要求1-5任意一项的化合物对所述患者给药,如果需要的话,与一种或几种其他治疗活性组分一起或伴随给药。
7.根据权利要求6的方法,用于治疗和预防以例如皮肤细胞和癌细胞中的不良细胞增生为特征的疾病状态。
9.权利要求1的化合物在制备治疗和预防大量疾病状态的药物中的用途,这些疾病状态是以例如皮肤细胞和癌细胞的不良细胞增生为特征的。
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GB9711123.1 | 1997-05-29 | ||
GBGB9711123.1A GB9711123D0 (en) | 1997-05-29 | 1997-05-29 | Novel cyanoguanidines |
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CN1258277A true CN1258277A (zh) | 2000-06-28 |
CN1121389C CN1121389C (zh) | 2003-09-17 |
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CN98805591A Expired - Lifetime CN1121389C (zh) | 1997-05-29 | 1998-05-15 | 细胞增生抑制剂氰基胍 |
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US (2) | US6346520B1 (zh) |
EP (1) | EP0984936B1 (zh) |
JP (1) | JP4349476B2 (zh) |
KR (1) | KR100549631B1 (zh) |
CN (1) | CN1121389C (zh) |
AT (1) | ATE248819T1 (zh) |
AU (1) | AU733000B2 (zh) |
CA (1) | CA2292775C (zh) |
CZ (1) | CZ293275B6 (zh) |
DE (1) | DE69817810T2 (zh) |
DK (1) | DK0984936T3 (zh) |
ES (1) | ES2206931T3 (zh) |
GB (1) | GB9711123D0 (zh) |
HK (1) | HK1027568A1 (zh) |
HU (1) | HUP0003823A3 (zh) |
NZ (1) | NZ501266A (zh) |
PL (1) | PL190249B1 (zh) |
PT (1) | PT984936E (zh) |
RO (1) | RO119880B1 (zh) |
RU (1) | RU2194697C2 (zh) |
WO (1) | WO1998054141A1 (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2010088842A1 (zh) * | 2009-02-06 | 2010-08-12 | 天津和美生物技术有限公司 | 含有吡啶基氰基胍的药物组合物及其制备和应用 |
Families Citing this family (10)
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WO2000061561A1 (en) | 1999-04-09 | 2000-10-19 | Shionogi Bioresearch Corp. | Cyanoguanidine compounds |
AU1494702A (en) | 2000-11-21 | 2002-06-03 | Leo Pharma As | Cyanoguanidine prodrugs |
US20030045515A1 (en) * | 2001-05-24 | 2003-03-06 | Lise Binderup | Combination medicament for treatment of neoplastic diseases |
HUP0400021A3 (en) | 2001-05-24 | 2008-03-28 | Leo Pharma As | Novel pyridyl cyanoguanidine derivatives and pharmaceutical compositions containing them |
US7253193B2 (en) | 2002-05-17 | 2007-08-07 | Leo Pharma A/S | Cyanoguanidine prodrugs |
JP5189367B2 (ja) | 2004-12-22 | 2013-04-24 | レオ ファーマ アクティーゼルスカブ | 新規シアノグアニジン化合物 |
EP2197443A4 (en) | 2007-09-26 | 2014-01-01 | Gemin X Pharmaceuticals Canada Inc | COMPOSITIONS AND METHODS FOR INFLUENCING NAD + CONTENT USING A NICOTINAMIDE PHOSPHORIBOSYL TRANSFERASE INHIBITOR |
US8173677B2 (en) | 2007-09-26 | 2012-05-08 | Gemin X Pharmaceuticals Canada Inc. | Compositions and methods for effecting NAD+ levels using a nicotinamide phosphoribosyl transferase inhibitor |
US8912184B1 (en) | 2010-03-01 | 2014-12-16 | Alzheimer's Institute Of America, Inc. | Therapeutic and diagnostic methods |
JP2013540781A (ja) | 2010-10-26 | 2013-11-07 | ティエンジン ホーメイ バイオ−テック カンパニー, リミテッド | N−(6−(4−クロロフェノキシ)ヘキシル)−n’−シアノ−n’’−(4−ピリジル)グアニジンの結晶多形とその製造及び使用 |
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GB9219472D0 (en) * | 1992-09-15 | 1992-10-28 | Leo Pharm Prod Ltd | Chemical compounds |
GB9711125D0 (en) * | 1997-05-29 | 1997-07-23 | Leo Pharm Prod Ltd | Novel cyanoguanidines |
AU1494702A (en) * | 2000-11-21 | 2002-06-03 | Leo Pharma As | Cyanoguanidine prodrugs |
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1997
- 1997-05-29 GB GBGB9711123.1A patent/GB9711123D0/en active Pending
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- 1998-05-15 PL PL98337059A patent/PL190249B1/pl not_active IP Right Cessation
- 1998-05-15 US US09/424,631 patent/US6346520B1/en not_active Expired - Lifetime
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- 1998-05-15 RU RU99128101/04A patent/RU2194697C2/ru active
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2000
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010088842A1 (zh) * | 2009-02-06 | 2010-08-12 | 天津和美生物技术有限公司 | 含有吡啶基氰基胍的药物组合物及其制备和应用 |
JP2012516857A (ja) * | 2009-02-06 | 2012-07-26 | ティエンジン ホーメイ バイオ−テック カンパニー, リミテッド | ピリジルシアノグアニジンを含む薬物組成物、該組成物の製造方法及び応用 |
Also Published As
Publication number | Publication date |
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JP2001526692A (ja) | 2001-12-18 |
GB9711123D0 (en) | 1997-07-23 |
US20020107400A1 (en) | 2002-08-08 |
HUP0003823A2 (en) | 2001-03-28 |
DK0984936T3 (da) | 2004-01-05 |
WO1998054141A1 (en) | 1998-12-03 |
PT984936E (pt) | 2004-02-27 |
US6646129B2 (en) | 2003-11-11 |
HUP0003823A3 (en) | 2001-09-28 |
ES2206931T3 (es) | 2004-05-16 |
CZ9904240A3 (cs) | 2001-01-17 |
EP0984936A1 (en) | 2000-03-15 |
CN1121389C (zh) | 2003-09-17 |
RU2194697C2 (ru) | 2002-12-20 |
AU7638398A (en) | 1998-12-30 |
KR20010013164A (ko) | 2001-02-26 |
DE69817810D1 (de) | 2003-10-09 |
CZ293275B6 (cs) | 2004-03-17 |
CA2292775A1 (en) | 1998-12-03 |
EP0984936B1 (en) | 2003-09-03 |
RO119880B1 (ro) | 2005-05-30 |
CA2292775C (en) | 2009-10-13 |
JP4349476B2 (ja) | 2009-10-21 |
NZ501266A (en) | 2001-09-28 |
PL337059A1 (en) | 2000-07-31 |
KR100549631B1 (ko) | 2006-02-08 |
PL190249B1 (pl) | 2005-11-30 |
ATE248819T1 (de) | 2003-09-15 |
US6346520B1 (en) | 2002-02-12 |
HK1027568A1 (en) | 2001-01-19 |
AU733000B2 (en) | 2001-05-03 |
DE69817810T2 (de) | 2004-07-01 |
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