CN1141292C - 细胞生长抑制剂 - Google Patents
细胞生长抑制剂 Download PDFInfo
- Publication number
- CN1141292C CN1141292C CNB988138476A CN98813847A CN1141292C CN 1141292 C CN1141292 C CN 1141292C CN B988138476 A CNB988138476 A CN B988138476A CN 98813847 A CN98813847 A CN 98813847A CN 1141292 C CN1141292 C CN 1141292C
- Authority
- CN
- China
- Prior art keywords
- methyl
- amino
- hydroxyl
- isobutyl
- formyl radical
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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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
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 239000000273 veterinary drug Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
- C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
- C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
Abstract
2(R或S)-[2R-(S-羟基-羟基氨甲酰基-甲基)-4-甲基-戊酰基胺]-2-苯基-乙酸环戊基酯,2(R或S)-(3S-羟基氨基甲酰基-2R-异丁基-己-5-烯酰基氨基)-2-苯基乙酸异丙基酯,2(R或S)-[2R-(S-羟基氨基甲酰基-甲氧基-甲基)-4-甲基-戊酰基氨基]-3-苯基乙酸环戊酯,2(R或S)-(3S-羟基氨基甲酰基-2R-异丁基-己-5-烯酰基氨基)-2-(4-甲氧基苯基)乙酸环戊酯,2(R或S)-(3S-羟基氨基甲酰基-2R-异丁基-己-5-烯酰基氨基)-2-(噻吩-2-基)乙酸环戊酯和2(R或S)-(3S-羟基氨基甲酰基-2R-异丁基-己-5-烯酰基氨基)-2-(噻吩-3-基)乙酸环戊酯是细胞生长抑制剂。
Description
本发明涉及治疗活性的酯和硫代酯,涉及它们的制备方法,涉及含所述酯和硫代酯的药物组合物,以及在药物中使用这类化合物的应用。特别是,化合物是一定范围里的快速分裂的肿瘤细胞,如黑素瘤和/或淋巴瘤细胞增殖的抑制剂。
发明背景
我们的国际专利申请PCT/GB 97/02398揭示了抑制哺乳动物中肿瘤细胞增殖的方法并对其提出权利要求,该方法包括对患有这类增殖的哺乳动物给予足以抑制这类增殖的一定量的通式(I)化合物或其药学上可接受的盐、水合物或溶剂合物:其中
R是氢或(C1-C6)烷基;
R1是氢;
(C1-C6)烷基;
(C2-C6)链烯基;
苯基或取代苯基;
苯基(C1-C6)烷基或取代苯基(C1-C6)烷基;
苯基(C2-C6)烯基或取代苯基(C2-C6)烯基
杂环基或取代杂环基;
杂环基(C1-C6)烷基或取代杂环基(C1-C6)烷基;
基团BSOnA-,其中n是0,1或2,B是氢或(C1-C6)烷基、苯基、取代苯基、杂环基取代的杂环基、(C1-C6)酰基、苯甲酰甲基或取代的苯甲酰甲基,A代表(C1-C6)亚烷基;
羟基或(C1-C6)烷氧基;
氨基、被保护的氨基、酰氨基、(C1-C6)烷氨基或二-(C1-C6)烷氨基;
巯基或(C1-C6)烷硫基;
氨基(C1-C6)烷基、(C1-C6)烷氨基(C1-C6)烷基、二(C1-C6)烷氨基(C1-C6)烷基、羟基(C1-C6)烷基、巯基(C1-C6)烷基或羧基(C1-C6)烷基,其中氨基-、羟基-、巯基-或羧基-基团被任选地保护,或羧基-基团被酰胺化;
低级烷基,它被氨甲酰基、单(低级烷基)氨甲酰基、二(低级烷基)氨甲酰基、二(低级烷基)氨基或羧基-低级烷酰基氨基所取代;或是
环烷基、环烯基或含最高达3个杂原子的非芳族杂环,它们中的任一个基团可(i)被一个或多个选自C1-C6烷基、C2-C6烯基、卤素、氰基(-CN)、-CO2H、-CO2R、-CONH2、-CONHR、-CON(R)2、-OH、-OR、氧基-、-SH、-SR、-NHCOR和-NHCO2R的取代基所取代,其中R是C1-C6烷基或苄基和/或(ii)与环烷基或杂环稠合;
R2是C1-C12烷基,
C2-C12烯基,
C2-C12炔基,
苯基(C1-C6烷基)-,
杂芳基(C1-C6烷基)-,
苯基(C2-C6烯基)-,
杂芳基(C2-C6烯基)-,
苯基(C2-C6炔基),
杂芳基(C2-C6炔基)-,
环烷基(C1-C6烷基)-,
环烷基(C2-C6烯基)-,
环烷基(C2-C6炔基)-,
环烯基(C1-C6烷基)-,
环烯基(C2-C6烯基)-,
环烯基(C2-C6炔基)-,
苯基(C1-C6烷基)O(C1-C6烷基)-,或
杂芳基(C1-C6烷基)O(C1-C6烷基)-,
它们中的任一个基团可任选地被下列取代基取代:
C1-C6烷基,
C1-C6烷氧基,
卤素,
氰基(-CN),
苯基,或
被C1-C6烷基,
C1-C6烷氧基,
卤素或氰基(-CN)取代的苯基;
R3是天然或非天然的α氨基酸的特征基团,其中的官能团可被保护;和
R4是酯或硫代酯基团,
或它的药学上可接受的盐、水合物或溶剂合物。
发明概述
本发明涉及作为哺乳动物肿瘤细胞增殖抑制剂的特定的化合物。本文讨论的化合物未在PCT/GB 97/02398里作特别的揭示,作为肿瘤细胞抑制剂,具有有价值的药理和药物动力学性质。
发明详述
本发明提供了选自下组的化合物和其药学上或兽药学上可接受的盐、水合物或溶剂合物:
2(R或S)-[2R-(S-羟基-羟基氨甲酰基-甲基)-4-甲基-戊酰基胺]-2-苯基-乙酸环戊基酯,
2(R或S)-(3S-羟基氨基甲酰基-2R-异丁基-己-5-烯酰基氨基)-2-苯基乙酸异丙基酯,
2(R或S)-[2R-(S-羟基氨基甲酰基-甲氧基-甲基)-4-甲基-戊酰基氨基]-3-苯基乙酸环戊酯,
2(R或S)-(3S-羟基氨基甲酰基-2R-异丁基-己-5-烯酰基氨基)-2-(4-甲氧基苯基)乙酸环戊酯,
2(R或S)-(3S-羟基氨基甲酰基-2R-异丁基-己-5-烯酰基氨基)-2-(噻吩-2-基)乙酸环戊酯,
2(R或S)-(3S-羟基氨基甲酰基-2R-异丁基-己-5-烯酰基氨基)-2-(噻吩-3-基)乙酸环戊酯。
优选的是上述化合物的2-S非对映异构体。
本发明化合物的盐包括生理上可接受的酸加成盐,如盐酸盐、氢溴酸盐、硫酸盐、甲磺酸盐、对-甲苯磺酸盐、磷酸盐、乙酸盐、柠檬酸盐、琥珀酸盐、乳酸盐、酒石酸盐、富马酸盐和马来酸盐。也可用碱成盐,如钠盐、钾盐、镁盐和钙盐。
一方面,本发明包括抑制哺乳动物里肿瘤细胞增殖的方法,该方法包括对患有这类增殖的哺乳动物给予足以抑制这类增殖的用量的上述化合物或其药学上或兽药学上可接受的盐、水合物或溶剂合物。
另一方面,本发明包括上述化合物或其药学上或兽药学上可接受的盐、水合物或溶剂合物在制备用于抑制哺乳动物肿瘤细胞增殖的组合物中的应用。
本发明化合物可用于人药或兽药,因为它们是癌症细胞增殖的抑制剂。因此本发明的实用性在于能治疗癌症,如由淋巴瘤、白血病、骨髓瘤、腺癌、癌、间皮瘤、畸形癌、绒毛膜癌、小细胞癌、大细胞癌、黑素瘤、视网膜神经胶质瘤、纤维肉瘤、平滑肌肉瘤、成胶质细胞瘤或内皮瘤细胞的过度增殖引起的癌症。应当明白,本发明不同的化合物作为增殖抑制剂根据被治疗的癌症类型有不同的效力。任何本发明特定的化合物对任何特定细胞类型的增殖的抑制活性都可用标准的方法,如类似于本文生物实施例所述的方法进行常规测定。
本发明的再一方面提供了药物或兽药组合物,包括本发明的化合物和药学上或兽药学上可接受的赋形剂或载体。本发明的一个或多个化合物可与一种或多种赋形剂或载体一起存在于组合物中。
口服给药组合物的剂型为片剂、胶囊、粉末剂、颗粒剂、锭剂、液体或凝胶制剂,如口服、局部或无菌的非胃肠道溶液或悬浮液。口服给药的片剂和胶囊剂可为单位剂型,可含有诸如粘合剂的常规赋形剂,如糖浆、阿拉伯胶、明胶、山梨醇、黄蓍胶或聚乙烯基-吡咯烷酮;填料,如乳糖、糖、玉米淀粉、磷酸钙、山梨醇或甘氨酸;片剂润滑剂,如硬脂酸镁、滑石粉、聚乙二醇或二氧化硅;崩解剂,如土豆淀粉,或可接受的湿润剂,如十二烷基硫酸钠。片剂可根据正常的药学实践里公知的方法进行包衣。口服液体制剂可为含水或油状悬浮液、溶液、乳液、糖浆剂或酏剂,或可为无水产品,在使用前与水或其它合适的赋形剂重建。这类液体制剂可含有诸如悬浮剂的常规添加剂,例如山梨醇、糖浆、甲基纤维素、葡萄糖糖浆、明胶、氢化的可食脂肪;乳化剂,如卵磷脂、单油酸失水山梨醇酯或阿拉伯胶;非水性赋形剂(可包括可食油),例如杏仁油、分级的椰子油、油状酯,如甘油、丙三醇或乙醇;防腐剂,如对-羟基苯甲酸甲酯或丙酯或山梨酸,需要时,还有常规的调味剂或着色剂。
对于局部施用于皮肤,药物可制成霜剂、洗剂或软膏剂。霜剂或软膏剂是本技术领域公知的常规的药物制剂,如在诸如英国药典的药学标准手册里所揭示的。
活性组分也可在无菌介质里非胃肠道地给药。根据所用的赋形剂和浓度,药物可悬浮或溶于该赋形剂中。有利的是,诸如局部麻醉剂、防腐剂和缓冲剂的佐剂可溶于赋形剂。
应当明白,对于任何特定病人的特定剂量水平要根据各种因素,包括所用特定化合物的活性、被治疗者的年龄、体重、总体健康水平、性别、饮食、给药时间、给药途径、排泄速率、药物组合和被治疗的特定疾病的严重程度而定。
用与我们的国际申请PCT/GB 97/02398中实施例8、16、3和41揭示的相似方法来制备本发明化合物(实施例1-6)。这些实施例在下面依次称为制备实施例A-D。作为非对映异构体混合物得到的产物通过反相HPLC分离。在实施例中使用了下列缩略词:
DCM-二氯甲烷
DMF-N,N-二甲基甲酰胺
NMM-N-甲基吗啉
TFA-三氟乙酸
HOBT-1-羟基苯并三唑
柱层析用快速级硅胶进行。在Bruker AC 250E分光计上,分别在250.1和62.9MHz下记录1H-NMR和13C-NMR。CDCl3甲醇-d4和二甲亚砜-d6(DMSO-d6)用作溶剂和内标物,光谱被记录为距离TMS的δppm。
制备实施例A
(a)2S-[2R-(2,2-二甲基-5-氧基-[1,3]-二氧戊环-4S-基)-4-甲基-戊酰基氨基]-3-苯基丙酸异丙基酯。
让2R-(2,2-二甲基-5-氧基-[1,3-二氧戊环-4S-基)-4-甲基-戊酸五氟苯基酯(WO 95/19956)(2.87g 7.3毫摩尔)和L-苯丙氨酸异丙基酯(1.5g,7.3毫摩尔)在DCM里的溶液在室温下静置96小时。反应混合物用DCM稀释,用1M碳酸钠水溶液、1M盐酸和盐水洗涤,然后用硫酸镁干燥,过滤,减压浓缩。产物用乙酸乙酯/己烷重结晶,得到2S-[2R-(2,2-二甲基-5氧基-[1,3]-二氧戊环-4S-基)-4-甲基-戊酰基氨基]-3-苯基丙酸异丙基酯的白色针晶(810毫克,29%)。
(b)2S-[2R-(S-羟基-羟基氨基甲酰基-甲基)-4-甲基-戊酰基胺]-3-苯基-丙酸异丙基酯。
使甲氧化钠(325毫克,6.1毫摩尔)和盐酸羟基胺(396毫克,6.1毫摩尔)在甲醇(15毫升)里的溶液在室温下搅拌2小时。然后将该溶液过滤入2S-[2R-(2,2-二甲基-5-氧基-[1,3]-二氧戊环-4S-基)-4-甲基-戊酰基氨基]-3-苯基丙酸异丙基酯(800毫克,2.1毫升)在甲醇(10毫升)里的溶液里。让反应在室温下放置18小时。减压浓缩反应混合物,残留物在乙酸乙酯和水之间分配。用水洗涤有机层,用硫酸镁干燥,过滤,减压浓缩。用乙酸乙酯重结晶,得到2S-[2R-(S-羟基-羟基氨基甲酰基-甲基)-4-甲基-戊酰基胺]-3-苯基-丙酸异丙基酯的白色晶体,它经真空干燥(465毫克,58%)。
制备实施例B
(a)2R-(S-苄基氧基氨基甲酰基-甲氧基-甲基)-4-甲基-戊酸。
使3R-异丁基-4S-甲氧基-二氢呋喃-2,5-二酮(WO 97/02239)(609毫克,3.27毫摩尔)和O-苄基羟基胺(403毫克,3.27毫摩尔)在乙酸乙酯(5毫升)里的溶液在室温下搅拌1小时。真空浓缩反应混合物,得到2R-(S-苄氧基氨基甲酰基-甲氧基-甲基)-4-甲基-戊酸的白色泡沫(1.01克,100%)。
(b)2S-[2R-(S-苄氧基氨基甲酰基-甲氧基-甲基)-4-甲基-戊酰基氨基]-3-苯基-丙酸异丙基酯。
在0℃下,用L-苯丙氨酸异丙酯(810毫克,3.9亳摩尔)和N-(3-二甲氨基丙基)-N’-乙基碳化二亚胺盐酸盐(750毫克,3.9毫摩尔)处理2R-(S-苄基氧基氨基甲酰基-甲氧基-甲基)-4-甲基-戊酸(1.01g,3.3毫摩尔)在四氢呋喃(15毫升)里的溶液。让反应混合物温热到室温,搅拌18小时。减压浓缩溶液,残留物溶于DCM。该溶液用1M盐酸、饱和的碳酸氢钠和盐水洗涤。有机相用硫酸钠干燥,过滤,减压浓缩。产物经柱层析纯化,用2%甲醇/DCM洗脱。合并含产物的组分,减压浓缩,得到2S-[2R-(S-苄氧基氨基甲酰基-甲氧基-甲基)-4-甲基-戊酰基氨基]-3-苯基-丙酸异丙基酯的白色固体(1.39g,85%)。
(c)2S-[2R-(S-羟基氨基甲酰基-甲氧基-甲基)-4-甲基-戊酰基氨基]-3-苯基-丙酸异丙基酯。
用在乙酸乙酯(5毫升)里的钯催化剂(274毫克,10%Pd/碳)的浆状物处理2S-[2R-(S-苄氧基氨基甲酰基-甲氧基-甲基)-4-甲基-戊酰基氨基]-3-苯基-丙酸异丙基酯(1.37克,2.8毫摩尔)在乙醇(30毫升)中的溶液。向悬浮液里通氢气达2小时。过滤反应混合物,减压浓缩。产物用乙酸乙酯/己烷重结晶,得到2S-[2R-(S-羟基氨基甲酰基-甲氧基-甲基)-4-甲基-戊酰基氨基]-3-苯基-丙酸异丙基酯的白色固体(778毫克,70%)。
制备实施例C
(a)2S-(3S-叔丁氧基羰基-2R-异丁基-己-5-烯酰基氨基)-3-苯基丙酸异丙基酯。
使L-苯丙氨酸异丙基酯(3.9克,18.8毫摩尔)在DMF(15毫升)中的溶液在冰浴里冷却,用3S-叔丁氧基羰基-2R-异丁基-己-5-烯酸五氟苯基酯(9.03克,20.7毫摩尔)处理。让反应物温热至室温,并搅拌过夜。减压浓缩反应混合物。残留物溶于乙酸乙酯,用1M盐酸、1M碳酸钠和盐水洗涤。用硫酸钠干燥溶液,过滤,减压浓缩。产物经柱层析纯化,用100%DCM到10%甲醇/DCM进行梯度洗脱。合并含产物的组分,除去溶剂,得到2S-(3S-叔丁氧基羰基-2R-异丁基-己-5-烯酰基氨基)-3-苯基丙酸异丙基酯的黄色固体(3.5克,41%)。
(b)2S-(3S-羟基羰基-2R-异丁基-己-5-烯酰氨基)-3-苯基丙酸异丙基酯。
让2S-(3S-叔丁氧基羰基-2R-异丁基-己-5-烯酰基氨基)-3-苯基丙酸异丙基酯(3.5克,7.6毫摩尔)在TFA与DCM混合液(1∶1,10毫升)中的溶液在5℃下静置过夜。减压浓缩反应混合物。向残留物里加入乙醚,得到2S-(3S-羟基羰基-2R-异丁基-己-5-烯酰基氨基)-3-苯基丙酸异丙基酯的白色固体(261毫克,8%)。
(c)2S-(3S-羟基氨基甲酰基-2R-异丁基-己-5-烯酰基氨基)-3-苯基丙基酸异丙基酯。
使2S-(3S-羟基羰基-2R-异丁基-己-5-烯酰基氨基)-3-苯基丙酸异丙基酯(260毫克,0.64毫摩尔)在DMF(10毫升)中的溶液在冰水浴里冷却。搅拌下加入N-(3-二甲氨基丙基)-N’-乙基碳化二亚胺盐酸盐(148毫克,0.77毫摩尔)和HOBT(104毫克,0.77毫摩尔)。让反应物温热到室温,2小时后加入羟基胺盐酸盐(67毫克,0.96毫摩尔)和NMM(0.1毫升,0.96毫摩尔)在DMF(5毫升)中的溶液。使反应混合物搅拌过夜后,减压浓缩反应混合物,经酸洗涤的硅胶上的层析纯化产物,用5-10%在DCM中的甲醇洗脱。用乙酸乙酯/己烷重结晶,得到2S-(3S-羟基氨基甲酰基-2R-异丁基-己-5-烯酰基氨基)-3-苯基丙酸异丙基酯的白色固体(12毫克,4%)。
制备实施例D
用L-苯基甘氨酸环戊酯代替L-苯丙氨酸异丙基酯,按制备实施例C所述的类似途径制备标题化合物。
实施例1
按制备实施例A揭示的相似方法,用苯基甘氨酸环戊酯制备。
非对映异构体A
1H-NMR;δ(MeOD),7.4-7.29(5H,m),5.43(1H,s),5.2-5.14(1H,m),4.02(1H,d,J=6.9Hz),2.94-2.85(1H,m),1.91-1.34(10H,bm),1.25-1.14(1H,m)和0.86(6H,dd,J=6.5,11.5Hz).
13C-NMR;δ(MeOD),175.6,171.8,171.4,137.8,129.8,129.4,128.6,80.0,73.2,58.5,49.2,39.1,33.3,33.3,26.8,24.5,24.4,23.7和22.1.
非对映异构体B
1H-NMR;δ(MeOD),7.33-7.19(5H,m),5.3(1H,s),5.11-5.06(1H,m),3.81(1H,d,J=7.3Hz),2.83-2.74(1H,m),1.83-1.45(10H,bm),1.12-1.03(1H,m)和0.88-0.81(6H,dd,J=6.4,12.3Hz).13C-NMR;δ(MeOD),175.8,171.8,171.5,137.3,129.8,129.5,128.8,79.9,73.3,58.7,48.9,39.2,33.3,33.3,26.7,24.5,24.5,24.0和22.2。
实施例2
2-(3S-羟基氨基甲酰基-2R-异丁基-己-5-烯酰基氨基)-2-苯基乙酸异丙基酯。
用与制备实施例D所述相似的方法,使用苯基甘氨酸异丙基酯进行制备。
非对映异构体A
1H-NMR;δ(MeOD),7.34-7.24(5H,m),5.59-5.42(1H,m),5.36(1H,s),5.02-4.77(3H,m),2.63-2.53(1H,m),2.17-2.02(2H,m),1.89-1.78(1H,m),1.63-1.45(2H,m),1.18(3H,d,J=6.3Hz),1.05(3H,d,J=6.2Hz),1.00-0.93(1H,m),0.88(3H,d,J=6.5Hz)和0.81(3H,d,J=6.5Hz)。13C-NMR;δ(MeOD),176.2,172.4,171.3,137.6,136.0,129.9,129.6,129.0,117.4,70.5,58.7,47.4,41.5,36.0,26.7,24.5,21.9,21.7和21.7。
非对映异构体B
1H-NMR;δ(MeOD),7.4-7.34(5H,m),5.77-5.61(1H,m),5.42(1H,s),5.1-4.98(3H,m),2.7-2.6(1H,m),2.44-2.17(3H,m),1.61-1.5(1H,m),1.42-1.29(1H,m),1.25(3H,d,J=6.3Hz),1.13(3H,d,J=6.2Hz),1.09-1.00(1H,m)和0.81(6H,d,J=6.4Hz)。13C-NMR;δ(MeOD),176.4,172.5,171.5,137.2,136.4,129.9,129.6,129.0,117.5,70.5,58.8,48.4,47.4,41.3,36.0,27.1,24.3,21.9,21.8和21.6。
实施例3
用制备实施例B相似的方法,使用苯基甘氨酸环戊酯进行制备。
非对映异构体A
1H-NMR;δ(MeOD),8.83(1H,d,J=6.6Hz),7.48-7.29(5H,m),5.44-5.42(1H,m),5.20-5.16(1H,m),3.53(1H,d,J=9.7Hz),3.17(3H,s),2.89-2.79(1H,m),1.90-1.54(10H,bm),1.06-0.99(1H,m),0.95(3H,d,J=6.5Hz)和0.90(3H,d,J=6.4Hz)。13C-NMR;δ(MeOD),175.3,171.6,169.4,137.5,129.7,129.4,128.7,83.1,79.9,58.7,58.1,48.5,38.4,33.4,33.3,26.7,24.6,24.5,24.3和21.8。
非对映异构体B
1H-NMR;δ(MeOD),7.39-7.30(5H,m),5.45(1H,s),5.21-5.15(1H,m),3.59(1H,d,J=9.4Hz),3.29(3H,s),2.89-2.79(1H,m),1.93-1.49(9H,bm),1.42-1.21(1H,m),1.01(1H,ddd,J=3.7,9.9,13.3Hz),0.83(3H,d,J=6.5Hz)和0.79(3H,d,J=6.6Hz)。13C-NMR;δ(MeOD),175.1,171.5,169.5,137.9,129.7,129.4,128.7,83.0,79.8,58.5,58.3,48.6,38.5,33.3,27.8,24.5,24.4,24.1和21.7。
实施例4
按与制备实施例D相似的方法,使用4-甲氧基苯基甘氨酸环戊酯进行制备。
非对映异构体A
1H-NMR;δ(MeOD),8.94(1H,d,J=6.4Hz),7.32(2H,d,J=8.7Hz),6.93(2H,d,J=8.7Hz),5.67-5.50(1H,m),5.36-5.33(1H,m),5.20-5.14(1H,m),4.93-4.87(2H,m),3.79(3H,s),2.68-2.59(1H,m),2.24-2.09(2H,m),1.97-1.55(11H,bm),1.11-1.00(1H,m),0.95(3H,d,J=6.5Hz)和0.88(3H,d,J=6.5Hz)。13C-NMR;δ(MeOD),176.2,172.4,171.9,161.4,136.0,130.2,129.4,117.4,115.2,79.7,58.2,55.8,48.3,47.3,41.5,36.0,33.4,33.3,26.7,24.6,24.5和21.7。
非对映异构体B
1H-NMR;δ(MeOD),8.96(1H,d,J=6.7Hz),7.29(2H,d,J=8.7Hz),6.93(2H,d,J=8.7Hz),5.77-5.61(1H,m),5.32(1H,s),5.20-5.15(1H,m),5.09-4.97(2H,m),3.80(3H,s),2.64(1H,dt,J=3.3,11.4,13.5Hz),2.43-2.16(3H,m),1.91-1.49(9H,bm),1.42-1.29(1H,m),1.05(1H,ddd,J=3.3,10.1,13.2Hz)和0.81(6H,d,J=6.5Hz)。13C-NMR;δ(MeOD),176.3,172.5,172.0,161.4,136.4,130.2,129.0,117.5,115.2,79.8,58.2,55.8,48.4,47.4,41.3,36.1,33.4,27.1,24.5,24.3和21.6。
实施例5
2-(3S-羟基氨基甲酰基-2R-异丁基-己-5-烯酰基氨基)-2-(噻吩-2-基)乙酸环戊酯
按与制备实施例D相似的方法,使用噻吩-2-基甘氨酸环戊酯进行制备。
非对映异构体A
1H-NMR;δ(MeOD),7.41(1H,dd,J=5.1,1.2Hz),7.12(1H,d,J=3.5Hz),7.01(1H,dd,J=5.1,3.5Hz),5.72(1H,s),5.69-5.52(1H,m),5.26-5.18(1H,m),5.00-4.89(2H,m),2.70-2.59(1H,m),2.28-2.13(2H,m),2.09-1.50(11H,m),1.05(1H,ddd,J=13.8,11.0,2.9Hz),0.93(3H,d,J=6.4Hz)和0.87(3H,d,J=6.5Hz)。13C-NMR;δ(MeOD),176.5,172.7,171.1,139.5,136.4,128.4,128.3,127.7,117.9,80.7,54.1,48.7,47.7,41.9,36.5,33.8,33.7,27.2,25.1,25.0,24.9,和22.1。
非对映异构体B
1H-NMR;δ(MeOD),7.42(1H,dd,J=5.0,0.7Hz),7.10(1H,d,J=3.6Hz),7.01(1H,dd,J=5.0,3.6Hz),5.79-5.59(2H,m),5.28-5.19(1H,m),5.10-4.94(2H,m),2.71-2.59(1H,m),2.36-2.16(3H,m),1.97-1.34(10H,m),1.13-1.00(1H,m),0.86(3H,d,J=6.2Hz)和0.84(3H,d,J=6.3Hz)。13C-NMR;δ(MeOD),176.7,172.8,171.2,139.3,136.7,128.3,128.2,127.6,117.9,80.7,54.2,48.8,47.8,41.7,36.4,33.8,27.5,25.1,25.0,24.8和22.1。
实施例6
按与制备实施例D相似的方法,用噻吩-3-基甘氨酸环戊酯进行制备。
非对映异构体A
1H-NMR;δ(MeOD),7.48-7.42(2H,m),7.13(1H,dd,J=4.2,2.0Hz),5.69-5.52(2H,m),5.21-5.16(1H,m),4.98-4.90(2H,m),2.71-2.59(1H,m),2.28-2.11(2H,m),2.00-1.50(11H,m),1.12-0.98(1H,m),0.94(3H,d,J=6.4Hz)和0.88(3H,d,J=6.5Hz)。13C-NMR;δ(MeOD),176.6,172.8,171.8,137.8,136.4,128.3,128.0,125.2,117.9,80.3,54.6,41.9,36.5,33.8,33.8,27.1,25.0,24.9和22.1。
非对映异构体B
1H-NMR;δ(MeOD),7.45(1H,dd,J=4.9,3.0Hz),7.43-7.40(1H,m),7.12(1H,dd,J=5.0,1.3Hz),5.68(1H,ddt,J=17.0,10.1,6.8Hz),5.53(1H,s),5.23-5.17(1H,m),5.10-4.96(2H,m),2.70-2.60(1H,m),2.41-2.16(3H,m),1.94-1.49(9H,m),1.44-1.29(1H,m),1.05(1H,ddd,J=12.9,10.3,3.3Hz),0.84(3H,d,J=6.5Hz)和0.83(3H,d,J=6.5Hz)。
生物实施例
实施例1-6的化合物在下列细胞增殖试验里进行试验,以测定它们各自的对讨论中的细胞类型增殖的抑制能力。
人细胞系,即组织细胞的淋巴瘤(U937)以250细胞/毫米2密度的被接种到补充10%胎牛血清合适培养介质里的30毫米2的组织培养坑里。6小时后,在相同的培养介质里,将试验化合物加到细胞里,其最终浓度为6μM。含细胞的对照坑供给相同的培养基,它含有等当量药物赋形剂,在本试验中为DMSO,其最终浓度为0.08%。在培养基中72小时后,用[甲基-3[H]胸腺嘧啶核苷](2μCi/毫升)对细胞脉冲3小时,然后在过滤垫上收集,对DNA相关的放射活性进行计数。结果表达为对照的3[H]胸腺嘧啶核苷结合百分数(n=6±1标准误差)。在所有的试验化合物里都观察到对增殖的抑制。
Claims (5)
1.一种化合物,它选自以下化合物:
2R或2S-[2R-(S-羟基-羟基氨甲酰基-甲基)-4-甲基-戊酰基胺]-2-苯基-乙酸环戊基酯,
2R或2S-(3S-羟基氨基甲酰基-2R-异丁基-己-5-烯酰基氨基)-2-苯基乙酸异丙基酯,
2R或2S-[2R-(S-羟基氨基甲酰基-甲氧基-甲基)-4-甲基-戊酰基氨基]-3-苯基乙酸环戊酯,
2R或2S-(3S-羟基氨基甲酰基-2R-异丁基-己-5-烯酰基氨基)-2-(4-甲氧基苯基)乙酸环戊酯,
2R或2S-(3S-羟基氨基甲酰基-2R-异丁基-己-5-烯酰基氨基)-2-(噻吩-2-基)乙酸环戊酯,
2R或2S-(3S-羟基氨基甲酰基-2R-异丁基-己-5-烯酰基氨基)-2-(噻吩-3-基)乙酸环戊酯,
和它们的药学上或兽药学上可接受的盐。
2.根据权利要求1所述的化合物,它是2-S非对映异构体。
3.一种抑制哺乳动物肿瘤细胞增殖的药物组合物或兽药组合物,包括如权利要求1或2所述的化合物和药学上或兽药学上可接受的赋形剂或载体。
4.如权利要求1或2所述的化合物在制备抑制哺乳动物肿瘤细胞增殖的药物中的应用。
5.根据权利要求4所述的应用,其中被治疗的细胞增殖是淋巴瘤、白血病、骨髓瘤、腺癌、癌、间皮瘤、畸形癌、绒毛膜癌、小细胞癌、大细胞癌、黑素瘤、视网膜神经胶质瘤、纤维肉瘤、平滑肌肉瘤、成胶质细胞瘤或内皮瘤细胞的过度增殖。
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DE69810817T2 (de) | 2003-11-20 |
PL190637B1 (pl) | 2005-12-30 |
HUP0100999A2 (hu) | 2001-08-28 |
NZ506293A (en) | 2003-05-30 |
CA2323414C (en) | 2008-05-13 |
GB0019414D0 (en) | 2000-09-27 |
IL137774A (en) | 2006-07-05 |
AU747977B2 (en) | 2002-05-30 |
NO20004528L (no) | 2000-09-11 |
KR20010041661A (ko) | 2001-05-25 |
CZ299610B6 (cs) | 2008-09-17 |
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