CN87104596A - 4(3H)-氧代-5,6,7,8-四氢吡啶并[2,3-d]嘧啶衍生物的制备方法 - Google Patents
4(3H)-氧代-5,6,7,8-四氢吡啶并[2,3-d]嘧啶衍生物的制备方法 Download PDFInfo
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- CN87104596A CN87104596A CN87104596.6A CN87104596A CN87104596A CN 87104596 A CN87104596 A CN 87104596A CN 87104596 A CN87104596 A CN 87104596A CN 87104596 A CN87104596 A CN 87104596A
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- 238000002360 preparation method Methods 0.000 title claims description 14
- 150000003230 pyrimidines Chemical class 0.000 title claims description 4
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 title description 2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- 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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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- General Health & Medical Sciences (AREA)
- Public Health (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
N-[-(N-[2-氨基-(4(3H)-氧代-5,6,7,8-四氢吡啶并-6-基甲基]-氨基)苯甲酰基]-L谷氨酸的衍生物是抗仲瘤药剂这类化合物可通过水解相应的化合物(其中2-氨基和谷氨酸羧基是被保护着的)来制备。
Description
本发明涉及N-[4-(N-(2-氨基-4(3H)-氧代-5,6,7,8-四氢吡啶并-[2,3-d]嘧啶-6-基甲基]氨基)苯甲酰基]-L-谷氨酸的衍生物(这些衍生物是抗肿瘤药剂)及它们的制备和应用,以及在这些衍生物的制备中有用的中间物。
叶酸抗代谢物氨基蝶呤和氨甲蝶呤(也称为10-甲基氨基蝶呤)是抗肿瘤药剂,这些化合物抑制包括叶酸的代谢衍生物的酶促转化作用。例如氨甲蝶呤抑制二氢叶酸还原酶(它是一种由二氢叶酸盐还原成四氢叶酸盐所必需的酶)而二氢叶酸是在用胸苷酸合成酶使2-脱氧尿苷酸转化为胸苷酸时形成的。
已经合成了叶酸的及氨基蝶呤的其他衍生物并已作为抗代谢物进行了试验。在这些化合物中即在分子中通常为亚氨基或次氮基占据的位置上分别为亚甲基或次甲基所占据的化合物。这些化合物具有不同程度的代谢拮抗活性。10-脱氮杂氨基蝶呤具有高度的活性(Sirotak等人,癌症治疗报告书,1978,62,1047)而5-脱氮杂氨基蝶呤则具有与氨甲蝶呤相似的活性(Taylor等人,有机化学杂志,1983,48,4852)。据报告8,10-二脱氮杂氨基蝶呤具有活性(美国专利第4,460,591号)而5,8,10-三脱氮杂氨基蝶呤显示抗小鼠L1210白血病的活性(Yan等人,杂环化学杂志,1979,16,541)。另一方面10-脱氮杂叶酸却没有显示出显著的活性(Struck等人,医药化学杂志,1971,14,693)而5-脱氮杂叶酸仅有微弱的细胞毒性。8,10-二脱氮杂叶酸作为二氢叶酸还原酶抑制剂仅有一定程度的效力(De Graw等人,“蝶啶的化学和生物学”,Elsevier,1979,229)而5,8,10-三脱氮杂叶酸也仅仅显示出一定程度的抗小鼠L1210白血病的活性(Oatis等人,医药化学杂志,1977,20,1393)。在医药化学杂志,28∶7,914(1985)中Taylor等人发表了5,10-二脱氮杂氨基蝶呤和5,10-二脱氮杂-5,6,7,8-四氢氨基蝶呤以及相应的5,10-二脱氮杂蝶呤衍生物。
R1是氢、甲基、乙基、或R5CO-在此基团中R5是氢或具有1至6个碳原子的烷基;标有*符号的碳原子的构型是L型;(ii)此化学式的互变异构体;(iii)它的可做药用的盐。
本发明也涉及这类化合物的制备方法和在这些制备中有用的中间物,并涉及在抗肿瘤中应用这些化合物的组合物及方法。
本发明的化合物是5,6,7,8-四氢吡啶并[2,3-d]嘧啶杂环的衍生物,此杂环上的原子其位次编号如下:
为了方便起见,上述用4(3H)-氧代的形式来描述而且本说明书中全部应用相应的命名原则,应该理解在每一种情况下这一名词包括互变异构的3,4-脱氧-4-羟基式。
在谷氨酸链上,标有*号的碳原子的绝对构型是L型,与在丙氨酸上的相应的α-碳原子的绝对构型相同。在5,6,7,8-四氢吡啶并[2,3-d]嘧啶环系统的6-位上的碳原子也是一个手性中心,导致产生d,L-和1,L-非对映异构体,这两种形式的异构体(当应用色谱法时,可用机械方法将它们分离)也包括在本发明的范围内。
本发明包括可作医药用的盐类,这些盐类要未与酸形成(包括在8-位上的氮原子上形成的盐)要未与碱形成(包括在谷氨酸残基上的羧酸基团上形成的盐)。与碱形成的盐类包括碱金属、碱土金属、无毒性金属、铵、取代的铵等的盐类,例如钠、钾、锂、钙、镁、铝、锌、铵、三甲铵、三乙铵、三乙醇铵、吡啶鎓、取代的吡啶鎓等等。与酸形成的盐类包括可作医药用的、无毒的酸加成盐类,例如由(i)无机酸,例如盐酸、氢溴酸、硝酸、硫酸、磷酸等等所成的盐,(ii)有机羧酸,例如乙酸、丙酸、乙醇酸、丁二酸、马来酸、羟基马来酸、甲基马来酸、富马酸、苹果酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、水杨酸、4-氨基水杨酸、4-苯氧基苯甲酸、2-乙酸氧基苯甲酸、4,4′-亚甲基双(3-羟基-2-萘酸)、烟酸或异烟酸、和(iii)有机磺酸,例如甲磺酸、乙磺酸、2-羟基乙磺酸、乙基-1,2-二磺酸、苯磺酸、对甲苯磺酸或萘-2-磺酸。
本发明的化合物作为一种底物对应用于叶酸特别是叶酸代谢衍生物的一种或几种酶有作用。
R1的定义如前;
R2和R3是相同或不相同的羧酸保护基团;
R4是一种氨基保护基团;而标有*号的碳原子构型是L型。
保护基包括R2、R3和R4而对于除去它们的反应,在文献中已有叙述例如在以下文献中:“有机化学的保护基团”Plenum出版,伦敦和纽约(1973);Greene,“在有机合成中的保护基团“Wiley,纽约(1981);“肽”第1卷,Schroder和Lubke,Academic出版,伦敦和纽约(1965);“有机化学方法”Houben-Weyl,第4版,15/I卷,Georg Thieme Verlag,Stuttgart(1974)。
羧酸保护基团理论上可以是例如由具有1至6个碳原子的低级烷醇得到的酯,包括在1-位上有侧链的和由一个或多个芳香基团(如苯基)或由卤素或烷氧基取代的酯,例如甲基、乙基、叔丁基、苄基、4-硝基苄基、二苯基甲基、甲氧基甲基取代的以及类似的酯类。也可以使用正硅烷酯类如三甲基硅烷酯。
氨基保护基包括脂酰基,特别是2至6个碳原子的烷酰基、烷氧羰基(它们可以被卤素、烷氧基或苯基取代);例如乙酰基、新戊酰基、2,2,2-三氯乙酰基、苯甲酰基、叔丁氧羰基、4-硝基苄氧基羰基等等。
水解作用是在正常的温度下利用稀碱水溶液(例如0.1-0.3N碱金属的氢氧化物水溶液),任选地在一种与水混溶的有机溶剂如甲醇、乙醇、四氢呋喃、二甲基甲酰胺等等或一种酸例如三氟乙酸存在下进行。如果有-N′-COR5基团存在的话,应用酸或强碱将导致水解作用发生。可以观察到分子的谷氨酸部分的某些外消旋作用。
水解作用所形成的初步产物是双阳离子谷氨酸盐,而使用酸性如乙酸或0.5N盐酸进行酸化调节pH值,则此谷氨酸盐很易变为游离酸而测定出来。得到的产物通常是高熔点的结晶或微结晶固体。
另一方面,化学式I的化合物的制备,正如可由化学式II的谷氨酸中间物来制备那样,可由化学式III的吡啶并[2,3-d]嘧啶化合物的氢化作用来制备在式中R1的定义如前;R2′、R3′、各是氢或一种羧酸保护基,其定义与上述的R2和R3相同而R4是氢或一种氨基保护基团,其定义与上述R4相同。
氢化作用是在一种酸性介质中在一种贵金属催化剂如铂、钌或铑(包括它们的氧化物以及它们的截体)存在下进行的。而以氧化铂做催化剂较好。反应时间、温度、压力的选择是以能使吡啶环还原(不包括嘧啶环)为准。例如当应用氧化铂为催化剂在室温下在氢压力为50至60磅/英寸2时约反应15分钟即可得到所需的产品。
当R2′、R3′和R4′是氢时,其还原的产物是化学式I的化合物。如果R2′、R3′和R4′都不是氢则产物是化学式II的化合物。
化学式III的化合物是已知的或可用通常的方法制备。例如可以用适当的试剂处理2-氨基-4(3H)-氧代-6-甲酰基吡啶并[2,3-d]嘧啶以引入R保护基如乙酸酐,再使生成的化合物与一种被保护的N-(4-氨基苯甲酰基)-L-谷氨酸衍生物反应而产生化学式III的化合物,在此合物中R1=H[见Taylor等人,有机化学杂志,48,4852(1983)]。应用相应的N-(4-甲基氨基苯甲酰基)-L-谷氨酸或N-(4-乙基氨基苯甲酰基)-L-谷氨酸产生化学式III的相应的化合物,其中的R1分别是甲基或乙基。
R1是H的化学式III的化合物经乙酰化作用就可得到R1是R5CO-的化学式III的化合物。
当R5是氢时,可应用过量的甲酸[见Haynes等人,医药化学杂志20,588-591(1977)]或甲酸的活性乙酰化衍生物例如混合的甲酸酐(例如它可由甲酸与乙酸酐形成)进行乙酰化作用。
当R5是烷基时,则可应用羧酸的活性衍生物例如象乙酰氯这样的卤化酸。
R1是R5CO-的化学式II和III的化合物是有价值的中间物,对于制备R1是氢的化学式I的最终化合物即N-[4-(N’-(2-氨基-4(3H)-氧代-5,6,7,8-四氢吡啶并[2,3-d]嘧啶-6-基甲基]氨基)苯甲酰基]-L-谷氨酸时尤其如此。这个化合物具有抗肿瘤活性并可通过化学式IV的化合物的直接氢化作用,任选的接着除去任何保护基团R、R和R而制备成。但是在还原作用之前,引入N’-酰基基团如甲酰基、提供增加对易于氢解的氨基[由于苯甲基的胺(benzylic amine)的本性]的保护作用。因此首先要形成化学式III的N’-甲酰基衍生物,再氢解而产生化学式II的N’-甲酰基-四氢中间物,然后使其水解,最好是酸水解与碱水解相继进行,而得到N-[4-(N’-(2-氨基-4(3H)-氧代-吡啶并[2,3-d]嘧啶-6-基甲基]氨基)苯甲酰基]-L-谷氨酸
在最终产物的分子上存在着两个手性中心:在四氢吡啶并[2,3-d]嘧啶环的-6-位上的碳原子和在谷氨酸基团上的α-碳原子。至于该化合物在理论上的四种型式,在制备化学式III的化合物还原作用之前,引入N’-酰基基团如甲酰基、提供增加对易于氢解的氨基[由于苯甲基本的胺(benzylic amiuc)的本性]的保护作用。因此首先要形成化学式III的N’-甲酰基衍生物,再氢解而产生化学式II的N’-甲酰基-四氢中间物,然后使其水解,最好是酸水解与碱水解相继进行,而得到N-[4-(N’-(2-氨基-4(3H)-氧代-吡啶并[2,3-d]嘧啶-6-基甲基]氨基)苯甲酰基]-L-谷氨酸
在最后产物的分子上存在着两个手性中心:在四氢吡啶并[2,3-d]嘧啶环的6-位上的碳原子和在谷氨酸基团上的α-碳原子。至于该化合物在理论上的四种型式,在制备化学式III的化合物时,对被保护的N-(4-氨基苯甲酰基)-L-谷氨酸试剂的应用降低其可能性至两个。然而,这两者都是在相继的氢化成化学式II的化合物时产生的,在除去了保护基团之后,结果就生成了以(S,S)和(R,S)非对映异构体混合物状态存在的所需要的化合物。这两个化合物(其中R2′、R3′和R4′都是氢)可表示如下:
应用色谱法可将这两个非对映异构体机械地分开,因此每一个化合物都大体上不混有另一个,即其旋光纯度达到95%以上。另一方面,用一种合用的手性酸处理化学式I的非对映异构体化合物可随即形成一种盐。然后通过一次或多次分部结晶法将所得到的非对映异构体分离再通过用碱处理并除去保护基,至少一种分离出来的盐的阳离子部分的游离碱被释放出来。在除去保护基之前之后,或者在碱性条件下,当这些基团轻易地被除去时随着除去这些基团,可以用不连续的步骤进行而释放出盐的阳离子,即进行碱性水解。
适合的手性酸包括10-樟脑磺酸的个别对映体、樟脑酸、α-溴樟脑酸、薄菏氧乙酸、酒石酸、二乙酰酒石酸、苹果酸、吡咯烷酮-5-羧酸等等。
可以单独或混合的形式使用化学式I的化合物治疗过去用氨甲蝶呤治疗的肿瘤,包括绒毛膜癌、白血病、女性的乳腺癌、头和颈的表皮癌、鳞状的或小细胞肺癌,以及各种淋巴肉瘤。有代表性的化合物例如N-[4-(N′-(2-氨基-4(3H)-氧代-5,6,7,8-四氢吡啶并[2,3-d]嘧啶-6-基甲基]氨基)苯甲酰基]-L-谷氨酸在72小时检测抗CCRF-CEM细胞系(一种人类T-细胞衍生的白血病)中显示出IC50为0.0052-0.0079微克/毫升(2.2×10-7摩尔)。而其非对映异构体所显示的IC50分别为0.0026和0.0027微克/毫升。N-[4-(N′-[2-氨基-4(3H)-氧代-5,6,7,8-四氢吡啶并[2,3-d]嘧啶-6-基甲基]-N’-甲酰氨基)苯甲酰基]-L-谷氨酸在同样的测试中显示的IC50为0.011。在另一方面,在这个测试中5-脱氮杂叶酸则相对地无活性,这些化合物也可以用来治疗蕈样真菌病和牛皮癣。
这些化合物可通过口服或较好是通过非肠道施用,可单独或与其他的抗肿瘤剂,甾类化合物等结合施用于患肿瘤而需要治疗的哺乳动物。非肠道施药的途径包括肌肉内注射、鞘内的注射、静脉内注射或动脉内的施用。通常,施用这些化合物的方式与施用氨甲蝶呤的方式很相似,但是由于作用的方式不同,这些化合物的施用剂量较高于通常使用氨甲蝶呤的剂量不需要甲酰四氢叶酸解救。剂量的规定方案必须要滴注到特定的肿瘤处,按病人的条件和反应而定,但通常的剂量是在5-10天内每天约从10至100毫克或单次一日施用250-500毫克,周期性地重复使用如每14天一周期,口服剂量的形式包括每单位剂量含有1-10毫克药物的片剂和胶囊。含有20-100毫克/毫升的等渗盐水溶液可以用作肠道的施药。
下面的实施例中将用作进一步说明本发明
实施例1N-[4-(N’-[2-乙酰氨基-4(3H)-氧代吡啶并[2,3-d]嘧啶-6-基甲基]氨基)苯甲酰基]谷氨酸二乙酯。
将800毫克2-乙酰氨基-6-甲酰基-4(3H)-氧代吡啶并[2,3-d]嘧啶[Taylor等人,有机化学杂志48,4852(1983)]在55毫升冰醋酸中和1.2克对氨基苯甲酰-L-谷氨酸二乙酯的混合物在室温下静置5小时。然后向此混合物中加入0.19毫升的氢化硼:三乙胺复合物。在室温下搅拌此混合物40分钟然后在60℃加热10分钟。使此反应混合物冷却,并在真空中浓缩。将所得到的残留物溶于90毫升甲醇中,将溶液过滤。用20毫升甲醇和360毫升乙醚洗涤从过滤收集到的固体。将滤液合并并蒸发至干。用硅胶快速色谱法[见still等人,有机化学杂志,43,2923(1978)](洗脱液为氯仿∶甲醇97∶3)分离提纯残余物,得到1.08克N-[4-(N’-(2-乙酰氨基-4(3H)-氧代吡啶并[2,3-d]嘧啶-6-基甲基]氨基)苯甲酰基]-L-谷氨酸二乙酯。
实施例2N-[4-(N’-[2-乙酰氨基-4(3H)-氧代-5,6,7,8-四氢吡啶并[2,3-d]嘧啶-6-基甲基]氨基)苯甲酰基]-L-谷氨酸二乙酯。
将含有340毫克N-[4-(N’-(2-乙酰氨基-4(3H)-氧代吡啶并[2,3-d]嘧啶-6-基甲基]氨基)苯甲酰基]-L-谷氨酸二乙酯的80毫升甲醇与40毫升冰醋酸的混合物放置于氢化作用装置(Adams)的容器内。加入55毫克的氧化铂催化剂并将该混合物在60磅/英寸2压力及室温下氢化15分钟。过滤除去催化剂,并在真空中浓缩滤液。用硅胶快速色谱法,洗脱液成份为氯仿∶甲醇(97∶3至95.5∶5)分离残余物,收集各液份各20毫升。液份62-73含有副产物2-乙酰氨基-6-甲基-4(3H)-氧代吡啶并[2,3-d]嘧啶。液份74-88含有15.4毫克所需的产物N-[4-(N’-(2-乙酰氨基-4(3H)-氧代-5,6,7,8-四氢吡啶并[2,3-d]嘧啶-6-基甲基]氨基)苯甲酰基]-L-谷氨酸二乙酯。
实施例3N-[4-(N’-[2-乙酰氨基-4(3H)-氧代-5,6,7,8-四氢吡啶并[2,3-d]嘧啶-6-基甲基]氨基)苯甲酰基]-L-谷氨酸
将20毫克N-[4-(N’-(2-乙酰氨基-4(3H)-氧代-5,6,7,8-四氢吡啶并[2,3-d]嘧啶-6-基甲基]氨基)苯甲酰基]-L-谷氨酸二乙酯溶于8毫升甲醇中并加入0.4毫升的1.0N的氢氧化钠水溶液。将此混合物在室温搅拌96小时然后加入0.1毫升冰醋酸。在真空中除去甲醇并将残留物溶于5毫升水中。用0.16毫升冰醋酸将此混合物酸化,经过滤收集所形成的溶液,得到6.0毫克产物N-[4-(N’-[2-乙酰氨基-4(3H)-氧代-5,6,7,8-四氢吡啶并[2,3-d]嘧啶-6-基甲基]氨基)苯甲酰基]-L-谷氨酸。质谱于444。
实施例4N-[4-(N’-[2-乙酰氨基-4(3H)-氧代吡啶并[2,3-d]嘧啶-6-基甲基]-N’-甲酰氨基苯甲酰基]谷氨酸二乙酯。
将98%的甲酸(25毫升)和乙酸酐(4.9毫升,5.25克,51.5毫摩尔)的混合物在25℃搅拌2小时。向此溶液加入2.43克(4.5毫摩尔)的N-[4-(N’-[2-乙酰氨基-4(3H)-氧代吡啶并[2,3-d]嘧啶-6-基甲基]氨基)苯甲酰基]-L-谷氨酸二乙酯[Taylor等人,有机化学杂志48,4852(1983)]。将此混合物在55℃搅拌15分钟并在25℃搅拌1小时。在减压下将溶剂除去并将残留物在乙醚中研磨,滤出固体物质,从2-丙醇中重结晶得到2.0克(78%)的N-[4-(N’-[2-乙酰氨基-4(3H)-氧代吡啶并[2,3-d]嘧啶-6-基甲基]-N’-甲酰氨基)苯甲酰基]谷氨酸二乙酯:熔点180-182℃ 1H NMR(Me2SO-d6)delta 1.05-1.23(m,6H),1.95-2.10(m,2H),2.16(s,3H),2.49(t,1H,J=7.36Hz),3.97-4.10(m,4H),4.36-4.39(m,1H),5.24(m,2H),7.51-7.54(m,2H,AA′BB′),7.84-7.87(m,2H,AA′BB′),8.21(m,1H),8.69-8.75(m,2H),8.82(s,1H).分析计算: C27H30N6O8: C,57.24;H,5.34;N,14.83.实测: C,56.94;H,5.11;N,14.57.
实施例5N-[4-(N’-[2-新戊酰基氨基-4(3H)-氧代吡啶并[2,3-d]嘧啶-6-基甲基]-N’-甲酰氨基)苯甲酰基]-谷氨酸二乙酯。
用相似于实施例4的方法利用N-[4-(N’-[2-新戊酰基氨基-4(3H)-氧代吡啶并[2,3-d]嘧啶-6-基甲基]氨基)苯甲酰基]-L-谷氨酸二乙酯制备标题化合物; 1H NMR(Me2SO-d6)delta 1.09-1.16(m,6H),1.21(s,9H),1.90-2.10(m,2H),2.39(t,2H,J=7.37Hz),3.96-4.09(m,4H),4.31-4.43(m,1H),5.22(s,2H),7.50-7.53(AA′BB′,2H),7.83-7.86(AA′BB′),8.21(m,1H),8.71(d,1H,J=5.87Hz),8.72(m,1H),8.80(s,1H).
实施例6N-[4-(N’-[2-新戊酰氨基-4(3H)-氧代吡啶并[2,3-d]嘧啶-6-基甲基]-N’-乙酰氨基)苯甲酰基]-谷氨酸二乙酯。
将0.097克(1.2毫摩尔)的乙酰氯加到N-[4-(N’-[2-新戊酰氨基-4(3H)-氧代吡啶并[2,3-d]-嘧啶-6-基甲基]-氨基)苯甲酰基]谷氨酸二乙酯(1.1毫摩尔)与含有0.22克(2.2毫摩尔)的碳酸氢钾冷却至0-5℃的10毫升二氯甲烷的搅拌悬浮液中。将反应混合物在0-5℃搅拌10分钟,然后使其达到室温。在室温搅拌45分钟之后,加入50毫升二氯甲烷。用25毫升水,25毫升碳酸氢钠饱和溶液萃取该混合物,然后再用25毫升水萃取。合并水萃取液并再用50毫升二氯甲烷再萃取该水萃取液。用无水硫酸镁干燥有机萃取液,过滤,在减压下除去溶剂得到0.7克N-4-(N’-[2-新戊酰氨基-4(3H)-氧代吡啶并[2,3-d]嘧啶-6-基甲基]N’-乙酰氨基)苯甲酰基]谷氨酸二乙酯,1H NMR(Me2SO-d6)delta 1.10-1.17(m,6H),1.22(s,9H),1.88(s,3H),1.88-2.13(m,2H),2.40(t,2H,J=7.46Hz),3.97-4.08(m,4H),4.30-4.42(m,1H),5.02(s,2H),7.34-7.36(AA′BB′,2H),7.83-7.86(AA′BB′,2H),8.19(m,1H),8.64(m,1H),8.75(d,1H,J=7.39Hz).
实施例7N’-〔4-(N-(2-乙酰氨基-4(3H)-氧代-5,6,7,8-四氢吡啶并〔2,3-d〕嘧啶-6-基甲基〕N’-甲酰氨基)苯甲酰基〕-L-谷氨酸二乙酯。
将0.743克(0.36毫摩尔的N-〔4-(N’-〔2-乙酰氨基-4(3H)-氧代吡啶并〔2,3-d〕嘧啶-6-基甲基〕-N’-甲酰氨基)苯甲酰基〕-L-谷氨酸二乙酯和含有230毫克氧化铂的75毫升2∶1 乙醇∶乙酸溶液的混合物在氢气氛下(40磅/英寸)振荡1.5小时。将反应混合物通过硅藻土过滤并蒸发滤液(先在吸气真空下蒸发然后在高真空下蒸发并保持尽可能的低温)。将残留物溶于二氯甲烷中用色谱法(Chromatotron)分离提纯用5%甲醇的二氯甲烷溶液洗脱,得到0.684克(93%)的N-〔4-(N’-(2-乙酰氨基-4(3H)-氧代-5,6,7,8-四氢吡啶并〔2,3-d〕嘧啶-6-基甲基〕-N’-甲酰氨基)苯甲酰基〕-L-谷氨酸二乙酯)熔点188°-190℃; 1H NMR(Me2SO-d6)delta 1.12-1.19(M,6H,CH3的酯),1.89-2.11(m,4H),2.08(s,3H),2.42(t,2H,J=7.26Hz),2.78-2.91(m,1H),3.09-3.19(m,1H),3.89(d,2H,J=5.98Hz),3.99-4.12(m,4H),4.42(m,1H),6.64(m,1H),7.51-7.54(m,2H,AA′BB′),7.91-7.94(m,2H,AA′BB′),8.61(s,1H),8.74(d,1H,J=7.32Hz).
用色谱法处理一部分上述样品取其中间的液份而制备出分析用的样品。在除去溶剂以后在乙醚中研磨该样品并收集固体。分析计算C27H34N6O8:C,56.83;H,6.01;N,14.72实测:C,56.60;H,5.90;N,14.43
实施例8N-〔4-(N,-〔2-新戊酰氨基-4(3H)-氧代-5,6,7,8-四氢吡啶并〔2,3-d〕嘧啶-6-基甲基〕-N’-甲酰氨基)苯甲酰基〕-L-谷氨酸二乙酯。
用相似的方法还原N-〔4-(N’-(2-新戊酰氨基-4(3H)-氧代吡啶并〔2,3,-d〕嘧啶-6-基甲基-N-甲酰氨基)苯甲酰基〕谷氨酸二乙酯得到N-〔4-(N’-(2-新戊酰氨基-4(3H)-氧代-5,6,7,8-四氢吡啶并〔2,3,-d〕嘧啶-6-基甲基〕-N’-甲酰氨基)苯甲酰基〕-L-谷氨酸二乙酯;熔点152-153℃; IR(KBr)Vmax 3369和3250-(NH),1732,1637,和1605(C=O)cm-1;1H NMR(Me2SO-d6)delta 1.12-1.2(m,6H),1.17(s,9H),1.90-2.18(m,4H),2.43(t,2H,J=7.4Hz),2.80-2.94(m,1H),3.12-3.20(m,1H),3.89(d,2H,J=5.59Hz),4.00-4.11(m,4H),3.90-4.47(m,1H),6.40(m,1H),7.52-7.55(AA′BB′,2H),7.92-7.94(AA′BB′,2H),8.62(s,1H),8.75(d,1H,J=7.33Hz).
分析计算C30H40N6O6:C,58.81;H,6.58;N,13.72。
实测:C,58.53;H,6.60;N,13.61
实施例9N-〔4-(N’-(2-新戊酰氨基-4(3H)-氧代-5,6,7,8-四氢吡啶并〔2,3,-d〕嘧啶-6-基甲基〕-N’-乙酰氨基)苯甲酰基〕-L-谷氨酸二乙酯。
将96毫克氧化铂加入含有0.64克(1.03毫摩尔)N-〔4-(N’-〔2-新戊酰基氨基-4(3H)-氧代吡啶并〔2,3,-d〕嘧啶-6-基甲基〕-N’-乙酰氨基)苯甲酰基〕-L-谷氨酸二乙酯的40毫升冰醋酸溶液中。将此悬浮液在氢气氛中(45磅/英寸2)振荡2.5小时,用100毫升二氯甲烷稀释混合物并通过硅藻土过滤以除去催化剂。将滤液在减压下蒸发并将残留物溶于100毫升二氯甲烷中,用饱和的碳酸氢钠溶液萃取两次每次用75毫升。再用75毫升二氯甲烷萃取水层,合并各有机层并用无水硫酸镁干燥。过滤除去干燥剂之后,在减压下除去滤液的溶剂,得到0.54克(84%产率)的N-〔4-(N’-〔2-新戊酰氨基-4(3H)-氧代-5,6,7,8-四氢吡啶并〔2,3,-d〕嘧啶-6-基甲基〕-N’-乙酰氨基)苯甲酰基〕-L-谷氨酸二乙酯,此化合物可从乙酸乙酯中重结晶而进一步纯化;熔点120-123℃。1H-NMR-(Me2SO-d6)delta 1.06-1.19(m,6H),1.16(s,9H),1.82(s,3H)1.84-2.17(m,6H),2.42(t,2H,J=7.40Hz),2.80-2.94(m,1H),3.17-3.23(m,1H),3.68(d,2H,J=5.59Hz),3.98-4.10(m,4H),4.39-4.45(m,1H),6.38(s,1H),7.43-7.46(AA′BB′,2H),7.90-7.93(AA′BB′,2H),8.79(d,1H,J=7.33Hz).
实施例10N-〔4-(N’-〔2-氨基-4(3H)-氧代-5,6,7,8-四氢吡啶并〔2,3,-d〕嘧啶-6-基甲基〕-N’-甲酰氨基)苯甲酰基〕-L-谷氨酸。
将0.092克(0.16毫摩尔)的N-〔4-(N’-〔2-乙酰氨基-4(3H)-氧代-5,6,7,8-四氢吡啶并〔2,3,-d〕嘧啶-6-基甲基〕-N’-甲酰氨基)苯甲酰基〕-L-谷氨酸与10毫升0.25N氢氧化钠水溶液的混合物在25℃搅拌72小时,然后在减压下蒸发水份。将残留物溶于15毫升水中,使此溶液冷却至0℃并用乙酸酸化。30分钟后收集固体得到0.046克(60.5%)的N-〔4-(N’-〔2-氨基-4(3H)-氧代-5,6,7,8-四氢吡啶并〔2,3,-d〕吡啶-6-基甲基〕-N’-甲酰氨基)苯甲酰基〕-L-谷氨酸。
1H NMR(Me2SO-d6)delta1.81-2.2(m,4H),2.33(m,3H),2.73(m,1H)3.1(m,1H),3.85(m,2H),4.39(m,1H),6.2(m,1H),7.49-7.51(m,2H,AA′BB′),7.90-7.93(m,2H,AA′BB′),8.59-8.62(m,2H)。
用类似的方法,将200毫克N’-〔4-(N’-〔2-新戊酰氨基-4(3H)-氧代-5,6,7,8-四氢吡啶并〔2,3,-d〕嘧啶-6-基甲基〕-N’-乙酰氨基)苯甲酰基〕-L-谷氨酸二乙酯与5毫升0.2N氢氧化钠溶液搅拌72小时。用0.5N盐酸中和该反应混合物,冷却至0℃并过滤收集所形成的固体,产生N-〔4-(N’-〔2-氨基-4(3H)-氧代-5,6,7,8-四氢吡啶并〔2,3,-d〕嘧啶-6-基甲基〕-N’-乙酰氨基)苯甲酰基〕-L-谷氨酸。
实施例11N-〔4-(N’-〔2-氨基-4(3H)-氧代-5,6,7,8-四氢吡啶并〔2,3,-d〕嘧啶-6-基甲基〕-N’-甲酰氨基)苯甲酰基〕-L-谷氨酸。
将20毫克N-〔4-(N’-〔2-氨基-4(3H)-氧代-5,6,7,8-四氢吡啶并〔2,3,-d〕嘧啶-6-基甲基〕-氨基)苯甲酰基〕-L-谷氨酸。在0.5毫升97%的甲酸中所成的溶液在90℃加热1小时。在减压下除去该溶剂并在乙醚中研磨残留物。收集不溶的固体而得到17毫克的产物N-〔4-(N’-〔2-氨基-4(3H)-氧代-5,6,7,8-四氢吡啶并〔2,3,-d〕嘧啶-6-基甲基〕-N’-甲酰氨基)苯甲酰基〕-L-谷氨酸,将该化合物溶于0.1N氢氧化钠中并加入冰醋酸使之沉淀以进一步纯化。
实施例12N-〔4-(N’-〔2-氨基-4(3H)-氧代-5,6,7,8-四氢吡啶并〔2,3,-d〕嘧啶-6-基甲基〕-氨基)苯甲酰基〕-L-谷氨酸。
将0.717克(1.3毫摩尔)的N-〔4-(N’-〔2-乙酰氨基-4(3H)-氧代-5,6,7,8-四氢吡啶并〔2,3,-d〕嘧啶-6-基甲基〕-N’-甲酰氨基)苯甲酰基〕-L-谷氨酸二乙酯(制备如实施例2)加到32毫升5%盐酸在甲醇中的溶液(由2毫升浓盐酸用60毫升甲醇稀释而制备成)中。在45℃搅拌该反应混合物18小时。在使反应混合物冷却在25℃之后,加入4毫升氢氧化钠(6N),再将该混合物在25℃搅拌72小时。在减压下浓缩此溶液。加入20毫升水并滴加冰醋酸使该混合物酸化。在0℃静置2小时后收集固体物质得到0.485克(产率88%)的N-〔4-(N’-〔2-氨基-4(3H)-氧代-5,6,7,8-四氢吡啶并〔2,3,-d〕嘧啶-6-基甲基〕氨基)苯甲酰基〕-L-谷氨酸;熔点198℃(开始分解): 1H NMR(Me2SO-d6)delta 1.86-2.1(m,6H),2.31(t,2H,J=7.2),2.8-2.86(m,1H),3.24-3.28(m,2H),4.2-4.4(m,1H),5.94(s,2H),6.29(s,1H),6.34(t,1H,J=5.24),6.56-6.58(AA′BB′,2H),7.62-7.65(AA′BB′,2H),8.06(d,J=5.15),9.7(br,s,1H).
通过水解N-〔4-(N’-〔2-新戊酰氨基-4(3H)-氧代吡啶并〔2,3,-d〕嘧啶-6-基甲基〕-N’-甲酰氨基)苯甲酰基〕-L-谷氨酸二乙酯可得到同样的产物。
另一方面,将1.44克(2.4毫摩尔)的N’-〔4-(N-〔2-新戊酰氨基-4(3H)-氧代-5,6,7,8-四氢吡啶并〔2,3,-d〕嘧啶-6-基甲基〕-N’-甲酰氨基)-苯甲酰基〕-L-谷氨酸二乙酯溶于1N氢氧化钠中并将此溶液在25℃搅拌72小时。加入活性碳并搅拌此悬浮液然后过滤。用冰醋酸酸化滤液,在0℃冷冻30分钟后收集白包固体物质,得到0.87克(产率84%)相同的产物;熔点198℃以上缓慢地分解; IR(KBr)Vmax 3460-2500(NH和COOH),1695,1655,and 1600(C=O)cm-1;1H NMR(Me2SO-d6)delta 1.85-2.02(m,6H),2.3(t,2H,J=7.4Hz),2.81-2.88(m,1H)3.23-3.32(m,2H)4.2-4.4(m,1H),5.92(s,2H),6.34(t,1H,J=5.28Hz),6.55-6.57(m,2H AA′BB′),7.61-7.64(AA′BB′,2H),8.08(d,1H,J=7.64Hz),9.7(br,s,1H)。
实施例13
制备每毫升含1毫克N-〔4-(N’-〔2-氨基-4(3H)-氧代-5,6,7,8-四氢吡啶并〔2,3,-d〕嘧啶-6-基甲基〕氨基)苯甲酰基〕-L-谷氨酸在含15%的乙腈和含85%的0.1%三乙胺-乙酸溶液(缓冲调节至pH7.0)中的溶液。将此溶液引入一支利用相同溶剂体系的10毫米×50厘米的Cyclobond I逆相高效液体色谱柱中,应用的流速为1.10毫升/分钟紫外光监测在254毫微米。
得到基本上没有其他化合物的第一种非对映异构体持续时间为45.58分钟,在此将其定名为异构体“A”。得到基本上没有第一种化合物的第二种非对映异构体持续时间为48.32分钟,在此定名为异构体“B”。
实施例14
用10只C3H雌鼠为一组,用C3H乳线癌细胞在其腋窝区进行腹膜内移植。然后施用在0.5毫升乳化剂IP(Emulphor IP)中的试验化合物10天,对照组接受同样的处理但没有试验化合物。
应用N-〔4-(N’-〔2-氨基-4(3H)-氧代-5,6,7,8-四氢吡啶并〔2,3,-d〕嘧啶-6-基甲基〕氨基)苯甲酰基〕-L-谷氨酸,剂量为6.25毫克/公斤在10只存活者中有7只得到90%的抑制作用。
用同样的化合物治疗6C3HED淋巴肉瘤,经过8天的治疗期可观察到以下的结果。
剂量 抑制作用 存活者
(毫克/公斤)
6.0 77 10/10
12.5 100 9/10
25.0 100 7/10
50.0 100 4/10
100.0 100 1/10
Claims (22)
2.根据权利要求1的方法,其中R1是氢,R2和R3分别是具有1至6个碳原子的烷基而R4是具有2至6个碳原子的烷酰基。
3.根据权利要求2的方法,其中R2和R3分别是乙基,而R4是乙酰基。
4.根据权利要求2的方法,其中R2和R3分别是乙基,而R4是新戊酰基。
5.根据权利要求1的方法,其中R1是甲酰基,R2和R3分别是具有1至6碳原子的烷基而R4是具有2至6个碳原子的烷酰基。
6.根据权利要求5的方法,其中R2和R3分别是乙基,而R4是乙酰基。
7.根据权利要求5的方法,其中R2和R3分别是乙基,而R4是新戊酰基。
8.根据权利要求1的方法,其中R1是乙酰基,R2和R3分别是具有1至6个碳原子的烷基而R4是具有2至6个碳原子的烷酰基。
9.根据权利要求8的方法,其中R2和R3分别是乙基,而R4是乙酰基。
10.根据权利要求8的方法,其中R2和R3分别是乙基,而R4是新戊酰基。
11.制备由一组化合物中挑选出的化合物的方法,该组化合物包括:
R1是R5CO-
R2′和R3′是氢或者是相同或不相同的羧酸保护基团,
R4′是氢或一种氨基保护基团,
R5是氢或具有1至6个碳原子的烷基,而标有*号的碳原子的构型是L型,
(ii)上述化合物的互变异构体,
R2′和R3′是氢或者是相同或不相同的羰基保护基团,
R4′是氢或一种氨基保护基团,标有*号的碳原子的构型是L型。
12.根据权利要求11的方法,其中R2′,R3′,R4和R5分别是氢。
13.根据权利要求12的方法,其中R2′和R3′分别是具有1至6个碳原子的烷基,R4′是具有2至6个碳原子的烷酰基而R5是氢。
15.根据权利要求14的方法,其中R1是氢,R2′和R3′分别是具有1至6个碳原子的烷基而R4′是具有2至6个碳原子的烷酰基。
16.根据权利要求15的方法,其中R2′和R3′分别是乙基,而R4′是乙酰基。
17.根据权利要求15的方法,其中R2′和R3′分别是乙基,而R4′是新戊酰基。
18.根据权利要求14的方法,其中R2′,R3′和R4′分别是氢。
19.根据权利要求14的方法,其中R1是甲酰基,R2′和R3′分别是具有1至6个碳原子的烷基,而R4′是具有2至6个碳原子的烷酰基。
20.根据权利要求19的方法,其中R2′和R3′分别是乙基而R4′是乙酰基。
21.根据权利要求19的方法,其中R2′和R3′分别是乙基而R4′是新戊酰基。
22.根据权利要求14的方法,其中R1是甲酰基而R2′,R3′和R4′分别是氢。
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US5223620A (en) * | 1988-04-01 | 1993-06-29 | Takeda Chemical Industries, Ltd. | Pyrido[2,3-d]pyrimidine compounds useful as intermediates |
DK172753B1 (da) * | 1988-05-25 | 1999-06-28 | Lilly Co Eli | N-(5,6,7,8-tetrahydropyrido[2,3--d]pyrimidin-6-yl-alkanoyl)-glutaminsyrederivater, deres anvendelse, farmaceutiske præparat |
US4871746A (en) * | 1988-05-31 | 1989-10-03 | The Trustees Of Princeton University | N-[N-(tetrahydropyrido[2,3-D]pyrimidinylmethyl)-aminomethylbenzoyl]glutamic acid derivatives as neoplastic growth inhibitors |
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US5159079A (en) * | 1991-12-20 | 1992-10-27 | Eli Lilly And Company | 2-piperidones as intermediates for 5-deaza-10-oxo- and 5-deaza-10-thio-5,6,7,8-tetrahydrofolic acids |
WO1993020075A1 (en) * | 1992-04-01 | 1993-10-14 | The University Of Sydney | 8-substituted-n5-deazapterins as antifolates |
CN1962658B (zh) * | 2005-11-10 | 2010-05-12 | 北京大学 | 一种四氢吡啶并[3,2-d]嘧啶类化合物及制备抗肿瘤药物的用途 |
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---|---|
JPH07116189B2 (ja) | 1995-12-13 |
NZ220871A (en) | 1989-07-27 |
EP0255228A1 (en) | 1988-02-03 |
EG18301A (en) | 1993-02-28 |
IL82896A0 (en) | 1987-12-20 |
HUT44548A (en) | 1988-03-28 |
EP0255228B1 (en) | 1991-05-02 |
GR870943B (en) | 1987-10-19 |
IE871586L (en) | 1987-12-30 |
DE3769721D1 (de) | 1991-06-06 |
PT85090B (pt) | 1990-03-08 |
IE60038B1 (en) | 1994-05-18 |
PT85090A (en) | 1987-07-01 |
SU1581222A3 (ru) | 1990-07-23 |
ES2031894T3 (es) | 1993-01-01 |
DK307387D0 (da) | 1987-06-17 |
HU198482B (en) | 1989-10-30 |
AU7426287A (en) | 1988-01-07 |
DK307387A (da) | 1987-12-31 |
CA1301156C (en) | 1992-05-19 |
KR950001017B1 (ko) | 1995-02-07 |
CN1014895B (zh) | 1991-11-27 |
KR880000432A (ko) | 1988-03-25 |
JPS6333379A (ja) | 1988-02-13 |
IL82896A (en) | 1991-06-10 |
DK172896B1 (da) | 1999-09-20 |
AU594163B2 (en) | 1990-03-01 |
ES2007064A6 (es) | 1989-06-01 |
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