CN1100046C - 喹唑啉衍生物 - Google Patents

喹唑啉衍生物 Download PDF

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CN1100046C
CN1100046C CN96193526A CN96193526A CN1100046C CN 1100046 C CN1100046 C CN 1100046C CN 96193526 A CN96193526 A CN 96193526A CN 96193526 A CN96193526 A CN 96193526A CN 1100046 C CN1100046 C CN 1100046C
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quinazoline
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K·H·吉布森
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Syngenta Ltd
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D403/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D239/00Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72Quinazolines; Hydrogenated quinazolines
    • C07D239/86Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94Nitrogen atoms

Abstract

本发明涉及式I喹唑啉衍生物或其可药用盐,其中n为1,2或3并且每一R2各自独立地代表卤素、三氟甲基或(1-4C)烷基;R3为(1-4C)烷氧基;并且R1为二-〔(1-4C)烷基〕氨基-(2-4C)烷氧基,吡咯烷-1-基-(2-4C)烷氧基,哌啶子基-(2-4C)烷氧基,吗啉代-(2-4C)烷氧基,哌嗪-1-基-(2-4C)烷氧基,4-(1-4C)烷基哌嗪-1-基-(2-4C)烷氧基,咪唑-1-基-(2-4C)烷氧基,二-〔(1-4C)烷氧基-(2-4C)烷氧基〕氨基-(2-4C)烷氧基,硫吗啉代-(2-4C)烷氧基,1-氧代硫吗啉代-(2-4C)烷氧基或1,1-二氧代硫吗啉代-(2-4C)烷氧基,并且其中任一上述包含不与N或O原子连接的CH2(亚甲基)的R1取代基都在所述CH2基上任选地携带羟基取代基;涉及其制备方法,含有它们的药物组合物,并涉及利用这些化合物的受体酪氨酸激酶抑制特性在治疗增生性疾病如癌症中的应用。

Description

喹唑啉衍生物
本发明涉及喹唑啉衍生物或其可药用盐,它们具有抗增生活性如抗癌活性并因此可在人或动物的治疗方法中应用。本发明也涉及生产所述喹唑啉衍生物的方法,涉及包含它们的药物组合物及其在生产药物中的应用,所述药物用于在温血动物如人中产生抗增生作用。
目前,很多治疗细胞增生性疾病如牛皮癣和癌的方法都应用抑制DNA合成的化合物。这些化合物通常具有细胞毒性,但它们对分化快的细胞如肿瘤细胞的毒性作用可能是有益的。其它不通过抑制DNA合成机理而发挥作用的抗增生剂方法具有选择性增强的作用。
近几年发现,细胞由于其DNA的某一部分转化为致癌基因,即当激活时,形成恶性肿瘤细胞的基因而可能变为癌性的(Bradshaw,诱变( Mutagenesis,)1986,1,91,)几种这样的致癌基因使得所产生的作为生长因子受体的肽增多。随后,生长因子受体复合物导致细胞增生作用加强。例如,已知几种致癌基因编码酪氨酸激酶并且某些生长因子受体也是酪氨酸激酶(Yarden等人,生物化学年度综述( Ann.Rev.Biochem),1988, 57,443:Larsen等人,医学化学年度报告(Ann.Reports in Med.Chem)1989,Chpt.13)。
受体酪氨酸激酶在引发细胞复制的生化信号传递中是重要的。它们是跨跃细胞膜的较大的酶并且具有用于与生长因子如表皮生长因子(EGF)结合的细胞外结合区和作为蛋白质中酪氨酸磷酸化激酶的细胞内部分并因此影响细胞增生。基于结合到不同受体酪氨酸激酶上的生长因子的种类己知各种类型的受体酪氨酸激酶(Wilks.癌研究进展( Advances in Cancer Research),1993, 60,43-73)。该分类包括I类受体酪氨酸激酶,它包括EGF族受体酪氨酸激酶如EGF,TGFα,NEU,erbB,Xmrk,HER和Let23受体,II类受体酪氨酸激酶,它包括胰岛素族受体酪氨酸激酶如胰岛素,IGFI和胰岛素相关受体(IRR)受体,和III类受体酪氨酸激酶,它包括血小板衍生生长因子(PDGF)族受体酪氨酸激酶如PDGFα,PDGFβ和菌落刺激因子1(CSF1)受体。已知,I类激酶如EGF族受体酪氨酸激酶通常存在于常见的人类癌中,如乳腺癌(Sainsbury等人,英国癌杂志(Brit.J.Cancer),1988, 58,458;Guerin等人,癌症研究(Oncogene Res),1988, 3,21和Keijn等人,乳腺癌研究治疗( Breast Cancer Res,Treat.),1994, 29,73,非小细胞肺癌(NSCLCs)包括腺癌(Cerny等人,英国癌杂志( Brit.J.Cancer),1986, 54,265;Reubi等人,国际癌研究( Int.J.Cancer),1990, 45,269;和Rusch等人,癌研究( Cancer Researeh),1993, 53,2379)和肺磷状细胞癌( Hendler等人,癌细胞( Cancer Cell),1989, 7,347),膀胱癌( Neal等人,柳叶刀( Lancet),1985,366)食管癌( Mukaida等人,癌( Cancer),1991, 68,142),胃肠癌如结肠、直肠或胃癌(Bolen等人,癌研究(Oncogene Res),1987, 1,149),前列腺癌(Visakorpi等人, Histochem.J.,1992, 24,481),白血病(Konaka等人,细胞( Cell),1984, 37,1035)和卵巢癌,支气管癌或胰腺癌(欧洲专利说明书0400586)。预计,利用其它人组织检测EGF族受体酪氨酸激酶将广泛用于其它癌如甲状腺癌和子宫癌中。也己知,在正常细胞中几乎检测不到EGF型酪氨酸激酶的活性,而在恶性细胞中经常可以发现(Hunter,细胞( Cell),1987, 50,823)。最近发现(W J Gullick,英国医学公报(Brit.Med.Bull.1991,47,87)),在很多人类肿瘤如脑,肺,磷状细胞,膀胱,胃,乳腺,头和颈,食管,妇科和甲状腺肿瘤中,具有酪氨酸激酶活性的EGF受体被过度表达。
因此认识到,受体酪氨酸激酶抑制剂作为哺乳动物癌细胞生长的选择性抑制剂是重要的(Yaish等人,科学( Science),1988, 242,933)。本观点可通过下列证明来支持:erbstatin,即EGF受体酪氨酸激酶抑制剂特异性地抑制移植了人类表达EGF受体酪氨酸激酶乳腺癌、无胸腺(athymic)裸鼠的生长,但对其它不表达EGF受体酪氨酸激酶癌的生长无作用(Toi等人,欧洲临床癌杂志(Eur.J.Cancer Clin.Onconl.),1990, 26,722)。各种苯乙烯衍生物也被阐明具有酪氨酸激酶抑制性(欧洲专利申请0211363,0304493和0322738)并且可用作抗肿瘤剂。已证明,两种该苯乙烯衍生物,它们是EGF受体酪氨酸激酶抑制剂,其体内抑制作用为抑制植入人类磷状细胞癌裸体鼠的生长(Yoneda等人,癌研究(CancerResearch),1991, 51,4430)。在最近T R Burker Jr.的评论中公开了各种已知的酪氨酸激酶抑制剂(《将来的药物》Drugs of Future),1992, 17,119)。
从欧洲专利申请0520722,0566226和0635498中已知,某些在4-位具有苯胺取代基的喹唑啉衍生物具有受体酪氨酸激酶抑制剂活性。从欧洲专利申请0602851中进一步已知,某些在4-位具有杂芳氨基取代基的喹唑啉衍生物也具有受体酪氨酸激酶抑制剂活性。
从国际专利申请WO 92/20642中进一步已知,某些芳基和杂芳基化合物抑制EGF和/或PDGF受体酪氨酸激酶。其中公开了某些喹唑啉衍生物,但未提到4-苯胺基喹唑啉衍生物。
Fry等人在 科学( Science),1994, 265,1093中公开了4-苯胺基喹唑啉衍生物的体内抗增生作用。并阐明,化合物4-(3′-溴代苯胺基)-6,7-二甲氧基喹唑啉是高效EGF受体酪氨酸激酶抑制剂。
已证明,EGF族受体酪氨酸激酶抑制剂4,5-二苯胺基邻苯二甲酰亚胺衍生物的体内抑制作用为抑制BALB/C裸鼠中所移植的人表皮样癌A-431或人卵巢癌SKOV-3的生长(Buchdunger等人, Proc.Nat. Acad.Sci.,1994, 91,2334)。
从欧洲专利申请0635507中进一步已知,包含稠和于喹唑啉的苯并环上的5-或6-元环的某些三环化合物具有受体酪氨酸激酶抑制活性。从欧洲专利申请0635498中也已知,某些在6-位具有氨基和在7-位具有卤原子的喹唑啉衍生物具有受体酪氨酸激酶抑制活性。
因此表明,I类受体酪氨酸激酶抑制剂可用于治疗各种人类癌症。
EGF型受体酪氨酸激酶也与非恶性增生性病如牛皮癣有关(Elder等人, 科学( Science),1989, 243,811)。因此预计,EGF型受体酪氨酸激酶抑制剂可用于治疗非恶性多细胞增生性疾病如牛皮癣(其中认为TGFα是最重要的生长因子),良性前列腺肥大(BPH),动脉粥样硬化和再狭窄。
在这些文献中未公开在4-位携带苯胺基取代基并且也在7-位携带烷氧基取代基和在6-位携带二烷基氨基烷氧基取代基的喹唑啉衍生物。现在我们已发现,这些化合物具有有效的体内抗增生性,并认为该特性是由其I类受体酪氨酸激酶抑制活性产生的。
本发明提供式I喹唑啉衍生物或其药用盐其中(R2)n为3′-氟-4′-氯或3′-氯-4′-氟;
R3为甲氧基;并且
R1为2-二甲基氨基乙氧基,2-二乙基氨基乙氧基,3-二甲基氨基丙氧基,3-二乙基氨基丙氧基,2-(吡咯烷-1-基)乙氧基,3-(吡咯烷-1-基)丙氧基,2-哌啶子基乙氧基,3-哌啶子基丙氧基,2-吗啉代乙氧基,3-吗啉代丙氧基,2-(4-甲基哌嗪-1-基)乙氧基,2-(咪唑-1-基)乙氧基,3-(咪唑-1-基)丙氧基,2-〔二-(2-甲氧基乙基)氨基〕乙氧基或3-吗啉代-2-羟基丙氧基。
本发明已知,某些式I化合物由于其一个或多个取代基包含不对称碳原子,因而可以以光学活性或外消旋形式存在,本发明包括任何具有抗增生活性的该种光学活性或外消旋体形式。可通过本领域公知的,标准有机化学技术,例如通过从光学活性原料合成或通过拆分外消旋体来合成光学活性物质。
式I喹唑啉的2-,5-和8-位是未取代的。
也已知,某些式I喹唑啉衍生物可以以溶剂化物或非溶剂化物形式,例如水合物形式存在。应当明白,本发明包括各种具有抗增生活性的该种溶剂化物。
例如,适宜的本发明喹唑啉衍生物的药用盐为碱性足够强的本发明喹唑啉衍生物的酸加成盐,例如,与无机酸或有机酸的单或二酸加成盐,所述酸如盐酸,氢溴酸,硫酸,磷酸,三氟乙酸,构橼酸,马来酸,酒石酸,富马酸,甲磺酸或4-甲苯磺酸。
优选的本发明化合物为式I喹唑啉衍生物或其可药用酸加成盐。其中(R2)n为3′,4′-二氟,3′,4′-二氯,3′-氟-4′-氯或3′-氯-4′-氟;
R3为甲氧基;并且
R1为3-吗啉代丙氧基。
具体优选的本发明化合物为下述式I喹唑啉衍生物或其可药用酸加成盐:
4-(3′-氯-4′-氟代苯胺基)-7-甲氧基-6-(2-吡咯烷-1-基乙氧基)喹唑啉。
进一步具体优选的本发明化合物为下述式I喹唑啉衍生物或其可药用酸加成盐:
4-(3′-氯-4′-氟代苯胺基)-7-甲氧基-6-(2-吗啉代代乙氧基)喹唑啉。
进一步具体优选的本发明化合物为下述式I喹唑啉衍生物或其可药用酸加成盐:
4-(3′-氯-4′-氟代苯胺基)-7-甲氧基-6-〔2-(4-甲基哌嗪-1-基)乙氧基〕喹唑啉。
进一步具体优选的本发明化合物为下述式I喹唑啉衍生物或其可药用酸加成盐:
4-(3′-氯-4′-氟代苯胺基)-7-甲氧基-6-{2-〔二-(2-甲氧基乙基)氨基〕乙氧基}喹唑啉。
进一步具体优选的本发明化合物为下述式I喹唑啉衍生物或其可药用酸加成盐:
4-(3′-氯-4′-氟代苯胺基)-6-(2-二甲基氨基乙氧基)-7-甲氧基喹唑啉。
进一步具体优选的本发明化合物为下述式I喹唑啉衍生物或其可药用酸加成盐:
4-(3′-氯-4′-氟代苯胺基)-6-(2-二乙基氨基乙氧基)-7-甲氧基喹唑啉。
进一步具体优选的本发明化合物为下述式I喹唑啉衍生物或其可药用酸加成盐:
4-(2′,4′-二氟代苯胺基)-6-(3-二甲基氨基丙氧基)-7-甲氧基喹唑啉。
进一步具体优选的本发明化合物为下述式I喹唑啉衍生物或其可药用酸加成盐:
4-(3′-氯-4′-氟代苯胺基)-6-(2-羟基-3-吗啉代丙氧基)-7-甲氧基喹唑啉。
进一步具体优选的本发明化合物为下述式I喹唑啉衍生物或其可药用酸加成盐:
4-(2′,4′-二氟代苯胺基)-7-甲氧基-6-(3-吗啉代丙氧基)喹唑啉。
进一步具体优选的本发明化合物为下述式I喹唑啉衍生物或其可药用酸加成盐:
4-(3′-氯-4′-氟代苯胺基)-6-(2-咪唑-1-基乙氧基)-7-甲氧基喹唑啉。
进一步具体优选的本发明化合物为下述式I喹唑啉衍生物或其可药用酸加成盐:
4-(3′-氯-4′-氟代苯胺基)-6-(3-二乙基氨基丙氧基)-7-甲氧基喹唑啉。
进一步具体优选的本发明化合物为下述式I喹唑啉衍生物或其可药用酸加成盐:
4-(3′-氯-4′-氟代苯胺基)-7-甲氧基-6-(3-吡咯烷-1-基丙氧基)喹唑啉。
进一步具体优选的本发明化合物为下述式I喹唑啉衍生物或其可药用酸加成盐:
4-(3′-氯-4′-氟代苯胺基)-6-(3-二甲基氨基丙氧基)-7-甲氧基喹唑啉。
进一步具体优选的本发明化合物为下述式I喹唑啉衍生物或其可药用酸加成盐:
4-(3′,4′-二氟代苯胺基)-6-(3-二甲基氨基丙氧基)-7-甲氧基喹唑啉。
进一步具体优选的本发明化合物为下述式I喹唑啉衍生物或其可药用酸加成盐:
4-(3′,4′-二氟代苯胺基)-7-甲氧基-6-(3-吗啉代丙氧基)喹唑啉。
进一步具体优选的本发明化合物为下述式I喹唑啉衍生物或其可药用酸加成盐:
6-(3-二乙基氨基丙氧基)-4-(3′,4′-二氟代苯胺基)-7-甲氧基喹唑啉。
进一步具体优选的本发明化合物为下述式I喹唑啉衍生物或其可药用酸加成盐:
4-(3′-氯-4′-氟代苯胺基)-7-甲氧基-6-(3-哌啶子基丙氧基)喹唑啉。
进一步具体优选的本发明化合物为下述式I喹唑啉衍生物或其可药用酸加成盐:
4-(3′-氯-4′-氟代苯胺基)-7-甲氧基-6-(2-哌啶子基乙氧基)喹唑啉。
进一步具体优选的本发明化合物为下述式I喹唑啉衍生物或其可药用酸加成盐:
4-(3′-氯-4′-氟代苯胺基)-6-(3-咪唑-1-基丙氧基)-7-甲氧基喹唑啉。
本发明另一方面发现,某些本发明化合物不仅具有有效的体内抗增殖性并因此减慢肿瘤组织的生长速度,而且还具有抑制肿瘤组织生长并在高剂量下减小原始肿瘤体积的特性。
为此,本发明提供式I喹唑啉衍生物或其可药用酸加成盐:
4-(3′-氯-4′-氟代苯胺基)-7-甲氧基-6-(3-吗啉代丙氧基)喹唑啉。
本发明也提供下述式I喹唑啉衍生物的盐酸盐:
4-(3′-氯-4′-氟代苯胺基)-7-甲氧基-6-(3-吗啉代丙氧基)喹唑啉。
本发明也提供下述式I喹唑啉衍生物的二盐酸盐:
4-(3′-氯-4′-氟代苯胺基)-7-甲氧基-6-(3-吗啉代丙氧基)喹唑啉。
式I喹唑啉衍生物或其可药用酸加成盐可通过已知用于制备化学相关化合物的任何方法制备。例如,适宜的方法包括在欧洲专利申请号0520722,0566226,0602851,0635498和0635507中所阐述的那些。当用于制备式I喹唑啉衍生物或其可药用盐时,提供这些方法是本发明的另一方面,并且这些方法可通过下列有代表性的实施例来说明,其中,除另外说明外,n,R2,R3和R1具有上文对于式I喹唑啉衍生物定义的任何含义。可通过标准有机化学方法得到必需原料。在附属的非限定性实施例中,描述了这些原料的制备。或者可通过一般有机化学中所阐述方法的类似方法获得必需原料。
(a)通常在适宜的碱存在下,式II喹唑啉
Figure C9619352600121
其中Z为可置换的基团,与式III苯胺的反应。
例如,适宜的可置换基Z为卤素,烷氧基,芳氧基或磺酰氧基,例如氯、溴、甲氧基、苯氧基、甲磺酰氧基或甲苯-4-磺酰氧基。
例如,适宜的碱为有机胺碱,如吡啶,2,6-二甲基吡啶,可力丁,4-二甲基氨基吡啶,三乙胺,吗啉, N-甲基吗啉或二氮杂二环〔5.4.0〕十一碳-7-烯,或者为碱金属或者碱土金属的碳酸盐或氢氧化物,如碳酸钠,碳酸钾,碳酸钙,氢氧化钠或氢氧化钾。或者,例如,适宜的碱为碱金属或碱土金属氨化物,如氨基化钠或双(三甲硅烷基)氨化钠。
优选地,在适宜的惰性溶剂或稀释剂存在下进行反应,所述惰性溶剂或稀释剂包括链烷醇或酯如甲醇,乙醇,异丙醇或乙酸乙酯,卤代溶剂如二氯甲烷,氯仿或四氯化碳,醚如四氢呋喃或1,4-二噁烷,芳族溶剂如甲苯,或偶极性非质子传递溶剂如 NN-二甲基甲酰胺, N,N-二甲基乙酰胺, N-甲基吡咯烷-2-酮或二甲基亚砜。例如,通常在10~150℃,优选20~80℃温度范围内进行反应。
通过该方法可得到式I喹唑啉衍生物的游离碱形式,或者可得到式I喹唑啉衍生物与式H-Z酸形成的盐,其中Z具有上文所定义的含义。当要求从盐得到游离碱时,可按常规方法,用上文所规定的适宜的碱来处理该盐。
(b)为了制备式I化合物,其中R1为氨基取代的乙氧基或丙氧基,通常在上文所规定的适宜的碱存在下,将式I喹唑啉衍生物烷基化,其中R1为羟基。
例如,适宜的烷基化试剂为任何本领域已知的,在上文所规定的适宜的碱存在下,在如上文中所规定的适宜的惰性溶剂或稀释剂中,在10-140℃范围内,通常在或接近80℃温度下,用于将羟基烷基化成氨基取代的乙氧基或丙氧基的试剂,例如氨基取代的乙基或丙基卤如氨基取代的乙基或丙基氯、溴或碘。
(c)为了制备式I化合物,其中R1为氨基取代的乙氧基或丙氧基,通常在上文所规定的适宜的碱存在下,将式I化合物(其中R1为羟-乙氧基或丙氧基)或其活性衍生物与适宜的胺反应。
例如,适宜的式I化合物的活性衍生物(其中R1为羟基-乙氧基或丙氧基)为卤代-或磺酰氧基-乙氧基或丙氧基如溴代或甲磺酰氧基-乙氧基或丙氧基。
优选地,在上文所规定的适宜的惰性溶剂或稀释剂存在下,在10-150℃范围内,通常在或接近50℃下进行反应。
(d)为了制备式I化合物,其中R1为3-吗啉代-2羟基丙氧基,将式I化合物,其中R1为2,3-环氧丙氧基,与吗啉反应。
优选地,在上文所规定的适宜的惰性溶剂或稀释剂存在下,在10-150℃范围内,通常在或接近70℃下进行反应。
当需要式I喹唑啉衍生物的药用盐,例如式I喹唑啉衍生物的一或二元酸加成盐时,可利用常规方法,通过将所述化合物与适宜的酸反应获得。
如上所述,本发明所定义的喹唑啉衍生物具有抗增生活性,并认为该活性是由化合物的I类受体酪氨酸激酶抑制活性产生的。例如,可通过使用一种或多种下文所阐述的方法来测定这些性质。
(a)体内测定法,该方法测定试验化合物抑制酶EGF受体酪氨酸激酶的能力。可通过下文所描述的方法,该方法与Carpenter等人在生物化学杂志(J.Biol.Chem.),1979, 254,4884,Cohen等人在生物化学杂志杂志(J.Biol.Chem.),1982, 257,1523和Braun等人在生物化学杂志(J.Biol.Chem.),1984, 259,2051中所描述的方法是相关的,从A-431细胞中得到部分纯化形式的受体酪氨酸激酶。
利用含5%胎牛血清(FCS)的杜皮克化改良爱哥尔氏培养基(DMEM)中,A-431细胞生长至融合。将所得到的细胞在pH10.1下的低渗硼酸盐/EDTA缓冲剂中均化。将均化物在0-4℃下,在400g离心10分钟。将上清液在0-4℃下,在25,000g离心30分钟。将离心沉淀物悬浮在pH7.4,含5%甘油,4mM苄脒和1%Triton X-100的30mM Hepes缓冲剂中,在0-4℃下搅拌1小时,并在0-4℃下,在100,000g再离心1小时。将含可溶性受体酪氨酸激酶的上清液贮存在液氮中。
为了试验,将40μl如此得到的酶溶液加到包含400μl由pH7.4的150mM Hepes缓冲剂,500μM原钒酸钠,0.1% Triton X-100,10%甘油组成的混合物,200μl水,80μl 25mM DTT和80μl由12.5mM氯化镁,125mM氯化镁和蒸馏水组成的混合物的混合液中。因此得到试验酶溶液。
将各试验化合物溶解在二甲基亚砜(DMSO)中得到50mM溶液,将该溶液用40mM含0.1% Triton X-100,100%甘油和10% DMSO的Hepes缓冲剂稀释,得到500μM溶液。将等体积的该溶液和表皮生长因子溶液(EGF;20μl/ml)混合。
通过加入ATP(100μm)的蒸馏水溶液,将〔γ-32P〕ATP(3000Ci/mM,250μCi)稀释到体积为2ml。加入等体积4mg/ml肽Arg-Arg-Leu-Ile-Glu-Asp-Ala-Glu-Tyr-Ala-Ala-Arg-Gly在pH7.4的40mM Hepes缓冲剂,0.1% Triton X-100和10%甘油混合物中的溶液。
将试验化合物/EGF混合物溶液(5μl)加到试验酶溶液(10μl)中并将该混合物在0-4℃下培养30分钟。加入ATP/肽混合物(10μl)并将混合物在25℃下培养10分钟。通过加入5%三氯乙酸(40μl)和牛血清白蛋白(BSA;1mg/ml,5μl)将磷酰化反应终止。将混合物在4℃下放置30分钟然后离心。将部分(40μl)上清液放到Whatman 81磷酸纤维素纸条上。将该纸条在75mM磷酸(4×10ml)中洗涤并吸干。用液体闪烁计数器测定滤纸上存留的放射性(顺序A)。将反应在不含EGF下重复(顺序B)并再次在不含试验化合物下重复(顺序C)。
如下计算受体酪氨酸激酶的抑制作用:
在试验化合物浓度范围内测定抑制程度,得到IC50值。
(b)体外测定法,该方法测定试验化合物抑制EGF刺激的,人鼻咽癌细胞系KB生长的能力。
将KB细胞以1×104-1.5×104个细胞/孔的密度接种在培养板中并在补加有5%FCS(活性炭脱色的)的DMEM中生长24小时。培养3天后,通过MTT四唑鎓染料代谢形成蓝色的程度来测定细胞的生长。然后在EGF(10ng/ml)存在下或在EGF(10ng/ml)和一定浓度范围的试验化合物存在下测定细胞的生长。然后可计算IC50值。
(c)一组无胸腺裸鼠(种ONU:Alpk)的体内测定法,该方法测定试验化合物(通常以在0.5%聚山梨酸酯中的球磨悬浮液形式口服给予)抑制人外阴表皮样癌细胞系A-431异种移植物生长的能力。
将A-431细胞保存在补加有5% FCS和2mM谷氨酰胺的DMEM培养基中。通过胰蛋白酶作用收集新培养的细胞并通过皮下注射(1千万个细胞/0.1ml/鼠)到许多供体裸鼠的双侧腹部。当获得足够多的肿瘤物质时(大约9-14天后),将肿瘤组织的碎片移植到受体裸鼠的双侧腹部(试验时间为0天)。通常,在移植后的第7天(试验时间为第7天),将肿瘤大小类似的7-10只鼠筛选出来作为一组并开始给予试验化合物。每天一次,连续给予试验化合物共13天(试验时间7-19天,包括第7及第19天)。在某些研究中,连续给予试验化合物超过试验时间19天,例如长达26天。在各实例中,当试验时间满后,将动物处死并通过测定肿瘤的长度和宽度来计算最终肿瘤的体积。将结果换算为相对对照组肿瘤体积的抑制百分数。
尽管式I化合物的药理活性可随着结构的变化而改变,但通常可在下列浓度或剂量下,在一种或多种上述试验(a),(b)和(c)中证明式I化合物所具有的活性:
试验(a):例如,IC50在0.01-1μM范围内;
试验(b):例如,IC50在0.05-1μM范围内;
试验(c):例如,在每日剂量为12.5-200mg/kg下肿瘤体积受到20-90%抑制。
因此,通过实施例方法已知,在试验(a)和(b)中,附属实施例中所描述的化合物在大约下列浓度或剂量下具有活性。
实施例               试验(a)        试验(b)
                     IC50(μM)      IC50(μM)
  1                    0.02             0.1
  2                    0.09             0.7
  3                    0.01             0.4
  4                    0.01             0.1
  5                    0.06             0.2
  6                    0.01             0.1
  7                    0.09             0.3
  8                    0.48             0.9
  9                    0.01             0.1
  12                   0.06             0.16
  13                   0.07             0.12
  14                   0.67             0.3
  15                   0.07             0.64
  17                   0.05             0.15
  18                   0.27             0.39
  19                   0.52             0.45
  20                   0.67             0.55
  21                   0.08             0.12
  22                   0.1              0.19
  23                   0.08             0.16
另外,在试验(c)中,当ED50值低于或等于200mg/kg/天时,实施例中所描述的所有化合物都具有活性。尤其,在试验(c)中,当ED50值大约为12.5mg/kg时,下文实施例1中所描述的化合物具有活性。
本发明另一方面提供药物组合物,它包含上述式I喹唑啉衍生物或其可药用盐和可药用稀释剂或载体。
药用组合物的形式可以为通过口服给药的,例如片剂或胶囊剂,通过非肠道注射的(包括静脉内,皮下,肌肉内,血管内或输注)灭菌溶液,悬浮液或乳浊液,通过局部给药的如软膏剂或霜剂,或通过肠道给药的如栓剂。
通常,可在常规方法中,利用常规赋形剂来制备上述组合物。
通常,将喹唑啉衍生物以每平方米动物体表面积5-10000mg范围内,即大约0.1-200mg/kg的单位剂量给予温血动物,并且通常这提供治疗有效的剂量。通常,例如,单位剂量形式如片剂或胶囊剂包含1-250mg活性组分。优选地,所使用的日剂量在1-100mg/kg范围内。对于实施例1中的喹唑啉衍生物或其可药用盐来说,日剂量大约为1-20mg/kg,优选1-5mg/kg。但是,日剂量必须依赖所治疗的宿主,给药的具体途径和所治疗疾病的严重性而改变。因此,最佳剂量可由治疗任何特定病人的医生来决定。
本发明另一方面提供上述式I喹唑啉衍生物在治疗人或动物体方法中的应用。
我们发现,本发明化合物具有抗增生性如抗癌性,并认为这是由其I类受体酪氨酸激酶抑制活性产生的。因此,预计本发明化合物可用于治疗单独或部分由I类受体酪氨酸激酶介导的疾病,即所述化合物可用于在需要这种治疗的温血动物中产生I类受体酪氨酸激酶抑制作用。因此,本发明化合物提供用于治疗恶性细胞增生的方法,其特点是抑制I类受体酪氨酸激酶,即所述化合物可用于产生抗增生作用,该作用单独或部分由抑制I类受体酪氨酸激酶介导。因此,预计本发明可通过提供抗增生作用而用于治疗牛皮癣和/或癌症,尤其用于治疗I类受体酪氨酸激酶敏感性癌症如乳腺癌,肺癌,结肠癌,直肠癌,胃癌,前列腺癌,膀胱癌,胰腺癌和卵巢癌。
因此,本发明提供上述式I喹唑啉衍生物或其可药用盐在生产用于在温血动物如人体内产生抗增生作用药物中的应用。
如上所述,治疗或预防性治疗特定增生性疾病所需要的剂量大小必须依赖于所治疗的宿主,给药途径和所治疗疾病的严重性而变化。例如,预想单位剂量范围在1-200mg/kg,优选1-100mg/kg,更优选1-10mg/kg。
上文所述的抗增生治疗可被单独用于治疗,或者除本发明的喹唑啉衍生物之外还可包含一种或多种其它抗肿瘤物质,如细胞毒性的或细胞抑制的抗肿瘤物质,例如选自如有丝分裂抑制剂(如长春花碱、长春地辛和长春瑞宾);微管蛋白分解抑制剂(如紫杉醇);烷基化剂(例如顺铂,苄铂和环磷酰胺);抗代谢药(例如5-氟尿嘧啶,替加氟,甲氨喋呤,阿糖胞苷和羟基脲,或者例如,一种在欧洲专利申请239362中所公开的优选的抗代谢药物如N-{ 5-〔 N-(3,4-二氢-2-甲基-4-氧代喹唑啉-6-基甲基)- N-甲基氨基〕-2-噻吩甲酰基}-L-谷氨酸);嵌入抗生素(例如阿霉素,丝裂霉素和博来霉素);酶(例如天冬酰胺酶);拓扑异构酶抑制剂(例如依托泊甙和喜树碱);生物学反应修饰因子(例如干扰素);激素拮抗剂(例如雌激素拮抗剂如他莫昔芬,例如雄激素拮抗剂如4′-氰基-3-(4-氟代苯基磺酰基)-2-羟基-2-甲基-3′-(三氟甲基)-丙基苯胺或者例如LHRH拮抗剂或LHRH激动剂如戈舍瑞林,亮丙瑞林或布舍瑞林)和激素合成抑制剂(例如芳香酶抑制剂如在欧洲专利申请号0296749中所公开的那些物质,如2,2′-〔5-(1 H-1,2,4-三唑-1-甲基)-1,3-亚苯基〕双(2-甲基丙腈)和例如5α-还原酶抑制剂如17β-( N-叔丁基氨基甲酰基)-4-氮杂-5α-雄甾-1-烯-3-酮。该联合治疗可通过同时,连续或分别给予各治疗组分获得。因此,本发明提供药用产品,它包含上述式I喹唑啉衍生物和上述用于联合治疗癌症的其它抗肿瘤物质。
如上所述,本发明喹唑啉衍生物是有效的抗癌剂,并认为,该特性是由其I类受体酪氨酸激酶抑制性产生的。预计本发明喹唑啉衍生物具有广泛的抗癌性,因为I类受体酪氨酸激酶与很多常见的人类癌症疾病有关,所述癌症疾病如白血病和乳腺癌,肺癌,结肠癌,直肠癌,胃癌,前列腺癌,膀胱癌,胰腺癌和卵巢癌。因此预计,本发明喹唑啉衍生物将具有抗这些癌的抗癌性。另外预计,本发明喹唑啉衍生物将具有抗白血病,淋巴系统噁性肿瘤和固体瘤如在肝,肾,前列腺和胰腺的癌和肉瘤的特性。
进一步预计,本发明喹唑啉衍生物将具有抗其它与细胞过多增生有关的疾病如牛皮癣和良性前列腺肥大(BPH)。
也预计,本发明喹唑啉衍生物将对于治疗其它细胞生长的疾病是有用的,其中包括通过受体酪氨酸激酶或非受体酪氨酸激酶传递非正常的细胞信息,其中也包括未确定的酪氨酸激酶。所述的疾病例如炎症、血管生长、血管再狭窄、免疫疾病、胰腺炎、肾脏疾病和胚细胞突变和移植。
现在用下列非限定性实施例中描述本发明,其中使用下列术语,除非另有说明:
(i)蒸发通过在真空中旋转蒸发来进行,后处理步骤是在滤除去残留固体如干燥剂后过滤来进行。硫酸镁被用作有机溶剂的干燥剂,除非另有说明;
(ii)在室温(其范围在18-25℃)和惰性气体(如氩气)环境中进行操作;
(iii)在Merck Kieselgel硅胶(Art.9385)或Merck Lichroprep RP-18(Art.9303)反相硅胶上进行柱层析(通过闪式过程)和中压液相层相(MPLC),所述硅胶从E.Merck.Darmstadt.Germany获得;
(iv)给出的产量是说明性的,并不一定是获得的最大产量;
(v)使用Mettler SP62自动熔点仪、油浴装置或Koffler热板装置确定熔点;
(vi)通过核(通常为质子)磁共振(NMR)和质谱技术确定式I最终产物的结构;以δ刻度测量质子磁共振的化学位移值并如下表示峰形:s.单峰;d.双峰;t.三重峰;m.多重峰。除非另有说明,式I的最终产物被溶于CD3SOCD3中来确定NMR值。
(vii)通常不对中间体进行全面测定,通过薄层色谱层析(TLC)、红外(IR)或NMR分析来评价其纯度;
(viii)使用下列缩写:
DMF    N,N-二甲基甲酰胺;
DMSO   二甲基亚砜;
THF    四氢呋喃;
DMA    N,N-二甲基乙酰胺。实施例1:
将4-(3′-氯-4′-氟代苯胺基)-6-羟基-7-甲氧基喹唑啉(1g)3-吗啉代丙基氯(美国化学会志(J.Amer.Chem.Soc.)1945, 67,736;0.62g),碳酸钾(2.5g)和DMF(50ml)的混合物搅拌并加热至80℃2小时。再加入部分(0.1g)3-吗啉代丙基氯并将混合物加热至80℃1小时。将混合物过滤并将滤液蒸发。将残留物通过柱色谱层析纯化,并利用乙酸乙酯和甲醇的混合物(4∶1)作为洗脱剂。将由此得到的物质从甲苯中重结晶。因此得到4-(3′-氯-4′-氟代苯胺基)-7-甲氧基-6-(3-吗啉代丙氧基)喹唑啉(0.69g,50%)m.p.119-120℃;NMR谱:2.0(m,2H),2.45(m,6H),3.6(m,4H),3.95(s,3H),4.2(t,2H),7.2(s,1H),7.4(t,1H),7.8(m,2H),8.1(m,1H),8.5(s,1H),9.5(s,1H);元素分析C22H24ClFN4O3:实测值C,58.7;H,5.3;N,12,2;
                         理论值C,59.1;H,5.4;N12.5%.
如下得到用作原料的4-(3′-氯-4′-氟代苯胺基)-6-羟基-7-甲氧基喹唑啉:
将6,7-二甲氧基-3,4-二氢喹唑啉-4-酮(欧洲专利申请0566226,中的实施例1;26.5g)分次加到搅拌下的甲磺酸(175ml)中,加入L-甲硫氨酸(22g)并将得到的混合物搅拌和加热回流5小时。将混合物冷却至室温并倾入冰水混合物(750ml)中。通过加入浓(40%)氢氧化钠水溶液来中和混合物。将沉淀分离,用水洗涤并干燥。因此得到6-羟基-7-甲氧基-3,4-二氢喹唑啉-4-酮(11.5g)。
重复上面的反应后,将6-羟基-7-甲氧基-3,4-二氢喹唑啉-4-酮(14.18g),乙酸酐(110ml)和吡啶(14ml)的混合物搅拌并加热至100℃2小时。将混合物倾入冰水混合物(200ml)中。将沉淀分离,用水洗涤并干燥。因此得到6-乙酰氧基-7-甲氧基-3,4-二氢喹唑啉-4-酮(13g,75%);NMR谱:2.3(s,3H),3.8(s,3H),7.3(s,1H),7.8(s,1H),8.1(s,1H),12.2(宽单峰,1H)。
重复上面的步骤后,将6-乙酰氧基-7-甲氧基-3,4-二氢喹唑啉-4-酮(15g),亚硫酰氯(215ml)和DMF(4.3ml)的混合物搅拌并加热至90℃反应4小时。将混合物冷却至室温并将亚硫酰氯蒸发掉。因此得到6-乙酰氧基-4-氯-7-甲氧基喹唑啉盐酸盐,该盐不需要进一步纯化即可使用。
将由此得到的物质,3-氯-4-氟代苯胺(9.33g)和异丙醇(420ml)的混合物搅拌并加热至90℃5小时。将混合物冷却至室温并将沉淀分离,依次用异丙醇和甲醇洗涤,然后干燥。因此得到6-乙酰氧基-4-(3′-氯-4′-氟代苯胺基)-7-甲氧基喹唑啉盐酸盐(14g,56%);NMR谱:2.4(s,3H),4.0(s,3H),7.5(t,1H),7.6(s,1H),7.75(m,1H),8.05(m,1H),8.8(s,1H),8.95(s,1H),11.5(broad s,1H).
将浓氢氧化铵水溶液(30%重量/体积,7.25ml)加到由此得到的物质和甲醇(520ml)的搅拌混合物中,将混合物在室温下搅拌17小时,然后加热至100℃反应1.5小时。将混合物冷却并将沉淀分离、干燥。因此得到4-(3′-氯-4′-氟代苯胺基)-6-羟基-7-甲氧基喹唑啉(10.62g,95%)。m.p.>270℃(分解);NMR谱:4.0(s,3H),7.2(s,1H),7.4(t,1H),7.8(s,1H),7.85(m,1H),8.2(m,1H),8.5(s,1H),9.45(s,1H),9.65(s,1H).
实施例2
将4-(3′-氯-4′-氟代苯胺基)-6-羟基-7-甲氧基喹唑啉(1.14g),2-(吡咯烷-1-基)乙基氯盐酸盐(0.607g),碳酸钾(3g)和DMF(28.5ml)的混合物搅拌并加热至90℃反应5小时。将混合物冷却至室温并倾入水中。将沉淀分离,干燥并通过柱色谱层析纯化,用9∶1的二氯甲烷和甲醇的混合物作为洗脱剂。将由此得到物质从乙醇中重结晶。因此得到4-(3′-氯-4′-氟代苯胺基)-7-甲氧基-6-(2-吡咯烷-1-基乙氧基)喹唑啉(0.813g,55%),m.p.187-188℃;NMR谱:1.7(m,4H),2.6(m,4H),2.9(t,2H),3.9(s, 3H),4.2(t,2H),7.2(s,1H),7.4(t,1H),7.8(m,2H),8.1(m,1H),8.5(s,1H),9.5(s,1H);元素分析C21H22ClFN4O2;实测值C,60.1;H,5.4;N,13.4;
                         理论值C,60.5;H,5.3;N,13.4%。
实施例3
将4-(3′-氯-4′-氟代苯胺基)-6-羟基-7-甲氧基喹唑啉(1.62g),2-吗啉代乙基氯盐酸盐(0.95g),碳酸钾(3.6g)和DMF(40ml)的混合物搅拌并加热至90℃反应1.5小时。将混合物冷却至室温并倾入水中。将沉淀分离,干燥并通过柱色谱层析纯化,用9∶1二氯甲烷和甲醇的混合物作为洗脱剂。将由此得到的物质从异丙醇中重结晶。因此得到4-(3′-氯-4′-氟代苯胺基)-7-甲氧基-6-(2-吗啉代乙氧基)喹唑啉(1.2g,55%)。m,p,229-230℃;NMR谱:2.6(m,4H),2.85(t,2H),3.6(m,4H),3.9(s,3H),4.3(t,2H),7.2(s,1H),7.4(t,1H),7.8(m,2H),8.1(m,1H),8.5(s,1H),9.5(s,1H);元素分析C21H22ClFN4O30.25H2O:
    实测值C,57.5;H,4.9;N,12.7;
    理论值C57.6;H,5.1;N,12.8%
实施例4
将1-甲基哌嗪(43ml),6-(2-溴乙氧基)-4-(3′-氯-4′-氟代苯胺基)-7-甲氧基喹唑啉(1.6g)和乙醇(48ml)的混合物搅拌并加热至回流20小时,将混合物蒸发并将残留物通过柱色谱层析纯化,用4∶1二氯甲烷和甲醇的混合物作为洗脱剂。将由此得到的物质溶解在二氯甲烷和甲醇的混合物中并加入饱和碳酸氢钠水溶液。将混合物搅拌并加热至回流。将混合物冷却至室温并将沉淀分离,干燥。因此得到4-(3′-氯-4′-氟代苯胺基)-7-甲氧基-6-〔2-(4-甲基哌嗪-1-基)乙氧基〕喹唑啉(0.956g,58%)。m.p.88-92℃;NMR谱:2.15(s,3H),2.3(broad m,4H),2.5(broad m,4H),2.8(t,2H),3.9(s,3H),4.2(t,2H),7.2(s,1H),7.4(t,1H),7.8(m,2H),8.1(m,1H),8.5(s,1H),9.5(s,1H);元素分析C22H25ClFN5O20.75H2O:
    实测值C,57.3;H,5.6;N,15.1;
    理论值C57.5;H,5.8;N,15.2%。
如下得到用作原料的6-(2-溴乙氧基)-4-(3′-氯-4′-氟代苯胺基)-7-甲氧基喹唑啉:
将4-(3′-氯-4′-氟代苯胺基)-6-羟基-7-甲氧基喹唑啉(10g),1,2-二溴乙烷(27ml),碳酸钾(20g)和DMF(1升)和混合物搅拌并加热至85℃反应2.5小时。将混合物过滤并将滤液蒸发。将残留物通过柱色谱层析,用乙酸乙酯作为洗脱剂。因此得到6-(2-溴乙氧基)-4-(3′-氯-4′-氟代苯胺基)-7-甲氧基喹唑啉(10.26g,77%),m.p.232℃(分解);NMR谱:3.9(m,2H),3.95(s,3H),4.5(m,2H),7.2(s,1H),7.4(t,1H),7.75(m,1H),7.85(s,1H),8.1(m,1H),8.5(s,1H),9.5(s,1H):元素分析C17H14BrClFN3O2
     实测值C,48.0;H,3.3;N,9.8;
     理论值C,47.9;H,3.3;N,9.8%。
实施例5
将二-(2-甲氧基乙基)胺(1.66ml),6-(2-溴乙氧基)-4-(3′-氯-4′-氟代苯胺基)-7-甲氧基喹唑啉(1.6g)和乙醇(48ml)的混合物搅拌并加热回流18小时。加入第二部分(0.53ml)二-(2-甲氧基乙基)胺并将混合物再加热回流18小时。将混合物蒸发并将残留物在乙酸乙酯和饱和碳酸氢钠溶液之间分配。将有机相干燥(Na2SO4)并蒸发。将残留物通过柱色谱层析纯化,用97∶3二氯甲烷和甲醇的混合物作为洗脱剂。将由此得到的物质溶解在异丙醇中。加入水并将混合物搅拌1小时。将沉淀分离并干燥。因此得到4-(3′-氯-4′-氟代苯胺基)-7-甲氧基-6-{2-〔二-(2-甲氧基乙基)氨基〕乙氧基}喹唑啉(0.95g,53%),m.p.73-74℃。NMR谱:2.6(t,4H),3.05(t,2H),3.25(s,6H),3.45(t,4H),3.95(s,3H),4.2(t,2H),7.2(s,1H),7.4(t,1H),7.8(m,2H),8.1(m,1H),8.5(s,1H),9.5(s,1H);元素分析C23H28ClFN4O40.7H2O:
    实测值C,56.2;H,6.2;N,11,3;
    理论值C,56.2;H,6.0;N,11.4%。
实施例6
将4-(3′-氯-4′-氟代苯胺基)-6-羟基-7-甲氧基喹唑啉(3g),2-二甲基氨基乙基氯盐酸盐(1.5g)碳酸钾(7,5g)和DMF(60ml)的混合物搅拌并加热至80℃反应5小时。将混合物冷却至室温并倾入水中。将沉淀分离并干燥。将由此得到的物通过柱色谱层析纯化,用9∶1二氯甲烷和甲醇的混合物作为洗脱剂。将由此得到的物质在乙醚中研制并从含水乙醇中重结晶。因此得到4-(3′-氯-4′-氟代苯胺基)-6-(2-二甲基氨基乙氧基)-7-甲氧基喹唑啉(1.7g,46%),m.p.133-135℃。NMR谱:2.3(s,6H),2.75(t,2H),4.0(s,3H),4.25(t,2H),7.2(s,1H),7.3(m,2H),7.4(t,1H),8.1(m,2H),8.5(s,1H),9.5(broad s,1H);元素分析C19H20ClFN4O2
    实测值C,58.2;H,5.2;N,14.3;
    理论值C,58.4;H,5.1;N,14.3%。
实施例7
将4-(3′-氯-4′-氟代苯胺基)-6-羟基-7-甲氧基喹唑啉(1.5g),2-二乙基氨乙基氯盐酸盐(0.82g),碳酸钾(3.5g)和DMF(38ml)的混合物搅拌并加热至90℃反应2小时。将混合物冷却至室温并倾入冰(75ml)中。将沉淀分离,从2∶1异丙醇和水的混合物中重结晶并干燥。因此得到4-(3′-氯-4′-氟代苯胺基)-6-(2-二乙基氨基乙氧基)-7-甲氧基喹唑啉(0.98g,50%),m.p.154-156℃。NMR谱:1.0(t,6H),2.6(m,4H),2.9(t,2H),3.9(s,3H),4.2(t,2H),7.2(s,1H),7.4(t,1H),7.8(m,2H),8.1(m,1H),8.5(s,1H),9.5(s,1H);元素分析C21H24ClFN4O2
    实测值C,60.0;H,5.7;N,13.2;
    理论值C,60.2;H,5.8;N,13.4%。
实施例8
将4-(2′,4′-二氟代苯胺基)-6-羟基-7-甲氧基喹唑啉(1.36g),3-二甲基氨基丙基氯盐酸盐(0.82g),碳酸钾(3g)和DMF(50ml)的混合物搅拌并加热至80℃反应4小时。将混合物冷却至环境温度在乙酸乙酯和水之间分配。将有机相用水洗涤,干燥(MgSO4)并蒸发。将残留物在己烷和乙酸乙酯的混合物中研制。因此得到4-(2′,4′-二氟代苯胺基)-6-(3-二甲基氨基丙氧基)-7-甲氧基喹唑啉(0.56g,32%),m.p.131-134℃。NMR谱:1.85-2.05(m,2H),2.35(s,6H),2.42(t,2H),3.95(s,3H),4.16(t,2H),7.13(m,1H),7.16(s,1H),7.35(m,1H),7.55(m,1H),7.75(s,1H),8.3(s,1H),9.5(broad s,1H);元素分析C20H22F2N4O20.3H2O:
    实测值C,60.9;H,5.7;N,14.1;
    理论值C,61.0;H,5.7;N,14.2%。
如下得到用作起始物质的4-(2′,4′-二氟代苯胺基)-6-羟基-7-甲氧基喹唑啉:
将6-乙酰氧基-4-氯-7-甲氧基喹唑啉盐酸盐(5.4g),2,4-二氟代苯胺(2.5ml)和异丙醇(100ml)的混合物搅拌并加热回流2小时。将沉淀分离,用丙酮和乙醚洗涤并干燥。因此得到6-乙酰氧基-4-(2′,4′-二氟代苯胺基)-7-甲氧基喹唑啉盐酸盐(3.9g,53%)。m.p.207-210℃;NMR谱:2.4(s,3H),4.05(s,3H),7.25(m,1H),7.48(m,1H),7.55(s,1H),7.63(m,1H),8.7(s,1H),8.85(s,1H),11.6(broad s,1H).
将部分(3.7g)由此得到的物质,浓氢氧化铵水溶液(30%重量/体积,2ml)和甲醇(140ml)的混合物在环境温度下搅拌2小时。将沉淀分离并用乙醚洗涤。因此得到4-(2′,4′-二氟代苯胺基)-6-羟基-7-甲氧基喹唑啉(1.3g,40%);NMR谱:3.97(s,3H),7.1(m,1H),7.2(s,1H),7.54(m,1H),7.67(s,1H),8.3(s,1H),9.3(s,1H),9.65(broad s,1H).
实施例9
将4-(3′-氯-4′-氟代苯胺基)-6-(2,3-环氧丙氧基)-7-甲氧基喹唑啉(2g),吗啉(0.5ml),和异丙醇(20ml)的混合物搅拌并加热回流1小时。将混合物冷却至环境温度并蒸发。将残留物通过柱色谱层析,用9∶1二氯甲烷和甲醇的混合物作为洗脱剂。将由此得到的物质从乙酸乙酯中重结晶。因此得到4-(3′-氯-4′-氟代苯胺基)-6-(2-羟基-3-吗啉代丙氧基)-7-甲氧基喹唑啉(1.4g,57%)m.p.206-207℃。NMR谱:2.5(broad m,6H),3.6(t,4H),3.9(s,3H),4.1(broad m,3H),5.0(broad m,1H),7.2(s,1H),7.4(t,1H),7.8(m,2H),8.1(m,1H),8.5(s,1H),9.5(s,1H);元素分析C22H24ClFN4O4
    实测值C,57.0;H,5.2;N,11.9;
    理论值C,57.1;H,5.2;N,12.1%。
如下得到用作原料的4-(3′-氯-4′-氟代苯胺基)-6-(2,3-环氧丙氧基)-7-甲氧基喹唑啉:
将4-(3′-氯-4′-氟代苯胺基)-6-羟基-7-甲氧基喹唑啉(5g)2,3-环氧丙基溴(1.6ml),碳酸钾(5g)和DMSO(50ml)的混合物在环境温度下搅拌16小时。将混合物倾入冰水混合物中。将沉淀分离,用水洗涤并干燥。因此得到所需要的起始物质,该物质不需要进一步纯化即可使用并给出下列特征数据:m.p.125-126℃(分解);NMR谱:2.8(m,1H),2.9(m,1H),3.5(m,1H),4.0(s,3H),4.1(m,1H),4.5(m,1H),7.2(s,1H),7.4(t,1H),7.8(m,1H),7.85(s,1H),8.1(m,1H),8.5(s,1H),9.5(s,1H)
实施例10
将吗啉(13.75ml),6-(3-溴丙氧基)-4-(3′-氯-4′-氟代苯胺基)-7-甲氧基喹唑啉(2.94g)和DMF(67ml)的混合物在环境温度下搅拌30分钟。将混合物在乙酸乙酯和水之间分配。将有机相用饱和碳酸氢钠水溶液和盐水洗涤。干燥(Na2SO4)并蒸发。将残留物通过柱色谱层析,用9∶1二氯甲烷和甲醇的混合物作为洗脱剂。将由此得到的物质从甲苯中重结晶。因此得到4-(3′-氯-4′-氟代苯胺基)-7-甲氧基-6-(3-吗啉代丙氧基)喹唑啉(0.78g,27%);NMR谱:2.0(m,2H),2.45(m,6H),3.6(m,4H),3.95(s,3H),4.2(t,2H),7.2(s,1H),7.4(t,1H),7.8(m,2H),8.1(m,1H),8.5(s,1H),9.5(s,1H).
如下得到用作原料的6-(3-溴丙氧基)-4-(3′-氯-4′-氟代苯胺基)-7-甲氧基喹唑啉:
将4-(3′-氯-4′-氟代苯胺基)-6-羟基-7-甲氧基喹唑啉(2g),1,3-二溴丙烷(6.36ml),碳酸钾(4g)和DMF(200ml)的混合物在环境温度下搅拌1小时,将混合物过滤并将滤液蒸发。将残留物通过柱色谱层析纯化,用乙酸乙酯作为洗脱剂。因此定量得到6-(3-溴丙氧基)-4-(3′-氯-4′-氟代苯胺基)-7-甲氧基喹唑啉,该物质不需要进一步纯化即可使用;NMR谱:2.4(m,2H),3.7(t,2H),3.95(s,3H),4.3(t,2H),7.2(s,1H),7.4(t,1H),7.8(m,2H),8.1(m,1H),8.5(s,1H),9.5(s,1H).
实施例11:
将吗啉(0.17ml),6-(2-溴乙氧基)-4-(3′-氯-4′-氟代苯胺基)-7-甲氧基喹唑啉(0.4g)和乙醇(12ml)的混合物搅拌并加热回流27小时。将混合物蒸发并将残留物在乙酸乙酯和水之间分配。将有机相用水和盐水洗涤,干燥(Na2SO4)并蒸发。将残留物通过柱色谱层析纯化,用9∶1二氯甲烷和甲醇的混合物作为洗脱剂。因此得到4-(3′-氯-4′-氟代苯胺基)-7-甲氧基-6-(2-吗啉代乙氧基)喹唑啉(0.14g,35%);NMR谱:2.6(m,4H),2.85(t,2H),3.6(m,4H),3.9(s,3H),4.3(t,2H),7.2(s,1H),7.4(t,1H),7.8(m,2H),8.1(m,1H),8.5(s,1H),9.5(s,1H).
实施例12
将4-(3′-氯-4′-氟代苯胺基)-6-羟基-7-甲氧基喹唑啉(1.1g),3-二乙基氨基丙基氯盐酸盐(0.7g),碳酸钾(3g)和DMF(30ml)的混合物搅拌并加热至80℃反应3小时。将混合物冷却至环境温度并过滤。将滤液蒸发并将残留物通过柱色谱层析纯化,用4∶1二氯甲烷和甲醇的混合物作为洗脱剂。将由此得到的物质在5∶1甲醇和水的混合物中研制。将由此得到的固体干燥。因此得到4-(3′-氯-4′-氟代苯胺基)-6-(3-二乙基氨基丙氧基)-7-甲氧基喹唑啉(1.03g,70%);NMR谱:0.95(t,6H),1.9(m,2H),2.5(m,6H),3.95(s,3H),4.2(t,2H),7.2(s,1H),7.4(t,1H),7.8(m,2H),8.1(m,1H),8.5(s,1H),9.5(s,1H).元素分析:C22H26ClFN4O20.7H2O:
    实测值C,59.4;H,6.2;N,12.5;
    理论值C,59.4;H,6.2;N,12.6%。
实施例13
将4-(3′-氯-4′-氟代苯胺基)-6-羟基-7-甲氧基喹唑啉(1.28g),3-(吡咯烷-1-基)丙基氯盐酸盐(化学文摘( Chem. Abs.), 82.57736;1.5g),碳酸钾(2.8g)和DMF(20ml)的混合物搅拌并加热至80℃反应5小时。将混合物冷却至环境温度并在乙酸乙酯和水之间分配。将有机相用水洗涤,干燥(MgSO4)并蒸发。将残留物通过柱色谱层析,用20∶3二氯甲烷和甲醇的混合物作为洗脱剂。将由此得到的物质(1.1g)在乙酸乙酯中研制,得到4-(3′-氯-4′-氟代苯胺基)-7-甲氧基-6-(3-吡咯烷-1-基丙氧基)喹唑啉(0.094g)。将有机溶液蒸发并将残留固体从乙腈中重结晶。因此得到第二批(0.85g)相同的产品。该物质的特征数据如下:m.p.159-161℃;NMR谱:1.95(m,4H),3.3(m,6H),3.95(s,3H),4.3(t,2H),7.2(s,1H),7.4(t,1H),7.9(m,1H),8.1(s,1H),8.2(m,1H),8.5(s,1H),9.8(broad s,1H);元素分析:C22H24ClFN4O2
实测值C,61.0;H,5.7;N,13.1;
理论值C,61,3;H,5.6;N,13.0%。
实施例14
将4-(2′,4′-二氟代苯胺基)-6-羟基-7-甲氧基喹唑啉(2.5g),3-吗啉代丙基氯盐酸盐(1.6g),碳酸钾(6g)和DMF(100ml)的混合物搅拌并加热至60℃1小时。将混合物冷却至环境温度并在乙酸乙酯和水之间分配。将有机相用水和盐水洗涤,干燥(MgSO4)并蒸发。将残留物通过柱色谱层析,用9∶1二氯甲烷和甲醇的混合物作为洗脱剂。因此得到4-(2′,4′-二氟代苯胺基)-7-甲氧基-6-(3-吗啉代丙氧基)喹唑啉(1.05g,30%),m.p.151-153℃;NMR谱:2.0(m,2H),2.35-2.67(m,6H),3.58(t,2H),3.94(s,3H),4.16(t,2H),7.13(m,1H),7.16(s,1H),7.33(m,1H),7.54(m,1H),7.78(s,1H),8.1(s,1H),9.4(broad s,1H);元素分析:C22H24F2N4O3
    实测值C,61.4;H5.5;N12.8;
    理论值C,61.4;H,5.6;N13.0%。
实施例15
将4-(3′-氯-4′-氟代苯胺基)-6-羟基-7-甲氧基喹唑啉(1.24g),2-(咪唑-1-基)乙基氯(欧洲专利申请0421210;2.51g),碳酸钾(1.5g)和DMF(31ml)搅拌并加热至90℃反应4小时,然后在环境温度下放置16小时。将混合物倾入冰水混合物中。将沉淀分离,干燥并通过柱色谱层析纯化,用9∶1二氯甲烷和甲醇的混合物作为洗脱剂。将由此得的固体在甲醇中研制。因此得到4-(3′-氯-4′-氟代苯胺基)-6-(2-咪唑-1-基乙氧基)-7-甲氧基喹唑啉(0.55g,34%)。m.p.239-241℃;NMR谱:4.0(s,3H),4.4(t,2H),4.5(t,2H),6.9(s,1H),7.2(s,1H),7.3(s,1H),7.4(t,1H),7.7(s,1H),7.75(m,1H),7.8(s,1H),8.1(m,1H),8.5(s,1H),9.5(s,1H);元素分析C20H17ClFN5O2
  实测值C,57.5;H,4.3;N,16.7;
  理论值C,58.0;H,4.1;N,16.9%。
实施例16
将咪唑(0.128g),6-(2-溴代乙氧基)-4-(3′-氯-4′-氟代苯胺基)-7-甲氧基喹唑啉(0.4g)和乙醇(12ml)的混合物搅拌并加热回流66小时。将混合物蒸发并将残渣在乙酸乙酯和水之间分配。将有机相用水洗涤,干燥(Na2SO4)并蒸发。将残留物通过柱色谱层析纯化,用9∶1二氯甲烷和甲醇的混合物作为洗脱剂。因此得到4-(3′-氯-4′-氟代苯胺基)-6-(2-咪唑-1-基乙氧基)-7-甲氧基喹唑啉(0.13g,33%);NMR谱:4.0(s,3H),4.4(t,2H),4.5(t,2H),6.9(s,1H),7.2(s,1H),7.3(s,1H),7.4(t,1H),7.7(s,1H),7.75(m,1H),7.8(s,1H),8.1(m,1H),8.5(s,1H),9.5(s,1H).
实施例17
将4-(3′-氯-4′-氟代苯胺基)-6-羟基-7-甲氧基喹唑啉(2g),3-二甲基氨基丙基氯盐酸盐(0.99g),碳酸钾(5g)和DMF(100ml)的混合物搅拌并加热至90℃反应2小时。将混合物冷却至环境温度并倾入水中。将沉淀分离并从甲苯中重结晶。将得到的固体通过柱色谱层析纯化,用极性逐步增加的二氯甲烷和甲醇混合物作为洗脱剂。因此得到4-(3′-氯-4′-氟代苯胺基)-6-(3-二甲基氨基丙氧基)-7-甲氧基喹唑啉(0.97g);NMR谱:1.95(m,2H),2.2(s,6H),2.45(t,2H),3.95(s,3H),4.18(t,2H),7.2(s,1H),7.42(t,1H),7.8(m,2H),8.12(m,1H),8.5(s,1H),9.5(s,1H);元素分析C20H22ClFN4O2
  实测值C,59.1;H,5.3;N,13.6;
  理论值C,59.3;H,5.5;N,13.8%。
实施例18
将4-(3′,4′-二氟代苯胺基)-6-羟基-7-甲氧基喹唑啉(1.8g),3-二甲基氨基丙基氯盐酸盐(0.94g)碳酸钾(4.5g)和DMF(90ml)的混合物搅拌并加热至90℃反应1小时。将混合物冷却至环境温度并倾入水中。将得到的沉淀分离并通过柱色谱层析纯化,用4∶1二氯甲烷和甲醇的混合物作为洗脱剂,将由此得到的物质从甲苯中重结晶。因此得到4-(3′,4′-二氟代苯胺基)-6-(3-二甲基氨基丙氧基)-7-甲氧基喹唑啉(0.93g);NMR谱:2.0(m,2H),2.2(s,6H),2.45(m,2H),3.9(s,3H),4.2(t,2H),7.2(s,1H),7.4(m,1H),7.55(m,1H),7.8(s,1H),8.05(m,1H),8.5(s,1H),9.55(broad s,1H);元素分析C20H22F2N4O2
   实测值C,61.6;H,5.7;N,14.1;
   理论值C,61.8;H,5.7;N,14.4%。
如下得到用作原料的4-(3′,4′-二氟代苯胺基)-6-羟基-7-甲氧基喹唑啉;
将6-乙酰氧基-4-氯-7-甲氧基喹唑啉盐酸盐〔由6-乙酰氧基-7-甲氧基-3,4-二氢喹唑啉-4-酮(6g)和亚硫酰氯(87ml)得到〕,3,4-二氟代苯胺(2.9ml)和异丙醇(170ml)的混合物搅拌并加热回流4小时。将沉淀分离,用异丙醇洗涤并干燥。因此得到6-乙酰氧基-4-(3′,4′-二氟代苯胺基)-7-甲氧基喹唑啉盐酸盐(7.5g);NMR谱:2.4(s,3H),4.0(s,3H),7.45-7.6(m,3H),7.95(m,1H),8.8(s,1H),8.95(s,1H),11.5(broad s,1H).
将由此得到的物质,浓氢氧化铵水溶液(30%重量/体积,3.9ml)和甲醇(280ml)的混合物在环境温度下搅拌20小时。将沉淀分离并用甲醇洗涤。因此得4-(3′,4′-二氟代苯胺基)-6-羟基-7-甲氧基喹唑啉(5.5g);NMR谱4.0(s,3H),7.2(s,1H),7.4(q,1H),7.65(m,1H),7.8(s,1H),8.1(m,1H),8.45(s,1H),9.45(s,1H),9.6(s,1H).
实施例19
将4-(3′,4′-二氟代苯胺基)-6-羟基-7-甲氧基喹唑啉(1.2g),3-吗啉代丙基氯(0.72g),碳酸钾(2g)和DMF(30ml)的混合物搅拌并加热至80℃反应2小时。再加入另一部分(0.3g)3-吗啉代丙基氯并再将混合物加热至80℃反应2小时。将混合物冷却至环境温度,过滤并将滤液蒸发。将残留物通过柱色谱层析纯化,用4∶1乙酸乙酯和甲醇的混合物作为洗脱剂。因此得到4-(3′,4′-二氟代苯胺基)-7-甲氧基-6-(3-吗啉代丙氧基)喹唑啉(0.84g)。NMR谱:2.0(m,2H),3.6(t,4H),3.95(s,3H),4.2(t,2H),7.2(s,1H),7.4(m,1H),7.57(m,1H),7.82(s,1H),8.05(m,1H),8.48(s,1H),9.55(s,1H);元素分析C22H24F2N4O3
  实测值C,61.1;H,5.4;N,12.8;
  理论值C,61.4;H,5.6;N,13.0%。实施例20
将4-(3′,4′-二氟代苯胺基)-6-羟基-7-甲氧基喹唑啉(1.2g),3-二乙基氨基丙基氯盐酸盐(0.81g)碳酸钾(3.5g)和DMF(30ml)的混合物搅拌并加热至80℃反应2小时。将混合物冷却至环境温度,过滤并蒸发。将残留物通过柱色谱层析纯化,用4∶1二氯甲烷和甲醇的混合物作为洗脱剂。因此得到6-(3-二乙基氨基丙氧基)-4-(3′,4′-二氟代苯胺基)-7-甲氧基喹唑啉(1.14g);NMR谱:0.8(t,6H),1.8(m,2H),3.78(s,3H),4.0(t,2H),7.1(s,1H),7.3(m,1H),7.45(m,1H),7.65(s,1H),7.9(m,1H),8.34(s,1H),9.4(broad s,1H);元素分析C22H26F2N4O2
  实测值C,63.4;H,6.3;N,13.6;
  理论值C,63.4;H,6.3;N,13.5%。
实施例21
将4-(3′-氯-4′-氟代苯胺基)-6-羟基-7-甲氧基喹唑啉(1.2g),3-哌啶子基丙基氯盐酸盐(0.82g),碳酸钾(3g)和DMF(30ml)的混合物搅拌并加热至80℃反应2小时。将混合物冷却至环境温度,过滤并蒸发。将残留物通过柱色谱层析纯化,用9∶1二氯甲烷和甲醇的混合物作为洗脱剂。将由此得到的固体在乙醚中研制。因此得到4-(3′-氯-4′-氟代苯胺基)-7-甲氧基-6-(3-哌啶子基丙氧基)喹唑啉(0.94g);NMR谱:1.4-1.7(m,6H),2.0(m,2H),3.95(s,3H),4.2(t,2H),7.2(s,1H),7.4(t,1H),7.8-8.0(m,2H),8.1(m,1H),8.5(s,1H),9.55(s,1H);元素分析C23H26ClFN4O2
  实测值C,61.8;H,5.8;N,12.6;
  理论值C,62.1;H,5.9;N,12.6%。
实施例22
将4-(3′-氯-4′-氟代苯胺基)-6-羟基-7-甲氧基喹唑啉(1.5g),2-哌啶子基乙基氯盐酸盐(0.86g),碳酸钾(3g)DMF(40ml)的混合物搅拌并加热至90℃反应1小时。将混合物冷却至环境温度并过滤。将滤液蒸发并将残留物通过柱色谱层析纯化,用9∶1二氯甲烷和甲醇的混合物作为洗脱剂。将由此得到的物质从甲苯中重结晶。因此得到4-(3′-氯-4′-氟代苯胺基)-7-甲氧基-6-(2-哌啶子基乙氧基)喹唑啉(0.77g);NMR谱:1.3-1.6(m,6H),2.8(t,2H),3.95(s,3H),4.25(t,2H),7.2(s,1H),7.45(t,1H),7.8(m,2H),8.12(m,1H),8.48(s,1H),9.5(s,1H);元素分析C22H24ClFN4O2
   实测值C,61.0;H,5.7;N,13.0;
   理论值C,61.3;H,5.6;N,13.0%。
实施例23
将4-(3′-氯-4′-氟代苯胺基)-6-羟基-7-甲氧基喹唑啉(1.5g),3-(咪唑-1-基)丙基氯(0.67g),碳酸钾(3g)和DMF(40ml)的混合物搅拌并加热至90℃反应1小时。加入第二份(0.12g)丙基氯并再将混合物加热至90℃反应1小时。将混合物冷却至环境温度,过滤并蒸发,将残留物通过柱色谱层析纯化,用9∶1二氯甲烷和甲醇的混合物作为洗脱剂。因此得到4-(3′-氯-4′-氟代苯胺基)-6-(3-咪唑-1-基丙氧基)-7-甲氧基喹唑啉(0.66g);NMF谱:2.5(m,2H),4.12(s,3H),4.25(t,2H),4.35(t,2H),7.08(s,1H),7.4(d,2H),7.6(t,1H),7.8(s,1H),7.95(m,2H),8.25(m,1H),8.65(s,1H),9.7(broad s,1H);元素分析C21H19ClFN5O20.2H2O:
   实测值C,58.2;H,4.6;N,16.6;
   理论值C,58.5;H,4.5;N,16.2%。
如下得到用作原料的3-(咪唑-1-基)丙基氯:
将咪唑(5.4g)的DMF(20ml)溶液滴加到搅拌下的氢化钠〔60%矿物油分散液,3.3g,并用石油醚(b.p.40-60℃)洗涤过〕的DMF(10ml)混合物中。将得到的溶液加到在冰浴中冷却的3-溴氯丙烷(13g)的DMF(70ml)溶液中。将混合物在0℃下搅拌1小时。将混合物倾入饱和碳酸氢钠水溶液中。将得到的混合物过滤并将滤液用乙酸乙酯提取。将有机提取物干燥(Na2SO4)并蒸发。将残留物通过柱色谱层析纯化,用9∶1二氯甲烷和甲醇的混合物作为洗脱剂。因此得到3-(咪唑-1-基)丙基氯(8.3g);NMR谱:2.2(m,2H),3.55(t,2H),4.1(t,2H),6.9(s,1H),7.18(s,1H),7.6(s,1H).
实施例24
将氯化氢在乙醚(65ml)中的1M溶液加到4-(3′-氯-4′-氟代苯胺基)-7-甲氧基-6-(3-吗啉代丙氧基)喹唑啉(30.1g)在乙醚(545ml)和DMF(250ml)的溶液中。将混合物在环境温度下搅拌1小时。将沉淀分离,用乙醚洗涤并干燥。因此得到4-(3′-氯-4′-氟代苯胺基)-7-甲氧基-6-(3-吗啉代丙氧基)喹唑啉盐酸盐(32.1g),m.p.251-255℃;NMR谱:2.3(m,2H),3.2-3.4(m,6H),3.9(broad s,4H),3.95(s,3H),4.35(t,2H),7.22(s,1H),7.4(t,1H),7.9(m,1H),8.12(s,1H),8.2(m,1H),8.55(s,1H),10.0(s,1H):元素分析C22H24ClFN4O31HCl 0.08H2O:
   实测值C,54.5;H,5.3;N,11.7;
   理论值C,54.5;H,5.2;N,11.6%。
实施例25
将1M氯化氢/乙醚(15ml)溶液加到4-(3′-氯-4′-氟代苯胺基)-7-甲氧基-6-(3-吗啉代丙氧基)喹唑啉(2.2g)在DMF(20ml)的溶液中并将混合物在环境温度下搅拌2小时。将沉淀分离,用乙醚洗涤并在80℃下真空干燥。因此得到4-(3′-氯-4′-氟代苯胺基)-7-甲氧基-6-(3-吗啉代丙氧基)喹唑啉二盐酸盐(2.3g);NMR谱:2.3(m,2H),3.2-3.6(m,6H),4.0(m,7H),4.35(t,2H),7.4(s,1H),7.55(t,1H),7.8(m,1H),8.15(m,1H),8.6(s,1H),8.9(s,1H);元素分析C22H24ClFN4O32HCl:
   实测值C,50.7;H,5.0;N,10.5;Cl,13.1;
   理论值C,50.8;H,5.0;N,10.8;Cl,13.6%.
实施例26
将L-(2R,3R)-(+)-酒石酸(1.03g)的THF(50ml)溶液加到4-(3′-氯-4′-氟代苯胺基)-7-甲氧基-6-(3-吗啉代丙氧基)喹唑啉(1.53g)的THF(100ml)溶液中,并将混合物在环境温度下搅拌2小时。将混合物过滤,用THF洗涤并干燥,因此得到4-(3′-氯-4′-氟代苯胺基)-7-甲氧基-6-(3-吗啉代丙氧基)喹唑啉二-L-酒石酸盐(2g),m.p.136-140℃(在111℃下相转变),NMR谱:2.2(m,2H),2.5-2.6(m,6H),3.6(t,4H),3.95(s,3H),4.2(t,2H),4.3(s,4H),7.2(s,1H),7.45(t,1H),7.8(m,2H),8.15(m,1H),8.5(s,1H),9.5(s,1H);元素分析C22H24ClFN4O32酒石酸;
    实测值C,48.8;H,5.2;N,7.6;
    理论值C,48.4;H,4.6;N,7.5%。
实施例27
将富马酸(0.8g)在二氯甲烷和DMF混合物中的溶液加到4-(3′-氯-4′-氟代苯胺基)-7-甲氧基-6-(3-吗啉代丙氧基)-喹唑啉(1.5g)在二氯甲烷(50ml)和足够完全溶解的DMF量混合物的溶液中。将混合物在环境温度下搅拌2小时。将沉淀分离,用二氯甲烷洗涤并干燥。因此得到4-(3′-氯-4′-氟代苯胺基)-7-甲氧基-6-(3-吗啉代丙氧基)喹唑啉二富马酸盐(2.12g),m.p.199-201℃;NMR谱:2.0(m,2H),2.5-2.7(m,6H),3.6(t,4H),3.95(s,3H),4.2(t,2H),6.6(s,2H),7.2(s,1H),7.42(t,1H),7.8(m,2H),8.2(m,1H),8.48(s,1H),9.5(s,1H);元素分析C22H24ClFN4O31H2O2富马酸:
    实测值C,51.8;H,4.7;N,8.3;
    理论值C,51.5;H,5.2;N,8.0%。
实施例28
将4-(3′-氯-4′-氟代苯胺基)-7-甲氧基-6-(3-吗啉代丙氧基)-喹唑啉(1.4g)在微量THF中的溶液加到枸橼酸(1.5g)的THF(30ml)溶液中。将得到的混合物在环境温度下搅拌16小时。将沉淀分离并在丙酮中研制。因此得到4-(3′-氯-4′-氟代苯胺基)-7-甲氧基-6-(3-吗啉代丙氧基)喹唑啉(1.3g),其中包含1.8当量的枸橼酸,m.p.160-163℃;NMR谱2.1(m,2H),2.6-2.8(m,8H),3.65(t,4H),3.95(s,3H),4.2(t,2H),7.2(s,1H),7.4(t,1H),7.8(m,2H),8.2(m,1H),8.48(s,1H),9.6(s,1H);元素分析C22H24ClFN4O31.8枸橼酸:
    实测值C,50.0;H,5.2;N,7.2;
    理论值C,49.7;H,4.9;N,7.1%。
实施例29
将4-(3′-氯-4′-氟代苯胺基)-7-甲氧基-6-(3-吗啉代丙氧基)-喹唑啉(5g)的THF(250ml)溶液加到搅拌下的甲磺酸(2.4g)的THF(100ml)溶液中。将得到的混合物在环境温度下搅拌1小时,将沉淀分离,在丙酮中浆化并重新分离。因此得到4-(3′-氯-4′-氟代苯胺基)-7-甲氧基-6-(3-吗啉代丙氧基)喹唑啉二甲磺酸盐(6.5g),m.p.242-245℃;NMR谱:2.3(m,2H),2.45(s,6H),3.0-3.8(m,10H),4.1(s,3H),4.35(t,2H),7.4(s,1H),7.55(t,1H),7.75(m,1H),8.0(m,1H),8.15(s,1H),8.9(s,1H),9.6(s,1H),11.0(s,1H);元素分析C22H24ClFN4O31.13H2O2CH3SO3H:
    实测值C,44.1;H,5.2;N,8.6;
    理论值C,43.7;H,5.2;N,8.5%。
实施例30
将4-(3′-氯-4′-氟代苯胺基)-7-甲氧基-6-(3-吗啉代丙氧基)喹唑啉(1.5g)在DMF(10ml)和二氯甲烷(50ml)混合物中的溶液加到浓硫酸(1.5ml)和二氯甲烷(20ml)的混合物中。将得到的混合物在环境温度下搅拌16小时。将沉淀分离,用丙酮洗涤并干燥。因此得到4-(3′-氯-4′-氟代苯胺基)-7-甲氧基-6-(3-吗啉代丙氧基)喹唑啉二硫酸盐(2.7g)。m.p.>250℃;NMR谱:2.3(m,2H),3.0-3.8(m,10H),4.02(s,3H),4.35(t,2H),7.38(s,1H),7.53(t,1H),7.77(m,1H),8.05(m,1H),8.15(s,1H),8.92(s,1H);元素分析C22H24ClFN4O32H2O2H2SO4
    实测值C,39.0;H,4.2;N,8.2;
    理论值C,38.9;H,4.75;N,8.3%。
实施例31
将4-甲苯磺酸一水合物(1.12g)的THF(20ml)溶液加到4-(3′-氯-4′-氟代苯胺基)-7-甲氧基-6-(3-吗啉代丙氧基)喹唑啉(1.3g)的THF(60ml)溶液中。将得到的混合物在环境温度下搅拌4小时。将沉淀分离,相继用THF和丙酮洗涤并干燥。因此得到4-(3′-氯-4′-氟代苯胺基)-7-甲氧基-6-(3-吗啉代丙氧基)喹唑啉的二-4-甲苯磺酸盐(1.54g),m.p.169-173℃;NMR谱:2.3(m,8H),3.0-3.8(m,10H),4.0(s,3H),4.3(t,2H),7.1(d,4H),7.34(s,1H),7.5(d,4H),7.54(t,1H),7.7(m,1H),7.95(m,1H),8.1(s,1H),8.9(s,1H),11.0(broad s,1H);元素分析C22H24ClFN4O31.5H2O2CH3C6H4SO3H:
   实测值C,52.8;H,4.9;N,6.8;
   理论值C,52.8;H,5.3;N,6.85%。
实施例32
下面说明有代表性的包含式I化合物或其可药用盐(下文中的化合物X)的药物制剂形式,它们用于人类疾病的治疗或预防:
(a) 片剂I                       mg/片
化合物X                          100
乳糖(欧洲药典)                   182.75
微晶纤维素钠                     12.0
玉米淀粉糊(5%w/v糊剂)           2.25
硬脂酸镁                         3.0
(b) 片剂II                      mg/片
化合物X                          50
乳糖(欧洲药典)                   223.75
微晶纤维素钠                     6.0
玉米淀粉                         15.0
聚乙烯吡咯烷酮                   2.25
硬脂酸镁                         3.0
(c) 片剂III                     mg/片
化合物X                          1.0
乳糖(欧洲药典)                   93.25
微晶纤维素钠                     4.0
玉米淀粉糊(5%w/v糊剂)           0.75
硬脂酸镁                         1.0
(d) 胶囊                        mg/胶囊
化合物X                          10
乳糖(欧洲药典)                   488.5
硬脂酸镁                         1.5
(e)注射剂I                      (50mg/ml)
化合物X                          5.0%w/v
1M氢氧化钠溶液                   15.0%w/v
0.1M盐酸(调至pH7.6)
聚乙二醇400                      4.5%w/v
注射用水加至100%
(f)注射剂II                     (10mg/ml)
化合物X                         1.0%w/v
磷酸钠BP                        3.6%w/v
0.1M氢氧化钠                    15.0%w/v
注射用水加至100%
(g)注射剂III                 (1mg/ml缓冲至pH6)
化合物X                          0.1%w/v
磷酸钠BP                         2.26%w/v
枸橼酸                           0.38%w/v
聚乙二醇400                      3.5%w/v
注射用水加至100%附注:
上述制剂可通过本领域公知的常规方法获得。片剂(a)-(c)可通过常规方法包衣,例如得到乙酸邻苯二甲酸纤维素包衣。

Claims (13)

1.式I喹唑啉衍生物或其可药用盐:其中
(R2)n为3′-氯-4′-氟;
R3为甲氧基;并且
R1为2-二甲基氨基乙氧基,2-二乙基氨基乙氧基,3-二甲基氨基丙氧基,3-二乙基氨基丙氧基,2-(吡咯烷-1-基)乙氧基,3-(吡咯烷-1-基)丙氧基,2-哌啶子基乙氧基,3-哌啶子基丙氧基,2-吗啉代乙氧基,3-吗啉代丙氧基,2-(4-甲基哌嗪-1-基)乙氧基,2-(咪唑-1-基)乙氧基,3-(咪唑-1-基)丙氧基,2-〔二-(2-甲氧基乙基)氨基〕乙氧基或3-吗啉代-2-羟基丙氧基。
2.权利要求1的式I喹唑啉衍生物或其可药用的酸加成盐,其中(R2)n为3′-氯-4′-氟;
R3为甲氧基;并且
R1为3-吗啉代丙氧基。
3.权利要求1的式I喹唑啉衍生物或其可药用酸加成盐,所述化合物为4-(3′-氯-4′-氟代苯胺基)-7-甲氧基-6-(2-吡咯烷-1-基乙氧基)喹唑啉。
4.权利要求1的式I喹唑啉衍生物或其可药用的酸加成盐,所述化合物为4-(3′-氯-4′-氟代苯胺基)-7-甲氧基-6-(2-吗啉代乙氧基)喹唑啉。
5.权利要求1的式I喹唑啉衍生物或其可药用的酸加成盐,所述化合物为4-(3′-氯-4′-氟代苯胺基)-6-(3-二乙基氨基丙氧基)-7-甲氧基喹唑啉。
6.权利要求1的式I喹唑啉衍生物或其可药用的酸加成盐,所述化合物为4-(3′-氯-4′-氟代苯胺基)-7-甲氧基-6-(3-吡咯烷-1-基丙氧基)喹唑啉。
7.权利要求1的式I喹唑啉衍生物或其可药用的酸加成盐,所述化合物为4-(3′-氯-4′-氟代苯胺基)-6-(3-二甲基氨基丙氧基)-7-甲氧基喹唑啉。
8.权利要求1的式I喹唑啉衍生物或其可药用的酸加成盐,所述化合物为4-(3′-氯-4′-氟代苯胺基)-7-甲氧基-6-(3-哌啶子基丙氧基)喹唑啉。
9.权利要求1的式I喹唑啉衍生物或其可药用的酸加成盐,所述化合物为4-(3′-氯-4′-氟代苯胺基)-7-甲氧基-6-(3-吗啉代丙氧基)喹唑啉。
10.权利要求9中的式I喹唑啉衍生物的盐酸盐。
11.制备权利要求1-10任一项的式I喹唑啉衍生物或其可药用盐的方法,它包括:
(a)将式II喹唑啉衍生物
Figure C9619352600031
其中Z为可置换的基团,与式III苯胺反应。
Figure C9619352600032
(b)为了制备R1为氨基取代的乙氧基或丙氧基的式I化合物,将R1为羟基的式I喹唑啉衍生物烷基化;
(c)为了制备R1为氨基取代的乙氧基或丙氧基的式I化合物,将R1为羟基-乙氧基或丙氧基的式I化合物或其活性衍生物与适宜的胺反应,或者
(d)为了制备R1为3-吗啉代-2-羟丙基的式I化合物,将R1为2,3-环氧丙氧基的式I化合物与适宜的吗啉反应,
并且当需要式I喹唑啉衍生物的可药用盐时,可通过使用常规方法将所述化合物与适宜的酸反应来获得。
12.一种药物组合物,其中包括权利要求1-10任一项的式I喹唑啉衍生物或其可药用盐和可药用稀释剂或载体。
13.权利要求1-10任一项的式I喹唑啉衍生物或其可药用盐在制备用于在温血动物体内产生抗增生作用的药物中的应用。
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