CN1211240A - 作为抗肿瘤剂的喹唑啉衍生物 - Google Patents

作为抗肿瘤剂的喹唑啉衍生物 Download PDF

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CN1211240A
CN1211240A CN97192242A CN97192242A CN1211240A CN 1211240 A CN1211240 A CN 1211240A CN 97192242 A CN97192242 A CN 97192242A CN 97192242 A CN97192242 A CN 97192242A CN 1211240 A CN1211240 A CN 1211240A
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A·J·巴克
C·约翰斯通
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Abstract

本发明涉及式(Ⅰ)的喹唑啉衍生物,其中X1是直接连接或诸如CO,C(R2)2和CH(OR2)的基团;其中Q1是苯基,萘基或5-或6-员杂芳基部分,且Q1非强制性地带有最多3个取代基;其中m是1或2,各个R1可以是诸如氢,卤素和三氟甲基的基团;和其中Q2可以是苯基或9-或10-员双环杂环部分,且Q2非强制性地带有最多3个取代基;或其药用盐;其制备方法,含有它们的药物组合物和其受体酪氨酸激酶抑制剂性质在治疗增生疾病如癌症方面的用途。

Description

作为抗肿瘤剂的喹唑啉衍生物
本发明涉及喹唑啉衍生物或其药用盐,它们具有抗-增殖活性如抗癌活性,因而可以用于治疗人或动物体的方法中。本发明也涉及生产所说的喹唑啉衍生物的方法,也涉及含有它们的药物组合物,并涉及它们在生产用于对温血动物如人产生抗增殖作用的医药中的用途。
对于细胞增殖疾病如牛皮癣和癌症的许多最新治疗制度应用了抑制DNA合成的化合物。这类化合物一般对于细胞是有毒的,但其毒性作用对于快速分裂的细胞如肿瘤细胞可能是有利的。通过非抑制DNA合成的机理起作用的另一类抗增殖剂具有显示增强的选择性作用的潜力。
最近几年已经发现,细胞可以因为其DNA部分转化为癌基因,即在活化状态下可导致恶性肿瘤细胞形成的基因而变成癌细胞(Bradshaw,诱变,1986,1,91)。几种这类癌基因导致肽的产生,该肽是生长因子受体。生长因子受体复合物随后导致细胞增殖的增加。已知,例如,几种癌基因编码酪氨酸激酶,而某些生长因子受体也是酪氨酸激酶(Yarden等人,Ann.Rev.Bi ochem.,1988,57,443;Larsen等人,Ann.Reports in Med.Chem.1989,Chpt.13)。
受体酪氨酸激酶对于启动细胞复制的生化信号的传递是重要的。它们是跨越细胞膜的大酶,并具有结合生长因子,如表皮生长因子(EGF)的胞外结合区域和作为激酶起作用以使蛋白质中的酪氨酸氨基酸磷酸化,从而影响细胞增殖的胞内部分。基于与不同的受体酪氨酸激酶结合的生长因子的家族,已知很多类受体酪氨酸激酶(Wilks,癌症研究进展,1993,60,43-73)。分类包括Ⅰ类受体酪氨酸激酶,其中包括受体酪氨酸激酶的EGF家族,如EGF,转化生长因子α(TGFα),NEU,erbB,Xmrk,DER和let23受体,Ⅱ类受体酪氨酸激酶,其中包括受体酪氨酸激酶的胰岛素家族,如胰岛素,IGFI和胰岛素-相关受体(IRR)的受体,和Ⅲ类受体酪氨酸激酶,其中包括受体酪氨酸激酶的血小板-衍生的生长因子(PDGF)家族,如PDGFα,PDGFβ和集落刺激因子1(CSF1)受体。已知Ⅰ类激酶如受体酪氨酸激酶的EGF家族经常存在于普通的人类癌症中,如乳腺癌(Sainsbury等人,英国癌症杂志,1988,58,458;Guerin等人,癌基因研究,1988,3,21和Klijn等人,乳腺癌研究与治疗,1994,29,73),非-小细胞肺癌(NSCLCs)包括腺癌(Cerny等人,英国癌症杂志,1986,54,265;Reubi等人,Int.J.Cancer,1990,45,269和Rusch等人,癌症研究,1993,53,2379)和肺的鳞状细胞癌(Hendler等人,癌症细胞,1989,7,347),膀胱癌(Neal等人,Lancet,1985,366),食管癌(Mukaida等人,癌症,1991,68,142),胃肠癌如结肠,直肠或胃癌(Bolen等人,癌基因研究,1987,1,149),前列腺癌(Visakorpi等人,组织化学杂志,1992,24,481),白血病(Konaka等人,细胞,1984,37,1035)和卵巢,支气管或胰癌(欧洲专利说明书400586)。对另外一些人体肿瘤组织进行其受体酪氨酸激酶的EGF家族试验,可以预期其广泛流行将在其它癌症如甲状腺和子宫癌中证实。也已知EGF型酪氨酸激酶活性很少在正常细胞中检测到,而更经常在恶性细胞中检测到(Hunter,细胞,1987,50,823)。更最近已经显示(W.J.Gullick,Brit.Med.Bull.,1991,47,87)具有酪氨酸激酶活性的EGF受体在许多人体癌如脑,肺鳞状细胞,膀胱,胃,结肠直肠,乳腺,头和颈,食管,妇科和甲状腺肿瘤中过量表达。
已经认识到,受体酪氨酸激酶抑制剂的价值是作为哺乳动物癌细胞生长的选择性抑制剂(Yaish等人,科学,1988,242,933)。这一观点的支持通过证明,erbstatin,一种EGF受体酪氨酸激酶抑制剂,特别减弱在移植了表达EGF受体酪氨酸激酶的人乳腺癌的无胸腺裸鼠体内的生长,但对于不表达EGF受体酪氨酸激酶的其它癌的生长没有效果(Toi等人,Eur.J.Cancer Clin.Oncol.,1990,26,722)。各种苯乙烯衍生物也被描述为具有酪氨酸激酶抑制剂性质(欧洲专利申请0211363,0304493和0322738)并被用作抗肿瘤剂。作为EGF受体酪氨酸激酶抑制剂的两个这类苯乙烯衍生物的体内抑制作用已经被证明抗接种到裸鼠中的人体鳞状细胞癌的生长(Yoneda等人,癌症研究,1991,51,4430)。因此,已经指明Ⅰ类受体酪氨酸激酶抑制剂将证明可以用于治疗许多人体癌症。各种已知的酪氨酸激酶抑制剂最近由T.R.Burke Jr.综述公开(未来的药物,1992,17,119)。
EGF型受体酪氨酸激酶也已经与非恶性增生疾病如牛皮癣有关(Elder等人,科学,1989,243,811)。因此可以预期EGF型受体酪氨酸激酶抑制剂将可以用于治疗过度细胞增生的非-恶性疾病如牛皮癣(其中TGFα被认为是最重要的生长因子)和良性前列腺肥大(BPH),动脉粥样硬化和再狭窄。
从欧洲专利申请0520722和0566226和国际专利申请WO95/15758,WO95/19169,WO96/09294,WO96/15118,WO96/16960和WO96/30347已知,某些在4-位带有苯胺取代基的喹唑啉衍生物具有受体酪氨酸激酶抑制活性。从欧洲专利申请0602851和国际专利申请WO95/23141还知道,某些在4-位具有杂芳基氨基取代基的喹唑啉衍生物也具有受体酪氨酸激酶抑制活性。
从国际专利申请WO95/06648,WO92/20642还知道某些芳基和杂芳基化合物抑制EGF和/或PDGF受体酪氨酸激酶。其中披露了某些喹唑啉衍生物但没有提到4-苯氨基喹唑啉衍生物。
从欧洲专利申请0635507和国际专利申请WO95/06648、WO95/19970和WO96/29331还知道,某些包含与喹唑啉的苯并环稠合的5-或6-员环的三环化合物具有受体酪氨酸激酶抑制活性或磷酸二酯酶抑制活性。从欧洲专利申请0635498也知道在6-位带有氨基并在7-位带有卤素的某些喹唑啉衍生物具有受体酪氨酸激酶抑制活性。
4苯氨基喹唑啉衍生物的体外抗-增生作用已经由Fry等人(科学,1994,265,1093)披露。其中阐述了化合物4-(3-溴苯氨基)-6,7-二甲氧基喹唑啉是EGF受体酪氨酸激酶的高效抑制剂。
作为受体酪氨酸激酶EGF家族抑制剂的4,5-二苯氨基邻苯二亚胺衍生物的体内抑制作用已经被证明抗人表皮癌A-431或人卵巢癌SKOV-3的BALB/c裸鼠的生长(Buchdunger等人,Proc.Nat.Acad.Sci.,1994,91,2334)。
在国际专利申请WO96/33977,WO96/33978,WO96/33979,WO96/33980和WO96/33981中还披露了在4-位带有苯胺取代基的喹唑啉衍生物具有受体酪氨酸激酶抑制活性。
在这些文献中没有公开这样的喹唑啉衍生物,它们带有直接连接在6-位(不是在国际专利申请WO96/16960中公开的某些在6-位带有5-或9-员氮-连接的杂芳基部分的4-苯氨基喹唑啉),或通过1-或2-原子链连接在6-位的杂芳基部分,或直接连接在6-位或通过1-或2-原子链连接的芳基部分[不是在欧洲专利申请566226中公开的某些带有通过CONH,NHCH2,CH2NH,或SCH2连接链连接在6-位的芳基部分(芳基连接在这些2原子连接基的第一个原子上,例如在CONH基团中的碳原子)的某些4-苯氨基喹唑啉]。
我们现已发现这类化合物具有被认为是由于其Ⅰ类(EGF类)受体酪氨酸激酶抑制活性产生的抗-增生性质。
根据本发明提供式Ⅰ的喹唑啉衍生物
Figure A9719224200151
其中X1是直接连接或式CO,C(R2)2,CH(OR2),C(R2)2-C(R2)2,C(R2)=C(R2),C≡C,CH(CN),O,S,SO,SO2,N(R2),CON(R2),SO2N(R2),N(R2)CO,N(R2)SO2,OC(R2),SC(R2)2,N(R2)C(R2)2,C(R2)2O,C(R2)2S或C(R2)2N(R2)的基团,而各个R2独立地是氢或(1-4C)烷基;
其中Q1是苯基,萘基或含有最高3个选自氧,氮和硫的杂原子的5-或6-员杂芳基部分,该杂环部分是单环或与苯环稠合,且Q1非强制性地带有3个选自如下的取代基:卤素,羟基,氨基,三氟甲氧基,三氟甲基,氰基,硝基,羧基,氨基甲酰基,(1-4C)烷氧羰基,(1-4C)烷基,(1-4C)烷氧基,(2-4C)烯氧基,(2-4C)炔氧基,(1-3C)亚烷二氧基,(1-4C)烷基氨基,二-[(1-4C)烷基]氨基,吡咯烷-1-基,哌啶子基,吗啉代,哌嗪-1-基,4-(1-4C)烷基哌嗪-1-基,(2-4C)烷酰基氨基,N-(1-4C)烷基氨基甲酰基,N,N-二〔(1-4C)烷基〕氨基甲酰基,氨基-(1-4C)烷基,(1-4C)烷基氨基-(1-4C)烷基,二-[(1-4C)烷基]氨基-(1-4C)烷基,吡咯烷-1-基-(1-4C)烷基,哌啶子基-(1-4C)烷基,吗啉代-(1-4C)烷基,哌嗪-1-基-(1-4C)烷基,4-(1-4C)烷基哌嗪-1-基-(1-4C)烷基,卤代-(2-4C)烷氧基,羟基-(2-4C)烷氧基,(1-4C)烷氧基-(2-4C)烷氧基,氨基-(2-4C)烷氧基,(1-4C)烷基氨基-(2-4C)烷氧基,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,(1-4C)烷硫基-(2-4C)烷氧基,(1-4C)烷基亚磺酰基-(2-4C)烷氧基,(1-4C)烷基磺酰基-(2-4C)烷氧基,卤代-(2-4C)烷基氨基,羟基-(2-4C)烷基氨基,(1-4C)烷氧基-(2-4C)烷基氨基,氨基-(2-4C)烷基氨基,(1-4C)烷基氨基-(2-4C)烷基氨基,二-[(1-4C)烷基]氨基-(2-4C)烷基氨基,吡咯烷-1-基-(2-4C)烷基氨基,哌啶子基-(2-4C)烷基氨基,吗啉代-(2-4C)烷基氨基,哌嗪-1-基-(2-4C)烷基氨基,4-(1-4C)烷基哌嗪-1-基-(2-4C)烷基氨基,N-(1-4C)烷基-卤代-(2-4C)烷基氨基,N-(1-4C)烷基-羟基-(2-4C)烷基氨基,N-(1-4C)烷基-(1-4C)烷氧基-(2-4C)烷基氨基,卤代-(2-4C)烷酰基氨基,羟基-(2-4C)烷酰基氨基,(1-4C)烷氧基-(2-4C)烷酰基氨基,(3-4C)烯酰基氨基,(3-4C)炔酰基氨基,氨基-(2-4C)烷酰基氨基,(1-4C)烷基氨基-(2-4C)烷酰基氨基,二-[(1-4C)烷基]氨基-(2-4C)烷酰基氨基,吡咯烷-1-基-(2-4C)烷酰基氨基,哌啶子基-(2-4C)烷酰基氨基,吗啉代-(2-4C)烷酰基氨基,哌嗪-1-基-(2-4C)烷酰基氨基和4-(1-4C)烷基哌嗪-1-基-(2-4C)烷酰基氨基,其中任何上述包含不连接在卤素,SO或SO2基团或N,O或S原子上的CH2(亚甲基)的取代基非强制性地在所说的CH2基团上带有选自羟基,氨基,(1-4C)烷氧基,(1-4C)烷基氨基和二-[(1-4C)烷基]氨基的取代基;
其中m是1或2,各个R1独立地是氢,卤素,三氟甲基,羟基,氨基,硝基,氰基,羧基,氨基甲酰基,(1-4C)烷氧基氨基甲酰基,(1-4C)烷基,(1-4C)烷氧基,(1-4C)烷基氨基,二-[(1-4C)烷基]氨基,(2-4C)烷酰基氨基,N-(1-4C)烷基氨基甲酰基或N,N-二-[(1-4C)烷基]氨基甲酰基;
和其中Q2是苯基或含有1或2个氮杂原子和非强制性地进一步含有选自氧,氮和硫的杂原子的9-或10-员双环杂环部分,而且Q2非强制性地带有最多3个选自卤素,三氟甲基,氰基,羟基,氨基,硝基,羧基,氨基甲酰基,(1-4C)烷氧羰基,(1-4C)烷基,(1-4C)烷氧基,(1-4C)烷基氨基,二-[(1-4C)烷基]氨基,(2-4C)烷酰基氨基,N-(1-4C)烷基氨基甲酰基和N,N-二-(1-4C)烷基氨基甲酰基的取代基,
或Q2是式Ⅱ的基团
其中X2是式CO,C(R3)2,CH(OR3),C(R3)2-C(R3)2,C(R3)=C(R3),C≡C,CH(CN),O,S,SO,SO2,N(R3),CON(R3),SO2N(R3),N(R3)CO,N(R3)SO2,OC(R3)2SC(R3)2,C(R3)2O或C(R3)2S的基团,而各个R3独立地是氢或(1-4C)烷基,
Q3是苯基或萘基或含有最多3个选自氧,氮和硫的杂原子的5-或6-员杂芳基部分,该杂芳基是单环或与苯环稠合,其中所说的苯基或萘基或杂芳基部分非强制性地带有最多3个选自卤素,三氟甲基,氰基,羟基,氨基,硝基,羧基,氨基甲酰基,(1-4C)烷氧羰基,(1-4C)烷基,(1-4C)烷氧基,(1-4C)烷基氨基,二-[(1-4C)烷基]氨基,(2-4C)烷酰基氨基,N-(1-4C)烷基氨基甲酰基和N,N-二-〔(1-4C)烷基〕氨基甲酰基的取代基,n是1,2或3,而各个R4独立地是氢,卤素,三氟甲基,氰基,羟基,氨基,硝基,(1-4C)烷基,(1-4C)烷氧基,(1-4C)烷基氨基,二-[(1-4C)烷基]氨基,或(2-4C)烷酰基氨基;
或其药用盐;
条件是,当Q1是非强制性-取代的苯基时,X1不是N(R2)CO,N(R2)SO2,OC(R2)2,N(R2)C(R2)2,C(R2)2S或C(R2)2N(R2);和当X1是直接连接时,Q1不是含有最多3个氮杂原子的5-或9-员氮-连接的杂芳基部分。
根据本发明的另一方面,提供式Ⅰ的喹唑啉衍生物
其中X1是直接连接或式CO,C(R2)2,CH(OR2),C(R2)2-C(R2)2,C(R2)=C(R2),C≡C,CH(CN),O,S,SO,SO2,N(R2),CON(R2),SO2N(R2),N(R2)CO,N(R2)SO2,OC(R2)2,SC(R2)2,N(R2)C(R2)2,C(R2)2O,C(R2)2S或C(R2)2N(R2)的基团,而各个R2独立地是氢或(1-4C)烷基;
其中Q1是含有最高3个选自氧,氮和硫的杂原子的5-或6-员杂芳基部分,该杂环部分是单环或与苯环稠合,且Q1非强制性地带有3个选自如下的取代基:卤素,羟基,氨基,三氟甲氧基,三氟甲基,氰基,硝基,羧基,氨基甲酰基,(1-4C)烷氧羰基,(1-4C)烷基,(1-4C)烷氧基,(2-4C)烯氧基,(2-4C)炔氧基,(1-3C)亚烷二氧基,(1-4C)烷基氨基,二-[(1-4C)烷基]氨基,吡咯烷-1-基,哌啶子基,吗啉代,哌嗪-1-基,4-(1-4C)烷基哌嗪-1-基,(2-4C)烷酰基氨基,N-(1-4C)烷基氨基甲酰基,N,N-二[(1-4C)烷基]氨基甲酰基,氨基-(1-4C)烷基,(1-4C)烷基氨基-(1-4C)烷基,二-[(1-4C)烷基]氨基-(1-4C)烷基,吡咯烷-1-基-(1-4C)烷基,哌啶子基-(1-4C)烷基,吗啉代-(1-4C)烷基,哌嗪-1-基-(1-4C)烷基,4-(1-4C)烷基哌嗪-1-基-(1-4C)烷基,卤代-(2-4C)烷氧基,羟基-(2-4C)烷氧基,(1-4C)烷氧基-(2-4C)烷氧基,氨基-(2-4C)烷氧基,(1-4C)烷基氨基-(2-4C)烷氧基,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,(1-4C)烷硫基-(2-4C)烷氧基,(1-4C)烷基亚磺酰基-(2-4C)烷氧基,(1-4C)烷基磺酰基-(2-4C)烷氧基,卤代-(2-4C)烷基氨基,羟基-(2-4C)烷基氨基,(1-4C)烷氧基-(2-4C)烷基氨基,氨基-(2-4C)烷基氨基,(1-4C)烷基氨基-(2-4C)烷基氨基,二-[(1-4C)烷基]氨基-(2-4C)烷基氨基,吡咯烷-1-基-(2-4C)烷基氨基,哌啶子基-(2-4C)烷基氨基,吗啉代-(2-4C)烷基氨基,哌嗪-1-基-(2-4C)烷基氨基,4-(1-4C)烷基哌嗪-1-基-(2-4C)烷基氨基,N-(1-4C)烷基-卤代-(2-4C)烷基氨基,N-(1-4C)烷基-羟基-(2-4C)烷基氨基,N-(1-4C)烷基-(1-4C)烷氧基-(2-4C)烷基氨基,卤代-(2-4C)烷酰基氨基,羟基-(2-4C)烷酰基氨基,(1-4C)烷氧基-(2-4C)烷酰基氨基,(3-4C)烯酰基氨基,(3-4C)炔酰基氨基,氨基-(2-4C)烷酰基氨基,(1-4C)烷基氨基-(2-4C)烷酰基氨基,二-[(1-4C)烷基]氨基-(2-4C)烷酰基氨基,吡咯烷-1-基-(2-4C)烷酰基氨基,哌啶子基-(2-4C)烷酰基氨基,吗啉代-(2-4C)烷酰基氨基,哌嗪-1-基-(2-4C)烷酰基氨基和4-(1-4C)烷基哌嗪-1-基-(2-4C)烷酰基氨基,其中任何上述包含不连接在卤素,SO或SO2基团或N,O或S原子上的CH2(亚甲基)的取代基非强制性地在所说的CH2基团上带有选自羟基,氨基,(1-4C)烷氧基,(1-4C)烷基氨基和二-[(1-4C)烷基]氨基的取代基;
其中m是1或2,各个R1独立地是氢,卤素,三氟甲基,羟基,氨基,硝基,氰基,羧基,氨基甲酰基,(1-4C)烷氧基氨基甲酰基,(1-4C)烷基,(1-4C)烷氧基,(1-4C)烷基氨基,二-[(1-4C)烷基]氨基,(2-4C)烷酰基氨基,N-(1-4C)烷基氨基甲酰基或N,N-二-[(1-4C)烷基]氨基甲酰基;
和其中Q2是苯基,它非强制性地带有最多3个选自卤素,三氟甲基,氰基,羟基,氨基,硝基,羧基,氨基甲酰基,(1-4C)烷氧羰基,(1-4C)烷基,(1-4C)烷氧基,(1-4C)烷基氨基,二-[(1-4C)烷基]氨基,(2-4C)烷酰基氨基,N-(1-4C)烷基氨基甲酰基和N,N-二-(1-4C)烷基氨基甲酰基的取代基,
或其药用盐;
条件是,当X1是直接连接时,Q1不是含有最多3个氮杂原子的5-或9-员氮-连接的杂芳基部分。
在本说明书中,术语“烷基”包括直链和支链烷基,但对于单个烷基如“丙基”只特指直链形式。例如,当R1是羟基-(2-4C)烷氧基时,此统称基团的合适的值包括2-羟基乙氧基,2-羟基丙氧基,1-羟基丙-2-基氧基和3-羟基丙氧基。类似的约定适用于其它统称的术语。
在本发明中,应该理解式Ⅰ的喹唑啉衍生物可能存在互变异构现象,而在本说明书中的式图只能表示可能的互变异构形式的一种。应该理解本发明包括具有抗增生活性的任何互变异构形式,而不仅仅限于在式图中给出的任何一种互变异构形式。
式Ⅰ的喹唑啉是在2-位未取代的,因此被理解为R1基团只分布在喹唑啉的苯环部分。
也应该理解,某些式Ⅰ的喹唑啉衍生物可以以溶剂化以及非溶剂化形式,例如,水合的形式存在。应该理解,本发明包括所有这类具有抗增生活性的溶剂化形式。
与上面有关的统称基团的合适的值包括下面给出的那些。
对于在Q1,Q2或Q3上的取代基,对于在Q1上的CH2基团上的取代基,或对于R1,R2,R3或R4的合适的值,当其是卤素时是,例如,氟,氯,溴或碘;
当其是(1-4C)烷基时是,例如,甲基,乙基,丙基,异丙基或丁基;
当其是(1-4C)烷氧基时是,例如,甲氧基,乙氧基,丙氧基,异丙氧基或丁氧基;
当其是(1-4C)烷基氨基时是,例如,甲基氨基,乙基氨基或丙基氨基;
当其是二-[(1-4C)烷基]氨基时是,例如,二甲基氨基,二乙基氨基,N-乙基-N-甲基氨基或二丙基氨基;
当其是(2-4C)烷酰基氨基时是,例如,乙酰氨基,丙酰胺基或丁酰胺基;
当其是(1-4C)烷氧羰基时是,例如,甲氧羰基,乙氧羰基,丙氧羰基,丁氧羰基或叔丁氧羰基;
当其是N-(1-4C)烷基氨基甲酰基时是,例如,N-甲基氨基甲酰基或N-乙基氨基甲酰基;和当其是N,N-二-[(1-4C)烷基]氨基甲酰基时是,例如,N,N-二甲基氨基甲酰基,N-乙基-N-甲基氨基甲酰基和N,N-二乙基氨基甲酰基。
可能在Q1上存在的各个取代基的合适的值包括,例如:
  对于(2-4C)烯氧基:               乙烯氧基和烯丙氧基;
  对于(2-4C)炔氧基:                  2-丙炔氧基;
对于(1-3C)亚烷二氧基:    亚甲二氧基,亚乙二氧基和亚丙二氧基;
  对于4-(1-4C)烷基哌嗪-1-基:         4-甲基哌嗪-1-基和4-乙基哌嗪-1-基;
    对于氨基-(1-4C)烷基:             氨基甲基,2-氨基乙基和3-氨基丙基;
对于(1-4C)烷基氨基-(1-4C)烷基:    甲基氨基甲基,2-甲基氨基乙基和3-甲基氨基丙基;对于二-[(1-4C)烷基]氨基-(1-4C)烷基:二甲基氨基甲基,二乙基氨基甲基,2-二甲基氨基乙基,2-二乙
                                              基氨基乙基和3-二甲基氨基丙基;
对于吡咯烷-1-基-(1-4C)烷基:    吡咯烷-1-基甲基,2-吡咯烷-1-基乙基和3-吡咯烷-1-基丙基;
 对于哌啶子基-(1-4C)烷基:          哌啶子基甲基,2-哌啶子基乙基和3-哌啶子基丙基;
  对于吗啉代-(1-4C)烷基:              吗啉代甲基,2-吗啉代乙基和3-吗啉代丙基;
对于哌嗪-1-基-(1-4C)烷基:           哌嗪-1-基,2-哌嗪-1-基乙基和3-哌嗪-1-基丙基;对于4-(1-4C)烷基哌嗪-1-基-(1-4C)烷基: 4-甲基哌嗪-1-基甲基,2-(4-甲基哌嗪-1-基)乙基和3-(4-甲基
                                                  哌嗪-1-基)丙基;
  对于卤代-(2-4C)烷氧基:          2-氟乙氧基,2-氯乙氧基,2-溴乙氧基,3-氟丙氧基,3-氯丙氧
                                   基,2,2,2-三氟乙氧基,1,1,2,2,2-五氟乙氧基,2,2,
                                   3,3-四氟丙氧基,2,2,3,3,3-五氟丙氧基和1,1,2,2,
                                                   3,3,3-七氟丙氧基;
  对于羟基-(2-4C)烷氧基:              2-羟基乙氧基,3-羟基丙氧基和4-羟基丁氧基;对于(1-4C)烷氧基-(2-4C)烷氧基:  2-甲氧基乙氧基,2-乙氧基乙氧基,3-甲氧基丙氧基和3-乙氧基
                                                      丙氧基;
 对于氨基-(2-4C)烷氧基:                    2-氨基乙氧基和3-氨基丙氧基;对于(1-4C)烷基氨基-(2-4C)烷氧基:  2-甲基氨基乙氧基,2-乙基氨基乙氧基,2-丙基氨基乙氧基,3-
                                         甲基氨基丙氧基和3-乙基氨基丙氧基;对于二-[(1-4C)烷基]氨基-(2-4C)烷氧基:2-二甲基氨基乙氧基,2-(N-乙基-N-甲基氨基)乙氧基,2-二乙
                               基氨基乙氧基,2-二丙基氨基乙氧基,3-二甲基氨基丙氧基和3-
                                                 二乙基氨基丙氧基;对于吡咯烷-1-基-(2-4C)烷氧基:      2-(吡咯烷-1-基)乙氧基和3-(吡咯烷-1-基)丙氧基;
 对于哌啶子基-(2-4C)烷氧基:          2-哌啶子基乙氧基和3-哌啶子基丙氧基;
  对于吗啉代-(2-4C)烷氧基:             2-吗啉代乙氧基和3-吗啉代丙氧基;
对于哌嗪-1-基-(2-4C)烷氧基:         2-(哌嗪-1-基)乙氧基和3-(哌嗪-1-基)丙氧基;对于4-(1-4C)烷基哌嗪-1-基(2-4C)烷  2-(4-甲基哌嗪-1-基)乙氧基和3-(4-甲基哌秦-1-基)丙氧基;
         氧基:对于(1-4C)烷硫基-(2-4C)烷氧基:              2-甲硫基乙氧基和3-甲硫基丙氧基;对于(1-4C)烷基亚磺酰基-(2-4C)烷氧基:    2-甲基亚磺酰基乙氧基和3-甲基亚磺酰基丙氧基;对于(1-4C)烷基磺酰基-(2-4C)烷氧基:        2-甲基磺酰基乙氧基和3-甲基磺酰基丙氧基;
对于卤代-(2-4C)烷基氨基:      2-氟乙基氨基,2-氯乙基氨基,2-溴乙基氨基,3-氟丙基氨基和
                                                    3-氯丙基氨基;
 对于羟基-(2-4C)烷基氨基:            2-羟基乙基氨基,3-羟基丙基氨基和4-羟基丁基氨基;对于(1-4C)烷氧基-(2-4C)烷基氨基:  2-甲氧基乙基氨基,2-乙氧基乙基氨基,3-甲氧基丙基氨基和3-
                                                   乙氧基丙基氨基;
 对于氨基-(2-4C)烷基氨基:           2-氨基乙基氨基,3-氨基丙基氨基和4-氨基丁基氨基;对于(1-4C)烷基氨基-(2-4C)烷基氨基:2-甲基氨基乙基氨基,2-乙基氨基乙基氨基,2-丙基氨基乙基氨
                                       基,3-甲基氨基丙基氨基和4-甲基氨基丁基氨基;对于二-[(1-4C)烷基]氨基-(2-4C)烷基 2-二甲基氨基乙基氨基,2-(N-乙基-N-甲基氨基)乙基氨基,2-
          氨基:               二乙基氨基乙基氨基,2-二丙基氨基乙基氨基,3-二甲基氨基丙
                                基氨基,3-二乙基氨基丙基氨基和4-二甲基氨基丁基氨基;对于吡咯烷-1-基-(2-4C)烷基氨基:    2-(吡咯烷-1-基)乙基氨基和3-(吡咯烷-1-基)丙基氨基;对于哌啶子基-(2-4C)烷基氨基:           2-哌啶子基乙基氨基和3-哌啶子基丙基氨基;对于吗啉代-(2-4C)烷基氨基:               2-吗啉代乙基氨基和3-吗啉代丙基氨基;对于哌嗪-1-基-(2-4C)烷基氨基:         2-(哌嗪-1-基)乙基氨基和3-(哌嗪-1-基)丙基氨基;对于4-(1-4C)烷基哌嗪-1-基-(2-4C)烷   2-(4-甲基哌嗪-1-基)乙基氨基和3-(4-甲基哌嗪-1-基)丙基氨
         基氨基:                                         基;对于N-(1-4C)烷基-卤代-(2-4C)烷基氨N-(2-氯乙基)-N-甲基氨基,N-(2-溴乙基)-N-甲基氨基和N-(2-
           基:                                    溴乙基)-N-乙基氨基;对于N-(1-4C)烷基-羟基-(2-4C)烷基氨N-(2-羟基乙基)-N-甲基氨基,N-(3-羟基丙基)-N-甲基氨基和N-
           基:                                  乙基-N-(2-羟基乙基)氨基;对于N-(1-4C)烷基-(1-4C)烷氧基-(2-N-甲基-N-(2-甲氧基乙基)氨基,N-甲基-N-(3-甲氧基丙基)氨基
        4C)烷基氨基:                       和N-乙基-N-(2-甲氧基乙基)氨基;
对于卤代-(2-4C)烷酰基氨基:     2-氯乙酰胺基,2-溴乙酰胺基,3-氯丙酰胺基和3-溴丙酰胺基;
对于羟基-(2-4C)烷酰基氨基:         2-羟基乙酰胺基,3-羟基丙酰胺基和4-羟基丁酰胺基;对于(1-4C)烷氧基-(2-4C)烷酰基氨基: 2-甲氧基乙酰胺基,2-乙氧基乙酰胺基,2-丙氧基乙酰胺基,3-
                                   甲氧基丙酰胺基,3-乙氧基丙酰胺基和4-甲氧基丁酰胺基;
  对于(3-4C)烯酰基氨基:          丙烯酰胺基,甲基丙烯酰胺基,丁烯酰胺基和异丁烯酰胺基;
  对于(3-4C)炔酰基氨基:                              丙炔酰胺基;
对于氨基-(2-4C)烷酰基氨基:          2-氨基乙酰胺基,2-氨基丙酰胺基和3-氨基丙酰胺基;对于(1-4C)烷基氨基-(2-4C)烷酰基氨   2-甲基氨基乙酰胺基,2-乙基氨基乙酰胺基,2-甲基氨基丙酰胺
            基:                                 基和3-甲基氨基丙酰胺基;对于二-[(1-4C)烷基]氨基-(2-4C)烷酰  2-二甲基氨基乙酰胺基,2-二乙基氨基乙酰胺基,2-二甲基氨基
          基氨基:                            丙酰胺基和3-二甲基氨基丙酰胺基;对于吡咯烷-1-基-(2-4C)烷酰基氨基:  2-吡咯烷-1-基乙酰胺基,2-吡咯烷-1-基丙酰胺基和3-吡咯烷-
                                                     1-基丙酰胺基;对于哌啶子基-(2-4C)烷酰基氨基: 2-哌啶子基乙酰胺基,2-哌啶子基丙酰胺基和3-哌啶子基丙酰胺基;对于吗啉代-(2-4C)烷酰基氨基:     2-吗啉代乙酰胺基,2-吗啉代丙酰胺基和3-吗啉代丙酰胺基;对于哌嗪-1-基-(2-4C)烷酰基氨基:   2-哌嗪-1-基乙酰胺基,2-哌嗪-1-基丙酰胺基和3-哌嗪-1-基丙
                                                       酰胺基;对于4-(1-4C)烷基哌嗪-1-基-(2-4C)烷   2-(4-甲基哌嗪-1-基)乙酰胺基,2-(4-甲基哌嗪-1-基)丙酰胺
         酰基氨基:                          基和3-(4-甲基哌嗪-1-基)丙酰胺基。
当在Q1上有(1-3C)亚烷二氧基取代基时,其氧原子在Q1环上占据相邻的位置。
当m是1时,R1取代基优选地在喹唑啉环的7-位。
当在Q1上的任何包含不连接在卤素,SO或SO2基团或N,O或S原子上的CH2(亚甲基)的取代基在所说的CH2基团上带有选自羟基,氨基,(1-4C)烷氧基,(1-4C)烷基氨基和二-[(1-4C)烷基]氨基的取代基时,形成的合适的取代基包括,例如,取代的(1-4C)烷基氨基-(2-4C)烷氧基或二-[(1-4C)烷基]氨基-(2-4C)烷氧基,例如羟基-(1-4C)烷基氨基-(2-4C)烷氧基或羟基-二-[(1-4C)烷基]氨基-(2-4C)烷氧基如3-甲基氨基-2-羟基丙氧基和3-二甲基氨基-2-羟基丙氧基。
当其是萘基时,Q1和Q3的合适的值是,例如,1-萘基或2-萘基。
当其是含有最多3个选自氧,氮和硫杂原子的5-或6-员杂芳基部分时,Q1和Q3的合适的值其单环是,例如,呋喃基,吡咯基,噻吩基,吡啶基,噁唑基,异噁唑基,吡唑基,咪唑基,噻唑基,异噻唑基,吡嗪基,嘧啶基,哒嗪基,1,2,3-三唑基,1,2,4-三唑基,噁二唑基,呋咱基或噻二唑基,或其与苯环稠合是,例如,苯并呋喃基,吲哚基,苯并噻吩基,喹啉基,异喹啉基,苯并噁唑基,吲唑基,苯并咪唑基,苯并噻唑基,噌啉基,喹唑啉基,喹喔啉基或苯并三唑基。所说的杂芳基部分可以通过任何可能的位置与X1和X2连接。在Q1和Q3上非强制性的取代基可以在任何位置包括在任何可能的氮杂原子上。
当其是含有1或2个氮杂原子并非强制性地进一步含有选自氮,氧和硫的杂原子的9-或10-员双环杂环部分时,Q2的合适的值是,例如,苯并稠合的杂环部分如吲哚基,异吲哚基,中氮茚基,1H-苯并咪唑基,1H-吲唑基,苯并噁唑基,苯并[c]异噁唑基,苯并[d]异噁唑基,苯并噻唑基,苯并[c]异噻唑基,苯并[d]异噻唑基,1H-苯并三唑基,苯并[c]呋咱基,苯并[c][2,1,3]噻二唑基,苯并[d][2,1,3]噁二唑基,苯并[d][1,2,3]噻二唑基,喹啉基,1,2-二氢喹啉基,异喹啉基,噌啉基,喹唑啉基,喹喔啉基,2,3-二氮杂萘基,4H-1,4-苯并噁嗪基或4H-1,4-苯并噻嗪基。
杂环部分可以通过包括双环杂环部分的两个环的任何可能的位置连接。杂环部分可以在可能的氮原子上带有合适的取代基如(1-4C)烷基取代基。
也应该理解,在式Ⅰ的结构中,当X1是,例如,式C(R2)2O的基团时,连接在喹唑啉环上的是C原子,而连接在Q1上的是O原子。类似地,当X2是,例如,式N(R3)SO2的基团时,连接在亚苯基环上的是N原子,而连接在Q3上的是SO2基团。类似地,当X1是,例如,式CON(R2)的基团时,连接在喹唑啉环上的是CO基团,而连接在Q1上的是N原子。
本发明喹唑啉衍生物的合适的药用盐是,例如,足够碱性的本发明喹唑啉衍生物的酸加成盐,例如,与例如无机或有机酸,例如盐酸,氢溴酸,硫酸,磷酸,三氟乙酸,柠檬酸或马来酸的一-或二-酸加成盐。另外,足够酸性的本发明喹唑啉衍生物的合适的药用盐是碱金属盐,例如钠或钾盐,碱土金属盐,例如钙或镁盐,铵盐或与提供药用阳离子的有机碱的盐,例如与甲胺,二甲胺,三甲胺,哌啶,吗啉或三-(2-羟基乙基)胺的盐。
特别新颖的本发明化合物包括,例如,式Ⅰ的喹唑啉衍生物,或其药用盐,其中,除非另外说明,各个Q1,X1,m,R1和Q2具有前面定义的意义,或在与本发明特殊化合物有关的本节中定义:
(a)X1是直接连接;
(b)X1是式CO,CH2,CH(OH),CH2CH2,CH=CH,C≡C,O,S,SO,SO2,NH,CONH,SO2NH,NHCO,NHSO2,OCH2,SCH2,NHCH2,CH2O,CH2S或CH2NH;
(c)X1是式CH2,CH2CH2,O,S,SO,SO2,NH,NHCO,NHSO2,OCH2或NHCH2
(d)Q1是如前定义的非强制性取代的苯基;
(e)Q1是如前定义非强制性取代的,含有最多3个选自氧,氮和硫的杂原子的5-或6-员单环杂环部分;
(f)Q1是呋喃基,吡咯基,噻吩基,吡啶基,噁唑基,异噁唑基,吡唑基,咪唑基,噻唑基,异噻唑基,吡嗪基,嘧啶基,哒嗪基,1,2,3-三唑基或1,2,4-三唑基,它们以包括氮原子的任何可能的位置连接,并且如前定义地非强制性取代;
(g)Q1不带非强制性的取代基;
(h)Q1带有1或2个选自卤素,羟基,氨基,三氟甲氧基,三氟甲基,氰基,硝基,(1-4C)烷基,(1-4C)烷氧基,(1-4C)烷基氨基,二-[(1-4C)烷基]氨基和(2-4C)烷酰基氨基的取代基;
(i)Q1带有-个选自氨基-(1-4C)烷基,(1-4C)烷基氨基-(1-4C)烷基,二-[(1-4C)烷基]氨基-(1-4C)烷基,吡咯烷-1-基-(1-4C)烷基,哌啶子基-(1-4C)烷基,吗啉代-(1-4C)烷基,哌嗪-1-基-(1-4C)烷基和4-(1-4C)烷基哌嗪-1-基-(1-4C)烷基的取代基;
(j)m是1而R1是氢;
(k)m是1而R1是(1-4C)烷氧基;
(l)Q2是如前定义非强制性取代的苯基;
(m)Q2是式Ⅱ的基团
Figure A9719224200241
其中X2是式CO,CH2,CH(OH),S,SO2NH或OCH2的基团,Q3是非强制性地带有1或2个选自卤素,(1-4C)烷基和(1-4C)烷氧基取代基的苯基或吡啶基,n是1且R4是氢,卤素,(1-4C)烷基或(1-4C)烷氧基;
(n)Q2是式Ⅱ的基团,其中X2是式CO的基团,Q3是非强制性地带有1或2个选自卤素,(1-4C)烷基和(1-4C)烷氧基取代基的苯基,n是1且R4是氢,卤素,或(1-4C)烷基;和
(o)Q2是式Ⅱ的基团,其中X2是式OCH2的基团,Q3是吡啶基,n是1且R4是氢,卤素,或(1-4C)烷基;
条件是当Q1是非强制性取代的苯基时,X1不是N(R2)CO,N(R2)SO2,OC(R2)2,N(R2)C(R2)2,C(R2)2S或C(R2)2N(R2);并且当X1是直接连接时,Q1不是含有最多3个氮杂原子的5-或9-员氮-连接的杂芳基部分。
优选的本发明化合物是式Ⅰ的喹唑啉衍生物
其中X1是直接连接或式CH2,CH2CH2,NH,NHCO,NHSO2,OCH2,SCH2,NHCH2,CH2O或CH2S的基团;
Q1是2-呋喃基,3-呋喃基,2-噻吩基,3-噻吩基,2-吡啶基,3-吡啶基,4-吡啶基,2-噁唑基,4-噁唑基,5-异噁唑基,3-吡唑基,2-咪唑基,4-咪唑基,2-噻唑基,4-噻唑基,5-异噻唑基,或1,2,3-三唑-4-基,它们非强制性地带有选自甲基,氨基甲基,2-氨基乙基,甲基氨基甲基,2-甲基氨基乙基,二甲基氨基甲基,2-二甲基氨基乙基,吡咯烷-1-基甲基,2-吡咯烷-1-基乙基,哌啶子基甲基,2-哌啶子基乙基,吗啉代甲基,2-吗啉代乙基,哌嗪-1-基甲基,2-哌嗪-1-基乙基,4-甲基哌嗪-1-基甲基和2-(4-甲基哌嗪-1-基)乙基的取代基;
m是1而R1是氢或甲氧基;
而Q2是非强制性地带有1,2或3个选自氟,氯,溴,三氟甲基,氰基,甲基和甲氧基的取代基的苯基,
或Q2是式Ⅱ的基团
Figure A9719224200251
其中X2是式CO或OCH2的基团,Q3是非强制性地带有1或2个选自氟,氯,溴,三氟甲基,氰基,甲基和甲氧基的取代基的苯基或2-吡啶基,n是1且R4是氢,氟,氯,溴或甲基;
或其药用酸加成盐。
进一步优选的本发明化合物是式Ⅰ的喹唑啉衍生物
其中X1是直接连接或式NHCO,OCH2,或NHCH2的基团;
Q1是2-呋喃基,3-呋喃基,2-噻吩基,3-噻吩基,2-吡啶基,3-吡啶基,4-噁唑基,5-异噁唑基或4-咪唑基,它们非强制性地带有选自氨基甲基,吗啉代甲基和2-吗啉代乙基的取代基;
m是1而R1是氢或甲氧基;
而Q2是非强制性地带有1或2个选自氟,氯,溴和甲基的取代基的苯基,
或其药用酸加成盐。
特别优选的本发明化合物是式Ⅰ的喹唑啉衍生物:
4-(3-氯-4-氟苯胺基)-6-(3-呋喃基)喹唑啉,
4-(3-氯-4-氟苯胺基)-6-(2-噻吩基)喹唑啉,
4-(3-氯-4-氟苯胺基)-6-[5-(2-吗啉代乙基)噻吩-2-基]喹唑啉,
4-(3-氯-4-氟苯胺基)-6-(5-吗啉代甲基噻吩-3-基)喹唑啉或
4-(3-氯-4-氟苯胺基)-7-甲氧基-6-(3-吡啶基甲氧基)喹唑啉;
或其药用酸加成盐。
进一步优选的本发明化合物是式Ⅰ的喹唑啉衍生物
其中X1是直接连接;
Q1是带有选自氨基-(1-4C)烷基,(1-4C)烷基氨基-(1-4C)烷基,二-[(1-4C)烷基]氨基-(1-4C)烷基,吡咯烷-1-基-(1-4C)烷基,哌啶子基-(1-4C)烷基,吗啉代-(1-4C)烷基,哌嗪-1-基-(1-4C)烷基和4-(1-4C)烷基哌嗪-1-基-(1-4C)烷基的取代基的噻吩基;
m是1而R1是氢;
而Q2是非强制性地带有最多3个选自卤素,三氟甲基,氰基,羟基,氨基,硝基,羧基,氨基甲酰基,(1-4C)烷氧羰基,(1-4C)烷基,(1-4C)烷氧基,(1-4C)烷基氨基,二-[(1-4C)烷基]氨基,(2-4C)烷酰基氨基,N-(1-4C)烷基氨基甲酰基和N,N-二-(1-4C)烷基氨基甲酰基的取代基的苯基;
或其药用盐。
进一步优选的本发明化合物是式Ⅰ的喹唑啉衍生物
其中X1是直接连接;
Q1是非强制性地带有选自甲基,氨基甲基,2-氨基乙基,甲基氨基甲基,2-甲基氨基乙基,二甲基氨基甲基,2-二甲基氨基乙基,吡咯烷-1-基甲基,2-吡咯烷-1-基乙基,哌啶子基甲基,2-哌啶子基乙基,吗啉代甲基,2-吗啉代乙基,哌嗪-1-基甲基,2-哌嗪-1-基乙基,4-甲基哌嗪-1-基甲基和2-(4-甲基哌嗪-1-基)乙基的取代基的2-噻吩基;
m是1而R1是氢或甲氧基;
而Q2是非强制性地带有1,2或3个选自氟,氯,溴,三氟甲基,氰基,甲基和甲氧基的取代基的苯基;
或其药用盐。
进一步优选的本发明化合物是式Ⅰ的喹唑啉衍生物
其中X1是直接连接;
Q1是非强制性地带有选自氨基甲基,吗啉代甲基和2-吗啉代乙基的取代基的2-噻吩基;
m是1而R1是氢或甲氧基;
而Q2是非强制性地带有1或2个选自氟,氯,溴和甲基的取代基的苯基;
或其药用盐。
特别优选的本发明化合物是式Ⅰ的喹唑啉衍生物:
4-(3-氯-4-氟苯胺基)-6-[5-(2-吗啉代乙基)噻吩-2-基]喹唑啉,
或其药用酸加成盐。
进一步优选的本发明化合物是式Ⅰ的喹唑啉衍生物
其中X1是直接连接或式O的基团;
Q1是非强制性地带有1或2个选自氟,氯,溴,氨基,氰基,硝基,氨基甲基,甲基氨基甲基,二甲基氨基甲基,二乙基氨基甲基,吡咯烷-1-基甲基,哌啶子基甲基,吗啉代甲基,哌嗪-1-基甲基,和4-甲基哌嗪-1-基甲基的取代基的苯基;
m是1而R1是氢或甲氧基;
Q2是非强制性地带有1,2或3个选自氟,氯,溴,三氟甲基,氰基,甲基和甲氧基的取代基的苯基;
或Q2是式Ⅱ的基团
Figure A9719224200281
其中X2是式OCH2的基团,Q3是2-吡啶基,n是1而R4是氢,氟,氯或甲基;
或其药用盐。
进一步优选的本发明化合物是式Ⅰ的喹唑啉衍生物
其中X1是直接连接或式O的基团;
Q1是非强制性地带有1或2个选自氨基,氨基甲基,二乙基氨基甲基,吡咯烷-1-基甲基,哌啶子基甲基和吗啉代甲基的取代基的苯基;
m是1而R1是氢;和
而Q2是带有1或2个选自氟,氯和甲基的取代基的苯基;
或其药用盐。
特别优选的本发明化合物是式Ⅰ的喹唑啉衍生物:
4-(3-甲基苯胺基)-6-苯基喹唑啉,
6-(4-氨基甲基苯基)-4-(3-氯-4-氟苯胺基)喹唑啉,
6-(4-氨基苯氧基)-4-(3-氯-4-氟苯胺基)喹唑啉,
6-(4-氨基甲基苯氧基)-4-(3-氯-4-氟苯胺基)喹唑啉或
4-(3-氯-4-氟苯胺基)-6-(4-吗啉代甲基苯氧基)喹唑啉;
或其药用酸加成盐。
式Ⅰ的喹唑啉衍生物,或其药用盐,可以通过任何可以用于制备化学-相关化合物的已知方法制备。合适的方法包括,例如在欧洲专利申请0520722,0566226,0602851,0635507和0635498,和国际专利申请WO96/15118和WO96/16960中说明的。这类方法,当用于制备式Ⅰ的喹唑啉衍生物,或其药用盐时,作为本发明的进一步的特征被提供,并通过如下代表性的实施例说明,其中,除非另外说明,X1,Q1,m,R1和Q2具有前面对于式Ⅰ的喹唑啉衍生物定义的任何意义。必需的原料可以通过有机化学的标准工艺得到。这类原料的制备在后面的非限制性实施例中描述。另外必需的原料可以通过普通有机化学家熟悉的类似工艺获得。
(a)方便地在合适的碱存在下,式Ⅲ的喹唑啉
Figure A9719224200291
其中Z是可置换的基团,与式Q2-NH2的苯胺反应。
合适的碱是,例如,有机胺碱,例如,吡啶,2,6-二甲基吡啶,甲基吡啶,4-二甲基氨基吡啶,三乙胺,吗啉,N-甲基吗啉或二氮杂双环[5.4.0]十一碳-7-烯,或,例如,碱金属或碱土金属碳酸盐或氢氧化物,例如碳酸钠,碳酸钾,碳酸钙,氢氧化钠或氢氧化钾,或例如,碱金属氢化物,例如氢化钠。
合适的可置换的基团Z是,例如,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。反应方便地在合适的惰性溶剂或稀释剂,例如烷醇或酯如甲醇,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,芳香溶剂如甲苯,或二极非质子性溶剂如N,N-二甲基甲酰胺,N,N-二甲基乙酰胺,N-甲基吡咯烷-2-酮或二甲基亚砜存在下进行。反应在例如,10至250℃,优选地在40至80℃的温度范围方便地进行。
式Ⅰ的喹唑啉衍生物可以由此方法以游离碱的形式得到,或以与其中Z具有如前定义的意义的式H-Z的酸的盐形式得到。当需要从盐得到游离碱时,该盐可以用合适的碱,例如,有机胺,例如,吡啶,2,6-二甲基吡啶,甲基吡啶,4-二甲基氨基吡啶,三乙胺,吗啉,N-甲基吗啉或二氮杂双环[5.4.0]十一碳-7-烯,或,例如,碱金属或碱土金属碳酸盐或氢氧化物,例如碳酸钠,碳酸钾,碳酸钙,氢氧化钠或氢氧化钾处理。
(b)为了制备其中X1是直接连接的式Ⅰ化合物,方便地在合适的催化剂存在下,式Ⅳ的喹唑啉
Figure A9719224200301
其中Z是如前定义的可置换的基团,与其中各个L1和L2相同或不同,为合适的配位体的式Q1-B(L1)(L2)的有机硼试剂反应。
存在于硼原子上的配位体L1和L2的合适的值包括,例如,羟基,(1-4C)烷氧基或(1-6C)烷基配位体,例如羟基,甲氧基,乙氧基,丙氧基,异丙氧基,丁氧基,甲基,乙基,丙基,异丙基或丁基配位体。另外,配位体L1和L2可以这样连接,与它们所连接的硼原子一起,它们形成环。例如,L1和L2一起可以定义为氧基-(2-4C)亚烷基-氧基基团,例如氧基亚乙基氧基或氧基三亚甲基氧基基团,这样,与它们所连接的硼原子一起,它们形成环状硼酸酯基。特别合适的有机硼试剂包括,例如,式Q1-B(OH)2,Q1-B(Pri)2和Q1-B(Et)2化合物。
用于反应的催化剂包括,例如,金属催化剂如钯(0),钯(Ⅱ),镍(0)或镍(Ⅱ)催化剂,例如四(三苯膦)钯(0),氯化钯(Ⅱ),溴化钯(Ⅱ),氯化二(三苯膦)钯(Ⅱ),四(三苯膦)镍(0),氯化镍(Ⅱ),溴化镍(Ⅱ)或氯化二(三苯膦)镍(Ⅱ)。另外可以方便地加入自由基启动剂,例如诸如偶氮(二异丁腈)的偶氮化合物。
反应方便地在合适的惰性溶剂或稀释剂,例如醚如四氢呋喃,1,4-二噁烷或1,2-二甲氧基乙烷,芳香溶剂如苯,甲苯或二甲苯,或醇如甲醇或乙醇的存在下进行,反应方便地在例如10至250℃,优选地在60至120℃的温度范围进行。
式Q1-B(L1)(L2)的有机硼试剂可以通过普通有机化学家熟悉的标准有机化学工艺得到,例如通过其中M是,例如,锂或Grignard试剂的卤化镁部分的式Q1-M的有机金属化合物与其中Z是如前定义的可置换基团的式Z-B(L1)(L2)的有机硼化合物反应。优选地式Z-B(L1)(L2)的化合物是,例如,硼酸或三(1-4C)烷基硼酸酯如三-异丙基硼酸酯。
在另一工艺中,式Q1-B(L1)(L2)的有机硼化合物可以用其中M是金属原子或金属基团(即带有合适的配位体的金属原子)的式Q1-M的有机金属化合物代替。合适的金属原子包括,例如,锂和铜。合适的金属基团包括,例如,含有锡,硅,锆,铝,镁或汞原子的基团。在这类金属基团中的合适的配位体包括,例如,羟基,(1-6C)烷基如甲基,乙基,丙基,异丙基和丁基,卤素基团如氯,溴和碘基团,和(1-66)烷氧基如甲氧基,乙氧基,丙氧基,异丙氧基和丁氧基。特定的式Q1-M的有机金属化合物是,例如,有机锡化合物如式Q1-SnBu3的化合物,有机硅化合物如式Q1-Si(Me)F2的化合物,有机锆化合物如式Q1ZrCl3的化合物,有机铝化合物如式Q1-AlEt2的化合物,有机镁化合物如式Q1-MgBr的化合物,或有机汞化合物如式Q1-HgBr的化合物。
(c)为了制备其中X1是直接连接的式Ⅰ化合物,方便地在如前定义的合适的催化剂存在下,式Ⅴ的喹唑啉
Figure A9719224200311
其中各个L1和L2,可以相同或不同,是如前定义的合适的配位体,与其中Z是如前定义的可置换基团的式Q1-Z的化合物反应。
反应方便地在合适惰性溶剂或稀释剂中,在合适的温度,以与前面段落(b)所述类似的条件进行。
式Ⅴ的喹唑啉可以方便地通过与前面用于制备式Q1-B(L1)(L2)的有机硼试剂类似的工艺得到。
(d)为了生产其中X1是式N(R2)CO或N(R2)SO2基团的式Ⅰ化合物,式Ⅵ的胺
Figure A9719224200312
用式Q1CO2H的羧酸,或其反应活性衍生物,或式Q1-SO2OH的磺酸,或如果合适,其反应活性衍生物酰化。
合适的式Q1-CO2H羧酸的反应活性的衍生物是,例如,酰卤,例如通过酸和无机酰氯,例如亚硫酰氯反应形成的酰氯;混合酸酐,例如通过酸和氯代甲酸酯如氯代甲酸异丁基酯反应形成的酸酐;活性的酯,例如通过酸与酚如五氟苯酚、酯如五氟苯基三氟乙酸酯或醇如甲醇,乙醇,异丙醇,丁醇或N-羟基苯并三唑反应形成的酯;酰基叠氮化物,例如通过酸和叠氮化物如二苯基磷酰基叠氮化物反应形成的叠氮化物;酰基氰化物,例如,通过酸和氰化物如二乙基磷酰基氰化物反应形成的氰化物;或酸和碳化二亚胺如二环己基碳化二亚胺反应形成的产物。类似地,可以得到式Q1-SO2OH磺酸的合适的反应活性衍生物。
反应方便地在如前定义的合适的惰性溶剂或稀释剂中,在例如,0至120℃,优选地在接近室温的范围进行。
(e)为了生产其中X1是式OC(R2)2,SC(R2)2或N(R2)2C(R2)2基团的式Ⅰ化合物,方便地在如前定义的合适的碱存在下,适当的苯酚,硫代苯酚或苯胺与其中Z是如前定义的可置换基团的式Z-C(R2)2-Q1的烷基化剂进行烷基化。
反应方便地在如前定义的合适的惰性溶剂或稀释剂中,在例如,10至150℃,优选地在或接近80℃的温度范围进行。
(f)为了生产其中X1是式C(R2)2O,C(R2)2S或C(R2)2N(R2)基团的式Ⅰ化合物,方便地在如前定义的合适的碱存在下,式HO-Q1的适当的苯酚,式HS-Q1的硫代苯酚或式R2NH-Q1的苯胺与其中Z是如前定义的可置换基团的式Ⅶ的烷基化剂
Figure A9719224200321
进行烷基化。
反应方便地在如前定义的合适的惰性溶剂或稀释剂中,在例如,0至150℃,优选地在20至70℃的温度范围进行。
(g)为了生产具有氨基甲基取代基或其中X1是式N(R2)CH2或CH2N(R2)基团的式Ⅰ化合物,还原具有氰基取代基或其中X1是式N(R2)CO或CON(R2)基团的式Ⅰ化合物。
还原可以通过任何许多在本专业已知用于这类转化的工艺进行。合适的还原剂有,例如,氢化碱金属铝如氢化铝锂。
还原方便地在合适的惰性溶剂或稀释剂如乙醚或四氢呋喃中,在例如,0至80℃,优选地在15至50℃的温度进行。
(h)为了生产具有氨基取代基的式Ⅰ化合物,将具有硝基取代基的式Ⅰ化合物还原。
还原可以方便地通过许多已知用于这类转化的任何方法进行。还原可以,例如,通过在如前定义的惰性溶剂或稀释剂中,在合适的金属催化剂如钯或铂存在下将硝基化合物的溶液氢化。合适的还原剂有,例如,活化的金属如活化的铁(通过用稀酸如盐酸洗涤铁粉而产生)。这样,例如,还原可以通过在合适的溶剂或稀释剂如水和醇,例如,甲醇或乙醇的混合物中,将硝基化合物和活化的金属的混合物加热至例如,50至150℃,方便地在接近70℃的温度范围进行。
(i)为了生产其中X1是式NHCH(R2)基团的式Ⅰ化合物,将式R2-CO-Q1的酮化合物用式Ⅷ的胺
Figure A9719224200331
还原性胺化。
任何在本领域已知用于促进还原性胺化反应的还原剂都可以被应用。合适的还原剂有,例如,氢化物还原剂,例如氢化碱金属铝如氢化铝锂或,优选地,碱金属硼氢化物如硼氢化钠,氰基硼氢化钠,三乙基硼氢化钠,三甲氧基硼氢化钠和三乙酰氧基硼氢化钠。反应方便地在合适的惰性溶剂或稀释剂中进行,对于较强的还原剂如氢化铝锂,例如在四氢呋喃和乙醚中进行,对于较弱的还原剂如三乙酰氧基硼氢化钠和氰基硼氢化钠,例如在二氯甲烷或质子性溶剂如甲醇和乙醇中进行。还原在例如,10至80℃的温度范围,方便地在或接近室温进行。
(j)为了生产其中X1是式O,S或N(R2)基团的式Ⅰ化合物,方便地在如前定义的合适的碱存在下,适当的酚,硫代苯酚或苯胺与其中Z是如前定义可置换基团的式Z-Q1的化合物偶合。
方便地,反应可以在合适的催化剂,例如金属催化剂如钯(0)或铜(Ⅰ)催化剂,例如四(三苯膦)钯(0),氯化亚铜或溴化亚铜存在下进行。
偶合反应方便地在如前定义的合适的惰性溶剂或稀释剂,优选地在N,N-二甲基甲酰胺,N,N-二甲基乙酰胺,N-甲基吡咯烷-2-酮,二甲基亚砜或丙酮中,在例如,10至150℃,方便地在或接近100℃的温度范围进行。
当需要式Ⅰ喹唑啉衍生物的药用盐时,例如一-或二-酸加成盐时,它可以,例如,通过所说的化合物与,例如合适的酸用常规工艺反应而得到。
如前所述,在本发明中定义的喹唑啉衍生物具有抗-增生活性如据信由化合物的Ⅰ类受体酪氨酸激酶抑制活性引起的抗-癌活性。这些性质可以,例如,用下面给出的一种或多种方法试验:
(a)测定试验化合物抑制酶EGF受体酪氨酸激酶能力的体外试验。通过与Carpenter等人,生物化学杂志,1979,254,4884;Cohen等人,生物化学杂志,1982,257,1523和Braun等人,生物化学杂志,1984,259,2051所述有关的下述方法,从A-431细胞(衍生自人外阴癌)得到部分纯化形式的受体酪氨酸激酶。
用含有5%胎牛血清(FCS)的Dulbecco’s改进的Eagle’s培养基(DMEM)培养A-431细胞至铺满。将所得细胞在pH10.1的低渗硼酸盐/EDTA缓冲液中匀浆。在0-4℃下,将匀浆物以400g离心10分钟,在0-4℃下,将上清液以25000g离心30分钟,将沉淀物悬浮于含有5%甘油,4mM苄脒和1%Triton X-100的30mM Hepes缓冲液,pH7.4中,在0-4℃下搅拌1小时,在0-4℃下,以10000g再离心1小时,将含有溶解的受体酪氨酸激酶的上清液储存于液氮中。
为了进行检测,将40μl所得的酶溶液加入下述混合物中,该混合物含有400μl由150mM Hepes缓冲液,pH7.4,500μM正钒酸钠,0.1%Triton X-100,10%甘油组成的混合物,200μl水,80μl 25mM的DTT和80μl由12.5mM氯化锰,125mM氯化镁和蒸馏水组成的混合物,由此得到试验酶溶液。
将各个实验化合物溶于二甲亚砜(DMSO)中给出50mM溶液,再用含有0.1%的Triton X-100,10%甘油和10%DMSO的40mM的Hepes缓冲液稀释该溶液,给出500μM溶液。将等体积的此溶液与表皮生长因子溶液(EGF;20μg/ml)混合。
通过加入于蒸馏水中的ATP溶液(100μM)将[γ-32P]ATP(3000Ci/mM,250μCi)稀释成体积为2ml,加入等体积的于40mM Hepes缓冲液,pH7.4,0.1%的Triton X-100和10%甘油的混合物中的4mg/ml的肽Arg-Arg-Leu-Ile-Glu-Asp-Ala-Glu-Tyr-Ala-Ala-Arg-Gly溶液。
在试验酶溶液(10μl)中加入试验化合物/EGF混合溶液(5μl),将所得混合物在0-4℃下培育30分钟,加入ATP/肽混合物(10μl),将所得混合物在25℃下培育10分钟。通过加入5%三氯醋酸(40μl)和牛血清白蛋白(BSA:1mg/ml,5μl)终止磷酸化反应,将混合物在4℃下放置30分钟,然后离心。将上清液的等分试样(40μl)置于Whatman p81磷酸纤维素滤纸条上,用75mM磷酸(4×10ml)洗涤滤纸条并印干,使用液体闪烁计数仪(Sequence A)测量滤纸中存在的放射性,在缺乏EGF(Sequence B)和缺乏试验化合物(Sequence C)的情况下重复反应顺序。
按下式计算受体酪氨酸激酶的抑制作用:
                      100-(A-B)
                     %抑制作用=×100
                           C-B
然后在试验化合物的浓度范围内测定抑制的程度以给出IC50值。
(b)测定试验化合物抑制人鼻咽癌细胞系KB的EGF-刺激的生长能力的体外试验
以每井1×104-1.5×104个细胞的密度将KB细胞接种到井中,并在添加了5%FCS(用炭笔划条)的DMEM中培养24小时。培育3天后,通过MTT四唑氮染料代谢所提供的蓝色的程度测定细胞生长,然后在EGF(10ng/ml)的存在下或在EGF(10ng/ml)和一定浓度范围的试验化合物的存在下测定细胞生长,然后计算IC50的值。
(c)在雄性大鼠组中测定试验化合物(通常作为于0.5%聚山梨酸酯中的球状物
碾碎的悬浮液口服)抑制由施用生长因子TGFα(皮下注射400μg/kg,通常为两次剂量,分别为施用试验化合物之后的3和7小时给药)引起的刺激肝细胞生长的能力的体内试验。
在对照组大鼠中,施用TGFα导致平均为5倍的刺激肝细胞生长的作用。
按下述测定对照和试验动物的细胞生长:
在施用试验化合物(或在对照组中施用0.5%聚山梨酸酯)后的第二天上午,给动物施用溴脱氧尿苷(BrdU;腹膜内给药100mg/kg),4小时后杀死动物并摘除肝脏,从每个肝脏上切下切片,通过类似于Goldsworthy等人在论文,化学诱导的细胞增殖:风险评估暗示,Wiley-Liss Inc.,1991,p253-284中的p267-268描述的常规免疫组化技术测定BrdU的摄取。使用一定范围剂量的试验化合物进行进一步的试验以计算出通过BrdU摄取的抑制作用测定的对肝细胞增殖的抑制作用的大概的ED50值。
(d)在无胸腺裸鼠组(ONU:Alpk系)中测定试验化合物(通常作为于0.5%聚山梨酸酯中的球状物碾碎的悬浮液口服)抑制人外阴表皮癌细胞系A-431的异种移植生长的能力的体内试验。
在添加5%FCS和2mM谷氨酰胺的DMEM培养液中培养A-431细胞。通过胰蛋白酶消化收获新鲜培养的细胞,并将细胞皮下注射(1千万细胞/0.1ml/小鼠)到许多供体裸鼠的两肋。当可以得到足够的肿瘤材料时(大约9至14天之后),肿瘤组织的碎片被移植到受体裸鼠的两肋(试验天0)。一般地,在移植后第7天(试验天7),选择具有相似-大小肿瘤的7至10只小鼠的组,并且开始试验化合物的计量。试验化合物的一次-日计量继续总共13天(包括试验天7至19)。在一些研究中,试验化合物的计量超过试验天19,例如至试验天26。在各种情况下,在随后的一天将动物杀死,通过测量肿瘤的长和宽计算最终肿瘤的体积。以相对于未处理的对照的肿瘤体积的抑制百分数计算结果。
尽管式Ⅰ化合物的药理性质如预期的随结构的变化而变化,但一般地式Ⅰ化合物具有的活性可以以如下浓度或剂量在上述试验(a),(b),(c)和(d)的一个或多个中证明:
试验(a):IC50在例如,0.01-1μM的范围;
试验(b):IC50在例如,0.0-10μM的范围;
试验(c):ED50在例如,1-100mg/kg;
试验(d):在例如,50至400mg/kg范围日剂量,肿瘤体积的抑制作用为20至70%。
这样,举例来说,化合物4-(3-氯-4-氟苯胺基)-6-[5-(2-吗啉代乙基)噻吩-2-基]喹唑啉在试验(a)中具有0.04μM的IC50,在试验(b)中0.19μM的IC50,并且在试验(d)中在50mg/kg/天的剂量给出64%的抑制作用。
根据本发明的另一方面,提供一种药物组合物,它包括如前定义的式Ⅰ的喹唑啉衍生物,或其药用盐,与药理上可接受的稀释剂或载体结合。
组合物可以是适合口服给药的形式,例如片剂或胶囊,胃肠外注射(包括静脉内,皮下,肌内,血管内或输注)为无菌溶液,悬浮液或乳化液,对于局部给药为软膏或乳剂或直肠给药的栓剂。
一般地,上述组合物可以以常规方式用常规赋形剂制备。
喹唑啉衍生物将以动物每平方米体面积5-5000mg范围内的单位剂量对温血动物正常给药,即大约0.1-100mg/kg,这样正常地提供治疗有效的剂量。单位剂量形式如片剂或胶囊将一般含有,例如1-250mg活性成分。优选地在1-100mg/kg范围的日剂量被应用。然而日剂量必需依赖被治疗的主体,给药的具体途径,被治疗疾病的严重性而变化。而最佳剂量由治疗具体患者的医生确定。
根据本发明的另一方面,提供如前定义的式Ⅰ的喹唑啉衍生物在治疗人或动物体的方法中的用途。
我们现已发现本发明化合物具有抗增生性质,这被认为是由其Ⅰ类(EGF型)受体酪氨酸激酶抑制活性。本发明的化合物预期可以用于由Ⅰ类受体酪氨酸激酶单独或部分间介的疾病或病症的治疗,即化合物可以在需要这类治疗的温血动物体内用于产生Ⅰ类受体酪氨酸激酶抑制作用。这样本发明化合物提供治疗特征在于抑制Ⅰ类受体酪氨酸激酶的恶性细胞的增生的方法,即化合物可以用于产生通过抑制Ⅰ类受体酪氨酸激酶单独或部分间介的抗增生作用。本发明化合物被预期可以用于通过提供抗增生作用的癌症的治疗,尤其是治疗Ⅰ类受体酪氨酸激酶敏感的癌症如乳腺,肺,结肠,直肠,胃,前列腺,膀胱,胰腺和卵巢的癌。本发明化合物也被期望可以用于治疗其他细胞-增生疾病如牛皮癣,良性前列腺肥大,动脉粥样硬化和再狭窄。
根据本发明的这一方面,提供如前定义的式Ⅰ喹唑啉衍生物,或其药用盐在生产用于在温血动物如人体内产生抗增生作用的医药方面的用途。
根据本发明的另一方面,提供对需要这类治疗的温血动物如人体产生抗增生作用的方法,包括对所说的动物施用有效量的如前定义的喹唑啉衍生物。
如上所述,用于治疗或预防性治疗具体的细胞-增生疾病所需的剂量将必需随所治疗的主体,给药的途径,被治疗疾病的严重性而变化。在例如,1-100mg/kg,优选地1-50mg/kg范围的单位剂量被设想。
如前定义的抗增生治疗可以用作唯一的治疗,或可以包括,除本发明的喹唑啉衍生物之外,常规放射治疗或一种或多种其它抗-肿瘤物质,例如细胞毒性或细胞抑制的抗肿瘤物质,例如选自如下的那些,例如,有丝分裂抑制剂,例如长春花碱,长春花碱酰胺和维诺利宾;烷基化剂,例如顺氯氨铂,卡铂和环磷酰胺;抗代谢剂,例如5-氟尿嘧啶,喃氟啶,甲氨喋呤,阿糖胞苷和羟基脲,或,例如,在欧洲专利申请239362中公开的优选的抗代谢剂之一如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;插入的抗生素,例如阿霉素,巴丝裂霉素C和博来霉素;酶,例如天门冬酰胺酶;拓扑异构酶抑制剂,例如依托赛特和喜树碱;生物应答改进剂,例如干扰素;和抗-激素,例如抗雌性激素剂如他莫昔芬,例如抗雄性激素剂如4’-氰基-3-(4-氟苯基磺酰基)-2-羟基-2-甲基-3’-(三氟甲基)丙酰苯胺或,例如LHRH拮抗剂或LHRH激动剂如古色里林,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欧洲专利申请0296749中公开的,例如2,2’-[5-(1H-1,2,4-三唑-1-基甲基)-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。这类协同治疗可以通过同时,相继或分开服用治疗的单个组分而实现。根据本发明的此方面,提供包含如前定义的喹唑啉衍生物和用于癌症协同治疗的如前定义的附加抗肿瘤物质的药用产物。
如上所述,在本发明中定义的喹唑啉衍生物是有效的抗癌剂,该性质据信是由其Ⅰ类(EGF型)受体酪氨酸激酶抑制性质引起的。这类本发明喹唑啉衍生物预期具有广泛的抗癌性质,因为Ⅰ类受体酪氨酸激酶与许多普通人体癌如白血病和乳腺,肺,结肠,直肠,胃,前列腺,膀胱,胰腺和卵巢癌有关。这样预期本发明的喹唑啉衍生物将具有抗这些癌症的抗-癌活性。另外预期本发明的喹唑啉衍生物将具有抗白血病,淋巴恶性和固体肿瘤如在组织如肝,肾,前列腺和胰腺中的癌和肉瘤范围的活性。
进一步预期本发明的喹唑啉衍生物将具有抗其它细胞-增生疾病如牛皮癣,良性前列腺肥大,动脉粥样硬化和再狭窄的活性。
也预期本发明的喹唑啉衍生物将可以用于治疗其它细胞生长的疾病,其中包括通过受体酪氨酸激酶标记,包括还未确定的受体酪氨酸激酶的畸变细胞。这类疾病包括,例如,炎症,血管生成,血管再狭窄,免疫学疾病,胰腺病,肾病和胚细胞成熟和移植。
本发明现由下列非限制性实施例举例说明,其中,除非另外说明:
(ⅰ)蒸发通过真空旋转蒸发,而处理过程在通过过滤除去残留固体如干燥剂后进行;
(ⅱ)操作在室温进行,即在18-25℃的范围,在惰性气体如氩气氛下进行;
(ⅲ)柱层析(通过闪蒸操作)和中压液相层析(MPLC)用从E.Merck,Darmstadt,Germany得至的Merck Kieselgel硅胶(Art.9385)或Merck Lichroprep RP-18(Art.9303)逆相硅胶上进行;
(ⅳ)产率只用于举例说明,并不一定是可得到的最大值;
(ⅴ)熔点用Mettler SP62自动熔点仪,油浴装置或Koffler热板仪测定。
(ⅵ)式Ⅰ最终产物的结构通过核(一般是质子)磁共振(NMR)和质谱技术证明;以δ尺度和多重峰测量的质子磁共振化学位移值显示如下:s,单峰;d,双峰;t,三重峰;m,多重峰,除非另外说明,式Ⅰ的最终产物溶于CD3SOCD3用于测定NMR值。
(ⅶ)中间体一般不充分表征,纯度通过薄层层析在(TLC),红外(IR)或NMR分析测定;
(ⅷ)使用下列缩写:
DMFN,N-二甲基甲酰胺;
DMAN,N-二甲基乙酰胺;
NMPN-甲基吡咯烷-2-酮;
THF四氢呋喃;
DME1,2-二甲氧基乙烷。
实施例1
搅拌下将四(三苯膦)钯(0)(0.04g)加入6-溴-4-(3-氯-4-氟苯胺基)喹唑啉盐酸盐(0.25g),饱和碳酸氢钠水溶液(1.5ml),4-氰基苯基硼酸二异丙基酯和DMF(10ml)的混合物中。将产生的混合物搅拌并加热回流3小时。将混合物冷却至室温。依次加入氢氧化钠水溶液(5M,2ml)和水,产生的沉淀通过过滤分离,干燥并通过柱层析纯化,用二氯甲烷和甲醇的10∶1混合物作洗脱剂。得到4-(3-氯-4-氟苯胺基)喹唑啉-6-(4-氰基苯基)喹唑啉(0.05g,18%),m.p.>250℃;
NMR谱:7.5(t,1H),7.85(m,1H),7.9(d,1H),8.0-8.15(m,4H),8.2(m,1H),8.55(m,1H),8.65(s,1H),8.9(d,1H),10.0(宽s,1H);
元素分析:实测C,66.1;H,3.3,N,14.3;
C21H12ClFN40.35H2O计算C,66.2;H,3.4,N,14.7%。
用作原料的6-溴-4-(3-氯-4-氟苯胺基)喹唑啉盐酸盐如下得到:
将5-溴代蒽甲酸(15.2g)和甲酰胺(20ml)在140℃加热2小时,然后在190℃加热2小时。将混合物冷却至室温。加入甲醇(20ml),混合物加热回流5分钟。加入水(150ml)并将混合物冷却至室温。沉淀用水洗涤并干燥。得到6-溴-3,4-二氢喹唑啉-4-酮(14.1g)。
将所得的部分(2.85g)原料,亚硫酰氯(30ml)和DMF(4滴)的混合物搅拌并加热回流3小时。将混合物蒸发给出6-溴-4-氯喹唑啉,不经进一步纯化。
所得的原料,3-氯-4-氟苯胺(1.85g)和异丙醇(30ml)的混合物搅拌并加热回流3小时。将混合物冷却至室温并分离固体,依次用异丙醇和乙醚洗涤并干燥。得到6-溴-4-(3-氯-4-氟苯胺基)喹唑啉盐酸盐(2.65g);NMR谱:7.53(t,1H),7.8(m,1H),7.94(d,1H),8.09(m,1H),8.26(m,1H),8.98(s,1H),9.3(d,1H);元素分析:实测C,43.2;H,2.4;N,10.6;C14H8BrClFN31HCl计算C,43.2;H,2.3;N,10.8%.
用作原料的4-氰基苯基硼酸二异丙基酯如下得到:
搅拌下,将正丁基锂(1.6M己烷溶液,1ml)滴加到已经冷却至-78℃的4-溴苄腈(0.254g),硼酸三异丙基酯(0.4ml)和THF(10ml)的混合物中。产生的混合物被搅拌并温热至室温。将混合物蒸发给出所需的原料,不经进一步纯化。
实施例2
搅拌下,将四(三苯膦)钯(0)(0.019g)和苯基硼酸(0.083g)的乙醇(1ml)溶液依次加入6-溴-4-(3-甲基苯氨基)喹唑啉盐酸盐(欧洲专利申请0520722,其实施例9,0.245g),饱和碳酸钠水溶液(0.4ml)和甲苯(1.2ml)。将产生的混合物搅拌并加热回流6小时。将混合物冷却至室温并分配在二氯甲烷和水之间。有机相用水洗涤,干燥(硫酸镁)并蒸发。残余物通过柱层析纯化,用二氯甲烷和乙酸乙酯的4∶1混合物作洗脱剂。得到4-(3-甲基苯氨基)-6-苯基喹唑啉(0.159g),m.p.207-209℃;NMR谱:2.3(s,3H),6.95(d,1H),7.3(t,1H),7.4-7.9(m,8H),8.2(m,1H),8.6(s,1H),8.85(m,1H),9.8(broad s,1H);元素分析:实测C,78.8;H,5.5;N,12.7;C21H17N30.5H2O计算C,78.7;H,5.6;N,13.1%.
实施例3
搅拌下将氢化铝锂(1M乙醚溶液,20ml)滴加到4-(3-氯-4-氟苯胺基)-6-(4-氰基苯基)喹唑啉(0.706g),乙醚(25ml)和THF(25ml)的混合物中,产生的混合物在室温下搅拌16小时。将混合物冷却至0℃。依次加入水(2ml),5M氢氧化钠水溶液(2ml)和水(6ml)并温热至室温。将混合物过滤,滤液蒸发。残余物通过柱层析纯化,用二氯甲烷和甲醇的10∶1混合物作洗脱剂。得到6-(4-氨基甲基苯基)-4-(3-氯-4-氟苯胺基)喹唑啉(0.409g);NMR谱:4.0(s,2H),7.4(t,1H),7.6(d,2H),7.8-8.0(m,4H),8.2(m,2H),8.6(s,1H),8.9(s,1H),10.1(broad s,1H);
实施例4
搅拌下,依次将四(三苯膦)钯(0)(0.05g)和饱和碳酸氢钠水溶液(5ml)加入6-溴-4-(3-氯-4-氟苯胺基)喹唑啉盐酸盐(0.35g),3-呋喃基硼酸(J.Het.Chem.,1975,195;0.208g)和DMF(15ml)的混合物中。将产生的混合物搅拌并加热回流2小时。将混合物冷却至室温并分配在乙酸乙酯和水之间。有机相用水和食盐水洗涤,干燥(硫酸镁)并蒸发。残余物通过柱层析纯化,先用二氯甲烷然后用增加极性的二氯甲烷和甲醇的混合物作洗脱剂。得到4-(3-氯-4-氟苯胺基)-6-(3-呋喃基)喹唑啉;NMR谱:7.16(m,1H),7.48(t,1H),7.82(d,1H),7.85(m,2H),8.16(m,1H),8.18(m,1H),8.35(d,1H),8.61(s,1H),8.7(d,1H),9.88(s,1H);元素分析:实测C,62.8;H,3.4;N,10.8;C18H11ClFN3O0.25H2O计算C,62.8;H,3.3;N,12.2%.
实施例5
搅拌下将四(三苯膦)钯(0)(0.05g)加入6-溴-4-(3-氯-4-氟苯胺基)喹唑啉盐酸盐(0.613g),饱和碳酸氢钠水溶液(10ml),2-呋喃基硼酸二异丙基酯和DME(20ml)的混合物中。将产生的混合物搅拌并加热回流1.5小时。将混合物冷却至室温。依次加入氢氧化钠水溶液(5M,10ml)和水,产生的沉淀通过过滤分离,用少量二氯甲烷洗涤并干燥。得到4-(3-氯-4-氟苯胺基)-6-(2-呋喃基)喹唑啉(0.54g),m.p.232-234℃;NMR谱:6.7(m,1H),7.15(d,1H),7.4(t,1H),7.8(m,3H),8.2(m,2H),8.55(s,1H),8.8(d,1H),10.0(broad s,1H);元素分析:实测C,57.8;H,3.6;N,10.9;C18H11ClFN3O1.9H2O计算C,57.8;H,4.0;N,11.2%.
用作原料的2-呋喃基硼酸二-异丙基酯如下得到:
搅拌下将正丁基锂(1.6M己烷溶液,2.75ml)滴加到已经冷却至0℃的呋喃(0.25g)THF(10ml)溶液。产生的混合物在室温下搅拌20分钟。将混合物冷却至-78℃并滴加硼酸三异丙基酯(1ml)。将混合物温热至室温并搅拌2小时。将混合物蒸发给出所需的原料,不经纯化直接使用。
实施例6
用与实施例5所述类似的过程,所不同的是反应混合物加热回流3小时,6-溴-4-(3-氯-4-氟苯胺基)喹唑啉盐酸盐与2-噻吩基硼酸二-异丙基酯反应给出4-(3-氯-4-氟苯胺基)-6-(2-噻吩基)喹唑啉,产率36%,m.p.205-208℃;NMR谱:7.2(m,1H),7.4(t,1H),7.7(m,2H),7.8(m,2H),8.15(m,2H),8.55(s,1H),8.75(d,1H),10.0(broad s,1H);元素分析:实测C,58.6;H,3.1;N,11.3;C18H11ClFN3S0.75H2O计算C,58.5;H,3.4;N,11.4%.
用作原料的2-噻吩基硼酸二-异丙基酯如下得到:
搅拌下将正丁基锂(1.6M己烷溶液,2ml)滴加到已经冷却至-78℃的2-溴噻吩(0.515g)THF(6ml)溶液。滴加硼酸三异丙基酯(0.75ml),将产生的混合物搅拌并温热至室温。将混合物蒸发给出所需的原料,不经纯化直接使用。
实施例7
用与实施例5所述类似的过程,所不同的是反应混合物加热回流2小时,6-溴-4-(3-氯-4-氟苯胺基)喹唑啉盐酸盐与3-噻吩基硼酸二-异丙基酯反应给出4-(3-氯-4-氟苯胺基)-6-(3-噻吩基)喹唑啉,产率51%,m.p.195-197℃;NMR谱:7.5(t,1H),7.7-7.9(m,4H),8.05(m,1H),8.2(m,1H),8.25(m,1H),8.6(s,1H),8.8(d,1H),9.9(broad s,1H);元素分析:实测C,57.8;H,3.3;N,10.6;C18H11ClFN3S1.15H2O计算C,57.4;H,3.6;N,11.2%.
用作原料的3-噻吩基硼酸二-异丙基酯通过3-溴噻吩和硼酸三异丙基酯用与实施例6中与原料制备有关部分所述类似的过程反应而得到。
实施例8
用与实施例5所述类似的过程,所不同的是反应混合物加热回流4小时,6-溴-4-(3-氯-4-氟苯胺基)喹唑啉盐酸盐与5-(2-吗啉代乙基)噻吩-2-基硼酸二-异丙基酯反应。将反应混合物冷却至室温并分配在二氯甲烷和水之间。有机相用食盐水洗涤,干燥(硫酸镁)并蒸发。残余物用己烷和乙酸乙酯的混合物研制给出4-(3-氯-4-氟苯胺基)-6-[5-(2-吗啉代乙基)噻吩-2-基]喹唑啉,产率27%;NMR谱:2.6-2.7(t,2H),3.0(t,2H),3.65(t,4H),7.0(d,1H),7.45(t,1H),7.55(d,1H),7.8(m,2H),8.1(m,1H),8.2(m,1H),8.6(s,1H),8.75(d,1H),9.95(broad s,1H);元素分析:实测C,59.0;H,4.9;N,11.3;C24H22ClFN4OS1H2O计算C,59.2;H,5.0;N,11.5%.
用作原料的5-(2-吗啉代乙基)噻吩-2-基硼酸二-异丙基酯如下得到:
搅拌下将2-(2-噻吩基)乙酰氯(16g)慢慢加入吗啉(17.5ml)和二氯甲烷(150ml)的混合物中。再加入一批(5ml)吗啉,混合物在室温搅拌4小时。反应混合物依次用2M盐酸水溶液,饱和碳酸氢钠水溶液和食盐水洗涤。将有机相干燥并蒸发。残余物用己烷和乙醚的混合物研制给出N-[2-(2-噻吩基)乙酰基]吗啉(20.9g)。
搅拌下将氢化铝锂(1M乙醚溶液,28.3ml)慢慢加入N-[2-(2-噻吩基)乙酰基]吗啉(3g)的THF(100ml)溶液。产生的混合物加热至45℃30分钟。滴加2M盐酸水溶液破坏过量的还原剂,混合物分配在二氯甲烷和2M氢氧化钠水溶液之间。有机相用食盐水洗涤,干燥(硫酸镁)并蒸发给出2-(2-吗啉代乙基)噻吩(1.7g)。
将所得的部分(1.22g)原料溶于THF(75ml),并将溶液冷却至-78℃。滴加正丁基锂(1.6M己烷溶液,3.86ml),混合物在-78℃搅拌30分钟。加入硼酸三-异丙基酯(1.16ml)的THF(25ml)溶液,然后将反应混合物温热至室温。将混合物蒸发给出5-(2-吗啉代乙基)噻吩-2-基硼酸二-异丙基酯,不经进一步纯化而使用。
实施例9
用与实施例5所述类似的过程,所不同的是反应混合物加热回流2小时,6-溴-4-(3-氯-4-氟苯胺基)喹唑啉盐酸盐与5-吗啉代甲基噻吩-3-基硼酸二-异丙基酯反应。将反应混合物冷却至室温并分配在二氯甲烷和水之间。有机相用食盐水洗涤,干燥并蒸发。残余物通过柱层析纯化,用二氯甲烷和甲醇的25∶1混合物作洗脱剂,得到4-(3-氯-4-氟苯胺基)-6-(5-吗啉代甲基噻吩-3-基)喹唑啉,产率30%;NMR谱:2.5(t,4H),3.6(t,4H),3.75(s,2H),7.45(t,1H),7.6(d,1H),7.8(m,2H),7.95(d,1H),8.22(m,2H),8.6(s,1H),8.75(d,1H),9.9(broad s,1H);元素分析:实测C,58.5;H,4.8;N,11.7;C23H20ClFN4OS1H2O计算C,58.4;H,4.7;N,11.8%.
用作原料的5-吗啉代甲基噻吩-3-基硼酸二-异丙基酯如下得到:
搅拌下将氰基硼氢化钠(2g)分批加入4-溴-2-噻吩甲醛(4.78g),吗啉(2.1g),冰乙酸(1.8g)和乙醇(125ml)的混合物中。混合物在室温搅拌1小时。混合物倒入饱和碳酸氢钠水溶液中,用二氯甲烷萃取。有机相用食盐水洗涤并蒸发。产生的油状物分配在稀(10%)盐酸水溶液和二氯甲烷之间。水相通过加入饱和碳酸氢钠水溶液而碱化,用二氯甲烷萃取。有机萃取液干燥(硫酸镁)并蒸发给出4-溴-2-吗啉代甲基噻吩(3.2g);NMR谱:2.4(t,4H),3.55(t,4H),3.65(s,2H),6.95(d,1H),7.5(d,1H).
将所得的部分(1.22g)原料溶于THF(100ml),并将溶液冷却至-78℃。依次加入硼酸三异丙基酯(0.963g)和正丁基锂(1.6M己烷溶液,2.91ml)。混合物在-78℃搅拌30分钟然后温热至室温。将混合物蒸发给出5-吗啉代甲基噻吩-3-基硼酸二-异丙基酯,不经进一步纯化而使用。
实施例10
将6-(2-氯代乙酰基)-4-(3-氯-4-氟苯胺基)喹唑啉(0.5g)和甲酰胺(2ml)的混合物搅拌并加热至140℃2小时。将混合物冷却至室温并加入水。分离出沉淀并在C18逆相硅胶柱上用水和甲醇(含有0.2%三氟乙酸)的降低极性的混合物作洗脱剂纯化。依次得到:
4-(3-氯-4-氟苯胺基)-6-(4-咪唑基)喹唑啉(0.135g);NMR谱:7.54(t,1H),7.78(m,1H),7.94(d,1H),8.07(d,1H),8.12(m,1H),8.38(m,1H),8.81(s,1H),8.82(s,1H),9.01(s,1H);元素分析:实测C,42.9;H,2.5;N,11.4;C17H11ClFN51.4H2O2CF3CO2H计算C,42.5;H,2.7;N,11.8%.
4-(3-氯-4-氟苯胺基)-6-(4-噁唑基)喹唑啉(0.056g);NMR谱:7.53(t,1H),7.8(m,1H),7.93(d,1H),8.12(m,1H),8.42(m,1H),8.65(s,1H),8.8(s,1H),8.88(s,1H),9.1(d,1H);元素分析:实测C,47.0;H,2.3;N,11.2;C17H11ClFN4O1.5CF3CO2H计算C,46.9;H,2.3;N,10.9%.
用作原料的6-(2-氯代乙酰基)-4-(3-氯-4-氟苯胺基)喹唑啉如下得到:
搅拌下将三苯膦(0.063g)加入6-溴-4-(3-氯-4-氟苯胺基)喹唑啉盐酸盐(2.34g),三乙胺(3.4ml),(三甲基甲硅烷基)乙炔(1.33ml),氯化钯(Ⅱ)(0.021g),碘化亚铜(0.045g)和DMF(15ml)的混合物中。将混合物搅拌并加热至90℃2小时。将混合物蒸发,残余物通过柱层析纯化,用二氯甲烷和甲醇增加极性的混合物作洗脱剂。得到4-(3-氯-4-氟苯胺基)-6-(2-三甲基甲硅烷基乙炔基)喹唑啉(2.2g)。
将部分(2g)这样得到的物质,碳酸钾(0.25g)和甲醇(100ml)的混合物在室温下搅拌2小时。混合物通过加入冰乙酸酸化至pH5。将产生的混合物蒸发,残余物分配在二氯甲烷和水之间。将有机相干燥(硫酸镁)并蒸发。得到4-(3-氯-4-氟苯胺基)-6-乙炔基喹唑啉(1.68g),m.p.224-226℃;NMR谱:4.42(s,1H),7.45(t,1H),7.59(d,1H),7.8-7.93(m,2H),8.23(m,1H),8.65(s,1H),8.77(s,1H),9.8(broad s,1H);
部分(1.2g)所得的物质,三氟乙酸汞(0.1g),水(1ml)和三氟乙酸(15ml)的混合物搅拌并加热回流4小时。将混合物蒸发,残余物通过柱层析纯化,用二氯甲烷和甲醇增加极性的混合物作洗脱剂。所得的物质用二氯甲烷研制。得到6-乙酰基-4-(3-氯-4-氟苯胺基)喹唑啉(0.37g),m.p.211-213℃;NMR谱:2.75(s,3H),7.47(t,1H),7.83(m,1H),7.88(d,1H),8.14(m,1H),8.33(m,1H),8.69(s,1H),9.19(d,1H);
搅拌下将氯气导入6-乙酰基-4-(3-氯-4-氟苯胺基)喹唑啉(0.11g),二氯甲烷(40ml)和乙醇(60ml)的混合物中,将混合物冷却至20至25℃的温度范围。10分钟后停止供应氯气,反应混合物在室温下搅拌1小时。将混合物蒸发给出6-(2-氯代乙酰基)-4-(3-氯-4-氟苯胺基)喹唑啉(0.114g),不经纯化直接使用。
实施例11
6-溴-4-(3-氯-4-氟苯胺基)喹唑啉(0.5g),2-吡啶基-三-正丁基锡(J.Het.Chem.,1990,2165;0.8g),四(三苯膦)钯(0)(0.05g)和THF(20ml)的混合物搅拌并在60℃加热4天。将混合物蒸发,残余物通过柱层析纯化,先用二氯甲烷,然后用二氯甲烷和甲醇增加极性的混合物作洗脱剂。得到4-(3-氯-4-氟苯胺基)-6-(2-吡啶基)喹唑啉(0.11g);NMR谱:7.45(m,1H),7.47(t,1H),7.88(m,1H),7.9(d,1H),8.03(m,1H),8.18(d,1H),8.22(d,1H),8.63(m,1H),8.66(s,1H),8.75(m,1H),9.19(d,1H);元素分析:实测C,61.5;H,3.6;N,14.9;C19H12ClFN41.1H2O计算C,61.6;H,3.8;N,15.1%.
实施例12
将二乙基-3-吡啶基硼烷(0.176g)加入6-溴-4-(3-氯-4-氟苯胺基)喹唑啉(0.53g),粉状氢氧化钾(0.202g),溴化四正丁基铵(0.042g),四(三苯膦)钯(0)(0.069g)和THF(10ml)的混合物中。将产生的混合物搅拌并加热回流16小时。将混合物蒸发,残余物通过柱层析纯化,先用二氯甲烷然后用二氯甲烷和甲醇增加极性的混合物作洗脱剂。得到4-(3-氯-4-氟苯胺基)-6-(3-吡啶基)喹唑啉(0.125g);NMR谱:7.5(t,1H),7.6(m,1H),7.88(m,1H),7.93(d,1H),8.2(m,1H),8.28(m,1H),8.3(m,1H),8.68(m,2H),8.91(d,1H),9.16(d,1H),10.02(broad s,1H);元素分析:实测C,64.3;H,3.3;N,15.6;C19H12ClFN40.25H2O计算C,64.2;H,3.5;N,15.8%.
实施例13
将6-氨基-4-(3-氯-4-氟苯胺基)喹唑啉(0.576g),4-氯喹唑啉盐酸盐(0.83g)和异丙醇(10ml)的混合物搅拌并加热回流5小时。将热的反应溶液过滤,将滤液冷却至室温。分离产生的固体,用异丙醇和乙醚洗涤并干燥。得到4-(3-氯-4-氟苯胺基)-6-(4-喹唑啉二盐酸盐(0.86g);NMR谱:7.54(t,1H),7.8(m,1H),7.92(t,1H),8.0-8.2(m,4H),8.38(m,1H),8.97(s,1H),9.06(d,1H),9.28(d,1H),11.75(broads,1H),12.26(broad s,1H);元素分析:实测C,53.4;H,3.4;N,16.9;C22H14ClFN62HCl0.33H2O计算C,53.2;H,3.4;N,16.9%.
用作原料的6-氨基-4-(3-氯-4-氟苯胺基)喹唑啉如下得到:
搅拌下将3-氯-4-氟苯胺(3.6g)加入4-氯-6-硝基喹唑啉(欧洲专利申请0566226,其实施例8;5g),THF(10ml)和DMF(10ml)的混合物中。产生的混合物在室温下搅拌5小时。分离出沉淀并分配在水和二氯甲烷和甲醇的9∶1混合物之间。水相通过加入饱和碳酸氢钠水溶液中和并用二氯甲烷再萃取。将有机相合并并蒸发。残余物用乙醇和水9∶1混合物研制。分离产生的固体并干燥。得到4-(3-氯-4-氟苯胺基)-6-硝基喹唑啉(2.5g)。
部分(2.3g)所得的物质,10%Pd/C催化剂(0.4g),乙醇(25ml)和DMF(25ml)的混合物在氢气氛中搅拌2小时。将混合物过滤,滤液蒸发。残余物用乙醇和水4∶1的混合物研制。产生的固体被分离和干燥。得到6-氨基-4-(3-氯-4-氟苯胺基)喹唑啉(0.35g,17%);NMR谱:5.6(broad s,2H),7.27(m,1H),7.32(s,1H),7.41(t,1H),7.55(d,1H),7.8(m,1H),8.19(m,1 H),8.38(s,1H),9.53(broads,1H);元素分析:实测C,58.1;H,3.6;N,19.0;C14H10ClFN4计算C,58.2;H,3.5;N,19.4%.
实施例14
将6-氨基-4-(3-甲基苯氨基)喹唑啉(欧洲专利申请0566226,其实施例8;0.2g),2-氟咪唑4-甲苯磺酸盐(0.2g),4-甲苯磺酸(0.26g)和DMF(1ml)的混合物搅拌并加热至100℃16小时。将混合物冷却至室温并分配于二氯甲烷和饱和碳酸氢钠水溶液之间。有机相被干燥(硫酸镁)并蒸发,残余物通过柱层析纯化,用二氯甲烷和甲醇9∶1的混合物作洗脱剂。得到6-(2-咪唑基氨基)-4-(3-甲基苯氨基)喹唑啉(0.09g),m.p.256-258℃;NMR谱:2.33(s,3H),6.77(d,2H),6.95(d,1H),7.24(t,1H),7.6(m,3H),7.85(m,1H),8.11(m,1H),8.39(s,1H),8.94(s,1H),9.4(s,1H),11.0(s,1H);元素分析:实测C,68.1;H,5.3;N,26.4;C18H16N6计算C,68.3;H,5.1;N,26.6%.
用作原料的2-氟咪唑4-甲苯磺酸盐从2-氨基咪唑用与J.Het.Chem.,1978,1227和J.Amer.Chem.Soc.,1973,4619所述类似的方法获得。
实施例15
搅拌下将1-甲基咪唑-4-磺酰氯(0.181g)加入6-氨基-4-(3-甲基苯氨基)喹唑啉(0.25g)和吡啶(10ml)的混合物中,混合物在室温下搅拌16小时。将混合物蒸发,残留的油状固体用二氯甲烷和饱和碳酸氢钠水溶液洗涤。固体然后用水和丙酮洗涤并干燥。得到4-(3-甲基苯氨基)-6-(1-甲基咪唑-4-磺酰氨基)喹唑啉(0.07g),m.p.>250℃;NMR谱:(CD3SOCD3+CD3CO2D)2.37(s,3H),3.64(s,3H),6.98(d,1H),7.27(t,1H),7.5-7.8(m,6H),8.2(d,1H),8.48(s,1H);元素分析:实测C,54.7;H,4.4;N,19.7;C19H18N6O2S1.2H2O计算C,54.8;H,4.9;N,20.2%.
实施例16
搅拌下将氰基硼氢化钠(0.126g)分批加入6-氨基-4-(3-甲基苯氨基)喹唑啉(0.25g),3-噻吩甲醛(0.26ml),冰乙酸(0.114ml)和乙醇(20ml)的混合物中。产生的混合物在室温下搅拌16小时。混合物通过加入饱和碳酸氢钠水溶液碱化并蒸发。残余物用水洗涤并干燥。得到4-(3-甲基苯氨基)-6-(3-噻吩基甲基氨基)喹唑啉(0.335g),m.p.207-208℃;NMR谱:2.3(s,3H),4.45(d,2H),6.52(d,1H),6.9(t,1H),7.2(m,1H),7.3(m,3H),7.5(m,3H),7.65(m,2H),8.3(s,1H),9.2(broad s,1H);元素分析:实测C,68.6;H,5.2;N,15.3;C20H18N4S0.3H2O计算C,68.3;H,5.3;N,15.9%.
实施例17
搅拌下将氰基硼氢化钠(0.126g)分批加入6-氨基-4-(3-甲基苯氨基)喹唑啉(0.25g),2-咪唑甲醛(0.192g),冰乙酸(0.114ml)和乙醇(20ml)的混合物中。产生的混合物在室温下搅拌3小时。混合物通过加入饱和碳酸氢钠水溶液碱化并蒸发。残余物用水洗涤并干燥。得到6-(2-咪唑基甲基氨基)-4-(3-甲基苯氨基)-喹唑啉(0.096g),m.p.235-237℃;NMR谱:(CD3SOCD3+CD3CO2D,100℃)2.3(s,3H),4.45(d,2H),6.5(t,1H),6.9(d,1H),7.1(s,2H),7.3(m,3H),7.5(d,1H),7.65(m,2H),8.3(s,1H),9.2(s,1H),12.0(s,1H);元素分析:实测C,67.4;H,5.3;N,24.8;C19H18N60.5H2O计算C,67.3;H,5.6;N,24.8%.
实施例18
搅拌下将2-噻吩羰基氯(0.6g)分批加入6-氨基-4-(3-氯-4-氟苯胺基)喹唑啉(1.04g)的DMA(10ml)溶液中。混合物在室温下搅拌30分钟。加入二氯甲烷(25ml),将沉淀分离并干燥。得到4-(3-氯-4-氟苯胺基)-6-(噻吩-2-甲酰胺基)喹唑啉盐酸盐(1.35g),m.p.>250℃;NMR谱:7.27(m,1H),7.54(t,1H),7.7(m,1H),7.9(m,1H),8.0(m,2H),8.28(m,2H),8.9(s,1H),9.2(d,1H),10.99(s,1H),11.52(broads,1H);元素分析:实测C,52.1;H,3.3;N,12.9;C19H12ClFN4OS1HCl0.15DMA计算C,52.5;H,3.2;N,13.0%.
实施例19
搅拌下将氢化铝锂(1M乙醚溶液,7.1ml)滴加到4-(3-氯-4-氟苯胺基)-6-(噻吩-2-甲酰胺基)喹唑啉盐酸盐(1g)和THF(200ml)的混合物中。混合物在室温下搅拌2小时然后加热至45℃1小时。将混合物冷却至室温,并加入冰乙酸(5ml)破坏过量的还原剂。将混合物蒸发,残余物分配在二氯甲烷和5M氢氧化钠水溶液之间。有机相用食盐水洗涤,干燥并蒸发。残余物通过柱层析纯化,用二氯甲烷和甲醇99∶1的混合物作洗脱剂。所得的产物用乙醚研制。得到4-(3-氯-4-氟苯胺基)-6-(2-噻吩基甲基氨基)喹唑啉(0.095g),m.p.193-195℃;NMR谱:4.65(d,2H),6.75(t,1H),7.0(m,1H),7.4(m,4H),7.55(d,1H),7.8(m,1H),8.15(m,1H),8.4(s,1H),9.4(broads,1H);元素分析:实测C,59.3;H,3.8;N,14.0;C19H14ClFN4S0.1Et2O计算C,59.4;H,3.85;N,14.3%.
实施例20
搅拌下将2-呋喃甲酰氯(0.287g)分批加入6-氨基-4-(3-氯-4-氟苯胺基)喹唑啉(0.577g)的DMA(3ml)溶液,产生的混合物在室温下搅拌18小时。将混合物蒸发,残余物通过柱层析纯化,用二氯甲烷和甲醇增加极性的混合物作洗脱剂。得到4-(3-氯-4-氟苯胺基)-6-(呋喃-2-甲酰胺)喹唑啉(0.436g);NMR谱:6.7(m,1H),7.56(m,2H),7.69(m,1H),8.0(m,3H),8.27(m,1H),8.91(s,1H),9.13(d,1H),10.85(broad s,1H),11.5(broad s,1H);元素分析:实测C,54.3;H,3.1;N,13.3;C19H12ClFN4O2计算C,54.3;H,3.1;N,13.4%.
实施例21
用与实施例19所述类似的方法,将4-(3-氯-4-氟苯胺基)-6-(呋喃-2-甲酰胺基)喹唑啉还原给出4-(3-氯-4-氟苯胺基)-6-(2-呋喃基氨基)喹唑啉,产率16%,m.p.197-199℃;NMR谱:4.45(d,2H),6.4(m,1H),6.7(m,1H),7.3-7.6(m,5H),7.8(m,1H),8.15(m,1H),8.4(s,1H),9.5(m,1H);元素分析:实测C,59.8;H,3.7;N,14.5;C19H14ClFN4O0.2CH2Cl2计算C,59.8;H,3.8;N,14.5%.
实施例22
用与实施例18所述类似的方法,6-氨基-4-(3-氯-4-氟苯胺基)喹唑啉与5-异噁唑羰基氯反应给出4-(3-氯-4-氟苯胺基)-6-(异噁唑-5-甲酰胺基)喹唑啉盐酸盐,产率87%,m.p.>250℃;NMR谱:7.4(d,1H),7.5(t,1H),7.65(m,2H),8.0(m,2H),8.85(d,1H),8.9(s,1H),11.4(s,1H);元素分析:实测C,50.8;H,3.3;N,16.3;C18H11ClFN5O21HCl0.4H2O0.24CMA计算C,50.8;H,3.4;N,16.4%.
实施例23
搅拌下将N,N’-二环己基碳环二亚胺(0.416g)分批加入1,2,3-三唑-4-羧酸(0.226g)和DMA(10ml)的混合物中。产生的混合物在室温下搅拌2小时。将6-氨基-4-(3-氯-4-氟苯胺基)喹唑啉(0.576g)的DMA(5ml)溶液加入,混合物在室温下搅拌16小时。将混合物蒸发,残余物通过柱层析纯化,用二氯甲烷∶甲醇∶三乙胺的9∶1∶0.2混合物作洗脱剂。得到4-(3-氯-4-氟苯胺基)-6-(1,2,3-三唑-4-甲酰胺基)喹唑啉(0.145g);NMR谱:7.43(m,1H),7.82(d,1H),7.95(m,1H),8.18(m,2H),8.43(s,1H),8.58(s,1H),8.88(d,1H),9.89(s,1H),10.55(s,1H);元素分析:实测C,55.6;H,5.8;N,21.4;C17H11ClFN7O0.8H2O1.1Et3N计算C,55.6;H,5.7;N,22.3%.
实施例24
搅拌下将3-吡啶羰基氯盐酸盐(0.107g)分批加入6-氨基-4-(3-氯-4-氟苯胺基)-7-甲基氨基喹唑啉(欧洲专利申请0635507,其实施例3中;0.11g),三乙胺(0.101g)和DDMA(1ml)的混合物中。将混合物加热至100℃3小时。将混合物蒸发,残余物通过柱层析纯化,用C18逆相硅胶柱和水和甲醇(含0.2%三氟乙酸)增加极性的混合物作洗脱剂。所得的物质悬浮于水中,通过加入氢氧化铵水溶液碱化。产生的混合物在室温下搅拌2小时。分离固体用水洗涤并干燥。得到4-(3-氯-4-氟苯胺基)-7-甲基氨基-6-(吡啶-3-甲酰胺基)喹唑啉(0.061g),m.p.>260℃;NMR谱:2.83(d,3H),6.41(m,1H),6.7(s,1H),7.38(m,1H),7.6(m,1H),7.84(m,1H),8.19(m,1H),8.29(s,1H),8.42(m,1H),8.48(s,1H),8.79(m,1H),9.24(d,1H),9.5(s,1H);元素分析:实测C,55.1;H,4.0;N,18.4;C21H16ClFN6O2H2O计算C,54.9;H,4.4;N,18.3%.
实施例25
将4-(3-氯-4-氟苯胺基)-6-羟基喹唑啉(0.87g),4-氟苄腈(0.423g),碳酸钾(0.828g)和DMA(5ml)的混合物搅拌并加热至120℃4小时。将混合物冷却至室温并分配在乙酸乙酯和水之间。将有机相干燥(硫酸镁)并蒸发。残余物用二氯甲烷和甲醇的混合物研制。得到4-(3-氯-4-氟苯胺基)-6-(4-氰基苯氧基)喹唑啉(0.54g);NMR谱:7.21(d,2H),7.43(t,1H),7.72(m,1H),7.82(m,1H),7.88(d,2H),7.93(d,1H),8.18(m,1H),8.39(d,1H),8.68(s,1H);元素分析:实测C,63.9;H,3.0;N,14.1;C21H12ClFN4O0.2H2O计算C,64.0;H,3.2;N,14.2%.
用作原料的4-(3-氯-4-氟苯胺基)-6-羟基喹唑啉如下得到:
将6-乙酰氧基-4-氯喹唑啉(欧洲专利申请0566226,实施例34,Note c;54g),3-氯-4-氟苯胺(35.6g)和异丙醇(850ml)的混合物搅拌并加热回流90分钟,然后在室温下放置16小时。分离沉淀并轮流用异丙醇和乙醚洗涤。得到6-乙酰氧基-4-(3-氯-4-氟苯胺基)喹唑啉(43.7g,49%)。
搅拌下将浓氢氧化铵水溶液(30%重量/体积,35ml)加入G-乙酰氧基-4-(3-氯-4-氟苯胺基)喹唑啉(22g)和甲醇(200ml)的混合物中,混合物加热回流3小时。将混合物蒸发,往残余物中加入水(300ml)。将固体分离,轮流用水(100ml)和乙醇(60ml)洗涤并干燥。得到4-(3-氯-4-氟苯胺基)-6-羟基喹唑啉(16.1g,93%);NMR谱:7.43(t,1H),7.45(m,1H),7.70(d,1H),7.78(d,1H),7.88(m,1H),8.24(m,1H),8.5(s,1H),9.6(broad s,1H),10.1(broads,1H);
实施例26
将4-(3-氯-4-氟苯胺基)-6-羟基喹唑啉(5g),4-氟硝基苯(2.67g),碳酸钾(4.74g)和DMA(50ml)的混合物搅拌并加热至70℃10分钟。将混合物冷却至室温,然后搅拌下滴加到冰和水的浆状物中。将产生的沉淀分离,轮流用水,小体积的甲醇和乙醚洗涤并干燥。得到4-(3-氯-4-氟苯胺基)-6-(4-硝基苯氧基)喹唑啉(6.8g);NMR谱:7.27(d,2H),7.43(t,1H),7.75(m,1H),7.8(m,1H),7.97(d,1H),8.18(m,1H),8.29(d,2H),8.42(d,1H),8.69(s,1H);元素分析:实测C,58.1;H,2.8;N,13.4;C20H12ClFN4O3计算C,58.5;H,2.9;N,13.6%.
实施例27
将4-(3-氯-4-氟苯胺基)-6-(4-硝基苯氧基)喹唑啉(6g),10%Pd/C催化剂(0.6g)和DMA(250ml)的混合物搅拌并在氢气氛中加热至60℃2小时。将混合物过滤,滤液被蒸发。残余物通过柱层析纯化,先用二氯甲烷然后用二氯甲烷和甲醇增加极性的混合物作洗脱剂。所得的产物用甲醇研制。得到6-(4-氨基苯氧基)-4-(3-氯-4-氟苯胺基)喹唑啉(2.3g);NMR谱:5.0(broad s,2H),6.63(d,2H),6.84(d,2H),7.42(t,1H),7.45(m,1H),7.78(d,1H),7.85(m,1H),8.08(d,1H),8.17(m,1H),8.57(s,1H),9.75(s,1H);元素分析:实测C,62.7;H,3.8;N,14.7;C20H14ClFN4O计算C,63.1;H,3.7;N,14.7%.
实施例28
搅拌下将亚硝酸叔丁基酯(0.243g)加入6-(4-氨基苯氧基)-4-(3-氯-4-氟苯胺基)喹唑啉(0.45g)的DMF(25ml)溶液中,混合物加热至90℃3小时。将混合物冷却至室温,并通过加入冰乙酸而酸化。将混合物蒸发,残余物通过柱层析纯化,用二氯甲烷和甲醇增加极性的混合物作洗脱剂。得到4-(3-氯-4-氟苯胺基)-6-苯氧基喹唑啉(0.207g);NMR谱:7.0-7.3(m,5H),7.32(d,1H),7.35-7.6(m,3H),7.9(m,1H),7.93(d,1H),8.73(s,1H);元素分析:实测C,62.6;H,3.9;N,11.5;C20H13ClFN3O1H2O计算C,62.6;H,3.9;N,11.5%.
实施例29
搅拌下将4-(3-氯-4-氟苯胺基)-6-(4-氰基苯氧基)喹唑啉(2.7g)分批加入氢化铝锂(1M THF溶液,10ml)和乙醚(50ml)的混合物中。产生的混合物在室温下搅拌1小时。滴加冰乙酸破坏过量的还原剂。将混合物分配在乙酸乙酯和稀氢氧化铵溶液之间。将有机相干燥(硫酸镁)并蒸发。残余物通过柱层析纯化,用二氯甲烷和甲醇增加极性的混合物作洗脱剂。得到6-(4-氨基甲基苯氧基)-4-(3-氯-4-氟苯胺基)喹唑啉(1.8g);NMR谱:3.23(s,2H),3.8(broad s,2H),7.18(d,2H),7.43(d,2H),7.47(t,1H),7.6(m,1H),7.86(m,1H),7.9(d,1H),8.22(m,1H),8.31(d,1H),8.65(s,1H);元素分析:实测C,61.0;H,4.4;N,13.3;C21H16ClFN4O1H2O计算C,61.1;H,4.4;N,13.6%.
实施例30
搅拌下将二-(2-溴代乙基)醚(0.28g)加入6-(4-氨基甲基苯氧基)-4-(3-氯-4-氟苯胺基)喹唑啉(0.5g),碳酸钾(0.33g)和DMA(5ml)的混合物中。将产生的混合物搅拌并加热至70℃30分钟。将混合物蒸发,残余物通过柱层析纯化,用二氯甲烷和甲醇增加极性的混合物作洗脱剂。得到4-(3-氯-4-氟苯胺基)-6-(4-吗啉代甲基苯氧基)喹唑啉(0.192g);NMR谱:2.37(broad s,4H),3.49(s,2H),3.62(broad s,4H),7.02(d,2H),7.34(d,2H),7.41(t,1H),7.58(m,1H),7.82(m,2H),8.2(m,2H),8.62(s,1H),9.79(broad s,1H);元素分析:实测C,63.4;H,5.0;N,12.0;C25H22ClFN4O20.5H2O计算C,63.4;H,4.9;N,11.8%.
实施例31
将6-溴代甲基-4-(3-甲基苯氨基)喹唑啉(欧洲专利申请0566226,其实施例35;0.3g),咪唑(0.264g)和乙醇(4ml)的混合物在室温下搅拌4小时。将混合物蒸发,残余物在C18逆相硅胶柱上用水和甲醇,各含0.2%三氟乙酸,降低极性的混合物作洗脱剂。得到6-(1-咪唑基甲基)-4-(3-甲基苯氨基)喹唑啉(0.27g),m.p.151-155℃;NMR谱:2.37(s,3H),5.66(s,2H),7.07(d,1H),7.36(t,1H),7.53(s,1H),7.58(d,1H),7.74(m,1H),7.8(d,1H),7.88(d,1H),7.97(m,1H),8.69(s,1H),8.79(s,1H),9.26(s,1H),10.78(broads,1H);元素分析:实测C,49.1;H,3.8;N,12.2;C19H17N52CF3CO2H1H2O计算C,49.2;H,3.7;N,12.5%.
实施例32
将4-(3-氯-4-氟苯胺基)-6-羟基-7-甲氧基喹唑啉(0.5g),2-氯甲基吡啶盐酸盐(0.282g),碳酸钾(1.5g)和DMF(15ml)的混合物搅拌并加热至80℃2小时。将混合物冷却至室温并倒入水中。将沉淀分离并用甲醇重结晶。得到4-(3-氯-4-氟苯胺基)-7-甲氧基-6-(2-吡啶基甲氧基)喹唑啉(0.37g);NMR谱:3.98(s,3H),5.35(s,2H),7.26(s,1H),7.4(m,2H),7.64(m,1H),7.8(m,1H),7.9(m,1H),8.01(s,1H),8.15(m,1H),8.51(s,1H),8.62(m,1H),9.56(s,1H);元素分析:实测C,61.1;H,4.0;N,13.5;C21H16ClFN4O2计算C,61.4;H,3.9;N,13.6%.
用作原料的4-(3-氯-4-氟苯胺基)-6-羟基-7-甲氧基喹唑啉如下得到:
搅拌下将6,7-二甲氧基-3,4-二氢喹唑啉-4-酮(欧洲专利申请0566226,其实施例1;26.5g)分批加入甲磺酸(175ml)中。加入L-甲硫氨酸(22g),将产生的混合物搅拌并加热回流5小时。将混合物冷却至室温并倒入冰和水的混合物(750ml)中。混合物通过加入浓(40%)氢氧化钠水溶液而中和。将沉淀分离,用水洗涤并干燥。得到6-羟基-7-甲氧基-3,4-二氢喹唑啉-4-酮(11.5g)。
重复前面的反应后,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)搅拌并加热至100℃2小时。将混合物倒入冰和水的混合物(200ml)中。将沉淀分离,用水洗涤并干燥。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(broad s,1H);
重复前面的反应后,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℃4小时。将混合物冷却至室温,蒸发亚硫酰氯。得到6-乙酰氧基-4-氯-7-甲氧基喹唑啉盐酸盐,不经纯化直接使用。
所得的物质,3-氯-4-氟苯胺(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,分离沉淀物,轮流用异丙醇和甲醇洗涤然后干燥。得到6-乙酰氧基-4-(3-氯-4-氟苯胺基)-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);
搅拌下将浓氢氧化铵水溶液(30重量/体积,7.25ml)加入所得的物质和甲醇(520ml)的混合物中。将混合物在室温下搅拌17小时然后加热至100℃1.5小时。将混合物冷却,分离沉淀并干燥。得到4-(3-氯-4-氟苯胺基)-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33
用与实施例32类似的方法,4-(3-氯-4-氟苯胺基)-6-羟基-7-甲氧基喹唑啉与3-氯甲基吡啶盐酸盐反应给出4-(3-氯-4-氟苯胺基)-7-甲氧基-6-(3-吡啶基甲氧基)喹唑啉,产率18%;NMR谱:3.93(s,3H),5.28(s,2H),7.16(s,1H),7.4(m,2H),7.75(m,1H),7.95(m,1H),8.1(m,2H),8.4(s,1H),8.6(m,1H),8.75(m,1H);元素分析:实测C,61.0;H,3.9;N,13.5;C21H16ClFN4O2计算C,61.4;H,3.9;N,13.6%.
实施例34
将6-溴代甲基-4-(3-甲基苯氨基)喹唑啉(0.3g),4-巯基-1,2,3-三唑二钠盐(0.535g)和DMF(3ml)的混合物在室温下搅拌3小时。将混合物蒸发,残余物通过柱层析纯化,用C18逆相硅胶柱,甲醇和水,各含0.2%三氟乙酸,的1∶1混合物作洗脱剂。得到4-(3-甲基苯氨基)-6-(1,2,3-三唑-4-基硫基甲基)喹唑啉(0.22g),m.p.64-68℃;NMR谱:2.38(s,3H),4.36(s,2H),7.15(d,1H),7.38(t,1H),7.49(m,2H),7.83(s,1H),8.0(m,1H),8.58(d,1H),8.87(s,1H),11.2(broad s,1H);元素分析:实测C,47.5;H,3.4;N,16.0;C18H16N6S1.6CF3CO2H0.25H2O计算C,47.6;H,3.4;N,15.7%.
实施例35
用与实施例34所述类似的方法,6-溴甲基-4-(3-甲基苯氨基)喹唑啉与2-巯基-1-甲基咪唑钠盐[通过2-巯基-1-甲基咪唑和乙醇钠乙醇溶液反应而制备]给出4-(3-甲基苯氨基)-6-(N-甲基咪唑-2-基硫基甲基)喹唑啉,产率65%,m.p.137-139℃;NMR谱:2.42(s,3H),3.6(s,3H),4.48(s,2H),6.97(d,1H),7.13(d,1H),7.39(t,1H),7.55(m,2H),7.6(d,1H),7.83(d,1H),7.93(m,1H),8.5(s,1H),8.83(s,1H),10.9(broad s,1H);元素分析:实测C,48.3;H,3.6;N,11.6;C20H19N5S2CF3CO2H0.5H2O计算C,48.1;H,3.5;N,11.7%.
实施例36
将6-溴甲基-4-(3-甲基苯氨基)喹唑啉(1.6g),2-巯基咪唑(0.316g)和DMF(20ml)的混合物搅拌并在60℃加热6小时。将混合物冷却至室温并蒸发。残余物通过柱层析纯化,用二氯甲烷和甲醇增加极性的混合物作洗脱剂。得到6-(2-咪唑基硫基甲基)-4-(3-甲基苯氨基)喹唑啉(0.43g),m.p.217-219℃;NMR谱:2.33(s,3H),4.45(s,2H),6.97(d,1H),7.12(s,2H),7.29(m,1H),7.64(m,2H),7.72(m,2H),8.47(s,1H),8.57(s,1H);元素分析:实测C,65.8;H,4.6;N,19.9;C19H17N5S计算C,65.7;H,4.9;N,20.2%.
实施例37
用与实施例34所述类似的方法,6-溴甲基-4-(3-甲基苯氨基)喹唑啉与2-巯基苯并咪唑钠盐反应给出6-(2-苯并咪唑基硫基甲基)-4-(3-甲基苯氨基)喹唑啉,产率59%,m.p.123-129℃;NMR谱:2.34(s,3H),4.77(s,2H),6.96(d,1H),7.13(m,2H),7.28(t,1H),7.46(broad s,2H),7.68(m,3H),7.96(m,1H),8.57(s,1H),8.65(d,1H),9.79(broad s,1H);元素分析:实测C,64.9;H,5.3;N,15.9;C23H19N5S1.6H2O0.1CH3OH计算C,64.5;H,5.3;N,16.3%.
实施例38
用与实施例5所述类似的方法,6-溴-4-[3-甲基-4-(2-吡啶基甲氧基)苯氨基]喹唑啉二盐酸盐与2-噻吩基硼酸二-异丙基酯反应给出4-[3-甲基-4-(2-吡啶基甲氧基)苯氨基]-6-(2-噻吩基)喹唑啉,产率70%,m.p.205-206℃;NMR谱:2.3(s,3H),5.2(s,2H),7.0(d,1H),7.2(m,1H),7.35(m,1H),7.5(m,3H),7.6(m,1H),7.7(m,1H),7.75(d,1H),7.85(m,1H),8.1(m,1H),8.48(s,1H),8.55(m,1H),8.75(d,1H),9.8(broads,1H);元素分析:实测C,70.8;H,4.7;N,13.0;C25H20N4OS计算C,70.7;H,4.75;N,13.2%.
用作原料的6-溴-4-[3-甲基-4-(2-吡啶基甲氧基)苯氨基]喹唑啉二盐酸盐如下制备:
将氢化钠(在矿物油中60%分散液,1.24g)加入2-吡啶基甲醇(2.49ml)的NMP(100ml)溶液中,混合物在室温下搅拌15分钟。加入2-氟-5-硝基甲苯(4g),混合物在140℃加热2.5小时。将混合物冷却至室温,倒入水(300ml)中并搅拌30分钟。分离出沉淀,用水洗涤并干燥。所得的物质通过柱层析纯化,用二氯甲烷和甲醇增加极性的混合物作洗脱剂。得到5-硝基-2-甲苯基-2-吡啶基甲基醚(1.61g,26%);NMR谱:2.32(s,3H),5.35(s,2H),7.21(d,1H),7.35(m,1H),7.55(d,1H),7.85(m,1H),8.09(m,1H),8.1(s,1H),8.6(m,1H);
将5-硝基-2-甲苯基-2-吡啶基甲基醚(2g),铁粉(1g),浓盐酸(1ml),水(2ml)和乙醇(50ml)的混合物搅拌并加热回流4小时。将混合物冷却至室温,通过加入2M氢氧化钠水溶液碱化,用二氯甲烷萃取,将有机相干燥(硫酸镁)并蒸发。得到5-氨基-2-甲苯基2-吡啶基甲基醚,产率97%;NMR谱:2.09(s,3H),4.61(s,2H),5.0(s,2H),6.32(m,1H),6.42(d,1H),6.67(d,1H),7.31(m,1H),7.50(d,1H),7.81(m,1H),8.54(m,1H);
用与涉及原料制备的实施例1中第三段所述类似的方法,所不同的是产物用甲醇和乙醇的混合物重结晶,6-溴-4-氯喹唑啉与5-氨基-2-甲苯基2-吡啶基甲基醚反应,给出6-溴-4-[3-甲基-4-(2-吡啶基甲氧基)苯氨基]喹唑啉二盐酸盐,产率68%,m.p.232-234℃;NMR谱:2.3(s,3H),5.35(s,2H),7.13(m,1H),7.52(m,3H),7.63(d,1H),7.9(d,1H),8.08(m,1H),8.25(m,1H),8.7(m,1H),8.92(s,1H),9.17(d,1H),11.62(d,1H);元素分析:实测C,48.4;H,4.2;N,10.6;C21H17BrN4O2HCl1.5H2O计算C,48.4;H,4.25;N,10.7%.
实施例39
用与实施例5所述类似的方法,6-溴-4-[3-甲基-4-(2-吡啶基甲氧基)苯氨基)喹唑啉二盐酸盐与3-呋喃基硼酸二-异丙基酯反应给出6-(3-呋喃基)-4-[3-甲基-4-(2-吡啶基甲氧基)苯氨基]喹唑啉,产率55%,m.p.206-208℃;NMR谱:2.32(s,3H),5.22(s,2H),7.05(d,1H),7.15(d,1H),7.36(m,1H),7.55(m,3H),7.75(d,1H),7.87(m,2H),8.1(m,2H),8.33(d,1H),8.48(s,1H),8.6(m,1H),8.69(d,1H),9.62(s,1H);元素分析:实测C,73.2;H,4.9;N,13.6;C25H20N4O2计算C,73.5;H,4.9;N,13.7%.
用作原料的3-呋喃基硼酸二-异丙基酯如下制备:
搅拌下将正丁基锂(1.6M己烷溶液,1ml)滴加到已经冷却到-78℃的3-溴呋喃(0.21g),硼酸三-异丙基酯(0.4ml)和THF(5ml)混合物中。将混合物搅拌并温热至室温。将混合物蒸发给出所需的原料,不经纯化直接使用。
实施例40
下面举例说明含有式Ⅰ化合物,或其药用盐(后面称为化合物X),用于人体治疗或预防的代表性剂量形式:
(a)    片剂Ⅰ                 mg/片
       化合物X                100
       乳糖Ph.Eur             182.75
交联羧甲纤维素钠                    12.0
玉米淀粉糊(5%w/v糊)                2.25
硬脂酸镁                            3.0(b) 片剂Ⅱ                              mg/片
化合物X                             50
乳糖Ph.Eur                          223.75
交联羧甲纤维素钠                    6.0
玉米淀粉                            15.0
聚乙烯基吡咯烷酮                    2.25
硬脂酸镁                            3.0(c) 片剂Ⅲ                              mg/片
化合物X                             1.0
乳糖Ph.Eur                          93.25
交联羧甲纤维素钠                    4.0
玉米淀粉糊(5%w/v糊)                0.75
硬脂酸镁                            1.0(d) 胶囊                                mg/胶囊
化合物X                             10
乳糖Ph.Eur                          488.5
硬脂酸镁                            1.5(e) 注射剂                              (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(调节pH至7.6)
聚乙二醇400                         4.5%w/v
注射用水至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氢氧化钠溶液               15.0%v/v
注射用水至100%(g) 注射剂Ⅲ                       (1mg/ml,缓冲至pH6)
化合物X                        0.1%w/v
磷酸钠BP                       2.26w/v
柠檬酸                         0.38%w/v
聚乙二醇400                    3.5%w/v
注射用水至100%
上述制剂可以通过药学专业公知的常规方法得到。片剂(a)-(c)可以通过常规手段包衣,例如提供乙酸邻苯二甲酸纤维素包衣。

Claims (15)

1.式Ⅰ的喹唑啉衍生物
Figure A9719224200021
其中X1是直接连接或式CO,C(R2)2,CH(OR2),C(R2)2-C(R2)2,C(R2)=C(R2),C≡C,CH(CN),O,S,SO,SO2,N(R2),CON(R2),SO2N(R2),N(R2)CO,N(R2)SO2,OC(R2),SC(R2)2,N(R2)C(R2)2,C(R2)2O,C(R2)2S或C(R2)2N(R2)的基团,而各个R2独立地是氢或(1-4C)烷基;
其中Q1是苯基,萘基或含有最高3个选自氧,氮和硫的杂原子的5-或6-员杂芳基部分,该杂环部分是单环或与苯环稠合,且Q1非强制性地带有3个选自如下的取代基:卤素,羟基,氨基,三氟甲氧基,三氟甲基,氰基,硝基,羧基,氨基甲酰基,(1-4C)烷氧羰基,(1-4C)烷基,(1-4C)烷氧基,(2-4C)烯氧基,(2-4C)炔氧基,(1-3C)亚烷二氧基,(1-4C)烷基氨基,二-[(1-4C)烷基]氨基,吡咯烷-1-基,哌啶子基,吗啉代,哌嗪-1-基,4-(1-4C)烷基哌嗪-1-基,(2-4C)烷酰氧基氨基,N-(1-4C)烷基氨基甲酰基,N,N-二〔(1-4C)烷基〕氨基甲酰基,氨基-(1-4C)烷基,(1-4C)烷基氨基-(1-4C)烷基,二-[(1-4C)烷基]氨基-(1-4C)烷基,吡咯烷-1-基-(1-4C)烷基,哌啶子基-(1-4C)烷基,吗啉代-(1-4C)烷基,哌嗪-1-基-(1-4C)烷基,4-(1-4C)烷基哌嗪-1-基-(1-4C)烷基,卤代-(2-4C)烷氧基,羟基-(2-4C)烷氧基,(1-4C)烷氧基-(2-4C)烷氧基,氨基-(2-4C)烷氧基,(1-4C)烷基氨基-(2-4C)烷氧基,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,(1-4C)烷硫基-(2-4C)烷氧基,(1-4C)烷基亚磺酰基-(2-4C)烷氧基,(1-4C)烷基磺酰基-(2-4C)烷氧基,卤代-(2-4C)烷基氨基,羟基-(2-4C)烷基氨基,(1-4C)烷氧基-(2-4C)烷基氨基,氨基-(2-4C)烷基氨基,(1-4C)烷基氨基-(2-4C)烷基氨基,二-[(1-4C)烷基]氨基-(2-4C)烷基氨基,吡咯烷-1-基-(2-4C)烷基氨基,哌啶子基-(2-4C)烷基氨基,吗啉代-(2-4C)烷基氨基,哌嗪-1-基-(2-4C)烷基氨基,4-(1-4C)烷基哌嗪-1-基-(2-4C)烷基氨基,N-(1-4C)烷基-卤代-(2-4C)烷基氨基,N-(1-4C)烷基-羟基-(2-4C)烷基氨基,N-(1-4C)烷基-(1-4C)烷氧基-(2-4C)烷基氨基,卤代-(2-4C)烷酰基氨基,羟基-(2-4C)烷酰基氨基,(1-4C)烷氧基-(2-4C)烷酰基氨基,(3-4C)烯酰基氨基,(3-4C)炔酰基氨基,氨基-(2-4C)烷酰基氨基,(1-4C)烷基氨基-(2-4C)烷酰基氨基,二-[(1-4C)烷基]氨基-(2-4C)烷酰基氨基,吡咯烷-1-基-(2-4C)烷酰基氨基,哌啶子基-(2-4C)烷酰基氨基,吗啉代-(2-4C)烷酰基氨基,哌嗪-1-基-(2-4C)烷酰基氨基和4-(1-4C)烷基哌嗪-1-基-(2-4C)烷酰基氨基,其中任何上述包含不连接在卤素,SO或SO2基团或N,O或S原子上的CH2(亚甲基)的取代基非强制性地在所说的CH2基团上带有选自羟基,氨基,(1-4C)烷氧基,(1-4C)烷基氨基和二-[(1-4C)烷基]氨基的取代基;
其中m是1或2,各个R1独立地是氢,卤素,三氟甲基,羟基,氨基,硝基,氰基,羧基,氨基甲酰基,(1-4C)烷氧基氨基甲酰基,(1-4C)烷基,(1-4C)烷氧基,(1-4C)烷基氨基,二-[(1-4C)烷基]氨基,(2-4C)烷酰基氨基,N-(1-4C)烷基氨基甲酰基或N,N-二-[(1-4C)烷基]氨基甲酰基;和其中Q2是苯基或含有1或2个氮杂原子和非强制性地进一步含有选自氧,氮和硫的杂原子的9-或10-员双环杂环部分,而且Q2非强制性地带有最多3个选自卤素,三氟甲基,氰基,羟基,氨基,硝基,羧基,氨基甲酰基,(1-4C)烷氧羰基,(1-4C)烷基,(1-4C)烷氧基,(1-4C)烷基氨基,二-[(1-4C)烷基]氨基,(2-4C)烷酰基氨基,N-(1-4C)烷基氨基甲酰基和N,N-二-(1-4C)烷基氨基甲酰基的取代基,
或Q2是式Ⅱ的基团
Figure A9719224200031
其中X2是式CO,C(R3)2,CH(OR3),C(R3)2-C(R3)2,C(R3)=C(R3),C≡C,CH(CN),O,S,SO,SO2,N(R3),CON(R3),SO2N(R3),N(R3)CO,N(R3)SO2,OC(R3)2,SC(R3)2,C(R3)2O或C(R3)2S的基团,而各个R3独立地是氢或(1-4C)烷基,Q3是苯基或萘基或含有最多3个选自氧,氮和硫的杂原子的5-或6-员杂芳基部分,该杂芳基是单环或与苯环稠合,其中所说的苯基或萘基或杂芳基部分非强制性地带有最多3个选自卤素,三氟甲基,氰基,羟基,氨基,硝基,羧基,氨基甲酰基,(1-4C)烷氧羰基,(1-4C)烷基,(1-4C)烷氧基,(1-4C)烷基氨基,二-[(1-4C)烷基]氨基,(2-4C)烷酰基氨基,N-〔(1-4C)烷基〕氨基甲酰基和N,N-二-[(1-4C)烷基]氨基甲酰基的取代基,n是1,2或3,而各个R4独立地是氢,卤素,三氟甲基,氰基,羟基,氨基,硝基,(1-4C)烷基,(1-4C)烷氧基,(1-4C)烷基氨基,二-[(1-4C)烷基]氨基,或(2-4C)烷酰基氨基;或其药用盐;条件是,当Q1是非强制性-取代的苯基时,X1不是N(R2)CO,N(R2)SO2,OC(R2)2,N(R2)C(R2)2,C(R2)2S或C(R2)2N(R2);和当X1是直接连接时,Q1不是含有最多3个氮杂原子的5-或9-员氮-连接的杂芳基部分。
2.根据权利要求1的式Ⅰ的喹唑啉衍生物
其中X1是直接连接或式CO,C(R2)2,CH(OR2),C(R2)2-C(R2)2,C(R2)=C(R2),C≡C,CH(CN),O,S,SO,SO2,N(R2),CON(R2),SO2N(R2),N(R2)CO,N(R2)SO2,OC(R2)2,SC(R2)2,N(R2)C(R2)2,C(R2)2O,C(R2)2S或C(R2)2N(R2)的基团,而各个R2独立地是氢或(1-4C)烷基;
其中Q1是含有最高3个选自氧,氮和硫的杂原子的5-或6-员杂芳基部分,该杂环部分是单环或与苯环稠合,且Q1非强制性地带有3个选自如下的取代基:卤素,羟基,氨基,三氟甲氧基,三氟甲基,氰基,硝基,羧基,氨基甲酰基,(1-4C)烷氧羰基,(1-4C)烷基,(1-4C)烷氧基,(2-4C)烯氧基,(2-4C)炔氧基,(1-3C)亚烷二氧基,(1-4C)烷基氨基,二-[(1-4C)烷基]氨基,吡咯烷-1-基,哌啶子基,吗啉代,哌嗪-1-基,4-(1-4C)烷基哌嗪-1-基,(2-4C)烷酰基氨基,N-(1-4C)烷基氨基甲酰基,N,N-二-[(1-4C)烷基]氨基甲酰基,氨基-(1-4C)烷基,(1-4C)烷基氨基-(1-4C)烷基,二-[(1-4C)烷基]氨基-(1-4C)烷基,吡咯烷-1-基-(1-4C)烷基,哌啶子基-(1-4C)烷基,吗啉代-(1-4C)烷基,哌嗪-1-基-(1-4C)烷基,4-(1-4C)烷基哌嗪-1-基-(1-4C)烷基,卤代-(2-4C)烷氧基,羟基-(2-4C)烷氧基,(1-4C)烷氧基-(2-4C)烷氧基,氨基-(2-4C)烷氧基,(1-4C)烷基氨基-(2-4C)烷氧基,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,(1-4C)烷硫基-(2-4C)烷氧基,(1-4C)烷基亚磺酰基-(2-4C)烷氧基,(1-4C)烷基磺酰基-(2-4C)烷氧基,卤代-(2-4C)烷基氨基,羟基-(2-4C)烷基氨基,(1-4C)烷氧基-(2-4C)烷基氨基,氨基-(2-4C)烷基氨基,(1-4C)烷基氨基-(2-4C)烷基氨基,二-[(1-4C)烷基]氨基-(2-4C)烷基氨基,吡咯烷-1-基-(2-4C)烷基氨基,哌啶子基-(2-4C)烷基氨基,吗啉代-(2-4C)烷基氨基,哌嗪-1-基-(2-4C)烷基氨基,4-(1-4C)烷基哌嗪-1-基-(2-4C)烷基氨基,N-(1-4C)烷基-卤代-(2-4C)烷基氨基,N-(1-4C)烷基-羟基-(2-4C)烷基氨基,N-(1-4C)烷基-(1-4C)烷氧基-(2-4C)烷基氨基,卤代-(2-4C)烷酰基氨基,羟基-(2-4C)烷酰基氨基,(1-4C)烷氧基-(2-4C)烷酰基氨基,(3-4C)烯酰基氨基,(3-4C)炔酰基氨基,氨基-(2-4C)烷酰基氨基,(1-4C)烷基氨基-(2-4C)烷酰基氨基,二-[(1-4C)烷基]氨基-(2-4C)烷酰基氨基,吡咯烷-1-基-(2-4C)烷酰基氨基,哌啶子基-(2-4C)烷酰基氨基,吗啉代-(2-4C)烷酰基氨基,哌嗪-1-基-(2-4C)烷酰基氨基和4-(1-4C)烷基哌嗪-1-基-(2-4C)烷酰基氨基,其中任何上述包含不连接在卤素,SO或SO2基团或N,O或S原子上的CH2(亚甲基)的取代基非强制性地在所说的CH2基团上带有选自羟基,氨基,(1-4C)烷氧基,(1-4C)烷基氨基和二-[(1-4C)烷基]氨基的取代基;其中m是1或2,各个R1独立地是氢,卤素,三氟甲基,羟基,氨基,硝基,氰基,羧基,氨基甲酰基,(1-4C)烷氧基氨基甲酰基,(1-4C)烷基,(1-4C)烷氧基,(1-4C)烷基氨基,二-[(1-4C)烷基]氨基,(2-4C)烷酰基氨基,N-(1-4C)烷基氨基甲酰基或N,N-二-[(1-4C)烷基]氨基甲酰基;和其中Q2是苯基,它非强制性地带有最多3个选自卤素,三氟甲基,氰基,羟基,氨基,硝基,羧基,氨基甲酰基,(1-4C)烷氧羰基,(1-4C)烷基,(1-4C)烷氧基,(1-4C)烷基氨基,二-[(1-4C)烷基]氨基,(2-4C)烷酰基氨基,N-(1-4C)烷基氨基甲酰基和N,N-二-(1-4C)烷基氨基甲酰基的取代基,或其药用盐;条件是,当X1是直接连接时,Q1不是含有最多3个氮杂原子的5-或9-员氮-连接的杂芳基部分。
3.如权利要求1的式Ⅰ喹唑啉衍生物
其中X1是直接连接或式CH2,CH2CH2,NH,NHCO,NHSO2,OCH2,SCH2,NHCH2,CH2O或CH2S的基团;
Q1是2-呋喃基,3-呋喃基,2-噻吩基,3-噻吩基,2-吡啶基,3-吡啶基,4-吡啶基,2-噁唑基,4-噁唑基,5-异噁唑基,3-吡唑基,2-咪唑基,4-咪唑基,2-噻唑基,4-噻唑基,5-异噻唑基,或1,2,3-三唑-4-基,它们非强制性地带有选自甲基,氨基甲基,2-氨基乙基,甲基氨基甲基,2-甲基氨基乙基,二甲基氨基甲基,2-二甲基氨基乙基,吡咯烷-1-基甲基,2-吡咯烷-1-基乙基,哌啶子基甲基,2-哌啶子基乙基,吗啉代甲基,2-吗啉代乙基,哌嗪-1-基甲基,2-哌嗪-1-基乙基,4-甲基哌嗪-1-基甲基和2-(4-甲基哌嗪-1-基)乙基的取代基;m是1而R1是氢或甲氧基;而Q2是非强制性地带有1,2或3个选自氟,氯,溴,三氟甲基,氰基,甲基和甲氧基的取代基的苯基,或Q2是式Ⅱ的基团
Figure A9719224200061
其中X2是式CO或OCH2的基团,Q3是非强制性地带有1或2个选自氟,氯,溴,甲基和甲氧基的取代基的苯基或2-吡啶基,n是1且R4是氢,氟,氯,溴或甲基;
或其药用酸加成盐。
4.如权利要求1的式Ⅰ的喹唑啉衍生物其中X1是直接连接或式NHCO,OCH2,或NHCH2的基团;Q1是2-呋喃基,3-呋喃基,2-噻吩基,3-噻吩基,2-吡啶基,3-吡啶基,4-噁唑基,5-异噁唑基或4-咪唑基,它们非强制性地带有选自氨基甲基,吗啉代甲基和2-吗啉代乙基的取代基;m是1而R1是氢或甲氧基;而Q2是非强制性地带有1或2个选自氟,氯,溴和甲基的取代基的苯基,或其药用酸加成盐。
5.如权利要求1的式Ⅰ的喹唑啉衍生物选自:
4-(3-氯-4-氟苯胺基)-6-(3-呋喃基)喹唑啉,
4-(3-氯-4-氟苯胺基)-6-(2-噻吩基)喹唑啉,
4-(3-氯-4-氟苯胺基)-6-[5-(2-吗啉代乙基)噻吩-2-基]喹唑啉,
4-(3-氯-4-氟苯胺基)-6-(5-吗啉代甲基噻吩-3-基)喹唑啉和
4-(3-氯-4-氟苯胺基)-7-甲氧基-6-(3-吡啶基甲氧基)喹唑啉;
或其药用酸加成盐。
6.如权利要求1的式Ⅰ的喹唑啉衍生物:
其中X1是直接连接;
Q1是带有选自氨基-(1-4C)烷基,(1-4C)烷基氨基-(1-4C)烷基,二-[(1-4C)烷基]氨基-(1-4C)烷基,吡咯烷-1-基-(1-4C)烷基,哌啶子基-(1-4C)烷基,吗啉代-(1-4C)烷基,哌嗪-1-基-(1-4C)烷基和4-(1-4C)烷基哌嗪-1-基-(1-4C)烷基的取代基的噻吩基;
m是1而R1是氢;
而Q2是非强制性地带有最多3个选自卤素,三氟甲基,氰基,羟基,氨基,硝基,羧基,氨基甲酰基,(1-4C)烷氧羰基,(1-4C)烷基,(1-4C)烷氧基,(1-4C)烷基氨基,二-[(1-4C)烷基]氨基,(2-4C)烷酰基氨基,N-(1-4C)烷基氨基甲酰基和N,N-二-(1-4C)烷基氨基甲酰基的取代基的苯基;
或其药用盐。
7.如权利要求1的式Ⅰ的喹唑啉衍生物
其中X1是直接连接;
Q1是非强制性地带有选自甲基,氨基甲基,2-氨基乙基,甲基氨基甲基,2-甲基氨基乙基,二甲基氨基甲基,2-二甲基氨基乙基,吡咯烷-1-基甲基,2-吡咯烷-1-基乙基,哌啶子基甲基,2-哌啶子基乙基,吗啉代甲基,2-吗啉代乙基,哌嗪-1-基甲基,2-哌嗪-1-基乙基,4-甲基哌嗪-1-基甲基和2-(4-甲基哌嗪-1-基)乙基的取代基的2-噻吩基;
m是1而R1是氢或甲氧基;
而Q2是非强制性地带有1,2或3个选自氟,氯,溴,三氟甲基,氰基,甲基和甲氧基的取代基的苯基;
或其药用酸加成盐。
8.如权利要求1的式Ⅰ的喹唑啉衍生物
其中X1是直接连接;
Q1是非强制性地带有选自氨基甲基,吗啉代甲基和2-吗啉代乙基的取代基的2-噻吩基;
m是1而R1是氢或甲氧基;
而Q2是非强制性地带有1或2个选自氟,氯,溴和甲基的取代基的苯基;
或其药用酸加成盐。
9.如权利要求1的式Ⅰ的喹唑啉衍生物:
4-(3-氯-4-氟苯胺基)-6-[5-(2-吗啉代乙基)噻吩-2-基]喹唑啉,
或其药用酸加成盐。
10.如权利要求1的式Ⅰ的喹唑啉衍生物
其中X1是直接连接或式O的基团;
Q1是非强制性地带有1或2个选自氟,氯,溴,氨基,氰基,硝基,氨基甲基,甲基氨基甲基,二甲基氨基甲基,二乙基氨基甲基,吡咯烷-1-基甲基,哌啶子基甲基,吗啉代甲基,哌嗪-1-基甲基,和4-甲基哌嗪-1-基甲基的取代基的苯基;
m是1而R1是氢或甲氧基;
Q2是非强制性地带有1,2或3个选自氟,氯,溴,三氟甲基,氰基,甲基和甲氧基的取代基的苯基;
或Q2是式Ⅱ的基团
Figure A9719224200081
其中X2是式OCH2的基团,Q3是2-吡啶基,n是1而R4是氢,氟,氯或甲基;
或其药用酸加成盐。
11.如权利要求1的式Ⅰ的喹唑啉衍生物
其中X1是直接连接或式O的基团;
Q1是非强制性地带有1或2个选自氨基,氨基甲基,二乙基氨基甲基,吡咯烷-1-基甲基,哌啶子基甲基和吗啉代甲基的取代基的苯基;
m是1而R1是氢;和
而Q2是带有1或2个选自氟,氯和甲基的取代基的苯基;
或其药用酸加成盐。
12.如权利要求1的式Ⅰ的喹唑啉衍生物选自:
4-(3-甲基苯胺基)-6-苯基喹唑啉,
6-(4-氨基甲基苯基)-4-(3-氯-4-氟苯胺基)喹唑啉,
6-(4-氨基苯氧基)-4-(3-氯-4-氟苯胺基)喹唑啉,
6-(4-氨基甲基苯氧基)-4-(3-氯-4-氟苯胺基)喹唑啉或
4-(3-氯-4-氟苯胺基)-6-(4-吗啉代甲基苯氧基)喹唑啉;
或其药用酸加成盐。
13.制备如权利要求1至12任一项的式Ⅰ的喹唑啉衍生物,或其药用酸加成盐的方法,该方法包括:
(a)式Ⅲ的喹唑啉
Figure A9719224200091
其中Z是可置换的基团,与式Q2-NH2的苯胺反应;
(b)为了制备其中X1是直接连接的式Ⅰ化合物,式Ⅳ的喹唑啉
Figure A9719224200092
其中Z是可置换的基团,与其中各个L1和L2相同或不同,为合适的配位体的式Q1-B(L1)(L2)的有机硼试剂反应;
(c)为了制备其中X1是直接连接的式Ⅰ化合物,式Ⅴ的喹唑啉
Figure A9719224200093
其中各个L1和L2,可以相同或不同,是合适的配位体,与其中Z是可置换基团的式Q1-Z的化合物反应;
(d)为了生产其中X1是式N(R2)CO或N(R2)SO2基团的式Ⅰ化合物,式Ⅵ的胺
用式Q1CO2H的羧酸,或其反应活性衍生物,或式Q1-SO2OH的磺酸,或如果合适,其反应活性衍生物酰化;
(e)为了生产其中X1是式OC(R2)2,SC(R2)2或N(R2)2C(R2)2基团的式Ⅰ化合物,适当的苯酚,硫代苯酚或苯胺与其中Z是可置换基团的式Z-C(R2)2-Q1的烷基化剂进行烷基化;
(f)为了生产其中X1是式C(R2)2O,C(R2)2S或C(R2)2N(R2)基团的式Ⅰ化合物,式HO-Q1的适当的苯酚,式HS-Q1的硫代苯酚或式R2NH-Q1的苯胺与其中Z是可置换基团的式Ⅶ的烷基化剂
Figure A9719224200102
进行烷基化;
(g)为了生产具有氨基甲基取代基或其中X1是式N(R2)CH2或CH2N(R2)基团的式Ⅰ化合物,还原具有氰基取代基或其中X1是式N(R2)CO或CON(R2)基团的式Ⅰ化合物;
(h)为了生产具有氨基取代基的式Ⅰ化合物,将具有硝基取代基的式Ⅰ化合物还原;
(i)为了生产其中X1是式NHCH(R2)基团的式Ⅰ化合物,将式R2-CO-Q1的酮化合物用式Ⅷ的胺
还原性胺化;
或(j)为了生产其中X1是式O,S或N(R2)基团的式Ⅰ化合物,适当的酚,硫代苯酚或苯胺与其中Z是可置换基团的式Z-Q1的化合物偶合;
当需要式Ⅰ的喹唑啉衍生物的药用盐时,可以通过所说的化合物用常规方法反应而得到。
14.一种药物组合物,包括如权利要求1至12任一项的式Ⅰ的喹唑啉衍生物,或其药用盐与药学上可接受的稀释剂或载体。
15.如权利要求1至12任一项的式Ⅰ的喹唑啉衍生物或其药用盐作为在制备对温血动物如人产生抗增生作用的医药方面的应用。
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