CN1129582C - 作为钾通道调节剂的3-取代-4-芳基喹啉-2-酮衍生物 - Google Patents
作为钾通道调节剂的3-取代-4-芳基喹啉-2-酮衍生物 Download PDFInfo
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- CN1129582C CN1129582C CN99813902A CN99813902A CN1129582C CN 1129582 C CN1129582 C CN 1129582C CN 99813902 A CN99813902 A CN 99813902A CN 99813902 A CN99813902 A CN 99813902A CN 1129582 C CN1129582 C CN 1129582C
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- China
- Prior art keywords
- trifluoromethyl
- chloro
- quinolinone
- phenyl
- hydroxy phenyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 108020001213 potassium channel Proteins 0.000 title abstract description 13
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- 108010045489 Calcium-Activated Potassium Channels Proteins 0.000 claims abstract 2
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- -1 methoxyl group Chemical group 0.000 claims description 34
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- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 9
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- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
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- QUKGHUWTRXCPOA-UHFFFAOYSA-N 4-(5-chloro-2-hydroxyphenyl)-3-(4-hydroxyphenyl)-6-(trifluoromethyl)-1h-quinolin-2-one Chemical compound C1=CC(O)=CC=C1C(C(NC1=CC=C(C=C11)C(F)(F)F)=O)=C1C1=CC(Cl)=CC=C1O QUKGHUWTRXCPOA-UHFFFAOYSA-N 0.000 claims description 4
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- JETCKZALJDZAMQ-XFFZJAGNSA-N 4-(5-chloro-2-hydroxyphenyl)-3-[(z)-2-fluoro-3-hydroxyprop-1-enyl]-6-(trifluoromethyl)-1h-quinolin-2-one Chemical compound C12=CC(C(F)(F)F)=CC=C2NC(=O)C(/C=C(F)/CO)=C1C1=CC(Cl)=CC=C1O JETCKZALJDZAMQ-XFFZJAGNSA-N 0.000 claims description 3
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- JETCKZALJDZAMQ-YRNVUSSQSA-N 4-(5-chloro-2-hydroxyphenyl)-3-[(e)-2-fluoro-3-hydroxyprop-1-enyl]-6-(trifluoromethyl)-1h-quinolin-2-one Chemical compound C12=CC(C(F)(F)F)=CC=C2NC(=O)C(\C=C(F)/CO)=C1C1=CC(Cl)=CC=C1O JETCKZALJDZAMQ-YRNVUSSQSA-N 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
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- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
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- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000011505 plaster Substances 0.000 description 1
- 150000003109 potassium Chemical class 0.000 description 1
- 108010083133 potassium channel protein I(sk) Proteins 0.000 description 1
- 229910001414 potassium ion Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 238000011471 prostatectomy Methods 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 150000003248 quinolines Chemical class 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000011808 rodent model Methods 0.000 description 1
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- 238000000926 separation method Methods 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 230000036259 sexual stimuli Effects 0.000 description 1
- 229960003310 sildenafil Drugs 0.000 description 1
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 150000004685 tetrahydrates Chemical class 0.000 description 1
- RBNBDIMXFJYDLQ-UHFFFAOYSA-N thieno[3,2-d]pyrimidine Chemical compound C1=NC=C2SC=CC2=N1 RBNBDIMXFJYDLQ-UHFFFAOYSA-N 0.000 description 1
- 208000037816 tissue injury Diseases 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 238000002834 transmittance Methods 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- C07D215/20—Oxygen atoms
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Abstract
本发明提供通式(I)的新型3-取代-4-芳基喹啉-2-酮衍生物,式中R、R1、R2、R3、R4、R5、R6和R7如同本说明书中所定义,或其医药上可接受的无毒盐,这些是大电导钙活化的K+通道的调节剂,而且可用于治疗那些对钾通道的打开有反应的病症。
Description
技术领域
本发明涉及新型3-取代-4-芳基喹啉-2-酮衍生物,即大电导钙活化的钾(BK)通道的调节剂,因此,可用于保护神经元细胞和治疗细胞膜极化和电导机能障碍引起的疾病。本发明也提供用这些新型有取代喹啉-2-酮衍生物的治疗方法,还涉及其医药组合物。
背景技术
钾通道在细胞膜电位的调节和细胞应激性的调整方面发挥关键作用。钾通道主要由电压、细胞代谢、钙和受体传递过程来调节[Cook,N.S.,
Trends in Pharmacol.Sciences(1988),
9,21;和Quast,U.等人,
Trends in Pharmacol.Sciences(1989),
10,431]。钙活化的钾(KCa)通道是一个多种多样的离子通道群,其活性均依赖于细胞内钙离子。KCa通道的活性受细胞内[Ca2+]、细胞膜电位和磷酰化作用的调节。根据它们在对称K+溶液中的单一通道电导,把KCa通道分成三小类:大电导(BK)>150pS;中电导50~150pS;小电导<50pS。大电导钙活化的钾(Maxi-K或BK)通道存在于许多可激发的细胞中,包括神经元、心细胞和各种类型的平滑肌细胞[Singer,J.等人,pflugers Archiv.(1987)
408,98;Baro,I.等人,
Pflugers Archiv.(1989)
414(Suppl.1),S168;和Ahmed,F.等人,
Br.J.Pharmacol.(1984)
83,227]。
钾离子在控制大多数可激发细胞中的静止膜电位方面发挥主导作用,并使跨膜电压保持在约90mV的K+平衡电位(Ek)。已经有人显示,钾通道的打开使细胞膜电位漂移到平衡钾膜电位(Ek),导致该细胞的超极化[Cook,N.S.,
Trends in Pharmacol.Sciences(1988),9,21]。超极化的细胞显示出降低了对潜在损害性去极化刺激的响应。受电压和细胞内Ca2+两者调控的BK通道起到限制去极化和钙进入的作用,而且可以特别有效地阻滞损害性刺激。因此,通过BK通道的打开而发生的细胞超极化可能导致神经元细胞的保护。
有BK打开活性的一系列合成化合物和天然存在的化合物已有人报告。从普通燕麦(
Avena sativa)中提取的燕麦吡喃酮已经用脂质双层技术确认为一种BK通道打开剂[国际专利申请WO 93/08800,1993年5月13日公布]。已经有人用非常有限的电生理实验把6-溴-8-(甲胺基)咪唑并[1,2-a]吡嗪-2-腈(SCA-40)描述为一种BK通道打开剂[Laurent,F.等人,
Br,J.Pharmacol.(1993)
108,622-626]。已经发现flavanoid即根皮素采用外敷贴剂能提高爪蟾(
Xenopus laevis)的有髓鞘神经纤维中Ca2+活化钾通道的打开概率[Koh,D-S.,等人,
Neuroseience Lett.(1994)
165,167-170]。
在1992年1月4日公布的欧洲专利申请EP-477,819和1993年4月6日颁发给Olesen等人的对应美国专利No.5,200,422中,通过把单一通道和整体细胞贴夹实验用于主动脉平滑肌细胞,公开了作为BK通道打开剂的一批苯并咪唑衍生物。在
European J.Pharmacol.,251,53-59(1994)中,Olesen等人报告了进一步的工作。
在1996年10月15日公布的美国专利No.5,565,483中,P.Hewawasan等人公开了作为BK通道打开剂的一批有取代羟吲哚。
Sit等人在1998年6月4日公布的国际专利申请WO 98/23273和1999年4月6日公布的对应美国专利No.5,892,045中公开了一系列4-芳基-3-羟基喹啉-2-酮衍生物,而Hewawasam等人在1999年3月4日公布的国际专利申请WO 99/09983中公开了一系列4-芳基-3-氨基喹啉-2-酮衍生物,这些化合物是BK通道打开剂而且可用于治疗对钾通道打开活性敏感的病症。
E.S.Hamanaka在1996年10月15日公布的美国专利No.5,565,472中公开了一批4-芳基-3-(杂芳基脲基)-1,2-二氢-2-氧代喹啉衍生物,这些是酰基辅酶A、胆甾醇酰基转移酶的抑制剂,而且可用来作为低脂血剂和抗动脉粥样硬化剂。
本发明的目的是提供能调节钾通道、尤其大电导钙活化的钾(BK)通道、可用于细胞膜极化和电导机能障碍引起的疾病的新型化合物。
发明内容
具体实施方式
本发明提供作为高电导钙活化K+通道(BK通道)的强打开剂而且有下式结构的新型3-取代-4-芳基喹啉-2-酮衍生物或其医药上可接受的无毒盐式中
R和R1各自独立地是氢或甲基;
R2、R3和R4各自独立地是氢、卤素、硝基或三氟甲基,前提是R2、R3和R4不全部为氢;
R5是溴、氯或硝基;
R6是氢或氟;
n是0~6的整数;
m是0或1的整数;和
R7是CH3、-CRR1OH、-CHO、-C=NOH、-COCH3或也可以有从卤素、羟基、甲氧基、氨基、乙酰胺基和三氟甲基组成的一组中选择的一个或两个取代基取代的芳基。
本发明也提供与BK通道相联系的病症例如局部缺血、中风、惊厥、癫痫、哮喘、刺激性肠综合征、偏头痛、创伤性脑损伤、脊髓损伤、性机能障碍和尿失禁、尤其男性勃起机能障碍的治疗或缓解方法,包含连同惯常辅药、载体或稀释剂一起给药某一治疗有效量的式I化合物或其医药上可接受的无毒盐。
这里和权利要求书中使用的“医药上可接受的无毒盐”这一术语意在包括与无机碱的无毒碱加成盐。适用的无机碱例如碱金属碱和碱土金属碱,包括金属阳离子例如钠、钾、镁、钙等。除非另有说明,否则这里和权利要求书中使用的“卤素”这一术语意在包括溴、氯、碘和氟,而“卤化物”这一术语意在包括溴化物、氯化物和碘化物阴离子。
本发明的某些化合物既能以未溶剂化形式存在,也能以溶剂化形式存在,其中包括水合形式,例如一水合物、二水合物、半水合物、三水合物、四水合物等。这些产物可能是真溶剂合物,而在其它情况下这些产物可能只保留不固定溶剂或者是溶剂合物加某种不固定溶剂的一种混合物。熟悉本门技术的人员应当知道,溶剂化形式等效于未溶剂化形式,而且意在使之涵盖在本发明的范围内。式I的某些化合物能以两种互变异构体形式存在。熟悉本门技术的人员应当知道,当R1在毗邻羰基碳原子的氮原子上是氢时,喹啉环能以烯醇形式存在。其意图是把式I化合物的两种烯醇互变异构体都纳入本发明的范围内。
在本发明的方法中,“治疗有效量”这一术语系指足以显示有意义的患者效益即治愈以大电导钙活化K+通道的打开剂为特征的急性病症或提高此类病症的治俞率的该方法中每种有效成分的总量。当用于单独给药的单个有效成分时,这一术语仅指该成分。当用于一种组合时,这一术语系指导致该治疗效果的各有效成分的合并量,而不管是组合给药、系列式给药还是同时给药。这里和权利要求书中使用的“治疗”(treat,treating,treatment)系指预防或改善与细胞膜极化和电导机能障碍相联系的疾病、组织损伤和/或症状。
本发明方法中使用的较好化合物包括以下列出的式I化合物:
4-(5-氯-2-甲氧基苯基)-3-(羟甲基)-6-(三氟甲基)-2(1H)-喹啉酮;
4-(5-氯-2-甲氧基苯基)-3-(羟甲基)-7-(三氟甲基)-2(1H)-喹啉酮;
4-(5-氯-2-甲氧基苯基)-1,2-二氢-2-氧代-6-(三氟甲基)-3-喹啉甲醛;
4-(5-氯-2-甲氧基苯基)-3-(3-羟基-1-丙烯基)-6-(三氟甲基)-2(1H)-喹啉酮;
4-(5-氯-2-甲氧基苯基)-3-(羟基丙基)-6-(三氟甲基)-2(1H)-喹啉酮;
4-(5-氯-2-羟基苯基)-3-(羟甲基)-6-(三氟甲基)-2(1H)-喹啉酮;
4-(5-氯-2-羟基苯基)-3-(3-羟基-1-丙烯基)-6-(三氟甲基)-2(1H)-喹啉酮;
4-(5-氯-2-羟基苯基)-3-(3-羟基丙基)-6-(三氟甲基)-2(1H)-喹啉酮;
(E)-4-(5-氯-2-羟基苯基)-3-(2-氟-3-羟基-1-丙烯基)-6-(三氟甲基)-2(1H)-喹啉酮;
(Z)-4-(5-氯-2-羟基苯基)-3-(2-氟-3-羟基-1-丙烯基)-6-(三氟甲基)-2(1H)-喹啉酮;
(E)-4-(5-氯-2-甲氧基苯基)-3-(2-氟-3-羟基-1-丙烯基)-6-(三氟甲基)-2(1H)-喹啉酮;
(Z)-4-(5-氯-2-甲氧基苯基)-3-(2-氟-3-羟基-1-丙烯基)-6-(三氟甲基)-2(1H)-喹啉酮;
4-(5-氯-2-羟基苯基)-3-(2-羟基乙基)-6-(三氟甲基)-2(1H)-喹啉酮;
4-(5-氯-2-甲氧基苯基)-3-(2-羟基乙基)-6-(三氟甲基)-2(1H)-喹啉酮;
4-(5-氯-2-甲氧基苯基)-3-(4-甲氧基苯基)-6-(三氟甲基)-2(1H)-喹啉酮;
4-(5-氯-2-甲氧基苯基)-3-[(4-甲氧基苯基)甲基]-6-(三氟甲基)-2(1H)-喹啉酮;
4-(5-氯-2-甲氧基苯基)-3-(4-硝基苯基)-6-(三氟甲基)-2(1H)-喹啉酮;
4-(5-氯-2-甲氧基苯基)-3-(4-氨基苯基)-6-(三氟甲基)-2(1H)-喹啉酮;
4-(5-氯-2-羟基苯基)-3-(3,4-二甲氧基苯基)-6-(三氟甲基)-2(1H)-喹啉酮;
4-(5-氯-2-羟基苯基)-3-(2,4-二羟基苯基)-6-(三氟甲基)-2(1H)-喹啉酮;
4-(5-氯-2-羟基苯基)-3-(4-羟基苯基)-6-(三氟甲基)-2(1H)-喹啉酮;
4-(5-氯-2-羟基苯基)-3-[(4-羟基苯基)甲基]-6-(三氟甲基)-2(1H)-喹啉酮;
4-(5-氯-2-羟基苯基)-3-(4-乙酰胺基苯基)-6-(三氟甲基)-2(1H)-喹啉酮;
4-(5-氯-2-羟基苯基)-3-(4-氨基苯基)-6-(三氟甲基)-2(1H)-喹啉酮;
4-(5-氯-2-羟基苯基)-3-[2-(4-羟基苯基)乙基]-6-(三氟甲基)-2(1H)-喹啉酮;
4-(5-氯-2-羟基苯基)-3-甲基-6-(三氟甲基)-2(1H)-喹啉酮;
4-[4-(5-氯-2-羟基苯基)-1,2-二氢-2-氧代-6-(三氟甲基)喹啉-3-基]-3-丁烯-2-酮;
4-(5-氯-2-羟基苯基)-1,2-二氢-2-氧代-6-(三氟甲基)-3-喹啉甲醛肟;
4-(5-氯-2-甲氧基苯基)-1,2-二氢-2-氧代-6-(三氟甲基)-3-喹啉甲醛肟;和
4-(5-氯-2-羟基苯基)-3-(2-羟基-2-甲基丙基)-6-(三氟甲基)-2(1H)-喹啉酮。
式I化合物可以通过各种程序,例如本文实施例中和具体实施方案中所述反应方案及其变种中所说明的那些程序来制备,这些对熟悉本门技术的人员来说是显而易见的。
以下反应方案1~11说明按照本发明的中间体制备的代表性一般程序和产品制备方法。对于熟悉本门技术的人员来说也应当显而易见的是,这里所公开的材料和方法两者的适当替代将产生以下列举的实施例和本发明范围所涵盖的那些内容。反应方案1
(a)ClC(O)CH2CO2Ra,吡啶,CH2Cl2,0℃~回流温度
(b)KotBu,THF,回流
(c)Dibal-H,THF-己烷,-78℃~回流温度
(d)MnO2,CH2Cl2
Dibal-H=氢化二异丁基铝
反应方案1中说明式4和5的2(1H)-喹啉酮的制备。如该反应方案中所示,式1化合物与酰氯的酰化提供了式2的酰胺,其中Ra是氢或C1-4烷基,后者通过在一种惰性有机溶剂中用一种碱例如叔丁醇钾处理就可以环化和脱水而成为式3的喹啉酮。式3的酯对一种还原剂例如氢化二异丁基铝的暴露可提供式4的伯醇,然后,后者可以用一种氧化剂例如二氧化锰有利地氧化,产生所希望的式5的醛。反应方案2
(a)EtOC(O)CH2P(O)(OEt)2,NaH,DMF
(b)Dibal-H,THF,-78℃
(d)PtO2,EtOH-HCl,H2(60psi)
Dibal-H=氢化二异丁基铝
如反应方案2中所说明的,式5的醛的均裂可以容易地用膦酸酯试剂进行,产生作为(E)-异构体和(Z)-异构体的-种混合物的式6的不饱和酯,然后用柱色谱法将其分离。式6的酯的还原可以用一种还原剂例如氢化二异丁基铝进行,给出式7的对应烯丙醇。替而代之,当希望制备式9的化合物时,式6的酯就在能使该双键还原的加氢条件下选择性还原,提供式8的饱和酯。在与式6的酯的还原类似的条件下进行式8的酯的处理,会给出式9的对应醇。反应方案3
(a)BBr3,CH2Cl2,-78~0℃
(b)ClC(O)CH2CO2Me,吡啶,CH2Cl2
(c)KotBu,THF,回流
(d)Dibal-H,THF,-78℃
(e)Dibal-H,CH2Cl2,-78℃
Dibal-H=氢化二异丁基铝
在反应方案3中,通过用三溴化硼(BBr3)处理式1a化合物,要以同时脱除丁氧羰基(BOC)和甲基,给出式10的苯胺。式10的苯胺的酰化给出式11的对应酰胺,后者在用叔丁醇钾的碱性条件下容易地进行环化和脱水,提供式12的内酯。该内酯在THF中用氢化二异丁基铝进行部分还原,产生式13的中间体内半缩醛。替而代之,已经发现,通过把溶剂从THF换成二氯甲烷,式12的内酯就可以用氢化二异丁基铝还原而提供式14的所希望醇。反应方案4
(a)EtOC(O)CH2P(O)(ORa)2,NaH,DMF
(b)Dibal-H,THF-己烷,-78℃~回流温度
(d)PtO2,EtOH-HCl,H2(60 psi)
(e)NaOH,EtOH,~回流温度
Dibal-H=氢化二异丁基铝
当希望制备式17和20的化合物时,式13的中间体内半缩醛可以如反应方案4中所示那样用膦酸酯试剂处理,给出式15的不饱和酯,然后,如果愿意,再进行皂化以产生式16的不饱和酸。式15的酯用氢化铝还原给出式17的对应不饱和醇。替而代之,式15化合物的双键的加氢产生式18的酯,后者既可以皂化以产生式19的酸,也可以用氢化铝还原以产生式20的所希望的醇。反应方案5
(a)EtOC(O)CHFP(O)(OEt)2,NaH,DMF
(b)Dibal-H,CH2Cl2,-78℃~回流温度
Dibal-H=氢化二异丁基铝
反应方案5说明式13的中间体内半缩醛如反应方案步骤(a)中所述那样用氟膦酸酯进行均裂,给出作为(E)-异构体和(Z)-异构体的混合物的式21的不饱和α-氟酯酯。式21的酯的粗混合物可以用氢化铝还原,所得到的醇的混合物用柱色谱法有利地进行分离,给出式23的(E)-烯烃和式25的(Z)-烯烃。以类似的方式,可以使含有甲醚的式5的醛转化成式24和26的对应所希望的烯烃。反应方案6
(a)ClC(O)(CH2)nCO2Ra,吡啶,CH2Cl2
(b)KHMDS,THF,-78℃
(c)35%HBr-AcOH,甲苯,80-90℃
(d)吡啶,HCl,180-200℃
(e)BH3-SMe2,THF,-10℃~回流温度
式31a和31b化合物的制备在反应方案6中予以说明。式1的苯胺用一种酰氯进行酰化,提供对应的酰胺。式27的酰胺可以在碱性条件下环化而给出式28的脱氢羟基喹啉酮,然后可以在酸性条件例如HBr/AcOH或pTsOH下脱水和脱酯,给出式29的喹啉酮。如果愿意,可以在高温用盐酸吡啶进行甲醚脱除,给出式30的对应苯酚。然后,式30的酸的还原提供作为苯酚的式31a的醇。替而代之,如果该苯酚的甲醚是所希望的,则式29的羧酸用硼烷直接还原能提供式31b的对应的醇。反应方案7
(a)ClC(O)(CH2)n+1R8,吡啶,CH2Cl2
(b)KHMDS,THF,-78℃
(c)H+
(d)吡啶,HCl,180-200℃
采用与反应方案6中所述那种类似的思路,可以制备式34和35的化合物,式不n是0~6且R8是可以有从卤素、羟基、甲氧基、氨基、乙酰胺基和三氟甲基组成的一组中选择的一个或两个取代基取代的C1-4烷基或芳基。因此,反应方案7说明式1化合物的酰化、随后环化和脱水而给出作为甲醚的式34的3-取代喹啉。式34的化合物在高温用盐酸吡啶脱甲基化,提供了式35的对应苯酚化合物。反应方案8
(a)(MeO)2P(O)CH2X,NaH,DMF
(b)NH2OH.HCl,Et3N,THF
(c)NH2OH.HCl,an.NaOAc,EtOH
如反应方案8中所示,式13的中间体内半缩醛用一种氰基膦酸酯或膦酰基乙酸酯试剂进行均裂,分别提供对应不饱和的式36a的腈或式37a的乙酸酯。类似地,从式5的醛出发而且要么用一种氰基膦酸酯要么用一种膦酰基乙酸酯试剂处理,分别可以合成式36b和37b的甲醚类似物。通过用羟胺处理该内半缩醛,可以从式13的中间体内半缩醛制备式38a的肟。类似地,从式5的醛可以制备式38b的甲醚。反应方案9
(a)催化剂p-TsOH,甲苯,回流
(b)MeOH,硅胶
(c)RRLl,THF,-78℃
反应方案9说明当式30a的羟基酸在回流甲苯中用催化量的酸处理时式39的内酯的生成。当尝试在硅胶上采用甲醇作为洗脱溶剂之一对式39的内酯进行精制时,可以使该内酯转化成式30b的酯。当希望制备式40的有取代醇时,就用过量锂试剂例如甲基锂处理式39的内酯,以产生式40的二取代醇,或用当量锂试剂处理以产生一种一取代醇。反应方案10
(a)TlPSCl,咪唑,DMF
(b)nBuLi,CH3l,THF
(c)TBAF,THF,
(d)K2CO3,(CH3O)2SO2,丙酮
反应方案10中说明了式43和44的N-甲基化合物的制备。式31a的醇用三异丙基甲硅烷基(TIPS)氯进行甲硅烷基化,提供了式41的有甲硅烷基保护的醚。用烷基卤例如甲基碘进行的N-烷基化给出式42的化合物,后者可以用一种氟化物试剂进行脱甲硅烷基(步骤(c))而给出式43的醇。当希望制备甲基化苯酚时,就用硫酸二甲酯处理式41的化合物,随后脱甲硅烷基,而给出式44的二甲基类似物。反应方案11
(a)LiHMDS/THF,-78℃~回流温度
(b)12N HCl
(c)pTSA,甲苯,回流
(d)LiHMDS
(e)hv,MeOH
式31a化合物的制备有利地用反应方案11中所示反应进行。式45的香豆素化合物是通过使γ-丁内酯与氯水杨酸甲酯缩合有利地制备的,然后容易地用酸环化而产生式46的苯并吡喃-4-酮。如步骤(d)中所示,化合物46用对三氟甲基苯胺处理产生式47的二氢呋喃,然后在一种惰性有机溶剂中进行光环化,给出式31a的化合物。
在本发明的较好实施方案中,式I化合物有下式或其医药上可接受的无毒盐式中,R和R1各自独立地是氢或甲基;R2、R3和R4各自独立地是氢、卤素、硝基或三氟甲基,只要R2、R3和R4不全是氢即可;R5是溴、氯或硝基;R6是氢或氟;n是0~6的整数;m是0或1的整数;且R7是-CH3、-CRR1OH、-CHO、-C=NOH、-COCH3或也可以有从卤素、羟基、甲氧基、氨基、乙酰胺基和三氟甲基组成的一组中选择的一个或两个取代基取代的芳基。
在本发明的另一个较好实施方案中,本发明的化合物包括这样一些化合物或其医药上可接受的无毒盐,其中:R和R1各自独立地是氢或甲基;R2、R3和R4各自独立地是氢、氯、硝基或三氟甲基,只要R2、R3和R4不全是氢即可;R5是氯;R6是氢或氟;n是0、1或2;m是0或1;且R7是-CH3、-CH2OH、-CHO、-CH=NOH、-COCH3或也可以有卤素、羟基、甲氧基、氨基、乙酰胺基和三氟甲基取代的芳基。
在本发明的又另一个更好的实施方案中,式I化合物包括这样一些化合物或其医药上可接受的无毒直,其中:R是氢或甲基;R1和R4是氢;R2和R3各自独立地是三氟甲基;R5是氯;R6是氢;n是0、1或2;m是0或1;且R7是-CH2OH或也可以有卤素、羟基、甲氧基、氨基、乙酰胺基和三氟甲基取代的芳基。
在另一个方面,本发明提供在有其需要的哺乳动物中经由大电导钙活化K+通道(BK通道)的打开而传递的疾病的治疗或防护方法,包含对所述哺乳动物给药某一治疗有效量的式I化合物或其医药上可接受的无毒盐。较好的是,式I化合物可用于治疗局部缺血、中风、惊厥、哮喘、刺激性肠综合征、偏头痛、创伤性脑损伤、尿失禁,和通过改善进入生殖器尤其海绵体的血流量来治疗男人(例如由于糖尿病、脊髓损伤、根本性前列腺切除术、心原性病因学或任何其它原因引起的勃起机能障碍)和女人的性机能障碍,及其它对BK通道活化活性敏感的病症。
在又另一个方面,本发明提供医药组合物,其中包含与辅药,载体或稀释剂组合的至少一种式I化合物。生物学活性
钾(K+)通道是结构上和功能上多种多样的、在细胞中随遇的K+选择性通道蛋白质家族,这表明它们在调控许多关键细胞功能方面的核心重要性[Rudy,B.,
Neuroscience,25:729-749(1988)]。虽然作为一个类别是广泛分布的,但作为这个类别的各个成员或作为各家族,K+通道的分布是有差异的[Gehlert,D.R.等人,
Neuroscience,52:191-205(1993)]。一般来说,细胞中,尤其可激发细胞例如神经元和肌肉细胞中,K+通道的活化导致细胞膜的超极化,或在去极化细胞的情况下导致再极化。除了充当一种内源膜电压钳外,K+通道还能对重要的细胞事件例如细胞内ATP浓度或细胞内钙(Ca2+)浓度的变化作出回应。K+通道在调控许多细胞功能方面的核心作用使其成为特别重要的治疗发展目标[Cook,N.S.,钾通道:结构、分类、功能和治疗潜力。Ellis Horwood,Chinchester(1990)]。钾通道的一个类别,即大电导Ca2+活化K+通道(Maxi-K或BK通道),受到跨膜电压、细胞内Ca2+、和各种各样其它因素例如通道蛋白质的磷酰化状态调控[Latorre,R.等人,
Ann.Rev.Physiol.,51:385-399(1989)]。BK通道对K+的大单一通道电导(一般>150pS)和高度专一性表明少数通道可能显著影响膜电导和细胞可激发性。此外,打开概率随细胞内Ca2+的增加而增大,表明BK通道参与Ca2+依赖型现象例如分泌和肌肉收缩的调制[Asano,M.等人,
J.Pharmacol.Exp. Ther.,267:1277-1285(1993)]。
BK通道打开剂通过提高这些通道的打开概率施加其细胞影响[McKay,M.C.等人,
J.Neurophysiol.,71:1873-1882(1994);和Olesen,S.-P.,
Exp.Opin.Invest.Drugs,3:1181-1188(1994)]。各个BK通道打开的增加,总体上导致由于整个细胞经由BK的电导的显著增加而产生的、尤其去极化细胞中的细胞膜超极化。
本发明中所述化合物打开BK通道和增加整个细胞向外经由(K+)BK传递的电流是在电压钳条件下通过测定它们增加在爪蟾卵母细胞中异种表达的克隆哺乳动物(mSlo或hSlo)经由BK传递的向外电流的能力来评价的[Butler,A.等人,
Science,261:221-224(1993);和Dworetzky,S.I.等人,
Mol.Brain Res.,27:189-193(1994)]。所采用的这两种BK建群代表结构上几乎同一的同源蛋白质,并证明在我们的试验中是药理学上同一的。为了把BK电流与土著(背景、非BK)电流分离开,以超大浓度(50 nM)采用了专一和强力的BK通道阻滞性毒素iberiotoxin(IBTX)[Galvez,A.等人,
J.Biol. Chem.,265:11083-11090(1990)]。BK通道电流对总外向电流的相对分布是通过从所有其它实验条件(对照、药物、和洗涤)下得到的电流分布减去IBTX存在下剩余的电流(非BK电流)来确定的。已确定,在所试验的浓度时,所剖析的化合物在卵母细胞中不产生非BK土著电流。所有化合物都用至少5个卵母细胞测试,并以20μm的单一浓度报告;所选择式I化合物对BK电流的影响表示为对照组IBTX-敏感电流的百分率,而且列于表1中。记录是用标准双电极电压钳技术进行的[Stuhmer,W.等人,
Methods in Enzymology,Vol.207:319-339(1992)];电压钳试验方案的组成为:以20mV步长,从-60mV到+140mV的持有电位,进行500~750ms持续时间步进去极化。实验介质(改性Barth溶液)的组成(以mM表示)为:NaCl(88),NaHCO3(2.4),KCl(1.0),HEPES(10),MgSO4(0.82),Ca(NO3)2(0.33),CaCl2(0.41);pH7.5.
表1
*在20μm,表示为比对照组中BK电流增加的百分率
实施例号 | BK电流* |
3 | + |
4 | + |
8 | ++ |
9 | ++ |
17 | + |
18 | + |
20 | ++ |
21 | ++ |
30 | ++ |
32 | ++ |
34 | ++ |
39 | ++ |
+=100-200%
++=>200%
为确定这些化合物减少因神经元局部缺血而造成的细胞损失的能力,采用了一种有永久病灶性局部缺血的标准啮齿动物模型,涉及自发高血压大鼠中脑动脉闭塞(中脑动脉闭塞(MCAO)模型)[Tamura,A.等人,
Journal of Cerebral Blood Flow and Metabolism,Vol.1,53-60(1982)]。
所选择的化合物用自发高血压大鼠中涉及永久性MCAO的病肚性中风模型进行评估。这种程序导致可靠的大规模新皮层梗塞体积,这是在MCAO后24小时借助于大脑连续切片活体染料排除法测定的。在本试验中,化合物是在闭塞后2小时用静脉内给药途径给药的。例如,在这种模型中,实施例21的化合物当在中脑动脉闭塞后2小时作为单一药团给药(0.003mg/kg)时,与载体(2%DMSO,98%丙二醇)处理的对照组比较,使皮层梗塞体积减少约25%。
勃起功能活体模型在科学文献中有充分描述[Rehman,J.,Chenven,E.,Brink,P.,Peterson,B.,Wolcott,B.,Wen,Y.P.,Metman,A.,Christ,G.:减少2~3个月实验糖尿病F-344大鼠中神经原的而不是药理学的勃起。
Am.J.Physiol.
272:H1960-1971(1997)]。简而方之,大鼠(250~600g)用戊巴比妥钠麻醉,开腹,确认海绵体神经。把一根压力导管放进右海绵体(脚)内,以测量海绵体内压力(ICP)。把第二根导管引进颈动脉中以测量血压。试验化合物(0.1、0.3和1mg/kg,静脉内给药)或载体(PEG400)是经由置入颈静脉内的一根导管给予的。
对照海绵体内压力响应是通过经由双极刺激电极(20Hz,0.22ms脉冲宽度)对海绵体神经进行电刺激来激发的。调整刺激辐度(0.2~20mA),以产生一个亚最大海绵体内压力响应(典型地是0.2或0.5mA)。然后,用一个恒定刺激辐度得到一系列对照海绵体内压力响应。然后给药(200μl,经静脉内一次给药)试验化合物或载体,重新刺激海绵体神经以在给药后不同时间引起海绵体压力响应。如果对神经刺激的初始ICP响应是不稳定的(“大钉似的”响应)或者如果在对照响应的量级上有时间依赖型变异,就把那些动物从研究中排除出去。如果对照ICP/BP响应落在0.3~0.6范围之外,也将那些动物排除在外。用重复量度ANOVA进行统计意义评估。
实施例20的化合物(0.1~1mg/kg)产生了海绵体神经亚最大刺激引起的ICP/BP响应增大。在0.1~1.0mg/kg试验化合物剂量时观察到ICP/BP比值显著增大。
以上生物学试验结果证实,本发明的化合物是大电导钙化K+通道(Maxi-K或BK通道)的强力打开剂。因此,本发明化合物可用于治疗因细胞膜极化和电导机能障碍引起的人类病症,较好用于治疗局部缺血、中风、惊厥、癫痫、哮喘、刺激性肠综合征、偏头痛、创伤性脑损伤、脊髓损伤、性机能障碍、尿失禁、尤其男性勃起机能障碍,及其它对BK通道活化活性敏感的病症。
在另一个实施方案中,本发明包括医药组合物,包含与辅药、载体或稀释剂组合的式I的至少一种化合物。
在又另一个实施方案中,本发明涉及在有其需要的哺乳动物中对钾通道的打开有反应的病症的治疗或预防方法,包含对所述哺乳动物给药某一治疗有效量的式I化合物或其医药上可接受的无毒盐。
对于医疗用途来说,式I的药理学活性化合物通常以医药组合物形式给药,其中作为该(或一种)基本有效成分,包含至少一种这样的化合物,并配合一种固体或液体的医药上可接受的载体,而且也可以有医药上可接受的辅药和赋形剂,采用标准和惯常技术配制。
该医药组合物包括经口、非经肠(包括经皮下、经肌内、经真皮内、经静脉内)、经支气管或经鼻给药的适用剂型。因此,如果使用一种固体载体,则该制剂可以压片、以粉末或粒料形式放进硬质胶囊中、或呈含锭或糖锭形式。该固体载体可以含有惯常赋形剂,例如粘结剂、填充剂、压片润滑剂、崩解剂、润湿剂等。该片剂,如果愿意,可以用惯常技术进行薄膜包衣。如果采用一种液体载体,则该制剂可以呈糖浆、乳液、软胶囊、注射用无菌载体、水基或非水基液体悬浮液的剂型,也可以是一种在使用前用水或其它适用载体再构建用干产品。液体制剂可以含有惯常添加剂,例如悬浮剂、乳化剂、润湿剂、非水载体(包括食用油)、防腐剂、以及矫味矫臭剂和/或着色剂。对于非经肠给药来说,载体通常包含无菌水,至少大部分如此,尽管可以利用食盐水溶液、葡萄糖溶液等。也可以使用可注射悬浮液,在这种情况下可以采用惯常悬浮剂。也可以向非经肠剂型中添加惯常防腐剂、缓冲剂等。特别有用的是式I化合物直接以非经肠配方给药。这些医药组合物是用适合于含有适量有效成分即按照本发明的式I化合物的所希望制剂的惯用技术制备的。见诸如
Remington’s Pharmaceutical Sciences,Mack出版公司,宾夕法尼亚州伊斯顿,第17版,1985年。
式I化合物达到疗效的剂量不仅将取决于患者的年龄、体重和性别等因素,而且也将取决于所希望的钾通道活化活性程度和特定化合物用于所涉及疾病的特定病症的药效。也预料到的是,特定化合物的治疗和剂量可以以单元剂型给药,而且该单元剂型可以由熟悉本门技术的人员按常规调整以反映相对活性水平。关于要采用的特定剂量(和每日要给药的次数)的决定要遵医嘱,而且可以通过适合于本发明特定情况的剂量滴定加以改变以产生所希望的疗效。
对于经口给药来说,患有或可能患有这里所述任何一种病症的哺乳动物(包括人类)适用的式I化合物或其医药组合物剂量,是有效成分数量为约0.01μg/kg~10mg/kg体重,较好为约0.1μg/kg~5mg/kg体重。对于非经肠给药来说,经静脉内给药的剂量可以在0.1μg/kg~1mg/kg体重的范围内。该有效成分较好以每日1~4次等剂量给药。然而,通常是给药某一小剂量,再逐渐增加该剂量,直至确定该治疗主体的最佳剂量为止。
本发明化合物可以单独使用,也可以与其它可用于性机能障碍治疗的适用治疗剂例如cGMP PDE抑制剂,尤其cGMP PDE V抑制剂如Sildenafil,组合使用。这些治疗剂的实例是PDE V抑制剂,可选自咪唑并喹唑啉(见WO 98/08848)、咔唑(见WO 97/03675,WO97/03985和WO 95/19978)、咪唑并-6-羟基嘌呤(见WO 97/19947)、苯并咪唑(见WO 97/24334)、吡唑并喹啉(见美国专利5,488,055)、邻氨基苯甲酸衍生物(见WO 95/18097)、稠合杂环(见WO 98/07430)和噻吩并嘧啶(见DE 19632423)。
以上治疗剂,当与本发明化合物组合使用时,可以诸如以《医生案头参考资料)》(PDR)中指出的或者有本门技术一般技能的人员用其它方式确定的那些数量使用。
然而,要理解的是,该化合物的实际给药量将由医生根据有关情况来确定,其中包括要治疗的病症,要给药的化合物的选择,所选择的给药途径,个体患者的年龄、体重、和反应,和该患者症状的严重性。
以下实施例是举例说明方式给出的,而且不要理解成以任何方式对本发明的限制,因为在本发明范围内本发明的许多变异是可能的。
具体实施方案说明
在以下实施例中,温度全都以摄氏度表示。熔点用一台Gallenkamp毛细管熔点仪记录,且未进行修正。质子核磁共振(1HNMR)谱是用一台Bruker AC 300谱仪记录的。所有谱线都用所指出的溶剂测定,化学位移是以从内标物四甲基甲硅烷(TMS)向低磁场方向漂移的δ单位报告的,质子间偶合常数以赫兹(Hz)报告。谱线分裂方式指定如下:s,单峰;d,双峰;t,三峰;q,四峰;m,多峰;br,宽峰;dd,双峰之双峰;bd,宽双峰;dt,三峰之双峰;bs宽单峰;dq,四峰之双峰。采用溴化钾(KBr)测定的红外(IR)光谱是用一台Perkin Elmer 781谱仪从4000cm-1~400cm-1测定的,对聚苯乙烯薄膜的1601cm-1进行校准,以厘米倒数(cm-1)报告。低分辨质谱(MS)和表观分子量(MH+)或(M-H)-是用一台Finnigan TSQ7000测定的。元素分析是以重量百分率报告的。除非在这些具体实施方案中另有所指,否则在实施例的描述性标题下R2和R4是H。
实施例1
4-(5-氯-2-甲氧基苯基)-1,2-二氢-2-氧代-6-(三氟甲基)-3-喹啉羧酸甲酯(3,R3=CF3,Ra=CH3)
步骤A:N-[2-[(5-氯-2-甲氧基苯基)羰基]-4-(三氟甲基)苯基]氨基羧酸1,1-二甲基乙酯
4-氨基三氟甲苯(35g,0.218mol)和(Boc)2O(52.4g,0.24mol)的搅拌净相混合物在80℃加热2~3小时,直至CO2释放停止。让该混合物冷却,旋转蒸发tBuOH。所得到的白色固体用己烷/乙醚重结晶,提供白色针状(50.6g,89%)N-(叔丁氧羰基)-4-氨基三氟甲苯。
在氩气下,用20分钟时间,向N-Boc-4-氨基三氟甲苯(26.2g,0.1mol)在干燥THF(130mL)中的冷却(-78℃)搅拌溶液中添加tBuLi(130mL,0.22mol,1.74M环己烷溶液)。所得到的黄色部分溶液升温到-45°~-40℃并保持2小时。所得到的双阴离子稠黄色浆状物冷却到-78℃,迅速添加净相干燥5-氯-2-甲氧基苯甲酸甲酯(22.1g,0.11mol)。所得到的黄褐色溶液升温到-40℃并保持1小时。反应物用乙醚(200mL)稀释,用1N HCl(250mL)终止反应,然后使之升温到室温。将有机层分离,用水、食盐水洗涤,然后干燥(Na2SO4)。溶剂蒸发给出一种浅黄色固体(49.9g),再用乙醚研制给出31.9g所希望的标题化合物:mp 148-150℃;IR(KBr,cm-1)3280,1725,1640,1530,1320,1250,1150;1H NMR(300MHz,DMSO-d6):δ1.41(9H,s),3.58(3H,s),7.19(1H,d,J=8.9Hz),7.49(1H,d,J=2.7Hz),7.58(1H,d,J=2.6Hz),7.60(1H,dd,J=8.9和2.7Hz),7.93(1H,dd,J=8.7和1.9Hz),8.12(1H,s),8.15(1H,m),10.35(1H,s);MS m/e 430(MH+).分析计算C20H19ClF3NO4:C,55.88;H,4.45;N,3.25.
实测:C,55.51;H,4.38;N,3.26.
步骤B:1-[2-氨基-5-(三氟甲基)苯基]-1′-(5-氯-2-甲氧基苯基)甲酮(1,R3=CF3)
向N-[2-[(5-氯-2-甲氧基苯基)羰基]-4-(三氟甲基)苯基]氨基羧酸1,1-二甲基乙酯(19g,0.044mol)的乙醇(300mL)搅拌溶液中,添加3N HCl。所得到的悬浮液加热回流3小时。用TLC监测水解过程。将反应混合物冷却,并倾入冷水(500mL)中。产物用乙醚(2×200mL)萃取,合并的乙醚萃取物用水、食盐水洗涤、然后干燥(Na2SO4)。乙醚蒸发给出一种金黄色粘稠油状物,后者静置过液时凝固给出一种米黄色固体(14.6g,100%):mp 90-92℃;IR(KBr,cm-1)3340,3470,1640,1320,1240,1150,1025;1H NMR(300MHz,DMSO-d6):δ3.68(3H,s),6.97(1H,d,J=8.8Hz),7.19(1H,d,J=8.9Hz),7.26(1H,d,J=1.1Hz),7.36(1H,d,J=2.7Hz),7.53(2H,m),7.92(2H,brds);MS m/e330(MH+).分析计算C15H11ClF3NO2:C,54.64;H,3.36;N,4.25.
实测:C,54.65;H,3.37;N,4.16.
步骤C:3-[[2-[(5-氯-2-甲氧基苯基)羰基]-4-(三氟甲基)苯基]氨基]-3-氧代丙酸甲酯(2,R3=CF3,Ra=CH3)
向步骤B制备的1-[2-氨基-5-(三氟甲基)苯基]-1′-(5-氯-2-甲氧基苯基)甲酮(3.3g,10mmol)和无水吡啶(0.97mL,12mmol)的无水CH2Cl2(30mL)搅拌冷溶液(0℃)中,在氮气下,滴加丙二酸甲酯酰氯(1.3mL,12mmol)的无水CH2Cl2(10mL)溶液。让所得到的混合物回升到室温并保持1小时。使反应物冷却到0℃,然后用1N HCl(1mL)终止反应。将有机层分离,用饱和NaHCO3、水、食盐水相继洗涤,然后干燥(MgSO4)。CH2Cl2蒸发给出米黄色固体(4.28g),后者用乙醚研制,给出浅黄色固体状标题化合物(3.98g,93%):mp 138-140℃;IR(KBr,cm-1)1120,1314,1530,1644,1712,1738;1H NMR(300MHz,CDCl3):δ3.57(2H,s),3.66(3H,s),3.81(3H,s),6.92(1H,d,J=8.8Hz),7.38(1H,d,J=2.6Hz),7.47(1H,dd,J=8.8和2.6Hz),7.65(1H,s),7.75(1H,d,J=8.9Hz),8.84(1H,d,J=8.8Hz),11.91(1H,brd s);MS m/e 428(M-H)-.
步骤D:4-(5-氯-2-甲氧基苯基)-1,2-二氢-2-氧代-6-(三氟甲基)-3-喹啉羧酸甲酯(3,R3=CF3,Ra=CH3)
在氮气下,向步骤C制备的3-[[2-[(5-氯-2-甲氧基苯基)羰基]-4-(三氟甲基)苯基]氨基]-3-氧代丙酸甲酯(2.0g,4.65mmol)的无水THF(30mL)搅拌溶液中添加叔丁醇钾(0.63g,5.6mmol)。所得到的混合物加热回流30分钟。让反应物冷却,用乙醚(30mL)稀释,然后用1N HCl(20mL)酸化。将有机层分离,用食盐水洗涤,然后干燥(Na2SO4)。溶剂蒸发给出一种米黄色固体(1.94g),后者用EtAc/己烷重结晶,给出白色固体状标题化合物(1.82g,95%):mp 214-216℃;IR(KBr,cm-1)1128,1256,1322,1662,1742;1H NMR(300MHz,CDCl3):δ3.68(3H,s),3.70(3H,s),6.97(1H,d,J=8.8Hz),7.20(1H,d,J=2.5Hz),7.36(1H,s),7.44(1H,dd,J=8.8和2.5Hz),7.53(1H,d,J=8.6Hz),7.73(1H,d,J=8.6Hz),12.43(1H,brd s);MS m/e 412(MH+).分析计算C19H13ClF3NO4:C,55.42;H,3.18;N,3.40.
实测:C,55.27;H,2.94;N,3.30.
实施例2
4-(5-氯-2-甲氧基苯基)-3-(羟甲基)-6-(三氟甲基)-2(1H)-喹啉酮(4,R3=CF3)
向实施例1化合物(0.22g,0.54mmol)的无水THF(10mL)冷(-78℃)搅拌溶液中滴加氢化二异丁基铝(2.16mL 1M己烷溶液,2.16mmol)溶液。让混合物回升到室温,搅拌2~3小时。反应混合物用冰浴冷却,然后滴加1N HCl(10mL)小心地终止反应。反应混合物用EtOAc(20mL)稀释,将有机层分离,用水、食盐水洗涤,然后干燥(MgSO4)。溶剂蒸发给出一种纯白色固体(263mg),后者用乙醚研制,给出白色固体状标题化合物(178mg,86%):mp232-235℃;IR(KBr,cm-1)1126,1264,1322,1654,3442;1H NMR(300MHz,CDCl3):δ3.70(3H,s),4.41(1H,d,J=12.5Hz),4.53(1H,d,J=12.5Hz),7.01(1H,d,J=8.8Hz),7.15(1H,d,J=2.6Hz),7.33(1H,s),7.47(1H,dd,J=8.8和2.6Hz),7.52(1H,d,J=8.6Hz),7.71(1H,d,J=8.6Hz),12.33(1H,brd s);MS m/e 384(MH+).分析计算C18H13ClF3NO3:C,56.34;H,3.41;N,3.65.
实测:C,55.72;H,3.44;N,3.55.
实施例3
4-(5-氯-2-甲氧基苯基)-3-(羟甲基)-7-(三氟甲基)-2(1H)-喹啉酮(4,R3=R4=H,R2=CF3)
遵照实施例1和2中所述的一般程序,制备了标题化合物。mp 174-176℃;MS m/e 384(MH+);1H NMR(300MHz,DMSO-d6):δ3.64(3H,s),3.88(1H,d,J=11.0Hz),4.31(1H,d,J=11.0Hz),4.70(1H,brd s),7.05(1H,d,J=8.4Hz),7.23(1H,d,J=8.9Hz),7.29(1H,d,J=2.4Hz),7.36(1H,d,J=8.4Hz),7.55(1H,dd,J=8.7和2.4Hz),7.65(1H,s),1223(1H,s).
实施例4
4-(5-氯-2-甲氧基苯基)-1,2-二氢-2-氧代-6-(三氟甲基)-3-喹啉甲醛(5,R3=CF3)
向实施例2化合物(384mg,1mmol)的无水CH2=Cl2(10mL)搅拌溶液中添加二氧化锰(0.44g,5mmol)。所得到的悬浮液在氮气下搅拌过夜。再添加一份MnO2(0.44g,5mmol),继续搅拌该悬液,直至氧化完成(2~3天)。该悬浮液通过一层硅藻土过滤,用另一份CH2Cl2洗涤。溶剂蒸发给出淡黄色固体状标题化合物(206mg,54%):mp 238-240℃;IR(KBr,cm-1)1120,1268,1320,1678,1707;1H NMR(300MHz,CDCl3):δ3.71(3H,s),7.01(1H,d,J=8.9Hz),7.10(1H,d,J=2.6Hz),7.48(1H,m),7.51(1H,d,J=2.6Hz),7.59(1H,d,J=8.6Hz),7.82(1H,dd,J=8.7和1.8Hz),10.29(1H,s),12.53(1H,brd s);MS m/e 380(M-H)-.
实施例5
(E)-3-[4-(5-氯-2-甲氧基苯基)-1,2-二氢-2-氧代-6-(三氟甲基)-3-喹啉基]-2-丙烯酸乙酯(6,R3=CF3)
向NaH(84mg,2.1mmol,60%矿物油悬浮液)的无水DMF(2mL)搅拌冷悬浮液中,在氮气下,滴加膦酰乙酸三乙酯(0.43g,1.95mmol)的DMF(1mL)溶液。混合物搅拌30分钟,然后添加净相4-(5-氯-2-甲氧基苯基)-1,2-二氢-2-氧代-6-(三氟甲基)-3-喹啉甲醛(0.60g,1.62mmol)。让所得到的混合物回升到室温,搅拌3小时。这一段时间之后,TLC显示该醛不存在和酯异构体混合物的生成。该反应用冰浴冷却,用1N HCl终止反应。产物用1∶1乙醚/EtOAc萃取,用饱和NaHCO3、水、食盐水洗涤,然后干燥(Na2SO4)。溶剂蒸发给出一种米黄色固体(0.765g),后者用EtOAc/己烷重结晶,提供纯反式(E)异构体的标题化合物(0.497g)。母液浓缩,随后用乙醚研制,给出另外123mg异构体混合物的酯。该精制酯的合并总产率是0.62g(86%)。标题化合物的分析数据:mp 270-273℃;IR(KBr,cm-1)1 126,1284,1322,1664,1713;1H NMR(300MHz,CDCl3):δ1.28(3H,t,J=7.1Hz),3.70(3H,s),4.20(2H,q,J=7.1Hz),7.04(1H,d,J=8.9Hz),7.11(1H,d,J=2.6 Hz),7.24-7.33(2H,m),7.43(1H,s),7.48-7.52(2H,m),7.76(1H,d,J=8.6Hz),12.02(1H,brd s);MS m/e 450(M-H)-.
实施例6
(E)-4-(5-氯-2-甲氧基苯基)-3-(3-羟基-1-丙烯基)-6-(三氟甲基)-2(1H)-喹啉酮(7,R3=CF3)
在氮气下,向实施例5化合物的酯(0.3g,0.66mmol)的无水THF(9mL)搅拌冷(-78℃)溶液中滴加Dibal-H(氢化二异丁基铝)己烷溶液(3mmol,3mL 1M溶液)。让该混合物回升到室温,搅拌2小时。反应混合物用冰浴冷却,然后用1N HCl(10mL)小心终止反应。添加乙酸乙酯(30mL),分离,用水、食盐水洗涤,然后干燥(MgSO4)。溶剂蒸发给出一种白色固体(0.29g),后者用乙醚研制,给出作为一种醇的标题化合物(234mg):mp 266-268℃;1H NMR(300MHz,DMSO-d6):δ3.67(3H,s),3.96(2H,m),4.76(1H,t,J=5.3Hz),6.11(1H,d,J=15.7Hz),7.01(1H,s),7.18(1H,dt,J=15.7和4.6Hz),7.27-7.31(2H,m),7.52(1H,d,J=8.6Hz),7.60(1H,dd,J=8.9和2.7Hz),7.79(1H,dd,J=8.6和1.8Hz),12.36(1H,s);MS m/e 408(M-H)-.分析计算C20H15ClF3NO3:C,58.62;H,3.69;N,3.42.
实测:C,58.50;H,3.74;N,3.35.
实施例7
-4-(5-氯-2-甲氧基苯基)-1,2-二氢-2-氧代-6-(三氟甲基)-3-喹啉丙酸乙酯(8,R3=CF3)
向Parr摇瓶内实施例5制备的酯的乙醇和无水HCl溶液中,在氮气下添加PtO2(5~10%重量)进行处理。所得到的悬浮液在60psi加氢过夜。将催化剂滤出,滤液进行旋转蒸发,给出标题化合物:mp193-195℃;1H NMR(300MHz,CDCl3):δ1.16(3H,m),2.43(2H,m),2.65(2H,m),3.65(3H,s),4.01(2H,m),6.96-7.01(2H,m),7.14(1H,s),7.25(2H,s),7.40-7.43(2H,m),7.60(1H,brd s);MS m/e 452(M-H)-.
实施例8
4-(5-氯-2-甲氧基苯基)-3-(3-羟基丙基)-6-(三氟甲基)-2(1H)-喹啉酮(9,R3=CF3)
遵照实施例6所述的一般程序,使实施例7的化合物还原,提供标题化合物。Mp 200-202℃;1H NMR(300MHz,CDCl3):δ1.60(2H,m),2.20(3H,brd m),3.50(2H,m),3.63(3H,s),6.97(1H,d,J=8.8Hz),7.04(1H,d,J=2.6Hz),7.16(1H,s),7.19(1H,s),7.41(1H,dd,J=8.8和2.6Hz),7.49(1H,d,J=8.3Hz),7.65(1H,J=7.36Hz),12.45(1H,brd s);MS m/e 412(MH)+.
实施例9
4-(5-氯-2-羟基苯基)-3-(羟甲基)-6-(三氟甲基)-2(1H)-喹啉酮(14,R3=CF3)
步骤A:[2-氨基-5-(三氟甲基)苯基](5-氯-2-羟基苯基)甲酮(10,R3=CF3)
向实施例1步骤A制备的N-[2-[(5-氯-2-甲氧基苯基)羰基]-4-(三氟甲基)苯基]氨基羧酸1,1-二甲基乙酯(7.0g,21.2mmol)的二氯甲烷(60mL)冷(-78℃)溶液中,滴加1.0M BBr3的二氯甲烷溶液(46.7mL,46.7mmol)。让所得到的红色溶液回升到室温,搅拌过夜。用饱和NaHCO3溶液使反应混合物终止反应。将有机层分离,用水、食盐水洗涤,然后干燥(MgSO4)。溶剂蒸发给出一种红黄色固体,后者用CH2Cl2/己烷重结晶,给出黄色固体状标题化合物(6.58g,98%)。
步骤B:3-[[2-[(5-氯-2-羟基苯基)羰基]-4-(三氟甲基)苯基]氨基]-3-氧代丙酸甲酯(11,R3=CF3)
在0℃,向[2-氨基-5-(三氟甲基)苯基](5-氯-2-羟基苯基)甲酮(0.5g,1.58mmol)和吡啶(0.25mL,3.17mmol)的二氯甲烷(15mL)溶液中,滴加丙二酸甲酯酰氯(0.34mL,3.17mmol)的二氯甲烷(10mL)溶液。然后,让反应混合物回升到室温,搅拌2小时。用1N HCl使反应混合物酸化,将有机层分离。然后用饱和NaHCO3洗涤2次、用水、食盐水洗涤,干燥(MgSO4)。溶剂蒸发给出黄色油状标题化合物。
步骤C:2-氯-6,8-二氢-11-(三氟甲基)-7H-[1]苯并吡喃并[3,4-C]喹啉-6,7-二酮(12,R3=CF3)
把步骤B制备的粗3-[[2-[(5-氯-2-羟基苯基)羰基]-4-(三氟甲基)苯基]氨基]-3-氧代丙酸甲酯溶解在THF(15 mL)中,添加叔丁醇钾溶液(1M THF溶液,1.74mmol,1.74mL)。反应混合物加热回流15分钟,然后用1N HCl酸化,将有机层分离。有机层用水、食盐水洗涤,干燥(MgSO4)。溶剂蒸发给出一种黄色固体,后者用乙酸乙酯/已烷研制,给出黄色固体状标题化合物(0.48g,83%):mp>250℃。MS m/e 366(MH+)。分析计算C17H7ClF3NO3·0.5H2O:C,54.49;H,2.15;N,3.74.
实测:C,54.10;H,1.85;N,3.63.1H NMR(DMSO-d6):δ7.48(d,J=8.8Hz,1H),7.55(d,J=8.5Hz,1H),7.76(dd,J=8.9Hz,2.2Hz,1H),7.98(d,J=8.7Hz,1H),8.10(d,J=2.1Hz,1H),8.42(s,1H).IR(KBr,cm-1):3479,3074,1761,1652,1630,1577,1368,1325,1141.
步骤D:4-(5-氯-2-羟基苯基)-3-(羟甲基)-6-(三氟甲基)-2(1H)-喹啉酮(14,R3=CF3)
向步骤C制备的2-氯-6,8-二氢-11-(三氟甲基)-7H-[1]苯并吡喃并[3,4-C]喹啉-6,7-二酮(1.0g,2.73mmol)的二氯甲烷(20mL)冷(-78℃)悬浮液中,滴加氢化二异丁基铝溶液(二氯甲烷中1M,13.7mL,13.7mmol)。让反应混合物回升到0℃,保持3小时。反应混合物用1N HCl酸化,用乙酸乙酯萃取2次。将有机层分离,用水、食盐水洗涤,然后干燥(MgSO4)。溶剂蒸发,随后粗产物用乙酸乙酯/己烷重结晶,给出白色固体状标题化合物(0.7g,69%):mp>250℃;MS m/e 368(M-H)-。分析计算C17H11ClF3NO3:C,55.23;H,3.00;N,3.79.
实测:C,56.59;H,4.02;N,3.36.1H NMR(DMSO-d6):δ3.90(dd,J=10.9Hz,5.3Hz,1H),4.36(dd,J=10.9Hz,5.6Hz,1H),4.70(t,J=5.4Hz,1H),7.03(d,J=8.7Hz,1H),7.17(s,1H),7.26(d,J=2.7Hz,1H),7.39(dd,J=8.7Hz,2.7Hz,1H),7.53(d,J=8.6Hz,1H),7.81(dd,J=8.9Hz,1.9Hz,1H),9.95(s,1H),12.31(s,1H).
实施例10
3-[4-(5-氯-2-羟基苯基)-1,2-二氢-2-氧代-6-(三氟甲基)-3-喹啉基]-2-丙烯酸乙酯(15,R3=CF3)
步骤A:2-氯-6,8-二氢-6-羟基-11-(三氟甲基)-7H-[1]苯并吡喃并[3,4-c]喹啉-7-酮(13,R3=CF3)
向实施例9步骤C制备的2-氯-6,8-二氢-11-(三氟甲基)-7H-[1]苯并吡喃并[3,4-c]喹啉-6,7-二酮(1.15g,3.15mmol)的THF(30mL)冷(-78℃)溶液中滴加氢化二异丁基铝溶液(THF中1M,15.7mL,15.7mmol)。反应混合物在-78℃保持4小时。反应混合物用1N HCl酸化,用乙酸乙酯萃取2次。将有机层分离,用水、食盐水洗涤,然后干燥(MgSO4)。溶剂蒸发,随后粗产品用乙酸乙酯研制,给出白色固体状标题化合物(0.9g,78%):mp>260℃;MS m/e 366(M-H)-。分析计算C17H9ClF3NO3·0.25H2O:C,54.86;H,2.57;N,3.76.
实测:C,54.92;H,2.92;N,3.46.1H NMR(DMSO-d6):δ6.40(d,J=6.2Hz,1H),7.31(d,J=8.7Hz,1H),7.55-7.63(m,3H),7.94(d,J=8.7Hz,1H),8.07(d,J=2.4Hz,1H),8.38(s,1H),12.44(s,1H).1R(KBr,cm-1):3300,1669,1631,1605,1575,1326,1279,1133.
步骤B:3-[4-(5-氯-2-羟基苯基)-1,2-二氢-2-氧代-6-(三氟甲基)-3-喹啉基]-2-丙烯酸乙酯(15,R3=CF3)
向NaH(矿物油中60%,41mg,1.0mmol)的DMF(3mL)冷(0℃)悬浮液中滴加膦酰乙酸三乙酯(0.1mL,0.5mmol)。反应混合物在0℃搅拌0.5小时,然后添加实施例10步骤A制备的2-氯-6,8-二氢-6-羟基-11-(三氟甲基)-7H-[1]苯并吡喃并[3,4-c]喹啉-7-酮(0.15g,0.41mmol)的DMF(5mL)溶液。让红色反应混合物回升到室温,搅拌4小时。反应混合物用1N HCl溶液小心终止反应,用乙酸乙酯萃取。将有机层分离,用饱和NaHCO3、水、食盐水洗涤,干燥(MgSO4)。溶剂蒸发,随后用乙酸乙酯/己烷重结晶,给出白色固体状标题化合物(127mg,72%):mp 262-268℃(分解);MS m/e 436(M-H)-。分析计算C21H15ClF3NO4:C,57.61;H,3.45;N,3.20.
实测:C,57.31;H,3.46;N,3.15.1H NMR(DMSO-d6):δ1.18(t,J=7.1Hz,3H),4.09(q,J=7.0Hz,1H),7.08(d,J=8.8Hz,1H),7.16(d,J=15.7Hz,1H),7.20(s,1H),7.29(d,J=2.7Hz,1H),7.34(d,J=15.7Hz,1H),7.48(dd,J=8.7Hz,2.7Hz,1H),7.57(d,J=8.6Hz,1H),7.90(dd,J=8.8Hz,1.8Hz,1H),10.1(s,1H),12.6(s,1H).IR(KBr,cm-1):3225,1683,1662,1626,1323,1301,1115.
实施例11
3-[4-(5-氯-2-羟基苯基)-1,2-二氢-2-氧代-6-(三氟甲基)-3-喹啉基]-2-丙烯酸(16,R3=CF3)
向实施例10化合物(40mg,0.09mmol)的EtOH(2mL)溶液中添加10N NaOH(1mL),混合物在室温搅拌过夜。反应混合物用1N HCl酸化,收集析出的标题化合物的淡黄色固体(34mg,产率91%):mp 258-261℃;MS m/e 408(M-H)-。分析计算C19H11ClF3NO4·0.5H2O:C,52.79;H,3.15;N,3.24.
实测:C,52.93;H,2.82;N,3.10.1H NMR(DMSO-d6):δ7.07-7.13(m,2H),7.18(s,1H),7.25-7.30(m,2H),7.47(dd,J=8.7Hz,2.7Hz,1H),7.57(d,J=8.7Hz,1H),7.89(dd,J=8.7Hz,1.7Hz,1H),10.11(s,1H),12.37(s,br,1H),12.57(s,1H).IR(KBr,cm-1):3144,2996,1676,1628,1323,1270,1252,1130.
实施例12
4-(5-氯-2-羟基苯基)-3-(3-羟基-1-丙烯基)-6-(三氟甲基)-2(1H)-喹啉酮(17,R3=CF3)
向实施例10化合物(0.2g,0.46mmol)的二氯甲烷(10mL)冷(-78℃)悬浮液中滴加氢化二异丁基铝溶液(二氯甲烷中1M,2.3mL,2.3mmol)。让反应混合物回升到室温,搅拌4小时。反应混合物用1N HCl酸化,用乙酸乙酯萃取2次。将有机层分离,用水、食盐水洗涤,干燥(MgSO4)。溶剂蒸发,随后用乙酸乙酯/己烷重结晶,给出纯白色固体状标题化合物(0.14g,77%):mp 203-209℃(分解);MS m/e 394(M-H)-。分析计算C19H13ClF3NO3·0.5H2O:C,56.38;H,3.49;N,3.48.
实测:C,56.35;H,3.72;N,3.29.1H NMR(DMSO-d6):δ3.97(dt,J=1.7Hz,4.9Hz,2H),4.77(t,J=5.3Hz,1H),6.16(dd,J=15.8Hz,1.9Hz,1H),7.05(d,J=8.7Hz,1H),7.10(s,1H),7.16(d,J=2.7Hz,1H),7.21(dt,J=15.7Hz,4.7Hz,1H),7.41(dd,J=8.7Hz,2.7Hz,1H),7.51(d,J=8.5Hz,1H),7.78(dd,J=8.7Hz,1.8Hz,1H),9.90(s,1H),12.32(s,1H)。IR(KBr,cm-1):3286,1656,1641,1322,1294,1169,1120,1075.
实施例13
4-(5-氯-2-羟基苯基)-1,2-二氢-2-氧代-6-(三氟甲基)-3-喹啉丙酸乙酯(18,R3=CF3)
向实施例10化合物(0.4g,0.91mmol)的乙醇(20mL)溶液中添加PtO2(38mg)和3滴1N HCl。该混合物在一台帕尔装置中以50psi加氢过夜。催化剂通过一层硅藻土滤出,用乙醇洗涤。滤液蒸发至干,白色残留物用闪急色谱法(硅胶,2∶1=乙酸乙酯∶己烷)精制,给出白色固体状标题化合物(0.29g,72%):mp 241-245℃(分解);MS m/e 438(M-H)-。分析计算C21H17ClF3NO4:C,57.35;H,3.90;N,3.18.
实测:C,57.27;H,4.02;N,2.99.1H NMR(CD3OD):δ1.18(t,J=7.1Hz,3H),2.49-2.55(m 2H),2.69-2.75(m,2H),4.05(q,J=7.1Hz,2H),7.02(d,J=8.7Hz,1H),7.13(d,J=2.6Hz,1H),7.26(s,1H),7.38(dd,J=8.7Hz,2.6Hz,1H),7.51(d,J=8.6Hz,1H),7.73(dd,J=8.6Hz,1.7Hz,1H).IR(KBr,cm-1):3353,1698,1656,1626,1376,1311,1270,1167,1128,1074.
实施例14
4-(5-氯-2-羟基苯基)-1,2-二氢-2-氧代-6-(三氟甲基)-3-喹啉丙酸(19,R3=CF3)
向实施例13化合物(38mg,0.087mmol)的乙醇(2mL)溶液中添加10N NaOH(1mL),混合物在室温搅拌过夜。反应物用1N HCl酸化,收集析出的白色固体,给出标题化合物(30mg,84%):mp255-258℃;MS m/e 410(M-H)-。分析计算C19H13ClF3NO4·0.5H2O:C,54.24;H,3.35;N,3.33.
实测:C,54.10;H,3.10;N,3.28.1H NMR(DMSO-d6):δ2.32-2.37(m,2H),2.47-2.51(m,2H),7.04-7.07(m,2H),7.25(d,J=2.6Hz,1H),7.40(dd,J=8.7Hz,2.7Hz,1H),7.52(d,J=8.6Hz,1H),7.79(dd,J=.8.7Hz,1.9Hz,1H),9.98(s,1H),12.10(s,br,1H),12.31(s,1H).IR(KBr,cm-1):3283,3155,1714,1626,1560,1405,1275,1194,1167,1132.
实施例15
4-(5-氯-2-羟基苯基)-3-(3-羟基丙基)-6-(三氟甲基)-2(1H)-喹啉酮(20,R3=CF3)
向实施例13化合物(0.2g,0.45mmol)的二氯甲烷(10mL)冷(-78℃)悬浮液中,滴加氢化二异丁基铝溶液(二氯甲烷中1M,3.7mL,3.7mmol)。让反应混合物回升到室温,搅拌4小时。反应混合物用1N HCl酸化,用乙酸乙酯萃取2次。将有机层分离,用水、食盐水洗涤,干燥(MgSO4)。溶剂蒸发,随后用乙酸乙酯/己烷重结晶,给出白色固体状标题化合物(145mg,80%):mp 257-259℃(分解);MS m/e 398(MH+)。分析计算C19H15ClF3NO3·0.67 EtOAc:
C,57.00;H,4.49;N,3.07.
实测:C,57.17;H,4.62;N,2.88.1H NMR(DMSO-d6):δ1.5(m,2H),2.3(m,2H),3.25(m,2H),4.35(m,1H),7.02-7.07(m,2H),7.21(d,J=2.5Hz,1H),7.39(dd,J=8.7Hz,2.7Hz,1H),7.51(d,J=8.5Hz,1H),7.77(d,J=8.5Hz,1H),9.90(s,1H),12.24 (s,1H).IR(KBr,cm-1):3315,1654,1624,1569,1324,1273,1125,1073.
实施例16和17
(E)-和(Z)-4-(5-氯-2-羟基苯基)-3-(2-氟-3-羟基-1-丙烯基)-6-(三氟甲基)-2(1H)-喹啉酮(23,R3=CF3)和(25,R3=CF3)
步骤A:向NaH(矿物油中60%,68mg,1.7mmol)的DMF(5mL)冷(0℃)悬浮液中添加2-氟-2-膦酰基乙酸三乙酯(0.165mL,0.82mmol)。所得到的混合物在0℃搅拌0.5小时,然后添加实施例10步骤A制备的2-氯-6,8-二氢-6-羟基-11-(三氟甲基)-7H-[1]苯并吡喃并[3,4-c]喹啉-7-酮(0.25g,0.68mmol)的DMF(5mL)溶液。让红色的反应混合物回升到室温,搅拌4小时。反应混合物用1N HCl终止反应,然后用乙酸乙酯萃取。将有机层分离,有饱和NaHCO3、水食盐水洗涤,然后干燥(MgSO4)。溶剂蒸发给出无色油状式(21)的酯异构体混合物(E∶Z=1∶2.5,224mg,72%)。
步骤B:向步骤A的粗酯(210mg,0.46mmol)的二氯甲烷(10mL)冷(-78℃)悬浮液中,滴加氢化二异丁基铝溶液(二氯甲烷中1M,3.3mL,3.3mmol)。让反应混合物回升到室温,搅拌过夜。反应混合物用1N HCl酸化,用乙酸乙酯萃取2次。将有机层分离,用水、食盐水洗涤,然后干燥(MgSO4)。粗异构体醇用柱色谱法(硅胶,2∶1乙酸乙酯/己烷)精制,给出实施例16的个体E-异构体(E)-4-(5-氯-2-羟基苯基)-3-(2-氟-3-羟基-1-丙烯基)-6-(三氟甲基)-2(1H)-喹啉酮(23,R3=CF3)和实施例17的个体Z-异构体(Z)-4-(5-氯-2-羟基苯基)-3-(2-氟-3-羟基-1-丙烯基)-6-(三氟甲基)-2(1H)-喹啉酮(25,R3=CF3)。以下说明(E)-和(Z)-异构体化合物的物理特征。
实施例16:(E)-4-(5-氯-2-羟基苯基)-3-(2-氯-3-羟基-1-丙烯基)-6-(三氟甲基)-2(1H)-喹啉酮(23,R3=CF3)mp 215-218℃(分解);MS m/e 412(M-H)-。分析计算C19H12ClF3NO3·0.33H2O:C,54.37;H,3.04;N,3.34.
实测:C,54.72;H,3.11;N,3.18.1H NMR(DMSO-d6):δ3.64(m,1H),3.83(m,1H),4.99(m,1H),5.61(d,J=19.6Hz,1H),7.03(d,J=8.7Hz,1H),7.20-7.23(m,2H),7.38(dd,J=8.7Hz,2.7Hz,1H),7.54(d,J=8.7Hz,1H),7.84(d,J=8.9Hz,1H),10.09(s,1H),12.42(s,1H).
实施例17:(Z)-4-(5-氯-2-羟基苯基)-3-(2-氯-3-羟基-1-丙烯基)-6-(三氟甲基)-2(1H)-喹啉酮(25,R3=CF3)mp 242-245℃(分解);MS m/e 412(M-H)-。分析计算C19H12ClF3NO3·0.33H2O:C,54.37;H,3.04;N,3.34.
实测:C,54.62;H,3.27;N,3.11.1H NMR(DMSO-d6):δ3.81-3.86(m,2H),5.35(t,J=5.9Hz,1H),5.57(d,J=40.3Hz,1H),7,00(d,J=8.7Hz,1H),7.12(d,J=2.6Hz,1H),7.21(s,1H),7.34(dd,J=8.7Hz,2.7Hz,1H),7.51(d,J=8.6Hz,1H),7.81(dd,J0=8.6Hz,1.6Hz,1H),9.90(s,1H),12.32(s,1H).
实施例18和19
遵照为实施例16和17的化合物所述的一般程序,如反应方案5中说明的那样,从实施例4制备的式(5)化合物,制备了实施例18的化合物(24,R3=CF3)(E-异构体)和实施例19的化合物(26,R3=CF3)(Z-异构体)。以下说明(E)-和(Z)-异构体的物理表征数据。
实施例18:(E)-4-(5-氯-2-甲氧基苯基)-3-(2-氟-3-羟基-1-丙烯基)-6-(三氟甲基)-2(1H)-喹啉酮(24,R3=CF3)mp 180-182℃;MS m/e:426(M-H)-.1H NMR(CDCl3):δ3.68(3H,s),4.10(2H,d,J=24.0Hz),5.54(1H,d,J=18.0Hz),7.01(1H,d,J=8.9Hz),7.04(1H,d,J=2.4Hz),7.32(1H,s),7.46(1H,dd,J=8.9和2.3Hz),7.52(1H,d,J=8.5Hz),7.73(1H,d,J=7.6Hz),11.65(1H,brd s).
实施例19:(Z)-4-(5-氯-2-甲氧基苯基)-3-(2-氟-3-羟基-1-丙烯基)-6-(三氟甲基)-2(1H)-喹啉酮(26,R3=CF3)mp 230-232℃;MS m/e:426(M-H)-.1H NMR(CDCl3):δ3.69(3H,s),4.09(2H,d,J=10.7Hz),5.70(1H,d,J=38.1Hz),6.98(1H,d,J=8.8Hz),7.09(1H,s),7.35(1H,s),7.41(1H,d,J=8.8Hz),7.50(1H,m),7.67(1H,brd s),11.75(1H,brd s).
实施例20
4-(5-氯-2-羟基苯基)-3-(2-羟基乙基)-6-(三氟甲基)-2(1H)-喹啉酮(31a,R3=CF3,n=2)
步骤A:4-[[2-[(5-氯-2-甲氧基苯基)羰基]-4-(三氟甲基)苯基]氨基]-4-氧代丁酸甲酯(27,R3=CF3,Ra=CH3,n=2)
把净相3-甲酯基丙酰氯(4.8mL,O.039mmol)添加到实施例1步骤B制备的1-[2-氨基-5-(三氟甲基)苯基]-1′-(5-氯-2-甲氧基苯基)甲酮(7.0g,0.021mol)和无水吡啶(4.8mL,O.059mol)的无水CH2Cl2(80mL)搅拌冷(O℃)溶液中。让所得到的混合物回升到室温,并保持2小时。反应物用1N HCl(50mL)酸化。将有机层分离,相继用饱和NaHCO3、水、食盐水洗涤,然后干燥(MgSO4)。CH2Cl2蒸发,所得到的残留物研制,给出7.71g(82%)标题化合物酰胺。1H NMR(300MHz,CDCl3):δ2.7(4H,m),3.06(3H,s),3.63(3H,s),6.85(1H,d,J=8.9Hz),7.16(1H,s),7.30(1H,d,J=2.6Hz),7.39(1H,dd,J=8.8,2.6Hz),7.57(1H,s),7.66(1H,dd,J=8.9,1.9Hz),8.79(1H,d,J=8.8Hz);MS m/e 444(MH+)
步骤B:4-(5-氯-2-甲氧基苯基)-4-羟基-1,2,3,4-四氢-2-氧代-6-(三氟甲基)-3-喹啉乙酸甲酯(28,R3=CF3,Ra=CH3,n=2)
把二(三甲基甲硅烷基)氨化钾溶液(甲苯中0.5M,57mL,28.5mmol)添加剂步骤A制备的4-[[2-[(5-氯-2-甲氧基苯基)羰基]-4-(三氟甲基)苯基]氨基]-4-氧代丁酸甲酯(4.05g,9.1mmol)的无水THF(25mL)搅拌冷(-78℃)溶液中,在-78℃保持3小时。用1N HCl酸化处理,随后用EtOAc萃取,给出粗标题化合物(4.05g,100%)。
步骤C:4-(5-氯-2-甲氧基苯基)-1,2-二氢-2-氧代-6-(三氟甲基)-3-喹啉乙酸(29,R3=CF3,n=2)
步骤B制备的粗4-(5-氯-2-甲氧基苯基)-4-羟基-1,2,3,4-四氢-2-氧代-6-(三氟甲基)-3-喹啉乙酸甲酯(2g,4.5mmol)的甲苯(25mL)搅拌悬浮液用35%HBr的乙酸(5mL)溶液处理。所得到的混合物在85℃加热过夜。反应混合物蒸发至干,使残留物在水与EtOAc之间分配。EtOAc萃取液用食盐水洗涤、干燥(MgSO4)、然后蒸发,给出标题化合物(1.45g,78%)。
步骤D:4-(5-氯-2-羟基苯基)-1,2-二氢-2-氧代-6-(三氟甲基)-3-喹啉乙酸(30,R3=CF3,n=2)
步骤C制备的粗4-(5-氯-2-甲氧基苯基)-1,2-二氢-2-氧代-6-(三氟甲基)-3-喹啉乙酸(1.45g,3.5mmol)和吡啶鎓盐酸盐(5g,43.3mmol)的净相混合物在185℃加热3小时。让反应混合物冷却,添加1N HCl,然后用EtOAc萃取,给出标题化合物(1.20g,86%):mp 158-160℃;1H NMR(300MHz,CD3OD):δ3.21(1H,d,J=16.7Hz),3.60(1H,d,J=16.7Hz),7.0(1H,d,J=8.8Hz),7.13(1H,d,J=2.6Hz),7.31(1H,m),7.37(1H,dd,J=8.8,2.6Hz),7.52(1H,d,J=8.6Hz),7.75(1H,d,J=8.6Hz);MS m/e 398(MH+).
步骤E:4-(5-氯-2-羟基苯基)-3-(2-羟基乙基)-6-(三氟甲基)-2(1H)-喹啉酮(31a,R3=CF3,n=2)
在氮气下,用20分钟时间,向步骤D制备的4-(5-氯-2-羟基苯基)-1,2-二氢-2-氧代-6-(三氟甲基)-3-喹啉乙酸(20g,0.05mol)这种酸的无水THF(125mL)搅拌冷(-10℃)部分溶液中滴加硼烷-二甲硫配合物溶液(THF中2M,125mL,0.25mol)。让所得到的清澈反应混合物回升到室温,继续搅拌2~3天(HPLC分析显示起始原料不存在)。反应混合物用冰浴冷却,然后滴加1N HaOH(125mL)直至呈碱性来终止反应,然后用1N HCl酸化。添加乙醚(250mL),分层,用水、食盐水洗涤,然后干燥(Na2SO4)。溶剂蒸发给出一种褐色固体(21.4g),后者用EtOAc-MeOH重结晶,作为第一茬给出2.6g纯白色固体。浓缩的母液用乙醚研制,作为第二茬给出8.7g灰白色固体.第二茬用EtOAc-MeOH重结晶,与第一茬合并,给出合计11.1g白色固体状标题化合物:mp 255-256℃;1H NMR(300MHz,CD3OD):δ2.73(2H,m),3.64(2H,t,J=7.4Hz),7.0(1H,d,J=8.8Hz),7.15(1H,d,J=2.6Hz),7.23(1H,宽s),7.36(1H,dd,J=8.8,2.6Hz),7.48(1H,d,J=8.6Hz),7.71(1H,dd,J=8.6,1.8Hz);MS m/e 384(MH+).分析计算C18H13ClF3NO3:C,56.34;H,3.41;N,3.65.
实测:C,56.18;H,3.58;N,3.48.
实施例21
4-(5-氯-2-甲氧基苯基)-3-(2-羟基乙基)-6-(三氟甲基)-2(1H)-喹啉酮(31b,R3=CF3,n=2)
实施例20步骤C的化合物按照实施例20步骤E中所述的一般程序进行反应,就给出标题化合物。mp 219-221℃;1H(300MHz,CDCl3):δ7.71(1H,d,J=8.4Hz),7.53-7.46(m,2H),7.23(1H,s),7.11(d,1H,J=2.7Hz),7.02(d,1H,J=8.7Hz),3.79(m,2H),3.70(s,3H),3.79(t.2H);MS m/e 397(MH+).分析计算C19H15ClF3NO3:C,57.37,H,3.80,N,3.52.
实测:C,57.31,H,3.94,N.3.38.
实施例22~23
式(34)和(35)化合物制备的一般程序
步骤A:式(1)的氨基苯酰苯的酰化
把净相酰氯(1.2当量)添加到式(1)的氨基苯酰苯(1当量)和无水吡啶(1.3当量)的无水CH2Cl2搅拌冷(0℃)溶液中。让所得到的混合物回升到室温,保持2~3小时。反应物用1N HCl酸化,分层,有机层用饱和NaHCO3、水、食盐水洗涤,然后干燥(MgSO4)。CH2Cl2蒸发给出通式(32)的对应酰胺。
步骤B:式(32)酰胺的环化
把二(三甲基甲硅烷基)氨化钾溶液(甲苯中0.5M,3当量)添加到式(32)酰胺(1当量)的无水THF搅拌冷(-78℃)溶液中,在-78℃保持3小时。用1N HCl进行酸化处理,随后用EtOAc萃取,给出式(33)的喹啉。
步骤C:式(33)喹啉的脱水
式(33)的粗化合物在甲苯中的搅拌悬浮液用35%HBr的乙酸溶液处理。所得到的混合物在85℃加热过夜。反应混合物蒸发至干,残渣在水与EtOAc之间分配。EtOAc萃取物用食盐水洗涤,干燥(MgSO4),然后蒸发,给出式(34)喹啉。
步骤D:式(34)化合物的脱甲基
式(34)的粗喹啉(1当量)和吡啶鎓盐酸盐(5当量)的净相混合物在185℃加热3小时。让反应混合物冷却,添加1N HCl,然后用EtOAc萃取,给出式(35)的对应羟基化合物。
实施例22
4-(5-氯-2-甲氧基苯基)-3-(4-甲氧基苯基)-6-(三氟甲基)-2(1H)-喹啉酮(34a,R3=CF3,R8=4-甲氧基苯基,n=0)mp 130-135℃;1H NMR(300MHz,CDCl3):δ7.62(1H,d,J=8.7Hz),7.36-7.25(3H,m),7.10(3H,d,J=8.7Hz),6.93(1H,d,J=2.7Hz),6.81(1H,d,J = 8.7Hz),6.77(2H,d,J=8.7Hz),3.77(s,3H),3.62(s,3H);MS m/e 459(MH+).分析计算C24H17ClF3NO3:C,62.69,H,3.73,N,3.05.
实测:C,62.74,H,3.92,N,2.89
实施例23
4-(5-氯-2-甲氧基苯基)-3-[(4-甲氧基苯基)甲基]-6-(三氟甲基)-2(1H)-喹啉酮(34b,R3=CF3,R8=4-甲氧基苯基,n=1)mp 110-114℃;1H NMR(300MHz,CDCl3):δ7.62(1H,d,J=8.7Hz),7.47-7.43(1H,dd,J=2.7Hz和8.7Hz),7.29(d,1H,J=2.7 Hz),7.23(s,1H),7.00-6.92(m,3H),6.70(d,1H,J=8.7Hz),3.78(dd,2H),3.72(s,3H),3.57(s,3H);MSm/e 473(MH+).
实施例24
4-(5-氯-2-甲氧基苯基)-3-(4-硝基苯基)-6-(三氟甲基)-2(1H)-喹啉酮(34c,R3=CF3,R8=4-硝基苯基,n=0)mp 218-22℃;1H(300MHz,CDCl3):δ8.12(2H,d,J=8.7Hz),7.72(1H,d,J=8.7Hz),7.43-7.36(m,4H),7.33-7.29(dd,1H,J=2.7和8.7Hz),6.95(d,1H,J=2.7Hz),6.82(d,1H,J=8.7Hz);MS m/e 474(MH+).分析计算C23H14ClF3N2O4:C,58.18,H,2.97,N,5.90.
实测:C,57.70,H,3.20,N,5.65.
实施例25
4-(5-氯-2-甲氧基苯基)-3-(4-氨基苯基)-6-(三氟甲基)-2(1H)-喹啉酮(34d,R3=CF3,R8=4-氨基苯基,n=0)mp 287℃;1H(300MHz,CDCl3):δ7.62(1H,d,J=8.4Hz),7.44(1H,d,J=8.4Hz),7.31(s,1H),7.27-7.23(m,4H),6.94-6.79(dd,1H,J=3.6和8.7Hz),6.82(s,1H),6.52(d,1H,J=8.7Hz);MS m/e 444(MH+).分析计算C23H16ClF3NO2:C,62.10,H,3.62,N,6.30.
实测:C,61.89,H,3.81,N,6.06.
实施例26
4-(5-氯-2-甲氧基苯基)-3-甲基-6-(三氟甲基)-2(1H)-喹啉酮(34e,n=0,R8=Me,R3=CF3)
式(33)的对应化合物(5.63mmol)、33%HBr的AcOH溶液(38.3mmol)和10mL AcOH的一种溶液在75℃加热3小时。让该溶液冷却到室温,用H2O(50mL)终止反应,然后搅拌12小时。沉淀物过滤、用H2O洗涤、真空干燥。浅褐色固体用乙酸乙酯/己烷重结晶,给出白色固体状标题化合物(0.550g,27%产率)。1H NMR(300MHz,CDCl3):δ2.04(s,3H),3.72(s,3H),7.03(d,1H,J=9.0Hz),7.12(s,1H),7.44 (m,3H),7.65(d,1H,J=8.4Hz),10.93(br s,1H);MS m/e 368(MH+);分析计算C18H13ClF3NO3·0.33H2O:C,58.79;H,3.56;N,3.81.
实测:C,58.89;H,3.82;N,3.53.
实施例27
4-(5-氯-2-羟基苯基)-3-(3,4-二甲氧基苯基)-6-(三氟甲基)-2(1H)-喹啉酮(35a,R3=CF3,R8=3,4-二甲氧基苯基,n=0)mp 140-142℃;1H NMR(300MHz,CDCl3):δ7.65(1H,d,J=8.7Hz),7.37(1H,d,J=8.7Hz),7.35(1H,s),7.29-7.25(1H,dd,J=2.7Hz和J=8.7Hz),6.96(1H,d,J=2.4Hz),6.87-6.76(2H,m),6.63(1H,d,J=1.8Hz),3.85(s,3H),3.69(s,3H),3.62(3H,s);MS m/e 489(MH+).分析计算C25H19ClF3NO4:C,61.30,H,3.91,N,2.86.
实测:C,81.42,H,3.89,N,2.75.
实施例28
4-(5-氯-2-羟基苯基)-3-(2,4-二羟基苯基)-6-(三氟甲基)-2(1H)-喹啉酮(35b,R3=CF3,R8=2,4-二羟基苯基,n=0)mp 295℃(分解);1H NMR(300MHz,CD3OD):δ7.73(1H,d,J=8.7Hz),7.49(1H,d,J=6.7Hz),7.31-7.27(2H,dd,J=2.7和J=8.7Hz),7.03-7.00(2H,m),6.89(1H,d,J=8.7Hz),6.53-6.49(2H,m);MS m/e 462(MH+).分析计算C22H13ClF3NO4:C,59.01,H,2.93,N,3.13.
实测:C,58.38,H,3.15,N,2.96.
实施例29
4-(5-氯-2-羟基苯基)-3-(4-羟基苯基)-6-(三氟甲基)-2(1H)-喹啉酮(35c,R3=CF3,R8=4-羟基苯基,n=0)mp 220-240℃;1H NMR(300MHz,CDCl3):δ7.53(1H,d,J=8.7Hz),7.20(1H,d,J=8.7Hz),7.24-7.17(2H,m),6.97-6.88(4H,dd,J=8.7和1.9Hz),6.81(1H,d,J=8.7Hz),6.77(2H,d,J=8.7Hz),3.77(s,3H),3.62(s,3H);MS m/e 459(MH+).
实施例30
4-(5-氯-2-羟基苯基)-3-[(4-羟基苯基)甲基]-6-(三氟甲基)-2(1H)-喹啉酮(35d,R3=CF3,R8=4-羟基苯基,n=1)mp 242-250℃;1H NMR(300MHz,CD3OD):δ7.73(1H,d,J=8.7Hz),7.70(1H,d,J=8.7Hz),7.50(d,1H,J=8.7Hz),7.42-7.27(m,2H),6.70-6.87(m,2H),6.82(d,2H,J=8.7Hz),6.56(d,2H,J=8.1Hz),3.91-3.51(2H,dd,J=13.8和14.7Hz);MS m/e 445(MH+).分析计算C23H15ClF3NO3·0.5H2O:C,60.68,H,3.52,N,3.08.
实测:C,60.71,H,3.91,N,2.82.
实施例31
4-(5-氯-2-羟基苯基)-3-(4-乙酰胺基苯基)-6-(三氟甲基)-2(1H)-喹啉酮(35e,R3=CF3,R8=4-乙酰胺基苯基,n=0)mp 240-260℃;1H(300MHz,CD3OD):δ7.77(1H,d,J=8.7Hz)7.55(1H,d,J=8.Hz),7.48-7.38(m,3H),7.19-7.15(m,3H),6.87-6.83(m,2H),2.09(s,3H);MSm/e 472(MH+).分析计算C24H16ClF3N3O3:C,56.59,H,3.93,N,5.50.
实测:C,57.21,H,3.73,N,5.28.
实施例32
4-(5-氯-2-羟基苯基)-3-(4-氨基苯基)-6-(三氟甲基)-2(1H)-喹啉酮(35f,R3=CF3,R8=4-氨基苯基,n=0)mp 222-224℃;1H(300MHz,CD3OD):δ7.74(1H,d,J=8.4Hz),7.53(1H,d,J=8.4Hz),7.36(s,1H),7.15(dd,1H,J=2.7和Hz),6.99(d,J=8.4Hz,2H),6.85-6.81(m,2H),6.58(1H,d,J=8.4Hz);MS m/e 446.8(MH+).分析计算C22H14ClF3N2O:C,59.14,H,3.16,N,6.27.
实测:C,60.27,H,3.52,N,6.32.
实施例33
4-(5-氯-2-羟基苯基)-3-[2-(4-羟基苯基)乙基]-6-(三氟甲基)-2(1H)-喹啉酮(35g,R3=CF3,R8=4-羟基苯基,n=2)mp 205-207℃;1H(300MHz,CD3OD):δ7.73-7.69(1H,dd,J=1.8 and 8.7Hz),7.52(1H,d,J=8.7Hz),7.38-7.35(dd,1H,J=2.7和6.2Hz),7.23(1H,s),7.01(d,1H,J=8.7Hz),6.78-8.60(2H,dd,J=8.7和7.3Hz),2.68(m,4H);MS m/e 459(MH+).分析计算C24H17ClF3NO3·1.5H2O:C,59.16,H,4.11,N,2.88.
实测:C,58.71,H,3.78,N,2.86.
实施例34
4-(5-氯-2-羟基苯基)-3-甲基-6-(三氟甲基)-2(1H)-喹啉酮(35h,n=0,R8=Me,R3=CF3)MS m/z:352(MH-);IR(KBr)3183,1655,1321,1263,1131cm-1;1H NMR(DMSO-d6):δ1.86(3H,s),7.04(1H,d,J=8.8Hz),7.12(1H,s),7.22(1H,d,J=2.6Hz)),7.39(1H,dd,J=2.6,8,7Hz),7.52(1H,d,J=8.6Hz),7.78(1H,d,J=8.7Hz),9.92(1H,s),12.26(1H,s);分析计算C17H11ClF3NO2·0.5H2O:C,56.26;H,3.33;N,3.86.
实测:C,56.57;H,3.16;N,3.81.
实施例35
3-[4-(5-氯-2-羟基苯基)-1,2-二氢-2-氧代-6-(三氟甲基)喹啉-3-基]丙烯腈(36a,R=H,X=CN,R3=CF3)
向NaH(矿物油中60%,33mg,0.82mmol)的DMF(5mL)冷(0℃)悬浮液中滴加磷酸二乙酯·氰基甲酯(63μL,0.39mmol)。反应混合物在0℃搅拌0.5小时,添加实施例10步骤A制备的2-氯-6,8-二氢-6-羟基-11-(三氟甲基)-7H-[1]苯并吡喃并[3,4-c]喹啉-7-酮(120mg,0.33mmol)的DMF(5mL)溶液。让红色反应混合物回升到室温,搅拌2小时。反应混合物用1N HCl终止反应,然后用乙酸乙酯萃取。将有机层分离,用饱和NaHCO3、水、食盐水洗涤,然后干燥(MgSO4)。溶剂蒸发给出黄色油状物,然后用柱色谱法(硅胶,1∶1乙酸乙酯/己烷)精制,给出黄色固体状标题化合物(71mg,56%):mp>265℃;MS m/e 389(M-H)-.分析计算C19H10ClF3N2O2:C,58.40;H,2.58;N,7.17.
实测:C,58.16;H, 2.81;N,6.87.1H NMR(DMSO-d6):δ6.85(d,J=16.4Hz,1H),7.10(d,J=8.8Hz,1H),7.21(s,1H),7.23(d,J=16.4Hz,1H),7.30(d,J=2.7Hz,1H),7.49(dd,J=8.8Hz,2.7Hz,1H),7.59(d,J=8.6Hz,1H),7.93(dd,J=8.7Hz,1.7Hz,1H),10.19(s,1H),12.70(s,1H).IR(KBr,cm-1):3333,2224,1656,1625,1585,1321,1265,1118,1073.
实施例36
3-[4-(5-氯-2-甲氧基苯基)-1,2-二氢-2-氧代-6-(三氟甲基)喹啉-3-基]丙烯腈(36b,R=Me,X=CN,R3=CF3)
遵照实施例35中所述的一般程序,从实施例4中制备的式(5)化合物,制备了标题化合物。
mp>250℃;MS m/e 403(M-H)-。1H NMR(DMSO-d6):δ3.71(3H,s),6.92(1H,d,J=16.3Hz),7.08(2H,m),7.31(1H,s),7.32(1H,d,J=16.3Hz),7.54(2H,m),7.81(1H,dd,J=8.5 & 1.6Hz),12.41(1H,brd s).IR(KBr,cm-1):2216,1665,1321,1127.
实施例37(a)
4-[4-(5-氯-2-羟基苯基)-1,2-二氢-2-氧代-6-(三氟甲基)喹啉-3-基]-3-丁烯-2-酮(37a,R=H,X=Ac,R3=CF3)
遵照实施例35中所述的一般程序,从实施例10步骤A制备的化合物13,制备了标题化合物。mp 186-188℃.MS m/e:406(M-H)-.IR(KBr,cm-1):3185,1656,1629,1322,1284,1169,1125,1076分析计算C20H13ClF3NO3:C,58.91;H,3.21;N,3.43.
实测:C,58.64;H,3.05;N,3.23.
实施例37(b)
4-[4-(5-氯-2-甲氧基苯基)-1,2-二氢-2-氧代-6-(三氟甲基)喹啉-3-基]丁烯-2-酮(37b,R=Me,X=Ac,R3=CF3)
遵照实施例5中所述的一般程序,从实施例4制备的化合物5,制备了标题化合物。mp 232-234℃.MS m/e:422(MH+).IR(KBr,cm-1):2844,1686,1625,1656,1588,1320.分析计算C21H15ClF3NO3:C,59.80;H,3.58;N,3.32.
实测:C,59.60;H,3.56;N,3.22.
实施例38
4-(5-氯-2-羟基苯基)-1,2-二氢-2-氧代-6-(三氟甲基)-3-喹啉甲醛肟(38a,R=H,R3=CF3)
向实施例10步骤A制备的2-氯-6,8-二氢-6-羟基-11-(三氟甲基)-7H-[1]苯并吡喃并[3,4-c]喹啉-7-酮(41mg,0.11mmol)的THF(10mL)悬浮液中添加羟胺盐酸盐(9.3mg,0.13mmol)和三乙胺(0.038mL,0.28mmol)。反应混合物在室温搅拌过夜。使THF蒸发,添加水。收集浅黄色沉淀,风干,给出标题化合物(36mg,85%):mp 195-198℃(分解);MS m/e 383(MH+)分析计算C17H10ClF3N2O3:C,53.35;H,2.63;N,7.32.
实测:C,53.18;H,4.55;N,6.87.1H NMR(DMSO-d6):δ6.98(d,J=8.8Hz,1H),7.19-7.20(m,2H),7.34(m,1H),7.54(d,J=8.6Hz,1H),7.85(m,1H),7.95(s,1H),9.87(s,br,1H),11.30(s,1H),12.46(s,br,1H).IR(KBr,cm-1):3247,1661,1629,1322,1265,1168,1121,1078.
实施例39
4-(5-氯-2-甲氧基苯基)-1,2-二氢-2-氧代-6-(三氟甲基)-3-喹啉甲醛肟(38b,R=Me,R3=CF3)
实施例4制备的化合物(80mg,0.21mmol)、NH2OH·HCl(18mg,0.25mmol)和无水NaOAc(20mg,0.25mmol)的绝对乙醇(2mL)搅拌悬浮液加热回流1小时。该乙醇旋转蒸发,让残渣在EtOAc与水之间分配。将EtOAc分离,用水、食盐水洗涤,然后干燥(Na2SO4)。EtOAc蒸发,随后粗产品用乙醚研制,给出白色固体状标题化合物(56mg):mp 255-258℃;IR(KBr,cm-1)3207,1669,1323,1267,1122;1H NMR(DMSO-d6):δ3.66(3H,s),7.08(1H,s),7.22(1H,d,J=8.9Hz),7.28(1H,d,J=2.6Hz),7.53(2H,dd,J=8.9和2.8Hz),7.85(1H,dd,J=8.7和1.7Hz),7.97(1H,s),11.29(1H,s),12.50(1H,brd s);MS 397(MH+).
实施例40
4-(5-氯-2-羟基苯基)-1,2-二氢-2-氧代-6-(三氟甲基)-3-喹啉乙酸甲酯(30b,Ra=Me,R3=CF3)
步骤A:2-氯-7,9-二氢-12-(三氟甲基)[1]苯并氧杂并[4,5-c]喹啉-6,8-二酮(39,R3=CF3)
式(30a,Ra=H,R3=CF3)的羧酸(1.20g,3.0mmol)和催化量p-TsOH的搅拌混合物在甲苯中回流4小时。旋转蒸发脱除溶剂。残渣用饱和碳酸氢钠溶液处理,用EtOAc萃取。有机萃取物用MgSO4干燥,浓缩,给出标题内酯化合物(783mg,69%):1H NMR(300MHz,DMSO-d6):δ3.23(1H,d,J=13.3Hz),4.26(1H,d,J=13.3Hz),7.52(1H,d,J=8.8Hz),7.60(1H,m),7.76(1H,dd,J=8.8,2.6Hz),7.87(1H,d,J=2.6Hz),7.92(2H,m),12.62(1H,brd);MS m/e380(MH+).
步骤B:4-(5-氯-2-羟基苯基)-1,2-二氢-2-氧代-6-(三氟甲基)-3-喹啉乙酸甲酯(30b,Ra=Me,R3=CF3)
在用硅胶柱色谱法,以CH2Cl2-MeOH混合物作为洗脱剂,对步骤A制备的内酯2-氯-7,9-二氢-12-(三氟甲基)[1]苯并氧杂并[4,5-c]喹啉-6,8-二酮进行尝试性精制时,给出标题化合物的酯。1H NMR(300MHz,DMSO-d6):δ3.17(1H,d,J=16.4Hz),3.47(1H,d,J=16.4Hz),3.53(3H,s),7.05(1H,d,J=8.7Hz),7.11(1H,d,J=2,7Hz),7.18(1H,m),7.42(1H,dd,J=8.7,2.7Hz),7.55(1H,d,J=8.5Hz),7.84(1H,dd,8.7,2.7Hz),10.0(1H,s),12.4(1H,brd s);MS m/e 412(MH+).
实施例41
4-(5-氯-2-羟基苯基)-3-(2-羟基-2-甲基丙基)-6-(三氟甲基)-2(1H)-喹啉酮(40,R=R1=Me,R3=CF3)
在氮气下,向实施例40步骤A制备的2-氯-7,9-二氢-12-(三氟甲基)[1]苯并氧杂并[4,5-c]喹啉-6,8-二酮(16mg,0.3mmol)的无水THF(3mL)冷(-78℃)搅拌溶液中添加甲基锂溶液(THF中1M,1.6mL,1.6mmol)。在-78℃搅拌1小时后,撤去冷浴,继续搅拌16小时。用1N HCl使反应终止,然后用EtOAc萃取。粗产品用闪急色谱法(硅胶,19∶1 CH2Cl2/MeOH)精制,给出米黄色固体状标题化合物(21mg):MS m/z:412(MH+);1H NMR(DMSO-d6):δ0.95(6H,s),2.6(2H,dd),7.0(1H,d),7.1(1H,s),7.3(1H,s),7.39(1H,d),7.55(1H,d),7.8(1H,d),9.95(1H,s),12.5(1H,s).
实施例42
4-(5-氯-2-羟基苯基)-1-甲基-3-(2-羟基乙基)-6-(三氟甲基)-2(1H)-喹啉酮(43,R3=CF3)
步骤A:4-(5-氯-2-羟基苯基)-3-(2-三异丙基甲硅烷氧基乙基)-6-(三氟甲基)-2(1H)-喹啉酮(41,R3=CF3)
把净相三异丙基甲硅烷基氯(0.293mL,1.37mmol,1.05当量)添加到实施例20化合物和咪唑(0.134g,1.97mmol,1.5当量)的无水DMF(10mL)搅拌溶液中。在室温12小时后,所得到的混合物倾入1N HCl水溶液(50mL)中。水层用乙酸乙酯萃取(3×50mL)。合并的有机层用食盐水(25mL)洗涤,干燥(MgSO4),过滤,真空浓缩。粗残渣用硅胶柱色谱法(3∶1~2∶1己烷/乙酸乙酯)精制,给出0.357g清澈粘稠油状物(50%产率)。用乙酸乙酯/己烷结晶,得到标题化合物的分析样品:mp 209-210℃。1H NMR(300MHz,DMSO-d6):δ0.91(21H,s),2.58(2H,m),3.63(2H,m),7.04(1H,d,J=8.8),7.06(1H,s),7.23(1H,d,J=2.6),7.40(1H,dd,J=8.7,2.3),7.51(1H,d,J=8.6),7.78(1H,dd,J=8.6,1.7),9.92(1H,s),12.26(1H,s);MS m/e 540(MH+).
步骤B:4-(5-氯-2-羟基苯基)-1-甲基-3-(2-三异丙基甲硅烷氧基乙基)-6-(三氟甲基)-2(1H)-喹啉酮(42,R3=CF3)
把正丁基锂(0.593mL,0.950mmol,2.1当量,1.6M/已烷)添加到-78℃、步骤A的喹啉(0.244g,0.453mmol)的THF搅拌溶液中。15分钟后,添加净相碘甲烷,让所得到的混合物回升到室温。搅拌12小时后,用1N HCl水溶液(10mL)使反应终止,倾入H2O(50mL)中。水层用乙酸乙酯萃取(3×50mL)。合并的有机层用食盐水(25mL)洗涤,干燥(MgSO4),过滤,真空浓缩。粗残渣用硅胶柱色谱法(4∶1~3∶1已烷/乙酸乙酯)精制,给出0.202g白色固体状标题化合物(81%产率)。1H NMR(300MHz,DMSO-d6):δ0.92(21H,s),2.63(2H,m),3.86(2H,t,J=7.4),3.75(3H,s),7.05(1H,d,J=8.8),7.15(1H,s),7.24(1H,d,J=2.7),7.41(1H,dd,J=8.7,2.6),7.78(1H,d,J=8.9),7.91(1H,dd,J=9.0,1.9),9.95(1H,s).
步骤C:4-(5-氯-2-羟基苯基)-1-甲基-3-(2-羟基乙基)-6-(三氟甲基)-2(1H)-喹啉酮(43,R3=CF3)
把氟化四丁铵(0.380mL,0.308mmol,2当量,1.0M/THF)添加到步骤B的喹啉(0.105g,0.190mmol)的THF(10mL)搅拌溶液中。12小时后,粗反应混合物倾入H2O(50mL)中。水层用乙酸乙酯(3×50mL)萃取。合并的有机层用食盐水(25mL)洗涤、干燥(MgSO4)、过滤、真空浓缩。粗残渣用柱色谱法(硅胶,2.5%甲醇/氯仿)精制,给出74mg白色固体。该固体用乙酸乙酯/己烷重结晶,提供0.064g(86%产率)标题化合物:mp 229-230℃。1H NMR(300MHz,DMSO-d6):δ2.56(2H,m),3.40(2H,m),3.75(3H,s),4.57(1H,m),7.05(1H,d,J=8.8),7.14(1H,s),7.25(1H,d,J=2.6),7.41(1H,dd,J=8.7,2.7),7.77(1H,d,J=8.8),7.89(1H,dd,J=8.8,2,0),9.91(1H,s);MS m/e 398(MH+);分析计算C19H15ClF3NO3:C,57.37;H,3.80;N,3.52.
实测:C,57.69;H,3.88;N,3.28.
实施例43
4-(5-氯-2-甲氧基苯基)-1-甲基-3-(2-羟基乙基)-6-(三氟甲基)-2(1H)-喹啉酮(44,R3=CF3)
实施例42步骤B制备的喹啉酮化合物(0.202g,0.365mmol)、硫酸二甲酯(0.038mL,0.402mmol,1.1当量)、和碳酸钾(0.056g,0.402mmol,1.1当量)在丙酮(15mL)中的混合物加热回流3小时。所得到的混合物倾入H2O(25mL)中。水层用乙酸乙酯萃取(3×50mL)。合并的有机层用食盐水(25mL)洗涤、干燥(MgSO4)、过滤、真空浓缩。这种粗的甲硅烷基化喹啉(0.228g)未经精制或表征就用于随后的反应。
把氟化四相铵(0.802mL,0.802mmol,2当量,1.0M/THF)添加到甲硅烷基化喹啉(0.228g,0.401mmol)的THF(10mL)搅拌溶液中。12小时后,该粗反应混合物倾入H2O(50mL)中。水层用乙酸乙酯萃取(3×50mL)。合并的有机层用食盐水(25mL)洗涤、干燥(MgSO4)、过滤、真空浓缩。粗残渣用柱色谱法(硅胶,1∶1~1∶2己烷/乙酸乙酯)精制,给出0.148g的白色固体。该固体用乙酸乙酯/己烷重结晶,提供0.139g(84%产率)标题化合物:mp175-176℃。1H NMR(300MHz,DMSO-d6):δ2.48(2H,m),3.37(2H,m),3.67(3H,s),3.75(3H,s),4.57(1H,t,5.4),7.06(1H,s)7.29(1H,d,J=9.0),7.35(1H,d,J=1.3),7.61(1H,dd,J=8.8,2.7),7.77(1H,d,J=8.8),7.89(1H,dd,J=8.8,1.9);MS m/e 412(MH+);分析计算C20H17ClF3NO3:C,58.33;H,4.16;N,3.40.
实测:C,58.30;H,4.07;N,3.18.
实施例44
4-(5-氯-2-羟基苯基)-1-甲基-3-(2-羟基乙基)-6-(三氟甲基)-2(1H)-喹啉酮(43,R3=CF3)
步骤A:4-(5-氯-2-羟基苯基)-3-(2-三异丙基甲硅烷氧基乙基)-6-(三氟甲基)-2(1H)-喹啉酮(41,R3=CF3)
把净相三异丙基甲硅烷基氯(0.293mL,1.37mmol,1.05当量)添加到实施例20制备的喹诺酮31a和咪唑(0.134g,1.97mmol,1.5当量)的无水DMF(10mL)搅拌溶液中。在室温12小时后,所得到的混合物倾入1N HCl水溶液(50mL)中。水层用乙酸乙酯(3×50mL)萃取。合并有机层,用食盐水(25mL)洗涤,干燥(MgSO4),过滤,真空浓缩。粗残渣用硅胶柱色谱法(3∶1~2∶1己烷/乙酸乙酯)精制,给出0.357g清澈粘稠油状物(50%产率)。用乙酸乙酯/己烷结晶,得到一种分析样品:mp 209-210℃。1H NMR(300MHz,DMSO-d6):δ0.91(21H,s),2.58(2H,m),3.63(2H,m),7.04(1H,d,J=8.8),7.06(1H,s),7.23(1H,d,J=2.6),7.40(1H,dd,J=8.7,2.3),7.51(1H,d,J=8.6),7.78(1H,dd,J=8.6,1.7),9.92(1H,s),12.26(1H,s);MS m/e 540(MH+).
步骤B:4-(5-氯-2-羟基苯基)-1-甲基-3-(2-三异丙基甲硅烷氧基乙基)-6-(三氟甲基)-2(1H)-喹啉酮(42,R3=CF3)
把正丁基锂(0.593mL,0.950mmol,2.1当量,1.6M/已烷)添加到-78℃、步骤A制备的喹啉酮41(0.244g,0.453mmol)的THF搅拌溶液中。15分钟后,添加净相碘甲烷,让所得到的混合物回升到室温。搅拌12小时后,用1N HCl水溶液(10mL)使反应终止,倾入H2O(50mL)中。水层用乙酸乙酯(3×50mL)萃取。合并有机层,用食盐水(25mL)洗涤,干燥(MgSO4),过滤,真空干燥。粗残渣用硅胶柱色谱法(4∶1~3∶1己烷/乙酸乙酯)精制,给出0.202g白色固体状标题化合物(81%产率)。1H NMR(300MHz,DMSO-d6):δ0.92(21H,s),2.63(2H,m),3.66(2H,t,J=7.4),3.75(3H,s),7.05(1H,d,J=8.8),7.15(1H,s),724(1H,d,J=2.7),7.41(1H,dd,J=8.7,2.6),7.78(1H,d,J=8.9),7.91(1H,dd,J=9.0,1.9),9.95(1H,s).
步骤C:4-(5-氯-2-羟基苯基)-1-甲基-3-(2-羟基乙基)-6-(三氟甲基)-2(1H)-喹啉酮(43,R3=CF3)
把氟化四丁铵(0.380mL,0.308mmol,2当量,1.0M/THF)添加到步骤B-制备的喹啉酮42(0.105g,0.190mmol)的THF(10mL)搅拌溶液中。12小时后,粗反应混合物倾入H2O(50mL)中。水层用乙酸乙酯(3×50mL)萃取。合并有机层,用食盐水(25mL)洗涤,干燥(MgSO4),过滤,真空浓缩。粗残渣用柱色谱法(硅胶,2.5%甲醇/氯仿)精制,给出74mg白色固体。该固体用乙酸乙酯/己烷重结晶,提供0.064g(86%产率)标题化合物:mp 229-230℃。1H NMR(300MHz,DMSO-d6):δ2.56(2H,m),3.40(2H,m),3.75(3H,s),4.57(1H,m),7.05(1H,d,J=8.8),7.14(1H,s),725(1H,d,J=2.6),7.41(1H,dd,J=8.7,2.7),7.77(1H,d,J=8.8),7.89(1H,dd,J=8.8,2.0),9.91(1H,s);MS m/e 398(MH+);分析计算C19H15ClF3NO3:C,57.37;H,3.80;N,3.52.
实测:C,57.69;H,3.88;N,3.28.
实施例45
4-(5-氯-2-甲氧基苯基)-1-甲基-3-(2-羟基乙基)-6-(三氟甲基)-2(1H)-喹啉酮(44,R3=CF3)
实施例44步骤B制备的喹啉酮42(0.202g,0.365mmol)、硫酸二甲酯(0.038mL,0.402mmol,1.1当量)、和碳酸钾(0.056g,0.402mmol,1.1当量)在丙酮(15mL)中的混合物加热回流3小时。所得到的混合物倾入H2O(25mL)中。水层用乙酸乙酯(3×50mL)萃取。合并的有机层用食盐水(25mL)洗涤,干燥(MgSO4),过滤,真空浓缩。粗喹啉酮(0.228g)未经精制或表征就用于随后的反应。
把氟化四丁铵(0.802mL,0.802mmol,2当量,1.0M/THF)添加到以上制备的喹啉酮(0.228g,0.401mmol)的THF(10mL)搅拌溶液中。12小时后,粗反应混合物倾入H2O(50mL)中。水层用乙酸乙酯(3×50mL)萃取。合并的有机层用食盐水(25mL)洗涤,干燥(MgSO4),过滤,真空浓缩。粗残留用柱色谱法(硅胶,1∶1~1∶2已烷/乙酸乙酯)精制,给出0.148g白色固体。该固体用乙酸乙酯/已烷重结晶,提供0.139g(84%产率)标题化合物:mp 175-176℃。1H NMR(300MHz,DMSO-d6):δ2.48(2H,m),3.37(2H,m),3.67(3H,s),3.75(3H,s),4.57(1H,t,5.4),7.06(1H,s),729(1H,d,J=9.0),7.35(1H,d,J=1.3),7.61(1H,dd,J=8.8,2.7),7.77(1H,d,J=8.8),7.89(1Hdd,J=8.8,1.9);MS m/e 412(MH+);分析计算C20H17ClF3NO3:C,S8.33;H,4.16;N,3.40.
实测:C,58.30;H,4.07;N,3.18.
实施例46
4-(5-氯-2-甲氧基苯基)-3-甲基-6-(三氟甲基)-2(1H)-喹啉酮
化合物33(R3=CF3,R8=H,n=1)(5.63mmol)、33%HBr/AcOH(38.3mmol)和10mL AcOH的溶液在75℃加热3小时。使溶液冷却到室温,用H2O(50mL)终止反应,然后搅拌12小时。将沉淀物滤出、用H2O洗涤、真空干燥。浅褐色固体用乙酸乙酯/己烷重结晶。分离出白色固体状标题化合物(0.550g,27%产率)。1H NMR(300MHz,CDCl3):δ2.04(s,3H),3.72(s,3H),7.03(d,1H,J=9.0Hz),7.12(s,1H),7.44(m,3H),7.65(d,1H,J=8.4Hz),10.93(br s,1H);MS m/e 368(MH+);分析计算C18H13ClF3NO2·0.33H2O:C,58.79;H,3.56;N,3.81.
实测:C,58.89;H,3.82;N,3.53.
实施例47
4-(5-氯-2-羟基苯基)-3-(2-羟基乙基)-6-(三氟甲基)-2(1H)-喹啉酮(31a,R3=CF3,n=2)
步骤A:3-(2-羟基乙基)-4-羟基-6-氯香豆素(45)
在-78℃,向γ-丁内酯(15.5g,178.0mmol)的THF(100mL)溶液中添加1.0M LiHMDS/THF溶液(356mL,356mmol),所得到的混合物在-78℃搅拌1.5小时。添加5-氯水杨酸甲酯(16.6g,98%纯度,89.0mmol)的THF(95mL)溶液。在0℃搅拌1小时后,让混合物回升到室温过夜,以确保完全反应。冷却到0℃后,徐徐添加浓HCl(12N,150mL),使pH达到1.搅拌反应溶液,直至HPLC分析指出酮酯中间体不存在。向该混合物中添加400mL CH2Cl2和300mL H2O;将有机相分离,水层用CH2Cl2(100mL)萃取。有机层合并、用无水Na2SO4干燥,减压脱除溶剂,给出一种固体。把庚烷(165mL)添加到该固体的THF溶液(290mL)中,使该产品结晶。在约3小时内冷却到0~5℃之后,将该产品过滤分离、用庚烷洗涤。真空干燥后,得到合计13.9g(66%产率)灰白色结晶状标题化合物。m.p.185-186℃;MS m/z 240;1H NMR(DMSO,300MHz)δ7.84(d,1H,J=2.4Hz),7.61(dd,1H,J=2.4,8.8Hz),7.38(d,1H,J=8.8Hz),3.56(t,2H,J=6.6Hz),2.73(t,2H,J=6.6Hz);13C NMR(DMSO,75MHz)δ162.6,159.9,150.5,131.4,127.9,122.4,118.2,117.8,103.2,59.4,27.8;IR(cm-1)3247.2,2945.1,2458.6,1664.9,1623.9,1572.7,1311.5,1378.1,1070.8,825.0.
步骤B:2,3-二氢-8-氯-4H-呋喃并苯并吡喃-4-酮(46)
在室温,向3-(2-羟基乙基)-4-羟基-6-氯香豆素(45)(8g,33.3mmol)的甲苯(360mL)溶液中添加p-TSA(0.95g,5.0mmol),所得到的溶液用迪安-斯达克冷凝管脱水回流.让反应混合物冷却到室温,用饱和碳酸氢钠溶液洗涤2次。用常压蒸馏法脱除甲苯至最终体积为32mL。冷却到70℃之后,该产品开始结晶。让结晶浆状物在55~65℃保持30分钟,随后冷却到0~5℃。产品过滤分离、用冷甲苯洗涤、真空干燥。得到合计5.5g(74%产率)灰白色结晶状标题化合物。m.p.144-146℃;MS m/z 223(M+H);1H NMR(CDCl3,300MHz)δ7.58(d,1H,J=2.5Hz),7.49(dd,1H,J=2.3,8.8Hz),7.30(d,1H,J=8.9Hz),4.90(t,2H,J=9.3Hz),3.21(t,2H,J=9.5Hz);13C NMR(CDCl3,75MHz)δ166.4,160.3,153.4,132.6,129.6,122.4,118.6,113.8,103.6,74.9,27.1;IR(cm-1)3073.1,2975.8,1721.2,1644.4,1490.8,1403.7,1270.6,1111.8,1040.1.
步骤C:4-(4′-三氟甲基苯甲酰胺)-5-(2-羟基-5-氯苯基)-2,3-二氢呋喃(47)
在-15℃,向2,3-二氢-8-氯-4H-呋喃并苯并吡喃-4-酮(46)(1.02g,4.58mmol)和4-(三氟甲基)苯胺(0.74g,4.58mmol)的THF(50mL)溶液中添加LiHMDS(10.5mL,10.5mmol,1.0MTHF溶液)。清澈的红色溶液在-15℃搅拌,直至HPLC分析表明仍有<1%化合物(46)(大约30分钟)。添加NaH2PO4水溶液(50mL,H2O中10%重量)使反应混合物终止反应。添加MTBE(25mL)之后,分层,富有机相用NaH2PO4(50mL,H2O中10%重量)和饱和食盐水相继洗涤。用Na2SO4干燥后,溶液浓缩给出清澈橙色油状标题化合物(1.76g,100%产率),冷冻时结晶。添加二氯甲烷(20mL)给出白色结晶,后者过滤分离、用二氯甲烷(10mL)洗涤、干燥,给出1.6g(90%产率)标题化合物。m.p.180-180.5℃;MS m/z 384(M+H);1H NMR(DMSO,300MHz)δ9.76(s,1H),9.34(s,1H),7.76(d,2H,J=8.5Hz),7.60(d,2H,J=8.7Hz),7.26(s,1H),7.24(dd,1H,J=2.2,7.0Hz),6.83(dd,1H,J=2.4,7.1),4.52(t,2H,J=9.6Hz),3.16(t,2H,J=9.6Hz);13C NMR(DMSO,75MHz)δ165.5,159.7,155.9,144.7,132.0,131.3,127.3,123.7,121.7,121.2,119.5,110.1,71.5,32.9;IR(cm-1)3303.6,2950.2,1654.6,1608.5,1531.7,1408.8,1326.9,1116.9,1065.7,840.4.
步骤D:4-(5-氯-2-羟基苯基)-3-(2-羟基乙基)-6-(三氟甲基)-2(1H)-喹啉酮(31a,R3=CF3,n=2)
步骤C制备的4-(4′-三氟甲基苯甲酰胺)-5-(2-羟基-5-氯苯基)-2,3-二氢呋喃(47)(1.76g,4.58mmol)的MeOH(500mL)溶液用氮气吹扫,在30~40℃用450 W Hanovia灯照射,直至HPLC分析表明仍有<1%化合物(47)。然后使MeOH真空浓缩,所得到的油状物溶解于二氯甲烷(50mL)中。在室温搅拌1小时后形成结晶。浆状物冷却到0℃之后,将结晶过滤分离、干燥。得到合计0.54g(30%产率)结晶固体状标题化合物,其HPLC纯度为97%(面积),物理表征数据与实施例20的化合物相同。
Claims (13)
3.权利要求2的化合物或其医药上可接受的无毒盐,其中,R3是三氟甲基,R2和R4是氢,R7是-CH2OH。
4.权利要求2的化合物或其医药上可接受的无毒盐,其中,R3是三氟甲基,R2和R4是氢,R7是也可以有从羟基、甲氧基、氨基和乙酰氨基组成的一组中选择的一个或两个取代基取代的苯基。
5.权利要求1的化合物或其医药上可接受的无毒盐,选自下列组成的一组:
4-(5-氯-2-甲氧基苯基)-3-(羟甲基)-6-(三氟甲基)-2(1H)-喹啉酮;
4-(5-氯-2-甲氧基苯基)-3-(羟甲基)-7-(三氟甲基)-2(1H)-喹啉酮;
4-(5-氯-2-甲氧基苯基)-1,2-二氢-2-氧代-6-(三氟甲基)-3-喹啉甲醛;
4-(5-氯-2-甲氧基苯基)-3-(3-羟基-1-丙烯基)-6-(三氟甲基)-2(1H)-喹啉酮;
4-(5-氯-2-甲氧基苯基)-3-(羟基丙基)-6-(三氟甲基)-2(1H)-喹啉酮;
4-(5-氯-2-羟基苯基)-3-(羟甲基)-6-(三氟甲基)-2(1H)-喹啉酮;
4-(5-氯-2-羟基苯基)-3-(3-羟基-1-丙烯基)-6-(三氟甲基)-2(1H)-喹啉酮;
4-(5-氯-2-羟基苯基)-3-(3-羟基丙基)-6-(三氟甲基)-2(1H)-喹啉酮;
(E)-4-(5-氯-2-羟基苯基)-3-(2-氟-3-羟基-1-丙烯基)-6-(三氟甲基)-2(1H)-喹啉酮;
(Z)-4-(5-氯-2-羟基苯基)-3-(2-氟-3-羟基-1-丙烯基)-6-(三氟甲基)-2(1H)-喹啉酮;
(E)-4-(5-氯-2-甲氧基苯基)-3-(2-氟-3-羟基-1-丙烯基)-6-(三氟甲基)-2(1H)-喹啉酮;
(Z)-4-(5-氯-2-甲氧基苯基)-3-(2-氟-3-羟基-1-丙烯基)-6-(三氟甲基)-2(1H)-喹啉酮;
4-(5-氯-2-羟基苯基)-3-(2-羟基乙基)-6-(三氟甲基)-2(1H)-喹啉酮;
4-(5-氯-2-甲氧基苯基)-3-(2-羟基乙基)-6-(三氟甲基)-2(1H)-喹啉酮;
4-(5-氯-2-甲氧基苯基)-3-(4-甲氧基苯基)-6-(三氟甲基)-2(1H)-喹啉酮;
4-(5-氯-2-甲氧基苯基)-3-[(4-甲氧基苯基)甲基]-6-(三氟甲基)-2(1H)-喹啉酮;
4-(5-氯-2-甲氧基苯基)-3-(4-硝基苯基)-6-(三氟甲基)-2(1H)-喹啉酮;
4-(5-氯-2-甲氧基苯基)-3-(4-氨基苯基)-6-(三氟甲基)-2(1H)-喹啉酮;
4-(5-氯-2-羟基苯基)-3-(3,4-二甲氧基苯基)-6-(三氟甲基)-2(1H)-喹啉酮;
4-(5-氯-2-羟基苯基)-3-(2,4-二羟基苯基)-6-(三氟甲基)-2(1H)-喹啉酮;
4-(5-氯-2-羟基苯基)-3-(4-羟基苯基)-6-(三氟甲基)-2(1H)-喹啉酮;
4-(5-氯-2-羟基苯基)-3-[(4-羟基苯基)甲基]-6-(三氟甲基)-2(1H)-喹啉酮;
4-(5-氯-2-羟基苯基)-3-(4-乙酰氨基苯基)-6-(三氟甲基)-2(1H)-喹啉酮;
4-(5-氯-2-羟基苯基)-3-(3-氨基苯基)-6-(三氟甲基)-2(1H)-喹啉酮;
4-(5-氯-2-羟基苯基)-3-[2-(4-羟基苯基)乙基]-6-(三氟甲基)-2(1H)-喹啉酮;
4-(5-氯-2-羟基苯基)-3-甲基-6-(三氟甲基)-2(1H)-喹啉酮;
4-[4-(5-氯-2-羟基苯基)-1,2-二氢-2-氧代-6-(三氟甲基)喹啉-3-基]-3-丁烯-2-酮;
4-(5-氯-2-羟基苯基)-1,2-二氢-2-氧代-6-(三氟甲基)-3-喹啉甲醛肟;
4-(5-氯-2-甲氧基苯基)-1,2-二氢-2-氧代-6-(三氟甲基)-3-喹啉甲醛肟;和
4-(5-氯-2-羟基苯基)-3-(2-羟基-2-甲基丙基)-6-(三氟甲基)-2(1H)-喹啉酮。
6.权利要求5的化合物或其医药上可接受的无毒盐,选自下列组成的一组:
4-(5-氯-2-甲氧基苯基)-3-(3-羟基-1-丙烯基)-6-(三氟甲基)-2(1H)-喹啉酮;
4-(5-氯-2-甲氧基苯基)-3-(3-羟基丙基)-6-(三氟甲基)-2(1H)-喹啉酮;
4-(5-氯-2-羟基苯基)-3-(羟甲基)-6-(三氟甲基)-2(1H)-喹啉酮;
4-(5-氯-2-羟基苯基)-3-(3-羟基-1-丙烯基)-6-(三氟甲基)-2(1H)-喹啉酮;
4-(5-氯-2-羟基苯基)-3-(3-羟基丙基)-6-(三氟甲基)-2(1H)-喹啉酮;
4-(5-氯-2-羟基苯基)-3-(2-羟基乙基)-6-(三氟甲基)-2(1H)-喹啉酮;
4-(5-氯-2-甲氧基苯基)-3-(2-羟基乙基)-6-(三氟甲基)-2(1H)-喹啉酮;
4-(5-氯-2-羟基苯基)-3-(4-羟基苯基)-6-(三氟甲基)-2(1H)-喹啉酮;
4-(5-氯-2-羟基苯基)-3-[(4-羟基苯基)甲基]-6-(三氟甲基)-2(1H)-喹啉酮;和
4-(5-氯-2-羟基苯基)-3-(4-氨基苯基)-6-(三氟甲基)-2(1H)-喹啉酮。
7.权利要求1的化合物,该化合物是4-(5-氯-2-羟基苯基)-3-(2-羟基乙基)-6-(三氟甲基)-2(1H)-喹啉酮。
8.权利要求1的化合物,该化合物是4-(5-氯-2-甲氧基苯基)-3-(2-羟基乙基)-6-(三氟甲基)-2(1H)-喹啉酮。
9.权利要求1中所定义化合物用于制造治疗哺乳动物中大电导钙活化钾通道的打开有反应的病症的药物的用途。
10.权利要求9的用途,其中,所述病症是局部缺血、中风、惊厥、癫痫、哮喘、刺激性肠综合征、偏头痛、创伤性脑损伤、脊髓损伤、性机能障碍和尿失禁。
11.权利要求9的用途,其中,所述病症是男性勃起机能障碍。
12.权利要求10的用途,其中,所述病症是中风或创伤性脑损伤。
13.权利要求10的用途,其中,所述病症是性机能障碍。
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US11107998P | 1998-12-04 | 1998-12-04 | |
US60/111,079 | 1998-12-04 |
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EP (1) | EP1133474B1 (zh) |
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ID (1) | ID28959A (zh) |
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NZ (1) | NZ510987A (zh) |
PE (1) | PE20001327A1 (zh) |
PL (1) | PL196955B1 (zh) |
PT (1) | PT1133474E (zh) |
RU (1) | RU2240998C2 (zh) |
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