CN1039998C - 取代的环烷基乙酰胺及其制法、药物和用途 - Google Patents
取代的环烷基乙酰胺及其制法、药物和用途 Download PDFInfo
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- CN1039998C CN1039998C CN93116502A CN93116502A CN1039998C CN 1039998 C CN1039998 C CN 1039998C CN 93116502 A CN93116502 A CN 93116502A CN 93116502 A CN93116502 A CN 93116502A CN 1039998 C CN1039998 C CN 1039998C
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- isobutyl
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- phenyl
- acid
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Abstract
异丁基取代的甲磺酰基喹啉基甲氧基苯基-环烷基乙酰胺可以通过相应的外消旋或对映的酸与甲磺酰胺反应制得，可按常规方法将外消旋的最终产物拆分成对映体。异丁基取代的甲磺酰基-喹啉基甲氧基苯基-环烷基乙酰胺可作为活性化合物用于药物中。
Description
本发明涉及异丁基取代的甲磺酰基-喹啉基甲氧基苯基-环烷基乙酰胺，其制备方法、有关药物以及其在药物中的用途。
取代的4-(喹啉-2-基-甲氧基)苯基乙酸衍生物和α-取代的4-(喹啉-2-基-甲氧基)-苯基乙酸衍生物已在欧洲专利第344519(US4970215)和欧洲专利第339416中公开。
本发明涉及新的通式(I)异丁基取代的甲磺酰基-喹啉基甲氧基苯基-环烷基乙酰胺及其盐，通式(I)化合物结构如下：
式中R1代表环己基，为外消旋体和对映体的形式；本发明还涉及通式(I)化合物的两个对映体化合物及其盐，其中R1代表环戊基或环庚基。
在本发明范围内，优选生理上可接受的盐。按照本发明的化合物的生理上可接受的盐可以是本发明的物质与无机酸、羧酸或磺酸形成的盐。特别优选的盐例如是与下述酸形成的盐：盐酸、氢溴酸、硫酸、磷酸、甲磺酸、乙磺酸、甲苯磺酸、苯磺酸、萘二磺酸、乙酸、丙酸、乳酸、酒石酸、柠檬酸、富马酸、马来酸或苯甲酸。
另外本发明范围内的盐是金属盐，最好是一价金属盐和铵盐。优选的碱金属盐是诸如钠盐、钾盐和铵盐。
按照本发明的通式(I)化合物由通式(II)羧酸在惰性溶剂中及在碱和/或酸催化剂存在下与式(III)甲磺酰胺反应制得，必要时可将通式(II)羧酸预先活化，通式(II)羧酸结构如下：式中R1的定义同上，式(III)甲磺酰胺结构如下：
H2N-SO2-CH3 (III)若要得到对映体，或者直接利用对映异构纯的酸(II)或者按常规方法拆分外消旋体(I)。
对映异构体最好用柱层析拆分。
本发明方法可用下列反应方程式举例说明：
磺酰胺化一般在惰性溶剂中并在碱和脱水剂存在下进行。
在这方面适宜的溶剂是在反应条件下不发生变化的惰性有机溶剂，包括囟代烃类例如二氯甲烷、三氯甲烷、四氯甲烷、1，2-二氯乙烷、三氯乙烷、四氯乙烷、1，2-二氯乙烯或三氯乙烯，烃类例如苯、二甲苯、甲苯、己烷或环己烷或矿物油馏分，硝基甲烷，二甲基甲酰胺，乙腈或六甲基磷酰胺。也可以用这些溶剂的混合物。特别优选二氯甲烷。
磺酰胺化适用的碱是常规的碱性化合物，最好包括碱金属和碱土金属氢氧化物例如氢氧化锂、氢氧化钠、氢氧化钾或氢氧化钡，碱金属氢化物例如氢化钠，碱金属和碱土金属碳酸盐例如碳酸钠或碳酸钾，或碱金属醇盐例如甲醇钠或乙醇钠、甲醇钾或乙醇钾或叔丁醇钾，或有机胺类例如氢氧化苄基三甲基铵、氢氧化四丁基铵、二甲氨基吡啶、吡啶、三乙胺或N-甲基哌啶。
适宜的脱水剂是诸如碳化二亚胺类例如二异丙基碳化二亚胺、二环己基碳化二亚胺或N-(3-二甲基氨基丙基)-N′-乙基碳化二亚胺盐酸盐或羰基化合物例如碳酰二咪唑或1，2-噁唑鎓化合物例如2-乙基-5-苯基-1，2-噁唑鎓-3-磺酸盐或丙膦酸酐或氯甲酸异丁酯或苯并三唑氧基-三(二甲氨基)鏻六氟磷酸盐或氨基磷酸二苯酯或甲磺酰氯，必要时在下述碱存在下：例如三乙胺或N-乙基吗啉或N-甲基哌啶或二环已基碳化二亚胺和N-羟基琥珀酰亚胺。
在进行磺酰胺化时，碱的用量一般相对于1mol羟酸(II)为1-3mol，1-1.5mol为佳。
如果是用混合酐的反应，最好用二甲氨基吡啶作催化剂。
催化剂的用量一般为催化量至等摩尔量，等摩尔量为佳。
磺酰胺化一般在0℃-150℃、最好在25℃-40℃温度范围内进行。
磺酰胺化一般在常压下进行，然而也可以在减压或加压的条件下(例如在0.5-5巴范围内)进行。
除R1是环庚基这种情况外，作为实际物质的代表，具体讲是对是对映异构纯形式的通式(II)羧酸是新的并可用下述方法制得：例如将或者通式(IV)化合物或者通式(IVa)化合物用式(V)2-囟代甲基喹啉除去保护基后，在惰性溶剂中通过醚化转化成通式(VI)或(VIa)化合物，如果要得到通式(VIa)化合物，则将它们在第二步中用通式(VII)化合物在惰性溶剂中进行烷基化；然后用常规方法水解醚；若要得到对映体，则按常规方法用手性酸柱层析法拆分外消旋酸。通式(IV)和通式(IVa)化合物结构如下：式中R1定义同上，T和T′相同或不同，代表羟基保护基例如苄基或叔丁基且R2和R2′相同或不同，表示C1-C4烷基；式(V)2-囟代甲基喹啉的结构式如下：
式中V代表囟素，氯或溴为佳；通式(VI)和通式(VIa)结构如下：
通式(VII)化合物结构如下：
R1-W (VII)
式中R1定义同上，W代表氯、溴或碘。
将保护基团用常规方法从相应的醚(IV)和(IVa)中除去，所述常规方法为：例如在上述惰性溶剂中并在催化剂存在下用氢气氢解苄醚。
醚化可在惰性有机溶剂中，必要时可在碱存在下进行。醚化用溶剂可以是在反应条件下不发生改变的惰性有机溶剂，最好包括诸如醚类例如二噁烷、四氢呋喃或乙醚，囟代烃类例如二氯甲烷、三氯甲烷、四氯甲烷、1，2-二氯乙烷或三氯乙烯，烃类例如苯、二甲苯、甲苯、己烷、环己烷或矿物油馏分，硝基甲烷，二甲基甲酰胺，乙腈，丙酮或六甲基磷酰胺。也可以使用这些溶剂的混合物。
用于醚化的碱可以是无机或有机碱，最好包括诸如碱金属氢氧化钠或氢氧化钾，碱土金属氢氧化物例如氢氧化钡，碱金属碳酸盐例如碳酸钠或碳酸钾，碱土金属碳酸盐例如碳酸钙，或有机胺类(三烷基(C1-C6)胺类)例如三乙胺，或杂环类例如吡啶、甲基哌啶、哌啶或吗啉。
也可以使用碱金属如钠和其氢化物如氢化钠作为碱。
醚化一般在0℃～+150℃、最好在+10℃～+100℃温度范围内进行。
醚化一般在常压下进行，然而也可以在减压或加压条件下(例如在0.5-5巴范围内)进行。
相对于1mol反应物，囟化物(V)的用量一般为0.5-5mol，1-2mol为佳；碱的用量相对于囟化物一般为0.5-5mol，最好为1-3mol。
通式(IV)和通式(IVa)化合物本身是已知的，或可按常规方法制备。
通式(V)化合物及其制备也是已知的。
适宜于本发明方法和烷基化的溶剂是在反应条件下不变化的常规有机溶剂，最好包括醚类例如乙醚、二噁烷、四氢呋喃、乙二醇二甲醚，或烃类例如苯、甲苯、二甲苯、己烷、环己烷或矿物油馏分，或囟代烃类例如二氯甲烷、三氯甲烷、四氯甲烷、二氯乙烯、三氯乙烯或氯苯，或乙酸乙酯，或三乙胺，吡啶，二甲亚砜，二甲基甲酰胺，六甲基磷酰胺，乙腈，丙酮或硝基甲烷。也可以使用上述溶剂的混合物。优选二氯甲烷。
烷基化在上述溶剂中于0℃-+150℃、最好于室温至+100℃并在常压下进行。
通式(III)化合物本身是已知的。
作为实际物质的代表，通式(VI)化合物在某些情况下是新的并可按上述方法制备。
外消旋体一般通过手性HPLC柱诸如溶剂混合物例如正庚烷/2-丙醇柱层析或用非对映酯进行拆分。
本发明新的N-甲磺酰基-2-[3-异丁基-3-(喹啉-2-基-甲氧基)苯基]-2-环烷基乙酰胺可以作为活性化合物用在药物中。该物质在花生四烯酸代谢过程中可起到酶反应、具体讲是脂氧合酶的抑制剂作用。
因此它们尤其适于治疗和预防导气管疾病，例如过敏/气喘、支气管炎、肺气肿、肺性休克、肺动脉高血压症、炎症/风湿病以及水肿，血栓形成和血栓栓塞，局部缺血(外周、心脏和脑循环障碍)，心脑梗塞，心绞痛，动脉硬化，用在组织移植方面，皮肤病例如牛皮癣、皮炎和用于胃肠道中的细胞保护。
本发明的苯基取代的喹啉既能用在人用药中也能用在兽用药中。
本发明物质的药理作用用下述方法测定：作为脂氧合酶抑制测定，是按Borgeat，P.等人在Proc.Acad.Sci.，76，2148-2152页(1979)中所述方法，在加入本发明物质和Ca离子载体后用反相HPLC测定多核形人类白细胞(PMN)中白三烯B4(LTB4)的释放。
脂氧合酶抑制作用(人类PMNL)
实施例序号
IC50[mol/l]
1 5.2×10-8
6 5.8×10-8
7 7.0×10-8
本发明也包括药用制剂及其制备方法，所述药用制剂除含惰性、无毒、药学上适宜的助剂和赋形剂外，还含一种或一种以上通式(I)化合物，即含一种或一种以上式(I)活性化合物。
式(I)活性化合物在这些制剂中的浓度应该为混合物总重量的0.1-99.5％，0.5-95％为佳。
除式(I)活性化合物外，该药用制剂还可以含其它药用活性化合物。
上述药用制剂可以按常规方法例如用助剂或赋形剂来制备。
业已证明，式(I)活性化合物每24小时的服用总量为约0.01-100mg/Kg体重、最好为约1mg/Kg体重-50mg/Kg体重，必要时可以若干单剂的形式服用有利于达到需要的效果。
然而，有时偏离上述剂量也是有益的，这主要取决于患者的类型和体重、对药物的个体反应、疾病的性质和严重程度、制备和使用方法以及服用的时间和间隔。
原料化合物
实施例I
2-[3-异丁基-4-(喹啉-2-基-甲氧基)苯基]-2-环己基-乙酸甲酯
将12g(0.033mol)2-[3-异丁基-4-(喹啉-2-基-甲氧基)苯基乙酸甲酯和6.52g(0.04mol)＝4.9ml环己基溴溶于36mlDMF中并在氩气氛下冷却至0℃。将4.88g(0.04mol)叔丁醇钾溶于80ml DMF的溶液搅拌下滴加到该混合物中。反应约2小时后，将温度升至室温并将混合物用2N盐酸酸化并在真空条件下浓缩至干。残留物用100ml二氯甲烷和50ml水搅拌，分出有机相，用硫酸钠干燥并在真空条件下浓缩至体积很小。将该残留物用柱层析分离(硅胶60，洗脱剂∶二氯甲烷/乙酸乙酯＝100∶2)。产量：13g(收率为88.4％)，略带黄色的油状物。
实施例II
2-[3-异丁基-4-(喹啉-2-基-甲氧基)苯基]-2-环己基-乙酸
将10.2g(0.0236mol)得自实施例I的化合物溶于70ml 2-丙醇中并与50ml 1N氢氧化钠溶液一起加热至沸过夜。冷却后，该混合物用50ml 1N盐酸中和。吸滤出得到的沉淀，洗涤并干燥，然后用二异丙基醚重结晶。产量：9.5g(收率为96.3％)，无色晶体。M.P.：130℃。
实施例III和实施例IV
(+)-2-[3-异丁基-4-(喹啉-2-基-甲氧基)苯基]-2-环己基乙酸(实施例III)
(-)-2-[3-异丁基-4-(喹啉-2-基-甲氧基)苯基]-2-环己基乙酸(实施例IV)
用手性柱层析法拆分外消旋体(实施例II)，得标题化合物。(+)-对映体：spec.rotn：17.96°(CHCl3)(实施例III)mol.rotn：
77.41°(-)-对映体：spec.rotn：-18.86°(CHCl3)(实施例IV)mol.rotn：
-81.28°
实施例V
2-[3-异丁基-4-(喹啉-2-基-甲氧基)苯基]-2-环庚基乙酸甲酯
用与实施例I类似的方法使10g(0.0275mol)2-[3-异丁基-4-(喹啉-2-基-甲氧基)苯基乙酸甲酯与10.04g(0.055mol)环庚基溴和6.17g(0.055mol)叔丁醇钾反应，得标题化合物。产量：定量的棕黄色油状物。
实施例VI
2-[3-异丁基-4-(喹啉-2-基-甲氧基)苯基]-2-环庚基乙酸
用类似于实施例II的方法，由实施例V化合物和30ml 1N氢氧化钠溶液并随后酸化，制得标题化合物。产量：11.3g(收率为92.3％)，无色晶体M.P.：112℃
实施例VII和实施例VIII
(+)-2-[3-异丁基-4-(喹啉-2-基-甲氧基)苯基]-2-环庚基乙酸(实施例VII)
(-)-2-[3-异丁基-4-(喹啉-2-基-甲氧基)苯基]-2-环庚基乙酸(实施例VIII)
用层析拆分法拆分外消旋体(实施例VI)制得标题化合物。所述拆分的条件为：HPLC-H1050Chiralpak AS柱，洗脱剂为96％正庚烷和4％含1％水和0.2％三氟乙酸的2-丙醇混合物的溶剂混合物。(+)-对映体：spec.rotn：15.72°溶剂CHCl3，实施例VII
mol.rotn.：69.96°(-)-对映体：spec.rotn：-18.7°溶剂CHCl3实施例VIII
mol.rotn：-81.28°
实施例IX
2-[3-异丁基-4-(喹啉-2-基-甲氧基)苯基]-2-环庚基乙酸甲酯
用与实施例I和V类似的方法，由10g(0.0275mol)2-[3-异丁基-4-(喹啉-2-基-甲氧基)苯基]-乙酸甲酯、8.2g(0.055mol)环戊基溴和6.17g(0.055mol)叔丁醇钾制得标题化合物。产量：定量的棕黄色油状物。
实施例X
2-[3-异丁基-4-(喹啉-2-基-甲氧基)苯基]-2-环戊基乙酸
用类似于实施例II和VI的方法，由30ml氢氧化钠溶液水解实施例IX化合物并随后酸化制得标题化合物。产量：10.5g(收率：91.5％)，略带黄色的晶体，M.P.：120℃
实施例XI和XII
(+)-2-[3-异丁基-4-(喹啉-2-基-甲氧基)苯基]-2-环戊基乙酸(实施例XI)
(-)-2-[3-异丁基-4-(喹啉-2-基-甲氧基)苯基]-2-环戊基乙酸(实施例XII)
按与实施例VII和VIII类似的方法，将实施例X化合物层析拆分，得到标题化合物。(+)-对映体：spec.rotn：44.56°(THF)，实施例XI
mol.rotn.：185.84°(-)-对映体：spec.rotn.：-41.07°(THF)，实施例XII
mol.rotn.：-171.28°
实施例XIII
N-甲磺酰基-2-[3-异丁基-4-(喹啉-2-基-甲氧基)苯基]-2-环庚基乙酰胺
通氩气条件下将2g(0.0045mol)得自实施例VI的化合物悬浮于20ml无水THF中并用1.82g(0.018mol)三乙胺(d＝0.73)处理，得澄清液。在冰浴冷却下向该混合物中滴加1.14g(0.01mol)甲磺酰氯(d＝1.48)并在该温度下搅拌该混合物15分钟。然后搅拌下滴加1.52g(0.016mol)甲磺酰胺和1.1g(0.009mol)二甲氨基吡啶溶于10ml无水THF的溶液，使该混合物反应过夜，这期间温度开至室温。将混合物倒入甲苯中并用水和稀乙酸提取。将有机相分出，用硫酸钠干燥并真空浓缩至小体积。将淡棕色油状残留物(2.42g)用柱层析分离(硅胶60，洗脱剂，甲苯/乙酸乙酯/冰乙酸＝8∶2∶1)，得1.75g(收率为74.6％)无色产物(无定形)。
制备实施例 实施例1
N-甲磺酰基-2-[3-异丁基-4-(喹啉-2-基-甲氧基)苯基]-环己基乙酰胺
用与实施例XIII类似的方法，由3.5g(0.008mol)得自实施例II的化合物、1g(0.008mol)甲磺酰氯、0.912g甲磺酰胺、1.62g(0.016mol)三乙胺和0.98g(0.008mol)二甲氨基吡啶制得标题化合物。产量：3.48g(收率为84.9％)，无色无定形粉末M.P.：163-170℃
实施例2和实施例3
(+)-N-甲磺酰基-2-[3-异丁基-4-(喹啉-2-基-甲氧基)苯基]-2-环己基乙酰胺(实施例2)
(-)-N-甲磺酰基-2-[3-异丁基-4-(喹啉-2-基-甲氧基)苯基]-2-环己基乙酰胺(实施例3)
得自实施例1的化合物经柱层析拆分得到两个对映体。所述柱层析分条件为：HPLC-HP1050 Chiralcel OD柱，洗脱剂为86％正庚烷和14％含1％水和0.2％三氟乙酸的2-丙醇混合物的混合溶剂。(+)-对映体：spec.rotn.：+32.15°(CHCl3)实施例2
mol.rotn.：+163.32°(-)-对映体：spec.rotn.：-28.96°(CHCl3)实施例3
mol.rotn.：-147.12°
表1所示的纯对映体或者可按与实施例2和3类似的方法经外消旋体的拆分制得，或者可使用相应的对映纯的羧酸来制备。表1
实施例序号 R1 对映体 mol.rotn. spec.rotn.4
(+)5
(-)6
(+) +147.99° +28.35°
(CHCl3) (CHCl3)7
(-) -169.91° -32.55°
(CHCl3) (CHCl3)
Claims (5)
1.下式的异丁基取代的甲磺酰基喹啉基甲氧基苯基环烷基乙酰胺或其盐，该化合物为外消旋体、(+)-对映体或(-)-对映体形式：式中R1代表环己基。
2.制备权利要求1的异丁基取代的甲磺酰基喹啉基甲氧基环烷基苯基乙酰胺的方法，其特征在于：通式(II)羧酸在惰性溶剂中在碱和/或酸催化剂存在下与式(III)甲磺酰胺反应，必要时可将通式(II)羧酸预先活化；通式(II)羧酸结构如下：
式中R1的定义同上，式(III)甲磺酰胺结构如下：
H2N-SO2-CH3 (III)若要得到对映体，或者直接利用对映异构纯的酸(II)或者按常规方法拆分消旋体(I)。
3.按照权利要求2的方法，其特征在于，所述对映体用柱层析法拆分。
4.含至少一种权利要求1的异丁基取代的甲磺酰基喹啉基甲氧基苯基环烷基乙酰胺的药物组合物。
5.权利要求1的异丁基取代的甲磺酰基喹啉基甲氧基苯基环烷基乙酰胺在生产抑制脂氧合酶的药物中的用途。
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4226649A DE4226649A1 (de) | 1992-08-12 | 1992-08-12 | Neue isobutylsubstituierte Methansulfonyl-chinolylmethoxyphenyl-cycloalkylessigsäureaminole |
| DEP4226649.1 | 1992-08-12 |
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| JP (1) | JPH06157462A (zh) |
| KR (1) | KR940003937A (zh) |
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| DE (1) | DE4226649A1 (zh) |
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| HU (1) | HUT70171A (zh) |
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| DE4443892A1 (de) * | 1994-12-09 | 1996-06-13 | Bayer Ag | 4-(Chinolin-2-yl-methoxy)-phenyl-essigsäurederivate |
| DE4443891A1 (de) | 1994-12-09 | 1996-06-13 | Bayer Ag | Heterocyclisch substituierte Oxy-phenyl-(phenyl)glycinolamide |
| US5931170A (en) * | 1998-10-08 | 1999-08-03 | Addway Engineering Limited | Dental flosser |
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| EP0344519A1 (de) * | 1988-05-31 | 1989-12-06 | Bayer Ag | Substituierte 4-(Chinolin-2-yl-methoxy)phenyl-essigsäure-Derivate |
| US4929626A (en) * | 1988-04-29 | 1990-05-29 | Bayer Aktiengesellschaft | α-substituted 4-(quinolin-2-yl-methoxy)phenylacetic acids and esters and lipoxygenase inhibition therewith |
| EP0399291A2 (de) * | 1989-05-23 | 1990-11-28 | Bayer Ag | Substituierte (Chinolin-2-yl-methoxy)phenyl-acyl-sulfonamide und -cyanamide, Verfahren zu ihrer Herstellung und ihre Verwendung in Arzneimitteln |
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| DE4112533A1 (de) * | 1991-04-17 | 1992-10-22 | Bayer Ag | Verfahren zur herstellung von enantiomerenreinen substituierten (chinolin-2-yl-methoxy)phenyl-essigsaeuren |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4929626A (en) * | 1988-04-29 | 1990-05-29 | Bayer Aktiengesellschaft | α-substituted 4-(quinolin-2-yl-methoxy)phenylacetic acids and esters and lipoxygenase inhibition therewith |
| EP0344519A1 (de) * | 1988-05-31 | 1989-12-06 | Bayer Ag | Substituierte 4-(Chinolin-2-yl-methoxy)phenyl-essigsäure-Derivate |
| EP0399291A2 (de) * | 1989-05-23 | 1990-11-28 | Bayer Ag | Substituierte (Chinolin-2-yl-methoxy)phenyl-acyl-sulfonamide und -cyanamide, Verfahren zu ihrer Herstellung und ihre Verwendung in Arzneimitteln |
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| KR940003937A (ko) | 1994-03-14 |
| ZA935828B (en) | 1994-03-10 |
| NO179948C (no) | 1997-01-15 |
| SK86693A3 (en) | 1994-09-07 |
| IL106623A0 (en) | 1993-12-08 |
| PL300025A1 (en) | 1994-03-21 |
| JPH06157462A (ja) | 1994-06-03 |
| CZ282341B6 (cs) | 1997-07-16 |
| NO932731D0 (no) | 1993-07-29 |
| MY108716A (en) | 1996-11-30 |
| AU669913B2 (en) | 1996-06-27 |
| AU4425593A (en) | 1994-02-17 |
| NO932731L (no) | 1994-02-14 |
| CA2103600A1 (en) | 1994-02-13 |
| FI933529A0 (fi) | 1993-08-10 |
| CN1087084A (zh) | 1994-05-25 |
| EP0582916A1 (de) | 1994-02-16 |
| HUT70171A (en) | 1995-09-28 |
| HU9302320D0 (en) | 1993-10-28 |
| PL174102B1 (pl) | 1998-06-30 |
| NO179948B (no) | 1996-10-07 |
| NZ248350A (en) | 1994-12-22 |
| FI933529A (fi) | 1994-02-13 |
| MX9304608A (es) | 1994-02-28 |
| CZ163693A3 (en) | 1994-03-16 |
| DE4226649A1 (de) | 1994-02-17 |
| RU2103261C1 (ru) | 1998-01-27 |
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