CN1353692A - β2-肾上腺受体激动剂 - Google Patents
β2-肾上腺受体激动剂 Download PDFInfo
- Publication number
- CN1353692A CN1353692A CN00808487A CN00808487A CN1353692A CN 1353692 A CN1353692 A CN 1353692A CN 00808487 A CN00808487 A CN 00808487A CN 00808487 A CN00808487 A CN 00808487A CN 1353692 A CN1353692 A CN 1353692A
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- Prior art keywords
- hydroxyl
- alkyl
- hydrogen
- indane
- compound
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Abstract
本发明公开了游离形式、盐形式或溶剂化物形式的下式(I)的化合物,其中Ar为下式的基团(II),Y为碳或氮,R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、X、n、p、q和r如说明书定义,本发明还公开了所述化合物的制备方法,它们作为药物的用途,特别是用于治疗梗阻性或炎性气道疾病。式(I)化合物为游离,盐或溶剂化物形式,具有β2-肾上腺受体拮抗活性。
Description
本发明涉及有机化合物,它们的制备方法和其作为药物的用途。
R1为氢、羟基或烷氧基,
R2和R3彼此独立地为氢或烷基,
R4、R5、R6和R7彼此独立地为氢、卤素、氰基、羟基、烷氧基、芳基、烷基、被一个或多个卤原子或一个或多个羟基或烷氧基取代的烷基、被一个或多个杂原子间断的烷基、链烯基、三烷基甲硅烷基、羧基、烷氧基羰基或-CONR11R12,其中,R11和R12彼此独立地为氢或烷基,或R4和R5、R5和R6或者R6和R7连同与其相连的碳原子一起表示碳环或杂环,
R8为卤素、-OR13、-CH2OR13或-NHR13,其中,R13为氢、烷基、被一个或多个杂原子间断的烷基、-COR14,其中,R14为氢、-N(R15)R16、烷基或被一个或多个杂原子间断的烷基、或芳基,R15和R16彼此独立地为氢、烷基或被一个或多个杂原子间断的烷基,或R13为-C(=NH)R17、-SOR17或-SO2R17,其中,R17为烷基或被一个或多个杂原子间断的烷基,而R9为氢,或R8为-NHR18,其中,-NHR18和R9连同与其相连的碳原子一起表示5-或6-元杂环,
R10为-OR19或-NHR19,其中,R19为氢、烷基、被一个或多个杂原子间断的烷基或-COR20,其中,R20为-N(R21)R22、烷基或被一个或多个杂原子间断的烷基、或芳基,R21和R22彼此独立地为氢、烷基或被一个或多个杂原子间断的烷基,
X为卤素或卤代甲基或烷基,
Y为碳或氮,
n为1或2,
当Y为氮时,p为0,当Y为碳时,p为1,
q和r分别为0或1,q+r之和为1或2;
而当R1为羟基或烷氧基时,用星号标记的碳原子具有R或S构型或其混合物。
在本文中采用的术语具有以下含义:
“烷基”是指直链或支链的烷基,例如,其可以是C1-C10烷基,如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、直链或支链的戊基、直链或支链的己基、直链或支链的庚基、直链或支链的壬基或直链或支链的癸基。优选的烷基为C1-C4烷基。被一个或多个卤原子或一个或多个羟基或烷氧基取代的烷基可为被一个或多个卤素优选氟或氯原子取代的上述任一种C1-C10烷基,被一个或多个羟基或一个或多个C1-C10优选C1-C4烷氧基取代的取代的上述任一种C1-C10烷基。
“被一个或多个杂原子间断的烷基”是指直链或支链的烷基,如C2-C10烷基,其中,一对或多对碳原子被-O-、-NR-、-S-、-S(=O)-或-SO2-相连,其中,R为氢或C1-C10(优选C1-C4)烷基。优选的此类基团为烷氧基烷基,优选C1-C4-烷氧基-C1-C4-烷基。
“烷氧基”是指直链或支链的烷氧基,例如,其可为C1-C10烷氧基,如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基、或直链或支链的戊氧基、己氧基、庚氧基、辛氧基、壬氧基或癸氧基。优选的烷氧基为C1-C4烷氧基。
“链烯基”是指直链或支链的链烯基,其可以是未取代的或是取代的,例如,被一个或多个卤原子或一个或多个烷氧基取代,并且,其例如可为C2-C10链烯基,如乙烯基、1-丙烯基、2-丙烯基、1-丁烯基、异丁烯基,或直链或支链的戊烯基、己烯基、庚烯基、辛烯基、壬烯基或癸烯基。优选的链烯基为C2-C4链烯基。
“芳基”是指取代或未取代的芳基,如未取代的苯基或萘基,或者被一个或多个例如1-4个取代基取代的苯基或萘基,取代基选自C1-C4-烷基、羟基、C1-C4-烷氧基、卤素或卤代-C1-C4-烷基。优选芳基为未取代的苯基或被1或2个选自C1-C4-烷基或卤素的取代基取代的苯基。
“亚烷基”是指直链或支链的亚烷基,其例如可为C1-C10亚烷基,如亚甲基、亚乙基、1,2-亚丙基、1,3-亚丙基、亚丁基、亚戊基、亚己基、亚庚基、亚辛基、亚壬基或亚癸基。优选的亚烷基为C1-C4-亚烷基。
“亚烯基”是指直链或支链的亚烯基,其例如可为C2-C10-亚烯基,如亚乙烯基、亚丙烯基、亚丁烯基、亚戊烯基、亚己烯基、亚庚烯基、亚辛烯基、亚壬烯基或亚癸烯基。优选亚烯基为C2-C4-亚烯基。
在通式I中,n为1或2,即,在与所指示的苯环稠合的环中具有2或4个CH2基,从而环为5-元或7-元环。
其中R8为-NHR18且-NHR18和R9一起表示5-或6-元杂环的通式II中的基团Ar例如可以为下述基团,其中,Y为碳,R8为NHR18且NHR18与R9一起表示
式-NH-CO-R23-的基团,其中,R23为亚烷基、亚烯基或亚烷氧基,
式-NH-SO2-R24-的基团,其中,R24为亚烷氧基,
式-NH-R5(COOR26)-的基团,其中,R25为亚烷基或亚烯基且R26为烷基,或
式-NH-CO-NH-或-NH-CO-S-的基团,R10为-OR19,其中,R19如前定义,
X为烷基,p为1,q为1而r为0或1。
亚烷基、亚烯基和亚烷氧基优选具有1-4个碳原子。
其中R8为-NHR18且-NHR18和R9一起表示5-或6-元杂环的通式II中的基团Ar包括下述基团,其中
Y为碳,R8为-NHR18且-NHR18和R9一起表示式-NH-CO-C(R27)=C(R28)-或-NH-CO-CH2-O-或-NH-CO-CH2-或-NH-SO2-CH2-O-或NH-C(COOR26)=CH-或-NH-CO-NH-或-NH-CO-S-的基团,其中,R27和R28彼此独立地为氢或C1-C4-烷基,R26为C1-C4-烷基,R10为-OH,X为C1-C4-烷基,p为1,q为1而r为0或1。
其中,Z为-O-,-NH-或-S-。
其中R8为卤素而R9为氢的通式II的基团Ar例如可以为式II的基团,其中,Y为碳,R8为卤素,优选氯,R9为氢,R10为-NHR18,其中,R18为氢或C1-C4-烷基,优选氢或甲基,X为卤素或卤代甲基,优选氯或三氟甲基,而p、q和r均为1。其中,优选的基团Ar包括下式的那些:
其中R8为-OR13而R9为氢的通式II的Ar基团例如可为下列式II的基团,其中,Y为碳,R8为-OR13,其中,R13为氢、C1-C4-烷基、C1-C4-烷氧基-C1-C4-烷基、-COR14,其中,R14为C1-C4-烷基、C6-C10-芳基或-N(R15)R16,其中,R15和R16彼此独立地为氢、C1-C4-烷基,R10为-OR19或-NHR19,其中,R19为氢、C1-C4-烷基、C1-C4-烷氧基-C1-C4-烷基或-COR20,其中,R20为-N(R21)R22、C1-C4-烷基、C1-C4-烷氧基-C1-C4-烷基或C6-C10-芳基,R21和R22彼此独立地为氢或C1-C4-烷基,p和q分别为1而r为0。其中,优选的Ar基团包括下式的基团
其中R8为-CH2OR13的通式II的Ar基团例如可为下列式II的基团,其中,Y为碳,R8为-CH2OR13,其中,R13为氢、C1-C4-烷基或C1-C4-烷氧基-C1-C4-烷基,R9为氢、R10为-OR19,其中,R19为氢、C1-C4-烷基或C1-C4-烷氧基-C1-C4-烷基或R10为-NHR19,其中,R19为氢、C1-C4-烷基或-COR20,其中,R20为C1-C4-烷基、C6-C10-芳基或-N(R21)R22,其中,R21和R22彼此独立地为氢或C1-C4-烷基,p和q分别为1而r为0;或下式的基团,其中,Y为氮,R8为-CH2OR13,其中,R13为氢、C1-C4-烷基或C1-C4-烷氧基-C1-C4-烷基,R10为-OR19,其中,R19为氢、C1-C4-烷基或C1-C4-烷氧基-C1-C4-烷基,p和r为0而q为1。其中,优选的Ar基团包括下述的基团
其中R8为-NHR13的通式II的Ar基团例如可为下列式II的基团,其中,Y为碳,R8为-NHR13,其中,R13为氢、C1-C10烷基、被1-3个杂原子间断的C1-C10烷基、-COR14,其中,R14为氢、C1-C10-烷基或被1-3个杂原子间断的C1-C10烷基或R13为-C(=NH)R17、-SOR17或-SO2R17,其中,R17为C1-C10-烷基或被1-3个杂原子间断的C1-C10烷基,R9为氢,R10为-OR18,其中,R18为氢、C1-C4-烷基或C1-C4-烷氧基-C1-C4烷基,p和q均为1,r为0。其中,优选的Ar基团包括下式的基团:
特别是下述基团,其中,R13为氢、C1-C4-烷基、-COR14,其中,R14为氢或C1-C4-烷基或-SO2R17,其中,R17为C1-C4-烷基。
特别优选的基团Ar为如前所定义的通式III、IV、V、XII和XV的基团。
在通式I中,基团R1例如可为氢、羟基或C1-C4-烷氧基,如甲氧基、乙氧基、异丙氧基、正丁氧基或叔丁氧基。优选R1为羟基。
当R1为羟基或烷氧基时,通式I中用星号*标记的碳原子优选具有R构型。
通式I中基团R2和R3彼此独立地例如为氢或C1-C4-烷基,例如甲基或乙基。在本发明最优选的实施方案中,R2为氢,R3为氢或甲基。
通式I中的基团R4、R5、R6和R7彼此独立地例如为氢、氯、氟、氯甲基、三氟甲基、羟基、C1-C10烷氧基、C1-C10烷基、被一个或多个氧或硫原子或一个或多个NH、SO或SO2间断的C1-C10-烷基,C2-C4-链烯基、三甲基甲硅烷基、三乙基甲硅烷基、苯基、羧基、C1-C4-烷氧基羰基、-CONR11R12(其中,R11和R12彼此独立地为氢或C1-C4-烷基)或R4和R5,R5和R6或者R6和R7连同与其相连的碳原子一起可表示5-或6-元碳环,其优选为脂族环(其优选为饱和的),或包含1或2个氧原子的5-或6-元O-杂环。优选地,R4、R5、R6和R7可均为氢或它们使与其相连的苯环被对称取代,即,(a)R4和R7相同且R5和R6相同,或一起表示对称的环,或(b)R4和R5一起且R6和R7一起表示相同的环。更优选地,R4和R7相同且均为氢、C1-C4-烷基或C1-C4-烷氧基,或者R5和R6相同且均为氢、C1-C4-烷基、C1-C4-烷氧基或C1-C4烷氧基-C1-C4-烷基,或者R5和R6一起表示-(CH2)s-或-O(CH2)tO-,其中,s为3或4而t为1或2。
本发明特别优选的化合物包括以下的通式I的化合物,其中,Ar为式III、IV、V、XII或XV的基团,R1为羟基,R2和R3为氢,R4和R7相同并均为氢、C1-C4-烷基或C1-C4-烷氧基,R5和R6相同且均为氢、C1-C4-烷基、C1-C4-烷氧基或C1-C4-烷氧基-C1-C4-烷基,或者R5和R6一起表示-(CH2)4-或-O(CH2)2O-,为游离形式或盐形式或溶剂化物形式。在该化合物中,通式I中用星号*标记的碳原子优选具有R构型。特别优选的化合物为在以下的实施例中所描述的那些。
通式(I)的化合物能够形成酸加成盐,特别是可药用酸加成盐。通式I化合物的可药用酸加成盐包括下述酸的酸加成盐:无机酸,如氢卤酸,如氢氟酸、盐酸、氢溴酸或氢碘酸,硝酸、硫酸、磷酸;和有机酸,如甲酸、乙酸、丙酸、丁酸、苯甲酸、邻羟基苯甲酸、对羟基苯甲酸、对氯苯甲酸、二苯基乙酸、三苯基乙酸、1-羟基萘-2-甲酸、3-羟基萘-2-甲酸,脂族羟基酸如乳酸、柠檬酸、酒石酸或苹果酸,二元羧酸如富马酸、马来酸或琥珀酸,以及磺酸如甲磺酸或苯磺酸。这些盐可根据公知的成盐方法由通式I的化合物制备。
适宜的溶剂化物为可药用的溶剂化物,优选水合物。
本发明也提供了游离形式或盐形式或溶剂化物形式的通式I的化合物的制备方法,包括:
(a)为制备其中R1为羟基的化合物,
其中,Ar1、R2、R3、R4、R5、R6和R7如前定义,R32为氢或胺-保护基,或
其中,Ar1为如前定义的Ar或其保护形式,R2、R3、R4、R5、R6、R7和n如前定义,转化所示的酮基成-CH(OH)-;或
(b)为制备其中R1为氢的化合物,将相应的基团R1为羟基的通式I的化合物还原;或
(c)为制备其中R1为烷氧基的通式I的化合物,可以(i)O-烷基化相应的其中R1为羟基的通式I化合物,或(ii)使具有代替R1的离去基团的相应化合物与其中R1为烷氧基的式R1H的醇反应;
并且,选择性地,将形成的保护形式的通式I化合物转化成未保护形式的相应化合物;
并且回收形成的游离形式或盐形式或溶剂化物形式的通式I化合物。
方法(a)(i)可采用用于环氧化物-胺反应的公知过程完成。该反应便利地可在不存在溶剂或存在惰性溶剂中进行,惰性溶剂例如为烃,如甲苯或醇如正丁醇。反应温度方便地为25-200℃,优选80-150℃。通过常规的加热或通过微波辐射可达到所需温度。
方法(a)(ii)可采用常规方法进行,例如,通过在常规条件下与氢硼化钠反应。
方法(b)可采用将仲醇还原成烃的常规方法进行。方法(c)(i)可采用用于O-烷基化反应的公知方法进行,例如,与烷基化试剂在公知条件下进行反应,烷氧基试剂例如为烷基卤。方法(c)(ii)可采用用于苄基置换反应的公知方法进行,离去基团例如为甲苯磺酸根、甲磺酸根、卤素或羟基。
游离形式的通式I化合物可按照常规方式转化成盐形式或溶剂化物形式,反之亦然。
本发明的化合物可从反应混合物中回收并以常规方式纯化。异构体如对映体可以常规方式获得,例如由相应的不对称取代的如旋光原料通过分级结晶或不对称合成获得。
通式XVI的化合物为公知化合物,或者可以通过与用于制备公知化合物类似的方法制备,例如在下述文献中所述的方法:Journal ofMedicinal Chemistry 1987,30,1563-1566。其中由星号*标记的碳原子为手性的通式XVI化合物可由下式的化合物制备:
其中,Ar1和R2如前定义,L为离去原子或基团,如WO 95/25104所述。
通式XVI的化合物也可通过采用常规方法对以下通式的化合物进行环氧化反应制备
Ar1-CH=CH-R2 XX
其中,Ar1和R2如前定义,如在以下实施例中所采用的方法。
通式XX的化合物为公知化合物,或者也可通过与用于制备公知化合物类似的方法制备,如在以下实施例中所采用的方法。
通式XVII的化合物为公知化合物,或者也可通过与用于制备公知化合物类似的方法制备。在通式XVII中,R32为胺保护基,如在下述文献中所述:有机合成中的保护基(Protective Groups in OrganicSynthesis),T.W.Greene,P.G.M.Wuts,John Wiley & SonsInc,第二版,1991,优选苄基或三氟乙酰基。
其中,R4、R5、R6、R7和n均如前定义。该还原反应可按照将肟还原成胺的常规方法进行。例如,还原反应可通过催化氢化反应来完成,优选采用钯/炭作为催化剂。该氢化反应可采用公知方法完成,例如下述文献所述方法:R.D.Sindelar等,J.Med.Chem.(1982),25(7),858-864。通式XXI的肟可按照Sindelar等所述的方法制备,或者通过类似的方法制备。
R5-C≡C-R6 XXIII
其中,R3、R5、R6、R32和n如前定义。该反应可在催化剂存在下进行,催化剂例如为三(三苯基膦)氯化铑。反应温度例如为60-120℃。反应便利地在惰性溶剂如乙醇中进行,反应温度方便地为所用溶剂的回流温度。反应可采用公知方法进行,例如WO 96/23760所述方法。当R5和R6为三烷基甲硅烷基时,在通式XXII和XXIII间的反应可在金属羰基配合物催化剂存在下进行,例如采用下述文献所述方法:K.P.C.Vollhardt和R.Hillard,J.Am.Chem.Soc.1977,99(12),4058或类似的方法。通式XXII的化合物为公知的化合物或可通过公知方法制备。
其中R3为烷基特别是甲基,且n为1的通式XVII的化合物可通过用氨和K3FeCN6对相应的2-烷基-二氢化茚-1-酮进行胺化来制备,例如下述文献所述方法:Fornum和Carlson,Synthesis 1972,191。
在R4、R5、R6和R7使得与其相连的苯环对称取代时,所定义的通式XVII的化合物为新的,除了当R4、R5、R6、R7和R30均为氢的化合物,当R5、R6和R30均为氢而R4和R7为甲基或甲氧基的化合物,当R5和R6分别为羟基、氟或氯而R4、R7和R30为氢的化合物。特别是,优选的通式XVII的中间体为新的,其中,(i)R4和R7均为氢且R5和R6或者均为C2-C4-烷基、C2-C4-烷氧基、C1-C4-烷氧基-C1-C4-烷基,或者R5和R6一起表示-(CH2)s-或-O(CH2)tO-,其中,s为1-4而t为1或2;或(ii)R4和R7分别为C2-C4-烷基或C2-C4-烷氧基且R5和R6或者均为氢、C1-C4-烷基,C1-C4-烷氧基且R5和R6均为氢、C1-C4-烷基、C1-C4-烷氧基或C1-C4烷氧基-C1-C4-烷基或者R5和R6一起表示-(CH2)s-或-O(CH2)tO-,其中,s为1-4而t为1或2。
通式XVIII的化合物为新化合物,其可通过使式XXIV的化合物与如前定义的通式XVII的化合物进行反应制备,
Ar1-CO-Hal XXIV,
其中,Ar1如前定义而Hal为卤原子,优选氯或溴。该反应采用常规方法进行,例如下述文献所述方法:Yoshizaki等,J.Med.Chem(1976),19(9),1138-42。
需要时,在上述方法中,任何活泼基团的保护可以在任何适宜的步骤中进行。保护基适宜地为一种现有技术中常规使用的保护基,可采用常规方法引入和除去它们。例如,当在Ar1中的羟基由苄基进行保护时,所述的苄基可采用常规方法在Pd/C存在下通过催化氢化反应除去,如在实施例中所述的那些方法。
游离形式、盐形式或溶剂化物形式的通式I的化合物可用作药物。
因此,本发明也提供了用作药物的游离形式、盐形式或溶剂化物形式的通式I的化合物。游离形式、盐形式或溶剂化物形式的通式I的化合物也被称之为“本发明的试剂”,其具有优异的β2-肾上腺受体激动剂活性。本发明试剂的β2-激动剂活性,作用起效和作用时间可采用豚鼠气管磨带进行体外实验,采用下述文献所述的方法:R.A.Coleman和A.T.Nials,J.Pharmaco1.Methods(1989),21(1),71-86。相对于β1-肾上腺受体,β2-肾上腺受体的结合潜力和选择性可通过经典过滤结合试验来测量,采用以下的方法:药物学中的流行方法(Current Protocols in Pharmacology)(S.J.Enna(主编)等,JohnWiley & Son,Inc,1998),或者在表达β2-或β1-肾上腺受体细胞中通过测量cAMP来测量,采用的方法是B.January等,British J.Pharmacol.123:701-711(1998)。
本发明的试剂通常具有对β2-肾上腺受体迅速起效和刺激作用时间长的特点,以下实施例中的化合物的Ki(β2)值大约为0.1-1000nM,持续时间大约为1至大于12小时,相对于β1-肾上腺受体,对β2-肾上腺受体的结合选择性为1.5-500。例如,实施例1、2、4、5、6、8、27和29的化合物具有β2和β1结合潜力,根据在表达β2-或β1-肾上腺受体的细胞中进行cAMP测量,由EC50值(β2/β1)(单位nM)表示的值分别为0.92/9.52、0.23/1.25、6.07/14.5、0.3/3.60、0.79/6.10、0.57/8.46和0.012/0.5。在采用豚鼠气管磨带实验中,实施例2、4、5、27和29的化合物的T(50%)时间(单位分钟)值分别为,在71nM的浓度时,>400;在100 nM时为82,在100nM时为444,在1.0nm时为222,在10nM时为279,其中,T(50%)为抑制收缩减少至最大值的50%时的时间。
考虑到它们的β2-肾上腺受体激动剂活性,本发明的试剂适用于治疗那些通过活化β2-肾上腺受体来预防或缓减的病症。由于具有长期作用选择性β2-激动剂活性,本发明的试剂可用于弛缓支气管平滑肌并减轻支气管收缩。支气管收缩的减轻可通过以下的模型来测量:如体内体积描记法,Chong等,J.Pharmacol.Toxicol.Methods 1998,39,163-168,Hammelmann等,Am.J.Respir.Crit.Care Med.,1997,156,766-775和类似的模型。因此,本发明的试剂可用于治疗梗阻性或炎性气道疾病。由于具有长期作用效果,在治疗疾病时,可以采用一天给药一次的给药方式。另一方面,本发明的试剂通常还显示出能够降低一般β2激动剂通常会碰到的副作用如心动过速、震颤和坐立不安等的发生率,因此,这种试剂适用于即时(营救)治疗和预防治疗梗阻性或炎性气道疾病。
本发明进行的疾病治疗可以为有症状的治疗或预防性治疗。本发明所涉及的梗阻性或炎性气道疾病包括各种类型或成因的哮喘,包括内因性哮喘(非变应性哮喘)和外因性哮喘(变应性哮喘)。哮喘的治疗也被理解为是对患者进行包围性治疗,例如,年龄小于4或5岁,显示出气喘症状并诊断出或可诊断为“哮喘性婴儿”建立的主要涉及药物的患者种类以及目前经常认为初期或早期的哮喘症(为方便起见,这种特定的哮喘症被称之为“哮喘性婴儿综合征”)
在治疗哮喘中的预防功效可通过作为征候的发作如急性哮喘或支气管收缩发作的频率或严重性,肺功能的改善或气道高反应性的改善来证明。进而,还可对其它作为征候的治疗方法的需求减少来证明,即当发生时,用于或准备用于限制或中止作为征候的发作,例如消炎(如皮质类固醇)或支气管扩张剂。在哮喘中预防功效对倾向“早晨急压触诊(morning dipping)”的患者更为明显。“早晨急压触诊”是一种已认知的哮喘综合征,通常具有患哮喘症的实质上可能性,其特征是哮喘发作,例如在约早上4-6点发作,即通常基本上与先前给药的有症状的哮喘治疗相距较远的时间。
本发明可应用的其它梗阻性或炎性气道疾病和病症包括:成人呼吸窘迫综合征(ARDS),慢性梗阻性肺或气道疾病(COPD或COAD),包括慢性支气管炎或与其相关的呼吸困难,肺气肿,以及其它药物治疗引起的气道过度反应的恶化,特别是其它吸入药物治疗。
本发明也可用于治疗各种类型或成因的支气管炎,例如,包括急性支气管炎、花生性(arachidic)支气管炎、卡他性支气管炎、克鲁布性支气管炎、慢性支气管炎或痨病样支气管炎。
进而,本发明可用于治疗的梗阻性或炎性气道疾病包括各种类型或成因的肺尘埃沉着病(一种炎性的常规肺职业病,经常伴有气道梗阻,包括急性和慢性,诱因是重复吸入粉尘),例如包括,矾土肺,煤矽肺,石棉肺,石末肺,驼鸟毛尘肺,铁质沉着病,矽肺,烟末沉着病和棉屑肺。
由于具有β2激动剂活性,本发明的试剂也可用于治疗需要松弛子宫平滑肌或维管系统的疾病。因此,它们可用于预防或缓减在怀孕期间早产分娩疼痛。它们也可用于治疗慢性和急性荨麻疹,干癣,变应性结膜炎,痤疮疹,季节性变应性鼻炎和肥大细胞增生。
本发明的试剂也可用作与抗炎或支气管扩张药物结合使用的助治疗剂,特别是治疗如上所述的梗阻性或炎性气道疾病,例如作为这些药物治疗活性的强化因子,或者作为减少这些药物所需剂量或可能的副作用的手段。本发明的试剂可与抗炎药或支气管扩张药在固定的药物组合物中混合,或者,可以在给药抗炎药或支气管扩张药之前、同时或之后分开给药。这种抗炎药包括类固醇,特别是糖皮质类固醇,如布地奈德,丙酸倍氯米松,氟替卡松或莫米松,以及多巴胺受体激动剂,如卡麦角林,溴隐亭或罗平尼咯。这种支气管扩张药包括抗胆碱能药或抗毒蕈碱剂,特别是异丙托溴铵,氧托溴铵和氢溴酸利眠宁(tiotropiumbromide)。本发明的试剂与类固醇的组合例如可用于治疗COPD,特别是哮喘。本发明试剂与抗胆碱能药或抗毒草碱剂或多巴铵受体激动剂的组合例如可用于治疗哮喘,特别是COPD。
按照如上所述,本发明也提供了一种治疗梗阻性或炎性气道疾病的方法,包括向需要的患者,特别是人类给药如上所述的通式I的化合物或其可药用盐或溶剂化物。另一方面,本发明提供了如上所述的通式I的化合物或其可药用盐或溶剂化物在制备用于治疗梗阻性或炎性气道疾病的药物中的用途。
本发明的试剂可通过任何适宜的路径给药,例如,口服给药,如以片剂或胶囊剂给药;非肠道给药,如静脉注射;局部给药于皮肤,如用于治疗干癣;鼻内给药,如用于治疗季节性变应性鼻炎;或者,优选通过吸入法给药,特别是用于治疗梗阻性或炎性气道疾病。
另一方面,本发明也提供了一种药物组合物,其包含游离形式或其可药用盐形式或其溶剂化物形式的通式I的化合物,选择性地还包含可药用稀释剂或载体。该组合物可采用常规稀释剂或赋形剂以及医学中公知的技术制备。因此,口服剂型可包括片剂和胶囊。局部给药的制剂可形成霜剂、软膏剂、凝胶剂或透皮传送系统,如贴剂。吸入制剂可包含气溶胶或其它可雾化的制剂或干粉制剂。
本发明也包括(A)一种为可吸入形式的如前所述游离形式或其可药用盐形式或其溶剂化物形式的通式I的化合物;(B)一种可吸入的药物,其包含可吸入形式的该化合物以及可吸入形式的可药用载体;(C)一种药物产品,其包含可吸入形式的该化合物以及与其组合使用的吸入装置;和(D)包含可吸入形式的该化合物的吸入装置。
当然,实施本发明中所采用的剂量例如会根据具体治疗的疾病、所需效果和给药方式而变化。通常,吸入法给药时的每日适宜剂量大约为1-5000μg。
通过下述实施例说明本发明。用于这些实施例中的化合物按照下述过程制备:中间体15,6-二乙基-茚-2-基胺盐酸盐制备例13-氯-1-(3,4-二乙基苯基)-1-丙酮
在30分钟内,将1,2-二乙基苯(10.9g,74.6 mmol)和丙酰氯(9.7g,74.6mmol)滴加至在硝基甲烷(75mL)中的AlCl3(22.3g,167,8mmol)中。将反应混合物在室温下搅拌2小时,此后,加入70g的冰和14mL浓硫酸。用乙醚对水相进行萃取,将合并后的有机相用2N HCl和饱和NaCl水溶液萃取。有机相再用活性炭和硫酸镁处理,过滤,真空除去溶剂。1H-NMR(CDCl3)ppm:7.8(1H,s,Ar);7.7(1H,d,Ar);7.2(1H,d,Ar);3.9(2H,t,CH2);3.4(2H,t,CH2);2.8(4H,q,CH2CH3);1.2(6H,m,CH3).制备例22,3-二氢-5,6-二乙基-1H-茚-1-酮
将3-氯-1-(3,4-二乙基苯基)-1-丙酮(15.5 g)溶解于66mL浓硫酸中,并在90℃下加热4小时。将反应混合物冷却,加入冰(70g),将水溶液用甲苯萃取两次。有机相用碳酸氢钠,饱和NaCl水溶液洗涤,再用活性炭和硫酸镁处理。过滤后,真空除去溶剂。将产物经快速柱色谱(硅胶,己烷/乙酸乙酯10∶1)纯化,再在己烷中结晶。1H-NMR(CDCl3)ppm:7.6(1H,s,Ar);7.3(1H,d,Ar);3.1(2H,m,CH2);2.7(6H,m,CH2+CH2CH3);1.2(6H,m,CH3).制备例35,6-二乙基-3-肟-1H-茚-1,2(3H)-二酮
将甲醇(75mL)中的2,3-二氢-5,6-二乙基-1H-茚-1-酮(5g,26mmol)升温至40℃,滴加入亚硝酸正丁酯(3.0g,28.6mmol),随后,加入浓HCl(1.25mL)。1小时后,使反应物降至室温,滤出沉淀出的产物,用冰冷却的甲醇洗涤,干燥。1H-NMR(d6-DMSO)ppm:12.6(1H,s,OH);7.4(1H,s,Ar);7.3(1H,d,Ar);3.6(2H,s,CH2);2.6(4H,m,CH2CH3);1.1(6H,m,CH3).制备例45,6-二乙基-2,3-二氢化茚-2-基胺盐酸盐
将5,6-二乙基-3-肟-1H-茚-1,2(3H)-二酮(4.5g)加至乙酸(150mL)和浓硫酸(4.5mL)的混合物中。加入Pd/C 5%(1.5g),将反应混合物用氮气脱气,并氢化5小时。然后,过滤除去催化剂,用4M NaOH使pH值升至10,溶液用氯仿进行萃取。有机相用硫酸镁干燥,真空除去溶剂。将残余物再溶解于少量的乙醚中,加入HCl饱和的乙醚。滤出白色沉淀物,干燥,获得5,6-二乙基-2,3-二氢化茚-2-基胺的盐酸盐,为通式XVII的化合物,其中,R3,R4和R7为H,R5和R6均为CH3CH2-,R30为氢和n为1。1H-NMR(d6-DMSO)ppm:8.7(3H,bd s,NH3);7.3(2H,s,Ar);4.2(1H,bd s,CH);3.5(2H,dd,CH2);3.3(2H,dd,CH2);2.8(4H,q,CH2CH3);1.4(6H,t,CH3).
采用类型于中间体1的过程,或由可获得的化合物为原料,并采用类似于制备例3和4的方法可制备其它通式XVII的化合物。这些通式XVII的化合物示于下表中,R3为氢,n为1。中间体 R4 R5 R6 R72 CH3CH2 H H CH3CH23 H -(CH2)4- H4 H -O(CH2)2O- H5 H CH3(CH2)3 CH3(CH2)3 H6 H CH3(CH2)2 CH3(CH2)2 H7 H CH3O CH3O H
中间体2:ES+MSm/e(MH+):204
中间体3:1H-NMR(d6-DMSO)ppm:8.1(3H,bd s,NH3);6.9(2H,s,Ar);3.9(1H,bd s,CH);3.2(2H,dd,CH2);2.8(2H,dd,CH2);2.7(4H,m,CH2Ar);1.7(6H,t,CH2).
中间体4:1H-NMR(d6-DMSO)ppm:8.3(3H,bds,NH3);6.85(2H,s,Ar);4.2(4H,s,2CH2);3.1(2H,dd,CH2);2.85(2H,dd,CH2).
中间体5:1H-NMR(d6-DMSO)ppm:6.9(2H,s,Ar);3.8(1H,m,CH);3.1(2H,dd,CH2);2.6(2H,dd,CH2);2.5(4H,t,2CH2);1.65(2H,bds,NH2);1.55(4H,m,2CH2);1.4(4H,m,2CH2);0.95(6H,t,2CH3).
中间体6:1H-NMR(d6-DMSO)ppm:8.1(3H,bd s,NH3);7.0(2H,s,Ar);3.9(1H,bd s,CH);3.2(2H,dd,CH2);2.8(2H,dd,CH2);2.5(4H,q,EtCH2Ar);1.6(4H,q,CH2),0.9(6H,t,CH3).
中间体7:1H-NMR(d6-DMSO)ppm:8.3(3H,bd s,NH3),6.9(2H,s,H-Ar),3.9(1H,bd m,CHN),3.7(6H,s,CH3O),3.2(2H,dd,CH2),2.9(2H,dd,CH2).中间体82-(三氟乙酰氨基)-5,6-二(甲氧基甲基)2,3-二氢化茚
按照Magnus等的方法(Tetrahed.Lett.,34,23-26(1993)),将商购的1,4-二甲氧基-2-丁炔(1.32g,11.5mmol)在氮气脱气的乙醇中的溶液在氮气氛及搅拌下加热至80℃。在2小时内,分批加入三(三苯基膦)氯化铑(64mg,0.07mmol)和在氮气脱气的乙醇(2ml)中的2,2,2-三氟-N-[1-(2-丙炔基)-3-丁炔基]-乙酰胺(470mg,2.32mmol;按照文献方法制备:Romero,Arthur G.;Leiby,Jeffrey A PCT国际申请WO 9623760)。将混合物在氮气氛下于80℃搅拌3小时。真空除去溶剂,将残余物用硅胶快速色谱法纯化,用己烷/乙酸乙酯(2∶1)洗脱。1H-NMR(CDCl3)ppm:2.9(2H,dd),3.35(2H,dd),3.45(6H,s),4.57(4H,s),4.85(1H,m),6.4(1H,br s),7.30(2H,s).中间体92-氨基-5,6-二(甲氧基甲基)2,3-二氢化茚
将氢氧化钾(150mg,2.60mmol)的水(0.5ml)溶液加至2-(三氟乙酰氨基)-5,6-二(甲氧基甲基)2,3-二氢化茚(240mg,0.75mmol)的甲醇(3mL)溶液中,将混合物加热回流2.5小时。真空除去溶剂,将残余物在氢氧化钠水溶液(10mL)和乙酸乙酯(20mL)间进行分配。干燥有机相(MgSO4),真空除去溶剂,得到暗黑色油状产物。1H-NMR(CDCl3)ppm:2.60(2H,dd),3.10(2H,dd),3.33(6H,s),3.75(1H,m),4.42(4H,s),7.17(2H,s).中间体108-羟基-5-[(2,3-二氢化茚-2-基氨基)-乙酰基]-1H-喹啉-2-酮
将按照文献方法(Yoshizaki,Shiro;Tanimura,Kaoru;Tamada,Shigeharu;Yabuuchi,Youichi;Nakagawa,Kazuyuki.J.Med.Chem.(1976),19(9),1138-42)制备的5-(氯乙酰基)-8-羟基-2(1H)-喹啉酮(25mg,0.105mmol)与2,3-二氢化茚-2-基胺(205mg,1.21mmol)在25℃下反应2小时。将反应混合物用快速色谱纯化(硅胶,CH2Cl2/甲醇9∶1)。ES±MS m/e 335(MH±)。中间体11
采用类似于中间体10的过程制备下述通式XVIII的化合物,其中,Ar为式III的基团,R27,R28和R29为氢,R2,R3,R4和R7为氢,和R5和R6分别为甲氧基。ES+MS m/e(MH+):395。中间体128-苄氧基-3-甲基-5-环氧乙烷基(oxiranyl)-1H-喹啉-2-酮
按照下述文献的方法制备8-羟基-3-甲基-1H-喹啉-2-酮:Wang等,T.-C.Wang,Y.-L.Chen,K.-H.Lee,C.-C.Izeng Synthesis1997,87-90.)。1H-NMR(d4-CH3OH)ppm:2.14(s,3H),6.84-6.89(m,1H),6.95-7.03(m,2H),6.90(s,1H),7.71(s,1H).8-苄氧基-3-甲基-1H-喹啉-2-酮
在室温下,将苄基溴(1.28mL)加至碳酸钾(2.98g)在8-羟基-3-甲基-1H-喹啉-2-酮(1.26g)的丙酮(36mL)溶液中的悬浮液中。将反应混合物回流18小时,过滤,蒸发,用快速硅胶柱色谱纯化,用2%甲醇的二氯甲烷溶液洗脱。1H-NMR(CDCl3)ppm:2.11(s,3H),5.13(s,2H),6.92-6.98(m,1H),7.02-7.08(m,2H),7.29-7.40(m,5H),7.57(s,1H),9.23(s,1H).8-苄氧基-5-溴-3-甲基-1H-喹啉-2-酮
在室温下,将溴(0.57g)的乙酸(2mL)溶液滴加至8-苄氧基-3-甲基-1H-喹啉-2-酮(0.94g)和乙酸钠(0.96g)的乙酸(12mL)溶液中。将反应混合物在室温下搅拌3小时,蒸发,将残余物在水(5mL)和乙酸乙酯(5mL)间分配,用乙酸乙酯(5mL)萃取两次。将合并后的有机萃取液用硫酸镁干燥,用快速硅胶柱色谱纯化,用2%甲醇的二氯甲烷溶液洗脱。1H-NMR(CDCl3)ppm:2.27(s,3H),5.18(s,2H),6.83(d,1H),7.39(d,1H),7.37-7.41(m,5H),7.91(s,1H),9.08(s,1H).8-苄氧基-3-甲基-5-乙烯基-1H-喹啉-2-酮
在室温下,将四(三苯基膦)(30mg)加至8-苄氧基-5-溴-3-甲基-1H-喹啉-2-酮(239mg)和三丁基乙烯基锡(203μL)的甲苯(7mL)溶液中。将反应混合物在100℃下加热2小时,冷却至室温,蒸发,将产物用快速硅胶柱色谱纯化,用2%乙酸乙酯的二氯甲烷溶液洗脱。1H-NMR(CDCl3)ppm:2.24(s,3H),5.18(s,2H),5.32-5.39(m,1H),5.61-5.68(m,1H),6.95(d,1H),7.09-7.20(m,1H),7.21-7.26(m,2H),7.31-7.43(m,4H),7.89(s,1H),9.20(s,1H).8-苄氧基-3-甲基-5-环氧乙烷基-1H-喹啉-2-酮
将8-苄氧基-3-甲基-5-乙烯基-1H-喹啉-2-酮(300mg)加至0.1M二甲基二环氧乙烷的丙酮(12.4mL)溶液中。在室温下搅拌22小时后,真空除去溶剂,获得产物。1H-NMR(CDCl3)ppm:2.23(s,3H),2.77-2.81(m,1H),3.18-3.23(m,1H),4.17-4.21(m,1H),5.18(s,2H),6.91(d,1H),7.01(d,1H),7.93(s,1H),9.10(s,1H).中间体138-苄氧基-5-[2-(5,6-二乙基-2,3-二氢化茚-2-基氨基)-1-羟基-乙基]-3-甲基-1H-喹啉-2-酮
将中间体12(65mg)和5,6-二乙基-2,3-二氢化茚-2-基胺(120mg)的DMSO(1.5mL)溶液在90℃下加热18小时。真空除去溶剂,将产物用快速硅胶柱色谱纯化,用10%甲醇的二氯甲烷溶液洗脱。13C-NMR(d4-CH3OH)ppm:15.96,17.14,26.33,36.77,53.34,59.82,67.33,71.73,112.09,118.98,121.73,125.42,128.74,129.24,129.47,129.61,131.84,134.56,137.52,137.64,142.29,145.94,164.02.中间体148-甲氧基甲氧基-6-甲基-5-环氧乙烷基-1H-喹啉-2-酮
按照下述方法制备8-羟基-6-甲基-1H-喹啉-2-酮:Wang等,T.-C.Wang,Y.-L.Chen,K.-H.Lee,C.-C.Izeng Synthesis1997,87-90。1H-NMR(d6-DMSO)ppm:2.26(s,3H),6.45(d,1H),6.79(s,1H),6.90(s,1H),7.78(d,1H).5-溴-8-羟基-6-甲基-1H-喹啉-2-酮
在室温下,将45%的氢溴酸的乙酸(324μl)溶液滴加至8-羟基-6-甲基-1H-喹啉-2-酮(316mg)的二甲亚砜(9mL)溶液中。将反应混合物在室温下放置18小时,真空除去溶剂。1H-NMR(d6-DMSO)ppm:2.33(s,3H),6.58(d,1H),6.92(s,1H),8.03(d,1H),10.44(s,1H),10.67(s,br,1H).5-溴-8-甲氧基甲氧基-6-甲基-1H-喹啉-2-酮
在0℃下,将甲氧基甲基氯(410μL)加入碳酸钾(1.24g)在5-溴-8-羟基-6-甲基-1H-喹啉-2-酮(480mg)的二甲基甲酰胺(9mL)溶液中的悬浮液中。将反应混合物在室温下搅拌18小时,过滤,真空除去溶剂,将产物用快速硅胶柱色谱纯化,用2%甲醇的二氯甲烷溶液洗脱。13C-NMR(CDCl3)ppm:23.42,56.52,95.07,115.78,116.19,119.32,123.30,128.13,132.14,139.78,141.78,161.32.8-甲氧基甲氧基-6-甲基-5-乙烯基-1H-喹啉-2-酮
在室温下,将二(三苯基膦)钯(II)氯化物(98mg)加至5-溴-8-甲氧基甲氧基-6-甲基-1H-喹啉-2-酮(410mg)和三丁基乙烯基锡(603μL)的二甲基甲酰胺(14mL)溶液中。将反应混合物在90℃下加热24小时,蒸发和用快速硅胶柱色谱纯化,用2%甲醇的二氯甲烷溶液洗脱。1H-NMR(CDCl3)ppm:2.19(s,3H),3.41(s,3H),5.18(d,1H),5.20(s,2H),5.60(d,1H),6.52(d,1H),6.63-6.69(m,1H),6.96(s,1H),7.95(d,1H),9.78(s,1H).
按照中间体12所述方法最后的步骤,8-甲氧基甲氧基-6-甲基-5-环氧乙烷基-1H-喹啉-2-酮由8-甲氧基甲氧基-6-甲基-5-乙烯基-1H-喹啉-2-酮(186mg)获得。1H-NMR(CDCl3)ppm:2.38(s,3H),2.68-2.72(m,1H),3.19-3.23(m,1H),3.43(s,3H),3.97-4.01(m,1H),5.21(s,2H),6.60(d,1H),6.98(s,1H),8.22(d,1H),9.09(s,1H).
中间体15
(R)-2-(4-苄氧基-3-硝基苯基)-环氧乙烷按照下述文献所述方法制备,R.Hett等,Tetrahedron Lett.(1997),38(7),1125-1128。中间体16(S)-8-苄氧基-5-环氧乙烷基-1H-喹啉-2-酮8-苄氧基-5-((S)-2-氯-1-羟基-乙基)-1H-喹啉-2-酮
在炉中干燥的烧瓶中,将(S)-2-甲基-CBS-oxazaborolidine,1M的甲苯(0.30mL,0.30mmol)溶液加至无水THF(四氢呋喃)(10mL)中。然后滴加入硼烷-THF配合物的1M THF(3.05mL)溶液,将溶液在室温下搅拌15分钟,然后冷却至0℃。然后,在30分钟内,分多次加入8-苄氧基-5-氯乙酰基-1H-喹啉-2-酮(1.00g),按照WO 95/25104所述制备。将反应混合物在0℃下搅拌。在15分钟后,通过TLC(薄层色谱法)显示反应完成。加入甲醇(1mL)使反应混合物停止反应,真空除去溶剂,将残余物在0.2M H2SO4(100mL)和CHCl3(100mL)间进行分配。有机层用硫酸镁干燥,过滤和真空除去溶剂。进行乙酸乙酯结晶。TLC(硅胶,二氯甲烷/甲醇25∶1 Rf=0.30)。(S)-8-苄氧基-5-环氧乙烷基-1H-喹啉-2-酮
将8-苄氧基-5-((S)-2-氯-1-羟基-乙基)-1H-喹啉-2-酮(0.55g)溶解于丙酮(20mL)中。加入K2CO3(0.58g),将反应混合物回流。在18小时后,通过TLC显示反应完成。真空除去溶剂,将残余物在乙酸乙酯(100mL)和水(100mL)间分配。有机层用硫酸镁干燥,过滤和真空除去溶剂。将产物用乙醚研制,过滤和干燥。TLC(硅胶,二氯甲烷/甲醇25∶1 Rf=0.45)。中间体176,7,8,9-四氢-5H-苯并环庚烯-7-基胺苄基-(6,7,8,9-四氢-5H-苯并环庚烯-7-基)-胺
将5,6,8,9-四氢-苯并环庚烯-7-酮(3.00g)和苄基胺(2.00g)溶解于乙醇(50mL)中。加入催化量的10%钯/炭,将反应混合物置于氢气氛下。在室温下搅拌反应混合物,在24小时后,通过TLC显示反应完成。滤除催化剂,真空除去溶剂。产物无需进一步纯化。TLC(硅胶,正己烷/乙酸乙酯1∶2 Rf=0.50)。6,7,8,9-四氢-5H-苯并环庚烯-7-基胺
将苄基-(6,7,8,9-四氢-5H-苯并环庚烯-7-基)-胺(2.80g)溶解于甲醇(100mL)中,通过加入催化量的10%钯/炭使化合物脱保护,将溶液置于氢气氛下。在24小时后,通过TLC显示反应完成。滤除催化剂,真空除去溶剂。产物无需进一步纯化。TLC(硅胶,二氯甲烷/甲醇25∶1 Rf=0.15)。中间体18苄基-(5,6-二乙基-2,3-二氢化茚-2-基)-胺N-(5,6-二乙基-2,3-二氢化茚-2-基)-苯甲酰胺
将5,6-二乙基-2,3-二氢化茚-2-基胺(4.10g)溶解于二氯甲烷(DCM)(150mL)中,加入三乙胺(2.41g)。然后滴加入苯甲酰氯(3.20g),将反应混合物在室温下搅拌。在1小时后,通过TLC显示反应完成。溶液用0.2M HCl(100mL),水(100mL)和盐水(100mL)洗涤。有机层用硫酸镁干燥,过滤和真空除去溶剂。用乙酸乙酯结晶。TLC(硅胶,二氯甲烷/甲醇10∶1 Rf=0.85)。苄基-(5,6-二乙基-2,3-二氢化茚-2-基)-胺
将N-(5,6-二乙基-2,3-二氢化茚-2-基)-苯甲酰氯(3.30g)溶解于无水THF(100mL)中。然后滴加入氢化铝锂的1MTHF(22.52mol)溶液。将反应混合物在50℃下搅拌。在6小时后,通过TLC显示反应完成。将反应混合物冷却,缓慢地倒入冰-水(200mL)中,并用乙醚(2×150mL)萃取。有机层用硫酸镁干燥,过滤,真空除去溶剂。产物无需进一步纯化。TLC(硅胶,正己烷/乙酸乙酯2∶1 Rf=0.20)。中间体19(R)-1-3-氨基-4-苄氧基-苯基)-2-[苄基-(5,6-二乙基-2,3-二氢化茚-2-基)-氨基]-乙醇(R)-2-[苄基-(5,6-二乙基-2,3-二氢化茚-2-基)-氨基]-1-(4-苄氧基-3-硝基-苯基)-乙醇)
采用中间体15(3.01g)和中间体18(3.10g),按照实施例19中用于制备(S)-8-苄氧基-5-[2-(5,6-二乙基-2,3-二氢化茚-2-基氨基)-1-羟基-乙基]-1H-喹啉-2-酮的方法制备标题化合物。在24小时后,通过TLC显示反应完成。将产物进行快速柱色谱(硅胶,正己烷/乙酸乙酯4∶1)纯化。TLC(硅胶,正己烷/乙酸乙酯4∶1 Rf=0.25)。(R)-1-(3-氨基-4-苄氧基-苯基)-2-[苄基-(5,6-二乙基-2,3-二氢化茚-2-基)-氨基]-乙醇
将(R)-2-[苄基-(5,6-二乙基-2,3-二氢化茚-2-基)-氨基]-1-(4-苄氧基-3-硝基-苯基)-乙醇(3.00g)溶解于THF(50mL)和甲苯(50mL)中。加入催化量的PtO2,将溶液在氢气氛下进行搅拌。在6小时后,通过TLC显示反应完成。滤除催化剂,真空除去溶剂。产物无需进一步纯化。TLC(硅胶,正己烷/乙酸乙酯1∶1 Rf=0.75)。中间体201-(3-氨基-4-苄氧基-苯基)-2-[苄基-(5,6-二乙基-2,3-二氢化茚-2-基)氨基]-乙酮2-[苄基-(5,6-二乙基-2,3-二氢化茚-2-基)-氨基]-1-(4-苄氧基-3-硝基-苯基)-乙酮
将1-(4-苄氧基-3-硝基-苯基)-2-溴-乙酮(2.00g)(按照下述方法制备:Hett,Robert;Fang,Qun Kevin;Gao,Yun;Hong,Yaping;Butler,Hal T.;Nie,Xiaoyi;Wald,Stephen A.tetrahedronLett.1997,38,1125-1128.)溶解于甲基甲基酮(methymethylketone)(100mL)中。加入三乙胺(0.64g),随后加入苄基-(5,6-二乙基-2,3-二氢化茚-2-基)-胺(1.60g)。再将反应混合物回流。在3小时后,通过TLC显示反应完成。真空除去溶剂,将产物进行快速柱色谱(硅胶,正己烷/乙酸乙酯4∶1)纯化。TLC(硅胶,正己烷/乙酸乙酯2∶1 Rf=0.75)。
1-(3-氨基-4-苄氧基-苯基)-2-[苄基-(5,6-二乙基-2,3-二氢化茚-2-基)-氨基]-乙酮由2-[苄基-(5,6-二乙基-2,3-二氢化茚-2-基)-氨基]-1-(4-苄氧基-3-硝基-苯基)-乙酮(1.50g)制备,采用实施例19中用于制备(R)-1-(3-氨基-4-苄氧基-苯基)-2-[苄基-(5,6-二乙基-2,3-二氢化茚-2-基)-氨基]-乙醇类似的方法。在48小时后,通过TLC显示反应完成。滤除催化剂,真空除去溶剂。产物进行快速柱色谱(硅胶,正己烷/乙酸乙酯4∶1)纯化。TLC(硅胶,正己烷/乙酸乙酯2∶1 Rf=0.70)。1H NMR[CDCl3,400MHz]d 1.20(6H,t),1.60(2H,宽峰),2.60(4H,q),3.00(4H,m),3.90(6H,m),5.15(2H,s),6.80(1H,d),6.95(2H,s),7.30(12H,m)中间体21苄基-(4,5,6,7-四甲基-2,3-二氢化茚-2-基)-胺
3-氯-1-(2,3,4,5-四甲基-苯基)-丙-1-酮由1,2,3,4-四甲基-苯和3-氯丙酰氯按照与制备例1类似的方法制备。1H NMR(CD3OD)ppm:7.5(1H,s);4.2(2H,t);3.6(2H,t);2.6(3H,s);2.57(3H,s);2.52(3H,s);2.5(3H,s).4,5,6,7-四甲基-2,3-二氢化茚-1-酮由3-氯-1-(2,3,4,5-四甲基-苯基)-丙-1-酮按照与制备例2类似的方法制备。1H NMR(CD3OD)ppm:3.2(2H,t);2.9(2H,t);2.85(3H,s);2.6(3H,s);2.55(3H,s);2.5(3H,s).
4,5,6,7-四甲基-2,3-二氢化茚-1,2-二酮2-肟由4,5,6,7-四甲基-2,3-二氢化茚-1-酮按照与制备例3类似的方法制备。1H NMR(d6-DMSO)ppm:12.4(1H,s);3.65(2H,s);2.7(3H,s);2.4(3H,s);2.3(6H,s).
2-氨基-4,5,6,7-四甲基-2,3-二氢化茚-1-酮盐酸盐由4,5,6,7四甲基-2,3-二氢化茚-1,2-二酮-2-肟按照与制备例4类似的方法制备。1H NMR(d6-DMSO)ppm:9.0(3H,bd s);4.5(1H,bd t);3.7(1H,dd);3.2(1H,dd);2.8(3H,s);2.6(3H,s);2.5(6H,2 s).N-(4,5,6,7-四甲基-1-氧代-2,3-二氢化茚-2-基)-苯甲酰胺
在0℃下,将苯甲酰氯(1.635g)滴加至无水二氯甲烷(60ml)中的4,5,6,7-四甲基-2,3-二氢化茚-1,2-二酮2-肟(2.53g)和三乙胺(2.25g)中。将反应混合物在室温下搅拌1.5小时,此后,滤出固体产物,使其与水(150mL)搅拌,再过滤,干燥。将有机滤液用1M HCl,10%盐水,饱和碳酸氢钠溶液,10%盐水洗涤,再用硫酸镁处理。过滤后,真空除去溶剂,将产物用乙醚研制,过滤和干燥。1H NMR(CDCl3)ppm:7.8(2H,d);7.45(1H,m),7.4(2H,m);6.8(1H,bd d);4.6(1H,m);3.8(1H,dd);2.8(1H,dd);2.55(3H,s);2.25(3H,s);2.15(6H,2s).N-(1-羟基-4,5,6,7-四甲基-2,3-二氢化茚-2-基)-苯甲酰胺
将氢硼化钠(213mg)加至在氯仿(20ml)和甲醇(20ml)中的N-(4,5,6,7-四甲基-1-氧代-2,3-二氢化茚-2-基)-苯甲酰氯(495mg)中。将反应混合物在室温下搅拌2小时,用水(50ml)淹没和加入氯仿(20 ml)。水相用氯仿(x2)洗涤,合并有机相,用硫酸镁处理,过滤和真空除去溶剂。1H NMR(CDCl3)ppm:7.65(2H,d);7.4(1H,m),7.35(2H,m);6.3(1H,bd d);5.15(1H,d);4.5(1H,m);3.7(1H,bd s);3.5(1H,dd);2.65(1H,dd);2.25(3H,s);2.15(9H,3s).
N-(4,5,6,7-四甲基-2,3-二氢化茚-2-基)-苯甲酰胺由N-(1-羟基-4,5,6,7-四甲基-2,3-二氢化茚-2-基)-苯甲酰胺按照与制备例4类似的方法制备。1H NMR(CDCl3)ppm:7.65(2H,d);7.4(1H,m),7.3(2H,m);6.25(1H,bd d);4.85(1H,m);3.35(1H,dd);2.80(1H,dd);2.1(12H,2s).苄基-(4,5,6,7-四甲基-2,3-二氢化茚-2-基)-胺
在氮气氛及室温下,将1M氢化铝锂(2.4ml)的四氢呋喃溶液滴加至N-(4,5,6,7-四甲基-2,3-二氢化茚-2-基)-苯甲酰胺(352mg)的无水THF(10ml)溶液中。将反应混合物在50℃下搅拌20小时。4小时后,再加入1M氢化铝锂(1.2 ml,1.20 mmol)的THF溶液。在冷却后,用冰水使反应混合物停止反应。水相用乙醚(x3)萃取,合并有机层,用硫酸镁处理,过滤和真空除去溶剂。1H NMR(CDCl3)ppm:7.25(4H,m);7.15(1H,m);3.8(2H,s);3.55(1H,m);3.1(2H,dd);2.7(2H,dd);2.1(12H,2s).中间体22苄基-(2,3,5,6,7,8-六氢-1H-环戊[b]萘-2-基)-胺
在氮气氛及室温下,按照下述文献的方法,A.F.Abdel-Magid,等.J.Org.Chem.1996,61,3849-3862,将三乙胺(0.87mL,6.17mmol)加至搅拌中的2,3,5,6,7,8-六氢1H-环戊[b]萘-2-基胺在1,2-二氯乙烷(30mL)的悬浮液中。然后加入苯甲醛(0.52mL,5.14mmol),再加入三乙酰氧基氢硼化钠(1.64 g,7.7mmol)和乙酸(0.44mL,7.7mmol)。将反应混合物在室温下搅拌18小时。在用二氯甲烷稀释后,将混合物用NaOH水溶液(50mL,1M)洗涤,随后用盐水洗涤。除去溶剂,进行色谱处理(硅胶,乙酸乙酯/己烷,2∶1),得到一种油状物。1H-NMR(CDCl3)ppm:1.70(m,4H),2.65(m,4H),2.68(dd,2H),3.05(dd,2H),3.58(m,1H),3.78(s,2H),6.83(s,2H),7.25(m,5H).中间体232-甲基-2,3-二氢化茚-2-基胺2-氨基-2-甲基-2,3-二氢化茚-1-酮
按照Farnum等的方法(Synthesis 1972,191-192.),将水(1.35L)在80℃下搅拌,通过周期性地抽空而脱气,用氮气冲洗(3x)。加入K3FeCN6(202g,615mmol)和2-甲基-2,3-二氢化茚-1-酮(20g,137mmol)。将混合物在氮气氛及80℃下迅速搅拌,并在30分钟内加入浓氨水溶液(105mL)。在80℃下继续搅拌20小时。冷却时,通过加入氢氧化钠(2g)使溶液呈碱性,用乙酸乙酯(2×200mL)萃取。将有机萃取液浓缩至体积为200ml,将产物萃取进入HCl水溶液(200mL,1M)。分离酸性水相,用氢氧化钠碱化,再用乙酸乙酯(2×100mL)萃取。分离出有机层,干燥(Na2SO4),除去溶剂,得到一种橙色油。1H-NMR(CDCl3)ppm:1.38(s,3H),18(br.s,2H),3.07(d,1H),3.25(d,1H),3.45(m,2H),7.65(t,1H),7.80(d,1H).2,2,2-三氟-N-(2-甲基-1-氧代-2,3-二氢化茚-2-基)-乙酰胺
在氮气氛下,将2-氨基-2-甲基-2,3-二氢化茚-1-酮(16.4g)的THF(100mL)溶液冷却至0℃。加入三乙胺(21ml),再缓慢地加入三氟乙酸酐(18.5ml)。将反应混合物在室温下搅拌过夜,然后除去溶剂。将残余物溶解于二氯甲烷中,并用HCl水溶液洗涤,再用NaOH水溶液洗涤。干燥有机相(MgSO4),并除去溶剂。将产物用色谱法纯化(硅胶,乙酸乙酯),得到一种乳油状固体。1H-NMR(CDCl3)ppm:1.52(s,3H),3.44(d,1H),3.55(d,1H),7.05(br.s,1H),7.43(m,2H),7.70(t,1H),7.87(d,1H).2,2,2-三氟-N-(2-甲基-2,3-二氢化茚-2-基)-乙酰胺
在10%Pd/C存在下,在室温下,将2,2,2-三氟-N-(2-甲基-1-氧代-2,3-二氢化茚-2-基)-乙酰胺(3.41g)在乙酸(25mL)和H2SO4(0.5mL)中搅拌18小时。通过硅藻土对混合物过滤,将滤液进行真空浓缩。在用水稀释后,混合物用乙醚进行萃取。除去有机相,再用碳酸氢钠水溶液洗涤几次,干燥(Na2SO4)。除去溶剂,得到一种会固化的油。1H-NMR(CDCl3)ppm:1.55(s,3H),3.05(d,2H),3.28(d,2H),6.28(br.s,1H),7.12(s,4H)2-甲基-2,3-二氢化茚-2-基胺
将搅拌中的2,2,2-三氟-N-(2-甲基-2,3-二氢化茚-2-基)-乙酰胺(6.70g)和NaOH(4.0g)在甲醇(100mL)和水(1mL)中的溶液在70℃下搅拌2小时。除去溶剂,将残余物在HCl水溶液(100mL,2M)和乙酸乙酯(100mL)间进行分配。分离出水相,用NaOH水溶液碱化,用乙酸乙酯萃取。分离出有机相,干燥(MgSO4),除去溶剂,得到一种会固化的橙色油。1H-NMR(CDCl3)ppm:1.19(s,3H),1.5(br.s,2H),2.65(d,2H),2.79(d,2H),6.97(m,4H).中间体242-甲基-2,3,5,6,7,8-六氢-1H-环戊[b]萘-2-基胺1-(5,6,7,8-四氢-萘-2-基)-丙-1-酮
在0℃下,在1小时内,将丙酰氯(17.5mL)和1,2,3,3-四氢萘(27.5mL)缓慢地加至搅拌中的AlCl3(61.3g)的硝基甲烷(200mL)溶液中。在室温下搅拌18小时后,将反应混合物小心地加至冰与浓HCl的混合物中。产物用乙酸乙酯萃取,用盐水洗涤,干燥(Na2SO4)。1H-NMR(CDCl3)ppm:1.15(t,3H),1.72(m,4H),2.72(m,4H),2.88(q,2H),7.04(d,1H),7.60(m,1H).2-甲基-2,3,5,6,7,8-六氢-环戊[b]萘-1-酮
根据Bhattacharya等的方法(Synth.Commun 1996.,26,1775-1784.),将1-(5,6,7,8-四氢-萘-2-基)-丙-1-酮(37.6g),六亚甲基四胺(44.9g)和乙酸酐(38.8mL)的混合物在80℃下搅拌加热23小时。将混合物冷却,缓慢地加至搅拌中的乙酸乙酯(200mL)和氢氧化钠水溶液(200mL,2M)的混合物中。分离出有机层,用HCl和盐水洗涤,干燥(Na2SO4)。除去溶剂,得到一种褐色油。将其小心地加至浓硫酸(120mL)中,将形成的混合物在55℃下加热5小时,随后在室温下18小时。将反应混合物用水稀释,再用二氯甲烷萃取。干燥(Na2SO4)后,除去溶剂,得到一种油。将产物用色谱法纯化(硅胶,乙酸乙酯/己烷),得到包含2-甲基-1,2,6,7,8,9-六氢-环戊[.a.]萘-3-酮和标题化合物的几何异构体混合物。1H-NMR(CDCl3)ppm(混合物):1.4(m,3H),1.9(m,4H),2.5-3.0(m,6H),3.35(m,1H),7.15(m,1H),7.55(m,1H).2,2,2-三氟-N-(2-甲基-1-氧代-2,3,5,6,7,8-六氢-1H-环戊[b]萘-2-基)-乙酰胺
按照制备2,2,2-三氟-.N.-(2-甲基-1-氧代-2,3-二氢化茚-2-基)-乙酰胺所采用的方法,由包含2-甲基-2,3,5,6,7,8-六氢-环戊[b]萘-1-酮的异构体混合物制备该化合物。将产物的异构体混合物用乙酸乙酯/己烷进行重结晶,得到一种有利于标题化合物的4∶1混合物。1H-NMR(CDCl3)ppm(主组分):1.55(s,3H),1.85(m,4H),2.87(m,4H),6.88(br.s,1H),7.18(s,1H),7.57(s,1H).TOFMS ES-m/e310(M-H-)2-甲基-2,3,5,6,7,8-六氢-1H-环戊[b]萘-2-基胺
将主要包含2,2,2-三氟-.N.-(2-甲基-1-氧代-2,3,5,6,7,8-六氢-1H-环戊[b]萘-2-基)-乙酰胺的立体异构体的4∶1混合物在Pd/C上于乙酸/H2SO4中进行氢化,将产物按照制备2-甲基-2,3-二氢化茚-2-基胺的方法用NaOH进行皂化。将形成的产物混合物重复用己烷进行重结晶,获得标题化合物,为一种单一的异构体。1H-NMR(CDCl3)ppm:1.40(s,3H),1.6(br.s,NH2),1.75(m,4H),3.75(m,4H),2.78(d,2H),2.94(d,2H),6.93(s,2H).中间体252-乙基-2,3-二氢化茚-2-基胺
2-乙基-2,3-二氢化茚-1-酮按照用于制备2-甲基-2,3,5,6,7,8-六氢-环戊[b]萘-1-酮类似的方法由苯制备。1H-NMR(CDCl3)ppm:0.97(t,3H),1.50(m,1H),1.90(m,1H),2.55(m,1H),2.75(dd,1H),3.25(q,1H),7.29(t,1H),7.39(d,1H),7.50(t,1H),7.69(d,1H).
2-乙基-2,3-二氢化茚-2-基胺由2-乙基-2,3-二氢化茚-1-酮按照用于中间体23的类似的方法制备。1H-NMR(CDCl3)ppm:1.05(t,3H),1.5(br.s,NH2),2.70(q,2H),2.75(d,2H),3.01(d,2H),7.20(m,4H).中间体262,5,6-三甲基-2,3-二氢化茚-2-基胺
2,5,6-三甲基-2,3-二氢化茚-2-基胺由1,2-二甲基苯按照用于2-甲基-2,3,5,6,7,8-六氢-1H-环戊[b]萘-2-基胺的类似方法制备。1H-NMR(CDCl3)ppm:1.29(s,3H),2.16(s,6H),2.69(d,2H),2.84(d,2H),2.89(s,2H).中间体27乙酸(R)-1-(3-氨基-4-苄氧基-苯基)-2-[苄基-(2-甲基-2,3-二氢化茚-2-基)-氨基]-乙酯(R)-2-[苄基-(2-甲基-2,3-二氢化茚-2-基)-氨基]-1-(4-苄氧基-3-硝基-苯基)-乙醇
标题化合物由(R)-2-(4-苄氧基-3-硝基-苯基)-环氧乙烷(2.52g)和苄基-(2-甲基-2,3-二氢化茚-2-基)-胺(2.20g)按照实施例19中用于制备(S)-8-苄氧基-5-[2-(5,6-二乙基-2,3-二氢化茚-2-基氨基)-1-羟基-乙基]-1H-喹啉-2-酮的方法制备。在24小时后,通过TLC显示反应完成。将产物进行快速柱色谱纯化(硅胶,正己烷/乙酸乙酯4∶1)。TLC(硅胶,正己烷/乙酸乙酯4∶1 Rf=0.30)。1H NMR[CDCl3,400MHz]d 1.20(3H,s),2.65(1H,m),2.75(1H,m),2.90(2H,m),3.25(2H,m),3.60(1H,d),3.70(1H,宽峰),3.80(1H,d of d),4.10(1H,d),5.20(2H,s),7.00(1H,d),7.20(4H,m),7.35(11H,m),7.60(1H,d).
乙酸(R)-2-[苄基-(2-甲基-2,3-二氢化茚-2-基)-氨基]-1-(4-苄氧基-3-硝基-苯基)-乙酯
将(R)-2-[苄基-(2-甲基-2,3-二氢化茚-2-基)-氨基]-1-(4-苄氧基-3-硝基-苯基)-乙醇(2.75g)溶解于吡啶中(15mL)。加入乙酸酐(1.66g),将反应混合物在室温下搅拌。在18小时后,通过TLC显示反应完成。加入水(10mL)使反应停止。加入乙酸乙酯(250mL),溶液用1M KHSO4(3×100mL),饱和NaHCO3(100mL),水(100mL)和盐水(100mL)洗涤。有机层用硫酸镁干燥,过滤和真空除去溶剂。产物无需进一步纯化。TLC(硅胶,正己烷/乙酸乙酯4∶1 Rf=0.40)。1H NMR[CDCl3,400MHz]d 1.20(3H,s),1.90(3H,s),2.80(3H,m),3.00(1H,d),3.10(1H,m),3.20(1H,d),3.75(1H,d),3.90(1H,d),5.20(2H,s),5.25(1H,m),6.95(1H,d),7.10(4H,m),7.30(11H,m),7.55(1H,d).乙酸(R)-1-(3-氨基-4-苄氧基-苯基)-2-[苄基-(2-甲基-2,3-二氢化茚-2-基)-氨基]乙酯
标题化合物由乙酸(R)-2-[苄基-(2-甲基-2,3-二氢化茚-2-基)-氨基]-1-(4-苄氧基-3-硝基-苯基)-乙酯(2.90g)按照实施例19中用于制备(R)-1-(3-氨基-4-苄氧基-苯基)-2-[苄基-(5,6-二乙基-2,3-二氢化茚-2-基)-氨基]-乙醇的类似方法制备。在6小时后,通过TLC显示反应完成。滤除催化剂,真空除去溶剂。产物无需进一步纯化。TLC(硅胶,正己烷/乙酸乙酯2∶1 Rf=0.60)。1H NMR[CDCl3,400MHz]d 1.10(3H,s),1.80(3H,s),2.70(3H,m),3.05(2H,m),3.15(1H,d),3.65(2H,宽峰),3.75(1H,d),3.90(1H,d),4.95(2H,s),5.20(1H,m),6.40(2H,m),6.65(1H,d),7.20(14H,m).中间体28苄基-(2,5,6-三甲基-2,3-二氢化茚-2-基)-胺N-(2,5,6-三甲基-2,3-二氢化茚-2-基)-苯甲酰胺
在二氯甲烷/三乙胺中,用苯甲酰氯对中间体26处理1小时。将混合物用1N HCl洗涤,然后,用饱和NaHCO3溶液洗涤,干燥(Na2SO4)和蒸发。将残余物用乙醚/己烷研制,得到白色的结晶。1H-NMR(CDCl3)ppm:1.60(s,3H), 2.18(s,6H),3.02(d,2H),3.30(d,2H),6.17(br.s,NH),6.90(s,2H),7.34(m,2H),7.40(m,1H),7.63(d,1H).苄基-(2,5,6-三甲基-2,3-二氢化茚-2-基)-胺
在氮气氛下,向N-(2,5,6-三甲基-2,3-二氢化茚-2-基)-苯甲酰胺的THF溶液中加入LiAlH4,将混合物回流48小时。在0℃下用冰/水使反应停止,用乙醚萃取,干燥(Na2SO4),真空除去溶剂。进行色谱纯化(硅胶,乙酸乙酯/己烷1∶4),得到一种无色油状物。1H-NMR(CDCl3)ppm:1.58(s,3H),1.79(br.s.,NH),2.40(s,6H),3.00(d,2H),3.20(d,2H),3.99(s,2H),7.15(s,2H),7.37-7.53(m,5H).中间体29乙酸(R)-1-(3-氨基)-4-苄氧基-苯基)-2-[苄基-(2,5,6-三甲基-2,3-二氢化茚-2-基)-氨基]-乙酯(R)-1-(4-苄氧基-3-硝基-苯基)-2-[苄基-(2,5,6-三甲基-2,3-二氢化茚-2-基)-氨基]-乙醇
将2-(4-甲基-3-硝基-苯基)-环氧乙烷和苄基-(2,5,6-三甲基-2,3-二氢化茚-2-基)-胺的混合物在110℃下加热48小时。物质不经纯化即可使用。ES+MS m/e 538(MH+)乙酸(R)-1-(4-苄氧基-3-硝基-苯基)-2-[苄基-(2,5,6-三甲基-2,3-二氢化茚-2-基)-氨基]-乙酯
向(R)-1-(4-苄氧基-3-硝基-苯基)-2-[苄基-(2,5,6-三甲基-2,3-二氢化茚-2-基)-氨基]-乙醇的吡啶溶液中加入乙酸酐,将混合物搅拌18小时。用水使反应混合物停止反应,在加入乙酸乙酯后,用KHSO4水溶液洗涤两次,再用NaHCO3水溶液洗涤两次,用盐水洗涤一次。产物用色谱法纯化(硅胶,乙酸乙酯/己烷1∶4)。ES+MS m/e579(MH+)乙酸(R)-1-(3-氨基-4-苄氧基-苯基)-2-[苄基-(2,5,6-三甲基-2,3-二氢化茚-2-基)-氨基]-乙酯
将在THF和甲苯混合物中的乙酸(R)-1-(4-苄氧基-3-硝基-苯基)-2-[苄基-(2,5,6-三甲基-2,3-二氢化茚-2-基)-氨基]-乙酯在PtO2存在下,在室温下搅拌15小时。用硅藻土对混合物进行过滤,将滤液进行真空浓缩。ES+MS m/e 549(MH+)中间体305,6-二乙基-2-甲基-2,3-二氢化茚-2-基胺N-(5-乙酰基-2-甲基-2,3-二氢化茚-2-基)-苯甲酰胺
在0℃下,在氮气氛下,将氯化铝(3.7g)溶解于硝基甲烷(12ml)中,随后,加入N-(2-甲基-2,3-二氢化茚-2-基)-苯甲酰胺(3.0g)。在30分钟内滴加入乙酰氯(0.85ml)。在室温下4小时后,用冰和浓HCl使反应停止,用DCM萃取。有机层用稀HCl和盐水洗涤。蒸出溶剂后,获得所需产物。ES+MS m/e 294(MH+)N-(5-乙基-2-甲基-2,3-二氢化茚-2-基)-苯甲酰胺
在氢气氛下,在10%Pd/C存在下,在室温下,使N-(5-乙酰基-2-甲基-2,3-二氢化茚-2-基)-苯甲酰胺(3.4g)的乙醇(200ml)和浓HCl(2ml)搅拌48小时。将混合物用硅藻土过滤,将滤液进行真空浓缩,获得标题化合物。1H-NMR(CDCl3)ppm:1.20(t,3H),1.60(s,3H),2.55(q,2H),3.05(d,2H),3.35(d,2H),6.35(br.s,NH),6.90-7.10(m,3H),7.39(d,2H),7.65(s,2H)
N-(5-乙酰基-6-乙基-2-甲基-2,3-二氢化茚-2-基)-苯甲酰胺由N-(5-乙基-2-甲基-2,3-二氢化茚-2-基)-苯甲酰胺(2.6g)按照用于制备N-(5-乙酰基-2-甲基-2,3-二氢化茚-2-基)-苯甲酰胺的方法制备。产物经色谱法纯化(硅胶,己烷/乙酸乙酯,4∶1),得到标题化合物。ES+MS m/e 322(MH+)
N-(5,6-二乙基-2-甲基-2,3-二氢化茚-2-基)-苯甲酰胺由N-(5-乙酰基-6-乙基-2-甲基-2,3-二氢化茚-2-基)-苯甲酰胺(1.1g)按照用于制备N-(5-乙基-2-甲基-2,3-二氢化茚-2-基)-苯甲酰氯的方法制备。ES+MS m/e308(MH+)
苄基-(5,6-二乙基-2-甲基-2,3-二氢化茚-2-基)-胺由N-(5,6-二乙基-2-苯甲酰胺按照中间体18中用于制备苄基-(5,6-二乙基-2,3-二氢化茚-2-基)-胺的类似方法制备。ES+MS m/e 294(MH+)5,6-二乙基-2-甲基-2,3-二氢化茚-2-基-胺
在氢气氛下,在10% Pd/C存在下,在室温下,使苄基-(5,6-二乙基-2-甲基-2,3-二氢化茚-2-基)-胺(0.48g)的甲醇(10ml)溶液搅拌18小时。将混合物用硅藻土过滤,将滤液进行真空浓缩,获得标题化合物。ES+MS m/e 204(MH+)
实施例1(R)-8-苄氧基-5-[2-(4,7-二甲氧基-2,3-二氢化茚-2-基氨基)-1-羟基-乙基]-1H-喹啉-2-酮
将由文献方法(Beeley,Lee James;Dean,David Kenneth,PCT国际申请WO9525104)制备的(R)-8-苄氧基-5-环氧乙烷基喹诺酮(100,0.34mmol)由文献方法(Sindelar,R.D.;Mott,J.;Barfknecht,C.F.;Arneric,S.P.;Flynn,J.R.;Long,J.P.;Bhatnagar,R.K.J.Med.Chem.(1982),25(7),88-64)制备的4,7-二甲氧基-2,3-二氢化茚-2-基胺(66mg,0.34mmol)溶解于甲苯(1mL)中。将反应混合物加热至110℃,将溶剂蒸发掉。然后,将残余物在110℃下加热4小时。通过TLC显示反应完成。将产物通过快速柱色谱纯化(硅胶,二氯甲烷/甲醇20∶1)。
TLC(硅胶,二氯甲烷/甲醇25∶1 Rf=0.10)。ES+MS m/e 487(MH+)。(R)-8-羟基-5-[2-(4,7-二甲氧基-2,3-二氢化茚-2-基氨基)-1-羟基-乙基]-1H-喹啉-2-酮盐酸盐
将(R)-8-苄氧基-5-[2-(4,7-二甲氧基-2,3-二氢化茚-2-基氨基)-1-羟基-乙基]-1H-喹啉-2-酮(37mg,0.08mmol)溶解于甲醇(10mL)中,通过加入催化量的10%Pd/C以使化合物脱保护,将溶液置于氢气氛下。在4小时后,通过TLC显示反应完成。滤除催化剂,加入1M HCl/乙醚(1.1当量),真空除去溶剂。
TLC(硅胶,二氯甲烷/甲醇10∶1 Rf=0.15)。
ES+MS m/e 397(MH+)。
通式I的其它化合物由实施例11)中的(R)-8-苄氧基-5-环氧乙烷基喹诺酮((R)-2-(4-苄氧基-3-硝基苯基)-环氧乙烷(中间体15)和适宜的通式XVII的化合物按照与实施例1类似的方法制备。以下表中列出了这些化合物,其中R1为OH,R2和R3为H,Ar为下式III的基团,其中,R29、R30和R31为H(除实施例11,其中,Ar为下式XV的基团,其中R13为H)和n为1(除实施例9,其中,n为2)。实施例 R4 R5 R6 R7 ES+MS m/e(MH+)2 H CH3CH2 CH3CH2 H 3933 H CH3 CH3 H 3654 CH3CH2 H H CH3CH2 3935 H -(CH2)4- H 3916 H -O(CH2)2O- H 3957 H CH3(CH2)3 CH3(CH2)3 H 4498 H CH3(CH2)2 CH3(CH2)2 H 4219 H H H H 36510 H CH3OCH2 CH3OCH2 H11 H CH3CH2 CH3CH2 H 341实施例10:1H-NMR(d4-MeOH)ppm:2.78(2H,m),2.9(2H,m),3.15(2H,m),3.28(6H,s),3.7(1H,m),4.55(1H,br s),5.15(1H,m),6.58(1H,d),6.9(1H,d),7.11(2H,s),7.15(1H,s),8.25(1H,s).
实施例128-羟基-5-[1-羟基-2-(2,3-二氢化茚-2-基氨基)-乙基]-1H-喹啉-2-酮
将中间体10(18mg,0.054mmol)溶解于甲醇(2mL)中,并在冰上冷却。在2小时内加入氢硼化钠(6mg,0.12mmol)。然后加入浓HCl直至pH为1,将反应混合物过滤。将滤液用甲醇洗涤。将合并后的液相蒸发,将残余物溶解于甲醇中两次。在真空除去甲醇后,将残余物再溶解于水中,用1N KOH使其pH值变成12。真空除去溶剂,将残余物再与甲苯共蒸发两次。再将残余物用快速色谱纯化(硅胶,CH2Cl2/甲醇8∶2)。ES+MS m/e 337(MH+)。实施例135-[2-(5,6-二甲氧基-2,3-二氢化茚-2-基氨基)-1-羟基-乙基]-8-羟基-1H-喹啉-2-酮
该化合物由中间体11按照与实施例12类似的方法制备。ES+MSm/e 397(MH+)
实施例145-[2-(5,6-二乙基-2,3-二氢化茚-2-基氨基)-1-羟基-乙基]-8-羟基-3-甲基-1H-喹啉-2-酮
该化合物由中间体13(21mg)通过用于实施例1的脱除苄基的氢化过程制备。1H-NMR(d4-CH3OH)ppm 1.11(t,6H),2.11(s,3H),2.58(q,4H),3.01-3.37(m,6H),4.10-4.16(m,1H),5.31-5.38(m,1H),6.91(d,1H),7.00(s,2H),7.21(d,1H),8.13(s,1H)
实施例155-[2-(5,6-二乙基-2,3-二氢化茚-2-基氨基)-1-羟基-乙基]-8-甲氧基甲氧基-6-甲基-1H-喹啉-2-酮
该化合物由中间体14(20mg)和5,6-二乙基-2,3-二氢化茚-2-基胺(72mg)按照用于制备中间体13类似的方法制备。1H-NMR(CDCl3)ppm:1.14(t,6H),2.30(s,3H),2.51(q,4H),2.64-3.16(m,6H),3.41(s,3H),3.60-3.68(m,1H),5.18-5.25(m,3H),6.50(d,1H),7.89-7.94(m,3H),8.68(d,2H),9.15(s,br,1H).5-[2-(5,6-二乙基-2,3-二氢化茚-2-基氨基)-1-羟基-乙基]-8-羟基-6-甲基-1H-喹啉-2-酮
在室温下,将3N的盐酸(1mL)加至5-[2-(5,6-二乙基-2,3-二氢化茚-2-基氨基)-1-羟基-乙基]-8-甲氧基甲氧基-6-甲基-1H-喹啉-2-酮(12mg)在异丙醇(1mL)和四氢呋喃(1mL)中的溶液中,将反应混合物在40℃下加热18小时。真空除去溶剂,将产物用制备型HPLC在C8柱上进行纯化,采用水/乙腈/三氟乙酸梯度洗脱。13C-NMR(d4-CH3OH)ppm:15.97,20.09,26.34,36.87,51.75,59.72,67.33,118.41,119.12,121.21,125.45,126.11,128.60,133.35,137.52,137.55,142.32,142.50,145.69,163.24.
实施例168-羟基-5-[2-(5,6-二乙基-2,3-二氢化茚-2-基氨基)-1-羟基-乙基]-3,4-二氢-1H-喹啉-2-酮
在氢气氛下,对8-羟基-5-[2-(5,6-二乙基-2,3-二氢化茚-2-基氨基)-1-羟基-乙基]-1H-喹啉-2-酮(实施例2)的甲醇/乙醇溶液用10%Pd/C催化剂在30℃下进行氢化48小时,过滤和蒸发后,得到标题化合物。经制备HPLC进一步纯化(柱:Phenomenex Luna 10μm 150mm×50mm,洗脱液:梯度10%-95%乙腈的水溶液,包含0.1%三氟乙酸,在254 nm下进行UV检测)。13C-NMR(d6-DMSO)ppm:15.77,21.42,25.01,30.37,37.73,37.83,53.88,58.68,67.37,113.28,120.21,122.08,124.31,124.34,131.01,138.46,138.52,139.58,143.12,169.44.
实施例17(a)乙酸(R)-1-(4-苄氧基-3-甲酰基氨基-苯基)-2-[苄基-(2,5,6-三甲基-2,3-二氢化茚-2-基)-氨基]-乙酯
向甲苯/THF中的中间体29中缓慢地加入甲酸和乙酸酐的陈化的混合物,将反应混合物在室温下搅拌5小时。加入乙酸乙酯,用饱和NaHCO3溶液洗涤。进行色谱纯化(硅胶,乙酸乙酯/己烷1∶2),用乙醚研制,得到灰白色结晶。ES+MS m/e 577(MH+)(b)N-(2-苄氧基-5-{(R)-2-[苄基-(2,5,6-三甲基-2,3-二氢化茚-2-基)-氨基]-1-羟基-乙基}-苯基)-甲酰胺
将实施例17(a)的产物悬浮于乙醇中,加入催化量的甲醇中的NaOCH3。在70℃下2小时后,除去溶剂,将残余物用色谱法纯化(硅胶,乙酸乙酯/己烷2∶3),得到白色结晶。ES+MS m/e 535(MH+)
(c)N-{2-羟基-5-[(R)-1-羟基-2-(2,5,6-三甲基-2,3-二氢化茚-2-基氨基)-乙基]-苯基)甲酰胺由实施例17(b)的产物按照与实施例34(c)类似的方法制备。ES+MS m/e 355(MH+)
实施例18(a)8-苄基氨基-5-[(R)-2-(5,6-二乙基-2-甲基-2,3-二氢化茚-2-基氨基)-1-羟基-乙基]-1H-喹啉-2-酮
将5,6-二乙基-2-甲基-2,3-二氢化茚-2-基胺(0.28g)和8-苄氧基-5-环氧乙烷基-1H-喹啉-2-酮(0.42g)在正丁醇(0.7mol)中的混合物在Prolabo微波炉中在100℃下放置75分钟。将产物用色谱法纯化(硅胶,DCM/乙醇,5∶1),得到所需产物。ES+MS m/e 497(MH+)5-[(R)-2-(5,6-二乙基-2-甲基-2,3-二氢化茚-2-基氨基)-1-羟基-乙基]-8-羟基-1H-喹啉-2-酮
将实施例18(a)的产物(0.20g)的甲醇(20ml)溶液在氢气氛下,在10%Pd/C存在下,在室温下搅拌2小时。用硅藻土对混合物进行过滤,将滤液进行真空浓缩。用乙醚进行研制,得到所需产物。ES+MS m/e407(MH+)
实施例19(a)(S)-8-苄氧基-5-[2-(5,6-二乙基-2,3-二氢化茚-2-基氨基)-1-羟基-乙基]-1H-喹啉-2-酮是由中间体16(152mg)和中间体1(100mg)采用与实施例1(a)类似的方法制备。TLC(硅胶,二氯甲烷/甲醇10∶1 Rf=0.25)。(b)(S)-5-[2-(4,7-二乙基-2,3-二氢化茚-2-基氨基)-1-羟基-乙基]-1H-喹啉-2-酮盐酸盐是由实施例19(a)的产物按照与实施例1(b)类似的方法制备。TLC(硅胶,二氯甲烷/甲醇10∶1 Rf=0.05)。
实施例20(a)8-苄氧基-5-[(R)-1-羟基-2-(6,7,8,9-四氢-5H-苯并环庚烯-7-基氨基)-乙基]-1H-喹啉-2-酮是由(R)-8-苄氧基-5-环氧乙烷基喹诺酮(203mg)和中间体17(110mg)按照实施例1(a)类似的方法制备。TLC(硅胶,二氯甲烷/甲醇10∶1 Rf=0.30)。(b)5-[(R)-1-羟基-2-(6,7,8,9-四氢-5H-苯并环庚烯-7-基氨基)-乙基]-1H-喹啉-2-酮盐酸盐是由实施例20(a)的产物按照与实施例1(b)类似的方法制备。TLC(硅胶,二氯甲烷/甲醇10∶1 Rf=0.05)。
实施例21(a)(R)-8-苄氧基-5-{(S)-2-[苄基-(5,6-二乙基-2,3-二氢化茚-2-基)-氨基]-1-羟基-乙基}-1H-喹啉-2-酮
将(R)-8-苄氧基-S-环氧乙烷基喹诺酮(5.00g)和2-氨基-5,6-二乙基2,3-二氢化茚(3.87g)的正丁醇溶液在110℃下加热4小时。在冷却至室温后,加入甲苯(100mL),有机相用水(3×25ml)洗涤,负载于硅胶色谱柱上,用甲苯洗脱,随后用甲苯∶乙醇∶乙酸乙酯∶浓氨水(45∶10∶45∶2)的混合物洗脱,得到标题化合物。(b)(R)-5-[2-(5,6-二乙基-2,3-二氢化茚-2-基氨基)-1-羟基-乙基]-1H-喹啉-2-酮马来酸盐
将(R)-8-苄氧基-5-[2-(5,6-二乙基-2,3-二氢化茚-2-基氨基)-1-羟基-乙基]-1H-喹啉-2-酮(360mg)溶解于甲醇(10mL)中,通过加入催化量的10%Pd/C使化合物脱保护,将溶液置于氢气氛下。在4小时后,通过TLC显示反应完成。滤除催化剂,真空除去溶剂。将产物吸收于异丙醇中,加入马来酸的异丙醇溶液。在用乙醇进行重结晶后,获得标题化合物。TLC(硅胶,二氯甲烷/甲醇10∶1 Rf=0.05)。ES+MSm/e 393(MH+)。
实施例22(a)N-(5-{(R)-2-[苄基-(5,6-二乙基-2,3-二氢化茚-2-基)-氨基]-1-羟基-乙基}-2-苄氧基-苯基)-甲酰胺由中间体19(1.00g),甲酸(155mg)和乙酸酐(226mg)按照与实施例21(a)类似的方法制备。TLC(硅胶,正己烷/乙酸乙酯2∶1 Rf=0.20)。(b)N-{5-[(R)-2-(5,6-二乙基-2,3-二氢化茚-2-基氨基)-1-羟基-乙基]-2-羟基-苯基}-甲酰胺由实施例22(a)的产物按照与实施例1(b)类似的方法制备。TLC(硅胶,正己烷/乙酸乙酯2∶1 Rf=0.05)。
实施例23(a)(R)-2-[苄基-(5,6-二乙基-2,3-二氢化茚-2-基)-氨基]-1-(4-苄氧基-3-二甲基氨基-苯基)-乙醇
将中间体19(0.37g)溶解于CH3OH(50mL)中,加入溶解于水(10mL)中的甲醛(37%水溶液)(5mL),加入催化量的PtO2将溶液在氢气氛下搅拌。在24小时后,通过TLC显示反应完成。滤除催化剂,真空除去溶剂,将残余物在乙酸乙酯(100mL)和水(100mL)间进行分配。有机层用硫酸镁干燥,过滤和真空除去溶剂。将产物进行快速柱色谱纯化(硅胶,正己烷/乙酸乙酯4∶1)。TLC(硅胶,正己烷/乙酸乙酯2∶1 Rf=0.65)。(b)4-[(R)-2-(5,6-二乙基-2,3-二氢化茚-2-基氨基)-1-羟基-乙基]-2-二甲基氨基-苯酚盐酸盐由实施例23(a)的产物按照与实施例1(b)类似的方法制备。1H NMR[DMSO,400MHz]δ1.10(6H,t),2.55(4H,q),3.05(2H,m),3.10(6H,s),3.20(4H,m),4.00(1H,m),4.95(1H,m),7.00(2H,s),7.15(1H,d),7.35(1H,d),7.80(1H,s),9.20(1H,broad),9.75(1H,宽峰),11.40(1H,宽峰).
实施例24(a)(R)-2-[苄基-(5,6-二乙基-2,3-二氢化茚-2-基)-氨基]-1-(4-苄氧基-3-甲基氨基-苯基)乙醇
将实施例22的产物(260mg)溶解于二噁烷(20mL)中。加入氢硼化钠(90mg),随后滴加入乙酸酐(142mg)。将反应混合物在90℃下搅拌。在4小时后,通过TLC显示反应完成。真空除去溶剂,将残余物在乙酸乙酯(100mL)和水(100mL)间分配。有机层用硫酸镁干燥,过滤和真空除去溶剂。将产物进行快速柱色谱纯化(硅胶,正己烷/乙酸乙酯4∶1)。TLC(硅胶,正己烷/乙酸乙酯2∶1 Rf=0.65)。(b)4-[(R)-2-(5,6-二乙基-2,3-二氢化茚-2-基氨基)-1-羟基-乙基]-2-甲基氨基-苯酚盐酸盐由实施例24(a)的产物按照实施例1(b)类似的方法制备。1H NMR[DMSO,400MHz]δ1.10(6H,t),2.55(4H,q),2.85(3H,s),3.10(6H,m),4.00(1H,m),4.90(1H,m),7.00(3H,m),7.15(1H,m),7.40(1H,m),9.10(1H,宽峰),9.60(1H,宽峰),10.80(1H,宽峰).
实施例25(a)N-(5-{[苄基-(5,6-二乙基-2,3-二氢化茚-2-基)-氨基]-乙酰基}-2-苄氧基-苯基)-甲磺酰胺
将中间体20(240mg)溶解于二氯甲烷(10mL)。加入三乙胺(56mg)再加入甲磺酰氯(58mg)。将反应混合物在室温下进行搅拌。在24小时后,通过TLC显示反应完成。真空除去溶剂,将产物进行快速柱色谱纯化(硅胶,正己烷/乙酸乙酯4∶1)。TLC(硅胶,正己烷/乙酸乙酯2∶1 Rf=0.40)。(b)N-(5-{2-[苄基-(5,6-二乙基-2,3-二氢化茚-2-基)-氨基]-1-羟基-乙基}-2-苄氧基-苯基)-甲磺酰胺
将实施例25(a)的产物(120mg)溶解于乙醇(10mL)中。加入氢硼化钠(9mg),将反应混合物在室温下进行搅拌。在3小时后,通过TLC显示反应完成。用2M HCl(1mL)使反应停止,真空除去溶剂,将残余物在乙酸乙酯(50mL)和饱和NaHCO3(50mL)间进行分配。有机层用硫酸镁干燥,过滤和真空除去溶剂。产物无需进一步纯化。TLC(硅胶,正己烷/乙酸乙酯2∶1 Rf=0.45)。(c)N-{5-[2-(5,6-二乙基-2,3-二氢化茚-2-基氨基)-1-羟基-乙基]-2-羟基-苯基}-甲磺酰胺盐酸盐)是由实施例25(b)的产物按照与实施例1(b)类似的方法制备。1H NMR[CDCl3,400MHz]δ1.15(6H,t),2.55(4H,q)2.95(3H,s),3.10(6H,m),4.00(1H,m),4.85(1H,m),6.10(1H,宽峰),6.90(2H,d),7.00(2H,s),7.10(1H,d of d),7.25(1H,d),8.75(1H,s),8,95(1H,宽峰),9.25(1H,宽峰),10.00(1H,s).
实施例26(a)(R)-8-苄氧基-5-{(S)-2-[苄基-(4,5,6,7-四甲基-2,3-二氢化茚-2-基)-氨基]-1-羟基-乙基}-1H-喹啉-2-酮
在氮气氛下,将(R)-8-苄氧基-5-环氧乙烷基喹诺酮(204mg)和中间体21(194mg)溶解于正丁醇(0.5ml)中。将反应混合物在110℃下加热22小时。冷却后,真空除去溶剂。将产物进行快速柱色谱纯化(硅胶,乙酸乙酯/己烷50∶50)。ES+MS m/e 573(MH+)(b)(R)-8-羟基-5-[(S)-1-羟基-2-(4,5,6,7-四甲基-2,3-二氢化茚-2-基氨基)-乙基]-1H-喹啉-2-酮由实施例26(a)的产物按照与实施例1(b)类似的方法制备。1H NMR(CD3OD)ppm:8.55(1H,d);7.5(1H,d);7.25(1H,d);6.9(1H,d);5.6(1H,m);4.3(1H,m);3.7(2H,q);3.6(2H,dd);3.3(2H,dd);2.4(12H,s)
实施例27(a)8-苄氧基-5-[(R)-1-羟基-2-(2-甲基-2,3-二氢化茚-2-基氨基)-乙基]-1H-喹啉-2-酮
将8-苄氧基-5-(R)-环氧乙烷基-1H-喹啉-2-酮(500mg)和2-甲基-2,3-二氢化茚-2-基胺(276mg)在正丁醇(1mL)中的混合物进行微波照射,采用Prolabo Synthewave 402仪器,在110℃下照射90分钟。将残余物吸收于硅胶上,将产物进行快速色谱纯化(硅胶,氯仿/乙醇4∶1)。1H-NMR(CDCl3)ppm:1.30(s,3H),2.65(s,1H),2.95(dd,2H),3.07(m,3H),5.15(m,1H),5.18(s,2H),6.66(d,1H),7.17(m,4H),7.26(d,1H),7.45(m,5H),8.07(d,1H),8.8-9.5(br.d,1H)(b)8-羟基-5-[(R)-1-羟基-2-(2-甲基-2,3-二氢化茚-2-基氨基)-乙基]-1H-喹啉-2-酮
将实施例27(a)的产物(100mg,0.22mmol)溶解于甲醇(20mL)中,通过加入催化量的10%Pd/C使化合物脱保护,将溶液置于氢气氛下搅拌1小时。除去催化剂,蒸出溶剂,得到一种黄色固体。1H-NMR(d4-CH3OH)ppm:1.20(s,3H),2.75(m,4H),2.95(d,2H),5.03(m,1H),6.60(d,1H),6.82(d,1H),7.0(m,4H),7.08(d,1H),8.20(d,1H).
实施例285-[2-(5,6-二乙基-2,3-二氢化茚-2-基氨基)-乙基]-8-羟基-1H-喹啉-2-酮
该化合物由实施例2的产物按照下述文献的方法制备,Temple等,J.Med.Chem.,19,626-633(1976)。1H-NMR(d4-CH3OH)ppm:1.08(t,3H),2.55(q,4H),2.96(dd,2H),3.18(m,4H),3.28(dd,2H),3.99(m,1H),6.60(d,1H),6.90(d,1H),6.97(d,1H),6.00(s,2H),8.07(d,1H).
实施例29(a)8-苄氧基-5-[(R)-1-羟基-2-(2-甲基-2,3,5,6,7,8-六氢-1H-环戊[b]萘-2-基氨基)-乙基]-1H-喹啉-2-酮由8-苄氧基-5-(R)-环氧乙烷基-1H-喹啉-2-酮(220mg)和中间体24(150mg)按照与实施例27(a)类似的方法制备。1H-NMR(CDCl3)ppm:1.37(s,1H),1.78(m,4H),2.1(br.s,2H),2.72(m,5H),2.80(dd,2H),2.95(m,3H),5.08(m,1H),5.17(s,2H),6.65(d,1H),6.88(s,2H),7.02(d,2H),7.26(d,1H),7.4(m,5H),8.05(d,1H).(b)8-羟基-5-[(R)-1-羟基-2-(2-甲基-2,3,5,6,7,8-六氢-1H-环戊[b]萘-2-基氨基)-乙基]-1H-喹啉-2-酮是通过采用与实施例27(b)类似的方法通过氢化实施例29(a)的产物制备的。将产物进行HPLC纯化(H2O,CH3CN,CF3COOH,梯度洗脱)。1H-NMR(d4-CH3OH)ppm(TFA盐):1.65(s,3H),1.85(m,4H),2.85(m,4H),3.15(m,2H),3.4(m,4H),5.48(t,1H),6.83(d,1H),7.03(s,2H),7.15(d,1H),7.45(d,1H),8.40(d,1H).实施例30(a)5-{(S)-2-[苄基-(2,3,5,6,7,8-六氢-1H-环戊[b]萘-2-基)-氨基]-1-羟基-乙基}-8-苄氧基-1H-喹啉-2-酮
将中间体16(150mg)和苄基-(2,3,5,6,7,8-六氢-1H-环戊[b]萘-2-基)-胺(142mg)在甲苯(1mL)中的混合物在80℃下加热36小时。将残余物进行色谱纯化(硅胶,CHCl3/EtOH,20∶1),得到一种黄色泡沫物。1H-NMR(CDCl3)ppm:1.77(m,4H),2.72(m,6H),3.01(m,4H),3.70(d,1H),3.88(d,1H),4.82(m,1H),5.15(s,2H),6.50(d,1H),6.8-8(m,13H),9.05(br.s,1H)(b)5-[(S)-2-(2,3,5,6,7,8-六氢-1H-环戊[b]萘-2-基氨基)-1-羟基-乙基]-8-羟基-1H-喹啉-2-酮
将实施例30(a)的产物(150mg)的甲醇(20mL)溶液在氢气氛下,在10%Pd/C(20mg)存在下,在室温下搅拌5小时。将反应混合物过滤,将产物进行色谱纯化(硅胶,CHCl3/EtOH,20∶1),随后进行结晶(CH3OH)。1H-NMR(d4-CH3OH)ppm:1.65(m,4H),2.57(m,4H),2.86(dd,2H),3.1(m,4H),3.82(m,1H),5.25(m,1H),6.55(d,1H),6.78(s,2H),6.91(d,1H),7.19(d,1H),8.27(d,1H).
实施例31(a)乙酸(R)-2-[苄基-(2-甲基-2,3-二氢化茚-2-基)-氨基]-1-(4-苄氧基-3-甲烷磺酰基氨基-苯基)-乙酯由中间体27(476mg),三乙胺(231mg)和甲磺酰氯(210mg)按照与实施例25(b)类似的方法制备。TLC(硅胶,正己烷/乙酸乙酯2∶1 Rf=0.45)。(b)N-(5-{(R)-2-[苄基-(2-甲基-2,3-二氢化茚-2-基)-氨基]-1-羟基-乙基}-2-苄氧基-苯基)-甲磺酰胺
将实施例31(a)的产物(200mg)溶解于CH3OH(8mL)中。加入K2CO3(138mg),随后滴加入水(2mL)。将反应混合物在室温下搅拌。在24小时后,通过TLC显示反应完成。加入乙酸乙酯(100mL),将溶液用水(50mL)和盐水(50mL)洗涤。有机层用硫酸镁干燥,过滤和真空除去溶剂。将产物进行快速柱色谱纯化(硅胶,正己烷/乙酸乙酯3∶1)。TLC(硅胶,正己烷/乙酸乙酯2∶1 Rf=0.35)。(c)N-{2-羟基-5-[(R)-1-羟基-2-(2-甲基-2,3-二氢化茚-2-基氨基)-乙基]-苯基}-甲磺酰胺)由实施例31(b)的产物按照与实施例1(b)类似的方法制备。TLC(硅胶,二氯甲烷/甲醇10∶1 Rf=0.10)。
实施例32(a)乙酸(R)-2-[苄基-(2-甲基-2,3-二氢化茚-2-基)-氨基]-1-(4-苄氧基-3-乙磺酰基氨基-苯基)-乙酯由中间体27,三乙胺(242mg)和乙磺酰氯(247mg)按照与实施例25(b)类似的方法制备。TLC(硅胶,正己烷/乙酸乙酯2∶1 Rf=0.50)。(b)乙磺酸(5-{(R)-2-[苄基-(2-甲基-2,3-二氢化茚-2-基)-氨基]-1-羟基-乙基}-2-苄氧基-苯基)-酰胺由实施例32(a)的产物按照与实施例31(b)类似的方法制备。TLC(硅胶,正己烷/乙酸乙酯2∶1Rf=0.40)。(c)乙磺酸{2-羟基-5-[(R)-1-羟基-2-(2-甲基-2,3-二氢化茚-2-基氨基)-乙基]-苯基}-酰胺由实施例32(b)的产物按照与实施例1(b)类似的方法制备。TLC(硅胶,二氯甲烷/甲醇10∶1 Rf=0.10)。
实施例33(a)乙酸(R)-2-(苄基-(2-甲基-2,3-二氢化茚-2-基)-氨基]-1-[4-苄氧基-3-(丙-1-磺酰基氨基)-苯基]-乙酯)由中间体27(525mg),三乙胺(255mg)和1-丙磺酰氯(288mg)按照与实施例25(a)类似的方法制备。TLC(硅胶,正己烷/乙酸乙酯4∶1 Rf=0.25)。(b)丙-1-磺酸(5-{(R)-2-[苄基-(2-甲基-2,3-二氢化茚-2-基)-氨基]-1-羟基-乙基}-2-苄氧基-苯基)-酰胺由实施例33(a)的产物按照与实施例31(b)类似的方法制备。TLC(硅胶,正己烷/乙酸乙酯4∶1 Rf=0.15)。(c)丙-1-磺酸{2-羟基-5-[(R)-1-羟基-2-(2-甲基-2,3-二氢化茚-2-基氨基)-乙基]-苯基}-酰胺由实施例33(b)的产物按照与实施例1(b)类似的方法制备。TLC(硅胶,二氯甲烷/甲醇10∶1 Rf=0.05)。
实施例34(a)N-{2-苄氧基-5-[(2-乙基-2,3-二氢化茚-2-基氨基)-乙酰基]-苯基}-甲磺酰胺
将2-乙基-2,3-二氢化茚-2-基胺和N-(2-苄氧基-5-溴乙酰基-苯基)甲磺酰胺的混合物在乙腈中于室温下搅拌20小时。过滤分离出产物。ES+MS m/e 479(MH+)(b)N-(2-苄氧基-5-[(2-乙基-2,3-二氢化茚-2-基氨基)-1-羟基-乙基]-苯基}-甲磺酰胺
将实施例34(a)的产物悬浮于乙醇与二氯甲烷的混合物中。在0℃下加入氢硼化钠,将混合物在室温下搅拌3小时,然后过滤,进行色谱处理(硅胶,乙酸乙酯/乙醇4∶1),得到一种白色泡沫物。ES+MS m/e480(MH+)(c)N-{5-[2-(2-乙基-2,3-二氢化茚-2-基氨基)-1-羟基-乙基]-2-羟基-苯基}-甲磺酰胺
在氢气氛下,在10%Pd/C存在下,在室温下,将甲醇(20mL)中的实施例34(b)的产物(0.29g)搅拌18小时。用硅藻土对混合物进行过滤,将滤液进行真空浓缩,然后进行色谱处理(硅胶,乙酸乙酯/乙醇2∶1)。在用乙醚/乙酸乙酯研制后,获得灰白色的结晶(100mg)。1H-NMR(d4-CH3OH)ppm:0.85(t,3H),1.65(m,2H),2.75(m,2H),2.85(s,3H),2.95(m,4H),6.80(d,1H),7.05(m,5H),7.30(s,1H).ES+MS m/e 491(MH+)
实施例35(a)乙酸(R)-1-(4-苄氧基-3-甲烷磺酰基氨基-苯基)-2-[苄基-(2,5,6三甲基-2,3-二氢化茚-2-基)-氨基]-乙酯
在室温下,向中间体29的二氯甲烷和三乙胺溶液中加入甲磺酰氯,将混合物搅拌18小时。然后,用0.2N HCl,饱和NaHCO3溶液和盐水洗涤。将产物进行色谱纯化(硅胶,乙酸乙酯/己烷1∶4)。ES-MS m/e625(M-)(b)N-(2-苄氧基-5-{(R)-2-[苄基-(2,5,6-三甲基-2,3-二氢化茚-2-基)-氨基]-1-羟基-乙基}苯基)-甲磺酰胺
将实施例35(a)的产物在甲醇/水中与K2CO3一起搅拌3天,然后真空除去溶剂。将产物进行色谱纯化(硅胶,乙酸乙酯/己烷1∶2)。1H-NMR(CDCl3)ppm:1.21(s,3H),2.22(s,6H),2.63-2.82(m,4H),2.84(s,3H),3.20(br.d,2H),3.61(d,1H),3.64(br.s.,1H),3.83(m,1H),4.08(d,1H),5.09(s,2H),6.75(br.s,NH),6.90-7.05(m,4H),7.25-7.45(11H).(c)N-{2-羟基-5-[(R)-1-羟基-2-(2,5,6-三甲基-2,3-二氢化茚-2-基氨基)-乙基]-苯基}-甲磺酰胺由实施例35(b)的产物按照与实施例34(c)类似的方法制备。ES+MS m/e 405(MH+)
Claims (16)
R1为氢、羟基或烷氧基,
R2和R3彼此独立地为氢或烷基,
R4、R5、R6和R7彼此独立地为氢、卤素、氰基、羟基、烷氧基、芳基、烷基、被一个或多个卤原子或一个或多个羟基或烷氧基取代的烷基、被一个或多个杂原子间断的烷基、链烯基、三烷基甲硅烷基、羧基、烷氧基羰基或-CONR11R12,其中,R11和R12彼此独立地为氢或烷基,或R4和R5、R5和R6或者R6和R7连同与其相连的碳原子一起表示碳环或杂环,
R8为卤素、-OR13、-CH2OR13或-NHR13,其中,R13为氢、烷基、被一个或多个杂原子间断的烷基、-COR14,其中,R14为氢、-N(R15)R16、烷基或被一个或多个杂原子间断的烷基、或芳基,R15和R16彼此独立地为氢、烷基或被一个或多个杂原子间断的烷基,或R13为-C(=NH)R17、-SOR17或-SO2R17,其中,R17为烷基或被一个或多个杂原子间断的烷基,而R9为氢,或R8为-NHR18,其中,-NHR18和R9连同与其相连的碳原子一起表示5-或6-元杂环,
R10为-OR19或-NHR19,其中,R19为氢、烷基、被一个或多个杂原子间断的烷基或-COR20,其中,R20为-N(R21)R22、烷基或被一个或多个杂原子间断的烷基、或芳基,R21和R22彼此独立地为氢、烷基或被一个或多个杂原子间断的烷基,
X为卤素或卤代甲基或烷基,
Y为碳或氮,
n为1或2,
当Y为氮时,p为0,当Y为碳时,p为1,
q和r分别为0或1,q+r之和为1或2;
而当R1为羟基或烷氧基时,用星号标记的碳原子具有R或S构型或其混合物。
2.根据权利要求1的化合物,其中,Ar为下式II的基团,其中
Y为碳,
R8为-NHR18,且-NHR18与R9一起表示
式-NH-CO-R23-的基团,其中,R23为亚烷基,亚烯基或亚烷氧基,
式-NH-SO2-R24的基团,其中,R24为亚烷氧基,
式-NH-R25(COOR26)-的基团,其中,R25为亚烷基或亚烯基,且R26为烷基,或
式-NH-CO-NH-或-NH-CO-S-的基团,
R10为-OR19,其中,R19如权利要求1定义,
X为烷基,
p为1,q为1而r为0或1。
4.根据权利要求1的化合物,其中,Ar为下式的基团
其中,R29、R30和R31彼此独立地为氢或C1-C4-烷基。
5.根据权利要求1的化合物,其中,Ar为式II的基团,其中,Y为碳,R8为CH2OR13,其中,R13为氢、C1-C4-烷基,或C1-C4-烷氧基-C1-C4-烷基,R9为氢、R10为-OR19,其中,R19为氢、C1-C4-烷基或C1-C4-烷氧基-C1-C4-烷基或R10为-NHR19,其中,R19为氢、C1-C4-烷基或-COR20,其中,R20为C1-C4-烷基、C6-C10芳基或-N(R21)R22,其中,R21和R22彼此独立地为氢或C1-C4-烷基,p和q分别为1而r为0;或式II的基团,其中,Y为氮,R8为-CH2OR13,其中,R13为氢、C1-C4-烷基或C1-C4-烷氧基-C1-C4-烷基,R10为-OR19,其中,R19为氢、C1-C4-烷基或C1-C4-烷氧基-C1-C4-烷基,p和r为O而q为1。
7.根据权利要求1的化合物,其中,Ar为式II的基团,其中,Y为碳,R8为-NHR13,其中,R13为氢、C1-C10烷基、被1-3个杂原子间断的C1-C10烷基、COR14,其中,R14为氢、C1-C10烷基、被1-3个杂原子间断的C1-C10烷基,或者R13为-C(=NH)R17、-SOR17或-SO2R17,其中,R17为C1-C10-烷基或被1-3个杂原子间断的C1-C10-烷基,R9为氢,R10为-OR18,其中,R18为氢、C1-C4-烷基或C1-C4-烷氧基-C1-C4烷基,p和q分别为1而r为0。
9.根据前述任一项权利要求之一的化合物,其中,R4、R5、R6和R7分别为氢,或者使与其相连的苯环被对称取代。
10.根据权利要求1的化合物,其中,Ar为式III、IV、V、XII或XV的基团,R1为羟基,R2和R3为氢,而R4和R7相同,分别为氢、C1-C4-烷基或C1-C4-烷氧基,并且,或者R5和R6相同且均为氢、C1-C4-烷基、C1-C4-烷氧基或C1-C4-烷氧基-C1-C4-烷基,或者R5和R6一起表示-(CH2)4-或-O(CH2)2O-,为游离形式或盐形式或溶剂化物形式。
11.根据权利要求10的化合物,其中,在式I中用星号*标记的碳原子具有R构型。
其中,R29、R30和R31分别为H,R1为OH,R2和R3分别为H并且
(i)n为1,而R4和R7分别为CH3O-,R5和R6分别为H;或
(ii)n为1,而R4和R7分别为H,R5和R6分别为CH3CH2-;或
(iii)n为1,而R4和R7分别为H,R5和R6分别为CH3-;或
(iv)n为1,而R4和R7分别为CH3CH2-,R5和R6分别为H;或
(v)n为1,而R4和R7分别为H,R5和R6一起表示-(CH2)4-;或
(vi)n为1,而R4和R7分别为H,R5和R6一起表示-O(CH2)2O-;或
(vii)n为1,而R4和R7分别为H,R5和R6分别为CH3(CH2)3-;或
(viii)n为1,而R4和R7分别为H,R5和R6分别为CH3(CH2)2-;或
(ix)n为2,R4、R5、R6和R7分别为H;或
(x)n为1,R4和R7分别为H,R5和R6分别为CH3OCH2-;或
其中,R13为H,R1为OH,R2和R3分别为H,R4和R7分别为H,R和R6分别为H而n为1;或
(C)其为选自下述的化合物:
8-羟基-5-[1-羟基-2-(2,3-二氢化茚-2-基氨基)-乙基]-1H-喹啉-2-酮,
5-[2-(5,6-二甲氧基-2,3-二氢化茚-2-基氨基)-1-羟基-乙基]-8-羟基-1H-喹啉-2-酮,
5-[2-(5,6-二乙基-2,3-二氢化茚-2-基氨基)-1-羟基-乙基]-8-羟基-3-甲基-1H-喹啉-2-酮,
5-[2-(5,6-二乙基-2,3-二氢化茚-2-基氨基)-1-羟基-乙基]-8-甲氧基甲氧基-6-甲基-1H-喹啉-2-酮,
5-[2-(5,6-二乙基-2,3-二氢化茚-2-基氨基)-1-羟基-乙基]-8-羟基-6-甲基-1H-喹啉-2-酮,
8-羟基-5-[2-(5,6-二乙基-2,3-二氢化茚-2-基氨基)-1-羟基-乙基]-3,4-二氢-1H-喹啉-2-酮,
N-{2-羟基-5-[(R)-1-羟基-2-(2,5,6-三甲基-2,3-二氢化茚-2-基氨基)-乙基]-苯基}-甲酰胺,
5-[(R)-2-(5,6-二乙基-2-甲基-2,3-二氢化茚-2-基氨基)-1-羟基-乙基]-8-羟基-1H-喹啉-2-酮,
(S)-5-[2-(4,7-二乙基-2,3-二氢化茚-2-基氨基)-1-羟基-乙基]-1H-喹啉-2-酮盐酸盐,
5-[(R)-1-羟基-2-(6,7,8,9-四氢-5H-苯并环庚烯-7-基氨基)-乙基]-1H-喹啉-2-酮盐酸盐,
(R)-5-[2-(5,6-二乙基-2,3-二氢化茚-2-基氨基)-1-羟基-乙基]-1H-喹啉-2-酮盐酸盐,
N-{5-[(R)-2-(5,6-二乙基-2,3-二氢化茚-2-基氨基)-1-羟基-乙基]-2-羟基-苯基}-甲酰胺,
4-[(R)-2-(5,6-二乙基-2,3-二氢化茚-2-基氨基)-1-羟基-乙基]-2-二甲基氨基-苯酚盐酸盐,
4-[(R)-2-(5,6-二乙基-2,3-二氢化茚-2-基氨基)-1-羟基-乙基]-2-甲基氨基-苯酚盐酸盐,
N-{5-[2-(5,6-二乙基-2,3-二氢化茚-2-基氨基)-1-羟基-乙基]-2-羟基-苯基}-甲磺酰胺盐酸盐),
(R)-8-羟基-5-[(S)-1-羟基-2-(4,5,6,7-四甲基-2,3-二氢化茚-2-基氨基)-乙基]-1H-喹啉-2-酮,
8-羟基-5-[(R)-1-羟基-2-(2-甲基-2,3-二氢化茚-2-基氨基)-乙基]-1H-喹啉-2-酮,
5-[2-(5,6-二乙基-2,3-二氢化茚-2-基氨基)-乙基]-8-羟基-1H-喹啉-2-酮,
8-羟基-5-[(R)-1-羟基-2-(2-甲基-2,3,5,6,7,8-六氢-1H-环戊[b]萘-2-基氨基)-乙基]-1H-喹啉-2-酮,
5-[(S)-2-(2,3,5,6,7,8-六氢-1H-环戊[b]萘-2-基氨基)-1-羟基-乙基]-8-羟基-1H-喹啉-2-酮,
N-{2-羟基-5-[(R)-1-羟基-2-(2-甲基-2,3-二氢化茚-2-基氨基)-乙基]-苯基}-甲磺酰胺),
乙磺酸{2-羟基-5-[(R)-1-羟基-2-(2-甲基-2,3-二氢化茚-2-基氨基)-乙基]-苯基]-酰胺,
丙-1-磺酸(2-羟基-5-[(R)-1-羟基-2-(2-甲基-2,3-二氢化茚-2-基氨基)-乙基]-苯基}-酰胺,
N-{5-[2-(2-乙基-2,3-二氢化茚-2-基氨基)-1-羟基-乙基]-2-羟基-苯基}-甲磺酰胺,或
N-{2-羟基-5-[(R)-1-羟基-2-(2,5,6-三甲基-2,3-二氢化茚-2-基氨基)-乙基]-苯基}-甲磺酰胺。
13.一种药物组合物,其包含前述权利要求任一项的化合物,选择性地还包含可药用载体。
14.权利要求1-12任一项的化合物在制备用于治疗通过β2-肾上腺受体作用能够预防或缓减的疾病的药物中的用途。
15.权利要求1-12任一项的化合物在制备用于治疗梗阻性或炎性气道疾病的药物中的用途。
16.游离形式或盐形式或溶剂化物形式的通式I的化合物的制备方法,包括:
(a)为制备其中R1为羟基的化合物,或者
(i)使式XVI的化合物与式XVII的化合物反应
其中,Ar1为权利要求1中定义的Ar或其保护形式,R2、R3、R4、R5、R6、R7和n如权利要求1定义,R32为氢或胺-保护基,或
(ii)还原下式的化合物
其中,Ar1为权利要求1中定义的Ar或其保护形式,R2、R3、R4、R5、R6和R7如权利要求1定义,转化所示的酮基成-CH(OH)-;或
(b)为制备其中R1为氢的化合物,将相应的基团R1为羟基的通式I的化合物还原;或
(c)为制备其中R1为烷氧基的通式I的化合物,或者(i)O-烷基化相应的其中R1为羟基的通式I化合物,或(ii)使具有代替R1的离去基团的相应化合物与其中R1为烷氧基的式R1H的醇反应;
并且,选择性地,将形成的保护形式的通式I化合物转化成未保护形式的相应化合物;
并且回收形成的游离形式或盐形式或溶剂化物形式的通式I化合物。
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