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    重庆时时彩网易杀码: 取代的氮-及二氮杂环庚烷及-环辛烷化合物及其用途.pdf

    关 键 词:
    取代 二氮杂环 庚烷 辛烷 化合物 及其 用途
      专利查询网所有资源均是用户自行上传分享,仅供网友学习交流,未经上传用户书面授权,请勿作他用。
    摘要
    申请专利号:

    CN97192755.3

    申请日:

    1997.01.10

    公开号:

    CN1212692A

    公开日:

    1999.03.31

    当前法律状态:

    终止

    有效性:

    无权

    法律详情: 专利权有效期届满IPC(主分类):C07D 403/12申请日:19970110授权公告日:20011121|||授权||||||公开
    IPC分类号: C07D403/12; C07D403/04; C07D243/08; C07D409/12; C07D213/73; C07D403/14; C07D401/14; A61K31/505 主分类号: C07D403/12; C07D403/04; C07D243/08; C07D409/12; C07D213/73; C07D403/14; C07D401/14; A61K31/505
    申请人: BASF公司;
    发明人: H·J·特雷贝; S·布兰克; D·斯塔克; L·温格; H·J·特申多尔夫; K·维克
    地址: 联邦德国路德维希港
    优先权: 1996.01.12 DE 19600934.0
    专利代理机构: 中国专利代理(香港)有限公司 代理人: 吴玉和;温宏艳
    PDF完整版下载: PDF下载
    法律状态
    申请(专利)号:

    CN97192755.3

    授权公告号:

    |||1075070||||||

    法律状态公告日:

    2017.02.22|||2001.11.21|||1999.04.14|||1999.03.31

    法律状态类型:

    专利权的终止|||授权|||实质审查请求的生效|||公开

    摘要

    本发明涉及以下化学式之氮-及二氮杂环庚烷及-环辛烷化合物:Ar1-A-B-Ar2(Ⅰ),其中Ar1,A,B及Ar2具说明书所述之意义,所述化合物具多巴胺D3受体高亲和力,因而能够用以治疗感应多巴胺D3配位体之失调。

    权利要求书

    1: 一种式Ⅰ化合物 ????Ar 1 -A-B-Ar 2 ????(Ⅰ) 其中Ar 1 为 或是具1,2或3个杂原子之5-或6-元杂环,该杂原子彼此独立选 自O,N及S,其中Ar 1 可以具1,2,3或4个取代基,该取代基彼 此独立选自OR 1 ,未取代或经OH、OC 1 -C 8 -烷基或卤素取代之烷基, 或C 2 -C 6 -烯基,C 2 -C 6 -炔基,环烷基,卤素,CN,CO 2 R 1 ,NO 2 , NR 1 R 2 ,SR 1 ,CF 3 ,CHF 2 ,未取代或经C 1 -C 6 -烷基、OC 1 -C 6 -烷基、 ?;?、苯基、氨基、硝基、氰基或卤素取代之苯基,或未取代或经C 1 - C 6 -烷基、OC 1 -C 6 -烷基或卤素取代之苯氧基,或C 1 -C 6 -烷?;虮郊柞?基; R 1 为H,未取代或经OH、OC 1 -C 6 -烷基、苯基或卤素取代之烷基; R 2 具R 1 所述之意义,或为COR 1 或CO 2 R 1 ; 当Ar 1 为C 6 H 5 CONH时,A为C 3 -C 15 -亚烷基,或者,当Ar 1 为5 -或6-元杂环时,A为C 4 -C 15 -亚烷基或C 3 -C 15 -亚烷基,该基团包括 至少一个Z基,其选自O,S,NR 1 ,双键或三键,其中R 1 为如上所 定义, B为具1个或2个氮杂原子之7-或8-元饱和环,该氮杂原子位 于1,4或1,5位置,该环以位置1键结于基团A,以位置4或5键 结于基团Ar 2 ,且该环另外能够在位置3或4具有双键; Ar 2 为苯基,吡啶基,嘧啶基或三嗪基,Ar 2 能够具有1,2,3 或4个取代基,该取代基彼此独立选自OR 1 ,烷基,C 2 -C 6 -烯基,C 2 - C 6 -炔基,烷氧烷基,卤烷基,卤素,CN,CO 2 R 1 ,NO 2 ,SO 2 R 1 , NR 1 R 2 ,SO 2 NR 1 R 2 ,SR 1 ,5-或6-元碳环族、芳香族或非芳香族环 及5-或6-元杂环的具1至3个选自O,S及N之杂原子之芳香族或非 芳香族环,该碳环或杂环未取代或经C 1 -C 8 烷基、苯基、卤素、OC 1 -C 8 烷基、OH、NO 2 或CF 3 取代,并且Ar 2 亦可以稠合于上述形式之 碳环,且其中Ar 2 不能够是经2个羟基取代之嘧啶基, 及其生理耐受酸的盐。
    2: 根据权利要求1的式Ⅰ的化合物,其中Ar 1 为 其中R 3 至R 6 彼此独立为H或权利要求1中为基团Ar 1 所提及之取 代基,R 7 具权利要求1所述R 2 之意义,或为环烷基,且 X为N或CH。
    3: 根据权利要求1的式Ⅰ的化合物,其中Ar 1 为 其中R 3 至R 5 ,R 7 及X具有权利要求2地意义。
    4: 根据权利要求3的式Ⅰ的化合物,其中Ar 1 为 其中R 3 至R 5 ,R 7 及X具有权利要求2的意义。
    5: 根据权利要求4的式Ⅰ的化合物,其中R 3 ,R 4 及R 5 彼此独立 为H,OR 1 ,烷基,NR 1 R 2 ,卤素,苯氧基,CN,未取代或经C 1 - C 6 -烷基、?;蚵彼厝〈交?,或COOR 1 ;R 1 或R 2 彼此独立为H, 烷基或苄基; R 7 为H,烷基或环烷基;且 X为N或CH。
    6: 根据权利要求5的化合物,其中R 3 至R 6 彼此独立选自H,C 1 -C 6 -烷基,OR 1 ,NR 1 R 2 ,未取代或经C 1 -C 6 -烷基、?;蚵?素取代之苯基,及卤素,其中R 1 及R 2 具有上述意义,R 7 为H或烷基, X为N。
    7: 根据权利要求6的化合物,其中Ar 1 为未取代或经OH、烷氧基 或苄氧基取代之嘧啶基。
    8: 根据权利要求6的化合物,其中Ar 1 为 其中R 3 为NR 1 R 2 ,其中R 1 及R 2 具权利要求5之意义,且R 7 为H 或烷基。
    9: 根据权利要求6的化合物,其中Ar 1 为未取代或经NR 1 R 2 取代 之硫杂二唑,其中R 1 及R 2 具权利要求5之意义。
    10: 根据权利要求6的化合物,其中Ar 1 为 其中R 3 及R 5 彼此独立为H或卤素,烷基或苯基。
    11: 根据前述任一权利要求之式1化合物,其中A为-Z-C 3 -C 6 亚烷 基,尤指-Z-CH 2 CH 2 CH 2 -,-Z-CH 2 CH 2 CH 2 CH 2 -,-Z-CH 2 CH=CHCH 2 -, -Z-CH 2 C(CH 3 )=CHCH 2 -,-Z-CH 2 C(=CH 2 )CH 2 -,-Z-CH 2 CH(CH 3 )CH 2 -或一 直链-Z-C 7 -C 10 -亚烷基,其中Z键结于Ar 1 且为CH 2 ,O或S。
    12: 根据前述任一权利要求之式1化合物,其中B为
    13: 根据前述任一权利要求之式1化合物,其中Ar 2 为苯基,吡啶 基或嘧啶基,其可以具一或二个取代基,该取代基彼此独立选自C 1 - C 6 烷基,C 2 -C 6 -炔基,卤素,CN,卤烷基,烷氧基,NO 2 ,苯基, 吡咯基,咪唑基,吡唑基,噻吩基,环戊基及环己基。
    14: 根据权利要求13的式1化合物,其中该取代基彼此独立选自 C 1 -C 6 烷基,NO 2 及卤烷基,尤指CF 3 ,CHF 2 及CF 2 Cl。
    15: 一种药物组合物,其包括至少一种权利要求1至14中任一项 之化合物,含或不含生理上可接受之载体及/或辅助物质。
    16: 至少一种权利要求1至14中任一项之化合物在制备用以治疗 感应多巴胺D 3 受体拮抗剂或激动剂之失调的药物组合物中的应用。

    说明书


    取代的氮-及二氮杂环庚烷 及-环辛烷化合物及其用途

        本发明涉及取代的氮-及二氮杂环庚烷及-环辛烷化合物,及此类化合物之用途。该化合物具有重要的治疗性质,且尤其能够用以治疗感应多巴胺D3配位体之失调。

        以下讨论形式的具有生理活性的化合物已公开一些案例中。因而,DE2139082及DE2258561中叙述嘧啶衍生物及具碱性取代基之嘧啶酮衍生物作为降血压药。这些嘧啶及嘧啶酮衍生物具有以下化学式:其中,在(A)中X尤其为硫原子,A为C1-C6-亚烷基,R1,R2,R3及Z为各种取代基。在(B)中,X及Y为氧或硫原子,A为C2-C6-亚烷基,W为亚乙烯基且R及Z为各种取代基。

        EP-A-361271叙述以下化学式之吡啶基及嘧啶基衍生物:其中R1为卤素或氢,R2为卤素;X为氧,硫或亚甲基;R3及R4为相同或相异,系氢或低级烷基:n为2或3:A为2-嘧啶基或2-或3-吡啶基,这些基团可能被取代。这些化合物能够用以治疗精神焦虑。

        EP-A-454498描述以下化学式之化合物:其中A尤其为-(CH2)m-或-B-(CH2)k-,其中B为O,S,未取代的或取代的氨基,-CONH-或-COO-,R1及R2尤其能够一起形成亚烷基链,R2及R4为氢或低级烷基,X1,X2及X3为各种取代基。这些化合物能够用以治疗心律不齐。

        EP-A-452107及EP-A-369627叙述同样能够用以治疗心律不齐之结构类似化合物。

        此外,BE-A-628766叙述以下化学式之化合物:其中X为卤素原子或低级烷基,T为哌嗪,甲基哌嗪,高哌嗪或甲基高哌嗪;Z为亚烷基或亚烯基;A为O或S;Y为萘基,卤萘基或未取代的或一至三取代之苯基。这些化合物能够用以治疗血吸虫病。

        神经元尤其经由G-蛋白偶合受体得到其信息。有无数物质经由这些受体发挥其作用。其中之一为多巴胺。

        多巴胺存在下确认之信息及其作为神经递质之生理功能是可利用的。感应多巴胺之细胞与早发性痴呆及巴金森(ParkinSon)症病原有关。这些及其它疾病以与多巴胺受体互相作用之药物治疗。

        直到1990年,已以药理方式清楚地定义二种亚型多巴胺受体,主要是D1及D2受体。

        最近,已发现第三种亚型,即D3受体,其似乎介导一些抗精神病效果(J.C.史瓦兹(Schwartz)等,多巴胺D3受体于新颖抗精神病药物中作为抗精神病之目标(The?Dopamine?D3?Peceptor?as?a?Target?forAntipsychotics,in?Novel?Antipsychotic?Drugs),H.Y.梅尔兹(Meltzer),雷文(Raven)版,1992年纽约,第135-144页)。

        D3受体主要于边缘系统中表示。因而假设一选择性D3拮抗剂像是具有D2拮抗剂之抗神精病性质,但不具其神经病副作用(P.索扣罗夫(Sokoloff)等,D3多巴胺受体之集中及功能(Localization?andFunction?of?the?D3?Dopamine?Receptor),Arzneim.Forch./Drug?Res.42(1),224(1992);P.索扣罗夫(Sokoloff)等。新颖多巴胺受体(D3)之分子无性系及特征化作为镇神剂之目标(Molecular?Cloning?andCharacterization?of?a?Novel?Dopamine?Receptor(D3)as?a?Target?forNeuroleptics),自然(Nature),347,146(1990))。

        P.J.莫瑞(Murray)等,生化及药化文献(Bioorganic&MedicinalChemistry?Letters),第5册,第3号,219-222(1995)已叙述以下化学式之芳基哌嗪类化合物:其中R1及R2为H或CH3O,X为Br,4-乙酰苯基,4-甲基磺酰苯基或4-氨基苯基,具多巴胺D3受体较高亲和力及选择性。

        我们意外发现某些氮-及二氮杂环庚烷及-环辛烷化合物具多巴胺D3受体高亲和力及D2受体低亲和力。其因而为选择性D3配位体。

        本发明因而涉及通式Ⅰ之化合物:

        ????????Ar1-A-B-Ar2????(Ⅰ)其中Ar1为或是具1,2或3个杂原子之5-或6-元杂环,该杂原子彼此独立选自O,N及S,其中Ar1可以具1,2,3或4个取代基,该取代基彼此独立选自OR1,未取代或经OH,OC1-C8-烷基或卤素取代之烷基,或C2-C6-烯基,C2-C6-炔基,环烷基,卤素,CN,CO2R1,NO2,NR1R2,SR1,CF3,CHF2,未取代或经C1-C6-烷基,OC1-C6-烷基,?;?、苯基、氨基、硝基、氰基或卤素取代之苯基,或未取代或经C1-C6-烷基,OC1-C6-烷基或卤素取代之苯氧基,或C1-C6-烷?;虮郊柞;?;

        R1为H,未取代或经OH,OC1-C6-烷基,苯基或卤素取代之烷基;

        R2具R1所指之意义或为COR1或CO2R1;

        当Ar1为C6H5CONH时,A为C3-C15-亚烷基,或者当Ar1为5-或6-元杂环时,A为C4-C15-亚烷基或C3-C15-亚烷基,其包括至少一个基团Z,选自O,S,NR1,双键或三键,其中R1如上所定义,

        B为具一个或二个氮杂原子之7-8-元饱和环,该氮杂原子位于1,4或1,5位置,该环以位置1键结于基团A,以位置4或5键结于基团Ar2,且该环能够另外于单氮杂环位置3或4及1,4-二氮杂环位置6具有双键;

        Ar2为苯基,吡啶基,嘧啶基或三嗪基,Ar2能够具有1,2,3或4个取代基,该取代基彼此独立选自OR1,烷基,C2-C6-烯基,C2-C6-炔基,烷氧烷基,卤烷基,卤素,CN,CO2R1,NO2,SO2R1,NR1R2,SO2NR1R2,SR1,5-元或6-元碳环族,芳香族或非芳香族环,及具1至3个选自O,S及N杂原子之5-元或6-元杂环芳香族或非芳香族环,该碳环或杂环未被取代或经C1-C8烷基,苯基,苯氧基,卤素,OC1-C8烷基,OH,NO2或CF3取代,其中R1及R2具上述意义,且Ar2亦可以稠合于以上定义之碳环,其中Ar2不能够是经2个羟基取代之嘧啶基,

        及其与生理耐受酸之盐。

        根据本发明之化合物是具选择性之多巴胺D3受体配位体,由于对于D2受体之低亲和力,其区域选择地介于边缘系统中,且副作用小于D2受体拮抗剂之典型镇神剂。该化合物因而能够用以治疗感应多巴胺D3受体拮抗剂或激动剂之失调,例如治疗中枢神经系统失调,尤指早发性痴呆,忧郁症,精神官能症及精神病。

        为了本发明之目的,以下用词具有下文中所指之意义:

        烷基(如烷氧基,烷氨基等之基团亦然)为具1至8个碳原子之直链或支链烷基,1至6个碳原子较佳,尤指1至4个碳原子。该烷基可以具1个或多个取代基,该取代基彼此独立选自OH及OC1-C8烷基。

        烷基之实例为甲基,乙基,正丙基,异丙基,正丁基,异丁基,叔丁基等。

        环烷基尤指C3-C6环烷基,如环丙基,环丁基,环戊基及环己基。

        亚烷基较佳为具4至15个碳原子之直链或支链基团,4至10个碳原子尤其较佳,或具3至15个碳原子,尤指3至10个碳原子,当该亚烷基包括所述基团之一时。

        该亚烷基可以包括至少一个以上定义A中所指之Z基。恰如该双键或三键般,这可以位于该亚烷基链之任何位置或A基之位置1或2(从Ar1基团看)。A尤其较佳为根据其中A为-Z-C3-C6-亚烷基之化学式Ⅰ之化合物,尤指-Z-CH2CH2CH2-,-Z-CH2CH2CH2CH2-,-Z-CH2C=CHCH2-,-Z-CH2C(CH3)=CHCH2-,-Z-CH2C(=CH2)CH2-,-Z-CH2CH(CH3)CH2-或直链-Z-C7-C10-亚烷基。如此,当Ar1为未取代或取代的嘧啶或三唑残基时,A尤其较佳为-Z-C3-C6-亚烷基,当Ar1为未取代或取代的噻二唑残基时,A尤佳为-Z-C7-C10-亚烷基。如此,Z亦能够是CH2,较佳为CH2,O,尤指S。

        卤素为F,Cl,Br或I。

        卤烷基可以包括一个或多个卤素原子,尤指1,2或3个,其能够位于一个或多个碳原子上,α或ω位置较佳。CF3,CHF2,CF2Cl或CH2F尤其较佳。

        ?;霞盐狧CO或C1-C6烷基-CO,尤指乙?;?。倘若Ar1被取代,则该取代基亦能够位于氮杂原子上。

        Ar1较佳为以下化学式之基团:其中R3至R6为H或上述Ar1基团之取代基之一,R7具上述R2之意义,且X为N或CH。当苯甲酰胺残基被取代时,该取代基较佳为间或对位。Ar1尤其较佳为以下化学式之基团:其中R3至R5,R7及X具上述意义,尤指以下化学式之基团:其中R3至R5,R7及X具上述意义。

        R3至R6基团较佳为H,C1-C6烷基,OR1,NR1R2,SR1,未取代或经C1-C6烷基、?;?、或卤素取代的苯基,以及卤素其中R1及R2具上述意义。

        基团B较佳为

        基团Ar2可以具1,2,3或4个取代基,1或2个取代基较佳,其尤其位于间位及/或对位。其较佳彼此独立地选自C1-C6烷基,卤烷基,NO2,卤素,尤指氯,苯基,吡咯基,咪唑基,吡唑基,噻吩基,环戊基及环己基。倘若取代基之一为C1-C8烷基,则支链较佳,尤指异丙基或叔丁基。

        Ar2较佳为未取代或取代的之苯基,2-,3-,或4-吡啶基或2-,4(6)-或5-嘧啶基。

        倘若基团Ar2上取代基之一为5-或6-元杂环,则其为,例如,吡咯烷,哌啶,吗啉,哌嗪,吡啶,1,4-二氢吡啶,嘧啶,三嗪,吡咯,噻吩,噻唑,咪唑,噁唑,异噁唑,吡唑或噻二唑残基,而吡咯,咪唑,吡唑或噻吩基较佳。

        倘若基团Ar2上取代基之一为碳环基团,则其尤指苯基,环戊基或环己基。

        倘若基团Ar2稠合于碳环基团,则其尤指萘,二-或四氢萘残基。

        本发明亦包括化学式Ⅰ与生理耐受酸之化合物之酸加成盐类。适当生理耐受有机及无机酸之实例为盐酸,氢溴酸,磷酸,硫酸,草酸,顺丁烯二酸,反丁烯二酸,乳酸,酒石酸,己二酸或苯甲酸。其它能够使用之酸叙述于Fortschritte?der?Arzneimittelforschung,第10册,224页et?seqBirkhauser?Verlag,Basel及Stuttgart,1966。

        式Ⅰ之化合物可以具一个或多个非对称中心。本发明因而不仅包括外消旋物,亦包括相关之镜像异构物及非镜像异构物。特殊之互变异构形式亦包括于本发明中。

        制备化合物(Ⅰ)之方法包括:(a)将通式Ⅱ之化合物

        ????????Ar1-Z-A-y1????(Ⅱ)

        其中Y1为常规离去基,如Hal,烷磺酰氧基,芳磺酰氧基等,Z

        具上述之意义:

        与通式Ⅲ之化合物反应

        ????????H-B-Ar2????(Ⅲ)

        或(b)将通式(Ⅳ)之化合物与通式Ⅴ之化合物反应

        ????????Ar1-A1-Z1H????(Ⅳ)

        其中Z1为O,NR1或S,A1为C1-C15亚烷基或一键,

        ????????Y1-A2-B-Ar2????(Ⅴ)

        其中Y1具上述意义,A2为C2-C15亚烷基,其中A1及A2共具3

        至15个碳原子;或(c)将通式(Ⅵ)之化合物与通式Ⅶ之化合物反应

        ????????Ar1-Y1????(Ⅵ)其中Y1具上述意义,

        ????????H-Z1-A-B-Ar2????(Ⅶ)其中Z1具上述意义;或(d)将化学式(Ⅷ)之化合物转化为(Ⅸ)形式之化合物,

        ????????NC-A-B-Ar2????(Ⅷ)

        并将后者以常规方式与二羰基化合物反应;或(e)制备化学式Ⅰ的其中Ar1为苯甲酰胺残基之化合物:

        将通式(Ⅹ)的其中Y2为OH,OC1-C4烷基,Cl或与CO一起

        为活性酯基之化合物与化学式(Ⅺ)之化合物反应

        ????????Z2-A2-B-Ar2????(Ⅺ)

        其中A2具上述意义,且Z2为OH或NH2。

        化学式Ⅲ之化合物为制备化学式Ⅴ,Ⅶ及Ⅷ之化合物之起始

        化合物,由以下方法制备:a)将通式(Ⅻ)之化合物与通式(ⅩⅢ)之化合物以常规方式反应,

        ????????HB1????(Ⅻ)

        其中B1为

        ????????Y1-Ar2????(ⅩⅢ)

        其中Y1为上述离去基,Ar2具上述意义;或b)将通式(ⅩⅣ)之化合物与通式(ⅩⅤ)之化合物以所述已知之方

        法反应,例如以S.C.布奇瓦德(Buchwald)et?alAngew.Chem.1995,

        107.1456或J.F.哈特维格(Hartweg)et?al四面体(Tetrahedron)Lett1995,36,3604及J.K.史狄拉(Stille)et?alAngew?Chem.1986,98,504或配瑞耶(Pereyre)M.et?al有机合成(Organic?Synthesis),巴德渥司(Buterworth)1987;H-B2其中B2为

        n=1或2,

        Y2-Ar2

        其中Y2为Br,Cl或I,且Ar2具以上意义;或c)将通式(ⅩⅥ)之化合物与M-Ar2(其中M为如Li或MgY2之金

        属)之化合物反应。

        其中n=1或2

        MAr2能够从化学式ⅩⅤ之化合物以文献中已知之方法得到。

        Ar1及Ar2形式之化合物为已知或能够以所述之已知方法制备,例如,于A.R卡瑞兹奇(Katritzky),CW瑞司(Rees)(ed.)“综合杂环化学(Comprehensive?Heterocyclic?Chemistry)”中,佩格曼(Pergamon)版,或“杂环族化合物化学(The?Chemistry?of?HeterocyclicCompounds)”,J.威利桑司(Wiley&Sons)公司。NY及其中指出之文献。

        形式B之化合物是已知或能够以类似之已知方法制备,例如1,4-及1,5-二氮杂环烷类化合物:????L.Brjeson?et?al.Acta?Chem.

        ??????????????????????????????Scand.1991,45,6211,4-二氮杂环-6-辛烯类化合物:?????W.史卡洛司(Schroth)et?al.

        ??????????????????????????????Z.Chem.1969,9,1431-氮杂环辛酮类化合物:????????????N.J.里欧那(Leonard)et?alJ.

        ??????????????????????????????Org.Chem.1964,34,10661-氮杂环庚酮类化合物:????????????A.优酷(Yokoo)et?al布耳

        ??????????????????????????????(Bull)Chem.Soc.Jpn.1956,29,631

        该新颖化合物及起始物质及中间物亦能够以类似所列专利公告中所述之方法制备。

        上述反应通常在介于室温及所使用溶剂沸点间之温度于溶剂中发生。能够使用之溶剂为,例如,乙酸乙酯,四氢呋喃,二甲基甲酰胺,二甲基亚砜,二甲氧基乙烷,二甲苯,甲苯,一种如丙酮或甲基乙基酮之酮,或是如乙醇或丁醇之醇。

        视需要可以存在酸结合剂。适当酸结合剂为无机碱,如碳酸钠或钾,甲氧钠,乙氧钠,氢化钠或如丁基锂或烷基镁化合物之有机金属化合物,或三乙基胺或吡啶之有机碱。后者亦能够作为溶剂。

        反应于适用催化剂处发生,如过渡金属或其复合物,例如Pd(PPh3)4,Pd(OAc)2或Pd(P(oTol)3)4,或相转移催化剂,例如氯化四丁铵或溴化四丙铵。

        以常规方式将粗制产物分离出,例如过滤,以蒸馏去除溶剂,或从反应混合物萃取等。产生之化合物能够以常规方式纯化,例如从溶剂再结晶,层析或转化为酸加成化合物。

        酸加成盐系以常规方式,藉着将游离碱与适当酸混合而制备,其中于溶液中或有机溶剂中较适当,例如低级醇,如甲醇,乙醇或丙醇,如叔丁醚之醚,如丙酮或甲基乙基酮之酮,或如乙酸乙酯之酯。

        为了治疗上述失调,根据本发明之化合物系以常规方式经口服或非经肠道(皮下注射,静脉注射,肌肉注射,腹膜注射)给药。亦能够经由鼻咽空隙以蒸汽或喷雾给药。

        剂量系取决于患者的年龄,状态及重量,以及给药模式。通常,口服给药每个患者每天活性物质剂量为约10至1000毫克,非经肠道给药则每个患者每天约1至500毫克。

        本发明亦涉及包括根据本发明之化合物之药物组合物。这些组合物为常规固体或液体形式之药物,例如未包衣(薄膜)或未包衣片粒,胶囊,粉末,颗粒,栓剂,溶液或喷雾剂。能够用于此之活性物质能够以常规制药助剂加工处理,如锭粒结合剂,松散剂,防腐剂,锭粒粉碎剂,流动调整剂,塑化剂,湿润剂,崩解剂,乳化剂,溶剂,释缓剂,抗氧化剂及/或推进气体(参见H.沙克(Sucker)et?al制药技术(Pharmazeutische?Technologie),西姆佛列格(Thieme-Verlag),史塔格(Stuttgart),1978)。以此方式得到之形式通常包含1至99重量%活性物质。

        以下实例系用以说明本发明而非限制。

        实施例1

        1-[2-叔丁基-6-三氟甲基-嘧啶-4-基]-4-[3-[4-羟基-嘧啶-2-基巯基-丙基]-六氢-(1H)-1,4-二氮杂富马酸盐

        制备起始物质:a)??2-叔丁基-4-羟基-6-三氟甲基嘧啶

        以常规方式合成以上嘧啶,即在乙醇中缩合2,2-二甲基丙脒与三

        氟乙酰乙酸乙酯及乙氧钠,见杂环化合物(Heterocyclic

        Compounds),第52册,嘧啶,第189页et?seqD.J.布朗(Brown)

        et?al.(Eds.)约翰韦利桑司(John?Wiley?and?Sons),1994。

        熔点187-188℃

        以类似方式得到以下化学式之4-羟基嘧啶类化合物。????R????M.p.[℃]????t-C4H9????169????n-C3H7????120????CF2Cl????135-136b)??2-叔丁基-4-氯-6-三氟甲基嘧啶

        将步骤a)之羟基嘧啶以常规方式,使用氧氯化磷或二氯化硫转化为

        氯化合物,见杂环化合物(Heterocyclic?Compounds),第52册,

        嘧啶,第329页et?seq约翰韦利桑司(John?Wiley?and?Sons),

        1994?;衔镂粕托问?。

        以类似方式得到以下化学式4-氯嘧啶类化合物:R?M.p.[℃]t-C4H9油n-C3H7油CF2Cl油c)??1-[2-叔丁基-6-三氟甲基嘧啶-4-基]六氢-(1H)-1,4-二氮杂

        将18克(0.18摩尔)高哌啶溶于25毫升乙醇,回流,将7.2克(0.03

        摩尔)于b)中得到之氯化物溶于10毫升乙醇中,并以1小时滴入。

        再反应30分钟后,添加200毫升水并以全部200毫升二氯甲烷萃取

        几次,以整理冷却之混合物。继之以水清洗有机相,以无水硫酸钠

        干燥并浓缩。得到所需黄色油状之化合物,其经进一步未纯化处理。

        产率:98%理论值。

        以相应方式得到以下化合物:

        以下化学式之1-芳基-1,4-二氮杂d)??1-[2-叔丁基-6-三氟甲基嘧啶-4-基]-4-(3-氯丙基)六氢-(1H)-1,4-

        二氮杂

        将5克(0.0165摩尔)自c)得到之化合物与2.5克(0.025摩尔)

        三乙胺及3.15克(0.02摩尔)1-溴-3-氯丙烷于50毫升四氢

        呋喃中回流10小时。以蒸馏移除溶剂,以水清洗残余物并以二氯甲

        烷萃取。干燥浓缩后得到之残余物继以闪蒸层析(硅胶)纯化。

        产量:4.8克(77%理论值)黄色油。

        以类似方式得到以下所列之化合物:

        化学式如下之1-芳基-4-卤烷基-1,4-二氮杂

        制备最终产物

        将5克(0.013摩尔)d)中得到之产物溶于25毫升二甲基甲酰胺,并以1小时滴入在100℃搅拌之2.03克(0.016摩尔)2-硫尿嘧啶,0.38克(0.016摩尔)氢氧化锂及1克碘化钠/50毫升二甲基甲酰胺。反应3小时后,减压下蒸馏以移除溶剂,将残余物与150毫升水混合并以乙酸乙酯萃取2次。得到之残余物经水清洗,以硫酸钠干燥并浓缩后,以层析纯化(闪蒸层析,硅胶,具2.5-5%甲醇之二氯甲烷移动相)。产量:4克淡色油。NMR:CDCl3δ1.3(s,9H);1.85-2.25(m,4H);2.6(m,4H);2.8(m,2H);3.2

        ??(t,2H);3.5(m,2H);4.0(m,2H);6.2(d,1H);6.5(s,1H);7.8(d,1H)添加反丁烯二酸之乙醇溶液得到富马酸盐。C21H29F3N6OS·C4H4O4????MW?586.6熔点:188-189℃

        以类似方式使用各种卤烷基-1,4-二氮杂(例如1d)及各种巯基取代之杂环物,如硫尿嘧啶,5-氨基-2-巯基三唑类及5-氨基-2-巯基噻二唑得到下表1中之化合物:表1

        实施例24

        1-(4-溴苯甲酰氨基)-4-[4-(2,6-双-叔丁基-4-嘧啶基)六氢-(1H)-1,4-二氮杂-1-基]丁烷

        制备起始物质a)??六氢-1-[2-叔丁基-6-三氟甲基-4-嘧啶基]-4-(4-

        苯二甲酰亚氨基丁基-(1H)-1,4-二氮杂

        将10克(0.033摩尔)于实施例1c)中制备之二氮杂与9.8克

        (0.035摩尔)N-(4-溴丁基)苯二甲酰亚胺及9.1克(0.066

        摩尔)碳酸钾于120毫升乙腈中一起回流8小时。过滤混合物并浓

        缩滤液。处理残余物,进一步未纯化。

        产量:16.2克(98%理论值)

        从乙醇再结晶一样品。熔点97-99℃

        以类似方式得到以下化合物:b)??六氢-1H-[2-叔丁基-6-三氟甲基-4-嘧啶基]-4-(4

        -氨基丁基)-1,4-二氮杂

        将15克(0.03摩尔)上述a)之产物与6克水合肼于200毫升乙醇

        中回流2小时,吸滤沉淀物并将滤液蒸发。于乙酸乙酯中采取残余

        物,再次过滤,以水清洗,干燥并再次蒸发。

        得到9.2克(83%理论值)油。

        以类似方式得到以下化合物:

        制备最终产物:

        将3克(0.0083摩尔)b)中得到之产物以0.9克(0.009摩尔)三乙胺/60毫升四氢呋喃溶液溶解,在室温以10分钟滴入2克(0.009摩尔)4-溴苯甲酰氯/10毫升四氢呋喃溶液。1小时后,于减压下将溶剂蒸馏移除,将残余物与水混合并以二氯甲烷萃取二次。将干燥且浓缩之溶剂相以闪蒸层析(硅胶,具3%甲醇之二氯甲烷移动相)纯化。

        产量:4.2克(93%理论值)

        熔点:125-127℃(自二异丙醚/异丙醇)

        C28H42BrN5O????(544.6)

        使用各种氨基衍生物(类似24b)及已知之苯甲酰氯得到下表2中所列之化合物。表2

        实例31

        4-[4-{4-苄氧基-2-嘧啶氨基}-丁基]-1-[2-叔丁基-6-三氟甲基-4-嘧啶基]六氢-1H-1,4-二氮杂草酸盐

        将2.7克(0.007摩尔)实施例24b)中制备之氨基化合物与0.3克氢化钠(0.009摩尔)添加于20毫升二甲基甲酰胺。反应1小时后,将1.6克(0.006摩尔)4-苄氧基-2-甲基磺酰嘧啶(以氧化4-苄氧基2-甲基巯嘧啶制备)溶于10毫升二甲基甲酰胺之溶液加入,在室温搅拌72小时。

        其后添加水,以乙酸乙酯萃取混合物二次,将混合物干燥并浓缩。以柱层析(硅胶,具4%甲醇之二氯甲烷)纯化。

        纯产量:1.0克(30%理论值),

        草酸盐:熔点145-150℃

        C29H38F3N7O·C2H2O4(647.7)

        实施例32

        ?1-[2-叔丁基-6-三氟甲基-4-嘧啶基]-4-[4-{4-羟基-2-嘧啶氨基}丁基]六氢-(1H)-1,4-二氮杂

        将0.7克(0.001摩尔)前述实施例之化合物在甲醇中,以碳载钯催

        化剂(10%钯),于一般条件下氢化。

        产量:0.6克(理论之100%)

        熔点:111-115℃

        C22H32F3N7O·C2H4O4(557.5)

        实施例33

        1-[2-叔丁基-6-三氟甲基-4-嘧啶基]-4-[4-(4-羟基-2-嘧啶基)丁基]六氢-1H-1,4-二氮杂a)1-[2-叔丁基-6-三氟甲基-4-嘧啶基]-4-(4-氰基丁

        基)六氢-1,4-二氮杂

        将9.1克(0.03摩尔)实施例1c)之二氮杂溶于3.5克(0.03摩尔)

        5-氯戊腈及9.1克三乙胺(0.09摩尔)/100毫升二甲基甲酰胺,

        并于100℃加热24小时。

        继之于减压下蒸馏移除溶剂,添加水,以乙酸乙酯萃取该混合物,

        以硫酸钠干燥此相并浓缩。处理此残余物,进一步未纯化。

        产量:9.1克褐色油。b)1-[2-叔丁基-6-三氟甲基-4-嘧啶基]-4-(4-甲脒丁

        基)六氢-1,4-二氮杂盐酸盐

        将9.1克(0.024摩尔)上述腈溶于2毫升乙醇及50毫升二氯甲烷

        (皆无水),冷却至0-10℃,通入干燥氯化氢气体至饱和。搅拌

        过夜后,吸滤沉淀物并浓缩滤液。

        产量:7.6克(58%理论值)。

        制备最终产物

        将4.4克(0.01摩尔)上述脒与甲酰乙酸乙酯之钠化合物(制备J.Org.Chem.35(1970),2515et?seq.)(2.8克(0.02摩尔))于50毫升水及20毫升四氢呋喃中搅拌过夜。然后以乙酸乙酯萃取反应混合物数次。将有机相干燥并浓缩。以柱层析(硅胶,具4%甲醇之洗脱二氯甲烷)纯化残余物。

        产量:1.9克(42%)油

        NMR:(CDCl3)δ:1.3(s,9H);1.8-2.0(m,4H);2.0(m,2H);2.4-2.6

        ????(m/br,6H);2.5(t,2H);3.5(m,1H);4.0(m,2H);6.2(d,1H);6.5(s,1H);

        ??????7.8(d,1H)

        ????C22H31F3N6O(425.5)

        草酸盐:C22H31F3N6O·C2H2O4????(542.5)

        熔点:173-177℃(分解)

        实施例34

        1-[2-叔丁基-6-三氟甲基-4-嘧啶基]-4-[3-{4-苄氧

        基-2-嘧啶氧基}丙基]六氢-(1H)-1,4-二氮杂a)起始物质

        于50毫升纯THF中溶解8.9克(64.5毫摩尔)3-溴-1-丙醇,

        连续添加6.52克(64.5毫摩尔)三乙基胺,催化量之碘化钠及16.2

        克(53.7毫摩尔)实施例1c)中制备之氮杂,回流混合物16小时。

        滤除沉淀盐并于减压下浓缩母液。于二氯甲烷中吸取产生之油,以

        水清洗有机相,于硫酸钠上干燥,其后以管柱层析(SiO2,移动相

        CH2Cl2∶MeOH=98∶2)纯化以得到无色油。

        产量:10.11克(53%)b)??最终产物

        将0.26克(8.52毫摩尔)氢化钠(80%)逐份添加于2.45克上述

        产物,溶于25毫升纯DMF,在室温并于?;て宕笃瓜陆旌?br>
        物搅拌30分钟。然后滴入溶于15毫升纯DMF之1.5克(5.68毫摩

        尔)2-甲磺?;?4-苄氧嘧啶(以类似文献之方法制备:W.E.

        巴涅特,R.F.扣贝(Koebel)四方锥体文献(Tetrahedron?Lett.)

        1971,20,2867)。7小时后,将混合物倒入水中并以叔丁基甲基醚

        萃取处理。以水清洗有机相,用硫酸钠干燥,过滤并于减压下浓缩。

        以柱层析(SiO2,移动相CH2Cl2∶MeOH=98∶2)纯化产生之油,

        产生油状物质。

        产量:1.6克(2.9毫摩尔,52%)。

        为了形成盐酸盐,将该油溶于乙酸乙酯/Et2O,在?;て绿砑友嗡?br>
        乙醚溶液,以吸滤过滤产生之盐。

        熔点:110-112℃

        C28H36ClF3N6O2(581.1)

        实施例35

        1-[2-叔丁基-6-三氟甲基-2-嘧啶基]-4-[3-(4-羟基-2-嘧啶基氧)丙基]六氢-(1H)-1,4-二氮杂

        将1.4克(2.6毫摩尔)实施例34之物质,溶于40毫升乙酸乙酯,在室温与0.2克Pd/C(10%Pd)混合,并在大气压下于40-50℃以氢氢化。反应完全后,将催化剂以吸滤滤除,以乙酸乙酯清洗后,在减压下过滤并浓缩。

        产量:1.2克(100%)

        为了形成盐酸盐,将该油溶于乙酸乙酯/Et2O,在?;て绿砑友嗡嵋颐讶芤?,以吸滤过滤产生之盐。

        熔点:78-80℃

        C21H30ClF3N6O2(491)

        以类似方式得到下表3至17中叙述之化合物。

        在下列表3-17中,

        Me表示甲基,

        Et表示乙基,

        tBu表示叔丁基,

        iProP和nProP分别表示异丙基和正丙基,

        Pyrrolyl表示吡咯基,

        Napht表示萘基,

        chex和nHex分别表示环己基和正己基,

        Ph表示苯基,

        Acetyl表示乙?;?br>
        p表示对位,表3实施例号??R1????R2????R3????R6????R7????R8????R9?????R10????W????????????X-Y-Z??????A????????B36????????H?????H?????OH????H?????tBut??H?????Me??????H????CH2???????CH2-N-CH2?-CH2-???-(CH2)3-37????????H?????H?????OH????H?????tBut??H?????Ph??????H????CH2-CH2??CH=C-CH2?????S??????-(CH2)3-38????????Me????H?????OH????H?????tBut??H?1-Pyrrolyl??H????CH2???????CH=C-CH2?????S??????-(CH2)3-39????????H?????H?????NH2??H?????iProp?H???2-Napht???H????CH2-CH2??CH2-CH=C????S??????-(CH2)3-40????????H?????Me????OH????H?????Et????H????tBut?????H????CH2???????CH2-N-CH2?-CH2-???-(CH2)3-41????????H?????H?????OH????H?????CHF2?H????H????????H????CH2???????CH2-CH=C?????S??????-(CH2)3-42????????H?????H?????NH2??OMe???CF3??H????H????????H????CH2???????CH=C-CH2?????S??????-(CH2)3-43????????H?????H?????OH????H?????CF3??H????tBut?????H????CH2-CH2??CH2-N-CH2?-CH2-???-(CH2)3-44????????H?????H?????NHMe??H?????iProp?H????H????????H????CH2???????CH2-N-CH2???O??????-(CH2)4-45????????Me????H?????OH????H?????H?????CN???tBut?????H????CH2-CH2??CH2-N-CH2?-CH2-???-(CH2)3-46????????H?????H?????OH????H?????H?????F????tBut?????H????CH2-CH2??CH2-CH=C??????S?????-(CH2)3-47????????H?????Me????NH2??H?????H?????Cl???iProp????H????CH2-CH2??CH2-N-CH2?-CH2-??-(CH2)3-48????????H?????H?????NHMe??H?????tBut??H????H???????OMe???CH2???????CH2-CH=C??????S?????-(CH2)3-49????????H?????H?????OH????H?????iProp?H????H???????OMe???CH2???????CH2-N-CH2??-CH2-??-(CH2)4-50????H????H????OH????H????CHF2???H?????tBut????H????CH2-CH2??CH=C-CH2?????S??????-(CH2)3-51????H????H????OH????OMe??tBut????H?????CF3????H????CH2-CH2??CH2-N-CH2??-CH2-??-(CH2)3-52????Me???H????OH????H????CF3????H?????tBut????H????CH2???????CH2-N-CH2???O??????-(CH2)5-53????H????H????NH2??H????nProp???CN????tBut????H????CH2???????CH2-N-CH2??-CH2-??-(CH2)3-54????H????Me???OH????H????CF3????CN????iProp???H????CH2???????CH=C-CH2?????S??????-(CH2)3-55????H????H????OH????H????Ph????C=CH????tBut????H????CH2-CH2??CH2-N-CH2??-CH2-??-(CH2)3-56????H????H????NH2??H????tBut????CN????H???????H????CH2???????CH2-CH=C?????S??????-(CH2)3-57????H????H????NHMe??H????tBut????CN????CF3???OMe???CH2-CH2??CH2-N??-CH2-CH2-??-(CH2)5-58????H????H????OH????OMe??nProp????F????tBut????H????CH2???????CH2-N-CH2??-CH2-??-(CH2)4-59????H????H????OH????H????Ph??????CN????tBut????Me???CH2???????CH2-CH=C?????S??????-(CH2)3-60????H????H????OH????OMe??tBut?????F????H???????H????CH2-CH2??CH2-N-CH2??-CH2-??-(CH2)3-61????H????H????OH????H????tBut?????H????Me??????H????CH2???????CH2-N-CH2??-CH2-??-CH2-C(=CH2)-CH2-62????H????H????OH????H????tBut?????H????Ph??????H????CH2???????CH2-CH=C??????S??????-CH2-C(=CH2)-CH2-63????Me???H????OH????H????tBut?????H?1-Pyrrolyl?H????CH2-CH2??CH=C-CH2?????S??????-CH2-C(=CH2)-CH2-64????H????H????NH2??H????iProp????H????2-Napht?H????CH2-CH2??CH2-CH=C?????S??????-CH2-C(CH3)=CH-CH2-65????H????Me???OH????H????Et???????H????tBut????H????CH2???????CH2-N-CH2??-CH2-??-CH2-CH(CH3)-CH2-66????H????H????OH????H????CHF2????H????H???????H????CH2-CH2??CH=C-CH2?????S??????-CH2-C(=CH2)-CH2-67????H????H????NH2??OMe??CF3?????H????H???????H????CH2???????CH2-CH=C?????S??????-CH2-CH(CH3)-CH2-68????H????H????OH????H????CF3?????H????tBut????H????CH2-CH2??CH2-N-CH2??-CH2-??-CH2-C(=CH2)-CH2-69????H????H????NHMe??H????iProp????H????H???????H????CH2???????CH2-N-CH2???O??????-CH2-C(=CH2)-CH2-70????Me???H????OH????H????H???????CN????tBut????H????CH2???????CH2-N-CH2??-CH2-??-CH2-CH=CH-CH2-71????H????H????OH????H????H???????F????tBut????H????CH2-CH2?CH2-CH=C????S??????-CH2-C(CH3)=CH-CH2-72????H????Me???NH2??H????H???????Cl??iProp????H????CH2-CH2?CH2-N-CH2??-CH2-?-CH2-C(=CH2)-CH2-73????H????H????NHMe??H????tBut????H????H??????OMe???CH2??????CH2-CH=C?????S??????-CH2-CH(CH3)-CH2-74????H????H????OH????H????iProp???H????H??????OMe???CH2??????CH2-N-CH2??-CH2-??-CH2-CH(CH3)-CH2-75????H????H????OH????H????CHF2???H????tBut????H????CH2-CH2?CH2-CH=C?????S??????-CH2-C(=CH2)-CH2-76????H????H????OH????OMe??tBut????H????CF3????H????CH2??????CH2-N-CH2??-CH2-??-CH2-CH=CH-CH2-77????Me???H????OH????OMe??CF3????H????tBut????H????CH2??????CH2-N-CH2???O??????-CH2-C(=CH2)-CH2-78????H????H????NH2??H????nProp???CN???tBut????H????CH2-CH2?CH2-N-CH2??-CH2-??-CH2-C(CH3)=CH-CH2-79????H????Me???OH????H????CF3????CN???iProp???H????CH2??????CH2-CH=C?????S??????-CH2-CH(CH3)-CH2-80????H????H????OH????H????Ph????C=CH???tBut????H????CH2-CH2?CH2-N-CH2??-CH2-??-CH2-CH(CH3)-CH2-81????H????H????NH2??H????tBut????CN???H???????H????CH2??????CH2-CH=C?????S??????-CH2-C(CH3)=CH-CH2-82????H????H????NHMe??H????tBut????CN???CF3???OMe???CH2-CH2?CH2-N-CH2??-CH2-??-CH2-CH=CH-CH2-83????H????H????OH????H????nProp????F???tBut????H????CH2??????CH2-N-CH2??-CH2-??-CH2-CH(CH3)-CH2-84????H????H????OH????H????Ph??????CN???tBut????Me???CH2-CH2?CH2-CH=C?????S??????-CH2-C(CH3)=CH-CH2-85????H????H????OH????H????tBut?????F???H???????H????CH2??????CH2-N-CH2??-CH2-??-CH2-C(=CH2)-CH2-表4实施例号??R1???R2???R3????R7??????R9????R10????W?????????X-Y-Z?????????A????????B86????????H????H????OH????tBut????Ph??????H????CH2??????CH2-N-CH2?-CH2-?-(CH2)3-87????????H????H????OH????tBut????2-Napht?H????CH2??????CH2-N-CH2??S??????-(CH2)3-88????????Me???H????OH????tBut?1-Pyrrolyl?H????CH2??????CH2-N-CH2??S??????-CH2-C(=CH2)-CH2-89????????H????H????NH2??tBut????cHex????H????CH2-CH2?CH=C-CH2???-CH2-??-CH2-C(CH3)=CH-CH2-90????????H????H????OH????tBut????nHex????H????CH2-CH2?CH2-N-CH2??S??????-(CH2)3-91????????H????H????OH????tBut????H???????OMe??CH2??????CH2-N-CH2?-CH2-??-CH2-CH(CH3)-CH2-92????????H????Me???OH????iProp???F???????H????CH2-CH2?CH2-N-CH2??S??????-CH2-CH=CH-CH2-93????????H????H????NH2??CH3?1-Pyrrolyl?H????CH2??????CH2-C=CH????NH?????-(CH2)3-94????????H????H????OH????OMe??1-Pyrrolyl?H????CH2??????CH2-N-CH2??O??????-CH2-CH(CH3)-CH2-95????????H????H????OH????tBut????H???????CH3?CH2-CH2?CH=C-CH2????S??????-CH2-CH(CH3)-CH2-96????????H????H????OH????tBut????tBut????OMe??CH2-CH2?CH2-N-CH2??S??????-(CH2)3-97????????Me???H????OH????tBut????iProp???H????CH2??????CH2-N-CH2??S??????-CH2-C(=CH2)-CH2-98????????H????H????NH2??Ph??????tBut????Cl???CH2??????CH2-C=CH???-CH2-??-CH2-C(CH3)=CH-CH2-99????????H????H????OH????2-Napht?tBut????Me???CH2-CH2?CH=C-CH2????S??????-(CH2)3-100???????H????H????OH????tBut????CF3????Me???CH2??????CH2-N-CH2?-CH2-??-CH2-C(=CH2)-CH2-表5实施例号R1?????R2???R3????R7??????R8???R9????R10???W????????X-Y-Z???????A?????????B?101?????H??????H????OH????tBut????H????tBut??H????CH2??????CH2-N-CH2?S???????-(CH2)3-102?????H??????H????OH????tBut????CN???H?????H????CH2??????CH2-N-CH2?S???????-(CH2)3-103?????Me?????H????OH????tBut????H????Cl????H????CH2??????CH2-N-CH2?NH??????-CH2-C(=CH2)-CH2-104?????H??????H????OH????H???????CN???tBu???H????CH2-CH2?CH2-CH=C???-CH2-?-CH2-CH(CH3)-CH2-105?????H??????H????NH2??CF3????H????tBut??H????CH2??????CH2-N-CH2?S???????-(CH2)3-106?????H??????H????OH????nProp???H????iProp?H????CH2-CH2?CH=C-CH2???-CH2-??-CH2-CH(CH3)-CH2-107?????H??????Me???OH????H???????H????iProp?OMe??CH2-CH2?CH2-CH=C???S???????-(CH2)3-108?????H??????H????OH????tBut????H????tBut??H????CH2??????CH2-N-CH2?NH??????-CH2-C(=CH2)-CH2-109?????H??????H????OH????tBut????CN???H?????H????CH2-CH2?CH2-N-CH2?S???????-(CH2)4-110?????H??????H????NH2??tBut????H????Cl????H????CH2??????CH2-N-CH2?O???????-(CH2)3-111?????Me?????H????OH????H???????CN???tBu???H????CH2??????CH=C-CH2???S???????-CH2-C(CH3)=CH-CH2-112?????H??????H????OH????CF3????H????tBut??H????CH2-CH2?CH2-N-CH2?-CH2-??-CH2-C(=CH2)-CH2-113?????H??????H????OH????nProp???H????iProp?H????CH2??????CH2-N-CH2?S???????-(CH2)3-114????H????H????NHMe??H??????H?????iProp???OMe??CH2???????CH2-N-CH2??S??????-(CH2)3-115????H????H????OH????nProp??CN????tBut????H????CH2-CH2??CH2-N-CH2??S??????-(CH2)4-116????H????H????OH????CF3???CN????iProp???H????CH2-CH2??CH2-CH=C????S??????-(CH2)3-117????Me???H????OH????Ph?????C=CH??tBut????H????CH2???????CH2-N-CH2??NH?????-CH2-CH(CH3)-CH2-118????H????H????OH????tBut???CN????tBut????H????CH2-CH2??CH=C-CH2???-CH2-??-CH2-CH(CH3)-CH2-119????H????H????NH2??tBut???H?????nProp???H????CH2???????CH2-N-CH2??S??????-(CH2)3-120????H????H????OH????Ph?????H?????tBut????OMe??CH2???????CH2-CH=C???-CH2-??-(CH2)5-121????H????Me???OH????CF3???H?????tBut????F????CH2-CH2??CH=C-CH2????S??????-CH2-CH(CH3)-CH2-122????H????H????OH????tBut???F?????H???????Me???CH2???????CH2-N-CH2??NH?????-CH2-CH=CH-CH2-123????H????H????OH????nProp??CN????tBut????Me???CH2-CH2??CH2-CH=C????S??????-CH2-C(=CH2)-CH2-124????H????H????NH2??nProp??C=CH??tBut????H????CH2???????CH=C-CH2???-CH2-??-CH2-C(CH3)=CH-CH2-125????H????H????OH????tBut???CN????H???????Me???CH2???????CH2-N-CH2??S??????-(CH2)4-表6实施例号?R1???R2???R3????R6?????R8????R9??????R10???W??????????X-Y-Z???????A?????????B126??????H????H????OH????OMe????H????tBut?????H????CH2???????CH2-N-CH2??S??????-(CH2)3-127??????H????H????OH????OMe????H????CF3?????H????CH2???????CH2-N-CH2??S??????-(CH2)3-128??????Me???H????OH????OMe????H????tBut?????H????CH2-CH2??CH2-N-CH2??NH?????-CH2-C(=CH2)-CH2-129??????H????H????OH????H??????CN???tBut?????H????CH2???????CH=C-CH2???-CH2-??-CH2-C(CH3)=CH-CH2-130??????H????H????NH2??H??????F????tBut?????H????CH2???????CH2-N-CH2??S??????-(CH2)3-131??????H????H????OH????Me?????Cl???iProp????H????CH2???????CH2-CH=C???-CH2-??-CH2-C(=CH2)-CH2-132??????H????Me???OH????H??????H????iProp????H????CH2-CH2??CH=C-CH2????S??????-(CH2)3-133??????H????H????OH????H??????H????tBut?????OMe??CH2-CH2??CH2-N-CH2??NH?????-CH2-C(=CH2)-CH2-134??????H????H????OH????CN?????H????CF3?????H????CH2-CH2??CH2-N-CH2??S??????-(CH2)4-135??????H????H????NH2??H??????CN???H????????OMe??CH2???????CH2-N-CH2??O??????-CH2-CH(CH3)-CH2-136??????Me???H????OH????H??????H????tBu??????F????CH2???????CH2-CH=C????S??????-CH2-C(CH3)=CH-CH2-137??????H????H????OH????H??????CN???tBut?????H????CH2-CH2??CH2-N-CH2?-CH2-??-(CH2)3-138??????H????H????OH????Me?????H????iProp????H????CH2???????CH2-N-CH2??S??????-(CH2)3-139??????H????H????NHMe??OMe????H????iProp????H????CH2-CH2??CH2-N-CH2??S??????-CH2-CH(CH3)-CH2-140????H????H????OH????OMe???CN????tBut????H????CH2??????CH=C-CH2????S??????-(CH2)3-141????H????H????OH????OMe???Me????tBut????H????CH2??????CH2-N-CH2??S??????-(CH2)3-142????Me???H????OH????H?????CN????tBut????H????CH2-CH2?CH2-N-CH2??NH?????-CH2-CH=CH-CH2-143????H????H????OH????Me????H?????tBut????H????CH2??????CH2-CH=C???-CH2-??-CH2-C(=CH2)-CH2-144????H????H????NH2??H?????Cl????CF3???Me???CH2-CH2?CH2-N-CH2??S??????-(CH2)3-145????H????H????OH????OMe???CN????tBut????Me???CH2??????CH=C-CH2???-CH2-??-CH2-CH(CH3)-CH2-146????H????Me???OH????Me????Me????iprop???Me???CH2??????CH2-CH=C????S??????-(CH2)3-表7实施例号R1????R2???R3????R6??????R7??????R9?????????R10??????W??????????X-Y-Z???????A?????????B147?????H?????H????OH????H???????tBut????tBut???????H????????CH2???????CH2-N-CH2?S???????-(CH2)3-148?????H?????H????OH????H???????tBut????Ph?????????H????????CH2???????CH2-N-CH2?S???????-(CH2)3-149?????Me????H????OH????H???????tBut????1-Pyrrolyl?H????????CH2???????CH2-N-CH2?NH??????-CH2-C(=CH2)-CH2-150?????H?????H????OH????H???????nPropyl?tBut???????H????????CH2-CH2??CH2-CH=C???-CH2-??-CH2-C(CH3)=CH-CH2-151?????H?????H????NH2??H???????CF3????tBut???????H????????CH2???????CH2-N-CH2?S???????-(CH2)3-152?????H?????H????OH????H???????2-Napht?tBut???????H????????CH2-CH2??CH=C-CH2???-CH2-??-CH2-C(=CH2)-CH2-153?????H?????Me???OH????OMe?????tBut????H??????????H????????CH2-CH2??CH2-CH=C???S???????-(CH2)3-154?????H?????H????OH????OMe?????iProp???H??????????H????????CH2???????CH2-N-CH2?NH??????-CH2-C(=CH2)-CH2-155?????H?????H????OH????OMe?????H???????CF3???????H????????CH2-CH2??CH2-N-CH2?S???????-(CH2)4-156?????H?????H????NH2??H???????tBut????H??????????H????????CH2???????CH2-N-CH2?O???????-CH2-CH(CH3)-CH2-157?????Me????H????OH????H???????iProp???H??????????Me???????CH2???????CH=C-CH2???S???????-CH2-C(CH3)=CH-CH2-158?????H?????H????OH????CN??????tBut????H??????????H????????CH2-CH2??CH2-N-CH2?-CH2-??-(CH2)3-159?????H?????H????OH????H???????H???????CF3???????Mo???????CH2???????CH2-N-CH2?S???????-(CH2)3-160?????H?????H????NHMe??H???????nProp???tBut???????H????????CH2???????CH2-N-CH2?S???????-CH2-CH(CH3)-CH2-161????H????H????OH????OMe???tBut????iProp???H????CH2-CH2??CH2-N-CH2??S???????-(CH2)3-162????H????H????OH????OMe???CF3????tBut????H????CH2-CH2??CH=C-CH2????NH??????-(CH2)3-163????Me???H????OH????Me????tBut????nProp???H????CH2???????CH2-CH=C???-CH2-???-CH2-CH=CH-CH2-164????H????H????OH????Me????tBut????H???????H????CH2-CH2??CH2-N-CH2??S???????-CH2-C(=CH2)-CH2-165????H????H????NH2??H?????tBut????tBut????H????CH2???????CH=C-CH2???-CH2-???-(CH2)3-166????H????H????OH????Me????CF3????tBut????H????CH2???????CH2-CH=C????S???????-CH2-CH(CH3)-CH2-表8实施例号?O?????R2?????R5????R6?????R7???R8??????R9????W????????X-Y-Z????????A?????????B167????NCH3???NH2???H????tBut????H????Me??????H????CH2??????CH2-N-CH2??S??????-(CH2)3-168????S???????NH2???H????tBut????H????Ph??????H????CH2??????CH2-N-CH2??S??????-(CH2)3-169????NCH3???NH2???H????tBut????H?1-Pyrrolyl?H????CH2-CH2?CH2-N-CH2??NH?????-(CH2)3-170????NCH3???NH2???H????iProp???H????2-Napht?H????CH2??????CH2-CH=C???-CH2-??-(CH2)3-171????S???????NH2???H????Et??????H????tBut????H????CH2-CH2?CH2-N-CH2??S??????-(CH2)3-172????S???????NH2???H????CHF2???H????H???????H????CH2??????CH=C-CH2???-CH2-??-(CH2)8-173????NCH3???NH2???H????CHF2???H????tBut????H????CH2??????CH2-CH=C????S??????-(CH2)10-174????NCH3???NH2???H????CF3????H????tBut????H????CH2??????CH2-N-CH2??NH?????-(CH2)3-175????NCH3???NH2???H????iProp???F????H???????H????CH2-CH2?CH2-N-CH2??S??????-(CH2)3-176????NCH3???NH2???H????H???????CN???tBut????H????CH2??????CH2-CH=C????O??????-(CH2)3-177????S???????NH2???H????H???????F????tBut????H????CH2-CH2?CH=C-CH2????S??????-(CH2)3-178????NCH3???NH2???H????H???????Cl???iProp???H????CH2-CH2?CH2-N-CH2?-CH2-??-(CH2)3-179????NCH3???NH2???H????tBut????H????H???????OMe??CH2??????CH=C-CH2????S??????-(CH2)3-180????S???????NH2???H????nProp???CN???tBut????H????CH2-CH2?CH2-CH=C???-CH2-??-(CH2)3-181????NCH3???NH2???H????CF3????CN???iProp???H????CH2??????CH2-N-CH2??S??????-(CH2)3-182????NCH3???NH2???H????Ph??????C=CH?tBut????H????CH2??????CH=C-CH2???-CH2-??-(CH2)3-183????NCH3?????NH2???OMe??tBut????CN????H???????H????CH2???????CH2-CH=C????S??????-(CH2)3-184????S?????????NH2???H????tBut????CN????CF3????OMe??CH2-CH2??CH2-N-CH2??NH?????-(CH2)3-185????NCH3?????NH2???H????Ph??????CN????tBut????Me???CH2-CH2??CH2-N-CH2??O??????-(CH2)3-186????NCH3?????NH2???Me???tBut????F?????H???????H????CH2-CH2??CH2-CH=C????S??????-(CH2)3-187????S?????????NH2???H????iProp???H?????H???????OMe??CH2???????CH2-N-CH2??S??????-(CH2)3-188????N(iProp)??NH2???H????tBut????H?????Me??????H????CH2???????CH2-N-CH2??S??????-(CH2)3-189????N(iProp)??NH2???H????tBut????H?????Ph??????H????CH2-CH2??CH2-N-CH2??NH?????-(CH2)4-190????S?????????NH2???H????tBut????H?1-Pyrrolyl??H????CH2???????CH=C-CH2????S??????-(CH2)8-191????N(iProp)??NH2???H????iProp???H????2-Napht??H????CH2-CH2??CH2-N-CH2?-CH2-??-(CH2)3-192????S?????????NH2???H????Et??????H?????tBut????H????CH2???????CH2-N-CH2??S??????-(CH2)10-193????N(iProp)??NH2???H????CF3????H?????tBut????H????CH2-CH2??CH2-N-CH2?-CH2-??-(CH2)4-194????N(iProp)??NH2???H????H???????CN????tBut????H????CH2-CH2??CH=C-CH2????NH?????-(CH2)3-195????N(iProp)??NH2???H????H???????F?????tBut????H????CH2???????CH2-N-CH2??S??????-(CH2)3-196????N(iProp)??NH2???H????H???????Cl????iProp???H????CH2???????CH=C-CH2???-CH2-??-(CH2)3-197????S?????????NH2???H????tBut????H?????H???????OMe??CH2-CH2??CH2-N-CH2??S??????-(CH2)8-198????N(iProp)??NH2???H????nProp???CN????tBut????H????CH2???????CH2-CH=C???-CH2-??-(CH2)3-199????S?????????NH2???H????CF3????CN????iProp???H????CH2???????CH2-N-CH2??S??????-(CH2)4-200????N(iProp)??NH2???H????Ph??????C=CH??tBut????H????CH2-CH2??CH=C-CH2???-CH2-??-(CH2)3-201????N(iProp)??NH2???H????tBut????CN????CF3????OMe??CH2???????CH2-N-CH2??NH?????-(CH2)3-202????N(iProp)??NH2???H????Ph??????CN????tBut????Me???CH2-CH2??CH2-N-CH2??O??????-(CH2)3-203????S?????????NH2???H????iProp???H?????H???????OMe??CH2-CH2??CH2-N-CH2??S??????-(CH2)8-204????N(iProp)??NHMe???H????tBut????H?????Me??????H????CH2???????CH2-N-CH2??S??????-CH2-C(=CH2)-CH2-205????N(iProp)?NHMe??H????tBut????H????Ph??????H????CH2???????CH2-CH=C???-CH2-?-CH2-C(=CH2)-CH2-206????S????????NHMe??H????tBut????H?1-Pyrrolyl?H????CH2-CH2??CH=C-CH2????S??????-CH2-CH=CH-CH2-207????N(iProp)?NHMe??H????iProp???H????2-Napht?H????CH2???????CH2-N-CH2??NH?????-CH2-CH(CH3)-CH2-208????N(iProp)?NHMe??H????Et??????H????tBut????H????CH2-CH2??CH2-N-CH2??S??????-CH2-C(CH3)=CH-CH2-209????N(iProp)?OH????H????tBut????H????Cl??????H????CH2-CH2??CH2-N-CH2?-CH2-?-CH2-CH(CH3)-CH2-210????N(iProp)?OH????H????CF3????H????Cl??????H????CH2???????CH=C-CH2????NH?????-CH2-CH(CH3)-CH2-211????N(iProp)?OH????H????CF3????H????tBut????H????CH2-CH2??CH2-N-CH2??S??????-CH2-C(=CH2)-CH2-212????S????????OH????H????iProp???CN???F???????H????CH2-CH2??CH=C-CH2???-CH2-?-CH2-C(=CH2)-CH2-213????N(iProp)?OMe???H????H???????CN???tBut????H????CH2???????CH2-CH=C???-CH2-??-CH2-C(=CH2)-CH2-214????N(iProp)?OMe???H????H???????F????tBut????H????CH2???????CH2-CH=C????S??????-CH2-C(CH3)=CH-CH2-215????S????????OMe???H????H???????Cl???iProp???H????CH2???????CH=C-CH2????O??????-CH2-CH(CH3)-CH2-216????N(iProp)?OMe???H????tBut????H????H???????OMe??CH2-CH2??CH=C-CH2????NH?????-CH2-C(CH3)=CH-CH2-217????N(iProp)?NHMe??H????nProp???CN???tBut????H????CH2???????CH2-N-CH2??NH?????-CH2-CH(CH3)-CH2-218????S????????NHMe??H????CF3????CN???iProp???H????CH2-CH2??CH2-N-CH2??S??????-CH2-CH(CH3)-CH2-219????N(iProp)?OH????H????Ph??????C=CH?tBut????H????CH2-CH2??CH2-N-CH2?-CH2-??-CH2-C(CH3)=CH-CH2-220????N(iProp)?OH????OMe??tBut????CN???H???????H????CH2???????CH2-CH=C????NH?????-CH2-CH(CH3)-CH2-221????N(iprop)?OH????H????tBut????CN???CF3????OMe??CH2???????CH2-N-CH2??S??????-CH2-C(=CH2)-CH2-222????S????????OH????H????nProp???F????tBut????H????CH2-CH2??CH=C-CH2???-CH2-??-CH2-C(=CH2)-CH2-223????S????????OMe???H????Ph??????CN???tBut????Me???CH2???????CH2-CH=C???-CH2-??-CH2-C(=CH2)-CH2-224????N(iprop)?OMe???OMe??tBut????F????H???????H????CH2???????CH=C-CH2????S??????-CH2-CH(CH3)-CH2-225????N(iprop)?OMe???H????iProp???H????H???????OMe??CH2???????CH2-CH=C????S??????-CH2-C(CH3)=CH-CH2-表9实施例号?O?????R2??????R6?????R8???????R9????W?????????X-Y-Z???????A?????????B226????NCH3???NH2???tBut????Ph???????H????CH2??????CH2-N-CH2?-CH2-??-(CH2)3-227????NCH3???NH2???tBut???2-Napht???H????CH2??????CH2-N-CH2??S??????-CH2-C(=CH2)-CH2-228????NCH3???NH2???tBut??1-Pyrrolyl?H????CH2-CH2?CH2-N-CH2??S??????-(CH2)3-229????NCH3???NHMe???tBut????nHex?????H????CH2-CH2?CH2-CH=C???-CH2-??-(CH2)3-230????NCH3???NH2???tBut????nHex?????H????CH2??????CH2-N-CH2??S??????-(CH2)5-231????S???????NH2???tBut????Ph???????H????CH2??????CH2-N-CH2?-CH2-??-(CH2)8-232????S???????NHMe???iProp?1-Pyrrolyl?H????CH2??????CH2-N-CH2??S??????-CH2-CH(CH3)-CH2-233????S???????NH2???CH3????CH3?????H????CH2-CH2?CH2-CH=C????NH?????-(CH2)3-234????NCH3???NH2???H???????CHF2????H????CH2??????CH2-N-CH2??O??????-CH2-C(=CH2)-CH2-235????S???????NH2???tBut????tBut?????H????CH2??????CH2-N-CH2?-CH2-??-(CH2)10-236????S???????NHMe???tBut????iProp????H????CH2-CH2?CH2-N-CH2??S??????-CH2-C(CH3)=CH-CH2-237????NCH3???NH2???tBut????tBut?????H????CH2??????CH2-N-CH2??S??????-CH2-C(=CH2)-CH2-238????NCH3???NH2?2-Napht???tBut?????Me???CH2-CH2?CH=C-CH2???-CH2-??-CH2-CH(CH3)-CH2-239????S???????NH2???tBut????CF3?????H????CH2-CH2?CH2-CH=C????S??????-(CH2)8-240????NCH3???NH2???tBut????H????????CH3?CH2??????CH2-N-CH2??S??????-(CH2)3-241????N(iProp)????NH2?????tBut????Ph??????H????CH2-CH2?CH=C-CH2?????S??????-CH2-C(=CH2)-CH2-242????N(iProp)????NH2?????tBut????2-Napht?H????CH2??????CH2-CH=C?????NH?????-(CH2)3-243????N(iProp)????NH2?????tBut?1-Pyrrolyl?H????CH2??????CH2-N-CH2???O??????-CH2-CH(CH3)-CH2-244????N(iProp)????NH2?????tBut????cHex????H????CH2-CH2?CH2-N-CH2??-CH2-?-(CH2)3-245????S???????????NH2?????tBut????tBut????H????CH2??????CH2-N-CH2???S??????-CH2-C(=CH2)-CH2-246????S???????????OH???????tBut????F???????H????CH2-CH2?CH=C-CH2?????S??????-(CH2)10-247????N(nProp)????OMe??????iProP???tBut????H????CH2??????CH2-N-CH2??-CH2-??-CH2-CH=CH-CH2-248????N(nProp)????OMe??????CH3??1-Pyrrolyl?H????CH2??????CH2-N-CH2??-CH2-??-(CH2)3-249????N(nProp)????NCH2Ph??H???????iProp???H????CH2-CH2?CH2-N-CH2???S??????-CH2-C(CH3)=CH-CH2-250????N(iProp)????OH???????tBut????tBut????H????CH2??????CH=C-CH2????-CH2-??-(CH2)4-251????N(iProp)????OH???????tBut????iProp???F????CH2-CH2?CH2-N-CH2???S??????-CH2-CH=CH-CH2-252????N(iProp)????OMe??????Ph??????tBut????Cl???CH2??????CH2-N-CH2???S??????-(CH2)5-253????N(nProp)????OMe????2-Napht???tBut????Me???CH2??????CH=C-CH2????-CH2-??-(CH2)3-254????N(nProp)????NCH2Ph??tBut????CF3???OMe??CH2-CH2?CH2-N-CH2???S??????-(CH2)4-255????N(nProp)????NHMe?????tBut????H???????CH3?CH2??????CH=C-CH2?????S??????-CH2-CH(CH3)-CH2表10实施例号?O????????R2?????R6?????R7????R8????R9?????W?????????X-Y-Z????????A?????????B256????NCH3?????NH2???tBut????H????tBut????H????CH2??????CH2-N-CH2??S??????-(CH2)3-257????S??????????OH????tBut????CN???H???????H????CH2??????CH2-N-CH2??S??????-(CH2)8-258????N(iProp)??NHMe???tBut????H????Cl??????H????CH2??????CH2-N-CH2??NH?????-CH2-C(=CH2)-CH2-259????NCH3?????NH2???H???????CN???tBu?????H????CH2??????CH2-CH=C???-CH2-??-CH2-CH(CH3)-CH2-260????NCH3?????NHMe???CF3????H????tBut????H????CH2-CH2?CH2-N-CH2??S??????-(CH2)3-261????N(cProp)??NH2???nProp???H????iProp???H????CH2-CH2?CH=C-CH2???-CH2-??-CH2-C(=CH2)-CH2-262????S?????????NHMe???H???????H????iProp???H????CH2??????CH2-CH=C????S??????-(CH2)10-263????NCH3?????NH2???tBut????H????tBut????H????CH2-CH2?CH2-N-CH2??NH?????-CH2-C(=CH2)-CH2-264????N(iProp)??NH2???tBut????CN???H???????H????CH2-CH2?CH2-N-CH2??S??????-(CH2)4-265????NOH???????NHMe???tBut????H????H??????OMe???CH2??????CH2-CH=C????O??????-(CH2)3-266????NCH3?????OH?????H???????CN???tBu?????H????CH2??????CH=C-CH2????S??????-CH2-CH(CH3)-CH2-267????NEt???????NH2???CF3????H????tBut????H????CH2-CH2?CH2-N-CH2?-CH2-??-CH2-CH(CH3)-CH2-268????S?????????NH2???nProp???H????iProp???H????CH2??????CH2-N-CH2??S??????-CH2-C(=CH2)-CH2-269????NCH3?????NH2???nProp???CN???tBut????H????CH2??????CH2-N-CH2??S??????-(CH2)4-270????NCH3?????OH?????CF3????CN???iProp???H????CH2-CH2?CH=C-CH2????S??????-(CH2)3-271????N(iProp)?NHMe???Ph?????C=CH???tBut????H????CH2???????CH2-N-CH2??NH?????-CH2-C(=CH2)-CH2-272????S????????NH2???tBut???CN?????tBut????H????CH2-CH2??CH2-CH=C???-CH2-?-CH2-CH(CH3)-CH2-273????NCH3????NHMe???tBut???H??????nProp???OMe??CH2???????CH2-N-CH2??S??????-(CH2)3-274????N(cProp)?NH2???Ph?????H??????tBut????H????CH2???????CH=C-CH2???-CH2-??-(CH2)4-275????S????????NHMe???CF3???H??????tBut????H????CH2-CH2??CH2-CH=C????S??????-(CH2)3-276????NCH3????NH2???tBut???F??????H???????Me???CH2???????CH2-N-CH2??NH?????-CH2-CH=CH-CH2-277????S????????NH2???nProp??CN?????tBut????Me???CH2-CH2??CH=C-CH2????S??????-CH2-C(=CH2)-CH2-278????NCH3????OH?????nProp??C=CH???tBut????OMe??CH2???????CH=C-CH2???-CH2-??-CH2-C(CH3)=CH-CH2-279????N(iProp)?OMe????tBut???CN?????H???????H????CH2???????CH2-N-CH2??S??????-(CH2)4-280????NCH3????OMe????H??????H??????iProp???H????CH2-CH2??CH2-N-CH2??S??????-(CH2)3-表11实施例号?O??????R2????R5???R7????R8??????R9????W????????X-Y-Z????????A????????????B281????NCH3????NH2??H????CN????tBut????H????CH2??????CH=C-CH2???-CH2-??-CH2-C(=CH2)-CH2-282????NCH3????NHMe??H????F?????tBut????H????CH2??????CH2-N-CH2?S???????-(CH2)3-283????N(cProp)?NH2??Me???Cl????iProp???H????CH2??????CH2-CH=C???-CH2-??-(CH2)3-284????S????????NHMe??H????H?????iProp???H????CH2-CH2?CH=C-CH2???S???????-(CH2)10-285????NCH3????NH2??H????H?????tBut????OMe??CH2-CH2?CH2-N-CH2?NH??????-CH2-CH(CH3)-CH2-286????N(iProp)?NH2??CN???H?????CF3????H????CH2??????CH2-N-CH2?S???????-(CH2)4-287????S????????NHMe??H????CN????tBut????H????CH2??????CH2-N-CH2?O???????-(CH2)8-288????S????????OH????H????H?????tBu?????H????CH2-CH2?CH=C-CH2???S???????-CH2-C(=CH2)-CH2-289????NEt??????NH2??H????CN????CHF2???H????CH2??????CH2-N-CH2?-CH2-??-(CH2)3-290????NCH3????NH2??Me???H?????iProp???H????CH2??????CH2-CH=C???S???????-(CH2)3-291????N(iProp)?NH2??F????CN????tBut????H????CH2-CH2?CH2-N-CH2?S???????-(CH2)4-292????S????????NH2??OMe??Me????tBut????H????CH2??????CH2-N-CH2?S???????-(CH2)10-293????NCH3????NHMe??H????CN????tBut????F????CH2-CH2?CH2-N-CH2?NH??????-CH2-CH(CH3)-CH2-294????NCH3????NH2??H????C=CH??tBut????H????CH2-CH2?CH=C-CH2??-CH2-???-CH2-C(CH3)=CH-CH2-295????N(iProp)?NH2??H????Cl????CF3????Me???CH2??????CH2-N-CH2?S???????-(CH2)5-296????NEt????NHMe??H????CN????tBut?????Me????CH2-CH2?CH2-CH=C??-CH2-??-CH2-C(=CH2)-CH2-297????S??????OH????H????C=CH??iProp????Me????CH2??????CH2-CH=C???S??????-(CH2)8-298????NCH3???OH????Cl???H?????iProp????H?????CH2??????CH2-N-CH2?S??????-(CH2)3-表12实施例号?O??????R2?????R5????R6??????R8?????R9????W????????X-Y-Z?????????A?????????B299????NCH3????NH2???H????tBut????tBut????H????CH2??????CH2-N-CH2??S??????-(CH2)3-300????S????????OH?????H????tBut????Ph??????H????CH2??????CH2-N-CH2??S??????-CH2-C(=CH2)-CH2-301????N(iProp)?NHMe???H????tBut?1-Pyrrolyl?H????CH2??????CH2-N-CH2??NH?????-CH2-CH=CH-CH2-302????NCH3????NH2???H????nPropyl?tBut????H????CH2-CH2?CH=C-CH2???-CH2-??-CH2-CH(CH3)-CH2-303????NCH3????NHMe???H????CF3????tBut????H????CH2??????CH2-N-CH2??S??????-(CH2)3-304????N(cProp)?NH2???H????2-Napht?tBut????H????CH2-CH2?CH=C-CH2???-CH2-??-(CH2)3-305????S????????NHMe???H????tBut????H???????H????CH2-CH2?CH2-CH=C????S??????-(CH2)8-306????NCH3????NH2???H????iProp???CHF2???H????CH2??????CH2-N-CH2??NH?????-CH2-C(=CH2)-CH2-307????N(iProp)?NH2???OMe??H???????CF3????H????CH2??????CH2-N-CH2??S??????-(CH2)4-308????NOH??????NHMe???H????tBut????H???????F????CH2-CH2?CH2-CH=C????O??????-(CH2)3-309????NCH3????OH?????H????iProp???H???????Me???CH2??????CH=C-CH2????S??????-CH2-C(CH3)=CH-CH2-310????NEt??????NH2???CN???tBut????H???????H????CH2??????CH2-N-CH2?-CH2-??-(CH2)3-311????NCH3????NH2???H????H???????CF3????Me???CH2??????CH2-N-CH2??S??????-(CH2)3-312????S????????NHMe???H?1-Pyrrolyl?H???????H????CH2-CH2?CH2-N-CH2??S??????-(CH2)10-313????NCH3????OH?????H????CF3????tBut????H????CH2??????CH=C-CH2????NH?????-CH2-C(=CH2)-CH2-314????NEt??????NH2???Me????tBut????nProp????H????CH2-CH2??CH2-CH=C???-CH2-?-CH2-CH(CH3)CH2-315????NCH3????NH2???Me????tBut????H????????H????CH2???????CH2-N-CH2??S??????-(CH2)5-316????S????????NH2???H?????tBut????tBut?????H????CH2???????CH=C-CH2???-CH2-???-CH2-CH(CH3)-CH2-317????N(iProp)?NH2???Me????CF3????tBut?????H????CH2-CH2??CH2-CH=C????S??????-(CH2)4-318????NCH3????OH?????H?????nProp???tBut?????H????CH2???????CH2-N-CH2??S??????-(CH2)3-表13实施例号???R1???R2????????R3???R6????R7????R8????R9????R10????W????????????X-Y-Z?????????B319????????H????Br????????H????H????tBut???H?????Me?????H????CH2???????CH2-N-CH2??-(CH2)4-320????????H????I?????????H????H????tBut???H?????Ph?????H????CH2-CH2??CH=C-CH2????-(CH2)4-321????????H????Ph????????H????H????tBut???H?1-Pyrrolyl?H????CH2???????CH=C-CH2????-(CH2)4-322????????H?p(iProp)-Ph??H????H????iProp??H????2-Napht?H????CH2-CH2??CH2-CH=C????-(CH2)4-323????????H?pAcetyt-Ph???H????H????Et?????H????tBut????H????CH2???????CH2-N-CH2??-(CH2)3-324????????H????pBr-Ph????H????H????CHF2??H?????H??????H????CH2???????CH2-CH=C????-(CH2)4-325????????H????pI-Ph?????H????OMe??CF3???H?????H??????H????CH2???????CH=C-CH2????-(CH2)4-326????????H????iProp?????H????H????CF3???H????tBut????H????CH2-CH2??CH2-N-CH2??-(CH2)4-327????????H????tBut??????H????H????iProp??H?????H??????H????CH2???????CH2-N-CH2??-(CH2)4-328????????H????CN????????H????H????H??????CN???tBut????H????CH2-CH2??CH2-N-CH2??-(CH2)3-329????????H????COOEt?????H????H????H??????F????tBut????H????CH2-CH2??CH2-CH=C????-(CH2)4-330????????H????OPh???????H????H????H??????Cl???iProp???H????CH2-CH2??CH2-N-CH2??-(CH2)4-331????????Me???Br????????H????H????tBut???H?????H?????OMe???CH2???????CH2-CH=C????-(CH2)4-332????????CN???I?????????H????H????iProp??H?????H??????H????CH2???????CH2-N-CH2??-(CH2)4-333????????Me???Ph????????H????H????CHF2??H????tBut????H????CH2-CH2??CH=C-CH2????-(CH2)3-334????F???p(iProp)-Ph?H???OMe???tBut????H?????Cl3????H????CH2-CH2??CH2-N-CH2??-(CH2)4-335????Me???pAcetyt-Ph?H????H????CF3????H?????tBut????H????CH2???????CH2-N-CH2??-(CH2)5-336????H????pBr-Ph?????Me???H????nProp???CN????tBut????H????CH2???????CH2-N-CH2??-(CH2)4-337????H????pI-Ph??????F????H????CF3????CN????iProp???H????CH2???????CH=C-CH2????-(CH2)4-338????H????iProp??????Me???H????Ph??????C=CH??tBut????H????CH2-CH2??CH2-N-CH2??-(CH2)4-339????H????tBut???????CN???H????tBut????CN????H???????H????CH2???????CH2-CH=C????-(CH2)4-340????H????CN?????????Me???H????tBut????CN????CF3???OMe???CH2-CH2??CH2-N-CH2??-(CH2)5-341????H????COOEt??????Me???H????nProp???F?????tBut????H????CH2???????CH2-N-CH2??-(CH2)4-342????H????OPh????????F????H????Ph??????CN????tBut????Me???CH2???????CH2-CH=C????-(CH2)3-343????Cl???F??????????H????H????tBut????F?????H???????H????CH2-CH2??CH2-N-CH2??-(CH2)4-344????H????Br?????????H????H????tBut????H?????Me??????H????CH2???????CH2-N-CH2??-CH2-C(=CH2)-CH2-345????H????I??????????H????H????tBut????H?????Ph??????H????CH2???????CH2-CH=C????-CH2-C(=CH2)-CH2346????H????Ph?????????H????H????tBut????H?1-Pyrrolyl??H????CH2-CH2??CH=C-CH2????-CH2-C(=CH2)-CH2-347????H????NEt2??????H????H????iProp???H???2-Napht???H????CH2-CH2??CH2-CH=C????-CH2-C(CH3)=CH-CH2-348????H????pAcetyt-Ph?H????H????Et??????H?????tBut????H????CH2???????CH2-N-CH2??-CH2-CH(CH3)-CH2-349????H????pBr-Ph?????H????H????CHF2???H?????H???????H????CH2-CH2??CH=C-CH2????-CH2-C(=CH2)-CH2-350????H????pI-Ph??????H????F????CF3????H?????H???????H????CH2???????CH2-CH=C????-CH2-CH(CH3)-CH2-351????H????iProp??????H????H????CF3????H?????tBut????H????CH2-CH2??CH2-N-CH2??-CH2-C(=CH2)-CH2-352????H????tBut???????H????H????iProp???H?????H???????H????CH2???????CH2-N-CH2??-CH2-C(=CH2)-CH2-353????H????CN?????????H????H????H???????CN????tBut????H????CH2???????CH2-N-CH2??-CH2-CH=CH-CH2-354????H????COOEt??????H????H????H???????F?????tBut????H????CH2-CH2??CH2-CH=C????-CH2-C(CH3)=CH-CH2-355????H?????OPh???????H?????H?????H??????Cl???iProp???H????CH2-CH2??CH2-N-CH2??-CH2-C(=CH2)-CH2-356????Me????Br????????H?????H????tBut????H????H??????OMe???CH2???????CH2-CH=C????-CH2-CH(CH3)-CH2-357????Me????I?????????H?????H????iProp???H????H??????OMe???CH2???????CH2-N-CH2??-CH2-CH(CH3)-CH2-358????Cl????Ph????????H?????H????CHF2???H????tBut????H????CH2-CH2??CH2-CH=C????-CH2-C(=CH2)-CH2359????CN??p(iProp)-Ph?H?????OMe??tBut????H????CF3????H????CH2???????CH2-N-CH2??-CH2-CH=CH-CH2-360????F???pAcetyt-Ph??H?????OMe??CF3????H????tBut????H????CH2???????CH2-N-CH2??-CH2-C(=CH2)-CH2-361????Me???pBr-Ph?????H?????H????nProp???CN???tBut????H????CH2-CH2??CH2-N-CH2??-CH2-C(CH3)=CH-CH2-362????H????PI-Ph??????CN????H????CF3????CN???iProp???H????CH2???????CH2-CH=C????-CH2-CH(CH3)-CH2-363????H????iProp??????Cl????H????Ph??????C=CH?tBut????H????CH2-CH2??CH2-N-CH2??-CH2-CH(CH3)-CH2-364????H????tBut???????F?????H????tBut????CN???H???????H????CH2???????CH2-CH=C????-CH2-C(CH3)=CH-CH2-365????H????CN?????????Cl????H????tBut????CN???CF3???OMe???CH2-CH2??CH2-N-CH2??-CH2-CH=CH-CH2-366????H????COOEt??????CN????H????nProp???F????tBut????H????CH2???????CH2-N-CH2??-CH2-CH(CH3)-CH2-367????H????OPh????????Cl????H????Ph??????CN???tBut????Me???CH2-CH2??CH2-CH=C????-CH2-C(CH3)-CH-CH2-368????H????F??????????Me????H????tBut????F????H???????H????CH2???????CH2-N-CH2??-CH2-C(=CH2)-CH2-表14实施例号???R1???R2???????R3????R7?????R9??????R10???W???????????X-Y-Z??????????B369????????H????Br???????H????tBut????Ph??????H????CH2???????CH2-N-CH2??-(CH2)4-370????????H????I????????H????tBut????2-Napht?H????CH2???????CH2-N-CH2??-(CH2)4-371????????H????Ph???????H????tBut?1-Pyrrolyl?H????CH2???????CH2-N-CH2??-CH2-C(=CH2)-CH2-372????????H?p(iProp)-Ph?H????tBut????cHex????H????CH2-CH2??CH=C-CH2????-CH2-C(CH3)-CH-CH2-373????????H??pAcetyt-Ph?H????tBut????nHex????H????CH2-CH2??CH2-N-CH2??-(CH2)4-374????????H????pBr-Ph???H????tBut????H??????OMe???CH2???????CH2-N-CH2??-CH2-CH(CH3)-CH2-375????????H????pI-Ph????H????iProp???F???????H????CH2-CH2??CH2-N-CH2??-CH2-CH=CH-CH2-376????????H????iProp????H????CH31-Pyrrolyl??H????CH2???????CH2-C=CH????-(CH2)4-377????????H????tBut?????H????OMe?1-Pyrrolyl??H????CH2???????CH2-N-CH2??-CH2-CH(CH3)-CH2-378????????H????CN???????H????tBut????H??????CH3??CH2-CH2??CH=C-CH2????-CH2-CH(CH3)-CH2-379????????H????COOEt????H????tBut????tBut???OMe???CH2-CH2??CH2-N-CH2??-(CH2)4-380????????H????OPh??????H????tBut????iProp???H????CH2???????-CH2-N-CH2?-CH2-C(=CH2)-CH2-381????????Me???Br???????H????Ph??????tBut????Cl???CH2???????CH2-C=CH????-CH2-C(CH3)=CH-CH2-382????????CN???I????????H????2-Napht?tBut????Me???CH2-CH2??CH=C-CH2????-(CH2)4-383????????Me???Ph???????H????tBut????CF3????Me???CH2???????CH2-N-CH2??-CH2-C(=CH2)-CH2-表15实施例号R1???R2???????R3????R7????R8????R9????R10????W???????????X-Y-Z?????????B????384?????H????Br???????H????tBut???H????tBut????H????CH2???????CH2-N-CH2?-(CH2)4-385?????H????I????????H????tBut???CN????H??????H????CH2???????CH2-N-CH2?-(CH2)4-386?????H????Ph???????H????tBut???H?????Cl?????H????CH2???????CH2-N-CH2?-CH2-C(=CH2)-CH2-387?????H?p(iProp)-Ph?H?????H?????CN???tBu?????H????CH2-CH2-?CH2-CH=C???-CH2-CH(CH3)-CH2-388?????H?pAcetyt-Ph??H????CF3???H????tBut????H????CH2???????CH2-N-CH2?-(CH2)4-389?????H????pBr-Ph???H????nProp??H????iProp???H????CH2-CH2??CH=C-CH2???-CH2-CH(CH3)-CH2-390?????H????pI-Ph????H????H??????H????iProp??OMe???CH2-CH2??CH2-CH=C???-(CH2)4-391?????H????iProp????H????tBut???H????tBut????H????CH2???????CH2-N-CH2?-CH2-C(=CH2)-CH2-392?????H????tBut?????H????tBut???CN????H??????H????CH2-CH2??CH2-N-CH2?-(CH2)4-393?????H????CN???????H????tBut???H?????Cl?????H????CH2???????CH2-N-CH2?-(CH2)3-394?????H????COOEt????H????H??????CN???tBu?????H????CH2???????CH=C-CH2???-CH2-C(CH3)=CH-CH2-395?????H????OPh??????H????CF3???H????tBut????H????CH2-CH2??CH2-N-CH2?-CH2-C(=CH2)-CH2-396?????Me???Br???????H????nProp??H????iProp???H????CH2???????CH2-N-CH2?-(CH2)4-397?????CN???I????????H????H??????H????iProp??OMe???CH2???????CH2-N-CH2?-(CH2)4-398????Me?????Ph??????H?????nProp??CN????tBut??H????CH2-CH2??CH2-N-CH2?-(CH2)4-399????F??p(iProp)-Ph?H?????CF3???CN????iProp?H????CH2-CH2??CH2-CH=C???-(CH2)4-400????Me?pAcetyt-Ph??H?????Ph?????C=CH??tBut??H????CH2???????CH2-N-CH2?-CH2-CH(CH3)-CH2-401????H????pBr-Ph????Me????tBut???CN????tBut??H????CH2-CH2??CH=C-CH2???-CH2-CH(CH3)-CH2-402????H????pI-Ph?????F?????tBut???H?????nProp?H????CH2???????CH2-N-CH2?-(CH2)3-403????H????iProp?????Me????Ph?????H?????tBut??OMe??CH2???????CH2-CH=C???-(CH2)5-404????H????tBut??????CN????CF3???H?????tBut??F????CH2-CH2??CH=C-CH2???-CH2-CH(CH3)-CH2-405????H????CN????????Me????tBut???F?????H?????Me???CH2???????CH2-N-CH2?-CH2-CH=CH-CH2-406????H????COOEt?????Me????nProp??CN????tBut??Me???CH2-CH2??CH2-CH=C???-CH2-C(=CH2)-CH2-407????H??pAcetyt-Ph??F?????nProp??C=CH??tBut??H????CH2???????CH=C-CH2???-CH2-C(CH3)=CH-CH2-408????Cl???F?????????H?????tBut???CN????H?????Me???CH2???????CH2-N-CH2?-(CH2)4-表16实施例号???R1???R2????????R3???R6?????R8????R9????R10????W?????????X-Y-Z?????????B

        409????H????Br????????H????OMe????H????tBut????H????CH2??????CH2-N-CH2?-(CH2)4-

        410????H????I?????????H????OMe????H????CF3????H????CH2??????CH2-N-CH2?-(CH2)4-

        411????H????Ph????????H????OMe????H????tBut????H????CH2-CH2?CH2-N-CH2?-CH2-C(=CH2)-CH2-

        412????H??p(iProp)-Ph?H????H??????CN???tBut????H????CH2??????CH=C-CH2???-CH2-C(CH3)=CH-CH2-

        413????H??pAcetyt-Ph??H????H??????F????tBut????H????CH2??????CH2-N-CH2?-(CH2)4-

        414????H????pBr-Ph????H????Me?????Cl???iProp???H????CH2??????CH2-CH=C???-CH2-C(=CH2)-CH2-

        415????H????pI-Ph?????H????H??????H????iProp???H????CH2-CH2?CH=C-CH2???-(CH2)4-

        416????H????iProp?????H????H??????H????tBut???OMe???CH2-CH2?CH2-N-CH2?-CH2-C(=CH2)-CH2-

        417????H????tBut??????H????CN?????H????CF3????H????CH2-CH2?CH2-N-CH2?-(CH2)4-

        418????H????CN????????H????H??????CN???H??????OMe???CH2??????CH2-N-CH2?-CH2-CH(CH3)-CH2-

        419????H????COOEt?????H????H??????H????tBu?????F????CH2??????CH2-CH=C???-CH2-C(CH3)=CH-CH2-

        420????H????OPh???????H????H??????CN???tBut????H????CH2-CH2?CH2-N-CH2?-(CH2)3-

        421????Me???Br????????H????Mo?????H????iProp???H????CH2??????CH2-N-CH2?-(CH2)4-

        422????CN???I?????????H????OMe????H????iProp???H????CH2-CH2?CH2-N-CH2?-CH2-CH(CH3)-CH2-

        423????Me???Ph????????H????OMe????CN???tBut????H????CH2?????CH=C-CH2????-(CH2)4-424????F???p(iProp)-Ph?H?????OMe???Me????tBut????H????CH2???????CH2-N-CH2??-(CH2)4-425????Me??pAcetyt-Ph??H?????H?????CN????tBut????H????CH2-CH2??CH2-N-CH2??-CH2-CH=CH-CH2-426????H????PBr-Ph?????Me????Me????H?????tBut????H????CH2???????CH2-CH=C????-CH2-C(=CH2)-CH2-427????H????pI-Ph??????F?????H?????Cl????CF3????Me???CH2-CH2??CH2-N-CH2??-(CH2)4-428????H????iProp??????Me????OMe???CN????tBut????Me???CH2???????CH=C-CH2????-CH2-CH(CH3)-CH2-429????H????tBut???????CN????Me????Me????iProp???Me???CH2???????CH2-CH=C????-(CH2)4-表17实施例号???R1???R2???????R3???R6????R7??????R9???????R10???W??????????X-Y-Z??????????B

        430????H????Br???????H????H????tBut????tBut??????H????CH2???????CH2-N-CH2??-(CH2)4-

        431????H????I????????H????H????tBut????Ph????????H????CH2???????CH2-N-CH2??-(CH2)4-

        432????H????Ph???????H????H????tBut???1-Pyrrolyl?H????CH2???????CH2-N-CH2??-CH2-C(=CH2)-CH2-

        433????H?p(iProp)-Ph?H????H????nPropyt?tBut??????H????CH2-CH2??CH2-CH=C????-CH2-C(CH3)=CH-CH2-

        434????H?pAcetyt-Ph??H????H????CF3????tBut??????H????CH2???????CH2-N-CH2??-(CH2)4-

        435????H????pBr-Ph???H????H????2-Napht?tBut??????H????CH2-CH2??CH=C-CH2????-CH2-C(=CH2)-CH2-

        436????H????pI-Ph????H????OMe??tBut????H?????????H????CH2-CH2??CH2-CH=C????-(CH2)4-

        437????H????iProp????H????OMe??iProp???H?????????H????CH2???????CH2-N-CH2??-CH2-C(=CH2)-CH2-

        438????H????tBut?????H????OMe??H???????CF3??????H????CH2-CH2??CH2-N-CH2??-(CH2)4-

        439????H????CN???????H????H????tBut????H?????????H????CH2???????CH2-N-CH2??-CH2-CH(CH3)-CH2-

        440????H????COOEt????H????H????iProp???H?????????Me???CH2???????CH=C-CH2????-CH2-C(CH3)=CH-CH2-

        441????H????OPh??????H????CN???tBut????H?????????H????CH2-CH2??CH2-N-CH2??-(CH2)3-

        442????Me???Br???????H????H????H???????CF3??????Me???CH2???????CH2-N-CH2??-(CH2)4-

        443????CN???I????????H????H????nProp???tBut??????H????CH2???????CH2-N-CH2??-CH2-CH(CH3)-CH2-

        444????Me???Ph???????H????OMe??tBut????iProp?????H????CH2-CH2??CH2-N-CH2??-(CH2)4-445????F????p(iProp)-Ph??H?????OMe???CF3????tBut????H?????CH2-CH2??CH=C-CH2???-(CH2)4-446????ME???pAcetyt-Ph???H?????Me????tBut????nProp???H?????CH2???????CH2-CH=C???-CH2-CH=CH-CH2-447????H????pBr-Ph???????Me????Me????tBut????H???????H?????CH2-CH2??CH2-N-CH2?-CH2-C(=CH2)-CH2-448????H????pI-Ph????????F?????H?????tBut????tBut????H?????CH2???????CH=C-CH2???-(CH2)3-449????H????iProp????????Me????Me????CF3?????tBut????H?????CH2???????CH2-CH=C???-CH2-CH(CH3)-CH2-

        药物制剂实施例

        A)片剂

        以常规方式在制片机中压缩以下组合物之片粒:40毫克????实施例1之物质120毫克?????玉米粉13.5毫克????明胶粉45毫克??????乳糖2.25毫克????Aerosil(半微球细密分布之化学纯二氧化硅)6.75毫克????马铃薯粉(6%膏)

        B)包衣片剂20毫克????实施例4之物质60毫克????片心组合物70毫克????糖包衣组合物

        片心组合物包括9份玉米粉,3份乳糖及1份乙烯吡咯烷酮/乙酸乙烯酯60∶40之共聚物。糖包衣组合物包括5份蔗糖,2份玉米粉,2份碳酸钙及1份滑石粉。以此方式产生之包衣片粒因而具备肠溶包衣。

        生物调查-受体结合研究

        1)D3结合分析

        使用无性繁殖之CCL?1,3小鼠纤维母细胞作为结合研究,其表达人体D3受体且可得自Res.生化机构(Biochemicals?Internat.)万史翠莫路(One?Strathmore?Rd.),那提克(Natick),MA01760-2418?USA。

        制备细胞

        以10%胎牛血清(GIBCO编号041-32400N):100U/ml青霉素及0.2%链霉素(GIBCO?BRL,盖德斯堡)(Gaithersburg,MD,USA)于RPMI-1640中成长D3表达之细胞。48小时后,以PBS清洗细胞并以含0.05%蛋白酶之PBS培养5分钟。以介质中和后,以300克离心收集细胞。关于细胞溶解,以溶解缓冲剂(5mM?tris-HCl,pH?7.4,含10%甘油)简单清洗该沉淀物,其后在4℃于浓度为107细胞/毫升之溶解缓冲剂培养30分钟。以200克离心收集细胞10分钟并将该沉淀物保存于液态氮中。

        结合分析

        关于D3受体结合分析,将膜分散于培养缓冲剂(50mM?Tris-HCl,pH?7.4,含120mM?NaCl,5mM?KCl,2mM?CaCl2,2mM?MgCl2,10μM喹啉醇,0.1%抗坏血酸及0.1%BSA),浓度为约106细胞/250μl分析混合物,并以0.1nM125I-舒必利在有无测试物质存在下于30℃培养。以10-6M螺哌隆测定非特定结合。

        60分钟后,经由史格壮(Skatron)细胞收集器(史格壮,莱耳(Lier),挪威)中之GF/B玻璃纤维过滤器(怀特曼(Whatman),英国)过滤,分离游离态及结合之辐射配位体,并以pH7.4之冰冷tris-HCl缓冲剂清洗过滤器。使用派克(Packard)2000CA液体闪烁计数器定量过滤器上收集之辐射性。

        使用LIGAND程序以非线性回归分析测定Ki值。

        2)D2结合分析

        细胞培养

        于具10%胎牛血清白蛋白之25mM?HEPES及具Glutamax?ITM之RPMI?1640中培养具稳定表达人体多巴胺D2A受体之HEK-293细胞。所有介质每毫升含100单位青霉素及100μg/ml链霉素。将该细胞在具5%CO2湿气大气中维持于37℃。

        在室温以胰蛋白酶化(0.05%胰蛋白溶液)制备用于结合研究之细胞3-5分钟。然后以250克离心该细胞10分钟,并在4℃以溶解缓冲剂(5mM?tris-HCl,10%甘油,pH7.4)处理30分钟。以250克离心10分钟后,将残余物保存于-20℃直到使用。

        受体结合分析

        1)具125I-螺哌隆(81?TBq/mmol,杜邦公司(Du?Pont?deNemours),德瑞克(Dreieich))之多巴胺D3受体“低亲和力态”

        该混合物(1毫升)包括培养缓冲剂(50mM?tris,120mM?NaCl,5mM?KCl,2mM?MgCl2及2mM?CaCl2,pH7.4,含HCl)中之1×105个细胞及0.1nM?125I-螺哌隆(总结合)或添加1μM氟哌啶醇(非特定结合)或测试物质。

        在25℃培养60分钟后,经由史格壮细胞收集器(辛瑟(Zinsser),法兰克福)中之GF/B玻璃纤维过滤器(怀特曼,英国)过滤该混合物,并以冰冷之50mM?tris-HCl缓冲剂,pH?7.4清洗过滤器。使用派克(Packard)2200?CA闪烁计数器定量过滤器上收集之辐射性。

        如a)般评估。

        使用配位体程序以非线性回归分析或使用承恩及普鲁索夫(Chengand?Prusoff)方程式转换IC50值测定Ki值。

        在这些分析中,根据本发明之化合物在D3受体上显现非常良好之亲和力,及对于D3受体之高选择性。

        以相似的方式制得下列化合物:??????????????????????????????????????Ph=苯基

        上述未以熔点为特征之化合物具如下之NMR光谱(d6-DMSO):实施例号476?????????1,8-2,1(m,4H);2,6-2,7(m,4H);2,8(t,2H);3,2

        ????????(t,2H);?3,5-3,7(b,2H);3,7-3,9(b,2H);4,5

        ????????(d,2H);5,1(t,1H);5,2(s,1H);6,1(d,1H);6,2

        ????????(m,2H);7,3(m,5H);7,7(m,2H);7,8(d,1H)477?????????1,8-1,9(m,4H);2,5-2,6(m,4H);2,7(t,2H);3,0

        ????????(t,2H);3,3(s,3H);3,5-3,8(b,4H);4,2(s,2H);

        ????????4,5(d,2H);5,1(t,1H);5,2(s,1H);6,2(m,2H);

        ????????7,3-7,4(m,5H);7,7(m,2H)481?草酸盐??2,1(b,4H);3,2-3,4(m,8H);3,6(s,3H);3,7

        ????????(b,2H);6,6-6,8(m,3H);7,2(t,1H);7,6(m,3H);

        ????????7,7(m,2H)484?草酸盐??2,0(b,2H);2,8-3,0(b,4H);3,4-3,5(m,4H);3,6-

        ????????3,7(b,2H);3,9(s,2H);5,3(d,2H);6,1(d,1H);

        ????????6,5-6,8(m,3H);7,21(t,1H);7,9(d,1H);491?草酸盐??2,0-2,3(b,4H);3,0-3,4(b,8H);3,6(s,3H);3,9

        ????????(b,2H);4,1(b,2H);7,1-7,3(b,1H);7,5(m,3H);

        ????????7,6(m,2H);8,6(s,1H);492?????????1,7-1,9(m,4H);2,6(b,2H);2,8(b,2H);3,1

        ????????(t,2H);3,6-3,9(b,4H);6,1(d,1H);7,0(d,1H);

        ????????7,8(d,1H);8,5(s,1H);493?草酸盐??1,9-2,1(b,4H);2,7(s,3H);2,8(t,2H);3,0-3,3

        ????????(b,6H);3,3(s,3H);3,4(t,2H);3,7(b,2H);6,3

        ????????(b,1H);6,4-6,5(m,3H);7,0(m,1H);495?富马酸盐1,6-1,8(b,4H);2,6(m,2H);2,7(t,2H);3,2

        ????????(s,3H);3,3-3,5(m,4H);5,9(s,2H);6,2-6,5

        ????????(m,3H);7,0(m,1H);497?富马酸盐1,6-1,8(m,2H);1,8-2,0(b,2H);2,5-2,7(b,4H);

        ????????2,8-2,9(m,4H);3,2(s,3H);3,7-3,9(m,4H);5,9

        ????????(b,2H);6,5(s,2H);7,4(d,1H);498?富马酸盐1,3(s,9H);1,8-2,1(b,4H);2,7-3,0(b,6H);3,3

        ????????(s,3H);3,5-3,8(b,6H);6,1(b,2H);6,6(s,2H);

        ????????6,7(s,1H);499?盐酸盐??1,3(s,9H);1,9(b2H);2,2(s,2H);2,5(b,2H);

        ????????2,7(b,2H);3,1(s,2H);3,4(s,3H);3,7(s,2H);

        ????????3,8(s,3H);3,9(s,3H);5,0(d,2H);6,5(s,1H);

        ????????6,9(d,1H);7,5(d,1H);7,7(s,1H);11,3(b,1H);500?富马酸盐1,3(s,9H);1,7-1,9(b,4H);2,5-2,7(b,4H);2,8-

        ????????2,9(b,2H);3,1(t,2H);3,6-3,7(b,2H);3,8-4,0

        ????????(b,2H);6,1(d,1H);6,6(s,2H);6,9(d,1H);7,8

        ????????(d,1H)501?????????1,3(s,9H);1,8-2,0(m,4H);2,6(m,4H);2,8

        ????????(b,2H);3,1(t,2H);3,4(s,3H);3,5(b,2H);3,9-

        ????????4,1(b,2H);4,4(b,2H);6,5(s,1H)502?富马酸盐1,3(s,9H);1,8-1,9(b,2H);2,5-2,6(b,2H);2,7

        ????????(b,2H);3,1(s,2H);3,6-3,7(b,2H);3,7-4,0

        ????????(m,4H);5,1(s,1H);5,2(s,1H);6,1(d,1H);6,6

        ????????(s,2H);6,9(d,1H);7,8(d,1H)503?富马酸盐1,3(s,9H);1,8-1,9(b,2H);2,5-2,6(b,2H);2,7-

        ????????2,8(b,2H);3,2(s,2H);3,6(s,3H);3,6-3,7

        ????????(b,2H);3,7(s,2H);3,8-4,0(b,2H);5,0(s,1H);

        ????????5,1(s,1H);6,6(s,2H);6,9(d,1H);7,6(m,3H);

        ????????7,7(m,2H)504?富马酸盐1,3(s,9H);1,8-1,9(b,2H);2,5(b,2H);2,6-2,7

        ????????(b,2H);3,1(s,2H);3,3(s,3H);3,4(s,2H);3,5-

        ????????3,7(b,2H);3,8-4,0(b,2H);4,9(d,2H);6,0

        ????????(s,2H);6,6(s,2H);6,9(d,1H)505?富马酸盐1,3(s,9H);1,7-1,9(b,4H);2,5-2,7(b,4H);2,8

        ????????(t,2H);3,1(t,2H);3,4-4,0(b,4H);6,1(d,1H);

        ????????6,5(d,1H);6,6(s,2H);7,8(d,1H);8,2(d,1H)506?????????1,4(s,9H);1,8(m,2H);2,1-2,2(b,2H);2,6

        ????????(m,4H);2,7(t,2H);3,0(t,2H);3,4(s,3H);3,5-

        ????????4,0(b,4H);4,6(b,2H);6,2(d,1H);8,2(d,1H)507?????????0,9(t,3H);1,3(s,9H);1,4(m,2H);1,7(m,2H);

        ????????2,1(b,2H);2,6(t,2H);2,7(t,2H);2,8(t,2H);

        ????????3,3(s,2H);3,6-3,7(b,2H);3,8(s,2H);3,9-4,0

        ????????(b,2H);5,1(s,1H);5,2(s,1H);6,1(s,1H);6,2

        ????????(d,1H);7,8(d,1H)508?????????0,9(t,3H);1,3(s,9H);1,4(m,2H);1,7(m,2H);

        ????????1,9(m,2H);2,6(m,4H);2,7(t,2H);3,1(d,3H);

        ????????3,2(s,2H);3,3(s,3H);3,6(m,1H);3,7(s,2H);

        ????????3,6-3,8(b,4H);5,0(d,2H);6,0(s,1H)509?二盐酸盐0,9(t,3H);1,3(m,2H);1,4(s,9H);1,7(m,2H);

        ????????2,4-2,5(b,2H);2,9(t,2H);3,2-3,4(b,4H);3,5

        ????????(s,3H);3,7-3,8(b,2H);3,9(s,2H);3,9-4,2

        ????????(b,2H);4,1(s,2H);5,4(s,2H);6,9(s,1H);8,5

        ????????(s,2H);11,7(b,1H);14,0(b,1H)510?????????1,3(s,9H);2,0-2,1(b,2H);2,7(t,2H);2,8

        ????????(t,2H);3,3(s,2H);3,5-3,8(b,2H);3,8(s,2H);

        ????????3,8-4,1(b,2H);5,1(s,1H);5,2(s,1H);6,2

        ????????(m,2H);7,8(d,1H);8,2(d,1H)511?????????1,3(s,18H);1,6-1,9(b,4H);2,4(b,2H);2,7

        ????????(b,2H);2,8(t,2H);3,2(s,3H);3,7(m,4H);5,8

        ????????(s,1H);512?????????1,3(s,18H);1,7-1,8(m,4H);2,5(b,2H);2,7

        ????????(b,2H);3,0(t,2H);3,7-3,8(m,4H);6,0(d,1H);

        ????????7,8(d,1H);513?????????1,6-2,1(m,17H);2,7(s,2H);3,1(s,2H);3,3-3,6

        ????????(b,6H);3,4(s,3H);3,8-3,9(b,2H);4,8(b,2H);

        ????????6,0(b,2H);6,8(s,1H);514?????????1,6-2,0(m,17H);2,5(s,2H);2,6(s,2H);3,0

        ????????(s,2H);3,5-3,9(b,6H);5,0(d,2H);6,0(d,1H);

        ????????6,8(d,1H);7,8(d,1H);515?????????1,7-2,0(m,19H);2,5(b,2H);2,7(s,2H);3,0

        ????????(t,2H);3,5-3,8(b,4H);6,0(d,1H);6,8(d,1H);

        ????????7,8(d,1H);517?二盐酸盐1,4(s,9H);2,4-2,5(b,2H);3,3-3,6(b,4H);3,5

        ????????(s,3H);3,7-3,8(b,2H);3,8-3,9(b,2H);3,9-4,2

        ????????(b,4H);5,4(s,2H);7,1(d,1H);8,3(d,1H);8,5

        ????????(s,2H);11,7(b,1H);14,5(b,1H)518?????????1,3(s,9H);1,8-2,0(b,2H);2,6(t,2H);2,7

        ????????(t,2H);3,0(d,3H);3,2(s,2H);3,3(s,3H);3,6

        ????????(s,2H);3,6-3,9(b,5H);5,0(d,2H);6,2(s,1H);

        ????????6,3(m,2H);7,8(m,2H)519?????????1,4(s,9H);1,9(m,2H);2,6(t,2H);2,7(t,2H);

        ????????3,0(d,3H);3,2(s,2H);3,3(s,3H);3,7(s,2H);

        ????????3,6-3,9(b,5H);5,0(d,2H);6,1(s,1H);6,3

        ????????(m,2H);7,6(m,2H)527?盐酸盐??1,2-1,5(b,10H);1,5-1,8(b,4H);3,1(m,4H);3,5

        ????????(m,4H);3,8-4,0(b,4H);6,8(t,1H);6,9(b,3H);

        ????????7,1(t,1H);10,5(b,1H);526?草酸盐??1,3(s,9H);1,9-2,1(b,2H);2,7-3,0(b,4H);3,4

        ????????(b,2H);3,6(s,3H);3,6-3,8(b,2H);3,8(s,2H);

        ????????3,9-4,1(b,2H);5,2(d,2H);6,2(m,2H);6,4

        ????????(s,1H);7,6(m,3H);7,7(m,4H)528?草酸盐??0,9(t,3H);1,3(s,9H);1,4(m,2H);1,6(m,2H);

        ????????1,9-2,2(b,4H);2,5(m,2H);3,0-3,2(b,4H);3,2-

        ????????3,4(b,4H);3,5-3,7(b,2H);3,9-4,1(b,2H);6,1

        ????????(d,1H);6,4(s,1H);7,8(d,1H)529?二盐酸盐0,9(t,3H);1,3(m,2H);1,4(s,9H);1,7(m,2H);

        ????????2,2(b,3H);3,0(t,2H);3,2(b,5H);3,5(s,3H)

        ????????3,5-4,2(b,7H);4,5-4,7(b,1H);7,0(d,1H);S,6

        ????????(s,2H);11,7(b,1H);14,2(b,1H)530?草酸盐??1,3(s,9H);1,9-2,1(b,2H);2,7-3,0(b,4H);2,3-

        ????????2,4(b,2H);2,6-4,1(b,4H);3,9(s,2H);5,2

        ????????(s,1H);5,3(s,1H);6,1(d,1H);6,2(m,2H);6,4

        ????????(s,1H);7,7(m,2H);7,8(d,1H)531?????????1,3(s,9H);1,9(m,2H);2,6(t,2H);2,7(t,2H);

        ????????3,2(s,2H);3,3(s,3H);3,7(s,2H);3,6-3,9

        ????????(b,4H);4,3(s,2H);5,0(d,2H);6,2(s,1H);6,3

        ????????(m,2H);7,8(m,2H)533?????????1,3(s,9H);2,1(m,2H);2,7(m,2H);2,9(m,2H);

        ????????3,3(s,2H);3,6-3,8(b,2H);3,8(s,2H);3,9-4,1

        ????????(b,2H);5,1(s,1H);5,2(s,1H);6,1(s,1H);6,2

        ????????(d,1H);6,3(m,2H);7,5(m,2H);7,8(d,1H)532?????????1,3(s,9H);1,9(m,2H);2,6(t,2H);2,7(t,2H);

        ????????3,2(s,2H);3,3(s,3H);3,7(s,2H);3,6-3,6

        ????????(b,4H);4,3(s,2H);5,0(s,2H);6,1(s,1H);6,3

        ????????(m,2H);7,6(m,2H)539?盐酸盐??2,2-2,3(b,2H);3,0-3,2(b,2H);3,5-4,0(b,8H),

        ????????4,2(s,2H);5,5(d,2H);6,2(d,1H);6,9-7,0

        ????????(m,3H);7,0(t,1H);7,4(m,1H);7,9(d,1H);10,9

        ????????(b,1H);540?盐酸盐??2,4(b,2H);3,2(b,4H);3,4(s,3H);3,5(m,2H);

        ????????3,7(b,4H);4,0(s,2H);5,3(d,2H);6,8-7,1

        ????????(m,4H);7,2-7,4(m,3H);542?????????1,3(s,9H);1,9(m,2H);1,9-2,1(b,2H);2,6

        ????????(m,4H);2,8(b,2H);3,2(t,2H);3,5-3,7(b,2H);

        ????????3,9-4,2(b,2H);6,2(d,1H);6,5(s,1H);6,8

        ????????(d,1H)543?????????1,3(s,9H);1,9(m,2H);1,9-2,0(b,2H);2,6-2,7

        ????????(b,4H);2,8(b,2H);3,1(t,2H);3,2(s,3H);3,5-

        ????????3,6(b,2H);3,9-4,1(b,2H);6,5(s,1H);10,8

        ????????(b,1H)544?????????1,3(s,9H);1,8-2,0(b,4H);2,6(m,4H);2,7-2,8

        ????????(b,2H);3,0(m,5H);3,3(s,3H);3,5-3,6(b,2H);

        ????????3,9-4,1(b,3H);6,5(s,1H)545?盐酸盐??1,3(s,9H);2,1-2,2(b,3H);2,5-2,6(b,1H);3,1-

        ????????3,3(b,6H);3,4(s,3H);3,4-3,8(b,4H);4,0-4,1

        ????????(b,1H);4,6-4,7(b,1H);7,0(s,1H);8,6(s,2H);

        ????????11,3(b,1H)546?????????1,3(s,9H);1,9(m,2H);2,1(m,2H);2,7(m,4H);

        ????????2,9(m,2H);3,2(t,2H);3,8-3,9(b,2H);3,9-4,0

        ????????(b,2H);6,2(d,2H);6,3(m,2H);7,8(m,3H)547?????????1,3(s,9H);1,9(m,4H);2,6(m,4H);2,8(t,2H);

        ????????3,1(t,2H);3,2(s,3H);3,6-4,0(b,4H);6,2

        ????????(s,1H);6,3(m,2H);7,8(m,2H);9,2(s,1H)548?????????1,3(s,9H);1,9(m,4H);2,6(t,4H);2,8(t,2H);

        ????????3,1(t,2H);3,3(s,3H);3,5-3,9(b,4H);4,1

        ????????(s,2H);6,2(s,1H);6,3(m,2H);7,8(m,2H)549?????????1,4(s,9H);1,9(m,2H);2,0-2,1(b,2H);2,7

        ????????(m,4H);2,9(m,2H);3,2(t,2H);3,6-3,8(b,2H);

        ????????3,8-4,1(b,2H);6,1(s,1H);6,2(d,1H);6,3

        ????????(m,2H);7,6(m,2H),7,8(d,1H)550?????????1,4(s,9H);1,9(m,4H);2,6(m,4H);2,8(b,2H);

        ????????3,1(t,2H);3,2(s,3H);3,6-4,0(b,4H);6,1

        ????????(s,1H);6,3(m,2H);7,5(m,2H);10,0(b,1H)551?????????1,4(s,9H);1,9(m,4H);2,6(m,4H);2,8(b,2H);

        ????????3,1(t,2H);3,4(s,3H);3,5-4,0(b,4H);4,3

        ????????(s,2H);6,1(s,1H);6,3(m,2H);7,5(m,2H)552?????????1,3(s,9H);2,1(m,2H);2,8(m,2H);2,9(m,2H);

        ????????3,3(s,2H);3,8(s,2H);3,9(t,2H);4,1(b,2H);

        ????????5,1(s,1H);5,2(s,1H);6,2(d,1H);6,5(d,1H);

        ????????7,8(d,1H);8,2(d,1H)553?盐酸盐??1,3(s,9H);2,2-2,3(b,1H);2,5-2,7(b,1H);3,1

        ????????(s,3H);3,0-3,2(b,2H);3,5-3,7(b,3H);3,8-4,1

        ????????(m,6H);4,4-4,5(b,1H);5,4(d,2H);6,8(d,1H);

        ????????8,3(d,1H);11,2(b,1H);11,9(s,1H)554?????????1,3(s,9H);1,9(m,2H);2,6(t,2H);2,7(t,2H);

        ????????3,2(s,2H);3,4(s,3H);3,7(s,2H);3,8(m,4H);

        ????????4,4(s,2H);5,0(s,2H);6,5(d,1H);8,2(d,1H)555?????????1,3(s,18H);2,1(m,2H);2,8(t,2H);3,0(t,2H);

        ????????3,3(s,2H);3,8(s,2H);3,9(t,2H);4,1(t,2H);

        ????????5,1(s,1H);5,2(s,1H);6,2(d,1H);6,5(s,1H);

        ????????7,8(d,1H)556?????????1,3(s,18H);1,9(m,2H);2,6(t,2H);2,7(t,2H);

        ????????3,2(s,2H);3,4(s,3H);3,6(s,2H);3,9(m,4H);

        ????????4,2(s,2H);5,0(s,2H);6,5(s,1H)557?盐酸盐??1,3(d,6H);2,2(b,1H);2,6(b,1H);3,0(b,4H);

        ????????3,4(s,3H);3,5-3,7(b,4H);3,8(s,2H);4,1

        ????????(s,2H);5,4(s,2H);6,8(t,1H);6,9(s,1H);8,5

        ????????(b,2H);11,6(b,1H);559?盐酸盐??1,2(d,6H);2,1(b,4H);3,0-3,2(b,8H);3,5-4,2

        ????????(b,4H);6,1(d,1H);6,8(t,1H);6,9(b,1H);7,8

        ????????(d,1H);11,3(b,1H);561?????????1,3(s,18H);1,9(m,2H);2,0(m,2H);2,7(t,2H);

        ????????2,8(t,2H);3,0(t,2H);3,2(t,2H);3,9(t,2H);

        ????????4,0(t,2H);6,1(d,1H);6,5(s,1H);7,8(d,1H)562?????????1,3(s,18H);1,9(m,4H);2,6(m,4H);2,8(t,2H);

        ????????3,0(t,2H);3,4(s,3H);3,8(t,2H);3,9(t,2H);

        ????????4,3(s,2H);6,5(s,1H)564?草酸盐??1,3(s,9H);2,0(b,2H);2,2(b,2H);3,1-3,4

        ????????(b,8H);3,3(b,2H);3,8(s,3H);4,0(b,2H);6,1

        ????????(d,2H);6,9(s,1H);7,0(d,1H);7,8(d,1H);8,1

        ????????(d,1H);563?草酸盐??1,3(s,9H);1,9(b,2H);2,2(b,2H);2,9(t,2H);

        ????????3,1(t,2H);3,3(b,4H);3,4(s,3H);3,7(b,2H);

        ????????3,8(s,3H);4,0(b,2H);5,3(b,2H);6,8(s,1H);

        ????????6,9(d,1H);8,0(d,1H);566?????????1,4(s,9H);1,9(b,2H);2,5(b,2H);2,8(b,2H);

        ????????3,2(s,2H);3,3(s,3H);3,6(s,2H);3,6-3,8

        ????????(b,4H);3,8(s,3H);4,8(b,2H);5,0(s,2H);6,5

        ????????(s,1H);7,0(d,1H);8,0(d,1H);567?草酸盐??2,0(b,2H);2,8(b,2H);3,0(b,2H);3,3(s,3H);

        ????????3,4(s,2H);3,6(b,4H);3,8(b,2H);5,1(s,2H);

        ????????5,5(b,2H);7,0(m,2H);7,7(t,1H);568?草酸盐??2,0(b,2H);2,2(b,2H);3,0(t,2H);3,1(m,2H);

        ????????3,2(b,4H);3,4(s,3H);3,6(m,2H);3,9(b,2H);

        ????????6,7(b,2H);7,0(t,2H);7,7(t,1H);569?草酸盐??2,0-2,2(b,4H);3,0-3,4(m,8H);3,5(m,2H);3,9

        ????????(b,2H);6,1(d,1H);6,5(b,2H);7,0(t,2H);7,7

        ????????(t,1H);7,8(d,1H);570?盐酸盐??1,3(s,9H);2,0-2,2(b,3H);2,3-2,4(b,1H);3,2

        ????????(m,6H);3,4-4,0(b,5H);4,3-4,5(b,1H);6,2

        ????????(d,1H);6,8(d,1H);7,9(d,1H);8,3(d,1H);10,8

        ????????(b,1H)571?盐酸盐??1,3(s,9H);2,0-2,2(b,3H);2,3-2,4(b,1H);3,1

        ????????(s,3H);3,0-3,2(m,6H);3,4-4,0(b,5H);4,3-4,5

        ????????(b,1H);6,8(d,1H);8,3(d,1H);10,9(b,1H);

        ????????11,9(s,1H)572?????????1,3(s,9H);1,9-2,0(m,4H);2,6(m,4H);2,8

        ????????(t,2H);3,0(t,2H);3,4(s,3H);3,8(t,2H);3,9

        ????????(b,2H);4,6(b,2H);6,5(d,1H);8,2(d,1H)

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