CN1231467C - 伤害感受蛋白受体orl－1的高亲合性配体，包含它们的药物组合物以及它们的用途 - Google Patents

伤害感受蛋白受体orl－1的高亲合性配体，包含它们的药物组合物以及它们的用途 Download PDF

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CN1231467C
CN1231467C CNB998092215A CN99809221A CN1231467C CN 1231467 C CN1231467 C CN 1231467C CN B998092215 A CNB998092215 A CN B998092215A CN 99809221 A CN99809221 A CN 99809221A CN 1231467 C CN1231467 C CN 1231467C
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alkyl
compound
aryl
hydrogen
cycloalkyl
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CN1311777A (zh
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D·图尔施安
G·D·候
L·S·斯尔维曼
J·J·马塔斯
R·L·麦莱奥德
J·A·赫伊
R·W·查普曼
A·贝尔科维茨
F·M·库斯
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Merck Sharp and Dohme Corp
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Schering Corp
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Abstract

本发明公开了式(I)的化合物或其可药用盐或溶剂化物，其中，取代基定义见说明书。本发明还公开了药物组合物及所述化合物作为伤害感受蛋白受体抑制剂在治疗疼痛、焦虑、咳嗽、哮喘、抑郁和酒精滥用中的用途。

Description

伤害感受蛋白受体ORL-1的高亲合性配体、包含它们的药物组合物 以及它们的用途
发明背景
伤害感受蛋白(nociceptin)受体ORL-1已表明可用来在动物模型中进行疼痛调节。已发现ORL-1(伤害感受蛋白受体)是一种“孤(orphan)***类物质受体”，即其是一种配体未知的受体。伤害感受蛋白受体是一种G蛋白偶联的受体。其在结构上与三类***类物质受体紧密相关，即用作传统***镇痛剂，但其不被内源性***剂活化的靶。类似地，内源性的***类物质并不能活化伤害感受蛋白受体。与常规***类物质受体类似，伤害感受蛋白受体在中枢神经***中分布广泛。
在1995年末，发现了伤害感受蛋白，其显示出为一种能够激活伤害感受蛋白受体的内源性肽配体。包含于初始出版物中的数据表明，伤害感受蛋白和其受体成为在感觉疼痛刺激相关的新发现的路径的一部分。以后的大量实验室工作表明，当脊柱内给药于啮齿动物时，伤害感受蛋白是一种镇痛剂。伤害感受蛋白的效力与内源性***类肽类似。近来的数据表明，当将伤害感受蛋白直接给药于啮齿动物的脑部时，其可用作抗焦虑药。当在标准的焦虑动物模型中进行试验时，伤害感受蛋白的功效类似于传统的苯并二氮杂抗焦虑药。这些数据表明，伤害感受蛋白受体的小分子激动剂具有很强的止痛或抗焦虑活性。
近来的其它数据(Rizzi等， Life Sci.， 64，(1999)，p.157-163)表明，在离体的豚鼠支气管中，伤害感受蛋白受体的活化可抑制速激肽能非肾上腺素能-非胆碱能的收缩，这表明，伤害感受蛋白受体激动剂能够用于治疗哮喘。另外，还有报导(Ciccocioppo等，Physchpharmacology，141(1999)，p.220-224)指出，伤害感受蛋白还能在嗜好msP醇的大鼠中降低酒精的奖赏作用，这表明，伤害感受蛋白的介入可用于治疗酒精滥用。EP 856,514中，发现了8-取代的1，3，8-三氮杂螺[4，5]癸-4-酮衍生物，其可用作orphanin FQ(即伤害感受蛋白)的激动剂和/或拮抗剂，用于治疗各种疾病，包括抑郁症；公开于WO98/54168中的2-氧代咪唑衍生物具有类似的用途。早期，U.S.3,318,900描述了苯并咪唑基哌啶具有镇痛活性。
一些有效的镇痛剂如传统的***类物质如吗啉存在严重的副作用。临床相关的副作用包括耐受性、身体依赖、呼吸抑制和胃肠动力降低。对于许多患者，特别是那些进行慢性***类物质治疗的患者、即癌症患者来说，这些副作用限制了可给药的***类物质的用量。临床数据表明，超过三分之一的癌症患者存在目前的药物难以控制的疼痛。采用伤害感受蛋白获得的数据显示出优于***类物质的潜力。与采用吗啉不同，当将伤害感受蛋白长期给药于啮齿动物时，未显示出成瘾倾向。此外，慢性吗啉治疗不会导致对伤害感受蛋白的“交叉耐受性”，这表明这些试剂经不同的路径作用。
考虑到目前在疼痛缓减方面的要求，对现有技术更为有益的贡献应是提供改善对ORL-1的天然配体伤害感受蛋白的作用的其它化合物，从而用于治疗疼痛和焦虑。本发明满足了这样一种要求。
发明概述
本发明的化合物为由式I表示的化合物或其可药用盐或溶剂化物，
其中：
虚线代表任选的双键；X1为R5-(C1-C12)烷基、R6-(C3-C12)环烷基、R7-芳基、R8-杂芳基或R10-(C3-C7)杂环烷基；
X2为-CHO、-CN、-NHC(＝NR26)NHR26、-CH(＝NOR26)、-NHOR26、R7-芳基、R7-芳基(C1-C6)烷基、R7-芳基(C1-C6)链烯基、R7-芳基(C1-C6)-链炔基、-(CH2)vOR13、(CH2)vCOOR27、-(CH2)vCONR14R15、-(CH2)vNR21R22或-(CH2)vNHC(O)R21，其中，v为0、1、2或3，其中，q为1-3，a为1或2；
或X1为
或
Figure C9980922100093
X2为氢；
或者X1和X2一起形成下式的螺基团
Figure C9980922100094
或
m为1或2；
n为1、2或3，条件是，当n为1时，R16和R17之一为-C(O)R28：
p为0或1；
Q为-CH2-、-O-、-S-、-SO-、-SO2-或-NR17-；
R1、R2、R3和R4独立地选自：氢和(C1-C6)烷基，或者(R1和R4)或(R2和R3)或(R1和R3)或(R2和R4)一起形成具有1-3个碳原子的亚烷基桥；
R5为1-3个取代基，其独立地选自H、R7-芳基、R6-(C3-C12)环烷基、R8-杂芳基、R10-(C3-C7)杂环烷基、-NR10R20、-OR13和-S(O)0-2R13；
R6为1-3个取代基，其独立地选自H、(C1-C6)烷基、R7-芳基、-NR19R20、-OR13和-SR13；
R7为1-3个取代基，其独立地选自氢、卤素、(C1-C6)烷基、R25-芳基、(C3-C12)环烷基、-CN、-CF3、-OR19、-(C1-C6)烷基-OR19、-OCF3、-NR19R20、-(C1-C6)烷基-NR19R20、-NHSO2R19、-SO2N(R26)2、-SO2R19、-SOR19、-SR19、-NO2、-CONR19R20、-NR20COR19、-COR19、-COCF3、-OCOR19、-OCO2R19、-COOR19、-(C1-C6)烷基-NHCOOC(CH3)3、-(C1-C6)烷基-NHCOCF3、-(C1-C6)烷基-NHSO2-(C1-C6)烷基、-(C1-C6)烷基-NHCONH-(C1-C6)烷基或
Figure C9980922100101
其中，f为0-6；或相邻环碳原子上的R7取代基可一起形成亚甲二氧基或亚乙二氧基环；
R8为1-3个取代基，其独立地选自氢、卤素、(C1-C6)烷基、R25-芳基、(C3-C12)环烷基、-CN、-CF3、-OR19、-(C1-C6)烷基-OR19、-OCF3、-NR19R20、-(C1-C6)烷基-NR19R20、-NHSO2R19、-SO2N(R26)2、-NO2、-CONR19R20、-NR20COR19、-COR19、-OCOR19、-OCO2R19和-COOR19；
R9为氢、(C1-C6)烷基、卤素、-OR19、-NR19R20、-NHCN、-SR19或-(C1-C6)烷基-NR19R20；
R10为H、(C1-C6)烷基、-OR19、-(C1-C6)烷基-OR19、-NR19R20或-(C1-C6)烷基-NR19R20；
R11独立地选自H、R5-(C1-C6)烷基、R6-(C3-C12)环烷基、-(C1-C6)烷基(C3-C12)环烷基、-(C1-C6)烷基-OR19、-(C1-C6)烷基-NR19R20和
Figure C9980922100102
其中，q和a如前定义；
R12为H、(C1-C6)烷基、卤素、-NO2、-CF3、-OCF3、-OR19、-(C1-C6)烷基-OR19、-NR19R20或-(C1-C6)烷基-NR19R20；
R13为H、-(C1-C6)烷基、R7-芳基、-(C1-C6)烷基-OR19、-(C1-C6)烷基-NR19R20；-(C1-C6)烷基-SR19；或芳基(C1-C6)烷基；
R14和R15独立地选自H、R5-(C1-C6)烷基、R7-芳基和
其中，q和a如前定义；
R16和R17独立地选自氢、R5-(C1-C6)烷基、R7-芳基、(C3-C12)环烷基、R8-杂芳基、R8-杂芳基(C1-C6)烷基、-C(O)R28、(C1-C6)烷基(C3-C7)-杂环烷基、-(C1-C6)烷基-OR19和-(C1-C6)烷基-SR19；
R19和R20独立地选自氢、(C1-C6)烷基、(C3-C12)环烷基、芳基和芳基(C1-C6)烷基；
R21和R22独立地选自氢、(C1-C6)烷基、(C3-C12)环烷基、(C3-C12)环烷基(C1-C6)烷基、(C3-C7)杂环烷基、-(C1-C6)烷基(C3-C7)-杂环烷基、R7-芳基、R7-芳基(C1-C6)烷基、R8-杂芳基(C1-C12)烷基、-(C1-C6)烷基-OR19、-(C1-C6)烷基-NR19R20、-(C1-C6)烷基-SR19、-(C1-C6)烷基-NR18-(C1-C6)烷基-O-(C1-C6)烷基和-(C1-C6)烷基-NR18-(C1-C6)烷基-NR18-(C1-C6)烷基；
R18为氢或(C1-C6)烷基；
Z1为R5-(C1-C12)烷基、R7-芳基、R8-杂芳基、R6-(C3-C12)环烷基、R10-(C3-C7)杂环烷基、-CO2(C1-C6)烷基、CN或-C(O)NR19R20；Z2为氢或Z1；Z3为氢或(C1-C6)烷基；或
Z1、Z2和Z3和与其相邻的碳一起形成下述基团：
或
其中，r为0-3；w和u各自为0-3，条件是：
w与u之和为1-3；c和d独立地为1或2；s为1-5；和环A为稠合的R7-苯基或R8-杂芳基环；
R23为1至3个取代基，其独立地选自H、(C1-C6)烷基、-OR19、-(C1-C6)烷基-OR19、-NR19R20和-(C1-C6)烷基-NR19R20；
R24为1至3个取代基，其独立地选自R23、-CF3、-OCF3、NO2或卤素，或者相邻环碳原子上的R24取代基可一起形成亚甲二氧基或亚乙二氧基环；
R25为1-3个取代基，其独立地选自H、(C1-C6)烷基、(C1-C6)烷氧基和卤素；
R26独立地选自H、(C1-C6)烷基和R25-C6H4-CH2-；
R27为H、(C1-C6)烷基、R7-芳基(C1-C6)烷基、or(C3-C12)环烷基；
R28为(C1-C6)烷基、-(C1-C6)烷基(C3-C12)环烷基、R7-芳基、R7-芳基-(C1-C6)烷基、R8-杂芳基、-(C1-C6)烷基-NR19R20、-(C1-C6)烷基-OR19或-(C1-C6)烷基-SR19；
条件是，当X1为
Figure C9980922100121
或X1和X2一起为
Figure C9980922100122
时，
且Z1为R7-苯基时，Z2不为氢或(C1-C3)烷基；
条件是，当Z1、Z2和Z3和与其相连的碳一起形成
Figure C9980922100123
或
Figure C9980922100124
并且X1和X2一起为下式结构时
Figure C9980922100125
R11不为H、(C1-C6)烷基、(C1-C6)烷氧基(C1-C6)烷基或(C1-C6)羟基烷基；
条件是，当R2和R4形成亚烷基桥时，Z1、Z2和Z3和与其相连的碳一起不为
Figure C9980922100126
或
；并且
条件是，当X1为
且Z1为R6-(C3-C12)-环烷基时，Z2不为H。
本发明优选的化合物为如下的化合物，其中，Z1和Z2均为R7-芳基，特别是R7-苯基。优选R7取代基为(C1-C6)烷基和卤素，更优选邻位取代。
优选其中R1、R2、R3和R4均为氢的化合物，以及其中R1和R3均为氢并且R2和R4均为2或3个碳原子的亚烷基桥的化合物。
优选以下的化合物：其中，X1为R7-芳基，例如R7-苯基，X2为OH(即，X2为-(CH2)vOR13，其中，v为O和R13为H)或-NC(O)R28；其中，
X1为
其中，R12为氢和R11为(C1-C6)烷基、-(C1-C6)烷基(C3-C12)环烷基、-(C1-C6)烷基-OR19或-(C1-C6)烷基-NR19R20的化合物；和其中，X1和X2一起形成下式螺环基团的化合物：
其中，m为1、R17为苯基和R11为-(C1-C6)烷基-OR19或-(C1-C6)烷基-NR19R2，或
另一方面，本发明涉及一种药物组合物，其包含式I的化合物和可药用载体。
本发明的化合物是ORL-1受体的激动剂和/或拮抗剂。因此，另一方面，本发明涉及一种治疗疼痛、焦虑、咳嗽、哮喘、酒精滥用或抑郁症的方法，包括向需要进行这种治疗的哺乳动物给药有效量的式I的化合物。
另一方面，本发明涉及治疗咳嗽的方法，包括向需要进行这种治疗的哺乳动物给药：(a)有效量的伤害感受蛋白受体ORL-1激动剂；和(b)有效量的治疗咳嗽、变应性或哮喘症状的第二种试剂，其选自：抗组胺药、5-脂氧合酶抑制剂、白三烯抑制剂、H3抑制剂、β-肾上腺素能的受体激动剂、黄嘌呤衍生物、α-肾上腺素能的受体激动剂、嗜碱白细胞稳定剂、抗咳嗽药、祛痰药、NK1、NK2和NK3速激肽受体拮抗药和GABAB激动剂。
另一方面，本发明涉及一种药物组合物，其包含伤害感受蛋白受体ORL-1激动剂和第二种试剂，其选自：抗组胺药、5-脂氧合酶抑制剂、白三烯抑制剂、H3抑制剂、β-肾上腺素能的受体激动剂、黄嘌呤衍生物、α-肾上腺素能的受体激动剂、嗜碱白细胞稳定剂、抗咳嗽药、祛痰药、NK1、NK2和NK3速激肽受体拮抗药和GABAB激动剂。
也就是说，本发明涉及权利要求1的化合物在治疗疼痛、焦虑、咳嗽、哮喘、酒精滥用或抑郁症中的用途，并涉及伤害感受蛋白受体ORL-1激动剂单独或与用于治疗咳嗽、变应性或哮喘症状的第二试剂组合的用途。
另一方面，本发明涉及不包括在式I结构中的新化合物，所述化合物为：
Figure C9980922100141
附图的简要说明
图1说明较之与巴氯芬，化合物A和B(参见实施例12)对豚鼠由辣椒辣素引起的咳嗽的作用。
图2A和2B显示了在给药化合物A或巴氯芬后潮流(Tidal)体积的变化，图2C显示了在给药化合物A或巴氯芬后呼吸频率的变化。
发明详述
本发明中，除非另有说明，下述术语以如下定义使用：
M+代表质谱中分子的分子离子，MH+代表在质谱中分子的分子离子加氢；
Bu为丁基；Et为乙基；Me为甲基；和Ph为苯基；
烷基(包括烷氧基、烷氨基和二烷氨基的烷基部分)表示直链和支链的含1至12个碳原子或1至6个碳原子的碳链；例如，甲基、乙基、丙基、异丙基、正丁基、叔丁基、正戊基、异戊基、己基等；
链烯基表示在链中含有一个或两个双键的2至6个碳原子的烷基，如乙烯基、丙烯基或丁烯基；
链炔基表示在链中含有一个叁键的2至6个碳原子的烷基链，如乙炔基或丙炔基；
烷氧基表示烷基通过氧原子与相邻的结构元素共价键合的烷基部分，例如，甲氧基、乙氧基、丙氧基、丁氧基、戊氧基、己氧基等；
芳基(包括芳烷基的芳基部分)表示含有6至15个碳原子并具有至少一个芳环的碳环(如芳基为苯基)，其中，所述的芳基可任选地与芳基、(C3-C7)环烷基、杂芳基或杂(C3-C7)环烷基环稠合；并且，其中，R7-芳基意味着在所述芳基和/或所述的稠环上的任一种可取代的碳原子和氮原子可被任选和彼此独立地取代，其中，芳环被1至3个R7基团取代。芳基的实例为苯基、萘基和蒽基；
芳基烷基表示如前定义的烷基，其中，烷基部分的一个或多个氢原子被1至3个芳基取代；其中，芳基如前定义；
芳氧基表示如前定义的芳基，其中，所述芳基通过氧原子与相邻的结构元素共价键合，例如苯氧基；
环烷基表示3至12，优选3至7个碳原子的饱和碳环；其中，R6-环烷基是指在所述环烷基基团中任一个可利用的可取代的碳原子任选并彼此独立地被取代，并且，其中，环烷基环被1-3个R6基团取代；
环烷基烷基表示如前定义的烷基，其中，烷基部分的一个或多个氢原子被1至3个环烷基取代；其中，环烷基如前定义；
卤素表示氟、氯、溴或碘；
杂芳基表示具有1至3个选自O、S和N的杂原子的环状基团，所述的杂原子***碳环结构中并具有足够数量的离域的pi电子以提供芳族特性，芳杂环基团包含5至14个碳原子，其中，所述杂芳基选择性地可与一个或多个芳基、环烷基、杂芳基或杂环烷基环稠合；并且，其中，在所述杂芳基和/或所述稠合环中任一个可利用可取代的碳或氮原子可被任选且独立地取代，并且其中杂芳基环可被1-3个R8基团取代；代表性的杂芳基可包括，例如，呋喃基、噻吩基、咪唑基、嘧啶基、***基、2-，3-或4-吡啶基或2-、3-或4-吡啶基N-氧化物，其中，吡啶基N-氧化物可表示为：
Figure C9980922100161
或
Figure C9980922100162
杂芳基烷基表示如前定义的烷基，其中，一个或多个氢原子被一个或多个如前定义的杂芳基取代；
杂环烷基表示含3至7个碳原子，优选4至6个碳原子的饱和环，该环被1至3个选自-O-、-S-和-NR21-的杂原子间断，其中，R21如前定义，并且，其中，选择性地，所述环可包含一个或两个不会使环具有芳族特性的不饱和键；并且，其中，在环上的任一个可利用的可取代的碳原子可被取代，并且，其中，杂环烷基环可被1-3个R10基团取代；杂环烷基基团的代表性实例包括2-或3-四氢呋喃基、2-或3-四氢噻吩基、1-、2-、3-或4-哌啶基、2-或3-吡咯烷基、1-、2-或3-哌嗪基、2-或4-二氧六环基、吗啉基、
Figure C9980922100163
或
Figure C9980922100164
其中，R17如前定义，t为0、1或2。
当在式I的哌啶环中存在选择性的双键时，X1和X2之一与3-位碳形成键，其余的X1或X2不为氢。
当X1和X2形成如前定义的螺环时，示于定义中的结构中的波浪线指示与哌啶环的4-位碳连接的点，例如形成下式的化合物：
Figure C9980922100165
本发明的某些化合物可能存在不同的立体异构形式(例如，旋光异构体、非对映异构体和阻转异构体(atropisomer))。本发明包含所有这些异构体，包括其纯形式和混合物，包括外消旋混合物。
某些化合物本质上为酸性化合物，这些化合物具有羧基或酚性羟基。这些化合物可形成可药用盐。这种盐的实例包括钠盐、钾盐、钙盐、铝盐、金盐和银盐。本发明也包含与可药用胺形成的盐，如氨、烷基胺、羟基烷基胺、N-甲基葡糖胺等。
某些碱性化合物也形成可药用盐，例如酸加成盐。例如，吡啶并-氮原子可与强酸形成盐，具有碱性取代基如氨基的化合物也与弱酸形成盐。用于成盐的适宜的酸的实例为盐酸、硫酸、磷酸、乙酸、柠檬酸、草酸、丙二酸、水杨酸、苹果酸，富马酸、琥珀酸、抗坏血酸、马来酸、甲磺酸和其它本领域技术人员公知的无机酸和羧酸．可通过使游离碱形式与足量的所需酸进行接触而产生盐，以制备按常规方式产生的盐。游离碱形式可通过使盐用适宜的稀碱水溶液处理而再生，例如稀氢氧化钠水溶液、碳酸钾、氨或碳酸氢钠。游离碱形式在某些物理性质方面不同于其盐形式，如在极性溶剂中的溶解度，但对本发明的目的而言，酸和碱盐分别与其游离碱形式是等效的。
所有这些酸和碱盐均应为在本发明范围内的可药用盐，所有的酸和碱盐对于本发明目的而言被认为等效于相应的化合物的游离形式。
本发明的化合物可由现有技术中公知的原料或用现有技术中公知方法能够制备的原料用通常公知方法制得。以下给出一般方法的实例和具体制备例的实例。
通常，在过量碱如K2CO3和Et3N存在下，在溶剂如DMF、THF或CH3CN中，在室温或升高温度下，采用Z1、Z2、Z3-取代的卤代甲烷对X1，X2-取代的哌啶类进行烷基化处理。
X1，X2-取代的哌啶类可商购，或者通过公知方法制备．例如，可以按照下述反应路线，将4-羟基-4-苯基-哌啶转化成4-tBoc-氨基-4-苯基哌啶，其中，Bn为苄基，Ph为苯基，tBoc为叔丁氧羰基：
Figure C9980922100171
将商购的4-苯基-4-哌啶醇用苄基保护，将形成的中间体用Me3SiCN进行处理．再将形成的酰胺用含水HCl在CH3OH中进行水解，产生4-氨基化合物。再将氨基基团用tBoc进行保护，通过氢解使N-苄基除去，产生所需的4-氨基-哌啶衍生物。
然后，将4-(保护的)氨基-哌啶与Z1、Z2、Z3-卤代甲烷反应，并除去保护基。胺(即，X2为-NH2)可进行各种标准转化以获得胺衍生物。例如，式I的胺可与R22-甲醛反应，反应在温和的还原剂如Na(OAc)3BH存在下进行，或者与式R22-L的化合物反应，其中，L为离去基团例如Cl或Br，该反应在碱如Et3N存在下进行。
另一种制备式I化合物(其中，X1为R7-芳基和X2为OH)的方法包括用Z1、Z2、Z3-卤代甲烷对4-哌啶酮盐酸盐进行烷基化反应，然后，使酮与适宜的取代的R7-苯基溴化镁反应，或者与式X1-L1的化合物和正丁基锂反应，其中，L1为Br或I。
式I的X1，X2-取代的化合物可通过进行本领域中公知的对X1和/或X2-取代基的反应过程而转化成其它式I的化合物。例如，甲醛-取代的哌啶(即，X2为-CHO)可转化成取代的哌啶，其中，X2为R13-O-CH2-，如下述对式I化合物的过程所示，其中，X1为苯基，Z1和Z2均为苯基，R1、R2、R3和R4及Z3均为H：
氰基-取代的哌啶(即，X2为-CN)可转化成取代的哌啶，其中，X2为R21R22N-CH2-或X2为R28C(O)NH-CH2-，如下述对式I化合物的过程所示，其中，X1为苯基，R21、R1、R2、R3和R4，和Z3均H，L为离去基团，例如Cl或Br：
式I的化合物(其中，X1为苯并稠合含氮杂环，具有除氢之外的R11取代基)可通过相应的化合物(其中，R11为氢)与式R11L(R11不为H，L如前定义)的化合物反应制得。
或者，X1，X2-取代的哌啶原料可通过类似的过程转化成其它X1，X2-取代的哌啶，再与Z1、Z2、Z3-取代的卤代甲烷反应。
对于式I的化合物(其中，R1、R2、R3和R4各自形成亚烷基桥)，将商购的N-保护的4-哌啶酮用苯基锂处理，将形成的中间体脱保护产生所需的化合物，例如：
其中，Pr为N-保护的基团，Ph为苯基和z为1-2。
Z1、Z2、Z3-卤代甲基衍生物(其中，Z1和Z2为R7-苯基)或者可商购，或者可采用下述反应路线所述过程制备：
Figure C9980922100201
类似的反应过程或其它本领域中公知的方法可用于制备其中Z取代基不为苯基的化合物。
本发明的化合物及其所采用的制备原料通过下述实施例举例说明，但它们不应理解为对本发明范围的限定。
下述溶剂和反应试剂在本发明中通过简写表示：四氢呋喃(THF)；乙醇(EtOH)；甲醇(MeOH)；乙酸(HOAc或AcOH)；乙酸乙酯(EtOAc)；N，N-二甲基甲酰胺(DMF)；和***(Et2O)。室温缩写为rt。
                        实施例1
Figure C9980922100202
将4-羟基-4-苯基哌啶(1.5g.8.47mmol)和K2CO3(3.0g，21.73mmol)在CH3CN中的混合物于室温下搅拌。向其中加入α-溴-二苯基甲烷(2.5g，10.12mmol)，将反应混合物搅拌过夜。将反应混合物浓缩，再溶解于CH2Cl2，用水洗涤，干燥(MgSO4)和浓缩。色谱处理(SiO2，9∶1己烷/EtOAc)，得到标题化合物(2.6g，90％)。1H NMR(CDCl3)：δ1.80(m，2H)，2.25(m，2H)，2.42(m，2H)，2.90(m，2H)，4.40(s，1H)，7.2-7.6(m，15H)。
                        实施例2
Figure C9980922100211
步骤1：采用实施例1所述的过程对4-哌啶酮-水合物盐酸盐(5g，32.6 (mmol)在CH3CN中的溶液进行烷基化处理．将残余物在硅胶上进行色谱处理(95∶5己烷/EtOAc)，得到所需的化合物。
步骤2：将4-甲基苯基溴化镁(0.5 M的THF溶液，1.75 ml，O.87mmo1)于0℃下滴加至步骤1的产物(191mg，O.72 mmo1)的THF溶液中．将溶液在0℃下搅拌2小时，再用冰-H2O停止反应，用EtOAc萃取，用H2O和盐水洗涤，干燥，浓缩。将残余物进行硅胶色谱处理(95∶5己烷/EtOAc，93∶7己烷/EtOAc)，得到标题化合物(0.091 g，30％)。1H NMR(CDCl3)δ 7.5(m，6H，ArH)，7.3(t，4H，ArH)，7.2(t，4H，ArH)，4.35(s，lH)，2.8(d，2H)，2.4(m，5H)，2.2(td，2H)，1.75(d，2H)：MS(Cl)358(M+1)：元素分析C25H27NO.1.2 H2O：计算值：C 79.2，H 7.82，N 3.69：实测值：C 78.90，H 8.02，N 3.85.
实施例3
在-70℃下，将n-BuLi(2.5 M，0.38 ml，O.95 mmo1)滴加至3-溴-噻吩(0.1 5g，0.95 mmo1)的Et2O溶液中并搅拌2小时。将实施例2步骤1的产物(230 mg，0.87 mmol)的Et2O(4 m1)溶液加至反应混舍物中，在3小时内缓慢地升温至室温，用冰-冷却下的NH4Cl(水溶液)使反应停止，用Et2O萃取，用H2O和盐水洗涤，干燥，浓缩。将残余物进行色谱处理(95：5己烷／EtOAc)，得到标题化合物(90mg)．1H NMR(CDCl3)δ 7.5(d，2H)，7.35(bt，4H)，7.25(m，3H)，7.2  (m，2H)，  4.4  (s，1H)，  2.8  (d，2H)，  2.5  (t，2H)，  2.3  (dt，2H)，2.0(d，2H)；  Ms(Cl)350(M+1)：元素分析C22H22NOs.l.1HCl.0.9H2O：计算值：C 65.11，H 6.43，N 3.54，S 7.8，Cl 9.61；实测值：C 65.27，H 6.54，N 3.45，S 7.30，Cl 9.43。
                        实施例4
Figure C9980922100221
步骤1：采用实施例1步骤1所述过程将4-苯基-4-哌啶甲醛(1.0g，5.29mM)进行烷基化处理，得到所需的产物(1.69g，90％)。1H NMR(CDCl3)：δ2.40(m，4H)，2.50(m，2H)，2.85(m，2H)，4.25(s，1H)，7.20-7.50(m，15H)，9.42(s，1H)。
步骤2：将步骤1的产物(3.0g，8.45mmol)的溶液冷却至0℃，用NaBH4(1.0g，26.32mmol)处理。0.5小时后，将反应混合物用1N HCl处理和浓缩。将残余物用CH2Cl2萃取，干燥(MgSO4)，蒸发。将残余物进行柱色谱处理(4∶1己烷∶EtOAc)，产生所需的伯醇，1HNMR(CDCl3)：δ2.00(m，2H)，2.25(m，4H)，2.65(m，2H)，3.65(d，2H)，4.20(s，1H)，4.25(d，1H)，7.2-7.6(m，15H)。
步骤3：将步骤2的产物用NaH在DMF中于0℃下处理0.5小时。加入CH3I，将反应混合物升温至室温。在搅拌过夜后，将反应混合物倒入冰中，用Et2O萃取，干燥(MgSO4)和蒸发。对残余物进行柱色谱处理，产生标题化合物，1H NMR(CDCl3)：δ2.10(m，4H)，2.40(m，2H)，2.78(m，2H)，2.90(m，2H)，3.00(s，3H)，4.38(s，1H)，7.21-7.52(m，15H)。
                    实施例5
步骤1：将4-氰基-4-苯基哌啶盐酸盐(5.0g，22.4mM)的DMF(30ml)溶液用Et3N(7.20ml，47mM)和溴代二苯基甲烷(6.38g，25.80mM)处理，并在室温及N2下搅拌20小时。将反应混合物进行真空浓缩，使其在EtOAc和H2O间分配。有机层用水洗涤两次，再用盐水洗涤，干燥(MgSO4)，过滤和浓缩。进行色谱处理(SiO2，19∶1己烷/EtOAc)，得到6.0g(76％)的所需产物。1H NMR(CDCl3)：δ2.21(m，4H)，2.49(t，J＝12.3Hz，2H)，3.11(d，J＝12.5Hz，2H)，4.46(s，1H)，7.45(m，15H)。
步骤2：将步骤1的产物(6.0g，17mM)的Et2O(40ml)溶液冷却至0℃，用1M LAH(34.10ml，34mM)溶液滴加处理，在N2气氛下进行0.5小时。将反应混合物升温至室温，然后回流4小时。再将反应混合物冷却至0℃和用水处理(8当量)。将反应混合物升温至室温，再搅拌1小时。将形成的固体过滤，用Et2O漂洗，将滤液浓缩，得到5.45g(90％)的所需产物，1H NMR(CD3OD)：δ1.84(m，2H)，2.16(m，4H)，2.56(m，2H)，2.68(m，2H)，4.07(s，1H)，7.25(m，15H)。
步骤3：将步骤2的产物(0.2g，0.56mM)的CH2Cl2(3ml)溶液用苯甲酰氯(0.078ml，0.673mM)和吡啶(0.045g，0.568mM)于室温及N2下处理18小时。将反应混合物浓缩，然后，使其在H2O和CH2Cl2间分配。有机层用水(2x)和盐水洗涤，干燥(MgSO4)，过滤和浓缩。进行色谱处理(SiO2，3∶1己烷/EtOAc)，得到0.2g(77％)的所需产物，1H NMR(CD3OD)：δ2.13(m，6H)，2.66(m，4H)，3.50(s，2H)，4.07(s，1H)，7.11-7.65(m，20H)。
步骤4：将步骤3的产物(0.075g，0.16mM)的THF(3ml)溶液在搅拌下冷却至0℃。在N2下，加入LAH(固体，0.025g，0.65mM)，继续搅拌0.25小时。然后，将反应混合物回流5小时，再于室温下搅拌18小时。再将反应混合物冷却至0℃，用水(8当量)停止反应。将反应混合物升温至室温，再搅拌1小时。将形成的固体过滤，用Et2O冲洗，将滤液干燥(MgSO4)和浓缩。进行色谱处理(中性Al2O3，CH2Cl2，再用3∶1CH2Cl2∶EtOAc)，得到0.014g(20％)的标题化合物。1H NMR(CD3OD)：δ1.90(m，2H)，2.15(m，4H)，2.48(m，2H)，2.68(s，2H)，3.53(s，2H)，4.05(s，1H)，7.01-7.38(m，20H)。
                        实施例6
将实施例5步骤2的产物(0.2g，0.561mM)、乙酸酐(3ml)和Et3N(0.096ml，0.67mM)合并，在室温下搅拌18小时。将反应混合物浓缩，并在H2O和CH2Cl2间分配。有机层用水(2x)和盐水洗涤，然后干燥(MgSO4)，过滤和浓缩，得到0.214g(95％)的标题化合物，1HNMR(CD3OD)：δ1.87(m，5H)，2.16(m，4H)，2.61(m，2H)，3.31(s，2H)，4.07(s，1H)，7.12-7.40(m，20H)。
                        实施例7
步骤1：4-苯基-4-羟基哌啶(10.0g，56.4mM)的DMF(60ml)溶液用Et3N(8.28ml，59.2mM)和苄基溴(7.37ml，62.10mM)处理，在室温及N2下搅拌20小时。将反应混合物进行真空浓缩，用饱和NaHCO3碱化至pH值为8，在EtOAc和H2O间分配。有机层用水洗涤两次，再用盐水洗涤，干燥(MgSO4)，过滤和浓缩。进行色谱处理(中性Al2O3，己烷，然后1∶1己烷∶EtOAc)，得到11.95g(80％)的所需产物。
步骤2：在乙二醇/CO2浴中冷却至-15℃及在N2气氛下，向步骤1的产物(30.0g，0.112mol)和(CH3)3SiCN(59.94ml，0.448mol)的混合物中滴加入冰醋酸(47ml)，同时保护内部温度为-15℃。在剧烈搅拌下，滴加入浓H2SO4(47ml，0.34M)，同时保护内部温度为-15℃。然后除去冷却浴，将反应混合物在室温下搅拌18小时。将反应混合物倒入冰中，用50％NaOH溶液调节pH值至7，同时保持温度在25℃。然后将反应混合物用CH2Cl2萃取，有机层用水洗涤(2x)，然后用盐水洗涤，干燥(MgSO4)，过滤和浓缩。用EtOAc/己烷(1∶10)进行重结晶，得到22.35g(68％)的所需化合物，1H NMR(CD3OD)：δ2.10(m，2H)，2.40(m，4H)，2.82(d，J＝11.50Hz，2H)，3.57(s，2H)，7.20-7.43(m，10H)，8.05(s，1H)。
步骤3：将步骤2的产物(20g，67.9mM)和5％(w/w)的浓盐酸水溶液/CH3OH(350ml)在N2气氛下搅拌48小时。将混合物浓缩得到一种泡沫物，其悬浮于Et2O中，浓缩除去过量HCl。将所得固体重新悬浮于***中，通过真空过滤收集该固体，用Et2O洗涤，真空干燥，得到(23g，100％)的所需产物。二盐酸盐的1H NMR(CD3OD)：δ2.59(t.J＝13.3Hz，2H)，2.93(t，J-13.3Hz，2H)，3.07(d，J＝13.50Hz，2H)，3.58(d，J＝13Hz，2H)，4.26(s，2H)，7.56(m，10H)。
步骤4：将步骤3的产物(24.10g，71mM)、CH2Cl2(300ml)，(tBoc)2O(17.0g，78.1mM)和Et3N(14.37g，0.142M)合并，并在N2气氛及室温下搅拌18小时。使反应混合物在CH2Cl2和H2O分配，水层用CH2Cl2萃取。合并后的有机层用水洗涤(2x)，然后用盐水洗涤，干燥(MgSO4)，过滤和浓缩。将形成的固体悬浮于Et2O中并进行声波处理，过滤和干燥，得到所需的化合物(21.98g，90％)。1H NMR(CD3OD)：δ1.09(bs，2H)，1.39(s，1H)，2.05(m，2H)，2.34(m，4H)，2.65(d，J＝11.8Hz，2H)，3.56(s，2H)，7.18-7.40(m，10H)。
步骤5：将步骤4的产物(5.22g，14.2mM)、CH3OH(430ml)、Pd(OH)2/C(3.0g)和NH4COOH(18.86g，0.298M)合并，并在N2气氛下回流8小时。将反应混合物用硅藻土过滤，用CH3OH洗涤。将合并后的滤液浓缩得到(3.90g，97％)的所需产物，1H NMR(CD3OD)：δ1.10(bs，2H)，1.39(s，7H)，1.90(m，2H)，2.26(m，4H)，2.92(m，4H)，7.17-7.41(m，5H)。
步骤6：将步骤5的产物(2.74g，9.91mM)、CH3CN(85ml)、Et3N(1.75ml，12.40mM)和溴代二苯基甲烷(2.70g，10.9mM)合并，并在室温及N2气氛下搅拌18小时。将混合物浓缩，将形成的残余物在H2O与EtOAc间分配。EtOAc层用水洗涤(2x)，再用盐水洗涤，然后干燥(MgSO4)，过滤和浓缩。进行色谱处理(中性Al2O3，己烷，然后4∶1己烷∶EtOAc)，得到2.85g(65％)的所需产物，1H NMR(CD3OD)：δ1.07(bs，2H)，1.37(s，7H)，2.23(m，2H)，2.24(m，4H)，2.74(d，J＝12.1Hz，2H)，4.27(s，1H)，7.10-7.47(m，15H)。
步骤7：将步骤6的产物(4.69，10mM)、1，4-二噁烷(38ml)和4M HCl的1，4-二噁烷中的溶液(25ml，101mM)合并，在室温及N2气氛下搅拌4小时。将混合物浓缩，将残余物悬浮于Et2O中，再进行浓缩。将形成的固体再悬浮于Et2O中，进行声波处理，真空过滤收集产物，干燥，得到3.27g(80％的所需产物)，二盐酸盐的1H NMR(CD3OD)：δ2.91(m，8H)，5.34(s，1H)，7.37-7.77(m，15H)。
步骤8：在N2及室温下，向步骤7的产物(0.3g，0.722mM)在CH2Cl2(3ml)中的悬浮液中加入2-噻吩甲醛(0.133ml，1.44mM)。用Et3N将反应物的pH调节至6，将混合物搅拌0.5小时。然后加入Na(OAc)3BH(0.230g，1.08mM)，将反应混合物在N2及室温下搅拌3小时。反应用饱和NaHCO3(水溶液)停止，并在Et2O和H2O间分配。有机层用H2O(2x)洗涤，再用盐水洗涤，干燥(MgSO4)，过滤和浓缩。进行色谱处理(SiO2，甲苯，然后1∶19EtOAc∶甲苯)，得到0.158g(50％)的所需产物。1H NMR(CD3OD)：δ1.96(m，2H)，2.17(m，2H)，2.52(m，4H)，3.45(s，2H)，4.24(s，1H)，6.76(d.J＝3.5Hz，1H)，6.85(dd，J＝3.6Hz，1H)，7.13-7.50(m，16H)。
                    实施例8
Figure C9980922100261
步骤1：采用实施例1步骤1所述过程对4-(2-氧代-1-苯并咪唑基)-哌啶的CH3CN溶液进行烷基化处理，产生所需的化合物。
步骤2：将NaH加至3-[1-(二苯基甲基)-4-哌啶基]-1，3-二氢-2H-苯并咪唑-1-酮(2.5g，6.6mmol)的DMF(25ml)溶液中，并在室温下搅拌1小时。将正丁基碘于室温下加至混合物中并搅拌过夜。用冰-H2O使反应停止，用EtOAc萃取，再用H2O和盐水洗涤，干燥(MgSO4)和浓缩。对残余物进行硅胶色谱处理(1∶9EtOAc/己烷)，得到标题化合物(2.35g)。将标题化合物溶解于Et2O中，加入HCl的Et2O溶液(8ml，1M)，搅拌1小时，过滤，得到盐酸盐。1H NMR(CDCl3)δ7.55(m，4H，ArH)，7.35(m，5H，ArH)，7.25(m，2H，ArH)，7.15(m，2H，ArH)，7.1(m，1H，ArH)，4.4(m，2H)，3.95(t，2H)，3.15(d，2H)，2.6(dq，2H)，2.1(t，2H，1.8，m，4H)，1.5(m，2H)，1.0(t，3H)；ESI-MS 440(M+1)；元素分析C29H33N3O.HCl.H2O：计算值：C 70.5，H 7.3，N 8.5，Cl 7.18；实测值：C 70.48，H 7.28，N 8.49，Cl 7.49。
                    实施例9
Figure C9980922100271
在室温下，将SOCl2(247mg，2.07mmol)加至2-(氯-苯基)苯基甲醇(300mg，1.38mmol)的CH2Cl2溶液中，在室温下搅拌5小时，浓缩。将残余物溶解于CH3CN中，加入K2CO3、4-羟基-4-苯基哌啶和NaI。将溶液搅拌回流过夜，过滤，浓缩。将残余物进行硅胶色谱处理(9∶1己烷/EtOAc)，得到标题化合物。1H NMR(CDCl3)δ7.91(d，1H)，7.58(d，2H)，7.54(d，2H)，7.42(t，2H)，7.32(m，5H)，7.26(t，3H)，7.16(t，3H)，5.0(s，1H)，2.8(dd，2H)，2.5(dq，2H)，2.2(dt，2H)，1.75(d，2H)。将标题化合物溶解于***中，加入HCl/Et2O(1M)，得到HCl盐，MS Cl 378(M+1)；元素分析C24H24NOCl.HCl.0.2H2O：计算值：C 68.97，H 6.13，N 3.35，Cl 16.96；实测值：C 68.87，H 6.04，N 3.35，Cl 17.00。
                    实施例10
步骤1：采用实施例9所述的过程，用扁桃腈(1g，7.51mmol)对4-哌啶酮一水合物盐酸盐(880mg，5mmol)的CH3CN溶液进行烷基化处理。对残余物进行硅胶色谱处理，再进行重结晶(EtOAc)，得到所需的化合物(630mg)。
步骤2：在0℃下，将2-甲氧基苯基溴化镁的THF(24ml，0.5M，11.85mmol)溶液加至步骤1的产物(330mg，1.185mmol)的THF溶液中。除去冰浴，将反应混合物回流下搅拌6小时。用NH4Cl(水溶液)使反应停止，用EtOAc萃取，用盐水洗涤，干燥和浓缩。对残余物进行色谱处理(95∶5，9∶1己烷/EtOAc)，得到标题化合物(330mg)。1H NMR(CDCl3)δ7.76(d，1H)，7.62(d，1H)，7.55(d，1H)，7.45(t，1H)，7.34(m，3H)，7.24(m，2H)，7.03(t，1H)，6.90(d，2H)，4.88(s，1H)，3.89(s，3H)，2.94(d，1H)，2.82(d，1H)，2.45(td，2H)，2.26(t，2H)，1.78(d，2H)。将标题化合物溶解于Et2O中，加入HCl的Et2O溶液，搅拌1小时，过滤，得到HCl盐。MS FAB 374.1(M+1)；元素分析C25H27NO2.HCl.0.15H2O：计算值：C 72.77，H 6.91，N 3.39，Cl 8.59；实测值：C 72.76，H 7.02，N 3.59.Cl 8.83。
                     实施例11
Figure C9980922100281
步骤1：采用实施例1步骤1所述的过程将1-苯基-1，3，8-三氮杂螺[4，5]癸-4-酮(0.5g)的CH3CN溶液进行烷基化处理，产生所需的化合物。
步骤2：采用实施例1步骤2所述的过程将步骤1的产物1-苯基-8-(二苯基甲基)-1，3，8-三氮杂螺[4，5]癸-4-酮(0.4g)用CH3I进行烷基化处理，产生所需的化合物(0.25g)。
1H NMR(CDCl3)δ1.70(d，2H)，2.85(m，6H)，3.05(s，3H)，4.50(s，1H)，4.72(s，2H)，6.95(t，1H)，7.05(d 2H)，7.20-7.60(m，12H)。
采用实施例1至11的过程，采用适宜的原料，制备在下表中所示的化合物。
                        表1
其中X2定义如下：
Figure C9980922100301
Figure C9980922100321
                        表2
其中X1定义如下
Figure C9980922100331
Figure C9980922100351
                    表3
其中Z1和Z2定义如下：
Figure C9980922100353
Figure C9980922100371
                        表4
Figure C9980922100381
其中X1，X2，Z1和Z2定义如下：
Figure C9980922100391
Figure C9980922100411
                        表5
其中R11，Z1和Z2如下表定义：，其中Ac是乙酰基，Me是甲基和Et是乙基：
Figure C9980922100432
                    表6
Figure C9980922100462
其中R11，Z1和Z2如下表定义：
Figure C9980922100463
Figure C9980922100501
Figure C9980922100551
                    表7
显示下列各式化合物，其ph是苯基
Figure C9980922100591
Figure C9980922100621
                        表8
Figure C9980922100631
其中Z1和Z2如下表所定义：
实验
伤害感受蛋白结合实验
将表达ORL-1受体的CHO细胞膜制剂(2mg)采用不同浓度的[125I][Tyr14]伤害感受蛋白(3-500pM)在包含50mM HEPES(pH7.4)、10nM NaCl、1mM MgCl2、2.5mM CaCl2、1mg/ml牛血清白蛋白和0.025％枯草杆菌肽的缓冲液中进行培育。在大量研究中，实验在缓冲液50mM tris-HCl(pH 7.4)、1mg/ml牛血清白蛋白和0.025％枯草杆菌肽中进行。在室温(22℃)下将样品培育1小时。在预浸0.1％聚亚乙基亚胺的GF/B过滤器上采用Brandell细胞收集装置收集结合至膜上的放射标记配体，用5ml冷蒸馏水洗涤五次。通过在1μM伤害感受蛋白存在下进行的类似实验平行测定非特异性结合。所有的实验点均重复进行总结合实验和非特异性实验。
采用现有技术中公知的方法计算Ki值。
对于本发明的化合物来说，测得的Ki值为0.6至3000nM，优选Ki值低于10nM的那些化合物。本发明代表性化合物的Ki值如下：
采用下述文献所述方法，测量本发明化合物的激动剂活性：European Journal of Pharmacology， 336(1997)，p.233-242：
Figure C9980922100661
Figure C9980922100671
                         实施例12
Figure C9980922100681
      化合物A                       化合物B
咳嗽研究
按照下述文献所述的方法，对由豚鼠由辣椒辣素引起的咳嗽评价伤害感受蛋白激动剂化合物A(0.3-10mg/kg.p.o.)和化合物B(10mg/kg，p.o.)的作用：Bolser等， British Journal of Pharmacology(1995)114，735-738。该模型是一种广泛用于评价潜在镇咳药活性的方法。将禁食一夜的雄性Hartley豚鼠(350-450g，Charles River，Bloomington，MA，USA)放置在12″×14″透明室中。使动物置于通过喷射式喷雾器(Puritan Bennett，Lenexa，KS，USA)产生的雾化的辣椒辣素(300μM，4分钟)中以引起其咳嗽反射。每一支豚鼠仅置于辣椒辣素中一次。通过设置在所述透明室中的扩音器探测咳嗽的数量，并通过经训练的观察者进行检验。来自扩音器的信号转播至记录咳嗽数据的多种波动记录仪。在雾化辣椒辣素之前2小时服用赋形剂(甲基纤维素1ml/kg，p.o.)或化合物A或化合物B。作为阳性对照，也测试巴氯芬(3mg/kg，p.o.)的镇咳活性。结果以柱状图图示于图1中。
                         实施例13
呼吸测量
对体重为450至550g的雄性Hartley豚鼠进行研究。将这些动物禁食一夜，但服用水和LIbitum。将豚鼠放置在完整驱体头在外的体积描记器中，在动物的头上放置橡胶颈圈以提供在豚鼠与体积描记器间的气密密封。以穿过丝网筛的压差测量气流，所述筛覆盖了体积描记器的壁上1英寸的孔。采用前置放大器电路和与肺有关的功能计算机(Buxco Electronics，Sharon，CT.，XA型)将气流信号集成与体积成比例的信号。头室与体积描记器连接，在整个研究过程中，来自压缩空气源的空气(21％氧气，其余为氮气)循环通过头室。在豚鼠呼吸这种循环空气的同时，对所有的呼吸进行测量。
将来自每一支动物的体积信号输入数据获得/分析***(BuxcoElectronics，XA型)，基于呼吸-呼吸，由其计算潮流体积和呼吸速率。这些信号目视显示于监视器上。记录每分钟内潮流体积和呼吸速率的平均值。
将豚鼠在体积描记器中平衡30分钟。在30分钟结束时获得基线测量值。然后，从体积描记器中取出豚鼠，口服给药实施例12的化合物A(10mg/kg，p.o.)、巴氯芬(3mg/kg，p.o.)或甲基纤维素赋形剂安慰剂(2ml/kg，p.o.)。在给药后，立即将豚鼠放置在体积描记器中，重新连接头室和循环空气，测量在处理后30、60、90和120分钟时的呼吸变量。该研究按照下述指示进行：ACUC protocol #960103。
数据分析
获得基线条件下和在每次给药或服用赋形剂时的潮流体积(VT)、呼吸速率(f)和分钟量(MV＝VT×f)。结果以平均值±SEM表示。结果示于图2A、2B和2C。图2A显示了潮流体积的变化，图2B显示出潮流体积的变化，图2C显示了呼吸频率的变化。
令人惊奇地发现，伤害感受蛋白受体ORL-1激动剂显示出镇咳活性，使得它们可用于抑制哺乳动物的咳嗽。伤害感受蛋白受体ORL-1激动剂的非限定性实例包括本发明所述的伤害感受蛋白受体ORL-1激动剂化合物。对于治疗咳嗽的哺乳动物来说，伤害感受蛋白受体ORL-1激动剂可与一种或多种其它治疗咳嗽、***反应或哮喘症状的其它试剂一起给药，这些试剂选自：抗组胺药、5-脂氧合酶抑制剂、白三烯抑制剂、H3抑制剂、β-肾上腺素能的受体激动剂、黄嘌呤衍生物、α-肾上腺素能的受体激动剂、嗜碱白细胞稳定剂、镇咳剂、祛痰剂、NK1、NK2和NK3速激肽受体拮抗剂和GABAB激动剂。
抗组胺药的非限定性实例包括：阿斯咪唑、阿扎他定、氮斯丁、阿伐斯丁、溴苯那敏、certirizine、氯非尼腊明、氯马斯汀、赛克利嗪、卡瑞斯汀、赛庚啶、卡比沙明、descarboethoxyloratadine(也称为SCH34117)、杜克西拉明、二甲茚定、艾巴停、依匹那丁、efletirizine、fexofenadine、盐酸羟嗪、酮替芬、氯雷他定、左卡巴司汀、咪唑斯汀、equitazine、米安色林、诺拉斯丁、美克洛嗪、norastemizole、匹库马特、美吡拉敏、普鲁米近、特非那定、特赖皮伦胺、替美斯汀、阿利马嗪和曲普利啶。
组胺H3受体拮抗剂的非限定性实例包括：thioperamide、双咪硫胍、丁咪胺、clobenpropit、impentamine、咪芬替丁、S-双咪硫胍、R-双咪硫胍、SKF-91486、GR-175737、GT-2016、UCL-1199和氯氮平。其它化合物易于通过公知方法进行评价测定H3受体的活性，包括豚鼠脑膜实验和豚鼠神经元回肠收缩实验，这两个实验均在下述文献中有述：U.S.专利5,352,707。另一个有用的实验采用大鼠脑膜进行，在下述文献中有述：West等，“二-H3-组胺受体亚型的签别”，Molecular Pharmacology，Vol.38，610-613页(1990)。
术语“白三烯抑制剂”包括抑制、阻止、延迟或与白三烯的作用或活性相作用的试剂或化合物。白三烯抑制剂的非限定性实例包括：montelukast[R-(E)]-1[[[1-[3-[2-(7-氯-2-喹啉基)-乙烯基]苯基]-3-[2-(1-羟基-1-甲基乙基)苯基]丙基]硫基]甲基]环丙烷乙酸和其钠盐，如EP 0 480 717所述；1-(((R)-(3-(2-(6，7-二氟-2-喹啉基)乙烯基)苯基)-3-(2-(2-羟基-2-丙基)苯基)硫基)甲基环丙烷乙酸和其钠盐，如WO 97/28797和U.S.专利5,270,324所述；1-(((1(R)-3(3-(2-(2，3-二氯噻吩并[3，2-b]吡啶-5-基)-(E)-乙烯基)苯基)-3-(2-(1-羟基-1-甲基乙基)苯基)丙基)硫基)甲基)环丙烷乙酸和其钠盐，如WO 97/28797和U.S.专利5,472,964所述；pranlukast，N-[4-氧代-2-(1H-四唑-5-基)-4H-1-苯并吡喃-8-基]-对-(4-苯基丁氧基)苯甲酰胺)，如WO 97/28797和EP 173,516所述；zafirlukast，(环戊基-3-(2-甲氧基-4-[(邻甲苯基磺酰基)氨基甲酰基]苄基]-1-甲基吲哚-5-氨基甲酸酯)，如WO 97/28797和EP199,543所述；和[2-[[2(4-叔丁基-2-噻唑基)-5-苯并呋喃基]氧甲基]苯基]乙酸，如U.S.专利5,296,495和日本专利JP 08325265 A所述。
术语“5-脂氧合酶抑制剂”或“5-LO抑制剂”包括任一种抑制、阻止、延迟或与5-脂氧合酶的酶活性作用的试剂或化合物。5-脂氧合酶抑制剂的非限定性实例包括：弃白通、多西苯醌、piripost、ICl-D2318和ABT 761。
β-肾上腺素能的受体激动剂的非限定性实例包括：沙丁胺醇、比托特罗、异他林、mataproterenol、perbuterol、沙美特罗、特布他林、异丙肾上腺素、麻黄碱和肾上腺素。
黄嘌呤衍生物的非限定性实施例为茶碱。
α-肾上腺素能的受体激动剂的非限定性实例包括：芳基烷基胺(例如苯基丙醇胺和伪麻黄素)、咪唑类(如，萘唑啉、氧甲唑啉、四氢唑啉和赛洛唑啉)和环烷基胺(如，六氢脱氧麻黄碱)。
嗜碱白细胞稳定剂的非限定性实例为萘多罗米钠。
镇咳剂的非限定性实例包括：可待因、右甲吗南、对丁氨苯甲酸甲氧聚乙烯氧基乙酯、氯苯达诺和那可丁。
祛痰剂的非限定性实例为愈创甘油醚。
NK1、NK2和NK3速激肤受体拮抗剂的非限定性实例包括：CP-99,994和SR 48968。
GABAB激动剂的非限定性实例包括：巴氯芬和3-氨基丙基-次膦酸。
为了由本发明所述的化合物制备药物组合物，惰性的可药用载体可为固体或液体。固体形式制剂包括粉剂、片剂、分散颗粒、胶囊、扁囊剂和栓剂。粉剂和片剂可包含约5至约70％的活性成分。适宜的固体载体是本领域中公知的，例如，碳酸镁、硬脂酸镁、滑石、糖、乳糖。片剂、粉剂、扁囊剂和胶囊可作为固体剂型口服给药。
为制备栓剂，首先将低熔点的蜡如脂肪酸甘油酯或椰子油的混合物熔化，然后在搅拌下将活性成分均匀地分散于其中。熔化后的均匀混合物再倒入适当尺码的模型中，冷却，固化。
液体形式的制剂包括溶液、悬浮液和乳液。可提及的实例为用于肠胃外注射的水或水-丙二醇溶液。
液体形式制剂也可以包括经鼻给药的溶液。
适用于吸入给药的气雾剂可包括溶液和粉末形式的固体，其可与可药用载体如惰性压缩空气组合。
本发明还包括固体形式制剂，其可在使用前转化成用于口服或非肠道给药的液体形式制剂。这种液体形式包括溶液、悬浮液和乳液。
本发明的化合物也可通过透皮进行传送。透皮组合物可为霜剂、洗液、气雾剂和/或乳液，其可包含于如用于此目的的现有技术常规采用的基质或贮器型透皮贴袋中。
优选化合物通过口服给药。
优选药物制剂为单位剂量形式。以这种形式，制剂被细分成包含适当量活性成分，例如实现所述目的有效量的单位剂量。
在单位剂量制剂中活性化合物的量可为约0.1mg至1000mg，更优选约1mg至300mg，可根据具体应用情况变化。
实际采用的剂量可根据患者的需要和所治疗的疾病严重程度改变。本领域的技术人员可根据具体情况确定适宜的剂量。通常，治疗初始采用低于化合物最佳剂量的较低剂量。此后，通过小的增量增加剂量，直至达到最佳效果。为方便起见，如果需要的话，可将一天内的总每日剂量细分并分几次服用。
本发明化合物和其可药用盐的给药量和给药频率由临床医师进行判断后调节，考虑如下的因素：患者的年龄、疾病和大小，以及被治疗病症的严重程度。典型推荐剂量口服为10mg至2000mg/天，优选10至1000mg/天，分成两次至四次剂量，以缓减疼痛、焦虑、抑郁、哮喘或酒精滥用。当在该剂量范围内给药时，化合物是无毒的。
为治疗咳嗽，伤害感受蛋白受体ORL-1激动剂单剂量的用量优选为约0.1mg至1000mg，更优选约1mg至300mg。典型的推荐剂量口服为1mg至2000mg/天，优选1至1000mg/天，分成两次至四次剂量。当治疗咳嗽时，伤害感受蛋白受体ORL-1激动剂可与一种或多种其它用于治疗咳嗽、变应性***反应或哮喘症状的试剂一起给药，这些试剂选自：抗组胺药、5-脂氧合酶抑制剂、白三烯抑制剂、H3抑制剂、β-肾上腺素能的受体激动剂、黄嘌呤衍生物、α-肾上腺素能的受体激动剂、嗜碱白细胞稳定剂、抗咳嗽药、祛痰药、NK1、NK2和NK3速激肤受体拮抗药和GABAB激动剂。伤害感受蛋白受体ORL-1激动剂和其它试剂优选以组合剂量形式给药(例如，单一片剂)，当然，它们也可分别给药。其它试剂的给药量应有效地缓减咳嗽、变应性***反应或哮喘症状，其用量优选为约0.1mg至1000mg，更优选约1mg至300mg每单位剂量。其他试剂的典型的推荐剂量为1mg至2000mg/天，优选1至1000mg/天，分成两次至四次剂量。
以下为包含本发明化合物的药物剂量形式的实例。本发明药物组合物方面的范围不受所提供的实施例的限制。
                   药物剂量形式实例
                     实施例A-片剂
  序号   成分   mg/片   mg/片
  1   活性化合物   100   500
  2   乳糖USP   122   113
  3   玉米淀粉，食用级，为在纯水中的10％的糊   30   40
  4   玉米淀粉，食用级   45   40
  5   硬脂酸镁   3   7
          总计   300   700
                       生产方法
在适宜的混合机中将序号物质1和2混合10至15分钟。用3号混合物进行造粒。如果需要的话，用粗筛(例如1/4″，0.63cm)将湿颗粒粉碎。将湿颗粒干燥。如果需要的话，筛分干颗粒，再与4号物质混合并混合10至15分钟。加入5号物质，再混合1至3分钟。将混合物压至适宜的尺寸，并在适宜的压片机上称重。
                     实施例B-胶囊
  序号   成分   mg/胶囊   mg/胶囊
  1   活性化合物   100   500
  2   乳糖USP   106   123
  3   玉米淀粉，食用级   40   70
  4   硬脂酸镁NF   7   7
          总计   253   700
                     生产方法
在适宜的混合机中将序号1、2和3物质混合10至15分钟。再加入4号物质并混合1至3分钟。在适宜的包胶机上，将混合物填充于适宜的两段硬明胶胶囊中。
以上结合具体的实施方案描述了本发明，但对本领域的技术人员来说，其许多的变化、改变和改进均是明显的。所有这些变化、改变和改进均在本发明的精神和保护范围之内。

Claims (9)

1、一种由下式表示的化合物或其可药用盐或溶剂化物，
Figure C998092210002C1
其中X1为R5-(C1-C12)烷基、R6-(C3-C12)环烷基、R7-芳基或R8-杂芳基；
X2为-CN、-(CH2)vOR13、-(CH2)vNR21R22或-(CH2)vNHC(O)R21，其中，v为0、1、2或3 ；
或X1为
或
X2为氢；
或者X1和X2一起形成下式的螺基团
或
其中m为1或2；
p为0或1；
Q为-CH2-或-O-；
R1、R2、R3和R4独立地选自：氢和(C1-C6)烷基，或者(R2和R4)一起形成具有2-3个碳原子的亚烷基桥；
R5为H或R7-芳基；
R6为氢；
R7为1或2个取代基，其独立地选自氢、卤素、(C1-C6)烷基、-CF3、-OR19、-(C1-C6)烷基-OR19、-NR19R20、-(C1-C6)烷基-NR19R20、-COR19、-COOR19、-(C1-C6)烷基-NHSO2-(C1-C6)烷基；
R8为氢或(C1-C6)烷基；
R9为卤素或-OR19；
R11独立地选自H、R5-(C1-C6)烷基、-(C1-C6)烷基(C3-C12)环烷基、-(C1-C6)烷基-OR19、-(C1-C6)烷基-NR19R20、-(C1-C6)烷基-COOR18，-(C3-C6)链烯基和-(C3-C6)链炔基；和
其中，q为1-3，a为1或2；
R12为H；
R13为H或-(C1-C6)烷基；
R17是苯基；
R19和R20独立地选自氢、(C1-C6)烷基和(C3-C12)环烷基；
R21和R22独立地选自氢、(C1-C6)烷基、(C3-C12)环烷基、(C3-C12)环烷基(C1-C6)烷基、-(C1-C6)烷基(C3-C7)-杂环烷基、R7-芳基、R7-芳基(C1-C6)烷基、R8-杂芳基(C1-C12)烷基、-(C1-C6)烷基-CR9、-(C1-C6)烷基-NR19R20或-(C1-C6)烷基-SR19；
Z1为R7-芳基； Z2为R7-芳基； Z3为氢或(C1-C6)烷基；
R26独立地选自H和(C1-C6)烷基；
条件是，当X1为
Figure C998092210003C2
或X1和X2一起为
且Z1为R7-苯基和Z2为R7-苯基时，至少一个R7是邻位卤代或邻位C1-C6烷基；
其中，芳基为苯基，杂芳基选自：吲哚基，噻唑基，吡啶基，呋喃基和噻吩基；杂环基为哌啶基。
2、根据权利要求1的化合物，其中，X1为R7-芳基，X2为OH或-NHC(O)R21。
3、根据权利要求1的化合物，其中，X1为
Figure C998092210004C1
并且X2为氢。
4、根据权利要求1的化合物，其中，X1和X2一起形成螺环基团
Figure C998092210004C2
5、权利要求1的化合物，其选自：
Figure C998092210005C1
6、一种药物组合物，其包含治疗有效量的权利要求1的化合物和与之相结合的可药用载体。
7、一种药物组合物，其包含治疗有效量的权利要求1-5之任一的化合物，该化合物是伤害感受蛋白受体ORL-1激动剂；治疗有效量的第二种试剂，其选自：抗组胺药、5-脂氧合酶抑制剂、白三烯抑制剂、H3抑制剂、β-肾上腺素能的受体激动剂、黄嘌呤衍生物、α-肾上腺素能的受体激动剂、肥大细胞稳定剂、抗咳嗽药、祛痰药、NK1、NK2和NK3速激肽受体拮抗药和GABAB激动剂；及可药用载体。
8、权利要求1的化合物在制备用于治疗疼痛、焦虑、咳嗽、哮喘、抑郁症或酒精滥用的药物中的用途。
9、权利要求1-5之任一的化合物单独或与用于治疗咳嗽、变应性或哮喘症状的第二试剂组合在制备用于治疗咳嗽中的药物中用途，该试剂选自：抗组胺药、5-脂氧合酶抑制剂、白三烯抑制剂、H3抑制剂、β-肾上腺素能的受体激动剂、黄嘌呤衍生物、α-肾上腺素能的受体激动剂、肥大细胞稳定剂、抗咳嗽药、祛痰药、NK1、NK2和NK3速激肽受体拮抗药和GABAB激动剂，其中，所述化合物是伤害感受蛋白受体ORL-1激动剂。
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