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CN1212689A - 新颖芳基甘氨酰胺衍生物,其制法及含这些化合物的药物组合物 - Google Patents

新颖芳基甘氨酰胺衍生物,其制法及含这些化合物的药物组合物 Download PDF

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CN1212689A
CN1212689A CN97192786A CN97192786A CN1212689A CN 1212689 A CN1212689 A CN 1212689A CN 97192786 A CN97192786 A CN 97192786A CN 97192786 A CN97192786 A CN 97192786A CN 1212689 A CN1212689 A CN 1212689A
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alkyl
phenyl
compound
independently
methyl
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CN1072664C (zh
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弗朗兹·埃瑟
格尔德·施诺伦伯格
库尔特·施罗姆
霍斯特·多林格
伯吉特·琼
乔治·斯佩克
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Abstract

本发明是关于新颖的通式Ⅰ芳基甘氨酰胺衍生物及其药物上可用的盐,其中R1及R2共同和与其键合的N形成式(a)、(b)、(c)或(d)的环中之一,其中,R3,R4,R5,Ar,R6,R7,R8,R9,R10,R11,r,s及t的定义如说明书所述,并公开其制备及用途。这些新颖化合物是有价值的神经激肽(速激肽)拮抗剂。

Description

新颖芳基甘氨酰胺衍生物， 其制法及含这些化合物 的药物组合物
本发明涉及如下通式的新颖芳基甘氨酰胺衍生物
Figure A9719278600131
及其药物上可用盐，其制备方法，及含有这些化合物的药物组合物。这些化合物是有价值的神经激肽(速激肽)拮抗剂。
于本说明书及权利要求中所用的缩写有以下解释：CDI=羰基二咪唑DCCI=二环己基碳化二亚胺HOBt=1-羟基苯并三唑THF=四氢呋喃DMF=二甲基甲酰胺RT=室温DMAP=4-二甲基氨基吡啶TBTU=O-苯并三唑基-四甲基 四氟硼酸酯
用简化方式表示各结构式。在表示化合物中，例如，所有的CH3-取代基都以一个短线代表，CH以≡代表，这样，例如：
Figure A9719278600133
是指
Figure A9719278600141
本发明是关于通式Ⅰ的新颖芳基甘氨酰胺衍生物
Figure A9719278600142
或其药物上可用盐，其中Ar是未取代的或单-至五-取代的苯基，或者未取代的或单-至二-取代的
萘基[其中苯基及萘基的取代基彼此独立是卤素(F,Cl,Br,I),(C1-4
)烷基，O-(C1-4)烷基，CF3,OCF3或NR12R13(其中R12及R13彼此独
立是H，甲基或乙酰基)]或Ar是以-O-CH2-O-或-O-(CH2)2-O
取代的苯基；R1和R2与和其键合的N共同形成下式的环
Figure A9719278600143
或
其中r,s及t是2或3；R6是H,(C1-5)烷基，(C3-5)烯基，丙炔基，羟基(C2-4)烷基，甲氧基(C2-4)烷基，二(C1-3)烷基氨基(C2-4)烷基，氨基(C2-4)烷基，氨基，二(C1-3)烷基氨基，单氟-至全氟(C1-2)烷基，N-甲基哌啶基，吡啶基，嘧啶基，吡嗪基，哒嗪基，或-CH2-C(O)NR14R15基团，其中R14是H或(C1-4)烷基及R15是H,(C1-4)烷基，(C3-6)环烷基，羟基(C2-4)烷基，烷氧基(C2-3)烷基，苯基(C1-4)烷基，或R14及R15共同和与其键合的N形成一个环(1-吡咯烷基，1-哌啶基，N吗啉基或1-甲基哌嗪-4-基)；R7有(a)至(d)中的定义，
(a)羟基
(b)4-哌啶基哌啶基，
Figure A9719278600161
其中R16及R17彼此独立是H,(C1-4)烷基，(C3-6)环烷基，羟基(C2-4)烷基，(C1-3)烷氧基(C2-4)烷基，苯基(C1-4)烷基或二(C1-3)烷基氨基(C2-4)烷基，或者如R16是H或(C1-4)烷基，则R17也可以是-CH2C(O)NR18R19，其中R18及R10的定义如前述的R14和R15；
Figure A9719278600162
其中R20是
H,
(C1-4)烷基，
(C4-6)环烷基或
-CH2C(O)NR21R22，
其中R21及R22的定义如前述的R14及R15；R8是HR9及R10各自独立，是(C1-4)烷基，R11是H,(C1-5)烷基，(C3-5)烯基，丙炔基，羟基(C2-4)烷基，甲氧基(C2-3)烷基，二(C1-3)烷基氨基(C2-3)烷基，氨基(C2-3)烷基，氨基，二(C1-3)烷基氨基，单氟-至全氟(C1-2)烷基，N-甲基哌啶基，吡啶基，嘧啶基，吡嗪基，哒嗪基，或-CH2-C(O)NR23R24基团，其中R23及R24的定义如前述的R14及R15；R3是H,(C1-4)烷基，未取代的或单-至三-取代的苯基，其中取代基彼此独立是卤素(F,Cl,Br,I),(C1-4)烷基，O-(C1-4)烷基，CF3,OCF3或NR25R26(其中R25及R26彼此独立是H，甲基或乙酰基)；R4是苯基(C1-4)烷基或萘基(C1-4)烷基，其中苯基可被1至3个取代基取代，其中所述取代基各自独立是(F,Cl,Br,I),(C1-4)烷基，O-(C1-4)烷基，CF3,OCF3或NR27R28(其中R27及R28彼此独立是H，甲基或乙酰基)；和R5是H,(C1-4)烷基，(C3-6)环烷基，CH2COOH,CH2C(O)NH2,OH或苯基(C1-4)烷基。优选的通式Ⅰ化合物是；其中Ar是未取代的或单-或二取代的苯基，或未取代的萘基，或Ar是以
-O-CH2-O-或-O(CH2)2-O-取代的苯基；
R1及R2和与其键合的N共同形成下式的环
Figure A9719278600181
或
Figure A9719278600182
其中r是2或3和s及t是2；R6,R7,R8,R9,R10及R11的定义如前述；R3是H或(C1-4)烷基，R4是苯基(C1-4)烷基或萘基(C1-4)烷基，其中苯基可被1或2个取代基取代，
而其中这些取代基各自独立是卤素(F,Cl,Br,I),(C1-4)烷基，
O-(C1-4)烷基，CF3或OCF3；及R5是H,(C1-4)烷基，(C3-6)环烷基，OH或(C1-4)烷基苯基。
优选的式Ⅰ化合物是，其中Ar是未取代的或单-或二取代的苯基，或未取代的萘基[其中苯基的取代
基各自独立是卤素(F,Cl,Br,I)，甲基，甲氧基，CF3或OCF3]或Ar
是被-O-CH2-O-或-O-(CH2)2-O-取代的苯基；特别是那些式Ⅰ化合物，其中Ar是苯基，萘基，在3和/或4位被甲氧基或卤素取代的苯基，或2和3位或3和4位以-O-CH2-O-连结的苯基，特别优选的化合物是，其中Ar是苯基，在3和4位被甲氧基取代的苯基或在3和4或2和3位被-O-CH2-O-连结的苯基。
上述化合物中，特别优选的化合物是其中，在下环中
Figure A9719278600191
r是2或3及R6是H,(C1-5)烷基，(C3-5)烯基，丙炔基，羟基(C2-4)烷基，甲氧基(C2-4)烷基，二(C1-3)烷基氨基(C2-4)烷基，氨基(C2-4)烷基，氨基，二(C1-3)烷基氨基，单氟-至全氟(C1-2)烷基，N-甲基哌啶基，吡啶基，嘧啶基，或
Figure A9719278600192
特别优选的化合物是，其中r是3和R6是甲基；以及，其中r是2及R6是H,(C1-4)烷基，丙烯基，丙炔基，羟基(C2-3)烷基，甲氧基乙基，二(C1-2)烷基氨基(C2-3)烷基，氨基乙基，氨基，二甲基氨基，CH2CF3,N-甲基哌啶基，吡啶基，嘧啶基，或较佳化合物是，其中r是2及R6是H,(C1-3)烷基，烯丙基，2-丙炔基，-CH2CH2OCH3,-CH2-CH2N(CH3)2,N-甲基哌啶基，2-嘧啶基或
Figure A9719278600202
特别是这些化合物，其中r是2及R6是H,CH3,C3H7,CH(CH3)2,CH2CH2OH,CH2CH2OCH3或
CH2CH2N(CH3)2。
上述化合物中，特别突出的化合物是，其中，R1及R2和与其键合的N共同形成以下的环其中R8是H及R7是OH
Figure A9719278600212
其中R16及R17彼此独立地是：H(C1-3)烷基，
Figure A9719278600213
(CH2)nOH其中n是2,3或4(CH2)2OCH3-(CH2)nPh其中n是2或4(CH2)2N(CH3)2
Figure A9719278600214
或
Figure A9719278600215
尤其是这些化合物，其中R16及R17都是CH3或C2H5或R16是H或CH3，及R17是(C1-3)烷基，
Figure A9719278600216
(CH2)2OH,(CH2)4OH或
Figure A9719278600221
R7是N(CH3)2
Figure A9719278600223
或
Figure A9719278600224
特别是这些化合物，其中R1及R2和与其键合的N共同形成如下的环
Figure A9719278600225
其中(a)R8是H及
R7是
Figure A9719278600226
其中R16及R17二者都是CH3,C2H5或CH2CH2OH或R16是H或CH3而R17是(C1-3)烷基，
Figure A9719278600227
(CH2)2OH或(CH2)4OH或(b)R8是H和R7是
Figure A9719278600231
上述化合物中，更突出的化合物是，其中，R1及R2和与其键合的N共同形成如下的环
上述化合物中，更为突出的化合物是，其中，R1及R2和与其键合的N共同形成如下的环
Figure A9719278600233
其中R11是H或(C1-3)烷基，特别是这些化合物其中R11是-CH(CH3)2。
上述化合物中，特佳的是这些化合物，其中R3是H；和/或R4是苯基(C1-4)烷基，其中苯基可被1或2个取代基取代，而其中取代基彼
此独立并是卤素(F,Cl,Br,I),(C1-4)烷基，O-(C1-4)烷基，CF3
或OCF3；和/或R5是H,(C1-4)烷基，(C3-6)环烷基，-OH或苯基(C1-4)烷基，特别是这些化合物，其中R4是苯基(C2-4)烷基，其中取代基是位于苯基环的3和/或5位和/或R5是H，甲基，OH或苯乙基，优选的是这些化合物，其中R4是及R5是甲基。
通式Ⅰ化合物可以有酸基团，主要是羧基，和/或碱基团，如氨基，所以通式Ⅰ化合物可以以内盐形式存在，例如和药物上可用的无机酸，如盐酸，硫酸，磷酸，磺酸，或有机酸(如马来酸，富马酸，柠檬酸，酒石酸或醋酸)所形成的盐，或和药物上可用的碱，如碱金属或碱土金属的氢氧化物或碳酸盐，或和有机胺，如二甲基胺，三乙基胺，三乙醇胺等所成的盐。
根据本发明的化合物可以以外消旋物存在，但也可制得纯的对映体，即(R)-或(S)-型。
上面所用的“萘基”一词包括1-萘基及2-萘基。
根据本发明化合物的试验结果：
对NK1-受体(P-受体物质)的受体亲合性是用无性繁殖的NK1-受体在人的成淋巴细胞瘤的细胞(IM-9)上，通过测量125I-标记的物质P的置换而进行测定。这样得到的Ki-值表明这些化合物的有效性：
        Ki[nM]
实例1    1.2
实例2    1.0
实例3    19
实例4    1.4
实例5    1.5
实例8    1.8
实例9    2.5
实例11   3.8
实例12   5.0
实例13   2.4
实例15   0.98
实例16   0.90
实例17   7.75
实例18    0.96
实例19    1.17
实例20    2.0
实例22    2.2
实例23    2.5
实例24    2.2
实例25    6.0
实例26    1.6
实例28    1.3
实例30    1.8
实例32    1.3
实例33    7.4
实例34    2.9
实例47    1.7
实例55    1.25
实例63    1.4
实例64    1.1
实例65    5.7
实例73    2.0
实例74    1.5
实例75    0.44
实例76    2.0
根据本发明的化合物是有价值的神经激肽(速激肽)拮抗剂，不但具有物质P拮抗作用也有神经激肽A或神经激肽B拮抗性质。这些化合物可用于治疗及预防由神经激肽所致的疾病：
用于治疗或预防呼吸道发炎及过敏疾病，如哮喘，慢性气管炎，呼吸道敏感，肺气肿，鼻炎及咳嗽，及治疗或预防眼睛疾病，如结膜炎及虹膜炎，治疗或预防皮肤疾病，如接触性皮炎，荨麻疹，牛皮癣，晒斑，昆虫咬螫，痒，敏感性或过敏性皮肤，治疗或预防胃肠道疾病，如胃及十二指肠溃疡，溃疡性结肠炎，节段性回肠炎，结肠痉挛及先天性巨肠炎(Hirschsprung)。
治疗或预防关节疾病，如类风湿性关节炎，反应性(reactive)关节为及赖特尔(Reiter)氏综合症；供治疗中枢神经系统疾病，如痴呆，初老期痴呆，精神分裂症，精神病，抑郁，头痛(例如偏头痛或紧张性头痛)，癫痫，帕金森氏病及中风；
供治疗带状疱疹及疱疹后疼痛，肿瘤，胶原性疾病，输精泌尿道机能障碍，痔疮，恶心及呕吐，例如因辐射或抑制细胞生长的治疗或运动及各种疼痛所引起的。
本发明也关于本发明的化合物在作为治疗剂及含这些化合物的药物制剂中的用途。这些化合物优选使用于人类。本发明的化合物可以以静脉内、皮下、肌肉内、腹腔内或鼻内的途径给药，可以吸入、经皮的途径给药，视需要可通过离子电渗疗法或文献中已知的增强剂给药，或经口服给药。
对非结肠胃给药时，式Ⅰ化合物或其生理可用盐可与常用的物质，如增溶剂，乳化剂或其他佐剂组合以溶液、悬浮或乳化形式存在。可用的溶剂包括：水，生理食盐水溶液或醇，例如乙醇、丙二醇或甘油，糖溶液如葡萄糖或甘露糖溶液或几种溶剂的混合物。
此外，这种化合物可通过植入物给药，例如聚交酯，聚乙二醇酯或聚羟基丁酸或鼻内制剂。
通式Ⅰ化合物的口服效果可通过下述标准试验表示：抑制麻醉的天竺鼠因NK1引起的血压降低。
将重300-500克的天竺鼠以戊巴比妥(50毫克/公斤，腹腔内给予)麻醉，插管，人工呼吸。人工呼吸是10毫升/公斤空气，每分钟60次。在颈动脉插管，并记录动脉血压。将聚乙烯管插入颈静脉以便静脉内给予物质。
每10分钟静脉内给予NK1-激动剂[βAla4,Sar9,Met(O2)11]SP(4-11)
Figure A9719278600271
使血压暂时降低，所给剂量为0.2μmol/公斤。在测出这样产生的血压后，将试验化合物引入十二指肠，并再在每10分钟注射一次NK1-激动剂。
结果以抑制因特定的NK1-激动剂引起的血压降低的％表示。
实施例1化合物在剂量为1毫克/公斤(给予人十二指肠)时，对NK1-激动剂导致的血压降低的抑制为80％。
本发明的化合物可以按通常已知方法制备。
这些化合物可以用各种方法制备。最普通的二种制备方法说明如下：方法A。将羧酸以各种方法与胺HN(R5)R4连结。常用的方法是偶合方法，如肽化学上所用的方法。以几乎等量的偶合剂，如TBTU,DCCI/HOBt,CDI，等，加到偶合参与者(coupling partners)中。适宜的溶剂是DMF,THF,CH2Cl2,CHCl3，乙腈其他惰性溶剂或其混合物。适宜的温度是-50℃至+120℃，较佳是0℃到40℃。
也可先将羧酸按已知方法使用SOCl2,SO2Cl2,PCl3,PCl5或PBr3，或其混合物转化成相应的酰基卤化物，使酰基卤化物与胺HN(R5)R4在惰性溶剂，如CH2Cl2,THF或二噁烷中于-50℃至+100℃，一般是0℃至20℃温度下进行反应。
另一方法是先将羧酸用已知方法转化成烷基酯，一般是甲基酯，然后将该酯与胺HN(R5)R4在惰性溶剂，如DMF，二噁烷或THF中进行反应。反应温度是20℃至150℃，一般是50℃至120℃。此反应也可在加压容器内进行。方法B．本方法是将按已知方法制得的α-卤基-芳基乙酰胺衍生物与胺R1(R2)NH在卤化氢的裂解下进行反应。使用无机碱，如K2CO3,NaHCO3或CaCO3，或有机碱，如三乙基胺，亨尼格(Hunig)碱，吡啶或DMAP，也可使用过量的胺R1(R2)NH清除裂解的(或过多的)卤化氢。使用DMF,THF，二噁烷或其他惰性溶剂。反应温度是0℃至100℃，一般是10℃至80℃。方法C．本发明化合物，其中R5不是H，也可如下制备：首先，按方法A或B合成R5是H的对应化合物。然后，以下方法进行N-烷基化，引入烷基，环烷基或CH2COOH。根据本发明R5是H的化合物用等当量的NaH,NaNH2,KOH,NaOCH3或其他强碱进行去质子化。该反应使用无水惰性溶剂，如THF，二噁烷或二乙基醚。然后缓慢加入对应卤化物，甲苯磺酸酯或甲磺酸酯形式的烷基化剂。该反应是在-50℃至+100℃，一般是0℃至+50℃进行。
实施例1：熔点：105-115℃FAB-MS:(M+H)+=516,3第一步骤：将0.71克1-异丙基哌嗪溶于55毫升无水DMF内，与0.64克Na2CO3混合，于室温搅拌20分钟，然后冷至5℃。加1.15克(R,S)-α-溴苯基醋酸甲酯，该悬浮液在室温下搅拌过夜。滤去沉淀，蒸发滤液。残余物溶于醋酸乙酯内，用10％的KHCO3溶液萃取二次，再用饱和NaCl溶液萃取一次。有机相于Na2SO4上干燥，过滤，蒸发，制得1.23克(R,S)-1-异丙基-4-(2-苯基醋酸)甲酯哌嗪，呈粘稠油体。产率：约89％。第二步骤；将1.23克第一步骤中的产物溶于10毫升甲醇及10毫升THF内，与10毫升1NNaOH混合，将该混合物于室温搅拌过夜。加10毫升1NHCl中和澄清的反应溶液，蒸发至干，残余物用DMF处理，吸滤出固体，滤液蒸发至干，残余物用乙醚研制，吸滤固体并于干燥器内干燥。这样即制得1.1克(R,S)-1-异-丙基-4-(2-苯基醋酸)-六氢哌嗪，呈白色固体。产率：92％第三步骤：将0.37克第二步骤的产物和0.42克N-甲基-3.5-双(三氟甲基)-苯基乙基胺溶于14毫升DMF中，加入约0.4毫升TEA调整至pH8.5。加0.48克TBTU，将该混合物在室温下搅拌过夜。将该澄清溶液真空蒸发。残余物用NaHCO3溶液搅拌，用醋酸乙酯萃取二次。将合并的有机相过滤，再将滤液蒸发。残余物在硅胶上进行色谱纯化，用CH2Cl2/MeOH(9∶1)作淋洗液。将所得的同样部分蒸发，并溶于少量MeOH中，用醚化HCl酸化，再蒸发。残余物用乙醚研磨，于干燥器内干燥。制得0.58克(R,S)-1-异-丙基-4-[2-苯基醋酸-N-甲基-N-(3,5-双三氟甲基苯基乙基)]酰胺二盐酸化物，呈白色固体。产率：75％。本发明其他化合物可以类似方法制备，如以下实施例：
实施例2：
Figure A9719278600301
熔点：141-146℃FAB-MS(M+H)+=474,3实施例3：
Figure A9719278600302
熔点：122-132℃FAB-MS:(M+H)+=552,4实施例4：
Figure A9719278600311
熔点：138-148℃FAB-MS:(M+H)+=502,3实施例5：
Figure A9719278600312
熔点：231-241℃(Zers.)FAB-MS:(M+H)+=516,4实施例6：
Figure A9719278600313
熔点：122-132℃FAB-MS:(M+H)+=518,1实施例7：熔点：168-174℃(Zers)FAB-MS:M+=502,3实施例8：熔点：＞240℃实施例9：
Figure A9719278600323
熔点：＞230℃实施例11：
Figure A9719278600331
沸点：130-160℃熔点：215-218℃(分解)实施例12：熔点：＞230℃实施例13：
Figure A9719278600333
熔点：＞230℃实施例15：沸点：～120-143℃实施例16：
Figure A9719278600342
熔点：168-170℃实施例17：
Figure A9719278600343
熔点：142-150℃实施例18：熔点：＞230℃实施例19：
Figure A9719278600352
熔点：202°-204℃实施例20：
Figure A9719278600353
熔点：178°-180℃实施例22：
Figure A9719278600361
熔点：191°-193℃实施例23：
Figure A9719278600362
熔点：162°-164℃实施例24：熔点：220-224℃(分解)：FAB-MS:(M+H)+=514,3实施例25：熔点：102-117℃:FAB-MS:(M+H)+=512,4实施例26：熔点：225°-232℃(分解),FAB-MS(M+H)+=518,3实施例27：
Figure A9719278600373
实施例28：熔点：242-245℃(分解)FAB-MS:(M+H)+=545,2实施例29：
Figure A9719278600382
实施例30：
Figure A9719278600383
熔点：115°-124℃；FAB-MS:(M+H)+=532,3实施例31：
Figure A9719278600391
实施例32：
Figure A9719278600392
熔点：107-112℃；FAB-MS:(M+H)+=530,2实施例33：
Figure A9719278600393
熔点：133-143℃,FAB-MS:(M+H)+=530,4实施例34：
Figure A9719278600401
熔点：178-182℃；FAB-MS:(M+H)+=488,3实施例35：
Figure A9719278600402
实施例36：
Figure A9719278600403
实施例37：
Figure A9719278600411
实施例38：
Figure A9719278600412
实施例39：
Figure A9719278600413
实施例40：
Figure A9719278600414
实施例41：
Figure A9719278600421
实施例42：
Figure A9719278600422
实施例43：
Figure A9719278600423
实施例44：
Figure A9719278600431
实施例45：
Figure A9719278600432
实施例46：
Figure A9719278600433
实施例47：
Figure A9719278600441
熔点：149-159℃FAB-MS:(M+H)+=534,3实施例48：
Figure A9719278600442
实施例49：
Figure A9719278600443
实施例50：实施例51：
Figure A9719278600452
实施例53：
Figure A9719278600453
实施例54：
Figure A9719278600461
实施例55：
Figure A9719278600462
熔点：115-119℃实施例56：
Figure A9719278600463
实施例57：
Figure A9719278600471
实施例58：
Figure A9719278600472
实施例59：
Figure A9719278600473
实施例60：
Figure A9719278600481
实施例61：
Figure A9719278600482
实施例63：熔点：218-228℃(分解)FAB-MS:(M+H)+=516,3实施例64：
Figure A9719278600491
熔点：92-96℃FAB-MS:(M+H)+=488,2实施例65：
Figure A9719278600492
熔点：132-142℃FAB-MS:(M+H)+=576,5实施例66：
Figure A9719278600493
熔点：131-141℃FAB-MS:(M+H)+=560,1实施例67：熔点：228-231℃(分解)FAB-MS:(M+H)+=502,3实施例68：
Figure A9719278600502
实施例69：
Figure A9719278600503
实施例70：实施例71：
Figure A9719278600512
实施例72：实施例73：
Figure A9719278600514
熔点：108-118℃FAB-MS(M+H)+=560,4实施例74：熔点：138-148℃[α]D 20=+45,5°(MeOH)实施例75：
Figure A9719278600522
熔点：166-176℃[α]D 20=+19,0°(DMSO).实施例76：
Figure A9719278600523
熔点：132-134℃
这些化合物中，以实施例1和8化合物优选。
本文使用的上述结构式中，CH3基团并未画出。
例如，化合物1含有甲基作为R5。药物制剂注射溶液
200mg活性物质*
1.2mg磷酸二氢钾=KH2PO4         )
0.2mg磷酸氢二钠=Na2HPO42H2O= )(缓冲液)
94mg氯化钠                         )(等渗液)
520mg葡萄糖                        )
4mg白蛋白                          (保护蛋白酶)
适量氢氧化钠溶液                   )
适量盐酸                           )调整至pH6
注射用水加至10ml
注射液
200mg活性物质*
94mg氯化钠
或520mg葡萄糖
4mg白蛋白
适量氢氧化钠溶液                   )
适量盐酸                           )调整至pH9
注射用水加至10ml
冷冻干燥剂
200mg活性物质*
520mg甘露糖(等渗剂/结构成形剂(Gerustbilder))
4mg白蛋白
冷冻干燥剂用的溶剂1
10ml注射用水
冷冻干燥剂用的溶剂2
20mg多乙氧基醚80=吐温80(表面活性剂)
10ml注射用水
*活性物质：本发明的化合物，例如实例1至76之一
重67公斤的成人剂量：1至500毫克

Claims (25)

1．一种通式Ⅰ的芳基甘氨酰胺衍生物或其药物上可用盐：其中Ar指未取代的或单-至五-取代的苯基，或者未取代的或单-至二-取代的萘基[其中苯基及萘基的取代基彼此独立并是卤素(F,Cl,Br,I),(C1 -4)烷基，O-(C1-4)烷基，CF3,OCF3或NR12R13(其中R12及R13彼此独立并是H，甲基或乙酰基)]或Ar是以-O-CH2-O-或-O-(CH2)2-O取代的苯基；R1和R2与和其键合的N共同形成下式的环
Figure A9719278600022
或
Figure A9719278600023
其中r,s及t是2或3；R6是H,(C1-5)烷基，(C3-5)烯基，丙炔基，羟基(C2-4)烷基，甲氧基(C2-4)烷基，二(C1-3)烷基氨基(C2-4)烷基，氨基(C2-4)烷基，氨基，二(C1-3)烷基氨基，单氟-至全氟(C1-2)烷基，N-甲基哌啶基，吡啶基，嘧啶基，吡嗪基，哒嗪基，或-CH2-C(O)NR14R15基团，其中R14是H或(C1-4)烷基和R15是H,(C1-4)烷基，(C3-6)环烷基，羟基(C2-4)烷基，烷氧基(C2-3)烷基，苯基(C1-4)烷基，或R14及R15与和其键合的N共同形成一个环(1-吡咯烷基，1-哌啶基，N-吗啉基或1-甲基哌嗪-4-基)；R7有(a)至(d)的定义，(a)羟基(b)4-1-哌啶基哌啶基，
Figure A9719278600031
其中R16及R17彼此独立是H,(C1-4)烷基，(C3-6)环烷基，羟基(C2-4)烷基，(C1-3)烷氧基(C2-4)烷基，苯基(C1-4)烷基或二(C1-3)烷基氨基(C2-4)烷基，或如果R16是H或(C1-4)烷基，则R17也可以是-CH2C(O)NR18R19，其中R18及R19的定义如上述的R14和R15的定义；
Figure A9719278600041
其中R20是H,(C1-4)烷基，(C4-6)环烷基或-CH2C(O)NR21R22，其中R21及R22如上述R14及R15所定义；R8是HR9及R10各自独立是(C1-4)烷基，R11是H,(C1-5)烷基，(C3-5)烯基，丙炔基，羟基(C2-4)烷基，甲氧基(C2-3)烷基，二(C1-3)烷基氨基(C2-3)烷基，氨基(C2-3)烷基，氨基，二(C1-3)烷基氨基，单氟-至全氟(C1-2)烷基，N-甲基哌啶基，吡啶基，嘧啶基，吡嗪基，哒嗪基，或-CH2-C(O)NR23R24基团，其中R23及R24如上述R14及R15所定义；R3是H,(C1-4)烷基，未取代的或单-至三-取代的苯基，其中取代基彼此
独立是卤素(F,Cl,Br,I),(C1-4)烷基，O-(C1-4)烷基，CF3,
OCF3或NR25R26(其中R25及R26彼此独立是H，甲基或乙酰基)；R4是苯基(C1-4)烷基或萘基(C1-4)烷基，其中苯基可被1至3个取代基取代，
其中这些取代基各自独立是卤素(F,Cl,Br,I),(C1-4)烷基，
O-(C1-4)烷基，CF3,OCF3或NR27R28(其中R27及R28彼此独立是H，甲基或
乙酰基)；及R5是H,(C1-4)烷基，(C3-6)环烷基，CH2COOH,CH2C(O)CH2,OH或
苯基(C1-4)烷基。
2．根据权利要求1的化合物，其中Ar是未取代的或单-或二取代的苯基，或未取代的萘基，或Ar是以
-O-CH2-O-或-O(CH2)2-O取代的苯基；R1及R2与和其键合的N共同形成下式的环 或
Figure A9719278600062
其中r是2或3及s及t是2；R6,R7,R8,R9,R10及R11如权利要求1所述定义；R3是H或(C1-4)烷基，R4是苯基(C1-4)烷基或萘基(C1-4)烷基，其中苯基可被1或2个取代基取
代，而其中这些取代基各自独立是卤素(F,Cl,Br,I),(C1-4)烷基，
O-(C1-4)烷基，CF3或OCF3；及R5是H,(C1-4)烷基，(C3-6)环烷基，OH或苯基(C1-4)烷基。
3．根据权利要求1或2的化合物，其中Ar是未取代的或单-或二取代的苯基，或未取代的萘基[其中苯基的取代
基彼此独立是卤素(F,C,1Br,I)，甲基，甲氧基，CF3或OCF3]或Ar
是被-O-CH2-O-或-O-(CH2)2-O-取代的苯基。
4．根据权利要求3的化合物，其中Ar是苯基，萘基，以甲氧基或卤素在3及/或4位取代的苯基，或在2与3位或3与4位通过-O-CH2-O-相连的苯基。
5．根据权利要求4的化合物，其中Ar是苯基，被甲氧基于3及4位取代的苯基，或在3与4位或2与3位通过-O-CH2-O-连结的苯基。
6．根据权利要求1至5中之一的化合物，其中在环中
Figure A9719278600063
r是2或3及R6是H,(C1-5)烷基，(C3-5)烯基，丙炔基，羟基(C2-4)烷基，甲氧基(C2-4)烷基，二(C1-3)烷基氨基(C2-4)烷基，氨基(C2-4)烷基，氨基，二(C1-3)烷基氨基，单氟-至全氟(C1-2)烷基，N-甲基哌啶基，吡啶基，嘧啶基，或
Figure A9719278600071
7．根据权利要求6的化合物，其中r是3和R6是甲基。
8．根据权利要求6的化合物，其中r是2及R6是H,(C1-4)烷基，丙烯基，丙炔基，羟基(C2-3)烷基，甲氧基乙基，二(C1-2)烷基氨基(C2-3)烷基，氨基乙基，氨基，二甲基氨基，CH2CF3,N-甲基哌啶基，吡啶基，嘧啶基，或
Figure A9719278600081
9．根据权利要求8的化合物，其中r是2及R6是H,(C1-3)烷基，烯丙基，2-丙炔基，-CH2CH2OCH3,-CH2CH2N(CH3)2,N-甲基哌啶基，2-嘧啶基或
Figure A9719278600082
10．根据权利要求9的化合物，其中r是2及R6是H,CH3,C3H7,CH(CH3)2,CH2CH2OH,CH2CH2OCH3或CH2CH2N(CH3)2。
11．根据权利要求1至5中之一的化合物，其中R1及R2与和其相连的N共同形成以下的环其中R8是H，而R7是OH
Figure A9719278600084
其中R16及R17彼此独立地是：H(C1-3)烷基，(CH2)nOH，其中n是2,3或4(CH2)2OCH3-(CH2)nPh其中n是2或4(CH2)2N(CH3)2
Figure A9719278600092
Figure A9719278600093
或
Figure A9719278600094
12．根据权利要求11的化合物，其中R16及R17都是CH3或C2H5或R16是H或CH3，及R17是(C1-3)烷基，
Figure A9719278600095
(CH2)2OH,(CH2)4OH或
Figure A9719278600096
13．根据权利要求11的化合物，其中R7是
Figure A9719278600101
N(CH3)2
Figure A9719278600102
或
Figure A9719278600103
14．根据权利要求11的化合物，其中R1及R2与和其相连的N共同形成如下的环
Figure A9719278600104
其中(a)R8是H而R7是
Figure A9719278600105
其中R16及R17都代表CH3,C2H5或CH2CH2OH或R16是H或CH3，而R17是(C1-3)烷基，
Figure A9719278600106
(CH2)2OH或(CH2)4OH或(b)R8是H而R7是
Figure A9719278600111
15．根据权利要求1至5中之一的化合物是其中，R1及R2与和其键合的N共同形成如下的环
Figure A9719278600112
16．根据权利要求1至5中之一的化合物是，其中，R1及R2与和其键合的N共同形成如下的环
其中R11是H或(C1-3)烷基。
17．根据权利要求16的化合物，其中
R11是-CH(CH3)2。
18．根据权利要求1至17中之一的化合物，其中R3是H。
19．根据权利要求1至18中之一的化合物，其中
R4是苯基(C1-4)烷基，其中苯基可被1或2个取代基取代的，其中这些
取代基彼此独立、是卤素(F,Cl,Br,I),(C1-4)烷基，O-(C1-4)
烷基，CF3或OCF3；及
R5是H,(C1-4)烷基，(C3-6)环烷基，-OH或苯基(C1-4)烷基。
20．根据权利要求19的化合物，其中
R4是苯基(C2-4)烷基，其中取代基是位于苯基环的3及/或5位及
R5是H，甲基，OH或苯乙基。
21．根据权利要求20的化合物，其中R4是
Figure A9719278600114
而R5是甲基。
22．一种制备权利要求1至21中之一的通式Ⅰ化合物的方法，其特征在于(a)将下式酸
Figure A9719278600121
或其卤化物或烷基酯和下式的胺反应
Figure A9719278600122
(b)将下式的α-卤基芳基乙酰胺
Figure A9719278600123
与下式的胺反应
Figure A9719278600124
(c)将R5为H的式Ⅰ化合物进行N-烷基化；
再将这样制得的化合物分离成呈游离态化合物或其药物上可用盐。
23．一种药物制剂，它含权利要求1至21中之一项的化合物和惯用的载体和/或赋形剂。
24．权利要求1至22中之一的化合物在制备治疗及预防神经激肽引起的疾病用的药物制剂中的用途。
25．权利要求1至22中之一的化合物在治疗及预防神经激肽引起的疾病中的用途。
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