CN1180352A - 新颖的芳基甘氨酰胺衍生物,其制造方法及含该化合物的药物组合物 - Google Patents

新颖的芳基甘氨酰胺衍生物,其制造方法及含该化合物的药物组合物 Download PDF

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CN1180352A
CN1180352A CN96193094A CN96193094A CN1180352A CN 1180352 A CN1180352 A CN 1180352A CN 96193094 A CN96193094 A CN 96193094A CN 96193094 A CN96193094 A CN 96193094A CN 1180352 A CN1180352 A CN 1180352A
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格尔德·施诺伦伯格
霍斯特·多林格
弗朗兹·埃瑟
汉斯·布里姆
伯吉特·琼格
乔格·斯佩克
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Boehringer Ingelheim GmbH
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Abstract

本发明有关一种新颖的通式Ⅰ的芳基甘氨酰胺衍生物和其医药上可接受的盐以及其制备和用途,其中R1及R2及和它键合的N一起形成以下的环（右下式），其中,p是2或3,且X表示氧、N(CH2)nR6或CR7R8,且R3、R4、R5、R6、R7、R8、Ar及n具有说明书中所示的定义,这种新颖化合物是有价值的神经激肽(速激肽)－拮抗剂。

Description

新颖的芳基甘氨酰胺衍生物， 其制造方法及含该化合物 的药物组合物
本发明有关一种新颖的通式I的芳基甘氨酰胺衍生物和其医药上可接受的盐，以及其制备方法和含有该化合物的药物组合物。该化合物是有价值的神经激肽(速激肽)-拮抗剂。
说明书及权利要求书中所用的缩写说明如下：
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＝4-二甲胺基吡啶
TBTU＝四氟硼酸O-苯并三唑基-四甲基糖醛鎓
为了表示该式，使用简化的表示法。在化合物的表示中，所有CH3取代基都以单键表示，例如下式
Figure A9619309400102
表示
Figure A9619309400111
本发明有关一种新颖的通式I芳基甘氨酰胺衍生物或其药物上可接受的盐，其中Ar表示未经取代或经单-至五-取代的苯基，或不经取代或经单-或双-
取代的萘基[其中苯基及萘基的取代基各为卤素(F、Cl、Br、I)、
OH、(C1-4)烷基、O-(C1-4)烷基、CF3、OCF3或NR9R10(其中R9
和R10分别表示H、甲基或乙酰基)]或Ar是经-OCH2O-或-O(CH2)2O-
取代的苯基；R1  及R2和与其键合的N一起形成下式的环其中p是2或3，X表示氧、N(CH2)nR6或CR7R8，其中n是0、1或2，R6是(C3-7)环烷基、苯基或萘基，其中苯基可由卤素(F、Cl、Br、I)、(
C1-4)烷基、O-(C1-4)烷基、CF3、OCF3或NR15R16(其中R15及R16分
别表示H、甲基或乙酰基)单-至三-取代；R7及R8具有下述定义中之一：a)若R3是不被取代或取代的苯基，则R7及R8是H，b)若R8是H，-CONH2，-NHC(O)CH3，-N(CH3)C(O)CH3，CN烷基    或-C(O)N((C1-3)烷基)2则R7是苯基、经1至3个取代基取代的苯基[其中该取代基分别为卤素(F、Cl、Br、I)、(C1-4)烷基、O-(C1-4)烷基、CF3或OCF3]哌啶基、1-甲基哌啶基，
Figure A9619309400122
或
Figure A9619309400124
或者c)R7及R8一起形成基团
Figure A9619309400131
R3表示H、(C1-4)烷基、未取代或单-至三-取代的苯基，其中取代基分
别是卤素(F、Cl、Br、I)、(C1-4)烷基、O-(C1-4)烷基、CF3、OCF3
或NR17R18(其中R17及R18分别表示H、甲基或乙酰基)；R4表示苯基(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，其中该取代基分别为卤素(F、Cl、Br、I)、(C1-4)烷基、O-
(C1-4)烷基、CF3、OCF3或NR19R20(其中R19及R20分别表示H、甲基
或乙酰基)；且R5  表示H、(C1-4)烷基、(C3-6)环烷基、CH2COOH、-CH2C(O)NH2、
-OH或苯基(C1-4)烷基。
本发明化合物是有价值的神经激肽(速激肽)拮抗剂，它既有物质P拮抗作用也有神经激肽A-或神经激肽B-拮抗性质。它可用于治疗及预防神经激肽调节性疾病。
通式I化合物可含有酸基，主要是羧基，和/或碱基，如氨基基团。因此可得到内盐形式的通式I化合物，如和药物上可接受的无机酸所形成的盐，诸如盐酸、硫酸、磷酸或磺酸或有机酸(如顺丁烯二酸、反丁烯二酸、柠檬酸、酒石酸或乙酸)或和药物可接受的碱所形成的盐，如碱或碱土金属氢氧化物或碳酸盐，锌或铵氢氧化物或有机胺，例如二乙胺、三乙胺或三乙醇胺等。
本发明化合物可以消旋体形式存在，也可以是纯对映体，即(R)-或(S)-型。也可以是非对映体或其混合物。
优选的通式I化合物是其中R1及R2和与其键合的N一起形成下式的6-员环其中X表示N(CH2)nR6或CR7R8，其中n、R6、R7及R8是按权利要求1所定义。特别优选的式I化合物，其
中X是N(CH2)nR6，其中n是0、1或2且R6是(C3-7)环烷基或苯基，尤其是其中n是0且R6是(C3-7)环烷基的化合物，特别是其中R6是环丁基或环己基的化合物。
还要提及的式I化合物为其中R7及R8具有下列意义：
a)当R3是不经取代或经取代的苯基时，R7及R8是H，
b)当R8是H、-CONH2、-NHC(O)CH3、-N(CH3)C(O)CH3或CN
  时R7是苯基、哌啶基
Figure A9619309400151
Figure A9619309400152
或
Figure A9619309400153
c)R7及R8一起形成基团
Figure A9619309400154
尤其是其中R7及R8具有以下定义之一：
a)当R3是未经取代或经取代的苯基时，R7及R8是H，
b)当R8是H，-CONH2或CN时，R7是苯基， 或
Figure A9619309400163
c)R7及R8一起形成基团
Figure A9619309400164
优选的化合物是其中R7是苯基，
Figure A9619309400171
或 且R8是H或CN，尤其是其中R7是吡啶基且R8是H。上文所定义的化合物
中，优选的是其中Ar表示未经取代或单-或二-取代的苯基，或未经取代的萘基[其中苯基的
取代基分别是卤素(F、Cl、Br、I)、OH、甲基、甲氧基、CF3、OCF3
或二甲氨基]或Ar是经-OCH2O-取代的苯基，该基团连结苯基中位置
2和3或3和4，尤其是其中Ar表示未经取代或单-或二-取代的苯基，或未经取代的萘基[其中苯基的
取代基分别是卤素(F、Cl、Br)、甲氧基或CF3]或Ar是经-OCH2O-
取代的苯基，该基团连结苯基中的位置2和3或3和4。
优选的化合物是其中Ar是苯基、3，4-二氯苯基、3，4-二甲氧苯基
或3，4-亚甲基二氧苯基。
上述化合物中，应特别提及其中R3是苯基或优选的H。
上述化合物中，也应提及的是其中R4  是苯基(C1-3)烷基，其中苯基可经1个或2个取代基所取代，该取代基
分别是卤素(F、Cl、Br、I)、甲基、甲氧基、CF3或OCF3；且R5  表示H、(C1-3)烷基、CH2COOH、-CH2C(O)NH2、或苯乙基，特别的是其中
R4是且R5是H或CH3。
下列化合物是优选的：
Figure A9619309400182
Figure A9619309400183
Figure A9619309400184
和
Figure A9619309400185
上述所用的萘基包括1-萘基及2-萘基。
本发明化合物的试验结果：
在具有克隆的NK1-受体的人类成淋巴细胞瘤细胞上，测定对NK1-受体(物质P-受体)的受体亲和力，测定125I-标记的物质P的置换。所得的Ki值说明化合物的效果：
                    Ki
实施例3的化合物：1.4nM
实施例4的化合物：1.0nM
实施例5的化合物：1.3nM
实施例33的化合物：1.3nM
实施例45的化合物：1.6nM
实施例46的化合物：1.4nM
实施例52的化合物：1.1nM
实施例53的化合物：2.3nM
实施例58的化合物：6.4nM
实施例59的化合物：4.2nM
实施例65的化合物：9.2nM
实施例66的化合物：1.4nM
实施例68的化合物：1.5nM
实施例70的化合物：2.8nM
实施例71的化合物：2.1nM
实施例72的化合物：6.8nM
实施例73的化合物：1.7nM
实施例74的化合物：11.8nM
实施例75的化合物：180nM
实施例76的化合物：7.0nM
本发明化合物是有价值的神经激肽(速激肽)拮抗剂，尤其是NK1-拮抗剂，也具有NK2-及NK3-拮抗性质。
本发明化合物是有价值的神经激肽(速激肽)拮抗剂，它既有物质P拮抗性质也有神经激肽A-或神经激肽B-拮抗性质。它可用于治疗及预防神经激肽调节性的疾病：治疗及预防呼吸道的炎症及过敏疾病，诸如气喘、慢性支气管炎、肺气肿、鼻炎或咳嗽，眼病，如结膜炎及虹膜炎，皮肤疾病，如接触性湿疹的皮炎、荨麻疹、牛皮癣、晒斑、昆虫咬伤及螫伤，神经性皮炎、搔痒症和疱疹后疼痛、肠胃道的疾病，如胃及十二指肠溃疡、溃疡性结肠炎、节段性回肠炎、过敏性结肠、先天性巨结肠症(Hirschsprung′s disease)；关结的疾病，如风湿性关节炎、反应性关节炎及赖特尔综合(Reiter syndrome)；
用于治疗中枢神经系统的疾病，如痴呆症、初老年痴呆症(Alzheimer′sdisease)、精神分裂症、精神病、抑郁、头痛(例如偏头痛或压力性头痛)及癫痫；
用于治疗肿瘤、胶原性病、尿道的机能障碍、痔核、噁心及呕吐，例如因放射性或胞毒性治疗或运动及所有种类的疼痛所引发。
因此，本发明也涉及一种本发明化合物的用途，它是用作含有该化合物的药物及药物制剂。优选用于人类。本发明化合物可通过静脉、皮下、肌肉、腹膜内或鼻内途径或通过吸入、通过经皮途径，若需要，可借助离子电渗疗法或文献已知的促进剂以及经口服而给药。
非经肠给药时，式I的化合物或其药物上可接受的盐，可任选地与诸如溶解剂、乳化剂或其他助剂等惯用物质制成溶液、悬浮液或乳液。适当的溶剂包括例如水、生理盐溶液或醇类，例如乙醇、丙二醇或甘油、糖溶液，诸如葡萄糖或甘露糖醇溶液或各种溶剂的混合物。
此外，该化合物可通过植入物，例如聚交酯、聚乙交酯或聚羟基丁酸，或通过鼻内的制剂而给药。
通式I化合物的口服效用可使用下列标准试验证明：
在被麻醉的天竺鼠体内抑制因NK1所致的血压降低。
重300-500克的天竺鼠以戊巴比妥(pentobarbital)(50mg/kg i.p.)麻醉、插管并在每分钟呼吸60次的速率下，以每公斤体重10ml环境空气机械性地换气。在通过颈动脉的血流内测定血压。为了在静脉内导入物质，在颈静脉插上套管。
在静脉内给予NK1-兴奋剂[β Aa4、Sar9、Met(O2)11]SP(4-11)(0.2μmol/kg)，引发短暂的血压降低，通过重复给予NK1-兴奋剂，而于10分钟间隔下重复该现象。
Figure A9619309400211
随后通过十二指肠内途径，并于10分钟间隔下给予神经激肽拮抗剂，通过NK1-兴奋剂引发血压的降低。
在以神经激肽拮抗剂处理前后，测定对由上述NK1-兴奋剂所引发的血压降低的抑制性。
实施5的化合物产生1.4mg/kg的D50(ID50是抑制由NK1-兴奋剂所引发的血压降低的50％的剂量)。
本发明化合物可用一般已知方法制备。
化合物可使用各种方式制备。下列图表表示两种最常见的方法：
Figure A9619309400221
方法A.羧酸可使用各种方式连结到胺NH(R5)R4上。常用的方法是诸如肽化学中所用者的偶联法。诸如TBTU、DCCI/HOBt、CDI等偶联剂以约等量添加到偶联参与物中。适当溶剂有DMF、THF、CH2Cl2、CHCl3、乙腈或其他惰性溶剂或其混合物。适当的温度范围在-50℃及+120℃之间，优选的在0及40℃之间。羧酸也可预先通过SOCl2、SO2Cl2、PCl3、PCl5或PBr3或其混合物，按已知方法转化而成对应的酸卤化物，接着在-50℃及+100℃间，一般是在0℃及20℃间的温度下，在如CH2Cl2、THF或二噁烷的惰性溶剂中，和胺HN(R5)R4反应。
另一种方法是用已知方法，先将羧酸转化成烷基酯，通常是甲酯，然后在诸如DMF、二噁烷或THF等惰性溶剂中，使该酯与胺HN(R3)R4反应。反应温度在20℃和150℃之间，一般为50℃和120℃之间。反应也可在加压容器内进行。方法B.这方法中，将按已知方法所得的α-卤素-芳基乙酰胺衍生物和胺R1(R2)NH反应，而产生卤化氢。为了去除经分裂(过量)的卤化氢，可使用如K2CO3、NaHCO3或CaCO3等无机碱，或诸如三乙胺、Hunig碱、吡啶或MDAP等有机碱，或过量的胺R1(R2)NH。使用MDF、THF、二噁烷或其他惰性溶剂。反应的温度范围是由0至100℃，一般是由10至80℃。方法C其中R5不是H的本发明化合物，也可按下文制备：首先，根据方法A或B，合成其中R5是H的相应化合物。随后按以下进行N-烷基化，以导入烷基、环烷基或CH2COOH。本发明的其中R5是H的化合物使用等量的NaH、NaNH2、KOH、NaOCH3或某些其他强碱以去质子。使用无水惰性溶剂，诸如THF、二噁烷或二乙醚。随后慢慢添加以相应卤化物、甲苯磺酸盐或甲磺酸盐形式存在的相应的烷基化剂。反应是在-50℃至+100℃的温度范围内，一般在0℃和+50℃之间的温度下进行。该法详述于实例33。实施例1
Figure A9619309400231
步骤1：2.2g1-环己基哌嗪溶于150ml无水DMF，与2gK2CO3混合，在室温下搅拌20分钟并冷却至5℃。添加2.7g(R，S)-α-溴苯基乙酸甲基酯，悬浮液于室温搅拌过夜。滤出沉淀物，蒸掉滤液。残留物溶于乙酸乙酯中，以10％KHCO3溶液萃取两次，饱和NaCl溶液萃取一次。有机相以Na2SO4干燥，过滤并蒸干，得到3.7g黄色油状的(R，S)-1-环己基-4-(2-苯基乙酸甲酯)-哌嗪。产率：约100％。步骤2：将2.3g步骤1的产物溶于10ml甲醇中，与14ml 1N NaOH混合，形成的乳液在室温下搅拌过夜。澄清反应溶液通过加入14ml 1N HCl而中和，蒸干，残留物用异丙醇处理，抽气过滤收集固体物质。蒸掉滤液，残留物再次以异丙醇研制，抽气过滤固体物质，并与先前所得的固体合并。因而，得到1.6g白色固状(R，S)-1-环己基-4-(2-苯基乙酸)-哌嗪。产率：约75％。步骤3：将0.6g步骤2的产物、048g3，5-双-(三氟甲基)-苄胺及0.32gHOBT悬浮于60ml THF/CH2Cl2(1∶1)中，并添加约0.7ml Hunig碱，将pH调至8.5。添加0.77g TBTU，混合物于室温下搅拌过夜。澄清反应溶液在真空中蒸发，残留物溶于CH2Cl2中并以10％KHSO4溶液萃取两次，饱和NaCl溶液萃取一次，10％KHCO3溶液萃取二次且饱和NaCl溶液再萃取一次。有机相以Na2SO4干燥、过滤并蒸发，而产生结晶。得到0.685g带黄色固体(R，S)-1-环己基-哌嗪-4-[2-苯基乙酸-N-(3，5-双-三氟甲苄基)酰胺]。产率64％。Mp.：124-129℃。FAB-MS：(M+H)+＝528.2实施例2步骤1：0.49g 3，5-双-(三氟甲基)-苄胺溶于30ml无水CH2Cl2中，添加0.3ml三乙胺，混合物于冰浴中冷却20分钟后逐滴添加0.46g(R，S)-α-溴苯基乙酰氯在10ml CH2Cl2中的溶液。混合物于室温下放置一周后，去除溶剂，固体残留物以二乙醚研制，抽气过滤，并蒸发滤液。得到0.6g淡灰褐色固状的-α-溴苯基乙酸-N-(双-三氟甲苄基)-酰胺。产率：约43.5％。步骤2：0.21g 4-丙酰胺基哌啶盐酸盐溶于30ml无水DMF中，添加0.33gK2CO3，混合物于室温下搅拌30分钟。用20分钟，将0.68g步骤1中的产物在10ml DMF中的溶液逐滴添加于该混合物中，随后在室温下搅拌过夜。过滤悬浮液，蒸发滤液，所得的油状残留物溶于乙酸乙酯中，以10％KHCO3溶液萃取两次，饱和NaCl溶液萃取一次。有机相以Na2SO4干燥，过滤，且蒸发滤液，所得的半固体残留物以二乙醚研制并抽气过滤。得到0.33g白色固体的(R，S)-4-丙酰氨基-1-[2-苯基乙酸-N(3，5-双-三氟甲基苄基)酰胺]-哌啶。产率：64％。Mp：189-191℃FAB-MS：(M+H)+＝516.4实施例33：Mp.：＞240℃；FAB-MS：(M+H)+＝556.4
0.3g实施例25的化合物通过用KHCO3处理而转化成相应的碱，并干燥。形成的产物溶于5ml无水THF中，添加34mgNaH(在油中60％)，并于室温下搅拌1.5小时。随后添加0.1g甲基碘，混合物搅拌过夜。在反应混合物中加入2ml THF/水(1∶1)混合物，随后加入25ml水，并以醚萃取3次。合并的乙醚萃取物以Na2SO4干燥，并于真空下蒸发，而得到170mg游离碱形式的所要求的化合物(油状)。通过添加过量的HCl乙醚溶液而转化成二盐酸盐，所得的二盐酸盐呈黄色晶体。产率：113mg(36％)
按类似法可制备其他本发明化合物，例如下面实施例：实施例3：Mp.：235-238℃.FAB-MS：(M+H)+＝542.2.实施例4：
Figure A9619309400253
Mp.：＞240℃(分解).FAB-MS：(M+H)+＝542.3.实施例5：Mp.：158-164℃；FAB-MS：(M+H)+＝556.4.实施例6：
Figure A9619309400262
Mp.：97-99℃；FAB-MS：(M+H)+＝556.3.实施例7：
Figure A9619309400263
Mp.：＞240°(分解)；FAB-MS：(M+H)+＝528 4.实施例8：Mp.：102-105℃；  FAB-MS：(M+H)+＝640.3.实施例9：
Figure A9619309400271
Mp.：141-149℃；FAB-MS：(M+H)+＝579.2.实施例10：
Figure A9619309400272
Mp.：218-223℃；FAB-MS：(M+H)+＝579.3.实施例11：
Figure A9619309400273
Mp.：＞220°(分解)；FAB-MS：(M+H)+＝571.3.实施例12：
Figure A9619309400274
Mp.：205-210℃；FAB-MS：(M+H)+＝591.3.实施例13：Mp.：87-95℃；FAB-MS：(M+H)+＝571.2.实施例14：Mp.：164-166℃；FAB-MS：(M+H)+＝537.3.实施例15：Mp.：208-210℃；FAB-MS：(M+H)+＝578.3.实施例16：
Figure A9619309400284
Mp.：110-115℃；FAB-MS：(M+H)+＝542.3.实施例17：
Figure A9619309400291
Mp.：118-123℃；FAB-MS：(M+H)+＝556.3实施例18：
Figure A9619309400292
Mp.：134-136℃；FAB-MS：(M+H)+＝514.3实施例19：Mp.：＞240°(分解)；FAB-MS：(M+H)+＝564实施例20：
Figure A9619309400294
Mp.：180-185℃；FAB-MS：(M+H)+＝564.3实施例21：Mp.： 228-232℃；FAB-MS：(M+H)+＝606/608实施例22：
Figure A9619309400302
Mp.：70-73℃；FAB-MS：(M+H)+＝586实施例23：
Figure A9619309400303
Mp.：248-254℃；FAB-MS：(M+H)+＝596/598/600实施例24：Mp.：210℃；FAB-MS：(M+H)+＝664.1实施例25：Mp.：192-199℃；FAB-MS：(M+H)+＝542.3实施例26：
Figure A9619309400313
Mp.：112-118℃；FAB-MS：(M+H)+＝562/564实施例27：
Figure A9619309400314
Mp.：124-127℃；FAB-MS：(M+H)+＝606/608实施例28：
Figure A9619309400321
Mp.：118-120℃；FAB-MS：(M+H)+＝606/608实施例29：Mp.：120-120℃；FAB-MS：(M+H)+＝562/564实施例30：Mp.：＞240℃；FAB-MS：(M+H)+＝562/564实施例31：
Figure A9619309400324
Mp.：＞240℃；FAB-MS：(M+H)+＝546.3实施例32：
Figure A9619309400331
Mp.：125-130℃(分解)；FAB-MS：(M+H)+＝610.4实施例33：
Figure A9619309400332
Mp.：＞240℃；FAB-MS：(M+H)+＝556.4实施例34：
Figure A9619309400333
Mp.：145-151℃；FAB-MS：(M+H)+＝641.3实施例35：实施例36：
Figure A9619309400341
Mp.：175-176.5℃实施例37：
Figure A9619309400342
Mp.：157-158℃实施例38：
Figure A9619309400343
Mp.：155-172℃FAB-MS：(M+H)+＝592.2实施例39：
Figure A9619309400351
实施例40：
Figure A9619309400352
实施例41：
Figure A9619309400353
实施例42：
Figure A9619309400354
Mp.：142-150℃FAB-MS：(M+H)+＝558.2实施例43：实施例44：Mp.：107-111℃；FAB-MS：(M+H)+＝575.6实施例45：
Figure A9619309400363
M.p.：＞230℃实施例46：M.p.：＞230℃实施例47：M.p.：127-137℃FAB-MS：(M+H)+＝592实施例48：
Figure A9619309400372
实施例49：实施例50：
Figure A9619309400374
M.p.：106-110℃FAB-MS：(M+H)+＝549.4实施例51：
Figure A9619309400381
实施例52：Mp.：133-143℃FAB-MS：(M+H)+＝542.3实施例53：
Figure A9619309400383
M.p.：110-120℃FAB-MS：(M+H)+＝570.4实施例54：
Figure A9619309400391
实施例55：
Figure A9619309400392
实施例56：实施例57：
Figure A9619309400394
实施例58：
Figure A9619309400401
Mp.：212-216℃(分解)FAB-MS：(M+H)+＝624.3/626.3/628.3实施例59：
Figure A9619309400402
Mp.：224-246℃(分解)FAB-MS：(M+H)+＝624.1/626.2/628实施例60：Mp.：113-123℃FAB-MS：(M+H)+＝550.3实施例61：Mp.：195-205℃实施例62：Mp.：210-218℃FAB-MS：(M+H)+＝620/622实施例63：Mp.：215-224℃FAB-MS：(M+H)+＝576/578实施例64：
Figure A9619309400421
Mp.：85-92℃FAB-MS：(M+H)+＝572.5实施例65：
Figure A9619309400422
Mp.：148-156℃FAB-MS：(M+H)+＝578.4实施例66：
Figure A9619309400423
Mp.：113-117℃(分解)FAB-MS：(M+H)+＝528.5实施例67：Mp.：265-268℃(分解)FAB-MS：(M+H)+＝619.3实施例68：
Figure A9619309400432
Mp.：236-238℃(分解)FAB-MS：(M+H)+＝528.3实施例69：
Figure A9619309400433
Mp.：177-187℃FAB-MS：(M+H)+＝605.3实施例70：
Figure A9619309400441
Mp.：123-133℃(分解)FAB-MS：(M+H)+＝616.3实施例71：Mp.：87-97℃FAB-MS：(M+H)+＝600.2实施例72：
Figure A9619309400443
Mp.：＞230℃实施例73：Mp.：＞230℃实施例74：Mp.：＞230℃实施例75：Mp.：91-98℃.FAB-MS：(M+H)+＝574.4实施例76：Mp.：234-236℃实施例77：
Figure A9619309400461
Mp.：195-198实施例78：
Figure A9619309400462
药物制剂：注射溶液200mg         活性物质*1.2mg         磷酸二氢钾＝KH2PO4)
                                              (缓冲剂)0.2mg         磷酸氢二钠＝NaH2PO4·2H2O)94mg          氯化钠)                             (等渗剂)或                     )520mg         葡萄糖)4mg           白蛋白                              (蛋白酶保护)适量          氢氧化钠溶液)适量          盐酸            )将pH调至pH6足以加到10ml注射溶液的水注射溶液200mg         活性物质*94mg               氯化钠或520mg              萄萄糖4mg                白蛋白适量               氢氧化钠溶液)适量               盐酸        )将pH调至pH9足以加到10ml注射液的水冷冻干燥物200mg              活性物质*520mg              甘露糖醇(等渗剂/结构成分)4mg                白蛋白冷冻干燥物所用的溶剂110ml               注射用水冷冻干燥物的用的溶剂220mg                Polysorbate80＝Tween 80(表面活性剂)10ml                注射用水* 活性物质：本发明化合物，例如实施例1至78
重67kg的人类所用剂量：1至500mg

Claims (21)

1.一种通式I的芳基甘氨酰胺衍生物
Figure A9619309400021
或其药物上可接受的盐，其中Ar表示未经取代或经单-至五-取代的苯基，或未经取代或经单-或双-取代的萘基，其中苯基和萘基的取代基分别表示卤素(F、Cl、Br、I)、OH、(C1-4)烷基、O-(C1-4)烷基、CF3、OCF3或NR9R10(其中R9和R10分别表示H、甲基或乙酰基)]或Ar为经-OCH2O-或-O(CH2)2O-取代的苯基；R1及R2和与其键合的N一起形成下式的环
Figure A9619309400022
其中p是2或3，X表示氧、N(CH2)nR6或CR7R8，其中n是0、1或2，R6是(C3-7)环烷基、苯基或萘基，其中苯基可经卤素(F、Cl、Br、I)、
(C1-4)烷基、O-(C1-4)烷基、CF3、OCF3或NR15R16(其中R15及
R16分别表示H、甲基或乙酰基)单-至三-取代；R7及R8具有下述定义中之一：a)若R3是未经取代或经取代的苯基，则R7及R8表示H，b)若R8是H，-CONH2，-NHC(O)CH3，-N(CH3)C(O)CH3，CN或-C(O)N((C1-3)烷基)2，则R7是苯基、经1至3个取代基取代的苯基[其中该取代基分别为卤素(F、Cl、Br、I)、(C1-4)烷基、O-(C1-4)烷基、CF3或OCF3]、哌啶基、1-甲基哌啶基， 或
Figure A9619309400034
或者
c)R7及R8一起形成下式基团  R3表示H、(C1-4)烷基、未经取代或经单-至三-取代的苯基，其中取
代基分别为卤素(F、Cl、Br、I)、(C1-4)烷基、O-(C1-4)烷基、
CF3、OCF3或NR17R18(其中R17及R18分别表示H、甲基或乙酰基)；R4表示苯基(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，其中该取代基分别为卤素(F、Cl、Br、I)、(C1-4)烷基、
O-(C1-4)烷基、CF3、OCF3或NR19R20(其中R19及R20分别表示H、
甲基或乙酰基)；
且R5表示H、(C1-4)烷基、(C3-6)环烷基、CH2COOH、-CH2C(O)NH2、
-OH或苯基(C1-4)烷基。
2.根据权利要求1的化合物，其中R1及R2和与其键合的N一起形成下式的6-员环
Figure A9619309400041
其中X表示N(CH2)nR6或CR7R8，其中n、R6、R7及R8如权利要求1所定义。
3.根据权利要求2的化合物，其中X是N(CH2)nR6，其中n是0、1或2，而R6是(C3-7)环烷基或苯基。
4.根据权利要求3的化合物，其中n是0且R6是(C3-7)环烷基。
5.根据权利要求4的化合物，其中R6是环丁基或环己基。
6.根据权利要求2的化合物，其中X是CR7R8，其中R7和R8具有下列意义之一：a)当R3未经取代或经取代的苯基时，R7及R8是H，b)当R8是H、-CONH2、-NHC(O)CH3、-N(CH3)C(O)CH3或CN，
则R7是苯基、哌啶基，
Figure A9619309400051
Figure A9619309400052
或
Figure A9619309400053
或者
c)R7及R8一起形成下式基团
Figure A9619309400054
7.根据权利要求6的化合物，其中R7及R8具有下列定义之一：
a)当R3未经取代或经取代的苯基时，R7及R8是H，
b)当R8是H，-CONH2或CN时，R7是苯基，
或者
c)R7及R8一起形成下式基团
8.根据权利要求7的化合物，其中R7是苯基，
Figure A9619309400063
或   且R8是H或CN。
9.根据权利要求8的化合物，其中R7是吡啶基且R8是H。
10.根据权利要求1至9中之一的化合物，其中Ar表示未经取代或经单-或二-取代的苯基，或未经取代的萘基[其中苯
基的取代基分别为卤素(F、Cl、Br、I)、OH、甲基、甲氧基、CF3、
OCF3或二甲氨]或Ar是经-OCH2O-取代的苯基，该基团联结苯基的
位置2及3或3及4。
11.根据权利要求10的化合物，其中Ar表示未经取代或经单-或二-取代的苯基，或未经取代的萘基[其中苯
基的取代基分别为卤素(F、Cl、Br)、甲氧基或CF3]或Ar是经
-OCH2O-取代的苯基，该基团联结苯基的位置2及3或3及4。
12.根据权利要求11的化合物，其中Ar是苯基、3，4-二氯苯基、3，4-
二甲氧苯基或3，4-亚甲基二氧苯基。
13.根据权利要求1至12中之一的化合物，其中R3是H。
14.根据权利要求1至12中之一的化合物，其中R3是苯基。
15.根据权利要求1至14中之一的化合物，其中R4表示苯基(C1-3)烷基，其中苯基可经1个或2个取代基取代，该取代
基分别为卤素(F、Cl、Br、I)、甲基、甲氧基、CF3、OCF3；且R5表示H、(C1-3)烷基、CH2COOH、-CH2C(O)NH2、或苯乙基。
16.根据权利要求15的化合物，其中R4是且R5表示H或CH3。
17.根据权利要求1的化合物，它是
Figure A9619309400081
Figure A9619309400082
Figure A9619309400083
Figure A9619309400084
或
18.一种制备根据权利要求1至17中之一的通式I化合物的方法，其特征为：a)由酸
Figure A9619309400091
或其卤化物或烷基酯和胺反应；b)由α-卤芳基乙酰胺和胺
Figure A9619309400094
反应；或c)由其中R5是H的化合物I经N-烷基化；而所得的化合物，它以游离化合物或其药物上可接受的盐的形式分离。
19.一种药物制剂，它含有权利要求1至17中之一的化合物。
20.一种根据权利要求1至17中之一的化合物在制备治疗及预防神经激肽所
调节的疾病的医药制剂中的用途。
21.一种根据权利要求1至17中之一的化合物在治疗和预防神经激肽所调节
的疾病中的用途。
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