CN1071329C - 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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CN1071329C
CN1071329C CN96193094A CN96193094A CN1071329C CN 1071329 C CN1071329 C CN 1071329C CN 96193094 A CN96193094 A CN 96193094A CN 96193094 A CN96193094 A CN 96193094A CN 1071329 C CN1071329 C CN 1071329C
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phenyl
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halogen
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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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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
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
表示
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
Figure C9619309400133
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 C9619309400142
或者
c)R7及R8一起形成基团
Figure C9619309400151
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
Figure C9619309400161
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
c)R7及R8一起形成基团
Figure C9619309400172
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，
Figure C9619309400181
c)R7及R8一起形成基团
优选的化合物是其中
R7是苯基，
Figure C9619309400191
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
Figure C9619309400192
且R5是H或CH3。
下列化合物是优选的：
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)(50 mg/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[βAla4、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。
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-兴备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ID50(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 C9619309400241
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(R5)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步骤1：2.2gl-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、0.48g 3,5-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CH2C12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34mg NaH(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：
Figure C9619309400272
Mp.:235-238℃.FAB-MS:(M+H)+=542.2.
实施例4：
Figure C9619309400273
Mp.:＞240℃(分解).FAB-MS:(M+H)+=542.3.
实施例5：
Figure C9619309400281
Mp.:158-164℃；FAB-MS:(M+H)+=556.4.
实施例6：
Figure C9619309400282
Mp.:97-99℃；FAB-MS:(M+H)+=556.3.
实施例7：
Figure C9619309400283
Mp.:＞240°(分解)；FAB-MS:(M+H)+=528.4.
实施例8：
Figure C9619309400284
Mp.:102-105℃；FAB-MS:(M+H)+=640.3.
实施例9：
Figure C9619309400291
Mp.:141-149℃；FAB-MS:(M+H)+=579.2.
实施例10：Mp.:218-223℃；FAB-MS:(M+H)+=579.3.
实施例11：Mp.:＞220°(分解)；FAB-MS:(M+H)+=571.3.
实施例12：
Figure C9619309400294
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：
Figure C9619309400303
Mp.:208-210℃；FAB-MS:(M+H)+=578.3.
实施例16：Mp.:110-115℃；FAB-MS:(M+H)+=542.3.
实施例17：Mp.:118-123℃；FAB-MS:(M+H)+=556.3
实施例18：
Figure C9619309400312
Mp.:134-136℃；FAB-MS:(M+H)+=514.3
实施例19：
Figure C9619309400313
Mp.:＞240°(分解)；FAB-MS:(M+H)+=564
实施例20：Mp.:180-185℃；FAB-MS:(M+H)+=564.3
实施例21：
Figure C9619309400321
Mp.:228-232℃；FAB-MS:(M+H)+=606/608
实施例22：
Figure C9619309400322
Mp.:70-73℃；FAB-MS:(M+H)+=586
实施例23：
Figure C9619309400323
Mp.:248-254℃；FAB-MS:(M+H)+=596/598/600
实施例24：
Figure C9619309400331
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 C9619309400333
Mp.:112-118℃；FAB-MS:(M+H)+=562/564
实施例27：
Figure C9619309400334
Mp.:124-127℃；FAB-MS:(M+H)+=606/608实施例28：Mp.:118-120℃；FAB-MS:(M+H)+=606/608
实施例29：
Figure C9619309400342
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 C9619309400344
Mp.:＞240℃；FAB-MS:(M+H)+=546.3
实施例32：
Figure C9619309400351
Mp.:125-130℃(分解)；FAB-MS:(M+H)+=610.4
实施例33：Mp.:＞240℃；FAB-MS:(M+H)+=556.4
实施例34：
Figure C9619309400353
Mp.:145-151℃；FAB-MS:(M+H)+=641.3
实施例35：实施例36：Mp.:175-176.5℃
实施例37：
Figure C9619309400362
Mp.:157-158℃
实施例38：
Figure C9619309400363
Mp.:155-172℃FAB-MS:(M+H)+=592.2
实施例39：
Figure C9619309400371
实施例40：
Figure C9619309400372
实施例41：
Figure C9619309400373
实施例42：
Figure C9619309400374
Mp.:142-150℃FAB-MS:(M+H)+=558.2
实施例43：
Figure C9619309400381
实施例44：Mp.:107-111℃；FAB-MS:(M+H)+=575.6
实施例45：
Figure C9619309400383
M.p.:＞230℃
实施例46：
Figure C9619309400384
M.p.:＞230℃实施例47：
Figure C9619309400391
M.p.:127-137℃FAB-MS:(M+H)+=592
实施例48：
实施例49：
实施例50：
Figure C9619309400394
M.p.:106-110℃FAB-MS:(M+H)+=549.4
实施例51：
实施例52：
Figure C9619309400402
Mp.:133-143℃FAB-MS:(M+H)+=542.3
实施例53：M.p.:110-120℃FAB-MS:(M+H)+=570.4
实施例54：
Figure C9619309400411
实施例55：
Figure C9619309400412
实施例56：
Figure C9619309400413
实施例57：
Figure C9619309400414
实施例58：
Figure C9619309400421
Mp.:212-216℃(分解)FAB-MS:(M+H)+=624.3/626.3/628.3
实施例59：
Figure C9619309400422
Mp.:224-246℃(分解)FAB-MS:(M+H)+=624.1/626.2/628
实施例60：
Figure C9619309400423
Mp.:113-123℃FAB-MS:(M+H)+=550.3
实施例61：
Figure C9619309400431
Mp.:195-205℃
实施例62：
Figure C9619309400432
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 C9619309400441
Mp.:85-92℃FAB-MS:(M+H)+=572.5
实施例65：Mp.:148-156℃FAB-MS:(M+H)+=578.4
实施例66：Mp.:113-117℃(分解)FAB-MS:(M+H)+=528.5
实施例67：
Figure C9619309400451
Mp.:265-268℃(分解)FAB-MS:(M+H)+=619.3
实施例68：
Figure C9619309400452
Mp.:236-238℃(分解)FAB-MS:(M+H)+=528.3
实施例69：Mp.:177-187℃FAB-MS:(M+H)+=605.3
实施例70：
Figure C9619309400461
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 C9619309400463
Mp.:＞230℃
实施例73：Mp.:＞230℃
实施例74：
Figure C9619309400472
Mp.:＞230℃
实施例75：
Figure C9619309400473
Mp.:91-98℃.FAB-MS:(M+H)+=574.4
实施例76：
Figure C9619309400474
Mp.:234-236℃
实施例77：Mp.:195-198℃
实施例78：
Figure C9619309400482
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 (20)

1．一种通式Ⅰ的芳基甘氨酰胺衍生物
Figure C9619309400021
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、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 C9619309400022
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C1-4烷基、O-C1-4烷基、CF3、OCF3或NR15R16单-至三-取代，其中R15及R16分别表示H、甲基或乙酰基；
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
Figure C9619309400031
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、C1-4烷基、O-C1-4烷基、CF3或OCF3、哌啶基、1-甲基哌啶基，
Figure C9619309400032
或者
c)R7及R8一起形成下式基团
Figure C9619309400033
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、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、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元环
Figure C9619309400041
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，
或者
c)R7及R8一起形成下式基团
Figure C9619309400052
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，
或
Figure C9619309400064
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、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、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12的化合物，其中R5是H。
14．根据权利要求12的化合物，其中R3是苯基。
15．根据权利要求14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、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是一
且R5表示H或CH3。
17．根据权利要求1的化合物，它是
Figure C9619309400081
或
Figure C9619309400082
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 C9619309400091
或其卤化物或烷基酯和胺
Figure C9619309400092
反应：
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、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 C9619309400093
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C1-4烷基、O-C1-4烷基、CF3、OCF3或NR15R16单-至三-取代，其中R15及R16分别表示H、甲基或乙酰基；
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、C1-4烷基、O-C1-4烷基、CF3或OCF3、哌啶基、1-甲基哌啶基，
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、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、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；
b)由α-卤芳基乙酰胺
Figure C9619309400111
和胺-
Figure C9619309400112
反应；其中Hal表示卤素，R3、R4和R5定义同上；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。
19．一种药物组合物，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组合物中的用途。
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