CN1108290C - 新的尿素衍生物 - Google Patents
新的尿素衍生物 Download PDFInfo
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- CN1108290C CN1108290C CN98118692A CN98118692A CN1108290C CN 1108290 C CN1108290 C CN 1108290C CN 98118692 A CN98118692 A CN 98118692A CN 98118692 A CN98118692 A CN 98118692A CN 1108290 C CN1108290 C CN 1108290C
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
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Abstract
本文说明了式I化合物及其生理耐受性酸加成盐、和含有这些化合物的药物以及制备这些化合物的方法,其中R1为氢原子或低级烷基,R2为氢原子或卤素和R3为氢原子或低级烷氧基。
Description
本发明涉及新的尿素衍生物,其中一个氮原子为一个哌嗪环的组成部分,而另一个氮原子被苄基氨基乙基所取代。这些新的尿素衍生物的特征为具有神经激肽-受体-拮抗特性,它具有有益的作用方式,可用以治疗较大哺乳动物、尤其是人类胃肠道的功能性和炎症性疾病。此外本发明还涉及含有这些新的化合物的药物以及制备这些化合物的方法。
本发明的目的是,研制出用以治疗胃肠道功能性和炎症性疾病的新的活性物质。
由欧洲专利申请公开号655442已知,哌嗪衍生物具有神经激肽-拮抗特性。
现已发现,有一组新的哌嗪衍生物,在其2-位被吲哚基甲基所取代,并且在其哌嗪环上4-位的氮原子为带有苄基氨基乙基取代基的尿素骨架的一部分,则它们所具有的作用方式使之适合于治疗胃肠道疾病的功能性和炎症性疾病。本发明的物质组的另一特征为良好的耐受性和良好的口服生物可利用性。
其中R1为氢原子或低级烷基,R2为氢原子或卤素和R3为氢原子或低级烷氧基。
如果式I化合物中取代基为或含有低级烷基,则后者可为直链或支链的,并且含有1至4个、优选1至2个碳原子。
如果R1为低级烷基,则优选甲基。
如果取代基R2为卤素,则优选氟。
如果取代基R3为低级烷氧基,则优选甲氧基。
优选R2为氢原子和R3为甲氧基的式I化合物,或者优选R2为氟和R3为氢的式I化合物。
1H-吲哚-3-基-甲基优选位于哌嗪环的2R-位。
可以按照本身已知的方法制备这些化合物。按照以下方法制备式I化合物尤其有利,其中
其中Y为一个可以通过伯胺或仲胺的亲核性攻击而被替代的离去基团,反应生成通式IV的氨基甲酰基化合物,
其中Y具有上述的含义,如果通过由所获得的式IV化合物分裂出离去基团Y,可以生成一种酸,向式IV化合物添加一种非亲核性有机碱,接着将式IV化合物与通式V化合物反应,
其中R101为低级烷基或一个氨基保护基,R2和R3具有上述含义,并且接着将可能出现的保护基R101再次分裂或者
b)将式II化合物与通式VI化合物反应,
其中R101、R2和R3具有上述含义,接着将可能出现的保护基R101再次分裂,
和任选地将所获得的R1为氢原子的式I化合物烷基化,生成R1为低级烷基的式I化合物,以及任选地将所获得的式I化合物转化成其酸加成盐,或者将酸加成盐转化成游离的式I化合物。
较为合适的是,按照方法的变通方案a)首先将式II化合物与式III的反应性羰基化合物反应,转化成式IV的氨基甲酰基-化合物,后者可以直接地现场、任选添加一种非亲核性有机碱后与式V的胺发生反应。作为式III化合物中的离去基团Y,合适的有例如卤素,优选氯,三卤甲氧基,优选三氯甲氧基,或者也可以是咪唑基。作为式III反应性羰基化合物可以用光气、双-(三氯甲基)-碳酸盐(三光气)、氯蚁酸-三氯甲基酯(二光气)或者羰基二咪唑。式V的胺与式IV的氨基甲酰基-化合物转化时,离去基团Y由式IV化合物中被替代掉。如果由在此游离释放的基团Y可生成一种酸,则较为合适的是,在与式V化合物发生转化前,向式IV化合物中添加一种非亲核性有机碱。如果Y例如为氯,则可以通过添加上述碱将在Y分裂时产生的氯氢酸束缚。作为非亲核性碱,适合于反应混合物中的有可溶性有机碱如叔氮碱,例如含氮的N-烷基化的杂环如N-低级烷基-吗啉或者N-低级烷基-哌啶或叔式低级烷基胺和吡啶,例如三乙胺、三丙胺二异丙基乙基胺、吡啶、4-二甲基氨基吡啶、4-二乙基氨基吡啶或者4-吡咯烷基吡啶。过量加入的碱也可以作为溶剂应用。反应顺序可以作为单罐反应在极性质子惰性的溶剂中,如在部分卤化的低级烃如二氯甲烷中,在-20℃至室温之间的温度下,优选在室温下进行。
式II化合物与式VI异氰酸盐的转化可以按照方法的变通方案b)以本身已知的方式进行。式VI化合物可以例如由式V的胺通过与合适的反应性羰基化合物转化生成。作为反应性羰基化合物,合适的有例如式III化合物。合适的是,首先由式V的胺制备式VI的异氰酸酯,然后将它直接与式II化合物现场转化。可以在上述按照方法a)制备式I化合物所给定的条件下以单罐反应完成反应。合适的是向反应混合物添加一种缚酸试剂。作为缚酸试剂合适的有上述非亲核性碱。
作为氨基保护基,R101可以考虑例如肽化学本身已知的氨基保护基,它们可以按照本身已知的方法被导入,然后再被分裂。合适的保护基例如由J.A.W.McOmie“有机化学中的保护基”Plenum出版社,1973年或者T.W.Green和P.G.M.Wuts “有机合成中的保护基”,Wiley和Sons,1991年已知。
例如合适的保护基R101有在酸性和碱性环境中稳定的基团,它们可以在氢解条件下被分裂。属于此类的例如有苯基低级烷氧基羰基如苄氧基羰基(下面缩写为CbO)。作为氨基保护基R101可以优选应用苄氧基羰基,它们可以按照本身已知的方式,例如通过催化作用下的氢化而被裂解,以获得R1为氢原子的式I化合物。可以在反应条件下的惰性有机溶剂中、如在低级脂族醚例如四氢呋喃(下面简写为THF)或者二乙醚中、或者在低级链烷醇例如甲醇或乙醇中、或者在有机酸例如低级脂族羧酸如醋酸中、或者在上述这些溶剂的混合液中、以及在有氢化反应催化剂存在的条件下进行保护基的裂解。作为氢化反应催化剂,合适的有例如贵金属催化剂如载于活性炭上的钯。合适的是在室温下进行反应。适合于氢化反应的氢气压为2-7巴之间,优选为3-5巴之间。
可以将R1为氢原子的式I化合物按照本身已知的氨基烷基化方法转化为R1为低级烷基的式I化合物。在此可以例如通过与低级脂族醛类如甲醛的反应,将式I化合物作还原性烷基化。可以在胺类还原性烷基化本身通常的条件下,例如在催化氢化反应的条件下进行转化。作为氢化反应催化剂,合适的有金属催化剂如阮内镍。作为溶剂优选应用低级链烷醇。可以在上述氨基保护基R101进行氢解裂解反应的条件下进行催化氢化反应。
另一种烷基化的方法是,在亲核性取代反应的通常条件下,将R1为氢原子的式I化合物与低级脂族烷基卤化物如烷基溴化物或烷基碘化物,优选甲基碘化物,烷基硫酸酯或烷基磺酸酯进行转化。在极性质于惰性溶剂如二甲基甲酰胺(下面简写为DMF)、二甲基亚砜(下面简写为DMSO)或乙腈中,在-20℃至100℃之间,优选60℃至90℃之间的温度下,和在应用缚酸试剂的条件下进行该反应。作为缚酸试剂合适的有例如上面在式IV化合物与式V化合物转化中指定的有机碱。
作为式I化合物的生理耐受盐可以考虑的有,其与无机酸例如硫酸、磷酸或氢卤酸、优选氢氯酸的盐类,或者与有机酸例如低级脂族单-、双-或三羧酸如马来酸、富马酸、乳酸、酒石酸、柠檬酸的盐类,或者与磺酸例如低级烷基磺酸如甲烷磺酸、或任选其苯环被卤素或低级烷基取代的苯磺酸如对甲苯磺酸的盐类。
可以按照本身已知的方法,由反应混合物将式I化合物分离和提纯。可以按照通常的方式将酸加成盐转化成游离碱,以及必要时按照已知的方式将游离碱转化成药理学耐受的酸加成盐。
式I化合物含有一个手性碳原子,即带有1H-吲哚-3-基-甲基残基的碳原子位于哌嗪基础骨架的2-位上。因此式I化合物可以多种立体异构体的形式存在。本发明既包括式I化合物的光学异构体混合物,又包括其纯异构体。优选的式I化合物中,其吲哚甲基残基位于哌嗪环的2R-位上。
如果在式I化合物的合成中应用式II起始化合物的光学异构体混合物,则所得式I化合物为光学异构体混合物的形式。由立体化学上单纯的起始化合物出发,也可以获得立体化学上单纯的式I化合物,例如通过在手性分离材料上进行色谱分离,或者通过与合适的光学活性酸如酒石酸或莰烯-10-磺酸转化,接着在光学活性的对映体中通过分馏结晶所得非对映体盐进行分离。
式II化合物的二种对映体已经由EP-A655422已知,也可以按照本专利申请书说明的方法或者与此类似的方法制备。
式V的胺类可以由双重氨基保护的式VII的二氨基化合物获得,
其中R101、R2和R3具有上述含义,R401为一个氨基保护基,该方法是按照已知的方式,由式VII化合物选择性地分裂出氨基保护基R401。
作为氨基保护基R401,合适的一般有例如由肽化学已知的氨基保护基,如由上述来源已知的那些。例如,作为氨基保护基,R401在至少中等的酸性环境中,例如通过添加对甲苯磺酸、三氟乙酸或气体状的或溶解于溶剂中的盐酸,可选择性地分裂的基团,它们对氢解的和碱性的条件更加稳定。属于此类的还有例如支链的低级烷氧基羰基如叔-丁氧基羰基(下面简写为BOC)。R401可以优选地为叔-丁氧基羰基。
式VII化合物可以按照本身已知的方式获得,例如通过还原通式VIII的酰胺,
其中R1、R2、R3和R401具有以上含义,以及,如果R1为氢原子,则接着导入一个保护基R101。还原反应可以以复合的碱金属氢化物如氢化锂铝作为还原剂进行。作为溶剂合适的有在反应条件下为惰性的有机溶剂如低级脂族醚,例如二噁烷、THF或二乙醚或这些溶剂的混合物。合适的温度范围在-20℃至反应混合液的沸点温度之间。优选在室温下进行还原反应。
其中R1、R2、和R3具有以上含义,制备式VIII的酰胺。作为酰化剂,可以应用式IX的酸或其反应性衍生物。作为反应性衍生物,尤其考虑式IX的酸与氯蚁酸或与有机磺酸例如芳香磺酸如被低级烷基或卤素取代的苯磺酸如对甲苯磺酸形成的混合酸酐和酰氯或酰溴或者混合酯。可以在反应条件下的惰性有机溶剂中、在-20℃至室温的温度之间、优选在室温下进行酰基化。作为溶剂,合适的有芳香烃如苯或甲苯、脂族醚如二乙基醚、THF或二噁烷、部分卤化的低级烃如二氯甲烷或者这些溶剂的混合物。
合适的是,尤其是当应用式IX酸的酰卤作为酰化剂时,在缚酸试剂存在下进行酰基化。作为缚酸试剂合适的有上述在式IV的氨基甲酰基-化合物与式V化合物转化时指定的非亲核性有机碱。
如果应用式IX的酸本身作为酰化剂,则较为合适的是,在由肽化学中适于酰胺生成的已知的偶联试剂存在的条件下,进行式X的胺与式IX的酸的转化反应。作为促进与游离酸如上生成酰胺的偶联试剂,即它们与酸现场反应,生成反应性酸衍生物,尤其可以举例的有:烷基碳化二亚胺,例如环烷基碳化二亚胺如二环己基碳化二亚胺或1-乙基-3-[(二甲基氨基)-丙基]-碳化二亚胺、二异丙基碳化二亚胺,以及羰基二咪唑。在-30℃至+50℃之间的温度下,在溶剂如卤代烃和/或芳香溶剂如任选取代的苯中,以及任选在一种缚酸的有机化合物例如前面所说明的非亲核性氮碱存在的条件下、存在偶联试剂的条件下进行转化反应较为合适。式IX的酸为2-氨基乙酸衍生物的氨基被保护了的衍生物,已知它的未保护的形式,并且可以按照本身已知的方法被转化成氨基被保护了的衍生物。
式X的化合物为已知,或者可以按照本身已知的方式由已知的化合物制备。
式I化合物及其酸加成盐具有神经激肽(=NK)-受体-拮抗的特性,适合于治疗神经激肽作为载体参与发病的疾病状态。在此,本发明化合物的特征为具有尤其有利的选择性作用方式,其特征为对NK-1-受体具有高度的亲和性,而比较之下,对NK-2-受体具有低级的亲和性。此外这些化合物具有良好的口服作用效果。
基于其作用方式,本发明物质组尤其适合于抑制那些结合NK-1-受体的神经激肽如物质P所参与的过程。所以这些物质选择性地适合于治疗那些物质P参与的疾病状态。物质P例如在疼痛传导、呕吐、神经原性炎症、膀胱炎症、炎症性关节疾病和哮喘性疾病中起作用。由于它以有利的方式对胃肠道起作用,该类物质的作用方式适合于治疗胃肠道的功能性和炎症性疾病。此外还证明,这些化合物除对NK-1-受体具有较高亲和性外,对NK-2-受体也具有一定的亲和性,一般认为,这二种作用成份对参与同一疾病征象的机理具备有利的协同作用。属于可用本发明化合物治疗的功能性疾病有,尤其是所谓的“过敏性肠综合征”(=IBS)或刺激肠道综合征,为已知的下消化道疾病。IBS主要的症状为下腹疼痛、其原因似乎为内脏传入神经系统的超过敏性,以及大便异常,尤其是结肠内大便通过异常加快。由于对胃肠道内机械性和化学性刺激的内脏疼痛敏感性提高,即使在生理性消化过程中所引起的结肠轻微扩张,例如少量气体产生和轻微鼓胀,在正常人几乎没有感觉,IBS病人即已有剧烈的内脏疼痛。本发明化合物可有利地影响某些胃肠道炎症性疾病,属于此类的疾病有,一般统称为IBD(=炎症性肠综合征)的小肠和大肠的炎症性疾病、以及溃疡性结肠炎和Crohn氏病。这些物质的作用方式特征为良好的生物可用性,和相对于不希望的副作用而言具有神经激肽-受体-拮抗作用的有利选择性。在阻滞NK-1-受体的剂量范围内所进行的药理学试验中确定没有心血管钙拮抗作用。
所给出的实施例号涉及后面说明的制备实施例。
关于药理学试验方法的说明
1.试管内测定受测物质对NK-1-受体的结合能力。
试管内测定受测物质对人类NK-1-受体的亲和性。测定对生理性神经激肽(物质P)结合在NK-1-受体上的抑制作用。
用[3H]-物质P作为配位体进行受体-结合试验。为了进行结合试验,将各种样品的CHO-细胞(=中国仓鼠的卵细胞,chinese hamsteroocytes)的膜涂片,它们能测试人类NK-1-受体,用标记配位体的溶剂孵育,孵育沉淀物在此不含有受测物质或受测物质各种浓度的添加物。接着在样品中借助于玻璃纤维-过滤法分别将结合的和游离的配位体分离。将滤液中剩余的分馏物多次用缓冲剂洗涤,接着用β-闪烁计数器测定滤液中剩余分馏物的放射性。测出相应的浓度作为相应受测物质的IC50,在此浓度下结合的配位体被50%最大限度地排挤。由此数值可以计算出受测物质的相应抑制常数(Ki-值)。在这个试验模式中,实施例1的物质对人类NK-1-受体亲和性的Ki-值为2.1nmol/l。
2.试管内测定受测物质对NK-2-受体的结合能力。
在试管内测定受测物质对人类NK-2-受体的亲和性。测定对化合物SR-48,968结合在NK-2-受体上的抑制作用。SR-48,968是一种合成制备的化合物,为已知的特异性NK-2-拮抗剂。
用SR-48,968作为配位体进行受体-结合试验。试验的操作方法与药理学试验中试管内测定受测物质对NK-1-受体的结合力的方法相似。区别在于,这里应用各种CHO-细胞的膜涂片样品对人类NK-2-受体进行试验。在这个试验模式中,以下列表格1列举实施例物质对人类NK-2-受体亲和性的Ki-值。表1:受测物质对人类NK-2-受体的亲和性
3.试管内测定受测物质对豚鼠离体组织的功能性NK-1-拮抗作用
实施例号 | Ki[μmol/l] |
123 | 0.060.050.30 |
在维持在氧化营养液中的离体Pirbright-白豚鼠主动脉环标本上,进行试管内测定受测物质的NK-1-受体-拮抗作用。测定受测物质对用NK-1-协同剂物质P激发后出现的主动脉标本张力性弛缓的抑制作用。
为了测定血管肌的收缩,将标本固定在一个钩子上,用一根线与力测量器连结,每一次收缩都被记录在记录器上。用苯基麻黄碱使主动脉标本紧张。接着在添加检测物质之前和之后用0.01μmol物质P激发标本的NK-1-受体,引起张力的弛缓。将添加检测物质之前和之后的弛缓分别用百分数表示。计算出产生50%最大抑制的浓度(=IC50)作为特征数值,它表明50%最大限度地抑制张力弛缓时的浓度。
在这个试验模式中,以下列表格2列举实施例物质产生50%最大抑制时的IC50-值。
表2:受测物质对离体豚鼠组织的功能性NK-1-拮抗作用
4.试管内测定受测物质的物质-P-拮抗作用
实施例号 | IC50[μmol/l] |
123 | 0.0010.00120.0015 |
作为测定物质-P诱发的药理学效应的标准试验模式,通过以物质-P用药所引起的豚鼠低血压,验证受测物质的物质-P-拮抗作用。静脉内(=i.v.)和十二指肠内(=i.d.)以受测物质用药后,测定受测物质对物质P所引起的血压下降的抑制作用。
对雄性豚鼠在麻醉下将导管分别插入至颈总动脉内和颈静脉内。动脉导管用以测定血压。用斯特瑟姆氏23d/B压力接受器测量。通过静脉通道注入物质P以及受测物质。经过20分钟的平衡期后,将物质P以50pmol/只动物的剂量静脉内团注。然后注入受测物质。在静脉内用药的试验过程中,受测物质的静脉内用药剂量为0.1、0.46和1.0μmol/kg每4至6只动物一组。对照组用相应剂量的生理盐水。注入受测物质1、15、30、45和60分钟后,分别注入50pmol物质P。在十二指肠内用药的试验中与以上试验不同之处是,附加在试验动物的十二指肠内插入一导管。受测物质以每3至6只动物0.046、0.1、0.46、1.0、4.6和10.0μmol/kg的剂量通过导管给药。在这些试验中,纤基乙酸钠作为媒介物。在物质-P首次用药前和用药后约1分钟测定平均动脉压,并且由此测定物质-P所引起的最大血压下降。60分钟后,比较单独用物质P治疗的对照组动物和用物质P以及受测物质治疗的动物的平均动脉压,并且由此差值计算出相应受测物质剂量对物质-P诱发的最大血压下降所产生的抑制作用,以百分数表示。测定50%地抑制物质P诱发的血压下降时的相应剂量作为ED50。
在该试验模式中,实施例1物质在静脉内用药后的ED50值为0.2μmol/kg、在十二指肠内用药后的ED50值为0.08μmol/kg。这种i.d.效应对i.v.效应的比例可以作为指标,用以说明:该物质良好地适合于口服用药,并且它优选在十二指肠内发挥作用。
在同一试验模式中,检测了受测物质对以钙拮抗特性为基础的血压下降的作用。在此对照组动物只是以受测物质用药,而不给予物质-P。实施例1物质在检测的剂量范围内(i.v.剂量至多1μmol/kg、i.d.剂量至多10μmol/kg)没有明显的血压下降。这一指标说明,在该剂量范围内没有钙拮抗副作用。本发明化合物这种令人惊异的微小钙拮抗副作用也可以通过试管内的标准试验模式、例如在豚鼠的离体主动脉组织上得以证实。
这些物质也可以以通常的药物制剂形式用药。所应用的剂量可以存在个体差异,根据所治疗状态的不同和所应用物质的不同自然有所变化。一般来说,适于人类和较大哺乳动物用药的药物剂量为0.1至80mg活性物质含量,尤其是1至10mg/单个剂量。
本发明化合物可以与通常的制药学佐剂和/或载体物质一起制备成固态或液态的药剂形式。固态制剂例如可以是口服用药制剂如片剂、糖衣丸剂、胶囊、粉剂或粒剂,或者也可以是栓剂。这些药物制剂可以含有制药学常用的无机或/和有机载体物质,例如滑石粉、乳糖或淀粉,此外还可以含有制药学常用的佐剂,例如润滑剂或片剂崩解剂。液态制剂如活性物质的悬浮液或乳剂可以含有常用的稀释剂,如水、油和/或悬浮剂如聚乙二醇和类似物质。还可以添加其它的佐剂,例如贮藏剂、矫味剂和类同物质。
活性物质可以与制药学佐剂和/或载体物质按照本身已知的方式相混合或者配制。为了制备固态药物剂型,例如可以将活性物质与佐剂和/或载体物质以通常的方式相混合,然后制成湿的或干的粒剂。粒剂或粉剂可以直接充填成胶囊,或者以通常的方式压制成片剂丸。这些可以在必要时以通常的方式制成糖衣丸剂。
以下实施例能进一步说明本发明,但其范围并非仅限于此。
实施例1:(2R)-1-[3,5-双(三氟甲基)苯甲酰基]-2-(1H-吲哚-3-基-甲基-)-4-{2-[N-(2-甲氧基苄基)氨基乙基]氨基羰基}哌嗪
A)将101.5g叔-丁氧基羰基甘氨酸在氮气氛下溶于800ml二氯甲烷中,并且与96.5ml三乙胺混合。冰冷下缓慢滴加58ml氯蚁酸乙酯,室温下搅拌所形成的混合物2小时,然后接着滴加79.8g2-甲氧基苄基胺于400ml二氯甲烷中的溶液。过夜搅拌,然后添加1400ml 15%水溶性酒石酸溶液,并且重新搅拌30分钟。接着将有机相分离、经硫酸钠干燥和在减压下蒸发。将剩余物由二乙醚/二氯甲烷结晶和在真空中干燥。得88.9gN-BOC-C-(2-甲氧基)-苄基氨基甘氨酸为白色粉状物,Fp.(熔点)=97-97.7℃。
B)将40.0g上述所得产物在氮气氛下溶于600ml甲苯和THF(1∶1)的混合液中,并且滴加至冰冷的21.0g LiAlH4于500ml THF中的溶液中。室温下搅拌混合液过夜,然后在冰冷却下按顺序滴加20ml水和150mlTHF的混合液、接着在室温下首先添加20ml 15%水溶性氢氧化钠溶液。然后60ml水。将形成的溶液从生成的沉淀物中吸去和将滤液在减压下蒸发。将剩余物吸收进240ml 7.5%水溶性酒石酸溶液中,将水相用二氯甲烷萃取。接着将水相通过添加200ml10%水溶性氢氧化钠溶液,使其pH=10,然后用二氯甲烷萃取3次。将合并的二氯甲烷相经硫酸钠干燥、在减压下蒸发和真空中干燥。得28.0g油性N-BOC-N′-(2-甲氧基)-苄基-1,2-二氨基乙烷,它不需提纯可进一步转化。
C)将5.0g以上所得产物在氮气氛下溶于50mlTHF中。添加20ml1N水溶性氢氧化钠溶液。冰冷却下向所形成的反应混合液同时滴加共3.05g氯蚁酸苄基酯和1N水溶性氢氧化钠溶液,使其pH值不低于10。添加结束后室温下搅拌过夜。接着添加150ml甲基-叔-丁基醚,分离水相,然后按顺序2次用50ml水、1次用50ml 15%水溶性酒石酸溶液和重新2次用50ml水洗涤有机相。将有机相然后经硫酸钠干燥、在减压下蒸发和真空中干燥。得4.9gN-BOC-N′-(2-甲氧基)-苄基-N′-Cbo-1,2-二氨基乙烷,它不需提纯可进一步转化。
D)将4.8g以上所得产物溶于50ml二氯甲烷中。添加4.4g对甲苯磺酸和搅拌反应混合液过夜。接着添加7.5gNaOH于75ml水中的溶液。将有机相分离,用75ml水洗涤1次和经硫酸钠干燥。将溶液在减压下蒸发和将产物在真空中干燥。得3.5g油性N-(2-甲氧基)-苄基-N-Cbo-1,2-二氨基乙烷,它不需提纯可进一步转化。
E)将2.0g(2R)-1-[3,5-双(三氟甲基)苯甲酰基]-2-(1H-吲哚-3-基-甲基)-哌嗪溶于100ml二氯甲烷中。先后添加溶于20ml二氯甲烷中的0.6g三光气和溶于20ml二氯甲烷中的12.0ml二异丙基乙胺。室温下搅拌所形成的混合物1小时,接着滴加溶于20ml二氯甲烷中的2.8g以上所得氨基化合物。将反应混合物再搅拌18小时,接着按顺序用10%水溶性硫酸氢钾溶液、水和重新用饱和的碳酸氢钾溶液洗涤。然后将二氯甲烷相经硫酸钠干燥和减压下蒸发。将剩余物经过硅胶(洗脱剂∶二氯甲烷/甲醇3∶1)色谱分离,得2.5g油性(2R)-1-[3,5-双(三氟甲基)苯甲酰基]-2-(1H-吲哚-3-基-甲基-)-4-{2-[N-(2-甲氧基苄基)-N-Cbo-氨基乙基]氨基羰基}哌嗪,它不需提纯可进一步转化。
F)将2.5g以上所得产物溶于400ml乙醇中,并且与0.5g 10%载于活性炭上的钯催化剂混合。接着在4巴的氢压下氢化6小时。滤去催化剂和减压下将溶剂蒸发。经过硅胶(洗脱剂:二氯甲烷/甲醇9∶1)色谱分离,得1.0g标题化合物,将它用HCl-饱和的二乙醚处理,转化成氢氯化物,Fp.=138-140℃。
按照以上的说明,还可以制备以下表3中列举的式I化合物:表3:式I的其它化合物
实施例号 | R1 | R2 | R3 |
23 | CH3H | HF | OCH3H |
实施例I:含有(2R)-1-[3,5-双(三氟甲基)苯甲酰基]-2-(1H-吲哚-3-基-甲基-)-4-{2-[N-(2-甲氧基苄基)氨基乙基]-氨基羰基}哌嗪的片剂
按照每一片剂含以下成份来制备片剂:(2R)-1-[3,5-双(三氟甲基)苯甲酰基]-2-(1H-吲哚-3-基-甲基-)-4-{2-[N-(2-甲氧基苄基)氨基乙基]-氨基羰基}哌嗪-氢氯化物 20mg玉米淀粉 60mg乳糖 135mg明胶(为10%溶液) 6mg
将活性物质、玉米淀粉和乳糖与10%明胶溶液浓缩。将糊剂研碎,将所形成的粒剂放置至合适的金属薄片上,在45℃下干燥。将干燥的粒剂通过粉碎机,然后在混合机中与以下其它佐剂混合:滑石粉 5mg硬脂酸镁 5mg玉米淀粉 9mg然后压制成240mg的片剂。
Claims (4)
1.通式I化合物及其生理耐受性酸加成盐
其中
R1为氢原子或C1-C4烷基,
R2为氢原子或卤素和
R3为氢原子或C1-C4烷氧基。
2.按照权利要求1的(2R)-1-[3,5-双(三氟甲基)苯甲酰基]-2-(1H-吲哚-3-基-甲基-)-4-{2-[N-(2-甲氧基苄基)氨基乙基]-氨基羰基}哌嗪及其生理耐受性酸加成盐。
3.含有按照权利要求1化合物的药理作用剂量以及常用的制药学佐剂和/或载体物质的药物。
其中
R1为氢原子或C1-C4烷基,
R2为氢原子或卤素和
R3为氢原子或C1-C4烷氧基
其特征为,
a)将式II化合物
与通式III的反应性羰基化合物反应,
其中R101为C1-C4烷基或一个氨基保护基,R2和R3具有上述含义,并且接着将可能出现的保护基R101再次裂解或者
其中R101、R2和R3具有上述含义,接着将可能出现的保护基R101再次裂解
和任选地将所获得的R1为氢原子的式I化合物烷基化,生成R1为C1-C4烷基的式I化合物,以及任选地将所获得的式I化合物转化成其生理耐受性酸加成盐,或者将生理耐受性酸加成盐转化成游离的式I化合物。
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UA75425C2 (en) * | 2001-07-09 | 2006-04-17 | Piperazine oxime derivatives with antagonistic activity to nk-1 receptor, use thereof, a pharmaceutical composition based thereon, a method for producing and a method for producing intermediary compounds | |
ITBO20020198A1 (it) * | 2002-04-12 | 2003-10-13 | Univ Bologna | Derivati 2 , 5 bis diammino 1 , 4 benzochenionici utili per il trattamento della malattia di alzheimer , metodo per la loro preparazione ed |
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EP0655442A1 (en) * | 1993-11-29 | 1995-05-31 | Fujisawa Pharmaceutical Co., Ltd. | Piperazine derivatives as Tachykinin antagonists |
WO1996037489A1 (en) * | 1995-05-25 | 1996-11-28 | Fujisawa Pharmaceutical Co., Ltd. | 1-benzoyl-2-(indolyl-3-alkyl)-piperazine derivatives as neurokinin receptor antagonists |
WO1997028141A1 (fr) * | 1996-02-02 | 1997-08-07 | Pierre Fabre Medicament | Nouvelles piperazines aromatiques derivees de cycloazanes substitues, ainsi que leur procede de preparation, les compositions pharmaceutiques et leur utilisation comme medicaments |
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EP0655442A1 (en) * | 1993-11-29 | 1995-05-31 | Fujisawa Pharmaceutical Co., Ltd. | Piperazine derivatives as Tachykinin antagonists |
WO1996037489A1 (en) * | 1995-05-25 | 1996-11-28 | Fujisawa Pharmaceutical Co., Ltd. | 1-benzoyl-2-(indolyl-3-alkyl)-piperazine derivatives as neurokinin receptor antagonists |
WO1997028141A1 (fr) * | 1996-02-02 | 1997-08-07 | Pierre Fabre Medicament | Nouvelles piperazines aromatiques derivees de cycloazanes substitues, ainsi que leur procede de preparation, les compositions pharmaceutiques et leur utilisation comme medicaments |
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DE19824865A1 (de) | 1999-03-04 |
RU2198883C2 (ru) | 2003-02-20 |
CN1218044A (zh) | 1999-06-02 |
HK1019604A1 (en) | 2000-02-18 |
JP4250228B2 (ja) | 2009-04-08 |
AU744104B2 (en) | 2002-02-14 |
TW520368B (en) | 2003-02-11 |
HUP9801889A1 (hu) | 2000-11-28 |
ID20787A (id) | 1999-03-04 |
TR199801683A3 (tr) | 1999-03-22 |
NO983918D0 (no) | 1998-08-26 |
BR9803237B1 (pt) | 2009-05-05 |
CZ267198A3 (cs) | 1999-03-17 |
HU9801889D0 (en) | 1998-10-28 |
UA60300C2 (uk) | 2003-10-15 |
KR19990023605A (ko) | 1999-03-25 |
AU8189998A (en) | 1999-03-11 |
AR015147A1 (es) | 2001-04-18 |
DZ2597A1 (fr) | 2003-03-01 |
US6001833A (en) | 1999-12-14 |
IL125885A0 (en) | 1999-04-11 |
NO983918L (no) | 1999-03-01 |
SK111098A3 (en) | 1999-05-07 |
TR199801683A2 (xx) | 1999-03-22 |
JPH11140082A (ja) | 1999-05-25 |
CA2245484C (en) | 2008-04-29 |
NO314939B1 (no) | 2003-06-16 |
PL328221A1 (en) | 1999-03-01 |
CA2245484A1 (en) | 1999-02-27 |
PL193724B1 (pl) | 2007-03-30 |
BR9803237A (pt) | 2000-02-08 |
NZ331524A (en) | 2000-02-28 |
IL125885A (en) | 2000-08-13 |
ZA986721B (en) | 1999-02-02 |
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