CN101180267A - 胺和氨基酸的苯基-n-酰基衍生物、其制备过程、其药物组合物和用途 - Google Patents
胺和氨基酸的苯基-n-酰基衍生物、其制备过程、其药物组合物和用途 Download PDFInfo
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- CN101180267A CN101180267A CNA2006800173042A CN200680017304A CN101180267A CN 101180267 A CN101180267 A CN 101180267A CN A2006800173042 A CNA2006800173042 A CN A2006800173042A CN 200680017304 A CN200680017304 A CN 200680017304A CN 101180267 A CN101180267 A CN 101180267A
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- hydrogen
- compound
- phenyl
- hydroxyl
- propionyl
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Abstract
本发明涉及生物源性胺和氨基酸的新颖的通式(I)苯基-N-酰基衍生物,作为环加氧酶抑制剂,具备止痛和抗炎性质,避免副作用,特别是致溃疡性和促痉挛作用,以及加强其他止痛剂的效果,另外具备抗缺氧、抗抑郁和抗震颤麻痹作用,以及制备生物源性胺的新颖与已知的苯基-N-酰基衍生物的方法,包含通式(I)化合物的药物组合物和药物,以及其用途和治疗方法。
Description
本发明涉及生物有机化学的领域,涉及新颖的化合物、即生物源性胺的苯基-N-酰基衍生物以及新颖的与已知的化合物的合成过程,其在医学中作为潜在的止痛、抗炎、解痉和抗低氧剂以及具备抗抑郁、抗震颤麻痹效果和增强其他止痛剂效果的能力的药物的用途。
在先技术
国际申请WO97/23202的公报公开了通式(XV)胺的苯基-N-酰基衍生物
其中涵盖了3-(对-羟基苯基)-丙酰基苯基乙基胺、3-(对-羟基苯基)-丙酰基酪胺和3-苯基丙酰基苯基乙基胺(分别为本发明的化合物IX、X、XI)。这份公报公开了通式(XV)化合物的合成和其作为选择性NMDA受体亚型配体的用途,可用于治疗慢性疼痛、偏头痛以及麻醉。不过,所示公报没有公开或鉴别相当于本发明化合物X和XI的特定结构,也没有提供任何支持所称活性的数据,仅在其他胺衍生物的制备过程中公开了作为中间体化合物的化合物IX和其合成。
本发明的化合物IX、X和XI也被公开在早期公报中,它们在如上所示国际申请WO 97/23202的优先权日之前普遍为公众所获得,用于不同的目的。
3-(对-羟基苯基)-丙酰基苯基乙基胺(IX)被公开在JacobsonK.A.,Kirk K.L.New high-performance liquid chromatographicprocedure for the detection and quantification of β-phenylethylamine.//J.Chromatography.1987.V.415.P.124-128中;3-(对-羟基苯基)-丙酰基酪胺(X)被公开在R.B.Herbert,A.E.Kattah.The biosynthesis of Sceletium alkaloids inSceletium subvelutinum L.Bolus.//Tetrahedron.1990.V.46.No 20.P.7105-7118中;3-苯基丙酰基苯基乙基胺(XI)被公开在Maldonado E.,He rnandez E.,Ortega A.Amides,coumarine andother constituents from Simsia cronquistii.//Phytochem.1992.P.1413-1414中。
国际申请WO 97/23202的公报注意到使用通式(XV)化合物预防一些特定种类疼痛的可能性,例如偏头痛、慢性疼痛,以及其用于麻醉的用途,因为所述化合物能够充当选择性NMDA受体亚型配体。不过,WO 97/23202缺乏任何支持这组化合物所称活性的数据,因而,这类化合物用于所示目的、确切为针对体内动物模型的可能性,进而关于可能的药理作用的结论,仅仅基于所有被公开在所示国际申请中的化合物都是选择性NMDA受体亚型配体的断言。
国际申请WO 97/23202的公报公开了3-(对-羟基苯基)-丙酰基苯基乙基胺(IX)的合成过程,在N,N’-二环己基碳二亚胺(DCC)的存在下使用1-羟基苯并***。分离和纯化所述化合物的过程未被公开;在理化常数中,仅给出了熔点和1H-NMR光谱。
文章Jackson K.A.,Kirk K.L.New high-performance liquidchromatographic procedure for the detection and quantificationof β-phenylethylamine.//J.Chromatography.1987.V.415.P.124-128公开了3-(对-羟基苯基)-丙酰基苯基乙基胺(IX)的合成,使用3-(对-羟基苯基)-丙酸的改性N-羟基琥珀酰亚胺酯。反应是在甲醇-1M Na2HPO4,pH8混合物(1∶1)中进行的,使用磺基琥珀酰亚氨基-3-(对-羟基苯基)-丙酸酯(硫酸化Bolton-Hunte试剂)。仅用熔点鉴别了所制备的产物。按照这篇文章,在利用HPLC法量化测定体液中内源性苯基乙基胺水平的电化学检测器中使用所制备的3-(对-羟基苯基)-丙酰基苯基乙基胺作为内部标准。
文章Herbert R.B.,Kattah A.E.The biosynthesis of Sceletiumalkaloids in Sceletium subvlutinum L.Bolus.//Tetrahedron.1990.V.46.No 20.P.7105-7118公开了3-(对-羟基苯基)-丙酰基酪胺(X)作为中间体在Sceletium subvlutinum生物碱合成中的用途以及其采用DCC法的合成过程。该过程的缺点是必须使用柱色谱纯化目标产物,并且收率较低(约48%)。
文章Maldonado E.,Hernandez E.,Ortega A.Amides,coumarineand other constituents from Simsia cronquistii.//Phytochem.1992.P.1413-1414公开了从Simsia cronquistii植物的地上部分分离3-苯基丙酰基苯基乙基胺(XI),并且提供了质谱、1H-NMR光谱数据以及熔点。没有提供生物活性数据。
使用缩合剂4-(4,6-二甲氧基-1.3.5-三嗪-2-基)-4-甲基吗啉氯化物(DMT-MM)合成化合物XI被公开在Kumishima M.,KawachiC.,HiokiK.et al.Formation of carboxamides by direct condensationof carboxylic acids and amines in alcohols using a new alcohol-and water-soluble condensing agent:DMT-MM.//Tetrahedron.2001.V.57.No 8.P.1551-1558中。这种合成方法的缺点是生成副产物和需要使用制备型薄层色谱纯化目标产物,这使过程复杂化,不可避免地降低收率。尽管如此,产物(XI)的收率高达99%。合成化合物XI是为了研究新颖的缩合剂DMT-MM的实用性。
酪氨酸和苯丙氨酸类氨基酸衍生物、例如3-(对-羟基苯基)-丙酰基酪氨酸、苯基丙酰基酪氨酸、苯基乙酰基酪氨酸、苯基丙酰基丙氨酸和苯基丙酰基酪氨酸甲基酯(分别为本发明的化合物XIV、XV、XVI、XVIII和XXI)的合成和它们对Achatina fulica farussae蜗牛神经节中TAN神经元的抑制效果的研究被公开在文章Takeuchi H.,Ariyoshi Y.,Effects of N-beta-phenyl propionyl-L-tyrosine andits derivatives on the excitability of an identifiable giantneuron of Achatina fulica ferussac.//Comparative biochemistryand physiology.C:Comparative pharmacology.1982.V.72.No 2.P.225-229和Y.Ariyoshi,H.Takeuchi.Structure-activityrelationships of N-β-phenylpropionyl-L-tyrosine and itsderivatives on the inhibition of an identifiable giant neuronof an African giant snail.//Br.J.Pharmacol.1982.V.77.P.631-639中。在文章Y.Ariyoshi,H.Takeuchi.Structure-activity relationships of N-β-phenylpropionyl-L-tyrosine andits derivatives on the inhibition of an identifiable giantneuron of an African giant snail.//Br.J.Pharmacol.1982.V.77.P.631-639中,描述了化合物XIV、XV、XVI、XVIII和XXI的典型合成技术,使用酪氨酸甲基酯作为胺衍生物进行活化N-羟基琥珀酰亚胺法,随后皂化(就化合物XIV、XV、XVI、XVIII而言),但是没有给出所述化合物的理化常数和收率。此外,使用1-羟基苯并***和乙基-3-(3-二甲氨基)丙基碳二亚胺合成苯基乙酰基酪氨酸(XV)被公开在Tangpasuthadol V.,Pendharkar S.M.,Kohn J.Hydrolyticdegradation of tyrosine-derived polycarbonates,a class of newbiomaterials.Part I:Study of model compounds.//Biomaterials.2000.V.21.No 23.P.2371-2378中,收率高(94%),使用酪氨酸乙酯和苯基丙酸作为起始化合物,随后皂化乙基酯。提供了1H-NMR光谱和熔点。
在KOH的存在下借助氯酐法合成苯基丙酰基苯基丙氨酸(XVIII)被公开在Lustig N.,Spiegelstain-Klarfeld H.,Scheider E.,Lichtenstein N.Phenylacetyl and phenylpropionyl amino acids.Their inhibitory effect on glutamine synthetase and theirresistance to acylase.I.//Israel Journal of Chemistry.1974.V.12.No 3.P.757-763中。提供了熔点和元素分析。进行合成是为了研究化合物XVIII对谷氨酰胺合成酶的抑制程度。
苯基丙酰基酪氨酸甲基酯(XXI)在日本专利57193437中被提到过(实施例4),其中其合成是借助活化N-羟基琥珀酰亚胺酯的方法实现的。
与化合物XVIII的合成相似使用苯基乙酸的氯酐合成苯基乙酰基苯基丙氨酸(XIX)被公开在Chen H.M.,Hsu M.S.,Huang L.J.,et al.Effect of N-phenylacetyl L-amino acids on the differentiationof HL-60 cells.//Chinese Pharmaceutical Journal.2001.V.53.No 3.P.157-167中。提供了目标化合物的理化特征(熔点、1H-NMR-与IR-光谱、质谱)。苯基乙酰基苯基丙氨酸(XIX)已被确定是细胞分化的诱导剂。
3-(对-羟基苯基)-丙酰基酪氨酸甲基酯(XX)在国际申请WO97/23202的公报中被提到过,不过没有提供其合成和理化特征。合成化合物(XX)是为了用作制备与组织相比较的生物降解性聚合物的单体。
从共生细菌Xenorhabdus nematophilus分离的天然化合物苯基乙酰基乙基胺(XXIII)在国际申请WO 01/49656的公报中是借助氯酐法合成的,是借助1H-NMR-、13C-NMR-与IR-光谱、质谱、熔点的数据鉴别的。已经研究了化合物XXIII的体外抗肿瘤活性。
在国际申请WO 01/49656的公报中公开的通式化合物也涵盖本发明的其他化合物:对-羟基苯基乙酰基酪胺、对-羟基苯基乙酰基苯基乙基胺和苯基乙酰基酪胺(分别为本发明的化合物VII、VIII和VI)。不过,所述公报没有公开所示化合物的确切结构式、其合成、理化常数、生物活性数据。
苯基丙酰基酪胺(XII)在文章Takeuchi Hiroshi,Tamura Hiroko.The effects of aromatic amino acid derivatives on theexcitability of an identifiable giant neuron of an African giantsnail(Achatina fulica ferussac).//British Journal ofPharmacology.1980.V.69.No 1.P.29-34中被提到过,但是没有公开其合成和其理化特征和目的。
在文章Garrett C.E.,Jiang X.,Prasad K,Pepic O.Newobservations on peptide bond formation using CDMT.//Tetrahedr on Letters.2002.V.43,No 23.p,4161-4165中,公开了苯基丙酰基苯基丙氨酸甲基酯(XXIV)和其合成过程,在N-甲基吗啉的存在下使用缩合剂2-氯-4,6-二甲氧基-1,3,5-三嗪(CDMT)。不过,没有提供所述化合物的理化特征和活性数据。仅仅提及该过程具有下列优点:在一步中完成合成和用水沉淀分离产物导致色谱纯的产物收率高达90%。
文章Peric M.,Vercek B.,Petric A.ω-Diazoacetophenonesas reagents for a mild and selective protection of an amino group.//Acta Chimica Sloyenica.1996.V.43.No 2.P.163-173公开了一种肽合成中间体苯基乙酰基酪氨酸甲基酯(XXII)的合成,通过重氮酮(diasoketone)的生成缩合苯基乙酸与酪氨酸甲酯。就纯化化合物XXII而言,柱色谱的使用是必须的。提供了熔点、1H-NMR-光谱和元素分析数据。
按照Votano J.R.,Altman J.,Wilchek M.,Potential use ofbiaromatic L-phenylalanyl derivatives as therapeutic agents inthe treatment of sickle cell disease.//Proceedings of theNational Academy of Sciences of the United States of America.1984.V.81.No 10.P.3190-3194,苯基乙酰基苯基丙氨酸甲基酯(XXV)是借助活化N-羟基琥珀酰亚胺酯的方法合成的,随后经过柱色谱纯化。没有提供所述化合物的理化常数。在这篇文章中,化合物XXV是化合物XIX合成中的中间体,后者正在被研究作为治疗镰状细胞疾病的候选药物。
此外,化合物XXV的酶合成方法是已知的[Didziapetris R.,Drabnig B.,Schellenberger V.,Jakubke H.D.,Svedas V.Penicillina cylase-Catalyzed protection and deprotection ofamino groups as a promising approach in enzymatic peptidesynthesis.//FEBS Letters.1991.V.287.No 1-2.P.31-33]。
专利US 2003199566(Bok S.,Lee S.,Jeong T.,Phenolic acidderivatives and composition for preventing or treating bloodlipid level-related diseases comprising the same)公开了3-(对-羟基苯基)-丙酰基苯基丙氨酸(XVII)和3-(对-羟基苯基)-丙酰基苯基丙氨酸甲基酯(XIII)的合成是在三乙胺的存在下使用1-羟基苯并***和1-[3-(二甲氨基)丙基]-3-乙基碳二亚胺盐酸盐。就制备3-(对-羟基苯基)-丙酰基苯基丙氨酸(XVII)而言,进一步进行化合物(XIII)的皂化,目标产物的收率为78%。就两种化合物而言,提供了1H-NMR-与13C-NMR-光谱的数据。化合物XVII和XIII被提出用于预防和治疗与血液脂质水平有关的疾病。
国际申请公报WO 9952962公开了3-(对-羟基苯基)丙酰基-酪氨酸苄基酯(XXXIV)。提供了熔点、1H-NMR-与13C-NMR-光谱的数据。
止痛效果已知牵涉不同的机理,尤其是通过抑制花生四烯酸级联中的环加氧酶[Mashkovsky PPM Lekarstvennye sredstva(Medicaments).//Moscow.Novaya volna publishers.2005.P.163-164]。
非麻醉性止痛剂和非甾类抗炎剂在降低疼痛原合成的药物中具备最大所表现的止痛效果。非麻醉性止痛剂以水杨酸盐(阿司匹林)、吡唑酮衍生物(amidopirin、安乃近)和对-氨基苯酚(对乙酰氨基酚)为代表。对属于非甾类抗炎剂的水杨酸、乙酸、丙酸和邻氨基苯甲酸的衍生物来说,非麻醉性止痛剂和具有止痛效果的非甾类抗炎剂具备抗炎和退热作用[Kukushkin M.L.,Khitrov N.K.Obshchayapatologiya boli(General pathology of pain)/Moscow.Meditsinapublishers.2004.142 pages]。致溃疡性是非甾类抗炎剂的主要副作用。在具有不同作用机理的止痛剂中经常观察到促痉挛性副作用[Mashkovsky PPM Lekarstvennye sredstva(Medicaments).//Moscow.Novaya volna publishers.2005.P.154]。
非甾类抗炎药水杨酸钠、消炎痛和吡罗昔康的抗震颤麻痹性质是已知的[M.G.Kadieva,E.T.Oganesyan,S.Kh.Matsueva.Nejrotoxiny I sredstva dlya lecheniya bolezni Parkinsona.III.Sredstva,oposredovanno vlijaushchiye na dofaminergicheskuyusistemu.(Neurotoxines and agents for treating Parkinson’sdisease.III.Agents with mediated effect on the dopaminergicsystem).Khimiko-pharmacevticheskij zhurnal.2005.T.39.No 11.S.3-11]。这类活性被提出是部分通过影响多巴胺能***的***素介导实现的。
抗血清素药也已知在帕金森氏病中对多巴胺***发挥积极影响,促进受体与多巴胺拮抗剂结合[M.G.Kadieva,E.T.Oganesyan,S.Kh.Matsueva.Nejrotoxiny I sredstva dlya lechenija bolezniParkinsona(Neurotoxines and agents for treating Parkinson’s disease)Khimiko-pharmacevticheskij zhurnal.2005.T.39.No11.S.3-11]。抗震颤麻痹药也存在其他作用机理[Mashkovsky PPMLekarstvennye sredstva(Medicaments).//Moscow.Novaya volnapublishers.2005.P.138]。
依赖于作用机理,抗抑郁剂被细分为若干组,确切为单胺氧化酶抑制剂、三环抗氧化剂、组胺、血清素、缩胆囊肽、α-肾上腺素能受体的阻滞剂[Ma shkovsky PPM Lekarstvennye sredstva(Medicaments).//Moscow.Novaya volna publishers.2005.P.109]。
由于已知抗抑郁剂和结构相关性化合物的使用伴有大量严重的副作用,因此寻找新颖的具有这类作用的安全、有效药物正是时候。本发明化合物预防和治疗抑郁症的用途是未知的。
在大量病理状态中都观察到缺氧,包括脑功能疾患。抗氧化剂提高机体对于循环氧的利用,增强机体对于氧不足的抵抗性。具有这类作用的药物不是很多[Mashkovsky PPM Lekarstvennye sredstva(Medicaments).//Moscow.Novaya volna publishers.2005.P.729]。很多药物、包括控制CNS活性的那些另外具备抗缺氧性质,增强它们作用的功效。就本发明化合物群而言,抗缺氧效果在以前尚未被公开过。
本发明的客体是新颖的和已知的生物源性胺和胺酸的苯基-N-酰基衍生物的合成和用途,用作无毒的、更有效的止痛剂和抗炎剂,没有副作用,尤其是致溃疡性和促痉挛作用,它们也具备抗缺氧、抗抑郁和抗震颤麻痹作用以及加强其他止痛剂效果的能力。
发明概述
本发明涉及新颖的通式I胺的苯基-N-酰基衍生物:
R4是氢或羟基;
其条件是通式I化合物不是
苯基乙酰基酪胺,
3-(对-羟基苯基)丙酰基苯基乙基胺,
3-(对-羟基苯基)丙酰基酪胺,
3-苯基丙酰基苯基乙基胺,
3-苯基丙酰基酪胺,
3-(对-羟基苯基)丙酰基苯基丙氨酸甲基酯,
3-(对-羟基苯基)丙酰基酪氨酸,
3-苯基丙酰基酪氨酸,
苯基乙酰基酪氨酸,
3-(对-羟基苯基)丙酰基苯基丙氨酸,
3-苯基丙酰基苯基丙氨酸,
苯基乙酰基苯基丙氨酸,
3-(对-羟基苯基)丙酰基酪氨酸甲基酯,
3-苯基丙酰基酪氨酸甲基酯,
苯基乙酰基酪氨酸甲基酯,
苯基乙酰基苯基乙基胺,
3-苯基丙酰基苯基丙氨酸甲基酯,
苯基乙酰基苯基丙氨酸甲基酯,
3-(对-羟基苯基)丙酰基-酪氨酸苄基酯;
或其药学上可接受的盐,具备环加氧酶抑制活性、抗炎与止痛作用、解痉、抗缺氧、抗震颤麻痹和抗抑郁作用以及加强其他止痛剂效果的能力。
本发明也涉及通式I化合物或其药学上可接受的盐的用途:
R4是氢或羟基,
用作环加氧酶抑制剂、止痛与抗炎剂、解痉剂、抗缺氧剂、抗震颤麻痹药与抗抑郁剂以及能够加强其他止痛剂效果的药物。
进而,本发明涉及具备环加氧酶抑制活性、抗炎与止痛作用以及抗抑郁、解痉、抗缺氧、抗震颤麻痹作用的药物组合物或药物,含有有效量的式I化合物或其药学上可接受的盐和可选的药学上可接受的载体。
本发明另一主题是治疗不同起源的疼痛综合征以及伴有炎症、痉挛、缺氧、抑郁和震颤麻痹迹象的疾病的方法,包含有效量的通式I化合物或其药学上可接受的盐可选地与其他止痛剂联合给药。
本发明也涉及新颖的制备通式I化合物的方法。
发明的详细说明
优选的式I化合物是其中R3是-COOH、-COOCH3的化合物。
新颖的优选的式I化合物列在表1中。
表1
通式I化合物是如下制备的,在有机溶剂中,优选N,N-二甲基甲酰胺、乙酸乙酯,在冷却下,优选在-25℃至0℃的温度下,与二苯基叠氮化磷酰(DPPA)和三乙胺(TEA)反应活化对-羟基苯基乙酸或苯基乙酸的羧基,继之以与氨基衍生物反应。优选地,羧基的活化是使用1-1.2当量DPPA和TEA实现的。作为氨基衍生物,可以使用酪氨酸和苯基丙氨酸酯。就制备化合物II和III而言,作为起始性氨基衍生物,分别使用酪氨酸和苯基丙氨酸苄基酯,继之以借助催化性氢解作用除去苄基。不象以前采用的已知式I化合物的合成方法,二苯基叠氮化磷酰法可以减少步骤数量,也就是删去分离羧酸组分的活化衍生物的步骤,仅通过萃取分离目标物质,增加收率(≥90%)。
二苯基磷酰酶法的通用合成流程列在流程1中。
流程1
新颖的化合物II、III、IV、V、VII、VIII、包括在苯基中包含羟基取代基的那些,也可以利用活化N-羟基琥珀酰亚胺酯的方法制备,其优点是试剂的可用性、所释放的N-羟基琥珀酰亚胺的水溶性、制备酰化剂的N-羟基琥珀酰亚胺酯的反应和酰胺键生成反应的快速进行、和尽管在苯基中存在羟基取代基也达到目标产物高收率(70-80%)的可能性。按照所提出的过程,酰化剂的N-羟基琥珀酰亚胺酯的合成是如下实现的,利用N,N’-二环己基碳二亚胺法(DCC-法)转化对-羟基苯基乙酸或苯基乙酸为活化的N-羟基琥珀酰亚胺酯,收率高(约90%),随后借助N-羟基琥珀酰亚胺酯与氨基衍生物之间的反应生成酰胺键,收率也高(70-80%),时间短(1-2小时),无需采用目标产物的色谱纯化。作为氨基衍生物,可以使用酪氨酸和苯基丙氨酸酯。与之相似,可以制备已知的化合物X、XI、XII、XIII、XV、XVII、XIX、XX、XXII、XXIII、XXIV,使用活化N-羟基琥珀酰亚胺酯的方法的合成在在先技术中没有被公开过。
采用活化N-羟基琥珀酰亚胺酯方法的通式I化合物的通用合成流程列在流程2中。
流程2
羟基苯基丙酰基酪氨酸(XIV)的合成也可以利用活化N-羟基琥珀酰亚胺酯的方法实现,为了减少步骤数量,有可能使用未保护的C-末端酪氨酸。此外,这可以避免长期暴露于碱,这将是酪氨酸甲基酯的皂化所必需的,它可能对目标化合物的光学纯度产生不利影响[Schreder E.,Lübke K.//Peptidy(Peptides)./Moscow.“Mir”publishers.1967.2 volumes;Gross E.,Meienhoffer I.//Peptidy.Osnovniye metody obrazovanija peptidnoj svyazi(Peptides.Mainformation methods of peptide bond)/Moscow.“Mir”publishers.1983.p.422]。未保护的酪氨酸在有机溶剂和水中的溶解度都低的问题是如下解决的,向酪氨酸的DMF悬液加入两当量的1N NaOH溶液转化为可溶性钠盐,导致所观察到的氨基酸的完全溶解。所得氨基衍生物溶液与3-(对-羟基苯基)丙酸的N-羟基琥珀酰亚胺酯之间的反应几乎完全地并且快速地(2小时)发生。分离后萃取,无需应用色谱纯化,目标产物(XIV)的收率达到约63%。
通式I化合物也可以被制备成与无毒性酸的药学上可接受的加成盐形式,酸例如富马酸、马来酸、琥珀酸、乙酸、柠檬酸、酒石酸等,和碱盐形式,碱例如氢氧化钠、氢氧化钾、碳酸钠等。
通式I化合物具备环加氧酶抑制活性,可用于治疗不同起源的疼痛综合征、关节与***以及骨骼-肌肉***的炎性与炎性-变性疾病、伴有炎症、痉挛、缺氧的不同疾病,加强其他止痛剂,以及由抑郁和帕金森氏病导致的疾患。
确切而言,本发明化合物可以用于治疗术后疼痛、创伤后疼痛以及妇科、神经科、癌性、牙齿来源、类风湿性关节炎、关节病、Bekhterev氏病、非特异性脊椎关节炎、痛风性关节炎、骨关节病、关节外风湿热和血栓静脉炎的疼痛综合征、其他伴有炎症、痉挛、缺氧的疾病以及由帕金森氏病、情绪紧张状态导致的疾患。
本发明化合物是以提供所需治疗结果的有效量给药的。
式(I)化合物可以以单元剂型的形式被口服、局部、肠胃外、吸入和直肠给药,其中包含无毒的药学上可接受的载体。本文所用的“肠胃外给药”表示皮下、静脉内、肌内或腹膜内注射或输注。
本发明化合物可以对患者给药的剂量为0.1至10mg/kg体重每天,优选0.5至5mg/kg,每天一次或多次。
与此同时,应当注意,就每一个别患者而言的特定剂量将依赖于很多因素,包括所用既定化合物的活性、患者的年龄、体重、性别、一般健康条件和他的营养方案与给予药物的方式、消除速率、所用特定的药物组合以及所治疗疾病的严重性。
根据本发明的药物组合物包含有效达到所需结果量的根据本发明的化合物,它们可以作为单元剂型给药(例如固体、半固体或液体形式),其中包含本发明化合物作为活性成分,混合有适合于肌内、静脉内、口服、舌下、吸入和直肠内给药的载体或赋形剂。活性成分可以与常用的无毒性药学上可接受的载体一起被包括在组合物中,适合于制备溶液、片剂、小丸剂、胶囊剂、锭剂、栓剂、乳液、悬液、软膏剂、凝胶剂和任何其他剂型。
作为赋形剂,可以使用不同的物质,例如糖类,例如葡萄糖、乳糖或蔗糖,甘露糖醇或山梨糖醇,纤维素衍生物和/或钙的磷酸盐,例如磷酸三钙或酸性磷酸钙;作为粘合剂,可以使用的物质例如淀粉糊,例如玉米、小麦、水稻、马铃薯淀粉,明胶,黄蓍胶,甲基纤维素,羟丙基甲基纤维素,羧甲基纤维素钠和/或聚乙烯吡咯烷酮。在必要时,可以使用崩解剂,例如上面提到的淀粉和羧甲基淀粉、交联聚乙烯吡咯烷酮、琼脂或者藻酸或其盐,例如藻酸钠。
可以使用可选的添加剂,例如调节流动性的试剂和润滑剂,例如二氧化硅、滑石、硬脂酸及其盐,例如硬脂酸镁或硬脂酸钙,和/或丙二醇。
锭剂芯通常包有一个耐受胃液作用的层。为此,可以使用浓糖溶液,其中可以可选地包含***胶、滑石、聚乙烯吡咯烷酮、聚乙二醇和/或二氧化钛和适合的有机溶剂或其混合物。
作为添加剂,也可以使用稳定剂、增稠剂、染剂和矫味剂。
作为软膏基质,可以使用碳水化合物软膏基质,例如白色与黄色凡士林(白凡士林、黄凡士林)、凡士林软膏(石蜡油)、白色与黄色软膏(白软膏、黄软膏),作为赋予更多致密一致性的添加剂,可以使用硬石蜡和蜡类;作为吸收性软膏基质,可以使用亲水性凡士林(亲水凡士林)、羊毛脂(羊毛脂)、冷霜(Unguentum leniens);作为可被水洗涤的软膏基质,可以使用亲水性软膏(亲水软膏);作为水溶性软膏基质,可以使用聚乙二醇软膏(聚乙二醇软膏)、膨润土基质和其他。
作为凝胶基质,可以使用甲基纤维素、羧甲基纤维素钠盐、羟丙基纤维素、聚乙二醇或聚氧乙烯、卡波普(carbopol)。
作为栓剂基质,可以使用不溶于水的基质,例如可可脂;可溶于水或者可与水混合的基质,例如明胶-甘油或聚氧乙烯;组合基质,例如皂性-甘油性基质。
在制造单元剂型时,与载体联合使用的活性成分的量可以因所治疗的接受者、给予药物的确切方式而异。
因而例如,在使用本发明化合物的注射溶液形式时,其中的活性成分含量为0.01-5%。作为稀释剂,可以使用0.9%氯化钠溶液、蒸馏水、注射用奴佛卡因溶液、林格溶液、葡萄糖溶液、溶解专用添加剂。在向机体给予本发明化合物的片剂和栓剂时,它们的量为5.0-500mg每单元剂型。
本发明的剂型是按照标准技术制造的,例如混合、造粒、糖衣的形成、溶解和冷冻干燥的过程。
应当注意,本发明化合物表现生物活性的剂量与用于对比的已知药物相比低三分之二,功效基本上相似,并且没有显示消极的副作用,也没有发现其使用禁忌。与此同时,在1000μg/kg的口服剂量下研究本发明化合物的毒性时,没有记录到实验动物的死亡。
本发明化合物、其制备和它们药理活性的检查的详细说明列在下列实施例中,它们阐述优选的本发明变体,不限制其范围。
本发明化合物的合成实例
在下列溶剂***中,在平板“Kiesegel 60 F254”(“Merck”,Germany)上,利用TLC法检查所制备的化合物的特征:氯仿-甲醇9∶1(1),氯仿-甲醇-乙酸乙酯6∶1∶3(2),氯仿-甲醇-氨6∶3∶0.5(3)。
利用氯-联甲苯胺试剂、水合茚三酮、碘和通过UV光中的发光显影色谱。
在仪器“AMX-400Bruker”(Germany)上记录1H-NMR。
在仪器“Magna 750”(“Nicolet”USA)上,在KBr片中采集IR-傅立叶光谱。
在仪器“Boetius”(Germany)上测定熔点。
在仪器REFLEXTM III(Bruker,Germany)上,使用2,5-二氢苯甲酸作为基质,借助基质激光-解吸电离法,在渡越时间质谱计上得到高分辨率质谱。
在如下仪器上进行分析型反相HPLC:
-色谱“Breeze”,检测器“Waters”(USA),检测波长214nm,洗脱速率1ml/min,条件(1):柱子Symmetry 300 C18,3.9×150mm,5μm,用0.1%含水TFA洗脱,乙腈梯度0%至60%,时间18分钟;
-色谱“System Gold”(:Beckman”,USA),洗脱速率0.25ml/min,检测波长220nm,条件(2):柱子“Phenomenex”(USA)C18,2×250mm,5μm,用0.1%含水TFA洗脱,梯度为0.08%TFA在100%MeCN中从0%至100%,时间50分钟;
-色谱“Breeze”,检测器“Waters”(USA),检测波长214nm,洗脱速率1ml/min,条件(3):柱子Symmetry 300 C18,4.6×250mm,20μm,用0.1%TFA洗脱,梯度为0.09%TFA在60∶40乙腈-水的混合物中从0%至100%,时间15分钟。
实施例1
对-羟基苯基乙酰基酪胺(VII)
工艺A
向0.40g(2.63mmol)对-羟基苯基乙酸的3.5ml DMF溶液加入0.35g(2.63mmol)酪胺,同时搅拌。将溶液冷却至-10℃,加入0.68ml(3.16mmol)二苯基叠氮化磷酰和0.44ml(3.16mmol)三乙胺。将溶液在-10℃下搅拌两小时,在20℃下放置15小时。向反应物加入35ml水,用20ml乙酸乙酯萃取。将乙酸乙酯层用10ml 5%Na2CO3溶液洗涤,用水洗至pH7,用10m l5%HCl溶液洗涤,用水洗至pH7。乙酸乙酯层经Na2SO4干燥,滤出Na2SO4,在真空下除去乙酸乙酯。油性残余物用酯-己烷混合物(1∶1)研制。滤出所生成的白色沉淀,在真空下经CaCl2干燥。收率0.68g(95%)。
Rf 0.7 (1).
Tm=147-149°。
[M]+271.6。
1H-NMR,CD3OD,δ,ppm:2.65(t,J=7Hz,2H,α-CH2-TA),3.29-3.32(m,4H,β-CH2-TA,CH2-(OH-PhAc)),6.63-6.75(m,4H,o-CH-芳族),6.90-7.06(m,4H,m-CH-芳族)。
IR-Fourier,cm-1:3276(val.OH);3108(val.,=C-H,芳族);1612(酰胺I);1591(酰胺II);1515(芳族-C-C-);1226(val.,-C-O,酚型)。
实测,%:C 70.57;H 6.43;N 5.50 C16H17NO3。
计算,%:C 70.83;H 6.32;N 5.16。
HPLC条件(1):个别的峰,保留时间8.71分钟。
工艺B
向0.70g(4.60mmol)对-羟基苯基乙酸的17ml乙酸乙酯溶液加入0.53g(4.60mmol)N-羟基琥珀酰亚胺,同时搅拌,将溶液冷却至0℃,加入0.95g(4.60mmol)N,N’-二环己基碳二亚胺(DCC)。将溶液在0℃下搅拌两小时,在4℃下放置20小时。滤出N,N’-二环己基脲(DCU)的沉淀。在真空下除去溶剂。油性残余物用己烷研制。滤出所生成的白色固体沉淀,用己烷洗涤,在真空下经CaCl2干燥。收率为1.08g(94.6%)。Rf 0.58 (1)。
向0.30g(1.2mmol)对-羟基苯基乙酸的N-羟基琥珀酰亚胺酯的8ml N,N-二甲基甲酰胺(DMF)溶液加入0.16g(1.2mmol)酪胺,同时搅拌。将溶液在20℃下搅拌两小时,在4℃下放置20小时。在真空下除去DMF。油性残余物用水研制。滤出所生成的白色沉淀,用水洗涤。收率0.26g(80%)。
Rf 0.68 (1).
Tm=146-148 °.
[M+H]+272.3.
实测,%:C 71.05;H 6.10;N 5.25 C16H17NO3.计算,%:C 70.83;H 6.32;N 5.16.
实施例2
对-羟基苯基乙酰基苯基乙基胺(VIII)
按照化合物VII所列工艺A进行合成。
收率0.57g(90.5%).
Rf 0.82 (1).
Tm=69-70°.
[M]+255.5.
1NMR DMSO-d6,δ,ppm:2.68(t,J=8Hz,2H,β-CH2-PEA),3.22-3.26(m,α-CH2-PEA),3.36(s,2H,CH2-(OH-PhAc)),6.66(d,J=4Hz,2H,m-CH-芳族OH-PhAc),7.00(d,J=4Hz,2H,m-CH-芳族OH-PhAc),7.14-7.28(m,5H,芳族-CH-PEA),8.0(br.s,1H,NH-PEA),9.20(s,1H,OH-(OH-PhAc)).
IR-Fourier,cm-1:3332(val.OH);3087(val.,=C-H,芳族);1626(酰胺I);1558(酰胺II);1515(芳族-C-C-);1249(val.,-C-O,酚型).
实测,%:C 75.57;H 6.80;N 5.77 C16H17NO2.计算,%:C 75.27;H 6.71;N 5.49.
HPLC条件(1):个别的峰,保留时间11.17分钟.
按照化合物VII所列工艺B进行合成。
收率0.50g(79.4%).
Rf 0.85 (1).
Tm=68-70°.
[M]+255.7.
实测,%:C 75.17;H 6.87;N 5.75 C16H17NO2.计算,%:C 75.27;H 6.71;N 5.49.
实施例3
3-(对-羟基苯基)-丙酰基酪胺(X)
按照化合物VII所列工艺A进行合成。
收率0.41g(95%).
Rf 0.38 (1).
Tm=174-176°.
1NMR DMSO-d6,δ,ppm:2.26(t,J=8Hz,2H,α-CH2-(HO-PhPr)),2.53(t,J=6Hz,2H,β-CH2-Tyra),2.67(t,J=8Hz,2H,β-CH2-(HO-PhPr)).3.16(t,J=6Hz,2H,α-CH2-Tyra),6.62(d,J=7Hz,2H,m-CH-Bzl-Tyra),6.65(d,J=7Hz,m-CH-Bzl-(HO-PhPr)),6.92-6.96(m,4H,o-CH-Bzl-Tyra and o-CH-Bzl-(HO-PhPr)),7.79(s,1H,NH-Tyra),9.09(br.s,2H,OH-Tyra and OH-(HO-PhPr)).
IR-Fourier,cm-1:3249(val.OH);1621(酰胺I);1515(芳族);1541(酰胺II).
实测,%:C 71.56;H 6.78;N 4.97 C16H17NO2.计算,%:C 71.56;H 6.71;N 4.91,C17H19NO3.
HPLC条件(2):个别的峰,保留时间25.62分钟.
按照化合物VII所列工艺B进行合成。
收率0.37g(85%).
Rf 0.35 (1).
Tm=172-174°.
[M]+285.3.
实施例4
3-苯基丙酰基苯基乙基胺(XI)
按照化合物VII所列工艺A进行合成。
收率0.26g(97%).
Rf 0.78 (1).
Tm=94-96 °.
1NMR DMSO-d6,δ,ppm:2.34(t,J=8Hz,2H,α-CH2-(HO-PhPr)),2.66(t,J=6Hz,2H,β-CH2-PEA),2.79(t,J=8Hz,2H,β-CH2-PhPro)),3.24(t,J=6Hz,2H,α-CH2-PEA),7.25-7.30(m,10H,CH-芳族),7.89(br.s,1H,NH-PEA).
IR-Fourier,cm-1:1637(酰胺I);1546(酰胺II).
实测,%:C 80.24;H 7.61;N 5.54.计算,%:C 80.60;H 7.56;N 5.53,C17H19NO3.
HPLC条件(2):个别的峰,保留时间37.86分钟.
按照化合物VII所列工艺B进行合成。
收率0.20g(77%).
Rf 0.80 (1).
实测,%:C 80.39;H 7.53;N 5.30.计算,%:C 80.60;H 7.56;N 5.53,C17H19NO3.
实施例5
3-(对-羟基苯基)-丙酰基苯基乙基胺(IX)
按照化合物VII所列工艺A进行合成。
收率0.20g(90%).
Rf (II)0.4.
Tm=102-104 °.Cast.[84]102-104 °.
[M]+269.6.
1NMR CDCl3,δ,ppm:2.39(t,J=7Hz,2H,α-CH2-(HO-PhPr)),2.73(m,2H,β-CH2-PEA),2.86(t,J=7Hz,2H,β-CH2-(HO-PhPr)),3.48(m,2H,α-CH2-PEA),6.75(m,2H,m-CH-芳族HO-PhPr),7.03(m,2H o-CH-芳族HO-PhPr),7.09(m,2H,o-CH-芳族PEA),7.3(m,3H,m,p-CH-芳族PEA).
IR-Fourier,cm-1:3263(val.OH);1618(酰胺I);1537(酰胺II).
实测,%:C 75.57;H 6.93;N 5.09.C17H19NO2.计算,%:C 75.81;H 7.11;N 5.20.
HPLC条件(3):个别的峰,保留时间14.77分钟.
实施例6
对-羟基苯基乙酰基酪氨酸甲基酯(IV)
按照化合物VII所列工艺A进行合成。
收率0.17g(3 9%).
Rf 0.56 (2).
[M]+329.85.
[α]D 25+12.22°(C0.36;MeOH).
1NMR DMSO-d6,δ,ppm:2.78(dd,1H,CH2-Tyr),2.9(dd,1H,CH2-Tyr),3.25-3.45(m,2H,CH2-HOPhAc),4.3-4.4(m,1H,α-CH-Tyr),3.6(s,3H,OCH3 Tyr),6.55-7.1(m,8H,芳族H),8.25(d,1H,NH-Tyr).
IR-Fourier,δ,cm-1:1649(酰胺I);1515(酰胺II);1263(酰胺III).
实测,%:C 65.75;H 5.75;N 4.23.计算,%:C 65.64;H 5.81;N 4.25.
HPLC条件(3):个别的峰,保留时间7.25分钟.
实施例7
对-羟基苯基乙酰基苯基丙氨酸甲基酯(V)
按照化合物VII所列工艺A进行合成。
收率0.40g(3 9%),油.
Rf 0.70 (2).
[M]+313.83.
[α]D 20+35.05°(C 0.19;乙酸乙酯).
1NMR DMSO-d6,δ,ppm:2.9(dd,1H,CH2-Phe),3.05(dd,1H,CH2-Phe),3.25-3.4(m,2H,CH2-HOPhAc),3.6(s,3H,OCH3 Phe),4.4-4.5(m,1H,α-CH-Phe),6.55-6.95(m,4H,芳族H HOPhAc),7.1-7.3(m,5H,芳族H Phe),8.3(d,1H,NH-Phe),9.2(s,1H,OH-Ar HOPhAc).
IR-Fourier,δ,cm-1:1663(酰胺I);1515(酰胺II);1263(酰胺III).
实测,%:C 69.08;H 6.05;N 4.45.计算,%:C 68.99;H 6.11;N 4.47.
HPLC条件(3):个别的峰,保留时间8.57分钟.
实施例8
苯基乙酰基酪胺(VI)
按照化合物VII所列工艺A进行合成。
收率0.35g(37.6%).
Rf 0.85 (2).
Tm105-108°.
[M+1]+256.2.
1NMR DMSO-d6,δ,ppm:2.6(t,2H,α-CH2-TA),3.2(q,2H,β-CH2-TA),3.4(s,2H,CH2-PhAc),6.6-7.0(m,4H,芳族H TA),7.15-7.3(m,5H,芳族H PhAc),8.0(t,1H,NH-TA),9.1(s,1H,OH-TA).
IR-Fourier,δ,cm-1:1646(酰胺I);1516(酰胺II);1264(酰胺III).
实测,%:C 75.37;H 6.69;N 5.45.计算,%:C 75.27;H 6.71;N 5.49.
HPLC条件(3):个别的峰,保留时间8.06分钟.
实施例9
3-(对-羟基苯基)-丙酰基苯基丙氨酸甲基酯(XIII)
按照化合物VII所列工艺A进行合成。
收率0.37g(38%),油.
Rf 0.73 (2).
[M+1]+328.21.
[α]D 25-6.95°(C 0.46;MeOH).
1NMR DMSO-d6,δ,ppm:2.3(t,2H,1-CH2 HOPhPr),2.6(t,2H,2-CH2 HOPhPr),2.85(dd,1H,CH2-Phe),3.0(dd,1H,CH2-Phe),3.6(s,3H,OCH3 Phe),4.4-4.5(m,1H,α-CH-Phe),6.6-6.95(m,4H,芳族H HOPhPr),7.15-7.3(m,5H,芳族H Phe),8.22(d,1H,NH-Phe),9.1(s,1H,OH-Ar HOPhAc).
IR-Fourier,δ,cm-1:1651(酰胺I);1516(酰胺II);1266(酰胺III).
实测,%:C 69.61;H 6.49;N 4.29.计算,%:C 69.71;H 6.47;N 4.28.
HPLC条件(3):个别的峰,保留时间8.9分钟.
实施例10
对-羟基苯基乙酰基酪氨酸苄基酯(XIII)
按照化合物VII所列工艺A进行合成。
收率0.59g(55.7%),油.
Rf 0.57 (2).
[M+1]+406.0.
[α]D 20-9.18 °(C 0.20;MeOH).
IR-Fourier,δ,cm-1:1649(酰胺I);1515(酰胺II);1737(val C=0酯).
实测,%:C 71.05;H 5.70;N 3.43.计算,%:C 71.10;H 5.72;N 3.45.
实施例11
对-羟基苯基乙酰基酪氨酸(II)
向0.59g(1.47mole)对-羟基苯基乙酰基酪氨酸苄基酯的10ml甲醇溶液加入0.20g 10%披钯碳,在剧烈搅拌下,在氢流中进行水合达1.5小时。滤出催化剂。在真空下除去滤液中的溶剂。油性残余物用酯-己烷混合物(1∶1)研制。滤出所生成的白色沉淀,在真空下经CaCl2和P2O5干燥。得到0.32g(68%)。
收率37%.
Rf 0.28 (3).
[M+1]+316.07.
[α]D 25+28.03°(C 0.31;MeOH).
1NMR DMSO-d6,δ,ppm:2.75(dd,1H,CH2-Tyr),2.9(dd,1H,CH2-Tyr),3.2-3.4(m,2H,CH2-HOPhAc),4.3-4.4(m,1H,α-CH-Tyr),6.55-7.1(m,8H,芳族),8.05(d,1H,NH-Tyr).
IR-Fourier,δ,cm-1:1614(酰胺I);1516(酰胺II);1254(酰胺III).
实测,%:C 64.65;H 5.41;N 4.37.C17H17NO5;计算,%:C 64.75;H 5.43;N 4.44.
HPLC条件(1):个别的峰,保留时间6.33分钟.
实施例12
对-羟基苯基乙酰基苯基丙氨酸苄基酯(XXVII)
按照化合物VII所列工艺A进行合成。
收率0.76g(74%).
Rf 0.87 (2).
[M+1]+390.1.
[α]D 20-19.47°(C 0.19;MeOH).
IR-Fourier,δ,cm-1:1649(酰胺I);1515(酰胺II);1737(val C=0酯).
实测,%:C 74.12;H 5.92;N 3.57.计算,%:C 74.02;H 5.95;N 3.60.
实施例13
对-羟基苯基乙酰基苯基丙氨酸(III)
向0.65g(1.67mole)对-羟基苯基乙酰基苯基丙氨酸苄基酯的10ml甲醇溶液加入0.30g 10%披钯碳,在剧烈搅拌下,在氢流中进行水合达1.5小时。滤出催化剂。在真空下除去滤液中的溶剂。油性残余物用酯-己烷混合物(1∶1)研制。滤出所生成的白色沉淀,在真空下经CaCl2和P2O5干燥。得到0.27g(53%)。
收率39.2%.
Rf 0.42 (3).
[M+1]+300.09.
[α]D 25+18.57°(C 0.44;MeOH).
1NMR DMSO-d6,δ,ppm:2.85(dd,1H,CH2-Phe),3.1(dd,1H,CH2-Phe),3.2-3.35(m,2H,CH2-HOPhAc),4.4-4.5(m,1H,α-CH-Phe),6.55-6.95(m,4H,芳族H HOPhAc),7.1-7.3(m,5H,芳族H Phe),8.15(d,1H,NH-Phe).
IR-Fourier,δ,cm-1:1611(酰胺I);1512(酰胺II).实测,%:C 68.30;H 5.68;N 4.65.
计算,%:C 68.21;H 5.72;N 4.68.
HPLC条件(3):个别的峰,保留时间7.59分钟.
实施例14
3-苯基丙酰基酪氨酸苄基酯(XXX)
按照化合物VII所列工艺A进行合成。
收率0.94g(70%).
Rf 0.72 (1).
[M]+403.5.
[α]D 20-11.93°(C 0.18;MeOH).
实测,%:C 74.22;H 6.92;N 3.57.计算,%:C 74.42;H 6.25;N 3.47.
实施例15
乙酰基酪氨酰基苯基乙基胺(XXVIII)
按照化合物VII所列工艺A进行合成。
收率0.36g(50%).
Rf 0.57 (1).
[M]+326.9.
[α]D 20-9.06°(C 0.30;MeOH).
IR-Fourier,δ,cm-1:1651(酰胺I);1616(酰胺II).
实测,%:C 69.22;H 6.52;N 8.27.C24H23NO4;计算,%:C 69.92;H 6.79;N 8.58.
实施例16
乙酰基酪氨酰基酪胺(XXIX)
按照化合物VII所列工艺A进行合成。
收率0.77g(6 5%).
Rf 0.41 (1).
[M]+342.7.
实测,%:C 66.25;H 6.32;N 8.25.C24H23NO4;计算,%:C 66.65;H 6.48;N 8.18.
生物活性试验
实施例17
通式I化合物对鼠肺组织的无细胞匀浆中[14C]花生四烯酸代谢的体外作用的研究
对饲喂标准动物饲料的雌性CBA小鼠进行花生四烯酸代谢的研究。处死动物(小鼠),取出肺,在4℃下,在10体积的0.05M Tris-HCl中,在由“Wheaton”(USA)制造的玻璃匀化器中匀化。在37℃下,将上清液的等分试样(0.5ml)在0.5μCi[1-C14]-花生四烯酸([C14]-AA,“Amersham”,England;比活度50-60μCi/mmol)中温育30分钟。在20体积的氯仿与甲醇混合物(1∶1)中提取未代谢的[C14]-AA和其代谢产物,利用[C14]-PGF2α评估提取效率不小于90%。分离[C14]-AA和其代谢产物,利用TLC鉴别(平板Kieselgel 60,”Merck”,Germany),使用作为有机相的溶剂***(乙酸乙酯,异辛烷,乙酸,水-110∶50∶20∶100)和已标记的标准。在密度扫描仪KS 3(“Kipp andZonnen”,Holland)上进行在X-射线膜X-Omat AR(“Kodak”,USA)和HS 11(“ORWO”,Germany)上所得放射自显影图的密度测定。利用高效液相色谱(HPLC-***“Gilson”,France;柱子ZORBAX C8,“DuPont”,USA)和洗脱TLC平板斑点所得级分的放射测量进行个别二十碳类的定量分析。给予浓度10-4M的供试化合物。
所得数据列在表3中。
表3
通式I化合物对鼠肺组织的无细胞匀浆中[14C]花生四烯酸代谢的体外作用
化合物的编号 | 6-酮基-PGF1α | PGF2α | TXB2 | PGE2 | AA | 类***素 |
IX | -30 | -27 | -40 | -38 | +47 | -33 |
X | -9 | -15 | -42 | -38 | +27 | -22 |
XIV | -24 | -24 | -49 | -54 | +84 | -35 |
XII | -42 | -47 | +42 | -44 | ||
VII | -45 | -32 | +22 | -40 | ||
VIII | -45 | -33 | +40 | -40 |
PG-***素
TX-血栓烷
AA-花生四烯酸
所得二十碳类数据证明通式I化合物抑制环加氧酶达22÷44%的能力,提示了它们可用作潜在的止痛和抗炎剂。
实施例18
通式(I)化合物的止痛和抗炎活性
对“乙酸扭转”模型的止痛活性的研究
对体重22-24克的雄性白色杂交小鼠进行试验。向小鼠腹膜内给予0.75%乙酸溶液,引发特殊的疼痛响应(“扭转”)。考虑下列迹象:腹部肌肉的发作性收缩的次数,伴有伸展后肢和松弛背部。借助乙酸给药后15分钟内动物扭转次数相对于对照减少次数的百分比评估止痛效果。试验工艺被公开在Koster R.,Anderson M.,deBeer B.//Fed.Proc.1959.V.18.P.412中。在酸的注射之前60分钟,腹膜内(利用探针)给予供试化合物,剂量为10μg/kg。使用双氯芬酸(10mg/kg)作为参照药物。按照下式计算止痛效果:
其中Ck是对照组的扭转次数,
Co是试验组的扭转次数。
所得数据列在表4中。
表4
10mg/kg通式I供试化合物在“乙酸扭转”试验中的止痛活性(15分钟的扭转次数)
化合物 | 小鼠数量 | C±m | C,相对于对照的% | 止痛效果(%) |
II | 10 | 24.2±1.9* | 75.2 | 24.8 |
III | 8 | 19.4±3.3* | 60.2 | 39.9 |
对照1 | 19 | 32.2±1.6 | 100 | - |
IV | 10 | 20.8±1.9* | 77.9 | 22.1 |
V | 10 | 16.2±2.6* | 60.7 | 39.3 |
对照2 | 10 | 26.7±0.79 | 100 | - |
VIII | 8 | 16.0±4.5 | 43.5 | 56.5 |
对照3 | 8 | 36.8±3.5 | 100 | - |
IX | 8 | 11.8±2.9 | 32 | 68 |
对照4 | 8 | 36.8±3.5 | 100 | - |
X | 8 | 11.0±2.4* | 46.0 | 54 |
双氯芬酸10μg/kg | 8 | 12.9±2.13* | 50.8 | 49.2 |
对照5 | 8 | 25.4±2.4 | 100 | 0 |
XI | 10 | 21.2±2.5** | 61.8 | 38.2 |
XII | 10 | 20.1±2.1** | 58.6 | 41.4 |
对照6 | 9 | 34.3±3.0 | 100 | - |
VI | 8 | 21.1±1.8* | 74.5 | 25.5 |
XIII | 8 | 14.6±1.8** | 51.6 | 48.4 |
伏他林8μg/kg | 8 | 15.8±2.6* | 55.5 | 44.5 |
对照7 | 8 | 28.4±2.5 | 100 | - |
XXVI | 8 | 22.4±2.0* | 73 | 27 |
XXVII | 9 | 20.1±1.7* | 67.4 | 32.6 |
对照8 | 9 | 29.8±2.3 | 100 | - |
XXX | 8 | 11.9±1.7** | 63.9 | 36.1 |
对照9 | 8 | 18.6±1.4 | 100 | - |
XXVIII | 9 | 15.9±2.4* | 57.9 | 42.1 |
XXIX | 10 | 15.7±1.9* | 57.1 | 42.9 |
对照10 | 9 | 27.4±2.6 | 100 | - |
*P<0.05相对于对照组
**P<0.01相对于对照组
相应通式I的化合物在“扭转”中显示接近参照药物双氯芬酸和伏他林(参见表4)的止痛活性,大多数化合物的止痛效果为38至68%。
实施例19
通式I化合物对曲马多和安乃近对“乙酸扭转”模型止痛作用的影响
按照实施例18所列工艺进行研究。
表5
10mg/kg通式I化合物对曲马多(10mg/kg)止痛作用的影响
小鼠的数量n=10 | 15分钟的扭转次数 | |||
对照 | IX | 曲马多 | IX+曲马多 | |
M±m | 36.2±3.8 | 24.0±3.4* | 17.5±2.3* | 6.4±2.0*^^ |
止痛效果,% | 33.6 | 53 | 82 |
*-相对于对照组的统计学显著,p<0.05
^^-相对于曲马多的统计学显著,p<0.05
按照表5的数据,化合物IX与曲马多的组合的止痛效果显著强于化合物IX和曲马多单独的效果(分别为6.4±2.0相对于24.0±3.4和17.5±2.3)。
表6
10mg/kg通式I化合物在“乙酸扭转”试验中对安乃近(50mg/kg)止痛作用的影响
小鼠的数量n=10 | 15分钟的扭转次数 | |||
对照 | IX | 安乃近 | IX+安乃近 | |
M±m | 33.1±2.9 | 18.8±3.1* | 20.7±2.3* | 12.6±2.4*^^ |
止痛效果,% | 43.3 | 37.5 | 61.9 |
*-相对于对照组的统计学显著,p<0.05
^^-相对于安乃近的统计学显著,p<0.05
化合物IX也增强安乃近的止痛作用(表6)。
因而,10mg/kg心室内给药的化合物IX显著增强曲马多的止痛作用,加强安乃近的止痛效果。
实施例20
对“热板”模型的止痛活性的研究
按照列在Woolfe G.,McDonald A.D.//The evaluation of theanalgetic action of pethidine hydrochloride(Demerol).//Pharmacol.Exp.Ther.1944.V.80.P.300-307中的工艺,利用“热板”法研究通式I化合物的止痛作用。对体重22-24克的雄性白色杂交小鼠进行试验。将动物单独放置在热板上(由“Ugo Basile”制造),其温度保持恒定,等于55℃。在物质给药之前(背景参数)和物质给药后0.5、1、2、3和4小时记录下列疼痛反应的首次表现:舔舐爪子、跳跃。物质是静脉内给药的(利用探针)。在0.1ml吐温80中充分混合所称量的物质,直至获得溶液,然后加入生理盐水至体积0.5ml。在每组中计算伤害感受阈(NT)的平均潜伏期。所得结果以背景值的百分比表示。按照下式计算止痛效果(%):
A-100%=X,其中A是背景参数;X是止痛效果(%)。
A是(给药后0.5至4小时的次数×100%):背景次数
作为参照药物,使用安乃近(150mg/kg)、对乙酰氨基酚(200mg/kg)、酮洛酸(10mg/kg)。
所得数据列在表7中。
表7
借助伤害感受阈的潜伏期值(NT秒),在小鼠“热板”试验中对比评估10mg/kg通式I化合物与参照药物安乃近和对乙酰氨基酚的止痛作用
小鼠数量n=10 | 化合物给药后的时间,分钟 | |||||
0(背景) | 30 | 60 | 120 | 180 | 240 | |
化合物II | ||||||
M±m | 3.4±0.3 | 6.0±0.6* | 6.1±0.8* | 7.3±0.6** | ||
NT的潜伏期(%) | 100 | 176.5 | 179.4 | 214.7 | ||
止痛(%) | 76.5 | 79.4 | 114.7 | |||
化合物III | ||||||
M±m | 3.7±0.3 | 6.7±0.9* | 5.9±0.8* | 7.0±0.6** | ||
NT的潜伏期(%) | 100 | 181.0 | 159.5 | 189.2 | ||
止痛(%) | 81.0 | 59.5 | 89.2 | |||
化合物IV | ||||||
M±m | 5.03±0.16 | 5.24±0.88 | 5.54±0.32 | 5.93±0.59 | ||
NT的潜伏期(%) | 100 | 104.2 | 110.1 | 117.9 |
止痛(%) | 4.2 | 10.1 | 17.9 | |||
化合物V | ||||||
M±m | 3.74±0.16 | 4.85±0.39* | 5.9±0.81* | 6.58±0.72* | ||
NT的潜伏期(%) | 100 | 129.7 | 157.8 | 175.9 | ||
止痛(%) | 29.7 | 57.8 | 75.9 | |||
化合物VI | ||||||
M±m | 5.9±0.4 | 7.8±0.8* | 8.3±1.0* | 6.8±0.5 | ||
NT的潜伏期(%) | 100 | 132.2 | 140.7 | 115.3 | ||
止痛(%) | 32.2 | 40.7 | 15.3 | |||
化合物VII | ||||||
M±m | 5.1±0.49 | 6.9±0.72 | 8.2±0.94** | |||
NT的潜伏期(%) | 100 | 134.5 | 158.9 | |||
止痛(%) | 34.5 | 58.9 | ||||
化合物VIII | ||||||
M±m | 5.1±0.49 | 8.5±0.27** | 6.5±1.16 | |||
NT的潜伏期(%) | 100 | 159.6 | 123.3 | |||
止痛(%) | 59.6 | 23.3 | ||||
化合物IX | ||||||
M±m | 4.14±0.25 | 8.4±1.23** | 7.36±1.04** | 9.83±2.52** | 7.72±0.24** | |
NT的潜伏期(%) | 100 | 202.9 | 177.8 | 237.0 | 186.5 | |
止痛(%) | 102.9 | 77.8 | 137.0 | 86.5 | ||
化合物X | ||||||
M±m | 4.3±0.25 | 7.54±0.78** | 5.75±0.83 | 8.50±1.03** | 8.84±0.925** | |
NT的潜伏期(%) | 100 | 175.3 | 133.7 | 197.7 | 200.6 | |
止痛(%) | 75.3 | 33.8 | 97.7 | 100.6 | ||
化合物XI | ||||||
M±m | 3.73±0.19 | 5.35±0.98 | 6.49±1.1** | 6.27±0.33 | 4.07±0.26 | |
NT的潜伏期(%) | 100 | 143.4 | 174.0 | 141.3 | 135.9 | |
止痛(%) | 43.4 | 74.0 | 41.3 | 35.9 | ||
化合物XIII | ||||||
M±m | 5.5±0.4 | 5.9±0.3 | 6.7±0.7 | 6.8±0.3* | ||
NT的潜伏期(%) | 100 | 107.3 | 121.8 | 123.6 | ||
止痛(%) | 7.3 | 21.8 | 23.6 | |||
化合物XIV | ||||||
M±m | 3.72±0.42 | 5.59±1.12 | 4.7±0.51 | 7.3±1.09** | 6.78±0.504** | |
NT的潜伏期(%) | 100 | 150.3 | 126.3 | 196.2 | 182.3 | |
止痛(%) | 50.3 | 26.3 | 96.2 | 82.3 | ||
化合物XXVI |
M±m | 5.7±0.6 | 8.3±0.9* | 10.2±1.2* | 7.1±0.4* | ||
NT的潜伏期(%) | 100 | 143.1 | 176.4 | 124.1 | ||
止痛(%) | 43.1 | 76.4 | 24.1 | |||
化合物XXVII | ||||||
M±m | 5.3±0.5 | 8.5±0.9* | 10.7±1.1** | 9.1±1.3* | ||
NT的潜伏期(%) | 100 | 160.0 | 201.9 | 171.7 | ||
止痛(%) | 60.0 | 101.9 | 71.7 | |||
化合物XXVIII | ||||||
M±m | 4.8±0.7 | 9.2±1.8* | 8.1±1.0* | 11.6±2.5* | ||
NT的潜伏期(%) | 100 | 191.7 | 168.8 | 241.7 | ||
止痛(%) | 91.7 | 68.8 | 141.7 | |||
化合物XXIX | ||||||
M±m | 3.2±0.2 | 6.3±1.2* | 7.2±0.8* | 8.0±1.0* | ||
NT的潜伏期(%) | 100 | 196.9 | 225 | 250 | ||
止痛(%) | 196.9 | 125 | 150 | |||
化合物XXX | ||||||
M±m | 4.1±0.3 | 6.9±0.8* | 9.0±0.9** | 9.1±1.4* | ||
NT的潜伏期(%) | 100 | 168.3 | 213.8 | 221.9 | ||
止痛(%) | 68.3 | 113.8 | 121.9 | |||
安乃近,150mg/kg | ||||||
M±m | 4.85±0.44 | 7.44±1.22** | 7.29±0.71* | 6.25±0.75 | 5.35±0.38 | |
NT的潜伏期(%) | 100 | 153.4 | 150.3 | 128.9 | 110.3 | |
止痛(%) | 53.4 | 50.3 | 28.9 | 10.3 | ||
对乙酰氨基酚,200mg/kg | ||||||
M±m | 3.95±0.21 | 9.44±1.3** | 6.24±0.82** | 7.6±1.15** | ||
NT的潜伏期(%) | 100 | 238.9 | 158 | 192.0 | ||
止痛(%) | 138.9 | 58.0 | 92.0 |
*-P<0.05;**-0.01相对于背景参数
所得数据显示,通式I化合物在“热板”试验中证明有显著的升高伤害感受阈的活性。与此同时,在0.1至10mg/kg的剂量下,止痛效果相当于参照药物,有利地在1至10mg/kg剂量下,比参照药物对乙酰氨基酚具备止痛和退热作用的剂量低1-2个数量级。表7所列数据也显示,通式I化合物的止痛效果平均为50至最大150%,这可以被视为长效的,因为在一些情况下保持四小时以上。
因而,通式I化合物的止痛效果相当于已知的非麻醉性止痛剂(安乃近,对乙酰氨基酚),止痛效果的持续时间超过参照药物,发挥作用的剂量比参照的非麻醉性止痛剂低一个数量级。
实施例21
通式I化合物对大鼠爪子角叉菜胶水肿的效果的研究
对体重250-270克的雄性远系繁殖白色大鼠进行试验。采用角叉菜胶水肿的模型,该模型被描述在Winter et al.In:DeRosa M.,Giroud J.P.Willoughby D.A.Studies of the mediators of acuteinflammatory response induced in rats in different sites bycarrageenan and turpentine.//J.Pharmacol.1971.V.104.P.15-29中。
将0.1ml 1%角叉菜胶溶液(SERVA)跖下注射到大鼠右爪中。将动物置于个别的笼子中。在角叉菜胶给药后立即和1与2小时后在爪子上涂抹1%软膏。在角叉菜胶给药后4小时利用体积计(Ugo Besile)测量爪子体积。与给定动物的完整左爪和对照(未处置)组的爪子反应比较炎性反应的抑制程度,评估软膏的治疗效果。按照下式计算以百分比评估的炎性反应抑制作用:
所得数据列在表8中。
表8
通式I化合物(1%软膏)对大鼠爪子角叉菜胶水肿形成的效果(M±m)
大鼠的数量n=8 | 爪子体积增长(%) | 水肿抑制率(%) |
对照 | 70.2 | - |
化合物IX(1%软膏) | 32,9 | 53.1 |
消炎痛(10%软膏) | 45.0 | 50.0 |
表8所列结果证明式I化合物具有突出的抗炎活性,相当于NSAID类参照药物消炎痛的活性,化合物的有效剂量比参照药物低一个数量级。
实施例22
通式I化合物的致溃疡效果的研究
对体重300-320克的雌性远系繁殖大鼠进行试验。在试验之前,对禁食24小时的大鼠胃内给予剂量30mg/kg的供试化合物一次。对对照组动物给予相同体积的蒸馏水。24小时时处死动物,切取胃。向空胃灌注2%***溶液,将其置于***烧杯中。30分钟后,沿着大弯打开胃,在载玻片上展开固定,用蒸馏水洗涤。利用放大镜MBS-9(8倍放大率)测量胃粘膜缺损的长度和宽度,计算面积,以mm2计(放大镜标尺的1刻度=0.1mm)。按照在Rukovodstvo poexperimental’nomu(doklinicheskomu)izucheniju novykh pharmacologicheskikhveshchestv(the Guide on Experimental(pre-clinical)Study ofNovel Pharmacological Substances)./Moscow.“Remedium”publishers.2000,398页中提供的技术,借助胃粘膜的溃疡损伤面积评估物质的致溃疡效果。
所得数据列在表9中。
表9
30mg/kg通式I化合物和消炎痛对大鼠胃粘膜的影响的对比研究(M±m)
大鼠的数量n=5 | 溃疡损伤的面积,mm2 |
对照 | 0 |
化合物IX | 0 |
消炎痛 | 7.3±1.75 |
所得数据显示,在剂量30mg/kg的通式I化合物的胃内给药中不存在胃粘膜的溃疡损伤。
实施例23
通式I化合物的解痉作用的研究
对体重300-350克的雌性Wistar大鼠创建血清素-诱导的软性子宫角肌肉挛缩模型[Blattner H.G.,Dehnert H.et al.Experimentson isolated smooth muscle preparation.Ed.J.M.Barnden and R.Colson,1980]。将所制备的平滑肌制备物(SMP)置于温度-调节的容器(+37℃)中,其中含有降低了钙含量的Tirode溶液,目的是防止平滑肌制备物的自发性收缩活动。利用与多种波动记录仪KPS-4连接的mechanotron 6M×2B记录子宫角的收缩;初始对象负载为0.5-0.7克。
向培养基引入浓度10-5M的0.1ml血清素(Sigma),诱导SMP的挛缩。介质给药后30-60秒,记录子宫角的峰收缩幅度。在峰收缩幅度下或者在温育条件下(在相同的浓度范围内)向容器引入化合物IX达15分钟。
借助收缩次数和幅度值降低评估化合物IX的效果。
结果列在表10中。
表10
通式I化合物对血清素-诱导的大鼠子宫角SMP挛缩的影响
大鼠子宫角SMP在5分钟内的收缩率 | 大鼠子宫角SMP收缩的抑制,% | |
对照(血清素-诱导的挛缩) | 9 | 0 |
在血清素-诱导的峰挛缩下的化合物IX | 5 | 44.4 |
化合物IX的预温育 | 4(随后阻断) | 55.6 |
在血清素-诱导的子宫角SMP峰挛缩时加入化合物IX,延缓大鼠子宫角平滑肌制备物的收缩率(在5分钟内)从对照组中的9次收缩降至试验组中的5次收缩(参见表10)。
在化合物IX的预温育条件下,也观察到延缓响应于血清素的收缩率(5分钟内4次收缩),随后完全阻断SMP挛缩(表10)。
因而,化合物IX在体外条件下显示解痉作用(在血清素-诱导的峰SMP收缩下),在预防性给药中抑制SMP挛缩的形成。
实施例24
通式I化合物的抗缺氧作用的研究
为了模仿急性氧不足,采用在密封容器中伴有高碳酸血的缺氧模型(Luk’yanovaL.D.,Gatsura V.V.,Pastushenkov L.V.Metodicheskiye recomendatsii po experimental’nomu izuchenijupreparatov,predlagajemykh dlya klinicheskogo isuchenija vkachestve antihypoxicheskikh sredsyv (Methodologicalrecommendations on experimental study of preparations proposed forclinical examination as anti-hypoxic agents).Moscow.1960.P.1-19]。将体重27-29克的雄性大鼠分别置于260ml玻璃罐中,密封。随着动物消耗氧气,容器中的浓度降低,导致动物死亡。记录小鼠的寿命,以分钟计。
所得数据列在表11中。
表11
通式I化合物在伴有高碳酸血的缺氧性低血氧模型中对小鼠寿命的影响
小鼠的数量n=10 | 缺氧的持续时间,分钟 | ||
对照 | 化合物IX10mg/kg | 化合物IX50mg/kg | |
M±m | 25.6±0.6 | 25.3±0.8 | 32.6±2.6* |
与对照的变化% | 0 | +27 |
“-P<0.05;相对于对照组的统计学显著差异
剂量50mg/kg的化合物IX在缺氧性低血氧条件下显著延长小鼠的寿命达27.3%。
实验结果提示化合物IX显示抗缺氧作用。
实施例25
通式I化合物在“行为性绝望”试验中的抗抑郁作用的研究(对制动持续时间的影响)
根据Porsolt的“行为性绝望”试验[R.D.Porsolt,A.Bertinand M.Jalfre.//in mice:A primary Screening Test forAntidepressants.Arch.Int.Pharmacodyn.,1977,229,p.327-336]是具有抗抑郁作用的药物的预示试验。
被迫游泳诱发小鼠(体重27-30克)的紧张状态。将动物置于灌注21-23℃的水至1/3的圆筒中(高度25cm,直径10cm)。动物不能自行从圆筒中逃脱。在短时间活动后,动物形成所谓的“行为性抑郁”,以动物的盘旋为特征,制动的持续时间可以是不变的。实验分两天进行。第一天,将动物置于圆筒中达15分钟(预试验)。从水中取出后,使动物干燥,给予供试制备物。24小时时,再次给予制备物,一小时后,将动物置于圆筒中达6分钟。在前两分钟内动物主动游泳,在随后的四分钟内形成行为性抑郁,以固定不动为表现(盘旋),这持续4分钟,测量之,以秒计。化合物IX和参照抗抑郁药氟西汀是以50mg/kg的剂量口服给药的。
所得数据列在表12中。
表12
化合物IX和氟西汀在“行为性绝望”试验中对制动时间的影响
缺氧的持续时间,分钟 | |||
对照 | 化合物IX50mg/kg | 氟西汀50mg/kg | |
M±m | 195.0±10.3 | 154.0±11.7* | 131.0±16.5** |
与对照的变化% | -21 | -33 |
“-P<0.05,**-P<0.01-相对于对照组的统计学显著差异
在“行为性绝望”试验中,化合物IX以及抗抑郁剂氟西汀导致统计学显著的小鼠制动时间缩短。
因而在化合物IX的作用谱中,已经发现抗抑郁剂类特有的药理效果(在根据Porsolt的“行为性绝望”试验中缩短制动时间)。
单元剂型的实例
实施例26
A.片剂
使用下列成分制造片剂:
相当于通式(I)的化合物 5-100mg
马铃薯淀粉 20-50mg
硬脂酸镁 3mg
Aerosyl 1mg
乳糖 至300mg
混合各组分,压制成片,每片300mg。
B.栓剂
栓剂组合物的实例:
相当于通式(I)的化合物 5-100mg
可可脂 制造栓剂所需的量
如果需要的话,使用各自的赋形剂制造直肠、***和尿道栓剂都是可能的。
C.软膏剂
软膏剂组合物的实例:
相当于通式(I)的化合物 0.05-0.5g
凡士林油 10g
按照公知技术制造软膏剂。
D.凝胶剂
凝胶剂组合物的实例:
相当于通式(I)的化合物 100mg
卡波普 200mg
苄醇 20mg
乙醇 300mg
水 至10g
因而,本发明涉及新颖的通式I化合物、新颖和已知化合物的简单制备性合成方法和其作为非甾类抗炎剂、环加氧酶抑制剂的用途,具备抗炎和有利的止痛作用,不显示不良的致溃疡效果。
药理研究的结果提示,所要求保护的化合物具备在下列极端因素下发挥治疗效果的独特能力:情绪性紧张、疼痛综合征、缺氧、炎症、痉挛以及应对由帕金森氏病导致的疾患,以及加强其他止痛剂。
Claims (21)
1.通式I的生物源性胺的苯基-N-酰基衍生物:
其中R1是
R5是氢或羟基;
R2是氢或可选被CH3(CH2)mCO-取代的氨基,其中m是0至4;
R4是氢、羟基;
或其药学上可接受的盐,
其条件是通式I化合物不是
苯基乙酰基酪胺,
3-(对-羟基苯基)丙酰基苯基乙基胺,
3-(对-羟基苯基)丙酰基酪胺,
3-苯基丙酰基苯基乙基胺,
3-苯基丙酰基酪胺,
3-(对-羟基苯基)丙酰基苯基丙氨酸甲基酯,
3-(对-羟基苯基)丙酰基酪氨酸,
3-苯基丙酰基酪氨酸,
苯基乙酰基酪氨酸,
3-(对-羟基苯基)丙酰基苯基丙氨酸,
3-苯基丙酰基苯基丙氨酸,
苯基乙酰基苯基丙氨酸,
3-(对-羟基苯基)丙酰基酪氨酸甲基酯,
3-苯基丙酰基酪氨酸甲基酯,
苯基乙酰基酪氨酸甲基酯,
苯基乙酰基苯基乙基胺,
3-苯基丙酰基苯基丙氨酸甲基酯,
苯基乙酰基苯基丙氨酸甲基酯,
3-(对-羟基苯基)丙酰基酪氨酸苄基酯。
2.根据权利要求1的化合物,其中R3是-COOH、-COOCH3。
3.根据权利要求1的化合物,选自
对-羟基苯基乙酰基酪氨酸,
对-羟基苯基乙酰基苯基丙氨酸,
对-羟基苯基乙酰基酪氨酸甲基酯,
对-羟基苯基乙酰基苯基丙氨酸甲基酯,
3-苯基丙酰基酪氨酸苄基酯,
对-羟基苯基乙酰基酪氨酸苄基酯,
对-羟基苯基乙酰基苯基丙氨酸苄基酯,
N-乙酰基酪氨酰基苯基乙基胺,
N-乙酰基酪氨酰基酪胺,
对-羟基苯基乙酰基酪胺,
对-羟基苯基乙酰基苯基乙基胺,
或其药学上可接受的盐。
4.根据权利要求1至3任意一项的化合物,具备环加氧酶抑制活性。
5.根据权利要求4的化合物,具备止痛、抗炎、解痉、抗缺氧、抗抑郁和抗震颤麻痹效果。
6.根据权利要求4的化合物,能够加强其他止痛剂,特别是曲马多和安乃近的效果。
8.根据权利要求6的方法,其中使用1-1.2当量的二苯基叠氮化磷酰和三乙胺。
9.根据权利要求6或7的方法,其中使用酪氨酸或苯基丙氨酸酯作为氨基衍生物。
10.根据权利要求6-9任意一项的方法,其中使用N,N-二甲基甲酰胺或乙酸乙酯作为有机溶剂。
11.根据权利要求6-9任意一项的方法,它是在-25℃至0℃的温度下进行的。
13.根据权利要求12的方法,其中使用酪氨酸或苯基丙氨酸酯作为氨基衍生物。
15.根据权利要求14的药物组合物,具备抑制环加氧酶活性的能力、止痛、抗炎、解痉、抗缺氧、抗抑郁和抗震颤麻痹性质以及加强其他止痛剂效果的能力。
18.根据权利要求16的用途,用作止痛、抗炎、解痉、抗缺氧、抗抑郁和抗震颤麻痹剂以及具备加强其他止痛剂效果能力的药物。
20.根据权利要求19的方法,治疗手术后疼痛、创伤后疼痛以及妇科、神经、癌性、牙齿来源、类风湿性关节炎、关节病、Bekhterev氏病、非特异性脊椎关节炎、痛风性关节炎、骨关节病、关节外风湿热和血栓静脉炎的疼痛综合征,以及情绪-紧张状态和由痉挛、缺氧和伴随性帕金森氏病导致的疾患。
21.根据权利要求19或20的方法,其中通式(I)化合物是与其他止痛剂联合给药的。
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CN110167547B (zh) * | 2017-05-26 | 2024-04-05 | 欧亚制药有限责任公司 | 用于在哺乳动物中治疗疾病的多靶标药物 |
CN112384495A (zh) * | 2018-05-11 | 2021-02-19 | Ibd治疗学有限责任公司 | 新的代谢型和离子通道型跨膜受体调节剂及其用途 |
CN112384495B (zh) * | 2018-05-11 | 2023-07-18 | Ibd治疗学有限责任公司 | 新的代谢型和离子通道型跨膜受体调节剂及其用途 |
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US20090111874A1 (en) | 2009-04-30 |
MX2007011852A (es) | 2008-02-21 |
KR101383580B1 (ko) | 2014-04-09 |
ES2564238T3 (es) | 2016-03-21 |
JP5384096B2 (ja) | 2014-01-08 |
EP1876169A1 (en) | 2008-01-09 |
JP2008534495A (ja) | 2008-08-28 |
US20130109880A1 (en) | 2013-05-02 |
CY1117449T1 (el) | 2017-04-26 |
EP1876169B1 (en) | 2015-12-30 |
RU2309144C2 (ru) | 2007-10-27 |
EA013644B1 (ru) | 2010-06-30 |
SI1876169T1 (sl) | 2016-05-31 |
KR20080008345A (ko) | 2008-01-23 |
CA2602545C (en) | 2014-08-19 |
HUE027009T2 (en) | 2016-10-28 |
DK1876169T3 (en) | 2016-03-07 |
EP1876169A4 (en) | 2009-11-04 |
HK1118798A1 (zh) | 2009-02-20 |
US8309766B2 (en) | 2012-11-13 |
PL1876169T3 (pl) | 2016-06-30 |
WO2006101422A1 (fr) | 2006-09-28 |
UA88688C2 (ru) | 2009-11-10 |
CA2602545A1 (en) | 2006-09-28 |
EA200702072A1 (ru) | 2008-02-28 |
CN101180267B (zh) | 2015-06-17 |
US8546612B2 (en) | 2013-10-01 |
RU2005108492A (ru) | 2006-10-10 |
PT1876169E (pt) | 2016-03-21 |
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