摘要
缓激肽B2受体拮抗剂作为一类能与人体内缓激肽B2受体作用的药物,对一些临床疾病如哮喘、胰腺炎、老年痴呆症、创伤性脑损伤、过敏性鼻炎、血管性水肿、骨关节炎等具有显著的疗效。自此类药物出现以来,得到了研究人员的广泛关注。近年来,一些课题组通过对缓激肽及其受体的深入研究,结合具体的药物构效关系,经过合理的设计,合成出很多具有良好生物活性的缓激肽B2受体拮抗剂分子,其中一些已进入临床试验阶段并取得了突破性的进展。针对缓激肽B2受体拮抗剂的研究与开发对人类的健康具有十分重要的意义。
本文从以往研究人员针对此类药物的构效关系出发,结合日本Fujisawa制药公司的设计思路与合成方法,设计了两类非肽类缓激肽B2受体拮抗剂分子,并同时设计了合理的合成路线,对目标分子的合成方法进行了初步探索和优化。具体工作如下：
以2,6-二氯甲苯为原料,经过F-C酰基化、酯化、溴代、取代、水解等一系列反应,合成了一系列新型B2受体拮抗剂候选化合物分子。同时对所设计的另一类拮抗剂分子进行了初步的合成探索。
As a series of drugs that are able to effectively work on human Bradykinin B2Receptor, Bradykinin B2Receptor Antagonists have definite effect on some clinical diseases such as asthma, pancreatitis, Alzheimer's Disease, traumatic brain injury, allergic rhinitis, angioedema, osteoarthritis, etc. Much more attentions have been paid to this kind of drugs since it was discovered. In recent years, some groups have designed and synthesized lots of Bradykinin B2Receptor Antagonists containing good biological activity through doing further research on the specific structure and activity relationship (SAR). Some novel antagonists have been used for clinical test and proved to be potential drugs. So it does make great sense for human health to do more study on the Bradykinin B2Receptor Antagonists.
Based on the SAR of these kinds of drugs and great works that have been done by Fujisawa Pharmaceutical Co. Ltd., two kinds of non-peptide Bradykinin B2Receptor Antagonists were synthesized, and the synthetic route was explored and optimized. Specifically as follows:
Beginning with2,6-dichlorotoluene, a series of B2Receptor Antagonists were synthesized through multi-step reactions, such as Fridel-Crafts acylation, esterification, bromination, substitution, hydrolysis and etc. Preliminary exploration for synthesis of another designed kind of Antagonists was already done.
引文
[1]Shimamoto, K.; Iimura, O. Physiological role of renal kallikrein-kinin system in human. Advances in Experimental Medicine and Biolog,1989,247AA (Kinins 5, Pt. A),87-96.
[2]Chase, A.; Volicer, L. Bradykinin receptors in isolated intestinal smooth muscle. Drug Development Research,1982,2 (1),1-16.
[3]Church, M.K.; Investigating Bradykinin-induced reactions in the skin through microdialysis. Clinical and Experimental Allergy,1997,27(2),28-32.
[4]Camargo, Ramalho-Pinto, F.J.; Greene, L.J. Brain peptidase-conversion and inactivation of kinin hormones. Journal ofNeurochemistry,1972,19(1),37-49.
[5]Sotiropoulou, G.; Pampalakis, G.; Diamandis, E. Functional roles of human kallikrein-related peptidases. The Journal of biological chemistry,2009,284(48), 32989-32994.
[6]Scicli, A.G. Kallikrein-kinin system. Kidney international,1986,29(1),120-30.
[7]Kobayashi, H. Structural and functional analysis of the serine protease from Aeromonas sobria. Yakugaku Zasshi,2011,131(12),1781-1786.
[8]Yukako, K.; Oliver, S.; Masao, K.; The kallikrein-kinin system and oxidative stress. Current opinion in nephrology and hypertension,2012,21 (1),92-96.
[9]Gaddum, J.H.; Guth, P.S.; A comparison of the kallikrein-kinin system in sheep and dogs. British journal of pharmacology and chemotherapy,1960,15,181-184.
[10]Sharma, J.N.; Uma, K.; Noor, A.R.; Rahman, A.R.; Blood pressure regulation by the kallikrein-kinin system. General pharmacology,1996,27(1),55-63.
[11]Shen, B.; Dahr, Samir, S.; Cross-talk of the renin-angiotensin and kallikrein-kinin systems. Biological chemistry,2006,387(2),145-150.
[12]Dielis, A.; Smid, M.; Spronk, H.; et al. Role of therenin-angiotensin and kallikrein-kinin systems. Hypertension,2005546(6),1236-1242.
[13]Morand, Contant M.; Anand-Srivastava, M.B.; Couture, R. Kinin B1 receptor upregulation by angiotensin Ⅱ and endothelin-1 in rat vascular smooth muscle cells. Receptors and mechanisms,2010,299(1),1625-1632.
[14]Kuhr, F.; Lowry. J.; Zhang, Y. Differential regulation of inducible and endothelial nitric oxide synthase by kinin B1 and B2 receptors. Neuropeptides,2010,44,145-154.
[15]Kakoki, M.; Smithies,O. The kallikrein-kinin system in health and in diseases of the kidney. Kidney International,2009,75,1019-1030.
[16]Xia, C.F.; Yin, H.; Borlongan, C. V.; Kallikrein gene transfer protects against is chemicstrokebypromoting glialcell migration andinhibitin gapoptosis. Hypertension,2004, 43,452-459.
[17]Jaspard, E.; Wei, L.; Alhenc-Gelas, F.; Differences in the properties and enzymatic specific of the two active sites of angiotensin Ⅰ-converting enzyme (kininase Ⅱ). Journal Biol ogical Chemistry,1993,268,9496-9503.
[18]Manolis, A.J.; Marketou, M.E.; Gavras, I.; Gavras, H. Cardioprotective properties of bradykinin:role of the B2 receptor. Hypertens Research,2010,33,772-777.
[19]Kakoki, M.; Kizer, C.M.; Yi, X. Senescence-associated phenotypes in Akita diabetic mice are enhanced by absence of bradykinin B2 receptors. Journal of Clinical Investigation,2006, 116,1302-1309.
[20]Westermann, D.; Walther, T.; Sawatis, K. Gene deletion of the kinin receptor B1 attenuates cardiac inflammation and fibrosis during the development of experimental diabeticc ardiomyopathy Diabetes,2009,58,1373-1381.
[21]Klein, J.; Gonzalez, J.; Duchene, J. Delayed blockade of the kinin B1 receptor reduces renal inflammation and fibrosis in obstructive nephropathy. FASEB Journal,2009,23,134-142.
[22]Pereira, R.L.; Buscariollo, B.N.; Correa-Costa, M. Bradykinin receptor 1 activation exacerbates experimental focal and segmental glomerulosclerosis. Kidney International, 2011,79,1217-1227.
[23]Rust, N.M.; Papa, M.P.; Scovino, A.M. Bradykinin enhances Sindbis virus infection in human brain microvascular endothelial cells. Virology,2012,422(1),81-91.
[24]Laura, N.; Hanna, M.; Heikkil, H.V.; Petri, T.; Kovanen, K. A. Downregulation of Bradykinin type 2 receptor expression in cardiac endothelial cells during Senescence. Journal Vascular Research,2012,49,13-23.
[25]Christian, M.P.; Michael, R.S.; Gareth, B. Bradykinin does not mediate remoteischaemic preconditioning or ischaemia-reperfusion injury in vivo in man. Heart,2011,97,1857-1861.
[26]John, M.S. Bradykinin B2 receptor antagonists:development and applications. Canadian Journal of Physiology and Pkarrnacology,1995,73,787-790.
[27]Yoshito, A.; Hiroshi, K.; Takayuki, I.; etal. A novel class of orally active non-peptide bradykinin B2 receptor antagonists 4:discovery of novel frameworks mimicking the active conformation. Journal of Medicinal Chemistry,1998,41,4587-4598.
[28]Yoshito, A.; Hiroshi, K.; Shigeki, S.; et al. A novel class of orally active non-peptide bradykinin B2 receptor antagonists 1:construction of the basic framework. Journal of Medicinal Chemistry,1998,41,564-578.
[29]Yoo, L.K.; Jai, Youl, R.; Hwa-Jung, K.; et al. Antagonistic effects of novel non-peptide chlorobenzhydryl piperazine compounds on contractile response to bradykinin in the guinea-pig ileum. European Journal of Pharmacology,2005,523,143-150.
[30]Yuki, S.; Hiroshi, K.; Yoshito, A.. et al. Discovery of the first non-peptide full agonists for the human bradykinin B2 receptor incorporating 4-(2-Picolyloxy)quinoline and 1-(2-Picolyl)benzimidazole frameworks. Journal of Medicinal Chemistry,2004,47, 2853-2863.
[31]Christophe, T.; Philippe, H.; Eric, R.; Design and synthesis of new linear and cyclic bradykinin antagonists. Journal of Medicinal Chemistry,1996,39,2095-2101.
[32]Thomas, R. The procoagulant and proinflammatory plasma contact system.Semin Immunopathol,2012,34,31-41.
[33]Mark, A.; Youngman, J.R.; Carson, J.S.. et al. Synthesis and structure activity relationships of aroylpyrrole alkylamide Bradykinin B2 antagonists, Bioorganic& Medicinal Chemistry Letters,2003,13,1341-1344.
[34]Xiaoyan, Z.; Kenner, C; Rice, S.N.; et al. Probes for narcotic receptor mediated phenomena, synthesis and biological evaluation of diarylmethylpiperazines and diarylmethyl piperidines as novel, nonpeptidic a opioid receptor ligands. Journal of Medicinal Chemistry,1999,42,5455-5463.
[35]Avetisyan, A.A.; Aleksanyan, I.L.; Ambartsumyan, L.P. Synthesis of 6,8-Substituted 4-(Hydroxyphenylamino)-and 4-(Aminophenylamino)-2-methylquinolines, Zhurnal Organicheskoi Khimii,2007,43,1054-1057.
[36]McCarthy, J.R.; Cregge, R.J. A convenient new method for converting aromatic methyl ethers to phenols with sodium cyanide-dimethyl sulfoxide. Tetrahedron Letters, 1978,52,5183-5186.
[37]Yuki, S.; Yoshito, A. A new class of nonpeptide bradykinin B2 receptor, incorporating a 4-aminoquinoline framework. Journal of Medicinal Chemistry,2004,47, 2667-2677.
[38]Bandini, M.; Melloni, A.; Umani, R. Angewwandte Chemie InternationalEditional,2004,43,
550-556.
[39]Alam, M.M.; Asif, H.; Hasan, S.M.; et al. Synthesis and pharmacological evaluation of 2(3H)-furanones and 2(3H)-pyrrolones, combining analgesic and anti-inflammatory properties with reduced gastrointestinal toxicity and lipid peroxidation. European Journal of Medicinal Chemistry,2009,44,2636-2642.
[40]Patent; Fujwaswa Pharmaceutical co. Ltd.; Publ:EP1132087 A1 (2001/09/12), Appl.: EP1999-972100 (1999/11/10)
[41]Jason, B.; Josef, R.; Athula, B. An unprecedented rearrangement in collision-induced mass spectrometric fragmentation of protonated benzylamines, Journal of Mass Spectrometry, 2006,41,1195-1204.
[42]Ramon, M.; Jesus, P. High atomic yield bromine-less benzylic bromination. Green Chemistry,2002,4,314-316.
[43]Olivier, R.; Jean-Louis, R. Synthesis of ether oligomers. Organic Letters,2004,6,398-400.
[44]Tor, E.K.; Finn, K.H.; Tore, H. The selective O-acylation of hydroxyproline as a convenient method for the large-scale preparation of novel proline. Polymers and Amphiphiles. European of Journal Organic Chemistry,2009,387-395.
[45]Balcom, B.J. Solvent dependence of carboxylic acid condensations with dicyclohexyl carbodimide. Journal of Organic Chemistry,1989,54,1922-1927.
[46]William, R.; Perrault, K.; Paul, S. Production scale synthesis of the non-nucleoside reverse transcriptase inhibitor atevirdine mesylate (U-87,201E). Organic Process Research & Development,1997,1,106-116.
[47]Daisuke, K.; Satoshi, S.; Yasutaka, I. An alternative method for the selective bromination of alkylbenzenes using NaBrO3/NaHSO3 reagent. Journal of Organic Chemistry,1998,63, 6023-6026.
[48]Ajda, P.; Stojan, S.; Marko, Z. et al. Environmentally benign electrophilic and radical bromination'on water':H2O2-HBr system versus N-bromosuccinimide. Tetrahedron,2009, 65,4429-4439.
[49]Sharma, A. Chattopadhyay. Journal of Organic Chemistry,1999,64,8059.
[50]Marie, G.; Jean-Marie, R.; Thomas, M.F.; Novel selective thiazoleacetic acids as CRTH2 antagonists developed from in silico derived hits. Bioorganic & Medicinal Chemistry Letters, 2010,20,1177-1180.
[51]Habib, F.; Nasser, I.; Kamal, A.; et al. Tungstophosphoric acid (H3PW12O40) as a heterogeneous inorganic catalyst. Activation of hexamethyl disilazane (HMDS)by tungstophosphoric acid for efficient and selective solvent-free O-silylation reactions. Journal of the Chemistry Society,2002,1,2601-2604.
[52]Abu, T.K.; Ejabul, M.; Priti, R.S.; et al. Nickel(Ⅱ) chloride as an efficient and useful catalyst for chemoselective thioacetalization of aldehydes. Tetrahedron Letters,2003,44,919-922.