哌嗪类化合物的合成及其抗过敏活性研究
|
摘要
过敏反应是指过高的异常的免疫反应,是一类严重威胁公众健康的慢性疾病。过敏反应病是临床多发病,且近年来其发病率有逐年增加的趋势。对过敏反应病的治疗,目前有多种方法,其中行之有效的方法之一是利用H_1受体拮抗剂(抗组胺药)进行的非特异性治疗。传统抗组胺药大都时效短且有中枢神经抑制等副作用,新一代抗组胺药在一定程度上克服了上述缺点,但近年来临床发现它们当中有些具有潜在的心血管系统不良反应及其它副作用。因此研究和开发药效更好、副作用更小的抗组胺新药意义深远。
西替利嗪是具有较好疗效的哌嗪类药物之一,近年来发现左西替利嗪较其混旋体药效更强,因而以左西替利嗪为先导化合物,本文合成了19个左旋二苯甲基哌嗪类化合物。同时,鉴于扑尔敏也是药效很好的抗组胺药物,所以用吡啶环取代了其中一个苯环合成了2个苯杂环哌嗪类化合物。所合成的目标化合物经元素分析、质谱、红外、核磁共振氢谱等确证其化学结构。
初步的抗过敏性哮喘和止痒的活性测试表明:有15个化合物有平喘作用,在扑尔敏组给药0.5mg/kg,WTW系列化合物组给药50mg/kg情况下,WTW-08、WTW-10、WTW-13、WTW-17和WTW-19活性与阳性对照药扑尔敏相当,化合物WTW-04、WTW-09、WTW-18和WTW-20与扑尔敏相比有较高的活性;有17个化合物有止痒作用,在扑尔敏组给药0.5mg/kg,WTW系列化合物组给药50mg/kg情况下,WTW-11、WTW-15和WTW-18活性与阳性对照药扑尔敏相当,化合物WTW-07和WTW-19与扑尔敏相比有较高的活性。
Allergy is a kind of excessive immune reaction. Allergic diseases are abroad in clinic. However, the incidence of the kind of disease tends to increase recently. Among the therapies for it, H_1 receptor antagonists (antihistamines) have shown to be effective clinically in the treatment of allergies. The classical antihistamines have some side effects such as restraining the central nervous system (CNS) and lasting shortly. Although the new antihistamines have no such side effect, some of them still have other side effects such as the latent harm to the heart and vessel system. It is important to study and explore the new antihistamines that have more significant effect and less side effect.
Cetirizine is an kind of excellent antihistaminic drug, bearing diphenylmethylpiperazine skeleton. Recently, it was repoted that levocetirizine displayed a better pharmacological profile than the racemic mixture. Therefore, we decided to synthesize some levogyrate enantiomers of them. Nineteen levogyrate compounds were synthesized. At the same time, through investigating the antihistaminic drugs of Chlorpheniramine, we replaced pyridine ring to one phenyl ring of diphenylmethylpiperazine skeleton, two compounds which include pyridine ring were synthesized. All the compounds were identified by MS, IR, ~1H-NMR and elemental analysis.
The results of the initial anti-allergic asthma and antipruritic tests showed that seventeen compounds had significant effect in asthma, the activities of WTW-08, WTW-10, WTW-13, WTW-17 and WTW-19 was equel to the activities of the positive comparison drug Chlorpheniramine, the activities of WTW-04, WTW-09, WTW-18 and WTW-20 was higher than Chlorpheniramine; fifteen compounds had significant antipruritic effect, the activities of WTW-11, WTW-15 and WTW-18 was equel to the activities of the positive comparison drag Chlorpheniramine, the activities of WTW-07 and WTW-19 was higher than Chlorpheniramine.
西替利嗪是具有较好疗效的哌嗪类药物之一,近年来发现左西替利嗪较其混旋体药效更强,因而以左西替利嗪为先导化合物,本文合成了19个左旋二苯甲基哌嗪类化合物。同时,鉴于扑尔敏也是药效很好的抗组胺药物,所以用吡啶环取代了其中一个苯环合成了2个苯杂环哌嗪类化合物。所合成的目标化合物经元素分析、质谱、红外、核磁共振氢谱等确证其化学结构。
初步的抗过敏性哮喘和止痒的活性测试表明:有15个化合物有平喘作用,在扑尔敏组给药0.5mg/kg,WTW系列化合物组给药50mg/kg情况下,WTW-08、WTW-10、WTW-13、WTW-17和WTW-19活性与阳性对照药扑尔敏相当,化合物WTW-04、WTW-09、WTW-18和WTW-20与扑尔敏相比有较高的活性;有17个化合物有止痒作用,在扑尔敏组给药0.5mg/kg,WTW系列化合物组给药50mg/kg情况下,WTW-11、WTW-15和WTW-18活性与阳性对照药扑尔敏相当,化合物WTW-07和WTW-19与扑尔敏相比有较高的活性。
Allergy is a kind of excessive immune reaction. Allergic diseases are abroad in clinic. However, the incidence of the kind of disease tends to increase recently. Among the therapies for it, H_1 receptor antagonists (antihistamines) have shown to be effective clinically in the treatment of allergies. The classical antihistamines have some side effects such as restraining the central nervous system (CNS) and lasting shortly. Although the new antihistamines have no such side effect, some of them still have other side effects such as the latent harm to the heart and vessel system. It is important to study and explore the new antihistamines that have more significant effect and less side effect.
Cetirizine is an kind of excellent antihistaminic drug, bearing diphenylmethylpiperazine skeleton. Recently, it was repoted that levocetirizine displayed a better pharmacological profile than the racemic mixture. Therefore, we decided to synthesize some levogyrate enantiomers of them. Nineteen levogyrate compounds were synthesized. At the same time, through investigating the antihistaminic drugs of Chlorpheniramine, we replaced pyridine ring to one phenyl ring of diphenylmethylpiperazine skeleton, two compounds which include pyridine ring were synthesized. All the compounds were identified by MS, IR, ~1H-NMR and elemental analysis.
The results of the initial anti-allergic asthma and antipruritic tests showed that seventeen compounds had significant effect in asthma, the activities of WTW-08, WTW-10, WTW-13, WTW-17 and WTW-19 was equel to the activities of the positive comparison drug Chlorpheniramine, the activities of WTW-04, WTW-09, WTW-18 and WTW-20 was higher than Chlorpheniramine; fifteen compounds had significant antipruritic effect, the activities of WTW-11, WTW-15 and WTW-18 was equel to the activities of the positive comparison drag Chlorpheniramine, the activities of WTW-07 and WTW-19 was higher than Chlorpheniramine.
引文
[1]何卫华,杨锁泉.中药治疗变态反应性疾病研究进展[J].海军医学杂志,2007,28(2):181-183
[2]张晓春.运用中医卫气营血辨证治疗变态反应性皮肤病258例疗效分析[J].湖南中医杂志,2007,23(6):23-25
[3]顾瑞金.变态反应病治疗学[M].北京:北京医科大学,中国协和医科大学联合出版社,1998.47-51
[4]Tanidam,Kanekoh,Shen J,et al.Involvement of the histaminergic system in renal sympathetic and cardio vascular responses to leptin and ghrelin[J].Neuro Sci Lea,2007,413(7):88-92
[5]王茂,许以平.Ⅱ-4在支气管哮喘发病中的作用研究[J].中华微生物和免疫学杂志,2000,20(2):116
[6]杨正安.变态反应疾病的防治[J].江苏医药,1996,22(12):881-882
[7]王佩,徐建华.抗变态反应药物的研究进展[J].中国现代应用药学杂志,1998,15(6):4-7
[8]Slater J W,Zerchnich A D,Haxby D G.Second generate on antihistamines:a comparactive review[J].Drugs,1999,57(1):102-105
[9]林凡程,周宁,刘克良.促组胺释放的肽类物质[J].中国新志,2007,16(22):1834-1838
[10]Herbest K L.Gonadotropin releasing hormone antagonists[J].Curr Otinion Pharmacol,2003,3(6):660-666
[11]郑武飞.医学免疫学(第3版)[M].北京:人民卫生出版社,1993.176-171
[12]叶世泰.变态反应学[M].北京:科学出版社,1998.650-664
[13]Banu Y,Watanabe T.Augmentation of antigenreceptor-mediateresponses by histamine H_1 receptor signaling[J].Exp Med,1999,189(11):673-682
[14]Yanai S LZ,Endou M.Targeting disruption of histamine H_1 receptors in mice:behavioral and neuroch mical characterization[J].Life Sci,1998,62(11):1607-1610
[15]Cobb D B,Watson W A,Fernandez M C.High-dose loratadine exposure in a six-year-old child[J].Vet Hum Toxicol.2001,43(12):163-164
[16]De Bruin M L,Van Puijenbroek E P,Egberts A C,et al.Non-sedating antihistamine drugs and cardiac arrhythmias-biased risk estimatesfrom spontaneous reporting systems [J].Br J Olin Pharmaeol,2002,53(12):370-374
[17]Reimers A,Hari Y,Muller U.Reduction of side-efects from ultrarush immuno-therapy with honeybee venom by pretreatment with fexofenadine,a doubleblind,plaee boeonlxolled trial[J].Allergy,2000,55(12):484-488
[18]郑珩.抗组胺新药Norastemizole[J].药学进展,1999,23(3):182-183
[19]祝宏.组胺H_1受体拮抗剂研制进展[J].国外医药-合成药生化药制剂分册,1999,20(1):3-6
[20]李明华.抗过敏药物的种类.药理学和临床应用[J].中国临床医生,2003,31(9):15-18
[21]张石革.H_1受体拮抗剂的研究进展与临床评价[J].中国药业,2002,11(4):35-38
[22]仉文升,李安良.药物化学[M].北京:高等教育出版社,1999.389-390
[23]闻韧.药物化学[M].北京:科学技术文献出版社,2005.15-17
[24]许文方,新药设计与开发[M].北京:科学出版社,2001.72-73
[25]张骁,束梅英.手性药物研发进展[J].中国制药信息,2007,23(12):7-9
[26]Christophe B,Carlier B,Gillard M,et al.HistamineH_1 receptor antagonism by cetirizine in isolated guineapig tissues:influence of receptor reserve and dissoceation kinetics[J].European Journal of Pharmacol,2003,470(12):87-94
[27]Wang D Y,Hanotte F.Effect of cetirizine,levocetirizine,dextro cetirizine on histamine -induced nasalresponsein healthy adult volunteers[J].Allergy(Copenhagen),2001,56(4):339-343
[28]Giustiziert M L,Albanesl C,Fluhr J.H_1 histamine receptor modiates inflammatory responses in human keratinocytes[J].Allergy Clin Immunol,2004,114(15):1176-1182
[29]Divalia J L,De Vos C,Hanotte F,et al.A randomized,double-blind,crossover comparison among cetirizine,levocetirizine,and ucb 28557 on histamine induced cutaneous responses in healthy adult volunteers[J].Allergy,2001,56(16):50-57
[30]Day J H,Ellis A K,Rafeiro E.Ievocetirizine:a newselective H_1 receptor antagonist for use in allergic disorders[J].Drugs Today,2004,40(4):415-421
[31]Gandon J M,Allain H.Lack of effect of single and repeated doses of levocetirizine-a new antihistamine drug,on cognitive and psychomotor functions in healthy volunteers[J].Br J Clin Pharmacol,2002,54:51-58
[32]Chen X Q,Wang W B.Theuse of bioisosteric groups in lead optimization[J].Annu Rep Med Chem,2003,38:333-346
[33]Patani G A,Lavoie E J.Bioisosterism:a rational approach in drug design[J].Chem Rev,1996,96(8):3147-3176
[34]Olesen P H.The use of bioisosteric groups in lead optimization Curr Opin Drug Disc Develop[J].2001,4(4):471-478
[35]郭宗儒.新药研制和重要中间体[J].精细化工原料及中间体,2006,8:10-10
[36]Fujikura T,Shimosawa T,Yakuo I.Regulatory efect of histamine H_1 receptor antagonist on the expression of messenger RNA ellcoding CC chemokines in the human nasal mucosa[J].Allergy Clin Immunol,2001,107:123-128
[37]Yanai S L Z,Endou M,et al.Targeting disruption of histamine H_1 receptors in mice:behavioral and neurochmical characterization[J].Life Sci,1998,62:1607-1610
[38]Kawashima M,Tango T,Noguchi T,et al.Addition of fexofenadine to a topical cortico steroid reduces the pruritus associated with a topic dermatitis in a 1-week randomized,multi centre,double blind,placebo controlled,parallel group study[J].Br J Dermatol,2003,148:1212-1221
[39]张罗,韩德民,顾之燕.抗组胺药物H1受体拮抗剂的临床药理学(一):组胺、组胺受体和抗组胺药物[J].中国耳鼻咽喉头颈外科,2005,12(1):61-63
[40]Karppinen A,Kautiainen H,Petman L,et al.Comparison of cetirizine,ebastine and loratadine in the treatment of immedia temosquito bit allergy[J].Allergy,2002,57:534-537
[41]Chen C,Hanson E,Watson J W,et al.Pglycoprotein limits the brain penetration of nonse dating but not sedating H_1-antagonists[J].Drug Metab Dispos,2003,31:312-318
[42]王睿,陈鑫,郭子黄,等.组胺受体拮抗剂对静脉“桥”保护作用的研究[J].中国心血管病研究杂志,2005,3(2):103-105
[43]Diepgen T L.Long-term treatment with cetirizine of infants with a topic derm atitis:a multicountry,double-blind,randomized placebo controlled trial(the ETAC trial)over 18months[J].Pediatr Allergy Immuno,2002,13:278-286
[44]Kiss R,Kovori Z,Keseru G M.Homology modelling and binding site mapping of the human histamine H_1 receptor[J].Eur J Med Chem,2004,9(11):959-967
[45]王立升.哌嗪类衍生物的设计、合成和生物活性研究[D].沈阳:沈阳药科大学,1994:26-32
[46]姜红宇.二苯甲基哌嗪类化合物的合成及其抗变态反应活性[D].南宁:广西大学,2001:18-19
[47]朱红元.手性二苯甲基哌嗪类化合物的合成及其抗变态反应活性[D].南宁:广西大学,2004:20-23
[48]张丹参.药理学(第五版)[M].北京:人民卫生出版社,1981:147
[49]Clemo G.R,Gardner C.The optical rotatory powers of some 4-substituted benzhydrylamines[J].Chem Soc,1939:1958-1961
[50]Opalka C J,DAmbra T E.Anovel synthesis of enantiomers of an antihistamine drug by piperazine formation from a primary amine[J].Synthesis,1995:766-768
[51]Cossement E,Bodson G,Gobert J.Enantiomer 1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methylphenyl)sulfonyl]piperazine[P].U.S.:US5478941,1995.12.26
[52]费楚华,沈竞康,刘进军.N,N-二(2-羟乙基)对甲苯磺酰胺与氯化亚砜的反应[J].化学学报,1984,42:829-830
[53]David A.Sulfonamide wax emulsions[P].U.S.:US2505931,1948.2.24
[54]Cossement E,Motte G.Process for preparation of a 1-piperazine-ethoxyacetic acid[P].UK:GB2225321,1990.5.30
[55]Howard K L,Stewart H W,Conroy E A,et al.Piperazines(Ⅱ)1-Heterocyclic piperazines and 1-heterocyclic-4-carbethoxy-piperazines[J].Org Chem,1953,18:1484-1488
[56]Hanlin K E,Weston A W,Fischer F E,et al.Histamine antagonists Ⅲ.1-and 1,4-disubstituted piperazines derivatives[J].Am Chem Soc,1949,71:2734-2736
[57]Isobe Y,Obara F,Inoue Y,et al.Preparation of uracil derivatives as therapeutic agents for allergic diseases[P].JP:WO2004026841,2004.04.01
[58]Fukumi H,Sakamoto T,Sugiyama M,et al.Thiazolidine carboxylic acid amide derivatives and their therapeutic uses as antiallergics and PAF Antagonists[P].Japan,U.S:US5470851,1995.11.28
[59]Takahashi T,Imaoka T,Tomioka H,et al.Preparation of nitrogen containing compounds as the active ingredient of CCR3 inhibitors[P].Japan:WO2002026708,2002.04
[60]高凯,韩邦友,朱红军,等.手性环(L-苯丙-L-组)和(D-苯丙-L-组)二肽的合成[J].南京工业大学学报,2004,26(2):67-70
[61]王健,杨祖幸,张清华,等.手性芳酰胺类分子钳的设计与微波合成[J].有机化学,2005,25(7):850-853
[62]彭小三,陈钧辉,张昕,等.甘氨酰组氨酰赖氨酸(GHK)的液相合成及其酶促降解[J].中国生物化学与分子生物学报,2003,19(3):406-409
[63]龙姝,陈敏,莫文妍,等.N-[甲氧(乙氧)羰基亚甲基]5-取代苯基-2E,4E-戊二烯酰胺的合成与生物活性研究[J].华中师范大学学报(自然科学版),2002,36(2):185-187
[64]曾向潮,徐石海,李毅群,等.N-(2-吡咯甲酰基)氨基酸甲酯的合成[J].有机化学,2004,24(7):802-805
[65]王建平,陈庆华.手性亲核试剂的合成及表征[J].化学试剂,2001,3(2):115-116
[66]Liakopoujou K M,Pachatouridis C,Ekateriniadou L,et al.A new syn thesis of the tripeptide Gly-His-Lys with an timi cmbial activity.Amino Acids,1997,13(2):155-161
[67]秦建军,曹小岗,杨建明.N-苄基甘氨酸乙酯的生产方法[P].中国:CN1477095A,2004.2.25
[68]陈芬儿.有机药物合成法[M].上海:中国医药科技出版社,1998.334-335
[69]肖明耿,孙庆生,严桂珍,等.力克喘气雾剂的平喘实验研究[J].甘肃中医学院学报,2006,23(1):26-28
[70]郭胜典.妇炎康洗剂的抗炎、止痒实验研究[J].中国实验方剂学杂志,1998,4(6):33-35
[71]张开明,王刚,尹国华,等.最新皮肤科学理论与实践[M].北京:中国医学科技出版社.2000:16
[72]苗明三,刘方洲,金树兴,等.实验动物和动物实验技术[M].北京:中国中医药出版社,1997:256
[2]张晓春.运用中医卫气营血辨证治疗变态反应性皮肤病258例疗效分析[J].湖南中医杂志,2007,23(6):23-25
[3]顾瑞金.变态反应病治疗学[M].北京:北京医科大学,中国协和医科大学联合出版社,1998.47-51
[4]Tanidam,Kanekoh,Shen J,et al.Involvement of the histaminergic system in renal sympathetic and cardio vascular responses to leptin and ghrelin[J].Neuro Sci Lea,2007,413(7):88-92
[5]王茂,许以平.Ⅱ-4在支气管哮喘发病中的作用研究[J].中华微生物和免疫学杂志,2000,20(2):116
[6]杨正安.变态反应疾病的防治[J].江苏医药,1996,22(12):881-882
[7]王佩,徐建华.抗变态反应药物的研究进展[J].中国现代应用药学杂志,1998,15(6):4-7
[8]Slater J W,Zerchnich A D,Haxby D G.Second generate on antihistamines:a comparactive review[J].Drugs,1999,57(1):102-105
[9]林凡程,周宁,刘克良.促组胺释放的肽类物质[J].中国新志,2007,16(22):1834-1838
[10]Herbest K L.Gonadotropin releasing hormone antagonists[J].Curr Otinion Pharmacol,2003,3(6):660-666
[11]郑武飞.医学免疫学(第3版)[M].北京:人民卫生出版社,1993.176-171
[12]叶世泰.变态反应学[M].北京:科学出版社,1998.650-664
[13]Banu Y,Watanabe T.Augmentation of antigenreceptor-mediateresponses by histamine H_1 receptor signaling[J].Exp Med,1999,189(11):673-682
[14]Yanai S LZ,Endou M.Targeting disruption of histamine H_1 receptors in mice:behavioral and neuroch mical characterization[J].Life Sci,1998,62(11):1607-1610
[15]Cobb D B,Watson W A,Fernandez M C.High-dose loratadine exposure in a six-year-old child[J].Vet Hum Toxicol.2001,43(12):163-164
[16]De Bruin M L,Van Puijenbroek E P,Egberts A C,et al.Non-sedating antihistamine drugs and cardiac arrhythmias-biased risk estimatesfrom spontaneous reporting systems [J].Br J Olin Pharmaeol,2002,53(12):370-374
[17]Reimers A,Hari Y,Muller U.Reduction of side-efects from ultrarush immuno-therapy with honeybee venom by pretreatment with fexofenadine,a doubleblind,plaee boeonlxolled trial[J].Allergy,2000,55(12):484-488
[18]郑珩.抗组胺新药Norastemizole[J].药学进展,1999,23(3):182-183
[19]祝宏.组胺H_1受体拮抗剂研制进展[J].国外医药-合成药生化药制剂分册,1999,20(1):3-6
[20]李明华.抗过敏药物的种类.药理学和临床应用[J].中国临床医生,2003,31(9):15-18
[21]张石革.H_1受体拮抗剂的研究进展与临床评价[J].中国药业,2002,11(4):35-38
[22]仉文升,李安良.药物化学[M].北京:高等教育出版社,1999.389-390
[23]闻韧.药物化学[M].北京:科学技术文献出版社,2005.15-17
[24]许文方,新药设计与开发[M].北京:科学出版社,2001.72-73
[25]张骁,束梅英.手性药物研发进展[J].中国制药信息,2007,23(12):7-9
[26]Christophe B,Carlier B,Gillard M,et al.HistamineH_1 receptor antagonism by cetirizine in isolated guineapig tissues:influence of receptor reserve and dissoceation kinetics[J].European Journal of Pharmacol,2003,470(12):87-94
[27]Wang D Y,Hanotte F.Effect of cetirizine,levocetirizine,dextro cetirizine on histamine -induced nasalresponsein healthy adult volunteers[J].Allergy(Copenhagen),2001,56(4):339-343
[28]Giustiziert M L,Albanesl C,Fluhr J.H_1 histamine receptor modiates inflammatory responses in human keratinocytes[J].Allergy Clin Immunol,2004,114(15):1176-1182
[29]Divalia J L,De Vos C,Hanotte F,et al.A randomized,double-blind,crossover comparison among cetirizine,levocetirizine,and ucb 28557 on histamine induced cutaneous responses in healthy adult volunteers[J].Allergy,2001,56(16):50-57
[30]Day J H,Ellis A K,Rafeiro E.Ievocetirizine:a newselective H_1 receptor antagonist for use in allergic disorders[J].Drugs Today,2004,40(4):415-421
[31]Gandon J M,Allain H.Lack of effect of single and repeated doses of levocetirizine-a new antihistamine drug,on cognitive and psychomotor functions in healthy volunteers[J].Br J Clin Pharmacol,2002,54:51-58
[32]Chen X Q,Wang W B.Theuse of bioisosteric groups in lead optimization[J].Annu Rep Med Chem,2003,38:333-346
[33]Patani G A,Lavoie E J.Bioisosterism:a rational approach in drug design[J].Chem Rev,1996,96(8):3147-3176
[34]Olesen P H.The use of bioisosteric groups in lead optimization Curr Opin Drug Disc Develop[J].2001,4(4):471-478
[35]郭宗儒.新药研制和重要中间体[J].精细化工原料及中间体,2006,8:10-10
[36]Fujikura T,Shimosawa T,Yakuo I.Regulatory efect of histamine H_1 receptor antagonist on the expression of messenger RNA ellcoding CC chemokines in the human nasal mucosa[J].Allergy Clin Immunol,2001,107:123-128
[37]Yanai S L Z,Endou M,et al.Targeting disruption of histamine H_1 receptors in mice:behavioral and neurochmical characterization[J].Life Sci,1998,62:1607-1610
[38]Kawashima M,Tango T,Noguchi T,et al.Addition of fexofenadine to a topical cortico steroid reduces the pruritus associated with a topic dermatitis in a 1-week randomized,multi centre,double blind,placebo controlled,parallel group study[J].Br J Dermatol,2003,148:1212-1221
[39]张罗,韩德民,顾之燕.抗组胺药物H1受体拮抗剂的临床药理学(一):组胺、组胺受体和抗组胺药物[J].中国耳鼻咽喉头颈外科,2005,12(1):61-63
[40]Karppinen A,Kautiainen H,Petman L,et al.Comparison of cetirizine,ebastine and loratadine in the treatment of immedia temosquito bit allergy[J].Allergy,2002,57:534-537
[41]Chen C,Hanson E,Watson J W,et al.Pglycoprotein limits the brain penetration of nonse dating but not sedating H_1-antagonists[J].Drug Metab Dispos,2003,31:312-318
[42]王睿,陈鑫,郭子黄,等.组胺受体拮抗剂对静脉“桥”保护作用的研究[J].中国心血管病研究杂志,2005,3(2):103-105
[43]Diepgen T L.Long-term treatment with cetirizine of infants with a topic derm atitis:a multicountry,double-blind,randomized placebo controlled trial(the ETAC trial)over 18months[J].Pediatr Allergy Immuno,2002,13:278-286
[44]Kiss R,Kovori Z,Keseru G M.Homology modelling and binding site mapping of the human histamine H_1 receptor[J].Eur J Med Chem,2004,9(11):959-967
[45]王立升.哌嗪类衍生物的设计、合成和生物活性研究[D].沈阳:沈阳药科大学,1994:26-32
[46]姜红宇.二苯甲基哌嗪类化合物的合成及其抗变态反应活性[D].南宁:广西大学,2001:18-19
[47]朱红元.手性二苯甲基哌嗪类化合物的合成及其抗变态反应活性[D].南宁:广西大学,2004:20-23
[48]张丹参.药理学(第五版)[M].北京:人民卫生出版社,1981:147
[49]Clemo G.R,Gardner C.The optical rotatory powers of some 4-substituted benzhydrylamines[J].Chem Soc,1939:1958-1961
[50]Opalka C J,DAmbra T E.Anovel synthesis of enantiomers of an antihistamine drug by piperazine formation from a primary amine[J].Synthesis,1995:766-768
[51]Cossement E,Bodson G,Gobert J.Enantiomer 1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methylphenyl)sulfonyl]piperazine[P].U.S.:US5478941,1995.12.26
[52]费楚华,沈竞康,刘进军.N,N-二(2-羟乙基)对甲苯磺酰胺与氯化亚砜的反应[J].化学学报,1984,42:829-830
[53]David A.Sulfonamide wax emulsions[P].U.S.:US2505931,1948.2.24
[54]Cossement E,Motte G.Process for preparation of a 1-piperazine-ethoxyacetic acid[P].UK:GB2225321,1990.5.30
[55]Howard K L,Stewart H W,Conroy E A,et al.Piperazines(Ⅱ)1-Heterocyclic piperazines and 1-heterocyclic-4-carbethoxy-piperazines[J].Org Chem,1953,18:1484-1488
[56]Hanlin K E,Weston A W,Fischer F E,et al.Histamine antagonists Ⅲ.1-and 1,4-disubstituted piperazines derivatives[J].Am Chem Soc,1949,71:2734-2736
[57]Isobe Y,Obara F,Inoue Y,et al.Preparation of uracil derivatives as therapeutic agents for allergic diseases[P].JP:WO2004026841,2004.04.01
[58]Fukumi H,Sakamoto T,Sugiyama M,et al.Thiazolidine carboxylic acid amide derivatives and their therapeutic uses as antiallergics and PAF Antagonists[P].Japan,U.S:US5470851,1995.11.28
[59]Takahashi T,Imaoka T,Tomioka H,et al.Preparation of nitrogen containing compounds as the active ingredient of CCR3 inhibitors[P].Japan:WO2002026708,2002.04
[60]高凯,韩邦友,朱红军,等.手性环(L-苯丙-L-组)和(D-苯丙-L-组)二肽的合成[J].南京工业大学学报,2004,26(2):67-70
[61]王健,杨祖幸,张清华,等.手性芳酰胺类分子钳的设计与微波合成[J].有机化学,2005,25(7):850-853
[62]彭小三,陈钧辉,张昕,等.甘氨酰组氨酰赖氨酸(GHK)的液相合成及其酶促降解[J].中国生物化学与分子生物学报,2003,19(3):406-409
[63]龙姝,陈敏,莫文妍,等.N-[甲氧(乙氧)羰基亚甲基]5-取代苯基-2E,4E-戊二烯酰胺的合成与生物活性研究[J].华中师范大学学报(自然科学版),2002,36(2):185-187
[64]曾向潮,徐石海,李毅群,等.N-(2-吡咯甲酰基)氨基酸甲酯的合成[J].有机化学,2004,24(7):802-805
[65]王建平,陈庆华.手性亲核试剂的合成及表征[J].化学试剂,2001,3(2):115-116
[66]Liakopoujou K M,Pachatouridis C,Ekateriniadou L,et al.A new syn thesis of the tripeptide Gly-His-Lys with an timi cmbial activity.Amino Acids,1997,13(2):155-161
[67]秦建军,曹小岗,杨建明.N-苄基甘氨酸乙酯的生产方法[P].中国:CN1477095A,2004.2.25
[68]陈芬儿.有机药物合成法[M].上海:中国医药科技出版社,1998.334-335
[69]肖明耿,孙庆生,严桂珍,等.力克喘气雾剂的平喘实验研究[J].甘肃中医学院学报,2006,23(1):26-28
[70]郭胜典.妇炎康洗剂的抗炎、止痒实验研究[J].中国实验方剂学杂志,1998,4(6):33-35
[71]张开明,王刚,尹国华,等.最新皮肤科学理论与实践[M].北京:中国医学科技出版社.2000:16
[72]苗明三,刘方洲,金树兴,等.实验动物和动物实验技术[M].北京:中国中医药出版社,1997:256