Chapter 9 Antiallergic and antiulcer drugs

Histamine widely exists in a variety of plants, animals and micro-organisms. It comes from histidine which is decarboxylated by histidine decarboxylase. Its chemical name is 4 (5) - (2 - aminoethyl) imidazole, has a tautomer (a) and (b).

There are at least three histamine receptor subtypes: H1, H2 and H3 receptors. Acting on H1 receptor, causing intestinal, uterine, bronchial smooth muscle contractions, even in bronchial smooth muscle cramp and difficulty breathing, also caused capillary relaxation, resulting in increasing permeability of the blood vessel wall, resulting in swelling and itching, to take part in the occurrence of allergy.

Acting on H2 receptors, Histamine lead to the increasing secretion of gastric acid and pepsin. Excessive gastric acid is closely related with peptic ulcer. Although histamine H3 receptor has been discovered in the central nervous system and some peripheral tissues, but the mechanism is not clear.

9.1 antiallergic drugs 1, ethanediamines 2, amino ethers 3, propylamines 4, tricycles 5, piperazines 6, Piperidines

马来酸氯苯那敏 Chlorphenamine Maleate

化学名为 N ， N- 二甲基 -γ - （ 4- 氯苯基） -2- 吡啶 丙胺顺丁烯二酸盐, 又名扑尔敏 γ - （ 4-Chlorophenyl ） -N,N-dimethyl-2-pyridine propanamine maleata(1:1)

White crystalline powder, odorless, bitter taste. Mp.131 ~ 135 ℃, with sublimation property. soluble in water, ethanol and chloroform, slightly soluble in diehtyl ether. 1% aqueous solution of pH 4.0 ~ 5.0. belong to Propylamine antihistamines. A quick and complete absorption after taking, excretion slow, long lasting time. N-demethylation, N- dedimethylation, N-oxidization and unknown polar metabolites excrete with the urine.

Synthesis of chlorphenamine

盐酸赛庚啶 Cyproheptadine Hydrochloride

1- 甲基 -4- （ 5H- 二苯并 [a ， d] 环庚三烯 -5- 亚基）哌 啶盐酸盐倍半水合物 4- （ 5H-Dibenzo[a,d]cyclohepten-5-ylidene ） -1- methylpiperidine hydrochloride sesquihydrate

White or slightly yellow crystalline powder; almost odorless, bitter taste. Soluble in methanol,chloroform, slightly soluble in ethanol,slightly soluble in water, almost insoluble in ether. Aqueous solution is acidic.

Cyproheptadine is a strong H1 receptor antagonist with mild to moderate anti-5 – hydroxytryptamine serotonin and anticholine effects. Drugs for urticaria, eczema, skin itching and other allergic diseases. Can also inhibit hypothalamic satiety center, stimulating the appetite, so getting weight after a certain period of time.

Metabolism of Cyproheptadine

1 、将 Cyproheptadine 的 -CH=CH- 换成 -CH2CO-, 并用噻吩环代替靠近羟基的苯环，得到的酮替芬 （ Ketotifen ），具有强大的的 H1 受体拮抗作用， 还可以抑制过敏介质的释放，临床用其富马酸盐 治疗和预防各类哮喘和支气管痉挛。 2 、将 Cyproheptadine 的 -CH= 换成 -CH 2 CH 2 - ， 并用吡啶环代替一个苯环，就成阿扎他定 （ Azatadine ），作用类似 Cyproheptadine 。 3 、在 Azatadine 苯环上引入 Cl 原子，并将碱性 的叔氨基改变为中性的氨基甲酸乙酯，就成为 氯雷他定（ Loratadine ）.

Cyproheptadine 的合成

盐酸西替利嗪 Cetirizine Hydrochloride

2-[4-[ （ 4- 氯苯基）苯基甲基 ]-1- 哌啶基 ] 乙氧基乙 酸二盐酸盐 [2-[4- （ 4-Chlorophenyl ） phenylmethyl]-1- piperazinyl]ethoxy]acetic acid dihydrochloride

White or almost white powder, mp.225 ℃. Soluble in water, almost insoluble in acetone and dioxane methane. Cetirizine is the piperazine antihistamine. Cetirizine selectively acts on H1 receptor, strong and durable. Clinical for antiallergics, Cetirizine is rapidly and well absorbed after taking. Vast majority eliminate through renal without metabolism.

Synthesis of Cetirizine

咪唑斯汀 Mizolastine

2- 〔〔 1- 〔（ 4- 氟甲基）甲基〕 -1H- 苯并咪唑 -2- 基〕 哌啶基 -4- 基〕甲基氨基〕嘧啶 -4 （ 3H ） - 酮 2-[[1-[ （ Fluorophenyl ） methyl]-1H-benzimidazol- 2-yl]-4-piperidinyl]methyl amino]-4(1H)- Pyrimidinone

Preparation of Mizolastine

Development and discovery of Mizolastine R & D by a French company named Syntelabo and came into the market in 1998 for the first time in European market, commodity called Mizolastine (Mizollen). Belong to the Second-generation histamine H1 receptor antagonist, is a highly specific and selective antagonists, fast onset, potent and durable, and inhibiting the release of other inflammatory mediators.

9.2 Antiulcer drugs

胃的解剖图

H 2 receptor antagonist Ranitidine Cimetidine

N’- 甲基 -N”-[2-[[(5- 甲基 -1H- 咪唑 - 4- 基 )- 甲 基 ] 硫代 ]- 乙基 ]-N- 氰基胍 N-Cyano-N′-methyl-N’’-[2-[[ （ 5-methyl-1H- imidazol-4-yl ） -methyl]thio]-ethyl] guanidine

Cimetidine 的合成分析

Synthesis of cimetidine

Good absorption in case of oral taking Bioavailability is 70% of intravenous injection Excrete mostly together with urine in prototype, 40-50% in 12 hours.

Clinical application Treatment for active duodenal ulcer, prevention of gastric ulcer recurrence, effective to reflux esophagitis, prevention and treatment of stress ulcer. High relapse after treatment, need maintenance therapy. Can be used to enhance immune function. Side effects Have estrogen-like effects,Can lead to impotence to men and breast to women, but the side effect will disappear after drug stopping.

Ranitidine The second listing H2 receptor antagonist

N’- 甲基 -N-[2-[ [ [ 5- （二甲氨甲基） -2- 呋喃基 ] 甲基 ] 硫代 ] 乙基 ] -2- 硝基 -1,1- 乙烯二胺盐酸盐

Isomer

Treatment of duodenal ulcer, benign gastric ulcer, postoperative ulcer, reflux esophagitis and so on. Effective stronger than Cimetidine for 5-8 times. Highly effective to the stomach and duodenal ulcer, quick onset and durable. 较西咪替丁小 – 无抗雄性激素的副作用  与其它药物的相互作用也较 小

Treatment of duodenal ulcer, benign gastric ulcer, postoperative ulcer, reflux esophagitis and so on. Effective stronger than Cimetidine for 5-8 times. Highly effective to the stomach and duodenal ulcer, quick onset and durable. Side effect is smaller than cimetidine, without anti- androgen effect.

Other H 2 receptor antagonists

SAR of H 2 receptor antagonists

Proton pump inhibitor 胃酸分泌原理示意

Characteristics of proton pump inhibitor Wide-ranging acting, effective, specific and high selective, samller side-effects.

Omeprazole 5- 甲氧基 -2-(4- 甲氧基 -3,5- 二甲基 - 吡啶 -2- 基 - 甲基氧硫基 ) 苯并咪唑

L-body of Omeprazole has the activity, but medicinal usage is raceme.

Synthesis of omeprazole

Clinical use: treatment of duodenal ulcer, benign gastric ulcer, postoperative ulcer, reflux esophagitis and so on. Effective 5-8 times stronger than cimetidine.