Ambrisentan.doc

肺动脉高压治疗药物凡瑞克（安立生坦，ambrisentan）窗体顶端符合检索条件的物质共1个 【记录号】282368【通用名】Ambrisentan, BSF-208075, LU-208075【化学名】(+)-2(S)-(4,6-Dimethylpyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropionic acid【CAS登记号】177036-94-1【分子式】C22-H22-N2-O4 C22H22N2O4【分子量】378.4258【化学活性】Cardiovascular Drugs, Heart Failure Therapy, Hypertension, Treatment of, Pulmonary Hypertension, Treatment of, Renal Failure, Agents for, Renal-Urologic Drugs, Respiratory Drugs, Treatment of Renal Diseases, Endothelin ETA Receptor Antagonists【开发阶段】Phase III【研究机构】Myogen (Orphan Drug), Abbott (Originator), Myogen (Licensee)窗体底端商品名：LETAIRIS 窗体顶端【药物名称】Ambrisentan, BSF-208075, LU-208075化学结构式(Chemical Structure):参考文献No.381060标题:Discovery and optimization of a novel class of orally active nonpeptidic endothelin-A receptor antagonists作者:Albrecht, H.-P.; Riechers, H.; Amberg, W.; Baumann, E.; Bernard, H.; Bohm, H.J.; Klinge, D.; Kling, A.; Muller, S.; Raschack, M.; Unger, L.; Walker, N.; Wernet, W.来源:J Med Chem 1996,39(11),2123合成路线图解说明: The condensation of benzophenone (I) with chloroacetic acid methyl ester (II) by means of sodium methoxide in THF gives the epoxide (III), which is treated with methanol/BF3.Et2O, yielding 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester (IV). The condensation of (IV) with 4,6-dimethoxy-2-(methylsulfonyl)pyrimidine (V) by means of K2CO3 in DMF affords 2-(4,6-dimethoxypyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropionic acid methyl ester (VI), which is hydrolyzed with NaOH in hot dioxane/water to give the corresponding free acid (VII). Finally, this compound is submitted to optical resolution, affording LU-135252. Optical resolution of (VIII), the free acid derivative of (IV), with (R)-phenylethylamine, L-proline methyl ester, (S)-1-(4-nitrophenyl)ethylamine or (S)-1-(4-chlorophenyl)ethylamine leads to the enantiomerically pure (S)-enatiomer (IX), which by reaction with 4,6-dimethoxy-2-(methylsulfonyl)pyrimidine (V) directly affords LU-135252.合成路线图解说明: The condensation of benzophenone (I) with methyl 2-chloroacetate (II) by means of NaOMe in THF gives 3,3-diphenyloxirane-2-carboxylic acid methyl ester (III), which by treatment with BF3/Et2O and methanol, followed by optical resolution, yielded the pure enantiomer 2(S)-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester (IV). The condensation of (IV) with 4,6-dimethyl-2-(methylsulfonyl)pyrimidine (V) by means of K2CO3 in DMF affords 2-(4,6-dimethylpyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropionic acid methyl ester (VI), which is finally hydrolyzed with KOH in hot dioxane to afford the target propionic acid as a racemic mixture.窗体底端资料来自 Drug future 英文别名：2-(4,6-Dimethylpyrimidin-2-yl)oxy-3-methoxy-3,3-di(phenyl)propanoic acid; (aS)-a-(4,6-Dimethyl-2-pyrimidinyl)oxy-methoxy-phenylbenzenepropanoic Acid; BSF 208075; LU 208075; (2S)-2-(4,6-dimethylpyrimidin-2-yl)oxy-3-methoxy-3,3-diphenylpropanoic acid/cerebrovascular/PAH/ypml/20110817154718531.htm 说明书肺动脉高压治疗药物凡瑞克（安立生坦，ambrisentan）在华上市2-(4,6-二嘧啶-2-基)氧基-3-甲氧基-3,3-二苯基丙酸; 安立生坦葛兰素史克公司日前宣布在中国上市凡瑞克（安立生坦，ambrisentan），为肺动脉高压患者带来新选择。该药品是一种新型的高选择性内皮素受体拮抗剂，可通过作用于肺动脉高压患者体内功能发生改变的内皮素及其受体，防止血管过度收缩，进而缓解疾病症状，提高患者的生活质量。其治疗肺动脉高压的疗效已获得中国食品药品监督管理局、美国食品和药品管理局及欧洲药品质量管理局等药品管理机构的认可。据了解，肺动脉高压是一种极度恶性的罕见病，每100万人中大约有1525人会患肺动脉高压。它可以发生在任何年龄和性别的人群中，通常成以上的患者是年轻人，而女性的发病率是男性的近2倍。而且肺动脉高压的危害非常大，如果不能及时得到正确诊断和有针对性的治疗，大多数患者会在23年甚至更短的时间死亡。因此，肺动脉高压被喻为“心血管疾病中的恶性肿瘤”。“肺动脉高压是一种被大家所忽视，但又极其严重的罕见病，我很高兴看到凡瑞克进入中国，为肺动脉高压患者带来福音。”葛兰素史克（中国）投资有限公司处方药部总经理马克瑞（Mark Reilly）表示：“要在开发罕见病新治疗方法领域取得重大进展，需要独特的技术与长期的承诺，更重要的是对于这些疾病状况的深入了解。【药理作用】 内皮素-1（ET-1）是一种有效的自分泌和旁分泌肽。两种受体亚型（ETA和ETB）共同调节ET-1在血管平滑肌和内皮细胞中的作用。ETA的主要作用是血管收缩和细胞增殖，而ETB的主要作用是血管舒张、抑制增殖、以及清除ET-1。在患有肺动脉高压的患者中，血浆ET-1的浓度增高了10倍，并且与右心房平均压力的增加和疾病的严重程度相关。肺动脉高压患者肺组织中ET-1和ET-1 mRNA浓度增加9倍，主要集中在肺动脉内皮细胞。这些发现提示了ET-1可能在肺动脉高压的发病和发展中起了重要的作用。安立生坦是一种与ETA高度结合（Ki=0.011 nM）的受体拮抗剂，与ETB相比对，ETA有高选择性（4000倍），有关对ETA高选择性的临床影响还是未知。药效学-心脏电生理 ：在一项随机、阳性和安慰剂对照、平行组研究中，健