公开(公告)号：US20160016965A1

公开(公告)日：2016-01-21

申请号：US14772592

申请日：2014-03-06

申请人： Andrew COOP ,  Alexander D. MACKERELL ,  Rae MATSUMOTO

发明人： Andrew Coop ,  Alexander D. Mackerell ,  Rae Matsumoto

IPC分类号： C07D489/08 ,  C07D489/02

CPC分类号： C07D489/08 ,  C07D489/02

摘要： An opioid narcotics used for the treatment of moderate-to-severe pain that primarily exert their analgesic effects through μ receptors. Although, traditional μ agonists can cause undesired side effects, including tolerance, addition of δ antagonists can attenuate said side effects. The present invention includes 4a,9-dihydroxy-7a-(hydroxymethyl)-3-methyl-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one (UMB 425) a 5,14-bridged morphinan-based orvinol precursor, along with analogs of morphine, dihydromorphine, hydromorphone, codeine, dihydrocodeine, hydrocodone and ethylmorphine. Although UMB 425 lacks δ-specific motifs, conformationally sampled pharmacophore models for μ and δ receptors predict it to have efficacy similar to morphine at μ receptors and similar to naltrexone at δ receptors, due to the compound sampling conformations in which the hydroxyl moiety interacts with the receptors similar to orvinols. UMB 425 exhibits a mixed μ agonist/δ antagonist profile as determined in receptor binding. UMB 425 has mixed μ agonist/δ antagonist properties in vitro that translate to reduced tolerance liabilities in vivo.

摘要翻译： 用于治疗主要通过μ受体发挥其镇痛作用的中度至重度疼痛的阿片样麻醉药物。 尽管传统的μ激动剂可能引起不希望的副作用，包括耐受性，δ拮抗剂的添加可以减弱所述副作用。 本发明包括4a，9-二羟基-7a-（羟甲基）-3-甲基-2,3,4,4a，5,6-六氢-1H-4,12-甲基苯并呋喃并[3,2-e] 7（7aH） - 酮（UMB 425）5,14-桥连的吗啡喃基的月桂醇前体，以及吗啡，二氢吗啡，氢吗啡酮，可待因，二氢可待因，氢可酮和乙基吗啡的类似物。 虽然UMB 425缺乏δ特异性基序，但是构象取样的μ和δ受体的药效团模型预测其在μ受体上具有与吗啡相似的功效，并且与δ受体的纳曲酮类似，这是由于羟基部分与 类似于orvinols的受体。 UMB 425显示在受体结合中测定的混合μ激动剂/δ拮抗剂谱。 UMB 425在体外具有混合的μ激动剂/δ拮抗剂性质，其在体内转化为降低的耐受负荷。