CN1395556A - 顺式－4－氰基－4－[3－(环戊氧基)－4－甲氧基苯基]环己烷羧锂－水合物 - Google Patents

顺式－4－氰基－4－[3－(环戊氧基)－4－甲氧基苯基]环己烷羧锂－水合物 Download PDF

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CN1395556A
CN1395556A CN01804016A CN01804016A CN1395556A CN 1395556 A CN1395556 A CN 1395556A CN 01804016 A CN01804016 A CN 01804016A CN 01804016 A CN01804016 A CN 01804016A CN 1395556 A CN1395556 A CN 1395556A
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凯文·S·韦布
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Abstract

本发明提供新药物制剂成分顺式4－氰基－4－[3－(环戊氧基)－4－甲氧基苯基]环己烷羧酸锂一水合物的制备方法。

Description

顺式-4-氰基-4-[3-(环戊氧基)-4-甲氧基 苯基]环己烷羧锂一水合物
发明领域
本发明涉及顺式4-氰基-4-[3-(环戊氧基)-4-甲氧基苯基]环己烷羧酸锂的一水合物的制备方法，以及水合物本身。
发明背景
环核苷酸磷酸二酯酶(PDEs)，代表将无处不在的细胞内第二信使-腺苷3′，5′-一磷酸(cAMP)和鸟苷3′，5′-一磷酸(cGMP)水解成其相应的无活性5′-一磷酸代谢物的酶家族。据信存在至少10种不同种类的PDE同工酶，各自具有独特的物理动力学特性，而且每一种代表了不同基因家族的产物。用阿拉伯数字1-10加以区别。
关于改善PDE抑制剂的副作用方面的新方法，是设计仅仅抑制单一PDE同工酶(即在重要细胞的组织中占优势的PDE同工酶)的新一代化合物。在免疫和炎症细胞中占优势的cAMP PDE同工酶是PDE4。它也是气道平滑肌中cAMP浓度的主要调节剂。因此，选择性抑制PdE4，则提高免疫和炎症细胞以及气道平滑肌中的cAMP浓度。这将导致抗炎效果和支气管扩张。这些治疗作用的一两个在治疗各种疾病中是有效的，所述疾病包括但不限于哮喘和COPD。PDE4抑制剂，尤其是PDE4-特异性抑制剂，在治疗炎症方面的其它疾病(如哮喘、慢性阻塞性肺部疾病、炎症性肠道疾病、类风湿性关节炎)、涉及肿瘤坏死因子和认知损害(如多发性脑梗塞性痴呆、认知障碍或中风)的疾病中也是有效的。本发明涉及较先前的PDE4抑制剂具有更好耐受性的化合物，即顺式-4-氰基-4-[3-(环戊氧基)-4-甲氧基苯基]环己烷-1-羧酸。更具体而言，本发明提供该酸的锂盐水合物。
附图说明
图1是Li盐一水合物的紫外光谱。
图2是Li盐一水合物的红外光谱。
图3是式(I)一水合物MS输出的示踪图。
图4.是式(I)一水合物MS电离产物的流程图
发明概述
如后面将要描述的那样，本发明涉及具有式(I)所示结构的顺式-4-氰基-4-[3-(环戊氧基)-4-甲氧基苯基]环己烷羧酸锂一水合物及其制备方法：
具体实施例
顺式-4-氰基-4-[3-(环戊氧基)-4-甲氧基苯基]环己烷-1-羧酸的制备方法描述在数个出版物中。参见例如1996年9月3日颁布的美国专利5552438和1998年8月13日以WO 98/34584公布的待审批的PCT申请PCT/US98/02749或于1999年4月22日以WO 99/18793公布的PCT申请US98/21-61。这些出版物和其它的出版物，教导如何制备所述酸的Li盐。但是，这些方法均不能制备Li盐的水合物，包括一水合物。
实施例1
使用详细描述于前述PCT申请WO 98/34584和WO 99/18793中的方法，制备批量酸的无水锂盐。从80mL乙腈和4mL水中将批量酸的无水锂盐进行结晶，并用9.5mL乙腈和0.5mL水漂洗。然后，从乙腈和4mL水中结晶滤饼并用9.50mL乙腈和0.5mL水漂洗。将所得物质在真空烘箱中干燥(50℃，20英寸)48小时，得到一水合物。
外观：白色粉末。
紫外光谱
使用Perkin-Elmer Lambda 7分光光度计，测定一水合物的紫外吸收光谱，一水合物试样为0.0076mg/mL的甲醇溶液。该光谱以芳族生色团占优势，与表1和图1所示系列的其它化合物一致。
                表1紫外吸收谱带
    波长(nm)     ε     分配
    206     38,400     1B(芳族)
    231     9,600     1La
    280     3,500     1Lb
红外光谱
使用Nicolet Magna 760 FT-IR光谱仪，得到以溴化钾片形式的Li盐一水合物的红外吸收光谱。用4cm-1分辨率测定该光谱。光谱具有表2所示的谱带分配。红外光谱示于图2.
               表2 Lot KW-27173-68C0的红外谱带分配
    波数(cm-1)     分配
    3573 O-H伸缩振动(水)
    3319，3208 O-H伸缩振动(化合水)
    3100-3000 ＝C-H伸缩振动
    3000-2800 -C-H伸缩振动
    2230 腈伸缩振动
    1647 C＝O伸缩振动(酸)
    1566 C＝O伸缩振动(羧化物)和C＝C伸缩振动
    1517，1505 C＝C伸缩振动
    1425 C-H变形和C＝C伸缩振动
    1258，1167，1142 C-O伸缩振动
    811，777，734 芳族C-H变形
实施例2-卡尔-费歇尔滴定
通过卡尔-费歇尔滴定测定水。使用一个Mettler DL18仪器进行此测定。试剂购自Cresent Chemical Co.，Hauppauge，NY，USA，商品名Hydranal(标准：酒石酸钠-2-水合物；滴定标准液；和溶剂)。发现水的含量为5.14％w/w，这与一分子水的理论值(4.91％w/w)一致。
实施例3—热重量分析
使用标准操作对实施例1制备的批量产品进行TG分析。观察到：在约137℃时总重量减少4.96％。该重量损失与一水合物的重量是一致的。
实施例4
NMR光谱
使用保持在25℃的Bruker Instruments AMX 400光谱仪，分别于400.13MHz和100.63MHz测定锂盐一水合物的1H和13C NMR波谱。将20.1mg锂盐一水合物溶于0.8mL DMSO-d6(99.96原子％D，ISOTEC)制得试样，波谱以作为第二参比溶剂的四甲基硅烷对照。质子和13C GASPE(通过GAted自旋回波序列编辑的13C多重性)NMR波谱示于图3和图4，1H和13C数据与式(I)锂盐一水合物的结构一致。
用于结构分配的同核二维信息包括用于鉴定每一个质子自旋系统数量的COSY(二维波谱)数据和表明穿透-空间nOe相互作用的NOESY(核欧沃豪斯效应波谱)数据。nOe数据有助于建立独立自旋系统之间的空间关系并且有助于确定1-和4-取代基之间的立体化学关系。
用于结构分配的异核二维信息包括考虑到通过一个键联系的质子化的13C信号分配的HMQC(异核多量子相干性)数据和考虑到通过多个键联系的季13C信号分配的HMBC(异核多键相干性)数据。HMBC数据也用于校验所有前述的1H和13C分配。一水合物盐在DMSO-d6中化学移位分配总结于表3。
表3
    13C位置 13C化学位移，δ(多重性) 1H化学位移，δ(积分)   1H多重性(J＝Hz)
    5     178.9(s)
    4′     149.2(s)
    3′     147.0(s)
    1′     133.7(s)
    CN     123.1(s)
    6′     117.5(d)     6.99(1H)     dd(J＝2.3，9.2Hz)
    2′     112.7(d)     7.00(1H)     d(J＝2.3Hz)
    5′     112.2(d)     6.93(1H)     d(J＝9.2Hz)
    1″     79.6(d)     4.81(1H)     m
    CH3O     55.6(q)     3.72(3H)     s
    1     44.5(d)     1.96(1H)     m
    4     43.0(s)
    3     36.5(2C，t)     2.06(2H)1.76(2H)     mm
    2″     32.2(2C，t)     1.87(2H)1.69(2H)     mm
    2     27.5(2C，t)     2.01(2H)1.63(2H)     mm
    3″     23.6(2C，t)     1.69(2H)1.56(2H)     mm
实施例5
解析化学电离质谱
使用Nermag R30-10三重四极质谱仪，得到锂盐一水合物的解析化学电离质谱(DCI/MS)。配制浓度为0.1mg/mL一水合物的1∶1甲醇∶二氯甲烷溶液。使用DCI探头把试样引入质谱仪。以20℃/s的速度加热探头。试剂气体是氨。以1.0/s扫描速度从60至860Da扫描质谱。使用Mass EvolutionEZScan数据系统获得质谱，并用HP MS ChemStation软件进行处理(图3)。
观察到如下分子离子加合物：在m/z 344处的[M+H]+和在m/z 361处的[M+NH4]+。观察到的与式(I)一水合物结构一致的碎片的似乎真实的离子结构示于图4所示。

Claims (3)

1.一种化合物，顺式-4-氰基-4-[3-(环戊氧基)-4-甲氧基苯基]环己烷羧酸锂一水合物。
2.一种药物制剂，由顺式-4-氰基-4-[3-(环戊氧基)-4-甲氧基苯基]环己烷羧酸锂一水合物与可药用赋形剂组成。
3.顺式-4-氰基-4-[3-(环戊氧基)-4-甲氧苯基]环己烷羧酸锂一水合物的制备方法，所述方法包括用乙腈和水处理批量的无水锂盐。
CNB018040160A 2000-01-26 2001-01-18 顺式-4-氰基-4-[3-(环戊氧基)-4-甲氧基苯基]环己烷羧锂一水合物 Expired - Fee Related CN1157371C (zh)

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ZA200205925B (en) 2003-11-21
DK1250313T3 (da) 2007-02-12
MA25652A1 (fr) 2002-12-31
NZ519799A (en) 2004-04-30
DE60124221D1 (de) 2006-12-14
EA200200791A1 (ru) 2002-12-26
JP2003520842A (ja) 2003-07-08
US20030032670A1 (en) 2003-02-13
HUP0204150A2 (hu) 2003-04-28
ATE344235T1 (de) 2006-11-15
KR20020073183A (ko) 2002-09-19
PT1250313E (pt) 2007-01-31
ES2273804T3 (es) 2007-05-16
DE60124221T2 (de) 2007-09-13
CA2397758A1 (en) 2001-08-02
HK1051030A1 (zh) 2003-07-18
EG24065A (en) 2008-05-08

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