CN1140710A - N，n-二乙基-8，8-二丙基-2-氮杂螺[4.5]癸烷-2-丙胺马来酸氢盐 - Google Patents

N，n-二乙基-8，8-二丙基-2-氮杂螺[4.5]癸烷-2-丙胺马来酸氢盐 Download PDF

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CN1140710A
CN1140710A CN96110820A CN96110820A CN1140710A CN 1140710 A CN1140710 A CN 1140710A CN 96110820 A CN96110820 A CN 96110820A CN 96110820 A CN96110820 A CN 96110820A CN 1140710 A CN1140710 A CN 1140710A
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R·E·达格
C·W·格拉迪
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Abstract

一种改进的免疫调节剂——N，N-二乙基-8，8-二丙基-2-氮杂螺[4.5]癸烷-2-丙胺的马来酸氢盐。

Description

N，N-二乙基-8，8-二丙基-2-氮杂螺[4.5]癸烷 -2-丙胺马来酸氢盐
本发明涉及改进的免疫调节剂N，N-二乙基-8，8-二丙基-2-氮杂螺[4.5]癸烷-2-丙胺的马来酸氢盐。该化合物具如下结构式I：
Figure A9611082000031
本发明化合物可用作免疫调节剂，尤其可用来治疗类风湿性关节炎。
关于N，N-二乙基-8，8-二丙基-2-氮杂螺[4.5]癸烷-2-丙胺及其药学上可接受的盐、水合物和溶剂化物可用作免疫调节剂、特别是用来治疗类风湿性关节炎的内容在美国专利第4,963,557号上已被公开，本文参考引用其全部内容。在美国专利4963557号中所述的药学上可接受的盐中特别优选的且其中制备的唯一盐形式是二盐酸盐。N，N-二乙基-8，8-二丙基-2-氮杂螺[4.5]癸烷-2-丙胺(下文中的化合物A)和化合物A的二盐酸盐(N，N-二乙基-8，8-二丙基-2-氮杂螺[4.5]癸烷-2-丙胺二盐酸盐--下文中的化合物B)可依照例如美国专利第4963557号中所述方法来制备。
现已惊人地发现化合物A的马来酸氢盐形式(N，N-二乙基-8，8-二丙基-2-氮杂螺[4.5]癸烷-2-丙胺马来酸氢盐--下文中的化合物C)具有优于二盐酸盐的许多优点。该马来酸氢盐尽管与二盐酸盐一样溶解性强，但在制剂前尤其在压片前散装贮存时更稳定。而二盐酸盐具吸湿性，所以在贮存过程中吸收水分。化合物C的较低的吸湿性能是非常重要的，因为如果该化合物的重量部分由于水合作用而增加，则会影响制剂和分析过程中、尤其是在压片中称量散装化合物的准确性。所以，要求恒定的分析结果以确保提供恰当量的活性药物。剂量的准确是致关重要的，因为该药物在小剂量下即有效。
尽管化合物B完全可用作免疫调节剂，但化合物C还具易合成的优点，适宜于更精确的制剂操作，尤其是压片操作，并且具很低的吸湿性，这导致较强的物理稳定性和较易于分析药物的含量。
本发明化合物--化合物C可用作免疫调节剂，尤其用来治疗类风湿性关节炎。化合物C(活性成分)可以常规剂型来使用；所述常规剂型按照现有技术，例如美国专利第4963557号中所述技术，将化合物C与常规药学上可接受的载体或稀释剂混合制成。给药途径可以是口服、非胃肠道或局部给药。其中所述非胃肠道给药途径包括静脉、肌内、皮下、鼻内、直肠内、阴道内或腹膜内给药。非胃肠道给药的皮下和肌内形式通常是优选的。日口服剂量规范以约0.01～10mg/kg总体重为好，以约0.1～1mg/kg总体重为最佳。每个口服剂量单位最好含活性成分的量为约0.1～100mg。日非胃肠给药剂量规范以约0.01～10mg/kg总体重为好，以约0.1～1mg/kg总体重为最佳。每个非胃肠道剂量单位最好含所述活性成分的量为约0.1～100mg。日局部给药剂量规范优选每个给药部位为约1～100mg。以上剂量为以游离碱表示的N，N-二乙基-8，8-二丙基-2-氮杂螺[4.5]癸烷-2-丙胺的优选量。本领域技术人员应知道化合物C单剂的最适剂量和每次剂量的间隔时间将由待治疗疾病的性质和程度、剂型、给药途径和给药部位和待治疗病人的具体情况所决定，该最适剂量可用常规技术来确定。本领域技术人员还知道最佳疗程即在确定的一段时间内每日给与化合物C的剂量的数目可由本领域技术人员利用常规的疗程确定试验来确定。
一般地说来，本发明化合物按照如下方法来制备：将碱--N，N-二乙基-8，8-二丙基-2-氮杂螺[4.5]癸烷-2-丙胺溶解于适当的有机溶剂例如脱氧(dexoygenated)合乙酸乙酯中，接着加入2当量或2个以上当量的马来酸。将本发明化合物滤出，并在真空下干燥或在加温下在空气中干燥。
马来酸，99％纯度，购自Aldrich Chemical Company，Milwaukee，Wisconsin。
下列实施例进一步举例说明本发明。这些实施例对上面所述的和下述的要求保护的本发明的范围将没有限制。
                      实施例1
N，N-二乙基-8，8-二丙基-2-氮杂螺[4.5]癸烷-2-丙胺马来酸氢盐的制备
Figure A9611082000051
将含N，N-二乙基-8，8-二丙基-2-氮杂螺[4.5]癸烷-2-丙胺的458g带有残留溶剂的油状物粗品[经HPLC分析，其纯度为89.1％(重量)，即408g，1.21mol纯化合物]置于12L三颈玻璃瓶中并溶于脱氧合乙酸乙酯(6.9L)中；所述玻璃瓶在正氮气压下并装配有空气驱动搅拌器。将马来酸(281.9g，2.43mol)加到该剧烈搅拌的溶液中。将该浆液在环境温度搅拌3小时，然后滤出白色固体。用乙酸乙酯(500ml)洗涤该白色固体，并将其在高真空下干燥120小时，得到目标化合物667g(1.17mol，96.7％)。将该物质用带18R筛网的锥形磨(Quadro)研磨，得到629.5g(91.2％)的目标化合物：mp141-142℃；IR(KBr)3400，3100-3000，3000-2800，2679，1646，1584，1504，1386，1367，1194，876，和864cm-1；NMR(CDCl3，360MHz)δ0.88(s，6H)，1.18(s，8H)，1.26(m，4H)，1.33(t，6H，J＝7.9，10.9Hz)，1.52(m，4H)，1.93(t，2H，J＝10.0，14.1Hz)，2.32(m，2H)，3.19(m，6H)，3.30(m，2H)，和6.25(s，4H)；13C-NMR(CDCl3，360MHz)δ8.4，14.9，16.1，20.7，31.7，32.5，34.0，35.2，38.8，42.3，46.6，48.7，52.6，52.9，63.7，135.7，和169.3.元素分析计算值C22H44N2-2(C4H4O4)63.35 C，9.22 H，4.93 N实测值63.17 C，9.28 H，4.92 N。
比较了化合物B和化合物C的物理性质。
                    实施例2
                      熔点
化合物B和化合物C的熔点列于下表1中。
              表1
    化合物B     240-245℃分解
    化合物C     141-142℃
                     实施例3
                     吸湿性
利用带有相应软件程序的综合微量天平系统(IntegratedMicrobalance System)MODEL MB 300G(VTI Corporation，Hialeah，Florida)分别测试化合物B和化合物C的吸湿率。在同样参数下分析两个化合物，参数列于下表2(a)中。为进行比较，将对两个化合物的测定结果汇总于下表2(b)中。
                  表2(a)
           综合微量天平系统为
          化合物B和C设定的参数样品重量：                    约10mg干燥温度：                      60℃加热速率：                      10℃/min平衡标准，wt.：                  6Ug平衡标准，％wg.：              200％of wg平衡标准，时间：               240min取样间隔：                       2min实验温度：                      25℃％相对湿度，开始：              10％％相对湿度，最高：             100％％相对湿度，跨距：               5％平衡标准，wg.：                  6Ug.取样间隔：                       2minDES.CUT-OFF：                    0％相对湿度收集数据间隔：                   3min.
           表2(b)
            吸湿序号    ％相对湿度    化合物B      化合物C
                ％重量增加    ％重量增加1            0          0            02            10         0.20         -0.213            15         1.81         -0.184            20         2.17         -0.085            25         2.84         -0.126            30         3.74         -0.087            35         3.15         -0.088            40         3.30         -0.089            45         4.74         -0.0510           50         5.49         -0.0411           55         9.07         0.0412           60         9.26         0.113           65         9.50         0.1814           70         15.47        0.4115           75         31.30        0.5616           80         36.53        0.8917           85         44.16        1.7018           90         -            5.3719           95         -            42.88
                     实施例4
                    相对溶解度
在三种不同系统：水、0.1 HCl和甲醇中测定了化合物B和化合物C的溶解度。数据汇总于下表3中。
                        表3
溶剂                 化合物Bmg/ml            化合物Cmg/ml
水                       ＞100                 ＞100
0.1％HCl                 ＞100                 ＞100
甲醇                     ＞100                 ＞100
在本发明范围内，本发明包括含作为活性成分的化合物C以及药学上可接受的稀释剂或载体的药用组合物。本发明的化合物可通过口服或非胃肠道途径来使用，并可被制成适宜各种使用途径的剂型，包括胶囊、片剂、丸剂、粉剂和颗粒剂。在这样的固体剂型中，将活性化合物与至少一种惰性稀释剂例如蔗糖、乳糖或淀粉混合。按照常规，口服剂型也可含除惰性稀释剂外的附加物质，例如润滑剂如硬脂酸镁；glidants如胶体二氧化硅；抗氧化剂如二叔丁对甲酚。在胶囊剂、片剂和丸剂情况下，剂型中也可含缓冲剂。此外，片剂和丸剂还可制备成缓释的或包肠溶衣的片剂和丸剂。
尽管可使用非水性混悬乳剂，但按照本发明供非胃肠道使用的制剂包括灭菌水溶液。这样的剂型还可含有下列辅料如：防腐剂、润湿剂、渗透剂、缓冲剂、乳化剂和分散剂。可采用例如下列方法将制剂来菌：用除菌滤器过滤，在该组合物中加入灭菌剂，辐照该组合物或加热该组合物。
下列实施例进一步说明作为本发明特征的药用组合物。
                        实施例5
                     片剂组合物
将乳糖、微晶纤维素、淀粉羟基乙酸钠、硬脂酸镁和化合物C按照下表4中所示比例混合。然后将该混合物压制成片。
                      表4
成分                            mg.
N，N-二乙基-8，8-二丙基         8.45
-2-氮杂螺[4.5]癸烷-2-丙胺马来酸氢盐微晶纤维素                      112乳糖                            70淀粉羟基乙酸钠                  8硬脂酸镁                        2
                 实施例6
          非胃肠道注射用组合物
将5.0mg N，N-二乙基-8，8-二丙基-2-氮杂螺[4.5]癸烷-2-丙胺的马来酸氢盐搅拌下溶于1.0ml生理盐水中制得化合物C的注射剂。
尽管上面举出了本发明的优选实施方案，但应当懂得，本发明并不局限于本文所公开的刻板的说明，并对来自下列权利要求范围内的所有变更保留权利。

Claims (4)

1.化合物N，N-二乙基-8，8-二丙基-2-氮杂螺[4.5]癸烷-2-丙胺的马来酸氢盐。
2.含N，N-二乙基-8，8-二丙基-2-氮杂螺[4.5]癸烷-2-丙胺的马来酸氢盐和药学上可接受的载体或稀释剂的药用组合物。
3.进行免疫调节的方法，它包括给与需要这种治疗的患者免疫调节有效量的N，N-二乙基-8，8-二丙基-2-氮杂螺[4.5]癸烷-2-丙胺的马来酸氢盐。
4.权利要求3的方法，其中所述患者是需要类风湿性关节炎的治疗的病人。
CN96110820A 1995-07-13 1996-07-12 N,n－二乙基－8,8－二丙基－2－氮杂螺[4.5]癸烷－2－丙胺二马来酸盐 Expired - Fee Related CN1067378C (zh)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1293054C (zh) * 2000-08-08 2007-01-03 第一制药株式会社 双环化合物的制备方法和中间体
WO2014177011A1 (zh) * 2013-04-28 2014-11-06 齐鲁制药有限公司 二氢吲哚酮衍生物的二马来酸盐及其多晶型物

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NO306672B1 (no) 1999-12-06
SK281254B6 (sk) 2001-01-18
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CA2181006C (en) 2007-04-03
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TR199600579A2 (tr) 1997-01-21
CZ203696A3 (en) 1997-03-12
EP0753512B1 (en) 1998-03-18
NO962931L (no) 1997-01-14
CA2181006A1 (en) 1997-01-14
PL191019B1 (pl) 2006-03-31
TW419462B (en) 2001-01-21
BG100710A (bg) 1997-03-31
KR970069987A (ko) 1997-11-07
CN1067378C (zh) 2001-06-20
RO117376B1 (ro) 2002-02-28
MA23936A1 (fr) 1997-04-01
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