CN1161363C - 用于治疗骨质疏松症的双膦酸盐 - Google Patents
用于治疗骨质疏松症的双膦酸盐 Download PDFInfo
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- XQRLCLUYWUNEEH-UHFFFAOYSA-N diphosphonic acid Chemical class OP(=O)OP(O)=O XQRLCLUYWUNEEH-UHFFFAOYSA-N 0.000 title 1
- XQRLCLUYWUNEEH-UHFFFAOYSA-L diphosphonate(2-) Chemical compound [O-]P(=O)OP([O-])=O XQRLCLUYWUNEEH-UHFFFAOYSA-L 0.000 claims abstract description 29
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- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
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Abstract
本发明涉及双膦酸盐，或双膦酸与直链、支链取代和未取代的、环状、杂环和芳族氨基醇形成的盐，以及它们在治疗骨质疏松症中的应用，本发明还涉及用于治疗骨质疏松症的含有至少一种作为有效成分的双膦酸盐的药物组合物。
Description
发明目的
本发明的目的是提供双膦酸的盐和双膦酸盐以及它们的制备方法。
本发明的另一个目的是提供上述双膦酸的盐和双膦酸盐在治疗骨质疏松症中的应用。
本发明的又一个目的是提供含有上述双膦酸的盐和双膦酸盐作为有效成分的药物组合物以及它们在治疗骨质疏松症中的应用。
现有技术
众所周知，骨质疏松症是一种骨骼疾病，其特点是骨组织的紊乱和损伤，并伴随有骨骼脆性的增加且易患骨折。
例如，据报道在美国受这种疾病折磨的人超过2,500万人，并且每年导致1,300,000例骨折。
因此社会耗费非常高，每年要耗费100多亿美元。同样的数字在欧洲和日本也有报道。老年人是这种疾病的高发人群。不幸地是这个问题随着人口老龄化的不断加剧也正变得越来越严重。在未来的六十年内骨折发生率预计将至少增加三倍。妇女比男人要更易遭受影响，尤其是在绝经期后的头五年。
目前，从治疗的角度出发，或者是采用如Melmon&Morrelli在临床药物学：治疗学的基本原理，497(1992)，N.Engl.J.Med.306，446(1982)中报道的采用氟化物的单独疗法，或者是结合采用钙、氟化物和雌激素的结合疗法，据报道，与单独疗法相比，这种结合疗法有一些优点。
此外，另一系列用于治疗骨质疏松症的化合物包括双膦酸盐；这些药物最大多数口服，但是除了较差的吸收效果(1-5％的剂量)这一不可解决的问题以外，作为主要的副作用它们也导致中度的食道炎和胃肠功能紊乱。
为了克服这一不便，在寻找新化合物的过程中已经进行了几个临床研究，与已有的化合物相比这些新化合物同时具有更好耐药性的高药理活性和提高的生物利用率。
例如，美国专利US 4,621,077描述了双膦酸及其盐类在治疗尿石病和抑制骨吸收中的应用；也就是说，报道了所述的双膦酸或它的相应钠盐的生物活性。然而，这些化合物的吸收度即生物利用率非常低，并且正是由于这一原因，为了在体内获得有效成分的有效浓度，就不得不服用高的剂量，这样就导致胃肠的不良反应，从而使胃肠耐药性更差。
JP 06,100,576(94,100,576)公开了1，3，5(10)-三烯甲雌醇核-3，17β-二醇17-(3，3-双膦酸)丙酸酯或它的盐类在治疗和预防骨质疏松症中作为有用的试剂。
发明目的
本发明的目的就是制备当口服时具有提高的生物利用率的可利用双膦酸盐。
本发明的目的也是制备与那些已知并可得到的化合物相比，治疗骨质疏松症更有效，同时可使食道和胃肠副作用的发生率更低的可利用双膦酸盐。
本发明的另一个目的是制备既可口服又可静脉注射的可利用双膦酸盐。
本发明的另一个目的是制备与已知的并且现在应用于医疗实践中药物相比，在治疗骨质疏松症中显示出提高的治疗指数的可利用双膦酸盐。
本发明的目的也是提供一种可用于制备双膦酸盐的有效方法。
本发明的目的也是提供一种含有至少一种双膦酸盐作为有效组分、容易服用、具有好的被耐受性并且能有高治疗指数的可利用药物配方。
发明描述
这些和下面要详述的具有其他优点的其它目的是通过双膦酸盐或双膦酸和直链、支链、取代和非取代、环状、杂环、芳族氨基醇衍生物形成的盐而达到的。所述的双膦酸盐具有如下通式：
其中，R＝R1或R≠R1并且R和R1选自H、OH、Cl、直链或支链、取代或非取代烷基、直链或支链、取代或非取代的亚烷基链，或从具有下述结构式的化合物中选取：
更特别的是，根据本发明，上述氨基醇选自直链和支链氨基醇，并且具体地从具有下述结构式的化合物中选取：
H2N-CH2CH2OH (XVI)
(CH3)3N+-CH2CH2OH (XX)
根据本发明，上述氨基醇是环状和杂环氨基醇，并且从具有下述结构式的化合物中选取：
此外，根据本发明，上述通式(I)定义的取代的亚烷基链等同于下述通式：
其中n是1-6，R2＝R3或R2≠R3，并且R2和R3选自H、直链或支链、环状、取代或非取代的烷基，或R2和R3表示含氮原子N的脂肪族或芳族杂环。
根据本发明，通式(I)中定义的取代亚烷基链也等同于如下通式：
其中n是1-6，并且R4选自具有下述结构式的基团：
根据本发明，特别有趣的是由双膦酸和支链氨基醇得到的盐，双膦酸通式为(I)，其中R≠R1，R为OH，R1选自分子式为(X)的取代直链亚烷基链，其中n＝3，根据结构式(XXVI)，R2和R3为H，或者该双膦酸为4-氨基-1-羟基丁烷-1，1-双膦酸(阿伦膦酸)。
支链氨基醇的结构式为(XIX)或2-氨基-2-羟甲基-1，3-丙二醇(氨丁三醇)。
根据本发明，上述盐通过双膦酸和氨基醇间相应基团以不同的摩尔比形成，这取决于制备步骤，同时它们可以便利地应用于治疗骨质疏松症中。上述摩尔比的变化范围为1∶1-1∶2(双膦酸∶氨基醇)。
双膦酸和氨基醇的一些衍生物是公知的。例如可从JP0953193[9753193](用作金属表面去污)；FR2142051(为了降低接触所述水的金属表面上的腐蚀用作循环水的调节剂)获知；EP292190公开了包含有双膦酸盐(例如双膦酸与氨丁三醇的盐)的导电性涂料组合物。US4830779公开了一种含有双膦酸衍生物(双膦酸与氨丁三醇形成的盐)的导电性树脂组合物，而US5389261公开了一种还原阳离子交换树脂的方法，其包括将一种有机盐(一种链烷醇胺和一种双膦酸衍生物形成的盐)的水溶液穿过所述树脂的步骤。EP781804公开了一种包含有一种双膦酸或例如其与氨丁三醇的盐的高吸收聚合物组合物，而DD273650公开了包含具有还原性能的双膦酸衍生物的三乙醇胺盐的某些组合物。现有技术的双膦酸盐的药物动力学曲线不令人满意，其特点是胃肠道的吸收非常差，系统生物利用率为口服剂量的1-5％。吸收剂量的大约50％在24小时中随尿排出，而剩下的剂量为骨组织吸收并随后缓慢地消失。而未吸收的双膦酸盐随粪便排出。
这种特性必定是由产品的物理化学性能(高度水溶性，几乎不透过脂肪膜)引起的。这样，有必要口服比生物利用率高得多的剂量并在目标位置(骨骼)中保持有治疗效果的浓度，这最终增加了局部胃肠的副作用例如恶心和腹泻。
本发明的双膦酸盐由于较低的溶解度和氨基醇的物理化学性能，与公知的双膦酸盐(钠盐)相比，双膦酸盐的特点是较低的水溶性和增长的脂肪溶解性。
这些特点在透过生物膜的吸收过程中赋予显著的优点，因此提高了生物利用性。
另外，本发明还提供治疗骨质疏松症的药物组合物，它含有由通式(I)的双膦酸和支链氨基醇之间形成的盐作为有效成分。
该治疗骨质疏松症的药物组合物(以下也简称作本发明的双膦酸盐)在治疗骨质疏松症的预期用途中的确表现出预期的药物毒理学曲线。
本发明的双膦酸盐在刺激骨骼生长上具有好的效果，这可能是由于由反应性种制得的除去了毒性基团的氨基醇的公知性能。本发明的双膦酸盐可容易地由非胃肠给药或静脉注射和口服。对于后者，使用能够控制有效成分释放的药物体系是尤其有利的。这些体系包括脂质体、聚乙二醇脂肪酸酯体(niosomes)和类似基体，且可包括使有效成分受控释放的合适载体。
本发明的双膦酸盐便利地通过通式(I)的双膦酸溶液或悬浮液与溶解在适当溶剂中的氨基醇的反应来制备；然后用公知方法纯化由冷却反应液得到的双膦酸和氨基醇之间的反应产物(盐)。作为本发明一个非限定性的实例，下面参考结构式(XXVI)的双膦酸与结构式(XIX)的氨基醇反应得到的盐的制备方法，描述某些实施例：
实施例1
将4-氨基-1-羟基丁烷-1，1-双膦酸(阿伦膦酸1g，4.016mmoles)溶解在20ml CH2Cl2/甲醇(9∶1)中。搅拌下，将溶解在5ml CH2Cl2/甲醇(9∶1)中的2-氨基-2-羟甲基-1，3-丙二醇(氨丁三醇，486mg，4.016mmoles)加入到阿伦膦酸中。将形成的白色沉淀物过滤并在真空下干燥。
得到1.263g阿伦膦酸氨丁三醇盐(alendronate trometamine salt)，产率85％。
实施例2
将4-氨基-1-羟基丁烷-1，1-双膦酸(阿伦膦酸1g，4.016mmoles)悬浮溶解在20ml水中。搅拌下，将2-氨基-2-羟甲基-1，3-丙二醇(氨丁三醇，486mg，4.016mmoles)加入到阿伦膦酸的水溶液中。固体迅速溶解在水中，悬浮液变清，同时将PH＝4.18的反应液冷冻并冻干得到白色粉末。
得到1.480g阿伦膦酸氨丁三醇盐，产率99％。
实施例3
将4-氨基-1-羟基丁烷-1，1-双膦酸(阿伦膦酸1g，4.016mmoles)悬浮溶解在40ml水中。搅拌下，将2-氨基-2-羟甲基-1，3-丙二醇(氨丁三醇，972mg，8.032mmoles)加入到阿伦膦酸的水溶液中。固体迅速溶解在水中，悬浮液变清，同时将PH＝7.14的反应液冷冻并冻干得到白色粉末。
得到1.97g阿伦膦酸氨丁三醇盐，产率99％。
实施例4
将4-氨基-1-羟基丁烷-1，1-双膦酸(阿伦膦酸1g，4.016mmoles)悬浮溶解在5ml水中。搅拌下，将2-氨基-2-羟甲基-1，3-丙二醇(氨丁三醇，486mg，4.016mmoles)加入到阿伦膦酸的水溶液中。固体迅速溶解在水中，悬浮液变清，同时反应液PH值为4.18。将10ml异丙醇加入到反应液中并将反应液在-10℃下冷冻一夜。将形成的沉淀物过滤，用冷的异丙醇洗涤两次，然后真空下干燥。
得到743mg阿伦膦酸氨丁三醇盐，产率50％。
将实施例1、2和4中描述的本发明方法制备的产物在IR和1H-NMR谱中进行分析。
熔点为180.53℃。
1H-NMR(300Mhz)，(D2O)δ＝3.615(S6H，CH2O)；2.920(t，2H，N+-CH2，J＝6.5Hz)；1.900(m，2H，NCH2CH2CH2)；1.890(t，2H，NCH2CH2CH2，J＝6.5Hz)。
参考由结构式(XXVI)的双膦酸与结构式(XIX)的氨基醇反应得到的盐的药物配方的制备，下面描述一个非限定性的实例：
实施例5
在脂质体基体中配制阿伦膦酸氨丁三醇盐。
-氢化卵磷脂(LECINOL S-10)，20重量％
-4-氨基-1-羟基丁烷-1，1-双膦酸(阿伦膦酸)和2-氨基-2-羟甲基-1，3-丙二醇(氨丁三醇)，15重量％
(阿伦膦酸与氨丁三醇之间的比例为1∶1)
-氨丁三醇碱；1重量％
-胆甾醇；4重量％
-丙二醇；10重量％
-乙醇；1重量％
-CARBOPOL ETD 2020；0.5重量％
-Na2EDTA；0.15重量％
-NIPAGIN；0.2重量％
-PHENONIP(防腐剂)；0.3重量％
-柠檬酸；0.2重量％
-丁化羟基甲苯(BHT)；0.01重量％
-水；使总量达到100重量％
评价本发明由通式(I)的双膦酸和氨基醇反应制备的盐的药物毒理学活性，将上述实施例得到的产物阿伦膦酸氨丁三醇盐作为进行生物实验的测试化合物。
功效
进行组织培养的研究(根据A.Togari，Gen.Pharmacol
24，1133，1993中描述的方法，制备新生老鼠的刮片)。在培养的最后阶段，将加有微摩尔浓度所述产物的组织在加有0.1％Triton X-100的盐水中均化。
得到的均化物用于鉴定碱性磷酸酶(作为成骨细胞的活性指数)和N-乙酰基葡糖胺酶(作为破骨细胞的活性指数)。从10微摩尔浓度开始的测试产物表现出能够以明显的方式激活成骨细胞的活性(碱性磷酸酶)并抑制破骨细胞的活性(N-乙酰基葡糖胺酶)。
毒性
当以50mg/kg的剂量(多倍于(×300倍)人体的治疗剂量)给老鼠口服该化合物时没有发生明显的毒性症状。
生物利用率
通过以10mg/kg的剂量给老鼠口服和静脉注射该测试化合物，阿伦膦酸氨丁三醇盐进行研究，计算出平均绝对生物利用率等于8％。根据色谱分析杂志(J.of Chromatography，
533，183-193，1992)中，“通过自动柱前导出和带有荧光和电子化学检测器的高效液相色谱，提高鉴定人类血浆和尿液中的双膦酸盐阿伦膦酸盐”的方法，进行计算0-24小时尿排出的阿伦膦酸。
Claims (9)
1、一种双膦酸盐，其特征在于，它是由通式为(I)的双膦酸和支链氨基醇得到的盐，
其中R≠R1，R为OH，R1为-(CH2)3NH2，则双膦酸的结构式为(XXVI)，或者该双膦酸为4-氨基-1-羟基丁烷-1，1-双膦酸；
所述支链氨基醇的结构式为(XIX)或2-氨基-2-羟甲基-1，3-丙二醇。
2、制备权利要求1所述的双膦酸盐的方法，该方法包括如下步骤：
·将溶解或悬浮在适当溶剂中的具有通式(I)的双膦酸与选择性地溶解在适当溶剂中的氨基醇混合，
·冷却得到的混合物和/或选择性地用适当的溶剂进行处理，以得到一种双膦酸盐或由具有通式(I)的所述双膦酸和所述氨基醇形成的一种盐，
·对上述所得盐进行过滤、洗涤、选择性的提纯、和干燥。
3、根据权利要求1所述的通式(I)的双膦酸和支链氨基醇之间形成的盐在治疗骨质疏松症中的用途。
4、治疗骨质疏松症的药物组合物，它含有权利要求1所述的由通式(I)的双膦酸和支链氨基醇之间形成的盐作为有效成分。
5、根据权利要求4的药物组合物，其特征在于，它被制备用作非胃肠给药或静脉注射。
6、根据权利要求4的药物组合物，其特征在于，它包括脂质体、聚乙二醇脂肪酸酯体和使有效成分受控释放的合适载体。
7、根据权利要求4的药物组合物，其特征在于，它们具有下述组分：
-氢化卵磷脂，20重量％
-4-氨基-1-羟基丁烷-1，1-双膦酸和2-氨基-2-羟甲基-1，3-丙二醇以1∶1的比例形成的盐，15重量％
-氨基丁三醇碱；1重量％
-胆甾醇；4重量％
-丙二醇；10重量％
-乙醇；1重量％
-CARBOPOL ETD 2020；0.5重量％
-Na2EDTA；0.15重量％
-NIPAGIN；0.2重量％
-PHENONIP；0.3重量％
-柠檬酸；0.2重量％
-丁化羟基甲苯；0.01重量％
-水；使总量达到100％。
8、根据权利要求7的药物组合物，其特征在于，所述组合物是脂质体形式。
9、根据权利要求1的双膦酸盐，其特征在于，所述双膦酸与氨基醇之间的摩尔比为1∶1-1∶2。
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| US20080286359A1 (en) | 2004-05-24 | 2008-11-20 | Richard John Dansereau | Low Dosage Forms Of Risedronate Or Its Salts |
| US20080287400A1 (en) | 2004-05-24 | 2008-11-20 | Richard John Dansereau | Low Dosage Forms Of Risedronate Or Its Salts |
| US7645460B2 (en) | 2004-05-24 | 2010-01-12 | The Procter & Gamble Company | Dosage forms of risedronate |
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| JPH06100576A (ja) * | 1992-09-21 | 1994-04-12 | Kirin Brewery Co Ltd | 骨粗鬆症治療剤または予防剤 |
| JP3238304B2 (ja) * | 1995-08-11 | 2001-12-10 | 三菱重工業株式会社 | スケール溶解液 |
| JP3445426B2 (ja) | 1995-12-26 | 2003-09-08 | 花王株式会社 | 高吸水性樹脂組成物 |
-
1997
- 1997-07-08 US US09/446,617 patent/US6410782B1/en not_active Expired - Fee Related
- 1997-07-09 IT IT97MI001628A patent/IT1293305B1/it active IP Right Grant
-
1998
- 1998-07-08 DK DK98939625T patent/DK0994884T3/da active
- 1998-07-08 HU HU0004679A patent/HUP0004679A3/hu unknown
- 1998-07-08 IL IL13317298A patent/IL133172A/xx not_active IP Right Cessation
- 1998-07-08 EP EP98939625A patent/EP0994884B1/en not_active Expired - Lifetime
- 1998-07-08 AU AU88067/98A patent/AU8806798A/en not_active Abandoned
- 1998-07-08 BR BR9810561-2A patent/BR9810561A/pt not_active Application Discontinuation
- 1998-07-08 CA CA002303210A patent/CA2303210A1/en not_active Abandoned
- 1998-07-08 WO PCT/EP1998/004238 patent/WO1999002539A1/en active IP Right Grant
- 1998-07-08 DE DE69818823T patent/DE69818823T2/de not_active Expired - Fee Related
- 1998-07-08 ES ES98939625T patent/ES2207853T3/es not_active Expired - Lifetime
- 1998-07-08 KR KR10-2000-7000135A patent/KR100396036B1/ko not_active IP Right Cessation
- 1998-07-08 CN CNB988069326A patent/CN1161363C/zh not_active Expired - Fee Related
- 1998-07-08 PT PT98939625T patent/PT994884E/pt unknown
- 1998-07-08 JP JP2000502060A patent/JP3681637B2/ja not_active Expired - Fee Related
- 1998-07-08 AT AT98939625T patent/ATE251631T1/de not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| DE69818823T2 (de) | 2004-05-06 |
| IL133172A0 (en) | 2001-03-19 |
| JP3681637B2 (ja) | 2005-08-10 |
| KR20010021577A (ko) | 2001-03-15 |
| CN1261892A (zh) | 2000-08-02 |
| ATE251631T1 (de) | 2003-10-15 |
| ITMI971628A1 (it) | 1999-01-09 |
| BR9810561A (pt) | 2000-08-15 |
| DK0994884T3 (da) | 2004-02-16 |
| WO1999002539A1 (en) | 1999-01-21 |
| CA2303210A1 (en) | 1999-01-21 |
| IT1293305B1 (it) | 1999-02-16 |
| JP2001509510A (ja) | 2001-07-24 |
| ES2207853T3 (es) | 2004-06-01 |
| EP0994884A1 (en) | 2000-04-26 |
| EP0994884B1 (en) | 2003-10-08 |
| US6410782B1 (en) | 2002-06-25 |
| IL133172A (en) | 2005-03-20 |
| HUP0004679A3 (en) | 2002-04-29 |
| PT994884E (pt) | 2004-02-27 |
| DE69818823D1 (de) | 2003-11-13 |
| ITMI971628A0 (zh) | 1997-07-09 |
| KR100396036B1 (ko) | 2003-08-27 |
| AU8806798A (en) | 1999-02-08 |
| HUP0004679A2 (hu) | 2001-08-28 |
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