CN1310885C - 4－氟－2－氰基吡咯烷衍生物苯磺酸盐 - Google Patents
4－氟－2－氰基吡咯烷衍生物苯磺酸盐 Download PDFInfo
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Abstract
本发明涉及一种(2S，4S)-2-氰基-4-氟-1-[(2-羟基-1，1-二甲基)乙氨基]乙酰吡咯烷·苯磺酸盐，其具有优良的DPPIV抑制活性，并同时具有稳定性等作为药物所必备的性质。本发明能够容易地获得高纯度且均一的结晶化合物，并具有优良的固体稳定性。
Description
技术领域
本发明涉及4-氟-2-氰基吡咯烷衍生物苯磺酸盐。
背景技术
二肽基肽酶IV(DPPIV)是丝氨酸蛋白酶的一种，广泛地分布于肾脏、肝脏等组织和血浆中，与各种生理活性肽的代谢有关。
作为DPPIV抑制性化合物，已知(2S，4S)-2-氰基-4-氟-1-[(2-羟基-1，1-二甲基)乙氨基]乙酰吡咯烷(WO02/38541)。但是游离体的固体稳定性差，该申请中所公开的与无机酸所成的盐和有机酸所成的盐化合物，具有固体稳定性、在潮湿环境下稳定性差，且合成方面存在困难等缺点。
本发明提供一种具有优良的DPPIV抑制活性、并同时具有稳定性等作为药物所必备的性质的4-氟-2-氰基吡咯烷衍生物。
发明内容
本发明者们为实现上述目的，对4-氟-2-氰基吡咯烷衍生物进行了各种研究，结果发现通过制成苯磺酸盐能够获得优选的稳定的化合物，从而完成了本发明。
即本发明为式(I)
表示的(2S，4S)-2-氰基-4-氟-1-[(2-羟基-1，1-二甲基)乙氨基]乙酰吡咯烷·苯磺酸盐。
实施本发明的最佳方式
本发明的苯磺酸盐通过以下方法制得：将按照WO02/38541所述的方法获得的(2S，4S)-2-氰基-4-氟-1-[(2-羟基-1，1-二甲基)乙氨基]乙酰吡咯烷溶于适当的溶剂中，将苯磺酸或其水合物直接或以溶解的状态进行混合，过滤出随后的析出物或者加入不良溶剂后的析出物，即为目标化合物。本发明化合物通过上述方法，可以容易地获得结晶性优良、且与其它盐化合物(例如甲苯磺酸盐)相比容易获得均一的晶型。此外，对于与通常药物制造时所用的添加剂混合时的稳定性，可以制备更加稳定的组合物。
本发明化合物可以在机体内抑制的二肽酶IV，因而能够增强胰岛素作用，从而改善糖代谢，此外，还能产生神经肽Y的代谢抑制、T细胞的活化抑制、癌细胞向内皮的粘附抑制、防止HIV病毒进入淋巴细胞的作用。
因此，本发明提供上述药物，用于预防或治疗通过抑制二肽酶IV能够改善的疾病或状况，例如糖尿病(特别是II型)，免疫疾病，关节炎、肥胖症、骨质疏松症、葡萄糖耐量损伤的状态，良性***肥大、皮肤病等。
作为用于免疫疾病的药物，可以列举组织移植中的免疫抑制剂；例如肠炎、多发性硬化病、慢性关节风湿病(RA)的各种自身免疫症中细胞因子释放抑制剂、通过防止HIV侵入T-细胞而预防和治疗AIDS所使用的有效药物、防止转移，特别是防止***或***肿瘤向肺部转移的药物等。
本发明药物可以通过全身或局部口服或直肠内、皮下、肌内、静脉内、经皮等非口服途径给药。
本发明化合物为了用作为药物，可以是固体组合物、液体组合物以及其它组合物中的任意一种形式，并根据需要选择最合适的形式。本发明的药物可以通过在本发明的化合物中混合药学上可接受的载体而制得。具体地说，可以通过加入常用的赋形剂、填充剂、粘合剂、崩解剂、包衣剂、糖衣剂、pH调节剂、溶解剂或者水性或非水性溶剂等，并通过常规的制剂技术，配制成片剂、丸剂、胶囊剂、颗粒剂、粉末剂、散剂、溶液剂、乳剂、混悬剂、注射剂等。
此外，可以通过使本发明化合物与α、β或γ-环糊精或者甲基化环糊精等形成包合物而制成制剂。
本发明的化合物的给药量根据疾病、症状、体重、年龄、性别、给药途径等而不同，对于成年人，在口服的情况下，优选为约1～约1000mg/人/日，更优选约10～约200mg/人/日，其可以一日一次或者分几次给药。
进一步通过参考例、实施例、试验例对本发明进行说明。
参考例1
(2S，4S)-2-氰基-4-氟-1-[(2-羟基-1，1-二甲基)乙氨基]乙酰吡咯烷·盐酸盐的合成
向(2S，4S)-2-氰基-4-氟-1-[(2-羟基-1，1-二甲基)乙氨基]乙酰吡咯烷(5.00g)的甲醇(75ml)混悬液中，加入4M盐酸(醋酸乙酯溶液，6.17ml)后，即形成透明的溶液。向该溶液中加入二异丙醚(300ml)并进行搅拌，滤出析出的粉末，得到无色粉末目标化合物(5.47g)。
熔点：197℃-198℃
参考例2
(2S，4S)-2-氰基-4-氟-1-[(2-羟基-1，1-二甲基)乙氨基]乙酰吡咯烷·甲磺酸盐的合成
向(2S，4S)-2-氰基-4-氟-1-[(2-羟基-1，1-二甲基)乙氨基]乙酰吡咯烷(0.15g)的甲醇(0.92ml)混悬液中，加入甲磺酸(0.042ml)的甲醇(0.08ml)溶液后，即形成透明的溶液。在搅拌的同时将此溶液滴加到二异丙醚(5ml)中，滤出析出的粉末，得到无色粉末目标化合物(0.20g)。
熔点：179℃-180℃
实施例1
(2S，4S)-2-氰基-4-氟-1-[(2-羟基-1，1-二甲基)乙氨基]乙酰吡咯烷·苯磺酸盐的合成
(1)(2S，4S)-2-氰基-4-氟-1-[(2-羟基-1，1-二甲基)乙氨基]乙酰吡咯烷
将2-氨基-2-甲基-1-丙醇(0.54g)溶于四氢呋喃(7.5ml)和乙醇(2.5ml)的混合溶剂中，在冰冷却下加入(2S，4S)-1-溴乙酰-2-氰基-4-氟吡咯烷(0.71g)，在室温下搅拌1小时。滤出析出的晶体，得到无色固体目标化合物(0.36g)。进一步将滤液通过硅胶柱层析(展开溶剂：氯仿∶甲醇∶25％氨水＝300∶10∶1)进行精制，得到目标化合物(0.22g)。
(2)(2S，4S)-2-氰基-4-氟-1-[(2-羟基-1，1-二甲基)乙氨基]乙酰吡咯烷·苯磺酸盐
将(2S，4S)-2-氰基-4-氟-1-[(2-羟基-1，1-二甲基)乙氨基]乙酰吡咯烷(20g)加热下溶解于甲醇(300ml)中，加入苯磺酸1水合物(15.2g)的甲醇(30ml)溶液后，立即析出粉末。向此混悬液中加入二异丙醚(330ml)后，滤出粉末，得到无色粉末目标化合物(31.5g)。
熔点：220-221℃
试验例1[在增湿下的重量变化试验]
在微管(直径8mm，长50mm)中称取各样品10.0mg，置于装满水的干燥器中，不与水接触。将干燥器室温放置。随着时间进行状态观察和重量测定，重量变化用百分率表示。
(重量变化和状态变化)
表1
| 第一天 | 第二天 | 第三天 | |
| 参考例1的化合物 | +44％潮解 | - | - |
| 参考例2的化合物 | +28％ | +71％潮解 | - |
| 实施例1的化合物 | ±0％ | ±0％ | ±0％无外观变化 |
参考例1的盐酸盐和参考例2的甲磺酸盐吸湿潮解，而实施例1的苯磺酸盐重量没发生变化，没有潮解。
试验例2[固体稳定性试验]
精确称取各样品约1mg，在升温条件下(70℃)放入避光(铝箔)密封的螺口试管中，以及在高温高湿条件下(40℃·75％RH)放入避光(铝箔)开口的螺口试管中进行保存。按照以下过程进行药物残留率测定。在所规定的保存时期结束后向试管中加入10mL HPLC流动相，溶解后通过HPLC进行定量测定，将所得值与高温或高温·高湿前的初始值进行面积对比，求出残留率。
*HPLC条件
色谱柱：CAPCELL PAKUG120，5μm，φ4.6×150mm(SHISEIDO)
柱温：40℃
检测：紫外分光光度计(检测波长：210nm)
流速：1.0ml/min
进样量：10μL
流动相：水/乙腈/磷酸/SDS(700∶300∶1∶2)
(药物残留率)
表2
| 70℃，3天 | 40℃，75％，1个月 | |
| 参考例1的化合物 | 97.0％ | 92.6％ |
| 参考例2的化合物 | 95.5％ | 95.9％ |
| 实施例1的化合物 | 99.3％ | 99.6％ |
参考例1的盐酸盐和参考例2的甲磺酸盐在任何条件下药物的残留率都在97％或以下，而实施例1的苯磺酸盐在任何条件下均在99％或以上。
试验例3[与添加剂配合变化试验]
按照Serajuddin A.T.M.等的报告(J.Pham.Sci.，88，696-704，1999)进行。以混合物A(原药10mg，结晶纤维素68mg，硬脂酸镁2mg)或混合物B(原药10mg，乳糖68mg，硬化油2mg)的计量，在螺口试管中对原药和添加剂进行称量后，在回转圆筒混合器(MIX-ROTAR VMR-5，井内盛荣堂)中混合1小时。混合物A中不添加任何物质，混合物B中加入精制水16μL，用涡流混合器(TOUCH MIXER MT-31，ヤマト科学)进行搅拌。将其在密封·完全避光状态下于65℃保存1周，测定保存后的含量，求出残留率。
含量按照下述过程求得。向保存后的样品中加入50％甲醇10ml，为了分散和萃取，用超声波(使用BRANSON公司的BRANSONIC 5200)照射30分钟，然后利用振荡器振荡1小时，向容量瓶中移入50ml此液体。用50％甲醇进行洗净，定容。将其进一步用超声波混匀30分钟。将此液体用0.45μm的滤膜过滤后取5ml，在10ml的容量瓶中用50％甲醇进行定容，以此液作为样品溶液，通过HPLC进行定量。HPLC条件与试验例2相同。
(药物残留率)
| 混合物A | 混合物B | |
| 参考例2的化合物 | 91.6％ | 74.5％ |
| 实施例1的化合物 | 99.1％ | 91.6％ |
混合物A的情况，对于参考例2的甲磺酸盐，药物的残留率下降到了91.6％，而对于实施例1的苯磺酸盐，几乎没有发现这种下降。此外，对于甲磺酸盐残留率下降至74.5％的混合物B的情况，苯磺酸盐也显示出90％以上的残留率。
实施例1的化合物在加入制造药物时所用的添加剂时也很少劣化，证实能够提供稳定的配合组合物作为药物。
产业实用性
本发明化合物能够容易地获得高纯度均一的晶型，在高湿度条件下具有优良的稳定性。因此，在制造时能够消除粉末附着于机械、流动性下降等，能够稳定地供给含此化合物的药物。并且，本化合物由于固体稳定性优良，不存在外观变化、晶型转变等问题，在作为药物的制备时，能够耐受严酷的条件，添加添加剂时也能够长期保持品质。
Claims (6)
1、(2S，4S)-2-氰基-4-氟-1-[(2-羟基-1，1-二甲基)乙氨基]乙酰吡咯烷·苯磺酸盐。
2、一种药物组合物，其包含权利要求1所述的苯磺酸盐和可药用载体。
3、权利要求1所述的苯磺酸盐或权利要求2所述的药物组合物在制备用于预防或治疗通过抑制二肽酶IV能够改善的疾病或状况的药物中的用途。
4、权利要求3所述的用途，其中所述疾病或状况为糖尿病、免疫疾病、关节炎、肥胖症、骨质疏松症、葡萄糖耐量损伤的状态、良性***肥大和皮肤病。
5、权利要求3所述的用途，其中所述疾病或状况为糖尿病。
6、权利要求3所述的用途，其中所述疾病或状况为免疫疾病。
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| ZA200802857B (en) | 2005-09-14 | 2009-09-30 | Takeda Pharmaceutical | Dipeptidyl peptidase inhibitors for treating diabetes |
| KR101368988B1 (ko) | 2005-09-16 | 2014-02-28 | 다케다 야쿠힌 고교 가부시키가이샤 | 디펩티딜 펩티다제 억제제 |
| WO2007112347A1 (en) | 2006-03-28 | 2007-10-04 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
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| TW200838536A (en) | 2006-11-29 | 2008-10-01 | Takeda Pharmaceutical | Polymorphs of succinate salt of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethy]-4-fluor-benzonitrile and methods of use therefor |
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| CL2008003653A1 (es) | 2008-01-17 | 2010-03-05 | Mitsubishi Tanabe Pharma Corp | Uso de un inhibidor de sglt derivado de glucopiranosilo y un inhibidor de dppiv seleccionado para tratar la diabetes; y composicion farmaceutica. |
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| AR077642A1 (es) | 2009-07-09 | 2011-09-14 | Arena Pharm Inc | Moduladores del metabolismo y el tratamiento de trastornos relacionados con el mismo |
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| WO2012135570A1 (en) | 2011-04-01 | 2012-10-04 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
| US20140066369A1 (en) | 2011-04-19 | 2014-03-06 | Arena Pharmaceuticals, Inc. | Modulators Of The GPR119 Receptor And The Treatment Of Disorders Related Thereto |
| WO2012145604A1 (en) | 2011-04-22 | 2012-10-26 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
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