CN1043610C - 新的治疗剂 - Google Patents
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Abstract
一种治疗和/或预防哺乳动物，如人的肥胖症或治疗Ⅱ型糖尿病的方法，该方法包括将治疗和/或预防有效量和/或预防无毒量的化合物1(1，3-二-环丙基甲基-8-氨基黄嘌呤)给药予需要的哺乳动物。
Description
本发明涉及治疗和/或预防肥胖或治疗Ⅱ型糖尿病的方法和用于这种方法中的化合物。
欧洲专利申请公开号0389282描述了式(A)化合物：或其适合的药学上可接受的盐，其中R1和R2分别代表烷基或式(a)部分：
-(CH2)mA (a)其中m代表0或整数1,2，或3,A代表取代的或未取代的环烃基，条件是当R1代表甲基时R2不是甲基；和
R3a代表卤原子，硝基，或基团-NR4R5其中R4和R5分别代表氢，烷基或烷基羰基或R4和R5与连接它们的氮形成一个任意取代的杂环基。
EP903030930.0的例9是1,3-二环丙基甲基-8-氨基黄嘌呤(此后优选作为化合物1)。
在欧洲申请号90303093.0中特别描述了具有治疗脑血管和神经元变性疾病活性的化合物和作为提高环AMP水平的磷酸二酯酶抑制剂。
现在我们惊奇地发现化合物1可以增加能量的消耗并且也可以减少食物的吸收，因此它对于治疗哺乳动物包括人的肥胖症是很有用的。
化合物Ⅰ也显示出对于改进胰岛素敏感性是有效的因此治疗Ⅱ型糖尿病是有效的。
因此，本发明提供一种治疗和/或预防哺乳动物，如人肥胖症或治疗Ⅱ型糖尿病的方法，该方法包括将治疗和/或预防有效量和/或预防，无毒量的化合物1给药予需要的哺乳动物。
本发明也提供用于治疗和/或预防肥胖症或治疗Ⅱ型糖尿病的化合物1。
本发明的另一方面是提供一种用于治疗和/或预防肥胖症或治疗Ⅱ型糖尿病的药物组合物，该组合物包括化合物1和药学上可接受的载体。
本发明还一方面提供了化合物1用于制备治疗和/或预防肥胖症或治疗Ⅱ型糖病的药物的用途。
给药予哺乳动物可以通过口服或非肠道给药。
治疗肥胖症或Ⅱ型糖尿病的有效量根据一般的因素如哺乳动物的本性，病情的严重程度和体重来决定。然后，单位剂量通常含0.1到200mg例如5到50mg或1到20mg的化合物1。单位剂量通常以每天一次或多于一次给药，例如每天1,2,3,4,5或6次，更通常每天1-4次，因此对于70Kg成人总的日剂量通常为0.5到500mg，例如50到250mg或10到150mg，即其范围约为0.001到10mg/Kg/天，更通常1到3mg/Kg/天或0.2到2.5mg/Kg/天，例如0.7到2mg/Kg/天。
优选地，化合物1以单位剂量组合物形式给药，如单位剂量口服或非肠道组合物。
通过混合制备这种组合物并且采用适当的口服或非肠道给药，如可以是片剂，胶囊，口服液体制剂，粉剂，粒剂，锭剂，再组合粉剂，注射剂和可输注溶液或悬乳剂。口服组合物是优选的，特别是成型口服组合物，因为对于通常使用它们更方便。
口服的片剂和胶囊通常以单位剂量存在，并且含有常规赋形剂如粘结剂，填充剂，稀释剂，成片剂，润滑剂，崩解剂，着色剂，调味剂和湿润剂。片剂可根据现有技术中的已知方法进行包衣。
可用的适合的填充剂包括纤维素，甘露糖醇，乳糖和其它类似填充剂。适合的崩解剂包括淀粉，聚乙烯吡咯烷酮及淀粉衍生物如淀粉乙醇酸钠。适合的润滑剂包括例如硬脂酸镁。适合的药学上可接受的湿润剂包括月桂硫酸钠。
这些固体口服组合物可以通过常规混合，填充，成片等方法来制备。可以使用再混合操作以利用大量填充剂分散整个组合物的活性剂。当然，这种操作是常规技术。
例如，口服液体制剂可以是水溶液或油状悬浮液，溶液，乳液，糖浆或酏剂的形式，或以干产品存在，在使用前与水或其它适当的赋形剂再混合。这种液体制剂可含有常规添加剂如悬浮剂，例如山梨糖醇，糖汁，甲基纤维素，明胶，羟乙基纤维素，羧甲基纤维素，硬脂酸铝胶或氢化食用脂肪。乳化剂，例如卵磷脂，单油酸脱水山梨糖醇酯，或阿拉伯树胶；非水赋形剂(可包括食用油)，例如杏仁油，分馏椰子油，油酯如甘油酯，丙二醇，或乙醇；防腐剂，例如对-羟基苯甲酸甲酯或丙酯或山梨酸；并且如果需要要含有常规调味剂或着色剂。
口服制剂也包括常规持续释放制剂如片剂或含有肠包衣的粒剂。
对于非肠道给药，可制备含有化合物1和灭菌赋形剂的液体单位剂量形式。根据赋形剂和浓度，化合物1既可悬浮也可溶解。非肠道溶液通常通过将化合物溶解在赋形剂中并在填充到适当的小瓶或安瓿瓶及封口前过滤灭菌。将佐剂如局部麻醉剂，防腐剂及缓冲剂溶解在赋形剂中也是有利的。为了提高稳定性，可将组合物在填充到小瓶之后冷冻并真空除去水。
非肠道悬浮液也可用基本相同的方法制备，除了将化合物悬浮在赋形剂中而不是溶解，和通过在悬浮在灭菌赋形剂中之前暴露在环氧乙烷中灭菌。有利地，在组合物中也包括表面活性剂或湿润剂，以便有利化合物的均匀分布。
下面药理数据证明了在试验中化合物1的活性，该试验说明化合物对于治疗肥胖症的潜在的用途。药理数据试验步骤
试验动物是12只雄性和12只雌性Sprague-Dawley鼠(体重200-270g，约8-10周龄)。
鼠被喂SQC鼠和小鼠维持饮食号1；饮食和水可随便得到。
将温度和相对湿度分别保持在21±2℃和55±10％，亮度控制在每24小时给12小时亮光。
经过6天适应后，将动物通过分层随机分配分成两组(对照组和治疗组)，以得到平均体重大约相等的组。每组含有6只雄鼠和6只雌鼠。将鼠3个一组住在一起。
4天基准观察后，将所有动物在同一天开始给药。将所有动物给药一天一次，共10天。
将试验化合物通过管饲法以1mg/Kg/天剂量水平的1％甲基纤维素的悬浮剂对治疗组口服给药。
将动物以1ml/100g体重的恒定剂量体积进行给药。对照组动物的相同剂量体积单独给赋形剂。
食物和水的摄入每天记录。结果1．组间的体重(g)比较天
雄性 对照组 治疗组1 平均 269.3 266.8NS
％差 - -1
S.D. 9.6 4.1
(N) (6) (6)11 平均值 318.3 268.5**
％差 - -16
S.D. 13.7 12.0
(N) (6) (6)
雌性1 平均值 210.3 206.8NS
％差 - -2
S.D. 5.4 3.0
(N) (6) (6)11 平均值 227.8 211.2*
％差 - -7
S.D. 12.4 8.5
(N) (6) (6)％差在不四舍五入的数据基础上计算。对于Student″t″-试验(2-尾的)显著水平：*P＜0.05**P＜0.01NS不显著的 NT没有试验的2．组间体重增加(g)比较
对照组 治疗组天
雄性1-11 平均值 49.0 1.7**
％差 - -97
S.D. 10.1 9.4
(N) (6) (6)
雌性1-11 平均值 17.5 4.3*
％差 - -75
S.D 9.5 7.5
(N) (6) (6)％差是在不四舍五入的数据基础上计算。对于Student″t″-试验(2-尾的)显著水平：*P＜0.05**＜0.013．组间食物消耗比较
(g/动物/天)
对照组 治疗组天
雄性1-10 平均值 28.7 22.1
％差 - -23
(N) (2) (2)
雌性1-10 平均值 21.5 19.9
％差 - -7
(N) (2) (2)％差在不四舍五入的数据基础上计算。4．组间水消耗比较
(g/动物/天)
对照组 治疗组天
雄性1-10 平均值 30.6 27.5
％差 - -10
(N) (2) (2)
雌性1-10 平均值 25.6 30.0
％差 - +17
(N) (2) (2)％差在不四舍五入的数据基础上计算。1．鼠的19小时食物摄入
将雄性Sprague-Dawley鼠(420-550g)随意喂丸状食物并单个放在光照循环中，灯从6pm-6am关闭。将化合物1或赋形剂在2.30pm给药并从这时到第二天10am测定食物的摄入和体重的改变。结果是平均值±SEM(n=6)。化合物1剂量 0 1 5(mg/Kg p.o.)食物摄入(g) 25.0±2.3 11.0±3.51 3.8±2.81体重损失(g) 1.0±1.9 27.0±1.21 32.0±3.411P＜0.001比较对照值2．小鼠20小时食物摄入
将雌性CFLP小鼠(29-37g)随意喂丸状食物并成对放在光照循环中，灯从6pm从6pm-6am关闭。将化合物1或赋形剂在2pm给药并在未来20小时内测定食物摄入和体重改变。结果是平均值±SEM5(食物摄入)或平均值±SEM10(体重)。化合物1剂量 0 0.3 1 3 5(mg/Kg p.o)食物摄入 12.1± 10.5± 6.5± 5.4± 4.2±每对(g) 1.2 1.1 1.5* 1.0** 0.8***体重损失(g) 0.94± 1.50± 2.71± 3.77± 4.45±
0.25 0.32 0.71* 0.29*** 0.57
*P＜0.05；**P＜0.01,***P＜0.001比较对照
值。3．小鼠4小时食物摄入
将雌性CFLP小鼠(22-34g)成对放置并喂丸状食物。使它们在1周内适应光照循环，该灯从中午12点至夜间12点关闭。在11.30am至12.15pm之间将化合物1或赋形剂给药并评价4小时后(3.30pm至4.15pm)食物摄入。结果是平均值±SEM(n=5)。化合物1 0 0.03 0.1 0.3 1.0 3.0剂量(mg/Kg p.o)食物摄入 5.83± 5.14± 4.88± 3.80± 3.06± 2.74±每对(g) 0.25 0.39 0.25* 0.36* 0.17*** 0.31***毒性
在上面提到的试验中没有产生不利毒理学效果。试验动物的身体条件揭示对于治疗没有显示任何副反应。
Claims (5)
1．化合物1,3-二-环丙基甲基-8-氨基黄嘌呤的用途，该用途包括将该化合物用于制造用作治疗和/或预防肥胖症或者用作治疗Ⅱ型糖尿病的药物。
2．根据权利要求1的用途，其中包括将1,3-二-环丙基甲基-8-氨基黄嘌呤用于制造适于口服治疗或非肠道给药治疗的药物。
3．根据权利要求1的用途，其中1,3-二-环丙基甲基-8-氨基黄嘌呤是以单位剂量在药物组合物的形式中应用的。
4．根据权利要求3的用途，其中该单位剂量含有0.1至200mg的1,3-二-环丙基甲基-8-氨基黄嘌呤。
5．根据权利要求3的用途，其中该单位剂量含有5至50mg或1至20mg的1,3-二-环丙基甲基-8-氨基黄嘌呤。
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|---|---|---|---|
| GB929215633A GB9215633D0 (en) | 1992-07-23 | 1992-07-23 | Novel treatment |
| GB9215633.0 | 1992-07-23 |
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| CN1114880A CN1114880A (zh) | 1996-01-17 |
| CN1043610C true CN1043610C (zh) | 1999-06-16 |
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| EP (1) | EP0651642A1 (zh) |
| JP (1) | JPH07509456A (zh) |
| CN (1) | CN1043610C (zh) |
| AU (1) | AU4714393A (zh) |
| GB (1) | GB9215633D0 (zh) |
| MX (1) | MX9304435A (zh) |
| TW (1) | TW258663B (zh) |
| WO (1) | WO1994002150A1 (zh) |
| ZA (1) | ZA935339B (zh) |
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| US5783408A (en) * | 1995-06-07 | 1998-07-21 | Hamilton; Bradford S. | Method for screening potential anti-obesity agents |
| SI1757606T1 (sl) * | 2001-02-24 | 2009-10-31 | Boehringer Ingelheim Pharma | Ksantinski derivati za uporabo kot zdravila kot tudi postopek za njihovo pripravo |
| US6869947B2 (en) | 2001-07-03 | 2005-03-22 | Novo Nordisk A/S | Heterocyclic compounds that are inhibitors of the enzyme DPP-IV |
| JP2005502624A (ja) * | 2001-07-03 | 2005-01-27 | ノボ ノルディスク アクティーゼルスカブ | 糖尿病を治療するための、ｄｐｐ−ｉｖを阻害するプリン誘導体 |
| EP1463727A2 (en) * | 2001-09-19 | 2004-10-06 | Novo Nordisk A/S | Heterocyclic compounds that are inhibitors of the enzyme dpp-iv |
| US7407955B2 (en) | 2002-08-21 | 2008-08-05 | Boehringer Ingelheim Pharma Gmbh & Co., Kg | 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions |
| DE10254304A1 (de) * | 2002-11-21 | 2004-06-03 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue Xanthinderivate, deren Herstellung und deren Verwendung als Arzneimittel |
| MXPA06002521A (es) | 2003-09-05 | 2006-06-20 | Altana Pharma Ag | Uso de inhibidores de pde4 para el tratamiento de diabetes mellitus. |
| US7501426B2 (en) | 2004-02-18 | 2009-03-10 | Boehringer Ingelheim International Gmbh | 8-[3-amino-piperidin-1-yl]-xanthines, their preparation and their use as pharmaceutical compositions |
| DE102004030502A1 (de) | 2004-06-24 | 2006-01-12 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue Imidazole und Triazole, deren Herstellung und Verwendung als Arzneimittel |
| DE102004054054A1 (de) | 2004-11-05 | 2006-05-11 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Verfahren zur Herstellung chiraler 8-(3-Amino-piperidin-1-yl)-xanthine |
| EP1874308A1 (en) | 2005-03-08 | 2008-01-09 | Nycomed GmbH | Roflumilast for the treatment of diabetes mellitus |
| DE102005035891A1 (de) | 2005-07-30 | 2007-02-08 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | 8-(3-Amino-piperidin-1-yl)-xanthine, deren Herstellung und deren Verwendung als Arzneimittel |
| KR101452915B1 (ko) | 2006-05-04 | 2014-10-21 | 베링거 인겔하임 인터내셔날 게엠베하 | 다형태 |
| EP1852108A1 (en) | 2006-05-04 | 2007-11-07 | Boehringer Ingelheim Pharma GmbH & Co.KG | DPP IV inhibitor formulations |
| PE20080251A1 (es) | 2006-05-04 | 2008-04-25 | Boehringer Ingelheim Int | Usos de inhibidores de dpp iv |
| PE20140960A1 (es) | 2008-04-03 | 2014-08-15 | Boehringer Ingelheim Int | Formulaciones que comprenden un inhibidor de dpp4 |
| KR20190016601A (ko) | 2008-08-06 | 2019-02-18 | 베링거 인겔하임 인터내셔날 게엠베하 | 메트포르민 요법이 부적합한 환자에서의 당뇨병 치료 |
| UY32030A (es) | 2008-08-06 | 2010-03-26 | Boehringer Ingelheim Int | "tratamiento para diabetes en pacientes inapropiados para terapia con metformina" |
| MX2011002558A (es) | 2008-09-10 | 2011-04-26 | Boehringer Ingelheim Int | Terapia de combinacion para el tratamiento de diabetes y estados relacionados. |
| US20200155558A1 (en) | 2018-11-20 | 2020-05-21 | Boehringer Ingelheim International Gmbh | Treatment for diabetes in patients with insufficient glycemic control despite therapy with an oral antidiabetic drug |
| AU2009331471B2 (en) | 2008-12-23 | 2015-09-03 | Boehringer Ingelheim International Gmbh | Salt forms of organic compound |
| AR074990A1 (es) | 2009-01-07 | 2011-03-02 | Boehringer Ingelheim Int | Tratamiento de diabetes en pacientes con un control glucemico inadecuado a pesar de la terapia con metformina |
| KR20120107080A (ko) | 2009-11-27 | 2012-09-28 | 베링거 인겔하임 인터내셔날 게엠베하 | 리나글립틴과 같은 ｄｐｐ－ｉｖ 억제제를 사용한 유전자형 검사된 당뇨병 환자의 치료 |
| KR101927068B1 (ko) | 2010-05-05 | 2018-12-10 | 베링거 인겔하임 인터내셔날 게엠베하 | 체중 감소 치료에 후속하는 dpp-4 억제제에 의한 순차적 병용 요법 |
| KR20220025926A (ko) | 2010-06-24 | 2022-03-03 | 베링거 인겔하임 인터내셔날 게엠베하 | 당뇨병 요법 |
| AR083878A1 (es) | 2010-11-15 | 2013-03-27 | Boehringer Ingelheim Int | Terapia antidiabetica vasoprotectora y cardioprotectora, linagliptina, metodo de tratamiento |
| CN103781788B (zh) | 2011-07-15 | 2016-08-17 | 勃林格殷格翰国际有限公司 | 经取代的喹唑啉、其制备及其在药物组合物中的用途 |
| US9555001B2 (en) | 2012-03-07 | 2017-01-31 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition and uses thereof |
| WO2013171166A1 (en) | 2012-05-14 | 2013-11-21 | Boehringer Ingelheim International Gmbh | A xanthine derivative as dpp-4 inhibitor for use in the treatment of sirs and/or sepsis |
| JP6224084B2 (ja) | 2012-05-14 | 2017-11-01 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 糸球体上皮細胞関連障害及び／又はネフローゼ症候群の治療に用いるｄｐｐ−４阻害薬としてのキサンチン誘導体 |
| WO2013174767A1 (en) | 2012-05-24 | 2013-11-28 | Boehringer Ingelheim International Gmbh | A xanthine derivative as dpp -4 inhibitor for use in modifying food intake and regulating food preference |
| JP6615109B2 (ja) | 2014-02-28 | 2019-12-04 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Ｄｐｐ−４阻害薬の医学的使用 |
| MX390363B (es) | 2016-06-10 | 2025-03-20 | Boehringer Ingelheim Int | Combinacion de linagliptina y metformina |
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|---|---|---|---|---|
| EP0389282A2 (en) * | 1989-03-23 | 1990-09-26 | BEECHAM - WUELFING GmbH & Co. KG | Xanthinederivatives, process for their preparation and their pharmaceutical use |
-
1992
- 1992-07-23 GB GB929215633A patent/GB9215633D0/en active Pending
-
1993
- 1993-07-21 WO PCT/GB1993/001539 patent/WO1994002150A1/en not_active Ceased
- 1993-07-21 JP JP6504294A patent/JPH07509456A/ja active Pending
- 1993-07-21 AU AU47143/93A patent/AU4714393A/en not_active Abandoned
- 1993-07-21 EP EP93917883A patent/EP0651642A1/en not_active Withdrawn
- 1993-07-22 CN CN93116874A patent/CN1043610C/zh not_active Expired - Lifetime
- 1993-07-22 MX MX9304435A patent/MX9304435A/es unknown
- 1993-07-23 ZA ZA935339A patent/ZA935339B/xx unknown
- 1993-07-27 TW TW082105967A patent/TW258663B/zh not_active IP Right Cessation
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0389282A2 (en) * | 1989-03-23 | 1990-09-26 | BEECHAM - WUELFING GmbH & Co. KG | Xanthinederivatives, process for their preparation and their pharmaceutical use |
Also Published As
| Publication number | Publication date |
|---|---|
| WO1994002150A1 (en) | 1994-02-03 |
| TW258663B (zh) | 1995-10-01 |
| GB9215633D0 (en) | 1992-09-09 |
| ZA935339B (en) | 1995-01-18 |
| JPH07509456A (ja) | 1995-10-19 |
| CN1114880A (zh) | 1996-01-17 |
| EP0651642A1 (en) | 1995-05-10 |
| MX9304435A (es) | 1994-04-29 |
| AU4714393A (en) | 1994-02-14 |
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