CN1324618A - 苯甲酸衍生物的制药应用 - Google Patents
苯甲酸衍生物的制药应用 Download PDFInfo
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- CN1324618A CN1324618A CN01117254A CN01117254A CN1324618A CN 1324618 A CN1324618 A CN 1324618A CN 01117254 A CN01117254 A CN 01117254A CN 01117254 A CN01117254 A CN 01117254A CN 1324618 A CN1324618 A CN 1324618A
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- Prior art keywords
- diabetic complication
- compd
- prevention
- benzyl
- diabetic
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Abstract
本发明涉及4-[α-羟基-2-甲基-5-(1-咪唑基)苄基]-3,5-二甲基苯甲酸、其光学活性体或其医药上允许的盐类在制备预防/治疗糖尿病并发症的药物中的应用。糖尿病并发症例如糖尿病性神经病变、肾病、眼病、动脉硬化等。
Description
本申请是1996年12月24日提交的题为“糖尿病并发症的预防/治疗药”的PCT/JP96/03776号发明专利申请的分案申请,原申请于1998年8月19日进入中国国家阶段,并获得中国专利申请号96180052.6。
本发明涉及糖尿病并发症的预防/治疗药,即糖尿病性神经病变、肾病、眼病以及动脉硬化的预防/治疗药。更具体地讲,涉及其特征为含有4-[α-羟基-2-甲基-5-(1-咪唑基)苄基]-3,5-二甲基苯甲酸、其光学活性体或其医药上允许的盐类为有效成分的糖尿病并发症的预防/治疗药。本发明还涉及糖尿病并发症的预防或治疗方法。
胰岛素的发现和临床应用使糖尿病的治疗取得了划时代的进步。以至于致死的疾病-糖尿病的生命维持得到了显著改善,但是慢性并发症的治疗成了新的课题。
糖尿病的治疗,其目的在于防止慢性并发症,包括血糖的进一步控制和并发症的直接治疗。已知这种糖尿病的主要的慢性并发症有神经病变、肾病、眼病、动脉硬化等(David M.et al.,N.Engl.J.Med.,328,p.1676-1685(1993))。
糖尿病慢性并发症的发病和进展被认为与各种因子的参与有关。例如,以产生山梨醇的多元醇代谢途径活性亢进为原因的山梨醇代谢异常学说(Gabbay K.H.et al.,N.Engl.J.Med.288,p.831-837(1973))、以血管疾病引起血流减少为原因的循环障碍学说(Dyck P.J.et al.,Proc.Natl.Acad.Sci.USA,82,p.2513-2517(1985))、以蛋白和还原糖的非酶结合反应产生的化合物(AGE:advanced glycation endproduct)为原因的学说(Brownlee M.et al.,N.Engl.J.Med.318,p.1315-1321(1988))等。根据各种假说已经开发出醛糖还原酶抑制剂、脂前列腺素E1,并正在开发AGE生成抑制剂。
另外,糖尿病患者血小板聚集能力亢进,其机制已知与高血糖引起血栓烷(以下简称TX)A2的生物合成亢进有关,据认为这是糖尿病慢性并发症的发病原因之一(Giovanni Davi M.D.et a1.,N.Engl.J.Med.322,p.1769-1774(1990))。因此,正在开发具有末梢循环改善作用或血小板聚集抑制作用的脂前列腺素E1(以下有时也称Lipo PGEl)、6-[4-(1-环己基-1,2,3,4,-四唑-5-基)丁氧基]-3,4-二氢喹诺酮(西洛他唑)、具有TXA2受体拮抗/合成抑制作用的6-[4(R)-氯苯亚磺酰氨基-1-(3-吡啶甲基)-吡咯烷-2(S)-基]-5-(Z)-己烯酸一盐酸盐(试验编号:KDI-792)作为糖尿病并发症的预防/治疗药。
另一方面,特公平5-41143号公报公布了具有强力抑制TXA2生物合成作用、血小板聚集抑制作用以及血管扩张作用等药理作用、对血栓形成、脑中风、心肌梗塞、急性心脏猝死、心绞痛、高血压、哮喘、肾炎等的预防和治疗有用的4-[α-羟基-2-甲基-5-(1-咪唑基)苄基]-3,5-二甲基苯甲酸、其光学活性体或其医药上允许的盐类。但是这些化合物是否可作为糖尿病并发症预防/治疗药尚不清楚。
这样的情况下,希望开发出在糖尿病的预防或治疗中直接作用于糖尿病慢性并发症,并使生活质量(Quality of Life)更高的新的治疗药。
上述因末梢循环改善作用、血小板聚集抑制作用、TXA2受体拮抗/合成抑制作用而作为糖尿病并发症的预防/治疗药正在开发的Lipo-PGEl、西洛他唑、KDI-792等药物,均作用持续时间短,需要每天服药2~3次,考虑到糖尿病患者治疗的生活质量,上述药物并不是十分满意的。
另外我们证实,具有TXA2合成抑制作用的奥扎格雷钠[(E)-对-(咪唑-1-基甲基)肉桂酸钠]虽然抑制糖尿病大鼠TXA2的生物合成亢进,但并不能改善尾神经传导速度的减慢。这意味着并不是所有的TXA2合成抑制剂都对糖尿病并发症有效。
发明内容
发明人基于上述观点进行深入细致研究的结果发现,具有TXA2生物合成抑制作用、血小板聚集抑制作用以及血管扩张作用等药理作用的4-[α-羟基-2-甲基-5-(1-咪唑基)苄基]-3,5-二甲基苯甲酸、其光学活性体或其医药上允许的盐类对糖尿病并发症即糖尿病性神经病变、肾病、眼病及动脉硬化的预防/治疗有用,并且其作用在极低的用量时就可持续,可以一天给药一次,从而完成了本发明。
即本发明涉及
1)糖尿病并发症的预防/治疗药,其特征在于含有4-[α-羟基-2-
甲基-5-(1-咪唑基)苄基]-3,5-二甲基苯甲酸、其光学活性体或其医药上允许的盐类为有效成分。
2)糖尿病并发症的预防/治疗药,其特征在于含有4-[α-羟基-2-甲基-5-(1-咪唑基)苄基]-3,5-二甲基苯甲酸钠·二水合物为有效成分。
3)糖尿病并发症的预防/治疗药,其特征在于含有(S)-(-)-4-[α-羟基-2-甲基-5-(1-咪唑基)苄基]-3,5-二甲基苯甲酸或其医药上允许的盐类为有效成分。
4)糖尿病并发症的预防/治疗药,其特征在于含有(S)-(-)-4-[α-羟基-2-甲基-5-(1-咪唑基)苄基]-3,5-二甲基苯甲酸钠·2/3水合物为有效成分。
5)前述1)~4)所记载的预防/治疗药,其中糖尿病并发症为选自神经病变、肾病、眼病及动脉硬化中的至少一种。
6)前述1)~4)所记载的预防/治疗药,其中糖尿病并发症为神经病变。
7)前述1)~4)所记载的预防/治疗药,其中糖尿病并发症为肾病。
8)前述1)~4)所记载的预防/治疗药,其中糖尿病并发症为眼病。
9)前述1)~4)所记载的预防/治疗药,其中糖尿病并发症为动脉硬化。
10)糖尿病并发症的预防或治疗方法,包括给予有效量的4-[α-羟基-2-甲基-5-(1-咪唑基)苄基]-3,5-二甲基苯甲酸、其光学活性体或其医药上允许的盐类。
11)糖尿病并发症的预防或治疗方法,包括给予有效量的4-[α-羟基-2-甲基-5-(1-咪唑基)苄基]-3,5-二甲基苯甲酸钠·二水合物。
12)糖尿病并发症的预防或治疗方法,包括给予有效量的(S)-(-)-4-[α-羟基-2-甲基-5-(1-咪唑基)苄基]-3,5-二甲基苯甲酸或其医药上允许的盐类。
13)糖尿病并发症的预防或治疗方法,包括给予有效量的(S)-(-)-4-[α-羟基-2-甲基-5-(1-咪唑基)苄基]-3,5-二甲基苯甲酸钠·2/3水合物。
14)前述10)~13)所记载的方法,其中糖尿病并发症为选自神经病变、肾病、眼病及动脉硬化中的至少一种。
15)前述10)~13)所记载的方法,其中糖尿病并发症为神经病变。
16)前述10)~13)所记载的方法,其中糖尿病并发症为肾病。
17)前述10)~13)所记载的方法,其中糖尿病并发症为眼病。
18)前述10)~13)所记载的方法,其中糖尿病并发症为动脉硬化。
19)4-[α-羟基-2-甲基-5-(1-咪唑基)苄基]-3,5-二甲基苯甲酸、其光学活性体或其医药上允许的盐类在制造糖尿病并发症的预防或治疗用药中的用途。
20)4-[α-羟基-2-甲基-5-(1-咪唑基)苄基]-3,5-二甲基苯甲酸钠·二水合物在制造糖尿病并发症的预防或治疗用药中的用途。
21)(S)-(-)-4-[α-羟基-2-甲基-5-(1-咪唑基)苄基]-3,5-二甲基苯甲酸或其医药上允许的盐类在制造糖尿病并发症的预防或治疗用药中的用途。
22)(S)-(-)-4-[α-羟基-2-甲基-5-(1-咪唑基)苄基]-3,5-二甲基苯甲酸钠·2/3水合物在制造糖尿病并发症的预防或治疗用药中的用途。
23)前述19)~22)所记载的用途,其中糖尿病并发症为选自神经病变、肾病、眼病及动脉硬化中的至少一种。
24)前述19)~22)所记载的用途,其中糖尿病并发症为神经病变。
25)前述19)~22)所记载的用途,其中糖尿病并发症为肾病。
26)前述19)~22)所记载的用途,其中糖尿病并发症为眼病。
27)前述19)~22)所记载的用途,其中糖尿病并发症为动脉硬化。
28)糖尿病并发症的预防或治疗用药物组合物,其含有有效量的4-[α-羟基-2-甲基-5-(1-咪唑基)苄基]-3,5-二甲基苯甲酸、其光学活性体或其医药上允许的盐类以及医药上允许的载体。
29)糖尿病并发症的预防或治疗用药物组合物,其含有有效量的4-[α-羟基-2-甲基-5-(1-咪唑基)苄基]-3,5-二甲基苯甲酸钠·二水合物以及医药上允许的载体。
30)糖尿病并发症的预防或治疗用药物组合物,其含有有效量的(S)-(-)-4-[α-羟基-2-甲基-5-(1-咪唑基)苄基]-3,5-二甲基苯甲酸或其医药上允许的盐类以及医药上允许的载体。
31)糖尿病并发症的预防或治疗用药物组合物,其含有有效量的(S)-(-)-4-[α-羟基-2-甲基-5-(1-咪唑基)苄基]-3,5-二甲基苯甲酸钠·2/3水合物以及医药上允许的载体。
32)前述28)~31)所记载的药物组合物,其中糖尿病并发症为选自神经病变、肾病、眼病及动脉硬化中的至少一种。
33)前述28)~31)所记载的药物组合物,其中糖尿病并发症为神经病变。
34)前述28)~31)所记载的药物组合物,其中糖尿病并发症为肾病。
35)前述28)~31)所记载的药物组合物,其中糖尿病并发症为眼病。
36)前述28)~31)所记载的药物组合物,其中糖尿病并发症为动脉硬化。
37)包括前述28)~31)中任何一项所记载的药物组合物以及与该药物组合物相关的说明书的商业包装,所述说明书记载该药物组合物可以或必须使用在糖尿病并发症的预防或治疗用途中。发明详述
作为本发明的糖尿病并发症即神经病变、肾病、眼病以及动脉硬化的预防/治疗药的作用可以通过例如大鼠尾神经传导速度、坐骨神经传导速度、肾小球损伤程度、尿中白蛋白排泄量、眼底检查以及血管肥厚程度等证实。
另外,本发明的糖尿病并发症中,神经病变指知觉、运动、自律神经等的对称性多发性神经病变和脑神经等的局限性/多灶性神经病变,眼病指白内障、青光眼、视网膜病、虹膜炎等。
本发明的化合物可以按特公平5-41143号公报以及特开平2-215771号公报所记载的方法合成。
本发明的化合物在医药上允许的盐类有盐酸、氢溴酸、硫酸等无机酸或富马酸、马来酸、扁桃酸、枸橼酸、酒石酸、水杨酸等有机酸的加成盐;或与钠、钾、锂、钙、镁、锌、铝等金属形成的盐;与赖氨酸等氨基酸形成的盐;另外还包括1/2水合物、1/3水合物、3/2水合物、一水合物、3/2水合物、二水合物等水合物。
作为本发明的优选化合物可举出4-[α-羟基-2-甲基-5-(1-咪唑基)苄基]-3,5-二甲基苯甲酸钠·二水合物(以下有时也称化合物A-1)、(S)-(-)-4-[α-羟基-2-甲基-5-(1-咪唑基)苄基]-3,5-二甲基苯甲酸钠·2/3水合物(以下有时也称化合物A-2)、(R)-(+)-4-[α-羟基-2-甲基-5-(1-咪唑基)苄基]-3,5-二甲基苯甲酸钠·2/3水合物(以下有时也称化合物A-3)、(S)-(-)-4-[α-羟基-2-甲基-5-(1-咪唑基)苄基]-3,5-二甲基苯甲酸(以下有时也称化合物A-4)以及(R)-(+)-4-[α-羟基-2-甲基-5-(1-咪唑基)苄基]-3,5-二甲基苯甲酸(以下有时也称化合物A-5)。化合物A-1是熔点为271~285℃的结晶,化合物A-2的旋光度为[α]D 23.5-149.5°(c=1.0,水),化合物A-3的旋光度为[α]D 24+147.2°(c=1.0,水),化合物A-4的熔点为286~288℃(分解),旋光度为[α]D 21-261.5°(c=1.0,二甲基甲酰胺),化合物A-5的熔点为286~287℃(分解),旋光度为[α]D 21+260.5°(c=1.0,二甲基甲酰胺)。
本发明的糖尿病并发症预防/治疗药可配制成一般的药物制剂。例如,本发明的化合物和允许的载体(赋形剂、粘合剂、崩解剂、矫味剂、矫臭剂、乳化剂、稀释剂、助溶剂等)混合后配制成药物组合物或片剂、丸剂、散剂、颗粒剂、胶囊剂、锭剂、糖浆剂、水剂、乳剂、混悬剂、注射剂(水剂、混悬剂)、栓剂、吸入剂、透皮吸收剂、滴眼剂、眼软膏等口服给药或非口服给药适合的制剂形式。
配制成固体制剂时,添加剂可使用蔗糖、乳糖、纤维素、D-甘露醇、maltitol、右旋糖苷、淀粉类、琼脂、arginates、甲壳质类、脱乙酰壳多糖类、果胶类、拢须胶类、阿拉伯树胶类、明胶类、胶原类、酪蛋白、白蛋白、磷酸钙、山梨醇、甘氨酸、羧甲基纤维素、聚乙烯吡咯烷酮、羟丙基纤维素、羟丙基甲基纤维素、甘油、聚乙二醇、碳酸氢钠、硬脂酸镁、滑石等。片剂根据需要可制成含通常包衣的片剂,如糖衣片、肠溶性包衣片、薄膜包衣片或双层片、多层片。
配制成半固体制剂时,可使用动植物性油脂(橄榄油、玉米油、蓖麻油等)、矿物性油脂(凡士林、白凡士林、固体石蜡等)、蜡类(希蒙得木蜡、加拿巴蜡、蜂蜡等)、部分合成或全合成的甘油脂肪酸酯(十二烷酸酯、十四烷酸酯、棕榈酸酯等)等。这些物质市售品有Witepsol(Dynamite Novel公司制)、Pharmasol(日本油脂公司制)等。
配制成液体制剂时添加剂可举出氯化钠、山梨醇、甘油、橄榄油、丙二醇、乙醇等。特别是配制成注射剂时可使用无菌水溶液(例如生理盐水、等渗溶液)、油性液(例如芝麻油、大豆油)。并且根据需要可以同时使用悬浮剂如羧甲基纤维素钠、非离子型表面活性剂、助溶剂如苯甲酸苄酯、苯甲醇等。配制成滴眼剂时可使用水性液体或水溶液,尤其是无菌注射用水溶液。在滴眼剂中也可以适当添加缓冲剂(为了减少刺激优选使用硼酸盐缓冲液、醋酸盐缓冲液、碳酸盐缓冲液等)、等渗化剂、助溶剂、防腐剂、增粘剂、螯合剂、pH调节剂(pH通常优选调节到6~8.5)芳香剂等各种添加剂。
这些制剂的有效成分量为0.1~100重量%,适当的是1~50重量%。给药量可以根据症状、体重、年龄等调整。通常经口给药时成人每公斤体重约0.01~50mg/日,优选一次或分几次服用。
实施例
下面举出制剂处方例以及药理作用来更具体地说明本发明的糖尿病并发症的预防/治疗药,但本发明并非局限于此。
制剂例1:薄膜衣片
化合物A-1 50.0mg
D-甘露醇 70.5mg
玉米淀粉 16.0mg
碳酸氢钠 15.0mg
羟丙基甲基纤维素 3.0mg
滑石 5.0mg
硬脂酸镁 0.5mg
将化合物A-1、D-甘露醇、玉米淀粉以及碳酸氢钠混合,并用羟丙基甲基纤维素水溶液喷雾流动制粒。制粒物过24目筛后加滑石和硬脂酸镁并用旋转式打片机(菊水制作所)按每片160mg打片。接着在片剂上以羟丙基甲基纤维素为包衣主剂按每片6mg裹上包衣。
制剂例2:细颗粒剂
化合物A-1 10%
D-甘露醇 89.5%
羟丙基甲基纤维素 0.5%
将化合物A-1和D-甘露醇混合后加羟丙基甲基纤维素水溶液粘合、制粒并在50℃下干燥。制粒物过32目筛做成细颗粒剂。
制剂例3:片剂
化合物A-1 50.0mg
D-甘露醇 30.0mg
玉米淀粉 19.0mg
碳酸氢钠 15.0mg
羟丙基甲基纤维素 1.5mg
滑石 4.0mg
硬脂酸镁 0.5mg
将化合物A-1、D-甘露醇、玉米淀粉以及碳酸氢钠混合,并用羟丙基甲基纤维素水溶液喷雾流动制粒。制粒物过24目筛后加滑石和硬脂酸镁并用旋转式打片机(菊水制作所)按每片120mg打片。
制剂例5:细颗粒剂
化合物A-2 5%
D-甘露醇 92%
羟丙基甲基纤维素 3%
将化合物A-2和D-甘露醇混合后加羟丙基甲基纤维素水溶液粘合、制粒并在50℃下干燥。制粒物过32目筛做成细颗粒剂。
下面通过实施例说明本发明药物的药理作用。
实施例1
6周龄的雄性SD大鼠静脉给予链脲霉素(65mg/kg)而诱发糖尿病。从糖尿病发病2~4周以后开始每天经口给药一次含本发明化合物的0.5%羟丙基甲基纤维素悬浮液。给药4~7周后利周诱发电位检查装置(Neuropack2,日本光电公司制)按三好方法(福岗医志、第62卷、第588-603页(1971年))的改良法测定尾神经传导速度。即维持尾部皮下温度37℃,在两个刺激点(间隔6cm)经皮电刺激尾神经。刺激点间距离除以诱发的肌电图潜伏期差而求得神经传导速度。对表1中的试验组,于给药6周后测定血糖值。并在给药7周后测定TXA2的稳定代谢物TXB2在尿中的排泄量。
表1试验组 给药量 血糖 尿中TXB2排泄量 尾神经传导速度
mg/kg/天 mg/dl ng/天/100g体重 m/秒
给药7周正常组 0 122.0±3.8** 4.1±0.4** 44.6±0.5**糖尿病组 0 870.3±78.5 16.9±1.7 41.3±0.5化合物A-1给药组 0.03 718.3±50.7 10.6±1.4** 42.0±0.5化合物A-1给药组 0.1 772.1±32.4 6.9±0.8** 43.4±0.4**化合物A-1给药组 0.3 791.9±65.5 5.1±0.5** 43.7±0.3**化合物A-1给药组 1.0 718.4±64.1 3.4±0.3** 44.8±0.4**
数据表示每组11~12例的平均值±标准误。各组与糖尿病组的比较按Dunnett法进行。(**P<0.01)。
上述实施例表明,本发明的化合物A-1不影响血糖,而剂量依赖性地改善了糖尿病引起的TXB2在尿中排泄量的增加及尾神经传导速度的降低。
表2试验组 给药量 尾神经传导速度
mg/kg/天 m/秒
给药5周正常组 0 43.7±0.4**糖尿病组 0 39.4±0.2化合物A-2给药组 0.03 40.7±0.5**化合物A-2给药组 0.1 42.6±0.4**化合物A-2给药组 0.3 43.0±0.3**化合物A-2给药组 1 42.6±0.5**
数据表示每组10例的平均值±标准误。各组与糖尿病组的比较按Dunnett法进行。(**P<0.01)。
表3试验组 给药量 尾神经传导速度
mg/kg/ m/秒
给药4周正常组 0 43.0±0.5糖尿病组 0 38.8±0.5化合物A-4给药组 0.3 40.9±0.5**化合物A-4给药组 1 41.3±0.4**化合物A-4给药组 3 41.7±0.5**
数据表示每组10例的平均值±标准误。各组与糖尿病组的比较按Dunnett法进行。(**P<0.01)。
上述实施例表明,本发明的化合物A-2及A-4剂量依赖性地抑制尾神经传导速度的降低。
实施例2
9周龄的雄性自发糖尿病小鼠(db/db)每日经口给药一次含本发明化合物的0.5%羟丙基甲基纤维素悬浮液。给药4~5周后利用诱发电位检查装置(Neuropack2,日本光电公司制)按Yusuda等的方法(Diabetes38,p832-838(1989年))的改良法测定坐骨神经传导速度。即维持直肠温度37℃,经皮电刺激坐骨切迹(sciatic notch)和踝骨两个点。刺激点间距离除以诱发的肌电图潜伏期差而求得神经传导速度。
表4试验组 给药量 坐骨神经传导速度
mg/kg/天 m/秒
给药4周糖尿病组 0 44.3±1.1化合物A-2给药组 0.05 46.6±1.5化合物A-2给药组 0.5 51.9±1.2**化合物A-2给药组 5 51.7±1.4**
数据表示每组7~9例的平均值±标准误。各组与糖尿病组的比较按Dunnett法进行。(**P<0.01)。
表5试验组 给药量 坐骨神经传导速度
mg/kg/天 m/秒
给药5周糖尿病组 0 39.6±1.2化合物A-4给药组 0.3 45.2±1.2**化合物A-4给药组 1 45.9±0.7**化合物A-4给药组 3 45.3±0.8**
数据表示每组8~9例的平均值±标准误。各组与糖尿病组的比较按Dunnett法进行。(**P<0.01)。
上述实施例表明,本发明的化合物A-2及A-4增加自发糖尿病小鼠的坐骨神经传导速度。
实施例3
6周龄的雄性SD大鼠静脉给予链脲霉素(65mg/kg)而诱发糖尿病。从糖尿病发病16周以后开始每天经口给药一次含本发明化合物A-1的0.5%羟丙基甲基纤维素悬浮液。给药5周后利用诱发电位检查装置(Neuropack2,日本光电公司制)按三好方法(福岗医志、第62卷、第588-603页(1971年))的改良法测定尾神经传导速度。即维持尾部皮下温度37℃,在两个刺激点(间隔6cm)经皮电刺激尾神经。刺激点间距离除以诱发的肌电图潜伏期差而求得神经传导速度。
表6试验组 给药量 尾神经传导速度
mg/kg/天 m/秒
给药前 给药5周正常组 0 54.0±0.5 54.4±0.5糖尿病组 0 46.4±0.5 46.9±0.3化合物A-1给药组 0.3 46.2±0.5 48.3±0.6化合物A-1给药组 1 46.1±0.4 49.4±0.4**化合物A-1给药组 3 46.0±0.3 50.2±0.5**
数据表示每组10例的平均值±标准误。化合物给药组与糖尿病组的比较进行Dunnett检验。(**P<0.01)。
上述实施例表明,本发明的化合物A-1剂量依赖性地增加随着糖尿病进程而降低的尾神经传导速度。
实施例4
5周龄的雄性SD大鼠静脉给予链脲霉素(65mg/kg)而诱发糖尿病。从糖尿病发病9周以后开始每天经口给药一次含本发明化合物A-1的0.5%羟丙基甲基纤维素悬浮液。给药9周以后为了测定肾小球的损伤程度,取出肾脏用10%中性福尔马林缓冲液固定。组织切片进行苏木精/伊红染色,根据肾小球的阻塞程度分为5个阶段评价(0:无阻塞,1:~25%,2:~50%,3:~75%,4:~100%)。每个标本评价50个肾小球,将级数的合计作为肾小球阻塞度的指标。上述操作在单盲的条件下进行。
表7试验组 给药量 例数 肾小球阻塞程度
mg/kg/天 级数糖尿病组 0 9 90.2±7.9化合物A-1给药组 0.3 5 90.8±10.0化合物A-1给药组 1 7 65.7±12.0化合物A-1给药组 10 8 55.4±9.2*
数据表示平均值±标准误。各组与糖尿病组的比较按Dunnett法进行。(*P<0.05)。
上述实施例表明,本发明的化合物A-1剂量依赖性地抑制糖尿病引起的肾小球损伤。
实施例5
6周龄的雄性SD大鼠静脉给予链脲霉素(65mg/kg)而诱发糖尿病。从糖尿病发病2周以后开始每天经口给药一次含本发明化合物A-1的0.5%羟丙基甲基纤维素悬浮液。以数周间隔采集24小时内的尿,用酶免疫测定法测定尿中的白蛋白排泄量。另外进行眼底摄影以及测定新生血管数等的眼底检查。给药结束后,处死动物,取出大动脉等血管制作组织标本。苏木精/伊红染色的标本在光学显微镜下观察,测量内膜的肥厚程度。
上述制剂处方例及药理实施例表明,本发明的药物对糖尿病并发症即糖尿病性神经病变、肾病、眼病、动脉硬化等的预防/治疗有用,而且其作用在极低的用量时也可持续,可以每天只给药一次。
Claims (8)
1.4-[α-羟基-2-甲基-5-(1-咪唑基)苄基]-3,5-二甲基苯甲酸、其光学活性体或其医药上允许的盐类在制造糖尿病并发症的预防或治疗用药中的用途。
2.4-[α-羟基-2-甲基-5-(1-咪唑基)苄基]-3,5-二甲基苯甲酸钠·二水合物在制造糖尿病并发症的预防或治疗用药中的用途。
3.(S)-(-)-4-[α-羟基-2-甲基-5-(1-咪唑基)苄基]-3,5-二甲基苯甲酸或其医药上允许的盐类在制造糖尿病并发症的预防或治疗用药中的用途。
4.(S)-(-)-4-[α-羟基-2-甲基-5-(1-咪唑基)苄基]-3,5-二甲基苯甲酸钠·2/3水合物在制造糖尿病并发症的预防或治疗用药中的用途。
5.权利要求1-4中任何一项的用途,其中糖尿病并发症为选自神经病变、肾病、眼病及动脉硬化中的至少一种。
6.权利要求1-4中任何一项的用途,其中糖尿病并发症为肾病。
7.权利要求1-4中任何一项的用途,其中糖尿病并发症为眼病。
8.权利要求1-4中任何一项的用途,其中糖尿病并发症为动脉硬化。
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CNB011172541A Expired - Fee Related CN1159009C (zh) | 1995-12-27 | 1996-12-24 | 苯甲酸衍生物的制药应用 |
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EP0881218B1 (en) * | 1995-12-27 | 2003-10-22 | Mitsubishi Pharma Corporation | Preventives/remedies for complications of diabetes |
DE60034448D1 (de) * | 1999-05-25 | 2007-05-31 | Mitsubishi Pharma Corp | PROMOTOREN FüR DIE EXPRESSION DES MYELIN ASSOZIIERTEN GLYCOPROTEINS (MAG) |
US6482844B1 (en) * | 2000-04-07 | 2002-11-19 | Neurogen Corporation | 1-benzylimidazole derivatives |
US6423309B1 (en) * | 2000-11-24 | 2002-07-23 | Toyo Shinyaku Co., Ltd. | Composition containing grass plant, water-soluble dietary fibers, oligosaccharides, lactic acid bacteria and green tea |
DE10229180A1 (de) | 2002-06-28 | 2004-01-29 | Aventis Pharma Deutschland Gmbh | Verwendung von Vasopeptidase-Inhibitoren bei der Behandlung von metabolischen Erkrankungen, Nephropathie und mit AGE assoziierten Erkrankungen |
WO2004021014A2 (en) * | 2002-08-29 | 2004-03-11 | University Of Florida Research Foundation, Inc. | Cox-2 mediated altered prostaglandin balance in diabetes complications |
GB0314945D0 (en) * | 2003-06-26 | 2003-07-30 | Black & Decker Inc | Vacuum cleaner |
EP2543368A1 (en) | 2007-12-11 | 2013-01-09 | Viamet Pharmaceuticals, Inc. | Metalloenzyme inhibitors using metal binding moieties in combination with targeting moieties |
RU2741715C1 (ru) * | 2020-03-20 | 2021-01-28 | Федеральное государственное бюджетное образовательное учреждение высшего образования "Пермский государственный медицинский университет имени академика Е.А. Вагнера" Министерства здравоохранения Российской Федерации | Способ прогнозирования формирования микрососудистых осложнений сахарного диабета 2 типа |
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DK531479A (da) * | 1979-01-19 | 1980-07-20 | Pfizer | Fremgangsmaade til fremstilling af imidazolderivater og salte deraf |
US4661603A (en) * | 1982-03-03 | 1987-04-28 | Yoshitomi Pharmaceutical Industries, Ltd. | Imidazole derivatives |
JPS61277670A (ja) * | 1985-06-03 | 1986-12-08 | Yoshitomi Pharmaceut Ind Ltd | イミダゾ−ル誘導体 |
JPS6147477A (ja) * | 1984-08-14 | 1986-03-07 | Kowa Co | 新規1,4−ジヒドロピリジン−3,5−ジカルボン酸エステル誘導体 |
JPS63119425A (ja) * | 1986-11-07 | 1988-05-24 | Yoshitomi Pharmaceut Ind Ltd | 免疫機能改善薬 |
PH24144A (en) * | 1987-06-03 | 1990-03-22 | Erba Carlo Spa | A method of treating nephropathies using n-imidazolyl derivatives of bicyclic compounds |
JP2814513B2 (ja) * | 1988-02-03 | 1998-10-22 | 吉富製薬株式会社 | 溶出性の改良された製剤組成物 |
WO1989006959A1 (en) * | 1988-02-03 | 1989-08-10 | Yoshitomi Pharmaceutical Industries, Ltd. | Pharmaceutical composition having improved releasability |
JPH037281A (ja) * | 1989-03-31 | 1991-01-14 | Kyoto Yakuhin Kogyo Kk | 新規イミダゾール誘導体およびその医薬用途 |
WO1990012009A1 (fr) | 1989-03-31 | 1990-10-18 | Kyoto Pharmaceutical Industries, Ltd. | Nouveaux derives d'imidazole, leur production, et leurs emplois comme medicaments |
US5401851A (en) * | 1992-06-03 | 1995-03-28 | Eli Lilly And Company | Angiotensin II antagonists |
EP0881218B1 (en) | 1995-12-27 | 2003-10-22 | Mitsubishi Pharma Corporation | Preventives/remedies for complications of diabetes |
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