CN1150901C - 1-芳(烷)基咪唑啉-2-酮在治疗焦虑和紧张状态中的应用 - Google Patents
1-芳(烷)基咪唑啉-2-酮在治疗焦虑和紧张状态中的应用Info
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Abstract
本发明涉及通式I的1-芳(烷)基咪唑啉-2-酮或其可药用盐在治疗焦虑和紧张性疾病的应用。1-(4-氯苯基)-4-吗啉-咪唑啉-2-酮作为一个实施例。
Description
本发明涉及通式I的1-芳(烷)基咪唑啉-2-酮或其可药用盐在治疗焦虑和紧张性疾病的应用。
在德国19532668.7号专利申请中记载了通式I的化合物：
n＝0，1
m＝0，1，2，3，4，5
其中X＝氢、C1-C4烷基、C1-C4烷氧基、三氟甲基、卤素，
R1和R2＝C1-C4烷基、环烷基、杂原子取代的烷基或者
R1和R2共同为具有2-6个碳原子的亚烷基，并且该亚烷基中的一个CH2可被氧、氮或硫置换，CH2的数目可以是0(1-芳基-咪唑啉-2-酮)或1(1-芳烷基咪唑啉-2-酮)。
药理学结果表明：通式I的化合物适合治疗各种癫痫。
直至今天，各种原因和程度的焦虑和紧张状态并不是在所有情况下均能得到满意的治疗。大约从1960年以来，苯并二氮杂衍生物已经用作一种治疗焦虑和紧张性疾病的优选物质。具有这种性质的物质通常具有镇静和情绪衰减作用。简言之，这些药物是非常有用的，但是即使在治疗剂量情况下，也产生副作用如镇静、嗜睡和反应性降低。
由于镇静作用，从而对精神活动有副作用。在一定程度上，会观测到影响功能的运动失调和协调性障碍。持续用药时，这些苯并二氮杂类化合物可以导致习惯性作用，即所谓的耐受性。因此，制剂的疗效降低，用药剂量必须加大。并可发展为心理依赖性甚至生理依赖性。因此在停药试验中产生停药综合症。
已经上市的抗焦虑药中最典型的代表为活性化合物安定、氯硝基安定、去氧安定。
安定为了达到抗焦虑作用，必须具有300-400mg/ml(sic)的血浆浓度。然而，在同样浓度下，同样产生上面提到的副作用例如：镇静、精神性运动障碍表现为白天的镇静、催眠以及注意力和反应性降低。由于安定和氯硝基安定半衰期长，因此产生严重的“宿醉”(hang-over)作用，同样地伴有嗜睡、智力和运动能力减退以及反应减慢。氯硝基安定的抗焦虑作用被其镇静催眠作用所掩盖。高剂量的去氧安定同样有嗜睡和肌肉松弛现象。
这三种药物均能增强许多中枢活性药物和酒精的作用。这样，服用单个药物后，其效果几乎看不出来。
迄今为此，对于相对长期的焦虑状态，其治疗效果一直不能令人满意。目前，尚不能确保抗焦虑药物的长期治疗作用。
因此，本发明的目的是提供有效的药物用于治疗各种焦虑和紧张状态，并且其有非常大的治疗宽度。
令人惊奇的是，已经发现：在动物试验中，通式I的化合物具有显著的抗焦虑作用并且没有镇静的副作用。
药理学研究
研究通式I化合物的目的是评价这些化合物在所研究动物模型中抗焦虑作用可能的效果。为此，使这些动物处于不同的冲突环境中，测定了例如化合物1-(4-氯苯基)-4-吗啉咪唑啉-2-酮(实施例1)的作用。
Vogel冲突测试中抗焦虑的研究
在该模型中，对动物持续供应的饮用水停止一段时间。这段时间过后，再使动物能自由接近饮用水，但接近饮用水处有温和的电刺激。动物的冲突在于：其要么接受电刺激，要么不喝水。
这种冲突环境的反应和第二种人焦虑现象是相似的。产生了回避反应，该回避反应能被抗焦虑物质抑制。抗焦虑作用的测定是这样进行的：确定用测试物质处理的动物所能耐受的电流脉冲的数目，将其与载体处理的对照组进行比较。表1中得到的结果示于图1。
表1
在Vogel冲突测试/大鼠中物质的抗焦虑作用
X±SEM；*P＜0.05，**P＜0.01
| 物质 | mg/kg p.o. | 脉冲数 | 脉冲变化数目相对于对照组的百分比 |
| 对照实施例1对照 | -1310-30 | 51.4±7.7361.3±8.7283.2±7.19**80.1±9.23**39.6±7.20126.0±15.7** | 19.361.955.8218.0 |
| 对照安定 | -0.10.31.03.0 | 62.3±7.0758.4±6.4770.9±6.8592.1±3.22**104.4±11.9** | -6.313.847.867.6 |
| 对照氯硝基安定 | -0.10.31.0 | 63.9±6.6377.7±8.5481.8±7.81110.3±13.5* | 21.628.072.6 |
| 对照去氧安定 | -0.31.03.0 | 54.6±7.8954.8±8.8571.3±10.042.7±4.54 | 0.430.6-21.8 |
对于实施例1中的化合物，检测其抗焦虑作用，口服剂量从3mg/kg到10mg/kg，其抗焦虑作用并不增强。增加口服剂量到30mg/kg后，有可能检测到作用的加强。安定和氯硝基安定的等效剂量是口服1-3mg/kg和口服1mg/kg。
对于去氧安定，在0.3-3mg/kg的口服剂量范围，不可能检测出其作用。
未处理动物饮水明显减少，这表明它们比用抗焦虑物质处理的动物更焦虑。实施例1中的化合物，从口服3mg/kg开始，动物所耐受电刺激数目明显增加。这种作用确证了通式I化合物具有良好的抗焦虑活性。
因此，可以预料，特别是在冲突环境中，通式I的化合物能够产生抗焦虑作用。
在高位迷宫中抗焦虑的研究
在该模型中，大鼠臂置于具有开臂和关臂的高位通道系统中(Pellow，S.，Chopin，P.，File S.E.，Briley，M.：Validation ofopen：在高位迷宫中关臂进入作为大鼠的焦虑方式，神经学方法杂志(J.of Neuroscience Methods)14：149-167，1985；Hogg，S.：高位迷宫作为焦虑动物模型的有效性和可变性，药理学生物化学和行为(Pharmacology Biochemistry and Behavior：21-30，1996)。未处理动物重复尝试关闭的通道。焦虑的抑制是通过进入开臂的数目和停留在开臂中的时间作为总进入数目的百分比或停留总时间的百分比来测定的。用通式I化合物处理后，进入开臂的数目和停留时间的百分比值增加，这从图2可以看出。经腹膜给药10或30mg/kg实施例1中的化合物后，进入开臂的数目和在开臂中停留时间的比例显著增加。
在药理学试验中，通式I的化合物在抗焦虑作用和镇静作用之间显示出明显的区分。图3中可以明显看出，例如，实施例1的化合物与对照物安定相比，显示出明显较低的镇静作用。
在小鼠中研究了通式I化合物的中枢镇静作用。给动物服用一定量的酒精，注意服用量不能导致任何小鼠侧卧。检测酒精催眠作用被加强的程度，通过另外服用通式I的化合物诱导小鼠侧卧。例如对于实施例1中的化合物，其抗焦虑剂量15-66倍的剂量对酒精的作用仅仅引起较低的和非剂量依赖性的加强。作为对照，研究了抗焦虑剂量范围的安定和氯硝基安定。对于这两个标准的化合物，有可能检测出对酒精作用有明显的和剂量依赖性的加强(图3)。
与对照物质安定和氯硝基安定相比，通式I的化合物仅仅有很低的神经毒性。
在rotorod试验中，实施例1中化合物口服的最低神经毒性剂量确定为998mg/kg。
治疗指数，以rotorod试验中最低神经毒性剂量和抗焦虑剂量的商计算，非常高，达到333，并且有非常大的治疗宽度，这可从图4中看出。
物质的治疗宽度作为一个重要的药理学特性参数，它是治疗作用和毒性作用之间安全性的一个测量尺度。因此，与上市的抗焦虑活性物质相比，通式I中的化合物具有非常大的治疗宽度是更为令人惊奇的。
结果，对焦虑和紧张状态患者的治疗，特别是在相对长的一段时间内的治疗，得到了明显的改进。
可以通过已知的方式把通式I的化合物及其可药用盐转变成药物制剂例如片剂、胶囊、包衣片剂、粒剂、乳剂、混悬剂或溶液剂。
可以应用传统的药用赋形剂和辅料来生产这些制剂。这样，每日剂量应该优选3-30mg/天。
Claims (1)
1、通式I的化合物：
n＝0，1
m＝0，1，2，3，4，5
其中X＝氢、C1-C4烷基、C1-C4烷氧基、三氟甲基、卤素，
R1和R2＝C1-C4烷基、环烷基、杂原子取代的烷基或者
R1和R2共同为具有2-6个碳原子的亚烷基，并且该亚烷基中的一个CH2可被氧、氮或硫置换，CH2的数目可以是0或1，
及其可药用盐在制备焦虑和紧张状态治疗药物中的应用。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19721580A DE19721580A1 (de) | 1997-05-23 | 1997-05-23 | Verwendung von 1-Ar(alk)yl-imidazolin-2-one zur Behandlung von Angst- und Spannungszuständen |
| DE19721580.7 | 1997-05-23 | ||
| US09/079,802 US5994347A (en) | 1997-05-23 | 1998-05-15 | For a process for treatment of anxiety and tension |
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| Publication Number | Publication Date |
|---|---|
| CN1260717A CN1260717A (zh) | 2000-07-19 |
| CN1150901C true CN1150901C (zh) | 2004-05-26 |
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| CNB988053748A Expired - Lifetime CN1150901C (zh) | 1997-05-23 | 1998-05-14 | 1-芳(烷)基咪唑啉-2-酮在治疗焦虑和紧张状态中的应用 |
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| EP (1) | EP0979083B1 (zh) |
| JP (1) | JP4838403B2 (zh) |
| CN (1) | CN1150901C (zh) |
| AR (1) | AR012746A1 (zh) |
| AT (1) | ATE246926T1 (zh) |
| AU (1) | AU745536B2 (zh) |
| BG (1) | BG63378B1 (zh) |
| BR (1) | BR9809666A (zh) |
| CA (1) | CA2291075C (zh) |
| DE (2) | DE19721580A1 (zh) |
| DK (1) | DK0979083T3 (zh) |
| ES (1) | ES2205516T3 (zh) |
| HU (1) | HUP0003108A3 (zh) |
| IL (1) | IL132652A0 (zh) |
| NO (1) | NO325346B1 (zh) |
| NZ (1) | NZ500849A (zh) |
| PL (1) | PL193589B1 (zh) |
| PT (1) | PT979083E (zh) |
| RU (1) | RU2203055C2 (zh) |
| SK (1) | SK284258B6 (zh) |
| TR (1) | TR199902815T2 (zh) |
| TW (1) | TW579294B (zh) |
| WO (1) | WO1998052548A2 (zh) |
| ZA (1) | ZA984197B (zh) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL166593A0 (en) | 2002-08-02 | 2006-01-15 | Racemization and enantiomer separation of clopidogrel | |
| US20050070537A1 (en) * | 2002-10-10 | 2005-03-31 | Chris Rundfeldt | Use of dihydroimidazolones for the treatment of dogs |
| CN101254189A (zh) * | 2003-07-11 | 2008-09-03 | 埃尔比昂股份公司 | 用对苯并二氮杂䓬受体的α3亚基具有选择性的化合物治疗或预防中枢神经系统病症的方法 |
| CA2576344C (en) | 2004-08-11 | 2010-10-05 | Cadbury Adams Usa Llc | Warming compositions and delivery systems therefor |
| US9820988B2 (en) | 2014-03-24 | 2017-11-21 | Boehringer Ingelheim Vetmedica Gmbh | Treatment of epileptic disorders in feline animals |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4044021A (en) * | 1971-10-21 | 1977-08-23 | American Cyanamid Company | Tetrasubstituted imidazolidine diuretics useful in the treatment of hyperaldosteronism |
| US5869481A (en) * | 1995-09-05 | 1999-02-09 | Arzneitmittelwerk Dresden G.M.B.H. | Anticonvulsive 1-ar(alk)ylimidazolin-2-ones and process for making |
| DE19532668A1 (de) * | 1995-09-05 | 1997-03-06 | Dresden Arzneimittel | Neue, antikonvulsiv wirkende 1-Ar(alk)yl-imidazolin-2-one, die in 4-Stellung einen disubstituierten Amin-Rest enthalten, und Verfahren zu deren Herstellung |
-
1997
- 1997-05-23 DE DE19721580A patent/DE19721580A1/de not_active Withdrawn
-
1998
- 1998-05-14 TR TR1999/02815T patent/TR199902815T2/xx unknown
- 1998-05-14 ES ES98933532T patent/ES2205516T3/es not_active Expired - Lifetime
- 1998-05-14 WO PCT/DE1998/001343 patent/WO1998052548A2/de active IP Right Grant
- 1998-05-14 EP EP98933532A patent/EP0979083B1/de not_active Expired - Lifetime
- 1998-05-14 DK DK98933532T patent/DK0979083T3/da active
- 1998-05-14 HU HU0003108A patent/HUP0003108A3/hu unknown
- 1998-05-14 BR BR9809666-4A patent/BR9809666A/pt not_active Application Discontinuation
- 1998-05-14 SK SK1584-99A patent/SK284258B6/sk not_active IP Right Cessation
- 1998-05-14 PL PL98337090A patent/PL193589B1/pl not_active IP Right Cessation
- 1998-05-14 AT AT98933532T patent/ATE246926T1/de not_active IP Right Cessation
- 1998-05-14 AU AU83326/98A patent/AU745536B2/en not_active Expired
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- 1998-05-14 RU RU99128109/14A patent/RU2203055C2/ru active
- 1998-05-14 DE DE59809285T patent/DE59809285D1/de not_active Expired - Lifetime
- 1998-05-14 PT PT98933532T patent/PT979083E/pt unknown
- 1998-05-14 CA CA002291075A patent/CA2291075C/en not_active Expired - Lifetime
- 1998-05-14 IL IL13265298A patent/IL132652A0/xx not_active IP Right Cessation
- 1998-05-14 CN CNB988053748A patent/CN1150901C/zh not_active Expired - Lifetime
- 1998-05-14 NZ NZ500849A patent/NZ500849A/en unknown
- 1998-05-15 US US09/079,802 patent/US5994347A/en not_active Expired - Lifetime
- 1998-05-19 ZA ZA9804197A patent/ZA984197B/xx unknown
- 1998-05-20 TW TW087107848A patent/TW579294B/zh not_active IP Right Cessation
- 1998-05-22 AR ARP980102409A patent/AR012746A1/es not_active Application Discontinuation
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1999
- 1999-10-29 NO NO19995300A patent/NO325346B1/no not_active IP Right Cessation
- 1999-11-04 BG BG103859A patent/BG63378B1/bg unknown
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