CN101096347A - 新萘化合物、其制备方法及其药物组合物 - Google Patents
新萘化合物、其制备方法及其药物组合物 Download PDFInfo
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- CN101096347A CN101096347A CNA2007101379640A CN200710137964A CN101096347A CN 101096347 A CN101096347 A CN 101096347A CN A2007101379640 A CNA2007101379640 A CN A2007101379640A CN 200710137964 A CN200710137964 A CN 200710137964A CN 101096347 A CN101096347 A CN 101096347A
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Abstract
本发明涉及新萘化合物、其制备方法及其药物组合物。本发明公开式(I)化合物，这些化合物可作为药物。
Description
技术领域
本发明涉及新萘化合物、其制备方法及以及含有该新化合物的药物组合物。
背景技术
本发明的化合物是新的，具有与褪黑素能受体相关的重要的药理学特性。
近十年来大量的研究证明了褪黑素(N-乙酰-5-甲氧基色胺)在许多病理生理学现象和昼夜节律控制中起着关键作用。然而，由于该物质代谢迅速，所以其半衰期很短。因此，能够为临床医师提供代谢更稳定、具有激动或拮抗特性并且疗效优于激素本身的褪黑素类似物具有重要的意义。
除了对昼夜节律失调(J.Neurosurg.1985，
63，第321-341页)和睡眠障碍(Psychopharmacology，1990，
100.第222-226页)具有有益的效果外，褪黑素能系统的配体还具有与中相神经系统相关的重要的药理学特性，尤其是抗焦虑和治疗精神病的特性(Neuropharmacology of Pineal Secretions，1990，
8(3-4)，第264-272页)和镇痛特性(Pharmacopsychiat.，1987，
20，第222-223页)，以及治疗帕金森氏症(J.Neurosurg.1985，
63，第321-341页)和阿尔茨海默氏病(Brain Research，1990，
528，第170-174页)的特性。还证明这些化合物对特定肿瘤(Melatonin-ClinicalPerspectives，Oxford University Press，1988，第164-165页)、排卵(Science 1987，227，第714-720页)、糖尿病(Clinical Endocrinology，1986，
24，第359-364页)，以及肥胖的治疗(International Journal of Eating Disorders，1996，
20(4)，第443-446页)方面具有活性。
上述各种作用是通过特殊的褪黑素受体发挥出来的。分子生物学研究已经证明存在许多能够与激素结合的受体亚型(Trends Pharmacol.Sci.，1995，
16，第50页；WO 97.04094)。对于包括哺乳动物在内的不同物种而言，有可能鉴定并表征其中的某些受体。为了更好地理解这些受体的生理机能，最好获得选择性受体。此外，通过选择性地与这些受体中的一个或多个相互作用，这些化合物可以成为临床医师治疗与褪黑素能系统相关的疾病很好的药物，其中一些已经在上文中提及。
本发明的化合物除了是新化合物之外，它们还对褪黑素受体具有强的亲合力。
而且，本发明的化合物还对5-HT2C受体具有强亲合力，这增强了褪黑素能受体的特性，特别是在抑郁症的情况下。
发明内容
更具体地讲，本发明涉及式(I)化合物、其对映异构体及其与药学可接受碱的加成盐：
在药学可接受碱中，可以非限定性地提及氢氧化钠、氢氧化钾、三乙胺、叔丁胺等。
更具体而言，本发明涉及以下化合物：2-氟-N-[3-羟基-2-(7-甲氧基-1-萘基)丙基]乙酰胺、2-氟-N-[(2S)-3-羟基-2-(7甲氧基-1-萘基)丙基]乙酰胺和2-氟-N-[(2R)-3-羟基-2-(7-甲氧基-1-萘基)丙基]乙酰胺。
本发明优选化合物与药学可接受碱的加成盐构成本发明不可分割的一部分。
本发明也涉及式(I)化合物的制备方法，其特征在于以式(II)化合物作为起始原料：
该化合物在碱性介质中与碳酸二甲酯作用生成式(III)化合物：
该化合物在氢化物存在下还原生成式(IV)化合物。
该化合物与氟乙酸乙酯缩合产生式(I)化合物，可以根据常规的分离技术纯化，如果需要的话，将该化合物转化为与药学可接受碱的加成盐，以及可以根据常规分离技术在手性柱上拆分的对映异构体。
经药理学研究证明，本发明的化合物无毒，对褪黑素受体具有强的选择性亲和力，对中枢神经系统具有显著作用，而且，特别地，已经发现了它们在治疗睡眠障碍、抗抑郁、抗焦虑、抗精神病和镇痛方面具有活性并且在微循环方面也具有治疗活性，从而使得本发明的化合物可以用于治疗紧张、睡眠障碍、焦虑、季节性情感障碍或抑郁症、心血管疾病、消化系统疾病、时差引起的失眠和疲劳、精神分裂症、恐慌症、忧郁症、食欲失调、肥胖、失眠、精神病、癫痫症、糖尿病、帕金森氏症、老年性痴呆、各种与正常或病理性衰老相关的紊乱、偏头痛、记忆下降和阿尔茨海默氏病、脑循环障碍。在另一作用领域，本发明的化合物可用于治疗性功能障碍，具有排卵抑制和免疫调节特性，可用于治疗肿瘤。
所述化合物优选用于治疗抑郁症、季节性情感障碍、睡眠障碍、心血管疾病、消化系统疾病、时差引起的失眠和疲劳、食欲不振和肥胖。
例如，所述化合物用于治疗抑郁症、季节性情感障碍和睡眠障碍。
本发明也涉及包括至少一种式(I)化合物本身或结合一种或多种药学可接受赋形剂的药物细合物。
在本发明的药物组合物中，特别可提及适用于口服、胃肠外、鼻内、经皮或透皮、直肠、经舌、眼或呼吸给药的药物组合物，尤其是片剂或糖衣剂、舌下片剂、袋装剂、药盒(paquets)、胶囊剂、舌下剂、锭剂、栓剂、乳剂、膏剂、皮肤凝胶剂和可饮用的或可注射的安瓿剂。
剂量根据病人的性别、年龄和体重、给药途径、治疗适应症的特性或任何结合的治疗的不同而不同，每24小时一次或多次给药0.01毫克至1克。
具体实施方式
以下实施例对本发明进行说明但不构成任何限定。
实施例1：2-氟-N-[3-羟基-2-(7-甲氧基-1-萘基)丙基]乙酰胺
步骤A：氰基(7-甲氧基-1-萘基)乙酸甲酯
将(7-甲氧基-萘基-1-基)乙腈(20g)溶于150ml无水四氢呋喃中。在环境温度下加入氢化钠(202.8mmol)，然后回流该混合物30分钟。缓慢加入碳酸二甲酯(12ml)，所得反应混合物回流30分钟。将混合物倒入冰水中，水相用21ml 37％的盐酸溶液酸化，之后用100ml乙醚萃取两次。有机相水洗、干燥、脱色、蒸干。所得的油状物用乙醚沉淀，抽滤所得沉淀物，然后重结晶得到白色固体形式的标题产物。
熔点：80-82℃
步骤B：3-氨基-2-(7-甲氧基-1-萘基)-1-丙醇盐酸盐
将氯化铝(80mmol)溶于200ml无水乙醚中，0℃下加入到300ml含氢化锂铝的无水乙醚悬浮液中。搅拌10分钟后，加入溶于200ml无水乙醚的步骤A所得化合物(20mmol)。30分钟之后，用氢氧化钠溶液(10g；40ml)在冷却状态下缓慢水解该混合物。过滤形成的沉淀，然后用大量乙醚洗涤。蒸发之后所得的残留物溶于水中，水相用二氯甲烷萃取。有机相用水洗涤，干燥和脱色，然后用气态氯化氢处理，蒸干。所得的油状物用乙酸乙酯沉淀，抽滤形成的沉淀物，然后重结晶，得到白色固体形式的标题产物。
熔点：164-166℃
步骤C：2-氟-N-[3-羟基-2-(7-甲氧基-1-萘基)丙基]乙酰胺
将碱的形式的步骤B所得的化合物(5.6mmol)溶于40ml 2，2，2-三氟乙醇中；加入氟乙酸乙酯(10.3mmol)，回流该混合物12小时。反应完成后将混合物倒入水中，水相用60ml乙醚萃取两次；有机相用水洗，干燥，蒸干。所得的油状物溶于30ml甲醇和10ml水中；加入氢氧化钠(8.25mmol)，在40℃下加热该混合物30分钟。然后将混合物倒入水中；水相用15ml盐酸溶液(1M)中和，然后用60ml乙醚萃取两次。有机相用水洗涤，干燥，蒸干。所得的油状物在乙醚和石油醚混合液(40/60)中沉淀；抽滤所形成的沉淀，之后从甲苯中重结晶得到白色固体形式的标题化合物。
熔点：110-112℃
元素的微量分析：
％ C H N
计算： 65.97 6.23 4.81
实测： 66.10 6.29 4.63
实施例1得到的化合物经过手性柱(R，R)WHELK 0-1纯化，洗脱液为异丙醇/正庚烷/二氯甲烷(60/40/5)，在275nm处检测，得到实施例2和3的化合物：
实施例2：2-氟-N-[(2S)-3-羟基-2-(7-甲氧基-1-萘基)丙基]乙酰胺
实施例3：2-氟-N-[(2R)-3-羟基-2-(7-甲氧基-1-萘基)丙基]乙酰胺
药理学研究
实施例A：急性毒性研究
各细动物口服给药之后进行急性毒性评价，每组包括8只小鼠(26±2g)。动物给药后两星期内第一天每隔一定时间观察，然后每天观察。用LD50值(致使50％动物死亡的剂量)进行评价，结果显示本发明化合物具有低毒性。
实施例B：强迫游泳试验
本发明的化合物采用行为模型强迫游泳试验进行检测。
仪器包括充满水的有机玻璃圆筒。每只动物试验6分钟。每次试验开始时，将动物置于圆筒中央。记录动物直到不动时所花费的时间。动物停止挣扎保持在水面上，仅仅作一些动作以保持头在水面上被认为是不动的。
给药40分钟后开始试验，本发明的化合物显著减少不动所花的时间，显示了它们的抗抑郁活性。
实施例C：褪黑素MT1和MT2受体结合研究
MT1或MT2受体结合试验使用2-[125I]-碘褪黑素作为参照放射性配体进行。保留的放射性用液体闪烁计数器检测。
然后用不同的测试化合物以一式三份进行竞争性结合试验。每种化合物在不同浓度范围进行试验。结果得出所试验的化合物的结合亲和性(Ki)。
举例来说，实施例1所得的化合物的Ki(MT1)为4.7nM和Ki(MT2)为0.5nM。
实施例D：5-羟色胺能5-HT2c受体结合研究
在稳定表达受体的CHO细胞膜制剂上评价化合物对人5-HT2c受体的亲合力。
在50mM pH为7.4、包含10mM MgCl2和0.1％牛血清蛋白的三羟甲基氨基甲烷缓冲液中，在[3H]-美舒麦角(1nM)和25fmol/ml受体存在进行结合试验。在10μM米安色林存在下测定非特异性结合。
加入50mM pH 7.4三羟甲基氨基甲烷缓冲液中止反应，然后过滤和连续漂洗3次：保留在过滤器(用0.1％PEI预处理的GF/B)上的薄膜上结合的放射性通过液体闪烁计数测量。
所得结果显示本发明的化合物对5-HT2c受体具有亲合性，Ki值＜10μM。
实施例E：本发明化合物对大鼠自发活动昼夜节律的作用
褪黑素参与通过昼夜节律影响大部分生理、生化和行为的事实使得能够建立一个用于研究褪黑素能配体的药理学模型。
检测化合物对多种参数的影响，特别是对自发活动昼夜节律的影响，其作为内源性昼夜节律钟活动的可靠指标。
在这项研究中，评估这些化合物对特殊实验模型，即被暂时隔离(永久黑暗)大鼠的影响。
实验方案
一个月龄的雄性大鼠一进入实验室就被置于每24小时光照12小时的光照循环中(LD 12：12)。
适应2到3周之后，将大鼠置于装有与记录系统连接的轮的箱中以观测自发活动期，并由此监测随昼夜差异而变化的节奏(LD)或昼夜节律(DD)。
当记录的节律在光循环LD 12：12期间一旦显示出稳定的特性，就将大鼠置于永久黑暗中(DD)。
两到三周以后，当明显地建立起自由进程时(反映出内源性时钟的节律)，对大鼠每天进行受试化合物的给药。
通过显示的活动节律进行观察：
-通过光/暗循环对活动节律的影响，
-永久性黑暗中对节律的影响消失，
-通过每天摄入化合物对活动的影响：暂时的或长期影响。
软件包可以用于进行如下工作：
-测量活动的持续时间和强度，自由进程和治疗期间动物的节律周期，
-可以通过光潜分析表明存在生理节奏和非生理节奏(例如超日)部分。
结论
本发明的化合物通过褪黑素能系统明显地表现出对昼夜节律的强大作用。
实施例F：明/暗箱试验
在行为模型明/暗箱中对本发明的化合物进行测试，证明化合物具有抗焦虑活性。
仪器包括两个带有树脂玻璃盖的聚乙烯箱。一个箱处于黑暗中。另一个箱上面置有灯，在箱中央产生大约4000lux的光强。不透明的塑料通道将明箱和暗箱分开。每只动物分别试验5分钟。每次试验之间清扫箱底板。每次试验开始时，将小鼠置于通道中，面向暗箱。记录小鼠第一次进入暗箱之后在明箱中渡过的时间和通过通道的次数。
化合物给药30分钟后开始进行试验，本发明的化合物显著地增加在明箱中渡过的时间和通过通道的次数，证明了本发明化合物的抗焦虑作用。
实施例G：药物组合物：片剂
1000片，每片含有5mg 2-氟-N-[3-羟基-2-(7-甲氧基-1-萘基)丙基]乙酰胺(实施例1) 5g
小麦淀粉 20g
玉米淀粉 20g
乳糖 30g
硬脂酸镁 2g
二氧化硅 1g
羟丙基纤维素 2g。
Claims (8)
1.式(I)化合物、其对映异构体及其与药学可接受碱的加成盐：
2.根据权利要求1的式(I)化合物，该化合物是2-氟-N-[3-羟基-2-(7-甲氧基-1-萘基)丙基]乙酰胺、其对映异构体及其与药学可接受碱的加成盐。
3.根据权利要求1的式(I)化合物，该化合物是2-氟-N-[(2S)-3-羟基-2-(7-甲氧基-1-萘基)丙基]乙酰胺及其与药学可接受碱的加成盐。
4.根据权利要求1的式(I)化合物，该化合物是2-氟-N-[(2R)-3-羟基-2-(7-甲氧基-1-萘基)丙基]乙酰胺及其与药学可接受碱的加成盐。
5.制备根据权利要求1所述的式(I)化合物的方法，其特征在于以式(II)化合物作为起始原料：
在碱性介质中使该化合物与碳酸二甲酯反应生成式(III)化合物：
该化合物在氢化物存在下还原生成式(IV)化合物，
该化合物与氟乙酸乙酯缩合产生式(I)化合物，
可以根据常规的分离技术纯化该化合物，如果需要的话，将该化合物转化为与药学可接受碱的加成盐，以及根据常规分离技术在手性柱上分离对映异构体。
6.药物组合物，该药物组合物包含至少一种权利要求1-4中任一项所述的式(I)化合物或其与药学可接受碱的加成盐和一种或多种药学可接受赋形剂。
7.根据权利要求6所述的药物组合物，该药物组合物用于制备治疗褪黑素能系统紊乱的药物。
8.根据权利要求6所述的药物组合物，该药物组合物用于生产治疗睡眠障碍、紧张、焦虑、抑郁症或季节性情感障碍、心血管疾病、消化系统疾病、时差引起的失眠和疲劳、精神分裂症、恐慌症、忧郁症、食欲失调、肥胖、失眠、精神病、癫痫症、糖尿病、帕金森氏症、老年性痴呆、各种与正常或病理性衰老相关的紊乱、偏头痛、记忆下降、阿尔茨海默氏病、脑循环障碍或性功能障碍的药物、作为排卵抑制剂或免疫调节剂，或用于生产治疗肿瘤的药物。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR0605918A FR2903103B1 (fr) | 2006-06-30 | 2006-06-30 | Nouveaux derives naphtaleniques, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
| FR06/05918 | 2006-06-30 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101096347A true CN101096347A (zh) | 2008-01-02 |
Family
ID=37993890
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2007101379640A Pending CN101096347A (zh) | 2006-06-30 | 2007-06-29 | 新萘化合物、其制备方法及其药物组合物 |
Country Status (22)
| Country | Link |
|---|---|
| US (1) | US7435850B2 (zh) |
| EP (1) | EP1873139A1 (zh) |
| JP (1) | JP2008013558A (zh) |
| KR (1) | KR100912162B1 (zh) |
| CN (1) | CN101096347A (zh) |
| AR (1) | AR061741A1 (zh) |
| AU (1) | AU2007203040A1 (zh) |
| BR (1) | BRPI0702769A (zh) |
| CA (1) | CA2593618C (zh) |
| EA (1) | EA012282B1 (zh) |
| FR (1) | FR2903103B1 (zh) |
| GE (1) | GEP20094744B (zh) |
| MA (1) | MA29224B1 (zh) |
| MX (1) | MX2007007900A (zh) |
| MY (1) | MY143486A (zh) |
| NO (1) | NO20073308L (zh) |
| NZ (1) | NZ556189A (zh) |
| SG (1) | SG138590A1 (zh) |
| TW (1) | TW200817310A (zh) |
| UA (1) | UA93864C2 (zh) |
| WO (1) | WO2008000967A1 (zh) |
| ZA (1) | ZA200704956B (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102875415A (zh) * | 2012-10-09 | 2013-01-16 | 江西同和药业有限责任公司 | 一种化合物及其制备方法和应用 |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2903101B1 (fr) * | 2006-06-30 | 2008-09-26 | Servier Lab | Nouveaux derives naphtaleniques, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2689124A1 (fr) * | 1992-03-27 | 1993-10-01 | Adir | Nouvelles naphtylalkylamines, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent. |
| FR2737725B1 (fr) * | 1995-08-08 | 1997-10-31 | Valentonine | Nouveaux derives acyles de la melatonine et d'analogues melatoninergiques, leur procede de preparation et leur utilisation en tant que medicament |
| FR2771739B1 (fr) * | 1997-11-28 | 2001-04-20 | Adir | Nouveaux composes naphtaleniques, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
| FR2903101B1 (fr) * | 2006-06-30 | 2008-09-26 | Servier Lab | Nouveaux derives naphtaleniques, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
-
2006
- 2006-06-30 FR FR0605918A patent/FR2903103B1/fr not_active Expired - Fee Related
-
2007
- 2007-06-14 MY MYPI20070962A patent/MY143486A/en unknown
- 2007-06-18 MA MA30016A patent/MA29224B1/fr unknown
- 2007-06-26 ZA ZA200704956A patent/ZA200704956B/xx unknown
- 2007-06-26 SG SG200704788-9A patent/SG138590A1/en unknown
- 2007-06-27 MX MX2007007900A patent/MX2007007900A/es active IP Right Grant
- 2007-06-27 UA UAA200707272A patent/UA93864C2/ru unknown
- 2007-06-28 KR KR1020070064102A patent/KR100912162B1/ko not_active Expired - Fee Related
- 2007-06-28 NZ NZ556189A patent/NZ556189A/en unknown
- 2007-06-28 NO NO20073308A patent/NO20073308L/no not_active Application Discontinuation
- 2007-06-29 CA CA2593618A patent/CA2593618C/fr not_active Expired - Fee Related
- 2007-06-29 EA EA200701177A patent/EA012282B1/ru not_active IP Right Cessation
- 2007-06-29 AU AU2007203040A patent/AU2007203040A1/en not_active Abandoned
- 2007-06-29 JP JP2007171623A patent/JP2008013558A/ja not_active Ceased
- 2007-06-29 CN CNA2007101379640A patent/CN101096347A/zh active Pending
- 2007-06-29 WO PCT/FR2007/001104 patent/WO2008000967A1/fr active Application Filing
- 2007-06-29 GE GEAP200710153A patent/GEP20094744B/en unknown
- 2007-06-29 AR ARP070102913A patent/AR061741A1/es not_active Application Discontinuation
- 2007-06-29 BR BRPI0702769-9A patent/BRPI0702769A/pt not_active IP Right Cessation
- 2007-06-29 EP EP07290818A patent/EP1873139A1/fr not_active Withdrawn
- 2007-06-29 US US11/824,392 patent/US7435850B2/en not_active Expired - Fee Related
- 2007-06-29 TW TW096123644A patent/TW200817310A/zh unknown
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102875415A (zh) * | 2012-10-09 | 2013-01-16 | 江西同和药业有限责任公司 | 一种化合物及其制备方法和应用 |
| CN102875415B (zh) * | 2012-10-09 | 2014-08-20 | 江西同和药业有限责任公司 | 一种化合物及其制备方法和应用 |
Also Published As
| Publication number | Publication date |
|---|---|
| MA29224B1 (fr) | 2008-02-01 |
| WO2008000967A1 (fr) | 2008-01-03 |
| JP2008013558A (ja) | 2008-01-24 |
| EA200701177A1 (ru) | 2008-02-28 |
| UA93864C2 (ru) | 2011-03-25 |
| TW200817310A (en) | 2008-04-16 |
| ZA200704956B (en) | 2008-08-27 |
| AU2007203040A1 (en) | 2008-01-17 |
| NZ556189A (en) | 2008-11-28 |
| KR20080003264A (ko) | 2008-01-07 |
| FR2903103A1 (fr) | 2008-01-04 |
| EP1873139A1 (fr) | 2008-01-02 |
| EA012282B1 (ru) | 2009-08-28 |
| CA2593618A1 (fr) | 2007-12-30 |
| CA2593618C (fr) | 2010-08-24 |
| BRPI0702769A (pt) | 2008-02-19 |
| FR2903103B1 (fr) | 2010-08-13 |
| MY143486A (en) | 2011-05-31 |
| US20080004350A1 (en) | 2008-01-03 |
| SG138590A1 (en) | 2008-01-28 |
| NO20073308L (no) | 2008-01-02 |
| US7435850B2 (en) | 2008-10-14 |
| KR100912162B1 (ko) | 2009-08-14 |
| MX2007007900A (es) | 2009-02-16 |
| AR061741A1 (es) | 2008-09-17 |
| GEP20094744B (en) | 2009-07-27 |
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