CN1323208A - 眼病治疗剂 - Google Patents
眼病治疗剂 Download PDFInfo
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- CN1323208A CN1323208A CN99812057A CN99812057A CN1323208A CN 1323208 A CN1323208 A CN 1323208A CN 99812057 A CN99812057 A CN 99812057A CN 99812057 A CN99812057 A CN 99812057A CN 1323208 A CN1323208 A CN 1323208A
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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- Animal Behavior & Ethology (AREA)
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- Pharmacology & Pharmacy (AREA)
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- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
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- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
Abstract
通式(Ⅰ)所示化合物在眼病治疗或预防中的用途。在所述式中,R1和R2各自独立地是低级烷基;而R3和R4各自独立地是氢或低级烷基。
Description
本发明涉及K-252a衍生物的眼病治疗剂和在眼病治疗上的用途。
背景技术
视网膜有接受外部光线的机能，并在视觉机能上发挥重要作用。在结构上，它由10层组成，始于网膜色素上皮层，包括内网状层、神经节细胞层、神经纤维层等，是厚度0.1～0.5mm的组织。在内网状层中，存在着与无长突细胞这样的神经节细胞突起配对而形成突触的神经细胞。这种神经细胞对光照射开始时和结束时能作出良好应答，因而可以认为起到光强度检测器的作用。神经节细胞层中，存在着其细胞存在于视网膜最内侧的神经细胞，与运动视、周边视、色觉、形态觉等有密切关系。此外，神经纤维层中，有作为网膜中心动静脉分枝的网膜血管分布，承担着向视神经供给氧气和营养的作用。
最近，所谓“神经保护”(neuro-protection)这样的见解日益流行，即认为在绿内障(青光眼)中，视网膜循环或视神经轴索输送的障碍导致最终因神经节细胞死亡而发生神经纤维脱落，从而向视野障碍推进，因此，考虑预防神经节细胞死亡或将其抑制到最低限度的治疗，关系到最终的绿内障治疗(眼科，40,251-273(1998))。实际上，有报告说，在高眼压缺血大鼠中，网膜神经节细胞层或视神经乳头的障碍，即使在45分钟缺血后也能观察到(Graefes Arch.Clin.Exp.Ophthalmol.,234,445-451(1996))，或者在甲基纤维素诱发高眼压兔中，在为期10天的高眼压后，发现网膜神经节细胞密度显著减少和神经胶质细胞密度显著增加，而且发现神经节细胞的脱落与细胞的大小相关(Craefes Arch.Clin.Exp.Ophthalmol.,234,S209-S213(1996))。
如果网膜血管由于痉挛、血栓、栓子、动脉硬化等要因而闭塞或狭窄，则网膜循环发生障碍，而且向网膜或视神经的氧气和营养供应受阻。网膜循环障碍在网膜疾病中占有特别重要的位置。作为网膜循环障碍伴随的症状的代表性实例，有网膜静脉或网膜动脉闭塞或狭窄的网膜血管闭塞症，有引起直至网膜剥离的可能性的糖尿病网膜症，和出现视机能障碍的缺血性视神经症。进而，这种网膜循环障碍会引起氧气或营养供给不足，并导致网膜神经系细胞死亡、即使在遗传性网膜疾病的黄斑变性症、网膜色素变性症、勒伯尔(Leber)病中，也认为这种神经系细胞死亡与发病有密切关系。
此外，已经查明，在眼病的多样病态中，都涉及程序化细胞死亡的一种形态，即apoptosis。例如，在缺血-再灌流引起的网膜障碍(J.Ocul.Pharmacol.Ther.,11,253-259(1995))、网膜剥离(Arc.Ophthalmol.113,880-886(1995))、网膜变性病(Proc.Natl.Acad.Sci.USA,91,974-978(1994)；Invest.Ophthalmol.Vis.Sci.,35,2693-2699(1994))、网膜光障碍(Invest.Ophthalmol.Vis.Sci.,37,775-782(1996))、绿内障(Invest.Ophthalmol.Vis.Sci.,36,774-786(1995)；Exp.Eye Res.,61,33-44(1995))等中，都报告在网膜神经系细胞中发生apoptosis。总之，即使原因是多样的，作为结果发生的视机能障碍，其原因很可能也是构成视觉情报网络的神经细胞的apoptosis。
因此，如果存在着有网膜神经节细胞保护作用的药物，则预期可用于网膜血管闭塞症、糖尿病网膜症、缺血性视神经症、黄斑变性症、网膜色素变性症、勒伯尔病为代表的网膜疾病或绿内障等眼病的治疗。
另一方面，国际专利WO94/02488号公开公报中，公开了对脊髓胆碱乙酰转移酶活性有强促进作用、可用于治疗阿尔茨海默病、肌萎缩硬化症、帕金森病、脑缺血症等神经细胞变性的K-252a衍生物。此外，关于这种衍生物，也有报告说能抑制运动神经元引起的apoptosis(J.Neurosci.,18,104-111(1998))或能抑制肿瘤坏死因子-α或间白细胞素-1β的过量产生(国际专利公开WO97/49406号公报)。
然而。尚无关于眼科领域的研究报告。
发明公开
找到作用机理上有特征的、对网膜血管闭塞症、糖尿病网膜症、缺血性视神经症、黄斑变性症、网膜色素变性症、勒伯尔病为代表的网膜疾病或绿内障等眼病的治疗剂，是非常有趣的课题。
本发明者等人，从神经保护的观点出发，着眼于用来作为神经细胞变性治疗剂的已知药物，探讨了对网膜神经节细胞的影响，确认K-252a衍生物能保护网膜神经系细胞免于障碍，并发现它可用来作为网膜血管闭塞症、糖尿病网膜症、缺血性视神经症、黄斑变性症、网膜色素变性症、勒伯尔病为代表的网膜疾病或绿内障等眼病的治疗剂。
本发明涉及以下通式(Ⅰ)所示K-252a衍生物(以下称本化合物)的绿内障治疗剂或网膜疾病治疗剂等眼病治疗剂，和对该疾病治疗法的用途。
通式(Ⅰ)：
式中，R1表示低级烷基，
R2表示低级烷基，
R3表示氢原子或低级烷基，
R4表示氢原子或低级烷基。
更具体地说，按照本发明，提供一种眼病治疗或预防用医药制剂，包含眼病治疗或预防有效量的通式(Ⅰ)所示化合物和赋形剂或添加剂。
作为另一种形态的本发明，是提供一种眼病的治疗或预防法，包含对需要眼病治疗或预防的对象给药对该治疗或预防足够数量的通式(Ⅰ)所示化合物。
作为又另一种形态的本发明，是提供通式(Ⅰ)所示化合物作为眼病治疗或预防用医药制剂中的有效成分的用途。
发明最佳实施形态
在本发明范畴内，低级烷基系指甲基、乙基、丙基、丁基、己基、异丙基、异丁基、叔丁基等有1～6个碳原子的直链或支链烷基。
作为本化合物的较好实例，可以列举R1和R2均为乙基、R3和R4均为甲基的化合物，最好的实例(以下称为化合物A)的具体结构可用以下式(Ⅱ)表示。式(Ⅱ)：
关于本化合物对网膜神经系细胞的影响，其细节在后述的药理试验项中说明，但在用缺血-再灌流网膜以及红藻氨酸处置眼探讨上述影响时，确认本化合物能抑制网膜神经节细胞层的细胞数减少。
本化合物的给药途径可以是非经口途径和经口途径中任何一种。作为非经口给药的剂型，可以列举点眼剂、注射剂、点鼻剂等；但作为经口给药的剂型，可以列举片剂、胶囊剂、散剂等，采用本技术领域中常用的赋形剂或添加剂以及技术，就可以使本化合物制剂化。例如，在点眼剂的情况下，作为赋形剂或添加剂，必要时用氯化钠、浓甘油等等渗剂，磷酸钠、乙酸钠等缓冲剂，聚氧乙烯缩水山梨糖醇单油酸酯(以下称Polysorbate 80)、硬脂酸多羟基40、聚氧乙烯硬化蓖麻油等表面活性剂，柠檬酸钠、乙二胺四乙酸盐等稳定剂，和氯化苯甲烃铵、对羟基苯甲酸酯类等防腐剂等，就可以使本化合物制剂化，pH只要在眼科制剂允许的范围就可以，较好的是在4～8的范围内。
给药量因症状、年龄、剂型等而异，可以适当选择，但若是点眼剂，则用0.01～10％(重量/体积)药剂1日点眼1次～数次即可，而若是注射剂，则通常以日剂量0.0001～1mg、1次或分数次给药即可。而若是经口剂型，则通常可以10μg～1g的日剂量，每日1次或分数次给药。
以下显示药理试验结果，但这些例子只是为了更好地理解本发明，并不限定本发明的范围。
实施例
药理试验：
为了考察本化合物的有用性、探讨了在缺血-再灌流网膜和红藻氨酸处置眼中对网膜的影响。
1．对于缺血-再灌流网膜
据报告，作为神经营养因子的脑衍生神经营养因子(以下称BDNF)，对网膜缺血引起的神经节细胞死亡有保护作用(Invest.Ophthalmol.Vis.Sci.,35,907-915(1994))。
因此，按照此文献中记载的方法，探讨了本化合物对网膜缺血-再灌流模型中网膜神经节细胞的影响。
(实验方法)
在Ketalar(盐酸氯胺酮)和Celactal的混合液的麻醉下，切开Sprague-Dawley系雄性大鼠(300～450g)的结膜以露出视神经，用缝合丝结扎，使之处于缺血状态。缺血60分钟后取下缝合丝，使网膜的血流再灌流。再灌流7日后摘出眼球，用多聚甲醛固定，用石蜡包埋后，从视神经露出的部分制作60μm间隔、厚度3μm的横断面的石蜡切片。这种切片用苏木精曙红染色，对距离视神经乳头部左右任意方向上约1mm的网膜进行照片拍摄，测定神经节细胞层中的细胞数。
要说明的是，本化合物溶解于聚乙二醇660羟基硬脂酸酯中，在缺血2日前向玻璃体内注射1μl。
(结果)
表1中，作为实验结果之一例，列出了在注射以3mg/ml的浓度制备的本化合物A溶液的情况下(注射量：3μg/眼)神经节细胞层中的细胞数。此外，还一起列出了不进行缺血-再灌流、不进行本化合物注射的情况(以下称正常组①)，以及进行缺血-再灌流但不进行本化合物注射而只注射聚乙二醇660羟基硬脂酸酯的情况(以下称对照组①)。
表1
| 神经节细胞层中的细胞数(个细胞/mm) | |
| 正常组①(5) | 38.8 |
| 对照组①(7) | 20.5 |
| 本化合物A注射组(3μg/眼)(10) | 27.5 |
注：表中的值是()内例数的平均值。
如表1中所示，注射本化合物A3μg时，可以确认能抑制缺血-再灌流引起的神经节细胞层中的细胞数减少，并恢复到正常组①的细胞数的70.9％。
这个事实表明，本化合物A对缺血再灌流引起的网膜神经细胞障碍有优异的保护作用。
2．对红藻氨酸处置眼中的网膜
有报告说，若将神经毒素红藻氨酸注入玻璃体内，则无长突细胞的细胞死亡会导致突触崩解从而使内网状层变薄，或使神经节细胞层中的细胞发生apoptosis而减少(Neurochem.Int.,31,251-260(1997))。
因此，按照此文献上记载的方法，向玻璃体内注入红藻氨酸，探讨本化合物对所诱发的网膜障碍的影响。
(实验方法)
向戊巴比妥麻醉下的Sprague-Dawley系雄性大鼠(180～250g)两眼的玻璃体内，在实体显微镜下注射5μl红藻氨酸的聚乙二醇660羟基硬脂酸酯溶液(1mM)。红藻氨酸处置7日后摘出眼球，用戊二醛-多聚甲醛固定，用石蜡包埋后，从视神经露出部位制作60μm间隔、3μm厚度的横断面的石蜡切片。这种切片用苏木精曙红染色，对距离视神经乳头部左右任意方向上约1mm的网膜进行照片拍摄，测定内网状层的厚度和神经节细胞层中的细胞数。
本化合物溶解于聚乙二醇660羟基硬脂酸酯中，在红藻氨酸处置2日前、与处置同时、和处置1日后，分别向玻璃体内注射5μl。
(结果)
表2中，作为实验结果之一例，列出了注射以6μg/ml浓度制备的本化合物A溶液的情况(注射量：30ng/眼)下和注射以600μg/ml浓度制备的本化合物A溶液的情况(注射量：3μg/眼)下内网状层的厚度和神经节细胞层中的细胞数。此外，还一并列出了不进行红藻氨酸和本化合物注射而只注射聚乙二醇660羟基硬脂酸酯的情况(以下称正常组②)以及进行红藻氨酸处置但不注射本化合物而只注射聚乙二醇660羟基硬脂酸酯的情况(以下称对照组②)。
表2
注：表中的值是5例的平均值。
| 内网状层厚度(μm) | 神经节细胞层中的细胞数(个细胞/mm) | |
| 正常组② | 47.5 | 64.2 |
| 对照组② | 20.8 | 36.8 |
| 本化合物A注射组(30ng/眼) | 23.8 | 42.3 |
| 本化合物A注射组(3μg/眼) | 28.8 | 51.8 |
如表2中所示，注射本化合物3μg，就能抑制红藻氨酸引起的内网状层薄化以及神经节细胞层中细胞数减少。尤其对神经节细胞层中的细胞数，确认了能恢复到正常组②的细胞数的80.7％。
这个事实表明，本化合物A具有对红藻氨酸处置引起的网膜神经系细胞障碍优异的保护作用。
产业上利用的可能性
已发现，本化合物能保护缺血-再灌流以及红藻氨酸处置造成的网膜神经系细胞的障碍，可用来作为网膜血管闭塞症、糖尿病网膜症、缺血性视神经症、黄斑变性症、网膜色素变性症、勒伯尔病为代表的网膜疾病或绿内障等眼病的治疗剂。
因此，本发明有在制药产业或医药业中利用的可能性。
Claims (5)
1．一种以如下通式(Ⅰ)所示化合物为有效成分的眼病治疗剂，
式中，R1表示低级烷基，
R2表示低级烷基，
R3表示氢原子或低级烷基，
R4表示氢原子或低级烷基。
2．以权利要求1记载的化合物为有效成分的眼病治疗剂，其中，R1和R2均为乙基，R3和R4均为甲基。
3．权利要求1或2记载的治疗剂，其中，眼病是绿内障。
4．权利要求1或2记载的治疗剂，其中，眼病是网膜疾病。
5．权利要求4记载的治疗剂，其中，网膜疾病是网膜血管闭塞症、糖尿病网膜症、缺血性视神经症、黄斑变性症、网膜色素变性症或勒伯尔病。
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| CA2557371C (en) | 2004-02-27 | 2012-09-25 | H. Lundbeck A/S | Crystalline forms of a pharmaceutical compound |
| MX2007001155A (es) * | 2004-07-29 | 2007-08-14 | Creabilis Therapeutics Spa | Uso de inhibidores de k-252a y de quinasa para la prevencion o el tratamiento de patologias asociadas con hmgb1. |
| US7803824B2 (en) * | 2004-10-29 | 2010-09-28 | Alcon, Inc. | Use of inhibitors of Jun N-terminal kinases to treat glaucoma |
| US20060094753A1 (en) * | 2004-10-29 | 2006-05-04 | Alcon, Inc. | Use of inhibitors of Jun N-terminal kinases for the treatment of glaucomatous retinopathy and ocular diseases |
| WO2006102333A2 (en) * | 2005-03-21 | 2006-09-28 | Alcon Manufacturing, Ltd. | Ophthalmic use of agents which inhibit connective tissue growth factor binding and signalling via the trka/p75ntr receptor complex |
| EP1864666B1 (en) * | 2005-03-31 | 2012-08-15 | Asahi Glass Company, Limited | Protective agent for retinal neuronal cell containing prostaglandin f2 alpha derivative as active ingredient |
| WO2007002670A2 (en) * | 2005-06-28 | 2007-01-04 | Bausch & Lomb Incorporated | Method of lowering intraocular pressure |
| JP2009521493A (ja) * | 2005-12-23 | 2009-06-04 | アルコン，インコーポレイテッド | 眼への受容体チロシンキナーゼ阻害（ＲＴＫｉ）化合物の送達のための医薬製剤 |
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| US5798380A (en) * | 1996-02-21 | 1998-08-25 | Wisconsin Alumni Research Foundation | Cytoskeletal active agents for glaucoma therapy |
| ATE224718T1 (de) | 1996-06-25 | 2002-10-15 | Cephalon Inc | Verwendung eines k-252a derivats zur behandlung von periphärer oder zentraler nervenerkrankungen und übermässiger cytokinbildung |
| US6200968B1 (en) * | 1998-08-06 | 2001-03-13 | Cephalon, Inc. | Particle-forming compositions containing fused pyrrolocarbazoles |
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| EP1121932A1 (en) | 2001-08-08 |
| US20030013701A1 (en) | 2003-01-16 |
| MXPA01003761A (es) | 2003-07-21 |
| WO2000021531A1 (fr) | 2000-04-20 |
| KR20010083884A (ko) | 2001-09-03 |
| US6451787B1 (en) | 2002-09-17 |
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