CN1450897A - 用于控制iop并治疗青光眼的5ht2兴奋剂 - Google Patents

用于控制iop并治疗青光眼的5ht2兴奋剂 Download PDF

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CN1450897A
CN1450897A CN00819345A CN00819345A CN1450897A CN 1450897 A CN1450897 A CN 1450897A CN 00819345 A CN00819345 A CN 00819345A CN 00819345 A CN00819345 A CN 00819345A CN 1450897 A CN1450897 A CN 1450897A
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aminopropyl
indazole
phenol
iop
percetage
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CN1231214C (zh
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J·A·梅
A·P·丹塔纳拉亚纳
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Novartis AG
Yamanouchi Pharmaceutical Co Ltd
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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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics

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Abstract

本发明公开了使用1－(2－氨基丙基)－吲唑－6－酚控制眼内压并治疗青光眼的组合物和方法。

Description

用于控制IOP并治疗青光眼的5HT2兴奋剂
本发明涉及1-(2-氨基丙基)-吲唑-6-酚在降低和控制眼内压(IOP)并治疗青光眼中的用途。
发明背景
称作青光眼的疾病状态的特征在于因视神经受到不可逆损害而导致的永久性视觉功能丧失。几种形态或功能上不同类型的青光眼的典型特征在于IOP升高，认为它在原因上与该病的病理过程相关。眼压过高是眼内压升高但没有发生明显的视觉功能丧失的疾病；这类患者被认为属于最终发展为与青光眼相关的视觉丧失的高危情况。某些患有青光眼性视野丧失的患者具有相对低的眼内压。这些所谓的压力正常或低压力的青光眼患者也可得益于降低和控制IOP的药剂。如果早期检测到青光眼或眼压过高并立即用有效降低升高的眼内压的药物进行治疗，那么视觉功能丧失或其逐步恶化的情况一般可以得到改善。已经证实可有效降低眼内压的药物疗法包括减少房水产生的药剂和促进流出的药剂。一般通过局部(直接施用于眼)或口服这两种可能的途径中之一给予这类治疗。
当用某些现有的青光眼疗法治疗时，有些个体的反应不好。因此，存在对控制IOP的其它局部用治疗剂的需求。
W098/30548中公开了化合物1-(2-氨基丙基)-吲唑-6-酚。该申请的实施例46中公开了1-(2-氨基丙基)-吲唑-6-酚的S-对映体。该申请所述的用途是用于治疗中枢神经系统疾病，诸如性功能障碍、生殖功能不全、食欲调节紊乱、焦虑、抑郁症和睡眠障碍。没有公开眼科适应症。
发明概述
本发明涉及1-(2-氨基丙基)-吲唑-6-酚的组合物及其在降低和控制IOP并治疗青光眼中的用途。优选实施方案的描述
已经令人意外地发现：当以300μg给予1-(2-氨基丙基)-吲唑-6-酚(“化合物”)及其S-(+)-异构体时，它们可以在激光照射的眼压过高猴模型中导致如下表中所示的IOP显著降低。在用0.1％丙美卡因实施眼角膜麻醉后用Alcon Pneumatonometer测定眼内压。在每次测定后用盐水洗涤眼。在进行基线IOP测定后，以一份30μL等分试样将测试化合物仅滴注入9只食蟹猴的右眼。将载体滴注入其它6只动物的右眼。随后在1、3和6小时时测定IOP值。如果在局部给药后激光照射(O.D.)的眼的基线IOP降低至少20％，则认为化合物在该眼压过高模型中有效。对1-(2-氨基丙基)-吲唑-6-酚及其S(+)-异构体的IOP反应
剂量(μg) 基线IOP(mmHg)                      IOP反应改变％(ΔmmHg)
  1小时      3小时   6小时
化合物 300 40.1 -17.6(7.3)      -28.1(11.8)   -33.8(14.6)
  载体   40.5   -6.5(3.0)      -13.6(5.7)   -8.1(3.8)
S-(+)-异构体 300 40.3 -15.0(6.4)      -35.3(14.8) -40.8(17.1)
  载体   38.0   -3.1(1.8)      -6.8(3.3)   -4.7(2.8)
1-(2-氨基丙基)-吲唑-6-酚的S-异构体是降低和控制IOP并治疗青光眼的优选异构体。
可以将该化合物混入各种类型的递送至眼部(例如经局部、经眼房内或通过植入物)的眼用制剂。优选将其混入递送至眼部的局部用眼用制剂。可以将该化合物与眼科上可接受的防腐剂、表面活性剂、增粘剂、增渗剂、缓冲剂、氯化钠和水混合而制成无菌含水眼用混悬液或溶液。可以通过将该化合物溶于生理上可接受的等渗含水缓冲液来制备眼用溶液制剂。此外，该眼用溶液可以包括眼科上可接受的表面活性剂以便辅助溶解该化合物。此外，该眼用溶液可以含有增加粘度的药剂以改善该制剂在结膜囊中的停留，所述的增加粘度的药剂诸如有羟甲基纤维素、羟乙基纤维素、羟丙基甲基纤维素、甲基纤维素、聚乙烯吡咯烷酮等。还可以使用胶凝剂，包括但不限于吉兰糖胶和黄原胶。为了制备无菌眼用软膏剂，在诸如矿物油、液态羊毛脂或白凡士林这样的适当载体中将化合物与防腐剂混合。可以按照用于类似眼用制剂的公开配制方法，通过将活性成分悬浮于由混合例如卡波姆-974等制备的亲水性基质来制备无菌眼用凝胶剂；可以混入防腐剂和张力剂。
优选将所述的化合物配制成pH约为5-8的局部用眼用混悬液或溶液。在这些制剂中化合物的含有量正常在0.01％至5％重量，而优选量在0.1％至2％重量。因此，就局部给药而言，按照熟练临床医师的判断，每天1-4次将这些制剂1-2滴滴至眼表面。
还可以将这些化合物与用于治疗青光眼的其它药剂联用，所述的其它药剂诸如但不限于β-阻断剂(例如噻吗洛尔、倍他洛尔、左倍他洛尔、卡替洛尔、左布诺洛尔、普萘洛尔)、碳酸酐酶抑制剂(例如brinzolamide和多佐胺)、α1拮抗剂(例如尼普地洛(nipradolol))、α2兴奋剂(例如iopidine和溴莫尼定)、缩瞳药(例如毛果芸香碱和肾上腺素)、前列腺素类似物(例如拉坦前列素、travaprost、乌诺前列酮以及美国专利US5,889,052、5,296,504、5,422,368和5,151,444中所列的化合物)、“低压脂类(hypotensivelipids)”(例如lumigan和5,352,708中所列的化合物)和神经保护剂(例如来自美国专利US 4,690,931的化合物，特别是待决申请U.S.S.N.06/203350中所列的依利罗地和R-依利罗地以及WO94/13275中公开的适当化合物，包括美金刚)。
按照熟练临床医师的判断每天给药1-4次，按照本发明下列局部眼用制剂是有用的。
                            实施例1
                  成分     量(wt％)
1-(2-氨基丙基)-吲唑-6-酚(S-(+)-异构体)     0.01-2％
羟丙基甲基纤维素     0.5％
磷酸氢二钠(无水)     0.2％
氯化钠     0.5％
EDTA二钠(乙二胺四乙酸二钠)     0.01％
聚山梨酯80     0.05％
苯扎氯铵     0.01％
氢氧化钠/盐酸     用于将pH调节至7.3-7.4
净化水     足量至100％
                     实施例2
    成分     量(wt％)
1-(2-氨基丙基)-吲唑-6-酚     0.01-2％
甲基纤维素     4.0％
磷酸氢二钠(无水)     0.2％
氯化钠     0.5％
EDTA二钠(乙二胺四乙酸二钠)     0.01％
聚山梨酯80     0.05％
苯扎氯铵     0.01％
氢氧化钠/盐酸     用于将pH调节至7.3-7.4
净化水     足量至100％
                               实施例3
    成分     量(wt％)
1-(2-氨基丙基)-吲唑-6-酚(S-(+)-异构体)     0.01-2％
瓜耳胶     0.4-6.0％
磷酸氢二钠(无水)     0.2％
氯化钠     0.5％
EDTA二钠(乙二胺四乙酸二钠)     0.01％
聚山梨酯80     0.05％
苯扎氯铵     0.01％
氢氧化钠/盐酸     用于将pH调节至7.3-7.4
净化水     足量至100％
                    实施例4
    成分     量(wt％)
1-(2-氨基丙基)-吲唑-6-酚     0.01-2％
白凡士林和矿物油和羊毛脂     软膏稠度
磷酸氢二钠(无水)     0.2％
氯化钠     0.5％
EDTA二钠(乙二胺四乙酸二钠)     0.01％
聚山梨酯80     0.05％
苯扎氯铵     0.01％
氢氧化钠/盐酸 用于将pH调节至7.3-7.4

Claims (12)

1.一种用于控制眼内压的方法，该方法包括给予包含药物有效量的1-(2-氨基丙基)-吲唑-6-酚的组合物。
2.权利要求1的方法，使用1-(2-氨基丙基)-吲唑-6-酚的S-(+)-异构体。
3.权利要求1的方法，其中1-(2-氨基丙基)-吲唑-6-酚的浓度为0.01至5重量百分数。
4.权利要求3的方法，其中所述的浓度为0.1至2重量百分数。
5.权利要求2的方法，其中1-(2-氨基丙基)-吲唑-6-酚的S-(+)-异构体的浓度为0.01至5重量百分数。
6.权利要求5的方法，其中所述的浓度为0.1至2重量百分数。
7.一种用于控制眼内压的局部眼用组合物，其包括药物有效量的1-(2-氨基丙基)-吲唑-6-酚。
8.权利要求7的组合物，其使用了1-(2氨基丙基)-吲唑-6-酚的S-(+)-异构体。
9.权利要求7的组合物，其中1-(2-氨基丙基)-吲唑-6-酚的浓度为0.01至5重量百分数。
10.权利要求9的组合物，其中所述的浓度为0.1至2重量百分数。
11.权利要求8的组合物，其中1-(2-氨基丙基)-吲唑-6-酚的S-(+)-异构体的浓度为0.01至5重量百分数。
12.权利要求11的组合物，其中所述的浓度为0.1至2重量百分数。
CNB008193452A 2000-03-17 2000-11-14 用于控制iop并治疗青光眼的5ht2兴奋剂 Expired - Fee Related CN1231214C (zh)

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EP1581209A4 (en) 2002-12-13 2009-03-11 Alcon Inc NEW BENZOPYRAN ANALOGUE AND ITS USE FOR THE TREATMENT OF GLAUKOM
WO2005053688A1 (en) * 2003-11-26 2005-06-16 Alcon, Inc. Substituted furo[2,3-g] indazoles for the treatment of glaucoma
WO2005058911A2 (en) 2003-12-15 2005-06-30 Alcon, Inc. Substituted [1,4]oxazino[2,3-g]indazoles for the treatment of glaucoma
US7129257B1 (en) 2003-12-15 2006-10-31 Alcon, Inc. Pyrazolo[3,4- e]benzoxazoles for the treatment of glaucoma
US7338972B1 (en) 2003-12-15 2008-03-04 Alcon, Inc. Substituted 1-alkylamino-1H-indazoles for the treatment of glaucoma
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