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Therapeutic agent for ocular disease or prophylactic agent for ocular disease

A technology of therapeutic and preventive agents, applied in the field of therapeutic or preventive agents for eye diseases, which can solve problems such as induced edema and increased vascular permeability

Active Publication Date: 2016-06-01
JAPAN TOBACCO INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, VEGF is known to increase vascular permeability and induce edema

Method used

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  • Therapeutic agent for ocular disease or prophylactic agent for ocular disease
  • Therapeutic agent for ocular disease or prophylactic agent for ocular disease
  • Therapeutic agent for ocular disease or prophylactic agent for ocular disease

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0095] Experiment 1. Inhibition of retinal vascular permeability by oral administration of Compound A in a rat VEGF-induced retinal vascular permeability increase model

[0096] Using a rat model of increased retinal vascular permeability induced by VEGF, the effect of Compound A on inhibiting increased retinal vascular permeability was evaluated. The animal model was created based on Non-Patent Document 3 and the like with appropriate modifications.

[0097] As the experimental animals, 8-week-old male BrownNorway rats (Charles River Co., Ltd., Japan) were used.

[0098] Intravitreal injection of rat VEGF into both eyes of rats 164 (400ng / eye, R&D Systems Company) (VEGF administration group). D-PBS(-) (Sigma-Aldrich) was intravitreally injected into the vitreous of both eyes of rats in the normal control group. The number of cases in each group was 4 (8 eyes).

[0099] Compound A suspended in 1% (w / v) aqueous methylcellulose was administered at 10 mg / kg, 30 mg / kg or 100 m...

Embodiment 2

[0109] Experiment 2. Inhibition of retinal vascular permeability by intravitreal injection of Compound A in a rat VEGF-induced increased retinal vascular permeability model

[0110] As the experimental animals, 8-week-old male BrownNorway rats (Charles River Co., Ltd., Japan) were used.

[0111] Intravitreal injection of rat VEGF into both eyes of rats 164 (400ng / eye, R&D Systems Company) and a mixture of compound A (10 μg / eye, 30 μg / eye or 100 μg / eye) dissolved or suspended with a base (compound A administration group). Intravitreal injection of rat VEGF into both eyes of rats in the base-administered group 164 A mixture of bases in the same volume as the above-mentioned Compound A administration group. As the base, an aqueous base was used. D-PBS(-) (SIGMA) was injected into the vitreous body of both eyes of rats in the normal control group. The number of cases in each group was 4 (8 eyes).

[0112] Twenty-four hours after the intravitreal injection of VEGF, the rats we...

Embodiment 3

[0120] Experiment 3. Ocular Tissue Distribution and Systemic Exposure of Oral or Intravitreal Compound A

[0121] As the experimental animals, 8-week-old male Crl:CD (SD) rats (Charles River Co., Ltd., Japan) were used.

[0122] Compound A suspended in 1% (w / v) aqueous methylcellulose solution was orally administered to rats at 100 mg / kg. After 0.5, 1, 2, 4, 6 and 24 hours from oral administration, plasma and neural retina were collected, and liquid chromatography mass spectrometry (LC-MS) was used to determine the concentration of Compound A in plasma and neural retina. concentration was quantified.

[0123] Compound A dissolved or suspended in the base for injection at 10 μg / eye, respectively, was injected into the vitreous of both eyes of rats. After 1, 2, 4 and 24 hours from the intravitreal injection, neural retinas were harvested, and the concentration of Compound A in the neural retinas was quantified by LC-MS. The number of cases in each group was 2-3 animals (4-6 e...

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Abstract

3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]octan-1-yl]-3-oxopropanenitrile suppresses increases in retinal blood vessel permeability induced by VEGF and therefore can be used as an active component in therapeutic agents or prophylactic agents for a variety of ocular diseases to which VEGF contributes, such as age-related macular degeneration, diabetic retinopathy, macular edema, neovascular maculopathy, retinal vein occlusion, and neovascular glaucoma.

Description

technical field [0001] The present invention relates to 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]octane Novel medicinal uses of alk-1-yl]-3-oxapropionitrile (referred to below as compound A). In more detail, the present invention relates to a compound A or a pharmaceutically acceptable salt thereof for ophthalmic diseases such as age-related macular degeneration, diabetic retinopathy, macular edema, retinal vein occlusion, angiogenesis maculopathy and angiogenesis glaucoma. Therapeutic or prophylactic. Background technique [0002] Compound A is described in Patent Document 1. However, the function of compound A for inhibiting vascular endothelial growth factor (Vascularendothelialgrowthfactor, hereinafter referred to as VEGF) is still unknown. [0003] Compound A is represented by the following chemical structural formula. [0004] [hua 1] [0005] [0006] Compound A can be produced by the method described in Patent Document 1. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/519A61K9/08A61P3/10A61P9/10A61P27/02A61P27/06A61P43/00
CPCA61K9/0048A61K9/0095A61K31/519A61P27/02A61P27/06A61P43/00A61P9/10A61P3/10A61K9/0019A61K9/08A61K31/407A61K9/0053
Inventor 沖上裕美黑濑达治藤泽幸史吉川千奈美
Owner JAPAN TOBACCO INC
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