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Reduced central corneal thickening by use of hydrophilic ester prodrugs of beta-chlorocyclopentanes

A technology of alkyl and hydroxyalkyl, applied in the field of amino-oxoalkyl ester prodrugs, can solve the problems of insufficient solubility, overesterification, entering into aqueous humor and the like

Inactive Publication Date: 2016-10-12
ALLERGAN INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, many esters are too hydrophobic to diffuse out of the relatively nonpolar outer layers of the cornea and into the aqueous humor
Furthermore, such compounds are often not soluble enough to be formulated in aqueous solution

Method used

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  • Reduced central corneal thickening by use of hydrophilic ester prodrugs of beta-chlorocyclopentanes
  • Reduced central corneal thickening by use of hydrophilic ester prodrugs of beta-chlorocyclopentanes
  • Reduced central corneal thickening by use of hydrophilic ester prodrugs of beta-chlorocyclopentanes

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0075] 1) A compound having the formula:

[0076]

[0077] in,

[0078] X is CH 2 CH 2 , cis-CH=CH, inner arylene, CH 2 S, CH 2 O or alkyne,

[0079] Y is C 1 –C 3 Alkyl, O, S, single bond, double bond or thiophene,

[0080] Z is an inner arylene group, C 1 –C 3 Alkyl, SCH 2 , OCH 2 , single or double bond,

[0081] U is O, Cl, H-H, H-OH, H-Cl, H-F or H-CN, and wherein the dashed bond represents a single or double bond,

[0082] R 1 independently selected from the group consisting of: H, C 1 -C 6 Alkyl and C 1 -C 6 Hydroxyalkyl, -OH and

[0083] R 2 independently selected from the group consisting of: H, C 1 –C 6 Alkyl, C 1 –C 6 Hydroxyalkyl and –OH,

[0084] R 3 independently H, C 1 –C 6 Alkyl and C 1 –C 6 Hydroxyalkyl, -OH or R,

[0085] n is 0-8,

[0086] Y 1 is C=O or a single bond,

[0087] Z 1 is N, NH, NH2, CH2 or -OH

[0088] n1 is 0-2,

[0089] R is H, alkyl and CH 2 Oh,

[0090] Ar is monosubstituted, disubstituted or trisub...

Embodiment 1

[0280] Example 1. (R)-2,3-dihydroxypropyl 5-(3-((1R,2R,3R,5R)-5-chloro-2-(3,5-dichlorophenethyl)- Synthesis of 3-hydroxycyclopentyl)propyl)thiophene-2-carboxylate (compound 3).

[0281] An exemplary synthesis of compound 3 is provided in Scheme 1 below.

[0282] ((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)methyl 5-(3-((1R,2R,3R,5R)-5-chloro-2- (3,5-Dichlorophenethyl)-3-hydroxycyclopentyl)propyl)thiophene-2-carboxylate (Compound 2).

[0283]

[0284] (R)-(-)-2,2-Dimethyl-1,3-dioxolane-4-methanol (572.2 mg, 4.33 mmol) was added to the carboxylic acid of compound 1 (200 mg, 0.433mmol), 4-(dimethylamino)pyridine (55.3mg, 0.453mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (91.3mg, 0.476 mmol) in DMF (3.0 mL). After stirring for 16 hours, the reaction solution was diluted with EtOAc and washed with 1N HCl, saturated aqueous NaHCO 3 , and then washed with brine. The organic portion was dried (MgSO 4 ), filtered and concentrated in vacuo. The residue was pu...

Embodiment 2

[0287] Example 2. ((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-methyl 5-(3-((1R,2R,3R,5R)-5 -Synthesis of chloro-2-(3,5-dichlorophenethyl)-3-hydroxycyclopentyl)propyl)thiophene-2-carboxylate (compound 4).

[0288]

[0289] According to the procedure described above for the preparation of compound 2, using 100 mg (0.216 mmol) of the carboxylic acid of compound 1 and 42.8 mg (0.324 mmol) of (S)-(+)-2,2-dimethyl-1, 3-Dioxolane-4-methanol afforded 72.3 mg (58%) of acetonide-protected ester compound 4.

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PUM

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Abstract

Compositions and methods for treating glaucoma are provided. In particular hydrophilic ester prodrugs of the below-mentioned formula and their use to reduce central corneal thickening is provided. (I)

Description

[0001] Cross References to Related Applications [0002] This application is a continuation-in-part of U.S. Application Serial No. 13 / 974,975, filed August 23, 2013, which claims the benefit of U.S. Provisional Application Serial No. 61 / 693,437, filed August 27, 2012, which both Incorporated herein by reference in its entirety. Field of invention: [0003] The present invention relates to amino-oxyalkyl ester prodrugs and their use in reducing intraocular pressure and treating glaucoma. Background of the invention: [0004] Glaucoma is one of the leading causes of blindness in the world, with more than 2.5 million people living with the disease in the United States and millions more at risk of developing it. As the population ages, the number of individuals with glaucoma will continue to grow, as older adults are being disproportionately affected. [0005] Based on its etiology, glaucoma can be classified into primary glaucoma and secondary glaucoma. Primary glaucoma, als...

Claims

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Application Information

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IPC IPC(8): C07D333/38C07D409/12
CPCC07D333/38C07D409/12A61P27/06A61K31/381
Inventor R·M·伯克W·B·艾姆
Owner ALLERGAN INC
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