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Therapeutic substituted cyclopentanes for reducing intraocular pressure

An intraocular pressure and hydroxycyclopentyl technology, which is applied in the directions of organic active ingredients, preparation of organic compounds, active ingredients of heterocyclic compounds, etc., can solve problems such as obstruction of aqueous humor discharge

Inactive Publication Date: 2010-08-04
ALLERGAN INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In chronic open-angle glaucoma, the anterior chamber and its anatomy appear normal, but the drainage of aqueous humor is obstructed

Method used

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  • Therapeutic substituted cyclopentanes for reducing intraocular pressure
  • Therapeutic substituted cyclopentanes for reducing intraocular pressure
  • Therapeutic substituted cyclopentanes for reducing intraocular pressure

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0215] 5-(3-((1R,2R,3R,5R)-5-chloro-2-(3,5-dichlorostyryl)-3-hydroxycyclopentyl)prop-1-enyl)thiophene- 2-Formic acid (8)

[0216] Step 1. Mesylation of 1 to give 2

[0217] Triethylamine (4.2 mL, 30.0 mmol) and methanesulfonyl chloride (1.9 mL, 24.1 mmol) were added sequentially to 1 at 0 °C (see U.S. Provisional Patent Application No. 60 / 805,285, 10.1 g, 19.9 mmol) in CH 2 Cl 2 (100mL) in solution. The reaction mixture was warmed to room temperature and stirred at room temperature for 3 h. Add saturated NaHCO 3 aqueous solution (400mL) and CH 2 Cl 2 (3x400 mL) extracted the mixture. The combined organic extracts were washed with water (200 mL) and brine (200 mL), then dried (MgSO 4 ), filtered and concentrated in vacuo to afford 11.5 g (ca. 98%) of the desired mesylate 2, which was used without further purification.

[0218] Step 2. Conversion of mesylate 2 to chloride 3 and alcohol 4

[0219] Tetrabutylammonium chloride (26.5 g, 95.4 mmol) was added to a solution o...

Embodiment 2

[0233] 5-(3-((1R,2R,3R,5R)-5-chloro-2-(3-chloro-5-(hydroxymethyl)styryl)-3-hydroxycyclopentyl)propyl)- Thiophene-2-carboxylic acid (15a)

[0234] Oxidation in step 1.9 yields 10

[0235] DMSO (32 μL, 0.45 mmol) was added to oxalyl chloride (0.1 mL 2.0 M in CH 2 Cl 2 Solution in, 0.2mmol) in CH 2 Cl 2 (0.3 mL) in solution. After 30 min, alcohol 9 (see U.S. Provisional Patent Application No. 60 / 805,285, 70 mg, 0.17 mmol) was added via syringe in CH 2 Cl 2 (0.54 mL). After 15 min at -78 °C, triethylamine (187 μL, 1.34 mmol) was added and the reaction was allowed to warm to room temperature. After 5 h at room temperature, the reaction mixture was dissolved in saturated NaHCO 3 aqueous solution (10 mL) and CH 2 Cl 2 (20mL). Separate the phases and wash with CH 2 Cl 2 (2x10 mL) to extract the aqueous phase. The combined organic phases were dried (MgSO 4 ), filtered and concentrated in vacuo to afford 69 mg of crude aldehyde 10 which was used without further purificat...

Embodiment 3

[0243] 5-(3-((1R,2R,3R,5R)-5-chloro-2-((E)-2-(5-chloropyridin-3-yl)vinyl)-3-hydroxycyclopentyl) Propyl)-thiophene-2-carboxylic acid (15b)

[0244] Step 1.10 carries out Wittig reaction to obtain 11b

[0245] Following the procedure in step 2 of Example 2, aldehyde 10 (190 mg, 0.46 mmol) and ((5-chloro-3-pyridyl)methyl)triphenylphosphonium chloride (Formulation 2, 100 mg, 0.24 mmol) were converted to 104 mg (84%) alkene 11b (contains about 5% cis-alkene 12b impurity).

[0246] Step 2.11b deprotection gives 13b

[0247] Following the procedure in step 3 of Example 2, THP-ether 11b (104 mg, 0.20 mmol) was converted to 40 mg (46%) of alkene 13b (with about 5% cis alkene 14b impurity).

[0248] Step 3.13b saponification gives 15b

[0249] Following the procedure in Example 2, Step 4, ester 13b (10 mg, 0.023 mmol) was converted to 3 mg (31%) of the title compound (containing about 5% cis-olefin 16b impurity).

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Abstract

Disclosed herein are compounds having formula (I) wherein a dashed line represents the presence or absence of a bond; Y is an organic acid functional group, or an amide or ester thereof; or Y is hydroxymethyl or an ether thereof; or Y is a tetrazolyl functional group; A is -(CH2)6-, cis -CH2CH=CH-(CH2)3-, or -CH2C=C-(CH2)3-, wherein 1 or 2 carbon atoms may be replaced by S or O; or A is -(CH2)m-Ar-(CH2)o- wherein Ar is interarylene or heterointerarylene, the sum of m and o is 1, 2, 3, or 4, and wherein 1 -CH2- may be replaced by S or O, and 1 -CH2-CH2- may be replaced by -CH=CH- or -C=C-; U1 and U2 are independently selected from -H, =O, -OH, -F, -Cl, and -CN; and B is aryl or heteroaryl, for use as acular hypotensive agent.

Description

[0001] inventor [0002] D.W. Alder, V.X. Ngo, M. Holobowski and M.F. Posner [0003] cross reference [0004] This application claims priority to US Application Serial No. 60 / 947,904, filed July 3, 2007, which is incorporated herein by reference in its entirety. Background technique [0005] Ocular hypotensive agents are used in the treatment of many different symptoms of ocular hypertension, such as post-surgical trabeculectomy and laser trabeculectomy episodes of ocular hypertension, in glaucoma, and as a preoperative adjuvant. [0006] Glaucoma is an eye disease characterized by elevated intraocular pressure. Based on its cause, glaucoma is classified as primary or secondary. For example, primary glaucoma (congenital glaucoma) in adults can be open-angle or acute or chronic angle-closure glaucoma. Secondary glaucoma results from pre-existing ocular disease such as uveitis, intraocular tumors, or enlarged cataracts. [0007] The underlying cause of primary glaucoma rem...

Claims

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Application Information

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IPC IPC(8): A61K31/5575A61K31/559C07C405/00A61P27/06
CPCC07C405/00A61K31/559C07C2101/08A61K31/5575C07D257/04C07C2601/08A47G19/06A61K31/38A61K31/381A61K31/41C07D277/56C07D333/10C07D333/40C07D409/08A61P27/06A61P43/00
Inventor D·W·奥尔德V·X·恩戈M·霍洛博斯基M·F·波斯纳
Owner ALLERGAN INC
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