Oral formulations of diphenylsulfonamide endothelin and angiotensin ii receptor agonists to treat elevated blood pressure and diabetic nephropathy

a diphenylsulfonamide and endothelin technology, applied in the field of biphenyl sulfonamide compounds, can solve the problems of limiting the production of et-1, and achieve the effects of improving friability, dissolvability, and uniformity

Inactive Publication Date: 2014-05-22
LIGAND PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0018]In some embodiments, the compound of formula I is provided as rapidly dissolving dosage forms. In some embodiments, the formulations have one or more of: improved friability, compression, dissolution, uniformity, dissolvability, palatability, and the like. Also, in some embodiments, the formulations can permit at least one or more of: rapid onset, greater and / or more rapid plasma levels, and the like.

Problems solved by technology

For example, ARBs not only block the action of AngII at its receptor, but also limit the production of ET-1.

Method used

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  • Oral formulations of diphenylsulfonamide endothelin and angiotensin ii receptor agonists to treat elevated blood pressure and diabetic nephropathy
  • Oral formulations of diphenylsulfonamide endothelin and angiotensin ii receptor agonists to treat elevated blood pressure and diabetic nephropathy
  • Oral formulations of diphenylsulfonamide endothelin and angiotensin ii receptor agonists to treat elevated blood pressure and diabetic nephropathy

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0209]

Name: 4′-[(2-Butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-2′-formyl-N-(4,5-dimethyl-3-isoxazolyl)-[[1,1′-biphenyl]-2-sulfonamide]

A. 4′-[(2-Butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-2′-formyl-N-(4,5-dimethyl-3-isoxazolyl)-N-(2-methoxyethoxymethyl)[1,1′-biphenyl]-2-sulfonamide

[0210]Palladium catalyzed Suzuki coupling of 4-bromo-3-(ethoxymethyl)benzaldehyde and [2-[[(4,5-dimethyl-3-isoxazolyl)[(2-methoxyethoxy)methyl]amino]sulfonyl]phenyl]boronic acid was performed according to General Method 3 to afford N-(4,5-dimethyl-3-isoxazolyl)-4′-(ethoxycarbonyl)-2′-(formyl)-N-((methoxyethoxy)methyl)[1,1′-biphenyl]-2-sulfonamide (81%) following silica-gel chromatography.

B. 4′-[(2-Butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-2′-formyl-N-(4,5-dimethyl-3-isoxazolyl)-[1,1′-biphenyl]-2-sulfonamide

[0211]Treatment of N-(4,5-dimethyl-3-isoxazolyl)-4′-(ethoxycarbonyl)-2′-(formyl)-N-((methoxyethoxy)methyl)[1,1′-biphenyl]-2-sulfonamide with 6N aqueous hydrochloric acid acco...

example 2

[0212]4′-[(2-Butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-N-(4,5-dimethyl-3-isoxazolyl)-2′-(ethoxymethyl)-[1,1′-biphenyl]-2-sulfonamide was synthesized by combinations of the General Methods.

Name: 4′-[(2-Butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-N-(4,5-dimethyl-3-isoxazolyl)-2′-(ethoxymethyl)-[1,1′-biphenyl]-2-sulfonamide

[0213]

[0214]Starting Material: X—Br or OMs

[0215]General Methods Applied (yield, %): General Method 1, EtOH (77); General Method 2 (80); General Method 3 (70); General Method 4 (98); General Method 5 (80); General Method 1 (83); General Method 6 (86)

[0216]M / z (MH)+: 593

[0217]HPLC % Purity: >98

[0218]HPLC retention time, min (HPLC method): 18.75 (E)

example 3

4′-[(2-Butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-N-(4,5-dimethyl-3-isoxazolyl)-2′-(ethoxymethyl)[1,1′-biphenyl]-2-sulfonamide [crystalline]

[0219]

Alternative Synthesis of 4′-[(2-Butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-N-(4,5-dimethyl-3-isoxazolyl)-2′-(ethoxymethyl)[1,1′-biphenyl]-2-sulfonamide

Step A. Ethyl 4-bromo-3-(bromomethyl)benzoate

[0220]Ethyl 4-bromo-3-methylbenzoate (110 g, 450 mmol.) was treated with NBS according to the procedure of Example 5. Silica gel chromatography with hexanes / ethyl acetate as eluant provided ethyl 4-bromo-3-(bromomethyl)benzoate (91 g, 62%) as a white solid.

Step B. Ethyl 4-bromo-3-(ethoxymethyl)benzoate

[0221]A solution of ethyl 4-bromo-3-(bromomethyl)benzoate (89 g, 280 mmol.) in a mixture of ethanol (300 mL) and DMF (50 mL) was treated at 0° C. with sodium ethoxide (135 mL of a 21% solution in ethanol). The mixture was allowed to warm to rt and was stirred for 16 h. The ethanol was evaporated under reduced pressure. Ethyl aceta...

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Abstract

Methods of administering and pharmaceutical compositions of a biphenyl sulfonamide compound which is a dual angiotensin and endothelin receptor antagonist are disclosed for treating diseases.

Description

BACKGROUND OF THE INVENTION[0001]1. Field of the Invention[0002]The present invention relates to a biphenyl sulfonamide compound which is a dual angiotensin and endothelin receptor antagonist, to pharmaceutical compositions containing such compound, to methods of manufacturing the pharmaceutical formulations containing such compound, and to methods of using such compound in the treatment of endothelin-dependent or angiotensin II-dependent disorders and other diseases.[0003]2. Description of the Related Art[0004]Angiotensin II (AngII) and endothelin-1 (ET-1) are two of the most potent endogenous vasoactive peptides currently known and are believed to play a role in controlling both vascular tone and pathological tissue remodeling associated with a variety of diseases including diabetic nephropathy, heart failure, and chronic or persistently elevated blood pressure. Currently, angiotensin receptor blockers (ARBs), which block the activity of AngII, are widely used as a treatment for d...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D413/12
CPCC07D413/12A61K9/2013A61K9/2018A61K9/2054A61K9/2059A61K31/422A61P1/04A61P1/12A61P1/16A61P1/18A61P11/00A61P11/06A61P13/00A61P13/02A61P13/08A61P13/10A61P13/12A61P17/00A61P17/06A61P19/02A61P19/08A61P25/00A61P25/06A61P25/08A61P25/14A61P27/02A61P29/00A61P35/00A61P37/02A61P43/00A61P7/00A61P9/00A61P9/04A61P9/06A61P9/08A61P9/10A61P9/12A61P3/10A61K9/2031
Inventor ZHANG, JINKUNDZIEWANOWSKA, ZOFIA E.BELDER, RENEHENDERSON, IANBOGARDUS, JOSEPH B.ZHANG, ZHAOYING
Owner LIGAND PHARMA INC
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