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Phosphate transport inhibitors

a phosphate transport and inhibitor technology, applied in drug compositions, metabolic disorders, cardiovascular disorders, etc., can solve the problems of increased risk of cardiovascular events, serious side effects, and progression of renal failure, and achieve the effect of effective inhibitors of phosphate transpor

Inactive Publication Date: 2007-01-25
JOZEFIAK THOMAS +3
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

These compounds demonstrate significant inhibition of phosphate transport, offering a therapeutic option for hyperphosphatemia, chronic renal failure, and associated disorders by reducing serum phosphate levels and slowing renal disease progression without the side effects of hypercalcemia.

Problems solved by technology

For patients who exhibit renal insufficiency, elevation of serum phosphorus within the normal range has been associated with progression of renal failure and increased risk of cardiovascular events.
The major problem with all of these therapeutics is the hypercalcemia which often results from absorption of high amounts of ingested calcium.
Hypercalcemia causes serious side effects such as cardiac arrhythmias, renal failure, and skin and visceral calcification.
Other, calcium and aluminum-free phosphate binders have drawbacks including the amount and frequency of dosing required to be therapeutically active.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

Methyl 5-bromo-2-[(4′-trifluoromethoxyphenyl)sulfonyl]amino benzoate

[0086]

[0087] Methyl 2-amino-5-bromo benzoate (2.78 g, 0.012 mol) was dissolved in pyridine (3 mL). The mixture was cooled in an ice bath below 5° C. and 4-trifluoromethoxy benzene sulfonyl chloride (3.5 g, 0.013 mol, 1.1 equivalents) was added slowly to the mixture. The mixture was warmed to room temperature, and stirred for 1 hour. The solvent was removed and the resulting solid was suspended in HCl (1M, 40 mL) for 30 minutes. The mixture was filtered, the solid suspended in hexane (40 mL) and stirred for 30 minutes. The mixture was filtered and the solid was washed with hexane (2×20 mL). Solid was dried in a vacuum oven at 40° C. Recovery=4.63 g (85% yield).

example 2

5-Bromo-2-[(4′-trifluoromethoxyphenyl)sulfonyl]amino benzoic acid

[0088]

[0089] Methyl 5-bromo-2-[(4′-trifluoromethoxyphenyl)sulfonyl]amino benzoate (0.854 g, 0.019 mmol) was dissolved in a mixture of tetrahydrofuran (20 mL) / water (10 mL). A solution of sodium hydroxide (50%, 5 mL) was added and the mixture was heated to reflux for 2-3 hours. The tetrahydrofuran was removed by rotary evaporation and the mixture was acidified with HCl (2 M). The mixture was extracted with ethyl acetate (20 mL). The organic solvent was removed to dryness and then dissolved in ethyl acetate (3×15 mL), and solvent removed. The oil was triturated in hexane (20 mL) until a solid formed. The mixture was filtered and the solid was dried in a vacuum oven at 40° C. Recovery=0.691 g (83% yield). M / Z of (M-H)−=432, 1H NMR (DMSO) δ=7.42-7.48 (1H), 7.55-7.6 (2H), 7.74-7.8 (1H), 7.92-8.0 (3H), 11.2 (br, 1H).

example 3

5-Bromo-2-[(4′-trifluoromethoxyphenyl)sulfonyl]amino benzoyl chloride

[0090]

[0091] 5-bromo-2-[(4′-trifluoromethoxyphenyl)sulfonyl]amino benzoic acid (3.27 g, 7.4 mmol) was suspended in thionyl chloride (30 mL) and the mixture was heated to reflux for 4 hours. The solvent was removed to dryness and the residue was dissolved in anhydrous ethyl acetate (2×20 mL), and solvent removed. The solid was dried at 40° C. in vacuum oven overnight.

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Abstract

Disclosed are compounds which have been identified as inhibitors of phosphate transport. Many of the compounds are represented by Structural Formula (I): Ar1—W—X—Y—Ar2; or a pharmaceutically acceptable salt thereof. Ar1 and Ar2 are independently a substituted or unsubstituted aryl group or an optionally substituted five membered or six membered non-aromatic heterocylic group fused to an optionally substituted monocylic aryl group. W and Y are independently a covalent bond or a C1-C3 substituted or unsubstituted alkylene group. X is a heteroatom-containing functional group, an aromatic heterocyclic group, substituted aromatic heterocyclic group, non-aromatic heterocyclic group, substituted non-aromatic heterocyclic group, an olefin group or a substituted olefin group. Also disclosed are methods of treating a subject with a disease associated with hyperphosphatemia, as well as a disease mediated by phosphate-transport function. The methods comprise the step of administering an effective amount of the one of the compounds described above.

Description

RELATED APPLICATIONS [0001] This application is a continuation of U.S. application Ser. No. 10 / 327,627, filed Dec. 20, 2002, which claims the benefit of U.S. Provisional Application Nos. 60 / 344,660, filed on Dec. 26, 2001 and 60 / 371,649, filed on Apr. 10, 2002. The entire teachings of the above applications are incorporated herein by reference.BACKGROUND OF THE INVENTION [0002] People with inadequate renal function, hypoparathyroidism, or certain other medical conditions often have hyperphosphatemia, or elevated serum phosphate levels (over 6 mg / dL). Hyperphosphatemia, especially if present over extended periods of time, leads to severe abnormalities in calcium and phosphorus metabolism, often manifested by hyperparathyroidism, bone disease and calcification in joints, lungs, eyes and vasculature. For patients who exhibit renal insufficiency, elevation of serum phosphorus within the normal range has been associated with progression of renal failure and increased risk of cardiovascul...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/18A61K31/121C07D333/34A61K31/166A61K31/167A61K31/17A61K31/245A61K31/341A61K31/381A61K31/415A61K31/42A61K31/47A61K31/63A61K31/662A61K33/38A61K45/06A61P3/14A61P5/18A61P13/12A61P19/08A61P19/10C07D215/36C07D231/12C07D261/10C07D307/46C07D333/62C07D405/04C07D413/04
CPCA61K31/166A61K31/17A61K31/18A61K31/415A61K31/63A61K45/06A61K33/38A61K2300/00A61P13/12A61P19/00A61P19/08A61P19/10A61P3/00A61P3/14A61P5/18A61P9/14
Inventor JOZEFIAK, THOMASBASTOS, CECILIAPAPOULIS, ANDREWHOLMES-FARLEY, STEPHEN
Owner JOZEFIAK THOMAS
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