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Therapeutic dinucleotide and derivatives

A drug, acute technology, applied in the field of therapeutic dinucleotides and derivatives, can solve the problem of frequent dripping, etc.

Inactive Publication Date: 2001-06-27
INSPIRE PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Currently, medical treatment for dry eye disease is limited to temporary re-wetting of the eye by administering artificial tears (saline solution)
However, relief is temporary and frequent instillations are required

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] P 1 -(cytidine 5'-)-P 4 -(uridine 5'-)tetraphosphate, preparation of quaternary ammonium salt

[0041] A 0.34M solution of tributylammonium uridine 5'-monophosphate was prepared by dissolving the free acid of uridine 5'-monophosphate (Sigma) (3.0 g) and tributylammonium (2.0 mL) in DMF. Anhydrous DMF solution (5.6ml, 1.89mmol, 0.34M) of uridine 5'-monophosphate tributylammonium salt in N 2 Pour down into a 10ml round bottom flask, and add carbonyldiimidazole (459mg, 2.83mmol), and stir the solution at 25°C for 30 minutes. Add the trisodium salt of cytidine 5' triphosphate with Dowex 50H 4 Resin treatment was followed by the addition of a DMF solution of cytidine 5'-tributylammonium triphosphate prepared by treatment with tributylamine in DMF, and the reaction mixture was stirred at 65C for 3 hours. The solution was evaporated in vacuo and purified twice by column chromatography (DEAE Sephadex:H 2 O→0.3M NH 4 HCO 3 gradient). Concentrate the pure c...

Embodiment 2

[0043] P 1 -(cytidine 5'-)-p 4 -(uridine 5'-)tetraphosphate, preparation of quaternary ammonium salt

[0044] A solution of uridine 5'-triphosphate (UTP) trisodium salt (5.86g, 0.01mol) dissolved in water (5mL) was placed on a BioRad AG-MP50 strong cation exchange resin column (in the form of its pyridinium salt) (50ml bed volume) and eluted with distilled water (approximately 300 mL) into a flask containing tributylamine (5.55 g, 0.03 mol). The suspension was shaken with ethanol, and the mixture was kept in the refrigerator overnight. The solution was filtered to remove a small oily residue, evaporated to dryness under reduced pressure, and the residue was dried at room temperature for 1 hour at 0.08 mm Hg. The residue was evaporated to dryness with 2 x 20 mL of anhydrous dimethylformamide (DMF) at 0.1 mm Hg. The resulting anhydrous tributylammonium salt was made up to 100 mL with anhydrous acetone to obtain a stock solution (0.1 M in UTP). Dicyclohexylcarbodiimide (DCC)...

Embodiment 3

[0046] Pharmacological activity measured by inositol phosphate assay

[0047] by P2Y 2 Inositol phosphate assays for activity at and other P2Y receptors demonstrate the pharmaceutical utility of the compounds of the invention. This is a widely used assay method described by E. Lazarowski et al., British Journal of Pharmacology, 116, 1619-27 (1995), using inositol phosphate formation as a measure of the linking of compounds activating receptors and phospholipase C by G-proteins. standard of vitality.

[0048] Induction of P2Y by compounds of formula I was tested using the inositol phosphate assay described by E. Lazarowski et al., British Journal of Pharmacology, 116, 1619-27 (1995). 1 、P2Y 2 、P2Y 4 and P2Y 6 Vitality of receptor activity. For CP 4 U and all cytidine-containing dinucleotides C 2 P 4 The results are summarized in Table I below.

[0049] compound

P2Y 1

P2Y 2

P2Y 4

P2Y 6

C 2 P 4

IA *

IA *

IA * ...

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PUM

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Abstract

The present invention relates to P1-(cytidine 5'-)-P-(uridine 5'-)tetraphosphates and its salts, esters and amides, and formulations thereof which are highly stable and selective agonists of the P2Y2 and / or P2Y4 purinergic receptor. The compounds of the invention are useful in the treatment of chronic obstructive pulmonary diseases such as chronic bronchitis, primary ciliary dyskinesia, cystic fibrosis, as well as prevention of pneumonia due to immobility, and the induction of sputum and its expectoration. Furthermore, because of their general ability to clear retained mucus secretions and stimulate ciliary beat frequency, the compounds of the present invention are also useful in the treatment of sinusitis and otitis media.

Description

technical field [0001] The present invention relates to the application of P 1 -(cytidine 5'-)-P 4 -(Uridine 5'-)tetraphosphate (CP 4 U) or a pharmaceutically acceptable ester, amide or salt thereof to increase the hydration of residual mucus secretions, stimulate the production of mucin, and increase the beating frequency of cilia to enhance secretion clearance. Background of the invention [0002] Chronic Obstructive Pulmonary Disease (COPD) affects 15 million people in the United States and is the sixth leading cause of death. It is characterized by residual mucus secretion in the lungs, resulting in progressive pulmonary dysfunction over time. Many patients diagnosed with COPD have a condition known as chronic bronchitis (CB), and 600,000 patients are hospitalized each year for acute exacerbations of CB. Cystic fibrosis (CF) and primary ciliary dyskinesia (PCD) are hypothesized cases of similar clinical symptoms of COPD. Ciliary dyskinesias, whether primary or secon...

Claims

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Application Information

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IPC IPC(8): C07H19/10A61K31/70A61K31/7042A61K31/7052A61K31/7064A61K31/7072A61K31/7084A61P11/00A61P11/10A61P11/12A61P27/04A61P27/16C07H19/207C07H21/00
CPCA61K31/7048C07H21/00C07H19/207A61K31/70A61P11/00A61P11/10A61P11/12A61P27/04A61P27/16
Inventor B·R·叶克W·彭德格斯特J·L·里德乌M·皮彻R·C·鲍彻M·J·斯塔茨
Owner INSPIRE PHARMA
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