Composition and method for inhibiting platelet aggregation

A compound, hydrate technology, applied in the field of mono- and dinucleoside polyphosphate compounds, which can solve problems such as high bleeding risk

Inactive Publication Date: 2007-08-15
INSPIRE PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] ●Since these inhibitors have no effect on P2Y 12 Due to the irreversible nature of the receptor, subjects treated with thienopyridines are at high risk of bleeding if surgery is necessary

Method used

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  • Composition and method for inhibiting platelet aggregation
  • Composition and method for inhibiting platelet aggregation
  • Composition and method for inhibiting platelet aggregation

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0301] Compound preparation

[0302] Those skilled in the art can easily synthesize the compounds of the present invention by well-known chemical methods. Mono-, di-, and triphosphate mononucleosides can be obtained from commercial sources or synthesized from nucleosides using various phosphorylation reactions found in the chemical literature. Nucleoside mono-, di-, or triphosphates can be activated by coupling agents such as, but not limited to, dicyclohexylcarbodiimide or 1,1'-carbonyldiimidazole, and then combined with another nucleoside mono-, di-, or triphosphate ( Can be the same (or different) condensation with the activated molecule to prepare symmetrical or asymmetrical dinucleoside polyphosphates. Activation of nucleoside triphosphates with dicyclohexylcarbodiimide yields cyclic trimetaphosphate as an activated species, which can advantageously react with various nucleophiles to add specific substituents to the terminal phosphate of the triphosphate superior.

[0...

Embodiment 1

[0352] 2'(3')-O-((phenylaminocarbonyl)-uridine 5'-)triphosphate

[0353] Dissolve 5'-uridine ditributylammonium triphosphate (100mg, 0.176mmol; from trisodium salt by using Dowex 50Wx4H +Work up in water, then react the protonated material with excess tributylamine, strip and lyophilize), add phenylisocyanate (19 μL, 0.176 mmol). The reaction mixture was heated at 45°C for 15 minutes, at which time an additional portion of phenylisocyanate (19 μL, 0.176 mmol) was added. The solution was heated at 45°C overnight and DMF was removed on a rotary evaporator. The remaining oil was partitioned between water (2 mL) and ethyl acetate (2 mL), and the layers were separated. The aqueous layer was extracted two more times with ethyl acetate (2 ml each) and the water was removed on a rotary evaporator. The residue was dissolved in water (1.5ml), and the product was repeatedly injected into a preparative HPLC column (Alltech nucleotide / nucleoside C18, 7 microns, 10×250mm, gradient of 0.1...

Embodiment 2

[0356] 2'(3')-O-(phenylaminocarbonyl)-P 1 , P 4 - bis(uridine 5′-)tetraphosphate ["monophenylcarbamate Up4U"], bis-2′(3′)-O-(phenylaminocarbonyl)-P 1 , P 4 - bis(uridine 5'-)tetraphosphate ["diphenylcarbamate Up4U"] and tris-2'(3')-O-(phenylaminocarbonyl)-P 1 , P 4 - Di(uridine 5′-)tetraphosphate ["triphenylcarbamate Up4U"]

[0357] Dissolve P in anhydrous DMF (2ml) 1 , P 4 - Di(uridine 5')'-tetraphosphate ditributyl modified salt (211 mg, 0.182 mmol; obtained from the tetrasodium salt by using Dowex 50Wx4H + , then reacted the protonated material with excess tributylamine, stripped and lyophilized), and added a portion of phenylisocyanate (40 μL, 3.64 mmol). The homogeneous reaction mixture was heated at 45°C overnight at which time TLC (silica gel, 50% isopropanol / 50% ammonium hydroxide) indicated substantial conversion to two products. The solvent was removed on a rotary evaporator and the residue was partitioned between water (7 mL) and ethyl acetate (10 mL). The ...

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Abstract

This invention is directed to a method of preventing or treating diseases or conditions associated with platelet aggregation. The method is also directed to a method of treating thrombosis. The method comprises administering to a subject a pharmaceutical composition comprising a therapeutic effective amount of P2Y<12> receptor antagonist compound, wherein said amount is effective to bind the P2Y<12> receptors on platelets and inhibit ADP-induced platelet aggregation. The P2Y12 receptor antagonist compounds useful for this invention include mononucleoside 5'-monophosphates, mononucleoside polyphosphates, and dinucleoside polyphosphates of general Formula I, or salts thereof. The present invention also provides novel compounds of mononucleoside 5'-monophosphates and dinucleoside diphosphates. The present invention further provides pharmaceutical formulations comprising a pharmaceutical carrier and mononucleoside 5'-monophosphates or dinucleoside diphosphates.

Description

technical field [0001] This invention relates to mono- and dinucleoside polyphosphate compounds and methods of using these compounds to prevent or treat diseases or conditions associated with platelet aggregation, including thrombosis in humans and other mammals. Background of the invention [0002] Hemostasis is the spontaneous process by which damaged blood vessels stop bleeding. When incised, the anterior capillary constricts immediately; within seconds, thrombus cells, or platelets, collect on the stroma exposed by the damaged vessel through a process called platelet adhesion. Platelets also stick to each other to form a platelet plug to stop bleeding quickly, in a phenomenon called platelet aggregation. [0003] Pathological disturbance of hemostasis caused by intravascular thrombus. Platelet adhesion and aggregation are key events in intravascular thrombus formation. Under the conditions of turbulent blood flow in a diseased vessel, or due to the release of mediator...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/20C07H19/207C07H19/10A61K31/7076A61K31/7084A61K31/7072A61K31/708A61K38/43A61K45/00A61P7/00A61P7/02A61P7/08A61P7/12A61P9/00A61P9/04A61P9/10A61P9/14A61P13/00A61P13/12A61P15/00A61P15/06A61P17/02A61P19/04A61P25/06A61P29/00A61P31/04A61P37/00A61P39/00A61P41/00A61P43/00C07F9/6561C07H19/04C07H21/00C07H21/02C07H21/04
CPCC07H19/10A61K31/675A61K31/7072C07H21/00C07H19/04A61K31/7084A61K31/7076C07H19/20C07H19/207A61P7/00A61P7/02A61P7/08A61P7/12A61P9/00A61P9/04A61P9/10A61P9/14A61P13/00A61P13/12A61P15/00A61P15/06A61P17/02A61P19/04A61P25/06A61P29/00A61P31/04A61P37/00A61P39/00A61P41/00A61P43/00
Inventor J·博耶J·G·道格拉斯三世S·R·谢弗P·S·沃森R·克里希纳穆斯
Owner INSPIRE PHARMA
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