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Prostaglandin compound, compositions and methods of treating peripheral vascular disease and pulmonary hypertension

A prostaglandin and compound technology, applied in the field of modified prostaglandin compounds, can solve the problems of patients, short effective life, etc.

Inactive Publication Date: 2002-06-19
UNITED THERAPEUTICS CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Short active life requires patients to take the drug frequently, making dosing a problem for patients, especially those with chronic diseases

Method used

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  • Prostaglandin compound, compositions and methods of treating peripheral vascular disease and pulmonary hypertension
  • Prostaglandin compound, compositions and methods of treating peripheral vascular disease and pulmonary hypertension
  • Prostaglandin compound, compositions and methods of treating peripheral vascular disease and pulmonary hypertension

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0102] Synthesis of mPEG-5kDa-amide-Compound X

[0103] Hereinafter referred to as "Compound 1"

[0104] Compounds of group 4 were prepared in the following manner, wherein Z 1 is mPEG with a molecular weight of approximately 5,000 Daltons, X is NH and Z 2 for hydrogen.

[0105] 200 mg of Compound X having the following structural formula:

[0106]Placement containing mPEG5k amine (2.5g), 2-hydroxybenzyltriazole (HOBT, 67mg), 4-(dimethylamino)pyridine (DMAP, 61mg) and dicyclohexylcarbodiimide (DCC, 140mg) inside the round bottom flask. The reactants were mixed with 60 ml of anhydrous dichloromethane. The mixture was stirred at room temperature overnight, after which time the solvent was evaporated. The residue was dissolved in 25 ml of 1,4-dioxane, and the insolubles were removed by filtration. The solvent was concentrated and then precipitated into 100 ml of 50:50 / diethyl ether:isopropanol. The precipitate was collected by filtration and dried under vacuum. The pro...

Embodiment 2

[0108] Synthesis of mPEG5kDa-ester-compound X diacetate

[0109] Hereinafter referred to as "Compound 2"

[0110] Compounds of group 4 were prepared in the following manner, wherein Z 1 is mPEG with a molecular weight of approximately 5,000 Daltons, X is O and each Z 2 for the acetyl group.

[0111] In a round bottom flask, compound X (400 mg) and pyridine (200 μl) were mixed in 35 ml of dry dichloromethane, and 500 μl of acetic anhydride was added to the suspension. The compound became homogeneous within a few hours and the solution was stirred at room temperature overnight. The solvent was concentrated, and phosphate buffer (0.1 M, pH 7.4) was added to the residue. The mixture was stirred rapidly for 30 minutes, and the mixture was extracted 3 times with dichloromethane. The combined organic phases were dried over sodium sulfate and the solvent was evaporated. An oily product was obtained, Compound X diacetate. The yield was 340 mg (80%). 1 H NMR (DMSO-d 6 ): 1.91(s...

Embodiment 3

[0114] Synthesis of mPEG20KDa-ester-compound X

[0115] Hereinafter referred to as "Compound 3"

[0116] Compounds of group 5 were prepared in the following manner, wherein each Z 2 is -CO-(CH with a molecular weight of about 20,000 Daltons 2 ) 2 -O-linked mPEG.

[0117] In a round bottom flask, compound X (200 mg) and sodium hydroxide (21 mg) were mixed in 40 ml of anhydrous acetonitrile. To the suspension was added 90 mg of benzyl bromide, and the mixture was refluxed for 2 days. The solids were removed by filtration, the solvent was concentrated, and the residue was dried under vacuum. An oily product is obtained, compound X-benzyl ester. The yield is 210mg (100%). 1 H NMR (DMSO-d 6 ): δ7.37(s, C 6 H 5 -CH 2 -OCO-(Compound X)), 5.19(s, C 6 H 5 -CH 2 -OCO-(Compound X)), 4.83(s, (Compound X)-CH 2 COOBz), 4.49(d, (Compound X)-OH 1 ), 4.24(d, (Compound X)-OH 1 ), 0.864(t, (Compound X)-CH 3 ), 7.025 (t, compound X aromatic proton), 6.7 (d+d, compound X aromatic...

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Abstract

Prostaglandin and analogs thereof which include protective groups attached to at least one site which are pharmaceutically acceptable and which are capable of slowing the metabolic rate of the active groups for administration to a warm blooded animal for the treatment of peripheral vascular disease and pulmonary hypertension. In fact, Figure 1 graphically shows the effects on pulmonary arterial pressure of a dose of mPEG20kDa-aminde-Compound X, given as an intravenous infusion to a sheep intravenously-induced with a pulmonary hypertensive agent.

Description

Field of Invention [0001] The present invention relates to modified prostanoids, in particular to long-acting prostaglandin-containing compositions for the treatment of peripheral vascular disease and pulmonary hypertension. Background of the Invention [0002] Almost all kinds of tissues in the body can produce prostaglandins. No other endocrine or hormone can exhibit as diverse or variable effects as prostaglandins. Most prostanoids have an effective lifespan of only 3 to 10 minutes due to the rapid degradation often caused by enzymes in the blood and lungs. [0003] Prostaglandins include prostacyclin, an analog of prostaglandins produced by the body and involved in maintaining the normal function of blood vessels. Natural prostacyclins are inherently unstable and have an effective lifespan of less than about 6 minutes. Prostaglandins, including prostacyclins, appear to maintain the proper functioning of blood vessels in three ways, 1) they dilate blood vessels and, if...

Claims

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Application Information

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IPC IPC(8): A61K47/48A61K31/192A61K31/22A61K31/343A61P9/00A61P9/12A61P11/00C07C69/712C07C235/34C07C405/00C07D307/937
CPCC07D307/937C07C405/0083A61K47/48215A61K47/60A61P9/00A61P9/12A61P11/00Y02P20/55A61K47/50
Inventor 罗伯特·肖尔马蒂纳·罗思布拉特迈克尔·D·本特利赵宣
Owner UNITED THERAPEUTICS CORP
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