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Nitrosated and nitrosylated potassium channel activators, compositions and methods of use

a potassium channel activator and nitrosylated technology, applied in the field of nitrosated and nitrosylated potassium channel activators, compositions and methods of use, can solve the problems of not being previously investigated, postural hypotension, nausea and vomiting,

Inactive Publication Date: 2004-11-18
GARVEY DAVID S +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0034] "Potassium channel activator" refers to any compound that results in the opening of the potassium channel such that the permeability of potassium is increased, thereby resulting in hyperpolarization and relaxation of smooth muscles.
[0311] The pharmaceutical preparations can be sterilized and if desired, mixed with auxiliary agents which do not deleteriously react with the active compounds, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavoring and / or aromatic substances, and the like. For parenteral application, particularly suitable vehicles consist of solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants. Aqueous suspensions may contain substances which increase the viscosity of the suspension and include, for example, sodium carboxymethyl cellulose, sorbitol and / or dextran. Optionally, the suspension may also contain stabilizers.
[0314] The bioavailabilty of the compositions can be enhanced by micronization of the formulations using conventional techniques such as grinding, milling, spray drying and the like in the presence of suitable excipients or agents such as phospholipids or surfactants. The bioavailability and absorption of the potassium channel activators can be increased by the addition of tabletting excipients, such as, for example .beta.-cyclodextrin, a .beta.-cyclodextrin derivative, such as for example, hydroxypropyl-.beta.-cyclodextrin (HPBCD), and the like.

Problems solved by technology

However, the effects of modified potassium channel activators, which are directly or indirectly linked with a nitric oxide adduct, and which are optionally used in conjunction with NO donors, have not been previously investigated.
Such adverse effects include postural hypotension, headaches, dizziness, palpitations, gastric pain, nausea and vomiting.

Method used

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  • Nitrosated and nitrosylated potassium channel activators, compositions and methods of use
  • Nitrosated and nitrosylated potassium channel activators, compositions and methods of use
  • Nitrosated and nitrosylated potassium channel activators, compositions and methods of use

Examples

Experimental program
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Effect test

example 1

N-[2-methyl-2-(nitrosothio)propyl]-3-pyridylcarboxamide

[0324] 1a N-(2-methyl-2-sulfanylpropyl)-3-pyridylcarboxamide

[0325] 1-Amino-2-methylpropane-2-thiol hydrochloride (1.10 g, 6.18 mmol) was dissolved in DMF and nicotinoyl chloride hydrochloride (1.14 g, 8.03 mmol) was slowly added as a solid. The mixture was cooled to 0.degree. C. and triethylamine (3.0 mL, 21.63 mmol) was slowly added. The mixture was stirred for one half hour at 0.degree. C., allowed to warm to room temperature, and stirred overnight. The reaction mixture was diluted with methylene chloride, washed with saturated sodium bicarbonate, brine, and dried over magnesium sulfate. The volatiles were removed under reduced pressure to give a pink oil. An excess of hydrogen chloride in ether was added to precipitate 831 mg. (55%) of the title compound, mp. 163-165.degree. C. .sup.1H NMR (300 MHz, DMSO) .delta. 9.00 (br s, 1H), 8.71 (dd, 1H, J=2.0, 4.9), 8.20 (dt, 1H, J=2.0, 7.9), 7.51 (dd, 1H, J=4.9, 7.9), 3.44 (d, 2H, J=6...

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Abstract

The present invention describes novel nitrosated and / or nitrosylated potassium channel activators, and novel compositions comprising at least one nitrosated and / or nitrosylated potassium channel activator, and, optionally, at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase and / or at least one vasoactive agent. The present invention also provides novel compositions comprising at least one potassium channel activator, and at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase and / or at least one vasoactive agent. The present invention also provides methods for treating or preventing sexual dysfunctions in males and females, for enhancing sexual responses in males and females, and for treating or preventing cardiovascular disorders, cerebrovascular disorders, hypertension, asthma, baldness, urinary incontinence, epilepsy, sleep disorders, gastrointestinal disorders, migraines, irritable bowel syndrome and sensitive skin.

Description

[0001] This application claims priority to U.S. Provisional Application No. 60 / 133,888 filed May 12,1999.[0002] The present invention describes novel nitrosated and / or nitrosylated potassium channel activators, and novel compositions comprising at least one nitrosated and / or nitrosylated potassium channel activator, and, optionally, at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase and / or at least one vasoactive agent. The present invention also provides novel compositions comprising at least one potassium channel activator, and at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase and / or at least one vasoactive agent. The present ...

Claims

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Application Information

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IPC IPC(8): A61K31/4406A61K31/455C07D213/82
CPCA61K31/4406A61K31/455C07D213/82
Inventor GARVEY, DAVID S.SAENZ DE TEJADA, INIGO
Owner GARVEY DAVID S
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