1,2,3,6-tetrahydropyrimidine-2-one compositions and therapeutic methods therewith for gastrointestinal dysfunction

a technology of pyrimidine and composition, applied in the field of gastrointestinal dysfunction, can solve problems such as local irritation at high concentrations

Inactive Publication Date: 2003-11-06
CRAGMONT PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Colpermin.RTM. is approved for sale in Europe and in the United Kingdom, but not in the United States perhaps because some of the constituents of the oil, for example, pulgeone may be toxic to the liver.
However, menthol is not very potent, can cause local irritation at high concentrations, and has a relatively short duration of action of about 5 to 15 minutes because it is rapidly re-distributed in tissues and is metabolized.

Method used

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  • 1,2,3,6-tetrahydropyrimidine-2-one compositions and therapeutic methods therewith for gastrointestinal dysfunction
  • 1,2,3,6-tetrahydropyrimidine-2-one compositions and therapeutic methods therewith for gastrointestinal dysfunction

Examples

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example a

[0055] Chemical Synthesis of Icilin and Analogs. The methods of chemical synthesis are as described by Podesva and Do Nascimento in U.S. Pat. No. 3,821,221, herein incorporated by reference. Briefly, a substituted acetophenone, e.g. 3-nitroacetophenone or 3-trifluoromethylacetophenone, readily obtainable from commercial sources such as Sigma-Aldrich, Co., was mixed with diethylamine or dimethylamine in formaldehyde and refluxed in acidic solutions. After addition of a second substituent (e.g. ortho-aminophenol), the Mannich reaction produced a .beta.-amino-ketone compound (e.g. [.beta.-ortho-hydroxyanilino]-meta-nitropropiophenone) which was isolated. This reagent was then reacted with potassium cyanate or sodium cyanate to produce an unstable urea intermediate that proceeds to cyclize into the tetrahydropyridimine-2-one ring, with the appropriate groups on position 1 (2-hydroxyphenyl) and 4 (3-nitrophenyl) on the 1,2,3,6-tetrahydropyrimidine-2-one ring. The precipitated product was...

example 1

[0056] A male subject spread 10 mg of icilin with a swab-stick between two sticks of a fruit-flavored chewing gum and chewed the gum for 10 minutes. No sensations of coolness were noted in the mouth or throat. But after 10 minutes general sensations of coolness were felt in the retrostemal and epigastric areas. These cooling effects lasted for about 1 hour. By contrast, the chewing of mentholated gum or mentholated candy produced, after an initial harsh taste, strong cooling of the mouth and throat that lasted only about 10 minutes. The next day the subject consumed a quick meal consisting of a large-size pepperoni-sausage pizza, washed down with coca-cola. The subject reported feelings of satiety, bloating, and severe epigastric discomfort. Consumption of 5 mentholated candies (Mentos) did not affect these symptoms. However, using the icilin-chewing gum reduced all symptoms.

example 2

[0057] A female subject who met the diagnostic criteria for gastroesophageal reflux disease (GERD) would, on occasions after a big meal, wake in the middle of night with severe epigastric discomfort, eructations, a sour taste in the mouth, and a sense of nausea and pain. Ingestion of Tagamet.RTM. would provide some degree of relief from pain, but the other symptoms persisted. The subject was given the icilin-chewing gum wafer and instructed on its use. She reported that using the icilin-chewing gum on two different evenings helped relieve her discomfort and allowed her to go to sleep uneventfully.

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Abstract

A therapeutic composition is provided that comprises a 1-R1-phenyl, 4-R2-phenyl substituted 1,2,3,6-tetrahydropyrimidine-2-one sensory nerve receptor agonist in a therapeutically effective amount. The sensory nerve receptor agonist may be represented by the general formula 1-[R1-phenyl]-4-[R2-phenyl]-1,2,3,6-tetrahydropyrimidine-2-one wherein: R1 may be -hydroxy, -chloro, -fluoro, -alkyl, -acetoxy, -trifluoromethyl ; and R2 is -nitro, -chloro, -fluoro, -alkyl, -trifluoromethyl. Therapeutic compositions of the invention reduce pain, a sense of abdominal distension, tenesmus, and abnormal bowel function when formulated for oral delivery to human gastrointestinal tract and are useful to alleviate gastrointestinal dysfunction.

Description

[0001] This application is a continuation-in-part of Ser. No. 10 / 139193, filed May 2, 2002, inventor Wei, entitled "Therapeutic 1,2,3,6-Tetrahydropyrimidine-2-One Compositions and Methods Therewith", incorporated by reference.[0002] Not applicable.[0003] 1. Field of the Invention[0004] This invention generally relates to a class of chemicals that activate receptors on sensory nerve endings of the human gastrointestinal tract and therapeutic use of these chemicals for gastrointestinal dysfunction. This invention more particularly relates to therapeutic compositions preferably formulated for oral intake and delivery to the luminal surfaces of the human esophagus, ileum, colon and rectum. The particularly preferred embodiment compositions are formulated as chewing gum, tablet or enteric-coated pill or capsule, and comprise "icilin", a 1,2,3,6-tetrahydropyrimidine-2-one compound.[0005] 2. Description of Related Art[0006] Background on icilin. 1,2,3,6-Tetrahydropyrimidine-2-one compounds...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K9/00A61K31/00A61K31/513A61K31/56A61K31/573A61K45/06A61M15/08
CPCA61K9/0043A61K9/0075A61M2202/064A61M15/08A61K45/06A61K31/573A61K31/56A61K31/00A61K31/513A61K2300/00
Inventor WEI, EDWARD T.
Owner CRAGMONT PHARMA
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