Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Materials and methods for the treatment of gastroesophageal reflux disease

a gastroesophageal reflux disease and material technology, applied in the direction of biocide, cardiovascular disorder, drug composition, etc., can solve the problems of nausea and vomiting, failure of the lower esophageal sphincter, administration of cisapride to a human, etc., to achieve safe and effective treatment of gastroesophageal reflux disease, reduce adverse effects, and potent activity

Inactive Publication Date: 2003-11-20
ARYX THERAPEUTICS
View PDF4 Cites 14 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The esterified cisapride analogs provide effective treatment for gastroesophageal reflux and related conditions with reduced side effects and toxicity, offering a safer metabolic profile and stable storage, allowing for lower incidence of adverse events.

Problems solved by technology

This stimulating action is also associated with nausea and vomiting.
Failure of the lower esophageal sphincter can arise due to a low basal pressure, sphincter relaxation, or to a non-compensated increase in intragastric pressure.
The administration of cisapride to a human has been found to cause adverse effects including, CNS disorders, increased systolic pressure, interactions with other drugs, diarrhea, and abdominal cramping.
Further, it has been reported that intravenous administration of cisapride demonstrates the occurrence of additional adverse (side) effects not experienced after oral administration of cisapride (Stacher et al.

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Materials and methods for the treatment of gastroesophageal reflux disease
  • Materials and methods for the treatment of gastroesophageal reflux disease
  • Materials and methods for the treatment of gastroesophageal reflux disease

Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of Specific Compounds of the Subject Invention

[0093] Preferred compounds of the subject invention have the Formula (lb) where the substituents at the 3- and 4-positions of the piperidine ring have the cis-configuration, R.sub.1 is methoxy, R.sub.2 is hydrogen, R.sub.4 is methoxy, R.sub.5 is amino, R.sub.6 is chloro in the 2-, 4-, and 5-positions of the benzamide ring, respectively. In particularly preferred compounds, L has the Formula (II) wherein n=2, m=O, X is a direct bond, and Y is hydrogen, methyl, ethyl, isopropyl, sec-butyl, or 4-fluorophenyl. The common intermediate to these preferred compounds is compound 9 as described below.

[0094] The synthesis can be described in more details as follows:

[0095] 1-carbethoxy-4-piperidone 1 reacts with bromine in an inert solvent such as dichloromethane to give high yields of 1-carbethoxy-3-bromo-4-pip-eridone 2. The bromo compound 2 reacts with sodium methoxide in methanol to give 1-carbethoxy-3-hydroxy-4,4-dimethoxypiperidine 3...

example 2

Additional Synthesis Protocols

[0098] In addition to the general synthetic methods described above, the following procedures can also be utilized:

[0099] The compounds of Formula (I) wherein X is oxygen and RI is methoxy can be prepared by reduction of a compound of Formula (VIII) with sodium borohydride in lower alkanol solvent, followed by coupling of the resulting alcohol (X) with a substituted benzoic acid of Formula (V) in the presence of a coupling reagent such as a dialkylcarbodiimide. 8

[0100] Compounds of Formula I where L is CH.sub.2CHMeCOOR can be prepared by reacting the amine intermediate IX with methacrylic acid or an ester thereof, optionally in the presence of a base such as Triton B or triethylaamine.

[0101] Compounds of Formula I where L is CH.sub.2CMe.sub.2COOR can be prepared according to Katritzky et al., Synthesis (1989), 747 by reacting the benzotriazolylmethyl derivative of the amine intermediate IX with a 2-bromoisobutyric acid ester in the presence of zinc and ...

example 3

Additional Synthesis Procedures

[0104] 3-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin--1-yl]-propionic Acid 9

[0105] A solution of 4-amino-5-chloro-2-methoxy-N-(3-methoxy-piperidin-4-y-l)-benzamide (1 g, 3.2 mmol), and 241 uL of acrylic acid in 50 ml dichloromethane was stirred under nitrogen for 6 hr then concentrated in vacuo. The residue was slurried with hot ethyl acetate and filtered at room temperature to yield 1.15 g of product as a white solid.

[0106] Substituting Methacrylic Acid for Acrylic Acid Provided:

[0107] 3-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin--1-yl]-2-methyl-propionic Acid 10

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The subject invention provides novel compounds and compositions for the safe and effective treatment of gastroesophageal reflux and related conditions. In a preferred embodiment, the compositions of the subject invention comprise esterified cisapride derivatives. These compositions possess potent activity in treating gastroesophageal reflux disease and substantially reduce adverse effects associated with the administration of cisapride. These adverse effects include, but are not limited to, diarrhea, abdominal cramping and elevations of blood pressure and heart rate.

Description

[0001] This application is a continuation of co-pending application Ser. No. 09 / 876,698, filed Jun. 7, 2001 (pending). The subject application also claims priority to provisional application U.S. Serial No. 60 / 209,926, filed Jun. 7, 2000.BACKGROUND OF INVENTION[0002] Cisapride is one of a class of compounds known as benzamide derivatives, the parent compound of which is metoclopramide. U.S. Pat. Nos. 4,962,115 and 5,057,525 (collectively "Van Daele" and incorporated by reference in their entireties) disclose N-(3-hydroxy-4-piperidenyl) benzamides of cisapride. Van Daele discloses that these compounds, the pharmaceutically acceptable acid addition salts thereof and the stereochemically isomeric forms thereof, stimulate the motility of the gastrointestinal system.[0003] As a class, these benzamide derivatives have several prominent pharmacological actions. The prominent pharmacological activities of the benzamide derivatives are due to their effects on the neuronal systems which are m...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/4468A61P1/00A61P1/04A61P1/14A61P9/12A61P25/00A61P25/14A61P25/18A61P25/20A61P25/22A61P25/24A61P25/28C07D211/46C07D211/58
CPCA61K31/4468C07D211/58C07D211/46A61P1/00A61P1/04A61P1/14A61P9/12A61P25/00A61P25/14A61P25/18A61P25/20A61P25/22A61P25/24A61P25/28
Inventor DRUZGALA, PASCALMILNER, PETER G.PFISTER, JURGBECKER, CYRUS
Owner ARYX THERAPEUTICS
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com