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Synthetic Methods and Intermediates for Stereoisomeric Compounds Useful for the Treatment of Gastrointestinal and Central Nervous System Disorders

a technology of stereoisomeric compounds and intermediates, which is applied in the direction of digestive system, drug compositions, organic chemistry, etc., can solve the problems of cisapride administration to a human, failure of the lower esophageal sphincter, nausea and vomiting, etc., and achieve the effect of avoiding the cytochrome p450 drug detoxification system and reducing the incidence of such adverse events

Inactive Publication Date: 2008-03-27
ARYX THERAPEUTICS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0036] The compounds of formula (X) that are made by the methods and / or processes of the invention are useful in the treatment or prevention of 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.
[0039] Advantageously, compounds made according to the methods and / or processes of the subject invention for making stereoisomeric compounds generally contain an ester moiety that does not detract from the ability of these compounds to provide a therapeutic benefit, but which makes them more susceptible to degradation by serum and / or cytosolic esterases, thereby avoiding the cytochrome P450 drug detoxification system associated with adverse effects caused by cisapride and reducing the incidence of such adverse events.
[0041] Advantageously, the therapeutic compounds made utilizing the methods and / or processes of the subject invention are stable in storage and provide for safer metabolism of the drugs as compared to other drugs; therefore, the compounds of the subject invention can be used with a lower incidence of side effects and toxicity.

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 serious 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 effects not experienced after oral administration of cisapride (Stacher et al.
Cisapride is also subject to a number of undesirable drug / drug interactions that are also a result of metabolism by the cytochrome P450 system.
As a result of these adverse effects, the product was voluntarily withdrawn from the open market in the United States; however, the drug is available through an investigational limited access program.
The safety of 5HT4 receptor agonists with gastrointestinal (GI) prokinetic activity has been limited due to cardiac effects (prolongation of QTc intervals, tachycardia, torsades de pointes) and adverse drug interactions due to hepatic cytochrome P-450 metabolism.

Method used

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  • Synthetic Methods and Intermediates for Stereoisomeric Compounds Useful for the Treatment of Gastrointestinal and Central Nervous System Disorders
  • Synthetic Methods and Intermediates for Stereoisomeric Compounds Useful for the Treatment of Gastrointestinal and Central Nervous System Disorders
  • Synthetic Methods and Intermediates for Stereoisomeric Compounds Useful for the Treatment of Gastrointestinal and Central Nervous System Disorders

Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of 6-[4R-(4-amino-5-chloro-2-methoxy-benzoylamino)-3S-methoxy-piperidin-1-yl]-hexanoic acid 1-aza-bicyclo[2.2.2]oct-3′R-yl ester, dihydrochloride salt

[0373]

Step 1: Resolution of Racemic Norcisapride

[0374] (−)-2,3-Dibenzoyl-L-tartaric acid ((−)-DBT, about 1 part by weight) was dissolved in ethanol and filtered to remove residual particulates. Separately, racemic norcisapride (about 0.8 part by weight) was dissolved in a mixture of ethanol and water and then filtered. The filtrate was heated to about 75° C. before adding the (−)-DBT solution. After stirring at this temperature for about 30 minutes, the mixture was slowly cooled for several hours to about 5° C. and the product salt was collected under vacuum filtration and washed with EtOH / H2O mixture. The wetcake was recrystallized from EtOH / H2O by heating to about 79° C. and slow cooling to about 5° C. as before. The product was collected on a vacuum filter and washed with EtOH / H2O to give a wetcake.

[0375] The wetcake ...

example 2

[0380] (+) and (−)-norcisapride can be made from its racemic mixture by resolution of the enantiomers using conventional means such as optically resolving acids, according to the method described in U.S. Pat. No. 6,147,093, or in “Enantiomers, Racemates and Resolutions”, by J. Jacques, A. Collet, and S. H. Wilen (Wiley-Interscience, New York, N.Y.), or in S. H. Wilen et al., Tetrahedron (1977) 33:2725.

[0381] The 4 isomers can be obtained in low-mg amounts by using preparative column chromatography followed by evaporation of the solvent. This method is useful for preparing small amounts for analytical and characterization purposes. This is a standard separation method used routinely in analytical labs in order to isolate and characterize metabolites.

[0382] Possible synthetic routes to Compound IV, Compound VI and (+)-Compound II are described below using (+)-norcisapride as a starting material. The routes to Compound III, Compound V and (−)-Compound II are identical except that the...

example 3

Production of (+)-Compound II, Ethyl Ester

[0383] A equimolar mixture of (+)-norcisapride and ethyl 6-bromohexanoate (1 equivalent each), a catalytic amount of KI, and K2CO3 (2 equivalents) in DMF is heated at about 60° C. for several hours or until TLC analysis indicates that the reaction is over. After cooling to room temperature, water is added and the mixture is extracted with EtOAc. The combined organic extracts are washed successively with water, 10% LiCl(aq) solution and brine, then dried over Na2SO4. Concentration gives (+)-compound II, ethyl ester.

[0384] Production of (+)-Compound II

[0385] A mixture of crude (+)-compound II, ethyl ester, from above (1 eq.), KOH (2M, 5 eq.). in MeOH and THF (enough to dissolve) is stirred at room temperature for approximately 1 to 2 hours. The MeOH and THF are removed under vacuum, and the residue is diluted with water. Wash with an organic solvent such as EtOAc. The aqueous layer is acidified to pH ˜5 using HCl. The precipitate is filtere...

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Abstract

The subject invention provides methods and / or processes for making stereoisomeric compounds of formula (X): wherein the variables are as defined herein, and compositions for the safe and effective treatment of various gastrointestinal disorders including, but not limited to, gastroparesis, gastroesophageal reflux and related conditions. The compounds of the subject invention are also useful in treating a variety of conditions involving the central nervous system.

Description

[0001] This application claims the benefit of U.S. provisional application No. 60 / 713,149, filed Aug. 31, 2005, and U.S. provisional application no. 60 / 747,762, filed May 19, 2006.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 modulated by the neurotransmitter serotonin. The role of s...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D453/02C07D211/40
CPCC07D453/02C07D211/58A61P1/04A61P1/08A61P1/10A61P1/14A61P43/00Y02P20/55
Inventor BY, KOLBOTYEH, JINUN-BANPANG, PONNY
Owner ARYX THERAPEUTICS
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