Synthetic methods and intermediates for stereoisomeric compounds useful for the treatment of gastrointestinal and central nervous system disorders

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 priority to US Provisional Application No. 60 / 713,149, filed August 31, 2005, and US Provisional Application No. 60 / 747,762, filed May 19, 2006. Background technique

[0002] Cisapride is one of a class of compounds known as benzamide derivatives, whose parent compound is metoclopramide. US Patent Nos. 4,962,115 and 5,057,525 (collectively "Van Daele" and incorporated herein by reference in their entirety) disclose N-(3-hydroxy-4-piperidinyl)benzamides of cisapride. Van Daele discloses that these compounds and their pharmaceutically acceptable acid addition salts and their stereoisomeric forms stimulate the motility of the gastrointestinal system.

[0003] As a class of compounds, these benzamide derivatives have several remarkable pharmacological effects. The pronounced pharmacological activity of benzamide derivatives is attributed to their effects on the nervous system regulated by the neurotransmitter serotonin. It has been generally accept...

Examples

preparation example Construction

[0306] Compound preparation

[0307] Although the chemical synthesis of various analogs of cisapride can be carried out according to European Patent Application No. 0,076,530 A2 published on April 13, 1983, WO 01 / 093849, U.S. Patent No. 4,962,115, No. 5,057,525 and Van Daele et al., Drug Development Res. 8:225-232 (1986) (the content of which is incorporated herein by reference in its entirety), the compounds of the present invention are preferably prepared according to the disclosure of Methods 3-6.

Embodiment 1

[0485] 6-[4R-(4-Amino-5-chloro-2-methoxy-benzamido)-3S-methoxy-piperidin-1-yl]-hexanoic acid 1-aza-bicyclo[ 2.2.2] Preparation of octa-3'R-yl ester dihydrochloride

[0486]

[0487] Step 1: Resolution of racemic norcisapride

[0488] (-)-2,3-Dibenzoyl-L-tartaric acid ((-)-DBT, about 1 part by weight) was dissolved in ethanol and filtered to remove residual particles. Separately, racemic norcisapride (approximately 0.8 parts by weight) was dissolved in a mixture of ethanol and water and filtered. The filtrate was heated to about 75°C, and then the (-)-DBT solution was added. After stirring at this temperature for about 30 minutes, the mixture was cooled slowly to about 5 °C for several hours, and the product salt was collected by vacuum filtration and washed with EtOH / H 2 O mixture wash. The filter cake was removed from EtOH / H by heating to about 79°C and then slowly cooling to about 2 recrystallized from O. The product was collected on a vacuum filter and washed with ...

example 2

[0497] According to U.S. Patent No. 6,147,093, or "Enantiomaers, Racemates and Resolutions" by J. Jacques, A. Collet and S.H. Wilen (Wiley-Interscience, New York, NY) (Enantiomers, Racemates and Resolutions) separation), or by the method described in S.H.Wilen et al., Tetrahedron (1977) 33:2725, by resolution of enantiomers using conventional means such as optical resolution acids, can be prepared from their racemic mixture ( +) and (-)-norcisapride.

[0498] The 4 isomers were obtained in low amounts (mg) by preparative column chromatography followed by evaporation of the solvent. This method can be used to prepare small amounts of isomers for analysis and identification purposes. This is a standard separation method routinely used by analytical laboratories to isolate and identify metabolites.

[0499] The possible routes for the synthesis of compound IV, compound VI and (+)-compound II using (+)-norcisapride as starting materials are described below. Except for using (-)...

[0001] This application claims priority to US Provisional Application No. 60 / 713,149, filed August 31, 2005, and US Provisional Application No. 60 / 747,762, filed May 19, 2006. Background technique

[0002] Cisapride is one of a class of compounds known as benzamide derivatives, whose parent compound is metoclopramide. US Patent Nos. 4,962,115 and 5,057,525 (collectively "Van Daele" and incorporated herein by reference in their entirety) disclose N-(3-hydroxy-4-piperidinyl)benzamides of cisapride. Van Daele discloses that these compounds and their pharmaceutically acceptable acid addition salts and their stereoisomeric forms stimulate the motility of the gastrointestinal system.

[0003] As a class of compounds, these benzamide derivatives have several remarkable pharmacological effects. The pronounced pharmacological activity of benzamide derivatives is attributed to their effects on the nervous system regulated by the neurotransmitter serotonin. It has been generally accept...

Examples

preparation example Construction

[0306] Compound preparation

[0307] Although the chemical synthesis of various analogs of cisapride can be carried out according to European Patent Application No. 0,076,530 A2 published on April 13, 1983, WO 01 / 093849, U.S. Patent No. 4,962,115, No. 5,057,525 and Van Daele et al., Drug Development Res. 8:225-232 (1986) (the content of which is incorporated herein by reference in its entirety), the compounds of the present invention are preferably prepared according to the disclosure of Methods 3-6.

Embodiment 1

[0485] 6-[4R-(4-Amino-5-chloro-2-methoxy-benzamido)-3S-methoxy-piperidin-1-yl]-hexanoic acid 1-aza-bicyclo[ 2.2.2] Preparation of octa-3'R-yl ester dihydrochloride

[0486]

[0487] Step 1: Resolution of racemic norcisapride

[0488] (-)-2,3-Dibenzoyl-L-tartaric acid ((-)-DBT, about 1 part by weight) was dissolved in ethanol and filtered to remove residual particles. Separately, racemic norcisapride (approximately 0.8 parts by weight) was dissolved in a mixture of ethanol and water and filtered. The filtrate was heated to about 75°C, and then the (-)-DBT solution was added. After stirring at this temperature for about 30 minutes, the mixture was cooled slowly to about 5 °C for several hours, and the product salt was collected by vacuum filtration and washed with EtOH / H 2 O mixture wash. The filter cake was removed from EtOH / H by heating to about 79°C and then slowly cooling to about 2 recrystallized from O. The product was collected on a vacuum filter and washed with ...

example 2

[0497] According to U.S. Patent No. 6,147,093, or "Enantiomaers, Racemates and Resolutions" by J. Jacques, A. Collet and S.H. Wilen (Wiley-Interscience, New York, NY) (Enantiomers, Racemates and Resolutions) separation), or by the method described in S.H.Wilen et al., Tetrahedron (1977) 33:2725, by resolution of enantiomers using conventional means such as optical resolution acids, can be prepared from their racemic mixture ( +) and (-)-norcisapride.

[0498] The 4 isomers were obtained in low amounts (mg) by preparative column chromatography followed by evaporation of the solvent. This method can be used to prepare small amounts of isomers for analysis and identification purposes. This is a standard separation method routinely used by analytical laboratories to isolate and identify metabolites.

[0499] The possible routes for the synthesis of compound IV, compound VI and (+)-compound II using (+)-norcisapride as starting materials are described below. Except for using (-)...

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