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Selective histamine h3 antagonist acid addition salts and process for the preparation thereof

A citrate, acetone dicitrate technology, applied in the direction of organic active ingredients, organic chemical methods, medical preparations containing active ingredients, etc.

Pending Publication Date: 2022-01-07
RICHTER GEDEON NYRT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Histamine H 3 Receptor antagonists / inverse agonists may also be suitable for pharmacotherapeutic treatment of sleep disorders (Barbier and Bradbury, CNS Neurol. Disord. Drug Targets 2007, 6(1):31-43), but so far, Only one histamine H 3 The receptor antagonist pitolisant (Wakix brand) has been approved for the treatment of narcolepsy in adults with or without cataplexy (Kollb-Sielecka et al., Sleep Med. 2017, 33: 125-129)

Method used

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  • Selective histamine h3 antagonist acid addition salts and process for the preparation thereof
  • Selective histamine h3 antagonist acid addition salts and process for the preparation thereof
  • Selective histamine h3 antagonist acid addition salts and process for the preparation thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0146] 1-[4-(4-{3-[(2R)-2-Methyl-pyrrolidin-1-yl]-propoxy}-phenoxy)-piperidin-1-yl]-ethanone

[0147] 40 g of 1-[4-(4-{3-[(2R)-2-methyl-pyrrolidin-1-yl]-propoxy}-phenoxy prepared according to Example 11 of WO 2014 / 136075 )-piperidin-1-yl]-ethanone hydrochloride was dissolved in 480 mL of dichloromethane at 0-5 °C, and then 168 mL of 1M aqueous NaOH was added. After stirring for 10 minutes, the aqueous and organic phases were separated, and the organic phase was washed twice with 120 mL of deionized water, dried with 25 g of sodium sulfate and filtered. The solution was concentrated in vacuo to an oil. Evaporation residue: 32.8 g oil.

Embodiment 2

[0149] 1-[4-(4-{3-[(2R)-2-Methyl-pyrrolidin-1-yl]-propoxy}-phenoxy)-piperidin-1-yl]-ethanone Dihydrochloride

[0150] At room temperature, 2.0 g (5.55 mmol) of 1-[4-(4-{3-[(2R)-2-methyl-pyrrolidin-1-yl]-propoxy}-phenoxy)-piper Pyridin-1-yl]-ethanone was dissolved in 20 mL of acetone. The reaction mixture was cooled to 0 to 5 °C and 0.8 mL > 37% hydrochloric acid solution was added dropwise. After stirring at 0 to 5°C for 30 minutes, the crystals were filtered, covered with 1.5 mL of cold acetone, and dried at room temperature. White crystalline substance. Yield: 1.7g.

Embodiment 3

[0152] 1-[4-(4-{3-[(2R)-2-Methyl-pyrrolidin-1-yl]-propoxy}-phenoxy)-piperidin-1-yl]-ethanone Dihydrochloride

[0153] At room temperature, 0.548 g of 1-[4-(4-{3-[(2R)-2-methyl-pyrrolidin-1-yl]-propoxy}-phenoxy)-piperidine-1 -yl]-ethanone was dissolved in 1.1 mL of isopropanol. At room temperature, 0.391 g of 30% isopropanol hydrochloride was added dropwise to the alkaline solution. The precipitated slurry was filtered, then vacuum dried at 40°C under nitrogen for 2 hours. Yield: 0.42g.

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Abstract

The present invention relates to physically and chemically stable salts of the selective histamine preceptor antagonist compound of l-[4-(4-{3-[(2R)-2-methyl-pyrrolidin-l-yl]-propoxy}-phenoxy)- piperidin-l-yl]-ethanone of formula (1) and / or polymorphs thereof and / or hydrates / solvates thereof, the process for the preparation thereof, pharmaceutical compositions comprising them, and for use in the treatment and / or prevention of conditions requiring the modulation of histamine H3 receptors (e.g. Alzheimer's disease, obesity, schizophrenia, miochardial ischaemia, migraine, autism spectrum disorder).

Description

[0001] field of invention [0002] The present invention relates to 1-[4-(4-{3-[(2R)-2-methyl-pyrrolidin-1-yl]-propoxy}-phenoxy)-piperidine- Selective histamine H of 1-yl]-ethanone 3 Physically and chemically stable salts of receptor antagonist compounds, [0003] [0004] And / or polymorphs thereof and / or hydrates / solvates thereof, methods for their preparation, pharmaceutical compositions comprising them, and for the treatment and / or prevention of the need to regulate histamine H 3 Disorders of the recipient (eg Alzheimer's disease, obesity, schizophrenia, myocardial ischemia, migraine, autism spectrum disorder). [0005] Background of the invention [0006] Histamine H 3 Receptor antagonists are extensively studied with the aim of producing drugs capable of treating various diseases such as Alzheimer's disease, obesity, schizophrenia, myocardial ischemia, migraine, nasal congestion, and the like. (Leurs et al., Nat. Rev. Drug. Disc. 2005, 4(2): 107-120; Berlin et al., ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12A61K31/454A61P25/00
CPCA61P25/00C07D401/12A61K31/454C07B2200/13
Inventor F·塞布A·迈斯特利克斯A·得墨忒耳
Owner RICHTER GEDEON NYRT
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