Pyrrolidine compounds

a technology of pyrrolidine and compounds, applied in the field of pyrrolidine compounds, can solve the problems of hampered efforts and lack of knowledge about the cause and nature of this diseas

Inactive Publication Date: 2011-06-23
F HOFFMANN LA ROCHE & CO AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0022]The present compounds are high potential NK-3 receptor antagonists for the treatment of depression, pain, bipolar disorders, psychosis, Parkinson's disease, schizophrenia, anxiety and attention deficit hyperactivity disorder (ADHD).

Problems solved by technology

However, the complexity of the disorders, due to a wide array of symptoms, has hampered those efforts.
The major difficulty in the development of a new drug for schizophrenia is the lack of knowledge about the cause and nature of this disease.

Method used

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  • Pyrrolidine compounds
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Examples

Experimental program
Comparison scheme
Effect test

example 1

rac-{(3S,4R)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl ester

[0254]

a) rac-(3R,4S)-1-Benzyl-3-(3,4-dichloro-phenyl)-4-nitro-pyrrolidine

[0255]A solution of N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methylamine (32.50 g, 0.135 mol) in CH2Cl2 (70 mL) was added drop wise, over a 30 minutes period, to a stirred solution of 1,2-dichloro-4-((E)-2-nitro-vinyl)-benzene (19.60 g, 0.09 mol) and trifluoroacetic acid (1.54 mL, 0.013 mol) in CH2Cl2 (160 mL) at 0° C. The ice bath was removed, and the solution was stirred at 25° C. for an additional 48 h. It was then concentrated and purification by flash chromatography (SiO2, EtOAc / H 1:6) afforded 25.0 g (79%) of the title compound as a yellow oil. MS m / e: 351.0 (M+H+).

b) rac-(3S,4R)-1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylamine

[0256]To a stirred solution of rac-(3R,4S)-1-benzyl-3-(3,4-dichloro-phenyl)-4-nitro-pyrrolidine (11.60 g, 33.0 ...

example 2

rac-{(3S,4R)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-isopropyl-carbamic acid 4-fluoro-phenyl ester

[0263]

a) rac-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-isopropylamino-pyrrolidin-1-yl]-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone

[0264]To a solution of rac-(3S,4R)-[3-Amino-4-(3,4-dichloro-phenyl)-pyrrolidin-1-yl]-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone (120 mg, 0.28 mmol) in dichloromethane (1 mL) were added acetone (21 uL, 0.28 mmol) and sodiumtriacetoxy-borohydride (72 mg, 0.34 mmol) and acetic acid (16 uL, 0.28 mmol) and the reaction mixture was stirred at ambient temperature for 3 h. It was diluted with dichloromethane and washed with aqueous sodiumhydrogenecarbonate (1M). The organic layer was dried over sodium sulfate and concentrated affording the title compound (95 mg, 72%) as a light yellow foam. MS m / e: 466.3 [M]+.

b) rac-{(3S,4R)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarb...

example 3

rac-{(3S,4R)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-isobutyl-carbamic acid 4-fluoro-phenyl ester

[0266]

a) rac-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-isobutylamino-pyrrolidin-1-yl]-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone

[0267]To a solution of rac-(3S,4R)-[3-Amino-4-(3,4-dichloro-phenyl)-pyrrolidin-1-yl]-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone (150 mg, 0.35 mmol) in dichloromethane (1 mL) were added isobutylaldehyde (39 uL, 0.42 mmol) and sodiumcyanoborohydride (27 mg, 0.42 mmol) and acetic acid (51 uL, 0.88 mmol) and the reaction mixture was stirred at ambient temperature for 3 h. It was diluted with dichloromethane and washed with aqueous sodiumhydrogenecarbonate (1M). The organic layer was dried over sodium sulfate and concentrated affording the title compound (140 mg, 82%) as a light yellow oil. MS m / e: 480.3 [M]+.

b) rac-{(3S,4R)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecar...

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Abstract

The present application relates to compounds of formula
wherein R1, R2, R3, R4, and n are defined herein
or to a pharmaceutically active salt thereof. The present compounds are high potential NK-3 receptor antagonists for the treatment of depression, pain, psychosis, Parkinson's disease, schizophrenia, anxiety and attention deficit hyperactivity disorder (ADHD).

Description

PRIORITY TO RELATED APPLICATION(S)[0001]This application claims the benefit of European Patent Application No. 09179797.7, filed Dec. 18, 2009, which is hereby incorporated by reference in its entirety.BACKGROUND OF THE INVENTION[0002]The three main mammalian tachykinins, substance P(SP), neurokinin A (NKA) and neurokinin B (NKB) belong to the family of neuropeptides sharing the common COOH-terminal pentapeptide sequence of Phe-X-Gly-Leu-Met-NH2. As neurotransmitters, these peptides exert their biological activity via three distinct neurokinin (NK) receptors termed as NK-1, NK-2 and NK-3. SP binds preferentially to the NK-1 receptor, NKA to the NK-2 and NKB to the NK-3 receptor.[0003]The NK-3 receptor is characterized by a predominant expression in CNS and its involvement in the modulation of the central monoaminergic system has been shown. These properties make the NK-3 receptor a potential target for central nervous system disorders such as anxiety, depression, bipolar disorders, ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/397A61K31/501A61K31/4965A61K31/506A61K31/4545C07D405/14C07D401/14C07D401/08
CPCC07D207/14C07D405/14C07D401/14C07D401/06A61P25/00A61P25/16A61P25/18A61P25/22A61P25/24A61P25/28A61P29/00A61K31/4439
Inventor KNUST, HENNERKOBLET, ANDREASNETTEKOVEN, MATTHIASRATNI, HASANERIEMER, CLAUSVIFIAN, WALTER
Owner F HOFFMANN LA ROCHE & CO AG
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