Dual NK1/NK3 receptor antagonists

a technology of nk1/nk3 receptor and antagonist, which is applied in the field of neuropsychiatric disorders, can solve the problems of hampered efforts and lack of knowledge about the cause and nature of this diseas

Inactive Publication Date: 2005-04-28
F HOFFMANN LA ROCHE & CO AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0011] The present invention relates to the use of compounds of formula I and pharmaceutically acceptable salts thereof for the treatment of positive and negative symptoms in schizophrenia, novel compounds of formulas I, pharmaceutically active acid-addition salts thereof, all sterioisomeric forms of the compounds of formula I, including each of the individual enantiomers and mixtures thereof, the preparation of the above-mentioned novel compounds, medicaments containing them and their manufacture as well as the use of the above-mentioned compounds in the control or prevention of illnesses, especially of illnesses and disorders of the kind referred to earlier or in the manufacture of corresponding medicaments.

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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  • Dual NK1/NK3 receptor antagonists
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  • Dual NK1/NK3 receptor antagonists

Examples

Experimental program
Comparison scheme
Effect test

example 1

N-[4-(2-Chloro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-2-(3,5-dichloro-phenyl)-N-methyl-isobutyramide

a) N-[6-Chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-dichloro-phenyl)-N-methyl-isobutyramide

[1445] To a solution of 1.20 g (4.74 mmol) [6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-methyl-amine and 1.43 g (5.68 mmol) 2-(3,5-dichloro-phenyl)-2-methyl-propionyl chloride in 20 ml toluene 1.27 g (10.42 mmol) 4-dimethylaminopyridine was added and the resulting solution stirred at 120° for 48 h. After cooling to ambient temperature, the solution was poured into 100 ml 0.5 N NaHCO3-solution and extracted three times with 50 ml CH2Cl2. The combined organic layers were dried (Na2SO4), filtered and evaporated. The residue was purified by flash-chromatography (SiO2, hexanes / ethyl acetate 4:1) to give 1.90 g (85%) of the title compound as a white solid.

[1446] MS m / e (%): 469.1 (M+H+, 100).

b) N-[4-(2-Chloro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-2-(3,5-dichloro-phenyl)-N-met...

example 2

(S)-N-[4-(2-Chloro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-2-(3,5-dichloro-phenyl)-N-methyl-isobutyramide

[1449] To a solution of 0.15 g (0.32 mmol) N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-dichloro-phenyl)-N-methyl-isobutyramide and 0.25 g (2.47 mmol) L-prolinol in 2 ml dimethyl sulfoxide 0.2 g (1.55 mmol) Na2CO3 was added and the solution was stirred at 130° C. for 22 h. After cooling to ambient temperature, the solution was poured into 20 ml 0.5 N NaHCO3-solution and extracted three times with 30 ml CH2Cl2. The combined organic layers were dried (Na2SO4), filtered and evaporated. The residue was purified by flash-chromatography (SiO2, CH2Cl2 / ethyl acetate 1:2) to give 0.15 g (87%) of the title compound as a white foam.

[1450] MS m / e (%): 532.2 (M+H+, 100).

example 3

(2S,4R)-N-[4-(2-Chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-2-(3,5-dichloro-phenyl)-N-methyl-isobutyramide

[1451] To a solution of 0.15 g (0.32 mmol) N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-dichloro-phenyl)-N-methyl-isobutyramide and 0.25 g (2.13 mmol) (2S,4R)-4-hydroxy-2-hydroxymethyl-pyrrolidine in 2 ml dimethyl sulfoxide 0.2 g (1.55 mmol) Na2CO3 was added and the solution was stirred at 130° C. for 9 h After cooling to ambient temperature, the solution was poured into 20 ml 0.5 N NaHCO3-solution and extracted three times with 30 ml CH2Cl2. The combined organic layers were dried (Na2SO4), filtered and evaporated. The residue was purified by flash-chromatography (SiO2, CH2Cl2 / ethyl acetate 1:2) to give 0.05 g (31%) of the title compound as a white foam.

[1452] MS m / e (%): 548.3 (M+H+, 100).

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Abstract

The present invention provides a method for the treatment of schizophrenia which comprises administering a compound of formula
wherein the substituents are as described herein or a pharmaceutically active acid-addition salt thereof. In particular, the invention provides methods for treating both positive and negative symptoms of schizophrenia through dual inhibition of NK1 and NK3 receptors. The invention also provides novel compounds with formula I and methods for preparing compounds of the invention.

Description

BACKGROUND OF THE INVENTION [0001] Schizophrenia is one of the major neuropsychiatric disorders, characterized by severe and chronic mental impairment. This devastating disease affects about 1% of the world's population. Symptoms begin in early adulthood and are followed by a period of interpersonal and social dysfunction. Schizophrenia manifests as auditory and visual hallucinations, paranoia, delusions (positive symptoms), blunted affect, depression, anhedonia, poverty of speech, memory and attention deficits as well as social withdrawal (negative symptoms). [0002] For decades scientists and clinicians have made efforts with the aim of discovering an ideal agent for the pharmacological treatment of schizophrenia. However, the complexity of the disorders, due to a wide array of symptoms, has hampered those efforts. There are no specific focal characteristics for the diagnosis of schizophrenia and no single symptom is consistently present in all patients. Consequently, the diagnosis...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/44A61K31/4418A61K31/4427A61K31/4439A61K31/444A61K31/46A61K31/496A61K31/4995A61K31/5377A61K31/5386A61K31/541A61K31/547A61K31/551A61K31/554C07D213/75C07D401/04C07D413/04C07D417/04C07D419/04C07D451/04C07D487/08C07D491/10C07D495/10C07D497/10C07D498/08C07D513/08
CPCA61K31/44C07D513/08A61K31/4427A61K31/4439A61K31/444A61K31/46A61K31/496A61K31/4995A61K31/5377A61K31/5386A61K31/541A61K31/547A61K31/551A61K31/554C07D213/75C07D401/04C07D413/04C07D417/04C07D419/04C07D451/04C07D487/08C07D491/10C07D495/10C07D497/10A61K31/4418A61P25/00A61P25/18
Inventor HOFFMANN, TORSTENKOBLET, ANDREASPETERS, JENS-UWESCHNIDER, PATRICKSLEIGHT, ANDREWSTADLER, HEINZ
Owner F HOFFMANN LA ROCHE & CO AG
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