- Method for preparing netupitant
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The invention discloses a method for preparing netupitant, and belongs to the field of medicine compounds. The method includes the steps: performing condensation on 2-chloro-5-aminopyridine and formicacid; performing reduction, Boc protection and iodination; performing coupling and deprotection and then performing condensation on products and 2-(3, 5-bis-trifluoromethyl-phenyl)-2-methyl propionicacid; performing substitution on products and N-methylpiperazine to obtain the netupitant. The method has the advantages that the steps of processes for preparing the netupitant have fewer side effects, the method is high in yield and less in environmental pollution, after-treatment is simple, and the netupitant which is a product prepared by the aid of the method is high in purity and low in individual impurity content.
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- Netupitant free alkali crystal form A and preparation method thereof
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The invention discloses a new crystal form A of 2-(3,5-ditrifluoromethylphenyl)-N-methyl-N-[6-(4-methylpiperazinyl-1-yl)-4-ortho-tolylpyridyl-3-yl]-isobutyramide free alkali, a pharmaceutical composition and a preparation method thereof. The crystal form A has favorable stability. The preparation method is simple and easy to operate.
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Paragraph 0025; 0026
(2017/07/22)
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- 4-(5-(2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethylpropanamido)-4-(o-tolyl)pyridin-2-yl)-1-methyl-1-((phosphonooxy)methyl)piperazin-1-ium as a neurokinin receptor modulator
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Compounds and methods for the prevention and/or treatment of diseases which are pathophysiologically mediated by the neurokinin (NK1) receptor, based on 4-(5-(2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethylpropanamido)-4-(o-tolyl)3yridine-2-yl)-1-methyl-1-((phosphonooxy)methyl)piperazin-1-ium and pharmaceutically acceptable salts thereof.
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Page/Page column 32
(2016/08/29)
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- SUBSTITUTED 4-PHENYL-PYRIDINES FOR TREATMENT OF NK-1 RECEPTOR RELATED DISEASES
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PROBLEM TO BE SOLVED: To provide new derivatives of 4-phenyl-pyridine compounds that are effective NK1 receptor antagonists, with enhanced physicochemical and/or biological properties, and methods for producing the 4-phenyl-pyridine compounds. SOLUTION: Disclosed are compounds, compositions and methods for the prevention and/or treatment of diseases which are pathophysiologically mediated by the neurokinin (NKj) receptor. The compounds have the general formula (I). COPYRIGHT: (C)2015,JPOandINPIT
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- METHODS OF MAKING NETUPITANT AND INTERMEDIATES THEREOF
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Methods are disclosed for the preparation of netupitant and pharmaceutically acceptable salts thereof which are novel, easily reproducible, environmentally safe and cost effective. The methods may employ inexpensive starting materials and the preparation processes for intermediates are simple and highly reproducible. Novel intermediates for the preparation of netupitant and pharmaceutically acceptable salts thereof are also disclosed. Amorphous netupitant and methods of making same are disclosed.
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- Substituted 4-phenyl pyridines having anti-emetic effect
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Disclosed are compounds, compositions and methods for the prevention and/or treatment of diseases which are pathophysiologically mediated by the neurokinin (NK1) receptor. The compounds have the general formula (I):
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- Research and development of an efficient process for the construction of the 2,4,5-substituted pyridines of NK-1 receptor antagonists
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Roche has identified a 2,4,5-trisubstituted pyridine template for a new class of potent NK1 receptor antagonists. Previous strategies for construction of the pyridine core of these NK-1 receptor antagonists involved functionalization of a 2,5-disubstituted pyridine. We now report on construction of the pyridine core from commodity components. Shestopalov reported the synthesis of trans-4′-aryl-5′-cyano-1′,2′,3′, 4′-tetrahydro-6′-hydroxy-2′-oxo-1,3′-bipyridinium inner salts from 1-(2-amino-2-oxo-ethyl)pyridinium chloride, aromatic aldehydes, and ethyl cyanoacetate in the presence of a base. Reaction of these salts with phosphorus oxychloride affords 4-aryl-3-cyano-2,6-dichloropyridines. These are efficiently converted to nicotinamide precursors of the Roche NK-1 receptor antagonists by regioselective displacement of one chlorine by an amine, hydrogenolysis of the remaining chlorine, and nitrile hydrolysis.
- Harrington, Peter J.,Johnston, Dave,Moorlag, Henk,Wong, Jim-Wah,Hodges, L. Mark,Harris, Les,McEwen, Gerald K.,Smallwood, Blair
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p. 1157 - 1166
(2012/12/23)
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- Design and synthesis of a novel, achiral class of highly potent and selective, orally active neurokinin-1 receptor antagonists
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The discovery of a novel, achiral pyridine class of potent and orally active neurokinin-1 (NK1) receptor antagonists is described. The evaluation of this class is briefly outlined, leading to the identification of netupitant 21 and befetupitant 29, two new proprietary chemical entities with high affinity and excellent CNS penetration.
- Hoffmann, Torsten,Boes, Michael,Stadler, Heinz,Schnider, Patrick,Hunkeler, Walter,Godel, Thierry,Galley, Guido,Ballard, Theresa M.,Higgins, Guy A.,Poli, Sonia M.,Sleight, Andrew J.
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p. 1362 - 1365
(2007/10/03)
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- Efficient synthesis of novel NK1 receptor antagonists: Selective 1,4-addition of Grignard reagents to 6-chloronicotinic acid derivatives
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A new efficient synthesis of two novel classes of NK1 receptor antagonists, among them befetupitant and netupitant, starting from 6-chloronicotinic acid is described. The introduction of the o-tolyl substituent at C(4) of the pyridine ring was achieved by a one-pot selective 1,4-Grignard addition/oxidation sequence to 6-chloronicotinic acid or a derivative of it. The scope of this addition/oxidation sequence was examined. It was also shown that the carboxylic function can be converted to a methyl amino group by a Hofmann rearrangement followed by reduction. Furthermore, a new high-yielding synthesis of 2-(3,5-bistrifluoromethylphenyl)-2-methyl propionic acid based on the carbonylation of the tertiary alcohol obtained by Grignard addition of 3,5-bis(trifluoromethyl)bromobenzene to acetone was established.
- Hoffmann-Emery, Fabienne,Hilpert, Hans,Scalone, Michelangelo,Waldmeier, Pius
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p. 2000 - 2008
(2007/10/03)
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- Use of NK-1 receptor antagonists against benign prostatic hyperplasia
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The invention relates to the use of an NK-1 receptor antagonist for the treatment or prevention of benign prostatic hyperplasia (BPH). The preferred NK-1 receptor antagonists are compounds of the general formula wherein the meanings of R, R1, R2, R2′, R3, R4 are explained in the specification and the pharmaceutically acceptable acid addition salts and the prodrugs thereof Preferred compounds are 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide, 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-[6-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-isobutyramide, 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(1,1-dioxo-1λ6-thiomorpholin-4-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide and 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(1,1-dioxo-1λ6-thiomorpholin-4-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide. The invention also relates to pharmaceutical composition comprising one or more such NK-1 receptor antagonists and a pharmaceutically acceptable excipient for the treatment and/or prevention of benign prostatic hyperplasia.
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- Method of treatment and/or prevention of brain, spinal or nerve injury
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The invention relates to a method of treatment and/or prevention of brain, spinal or nerve injury comprising administration to a person in need of such treatment, of a therapeutically effective amount of an NK-1 receptor antagonist compound of the formula wherein the meanings of R, R1, R2, R2', R3, R4 are explained in the specification and the pharmaceutically acceptable acid addition salts and the prodrugs thereof either alone or in combination with a magnesium salt. Exemplified is the use of N-(3,5-bis-trifluoromethyl-benzyl)-N-methyl-6-(4-methyl-piperazin-1-yl)-4-o-tolyl-nicotinamide. The invention also relates to pharmaceutical composition comprising one or more such NK-1 receptor antagonists, optionally in combination with a magnesium salt, and a pharmaceutically acceptable excipient for the treatment and/or prevention of brain, spinal or nerve injury.
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- 4-phenyl-pyridine derivatives
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The compounds of the related invention are related to 4-phenyl-pyridine derivatives connected by a bridge containing oxygen or nitrogen to a phenyl derivative.
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