- Development of an efficient and practical route for the multikilogram manufacture of ethyl 5-cyano-2-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate and ethyl 6-chloro-5-cyano-2-methylnicotinate, key intermediates in the preparation of P2Y12 antagonists
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Elucidation of the mechanism of formation of two major impurities in the synthetic route towards key intermediate ethyl 5-cyano-2-methyl-6-oxo-1,6- dihydropyridine-3-carboxylate 1, led directly to the development of a route with significant process improvements in terms of yield, purity, and operability. The overall process yield increased from 15% to 73% without the need for extra purification steps, giving the key intermediate ethyl 6-chloro-5-cyano-2- methylnicotinate, 2, in excess of 80 kg to support clinical development.
- Bell, Stephen J.,McIntyre, Steve,Garcia, Conchita F.,Kitson, Sean L,Therkelsen, Frans,Andersen, Soren M,Zetterberg, Fredrik,Aurell, Carl-Johan,Bollmark, Martin,Ehrl, Robert
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Read Online
- MACROCYCLIC BROAD SPECTRUM ANTIBIOTICS
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Provided herein are antibacterial compounds, wherein the compounds in some embodiments have broad spectrum bioactivity. In various embodiments, the compounds act by inhibition of bacterial type 1 signal peptidase (SpsB), an essential protein in bacteria. Pharmaceutical compositions and methods for treatment using the compounds described herein are also provided.
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Paragraph 00982
(2018/09/12)
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- HETEROCYCLIC COMPOUND
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A compound having an SSTR5 antagonist action and use of the compound as a medicament are provided. Specifically, a compound represented by the following formula: wherein each symbol is as defined herein, or a salt thereof, a medicament comprising the compound or a salt thereof, and use of the compound or a salt thereof as an agent for the prophylaxis or treatment of diabetes mellitus are provided.
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Paragraph 0287; 0298; 0299
(2015/04/15)
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- Development of a Multi-Kilogram-Scale Synthesis of AZD1283: A Selective and Reversible Antagonist of the P2Y12 Receptor
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Ethyl 6-chloro-5-cyano-2-methylnicotinate (4) was coupled with 4-piperidinecarboxylic acid (isonipecotic acid) in 81% yield to pyridine acid 10. An amide coupling between 10 and benzylsulfonamide (6) afforded AZD1283 (1) in 79% yield using CDI as coupling reagent. The synthesis has been developed and scaled up to 20 kg batches of 1, supporting preclinical and clinical studies. Development work towards 2-chloropyridine 4 and benzylsulfonamide (6) is included.
- Andersen, Soren M.,Aurell, Carl-Johan,Zetterberg, Fredrik,Bollmark, Martin,Ehrl, Robert,Schuisky, Peter,Witt, Anette
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p. 1543 - 1551
(2014/01/06)
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- Synthesis, inhibitory activity of cholinesterases, and neuroprotective profile of novel 1,8-naphthyridine derivatives
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1,8-Naphthyridine derivatives related to 17 (ITH4012), a neuroprotective compound reported by our research group, have been synthesized. In general, they have shown better inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) than mo
- De Los Ríos, Cristóbal,Egea, Javier,Marco-Contelles, José,León, Rafael,Samadi, Abdelouahid,Iriepa, Isabel,Moraleda, Ignacio,Gálvez, Enrique,García, Antonio G.,López, Manuela G.,Villarroya, Mercedes,Romero, Alejandro
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experimental part
p. 5129 - 5143
(2010/09/14)
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- 2-AMINO-6-ALKYL SUBSTITUTED PYRIDINE DERIVATIVES USEFUL AS P2Y12 INHIBITORS 308
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The present invention relates to certain new pyridin analogues of Formula ( I ) to processes for preparing such compounds, to their utility as P2Y12 inhibitors and as anti-trombotic agents etc, their use as medicaments in cardiovascular disease
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Page/Page column 77-78; 85-86
(2010/04/03)
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- New Pyridine Analogues IV
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The present invention relates to certain new pyridin analogues of Formula (I) to processes for preparing such compounds, to their utility as P2Y12 inhibitors and as anti-trombotic agents etc, their use as medicaments in cardiovascular diseases
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Page/Page column 19
(2008/06/13)
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- NEW PYRIDINE ANALOGUES
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The present invention relates to certain new pyridin analogues of Formula ( I ) to processes for preparing such compounds, to their utility as P2Y12 inhibitors and as anti-trombotic agents etc, their use as medicaments in cardiovascular disease
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Page/Page column 59-60
(2008/06/13)
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- NEW PYRIDINE ANALOGUES
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The present invention relates to certain new pyridin analogues of Formula ( I ) to processes for preparing such compounds, to their utility as P2Y12 inhibitors and as anti-trombotic agents etc, their use as medicaments in cardiovascular disease
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Page/Page column 56
(2010/11/29)
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- New Pyridine Analogues VII 543
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The present invention relates to certain new pyridin analogues of Formula (I) to processes for preparing such compounds, to their utility as P2Y12 inhibitors and as anti-trombotic agents etc, their use as medicaments in cardiovascular diseases
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Page/Page column 18
(2008/12/07)
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- NEW PYRIDINE ANALOGUES VIII 518
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The present invention relates to certain new pyridin analogues of Formula ( I ) to processes for preparing such compounds, to their utility as P2Y12 inhibitors and as anti-trombotic agents etc, their use as medicaments in cardiovascular diseases as well as pharmaceutical compositions containing them.
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Page/Page column 103-104
(2008/12/07)
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- NEW PYRIDINE ANALOGUES II
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The present invention relates to certain new pyridin analogues of Formula (I) to processes for preparing such compounds, to their utility in medicine in general and especially as P2Y12 inhibitors and as anti-thrombotic agents, etc, their use as medicaments in cardiovascular diseases as well as pharmaceutical compositions containing them.
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Page/Page column 38
(2008/06/13)
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- NEW PYRIDINE ANALOGUES
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The present invention relates to certain new pyridin analogues of Formula (I) Chemical formula should be inserted here. Please see paper copy Formula (I) to processes for preparing such compounds, to their utility as P2Y12 inhibitors and as anti-trombotic agents etc, their use as medicaments in cardiovascular diseases as well as pharmaceutical compositions containing them.
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Page/Page column 86
(2008/06/13)
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- NOVEL PYRIDINE COMPOUNDS
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The present invention relates to certain novel pyridin compounds of Formula ( I ) to processes for preparing such compounds, to their utility as P2Y12 inhibitors and as anti-trombotic agents etc, and processes for their preparation, their use as medicaments in cardiovascular diseases as well as pharmaceutical compositions containing them.
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Page/Page column 147-148
(2008/06/13)
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- Synthesis of 2,3,5,6-tetrasubstituted pyridines from enamines derived from N,N-dimethylformamide dimethyl acetal
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Reactions of 1,3-dicarbonyl compounds with N,N-dimethylformamide dimethyl acetal, followed by cyanothioacetamide or cyanoacetamide and sodium hydride, then acidification, give 5,6-disubstituted 3-cyanopyridine-2(1H)-thiones or 5,6-disubstituted 3-cyanopyridin-2(1H)-ones 4. Analogous reactions with the malononitrile dimer give 5,6-disubstituted 3-cyano-2-(dicyanomethylene)-1,2-dihydropyridines 9.
- Abu-Shanab,Redhouse,Thompson,Wakefield
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p. 557 - 560
(2007/10/02)
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- Synthesis and cardiotonic activity of esters of 2-substituted 5-cyano-1,6-dihydro-6-oxo-3-pyridinecarboxylic acids. Crystal structure of 2-methyl, 2-t-butyl and 2-phenyl esters
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The synthesis of ethyl and methyl esters of 2-substituted 5-cyano-1,6-dihydro-6-oxo-3-pyridinecarboxylic acids by reaction of ethyl or methyl 2-dimethylaminomethylene-3-oxoalkanoates with sodium cyanoacetamide is described. These esters gave by alkaline hydrolysis the corresponding carboxylic acids, which were decarboxylated to 6-substituted 1,2-dihydro-2-oxo-3-pyridinecarbonitriles. As milrinone analogues, nearly all the above compounds were tested on contractile activity and frequency rate of spontaneously beating atria and electrically driven left atria from guinea pigs. Among the esters, ethyl 5-cyano-1,6-dihydro-2-methyl-6-oxo-3-pyridinecarboxylate induced positive inotropic and chronotropic effects superior to those caused by milrinone. By increasing or branching the 2-substituent, the activity decreased until faded or even reversed. Carboxylic acids and nitriles were less active than milrinone. Some aspects of the structure-activity relationship of these compounds are discussed on the basis of X-ray structural analyses of 2-methyl, 2-t-butyl and 2-phenyl esters.
- Mosti,Menozzi,Schenone,Dorigo,Gaion,Benetollo,Bombieri
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p. 517 - 529
(2007/10/02)
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- Novel alkoxyimino ether derivatives of 5-acyl-2(1H)-pyridinones
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This invention relates to alkoxyimino ether derivatives of 5-acyl-2(1H)-pyridinones and to their use as cardiotonic agents useful in treating cardiac failure, and to the process useful in the preparation thereof.
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- Cardiotonic 5-benzoyl-1,2-dihydro-2-oxo-3-pyridinecarboxylates
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Novel 3-carboxy- and 3-carbalkoxy-5-benzoyl-2(1H)-pyridinones as well as the pharmaeutically acceptable salts thereof are cardiotonic agents useful in the treatment of heart failure.
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- Pyridone esters as inotropic agents
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Described are compounds of the formula STR1 wherein R is hydrogen, lower alkyl, halo, cyano, hydroxy, amino, lower alkylamino, --CH2 NH2, --CH2 OH or --COOR"; R' is hydrogen, lower cycloalkyl or lower alkyl; R' is lower alkenyl, lower alkynyl, lower cycloalkyl, --(W)n Y wherein W is straight or branched chain lower alkyl or lower alkenyl, n is 0 to 5, and Y is Ar, lower cycloalkyl, lower alkenyl, lower alkynyl, --COOZ wherein Z is lower alkyl, STR2 or NAB wherein A and B are, independently, lower alkyl, benzyl or substituted benzyl, and Ar is 2, 3 or 4-pyridyl, pyridazinyl, pyrimidinyl, quinolyl, isoquinolyl, phthalazinyl, quinazolinyl, thiazolyl, phenyl, benzyl, furyl, tetrahydrofuryl or thienyl, unsubstituted or substituted with lower alkyl, lower alkoxy, halo, amino, or --CF3 ; R"' is --COOR", STR3 and X is oxygen or nitrogen; or a pharmaceutically acceptable salt thereof, and their use in the treatment of impaired ventricular myocardial contractility. The compounds exhibit cardiotonic activity.
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- 5-Acyl-2-(1H)-pyridinones
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Novel 5-acyl-2-(1H)pyridinones and their use as cardiotonic agents. Typical of the compounds is 5-acetyl-1,2-dihydro-6-methyl-2-oxo-3-pyridinecarbonitrile which is prepared by condensing anionic cyano acetamide with 3-[(dimethylamino)methylenyl]-2,4-penta
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- Pyridone esters as inotropic agents
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Described are compounds of the formula STR1 wherein R is hydrogen, lower alkyl, halo, cyano, hydroxy, amino, lower alkylamino, --CH2 NH2, CH2 OH or COOR"; R' is hydrogen, lower cycloalkyl or lower alkyl; R" is lower alkyl or --CH2 Ar wherein Ar is phenyl, substituted phenyl, furan or thiophene; R'" is COOR", STR2 and x is oxygen or nitrogen; or a pharmaceutically acceptable salt thereof and their use in the treatment of impaired ventricular myocardial contractility. The compounds exhibit cardiotonic activity.
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- A Novel Method for the Synthesis of Pyridones
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A novel method for the synthesis of pyridones has been developed.It consists of the reaction of β-dicarbonyl compounds or conjugated enol ethers with cyanoacetamide in the presence of triethylbenzylammonium chloride in aq.NaOH solution.The present method is superior to the literature methods with respect to yield, ease of preparation and absence of organic solvent.
- Hawaldar, V. S.,Sunthankar, S. V.
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p. 151 - 152
(2007/10/02)
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