- UROTENSIN II RECEPTOR ANTAGONISTS
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Compounds of the formula (I) wherein R1, R2, R3, R4, R5, R6, W, and Y are as described herein, or a tautomer, prodrug, solvate, or salt thereof. These compounds are useful as inhibitors of Urotensin II and are thus useful for treating a variety of disease
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Page/Page column 43
(2009/01/20)
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- 3-Hydroxypyrroles and 1H-Pyrrol-3(2H)-ones. Part 13. Reactions of Methoxymethylene Meldrum's Acids with 3-Hydroxypyrroles, with 3-Methoxypyrroles and with other Active Substrates, and Pyrolytic Heterocyclizations of the Products
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Methoxymethylene Meldrum's acid 2 in acetonitrile solution acts a useful C-electrophile for active substrates such as pyrrole, indole or tertiary enaminones to give substitution products (e.g. 5, 6 or 12, respectively).Primary enaminones react exlusively at the nitrogen atom under these conditions.The effect of the ring substituents on the regiochemistry of electrophilic substitution of 3-hydroxypyrroles and 3-methoxypyrroles was studied using methoxymethylene Meldrum's acid as the electrophile.Flash vacuum pyrolysis of the Meldrum's acid derivatives obtained in many of these reactions gave access to a range of heterocyclic systems, including the pyridone 48, quinolinedione 43, benzazepinedione 41 and fused pyrones 50, 52 and 54.
- Derbyshire, Paul A.,Hunter, Gordon A.,McNab, Hamish,Monahan, Lilian C.
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p. 2017 - 2026
(2007/10/02)
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- Imidazo[1,2-a]pyridines. Synthesis and inotropic activity of new 5-imidazo[1,2-a]pyridinyl-2(1H)-pyridinone derivatives
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A series of 1,2-dihydro-5-imidazo[1,2-a]pyridinyl-2(1H)-pyridinones was synthesized and evaluated for positive inotropic activity. 1,2-Dihydro-5-imidazo[1,2-a]pyridin-6-yl-6-methyl-2-oxo-3- pyridinecarbonitrile (11a) hydrochloride monohydrate (E-1020) was found to be a potent and selective inhibitor of phosphodiesterase III and a long-acting, potent, orally active positive inotropic agent. Additional imidazo[1,2-a]pyridin-2-yl (3a), -3-yl (16), -7-yl (20) and -8-yl (24a) compounds were also prepared. Altering the pyridine substitution from the 2-position to the 6-position produced a 2-fold increase in the i.v. cardiotonic potency (ED50) from 52 to 23 μg/kg, while substitution at the 3-, 7- or 8-position reduced potency. In the 2-positional isomers, introduction of halogen groups enhanced the activity and 3-chloro-1,2-dihydro-5-(6-fluoroimidazo[1,2-a]pyridin-2-yl)-6-methyl-2(1H)- pyridinone (3a) was the most potent (i.v. ED50 11 μg/kg) in this seris. E-1020 is presently under development for the treatment of congestive heart failure.
- Yamanaka,Miyake,Suda,Ohhara,Ogawa
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p. 1556 - 1567
(2007/10/02)
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- A Facile and Novel Synthesis of 1,6-Naphthyridin-2(1H)-ones
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A new and convenient procedure for the synthesis of 1,6-naphthyridin-2(1H)-ones and their derivatives is described.In the first scheme 5-acetyl-6--1,2-dihydro-2-oxo-3-pyridinecarbonitrile (4) obtained by the reaction of N,N-dimet
- Singh, Baldev,Lesher, George Y.
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p. 2085 - 2091
(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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- 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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- Reaction of 2-Dimethylaminomethylene-1,3-diones with Dinucleophiles.V. Synthesis of 5-Acyl-1,2-dihydro-2-oxo-3-pyridinecarbonitriles and 1,2,5,6,7,8-Hexahydro-2,5-dioxo-3-quinolinecarboxamides
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The reaction of open-chain sym-2-dimethylaminomethylene-1,3-diones Ia-d with sodium cyanoacetamide gave, generally in good yields, 6-substituted 5-acyl-1,2-dihydro-2-oxo-3-pyridinecarbonitriles IIa-d, whereas cyclohexane sym-2-dimethylaminomethylene-1,3-diones Ie-h afforded in general a mixture of 1,2,5,6,7,8-hexahydro-2,5-dioxo-3-quinolinecarbonitriles and 5,6,7,8-tetrahydro-2,5-dioxo-2H-1-benzopyran-3-carboxamides, the latter being isolated in two cases.The reaction of Ie-h with cyanoacetamide in refluxing anhydrous ethanol gave 1,2,5,6,7,8-hexahydro-2,5-dioxo-3-quinolinecarboxamides IIIe-h in excellent yields, whereas Ia-d did not react with the exception of Ia which afforded in good yield 3-pyridinecarboxamide IIIa.Other 3-pyridinecarboxamides were obtained by partial hydrolysis of nitriles IIb,d. 3-Pyridine and 3-quinoline carboxamides were hydrolyzed in satisfactory yields with hydrochloric acid to the corresponding carboxylic acids, which were decarboxylated in good yields to 5-acyl-2(1H)-pyridinones and 7,8-dihydro-2,5-(1H,6H)-quinolinediones, respectively, by reflux in quinoline containing a catalytic amount of copper powder.
- Mosti, Luisa,Schenone, Pietro,Menozzi, Giulia
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p. 1503 - 1509
(2007/10/02)
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- 5-Alkyl-1,6-naphthyridin-2(1H)-ones and cardiotonic use thereof
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1-R"-3-Q-4-R'-5-R-1,6-naphthyridin-2(1H)-ones (I) or salts thereof, where R is lower-alkyl, R' is hydrogen or methyl, R" is hydrogen or lower-alkyl, and Q is hydrogen, hydroxy, amino, cyano, carbamyl, carboxy or aminocarbamyl, are useful as cardiotonic ag
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- 5-Alkanoyl-6-alkyl-2(1H)-pyridinones, their preparation and their cardiotonic use
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4-R2 -5-(Lower-alkanoyl)-6-(lower-alkyl)-2(1H)-pyridinones (I), useful as cardiotonics, where R2 is hydrogen or methyl, are prepared by reacting 2-(lower-alkanoyl)-1-(lower-alkyl)ethenamine (II) with lower-alkyl 2-propynoate or 2-butynoate respectively or by hydrolyzing 4-R2 -5-(lower-alkanoyl)-6-(lower-alkyl)-1,2-dihydro-2-oxonicotinonitrile (III), Q is CN) or corresponding 4-R2 -5-(lower-alkanoyl)-6-(lower-alkyl)-1,2-dihydro-2-oxonicotinamide to produce the corresponding 5-(lower-alkanoyl)-6-(lower-alkyl)-1,2-dihydro-2-oxonicotinic acid and decarboxylating said substituted nictotinic acid to produce I. Also disclosed and claimed are cardiotonic uses of 3-Q-4-R2 -5-(lower-alkanoyl)-6-(lower-alkyl)-2(1H)-pyridinones where Q is hydrogen or cyano and R2 is hydrogen or methyl (III). Also shown and claimed is methyl 4-acetyl-5-amino-2,4-hexadienoate or acid-addition salt thereof, useful as intermediate or cardiotonic.
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- 5-(Hydroxyalkyl or alkanoyloxymethyl)-1,6-naphthyridin-2(1H)-one and cardiotonic use thereof
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4-R'-5-Q-1,6-naphthyridin-2(1H)-ones (I), where R' is hydrogen or methyl and Q is hydroxymethyl, 1-hydroxyethyl alkanoyloxymethyl or 1-alkanoyloxyethyl, are produced by first reacting 4-R'-5-acetyl(or n-propanoyl)-6-[2-(di-lower-alkylamino]-2(1H)-pyridinone [III] with hydroxylamine or salt thereof to produce 4-R'-5-Q'-1,6-naphthyridin-2(1H)-one-6-oxide (II), where R' is defined as above and Q' is methyl or ethyl; next reacting II with an alkanoic anhydride to produce I where Q is alkanoyloxymethyl or 1-alkanoyloxyethyl; and, then hydrolyzing said alkanoyloxymethyl or -ethyl compound to produce I where Q is hydroxymethyl or 1-hydroxyethyl. Also shown is the cardiotonic use of II and I where Q is hydroxymethyl, 1-hydroxyethyl or alkanoyloxymethyl.
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- Process for preparing 5-(lower-alkanoyl)-6-(lower-alkyl)-2(1H)-pyridinone
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4-R2 -5-(Lower-alkanoyl)-6-(lower-alkyl)-2(1H)-pyridinones (I), useful as cardiotonics, where R2 is hydrogen or methyl, are prepared by reacting 2-(lower-alkanoyl)-1-(lower-alkyl)ethenamine (II) with lower-alkyl 2-propynoate or 2-butynoate respectively or by hydrolyzing 4-R2 -5-(lower-alkanoyl)-6-(lower-alkyl)-1,2-dihydro-2-oxonicotinonitrile (III, Q is CN) or corresponding 4-R2 -5-(lower-alkanoyl)-6-(lower-alkyl)-1,2-dihydro-2-oxonicotinamide to produce the corresponding 5-(lower-alkanoyl)-6-(lower-alkyl)-1,2-dihydro-2-oxonicotinic acid and decarboxylating said substituted nictotinic acid to produce I. Also disclosed and claimed are cardiotonic uses of 3-Q-4-R2 -5-(lower-alkanoyl)-6-(lower-alkyl)-2(1H)-pyridinones where Q is hydrogen or cyano and R2 is hydrogen or methyl (III). Also shown and claimed is methyl 4-acetyl-5-amino-2,4-hexadienoate or acid-addition salt thereof, useful as intermediate or cardiotonic.
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- Certain 2-(1H)-pyridinones cardiotonic compositions containing same and method of using same
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1-R"-3-Q-4-R'-5-R-1,6-naphthyridin-2(1H)-ones (I) or salts thereof, where R is lower-alkyl, R' is hydrogen or methyl, R" is hydrogen or lower-alkyl, and Q is hydrogen, hydroxy, amino, cyano, carbamyl, carboxy or aminocarbamyl, are useful as cardiotonic ag
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- Synthesis of Methylpyridine Derivatives. XXXV (1). Reaction of Acetylpyridine with Phosphoryl Chloride to Give Alkynylpyridine
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Reaction of 3-acetyl-4,6-dimethyl-2-(1H)pyridone (9a) with phosphoryl chloride gives 2-chloro-3-ethynyl-4,6-dimethylpyridine (10a). 3-Acetyl-4-hydroxy-6-methyl-2(1H)pyridone (14a) and 3-acetyl-2,6-dimethyl-4-(1H)pyridone (21) undergoes similar reaction to
- Kato, Tetsuzo,Sato, Masayuki,Wagai, Akihiro
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p. 603 - 606
(2007/10/02)
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