- SAR of a series of 5,6-dihydro-(9H)-pyrazolo[3,4-c]-1,2,4-triazolo[4,3- α]pyridines as potent inhibitors of human eosinophil phosphodiesterase
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The potency and physical properties of a previously reported 7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]-pyridine series of human eosinophil phosphodiesterase inhibitors were improved by tying the lactam moiety into a triazolo ring. The resulting 5,6-dihy
- Duplantier, Allen J.,Bachert, Elizabeth L.,Cheng, John B.,Cohan, Victoria L.,Jenkinson, Teresa H.,Kraus, Kenneth G.,McKechney, Michael W.,Pillar, Joann D.,Watson, John W.
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- Process research and large-scale synthesis of a novel 5,6-dihydro-(9H)-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine PDE-IV inhibitor
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An efficient synthesis of the PDE IV inhibitor, 9H-cyclopentyl-7-ethyl-3-(thiophen-2-yl)-pyrazolo[3,4-c]-1,2,4-triazolo-5,6- dihydro-[4,3-a]pyridine 1 is described. Starting from commercially available γ-caprolactone, the synthesis was carried out in 10 steps. Key transformations were the selective O-methylation of diketone, 3-hydroxy-1-(4-methoxybenzyl)-4-propionyl-5,6-dihydro-1H-pyridin-2-one, with dimethyl sulfate and cesium carbonate in dimethylformamide, a one-pot pyrazole formation with subsequent acidic deprotection to provide lactam, 1-cyclopentyl-3-ethyl-1,4,5,6-tetrahydropyrazolo[3,4-c]pyridin-7-one, and finally the utilization of imidate, 1-cyclopentyl-7-ethoxy-3-ethyl-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine for the introduction of the triazole moiety. This process avoided the use of harsh reaction conditions, undesirable reagents and overcame the environmental concerns in the original synthesis.
- Urban, Frank J.,Anderson, Bruce G.,Orrill, Susan L.,Daniels, Peter J.
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p. 575 - 580
(2013/09/07)
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- Process for preparing 8-cyclopentyl-6-ethyl-3-[substituted]-5,8-dihydro-4h-1,2,3a,7,8-pentaaza-as-indacenes and intermediates useful therein
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The invention concerns a method of preparing an 8-cyclopentyl-6-ethyl-3-[substituted]-5,8-dihydro-4H-1,2,3a,7,8-pentaaza-as-indacene compound of Formula (1.0.0): and pharmaceutically acceptable salt forms thereof, where R1 is hydrogen; alkyl; alkoxy; alkoxyalkyl; alkenyl; cycloalkyl, cycloalkylalkyl; a saturated or unsaturated heterocyclic-(CH2)n— group; or a group of Formula (1.1.0): wherein all of said substituents are defined in more detail in the instant specification; comprising (a) subjecting a solventless reaction mixture of γ-caprolactone and p-methoxybenzylamine to heating whereby there is produced an amide compound N-protected by p-methoxybenzyl, of Formula (2.0.0): (b) reducing said amide compound of Formula (2.0.0) whereby there is produced an amino alcohol compound N-protected by p-methoxybenzyl, of Formula (3.0.0): (c) acylating said aminoalcohol compound of Formula (3.0.0) with ethyl oxalyl chloride whereby there is produced an oxalamic acid ethyl ester compound N-protected by p-methoxybenzyl, of Formula (4.0.0): (f) oxidizing said oxalamic acid ethyl ester compound of Formula (4.0.0) whereby there is produced an oxalamide ketone compound N-protected by p-methoxybenzyl, of Formula (5.0.0): (e) ring closing said oxalamide ketone compound of Formula (5.0.0) whereby there is produced a pyridinone compound N-protected by p-methoxybenzyl, of Formula (6.0.0): (f) O-methylating said pyridinone compound of Formula (6.0.0) whereby there is produced a 3-methoxy-pyridinone compound N-protected by p-methoxybenzyl, of Formula (7.0.0): (g) treating said 3-methoxy-pyridinone compound of Formula (7.0.0) with cyclopentylhydrazine, whereby there is produced a pyrazolopyridinone compound N-protected by p-methoxybenzyl, of Formula (8.0.0) (h) deprotecting said pyrazolopyridinone compound of Formula (8.0.0) by removing said p-methoxybenzyl group therefrom, whereby there is produced a lactam compound of Formula (9.0.0): (i) esterifying said lactam compound of Formula (9.0.0) whereby there is produced a corresponding imino ester (imidate) compound of Formula (10.0.0): (j) treating said imino ester (imidate) compound of Formula (10.0.0) with a carboxylic hydrazide compound of Formula (11.0.0): where R1 has the same meaning as set out further above; whereby there is produced said 8-cyclopentyl-6-ethyl-3-[substituted]-5,8-dihydro-4H-1,2,3a,7,8-pentaaza-as-indacene compound of Formula (1.0.0).
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