Patent ID: 6326495
Filing Date: 2001-12-04
Classification: A61P,C07D

Abstract:
A method of preparing an 8-cyclopentyl-6-ethyl-3-[substituted]-5,8-dihydro-4H-1,2,3a,7,8-pentaaza-a s-indacene compound of Formula (1.0.0): ##STR111##and pharmaceutically acceptable salt forms thereof, wherein:R.sup.1 is a member independently selected from the group consisting of hydrogen; (C.sub.1 -C.sub.6) alkyl; (C.sub.1 -C.sub.4) alkoxy; (C.sub.1 -C.sub.4) alkoxy(C.sub.1 -C.sub.4) alkyl; (C.sub.2 -C.sub.8) alkenyl; (C.sub.3 -C.sub.7) cycloalkyl and 1'-methyl thereof; (C.sub.3 -C.sub.7) cycloalkyl(C.sub.1 -C.sub.2) alkyl; a saturated or unsaturated (C.sub.4 -C.sub.7) heterocyclic-(CH.sub.2).sub.n -- group where n is an integer selected from 0, 1, and 2, comprising one or two heteroatoms independently selected from O, S, S(.dbd.O).sub.2, N, NR.sup.3, O together with N or NR.sup.3, S or S(.dbd.O).sub.2 together with N or NR.sup.3, and N or NR.sup.3 together with N or NR.sup.3 ; where:R.sup.3 is hydrogen or (C.sub.1 -C.sub.4) alkyl; orR.sup.1 is a group of Formula (1.1.0): ##STR112##wherein:a is an integer selected from 1 through 5, inclusive;b and c are each independently an integer selected from 0 and 1;R.sup.5 is a member independently selected from the group consisting of hydrogen; hydroxy; (C.sub.1 -C.sub.4) alkyl; (C.sub.2 -C.sub.4) alkenyl; (C.sub.1 -C.sub.4) alkoxy; (C.sub.3 -C.sub.6) cycloalkoxy; halogen; trifluoromethyl; CO.sub.2 R.sup.3a ; CONR.sup.3a R.sup.3b ; NR.sup.3a R.sup.3b ; NO.sub.2 ; and SO.sub.2 NR.sup.3a R.sup.3b ; whereR.sup.3a and R.sup.3b are each independently selected from the group consisting of hydrogen and (C.sub.1 -C.sub.4) alkyl;Z is O, S, S(.dbd.O).sub.2, C(.dbd.O), or NR.sup.3 ; andY is --(C.sub.1 -C.sub.4) alkylene- or --(C.sub.2 -C.sub.4) alkenylene-, either of which is optionally mono-substituted by hydroxy; wherein:each above-recited alkyl, alkenyl, cycloalkyl, alkoxyalkyl and heterocyclic group is substituted by 0 to 3 substituents comprising a member independently selected from group consisting of (C.sub.1 -C.sub.2) alkyl, trifluoromethyl, and halogen; comprising:(a) subjecting a solventless reaction mixture of .gamma.-caprolactone and p-methoxybenzylamine to heating whereby there is produced an amide compound N-protected by p-methoxybenzyl, of Formula (2.0.0): ##STR113##(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): ##STR114##(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): ##STR115##(e) 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): ##STR116##(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): ##STR117##(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): ##STR118##(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): ##STR119##(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): ##STR120##(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): ##STR121##(j) treating said imino ester (imidate) compound of Formula (10.0.0) with a carboxylic hydrazide compound of Formula (11.0.0): ##STR122##where R.sup.1 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-a s-indacene compound of Formula (1.0.0).