Patent ID: 6849605
Filing Date: 2005-02-01
Classification: A61K

Abstract:
1. A method for inhibiting human immunodeficiency virus (HIV) replication in a patient harboring said HIV comprising administering to the patient a combination comprising: at least one first compound exhibiting α1-antitrypsin (AAT)-like protease inhibiting activiity, wherein said compound exhibiting AAT-like proteaase inhibiting activity is a i. (benzyloxycarbonyl)-L-valyl-N-[1-(3-(5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl)carbonyl)-2-(S)-methylpropyl]-L-prolinamide; ii. (benzyloxycarbonyl)-L-valyl-N-[1-(3-(5-(2-phenylethyl)-1,2,4-oxadiazolyl)carbonyl)-2-(S)-methylpropyl]-L-prolinamide; iii. (benzyloxycarbonyl)-L-valyl-N-[1-(3-(5-(2-methoxybenzyl)-1,2,4-oxadiazolyl)carbonyl)-2-(S)-methylpropyl]-L-prolinamide: iv. (benzyloxycarbonyl)-L-valyl-N-[1-(3-(5-(trifluoromethyl)-1,2,4-oxadiazolyl)carbonyl)-2-(S)-methylpropyl]-L-prolinamide; v. (benzyloxycarbonyl)-L-valyl-N-[1-(3-(5-(methyl)-1 2,4-oxadiazolyl)carbonyl)-2S)-methylpropyl]-L-prolinamide; vi. (benzyloxycarbonyl)-L-valyl-N-1-(3-(5-(difluoromethyl)-1,2,4-oxadiazolyl)carbonyl)-2-(S)-methylpropyl]-L-prolinamide; vii. (benzyloxycarbonyl)-L-valyl-N-[1-(3-(-5-(1benzyl)-1,2,4-oxadiazolyl)carbonyl)-2-(S)-methylpropyl]-L-prolinamide; viii. (benzyloxycarbonyl)-L-valyl-N-[1-(3-(5-(3-methoxybenzyl)-1,2,4-oxadiazolyl)carbonyl)-2-(S)-methylpropyl]-L-prolinamide: ix. (benzyloxycarbonyl)-L-valyl-N-[-(3-(5-(2,6-difluorobenzyl)-1,2,4-oxadiazolyl)carbonyl)-2-(S)-methylpropyl-L-prolinamide, x. (benzyloxycarbonyl)-L-valyl-N-[1-(3-(5-(trans-styryl-1,2,4-oxadiazolyl)carbonyl)-2-(S)-methylpropyl]-L-prolinamide, xi. (benzyloxycarbonyl)-L-valyl-N-[1-(3-(5-(trans-4-trifluoromethylstryryl)-1,2,4-oxadiazolyl)carbonyl)-2-(S)-methylpropyl]-L-prolinamide: xii. (benzyloxycarbonyl)-L-valyl-N-[1-(3-(5-(trans-4-methoxystyryl)-1,2,4-oxadiazolyl)carbonyl)-24S)-methylpropyl]-L-prolinamide: xiii. (benzyloxycarbonyl)-L-valyl-N-[1-(3-(5-(3-thienylmethyl)-1,2,4-oxadiazolyl)carbonyl)-2-(S)-methylpropyl]-L-prolinamide xiv. (benzyloxycarbonyl)-L-valyl-N-[1-(3-(5-(phenyl)-1,2,4-oxadiazolyl)carbonyl)-2-(S)-methylpropyl]-L-prolinamide; xv. (benzyloxycarbonyl)-L-valyl-N-[1-(3-(5(-3-phenylpropyl)-1,2,4-oxadiazolyl)carbonyl)-2-(S)-methylpropyl]-L-prolinamide. xvi. (benzyloxycarbonyl)-L-valyl-N-[1-(2-(3-(methylbenzyl)-1-(3-oxadiazolyl)carbonyl)-2-(S)-methylpropyl]-L-prolinamide, xvii. (benzyloxycarbonyl)-L-valyl-N-[1-(2-(5-(methyl)-1,3,4-oxadiazolyl)carbohyl)-2-(S)-methylpropyl]-L-prolinamide; xviii. (benzyloxycarbonyl)-L-valyl-N-[1-(2-(5-(3-trifluoromethylbenzyl)-1,3,4-oxadiazolyl)carbonyl)-2-(S)-methylpropyl]-L-prolinamide: xix. (benzyloxycarbonyl)-L-valyl-N-[1-(2-(5-(4-dimethylamino benzyl)-1,3,4-oxadiazolyl)carbonyl)-2-(S)-methylpropyl]-L-prolinamide: xx. (benzyloxycarbonyl)-L-valyl-N-[1-(2-(5-(1-napthylenyl)-1,3,4-oxadiazolyl)carbonyl)-2-(S)-methylpropyl]-L-prolinamide: xxi. (benzyloxycarbonyl)-L-valyl-[1-(3-(5-(3,4-methylenedioxybenzyl)-1,2,4-oxadiazolyl)carbonyl)-2-(S)-methylpropyl]-L-prolinamide: xxii. (benzyloxycarbonyl)-L-valyl-N-[1-(3-(5-(3,5-dimethylbenzyl)-1,2,4-oxadiazolyl)carbonyl)-2-(S)-methylpropyl]-L-prolinamide; xxiii. (benzyloxycarbonyl)-L-valyl-N-[1-(3-(5-(3,5-dimethoxybenzyl)-1,2,4-oxadiazolyl)carbonyl)-2-(S)-methylpropyl]-L-prolinamide: xxiv. (benzyloxycarbonyl)-L-valyl-N-[1-(3-(5-(3-(5-ditrifluoromethylbenzyl)-1,2,4-oxadiazolyl)carbonyl)-2-(S)-methylpropyl]-L-prolinamide, xxv. (benzyloxycarbonyl)L-valyl-N-[1-(3-(5-(3-methylbenzyl)-1,2,4-oxadiazolyl)carbonyl)-2-(S)-methylpropyl]-L-prolinamide: xxvi. (benzyloxycarbonyl)-L-valyl-N-[1-(3-(5-(biphenylmethine)-1,2,4-oxadiazolyl)carbonyl)-2-(S)-methylpropyl]-L-Prolinamide; xxvii. (benzyloxycarbonyl)-L-valyl-N-[1-(3-(5-(4-phenylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide; xxiii. (benzyloxycarbonyl)-L-valyl-N-[1-(3-(5-(3-phenylbenzyl)-1,2,4-oxadiazolyl)carbonyl)-2-(S)-methylpropyl]-L-prolinamide; xxix. (benzyloxycarbonyl)-L-valyl-N-[1-(3-(5-(3-phenoxybenzyl)-1,2,4-oxadiazolyl)carbonyl) -2-(S)-methylpropyl]-L-prolinamide: xxx. (benzyloxycarbonyl)-L-valyl-N-[1-(3-(5-(cyclohexylmethylene)-1,2.4 oxadiazolyl)carbonyl)-2-(S)-methylpropyl]-L-prolinamide; xxxi. (benzyloxycarbonyl)-L-valyl-N-[1-(3-(5-(3-trifluoromethyldimethylmethylene) 1,2,4-oxadiazolyl)carbonyl)-2-(S)-methylpropyl]-L-prolinamide; xxxii. (benzyloxycarbonyl)-L-valyl-N-[1-(3-(5-(1-napthylmethylene)-1,2,4-oxadiazolyl)carbonyl)-2-(S)-methylpropyl]-L-prolinamide; xxxiii. (benzyloxycarbonyl)-L-valyl-N-[1-(3-(5-(3-pyridylmethyl)-1,2,4-oxadiazolyl)carbonyl)-2-(S)-methylpropyl]-L-prolinamide; xxxiv. (benzoxycarbonyl)-L-valyl-N-[1-(3-(5-(3,5-diphenylbenzyl)-1,2,4-oxadiazolyl)carbonyl)-2-(S)-methylpropyl]-L-prolinamide; xxxv. (benzyloxycarbonyl)-L-valyl-N-[1-(3-(5-(4-dimethylaminobenzyl)-1,2,4-oxadiazolyl)carbonyl)-2-(S)-methylpropyl]-L-prolinamide; xxxvi. 2-(5-[(benzyloxycarbonyl)amino]-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl-N-[1-(3-(5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl)carbonyl)-(S)-2-methylpropyl]acetamide; xxxvvii. 2-(5-amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(3-(5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl)carbonyl)-2-(S)-methylpropyl]acetamide; xxxviii. 2-[5-[(benzyloxycarbonyl)amino]-6-oxo-2-(4-fluorophenyl)-10.6-dihydro-1-pyrimidinyl]-N-f 1-(2-(5-(3-methylbenzyl)-1,3,4-oxadiazolyl)carbonyl)-(S)-2-methylpropyl]acetamide; xxxix. 2-[5-amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-(5-(3-methylbenzyl)-1,3,4-oxadiazolyl)carbonyl)-2-methylpropyl]acetamide; xl. (pyrrole-2-carbonyl)-N-(benzyl)glycyl-N-[1-(245-(3-methylbenzyl)-1,3,4-oxadiazolyl)carbonyl)-2-(S)-methylpropyl]amide; xli. (pyrrole-2-carbonyl)-N-(benzyl)glycyl-N-[1-(3-(5-(3-trifluoromethylbenzyl)(1,2,4-oxadiazolyl)-(S)-methylpropyl]amide; xlii. (2S, 5S)-5-amino-1,2,4,5,6,7-hexahydroazepino-[3,2, 1-indole-4-one-carbonyl-N-[2-(5-(3-methylbenzyl)-1,3,4-oxadiazolyl)carbonyl)-(R,S)-2-methylpropyl]amide; xliii. BTD-[1-(2-(5-(3-methylbenzyl)-1,3,4-oxadiazolyl)carbonyl)-2-(S)-methylpropyl]amide; xliv. (R,S)-3-amino-2-oxo-5-phenyl-1,4-benzodiazepine-N-[1-(2-(5-(3-methylbenzyl)-1,3,4-oxadiazolyl)carbonyl)-2-(S)-methylpropyl]acetamide; xlv. (benzyloxycarbonyl)-L-valyl-2-L-(2,3-dihydro-1H-indole)-N-[1-(2-(5-(3-methylbenzyl)-1,3,4-oxadiazolyl)carbonyl)-2-(S)-methylpropyl]amide; xlvi. (benzyloxycarbonyl)-L-valyl-2-L-(2,3-dihydro-1H-indole)-N-[1-(3-(5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl)carbonyl)-2-(S)-methylpropyl]amide; xlvii. acetyl-2-L-(2,3-dihydro-1H-indole)-N-[1-(2-(5-(3-methylbenzyl)-1,3,4-oxadiazolyl)carbonyl)-2-(S)-methylpropyl]amide; xlviii. 3-(S)-(benzyloxycarbonyl)amino)-e-lactam-N-[1-(2-(5-(3-methylbenzyl)-1,3,4-oxadiazolyl)carbonyl)-2-(S)-methylpropyl]acetamide; xlix. 3-(S)-(amino)-e-lactam-N-[1-2-(5-(3-methylbenzyl)-1,3,4-oxadiazolyl)carbonyl)-2-(S)-methylpropyl]acetamide trifluoroacetic acid salt; 1,3-(S)-[(4-morpholinocarbonyl-butanoyl)amino]-e-lactam-N-[1-(2-(5-(3-methylbenzyl)-1,3,4-oxadiazolyl)carbonyl)-2-(R,S)-methyl propyl]acetamide; li. 6-[4-fluorophenyl]-e-lactam-N-[1-(2-(5-(3-methylbenzyl)-1,3,4-oxadiazolyl)carbonyl)-2-(S)-methylpropyl]acetamide; lii. 2-(2-(R,S)-phenyl-4-oxothiazolidin-3-yl]-N-[1-(2-(5-(3-methylbenzyl)-1,3,4-oxadiazolyl)carbonyl)-2-(S)-methylpropyl]acetamide; liii. 2-(2-(R,S)-phenyl-4-oxothiazolidin-3-yl]-N-[1-(2-(5-(3-methylbenzyl)-1,3,4-oxadiazolyl(hydroxymethyl)-2-(S)-methylpropyl]acetamide; liv. 2-(2-(R,S)-benzyl-4-oxothiazolidin-3-yl]-N-1-(2-(5-(3-methylbenzyl)-1,3,4 oxadiazolyl)carbonyl)-2-(S)-methylpropyl]acetamide; lv. 2-(2-(R,S)-benzyl-4-oxothiazolidin-3-yl oxide]-N-[1-(3-(5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl)carbonyl)-2-(R,S,)-methylpropyl]acetamide; lvi. (1-benzoyl-3,8-quinazolinedione)-N-[1 1-(2-(5-(3-methylbenzyl)-1,3,4-oxadiazolyl)carbonyl)-2-(S)-methylpropyl]acetamide; lvii. (1-benzoyl-3.6-piperazinedione)-N-[1-(2-(5-(3-methylbenzyl)-1,3,4-oxadiazolyl)carbonyl)-2-(S)-methylpropyl]acetamide; lvii. (1-phenyl-3,6-piperazinedione)-N-[1-(2-(5-(3-methylbenzyl)-1,3,4-oxadiazolyl)carbonyl)-2-(S)-methylpropyl]acetamide; lix. (1-phenyl-3,6-piperazinedione)-N-[1-(3-(5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl)carbonyl)-2-(S)-methylpropyl]acetamide; lx. 3-[(benzyloxycarbonyl)amino]-quinolin-2-one-N-[1-(2(5-(3-methylbenzyl)-1,3,4-oxadiazolyl)carbonyl)]-2-(S)-methylpropyl]acetamide; lxi. 3-[(benzyloxycarbonyl)amino]-7-piperidinyl-quinolin-2-one-N-[1-(2-(5-(3-methylbenzyl)-1,3,4-oxadiazolyl)carbonyl)-2-(S)-methyl]propyl]acetamide; lxii. 3-(carbomethoxy-quinolin-2-one-N-[1-(2-(5-(3-methybenzyl)-1,3,4-oxadiazolyl)carbonyl)-2-(S)-methylpropyl]acetamide; lxiii. 3-(amino-quinolin-2-one)-N-[1-(2-(5-(3-methylbenzyl)-1,3,4-oxadiazolyl)carbonyl)-2-(S)-methylpropyl]acetamide; lxiv. 3-[(4-morpholino)aceto]amino-quinolin-2-one-N-[1-(2-(5-(3-methylbenzyl)-1,3,4-oxadiazolyl)carbonyl)-2-(S)-methylpropyl]acetamide; lxv. 3,4-dihydro-quinolin-2-one-N-[1-(2-(5-(3-methylbenzyl)-1,3,4-oxadiazolyl)carbonyl)-2-(S)-methylpropyl]acetamide; lxvi. 1-acetyl-3-(4-fluorobenzylidene)piperazine-2,5-dione-N-[1-(2-(5-(3-methylbenzyl)-1,3,4-oxadiazolyl)carbonyl-2-(S)-methylpropyl]acetamide; lxvii, 1-acetyl-3-(4-dimethylaminobenzylidene)piperazine-2,5-dione-N-[1-(2-(5-(3-methylbenzyl)-1,3,4-oxadiazolyl)carbonyl)-2-(S)-methylpropyl]acetamide; lxviii. 1-acetyl-3-(4-carbomethoxybenzylidene)piperazine-2,5-dione-N-[1-(2-(5-(3-methylbenzyl-1,3,4-oxadiazolyl)carbonyl)-2-(S)-methylpropyl]acetamide; lxix. 1-acetyl-3-[(4-pyridyl)methylene]piperazine-2,5-dione-N-[1-(2-(5-(3-methylbenzyl)-1,3,4-oxadiazolyl)carbonyl)-2-(S)-methylpropyl]acetamide; lxx. 4-[1-benzyl-3-(R)-benzyl-piperazine-2,5-dione]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl)carbonyl)-2S)-methylpropyl]acetamide; lxxi. 4-[1-benzyl-3-(S)-benzyl]piperazine-2,5-dione]-N-[1-(2-(5-(3-methylbenzyl)-1,3,4-oxadiazolyl)carbonyl)-2-(S)-methylpropyl]acetamide; lxxii. 4-[1-benzyl-3-(S)-benzylpiperazine-2,5-dione]-N-[1-(3-(5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl)carbonyl)-2-(S)-methylpropyl]acetamide; lxxiii. 4-[1-benzyl-3-(S)-benzylpiperazine-2,5-dione]-N-[1-(3-(5-(3-trifluoromethylbenzyl-1,2,4-oxadiazolyl)carbonyl)-2-(S)-methylpropyl]acetamide; lxxiv. 4-[1-benzyl-3-(S)-benzylpiperazine-2,5-dione]-N-[1-(3-(5-(2-dimethylaminoethyl)-1,2,4-oxadiazolyl)carbonyl)-2-(S)-methylpropyl]acetamide; lxxv. 4-[1-methyl-3-(R,S)-phenylpiperazine-2,5-dione]-N-[1-(3-(5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl)carbonyl)-2-(S)-methylpropyl]acetamide; lxxvi. 4-[methyl-3-(R,S)-phenylpiperazine-2,5-dione]-N-[1-(2-(5-(3-methylbenzyl)-1,3,4-oxadiazolyl)carbonyl)-2-(S)-methylpropyl]acetamide; lxxvii. 4-[1-(4-morpholinoethyl)-3-(R)-benzylpiperazine-2,5-dione]-N-[1 2-(5-(3-methylbenzyl)-1,3,4-oxadiazolyl)carbonyl)-2-(S)-methylpropyl]acetamide; lxxiviii. 5-(RS)-phenyl-2,4-imidazolidinedione-N-[1-(2-(5-(3-methylbenzyl)-1,3,4-oxadiazolyl)carbonyl)-2-(S)-methylpropyl]acetamide; lxxix. 5-(R)-benzyl-2,4imidazolidinedione-N-[1-(2-(5-(3-methylbenzyl)-1,3,4-oxadiazolyl)carbonyl)-2-(S)-methylpropyl]acetamide; lxxx. 5-(S)-benzyl-2,4-imidazolidinedione-N-[1-(2-(5-(3-methylbenzyl)-1,3,4-oxadiazolyl)carbonyl)-2-(S)-methylpropyl]acetamide; lxxxi. 5-(S)-benzyl-2,4-imidazolidinedione-N-[1-(3-(5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl)carbonyl)-2-(S)-methylpropyl]acetamide; lxxxii. 5-(R)-benzyl-2,4-imidazolidinedione-N-[1-(3-(5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl)carbonyl)-2-(S)-methylpropyl]acetamide; lxxxiii. 1-benzyl-4-(R)-benzyl-2,5-imidazolidinedione-N-[1-(2-(5-(3-methylbenzyl)-1,3,4-oxadiazolyl)carbonyl)-2(S)-methylpropyl]acetamide; lxxxiv. 1-benzyl-4-(R)-benzyl-2,5-imidazolidinedione-N-[1-(3-(5-(3-trifluoromethylbenzyl) 1,2,4-oxadiazolyl)carbonyl)-2-(S)-methylpropyl]acetamide, or pharmaceutically acceptable salts thereof, or combinations thereof [Benzyloxycarbonyl-L-valyl-N-[1-(2-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide (CE-2072) or a derivative thereof] that upon administration to a patient in need thereof, inhibits serine protease; and at least one second compound selected from the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors, for a time and under conditions effective to inhibit HIV replication.