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A retroviral protease inhibiting compound of the formula A--X--B is disclosed. Also disclosed are a composition and method for inhibiting a retroviral protease and for treating an HIV infection. Also disclosed are processes and intermediates useful for the preparation of the retroviral protease inhibitors.

Inventors: Dale J. Kempf, Daniel W. Norbeck, Lynn M. Codacovi, Hing L. Sham, Steven J. Wittenberger
Original Assignee: Abbott Laboraotries
Current U.S. Classification: 548/204; 548/193; 548/194; 548/195
International Classification: C07D27730

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Referenced by

Citing PatentFiling dateIssue dateOriginal AssigneeTitle
US6017928Oct 6, 1997Jan 25, 2000Abbott LaboratoriesRetroviral protease inhibiting compounds
US6150530Dec 8, 1998Nov 21, 2000Abbott LaboratoriesRetroviral protease inhibiting compounds
US6284767Dec 8, 1998Sep 4, 2001Abbott LaboratoriesRetroviral protease inhibiting compounds
US6472529Apr 18, 2001Oct 29, 2002Abbott LaboratoriesRetroviral protease inhibiting compounds
US6531610Jul 20, 2000Mar 11, 2003Abbott LaboratoriesRetroviral protease inhibiting compounds
US6667404Feb 7, 2003Dec 23, 2003Abbott LaboratoriesRetroviral protease inhibiting compounds
US6894171Jul 19, 1999May 17, 2005Abbott LaboratoriesPolymorph of a pharmaceutical
US6911214Sep 4, 2001Jun 28, 2005Abbott LaboratoriesFlavoring systems for pharmaceutical compositions and methods of making such compositions
US7148359May 4, 2005Dec 12, 2006Abbott LaboratoriesPolymorph of a pharmaceutical
US7183416Jul 29, 2004Feb 27, 2007Abbott LaboratoriesPolymorph of a pharmaceutical
US7279582Oct 25, 2002Oct 9, 2007Abbott LaboratoriesRetroviral protease inhibiting compounds
US7364752Nov 10, 2000Apr 29, 2008Abbott LaboratoriesSolid dispersion pharamaceutical formulations
US7659405Sep 21, 2006Feb 9, 2010Abbott LaboratoriesPolymorph of a pharmaceutical
US7781474Jul 5, 2007Aug 24, 2010InterMune, Inc.Inhibitors of hepatitis C virus replication
US7932277May 9, 2008Apr 26, 2011InterMune, Inc.
Array Biopharma Inc.		Peptide inhibitors of hepatitis C virus replication
US7968707Feb 27, 2007Jun 28, 2011Abbott LaboratoriesRetroviral protease inhibiting compounds
US8025899Aug 25, 2004Sep 27, 2011Abbott LaboratoriesSolid pharmaceutical dosage form
US8193367Dec 22, 2009Jun 5, 2012Abbott LaboratoriesPolymorph of a pharmaceutical

Claims

1. A compound of the formula: ##STR17## wherein R.sub.2 and R.sub.3 are independently selected from C.sub.3 -to-C.sub.7 -cycloalkyl-C.sub.1 -to-C.sub.6 -alkyl and (C.sub.6 -monocyclic or C.sub.9 - or C.sub.10 -bicyclic)aryl-C.sub.1 -to-C.sub.6 -alkyl; and

(a) A is thiazolyl-C.sub.1 -to-C.sub.6 -alkyl-R.sub.9 --C(O)--NH--CH(R.sub.5)--C(O)-- or (substituted-thiazolyl)-C.sub.1 -to-C.sub.6 -alkyl-R.sub.9 --C(O)--NH--CH(R.sub.5)--C(O)-- wherein R.sub.9 is --O--, --NH-- or --N(C.sub.1 -to-C.sub.6 -loweralkyl)- and R.sub.5 is C.sub.1 -to-C.sub.6 -loweralkyl and B is thiazolyl-C.sub.1 -to-C.sub.6 -alkyl-O--C(O)--, thiazolyl-C.sub.1 -to-C.sub.6 -alkyl-NH--C(O)--, thiazolyl-C.sub.1 -to-C.sub.6 -alkyl-N(C.sub.1 -to-C.sub.6 -loweralkyl)-C(O)--, (substituted-thiazolyl)-C.sub.1 -to-C.sub.6 -alkyl-O--C(O)--, (substituted-thiazolyl)-C.sub.1 -to-C.sub.6 -alkyl-NH--C(O)-- or (substituted-thiazolyl)-C.sub.1 -to-C.sub.6 -alkyl-N(C.sub.1 -to-C.sub.6 -loweralkyl)-C(O)-- and wherein at each occurrence substituted-thiazolyl is independently selected from a thiazolyl ring substituted with one or two substituents independently selected from C.sub.1 -to-C.sub.6 -loweralkyl, hydroxy, halo, amino, C.sub.1 -to-C.sub.6 -alkylamino, di-C.sub.1 -to-C.sub.6 -alkylamino, C.sub.1 -to-C.sub.6 -alkoxy, halo-C.sub.1 -to-C.sub.6 -alkyl, unsubstituted-C.sub.3 -to-C.sub.7 -cycloalkyl, unsubstituted (C.sub.6 -monocyclic or C.sub.9 - or C.sub.10 -bicyclic)aryl, unsubstituted (C.sub.6 -monocyclic or C.sub.9 - or C.sub.10 -bicyclic)aryl-C.sub.1 -to-C.sub.6 -alkyl, --COOH and --SO.sub.3 H; or
(b) A is thiazolyl-C.sub.1 -to-C.sub.6 -alkyl-O--C(O)--, thiazolyl-C.sub.1 -to-C.sub.6 -alkyl-NH--C(O)--, thiazolyl-C.sub.1 -to-C.sub.6 -alkyl-N(C.sub.1 -to-C.sub.6 -loweralkyl)-C(O)--, (substituted-thiazolyl)-C.sub.1 -to-C.sub.6 -alkyl-O--C(O)--, (substituted-thiazolyl)-C.sub.1 -to-C.sub.6 -alkyl-NH--C(O)-- or (substituted-thiazolyl)-C.sub.1 -to-C.sub.6 -alkyl-N(C.sub.1 -to-C.sub.6 -loweralkyl)-C(O)-- and B is thiazolyl-C.sub.1 -to-C.sub.6 -alkyl-R.sub.9 --C(O)--NH--CH(R.sub.5)--C(O)-- or (substituted-thiazolyl)-C.sub.1 -to-C.sub.6 -alkyl-R.sub.9 -C(O)--NH--CH(R.sub.5)--C(O)-- wherein R.sub.9 is --O--, --NH-- or --N(C.sub.1 -to-C.sub.6 -loweralkyl)- and R.sub.5 is C.sub.1 -to-C.sub.6 -loweralkyl and wherein at each occurrence substituted-thiazolyl is independently selected from a thiazolyl ring substituted with one or two substituents independently selected from C.sub.1 -to-C.sub.6 -loweralkyl, hydroxy, halo, amino, C.sub.1 -to-C.sub.6 -alkylamino, di-C.sub.1 -to-C.sub.6 -alkylamino, C.sub.1 -to-C.sub.6 -alkoxy, halo-C.sub.1 -to-C.sub.6 -alkyl, unsubstituted-C.sub.3 -to-C.sub.7 -cycloalkyl, unsubstituted (C.sub.6 -monocyclic or C.sub.9 - or C.sub.10 -bicyclic)aryl, unsubstituted (C.sub.6 -monocyclic or C.sub.9 - or C.sub.10 -bicyclic)aryl-C.sub.1 -to-C.sub.6 -alkyl, --COOH and --SO.sub.3 H;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 wherein A is thiazolyl-C.sub.1 -to-C.sub.6 -alkyl-R.sub.9 --C(O)--NH--CH(R.sub.5)--C(O)-- or (substituted-thiazolyl)-C.sub.1 -to-C.sub.6 -alkyl-R.sub.9 -C(O)--NH--CH(R.sub.5)--C(O)-- wherein R.sub.9 is --O--, --NH-- or --N(C.sub.1 -to-C.sub.6 -loweralkyl)- and R.sub.5 is C.sub.1 -to-C.sub.6 -loweralkyl and B is thiazolyl-C.sub.1 -to-C.sub.6 -alkyl-O--C(O)--, thiazolyl-C.sub.1 -to-C.sub.6 -alkyl-NH--C(O)--, thiazolyl-C.sub.1 -to-C.sub.6 -alkyl-N(C.sub.1 -to-C.sub.6 -loweralkyl)-C(O)--, (substituted-thiazolyl)-C.sub.1 -to-C.sub.6 -alkyl-O--C(O)--, (substituted-thiazolyl)-C.sub.1 -to-C.sub.6 -alkyl-NH--C(O)-- or (substituted-thiazolyl)-C.sub.1 -to-C.sub.6 -alkyl-N(C.sub.1 -to-C.sub.6 -loweralkyl)-C(O)-- and wherein at each occurrence substituted-thiazolyl is independently selected from a thiazolyl ring substituted with one or two substituents independently selected from C.sub.1 -to-C.sub.6 -loweralkyl, hydroxy, halo, amino, C.sub.1 -to-C.sub.6 -alkylamino, di-C.sub.1 -to-C.sub.6 -alkylamino, C.sub.1 -to-C.sub.6 -alkoxy, halo-C.sub.1 -to-C.sub.6 -alkyl, unsubstituted-C.sub.3 -to-C.sub.7 -cycloalkyl, unsubstituted (C.sub.6 -monocyclic or C.sub.9 - or C.sub.10 -bicyclic)aryl, unsubstituted (C.sub.6 -monocyclic or C.sub.9 - or C.sub.10 -bicyclic)aryl-C.sub.1 -to-C.sub.6 -alkyl, --COOH and --SO.sub.3 H.

3. The compound of claim 2 wherein R.sub.2 and R.sub.3 are benzyl, A is thiazolyl-C.sub.1 -to-C.sub.6 -alkyl-R.sub.9 --C(O)--NH--CH(R.sub.5)--C(O)-- or (substituted-thiazolyl)-C.sub.1 -to-C.sub.6 -alkyl-R.sub.9 --O(O)--NH--CH(R.sub.5)--C(O)-- wherein R.sub.9 is --O-- or --N(CH.sub.3)-- and R.sub.5 is C.sub.1 -to-C.sub.6 -loweralkyl and B is thiazolyl-C.sub.1 -to-C.sub.6 -alkyl-O--C(O)-- or (substituted-thiazolyl)-C.sub.1 -to-C.sub.6 -alkyl-O--C(O)-- and wherein at each occurrence substituted-thiazolyl is as defined therein.

4. The compound of claim 3 wherein R.sub.5 is isopropyl and at each occurrence substituted-thiazolyl is independently amino-substituted thiazolyl or C.sub.1 -to-C.sub.6 -loweralkyl-substituted thiazolyl.

5. The compound of claim 1 wherein A is thiazolyl-C.sub.1 -to-C.sub.6 -alkyl-O--C(O)--, thiazolyl-C.sub.1 -to-C.sub.6 -alkyl-NH--C(O)--, thiazolyl-C.sub.1 -to-C.sub.6 -alkyl-N(C.sub.1 -to-C.sub.6 -loweralkyl)-C(O)--, (substituted-thiazolyl)-C.sub.1 -to-C.sub.6 -alkyl-O--C(O)--, (substituted-thiazolyl)-C.sub.1 -to-C.sub.6 -alkyl-NH--C(O)-- or (substituted-thiazolyl)-C.sub.1 -to-C.sub.6 -alkyl-N(C.sub.1 -to-C.sub.6 -loweralkyl)-C(O)-- and B is thiazolyl-C.sub.1 -to-C.sub.6 -alkyl-R.sub.9 --C(O)--NH--CH(R.sub.5)--C(O)-- or (substituted-thiazolyl)-C.sub.1 -to-C.sub.6 -alkyl-R.sub.9 --C(O)--NH--CH(R.sub.5)--C(O)-- wherein R.sub.9 is --O--, --NH-- or --N(C.sub.1 -to-C.sub.6 -loweralkyl)- and R.sub.5 is C.sub.1 -to-C.sub.6 -loweralkyl and wherein at each occurrence substituted-thiazolyl is independently selected from a thiazolyl ring substituted with one or two substituents independently selected from C.sub.1 -to-C.sub.6 -loweralkyl, hydroxy, halo, amino, C.sub.1 -to-C.sub.6 -alkylamino, di-C.sub.1 -to-C.sub.6 -alkylamino, C.sub.1 -to-C.sub.6 -alkoxy, halo-C.sub.1 -to-C.sub.6 -alkyl, unsubstituted -C.sub.3 -to-C.sub.7 -cycloalkyl, unsubstituted (C.sub.6 -monocyclic or C.sub.9 - or C.sub.10 -bicyclic)aryl, unsubstituted (C.sub.6 -monocyclic or C.sub.9 - or C.sub.10 -bicyclic)aryl-C.sub.1 -to-C.sub.6 -alkyl, --COOH and --SO.sub.3 H.

6. The compound of claim 5 wherein R.sub.2 and R.sub.3 are benzyl, A is thiazolyl-C.sub.1 -to-C.sub.6 -alkyl-O--C(O)-- or (substituted-thiazolyl)-C.sub.1 -to-C.sub.6 -alkyl-O--C(O)-- and B is thiazolyl-C.sub.1 -to-C.sub.6 -alkyl-R.sub.9 --C(O)--NH--CH(R.sub.5)--C(O)-- or (substituted-thiazolyl)-C.sub.1 -to-C.sub.6 -alkyl-R.sub.9 --C(O)--NH--CH(R.sub.5)--C(O)-- wherein R.sub.9 is --O-- or --N(CH.sub.3)-- and R.sub.5 is C.sub.1 -to-C.sub.6 -loweralkyl and wherein at each occurrence substituted-thiazolyl is as defined therein.

7. The compound of claim 6 wherein R.sub.5 is isopropyl and at each occurrence substituted-thiazolyl is independently amino-substituted thiazolyl or C.sub.1 -to-C.sub.6 -loweralkyl-substituted thiazolyl.

8. The compound (2S,3S,5S)-2-(N-(N-((N-Methyl-N-((2-amino-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-5-(N-((5-thiazolyl)-methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane; or a pharmaceutically acceptable salt thereof.