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Details for Patent: 5,354,866

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Details for Patent: 5,354,866

Title: Retroviral protease inhibiting compounds
Abstract: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.
Inventor(s): Kempf; Dale J. (Libertyville, IL), Norbeck; Daniel W. (Lindenhurst, IL), Codacovi; Lynn M. (Antioch, IL), Plattner; Jacob J. (Libertyville, IL), Sham; Hing L. (Gurnee, IL), Zhao; Chen (Gurnee, IL)
Assignee: Abbott Laboratories (Abbott Park, IL)
Filing Date:Sep 14, 1993
Application Number:08/121,673
Claims:1. A compound of the formula: ##STR17## wherein R.sub.5 is C.sub.1 -C.sub.6 -loweralkyl and R.sub.7 is independently selected at each occurrence from unsubstituted pyridyl and pyridyl which is substituted with C.sub.1 -C.sub.6 -loweralkyl, C.sub.3 -C.sub.7 -cycloalkyl, C.sub.1 -C.sub.6 -alkoxy, hydroxy, amino, N-protected amino, C.sub.1 -C.sub.6 -alkylamino, (N-protected)-C.sub.1 -C.sub.6 -alkylamino, di-C.sub.1 -C.sub.6 -alkylamino or halo; or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein the acyl residue of the ester is (i) R*C(O)-- or R*C(S)-- wherein R* is hydrogen, C.sub.1 -C.sub.6 -loweralkyl, C.sub.1 -C.sub.6 -haloalkyl, C.sub.1 -C.sub.6 -alkoxy, C.sub.1 -C.sub.6 -thioalkoxy, C.sub.1 -C.sub.6 -alkoxy-C.sub.1 -C.sub.6 -alkyl, C.sub.1 -C.sub.6 -thioalkoxy-C.sub.1 -C.sub.6 -alkyl or C.sub.1 -C.sub.6 -haloalkoxy, (ii) R.sub.a --C(R.sub.b)(R.sub.d)--C(O)-- or R.sub.a --C(R.sub.b)(R.sub.d)--C(S)-- wherein R.sub.b and R.sub.d are independently selected from hydrogen and C.sub.1 -C.sub.6 -loweralkyl and R.sub.a is --N(R.sub.e)(R.sub.f), --OR.sub.e or --SR.sub.e wherein R.sub.e and R.sub.f are independently selected from hydrogen, C.sub.1 -C.sub.6 -loweralkyl and C.sub.1 -C.sub.6 -haloalkyl, (iii) R.sub.180 NH(CH.sub.2).sub.2 NHCH.sub.2 C(O)-- or R.sub.180 NH(CH.sub.2).sub.2 OCH.sub.2 C(O)-- wherein R.sub.180 is hydrogen, C.sub.1 -C.sub.6 -loweralkyl, aryl-C.sub.1 -C.sub.6 alkyl wherein the aryl group is phenyl, naphthyl, tetrahydronaphtyl, indanyl or indenyl, C.sub.3 -C.sub.7 -cycloalkyl-C.sub.1 -C.sub.6 -alkyl, C.sub.1 -C.sub.6 -alkanoyl or benzoyl, (iv) H.sub.2 O.sub.3 P-- or (v) --C(O)CH.sub.2 CH.sub.2 COOH and wherein the prodrug is a compound wherein the hydroxy group is functionalized with a substituent of the formula --CH(R.sub.g)OC(O)R.sub.181 or --CH(R.sub.g)OC(S)R.sub.181 wherein R.sub.181 is C.sub.1 -C.sub.6 -loweralkyl, C.sub.1 -C.sub.6 -haloalkyl, C.sub.1 -C.sub.6 -alkoxy, C.sub.1 -C.sub.6 -thioalkoxy or C.sub.1 -C.sub.6 -haloalkoxy and R.sub.g is hydrogen, C.sub.1 -C.sub.6 -loweralkyl, C.sub.1 -C.sub.6 -haloalkyl, C.sub.1 -C.sub.6 -alkoxycarbonyl, aminocarbonyl, C.sub.1 -C.sub.6 -alkylaminocarbonyl or di-(C.sub.1 -C.sub.6 -alkyl)aminocarbonyl.

2. The compound of claim 1 wherein R.sub.7 is independently selected at each occurrence from 2-pyridyl, 3-pryidyl and 4-pyridyl.

3. A compound of the formula: ##STR18## wherein R.sub.7 is independently selected at each occurrence from unsubstituted pyridyl and pyridyl which is substituted with C.sub.1 -C.sub.6 -loweralkyl, C.sub.3 -C.sub.7 -cycloalkyl, C.sub.1 -C.sub.6 -alkoxy, hydroxy, amino, N-protected amino, C.sub.1 -C.sub.6 -alkylamino, (N-protected)-C.sub.1 -C.sub.6 -alkylamino, di-C.sub.1 -C.sub.6 -alkylamino or halo; or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein the acyl residue of the ester is (i) R*C(O)-- or R*C(S)-- wherein R* is hydrogen, C.sub.1 -C.sub.6 -loweralkyl, C.sub.1 -C.sub.6 -haloalkyl, C.sub.1 -C.sub.6 -alkoxy, C.sub.1 -C.sub.6 -thioalkoxy, C.sub.1 -C.sub.6 -alkoxy-C.sub.1 -C.sub.6 -alkyl, C.sub.1 -C.sub.6 -thioalkoxy-C.sub.1 -C.sub.6 -alkyl or C.sub.1 -C.sub.6 -haloalkoxy, (ii) R.sub.a --C(R.sub.b)(R.sub.d)--C(O)-- or R.sub.a --C(R.sub.b)(R.sub.d)--C(S)-- wherein R.sub.b and R.sub.d are independently selected from hydrogen and C.sub.1 -C.sub.6 -loweralkyl and R.sub.a is --N(R.sub.e)(R.sub.f), --OR.sub.e or --SR.sub.e wherein R.sub.e and R.sub.f are independently selected from hydrogen, C.sub.1 -C.sub.6 -loweralkyl and C.sub.1 -C.sub.6 -haloalkyl, (iii) R.sub.180 NH(CH.sub.2).sub.2 NHCH.sub.2 C(O)-- or R.sub.180 NH(CH.sub.2).sub.2 OCH.sub.2 C(O)-- wherein R.sub.180 is hydrogen, C.sub.1 -C.sub.6 -loweralkyl, aryl-C.sub.1 -C.sub.6 -alkyl wherein the aryl group is phenyl, naphthyl, tetrahydronaphthyl, indanyl or indenyl, C.sub.3 -C.sub.7 -cycloalkyl-C.sub.1 -C.sub.6 -alkyl, C.sub.1 -C.sub.6 -alkanoyl or benzoyl, (iv) H.sub.2 O.sub.3 P-- or (v) --C(O)CH.sub.2 COOH and wherein the prodrug is a compound wherein the hydroxy group is functionalized with a substituent of the formula --CH(R.sub.g)OC(O)R.sub.181 or --CH(R.sub.g)OC(S)R.sub.181 wherein R.sub.181 is C.sub.1 -C.sub.6 -loweralkyl, C.sub.1 -C.sub.6 -haloalkyl, C.sub.1 -C.sub.6 -alkoxy, C.sub.1 -C.sub.6 -thioalkoxy or C.sub.1 -C.sub.6 -haloalkoxy and R.sub.g is hydrogen, C.sub.1 -C.sub.6 -loweralkyl, C.sub.1 -C.sub.6 -haloalkyl, C.sub.1 -C.sub.6 -alkoxycarbonyl, aminocarbonyl, C.sub.1 -C.sub.6 -alkylaminocarbonyl or di-(C.sub.1 -C.sub.6 -alkyl)aminocarbonyl.

4. A compound of the formula: ##STR19## wherein R.sub.7 is independently selected at each occurrence from 2-pyridyl, 3-pyridyl and 4-pyridyl; or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein the acyl residue of the ester is (i) R*C(O)-- or R*C(S)-- wherein R* is hydrogen, C.sub.1 -C.sub.6 -loweralkyl, C.sub.1 -C.sub.6 -haloalkyl, C.sub.1 -C.sub.6 -alkoxy, C.sub.1 -C.sub.6 -thioalkoxy, C.sub.1 -C.sub.6 -alkoxy-C.sub.1 -C.sub.6 -alkyl, C.sub.1 -C.sub.6 -thioalkoxy-C.sub.1 -C.sub.6 -alkyl or C.sub.1 -C.sub.6 -haloalkoxy, (ii) R.sub.a --C(R.sub.b)(R.sub.d)--C(O)-- or R.sub.a --C(R.sub.b)(R.sub.d)--C(S)-- wherein R.sub.b and R.sub.d are independently selected from hydrogen and C.sub.1 -C.sub.6 -loweralkyl and R.sub.a is --N(R.sub.e)(R.sub.f), --OR.sub.e or --SR.sub.e wherein R.sub.e and R.sub.f are independently selected from hydrogen, C.sub.1 -C.sub.6 -loweralkyl and C.sub.1 -C.sub.6 -haloalkyl, (iii) R.sub.180 NH(CH.sub.2).sub.2 NHCH.sub.2 C(O)-- or R.sub.180 NH(CH.sub.2).sub.2 OCH.sub.2 C(O)-- wherein R.sub.180 is hydrogen, C.sub.1 -C.sub.6 -loweralkyl, aryl-C.sub.1 -C.sub.6 -alkyl wherein the aryl group is phenyl, naphthyl, tetrahydronaphthyl, indanyl or indenyl, C.sub.3 -C.sub.7 -cycloalkyl-C.sub.1 -C.sub.6 -alkyl, C.sub.1 -C.sub.6 -alkanoyl or benzoyl, (iv) H.sub.2 O.sub.3 P-- or (v) --C(O)CH.sub.2 CH.sub.2 COOH and wherein the prodrug is a compound wherein the hydroxy group is functionalized with a substituent of the formula --CH(R.sub.g)OC(O)R.sub.181 or --CH(R.sub.g)OC(S)R.sub.181 wherein R.sub.181 is C.sub.1 -C.sub.6 -loweralkyl, C.sub.1 -C.sub.6 -haloalkyl, C.sub.1 -C.sub.6 -alkoxy, C.sub.1 -C.sub.6 -thioalkoxy or C.sub.1 -C.sub.6 -haloalkoxy and R.sub.g is hydrogen, C.sub.1 -C.sub.6 -loweralkyl, C.sub.1 -C.sub.6 -haloalkyl, C.sub.1 -C.sub.6 -alkoxycarbonyl, aminocarbonyl, C.sub.1 -C.sub.6 -alkylaminocarbonyl or di-(C.sub.1 -C.sub.6 -alkyl)aminocarbonyl.

5. A compound selected from the group consisting of: (2S,3S,5S)-2-(N-(N-((2-pyridinyl)methoxycarbonyl)-isoleucinyl)amino)-5-(N- ((3-pyridinyl)methoxycarbonyl)-amino)-1,6-diphenyl-3-hydroxyhexane; (2S,3S,5S)-2-(N-((6-Methylpyridin-2yl)methoxycarbonyl-valinylamino)-5-(N-( (pyridin-3-yl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane; (2S,3S,5S)-2-(N-((6-Methylpyridin-3-yl)methoxycarbonyl-valinylamino)-5-(N- (pyridin-3-yl)methoxycarbonyl)amino-1,6-diphenyl-3-hydroxyhexane; (2S,3S,5S)-2-(N-((5-Methyl-3-pyridinyl)-methoxycarbonyl)valinyl)amino)-5-( N-(3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane; and (2S,3S,5S)-2-(N-((6-Methoxy-3-pyridinyl)methoxycarbonyl)valinyl)amino)-5-( N-(3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane; or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein the acyl residue of the ester is (i) R*C(O)-- or R*C(S)-- wherein R* is hydrogen, C.sub.1 -C.sub.6 -loweralkyl, C.sub.1 -C.sub.6 -haloalkyl, C.sub.1 -C.sub.6 -alkoxy, C.sub.1 -C.sub.6 -thioalkoxy, C.sub.1 -C.sub.6 -alkoxy-C.sub.1 -C.sub.6 -alkyl, C.sub.1 -C.sub.6 -thioalkoxy-C.sub.1 -C.sub.6 -alkyl or C.sub.1 -C.sub.6 -haloalkoxy, (ii) R.sub.a --C(R.sub.b)(R.sub.d)--C(O)-- or R.sub.a --C(R.sub.b)(R.sub.d)--C(S)-- wherein R.sub.b and R.sub.d are independently selected from hydrogen and C.sub.1 -C.sub.6 -loweralkyl and R.sub.a is --N(R.sub.e)(R.sub.f), --OR.sub.e or --SR.sub.e wherein R.sub.e and R.sub.f are independently selected from hydrogen, C.sub. 1 -C.sub.6 -loweralkyl and C.sub.1 -C.sub.6 -haloalkyl, (iii) R.sub.180 NH(CH.sub.2).sub.2 NHCH.sub.2 C(O)-- or R.sub.180 NH(CH.sub.2).sub.2 OCH.sub.2 C(O)-- wherein R.sub.180 is hydrogen, C.sub.1 -C.sub.6 -loweralkyl, aryl-C.sub.1 -C.sub.6 -alkyl wherein the aryl group is phenyl, naphthyl, tetrahydronaphthyl, indanyl or indenyl, C.sub.3 -C.sub.7 -cycloalkyl-C.sub.1 -C.sub.6 -alkyl, C.sub.1 -C.sub.6 -alkanoyl or benzoyl, (iv) H.sub.2 O.sub.3 P-- or (v) --C(O)CH.sub.2 CH.sub.2 COOH and wherein the prodrug is a compound wherein the 3-hydroxy group is functionalized with a substituent of the formula --CH(R.sub.g)OC(O)R.sub.181 or --CH(R.sub.g)OC(S)R.sub.181 wherein R.sub.181 is C.sub.1 -C.sub.6 -loweralkyl, C.sub.1 -C.sub.6 -haloalkyl, C.sub.1 -C.sub.6 -alkoxy, C.sub.1 -C.sub.6 -thioalkoxy or C.sub.1 -C.sub.6 -haloalkoxy and R.sub.g is hydrogen, C.sub.1 -C.sub.6 -loweralkyl, C.sub.1 -C.sub.6 -haloalkyl, C.sub.1 -C.sub.6 -alkoxycarbonyl, aminocarbonyl, C.sub.1 -C.sub.6 -alkylaminocarbonyl or di-(C.sub. 1 -C.sub.6 -alkyl)aminocarbonyl.

6. (2S,3S,5S)-2-(N-(N- ((2-Pyridinyl)methoxycarbonyl)-valinyl)amino)-5-(N-((3-pyridinyl)methoxycar bonyl)amino)-1,6-diphenyl-3-hydroxyhexane; or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein the acyl residue or the ester is (i) R*C(O)-- or R*C(S)-- wherein R* is hydrogen, C.sub.1 -C.sub.6 -loweralkyl, C.sub.1 -C.sub.6 -haloalkyl, C.sub.1 -C.sub.6 -alkoxy, C.sub.1 -C.sub.6 -thioalkoxy, C.sub.1 -C.sub.6 -alkoxy-C.sub.1 -C.sub.6 -alkyl, C.sub.1 -C.sub.6 -thioalkoxy-C.sub.1 -C.sub.6 -alkyl or C.sub.1 -C.sub.6 -haloalkoxy, (ii) R.sub.a --C(R.sub.b)(R.sub.d)--C(O)-- or R.sub.a --C(R.sub.b)(R.sub.d)--C(S)-- wherein R.sub.b and R.sub.d are independently selected from hydrogen and C.sub.1 -C.sub.6 -loweralkyl and R.sub.a is --N(R.sub.e)(R.sub.f), --OR.sub.e or --SR.sub.e wherein R.sub.e and R.sub.f are independently selected from hydrogen, C.sub.1 -C.sub.6 -loweralkyl and C.sub.1 -C.sub.6 -haloalkyl, (iii) R.sub.180 NH(CH.sub.2).sub.2 NHCH.sub.2 C(O)-- or R.sub.180 NH(CH.sub.2).sub.2 OCH.sub.2 C(O)-- wherein R.sub.180 is hydrogen, C.sub.1 -C.sub.6 -loweralkyl, aryl-C.sub.1 -C.sub.6 -alkyl wherein the aryl group is phenyl, naphthyl, tetrahydronaphthyl, indanyl or indenyl, C.sub.3 -C.sub.7 -cycloalkyl-C.sub.1 -C.sub.6 -alkyl, C.sub.1 -C.sub.6 -alkanoyl or benzoyl, (iv) H.sub.2 O.sub.3 P-- or (v) --C(O)CH.sub.2 CH.sub.2 COOH and wherein the prodrug is a compound wherein the 3-hydroxy group is functionalized with a substituent of the formula --CH(R.sub.g)OC(O)R.sub.181 or --CH(R.sub.g)OC(S)R.sub.181 wherein R.sub.181 is C.sub.1 -C.sub.6 -loweralkyl, C.sub.1 -C.sub.6 -haloalkyl, C.sub.1 -C.sub.6 -alkoxy, C.sub.1 -C.sub.6 -thioalkoxy or C.sub.1 -C.sub.6 -haloalkoxy and R.sub.g is hydrogen, C.sub.1 -C.sub.6 -loweralkyl, C.sub.1 -C.sub.6 -haloalkyl, C.sub.1 -C.sub.6 -alkoxycarbonyl, aminocarbonyl, C.sub.1 -C.sub.6 -alkylaminocarbonyl or di-(C.sub.1 -C.sub.6 -alkyl)aminocarbonyl.

7. (2S,3S,5S)-2-(N-(N- ((2-Pyridinyl)methoxycarbonyl)-valinyl)amino)-5-(N-(3-pyridinyl)methoxycarb onyl)amino)-1,6-diphenyl-3-hydroxyhexane; or a pharmaceutically acceptable salt thereof.
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