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Details for Patent: 5,151,438

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Details for Patent: 5,151,438

Title: Retroviral protease inhibiting compounds
Abstract:Compounds are disclosed which are retroviral protease inhibitors. Also disclosed are methods of using the compounds and compositions for inhibiting a retroviral protease and for treating an HIV infection.
Inventor(s): Sham; Hing L. (Gurnee, IL), Norbeck; Daniel W. (Lindenhurst, IL), Kempf; Dale J. (Libertyville, IL), Zhao; Chen (Gurnee, IL)
Assignee: Abbott Laboratories (Abbott Park, IL)
Filing Date:Mar 27, 1991
Application Number:07/675,780
Claims:1. A compound of the formula: ##STR7## wherein R.sub.1 is loweralkyl, cycloalkyl, phenyl, substituted loweralkyl, substituted cycloalkyl or substituted phenyl wherein the loweralkyl, cycloalkyl or phenyl group is substituted with one or two substituents independently selected from hydroxy, alkoxy, thioalkoxy and halo;

R.sub.2 is phenyl or substituted phenyl wherein the phenyl ring is substituted with one or two substituents independently selected from hydroxy, alkoxy, thioalkoxy and halo;

R.sub.3 is ##STR8## wherein m is 2 and R.sub.4 is independently selected at each occurrence from hydrogen, loweralkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, thioalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl and aminocarbonylalkyl and

T is ##STR9## wherein R.sub.6 is pyridyl or substituted pyridyl wherein the pyridyl ring is substituted with one or two substituents independently selected from hydroxy, halo, amino, alkylamino, dialkylamino, alkoxy, polyalkoxy, haloalkyl, cycloalkyl, aryl, arylalkyl, --COOH, --SO.sub.3 H and loweralkyl, V is O or S, W is CH.sub.2, --CH.sub.2 CH.sub.2 --, --CH.dbd.CH--or --D--CH.dbd.CH--wherein D is O, S or NH and Y is absent, O, S or N(R.sub.7) wherein R.sub.7 is hydrogen or loweralkyl; and

Z is --C(O)--or --CH(OH)--; or a pharmaceutically acceptable salt thereof wherein the term alkyl as used herein refers to a straight or branched chain alkyl radical containing from 1 to 6 carbon atoms; wherein the terms alkoxy and thioalkoxy as used herein refer to R.sub.32 is an alkyl group or benzyl and wherein the term aryl as used herein refers to phenyl, naphthyl, tetrahydronaphthyl or indanyl.

2. The compound of claim 1 wherein R.sub.1 is phenyl; R.sub.2 is phenyl; R.sub.4 is independently selected at each occurrence from hydrogen and isopropyl; and Z is --C(O)--.

3. The compound of claim 1 wherein T is N-(2-pyridylmethyl)aminocarbonyl, N-(3-pyridylmethyl)aminocarbonyl, N-(4-pyridylmethyl)aminocarbonyl, 2-pyridylmethoxycarbonyl, 3-pyridylmethoxycarbonyl, 4-pyridylmethoxycarbonyl, N-(2-pyridylmethyl)-N-(methyl)-aminocarbonyl, N-(3-pyridylmethyl)-N-(methyl)-aminocarbonyl or N-(4-pyridylmethyl)-N-(methyl)-aminocarbonyl.

4. A compound of the formula: ##STR10## wherein R.sub.1 is phenyl;

R.sub.2 is phenyl;

R.sub.3 is ##STR11## wherein m is 2, R.sub.4 is independently selected at each occurrence from hydrogen and loweralkyl and

T is ##STR12## R.sub.6 is pyridyl or substituted pyridyl wherein the pyridyl ring is substituted with one or two substituents independently selected from hydroxy, alkoxy, thioalkoxy and halo, V is O or S, W is CH.sub.2, --CH.sub.2 CH.sub.2 --, --CH.dbd.CH--or --D--CH.dbd.CH--wherein D is O, S or NH and Y is absent, O, S or N(R.sub.7) wherein R.sub.7 is hydrogen or loweralkyl; wherein the term alkyl as used herein refers to a straight or branched chain alkyl radical containing from 1 to 6 carbon atoms; and wherein the terms alkoxy and thioalkoxy as used herein refer to R.sub.32 O--and R.sub.32 S--, respectively, wherein R.sub.32 is an alkyl group or benzyl; or a pharmaceutically acceptable salt thereof.

5. The compound of claim 4 wherein R.sub.4 is independently selected at each occurrence from hydrogen and isopropyl.

6. The compound of claim 4 wherein T is N-(2-pyridylmethyl)aminocarbonyl, N-(3-pyridylmethyl)aminocarbonyl, N-(4-pyridylmethyl)aminocarbonyl, 2-pyridylmethoxycarbonyl, 3-pyridylmethoxycarbonyl, 4-pyridylmethoxycarbonyl, N-(2-pyridylmethyl)-N-(methyl)-aminocarbonyl, N-(3-pyridylmethyl)-N-(methyl)-aminocarbonyl or N-(4-pyridylmethyl)-N-(methyl)-aminocarbonyl.

7. A compound of the formula: ##STR13## wherein R.sub.1 is phenyl;

R.sub.2 is phenyl;

R.sub.3 is ##STR14## wherein R.sub.4 is isopropyl and

T is ##STR15## wherein R.sub.6 is pyridyl or substituted pyridyl wherein the pyridyl ring is substituted with one or two substituents independently selected from hydroxy, alkoxy, thioalkoxy and halo, V is O or S, W is CH.sub.2, --CH.sub.2 CH.sub.2 --, --CH.dbd.CH--or --D--CH.dbd.CH--wherein D is O, S or NH and Y is absent, O, S or N(R.sub.7) wherein R.sub.7 is hydrogen or loweralkyl; wherein the term alkyl as used herein refers to a straight or branched chain alkyl radical containing from 1 to 6 carbon atoms; wherein the terms alkoxy and thioalkoxy as used herein refer to R.sub.32 O--and R.sub.32 S--, respectively, wherein R.sub.32 is an alkyl group or benzyl; or a pharmaceutically acceptable salt thereof.

8. The compound of claim 7 wherein T is N-(2-pyridylmethyl)aminocarbonyl, N-(3-pyridylmethyl)aminocarbonyl, N-(4-pyridylmethyl)aminocarbonyl, 2-pyridylmethoxycarbonyl, 3-pyridylmethoxycarbonyl, 4-pyridylmethoxycarbonyl, N-(2-pyridylmethyl)-N-(methyl)-aminocarbonyl, N-(3-pyridylmethyl)-N-(methyl)-aminocarbonyl or N-(4-pyridylmethyl)-N-(methyl)-aminocarbonyl.

9. A compound selected from the group consisting of:

5(S)-(N-(2-pyridyl)methoxycarbonyl-glycyl-(L)-valinyl)-amino-3,3-difluoro-1 ,6-diphenyl-4-oxo-hexane;

5(S)-(N-(3-pyridyl)methoxycarbonyl-glycyl-(L)-valinyl)-amino-3,3-difluoro-1 ,6-diphenyl-4-oxo-hexane;

5(S)-(N-(4-pyridyl)methoxycarbonyl-glycyl-(L)-valinyl)-amino-3,3-difluoro-1 ,6-diphenyl-4-oxo-hexane;

5(S)-(N-(2-pyridylmethyl)aminocarbonyl-glycyl-(L)-valinyl)-amino-3,3-difluo ro-1,6-diphenyl-4-oxo-hexane;

5(S)-(N-(3-pyridylmethyl)aminocarbonyl-glycyl-(L)-valinyl)-amino-3,3-difluo ro-1,6-diphenyl-4-oxo-hexane;

5(S)-(N-(4-pyridylmethyl)aminocarbonyl-glycyl-(L)-valinyl)-amino-3,3-difluo ro-1,6-diphenyl-4-oxo-hexane;

5(S)-(N-(2-pyridylmethyl)-N-(methyl)aminocarbonyl-glycyl-(L)-valinyl)-amino -3,3-difluoro-1,6-diphenyl-4-oxo-hexane;

5(S)-(N-(3-pyridylmethyl)-N-(methyl)aminocarbonyl-glycyl-(L)-valinyl)-amino -3,3-difluoro-1,6-diphenyl-4-oxo-hexane; and

5(S)-(N-(4-pyridylmethyl)-N-(methyl)aminocarbonyl-glycyl-(L)-valinyl)-amino -3,3-difluoro-1,6-diphenyl-4-oxo-hexane;

or a pharmaceutically acceptable salt thereof.

10. A method for inhibiting HIV-1 protease or HIV-2 protease comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 1.

11. A pharmaceutical composition for inhibiting HIV-1 protease or HIV-2 protease comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of claim 1.

12. A method for inhibiting HIV-1 protease or HIV-2 protease comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 9.

13. A pharmaceutical composition for inhibiting HIV-1 protease or HIV-2 protease comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of claim 9.
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