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Last Updated: March 28, 2024

Details for Patent: 5,597,927


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Title: Retroviral protease inhibiting compounds
Abstract:A retroviral protease inhibiting compound of the formula: ##STR1## is disclosed.
Inventor(s): Kempf; Dale J. (Libertyville, IL), Norbeck; Daniel W. (Crystal Lake, IL), Sham; Hing L. (Gurnee, IL), Zhao; Chen (Gurnee, IL)
Assignee: Abbott Laboratories (Abbott Park, IL)
Filing Date:Mar 29, 1995
Application Number:08/412,438
Claims:1. A compound of the formula: ##STR18## wherein R.sub.1 is monosubstituted thiazolyl or monosubstituted oxazolyl wherein the substituent is selected from (i) C.sub.1 -to-C.sub.6 -loweralkyl, (ii) C.sub.2 -to-loweralkenyl, (iii) C.sub.3 -to-C.sub.7 -cycloalkyl, (iv) C.sub.3 -to-C.sub.7 -cycloalkyl-C.sub.1 -to-C.sub.6 -alkyl, (v) C.sub.5 -to-C.sub.7 -cycloalkenyl, (vi) C.sub.5 -to-C.sub.7 -cycloalkenyl-C.sub.1 -to-C.sub.6 -alkyl, (vii) C.sub.1 -to-C.sub.6 -alkoxy-C.sub.1 -to-C.sub.6 -alkyl or benzyloxy-C.sub.1 -to-C.sub.6 -alkyl, (viii) C.sub.1 -to-C.sub.6 -thioalkoxy-C.sub.1 -to-C.sub.6 -alkyl or benzyl-S-C.sub.1 -to-C.sub.6 -alkyl, (ix) C.sub.1 -to-C.sub.6 -alkylamino, (x) di-C.sub.1 -to-C.sub.6 -alkylamino, (xi) phenyl wherein the phenyl ring is unsubstituted or substituted with a substituent selected from halo, C.sub.1 -to-C.sub.6 -loweralkyl, hydroxy, C.sub.1 -to-C.sub.6 -alkoxy, benzyloxy, benzyl-S-- and thioalkoxy, (xii) phenyl-C.sub.1 -to-C.sub.6 -alkyl wherein the phenyl ring is unsubstituted or substituted as defined above, (xiii) di-C.sub.1 -to-C.sub.6 -alkylamino-C.sub.1 -to-C.sub.6 -alkyl, (xiv) C.sub.1 -to-C.sub.6 -alkoxy or benzyloxy and (xv) C.sub.1 -to-C.sub.6 -thioalkoxy or benzyl-S--:

n is 1, 2 or 3;

R.sub.2 is hydrogen or C.sub.1 -to-C.sub.6 -loweralkyl;

R.sub.3 is C.sub.1 -to-C.sub.6 -loweralkyl;

R.sub.4 is phenyl wherein the phenyl ring is unsubstituted or substituted with a substituent selected from (i) halo, (ii) C.sub.1 -to-C.sub.6 -loweralkyl, (iii) hydroxy, (iv) C.sub.1 -to-C.sub.6 -alkoxy or benzyloxy and (v) C.sub.1 -to-C.sub.6 -thioalkoxy or benzyl-S--;

R.sub.4a is thiazolyl or oxazolyl wherein the thiazolyl or oxazolyl ring is unsubstituted or substituted with a substituent selected from (i) halo, (ii) C.sub.1 -to-C.sub.6 -loweralkyl, (iii) hydroxy, (iv) C.sub.1 -to-C.sub.6 -alkoxy or benzyloxy and (v) C.sub.1 -to-C.sub.6 -thioalkoxy or benzyl-S--;

R.sub.6 is hydrogen or C.sub.1 -to-C.sub.6 -loweralkyl;

R.sub.7 is thiazolyl or oxazolyl wherein the thiazolyl or oxazolyl ring is unsubstituted or substituted with C.sub.1 -to-C.sub.6 -loweralkyl;

X is hydrogen and Y is --OH; and

Z is absent, --O--, --S--, --CH.sub.2 -- or --N(R.sub.8)-- wherein R.sub.8 is C.sub.1 -to-C.sub.6 -loweralkyl, C.sub.3 -to-C.sub.7 -cycloalkyl, --OH or --NHR.sub.8a wherein R.sub.8a is hydrogen or C.sub.1 -to-C.sub.6 -loweralkyl; or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 wherein n is 1; R.sub.2 is hydrogen; R.sub.4 is phenyl; R.sub.5 is hydrogen; R.sub.6 is hydrogen and R.sub.7 is thiazolyl or oxazolyl.

3. The compound of claim 1 wherein R.sub.1 is 2-monosubstituted-4-thiazolyl or 2-monosubstituted-4-oxazolyl wherein the substituent is selected from (i) C.sub.1 -to-C.sub.6 -loweralkyl, (ii) C.sub.2 -to-C.sub.6 -loweralkenyl, (iii) C.sub.3 -to-C.sub.7 -cycloalkyl, (iv) C.sub.3 -to-C.sub.7 -cycloalkyl-C.sub.1 -to-C.sub.6 -alkyl, (v) C.sub.5 -to-C.sub.7 -cycloalkenyl, (vi) C.sub.5 -to-C.sub.7 -cycloalkenyl-C.sub.1 -to-C.sub.6 -alkyl, (vii) C.sub.1 -to-C.sub.6 -alkoxy-C.sub.1 -to-C.sub.6 -alkyl or benzyloxy-C.sub.1 -to-C.sub.6 -alkyl, (viii) C.sub.1 -to-C.sub.6 -thioalkoxy-C.sub.1 -to-C.sub.6 -alkyl or benzyl-S-C.sub.1 -to-C.sub.6 -alkyl, (ix) C.sub.1 -to-C.sub.6 -alkylamino, (x) di-C.sub.1 -to-C.sub.6 -alkylamino, (xi) phenyl wherein the phenyl ring is unsubstituted or substituted with a substituent selected from halo, C.sub.1 -to-C.sub.6 -loweralkyl, hydroxy, C.sub.1 -to-C.sub.6 -alkoxy, benzyloxy, benzyl-S-- and thioalkoxy, (xii) phenyl-C.sub.1 -to-C.sub.6 -alkyl wherein the phenyl ring is unsubstituted or substituted as defined above, (xiii) di-C.sub.1 -to-C.sub.6 -alkylamino-C.sub.1 -to-C.sub.6 -alkyl, (xiv) C.sub.1 -to-C.sub.6 -alkoxy or benzyloxy and (xv) C.sub.1 -to-C.sub.6 -thioalkoxy or benzyl-S--; n is 1; R.sub.2 is hydrogen; R.sub.4 is phenyl; R.sub.5 is hydrogen; R.sub.6 is hydrogen and R.sub.7 is 5-thiazolyl or 5-oxazolyl.

4. The compound of claim 1 wherein R.sub.1 is 2-monosubstituted-4-thiazolyl or 2-monosubstituted-4-oxazolyl wherein the substituent is C.sub.1 -to-C.sub.6 -loweralkyl; n is 1; R.sub.2 is hydrogen; R.sub.4 is phenyl; R.sub.5 is hydrogen; R.sub.6 is hydrogen; R.sub.7 is 5-thiazolyl or 5-oxazolyl; and Z is --O-- or --N(R.sub.8)-- wherein R.sub.8 is C.sub.1 -to-C.sub.6 -loweralkyl.

5. The compound of claim 1 wherein R.sub.1 is 2-monosubstituted-4-thiazolyl or 2-monosubstituted-4-oxazolyl wherein the substituent is ethyl or isopropyl; n is 1; R.sub.2 is hydrogen; R.sub.3 is methyl or isopropyl; R.sub.4 is phenyl; R.sub.5 is hydrogen; R.sub.6 is hydrogen; R.sub.7 is 5-thiazolyl or 5-oxazolyl; and Z is --O--.

6. The compound of claim 1 wherein R.sub.1 is 2-monosubstituted-4-thiazolyl or 2-monosubstituted-4-oxazolyl wherein the substituent is ethyl or isopropyl; n is 1; R.sub.2 is hydrogen; R.sub.3 is isopropyl; R.sub.4 is phenyl; R.sub.5 is hydrogen; R.sub.6 is hydrogen; R.sub.7 is 5-thiazolyl or 5-oxazolyl; and Z is --N(R.sub.8)-- wherein R.sub.8 is methyl.

7. The compound (2S,3S,5S)-2-(N-(N-((2-Isopropyl-4-thiazolyl)methoxycarbonyl)valinyl)amino )-1-phenyl-5-(N-((5-thiazolyl)methoxycarbonyl)amino)-6-(5-thiazolyl)-3-hydr oxyhexane; or a pharmaceutically acceptable salt thereof.

8. A compound of the formula: ##STR19## wherein R.sub.1 is monosubstituted thiazolyl or monosubstituted oxazolyl wherein the substituent is selected from (i) C.sub.1 -to-C.sub.6 -loweralkyl, (ii) C.sub.2 -to-C.sub.6 -loweralkenyl, (iii) C.sub.3 -to-C.sub.7 -cycloalkyl, (iv) C.sub.3 -to-C.sub.7 cycloalkyl-C.sub.1 -to-C.sub.6 -alkyl, (v) C.sub.5 -to-C.sub.7 -cycloalkenyl, (vi) C.sub.5 -to-C.sub.7 -cycloalkenyl-C.sub.1 -to-C.sub.6 -alkyl, (vii) C.sub.1 -to-C.sub.6 -alkoxy-C.sub.1 -to-C.sub.6 -alkyl or benzyloxy-C.sub.1 -to-C.sub.6 -alkyl, (viii) C.sub.1 -to-C.sub.6 -thialkoxy-C.sub.1 -to-C.sub.6 -alkyl or benzyl-S-C.sub.1 -to-C.sub.6 -alkyl, (ix) C.sub.1 -to-C.sub.6 -alkylamino, (x) di-C.sub.1 -to-C.sub.6 -alkylamino, (xi) phenyl wherein the phenyl ring is unsubstituted or substituted with a substituent selected from halo, C.sub.1 -to-C.sub.6 -loweralkyl, hydroxy, C.sub.1 -to-C.sub.6 -alkoxy, benzyloxy, benzyl-S-- and thioalkoxy, (xii) phenyl-C.sub.1 -to-C.sub.6 -alkyl wherein the phenyl ring is unsubstituted or substituted as defined above, (xiii) di-C.sub.1 -to-C.sub.6 -alkylamino-C.sub.1 -to-C.sub.6 -alkyl (xiv) C.sub.1 -to-C.sub.6 -alkoxy or benzyloxy and (xv) C.sub.1 -to-C.sub.6 -thioalkoxy or benzyl-S--;

n is 1, 2 or 3;

R.sub.2 is hydrogen or C.sub.1 -to-C.sub.6 -loweralkyl;

R.sub.4 is phenyl wherein the phenyl ring is unsubstituted or substituted with a substituent selected from (i) halo, (ii) C.sub.1 -to-C.sub.6 -loweralkyl, (iii) hydroxy, (iv) C.sub.1 -to-C.sub.6 -alkoxy or benzyloxy and (v) C.sub.1 -to-C.sub.6 -thioalkoxy or benzyl-S--;

R.sub.4a is thiazolyl or oxazolyl wherein the thiazolyl or oxazolyl ring is unsubstituted or substituted with a substituent selected from (i) halo, (ii) C.sub.1 -to-C.sub.6 -loweralkyl, (iii) hydroxy, (iv) C.sub.1 -to-C.sub.6 -alkoxy or benzyloxy and (v) C.sub.1 -to-C.sub.6 -thioalkoxy or benzyl-S--;

R.sub.6 is hydrogen or C.sub.1 -to-C.sub.6 -loweralkyl;

R.sub.7 is thiazolyl or oxazolyl wherein the thiazolyl or oxazolyl and is unsubstituted and R.sub.3 is C.sub.2 -to-C.sub.6 -loweralkyl and Z is absent, --O--, --S-- or --CH.sub.2 --; or

R.sub.7 is thiazolyl or oxazolyl wherein the thiazolyl or oxazolyl ring is substituted with C.sub.1 -to-C.sub.6 -loweralkyl and R.sub.3 is C.sub.1 -to-C.sub.6 -loweralkyl and Z is absent, --O--, --S--, --CH.sub.2 -- or --N(R.sub.8)-- wherein R.sub.8 is C.sub.1 -to-C.sub.6 -loweralkyl, C.sub.3 -to-C.sub.7 -cycloalkyl, --OH or --NHR.sub.8a wherein R.sub.8a is hydrogen or C.sub.1 -to-C.sub.6 -loweralkyl; and

X is --OH and Y is hydrogen; or a pharmaceutically acceptable salt thereof.

9. The compound of claim 8 wherein n is 1; R.sub.2 is hydrogen; R.sub.4 is phenyl; R.sub.5 is hydrogen; R.sub.6 is hydrogen and R.sub.7 is thiazolyl or oxazolyl.

10. The compound of claim 8 wherein R.sub.1 is 2-monosubstituted-4-thiazolyl or 2-monosubstituted-4-oxazolyl wherein the substituent is selected from (i) C.sub.1 -to-C.sub.6 -loweralkyl, (ii) C.sub.2 -to-C.sub.6 -loweralkenyl, (iii) C.sub.3 -to-C.sub.7 -cycloalkyl, (iv) C.sub.3 -to-C.sub.7 -cycloalkyl-C.sub.1 -to-C.sub.6 -alkyl, (v) C.sub.5 -to-C.sub.7 -cycloalkenyl, (vi) C.sub.5 -to-C.sub.7 -cycloalkenyl-C.sub.1 -to-C.sub.6 -alkyl, (vii) C.sub.1 -to-C.sub.6 -alkoxy-C.sub.1 -to-C.sub.6 -alkyl or benzyloxy-C.sub.1 -to-C.sub.6 -alkyl, (viii) C.sub.1 -to-C.sub.6 -thioalkoxy-C.sub.1 -to-C.sub.6 -alkyl or benzyl-S-C.sub.1 -to-C.sub.6 -alkyl, (ix) C.sub.1 -to-C.sub.6 -alkylamino, (x) di-C.sub.1 -to-C.sub.6 -alkylamino, (xi) phenyl wherein the phenyl ring is unsubstituted or substituted with a substituent selected from halo, C.sub.1 -to-C.sub.6 -loweralkyl, hydroxy, C.sub.1 -to-C.sub.6 -alkoxy, benzyloxy, benzyl-S-- and thioalkoxy, (xii) phenyl-C.sub.1 -to-C.sub.6 -alkyl wherein the phenyl ring is unsubstituted or substituted as defined above, (xiii) di-C.sub.1 -to-C.sub.6 -alkylamino-C.sub.1 -to-C.sub.6 -alkyl, (xiv) C.sub.1 -to-C.sub.6 -alkoxy or benzyloxy and (xv) C.sub.1 -to-C.sub.6 -thioalkoxy or benzyl-S--; n is 1; R.sub.2 is hydrogen; R.sub.4 is phenyl; R.sub.5 is hydrogen; R.sub.6 is hydrogen and R.sub.7 is 5-thiazolyl or 5-oxazolyl.

11. The compound of claim 8 wherein n is 1; R.sub.2 is hydrogen; R.sub.4 is phenyl; R.sub.5 is hydrogen; R.sub.6 is hydrogen; R.sub.7 is 5-thiazolyl or 5-oxazolyl; and Z is --O--.

12. The compound of claim 8 wherein n is 1; R.sub.2 is hydrogen; R.sub.3 is methyl or isopropyl; R.sub.4 is phenyl; R.sub.5 is hydrogen; R.sub.6 is hydrogen; R.sub.7 is 5-thiazolyl or 5-oxazolyl; and Z is --O--.

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