Details for Patent: 5,583,233
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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 30, 1995 |
Application Number: | 08/413,290 |
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) heterocyclic wherein the heterocyclic is selected from aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl and wherein the heterocyclic 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 or benzyloxy and C.sub.1 -to-C.sub.6 -thioalkoxy or benzyl-S-- and (ii) (heterocyclic)-C.sub.1 -to-C.sub.6 -alkyl wherein heterocyclic is defined as above; n is 1, 2or3; 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 and R.sub.4a are independently selected from 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.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) heterocyclic wherein the heterocyclic is selected from aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl and wherein the heterocyclic is unsubstituted or substituted with a substituent selected from halo, loweralkyl, hydroxy, alkoxy and thioalkoxy and (II) (heterocyclic)alkyl wherein heterocyclic is defined as above; 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 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 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 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; Z is --N(R.sub.8)-- wherein R.sub.8 is methyl; X is hydrogen and Y is --OH. 7. A compound selected from the group consisting of: (2S,3S5S)-5-(N-(N-((N-Methyl-N-((2-(2-thiazolyl)-4-thiazolyl)methyl)amino)- carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphe nyl-3-hydroxyhexane; (2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(2-thiazolyl)methyl-4-thiazolyl)methyl) aminocarbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6- diphenyl-3-hydroxyhexane; (2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(1-pyrrolidinyl)methyl-4-thiazolyl)meth yl)amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)- 1,6-diphenyl-3-hydroxyhexane; (2S,3S,5S)-5-(N-(N-((2-(4-Morpholinyl)-4-thiazolyl)methoxycarbonyl)valinyl) amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexa ne; (2S,3S,5S)-2-(N-(N-((2-(4-Morpholinyl)-4-thiazolyl)-methoxycarbonyl)valinyl )amino)-5-(N-((5-methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane; (2S,3S,5S)-5-(N-(N-((2-(1-Pyrrolidinyl)-4-thiazolyl)methoxycarbonyl)valinyl )amino)-2-(N-((5thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexa ne; (2S,3S,5S)-2-(N-(N-((2-(1-Pyrrolidinyl)-4-thiazolyl)-methoxycarbonyl)valiny l)amino)-5-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhe xane; (2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(1-pyrrolidinyl)methyl-4-thiazolyl)meth yl)amino)carbonyl)valinyl)amino)-2-(N-((5-oxazolyl)methoxycarbonyl)amino)-1 ,6-diphenyl-3-hydroxyhexane; (2S,3S,5S)-5-(N-(N-((2-(4-Morpholinyl)-4-thiazolyl)methoxycarbonyl)valinyl) amino)-2-(N-((5-oxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexan e; (2S,3S,5S)-2-(N-(N-((2-(4-Morpholinyl)-4-thiazolyl)-methoxycarbonyl)valinyl )amino)-5(N-((5-oxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexan e; (2S,3S,5S)-5-(N-(N-((2-(1-Pyrrolidinyl)-4-thiazolyl)methoxycarbonyl)valinyl )amino)-2-(N-((5-oxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexa ne; (2S,3S,5S)-2-(N-(N-((2-(1-Pyrrolidinyl)-4-thiazolyl)-methoxycarbonyl)valiny l)amino)-5-(N-((5-oxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhex ane; (2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(2-thiazolyl)-4-thiazolyl)methyl)aminoc arbonyl)valinyl)amino)-2-(N-((5-oxazolyl)methoxycarbonyl)amino)-1,6-dipheny l-3-hydroxyhexane; (2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(2-thiazolyl)methyl-4-thiazolyl)methyl) amino)carbonyl)valinyl)amino)-2-(N-((5-oxazolyl)methoxycarbonyl)amino)-1,6- diphenyl-3-hydroxyhexane; and (2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(1-pyrrolidinyl)-4-thiazolyl)methyl)ami no)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-di phenyl-3-hydroxyhexane; 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) heterocyclic wherein the heterocyclic is selected from aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl and wherein the heterocyclic 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 or benzyloxy and C.sub.1 -to-C.sub.6 -thioalkoxy or benzyl-S-- and (ii) (heterocyclic)-C.sub.1 -to-C.sub.6 -alkyl wherein heterocyclic is defined as above; n is 1,2 or 3; R.sub.2 is hydrogen or C.sub.1 -to-C.sub.6 -loweralkyl; R.sub.4 and R.sub.4a are independently selected from 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.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 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) heterocyclic wherein the heterocyclic is selected from aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl and wherein the heterocyclic is unsubstituted or substituted with a substituent selected from halo, loweralkyl, hydroxy, alkoxy and thioalkoxy and (ii) (heterocyclic)alkyl wherein heterocyclic is defined as above; 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--. |