Details for Patent: 6,150,530
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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 Leung (Gurnee, IL), Zhao; Chen (Gurnee, IL), Sowin; Thomas J. (Grayslake, IL), Reno; Daniel S. (Kenosha, WI), Haight; Anthony R. (Park City, IL) |
| Assignee: | Abbott Laboratories (Abbott Park, IL) |
| Filing Date: | Dec 08, 1998 |
| Application Number: | 09/207,881 |
| Claims: | 1. A process for the preparation of a compound of the formula: ##STR18## wherein R.sub.1 is monosubstituted thiazolyl, monosubstituted oxazolyl, monosubstituted isoxazolyl or monosubstituted isothiazolyl wherein the substituent is selected from (i) C.sub.1 - to -C.sub.6 -loweralkyl, (ii) C.sub.1 -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, -S-benzyl and C.sub.1 - to -C.sub.6 -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 -S-benzyl; 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 and R.sub.4a are independently selected from phenyl, thiazolyl and oxazolyl wherein the phenyl, 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 -S-benzyl; R.sub.6 is hydrogen or C.sub.1 - to -C.sub.6 -loweralkyl; R.sub.7 is thiazolyl, oxazolyl, isoxazolyl or isothiazolyl wherein the thiazolyl, oxazolyl, isoxazolyl or isothiazolyl ring is unsubstituted or substituted with 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; or a pharmaceutically acceptable salt thereof, comprising reaction of a compound of the formula: ##STR19## or a salt thereof wherein R.sub.4, R.sub.4a, R.sub.6 and R.sub.7 are as defined above with an activated ester derivative of a compound of the formula: ##STR20## wherein R.sub.1, R.sub.2, R.sub.3, Z and n are as defined above. 2. The process of claim 1 wherein R.sub.1 is C.sub.1 - to -C.sub.6 -loweralkyl-substituted thiazolyl, R.sub.2 is hydrogen, R.sub.3 is C.sub.1 - to -C.sub.6 -loweralkyl, R.sub.4a and R.sub.4 are phenyl, R.sub.6 is hydrogen, R.sub.7 is thiazolyl and n is 1. 3. The process of claim 2 wherein Z is --N(CH.sub.3)--. 4. The process of claim 1 wherein R.sub.1 is isopropyl-substituted thiazolyl, R.sub.2 is hydrogen, R.sub.3 is isopropyl, R.sub.4a and R.sub.4 are phenyl, R.sub.6 is hydrogen, R.sub.7 is thiazolyl, n is 1 and Z is --N(CH.sub.3)--. 5. The process of claim 1 wherein the activated ester derivative is an ester derived from N-hydroxysuccinimide, an ester derived from N-hydroxyphthalimide, an ester derived from N-hydroxybenzotriazole, an ester derived from N-hydroxy-5-norbornene-2,3-dicarboxamide or an ester derived from 2,4,5-trichlorophenol. 6. A process for the preparation of (2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)car bonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl -3-hydroxyhexane or a pharmaceutically acceptable salt thereof, comprising reacting (2S,3S,5S)-5-(amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-dipheny l-3-hydroxyhexane or a salt thereof with an activated ester derivative of N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine. 7. The process of claim 6 wherein the activated ester derivative is an ester derived from N-hydroxysuccinimide, an ester derived from N-hydroxyphthalimide, an ester derived from N-hydroxybenzotriazole, an ester derived from N-hydroxy-5-norbornene-2,3-dicarboxamide or an ester derived from 2,4,5-trichlorophenol. 8. The process of claim 6 wherein the activated ester derivative is an ester derived from N-hydroxysuccinimide. 9. The process of claim 6 wherein the activated ester derivative is an ester derived from N-hydroxyphthalimide. 10. The process of claim 6 wherein the activated ester derivative is an ester derived from N-hydroxybenzotriazole. 11. The process of claim 6 wherein the activated ester derivative is an ester derived from N-hydroxy-5-norbornene-2,3-dicarboxamide. 12. The process of claim 6 wherein the activated ester derivative is an ester derived from 2,4,5-trichlorophenol. 13. An activated ester derivative of a compound of the formula: ##STR21## or a salt thereof wherein R.sub.1 is monosubstituted thiazolyl, monosubstituted oxazolyl, monosubstituted isoxazolyl or monosubstituted isothiazolyl wherein the substituent is selected from (i) C.sub.1 - to -C.sub.6 -loweralkyl, (ii) C.sub.1 - 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, -S-benzyl and C.sub.1 - to -C.sub.6 -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 -S-benzyl; 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; 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 salt thereof. 14. The compound of claim 13 wherein R.sub.1 is C.sub.1 - to -C.sub.6 -loweralkyl-substituted thiazolyl, R.sub.2 is hydrogen, R.sub.3 is C.sub.1 - to -C.sub.6 -loweralkyl and n is 1. 15. The compound of claim 14 wherein Z is --N(CH.sub.3)--. 16. The compound of claim 13 wherein R.sub.1 is isopropyl-substituted thiazolyl, R.sub.2 is hydrogen, R.sub.3 is isopropyl, n is 1 and Z is --N(CH.sub.3)--. 17. The compound of claim 13 wherein the activated ester derivative is an ester derived from N-hydroxysuccinimide, an ester derived from N-hydroxyphthalimide, an ester derived from N-hydroxybenzotriazole, an ester derived from N-hydroxy-5-norbornene-2,3-dicarboxamide or an ester derived from 2,4,5-trichlorophenol. 18. An activated ester derivative of N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine; or a salt thereof. 19. The compound of claim 18 wherein the activated ester derivative is an ester derived from N-hydroxysuccinimide, an ester derived from N-hydroxyphthalimide, an ester derived from N-hydroxybenzotriazole, an ester derived from N-hydroxy-5-norbornene-2,3-dicarboxamide or an ester derived from 2,4,5-trichlorophenol. 20. The compound of claim 18 wherein the activated ester derivative is an ester derived from N-hydroxysuccinimide. 21. The compound of claim 18 wherein the activated ester derivative is an ester derived from N-hydroxyphthalimide. 22. The compound of claim 18 wherein the activated ester derivative is an ester derived from N-hydroxybenzotriazole. 23. The compound of claim 18 wherein the activated ester derivative is an ester derived from N-hydroxy-5-norbornene-2,3-dicarboxamide. 24. The compound of claim 18 wherein the activated ester derivative is an ester derived from 2,4,5-trichlorophenol. |
