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Details for Patent: 6,693,199

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Details for Patent: 6,693,199

Title: Method of making HIV protease inhibitors
Abstract:A method of making HIV protease inhibitors of general formula (1): ##STR1## These HIV compounds inhibit or block the biological activity of the HIV protease enzyme, causing the replication of the HIV virus to terminate. These compounds, as well as pharmaceutical compositions that contain these compounds and optically other antiviral agents as active ingredients, are suitable for treating patients or hosts infected with the HIV virus, which is known to cause AIDS.
Inventor(s): Dressman; Bruce A. (Indianapolis, IN), Fritz; James E. (Greenwoode, IN), Hammond; Marlys (Pasadena, CA), Hornback; William J. (Indianapolis, IN), Kaldor; Stephen W. (Indianapolis, IN), Kalish; Vincent J. (San Diego, CA), Munroe; John E. (Indianapolis, IN), Reich; Siegfried Heinz (San Diego, CA), Tatlock; John H. (Poway, CA), Shepherd; Timothy A. (Indianapolis, IN), Rodriguez; Michael J. (Indianapolis, IN)
Assignee: Agouron Pharmaceuticals, Inc. (San Diego, CA)
Filing Date:Nov 21, 2002
Application Number:10/300,638
Claims:1. A method of making a compound of formula (1): ##STR134##

wherein: Q.sub.1 and Q.sub.2 are independently selected from hydrogen and substituted and unsubstituted alkyl and aryl, and Q.sub.1 and Q.sub.2 may form a ring with G; Q.sub.3 is selected from mercapto and substituted and unsubstituted alkoxyl, aryloxyl, thioether, amino, alkyl, cycloalkyl, saturated and partially saturated heterocycle, and aryl; Q.sub.4 -Q.sub.8 are independently selected from hydrogen, hydroxyl, mercapto, nitro, halogen, --O--J, wherein J is a substituted or unsubstituted hydrolyzalble group, and substituted and unsubstituted alkoxyl, aryloxyl, thioether, acyl, sulfinyl, sulfonyl, amino, alkyl, cycloalkyl, saturated and partially saturated heterocycle and aryl, and further wherein any one of Q.sub.4 -Q.sub.8 may be a member of a spiro ring and any two of Q.sub.4 -Q.sub.8 may together be members of a ring; Y and G are independently selected from oxygen, --NH, --N--alkyl, sulfur, selenium, and two hydrogen atoms; D is carbon or nitrogen; E is carbon or nitrogen; Q.sub.9 is selected from hyrogen, halogen, hydroxyl, mercapto, and substituted and unsubstituted alkoxyl, aryloxyl, thioether, amino, alkyl, and aryl, wherein Q.sub.9 may form part of a ring; A is a carbocycle or heterocycle, which is optionally further substituted; and B is a carbocycle or heterocycle, which is optionally further substituted, said method comprising reacting a compound of formula (IA): ##STR135##

with a compound of formula (IB): ##STR136##

to obtain the compound of formula (1).

2. The method according to claim 1, wherein the compound of formula (IA) is reacted with the compound of formula (IB) in an aprotic solvent or a mixture of aprotic solvents.

3. The method according to claim 2, wherein the aprotic solvent is tetrahydrofuran, dimethylformamide or a mixture thereof.

4. The method according to claim 1, wherein the compound of formula (IA) is reacted with the compound of formula (IB) in the presence of a promoting agent, a coupling reagent or both.

5. The method according to claim 4, wherein the promoting agent is hydroxybenzotriazole hydrate.

6. The method according to claim 4, wherein the coupling reagent is selected from the group consisting of a carbodiimide, an imidazole, bis(2-oxo-3-oxazolidinyl)phosphinic chloride and N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline.

7. The method according to claim 6, wherein the carbodiimide is dicyclohexylcarbodiimide or N,N'-diethylcarbodiimide.

8. The method according to claim 7, wherein the carbodiimide is dicyclohexylcarbodiimide.

9. The method according to claim 6, wherein the imidizole is carbonyldiimidazole.

10. The method according to claim 1, wherein the compound of formula (IA) is reacted with an equimolar portion of the compound of formula (IB).

11. The method according to claim 1, wherein the reaction is carried out at a temperature from about -30.degree. C. to about 25.degree. C.

12. The method according to claim 1, further comprising a step of isolating the compound of formula (1) formed in the reaction by (i) crystallization and collection by filtration; or (ii) extraction, evaporation or decantation.

13. The method according to claim 1, further comprising a step of purifying the compound of formula (1) formed in the reaction.

14. The method according to claim 13, further comprising purifying the compound of formula (1) formed in the reaction by crystallization or chromatography over a solid support.

15. The method according to claim 14, wherein the solid support is silica gel or alumina.

16. The method of making a compound of formula (4): ##STR137##

comprising: deprotecting a compound of formula (5): ##STR138##

and reacting the deprotected compound with a compound of formula (3): ##STR139##

to obtain the compound of formula (4).

17. The method according to claim 16, wherein the deprotected compound is reacted with the compound of formula (3) in the presence of 1-hydroxybenzotriazole hydrate.

18. The method according to claim 16, further comprising a step of purifying the compound of formula (4) formed in the reaction.

19. The method according to claim 18, further comprising purifying the compound of formula (4) formed in the reaction by radial chromatography.

20. A method of making a compound of formula (4): ##STR140##

comprising reacting a compound of formula (3): ##STR141##

with a compound of formula (6): ##STR142##

to obtain the compound of formula (4).

21. The method according to claim 20, wherein the compound of formula (3) is reacted with the compound of formula (6) in the presence of 1-hydroxybenzotriazole hydrate.

22. The method according to claim 20, further comprising a step of purifying the compound of formula (4) formed in the reaction.

23. The method according to claim 22, further comprising purifying the compound of formula (4) formed in the reaction by radial chromatography.
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