Details for Patent: 5,977,062

Title:	Glycopeptide antibiotic derivatives
Abstract:	The present invention provides glycopeptide antibiotic derivative compounds. These derivative compounds possess antibacterial activity against a wide variety of bacteria, including activity against vancomycin-resistant isolates. Methods of making and using these glycopeptide antibiotic derivative compounds are also provided.
Inventor(s):	Cooper; Robin D. G. (Indianapolis, IN), Huff; Bret E. (Mooresville, IN), Nicas; Thalia I. (Indianapolis, IN), Quatroche; John T. (Indianapolis, IN), Rodriguez; Michael J. (Indianapolis, IN), Snyder; Nancy J. (Charlottesville, IN), Staszak; Michael A. (Indianapolis, IN), Thompson; Richard C. (Frankfort, IN), Wilkie; Stephen C. (Indianapolis, IN), Zweifel; Mark J. (Indianapolis, IN)
Assignee:	Eli Lilly and Company (Indianapolis, IN)
Filing Date:	Apr 17, 1998
Application Number:	09/062,235
Claims:	1. A compound of the formula: ##STR9## wherein X is hydrogen or chloro; R and R.sup.6 are 4-epi-vancosaminyul; R.sup.7 is (C.sub.1 -C.sub.12 alkyl)-R.sup.8 and is attached to the amino group of R.sup.6 ; and R.sup.8 is a group of the formula ##STR10## wherein q is 0 to 4; R.sup.12 is independently selected from the group consisting of: (i) halo, (ii) nitro, (iii) (C.sub.1 -C.sub.6)alkyl, (iv) (C.sub.1 -C.sub.6)alkoxy, (v) halo-(C.sub.1 -C.sub.6)alkyl, (vi) halo-(C.sub.1 -C.sub.6)alkoxy, (vii) hydroxy, and (vii) (C.sub.1 -C.sub.6)thioalkyl; r is 1 to 5; provided that the sum of q and r is no greater than 5; Z is selected from the group consisting of: (i) a single bond, (ii) divalent (C.sub.1 -C.sub.6)alkyl unsubstituted or substituted with hydroxy, (C.sub.1 -C.sub.6)alkyl, or (C.sub.1 -C.sub.6)alkoxy, (iii) divalent (C.sub.2 -C.sub.6)alkenyl, (iv) divalent (C.sub.2 -C.sub.6)alkynyl, or (v) a group of the formula --(C(R.sup.14).sub.2).sub.s --R.sup.15 -- or --R.sup.15 --(C(R.sup.14).sub.2).sub.s --, wherein s is 0-6; wherein each R.sup.14 substituent is independently selected from hydrogen, (C.sub.1 -C.sub.6)-alkyl, or (C.sub.4 -C.sub.10) cycloalkyl; and R.sup.15 is selected from --O--, --S--, --SO--, --SO.sub.2, --SO.sub.2 O--, --C(O)--, --OC(O)--, --C(O)O--, --NH--, --N(C.sub.1 -C.sub.6 alkyl)-, --C(O)NH--, --NHC(O)--, and N.dbd.N; R.sup.13 is independently selected from the group consisting of: (i) (C.sub.4 -C.sub.10)heterocyclyl, (ii) heteroaryl, (iii) (C.sub.4 -C.sub.10)cycloalkyl unsubstituted or substituted with (C.sub.1 -C.sub.6)alkyl, and (iv) phenyl unsubstituted or substituted with 1 to 5 substituents independently selected from: halo, hydroxy, nitro, (C.sub.1 -C.sub.10) alkyl, (C.sub.1 -C.sub.10)alkoxy, halo-(C.sub.1 -C.sub.3)alkoxy, halo-(C.sub.1 -C.sub.3)alkyl, (C.sub.1 -C.sub.3)alkoxyphenyl, phenyl, phenyl-(C.sub.1 -C.sub.3)alkyl, (C.sub.1 -C.sub.6)alkoxyphenyl, phenyl-(C.sub.2 -C.sub.3)alkynyl, and (C.sub.1 -C.sub.6)alkylphenyl; or a salt thereof. 2. A compound of claim 1 wherein R.sup.7 .dbd.--CH.sub.2 --R.sup.8. 3. A compound of claim 2 wherein R.sup.13 =heteroaryl. 4. The compound of claim 3 which is 4-(2-thienyl)benzyl A82846B or a salt thereof. 5. A compound of claim 2 wherein R.sup.13 =phenyl or substituted phenyl as defined. 6. A compound of claim 2 selected from the group consisting of: chlorophenylbenzyl-A82846B, phenylbenzyl-A82846B, benzylbenzyl-A82846B, methylphenylbenzyl-A82846B, pentylphenylbenzyl-A82846B, methoxyphenylbenzyl-A82846B, pentoxyphenylbenzyl-A82846B, nitrophenoxybenzyl-A82846B, fluorophenylbenzyl-A82846B, phenyl-ethynylbenzyl-A82846B, phenoxybenzyl-A82846B, benzyloxybenzyl-A82846B, nitrophenylbenzyl-A82846B, chlorophenoxybenzyl-A82846B, chlorobenzyloxybenzyl-A82846B, butylphenoxybenzyl-A82846B, trifluoromethylphenoxybenzyl-A82846B, dichlorophenoxybenzyl-A82846B, nitrobenzyloxybenzyl-A82846B, benzoyloxybenzyl-A82846B, cyclohexyloxybenzyl-A82846B, cyclohexanoyloxybenzyl-A82846B, thiophenylbenzyl-A82846B, chlorophenylsulfonylbenzyl-A82846B, cyclohexylbenzyl-A82846B, trifluoromethylphenylbenzyl-A82846B, butylphenylthiobenzyl-A82846B, and bromophenylbenzyl-A82846B, or a salt thereof. 7. The compound of claim 1 which is 4-phenylbenzyl A82846B or a salt thereof. 8. A pharmaceutical composition comprising a compound of claim 1, associated with one or more pharmaceutically acceptable carriers therefor. 9. A pharmaceutical composition comprising a compound of claim 2, associated with one or more pharmaceutically acceptable carriers therefor. 10. A pharmaceutical composition comprising a compound of claim 3, associated with one or more pharmaceutically acceptable carriers therefor. 11. A pharmaceutical composition comprising a compound of claim 4, associated with one or more pharmaceutically acceptable carriers therefor. 12. A pharmaceutical composition comprising a compound of claim 5, associated with one or more pharmaceutically acceptable carriers therefor. 13. A pharmaceutical composition comprising a compound of claim 6, associated with one or more pharmaceutically acceptable carriers therefor. 14. A pharmaceutical composition comprising a compound of claim 7, associated with one or more pharmaceutically acceptable carriers therefor. 15. A method of treating a susceptible bacterial infection which comprises administering an antibacterially effective amount of a composition of claim 8, to a host in need of such treatment. 16. A method of treating a susceptible bacterial infection which comprises administering an antibacterially effective amount of a composition of claim 9, to a host in need of such treatment. 17. A method of treating a susceptible bacterial infection which comprises administering an antibacterially effective amount of a composition of claim 10, to a host in need of such treatment. 18. A method of treating a susceptible bacterial infection which comprises administering an antibacterially effective amount of a composition of claim 11, to a host in need of such treatment. 19. A method of treating a susceptible bacterial infection which comprises administering an antibacterially effective amount of a composition of claim 12, to a host in need of such treatment. 20. A method of treating a susceptible bacterial infection which comprises administering an antibacterially effective amount of a composition of claim 13, to a host in need of such treatment. 21. A method of treating a susceptible bacterial infection which comprises administering an antibacterially effective amount of a composition of claim 14, to a host in need of such treatment. 22. A method of claim 15 wherein the bacterial infection comprises vancomycin-resistant enterococci. 23. The method of claim 16 wherein the bacterial infection comprises vancomycin-resistant enterococci. 24. The method of claim 17 wherein the bacterial infection comprises vancomycin-resistant enterococci. 25. The method of claim 18 wherein the bacterial infection comprises vancomycin-resistant enterococci. 26. The method of claim 19 wherein the bacterial infection comprises vancomycin-resistant enterococci. 27. The method of claim 20 wherein the bacterial infection comprises vancomycin-resistant enterococci. 28. The method of claim 21 wherein the bacterial infection comprises vancomycin resistant enterococci. 29. A process for the preparation of a compound of claim 1 which comprises: (a) reacting a compound of the formula ##STR11## wherein X is hydrogen or chloro, and R and R.sup.1 are 4-epi-vancosaminyl, with an aldehyde corresponding to the group R.sup.7 as defined in claim 1, in methanol at about 25.degree. C. to about 100.degree. C.; (b) continuing the reaction until formation of a Schiff's base; and (c) reducing the Schiff's base by addition of a metal borohydride to the mixture at about 25.degree. C. to about 100.degree. C. 30. The process of claim 29, wherein the aldehyde is p-phenoxybenzaldehyde. 31. The process of claim 29 wherein the aldehyde is p-phenylbenzaldehyde. 32. A process for the preparation of a compound of claim 1 which comprises reacting in a polar solvent at about 25.degree. C. to about 100.degree. C.: i) a glycopeptide antibiotic of the formula: ##STR12## wherein X is hydrogen or chloro and R and R.sup.1 are 4-epi-vancosaminyl, with ii) an aldehyde corresponding to the group R.sup.7 as defined in claim 1, in the presence of iii) a reducing agent selected from a metal borohydride, and a homogeneous or heterogeneous catalytic hydrogenation agent or agents; for a time sufficient to produce a compound of claim 1. 33. The process of claim 32 wherein the reaction is carried out for about 20 to 28 hours at a temperature of about 60.degree. C. to about 70.degree. C., and the reducing agent is sodium cyanoborohydride. 34. The process of claim 32 wherein the glycopeptide antibiotic is A82846B.