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Details for Patent: 5,977,062

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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.
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