Details for Patent: 6,620,781

Title:	Glycopeptide carboxy-saccharide derivatives
Abstract:	Disclosed are glycopeptide derivatives substituted at the C-terminus and/or the R-terminus with a substituent that comprises one or more saccharide groups and a carboxy group; and pharmaceutical compositions containing such glycopeptide derivatives. The disclosed glycopeptide derivatives are useful as antibacterial agents.
Inventor(s):	Linsell; Martin S. (San Mateo, CA), Fatheree; Paul R. (San Francisco, CA), Leadbetter; Michael R. (San Leandro, CA), Zhu; Yan (Foster City, CA), Judice; J. Kevin (El Granada, CA)
Assignee:	Theravance, Inc. (South San Francisco, CA)
Filing Date:	May 01, 2001
Application Number:	09/847,052
Claims:	1. A glycopeptide comprising a carboxy terminus, wherein the glycopeptide is substituted at the carboxy-terminus with a substituent comprising a dicarboxylic acid in which one of the carboxylic acid groups is coupled with a saccharide. 2. A glycopeptide comprising a 1,3-dihydroxyphenyl moiety, wherein the glycopeptide is substituted at the 2-position of the 1,3-dihydroxyphenyl moiety with a substituent comprising a dicarboxylic acid in which one of the carboxylic acid groups is coupled with a saccharide. 3. The glycopeptide of claim 1 wherein the substituent is a substituent of formula III: ##STR13## wherein one of R.sup.g and R.sup.h is a saccharide, and the other of R.sup.g and R.sup.h is OH. 4. The glycopeptide of claim 2 wherein the substituent is a substituent of formula IV: ##STR14## wherein one of R.sup.m and R.sup.n is a saccharide, and the other is OH. 5. The A glycopeptide comprising a 1,3-dihydroxyphenyl moiety, wherein the glycopeptide is substituted at the 2-position of the 1,3-dihydroxyphenyl moiety with a substituent of formula V: ##STR15## 6. A glycopeptide which is a compound of formula I: ##STR16## wherein: R.sup.1 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic and --R.sup.a --Y--R.sup.b --(Z).sub.x ; or R.sup.1 is a saccharide group optionally substituted with --R.sup.a --Y--R.sup.b --(Z).sub.x,R.sup.f, --C(O)R.sup.f, or --C(O)--R.sup.a --Y--R.sup.b --(Z).sub.x ; R.sup.2 is hydrogen or a saccharide group optionally substituted with --R.sup.a --Y--R.sup.b --(Z).sub.x, R.sup.f, --C(O)R.sup.f, or --C(O)--R.sup.a --Y--R.sup.b --(Z).sub.x ; R.sup.3 is --OR.sup.c, --NR.sup.c R.sup.c, --O--R.sup.a --Y--R.sup.b --(Z).sub.x, --NR.sup.c --R.sup.a --Y--R.sup.b --(Z).sub.x, --NR.sup.c R.sup.e, or --O--R.sup.e, or R.sup.3 is a is a substituent that comprises a saccharide group and a carboxy group; R.sup.4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, --R.sup.a --Y--R.sup.b --(Z).sub.x, --C(O)R.sup.d and a saccharide group optionally substituted with --R.sup.a --Y--R.sup.b --(Z).sub.x, R.sup.f, --C(O)R.sup.f, or --C(O)--R.sup.a --Y--R.sup.b --(Z).sub.x ; R.sup.5 is selected from the group consisting of hydrogen, halo, --CH(R.sup.c)--NR.sup.c R.sup.c, --CH(R.sup.c)--NR.sup.c R.sup.e, --CH(R.sup.c)--NR.sup.c --R.sup.a --Y--R.sup.b --(Z).sub.x, --CH(R.sup.c)--R.sup.x, and --CH(R.sup.c)--NR.sup.c --R.sup.a --C(.dbd.O)--R.sup.x, or R.sup.5 is a substituent that comprises a saccharide group and a carboxy group; R.sup.6 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, --R.sup.a --Y--R.sup.b --(Z).sub.x, --C(O)R.sup.d and a saccharide group optionally substituted with --NR.sup.c --R.sup.a --Y--R.sup.b --(Z).sub.x, or R.sup.5 and R.sup.6 can be joined, together with the atoms to which they are attached, to form a heterocyclic ring optionally substituted with --NR.sup.c R.sup.a --Y--R.sup.b --(Z).sub.x ; R.sup.7 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,--R.sup.a --Y--R.sup.b --(Z).sub.x, and --C(O)R.sup.d ; R.sup.8 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic; R.sup.9 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic; R.sup.10 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic; or R.sup.8 and R.sup.10 are joined to form --Ar.sup.1 --O--Ar.sup.2 --, where Ar.sup.1 and Ar.sup.2 are independently arylene or heteroarylene; R.sup.11 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic, or R.sup.10 and R.sup.11 are joined, together with the carbon and nitrogen atoms to which they are attached, to form a heterocyclic ring; R.sup.12 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic, --C(O)R.sup.d, --C(NH)R.sup.d, --C(O)NR.sup.c R.sup.c, --C(O)O.sup.d, --C(NH)NR.sup.c R.sup.c and --R.sup.a --Y--R.sup.b --(Z).sub.x, or R.sup.11 and R.sup.12 are joined, together with the nitrogen atom to which they are attached, to form a heterocyclic ring; R.sup.13 is selected from the group consisting of hydrogen and --OR.sup.14 ; R.sup.14 is selected from hydrogen, --C(O)R.sup.d and a saccharide group; each R.sup.a is independently selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, alkynylene and substituted alkynylene; each R.sup.b is independently selected from the group consisting of a covalent bond, alkylene, substituted alkylene, alkenylene, substituted alkenylene, alkynylene and substituted alkynylene, provided R.sup.b is not a covalent bond when Z is hydrogen; each R.sup.c is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic and --C(O)R.sup.d ; each R.sup.d is independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic; R.sup.e is a saccharide group; each R.sup.f is independently alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, or heterocyclic; R.sup.x is an N-linked amino saccharide or an N-linked heterocycle; X.sup.1, X.sup.2 and X.sup.3 are independently selected from hydrogen or chloro; each Y is independently selected from the group consisting of oxygen, sulfur, --S--S--, --NR.sup.c --, --S(O)--, --SO.sub.2 --, --NR.sup.c C(O)--, --OSO.sub.2 --, --OC(O)--, --NR.sup.c SO.sub.2 --, --C(O)NR.sup.c --, --C(O)O--, --SO.sub.2 NR.sup.c --, --SO.sub.2 O--, --P(O)(OR.sup.c)O--, --P(O)(OR.sup.c)NR.sup.c --, --OP(O)(OR.sup.c)O--, --OP(O)(OR.sup.c)NR.sup.c, --OC(O)O--, --NR.sup.c C(O)O--, --NR.sup.c C(O)NR.sup.c --, --OC(O)NR.sup.c --, --C(.dbd.O)--, and --NR.sup.c SO.sub.2 NR.sup.c --; each Z is independently selected from hydrogen, aryl, cycloalkyl, cycloalkenyl, heteroaryl and heterocyclic; n is 0, 1 or 2; and x is 1 or 2; or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof; provided at least one of R.sup.3 and R.sup.5 is a substituent comprising a dicarboxylic acid in which one of the carboxylic acid groups is coupled with a saccharide. 7. The glycopeptide of claim 6 wherein R.sup.1 is a saccharide group optionally substituted with --R.sup.a --Y--R.sup.b --(Z).sub.x, R.sup.f, --C(O)R.sup.f, or --C(O)--R.sup.a --Y--R.sup.b --(Z). 8. The glycopeptide of claim 6 wherein R.sup.1 is a saccharide group of the formula ##STR17## 9. The glycopeptide of claim 6 wherein R.sup.3 has the formula --N(R.sup.w)--R.sup.y --R.sup.x ; wherein R.sup.w is hydrogen or alkyl; R.sup.y is substituted alkylene, which is substituted with a carboxy group; and R.sup.x is a saccharide. 10. The glycopeptide of claim 6 wherein R.sup.5 is a substituent that comprises a saccharide group and a carboxy group having the formula --CH.sub.2 N(R.sup.w)--R.sup.y --R.sup.x ; wherein R.sup.w is hydrogen or alkyl; R.sup.y is substituted alkylene, which is substituted with a carboxy group; and R.sup.x is a saccharide. 11. The glycopeptide of claim 6 which is a compound of formula II: ##STR18## wherein: R.sup.19 is hydrogen; R.sup.20 is --R.sup.a --Y--R.sup.b --(Z).sub.x, R.sup.f, --C(O)R.sup.f, or --C(O)--R.sup.a --Y--R.sup.b --(Z).sub.x ; and R.sup.a, Y, R.sup.b, Z, x, R.sup.f, R.sup.3, and R.sup.5 have the values defined in claim 10; or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof; provided at least one of R.sup.3 and R.sup.5 is a substituent comprising a dicarboxylic acid in which one of the carboxylic acid groups is coupled with a saccharide. 12. The glycopeptide of claim 11 wherein R.sup.3 has the formula --N(R.sup.w)--R.sup.y --R.sup.x ; wherein R.sup.w is hydrogen or alkyl; R.sup.y is substituted alkylene, which is substituted with a carboxy group; and R.sup.x is a saccharide. 13. The glycopeptide of claim 12 wherein R.sup.3 is of the formula III: ##STR19## wherein one of R.sup.g and R.sup.h is a saccharide, and the other of R.sup.g and R.sup.h is OH. 14. The glycopeptide of claim 11 wherein R.sup.5 is a substituent that comprises a saccharide group and a carboxy group having the formula --CH.sub.2 N(R.sup.w)--R.sup.y --R.sup.x ; wherein R.sup.w is hydrogen or alkyl; R.sup.y is substituted alkylene, which is substituted with at least one carboxy group; and R.sup.x is a saccharide. 15. The glycopeptide of claim 14 wherein R.sup.5 is of the formula IV: ##STR20## wherein one of R.sup.m and R.sup.n is a saccharide, and the other is OH. 16. The glycopeptide of claim 11 wherein R.sup.5 is of the formula V: ##STR21## 17. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a glycopeptide of claim 1. 18. The pharmaceutical composition of claim 17, which comprises a cyclodextrin. 19. A method of treating a mammal having a bacterial disease, the method comprising administering to the mammal a therapeutically effective amount of a glycopeptide of claim 11. 20. A method of treating a mammal having a bacterial disease, the method comprising administering to the mammal a therapeutically effective amount of a glycopeptide of claim 6. 21. A method of treating a mammal having a bacterial disease, the method comprising administering to the mammal a therapeutically effective amount of a glycopeptide of claim 11. 22. A method of treating a mammal having a bacterial disease, the method comprising administering to the mammal a therapeutically effective amount of a pharmaceutical composition of claim 17. 23. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a glycopeptide of claim 2. 24. The pharmaceutical composition of claim 23, which comprises a cyclodextrin. 25. A method of treating a mammal having a bacterial disease, the method comprising administering to the mammal a therapeutically effective amount of a glycopeptide of claim 2. 26. A method of treating a mammal having a bacterial disease, the method comprising administering to the mammal a therapeutically effective amount of a pharmaceutical composition of claim 23.