Details for Patent: 6,770,621

Title:	Polyacid glycopeptide derivatives
Abstract:	Disclosed are derivatives of glycopeptides that are substituted at the C-terminus with a substituent that comprises two or more (e.g. 2, 3, 4, or 5) carboxy (CO.sub.2 H) groups; and pharmaceutical compositions containing such glycopeptide derivatives. The disclosed glycopeptide derivatives are useful as antibacterial agents.
Inventor(s):	Linsell; Martin S. (San Mateo, CA), Judice; J. Kevin (El Granada, CA)
Assignee:	Theravance, Inc. (South San Francisco, CA)
Filing Date:	May 01, 2001
Application Number:	09/847,041
Claims:	1. A glycopeptide substituted at the C-terminus with a substituent that comprises two or more carboxy groups; or a pharmaceutically acceptable salt, or stereoisomer, or prodrug thereof; provided the glycopeptide is not 1) teicoplanin A2 substituted at the C-terminus with a nitrogen-linked glutamic acid, 2) teicoplanin aglycon (TD) substituted at the C-terminus with a nitrogen-linked glutamic acid; or 3) a compound of formula II: ##STR11## a) wherein NR.sup.17 is nitrogen-linked aspartic acid; R.sup.18 is hydrogen; R.sup.19 is hydrogen; R.sup.20 is 2-(decylamino)ethyl; and R.sup.21 is hydrogen; b) wherein NR.sup.17 is nitrogen-linked aspartic acid; R.sup.18 is hydrogen; R.sup.19 is hydrogen; R.sup.20 is 2-(9-hydroxydecylamino)ethyl; and R.sup.21 is hydrogen; c) wherein R.sup.17 is 1,4-dicarboxybutyl; R.sup.18 is hydrogen; R.sup.19 is hydrogen; R.sup.20 is 2-(decylamino)ethyl; and R.sup.21 is hydrogen; d) wherein NR.sup.17 is nitrogen-linked aspartic acid; R.sup.18 is hydrogen; R.sup.19 is hydrogen; R.sup.20 is 2-(decylamino)ethyl; and R.sup.21 is --CH.sub.2 --N--(D-glucamine); e) wherein R.sup.17 is nitrogen-linked aspartic acid; R.sup.18 is hydrogen; R.sup.19 is hydrogen; R.sup.20 is 2-[4-(4-chlorobenzyloxy)benzylamino]ethyl; and R.sup.21 is hydrogen; f) wherein NR.sup.17 is 5-(2-carboxypyrrolidin-1-ylcarbonyl)-5-(2-carboxy-3-phenylpropylamino)pent ylamino; R.sup.18 is hydrogen; R.sup.19 is hydrogen; R.sup.20 is 2-(decylamino)ethyl; and R.sup.21 is hydrogen; g) wherein NR.sup.17 is nitrogen-linked aspartic acid; R.sup.18 is hydrogen; R.sup.19 is hydrogen; R.sup.20 is 2-(decylamino)ethyl; and R.sup.21 is --CH.sub.2 --N--(N--CH.sub.3 -D-glucamine); h) wherein NR.sup.17 is nitrogen-linked aspartic acid; R.sup.18 is hydrogen; R.sup.19 is hydrogen; R.sup.20 is 2-(decylamino)ethyl; and R.sup.21 is N--[2-(2-hydroxyethoxy)ethyl]-aminomethyl; or i) wherein NR.sup.17 is nitrogen-linked aspartic acid; R.sup.18 is hydrogen; R.sup.19 is hydrogen; R.sup.20 is 2-(4-isobutylbenzyl)ethyl; and R.sup.21 is N-[2-(2-hydroxyethoxy)ethyl]aminomethyl. 2. The glycopeptide of claim 1 wherein the substituent comprises two carboxy groups. 3. The glycopeptide of claim 2 wherein the substituent is a nitrogen-linked aspartic acid or a nitrogen linked glutamic acid. 4. The glycopeptide of claim 1 which is a compound of formula I: ##STR12## 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 a nitrogen-linked, oxygen-linked, or sulfur-linked substituent comprising two or more carboxy groups; 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.c, --CH(R.sup.c)--R.sup.x, --CH(R.sup.c)NR.sup.c --Ra--C(.dbd.O))--R.sup.x, and --CH(R.sup.c)--NR.sup.c --R.sup.a --Y--R.sup.b --(Z).sub.x ; 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, 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)OR.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 or --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 heterocyclic; X.sup.1, X.sup.2 and X.sup.3 are each 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, or stereoisomer, or prodrug thereof. 5. The glycopeptide of claim 4 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). 6. The glycopeptide of claim 4 wherein R.sup.1 is a saccharide group of the formula: ##STR13## wherein R.sup.15 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.16 is hydrogen or methyl. 7. The glycopeptide of claim 6 wherein R.sup.15 is --CH.sub.2 CH.sub.2 --NH--(CH.sub.2).sub.9 CH.sub.3 ; --CH.sub.2 CH.sub.2 CH.sub.2 --NH--(CH.sub.2).sub.8 CH.sub.3 ; --CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 --NH--(CH.sub.2).sub.7 CH.sub.3 ; --CH.sub.2 CH.sub.2 --NHSO.sub.2 --(CH.sub.2).sub.9 CH.sub.3 ; --CH.sub.2 CH.sub.2 --NHSO.sub.2 --(CH.sub.2).sub.11 CH.sub.3 ; --CH.sub.2 CH.sub.2 --S--(CH.sub.2).sub.8 CH.sub.3 ; --CH.sub.2 CH.sub.2 --S--(CH.sub.2).sub.9 CH.sub.3 ; --CH.sub.2 CH.sub.2 --S--(CH.sub.2).sub.10 CH.sub.3 ; --CH.sub.2 CH.sub.2 CH.sub.2 --S--(CH.sub.2).sub.8 CH.sub.3 ; --CH.sub.2 CH.sub.2 CH.sub.2 --S--(CH.sub.2).sub.9 CH.sub.3 ; --CH.sub.2 CH.sub.2 CH.sub.2 --S--(CH.sub.2).sub.3 --CH.dbd.CH--(CH.sub.2).sub.4 CH.sub.3 (trans); --CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 --S--(CH.sub.2).sub.7 CH.sub.3 ; --CH.sub.2 CH.sub.2 --S(O)--(CH.sub.2).sub.9 CH.sub.3 ;--CH.sub.2 CH.sub.2 --S--(CH.sub.2).sub.6 Ph; --CH.sub.2 CH.sub.2 --S--(CH.sub.2).sub.8 Ph; --CH.sub.2 CH.sub.2 CH.sub.2 --S--(CH.sub.2).sub.8 Ph; --CH.sub.2 CH.sub.2 --NH--CH.sub.2 -4-(4-Cl-Ph)-Ph; --CH.sub.2 CH.sub.2 --NH--CH.sub.2 -4-[4-(CH.sub.3).sub.2 CHCH.sub.2 -]-Ph; --CH.sub.2 CH.sub.2 --NH--CH.sub.2 -4-(4-CF.sub.3 -Ph)-Ph; --CH.sub.2 CH.sub.2 --S--CH.sub.2 -4-(4-Cl-Ph)-Ph; --CH.sub.2 CH.sub.2 --S(O)--CH.sub.2 -4-(4-Cl-Ph)-Ph; --CH.sub.2 CH.sub.2 CH.sub.2 --S--CH.sub.2 -4-(4-Cl-Ph)-Ph; --CH.sub.2 CH.sub.2 CH.sub.2 --S(O)--CH.sub.2 -4-(4-Cl-Ph)-Ph; --CH.sub.2 CH.sub.2 CH.sub.2 --S--CH.sub.2 -4-[3,4-di-Cl-PhCH.sub.2 O--)-Ph; --CH.sub.2 CH.sub.2 --NHSO.sub.2 --CH.sub.2 -4-[4-(4-Ph)-Ph]-Ph; --CH.sub.2 CH.sub.2 CH.sub.2 --NHSO.sub.2 --CH.sub.2 -4-(4-Cl-Ph)-Ph; --CH.sub.2 CH.sub.2 CH.sub.2 --NHSO.sub.2 --CH.sub.2 -4-(Ph-C.ident.C--) -Ph; --CH.sub.2 CH.sub.2 CH.sub.2 --NHSO.sub.2 -4-(4-Cl-Ph)-Ph; or --CH.sub.2 CH.sub.2 CH.sub.2 --NHSO.sub.2 -4-(naphth-2-yl)-Ph. 8. The glycopeptide of claim 6 wherein R.sup.3 comprises two carboxy groups. 9. The glycopeptide of claim 8 wherein R.sup.3 is a nitrogen-linked aspartic acid or a nitrogen linked glutamic acid. 10. The glycopeptide of claim 6 wherein R.sup.3 is a nitrogen-linked radical of formula III: ##STR14## wherein R.sup.8 is a saccharide group. 11. The glycopeptide of claim 10 wherein R.sup.8 is N-(D-glucamine) or N-(D-glucosamine). 12. The glycopeptide of claim 4 which is a compound of formula II: ##STR15## wherein: R.sup.17 is a dicarboxy-substituted alkyl group having from 3 to 10 carbon atoms; R.sup.18 is selected from the group consisting of hydrogen and alkyl; R.sup.19 is hydrogen; R.sup.20 is --R.sup.a --Y--R.sup.b --(Z).sub.x ; R.sup.21 is hydrogen; R.sup.a is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, alkynylene and substituted alkynylene; R.sup.b is 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; Y is selected from the group consisting of sulfur, --S(O)-- and --SO.sub.2 --; each Z is independently selected from hydrogen, aryl, cycloalkyl, cycloalkenyl, heteroaryl and heterocyclic; and x is 1 or 2; or a pharmaceutically acceptable salt, or stereoisomer, or prodrug thereof. 13. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 1. 14. The pharmaceutical composition of claim 13, which comprises a cyclodextrin. 15. 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 1. 16. 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 4. 17. 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 12. 18. 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 13.