Details for Patent: 6,887,976
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Title: | Glycopeptide phosphonate derivatives |
Abstract: | Disclosed are glycopeptides that are substituted with one or more substituents each comprising one or more phosphono groups; and pharmaceutical compositions containing such glycopeptide derivatives. The disclosed glycopeptide derivatives are useful as antibacterial agents. |
Inventor(s): | Leadbetter; Michael R. (San Leandro, CA), Linsell; Martin S. (San Mateo, CA) |
Assignee: | Theravance, Inc. (South San Francisco, CA) |
Filing Date: | Sep 24, 2003 |
Application Number: | 10/669,778 |
Claims: | 1. A process for preparing a compound of the formula: ##STR9## or a salt thereof; wherein R.sup.20 is --R.sup.a --Y--R.sup.b -(Z).sub.x or --R.sup.f ; Y is 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; each R.sup.a is independently selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, alkynylene and substituted alkynylenc; each R.sup.b is independently selected from the group consisting of a covalent bond, alkylene, substituted alkylene, alkenylene, substituted allenylene, 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.f is 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; and x is 1 or 2; the process comprising reacting a compound of the formula: ##STR10## or a salt thereof, with formaldehyde and H.sub.2 N--R.sup.a --P(O)(OH).sub.2 under basic conditions. 2. The process of claim 1, wherein R.sup.20 is --R.sup.a --Y--R.sup.b -(Z).sub.x and R.sup.a is alkylene. 3. The process of claim 2, wherein R.sup.b is alkylene. 4. The process of claim 3, wherein Z is hydrogen. 5. The process of claim 4, wherein Y is --NH--. 6. The process of claim 1, wherein R.sup.20 is selected from the group consisting of: --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--(C.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; and --CH.sub.2 CH.sub.2 CH.sub.2 --NHSO.sub.2 -4-(naphth-2-yl)-Ph. 7. The process of claim 1, wherein R.sup.20 is --CH.sub.2 CH.sub.2 --NH--(CH.sub.2).sub.9 CH.sub.3. 8. The process of claim 1, wherein R.sup.20 is --R.sup.f and R.sup.f is alkyl. 9. The process of claim 1, wherein R.sup.20 is 4-(4-chlorophenyl)benzyl or 4-(4chlorobenzyloxy)benzyl. 10. The process of claim 1, wherein R.sup.a in H.sub.2 N--R.sup.a --P(O)(OH).sub.2 is alkylene. 11. The process of claim 1, wherein H.sub.2 N--R.sup.a --P(O)(OH).sub.2 is H.sub.2 N--CH.sub.2 --P(O)(OH).sub.2. 12. A process for preparing a compound of the formula: ##STR11## or a salt thereof; the process comprising reacting a compound of the formula: ##STR12## or a salt thereof, with formaldehyde and H.sub.2 N--CH.sub.2 --P(O)(OH).sub.2 under basic conditions. 13. The process of claim 12, wherein the basic conditions are produced by adding diisopropylethylamine. 14. The process of claim 12, wherein the reaction is conducted in acetonitrile and water. |