Claims for Patent: 6,635,618

Summary for Patent: 6,635,618

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):	Michael R. Leadbetter, Martin S. Linsell
Assignee:	Cumberland Pharmaceuticals Inc
Application Number:	US09/847,042
Patent Claims:	1. A glycopeptide substituted with one or more substituents each comprising one or more phosphono groups; or a pharmaceutically acceptable salt, or stereoisomer, or prodrug thereof. 2. A glycopeptide comprising a carboxy-terminus, wherein the glycopeptide is substituted at the carboxy-terminus with a substituent comprising one or two phosphono groups. 3. 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 one or two phosphono groups. 4. The glycopeptide of claim 3, wherein the substituent is N-(phosphonomethyl)aminomethyl; N-(2-hydroxy(2-phosphonoethyl)aminomethyl; N-carboxymethyl-N-(phosphonomethyl)aminomethyl; N,N,-bis(phosphonomethyl)aminomethyl. or N-(3-phosphonopropyl)aminomethyl. 5. A glycopeptide of formula I: wherein: R1 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 —Ra—Y—Rb—(Z)x; or R1 is a saccharide group optionally substituted with —Ra—Y—Rb—(Z)x, Rf, —C(O)Rf, or —C(O)—Ra—Y—Rb—(Z)x; R2 is hydrogen or a saccharide group optionally substituted with —Ra—Y—Rb—(Z)x, Rf, —C(O)Rf, or —C(O)—Ra—Y—Rb—(Z)x; R3 is —ORc, —NRcRc, —O——Ra—Y—Rb—(Z)x, —NRc—Ra—Y—Rb—(Z)x, —NRcRe, or —O—Re; or R3 is a nitrogen-linked, oxygen-linked, or sulfur-linked substituent that comprises one or more phosphono groups; R4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, —Ra—Y—Rb—(Z)x, —C(O)Rd and a saccharide group optionally substituted with —Ra—Y—Rb—(Z)x, Rf, or —C(O)—Ra—Y—Rb—(Z)x, or R4 and R5 can be joined, together with the atoms to which they are attached, to form a heterocyclic ring optionally substituted with —NRc—Ra—Y—Rb—(Z)x; R5 is selected from the group consisting of hydrogen, halo, —CH(Rc)—NRcRc, —CH(Rc)—NRcRe, —CH(Rc)—NRc—Ra—Y—Rb—(Z)x, —CH(Rc)—Rx, —CH(Rc)—NRc—Ra—C(═O)—Rx, and a substituent that comprises one or more phosphono groups; R6 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, —Ra—Y—Rb—(Z)x, —C(O)Rd and a saccharide group optionally substituted with —Ra—Y—Rb—(Z)x, Rf, —C(O)Rf, or —C(O)—Ra—Y—Rb—(Z)x, or R5 and R6 can be joined, together with the atoms to which they are attached, to form a heterocyclic ring optionally substituted with —NRc—Ra—Y—Rb—(Z)x; R7 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, —Ra—Y—Rb—(Z)x, and —C(O)Rd; R8 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; R9 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; R10 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 R8 and R10 are joined to form —Ar1—O—Ar2—, where Ar1 and Ar2 are independently arylene or heteroarylene; R11 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 R10 and R11 are joined, together with the carbon and nitrogen atoms to which they are attached, to form a heterocyclic ring; R12 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)Rd, —C(NH)Rd, —C(O)NRcRc, —C(O)ORd, —C(NH)NRcRc, —Ra—Y—Rb—(Z)x, and —C(O)—Ra—Y—Rb—(Z)x, or R11 and R12 are joined, together with the nitrogen atom to which they are attached, to form a heterocyclic ring; R13 is selected from the group consisting of hydrogen or —OR14; R14 is selected from hydrogen, —C(O)Rd and a saccharide group; each Ra is independently selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, alkynylene and substituted alkynylene; each Rb is independently selected from the group consisting of a covalent bond, alkylene, substituted alkylene, alkenylene, substituted alkenylene, alkynylene and substituted alkynylene, provided Rb is not a covalent bond when Z is hydrogen; each Rc 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)Rd; each Rd 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; Re is a saccharide group; each Rf is independently alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, or heterocyclic; Rx is an N-linked amino saccharide or an N-linked heterocycle; X1, X2 and X3 are independently selected from hydrogen or chloro; each Y is independently selected from the group consisting of oxygen, sulfur, —S—S—, —NRc—, —S(O)—, —SO2, —NRcC(O)—, —OSO2—, —OC(O)—, —NRcSO2—, —C(O)NRc—, —C(O)O—, —SO2NRc, —SO2O—, —P(O)(ORc)O—, —P(O)(ORc)NRc—, —OP(O)(ORc)O—, —OP(O)(ORc)NRc—, —OC(O)O—, —NRcC(O)O—, —NRcC(O)NRc—, —OC(O)NRc, —C(═O)—, and —NRcSO2NRc—; each Z is independently selected from hydrogen, aryl, cycloalkyl, cycloalkenyl, heteroaryl and heterocyclic; n is 0, 1 or 2; and x is 1 or2; or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof; provided at least one of R3 and R5 is a substituent comprising one or more phosphono groups. 6. The glycopeptide of claim 5 wherein R1 is a saccharide group optionally substituted with —Ra—Y—Rb—(Z)x, Rf, —C(O)Rf, or —C(O)—Ra—Y—Rb—(Z). 7. The glycopeptide of claim 5 wherein R1 is a saccharide group of the formula: wherein R15 is —Ra—Y—Rb—(Z)x, Rf, —C(O)Rf, or —C(O)—Ra—Y—Rb—(Z)x; and R16 is hydrogen or methyl. 8. The glycopeptide of claim 6 wherein R2, R4, R6, and R7 are each hydrogen. 9. The glycopeptide of claim 8 wherein R3 is —OH. 10. The glycopeptide of claim 8 wherein R3 is a nitrogen-linked, oxygen-linked, or sulfur-linked substituent that comprises one or more phosphono groups. 11. The glycopeptide of claim 10 wherein R3 is a group of the formula —O—Ra—P(O)(OH)2, —S—Ra—P(O)(OH)2, or —NRc—Ra—P(O)(OH)2. 12. The glycopeptide of claim 8 wherein R5 is a group of the formula —CH(R21)—N(Rc)—Ra—P(O)(OH)2; wherein R21 is hydrogen or Rd. 13. The glycopeptide of claim 12 wherein R5 is —CH2—NH—Ra—P(O)(OH)2. 14. The glycopeptide of claim 5 which is a compound of formula II: wherein: R19 is hydrogen; R20 is —Ra—Y—Rb—(Z)x, Rf, —C(O)Rf, or —C(O)—Ra—Y—Rb—(Z)x; and Ra, Y, Rb, Z, x, Rf, R3, and R5 have the values defined in claim 5; or a pharmaceutically acceptable salt, or stereoisomer, or prodrug thereof; provided at least one of R3 and R5 is a substituent comprising one or more phosphono groups. 15. The glycopeptide of claim 14 wherein R3 is —OH. 16. The glycopeptide of claim 14 wherein R3 is a nitrogen-linked, oxygen-linked, or sulfur-linked substituent that comprises one or more phosphono groups. 17. The glycopeptide of claim 14 wherein R3 is a group of the formula —O—Ra—P(O)(OH)2, —S—Ra—P(O)(OH)2, or —NRc—Ra—P(O)(OH)2. 18. The glycopeptide of claim 14 wherein R5 is a group of the formula —(CH(R21)—N(Rc)—Ra—P(O)(OH)2; wherein R21 is hydrogen or Rd. 19. The glycopeptide of claim 14 wherein R20 is —CH2CH2—NH—(CH2)9CH3; —CH2CH2CH2—NH—(CH2)8CH3; —CH2CH2CH2CH2—NH—(CH2)7CH3; —CH2CH2—NHSO2—(CH2)9CH3; —CH2CH2—NHSO2—(CH2)11CH3; —CH2CH2—S—(CH2)8CH3; —CH2CH2—S—(CH2)9CH3; —CH2CH2—S—(CH2)10CH3; —CH2CH2CH2—S—(CH2)8CH3; —CH2CH2CH2—S—(CH2)9CH3; —CH2CH2CH2—S—(CH2)3—CH═CH—(CH2)4CH3 (trans); —CH2CH2CH2CH2—S—(CH2)7CH3; —CH2CH2—S(O)—(CH2)9CH3; —CH2CH2—S—(CH2)6Ph; —CH2CH2—S—(CH2)8Ph; —CH2CH2CH2—S—(CH2)8Ph; —CH2CH2—NH—CH2-4-(4-Cl—Ph)—Ph; —CH2CH2—NH—CH2-4-[4-(CH3)2CHCH2]—Ph; —CH2CH2—NH—CH2-4-(4-CF3—Ph)—Ph; —CH2CH2—S—CH2-4-(4-Cl—Ph)—Ph; —CH2CH2—S(O)—CH2-4-(4-Cl—Ph)—Ph; —CH2CH2CH2—S—CH2-4-(4-Cl—Ph)—Ph; —CH2CH2CH2—S(O)—CH2-4-(4-Cl—Ph)—Ph; —CH2CH2CH2—S—CH2-4-(3,4-di-Cl—PhCH2O—)—Ph; —CH2CH2—NHSO2—CH2-4-[4-(4-Ph)—Ph]—Ph; —CH2CH2CH2—NHSO2—CH2-4-(4-Cl—Ph)—Ph; —CH2CH2CH2—NHSO2—CH2-4-(Ph—C≡C—)—Ph; —CH2CH2CH2—NHSO2-4-(4-Cl—Ph)—Ph; or —CH2CH2CH2—NHSO2-4-(naphth-2-yl)—Ph. 20. The glycopeptide of claim 14 wherein R3 is —OH; R5 is N-(phosphonomethyl)-aminomethyl; R19 is hydrogen, and R20 is —CH2CH2—NH—(CH2)9CH3; or a pharmaceutically acceptable salt thereof. 21. The glycopeptide of claim 14 wherein R3 is —OH; R5 is N-(phosphonomethyl)-aminomethyl; R19 is hydrogen, and R20 is —CH2CH2—NH—(CH2)9CH3. 22. The glycopeptide of claim 20 which is the hydrochloride salt. 23. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a glycopeptide of any one of claims 1, 5, 14, and 20. 24. The pharmaceutical composition of claim 23, which comprises a cyclodextrin. 25. The composition of claim 24 wherein the cyclodextrin is hydroxypropyl-β-cyclodextrin. 26. The composition of claim 25 which comprises from about 250 mg to about 1000 mg of the glycopeptide and from about 250 mg to about 10 g hydroxypropyl-β-cyclodextrin. 27. The composition of claim 26 wherein the weight ratio of hydroxypropyl-β-cyclodextrin to the glycopeptide is from about 1:1 to about 10:1 inclusive. 28. A method for preparing a glycopeptide of claim 2, comprising derivatizing a corresponding starting glycopeptide wherein the carboxy-terminus is a carboxy group. 29. A method for preparing a glycopeptide of claim 3, comprising derivatizing a corresponding starting glycopeptide wherein the 2-position of the 1,3-dihydroxyphenyl moiety is unsubstituted. 30. 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 any one of claims 1, 5, 14, or 20. 31. 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.