Phosphonated rifamycins and uses thereof for the prevention and treatment of bone and joint infections

A compound of Formula (I) or a pharmaceutically acceptable salt, metabolite, solvate or prodrug thereof:

• wherein:
• A is a Rifamycin:
• L is a cleavable linker for coupling A to B;
• B is a phosphonated group selected from the group consisting of:
• wherein:
• each R* is independently selected from the group consisting of H, lower alkyl, cycloalkyl, aryl and heteroaryl, with the proviso that at least two R* are
• X is H, OH, NH2, or a halo group;
• and
• X1 are both H, or each;
• and
• n is 1, 2, 3, 4, 5, 6 or 7,
• wherein each B-L- is independently represented by the following Formula (BL1):
• wherein
• each
• and
• is independently selected from the group consisting of:
• T1 is selected from the group consisting of:
• each RB is independently selected from the group consisting of hydrogen,
• and CmHl, where m is an integer such that 0≦m≦6 and l is an integer ≦2m+1;
• each Q is independently nitro, chloro, bromo, iodo or fluoro;
• each RL is CmHl, where m is an integer such that 0≦m≦6 and l is an integer ≦2m+1;
• q is 2 or 3;
• y is an integer ≦10;
• and
• e and f are integers≧0 such that e+f=4.

A compound of Formula (I) or a pharmaceutically acceptable salt, metabolite, solvate or prodrug thereof:

• wherein:
• A is a Rifamycin;
• L is a cleavable linker for coupling A to B;
• B is a phosphorated group selected from the group consisting of:
• wherein:
• each R* is independently selected from the group consisting of H, lower alkyl, cycloalkyl, aryl and heteroaryl, with the proviso that at least two R* are H;
• X is H, OH, NH2, or a halo group;
• and
• X1 are both H, or each;
• and
• n is 1, 2, 3, 4, 5, 6 or 7,
• wherein each B-L- is independently represented by the following Formula (BL2):
• wherein
• is selected from the group consisting of:
• T1 is selected from the group consisting of:
• RC is RB, ORB or N(RB)2;
• X is —O—, —S— or —N(RB)—;
• each RB is independently selected from the group consisting of hydrogen,
• and CmHl, where m is an integer such that 0≦m≦6 and l is an integer ≦2m+1;
• each Q is independently nitro, chloro, bromo, iodo or fluoro;
• each RL is CmHl, where m is an integer such that 0≦m≦6 and l is an integer ≦2m+1;
• q is 2 or 3;
• y is an integer ≦10;
• and
• e and f are integers≧0 such that e+f=4.

A compound of Formula (I) or a pharmaceutically acceptable salt, metabolite, solvate or prodrug thereof:

• wherein:
• A is a Rifamycin;
• L is a cleavable linker for coupling A to B;
• B is a phosphonated group selected from the group consisting of:
• wherein:
• each R* is independently selected from the group consisting of H, lower alkyl, cycloalkyl, aryl and heteroaryl, with the proviso that at least two R* are H;
• X is H, OH, NH2, or a halo group;
• and
• Xt are both H, or each;
• and
• n is 1, 2, 3, 4, 5, 6 or 7,
• wherein each B-L- is independently represented by the following Formula (BL3):
• wherein
• is independently selected from the group consisting of:
• X1 is —O—, —S— or —N(RB)—;
• X2 is —N(RD)2, —ORD or —SRD;
• RD is hydrogen, RB or is selected from the group consisting of:
• RC is RB, ORB or N(RB)2;
• each RB is independently selected from the group consisting of hydrogen,
• and CmHl, where m is an integer such that 0≦m≦6 and l is an integer ≦2m+1;
• each Q is independently —SRc, —S(O)Rc, —S(O)2Rc, —CORc, nitro, chloro, bromo, iodo or fluoro;
• each RL is CmHl, where m is an integer such that 0≦m≦6 and l is an integer ≦2m+1;
• q is 2 or 3;
• y is an integer ≦10;
• e and f are integers≧0 such that e+f=4;
• and
• g and h are integers≧0 such that g+h=5.

A compound represented by Formula (II) or a pharmaceutically acceptable salt, metabolite, solvate or prodrug thereof:

• wherein:
• Q1 is H—, R1CO— or L1-, wherein R1 is a substituted or unsubstituted alkyl chain of 1-6 carbons;
• each Q2 is independently selected from the group consisting of H—, RxO— and L2O—, wherein Rx is H—, R1— or R1CO—, with R1 defined as above;
• each Q3 is independently selected from the group consisting of H— and L3-;
• is selected from the group consisting of Formulae IA1-IA9:
• wherein
• R2 is H—, a substituted or unsubstituted alkyl chain of 1-10 carbons or a dialkyl amino group, wherein said dialkyl amino group may be a substituted piperidine, a substituted morpholine or a substituted piperazine, wherein the substituent is one member selected from the group consisting of L4O—, L5S— and L6NR7—, wherein R7 is a substituted or unsubstituted alkyl chain of 1-7 carbons ;
• R3 is H—, a substituted or unsubstituted alkyl chain of 1-7 carbons or L7-;
• R4 is a hydroxyl group, a sulfhydryl group or a substituted or unsubstituted alkyl chain of 1-3 carbons, L8O— or L9S—;
• W1 is oxygen or —NR2, with R2 defined as above;
• W2 is a substituted or unsubstituted methylene, including
• wherein R5 and R6 are independently H— or a substituted or unsubstituted alkyl chain of 1-5 carbons, and Z′ is an oxygen atom, a sulfur atom, a substituted methylene, a carbonyl, —NR1 or —N(O)R1 where R1 is defined as above;
• E is a halogen or R2, where R2 is defined as above;
• Z is O, S or NR3, where R3 is defined as above;
• each L1, L2, L3, L4, L5, L6, L7, L8 and L9 is a group of Formula (Ia):
• wherein:
• each T is independently oxygen or sulfur;
• each R 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, amino, substituted amino, hydroxyl, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, and —Ra—Y—Rb—Y—Rb—B;
• W is a covalent bond or is selected from the group of
• each X is independently —O—, —S— or —N(R)—;
• each Q is independently nitro, chloro, bromo, iodo or fluoro;
• Z is selected from the group consisting of hydrogen, acyl, substituted acyl, aroyl, substituted aroyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryloxycarbonyl, substituted aryloxycarbonyl,
• each Ra is independently selected from the group consisting of a covalent bond, alkylene, substituted alkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, arylene, substituted arylene, —(CO)-alkylene-, —(CO)-(substituted alkylene)-, —(CO)- alkenylene-, —(CO)-(substituted alkenylene)-, —(CO)-alkynylene-, —(CO)-(substituted alkynylene)-, —(CO)-arylene- and —(CO)-(substituted arylene)-;
• each Rb is independently selected from the group consisting of a covalent bond, alkylene, substituted alkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, arylene and substituted arylene;
• each Y is independently selected from the group consisting of a covalent bond, —CH2—, —O—, —S—, —S—S—, —NRc—, —S(O)—, —SO2—, —NRcC(O)—, —OSO2—, —OC(O)—, —N(Rc)SO2—, —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—, —NRc(O)O—, —NRc(O)NRc—, —OC(O)NRc—, —C(O)—, and —N(W)SO2NRc—;
• 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;
• q is 2 or 3;
• r is 1, 2, 3, 4 or 5;
• w1 and w2 are each integers ≧0 such that their sum (w1+w2) is 1, 2 or 3;
• a, b, c, d are each integers >0 such that a+b+c+d<7;
• e and f are each integers >0 such that e+f=4;
• α is 0 or 1;
• and
• B is a phosphonated group selected from the group consisting of:
• wherein:
• each R* is independently selected from the group consisting of H, lower alkyl, cycloalkyl, aryl and heteroaryl, with the proviso that at least two R* are H;
• each X1 is independently selected from the group consisting of H, OH, NH2, and a halo group;
• with the proviso that at least one of R in Formula (Ia) is —Ra—Y—Rb—Y—Rb—B;
• with the further proviso that at least one of L1, L2, L3, L4, L5, L6, L7, L8 and L9 is present;
• and
• with the additional proviso that none of L1, L2, L3, L4, L5, L6, L7, L8 and L9 is one of the following structures:
• wherein:
• X, B, q, r, w1 and w2 are defined as above;
• each p is independently 0 or an integer ≦10;
• each RL independently H, ethyl or methyl;
• each Rz is independently H, ethyl or methyl;
• Ry is represented by CiHj, where i is an integer ≦20 and j is an integer ≦2i+1;
• and
• m is an integer <10.