Targeted therapeutics and uses thereof
View Patent ↗The invention features a method of delivering a drug to a diseased cell by linking the drug to a rifamycin derivative, compositions that include drug-rifamycin conjugates of the invention, and methods for treating disease using those compositions.
1. A compound of formula I:
wherein
(B) is a therapeutic drug;
(L) is a linker which forms linkage groups with rifamycin derivative (A) and therapeutic drug (B), wherein said linker (L) is described by any of formulas XXI–XXV:
wherein
Z 1 , Z 2 , Z 3 , and Z 4 are each, independently, selected from O, S, and NR 12 ;
Z 5 is selected from O, S, or NR 16 ;
R 12 is hydrogen or an alkyl group;
R 16 is hydrogen or an alkyl group;
R 15 is selected from hydrogen, alkyl, or heteroalkyl;
Y 1 , Y 2 , and Y 3 are each, independently, selected from carbonyl, thiocarbonyl, sulphonyl, and phosphoryl;
o, p, s, t, u, v, and w are each, independently, 0 or 1;
R 11 is a linear or branched alkyl of 1 to 10 carbon atoms, a linear or branched heteroalkyl of 1 to 10 atoms, a linear or branched alkene of 2 to 10 carbon atoms, a linear or branched alkyne of 2 to 10 carbon atoms, an aromatic residue of 5 to 10 carbon atoms, a cyclic system of 3 to 10 atoms, —(CH 2 CH 2 O) q CH 2 CH 2 — in which q is 1 to 4, or a chemical bond linking —(Z 1 ) o —(Y 1 ) u —(Z 2 ) s — to —(Z 3 ) t —(Y 2 ) v —(Z 4 ) p ;
R 13 represents a linear or branched alkyl of 1 to 10 carbon atoms, a linear or branched heteroalkyl of 1 to 10 atoms, a linear or branched alkene of 2 to 10 carbon atoms, a linear or branched alkyne of 2 to 10 carbon atoms, an aromatic residue of 5 to 10 carbon atoms, a cyclic system of 3 to 10 atoms, —(CH 2 CH 2 O) n CH 2 CH 2 — in which n is 1 to 4, or a chemical bond linking two nitrogens or two carbonyls;
R 14 is a linear or branched alkyl of 1 to 10 carbon atoms, a linear or branched heteroalkyl of 1 to 10 atoms, a linear or branched alkene of 2 to 10 carbon atoms, a linear or branched alkyne of 2 to 10 carbon atoms, an aromatic residue of 5 to 10 carbon atoms, a cyclic system of 3 to 10 atoms, —(CH 2 CH 2 O) n CH 2 CH 2 — in which n is 1 to 4, or a chemical bond linking —(Y 3 )—(Z 5 ) w — to the hydrazone carbon; and
X 4 is a hydrazone resulting from the condensation reaction of a drug B containing a hydrazide group and the precursor to linker XXV in which X 3 is the oxygen atom of a ketone or aldehyde; and
(A) is a rifamycin derivative of formula II:
wherein each methine proton, methylene proton, and methyl proton of formula II is optionally substituted by —OH or —OR*;
R represents a hydrogen atom, a hydroxyl group or —OR*;
R 1 represents a hydrogen atom, an acetyl group, or R*;
ring G is selected from formulas III–XI:
R′ represents a hydrogen atom or R*;
X 1 represents an oxygen atom or a sulfur atom;
H 1 represents an oxygen atom, N—R 3 or R*;
H 2 represents a group expressed by formulas XII or XIII:
R 2 represents a hydroxyl group, a sulfhydryl group, a hydrogen atom, or an alkyl group having 1 to 3 carbon atoms;
R 3 represents a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, or a group expressed by one of formulas XIV–XVI:
each R 4 is, independently, a hydrogen atom or an alkyl group having 1 to 7 carbon atoms;
each R 5 is, independently, an alkyl group having 1 to 7 carbon atoms, or two of R 5 in combination form a 3–8 membered cyclic system;
g represents an integer between 1 and 3;
R 6 and R 7 are each, independently, a hydrogen atom or an alkyl group having 1 to 3 carbon atoms;
X 2 represents an oxygen atom, a sulfur atom, a carbonyl group, or a group expressed by one of formulas XVII–XIX:
R 8 and R 9 are each, independently, a hydrogen atom, or an alkyl group having 1 to 3 carbon atoms, or R 8 and R 9 , in combination with each other, represent —(CH 2 ) k —;
k represents an integer between 1 and 4;
m represents 0 or 1;
R 10 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or —(CH 2 ) n X 3 ;
n represents an integer between 1 and 4;
X 3 represents an alkoxy group having 1 to 3 carbon atoms, a vinyl group, or an ethynyl group; and
R* is a bond in a linkage group between (A) and (L).
2. The compound of claim 1 , wherein (A) is a rifamycin derivative of formula XX:
wherein
R represents a hydrogen atom, a hydroxyl group or —OR*;
X 1 represents an oxygen atom or a sulfur atom;
R 1 represents a hydrogen atom, an acetyl group, or R*;
R 2 represents a hydroxyl group, a sulfhydryl group, a hydrogen atom, or an alkyl group having 1 to 3 carbon atoms;
R 10 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or —(CH 2 ) n X 3 ;
n represents an integer between 1 and 4;
X 3 represents an alkoxy group having 1 to 3 carbon atoms, a vinyl group, or an ethynyl group; and
R* is a bond in a linkage group formed with (L).
3. The compound of claim 2 , wherein
X 1 represents an oxygen atom;
R 2 represents a hydroxyl group or a sulfhydryl group; and
R 10 is selected from the group consisting of methyl, ethyl, iso-propyl, n-propyl, iso-butyl, (S)-sec-butyl, and (R)-sec-butyl.
4. A compound of formulas LXVI:
wherein R represents a hydrogen atom or a hydroxyl group;
R 1 represents a hydrogen atom or an acetyl group;
R 10 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or
—(CH 2 ) n X 3
in which n represents an integer between 1 and 4 and X 3 represents an alkoxy group having 1 to 3 carbon atoms, a vinyl group, or an ethynyl group;
(B) is a therapeutic drug; and
(L) is a linker described by any of formulas XXI–XXV:
wherein
Z 1 , Z 2 , Z 3 , and Z 4 are each, independently, selected from O, S, and NR 12 ;
Z 5 is selected from O, S, or NR 16 ;
R 12 is hydrogen or an alkyl group;
R 16 is hydrogen or an alkyl group;
R 15 is selected from hydrogen, alkyl, or heteroalkyl;
Y 1 , Y 2 , and Y 3 are each, independently, selected from carbonyl, thiocarbonyl, sulphonyl, and phosphoryl;
o, p, s, t, u, v, and w are each, independently, 0 or 1;
R 11 is a linear or branched alkyl of 1 to 10 carbon atoms, a linear or branched heteroalkyl of 1 to 10 atoms, a linear or branched alkene of 2 to 10 carbon atoms, a linear or branched alkyne of 2 to 10 carbon atoms, an aromatic residue of 5 to 10 carbon atoms, a cyclic system of 3 to 10 atoms, —(CH 2 CH 2 O) q CH 2 CH 2 — in which q is 1 to 4, or a chemical bond linking —(Z 1 ) o —(Y 1 ) u —(Z 2 ) s — to —(Z 3 ) t —(Y 2 ) v —(Z 4 ) p ;
R 13 represents a linear or branched alkyl of 1 to 10 carbon atoms, a linear or branched heteroalkyl of 1 to 10 atoms, a linear or branched alkene of 2 to 10 carbon atoms, a linear or branched alkyne of 2 to 10 carbon atoms, an aromatic residue of 5 to 10 carbon atoms, a cyclic system of 3 to 10 atoms, —(CH 2 CH 2 O) n CH 2 CH 2 — in which n is 1 to 4, or a chemical bond linking two nitrogens or two carbonyls;
R 14 is a linear or branched alkyl of 1 to 10 carbon atoms, a linear or branched heteroalkyl of 1 to 10 atoms, a linear or branched alkene of 2 to 10 carbon atoms, a linear or branched alkyne of 2 to 10 carbon atoms, an aromatic residue of 5 to 10 carbon atoms, a cyclic system of 3 to 10 atoms, —(CH 2 CH 2 O) n CH 2 CH 2 — in which n is 1 to 4, or a chemical bond linking —(Y 3 )—(Z 5 ) w — to the hydrazone carbon; and
X 4 is a hydrazone resulting from the condensation reaction of a drug B containing a hydrazide group and the precursor to linker XXV in which X 3 is the oxygen atom of a ketone or aldehyde.
5. The compound of claims 1 or 4 wherein linker (L) is cleavable.
6. The compound of claim 5 , wherein, upon cleavage of linker (L), the biological activity of (B) is substantially identical to biological activity of (B) when not linked to (A).
7. The compound of claims 1 or 4 , wherein said linker (L) is described by formula XXI:
wherein
Z 1 , Z 2 , Z 3 , and Z 4 are each, independently, selected from O, S, and NR 12 ;
R 12 is hydrogen or an alkyl group;
Y 1 and Y 2 are each, independently, selected from carbonyl, thiocarbonyl, sulphonyl, and phosphoryl;
o, p, s, t, u, and v are each independently 0 or 1; and
R 11 is a linear or branched alkyl of 1 to 10 carbon atoms, a linear or branched heteroalkyl of 1 to 10 atoms, a linear or branched alkene of 2 to 10 carbon atoms, a linear or branched alkyne of 2 to 10 carbon atoms, an aromatic residue of 5 to 10 carbon atoms, a cyclic system of 3 to 10 atoms, —(CH 2 CH 2 O) q CH 2 CH 2 — in which q is 1 to 4, or a chemical bond linking —(Z 1 ) o —(Y 1 ) u —(Z 2 ) s — to —(Z 3 ) t —(Y 2 ) v —(Z 4 ) p —.
8. The compound of claims 1 or 4 , wherein said linker (L) is described by one of formulas XXII–XXIV:
wherein R 13 represents a linear or branched alkyl of 1 to 10 carbon atoms, a linear or branched heteroalkyl of 1 to 10 atoms, a linear or branched alkene of 2 to 10 carbon atoms, a linear or branched alkyne of 2 to 10 carbon atoms, an aromatic residue of 5 to 10 carbon atoms, a cyclic system of 3 to 10 atoms, —(CH 2 CH 2 O) n CH 2 CH 2 — in which n is 1 to 4, or a chemical bond linking two nitrogens or two carbonyls.
9. The compound of claims 1 or 4 , wherein said linker (L) is described by formula XXV:
wherein
Z 5 is selected from O, S, or NR 16 ;
R 16 is hydrogen or an alkyl group;
R 15 is selected from hydrogen, alkyl, or heteroalkyl;
Y 3 is selected from carbonyl, thiocarbonyl, sulphonyl, and phosphoryl covalently bound to an oxygen atom of rifamycin derivative (A);
w is 0 or 1;
R 14 is a linear or branched alkyl of 1 to 10 carbon atoms, a linear or branched heteroalkyl of 1 to 10 atoms, a linear or branched alkene of 2 to 10 carbon atoms, a linear or branched alkyne of 2 to 10 carbon atoms, an aromatic residue of 5 to 10 carbon atoms, a cyclic system of 3 to 10 atoms, —(CH 2 CH 2 O) n CH 2 CH 2 — in which n is 1 to 4, or a chemical bond linking —(Y 3 )—(Z 5 ) w — to the hydrazone carbon; and
X 4 is a hydrazone resulting from the condensation reaction of a drug B containing a hydrazide group and the precursor to linker XXV in which X 3 is the oxygen atom of a ketone or aldehyde.
10. The compound of claims 1 or 4 , wherein (B) is a radical derived from the group consisting of isoniazid, ethambutol, azithromycin, pyrazinamide, p-aminosalicylic acid, ethionamide, cycloserine, 4-pyridinemethanol, 2-ethyl-4-pyridinemethanol, isonicotinic acid, and 2-ethyl-isonicotinic acid.
11. A compound having the chemical structure of any one of formulas XXVI–XXXIV:
wherein L is a linker described by formulas XXI, XXII, XXIII, XXIV, or XXV:
wherein
Z 1 , Z 2 , Z 3 , and Z 4 are each, independently, selected from O, S, and NR 12 ;
Z 5 is selected from O, S, or NR 16 ;
R 12 is hydrogen or an alkyl group;
R 16 is hydrogen or an alkyl group;
R 15 is selected from hydrogen, alkyl, or heteroalkyl;
Y 1 , Y 2 , and Y 3 are each, independently, selected from carbonyl, thiocarbonyl, sulphonyl, and phosphoryl;
o, p, s, t, u, v, and w are each, independently, 0 or 1;
R 11 is a linear or branched alkyl of 1 to 10 carbon atoms, a linear or branched heteroalkyl of 1 to 10 atoms, a linear or branched alkene of 2 to 10 carbon atoms, a linear or branched alkyne of 2 to 10 carbon atoms, an aromatic residue of 5 to 10 carbon atoms, a cyclic system of 3 to 10 atoms, —(CH 2 CH 2 O) q CH 2 CH 2 — in which q is 1 to 4, or a chemical bond linking —(Z 1 ) o —(Y 1 ) u —(Z 2 ) s — to —(Z 3 ) t —(Y 2 ) v —(Z 4 ) p ;
R 13 represents a linear or branched alkyl of 1 to 10 carbon atoms, a linear or branched heteroalkyl of 1 to 10 atoms, a linear or branched alkene of 2 to 10 carbon atoms, a linear or branched alkyne of 2 to 10 carbon atoms, an aromatic residue of 5 to 10 carbon atoms, a cyclic system of 3 to 10 atoms, —(CH 2 CH 2 O) n CH 2 CH 2 — in which n is 1 to 4, or a chemical bond linking two nitrogens or two carbonyls;
R 14 is a linear or branched alkyl of 1 to 10 carbon atoms, a linear or branched heteroalkyl of 1 to 10 atoms, a linear or branched alkene of 2 to 10 carbon atoms, a linear or branched alkyne of 2 to 10 carbon atoms, an aromatic residue of 5 to 10 carbon atoms, a cyclic system of 3 to 10 atoms, —(CH 2 CH 2 O) n CH 2 CH 2 — in which n is 1 to 4, or a chemical bond linking —(Y 3 )—(Z 5 ) w — to the hydrazone carbon; and
X 4 is a hydrazone resulting from the condensation reaction of a drug B containing a hydrazide group and the precursor to linker XXV in which X 3 is the oxygen atom of a ketone or aldehyde;
B is selected from one of formulas XXXVI–XLII:
R 1 is H, or —C(O)CH 3 ;
R 2 represents a hydroxyl group or a sulfhydryl group;
R 10 is selected from the group consisting of methyl, ethyl, iso-propyl, n-propyl, iso-butyl, (S)-sec-butyl, and (R)-sec-butyl;
D is a carbonyl, thiocarbonyl, or methylene;
E is —NR 21 , —O—, —S—, —NH—NH—, or —NH—N═;
f is 0 or 1;
R 20 is H or ethyl;
R 21 is H or alkyl; and
R 22 is methyl or cyclo-pentyl.
12. A method of increasing delivery of a therapeutic drug to a diseased cell, said method comprising linking said therapeutic drug to a rifamcyin derivative of formula II:
wherein each methine proton, methylene proton, and methyl proton of formula II is optionally substituted by —OH or —OR*;
R represents a hydrogen atom, a hydroxyl group or —OR*;
R 1 represents a hydrogen atom, an acetyl group, or R*;
ring G is selected from formulas III–XI:
R′ represents a hydrogen atom or R*;
X 1 represents an oxygen atom or a sulfur atom;
H 1 represents an oxygen atom, N—R 3 or R*;
H 2 represents a group expressed by formulas XII or XIII:
R 2 represents a hydroxyl group, a sulfhydryl group, a hydrogen atom, or an alkyl group having 1 to 3 carbon atoms;
R 3 represents a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, or a group expressed by one of formulas XIV–XVI:
each R 1 is, independently, a hydrogen atom or an alkyl group having 1 to 7 carbon atoms;
each R 5 is, independently, an alkyl group having 1 to 7 carbon atoms, or two of R 5 in combination form a 3–8 membered cyclic system;
g represents an integer between 1 and 3;
R 6 and R 7 are each, independently, a hydrogen atom or an alkyl group having 1 to 3 carbon atoms;
X 2 represents an oxygen atom, a sulfur atom, a carbonyl group, or a group expressed by one of formulas XVII–XIX:
R 8 and R 9 are each, independently, a hydrogen atom, or an alkyl group having 1 to 3 carbon atoms, or R 8 and R 9 , in combination with each other, represent —(CH 2 ) k —;
k represents an integer between 1 and 4;
m represents 0 or 1;
R 10 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or —(CH 2 ) n X 3 ;
n represents an integer between 1 and 4;
X 3 represents an alkoxy group having 1 to 3 carbon atoms, a vinyl group, or an ethynyl group; and
R* is a bond in a linkage group between said rifamycin derivative and a linker attached to said therapeutic drug, wherein said linker is degradable in vivo and is described by any of formulas XXI–XXV:
wherein
Z 1 , Z 2 , Z 3 , and Z 4 are each, independently, selected from O, S, and NR 12 ;
Z 5 is selected from O, S, or NR 16 ;
R 12 is hydrogen or an alkyl group;
R 16 is hydrogen or an alkyl group;
R 15 is selected from hydrogen, alkyl, or heteroalkyl;
Y 1 , Y 2 , and Y 3 are each, independently, selected from carbonyl, thiocarbonyl, sulphonyl, and phosphoryl;
o, p, s, t, u, v, and w are each, independently, 0 or 1;
R 11 is a linear or branched alkyl of 1 to 10 carbon atoms, a linear or branched heteroalkyl of 1 to 10 atoms, a linear or branched alkene of 2 to 10 carbon atoms, a linear or branched alkyne of 2 to 10 carbon atoms, an aromatic residue of 5 to 10 carbon atoms, a cyclic system of 3 to 10 atoms, —(CH 2 CH 2 O) q CH 2 CH 2 — in which q is 1 to 4, or a chemical bond linking —(Z 1 ) o —(Y 1 ) u —(Z 2 ) s — to —(Z 3 ) t —(Y 2 ) v —(Z 4 ) p ;
R 13 represents a linear or branched alkyl of 1 to 10 carbon atoms, a linear or branched heteroalkyl of 1 to 10 atoms, a linear or branched alkene of 2 to 10 carbon atoms, a linear or branched alkyne of 2 to 10 carbon atoms, an aromatic residue of 5 to 10 carbon atoms, a cyclic system of 3 to 10 atoms, —(CH 2 CH 2 O) n CH 2 CH 2 — in which n is 1 to 4, or a chemical bond linking two nitrogens or two carbonyls;
R 14 is a linear or branched alkyl of 1 to 10 carbon atoms, a linear or branched heteroalkyl of 1 to 10 atoms, a linear or branched alkene of 2 to 10 carbon atoms, a linear or branched alkyne of 2 to 10 carbon atoms, an aromatic residue of 5 to 10 carbon atoms, a cyclic system of 3 to 10 atoms, —(CH 2 CH 2 O) n CH 2 CH 2 — in which n is 1 to 4, or a chemical bond linking —(Y 3 )—(Z 5 ) w — to the hydrazone carbon; and
X 4 is a hydrazone resulting from the condensation reaction of a drug B containing a hydrazide group and the precursor to linker XXV in which X 3 is the oxygen atom of a ketone or aldehyde.
13. The method of claim 12 , wherein said drug is selected from the group consisting of isoniazid, ethambutol, azithromycin, pyrazinamide, p-aminosalicylic acid, ethionamide, cycloserine, 4-pyridinemethanol, 2-ethyl-4-pyridinemethanol, isonicotinic acid, and 2-ethyl-isonicotinic acid.
14. A pharmaceutical composition comprising an effective amount of a compound of claim 1 , 4 , or 11 or a suitable salt thereof, together with a pharmaceutically acceptable carrier or diluent.
15. A method of treating a bacterial infection in a mammal, said method comprising the step of administering to said mammal a pharmaceutical composition of claim 14 in an amount sufficient to treat said bacterial infection.
16. The method of claim 15 , wherein said bacterial infection is caused by an obligate intracellular bacterium.
17. The method of claim 16 , wherein said obligate intracellular bacterium is selected from the group consisting of Anaplasma bovis, A. caudatum, A. centrale, A. marginale A. ovis, A. phagocytophila, A. platys, Bartonella bacilliformis, B. clarridgeiae, B. elizabethae, B. henselae, B. henselae phage, B. quintana, B. taylorii, B. vinsonii, Borrelia afzelii, B. andersonii, B. anserina, B. bissettii, B. burgdorferi, B. crocidurae, B. garinii, B. hermsii, B. japonica, B. miyamotoi, B. parkeri, B. recurrentis, B. turdi, B. turicatae, B. valaisiana, Brucella abortus, B. melitensis, Chlamydia pneumoniae, C. psittaci, C. trachomatis, Cowdria ruminantium, Coxiella burnetii, Ehrlichia canis, E. chaffeensis, E. equi, E. ewingii, E. muris, E. phagocytophila, E. platys, E. risticii, E. ruminantium, E. sennetsu, Haemobartonella canis, H. felis, H. muris, Mycoplasma arthriditis, M. buccale, M. faucium, M. fermentans, M. genitalium, M. hominis, M. laidawii, M. lipophilum, M. orale, M. penetrans, M. pirum, M. pneumoniae, M. salivarium, M. spermatophilum, Rickettsia australis, R. conorii, R. felis, R. helvetica, R. japonica, R. massiliae, R. montanensis, R. peacockii, R. prowazekii, R. rhipicephali, R. rickettsii, R. sibirica, and R. typhi.
18. The method of claim 15 , wherein said mammal is a human.
19. The compound of claim 7 , wherein R 11 is a chemical bond linking —(Z 1 ) o —(Y 1 ) u —(Z 2 ) s — to —(Z 3 ) t —(Y 2 ) v —(Z 4 ) p —.