Cleavable conjugates of catechol compounds and water-soluble polymers and methods of treatment using the same
Described are conjugates comprising a water-soluble polymer linked to a compound comprising a catechol moiety via a cleavable linkage, wherein the cleavable linkage is formed between the water-soluble polymer and a first phenolic hydroxyl group of the catechol moiety and a second phenolic hydroxyl group of the catechol moiety is linked to a blocking group wherein the rate of hydrolytic release of the compound comprising the catechol moiety is controlled, at least in part, through structure or design of the blocking group on the second phenolic hydroxyl group of the catechol moiety. Therefore, the rate of hydrolytic release of the compound comprising the catechol moiety can be tuned through structural design of the group on the second phenolic hydroxyl group of the catechol moiety. Compounds used in the synthesis of the described conjugates and methods of using the described conjugate and other compounds in the treatment of dopamine-responsive disorders are also described.
1. A conjugate of formula I or a pharmaceutically acceptable salt thereof
POL n -(L-A-B) b (I)
wherein:
POL is a water-soluble polymer;
n represents the number of repeating units in the water-soluble polymer and is 1-1000;
b is 1 to 50, provided that n is always greater than or equal to b;
L is a linkage comprising a first cleavable moiety, linking A and POL;
B is a blocking group comprising a second cleavable moiety; and
A is a compound comprising a catechol moiety, the catechol moiety comprising at least a first and a second phenolic hydroxyl group, wherein the first phenolic hydroxyl group is linked to L and the second phenolic hydroxyl group is linked to B, wherein the first and second cleavable moieties differ, wherein the second cleavable moiety is ethyl succinate.
2. The conjugate of claim 1 , wherein the water-soluble polymer is a poly(oxazoline) polymer.
3. The conjugate of claim 1 , wherein the water-soluble polymer is co-polymer.
4. The conjugate of claim 1 , wherein the water-soluble polymer is a co-polymer comprising 50% to 99.5% of a poly(oxazoline) polymer.
5. The conjugate of claim 1 , wherein L is a direct linkage or a linking group.
6. The conjugate of claim 1 , wherein the first cleavable moiety comprises an ester, a carboxylate ester linkage (—C(O)—O—), a carbonate ester linkage (—O—C(O)—O—), a carbamate linkage (—O—C(O)—NH—), an amide linkage (—C(O)—NH—), or a disulfide linkage (S—S).
7. The conjugate of claim 1 , wherein the first cleavable moiety is an ester linkage.
8. The conjugate of claim 1 , wherein a free hydroxyl group is generated at the first phenolic hydroxyl of the catechol moiety when the first cleavable moiety is cleaved.
9. The conjugate of claim 1 , wherein a free hydroxyl group is generated at the second phenolic hydroxyl of the catechol moiety when the second cleavable moiety is cleaved.
10. The conjugate of claim 1 , wherein A is a compound of formula III or a pharmaceutically acceptable salt thereof
wherein:
R 11 , R 12 , R 13 and R 14 are independently selected from H, alkoxy, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclylalkyl, unsubstituted or substituted heteroarylalkyl, or any two of R 11 , R 12 , R 13 and R 14 that are adjacent to one another, taken together with the carbons to which they are attached, may form an optionally substituted aryl, heteroaryl, heterocyclyl ring; and
one of R 15 or R 16 is L; and
the other of R 15 or R 16 is B.
11. The conjugate of claim 10 , wherein the compound is arbutamine, carbidopa, dobutamine, dopamine, entacapone, epinephrine, fenoldopam, isoetharine, isoproterenol, levodopa, levonordefrin, masoprocol, methyldopa, methyldopate, norepinephrine, protokylol, tolcapone, or fenoldopam.
12. The conjugate of claim 1 , wherein the compound is a compound of formula IV or a pharmaceutically acceptable salt thereof
wherein:
one of R 15 or R 16 is L;
the other of R 15 or R 16 is B; and
R 19 is H, an unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted benzyl, acyl, tetrahydrofuranyl, tetrahydropyranyl, nicotinyl or a 1-aryltetrazolyl.
13. The conjugate of claim 12 , wherein R 19 is selected from the group consisting of —H, —CH 3 , —CH 2 —CH 3 , —CH 2 —CH 2 —CH 3 , —CH(CH 3 ) 2 —CH 2 —CH 2 —CH 2 —CH 3 , and
14. The conjugate of claim 12 , wherein the compound is apomorphine.
15. The conjugate of claim 1 , wherein the water-soluble polymer is a poly(oxazoline) polymer of formula IIB or a pharmaceutically acceptable salt thereof
R—{[N(COX)CH 2 CH 2 ] o1 —[N(COY)CH 2 CH 2 ] o2 —[N(COR 1 )CH 2 CH 2 ] n } a -T (IIB)
wherein:
R is an initiating group;
X is independently selected for each repeating unit is -L-A;
Y is independently selected for each repeating unit is -L-A, a non-reactive pendent moiety, or a pendent moiety containing an active functional group;
R 1 is independently selected for each repeating unit from an unsubstituted or substituted alkyl, an unsubstituted or substituted alkenyl, an unsubstituted or substituted aralkyl or an unsubstituted or substituted heterocyclylalkyl group;
a is ran which indicates a random co-polymer or block which indicates a block co-polymer;
o1 is an integer from 1 to 50;
o2 is and from 0 to 49, provided that the sum of o1 and o2 is less than or equal to 50;
n is an integer from 1 to 1000; and
T is a terminating group.
16. The conjugate of claim 15 , wherein the L is a direct linkage or a linking group.
17. The conjugate of claim 16 , wherein the linking group has structure
wherein
R 3 links the triazole moiety to the water-soluble polymer; and
R 4 links the triazole moiety to the compound, wherein R 4 forms a bond with the first phenolic hydroxyl of the compound.
18. The conjugate of claim 17 , wherein:
R 3 is —C(O)—R 5 —,
R 5 is absent or is an unsubstituted or substituted alkyl, an unsubstituted or substituted alkenyl, an unsubstituted or substituted aralkyl, or an unsubstituted or substituted heterocyclylalkyl group;
R 4 is —R 6 -R 7 -R 8 —;
R 6 is a substituted or unsubstituted alkyl, substituted or unsubstituted aralkyl, or a oligo(ethylene oxide);
R 7 is a group containing the first cleavable moiety or a portion thereof; and
R 8 is absent or O.
19. The conjugate of claim 18 , wherein R 7 and R 8 combine to form the first cleavable moiety.
20. The conjugate of claim 18 , wherein R 6 is a straight chain substituted or unsubstituted C 1 -C 4 alkyl, or a branched substituted or unsubstituted C 1 -C 4 alkyl, wherein R 7 is —C(O)—O—, and wherein R 8 is absent.
21. The conjugate of claim 18 , wherein R 6 is a straight chain substituted or unsubstituted C 1 -C 4 alkyl, or a branched substituted or unsubstituted C 1 -C 4 alkyl, wherein R 7 is —C(O)—, and wherein R 8 is —O— or absent.
22. The conjugate of claim 17 , wherein R 3 is —C(O)—(CH 2 ) 3 and R 4 is —(CH 2 ) d —C(O)—O—, —CH 2 —C(O)—O—, —CH 2 —CH 2 —C(O)—O—, —CH 2 —CH 2 —CH 2 —C(O)—O—, or —CH 2 (CH 3 )—C(O)—O—, wherein d is an integer from 1 to 10.
23. The conjugate of claim 17 , wherein R 3 is —C(O)—(CH 2 ) 3 and R 4 is —(CH 2 ) d —C(O)—, —CH 2 —C(O)—, —CH 2 —CH 2 —C(O)—, —CH 2 —CH 2 —CH 2 —C(O)—, or —CH 2 (CH 3 )—C(O)—, wherein d is an integer from 1 to 10.
24. The conjugate of claim 15 , wherein T is Z—B 1 -Q, Z is S, O, or N, B 1 is an optional linking group, and Q is a terminating nucleophile.
25. The conjugate of claim 24 , wherein B 1 is —(CH 2 ) 1-16 —, Z is S, and Q is —COOH, —COOCH 3 , —NH 2 , or NH-tBoc.
26. The conjugate of claim 15 , wherein R 1 is an unsubstituted or substituted alkyl.
27. The conjugate of claim 15 , wherein the compound is apomorphine or a derivative thereof.
28. The conjugate of claim 27 , wherein the conjugate has structure
wherein R 1 is an unsubstituted or substituted alkyl, an unsubstituted or substituted alkenyl, an unsubstituted or substituted aralkyl, or an unsubstituted or substituted heterocyclylalkyl group; R 6 is a substituted or unsubstituted alkyl or aryl group; R 16 is B; R 19 is H, an unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted benzyl, acyl, tetrahydrofuranyl, tetrahydropyranyl, nicotinyl or 1-aryltetrazolyl.
29. A method of treating a dopamine-responsive disease or condition in a subject, the method comprising administering to the subject an amount of the conjugate of formula I of claim 1 , wherein the compound is a dopamine agonist.
30. The method of claim 29 , wherein the dopamine-responsive disease or condition is Parkinson's disease, restless leg syndrome, pituitary tumors, schizophrenia, attention-deficit hyperactivity disorder, SSRI-induced sexual dysfunction, depression, obesity, or type II diabetes.
31. The method of claim 29 , wherein the dopamine agonist is apomorphine, arbutamine, carbidopa, dobutamine, dopamine, entacapone, epinephrine, fenoldopam, isoetharine, isoproterenol, levodopa, levonordefrin, masoprocol, methyl dopa, methyldopate, norepinephrine, protokylol, tolcapone, or fenoldopam.