Oligomer-Phenothiazine Conjugates
The invention relates to (among other things) oligomer-phenothiazine conjugates and related compounds. A conjugate of the invention, when administered by any of a number of administration routes, exhibits advantages over un-conjugated phenothiazine compounds.
1 . A compound comprising a phenothiazine residue covalently attached via a stable or degradable linkage to a water-soluble, non-peptidic oligomer.
2 . The compound of claim 1 , having the following structure:
wherein:
R 1 , R 2 , R 3 , and R 4 , each independently are selected from the group consisting of hydrogen, unsubstituted alkyl, and substituted alkyl; or R 3 and R 4 together with the nitrogen form a heterocycle;
n is an integer equal to or greater than one;
X is a spacer moiety; and
POLY is a water-soluble, non-peptidic oligomer.
3 . The compound of claim 1 , having the structure:
wherein:
R 1 , R 2 , and R 3 , each independently are selected from the group consisting of hydrogen, unsubstituted alkyl, and substituted alkyl;
n is an integer equal to or greater than one;
X is a spacer moiety; and
POLY is a water-soluble, non-peptidic oligomer.
4 . The compound of claim 1 , having the structure:
wherein:
R 1 , R 2 , R 3 , and R 4 , each independently are selected from the group consisting of hydrogen, unsubstituted alkyl, and substituted alkyl; or R 3 and R 4 together with the nitrogen form a heterocycle;
n is an integer equal to or greater than one;
X is a spacer moiety; and
POLY is a water-soluble, non-peptidic oligomer.
5 . The compound of claim 1 , wherein the phenothiazine residue is a residue of a phenothiazine having the formula:
wherein:
R 1 , R 2 , R 3 , and R 4 , each independently are selected from the group consisting of hydrogen, unsubstituted alkyl, and substituted alkyl; or R 3 and R 4 together with the nitrogen form a heterocycle; and
n is an integer equal to or greater than one.
6 . The compound of claim 1 , wherein the phenothiazine residue is a residue of a phenothiazine having the formula:
7 . The compound of claim 1 , wherein the phenothiazine residue is a residue of a phenothiazine having the formula:
8 . The compound of claim 1 , wherein the phenothiazine residue is selected from the group consisting of mequitazine, promethazine, promezine, and thiazinamium methylsulfate.
9 . The compound of claim 1 , wherein the water-soluble, non-peptidic oligomer is a poly(alkylene oxide).
10 . The compound of claim 9 , wherein the poly(alkylene oxide) is a poly(ethylene oxide).
11 . The compound of claim 1 , wherein the water-soluble, non-peptidic oligomer is made of from about 1 to about 30 monomers.
12 . The compound of claim 11 , wherein the water-soluble, non-peptidic oligomer is made of from about 1 to about 10 monomers.
13 . The compound of claim 9 , wherein the poly(alkylene oxide) includes an alkoxy or hydroxy end-capping moiety.
14 . The compound of claim 1 , wherein a single water-soluble, non-peptidic oligomer is attached to the phenothiazine residue.
15 . The compound of claim 1 , wherein more than one water-soluble, non-peptidic oligomer is attached to the phenothiazine residue.
16 . The compound of claim 1 , wherein the phenothiazine residue is covalently attached via a stable linkage.
17 . The compound of claim 1 , wherein the phenothiazine residue is covalently attached via a degradable linkage.
18 . The compound of claim 1 , wherein the linkage is an ether linkage.
19 . The compound of claim 1 , wherein the linkage is an ester linkage.
20 . A composition comprising a compound comprising a phenothiazine residue covalently attached via a stable or degradable linkage to a water-soluble and non-peptidic oligomer, and optionally, a pharmaceutically acceptable excipient.
21 . A composition of matter comprising a compound comprising a phenothiazine residue covalently attached via a stable or degradable linkage to a water-soluble, non-peptidic oligomer, wherein the compound is present in a dosage form.
22 . A method of making a phenothiazine conjugate, the method comprising covalently attaching a water-soluble, non-peptidic oligomer to a phenothiazine.
23 . A method of treatment comprising administering a compound comprising a phenothiazine residue covalently attached via a stable or degradable linkage to a water-soluble, non-peptidic oligomer to a subject in need thereof.