OLIGOMER CONJUGATES OF LIDOCAINE AND ITS DERIVATIVES
The invention provides small molecule drugs that are chemically modified by covalent attachment of a water-soluble oligomer.
1 . A compound comprising a lidocaine residue covalently attached via a linkage to a water-soluble, non-peptidic oligomer.
2 . The compound of claim 1 , wherein the linkage is a stable linkage.
3 . The compound of claim 1 , wherein the linkage is a degradable linkage.
4 . The compound of claim 1 , wherein the linkage is an amine linkage.
5 . The compound as in any one of claims 1 , 2 , 3 and 4 , wherein the weight average molecular weight of the water-soluble, non-peptidic oligomer is less than 400 Daltons.
6 . The compound of claim 1 , having the following structure:
wherein:
R 1 is hydrogen or lower alkyl;
R 2 is hydrogen or lower alkyl;
R 3 is hydrogen or lower alkyl;
R 4 is hydrogen or lower alkyl;
R 5 is hydrogen or lower alkyl;
R 6 is hydrogen or lower alkyl;
Y is selected from the group consisting of —O—, —O—CH 2 —, —CH 2 —O—, —NH—, —NHC(O)—, —C(O)NH—, —CH 2 — and —CH 2 —CH 2 —;
X is a spacer moiety; and
POLY is a water-soluble, non-peptidic oligomer.
7 . The compound of claim 1 , having the following structure:
wherein:
R 1 is hydrogen or lower alkyl;
R 2 is hydrogen or lower alkyl;
R 3 is hydrogen or lower alkyl;
R 4 is hydrogen or lower alkyl;
R 5 is hydrogen or lower alkyl;
R 6 is hydrogen or lower alkyl;
R 8 is hydrogen or lower alkyl;
Y is selected from the group consisting of —O—, —O—CH 2 —, —CH 2 —O—, —NH—, —NHC(O)—, —C(O)NH—, —CH 2 — and —CH 2 —CH 2 —;
X is a spacer moiety; and
POLY is a water-soluble, non-peptidic oligomer.
8 . The compound as in any one of claims 1 , 2 , 3 and 4 , wherein the lidocaine residue is a residue of a compound having the following structure:
wherein:
R 1 is hydrogen or lower alkyl;
R 2 is hydrogen or lower alkyl;
R 3 is hydrogen or lower alkyl;
R 4 is hydrogen or lower alkyl;
R 5 is hydrogen or lower alkyl;
R 6 is hydrogen or lower alkyl;
R 7 is hydrogen or lower alkyl;
R 8 is hydrogen or lower alkyl; and
Y is selected from the group consisting of —O—, —O—CH 2 —, —CH 2 —O—, —NH—, —NHC(O)—, —C(O)NH—, —CH 2 — and —CH 2 —CH 2 —.
9 . The compound as in any one of claims 1 , 2 , 3 and 4 , wherein the lidocaine residue is a residue of a Class IB antiarrhythmic drug.
10 . The compound as in any one of claims 1 , 2 , 3 and 4 , wherein the lidocaine residue is a residue of lidocaine.
11 . The compound as in any one of claims 1 , 2 , 3 and 4 , wherein the lidocaine residue is a residue of tocainide.
12 . The compound as in any one of claims 1 , 2 , 3 and 4 , wherein the lidocaine residue is a residue of mexiletine.
13 . The compound as in any one of claims 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 and 12 , wherein the water-soluble, non-peptidic oligomer is a poly(alkylene oxide).
14 . The compound of claim 13 , wherein the poly(alkylene oxide) is a poly(ethylene oxide).
15 . The compound of claim 1 , wherein the water-soluble, non-peptidic oligomer has a number of repeating monomers in the range of from 1 to 30.
16 . The compound of claim 15 , wherein the water-soluble, non-peptidic oligomer has a number of repeating monomers in the range of from 1 to 10.
17 . The compound of claim 13 , wherein the poly(alkylene oxide) includes an alkoxy or hydroxy end-capping moiety.
18 . The compound of claim 1 , wherein the compound has a single lidocaine residue covalently attached to a single water-soluble, non-peptidic oligomer.
19 . The compound of claim 1 , wherein the compound has a single lidocaine residue covalently attached to two water-soluble, non-peptidic oligomers.
20 . The compound of claim 1 , wherein the compound has two lidocaine residues covalently attached to a single water-soluble, non-peptidic oligomer.
21 . The compound of claim 1 , having the following structure:
wherein:
each R 1 is hydrogen or lower alkyl;
each R 2 is hydrogen or lower alkyl;
each R 3 is hydrogen or lower alkyl;
each R 4 is hydrogen or lower alkyl;
each R 5 is hydrogen or lower alkyl;
each R 6 is hydrogen or lower alkyl;
each Y is selected from the group consisting of —O—, —O—CH 2 —, —CH 2 —O—, —NH—, —NHC(O)—, —C(O)NH—, —CH 2 — and —CH 2 —CH 2 —;
each X is a spacer moiety; and
POLY is a water-soluble, non-peptidic oligomer.
22 . The compound of claim 1 , having the following structure:
wherein:
each R 1 is hydrogen or lower alkyl;
each R 2 is hydrogen or lower alkyl;
each R 3 is hydrogen or lower alkyl;
each R 4 is hydrogen or lower alkyl;
each R 5 is hydrogen or lower alkyl;
each R 6 is hydrogen or lower alkyl;
each R 8 is hydrogen or lower alkyl;
each Y is selected from the group consisting of —O—, —O—CH 2 —, —CH 2 —O—, —NH—, —NHC(O)—, —C(O)NH—, —CH 2 — and —CH 2 —CH 2 —;
each X is a spacer moiety; and
POLY is a water-soluble, non-peptidic oligomer.
23 . The compound of claim 1 , having the following structure:
wherein (n) is an integer having a value in the range of from 1 to 30.
24 . The compound of claim 1 , having the following structure:
wherein:
R 1 is hydrogen or lower alkyl
R 2 is hydrogen or lower alkyl;
R 3 is hydrogen or lower alkyl;
R 4 is hydrogen or lower alkyl;
R 5 is hydrogen or lower alkyl;
R 6 is hydrogen or lower alkyl;
R 8 is hydrogen or lower alkyl;
Y is selected from the group consisting of —O—, —O—CH 2 —, —CH 2 —O—, —NH—, —NHC(O)—, —C(O)NH—, —CH 2 — and —CH 2 —CH 2 —;
X is a spacer moiety;
X 1 is a spacer moiety;
POLY is a water-soluble, non-peptidic oligomer; and
POLY 1 is a spacer moiety.
25 . The compound of claim 1 , having the following structure:
wherein (n) is an integer in the range of from 1 to 30.
26 . The compound of claim 1 , having the following structure:
wherein (n) is in the range of 1 to 28.
27 . A composition comprising a compound comprising (i) a lidocaine residue covalently attached via a linkage to a water-soluble, non-peptidic oligomer, and (ii) optionally, a pharmaceutically acceptable excipient.
28 . A composition of matter comprising a compound comprising a lidocaine residue covalently attached via a linkage to a water-soluble, non-peptidic oligomer, wherein the compound is present in a dosage form.
29 . A method comprising covalently attaching a water-soluble, non-peptidic oligomer to a lidocaine residue.
30 . A method comprising administering to a subject a compound comprising a lidocaine residue covalently attached via a linkage to a water-soluble, non-peptidic oligomer.