US2013331443A1PendingUtilityA1
Multi-arm polymeric prodrug conjugates of taxane-based compounds
Est. expiryDec 22, 2030(~4.4 yrs left)· nominal 20-yr term from priority
C08G 65/33337C07D 305/14A61K 31/337C08L 2203/02C08G 65/329A61P 35/00A61K 47/60
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Claims
Abstract
Among other aspects, provided herein are multi-arm polymeric prodrug conjugates of taxane-based compounds and/or fluorinated forms thereof. Methods of preparing such conjugates as well as methods of administering the conjugates are also provided. Upon administration to a patient, release of the taxane-based compound is achieved.
Claims
exact text as granted — not AI-modified1 . A conjugate having a structure encompassed by the formula:
wherein:
R is a residue of a polyol, polythiol or polyamine bearing from 3 to about 50 hydroxyl, thiol or amino groups;
each Q is a linker;
each POLY 1 is a water-soluble, non-peptidic polymer;
each X is spacer moiety;
each R 1 is selected from the group consisting of H, a hydroxy protecting group and
and each of D 1 , D 2 and D 3 is independently selected from the group consisting of H, F, D and CF 3 ;
each R 2 is selected from the group consisting of H, a hydroxy protecting group and
and (a) is either zero or one and each of D 4 , D 5 and D 6 is independently selected from the group consisting of H, F, D and CF 3 ;
each R 3 is
and each of D 7 , D 8 , D 9 , D 10 , D 11 , D 12 , D 13 , D 14 and D 15 is independently selected from the group consisting of H, F, D and CF 3 ; and
q is a positive integer from 3 to about 50,
and pharmaceutically acceptable salts and solvates thereof, with the proviso that when each R 1 and R 2 are H, R 3 is
with at least one of D 7 , D 8 , D 9 , D 10 , D 11 , D 12 , D 13 , D 14 and D 15 is F, D or CF 3 .
2 . The conjugate of claim 1 , wherein R is a residue of a polyol.
3 . The conjugate of claim 2 , wherein the polyol is selected from the group consisting of glycerol, diglycerol, triglycerol, hexaglycerol, trimethylolpropane, pentaerythritol, dipentaerythritol, tripentaerythritol and ethoxylated forms of glycerol.
4 . The conjugate of claim 3 , wherein the polyol is pentaerythritol.
5 . The conjugate of claim 1 , wherein the linker is selected from the group consisting of —O—, —S—, —NH—, —NH—C(O)—, and —C(O)—NH—.
6 . The conjugate of claim 8 , wherein the linker is —O—.
7 . The conjugate of claim 1 , wherein the water-soluble, non-peptidic polymer is a poly(ethylene oxide).
8 . The conjugate of claim 1 , wherein the spacer moiety has the structure corresponding to —Y—Z—, where Y is
—(CR x R y ) a —K w —(CR x R y ) b —(CH 2 CH 2 O) c —(CR x R y ) d —K z —,
wherein:
each R x and R y , in each occurrence, is independently H or an organic radical selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, and substituted aryl,
(a) is zero or an integer of from 1 to 12;
(b) is zero or an integer of from 1 to 12;
(c) is zero or an integer of from 1 to 25;
(d) is zero or an integer of from 1 to 12;
K w is selected from the group consisting of —NH—, —C(O)—, —C(O)NH—, —NH—C(O)—, —O—, —S—, O—C(O)—, C(O)—O—, —O—C(O)—O—, O—C(O)—NH—, —NH—C(O)—O—; and
K z is selected from the group consisting of —NH—, —C(O)—, —C(O)NH—, —NH—C(O)—, —O—, —S—, —O—C(O)—, C(O)—O—, —O—C(O)—O—, —O—C(O)—NH—, —NH—C(O)—O—, and
Z is selected from —C(O)—O—, O—C(O)—O—, —O—C(O)—NH— and —NH—C(O)—O—.
9 . The conjugate of claim 1 , wherein the spacer moiety has the structure corresponding to —Y—, where Y is
—(CR x R y ) a —K w —(CR x R y ) b —(CH 2 CH 2 O) c —(CR x R y ) d —K z —,
wherein:
each R x and R y , in each occurrence, is independently H or an organic radical selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, and substituted aryl,
(a) is zero or an integer of from 1 to 12;
(b) is zero or an integer of from 1 to 12;
(c) is zero or an integer of from 1 to 25;
(d) is zero or an integer of from 1 to 12;
K w is selected from the group consisting of —NH—, —C(O)—, —C(O)NH—, —NH—C(O)—, —O—, —S—, O—C(O)—, C(O)—O—, —O—C(O)—O—, O—C(O)—NH—, —NH—C(O)—O—; and
K z is selected from the group consisting of —NH—, —C(O)—, —C(O)NH—, —NH—C(O)—, —O—, —S—, O—C(O)—, C(O)—O—, —O—C(O)—O—, O—C(O)—NH—, —NH—C(O)—O—.
10 . The conjugate of claim 1 , wherein the spacer moiety has the structure
—C(O)—(CH 2 ) b —(CH 2 CH 2 O) c —(CH 2 ) d —K z —,
wherein:
(b) is an integer of from 1 to 5;
(c) is an integer of from 1 to 5;
(d) is an integer of from 1 to 5; and
K z is selected from the group consisting of —NH—, —C(O)—, —C(O)NH—, —NH—C(O)—, —O—, —S—, —O—C(O)—, C(O)—O—, —O—C(O)—O—, O—C(O)—NH—, —NH—C(O)—O—.
11 . The conjugate of claim 1 , wherein the spacer moiety has the structure —[CH 2 ] m — or —CH 2 —C(O)—NH—C(R 4 )H—, wherein m is a positive integer and R 4 is selected from the group consisting of H, CH 3 , CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 and C(H)(CH 3 )CH 2 CH 3 .
12 . The conjugate of claim 1 , wherein “q” is an integer from 3 to 10.
13 . The conjugate of claim 1 , wherein each R 1 and R 2 is a hydroxy protecting group.
14 . The conjugate of claim 1 , wherein each R 1 is
and each of D 1 , D 2 and D 3 is independently selected from the group consisting of H, F, D and CF 3 .
15 . The conjugate of claim 1 , wherein each R 2 is
and (a) is either zero or one and each of D 4 , D 5 and D 6 is independently selected from the group consisting of H, F, D and CF 3 .
16 . The conjugate of claim 15 , wherein (a) is zero.
17 . The conjugate of claim 1 , wherein R 3 is
18 . The conjugate of claim 1 , wherein R 3 is
and each of D 7 , D 8 , D 9 , D 10 , D 11 , D 12 , D 13 , D 14 and D 15 is independently selected from the group consisting of H, F, D and CF 3 .
19 . The conjugate of claim 1 , wherein R 3 is
and each of D 7 , D 8 , D 9 , D 10 , D 12 , D 13 , D 14 and D 15 is D.
20 . A conjugate having a structure encompassed by the formula:
wherein:
each n is a positive integer from 10 to about 400;
each R 1 is selected from the group consisting of H, a hydroxy protecting group and
and each of D 1 , D 2 and D 3 is independently selected from the group consisting of H, F, D and CF 3 ;
each R 2 is selected from the group consisting of H, a hydroxy protecting group and
and (a) is either zero or one and each of D 4 , D 5 and D 6 is independently selected from the group consisting of H, F, D and CF 3 ; each R 3 is
and each of D 7 , D 8 , D 9 , D 10 , D 11 , D 12 , D 13 , D 14 and D 15 is independently selected from the group consisting of H, F, D and CF 3 ;
R 4 is selected from the group consisting of H, CH 3 , CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 and C(H)(CH 3 )CH 2 CH 3 ; and
q is a positive integer from 3 to about 50,
and pharmaceutically acceptable salts and solvates thereof, with the proviso that when each R 1 and R 2 are H, R 3 is
with at least one of D 7 , D 8 , D 9 , D 10 , D 11 , D 12 , D 13 , D 14 and D 15 is F, D or CF 3 .
21 . A conjugate having a structure encompassed by the formula:
wherein:
each n is a positive integer from 10 to about 400;
each m is a positive integer from 1 to about 12;
each R 1 is selected from the group consisting of H, a hydroxy protecting group and
and each of D 1 , D 2 and D 3 is independently selected from the group consisting of H, F, D and CF 3 ;
each R 2 is selected from the group consisting of H, a hydroxy protecting group and
and (a) is either zero or one and each of D 4 , D 5 and D 6 is independently selected from the group consisting of H, F, D and CF 3 ;
each R 3 is
and each of D 7 , D 8 , D 9 , D 10 , D 11 , D 12 , D 13 , D 14 and D 15 is independently selected from the group consisting of H, F, D and CF 3 ; and
q is a positive integer from 3 to about 50,
and pharmaceutically acceptable salts and solvates thereof, with the proviso that when each R 1 and R 2 are H, R 3 is
with at least one of D 7 , D 8 , D 9 , D 10 , D 11 , D 12 , D 13 , D 14 and D 15 is F, D or CF 3 .
22 . A conjugate having a structure encompassed by the formula:
wherein:
each n is a positive integer from 10 to about 400;
each L 1 is —(CH 2 ) 0-6 C(═O)—;
each L 2 is —NH(CH 2 CH 2 O) 1-10 (CHR 5 ) 1-6 —, wherein each R 5 is independently selected from the group consisting of H and lower alkyl;
each R 1 is selected from the group consisting of H, a hydroxy protecting group and
and each of D 1 , D 2 and D 3 is independently selected from the group consisting of H, F, D and CF 3 ;
each R 2 is selected from the group consisting of H, a hydroxy protecting group and
and (a) is either zero or one and each of D 4 , D 5 and D 6 is independently selected from the group consisting of H, F, D and CF 3 ;
each R 3 is
and each of D 7 , D 8 , D 9 , D 10 , D 11 , D 12 , D 13 , D 14 and D 15 is independently selected from the group consisting of H, F, D and CF 3 ; and
q is a positive integer from 3 to about 50,
and pharmaceutically acceptable salts and solvates thereof, with the proviso that when each R 1 and R 2 are H, R 3 is
with at least one of D 7 , D 8 , D 9 , D 10 , D 11 , D 12 , D 13 , D 14 and D 15 is F, D or CF 3 .
23 . A conjugate having a structure encompassed by the formula:
wherein:
each n is a positive integer from 10 to about 400;
each L 1 is —(CH 2 ) 0-6 C(═O)—;
each L 3 is —[NH(CHR 5 ) 1-6 C(═O)] 1-4 —, wherein each R 5 is independently selected from the group consisting of H and lower alkyl;
each R 1 is selected from the group consisting of H, a hydroxy protecting group and
and each of D 1 , D 2 and D 3 is independently selected from the group consisting of H, F, D and CF 3 ;
each R 2 is selected from the group consisting of H, a hydroxy protecting group and
and (a) is either zero or one and each of D 4 , D 5 and D 6 is independently selected from the group consisting of H, F, D and CF 3 ;
each R 3 is
and each of D 7 , D 8 , D 9 , D 10 , D 11 , D 12 , D 13 , D 14 and D 15 is independently selected from the group consisting of H, F, D and CF 3 ; and
q is a positive integer from 3 to about 50,
and pharmaceutically acceptable salts and solvates thereof, with the proviso that when each R 1 and R 2 are H, R 3 is
with at least one of D 7 , D 8 , D 9 , D 10 , D 11 , D 12 , D 13 , D 14 and D 15 is F, D or CF 3 .
24 . A conjugate having a structure encompassed by the formula:
wherein:
each n is a positive integer from 10 to about 400;
each L 1 is —C(═O)—;
each L 3 is —[NH(CHR 5 ) 1-6 C(═O)] 1-4 —, wherein each R 5 is independently selected from the group consisting of H and lower alkyl;
each R 1 is selected from the group consisting of H, a hydroxy protecting group and
and each of D 1 , D 2 and D 3 is independently selected from the group consisting of H, F, D and CF 3 ;
each R 2 is selected from the group consisting of H, a hydroxy protecting group and
and (a) is either zero or one and each of D 4 , D 5 and D 6 is independently selected from the group consisting of H, F, D and CF 3 ;
each R 3 is
and each of D 7 , D 8 , D 9 , D 10 , D 11 , D 12 , D 13 , D 14 and D 15 is independently selected from the group consisting of H, F, D and CF 3 ; and
q is a positive integer from 3 to about 50,
and pharmaceutically acceptable salts and solvates thereof, with the proviso that when each R 1 and R 2 are H, R 3 is
with at least one of D 7 , D 8 , D 9 , D 10 , D 11 , D 12 , D 13 , D 14 and D 15 is F, D or CF 3 .
25 . A conjugate selected from the group consisting of
wherein each n is a positive integer from 10 to about 400, and pharmaceutically acceptable salts of each of the foregoing.
26 . A composition comprising a plurality of conjugates, wherein at least 80% of the conjugates in the composition have a structure encompassed by claim 1 .
27 . The composition of claim 26 , further comprising a pharmaceutical excipient.Join the waitlist — get patent alerts
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