US2012197037A1PendingUtilityA1
Hydrolysable linkers and cross-linkers for absorbable polymers
Individually held — no corporate assignee on recordPriority: Sep 17, 2007Filed: Sep 23, 2011Published: Aug 2, 2012
Est. expirySep 17, 2027(~1.2 yrs left)· nominal 20-yr term from priority
Inventors:Rao S. Bezwada
A61L 31/10Y10T442/10Y10T24/44291A61L 27/58C08G 63/916C07C 217/84C07C 205/57A61L 27/52A61L 27/18C07C 229/60A61L 24/06Y02W90/10C07C 205/43A61L 17/105C07C 265/12C07C 229/18C08G 63/16C07C 69/708C07C 219/34A61L 31/145Y10T428/139A47F 5/0006A61L 27/34A61L 31/148B65D 25/22C07C 69/34C07C 225/22A61L 17/145C07C 205/37Y10T24/51A61L 17/12C07C 235/16A61L 17/00C07C 69/67
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Claims
Abstract
The present invention relates to the discovery of new class of linear and multiarmed hydrolysable linkers and cross linkers for use in the synthesis of biodegradable polymers such as, polyesters, polyurethanes, polyamides, polyureas and degradable epoxy amine resin. The linear and multiarmed hydrolysable linkers of the present invention include symmetrical and/or unsymmetrical ether carboxylic acids, amines, amide diols, amine polyols and isocyanates.
Claims
exact text as granted — not AI-modified1 . A linker or pharmaceutically acceptable salt thereof of formula I, II, III, or IV:
R[—C(═O)—(Y) a —O—R 1 ] w I
R[—(X) a —OC(═O)—R 2 ] w II
R[—(Y) a —O—R 3 ] w III
R 4 —O—(Y 1 ) c —O—(Y) d —O—R 4 IV
wherein:
each —O—R 1 , —O—R 3 , —O—R 4 , and R 4 —O— is independently:
each —OC(═O)—R 2 is independently:
each Z is independently: NH 2 , NH(Y 1 ) b H, N((X 1 ) b H) 2 , NCO, CH 2 CO 2 H, or CH═CHCO 2 H;
each X is independently:
—OC(═O)CH 2 — (inverse glycolic acid moiety), —OC(═O)CH(CH 3 )— (inverse lactic acid moiety), —OC(═O)CH 2 OCH 2 CH 2 — (inverse dioxanone acid moiety), —OC(═O)CH 2 CH 2 CH 2 CH 2 CH 2 — (inverse caprolactone acid moiety), —OC(═O)(CH 2 ) y —, or —OC(═O)CH 2 (OCH 2 CH 2 ) z —.
each X 1 is independently:
—CH 2 C(═O)O— (glycolic acid moiety), —CH(CH 3 )C(═O)O— (lactic acid moiety), —CH 2 CH 2 OCH 2 C(═O)O— (dioxanone acid moiety), —CH 2 CH 2 CH 2 CH 2 CH 2 C(═O)O— (caprolactone acid moiety), —(CH 2 ) y C(═O)O—, or —(CH 2 CH 2 O) z CH 2 C(═O)O—;
each Y is independently:
—OCH 2 C(═O)— (inverse glycolic ester moiety), —OCH(CH 3 )C(═O)— (inverse lactic ester moiety), —OCH 2 CH 2 OCH 2 C(═O)— (inverse dioxanone ester moiety), —OCH 2 CH 2 CH 2 CH 2 CH 2 C(═O)— (inverse caprolactone ester moiety), —O(CH 2 ) m C(═O)—, or —O(CH 2 CH 2 O) n OCH 2 C(═O)—;
each Y 1 is independently:
—C(═O)CH 2 O— (glycolic ester moiety), —C(═O)CH(CH 3 )O— (lactic ester moiety), —C(═O)CH 2 OCH 2 CH 2 O— (dioxanone ester moiety), —C(═O)CH 2 CH 2 CH 2 CH 2 CH 2 O— (caprolactone ester moiety), —C(═O)(CH 2 ) m O—, or —C(═O)CH 2 O(CH 2 CH 2 O) n —;
R is a di-, tri, tetra-, penta- or hexaradical derived from C 1-25 alkyl, aryl, or aryl-(C 1-6 alkyl) 1-3 -, wherein from 1-3 of the CH 2 groups within the alkyl chain are optionally independently replaced by O or S atoms, such that each of said O or S atoms is attached only to carbon atoms in the alkyl chain, with the proviso that multiple heteroatoms must be separated from each other and from the di-, tri, tetra-, penta- or hexaradical chain ends by at least one carbon atom; or R is —[CH 2 CH 2 O—] p —, wherein p is an integer from about 10 to about 50;
each a and b is independently an integer from about 1 to about 6;
each m, n, y, and z is independently an integer from about 2 to about 24;
w is an integer from about 2 to about 6; and
c and d are each an integer from 1 to 5, with the proviso that the sum of c+d is an integer from about 2 to about 6.
2 . A linker or pharmaceutically acceptable salt thereof of claim 1 , wherein Y and Y 1 are derived from different hydroxyacid or lactone precursors.
3 . A linker or pharmaceutically acceptable salt thereof of claim 1 , wherein R is (CH 2 ), (CH 2 ) 3 , CH(CH 2 ) 3 , C(CH 2 ) 4 , or C(CH 2 CH 3 )(CH 2 ) 3 .
4 . A linker or pharmaceutically acceptable salt thereof of claim 1 , wherein:
X is —OC(═O)CH 2 —, —OC(═O)CH(CH 3 )—, —OC(═O)CH 2 OCH 2 CH 2 —, or —OC(═O)CH 2 CH 2 CH 2 CH 2 CH 2 —; Y 1 is —C(═O)CH 2 O—, —C(═O)CH(CH 3 )O—, —C(═O)CH 2 OCH 2 CH 2 O—, or —C(═O)CH 2 CH 2 CH 2 CH 2 CH 2 O—, and Y is —OCH 2 C(═O)—, —OCH(CH 3 )C(═O)—, —OCH 2 CH 2 OCH 2 C(═O)—, or —OCH 2 CH 2 CH 2 CH 2 CH 2 C(═O)—.
5 . A linker or pharmaceutically acceptable salt thereof of claim 4 , wherein:
X is —OC(═O)CH 2 — or —OC(═O)CH(CH 3 )—; Y 1 is —C(═O)CH 2 O— or —C(═O)CH(CH 3 )O—; and Y is —OCH 2 C(═O)— or —OCH(CH 3 )C(═O)—.
6 . A linker or pharmaceutically acceptable salt thereof of claim 1 , wherein the linker of formula I, II, or III has the formula Ia-f, IIa-h, or IIIa-f, respectively:
(—CH 2 —)[C(═O)—(Y) a —O—R 1 ] 2 Ia;
(—CH 2 CH 2 —)[C(═O)—(Y) a —O—R 1 ] 2 Ib;
(—CH 2 CH 2 CH 2 —)[C(═O)—(Y) a —O—R 1 ] 2 Ic;
(—CH 2 CH 2 CH 2 CH 2 —)[C(═O)—(Y) a —O—R 1 ] 2 Id
(—CH 2 CH 2 —O—CH 2 CH 2 —)[C(═O)—(Y) a —O—R 1 ] 2 Ie;
[—O(—CH 2 CH 2 —O—) p ][C(═O)—(Y) a —O—R 1 ] 2 If;
(—CH 2 —)[(X) a —OC(═O)—R 2 ] 2 IIa;
(—CH 2 CH 2 —)[(X) a —OC(═O)—R 2 ] 2 IIb;
(—CH 2 CH 2 CH 2 —)[(X) a —OC(═O)—R 2 ] 2 IIc;
(—CH 2 CH 2 CH 2 CH 2 —)[(X) a —OC(═O)—R 2 ] 2 IId;
(—CH 2 CH 2 —O—CH 2 CH 2 —)[(X) a —OC(═O)—R 2 ] 2 IIe;
(>C(H)—)[(X) a —OC(═O)—R 2 ] 3 IIf;
(>C(CH 2 CH 3 )—)[(X) a —OC(═O)—R 2 ] 3 IIg;
(>C<)[(X) a —OC(═O)—R 2 ] 4 IIh;
(—CH 2 —)[—(Y) a —O—R 3 ] 2 IIIa;
(—CH 2 CH 2 —)[—(Y) a —O—R 3 ] 2 IIIb;
(—CH 2 CH 2 CH 2 —)[—(Y) a —O—R 3 ] 2 IIIc;
(—CH 2 CH 2 CH 2 CH 2 —)[—(Y) a —O—R 3 ] 2 IIId;
(—CH 2 CH 2 —O—CH 2 CH 2 —)[—(Y) a —O—R 3 ] 2 IIIe; or
[—O(—CH 2 CH 2 —O—) p ][—(Y) a —O—R 3 ] 2 IIIf.
7 . An absorbable polymer formed from a linker or pharmaceutically acceptable salt thereof of claim 1 .
8 . A biomedical device, comprising the polymer of claim 7 .
9 . The biomedical device of claim 8 , wherein the device is selected from a polymer coated stent, a polymer coated suture, and a polymer-based drug delivery matrix.
10 . The polymer of claim 7 , wherein the polymer is a hydrogel.
11 . A linker or pharmaceutically acceptable salt thereof of claim 1 , having formula IV:
R 4 —O—(Y 1 ) c —O—(Y) d —O—R 4 IV.
12 . A linker or pharmaceutically acceptable salt thereof of claim 11 , wherein:
each Y 1 is independently:
—C(═O)CH 2 O—, —C(═O)CH(CH 3 )O—, —C(═O)CH 2 OCH 2 CH 2 O—, or —C(═O)CH 2 CH 2 CH 2 CH 2 CH 2 O—; and
each Y is independently:
—OCH 2 C(═O)—, —OCH(CH 3 )C(═O)—, —OCH 2 CH 2 OCH 2 C(═O)—, or —OCH 2 CH 2 CH 2 CH 2 CH 2 C(═O)—.
13 . A linker or pharmaceutically acceptable salt thereof of claim 12 ,
wherein:
each Y 1 is independently:
—C(═O)CH 2 O— or —C(═O)CH 2 CH 2 CH 2 CH 2 CH 2 O—; and
each Y is independently:
—OCH 2 C(═O)— or —OCH 2 CH 2 CH 2 CH 2 CH 2 C(═O)—.
14 . A polyester of formula:
wherein:
each Y 1f is independently —C(═O)CH 2 O—, —C(═O)CH(CH 3 )O—, —C(═O)CH 2 OCH 2 CH 2 O—, —C(═O)CH 2 CH 2 CH 2 CH 2 CH 2 O—, —C(═O)(CH 2 ) m O—, or —C(═O)CH 2 O(CH 2 CH 2 O) n —;
each Y f is independently —OCH 2 C(═O)—, —OCH(CH 3 )C(═O)—, —OCH 2 CH 2 OCH 2 C(═O)—, —OCH 2 CH 2 CH 2 CH 2 CH 2 C(═O)—, —O(CH 2 ) m C(═O)—, or —O(CH 2 CH 2 O) n OCH 2 C(═O)—;
each m and n is independently an integer from about 2 to about 24;
k 1 is an integer from about 100 to about 5000; and
each k 2 and k 2b is independently 1 to about 5.
15 . A polyester of claim 14 , wherein:
X is —OC(═O)CH 2 —, —OC(═O)CH(CH 3 )—, —OC(═O)CH 2 OCH 2 CH 2 —, or —OC(═O)CH 2 CH 2 CH 2 CH 2 CH 2 —; Y 1 is —C(═O)CH 2 O—, —C(═O)CH(CH 3 )O—, —C(═O)CH 2 OCH 2 CH 2 O—, or —C(═O)CH 2 CH 2 CH 2 CH 2 CH 2 O—, and Y is —OCH 2 C(═O)—, —OCH(CH 3 )C(═O)—, —OCH 2 CH 2 OCH 2 C(═O)—, or —OCH 2 CH 2 CH 2 CH 2 CH 2 C(═O)—.
16 . A polyester of claim 15 , wherein:
X is —OC(═O)CH 2 — or —OC(═O)CH(CH 3 )—; Y 1 is —C(═O)CH 2 O— or —C(═O)CH(CH 3 )O—; and Y is —OCH 2 C(═O)— or —OCH(CH 3 )C(═O)—.
17 . A linker or pharmaceutically acceptable salt thereof of claim 6 , wherein:
each X is independently:
—OC(═O)CH 2 —, —OC(═O)CH(CH 3 )—, —OC(═O)CH 2 OCH 2 CH 2 —, or —OC(═O)CH 2 CH 2 CH 2 CH 2 CH 2 —.
18 . A linker or pharmaceutically acceptable salt thereof of claim 17 , wherein:
each X is independently —OC(═O)CH 2 — or —OC(═O)CH(CH 3 )—.
19 . A linker or pharmaceutically acceptable salt thereof of claim 3 , wherein R is (CH 2 ) 3 , and wherein the C-2 CH 2 group within the (CH 2 ) 3 chain is optionally replaced by an O moiety.
20 . A linker or pharmaceutically acceptable salt thereof of claim 1 , having formula II.
21 . A linker or pharmaceutically acceptable salt thereof of claim 20 , wherein R is (CH 2 ) 2 and w is 2.
22 . A linker or pharmaceutically acceptable salt thereof of claim 21 , wherein X is —CH 2 C(═O)O— or —CH 2 CH 2 CH 2 CH 2 CH 2 C(═O)O—.
23 . A linker or pharmaceutically acceptable salt thereof of claim 19 , wherein R is (CH 2 ) 2 , (CH 2 ) 3 , (CH 2 ) 4 , (CH 2 OCH 2 ), or (CH 2 CH 2 OCH 2 CH 2 ) and w is 2.
24 . A linker or pharmaceutically acceptable salt thereof of claim 20 , wherein R is (CH 2 CHCH 2 ), and w is 3.
25 . A linker or pharmaceutically acceptable salt thereof of claim 20 , wherein R is (C(CH 2 ) 4 ), and w is 4.
26 . A compound of formula IVa:
R 4a —O—(Y 1a ) c —O—(Y a ) d —O—R 4a IVa
wherein:
each Y 1a is independently:
—C(═O)CH 2 O—, —C(═O)CH(CH 3 )O—, —C(═O)CH 2 OCH 2 CH 2 O—, —C(═O)CH 2 CH 2 CH 2 CH 2 CH 2 O—, —C(═O)(CH 2 ) m O—, or —C(═O)CH 2 O(CH 2 CH 2 O) n —;
each Y a is independently:
—OCH 2 C(═O)—, —OCH(CH 3 )C(═O)—, —OCH 2 CH 2 OCH 2 C(═O)—, —OCH 2 CH 2 CH 2 CH 2 CH 2 C(═O)—, —O(CH 2 ) m C(═O)—, or —O(CH 2 CH 2 O) n OCH 2 C(═O)—;
each R 4a is independently H, alkyl, or aralkyl;
each m and n is independently an integer from about 2 to about 24; and
each c and d is an integer from about 1 to about 5, with the proviso that the sum of c+d is an integer from about 2 to about 6.
27 . A compound of claim 26 , wherein:
each Y 1a is independently:
—C(═O)CH 2 O—, —C(═O)CH(CH 3 )O—, —C(═O)CH 2 OCH 2 CH 2 O—, or —C(═O)CH 2 CH 2 CH 2 CH 2 CH 2 O—; and
each Y a is independently:
—OCH 2 C(═O)—, —OCH(CH 3 )C(═O)—, —OCH 2 CH 2 OCH 2 C(═O)—, or —OCH 2 CH 2 CH 2 CH 2 CH 2 C(═O)—.
28 . A compound of claim 27 ,
wherein:
each Y 1a is independently —C(═O)CH 2 O— or
—C(═O)CH 2 CH 2 CH 2 CH 2 CH 2 O—; and
each Y a is independently —OCH 2 C(═O)— or
—OCH 2 CH 2 CH 2 CH 2 CH 2 C(═O)—.
29 . A linker or pharmaceutically acceptable salt thereof of formula Iz, IIz, IIIz, IVz, or Vz:
R[—C(═O)—(Y) a —O—R 1b ] w Iz
R[—(X) a —OC(═O)—R 2b ] w IIz
R[—(Y) a —O—R 3b ] w IIIz
R 4 —O—(Y 1 ) c —O—(Y) d —O—R 4b IVz
R[—(X) a —O—R 5b ] w Vz
wherein:
each —O—R 1b , —O—R 3b , —O—R 4b , R 4b —O—, and —O—R 5b is independently:
each —OC(═O)—R 2b is independently:
each Z is independently: NH 2 , NH(Y 1 ) b H, N((X 1 ) b H) 2 , NCO, CH 2 CO 2 H, or CH═CHCO 2 H;
each X is independently:
—OC(═O)CH 2 — (inverse glycolic acid moiety), —OC(═O)CH(CH 3 )— (inverse lactic acid moiety), —OC(═O)CH 2 OCH 2 CH 2 — (inverse dioxanone acid moiety), —OC(═O)CH 2 CH 2 CH 2 CH 2 CH 2 — (inverse caprolactone acid moiety), —OC(═O)(CH 2 ) y —, or —OC(═O)CH 2 (OCH 2 CH 2 ) z —.
each X 1 is independently:
—CH 2 C(═O)O— (glycolic acid moiety), —CH(CH 3 )C(═O)O— (lactic acid moiety), —CH 2 CH 2 OCH 2 C(═O)O— (dioxanone acid moiety), —CH 2 CH 2 CH 2 CH 2 CH 2 C(═O)O— (caprolactone acid moiety), —(CH 2 ) y C(═O)O—, or —(CH 2 CH 2 O) z CH 2 C(═O)O—;
each Y is independently:
—OCH 2 C(═O)— (inverse glycolic ester moiety), —OCH(CH 3 )C(═O)— (inverse lactic ester moiety), —OCH 2 CH 2 OCH 2 C(═O)— (inverse dioxanone ester moiety), —OCH 2 CH 2 CH 2 CH 2 CH 2 C(═O)— (inverse caprolactone ester moiety), —O(CH 2 ) m C(═O)—, or —O(CH 2 CH 2 O) n OCH 2 C(═O)—;
each Y 1 is independently:
—C(═O)CH 2 O— (glycolic ester moiety), —C(═O)CH(CH 3 )O— (lactic ester moiety), —C(═O)CH 2 OCH 2 CH 2 O— (dioxanone ester moiety), —C(═O)CH 2 CH 2 CH 2 CH 2 CH 2 O— (caprolactone ester moiety), —C(═O)(CH 2 ) m O—, or —C(═O)CH 2 O(CH 2 CH 2 O) n —;
R is a di-, tri, tetra-, penta- or hexaradical derived from C 1-25 alkyl, aryl, or aryl-(C 1-6 alkyl) 1-3 -, wherein from 1-3 of the CH 2 groups within the alkyl chain are optionally independently replaced by O or S atoms, such that each of said O or S atoms is attached only to carbon atoms in the alkyl chain, with the proviso that multiple heteroatoms must be separated from each other and from the di-, tri, tetra-, penta- or hexaradical chain ends by at least one carbon atom; or R is —[CH 2 CH 2 O—] p —, wherein p is an integer from about 10 to about 50;
each a and b is independently an integer from about 1 to about 6;
each m, n, y, and z is independently an integer from about 2 to about 24;
w is an integer from about 2 to about 6; and
c and d are each an integer from 1 to 5, with the proviso that the sum of c+d is an integer from about 2 to about 6.
30 . A compound of formula Iz, IIz, IIIz, IVz, or Vz:
R[—C(═O)—(Y) a —O—R 1b ] w Iz
R[—(X) a —OC(═O)—R 2b ] w IIz
R[—(Y) a —O—R 3b ] w IIIz
R 4b —O—(Y 1 ) c —O—(Y) d —O—R 4b IVz
R[—(X) a —O—R 5b ] w Vz
wherein:
each R 1b , R 2b , R 3b , R 4b , R 4b , and R 5b is independently H, alkyl, or aralkyl;
each Z is independently: NH 2 , NH(Y 1 ) b H, N((X 1 ) b H) 2 , NCO, CH 2 CO 2 H, or CH═CHCO 2 H;
each X is independently:
—OC(═O)CH 2 — (inverse glycolic acid moiety), —OC(═O)CH(CH 3 )— (inverse lactic acid moiety), —OC(═O)CH 2 OCH 2 CH 2 — (inverse dioxanone acid moiety), —OC(═O)CH 2 CH 2 CH 2 CH 2 CH 2 — (inverse caprolactone acid moiety), —OC(═O)(CH 2 ) y —, or —OC(═O)CH 2 (OCH 2 CH 2 ) z —,
each X 1 is independently:
—CH 2 C(═O)O— (glycolic acid moiety), —CH(CH 3 )C(═O)O— (lactic acid moiety), —CH 2 CH 2 OCH 2 C(═O)O— (dioxanone acid moiety), —CH 2 CH 2 CH 2 CH 2 CH 2 C(═O)O— (caprolactone acid moiety), —(CH 2 ) y C(═O)O—, or —(CH 2 CH 2 O) z CH 2 C(═O)O—;
each Y is independently:
—OCH 2 C(═O)— (inverse glycolic ester moiety), —OCH(CH 3 )C(═O)— (inverse lactic ester moiety), —OCH 2 CH 2 OCH 2 C(═O)— (inverse dioxanone ester moiety), —OCH 2 CH 2 CH 2 CH 2 CH 2 C(═O)— (inverse caprolactone ester moiety), —O(CH 2 ) m C(═O)—, or —O(CH 2 CH 2 O) n OCH 2 C(═O)—;
each Y 1 is independently:
—C(═O)CH 2 O— (glycolic ester moiety), —C(═O)CH(CH 3 )O— (lactic ester moiety), —C(═O)CH 2 OCH 2 CH 2 O— (dioxanone ester moiety), —C(═O)CH 2 CH 2 CH 2 CH 2 CH 2 O— (caprolactone ester moiety), —C(═O)(CH 2 ) m O—, or —C(═O)CH 2 O(CH 2 CH 2 O) n —;
R is a di-, tri, tetra-, penta- or hexaradical derived from C 1-25 alkyl, aryl, or aryl-(C 1-6 alkyl) 1-3 -, wherein from 1-3 of the CH 2 groups within the alkyl chain are optionally independently replaced by O or S atoms, such that each of said O or S atoms is attached only to carbon atoms in the alkyl chain, with the proviso that multiple heteroatoms must be separated from each other and from the di-, tri, tetra-, penta- or hexaradical chain ends by at least one carbon atom; or R is —[CH 2 CH 2 O—] p —, wherein p is an integer from about 10 to about 50;
each a and b is independently an integer from about 1 to about 6;
each m, n, y, and z is independently an integer from about 2 to about 24;
w is an integer from about 2 to about 6; and
c and d are each an integer from 1 to 5, with the proviso that the sum of c+d is an integer from about 2 to about 6.Join the waitlist — get patent alerts
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