HYDROLYSABLE LINKERS AND CROSS-LINKERS FOR ABSORBABLE POLYMERS
First Claim
Patent Images
1. A linker or pharmaceutically acceptable salt thereof of formula I, II, III, or IV:
-
R[—
C(═
O)—
(Y)a—
O—
R1]w
I
R[—
(X)a—
OC(═
O)—
R2]w
II
R[—
(Y)a—
O—
R3]w
III
R4—
O—
(Y1)c—
O—
(Y)d—
O—
R4
IVwherein;
each —
O—
R1, —
O—
R3, —
O—
R4, and R4—
O—
is independently;
each —
OC(═
O)—
R2 is independently;
each Z is independently;
NH2, NH(Y1)bH, N((X1)bH)2, NCO, CH2CO2H, or CH═
CHCO2H;
each X is independently;
—
OC(═
O)CH2—
(inverse glycolic acid moiety), —
OC(═
O)CH(CH3)—
(inverse lactic acid moiety), —
OC(═
O)CH2OCH2CH2—
(inverse dioxanone acid moiety), —
OC(═
O)CH2CH2CH2CH2CH2—
(inverse caprolactone acid moiety), —
OC(═
O)(CH2)y—
, or —
OC(═
O)CH2(OCH2CH2)z—
. each X1 is independently;
—
CH2C(═
O)O—
(glycolic acid moiety), —
CH(CH3)C(═
O)O—
(lactic acid moiety), —
CH2CH2OCH2C(═
O)O—
(dioxanone acid moiety), —
CH2CH2CH2CH2CH2C(═
O)O—
(caprolactone acid moiety), —
(CH2)yC(═
O)O—
, or —
(CH2CH2O)nCH2C(═
O)O—
;
each Y is independently;
—
OCH2C(═
O)—
(inverse glycolic ester moiety), —
OCH(CH3)C(═
O)—
(inverse lactic ester moiety), —
OCH2CH2OCH2C(═
O)—
(inverse dioxanone ester moiety), —
OCH2CH2CH2CH2CH2C(═
O)—
(inverse caprolactone ester moiety), —
O(CH2)mC(═
O)—
, or —
O(CH2CH2O)nOCH2C(═
O)—
;
each Y1 is independently;
—
C(═
O)CH2O—
(glycolic ester moiety), —
C(═
O)CH(CH3)O—
(lactic ester moiety), —
C(═
O)CH2OCH2CH2O—
(dioxanone ester moiety), —
C(═
O)CH2CH2CH2CH2CH2O—
(caprolactone ester moiety), C(═
O)(CH2)mO—
, or —
C(═
O)CH2—
O—
(CH2CH2O)n—
;
R is a di-, tri, tetra-, penta- or hexaradical derived from C1-25 alkyl, aryl, or aryl-(C1-6alkyl)1-3-, wherein from 1-3 of the CH2 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 —
[CH2CH2O—
]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.
1 Assignment
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Accused Products
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.
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Citations
30 Claims
-
1. A linker or pharmaceutically acceptable salt thereof of formula I, II, III, or IV:
-
R[—
C(═
O)—
(Y)a—
O—
R1]w
I
R[—
(X)a—
OC(═
O)—
R2]w
II
R[—
(Y)a—
O—
R3]w
III
R4—
O—
(Y1)c—
O—
(Y)d—
O—
R4
IVwherein; each —
O—
R1, —
O—
R3, —
O—
R4, and R4—
O—
is independently;each —
OC(═
O)—
R2 is independently;each Z is independently;
NH2, NH(Y1)bH, N((X1)bH)2, NCO, CH2CO2H, or CH═
CHCO2H;each X is independently; —
OC(═
O)CH2—
(inverse glycolic acid moiety), —
OC(═
O)CH(CH3)—
(inverse lactic acid moiety), —
OC(═
O)CH2OCH2CH2—
(inverse dioxanone acid moiety), —
OC(═
O)CH2CH2CH2CH2CH2—
(inverse caprolactone acid moiety), —
OC(═
O)(CH2)y—
, or —
OC(═
O)CH2(OCH2CH2)z—
.each X1 is independently; —
CH2C(═
O)O—
(glycolic acid moiety), —
CH(CH3)C(═
O)O—
(lactic acid moiety), —
CH2CH2OCH2C(═
O)O—
(dioxanone acid moiety), —
CH2CH2CH2CH2CH2C(═
O)O—
(caprolactone acid moiety), —
(CH2)yC(═
O)O—
, or —
(CH2CH2O)nCH2C(═
O)O—
;each Y is independently; —
OCH2C(═
O)—
(inverse glycolic ester moiety), —
OCH(CH3)C(═
O)—
(inverse lactic ester moiety), —
OCH2CH2OCH2C(═
O)—
(inverse dioxanone ester moiety), —
OCH2CH2CH2CH2CH2C(═
O)—
(inverse caprolactone ester moiety), —
O(CH2)mC(═
O)—
, or —
O(CH2CH2O)nOCH2C(═
O)—
;each Y1 is independently; —
C(═
O)CH2O—
(glycolic ester moiety), —
C(═
O)CH(CH3)O—
(lactic ester moiety), —
C(═
O)CH2OCH2CH2O—
(dioxanone ester moiety), —
C(═
O)CH2CH2CH2CH2CH2O—
(caprolactone ester moiety), C(═
O)(CH2)mO—
, or —
C(═
O)CH2—
O—
(CH2CH2O)n—
;R is a di-, tri, tetra-, penta- or hexaradical derived from C1-25 alkyl, aryl, or aryl-(C1-6alkyl)1-3-, wherein from 1-3 of the CH2 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 —
[CH2CH2O—
]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. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 17, 18, 19, 20, 21, 22, 23, 24, 25)
wherein: -
each Y1 is independently; —
C(═
O)CH2O—
, —
C(═
O)CH(CH3)O—
, —
C(═
O)CH2OCH2CH2O—
, or —
C(═
O)CH2CH2CH2CH2CH2O—
; andeach Y is independently; —
OCH2C(═
O)—
, —
OCH(CH3)C(═
O)—
, —
OCH2CH2OCH2C(═
O)—
, or—
OCH2CH2CH2CH2CH2C(═
O)—
.
-
13. A linker or pharmaceutically acceptable salt thereof of claim 12,
wherein: -
each Y1 is independently; —
C(═
O)CH2O—
or —
C(═
O)CH2CH2CH2CH2CH2O—
; andeach Y is independently; —
OCH2C(═
O)—
or —
OCH2CH2CH2CH2CH2C(═
O)—
.
-
-
17. A linker or pharmaceutically acceptable salt thereof of claim 6, wherein:
each X is independently; —
OC(═
O)CH2—
, —
OC(═
O)CH(CH3)—
, —
OC(═
O)CH2OCH2CH2—
, or —
OC(═
O)CH2CH2CH2CH2CH2—
.
-
18. A linker or pharmaceutically acceptable salt thereof of claim 17, wherein:
each X is independently —
OC(═
O)CH2—
or —
OC(═
O)CH(CH3)—
.
-
19. A linker or pharmaceutically acceptable salt thereof of claim 3, wherein R is (CH2)3, and wherein the C-2 CH2 group within the (CH2)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 (CH2)2 and w is 2.
-
22. A linker or pharmaceutically acceptable salt thereof of claim 21, wherein X is —
- CH2C(═
O)O—
or —
CH2CH2CH2CH2CH2C(═
O)O—
.
- CH2C(═
-
23. A linker or pharmaceutically acceptable salt thereof of claim 19, wherein R is (CH2)2, (CH2)3, (CH2)4, (CH2OCH2), or (CH2CH2OCH2CH2) and w is 2.
-
24. A linker or pharmaceutically acceptable salt thereof of claim 20, wherein R is (CH2CHCH2), and w is 3.
-
25. A linker or pharmaceutically acceptable salt thereof of claim 20, wherein R is (C(CH2)4), and w is 4.
-
-
14. A polyester of formula:
-
wherein; each Y1f is independently —
C(═
O)CH2O—
, —
C(═
O)CH(CH3)O—
, —
C(═
O)CH2OCH2CH2O—
, —
C(═
O)CH2CH2CH2CH2CH2O—
, —
C(═
O)(CH2)mO—
, or —
C(═
O)CH2—
O—
(CH2CH2O)n—
;each Yf is independently —
OCH2C(═
O)—
, —
OCH(CH3)C(═
O)—
, —
OCH2CH2OCH2C(═
O)—
, —
OCH2CH2CH2CH2CH2C(═
O)—
, —
O(CH2)mC(═
O)—
, or —
O(CH2CH2O)nOCH2C(═
O)—
;each m and n is independently an integer from about 2 to about 24; k1 is an integer from about 100 to about 5000; and each k2a and k2b is independently 1 to about 5. - View Dependent Claims (15, 16)
-
-
26. A compound of formula IVa:
-
R4a—
O—
(Y1a)c—
O—
(Ya)d—
O—
R4a
IVawherein; each Y1a is independently; —
C(═
O)CH2O—
, —
C(═
O)CH(CH3)O—
, —
C(═
O)CH2OCH2CH2O—
, —
C(═
O)CH2CH2CH2CH2CH2O—
, —
C(═
O)(CH2)mO—
, or —
C(═
O)CH2—
O—
(CH2CH2O)n—
;each Ya is independently; —
OCH2C(═
O)—
, —
OCH(CH3)C(═
O)—
, —
OCH2CH2OCH2C(═
O)—
, —
OCH2CH2CH2CH2CH2C(═
O)—
, —
O(CH2)mC(═
O)—
, or —
O(CH2CH2O)nOCH2C(═
O)—
;each R4a 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. - View Dependent Claims (27, 28)
wherein: -
each Y1a is independently —
C(═
O)CH2O—
or—
C(═
O)CH2CH2CH2CH2CH2O—
; andeach Ya is independently —
OCH2C(═
O)—
or—
OCH2CH2CH2CH2CH2C(═
O)—
.
-
-
29. A linker or pharmaceutically acceptable salt thereof of formula Iz, IIz, IIIz, IVz, or Vz:
-
R[—
C(═
O)—
(Y)a—
O—
R1b]w
Iz
R[—
(X)a—
OC(═
O)—
R2b]w
IIz
R[—
(Y)a—
O—
R1b]w
IIIz
R[—
O—
(Y1)c—
O—
(Y)d—
O—
R4b]w
IVz
R[—
(X)a—
O—
R2b]w
Vzwherein; each —
O—
R1b —
O—
R3b, —
O—
R4b, R4b—
O—
, and —
O—
R5b is independently;each —
OC(═
O)—
R2b is independently;each Z is independently;
NH2, NH(Y1)bH, N((X1)bH)2, NCO, CH2CO2H, or CH═
CHCO2H;each X is independently; —
OC(═
O)CH2—
(inverse glycolic acid moiety), —
OC(═
O)CH(CH3)—
(inverse lactic acid moiety), —
OC(═
O)CH2OCH2CH2—
(inverse dioxanone acid moiety), —
OC(═
O)CH2CH2CH2CH2CH2—
(inverse caprolactone acid moiety), —
OC(═
O)(CH2)y—
, or —
OC(═
O)CH2(OCH2CH2)z—
.each X1 is independently; —
CH2C(═
O)O—
(glycolic acid moiety), —
CH(CH3)C(═
O)O—
(lactic acid moiety), —
CH2CH2OCH2C(═
O)O—
(dioxanone acid moiety),—
CH2CH2CH2CH2CH2C(═
O)O—
(caprolactone acid moiety), —
(CH2)yC(═
O)O—
, or —
(CH2CH2O)nCH2C(═
O)O—
;each Y is independently; —
OCH2C(═
O)—
(inverse glycolic ester moiety), —
OCH(CH3)C(═
O)—
(inverse lactic ester moiety), —
OCH2CH2OCH2C(═
O)—
(inverse dioxanone ester moiety), —
OCH2CH2CH2CH2CH2C(═
O)—
(inverse caprolactone ester moiety), —
O(CH2)mC(═
O)—
, or —
O(CH2CH2O)nOCH2C(═
O)—
;each Y1 is independently; —
C(═
O)CH2O—
(glycolic ester moiety), —
C(═
O)CH(CH3)O—
(lactic ester moiety), —
C(═
O)CH2OCH2CH2O—
(dioxanone ester moiety), —
C(═
O)CH2CH2CH2CH2CH2O—
(caprolactone ester moiety), C(═
O)(CH2)mO—
, or —
C(═
O)CH2—
O—
(CH2CH2O)n—
;R is a di-, tri, tetra-, penta- or hexaradical derived from C1-25 alkyl, aryl, or aryl-(C1-6alkyl)1-3-, wherein from 1-3 of the CH2 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 —
[CH2CH2O—
]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)—
O—
R1b]w
Iz
R[—
(X)a—
OC(═
O)—
R2b]w
IIz
R[—
(Y)a—
O—
R3b]w
IIIz
R4b—
O—
(Y1)n—
O—
(Y)d—
O—
R4b
IVz
R[—
(X)a—
O—
R5b]w
Vzwherein; each R1b, R2b, R3b, R4b, R4b, and R5b is independently H, alkyl, or aralkyl; each Z is independently;
NH2, NH(Y1)bH, N((X1)bH)2, NCO, CH2CO2H, or CH═
CHCO2H;each X is independently; —
OC(═
O)CH2—
(inverse glycolic acid moiety), —
OC(═
O)CH(CH3)—
(inverse lactic acid moiety), —
OC(═
O)CH2OCH2CH2—
(inverse dioxanone acid moiety), —
OC(═
O)CH2CH2CH2CH2CH2—
(inverse caprolactone acid moiety), —
OC(═
O)(CH2)y—
, or —
OC(═
O)CH2(OCH2CH2)z—
.each X1 is independently; —
CH2C(═
O)O—
(glycolic acid moiety), —
CH(CH3)C(═
O)O—
(lactic acid moiety), —
CH2CH2OCH2C(═
O)O—
(dioxanone acid moiety), —
CH2CH2CH2CH2CH2C(═
O)O—
(caprolactone acid moiety), —
(CH2)yC(═
O)O—
, or —
(CH2CH2O)nCH2C(═
O)O—
;each Y is independently; —
OCH2C(═
O)—
(inverse glycolic ester moiety), —
OCH(CH3)C(═
O)—
(inverse lactic ester moiety), —
OCH2CH2OCH2C(═
O)—
(inverse dioxanone ester moiety), —
OCH2CH2CH2CH2CH2C(═
O)—
(inverse caprolactone ester moiety), —
O(CH2)mC(═
O)—
, or —
O(CH2CH2O)nOCH2C(═
O)—
;each Y1 is independently; —
C(═
O)CH2O—
(glycolic ester moiety), —
C(═
O)CH(CH3)O—
(lactic ester moiety), —
C(═
O)CH2OCH2CH2O—
(dioxanone ester moiety), —
C(═
O)CH2CH2CH2CH2CH2O—
(caprolactone ester moiety), C(═
O)(CH2)mO—
, or —
C(═
O)CH2—
O—
(CH2CH2O)n;R is a di-, tri, tetra-, penta- or hexaradical derived from C1-25 alkyl, aryl, or aryl-(C1-6alkyl)1-3-, wherein from 1-3 of the CH2 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 —
[CH2CH2O—
]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.
-
Specification