US7087229B2
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Releasable polymeric conjugates based on aliphatic biodegradable linkers
Assignee: Belrose Pharma Inc
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Filing: 2003-05-30
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Granted: 2006-08-08
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Expires: 2023-05-30
Abstract
Abstract Activated polymeric bicine derivatives such as, as well as conjugates made therewith are disclosed. Methods of making and using the bicine derivatives are also disclosed.
Inventors
- 👤 Hong Zhao
- 👤 Richard B. Greenwald
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-31 05:48
CPC Classifications
C; C08; C08G; C08G63/00; C08G63/91; C07; C07D; C07D277/00; C07D277/02; C07D277/08; C07D277/12; C07D277/16; A; A61; A61K; A61K47/00; A61K47/50; A61K47/51; A61K47/56; A61K47/59; A61K47/60; A61P; A61P35/00; A61P35/04; C07D207/00; C07D207/02; C07D207/30; C07D207/34; C07D207/36; C07D207/40; C07D207/404; C07K; C07K5/00; C07K5/04; C07K5/06; G; G01; G01N; G01N33/00; G01N33/48; G01N33/50; G01N33/53
Claims Analysis
Total Claims: 35
Claim 1
Independent Claim
307 words
A compound comprising the Formula (I): wherein: R 1 and R 2 are independently selected from the group consisting of substantially non-antigenic polymer residues, H, C 1-6 alkyls, C 2-6 alkenyl, C 2-6 alkynyl, aralkyls, and terminal branching groups; Z is selected from the group consisting of hydrophobics moieties, bifunctional linking moieties, wherein L 3 is a bifunctional linker and Y 4 is O, S or NR 11 , and combinations thereof; Y 1-3 may be the same or different and are selected from among O, S or NR 11 ; L 1 and L 2 may be the same or different bifunctional linkers; R 3 –R 11 , R 24 and R 25 may be the same or different and are selected from the group consisting of hydrogen, C 1-6 alkyls, C 2-6 alkenyl, C 2-6 alkynyl, C 3-19 branched alkyls, C 3-8 cycloalkyls, C 1-6 substituted alkyls, C 2-6 substituted alkenyls, C 2-6 substituted alkynyls, C 3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, C 1-6 heteroalkyls, substituted C 1-6 heteroalkyls, C 1-6 alkoxy, phenoxy and C 1-6 heteroalkoxy; L 3 and L 4 may be the same or different and are selected from: —C(O)(CR 30 R 31 )Y 15 (CR 32 R 33 )C(O)— or —C(O)(CR 30 R 31 )(CR 32 R 33 )C(O)— wherein: Y 15 is selected from O, S, NR 34 or CH 2 , and R 30-34 may be the same or different and are selected from H, alkyl, alkenyl, alkynyl, heteroalkyl or aryl; A is selected from the group consisting of bioligically active proteins, leaving groups, functional groups, and OH; a, b, c, d, and e are independently 0 or 1 m, n, o, and p are independently positive integers, f and g are 0 or 1, provided that at least one of (f+a) or (g+c) is equal to 2.
Claim 2
Dependent Claim
307 words
A compound comprising the Formula (I): wherein: R 1 and R 2 are independently selected from the group consisting of substantially non-antigenic polymer residues, H, C 1-6 alkyls, C 2-6 alkenyl, C 2-6 alkynyl, aralkyls, and terminal branching groups; Z is selected from the group consisting of hydrophobics moieties, bifunctional linking moieties, wherein L 3 is a bifunctional linker and Y 4 is O, S or NR 11 , and combinations thereof; Y 1-3 may be the same or different and are selected from among O, S or NR 11 ; L 1 and L 2 may be the same or different bifunctional linkers; R 3 –R 11 , R 24 and R 25 may be the same or different and are selected from the group consisting of hydrogen, C 1-6 alkyls, C 2-6 alkenyl, C 2-6 alkynyl, C 3-19 branched alkyls, C 3-8 cycloalkyls, C 1-6 substituted alkyls, C 2-6 substituted alkenyls, C 2-6 substituted alkynyls, C 3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, C 1-6 heteroalkyls, substituted C 1-6 heteroalkyls, C 1-6 alkoxy, phenoxy and C 1-6 heteroalkoxy; L 3 and L 4 may be the same or different and are selected from: —C(O)(CR 30 R 31 )Y 15 (CR 32 R 33 )C(O)— or —C(O)(CR 30 R 31 )(CR 32 R 33 )C(O)— wherein: Y 15 is selected from O, S, NR 34 or CH 2 , and R 30-34 may be the same or different and are selected from H, alkyl, alkenyl, alkynyl, heteroalkyl or aryl; A is selected from the group consisting of bioligically active proteins, leaving groups, functional groups, and OH; a, b, c, d, and e are independently 0 or 1 m, n, o, and p are independently positive integers, f and g are 0 or 1, provided that at least one of (f+a) or (g+c) is equal to 2.
Claim 3
Dependent Claim
29 words
The compound of claim 1 , wherein R 3 –R 10 , R 24-25 and R 30-34 are each hydrogen; and Y 15 is O or NR 34 .
Claim 4
Dependent Claim
27 words
The compound of claim 1 , wherein a, b, c, d, f, g, m, n, o and p are each 1, and e is 0 or 1.
Claim 5
Dependent Claim
13 words
The compound of claim 1 , wherein (c and g) are each 0.
Claim 6
Dependent Claim
13 words
The compound of claim 1 , wherein (a and f) are each 0.
Claim 7
Dependent Claim
14 words
The compound of claim 1 , wherein (c, g, and d) are each 0.
Claim 8
Dependent Claim
14 words
The compound of claim 1 , wherein (a, b and f) are each 0.
Claim 9
Dependent Claim
13 words
The compound of claim 1 , wherein R 1 comprises a polyalkylene oxide.
Claim 10
Dependent Claim
13 words
The compound of claim 1 , wherein R 2 comprises a polyalkylene oxide.
Claim 11
Dependent Claim
13 words
The compound of claim 1 , wherein R 1 comprises a polyethylene glycol.
Claim 12
Dependent Claim
12 words
The compound of claim 1 wherein R 2 comprises a polyethylene glycol.
Claim 13
Dependent Claim
35 words
The compound of claim 1 wherein R 1 or R 2 further include a capping group J, selected from the group consisting of OH, NH 2 , SH, CO 2 H, C 1-6 alkyl moieties,
Claim 14
Dependent Claim
12 words
A compound of claim 10 , selected from the group consisting of:
Claim 15
Dependent Claim
176 words
The compound of claim 1 , wherein R 1 is selected from the group consisting of: J-O—(CH 2 CH 2 O) x —, J-O—(CH 2 CH 2 O) x —CH 2 C(O)—O—, J-O—(CH 2 CH 2 O) x —CH 2 CH 2 NR 12 —, J-O—(CH 2 CH 2 O) x —CH 2 CH 2 SH—, —OC(O)CH 2 —O—(CH 2 CH 2 O) x —CH 2 C(O)—O—, —NR 12 CH 2 CH 2 —O—(CH 2 CH 2 O) x —CH 2 CH 2 NR 12 — and —SHCH 2 CH 2 —O—(CH 2 CH 2 O) x —CH 2 CH 2 SH— wherein: x is the degree of polymerization; R 12 is selected from the group consisting of hydrogen, C 1-6 alkyls, C 2-6 alkenyl, C 2-6 alkynyl, C 3-19 branched alkyls, C 3-4 cycloalkyls, C 1-6 substituted alkyls, C 2-6 substituted alkenyls, C 2-6 substituted alkynyls, C 3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, C 1-6 heteroalkyls, substituted C 1-6 heteroalkyls, C 1-6 alkoxy, phenoxy and C 1-6 heteroalkoxy; and J is a capping group.
Claim 16
Dependent Claim
176 words
The compound of claim 1 , wherein R 2 is selected from the group consisting of: J-O—(CH 2 CH 2 O) x —, J-O—(CH 2 CH 2 O) x —CH 2 C(O)—O—, J-O—(CH 2 CH 2 O) x —CH 2 CH 2 NR 13 —, J-O—(CH 2 CH 2 O) x —CH 2 CH 2 SH—, —OC(O)CH 2 —O—(CH 2 CH 2 O) x —CH 2 C(O)—O—, —NR 13 CH 2 CH 2 —O—(CH 2 CH 2 O) x —CH 2 CH 2 NR 13 — and —SHCH 2 CH 2 —O—(CH 2 CH 2 O) x —CH 2 CH 2 SH—, wherein: x is the degree of polymerization; R 13 is selected from the group consisting of hydrogen, C 1-6 alkyls, C 2-6 alkenyls, C 2-6 alkynyls, C 3-12 branched alkyls, C 3-8 cycloalkyls, C 1-6 substituted alkyls, C 2-6 substituted alkenyls, C 2-6 substituted alkynyls, C 3-8 substituted cycloalkyls, aryls substituted aryls, aralkyls, C 1-6 heteroalkyls, substituted C 1-6 heteroalkyls, C 1-6 alkoxy, phenoxy and C 1-6 heteroalkoxy, and J is a capping group.
Claim 17
Dependent Claim
71 words
The compound of claim 1 , wherein R 1-2 are individually selected from the group consisting of: CH 3 —O—(CH 2 CH 2 O) x —, CH 3 —O—(CH 2 CH 2 O) x —CH 2 C(O)—O—, CH 3 —O—(CH 2 CH 2 O) x —CH 2 CH 2 NH— and CH 3 —O—(CH 2 CH 2 O) x —CH 2 CH 2 SH— wherein x is the degree of polymerization.
Claim 18
Dependent Claim
34 words
The compound of claim 1 , wherein R 1 and R 2 each comprise a polymer residue of the formula —O CH 2 CH 2 O x wherein x is the degree of polymerization.
Claim 19
Dependent Claim
28 words
The compound of claim 17 , wherein R 1 and R 2 each have a weight average molecular weight of from about 2,000 Da to about 25,000 Da.
Claim 20
Dependent Claim
300 words
The compound of claim 1 wherein L 1 and L 2 are independently selected from the group consisting of: —NR 19 (CR 14 R 15 ) t O—, —NR 19 (CR 14 R 15 ) t (CR 16 CR 17 O) q NR 19 —, —O(CR 14 R 15 ) t NR 19 —, —O(CR 14 R 15 ) t O—, —NR 19 (CR 14 R 15 ) t NR 19 —, —NR 19 (CR 14 R 15 ) t (CR 16 CR 17 O) q —, —NR 19 (CR 16 CR 17 O) t —, —NR 19 (CR 16 CR 17 O) t (CR 14 R 15 ) q NR 19 —, —NR 19 (CR 16 CR 17 O) t —, —O(CR 14 R 15 ) t —NR 19 —, —O(CR 14 R 15 ) t NR 19 —, —O(CR 16 CR 17 O) t NR 19 —, wherein: R 14 –R 17 and R 19 are independently selected from the group consisting of hydrogen, C 1-6 alkyls, C 2-6 alkenyls, C 2-6 alkynyls, C 3-12 branched alkyls, C 3-8 cycloalkyls, C 1-6 substituted alkyls, C 2-6 substituted alkenyls, C 2-6 substituted alkynyls, C 3-8 substituted cycloalkyls, aryls substituted aryls, aralkyls, C 1-6 heteroalkyls, substituted C 1-6 heteroalkyls, C 1-6 alkoxy, phenoxy and C 1-6 heteroalkoxy; and R 18 is selected from the group consisting of hydrogen, C 1-6 alkyls, C 2-6 alkenyls, C 2-6 alkynyls, C 3-12 branched alkyls, C 3-8 cycloalkyls, C 1-6 substituted alkyls, C 2-6 substituted alkenyls, C 2-6 substituted alkynyls, C 3-8 substituted cycloalkyls, aryls substituted aryls, aralkyls, C 1-6 heteroalkyls, substituted C 1-6 heteroalkyls, C 1-6 alkoxy, phenoxy and C 1-6 heteroalkoxy, NO 2 , haloalkyl and halogen; and t and q are individually selected positive integers from about 1 to about 4.
Claim 21
Dependent Claim
90 words
The compound of claim 1 wherein L 3 and L 4 are independently selected from the group consisting of: —C(O)CR 30 R 31 OCR 32 R 33 C(O)—; —C(O)CR 30 R 31 NR 34 CR 32 R 33 C(O)—; —C(O)CR 30 R 31 SCR 32 R 33 C(O)—, or —C(O)(CR 30 R 31 ) n C(O)—; wherein: R 30-34 are independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 heteroalkyl or aryl, and n is a positive integer from about 2 to about 3.
Claim 22
Dependent Claim
16 words
A compound of claim 1 , comprising the formula: where A 1 is a leaving group.
Claim 23
Dependent Claim
19 words
A compound of claim 1 , selected from the group consisting of wherein A 1 is a leaving group.
Claim 24
Dependent Claim
19 words
The compound of claim 1 , wherein A 1 is a leaving group selected from the group consisting of
Claim 25
Dependent Claim
10 words
The compound of claim 23 , wherein A 1 is:
Claim 26
Dependent Claim
27 words
The compound of claim 1 , wherein A is selected from the group consisting of maleimidyl, vinyl sulfonyl, hydroxy, amino, carboxy, mercapto, hydrazide, and carbazate functional groups.
Claim 27
Dependent Claim
243 words
The compound of claim 1 , wherein said terminal branching group comprises the formula: wherein: Y 5 is O, S or NR 46 ; L 6 is a bifunctional linker selected from the same group as that which defines L 1 ; L 8 is a bifunctional linker selected from the same group as that which defines L 3 ; R 40 –R 46 may be the same or different and are selected from the group consisting of hydrogen, C 1-6 alkyls, C 2-6 alkenyl, C 2-6 alkynyl, C 3-19 branched alkyls, C 3-8 cycloalkyls, C 1-6 substituted alkyls, C 2-6 substituted alkenyls, C 2-6 substituted alkynyls, C 3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, C 1-6 heteroalkyls, substituted C 1-6 heteroalkyls, C 1-6 alkoxy, phenoxy and C 1-6 heteroalkoxy; j,j′, k and k′ are each independently 0 or a positive integer; q is 0 or 1; g, h, v and w are independently selected positive integers; R 50 is selected from the group consisting of substantially non-antigenic polymer residues, C 1-6 alkyls, C 2-6 alkenyl, C 2-6 alkynyl, aralkyls, and wherein: L 7 is a bifunctional linker selected from the same group as that which defines L 1 ; L 9 is a bifunctional linker selected from the same group as that which defines L 3 ; and R 60 is selected from the group consisting of substantially non-antigenic polymer residues, C 1-6 alkyls, C 2-6 alkenyl, C 2-6 alkynyl, and aralkyls.
Claim 28
Dependent Claim
9 words
A compound of claim 26 , comprising the structure:
Claim 29
Dependent Claim
9 words
A compound of claim 26 , comprising the structure:
Claim 30
Dependent Claim
12 words
A compound of claim 1 , selected from the group consisting of
Claim 31
Dependent Claim
18 words
A compound of claim 1 , selected from the group consisting of wherein A is a leaving group.
Claim 32
Independent Claim
332 words
A method of preparing a polymer conjugate, comprising reacting a compound of the formula: wherein: A 1 is a leaving group; R 1 and R 2 are independently selected from the group consisting of substantially non-antigenic polymer residues, H, C 1-6 alkyls, C 2-6 alkenyl, C 2-6 alkynyl, aralkyls, and terminal branching groups, provided both R 1 and R 2 are not H; Z is selected from hydrophobic moieties, bifunctional linking moieties, wherein L 3 is a bifunctional linker and Y 4 is O, S or NR 11 , and combinations thereof; Y 1-3 may be the same or different and are selected from among O, S or NR 11 ; L 1 and L 2 may be the same or different bifunctional linkers; R 3 –R 11 , R 24 and R 25 may be the same or different and are selected from the group consisting of hydrogen, C 1-6 alkyls, C 2-6 alkenyl, C 2-6 alkynyl, C 3-19 branched alkyls, C 3-8 cycloalkyls, C 1-6 substituted alkyls, C 2-6 substituted alkenyls, C 2-6 substituted alkynyls, C 3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, C 1-6 heteroalkyls, substituted C 1-6 heteroalkyls, C 1-6 alkoxy, phenoxy and C 1-6 heteroalkoxy; L 3 and L 4 may be the same or different and are selected from: —C(O)(CR 30 R 31 )Y 15 (CR 32 R 33 )C(O)— or —C(O)(CR 30 R 31 )(CR 32 R 33 )C(O)— wherein: Y 15 is selected from O, S, NR 34 or CH 2 , and R 30-34 may be the same or different and are selected from H, alkyl, alkenyl, alkynyl, heteroalkyl or aryl; wherein a, b, c, d, and e are independently 0 or 1 m, n, o, and p are independantly positive integers, f and g are 0 or 1, provided that at least one of (f+a) or (g+c) is equal to 2; with a biologically active protein under conditions sufficient to form wherein A 2 is a residue of a biologically active agent.
Claim 33
Independent Claim
332 words
A method of preparing a polymer conjugate, comprising reacting a compound of the formula: wherein: A 1 is a leaving group; R 1 and R 2 are independently selected from the group consisting of substantially non-antigenic polymer residues, H, C 1-6 alkyls, C 2-6 alkenyl, C 2-6 alkynyl, aralkyls, and terminal branching groups, provided both R 1 and R 2 are not H; Z is selected from hydrophobic moieties, bifunctional linking moieties, wherein L 3 is a bifunctional linker and Y 4 is O, S or NR 11 , and combinations thereof; Y 1-3 may be the same or different and are selected from among O, S or NR 11 ; L 1 and L 2 may be the same or different bifunctional linkers; R 3 –R 11 , R 24 and R 25 may be the same or different and are selected from the group consisting of hydrogen, C 1-6 alkyls, C 2-6 alkenyl, C 2-6 alkynyl, C 3-19 branched alkyls, C 3-8 cycloalkyls, C 1-6 substituted alkyls, C 2-6 substituted alkenyls, C 2-6 substituted alkynyls, C 3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, C 1-6 heteroalkyls, substituted C 1-6 heteroalkyls, C 1-6 alkoxy, phenoxy and C 1-6 heteroalkoxy; L 3 and L 4 may be the same or different and are selected from: —C(O)(CR 30 R 31 )Y 15 (CR 32 R 33 )C(O)— or —C(O)(CR 30 R 31 )(CR 32 R 33 )C(O)— wherein: Y 15 is selected from O, S, NR 34 or CH 2 , and R 30-34 may be the same or different and are selected from H, alkyl, alkenyl, alkynyl, heteroalkyl or aryl; wherein a, b, c, d, and e are independently 0 or 1 m, n, o, and p are independantly positive integers, f and g are 0 or 1, provided that at least one of (f+a) or (g+c) is equal to 2; with a biologically active protein under conditions sufficient to form wherein A 2 is a residue of a biologically active agent.
Claim 34
Independent Claim
79 words
A method of preparing a bicine-based polymer transport system, comprising: a) reacting a blocked bifunctional linker with an anhydride to form an extended blocked bifunctional spacer of the formula: b) attaching the blocked bifunctional spacer to each hydroxyl of an acid protected bicine molecule; c) deblocking the resultant intermediate and reacting it with an activated polymer under basic coupling conditions, and d) deprotecting the bicine acid and thereafter activating the acid with a suitable activating group under coupling conditions.
Claim 35
Independent Claim
79 words
A method of preparing a bicine-based polymer transport system, comprising: a) reacting a blocked bifunctional linker with an anhydride to form an extended blocked bifunctional spacer of the formula: b) attaching the blocked bifunctional spacer to each hydroxyl of an acid protected bicine molecule; c) deblocking the resultant intermediate and reacting it with an activated polymer under basic coupling conditions, and d) deprotecting the bicine acid and thereafter activating the acid with a suitable activating group under coupling conditions.
References Cited (Backward Citations)
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