US5037883A
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Synthetic polymeric drugs
Assignee: Czech Academy of Sciences
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Filing: 1989-11-17
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Granted: 1991-08-06
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Expires: 2009-11-17
Abstract
Abstract A polymeric drug comprising an inert synthetic polymeric carrier combined through aminoacid or peptide spacers with a bioactive molecule, a targeting moiety, and an optional cross-linkage, comprises: (a) 5.0 to 99.7 mol % of units derived from N-(2-hydroxypropyl)methacrylamide, (b) 0.2 to 20.0 mol % of units derived from an N-methylacrylcylated peptide, the peptide groups being bound to a bioactive moiety, (c) 0.1 to 94.8 mol % of units derived from N-methacrylamide, N-methacrylic acid or an N-methacrylolated aminoacid or peptide, to which are bound a determinant capable of interacting with specific receptors on cell surfaces, (d) optionally, 0 to 5 mol % of units derived from an N-methacryloylated peptide, the peptide groups being bound to a linking group which is similarly to a similar peptide group attached to another polymer chain, and (e) optionally, as a bioassay label, 0 to 2 mol % units derived from N-methyacryloylated tyrosinamide.
Inventors
- 👤 Jindrich Kopecek
- 👤 Pavla Rejmanova
- 👤 Jiri Strohalm
- 👤 Karel Ulbrich
- 👤 Blanka Rihova
- 👤 Vladimir Chytry
- 👤 John B. Lloyd
- 👤 Ruth Duncan
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-06 13:40
CPC Classifications
A; A61; A61K; A61K47/00; A61K47/50; A61K47/51; A61K47/68; A61K47/6835; A61K47/6883; A61K47/56; A61K47/58; A61P; A61P35/00; Y; Y10; Y10S; Y10S530/00; Y10S530/81; Y10S530/811; Y10S530/812; Y10S530/815; Y10S530/816
Claims Analysis
Total Claims: 20
Claim 1
Independent Claim
238 words
A drug conjugate comprising an inert synthetic polymeric carrier combined through peptide spacers with a bioactive molecule, with a targeting moiety, and with an optional cross-linkage, which comprises (a) 5.0 to 99.7 mol % of units derived from N-(2-hydroxypropyl)methacrylamide; (b) 0.2 to 20.0 mol % of units derived from an N-methacryloylated peptide, the peptide being covalently bound to a bioactive molecule and also being subject to intracellular lysosomal hydrolysis, said peptide being selected from Gly-Gly, Gly-Phe-Gly, Gly-Phe-Phe, Gly-Leu-Gly, Gly-Val-Ala, Gly-Phe-Ala, Gly-Leu-Phe, Gly-Leu-Ala, Ala-Val-Ala, Gly-Phe-Leu-Gly, Gly-Phe-Phe-Leu, Gly-Leu-Leu-Gly, Gly-Phe-Tyr-Ala, Gly-Phe-Gly-Phe, Ala-Gly-Val-Phe, Gly-Phe-Phe-Gly, Gly-Phe-Leu-Gly-Phe, and Gly-Gly-Phe-Leu-Gly-Phe; (c) 0.1 to 94.8 mol % of units derived from N-methacrylamide, N-methacrylic acid or an N-methacryloylated amino acid or peptide, to which are covalently bound a targeting moiety which is a determinant capable of interacting with specific receptors on cell surfaces, the amino acid or peptide being selected from Leu, Phe, Gly-Gly, Gly-Leu-Gly, Gly-Val-Ala, Gly-Phe-Ala, Gly-Leu-Phe, Gly-Leu-Ala, Ala-Val-Ala, Gly-Phe-Leu-Gly, Gly-Phe-Phe-Leu, Gly-Leu-Leu-Gly, Gly-Phe-Tyr-Ala, Gly-Phe-Gly-Phe, Ala-Gly-Val-Phe, Gly-Phe-Phe-Gly, Gly-Phe-Leu-Gly-Phe, and Gly-Gly-Phe-Leu-Gly-Phe; (d) optionally, 0 to 5 mol % of units derived from an N-methacryloylated peptide, the peptide groups being covalently bound to a linking group which is covalently attached to a similar peptide group attached to another polymer chain, the peptide being selected from Gly-Leu-Gly, Gly-Val-Ala, Gly-Phe-Ala, Gly-Leu-Phe, Gly-Leu-Ala, Ala-Val-Ala, Gly-Phe-Leu-Gly, Gly-Phe-Phe-Leu, Gly-Leu-Leu-Gly, Gly-Phe-Tyr-Ala, Gly-Phe-Gly-Phe, Ala-Gly-Val-Phe, Gly-Phe-Phe-Gly, Gly-Phe-Leu-Gly-Phe, and Gly-Gly-Phe-Leu-Gly-Phe; and (e) optionally, as a bioassay label, 0 to 2 mol % of units derived from N-methacryloylated tyrosinamide.
Claim 2
Dependent Claim
238 words
A drug conjugate comprising an inert synthetic polymeric carrier combined through peptide spacers with a bioactive molecule, with a targeting moiety, and with an optional cross-linkage, which comprises (a) 5.0 to 99.7 mol % of units derived from N-(2-hydroxypropyl)methacrylamide; (b) 0.2 to 20.0 mol % of units derived from an N-methacryloylated peptide, the peptide being covalently bound to a bioactive molecule and also being subject to intracellular lysosomal hydrolysis, said peptide being selected from Gly-Gly, Gly-Phe-Gly, Gly-Phe-Phe, Gly-Leu-Gly, Gly-Val-Ala, Gly-Phe-Ala, Gly-Leu-Phe, Gly-Leu-Ala, Ala-Val-Ala, Gly-Phe-Leu-Gly, Gly-Phe-Phe-Leu, Gly-Leu-Leu-Gly, Gly-Phe-Tyr-Ala, Gly-Phe-Gly-Phe, Ala-Gly-Val-Phe, Gly-Phe-Phe-Gly, Gly-Phe-Leu-Gly-Phe, and Gly-Gly-Phe-Leu-Gly-Phe; (c) 0.1 to 94.8 mol % of units derived from N-methacrylamide, N-methacrylic acid or an N-methacryloylated amino acid or peptide, to which are covalently bound a targeting moiety which is a determinant capable of interacting with specific receptors on cell surfaces, the amino acid or peptide being selected from Leu, Phe, Gly-Gly, Gly-Leu-Gly, Gly-Val-Ala, Gly-Phe-Ala, Gly-Leu-Phe, Gly-Leu-Ala, Ala-Val-Ala, Gly-Phe-Leu-Gly, Gly-Phe-Phe-Leu, Gly-Leu-Leu-Gly, Gly-Phe-Tyr-Ala, Gly-Phe-Gly-Phe, Ala-Gly-Val-Phe, Gly-Phe-Phe-Gly, Gly-Phe-Leu-Gly-Phe, and Gly-Gly-Phe-Leu-Gly-Phe; (d) optionally, 0 to 5 mol % of units derived from an N-methacryloylated peptide, the peptide groups being covalently bound to a linking group which is covalently attached to a similar peptide group attached to another polymer chain, the peptide being selected from Gly-Leu-Gly, Gly-Val-Ala, Gly-Phe-Ala, Gly-Leu-Phe, Gly-Leu-Ala, Ala-Val-Ala, Gly-Phe-Leu-Gly, Gly-Phe-Phe-Leu, Gly-Leu-Leu-Gly, Gly-Phe-Tyr-Ala, Gly-Phe-Gly-Phe, Ala-Gly-Val-Phe, Gly-Phe-Phe-Gly, Gly-Phe-Leu-Gly-Phe, and Gly-Gly-Phe-Leu-Gly-Phe; and (e) optionally, as a bioassay label, 0 to 2 mol % of units derived from N-methacryloylated tyrosinamide.
Claim 3
Dependent Claim
26 words
The drug conjugate according to claim 1 wherein the determinant is a monosaccharide, disaccharide or oligosaccharide bound by an amide linkage, an antibody or a protein.
Claim 4
Dependent Claim
18 words
The drug conjugate according to claim 2 wherein the saccharide determinant is galactose, galactosamine, gluosamine, mannosamine or fucosylamine.
Claim 5
Dependent Claim
15 words
The drug conjugate according to claim 1 wherein the determinant is IgG or anti-θ antibody.
Claim 6
Dependent Claim
35 words
The drug conjugate according to claim 1 wherein the bioactive molecule is an anti-cancer agent, an antimicrobial agent, an antiparasitic agent, an anti-inflammatory agent, a cardio-vascular drug, or a drug acting on the nervous system.
Claim 7
Dependent Claim
24 words
The drug conjugate according to claim 1 wherein the bioactive molecule is daunomycin, puromycin, adriamycin, melphalan isopropyl ester (sarcolysine), bleomycin, desferioxamine, bestatin, or tritylcysteine.
Claim 8
Dependent Claim
48 words
The drug conjugate according to claim 1 wherein the linking group of (d) is present and is of the type -(amino acid)--NH(CH 2 ) x NH--(amino acid)-, where x is an integer of from 1 to 12, and which is attached to adjacent peptide groups by amide linkages.
Claim 9
Dependent Claim
22 words
The drug conjugate according to claim 7 wherein x is 6 and the amino acid is Phe, Tyr, Ala, Gly, or Leu.
Claim 10
Dependent Claim
17 words
The drug conjugate according to claim 7 wherein x is 2 and the amino acid is Ala.
Claim 11
Dependent Claim
21 words
The drug conjugate according to claim 1 wherein the bioactive molecule is daunomycin, and the determinant is galactose, galactosamine or fucosylamine.
Claim 12
Dependent Claim
24 words
The drug conjugate according to claim 10 cross-linked with a cross-linking spacer comprising Gly-Phe-Leu-Gly and the linking group comprises -(Phe)NH(CH 2 ) 6 NH(Phe)-.
Claim 13
Dependent Claim
44 words
The process for the synthesis of a drug conjugate according to claim 1 which comprises copolymerizing N-(2-hydroxypropyl)methacrylamide with either an N-methacryloylated amino acid or peptide or the p-nitrophenyl ester thereof, and reacting the resultant copolymer with a reactive bioactive molecule and a reactive determinant.
Claim 14
Dependent Claim
19 words
The process according to claim 12 wherein N-methacryloylated tryosinamide is included in the copolymerization step as a bioassay label.
Claim 15
Dependent Claim
28 words
The process according to claim 12 wherein a diamine cross-linking agent is included in the reaction between the resultant copolymer, the reactive bioactive molecule and the reactive determinant.
Claim 16
Dependent Claim
25 words
The process according to claim 12 wherein a diamine cross-linking agent is included in the reaction between the resultant copolymer and the reactive bioactive molecule.
Claim 17
Dependent Claim
47 words
The process for the synthesis of a drug conjugate according to claim 1 which comprises copolymerizing N-(2-hydroxypropyl)methacrylamide an N-methacryloylated determinant or N-methacryloylated amino acid or peptidyl determinant, and either an N-methacryloylated peptide or the p-nitrophenyl ester thereof, and reacting the resultant copolymer with a reactive bioactive molecule.
Claim 18
Dependent Claim
19 words
The process according to claim 16 wherein N-methacryloylated tryosinamide is included in the copolymerization step as a bioassay label.
Claim 19
Dependent Claim
19 words
A pharmaceutical composition comprising at least one drug conjugate according to claim 11 and an inert, physiologically acceptable carrier.
Claim 20
Dependent Claim
22 words
The pharmaceutical composition according to claim 18 wherein the carrier is a sterile aqueous medium and the composition is formulated for injection.
References Cited (Backward Citations)
USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1994-08-05 | 1995-02-04 | 1995-08-06 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1998-08-05 | 1999-02-04 | 1999-08-06 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 2002-08-05 | 2003-02-04 | 2003-08-06 | $7700.00 | Window Closed / Lapsed |