US5738864A
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Drug delivery agents incorporating mitomycin
Assignee: EUROPEAN COMMUNITY
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Filing: 1994-08-17
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Granted: 1998-04-14
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Expires: 2014-08-17
Abstract
Abstract PCT No. PCT/IB94/00259 Sec. 371 Date Feb. 20, 1996 Sec. 102(e) Date Feb. 20, 1996 PCT Filed Aug. 17, 1994 PCT Pub. No. WO95/05200 PCT Pub. Date Feb. 23, 1995A conjugate of a carrier polymer and aziridine ring containing mitomycin (MMC) drug molecules is prepared by coupling the MMC molecules via their aziridine imino groups to spacer groups that terminate in protected amino groups, deprotecting said amino groups, recovering and purifying the spacer-MMC derivatives, and then coupling these derivatives via said deprotected amino groups to the carrier polymer. Alternatively, the MMC may first be treated with an activating agent, e.g. carbodiimidazole, to form an activated MMC derivative which is then coupled directly to spacer groups linked to the carrier polymer.
Inventors
- 👤 Etienne Honore Schacht
- 👤 Ruth Duncan
- 👤 Paolo Ferruti
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-26 00:09
CPC Classifications
A; A61; A61K; A61K47/00; A61K47/50; A61K47/51; A61K47/56; A61K47/61; A61K47/62; A61K47/65
Claims Analysis
Total Claims: 31
Claim 1
Independent Claim
215 words
A process for synthesizing a polymer/drug conjugate comprising a polymer carrier covalently coupled through linking spacer units to molecules of mitomycin-C or another therapeutically active mitomycin compound containing an >NH group in the aziridine ring thereof, said process comprising a first step of: (a) modifying said mitomycin-C or mitomycin compound to produce a reactive derivative thereof, either by (i) reacting said mitomycin-C or mitomycin compound with an activating agent so as to convert the mitomycin aziridine ring >NH group into an activated group which reacts with aliphatic amines, or by (ii) coupling the mitomycin aziridine ring >NH group through a covalent bond to a side chain which provides said spacer unit and which terminates in a primary amine reactive amino group --NH 2 ; and then, in a subsequent separate stage, (b) a second step of reacting said reactive mitomycin derivative with said polymer carrier which is presented in a form that contains at least one reactive group, thereby to establish a coupling through a covalent linkage between said polymer carrier reactive group and said reactive mitomycin derivative, either via a said activated mitomycin aziridine ring >NH group or via a said primary amine reactive amino terminal group of a said side chain of the mitomycin-C or mitomycin compound, and thereby producing said polymer/drug conjugate.
Claim 2
Dependent Claim
215 words
A process for synthesizing a polymer/drug conjugate comprising a polymer carrier covalently coupled through linking spacer units to molecules of mitomycin-C or another therapeutically active mitomycin compound containing an >NH group in the aziridine ring thereof, said process comprising a first step of: (a) modifying said mitomycin-C or mitomycin compound to produce a reactive derivative thereof, either by (i) reacting said mitomycin-C or mitomycin compound with an activating agent so as to convert the mitomycin aziridine ring >NH group into an activated group which reacts with aliphatic amines, or by (ii) coupling the mitomycin aziridine ring >NH group through a covalent bond to a side chain which provides said spacer unit and which terminates in a primary amine reactive amino group --NH 2 ; and then, in a subsequent separate stage, (b) a second step of reacting said reactive mitomycin derivative with said polymer carrier which is presented in a form that contains at least one reactive group, thereby to establish a coupling through a covalent linkage between said polymer carrier reactive group and said reactive mitomycin derivative, either via a said activated mitomycin aziridine ring >NH group or via a said primary amine reactive amino terminal group of a said side chain of the mitomycin-C or mitomycin compound, and thereby producing said polymer/drug conjugate.
Claim 3
Dependent Claim
39 words
The process as claimed in claim 1 wherein the mitomycin aziridine ring >NH group in the polymer/drug conjugate is coupled to its associated said spacer unit by way of a urethane bond, an amide bond or a urea bond.
Claim 4
Dependent Claim
40 words
The process as claimed in claim 2 wherein the reactive derivative of the mitomycin-C or mitomycin compound has a structure selected from the group consisting of: ##STR12## wherein R comprises an aliphatic or aromatic moiety that provides said spacer unit.
Claim 5
Dependent Claim
149 words
The process as claimed in claim 3 wherein the structure of the reactive derivative of the mitomycin-C mitomycin compound is selected from the group consisting of: ##STR13## and is prepared by treating either a hydroxyamine H 2 N--R--OH or a terminally protected amino acid H 2 N--R--COOH with an activating agent which converts the hydroxyl or carboxyl group thereof into an activated form which reacts with the aziridine imino group of the mitomycin-C mitomycin compound, then reacting the amino-protected activated hydroxyamine or amino acid with said mitomycin-C mitomycin compound to produce an intermediate derivative in which said amino-protected hydroxyamine or amino acid is covalently coupled to the mitomycin via said activated hydroxyl or carboxyl group, followed by isolating and purifying said intermediate derivative and then treating said intermediate derivative to remove the amino protective group (Y) and form the reactive mitomycin derivative ready for step (b) of claim 1.
Claim 6
Dependent Claim
53 words
The process as claimed in claim 1, wherein the reactive derivative of the mitomycin-C or compound is prepared by one of the following reaction schemes, where R is an aliphatic or aromatic moiety that provides a said linking spacer unit, Y is an amino protective group and Z is an activated group ##STR14##
Claim 7
Dependent Claim
28 words
The process as claimed in claim 4 or 5 wherein the amino protective group (Y) is fluorenyl methyloxycarbony (Fmoc) or an allyloxycarbonyl group CH 2 ═CH--CH 2 --O--CO--.
Claim 8
Dependent Claim
78 words
The process as claimed in claim 4, wherein (a) the activating agent used in preparing the reactive mitomycin derivative is carbonyl diimidazole (CDI) or, alternatively, (b) in the case of preparing the derivative from hydroxyamine, activation of the --OH group is carried out by treatment with a chloroformate or, (c) in the case of preparing the derivative from an amino carboxylic acid, activation of the carboxyl group is carried out by forming a reactive ester or mixed anhydride.
Claim 9
Dependent Claim
67 words
The process as claimed in claim 3 wherein the reactive derivative of the mitomycin-C or compound has the structure (c) of claim 3 and is prepared by treating the mitomycin-C or mitomycin compound with an activating agent to provide an amino reactive group linked to the aziridine ring >NH group, and then reacting this product with an excess of a diamine compound H 2 N--R--NH 2 .
Claim 10
Dependent Claim
62 words
The process as claimed in claim 3 wherein group H 2 N--R-- is selected from the group consisting of: H 2 N--(CH 2 ) n --, H 2 N--(CH2) n --CO--NH--, and H 2 N--Ph--CO--NH--(CH 2 ) n --, where n is an integer in the range of 1 to 20 or is H 2 N--Ph-- is an amino acid or oligopeptide.
Claim 11
Dependent Claim
15 words
The process as claimed in claim 3 in which R is a tripeptide or tetrapeptide.
Claim 12
Dependent Claim
18 words
The process as claimed in claim 10 wherein R is a tetrapeptide selected from gly-phe-leu-gly, gly-phe-ala-leu and ala-leu-ala-leu.
Claim 13
Dependent Claim
15 words
The process as claimed in claim 10 wherein R comprises a hydrophobic terminal amino acid.
Claim 14
Dependent Claim
44 words
The process as claimed in claim 1 in which the polymer carrier is provided by a non-toxic polymer containing functional hydroxyl or carboxyl groups that are activated by treatment with an activating agent selected from the group consisting of carbonyl diimidazole and p-nitrophenyl chloroformate.
Claim 15
Dependent Claim
32 words
The process as claimed in claim 13 wherein the polymer carrier is a hydroxyl containing polymer selected from a polysaccharide, a poly(N-hydroxyalkylglutamine), a poly(amidoamines) having hydroxyl side groups, and a poly(phosphazene) derivative.
Claim 16
Dependent Claim
44 words
The process as claimed in claim 13 wherein the polymer carrier is a carboxyl containing polymer selected from a poly(amidoamine) derivative having a --COOH side group, poly(glutamic acid), succinylated polylysine, a copolymer of vinyl pyrrolidone and maleic anhydride, and a succinylated hydroxyl containing polymer.
Claim 17
Dependent Claim
210 words
A process for synthesising a polymer/drug conjugate incorporating mitomycin-C or another mitomycin compound having anticancer activity containing an >NH group in the aziridine ring, said process comprising the steps of: (a) preparing a derivative of a hydroxyamine H 2 N--R--OH or an aminoacid H 2 N--R--COOH wherein the terminal amino group is protected, (b) treating said derivative of step (a) with an activating agent to produce a derivative with hydroxyl or carboxyl group, (c) reacting the derivative of step (b with the mitomycin-C or mitomycin compound whereby the mitomycin aziridine ring >NH group is covalently coupled to said activated hydroxyl or carboxyl group to provide a side chain, to produce a drug/spacer conjugate (d) isolating and purifying the conjugate of step (c), (e) treating the conjugate of step (d) to remove the amino protective group to produce a mitomycin derivative, (f) reacting the mitomycin derivative produced in step (e) with a polymer carrier containing at least one amino reactive group that reacts to form a covalent linkage with said mitomycin derivative via the deprotected amino terminal group of said side chain, said side chain then forming a spacer unit between the polymer and the mitomycin compound, to produce a polymer/drug conjugate, and (g) recovering the polymer/drug conjugate of step (f).
Claim 18
Dependent Claim
210 words
A process for synthesising a polymer/drug conjugate incorporating mitomycin-C or another mitomycin compound having anticancer activity containing an >NH group in the aziridine ring, said process comprising the steps of: (a) preparing a derivative of a hydroxyamine H 2 N--R--OH or an aminoacid H 2 N--R--COOH wherein the terminal amino group is protected, (b) treating said derivative of step (a) with an activating agent to produce a derivative with hydroxyl or carboxyl group, (c) reacting the derivative of step (b with the mitomycin-C or mitomycin compound whereby the mitomycin aziridine ring >NH group is covalently coupled to said activated hydroxyl or carboxyl group to provide a side chain, to produce a drug/spacer conjugate (d) isolating and purifying the conjugate of step (c), (e) treating the conjugate of step (d) to remove the amino protective group to produce a mitomycin derivative, (f) reacting the mitomycin derivative produced in step (e) with a polymer carrier containing at least one amino reactive group that reacts to form a covalent linkage with said mitomycin derivative via the deprotected amino terminal group of said side chain, said side chain then forming a spacer unit between the polymer and the mitomycin compound, to produce a polymer/drug conjugate, and (g) recovering the polymer/drug conjugate of step (f).
Claim 19
Dependent Claim
169 words
A process for synthesising a polymer/drug conjugate incorporating mitomycin-C or another mitomycin compound having anticancer activity containing an >NH group in the aziridine ring, said process comprising the steps of: (a) treating the mitomycin-C or mitomycin compound with an activating agent to activate the mitomycin aziridine ring >NH, (b) reacting the activated mitomycin-C or mitomycin compound from step (a) with an excess amount of a diamine compound H 2 N--R--NH 2 thereby covalently to couple the latter as a side chain to the mitomycin-C mitomycin compound to produce a mitomycin derivative, (c) isolating and purifying the product of step (b), (d) reacting the mitomycin derivative obtained in step (c) with a polymer carrier containing at least one amino reactive group that reacts to form a covalent linkage with said mitomycin derivative via the amino terminal group of said side chain, said side chain then forming a spacer unit between the polymer and the mitomycin compound to produce a polymer/drug conjugate, and (e) recovering the polymer/drug conjugate of step (d).
Claim 20
Dependent Claim
169 words
A process for synthesising a polymer/drug conjugate incorporating mitomycin-C or another mitomycin compound having anticancer activity containing an >NH group in the aziridine ring, said process comprising the steps of: (a) treating the mitomycin-C or mitomycin compound with an activating agent to activate the mitomycin aziridine ring >NH, (b) reacting the activated mitomycin-C or mitomycin compound from step (a) with an excess amount of a diamine compound H 2 N--R--NH 2 thereby covalently to couple the latter as a side chain to the mitomycin-C mitomycin compound to produce a mitomycin derivative, (c) isolating and purifying the product of step (b), (d) reacting the mitomycin derivative obtained in step (c) with a polymer carrier containing at least one amino reactive group that reacts to form a covalent linkage with said mitomycin derivative via the amino terminal group of said side chain, said side chain then forming a spacer unit between the polymer and the mitomycin compound to produce a polymer/drug conjugate, and (e) recovering the polymer/drug conjugate of step (d).
Claim 21
Independent Claim
119 words
A method of preparing a conjugate compound of a polymer carrier molecule in the form of a biologically inert macromolecule and a mitomycin (MMC) drug molecule containing an >NH group in their aziridine ring, wherein the MMC molecules are covalently linked to the polymer carrier molecule through biodegradable spacer groups, said method comprising the steps of coupling said spacer groups in the form of an oligopeptide to a MMC molecule via the aziridine imino groups of the latter, purifying the oligopeptide derivative thus formed, and then coupling the purified oligopeptide derivative to the polymer carrier via reactive groups of the latter and reactive terminal amino groups of the oligopeptide spacers to produce the polymer/drug conjugate, and recovering said conjugate.
Claim 22
Independent Claim
119 words
A method of preparing a conjugate compound of a polymer carrier molecule in the form of a biologically inert macromolecule and a mitomycin (MMC) drug molecule containing an >NH group in their aziridine ring, wherein the MMC molecules are covalently linked to the polymer carrier molecule through biodegradable spacer groups, said method comprising the steps of coupling said spacer groups in the form of an oligopeptide to a MMC molecule via the aziridine imino groups of the latter, purifying the oligopeptide derivative thus formed, and then coupling the purified oligopeptide derivative to the polymer carrier via reactive groups of the latter and reactive terminal amino groups of the oligopeptide spacers to produce the polymer/drug conjugate, and recovering said conjugate.
Claim 23
Independent Claim
72 words
A method of preparing a polymeric prodrug of mitomycin-C (MMC) wherein the MMC molecule is coupled via a polymeric carrier, said method comprising: (a) covalently linking the MMC to oligopeptide spacers by reacting the MMC with an N-terminal protected oligopeptide to produce a MMC/oligopeptide derivative; (b) removing the protective group from the derivative of step (a); and (c) coupling the deprotected derivative of step (b) to activated groups on the polymer carrier.
Claim 24
Independent Claim
72 words
A method of preparing a polymeric prodrug of mitomycin-C (MMC) wherein the MMC molecule is coupled via a polymeric carrier, said method comprising: (a) covalently linking the MMC to oligopeptide spacers by reacting the MMC with an N-terminal protected oligopeptide to produce a MMC/oligopeptide derivative; (b) removing the protective group from the derivative of step (a); and (c) coupling the deprotected derivative of step (b) to activated groups on the polymer carrier.
Claim 25
Dependent Claim
60 words
The method as claimed in claim 19, wherein the terminal amino groups of the oligopeptides are protected by Fmoc protective groups and are activated as the pentafluorophenyl ester, and wherein the polymer carrier is poly N-hydroxyethyl)-L-glutamine! (PHEG) which is coupled via 4-nitrophenyl chloroformate activated groups to reactive terminal amino groups of the deprotected oligopeptide spacers linked to the MMC molecules.
Claim 26
Dependent Claim
92 words
The process as claimed in claim 1 wherein the mitomycin-C or mitomycin compound is modified by reacting said mitomycin compound with an activating agent so as to convert the mitomycin aziridine ring >NH group into an activated group which reacts with aliphatic amines, wherein the polymer carrier with which said reactive mitomycin derivative is reacted is a poly(amidoamine) polymer having pendant side chains providing said spacer units, said side chains terminating in a reactive amine group that couples covalently with said activated mitomycin aziridine ring >NH group to form the polymer/drug conjugate.
Claim 27
Dependent Claim
54 words
The process as claimed in claim 21 further comprising preliminary step of modifying a poly(amidoamine) polymer having side chains terminating in hydroxyl or carboxyl groups by treating with a carbonyl diimidazole (CDI) or other activating agent and a diamine compound to prepare the said poly(amidoamine) polymer with which said reactive mitomycin derivative is reacted.
Claim 28
Dependent Claim
66 words
The polymer/drug conjugate prepared by the process as claimed in claim 1 wherein the polymer carrier is poly N-(2-hydroxyethyl)-L-glutamine! (PHEG) or a salt thereof coupled to MMC molecules through tripeptide or tetrapeptide spacers which comprising a hydrophobic terminal amino acid and which are degradable in acidic solution by lysosomal enzymes and by the enzyme collagenase IV, said conjugate being less toxic towards bone marrow than MMC.
Claim 29
Dependent Claim
43 words
A mitomycin derivative having a side chain terminated with an amino or protected amino group for use as an intermediate compound in synthesising polymer carrier conjugates in accordance with a process as claimed in claims 1, said derivative having a general formula ##STR15##
Claim 30
Dependent Claim
41 words
A reactive mitomycin derivative, produced by treating a mitomycin compound containing an >NH group in the aziridine ring thereof with carbonyl diimidazole and isolating the product, for use as an intermediate compound in carrying out the process claimed in claim 1.
Claim 31
Dependent Claim
25 words
A pharmaceutical formulation containing a polymer carrier and mitomycin-C conjugate compound wherein said conjugate compound is prepared by the process as claimed in claims 1.
References Cited (Backward Citations)
No citation records indexed.
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| 7.5 Years (Year 8) | 2005-04-13 | 2005-10-13 | 2006-04-14 | $3760.00 | Window Closed / Lapsed |
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