WO1999061061A1 - Composites medicamenteux - Google Patents
Composites medicamenteux Download PDFInfo
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- WO1999061061A1 WO1999061061A1 PCT/JP1999/002681 JP9902681W WO9961061A1 WO 1999061061 A1 WO1999061061 A1 WO 1999061061A1 JP 9902681 W JP9902681 W JP 9902681W WO 9961061 A1 WO9961061 A1 WO 9961061A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/61—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
- A61K47/65—Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the present invention relates to a drug conjugate in which a drug carrier such as a polysaccharide derivative and a pharmaceutical compound such as an antitumor agent are bound via a spacer.
- Antitumor agents used in the treatment of solid cancers such as lung cancer and gastrointestinal cancer, and blood cancers such as leukemia are systemically administered by intravenous or oral administration routes and then migrate to specific tumor sites It inhibits or suppresses the growth of cancer cells and exerts a therapeutic effect.
- systemically administered antitumor agents are rapidly taken up from the blood into organs of the liver and retina, or excreted rapidly in the urine, resulting in lower blood levels and migration to tumor sites. May be restricted.
- ordinary antitumor agents themselves have low selectivity to transfer to tumor sites (tumor selectivity), so that the antitumor agent is distributed evenly throughout various cells and tissues throughout the body, resulting in normal cells and tissues. It also acts as a cytotoxin, causing a very high rate of side effects such as vomiting, fever, and hair loss. Therefore, there is a need to develop a means for efficiently and selectively transferring an antitumor agent to a tumor site.
- WO094 / 19376 discloses that a carboxyl group of a polysaccharide having a carboxyl group is linked to a peptide chain (1 to 8 amino acids), and that doxorubicin, daunorubicin, and mitomycin C are further linked via the peptide chain. And conjugates of bleomycin and the like. Also, Japanese Patent Publication No.
- the present inventors have conducted intensive research on drug conjugates in which a drug carrier such as a polysaccharide derivative and a pharmaceutical compound such as an antitumor agent are bound via a spacer containing 1 to 8 amino acids, We succeeded in providing a drug conjugate capable of site-selectively transferring a pharmaceutical compound such as an antitumor agent to a target tissue (W097 / 46260).
- a drug conjugate containing a peptide containing 1 to 8 amino acids the release rate of the pharmaceutical compound is not necessarily the rate of enzymatic degradation of part of the spacer (hydrolysis by peptidase). Independently, it has been found that the release rate may be affected by the steric structure of the pharmaceutical compound.
- an object of the present invention is to provide a drug conjugate in which a pharmaceutical compound such as an antitumor agent or an anti-inflammatory agent and a drug carrier are bound via a spacer containing 1 to 8 amino acids.
- Another object of the present invention is to provide a pharmaceutical compound having a release rate which is substantially unaffected by the three-dimensional structure of the pharmaceutical compound and which is expected from the enzymatic degradation rate of a part of the spacer.
- An object of the present invention is to provide a drug conjugate that can achieve the above.
- the present inventors have made intensive efforts to solve the above-mentioned problems, and as a result, linked a pharmaceutical compound such as an antitumor agent or an anti-inflammatory agent to a drug carrier via a spacer containing 1 to 8 amino acids.
- a pharmaceutical compound such as an antitumor agent or an anti-inflammatory agent
- a spacer containing 1 to 8 amino acids.
- the drug compound is released by non-enzymatic hydrolysis of the carbonyl group, and in this drug conjugate, the release rate of the drug compound is not affected by the steric structure of the drug compound, and is substantially free It was found that it was dependent on the enzymatic degradation rate of a part of the enzyme.
- the present invention has been completed based on these findings.
- the drug conjugate of the present invention is characterized in that the release rate of a pharmaceutical compound can be controlled based on the enzymatic degradation rate of a part of the spacer without considering the three-dimensional structure of the pharmaceutical compound.
- A represents a polymer that is a drug carrier; R represents a peptide containing one amino acid or a peptide containing 2 to 8 amino acids linked to a peptide; Y represents Represents a phenylene group which may have a substituent; Q represents a residue of the pharmaceutical compound)
- a drug conjugate represented is provided. This drug conjugate is useful, for example, as a DDS compound having a DDS (drag 'delivery system) function.
- R'-NH-Y-C--0-C0-Q (where R'- comprises one amino acid or 2 to 8 amino acids linked to a peptide, and the N-terminal is A protected or unprotected group; Y represents a phenylene group which may have a substituent; Q represents a residue of a pharmaceutical compound);
- A-R-NH-Y-C3 ⁇ 4-0-C0-X (where A represents a macromolecule which is a drug carrier; R is a dimer or peptide bond containing one amino acid)
- Y represents a phenylene group which may have a substituent;
- X represents a hydroxyl group; -0-M (M represents a lipoxyl group) Which represents a group) or represents a leaving group).
- the above drug conjugate wherein the drug carrier is a polysaccharide derivative having a carboxyl group; the above drug conjugate, wherein R is a peptide containing 2 to 8 amino acids bound by a peptide.
- the above-mentioned drug complex wherein ⁇ is a P-phenylene group which may have a substituent; the above-mentioned drug complex wherein Y is an unsubstituted P-phenylene group;
- the above drug conjugate which is a carboxy C 1-4 alkyl dextran polyalcohol; the dextran polyalcohol constituting the carboxy C 1-4 alkyl dextran polyalcohol can be converted to dextran under a condition that allows substantially complete polyalcoholization.
- the drug complex is dextran poly alcohol obtained by treating; carboxy C 1-4 alkyl dextran poly alcohol carboxymethyl
- the drug complex is a kiss Trang polyalcohol; pharmaceutical compound antitumor agent or an antiinflammatory agent and is the drug complex; A- R- NH- Y- CH 2 - 0- CO- and an amino group of a pharmaceutical compound
- the above drug conjugate wherein the (1S, 9S) -triamino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H, 12H
- the above drug conjugate which is -benzo [de] pyrano [3,4,: 6,7] indolizino [1,2-b] quinoline-10,13 (9H, 15H) -dione. ..— Brief description of drawings
- FIG. 1 shows a GPC (gel permeation chromatography) chart of the drug conjugate of the present invention (Example 1).
- FIG. 2 shows an ultraviolet absorption spectrum of the drug conjugate of the present invention (Example 1).
- FIG. 3 shows a GPC chart of the drug conjugate of the present invention (Example 5).
- FIG. 4 shows an ultraviolet absorption spectrum of the drug conjugate of the present invention (Example 5).
- FIG. 5 shows a GPC chart of the drug conjugate of the present invention (Example 7).
- FIG. 6 shows an ultraviolet absorption spectrum of the drug conjugate of the present invention (Example 7).
- Drug complex provided by the present invention represented by the AR-NH-Y-CH 2 -0-C0-Q.
- Q represents a residue of the drug compound
- the residue of the drug compound contained in the drug conjugate of the present invention includes, for example, human as a drug such as an antitumor agent, an anti-inflammatory agent, and an antibacterial agent
- It is a major part structure of a pharmaceutical compound used for treatment and / or prevention of a disease in a mammal, and means at least a part essential to the manifestation of its pharmaceutical action.
- the use of the pharmaceutical compound is not limited to the above, and the pharmaceutical compound can participate in the bond of the group represented by AR-NH-Y-C3 ⁇ 4-0-CO- with the carbonyl group.
- any compound having one or more reactive functional groups may be used.
- the term "pharmaceutical compound” also includes a prodrug compound which contains, as a partial structure, the main structure of a compound which itself has a medicinal effect, and which can regenerate the compound in vivo.
- the residue of a drug compound is defined as a bond between the carbonyl group of the group represented by A-R-NH-Y-C3 ⁇ 4-0-CO- and the residue of the drug compound, Functional group and A-
- AR-NH- Y- CH 2 - 0- C0-NH-D AR-NH- Y- C3 ⁇ 4- 0- CO- N (D,)-D
- AR-NH-Y-CH 2 -0-C0-0-D AR-NH-Y-C3 ⁇ 4-0-C0-S-D.
- AR-NH- Y- type coupling with CH 2 -0- CO- in groups and pharmaceutical compound residue represented is not limited to those described above.
- Pharmaceutical compounds include, for example, doxorubicin, daunorubicin, mitomycin C, bleomycin, cyclocytidine, vincristine, vinblastine, methotrexet, platinum antitumor agents (cisbratin or derivatives thereof), taxol or derivatives thereof, Camptothecin or a derivative thereof (the antitumor agent described in JP-A-6-87746, preferably the (1S, 9S) -1-amino-9-ethyl-5-fluoro-2 compound described in claim 2) , 3-Dihydro-9-hydroxy-4-methyl-1H, 12H-benzo [de] pyrano [3,4,6,7] indolizino [1,2-b] quinoline-10,13 (9H , 15H) -dione and the like can be suitably used.
- steroid anti-inflammatory drugs such as hydrocortisone succinate and prednisolone succinate, or residues of non-steroid anti-inflammatory drugs such as mefenamic acid, flufenamic acid, diclofenac, ibuprofen, and tinolidin are suitable. .
- phenylene group represented by Y either a 0-phenylene group or a p-phenylene group may be used.
- the phenylene group has a substituent
- the type of the substituent, the number of the substituents, and the substitution position are not particularly limited.
- the substituent that can be present on the ring of the phenylene group include, for example, a lower alkyl group (a linear or branched C 1-6 alkyl group, or a cyclic ( ⁇ 6 alkyl group.
- substitution groups containing a lower alkyl moiety halo lower alkyl groups (chloromethyl group, trifluoromethyl group, etc.), hydroxy lower alkyl groups (hydroxymethyl group, etc.), lower alkoxy groups (methoxy group, Ethoxy, etc.), lower alkenyl (vinyl, aryl, etc.), lower alkynyl (propargyl, etc.), hydroxyl, halogen (fluorine, chlorine, bromine, or iodine) Power .1 ruboxyl group, alkoxycarbonyl group (such as methoxycarbonyl group), alkanol group (such as acetyl group), haloalkanol group (such as trifluoroacetyl group), aryl group (such as phenyl group and naphthyl group) ), An aralkyl group (such as a benzyl group), an aryloxy group (such as a phenoxy group), an aralkyl group (such
- substituents When two or more substituents are present on the ring of the phenylene group, they may be the same or different. Further, these substituents may further have another one or more functional groups. Specific examples of such a substituent include a chlorine-containing phenyl group, a methylcarbamoyl group, a chlorine-containing benzyl group, an alkoxybenzyl group, and the like.
- the phenylene group represented by Y is preferably a substituted or unsubstituted p-phenylene group, particularly preferably an unsubstituted P-phenylene group.
- R indicates a spacer.
- spacer as used herein is a partial structure of the drug conjugate of the present invention, which is present between a polymer as a drug carrier and a residue of a pharmaceutical compound, and includes one amino acid or one amino acid. It refers to a portion consisting of 2 to 8 amino acids. In tissues where drug compounds should not be released or in blood, tissues where drug compound residues are retained in drug carriers and drug compounds are released (for example, In the case of tumor tissue, etc.), it has a role of liberating a drug conjugate by being degraded enzymatically.
- As the spacer a spacer containing one amino acid or a spacer containing 2 to 8 amino acids bonded by peptide can be used.
- the spacer is a residue of one amino acid (meaning a residue obtained by removing one hydrogen atom and one hydroxyl group from an amino group and a carboxyl group of an amino acid, respectively), or a peptide Oligopeptide residues containing 2 to 8 amino acids linked together (residues from the N-terminal amino group and the C-terminal carboxyl group, each of which has one hydrogen atom and one hydroxyl group removed) Has the form of means one), NH-Y-CH 2 carboxyl groups) when the C-terminal (one amino acid Fukumusupesa one - to peptide bond 0- CO- Q It is arranged as follows.
- the bond between the drug carrier represented by A and the probe is formed by binding the carboxyl group of the drug carrier to the N-terminus of the oligonucleotide spacer (a probe containing one amino acid).
- a probe containing one amino acid In one case, an amino group.
- the bond between the spacer and the drug carrier is not limited to the peptide bond described above, and may be other chemical bonds or bonds using one or more spacers. Good.
- a dicarboxylic acid compound for example, a residue of a dicarboxylic acid such as succinic acid, etc.
- both terminals become carboxyl groups.
- a reactive amino group or the like in a drug carrier can be used for binding.
- Preferred spacers are oligopeptide residues containing 2 to 6 amino acids.
- the type of amino acid constituting the spacer is not particularly limited.
- L- or D-amino acid preferably L-amino acid can be used.
- ⁇ -alanine, £ -aminocapron Acids, aminoaminobutyric acid and the like may be used. It is preferable that such an amino acid other than the single amino acid is arranged at a position close to the drug carrier in the probe.
- the amino acid sequence when using a spacer containing an oligonucleotide is not particularly limited.
- a residue of a dipeptide represented by - ⁇ - ⁇ - (X is a residue of a hydrophobic amino acid)
- ⁇ indicates a residue of a hydrophilic amino acid
- -X- ⁇ - indicates that the hydrophobic amino acid (X) and the hydrophilic amino acid ( ⁇ ) are on the terminal side and the C-terminal side, respectively.
- a spacer containing a peptide residue as a partial peptide sequence can be suitably used.
- hydrophobic amino acids for example, phenylalanine, tyrosine, leucine and the like can be used.
- hydrophilic amino acids for example, glycine, Alanine can be used.
- the donor may have a repeating sequence of such a peptide residue (for example, -XZ-XZ-, -XZXZX-Z-, etc.).
- a peptide containing such a dipeptide structure is used, the peptide is hydrolyzed at a tumor site or an inflammatory site that is considered to be rich in peptidase, and the peptide is rapidly hydrolyzed at the site.
- the partial structure formed by combining the peptide-containing probe with the drug compound is a preferable partial structure of the drug complex of the present invention.
- Antineoplastic agents that exhibit concentration-dependent antitumor effects as residues of pharmaceutical compounds (antitumor agents that exhibit stronger antitumor effects at higher concentrations: concentration-dependent antitumor agents, such as doxorubicin, etc.)
- concentration-dependent antitumor agents such as doxorubicin, etc.
- a spacer consisting of the dipeptide residue represented by -XZ- or a spacer containing the dipeptide residue as a partial peptide sequence may be used. preferable.
- the above-mentioned spacer should be used.
- an antitumor agent for example, methotrexate or the like
- the present invention is not limited to the above-mentioned range, but is preferable in view of the pharmacokinetic characteristics and toxicity of the antitumor agent.
- the rate of release of the pharmaceutical compound from the drug conjugate of the present invention is determined by the fact that the enzymatic degradation of a part of the spacer is a substantially rate-limiting step.
- the desired release rate of the pharmaceutical compound can be easily achieved by choosing from the point of view.
- oligonucleotides are described in Table 1 of Japanese Patent Publication No. 5 and can be suitably used as a primer in the present invention.
- the drug carrier represented by A besides polysaccharide derivatives, synthetic polymers and the like can be used.
- the polysaccharide derivative and the synthetic polymer any one may be used as long as it has substantially no toxicity to the living body and can act as a drug carrier.
- polysaccharide derivatives and synthetic polymers conventionally used in the production of drug conjugates can be used for the drug conjugate of the present invention.
- a polysaccharide derivative having a carboxyl group can be suitably used for the drug conjugate of the present invention, and a polyalcoholized polysaccharide derivative is particularly preferable.
- Examples of the synthetic polymer include polyethylene glycols; polyamino acids such as polyglutamic acid, polyaspartic acid, and polylysine; and polyvinyl compounds such as N- (2-hydroxypropyl) methacrylamide derivative. And derivatives thereof.
- polysaccharide derivative having a carboxyl group for example, any polysaccharide or a derivative obtained by chemically or biologically modifying them and having a carboxyl group in the molecule can be used. May be used.
- polysaccharides such as hyaluronic acid, pectic acid, alginic acid, chondroitin, heparin
- polysaccharides such as pullulan, dextran, mannan, chitin, inulin, levan, xylan, araban, mannoglucan, chitosan, pullulan
- Those obtained by introducing a functional group having a carboxyl group into some or all of the hydroxyl groups can be used.
- polysaccharide derivative refers to a compound obtained by partially or completely enclosing a cyclic sugar moiety of a polysaccharide compound in addition to a polysaccharide compound containing a saccharide as a constituent element (for example, a polyalcohol compound and the like). ) Must be interpreted in the broadest sense.
- Polyalcohol degree of carboxy C M alkyl dextran Polya alcohol used in the preparation of the drug carrier of one invention is not particularly limited, dextran polyalcohol constituting the carboxy C M alkyl dextran polyalcohol is substantially completely polyalcohol It is preferable that the dextran polyalcohol obtained by treating dextran under the conditions that can be converted into a polyalcohol, is polyalcoholized to such an extent that it can be used as a DDS compound.
- the type of dextran used to produce the carboxy ( 4- alkyldextran polyalcohol is not particularly limited, and may contain an arbitrary ratio of ⁇ -D-1,6-bond.
- --D-1 Dextran having a ratio of 85 or more, 90% or more, or 95% or more can be used, but the molecular weight of dextran is not particularly limited, and for example, about 10,000 to about 2,000,000. things, preferably as C 1-4 alkyl Le constituting 50, from about 000 can be used at about 800, 000.
- carboxy C 1-4 alkyl dextran polyalcohol carboxy C 1-4 alkyl group, C 1-4 straight-chain or branched alkyl, such as methyl, Echiru group, n - propyl group, an isopropyl group, n- heptyl group, etc. can be used sec- butyl group, preferably It can be used methyl group.
- dextran polyalcohol in which dextran is substantially completely polyalcoholized.
- Carboxy C 1-4 alkylation can be carried out, for example, by adding chloroacetic acid, bromoacetic acid, polychloropropionic acid, polymethyl chloropropionic acid, chloropropionic acid, chloropropionic acid to the hydroxyl group of dextran polyalcohol.
- Halogenated C 1-4 alkyl carboxylic acids such as 5-chloropropionic acid, monochlorobutyric acid, chlorobutyric acid, and ⁇ -chlorobutyric acid, preferably chloroacetic acid are reacted to partially or completely convert hydroxyl groups to carboxy C. It can be carried out by 1-4 alkylation.
- dextran polyalcohol is dissolved in an inert solvent that does not participate in the reaction (eg, water, N, N-dimethylformamide, dimethyl sulfoxide, etc.) and a base (eg, sodium hydroxide, potassium hydroxide, etc.)
- an inert solvent eg, water, N, N-dimethylformamide, dimethyl sulfoxide, etc.
- a base eg, sodium hydroxide, potassium hydroxide, etc.
- Halogenated C 1-4 alkyl carboxylic acid or a salt thereof is added in the presence of water, and the reaction may be carried out for several minutes to several days under ice-cooling or a temperature range of about 100 ° C.
- the degree of introduction of the carboxy C 1-4 alkyl group can be easily determined, for example, by appropriately selecting the reaction temperature of the carboxy C 1-4 alkylation and the amounts of the halogenated C 1-4 alkyl carboxylic acid and the base used as the reagent. And such means are well known to those skilled in the art.
- the degree of carboxy C 1-4 alkylation to the hydroxyl group of dextran polyalcohol is not particularly limited, but is, for example, in the range of 0.01 to 2.0, preferably in the range of 0.1 to 1.0 per constituent sugar residue. In this manner, an aqueous solution in the form of an alkali metal salt such as a sodium or magnesium carboxy C 1-4 alkyl dextran polyalcohol can be prepared.
- a polysaccharide derivative in the form of an alkali metal salt prepared as described above may be used as a raw material for a drug carrier. Since the polysaccharide derivative in the form of a salt of an organic amine can be dissolved at a high concentration in a substantially water-free organic solvent, the use of this salt allows the reaction to be carried out in a non-aqueous system, and the reaction efficiency is remarkable. In some cases.
- Examples of the salts of organic amines include salts of aliphatic amines such as triethylamine, trimethylamine, and triethanolamine, as well as N-methylpyrrolidine, N-methylbiperidine, N-methylmorpholine, and dimethylaminopyridine. And quaternary ammonium salts such as tetramethylammonium chloride and tetraethylammonium chloride.
- Conversion of the sodium salt of the polysaccharide derivative to the salt of the organic amine can be carried out using an ion exchange resin or the like.
- sodium salt of carboxymethyl dextran polyalcohol is dissolved in water, applied to a column packed with Bio-Rad AG50W-X2 (200-400 mesh, H + type) resin, eluted with water, and then triethylamine.
- the organic amine can be added and freeze-dried.
- It is also possible to carry out the conversion in one step by dissolving the sodium salt of trampopolyalcohol in water and passing it through a triethylammonium type resin.
- the drug conjugate of the present invention can be produced, for example, by producing a compound represented by R′- ⁇ -Y-C3 ⁇ 4-0-CO-Q (the definition in the formula is as defined above) by an appropriate method, After removal of the protecting group if necessary, it can be produced by bonding the N-terminal amino group of the spacer and the carboxyl group of carboxymethyldextran polyalcohol by an acid amide bond.
- a N-terminal protected peptide compound is bonded to the amino group of NH 2 -Y-CH 2 -OH by acid amide bond, and the peptide chain is extended if necessary.
- a CO-Q part can be introduced. When the CO-X part is introduced, X can be further converted to Q.
- the reactants used to introduce the CO-X moiety include p-nitrophenyl dicarbonate, p-nitrophenyl chromate format (X corresponds to a P-nitrophenoxy group), 1,1, -carbonyldichloromethane Imidazole (X corresponds to an imidazole group) and the like can be used.
- a method for introducing the CO-Q moiety C1-C0-Q obtained by acting phosgene on Q, and X-C0-Q obtained by reacting P-nitrophenyl chloroformate on Q (where X is P -Corresponding to a nitrophenoxy group).
- - NH- Y- the CH 2 -0-C0- X when converting the R '-NH-Y-CH 2 -0-C0-Q is reacted pharmaceutical compounds or a protected drug compound
- a base such as triethylamine or diisopropylethylamine or an activator such as trihydroxybenzotriazole may be added to the reaction system depending on the types of X and Q.
- the desired product can be obtained by removing the protecting group by an appropriate method according to the type of the protecting group.
- the types of protecting groups and the method of removal are described in, for example, TW Green and PGM Wuts, "Protective Groups in Organic Synthesis, 2nd ed.”, John Wiley & Sons, Inc.
- acids such as trifluoroacetic acid, acetic acid, and formic acid can be used, and preferably a relatively weak acid such as formic acid can be used.
- a relatively weak acid such as formic acid can be used.
- an acid such as acetic acid can be used.
- bases such as piperazine can be used.
- N, N, -dicycloalkylcarbodiimides such as N, -dicyclohexylcarbodiimide (DCC)
- DCC dimethylaminopropyl carbodiimide
- EEDQ triethoxycarbonyl-2- Ethoxy-1,2-dihydroxyquinoline
- the reaction may be carried out by an active ester method or an acid halide method.
- the reaction using the polysaccharide derivative is carried out in a non-aqueous system
- the reaction is carried out using an organic solvent that does not substantially contain water, and the reactant (organic amine salt of the polysaccharide derivative and HR-NH-Y in free or salt form).
- the reactant organic amine salt of the polysaccharide derivative and HR-NH-Y in free or salt form.
- HR indicates that the N-terminus is unprotected).
- the amount of the drug compound residue introduced into the drug carrier is not particularly limited, but should be appropriately selected from the viewpoints of the type of the drug compound residue, the in vivo kinetics of the drug complex, the efficacy, the toxicity, and the like. Generally, a range of about 0.1 to 30% by weight, preferably about 2 to 15% by weight can be selected.
- the ratio of the drug compound residue introduced into the drug carrier can be easily determined by, for example, absorbance analysis.
- Examples show more specific examples of the method for producing the drug conjugate of the present invention. Those skilled in the art can appropriately select starting materials and reaction reagents based on the above general description and the specific description of the examples, and can appropriately modify or alter reaction conditions and steps as necessary. By the addition, the drug conjugate of the present invention encompassed by the general formula (I) can be produced.
- the drug conjugate of the present invention provides desired pharmaceutical activity to a tumor site, an inflammatory site, etc., depending on the type of the residue of the pharmaceutical compound (for example, the residue of a pharmaceutical compound such as an antitumor agent or an anti-inflammatory agent). It is characterized in that it can be specifically expressed locally and that the toxicity of the pharmaceutical compound itself can be reduced.
- the polysaccharide derivative moiety Drug conjugates with boxymethyl dextran polyalcohol have very good vascular permeability and have tumor selectivity and inflammatory site selectivity.
- the drug conjugate of the present invention when a part of the peptide is enzymatically hydrolyzed by a protease (peptidase) at a tumor site or an inflammation site, the amino benzoyloxycarbonylamide is immediately obtained. Is characterized in that the urethane bond is hydrolyzed. Therefore, in the drug conjugate of the present invention, no amino acid derived from spacer remains in the released drug compound, and the drug effect of the drug compound itself is not impaired. Further, the drug conjugate of the present invention has a feature that an appropriate release rate of a drug compound can be achieved by selecting a kind of a spacer.
- the medicament containing the drug conjugate of the present invention can be usually filled in vials or the like in the form of a lyophilized product, and is used as a preparation for parenteral administration such as a dissolvable injection or infusion formulation.
- parenteral administration such as a dissolvable injection or infusion formulation.
- the formulation of such a medicament is not limited to the above embodiment.
- preparation additives available in the art such as solubilizers, pH adjusters, and stabilizers, can be used.
- the dose of the drug is not particularly limited, but is usually the dose of the drug compound constituting the drug compound residue, the amount of the drug compound residue introduced into the drug conjugate, the condition of the patient or the type of disease. It should be decided in consideration of such factors.
- parenteral administration is required.
- the generally about 0.1 to 100 mg per body surface area lm 2 per day, preferably administered once in a range of about L ⁇ 30 mg, it is preferably repeated every 3 to 4 weeks.
- a compound of the present invention provided from another aspect is represented by the following general formula (II): R′—NH—Y—CH 2 —0—C0—Q (wherein, R ′ represents one amino acid or a peptide bond) N-terminal protected or unprotected group containing 2 to 8 amino acids; Y represents a phenylene group which may have a substituent; Q represents the remainder of the pharmaceutical compound Represents a group).
- Y is an unsubstituted P-phenylene group
- R is a group represented by H-Gly-Gly-Phe-Gly- or H-Gly-Gly-Gly-Phe-, Compound .
- A—R—NH—Y—CH 2 —0—C0—X [where A represents a polymer that is a drug carrier; Y represents a peptide or a peptide containing 2 to 8 amino acids bonded to each other; Y represents a phenylene group which may have a substituent; X represents a hydroxyl group; (M represents a carboxyl group-protecting group) or a leaving group].
- the kind of the protecting group for the carboxyl group is not particularly limited, and any one can be used as long as it can be used by those skilled in the art.
- Any leaving group may be used as long as it acts as a leaving group in the substitution reaction on the carbonyl carbon.
- Examples include a chlorine atom, a halogen atom such as a bromine atom, and an ethoxy group.
- Examples thereof include arylsulfonyloxy groups such as an alkoxyl group and a p-toluenesulfonyloxy group.
- Symbols such as Y, Q, or R in the formula (II) or (III) have the same meanings as those already described for the formula (I). These compounds represented by the formula (II) or (III) are useful as intermediates for producing the drug conjugate of the present invention.
- the degree of carboxymethylation of carboxymethyl dextran polyalcohol was 0.1 N after converting sodium salt of carboxymethyl dextran polyalcohol to free acid form. It was determined by dissolving in sodium hydroxide aqueous solution and titrating with 0.1N hydrochloric acid. An aqueous solution of sodium salt of carboxymethyl dextran polyalcohol was applied to a Bio-Rad AG50W-X2 (H +) type column, and the passed solution was lyophilized and used as a sample. This sample is dissolved in a predetermined excess amount of a 0.1N aqueous sodium hydroxide solution, and phenol is added.
- the solution was titrated with 0.1N hydrochloric acid using the solution as an indicator.
- the amount of sample collected is s (mg)
- the predetermined excess amount of 0.1N sodium hydroxide aqueous solution is a (ml)
- the titration amount of 0.1N hydrochloric acid is b (ml)
- the degree of hydroxypropyl methylation is 13.4 (ab). /[s-5.8(a-b)].
- the amount (% by weight) of the drug introduced was determined by absorbance analysis (around 362 nm) using the characteristic absorption of the drug. Further, the gel filtration method was performed under the following conditions (column: TSK gel G4000 PW X , eluent: 0.1 M NaCl, flow rate: 0.8 ml / min, column temperature: 40 ° C).
- DX-8951 is a pharmaceutical compound [(1S, 9S) -1-amino-9-ethyl-5-fluoro-2,3-dihydro-] described in claim 2 of Japanese Patent Application No. 6-87746. 9-Hydroxy-4-methyl-1H, 12H-benzo [de] pyrano [3,4,: 6,7] indolizino [1,2-b] quinoline-10,13 (9H, 15H) -dione] And -CO-DX-8951 indicates that it forms a peptide bond with the carbonyl group represented by the 1-position amino group s-CO- of the pharmaceutical compound.
- DX-8951 has a lactone ring in either the closed or open form or in a mixed form thereof.
- one or two carboxymethyl groups are introduced into the constituent units of the sugar chain shown in the following scheme, which are examples of the constituent units of the sugar chain,
- the drug carrier portion of the drug conjugate is not composed of repeating the above structural units.
- the compound numbers in the examples correspond to the compound numbers in the following schemes.
- compound 2a in Example 5 corresponds to compound 2a in the scheme, wherein the peptide portion of the structural formula in this scheme represents a compound of GGFG (described as Peptide ⁇ GGFG in the scheme) .
- Example 1 carboxymethyldextran polyalcohol - Synthesis of 0- C0-DX8951 - Gly-Gly- Phe- Gly-NH- p- C 6 H 4 -CH 2
- Dextran T500 (20 g, Pharmacia, molecular weight 500K) is dissolved in 0.1 M acetate buffer (pH 5.5, 2000 ml), and an aqueous solution (2000 ml) of sodium periodate (66.0 g) is dissolved. Was added. After stirring at 4 for 10 days while shielding from light, ethylene glycol (14.0 ml) was added, and the mixture was stirred overnight. The reaction solution was adjusted to pH 7 using an 8 M aqueous sodium hydroxide solution. After adding and dissolving sodium borohydride (28 g), the mixture was stirred overnight.
- the reaction solution was ice-cooled, adjusted to pH 5.5 with acetic acid, stirred at 4 ° C for 1 hour, and adjusted to pH 7.5 using 8M aqueous sodium hydroxide solution.
- the obtained aqueous solution was subjected to desalting by ultrafiltration using a Biomatsux-50 membrane. The remaining solution that did not pass through the membrane was lyophilized to give dextran polyalcohol (10.5 g).
- the molecular weight of this material (gel filtration, pullulan standard) was 159K.
- This dextran polyalcohol (7.5 g) was added to an aqueous solution obtained by dissolving sodium hydroxide (31.5 g) in water (225 ml), and dissolved at room temperature. Monochloroacetic acid (45 g) was added to this solution under ice cooling to dissolve it, and then reacted at room temperature overnight. The pH of this reaction solution was adjusted to 8 with acetic acid, and then desalted by an ultrafiltration method using a Biomax-50 membrane. The remaining solution that did not pass through the membrane was lyophilized to give sodium salt of carboxymethyl dextran polyalcohol (8.5 g). The molecular weight (gel filtration, pullulan standard) of this material was 274K and the carboxymethylation degree was 0.4.
- the residual solution that did not pass through the membrane was adjusted to pH 9 with a 0.1N aqueous sodium hydroxide solution, and passed through a filtration membrane (0.16 JUL m, manufactured by Filtron).
- the passed solution was desalted by an ultrafiltration method using a Biomax-50 membrane.
- the residual solution that did not pass through the membrane was filtered through Millipore Fil- (0.22 ⁇ m), and lyophilized to obtain 490 mg of compound (6). This compound .
- the drug complex obtained in Example 1 was dissolved (378 g / ml) in Meth A (murine fibrosarcoma Meth A) homogenate or buffer at 37 ° C, and DX-8951 released 20 hours later was quantified.
- Meth A murine fibrosarcoma Meth A
- buffer at 37 ° C
- DX-8951 released 20 hours later was quantified.
- a compound in which spacer and DX-8951 were bonded without via a p-aminobenzyloxycarbonyl group was produced and used as a comparative compound.
- Table 1 shows the results.
- the amount of drug released was shown as the amount of drug released (%) based on the amount of drug in the drug complex used.
- the drug conjugate of the present invention was rapidly released in the weakly acidic homogenate, but was hardly released in the buffer. On the other hand, only a small amount of the comparative compound was released in the slightly acidic homogenate, but not released in the buffer.
- Meth A cells were transplanted into BALB / c mice to produce Meth A tumor-bearing mice, and a single dose of the drug conjugate of Example 1 was administered on day 20. After administration, body weight was measured over time, and the presence or absence of toxic death was observed. The maximum weight loss rate and mortality were summarized in Table 2. The dose is shown in terms of the weight of the anhydrous free base of DX-8951. Since slight weight loss was observed at the dose of 2.5 mg / kg and toxic death was observed in all cases at the dose of 10 mg / kg, the MTD of Example 1 was determined to be 5 to 7.5 mg / kg.
- Example 4 Antitumor activity of the drug conjugate of Example 1
- Meth A cells (murine fibrosarcoma Meth A) were transplanted into BALB / c mice to produce Meth A tumor-bearing mice, and a single dose of the drug conjugate of Example 1 was administered 7 days after the transplantation. Tumor weights were measured on day 21 to assess tumor inhibitory effects and toxicity. Table 3 shows the results. In the table, * indicates significant difference by Dunnett's test (*** P 0.001, ** _
- the dose is expressed in terms of the weight of DX-8951 anhydrous free base, and the IR indicates the reduction ratio of the tumor. It is clear that the drug conjugate of Example 1 exerts a tumor reducing effect in a dose-dependent manner.
- Example 5 Using formic acid as a deprotecting agent, carboxymethyl dextran poly alcohol - Gly- Gly- Phe-Gly-NH- P- C 6 H 4 - CH 2 - Synthesis of 0-CO- DX8951
- Dextran T500 (20 g, manufactured by Pharmacia, molecular weight 500K) was dissolved in 0.1 M acetate buffer (pH 5.5, 2000 ml), and an aqueous solution (2000 ml) of sodium periodate (66.0 g) was added. After stirring at 4 ° C for 10 days while shielding from light, ethylene glycol (14.0 ml) was added, and the mixture was stirred overnight. The reaction solution was adjusted to pH 7 using an 8 M aqueous sodium hydroxide solution. After adding and dissolving sodium borohydride (28 g), the mixture was stirred overnight.
- reaction solution was ice-cooled, adjusted to pH 5.5 with acetic acid, stirred at 4 ° C for 1 hour, and adjusted to pH 7.5 with 8M aqueous sodium hydroxide solution.
- the resulting aqueous solution was desalted by ultrafiltration using a Biomatsux-50 membrane. The remaining solution that did not pass through the membrane was lyophilized to give dextran polyalcohol (10.5 g). Molecules of this substance The volume (gel filtration, pullulan standard) was 159K.
- This dextran polyalcohol (7.5 g) was added to an aqueous solution obtained by dissolving sodium hydroxide (31.5 g) in water (225 ml), and dissolved at room temperature. Monochloroacetic acid (45 g) was added to this solution under ice cooling to dissolve it, and then reacted at room temperature overnight. This reaction solution was adjusted to pH 8 with acetic acid, and then desalted by an ultrafiltration method using a Biomax-50 membrane. The remaining solution that did not pass through the membrane was lyophilized to give sodium salt of carboxymethyl dextran polyalcohol (8.5 g). The molecular weight (gel filtration, pullulan standard) of this material was 274K and the carboxymethylation degree was 0.4.
- the obtained amorphous was purified using a Sep-Pak cartridge (War Yuichizu) and a Mo-Rad AG50W-X8 (Na + form) column, and then subjected to ultrafiltration using a Biomax-50 membrane again. For desalination. The residual solution that did not pass through the membrane was filtered through Milliporefil Yuichi (0.22 zm) and lyophilized to give Compound 6a (700 mg).
- Dextran T500 (20 g, Pharmacia, molecular weight 500K) was dissolved in 0.1 M acetate buffer (pH 5.5, 2000 ml), and an aqueous solution (2000 ml) of sodium periodate (66.0 g) was added. After stirring at 4 ° C for 10 days while shielding from light, ethylene glycol (14.0 ml) was added, and the mixture was stirred overnight. The reaction solution was adjusted to pH 7 using an 8 M aqueous sodium hydroxide solution. After adding and dissolving sodium borohydride (28 g), the mixture was stirred overnight. The reaction solution was ice-cooled, adjusted to pH 5.5 with acetic acid, stirred at 4 ° C.
- dextran polyalcohol (10.5 g). The molecular weight of this material (gel filtration, pullulan standard) was 159K.
- This dextran polyalcohol (7.5 g) was added to an aqueous solution obtained by dissolving sodium hydroxide (31.5 g) in water (225 ml), and dissolved at room temperature. Monochloroacetic acid (45 g) was added to this solution under ice cooling to dissolve it, and then reacted at room temperature.
- Dextran T500 (20 g, Pharmacia, molecular weight 500K) was dissolved in 0.1 M acetate buffer (pH 5.5, 2000 ml), and an aqueous solution (2000 ml) of sodium periodate (66.0 g) was added. After stirring at 4 ° C for 10 days while shielding from light, ethylene glycol (14.0 ml) was added, and the mixture was stirred overnight. The reaction solution was adjusted to pH 7 using an 8 M aqueous sodium hydroxide solution. After adding and dissolving sodium borohydride (28 g), the mixture was stirred overnight.
- the reaction solution was ice-cooled, adjusted to pH 5.5 with acetic acid, stirred at 4 ° C for 1 hour, and adjusted to pH 7.5 with 8M aqueous sodium hydroxide solution.
- the obtained aqueous solution was subjected to desalting by ultrafiltration using a Biomatsux-50 membrane. The remaining solution that did not pass through the membrane was lyophilized to give dextran polyalcohol (10.5 g).
- the molecular weight of this material (gel filtration, pullulan standard) was 159K.
- This dextran polyalcohol (7.5 g) was added to an aqueous solution obtained by dissolving sodium hydroxide (31.5 g) in water (225 ml), and dissolved at room temperature. Monochloroacetic acid (45 g) was added to this solution under ice cooling to dissolve it, and then reacted at room temperature overnight. This reaction solution was adjusted to pH 8 with acetic acid, and then desalted by an ultrafiltration method using a Biomax-50 membrane. The remaining solution that did not pass through the membrane was lyophilized to give sodium salt of carboxymethyl dextran polyalcohol (8.5 g). The molecular weight of this substance Filtration, pullulan standard) was 274K and the degree of carboxymethylation was 0.4.
- MethA homogenate (pH 5.5) 110.31 4.97 0.37 0.12
- Example 9 MTDs Maximum Tolerated Dose of the drug conjugates of Examples 5, 6, and 7 in Meth A tumor-bearing mice
- Meth A cells were transplanted into BALB / c mice to produce Meth A cancer-bearing mice, and on day 13, the drug conjugates obtained in Examples 5, 6, and 7 were administered once. After administration, body weight was measured over time, and the presence or absence of toxic death was observed. The maximum weight loss rate and mortality were summarized in Table 5. The dose is shown in terms of the weight of the anhydrous free base of DX-8951.
- the MTD of each complex was determined as follows from the dose at which weight loss and death were observed. Table 6
- the MTD of the drug conjugate obtained in Example 5 is about 1/3 of the MTD of the drug conjugate obtained in Example 1 (see Example 3), and DX-8951 using the drug conjugate obtained in Example 1 is used.
- Release rate (see table in Example 2) is about 1/3 of the release rate of DX-8951 using the drug conjugate obtained in Example 5.
- Example 10 Antitumor activity of the conjugate shown in Example 5 and Example 6
- Meth A cells were transplanted into BALB / c mice to produce Meth A tumor-bearing mice, and a single administration of the drug conjugates shown in Examples 1, 5 and 6 was made 7 days after the transplantation. Tumor weights were measured on day 21 to assess tumor inhibitory effects and toxicity. The results are shown in the table. In the table, * indicates significant difference by the Dunnett's test (*** P * 0.001, ** P * 0.01, * P * 0.05), and the dose is based on the weight of anhydrous free base of M-8951. And IR indicates tumor shrinkage. It is clear that the drug conjugates shown in Examples 5 and 6 exert a tumor reducing effect in a dose-dependent manner.
- Example 5 the minimum effective dose of the drug conjugate shown in Example 5 was about 1/3 of the minimum effective dose of the drug conjugate shown in Example 1, and the release rate of DX-8951 in the tumor homogenate (Example 2) And Table 8 in Example 8) and MTD in Meth A tumor-bearing mice (see Table in Example 3 and Example 9).
- Table 7 the minimum effective dose of the drug conjugate shown in Example 5 was about 1/3 of the minimum effective dose of the drug conjugate shown in Example 1, and the release rate of DX-8951 in the tumor homogenate (Example 2) And Table 8 in Example 8) and MTD in Meth A tumor-bearing mice (see Table in Example 3 and Example 9).
- the drug conjugate of the present invention can transfer a pharmaceutical compound such as an antitumor agent or an anti-inflammatory agent to a tumor site or the like in a site-selective manner, and rapidly release the drug compound at the site.
- a pharmaceutical compound such as an antitumor agent or an anti-inflammatory agent
- the released pharmaceutical compound does not contain any amino acid derived from a part of the spacer, it has a feature that the expected pharmaceutical effect of the pharmaceutical compound can be reliably exhibited.
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JP2000550520A JP4560210B2 (ja) | 1998-05-22 | 1999-05-21 | 薬物複合体 |
AU37333/99A AU3733399A (en) | 1998-05-22 | 1999-05-21 | Drug composites |
US09/674,526 US6835807B1 (en) | 1998-05-22 | 1999-05-21 | Drug complex and drug delivery system |
EP99919664A EP1080732A4 (en) | 1998-05-22 | 1999-05-21 | DRUG COMPOSITION |
CA002333321A CA2333321A1 (en) | 1998-05-22 | 1999-05-21 | Drug complex |
EA200001217A EA003398B1 (ru) | 1998-05-22 | 1999-05-21 | Лекарственный комплекс c полимерным носителем |
NO20005913A NO20005913L (no) | 1998-05-22 | 2000-11-22 | Legemiddelsammensetning |
HK02101369.9A HK1040052B (zh) | 1998-05-22 | 2002-02-22 | 藥物復合物 |
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CN (1) | CN1250293C (ja) |
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CA (1) | CA2333321A1 (ja) |
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HK (1) | HK1040052B (ja) |
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EP1298145A1 (en) * | 2000-06-29 | 2003-04-02 | Daiichi Pharmaceutical Co., Ltd. | Dds compound and process for the preparation thereof |
US6811996B1 (en) | 1998-10-30 | 2004-11-02 | Daiichi Pharmaceutical Co., Ltd. | DDS compounds and method for assaying the same |
JP2006511526A (ja) * | 2002-12-13 | 2006-04-06 | イミューノメディクス、インコーポレイテッド | 細胞内で開裂可能な結合を有する免疫接合体 |
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CA2968447A1 (en) | 2014-11-25 | 2016-06-02 | Adc Therapeutics Sa | Pyrrolobenzodiazepine-antibody conjugates and their use to treat neoplasms |
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GB201506389D0 (en) | 2015-04-15 | 2015-05-27 | Berkel Patricius H C Van And Howard Philip W | Site-specific antibody-drug conjugates |
GB201506411D0 (en) | 2015-04-15 | 2015-05-27 | Bergenbio As | Humanized anti-axl antibodies |
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EP3359191A4 (en) | 2015-10-05 | 2019-05-29 | Merck Sharp & Dohme Corp. | ANTIBODY-PEPTIDE CONJUGATES HAVING AGONIST ACTIVITY AT GLUCAGON AND PEPTIDE-1 RECEPTORS SIMILAR TO GLUCAGON |
US11510993B2 (en) | 2015-10-06 | 2022-11-29 | Merck Sharp & Dohme Llc | Antibody drug conjugate for anti-inflammatory applications |
EP3386956B1 (en) | 2015-12-10 | 2021-07-14 | Syndevrx, Inc. | Fumagillol derivatives and polymorphs thereof |
WO2017123603A1 (en) | 2016-01-11 | 2017-07-20 | Syndevrx, Inc. | Treatment for tumors driven by metabolic dysfunction |
GB201601431D0 (en) | 2016-01-26 | 2016-03-09 | Medimmune Ltd | Pyrrolobenzodiazepines |
EP3407916B1 (en) | 2016-01-29 | 2023-12-20 | Merck Sharp & Dohme LLC | Phosphonate linkers and their use to facilitate cellular retention of compounds |
GB201602356D0 (en) | 2016-02-10 | 2016-03-23 | Medimmune Ltd | Pyrrolobenzodiazepine Conjugates |
GB201602359D0 (en) | 2016-02-10 | 2016-03-23 | Medimmune Ltd | Pyrrolobenzodiazepine Conjugates |
GB201607478D0 (en) | 2016-04-29 | 2016-06-15 | Medimmune Ltd | Pyrrolobenzodiazepine Conjugates |
GB201617466D0 (en) | 2016-10-14 | 2016-11-30 | Medimmune Ltd | Pyrrolobenzodiazepine conjugates |
CN110049779A (zh) | 2016-12-12 | 2019-07-23 | 第一三共株式会社 | 抗体-药物缀合物和免疫检查点抑制剂的组合 |
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KR20200032243A (ko) | 2017-02-08 | 2020-03-25 | 에이디씨 테라퓨틱스 에스에이 | 피롤로벤조디아제핀-항체 컨주게이트 |
PT3612537T (pt) | 2017-04-18 | 2022-08-29 | Medimmune Ltd | Conjugados de pirrolobenzodiazepina |
EP3612234B1 (en) | 2017-04-20 | 2024-03-13 | ADC Therapeutics SA | Combination therapy with an anti-axl antibody-drug conjugate |
TW202330036A (zh) | 2017-05-15 | 2023-08-01 | 日商第一三共股份有限公司 | 抗體-藥物結合物之製造方法 |
UA127900C2 (uk) | 2017-06-14 | 2024-02-07 | Ейдісі Терапьютікс Са | Схема дозування для введення adc до cd19 |
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GB201803342D0 (en) | 2018-03-01 | 2018-04-18 | Medimmune Ltd | Methods |
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RS64379B1 (sr) | 2018-05-18 | 2023-08-31 | Glycotope Gmbh | Anti-muc1 antitelo |
JP2022512826A (ja) | 2018-10-26 | 2022-02-07 | シンデブルックス,インコーポレイティド | MetAP2阻害剤のバイオマーカーとその応用 |
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GB201908128D0 (en) | 2019-06-07 | 2019-07-24 | Adc Therapeutics Sa | Pyrrolobenzodiazepine-antibody conjugates |
CN110339181A (zh) * | 2019-07-02 | 2019-10-18 | 中国药科大学 | 一种基于点击反应的pH响应型纳米制剂及其制法和应用 |
AU2020311925A1 (en) | 2019-07-10 | 2022-02-03 | Cybrexa 3, Inc. | Peptide conjugates of microtubule-targeting agents as therapeutics |
WO2021007435A1 (en) | 2019-07-10 | 2021-01-14 | Cybrexa 2, Inc. | Peptide conjugates of cytotoxins as therapeutics |
AU2021213421A1 (en) | 2020-01-31 | 2022-06-23 | Innate Pharma | Treatment of cancer |
WO2022043256A1 (en) | 2020-08-23 | 2022-03-03 | Cobiores Nv | Synergistic combinations of anticancer drugs linked to a tetrapeptidic moiety and immunotherapeutic agents |
KR20230112656A (ko) | 2020-11-25 | 2023-07-27 | 이나뜨 파르마 에스.에이. | 암의 치료 |
WO2022136586A1 (en) | 2020-12-22 | 2022-06-30 | Cobiores Nv | Compounds comprising a tetrapeptidic moiety |
WO2022167664A1 (en) | 2021-02-07 | 2022-08-11 | Cobiores Nv | Compounds comprising a tetrapeptidic moiety |
US11806405B1 (en) | 2021-07-19 | 2023-11-07 | Zeno Management, Inc. | Immunoconjugates and methods |
WO2023194539A1 (en) | 2022-04-07 | 2023-10-12 | Heidelberg Pharma Research Gmbh | Methods of improving the therapeutic index of amatoxin-antibody conjugates |
WO2023227660A1 (en) | 2022-05-25 | 2023-11-30 | Innate Pharma | Nectin-4 binding agents |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH0687746A (ja) * | 1992-07-16 | 1994-03-29 | Dai Ichi Seiyaku Co Ltd | 抗腫瘍剤 |
WO1994019376A1 (en) * | 1993-02-26 | 1994-09-01 | Drug Delivery System Institute, Ltd. | Polysaccharide derivative and drug carrier |
WO1997046260A1 (en) * | 1996-06-06 | 1997-12-11 | Daiichi Pharmaceutical Co., Ltd. | Drug complexes |
Family Cites Families (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ATE166361T1 (de) | 1991-02-21 | 1998-06-15 | Drug Delivery System Inst Ltd | Carboxymethylmannoglukan und derivate davon |
US6214345B1 (en) * | 1993-05-14 | 2001-04-10 | Bristol-Myers Squibb Co. | Lysosomal enzyme-cleavable antitumor drug conjugates |
JPH0784481A (ja) | 1993-06-26 | 1995-03-31 | Ricoh Co Ltd | 画像形成装置 |
CA2192725C (en) | 1995-12-28 | 2004-04-20 | Kenji Tsujihara | Camptothecin derivatives |
TW409058B (en) * | 1996-06-06 | 2000-10-21 | Daiichi Seiyaku Co | Method for preparation of a drug complex |
US6368598B1 (en) * | 1996-09-16 | 2002-04-09 | Jcrt Radiation Oncology Support Services, Inc. | Drug complex for treatment of metastatic prostate cancer |
CA2264227A1 (en) | 1996-09-27 | 1998-04-02 | Raymond A. Firestone | Hydrolyzable prodrugs for delivery of anticancer drugs to metastatic cells |
CA2264610A1 (en) * | 1996-11-05 | 1998-05-14 | Bristol-Myers Squibb Company | Branched peptide linkers |
JPH1171280A (ja) * | 1997-06-26 | 1999-03-16 | Tanabe Seiyaku Co Ltd | 医薬組成物 |
JPH1192405A (ja) * | 1997-09-19 | 1999-04-06 | Dai Ichi Seiyaku Co Ltd | 薬物複合体 |
MXPA01004239A (es) * | 1998-10-30 | 2002-06-04 | Daiichi Seiyaku Co | Compuesto dds y metodo para la medicion del mismo. |
-
1999
- 1999-05-21 EP EP99919664A patent/EP1080732A4/en not_active Withdrawn
- 1999-05-21 WO PCT/JP1999/002681 patent/WO1999061061A1/ja active IP Right Grant
- 1999-05-21 EA EA200001217A patent/EA003398B1/ru not_active IP Right Cessation
- 1999-05-21 US US09/674,526 patent/US6835807B1/en not_active Expired - Fee Related
- 1999-05-21 CN CNB998089796A patent/CN1250293C/zh not_active Expired - Fee Related
- 1999-05-21 TW TW088108351A patent/TWI253935B/zh not_active IP Right Cessation
- 1999-05-21 AU AU37333/99A patent/AU3733399A/en not_active Abandoned
- 1999-05-21 JP JP2000550520A patent/JP4560210B2/ja not_active Expired - Fee Related
- 1999-05-21 KR KR1020007013102A patent/KR100581443B1/ko not_active IP Right Cessation
- 1999-05-21 CA CA002333321A patent/CA2333321A1/en not_active Abandoned
-
2000
- 2000-11-22 NO NO20005913A patent/NO20005913L/no not_active Application Discontinuation
-
2002
- 2002-02-22 HK HK02101369.9A patent/HK1040052B/zh not_active IP Right Cessation
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH0687746A (ja) * | 1992-07-16 | 1994-03-29 | Dai Ichi Seiyaku Co Ltd | 抗腫瘍剤 |
WO1994019376A1 (en) * | 1993-02-26 | 1994-09-01 | Drug Delivery System Institute, Ltd. | Polysaccharide derivative and drug carrier |
WO1997046260A1 (en) * | 1996-06-06 | 1997-12-11 | Daiichi Pharmaceutical Co., Ltd. | Drug complexes |
Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6436912B1 (en) | 1996-06-06 | 2002-08-20 | Daiichi Pharmaceutical Co., Ltd. | Drug complexes |
US6838450B2 (en) | 1996-06-06 | 2005-01-04 | Daiichi Pharmaceutical Co., Ltd | Drug complex |
US6811996B1 (en) | 1998-10-30 | 2004-11-02 | Daiichi Pharmaceutical Co., Ltd. | DDS compounds and method for assaying the same |
EP1619210A1 (en) * | 1998-10-30 | 2006-01-25 | Daiichi Pharmaceutical Co., Ltd. | DDS compounds and method for assaying the same |
US7041818B2 (en) | 1998-10-30 | 2006-05-09 | Daiichi Pharmaceutical Co., Ltd. | DDS compound and method for measurement thereof |
EP1298145A1 (en) * | 2000-06-29 | 2003-04-02 | Daiichi Pharmaceutical Co., Ltd. | Dds compound and process for the preparation thereof |
EP1298145A4 (en) * | 2000-06-29 | 2004-12-08 | Daiichi Seiyaku Co | DDS CONNECTION AND METHOD FOR PRODUCING THE SAME |
JP2006511526A (ja) * | 2002-12-13 | 2006-04-06 | イミューノメディクス、インコーポレイテッド | 細胞内で開裂可能な結合を有する免疫接合体 |
JP2007522245A (ja) * | 2004-02-12 | 2007-08-09 | ザ リサーチ ファウンデーション オブ ステイト ユニヴァーシティ オブ ニューヨーク | 医薬品複合体 |
JP2007527421A (ja) * | 2004-02-23 | 2007-09-27 | ジェネンテック・インコーポレーテッド | 複素環式自壊的リンカーおよび結合体 |
WO2007083984A1 (en) * | 2006-01-23 | 2007-07-26 | Gwangju Institute Of Science And Technology | Conjugate comprising pharmaceutical active compound covalently bound to mucoadhesive polymer and transmucosal delivery method of pharmaceutical active compound using the same |
Also Published As
Publication number | Publication date |
---|---|
KR20010052385A (ko) | 2001-06-25 |
CN1250293C (zh) | 2006-04-12 |
EP1080732A1 (en) | 2001-03-07 |
NO20005913D0 (no) | 2000-11-22 |
EA003398B1 (ru) | 2003-04-24 |
CA2333321A1 (en) | 1999-12-02 |
AU3733399A (en) | 1999-12-13 |
EA200001217A1 (ru) | 2001-06-25 |
JP4560210B2 (ja) | 2010-10-13 |
CN1310631A (zh) | 2001-08-29 |
US6835807B1 (en) | 2004-12-28 |
NO20005913L (no) | 2001-01-22 |
KR100581443B1 (ko) | 2006-05-23 |
TWI253935B (en) | 2006-05-01 |
HK1040052B (zh) | 2006-09-15 |
EP1080732A4 (en) | 2004-08-25 |
HK1040052A1 (en) | 2002-05-24 |
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