EP1631545A2 - Reactifs pour modifier des agents pharmaceutiques biologiques, leur preparation et leur utilisation - Google Patents

Reactifs pour modifier des agents pharmaceutiques biologiques, leur preparation et leur utilisation

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Publication number
EP1631545A2
EP1631545A2 EP04739807A EP04739807A EP1631545A2 EP 1631545 A2 EP1631545 A2 EP 1631545A2 EP 04739807 A EP04739807 A EP 04739807A EP 04739807 A EP04739807 A EP 04739807A EP 1631545 A2 EP1631545 A2 EP 1631545A2
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European Patent Office
Prior art keywords
formula
group
independently
occurrence
compounds
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EP04739807A
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German (de)
English (en)
Inventor
Ralf KRÄHMER
Frank Leenders
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celares GmbH
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celares GmbH
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
    • 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
    • A61K47/54—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 compound
    • 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
    • A61K47/59—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 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—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 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics

Definitions

  • the present invention relates to compounds which are suitable for coupling to pharmaceuticals, in particular biopharmaceuticals, and to conjugates from the compounds with biomolecules or pharmaceutical active substances.
  • the compounds of the invention can be easily formed by multi-component reactions.
  • Another object of the invention is the use of the conjugates as an improved formulation of pharmaceuticals and their preparation.
  • the invention also provides a laboratory kit for the in vitro production of conjugates from the compounds and pharmaceuticals according to the invention and biotechnological substances, in particular biopharmaceuticals, pharmaceutical active ingredients, synthetic molecules or surfaces.
  • the effectiveness and the duration of action of an active ingredient are determined by its pharmacological profile. Particularly in the case of biopharmaceuticals, a rapid loss of activity is very often observed in vivo, which is generally referred to as "clearance”. The clearance takes place through processes such as metabolism or metabolism, renal excretion and through the response of the immune system to the foreign connection. Proteinogenic substances in particular, an important group of biopharmaceuticals, produce a strong immune response when used therapeutically: this can lead to an allergic shock. In many cases, such adverse effects prevent the commercial or therapeutic use of this otherwise very advantageous class of active ingredient.
  • Abuchowski one of the pioneers in the field of polymer-mediated delivery of biopharmaceuticals, was able to show that covalent coupling of polyethylene glycol chains to a polypeptide molecule produces a positive pharmacological effect with this active ingredient.
  • Such a conjugate is characterized by reduced immunogenicity and an extended half-life in the blood (US Pat. No. 4,179,337, Davis et al .; Abuchowski & Davis "Enzymes as Drugs", Holcenberg & Roberts, ed.
  • the chemical reaction to couple a polyethylene glycol molecule to a biopharmaceutical requires the activation of one of the two components that are reacted.
  • the PEG molecule is provided with a connecting molecule, the so-called activated linker.
  • the entire range of long-established peptide chemistry is available for activation.
  • the linker is often activated in the form of an N-hydroxysuccinimide active ester. Harris, J.M. et al. (U.S. Patent No. 5,672,662) developed this method for propionic and butyric acid linkers, while Zaiipsky, S. et al. (U.S.
  • Patent No. 5,122,614 an activated carbonic acid ester is used.
  • the reaction of a lysine residue with such an activated linker leads to the formation of an amide or urethane bond.
  • Linking a PEG to a biopharmaceutical called PEGylation sometimes leads to a loss of biological activity.
  • One reason for this can be the loss of the positive charge due to the formation of an amide bond on the lysine residue.
  • Reductive amination using PEG aldehydes is a good alternative to using active esters (Harris, JM US Patent No. 5,252,714) because this coupling method leads to the formation of a secondary amine while maintaining the positive charge.
  • Other coupling options are the use of the maleimide method (cysteine residues) and the direct connection without a linker group when using tresyl or halogen compounds.
  • the most commonly used PEGs are linear monomethoxypolyethylene glycol chains (m-PEGs). These linear chains are not conformationally restricted and can 'freely rotate depending on the environment. As a result, the chain-shielded surface of the biopharmaceutical is relatively small.
  • branched modification reagents that contain several PEG chains in one molecule.
  • PEG chains There are few commercial examples of this class of substance.
  • a well-known example of this is an activated lysine provided with two m-PEG chains. Due to the fact that the bindings can also be freely rotated here, the shielding effect is only moderate (Veronese, FM Bioconjugate Chem. 1995, 6, 62-69).
  • P independently represents H, OH, CC 4 -alkyl, OR 2 or CO-R 3 on each occurrence,
  • R 2 independently represents a hydrocarbon radical with 1 to 6 C atoms with each occurrence, R 3 OH or Is NR 4 R 5 ,
  • R 4 and R 5 each independently represent H or a hydrocarbon radical which may contain heteroatoms, in particular O or / and N, where R 4 and R 5 together can also form a ring system, n each time an occurrence independently an integer from 1 is to 1000 and x is an integer from 1 to 10 every occurrence and y is an integer from 0 to 50 and q is independently 0 or 1 each occurrence.
  • the compounds according to the invention have a basic structure which can be obtained by a multi-component reaction, for example a Ugi or a Passerini reaction or by a Ugi reaction carried out in stages.
  • a multi-component reaction for example a Ugi or a Passerini reaction or by a Ugi reaction carried out in stages.
  • first three components are reacted with one another (amine, isonitrile and carbonyl component) and then the fourth component (acid component) is coupled to the reaction product.
  • the compounds according to the invention contain at least one binding group Y, which enables the compound according to the invention to be covalently bound to further molecules, in particular to biotechnological, pharmaceutical or synthetic active substances, and to surfaces or to biocatalysts.
  • the binding group Y is preferably a Compound which can covalently bind with a functional group present in the active substance to be coupled, for example around a binding group which has an amino group, a thiol group, a carboxyl group, a guanidine group, a carbonyl group, a hydroxyl group, a heterocycle, in particular with N as a hetero atom (eg in histidine residues), a C-nucleophilic group, a C-electrophilic group, a phosphate, a sulfate or the like is capable of binding.
  • a binding group which has an amino group, a thiol group, a carboxyl group, a guanidine group, a carbonyl group, a hydroxyl group, a heterocycle, in particular with N as a hetero atom (eg in histidine residues), a C-nucleophilic group, a C-electrophilic group, a phosphate,
  • Non-covalent bonds for example chelates, complexes with metals, for example on surfaces or with radioisotopes, as well as bonds to silicon-containing surfaces are also possible.
  • Suitable binding groups are, for example, a carboxylic acid or an activated carboxylic acid group.
  • the compounds according to the invention preferably contain an activated functionality Y.
  • Y is preferably selected from the group consisting of (O-alkyl) 2 , -OSO 2 CH 2 CF 3 (tresyl), (O-aryl) azides, -CO-Q, maleimidyl, -O-CO-nitrophenyl or trichlorophenyl, -SS-alkyl, -SS-aryl, -SO 2 -alkenyl (vinyl sulfone ), -Halogen (Cl, Br, I), where Q is selected independently from a group consisting of H, O-aryl, O-benzyl, ON-succinimide, ON-sulfosuccinimide, ON-phthalimide, ON-glutarimide, ON- tetrahydrophthalimide, N-norbomene-2,
  • the compounds according to the invention can be covalently bound to active substances and thus form highly desirable, stable conjugates.
  • the compounds according to the invention furthermore have at least one group of the formula (II).
  • the compounds preferably have at least two and more preferably three groups of the formula (II). Due to the flexibility provided by the multi-component reaction, it is possible to insert the groups of the formula (II) at different positions in the molecule. So it is possible to in groups of formula (II) various residues V, W, X or / and Z, in particular in X or / and Z, to be introduced.
  • the compounds of the formula (I) according to the invention have a molecular weight of 200 to 50,000 Da, in particular 1,000 to 20,000 Da. It has furthermore been found that compounds of the formula (I) according to the invention which contain more than one chain of the formula (II) provide good shielding even at lower molecular weights of the entire compound. In the case of compounds which have two to three groupings of the formula (II), a molecular weight of the total compounds of 500 to 25,000 Da, in particular from 500 to 10,000 Da, is sufficient.
  • Compounds which have four or five groupings of the formula (II) preferably have a molecular weight of 200 to 12,500 Da, in particular 500 to 7,500 Da.
  • the molecular weight is particularly preferably ⁇ 7,500 Da and more preferably ⁇ 5000 Da.
  • the groups of the formula (II) are preferably polyalkylene oxides, such as, for example, polyethylene glycol, polyolefin alcohols, such as, for example, polyvinyl alcohol or polyacrylmorpholine.
  • the residues or placeholders P, R 2 , R 3 , R 4 , R 5 , n, x, y and q in a molecule or a residue can in each case be the same or else different from one another ,
  • the rest of formula (II) can be a polyalkylene oxide consisting of polyethylene oxide and polypropylene oxide groups.
  • R 4 and R 5 can be hydrogen or a hydrocarbon radical having 1 to 30 C atoms, in particular 1 to 10 C atoms, more preferably 1 is 6 C atoms, which may contain heteroatoms, in particular one or more heteroatoms, selected from O, N, P and S.
  • the radicals R 4 and R 5 together can also form a ring, for example a morpholine ring.
  • the radical R 1 is hydrogen, hydroxyl or a hydrocarbon radical with 1 to 50 carbon atoms, more preferably 1 to 30 carbon atoms and most preferably 1 to 10 carbon atoms, which optionally contains heteroatoms, in particular O, N, S, P or / and Si.
  • the radical R 1 can be saturated or mono- or polyunsaturated as well as linear, branched or cyclic. HO, CH 3 -O, CH 3 - (CH 2 ) a -O, (CH 3 ) 2 CH-O is particularly preferred, where a is an integer between 1 and 20.
  • n is between 0 and 1000.
  • n (as used herein, for example in Formula II or Formula Ila) is independently an integer from 0 to 1000, more preferably from 1 to 500, even more preferably from 2 to 250, especially at least 3 and most preferably at least every occurrence 4 to 50.
  • n is independently an integer from 0 to 1000, more preferably from 1 to 500, even more preferably from 2 to 250, especially at least 3 and most preferably at least every occurrence 4 to 50.
  • compounds which contain 2 or 3 groups of the formula (II) are often particularly preferred.
  • x is independently an integer from 1 to 10, in particular 1 to 6, more preferably from 2 to 3, and y is an integer from 0 to 50, more preferably from 1 to 10, even more preferably from 2 to 6 .
  • q is 0 or 1 at each occurrence independently.
  • residues V, W, X and Z originate from the reactants reacted in the multicomponent reaction or become, in the event that one of the reactants has two or more functional groups (amine, ketone or aldehyde, isonitrile or acid grouping) exhibits, in the course of
  • Multi-component reaction established. Preference is given to compounds which are obtained in a multicomponent reaction or a multistage multicomponent reaction, in particular a four-component reaction and most preferably in a Ugi reaction, in which at least one starting material which is branched, ie at least two, more preferably at least three, is used Multi-component reaction reactive groups (eg amine, carbonyl, isonitrile or / and acid grouping).
  • the radical V comes from the acid component
  • the radical Z from the isonitrile component
  • the radical X from the amino component
  • the radical W from the carbonyl component.
  • the radicals V, W, X and Z each independently represent hydrogen or a hydrocarbon radical which may optionally contain heteroatoms.
  • a hydrocarbon radical here means a radical having 1 to 100,000 carbon atoms, more preferably a radical of 1 to 10,000 carbon atoms, in some preferred cases 1 to 50 carbon atoms, which is 0 to 10,000, more can preferably contain 1 to 1,000 heteroatoms, for example selected from O, P, N or S.
  • the hydrocarbon radicals can be linear or branched and can be saturated or mono- or polyunsaturated.
  • a hydrocarbon residue can also contain cyclic or aromatic sections.
  • hydrocarbon radicals are alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aroyl and heteroaroyl.
  • a hydrocarbon radical, as used herein, can also contain functional groups and in particular a targeting agent and for example an aminocarboxylic acid ester, for example a saturated or unsaturated omega-aminocarboxylic acid ester, a dye, a fluorescent label, an antibiotic, a minor or major groove binder Biotinyl residue, a streptavidin residue, an intercalating residue, an alkylating residue, a steroid, a lipid, a polyamine, folic acid, a receptor agonist or antagonist, an enzyme inhibitor, a peptide, an antibody or an antibody fragment, an amino sugar, a saccharide or oligosaccharide, eg Galactose, glucose or mannose, an antisense polymer, a modified surface, a sur
  • At least one of the residues V, W, X or / and Z comprises a targeting group which enables the targeted directing of the compounds according to the invention and in particular of the conjugates containing the compounds according to the invention to a desired target location, for example a location of a disease, such as an inflammatory focus or a cancer.
  • a targeting group which enables the targeted directing of the compounds according to the invention and in particular of the conjugates containing the compounds according to the invention to a desired target location, for example a location of a disease, such as an inflammatory focus or a cancer.
  • a targeting group which enables the targeted directing of the compounds according to the invention and in particular of the conjugates containing the compounds according to the invention to a desired target location, for example a location of a disease, such as an inflammatory focus or a cancer.
  • the invention it is also possible to provide molecules which contain two or more targeting groups. This enables an increased targeting effect to be achieved and / or the compound or a conjugate formed therewith to be directed to a number of desired locations.
  • the compounds according to the invention can also contain reporter groups, for example fluorescent dyes or fluorescent markers, which enables use for diagnostic purposes.
  • the radical X in the compounds according to the invention is preferably a targeting group, a radical of the formula (II) or a combination of both.
  • x 2, 3 or 4 is particularly preferred.
  • Particularly preferred subunits in the radical X are ethylene glycol, propylene glycol, butylene glycol or combinations thereof with a chain length of 3 to 500, in particular 4 to 100, units.
  • R 1 in the radical X is particularly preferably methoxy or ethoxy, in particular methoxy. Most preferably X is methoxypolyethylene glycol with 1 to 1000, especially 4 to 50 ethylene units.
  • radical X contains a targeting grouping, as indicated above.
  • the shielding function by the formula (II) and the targeting function are present in a radical X.
  • Such a radical X preferably has the formula (IIb)
  • the radical Z which originates from the isonitrile (Z-NC) in the preparation of the compounds according to the invention by means of the Ugi reaction, is preferably a C 1 -C 6 -alkyl radical or a radical which contains one, two or more groups of the formula (II) as well as a targeting function if necessary.
  • Z is particularly preferably a grouping of the formula (Xa), (Xb) or (Xc)
  • P on each occurrence independently represents H, OH, C 1 -C 4 alkyl, OR 2 or CO-R 3 (wherein R 2 and R 3 are as defined above),
  • R 1 is H, OH or a hydrocarbon radical having 1 to 50 carbon atoms , which can contain heteroatoms and is preferably a C 1 -C 4 alkoxy radical
  • a represents an integer from 0 to 50, in particular 1 to 3, in each occurrence, b an integer from 0 to 50, in particular 1 in each occurrence to 3
  • c is an integer from 1 to 10, especially 2 to 4 in each occurrence
  • d is independently an integer from 1 to 1,000, in particular 5 to 100 in each occurrence.
  • the radicals W which originate from the carbonyl compound in the preparation of the compounds according to the invention by a Ugi reaction, are each preferably independently hydrogen or a CC 6 hydrocarbon radical, in particular a C r C 4 alkyl radical and most preferably hydrogen, methyl or ethyl.
  • the use of symmetrical ketones prevents the formation of a center of symmetry on the carbon atom to which the radicals W are bound are prevented. As a result, there are no problems associated with chiral compounds in the formation of conjugates with active substances.
  • W is particularly preferably hydrogen on each occurrence.
  • the radical W is introduced by using an aldehyde as the starting material in the Ugi reaction.
  • one of the radicals W is hydrogen
  • the other radical W is preferably a C r C 6 hydrocarbon and in particular a C 1 -C 4 alkyl radical.
  • one of the radicals W can contain a group of the formula (II), a linker and / or a targeting group.
  • the radical V comes from the carboxylic acid compound in the preparation of the compounds according to the invention by means of the Ugi reaction.
  • the grouping V preferably contains a linker or a binding group Y for coupling the compounds according to the invention to further molecules, in particular to biotechnological, pharmaceutical or synthetic active substances.
  • the radical V can contain, in addition to the binding group, a linker group, preferably a C 1 -C 8 alkylene group or a glycol group, for example a tetraethylene glycol group.
  • the compounds of the formula (I) preferably have one to three, more preferably two to three, groups of the formula (II), namely one group in the radical X and one or two groups in the radical Z.
  • polyfunctional starting materials are used.
  • at least one of the starting materials of the Ugi reaction is used in polyfunctional form, that is to say in difunctional, trifunctional or higher functional form.
  • at least one bifunctional starting material that is to say a dicarboxylic acid, a diamine, a diisonitrile or / and a dialdehyde or diketone, and preferably at least one dicarboxylic acid or / and a diamine.
  • Compounds of the formula (III) can be prepared by a process based on a Ugi-4-component reaction in which a carbonyl, amino, isonitrile and acid component are involved. These components can optionally be reacted with one another at the same time and contain protective groups which are later removed or remain in the molecule.
  • the acid component in formula (purple) here is a 1, 1, 2-ethanetricarboxylic acid which additionally bears a linker group at the 1 position.
  • the carbonyl component used to prepare compounds of formula (purple) is preferably formaldehyde or a symmetrical carbonyl compound, e.g. Acetone or cyclohexanone. This prevents the formation of mixtures of diastereoisomers.
  • asymmetrical aldehydes e.g. Isobutyraldehyde, or ketones can be used.
  • the linker T is preferably represented by an alkyl chain which is branched or unbranched, saturated or unsaturated, and can contain heteroatoms, in particular N, S and O, for example between the branching and T.
  • T preferably has a carbon atom or a nitrogen atom as Link to the branch point in the compounds of formula (III) or (purple).
  • T is more preferably an alkyl chain of structure 1.
  • n is an integer from 1 to 10, but preferably an integer from 1 to 5.
  • the linker has the structure T ' ⁇
  • the present invention helps to reduce the disadvantages or limitations described in the prior art. It encompasses the synthesis of bifunctional compounds which can be used to modify natural products, technical products, biotechnological and synthetic products or pharmaceutical active ingredients.
  • the compounds according to the invention contain an activated linker group which forms a covalent bond with one or more amino functionalities or other functional groups of a biotechnological or synthetic product as part of a chemical reaction under mild reaction conditions and at least one polymer function which influence the biochemical and pharmacological properties of the conjugate.
  • the connections contain further functions, such as e.g. Targeting functions.
  • the present invention preferably provides a multi-branched structure, as well as its synthesis and application for the modification of biotechnological products.
  • the structure can be produced using a multi-component reaction, for example the Ugi reaction (Ugi, I. et al., Angew. Chem. Int. Ed. 2000, 39, 3168-3210; EP 1104677).
  • Ugi reaction Ugi, I. et al., Angew. Chem. Int. Ed. 2000, 39, 3168-3210; EP 1104677.
  • the use of the multi-component reaction enables one combinatorial approach as well as the automation of manufacturing.
  • the present invention preferably provides an unbranched or branched polymer compound that carries only a single activated linker group, thereby avoiding cross-linking reactions.
  • This polymer compound is hydrophilic and biologically compatible. It is easy to manufacture and opens up a wide range of applications for the modification of active pharmaceutical ingredients and technically used products. Conjugates of the polymer compound according to the invention with active pharmaceutical ingredients enable an improvement in the therapeutic use. Furthermore, these conjugates make it possible to reduce the amount of active ingredient to be administered, for example for the treatment of cancer and infectious diseases, when the duration of action is prolonged.
  • the invention further relates to a process for the preparation of the compounds according to the invention, the individual components of the formulas being used in a multicomponent reaction
  • V, W ⁇ X 'and Z' each independently represent a hydrocarbon radical which may optionally contain heteroatoms or / and V, W or / and X 'represent hydrogen, at least one of the radicals V, W, X' and Z 'carries a binding group Y and the radicals V, W, X' and Z ' together at least one, in particular at least two, groups of the formula (II)
  • P independently represents H, OH, OR 2 or CO-R 3 on each occurrence
  • R. H or a hydrocarbon radical having 1 to 50 carbon atoms, which can contain heteroatoms, in particular O, N, S, P or / and Si,
  • R 2 independently represents a hydrocarbon radical with 1 to 6 carbon atoms with each occurrence
  • R 3 is OH or NR 4 R 5 ,
  • R 4 and R 5 each independently represent H or a hydrocarbon radical which may contain heteroatoms, in particular O, N, S or / and P, where R 4 and R 5 together can also form a ring system, n each independently occurring is an integer from 1 to 1000 and x is an integer from 1 to 10 each occurrence and y is an integer from 0 to 50 and q is independently 0 or 1 each occurrence.
  • radicals X ', W, Z and V no longer have any further functionality which is reactive for the multicomponent reaction (ie NH 2 , CO, NC or COOH)
  • educts are 1, 1, 2-ethanetricarboxylic acid with three carboxylic acid residues, ie two carboxylic acid groups in residue V, or residues which contain at least two different functional groups, such as lysine (contains an acid group and an amine group at the same time) or ⁇ - aminobutyric acid.
  • the corresponding groupings V, W, X and Z in the product, starting from the functional group in the remainder V, W, X 'and Z' are only built up during the multicomponent reaction. In this way it is possible to build up highly branched and highly functional compounds in a one-pot reaction, in particular compounds which contain a large number of groupings of the formula (II).
  • h, i are independently 0 or 1 with each occurrence, g and f are independently with each occurrence an integer between 0 and 10, preferably between 0 and 5,
  • A stands for H or - (CO) -NX 2 at each occurrence and
  • XX 2 , X 3 and X 4 and X each independently have the meanings given for X above.
  • achiral molecules can be prepared according to the invention which contain up to 6 (in the case of dicarboxylic acids) or up to 9 (in the case of tricarboxylic acids) groups of the formula ( II) have. Since the coupling of amines to di- or tricarboxylic acids, which are not amino acids, takes place according to the invention, the coupling can be carried out in a simple manner, without the need for a complex synthesis process using protective groups.
  • conjugates of the bifunctional, branched polymer compound with biologically active substances such as proteins (for example human growth factors), enzymes, co-factors for enzymes (for example NAD + / NADH), liposomes, antibodies, synthetic, small active substances, phosphoiipids , Lipids, nucleosides, oligonucleotides, microorganisms, human cells and surfaces.
  • biologically active substances such as proteins (for example human growth factors), enzymes, co-factors for enzymes (for example NAD + / NADH), liposomes, antibodies, synthetic, small active substances, phosphoiipids , Lipids, nucleosides, oligonucleotides, microorganisms, human cells and surfaces.
  • the invention therefore also relates to conjugates comprising compounds of the formula (I) in a covalent linkage to other molecules, in particular to active substances, such as biopharmaceuticals or synthetic active substances, or biotechnological substances which are used in the field of life science, for example in the field of proteomics Such substances are, for example, enzymes, in particular proteases, such as trypsin or chymotrypsin.
  • active substances such as biopharmaceuticals or synthetic active substances, or biotechnological substances which are used in the field of life science, for example in the field of proteomics
  • Such substances are, for example, enzymes, in particular proteases, such as trypsin or chymotrypsin.
  • the compounds linked to the compounds according to the invention in the conjugates are preferably biopharmaceuticals, peptide active substances or other biologically active substances. Conjugates with surfaces or biocatalysts can also be formed ,
  • the invention further relates to conjugates comprising compounds of the formula (I) in covalent linkage to medical devices or auxiliaries Presentation of active ingredients.
  • tissues for heterografts such as heart valves, for example, can be made more tolerable for the recipient.
  • auxiliary agents for the administration of active substances for example liposomes or nanocapsules, can be modified in order to impart desired properties, in particular a longer half-life in the body.
  • the invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the compounds according to the invention and in particular the conjugates according to the invention.
  • Compositions can be used, for example, for the prevention or treatment of cancer, cardiovascular diseases, metabolic diseases, neuronal or cerebral diseases or inflammatory processes such as infections, immune diseases or autoimmune diseases (e.g. rheumatoid arthritis).
  • the compounds or conjugates according to the invention are also outstandingly suitable as diagnostic agents.
  • kits which comprises all the reagents and instructions as well as the compounds according to the invention which make it possible to obtain a Modification of proteins, nucleic acids or other active substances or even surfaces with polymers can be carried out in vitro in a simple manner.
  • the reaction of a substance with the compounds according to the invention takes place, for example, in such a way that, to a solution or a suspension of the substance to be modified, for example a protein, in aqueous buffer the polymer compound according to the invention is at least in molar amount based on the number of modifiable reactive groups, for example amino groups (Lysine residues, histidine, N-terminus), carboxyl groups (aspartic acid, glutamic acid, C-terminus), thiol groups (cysteine), hydroxyl groups (serine, threonine, tyrosine) or carbonyl groups (aldehydes).
  • the polymer compounds according to the invention are preferably used in a molar excess of 1 to 1000, more preferably in a molar excess of 1 to 100 and particularly preferably in a molar excess of 1 to 20, based on the modifiable groups.
  • Suitable reaction solutions are aqueous buffers such as 0.001 to 1.0 molar solutions of sodium or potassium dihydrogen phosphate with disodium or dipotassium hydrogen phosphate or sodium, potassium or ammonium hydrogen carbonate with disodium, disodium or diammonium carbonate or Tris ( hydroxymethyl) aminoethane with hydrochloric acid, buffer solutions are preferably suitable for the pH range between pH 4 and pH 10, particularly preferably between pH 5 and pH 9.
  • the cosolvents methanol, ethanol, propanol, i-propanol, butanol, ethyl acetate, methyl acetate, dimethylformamide, acetonitrile, dimethyl sulfoxide or sulfolane can be added to the buffer in amounts of 0.1 to 50% by volume, more preferably 0.1 to 20 vol% are added, depending on the solubility of the reactants.
  • the reaction temperature is between 0 ° C and 90 ° C, preferably 4 ° C to 40 ° C.
  • stabilizers or detergents can be added to the buffers, for example sodium azide, glycerol, ethylene glycols or ionic or non-ionic detergents.
  • the conjugate crude products obtainable by the process according to the invention can furthermore be purified by dialysis, chromatographic processes or ultrafiltration (including those for centrifuges) with aqueous buffer solutions or pure water and by processes familiar to the person skilled in the art and then used for further use.
  • the structural evidence of the products (conjugates), i.e. the analytical number of covalently bound polymer compounds according to the invention is carried out by direct measurement of the molecular weight, e.g. by means of MALDI-TOF mass spectrometry, by selective determination of one or more covalently bound components or by indirect detection of the unmodified groups.
  • a dye molecule introduced via the compound according to the invention can be determined in a simple manner by measuring the absorbance (UV ⁇ IS).
  • the number of unmodified amino groups for example, can be determined fluorometrically by reaction with fluorescamine.
  • the stability of the conjugate towards proteases can be investigated, for example, as direct evidence of the improvement in the properties of the conjugate from a polymer compound according to the invention.
  • Figure 1 Analysis of conjugates from L-asparaginase and substance 16 using SDS-PAGE.
  • the samples are: lanes 1) and 9) protein standard (Low Molecular Weight Marker, Amersham Pharmacia), lane 2) L-asparaginase (control, 2 ⁇ g), lane 3) modified L-asparaginase (0.5eq. Substance 16), Lane 4) modified L-asparaginase (1eq. Substance 16), lane 5) modified L-asparaginase (2eq. Substance 16), lane 6) modified L-asparaginase (5eq. Substance 16), lane 7) modified L-asparaginase ( 10eq. Substance 16) and lane 8) modified L-asparaginase (20eq. Substance 16).
  • Figure 2 Protease stability of a conjugate of L-asparaginase and substance 16: Influence of the modification of L-asparaginase with substance 16 on the Stability of L-asparaginase against trypsin derived from residual activity. Modification with substance 16 significantly increases the stability towards trypsin.
  • Figure 3 Influence of the modification of L-asparaginase with substance 16 on the stability of L-asparaginase against chymotrypsin derived from the residual activity. Modification with substance 16 significantly increases the stability towards chymotrypsin.
  • Figure 4 Analysis of conjugates from streptokinase and substance 16 using SDS-PAGE.
  • the samples are: lanes 1) and 8) Protein Standard (Low Molecular Weight Marker, Amersham Pharmacia), lane 2) streptokinase (control, 2 ⁇ g), lane 3) modified streptokinase (0.5eq. Substance 16), lane 4) Streptokinase (1eq. Substance 16), lane 5) modified streptokinase (2eq. Substance 16), lane 6) modified streptokinase (5eq. Substance 16) and lane 7) modified streptokinase (10eq. Substance 16).
  • Figure 5 Analysis of conjugates from trypsin and substance 16 using SDS-PAGE.
  • the samples are: lanes 1), 2) and 9) Protein Standard (Low Molecular Weight Marker, Amersham Pharmacia), lane 2) trypsin (control, 2 ⁇ g), lane 3) modified trypsin (0.5eq. Substance 16), lane 4) modified trypsin (1eq. Substance 16), lane 5) modified trypsin (2eq. Substance 16), lane 6) modified trypsin (5eq. Substance 16) and lane 7) modified trypsin (10eq. Substance 16).
  • an amino component, an oxo or carbonyl component, an isocyanine component and an acid component are reacted to the compound according to the invention.
  • the primary amines used are commercially available or, starting from the monomethoxypolyethylene glycols, can be prepared by a Gabriel synthesis or from the corresponding azido compound by catalytic hydrogenation.
  • Secondary amines, symmetrical or asymmetrical, are obtainable from a primary amine by reductive amination with a corresponding aldehyde, which is obtained, for example, by Swern oxidation from monomethoxypolyethylene glycol, or can be obtained by simple substitution reactions.
  • Isonitriles are commercially available on a large scale. A large number of synthetic methods are also available for their production. A very reliable method is the preparation of isonitriles from primary amines via the conversion to formamide with subsequent dehydration using phosgene or POCI 3 (I. Ugi; R. Meyr, Angew. Chem. 1958, 70, 702). Alternatively, isonitriles can be obtained in a simple manner by reacting a primary or secondary amine with a methyl or ethyl ⁇ -isocyanocarboxylic acid ester.
  • aldehydes or ketones can be used as the oxo or carbonyl component.
  • symmetrical ketones such as acetone, and the simple formaldehyde are preferably used.
  • the acid component also serves as a linker for later coupling to the active substance, so that carboxylic acids are preferably used, which can be converted into an activated form of the compound according to the invention by a few synthetic steps after a successful multi-component reaction.
  • carboxylic acids are preferably used, which can be converted into an activated form of the compound according to the invention by a few synthetic steps after a successful multi-component reaction.
  • These can be monoesters of dicarboxylic acids (e.g. succinic acid mono-tert-butyl ester) or unsaturated monocarboxylic acids (e.g. 4-pentenecarboxylic acid).
  • N-substituted amino acids e.g. N-Boc-L-glutamic acid, N-Boc-L-aspartic acid
  • more highly branched carboxylic acids e.g. tricarboxylic acid 7
  • the main step in the synthesis of the compounds according to the invention takes place by a multicomponent reaction, the Ugi reaction with three (U-3CR) or four (U-4CR) components in the liquid phase being preferred.
  • U-3CR three
  • U-4CR four
  • the amine component is reacted in the liquid phase with the oxo component, the acid component and an isocyano component according to the following general formula:
  • azomethine it is advantageous to use one equivalent each of the individual components in the implementation. It may also be advantageous to form the azomethine by precondensation.
  • Aprotic, polar and non-polar, and protic, polar can be used as solvents.
  • Alcohols such as methanol, ethanol, water or water / alcohol mixtures and DMF or are particularly suitable as protic solvents for this Acetonitrile.
  • aprotic solvents dichloromethane, tetrahydrofuran or chloroform are often used.
  • Lewis acids such as boron trifluoride etherate or zinc chloride, have a beneficial effect on the Ugi reaction. The reactions are usually carried out at from -20 ° C. to 100 ° C., but reaction temperatures between 0 ° C. and 50 ° C. are preferred.
  • acid components which simultaneously serve as a protective group for the amino functionality.
  • Such protective groups can then be removed so that the secondary amine formed can also be coupled to carboxylic acids later using generally known methods from peptide chemistry.
  • examples for such acids are trifluoroacetic acid or 4-pentenecarboxylic acid.
  • the acid component In some cases it can be advantageous to replace the acid component with an acid that does not react in the sense of the Ugi reaction.
  • acids used are mineral acids, such as hydrochloric or sulfuric acid, sulfonic acids and Lewis acids, such as boron trifluoride etherate or INCI 3 .
  • water takes on the function of the acid component, forming a secondary amine.
  • This secondary amine can then be coupled to branched or unbranched carboxylic acid functionalities by various amidation methods which are already known from peptide chemistry.
  • the amine component with the oxo component, the acid component (eg sulfuric acid) and an isocyanocomponent are in the liquid phase reacted according to the following general formula:
  • azomethine it is advantageous to use one equivalent each of the individual components in the implementation. It may also be advantageous to form the azomethine by precondensation.
  • Aprotic, polar and non-polar, and protic, polar can be used as solvents.
  • Alcohols such as methanol, ethanol, water or water / alcohol mixtures and DMF or acetonitrile are particularly suitable as protic solvents for this.
  • aprotic solvents dichloromethane, tetrahydrofuran or chloroform are often used. The reactions are usually carried out at from -20 ° C. to 100 ° C., but reaction temperatures between 0 ° C. and 50 ° C. are preferred.
  • the tert-butyl ester is cleaved under standard conditions e.g. with mineral acids such as HCI or HCI in dioxane. Alternatively, trifluoroacetic acid can also be used.
  • Bovine serum albumin (short: BSA, Sigma), L-asparaginase (short: ASNase, ProThera), streptokinase (Sigma), trypsin (Sigma) and chymotrypsin (Sigma) were used for the experiments.
  • L-asparaginase catalyzes the deamidation of L-asparagine to L-aspartic acid. Ammonium released during this reaction was quantified by means of a Nessler reagent to determine the enzyme activity. Streptokinase activates plasminogen. Plasminogen activated in this way catalyzes the hydrolysis of the tripeptide derivative D-Val-Leu-Lys-para-nitroanilide (S-2251). For indirect determination of the activity of streptokinase, the amount of nitroaniline released was quantified photometrically at 405nm. The peptidolytic activity of trypsin was determined using the para-nitroanilide derivative ⁇ -benzoyl-arginine-para-nitroanilide by quantification of the released nitroaniline photometrically at 405nm.
  • the conjugates comprising a compound according to the invention covalently coupled to one biopharmaceutical, pharmaceutical or synthetic active ingredient were incubated in the presence of trypsin or chymotrypsin for at least 90min at 37 ° C. Aliquots were taken at various times and the residual activity of the conjugate to be examined was determined from these. Trypsin cleaves peptides and proteins preferably at the C-terminal of basic amino acids (lysine and arginine residues), chymotrypsin preferably at the C-terminal of aromatic amino acids (tryptophan, phenylalanine and tyrosine residues).
  • Substance 16 (0.5eq. / 0.7 ⁇ L, 1eq./1, 4 ⁇ L, 2eq.) was added to 75 ⁇ L of an L-asparaginase solution (0.5 mg / mL) in sodium carbonate buffer (pH 8.5 to 9.5) ./2.7 ⁇ L, 5eq./6.8 ⁇ L, 10eq./13.7 ⁇ L or 20eq./27.3 ⁇ L) dissolved in dimethyl sulfoxide (10mg / mL) and with sodium carbonate buffer (pH 8.5 to 9, 5) filled up to a total volume of 150 ⁇ L.
  • the reaction mixture was incubated for 1 h at 25 ° C. and 300 rpm on a thermomixer. Excess substance 16 was then removed by filtration in centrifuge filtration units (10 kDa cut-off) with water as the rinsing liquid.
  • the modification reduces the activity of the L-asparaginase only slightly. With a degree of PEGylation from 41% to 75% residual activity, with a degree of PEGylation from 43% to 60% residual activity (see Table 1)
  • Streptokinase is modified to 100% of the lysine residues when 10 equivalents of substance 16 are used (see Table 2)
  • Substance 16 (0.5eq. / 1, 5 ⁇ L, 1eq./2.7 ⁇ L, 2eq./ to 120 ⁇ L of a tr ⁇ psin solution (1.0 mg / mL) in sodium carbonate buffer (pH 8.5 to 9.5)) 5.4 ⁇ L, 5eq. I3.8 ⁇ L or 10eq./27.3 ⁇ L) dissolved in dimethyl sulfoxide (10mg / mL) and filled with sodium carbonate buffer (pH 8.5 to 9.5) to a total volume of 150 ⁇ L.
  • the reaction mixture was incubated for 1 h at 25 ° C. and 300 rpm on a thermomixer. Excess substance 16 was then removed by filtration in centrifuge filtration units (10 kDa cut-off) with water as the rinsing liquid.
  • Trypsin is modified with 10 equivalents of substance 16 to 44% of the lysine residues.
  • the residual activity increases to 137%.
  • the increase in activity by modification with reagents containing polyethylene glycol is explained in the literature by a change in the microenvironment of the active center (Zhang, Z., He, Z. & Guan, G. (1999) in Biotechnology Techniques 13: 781-786).
  • R 4 and R 5 each independently represent H or a hydrocarbon radical which may contain heteroatoms, in particular O or / and N, where R 4 and R 5 together can also form a ring system, d, n independently on each occurrence an integer of 1 up to 1000, c, x independently each time an integer from 1 to 10 and a, b, p, y independently an integer from 0 to 50 and q independently each time 0 or 1.

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Abstract

La présente invention concerne des composés qui peuvent être combinés à des agents pharmaceutiques, notamment à des agents pharmaceutiques biologiques, ainsi que des conjugués formés de ces composés et de molécules biologiques ou principes actifs pharmaceutiques. Les composés de l'invention peuvent facilement être obtenus par des réactions entre plusieurs composés. L'invention a également pour objet l'utilisation des conjugués en tant que formulation améliorée d'agents pharmaceutiques, et leur préparation. L'invention concerne aussi un kit de laboratoire permettant la préparation in vitro de conjugués à partir des composés de l'invention et d'agents pharmaceutiques, ainsi que des substances de biotechnologie, en particulier des agents pharmaceutiques biologiques, des principes actifs pharmaceutiques, des molécules ou surfaces de synthèse.
EP04739807A 2003-06-11 2004-06-11 Reactifs pour modifier des agents pharmaceutiques biologiques, leur preparation et leur utilisation Withdrawn EP1631545A2 (fr)

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EP1604656A1 (fr) 2004-06-09 2005-12-14 Schwarz Pharma Ag Utilisation nouvelle de peptides pour le traitement de la sclérose amytrophique latérale (ALS)
DE102005041570A1 (de) * 2005-09-01 2007-03-22 Celares Gmbh Hoch verzweigte Reagenzien zur Modifaktion von Biopharmazeutika, deren Herstellung und Anwendung
EP1782826A1 (fr) * 2005-11-08 2007-05-09 GBF Gesellschaft für Biotechnologische Forschung mbH PQS, c-diGMP et leurs conjugués utilisés comme adjuvants et leur emploi dans des compositions pharmaceutiques
EP1787660A1 (fr) * 2005-11-22 2007-05-23 GBF Gesellschaft für Biotechnologische Forschung mbH Nouveaux adjuvants a base des conjugés de bisacyloxypropylcystéine et leurs utilisations en compositions pharmaceutiques
US8741966B2 (en) 2007-11-09 2014-06-03 Pronova Biopharma Norge As Lipid compounds for use in cosmetic products, as food supplement or as a medicament
EP2147910A1 (fr) * 2008-07-15 2010-01-27 Pronova BioPharma Norge AS Nouveaux composés lipidiques
AU2010244136B2 (en) 2009-05-08 2016-05-12 Pronova Biopharma Norge As Polyunsaturated fatty acids for the treatment of diseases related to cardiovascular, metabolic and inflammatory disease areas
WO2010140154A1 (fr) 2009-06-04 2010-12-09 Gavish-Galilee Bio Applications Ltd Protéines modifiées par un produit d'adduit (amino)-monosaccharide-biotine
JP2014505017A (ja) 2010-11-05 2014-02-27 プロノヴァ・バイオファーマ・ノルゲ・アーエス 脂質化合物を用いる処置方法
JP6537980B2 (ja) 2013-02-28 2019-07-03 プロノヴァ・バイオファーマ・ノルゲ・アーエスＰｒｏｎｏｖａ ＢｉｏＰｈａｒｍａ Ｎｏｒｇｅ ＡＳ 脂質化合物、トリグリセリドおよび界面活性剤を含む組成物、ならびにその使用方法
CN115025079A (zh) 2015-04-28 2022-09-09 普罗诺瓦生物医药挪威公司 结构增强的含硫脂肪酸在预防和/或治疗非酒精性脂肪性肝炎中的用途
WO2019111048A1 (fr) 2017-12-06 2019-06-13 Basf As Dérivés d'acide gras pour le traitement de la stéatohépatite non alcoolique
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