WO2004050089A1 - Analogues d'epothilone permettant l'administration specifique d'un site dans le traitement de maladies proliferatives - Google Patents

Analogues d'epothilone permettant l'administration specifique d'un site dans le traitement de maladies proliferatives Download PDF

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WO2004050089A1
WO2004050089A1 PCT/EP2003/013780 EP0313780W WO2004050089A1 WO 2004050089 A1 WO2004050089 A1 WO 2004050089A1 EP 0313780 W EP0313780 W EP 0313780W WO 2004050089 A1 WO2004050089 A1 WO 2004050089A1
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Prior art keywords
dione
dihydroxy
tetramethyl
oxacyclohexadec
methyl
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PCT/EP2003/013780
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English (en)
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Klaus Bosslet
Holger Hess-Stumpp
Jens Hoffmann
Ulrich Klar
Andrea Rotgeri
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Schering Ag
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Priority claimed from DE10256982A external-priority patent/DE10256982A1/de
Application filed by Schering Ag filed Critical Schering Ag
Priority to EP03785751A priority Critical patent/EP1581218A1/fr
Priority to AU2003294796A priority patent/AU2003294796A1/en
Priority to JP2004556300A priority patent/JP2006510626A/ja
Publication of WO2004050089A1 publication Critical patent/WO2004050089A1/fr

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    • C07—ORGANIC CHEMISTRY
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    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • 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
    • A61K47/68—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 antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/6807—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug or compound being a sugar, nucleoside, nucleotide, nucleic acid, e.g. RNA antisense
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    • A—HUMAN NECESSITIES
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    • 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
    • A61K47/68—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 antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—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 antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—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 antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/10—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages

Definitions

  • the relatively low cytotoxicity of the chemotherapy agent doxorubicin that was used and that required a high dosage of the prodrug proved disadvantageous, and on the other hand, the relatively quick development of resistance against doxorubicin itself proved disadvantageous.
  • the new structural class of the epothilones and analogs thereof primarily offers a possibility of avoiding these drawbacks.
  • Most natural or synthetically modified compounds from their structural class exert their full antiproliferative activity against the most varied tumor cells that are resistant to other chemotherapy agents.
  • the active strength relative to these cells can be up to 10,000 x greater, compared to chemotherapy agents that are used in clinical practice, such as, for example, taxol, doxorubicin, cis- platinum or camptothecin.
  • the object of this invention is thus based on, i.a.,
  • This invention correspondingly comprises conjugates of general formula I
  • R ⁇ a , Rib independently of one another, are hydrogen, Ci -CJQ alkyl, aryl, aralkyl, or together a -(CH2) m group, in which m is 2 to 5, R-- a , j 2b ; independently of one another, are hydrogen, Ci -CJQ alkyl, aryl, aralkyl, or together a -(CH2) n group, in which n is 2 to 5, or C2-C10 alkenyl, or C2-C10 alkinyl, R3 is hydrogen, C ⁇ -C ⁇ Q alkyl, aryl or aralkyl, and R4 & 5 R4b ?
  • R 5 is hydrogen, C1-C10 alkyl, aryl, aralkyl, CO2H, CO2alkyl, CH2OH,
  • Hal is a halogen atom, R6, R7. in each case, are hydrogen, or together an additional bond or together an oxygen atom, or together an NH group, or together an N-alkyl group, or together a CH2 group, and
  • G is an oxygen atom or CH2,
  • R ⁇ is hydrogen, C ⁇ -C ⁇ Q alkyl, aryl, aralkyl, halogen or CN, and
  • R9 is hydrogen or a protective group PG ⁇
  • RlO, Ri 1 in each case independently of one another, are hydrogen
  • Z can represent oxygen or H/ORl2 5
  • Ri 2 can represent hydrogen or a protective group PG ⁇ ,
  • R can represent C ⁇ -C20 alkyl
  • R 2 1 can represent a hydrogen atom or C 1 -C ⁇ Q alkyl
  • L 1 , L,2, iA independently of one another, can represent hydrogen, a group
  • R_22a 5 j ⁇ 22b ? independently of one another, can represent hydrogen, C1 -C20
  • alkyl C1-C20 acyl, C1-C20 acyloxy, aryl, aralkyl, hydroxy, alkoxy, CO 2 H, CO 2 alkyl, halogen, CN, NO 2 , NH 2 , or N3,
  • R 3 can represent hydrogen or C 1 -C 1 Q alkyl
  • EG is a recognition unit of general formula IV
  • R24 can represent a group CH2OPG or a group CO2R26, PGl, PG2, PG3, and PG4, independently of one another, can represent hydrogen or a protective group PG
  • R26 can represent hydrogen, C ⁇ -C20 alkyl, C ⁇ -C20 alkenyl, C4-C7 cycloalkyl, which can contain an oxygen atom, aryl, aralkyl, tris(C ⁇ -C20 alkyl)silyl, bis(Cj-C20 alkyl)-arylsilyl, (C1-C20 alkyl)-diarylsilyl, or tris(aralkyl)-silyl
  • PG ⁇ -, PG , and PG ⁇ can represent a protective group PG, as a uniform isomer or a mixture of different isomers and/or as a pharmaceutically acceptable salt thereof.
  • the above-mentioned conjugates can comprise one or more recognition units; in this case, the recognition units that are related to a conjugate can be identical or different. It is preferred that the recognition units of a conjugate be identical.
  • the compounds of general formula I can be used in the form of their ⁇ -, ⁇ - or ⁇ -
  • the conjugates according to the invention are preferably used for the treatment of diseases that are linked with proliferative processes.
  • diseases that are linked with proliferative processes.
  • the therapy of widely varying tumors the therapy of inflammatory and/or neurodegenerative diseases, such as multiple sclerosis or Alzheimer's disease, the therapy of angiogenesis-associated diseases, such as the growth of solid tumors, rheumatoid arthritis or diseases of the ocular fundus can be mentioned.
  • conjugates according to the invention for the treatment of primary tumors and/or metastases that are not operatively accessible, either as monotherapy or in combination with substances that increasingly trigger cell death (apoptosis) and necrosis, so that when cells decompose, it results in an elevated release of normally intracellular, lysosomal enzymes, such as, e.g., glucuronidase, which results in a stronger reaction of the conjugates according to the invention.
  • lysosomal enzymes such as, e.g., glucuronidase
  • substances that are used for the so-called "vascular targeting” can be mentioned. These substances result in destruction in particular of the tumor endothelium, which subsequently results in an increased necrosis of the tumor because of the deficient nutrient supply.
  • LI 9 constructs such as, for example, the EDB fibronectin or combrestatin A4-prodrugs
  • the production of epothilones, their precursors and derivatives of general formula II is carried out according to the methods that are known to one skilled in the art, as they are described in, for example, DE 19907588, WO 98/25929, WO 99/58534, WO 99/2514, WO 99/67252, WO 99/67253, WO 99/7692, EP 99/4915, WO 00/485, WO 00/1333, WO 00/66589, WO 00/49019, WO 00/49020, WO 00/49021, WO 00/71521, WO 00/37473, WO 00/57874, WO 01/92255, WO 01/81342, WO 01/73103, WO 01/64650, WO 01/70716, US 6204388, US 6387927,
  • R 26 g ⁇ R 27 straight-chain or branched-chain alkyl
  • groups with 1-20 carbon atoms can be considered, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl, and decyl.
  • R la , R lb , R 2a R2b R 3, R 4a R 4b R 5 ; R 8, R 10 ; R l l 5 R 20 5 R 21 3 R 22a ? 22b 5 R 25 ? R 26 and R 27 can a ⁇ so t ⁇ e perfluorinated or substituted by 1-5 halogen
  • R 22b 5 R 26 an ⁇ R 27 substituted and unsubstituted carbocyclic or heterocyclic radicals with one or more heteroatoms, such as phenyl, naphthyl, furyl, thienyl, pyridyl, pyrazolyl, pyrimidinyl, oxazolyl, pyridazinyl, pyrazinyl, quinolyl, thiazolyl, benzothiazolyl, benzoxazolyl, which can be substituted in one or more places by halogen, OH, O-alkyl, CO 2 H, CO 2 -alkyl, -NH 2 , -NO 2 , -N 3 , -CN, C 1 -C 2 o-alkyl, C ⁇ C20- ac yl .
  • heteroatoms such as phenyl, naphthyl, furyl, thienyl, pyridyl, pyrazolyl, pyrimi
  • C ⁇ -C20 _ acyloxy groups are suitable.
  • the heteroatoms can be oxidized if as a result the aromatic character is not lost, such as, for example, the oxidation of a pyridyl to a pyridyl-N-oxide.
  • bi- and tricyclic aryl radicals W substituted and unsubstituted carbocyclic or heterocyclic radicals with one or more heteroatoms, such as naphthyl, anthryl, benzothiazolyl, benzoxazolyl, benzimidazolyl, quinolyl, isoquinolyl, benzoxazinyl, benzofuranyl, indolyl, indazolyl, quinoxalinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thienopyridinyl, pyridopyridinyl, benzopyrazolyl, benzotriazolyl, or dihydroindolyl, which can be substituted in one or more places by halogen, OH, O- alkyl, CO H, CO 2 -alkyl, -NH 2 , -NO , -N 3 , -CN, C ⁇ -C 2 o-alky
  • R22 ? 22b ⁇ R 26 ⁇ d R 27 C an contain in the ring up to 14 C atoms, preferably 6 to 10 C
  • aralkyl radicals for example, benzyl, phenylethyl, naphthylmethyl, naphthylethyl, furylmethyl, thienylethyl, and pyridylpropyl are considered.
  • the rings can be substituted in one or more places by halogen, OH, O-alkyl, CO 2 H, CO 2 -alkyl, -NO 2 , -N 3 , -CN, C ⁇ -C 2 o-alkyl. C 1 -C 2 o- a cyl . or C i -C20- yloxy groups.
  • protective groups PG tris(Cj-C20 alkyl)silyl, bis(Cj-C20 alkyl)-arylsilyl, (C1 -C20 alkyl)-diarylsilyl, tris(aralkyl)-silyl, C ⁇ -C20 _ lkyl, C2-C20- alkenyl, C4-C7-cycloalkyl, which in addition can contain an oxygen atom in the ring, aryl, C7-C2()- ralkyl, Cj-C20- cyl, aroyl, C ⁇ -C20-alkoxycarbonyl, C1 -C20- alkylsulfonyl as well as arylsulfonyl can be mentioned.
  • alkyl, silyl and acyl radicals for protective groups PG in particular the radicals that are known to one skilled in the art are considered.
  • alkyoxycarbonyl radical e.g., trichloroethyloxycarbonyl (Troc) is suitable.
  • acyl radicals e.g., formyl, acetyl, propionyl, isopropionyl, trichloromethylcarbonyl, pivalyl, and butyryl or benzoyl, which can be substituted with amino groups and/or hydroxy groups, are suitable.
  • amino protective groups PG the radicals that are known to one skilled in the art are considered.
  • Alloc, Boc, Z, benzyl, f-Moc, Troc, Stabase or benzostabase group can be mentioned.
  • halogen atoms fluorine, chlorine, bromine or iodine is considered.
  • the acyl groups can contain 1 to 20 carbon atoms, whereby formyl, acetyl, propionyl, isopropionyl and pivalyl groups are preferred.
  • the C2-C ⁇ o-alkylene- ⁇ , ⁇ -dioxy group that is possible for X is preferably an ethyleneketal or neopentylketal group.
  • preferred recognition units EG those are considered that, for example, by overexpression of suitable enzymes in proliferating tissues can be cleaved from the latter.
  • suitable enzymes in proliferating tissues can be cleaved from the latter.
  • glucuronidase can be mentioned here.
  • Preferred compounds of general formula I are those in which A-Y represents O-
  • G represents a CH2 group
  • Z represents an oxygen atom
  • Rla, Rlb i n each case represent C1-C10 alkyl or together a -(CH2)p group with p equal to 2 or 3 or 4
  • R2a, R 2b ? independently of one another, represent hydrogen, C1 -CI Q alkyl, C2-C10 alkenyl, or C2-C10 alkinyl
  • R3 represents hydrogen
  • R ⁇ independently of one anotlier, represent hydrogen or C ⁇ -C ⁇ Q alkyl;
  • R ⁇ represents hydrogen or C1 -C4 alkyl or CH2OH or CH2NH2 or CH2N(alkyl, acyl) ⁇ 2 or CH2Hal;
  • X represents a CRI ⁇ RH group;
  • R represents hydrogen or C1-C4 alkyl or a fluorine atom or a chlorine atom or a bromine atom;
  • R10/R11 represent hydrogen/2 -methylthiazol-4-yl or hydrogen/2-pyridyl or hydrogen/2- methyloxazol-4-yl or hydrogen/2-amino
  • radicals R22a g ⁇ R 22b ⁇ -Q selected from the group that consists of C ⁇ -Cg-alkyl, Cj-Cg-alkoxy, halogen, nitro, CN, N3, NH2 and CO2-(Ci-
  • Cg-alkyl Especially preferred in this connection are the radicals methyl, ethyl, propyl, i-propyl, t-butyl, CF3, C 2 F 5 , F, CI, nitro, CN, N3, NH , CO2-methyl, CO2-ethyl, CO2- propyl and CO2-i-propyl.
  • radical R ° is selected from the group that consists of C1 -Cg-alkyl and C2-Cg-alkenyl. Especially preferred in this connection are the radicals methyl, ethyl, propyl, i-propyl, t-butyl, CF3, propenyl and butenyl.
  • radicals R2a and R b are selected such that one of radicals R2a or R2b represents hydrogen, while the other radical in each case is selected from the group that consists of C ⁇ -C7-alkyl, C2-C7-alkenyl and C2-C7-alkinyl.
  • radicals methyl, ethyl, propyl, i-propyl, propenyl, butenyl, propinyl and butinyl are especially preferred in this connection.
  • the invention also relates to linker-recognition units of general formula III 1 :
  • RG2 represents an HO-CH2 group or an HNR 3-CH2 group; and R2 a 5 R 22b a ⁇ EQ nave me above-mentioned meanings;
  • R27 is C ⁇ -C ⁇ o alkyl, aryl or aralkyl; and 22a 5 22b mc ⁇ JIQ h a ⁇ e t ne above-mentioned meanings;
  • the invention also relates to processes
  • a linker-recognition unit of general formula III 3 for reacting a linker-recognition unit of general formula III 3 with a compound of general formula I, in which the condition that at least one group 1-1, 1-2 or 1-4 represent a linker-recognition unit need not be met, and 1-1 and/or 1-2 and/or 1-4 have the meaning of a hydrogen atom, and free hydroxyl groups and/or amino groups that are not required for the reaction are optionally protected.
  • the invention also relates to the use of a linker-recognition unit of general formula III 1 , III 2 or III 3 for the production of an effector-recognition unit conjugate, as described above.
  • the invention also relates to the use of a linker-recognition unit of general formula III 1 , III 2 or III 3 in one of the processes according to the invention for the production of an effector-recognition unit conjugate as described above.
  • the invention also relates to the conjugates according to the invention that contain effectors, linkers and recognition units for use as medications or for the production of a medication or a pharmaceutical composition.
  • the invention also relates to the use of the conjugates according to the invention for the production of medications for the treatment of diseases that are linked with proliferative processes, such as tumors, inflammatory and/or neurodegenerative diseases, multiple sclerosis, Alzheimer's disease, or for the treatment of angiogenesis- associated diseases, such as the growth of solid tumors, rheumatoid arthritis, or diseases of the ocular fundus.
  • diseases that are linked with proliferative processes such as tumors, inflammatory and/or neurodegenerative diseases, multiple sclerosis, Alzheimer's disease, or for the treatment of angiogenesis- associated diseases, such as the growth of solid tumors, rheumatoid arthritis, or diseases of the ocular fundus.
  • the invention also relates to the use of the conjugates according to the invention for the production of medications for the treatment of primary tumors and/or metastases that are not operatively accessible, either as monotherapy or in combination with substances that increasingly trigger cell death (apoptosis) and necrosis, so that when tumor cells decompose, it results in an elevated release of normally intracellular, lysosomal enzymes, such as, e.g., glucuronidase, which results in a stronger reaction of the above-mentioned conjugates.
  • normally intracellular, lysosomal enzymes such as, e.g., glucuronidase
  • Treatment or administration in combination with the above-mentioned substances in this case comprises the simultaneous (both in the mixture and in separate doses) but also the respectively separate administration of the individual components of the combination, for example an alternating administration, as well as administration schemes, in which one component is given as a long-term medication, and the other component is administered in addition at regular or irregular intervals for shorter periods.
  • the components of the combination can be fed via the same or via different administration paths.
  • administrations in combination are preferably those in which the components of the combination achieve an additive action; especially preferred are those administration schemes in which a synergistic action is set.
  • Example LEI a in a mixture that consists of 110 ml of tetrahydrofuran and 22 ml of methanol is mixed at 0°C with 224 mg of sodium borohydride, and it is stirred for 30 minutes. It is mixed with saturated ammonium chloride solution, diluted with water and extracted several times with ethyl acetate. The combined organic extracts are washed with saturated sodium chloride solution, dried on sodium sulfate, and the residue that is obtained after filtration and removal of the solvent is purified by chromatography on fine silica gel. 5.62 g (11.6 mmol, 98%) of the title compound is isolated.
  • (2S,3S,4S,5R,6S)-3,4,5-Triacetoxy-6-(2-[l,3]dioxolan-2-yl-4-nitro-phenoxy)- tetrahydro-pyran-2-carboxylic acid methyl ester 20.0 g (50.4 mmol) of (2S,3S,4S,5R,6S)-3,4,5-triacetoxy-6-bromo-tetrahydro- pyran-2-carboxylic acid methyl ester is reacted analogously to Example LEI a with the compound that is presented according to Example LE3a, and after working-up and purification, 21.9 g (41.5 mmol, 82%) of the title compound is isolated.
  • Example LE3c in 560 ml of dichloromethane, is mixed with 22.9 ml of tert-butyl- dimethyl-silyltriflate as well as 23.8 ml of 2,6-lutidine, and it is stirred for 24 hours at 23 °C. It is poured into water, extracted several times with dichloromethane, the combined organic extracts are washed with saturated sodium chloride solution and dried on magnesium sulfate. The residue that is obtained after filtration and removal of the solvent is purified by chromatography on fine silica gel, and 9.90 g (13.3 mmol, 67%) of the title compound as well as 2.17 g (29.2 mmol, 15%) of a stereoisomer are isolated.
  • Example LE3f in 2 ml of acetone is mixed with 12.9 mg of p-toluenesulfonic acid monohydrate, and it is stirred for 24 hours at 23 °C. It is poured into saturated sodium bicarbonate solution, extracted several times with ethyl acetate, the combined organic extracts are washed with saturated sodium chloride solution and dried on magnesium sulfate. The residue that is obtained after filtration and removal of the solvent is purified by chromatography on fine silica gel, and 25.9 mg (35.7 ⁇ mol, 58%) of the title compound is isolated.
  • Example LE3g 720 mg (0.99 mmol) of the compound that is presented according to Example LE3g is reacted analogously to Example LEI, and after working-up, 710 mg (0.975 mmol, 98%) of the title compound, which is further reacted without purification, is isolated.
  • Example LE3a Analogously to Example LE3a, 25 g (149.6 mmol) of 4-hydroxy-3- nitrobenzaldehyde is reacted, and after working-up, 27.6 g (131 mmol, 87%) of the title compound is isolated.
  • Example LE4b 358 mg (679 ⁇ mol) of the compound that is presented according to Example LE4b is reacted analogously to Example LE3c, and after working-up, 270 mg (673 ⁇ mol, 99%o) of the title compound is isolated.
  • Example LE4c 268 mg (668 ⁇ mol) of the compound that is presented according to Example LE4c is reacted analogously to Example LE3d, and after working-up and purification, 183 mg (246 ⁇ mol, 37%) of the title compound is isolated.
  • Example LE4f 2.51 g (3.26 mmol) of the compound that is presented according to Example LE4f is reacted analogously to Example LE3g, and after working-up, 2.35 g (3.24 mmol, 99%) of the title compound, which is further reacted with purification, is isolated.
  • Example LE5a is reacted analogously to Example LEI, and after working-up, 17.4 g (max. 37.7 mmol) of the title compound, which is further reacted without being purified, is isolated.
  • Example LE5c is reacted analogously to Example LEI, and after working-up, 17.4 g (max. 37.7 mmol) of the title compound, which is further reacted without being purified, is isolated.
  • Example LE5b 17.4 g (max. 37.7 mmol) of the compound that is presented according to Example LE5b is reacted analogously to Example LE3c, and after working-up, 13.9 g (max. 37.7 mmol) of the title compound, which is further reacted without being purified, is isolated.
  • Example LE5c 13.9 g (max. 37.7 mmol) of the compound that is presented according to Example LE5c is reacted analogously to Example LE3d, and after working-up and purification, 21.5 g (27.9 mmol, 74%) of the title compound is isolated.
  • Example LE6a 2-Chloro-4-[l,3]dioxolan-2-yl-phenol 25 g (160 mmol) of 3-chloro-4-hydroxybenzaldehyde is reacted analogously to Example LE3a, and after working-up, 26.1 g (130 mmol, 81%) of the title compound, which is further reacted without being purified, is isolated.
  • Example LE6b is reacted analogously to Example LE3c, and after working-up, 17.2 g (44.0 mmol, 90%) of the title compound, which is further reacted without being purified, is isolated.
  • Example LE6e is reacted analogously to Example LE3f, and after working-up and purification, 12.9 g (17.7 mmol, 100%) of the title compound is isolated.
  • Example LE6g is reacted analogously to Example LE3f, and after working-up and purification, 12.9 g (17.7 mmol, 100%) of the title compound is isolated.
  • Example LE6f 12.9 g (17.7 mmol) of the compound that is presented according to Example LE6f is reacted analogously to Example LE3g, and after working-up, 12.0 g (17.5 mmol, 99%) of the title compound, which is further reacted without being purified, is isolated.
  • Example LE6f 12.0 g (17.5 mmol) of the compound, presented according to Example LE6f, is reacted analogously to Example LEI, and after working-up and purification, 11.4 g (16.6 mmol, 95%) of the title compound is isolated.
  • Example LE7b is reacted analogously to Example LE3c, and after working-up, 4.64 g (max. 11.2 mmol) of the title compound, which is further reacted without being purified, is isolated.
  • Example LE7c is reacted analogously to Example LE3d, and after working-up and purification, 8.43 g (10.5 mmol, 94%) of the title compound is isolated.
  • Example LE7 8.43 g (10.5 mmol) of the compound that is presented according to Example LE7d is reacted analogously to Example LE5e, and after working-up, 8.38 g (10.1 mmol, 96%) of the title compound, which is further reacted without being purified, is isolated.
  • Example LE7
  • Example LE7e 8.38 g (10.1 mmol) of the compound that is presented according to Example LE7e is reacted analogously to Example LE5, and after working-up and purification, 5.92 g (8.3 mmol, 82%) of the title compound is isolated.
  • Example LE8b is reacted analogously to Example LE3c, and after working-up, 11.2 g (max. 29.0 mmol) of the title compound, which is further reacted without being purified, is isolated.
  • Example LE8c is reacted analogously to Example LE3d, and after working-up and purification, 18.5 g (23.4 mmol, 81%) of the title compound is isolated.
  • Example ELEla in 20 ml of dichloromethane is mixed at 0°C with the solution of 285 mg of triphosgene in 6 ml of dichloromethane, 160 ⁇ l of pyridine, and it is stirred for 2.5 hours at 23°C. It is concentrated by evaporation, the residue is taken up in ethyl acetate, washed with water and saturated sodium chloride solution, and dried on magnesium sulfate. The residue that is obtained after filtration and removal of the solvent is purified by chromatography on fine silica gel. 1.08 g (1.53 mmol, 98%) of the title compound is isolated.
  • Example ELElc Analogously to Example ELElc, 265 mg (376 ⁇ mol) of the compound that is presented according to Example ELElb is reacted with the compound that is presented according to Example LEI, and after working-up and purification, 180 mg (156 ⁇ mol, 42%) of the title compound is isolated.
  • Example ELE Analogously to Example ELE 1,173 mg (150 ⁇ mol) of the compound that is presented according to Example ELE3a is reacted, and after working-up and purification, 58 mg (55.8 ⁇ mol, 37%) of the title compound is isolated. -64-
  • Example ELE2 Analogously to Example ELE2, 151 mg (145 ⁇ mol) of the compound that is presented according to Example ELE3 is reacted, and after working-up and purification, 75 mg (71.1 ⁇ mol, 49%) of the title compound as well as 28 mg (26.5 ⁇ mol, 18%) of (2S,3S,4S,5R,6S)-3,4,5-triacetoxy-6- ⁇ 2-[(lR,3S,7S,10R,llS,12S, 16S)-10-allyl-l l- hydroxy-8,8, 12, 16-tetramethyl-3-(2-methyl-benzothiazol-5-yl)-5,9-dioxo-4, 17-dioxa- bicyclo[14.1.0]heptadec-7-yloxycarbonyloxymethyl]-4-nitro-phenoxy ⁇ -tetrahydro- pyran-2-carboxylic acid methyl ester are isolated.
  • Example ELElc Analogously to Example ELElc, 230 mg (312 ⁇ mol) of the compound that is presented according to Example ELElb is reacted with 1.32 g of the compound that is presented according to Example LE4, and after working-up and purification, 132 mg (95 ⁇ mol, 30%) of the title compound is isolated.
  • Example ELE2 Analogously to Example ELE2, 50 mg (53 ⁇ mol) of the compound that is presented according to Example ELE5 is reacted, and after working-up and purification, 26 mg (27 ⁇ mol, 51%) of the title compound as well as 7 mg (7 ⁇ mol, 14%) of (2S,3S,4S,5R,6S)-6- ⁇ 4-[(lR,3S,7S,10R,l lS,12S,16S)-10-allyl-l l-hydroxy-8,8,12,16- tetramethyl-3-(2-methyl-benzothiazol-5-yl)-5,9-dioxo-4,17-dioxa- bicyclo[14.1.0]heptadec-7-yloxycarbonyloxymethyl]-2-nitro-phenoxy ⁇ -3,4,5- trihydroxy-tetrahydro-pyran-2-carboxylic acid allyl ester are isolated. -67-
  • Example ELElb Analogously to Example ELElb, 1.0 g (1.56 mmol) of the compound that is presented according to Example ELE8a is reacted, and 1.05 g (1.49 mmol, 96%) of the title compound is isolated.
  • Example ELE2 Analogously to Example ELE2, 766 mg (857 ⁇ mol) of the compound that is presented according to Example ELE 11 is reacted, and after working-up and purification, 616 mg (677 ⁇ mol, 79%) of the title compound is isolated.
  • Example ELE10 Analogously to Example ELE10, 320 mg (352 ⁇ mol) of the compound that is presented according to Example ELE 12 is reacted, and after working-up and purification, 165 mg (190 ⁇ mol, 54%) of the title compound is isolated.
  • Example ELE11 Analogously to Example ELE11, 2.78 g (2.06 mmol) of the compound that is presented according to Example ELE 14a is reacted, and after working-up and purification, 1.00 g (1.12 mmol, 54%) of the title compound is isolated.
  • Example ELE 10 Analogously to Example ELE 10, 354 mg (389 ⁇ mol) of the compound that is presented according to Example ELE 15 is reacted, and after working-up and purification, 187 mg (215 ⁇ mol, 55%) of the title compound is isolated.
  • Example ELE11 Analogously to Example ELE11, 1.54 g (1.14 mmol) of the compound that is presented according to Example ELE 17a is reacted, and after working-up and purification, 612 mg (659 ⁇ mol, 58%) of the title compound is isolated.
  • Example ELE2 Analogously to Example ELE2, 610 mg (657 ⁇ mol) of the compound that is presented according to Example ELE 17 is reacted, and after working-up and purification, 517 g (547 ⁇ mol, 83%) of the title compound is isolated.
  • Example ELE17a Analogously to Example ELE17a, 2.13 g (3.02 mmol) of the compound that is presented according to Example ELE8b is reacted with the compound that is presented according to Example LE6, and after working-up and purification, 1.71 g (1.26 mmol, 42%) of the title compound is isolated.
  • Example ELE11 Analogously to Example ELE11, 930 mg (686 ⁇ mol) of the compound that is presented according to Example ELE20a is reacted, and after working-up and purification, 460 mg (495 ⁇ mol, 72%>) of the title compound is isolated.
  • Example ELE2 Analogously to Example ELE2, 610 mg (657 ⁇ mol) of the compound that is presented according to Example ELE20 is reacted, and after working-up and purification, 601 mg (636 ⁇ mol, 97%) of the title compound is isolated.
  • Example ELE 10 Analogously to Example ELE 10, 302 mg (320 ⁇ mol) of the compound that is presented according to Example ELE21 is reacted, and after working-up and purification, 178 mg (197 ⁇ mol, 62%>) of the title compound is isolated.
  • Example ELElc Analogously to Example ELElc, 1.15 g (1.63 mmol) of the compound that is presented according to Example ELElb is reacted with the compound that is presented according to Example LE7, and after working-up and purification, 1.44 g (1.04 mmol, 64%o) of the title compound is isolated.
  • Example ELE11 Analogously to Example ELE11, 1.44 g (1.04 mmol) of the compound that is presented according to Example ELE23a is reacted, and after working-up and purification, 386 mg (418 ⁇ mol, 40%) of the title compound is isolated.
  • Example ELE2 Analogously to Example ELE2, 384 mg (416 ⁇ mol) of the compound that is presented according to Example ELE23 is reacted, and after working-up and purification, 278 mg (296 ⁇ mol, 71%) of the title compound is isolated.
  • Example ELE10 100 mg (106 ⁇ mol) of the compound that is presented according to Example ELE24 is reacted, and after working-up and purification, 64 mg (71 ⁇ mol, 67%) of the title compound is isolated.
  • Example ELElc Analogously to Example ELElc, 2.0 g (2.84 mmol) of the compound that is presented according to Example ELElb is reacted with the compound that is presented according to Example LE8, and after working-up and purification, 2.06 g (1.50 mmol, 53%) of the title compound is isolated.
  • Example ELE11 Analogously to Example ELE11, 2.06 g (1.50 mmol) of the compound that is presented according to Example ELE26a is reacted, and after working-up and purification, 1.01 g (l.l l mmol, 74%>) of the title compound is isolated.
  • Example ELE2 Analogously to Example ELE2, 1.01 g (1.11 mmol) of the compound that is presented according to Example ELE26 is reacted, and after working-up and purification, 657 mg (708 ⁇ mol, 64%) of the title compound is isolated.
  • Example ELE 10 Analogously to Example ELE 10, 350 mg (377 ⁇ mol) of the compound that is presented according to Example ELE27 is reacted, and after working-up and purification, 234 mg (264 ⁇ mol, 70%») of the title compound is isolated.

Abstract

L'invention concerne des conjugués d'épothilones et des dérivés d'épothilones (en tant qu'effecteurs) associés à des saccharides ou à des dérivés de saccharides appropriés (en tant qu'unités de reconnaissance). Le procédé de production selon l'invention consiste à faire réagir les unités de reconnaissance avec des lieurs appropriés, les composés qui sont produits étant conjugués aux effecteurs. L'invention concerne l'utilisation desdits conjugués pour traiter des processus prolifératifs ou associés à l'angiogenèse.
PCT/EP2003/013780 2002-12-05 2003-12-05 Analogues d'epothilone permettant l'administration specifique d'un site dans le traitement de maladies proliferatives WO2004050089A1 (fr)

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EP03785751A EP1581218A1 (fr) 2002-12-05 2003-12-05 Analogues d'epothilone permettant l'administration specifique d'un site dans le traitement de maladies proliferatives
AU2003294796A AU2003294796A1 (en) 2002-12-05 2003-12-05 Epothilone analogs for site specific delivery in the treatment of proliferative diseases
JP2004556300A JP2006510626A (ja) 2002-12-05 2003-12-05 増殖疾患の処理における部位特異的供給のためのエポチロン類似体

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DE10256982.7 2002-12-05
DE10256982A DE10256982A1 (de) 2002-12-05 2002-12-05 Neue Effektor-Konjugate, Verfahren zu Ihrer Herstellung und Ihre Pharmazeutische Verwendung
US43119702P 2002-12-06 2002-12-06
US60/431,197 2002-12-06

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Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005074901A2 (fr) * 2004-01-30 2005-08-18 Schering Ag Nouveaux conjugues d'effecteurs, leurs procedes de production et leur utilisation pharmaceutique
WO2006032537A2 (fr) * 2004-09-24 2006-03-30 Bayer Schering Pharma Aktiengesellschaft Utilisation d'epothilones dans le traitement de metastase osseuse
US7759374B2 (en) 2002-08-23 2010-07-20 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto and analogues thereof
US7875638B2 (en) 2002-08-23 2011-01-25 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto, analogues and uses thereof
US20160184451A1 (en) * 2014-05-28 2016-06-30 Legochem Biosciences, Inc. Compounds comprising self-immolative group
US10118965B2 (en) 2015-09-25 2018-11-06 Legochem Biosciences, Inc. Compositions and methods related to anti-EGFR antibody drug conjugates
US10183997B2 (en) 2015-09-25 2019-01-22 Legochem Biosciences, Inc. Compositions and methods related to anti-CD19 antibody drug conjugates
CN111138444A (zh) * 2020-01-08 2020-05-12 山东大学 一组埃博霉素b葡萄糖苷类化合物及其酶法制备与应用
CN111205343A (zh) * 2020-01-08 2020-05-29 山东大学 埃博霉素b的氮乙酰葡萄糖苷或半乳糖苷化合物及其酶法制备与应用
US11167040B2 (en) 2015-11-25 2021-11-09 Legochem Biosciences, Inc. Conjugates comprising peptide groups and methods related thereto
US11173214B2 (en) 2015-11-25 2021-11-16 Legochem Biosciences, Inc. Antibody-drug conjugates comprising branched linkers and methods related thereto
US11413353B2 (en) 2015-11-25 2022-08-16 Legochem Biosciences, Inc. Conjugates comprising self-immolative groups and methods related thereto
US11654197B2 (en) 2017-03-29 2023-05-23 Legochem Biosciences, Inc. Pyrrolobenzodiazepine dimer prodrug and ligand-linker conjugate compound of the same
US11707533B2 (en) 2019-09-04 2023-07-25 Legochem Biosciences, Inc. Antibody-drug conjugate comprising antibody against human ROR1 and use for the same
US11827703B2 (en) 2018-05-09 2023-11-28 Legochem Biosciences, Inc. Compositions and methods related to anti-CD19 antibody drug conjugates

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0595133A2 (fr) * 1992-10-27 1994-05-04 BEHRINGWERKE Aktiengesellschaft Prodroques, leur préparation, et utilisation comme médicaments
EP0647450A1 (fr) * 1993-09-09 1995-04-12 BEHRINGWERKE Aktiengesellschaft Prodrogues améliorées pour activation médiée par enzyme
EP0648503A1 (fr) * 1993-09-22 1995-04-19 BEHRINGWERKE Aktiengesellschaft Pro-prodrugs leur préparation et application
WO2004012735A2 (fr) * 2002-07-31 2004-02-12 Schering Ag Nouveaux conjugues d'effecteurs, procedes permettant de les produire et utilisation pharmaceutique de ceux-ci

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0595133A2 (fr) * 1992-10-27 1994-05-04 BEHRINGWERKE Aktiengesellschaft Prodroques, leur préparation, et utilisation comme médicaments
EP0647450A1 (fr) * 1993-09-09 1995-04-12 BEHRINGWERKE Aktiengesellschaft Prodrogues améliorées pour activation médiée par enzyme
EP0648503A1 (fr) * 1993-09-22 1995-04-19 BEHRINGWERKE Aktiengesellschaft Pro-prodrugs leur préparation et application
WO2004012735A2 (fr) * 2002-07-31 2004-02-12 Schering Ag Nouveaux conjugues d'effecteurs, procedes permettant de les produire et utilisation pharmaceutique de ceux-ci

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
BOSSLET ET AL: "Elucidation of the mechanism enabling tumor selective prodrug monotherapy", CANCER RESEARCH, AMERICAN ASSOCIATION FOR CANCER RESEARCH, BALTIMORE, MD, US, 15 March 1998 (1998-03-15), pages 1195 - 1201, XP002108804, ISSN: 0008-5472 *
DATABASE CROSSFIRE BEILSTEIN [online] Beilstein Institut zur Förderung der Chemischen Wissenschaften, Frankfurt am Main, DE; XP002278521, Database accession no. BRN 7717244 *
DATABASE CROSSFIRE BEILSTEIN [online] Beilstein Institut zur Förderung der Chemischen Wissenschaften, Frankfurt am Main, DE; XP002278522, Database accession no. BRN 52924 *
DATABASE CROSSFIRE BEILSTEIN [online] Beilstein Institut zur Förderung der Chemischen Wissenschaften, Frankfurt am Main, DE; XP002278523, Database accession no. BRN 1276877 *
NICOLAOU K C ET AL: "Chemical Biology of Epothilones", ANGEWANDTE CHEMIE. INTERNATIONAL EDITION, VERLAG CHEMIE. WEINHEIM, DE, vol. 37, no. 15, August 1998 (1998-08-01), pages 2014 - 2045, XP002131418, ISSN: 0570-0833 *

Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7875638B2 (en) 2002-08-23 2011-01-25 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto, analogues and uses thereof
US8513429B2 (en) 2002-08-23 2013-08-20 Sloan-Kettering Insitute For Cancer Research Synthesis of epothilones, intermediates thereto and analogues thereof
US8110590B2 (en) 2002-08-23 2012-02-07 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto and analogues thereof
US7759374B2 (en) 2002-08-23 2010-07-20 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto and analogues thereof
WO2005074901A2 (fr) * 2004-01-30 2005-08-18 Schering Ag Nouveaux conjugues d'effecteurs, leurs procedes de production et leur utilisation pharmaceutique
WO2005074901A3 (fr) * 2004-01-30 2006-03-30 Schering Ag Nouveaux conjugues d'effecteurs, leurs procedes de production et leur utilisation pharmaceutique
WO2006032537A3 (fr) * 2004-09-24 2006-05-04 Schering Ag Utilisation d'epothilones dans le traitement de metastase osseuse
JP2008514569A (ja) * 2004-09-24 2008-05-08 バイエル・シエーリング・ファーマ アクチエンゲゼルシャフト 骨転移の治療へのエポチロンの使用
WO2006032537A2 (fr) * 2004-09-24 2006-03-30 Bayer Schering Pharma Aktiengesellschaft Utilisation d'epothilones dans le traitement de metastase osseuse
US10383949B2 (en) 2014-05-28 2019-08-20 Legochem Biosciences, Inc. Compounds comprising self-immolative group
US20160184451A1 (en) * 2014-05-28 2016-06-30 Legochem Biosciences, Inc. Compounds comprising self-immolative group
US9919057B2 (en) * 2014-05-28 2018-03-20 Legochem Biosciences, Inc. Compounds comprising self-immolative group
US9993568B2 (en) 2014-05-28 2018-06-12 Legochem Biosciences, Inc. Compounds comprising self-immolative group
US10980890B2 (en) 2014-05-28 2021-04-20 Legochem Biosciences, Inc. Compounds comprising self-immolative group
US10118965B2 (en) 2015-09-25 2018-11-06 Legochem Biosciences, Inc. Compositions and methods related to anti-EGFR antibody drug conjugates
US10183997B2 (en) 2015-09-25 2019-01-22 Legochem Biosciences, Inc. Compositions and methods related to anti-CD19 antibody drug conjugates
US11167040B2 (en) 2015-11-25 2021-11-09 Legochem Biosciences, Inc. Conjugates comprising peptide groups and methods related thereto
US11173214B2 (en) 2015-11-25 2021-11-16 Legochem Biosciences, Inc. Antibody-drug conjugates comprising branched linkers and methods related thereto
US11413353B2 (en) 2015-11-25 2022-08-16 Legochem Biosciences, Inc. Conjugates comprising self-immolative groups and methods related thereto
US11654197B2 (en) 2017-03-29 2023-05-23 Legochem Biosciences, Inc. Pyrrolobenzodiazepine dimer prodrug and ligand-linker conjugate compound of the same
US11827703B2 (en) 2018-05-09 2023-11-28 Legochem Biosciences, Inc. Compositions and methods related to anti-CD19 antibody drug conjugates
US11707533B2 (en) 2019-09-04 2023-07-25 Legochem Biosciences, Inc. Antibody-drug conjugate comprising antibody against human ROR1 and use for the same
CN111138444A (zh) * 2020-01-08 2020-05-12 山东大学 一组埃博霉素b葡萄糖苷类化合物及其酶法制备与应用
CN111205343A (zh) * 2020-01-08 2020-05-29 山东大学 埃博霉素b的氮乙酰葡萄糖苷或半乳糖苷化合物及其酶法制备与应用
CN111205343B (zh) * 2020-01-08 2022-06-14 山东大学 埃博霉素b的氮乙酰葡萄糖苷或半乳糖苷化合物及其酶法制备与应用

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