WO2002038590A1 - Composes antitumoraux actives par la proteine fap-alpha - Google Patents

Composes antitumoraux actives par la proteine fap-alpha Download PDF

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WO2002038590A1
WO2002038590A1 PCT/EP2001/012812 EP0112812W WO0238590A1 WO 2002038590 A1 WO2002038590 A1 WO 2002038590A1 EP 0112812 W EP0112812 W EP 0112812W WO 0238590 A1 WO0238590 A1 WO 0238590A1
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group
compound
prodrug
amino
xxx
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PCT/EP2001/012812
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Stefan Peters
Juergen Mack
Dietmar Leipert
Christian Eickmeier
John-Edward Park
Martin Lenter
Pilar Garin-Chesa
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Boehringer Ingelheim Pharma Gmbh & Co. Kg
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Priority to AU2002220684A priority Critical patent/AU2002220684A1/en
Publication of WO2002038590A1 publication Critical patent/WO2002038590A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/65—Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1019—Tetrapeptides with the first amino acid being basic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1024—Tetrapeptides with the first amino acid being heterocyclic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to the field of tumor treatment by administration of a prodrug that is converted into a drug at the site of the tumor.
  • the invention relates to prodrugs which may be converted into a drug by the catalytic action of FAP ⁇ , their manufacture and pharmaceutical use.
  • the human fibroblast activation protein is a M r 95,000 cell surface molecule originally identified with monoclonal antibody (mAb) F19 ( ettig et al. (1988) Proc. Natl. Acad. Sci. USA 85, 3110-3114; Rettig et al. (1993) Cancer Res. 53, 3327-3335).
  • the FAP ⁇ cDNA codes for a type II integral membrane protein with a large extracellular domain, trans-membrane segment, and short cytoplasmic tail (Scanlan et al. (1994) Proc. Natl. Acad. Sci. USA 91, 5657-5661; WO 97/34927).
  • FAP ⁇ shows 48 % amino acid sequence identity to the T-cell activation antigen CD26, also known as dipeptidyl peptidase IV (DPPIV; EC 3.4.14.5), a membrane-bound protein with dipeptidyl peptidase activity (Scanlan et al., loc. cit).
  • DPPIV dipeptidyl peptidase IV
  • FAP ⁇ has enzymatic activity and is a member of the serine protease family, with serine 624 being critical for enzymatic function (WO 97/34927).
  • FAP ⁇ is selectively expressed in reactive stromal fibroblasts of many histological types of human epithelial cancers, granulation tissue of healing wounds, and malignant cells of certain bone and soft tissue sarcomas. Normal adult tissues are generally devoid of detectable FAP ⁇ , but some foetal mesenchymal tissues transiently express the molecule. In contrast, most of the common types of epithelial cancers, including >90% of breast, non-small-cell lung, and colorectal carcinomas, contain FAP ⁇ -reactive stromal fibroblasts (Scanlan et al, loc. cit.).
  • FAP ⁇ + fibroblasts accompany newly formed tumor blood vessels, forming a distinct cellular compartment interposed between the tumor capillary endothelium and the basal aspect of malignant epithelial cell clusters (Welt et al. (1994) J Clin. Oncol. 12(6), 1193-1203). While FAP ⁇ + stromal fibroblasts are found in both primary and meta- static carcinomas, the benign and premalignant epithelial lesions tested (Welt et al., loc. cit.), such as fibroadenomas of the breast and colorectal adenomas, only rarely contain FAP ⁇ + stromal cells.
  • trigger mechanisms can be designed so that the toxic agents synthesis ed in their prodrug or inactive forms are rendered active when and where required, notably in the cancerous tissues (Panchal (1998) Biochem. Pharmacol 55, 247-252).
  • Triggering mechanisms may include either exogenous factors such as light or chemicals or endogenous cellular factors, such as enzymes with restricted expression in cancer tissues.
  • ADEPT 'antibody-directed enzyme prodrug therapy'
  • ADC 'antibody-directed catalysis'
  • an antibody directed at a tumor- associated antigen is used to target a specific enzyme to the tumor site.
  • the tumor-located enzyme converts a subsequently administered prodrug into an active cytotoxic agent.
  • the antibody-enzyme conjugate binds to a target antigen on cell membranes or to free antigen in extracellular fluid (ECF).
  • ECF extracellular fluid
  • a time interval between giving the AEC and prodrug allows for the AEC to be cleared from normal tissues so that the prodrug is not activated in the normal tissues or blood.
  • some disadvantages of ADEPT are related to the properties of the AEC (Bagshawe, loc. cit.). For example, in humans, only a small fraction of the administered dose of the targeting AEC binds to tumor tissue and the remainder is distributed through body fluids from which it is cleared with significant time delays. Even very low concentrations of unbound enzyme can catalyse enough prodrug to have toxic effects because plasma and normal ECF volumes are much greater than those of tumor ECF.
  • the AEC may also be immunogenic, thus preventing repeat administration, in many instances.
  • oligopeptides including the following penta- and hexapeptide (SEQ.ID.NOs.: 151 and 177: hArg-Tyr-Gln-Ser-Ser-Pro; hArg-Tyr-Gln-Ser-Pro;), comprising amino acid sequences, which are recognized and proteolytically cleaved by free prostate specific antigen (PSA) and therapeutic agents which comprise conjugates of such oligopeptides and known therapeutic or cytotoxic agents.
  • PSA prostate specific antigen
  • therapeutic agents which comprise conjugates of such oligopeptides and known therapeutic or cytotoxic agents.
  • the problem underlying the present invention was to provide methods and means for improving normal tissue tolerability of cytotoxic or cytostatic agents with known efficacy against a broad range of tumor tissues, which can be administered to patients in need thereof in a safe and convenient way.
  • the present invention relates to enzyme-activated anti-tumor compounds.
  • the invention provides prodrugs which are capable of being converted into a cytotoxic or cytostatic drug, by the catalytic action of FAP ⁇ , said prodrugs exhibit an oligomeric part comprising up to 13 amino carboxylic residues, the C-terminal amino cafboxylic thereof is recognised by FAP ⁇ , and a cytotoxic or cytostatic part, wherein the N-terminal amino function of the oligomeric part is attached to a capping group (Cg) which is capable of enhancing the chemical stability of said prodrug under physiological conditions and the physical stability of an aqueous pharmaceutical formulations comprising said prodrug.
  • a "drug” shall mean a chemical compound that may be administered to humans or animals as an aid in the treatment of disease.
  • a drug is an active pharmacological agent.
  • cytotoxic compound shall mean a chemical compound which is toxic to living cells, in particular a drug that destroys or kills cells.
  • cytostatic compound shall mean a compound that suppresses cell growth and multiplication and thus inhibits the proliferation of cells.
  • examples for cytotoxic or cytostatic compounds suitable for the present invention are anthracycline derivatives such as doxorubicin, analogs of methotrexate such as methothrexate, pritrexime, trimetrexate or DDMP, melphalan, analogs of cisplatin such as cisplatin, JM216, JM335, bis(platinum) or carboplatin, analogs of purines and pyrimidines such as cytarbine, gemcitabine, azacitidine, 6-thioguanine, flurdarabine or 2- deoxycoformycin, and analogs of other chemotherapeutic agents such as 9- aminocamptothecin, D,L-aminoglutethimide, trime
  • prodrug shall mean a compound that, on administration, must undergo chemical con- version by metabolic processes before becoming an active pharmacological agent.
  • a prodrug is a precursor of a drug.
  • the pro- drug is significantly less cytotoxic or cytostatic than the drug it is converted into upon the catalytic action of FAP ⁇ .
  • the expert knows methods of determining cytotoxicity of a compound, see e.g. example 45 herein, or Mosmann ((1983) J. Immun. Meth. 65, 55-63).
  • the prodrug is at least three times less cytotoxic as compared to the drug in an in vitro assay.
  • a “drug being cytostatic or cytotoxic under physiological conditions” shall mean a chemical compound which is cytostatic or cytotoxic in a living human or animal body, in par- ticular a compound that kills cells or inhibits proliferation of cells within a living human or animal body.
  • a "prodrug having a cleavage site which is recognised by FAP ⁇ ” shall mean a prodrug which can act as a substrate for the enzymatic activity of FAP ⁇ .
  • the enzymatic activity of FAP ⁇ can catalyse cleavage of a covalent bond of the prodrug under physiological conditions. By cleavage of this covalent bond, the prodrug is converted into the drug, either directly or indirectly.
  • the cleavage product of the FAP ⁇ catalysed step is not the pharmacologically active agent itself but undergoes a further reaction step, e.g. hydrolysis, to become active.
  • the cleavage site of the prodrug is specifically recognised by FAP ⁇ , but not by other proteolytic enzymes present in the human or animal body.
  • the cleavage site is specifically recognised by FAP ⁇ , but not by proteolytic enzymes present in human or animal body fluids, especially plasma.
  • the prodrug is stable in plasma, other body fluids, or tissues, in which biologically active FAP ⁇ is not present or detectable.
  • the cleavage site should most preferably be specific for FAP ⁇ .
  • the cleavage site comprises a L-proline residue which is linked to a cytotoxic or cytostatic drug via an amide bond.
  • An example of this class is a doxorubicin-peptide conjugate.
  • FAP ⁇ may catalyse the cleavage of a peptidic bond between the C-terminal amino acid residue of the peptide, which is preferably L-proline, and the cytotoxic or cytostatic compound.
  • Preferred compounds show at least 10% conversion to free drug, under standard conditions listed below. More preferred are compounds that show at least 20% conversion to free drug, under standard conditions. Even more preferred are compounds that show at least 50% conversion to free drug, under standard conditions.
  • standard conditions are defined as follows: Each compound is dissolved in 50 mM Hepes buffer, 150 mM NaCl, pH 7.2, at a final concentration of 5 ⁇ M and incubated with 100 ng CD ⁇ FAP ⁇ (see example 43) for 24 hours at 37 °C. Release of free drug by CD ⁇ FAP ⁇ is determined as de- scribed in example 44.
  • the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein
  • R 1 represents an amino alkanoyl or oligopeptidoyl group, the N-terminal amino function of which is attached to a capping group (Cg) which is capable of enhancing the chemical stability of said compound under physiological conditions and the physical stability of aqueous pharmaceutical formulations comprising said compound;
  • R a and R b together with the interjacent N-C group form an optionally substituted, optionally benzo- or cyclohexano-condensed 3- to 7-membered saturated or unsaturated heterocyclic ring, in which one or two CH 2 groups may also be replaced by NH, O or S;
  • R 3 represents H, C ⁇ -C 6 -alkyl, C 3 -C 8 -cycloalkyl, aryl or heteroaryl; and
  • Cyt' represents the residue of a cytotoxic or cytostatic compound.
  • m isl, an optionally substituted 5- to 6-membered heteroaryl group, preferably selected from pyridine and pyrimidine;
  • Z represents -CO-, -O-CO-, -SO 2 - 5 NH-CO- or a single bond;
  • m is 0, 1 or 2, preferably 0 or 1.
  • R 1 represents a residue of formula Cg-A, Cg-B-A or Cg-(D) n -B-A, in which Cg represents a capping group of formula R 2 -CH 2 -Z-, wherein R 2 is an optionally substituted saturated heterocyclyl or heteroaryl group;
  • A, B and D each independently represent moieties derived from amino carboxylic acids of the formula -[NR 4 -(X) p -COJ- wherein X represents CR 5 R 6 and wherein R 4 , R 5 and R 6 each independently represent a hydrogen atom, an optionally substituted C ⁇ -C 6 -alkyl, C 3 -C 8 - cycloalkyl, aryl, aralkyl, heteroaryl or heteroarylalkyl group, and p is 1, 2, 3, 4, 5; or
  • A, B and D each independently represent moieties derived from cyclic amino carboxylic acids of formula
  • R 7 represents C]-C 6 -alkyl, OH, or NH 2
  • n is an integer from 1 to 10; is 0, 1 or 2
  • r is 0, 1 or 2
  • R 1 represents an aminoalkanoyl, or an oligopeptidoyl group, which is derived from glycine (Gly), or the D- or L-forms, in particular the (L)-configuration of alanine (Ala), valine (Nal), leucine (Leu), isoleucine (He), phenylalanine (Phe), tyrosine (Tyr), tryptophan (Trp), cysteine (Cys), methionine (Met), serine (Ser), threonine (Thr), lysine (Lys), arginine (Arg), histidine (His), aspartatic acid (Asp), glutamic acid (Glu), asparagine (Asn), glutamine (Gin), proline (Pro), 4-
  • R 1 is a group selected from the formulae (1) to (14):
  • Cg represents a capping group selected from pyridinyloxycarbonyl, pyridinylacetyl, pyridinylmethylsulfonyl and pyridylmethylaminocarbonyl;
  • Xxx represents a moiety derived from an amino carboxylic acid; and
  • n is an integer from 1 to 6.
  • the heterocyclic ring formed by R a , R b and the interjacent N-C is substituted by R 8 and R 9 , wherein R 8 and R 9 each independently represent a hydrogen or halogen atom or a C ⁇ -C 6 -alkyl, C ⁇ -C 6 -alkylamino, di-Ci-C ⁇ -alkylamino, C ⁇ -C 6 -alkoxy, thiol, C ⁇ -C 6 -alkylthio, oxo, imino, fomyl, C ⁇ -C 6 - alkoxy carbonyl, amino carbonyl, C 3 -C 8 -cycloalkyl, aryl, or heteroaryl group.
  • R 1 , R 3 , R 8 , Cyt' are defined as hereinabove and hereinbelow, and
  • R 10 and R n each independently represent a hydrogen atom, an optionally substituted Ci- C 6 -alkyl, C 3 -Cs-cycloalkyl, aryl or heteroaryl group or R 10 and R 11 together with the interjacent N-C group form an optionally substituted, optionally benzo- or cyclohexano-condensed 3- to 7-membered saturated or unsaturated heterocyclic ring, in which one or two CH 2 groups may also be replaced by NH, O or S.
  • C ⁇ -C 6 -alkyl generally represents a straight-chained or branched hydrocarbon radical having 1 to 6 carbon atoms.
  • Ci-Cg-alkyl is preferably d, more preferably a methylene group.
  • amino alkanoyl and “oligopeptidoyl” including “di- or tripeptidoyl” as used hereinabove or hereinbelow with respect to radical R 1 describe a radical in which an amino acid or an oligomer comprising up to 12, preferably 2 or 3 amino acid moieties is attached C-terminally to the nitrogen atom of the heterocyclic ring via an amide bond.
  • amino acids and oligopeptides may be replaced by other homologous, isosteric and/or isolectronic amino acids wherein the biological activity of the original amino acid or oligopeptide has been conserved upon modification.
  • Certain unnatural and modified natural amino acids may also be utilized to replace the corresponding natural amino acid.
  • tyrosine may be replaced by 3-iodotyrosine, 2- or 3-methyltyrosine, 3- fluorotyrosine.
  • capping group as used hereinabove or hereinbelow with respect to a group which is attached to the N-terminal nitrogen atom of the amino alkanoyl or oligopeptidoyl group of radical R 1 defines a group or moiety which reduces or eliminates the enzymatic degradation of the compounds of the present invention by the action of amino peptidases which are present in the blood plasma of warm blooded animals and enhances the physical stability of an aqueous pharmaceutical formulations comprising said prodrug.
  • Heterocyclic ring as used hereinabove and hereinbelow with respect to the group formed by R a and R b together with the interjacent N-C group generally represents a 3 to 7- membered, preferably 4-, 5- or 6-membered non-aromatic heterocyclic ring system, containing one nitrogen atom and optionally 1 or 2 additional heteroatoms selected from the group of nitrogen, oxygen and sulfur, which may be substituted by one or several halogen atoms or C ⁇ -C 6 -alkyl, C ⁇ -C 6 -alkylamino, di-C ⁇ -C 6 -alkylamino, C ⁇ -C 6 -alkoxy, thiol, Ci-C ⁇ -alkylthio, oxo, imino, fomyl, C ⁇ -C 6 -alkoxy carbonyl, amino carbonyl, C -C 8 - cycloalkyl, aryl, or heteroaryl groups, which may be identical to one another or different,
  • Such heterocyclic rings are preferably azetidine or are derived from a fully or partially hydrogenated pyrrole, pyridine, thiazole, isoxazole, pyrazole, imidazole, indole, benzimidazole, indazole, pyridazine, pyrimidine, pyrazin group.
  • Most preferred are azetidine, pyrrolidine, 3,4- dehydropyrrolidine, piperidine, hexahydro-lH-azepine, octahydroindole, imidazolidine, thiazolidine.
  • the substituents are preferably methyl, ethyl, propyl, 1-methylethyl (isopropyl), butyl, 1-methylpropyl, 2-methylpropyl, 1,1- dimethylethyl, hydroxyl, amino, dimethyl-amino, diethyl-amino, thiol, methyl-thiol, methoxy, ethoxy, -CHO, -COOH, -COOCH 3 , -COOCH 2 CH 3 , or -CONH 2 .
  • Aryl generally represents an aromatic ring system with 6 to 10, preferably 6 carbon at- oms which may optionally be substituted by one or several hydroxyl, amino, Ci -C 6 -alkyl- amino, di- C ⁇ -C 6 -alkyl-amino, C ⁇ -C 6 -alkyl, C ⁇ -C 6 -alkyloxy, thiol, C ⁇ -C 6 -alkyl-thio, -CHO, -COOH, -COOCH 3 , -COOCH 2 CH 3 , -CONH 2 , or halogen substituents, which may be identical to one another or different, and which optionally may be benzocondensed.
  • Aryl substituents may be preferably derived form benzene, preferred examples being phenyl, 2-hy- droxy-phenyl, 3-hydroxy-phenyl, 4-hydroxy-phenyl, 4-amino-phenyl, 2-amino-phenyl, 3- amino-phenyl.
  • the substituents are preferably methyl, ethyl, propyl, 1-methylethyl (isopropyl), butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, hydroxyl, amino, dimethyl-amino, diethyl-amino, thiol, methyl-thiol, methoxy, ethoxy, -CHO, -COOH, - COOCH 3 , -COOCH 2 CH 3 , or -CONH 2 .
  • Heteroaryl generally represents a 5 to 10-membered aromatic heterocyclic ring system, containing 1 to 5 heteroatoms selected from the group of nitrogen, oxygen, or sulfur, which may optionally be substituted by one or several hydroxyl, amino, Ci-Ce-alkyl-amino, di- C ⁇ -C 6 -alkyl-amino, C C 6 -alkyl, C ⁇ -C 6 -alkyloxy, thiol, C ⁇ -C 6 -alkyl-thio, -CHO, -COOH, - COOCH 3 , -COOCH 2 CH 3 , -CONH 2 , or halogen substituents, which may be identical to one another or different, and which optionally may be benzocondensed.
  • Heteroaryl substituents may preferably be derived from furane, pyrrole, thiophene, pyridine, thiazole, isoxazole, pyrazole, imidazole, benzofuran, thianaphthene, indole, benzimidazole, indazole, quino- line, pyridazine, pyrimidine, pyrazine, chinazoline, pyrane, purine, adenine, guanine, thy- mine, cytosine, uracil.
  • the substituents are preferably methyl, ethyl, propyl, 1-methylethyl (isopropyl), butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, hydroxyl, amino, dimethyl-amino, diethyl-amino, thiol, methyl-thiol, methoxy, ethoxy, -CHO, - COOH, -COOCH 3 , -COOCH 2 CH 3 , or -CONH 2 .
  • Residue of a cytotoxic or cytostatic compound means that the compound H 2 N-Cyt', which is released upon cleavage of the amide bond shown in formula (I), is either cytotoxic or cytostatic itself, or may be converted into a cytotoxic or cytostatic compound in a subse- quent step.
  • -Cyt' may be a residue of formula -L-Cyt", wherein L is a linker residue derived from a bif ⁇ mctional molecule, for instance a diamine H 2 N-L'-NH 2 , an amino alcohol H 2 N-L'-OH, for example p-amino-benzyl alcohol (PABOH), an amino carbonate, for example or an unnatural amino carboxylic acid.
  • L is a linker residue derived from a bif ⁇ mctional molecule, for instance a diamine H 2 N-L'-NH 2 , an amino alcohol H 2 N-L'-OH, for example p-amino-benzyl alcohol (PABOH), an amino carbonate, for example or an unnatural amino carboxylic acid.
  • PABOH p-amino-benzyl alcohol
  • the compound H 2 N-L'-Cyt' ' may be cytotoxic or cytostatic itself or the linker residue cleaved off from Cyt" in a subsequent step releasing the cytotoxic or cytostatic agent.
  • the compound H N-L'-Cyt maybe hydrolysed under physiological conditions into a compound H 2 N-L'-OH and the cytotoxic or cytostatic compound H-Cyt", which is the active therapeutic agent (In the following, only the term Cyt' is used for both Cyt' and Cyt", and only the term L is used for both L and L', for simplicity).
  • the pharmaceutically acceptable salts of the compounds of the present invention include the conventional non-toxic salts formed from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include those from inorganic acids such as hydrochloric acid, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, maleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, oxalictrifluoroacetic and the like.
  • H N-Cyt' is preferably an anthracycline derivative of formula II
  • R c represents C]-C 6 alkyl, C ⁇ -C 6 hydroxyalkyl or C ⁇ -C 6 alkanoyloxy C ⁇ -C 6 alkyl, in particular methyl, hydroxymethyl, diethoxyacetoxymethyl or butyryloxymethyl;
  • R d represents hydrogen, hydroxy or C ⁇ -C 6 alkoxy, in particular methoxy;
  • one of R e and R f represents a hydrogen atom; and the other represents a hydrogen atom or a hydroxy or tetrahydropyran-2-yloxy (OTHP) group.
  • Paricularly preferred are the following compounds of formula II:
  • Cyt' may be derived for example from methotrexate, trimetrexate, pyritrexim, 5,10- dideazatetrahydrofolatepyrimetamine, trimethoprim, 10-propargyl-5,8-dideazafolate2,4- diammo-5(3',4'-dichloropheyl)-6-methylpyrimidine, aminoglutethimide, goreserelin, melphalan, chlorambucil, analogs of other chemotherapeutic agents such as 9- aminocamtothecin (for examples see e.g. Burns HA, r. d. and S. M.
  • Cyt' may also be a biological effector molecule which either directly or indirectly effects destruction of tumor cells, like for example TNF ⁇ .
  • Preferred anthracycline prodrugs are the compounds of formula III wherein R a , R , R c , R d , R e , R f and R 1 are as defined hereinabove.
  • the compound of the invention may contain one or more disulfide bonds.
  • One class of cytotoxic or cytostatic compounds which may be used for the present invention has a primary amino function which is available for formation of an amidic bond as shown in formula (I), like doxorubicin. In this case, a linker molecule L is not necessary. If a cytostatic or cytotoxic compound does not have such an amino function, such a function may be created in such a compound by way of chemical modification, e.g. by introducing or converting a functional group or attaching a linker molecule to the compound.
  • a linker molecule may also be inserted between the oligomeric part (i.e. the part comprising the amino carboxylic residues) and the cytostatic or cytotoxic part of the compound of the invention to ensure or optimise cleavage of the amide bond between the oligomeric part and the cytotoxic or cytostatic part.
  • a linker molecule is present, i.e. in compounds containing the structure L-Cyt', the bond between L and Cyt' is preferably an amidic or ester bond.
  • such a linker molecule is hydrolysed off the cytostatic or cytotoxic compound under physiological conditions after the enzymatic cleavage and thus the free cytostatic or cytotoxic compound is generated.
  • the compound of the invention must have the property of being cleavable upon the catalytic action of FAP ⁇ and, as a direct or indirect consequence of this cleavage, releasing under physiological conditions a cytostatic or cytotoxic compound.
  • the present invention relates to prodrug that is capable of being converted into a cytotoxic or cytostatic drug, by the catalytic action of FAP ⁇ , said prodrug exhibits an oligomeric part comprising up to 13 amino carboxylic residues, the C-terminal amino carboxylic thereof is recognised by FAP ⁇ , and a cytotoxic or cytostatic part, characterized in that the N-terminal amino function of the oligomeric part is attached to a capping group (Cg) which is capable of enhancing the chemical stability of said prodrug under physiological conditions and the physical stability of an aqueous pharmaceutical formulations comprising said prodrug.
  • Cg capping group
  • the oligomeric part is preferably a peptide.
  • the oligomeric part comprises two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve amino carboxylic acid residues, more preferably two, three, or four amino carboxylic residues.
  • the N-terminal amino function is preferably protected by a capping group.
  • the compounds of the invention may be synthesized by processes known in the art (E. W ⁇ nsch, Synthese von Peptiden, in "Methoden der organischen Chemie", Houben-Weyl (Eds. E. M ⁇ ller, O. Bayer), Vol. XV, Part 1 and 2, Georg Thieme Verlag, Stuttgart, 1974).
  • the compounds could be synthesized in a block synthetic fashion by conden- sation of the terminal carboxy function of the oligomeric part, wherein X may be OH or an activation leaving group, with the amino group of the cytotoxic or cytostatic molecule H 2 N-Cyt' resulting in an amide formation.
  • the linker molecule can be an amine or an amino alcohol and the block synthesis of such compounds can be carried out in a similar way by reaction of the activated XOC-Cyt' with either the hydroxy or the amino component.
  • the linker residue may be an amino carboxylic acid and a block synthesis can be done similarly.
  • other functional groups in the units Cyt', L, hydroxyproline, A, B and D which shall not react during the assembly of the target molecules may be protected by suitable protecting groups.
  • suitable protecting groups are well known from the state of the art (P.G.M. Wuts, "Protective groups in organic synthesis", John Wiley and Sons Inc., New York 1991). These protecting groups are removed at the end of the synthesis.
  • useful amino-protecting groups may include, for example, d-Cio alkanoyl groups such as formyl, acetyl dichloroacetyl, propionyl, 3,3-diethylhexanoyl, and the like, Ci-Cio alkoxycarbonyl and C 6 -C ]7 aralkyloxycarbonyl groups such as tert- butoxycarbonyl (BOC), benzyloxycarbonyl, fluorenyhnethoxycarbonyl, and the like. Most preferred is fluorenylmethoxycarbonyl (FMOC).
  • d-Cio alkanoyl groups such as formyl, acetyl dichloroacetyl, propionyl, 3,3-diethylhexanoyl, and the like
  • Ci-Cio alkoxycarbonyl and C 6 -C ]7 aralkyloxycarbonyl groups such as tert- butoxycarbonyl (BOC
  • Suitable carboxy-protecting groups may include, for example, Ci-Cio alkyl groups such as methyl, tert-butyl, decyl; C 6 -C ⁇ aralkyl such as benzyl, 4-methoxybenzyl, diphenylmethyl, triphenylmethyl, fluorenyl; tri-(C ⁇ -do alkyl)silyl or (d-C 10 alkyl)-diarylsilyl such as trimethylsilyl, dimethyl-tert-butylsilyl, diphenyl-tert-butylsilyl and related groups.
  • Ci-Cio alkyl groups such as methyl, tert-butyl, decyl
  • C 6 -C ⁇ aralkyl such as benzyl, 4-methoxybenzyl, diphenylmethyl, triphenylmethyl, fluorenyl
  • ester- or amide formations it may be necessary to activate the carbonyl group of the carboxylic acid for a nucleophilic attack of an amine or alcohol, i.e. X to be an activation group or leaving group which is suitable to be substituted by an amino group.
  • This activation can be done by conversion of the carboxylic acid into an acid chloride or acid fluoride or by conversion of the carboxylic acid into an activated ester, for instance a N-hydroxysuccinimidyl ester or a pentafluorophenyl ester.
  • Another method of activation is the transformation into a symmetrical or unsymmetrical anhydride.
  • the for- mation of the amide- or ester bonds can be achieved by the use of in situ coupling reagents like benzotriazole-1-yl-oxy-tris- ⁇ yrrolidino- ⁇ hos ⁇ honium hexafluorophosphate (PyBOP) (E. Frerot et al., Tetrahedron, 1991, 47, 259-70), l,l '-carbonyldimidazole (CDI) (K. Akaji et al., EHE, 35, 1994, 3315-18), 2-(l ⁇ -benzotriazole-l-yl)-l,l,3,3-tetramethyluronium tetrafluoroborate (TBTU) (R.
  • in situ coupling reagents like benzotriazole-1-yl-oxy-tris- ⁇ yrrolidino- ⁇ hos ⁇ honium hexafluorophosphate (PyBOP) (E. Frerot et al., Te
  • the units L, proline/hydroxyproline, A, B and D are at least bifunctional molecules containing an amino- and (at least the units A, B, D, and the cyclic amino acid group formed by Ra, Rb and the interjacent N-C group, in particular proline/hydroxyproline) a carboxy group
  • the amino group needs to be blocked by a protecting group (PG) prior to the activation of the carboxylic function.
  • PG protecting group
  • the group BOC or preferably the group FMOC can be applied. After the coupling reaction the amino protecting group has to be removed and the coupling with the next Fmoc- or Boc-protected unit can be carried out.
  • Capping groups as defined in the context of formula (I) may also serve as protection groups, in particular when the last (N-terminal) amino carboxylic acid unit is added. In this latter case the protecting group is not removed as it is a part of the target molecule.
  • the capping group may be added after the last amino carboxylic acid xinit has been coupled and deprotected.
  • the step by step synthesis is outlined in the following schemes.
  • the second scheme is exemplary as the linker residue as well as the Cyt' residue may contain other functional groups as indicated in this scheme (see above):
  • X is a leaving group, for example -CI, -F, N-hydroxysuccinimidyl, pentafluorophenyl, or a carboxylate.
  • X 2 may be OH and condensation is achieved by the use of an in situ coupling reagent, for example benzotriazole-1-yl-oxy-tris- pyrrolidino-phosphonium hexafluorophosphate (PyBOP), l,r-carbonyldimidazole (CDI), 2-(lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium tetrafluoroborate (TBTU), or 1- (mesitylene-2-sulfonyl)-3-nitro-lH-l,2,4-triazole (MSNT).
  • PyBOP benzotriazole-1-yl-oxy-tris- pyrrolidino-phosphonium hexafluorophosphate
  • CDI 2-(
  • PG is a protecting group for example BOC, or preferably FMOC .
  • the compounds of the invention are intended for medical use.
  • these com- pounds are useful for the treatment of tumors which are associated with stromal fibroblasts that express FAP ⁇ and which are generally not optimally treated with available cytotoxic and/or cytostatic agents.
  • Tumors with this property are, for example, epithelial cancers, such as lung, breast, and colon carcinomas.
  • Tumors, such as bone and soft tissue sarcomas which express FAP ⁇ may also be treated with these compounds.
  • compositions comprising a compound of the present invention and optionally one or more suitable and pharmaceutically acceptable excipients, as exemplified in: Remington: the science and practice of pharmacy. 19th ed. Easton : MackPubl, 1995.
  • the pharmaceutical compositions may be formulated as solids or solutions. Solid formulations may be for preparation of a solution before injection.
  • the pharmaceutical compositions of the invention are solutions for injection. They maybe administered systemically, e.g. by intravenous injection, or topically, e.g. by direct injection into the tumor site.
  • the dosage will be adjusted according to factors like body weight and health status of the patient, nature of the underlying disease, therapeutic window of the compound to be applied, solubility, and the like. It is within the knowledge of the expert to adjust dosage appropriately.
  • the dose will preferably be in the range from 10 mg/m 2 to 2000 mg/m 2 , but also higher or lower doses may be appropriate.
  • a further aspect of the present invention is the use of a compound of the in- vention in the preparation of a pharmaceutical composition for the treatment of cancer.
  • an aspect of the invention is a method of treatment of cancer, comprising administering an effective amount of a pharmaceutical composition of the invention to a patient.
  • Indications include the treatment of cancer, specifically:
  • epithelial carcinomas including breast, lung, colorectal, head and neck, pancreatic, ovarian, bladder, gastric, skin, endometrial, ovarian, testicular, esophageal, prostatic and renal origin; 2) Bone and soft-tissue sarcomas: Osteosarcoma, chondrosarcoma, fibrosarcoma, malignant fibrous histiocytoma (MFH), leiomyosarcoma; 3) Hematopoietic malignancies: Hodgkin's and non-Hodgkin's lymphomas;
  • Neuroectodermal tumors Peripheral nerve tumors, astrocytomas, melanomas;
  • Mesotheliomas are also included. Also included are the treatment of chronic inflammatory conditions such as rheumatoid arthritis, osteoarthritis, liver cirrhosis, lung fibrosis, arteriosclerosis, and abnormal wound healing.
  • a further aspect of the invention is a method of treatment of cancer, wherein a prodrug is administered to a patient wherein said prodrug is capable of being converted into a cytotoxic or cytostatic drug by an enzymatic activity, said enzymatic activity being the expression product of cells associated with tumor tissue.
  • said enzymatic activity is the proteolytic activity of FAP ⁇ .
  • One method of administration of the compounds is intravenous infusion.
  • Other possible routes of administration include intraperitoneal (either as a bolus or infusion), intramuscular or intratumoral injection. Where appropriate, direct application may also be possible (for example, lung fibrosis).
  • the resin was washed with DMF (six times with 7 ml), dichloromethane (DCM) (six times with 7 ml), methanol (MeOH) (six times with 7 ml), and Et 2 O (six times with 7 ml) and treated with a solution of trifluoroacetic acid/water 95:5 (6 ml). After incubation for 2 h, the cleavage solution was placed into a flask and the resin was washed additionally with DCM (twice with 3 ml).
  • H-Pro-2-chlorotritylchloride-resin 200 mg, 0.158 was added to a reaction vessel and washed with DMF (three times with 7 ml).
  • Fmoc-Gly-OH 284.4 mg, 0.95 mmol
  • HOBt (128.1, 0.95 mmol
  • DIC 146.8 ⁇ l, 0.95 mmol
  • DMF 6 ml
  • the resin was washed with DCM (six times with 7 ml), MeOH) (six times with 7 ml), and Et 2 O (six times with 7 ml) and treated with a solution of trifluoroacetic acid/water 95:5 (6 ml). After incubation for 2 h, the cleavage solution was placed into a flask and the resin was washed additionally with DCM (twice with 3 ml).
  • Doxorubicin ⁇ Cl (100 mg, 0.38 mmol) was weighed into a separate vial. N,N- dimethylformamide (3 ml) and NN-Diisopropylethylamine (33.1 ⁇ l, 0.19 mmol) were added to the vial with stirring. The doxorubicin solution was added via syringe to the peptide solution, and the vial was rinsed with an additional 2 ml of N,N- dimethylformamide. The ice bath was removed and reaction mixture was stirred for approximately 48 hours at room temperature.
  • FAP ⁇ -expressing cell lines Mammalian cell lines expressing recombinant FAP ⁇ were prepared.
  • HT1080 fibrosarcoma cells widely known and available from the DSMZ (German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany) under the accession number DSMZ ACC 315, were maintained in a DMEM/F12 mix 50:50 containing 10% fetal bovine serum in an atmosphere of 95% air and 5% CO 2 .
  • HT1080 cells were transfected with FAP.38 vector (WO 97/34927, Scanlan et al, loc. cit.) using the Lipofectin method according to the manufacturer's instructions (Gibco/BRL).
  • Transfectants were selected for resistance to antibiotics (200 ug/ml Geneticin) and thereafter maintained in medium containing Geneticin. Individual colonies of resistant cells were picked, grown to confluence in 10 cm tissue culture petri dishes and tested for FAP ⁇ expression in an immunofluorescence assay using the FAP ⁇ -specific monoclonal antibody F19, as described (Garin-Chesa et al. (1990) Proc. Natl. Acad. Sci. USA 87(18), 7235-7239). The parental HT1080 cell line showed no detectable FAP ⁇ expression in this immunofluorescence assay, while one clone, referred to hereafter as HT1080 clone 33, was positive for FAP ⁇ .
  • human embryonic kidney 293 cells widely known and available from American Tissue Type Collection (Rockville, MD), were maintained in a DMEM containing 10% fetal bovine serum in an atmosphere of 95% air and 5% CO 2 .
  • Cells were transfected with a FAP ⁇ expression vector, pFAP.38 using calcium phosphate transfection as described (Park, J. E., Chen, H. H., Winer, J., Houck, K. A. & Ferrara, N. (1994). Placenta growth factor. Potentiation of vascular endothelial growth factor bioactivity, in vitro and in vivo, and high affinity binding to Flt-1 but not to Flk-1/ DR. J. Biol. Chem.
  • FAP ⁇ expression was examined in the HT1080 and HT1080 clone 33 cells. Metabolic labeling, immunoprecipitations and fluorography were performed essentially as described (Park et al. (1991) Somatic CellMol Genet. 17(2), 137-150). HT1080 and HT1080 clone 33 cells were metabolically labelled with 35 S-methionine. Detergent extracts of these cells were immunoprecipitated with monoclonal antibody F19 or with mouse IgGl antibody as a negative control.
  • Precipitates were boiled in sample buffer and separated by sodium dode- cyl sulfate gel electrophoresis (as described by Laemmli (1970) Nature 227(259), 680- : 685). Fluorographic analysis of the resulting gel confirmed that the HT1080 clone 33 cells produce FAP ⁇ protein. No FAP ⁇ protein was detectable in extracts of the parental HT1080 cells nor in immunoprecipitates with mouse IgGl.
  • a soluble recombinant form of FAP ⁇ protein was prepared as follows.
  • the cDNAs were verified by sequencing and inserted into the pNL1393 vector.
  • HPLC HPLC assay that was established to measure cleavage of doxorubicin-peptide conjugates.
  • the HPLC system consisted of a Waters 717 autosampler equipped with a 100 microliter ( ⁇ l) loop and two Waters model 510 pumps to deliver solvents. Separations were performed under isocratic conditions at a flow rate of 0.7 ml/min on a Nucleosil C-18 column, 100 mm long x4 mm I.D. with 5 ⁇ m particle size (Dr. Ing. H. Knauer GmbH, Berlin).
  • the mobile phase consisted of methanol: water (70:30, v/v) containing 0.2 M ammonium acetate, adjusted to pH 3.2.
  • Free doxorubicin and doxorubicin-peptide conjugates were detected by fluorescence (excitation, 475 nm; emission, 585 nm) using a Waters 474 fluorescence detector. Injection, solvent delivery, data acquisition, and data analysis were all per- formed using the Millennium 2010 chromatography software package (Waters Corp., Mil- ford, MA, USA). Substances to be tested were first dissolved in dimethyl sulfoxide at a concentration of 5 mM and subsequently diluted in aqueous solution before being applied to the HPLC column.
  • Doxorubicin-peptide conjugate stock solutions (5 mM) were diluted with Hepes-buffered saline pH 7.4 to a final concentration of 50 to 100 ⁇ M. Twenty ⁇ l of the resulting solution was mixed with 50 ⁇ l of purified FAPmCD8 fusion protein (approximately 20 ng) described above and 30 ⁇ l Hepes-buffered saline, pH 7.4. The mixture was allowed to incubate at 37° C for 1 day and release of free doxorubicin was measured in the HPLC assay described.
  • FAP ⁇ -cleavable peptides to block the cytotoxic action of doxorubicin on FAP ⁇ -negative, doxorubicin-sensitive cells was determined.
  • K562 cells available from American Type Tissue Culture Collection, Rockville, MD, USA (ATCC Number: CCL- 243), were seeded in 96 well plates (Greiner Scientific) at a density of 1000 cells / well. Serum-free cell culture media containing various concentrations of free doxorubicin or equivalent molar concentrations of doxorubicin-peptide conjugates were added to the cells. Four days later, cell number was determined using an automated CASYTM cell counter (Scharfe System GmbH, Reutlingen, Germany).
  • FAP ⁇ FAP ⁇ to generate free doxorubicin capable of killing doxorubicin-sensitive cells was determined.
  • K562 cells available from American Type Tissue Culture Collec- tion, Rockville, MD, USA (ATCC Number: CCL-243), were seeded in 96 well plates (Greiner Scientific) at a density of 1000 cells / well. Serum-free cell culture media containing 1 ⁇ M doxorubicin-peptide conjugate was added to HT1080 or HT1080 clone 33 cells dishes for 19 hours at 37° C. The media were removed and release of doxorubicin was confirmed as in Example 44. Sixty-six ⁇ l of this medium was then added per well to the K562 cells. Four days later, cell number was determined using an automated CASYTM cell counter.
  • Plasma stability of doxorubicin-peptide conjugates was measured using methods described in Example 61. Samples containing doxorubicin-peptide conjugates (at a concentration of 1 ⁇ M) were incubated in the presence of 10% (v/v) mouse or human plasma for the times indicated at 37° C.
  • Assay for cleavage ofMNA substrates by FAP Buffer A: lOOmM Tris HC1 pH 7.8, 100 mM NaCl Cell extract from 293 cells stably transfected with FAP prepared as described (see Park, et al, Fibroblast Activation Protein, a Dual Specificity Serine Protease expressed in human tumor stromal fibroblasts. (1999) J. Biol. Chem. 36505-12.). A similar extract was also prepared from parental 293 control cells without FAP. The FAP concentration in the FAP- transfected cell extract was estimated by immunoassay and 1 ng enzyme (diluted in buffer A) was used per assay.
  • FAP-negative 293 control cell extract was used at the same dilution (also in buffer A) as a negative control.
  • Substrate was initially dissolved in dimethylformamide at a concentration of 200 mM and diluted in buffer A to a final concentration of 2.5 mM. A few substrates were not soluble at this concentration and had to be diluted further.
  • the resin was washed with DMF (six times with 7 ml), dichloromethane (DCM) (six times with 7 ml), methanol (MeOH) (six times with 7 ml), and Et 2 O (six times with 7 ml) and treated with a solution of trifluoroacetic acid/water 95:5 (6 ml). After incubation for 2 h, the cleavage solution was placed into a flask and the resin was washed additionally with DCM (twice with 3 ml).
  • H-Gly- Wang-resin 200 mg, 0.158 was added to a reaction vessel and washed with DMF (three times with 7 ml).
  • Fmoc-Ala-OH 295.7 mg, 0.95 mmol
  • HOBt (128.1, 0.95 mmol
  • DIC 146.8 ⁇ l, 0.95 mmol
  • DMF 6 ml
  • the resin was then filtered, washed with DMF (eight times with 7 ml) and 20% piperidine in DMF (4 ml) was added to the reaction vessel. After agitation for 30 min, the resin was filtered and washed with DMF (eight times with 7 ml).
  • Fmoc-Pro-OH was incorporated in the same manner.
  • the Fmoc-group of pro line was removed and the resin was washed with DMF (eight times with 7 ml)and DCM (six times with 7 ml).
  • 3- Pyridylcarbinol 99 ⁇ l, 0.25 mmol
  • 4-nitrophenyl chloroformate 156 mg, 0.20 mmol
  • triethylamine 225 ⁇ l, 0.4 mmol
  • the resin was washed with DCM (six times with 7 ml), MeOH) (six times with 7 ml), and Et 2 O (six times with 7 ml) and treated with a solution of trifluoroacetic acid/water 95:5 (6 ml). After incubation for 2 h, the cleavage solution was placed into a flask and the resin was washed additionally with DCM (twice with 3 ml).
  • the following table shows the peptide-MNA-conjugates which have been prepared analogously and includes cleavage data by FAP.
  • Pip represents a piperidin-2-ylcarboxylic acid moiety
  • 2-Aze represents an azetidin-2-ylcarboxylic acid moiety
  • MeAla represents a N-methylalanin moiety

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Abstract

L'invention concerne un promédicament pouvant être transformé en médicament sous l'action catalytique de la protéine d'activation des fibroblastes humains (FAPα). Ledit promédicament est chimiquement stable dans des conditions physiologiques, et peut être utilisé pour la fabrication de compositions aqueuses physiquement stables. Le promédicament présente un site de restriction reconnu par la protéine FAPα, et le médicament libéré par l'action enzymatique de la protéine FAPα est cytotoxique ou cytostatique dans des conditions physiologiques.
PCT/EP2001/012812 2000-11-10 2001-11-06 Composes antitumoraux actives par la proteine fap-alpha WO2002038590A1 (fr)

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Cited By (9)

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EP1963537A2 (fr) * 2005-12-14 2008-09-03 The Ludwig Institute for Cancer Research Procede permettant de diagnostiquer une arthrite rhumatoide par le dosage des synoviocytes de type fibroblastique pour la proteine d'activation des fibroblastes
WO2014102312A3 (fr) * 2012-12-28 2014-08-21 Life Sciences Research Partners Vzw Promédicaments minimalement toxiques
US9062094B2 (en) 2010-01-22 2015-06-23 Ascendis Pharma As Dipeptide-based prodrug linkers for aliphatic amine-containing drugs
US9533056B2 (en) 2010-01-22 2017-01-03 Ascendis Pharma As Dipeptide-based prodrug linkers for aliphatic amine-containing drugs
CN106573073A (zh) * 2014-06-13 2017-04-19 塔夫茨大学信托人 Fap激活的治疗剂以及其相关用途
WO2018129497A1 (fr) 2017-01-09 2018-07-12 Bioxcel Therapeutics, Inc. Procédés prédictifs et diagnostiques pour le cancer de la prostate
US10709722B2 (en) 2014-06-13 2020-07-14 Bach Biosciences, Llc FAP-activated therapeutic agents, and uses related thereto
WO2022136586A1 (fr) 2020-12-22 2022-06-30 Cobiores Nv Composés comprenant une fraction tétrapeptidique
WO2022167664A1 (fr) 2021-02-07 2022-08-11 Cobiores Nv Composés comprenant une fraction tétrapeptidique

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WO1997012624A1 (fr) * 1995-10-06 1997-04-10 Merck & Co., Inc. Nouveaux peptides
WO1997014416A1 (fr) * 1995-10-18 1997-04-24 Merck & Co., Inc. Conjugues utiles pour traiter l'adenome prostatique benin
WO2000071571A2 (fr) * 1999-05-14 2000-11-30 Boehringer Ingelheim Pharma Kg Composes anti-tumoraux actives par la proteine fap

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Cited By (24)

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Publication number Priority date Publication date Assignee Title
EP1963537A4 (fr) * 2005-12-14 2009-11-11 Ludwig Inst For Cancer Res Ltd Procede permettant de diagnostiquer une arthrite rhumatoide par le dosage des synoviocytes de type fibroblastique pour la proteine d'activation des fibroblastes
EP1963537A2 (fr) * 2005-12-14 2008-09-03 The Ludwig Institute for Cancer Research Procede permettant de diagnostiquer une arthrite rhumatoide par le dosage des synoviocytes de type fibroblastique pour la proteine d'activation des fibroblastes
US9062094B2 (en) 2010-01-22 2015-06-23 Ascendis Pharma As Dipeptide-based prodrug linkers for aliphatic amine-containing drugs
US9533056B2 (en) 2010-01-22 2017-01-03 Ascendis Pharma As Dipeptide-based prodrug linkers for aliphatic amine-containing drugs
US10583194B2 (en) 2012-12-28 2020-03-10 Cobiores Nv Minimally toxic prodrugs
WO2014102312A3 (fr) * 2012-12-28 2014-08-21 Life Sciences Research Partners Vzw Promédicaments minimalement toxiques
CN104884091A (zh) * 2012-12-28 2015-09-02 生命科学研究合作伙伴公司 最低毒性的药物前体
CN113476616A (zh) * 2012-12-28 2021-10-08 科比欧尔斯公司 最低毒性的药物前体
CN104884091B (zh) * 2012-12-28 2021-07-20 科比欧尔斯公司 最低毒性的药物前体
AU2013369261B2 (en) * 2012-12-28 2018-08-09 Cobiores Nv Minimally toxic prodrugs
US10076576B2 (en) 2012-12-28 2018-09-18 Life Sciences Research Partners Vzw Minimally toxic prodrugs
EA034046B1 (ru) * 2012-12-28 2019-12-23 Кобиорес Нв Олигопептидные пролекарства с фосфоноацетильной кэпирующей группой
CN106573073A (zh) * 2014-06-13 2017-04-19 塔夫茨大学信托人 Fap激活的治疗剂以及其相关用途
US10709722B2 (en) 2014-06-13 2020-07-14 Bach Biosciences, Llc FAP-activated therapeutic agents, and uses related thereto
JP2020183448A (ja) * 2014-06-13 2020-11-12 バック バイオサイエンシーズ, エルエルシーBach BioSciences, LLC Ｆａｐ活性化治療剤及びそれに関連する使用
US11033525B2 (en) 2014-06-13 2021-06-15 Bach Biosciences, Llc Fap-activated therapeutic agents, and uses related thereto
JP2017519753A (ja) * 2014-06-13 2017-07-20 トラスティーズ オブ タフツ カレッジ Ｆａｐ活性化治療剤及びそれに関連する使用
US11266669B2 (en) 2014-06-13 2022-03-08 Bach Biosciences, Llc FAP-activated therapeutic agents, and uses related thereto
JP7093912B2 (ja) 2014-06-13 2022-07-01 バック バイオサイエンシーズ，エルエルシー Ｆａｐ活性化治療剤及びそれに関連する使用
JP2022116203A (ja) * 2014-06-13 2022-08-09 バック バイオサイエンシーズ，エルエルシー Ｆａｐ活性化治療剤及びそれに関連する使用
US11925655B2 (en) 2014-06-13 2024-03-12 Bach Biosciences, Llc FAP-activated therapeutic agents, and uses related thereto
WO2018129497A1 (fr) 2017-01-09 2018-07-12 Bioxcel Therapeutics, Inc. Procédés prédictifs et diagnostiques pour le cancer de la prostate
WO2022136586A1 (fr) 2020-12-22 2022-06-30 Cobiores Nv Composés comprenant une fraction tétrapeptidique
WO2022167664A1 (fr) 2021-02-07 2022-08-11 Cobiores Nv Composés comprenant une fraction tétrapeptidique

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