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WO2025146313A1 - Phosphinites utilisés en tant qu'agents de pontage de disulfure réducteur - Google Patents

Phosphinites utilisés en tant qu'agents de pontage de disulfure réducteur Download PDF

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Publication number
WO2025146313A1
WO2025146313A1 PCT/EP2024/085518 EP2024085518W WO2025146313A1 WO 2025146313 A1 WO2025146313 A1 WO 2025146313A1 EP 2024085518 W EP2024085518 W EP 2024085518W WO 2025146313 A1 WO2025146313 A1 WO 2025146313A1
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alkyl
optionally substituted
group
heteroalkyl
substituents
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Peter BAUERNSCHMITT
Aubry Miller
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Deutsches Krebsforschungszentrum DKFZ
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Deutsches Krebsforschungszentrum DKFZ
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    • 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
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/46—Phosphinous acids [R2POH], [R2P(= O)H]: Thiophosphinous acids including[R2PSH]; [R2P(=S)H]; Aminophosphines [R2PNH2]; Derivatives thereof
    • 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
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/655—Somatostatins

Definitions

  • the present invention generally relates to the field of bioconjugation. More specifically, it relates to phosphinites and their use as reductive disulfide rebridging agents.
  • the present invention concerns a compound selected from compounds of formulae (la) and (lb), a conjugate which is obtainable by linking such compounds to another moiety, a method of modifying a disulfide-containing compound using a compound selected from compounds of formulae (la) and (lb), as well as a compound obtainable by the method.
  • Bioconjugation i.e. the attachment of "cargo" molecules to large biomolecules in a predictable and uniform manner, has been successfully used in the past for producing antibody-drug conjugates and for developing probes to detect, visualize, and enrich certain compounds in cellular samples or extracts.
  • the two steps of reduction and rebridging at best typically lead to mixtures of two products; one wherein all interchain disulfides are natively rebridged, and one wherein some interchain disulfides have been scrambled, resulting in a "half-stapled" antibody.
  • the pyradazinedione scaffold is susceptible to cross reaction with native cysteines, and is conceptually different from the herein described use of a single functional group for both reduction and rebridging.
  • the phosphine reported by Lu et al. cross reacts with lysines and performs poorly at physiological pH. In view of these reports, it is unexpected that phosphinites, which would normally be expected to be less reactive than phosphines toward disulfides, perform so well as reductive disulfide rebridging agents.
  • Patent Literature 1 WO 2018/041985 Al
  • Patent Literature 2 WO 2022/223783 Al
  • Non-Patent Literature 1 ADC - Antibody-Drug-Conjugates, see Dumontet et. aL, Nature reviews Drug Discovery, 2023, 22, 641.
  • Non-Patent Literature 2 Fu et. al., Signal Transduction and Targeted Therapy 2022, 7, 93
  • Non-Patent Literature 3 Lu 2022, Chem. Commun., 2022, 58, 12439-12442,
  • Non-Patent Literature 5 C. E. Stieger et al, Angewandte Chemie International Edition
  • Non-Patent Literature 6 A. Beck et al., Nature Rev. Drug Discov. 2017, 16, 315-337.
  • Non-Patent Literature 7 S. C. Owen et aL, AAPS J. 2015, 17, 339-351.
  • Non-Patent Literature 8 C. P. R. hackenberger et al., Curr. Opin. Chem. Biol. 2020, 58, 28-
  • Non-Patent Literature 9 J. R. Baker et al., Chem. Commun. 2021, 57, 10689-10702.
  • Non-Patent Literature 10 A. Madder et al. ChemBioChem 2016, 17, 529-553.
  • Non-Patent Literature 12 C. P. R. hackenberger et al., J. Am. Chem. Soc. 2020, 142, 9544-
  • the present invention is defined in the appended claims and thus concerns a compound selected from compounds of formulae (la) and (lb), a conjugate which is obtainable by linking such compounds to another moiety, a method of modifying a disulfide-containing compound using a compound selected from compounds of formulae (la) and (lb), as well as a compound obtainable by the method.
  • the present inventors surprisingly found that both reduction of a disulfide and concomitant rebridging functions can be incorporated into one molecule by using a compound selected from compounds of formulae (la) and (lb). As result, it is possible to achieve more effective conjugation using such molecules without requiring two or more steps.
  • probes that can give a readout on the redox status (e.g. disulfide bonds) of proteins in cells or organisms can be obtained.
  • This is valuable for redox biology and cannot be done with current technologies.
  • the degree to which the compounds of the present invention react with proteins etc. is an indication of the absolute amount of disulfides present in a sample.
  • the redox status can then be determined by comparing this amount with the total amount of thiol groups (whether free thiols or oxidized this (e.g. in the form of disulfides)) known to be present in the sample.
  • Preferred Group A -OH, -OR, -NH 2 , -NHR, -NR 2 , -NHC(O)R, -NHC(O)OR, -OC(O)R, -OC(O)NH 2 , -
  • the compound of the first aspect has preferably the following formula:
  • the present invention relates to a conjugate of the compound of formulae (la) and (lb). It is to be understood that also the conjugate may be a salt or solvate as defined for the compound of formulae (la) and (lb).
  • the conjugate is typically obtainable by linking a compound of formula (la) or (lb), or a salt or solvate thereof, with one or more selected from a peptide, a protein, an antibody, a nucleotide, an oligonucleotide, a saccharide, a polysaccharide, a detectable label, a radioactive or non-radioactive nuclide, biotin, desthiobiotin, a reporter enzyme, a protein tag, a fluorophore such as CY5, fluorescein or EDANS, biotin, a linker, a drug, a linker-drug conjugate, a linker-fluorophore conjugate, a polymer, a small molecule drug such as N-Ac-y- calicheamicin (ozogamicin), mertansine, ravtansine, monomethyl auristatin, SN38, exatecan, deruxtecan, govitecan, or aman
  • the conjugate of the present invention preferably differs from the compound of the first aspect of the present invention in that the conjugate further contains a moiety which results from the reaction with the one or more selected from a peptide, a protein, an antibody, a nucleotide, an oligonucleotide, a saccharide, a polysaccharide, a detectable label, a radioactive or non-radioactive nuclide, biotin, desthiobiotin, a reporter enzyme, a protein tag, a fluorophore such as CY5, fluorescein or EDANS, biotin, a linker, a drug, a linker-drug conjugate, a linker-fluorophore conjugate, a polymer, a small molecule drug such as N-Ac-y- calicheamicin (ozogamicin), mertansine, ravtansine, monomethyl auristatin, SN38, exatecan, deruxtecan, go
  • the conjugate of the present invention differs from the compound of the first aspect of the present invention in that the conjugate further contains a moiety which results from the reaction with the one or more selected from a peptide, a protein, an antibody, biotin, desthiobiotin, a protein tag, a fluorophore such as CY5, fluorescein or EDANS, a linker, a drug, a linker-drug conjugate, a linker-fluorophore conjugate, a polymer, a small molecule drug such as N-Ac-y-calicheamicin (ozogamicin), mertansine, ravtansine, monomethyl auristatin, SN38, exatecan, deruxtecan, govitecan, or amanatin.
  • the conjugate of the present invention preferably differs from the compound of the first aspect of the present invention in that the conjugate further contains a moiety which results from the reaction with the one or more selected from a peptide, a protein, an antibody, a linker, a drug, a linker-drug conjugate, a linker-fluorophore conjugate, a polymer, a small molecule drug such as N-Ac-y-calicheamicin (ozogamicin), mertansine, ravtansine, monomethyl auristatin, SN38, exatecan, deruxtecan, govitecan, or amanatin.
  • the conjugate may also be formed by linking a compound of formula (la) or (lb), or a salt or solvate thereof, with other groups of interest not recited in the above list, depending on the actions intended to be performed with the conjugate.
  • the compound of formula (la) or (lb), or a salt or solvate thereof may be linked directly with the one or more selected from a peptide, protein etc. mentioned above, or may be linked via a spacer.
  • the use of an explicit spacer is not mandatory. Rather a direct link between the compound of formula (la) or (lb), or a salt or solvate thereof and the one or more selected from a peptide, protein etc. mentioned above is feasible.
  • Preferred spacers contain one or more groups (preferably 1 to 50, more preferably 1 to 20, even more preferably 1 to 10) selected from - N(R L ) ⁇ , -C1-10 alkylene-, -C(O)-, -O-, - heteroarylene-, -phenylene-, -S-, -S(O)- and -S(O)2 ⁇ wherein each R L is independently selected from hydrogen and C1-6 alkyl, each C1-10 alkylene is independently optionally substituted with one or more selected from halogen, C(O)OH and OH, each heteroarylene is independently 4 to 6 membered heteroarylene comprising 1 to 3 heteroatoms selected from N, O and S and the heteroarylene is optionally substituted with one or more selected from halogen and C1-6 alkyl, and each phenylene is optionally substituted with one or more selected from halogen and C1-6 alkyl.
  • groups preferably 1 to 50, more preferably 1 to 20, even more preferably 1 to
  • the spacer group may comprise one or two or three side chains which can be attached to the main chain of the spacer group by replacing one or two or three hydrogen residues, preferably in a -C1-10 alkylene- moiety, in the main chain of the spacer group by the side chain(s).
  • These side chains may comprise 1 to 10, preferably 1 to 8, groups selected from -N(R L )-, -C1-10 alkylene-, — C(O)— , -O-, -heteroarylene-, -phenylene-, -S-, -S(O)- and - S(O) 2 — and are terminated by -H, wherein the definitions of R L and the optional substituents of the other groups are as defined for the main chain of the spacer group.
  • the spacer group preferably consists of one or more groups selected from -N(R L )-, -Ci-io alkylene-, -C(O)-, -O-, -heteroarylene-, -phenylene-, -S-, -8(0)- and -S(O) 2 -.
  • the spacer group comprises or consists of 3 to 15, more preferably 3 to 12, even more preferably 3 to 10 and most preferably 4 to 8 of the above groups.
  • the linking of a carboxylic acid and an amine via the coupling agent HATU and a non- nucleophilic amine via the coupling agent HATU and a non- nucleophilic amine.
  • the linking of an amine with a succinic ester The linking of an amine with a carboxylic acid chloride in the presence of a non-nucleophilic amine.
  • the present invention relates to a method of modifying a disulfide-containing compound.
  • the method comprises reactingthe compound of the first aspect, or the conjugate of the second aspect, with a disulfide-containing compound.
  • the disulfide-containing compound is preferably a protein.
  • the disulfide-containing compound is preferably a protein containing at least one S-S bond.
  • the method preferably involves the reaction of: with a disulfide represented by sented by or the reaction of with a disulfide illustrated by esented by
  • each of R 1 , R 2 , R 3 , R 3a , R 3b and R 3c are as defined above for the compound of the present invention in the first aspect.
  • the disulfide which can be illustrated by can be any disulfide group capable of reacting with compound la and/or compound lb and/or the conjugate.
  • the disulfide is a disulfide in which both sulfurs of the disulfide are linked to carbon atoms.
  • Preferred disulfide groups are disulfide groups formed by the reaction of two cysteine amino acids that are preferably present in an amino acid containing polymer such as a protein, preferably an antibody.
  • the disulfide group participating in the reaction of the method of the present will be chemically modified and therefore cease to be a disulfide group in the common chemical sense because the two sulfur atoms of the disulfide group will no longer be bonded directly to each other but via a bridge containing at least two carbon atoms and a phosphorous atom between the two sulfurs.
  • the disulfide-containing compound may contain more than one disulfide group and that not all of the disulfide groups in such a disulfide-containing compound have to take part in the reaction of the method of modifying a disulfide-containing compound of the present invention. Rather, it is preferred that from 1 to 4, preferably 2 to 4, more preferably 3 or 4, most preferably 4 of the disulfide groups in such a disulfide-containing compound take part in the reaction of the method of modifying a disulfide-containing compound of the present invention.
  • the disulfide group reacting in the method of modifying a disulfide-containing compound of the present invention can be a cyclic disulfide group, i.e. a disulfide group, wherein the atoms to which the two sulfurs of the disulfide group are bound would be part of the same molecule if the two sulfurs were not bound to each other.
  • the disulfide group reacting in the method of modifying a disulfide-containing compound of the present invention may be an intramolecular disulfide group.
  • the disulfide group reacting in the method of modifying a disulfide-containing compound of the present invention be a non-cylic disulfide group, i.e. a disulfide group, wherein the atoms to which the two sulfurs of the disulfide group are bound would not be part of the same molecule if the two sulfurs were not bound to each other.
  • the disulfide group reacting in the method of modifying a disulfide-containing compound of the present invention is preferably an intermolecular disulfide group. More preferable, the disulfide group reacting in the method of modifying a disulfide-containing compound of the present invention is part of an interchain disulfide in an antibody.
  • the present invention relates to a compound obtainable by the method described above (third aspect).
  • This compound may also be referred to herein as "modified disulfide-containing compound”.
  • This compound preferably contains one or more of the following groups: wherein R 2 , R 3 , R 3a , R 3b and R 3c are as defined in the first aspect and may have been modified as described in the second aspect to form the conjugate.
  • This group (or these groups) is/are typically present in parts of the compound where there was a disulfide group before the reaction with compound la and/or compound lb and/or the conjugate.
  • R 2 in the above formulae comprises one or more selected from a peptide, a protein, an antibody, a nucleotide, an oligonucleotide, a saccharide, a polysaccharide, a detectable label, a radioactive or non-radioactive nuclide, biotin, desthiobiotin, a reporter enzyme, a protein tag, a fluorophore such as CY5, fluorescein or EDANS, biotin, a linker, a drug, a linker-drug conjugate, a linker-fluorophore conjugate, a polymer, a small molecule drug such as N-Ac-y-calicheamicin (ozogamicin), mertansine, ravtansine, monomethyl auristatin, SN38, exatecan, deruxtecan, govitecan, or amanitin.
  • a small molecule drug such as N-Ac-y-calicheamicin
  • the R 2 in the above formulae comprises a small molecule drug such as N-Ac-y-calicheamicin (ozogamicin), mertansine, ravtansine, monomethyl auristatin, SN38, exatecan, deruxtecan, govitecan, or amanitin.
  • a small molecule drug such as N-Ac-y-calicheamicin (ozogamicin), mertansine, ravtansine, monomethyl auristatin, SN38, exatecan, deruxtecan, govitecan, or amanitin.
  • the term "comprises one or more selected from” as used in the present paragraph means that a chemical link has been established between these and the rest of R 2 .
  • the compound of the fourth aspect may furthermore contain one or more disulfide groups, i.e. one or more disulfide groups which have not been reacted with compound la and/or compound lb and/or the conjugate.
  • the compound that has been modified is preferably a protein, more preferably an antibody, even more preferably an IgGl or IgGlx antibody.
  • antibodies include IgA, IgD, IgE, IgG, IgM, a humanized antibody, a chimeric antibody, a monoclonal antibody, and an isolated antibody.
  • Specific antibodies are the following antibodies: trastuzumab, cetuximab, brentuximab, inotuzumab, polatuzumab, belantamab, tisotumab, disitamab, mirvetuximab, loncastuximab and enfortumab.
  • the compound of the first aspect, the conjugate of the second aspect and the compound of the fourth aspect can be used in many areas of medicine.
  • Lysosomes are acidic (typically pH 4.5-5), and digestive cell compartments that contain several proteolytic enzymes.
  • the antibody-part of the antibody drug conjugate and optionally (part of a) linker are digested there, which finally leads to release of the now active drug into the cytoplasm where it causes cell death.
  • Antibody drug conjugates typically have two or three parts (see Figure 1): a monoclonal antibody, an optional linker and a cytotoxic payload.
  • the present invention preferably relates to antibody drug conjugates in which a cytotoxic compound has been attached to a monoclonal antibody by means of the compound of the first aspect or the conjugate of the second aspect.
  • the compound of the first aspect or the conjugate of the second aspect can be part of (preferably act as) the linker between the monoclonal antibody and the cytotoxic payload.
  • an antibody drug conjugate is preferably obtained by one of the following procedures A and B:
  • the present invention may furthermore be used for the enrichment of disulfide-containing molecules from complex mixtures, visualization of disulfide-containing molecules in in-vitro analysis (e.g. non-reducing gels, fixed and permeabilized cells), as well as for labelling of surfaces.
  • the compound of the first aspect, the conjugate of the second aspect and the compound of the fourth aspect are for use in the treatment of a cancer.
  • the cancer is preferably selected from anaplastic large-cell lymphoma (ALCL), acute lymphoblastic leukaemia (ALL), acute myeloid leukaemia (AML), breast cancers (BC) including triple-negative breast cancer (TNBC), B-cell lymphomas (BCL) including diffuse large-B-cell lymphoma (DLBCL), gastric cancers (GC), gastro-oesophageal junction cancer (GOJ), Hodgkin lymphoma (HL), multiple myeloma (MM), non small-cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), myeloproliferative neoplasm MPN), nasopharyngeal carcinoma (NPC), chronic lymphocytic leukemia (CLL), urethral cancers, epithelial ovarian cancer, fallopian tube cancer, primary peritoneal cancer, CD30-positive T cell lymphoma, TROP-2 positive tumors, HER2-positive tumors, and nect
  • hydrocarbon group refers to a group consisting of carbon atoms and hydrogen atoms.
  • alicyclic is used in connection with cyclic groups and denotes that the corresponding cyclic group is non-aromatic.
  • alkyl refers to a monovalent saturated acyclic (i.e., non-cyclic) hydrocarbon group which may be linear or branched. Accordingly, an “alkyl” group does not comprise any carbon-to-carbon double bond or any carbon-to-carbon triple bond.
  • a "Ci- 5 alkyl” denotes an alkyl group having 1 to 5 carbon atoms. Preferred exemplary alkyl groups are methyl, ethyl, propyl (e.g., n-propyl or isopropyl), or butyl (e.g., n-butyl, isobutyl, sec-butyl, or tert-butyl).
  • alkyl preferably refers to Ci-4 alkyl, more preferably to methyl or ethyl, and even more preferably to methyl.
  • heteroalkyl refers to alkyl in which one or more (preferably 1, 2, or 3) secondary carbon atoms have been replaced by NH, O or S, one or more (preferably 1, 2, or 3) tertiary carbon atoms have been replaced by N, and/or one or more (preferably 1, 2, or 3) quaternary carbon atoms have been replaced by N+ (with a counter anion).
  • the carbon atom replaced is preferably not the carbon atom of the attachment point of the heteroalkyl group (to the remainder of the molecule). This applies preferably to the first "optionally substituted heteroalkyl” mentioned in each of groups D and S. This preferably also applies to the "heteroalkyl” in "-O-heteroalkyl”. In contrast, this preferably does not apply to any other "optionally substituted heteroalkyl" groups.
  • Polyethylene glycol groups are a preferred type of heteroalkyl groups.
  • the other terminus of the polyethylene glycol groups is preferably capped with an alkyl group.
  • heteroalkyl may preferably refer to Me(O-CHR ox -CHR ox ) n oxO-, wherein each R ox is independently selected from H and alkyl (preferably C1-3 alkyl, such as methyl), and nox is an integer of from 1 to 50, preferably from 1 to 25, more preferably from 1 to 15, even more preferably from 1 to 10, still more preferably from 1 to 8, most preferably from 1 to 5.
  • one of the two R ox in each repeating unit is H and the other is H or methyl. Even more preferably all R ox are hydrogen.
  • the "heteroalkyl" group contains not more than 100 nonhydrogen atoms, more preferably not more than 50 non-hydrogen atoms, even more preferably not more than 20 non-hydrogen atoms.
  • heteroalkyl group combinations such as -N(R L )-N(R L )-, -C(O)-C(O)-, -O-O-, -S-S-, -S(O)-S(O)-, -S(O) 2 -S(O) 2 - , -N(R L )-O-, -O-N(R L )-, -N(R L )-S-, -S-N(R L )-, -N(R L )-S(O)-, -S(O)-N(R L )-, -C(O)-S-, -S- C(O)-, -C(O)-S(O)-, -S(O)-C(O)-S(O) 2 -, -S(O) 2 -C(O)-,
  • alkenyl refers to a monovalent unsaturated acyclic hydrocarbon group which may be linear or branched and comprises one or more (e.g., one or two) carbon- to-carbon double bonds while it does not comprise any carbon-to-carbon triple bond.
  • C 2 -s alkenyl denotes an alkenyl group having 2 to 5 carbon atoms.
  • Preferred exemplary alkenyl groups are ethenyl, propenyl (e.g., prop-l-en-l-yl, prop-l-en-2-yl, or prop-2-en-l-yl), butenyl, butadienyl (e.g., buta-l,3-dien-l-yl or buta-l,3-dien-2-yl), pentenyl, or pentadienyl (e.g., isoprenyl).
  • alkenyl preferably refers to C2-4 alkenyl.
  • alkynyl refers to a monovalent unsaturated acyclic hydrocarbon group which may be linear or branched and comprises one or more (e.g., one or two) carbon- to-carbon triple bonds and optionally one or more (e.g., one or two) carbon-to-carbon double bonds.
  • C2-5 alkynyl denotes an alkynyl group having 2 to 5 carbon atoms.
  • Preferred exemplary alkynyl groups are ethynyl, propynyl (e.g., propargyl), or butynyl.
  • alkynyl preferably refers to C2-4 alkynyl.
  • alkylene refers to an alkanediyl group, i.e. a divalent saturated acyclic hydrocarbon group which may be linear or branched.
  • a "C1-5 alkylene” denotes an alkylene group having 1 to 5 carbon atoms; the term “C0-5 alkylene” indicates that a covalent bond (corresponding to the option "Co alkylene”) or a C1-5 alkylene is present.
  • Preferred exemplary alkylene groups are methylene (-CH2-), ethylene (e.g., -CH2-CH2- or -CH(-CH3)-), propylene (e.g., -CH2-CH2-CH2-, -CH(-CH 2 -CH 3 )-, -CH 2 -CH(-CH 3 )-, or -CH(-CH 3 )-CH 2 -), or butylene (e.g., -CH2-CH2-CH2-).
  • alkylene preferably refers to C1-4 alkylene (including, in particular, linear C1-4 alkylene), more preferably to methylene or ethylene, and even more preferably to methylene.
  • alkynylene refers to an alkynediyl group, i.e. a divalent unsaturated acyclic hydrocarbon group which may be linear or branched and comprises one or more (e.g., one or two) carbon-to-carbon triple bonds and optionally one or more (e.g., one or two) carbon-to-carbon double bonds.
  • a "C2-5 alkynylene” denotes an alkynylene group having 2 to 5 carbon atoms.
  • alkynylene preferably refers to C2-4 alkynylene (including, in particular, linear C2-4 alkynylene).
  • carbocyclyl refers to a hydrocarbon ring group, including monocyclic rings as well as bridged ring, spiro ring and/or fused ring systems (which may be composed, e.g., of two or three rings), wherein said ring group may be saturated, partially unsaturated (i.e., unsaturated but not aromatic) or aromatic.
  • “carbocyclyl” preferably refers to aryl, cycloalkyl or cycloalkenyl.
  • heterocyclyl refers to a ring group, including monocyclic rings as well as bridged ring, spiro ring and/or fused ring systems (which may be composed, e.g., of two or three rings), wherein said ring group comprises one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from O, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) may optionally be oxidized, wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group), and further wherein said ring group may be saturated, partially unsaturated (i.e., unsaturated but not aromatic) or aromatic.
  • each heteroatom-containing ring comprised in said ring group may contain one or two 0 atoms and/or one or two S atoms (which may optionally be oxidized) and/or one, two, three or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which may optionally be oxidized) in the corresponding heteroatom-containing ring.
  • heterocyclyl preferably refers to heteroaryl, heterocycloalkyl or heterocycloalkenyl.
  • aryl is a bridged and/or fused ring system which contains, besides one or more aromatic rings, at least one non-aromatic ring (e.g., a saturated ring or an unsaturated alicyclic ring), then one or more carbon ring atoms in each non-aromatic ring may optionally be oxidized (i.e., to form an oxo group).
  • non-aromatic ring e.g., a saturated ring or an unsaturated alicyclic ring
  • carbon ring atoms in each non-aromatic ring may optionally be oxidized (i.e., to form an oxo group).
  • Aryl may, e.g., refer to phenyl, naphthyl, dialinyl (i.e., 1,2-dihydronaphthyl), tetralinyl (i.e., 1, 2,3,4- tetrahydronaphthyl), indanyl, indenyl (e.g., lH-indenyl), anthracenyl, phenanthrenyl, 9H-fluorenyl, or azulenyl.
  • dialinyl i.e., 1,2-dihydronaphthyl
  • tetralinyl i.e., 1, 2,3,4- tetrahydronaphthyl
  • indanyl e.g., indenyl (e.g., lH-indenyl), anthracenyl, phenanthrenyl, 9H-fluorenyl, or azulenyl.
  • an "aryl” preferably has 6 to 14 ring atoms, more preferably 6 to 10 ring atoms, even more preferably refers to phenyl or naphthyl, and most preferably refers to phenyl.
  • heteroaryl refers to an aromatic ring group, including monocyclic aromatic rings as well as bridged ring and/or fused ring systems containing at least one aromatic ring (e.g., ring systems composed of two or three fused rings, wherein at least one of these fused rings is aromatic; or bridged ring systems composed of two or three rings, wherein at least one of these bridged rings is aromatic), wherein said aromatic ring group comprises one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from O, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) may optionally be oxidized, and further wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group).
  • aromatic ring group comprises one or more (such as, e.g., one, two,
  • each heteroatom-containing ring comprised in said aromatic ring group may contain one or two O atoms and/or one or two S atoms (which may optionally be oxidized) and/or one, two, three or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which may optionally be oxidized) in the corresponding heteroatom-containing ring.
  • Heteroaryl may, e.g., refer to thienyl (i.e., thiophenyl), benzo[b]thienyl, naphtho[2,3- b]thienyl, thianthrenyl, furyl (i.e., furanyl), benzofuranyl, isobenzofuranyl, chromanyl, chromenyl (e.g., 2H-l-benzopyranyl or 4H-l-benzopyranyl), isochromenyl (e.g., 1H-2- benzopyranyl), chromonyl, xanthenyl, phenoxathiinyl, pyrrolyl (e.g., lH-pyrrolyl), imidazolyl, pyrazolyl, pyridyl (i.e., pyridinyl; e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl),
  • heteroaryl preferably refers to a 5 to 14 membered (more preferably 5 to 10 membered) monocyclic ring or fused ring system comprising one or more (e.g., one, two, three or four) ring heteroatoms independently selected from 0, S and N, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized; even more preferably, a “heteroaryl” refers to a 5 or 6 membered monocyclic ring comprising one or more (e.g., one, two or three) ring heteroatoms independently selected from 0, S and N, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized.
  • heteroaryl examples include pyridinyl (e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl), imidazolyl, thiazolyl, lH-tetrazolyl, 2H-tetrazolyl, thienyl (i.e., thiophenyl), or pyrimidinyl.
  • cycloalkyl refers to a saturated hydrocarbon ring group, including monocyclic rings as well as bridged ring, spiro ring and/or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings).
  • Cycloalkyl may, e.g., refer to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, decalinyl (i.e., decahydronaphthyl), or adamantyl.
  • cycloalkyl preferably refers to a C3-11 cycloalkyl, and more preferably refers to a C3-7 cycloalkyl.
  • a particularly preferred "cycloalkyl” is a monocyclic saturated hydrocarbon ring having 3 to 7 ring members.
  • particularly preferred examples of a “cycloalkyl” include cyclohexyl or cyclopropyl, particularly cyclohexyl.
  • cycloalkylene refers to a cycloalkyl group, as defined herein above, but having two points of attachment, i.e. a divalent saturated hydrocarbon ring group.
  • Cycloalkylene may, e.g., refer to cyclopropylene (e.g., cyclopropan-l,l-diyl or cyclopropan- 1,2-diyl), cyclobutylene (e.g., cyclobutan-l,l-diyl, cyclobutan-l,2-diyl, or cyclobutan-l,3-diyl), cyclopentylene (e.g., cyclopentan-1, 1-diyl, cyclopentan-1, 2-diyl, or cyclopentan-1, 3-diyl), or cyclohexylene (e.g., cyclohexan-1, 1-diyl, cyclohexylene (e.g.
  • cycloalkylene preferably refers to a C3-7 cycloalkylene, and more preferably refers to a C3-5 cycloalkylene. Moreover, unless defined otherwise, a particularly preferred example of a “cycloalkylene” is cyclopropylene.
  • heterocycloalkyl refers to a saturated ring group, including monocyclic rings as well as bridged ring, spiro ring and/or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings), wherein said ring group contains one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from O, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) may optionally be oxidized, and further wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group).
  • ring group contains one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from O
  • each heteroatom-containing ring comprised in said saturated ring group may contain one or two 0 atoms and/or one or two S atoms (which may optionally be oxidized) and/or one, two, three or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which may optionally be oxidized) in the corresponding heteroatom-containing ring.
  • Heterocycloalkyl may, e.g., refer to aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, azepanyl, diazepanyl (e.g., 1,4-diazepanyl), oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, morpholinyl (e.g., morpholin-4-yl), thiomorpholinyl (e.g., thiomorpholin-4-yl), oxazepanyl, oxiranyl, oxetanyl, tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydropyranyl, 1,4-dioxanyl, oxepanyl, thiiran
  • heterocycloalkyl preferably refers to a 3 to 11 membered saturated ring group, which is a monocyclic ring or a fused ring system (e.g., a fused ring system composed of two fused rings), wherein said ring group contains one or more (e.g., one, two, three, or four) ring heteroatoms independently selected from O, S and N, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized; more preferably, "heterocycloalkyl” refers to a 5 to 7 membered saturated monocyclic ring group containing one or more (e.g., one, two, or three) ring heteroatoms independently selected from O, S and N, wherein one or more S ring atoms (if present) and/or one or more N ring
  • heterocycloalkyl examples include tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, or tetrahydrofuranyl.
  • heterocycloalkylene refers to a heterocycloalkyl group, as defined herein above, but having two points of attachment.
  • Heterocycloalkylene may, e.g., refer to aziridinylene, azetidinylene, pyrrolidinylene, imidazolidinylene, pyrazolidinylene, piperidinylene, piperazinylene, azepanylene, diazepanylene (e.g., 1,4-diazepanylene), oxazolidinylene, isoxazolidinylene, thiazolidinylene, isothiazolidinylene, morpholinylene, thiomorpholinylene, oxazepanylene, oxiranylene, oxetanylene, tetrahydrofuranylene, 1,3-dioxolanylene, tetrahydropyranylene, 1,4-diox
  • heterocycloalkylene preferably refers to a divalent 3 to 7 membered saturated monocyclic ring group, wherein said ring group contains one or more (e.g., one, two, three, or four) ring heteroatoms independently selected from O, S and N, wherein the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized; more preferably, “heterocycloalkylene” refers to a divalent 3 to 5 membered saturated monocyclic ring group containing one or two (preferably one) ring heteroatoms independently selected from O, S and N, wherein the remaining ring atoms are carbon atoms.
  • ring group contains one or more (e.g., one, two, three, or four) ring heteroatoms independently selected from O, S and N, wherein the remaining
  • heterocycloalkylene examples include aziridinylene, oxiranylene, thiiranylene, azetidinylene (e.g., azetid i n-3,3-d iyl), oxetanylene (e.g., oxetan-3,3- diyl), thietanylene (e.g., thietan-3,3-diyl), pyrrolidinylene, tetrahydrofuranylene, or tetrahydrothiophenylene.
  • azetidinylene e.g., azetid i n-3,3-d iyl
  • oxetanylene e.g., oxetan-3,3- diyl
  • thietanylene e.g., thietan-3,3-diyl
  • pyrrolidinylene tetrahydrofuranylene, or
  • cycloalkenyl refers to an unsaturated alicyclic (non-aromatic) hydrocarbon ring group, including monocyclic rings as well as bridged ring, spiro ring and/or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings), wherein said hydrocarbon ring group comprises one or more (e.g., one or two) carbon-to-carbon double bonds and does not comprise any carbon-to-carbon triple bond.
  • Cycloalkenyl may, e.g., refer to cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, or cycloheptadienyl.
  • cycloalkenyl preferably refers to a C3-11 cycloalkenyl, and more preferably refers to a C3-7 cycloalkenyl.
  • a particularly preferred "cycloalkenyl” is a monocyclic unsaturated alicyclic hydrocarbon ring having 3 to 7 ring members and containing one or more (e.g., one or two; preferably one) carbon-to-carbon double bonds.
  • heterocycloalkenyl refers to an unsaturated alicyclic (non-aromatic) ring group, including monocyclic rings as well as bridged ring, spiro ring and/or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings), wherein said ring group contains one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from O, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) may optionally be oxidized, wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group), and further wherein said ring group comprises at least one double bond between
  • each heteroatom-containing ring comprised in said unsaturated alicyclic ring group may contain one or two 0 atoms and/or one or two S atoms (which may optionally be oxidized) and/or one, two, three or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which may optionally be oxidized) in the corresponding heteroatom-containing ring.
  • Heterocycloalkenyl may, e.g., refer to imidazolinyl (e.g., 2-imidazolinyl (i.e., 4,5-dihydro-lH-imidazolyl), 3-imidazolinyl, or 4-imidazolinyl), tetrahydropyridinyl (e.g., 1,2,3,6-tetrahydropyridinyl), dihydropyridinyl (e.g., 1,2- dihydropyridinyl or 2,3-d ihyd ropy rid inyl ), pyranyl (e.g., 2H-pyranyl or 4H-pyranyl), thiopyranyl (e.g., 2H-thiopyranyl or 4H-th iopyranyl), dihydropyranyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrazinyl, dihydroisoindo
  • heterocycloalkenyl preferably refers to a 3 to 11 membered unsaturated alicyclic ring group, which is a monocyclic ring or a fused ring system (e.g., a fused ring system composed of two fused rings), wherein said ring group contains one or more (e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) are optionally oxidized, wherein one or more carbon ring atoms are optionally oxidized, and wherein said ring group comprises at least one double bond between adjacent ring atoms and does not comprise any triple bond between adjacent ring atoms; more preferably, "heterocycloalkenyl” refers to a 5 to 7 membered monocyclic unsaturated non-aromatic ring group containing one or more (e.g
  • halogen refers to fluoro (-F), chloro (-CI), bromo (-Br), or iodo (-1).
  • haloalkyl refers to an alkyl group substituted with one or more (preferably 1 to 6, more preferably 1 to 3) halogen atoms which are selected independently from fluoro, chloro, bromo and iodo, and are preferably all fluoro atoms. It will be understood that the maximum number of halogen atoms is limited bythe number of available attachment sites and, thus, depends on the number of carbon atoms comprised in the alkyl moiety of the haloalkyl group.
  • Haloalkyl may, e.g., refer to -CF 3 , -CHF 2 , -CH 2 F, -CF 2 -CH 3 , -CH 2 -CF 3 , -CH 2 -CHF 2 , -CH 2 -CF 2 -CH 3 , -CH 2 -CF 2 -CF 3 , or -CH(CF 3 ) 2 .
  • a particularly preferred "haloalkyl” group is -CF 3 .
  • the terms “optional”, “optionally” and “may” denote that the indicated feature may be present but can also be absent.
  • the present invention specifically relates to both possibilities, i.e., that the corresponding feature is present or, alternatively, that the corresponding feature is absent.
  • the expression “X is optionally substituted with Y" (or “X may be substituted with Y”) means that X is either substituted with Y or is unsubstituted.
  • a component of a composition is indicated to be “optional”
  • the invention specifically relates to both possibilities, i.e., that the corresponding component is present (contained in the composition) or that the corresponding component is absent from the composition.
  • substituents such as, e.g., one, two, three or four substituents. It will be understood that the maximum number of substituents is limited by the number of attachment sites available on the substituted moiety.
  • the "optionally substituted" groups referred to in this specification carry preferably not more than two substituents and may, in particular, carry only one substituent.
  • the optional substituents of any “optionally substituted” groups are preferably one or more substituents selected from group X.
  • it is preferred that the optional substituents are absent, i.e.
  • compositions comprising “a” compound of formula (I) can be interpreted as referring to a composition comprising "one or more” compounds of formula (I).
  • the term “comprising” (or “comprise”, “comprises”, “contain”, “contains”, or “containing”), unless explicitly indicated otherwise or contradicted by context, has the meaning of “containing, inter alia”, i.e., “containing, among further optional elements, In addition thereto, this term also includes the narrower meanings of "consisting essentially of” and “consisting of”.
  • a comprising B and C has the meaning of "A containing, inter alia, B and C", wherein A may contain further optional elements (e.g., "A containing B, C and D" would also be encompassed), but this term also includes the meaning of "A consisting essentially of B and C” and the meaning of "A consisting of B and C" (i.e., no other components than B and C are comprised in A).
  • the scope of the present invention embraces all pharmaceutically acceptable salt forms of the compounds of the present formulae which may be formed, e.g., by protonation of an atom carrying an electron lone pair which is susceptible to protonation, such as an amino group, with an inorganic or organic acid, or as a salt of an acid group (such as a carboxylic acid group) with a physiologically acceptable cation.
  • Exemplary base addition salts comprise, for example: alkali metal salts such as sodium or potassium salts; alkaline earth metal salts such as calcium or magnesium salts; zinc salts; ammonium salts; aliphatic amine salts such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, procaine salts, meglumine salts, ethylenediamine salts, or choline salts; aralkyl amine salts such as N,N- dibenzylethylenediamine salts, benzathine salts, benethamine salts; heterocyclic aromatic amine salts such as pyridine salts, picoline salts, quinoline salts or isoquinoline salts; quaternary ammonium salts such as tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltriethylammoni
  • Exemplary acid addition salts comprise, for example: mineral acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate salts (such as, e.g., sulfate or hydrogensulfate salts), nitrate salts, phosphate salts (such as, e.g., phosphate, hydrogenphosphate, or dihydrogenphosphate salts), carbonate salts, hydrogencarbonate salts, perchlorate salts, borate salts, or thiocyanate salts; organic acid salts such as acetate, propionate, butyrate, pentanoate, hexanoate, heptanoate, octanoate, cyclopentanepropionate, decanoate, undecanoate, oleate, stearate, lactate, maleate, oxalate, fumarate, tartrate, malate, citrate, succinate, adipate, gluconate, glycolate, nic
  • a pharmaceutically acceptable salt of the compound of the present formulae is preferably not a hydroiodide salt.
  • Preferred pharmaceutically acceptable salts of the compounds of the present formulae include a hydrochloride salt, a hydrobromide salt, a mesylate salt, a sulfate salt, a tartrate salt, a fumarate salt, an acetate salt, an oxalate salt, a citrate salt, and a phosphate salt.
  • a particularly preferred pharmaceutically acceptable salt of the compound of the present formulae is a hydrochloride salt.
  • a compound of the present formulae including any one of the specific compounds of the present formulae described herein, is provided in the form of a pharmaceutically acceptable salt
  • the respective compound is in the form of a hydrochloride salt, a hydrobromide salt, a mesylate salt, a sulfate salt, a tartrate salt, a fumarate salt, an acetate salt, an oxalate salt, a citrate salt, or a phosphate salt
  • the present invention also specifically relates to the compound of the present formulae, including any one of the specific compounds of the present formulae described herein, in nonsalt form.
  • the scope of the invention embraces the compounds of the present formulae in any solvated form, including, e.g., solvates with water (i.e., as a hydrate) or solvates with organic solvents such as, e.g., methanol, ethanol, isopropanol, acetic acid, ethyl acetate, ethanolamine, DMSO, or acetonitrile. All physical forms, including any amorphous or crystalline forms (i.e., polymorphs), of the compounds of the present formulae are also encompassed within the scope of the invention. It is to be understood that such solvates and physical forms of pharmaceutically acceptable salts of the compounds of the present formulae are likewise embraced by the invention.
  • the compounds of the present formulae may exist in the form of different isomers, in particular stereoisomers (including, e.g., geometric isomers (or cis/trans isomers), enantiomers and diastereomers) or tautomers (including, in particular, prototropic tautomers, such as keto/enol tautomers or thione/thiol tautomers). All such isomers of the compounds of the present formulae are contemplated as being part of the present invention, either in admixture or in pure or substantially pure form.
  • stereoisomers the invention embraces the isolated optical isomers of the compounds according to the invention as well as any mixtures thereof (including, in particular, racemic mixtures/racemates).
  • the racemates can be resolved by physical methods, such as, e.g., fractional crystallization, separation or crystallization of diastereomeric derivatives, or separation by chiral column chromatography.
  • the individual optical isomers can also be obtained from the racemates via salt formation with an optically active acid followed by crystallization.
  • the present invention further encompasses any tautomers of the compounds of the present formulae. It will be understood that some compounds may exhibit tautomerism. In such cases, the formulae provided herein expressly depict only one of the possible tautomeric forms.
  • the formulae and chemical names as provided herein are intended to encompass any tautomeric form of the corresponding compound and not to be limited merely to the specific tautomeric form depicted by the drawing or identified by the name of the compound.
  • the scope of the invention also embraces compounds of the present formulae, in which one or more atoms are replaced by a specific isotope of the corresponding atom.
  • the invention encompasses compounds of the present formulae, in which one or more hydrogen atoms (or, e.g., all hydrogen atoms) are replaced by deuterium atoms (i.e., 2 H; also referred to as "D").
  • the invention also embraces compounds of the present formulae which are enriched in deuterium.
  • Naturally occurring hydrogen is an isotopic mixture comprising about 99.98 mol-% hydrogen-1 ( 1 H) and about 0.0156 mol-% deuterium ( 2 H or D).
  • the content of deuterium in one or more hydrogen positions in the compounds of the present formulae can be increased using deuteration techniques known in the art.
  • a compound of the present formulae or a reactant or precursor to be used in the synthesis of the compound of the present formulae can be subjected to an H/D exchange reaction using, e.g., heavy water (D2O).
  • D2O heavy water
  • deuteration techniques are described in: Atzrodt J et al., Bioorg Med Chem, 20(18), 5658-5667, 2012; William JS et al., Journal of Labelled Compounds and Radiopharmaceuticals, 53(11-12), 635-644, 2010; Modvig A et al., J Org Chem, 79, 5861-5868, 2014.
  • the content of deuterium can be determined, e.g., using mass spectrometry or NMR spectroscopy. Unless specifically indicated otherwise, it is preferred that the compound of the present formulae is not enriched in deuterium. Accordingly, the presence of naturally occurring hydrogen atoms or 1 H hydrogen atoms in the compounds of the present formulae is preferred.
  • the present invention also embraces compounds of the present formulae, in which one or more atoms are replaced by a positron-emitting isotope of the corresponding atom, such as, e.g., 18 F, n C, 13 N, 15 O, 76 Br, 77 Br, 120 l and/or 124 l.
  • a positron-emitting isotope of the corresponding atom such as, e.g., 18 F, n C, 13 N, 15 O, 76 Br, 77 Br, 120 l and/or 124 l.
  • Such compounds can be used as tracers, trackers or imaging probes in positron emission tomography (PET).
  • the invention thus includes (i) compounds of the present formulae, in which one or more fluorine atoms (or, e.g., all fluorine atoms) are replaced by 18 F atoms, (ii) compounds of the present formulae, in which one or more carbon atoms (or, e.g., all carbon atoms) are replaced by n C atoms, (iii) compounds of the present formulae, in which one or more nitrogen atoms (or, e.g., all nitrogen atoms) are replaced by 13 N atoms, (iv) compounds of the present formulae, in which one or more oxygen atoms (or, e.g., all oxygen atoms) are replaced by 15 O atoms, (v) compounds of the present formulae, in which one or more bromine atoms (or, e.g., all bromine atoms) are replaced by 76 Br atoms, (vi) compounds of the present formulae, in which one or more bromine atoms (or,
  • the compounds of the present formulae may be administered as compounds per se or may be formulated as medicaments.
  • the medicaments/pharmaceutical compositions may optionally comprise one or more pharmaceutically acceptable excipients, such as carriers, diluents, fillers, disintegrants, lubricating agents, binders, colorants, pigments, stabilizers, preservatives, antioxidants, and/or solubility enhancers.
  • the pharmaceutical compositions may comprise one or more solubility enhancers, such as, e.g., poly(ethylene glycol), including polyethylene glycol) having a molecular weight in the range of about 200 to about 5,000 Da (e.g., PEG 200, PEG 300, PEG 400, or PEG 600), ethylene glycol, propylene glycol, glycerol, a non-ionic surfactant, tyloxapol, polysorbate 80, macrogol- 15-hydroxystearate (e.g., Kolliphor HS 15, CAS 70142-34-6), a phospholipid, lecithin, dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, a cyclodextrin, a-cyclodextrin, P-cyclodextrin, y-cyclodextrin, hydroxyethyl-P-cyclodextrin,
  • the pharmaceutical compositions may also comprise one or more preservatives, particularly one or more antimicrobial preservatives, such as, e.g., benzyl alcohol, chlorobutanol, 2-ethoxyethanol, m-cresol, chlorocresol (e.g., 2-chloro-3-methyl-phenol or4-chloro-3-methyl- phenol), benzalkonium chloride, benzethonium chloride, benzoic acid (or a pharmaceutically acceptable salt thereof), sorbic acid (or a pharmaceutically acceptable salt thereof), chlorhexidine, thimerosal, or any combination thereof.
  • preservatives particularly one or more antimicrobial preservatives, such as, e.g., benzyl alcohol, chlorobutanol, 2-ethoxyethanol, m-cresol, chlorocresol (e.g., 2-chloro-3-methyl-phenol or4-chloro-3-methyl- phenol), benzalkonium chloride, benzethonium chloride
  • Such a partial or complete response may be followed by a relapse.
  • a subject/patient may experience a broad range of responses to a treatment (such as the exemplary responses as described herein above).
  • the treatment of a disorder or disease may, inter alia, comprise curative treatment (preferably leading to a complete response and eventually to healing of the disorder or disease) and palliative treatment (including symptomatic relief).
  • prevention of a disorder or disease is also well-known in the art.
  • a patient/subject suspected of being prone to suffer from a disorder or disease may particularly benefit from a prevention of the disorder or disease.
  • the subject/patient may have a susceptibility or predisposition for a disorder or disease, including but not limited to hereditary predisposition.
  • Such a predisposition can be determined by standard methods or assays, using, e.g., genetic markers or phenotypic indicators.
  • a disorder or disease to be prevented in accordance with the present invention has not been diagnosed or cannot be diagnosed in the patient/subject (for example, the patient/subject does not show any clinical or pathological symptoms).
  • the term "prevention" comprises the use of a compound of the present invention before any clinical and/or pathological symptoms are diagnosed or determined or can be diagnosed or determined by the attending physician.
  • the present invention specifically relates to each and every combination of features described herein, including any combination of general and/or preferred features.
  • the invention specifically relates to each combination of meanings (including general and/or preferred meanings) for the various groups and variables comprised in the present formulae.
  • the present invention relates to both the compound/example defined by the chemical formula and the compound/example defined by the chemical name, and particularly relates to the compound/example defined by the chemical formula.
  • P-Chloroethoxyphenylphosphine was prepared according to the following procedure Diethyl phenylphosphonite: Following a procedure by N. Kreutzkamp, J. Pluhatsch, Arch. Pharm. 1959, 292, 159-164, anhydrous ethanol (13.1 mL, 224 mmol, 2.0 eq.) and anhydrous pyridine (18.0 mL, 224 mmol, 2.0 eq.) were dissolved in anhydrous diethyl ether (125 mL) under an argon atmosphere.
  • P-Chloroethoxyphenylphosphine Similar to a procedure by E. Steininger, Chem. Ber. 1962, 95, 2993-2996, In a flame-dried flask, P,P-dichlorophenylphosphine (7.16 g, 40.0 mmol, 1.0 eq.) was added to diethyl phenylphosphonite (7.92 g, 40.0 mmol, 1.0 eq.) at 0 °C under an argon atmosphere. After 30 minutes, the cooling was removed and the reaction mixture was stirred for 1 h while warming to room temperature. Distillation of the crude material (69— 70 °C, 0.012 mbar) gave the product as a colorless liquid (9.85 g, 52.2 mmol, 65%).
  • 31 P NMR (162 MHz, CDCI 3 ): ⁇ 178.2 ppm. Although the compound is literature known, no sufficient NMR data for comparison were available. The 31 P-NMR chemical shift is in accordance with the one reported in C. J. Schaverien, R. Ernst, W. Terlouw, P. Schut, O. Sudmeijer, P. H. M. Budzelaar, J. Mol. Catal. A Chem. 1998, 128, 245-256.
  • Ethyl phenylvinylphosphinite To a solution of P-chloroethoxyphenylphosphine (4.50 g, 23.9 mmol, 1.0 eq.) and pyridine (3.77 g, 3.85 mL, 47.7 mmol, 2.0 eq.) in anhydrous THF (60 mL) was added vinylmagnesium bromide in THF (1 M, 23.9 mL, 23.9 mmol, 1.0 eq) at -78 °C dropwise during 45 min under an argon atmosphere with vigorous stirring. After the addition was complete, the cooling bath was removed and the mixture was stirred for 1 h while warming to room temperature.

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Abstract

La présente invention relève d'une manière générale du domaine de la bioconjugaison. Plus particulièrement, l'invention concerne des phosphinites et leur utilisation en tant qu'agents de pontage de disulfure réducteur. Ainsi, la présente invention concerne un composé choisi parmi les composés de formules (la) et (lb), un conjugué qui peut être obtenu par liaison de tels composés à une autre fraction, un procédé de modification d'un composé contenant du disulfure à l'aide d'un composé choisi parmi les composés de formules (la) et (lb), ainsi qu'un composé pouvant être obtenu par le procédé.
PCT/EP2024/085518 2024-01-04 2024-12-10 Phosphinites utilisés en tant qu'agents de pontage de disulfure réducteur Pending WO2025146313A1 (fr)

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