WO2016089208A2 - Dérivés sulfonamide, sulfamate et sulfamide d'agents anticancéreux - Google Patents

Dérivés sulfonamide, sulfamate et sulfamide d'agents anticancéreux Download PDF

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WO2016089208A2
WO2016089208A2 PCT/NL2015/050839 NL2015050839W WO2016089208A2 WO 2016089208 A2 WO2016089208 A2 WO 2016089208A2 NL 2015050839 W NL2015050839 W NL 2015050839W WO 2016089208 A2 WO2016089208 A2 WO 2016089208A2
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WO2016089208A3 (fr
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Philippe Lambin
Jean-Yves Winum
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Stichting Maastricht Radiation Oncology "Maastro-Clinic"
Université De Montpellier
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Publication of WO2016089208A2 publication Critical patent/WO2016089208A2/fr
Publication of WO2016089208A3 publication Critical patent/WO2016089208A3/fr

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    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4168—1,3-Diazoles having a nitrogen attached in position 2, e.g. clonidine
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
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    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
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    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
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    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—Ortho-condensed systems
    • C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom
    • C—CHEMISTRY; METALLURGY
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    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
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    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
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    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
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    • 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
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6509—Six-membered rings
    • C07F9/6512—Six-membered rings having the nitrogen atoms in positions 1 and 3
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    • 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
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6581—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms
    • C07F9/6584—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms having one phosphorus atom as ring hetero atom
    • C07F9/65842—Cyclic amide derivatives of acids of phosphorus, in which one nitrogen atom belongs to the ring
    • C07F9/65846—Cyclic amide derivatives of acids of phosphorus, in which one nitrogen atom belongs to the ring the phosphorus atom being part of a six-membered ring which may be condensed with another ring system
    • C—CHEMISTRY; METALLURGY
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention is directed to sulfonamide sulfamide and/or sulfamate derivatives of anticancer agents or agents having an antiproliferative activity.
  • the anticancer agents are functionalized with Sulfonamide, sulfamate and/or sulfamide to obtain a dual drug activity and an additional tumour targeting.
  • anticancer drugs Although many anticancer drugs have been used, many of them still lack specificity for the tumor. In addition, due to inadequate perfusion, tumours develop hypoxia and extracellular acidosis. This acidic environment is responsible for multidrug resistance and most anticancer drugs do not work well on cells that are present in extracellular acidic environment. In addition, many anticancer agents do not work at all or work less on stem cells. Furthermore, some anticancer agents need to be activated by intracellular low pH. Moreover, some anticancer agents have a fast pharmacokinetic with a short half life.
  • the compounds of the present invention address at least one of the issues described above.
  • Compounds of the present invention are more tumour specific.
  • the compounds of the present invention decrease the pH of cancer cells especially if they are in an acidic environment, making the cells more sensitive to the anticancer agent.
  • the compounds of the present invention are also suitable in normoxic conditions.
  • the compounds of the present invention are especially suitable for the tumour cells which are in an acidic environment but not hypoxic or recently reoxygenated.
  • the compounds of the present invention may also increase the extracellular pH, Increasing the extracellular pH increases the uptake of the anticancer agent.
  • the compounds of the present invention may also decrease the intracellular pH. Making the intracellulcar H more acidic ncreases the conversion in active compound (e.g.
  • the compounds of the present do not need irradiation to become active.
  • the compounds of the present invention may also be active in stem cells. Stem cells may be more sensitive to the compounds of the present invention. It was also found that the compounds of the present invention have a increased half life in plasma.
  • Calvert et al (Eur. J. Cancer, 4 (6), (1968) pages 627-636) discloses derivatives of sulphanilamide that accumulate in neoplastic tissue.
  • aryl-2-halogenoalkylamines which are nitrogen musters and have been shown to possess significant tumour growth inhibitory activity.
  • Calvert et al. discloses a sulfonamide (formula III). However when looking at the compounds without the sulfonamide, it can be seen that the
  • anticancer agent does not comprise a OH, NH or N3 ⁇ 4.
  • Lora-Tamayo et al: (Anales de la Real Sociedad Espanola de Fisica y Quimica,serie B: 62 (12) (1966), pages 1385-1390) describes the synthesis of bis (2-chloroethyl) amino benzamido-3-ethoxycarbonyl- propansulfonamide.
  • the anticancer agent therefrom does not comprise OH, NH or NH2
  • WO 2015/025283 is directed towards nimorazol derivatives however, nimorazol itself does not have an OH, NH, or NH2 group.
  • FR 2 489 825 Al discloses derivatives of oxazaphosphorines
  • the anticancer agent therefrom does not comprise OH, NH or NH2
  • WO 2012/087115 discloses sulfonamides.
  • the compounds without the sulfonamide are not anticancer agents.
  • A is an anticancer agent comprising at least one OH group or one NH group
  • n 1-12;
  • R 1 is SO 2 NR2R3, OSO 2 NR2R3, NR3 ⁇ 4O 2 NR 2 R3, NR3 ⁇ 4O 2 -phenyl, aryl substituted with SO 2 NR 2 R 3 , aryl substituted with OSO 2 NR 2 R 3 , aryl substituted with NR 7 SO 2 NR 2 R 3 ;
  • R 2 , R 3 is each independently hydrogen, halo, hydroxy, or Ci- 6alkyl, wherein the Ci-6alkyl is optionally substituted with with a substituent selected from the group comprising halo, hydroxy, amino, nitro, carbonyl,, cyano, or a leaving group;
  • R 4 , R 5 , R 6 , R 7 is each independently hydrogen, halo, hydroxy, or
  • R 8 and R 9 is each independently a Ci-i 2 alkyl, or C 2 -i 2 alkenyl
  • R 10 is hydrogen, Ci- 2 oalkyl, or C 2 . 2 oalkenyl, aryl, aminoCi-i 2 alkyl, carbonylCi-i 2 alkyl, hydroxy Ci-6alkyl, C i-6alkyloxy C i.6alkyl, or NR 4 R 5 ;
  • anticancer agent is a compound that has antiproliferative activity.
  • Anticancer agent include chemother apeutic agents, and agents used for targeted therapy or
  • Alkylating agents are the oldest group of chemotherapeutics in use today. Originally derived from mustard gas used in World War I, there are now many types of alkylating agents in use. They are so named because of their ability to alkylate many molecules, including proteins, RNA and DNA. This ability to bind covalently to DNA via their alkyl group is the primary cause for their anti-cancer effects. DNA is made of two strands and the molecules may either bind twice to one strand of DNA (intrastrand crosslink) or may bind once to both strands (interstrand crosslink). If the cell tries to replicate crosslinked DNA during cell division, or tries to repair it, the DNA strands can break. This leads to a form of programmed cell death called apoptosis. Alkylating agents will work at any point in the cell cycle and thus are known as cell cycle-independent drugs. For this reason the effect on the cell is dose dependent; the fraction of cells that die is directly proportional to the dose of drug.
  • alkylating agents are the nitrogen mustards, nitrosoureas, tetrazines, aziridines, and derivatives, and non-classical alkylating agents.
  • Nitrogen mustards include cyclophosphamide,
  • Nitrosoureas include N-Nitroso-N- methylurea (MNU), carmustine (BCNU), lomustine (CCNU) and semustine (MeCCNU), fotemustine and streptozotocin.
  • MNU N-Nitroso-N- methylurea
  • BCNU carmustine
  • CCNU lomustine
  • MeCCNU semustine
  • fotemustine and streptozotocin N-Nitroso-N- methylurea
  • BCNU carmustine
  • CCNU lomustine
  • MeCCNU semustine
  • fotemustine and streptozotocin streptozotocin.
  • SN 30444 (2-[bis(2- bromoethyl)amino]-N-(2-hydroxyethyl)-5-nitrobenzamide)
  • Chlorine- derivative of SN 30444 (2-[bis(2-chloroethyl)amino]-N-(2-hydroxyethyl)-5
  • NTR nitroreductase
  • Tetrazines include dacarbazine, mitozolomide and temozolomide.
  • Aziridines include thiotepa, mytomycin and diaziquone (AZQ).
  • Cisplatin and derivatives include cisplatin, carboplatin and oxaliplatin. They impair cell function by forming covalent bonds with the amino, carboxyl, sulfhydryl, and phosphate groups in biologically important molecules.
  • Non-classical alkylating agents include procarbazine and hexamethylmelamine.
  • cancer cells in general, proliferate faster and with less error-correcting than healthy cells, cancer cells are more sensitive to DNA damage—such as being alkylated.
  • Alkylating agents are used to treat several cancers. However, they are also toxic to normal cells (cytotoxic), leading to damage, in particular in cells that divide frequently, as those in the gastrointestinal tract, bone marrow, testicles and ovaries, which can cause loss of fertility. Most of the alkylating agents are also carcinogenic. Dialkylating agents can react with two different 7-N-guanine residues, and, if these are in different strands of DNA, the result is cross-linkage of the DNA strands, which prevents uncoiling of the DNA double helix. If the two guanine residues are in the same strand, the result is called limpet attachment of the drug molecule to the DNA.
  • Monoalkylating agents can react only with one 7-N of guanine.
  • Limpet attachment and monoalkylation do not prevent the separation of the two DNA strands of the double helix but do prevent vital DNA-processing enzymes from accessing the DNA.
  • the final result is inhibition of cell growth or stimulation of apoptosis, cell suicide.
  • Anti-metabolites are a group of molecules that impede DNA and
  • RNA synthesis Many of them have a similar structure to the building blocks of DNA and RNA.
  • the building blocks are nucleotides; a molecule comprising a nucleobase, a sugar and a phosphate group.
  • the nucleobases are divided into purines (guanine and adenine) and pyrimidines (cytosine, thymine and uracil).
  • Anti-metabolites resemble either nucleobases or nucleosides (a nucleotide without the phosphate group), but have altered chemical groups.
  • These drugs exert their effect by either blocking the enzymes required for DNA synthesis or becoming incorporated into DNA or RNA. By inhibiting the enzymes involved in DNA synthesis, they prevent mitosis because the DNA cannot duplicate itself.
  • Subtypes of the anti-metabolites are the anti -folates
  • fluoropyrimidines deoxynucleoside analogues and thiopurines.
  • the anti-folates include methotrexate and pemetrexed.
  • Methotrexate inhibits dihydrofolate reductase (DHFR), an enzyme that regenerates tetrahydrofolate from dihydrofolate.
  • DHFR dihydrofolate reductase
  • the enzyme is inhibited by methotrexate, the cellular levels of folate coenzymes diminish. These are required for thymidylate and purine production, which are both essential for DNA synthesis and cell division.
  • Pemetrexed is another anti- metabolite that affects purine and pyrimidine production, and therefore also inhibits DNA synthesis.
  • the fluoropyrimidines include fluorouracil and
  • Fluorouracil is a nucleobase analogue that is metabolised in cells to form at least two active products; 5-fluourouridine monophosphate (FUMP) and 5-fluoro-2'-deoxyuridine 5'-phosphate (fdUMP). FUMP becomes incorporated into RNA and fdUMP inhibits the enzyme thymidylate synthase; both of which lead to cell death.
  • Capecitabine is a prodrug of 5- fluorouracil that is broken down in cells to produce the active drug.
  • the deoxynucleoside analogues include cytarabine, gemcitabine, decitabine, Vidaza, fludarabine, nelarabine, cladribine, clofarabine and pentostatin.
  • the thiopurines include thioguanine and mercaptopurine.
  • Anti-microtubule agents are plant-derived chemicals that block cell division by preventing microtubule function.
  • Microtubules are an important cellular structure composed of two proteins; a-tubulin and 6- tubulin. They are hollow rod shaped structures that are required for cell division, among other cellular functions.
  • Microtubules are dynamic structures, which means that they are permanently in a state of assembly and disassembly.
  • Vinca alkaloids and taxanes are the two main groups of anti-microtubule agents, and although both of these groups of drugs cause microtubule disfunction, their mechanisms of action are completely opposite. The vinca alkaloids prevent the formation of the microtubules, whereas the taxanes prevent the microtubule disassembly.
  • these drugs can affect blood vessel growth; an essential process that tumours utilise in order to grow and metastasise.
  • Vinca alkaloids are derived from the Madagascar periwinkle, Catharanthus roseus (formerly known as Vinca rosea). They bind to specific sites on tubulin, inhibiting the assembly of tubulin into microtubules.
  • the original vinca alkaloids are completely natural chemicals that include vincristine and vinblastine.
  • semisynthetic vinca alkaloids were produced: vinorelbine, vindesine, and vinflunine.
  • vinorelbine vindesine
  • vinflunine are cell cycle -specific. They bind to the tubulin molecules in S-phase and prevent proper microtubule formation required for M-phase.
  • Taxanes are natural and semi-synthetic drugs.
  • the first drug of their class, paclitaxel was originally extracted from the Pacific Yew tree, Taxus brevifolia. Now this drug and another in this class, docetaxel, are produced semi-synthetically from a chemical found in the bark of another Yew tree; Taxus baccata. These drugs promote microtubule stability, preventing their disassembly. Paclitaxel prevents the cell cycle at the boundary of G2-M, whereas docetaxel exerts its effect during S-phase.
  • Taxanes present difficulties in formulation as medicines because they are poorly soluble in water.
  • Podophyllotoxin is an anti-neoplastic lignan obtained primarily from the American Mayapple (Podophyllum peltatum) and Himalayan Mayapple (Podophyllum hexandrum or Podophyllum emodi). It has anti- microtubule activity, and its mechanism is similar to that of vinca alkaloids in that they bind to tubulin, inhibiting microtubule formation.
  • Podophyllotoxin is used to produce two other drugs with different mechanisms of action: etoposide and teniposide.
  • Topoisomerase inhibitors are drugs that affect the activity of two enzymes: topoisomerase I and topoisomerase II.
  • topoisomerase I and topoisomerase II When the DNA double- strand helix is unwound, during DNA replication or transcription, for example, the adjacent unopened DNA winds tighter (supercoils), like opening the middle of a twisted rope. The stress caused by this effect is in part aided by the topoisomerase enzymes. They produce single- or double- strand breaks into DNA, reducing the tension in the DNA strand. This allows the normal unwinding of DNA to occur during replication or transcription. Inhibition of topoisomerase I or II interferes with both of these processes.
  • topoisomerase I inhibitors are semi-synthetically derived from camptothecin, which is obtained from the Chinese ornamental tree Camptotheca acuminata.
  • Drugs that target topoisomerase II can be divided into two groups.
  • the topoisomerase II poisons cause increased levels enzymes bound to DNA. This prevents DNA replication and transcription, causes DNA strand breaks, and leads to programmed cell death (apoptosis).
  • These agents include etoposide, doxorubicin, mitoxantrone and teniposide.
  • the second group, catalytic inhibitors are drugs that block the activity of topoisomerase II, and therefore prevent DNA synthesis and translation because the DNA cannot unwind properly. This group includes novobiocin, merbarone, and
  • the cytotoxic antibiotics are a varied group of drugs that have various mechanisms of action.
  • the group includes the anthracyclines and other drugs including actinomycin, bleomycin, plicamycin, and mitomycin.
  • Doxorubicin and daunorubicin were the first two anthracyclines, and were obtained from the bacterium Streptomyces peucetius. Derivatives of these compounds include epirubicin and idarubicin.
  • Other clinically used drugs in the anthracyline group are pirarubicin, aclarubicin, and mitoxantrone.
  • the mechanisms of anthracyclines include DNA intercalation (molecules insert between the two strands of DNA), generation of highly reactive free radicals that damage intercellular molecules and topoisomerase inhibition.
  • Actinomycin is a complex molecule that intercalates DNA and prevents RNA synthesis.
  • Bleomycin a glycopeptide isolated from Streptomyces verticillus, also intercalates DNA, but produces free radicals that damage DNA. This occurs when bleomycin binds to a metal ion, becomes chemically reduced and reacts with oxygen.
  • Mitomycin is a cytotoxic antibiotic with the ability to alkylate DNA.
  • Targeted agents or agents for targeted cancer therapies are drugs or other substances that block the growth and spread of cancer by
  • Targeted cancer therapies are sometimes called “molecularly targeted drugs,” “molecularly targeted therapies,” “precision medicines,” or similar names.
  • Targeted therapies differ from standard chemotherapy in that targeted therapies act on specific molecular targets that are associated with cancer, whereas most standard chemotherapies act on all rapidly dividing normal and cancerous cells.
  • targeted therapies are deliberately chosen or designed to interact with their target, whereas many standard chemotherapies were identified because they kill cells.
  • targeted therapies are often cytostatic (that is, they block tumour cell proliferation), whereas standard
  • chemotherapy agents are cytotoxic (that is, they kill tumour cells).
  • HER-2 Several targeted therapies are directed against HER-2, including trastuzumab (Herceptin®), which is approved to treat certain breast and stomach cancers that overexpress HER-2.
  • trastuzumab Herceptin®
  • the cell growth signaling protein BRAF is present in an altered form (known as BRAF V600E) in many melanomas.
  • Vemurafenib targets this mutant form of the BRAF protein and is approved to treat patients with inoperable or metastatic melanoma that contains this altered BRAF protein.
  • Targeted therapy includes small molecles and monoclonal antibodies.
  • the targeted agent include small molecules and not monoclonal antibodies.
  • Targeted agents may include tyrosine kinase inhbitors, ALK inhibitors, PARP inhibitors, Phosphoinositide 3-kinase inhibitors, VEGF receptor inhibitors, MEK inhibitors, CDK inhibitors, Hsp90 inhibitors, folate receptor targeting agents, serine/threonine kinase inhbitors, FGFR tyrosine kinase inhibitors, mTOR inhibitor, Bcl2 inhibitor, EZH2 inhibitor, Notch inhibitors, ATM inhibitors, MELK inhibitors, EGF receptor inhibititors.
  • the present invention is directed to compound having formula A-L-R 1 .
  • A is an anticancer agent comprising at least one group selected from the group comprising OH, NH and N3 ⁇ 4. It is to be understood that anticancer agent A comprises a OH, NH or N3 ⁇ 4 when in the original state and not being connected to L-R 1 or R 1 .
  • the linking of L-R 1 or R 1 is on the position of the OH, NH, NH2 of A. Such linking depends on the nature of A, whether it is an OH, or NH/NH2 and depends further on L and R 1 .
  • A is connected to either L-R 1 or R 1 via the O or N of OH, NH or NH2 and effectively replaces (one of) the hydrogen on OH, NH, or N3 ⁇ 4
  • L-R 1 or R 1 replaces the OH.
  • the L-R 1 or R 1 then comprises a NH group and this NH group replaces the OH group of active agent A.
  • examples are compounds 10, 11, 12, 56, 58,
  • Examples are compounds 13, 14, 15, 59
  • A comprises a O, NH, or N group that is linked to either L-R 1 or R 1 in case L is a direct bond.
  • the L may be substituted on O of OH or on N of NH or NH2 of A and wherein in the case L is a direct bond R 1 may be substituted on O of OH or on N of NH or NH2 of A.
  • anticancer agent A may be connected to either L-R 1 or R 1 via a N atom from a NH or NH2 group or via a O atom from an OH comprised in the original anticancer agent A.
  • the OH, NH or NH2 of A is present in the original anticancer agent, meaning before being linked to L-R 1 or R 1 .
  • A is connected to either L or R 1 at least one of the hydrogens is no longer present and A comprises a O, NH, or N group that is linked to either L-R 1 or R 1 in case L is a direct bond.
  • the linking of A to L-R 1 or R 1 may also occur by replacing the OH group of A by a NH2 group or by NH group from e.g. L or R 1 . See for examples compounds 10, 20-27.
  • a skilled person is well aware of how to link L or R 1 to A via a OH, NH, or NH2.
  • L is substituted on N of NH or NH2 of A and wherein in the case L is a direct bond R 1 is substituted on N of NH or NH2 of A.
  • R 1 is substituted on N of NH or NH2 of A.
  • L is a direct bond
  • L is substituted on the O of OH of A or L replaces OH of A, or wherein in the case L is a direct bond R 1 is substituted on O of OH of A, or R 1 replaces OH of A,
  • L is substituted on the O of OH of A or L replaces OH of A, or wherein in the case L is a direct bond R 1 is substituted on O of OH of A.
  • L replaces OH of A, or wherein in the case L is a direct bond R 1 replaces OH of A.
  • A is a nucleoside or nucleoside derivative.
  • L is substituted on the O of OH in sugar group of A or L replaces OH of the sugar group of A, or wherein in the case L is a direct bond R 1 is substituted on O of OH of sugar group of A, or R 1 replaces OH of the sugar group of A,
  • A comprises a N3 ⁇ 4 group.
  • the original anticancer agent A comprises a N3 ⁇ 4.
  • the compound of the present invention comprises an anticancer agent A comprising a NH linked to L-R 1 or to R 1 in the case L is a direct bond.
  • the NH group of the original compound A is not part of a
  • NH being part of a ringstructure means that the N of NH participates in the ring, such as in pyrimidine or imidazole.
  • A is an anticancer agent selected from the group comprising Alkylating agents, Anti-metabolites, Anti-microtubule agents, Topoisomerase inhibitors, Cytotoxic antibiotics, targeted agents, DNA repair inhibitors, and antiviral drugs having antiproliferative effect.
  • alkylating agents may be nitrogen mustards, nitrobenzamide mustards, nitrosoureas, tetrazines, aziridines, and derivatives thereof.
  • Nitrogen mustards include cyclophosphamide, melphalan, chlorambucil, ifosfamide, and prodrugs like SN 30444 (2-[bis(2-bromoethyl)amino]-N-(2- hydroxyethyl)-5-nitrobenzamide) Chlorine-derivative of SN 30444 (2-[bis(2- chloroethyl)amino]-N-(2-hydroxyethyl)-5-nitrobenzamide).
  • Nitrosoureas include N-Nitroso-N-methylurea (MNU), carmustine (BCNU), lomustine (CCNU) and semustine (MeCCNU), fotemustine and streptozotocin.
  • Tetrazines include dacarbazine, mitozolomide and temozolomide.
  • Aziridines include thiotepa, mytomycin and diaziquone (AZQ).
  • Non-classical alkylating agents include procarbazine and hexamethylmelamine.
  • suitable alkylating agents may be selected from the group consisting of Cyclophosphamide, , Uramustine or uracil mustard, Melphalan, Chlorambucil, SN 30444 (2- [bis(2-bromoethyl)amino]-N-(2-hydroxyethyl)-5-nitrobenzamide) Chlorine- derivative of SN 30444 (2-[bis(2-chloroethyl)amino]-N-(2-hydroxyethyl)-5- nitrobenzamide), Ifosfamide, Bendamustine, Nitrosoureas , PCNU,
  • Anti-metabolites may be divided into subtypes such as the anti- folates, fluoropyrimidines, deoxynucleoside analogues and thiopurines.
  • the anti-folates include methotrexate and pemetrexed.
  • the fluoropyrimidines include fluorouracil and capecitabine which is a prodrug of fluorouracil.
  • the deoxynucleoside analogues include cytarabine, gemcitabine, decitabine, Vidaza, fludarabine, nelarabine, cladribine, clofarabine and pentostatin.
  • the thiopurines include thioguanine and mercaptopurine.
  • nucleosides are substituted on the OH of the sugar moeiety with either L or R 1 in case L is a direct bond.
  • Suitable anti-metabolites may be methotrexate, methotrexate derivatives, NSC 174121, NSC 132483, NSC 184692, NSC 134033,
  • NSC623017 and pemetrexed, Trimetrexate, fluorouracil and
  • the thiopurines include thioguanine and mercaptopurine, Alanosine, Acivicin, Baker's Antifol soluble, Dichloroallyl lawsone, PALA, 3- HP, 5-HP, alpha-TGdR, beta- TGdR Aphidicolin glycinate, ancitabine hydrochloride, Guanazole, Hydroxyurea, Inosine dialdehyde, Macbecin II, Imidazole-Pyrazole, Thioguanine , 6 -Mercaptopurine.
  • Anti-microtubule agents may be vinca alkaloids and taxanes, or podophyllotoxin and derivatives therof. Suitable anti-microtubule and antimitotic agents are Vinca alkaloids and taxanes, vinorelbine, vindesine, and vinflunine, vinblastine, vincristine,, vincaminol, vincamajine,
  • Topoisomerase inhibitors may be divided into Topoisomerase I and II Inhibitors. Suitable topoisomerase inhibitors are irinotecan and topotecan, etoposide, doxorubicin, mitoxantrone and teniposide, novobiocin, merbarone, and aclarubicin. Suitable topoisomerase I inhibitors may be selected from the the group consisting of camptothecin, 9-amino
  • NSC295500 7-Chlorocamptothecin, camptothecin derivative NSC606985, Camptothecin derivative NSC374028, Camptothecin derivative NSC374028, 9-methoxycamptothecin, camptothecin derivative NSC295501, camptothecin derivative NSC606172, camptothecin derivative NSC606173, Camptothecin phosphate, Camptothecin lysinate HC1, Camptothecin glutamate,
  • esterhydrochloride and morpholinoadriamycin.
  • Suitable Topoisomerase II inhibitors may be selected from the group consisting of Amonafide, Amsacrine, anthrapyrazole ,
  • Cytotoxic antibiotics include the anthracyclines and other drugs including actinomycin, bleomycin, plicamycin, and mitomycin. Suitable cytotoxic antibiotics are anthracyclines actinomycin, bleomycin, plicamycin, and mitomycin. Doxorubicin daunorubicin,
  • pirarubicin pirarubicin, aclarubicin, and mitoxantrone, epirubicin, idarubicin,
  • Targeted agents or agents for targeted cancer therapies are drugs or other substances that block the growth and spread of cancer by
  • Suitable targets are tyrosine kinase, JAK (Janus kinase), ALK (anaplastic lymphoma kinase), PARP (poly ADP ribose polymerase), Phosphoinositide 3-kinase, VEGF receptor, B-Raf, MEK, CDK, Hsp90, folate receptor, Serine/threonine kinase, FGFR tyrosine kinase, mTOR, Bcl2, Notch, ATM (Ataxia telangiectasia mutated) kinase, MELK (maternal embryonic leucine zipper kinase), EGF receptor and EZH2.
  • Tyrosine kinase inhibitors are suitable targeted agents. Suitable tyrosine kinase inhibitors are imatinib mesylate Gefitinib, Erlotinib hydrochloride, Sorafenib, Sunitinib, Dasatinib, Lapatinib, Nilotinib,
  • Suitable Janus kinase (JAK) inhibitors are CYT387, Lestaurtinib, Pacritinib, and famitinib .
  • Suitable JAK-2 inhibitor is chloroquine which inhibits autophagy.
  • Suitable ALK inhibitors are Alectinib, AP26113, nerviano, PF- 06463922, CEP-37440, and X-396.
  • Suitable PARP inhibitor are olaparib iniparib, BMN-673, rucaparib, veliparib, CEP 8983, MK4827, 3-aminobenzamide, and AZD2461.
  • Suitable Phosphoinositide 3-kinase inhibitor are idelalisib, PX- 866, IPI- 145, BAY 80-6946, SF1126, GDC 0941, buparlisib, XL147, XL765, palomid 529, IC-87114, TG100-115, PI 103, GNE 477, and CUDC-907.
  • Suitable VEGF receptor inhibitors are apatinib, lenvatinib, motesanib, and Regorafenib.
  • Suitable B-Raf inhibitor are vemurafenib, dabrafenib, LGX818, sorafenib, PLX4720, and GDC-0879.
  • Suitable MEK inhibitors are trametinib, selumetinib, binimetinib, PD-325901, cobimetinib, and CI-1040,.
  • Suitable CDK inhibitors are Palbociclib and LEEO 11.
  • Suitable Hsp90 inhibitors are Geldanamycin, radicicol, and tanespimycin.
  • Suitable Folate receptor targeting agent is vintafolide.
  • Suitable Serine/threonine kinase inhibitor are temsirolimus and everolimus.
  • Suitable FGFR tyrosine kinase inhibitor is AZD4547.
  • Suitable mTOR inhibitor is AZD8055
  • Suitable Bcl2 inhibitors are navitoclax, Obatoclax, and gossypol.
  • Suitable EZH2 inhibitor is GSK126.
  • Suitable Notch inhibitors are MK0752, gamma-secretase inhibitors, DAPT (N-[N-(3,5-Difluorophenylacetyl-L-alanyl)]-S- phenylglycine t-Butyl ester), Lilly GSI L685,458, compound E ((s,s)-2-(3,5- Difluorophenyl)-acetylamino]-N-(l-methyl-2-oxo-5-phenyl-2,3-dihydro- lH- benzo[e] [l,4]diazepin-3-yl)-propionamide), diazepine-type structures, DBZ (dibenzazepine), JLK6 (7-amino-4-chloro-3-methoxyisocoumarin),
  • annulen-l l-yl)-thiophene-2 -sulfonamide alpha-secretase inhibitors
  • BMS-708163 Alpha-secretase inhibitors
  • gamma secretase modulator 3 gamma secretase modulator 2
  • gamma secretase modulator 1 RO4929097
  • Semagascestat LY450139
  • MK0752 MK0752
  • LY411575 LY2811376
  • Flurizan MRK560, L-685,458, Begacestat, TC-E-5006, PF3084014, LY3039478, LY900009, E2012, compound W, BMS 299897, FLI-06.
  • Suitable ATM (Ataxia telangiectasia mutated) kinase inhibitors are CP 466722, KU-60019, VE-821, VE-822, Torin 2, Mirin (CAS 299953-00- 7).
  • Suitable MELK (maternal embryonic leucine zipper kinase) inhibitor is OTSSP 167 (CAS#1431697-89-0).
  • Suitable EGF receptor inhibitor is PR610E, or its hypoxia activated prodrug Hypoxia, formally known as PR610, afatinib, gefitinib.
  • A is not a compound selected from the group
  • Tyrosine kinase inhibitors consisting of Tyrosine kinase inhibitors, JAK inhibitors, VEGF receptor inhibitors, B-Raf inhibitors, MEK inhibitors, PARP inhibitors,
  • Phosphoinositide 3-kinase inhibitors Hsp90 inhibitors, folate receptor targeting agents, serine/threonine kinase inhibitors, FGFR tyrosine kinase inhibitors, ALK inhibitorss, Bcl2 inhibitors, and EZH2 inhibitors.
  • A is not a compound selected from the group
  • Tyrosine kinase inhibitors consisting Tyrosine kinase inhibitors, JAK inhibitors, VEGF receptor inhibitors, B-Raf inhibitors, Hsp90 inhibitors, folate receptor targeting agents, serine/threonine kinase inhibitors, FGFR tyrosine kinase inhibitors, and Bcl2 inhibitors.
  • A is selected from the group consisting ALK inhibitors, PARP inhibitors, Phosphoinositide 3-kinase inhibitors, CDK inhibitors, mTOR inhibitors, MELK, inhibitors, ATM inhibitor, EZH2 inhibitors, EGFR inhibitors.
  • A is selected from the group consisting CDK
  • inhibitors and mTOR inhibitors, MELK inhibitors, ATM inhibitors, EGFR inhibitors. .
  • A is selected from the group consisting CDK
  • A is selected from the group consisting MELK inhibitors, ATM inhibitors.
  • A is CDK inhibitors.
  • A is mTOR inhibitor.
  • A is a MELK inhibitor.
  • A is an ATM inhibitor.
  • A is an EGFR inhibitor.
  • the LHRH receptor (gonadotropin-releasing hormone receptor) inhibitors such as AEZS-108 are not suitable.
  • A is a targeted agent.
  • A is selected from the group consisting of nerviano, tirapazemin, tirapazamin derivative, 7,8-dihydro-6H-indeno[5,6- e][l,2,4]triazine 1-oxide, chlorambucil, bromine-derivative of chlorambucil, VE-821, VE-822, SN 30444 (2-[bis(2-bromoethyl)amino]-N-(2-hydroxyethyl)- 5-nitrobenzamide) Chlorine-derivative of SN 30444 (2-[bis(2- chloroethyl)amino]-N-(2-hydroxyethyl)-5-nitrobenzamide), cidofovir, cyclophosphamide, bromine-derivative of cyclophosphamide, MK0752, PR610, PR610E, chloroquine, PF03084014, temozolomide, CP4667
  • A is selected from the group consisting of nerviano, dasatinib, CEP-37440, PF-06463922, iniparib, 3 aminobenzamide, BAY 80- 6946, Buparlisib, PI-103, Palomid 527, IC-87114, GNE 477, CUDC-907, Selumetinib, binimetinib, AZD8055, palbociclib, LEE011, Lestaurtinib, veliparib, MK4827, GCD-0879, MK0752, and GSK126.
  • A is selected from the group consisting of nerviano, dasatinib, CEP-37440, PF-06463922, iniparib, 3 aminobenzamide, BAY 80- 6946, Buparlisib, PI-103, Palomid 527, IC-87114, GNE 477, CUDC-907, Selumetinib, binimetinib, AZD8055, palbociclib, LEE011.
  • A is selected from the group consisting of nerviano, dasatinib, CEP-37440, PF-06463922, iniparib, 3 aminobenzamide, BAY 80- 6946, Buparlisib, PI-103, Palomid 527, IC-87114, GNE 477, CUDC-907, Selumetinib, binimetinib, AZD8055, palbociclib, LEE011, tirapazemin, tirapazamin derivative, 7,8-dihydro-6H-indeno[5,6-e][l,2,4]triazine 1-oxide, chlorambucil, bromine-derivative of chlorambucil, VE-821, VE-822, SN 30444, Chlorine-derivative of SN 30444, cidofovir, cyclophosphamide, bromine-derivative of cyclophosphamide, bromine-derivative of cyclophos
  • A is selected from the group consisting of tirapazemin, tirapazamin derivative, 7,8-dihydro-6H-indeno[5,6-e][l,2,4]triazine 1-oxide, chlorambucil, bromine-derivative of chlorambucil, VE-821, VE-822, SN 30444, Chlorine-derivative of SN 30444, cidofovir, cyclophosphamide, bromine-derivative of cyclophosphamide, MK0752, Notch inhibitor, temozolomide, CP466722, Torin 2, OTSSP167 (CAS#1431697-89-0 ), PR610, PR610E, chloroquine, PF03084014.
  • A is not a compound selected from the group
  • A is not ABT-737.
  • A is selected from the group comprising Alkylating agents, anti-metabolites, topoisomerase I inhibitors, and targeted agents. In a preferred embodiment of the present invention and/or embodiments thereof, A is selected from the group comprising alkylating agents and targeting agents.
  • A is an anticancer agent that does not comprise a nitro-imidazol group.
  • A is not a nitrosourea, taxane, vinca alkaloid, anthracycline, podophyllotoxin, or podophyllotoxin derivatives.
  • A is a Tetrazine or a
  • nitrogenmustard In a preferred embodiment of the invention and/or embodiments thereof A is not hepsulfam In a preferred embodiment of the invention and/or embodiments thereof A is selected from the group consisting of Tirapazamin, tirapazamin derivative, 7,8-dihydro-6H-indeno[5,6-e] [l,2,4]triazine 1-oxide,
  • chlorambucil bromine derivative of chlorambucil, MK0752, VE-821, VE- 822, cyclophosphamide, bromine derivative of cyclophosphamide, mephalan, bromine derivative of mehphalan, torin 2, OTSSP167 ((CAS#1431697-89-0 ), PR610, PR610E, chloroquine, PF03084014, bendamustine, procarbazine, dacarbazine, mitozolomide, temozolomide, SN 30444, chlorine derivative of SN 30444, ariziridinylbenzoquinone (NSC 182986), dianhydrogalactitol, hycanthone methanesulfonate, ethylnitrosourea, acivicin, hydroxyurea, nitrosourea, imidazole-pyazole, 3-tritylthio-L-alanine, mitoxantrone, camptothe
  • A is selected from the group consisting Tirapazamin, tirapazamin derivative, 7,8-dihydro-6H-indeno[5,6-e] [l,2,4]triazine 1-oxide,
  • A is selected from the group consisting Tirapazamin, tirapazamin derivative, 7,8-dihydro-6H-indeno[5,6-e] [l,2,4]triazine 1-oxide,
  • A is selected from the group consisting Tirapazamin, tirapazamin derivative, 7,8-dihydro-6H-indeno[5,6-e] [l,2,4]triazine 1-oxide chlorambucil, VE-821, VE-822, cyclophosphamide, bromine derivative of
  • cyclophosphamide mephalan bromine derivative of mephalan, bromine derivative of chlorambucil, MK0752, OTSSP 167 ((CAS#1431697-89-0 ), PR610, PR610E, chloroquine, PF03084014, bendamustine, procarbazine, mitozolomide, temozolomide, SN 30444, chlorine derivative of SN 30444, torin 2, ariziridinylbenzoquinone (NSC 182986), hycanthone
  • methanesulfonate ethylnitrosourea, acivicin, hydroxyurea, nitrosourea, imidazole-pyazole, 3-tritylthio-L-alanine, mitoxantrone, camptothecin, 9- amino camptothecin, 10-hydroxycamptothecin, 14-chloro-20(S)- camptothecin hydrate, 9-amino-20-(R,S)-camptothecin, 7- chlorocamptothecin, NSC606985, NSC374028, 9-methoxycamptothecin, NSC295501, NSC606172, NSC606173, campthothecin lysinate HC1, camptothecin glutamate, camptothecinhemisuccinate, amonafide, cidofovir, aphidicolin glycinate, 3-demethylthiocolchine, irinotecan, toptecan, campto
  • A is selected from the group consisting Tirapazamin, tirapazamin derivative, 7,8-dihydro-6H-indeno[5,6-e] [l,2,4]triazine 1-oxide,
  • A is not a compound selected from the group consisting of Improsan, ifosfamide, spiromustine, N-(2-Chloroethyl)-N'-(2,6-dioxo-3-piperidinyl)-N- nitrosourea (PCNU), peperazinedione (NSC- 135758), semustine,
  • pyrazoloacridine bisantrene, daunorubicin, deoxorubicin, menogaril, N,N- Dibenzyldaunorubicin hydrochloride, zorobicin, VM-26, VP- 16, epirubicin, idarubicin, valrubicin, actinomycin, bleomycin, plicamycin, mitomycin C, pirarubicin, Mithramycin, imatinib mesylate Gefitinib, Erlotinib
  • hydrochloride Sorafenib, Sunitinib, Lapatinib, Nilotinib, Bortezomib, tamoxifen, Pacritinib, and famitinib, CYT387, Alectinib, AP26113, X-396, ABT-737, Obatoclax, and gossypol, BMN-637, olaparib, rucaparib, CEP 8983, idelalisib, PX-866, IPI- 145, GDC-0941, SF 1126, XL 147, XL 765, TG100- 115, AZD2461, apatinib, lenvatinib, motesanib, and Regorafenib.
  • vemurafenib vemurafenib, dabrafenib, LGX818, sorafenib, PLX4720, PD-325901, cobimetinib, CI- 1040, trametinib, Geldanamycin, radicicol,
  • tanespimycin famitinib, salinomycin, vintafolide, temsirohmus, everolimus. AZD4547, and navitoclax,
  • A has 6 or less ring structures, preferably 5 or less, preferably 4 or less, preferably 3 or less, preferably 2 or less, preferably 1 ring structure.
  • A has a maximum of 6 ring structures, preferably a maximum of 5 ring structures, preferably a maximum of 4 ring structures, preferably a maximum of 3 ring structures, preferably a maximum of 2 ring structures.
  • a ring or ring structure is a cyclic structure comprising 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 15, 16, 18, 20, 22, 24, 26, 28, 30, 34, 36, 38, 40 or more atoms.
  • a ring or ring structure may be aromatic, saturated, partially unsaturated, or
  • the ring may be a carbon ring, wherein the atoms of the ring are all carbon atoms.
  • the ring may also be a hetero cycle wherein at least one of the atoms in the ring is a hetero atom such as O, N, P, or S, and the remainder being carbon atoms. Preferred hetero cycles are hetero cycles with O or N.
  • the rings may be fuses as in anthracene, naphthalene and quinoline. For single rings, i.e. not fused, the ring preferably comprise 4, 5, 6, 7, or 8 atoms, more preferably, 5 or 6 atoms.
  • the individual rings that are fused comprise each preferably 3, 4, 5, 6, 7, or 8 atoms, more preferably, 4, 5, or 6 atoms, more preferably 5 or 6 atoms.
  • the total number of atoms that are present in a ring is less than 40, more preferably less than 36, more preferably less than 30, more preferably less than 26, more preferably less than 22, more preferably less than 18, more preferably less than 16, more preferably less than 14, more preferably less than 12.
  • A does not comprise a sulfonamide, sulfamide, or a sulfamate group. It is to be understood that the original anticancer agent A preferably does not comprise a sulfonamide, sulfamide, or a sulfamate group.
  • sulphonamide is a SO2NR2 group
  • a sulfamate is a O-SO2NR2 group
  • a sulfamide is a NRSO2NR2 group, wherein R is a substituent such as hydrogen, halogen, alkyl.
  • A has a molecular weight of less than 1500 D, preferably less than 1200 D, preferably less than 1000 D, more preferably less than 800 D, more preferably less than 700 D, more preferably less than 600 D, more
  • A has a molecular weight from 150 D to 1200 D, more preferably from 180 D to 1000 D, more preferably from 200 D to 800 D, more preferably from 250 D to 700 D, more preferably from 300 D to 600 D, more preferably from 350 D to 500 D, more preferably from 400 D to 450 D, more preferably from 180 D to 1000 D, more preferably from 180 D to 750 D, more preferably from 180 D to 550 D, more preferably from 180 D to 500 D, more preferably from 180 D to 450 D.
  • the compound has a molecular weight of less than 1600 D, preferably less than 1400 D, preferably less than 1200 D, more preferably less than 1000 D, more preferably less than 800 D, more preferably less than 700 D, more preferably less than 600 D, more preferably less than 550 D, more
  • the compound has a molecular weight from 150 D to 1500 D, more preferably from 180 D to 1200 D, more preferably from 200 D to 1000 D, more preferably from 250 D to 800 D, more preferably from 300 D to 700 D, more preferably from 350 D to 600 D, more preferably from 400 D to 500 D, more preferably from 180 D to 1000 D, more preferably from 180 D to 750 D, more preferably from 180 D to 550 D, more preferably from 180 D to 500 D, more preferably from 180 D to 450 D.
  • A has no more than 7 hydrogen bond donors, preferably no more than 6 hydrogen bond donors, preferably no more than 5 hydrogen bond donors, preferably no more than 4 hydrogen bond donors, preferably no more than 3 hydrogen bond donors, preferably no more than 2 hydrogen bond donors.
  • a hydrogen bond donor is a OH or NH group. The number of hydrogen bond donors is expressed as the sum of OH and NH bonds.
  • the compound has no more than 7 hydrogen bond donors, preferably no more than 6 hydrogen bond donors, preferably no more than 5 hydrogen bond donors, preferably no more than 4 hydrogen bond donors, preferably no more than 3 hydrogen bond donors, preferably no more than 2 hydrogen bond donors.
  • A has no more than 15 hydrogen bond acceptors, preferably no more than 14 hydrogen bond acceptors, preferably no more than 12 hydrogen bond acceptors, preferably no more than 10 hydrogen bond acceptors, preferably no more than 9 hydrogen bond acceptors, preferably no more than 8 hydrogen bond acceptors, preferably no more than 7 hydrogen bond acceptors, preferably no more than 6 hydrogen bond acceptors, preferably no more than 5 hydrogen bond acceptors, preferably no more than 4 hydrogen bond acceptors.
  • Hydrogen bond acceptors is expressed as the sum of O and N atoms.
  • the compound has no more than 15 hydrogen bond acceptors, preferably no more than 14 hydrogen bond acceptors, preferably no more than 12 hydrogen bond acceptors, preferably no more than 10 hydrogen bond acceptors, preferably no more than 9 hydrogen bond acceptors, preferably no more than 8 hydrogen bond acceptors, preferably no more than 7 hydrogen bond acceptors, preferably no more than 6 hydrogen bond acceptors, preferably no more than 5 hydrogen bond acceptors, preferably no more than 4 hydrogen bond acceptors.
  • A has a octanol-water partition coefficient LogP of no greater than 7, preferably a LogP of no greater than 6, preferably a LogP of no greater than 5.5, preferably a LogP of no greater than 5, preferably a LogP of no greater than 4.5, preferably a LogP of no greater than 4, preferably a LogP of no greater than 3.5, preferably a LogP of no greater than 3, preferably a LogP of no greater than 2.5, preferably a LogP of no greater than 2, preferably a LogP of no greater than 1.5, preferably a LogP of no greater than 1,
  • A has a octanol-water partition coefficient LogP of less than 7, preferably a LogP of less than 6, preferably a LogP of less than 5.5, preferably a LogP of less than 5, preferably a LogP of less than 4.5, preferably a LogP of less than 4, preferably a LogP of less than 3.5, preferably a LogP of less than 3, preferably a LogP of less than 2.5, preferably a LogP of less than 2, preferably a LogP of less than 1.5,
  • a partition-coefficient (logP) or distribution-coefficient (logD) is the ratio of concentrations of a compound in a mixture of two immiscible phases at equilibrium. These coefficients are a measure of the difference in solubility of the compound in these two phases.
  • A has a octanol- water partition coefficient LogP from -0.9 to +7.0, preferably a LogP from -0.4 to +6.5, preferably a LogP from -0.1 to +6.1, preferably a LogP from +0.1 to +5.9, preferably a LogP from +0.4 to +5.6, preferably a LogP from -0.9 to +5.1, preferably a LogP from +1.2 to +4.8, preferably a LogP from +1.4 to +4.2, preferably a LogP from +1.8 to +3.8, preferably a LogP from +2.2 to +3.5, preferably a LogP from +2.8 to +3.2.
  • the compound has a octanol-water partition coefficient LogP of no greater than 7, preferably a LogP of no greater than 6, preferably a LogP of no greater than 5.5, preferably a LogP of no greater than 5, preferably a LogP of no greater than 4.5, preferably a LogP of no greater than 4, preferably a LogP of no greater than 3.5, preferably a LogP of no greater than 3, preferably a LogP of no greater than 2.5, preferably a LogP of no greater than 2, preferably a LogP of no greater than 1.5, preferably a LogP of no greater than 1, preferably a LogP of no greater than 0.5.
  • LogP of no greater than 7 preferably a LogP of no greater than 6, preferably a LogP of no greater than 5.5, preferably a LogP of no greater than 5, preferably a LogP of no greater than 4.5, preferably a LogP of no greater than 4, preferably a LogP of no greater than 3.5, preferably a LogP of no
  • the compound has a octanol-water partition coefficient LogP of less than 7, preferably a LogP of less than 6, preferably a LogP of less than 5.5, preferably a LogP of less than 5, preferably a LogP of less than 4.5, preferably a LogP of less than 4, preferably a LogP of less than 3.5, preferably a LogP of less than 3, preferably a LogP of less than 2.5, preferably a LogP of less than 2, preferably a LogP of less than 1.5, preferably a LogP of less than 1, preferably a LogP of less than 0.5.
  • LogP of less than 7 preferably a LogP of less than 6, preferably a LogP of less than 5.5, preferably a LogP of less than 5, preferably a LogP of less than 4.5, preferably a LogP of less than 4, preferably a LogP of less than 3.5, preferably a LogP of less than 3, preferably a LogP of less than 2.5, preferably a LogP of
  • the compound has a octanol-water partition coefficient LogP from -0.9 to +7.0, preferably a LogP from -0.4 to +6.5, preferably a LogP from -0.1 to +6.1, preferably a LogP from +0.1 to +5.9, preferably a LogP from +0.4 to +5.6, preferably a LogP from -0.9 to +5.1, preferably a LogP from + 1.2 to +4.8, preferably a LogP from + 1.4 to +4.2, preferably a LogP from + 1.8 to +3.8, preferably a LogP from +2.2 to +3.5, preferably a LogP from +2.8 to +3.2.
  • a octanol-water partition coefficient LogP from -0.9 to +7.0 preferably a LogP from -0.4 to +6.5, preferably a LogP from -0.1 to +6.1, preferably a LogP from +0.1 to +5.9, preferably a LogP from +0.4 to +5.6, preferably a LogP from -0.9 to +
  • A has a Molar refractivity from 20 to 150, preferably a Molar refractivity from 30 to 140, preferably a Molar refractivity from 40 to 130, preferably a Molar refractivity from 50 to 120, preferably a Molar
  • the compound has a Molar refractivity from 20 to 150, preferably a Molar refractivity from 30 to 140, preferably a Molar refractivity from 40 to 130, preferably a Molar
  • refractivity from 50 to 120 preferably a Molar refractivity from 60 to 100, preferably a Molar refractivity from 70 to 90, preferably a Molar refractivity from 75 to 85.
  • A comprises 20 to 70 atoms preferably 25 to 65 atoms, preferably 30 to 60 atoms, preferably 32 to 55 atoms, preferably 35 to 52 atoms, preferably 38 to 50 atoms, preferably 40 to 48 atoms, preferably 42 to 46 atoms, preferably 44 to 45 atoms.
  • the number of atoms includes H-bond donors e.g.;OH's and NH's and H-bond acceptors e.g.; N's and O's.
  • the compound comprises 20 to 70 atoms preferably 25 to 65 atoms, preferably 30 to 60 atoms, preferably 32 to 55 atoms, preferably 35 to 52 atoms, preferably 38 to 50 atoms, preferably 40 to 48 atoms, preferably 42 to 46 atoms, preferably 44 to 45 atoms.
  • A has a polar surface area no greater than 140 A 2 , preferably no greater than 120 A 2 , preferably no greater than 100 A 2 , preferably no greater than 90 A 2 , preferably no greater than 80 A 2 , preferably no greater than 75 A 2 , preferably no greater than 60 A 2 , preferably no greater than 50 A 2 .
  • the polar surface area (PSA) of a molecule is defined as the surface sum over all polar atoms, primarily oxygen and nitrogen, also including their attached hydrogens.
  • the compound has a polar surface area no greater than 140 A 2 , preferably no greater than 120 A 2 , preferably no greater than 100
  • a 2 preferably no greater than 90 A 2 , preferably no greater than 80 A 2 , preferably no greater than 75 A 2 , preferably no greater than 60 A 2 , preferably no greater than 50 A 2 .
  • A comprises not more than 15 rotatable bonds, preferably not more than 12 rotatable bonds, preferably not more than 10 rotatable bonds, preferably not more than 9 rotatable bonds, preferably not more than 8 rotatable bonds, preferably not more than 7 rotatable bonds, preferably not more than 6 rotatable bonds, preferably not more than 5 rotatable bonds, preferably not more than 4 rotatable bonds, preferably not more than 3 rotatable bonds, preferably not more than 2 rotatable bonds.
  • Rotatable bond is defined as any single non-ring bond, bounded to non-terminal heavy (i.e., non-hydrogen) atom.
  • the compound comprises not more than 15 rotatable bonds, preferably not more than 12 rotatable bonds, preferably not more than 10 rotatable bonds, preferably not more than 9 rotatable bonds, preferably not more than 8 rotatable bonds, preferably not more than 7 rotatable bonds, preferably not more than 6 rotatable bonds, preferably not more than 5 rotatable bonds, preferably not more than 4 rotatable bonds, preferably not more than 3 rotatable bonds, preferably not more than 2 rotatable bonds.
  • A has an cell proliferation inhibiting acitivity of less than 10 mM, less than 5 mM, less than 1 mM, less than 100 ⁇ , less than 10 ⁇ , less than 1 ⁇ , less than 100 nM, less than 10 nM, less than 1 nM, less than 100 M, less than 10 pM, less than 1 pM.
  • the proliferation inhibition activity means the lowest concentration wherein 50% of the maximal inhibition of cell proliferation is reached, or wherein 50% inhibition of the biological activity of cancer cells is reached.
  • the 50% of the maximal inhibition of cell proliferation is sometimes referred to as GI50.
  • the 50% inhibition of the biological activity of cancer cells is sometimes referred to as IC50.
  • A has an GI50 of less than 10 mM, less than 5 mM, less than 1 mM, less than 100 ⁇ , less than 10 ⁇ , less than 1 ⁇ , less than 100 nM, less than 10 nM, less than 1 nM, less than 100 pM, less than 10 pM, less than 1 pM.
  • A has an IC50 of less than 10 mM, less than 5 mM, less than 1 mM, less than 100 ⁇ , less than 10 ⁇ , less than 1 ⁇ , less than 100 nM, less than 10 nM, less than 1 nM, less than 100 pM, less than 10 pM, less than 1 pM.
  • A fulfils at least two of the rules defined below .
  • A has a molecular weight of less than 1500 D, preferably less than 1200 D, preferably less than 1000 D, more preferably less than 800 D, more preferably less than 700 D, more preferably less than 600 D, more preferably less than 550 D, more preferably less than 500 D, more
  • A has no more than 7 hydrogen bond donors, preferably no more than 6 hydrogen bond donors, preferably no more than 5 hydrogen bond donors, preferably no more than 4 hydrogen bond donors, preferably no more than 3 hydrogen bond donors, preferably no more than 2 hydrogen bond donors.
  • A has no more than 15 hydrogen bond acceptors, preferably no more than 14 hydrogen bond acceptors, preferably no more than 12 hydrogen bond acceptors, preferably no more than 10 hydrogen bond acceptors, preferably no more than 9 hydrogen bond acceptors, preferably no more than 8 hydrogen bond acceptors, preferably no more than 7 hydrogen bond acceptors, preferably no more than 6 hydrogen bond acceptors, preferably no more than 5 hydrogen bond acceptors, preferably no more than 4 hydrogen bond acceptors.
  • A has a octanol-water partition coefficient LogP of no greater than 7, preferably a LogP of no greater than 6, preferably a LogP of no greater than 5.5, preferably a LogP of no greater than 5, preferably a LogP of no greater than 4.5, preferably a LogP of no greater than 4, preferably a LogP of no greater than 3.5, preferably a LogP of no greater than 3, preferably a LogP of no greater than 2.5, preferably a LogP of no greater than 2, preferably a LogP of no greater than 1.5, preferably a LogP of no greater than 1, preferably a LogP of no greater than 0.5.
  • A has a Molar refractivity from 20 to 150, preferably a Molar refractivity from 30 to 140, preferably a Molar refractivity from 40 to 130, preferably a Molar refractivity from 50 to 120, preferably a Molar
  • refractivity from 60 to 100 preferably a Molar refractivity from 70 to 90, preferably a Molar refractivity from 75 to 85.
  • A comprises 20 to 70 atoms preferably 25 to 65 atoms, preferably 30 to 60 atoms, preferably 32 to 55 atoms, preferably 35 to 52 atoms, preferably 38 to 50 atoms, preferably 40 to 48 atoms, preferably 42 to 46 atoms, preferably 44 to 45 atoms.
  • A has a polar surface area no greater than 140 A 2 , preferably no greater than 120 A 2 , preferably no greater than 100 A 2 , preferably no greater than 90 A 2 , preferably no greater than 80 A 2 , preferably no greater than 75 A 2 , preferably no greater than 60 A 2 , preferably no greater than 50
  • A comprises not more than 15 rotatable bonds, preferably not more than 12 rotatable bonds, preferably not more than 10 rotatable bonds, preferably not more than 9 rotatable bonds, preferably not more than 8 rotatable bonds, preferably not more than 7 rotatable bonds, preferably not more than 6 rotatable bonds, preferably not more than 5 rotatable bonds, preferably not more than 4 rotatable bonds, preferably not more than 3 rotatable bonds, preferably not more than 2 rotatable bonds.
  • A has an IC50 of less than 10 mM, less than 5 mM, less than 1 mM, less than 100 ⁇ , less than 10 ⁇ , less than 1 ⁇ , less than 100 nM, less than 10 nM, less than 1 nM, less than 100 pM, less than 10 pM, less than 1 pM.
  • A comprises not more than 10 rotatable bonds and has a polar
  • A comprises not more than 10 rotatable bonds and has a polar surface area no greater than 90 A 2
  • the compound has a carbonic anhydrase inhibitory activity of of less than 10 mM, less than 5 mM, less than 1 mM, less than 100 ⁇ , less than 10 ⁇ , less than 1 ⁇ , less than 100 nM, less than 10 nM, less than 1 nM, less than 100 pM, less than 10 pM, less than 1 pM.
  • the compound has a carbonic anhydrase inhibitory IX activity of of less than 10 mM, less than 5 mM, less than 1 mM, less than 100 ⁇ , less than 10 ⁇ , less than 1 ⁇ , less than 100 nM, less than 10 nM, less than 1 nM, less than 100 pM, less than 10 pM, less than 1 pM.
  • the compound has a IC50 for carbonic anhydrase of of less than 10 mM, less than 5 mM, less than 1 mM, less than 100 ⁇ , less than 10 ⁇ , less than 1 ⁇ , less than 100 nM, less than 10 nM, less than 1 nM, less than 100 pM, less than 10 pM, less than 1 pM.
  • the compound has a IC50 for carbonic anhydrase IX of of less than 10 mM, less than 5 mM, less than 1 mM, less than 100 ⁇ , less than 10 ⁇ , less than 1 ⁇ , less than 100 nM, less than 10 nM, less than 1 nM, less than 100 pM, less than 10 pM, less than 1 pM.
  • the compound fulfils at least two of the rules defined below .
  • the compound has a molecular weight of less than 1500 D, preferably less than 1200 D, preferably less than 1000 D, more preferably less than 800 D, more preferably less than 700 D, more preferably less than 600 D, more preferably less than 550 D, more preferably less than 500 D, more preferably less than 450 D, more preferably less than 400 D.
  • the compound has no more than 7 hydrogen bond donors, preferably no more than 6 hydrogen bond donors, preferably no more than 5 hydrogen bond donors, preferably no more than 4 hydrogen bond donors, preferably no more than 3 hydrogen bond donors, preferably no more than 2 hydrogen bond donors.
  • the compound has no more than 15 hydrogen bond acceptors, preferably no more than 14 hydrogen bond acceptors, preferably no more than 12 hydrogen bond acceptors, preferably no more than 10 hydrogen bond acceptors, preferably no more than 9 hydrogen bond acceptors, preferably no more than 8 hydrogen bond acceptors, preferably no more than 7 hydrogen bond acceptors, preferably no more than 6 hydrogen bond acceptors, preferably no more than 5 hydrogen bond acceptors, preferably no more than 4 hydrogen bond acceptors.
  • the compound has a octanol- water partition coefficient LogP of no greater than 7, preferably a LogP of no greater than 6, preferably a LogP of no greater than 5.5, preferably a LogP of no greater than 5, preferably a LogP of no greater than 4.5, preferably a LogP of no greater than 4, preferably a LogP of no greater than 3.5, preferably a LogP of no greater than 3, preferably a LogP of no greater than 2.5, preferably a LogP of no greater than 2, preferably a LogP of no greater than 1.5, preferably a LogP of no greater than 1, preferably a LogP of no greater than 0.5.
  • the compound has a Molar refractivity from 20 to 150, preferably a Molar refractivity from 30 to 140, preferably a Molar
  • refractivity from 40 to 130 preferably a Molar refractivity from 50 to 120, preferably a Molar refractivity from 60 to 100, preferably a Molar
  • refractivity from 70 to 90, preferably a Molar refractivity from 75 to 85.
  • the compound comprises 20 to 70 atoms preferably 25 to 65 atoms, preferably 30 to 60 atoms, preferably 32 to 55 atoms, preferably 35 to 52 atoms, preferably 38 to 50 atoms, preferably 40 to 48 atoms, preferably 42 to 46 atoms, preferably 44 to 45 atoms.
  • the compound has a polar surface area no greater than 140 A 2 , preferably no greater than 120 A 2 , preferably no greater than 100 A 2 , preferably no greater than 90 A 2 , preferably no greater than 80 A 2 , preferably no greater than 75 A 2 , preferably no greater than 60 A 2 , preferably no greater than 50 A 2 .
  • the compound comprises not more than 15 rotatable bonds, preferably not more than 12 rotatable bonds, preferably not more than 10 rotatable bonds, preferably not more than 9 rotatable bonds, preferably not more than 8 rotatable bonds, preferably not more than 7 rotatable bonds, preferably not more than 6 rotatable bonds, preferably not more than 5 rotatable bonds, preferably not more than 4 rotatable bonds, preferably not more than 3 rotatable bonds, preferably not more than 2 rotatable bonds.
  • the compound has an IC50 for proliferation of less than 10 mM, less than 5 mM, less than 1 mM, less than 100 ⁇ , less than 10 ⁇ , less than 1 ⁇ , less than 100 nM, less than 10 nM, less than 1 nM, less than 100 pM, less than 10 pM, less than 1 pM.
  • the compound has IC50 for carbonic anhydrase IX of of less than 10 mM, less than 5 mM, less than 1 mM, less than 100 ⁇ , less than 10 ⁇ , less than 1 ⁇ , less than 100 nM, less than 10 nM, less than 1 nM, less than 100 M, less than 10 pM, less than 1 pM.
  • the compound comprises not more than 10 rotatable bonds and has a
  • the compound comprises not more than 10 rotatable bonds and has a polar surface area no greater than 90 A 2
  • the compound comprises a chelating agent comprising a metal ion suitable for imaging, fluorescent moiety, or a 18 F containing moiety.
  • Suitable chelating agents are chelating agents that can complex metal ions. Suitable chelating agents may be selected from DOTA, DTP A, Deferoxamine, DOTA-TATE, DOTATOC, DTPA-BMA, EOB-DTPA, HP- D03A, BOPTA.
  • the compound comprises a chelating agent comprising a metal ion suitable for imaging.
  • Metal ions suitable for imaging may be metal ions that are used in PET scans, MRI and so on.
  • Suitable metal ion for imaging may be selected from the group consisting of Cobalt-57 , Copper-64, Copper-67 , Gallium-67 , Gallium-68 , Germanium-68 , Indium- 111, Iodine- 123 , Iodine- 124, Krypton-81m, Rubidium-81, Rubidium, Strontium-82, Thallium-201, Iron, Iron oxide, Gadolinium-64, Zirkonium-89.
  • the compound comprises fluorescent moiety.
  • a fluorescent moiety is a fluorescent chemical compound that can re-emit light upon light excitation. Fluorescent moiety typically contain several combined aromatic groups, or plane or cyclic molecules with several n bonds. Fluorescent moieties may be used as a tracer in fluids, as a dye for staining of certain structures, as a substrate of enzymes, or as a probe or indicator. Suitable fluorescent moieties may be selected from the group comprising fluorescent protein such as GFP (green), YFP (yellow) and RFP (red) or Non-protein organic fluorescent moiety such as Xanthene
  • derivatives e.g. fluorescein, rhodamine, Oregon green, eosin, and Texas red
  • Cyanine derivatives e.g. cyanine, indocarbocyanine, oxacarbocyanine, thiacarbocyanine, and merocyanine
  • Naphthalene derivatives dansyl and prodan derivatives
  • Coumarin derivatives, , oxadiazole derivatives e.g.
  • pyridyloxazole nitrobenzoxadiazole and benzoxadiazole
  • Anthracene derivatives e.g. anthraquinones, including DRAQ5, DRAQ7 and CyTRAK Orange
  • Pyrene derivatives e.g.cascade blue
  • Oxazine derivatives e.g.Nile red, Nile blue, cresyl violet, oxazine 170
  • Acridine derivatives e.g.proflavin, acridine orange, acridine yellow
  • Arylmethine derivatives e.g. auramine, crystal violet, malachite green
  • Tetrapyrrole derivatives e.g.porphin, phthalocyanine, bilirubin.
  • the compound comprises a 18 F containing moiety.
  • 18 F containing moieties may be used for imaging and therapy.
  • Suitable 18 F containing moieties may be selected from the group consisting of 18 fluorothymidine, 18 F- miso (fluoromisonidazole), 18 F-choline, and 18 fluorodeoxyglucose, florbetapir- fluorine- 18, fallypride (18F), 18F-EF5.
  • Compounds of the present invention are more tumour specific.
  • the compounds of the present invention decrease the pH of cancer cells especially if they are in an acidic environment, making the cells more sensitive to the anticancer agent.
  • the compounds of the present invention are active in normoxic conditions.
  • the compounds of the present invention are active in tumour cells which are in an acidic environment.
  • the compounds of the present invention increase the extracellular pH.
  • the compounds of the present invention decrease the intracellular pH.
  • the compounds of the present do not need irradiation to become active.
  • the compounds of the present invention are active in stem cells.
  • the compounds of the present invention have a increased half hfe in plasma.
  • the compounds of the present invention inhibit carbonic anhydrase, preferably carbonic anhydrase IX.
  • the compounds of the present invention inhibit selectively carbonic anhydrase IX.
  • n 1-12;
  • L is a cleavable linker.
  • 6alkylN(R6)C( 0)N(R 6 ), (0-CH 2 CH 2 )n, (CH 2 CH2-0) n , Ci.6alkyl(CH 2 CH2- 0)nCi. 6 alkyl, Ci. 6 alkyl(CH2CH2.0) n , and (CH2CH2.0) n Ci. 6 alkyl.
  • L is a direct bond, Ci-6alkyl, (0-CH 2 CH 2 ) n , or (CH 2 CH 2 -0) n .
  • n 1-10.
  • n 1-8.
  • n is 1-6.
  • n is 1-4.
  • n is 1-2.
  • L is a direct bond
  • the compounds comprise a R 1 group.
  • the R 1 is S0 2 NR 2 R 3 , OS0 2 NR 2 R 3 , NR3 ⁇ 40 2 NR 2 R3, NR4S0 2 -phenyl, aryl substituted with S0 2 NR 2 R3, aryl substituted with OS0 2 NR 2 R 3 , or aryl substituted with NR3 ⁇ 40 2 NR 2 R 3 ;
  • the R 1 group is connected to L or A via the S atom of the SO2 group in case R 1 is S02NR 2 R 3 R 1 group is connected to L or A via the O in case R 1 is O-SO2NR 2 R 3 R 1 group is connected to L or A via the N of NR 4 in case R 1 is NR 4 S02-phenyl.
  • R 1 group is connected to L or A via the N of NR 7 in case R 1 is NR 7 SO2NR 2 R 3
  • R 1 group is connected to L or A via the aryl group in case R 1 aryl substituted with S02NR 2 R 3 , aryl substituted with OSO 2 NR 2 R 3 , or aryl substituted with NR 7 SO 2 NR 2 R 3 .
  • R 1 is not connected to L or A via N of the NR 2 R 3 group.
  • R 1 is not connected to L or A via the S atom of SO2 in cases R 1 is not S02NR 2 R 3 .
  • R 1 is not connected to L or A via the O atom of the SO2 group. Only when there is a O-SO2 group may R 1 be connected via an O atom, but this is the O atom of O-SO2 It should be noted that these connection are the only ones that make sense when looking at the groups as defined for R 1 .
  • R 1 is R 1 is SO 2 NR 2 R 3 , OSO 2 NR 2 R 3 , NR 7 SO 2 NR 2 R 3 , aryl substituted with SO 2 NR 2 R 3 , aryl substituted with OSO 2 NR 2 R 3 , or aryl substituted with NR 7 SO 2 NR 2 R 3 .
  • R 1 is R 1 is SO2NH2, OSO2NH2, NR 7 SO 2 NH 2 , aryl substituted with SO2NH2, aryl substituted with OSO2NH2, or aryl
  • aryl is an aromatic cyclic compound comprising 5-12 atoms, and may mono-cyclic, bi- or tricyclic.
  • Aryl may contain heteroatoms and may be referred to as heteroaryl.
  • the term aryl thus comprises aromatic cyclic compounds comprising only C-atoms and also aromatic cyclic compounds comprising heteroatoms next to C atoms.
  • Aryl may be selected from the group consisting of phenyl, thiadiazolyl, naphthalenyl, pyridmyl, indolyl, quinolinyl, imidazolyl, furanyl, thienyl, oxadiazolyl, tetrazolyl, benzofuranyl or tetrahydrofuranyl; each aryl can optionally be substituted with one, two or three substituents each independently selected from halo, hydroxy, hydroxyC ⁇ -ealkyl, Ci-ealkyl, amino, polyhaloCi-6alkyl and C i-6alkyloxy ; and each phenyl or naphthalenyl can optionally be substituted with a bivalent radical selected from
  • each pyridinyl, indolyl, quinolinyl, imidazolyl, furanyl, thienyl, oxadiazolyl, tetrazolyl, benzofuranyl, or tetrahydrofuranyl can optionally be substituted with one, two or three substituents each independently selected from halo, hydroxy, Ci-ealkyl, amino, polyhaloCi-6alkyl, aryl, arylC i-6alkyl or C i-6alkyloxy ; and each pyridinyl, indolyl, quinolinyl, imidazolyl, furanyl, thienyl, benzofuranyl, or tetrahydrofuranyl can optionally be substituted with a bivalent radical selected from methylene dioxy or ethylene dioxy.
  • aryl is phenyl, thiadiazolyl, or naphtenyl, more preferably phenyl or thiadiazolyl, more preferably phenyl.
  • the aryl is substituted with a substituent selected from the group comprising hydrogen, halo, hydroxy, amino, nitro,
  • Ci-ealkyl C2-6alkenyl, C2-6alkynyl, Ci-6alkyloxy, di(Ci- 6alkyl)amino, hydroxyamino, hydroxycarbonyl, carbonyl, carbonylCi-6alkyl, carbonylCi-6alkyloxy, Ci-6alkylcarbonyl, NR 4 R 5 , heterocyclic, C3-7cycloalkyl, hydroxy C i-6alkyl, aminoCi-6alkyl , cyano, or
  • the aryl is substituted with a substituent selected from the group comprising hydrogen, halo, hydroxy, amino, nitro,
  • the aryl is substituted with a substituent selected from the group comprising hydrogen, halo, hydroxy, amino, nitro, carboxyamine, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, Ci-6alkyloxy, NR 4 R 5 , or cyano.
  • the aryl is substituted with a substituent selected from the group comprising hydrogen, halo, hydroxy, amino, nitro, or cyano.
  • the aryl is substituted with a substituent selected from the group comprising hydrogen, halo, or cyano.
  • the aryl is not further substituted.
  • a substituent selected from the group comprising halo, hydroxy, amino, nitro, Ci-6alkyloxy, di(Ci-6alkyl)amino, hydroxyamino, hydroxycarbonyl, carbonyl, carbonylCi-6alkyl, carbonylCi-6alkyloxy, Ci-6alkylcarbonyl
  • a substituent selected from the group comprising halo, hydroxy, amino, nitro, C i-6alkyloxy , di(Ci-6alkyl) amino, hydroxyamino, hydroxycarbonyl, carbon
  • the Ci-6alkyl is optionally substituted with with a substituent selected from the group comprising halo, hydroxy, amino, nitro, hydroxyamino, hydroxycarbonyl, carbonyl, or cyano.
  • the R 2 , R 3 is each independently hydrogen, halo, hydroxy, or C i-6alkyl, wherein the Ci-6alkyl is optionally substituted with with a substituent selected from the group comprising halo, hydroxy, amino, nitro, carbonyl,, cyano, or a leaving group;
  • the R 4 , R 5 , R 6 , R 7 is each independently hydrogen, halo, hydroxy, or Ci-ealkyl, wherein the Ci-6alkyl is optionally substituted with with a substituent selected from the group comprising halo, hydroxy, amino, nitro, Ci-6alkyloxy, di(Ci-6alkyl)amino, hydroxyamino,
  • the R 8 and R 9 is each independently a Ci-ealkyl, or C2- i2alkenyl;
  • the R 10 is hydrogen, Ci-2oalkyl, or C2-2oalkenyl, aryl, aminoCi-i2alkyl, carbonylCi.i2alkyl, hydroxyCi-6alkyl, Ci-6alkyloxyCi-6alkyl, or NR 4 R5;
  • R 8 and R 9 is each independently a Ci-ealkyl, or C2- i2alkenyl, being straight or branched, more preferably Ci-6alkyl, or C2-
  • R 8 and R 9 are the same.
  • the compounds are functionalized with SiFR 8 R 9 , wherein R 8 and R 9 is each independently a Ci-ealkyl, tertiary butyl, isopropyl, preferably tertiary butyl, isopropyl,methyl, ethyl.
  • Compounds with SiFR 82 R 9 may be used for PET imaging by exchanging the normal 19 F by the radioactive 18 F.
  • the compound comprises a SiFR 8 R 9 group, and F is 18 F.
  • a leaving group is a molecular fragment that departs with a pair of electrons in heterolytic bond cleavage.
  • Leaving groups can be anions or neutral molecules.
  • Common anionic leaving groups are halides such as CI “ , Br-, and I " , and sulfonate esters, such as para-toluenesulfonate ("tosylate", TsO " ) or diazonium, oxonium.
  • Common neutral molecule leaving groups are water (H2O), and ammonia.
  • a leaving group is halogen, tosylate, mesylate, fluorosulfonates, triflates, brosylate, nonaflates, Ci-i2alkylN2, Ci.i2alkylOCi.
  • Ci-i2alkyl Ci-i2alkylOS02F, Ci-i2alkylOS02perfluoratedCi.6alkyl, nitrate, phosphate, Ci-6alkylSCi-6alkyl, tetraCi-6alkylammonium, halogenCi-6alkyl, Ci-6alkylOaryl, C i-6alkylhy droxy , carbonylCi-6alkyloxyCi.6alkyl .
  • a leaving group is halogen, tosylate, mesylate, fluorosulfonates, triflates, nonaflates, Ci-i2alkylN2, Ci-i2alkylOS02F, Ci-i2alkylOS02perfluoratedCi. 6alkyl, halogenCi-6alkyl.
  • a leaving group is halogen, tosylate, mesylate, fluorosulfonates, triflates, nonaflates, or halogenCi-6alkyl.
  • a leaving group is iodide, bromide, chloride, tosylate, or mesylate.
  • R 2 , R 3 is each independently hydrogen, hydroxy, or Ci- 6alkyl, more preferably Ci-3alkyl, more preferably Ci.2alkyl, more preferably Cialkyl.
  • R 2 , R 3 is each independently hydrogen, Ci-6alkyl, more preferably Ci-3alkyl, more preferably Ci.2alkyl, more preferably Cialkyl.
  • R 2 , R 3 is hydrogen
  • R 4 , R 5 is each independently hydrogen, hydroxy, or Ci- 6alkyl, more preferably Ci-3alkyl, more preferably Ci.2alkyl, more preferably Cialkyl.
  • R 4 , R 5 is each independently hydrogen, Ci-6alkyl, more preferably Ci-3alkyl, more preferably Ci.2alkyl, more preferably Cialkyl.
  • R 4 , R 5 is hydrogen
  • R 6 is hydrogen, hydroxy, or Ci-6alkyl, more preferably Ci-3alkyl, more preferably Ci.2alkyl, more preferably Cialkyl.
  • R 6 is hydrogen, Ci-6alkyl, more preferably Ci-ealkyl, more preferably Ci.2alkyl, more preferably Cialkyl.
  • R 6 is hydrogen
  • R 7 is hydrogen, hydroxy, or Ci-6alkyl, more preferably Ci-3alkyl, more preferably Ci.2alkyl, more preferably Cialkyl. In a more preferred embodiment of the present invention and/or embodiments thereof, R 7 is hydrogen, Ci-ealkyl, more preferably Ci-ealkyl, more preferably Ci.2alkyl, more preferably Cialkyl.
  • R 7 is hydrogen
  • R 10 is hydrogen, Ci-2oalkyl, or C2-2oalkenyl, aryl, aminoCi-i2alkyl, carbonylCi.i2alkyl, hydroxyCi-6alkyl, Ci-6alkyloxyCi-6alkyl, or NR 4 R 5 .
  • R 10 is hydrogen, Ci-i6alkyl, C2-i6alkenyl, aryl, aminoCi-i2alkyl, carbonylCi.i2alkyl, hydroxyCi-6alkyl, Ci-6alkyloxyCi-6alkyl, or NR 4 R 5 .
  • R 10 is hydrogen, Ci-6alkyl, C2-6alkenyl, aryl, aminoCi- 6alkyl, carbonylCi.i2alkyl, hydroxy C i-6alkyl, Ci-6alkyloxyCi-6alkyl, or NR 4 R 5 .
  • R 10 is hydrogen, Ci-6alkyl, C2-6alkenyl, aryl, aminoCi- 6alkyl, carbonylCi.i2alkyl, hydroxy C i-6alkyl, Ci-6alkyloxyCi-6alkyl, or NR 4 R 5 .
  • R 10 is hydrogen, Ci-2oalkyl, C2-2oalkenyl, aryl, aminoCi-i2alkyl, carbonylCi.i2alkyl, hydroxyCi-6alkyl, or NR 4 R 5 .
  • R 10 is hydrogen, Ci-2oalkyl, C2-2oalkenyl, aryl, aminoCi.i2alkyl, or NR 4 R 5 .
  • R 10 is hydrogen, Ci-2oalkyl, or C2-2oalkenyl, or aryl, or NR 4 R 5 .
  • R 10 is hydrogen, Ci-i6alkyl, C2-i6alkenyl, or aryl, or NR 4 R 5 .
  • R 10 is hydrogen, Ci-ealkyl, C2-i2alkenyl, or aryl, or NR 4 R 5 .
  • R 10 is hydrogen, Ci-6alkyl, C2-6alkenyl, or aryl, or NR 4 R 5 .
  • R 10 is hydrogen, Ci-2oalkyl, or C2-2oalkenyl, or NR 4 R 5 . In a more preferred embodiment of the present invention and/or embodiments thereof, R 10 is hydrogen, Ci-2oalkyl, or NR 4 R 5 .
  • the compounds may be used as a medicine, especially in the treatment of cancer.
  • the cancer is selected from the group of breast carcinoma, brain carcinoma, kidney carcinoma, colorectal carcinoma, lung carcinoma, head and neck carcinoma, esophageal carcinoma, hepatocellular carcinoma, cholangiocarcinoma, renal eel carcinomal, testis carcinoma, cervix carcinoma, endometrium carcinoma, ovarian carcinoma, Squamous cell carcinoma, Basal cell carcinoma, Glioma, Ependymoma, mesothelioma, papillary thyroid carcinoma, thyroid carcinoma, follicular thyroid
  • carcinoma follicular lymphoma, non-Hodgkin's lymphoma, adenocarcinoma, stomach carcinoma, duodenum carcinoma, biliary carcinoma, pancreas carcinoma, and bladder carcinoma, preferably the the cancer is colorectum cancer.
  • a aspect of the present invention is directed to treatment of cancer comprising administering a compound of aspects and/embodiments of the present invention.
  • the treatment of cancer may be in combination with other cancer therapies, such as radiotherapy and chemotherapy.
  • the treatment comprises administering to a patient in need of a treatment an effective dose of a compound of aspects
  • Suitable the effective dose of compounds of the present invention is the effective dose of the original anticancer agent A.
  • the effective dose will depend on the anticancer agent and the tumour to be treated. A skilled person is well aware of methods to determine the effective dose of a compound.
  • An effective dose is the dose or amount of compound that produces a therapeutic response or desired effect in some fraction of the subjects taking it.
  • a therapeutic response may be a decreased growth of the tumour, a reduction of the tumour size, reduction of metastasis, removal of metastasis, or removal of the primary tumour.
  • the present invention also features methods of using or preparing or formulating such pharmaceutical compositions.
  • the pharmaceutical compositions can be prepared using conventional pharmaceutical excipients and compounding techniques known to those skilled in the art of preparing dosage forms. It is anticipated that the compounds of the invention can be administered by oral, parenteral, rectal, topical, or ocular routes,
  • compositions may be administered by intravenous infusion or topical administration, but more preferably by oral administration.
  • the compounds of the invention may be provided in the form of tablets or capsules, or as a solution, emulsion, or suspension.
  • Tablets for oral use may include the active ingredient mixed with pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservatives.
  • suitable inert fillers include sodium and calcium carbonate, sodium and calcium
  • Starch, polyvinyl-pyrrolidone, sodium starch glycolate, microcrystalline cellulose, and alginic acid are suitable disintegrating agents. Binding agents may include starch and gelatin.
  • the lubricating agent if present, will generally be magnesium stearate, stearic acid or talc.
  • the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating.
  • Capsules for oral use include hard gelatin capsules in which the active ingredient is mixed with a solid, semi-solid, or liquid diluent, and soft gelatin capsules wherein the active ingredient is mixed with water, an oil such as peanut oil or olive oil, liquid paraffin, a mixture of mono and di- glycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol.
  • Liquids for oral administration may be suspensions, solutions, emulsions or syrups or may be presented as a dry product for reconstitution with water or other suitable vehicles before use.
  • Compositions of such liquid may contain pharmaceutically-acceptable excipients such as suspending agents (for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel and the like); non-aqueous vehicles, which include oils (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol or water;
  • suspending agents for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel and the like
  • non-aqueous vehicles which include oils (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol or water;
  • preservatives for example, methyl or propyl p- hydroxybenzoate or sorbic acid
  • wetting agents such as lecithin
  • flavoring or coloring agents for example, methyl or propyl p- hydroxybenzoate or sorbic acid
  • the compounds of this invention may also be administered by non- oral routes.
  • reaction mixture was carefully diluted with water and basifies with aqueous NH 4 OH and extracted with CHCI3. Organic layer dried over sodium sulfate and evaporated to get crude.
  • reaction mixture was carefully diluted with water and basifies with aqueous NH 4 OH and extracted with CHCI3. Organic layer dried over sodium sulfate and evaporated to get crude.
  • reaction mixture was added into water and extracted with ethyl acetate (50 mL x 2).
  • the combined organic layer was washed successively with 2 N HC1 solution (25 mL), 10% sodium bicarbonate solution (25 mL) and water (25 mL).
  • the organic layer was dried over anhydrous sodium sulphate and filtered. Evaporation of the solvent under reduced pressure gave the pale yellow solid as crude product.
  • the solid thus obtained was stirred in diethyl ether (25 mL, 5 vol.) and filtered to give the compound 9/10 as off-white solid (6.5 g, 87 %).
  • reaction mixture poured into 1 N HC1 (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layer was washed with saturated NaHCOe solution (200 mL) and dried over anhydrous Na2S0 4 . Evaporation of the solvent under reduced pressure gave pale yellow solid as crude product. The crude product was stirred with diisopropyl ether (100 mL) and filtered to obtain compound 11 as off-white solid (6.8 g, 66%).
  • Chlorambucil acid chloride (prepared from 25 g of chlorambucil) was dissolved in dichlorom ethane (125 mL) and to this was slowly added methanol (75 mL, 3 vol.) at 15-20 °C over a period of 1 h. The reaction mixture was stirred at ambient temperature for 2 h. The reaction mixture was concentrated and then the residue was dissolved in ethyl acetate (125 mL, 5 vol.) and washed successively with 5 % sodium bicarbonate solution and water. Evaporation of the solvent under reduced pressure gave the chlorambucil methyl ester (25 g, 95%) as hght brown oil which was used as such in the next step.
  • reaction mixture was cooled to 0-5 °C and quenched slowly with ethyl acetate (250 mL, 10 vol.) followed by water (100 mL, 4 vol.).
  • the reaction mixture was filtered through celite and the celite bed was washed with ethyl acetate (50 mL, 2 vol.).
  • the organic layer was washed with water (100 mL, 4 vol.) and dried over anhydrous sodium sulphate. Evaporation of the solvent under reduced pressure gave the crude alcohol (22.5 g, 99%) as pale yellow oil. The crude was used as such in the next step.
  • reaction mixture was concentrated and then the residue obtained was dissolved in ethyl acetate (150 mL, 10 vol.).
  • the organic layer was washed successively with 2 N HC1 solution (100 mL x 2), water and dried over anhydrous Na2S0 4 . Evaporation of the solvent under reduced pressure gave the pale yellow solid as crude product.
  • the crude product thus obtained was purified by column chromatography using silica gel (40% ethyl acetate in hexanes) to obtain compound 13 (10.5 g, 51 %) as off-white solid.
  • CA Carbonic Anhydrase
  • Phenol red (at a concentration of 0.2 mM) was used as an indicator, working at the absorbance maximum of 557 nm, with 20 mM Hepes (pH 7.5) as buffer and 20 niM Na2S04 (for maintaining constant the ionic strength), following the initial rates of the CA-catalyzed C02 hydration reaction for a period of 10-100 s.
  • the C02 concentrations ranged from 1.7 to 17 mM for the determination of the kinetic parameters and inhibition constants.
  • For each inhibitor at least six traces of the initial 5-10% of the reaction were used for determining the initial velocity. The uncatalyzed rates were determined in the same manner and subtracted from the total observed rates.
  • Exponentially growing colorectal (HT- 29, ATCC HTB-38) and cervical (HeLa, ATCC CCL-2) carcinoma cells were cultured in Dulbecco's Modified Eagle's Medium supplemented with 10% fetal bovine serum. Low oxygen conditions were acquired in a hypoxic workstation (Ruskinn
  • INVIV02 1000 The atmosphere in the chamber consisted of 0.2% 02 (hypoxia), 5% CO2, and residual N2.
  • normoxic (20% O2) dishes were incubated in air with 5% CO2. pH of the culture medium was immediately measured at the end of each experiment as previously described ((Dubois, L.; Douma, K.; Supuran, C. T.; Chiu, R. K.; van Zandvoort, M. A.; Pastorekova ' , S.; Scozzafava, A.; Wouters, B. G.; Lambin, P. Imaging the hypoxia surrogate marker CA IX requires expression and catalytic activity for binding fluorescent sulfonamide inhibitors. Radiother. Oncol. 2007, 83, 367-373).
  • the MTT assay is used as toxicity assay.
  • the MTT assay is a colorimetric assay for assessing cell viability.
  • NAD (P)H- dependent cellular oxidoreductase enzymes reflects the number of viable cells present. These enzymes are capable of reducing the tetrazolium dye MTT 3-(4,5- dimethylthiazol-2-yl)-2,5-diphenyltetrazohum bromide to its insoluble formazan, which has a purple color.
  • the Radio S assays t is a clonogenic assay of radiation with and without drug under hypoxic conditions: the clonogenic assay enables an assessment of the differences in reproductive viability (capacity of cells to produce progeny; i.e. a single cell to form a colony of 50 or more cells) between control untreated cells and cells that have undergone exposure to ionizing radiation under hypoxia with and without drug.
  • the assay has become the most widely accepted technique in radiation biology and has been widely used for evaluating the radiation sensitivity of different cell lines.
  • the clonogenic assay is commonly used for monitoring the efficacy of radiation modifying compounds and for determining the effects of cytotoxic agents and other anti-cancer therapeutics on colony forming ability, in different cell lines.
  • a typical clonogenic survival experiment using adherent cells lines involves three distinct components, 1) treatment of the cell monolayer in tissue culture flasks, 2) preparation of single cell suspensions and plating an appropriate number of cells in petri dishes and 3) fixing and staining colonies following a relevant incubation period, which could range from 1-3 weeks, depending on the cell line.

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Abstract

La présente invention concerne des composés ayant la formule (I) : A-L-R1, dans laquelle A représente un agent anticancéreux comprenant au moins un groupe choisi dans l'ensemble comprenant OH, NH et NH2 et L représente une liaison directe ou L représente un lieur et R1 représente un groupe sulfonamide, sulfamate ou sulfamide. L est substitué sur O de OH ou sur N de NH ou NH2 de A ou L remplace OH de A, ou O-L remplace un groupe C(=O)-OH de A et dans le cas où L représente une liaison directe R1 est substitué sur O de OH ou sur N de NH ou NH2 de A ou R1 remplace OH de A, ou O-R1 remplace un groupe C (=O)-OH de A. L'invention concerne également un traitement du cancer avec ces composés.
PCT/NL2015/050839 2014-12-04 2015-12-03 Dérivés sulfonamide, sulfamate et sulfamide d'agents anticancéreux WO2016089208A2 (fr)

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JPWO2019203255A1 (ja) * 2018-04-19 2021-06-10 公立大学法人横浜市立大学 再構成癌組織を用いた薬剤評価方法
US11040027B2 (en) 2017-01-17 2021-06-22 Heparegenix Gmbh Protein kinase inhibitors for promoting liver regeneration or reducing or preventing hepatocyte death
JP2022504578A (ja) * 2019-05-14 2022-01-13 テリジーン リミテッド キナーゼ阻害剤として有用な置換大員環類
CN115894385A (zh) * 2023-01-09 2023-04-04 中国科学院长春应用化学研究所 替拉扎明衍生物及其制备方法和应用
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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11040027B2 (en) 2017-01-17 2021-06-22 Heparegenix Gmbh Protein kinase inhibitors for promoting liver regeneration or reducing or preventing hepatocyte death
US11667651B2 (en) 2017-12-22 2023-06-06 Hibercell, Inc. Aminopyridine derivatives as phosphatidylinositol phosphate kinase inhibitors
JPWO2019203255A1 (ja) * 2018-04-19 2021-06-10 公立大学法人横浜市立大学 再構成癌組織を用いた薬剤評価方法
CN109574960A (zh) * 2018-11-15 2019-04-05 南京友怡医药科技有限公司 一种多西他赛衍生物及其制备方法和应用
CN109574960B (zh) * 2018-11-15 2023-03-21 南京友怡医药科技有限公司 一种多西他赛衍生物及其制备方法和应用
JP2022504578A (ja) * 2019-05-14 2022-01-13 テリジーン リミテッド キナーゼ阻害剤として有用な置換大員環類
JP7345901B2 (ja) 2019-05-14 2023-09-19 テリジーン リミテッド キナーゼ阻害剤として有用な置換大員環類
CN115894385A (zh) * 2023-01-09 2023-04-04 中国科学院长春应用化学研究所 替拉扎明衍生物及其制备方法和应用

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