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WO2015166043A1 - Composés - Google Patents

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Publication number
WO2015166043A1
WO2015166043A1 PCT/EP2015/059503 EP2015059503W WO2015166043A1 WO 2015166043 A1 WO2015166043 A1 WO 2015166043A1 EP 2015059503 W EP2015059503 W EP 2015059503W WO 2015166043 A1 WO2015166043 A1 WO 2015166043A1
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WO
WIPO (PCT)
Prior art keywords
compound
cancer
hydrogen
alkoxy
ring
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2015/059503
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English (en)
Inventor
Bhabatosh Chaudhuri
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
De Montfort University
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De Montfort University
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Filing date
Publication date
Priority claimed from GB201407697A external-priority patent/GB201407697D0/en
Priority claimed from GB201407696A external-priority patent/GB201407696D0/en
Application filed by De Montfort University filed Critical De Montfort University
Publication of WO2015166043A1 publication Critical patent/WO2015166043A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to compounds for use in the prevention and/or treatment of cancer.
  • Cytochrome P450 (CYP) enzymes belong to a large family of detoxification enzymes that are present in different organs of the human body.
  • the CYP isoform CYP1 B1 has been found to be expressed in all cancers, regardless of oncogenic origin, while being absent from healthy tissue. It is understood that CYP1 B1 may have a dominant role in the genesis of breast cancer.
  • Activated estrogen receptor is responsible for breast cell division (proliferation). ER is activated by its ligand, estradiol (a steroidal hormone). In pre-menopausal women, estradiol is primarily produced in the ovaries by the pituitary via a cascade of biochemical reactions initiated by the LH-RH receptor whereas, in post-menopausal women, estradiol is synthesised solely in the adrenal glands from testosterone. Hyper-activated ER, through constant overproduction of estradiol, is the cause of ER-positive breast cancers and 80% of breast cancers are ER-positive. It is thought that preventing the synthesis of the ER ligand, estradiol, could lead to an ideal treatment of ER-positive breast cancers. However, estradiol plays an essential role in most healthy tissues.
  • Estradiol is synthesised through the aromatisation of the 'A' ring of testosterone with the help of cytochrome P450 19 (CYP19) enzyme which is also known as aromatase.
  • CYP19 cytochrome P450 19
  • the CYP19 enzyme i.e. aromatase
  • Inhibitors of aromatase have been hugely successful for the treatment of estrogen receptor (ER)-positive post-menopausal breast cancers.
  • ER estrogen receptor
  • Unfortunately the use of aromatase inhibitors is restricted to the treatment of post-menopausal women suffering from breast cancer.
  • the inhibitors avert the formation of estradiol from testosterone thereby inhibiting cell division by preventing activation of ER.
  • aromatase inhibitors have profound adverse effects on pre-menopausal ER-positive breast cancer patients, as a result of a biochemical feedback loop that affects the pituitary.
  • aromatase inhibitors in premenopausal women, results in a decrease in estrogen, which activates the hypothalamus and pituitaries to increase gonadotropin secretion, which in turn stimulates the ovary to increase testosterone production.
  • the heightened gonadotropin levels also up-regulate the aromatase promoter, increasing aromatase production in a setting where the substrate, testosterone, levels have increased.
  • aromatase inhibitors results in the increase of total estrogen rather than the intended decrease in its levels.
  • aromatase inhibitors can only be used for the treatment of post-menopausal women.
  • the present invention provides compounds for selectively inhibiting CYP1 B1 for the prevention and treatment of ER-positive breast cancers in both pre- and post-menopausal women.
  • the inventors have recognised that preventing the 'conversion' of overproduced estradiol to the cancer-causing 4-hydroxy estradiol is an attractive way of preventing the onset and progression of majority of breast cancers.
  • the identification of CYP1 B1 - specific inhibitors provides a novel way of treating the majority (i.e. >80%) of breast cancers.
  • proteomic analysis has revealed that CYP1 B1 is over-produced in tumours which have become resistant to chemotherapy with cisplatin.
  • CYP1 B1 inhibitors would be able to re-sensitise cancer cells to currently available cancer therapies that involve platinum compounds, taxanes and also nucleoside analogues.
  • the present invention therefore provides CYP1 B1 inhibitors for use in the treatment of drug-resistant cancer cells, as alternatives to currently used aromatase inhibitors and in gynaecological cancers and prostate cancer.
  • the present invention therefore provides inhibitors which inhibit CYP1 B1 and more preferably provide some selectivity towards the inhibition of CYP1 B1.
  • the first aspect of the invention therefore provides a compound of formula (I) for use in the prevention and/or treatment of cancer, wherein rings A and B are independently an optionally substituted aryl or an optionally substituted heteroaryl.
  • the optionally substituted aryl or optionally substituted heteroaryl can be substituted with one or more substituents selected from the group consisting of aryl, aliphatic, alkoxy, thioalkyl, alkylamino, halogen, hydroxy, cyano, nitro, hydroxyalkyl, alkylcarbonyloxy, alkoxycarbonyl, alkylcarbonyl, haloalkyl, alkylsulfonylamino NH 2 , N0 2 , S0 2 R x , SOR x and COOR x , where R x is hydrogen, aliphatic or aryl.
  • Preferred substituents include aryl, aliphatic, halogen, hydroxy, alkoxy, thioalkyl, alkylamino or cyano, preferably aryl, hydroxyl, halogen or alkoxy.
  • the invention particularly relates to compounds of formula II,
  • ring A is an optionally substituted aryl and ring B is an optionally substituted heteroaryl.
  • an aryl group can comprise an optionally substituted phenyl or a polycyclic aryl group such as a naphthalene or a phenanthroline group and a heteroaryl group can comprise an optionally substituted monocyclic heteroaryl having 5 or 6 ring atoms, at least one ring atom being a heteroatom selected from O, N or S, preferably N. More preferably, one ring atom of the heteroaryl is a heteroatom, selected from O, N or S, preferably N.
  • the heteroaryl group is pyridine.
  • the optionally substituted aryl or optionally substituted heteroaryl can be substituted with one or more substituents selected from the group consisting of aliphatic, alkoxy, thioalkyi, alkylamino, halogen, hydroxy, cyano, nitro, hydroxyalkyl, alkylcarbonyloxy, alkoxycarbonyl, alkylcarbonyl, haloalkyl, alkylsulfonylamino NH 2 , N0 2 , S0 2 R x , SOR x and COOR x , where R x is hydrogen, aliphatic or aryl.
  • Preferred substituents include aliphatic, halogen, hydroxy, alkoxy, thioalkyi, alkylamino or cyano, preferably hydroxyl, halogen or alkoxy.
  • Ring A is an aryl group optionally substituted with one or more subsitutuents selected from aliphatic, halogen, hydroxy, alkoxy, thioalkyi, alkylamino or cyano, preferably hydroxyl, halogen or alkoxy.
  • the alkoxy group is particularly one or more Ci -6 alkoxy group, more particularly one or more Ci -4 alkoxy group, more particularly a methoxy, ethoxy, propoxy or butoxy group, more particularly a methoxy or ethoxy group, most particularly methoxy.
  • Ring A can be a phenyl group optionally substituted with one or more subsitutuents selected from aliphatic, halogen, hydroxy, alkoxy, thioalkyi, alkylamino or cyano, preferably hydroxyl, halogen or alkoxy.
  • the alkoxy group is particularly one or more Ci -6 alkoxy group, more particularly one or more Ci -4 alkoxy group, more particularly a methoxy, ethoxy, propoxy or butoxy group, more particularly a methoxy or ethoxy group, most particularly methoxy.
  • the aryl group and more particularly the phenyl group is preferably substituted with one, two or three substituents.
  • the compound of formula (II) will therefore preferably have the structure;
  • R 1 , R 2 , R 3 , R 4 or R 5 are independently hydrogen, aliphatic, halogen, hydroxy, alkoxy, thioalkyi, alkylamino or cyano, preferably hydrogen, hydroxyl, halogen or alkoxy.
  • R 1 , R 2 , R 3 , R 4 or R 5 are independently, aliphatic, halogen, hydroxy, alkoxy, thioalkyi, alkylamino or cyano, preferably hydroxyl, halogen or alkoxy.
  • R 5 position is unsubstituted (i.e. R 5 is hydrogen)
  • Ring B is preferably a heteroaryl group optionally substituted with one or more subsitutuents selected from aliphatic, halogen, hydroxy, alkoxy, thioalkyi, alkylamino or cyano, preferably hydroxyl, halogen or alkoxy.
  • Ring B is a pyridine group.
  • the pyridine group is preferably attached to the ketone functionality at the 3 or 4 position.
  • the pyridine group is optionally substituted with one or more of aliphatic, halogen, hydroxy, alkoxy, thioalkyi, alkylamino or cyano, preferably hydroxyl, halogen or alkoxy, more preferably alkoxy, such as methoxy or ethoxyl, more preferably methoxy.
  • the compound of formula (II) will therefore preferably have the structure:
  • R 1 , R 2 , R 3 , R 4 or R 5 are independently hydrogen, aliphatic, halogen, hydroxy, alkoxy, thioalkyi, alkylamino or cyano, preferably hydrogen, hydroxyl, halogen or alkoxy.
  • R 1 , R 2 , R 3 , R 4 or R 5 are independently, aliphatic, halogen, hydroxy, alkoxy, thioalkyi, alkylamino or cyano, preferably hydroxyl, halogen or alkoxy.
  • the R 5 position is unsubstituted (i.e. R 5 is hydrogen)
  • the invention provides a compound of formula (IIC) for use in the treatment of cancer
  • R 2 is hydrogen, alkoxy, halogen or hydroxyl
  • R 3 is hydrogen, alkoxy or halogen
  • R 4 is hydrogen or alkoxy
  • R 5 is hydrogen
  • the alkoxy group is particularly one or more C 1-6 alkoxy group, more particularly one or more C 1-4 alkoxy group, more particularly a methoxy, ethoxy, propoxy or butoxy group, more particularly a methoxy or ethoxy group, most particularly methoxy.
  • R 2 is hydrogen, methoxy, chloride, fluoride or hydroxyl
  • R 3 is hydrogen, methoxy, fluoride or chloride
  • R 4 is hydrogen or methoxy
  • R 5 is hydrogen
  • the phenyl ring is mono, di or tri substituted.
  • the ring is preferably mono-substituted with hydroxy or methoxy more preferably at R 1 or R 2 .
  • the ring is preferably di-substituted with hydroxyl, methoxy, chloride, or fluoride, preferably at R 2 and R 3 , more preferably R 2 and R 3 are the same.
  • the ring is preferably tri-substituted with methoxy, preferably at R 1 , R 2 and R 3 .
  • the compound is one or more selected from
  • the invention further provides a compound of formula (III)
  • ring A is an optionally substituted aryl and ring B is an optionally substituted heteroaryl.
  • an aryl group can comprise an optionally substituted phenyl or a polycyclic aryl group such as a naphthalene or a phenanthroline group.
  • a heteroaryl group can comprise an optionally substituted monocyclic heteroaryl having 5 or 6 ring atoms, at least one ring atom being a heteroatom selected from O, N or S, preferably N. More preferably, one ring atom of the heteroaryl is a heteroatom, selected from O, N or S, preferably N.
  • the heteroaryl group is pyridine or imidazole.
  • the optionally substituted aryl or optionally substituted heteroaryl can be substituted with one or more subsitutuents selected from the group consisting of aryl, aliphatic, alkoxy, thioalkyl, alkylamino, halogen, hydroxy, cyano, nitro, hydroxyalkyl, alkylcarbonyloxy, alkoxycarbonyl, alkylcarbonyl, haloalkyl, alkylsulfonylamino, NH 2 , N0 2 , S0 2 x , SOR x and COOR x , where R x is hydrogen, aliphatic or aryl.
  • Preferred substituents include aryl, aliphatic, halogen, hydroxy, alkoxy, thioalkyl, alkylamino or cyano, preferably aryl, hydroxyl, halogen or alkoxy.
  • Ring A is an aryl group optionally substituted with one or more subsitutuents selected from aryl, aliphatic, halogen, hydroxy, alkoxy, thioalkyl, alkylamino or cyano, preferably aryl, halogen or alkoxy.
  • the alkyl group is particularly one or more Ci -6 alkoxy group, more particularly one or more Ci -4 alkoxy group, more particularly a methoxy, ethoxy, propoxy or butoxy group, more particularly a methoxy or ethoxy group, most particularly methoxy.
  • the aryl group is substituted with an aryl group
  • the aryl group is preferably phenyl.
  • Ring A can be a phenyl group optionally substituted with one or more subsitutuents selected from aryl, aliphatic, halogen, hydroxy, alkoxy, thioalkyl, alkylamino or cyano, preferably aryl, halogen or alkoxy.
  • the alkoxy group is particularly one or more Ci -6 alkoxy group, more particularly one or more Ci -4 alkoxy group, more particularly a methoxy, ethoxy, propoxy or butoxy group, more particularly a methoxy or ethoxy group, most particularly methoxy.
  • the aryl group is preferably phenyl.
  • the aryl group and more particularly the phenyl group is preferably substituted with one, two or three substituents, more preferably one or two substituents.
  • the invention therefore relates to a compound of formula (III) wherein Ring A is an aryl ring optionally substituted with one or more of methoxy, chloride or phenyl and Ring B is a five or six membered heteroaryl group containing one or two nitrogen atoms, preferably pyridine, pyrrole, imidazole, pyridazine, pyrimidine or pyrazine, more preferably pyridine or imidazole.
  • the first aspect of the invention relates to a compound of formula (Ilia)
  • Ring A is an aryl ring optionally substituted with one or more of methoxy, chloride or phenyl
  • the aryl group of formula (III) or (Ilia) is preferably phenyl or a fused aryl group comprising two, three or four fused phenyl groups such as napthyl or phenanthroline.
  • fused aryl group can be selected from one or more of
  • the fused aryl group is napthyl, it is preferably substituted with methoxy.
  • the aryl group is a phenyl group, it can have the structure
  • R 1 , R 2 , R 3 , R 4 and R 5 are preferably hydrogen, methoxy, chloride or phenyl.
  • the phenyl ring can be mono, di or tri substituted. Where the phenyl ring is mono-substituted, it is preferably substituted with methoxy, chloride or phenyl preferably at the R 2 or R 3 position. When the phenyl ring is di-substituted, it is preferably substituted with methoxy, preferably at the R 1 and R 3 , R 2 and R 3 or R 2 and R 4 positions. When the phenyl ring is tri- substituted, it is preferably substituted with methoxy at the R 1 , R 2 and R 3 positions.
  • the compound is one or more selected from
  • aryl includes for example optionally substituted unsaturated monocyclic, bicyclic or tricyclic rings of up to 14 carbon atoms, such as phenyl, naphthy and phenanthroline.
  • aryl may include partially saturated bicyclic rings such as tetrahydro-naphthyl.
  • the aryl group is phenyl, naphthy or phenanthroline.
  • a heteroaryl group or moiety may be for example an optionally substituted 5- or 6- membered heterocyclic aromatic ring which may contain from 1 to 4 heteroatoms selected from O, N or S.
  • the heterocyclic ring may optionally be fused to a phenyl ring.
  • heteroaryl groups thus include furyl, thienyl, pyrrolyl, oxazolyl, oxazinyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazyl, pyrimidinyl, pyrazolyl, indolyl, indazolyl, isoxazolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzoxazinyl, quinoxalinyl, quinolinyl, quinazolinyl, cinnolinyl, benzothiazolyl and pyridopyrrolyl.
  • the heteroaryl group or moiety may be fully or partially reduced.
  • the terms 'reduced' or 'reduction' relate to the addition of one or more electrons to an atom or the addition of hydrogen to a moiety.
  • Examples of such reduced heteroaryl groups or moieties include any fully or partially saturated derivative of the aforementioned heteroaryl groups and include pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl and piperidinyl groups.
  • the heteroaryl group is preferably pyridyl, thienyl, furyl or pyrrolyl.
  • the heteroaryl group is preferably imidazoyl, pyridyl, thienyl, furyl or pyrrolyl.
  • aliphatic refers to a straight or branched chain hydrocarbon which is completely saturated or contains one or more units of unsaturation.
  • aliphatic may be alkyl, alkenyl or alkynyl, preferably having 1 to 12 carbon atoms, up to 6 carbon atoms or up to 4 carbon atoms.
  • alkyl relates to both straight chain and branched alkyl radicals of 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms and most preferably 1 to 4 carbon atoms including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec- butyl, isobutyl, tert-butyl n-pentyl, n-hexyl, n-heptyl, n-octyl.
  • alkyl therefore relates to radicals comprising 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 or 12 carbon atoms.
  • alkyl also encompasses cycloalkyl radicals of 3 to 12 carbon atoms, preferably 4 to 8 carbon atoms, and most preferably 5 to 6 carbon atoms including but not limited to cyclopropyl, cyclobutyl, CH 2 -cyclopropyl, CH 2 -cyclobutyl, cyclopentyl or cyclohexyl. Cycloalkyl groups may be optionally substituted or fused to one or more carbocyclyl or heterocyclyl group.
  • Haloalkyl relates to an alkyl radical preferably having 1 to 8 carbon atoms, preferably 1 to 4 carbon atoms substituted with one or more halide atoms for example CH 2 CH 2 Br, CF 3 or CCI 3 .
  • alkenyl means a straight chain or branched alkylenyl radical of 2 to 12 carbon atoms, preferably 2 to 6 carbon atoms and most preferably 2 to 4 carbon atoms, and containing one or more carbon-carbon double bonds and includes but is not limited to ethylene, n-propyl-1-ene, n-propyl-2-ene, isopropylene, etc..
  • alkynyl means a straight chain or branched alkynyl radical of 2 to 12 carbon atoms, preferably 2 to 6 carbon atoms and most preferably 2 to 4 carbon atoms, and containing one or more carbon-carbon triple bonds and includes but is not limited to ethynyl, 2-methylethynyl etc.
  • alkenyl and alkynyl therefore encompass radicals comprising 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 or 12 carbon atoms.
  • alkoxy refers to an oxy group that is bonded to an alkyl group as defined herein.
  • An alkoxy is preferably a "Ci -8 alkoxy group", even more preferably a "Ci-6 alkoxy group” and more preferably a "Ci -4 alkoxy group”.
  • the alkoxy group particularly includes 1 , 2, 3 or 4 carbon atoms.
  • Particularly preferably alkoxy groups include methoxy and ethoxy.
  • Halogen means F, CI, Br or I, preferably F.
  • Preferred compounds of the invention listed above extend to the tautomers thereof, as well as (but not limited to) pharmaceutically acceptable salts, esters, amides, carbamates, carbonates, ureides or prodrugs thereof or a derivative optionally with one or more lipid groups (natural or synthetic) attached.
  • the invention extends to prodrugs of the aforementioned compounds.
  • a prodrug is any compound that may be converted under physiological conditions or by solvolysis to any of the compounds of the invention or to a pharmaceutically acceptable salt of the compounds of the invention.
  • a prodrug may be inactive when administered to a subject but is converted in vivo to an active compound of the invention.
  • the compounds of the invention may contain one or more stereogenic (asymmetric) carbon atoms and may exist in racemic and optically active forms (enantiomers or diastereoisomers).
  • the first aspect of the invention includes all such enantiomers or diastereoisomers and mixtures thereof, including racemic mixtures.
  • Examples of pharmaceutically acceptable salts of the compounds of formulae (I), (II) and (III) include those derived from organic acids such as methanesulphonic acid, benzenesulphonic acid and p-toluenesulphonic acid, mineral acids such as hydrochloric and sulphuric acid and the like, giving methanesulphonate, benzenesulphonate, p- toluenesulphonate, hydrochloride and sulphate, and the like, respectively or those derived from bases such as organic and inorganic bases.
  • organic acids such as methanesulphonic acid, benzenesulphonic acid and p-toluenesulphonic acid
  • mineral acids such as hydrochloric and sulphuric acid and the like
  • methanesulphonate, benzenesulphonate, p- toluenesulphonate, hydrochloride and sulphate, and the like respectively or those derived from bases such as organic and
  • suitable inorganic bases for the formation of salts of compounds for this invention include the hydroxides, carbonates, and bicarbonates of ammonia, lithium, sodium, calcium, potassium, aluminium, iron, magnesium, zinc and the like. Salts can also be formed with suitable organic bases.
  • bases suitable for the formation of pharmaceutically acceptable base addition salts with compounds of the present invention include organic bases which are nontoxic and strong enough to form salts.
  • Such organic bases are already well known in the art and may include amino acids such as arginine and lysine, mono-, di-, or trihydroxyalkylamines such as mono-, di-, and triethanolamine, choline, mono-, di-, and trialkylamines, such as methylamine, dimethylamine, and trimethylamine, guanidine; N- methylglucosamine; N-methylpiperazine; morpholine; ethylenediamine; N- benzylphenethylamine; tris(hydroxymethyl) aminomethane; and the like.
  • amino acids such as arginine and lysine, mono-, di-, or trihydroxyalkylamines such as mono-, di-, and triethanolamine, choline, mono-, di-, and trialkylamines, such as methylamine, dimethylamine, and trimethylamine, guanidine; N- methylglucosamine; N-methylpiperazine; morpholine; ethylenediamine; N
  • Salts may be prepared in a conventional manner using methods well known in the art. Acid addition salts of said basic compounds may be prepared by dissolving the free base compounds according to the first or second aspects of the invention in aqueous or aqueous alcohol solution or other suitable solvents containing the required acid. Where a compound of formula (I), (II) or (III) contain an acidic function a base salt of said compound may be prepared by reacting said compound with a suitable base. The acid or base salt may separate directly or can be obtained by concentrating the solution eg. by evaporation. The compounds of this invention may also exist in solvated or hydrated forms. The compounds of the invention are provided for the prevention and/or treatment of cancer.
  • the compounds of formula (I), (II) and/or (III) as described above are therefore provided for the prevention and/or treatment of hormone-induced cancers, preferably breast, ovarian, uterine, endometrial and prostate cancer.
  • the compounds of formula (I), (II) and/or (III) are further provided for the prevention and/or treatment of hormone-induced cancers, preferably breast, ovarian, uterine, endometrial and prostate cancer in pre- and/or post-menopausal women, preferably pre-menopausal women.
  • prevention and/or treatment of cancer means any effect which mitigates any damage, to any extent.
  • treatment means any amelioration of disorder, disease, syndrome, condition, pain or a combination of two or more thereof.
  • prevention means to prevent the condition from occurring, lessening the severity of the condition or to prevent from deteriorating or getting worse for example by halting the progress of the disease without necessary ameliorating the condition.
  • a second aspect of the invention provides a composition comprising a compound, in particular a novel compound according to the first aspect of the invention, in combination with a pharmaceutically acceptable excipient.
  • the pharmaceutically acceptable excipient may comprise a pharmaceutically acceptable carrier and/or pharmaceutically acceptable diluent.
  • Suitable carriers and/or diluents are well known in the art and include pharmaceutical grade starch, mannitol, lactose, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, (or other sugar), magnesium carbonate, gelatin, oil, alcohol, detergents, emulsifiers or water (preferably sterile).
  • the composition may be a mixed preparation of a composition or may be a combined preparation for simultaneous, separate or sequential use (including administration).
  • a pharmaceutical composition may be provided in unit dosage form, will generally be provided in a sealed container and may be provided as part of a kit. Such a kit would normally (although not necessarily) include instructions for use. It may include a plurality of said unit dosage forms.
  • compositions according to the invention for use in the aforementioned indications may be administered by any convenient method, for example by oral (including by inhalation), parenteral, mucosal (e.g. buccal, sublingual, nasal), rectal or transdermal administration and the compositions adapted accordingly.
  • Such compositions may be prepared by any method known in the art of pharmacy, for example by admixing the active ingredient with a carrier(s) or excipient(s) under sterile conditions.
  • the compounds can be formulated as liquids or solids, for example solutions, syrups, suspensions or emulsions, tablets, capsules and lozenges.
  • Pharmaceutical compositions adapted for oral administration may be presented as discrete units such as capsules or tablets; as powders or granules; as solutions, syrups or suspensions (in aqueous or non-aqueous liquids; or as edible foams or whips; or as emulsions).
  • Suitable excipients for tablets or hard gelatine capsules include lactose, starch including maize starch or derivatives thereof, stearic acid or salts thereof, such as magnesium stearate, sucrose or microcrystalline cellulose.
  • a composition in the form of a capsule can be prepared using routine encapsulation procedures.
  • powders, granules or pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.
  • suitable excipients for use with soft gelatine capsules include for example vegetable oils, waxes, fats, semi-solid, or liquid polyols etc.
  • Compositions for oral administration may be designed to protect the active ingredient against degradation as it passes through the alimentary tract, for example by an outer coating of the formulation on a tablet or capsule.
  • a liquid formulation such as a solution or a syrup will generally consist of a suspension or solution of the compound or physiologically acceptable salt in a suitable aqueous or nonaqueous liquid carrier(s) for example water, ethanol, glycerine, sugars, polyethylene glycol or an oil.
  • a suitable aqueous or nonaqueous liquid carrier(s) for example water, ethanol, glycerine, sugars, polyethylene glycol or an oil.
  • suspensions oils e.g. vegetable oils
  • the formulation may also contain a suspending agent, preservative, flavouring or colouring agent.
  • compositions for nasal or oral administration may conveniently be formulated as aerosols, drops, gels and powders.
  • Aerosol formulations typically comprise a solution or fine suspension of the active substance in a physiologically acceptable aqueous or nonaqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomising device.
  • the sealed container may be a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal once the contents of the container have been exhausted.
  • the dosage form comprises an aerosol dispenser, it will contain a pharmaceutically acceptable propellant.
  • the aerosol dosage forms can also take the form of a pump- atomiser.
  • compositions adapted for nasal administration wherein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to 500 microns which is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • suitable compositions wherein the carrier is a liquid, for administration as a nasal spray or as nasal drops, include aqueous or oil solutions of the active ingredient.
  • compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
  • the compositions are preferably applied as a topical ointment or cream.
  • the active ingredient may be employed with either a paraffinic or a water-miscible ointment base.
  • the active ingredient may be formulated in a cream with an oil- in-water cream base or a water-in-oil base.
  • compositions adapted for topical administration to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.
  • Pharmaceutical compositions adapted for topical administration in the mouth include lozenges, pastilles and mouth washes.
  • Pharmaceutical compositions adapted for rectal administration may be presented as suppositories or enemas.
  • Pharmaceutical compositions adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.
  • Compositions for rectal or vaginal administration are conveniently in the form of suppositories (containing a conventional suppository base such as cocoa butter), pessaries, vaginal tabs, foams or enemas.
  • compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles, wherein the active ingredient is formulated with a carrier such as sugar and acacia, tragacanth, or gelatin and glycerin.
  • compositions suitable for transdermal administration include ointments, gels, patches and injections including powder injections.
  • composition is in unit dose form such as a tablet, capsule or ampoule.
  • compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solution which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation substantially isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • Excipients which may be used for injectable solutions include water, alcohols, polyols, glycerine and vegetable oils, for example.
  • compositions may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carried, for example water for injections, immediately prior to use.
  • sterile liquid carried, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.
  • compositions may contain preserving agents, solubilising agents, stabilising agents, wetting agents, emulsifiers, sweeteners, colourants, odourants, salts, buffers, coating agents or antioxidants. They may also contain an adjuvant and/or therapeutically active agents in addition to the substance of the present invention.
  • Dosages of the substance of the present invention can vary between wide limits, depending upon a variety of factors including the disease or disorder to be treated, the age, weight and condition of the individual to be treated, the route of administration etc. and a physician will ultimately determine appropriate dosages to be used.
  • the dosage adopted for each route of administration when a compound of the invention is administered to adult humans is 0.001 to 500 mg/kg.
  • Such a dosage may be given, for example, from 1 to 5 times daily by bolus infusion, infusion over several hours and/or repeated administration.
  • the compositions may be administered in conjunction with one or more other therapeutically active agents, especially those effective for treating cancers (i.e. a chemotherapeutic agent).
  • chemotherapeutic agent may be, for example, mitoxantrone, Vinca alkaloids, such as vincristine and vinblastine, anthracycline antibiotics such as daunorubicin and doxorubicin, alkylating agents such as chlorambucil and melphalan, taxanes such as paclitaxel, anti-folates such as methotrexate and tomudex, epipodophyllotoxins such as etoposide, camptothecins such as irinotecan and its active metabolite SN-38 and DNA methylation inhibitors.
  • Vinca alkaloids such as vincristine and vinblastine
  • anthracycline antibiotics such as daunorubicin and doxorubicin
  • alkylating agents such as chlorambucil and melphalan
  • taxanes such as paclitaxel
  • anti-folates such as methotrexate and tomudex
  • the other active compound(s) may be incorporated in the same composition as the compounds of the present invention or they may be administered alongside the compounds of the present invention, e.g. simultaneously or sequentially.
  • the invention provides a kit of parts comprising a compound of the invention and another chemotherapeutic agent, optionally with instructions for use.
  • the compound of the first aspect of the invention may be administered by their addition to a food or drink.
  • the compounds of the first aspect of the invention are formulated into a powder or liquid for addition to food or drink and administration by these means.
  • the compounds of the first or second aspects will be formulated with an excipient or diluent but such excipient or diluent does not need to be pharmaceutically acceptable but instead should be acceptable for consumption.
  • a third aspect of the invention provides a process for the manufacture of a composition according to the second aspect of the invention.
  • the manufacture can be carried out by standard techniques well known in the art and involves combining a compound according to the second aspect of the invention and a pharmaceutically acceptable carrier or diluent.
  • the composition may be in any form including a tablet, a liquid, a capsule, and a powder or in the form of a food product, e.g. a functional food. In the latter case the food product itself may act as the pharmaceutically acceptable carrier.
  • the fourth aspect of the invention provides a method of preventing and/or treating cancer comprising administering a compound of the first aspect of the invention to a patient in need thereof.
  • the method is particularly provided for the prevention and/or treatment of hormone- induced cancers, preferably breast, ovarian, uterine, endometrial and prostate cancer.
  • the compounds of formula (I), (II) and/or (III) are further provided for the prevention and/or treatment of hormone-induced cancers, preferably breast, ovarian, uterine, endometrial and prostate cancer in pre- and/or post-menopausal women, preferably premenopausal women.
  • the compounds of the present invention inhibit the conversion of pre- carcinogens into carcinogenic compounds thereby reducing or removing the risk of cancer.
  • the patient in need thereof does not therefore need to be suffering from cancer but can instead wish to reduce his or her risk of cancer.
  • the fourth aspect of the invention provides a method of reducing the risk of developing cancer, comprising administering a compound of the first aspect of the invention.
  • a person wishing to reduce this or her risk of cancer may be a person who is genetically predisposed to cancer or who is at risk of cancer due to environmental factors (i.e. smoking, pollution, exposure to toxins etc.).
  • the compound of the first aspect of the invention can be provided in combination with one or more other therapeutic agents, especially those effective for treating cancers (i.e. a chemotherapeutic agent) as described in the second aspect of the invention.
  • the fifth aspect of the invention relates to the use of the compounds of the first and/or second aspect of the invention in the manufacture of a medicament for the prevention and/or treatment of cancer.
  • the compounds of the present invention inhibit the conversion of pre- carcinogens into carcinogenic compounds thereby reducing or removing the risk of cancer.
  • the medicament can therefore be provided to patient who is not suffering from cancer but instead wishes to reduce his or her risk of cancer.
  • the sixth aspect of the invention relates to a composition
  • a composition comprising a compound of formula (I), (II) or (III) as defined in the first aspect of the invention and a drug for treating cancer.
  • the drug for treating cancer can be for example, mitoxantrone, Vinca alkaloids, such as vincristine and vinblastine, anthracycline antibiotics such as daunorubicin and doxorubicin, alkylating agents such as chlorambucil and melphalan, taxanes such as paclitaxel, anti- folates such as methotrexate and tomudex, epipodophyllotoxins such as etoposide, camptothecins such as irinotecan and its active metabolite SN-38 and DNA methylation inhibitors.
  • the drug for treating cancer is one or more of a platinum compound, such as cisplatin, a taxane or a nucleoside analogue.
  • the compound of formula (I), (II) or (III) acts to re-sensitise cancer cells which are resistant to currently available cancer therapies.
  • the seventh aspect of the invention therefore relates to a composition comprising a compound of formula (I), (II) or (III) as defined in the first aspect of the invention and a drug for treating cancer for use in treating cancer, wherein the cancer is resistant to the cancer treating drug.
  • the term "resistant” indicates that the cancer therapy either has a decreased effect or no effect on the cancer cells.
  • All preferred features of the first to seventh aspects of the invention relate to all other aspects of the invention mutandis mutandi.
  • cancer according to the fifth and sixth aspects of the invention is as defined in the first aspect of the invention.
  • Figure 1 illustrates the plasmid map of pcDNA3.1/n_CYP1 B1 ;
  • Figure 2 illustrates the confirmation of the presence of CYP1 B1 protein in HEK293 and CHO-K1 cells transferred with pcDNA3.1/n_CYP1 B1 by Western blotting;
  • Figure 3 illustrates confirmation of the presence of CYP1 B1 protein in A2780 and A2780 cis cells by western blotting. 1.74 ⁇ g of protein for A2780 and O ⁇ g of protein for A2780 cis cells were fractionated by 10% SDS-PAGE followed by immunoblotting.
  • IC50 values the concentration at which 50 % of the enzyme activity is inhibited
  • An IC50 assay includes microsomes which either contain cytochrome P450 enzymes, a chosen chemical compound in six serial dilutions, DMSO, 96-well flat-bottomed microtitre plate, substrates such as ER or CEC or EOMCC or DBF (which form fluorescent compounds upon CYP metabolism) and a fluorescent plate reader which ultimately determines IC50 values via endpoint fluorescence assays.
  • cytochrome P450 enzymes a chosen chemical compound in six serial dilutions
  • DMSO 96-well flat-bottomed microtitre plate
  • substrates such as ER or CEC or EOMCC or DBF (which form fluorescent compounds upon CYP metabolism)
  • a fluorescent plate reader which ultimately determines IC50 values via endpoint fluorescence assays.
  • Regenerating System consists of:
  • Solution A (183 mg of NADP + + 183 mg of glucose-6-phosphate + 654 ⁇ of 1.0 M magnesium chloride solution + 9.15 ml of sterile ultra-pure water) + 1 ⁇ Solution B (250 Units of glucose-6-phosphate dehydrogenase + 6.25 ml of 5 mM sodium citrate, mixed in a tube and made up to 10 ml with sterile ultra-pure water) + 39 ⁇ 0.2 M Kpi (0.6 ml of 1.0M K 2 HP0 4 + 9.4 ml of 1.0M KH 2 P0 4 were mixed and made up to 50 ml with sterile ultra-pure water) + 5 ⁇ potential inhibitory compound.
  • Enzyme System consists of:
  • CYP1 B1 0.5 pmoles; CYP Design Ltd
  • 1 .7 ⁇ control protein denatured proteins from yeast cells that do not contain recombinant CYP450 proteins
  • 42.8 ⁇ 0.1 M Kpi 0.3 ml of 1.0 M K 2 HP0 4 + 4.7 ml of 1.0 M KH2PO4 were mixed and made up to 50 ml with sterile ultra-pure water).
  • the Assay is performed using (a) Sensitivity (Gain): 65/70/75 of the Biotek Synergy plate reader (this would differ from one instrument to the other) and (b) Filters: 530/590 nm that monitors fluorescence excitation/ emission.
  • the computer was switched on and the KC4 software (on the BioTek plate reader) was opened to select the assay parameters and plate layout.
  • the plate reader machine was warmed at 37°C.
  • Compounds were serially diluted to six different concentrations with 10% DMSO in a Sero-Wel white microplate. Serial dilutions were made with a dilution factor of 1 :20. 45 ⁇ of regenerating system was prepared and pre-warmed at 37°C.
  • Table 1 The constitution of the regenerating system used per reaction in each single well for different CYPs was as follows.
  • CYP3A4 1.1 ⁇ 0.102 ⁇ 0.1 ⁇ 2 mM 25 ⁇ 0.2 ⁇ 23.96 ⁇
  • Tris-acetonitrile was added to all wells using an 8-channel multi-pipette to stop the reaction; after that 50 ⁇ of enzyme/substrate reaction was added into the background well.
  • the plate was left to shake for 10 seconds and an endpoint assay was run using appropriate settings.
  • Step 6 Added lower concentration than D which probably will lead to IC50 value •
  • Step 7: IC50 (50- low percentage below 50%) x (higher concentration - lower concentration) + lower concentration.
  • Example 2 The IC50s of potent inhibitors of CYP1 B1 based on their percentage inhibition
  • the IC50s were determined using the CYP1 B1 endpoint protocol.
  • the IC50 graphs were produced using GraphPad Prism 6 and the structures of compounds were drawn using Symyx Draw. The compounds are grouped together on the basis of their structural similarities. In the graphs shown in Table 3, effects of an inhibitor on EROD activity catalysed by CYP1 B1 are shown. All assays included the substrate 7-ER in the presence of indicated concentrations of the inhibitor. Each point represents the mean of triplicate readings; bars denote ⁇ SD. The X-axis represents the logarithmic values of the concentration of inhibitor in ⁇ .
  • Table 3 Structures and IC50 graphs of the compounds that inhibit in the CYP1 B1 assay.
  • the assays provide a rapid and inexpensive method of determining the inhibitory potential of compounds.
  • the assays could also be used to determine the expression levels of a particular CYP from different clones.
  • the cells can be grown and expressed at various time points and the metabolism of a fluorescence substrate can be analysed to determine the relative amounts of a CYP that is produced from different clones.
  • the cell-based enzyme inhibition assays were carried out to find if the earlier results obtained from the in vitro enzyme assays (using isolated microsomes) have any bearing in the cellular context. This can be achieved by comparing results from the in vitro assays with those obtained from cellular assays. As observed with microsomes, P450 activity is inhibited by certain compounds. However, it is important to consider if live cells expressing CYP1A1 , CYP1 B1 and CYP1A2 enzymes have the potential to take up the compounds of interest through the yeast cell wall.
  • the live cell procedures include the use of 96-well flat-bottomed microplates, the substrates and a multi-mode filter plate reader to obtain fluorescence outputs that help in determining IC50 values.
  • Procedure for live cell assays include the use of 96-well flat-bottomed microplates, the substrates and a multi-mode filter plate reader to obtain fluorescence outputs that help in determining IC50 values.
  • yeast strains were streaked out for growth on SD-minimal medium agar plates that contained the required nutrients and 2% glucose. The plates were then incubated at 30°C for 3 days. A loop-full of cells, from one of the many colonies that grew on the SD-minimal medium agar plate, were taken and were inoculated in 10 ml of autoclaved minimal medium broth that contained 0.02% casamino acids (SW6 broth) in a sterile conical flask. The broth was incubated in a shaking incubator at 30°C at 220 rpm for 16 hours. The culture was then diluted 1 :10 and optical density was measured at 600 nm.
  • CYP3A4 enzyme assays using CYP1A1 , CYP1 B1 and CYP1A2 yeast microsomes obtained from CYP Design Ltd
  • CYP1 B1 is expressed in high amounts in tissues which overproduce oestrogen, tissues 5 like the breast, uterus and ovaries. Overproduction of oestrogen causes the perpetual activation of the oestrogen receptor ultimately leading to tumour formation.
  • CYP1 B1 may offer a mechanism of anticancer drug resistance.
  • inhibition of CYP1 B1 by CYP1 B1 -specific inhibitors may offer a novel mechanism for overcoming drug resistance in some form of cancers.
  • a cell line which overproduces CYP1 B1 was created to confirm that CYP1 B1 overproduction indeed induces resistance to cisplatin and paclitaxel, two widely used anticancer agents.
  • the CYP1 B1 overproducing cell line was used to explore if a potent CYP1 B1 specific inhibitor would be able to overcome cisplatin resistance.
  • the plasmid pcDNA3.1/h_CYP1 B1 ( Figure 1 ) was used for the transfection of human embryonic kidney HEK-293 cells.
  • the plasmid pcDNA3.1/h_CYP1 B1 was introduced into HEK-293 and CHO cells (1 * 10 6 cells) via an electroporation device (Nucleofector I, Amaxa GmbH, Cologne, Germany).
  • the Nucleofector I is especially designed to facilitate high efficiency transfections.
  • a specific Nucleofector solution kit that has been developed by Amaxa for HEK-293 and CHO cells was used for transfections. After transfection, cells were expanded in T75 flasks in the presence of 1000 ⁇ g/ ⁇ l of G418 antibiotic.
  • cell lysates (12 ⁇ g/lane for HEK293 cells and 3 g/lane for CHO-K1 cells) were separated on 10 % SDS-polyacrylamide gels.
  • the proteins were electro- transferred to Immobilon-P-membranes (Millipore) by the semi-dry transfer method.
  • the membranes were blocked with 5 % non-fat dry milk in PBS.
  • the blots were probed first with primary antibody for CYP1 B1 (AbCam, Cat No Ab32649) and the secondary antibody (AbCam, Cat No Ab6721 ; goat polyclonal secondary antibody to rabbit IqG-HyL conjugated to HKP).
  • A2780 and A2780cis are epithelial human ovarian cancer cell lines; A2780 is the parent cell line, whereas A2780cis is a cisplatin-resistant cell line. It was developed by chronic exposure of the parent cisplatin-sensitive A2780 cells to increasing concentrations of cisplatin. It has been reported that cisplatin resistant lines overproduce CYP1 B1. Figure 3 confirms that this is true.
  • Table 6 depicts the EC50s obtained from MTT assays performed with different cisplatin concentrations (0.05-1 ⁇ ; each concentration in triplicate) to determine the cytotoxicity of cisplatin.
  • EC50 data for HEK293 cells HEK293 cells transfected with pcDNA3.1 and pcDNA3.1/h_CYP1 B1 , and treated with cisplatin. Cell growth was monitored via the MTT assay. EC50 is the concentration of cisplatin that gives half-maximal response to inhibition of cell growth.
  • Table 7 depicts that when CYP1 B1 -specific inhibitors (using IC50 concentrations obtained in in vitro enzyme assays) are co-administered with cisplatin in HEK-293 cells lines transfected with pcDNA3.1/h_CYP1 B1 , the EC50s are reversed completely suggesting that inhibition of CYP1 B1 effectively overcomes cisplatin resistance.
  • DMU 2105 In the presence of DMU 2105 the EC 50 goes down to 1 ⁇ from 61 ⁇ (seen in the presence of CYP1 B1 ). In the presence of CYP1 B1 inhibitor DMU 2139 the EC50 is back to 8.3 ⁇ from 61 ⁇ (seen in the presence of CYP1 B1 ) which is close to 8.7 ⁇ (seen with the cell line transfected with the control plasmid).
  • a-NF a-napthoflavone which is a known inhibitor of CYP1 enzymes only reduced the toxicity to 40 ⁇ from 61 ⁇ (seen in the presence of CYP1 B1 ).
  • the CYP1 B1 -specific inhibitors DMU 2105 and DMU2139 have also been used to treat A2780 and A2780cis (cisplatin resistant cells).
  • the EC50 of both DMU 2105 and DMY2139 in A2780 cells is at least 100-fold higher than in A2780cis cells indicating that cisplatin resistant cells are extremely sensitive to the CYP1 B1 -specific inhibitors.
  • HEK-293_pcDNA3.1/h_CYP1 B1 cells are resistant to paclitaxel; EC50 increases at least 10-fold from the parent line HEK-293_pcDNA3.1 .
  • Yeast produced CYP1 B1 was 5 ⁇ concentration of estradiol and incubated for 45 minutes at 37°C. The formation of 4-hydroxyestradiol was monitored via LC-MS (Agilent) and 500 MHz NMR (Bruker).
  • CYP1 B1 inhibitors prevent formation of 4-hydroxyestradiol. The results below were obtained using LC-MS. Similar results can be obtained using NMR.

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Abstract

L'invention concerne un composé de formule (I) utilisé pour prévenir et/ou traiter le cancer, les cycles A et B étant indépendamment un aryle éventuellement substitué ou un hétéroaryle éventuellement substitué. Les composés sont tout particulièrement prévus pour prévenir et/ou traiter les cancers induits par des hormones, comme le cancer du sein, le cancer des ovaires, le cancer de l'utérus, le cancer de l'endomètre et le cancer de la prostate.
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CN106699644A (zh) * 2016-11-17 2017-05-24 赵明根 一种新型芘基查尔酮类衍生物及其合成方法
WO2017125755A1 (fr) 2016-01-20 2017-07-27 De Montfort University Biocapteur électrochimique alternatif
WO2019081389A1 (fr) * 2017-10-25 2019-05-02 Merck Patent Gmbh Milieu à cristaux liquides et dispositif à cristaux liquides

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Publication number Priority date Publication date Assignee Title
WO2017125755A1 (fr) 2016-01-20 2017-07-27 De Montfort University Biocapteur électrochimique alternatif
CN106699644A (zh) * 2016-11-17 2017-05-24 赵明根 一种新型芘基查尔酮类衍生物及其合成方法
WO2019081389A1 (fr) * 2017-10-25 2019-05-02 Merck Patent Gmbh Milieu à cristaux liquides et dispositif à cristaux liquides
CN111263800A (zh) * 2017-10-25 2020-06-09 默克专利股份有限公司 液晶介质及液晶装置

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