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WO2025209007A1 - Composé thioéther hétérocyclique bis-aromatique substitué par une diamine alkyle, sa préparation et son application dans la préparation de médicaments pour le traitement et/ou la prévention de tumeurs - Google Patents

Composé thioéther hétérocyclique bis-aromatique substitué par une diamine alkyle, sa préparation et son application dans la préparation de médicaments pour le traitement et/ou la prévention de tumeurs

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Publication number
WO2025209007A1
WO2025209007A1 PCT/CN2025/074152 CN2025074152W WO2025209007A1 WO 2025209007 A1 WO2025209007 A1 WO 2025209007A1 CN 2025074152 W CN2025074152 W CN 2025074152W WO 2025209007 A1 WO2025209007 A1 WO 2025209007A1
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cancer
alk
μmol
compound
halogenated
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王春刚
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    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • 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
    • 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
    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/36—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/30—Hetero atoms other than halogen
    • C07D333/34—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D487/10—Spiro-condensed systems

Definitions

  • the present invention relates to the field of medical technology, and in particular to an alkyldiamine-substituted bis-aromatic heterocyclic sulfide compound and its application in preparing drugs for treating and/or preventing tumors.
  • Literature search has so far revealed no reports on the anti-tumor effects of alkyldiamine-substituted bis-heteroaromatic sulfide compounds.
  • the present invention designs and synthesizes alkyldiamine-substituted bis-heteroaromatic sulfide compounds and explores their anti-tumor effects.
  • R5 is a substituted chain alkyl group, including -CH2-, -CH2-CH2-, and -CH2-CH2-CH2-.
  • p 0, 1, 2, 3, 4, 5 or 6.
  • R4 is preferably -CH 2 -CH 2 -.
  • R5 is preferably -CH 2 -CH 2 -.
  • alkyldiamine-substituted bis-heteroaromatic sulfide compound is preferably the following compound:
  • alkyldiamine-substituted bis-heteroaromatic sulfide compound or its pharmaceutical composition is used for, but not limited to, surgical resection, chemotherapy or radiotherapy.
  • the effects of the alkyldiamine-substituted bis-heteroaromatic sulfide compound or its pharmaceutical composition include but are not limited to inhibiting tumor growth and/or metastasis.
  • preventive and/or therapeutic effects on liver cancer include but are not limited to preventive and/or therapeutic effects on liver cancer cells MHCC-97L.
  • preventive and/or therapeutic effects on renal clear cell adenocarcinoma include but are not limited to preventive and/or therapeutic effects on renal clear cell adenocarcinoma cell line 786-O.
  • preventive and/or therapeutic effects on gastric cancer include but are not limited to preventive and/or therapeutic effects on gastric cancer cell SGC-7901.
  • preventive and/or therapeutic effects on prostate cancer include but are not limited to preventive and/or therapeutic effects on prostate cancer cells PC-3.
  • preventive and/or therapeutic effects on esophageal cancer include but are not limited to preventive and/or therapeutic effects on esophageal cancer cells EC109.
  • preventive and/or therapeutic effects on melanoma include but are not limited to preventive and/or therapeutic effects on melanoma cells A375.
  • preventive and/or therapeutic effects on leukemia include but are not limited to preventive and/or therapeutic effects on leukemia cells HL60.
  • the present invention has the following beneficial effects:
  • the present invention synthesizes an alkyldiamine-substituted bis-heteroaromatic sulfide compound, explores its anti-tumor effect and its new use in preparing drugs for treating and/or preventing cancer, and there are no related reports at home and abroad.
  • the alkyldiamine-substituted bis-heteroaromatic sulfide compounds of the present invention exhibit significant broad-spectrum antitumor activity, inhibiting a variety of human tumor cells cultured in vitro, including breast cancer, liver cancer, pancreatic cancer, kidney cancer, lung cancer, gastric cancer, glioma, ovarian cancer, prostate cancer, esophageal cancer, melanoma, nasopharyngeal cancer, colon cancer, cervical cancer, lymphoma, and leukemia. Some compounds exhibit lower IC50 values than cisplatin against these tumor cells, demonstrating broad-spectrum antitumor activity.
  • alkyldiamine-substituted bis-heteroaromatic sulfide compounds of the present invention can be used to prepare antitumor drugs and prevent the occurrence and metastasis of tumors.
  • Compound T02 (Target 2) was prepared by the following method:
  • the combined organic phases were washed with saturated brine (15.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product.
  • the crude product was purified by high performance liquid chromatography (column model: Phenomenex luna C 18 150*25mm*10um; mobile phase: [water (NH 4 HCO 3 )-acetonitrile]; B%: 30%-60%, 9 min).
  • the product was placed in a 50.0 mL single-necked flask containing ethyl acetate hydrochloride (10.0 mL) and stirred at 25°C for 30 minutes.
  • tert-Butyl 4-(2-nitrophenyl)piperazine-1-carboxylate (16.0 g, 52.0 mmol, 1 equivalent) was placed in a 250 mL hydrogenation bottle containing ethanol (100 mL). Wet palladium on carbon (1.60 g, 1.50 mmol, 10% purity, 2.89 e-2 equivalent) was added. After argon replacement three times, the mixture was stirred at 50°C under a hydrogen atmosphere (50 PSI) for 5 hours. TLC indicated the reaction was complete. The reaction solution was filtered through celite and rinsed with methanol (100 mL x 3). After rinsing, the filtrate was concentrated under reduced pressure to yield tert-butyl 4-(2-aminophenyl)piperazine-1-carboxylate (16.0 g, crude) as a gray solid.
  • aqueous phase was adjusted to pH 2-3 by 1M HCl and extracted with ethyl acetate (20.0mL*3).
  • the combined organic phases were washed with saturated brine (20.0mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product.
  • the crude product was purified by reverse phase purification (0.1% HCl system) and lyophilized to give tert-butyl 4-(2-mercaptophenyl)piperazine-1-carboxylate (400 mg, 1.21 mmol, 46.5% yield, hydrochloride) as a white solid.
  • the combined organic phases were washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product.
  • the crude product was purified by high performance liquid chromatography (column model: Phenomenex luna C 18 150*25mm*10um; mobile phase: [water (NH 4 HCO 3 )-acetonitrile]; B%: 40%-70%, 9 min).
  • the product was placed in a 50.0 mL single-necked flask containing ethyl acetate hydrochloride (10.0 mL) and stirred at 25°C for 30 minutes.
  • tert-butyl 4-(2-bromophenyl)piperazine-1-carboxylate 200 mg, 586 ⁇ mol, 1 eq
  • 2,4-difluorobenzene-1-thiol 85.6 mg, 586 ⁇ mol, 1 eq
  • Sodium tert-butoxide 90.12 mg, 937.7 ⁇ mol, 1.6 eq
  • BINAP 14.6 mg, 23.44 ⁇ mol, 0.04 eq
  • Pd2(dba)3 (10.7 mg, 11.7 ⁇ mol, 0.02 eq) were added sequentially.
  • the crude product obtained by HPLC was purified by slurrying with ethyl acetate hydrochloride (4.00 mL) at 20°C for one hour, and the filter cake was concentrated under reduced pressure to yield 1- ⁇ 2-[(2,4-difluorophenyl)mercapto]phenyl ⁇ piperazine (25.3 mg, 73.8 ⁇ mol, 19.8% yield, 100% purity, hydrochloride) as a light yellow solid.
  • tert-butyl 4-(2-mercaptophenyl)piperazine-1-carboxylate hydrochloride 200 mg, 604 ⁇ mol, 1 eq, hydrochloride
  • 1-bromo-2-fluoro-4-methylbenzene 114 mg, 604 ⁇ mol, 1 eq
  • Sodium tert-butoxide 92.9 mg, 967 ⁇ mol, 1.6 eq
  • BINAP 15.0 mg, 24.1 ⁇ mol, 0.04 eq
  • Pd 2 (dba) 3 (11.0 mg, 12.0 ⁇ mol, 0.02 eq) were added sequentially.
  • Compound T12 (Target 12) was prepared by the following method:
  • Compound T13 (Target 13) was prepared by the following method:
  • Compound T14 (Target 14) was prepared by the following method:
  • tert-butyl 4- ⁇ 4-[(2,4-dimethylphenyl)mercapto]pyridin-3-yl ⁇ piperazine-1-carboxylate (141 mg, 352 ⁇ mol, eq) was dissolved in dichloromethane (1.50 mL), and trifluoroacetic acid (2.30 g, 20.1 mmol, 1.50 mL, 57.2 eq) was slowly added dropwise. The atmosphere was purged with nitrogen three times, and the mixture was stirred at 20°C for 1 hour. LC-MS/MS indicated the reaction was complete.
  • the reaction solution was adjusted to pH 9 with sodium bicarbonate and extracted with dichloromethane (10.0 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the crude product was purified by HPLC (column model: Waters Xbridge 150 x 25 mm x 5 ⁇ m; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; gradient: 30% to 60% B over 9 minutes).
  • the crude product obtained by HPLC was purified by slurrying with ethyl acetate hydrochloride (4.00 mL) at 20°C for one hour, and the filter cake was concentrated under reduced pressure to yield 1- ⁇ 4-[(2,4-dimethylphenyl)mercapto]pyridin-3-yl ⁇ piperazine (25.3 mg, 75.2 ⁇ mol, 21.3% yield, 99.7% purity, hydrochloride) as a yellow solid.
  • Compound T15 (Target 15) was prepared by the following method:
  • the reaction solution was adjusted to pH 8-9 with saturated aqueous sodium bicarbonate and extracted with dichloromethane (5.00 mL x 3).
  • the combined organic phases were washed with saturated brine (10.0 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product.
  • the crude product was purified by normal phase HPLC (column model: Welch Ultimate XB-SiOH 250*50mm*10um; mobile phase: [n-hexane-ethanol]; gradient: 10%-50% B over 15 minutes).
  • the combined organic phases were washed with saturated brine (10.0 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product.
  • Compound T18 (Target 18) was prepared by the following method:
  • the crude product was purified by high performance liquid chromatography (column model: Phenomenex luna C 18 150*25mm*10um; mobile phase: [water (hydrochloric acid)-acetonitrile]; B%: 23%-53%, 10 min) to give 2- ⁇ 2-[(2,4-dimethylphenyl)mercapto]phenyl ⁇ -octahydropyrrolo[3,4-c]pyrrole (25.2 mg, 69.9 ⁇ mol, 19.8% yield, 100% purity, hydrochloride) as an off-white solid.
  • Compound T19 (Target 19) was prepared by the following method:
  • tert-butyl 4- ⁇ 2-[(2,4-dimethylphenyl)thio]pyridin-3-yl ⁇ piperazine-1-carboxylate (163 mg, 407.96 ⁇ mol, 1 eq) was dissolved in dichloromethane (1.50 mL), and trifluoroacetic acid (2.30 g, 20.1 mmol, 1.50 mL, 57.2 eq) was slowly added dropwise. The atmosphere was purged with nitrogen three times, and the mixture was stirred at 20°C for 1 hour. LC-MS/MS indicated the reaction was complete.
  • the pH of the reaction solution was adjusted to 9 with sodium bicarbonate and extracted with dichloromethane (10.0 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the crude product was purified by HPLC (column model: Waters Xbridge 150 x 25 mm x 5 ⁇ m; mobile phase: [water (sodium bicarbonate)-acetonitrile]; gradient: 2% to 62% B over 9 minutes).
  • 19 alkyldiamine-substituted bis-heteroaryl sulfide compounds or cisplatin were diluted to concentrations of 0, 0.01, 0.1, 1, 5, 10, 20, 40, 80, and 160 ⁇ M, respectively.
  • Breast cancer MDA-MB-231LM2 cells or lung adenocarcinoma A549 cells were seeded at a density of 8,000 cells/well in 96-well plates. Twenty-four hours after inoculation, the culture medium in the original wells was discarded, and 100 ⁇ L of the diluted drug solution was added to each well, with four replicates per group. At 48 hours of treatment, 10 ⁇ L of CCK8 was added to each well and incubated for 3 hours. The OD value at A450 was measured using a multi-function microplate reader, and the inhibition rate was calculated.
  • the IC50-alkyldiamine-substituted bis-heteroaryl sulfide compounds exhibited IC50 values ranging from 2.41 to 21.86 ⁇ M, with IC50 values below 10 ⁇ M in most tumor cell lines.
  • pancreatic cancer Panc-1 In breast cancer MCF-7, MDA-MB-231, and MDA-MB-231LM2, pancreatic cancer Panc-1, lung cancer A549, glioma U251, ovarian cancer A2780, esophageal cancer EC109, melanoma A375, colon cancer HCT116, and cervical cancer Siha cells, the IC50-alkyldiamine-substituted bis-heteroaryl sulfide compounds exhibited significantly lower IC50 values than cisplatin, demonstrating a more pronounced inhibitory effect on these cells (see Table 2 for details).
  • a suspension of MDA-MB-231 cells in the logarithmic growth phase was obtained and the cell density was adjusted to 4 ⁇ 10 5 /well, seeded into 6-well plates.
  • the culture medium was replaced with compounds T03, T06, T09, T12, T13, T15, T16, and T18 (at half the IC 50 concentration of each compound for MDA-MB-231 cells, i.e., T03: 7.5 ⁇ M, T06: 9 ⁇ M, T09: 6 ⁇ M, T12: 7 ⁇ M, T13: 6 ⁇ M, T15: 6.5 ⁇ M, T16: 5 ⁇ M, and T18: 9 ⁇ M).
  • proteins were collected and analyzed by Western blot (see Figure 5).

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un composé thioéther hétérocyclique bis-aromatique substitué par une diamine alkyle, sa préparation et son application dans la préparation de médicaments pour le traitement et/ou la prévention de tumeurs. La formule structurale du composé est telle que représentée dans la formule (I) : le composé présente une bonne activité inhibitrice contre diverses cellules tumorales humaines, une bonne activité inhibitrice contre le cancer du sein, le cancer du foie, le cancer du pancréas, le cancer du rein, le cancer du poumon, le cancer de l'estomac, le gliome, le cancer de l'ovaire, le cancer de la prostate, le cancer de l'œsophage, le mélanome, le carcinome nasopharyngé, le cancer du côlon, le cancer du col de l'utérus, le lymphome, la leucémie et d'autres tumeurs de ce type, la concentration efficace en CI50 du composé contre des cellules tumorales, telles que le cancer du sein, le cancer du pancréas, le cancer du poumon, le gliome, le cancer de l'ovaire, le cancer de l'œsophage, le mélanome, le cancer du côlon, le cancer du col de l'utérus, étant inférieure à celle de la cisplatine, et des expériences montrent que le composé a une activité antitumorale à large spectre. Des expériences ont en outre détecté que le composé permettait de dégrader des protéines PD-L1 et était un immunomodulateur PD-L1. La présente invention concerne une nouvelle approche pour utiliser des composés thioéther hétérocycliques bis-aromatiques substitués par diamine d'alkyle dans la préparation de médicaments pour le traitement et/ou la prévention de tumeurs.
PCT/CN2025/074152 2024-04-02 2025-01-23 Composé thioéther hétérocyclique bis-aromatique substitué par une diamine alkyle, sa préparation et son application dans la préparation de médicaments pour le traitement et/ou la prévention de tumeurs Pending WO2025209007A1 (fr)

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CN202410390741.9A CN120774863A (zh) 2024-04-02 2024-04-02 一种烷基二胺取代双芳杂环基硫醚类化合物及其制备和在制备治疗和/或预防肿瘤药物中的应用
CN202410390741.9 2024-04-02

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CN1561336A (zh) * 2001-10-04 2005-01-05 H·隆德贝克有限公司 作为血清素再摄取抑制剂的苯基哌嗪衍生物
WO2016079751A2 (fr) * 2014-11-17 2016-05-26 Megafine Pharma (P) Ltd. Procédé de préparation de vortioxétine et de polymorphes de cette substance
WO2018014880A1 (fr) * 2016-07-22 2018-01-25 李勤耕 Analogue de vortioxétine, son utilisation et sa préparation
CN110804028A (zh) * 2019-11-14 2020-02-18 中山万远新药研发有限公司 一种哌嗪基取代的二芳基亚砜类化合物及其组合物和应用
CN111821303A (zh) * 2020-09-04 2020-10-27 郑州大学 沃替西汀及其盐在制备抗肿瘤药物中的应用
CN114209701A (zh) * 2022-01-18 2022-03-22 万宜合药业(海南)有限责任公司 沃替西汀及其衍生物的抗肿瘤活性和应用

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1561336A (zh) * 2001-10-04 2005-01-05 H·隆德贝克有限公司 作为血清素再摄取抑制剂的苯基哌嗪衍生物
WO2016079751A2 (fr) * 2014-11-17 2016-05-26 Megafine Pharma (P) Ltd. Procédé de préparation de vortioxétine et de polymorphes de cette substance
WO2018014880A1 (fr) * 2016-07-22 2018-01-25 李勤耕 Analogue de vortioxétine, son utilisation et sa préparation
CN110804028A (zh) * 2019-11-14 2020-02-18 中山万远新药研发有限公司 一种哌嗪基取代的二芳基亚砜类化合物及其组合物和应用
CN111821303A (zh) * 2020-09-04 2020-10-27 郑州大学 沃替西汀及其盐在制备抗肿瘤药物中的应用
CN114209701A (zh) * 2022-01-18 2022-03-22 万宜合药业(海南)有限责任公司 沃替西汀及其衍生物的抗肿瘤活性和应用

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