CN108794469A - A kind of new technique for synthesizing of azole compounds and the purposes of antitumor action - Google Patents
A kind of new technique for synthesizing of azole compounds and the purposes of antitumor action Download PDFInfo
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- CN108794469A CN108794469A CN201810396816.9A CN201810396816A CN108794469A CN 108794469 A CN108794469 A CN 108794469A CN 201810396816 A CN201810396816 A CN 201810396816A CN 108794469 A CN108794469 A CN 108794469A
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- chloro
- azole compounds
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- salt
- hydrate
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- 150000003851 azoles Chemical class 0.000 title claims abstract description 25
- 238000000034 method Methods 0.000 title claims abstract description 21
- 230000000259 anti-tumor effect Effects 0.000 title claims abstract description 17
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 32
- 150000003839 salts Chemical class 0.000 claims abstract description 32
- 238000006243 chemical reaction Methods 0.000 claims abstract description 27
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims abstract description 16
- 238000002360 preparation method Methods 0.000 claims abstract description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 11
- 238000003756 stirring Methods 0.000 claims description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 25
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 18
- 150000003222 pyridines Chemical class 0.000 claims description 17
- 239000002775 capsule Substances 0.000 claims description 16
- 239000000047 product Substances 0.000 claims description 14
- 239000007787 solid Substances 0.000 claims description 13
- 238000005406 washing Methods 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims description 11
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 10
- 201000007270 liver cancer Diseases 0.000 claims description 10
- 208000014018 liver neoplasm Diseases 0.000 claims description 10
- 239000007901 soft capsule Substances 0.000 claims description 10
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 claims description 10
- 206010006187 Breast cancer Diseases 0.000 claims description 9
- 208000026310 Breast neoplasm Diseases 0.000 claims description 9
- 108010010803 Gelatin Proteins 0.000 claims description 9
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 9
- 239000012065 filter cake Substances 0.000 claims description 9
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- 229920000159 gelatin Polymers 0.000 claims description 9
- 235000019322 gelatine Nutrition 0.000 claims description 9
- 235000011852 gelatine desserts Nutrition 0.000 claims description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 8
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 8
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 8
- 239000003292 glue Substances 0.000 claims description 7
- 239000007788 liquid Substances 0.000 claims description 7
- 239000000243 solution Substances 0.000 claims description 7
- 235000013871 bee wax Nutrition 0.000 claims description 6
- 201000004101 esophageal cancer Diseases 0.000 claims description 6
- 201000005296 lung carcinoma Diseases 0.000 claims description 6
- 238000012805 post-processing Methods 0.000 claims description 6
- MVXVYAKCVDQRLW-UHFFFAOYSA-N 1h-pyrrolo[2,3-b]pyridine Chemical class C1=CN=C2NC=CC2=C1 MVXVYAKCVDQRLW-UHFFFAOYSA-N 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- 230000002401 inhibitory effect Effects 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 5
- SRPWOOOHEPICQU-UHFFFAOYSA-N trimellitic anhydride Chemical compound OC(=O)C1=CC=C2C(=O)OC(=O)C2=C1 SRPWOOOHEPICQU-UHFFFAOYSA-N 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 4
- 230000006837 decompression Effects 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- 235000011187 glycerol Nutrition 0.000 claims description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 4
- 239000000843 powder Substances 0.000 claims description 4
- NWGKJDSIEKMTRX-AAZCQSIUSA-N Sorbitan monooleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-AAZCQSIUSA-N 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- 239000012043 crude product Substances 0.000 claims description 3
- 238000010790 dilution Methods 0.000 claims description 3
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- 238000000605 extraction Methods 0.000 claims description 3
- 239000000706 filtrate Substances 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 239000000463 material Substances 0.000 claims description 3
- 238000002844 melting Methods 0.000 claims description 3
- 230000008018 melting Effects 0.000 claims description 3
- 239000012074 organic phase Substances 0.000 claims description 3
- 239000012071 phase Substances 0.000 claims description 3
- 238000010791 quenching Methods 0.000 claims description 3
- 230000000171 quenching effect Effects 0.000 claims description 3
- 239000002994 raw material Substances 0.000 claims description 3
- 235000012424 soybean oil Nutrition 0.000 claims description 3
- 239000003549 soybean oil Substances 0.000 claims description 3
- 239000012166 beeswax Substances 0.000 claims description 2
- 150000007522 mineralic acids Chemical class 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims description 2
- 238000001556 precipitation Methods 0.000 claims description 2
- 206010011224 Cough Diseases 0.000 claims 1
- XCRBXWCUXJNEFX-UHFFFAOYSA-N peroxybenzoic acid Chemical compound OOC(=O)C1=CC=CC=C1 XCRBXWCUXJNEFX-UHFFFAOYSA-N 0.000 claims 1
- 150000003233 pyrroles Chemical class 0.000 claims 1
- 238000007873 sieving Methods 0.000 claims 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 12
- 238000003786 synthesis reaction Methods 0.000 abstract description 10
- 230000008569 process Effects 0.000 abstract description 6
- 238000005516 engineering process Methods 0.000 abstract description 3
- 125000001309 chloro group Chemical group Cl* 0.000 abstract 1
- 239000007858 starting material Substances 0.000 abstract 1
- 230000001988 toxicity Effects 0.000 abstract 1
- 231100000419 toxicity Toxicity 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 31
- 201000011510 cancer Diseases 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 206010028980 Neoplasm Diseases 0.000 description 11
- 230000000694 effects Effects 0.000 description 7
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 4
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 4
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 4
- 208000017897 Carcinoma of esophagus Diseases 0.000 description 4
- MNQZXJOMYWMBOU-VKHMYHEASA-N D-glyceraldehyde Chemical compound OC[C@@H](O)C=O MNQZXJOMYWMBOU-VKHMYHEASA-N 0.000 description 4
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 4
- 239000005642 Oleic acid Substances 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 4
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 4
- 210000004881 tumor cell Anatomy 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 3
- 201000008275 breast carcinoma Diseases 0.000 description 3
- 230000002147 killing effect Effects 0.000 description 3
- 201000005202 lung cancer Diseases 0.000 description 3
- 208000020816 lung neoplasm Diseases 0.000 description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- MNQZXJOMYWMBOU-GSVOUGTGSA-N L-(-)-glyceraldehyde Chemical compound OC[C@H](O)C=O MNQZXJOMYWMBOU-GSVOUGTGSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 239000000084 colloidal system Substances 0.000 description 2
- 238000004132 cross linking Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
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- 239000000499 gel Substances 0.000 description 2
- 238000000227 grinding Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 2
- 230000005311 nuclear magnetism Effects 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
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- 240000008397 Ganoderma lucidum Species 0.000 description 1
- 235000001637 Ganoderma lucidum Nutrition 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 102000057297 Pepsin A Human genes 0.000 description 1
- 108090000284 Pepsin A Proteins 0.000 description 1
- 239000001888 Peptone Substances 0.000 description 1
- 108010080698 Peptones Proteins 0.000 description 1
- 241000255964 Pieridae Species 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 206010043276 Teratoma Diseases 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
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- 230000001093 anti-cancer Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000002585 base Substances 0.000 description 1
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- 239000006227 byproduct Substances 0.000 description 1
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- 230000036952 cancer formation Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
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- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
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- 238000011081 inoculation Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- YOBAEOGBNPPUQV-UHFFFAOYSA-N iron;trihydrate Chemical compound O.O.O.[Fe].[Fe] YOBAEOGBNPPUQV-UHFFFAOYSA-N 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
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- 231100000053 low toxicity Toxicity 0.000 description 1
- 201000000289 malignant teratoma Diseases 0.000 description 1
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- 230000000116 mitigating effect Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- QCCWVNLOJADEAV-UHFFFAOYSA-N n,n-dimethyl-1h-pyrrol-3-amine Chemical class CN(C)C=1C=CNC=1 QCCWVNLOJADEAV-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 150000002829 nitrogen Chemical group 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 125000000018 nitroso group Chemical group N(=O)* 0.000 description 1
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- 235000019319 peptone Nutrition 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
-
- 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
- A61K31/4353—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
- A61K31/437—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 five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/26—Iron; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/37—Digestive system
- A61K35/413—Gall bladder; Bile
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/06—Fungi, e.g. yeasts
- A61K36/07—Basidiomycota, e.g. Cryptococcus
- A61K36/074—Ganoderma
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4816—Wall or shell material
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4816—Wall or shell material
- A61K9/4825—Proteins, e.g. gelatin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Public Health (AREA)
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- Medicinal Chemistry (AREA)
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- Natural Medicines & Medicinal Plants (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
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- Biotechnology (AREA)
- Medical Informatics (AREA)
- Alternative & Traditional Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
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- Cell Biology (AREA)
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- Developmental Biology & Embryology (AREA)
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Abstract
The invention discloses the purposes of a kind of new technique for synthesizing of azole compounds and antitumor action, more particularly to the chloro- 5- nitros -1H- pyrrolo-es of compound 1- benzenesulfonyls -4- [2, 3-b] pyridine, the purposes of the new synthesis process and antitumor action of hydrate and its salt, this synthesis technology is with 1H- pyrrolo-es [2, 3-b] pyridine be starting material, through chloro, the chloro- 5- nitros -1H- pyrrolo-es of 1- benzenesulfonyls -4- [2 are prepared in the reactions such as acylated, 3-b] pyridine, hydrate and its salt, provide one it is easy to operate, the new process of high income, preparation method is easy to operate, reaction condition is mild, the antitumor activity of compound is notable simultaneously, to normal cell small toxicity, be conducive to its being widely popularized in antitumor field.
Description
Technical field
The present invention relates to azole compounds fields, new technique for synthesizing more particularly, to a kind of azole compounds and antitumor
The purposes of effect.
Technical background
Medically, cancer refers to the malignant tumour originating from epithelial tissue, is most common one kind in malignant tumour.Relatively
It answers, the malignant tumour originating from mesenchymal tissue is referred to as sarcoma.There are a small number of malignant tumours not named by mentioned above principle, such as kidney mother
Cytoma, malignant teratoma etc.." cancer " described in general people traditionally refers to all malignant tumours.
For many years, although research of the scientific circles in cancer formation and development mechanism achieves great progress, so far
Effective therapy until the present for cancer still compares shortage.Nearly all antitumor drug is all on domestic and international market at present
Generally existing works the shortcomings of slow, side effect is big and is also easy to produce drug resistance, thus their Clinical practice receive it is certain
Limitation.It is current important science that new anticancer target spot and research and development, which are found, for the high-efficiency low-toxicity anticancer drug of these novel targets
Task.
Invention content
One of the objects of the present invention is to provide the new technique for synthesizing of a kind of azole compounds, hydrate and its salt, this conjunctions
Mild at new process reaction condition, reaction duration is shorter, not high to equipment requirement, and side reaction degree is relatively low, efficiency of pcr product
It is higher.
The second object of the present invention is to provide a kind of azole compounds, hydrate and its salt in terms of antitumor action
Chloro- 5- nitros -1H- pyrrolo-es [2, the 3-b] pyridine of purposes, specifically compound 1- benzenesulfonyls -4-, hydrate and its salt are anti-
Purposes in terms of tumour, chloro- 5- nitros -1H- pyrrolo-es [2, the 3-b] pyridines of 1- benzenesulfonyls -4-, hydrate and its salt can have
Effect inhibits HepG2（Human liver cancer）Cell, TE1（Human esophagus cancer）Cell, MCF7（Human breast carcinoma）Cell, lung carcinoma cell.
The present invention is directed to the problem of being mentioned in background technology, and the technical solution taken is：A kind of synthesis of azole compounds
The synthesis of chloro- 5- nitros -1H- pyrrolo-es [2, the 3-b] pyridine of new process, specially 1- benzenesulfonyls -4-, hydrate and its salt is new
The structural formula of technique, chloro- 5- nitros -1H- pyrrolo-es [2, the 3-b] pyridines of 1- benzenesulfonyls -4- is：
The structural formula of chloro- 5- nitros -1H- pyrrolo-es [2,3-b] hydrates of 1- benzenesulfonyls -4- and its salt is：
X indicates hydrate of this compound acceptable at salt any organic acid and inorganic acid and any ratio.
The synthetic method packet of chloro- 5- nitros -1H- pyrrolo-es [2,3-b] pyridines of 1- benzenesulfonyls -4-, hydrate and its salt
Include following steps：
Chloro- 5- nitros -1H- pyrrolo-es [2,3-b] pyridines of azoles 1- benzenesulfonyls -4-, its salt or its hydrate
Novel synthesis technology is specific as follows：
The synthesis of GXY2010-1：
The synthesis of GXY2010-2：
The synthesis of GXY2010-3：
The synthesis of GXY2010-4：
The a is, by raw material 7- azaindoles and dimethyl ether（DME）It mixes, stirring and dissolving, adds in batches under 0~10 DEG C of ice salt bath
Enter metachloroperbenzoic acid, controlled at 10~20 DEG C, reacts 1~3h.
The b is that reaction terminates, and normal heptane is added under stirring into reaction solution, is filtered after stirring half an hour, and filter cake is used
DME：Normal heptane=1:1 solution washed once, solid naturally dry, obtain field gray solid (Y:89%).
The c is that intermediate GXY2010-1 and phosphorus oxychloride are added in reaction vessel, and lower stirring is in bronzing mixed liquor,
After being warming up to 40~60 DEG C, 1h is stirred, continues to be heated to 90 DEG C, liquid temperature to be mixed is stablized, and 10~15h is stirred to react；Reaction
Terminating, is cooled to room temperature, decompression evaporates phosphorus oxychloride, and dilution in acetonitrile is added in extraction raffinate, is slowly added dropwise to water quenching and goes out phosphorus oxychloride,
It is 9 to adjust pH, and the khaki solid of precipitation filters, and washing washing is dried to obtain.
The d is that intermediate GXY2010-2, dichloromethane are sequentially added into reaction bulb（DCM）, 4- dimethylamino pyrroles
Pyridine（DMAP）And triethylamine（Et3N）, PhSO is added portionwise2Cl, temperature increase, water-bath cooling control charge temperature 35 DEG C with
Under, 60min is finished, and after finishing, room temperature continues to react and terminate after stirring 20h.
The e is post-processing, and dilute hydrochloric acid adjusts PH as 2~5, DCM phases, and alkali liquid washing, water washing takes organic phase to dry,
Evaporated under reduced pressure obtains crude product.
The f is that intermediate GXY2010-3, DCM and TBAN are added into reaction bulb, and stirring to solid is completely dissolved, point
It criticizes and trifluoroacetic anhydride is added（TFAA）, trimellitic anhydride（TMA）, control charge temperature is at -10~-20 DEG C hereinafter, 20min adds
Finish, after finishing, 0 DEG C~20 DEG C stirrings are for 24 hours.
The h is post-processing, is filtered, and filter cake is washed with acetonitrile, and filter cake is product；Filtrate is spin-dried for filtering.Drying is obtained
Light yellow this product, light yellow this product compound are chloro- 5- nitros -1H- pyrrolo-es [2, the 3-b] pyridines of 1- benzenesulfonyls -4-, nuclear-magnetism
Data are 1H-NMR (300MHz, CDCl3, ppm) δ:9.005 (s, 1H), 8.244 (m, 2H), 7.965 (d, J=3.9Hz, 1H),
7.696 (m, 1H), 7.584 (m, 2H), 6.886 (d, J=3.9Hz, 1H).
A kind of new technique for synthesizing of azole compounds and the purposes of antitumor action, the specifically chloro- 5- of 1- benzenesulfonyls -4-
Nitro -1H- pyrrolo-es [2,3-b] pyridine, hydrate and its salt are in the new application of anti-tumor aspect, the chloro- 5- of 1- benzenesulfonyls -4-
Nitro -1H- pyrrolo-es [2,3-b] pyridine, its salt or its hydrate can effectively inhibit HepG2（Human liver cancer）Cell, TE1（People
The cancer of the esophagus）Cell, MCF7（Human breast carcinoma）Cell, lung carcinoma cell, the chloro- 5- nitros -1H- pyrrolo-es of 1- benzenesulfonyls -4- [2,3-
B] pyridine, hydrate and its salt to above-mentioned cancer cell have more significant killing effect, can make for treat human liver cancer,
The drug of the malignant tumours such as breast cancer, cancer of the esophagus, lung cancer.
Preferably, with chloro- 5- nitros -1H- pyrrolo-es [2, the 3-b] pyridines of 1- benzenesulfonyls -4-, hydrate and its salt system
It is for the method for capsule preparations：
420~450 portions of soybean oils, 25~30 parts of beeswaxs, 5.5~6.0 parts of span-80 mixings are taken, being heated to 70~72 DEG C makes bee
Wax melts completely, and stirring is cooled to 35 DEG C, and 45~48 parts of Chinese medical concrete Ultramicro-powders, 0.03~0.05 part of 1- benzenesulfonyl-is added
Chloro- 5- nitros -1H- pyrrolo-es [2, the 3-b] pyridines of 4- or its hydrate or its salt, stir evenly, vacuumize cancellation bubble, standby
With；Take gelatin, glycerine, water according to 0.4~0.5:0.6~0.8:Water-bath type glue tank is added in 1 ratio, after stirring and melting
2h is kept the temperature, cancellation bubble is vacuumized, crosses 100~160 mesh screens, 50~60 DEG C of glue bucket heat preservations is placed in, stands 2h；24~25
DEG C, relative humidity be 45~50% in the environment of use soft capsule press, insert above-mentioned material, suppress soft capsule；25~26
DEG C, dry for 24 hours to get capsule preparations in the environment of relative humidity 10~15%；Capsule preparations prescription rationally, feasible process, content
Object is the sticky colloid of taupe, and gas is micro-, bitter, and the dosage form is high with bioavilability, toxic side effect is small, absorption is rapid, stablizes
Property it is good, convenient for taking the advantages that, the effective effectiveness ingredient Chinese herbal and crude drugs preparations of soft capsule and the chloro- 5- nitros -1H- of 1- benzenesulfonyls -4-
The dissolution rate of pyrrolo- [2,3-b] pyridine, its salt or its hydrate is higher, is conducive to the rapid absorption of body, to play it
Kill the effect of cancer cell.
Compared with the prior art, the advantages of the present invention are as follows：
1）The new technique for synthesizing of a kind of azole compounds, hydrate and its salt, this new technique for synthesizing reaction condition is mild, when reaction
Length is shorter, not high to equipment requirement, and side reaction degree is relatively low, and efficiency of pcr product is higher；
2）A kind of azole compounds, hydrate and its salt can effectively inhibit HepG2（Human liver cancer）Cell, TE1（Human esophagus cancer）
Cell, MCF7（Human breast carcinoma）Cell, lung carcinoma cell, chloro- 5- nitros -1H- pyrrolo-es [2, the 3-b] pyridines of 1- benzenesulfonyls -4-,
Its salt or its hydrate have more significant killing effect to above-mentioned cancer cell, can make for treating human liver cancer, mammary gland
The drug of the malignant tumours such as cancer, cancer of the esophagus, lung cancer.
Specific implementation mode
The present invention program is described further below by embodiment：
Embodiment 1：
The synthetic method of chloro- 5- nitros -1H- pyrrolo-es [2,3-b] pyridines of 1- benzenesulfonyls -4-, hydrate and its salt include with
Lower step：
In above-mentioned synthesis step, a is, by raw material 7- azaindoles and dimethyl ether（DME）Mixing, stirring and dissolving, 1 DEG C of cryosel
Metachloroperbenzoic acid is added portionwise under bath, controlled at 15 DEG C, reacts 2h；
The b is that reaction terminates, and normal heptane is added under stirring into reaction solution, is filtered after stirring half an hour, filter cake DME：Just
Heptane=1:1 solution washed once, solid naturally dry, obtain field gray solid (Y:89%)；
The c is that intermediate GXY2010-1 and phosphorus oxychloride are added in reaction vessel, and lower stirring is in bronzing mixed liquor, heating
To after 45 DEG C, 1h is stirred, continues to be heated to 90 DEG C, liquid temperature to be mixed is stablized, and 12h is stirred to react；Reaction terminates, and is cooled to room
Temperature, decompression evaporate phosphorus oxychloride, dilution in acetonitrile are added in extraction raffinate, are slowly added dropwise to water quenching and go out phosphorus oxychloride, and it is 9 to adjust pH, analysis
The khaki solid gone out filters, and washing washing is dried to obtain；
The d is that intermediate GXY2010-2, dichloromethane are sequentially added into reaction bulb（DCM）, 4-dimethylaminopyridine
（DMAP）And triethylamine（Et3N）, PhSO is added portionwise2Cl, temperature increase, water-bath cooling control charge temperature at 35 DEG C hereinafter,
60min is finished, and after finishing, room temperature continues to react and terminate after stirring 20h；
The e is post-processing, and dilute hydrochloric acid adjusts PH as 2.5, DCM phases, and alkali liquid washing, water washing takes organic phase to dry, and decompression is steamed
Do to obtain crude product；
The f is that intermediate GXY2010-3, DCM and TBAN are added into reaction bulb, and stirring to solid is completely dissolved, and is added in batches
Enter trifluoroacetic anhydride（TFAA）, trimellitic anhydride（TMA）, at -15 DEG C, 20min is finished control charge temperature, after finishing, 1 DEG C
Stirring is for 24 hours；In this f steps, trimellitic anhydride is added portionwise（TMA）One side TMA can with six in intermediate GXY2010-3
Nitrogen-atoms in member heterocyclic ring containing nitrogen forms hydrogen bond, to increase the steric hindrance of the nitrogen-atoms so that active nitroso base
Group is far from the carbon atom on the nitrogen-atoms ortho position, and then the probability of the hydrogen on substituted nitrogen atom meta position carbon atom substantially increases, from
And the formation of by-product can be greatly reduced, improve the yield and yield of product GXY2010-4；On the other hand, trifluoroacetic acid
In the case that acid anhydride coexists with trimellitic anhydride, the speed of f reaction system positive reactions increases significantly, and the speed of back reaction drops
It is low, to contribute to reactant to generate finished product GXY2010-4, makes the completion that is swift in response, improve the yield and yield of finished product.
The h is post-processing, is filtered, and filter cake is washed with acetonitrile, and filter cake is product；Filtrate is spin-dried for filtering.Drying is obtained
Light yellow this product, light yellow this product compound are chloro- 5- nitros -1H- pyrrolo-es [2, the 3-b] pyridines of 1- benzenesulfonyls -4-, nuclear-magnetism
Data are 1H-NMR (300MHz, CDCl3, ppm) δ:9.005 (s, 1H), 8.244 (m, 2H), 7.965 (d, J=3.9Hz, 1H),
7.696 (m, 1H), 7.584 (m, 2H), 6.886 (d, J=3.9Hz, 1H).
Embodiment 2：
The fragmentation effect of the compound on tumor cell is measured using external mtt assay：Take tumor cell density on 15000 left sides
The right side is inoculated with 3000 cells by tumor cell inoculation in 96 orifice plates per hole, after cell is adherent, administration, and the outer MTT of structure
People source breast cancer cell, liver cancer cells, esophageal cancer cell etc. have significantly been killed in experiment.
As shown in table 1, the various concentration of chloro- 5- nitros -1H- pyrrolo-es [2, the 3-b] pyridines of compound 1- benzenesulfonyls -4-
After administration, human breast cancer cell in external MTT experiment, liver cancer cells, human esophagus cancer cell, human lung carcinoma cell relative survival rate
It is decreased significantly, and positive correlation is presented with dosage in cancer cell lethality, illustrates compound 1- benzenesulfonyls -4-
Chloro- 5- nitros -1H- pyrrolo-es [2,3-b] pyridine is to human breast cancer cell, liver cancer cells, human esophagus cancer cell, human lung carcinoma cell
With more significant killing effect, can make for treating the malignant tumours such as human liver cancer, breast cancer, cancer of the esophagus, lung cancer
Drug.
The relative survival rate of associated cancer cell after table 1. is administered
Embodiment 3：
Capsule preparations are prepared with chloro- 5- nitros -1H- pyrrolo-es [2,3-b] pyridines of 1- benzenesulfonyls -4-, hydrate and its salt：
Prepare soft capsule：420 portions of soybean oils, 28 parts of beeswaxs, 5.5 parts of span-80 mixings are taken, being heated to 70 DEG C keeps beeswax completely molten
Melt, stirring is cooled to 35 DEG C, and 45 parts of Chinese medical concrete Ultramicro-powders, the chloro- 5- nitros -1H- pyrroles of 0.03 part of 1- benzenesulfonyls -4- is added
And [2,3-b] pyridine, hydrate and its salt, it stirs evenly, vacuumizes cancellation bubble, it is spare；Take gelatin, glycerine, water according to
0.4:0.6:Water-bath type glue tank is added in 1 ratio, stirs and keeps the temperature 2h after melting, vacuumizes cancellation bubble, sieve with 100 mesh sieve
Net is placed in 60 DEG C of glue bucket heat preservations, stands 2h；25 DEG C, relative humidity be 45% in the environment of soft capsule press, in filling
Material is stated, soft capsule is suppressed；It is dried for 24 hours to get capsule preparations in the environment of 25 DEG C, relative humidity 15%；At capsule preparations
Fang Heli, feasible process, content are the sticky colloid of taupe, and gas is micro-, bitter, which has bioavilability high, malicious secondary
Act on the advantages that small, absorption is rapid, stability is good, convenient for taking, the effective effectiveness ingredient Chinese herbal and crude drugs preparations of soft capsule and 1- benzene sulphurs
The dissolution rate of chloro- 5- nitros -1H- pyrrolo-es [2, the 3-b] pyridines of acyl group -4-, its salt or its hydrate is higher, is conducive to body
It is rapid to absorb, kill the effect of cancer cell to play it.
The preparation method of Chinese medical concrete Ultramicro-powder is：Take irexis sonchifolia, ganoderma lucidum, cow-bezoar, ochre according to mass ratio 100:
2:5:6 ratio mixing, smashes it through 60 mesh sieve, and 8 times of water are added and are cooked by slow fire 3h, takes solid content that 6 times of water are added and is cooked by slow fire
3h, merges liquid, and low temperature is concentrated into relative density 1.2 or more up to Chinese medical concrete, super up to Chinese medical concrete after ultramicro grinding
Micro mist；Soft capsule will be prepared after Chinese medical concrete ultramicro grinding, not only active ingredient dissolution rate increases, but also mobility of particle obtains
Improve, capsule charge loading amount is stable and production efficiency is high, and the mucilaginous substance after processing in pulvis can be greatly reduced, and deals with opposite
It is easy, is conducive to the labor intensity for mitigating producers, reduces production cost.
Containing 2.8 parts of oleic acid formicester in every 500 parts of glycerine, contain 1.7 parts of glyceraldehyde, glyceraldehyde in every 1000 parts of water
The mass ratio of middle L- (-)-glyceraldehyde and D- (-)-glyceraldehyde is 83:17；α chains, β chains and γ chains in gelatin can be in glyceraldehyde
Catalytic action under be crosslinked rapidly, the intersegmental formation covalent cross-linking of longer gelatin chain can be made, so as to effectively improve gelatin
Viscosity, solidification point and gel strength, improve the stability of capsule, extend the pot-life of capsule；Gelatin after crosslinking is glue
Former albumen group, into body after can be denaturalized by hydrochloric acid in gastric juice rapidly, gelatin is decomposed into peptone through pepsin, is further broken into small
Peptide, amino acid are absorbed by organisms utilization；On the other hand, hydrolysis can occur for part oleic acid formicester, generate oleic acid, oleic acid can
To seize the oxidant in system and react, to reduce the chloro- 5- nitros -1H- pyrrolo-es of 1- benzenesulfonyls -4- [2,
3-b] pyridine, hydrate and its salt oxidation probability, preserve the biological function of its inhibiting tumor cell；Special proportioning in glyceraldehyde
L- (-)-glyceraldehyde can act synergistically with D- (-)-glyceraldehyde, which can effectively reconcile hydroxypropyl cellulose
Interaction between gelatin is filled up in " gap " between the two, strengthens the mechanical strength and consistency of capsule gel coat, not only
It protects capsule 's content from oxidative degradation, but also the pot-life of capsule can be greatly prolonged, while not influencing glue again
Capsule enters the content dissolution rate after body, from every side the comprehensive quality for improving capsule.
Routine operation in operating procedure of the present invention is well known to those skilled in the art, herein without repeating.
Technical scheme of the present invention is described in detail in embodiment described above, it should be understood that the above is only
For specific embodiments of the present invention, it is not intended to restrict the invention, all any modifications made in the spirit of the present invention,
Supplement or similar fashion replacement etc., should all be included in the protection scope of the present invention.
Claims (10)
1. a kind of azole compounds, it is characterised in that：The azole compounds are the chloro- 5- nitros -1H- pyrroles of 1- benzenesulfonyls -4-
Simultaneously [2,3-b] pyridine, hydrate and its salt are coughed up,
The structural formula of chloro- 5- nitros -1H- pyrrolo-es [2,3-b] pyridines of 1- benzenesulfonyls -4- is：
The hydrate of chloro- 5- nitros -1H- pyrrolo-es [2,3-b] pyridines of 1- benzenesulfonyls -4- or the structural formula of its salt are：
2. a kind of new technique for synthesizing of azole compounds, it is characterised in that：The azole compounds are that 1- benzenesulfonyls -4- is chloro-
5- nitro -1H- pyrrolo-es [2,3-b] pyridine, hydrate and its salt, new technique for synthesizing include the following steps：
3. a kind of new technique for synthesizing of azole compounds according to claim 2, it is characterised in that：The X is indicated can be with
The hydrate at salt any organic acid and inorganic acid and any ratio received.
4. a kind of new technique for synthesizing of azole compounds according to claim 2, it is characterised in that：
The a is to mix raw material 7- azaindoles with dimethyl ether, stirring and dissolving, and m-chloro is added portionwise under 0~10 DEG C of ice salt bath
Benzoyl hydroperoxide reacts 1~3h controlled at 10~20 DEG C；
The b is that reaction terminates, and normal heptane is added under stirring into reaction solution, is filtered after stirring half an hour, filter cake DME:Just
Heptane=1:1 solution washed once, and solid naturally dry obtains field gray solid；
The c is that intermediate GXY2010-1 and phosphorus oxychloride are added in reaction vessel, and lower stirring is in bronzing mixed liquor, heating
To after 40~60 DEG C, 1h is stirred, continues to be heated to 90 DEG C, liquid temperature to be mixed is stablized, and 10~15h is stirred to react；Reaction terminates,
It is cooled to room temperature, decompression evaporates phosphorus oxychloride, and dilution in acetonitrile is added in extraction raffinate, is slowly added dropwise to water quenching and goes out phosphorus oxychloride, adjusts
PH is 9, and the khaki solid of precipitation filters, and washing washing is dried to obtain；
The d is that intermediate GXY2010-2, dichloromethane, 4-dimethylaminopyridine and three second are sequentially added into reaction bulb
PhSO is added portionwise in amine2Cl, temperature increase, water-bath cooling control charge temperature at 35 DEG C hereinafter, 60min is finished, after finishing,
Room temperature continues to react and terminate after stirring 20h；
The e is post-processing, and dilute hydrochloric acid adjusts PH as 2~5, DCM phases, and alkali liquid washing, water washing takes organic phase to dry, and depressurizes
It is evaporated to obtain crude product；
The f is that intermediate GXY2010-3, DCM and TBAN are added into reaction bulb, and stirring to solid is completely dissolved, and is added in batches
Enter trifluoroacetic anhydride, trimellitic anhydride, control charge temperature at -10~-20 DEG C hereinafter, 20min is finished, after finishing, 0 DEG C~
20 DEG C of stirrings are for 24 hours；
The h is post-processing, is filtered, and filter cake is washed with acetonitrile, and filter cake is product；Filtrate is spin-dried for filtering, and drying is obtained pale yellow
Color this product, light yellow this product compound are chloro- 5- nitros -1H- pyrrolo-es [2, the 3-b] pyridines of 1- benzenesulfonyls -4-.
5. a kind of purposes of azole compounds antitumor action, the azole compounds are the chloro- 5- nitros-of 1- benzenesulfonyls -4-
1H- pyrrolo-es [2,3-b] pyridine, hydrate and its salt, it is characterised in that：The chloro- 5- nitros -1H- pyrroles of 1- benzenesulfonyls -4-
Cough up simultaneously [2,3-b] pyridine, hydrate and its salt in the new application of anti-tumor aspect.
6. a kind of purposes of azole compounds antitumor action according to claim 5, it is characterised in that：The pyrrolesization
Close purposes of the object in inhibiting HepG2 human liver cancer cells.
7. a kind of purposes of azole compounds antitumor action according to claim 5, it is characterised in that：The pyrrolesization
Close purposes of the object in inhibiting TE1 human esophagus cancer cells.
8. a kind of purposes of azole compounds antitumor action according to claim 5, it is characterised in that：The pyrrolesization
Close purposes of the object in inhibiting MCF7 human breast cancer cells.
9. a kind of purposes of azole compounds antitumor action according to claim 5, it is characterised in that：The pyrrolesization
Close purposes of the object in inhibiting lung carcinoma cell.
10. a kind of purposes of azole compounds antitumor action according to claim 5, it is characterised in that：The pyrroles
The method that compound prepares capsule preparations is：Take 420~450 portions of soybean oils, 25~30 parts of beeswaxs, 5.5~6.0 parts of span-80
Mixing, heating make beeswax melt completely, and 45~48 parts of Chinese medical concrete Ultramicro-powders, 0.03~0.05 part of 1- benzene is added after stirring is cooling
Chloro- 5- nitros -1H- pyrrolo-es [2, the 3-b] pyridines of sulfonyl -4- or its hydrate or its salt, stir evenly, vacuumize cancellation gas
Bubble, it is spare；Gelatin, glycerine and water additionization glue tank are taken, stirs and is kept the temperature after melting, vacuumize cancellation bubble, kept the temperature after sieving
It stands；Above-mentioned material is inserted into soft capsule press, suppresses soft capsule；Up to capsule preparations after drying.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011002772A1 (en) * | 2009-06-29 | 2011-01-06 | Oncotherapy Science, Inc. | Imidazopyridine derivatives and pbk inhibitors containing the same |
| CN107001354A (en) * | 2014-04-11 | 2017-08-01 | 台北医学大学 | Inhibitors of histone deacetylase |
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2018
- 2018-04-28 CN CN201810396816.9A patent/CN108794469A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011002772A1 (en) * | 2009-06-29 | 2011-01-06 | Oncotherapy Science, Inc. | Imidazopyridine derivatives and pbk inhibitors containing the same |
| CN107001354A (en) * | 2014-04-11 | 2017-08-01 | 台北医学大学 | Inhibitors of histone deacetylase |
Non-Patent Citations (1)
| Title |
|---|
| JANUSZ J. KULAGOWSKI ET AL.: ""Identification of Imidazo - Pyrrolopyridines as Novel and Potent JAK1 Inhibitors"", 《J. MED. CHEM.》 * |
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