CN106632322A - Pyrazol purrocoline compound and preparation method and application thereof - Google Patents
Pyrazol purrocoline compound and preparation method and application thereof Download PDFInfo
- Publication number
- CN106632322A CN106632322A CN201611189752.2A CN201611189752A CN106632322A CN 106632322 A CN106632322 A CN 106632322A CN 201611189752 A CN201611189752 A CN 201611189752A CN 106632322 A CN106632322 A CN 106632322A
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- China
- Prior art keywords
- compound
- formula
- independently selected
- alkyl
- hydrogen
- Prior art date
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- Granted
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 70
- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 title abstract description 4
- 239000002260 anti-inflammatory agent Substances 0.000 claims abstract description 6
- 229940124599 anti-inflammatory drug Drugs 0.000 claims abstract description 5
- 150000003839 salts Chemical class 0.000 claims description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- -1 pyrazoles indolizine compounds Chemical class 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 150000002431 hydrogen Chemical class 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
- 238000006698 hydrazinolysis reaction Methods 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- NLHHRLWOUZZQLW-UHFFFAOYSA-N Acrylonitrile Chemical compound C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 claims description 3
- 239000011736 potassium bicarbonate Substances 0.000 claims description 3
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- WGLPBDUCMAPZCE-UHFFFAOYSA-N chromium trioxide Inorganic materials O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 claims description 2
- 238000009833 condensation Methods 0.000 claims description 2
- 230000005494 condensation Effects 0.000 claims description 2
- 125000004122 cyclic group Chemical group 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 235000019260 propionic acid Nutrition 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims 1
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 claims 1
- 239000000306 component Substances 0.000 claims 1
- 230000003110 anti-inflammatory effect Effects 0.000 abstract description 10
- 238000002474 experimental method Methods 0.000 abstract description 3
- 239000000203 mixture Substances 0.000 abstract description 3
- 238000012827 research and development Methods 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 9
- 125000000217 alkyl group Chemical group 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 6
- 239000006285 cell suspension Substances 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 150000002478 indolizines Chemical class 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 108010087230 Sincalide Proteins 0.000 description 4
- 238000010609 cell counting kit-8 assay Methods 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 239000002158 endotoxin Substances 0.000 description 4
- 229920006008 lipopolysaccharide Polymers 0.000 description 4
- 210000003024 peritoneal macrophage Anatomy 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- 102000009389 Prostaglandin D receptors Human genes 0.000 description 3
- 108050000258 Prostaglandin D receptors Proteins 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 239000005557 antagonist Substances 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- HOBCFUWDNJPFHB-UHFFFAOYSA-N indolizine Chemical compound C1=CC=CN2C=CC=C21 HOBCFUWDNJPFHB-UHFFFAOYSA-N 0.000 description 3
- 230000002757 inflammatory effect Effects 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- 0 *c(cc1C([n]2nc(*)cc2*)=*)c2[n]1c(*)c(*)c(*)c2 Chemical compound *c(cc1C([n]2nc(*)cc2*)=*)c2[n]1c(*)c(*)c(*)c2 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical group O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- YRKCREAYFQTBPV-UHFFFAOYSA-N acetylacetone Chemical compound CC(=O)CC(C)=O YRKCREAYFQTBPV-UHFFFAOYSA-N 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 231100000263 cytotoxicity test Toxicity 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- CFHGBZLNZZVTAY-UHFFFAOYSA-N lawesson's reagent Chemical compound C1=CC(OC)=CC=C1P1(=S)SP(=S)(C=2C=CC(OC)=CC=2)S1 CFHGBZLNZZVTAY-UHFFFAOYSA-N 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 238000007619 statistical method Methods 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- JYYNAJVZFGKDEQ-UHFFFAOYSA-N 2,4-Dimethylpyridine Chemical class CC1=CC=NC(C)=C1 JYYNAJVZFGKDEQ-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N DMSO-d6 Substances [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 238000008157 ELISA kit Methods 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 201000001431 Hyperuricemia Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 206010054094 Tumour necrosis Diseases 0.000 description 1
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 description 1
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 description 1
- 229940123769 Xanthine oxidase inhibitor Drugs 0.000 description 1
- XOCUXOWLYLLJLV-UHFFFAOYSA-N [O].[S] Chemical compound [O].[S] XOCUXOWLYLLJLV-UHFFFAOYSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000004855 amber Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
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- 230000001741 anti-phlogistic effect Effects 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- KDPAWGWELVVRCH-UHFFFAOYSA-N bromoacetic acid Chemical class OC(=O)CBr KDPAWGWELVVRCH-UHFFFAOYSA-N 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
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- 125000004432 carbon atom Chemical group C* 0.000 description 1
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- 239000003153 chemical reaction reagent Substances 0.000 description 1
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- GAMDZJFZMJECOS-UHFFFAOYSA-N chromium(6+);oxygen(2-) Chemical class [O-2].[O-2].[O-2].[Cr+6] GAMDZJFZMJECOS-UHFFFAOYSA-N 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 238000000205 computational method Methods 0.000 description 1
- 239000003636 conditioned culture medium Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
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- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
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- 238000001990 intravenous administration Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
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- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
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- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 239000003182 parenteral nutrition solution Substances 0.000 description 1
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- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
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- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
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- 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
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Abstract
The invention relates to a pyrazol purrocoline compound having anti-inflammatory activity and a preparation method and application of the compound serving as an anti-inflammatory drug. The invention further relates to a medical composition containing the pyrazol purrocoline compound. An experiment proves that the compound shown as a formula I has the remarkable anti-inflammatory activity and can be further used in research and development of the anti-inflammatory drug.
Description
Technical field
The present invention relates to a class have pyrazoles indolizine compounds of anti-inflammatory activity and preparation method thereof with as anti-inflammatory agent
The purposes of thing.The invention further relates to contain the Pharmaceutical composition of the pyrazoles indolizine compounds.
Background technology
In recent years, indolizine compound has a wide range of applications in field of medicaments, and for example used as FGF, (matrix is into fiber
Porcine HGF) with strong antagonist, xanthine oxidase inhibitor, the CRTH2 antagonists of receptor binding；Twist for treating the heart
Bitterly, the illness such as arrhythmia cordis, hyperuricemia.
Patent WO03/084956 discloses a kind of 3 introducing benzoyls in indolizine, and obtaining a class can suppress
The derivative of FGF, can suppress Tumor Angiongesis, for treating all kinds of tumours, cancer.
Patent EP0235111, EP0097636, US4378362, EP0382628 disclose some and can be used in treating heart strand
Pain and ARR Indoli zine derivatives, some of which compound also has the biologically active for suppressing calcium transport.
Patent CN101243086, WO2008/074966, CN101605789 are disclosed in 3 introducing thiophenyls of indolizine,
A class is obtained as the Indoli zine derivatives of CRTH2 antagonists；Patent WO2007031747 is then disclosed in 1 introducing of indolizine
Thiophenyl, the derivative for obtaining equally also has CRTH2 antagonisms, can be used to treat the exploitation of medicament for treating respiratory system thing.
Japanese Kissei Pharmaceutical Co., Ltd. discloses a class in patent WO2012043638 and there is xanthine to aoxidize
Enzyme inhibition activity simultaneously can be used to preventing or treating (azepine) Indoli zine derivatives of the disease extremely related to serum uric acid level.
In Acta Cryst. (2013) .E69, o450 discloses a kind of two pyrazoles carbonyls of 1,3 introducings to present inventor
The synthesis of the Indoli zine derivatives of base and its crystal structure.
Because indolizine compound has good medical usage, therefore, study such compound to drug development very
Meaningful, present inventor has designed and synthesized the novel pyrazoles Indoli zine derivatives of a class, and Jing biological activity tests are determined,
It is proved such compound and there is significant anti-inflammatory activity, can be used for anti-inflammatory drug research.
The content of the invention
The following compound of formula I with anti-inflammatory activity of present invention offer or its pharmaceutically acceptable salt：
Wherein：
A is oxygen or sulphur atom；
R1-R4Independently selected from：Hydrogen, alkyl, alkoxyl, cycloalkyl；
R5It is selected from：-CN；
R6Independently selected from：Hydrogen, alkyl；
Used as preferred embodiments of the present invention, A is selected from oxygen atom.
As another preferred version of the present invention, R1-R4It is preferred that alkyl, alkoxyl.
Presently preferred scheme, R6Independently selected from alkyl.
Compound shown in preferred following formula I-1 of compound of formula I of the present invention
Wherein,
R1And R3Independently selected from hydrogen, C1-6Alkyl, C1-6Alkoxyl；
R2And R4Independently selected from C1-6Alkyl, C1-6Alkoxyl；
R6Independently selected from：C1-6Alkyl.
The invention further relates to compound of formula I or its pharmaceutically acceptable salt are used to prepare the purposes of medicine, the present invention
Compound there is antiinflammatory action, can be used to prepare all kinds of inflammation related diseases for the treatment of.
The invention further relates to a kind of Pharmaceutical composition, it includes compound of formula I or its pharmaceutically acceptable salt as activity
Composition, it can further include pharmaceutically acceptable carrier, excipient.
Described Pharmaceutical composition, is prepared into the form of medication such as oral, subcutaneous, intramuscular, intravenous, transdermal.
Preferably, Pharmaceutical composition of the invention can prepare piece agent, capsule, pulvis, granule, oral liquid, suspension
Liquid or parenteral solution.
Term
" alkyl ", refers to the alkyl of the straight or branched with 1-10 carbon atom, preferred C1-6Alkyl, more preferably C1-3
Alkyl, suitable alkyl is such as：Methyl, ethyl, propyl group, isopropyl, normal-butyl, isobutyl group, tert-butyl group etc..
" alkoxyl ", refers to-O- alkyl.
" cycloalkyl ", refers to the cyclic alkyl of saturation, including 3-6 atom, preferred cyclopropyl, cyclobutyl, cyclopenta, ring
Hexyl.
" pharmaceutically acceptable salt ", including base addition salts and acid-addition salts, base addition salts preferably with NaOH, KOH,
Na2CO3、K2CO3、NaHCO3、KHCO3Formed salt, acid-addition salts preferably with hydrobromic acid, hydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid, amber
Amber acid, fumaric acid, maleic acid, malic acid, salicylic acid, citric acid, methanesulfonic acid, p-methyl benzenesulfonic acid, benzoic acid, benzene sulfonic acid, acetic acid,
Salt formed by mandelic acid.
The present invention also provides the synthetic method of the indolizine analog derivative shown in Formulas I：
Mainly include following synthesis step：
1) in organic solvent stirring reaction generates Formula V compound to Formula VII compound with VI compounds；
2) Formula V compound is in alkali and CrO3In the presence of react in DMF or DMA with acrylonitrile and obtain formula IV compound；
3) formula IV compound hydrazinolysis obtains formula III compound；
4) formula III compound is cyclic with Formula II compound condensation obtains the compound of Formulas I -1；
Or, also including 5) compound of Formulas I -1 being further converted to into the compound of Formulas I -2；
Or optionally Formulas I -1 and I-2 compounds are converted into into its pharmaceutically acceptable salt；Formulas I -1 is collectively constituted with Formulas I -2
The compound of formula I of the application.
Wherein, X is Cl, Br；RbFor C1-6Alkyl；R1-R6, A have and compound of formula I identical definition.
As the present invention preferred version, step 1) in, the organic solvent selected from ethyl acetate, dichloromethane, chloroform,
Tetrahydrofuran, acetone, acetonitrile.
As another preferred version of the present invention, step 1) in, Formula VII is 1-2 with the mol ratio of Formula IV compound:1.
In an embodiment of invention, step 2) in, the alkali is selected from NaOH, KOH, Na2CO3、K2CO3、NaHCO3、
KHCO3, triethylamine, pyridine etc., preferred triethylamine.
Invention another embodiment in, step 3) hydrazinolysis be under the conditions of ethanol as solvent, with 80% hydration
What hydrazine reaction was implemented.
Further, step 4) it is to be reacted in the case where aliphatic acid makees solvent condition, the preferred formic acid of the aliphatic acid, second
Acid, propionic acid.
Further, step 5) it is described it is further conversion be that 3 carbonyls are converted into into thiocarbonyl group with lawesson reagent.
Wherein, lawesson reagent of the present invention is that a kind of oxygen sulphur well-known to those skilled in the art exchanges reagent, can
Carbonyls is converted into into thiocarbonyls.
Description of the drawings
Fig. 1：Compound 41H-NMR spectrum；
Fig. 2：Cytotoxicity test result of the compound 4 to mouse primary peritoneal macrophage；
Fig. 3：The anti-inflammatory activity test result of compound 4
Specific embodiment
In the compounds of this invention Structural Identification：Fusing point test laboratory apparatus is X-4 micro melting point apparatus；1H-NMR is adopted
Bruker companies ACF-400 type NMRs, DMSO-d6For solvent, TMS is internal standard.
Embodiment 1
Step 1) pyridinium compound 1 synthesis
By 120mmol 2,4- lutidines and 60mmol bromoacetates are dissolved in 200mL ethyl acetate, stirring 20
Hour, suction filtration.After filter cake is washed with 50ml ethyl acetate, drying at room temperature, it is white powder to obtain product 1, and yield is 75%.
Step 2) compound 2 synthesis
By 30mmol compounds 1,180mmol triethylamines, 120mmol acrylonitrile and 120mmol chromium trioxides are added to
90 DEG C are heated in 180ml DMF (DMF), are kept for 2 hours.After cooling, reactant mixture pours 500ml into
In 5% hydrochloric acid, stand, suction filtration, after filtration cakes torrefaction, with petroleum ether (bp 60-90 DEG C)-ethyl acetate (volume ratio 4:1) post layer
Analysis, obtains yellow powder compound 2, and yield is 40%.
Step 3) hydrazide compound 3 synthesis
By 20mmol compounds 2 and 10ml ethanol, after the mixing of the hydrazine hydrates of 30ml 80%, flow back 8 hours.Cooling, suction filtration,
White powder compound 3 is obtained, yield is 74%.
Step 4) 5,7- dimethyl -1- cyano group -3- (3,5- dimethyl pyrazole oxazolyl carbonyls) indolizine synthesis
10mmol compounds 3 are dissolved in 20ml acetic acid, 40mmol acetylacetone,2,4-pentanediones are subsequently added dropwise.After stirring 2 hours, take out
Filter, after filtration cakes torrefaction, with petroleum ether (bp 60-90 DEG C)-ethyl acetate (volume ratio 4:1) column chromatography, obtains white powder end-product
4, yield is 70%.Jing is determined：Fusing point is 184-185 DEG C；1H-NMR(CD3SOCD3,400MHz):2.17(s,3H,–CH3),
2.40 (s, 3H ,-CH3), 2.46 (s, 3H ,-CH3), 2.55 (s, 3H ,-CH3), 6.31 (s, 1H, pyrazole=CH), 7.04
(s, 1H, ArH), 7.62 (s, 1H, ArH), 7.82 (s, 1H, ArH), is shown in Fig. 1.
Biological activity determination：
(1) cytotoxicity of compound 4 detection
We have carried out cytotoxicity detection to compound 4.It is thin for detection that mouse primary peritoneal macrophage is chosen first
Born of the same parents, the inoculating cell suspension (10 in 96 porocyte culture plates4Individual cell/100 μ l cell suspensions, 100 μ l cell suspensions/hole),
By culture plate in cell culture incubator preculture 12 hours (at 37 DEG C, 5%CO2Under conditions of), then add in culture plate
The compound 4 of variable concentrations (5 μ g/ml, 10 μ g/ml, 20 μ g/ml), continues for culture plate to be placed on incubator incubation 24 hours, to
10 μ l CCK-8 solution (being careful not to generate bubble in hole, they can affect O.D. value readings) are added per hole, then will be thin
Born of the same parents' culture plate is placed on lucifuge in incubator and is incubated 1 hour, finally determines the absorbance at 450nm with ELIASA.
Cell survival rate computational methods：Cell survival rate=[(As-Ab)/(Ac-Ab)] * 100%
As:Experimental port (culture medium containing cell, CCK-8 solution, compound 4)
Ac:Control wells (culture medium containing cell, CCK-8 solution, without compound 4)
Ab:Blank well (culture medium without cell and compound 4, CCK-8 solution)
In cytotoxicity test experience, our every group of Duplicate Samples arrange 5, and experiment repeats to do 3 times, so as to ensure data
It is credible.Data are shown by the form of mean+/-standard error (means ± SEM).Jing statistical analysis are different dense
The compound 4 of degree does not have overt toxicity to mouse primary peritoneal macrophage (referring to Fig. 2).
(2) the anti-inflammatory performance of compound 4 is probed in the inflammatory environment simulated in vitro
We have carried out anti-inflammatory performance detection to compound 4.It is thin for detection that mouse primary peritoneal macrophage is chosen first
Born of the same parents, the inoculating cell suspension (10 in 24 porocyte culture plates5Individual cell/500 μ l cell suspensions, 500 μ l cell suspensions/hole),
Then by culture plate incubator preculture 12 hours (at 37 DEG C, 5%CO2Under conditions of), then add not in culture plate
The compound 4 of same concentration (5 μ g/ml, 10 μ g/ml, 20 μ g/ml), after culture plate is placed on incubator incubation 1 hour, adds thin
Bacterium lipopolysaccharides (Lipopolysaccharides, LPS) (the final concentration of 1 μ g/ml of each hole LPS), is then placed on culture plate
Incubator is incubated 24 hours, takes cell conditioned medium, and 1000rpm is centrifuged 10min.With reference on ELISA kit specification detection cell
The content of inflammatory factor-tumor necrosis factor-alpha in clear.
In inflammatory factor test experience, our every group of Duplicate Samples arrange 3, and experiment repeats to do 3 times, so as to ensure data
It is credible.Data are shown by the form of mean+/-standard error (means ± SEM).Jing statistical analysis, 10 μ g/
The compound 4 of ml and 20 μ g/ml concentration has significant antiphlogistic effects (* p<0.05 indicates statistically difference, * * p<0.01 table
It is shown with statistically significantly sex differernce) (referring to Fig. 3).
It can be seen that, the compound of formula I of the present invention has significant anti-inflammatory activity, and the research that can be further used for anti-inflammatory drug is opened
In sending out.
Although present invention has been a certain degree of description, it will be apparent that, without departing from the spirit and scope of the present invention
Under the conditions of, can suitably be changed.It is appreciated that the invention is not restricted to the embodiment, and it is attributed to the scope of claim,
It includes the equivalent of each factor.
Claims (9)
1. pyrazoles indolizine compounds shown in a kind of Formulas I or its pharmaceutically acceptable salt,
Wherein：
A is oxygen or sulphur atom；
R1-R4Independently selected from hydrogen, C1-6Alkyl, C1-6Alkoxyl, C3-6Cycloalkyl；
R5Selected from-CN；
R6Independently selected from hydrogen, C1-6Alkyl.
2. compound of formula I according to claim 1, it is characterised in that A is oxygen atom；R1-R4Independently selected from hydrogen, C1-6Alkyl,
C1-6Alkoxyl.
3. compound of formula I according to claim 1, it is characterised in that it has the structure shown in Formulas I -1：
Wherein：
R1And R3Independently selected from hydrogen, C1-6Alkyl, C1-6Alkoxyl；
R2And R4Independently selected from C1-6Alkyl, C1-6Alkoxyl；
R6Independently selected from：Hydrogen, C1-6Alkyl.
4. compound of formula I according to claim 3, it is characterised in that R1And R3Independently selected from hydrogen；R2And R4Independently selected from C1-6
Alkyl, C1-6Alkoxyl.R6Independently selected from C1-6Alkyl.
5. compound of formula I according to claim 4, it is characterised in that R1And R3Independently selected from hydrogen；R2、R4And R6Independently selected from
Methyl, ethyl, propyl group, isopropyl.
6. the preparation method of the compound of formula I of any one of claim 1-5, it is characterised in that comprise the steps：
1) in organic solvent stirring reaction generates Formula V compound to Formula VII compound with Formula IV compound；
2) Formula V compound is in alkali and CrO3In the presence of react in DMF or DMA with acrylonitrile and obtain formula IV compound；
3) formula IV compound hydrazinolysis obtains formula III compound；
4) formula III compound is cyclic with Formula II compound condensation obtains the compound of Formulas I -1；
Or, also including 5) compound of Formulas I -1 being further converted to into the compound of Formulas I -2；
Or optionally Formulas I -1 and I-2 compounds are converted into into its pharmaceutically acceptable salt；
Wherein, X is Cl, Br；RbFor C1-6Alkyl；R1-R6, that A has is fixed with claim 1-5 any one compound of formula I identical
Justice.
7. the preparation method described in claim 6, it is characterised in that step 1) in, the organic solvent selected from ethyl acetate, two
Chloromethanes, chloroform, tetrahydrofuran, acetone, acetonitrile；Step 2) in, the alkali is selected from NaOH, KOH, Na2CO3、K2CO3、NaHCO3、
KHCO3, triethylamine, pyridine；Step 3) hydrazinolysis be under the conditions of ethanol as solvent, to be reacted with 80% hydrazine hydrate；Step
4) it is to make to be reacted under solvent condition in one or more in formic acid, acetic acid, the propionic acid.
8. pharmaceutical composition, it is characterised in that comprising the compound of formula I described in any one of claim 1-7 or its is pharmaceutically acceptable
Salt as active component, and pharmaceutically acceptable carrier or excipient.
9. compound of formula I or its pharmaceutically acceptable salt described in any one of claim 1-5 is treated in anti-inflammatory drug in preparation
Purposes.
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| CN110251513A (en) * | 2019-07-03 | 2019-09-20 | 南京大学 | A kind of indolizine compounds application in preparation of anti-tumor drugs containing pyrazoles |
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