CN113979851A - 2′-卤代查尔酮衍生物、其制法及药物组合物与用途 - Google Patents
2′-卤代查尔酮衍生物、其制法及药物组合物与用途 Download PDFInfo
- Publication number
- CN113979851A CN113979851A CN202010734890.4A CN202010734890A CN113979851A CN 113979851 A CN113979851 A CN 113979851A CN 202010734890 A CN202010734890 A CN 202010734890A CN 113979851 A CN113979851 A CN 113979851A
- Authority
- CN
- China
- Prior art keywords
- substituted
- substitution
- unsubstituted
- group
- cycloalkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 18
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 150000001788 chalcone derivatives Chemical class 0.000 title abstract description 17
- 150000001875 compounds Chemical class 0.000 claims abstract description 87
- 150000003839 salts Chemical class 0.000 claims abstract description 23
- 239000003814 drug Substances 0.000 claims abstract description 16
- 206010061218 Inflammation Diseases 0.000 claims abstract description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 12
- 230000004054 inflammatory process Effects 0.000 claims abstract description 12
- 239000000203 mixture Substances 0.000 claims abstract description 12
- 201000010099 disease Diseases 0.000 claims abstract description 10
- 238000006467 substitution reaction Methods 0.000 claims description 73
- -1 cyano, amino, carboxyl Chemical group 0.000 claims description 53
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 30
- 229910052794 bromium Inorganic materials 0.000 claims description 26
- 229910052801 chlorine Inorganic materials 0.000 claims description 26
- 229910052731 fluorine Inorganic materials 0.000 claims description 26
- 229910052740 iodine Inorganic materials 0.000 claims description 26
- GQNZGCARKRHPOH-RQIKCTSVSA-N miocamycin Chemical compound C1[C@](OC(C)=O)(C)[C@@H](OC(=O)CC)[C@H](C)O[C@H]1O[C@H]1[C@H](N(C)C)[C@@H](O)[C@H](O[C@@H]2[C@H]([C@H](OC(=O)CC)CC(=O)O[C@H](C)C/C=C/C=C/[C@H](OC(C)=O)[C@H](C)C[C@@H]2CC=O)OC)O[C@@H]1C GQNZGCARKRHPOH-RQIKCTSVSA-N 0.000 claims description 22
- 125000001424 substituent group Chemical group 0.000 claims description 15
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 14
- 229910018828 PO3H2 Inorganic materials 0.000 claims description 14
- 229910006069 SO3H Inorganic materials 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 14
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 14
- 125000005245 nitryl group Chemical group [N+](=O)([O-])* 0.000 claims description 14
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims description 14
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 10
- RHCSKNNOAZULRK-APZFVMQVSA-N 2,2-dideuterio-2-(3,4,5-trimethoxyphenyl)ethanamine Chemical compound NCC([2H])([2H])C1=CC(OC)=C(OC)C(OC)=C1 RHCSKNNOAZULRK-APZFVMQVSA-N 0.000 claims description 10
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 10
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 10
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 10
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 10
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 10
- 238000002347 injection Methods 0.000 claims description 9
- 239000007924 injection Substances 0.000 claims description 9
- 206010035664 Pneumonia Diseases 0.000 claims description 7
- 230000002757 inflammatory effect Effects 0.000 claims description 7
- 201000004624 Dermatitis Diseases 0.000 claims description 6
- 208000010668 atopic eczema Diseases 0.000 claims description 6
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 5
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 4
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 4
- 239000006187 pill Substances 0.000 claims description 4
- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 claims description 3
- 208000033222 Biliary cirrhosis primary Diseases 0.000 claims description 3
- 206010006811 Bursitis Diseases 0.000 claims description 3
- 206010008609 Cholangitis sclerosing Diseases 0.000 claims description 3
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 3
- 206010009944 Colon cancer Diseases 0.000 claims description 3
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 3
- 208000011231 Crohn disease Diseases 0.000 claims description 3
- 208000007882 Gastritis Diseases 0.000 claims description 3
- 201000005569 Gout Diseases 0.000 claims description 3
- 206010018634 Gouty Arthritis Diseases 0.000 claims description 3
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 3
- 208000007117 Oral Ulcer Diseases 0.000 claims description 3
- 208000012654 Primary biliary cholangitis Diseases 0.000 claims description 3
- 206010036772 Proctalgia Diseases 0.000 claims description 3
- 201000004681 Psoriasis Diseases 0.000 claims description 3
- 206010064993 Rectal fissure Diseases 0.000 claims description 3
- 206010042674 Swelling Diseases 0.000 claims description 3
- 208000004760 Tenosynovitis Diseases 0.000 claims description 3
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 3
- 230000000172 allergic effect Effects 0.000 claims description 3
- 206010003230 arteritis Diseases 0.000 claims description 3
- 230000001363 autoimmune Effects 0.000 claims description 3
- 206010006451 bronchitis Diseases 0.000 claims description 3
- 208000003167 cholangitis Diseases 0.000 claims description 3
- 201000001352 cholecystitis Diseases 0.000 claims description 3
- 230000006378 damage Effects 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 201000002491 encephalomyelitis Diseases 0.000 claims description 3
- 208000007565 gingivitis Diseases 0.000 claims description 3
- 208000015181 infectious disease Diseases 0.000 claims description 3
- 230000002458 infectious effect Effects 0.000 claims description 3
- 208000002551 irritable bowel syndrome Diseases 0.000 claims description 3
- 206010025135 lupus erythematosus Diseases 0.000 claims description 3
- 201000006417 multiple sclerosis Diseases 0.000 claims description 3
- 208000031225 myocardial ischemia Diseases 0.000 claims description 3
- 201000008383 nephritis Diseases 0.000 claims description 3
- 201000001245 periodontitis Diseases 0.000 claims description 3
- 208000010157 sclerosing cholangitis Diseases 0.000 claims description 3
- 230000001148 spastic effect Effects 0.000 claims description 3
- 230000008961 swelling Effects 0.000 claims description 3
- 208000011580 syndromic disease Diseases 0.000 claims description 3
- 206010043778 thyroiditis Diseases 0.000 claims description 3
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 2
- 208000027418 Wounds and injury Diseases 0.000 claims description 2
- 239000002671 adjuvant Substances 0.000 claims description 2
- 208000006673 asthma Diseases 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 208000014674 injury Diseases 0.000 claims description 2
- 239000011859 microparticle Substances 0.000 claims description 2
- 201000008482 osteoarthritis Diseases 0.000 claims description 2
- 238000009472 formulation Methods 0.000 claims 2
- 238000013270 controlled release Methods 0.000 claims 1
- 208000035475 disorder Diseases 0.000 claims 1
- 230000002265 prevention Effects 0.000 claims 1
- 238000013268 sustained release Methods 0.000 claims 1
- 239000012730 sustained-release form Substances 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 10
- 230000036039 immunity Effects 0.000 abstract description 3
- UFSLJQCZRHNOAH-XCVCLJGOSA-N 2-[4-[(e)-3-(4-chlorophenyl)-3-oxoprop-1-enyl]phenoxy]acetic acid Chemical class C1=CC(OCC(=O)O)=CC=C1\C=C\C(=O)C1=CC=C(Cl)C=C1 UFSLJQCZRHNOAH-XCVCLJGOSA-N 0.000 abstract 1
- 239000000178 monomer Substances 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 40
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 239000000243 solution Substances 0.000 description 20
- 238000005160 1H NMR spectroscopy Methods 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 18
- 239000007788 liquid Substances 0.000 description 18
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 17
- 239000007787 solid Substances 0.000 description 17
- 235000002639 sodium chloride Nutrition 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 230000000694 effects Effects 0.000 description 13
- 239000000047 product Substances 0.000 description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- 238000002114 high-resolution electrospray ionisation mass spectrometry Methods 0.000 description 12
- 238000000034 method Methods 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- 230000003110 anti-inflammatory effect Effects 0.000 description 9
- 125000004432 carbon atom Chemical group C* 0.000 description 9
- 239000002552 dosage form Substances 0.000 description 9
- 210000002540 macrophage Anatomy 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 8
- 239000002158 endotoxin Substances 0.000 description 8
- 229920006008 lipopolysaccharide Polymers 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 230000002829 reductive effect Effects 0.000 description 8
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 8
- DQFBYFPFKXHELB-UHFFFAOYSA-N Chalcone Natural products C=1C=CC=CC=1C(=O)C=CC1=CC=CC=C1 DQFBYFPFKXHELB-UHFFFAOYSA-N 0.000 description 7
- 125000000217 alkyl group Chemical group 0.000 description 7
- 230000037396 body weight Effects 0.000 description 7
- 235000005513 chalcones Nutrition 0.000 description 7
- 239000007795 chemical reaction product Substances 0.000 description 7
- 229940125904 compound 1 Drugs 0.000 description 7
- 239000003208 petroleum Substances 0.000 description 7
- WQXWIKCZNIGMAP-UHFFFAOYSA-N 3',5'-Dihydroxyacetophenone Chemical compound CC(=O)C1=CC(O)=CC(O)=C1 WQXWIKCZNIGMAP-UHFFFAOYSA-N 0.000 description 6
- XJUZRXYOEPSWMB-UHFFFAOYSA-N Chloromethyl methyl ether Chemical compound COCCl XJUZRXYOEPSWMB-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- 229920002472 Starch Polymers 0.000 description 6
- 229940061627 chloromethyl methyl ether Drugs 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- 238000007069 methylation reaction Methods 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 238000011160 research Methods 0.000 description 6
- 239000008107 starch Substances 0.000 description 6
- 235000019698 starch Nutrition 0.000 description 6
- 230000001225 therapeutic effect Effects 0.000 description 6
- GVSPXQVUXHMUMA-MDWZMJQESA-N (e)-3-(3,5-ditert-butyl-4-hydroxyphenyl)-1-(4-methoxyphenyl)prop-2-en-1-one Chemical compound C1=CC(OC)=CC=C1C(=O)\C=C\C1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 GVSPXQVUXHMUMA-MDWZMJQESA-N 0.000 description 5
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 5
- 229940125782 compound 2 Drugs 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 5
- 229930014626 natural product Natural products 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- DQFBYFPFKXHELB-VAWYXSNFSA-N trans-chalcone Chemical compound C=1C=CC=CC=1C(=O)\C=C\C1=CC=CC=C1 DQFBYFPFKXHELB-VAWYXSNFSA-N 0.000 description 5
- FGQOOHJZONJGDT-UHFFFAOYSA-N vanillin Natural products COC1=CC(O)=CC(C=O)=C1 FGQOOHJZONJGDT-UHFFFAOYSA-N 0.000 description 5
- RVFXUQLUGHXKDS-FNORWQNLSA-N (E)-1-(2-bromo-3,5-dimethoxyphenyl)-3-(3,4-dimethoxyphenyl)prop-2-en-1-one Chemical compound COC(C=C1OC)=CC(C(/C=C/C(C=C2)=CC(OC)=C2OC)=O)=C1Br RVFXUQLUGHXKDS-FNORWQNLSA-N 0.000 description 4
- KIMRHQQUVDQEMD-GQCTYLIASA-N (E)-1-(2-bromo-3-hydroxy-5-methoxyphenyl)-3-(3,4-dimethoxyphenyl)prop-2-en-1-one Chemical compound COC(C=C1O)=CC(C(/C=C/C(C=C2)=CC(OC)=C2OC)=O)=C1Br KIMRHQQUVDQEMD-GQCTYLIASA-N 0.000 description 4
- GZEBLAJMNZYUPU-HWKANZROSA-N (E)-1-(2-bromo-3-hydroxy-5-methoxyphenyl)-3-(4-hydroxy-3-methoxyphenyl)prop-2-en-1-one Chemical compound COC(C=C1O)=CC(C(/C=C/C(C=C2)=CC(OC)=C2O)=O)=C1Br GZEBLAJMNZYUPU-HWKANZROSA-N 0.000 description 4
- XVVAHBQMUILPNK-GQCTYLIASA-N (E)-1-(2-bromo-5-hydroxy-3-methoxyphenyl)-3-(3,4-dimethoxyphenyl)prop-2-en-1-one Chemical compound COC(C=CC(/C=C/C(C(C=C(C=C1OC)O)=C1Br)=O)=C1)=C1OC XVVAHBQMUILPNK-GQCTYLIASA-N 0.000 description 4
- BLLRAYYUXAYOKC-SOFGYWHQSA-N (E)-1-[2-bromo-3,5-bis(methoxymethyl)phenyl]-3-[3-methoxy-4-(methoxymethyl)phenyl]prop-2-en-1-one Chemical compound COCC(C=C1COC)=CC(C(/C=C/C2=CC(OC)=C(COC)C=C2)=O)=C1Br BLLRAYYUXAYOKC-SOFGYWHQSA-N 0.000 description 4
- RQTGRUWBAVOGTD-HWKANZROSA-N (E)-1-[2-bromo-3-hydroxy-5-(methoxymethyl)phenyl]-3-(4-hydroxy-3-methoxyphenyl)prop-2-en-1-one Chemical compound COCC(C=C1O)=CC(C(/C=C/C(C=C2)=CC(OC)=C2O)=O)=C1Br RQTGRUWBAVOGTD-HWKANZROSA-N 0.000 description 4
- WXJLEXKNEAEXTI-UHFFFAOYSA-N 1-(2-bromophenyl)-3-phenylprop-2-en-1-one Chemical compound BrC1=CC=CC=C1C(=O)C=CC1=CC=CC=C1 WXJLEXKNEAEXTI-UHFFFAOYSA-N 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 210000000683 abdominal cavity Anatomy 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 235000001727 glucose Nutrition 0.000 description 4
- 239000008103 glucose Substances 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 230000011987 methylation Effects 0.000 description 4
- 230000000144 pharmacologic effect Effects 0.000 description 4
- 238000012827 research and development Methods 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 235000012141 vanillin Nutrition 0.000 description 4
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 3
- PHDIJLFSKNMCMI-ITGJKDDRSA-N (3R,4S,5R,6R)-6-(hydroxymethyl)-4-(8-quinolin-6-yloxyoctoxy)oxane-2,3,5-triol Chemical compound OC[C@@H]1[C@H]([C@@H]([C@H](C(O1)O)O)OCCCCCCCCOC=1C=C2C=CC=NC2=CC=1)O PHDIJLFSKNMCMI-ITGJKDDRSA-N 0.000 description 3
- PMVWXBYAEVCIEV-DUXPYHPUSA-N (E)-1-(2-bromo-3,5-dihydroxyphenyl)-3-(4-hydroxy-3-methoxyphenyl)prop-2-en-1-one Chemical compound COC(C=C(/C=C/C(C(C=C(C=C1O)O)=C1Br)=O)C=C1)=C1O PMVWXBYAEVCIEV-DUXPYHPUSA-N 0.000 description 3
- BMJZOORSCWBTRL-GQCTYLIASA-N (E)-1-(2-bromo-3,5-dihydroxyphenyl)-3-[4-(cyclopropylmethoxy)-3-methoxyphenyl]prop-2-en-1-one Chemical compound COC(C=C(/C=C/C(C(C=C(C=C1O)O)=C1Br)=O)C=C1)=C1OCC1CC1 BMJZOORSCWBTRL-GQCTYLIASA-N 0.000 description 3
- HQMGKHRPMHGORS-CSKARUKUSA-N (E)-1-[2-bromo-3,5-bis(cyclopropylmethoxy)phenyl]-3-[4-(cyclopropylmethoxy)-3-methoxyphenyl]prop-2-en-1-one Chemical compound COC(C=C(/C=C/C(C(C=C(C=C1OCC2CC2)OCC2CC2)=C1Br)=O)C=C1)=C1OCC1CC1 HQMGKHRPMHGORS-CSKARUKUSA-N 0.000 description 3
- HBCSEYWMICHSAI-GQCTYLIASA-N (E)-1-[2-bromo-3,5-bis(methoxymethyl)phenyl]-3-(4-hydroxy-3-methoxyphenyl)prop-2-en-1-one Chemical compound COCC(C=C1COC)=CC(C(/C=C/C(C=C2)=CC(OC)=C2O)=O)=C1Br HBCSEYWMICHSAI-GQCTYLIASA-N 0.000 description 3
- KQQIUIVUVDVLEQ-SOFGYWHQSA-N (E)-1-[2-bromo-3-(cyclopropylmethoxy)-5-hydroxyphenyl]-3-[4-(cyclopropylmethoxy)-3-methoxyphenyl]prop-2-en-1-one Chemical compound COC(C=C(/C=C/C(C(C=C(C=C1OCC2CC2)O)=C1Br)=O)C=C1)=C1OCC1CC1 KQQIUIVUVDVLEQ-SOFGYWHQSA-N 0.000 description 3
- HYKPETPWJIRFHC-SOFGYWHQSA-N (E)-1-[2-bromo-5-(cyclopropylmethoxy)-3-hydroxyphenyl]-3-[4-(cyclopropylmethoxy)-3-methoxyphenyl]prop-2-en-1-one Chemical compound COC(C=C(/C=C/C(C(C=C(C=C1O)OCC2CC2)=C1Br)=O)C=C1)=C1OCC1CC1 HYKPETPWJIRFHC-SOFGYWHQSA-N 0.000 description 3
- XYCVDKOQECJFKX-HWKANZROSA-N (E)-1-[2-bromo-5-hydroxy-3-(methoxymethyl)phenyl]-3-(4-hydroxy-3-methoxyphenyl)prop-2-en-1-one Chemical compound COCC1=CC(O)=CC(C(/C=C/C(C=C2)=CC(OC)=C2O)=O)=C1Br XYCVDKOQECJFKX-HWKANZROSA-N 0.000 description 3
- WNWHHMBRJJOGFJ-UHFFFAOYSA-N 16-methylheptadecan-1-ol Chemical class CC(C)CCCCCCCCCCCCCCCO WNWHHMBRJJOGFJ-UHFFFAOYSA-N 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 3
- 125000005256 alkoxyacyl group Chemical group 0.000 description 3
- 229940124599 anti-inflammatory drug Drugs 0.000 description 3
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000005893 bromination reaction Methods 0.000 description 3
- AEILLAXRDHDKDY-UHFFFAOYSA-N bromomethylcyclopropane Chemical compound BrCC1CC1 AEILLAXRDHDKDY-UHFFFAOYSA-N 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 239000003795 chemical substances by application 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
- 238000004440 column chromatography Methods 0.000 description 3
- 229960003957 dexamethasone Drugs 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 239000008273 gelatin Substances 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 235000011852 gelatine desserts Nutrition 0.000 description 3
- 208000026278 immune system disease Diseases 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- 150000002611 lead compounds Chemical class 0.000 description 3
- 229920000609 methyl cellulose Polymers 0.000 description 3
- 239000001923 methylcellulose Substances 0.000 description 3
- 235000010981 methylcellulose Nutrition 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000002002 slurry Substances 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- HBENZIXOGRCSQN-VQWWACLZSA-N (1S,2S,6R,14R,15R,16R)-5-(cyclopropylmethyl)-16-[(2S)-2-hydroxy-3,3-dimethylpentan-2-yl]-15-methoxy-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-trien-11-ol Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@H]3[C@@]5(OC)CC[C@@]2([C@@]43CC1)C[C@@H]5[C@](C)(O)C(C)(C)CC)CC1CC1 HBENZIXOGRCSQN-VQWWACLZSA-N 0.000 description 2
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 2
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 239000005995 Aluminium silicate Substances 0.000 description 2
- UTRZNMOMOGQHPZ-HWKANZROSA-N COC(C=C(/C=C/C(C(C=C(C=C1OC)O)=C1Br)=O)C=C1)=C1O Chemical compound COC(C=C(/C=C/C(C(C=C(C=C1OC)O)=C1Br)=O)C=C1)=C1O UTRZNMOMOGQHPZ-HWKANZROSA-N 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- 229920001353 Dextrin Polymers 0.000 description 2
- 239000004375 Dextrin Substances 0.000 description 2
- 239000001856 Ethyl cellulose Substances 0.000 description 2
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 2
- 240000007472 Leucaena leucocephala Species 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 244000299461 Theobroma cacao Species 0.000 description 2
- 235000005764 Theobroma cacao ssp. cacao Nutrition 0.000 description 2
- 235000005767 Theobroma cacao ssp. sphaerocarpum Nutrition 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 239000002250 absorbent Substances 0.000 description 2
- 230000002745 absorbent Effects 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 125000004423 acyloxy group Chemical group 0.000 description 2
- 239000008272 agar Substances 0.000 description 2
- 235000010419 agar Nutrition 0.000 description 2
- 238000005882 aldol condensation reaction Methods 0.000 description 2
- 229940072056 alginate Drugs 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 125000004414 alkyl thio group Chemical group 0.000 description 2
- 235000012211 aluminium silicate Nutrition 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 235000014121 butter Nutrition 0.000 description 2
- 235000001046 cacaotero Nutrition 0.000 description 2
- 235000010216 calcium carbonate Nutrition 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 239000003405 delayed action preparation Substances 0.000 description 2
- 235000019425 dextrin Nutrition 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 235000019325 ethyl cellulose Nutrition 0.000 description 2
- 229920001249 ethyl cellulose Polymers 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 235000012907 honey Nutrition 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 239000013067 intermediate product Substances 0.000 description 2
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000008297 liquid dosage form Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 239000008176 lyophilized powder Substances 0.000 description 2
- 239000003094 microcapsule Substances 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 150000002796 natural product derivatives Chemical class 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 239000002547 new drug Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 229940124531 pharmaceutical excipient Drugs 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 229940083575 sodium dodecyl sulfate Drugs 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 238000005556 structure-activity relationship Methods 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- DCXXMTOCNZCJGO-UHFFFAOYSA-N tristearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 description 2
- 125000004417 unsaturated alkyl group Chemical group 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- DNIAPMSPPWPWGF-VKHMYHEASA-N (+)-propylene glycol Chemical compound C[C@H](O)CO DNIAPMSPPWPWGF-VKHMYHEASA-N 0.000 description 1
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 1
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- 125000006704 (C5-C6) cycloalkyl group Chemical group 0.000 description 1
- YPFDHNVEDLHUCE-UHFFFAOYSA-N 1,3-propanediol Substances OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 description 1
- 229940035437 1,3-propanediol Drugs 0.000 description 1
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 1
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 1
- JSHLOPGSDZTEGQ-UHFFFAOYSA-N 3-methoxy-4-phenylmethoxybenzaldehyde Chemical compound COC1=CC(C=O)=CC=C1OCC1=CC=CC=C1 JSHLOPGSDZTEGQ-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 241000208838 Asteraceae Species 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 206010053567 Coagulopathies Diseases 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 241000220485 Fabaceae Species 0.000 description 1
- 241000628997 Flos Species 0.000 description 1
- 241001112537 Gesneriaceae Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 208000037273 Pathologic Processes Diseases 0.000 description 1
- 241000199919 Phaeophyceae Species 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 240000006365 Vitis vinifera Species 0.000 description 1
- 235000014787 Vitis vinifera Nutrition 0.000 description 1
- YKTSYUJCYHOUJP-UHFFFAOYSA-N [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] Chemical compound [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] YKTSYUJCYHOUJP-UHFFFAOYSA-N 0.000 description 1
- 239000003655 absorption accelerator Substances 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000002924 anti-infective effect Effects 0.000 description 1
- 230000000078 anti-malarial effect Effects 0.000 description 1
- 230000000767 anti-ulcer Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 208000002399 aphthous stomatitis Diseases 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 208000015294 blood coagulation disease Diseases 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 235000011132 calcium sulphate Nutrition 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 235000013877 carbamide Nutrition 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 230000009852 coagulant defect Effects 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 201000003146 cystitis Diseases 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 239000002662 enteric coated tablet Substances 0.000 description 1
- HWJHWSBFPPPIPD-UHFFFAOYSA-N ethoxyethane;propan-2-one Chemical compound CC(C)=O.CCOCC HWJHWSBFPPPIPD-UHFFFAOYSA-N 0.000 description 1
- 229960004667 ethyl cellulose Drugs 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 239000013020 final formulation Substances 0.000 description 1
- 229930003935 flavonoid Natural products 0.000 description 1
- 235000017173 flavonoids Nutrition 0.000 description 1
- 150000002215 flavonoids Chemical class 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 241000411851 herbal medicine Species 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 238000013332 literature search Methods 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229960002900 methylcellulose Drugs 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 210000002200 mouth mucosa Anatomy 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000009054 pathological process Effects 0.000 description 1
- BNIXVQGCZULYKV-UHFFFAOYSA-N pentachloroethane Chemical class ClC(Cl)C(Cl)(Cl)Cl BNIXVQGCZULYKV-UHFFFAOYSA-N 0.000 description 1
- 210000003200 peritoneal cavity Anatomy 0.000 description 1
- 210000004303 peritoneum Anatomy 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 235000013824 polyphenols Nutrition 0.000 description 1
- 229920000166 polytrimethylene carbonate Polymers 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 238000000611 regression analysis Methods 0.000 description 1
- 201000003068 rheumatic fever Diseases 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 230000008685 targeting Effects 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
- 238000010998 test method Methods 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
- C07C49/84—Ketones containing a keto group bound to a six-membered aromatic ring containing ether groups, groups, groups, or groups
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- 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
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dermatology (AREA)
- Rheumatology (AREA)
- Cardiology (AREA)
- Biomedical Technology (AREA)
- Physical Education & Sports Medicine (AREA)
- Urology & Nephrology (AREA)
- Heart & Thoracic Surgery (AREA)
- Immunology (AREA)
- Neurology (AREA)
- Diabetes (AREA)
- Oncology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Communicable Diseases (AREA)
- Gastroenterology & Hepatology (AREA)
- Endocrinology (AREA)
- Neurosurgery (AREA)
- Vascular Medicine (AREA)
- Pain & Pain Management (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本发明属于医药领域,公开了2′‑卤代查尔酮衍生物、其制法及药物组合物与用途。具体涉及一类如通式(I)所示的2′‑卤代查尔酮衍生物及其医学上可接受的盐,及该类化合物单体或药用组合物在制备炎症和/或炎症免疫相关疾病治疗药物中的应用。
Description
技术领域
本发明属于医药领域,具体涉及到一类2′-卤代查尔酮衍生物或其医学上可接受的盐、含有这些衍生物的药用组合物及其在炎症和/或炎症免疫相关疾病的临床治疗中的应用。
背景技术
炎症是人类疾病的病症基础,与疾病的众多病变互为因果,为疾病病理过程的关键环节。然而,当前抗炎药物,如皮质激素类和非甾体类抗炎药,临床应用中仍存在较多的问题,如易引起消化道不适、出血,增加心脏病或全身凝血障碍性疾病发生等不良反应风险。因此,寻找更为安全有效的抗炎药物仍是当前抗炎药物研究与开发的重要任务。
以活性天然产物为基础研发新药,是现代药物研发的重要途径之一。天然产物及其类似物具有来源广泛、毒性低和副作用小等特点。从传统中草药中发现具有显著活性的天然先导化合物,通过结构修饰,结合系统的体内外活性测试以及成药性综合评价,从中寻找安全高效的候选化合物作为临床上有用的原型药物,是药物研究开发的重要方向。查尔酮是一类具有1,3-二苯基丙烯酮结构的黄酮类天然产物,文献报道其具有广泛的生物活性。该类化合物多分布于菊科植物红花、豆科植物甘草以及苦苣苔科等植物中。
查尔酮化合物分子结构柔性较大,能与多种受体结合,显示出较广泛的药理活性。该类化合物结构相对简单,且研究较早、合成方法成熟,为有机合成中的一个重要中间体,更是新药开发较为理想的分子结构之一。文献报道,对查耳酮类化合物的结构改造大多是在它的2个苯环上引入不同的取代基,将碳链骨架上的羰基还原取代,或者是对碳碳双键进行修饰、将查尔酮分子进行环化等。查尔酮类化合物具有广泛的生物活性,比如抗肿瘤、抗疟疾、抗真菌、抗氧化、抗炎、抗溃疡、抗病毒等,尤其在抗肿瘤、抗感染等活性方面研究较为广泛,具有深入研究开发成为新药的潜力。
发明内容
2′-卤代查尔酮衍生物是我们在长期对多酚类化合物进行合成及构效关系研究中发现的一类新结构类型的活性化合物,为天然产物查尔酮的类似物。文献检索结果显示,该类型化合物的结构和抗炎活性迄今为止均未见文献报道过。本专利对该类化合物进行了系统的结构改造和炎症因子NO抑制活性筛选实验,结果显示,2′-卤素取代极大地提高了该类化合物的活性,所得化合物抗炎活性显著,一些衍生物的IC50值达到了纳摩尔水平,是一类极具开发价值的活性化合物。本发明对深入开发利用该类化合物有重要意义。
本发明要解决的技术问题是,提供一类新结构的2′-卤代查尔酮衍生物及其制法、药物组合物与用途。
本发明技术方案的第一方面是提供一种如通式(I)、(II)、(III)、(IV)、(V)所示的新结构2′-卤代查尔酮衍生物。
本发明技术方案的第二方面是提供一种药物组合物,其中包括至少一个如通式(I)、(II)、(III)、(IV)、(V)所示的2′-卤代查尔酮衍生物、或其药学上可接受的盐和制药领域中常用的载体。
本发明技术方案的第三方面是提供如通式((I)、(II)、(III)、(IV)、(V)所示的2′-卤代查尔酮衍生物或其药学上可接受的盐,在制备用于预防、治疗和辅助治疗各种炎症免疫相关疾病的药物中的应用。
本发明技术方案的第四方面是提供第一方面所述衍生物的制备方法。
所述的各种炎症免疫疾病包括:类风湿性关节炎、骨关节炎、风湿性关节炎、痛风性关节炎、红斑狼疮综合症、支气管炎、滑囊炎、腱鞘炎、牛皮癣、湿疹、烧伤、皮炎、炎性肠病、克劳恩病、胃炎、过敏性肠综合症、溃疡性结肠炎、多发性硬化症、自身免疫性脑脊髓炎、结肠直肠癌、结节性动脉炎、甲状腺炎、风热湿、牙龈炎、牙周炎、口腔溃疡、肾炎、损坏后发生的肿胀、心肌缺血、各种感染性肺炎、理化性肺炎以及变态反应性肺炎、慢性阻塞性肺疾病、哮喘、痉挛性肛部痛和直肠裂、肝胆囊炎、胆管炎、硬化性胆管炎或原发性胆汁性肝硬变和胆囊炎。本发明所述的化合物包括其衍生物和药效学上可接受的盐。
具体而言,本发明涉及如通式(I)所示的2′-卤代查尔酮衍生物,或其药学上可接受的盐:
其中,X选自F、Cl、Br、I;
R1、R2各自独立地选自氢、取代或未取代的C1-6的烷基、取代或未取代的C1-6的酰基、取代或未取代的苄基、取代或未取代的C3-6环烷基、环丙甲基、MOM、Glu、SO3H、PO3H2;所述取代为单取代、二取代、三取代、四取代,取代基选自羟基、硝基、氰基、氨基、羧基、C1-6的烷氧基、C3-6的环烷基、F、Cl、Br、I;
R3为单取代或多取代,其中所述的单取代选自邻位、间位、对位单取代;所述的多取代选自二取代、三取代、四取代;R3选自氢、羟基、硝基、氰基、氨基、羧基、苯基、甲氨基、二甲氨基、取代或未取代的C1-6的烷基、取代或未取代的C1-6的烷氧基、取代或未取代的C1-6的酰基、取代或未取代的C1-6的酰氧基、取代或未取代的C1-6的烷氧酰基、取代或未取代的C2-6的不饱和烷氧基、取代或未取代的苄氧基、取代或未取代的C3-6的环烷氧基、取代或未取代的C1-6的烷硫基、环丙甲氧基、F、Cl、Br、I、Glu、MOMO、SO3H、PO3H2;所述取代选自单取代、二取代、三取代、四取代,取代基选自羟基、硝基、氰基、氨基、羧基、C1-6的烷氧基、C3-6的环烷基、F、Cl、Br、I;
MOM表示甲氧基甲基;Glu表示β-D吡喃葡萄糖基;SO3H表示磺酰基;PO3H2表示磷酰基。
根据本发明,优选的通式(I)所示的2′-卤代查尔酮衍生物包括,但不限定于通式(II)所示的化合物,或其药学上可接受的盐,其特征在于,所述化合物如通式(II)所示:
其中,X选自F、Cl、Br、I;
R1、R2各自独立地选自氢、取代或未取代的C1-6的烷基、取代或未取代的C1-6的酰基、取代或未取代的苄基、取代或未取代的C3-6环烷基、环丙甲基、MOM、Glu、SO3H、PO3H2;所述取代为单取代、二取代、三取代、四取代,取代基选自羟基、硝基、氰基、氨基、羧基、C1-6的烷氧基、C3-6的环烷基、F、Cl、Br、I;
R4、R5各自独立地选自氢、羟基、硝基、氰基、氨基、羧基、苯基、甲氨基、二甲氨基、取代或未取代的C1-6的烷基、取代或未取代的C1-6的烷氧基、取代或未取代的C1-6的酰基、取代或未取代的C1-6的酰氧基、取代或未取代的C1-6的烷氧酰基、取代或未取代的C2-6的不饱和烷氧基、取代或未取代的苄氧基、取代或未取代的C3-6的环烷氧基、取代或未取代的C1-6的烷硫基、环丙甲氧基、F、Cl、Br、I、Glu、MOMO、SO3H、PO3H2;所述取代为单取代、二取代、三取代、四取代,取代基选自羟基、硝基、氰基、氨基、羧基、C1-6的烷氧基、C3-6的环烷基、F、Cl、Br、I;
MOM表示甲氧基甲基;Glu表示β-D吡喃葡萄糖基;SO3H表示磺酰基;PO3H2表示磷酰基。
根据本发明,优选的通式(II)所示的2′-卤代查尔酮衍生物包括,但不限定于通式(III)所示的化合物,或其药学上可接受的盐,其特征在于,所述化合物如通式(III)所示:
其中,X选自F、Cl、Br、I;
R1、R2、R6、R7各自独立地选自氢、取代或未取代的C1-6的烷基、取代或未取代的C1-6的酰基、取代或未取代的苄基、取代或未取代的C3-6环烷基、环丙甲基、MOM、Glu、SO3H、PO3H2;所述取代为单取代、二取代、三取代、四取代,取代基选自羟基、硝基、氰基、氨基、羧基、C1-6的烷氧基、C3-6的环烷基、F、Cl、Br、I;
MOM表示甲氧基甲基;Glu表示β-D吡喃葡萄糖基;SO3H表示磺酰基;PO3H2表示磷酰基。
根据本发明,优选的通式(III)所示的2′-卤代查尔酮衍生物包括,但不限定于通式(IV)所示的化合物,或其药学上可接受的盐,其特征在于,所述化合物如通式(IV)所示:
其中,X选自F、Cl、Br、I;
R1、R2、R7各自独立地选自氢、取代或未取代的C1-6的烷基、取代或未取代的C1-6的酰基、取代或未取代的苄基、取代或未取代的C3-6环烷基、环丙甲基、MOM、Glu、SO3H、PO3H2;所述取代为单取代、二取代、三取代、四取代,取代基选自羟基、硝基、氰基、氨基、羧基、C1-6的烷氧基、C3-6的环烷基、F、Cl、Br、I;
MOM表示甲氧基甲基;Glu表示β-D吡喃葡萄糖基;SO3H表示磺酰基;PO3H2表示磷酰基。
根据本发明,优选的通式(IV)所示的2′-卤代查尔酮衍生物包括,但不限定于通式(V)所示的化合物,或其药学上可接受的盐,其特征在于,所述化合物如通式(V)所示:
其中,R1、R2、R7各自独立地选自氢、取代或未取代的C1-6的烷基、取代或未取代的C1-6的酰基、取代或未取代的苄基、取代或未取代的C3-6的环烷基、环丙甲基、MOM、Glu、SO3H、PO3H2;所述取代为单取代、二取代、三取代、四取代,取代基选自羟基、硝基、氰基、氨基、羧基、C1-6的烷氧基、C3-6的环烷基、F、Cl、Br、I;
MOM表示甲氧基甲基;Glu表示β-D吡喃葡萄糖基;SO3H表示磺酰基;PO3H2表示磷酰基。
具体来说,通式(I)、(II)、(III)、(IV)、(V)所示的2′-卤代查尔酮衍生物或其药学上可接受的盐,其特征在于,所述的化合物选自如下群组(化合物代号对应于实施例中的化合物代号):
本发明技术方案的第二方面是提供了一种含有药物有效剂量的如通式(I)、(II)、(III)、(IV)、(V)各情况所述的化合物和药学上可接受的载体的药物组合物。
根据本发明,本发明化合物可以以异构体的形式存在,而且通常所述的“本发明化合物”包括该化合物的异构体。
根据本发明的实施方案,所述的本发明化合物还包括其药学上可接受的盐、盐的水合物或前体药物。
本发明还涉及含有作为活性成分的本发明化合物和常规药物赋形剂或辅剂的药物组合物。通常本发明药物组合物含有0.1~95%重量的本发明化合物。在单元剂型中本发明化合物一般含量为0.1~100mg,优选的单元剂型含有4~50mg。
本发明化合物的药物组合物可根据本领域公知的方法制备。用于此目的时,如果需要,可将本发明化合物与一种或多种固体或液体药物赋形剂和/或辅剂结合,制成可作为人药或兽药使用的适当的施用形式或剂量形式。
本发明化合物或含有它的药物组合物可以单位剂量形式给药,给药途径可为肠道或非肠道,如口服、肌肉、皮下、鼻腔、口腔黏膜、皮肤、腹膜或直肠等。本发明化合物或含有它的药物组合物的给药途径可为注射给药。注射包括静脉注射、肌肉注射、皮下注射、皮内注射和穴位注射等。
给药剂型可以是液体剂型、固体剂型。如液体剂型可以是真溶液类、胶体类、微粒剂型、乳剂剂型、混悬剂型。其它剂型例如片剂、胶囊、滴丸、气雾剂、丸剂、粉剂、溶液剂、混悬剂、乳剂、颗粒剂、栓剂、冻干粉针剂等。
本发明化合物可以制成普通制剂,也可以是缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
例如为了将单位给药剂型制成片剂,可以广泛使用本领域公知的各种载体。关于载体的例子,如稀释剂与吸收剂,如淀粉、糊精、硫酸钙、乳糖、甘露醇、蔗糖、氯化钠、葡萄糖、尿素、碳酸钙、白陶土、微晶纤维素、硅酸铝等;湿润剂与粘合剂,如水、甘油、聚乙二醇、乙醇、丙醇、淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、紫胶、甲基纤维素、磷酸钾、聚乙烯吡咯烷酮等;崩解剂,例如干燥淀粉、海藻酸盐、琼脂粉、褐藻淀粉、碳酸氢钠与枸橼酸、碳酸钙、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠、甲基纤维素、乙基纤维素等;崩解抑制剂,例如蔗糖、三硬脂酸甘油酯、可可脂、氢化油等;吸收促进剂,例如季铵盐、十二烷基硫酸钠等;润滑剂,例如滑石粉、二氧化硅、玉米淀粉、硬脂酸盐、硼酸、液体石蜡、聚乙二醇等。还可以将片剂进一步制成包衣片,例如糖包衣片、薄膜包衣片、肠溶包衣片,或双层片和多层片。
例如为了将给药单元制成丸剂,可以广泛使用本领域公知的载体。关于载体的例子是,例如稀释剂与吸收剂,如葡萄糖、乳糖、淀粉、可可脂、氢化植物油、聚乙烯吡咯烷酮、单硬脂酸甘油酯、高岭土、滑石粉等;粘合剂,如阿拉伯胶、黄蓍胶、明胶、乙醇、蜂蜜、液糖、米糊或面糊等;崩解剂,如琼脂粉、干燥淀粉、海藻酸盐、十二烷基磺酸钠、甲基纤维素、乙基纤维素等。
例如为了将给药单元制成胶囊,将本发明化合物与上述的各种载体混合,并将由此得到的混合物置于硬的明胶胶囊或软胶囊中。也可将有效成分本发明化合物制成微囊剂,混悬于水性介质中形成混悬剂,亦可装入硬胶囊中或制成注射剂应用。
例如,将本发明化合物制成注射用制剂,如溶液剂、混悬剂溶液剂、乳剂、冻干粉针剂,这种制剂可以是含水或非水的,可含一种和/或多种药效学上可接受的载体、稀释剂、粘合剂、润滑剂、防腐剂、表面活性剂或分散剂。如稀释剂可选自水、乙醇、聚乙二醇、1,3-丙二醇、乙氧基化的异硬脂醇、多氧化的异硬脂醇、聚氧乙烯山梨醇酯、脂肪酸等。另外,为了制备等渗注射液,可以向注射用制剂中添加适量的氯化钠、葡萄糖或甘油,此外,还可以添加常规的助溶剂、缓冲剂、pH调节剂等。这些辅料是本领域常用的。
此外,如需要,也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂、甜味剂或其它材料。
为达到用药目的,增强治疗效果,本发明的药物或药物组合物可用任何公知的给药方法给药。
本发明化合物药物组合物的给药剂量取决于许多因素,例如所要预防或治疗疾病的性质和严重程度,患者或动物的性别、年龄、体重、性格及个体反应,给药途径、给药次数、治疗目的,因此本发明的治疗剂量可以有大范围的变化。一般来讲,本发明中药学成份的使用剂量是本领域技术人员公知的。可以根据本发明化合物组合物中最后的制剂中所含有的实际药物数量,加以适当的调整,以达到其治疗有效量的要求,完成本发明的预防或治疗目的。本发明化合物的每天的合适剂量范围:本发明的化合物的用量为0.001~100mg/kg体重,优选为0.1~60mg/kg体重,更优选为1~30mg/kg体重,最优选为2~15mg/kg体重。成人患者服用的本发明化合物每日为10~500mg,优选为10~100mg,可一次服用或分2~3次服用;儿童服用的剂量按照每kg体重5~30mg,优选为10~20mg/kg体重。上述剂量可以单一剂量形式或分成几个,例如二、三或四个剂量形式给药,这受限于给药医生的临床经验以及治疗手段的给药方案。本发明的化合物或组合物可单独服用,或与其它治疗药物或对症药物合并使用。
本发明技术方案的第三方面是提供一类2′-卤代查尔酮衍生物及其药学上可接受的盐、盐的水合物或前体药物在制备炎症免疫相关疾病药物中的应用。
所述的炎症免疫疾病包括、风湿性关节炎、痛风性关节炎红斑狼疮综合症、支气管炎、滑囊炎、腱鞘炎、牛皮癣、湿疹、烧伤、皮炎、炎性肠病、克劳恩病、胃炎、过敏性肠综合症、溃疡性结肠炎、多发性硬化症、自身免疫性脑脊髓炎、结肠直肠癌、结节性动脉炎、甲状腺炎、风湿热、牙龈炎、牙周炎、口腔溃疡、肾炎、损坏后发生的肿胀、心肌缺血、各种感染性肺炎、理化性肺炎以及变态反应性肺炎、、痉挛性肛部痛和直肠裂、肝胆囊炎、胆管炎、硬化性胆管炎、原发性胆汁性肝硬变和胆囊炎等。
炎症免疫性疾病在细胞水平上的普遍特征表现为:巨噬细胞过度活化,产生过量NO。因此,本发明进行了化合物对LPS诱导的原代小鼠腹腔巨噬细胞NO生成的抑制实验,从细胞水平上说明2′-卤代查尔酮衍生物具有抑制巨噬细胞NO生成的活性。
本发明技术方案的第四方面是提供第一方面所述衍生物的制备方法。
用于制备本发明化合物的原料,如3,5-二羟基苯乙酮和香草醛可通过商业购买获得,关键中间体1可参考文献[Adv.Synth.Catal.2019,361,3768-3776]的方法制备获得。关键中间体化合物1的基本合成方法包括如下步骤:
步骤一、3,5-二羟基苯乙酮与氯甲基甲醚反应制备MOM保护二个羟基的3,5-二羟基苯乙酮中间体(1a)。
3,5-二羟基苯乙酮在二氯甲烷溶液中,以DIPEA为催化剂,与氯甲基甲醚在室温条件下反应,反应产物经分离制备得到MOM保护二个羟基的3,5-二羟基苯乙酮化合物1a。
步骤二、化合物1a与NBS进行溴代反应制备其溴代产物(1b)。
步骤一所得产物在DMF中与NBS在室温下进行溴代反应,反应混合物经分离制备得到其溴代产物1b。
步骤三、香草醛与氯甲基甲醚反应制备MOM保护酚羟基的香草醛中间体化合物(1c)。
香草醛在二氯甲烷中,以DIPEA为催化剂,与氯甲基甲醚在室温条件下反应,反应产物经分离制备得到MOM保护羟基的香草醛衍生物1c。
步骤四、溴代产物1b与香草醛衍生物1c通过羟醛缩合反应制备关键中间体产物1。
溴代产物1b与香草醛衍生物1c在甲醇水混合溶液中,以NaOH为催化剂,在室温下进行羟醛缩合反应,反应产物经分离制备得到关键中间体产物1。
本发明所述化合物的基本合成方法包括如下步骤:
步骤一、MOM保护羟基的查尔酮类化合物在酸性条件下脱除MOM保护基制备相应的羟基衍生物。
MOM保护羟基的查尔酮衍生物在甲醇溶液中与盐酸在室温下进行反应,所得产物经分离制备得到全部或部分羟基脱除MOM保护基的查尔酮衍生物。
步骤二、带有羟基的查尔酮衍生物通过羟基全甲基化和羟基部分甲基化的方法制备相应的甲基化衍生物。
带有羟基的查尔酮衍生物在丙酮溶液中,在K2CO3的催化下与适量的碘甲烷试剂进行甲基化反应,反应产物经分离制备得到羟基全部甲基化或部分甲基化的查尔酮衍生物。
步骤三、带有羟基的查尔酮衍生物与溴甲基环丙烷反应,通过羟基全部或部分环丙甲基化的方法合成环丙甲基化产物。
带有羟基的查尔酮衍生物在无水丙酮溶液中,在K2CO3存在下,与适量的溴甲基环丙烷进行环丙甲基化反应,反应产物经分离制备得到羟基全部环丙甲基化和羟基部分环丙甲基化的查尔酮衍生物。
有益技术效果
本发明的发明人在天然产物全合成和活性研究的过程中,发现天然产物衍生物2′-溴代查尔酮具有较强的抗炎活性。在此基础上,进一步对2′-溴代查尔酮进行了合成和结构衍生化修饰,合成了一系列结构相关衍生物,并对所得到的衍生物进行了炎症抑制活性评价,确证了该类化合物的抗炎活性。该类化合物对LPS诱导原代小鼠腹腔巨噬细胞NO的生成具有显著的抑制活性,具有进一步开发研究的潜在应用价值。
2′-溴代查尔酮为一类新型结构的天然产物衍生物。迄今为止,该类化合物的结构研究未见有文献报道过,对该类化合物的抗炎活性和系统的构效关系研究尚未见文献报道。现有文献和技术中未见关于2′-溴代查尔酮衍生物或其医学上可接受的盐,及该类化合物用于治疗炎症性疾病的报道。因此,本发明的内容具有显著的创新性。
发明详述:
本发明使用的各种术语和短语具有本领域技术人员公知的一般含义,即便如此,本发明仍然希望在此对这些术语和短语作更详尽的说明和解释,提及的术语和短语如有与公知含义不一致的,以本发明所表述的含义为准。下面是本发明所用多种术语的定义,这些定义适用于本申请整个说明书中所用的术语,除非在具体情况中另作说明。
以下提供本发明化合物各种基团的定义,除另行定义外,它们在说明书和权利要求书中统一使用。
本发明所提及的术语“烷基”是指具有指定数目碳原子数的烷基,其可以为直链或支链的烷基,例如提及的“C3-6的环烷基”是指碳原子数为3、4、5、6的取代或未取代的环烷基,可以包括C3-5环烷基、C3-4环烷基、C4-6环烷基、C4-5环烷基、C5-6环烷基等表示的子范围的基团,以及优选的具体基团,例如环丙烷基、环戊烷基以及环己烷基。
本发明所提及的术语“C1-6的烷基”是指碳原子数为1、2、3、4、5、6的直链或支链烷基,可以包括C1-5烷基、C1-4烷基、C2-5烷基、C2-4烷基、C2-3烷基、C3-5烷基等表示的子范围的基团,以及优选的具体基团,例如甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基等。
本发明所提及的术语“C1-6烷氧基”是指碳原子数为1、2、3、4、5、6的烷氧基,包括C1-5烷氧基、C1-2烷氧基、C2-4烷氧基、C2-3烷氧基、C3-4烷氧基等表示的子范围的基团,以及优选的具体基团例如甲氧基、乙氧基、正丙基氧基、异丙基氧基、正丁基氧基、仲丁基氧基、叔丁基氧基等。
本发明所提及的术语“C1-6不饱和烷基”是指碳原子数为1、2、3、4、5、6的不饱和烷基,可以包括C1-5的不饱和烷基、C1-4的不饱和烷基、C2-5的不饱和烷基、C2-4的不饱和烷基等表示的子范围的基团,以及优选的具体基团,例如乙烯基、乙炔基、异丙烯基、异丙炔基、异丁烯基、异戊烯基、1,4-二丁烯基。
本发明所提及的术语“C1-6的酰基”是指碳原子数为1、2、3、4、5、6的酰基,可以包括C1-5酰基、C1-3酰基、C2-5酰基、C2-3酰基、C3-4酰基等表示的子范围的基团,以及优选的具体基团,例如甲酰基、乙酰基、丙酰基等。
本发明所提及的“C1-6的酰氧基”是指碳原子数为1、2、3、4、5、6的直链或支链酰氧基,可以包括C1-5酰氧基、C1-3酰氧基、C2-5酰氧基、C2-3酰氧基、C3-4酰氧基等表示的子范围的基团,以及优选的具体基团,例如甲酰氧基、乙酰氧基、丙酰氧基等。
本发明所提及的“C1-6的烷氧酰基”是指碳原子数为1、2、3、4、5、6的烷氧酰基,可以包括C1-5烷氧酰基、C1-3烷氧酰基、C2-5烷氧酰基、C2-3烷氧酰基、C3-4烷氧酰基等表示的子范围的基团,以及优选的具体基团,例如甲氧酰基、乙氧酰基等;
本发明所提及的术语“C1-6的烷硫基”是指碳原子数为1、2、3、4、5、6的直链或支链烷硫基,可以包括C1-5烷硫基、C1-3烷硫基、C2-5烷硫基、C2-3烷硫基、C3-4烷硫基等表示的子范围的基团,以及优选的具体基团,例如甲硫基、乙硫基等。
具体实施方式
为了进一步阐明本发明,下面给出一系列实施例,这些实施例完全是例证性的,它们仅用来对本发明进行具体描述,不应当理解为对本发明的限制。
实施例1:
1-(2-溴-3,5-二甲氧甲基苯基)-3-(3-甲氧基-4-甲氧甲基苯基)-(2E)-2-丙烯-1-酮(1)
化合物1的合成路线:
步骤一、3,5-二羟基苯乙酮10g(65.79mmol)溶解于300ml二氯甲烷中,室温搅拌下加入DIPEA(43.42ml,263mmol),缓慢滴加氯甲基甲醚液体(21.2g,263mmol),保持室温搅拌10h,停止反应。向反应液中加入300ml水,以二氯甲烷萃取,有机相依次以5%氢氧化钠溶液洗涤,饱和氯化钠溶液洗涤,无水硫酸镁干燥,减压抽虑,滤液减压浓缩。所得无色油状液体以200-300目硅胶进行柱层析分离,石油醚:丙酮(10:1)洗脱,得无色油状液体化合物1a(15.78g,产率80%)。化合物1a的理化常数如下:
化合物1a:无色油状液体,1H NMR(500MHz,acetone-d6):δ:7.26(d,J=2.29Hz,2H),6.93(t,J=2.27Hz,1H),5.19(s,4H),3.48(s,3H),2.56(s,3H);(+)-ESI-MS:m/z263.0[M+Na]+.
步骤二、化合物1a(0.7g,2.917mmol)溶解于40ml干燥的DMF中,搅拌下加入NBS(0.519g,2.916mmol),避光室温反应8h,停止反应。反应液中加入50ml水,乙酸乙酯萃取,有机相以饱和氯化钠溶液洗涤,无水硫酸镁干燥,减压浓缩,所得固体以200-300目硅胶柱层析分离,石油醚:乙酸乙酯:二氯甲烷(40:1:3)洗脱,得油状液体1b(0.6g,产率64.5%)。化合物1b的理化常数如下:
化合物1b:无色油状液体,1H NMR(500MHz,MeOH-d4)δ:6.96(d,J=2.69Hz,1H),6.76(d,J=2.69Hz,1H),5.27(s,2H),5.19(s,2H),3.49(s,3H),3.46(s,3H),2.55(s,3H);13C NMR(125MHz,MeOH-d4)δ:203.830,158.982,156.197,145.750,109.331,107.123,101.209,96.394,95.768,56.774,56.478,30.685;(+)-ESI-MS:m/z341.0[M+Na]+.
步骤三、3-甲氧基-4-羟基苯甲醛(10g,65.79mmol)溶解于300ml二氯甲烷中,搅拌下加入DIPEA(20.28ml,122.7mmol),缓慢滴加氯甲基甲醚液体(10ml,132.9mmol),保持室温搅拌10h,TLC检测反应完成。反应液中加入300ml水,二氯甲烷萃取,有机相依次用5%的氢氧化钠溶液洗涤,饱和的氯化钠溶液洗涤,无水硫酸镁干燥,减压抽虑,滤液浓缩。所得无色油状液体以200-300目硅胶进行柱层析分离,石油醚:乙酸乙酯:二氯甲烷(25:1:3)洗脱得无色油状液体化合物1c(11.3g,90%)。化合物1c的理化常数如下:
化合物1c:无色油状液体。1H NMR(500MHz,acetone-d6):δ:9.89(s 1H);7.51(dd,J=8.19Hz,1.52Hz,1H);7.47(d,J=1.93Hz,1H);7.28(d,J=8.23Hz,1H);5.31(s,2H).3.92(s,3H).3.43(s,3H).13C NMR(125MHz,MeOH-d4)δ:191.397,152.872,151.488,132.374,126.019,116.307,111.211,95.728,56.531,56.211.(+)-ESI-MS:m/z 197.1[M+H]+,219.0[M+Na]+.
步骤四、化合物1b 1g(3.13mmol)溶解于30ml甲醇水的混合溶剂(甲醇:水=2:1,v/v)中,加入NaOH固体125mg(1.2eq)。室温搅拌10分钟,加入化合物1c 613mg(3.13mmol),继续反应10h。反应液以30ml水稀释,乙酸乙酯萃取,有机相以饱和食盐水洗涤,无水硫酸镁干燥,硅胶柱层析分离得黄色油状液体1(1.26g,80%)。化合物1的理化参数如下:
化合物1:黄色油状液体(yield=80%);1H NMR(500MHz,MeOH-d4):δ:7.41(d,J=2.0Hz,1H);7.37(d,J=16.0Hz,1H);7.23(dd,J=8.0Hz,2.0Hz,1H);7.14(d,J=8.5Hz,1H);7.02(d,J=16.0Hz,1H);7.00(d,J=2.0Hz,1H);6.75(d,J=2.0Hz,1H);5.34(s,2H);5.24(s,3H);5.24(s,2H);3.90(s,3H);3.51(s,3H);3.45(s,6H);13C NMR(125MHz,MeOH-d4)δC:194.5,158.5,155.7,151.5,150.2,147.4,144.7,129.9,125.6,123.8,117.3,112.2,109.7,106.5,96.1,95.9,95.5,56.4,53.4,56.2,56.2;(+)-ESI-MS:m/z 497.0,499.0[M+H]+.
实施例2:
1-(2-溴-3,5-二羟基苯基)-3-(3-甲氧基-4-羟基苯基)-(2E)-2-丙烯-1-酮(2)
化合物2的合成路线:
化合物1 900mg(1.815mmol)溶解于130ml干燥甲醇中,在-10℃条件下缓慢加入浓盐酸甲醇溶液(15当量浓盐酸溶于2ml甲醇中),保持-10℃搅拌反应0.5小时后,室温继续避光反应24小时。反应液降温至-10℃,以饱和碳酸氢钠溶液调节PH至中性,乙酸乙酯萃取,有机相合并,饱和食盐水洗涤,无水硫酸镁干燥,减压浓缩,产物混合物以二氯甲烷:甲醇=10:1为洗脱剂硅胶柱层析分离得黄棕色油状液体化合物2(422mg,64%)。化合物2的理化参数如下:
化合物2:黄色油状液体(yield=64%);1H NMR(400MHz,MeOH)δH:7.74(d,J=16.0Hz,1H);7.64(d,J=2.0Hz,1H);7.54(dd,J=8.0Hz,2.0Hz,1H);7.30(d,J=16.0Hz,1H);7.25(d,J=8.0Hz,1H);6.93(d,J=2.4Hz,1H);6.72(d,J=2.4Hz,1H);4.31(s,3H);3.73(s,3H);13C NMR(125MHz,MeOH 4)δC:198.2,159.0,156.7,151.4,150.4,149.4,144.3,127.6,124.9,124.4,116.6,112.2,107.9,105.3,97.2,56.5;HR ESI MS:m/z 362.9868,calcd for C16H12O5Br[M-H]+,362.9874.
实施例中化合物3~5的合成路线:
化合物1 100mg(0.202mmol)溶解于16ml干燥甲醇中,在0℃条件下缓慢加入浓盐酸的甲醇溶液[90μl(4.5eq)浓盐酸溶于0.5ml甲醇中],搅拌反应0.5小时后,在室温条件下避光反应10小时,停止反应。在0℃条件下以饱和的碳酸氢钠溶液调节PH至中性,乙酸乙酯萃取,有机相合并,饱和氯化钠洗涤,无水硫酸镁干燥,减压浓缩,所得产物以石油醚:丙酮=6:1~2:1洗脱分离得到化合物3(21mg,21%)、化合物4(14.0mg,16%)及化合物5(11.2mg,18%)。
合成终产物3~5(化合物代号对应于实施例中的化合物代号)
实施例3:
1-(2-溴-3,5-二甲氧甲基苯基)-3-(3-甲氧基-4-羟基苯基)-(2E)-2-丙烯-1-酮(3)
化合物3:黄色油状液体(yield=21%);1H NMR(400MHz,Acetone-d6)δH:7.38(d,J=2.0Hz,1H),7.34(d,J=16.0Hz,1H),7.18(dd,J=8.0Hz,2.0Hz,1H),6.99(d,J=2.0Hz,1H),6.94(d,J=16.0Hz,1H),6.88(d,J=8.0Hz,1H),6.74(d,J=2.8Hz,1H),5.35(s,2H),5.24(s,2H),3.91(s,3H),3.51(s,3H),3.45(s,3H);13C NMR(125MHz,Acetone-d6)δC:194.6,158.4,155.6,150.8,148.9,148.0,144.8,127.5,124.8,124.3,116.2,111.7,109.7,106.4,102.0,96.1,95.4,56.7,56.4(2×C);HRESIMS:m/z 451.0389,calcd forC20H20O7Br[M-H]+,451.0398.
实施例4:
1-(2-溴-3-羟基-5-甲氧甲基苯基)-3-(3-甲氧基-4-羟基苯基)-(2E)-2-丙烯-1-酮(4)
化合物4:黄色油状液体(yield=16%);1H NMR(400MHz,CDCl3)δH:7.38(d,J=2.29Hz,1H),7.34(d,J=16.07Hz,1H),7.17(dd,J=8.23Hz,2.80Hz,1H),6.99(d,J=2.83Hz,1H),6.94(d,J=16.06Hz,1H),6.88(d,J=8.23Hz,1H),6.74(d,J=2.79Hz,1H),5.35(s,2H),5.24(s,2H),3.91(s,3H),3.51(s,3H),3.45(s,3H);13C NMR(125MHz,CDCl3)δc:191.0,151.8,150.2,144.2,143.5,142.2,138.4,122.2,120.0,119.5,119.1,110.2,105.2,104.5,100.5,95.3,90.5,51.8,51.3;HR ESI MS:m/z407.0127,calcd forC18H16O6Br[M-H]+,407.0136.
实施例5:
1-(2-溴-3-甲氧甲基-5-羟基苯基)-3-(3-甲氧基-4-羟基苯基)-(2E)-2-丙烯-1-酮(5)
化合物5:黄色固体(yield=18%);1H NMR(400MHz,CDCl3)δH:7.36(d,J=15.98Hz,1H),7.10(dd,J=8.19Hz,1H),7.06(d,J=1.94Hz,1H),6.93(d,J=8.19Hz,1H),6.87(d,J=15.98Hz,1H),6.86(d,J=8Hz,1H),6.70(d,J=2.84Hz,1H),5.6(s,2H),3.93(s,3H),3.47(s,3H);13C NMR(125MHz,CDCl3)δc:194.1,157.8,153.7,148.9,148.0,147.0,142.2,126.9,124.2,123.6,115.0,109.9,109.5,105.2,99.7,94.7,56.3,56.1;HR ESIMS:m/z 407.0130,calcd for C18H16O6Br[M-H]+,407.0136.
实施例6:
1-(2-溴-3,5-二甲氧基苯基)-3-(3,4-二甲氧基苯基)-(2E)-2-丙烯-1-酮(6)
化合物2 100mg(0.275mmol)溶解于10ml干燥丙酮中,加入无水碳酸钾228mg(1.65mmol),搅拌0.5小时后加入碘甲烷234mg(1.65mmol),继续室温搅拌72小时,TLC检测反应完成。反应液硅藻土过滤,滤液浓缩,产物以200-300目硅胶柱层析,石油醚:丙酮=9:1洗脱得到淡黄色结晶固体6(97mg,87%)。
化合物6:淡黄色结晶状(yield=87%);1H NMR(400MHz,Acetone-d6)δH:7.37(d,J=2.4Hz,1H),7.32(d,J=16.0Hz,1H),7.23(dd,J=8.0Hz,2.00Hz,1H),7.00(d,J=8.0Hz,1H),6.95(d,J=16.0Hz.1H),6.75(d,J=2.4Hz,1H),6.55(d,J=2.4Hz,1H),3.94(s,3H),3.87(s,3H),3.86(s,3H),3.86(s,3H);13C NMR(125MHz,Acetone-d6)δC:206.1,194.9,161.2,157.9,153.1,150.7,147.7,144.7,128.3,125.0,124.4,112.4,111.4,105.6,101.2,99.6,56.9,56.2(2×C),56.1;HR ESI MS:m/z407.0480,calcd for C19H20O5Br[M+H]+,407.0489.
化合物7~10的合成路线及合成方法:
化合物2 100mg(0.275mmol)溶解于10ml干燥丙酮中,加入无水碳酸钾228mg(1.65mmol),搅拌0.5小时后加入碘甲烷176mg(1.24mmol),室温搅拌反应72小时,停止反应。反应混合物以硅藻土过滤,滤液减压浓缩,产物以200-300目硅胶柱层析,石油醚:丙酮=9:1~4:1梯度洗脱分别得化合物7,8,9和10。
合成终产物7~10(化合物代号对应于实施例中的化合物代号)
实施例7:
1-(2-溴-3-羟基-5-甲氧基苯基)-3-(3,4-二甲氧基苯基)-(2E)-2-丙烯-1-酮(7)
化合物7:黄色固体(yield=9%);1H NMR(400MHz,CDCl3)δH:7.34(d,J=16.0Hz,1H),7.12(dd,J=8.0Hz,2.0Hz,1H),7.06(d,J=2.0Hz,1H),6.87(m,2H),6.53(d,J=2.0Hz,1H),6.45(d,J=2.0Hz,1H),3.91(s,3H),3.90(s,3H),3.87(s,3H);13C NMR(500MHz,CDCl3)δc:196.2,157.1,156.9,152.0,149.3,148.4,142.9,127.3,124.2,123.9,111.1,110.1,107.7,101.7,98.8,56.6,56.2,56.1;HR ESI MS:m/z393.0326,calcd forC18H18O5Br[M+H]+,393.0332.
实施例8:
1-(2-溴-3-甲氧基-5-羟基苯基)-3-(3,4-二甲氧基苯基)-(2E)-2-丙烯-1-酮(8)
化合物8:黄色固体(yield=11%);1H NMR(400MHz,CDCl3)δH:7.31(d,J=16.0Hz,1H),7.09(dd,J=8.0Hz,2.0Hz,1H),7.06(d,J=2.0Hz,1H),6.92(m,2H),6.57(d,J=2.0Hz,1H),6.50(d,J=2.0Hz,1H),3.93(s,3H),3.92(s,3H),3.82(s,3H);13C NMR(125MHz,CDCl3)δc:195.4,178.6,160.1,156.9,148.8,147.6,147.0,143.4,127.1,124.2,124.1,115.0,109.8,104.5,101.0,77.2,56.6,56.1,55.9;HRESI MS:m/z 393.0324,calcd forC18H18O5Br[M+H]+,393.0332.
实施例9:
1-(2-溴-3-羟基-5-甲氧基苯基)-3-(3-甲氧基-4-羟基苯基)-(2E)-2-丙烯-1-酮(9)
化合物9:黄色固体(yield=23%);1H NMR(400MHz,CDCl3)δH:7.37(d,J=16.0Hz,1H),7.12(dd,J=8.0Hz,2.00Hz,1H),7.06(d,J=2.0Hz,1H),6.88(d,J=8.0Hz,1H),6.85(br s,1H),6.66(br s,1H),6.50(br s,1H),3.90(s,6H);13C NMR(125MHz,CDCl3)δc:195.0,156.8,154.0,152.0,149.4,148.3,142.2,127.3,123.9(2×C),111.2,110.1,108.7,104.9,98.1,56.2,56.1;HR ESI MS:m/z 379.0171,calcd for C17H16O5Br[M+H]+,379.0176.
实施例10:
1-(2-溴-3-甲氧基-5-羟基苯基)-3-(3-甲氧基-4-羟基苯基)-(2E)-2-丙烯-1-酮(Z10)
化合物10:黄色固体(yield=16%);1H NMR(400MHz,CDCl3)δH:7.34(d,J=16.0Hz,1H),7.08(dd,J=8.0Hz,2.0Hz,1H),7.04(d,J=2.0Hz,1H),6.91(d,J=8.0Hz,1H),6.85(d,J=16.0Hz,1H),6.53(d,J=2.0Hz,1H),6.45(d,J=2.0Hz,1H),3.91(s,3H),3.90(s,3H);13C NMR(125MHz,CDCl3)δc:196.31,157.1,157.0,149.0,148.6,145.0,142.9,126.9,124.3,123.9,115.0,110.0,107.7,101.7,98.7,56.6,56.1;HRESIMS:m/z379.0169,calcd for C17H16O5Br[M+H]+,379.0176.
实施例11:
1-(2-溴-3,5-二苯甲氧基苯基)-3-(3-甲氧基-4-苯甲氧基苯基)-(2E)-2-丙烯-1-酮(11)
2-溴-3,5-二苄氧基苯乙酮20g(48.8mmol)溶解于2000ml甲醇和水的混合溶剂(甲醇:水=2:1,v/v)中,加入NaOH固体20g(48.8mmol)。室温搅拌10分钟,再加入3-甲氧基-4-苄氧基苯甲醛14.2g(58.6mmol),继续反应10h,TLC检测显示反应完毕。反应液硅藻土过滤得黄色固体化合物11(27.5g,87%)。
化合物11:黄色固体,1H NMR(400MHz,acetone-d6):δH:7.31-7.57(m,17H),7.19(dd,J=8.0Hz,2.0Hz,1H),7.09(d,J=8.0Hz,1H),6.97(d,J=16Hz,1H),6.96(d,J=2.6Hz,1H),5.29(s,2H),5.19(s,2H),5.18(s,2H),3.89(s,3H);13C NMR(100MHz,acetone-d6):δC:194.8,160.2,156.9,152.1,151.1,147.7,144.7,138.0,137.6(2×C),129-128.2(12×C),125.2,124.3,114.3,111.9,107.1,103.6,71.6,71.2,71.1,56.3;HR-ESI MS:m/z635.1424,calcd for C37H32O5Br[M+H]+,635.1428.
化合物12~15的合成方法:
100mg化合物2(0.275mmol)溶解于10ml干燥丙酮中,加入无水碳酸钾228mg(1.65mmol),搅拌0.5小时后加入溴甲基环丙烷168mg(1.24mmol),100℃下搅拌反应12小时,停止反应。反应液硅藻土过滤,滤液减压浓缩,所得产物以石油醚:乙酸乙酯:二氯甲烷=6:1:2~3:1:2为洗脱剂,硅胶柱层析分离得化合物12,13,14和15。
合成终产物12~15(化合物代号对应于实施例中的化合物代号)
实施例12:
1-(2-溴-3,5-二环丙甲氧基苯基)-3-(3-甲氧基-4-环丙甲氧基苯基)-(2E)-2-丙烯-1-酮(12)
化合物12:黄色固体(yield=32%);1H NMR(400MHz,CDCl3)δH:7.32(d,J=16.0Hz,1H),7.08(dd,J=8.0Hz,2Hz,1H),7.07(d,J=2.0Hz,1H),6.89(d,J=16.0Hz,1H),6.84(d,J=8.0Hz,1H),6.56(d,J=2.4Hz,1H),6.47(d,J=2.4Hz,1H),3.89(d,J=6.4Hz,2H),3.88(s,3H),3.87(d,J=6.4Hz,2H),3.78(d,J=6.4Hz,2H);13C NMR(125MHz,CDCl3)δc:195.3,159.3,156.5,151.4,149.7,147.2,143.4,127.4,124.3,123.5,112.8,110.5,105.4,103.0,100.5,74.1,74.0,73.4,56.1,29.8,10.2(2×C),3.6,3.4,3.3;HRESIMS:m/z527.1419,calcd for C28H32O5Br[M+H]+,527.1428.
实施例13:
1-(2-溴-3-环丙甲氧基-5-羟基苯基)-3-(3-甲氧基-4-环丙甲氧基苯基)-(2E)-2-丙烯-1-酮(13)
化合物13:黄色固体(yield=16%);1H NMR(400MHz,CDCl3)δH:7.33(d,J=16.0Hz,1H),7.07(m,2H),6.87(d,J=16.0Hz,1H),6.83(d,J=8.0Hz,2H),6.48(d,J=2.0Hz,1H),6.44(d,J=2.0Hz,1H),3.87(m,7H),0.69-0.31(m,5H);13C NMR(125MHz,CDCl3)δc:196.3,156.61 151.6,149.6,148.4,142.9,127.2,124.1,123.8,112.6,110.5,107.7,103.0,99.6,74.0,56.1,10.2(2×C),3.7(2×C),3.4(2×C);HRESI MS:m/z 473.0951,calcd for C24H26O5Br[M+H]+:473.0958.
实施例14:
1-(2-溴-3-羟基-5-环丙甲氧基苯基)-3-(3-甲氧基-4-环丙甲氧基苯基)-(2E)-2-丙烯-1-酮(14)
化合物14:黄色固体(yield=15%);1H NMR(400MHz,CDCl3)δH:7.32(d,J=16.0Hz,1H),7.07(m,2H),6.97(d,J=16.0Hz,1H),6.85(d,J=8.0Hz,2H),6.56(d,J=2.0Hz,1H),6.47(d,J=2.0Hz,1H),3.87(m,7H),0.69-0.31(m,5H);13C NMR(125MHz,CDCl3)δc:196.3,156.61 151.6,149.6,148.4,142.9,127.2,124.1,123.8,112.6,110.5,107.7,103.0,99.6,74.0,56.1,10.2(2×C),3.7(2×C),3.4(2×C);HRESIMS:m/z 473.0954,calcd for C24H26O5Br[M+H]+,473.0958.
实施例15:
1-(2-溴-3,5-二羟基苯基)-3-(3-甲氧基-4-环丙甲氧基苯基)-(2E)-2-丙烯-1-酮(15)
化合物15:黄色固体(yield=13%);1H NMR(400MHz,CDCl3)δH:7.33(d,J=16.0Hz,1H),7.08(dd,J=8.0Hz,2.0Hz,1H),7.04(d,J=2.0Hz,1H),6.88(m,2H),6.49(d,J=2.0Hz,1H),6.44(d,J=2.0Hz,1H),3.91(s,3H),3.86(d,J=6.4Hz,2H),0.88-0.39(m,5H);13C NMR(125MHz,CDCl3)δc:196.4,156.7,156.6,148.9,148.5,147.0,142.9,127.0,124.3,123.9,115.0,110.0,107.7,103.0,99.5,74.0,56.1,10.2,3.4(2×C);HRESIMS:m/z419.0479,calcd for C20H20O5Br[M+H]+,419.0489.
药理实验
本发明化合物的抗炎活性的药理试验方法与结果如下(药理实验部分的化合物代号对应于实施例中的化合物代号):
实施例1:葡萄藤戊素衍生物对LPS诱导原代小鼠腹腔巨噬细胞NO生成的抑制活性。
巨噬细胞,执行机体非特异性免疫功能,在细菌脂多糖LPS诱导下可产生NO等炎性因子,参与并介导炎症反应,在多种炎症免疫过程初期与病理发展过程中均有较高的水平。通过检测原代培养的小鼠巨噬细胞NO生成量,可作为体外初步观察和筛选有一定抗炎活性的组分或化合物的指标。
实验方法:
取原代小鼠腹腔巨噬细胞接种于96孔板中,加入不同待测化合物(10-5M)和阳性对照药地塞米松(Dex)预保护1h;然后,加入1μg/ml LPS于37℃、5%CO2培养箱中培养24h后,收集上清液, 同时,用MTT法测定细胞增殖抑制率;并测定对NO生成具有显著抑制活性化合物的IC50值(用Probit加权回归分析法计算)。
实验结果:
结果如表1所示,合成所得2′-卤代查尔酮衍生物NO生成抑制活性显著。其中,化合物1、3、7、10不仅具有显著的NO生成抑制活性,且细胞毒性显著低于阳性对照药地塞米松。
表1. 2′-卤代查尔酮衍生物对LPS诱导原代小鼠腹腔巨噬细胞NO生成的影响*.
*浓度:10-5M;治疗方向:抗炎;阳性对照:地塞米松(DEX,10-6M)。
# 化合物代号对应于实施例中的化合物代号。
Claims (11)
1.如通式(I)所示的2′-卤代查尔酮衍生物或其药学上可接受的盐:
其中,X选自F、Cl、Br、I;
R1、R2各自独立地选自氢、取代或未取代的C1-6的烷基、取代或未取代的C1-6的酰基、取代或未取代的苄基、取代或未取代的C3-6环烷基、环丙甲基、MOM、Glu、SO3H、PO3H2;所述取代为单取代、二取代、三取代、四取代,取代基选自羟基、硝基、氰基、氨基、羧基、C1-6的烷氧基、C3-6的环烷基、F、Cl、Br、I;
R3为单取代或多取代,其中所述单取代选自邻位、间位、对位单取代;所述多取代选自二取代、三取代、四取代;R3选自氢、羟基、硝基、氰基、氨基、羧基、苯基、甲氨基、二甲氨基、取代或未取代的C1-6的烷基、取代或未取代的C1-6的烷氧基、取代或未取代的C1-6的酰基、取代或未取代的C1-6的酰氧基、取代或未取代的C1-6的烷氧酰基、取代或未取代的C1-6的不饱和烷氧基、取代或未取代的苄氧基、取代或未取代的C3-6的环烷氧基、取代或未取代的C1-6的烷硫基、环丙甲氧基、F、Cl、Br、I、Glu、MOMO、SO3H、PO3H2;所述取代选自单取代、二取代、三取代、四取代,取代基选自羟基、硝基、氰基、氨基、羧基、C1-6的烷氧基、C3-6的环烷基、F、Cl、Br、I;
MOM表示甲氧基甲基;Glu表示β-D吡喃葡萄糖基;SO3H表示磺酰基;PO3H2表示磷酰基。
2.根据权利要求1的2′-卤代查尔酮衍生物或其药学上可接受的盐,其特征在于,所述化合物如通式(II)所示:
其中,X选自F、Cl、Br、I;
R1、R2各自独立地选自氢、取代或未取代的C1-6的烷基、取代或未取代的C1-6的酰基、取代或未取代的苄基、取代或未取代的C3-6的环烷基、环丙甲基、MOM、Glu、SO3H、PO3H2;所述取代为单取代、二取代、三取代、四取代,取代基选自羟基、硝基、氰基、氨基、羧基、C1-6的烷氧基、C3-6的环烷基、F、Cl、Br、I;
R4、R5各自独立地选自氢、羟基、硝基、氰基、氨基、羧基、苯基、甲氨基、二甲氨基、取代或未取代的C1-6的烷基、取代或未取代的C1-6的烷氧基、取代或未取代的C1-6的酰基、取代或未取代的C1-6的酰氧基、取代或未取代的C1-6的烷氧酰基、取代或未取代的C2-6的不饱和烷氧基、取代或未取代的苄氧基、取代或未取代的C3-6的环烷氧基、取代或未取代的C1-6的烷硫基、环丙甲氧基、F、Cl、Br、I、Glu、MOMO、SO3H、PO3H2;所述取代为单取代、二取代、三取代、四取代,取代基选自羟基、硝基、氰基、氨基、羧基、C1-6的烷氧基、C3-6的环烷基、F、Cl、Br、I;
MOM表示甲氧基甲基;Glu表示β-D吡喃葡萄糖基;SO3H表示磺酰基;PO3H2表示磷酰基。
7.一种药物组合物,由有效剂量的权利要求1-6任一项所述的2′-卤代查尔酮衍生物或其药学上可接受的盐和药学上可接受的载体或辅料组成。
8.根据权利要求7的药物组合物,其特征在于,所述的药物组合物选自片剂、胶囊、丸剂或注射剂。
9.根据权利要求7的药物组合物,其特征在于,所述药物组合物选自缓释制剂、控释制剂或各种微粒给药系统。
10.权利要求1-6任一项所述的2′-卤代查尔酮衍生物或其药学上可接受的盐在制备治疗和/或预防炎症和/或炎症免疫相关疾病药物中的应用。
11.根据权利要求10的应用,其中炎症和炎症免疫相关疾病包括:类风湿性关节炎、骨关节炎、风湿性关节炎、痛风性关节炎、红斑狼疮综合症、支气管炎、滑囊炎、腱鞘炎、牛皮癣、湿疹、烧伤、皮炎、炎性肠病、克劳恩病、胃炎、过敏性肠综合症、溃疡性结肠炎、多发性硬化症、自身免疫性脑脊髓炎、结肠直肠癌、结节性动脉炎、甲状腺炎、风热湿、牙龈炎、牙周炎、口腔溃疡、肾炎、损坏后发生的肿胀、心肌缺血、各种感染性肺炎、理化性肺炎以及变态反应性肺炎、慢性阻塞性肺疾病、哮喘、痉挛性肛部痛和直肠裂、肝胆囊炎、胆管炎、硬化性胆管炎或原发性胆汁性肝硬变和胆囊炎。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202010734890.4A CN113979851B (zh) | 2020-07-27 | 2020-07-27 | 2′-卤代查尔酮衍生物、其制法及药物组合物与用途 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202010734890.4A CN113979851B (zh) | 2020-07-27 | 2020-07-27 | 2′-卤代查尔酮衍生物、其制法及药物组合物与用途 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN113979851A true CN113979851A (zh) | 2022-01-28 |
CN113979851B CN113979851B (zh) | 2024-01-12 |
Family
ID=79731619
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202010734890.4A Active CN113979851B (zh) | 2020-07-27 | 2020-07-27 | 2′-卤代查尔酮衍生物、其制法及药物组合物与用途 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN113979851B (zh) |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102397269A (zh) * | 2011-09-20 | 2012-04-04 | 温州医学院 | 查尔酮类化合物在制备抗炎药物中的应用 |
CN103910691A (zh) * | 2014-04-18 | 2014-07-09 | 山东药品食品职业学院 | 卤代苯基查尔酮衍生物及其制备方法和应用 |
CN105085218A (zh) * | 2014-05-22 | 2015-11-25 | 中国医学科学院药物研究所 | 一类a环具有甲基的醌式查尔酮化合物,制法与抗炎活性 |
CN106008400A (zh) * | 2016-06-02 | 2016-10-12 | 云南省中医医院 | 一种新的查尔酮衍生物及其制备方法与在自身免疫病应用 |
CN111171018A (zh) * | 2018-11-13 | 2020-05-19 | 沈阳化工研究院有限公司 | 一种查尔酮类化合物及其应用 |
-
2020
- 2020-07-27 CN CN202010734890.4A patent/CN113979851B/zh active Active
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102397269A (zh) * | 2011-09-20 | 2012-04-04 | 温州医学院 | 查尔酮类化合物在制备抗炎药物中的应用 |
CN103910691A (zh) * | 2014-04-18 | 2014-07-09 | 山东药品食品职业学院 | 卤代苯基查尔酮衍生物及其制备方法和应用 |
CN105085218A (zh) * | 2014-05-22 | 2015-11-25 | 中国医学科学院药物研究所 | 一类a环具有甲基的醌式查尔酮化合物,制法与抗炎活性 |
CN106008400A (zh) * | 2016-06-02 | 2016-10-12 | 云南省中医医院 | 一种新的查尔酮衍生物及其制备方法与在自身免疫病应用 |
CN111171018A (zh) * | 2018-11-13 | 2020-05-19 | 沈阳化工研究院有限公司 | 一种查尔酮类化合物及其应用 |
Non-Patent Citations (2)
Title |
---|
BONG HYANG LEE等: "Stereoselective Palladium -Catalyzed r -Arylation of 3-Aryl-1-Indanones: An Asymmetric Synthesis of (+)-Pauciflorol F", J. ORG. CHEM, vol. 76, pages 6611, XP093014824, DOI: 10.1021/jo2009164 * |
CHANGHUI SHANG等: "Versatileand Enantioselective Total Synthesisof NaturallyActive Gnetulin", ADV. SYNTH. CATAL., vol. 361, pages 3768 * |
Also Published As
Publication number | Publication date |
---|---|
CN113979851B (zh) | 2024-01-12 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN109897021B (zh) | 葡萄藤戊素衍生物、其制法以及药物组合物与用途 | |
EP1980248A1 (en) | Composition for treating cancer cells and synthetic method for the same | |
CN109721580B (zh) | 3-苯基-7,8-脱氢葡萄藤戊素衍生物、其制法和药物组合物与用途 | |
CN101863934B (zh) | 水杨酸甲酯糖苷类化合物、其合成方法与用途 | |
CN109721579B (zh) | 7,8-脱氢葡萄藤戊素衍生物、其制法和药物组合物与用途 | |
CN114075102B (zh) | 2,3-二芳基茚衍生物、其制法及药物组合物与用途 | |
CN110433153A (zh) | 一类Amurensin H衍生物在治疗和预防肝脏相关疾病中的应用 | |
CN113979851A (zh) | 2′-卤代查尔酮衍生物、其制法及药物组合物与用途 | |
CN101781352A (zh) | 20-o-糖基及其原人参二醇类化合物及其制备方法 | |
CN115246802B (zh) | 一类葡萄素衍生物、其制法及药物组合物与用途 | |
CN113995738B (zh) | 2′-卤代查尔酮衍生物在制备治疗肝脏相关疾病药物中的应用 | |
US7842721B2 (en) | Composition for treating cancer cells and synthetic method for the same | |
JP2006176407A (ja) | 新規フラボン誘導体、その製造法およびそれらを含む医薬組成物 | |
CN115073406A (zh) | 一种桉烷型倍半萜内酯类tba衍生物及其用途 | |
US3836520A (en) | Digitoxigenin-3-alpha,l-rhamnosido-4'-acylates | |
CN117105763A (zh) | 卤代查尔酮杂环衍生物、其制法及药物组合物与用途 | |
CN110498755B (zh) | 二氢菲类衍生物及其制备方法和用途 | |
CN112745288A (zh) | β-烷氧基醇二苯并呫吨类化合物及其应用 | |
CN116986977A (zh) | 卤代查尔酮衍生物、其制法及药物组合物与用途 | |
CN114073688B (zh) | 2,3-二芳基衍生物在制备治疗肝脏相关疾病药物中的应用 | |
CN114644679B (zh) | 葡萄糖醛酸糖苷类化合物、其制备方法及应用 | |
KR101121805B1 (ko) | 항염증 활성을 갖는 헤테로 고리 치환 신규 플라보노이드 유도체 | |
CN109232251B (zh) | 青心酮衍生物、其制备方法、应用及药物组合物 | |
Olivier et al. | Two new germacranolides from Melampodium leucanthum and their reductive and oxidative rearrangements | |
CN110627644B (zh) | 一种辣椒素酯类化合物、其药学上可接受的盐及其制备方法和应用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |