CN107382967B - 咔唑磺酰胺衍生物或其可药用盐及其制备方法和应用 - Google Patents
咔唑磺酰胺衍生物或其可药用盐及其制备方法和应用 Download PDFInfo
- Publication number
- CN107382967B CN107382967B CN201610323036.2A CN201610323036A CN107382967B CN 107382967 B CN107382967 B CN 107382967B CN 201610323036 A CN201610323036 A CN 201610323036A CN 107382967 B CN107382967 B CN 107382967B
- Authority
- CN
- China
- Prior art keywords
- methyl
- dimethoxypyridin
- carbazolsulfonamide
- ethyl
- sulfonamide derivative
- 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.)
- Expired - Fee Related
Links
- 150000003839 salts Chemical class 0.000 title claims abstract description 42
- HMAKCHLSXJDBPZ-UHFFFAOYSA-N 9h-carbazole-1-sulfonamide Chemical class C12=CC=CC=C2NC2=C1C=CC=C2S(=O)(=O)N HMAKCHLSXJDBPZ-UHFFFAOYSA-N 0.000 title claims abstract description 37
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 230000000259 anti-tumor effect Effects 0.000 claims abstract description 9
- 229940122429 Tubulin inhibitor Drugs 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims description 41
- -1 2, 6-dimethoxypyridin-3-yl Chemical group 0.000 claims description 35
- 238000006243 chemical reaction Methods 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- 229910052751 metal Inorganic materials 0.000 claims description 6
- 239000002184 metal Substances 0.000 claims description 6
- 239000002246 antineoplastic agent Substances 0.000 claims description 5
- 229940080818 propionamide Drugs 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 125000002524 organometallic group Chemical group 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 229910000397 disodium phosphate Inorganic materials 0.000 claims description 2
- 235000019800 disodium phosphate Nutrition 0.000 claims description 2
- 239000001488 sodium phosphate Substances 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 24
- 238000003786 synthesis reaction Methods 0.000 abstract description 24
- 230000000694 effects Effects 0.000 abstract description 9
- 230000001946 anti-microtubular Effects 0.000 abstract description 2
- 231100000331 toxic Toxicity 0.000 abstract description 2
- 230000002588 toxic effect Effects 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 78
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 68
- 235000002639 sodium chloride Nutrition 0.000 description 33
- 238000005160 1H NMR spectroscopy Methods 0.000 description 31
- 239000000243 solution Substances 0.000 description 29
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 28
- 238000004440 column chromatography Methods 0.000 description 28
- 239000003921 oil Substances 0.000 description 25
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
- BNAZWLOQJWBWMT-UHFFFAOYSA-N N-(2-bromoethyl)-N-(2,6-dimethoxypyridin-3-yl)-9-methylcarbazole-3-sulfonamide Chemical compound BrCCN(S(=O)(=O)C=1C=CC=2N(C3=CC=CC=C3C=2C=1)C)C=1C(=NC(=CC=1)OC)OC BNAZWLOQJWBWMT-UHFFFAOYSA-N 0.000 description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 22
- VMJIQJZXSXLUKN-UHFFFAOYSA-N N-(3-chloropropyl)-N-(2,6-dimethoxypyridin-3-yl)-9-methylcarbazole-3-sulfonamide Chemical compound ClCCCN(S(=O)(=O)C=1C=CC=2N(C3=CC=CC=C3C=2C=1)C)C=1C(=NC(=CC=1)OC)OC VMJIQJZXSXLUKN-UHFFFAOYSA-N 0.000 description 15
- 206010028980 Neoplasm Diseases 0.000 description 14
- 238000001308 synthesis method Methods 0.000 description 14
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 13
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 13
- 210000004027 cell Anatomy 0.000 description 13
- 229910021529 ammonia Inorganic materials 0.000 description 12
- 239000003814 drug Substances 0.000 description 12
- 239000007787 solid Substances 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 239000004698 Polyethylene Substances 0.000 description 10
- 229940079593 drug Drugs 0.000 description 10
- 239000000706 filtrate Substances 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 9
- 125000000217 alkyl group Chemical group 0.000 description 8
- 235000001014 amino acid Nutrition 0.000 description 8
- 229940024606 amino acid Drugs 0.000 description 8
- 150000001413 amino acids Chemical class 0.000 description 8
- 210000004881 tumor cell Anatomy 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 238000011580 nude mouse model Methods 0.000 description 6
- 229910000104 sodium hydride Inorganic materials 0.000 description 6
- 229930012538 Paclitaxel Natural products 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 235000019441 ethanol Nutrition 0.000 description 5
- 235000019439 ethyl acetate Nutrition 0.000 description 5
- 150000002431 hydrogen Chemical class 0.000 description 5
- 201000007270 liver cancer Diseases 0.000 description 5
- 208000014018 liver neoplasm Diseases 0.000 description 5
- 230000011278 mitosis Effects 0.000 description 5
- 229960001592 paclitaxel Drugs 0.000 description 5
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 4
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- AAXYSUPGKKJLJE-UHFFFAOYSA-N N-(2,6-dimethoxypyridin-3-yl)-N-(2-hydroxyethyl)-9-methylcarbazole-3-sulfonamide Chemical compound COC1=NC(=CC=C1N(S(=O)(=O)C=1C=CC=2N(C3=CC=CC=C3C=2C=1)C)CCO)OC AAXYSUPGKKJLJE-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 125000003368 amide group Chemical group 0.000 description 4
- 229940041181 antineoplastic drug Drugs 0.000 description 4
- 239000001768 carboxy methyl cellulose Substances 0.000 description 4
- 238000012258 culturing Methods 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- SXQCTESRRZBPHJ-UHFFFAOYSA-M lissamine rhodamine Chemical compound [Na+].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=C(S([O-])(=O)=O)C=C1S([O-])(=O)=O SXQCTESRRZBPHJ-UHFFFAOYSA-M 0.000 description 4
- JTPDYODKXJLRLA-UHFFFAOYSA-N n-(2,6-dimethoxypyridin-3-yl)-9-methylcarbazole-3-sulfonamide Chemical compound COC1=NC(OC)=CC=C1NS(=O)(=O)C1=CC=C(N(C)C=2C3=CC=CC=2)C3=C1 JTPDYODKXJLRLA-UHFFFAOYSA-N 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical group NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 3
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 3
- DSMNVUWTIFKOAS-UHFFFAOYSA-N N-(2-aminoethyl)-N-(2,6-dimethoxypyridin-3-yl)-9-methylcarbazole-3-sulfonamide Chemical compound COC1=NC(=CC=C1N(S(=O)(=O)C=1C=CC=2N(C3=CC=CC=C3C=2C=1)C)CCN)OC DSMNVUWTIFKOAS-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 125000004103 aminoalkyl group Chemical group 0.000 description 3
- 239000003080 antimitotic agent Substances 0.000 description 3
- 239000001913 cellulose Substances 0.000 description 3
- 229920002678 cellulose Polymers 0.000 description 3
- 235000010980 cellulose Nutrition 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
- 238000000605 extraction Methods 0.000 description 3
- 125000000623 heterocyclic group Chemical group 0.000 description 3
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 3
- 239000007928 intraperitoneal injection Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 3
- 230000035755 proliferation Effects 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 150000004819 silanols Chemical class 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 125000000565 sulfonamide group Chemical group 0.000 description 3
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 2
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 2
- 238000004679 31P NMR spectroscopy Methods 0.000 description 2
- FUQWPFAUFIMXFV-UHFFFAOYSA-N 4-pyrrol-1-ylpiperidine Chemical compound C1CNCCC1N1C=CC=C1 FUQWPFAUFIMXFV-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 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
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 2
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 102000029749 Microtubule Human genes 0.000 description 2
- 108091022875 Microtubule Proteins 0.000 description 2
- 241000699660 Mus musculus Species 0.000 description 2
- COPNHXQZURRXSK-UHFFFAOYSA-N N-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-N-(2,6-dimethoxypyridin-3-yl)-9-methylcarbazole-3-sulfonamide Chemical compound [Si](C)(C)(C(C)(C)C)OCCN(S(=O)(=O)C=1C=CC=2N(C3=CC=CC=C3C=2C=1)C)C=1C(=NC(=CC=1)OC)OC COPNHXQZURRXSK-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 102000004243 Tubulin Human genes 0.000 description 2
- 108090000704 Tubulin Proteins 0.000 description 2
- 229940122803 Vinca alkaloid Drugs 0.000 description 2
- 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 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 235000003704 aspartic acid Nutrition 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 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
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- DIOQZVSQGTUSAI-UHFFFAOYSA-N decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 description 2
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000005917 in vivo anti-tumor Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 210000004688 microtubule Anatomy 0.000 description 2
- 125000004193 piperazinyl group Chemical group 0.000 description 2
- 125000003386 piperidinyl group Chemical group 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000008354 sodium chloride injection Substances 0.000 description 2
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 2
- 235000019345 sodium thiosulphate Nutrition 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 229940124530 sulfonamide Drugs 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 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
- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 description 1
- 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
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- GNIDSOFZAKMQAO-VIFPVBQESA-N (2s)-3-hydroxy-2-(phenylmethoxycarbonylamino)propanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)OCC1=CC=CC=C1 GNIDSOFZAKMQAO-VIFPVBQESA-N 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
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- RZWHKKIXMPLQEM-UHFFFAOYSA-N 1-chloropropan-1-ol Chemical compound CCC(O)Cl RZWHKKIXMPLQEM-UHFFFAOYSA-N 0.000 description 1
- BMVXCPBXGZKUPN-UHFFFAOYSA-N 1-hexanamine Chemical group CCCCCCN BMVXCPBXGZKUPN-UHFFFAOYSA-N 0.000 description 1
- KJIGIFAQYDIGRD-UHFFFAOYSA-N 2-(4-methylpiperazin-1-yl)acetic acid;hydrochloride Chemical compound Cl.CN1CCN(CC(O)=O)CC1 KJIGIFAQYDIGRD-UHFFFAOYSA-N 0.000 description 1
- VRPJIFMKZZEXLR-UHFFFAOYSA-N 2-[(2-methylpropan-2-yl)oxycarbonylamino]acetic acid Chemical compound CC(C)(C)OC(=O)NCC(O)=O VRPJIFMKZZEXLR-UHFFFAOYSA-N 0.000 description 1
- LDLCZOVUSADOIV-UHFFFAOYSA-N 2-bromoethanol Chemical compound OCCBr LDLCZOVUSADOIV-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- OULKIPPQVXRBPY-UHFFFAOYSA-N 8-methyl-2,8-diazaspiro[4.5]decane Chemical compound C1CN(C)CCC11CNCC1 OULKIPPQVXRBPY-UHFFFAOYSA-N 0.000 description 1
- 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 1
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical group NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 1
- 238000011729 BALB/c nude mouse Methods 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- UJOBWOGCFQCDNV-UHFFFAOYSA-N Carbazole Natural products C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 description 1
- KOCVBWMJODDTDF-UHFFFAOYSA-N ClC1=CC=CC=C1C1C(=O)NC(=O)C1 Chemical compound ClC1=CC=CC=C1C1C(=O)NC(=O)C1 KOCVBWMJODDTDF-UHFFFAOYSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical group NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 description 1
- 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 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
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 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
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical group CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 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 1
- 239000004471 Glycine Substances 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 1
- 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 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 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
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 229930006000 Sucrose Natural products 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
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 241000863480 Vinca Species 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 125000005233 alkylalcohol group Chemical group 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
- 239000004411 aluminium Substances 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- 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 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000037396 body weight Effects 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
- ABBZJHFBQXYTLU-UHFFFAOYSA-N but-3-enamide Chemical group NC(=O)CC=C ABBZJHFBQXYTLU-UHFFFAOYSA-N 0.000 description 1
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical group CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 235000001465 calcium Nutrition 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 239000001175 calcium sulphate Substances 0.000 description 1
- 235000011132 calcium sulphate Nutrition 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001719 carbohydrate derivatives Chemical class 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- GOWVNGFQFBKGHR-UHFFFAOYSA-N chloro(phenylmethoxy)phosphinous acid Chemical compound C1=CC=C(C=C1)COP(O)Cl GOWVNGFQFBKGHR-UHFFFAOYSA-N 0.000 description 1
- WRJWRGBVPUUDLA-UHFFFAOYSA-N chlorosulfonyl isocyanate Chemical compound ClS(=O)(=O)N=C=O WRJWRGBVPUUDLA-UHFFFAOYSA-N 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 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
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- XWBTVUZAXKOXKE-UHFFFAOYSA-N dibenzyl hydrogen phosphate;hydrochloride Chemical compound Cl.C=1C=CC=CC=1COP(=O)(O)OCC1=CC=CC=C1 XWBTVUZAXKOXKE-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 229960002598 fumaric acid Drugs 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 230000005918 in vitro anti-tumor Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- PGLTVOMIXTUURA-UHFFFAOYSA-N iodoacetamide Chemical compound NC(=O)CI PGLTVOMIXTUURA-UHFFFAOYSA-N 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
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([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
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical group CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000018977 lysine Nutrition 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229940098895 maleic acid Drugs 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 235000019426 modified starch Nutrition 0.000 description 1
- 125000002757 morpholinyl group Chemical group 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
- PCJWVQUPHYPGIE-UHFFFAOYSA-N n-butyl-4-methoxybenzamide Chemical group CCCCNC(=O)C1=CC=C(OC)C=C1 PCJWVQUPHYPGIE-UHFFFAOYSA-N 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 231100000189 neurotoxic Toxicity 0.000 description 1
- 230000002887 neurotoxic effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 229940116315 oxalic acid Drugs 0.000 description 1
- RQKYHDHLEMEVDR-UHFFFAOYSA-N oxo-bis(phenylmethoxy)phosphanium Chemical compound C=1C=CC=CC=1CO[P+](=O)OCC1=CC=CC=C1 RQKYHDHLEMEVDR-UHFFFAOYSA-N 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- DPBLXKKOBLCELK-UHFFFAOYSA-N pentan-1-amine Chemical group CCCCCN DPBLXKKOBLCELK-UHFFFAOYSA-N 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 238000012809 post-inoculation Methods 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 1
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical group CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 150000003233 pyrroles Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 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
- 150000003335 secondary amines Chemical class 0.000 description 1
- 229960001153 serine Drugs 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000012177 spermaceti Substances 0.000 description 1
- 229940084106 spermaceti Drugs 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 239000008399 tap water Substances 0.000 description 1
- 235000020679 tap water Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229960001367 tartaric acid Drugs 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
- CAAUZMMMFDVBFD-UHFFFAOYSA-N tert-butyl-(2-iodoethoxy)-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)OCCI CAAUZMMMFDVBFD-UHFFFAOYSA-N 0.000 description 1
- KTJOZDBANQOLHP-UHFFFAOYSA-N tert-butyl-(3-iodopropoxy)-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)OCCCI KTJOZDBANQOLHP-UHFFFAOYSA-N 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 239000003744 tubulin modulator Substances 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/58—Pyridine rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供一种咔唑磺酰胺衍生物或其可药用盐及其制备方法和应用。其中,咔唑磺酰胺衍生物或其可药用盐具有如下通式(1)。本发明提供的咔唑磺酰胺衍生物或其药用盐作为小分子的微管蛋白抑制剂不仅具有抗微管作用,还具有显著的抗肿瘤活性,同时该咔唑磺酰胺衍生物或其药用盐分子量小,合成简单且毒副作用小。
Description
技术领域
本发明涉及一种咔唑磺酰胺衍生物或其可药用盐及其制备方法和应用,属于医药技术领域。
背景技术
肿瘤细胞具有快速增值能力,通过有丝***来维持细胞的形态、功能和增值,若阻断有丝***的过程即可导致肿瘤细胞增值受阻。基于微管在有丝***过程中发挥的重要作用,以微管蛋白为靶点的抗肿瘤药物成为研究的热点。传统的抗有丝***剂,主要是微管蛋白抑制剂,如紫杉醇和长春碱类抗肿瘤药物,可以通过与微管蛋白的特殊位点相结合,抑制微管的聚合或解聚,使肿瘤细胞在有丝***过程中,纺锤体难以形成,进而阻断肿瘤细胞的生长。
作用于微管蛋白的紫杉醇和长春碱类抗有丝***剂已广泛地应用于临床治疗各类恶性肿瘤。但是,这些微管蛋白抑制剂类药物的应用和制备中都具有如下的问题:作为一种大分子的天然产物,其合成的难度很大;生物利用度差,具有神经毒副作用,特别是,多重耐药的糖蛋白(P-gp)的出现,使其治疗的有效性受到了严重的挑战,在某种程度上限制了紫杉醇和长春碱类微管蛋白抑制剂的开发和应用。因此,合成具有新型的作用机制,良好药理学性质,并对各类肿瘤细胞有效的小分子抗有丝***剂是非常有必要的。
发明内容
本发明提供一种咔唑磺酰胺衍生物或其药用盐,其作为小分子的微管蛋白抑制剂不仅具有抗微管作用,还具有显著的抗肿瘤活性,同时该咔唑磺酰胺衍生物或其药用盐分子量小,合成简单且毒副作用小。
本发明还提供了制备该类咔唑磺酰胺衍生物或其药用盐的方法。
本发明还提供了含有该咔唑磺酰胺衍生物或其药用盐作为活性成分的药物组合物。
本发明还提供了该类咔唑磺酰胺衍生物或其药用盐作为抗肿瘤药物的应用,其可以作为微管蛋白抑制剂,尤其是治疗实体肿瘤中的应用,包括与其它抗肿瘤的化疗药物和放疗等的联合应用。
为实现上述目的,本发明首先提供一种咔唑磺酰胺衍生物或其药用盐,其具有如下通式(1):
其中,n为1-6,R为通式(i)、通式(i)或通式(iii)表示的结构,
该式(i)和式(ii)中,R1和R2分别代表相同或不同的以下基团:氢、低级烷基、羟基烷基、胺基烷基、氨基酸或上述基团形成的盐,或者R1、R2和N原子共同形成5-7元环,例如吡咯基、哌啶基、哌嗪基、吗啉基等或上述基团形成的盐;
-CH2-O-R3 式(iii)
该通式(iii)中,R3代表以下基团:氢、酰胺基、磺酰胺基、磷酸基或上述基团形成的盐。
其中,以上定义中所述的“低级烷基”尤其是指碳原子数在1-6的直链烷基或碳原子数在3-6的支链烷基或环烷基。碳原子数在1-6的直链烷基例如可列举甲基、乙基、丙基、烯丙基、正丁基、正戊基、正己基或正庚基等;碳原子数在3-6的支链烷基例如可列举异丙基、异丁基、仲丁基、叔丁基、异戊基或异己基等;碳原子数在3-6的环烷基例如可列举环丙基、环丁基、环戊基或环己基等。
进一步地,R1和R2例如可为甲基或乙基。所述R3可为经亲水性基团取代的酰胺基、磺酰胺基或磷酸基。例如为经N杂环或氨基酸等取代基取代,其中N杂环可为取代或非取代的吡咯环、哌啶环、哌嗪环或吗啉环。上述N杂环或氨基酸等取代基是将酰胺基、磺酰胺基或磷酸基中的氢进行取代。
所述“氨基酸”一般可以是极性氨基酸,如甘氨酸、丝氨酸、苏氨酸、天冬氨酸或赖氨酸等。
所述“酰胺基”一般可以是甲基酰胺基、乙基酰胺基、正丙基酰胺基、异丙基酰胺基、烯丙基酰胺基、环丙基酰胺基、正丁基酰胺基、异丁基酰胺基、正戊基酰胺基、正己基酰胺基、苯基酰胺基或甲苯基酰胺基等。
本发明中的咔唑磺酰胺衍生物的示例可以有:
N-(2,6-二甲氧基吡啶-3-基)-N-(乙酰胺-2-基)-9-甲基-3-咔唑磺酰胺(1);
N-(2-溴乙基)-N-(2,6-二甲氧基吡啶-3-基)-9-甲基-3-咔唑磺酰胺(2)
N-(3-氯丙基)-N-(2,6-二甲氧基吡啶-3-基)-9-甲基-3-咔唑磺酰胺(3)
N-(N,N-二甲基乙基)-N-(2,6-二甲氧基吡啶-3-基)-9-甲基-3-咔唑磺酰胺(4);
N-(2,6-二甲氧基吡啶-3-基)-N-[2-(吡咯-1-基)-乙基]-9-甲基-3-咔唑磺酰胺(5);
N-(2,6-二甲氧基吡啶-3-基)-N-[2-(哌啶-1-基)-乙基]-9-甲基-3-咔唑磺酰胺(6);
N-(2,6-二甲氧基吡啶-3-基)-N-[2-(吗啉-4-基)-乙基]-9-甲基-3-咔唑磺酰胺(7);
N-(2,6-二甲氧基吡啶-3-基)-N-[2-(硫代吗啉-4-基)-乙基]-9-甲基-3-咔唑磺酰胺(8);
N-(2,6-二甲氧基吡啶-3-基)-N-[2-(N-甲基哌嗪-1-基)-乙基]-9-甲基-3-咔唑磺酰胺(9);
N-(2,6-二甲氧基吡啶-3-基)-N-{2-[4-(吡咯-1-基)-哌啶-1-基]-乙基}-9-甲基-3-咔唑磺酰胺(10);
N-(2,6-二甲氧基吡啶-3-基)-N-{2-(8-甲基-2,8-二氮螺[4,5]葵烷-2-基)-乙基}-9-甲基-3-咔唑磺酰胺(11);
N-(2,6-二甲氧基吡啶-3-基)-N-[2-(咪唑-1-基)-乙基]-9-甲基-3-咔唑磺酰胺(12);
N-(2,6-二甲氧基吡啶-3-基)-N-[(3-N,N-二甲基)丙基-1-基]-9-甲基-3-咔唑磺酰胺(14);
N-(2,6-二甲氧基吡啶-3-基)-N-[3-(N-甲基哌嗪-1-基)-丙基-1基]-9-甲基-3-咔唑磺酰胺(15);
N-(2,6-二甲氧基吡啶-3-基)-N-{2-[4-(吡咯-1-基)-哌啶-1-基]-丙基-1基}-9-甲基-3-咔唑磺酰胺(16);
N-(2,6-二甲氧基吡啶-3-基)-N-{3-(8-甲基-2,8-二氮螺[4,5]葵烷-2-基)-丙基-1基}-9-甲基-3-咔唑磺酰胺(17);
N-(2,6-二甲氧基吡啶-3-基)-N-[3-(咪唑-1-基)-丙基-1-基]-9-甲基-3-咔唑磺酰胺(18);
N-(2,6-二甲氧基吡啶-3-基)-N-(2-氨乙基)-9-甲基-3-咔唑磺酰胺(24);
N-(2-[N-(2,6-二甲氧基吡啶-3-基)-9-甲基-3-咔唑磺酰胺]-乙基)-2-氨基乙酰胺(28);
N-(2-[N-(2,6-二甲氧基吡啶-3-基)-9-甲基-3-咔唑磺酰胺]-乙基)-3-羟基-2(s)-氨基-丙酰胺(26);
N-(2,6-二甲氧基吡啶-3-基)-N-(2-羟基乙基)-9-甲基-3-咔唑磺酰胺(31);
N-(2,6-二甲氧基吡啶-3-基)-N-(3-羟基丙基)-9-甲基-3-咔唑磺酰胺(32);
2-N-(2,6-二甲氧基吡啶-3-基)-9-甲基-3-咔唑磺酰胺乙基二羟基磷酸酯(35);
2-N-(2,6-二甲氧基吡啶-3-基)-9-甲基-3-咔唑磺酰胺乙基磷酸二钠盐(37);
2-[N-(2,6-二甲氧基吡啶-3-基)-9-甲基-3-咔唑磺酰胺]-乙基-2-(N-甲基哌嗪-4-基)乙酸酯(39);或者
2-[N-(2,6-二甲氧基吡啶-3-基)-9-甲基-3-咔唑磺酰胺]-乙氧基-甲酸铵(40)。
作为一类新的小分子微管蛋白抑制剂,经药理实验表明,该类化合物不仅能将肿瘤细胞阻断在有丝***(M)期,还具有显著的抗肿瘤活性。
本发明进一步提供了该咔唑磺酰胺衍生物或其药用盐作为微管蛋白抑制剂的应用,及在制备抗肿瘤药物中的应用。
本发明另一方面还提供了一种抗肿瘤药物组合物,其包括治疗有效量的上述咔唑磺酰胺衍生物或其药用盐及药学上可接受的药用辅料,可将化合物本身或其药用盐与可药用赋形剂、稀释剂等混合制备成片剂、胶囊、颗粒剂、散剂、糖浆剂或注射剂等剂型。
上述制剂可通过常规制药方法制备。可用的药用辅剂的例子包括赋形剂(例如糖类衍生物如乳糖、蔗糖、葡萄糖、甘露糖醇和山梨糖醇;淀粉衍生物如玉米淀粉、土豆淀粉、糊精和羧甲基淀粉;纤维素衍生物如结晶纤维素、羟丙基纤维素、羧甲基纤维素、羧甲基纤维素钙、羧甲基纤维素钠;***胶;右旋糖酐;硅酸盐衍生物如偏硅酸镁铝;磷酸盐衍生物如磷酸钙;碳酸盐衍生物如碳酸钙;硫酸盐衍生物如硫酸钙等)、粘合剂(例如明胶、聚乙烯吡咯烷酮和聚乙二醇)、崩解剂(例如纤维素衍生物如羧甲基纤维素钠、聚乙烯吡咯烷酮)、润滑剂(例如滑石、硬脂酸钙、硬脂酸镁、鲸蜡、硼酸、苯甲酸钠、亮氨酸)、稳定剂(对羟基苯甲酸甲酯、对羟基苯甲酸丙酯等)、矫味剂(例如常用的甜味剂、酸味剂和香料等)、稀释剂和注射液用溶剂(例如水、乙醇和甘油等)。
本发明化合物的给药量随患者的年龄、性别和病情等的不同而不同。一般成人的给药量为大约50-5000mg/次,优选100-3000mg/次。
本发明的再一方面还提供上述咔唑磺酰胺衍生物或其可药用盐的制备方法,其中,
1、R为式(i)时,式(1)化合物的制备方法包括将化合物(1)与有机金属试剂反应制成金属盐,再将其与Br(CH2)nCONR1R2反应,反应过程如下所示。反应溶剂可使用干燥的四氢呋喃或DMF,有机金属试剂可例如NaH或叔丁醇钾。
其中,n为1-6,R1和R2分别代表相同或不同的以下基团:氢、低级烷基、羟基烷基、胺基烷基、氨基酸或上述基团形成的盐,或者R1、R2和N原子共同形成5-7元环或其盐。
上述化合物(1)N-(2,6-二甲氧基吡啶-3-取代)-9-甲基咔唑-3-磺酰胺(IMB105)可以通过参考文献(Mitsumori,Susumu;Tsuri,Tatsuo;Honma,Tsunetoshi;et al.Journalof Medicinal Chemistry(2003),46(12),2436-2445)的方法或其它相关报道的方法合成。
2、R为式(ii)时,通式(I)化合物的制备方法包括将化合物(1)与卤代烷基醇通过反应得到卤代衍生物,再与二级胺或酰胺反应,反应过程如下所示,
其中,n为1-6,R1和R2分别代表相同或不同的以下基团:氢、低级烷基、羟基烷基、胺基烷基、氨基酸或上述基团形成的盐,或者R1、R2和N原子共同形成5-7元环或其盐。
在上述合成路线中,式(ii)基团R1R2N-的具体示例可如表1所示。
表1
3、R为式(iii)时,通式(I)化合物的制备方法包括将化合物(1)与有机金属试剂反应制成金属盐,并将其与Br(CH2)nCH2OTBDMS反应获得咔唑磺酰胺的硅醇类衍生物,再将其中的-TBDMS转化为相应基团以制备具有通式(I)结构的咔唑磺酰胺,反应过程如下所示,
其中,n为1-6,R3代表氢、酰胺基、磺酰胺基、磷酸基或上述基团形成的盐。
得到的咔唑磺酰胺衍生物可以参照现有技术中的方法制备成药用盐,该药用盐例如可包括与无机酸,如盐酸、硫酸形成的盐,与有机酸,如乙酸、三氟乙酸、柠檬酸、马来酸、草酸、琥珀酸、苯甲酸、酒石酸、富马酸、扁桃酸、抗坏血酸或苹果酸形成的盐,以及氨基酸,如丙氨酸、天冬氨酸、赖氨酸形成的盐或与磺酸,如甲磺酸、对甲苯磺酸形成的盐。具体的制备方法可例如,在冰浴条件下,将得到的咔唑磺酰胺衍生物溶于适量的无水甲醇中,滴入盐酸甲醇溶液并搅拌,反应结束后提纯并固化得盐酸盐固体。
此外,得到的咔唑磺酰胺衍生物可以参照现有技术中的方法制备成前药。以下以化合物31和32以及其磷酸酯衍生物35和36为例,对其合成路线做详细说明。
如上述式(6)所示,IMB105在干燥的四氢呋喃或DMF中与有机金属试剂如NaH反应制成金属盐,端基溴取代的烷基硅醇类化合物(Br(CH2)nCH2OTBDMS)通过Sn2反应,得到硅醇类衍生物(29,30),进一步在TBAF条件下脱去硅基保护基,得到醇类衍生物(31,32),醇与氯代亚磷酸苄酯在吡啶中反应,得到苄基保护的磷酸酯衍生物(33,34),钯碳催化下氢化脱去苄基,得到磷酸酯衍生物(35,36),根据设计需要再进一步与甲醇钠反应得到相应的钠盐(37,38)。醇类衍生物(31,32)与2-(4-N-甲基)哌嗪乙酸在偶连试剂作用下偶连,合成乙酸酯类衍生物39。
本发明化合物的抗肿瘤活性和药理实验
利用本发明所制备出的部分咔唑磺酰胺化合物,发明人同时提供了以下的实验结果,旨在说明本发明化合物的药用功效。
一、体外抗肿瘤活性和水溶解度的测定
测试方法:磺酰罗丹明B(Sulforhodamine B,SRB)法。
试验材料:人肝癌细胞HepG2和Bel-7402,人乳腺癌细胞MCF-7,人胰腺癌细胞MIAPaCa-2
细胞培养:将以上的几种肿瘤细胞置于含有10%的胎牛血清(FBS)、1%双抗(青霉素和链霉素)的DMEM培养液中,37℃、5%CO2饱和湿度培养.
试验步骤:
1)取培养瓶中细胞至96孔板中,使每孔中的细胞数在4000-8000之间,置37℃,5%CO2,培养24小时;
2)加入不同浓度的药物(DMSO的浓度不超过0.5%,v/v),药物组一般设立5个浓度梯度,设3-4个复孔;
3)继续培养48小时后,贴壁细胞用经4℃预冷的50%TCA固定,96孔板置于4℃冰箱放置1小时;
4)1小时后,用蒸馏水或者自来水洗涤细胞孔5次,以除去TCA、培养液、低分子量代谢物以及血清蛋白等;
5)待其细胞板晾干后,用0.4%的SRB染色15-30分钟;
6)用1%的乙酸洗涤5次,晾干;
7)加入10mmol/L Tris溶液150μL溶解,低速震荡5-10分钟,用酶联免疫检测仪在波长490nm处测定吸收值。实验同时设置空白孔(加培养基、S RB和DMSO)、对照孔(加细胞、相同浓度的药物溶解介质、培养液、SRB和DMSO),每孔设定3个复孔。根据所测得的OD值,按照下列公式计算药物对细胞的抑制率IC50,结果参见表2。
抑制率=(对照孔OD值-加药孔OD值)/(对照孔OD值-空白孔OD值)×100%
表2
由表2可知,所列举的咔唑磺酰胺化合物对于多种肿瘤细胞有抑制活性,尤其对于HepG2和MIA PaCa-2具有较强的抑制活性。
此外,本发明人还对上述咔唑磺酰胺化合物的水溶解度进行了测定,结果参见表2,具体方法可参照现有技术。如表2所示,表中所列举的咔唑磺酰胺化合物或其盐酸盐的水溶解度大多在20mg/mL以上,与IMB105(IMB105的水溶解度为<0.009mg/mL)相比,有较大幅度的提高。
三、体内抗肿瘤活性测定
通常,咔唑磺酰胺化合物的水溶解度和其体内活性成一定程度上的正相关性。根据上述咔唑磺酰胺化合物的水溶解度试验,本发明人进一步对咔唑磺酰胺化合物的体内抗肿瘤活性进行了如下试验。
抗人体肝癌BALB/c裸鼠10只(雌性,4-8周龄,体重15-20克),裸鼠右侧腋窝皮下接种HepG2细胞瘤块,10天后瘤体积长到100mm3左右开始分空白对照组和治疗组给药各5只。
试验样品:将IMB-105用5%的Tween-80氯化钠注射液配制成10mg/mL的浓度每只裸鼠每次腹腔注射0.2ml,即100mg/kg;将化合物4,9,10和14用氯化钠溶液配成1mg/ml溶液,每只裸鼠每次腹腔注射0.2ml,即10mg/kg。空白对照组隔天给以腹腔注射氯化钠注射液0.2mL,治疗组隔天腹腔注射不同浓度的试验样品0.2mL,共4次。
每周测量肿瘤体积直到超过2000mm3时,结束实验。肿瘤体积=长×宽2×0.52。按照下式计算给药组与对照组的肿瘤生长抑制率,结果如表2所示。
生长抑制率(%)=(C-T)/C×100
T:给药组平均肿瘤体积-给药前平均肿瘤体积
C:对照组平均肿瘤体积-给药前平均肿瘤体积
表2
表2为本发明化合物对人肝癌HepG2裸鼠移植瘤模型的作用情况。由表2、图1和图2的数据结果表明,空白对照组和治疗组裸鼠的体重均有缓慢增长;且与空白对照组相比,治疗组裸鼠的肿瘤体积明显较小,说明本发明化合物具有显著的体内肿瘤抑制活性;与对照药IMB105和紫杉醇相比,可以看出本发明化合物在使用剂量较小的情况下,能够达到与对照药IMB105和紫杉醇相类似的抗肿瘤效果。
综上,本发明提供的含咔唑磺酰胺类衍生物及其可药用盐,在抗肿瘤方面表现出良好的活性,为开发新型抗肿瘤药物提供了可能,具有良好的应用前景;同时,本发明提供的含咔唑磺酰胺类衍生物及其可药用盐的合成路线简单,成本较低,利于工业化实施。
附图说明
图1为本发明的咔唑磺酰胺衍生物用于治疗人肝癌HepG2时肿瘤体积随接种后天数的变化曲线;
图2为本发明的咔唑磺酰胺衍生物用于治疗人肝癌HepG2时小鼠体重(g)随接种后天数的变化曲线。
具体实施方式
为使本发明的目的、技术方案和优点更加清楚,下面将对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
实施例1:N-(2,6-二甲氧基吡啶-3-基)-N-(乙酰胺-2-基)-9-甲基-3-咔唑磺酰胺(1)
N-(2,6-二甲氧基吡啶-3-基)-9-甲基-3-咔唑磺酰胺(IMB105)的制备按照Mitsumori,Susumu;Tsuri,Tatsuo;Honma,Tsunetoshi等,Journal of MedicinalChemistry(2003),46(12),2436-2445中的方法合成得到。将N-(2,6-二甲氧基吡啶-3-基)-9-甲基-3-咔唑磺酰胺(IMB105)(0.30g,0.78mmol)溶于5mL无水DMF中,加入碘代乙酰胺(0.20g,1.1mmol)和氢化钠(40mg,60%in oil,1.0mmol),70℃条件下反应8h,TLC检测反应完全。减压除去DMF,二氯甲烷提取剩余物,水和饱和食盐水依次洗涤,无水硫酸钠干燥,过滤,滤液柱层析(CDM/MeOH/浓氨水=40/1/0.1)分离纯化得固体0.35g(产率98%)。1HNMR(CDCl3,400MHz)δppm 3.73(3H,s),3.94(3H,s),3.98(3H,s),4.17(2H,br s),6.39(1H,d,J=8.4Hz),7.20(1H,d,J=8.4Hz),7.39(1H,t,J=8.0Hz),7.41(1H,br s),7.49(1H,d,J=8.8Hz),7.53(1H,d,J=8.0Hz),7.63(1H,td,J=8.4,1.6Hz),7.81(1H,dd,J=8.4,1.6Hz),8.14(1H,d,J=8.0Hz),8.47(1H,d,J=2.0Hz);HRMS(ESI+)455.1392,Calcd forC22H23N4O5S 455.1384[M+H]+.
实施例2:N-(N,N-二甲基乙基)-N-(2,6-二甲氧基吡啶-3-基)-9-甲基-3-咔唑磺酰胺(4)
(1)N-(2-溴乙基)-N-(2,6-二甲氧基吡啶-3-基)-9-甲基-3-咔唑磺酰胺的制备(2)
将IMB105(1.0g,2.5mmol)溶于20mL无水四氢呋喃中,加入溴乙醇(0.22mL,3.0mmol),三苯基磷(1.3g,5.0mmol),0℃条件下,加入DEAD(偶氮二甲酸二乙酯40%intoluene,2.0mL,4.25mmol),搅拌约10min,室温搅拌至TLC检测反应完全(约5h)。乙酸乙酯(50mL)加入反应液中,水和饱和食盐水洗涤,无水硫酸钠干燥,过滤,柱层析(PE/AcOEt=4/1-2/1)分离纯化得固体1.2g(产率95%)。1HNMR(CDCl3,400MHz)δppm 3.39(3H,s),3.51(2H,t,J=7.2Hz),3.90(3H,s),3.96(5H,br s),6.36(1H,d,J=8.4Hz),7.37(1H,t,J=8.4Hz),7.45(2H,d,J=8.8Hz),7.51(1H,d,J=8.4Hz),7.61(1H,dd,J=8.8,1.6Hz),7.62(1H,d,J=8.4Hz),7.81(1H,dd,J=8.8,2.0Hz),8.14(1H,d,J=8.4Hz),8.46(1H,d,J=1.6Hz);13CNMR(CDCl3,125Hz)δppm 29.57,30.09,51.37,53.23,54.00,101.57,108.17,109.21,113.51,120.38,120.91,122.46,122.56,125.24,127.06,129.62,141.79,142.96,144.54,159.03,162.70;HRMS(ESI+)504.0591,Calcd for C22H23Br N3O4S 504.0587[M+H]+.
(2)N-(N,N-二甲基乙基)-N-(2,6-二甲氧基吡啶-3-基)-9-甲基-3-咔唑磺酰胺的制备(4)
将N-(2-溴乙基)-N-(2,6-二甲氧基吡啶-3-基)-9-甲基-3-咔唑磺酰胺(2)(0.5g,1.0mmol)溶于干燥的DMF(10.0mL)中,加入碘化钠(1.5g,10.0mmol)和二甲胺(2.5mL,2.0Min THF,5.0mmol),70℃加热反应至原料反应完全(TLC检测,约4h)。减压除去DMF,剩余物用二氯甲烷提取,饱和碳酸氢钠溶液、水和饱和食盐水依次洗涤,无水硫酸钠干燥,过滤,柱层析(DCM/MeOH/浓氨水=15/1/0.1)分离纯化得油状物0.46g(产率98%)。1HNMR(CDCl3,500MHz)δppm 2.28(6H,s),2.50(2H,t,J=8.0Hz),3.41(3H,s),3.75(2H,br s),3.91(3H,s),3.94(3H,s),6.32(1H,d,J=8.4Hz),7.34(1H,t,J=8.0Hz),7.42(2H,d,J=8.4Hz),7.48(1H,d,J=8.6Hz),7.54(1H,d,J=8.0Hz),7.58(1H,t,J=8.6Hz),7.81(1H,dd,J=8.6,2.0Hz),8.11(1H,d,J=8.0Hz),8.48(1H,d,J=2.0Hz);HRMS(ESI+)469.1916,Calcdfor C24H29N4O4S469.1904[M+H]+。冰浴条件下,将油状物(0.30g,0.64mmoL)溶于无水甲醇中,滴入3M盐酸甲醇溶液(0.25mL,0.77mmoL),低温搅拌1h,将反应液浓缩,加入适量无水***,搅拌,析出白色固体,过滤得盐酸盐产物0.3g.
实施例3:N-(2,6-二甲氧基吡啶-3-基)-N-[2-(吡咯-1-基)-乙基]-9-甲基-3-咔唑磺酰胺(5)
合成方法同上述化合物(4)的合成。N-(2-溴乙基)-N-(2,6-二甲氧基吡啶-3-基)-9-甲基-3-咔唑磺酰胺(2)(0.5g,1.0mmol)与四氢吡咯(0.42mL,5.0mmoL)反应,柱层析(DCM/MeOH/浓氨水=20/1/0.1)分离纯化得油状物。1HNMR(CDCl3,400MHz)δppm 1.60(4H,brs),2.48(4H,br s),2.58(2H,br s),3.40(3H,s),3.82(2H,br s),3.88(3H,s),3.91(3H,s),6.32(1H,d,J=8.4Hz),7.35(1H,t,J=8.0Hz),7.44(2H,d,J=8.8Hz),7.50(1H,d,J=8.4Hz),7.54(1H,d,J=8.0Hz),7.59(1H,t,J=8.4Hz),7.83(1H,dd,J=8.0,1.6Hz),8.13(1H,d,J=8.0Hz),8.47(1H,d,J=1.6Hz);HRMS(ESI+)495.2070,Calcd forC26H31N4O4S495.2061[M+H]+.
实施例4:N-(2,6-二甲氧基吡啶-3-基)-N-[2-(哌啶-1-基)-乙基]-9-甲基-3-咔唑磺酰胺(6)
合成方法同上述化合物(4)的合成。N-(2-溴乙基)-N-(2,6-二甲氧基吡啶-3-基)-9-甲基-3-咔唑磺酰胺(2)(0.5g,1.0mmol)与哌啶(0.50mL,5.0mmoL)反应,柱层析(DCM/MeOH/浓氨水=20/1/0.1)分离纯化得油状物。1HNMR(CDCl3,500MHz)δppm 1.60(2H,br s),1.84(4H,m),2.89(6H,m),3.42(3H,s),3.90(3H,s),3.96(3H,s),3.95(2H,br s),6.33(1H,d,J=8.0Hz),7.37(1H,t,J=7.5Hz),7.48(3H,m),7.61(1H,t,J=7.5Hz),7.81(1H,d,J=8.5Hz),8.14(1H,d,J=7.5Hz),8.44(1H,s);13CNMR(CDCl3,125MHz)δppm 23.09,24.47,29.52,49.23,45.43,53.28,53.91,54.26,56.99,101.54,108.24,109.16,113.44,120.32,120.87,122.44,125.21,129.04,141.74,142.93,143.84,159.55,162.58;HRMS(ESI+)509.2229,Calcd for C27H33N4O4S 509.2217[M+H]+.
实施例5:N-(2,6-二甲氧基吡啶-3-基)-N-[2-(吗啉-4-基)-乙基]-9-甲基-3-咔唑磺酰胺(7)
合成方法同上述化合物(4)的合成。N-(2-溴乙基)-N-(2,6-二甲氧基吡啶-3-基)-9-甲基-3-咔唑磺酰胺(2)(0.5g,1.0mmol)与吗啉(0.43mL,5.0mmoL)反应,(柱层析(DCM/MeOH/浓氨水=30/1/0.1)分离纯化得油状物。1HNMR(DMSO-d6,400MHz)δppm 2.25(4H,brs),2.32(2H,t,J=8.0Hz),3.39(3H,s),3.44(4H,m),3.61(2H,br s),3.82(3H,s),3.96(3H,s),6.37(1H,d,J=8.4Hz),7.30(1H,t,J=7.2Hz),7.46(1H,d,J=8.4Hz),7.57(1H,d,J=8.4Hz),7.73(6H,m),8.33(1H,d,J=7.6Hz),8.52(1H,d,J=1.6Hz);HRMS(ESI+)511.2021,Calcd for C26H31N4O5S 511.2010[M+H]+.
实施例6:N-(2,6-二甲氧基吡啶-3-基)-N-[2-(硫代吗啉-4-基)-乙基]-9-甲基-3-咔唑磺酰胺(8)
合成方法同上述化合物(4)的合成。N-(2-溴乙基)-N-(2,6-二甲氧基吡啶-3-基)-9-甲基-3-咔唑磺酰胺(2)(0.5g,1.0mmol)与硫代吗啉(0.50mL,5.0mmoL)反应,柱层析(DCM/MeOH/浓氨水=30/1/0.1)分离纯化得油状物。1HNMR(CDCl3,400MHz)δppm 2.44(3H,brs),2.54(2H,t,J=6.4Hz),2.65(5H,br s),3.39(3H,s),3.77(2H,br s),3.90(3H,s),3.95(3H,s),6.33(1H,d,J=8.0Hz),7.36(1H,t,J=7.2Hz),7.45(1H,d,J=8.4Hz),7.50(1H,d,J=8.4Hz),7.58(1H,d,J=8.0Hz),7.60(1H,t,J=8.0Hz),7.83(1H,dd,J=8.4,1.6Hz),8.13(1H,d,J=8.0Hz),8.47(1H,d,J=1.6Hz);HRMS(ESI+)527.1788,Calcd forC26H31N4O4S2 527.1781[M+H]+.
实施例7:N-(2,6-二甲氧基吡啶-3-基)-N-[2-(N-甲基哌嗪-1-基)-乙基]-9-甲基-3-咔唑磺酰胺(9)
合成方法同上述化合物(4)的合成。N-(2-溴乙基)-N-(2,6-二甲氧基吡啶-3-基)-9-甲基-3-咔唑磺酰胺(2)(0.5g,1.0mmol)与N-甲基哌嗪(0.55mL,5.0mmoL)反应,柱层析(DCM/MeOH/浓氨水=15/1/0.1)分离纯化得油状物。1HNMR(CDCl3,500MHz)δppm 2.49(3H,s),2.54(2H,t,J=6.4Hz),2.72(8H,br s),3.39(3H,s),3.76(2H,br s),3.90(3H,s),3.95(3H,s),6.34(1H,d,J=7.5Hz),7.35(1H,t,J=7.5Hz),7.44(1H,d,J=8.4Hz),7.49(1H,d,J=8.0Hz),7.58(2H,t,J=8.0Hz),7.81(1H,d,J=8.4Hz),8.13(1H,d,J=8.0Hz),8.47(1H,s);HRMS(ESI+)524.2332,Calcd for C27H34N5O4S 524.2326[M+H]+.
实施例8:N-(2,6-二甲氧基吡啶-3-基)-N-{2-[4-(吡咯-1-基)-哌啶-1-基]-乙基}-9-甲基-3-咔唑磺酰胺(10)
合成方法同上述化合物(2)的合成。N-(2-溴乙基)-N-(2,6-二甲氧基吡啶-3-基)-9-甲基-3-咔唑磺酰胺(2)(0.5g,1.0mmol)与4-(吡咯-1-基)-哌啶(0.77g,5.0mmoL)反应,(柱层析(DCM/MeOH/浓氨水=15/1/0.1)分离纯化得油状物。1HNMR(DMSO-d6,400MHz)δppm1.22(2H,m),1.67(6H,m),1.84(3H,m),2.28(2H,t,J=6.4Hz),2.46(4H,br s),2.65(2H,m),3.40(3H,s),3.58(2H,br s),3.82(3H,s),3.96(3H,s),6.36(1H,d,J=8.4Hz),7.30(1H,t,J=7.6Hz),7.43(1H,d,J=8.0Hz),7.57(1H,t,J=8.0Hz),7.73(3H,m),8.34(1H,d,J=8.0Hz),8.53(1H,d,J=1.2Hz);HRMS(ESI+)578.2798,Calcd for C31H40N5O4S578.2796[M+H]+.
实施例9:N-(2,6-二甲氧基吡啶-3-基)-N-{2-(8-甲基-2,8-二氮螺[4,5]葵烷-2-基)-乙基}-9-甲基-3-咔唑磺酰胺(11)
合成方法同上述化合物(4)的合成。N-(2-溴乙基)-N-(2,6-二甲氧基吡啶-3-基)-9-甲基-3-咔唑磺酰胺(2)(0.5g,1.0mmol)与8-甲基-2,8-二氮螺[4,5]葵烷(0.38g,2.5mmoL)反应,柱层析(DCM/MeOH/浓氨水=10/1/0.1)分离纯化得油状物。1HNMR(CDCl3,400MHz)δppm 1.59(2H,t,J=6.8Hz),1.66(4H,br s),2.33-2.58(13H,m),3.40(3H,s),3.74(2H,br s),3.89(3H,s),3.95(3H,s),6.32(1H,d,J=8.4Hz),7.36(1H,t,J=7.6Hz),7.45(1H,d,J=8.8Hz),7.51(1H,d,J=8.0Hz),7.60(2H,m),7.83(1H,d,J=8.4Hz),8.13(1H,d,J=8.0Hz),8.48(1H,s);HRMS(ESI+)578.2801,Calcd for C31H40N5O4S 578.2796[M+H]+.
实施例10:N-(2,6-二甲氧基吡啶-3-基)-N-[2-(咪唑-1-基)-乙基]-9-甲基-3-咔唑磺酰胺(12)
合成方法同上述化合物(2)的合成。N-(2-溴乙基)-N-(2,6-二甲氧基吡啶-3-基)-9-甲基-3-咔唑磺酰胺(2)(0.5g,1.0mmol)与咪唑(0.34g,5.0mmoL)反应,柱层析(DCM/MeOH/浓氨水=40/1/0.1)分离纯化得白色固物。1HNMR(CDCl3,400MHz)δppm 3.33(3H,s),3.88(3H,s),3.95(5H,br s),4.25(2H,t,J=6.4Hz)6.29(1H,d,J=8.4Hz),7.00(1H,s),7.09(1H,s),7.34(1H,d,J=8.0Hz),7.37(1H,t,J=8.0Hz),7.44(1H,d,J=8.8Hz),7.51(1H,d,J=8.0Hz),7.61(1H,t,J=8.8Hz),7.63(1H,s),7.71(1H,dd,J=8.8,1.6Hz),8.39(1H,d,J=1.2Hz);HRMS(ESI+)492.1709,Calcd for C25H26N5O4S 492.1700[M+H]+.
实施例11:N-(2,6-二甲氧基吡啶-3-基)-N-[(3-N,N-二甲基)丙基-1-基]-9-甲基-3-咔唑磺酰胺(14)
(1)N-(3-氯丙基)-N-(2,6-二甲氧基吡啶-3-基)-9-甲基-3-咔唑磺酰胺的制备(3)
合成方法同上述化合物(2)的合成。将IMB105(2.0g,5.0mmol)溶于40mL无水四氢呋喃中,加入氯丙醇(0.62mL,7.5mmol),三苯基磷(2.6g,10.0mmol),0℃条件下,加入DIAD(偶氮二甲酸二异丙酯,1.68mL,8.5mmol),搅拌约10min,室温搅拌至TLC检测反应完全(约8h)。乙酸乙酯(50mL)加入反应液中,水和饱和食盐水洗涤,无水硫酸钠干燥,过滤,柱层析(PE/AcOEt=4/1-2/1)分离纯化得固体2.1g(产率85%)。1HNMR(CDCl3,400MHz)δppm1.98(2H,m),3.46(3H,s),3.68(2H,t,J=6.8Hz),3.76(2H,t,J=6.4Hz),3.91(3H,s),3.96(3H,s),6.34(1H,d,J=8.0Hz),7.49(3H,m),7.61(1H,dt,J=1.2,8.8Hz),7.82(1H,dd,J=8.8,2.0Hz),8.13(1H,d,J=7.6Hz),8.48(1H,d,J=1.6Hz);HRMS(ESI+)474.1253,Calcd forC23H25Cl N3O4S 474.1249[M+H]+.
(2)N-(2,6-二甲氧基吡啶-3-基)-N-[(3-N,N-二甲基)丙基-1-基]-9-甲基-3-咔唑磺酰胺的制备(14)
合成方法同上述化合物(4)的合成。N-(3-氯丙基)-N-(2,6-二甲氧基吡啶-3-基)-9-甲基-3-咔唑磺酰胺的制备(3)(0.48g,1.0mmoL)与N,N-二甲胺(2.5mL,2.0M in THF,5.0mmol)反应,柱层析(DCM/MeOH/浓氨水=15/1/0.1)分离纯化得油状物。1HNMR(CDCl3,400MHz)δppm 2.10(2H,br s),2.90(6H,m),3.45(2H,br s),3.53(3H,s),3.77(2H,br s),3.92(3H,s),3.96(3H,s),6.32(1H,d,J=8.0Hz),7.31(1H,d,J=8.8Hz),7.37(1H,t,J=8.0Hz),7.51(1H,dt,J=1.2,8.4Hz),7.82(1H,dd,J=8.4,2.0Hz),8.17(1H,d,J=8.0Hz),8.47(1H,d,J=1.2Hz);HRMS(ESI+)483.2074,Calcd for C25H31N4O4S 483.2061[M+H]+.
实施例12:N-(2,6-二甲氧基吡啶-3-基)-N-[3-(N-甲基哌嗪-1-基)-丙基-1基]-9-甲基-3-咔唑磺酰胺(15)
合成方法同上述化合物(4)的合成。N-(3-氯丙基)-N-(2,6-二甲氧基吡啶-3-基)-9-甲基-3-咔唑磺酰胺的制备(3)(0.48g,1.0mmoL)与N-甲基哌嗪(0.55mL,5.0mmoL)反应,柱层析(DCM/MeOH/浓氨水=15/1/0.1)分离纯化得油状物。1HNMR(DMSO-d6,400MHz)δppm1.43(2H,m),2.13(3H,s),2.25(10H,m),3.42(3H,s),3.47(2H,br s),3.81(3H,s),3.94(3H,s),6.35(1H,d,J=8.4Hz),7.28(1H,t,J=7.6Hz),7.41(1H,d,J=8.4Hz),7.55(1H,t,J=8.4Hz),7.69(2H,m),7.75(1H,d,J=8.4Hz),8.29(1H,d,J=7.6Hz),8.48(1H,d,J=7.6Hz);HRMS(ESI+)538.2485,Calcd for C28H36N5O4S 538.2483[M+H]+.
实施例13:N-(2,6-二甲氧基吡啶-3-基)-N-{2-[4-(吡咯-1-基)-哌啶-1-基]-丙基-1基}-9-甲基-3-咔唑磺酰胺(16)
合成方法同上述化合物(4)的合成。N-(3-氯丙基)-N-(2,6-二甲氧基吡啶-3-基)-9-甲基-3-咔唑磺酰胺的制备(3)(0.48g,1.0mmoL)与4-(吡咯-1-基)-哌啶(0.77g,5.0mmoL)反应,柱层析(DCM/MeOH/浓氨水=15/1/0.1)分离纯化得油状物。1HNMR(DMSO-d6,400MHz)δppm 1.29(2H,m),1.71(4H,m),1.95(6H,m),2.45(3H,br s),2.90(6H,m),3.44(3H,s),3.63(2H,br s),3.90(3H,s),3.95(3H,s),6.32(1H,d,J=8.0Hz),7.34(1H,m),7.48(3H,m),7.59(1H,s),7.82(1H,d,J=7.5Hz),8.12(1H,d,J=6.5Hz),8.45(1H,s);HRMS(ESI+)592.2958,Calcd for C32H42N5O4S 592.2952[M+H]+.
实施例14:N-(2,6-二甲氧基吡啶-3-基)-N-{3-(8-甲基-2,8-二氮螺[4,5]葵烷-2-基)-丙基-1基}-9-甲基-3-咔唑磺酰胺(17)
合成方法同上述化合物(4)的合成。N-(3-氯丙基)-N-(2,6-二甲氧基吡啶-3-基)-9-甲基-3-咔唑磺酰胺的制备(3)(0.48g,1.0mmoL)与8-甲基-2,8-二氮螺[4,5]葵烷(0.38g,2.5mmoL)反应,柱层析(CDM/MeOH/浓氨水=10/1/0.1)分离纯化得油状物。1HNMR(CDCl3,400MHz)δppm 1.61-1.72(8H,m),2.34(9H,m),2.53(4H,br s),3.43(3H,s),3.66(2H,br s),3.91(3H,s),3.95(3H,s),6.34(1H,d,J=8.4Hz),7.36(1H,t,J=8.0Hz),7.45(1H,d,J=8.4Hz),7.52(2H,t,J=8.0Hz),7.60(1H,t,J=8.0Hz),7.82(1H,d,J=8.8Hz),8.13(1H,d,J=8.0Hz),8.48(1H,s);HRMS(ESI+)592.2961,Calcd for C32H42N5O4S592.2952[M+H]+.
实施例15:N-(2,6-二甲氧基吡啶-3-基)-N-[3-(咪唑-1-基)-丙基-1-基]-9-甲基-3-咔唑磺酰胺(18)
合成方法同上述化合物(4)的合成。N-(3-氯丙基)-N-(2,6-二甲氧基吡啶-3-基)-9-甲基-3-咔唑磺酰胺的制备(3)(0.48g,1.0mmoL)与咪唑(0.34g,5.0mmoL)反应,柱层析(CDM/MeOH/浓氨水=40/1/0.1)分离纯化得固体。1HNMR(DMSO-d6,400MHz)δppm 1.75(2H,m),3.40(3H,s),3.49(2H,t,J=6.4Hz),3.83(3H,s),3.96(3H,s),4.04(2H,t,J=7.2Hz),6.38(1H,d,J=8.4Hz),6.88(1H,s),7.12(1H,s),7.31(1H,dt,J=0.8,8.0Hz),7.45(1H,d,J=8.0Hz),7.57(1H,t,J=8.0Hz),7.59(1H,s),7.68(2H,m),7.78(1H,d,J=8.8Hz),8.32(1H,d,J=8.0Hz),8.47(1H,d,J=1.6Hz);HRMS(ESI+)506.1862,Calcd for C26H28N5O4S506.1857[M+H]+.
实施例16:N-(2,6-二甲氧基吡啶-3-基)-N-(2-氨乙基)-9-甲基-3-咔唑磺酰胺(24)
合成步骤(1):N-(2,6-二甲氧基吡啶-3-基)-N-(2-苯并丁二酰亚胺乙基)-9-甲基-3-咔唑磺酰胺(13)
将苯并丁二酰亚胺(0.88g,5.96mmol)溶于30mL无水DMF中,0℃条件下,加入氢化钠(0.28g,60%in oil,6.96mmol)反应30min。将N-(2-溴-乙基)-N-(2,6-二甲氧基吡啶-3-基)-9-甲基-3-咔唑磺酰胺(2)(1.0g,1.99mmol)加入上述的溶液中,室温反应1h,70℃反应2d,TLC检测反应完全。二氯乙烷(70mL)加入反应液中,水和饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液浓缩,柱层析纯化(PE/AcOEt=3:1-1:1),得白色固体1.2g(产率99%)。1HNMR(CDCl3,500MHz)δppm 3.38(3H,s),3.51(2H,t,J=7.5Hz),3.90(3H,s),3.96(3H,s),3.96(2H,br s),6.35(1H,d,J=8.0Hz),7.37(1H,t,J=7.2Hz),7.46(1H,d,J=8.5Hz),7.52(1H,d,J=8.0Hz),7.61(1H,t,J=7.5Hz),7.62(1H,d,J=8.0Hz),7.80(1H,d,J=7.5Hz),8.14(1H,d,J=8.0Hz),8.46(1H,s);13CNMR(CDCl3,125MHz)δppm 29.46,37.23,47.32,53.18,53.96,101.40,107.96,109.04,113.52,120.26,120.81,120.94,122.34,122.56,123.11,125.28,126.92,130.19,132.11,133.70,141.69,142.68,145.27,158.99,162.61,168.49;HRMS(ESI+)571.1651,Calcd for C30H27 N4O6S 571.1646[M+H]+.
(2)N-(2,6-二甲氧基吡啶-3-基)-N-(2-氨乙基)-9-甲基-3-咔唑磺酰胺(24)
将化合物(13)(1.2g,2.1mmol)溶于干燥乙醇(10.0mL)中,加入甲胺醇溶液(30%,20mL),室温反应2d,TLC检测反应完全。减压除去溶剂,柱层析(DCM/MeOH/浓氨水=15:1:0.1)分离纯化得油状物(0.79g,85%)。1HNMR(CDCl3,500MHz)δppm 2.46(2H,br s),2.86(2H,s),3.56(3H,s),3.71(2H,s),3.90(3H,s),3.94(3H,s),6.31(1H,d,J=8.0Hz),7.35(1H,t,J=7.5Hz),7.41(1H,d,J=8.5Hz),7.46(1H,d,J=9.0Hz),7.51(1H,d,J=8.5Hz),7.60(1H,t,J=7.5Hz),7.86(1H,d,J=8.0Hz),8.13(1H,d,J=8.0Hz),8.50(1H,s);13CNMR(CDCl3,125MHz)δppm 29.53,40.20,52.18,53.47,53.95,101.78,108.33,109.16,113.67,120.37,120.95,121.07,122.54,122.60,125.36,127.05,129.54,141.82,142.98,143.26,159.82,162.61;HRMS(ESI+)441.1593,Calcd for C22H25 N4O4S 441.1591[M+H]+.
实施例17:N-(2-[N-(2,6-二甲氧基吡啶-3-基)-9-甲基-3-咔唑磺酰胺]-乙基)-3-羟基-2(s)-氨基-丙酰胺(26)
合成步骤(1):N-(2-[N-(2,6-二甲氧基吡啶-3-基)-9-甲基-3-咔唑磺酰胺]-乙基)-3-羟基-2-苄氧酰胺基-丙酰胺(25)
将N-(苄氧羰基)-L-丝氨酸(0.071g,0.30mmol)溶于2.0mL二氯甲烷中,0℃条件下,加入1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(EDCI,0.084g,0.44mmol),1-羟基-苯并***(HOBt,0.060g,0.44mmol)和二异丙基乙基胺(0.10mL,0.59mmol),反应1h后,加入化合物(24)(0.10g,0.23mmol),室温反应过夜,TLC检测反应完全。反应液加入20mL二氯甲烷稀释,碳酸氢钠溶液、水和饱和氯化钠溶液依次洗涤,无水硫酸钠干燥,过滤,滤液浓缩,柱层析(PE/AcOEt=1:1)分离纯化得油状物0.13g(产率88%)。1HNMR(CDCl3,500MHz)δppm3.36(2H,m),3.54(3H,s),3.54(1H,br s),3.75(1H,br s),3.80(1H,br s),3.86(3H,s),3.90(3H,s),3.90(1H,s),4.22(1H,m),4.33(1H,m),5.19(2H,s),6.00(1H,br s),6.26(1H,d,J=8.5Hz),7.18(1H,br s),7.39(8H,m),7.46(1H,d,J=8.0Hz),7.57(1H,t,J=8.0Hz),7.75(1H,d,J=8.0Hz),8.09(1H,d,J=8.0Hz),8.41(1H,s);13CNMR(CDCl3,125MHz)δppm29.36,37.90,49.24,53.36,53.87,56.32,62.82,67.18,101.80,108.25,109.11,112.87,120.25,120.67,120.71,122.27,122.31,124.90,126.98,128.11,128.50,129.11,136.27,141.62,142.76,156.55,159.64,162.60,171.24;HRMS(ESI+)662.2281,Calcd forC33H36N5O8S 662.2279[M+H]+.
(2)N-(2-[N-(2,6-二甲氧基吡啶-3-基)-9-甲基-3-咔唑磺酰胺]-乙基)-3-羟基-2(s)-氨基-丙酰胺(26)
将化合物(25)(0.12g,0.18mmol)溶于20mL甲醇/四氢呋喃(4:1),氮气保护下,加入钯碳(5%,0.1g),40psi氢气压力下,反应1.5h,TLC检测反应完全。硅藻土过滤,甲醇冲洗,滤液浓缩,柱层析(DCM/MeOH=10:1)分离纯化得油状物0.85g(90%)。1HNMR(CDCl3,500MHz)δppm 3.36(2H,m),3.54(3H,s),3.54(1H,br s),3.75(1H,br s),3.80(1H,br s),3.86(3H,s),3.90(3H,s),3.90(1H,s),4.22(1H,m),4.33(1H,m),5.19(2H,s),6.00(1H,brs),6.26(1H,d,J=8.5Hz),7.18(1H,br s),7.39(8H,m),7.46(1H,d,J=8.0Hz),7.57(1H,t,J=8.0Hz),7.75(1H,d,J=8.0Hz),8.09(1H,d,J=8.0Hz),8.41(1H,s);13CNMR(CDCl3,125MHz)δppm 29.41,37.79,49.33,53.33,53.90,56.19,64.92,101.68,108.27,109.11,113.14,120.24,120.76,122.32,122.38,125.07,126.95,129.39,141.66,142.80,143.71,159.59,162.60,173.98;HRMS(ESI+)528.1914,Calcd for C25H30N5O6S 528.1911[M+H]+.
实施例18:N-(2-[N-(2,6-二甲氧基吡啶-3-基)-9-甲基-3-咔唑磺酰胺]-乙基)-2-氨基乙酰胺(28)
合成步骤:(1)N-(2-[N-(2,6-二甲氧基吡啶-3-基)-9-甲基-3-咔唑磺酰胺]-乙基)-2-叔丁氧甲酰胺基-乙酰胺(27)
合成方法与化合物(25)相同,与N-叔丁氧羰基甘氨酸反应得到油状物(产率78%)。1HNMR(CDCl3,500MHz)δppm 1.54(9H,s),3.61(5H,br s),3.91(9H,m),6.34(1H,m),6.94(1H,br s),7.37(3H,m),7.51(2H,m),7.61(1H,d,J=7.5Hz),7.81(1H,t,J=7.5Hz),8.15(1H,t,J=7.5Hz),8.48(1H,s);HRMS(ESI+)598.2336,Calcd for C29H36N5O7S598.2330[M+H]+.
(2)N-(2-[N-(2,6-二甲氧基吡啶-3-基)-9-甲基-3-咔唑磺酰胺]-乙基)-2-氨基乙酰胺盐酸盐(28)
将化合物(27)(0.13g,0.22mmol)溶于甲醇/HCl溶液(5M,2.5mL)中,室温反应2h,TLC检测反应完全。减压出去溶剂,剩余物在DCM/AcOEt中析晶,得灰白色固体0.075g(产率68%)。1HNMR(DMSO-d6,500MHz)δppm 3.15(3H,s),3.46(2H,m),3.62(4H,br s),3.84(3H,s),3.98(3H,s),6.37(1H,d,J=8.0Hz),7.31(1H,t,J=7.5Hz),7.44(1H,d,J=8.0Hz),7.59(1H,t,J=8.0Hz),7.74(3H,m),8.37(1H,d,J=8.0Hz),8.53(1H,s);13CNMR(CDCl3,125MHz)δppm 29.68,31.02,38.96,48.82,53.61,54.27,104.27,109.12,109.35,113.05,119.87,120.40,120.62,121.67,122.21,125.31,126.66,129.01,141.31,142.50,144.74,158.95,162.21,167.46;HRMS(ESI+)534.1576,Calcd for C24H29ClN5O5S 534.1572[M+H]+.
实施例19:N-(2,6-二甲氧基吡啶-3-基)-N-(2-羟基乙基)-9-甲基-3-咔唑磺酰胺(31)
合成步骤(1)N-(2,6-二甲氧基吡啶-3-基)-N-(2-叔丁基二甲基硅氧基乙基)-9-甲基-3-咔唑磺酰胺(29)
将N-(2,6-二甲氧基吡啶-3-基)-9-甲基-3-咔唑磺酰胺(0.40g,1.0mmol)溶于10mL无水DMF中,加入叔丁基-(碘乙氧基)-二甲基硅烷(0.43g,1.50mmol)和氢化钠(60mg,60%in oil,1.5mmol),70℃条件下反应4h,TLC检测反应完全。减压除去DMF,二氯甲烷提取剩余物,10%HCl、水和饱和食盐水依次洗涤,无水硫酸钠干燥,过滤,滤液柱层析(PE/AcOEt=6/1)分离纯化得油状物0.47g(产率84%)。1HNMR(CDCl3,400MHz)δppm-0.005(6H,s),0.81(9H,s),3.35(3H,s),3.66(2H,m),3.73(2H,br s),3.85(3H,s),3.91(3H,s),6.28(1H,d,J=8.4Hz),7.31(1H,t,J=8.0Hz),7.40(1H,d,J=8.4Hz),7.45(1H,d,J=8.4Hz),7.53(1H,d,J=8.0Hz),7.55(1H,t,J=8.0Hz),7.78(1H,dd,J=8.4,1.6Hz),8.08(1H,d,J=8.0Hz),8.43(1H,d,J=2.0Hz);HRMS(ESI+)556.2298,Calcd for C28H38N3O5SSi 556.2296[M+H]+.
(2)N-(2,6-二甲氧基吡啶-3-基)-N-(2-羟基乙基)-9-甲基-3-咔唑磺酰胺(31)
将N-(2,6-二甲氧基吡啶-3-基)-(N-叔丁基-二甲基-硅氧乙基)-9-甲基-3-咔唑磺酰胺(17,0.42g,0.75mmol)溶于2.5mL无水THF中,0℃条件下,滴加入四叔丁基氟化胺(0.90mL,1.0M in THF,0.90mmol)反应至TLC检测反应完全。乙酸乙酯提取,10%硫代硫酸钠、水和饱和食盐水依次洗涤,无水硫酸钠干燥,过滤,滤液浓缩,柱层析(PE/AcOEt=2/1)分离纯化得油状物0.31g(产率94%)。1HNMR(CDCl3,400MHz)δppm 3.65(2H,br s),3.66(3H,s),3.72(2H,br s),3.93(3H,s),3.96(3H,s),6.33(1H,d,J=8.4Hz),7.37(1H,t,J=7.2Hz),7.37(1H,d,J=8.4Hz),7.49(1H,d,J=8.4Hz),7.52(1H,d,J=8.0Hz),7.61(1H,dt,J=1.2,8.4Hz),7.88(1H,dd,J=8.8,1.6Hz),8.14(1H,d,J=8.0Hz),8.53(1H,d,J=1.2Hz);13CNMR(CDCl3,125MHz)δppm 29.59,53.21,53.67,54.02,60.42,102.08,108.37,109.23,114.04,120.42,120.89,121.15,122.54,125.31,127.12,129.45,141.82,143.03,159.84,162.62;HRMS(ESI+)442.1430,Calcd for C22H24N3O5S 442.1431[M+H]+.
实施例20:2-N-(2,6-二甲氧基吡啶-3-基)-9-甲基-3-咔唑磺酰胺乙基磷酸二钠盐(37)
合成步骤(1):二苄基-2-N-(2,6-二甲氧基吡啶-3-基)-9-甲基-3-咔唑磺酰胺乙基磷酸酯(33)
将二苄基亚磷酸酯(0.52g,2.0mmol)溶于5.0mL无水甲苯中,0℃条件下,加入氯代苯并丁二酰亚胺(0.32g,2.4mmol),室温搅拌2h后备用。
将N-(2,6-二甲氧基吡啶-3-基)-N-(2-羟基乙基)-9-甲基-3-咔唑磺酰胺(31,0.22g,0.45mmol)溶于5.0mL无水吡啶中。0℃条件下,将上述新制备的二苄基磷酸基氯溶液过滤入吡啶反应液中,逐渐升温至室温反应5h,TLC检测反应完全。二氯甲烷提取,水和饱和食盐水依次洗涤,无水硫酸钠干燥,过滤,滤液浓缩,柱层析(PE/AcOEt=2/1)分离纯化得油状物0.18g(产率57%)。1HNMR(CDCl3,500MHz)δppm 3.34(3H,s),3.87(2H,br s),3.87(3H,s),3.92(3H,s),4.15(2H,q,J=6.0Hz),5.03(4H,d,J=8.0Hz),6.26(1H,d,J=8.0Hz),7.36(11H,m),7.41(1H,d,J=8.5Hz),7.50(1H,d,J=8.5Hz),7.55(1H,d,J=8.0Hz),7.60(1H,t,J=7.5Hz),7.78(1H,d,J=8.5Hz),8.11(1H,d,J=7.5Hz),8.44(1H,s);13CNMR(CDCl3,125MHz)δppm 29.53,49.45,49.53,53.14,53.93(3Jc-p=9.2Hz),65.76,65.82(2Jc-p=5.7Hz),69.44,69.49(2Jc-p=5.5Hz),101.48.108.12,109.17,113.70,120.35,120.88,120.91,122.43,122.58,125.28,127.02,128.05,128.61,128.64,128.68,129.83,135.87,135.94(3Jc-p=7.0Hz),141.78,142.90,144.62,159.03,162.57;31PNMR(DMSO-d6,162MHz)δpp-1.23;HRMS(ESI+)702.2041,Calcd for C36H37N3O8PS 702.2033[M+H]+.
(2)2-N-(2,6-二甲氧基吡啶-3-基)-9-甲基-3-咔唑磺酰胺乙基二羟基磷酸酯(35)
将化合物(33,0.20g,0.28mmol)溶于20.0mL甲醇/水(8:1)中,加入钯碳50mg,40psi氢气压力下反应1.5h,TLC检测反应完全。反应液通过硅藻土过滤,甲醇冲洗,滤液浓缩得白色固体102mg(产率70%)。1HNMR(DMSO-d6,500MHz)δppm 3.32(3H,s),3.75(2H,brs),3.83(3H,s),3.85(2H,br s),3.98(3H,s),6.40(1H,d,J=8.0Hz),7.32(1H,t,J=7.0Hz),7.50(1H,d,J=8.0Hz),7.59(1H,t,J=8.0Hz),7.72(2H,m),7.78(1H,d,J=7.5Hz),8.36(1H,d,J=7.5Hz),8.54(1H,s),11.12(0.5H,br s);13CNMR(DMSO-d6,125MHz)δppm29.38,49.23,49.29,52.99,53.62,63.24,101.14,109.22,109.85,113.68,119.97,120.38,121.00,121.54,121.77,124.74,126.88,129.16,141.44,142.50,144.47,158.77,161.77;31PNMR(DMSO-d6,162MHz)δppm-1.34;HRMS(ESI+)522.1096,Calcd for C22H25N3O8PS522.1094[M+H]+.
(3)2-N-(2,6-二甲氧基吡啶-3-基)-9-甲基-3-咔唑磺酰胺乙基磷酸二钠盐(37)
将化合物35(52mg,0.10mmol)溶于约10mL甲醇中,加入4倍当量的甲醇钠,室温下搅拌约10h。将反应液浓缩后,加入适量无水乙醇搅拌约30min,过滤得灰白色固体48mg,产率约85%。HRMS(ESI+)566.0738,Calcd for C20H19O8N3Na2PS 566.0733[M+H]+.
实施例21:N-(2,6-二甲氧基吡啶-3-基)-N-(3-羟基丙基)-9-甲基-3-咔唑磺酰胺(32)
合成步骤(1):N-(2,6-二甲氧基吡啶-3-基)-N-(3-叔丁基二甲基硅氧基丙基)-9-甲基-3-咔唑磺酰胺(30)
将N-(2,6-二甲氧基吡啶-3-基)-9-甲基-3-咔唑磺酰胺(0.80g,2.0mmol)溶于15mL无水DMF中,加入叔丁基-(碘代丙氧基)-二甲基硅烷(0.90g,3.0mmol)和氢化钠(120mg,60%in oil,3.0mmol),70℃条件下反应4h,TLC检测反应完全。减压旋去DMF,二氯甲烷提取剩余物,10%HCl中和、水和饱和食盐水依次洗涤,无水硫酸钠干燥,过滤,滤液柱层析(PE/AcOEt=6/1)分离纯化得油状物1.1g(产率97%)。1HNMR(CDCl3,400MHz)δppm0.032(6H,s),0.87(9H,s),1.70(2H,m),3.43(3H,s),3.68(4H,m),3.90(3H,s),3.94(3H,s),6.33(1H,d,J=8.4Hz),7.351(1H,dt,J=0.8,8.0Hz),7.45(1H,d,J=8.4Hz),7.51(1H,t,J=8.0Hz),7.52(1H,d,J=8.4Hz),7.60(1H,dt,J=1.6,8.0Hz),7.82(1H,dd,J=8.4,1.6Hz),8.13(1H,d,J=8.0Hz),8.48(1H,d,J=2.0Hz);HRMS(ESI+)570.2458,Calcd forC29H40N3O5SSi 570.2452[M+H]+.
(2)N-(2,6-二甲氧基吡啶-3-基)-N-(3-羟基丙基)-9-甲基-3-咔唑磺酰胺(32)
将N-(2,6-二甲氧基吡啶-3-基)-N-(3-叔丁基-二甲基-硅氧丙基)-9-甲基-3-咔唑磺酰胺(30,1.33g,2.33mmol)溶于8.0mL无水THF中,0℃条件下,滴加入四叔丁基氟化胺(2.8mL,1.0M in THF,2.80mmol)反应至TLC检测反应完全。乙酸乙酯提取,10%硫代硫酸钠、水和饱和食盐水依次洗涤,无水硫酸钠干燥,过滤,滤液浓缩,柱层析(PE/AcOEt=2/1)分离纯化得油状物1.02g(产率96%)。1HNMR(CDCl3,400MHz)δppm 1.65(2H,m),3.47(3H,s),3.75(2H,br s),3.90(2H,t,J=8.4Hz),3.92(3H,s),3.96(3H,s),6.34(1H,d,J=8.4Hz),7.37(1H,dt,J=0.8,8.0Hz),7.50(3H,m),7.61(1H,dt,J=1.2,8.4Hz),7.85(1H,dd,J=8.8,2.0Hz),8.14(1H,d,J=8.0Hz),8.49(1H,d,J=1.6Hz);13CNMR(CDCl3,125MHz)δppm29.57,31.01,45.95,53.24,53.97,58.97,101.49,108.19,109.20,113.51,120.37,120.90,122.49,122.60,125.24,127.04,129.83,141.81,142.91,144.05,159.51,162.53;HRMS(ESI+)456.1587,Calcd for C23H26N3O5S 456.1588[M+H]+.
实施例22:2-[N-(2,6-二甲氧基吡啶-3-基)-9-甲基-3-咔唑磺酰胺]-乙基-2-(N-甲基哌嗪-4-基)乙酸酯(39)
将2-(N-甲基哌嗪-4-基)-乙酸盐酸盐(0.1g,0.45mmol)溶于5.0mL二氯甲烷中,0℃条件下,加入1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(EDCI,0.10g,0.54mmol),
1-羟基-苯并***(HOBt,73mg,0.54mmol)和二异丙基乙基胺(0.26mL,1.57mmol),反应1h后,加入化合物(31)(0.20g,0.45mmol),室温反应过夜,TLC检测反应完全。反应液加入20mL二氯甲烷稀释,碳酸氢钠溶液、水和饱和氯化钠溶液依次洗涤,无水硫酸钠干燥,过滤,滤液浓缩,柱层析(DCM/MeOH=20:1)分离纯化得油状物0.18g(产率70%)。1HNMR(CDCl3,500MHz)δppm 2.39(3H,s),2.64(8H,br s),3.18(2H,s),3.36(3H,s),3.88(3H,s),3.93(3H,s),3.90(2H,br s),4.23(2H,s),6.35(1H,d,J=8.5Hz),7.35(1H,t,J=7.5Hz),7.43(1H,d,J=8.5Hz),7.59(2H,m),7.78(1H,d,J=8.5Hz),8.11(1H,d,J=7.5Hz),8.44(1H,s);13CNMR(CDCl3,125MHz)δppm 29.50,45.68,48.15,52.45,53.13,53.92,54.69,59.01,62.56,101.49,108.07,109.16,113.42,120.29,120.76,122.36,122.47,125.15,126.98,129.86,141.71,142.81,144.42,159.04,162.56,160.11;HRMS(ESI+)582.2380,Calcd forC29H36N5O6S 582.2381[M+H]+.
实施例23:2-[N-(2,6-二甲氧基吡啶-3-基)-9-甲基-3-咔唑磺酰胺]-乙氧基甲酸铵(40)
将氯磺酸异氰酸酯47μL(0.54mmol,1.2eq)溶于干燥的二氯甲烷中,0℃温度下滴加醇31(0.20g,0.45mmol,1.0eq)的二氯甲烷溶液(0.5mL),滴加完毕后,室温反应1h,反应液冷却至-5℃,加入1:5的水/THF溶液4mL,加热回流20min,冷至室温,加入二氯甲烷20mL,水洗,氯化钠溶液洗,无水硫酸钠干燥,溶液柱层析分离纯化(PE/EtOAc 2:1),得白色固体0.12g(55%)。1HNMR(DMSO-d6,500MHz)δppm 3.29(3H,s),3.71(2H,br s),3.80(3H,s),3.92(2H,s),3.95(3H,s),6.36(1H,d,J=7.5Hz),6.44(2H,br s),7.29(1H,t,J=7.5Hz),7.46(1H,d,J=8.0Hz),7.56(1H,t,J=7.5Hz),7.67(2H,m),7.74(1H,d,J=8.5Hz),8.31(1H,d,J=8.0Hz),8.49(1H,s);13CNMR(DMSO-d6,125MHz)δppm 29.33,48.35,52.91,53.56,61.40,101.12,109.16,109.80,113.53,119.93,120.30,120.92,121.50,121.74,124.69,126.84,129.15,141.42,142.46,144.27,156.32,158.81,161.73;HRMS(ESI+)485.1490,Calcd forC23H25N4O8S 485.1489[M+H]+.
最后应说明的是:以上各实施例仅用以说明本发明的技术方案,而非对其限制;尽管参照前述各实施例对本发明进行了详细的说明,本领域的普通技术人员应当理解:其依然可以对前述各实施例所记载的技术方案进行修改,或者对其中部分或者全部技术特征进行等同替换;而这些修改或者替换,并不使相应技术方案的本质脱离本发明各实施例技术方案的范围。
Claims (5)
1.一种咔唑磺酰胺衍生物或其可药用盐,其特征在于,所述咔唑磺酰胺衍生物为:
N-(2,6-二甲氧基吡啶-3-基)-N-(乙酰胺-2-基)-9-甲基-3-咔唑磺酰胺;
N-(N,N-二甲基乙基)-N-(2,6-二甲氧基吡啶-3-基)-9-甲基-3-咔唑磺酰胺;
N-(2,6-二甲氧基吡啶-3-基)-N-[2-(吡咯-1-基)-乙基]-9-甲基-3-咔唑磺酰胺;
N-(2,6-二甲氧基吡啶-3-基)-N-[2-(哌啶-1-基)-乙基]-9-甲基-3-咔唑磺酰胺;
N-(2,6-二甲氧基吡啶-3-基)-N-[2-(吗啉-4-基)-乙基]-9-甲基-3-咔唑磺酰胺;
N-(2,6-二甲氧基吡啶-3-基)-N-[2-(硫代吗啉-4-基)-乙基]-9-甲基-3-咔唑磺酰胺;
N-(2,6-二甲氧基吡啶-3-基)-N-[2-(N-甲基哌嗪-1-基)-乙基]-9-甲基-3-咔唑磺酰胺;
N-(2,6-二甲氧基吡啶-3-基)-N-{2-[4-(吡咯-1-基)-哌啶-1-基]-乙基}-9-甲基-3-咔唑磺酰胺;
N-(2,6-二甲氧基吡啶-3-基)-N-{2-(8-甲基-2,8-二氮螺[4,5]葵烷-2-基)-乙基}-9-甲基-3-咔唑磺酰胺;
N-(2,6-二甲氧基吡啶-3-基)-N-[2-(咪唑-1-基)-乙基]-9-甲基-3-咔唑磺酰胺;
N-(2,6-二甲氧基吡啶-3-基)-N-[(3-N,N-二甲基)丙基-1-基]-9-甲基-3-咔唑磺酰胺;
N-(2,6-二甲氧基吡啶-3-基)-N-[3-(N-甲基哌嗪-1-基)-丙基-1基]-9-甲基-3-咔唑磺酰胺;
N-(2,6-二甲氧基吡啶-3-基)-N-{2-[4-(吡咯-1-基)-哌啶-1-基]-丙基-1基}-9-甲基-3-咔唑磺酰胺;
N-(2,6-二甲氧基吡啶-3-基)-N-{3-(8-甲基-2,8-二氮螺[4,5]葵烷-2-基)-丙基-1基}-9-甲基-3-咔唑磺酰胺;
N-(2,6-二甲氧基吡啶-3-基)-N-[3-(咪唑-1-基)-丙基-1-基]-9-甲基-3-咔唑磺酰胺;
N-(2,6-二甲氧基吡啶-3-基)-N-(2-氨乙基)-9-甲基-3-咔唑磺酰胺;
N-(2-[N-(2,6-二甲氧基吡啶-3-基)-9-甲基-3-咔唑磺酰胺]-乙基)-3-羟基-2(s)-氨基-丙酰胺;
N-(2,6-二甲氧基吡啶-3-基)-N-(2-羟基乙基)-9-甲基-3-咔唑磺酰胺;
N-(2,6-二甲氧基吡啶-3-基)-N-(3-羟基丙基)-9-甲基-3-咔唑磺酰胺;
2-N-(2,6-二甲氧基吡啶-3-基)-9-甲基-3-咔唑磺酰胺乙基二羟基磷酸酯;
2-N-(2,6-二甲氧基吡啶-3-基)-9-甲基-3-咔唑磺酰胺乙基磷酸二钠盐;
2-[N-(2,6-二甲氧基吡啶-3-基)-9-甲基-3-咔唑磺酰胺]-乙基-2-(N-甲基哌嗪-4-基)乙酸酯;或,
2-[N-(2,6-二甲氧基吡啶-3-基)-9-甲基-3-咔唑磺酰胺]-乙氧基-甲酸铵。
2.权利要求1所述咔唑磺酰胺衍生物或其药用盐在制备微管蛋白抑制剂中的应用。
3.权利要求1所述咔唑磺酰胺衍生物或其药用盐在制备抗肿瘤药物中的应用。
4.一种抗肿瘤药物组合物,其包括治疗有效量的权利要求1所述的咔唑磺酰胺衍生物或其药用盐和药学上可接受的药用辅料。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201610323036.2A CN107382967B (zh) | 2016-05-16 | 2016-05-16 | 咔唑磺酰胺衍生物或其可药用盐及其制备方法和应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201610323036.2A CN107382967B (zh) | 2016-05-16 | 2016-05-16 | 咔唑磺酰胺衍生物或其可药用盐及其制备方法和应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN107382967A CN107382967A (zh) | 2017-11-24 |
CN107382967B true CN107382967B (zh) | 2021-02-19 |
Family
ID=60337718
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201610323036.2A Expired - Fee Related CN107382967B (zh) | 2016-05-16 | 2016-05-16 | 咔唑磺酰胺衍生物或其可药用盐及其制备方法和应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN107382967B (zh) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110467598B (zh) * | 2018-05-11 | 2021-04-13 | 中国医学科学院医药生物技术研究所 | 一种咔唑磺酰胺衍生物前药或其可药用盐及其制备方法和应用 |
CN115819322B (zh) * | 2023-02-14 | 2023-04-25 | 成都摩诃大龙医药科技有限公司 | 一种抗微生物的咔唑衍生物及其制备方法和用途 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1807413A (zh) * | 2005-09-28 | 2006-07-26 | 中国医学科学院医药生物技术研究所 | 咔唑磺酰胺衍生物及其制备方法 |
CN105906665A (zh) * | 2016-05-16 | 2016-08-31 | 中国医学科学院医药生物技术研究所 | 咔唑磺酰胺衍生物前药或其可药用盐及其制备方法和应用 |
CN105949174A (zh) * | 2016-05-16 | 2016-09-21 | 中国医学科学院医药生物技术研究所 | 咔唑磺酰胺衍生物或其药用盐及其制备方法和应用 |
-
2016
- 2016-05-16 CN CN201610323036.2A patent/CN107382967B/zh not_active Expired - Fee Related
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1807413A (zh) * | 2005-09-28 | 2006-07-26 | 中国医学科学院医药生物技术研究所 | 咔唑磺酰胺衍生物及其制备方法 |
CN105906665A (zh) * | 2016-05-16 | 2016-08-31 | 中国医学科学院医药生物技术研究所 | 咔唑磺酰胺衍生物前药或其可药用盐及其制备方法和应用 |
CN105949174A (zh) * | 2016-05-16 | 2016-09-21 | 中国医学科学院医药生物技术研究所 | 咔唑磺酰胺衍生物或其药用盐及其制备方法和应用 |
Non-Patent Citations (1)
Title |
---|
《N-(2,6-Dimethoxypyridine-3-yl)-9-Methylcarbazole-3-Sulfonamide》;Yue-Ming Wang等;《Clinical Cancer Research》;20160616;第14卷(第19期);6218-6227 * |
Also Published As
Publication number | Publication date |
---|---|
CN107382967A (zh) | 2017-11-24 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU2018204027B2 (en) | N-phenyl-carboxamide derivatives and the use thereof as medicaments for the treatment of Hepatitis B | |
AU2018201668B2 (en) | Bruton's Tyrosine Kinase Inhibitors | |
TWI791511B (zh) | 細胞凋亡誘導劑 | |
CA2997051C (en) | Novel pyrazolo[3,4-d]pyrimidine compound or salt thereof | |
AU2014222641B2 (en) | Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of Hepatitis B | |
US20230105745A1 (en) | Cycloalkyl and hetero-cycloalkyl inhibitors, preparation methods therefor, and use thereof | |
RU2666349C2 (ru) | Новое конденсированное пиримидиновое соединение или его соль | |
RU2738654C1 (ru) | Новый ингибитор циклинзависимой киназы cdk9 | |
AU2011319685B2 (en) | Pochoxime conjugates useful for the treatment of HSP90 related pathologies | |
JP2009507816A (ja) | 抗ウィルス薬としての四環式インドール誘導体 | |
EA020511B1 (ru) | Конформационно ограниченные бифенильные производные для применения в качестве ингибиторов вируса гепатита с | |
EP1725102A1 (en) | Hiv integrase inhibitors | |
AU2021339298A1 (en) | Compounds for suppressing egfr mutant cancer and pharmaceutical use thereof | |
WO2014146494A1 (zh) | β-氨基羰基类化合物、其制备方法、药物组合物及其用途 | |
CA3229591A1 (en) | Prodrugs and derivatives of psilocin and uses thereof | |
EP2857402A1 (en) | Pyrrole [2, 1-f][1, 2, 4]triazine derivative and antitumor effect thereof | |
KR102547709B1 (ko) | 아제티딘 유도체 | |
JP2022549030A (ja) | 複素環アミド化合物、その薬学的に許容される塩およびその調製方法と使用 | |
CN107382967B (zh) | 咔唑磺酰胺衍生物或其可药用盐及其制备方法和应用 | |
CA3196061A1 (en) | Cftr modulator compounds, compositions, and uses thereof | |
AU2009212072A1 (en) | Arylmethylidene heterocycles as novel analgesics | |
PT1641787E (pt) | Dicetopiperazinas substituídas e sua utilização como antagonistas da oxitocina | |
KR101169359B1 (ko) | 사이클릭 아미드라존 기를 가지는 신규한 옥사졸리디논 유도체 및 이를 함유하는 의약 조성물 | |
CA2972746C (en) | Production method of thiazole derivative | |
KR20220146348A (ko) | 아데노신 A2a 수용체 길항제로서의 화합물 및 이를 포함하는 약학적 조성물 |
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 | ||
CF01 | Termination of patent right due to non-payment of annual fee | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20210219 |