CN104447483B - Containing aniline and the compound of diene adamantane structure, Preparation Method And The Use - Google Patents
Containing aniline and the compound of diene adamantane structure, Preparation Method And The Use Download PDFInfo
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- CN104447483B CN104447483B CN201510017450.6A CN201510017450A CN104447483B CN 104447483 B CN104447483 B CN 104447483B CN 201510017450 A CN201510017450 A CN 201510017450A CN 104447483 B CN104447483 B CN 104447483B
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- 150000001875 compounds Chemical class 0.000 title claims description 30
- 238000002360 preparation method Methods 0.000 title abstract description 6
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 title description 4
- 239000003814 drug Substances 0.000 claims abstract description 11
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 10
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical group C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 8
- 230000008569 process Effects 0.000 claims description 6
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 5
- 238000006243 chemical reaction Methods 0.000 claims description 5
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 150000001993 dienes Chemical class 0.000 claims description 4
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 claims description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Substances C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- WKOVRQFUCLHTHB-UHFFFAOYSA-N n-(ethyliminomethylideneamino)-n-methylmethanamine Chemical class CCN=C=NN(C)C WKOVRQFUCLHTHB-UHFFFAOYSA-N 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 claims description 2
- 230000001732 thrombotic effect Effects 0.000 claims description 2
- 208000007536 Thrombosis Diseases 0.000 abstract description 15
- 229940098892 Protease-activated receptor-1 antagonist Drugs 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 15
- 239000000203 mixture Substances 0.000 description 13
- 239000000376 reactant Substances 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 239000002274 desiccant Substances 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 239000000047 product Substances 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000003146 anticoagulant agent Substances 0.000 description 6
- 239000012267 brine Substances 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 6
- 239000000284 extract Substances 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 102100037136 Proteinase-activated receptor 1 Human genes 0.000 description 5
- 101710121440 Proteinase-activated receptor 1 Proteins 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 230000002785 anti-thrombosis Effects 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 3
- 125000002648 azanetriyl group Chemical group *N(*)* 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 229910052710 silicon Inorganic materials 0.000 description 3
- 239000010703 silicon Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 3
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 208000032843 Hemorrhage Diseases 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- 108010070519 PAR-1 Receptor Proteins 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 102000002020 Protease-activated receptors Human genes 0.000 description 2
- 108050009310 Protease-activated receptors Proteins 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 108090000190 Thrombin Proteins 0.000 description 2
- 102000003790 Thrombin receptors Human genes 0.000 description 2
- 108090000166 Thrombin receptors Proteins 0.000 description 2
- 208000035896 Twin-reversed arterial perfusion sequence Diseases 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- 230000000702 anti-platelet effect Effects 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 208000034158 bleeding Diseases 0.000 description 2
- 230000000740 bleeding effect Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 2
- 210000000265 leukocyte Anatomy 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 210000002381 plasma Anatomy 0.000 description 2
- 230000000630 rising effect Effects 0.000 description 2
- -1 stirring Substances 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 229960004072 thrombin Drugs 0.000 description 2
- OVBICQMTCPFEBS-SATRDZAXSA-N (2s)-1-[(2s)-2-[[(2s)-2-[[(2r)-2-[[(2s)-2-[[(2s)-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-acetamido-3-naphthalen-2-ylpropanoyl]amino]-3-(4-chlorophenyl)propanoyl]amino]-3-pyridin-3-ylpropanoyl]amino]-3-hydroxypropanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-6-[bi Chemical compound CC(O)=O.CC(O)=O.C([C@@H](C(=O)N[C@H](CCCCN=C(NCC)NCC)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN=C(NCC)NCC)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](C)C(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](CC=1C=NC=CC=1)NC(=O)[C@@H](CC=1C=CC(Cl)=CC=1)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(C)=O)C1=CC=C(O)C=C1 OVBICQMTCPFEBS-SATRDZAXSA-N 0.000 description 1
- GMVPRGQOIOIIMI-UHFFFAOYSA-N (8R,11R,12R,13E,15S)-11,15-Dihydroxy-9-oxo-13-prostenoic acid Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CCCCCCC(O)=O GMVPRGQOIOIIMI-UHFFFAOYSA-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
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 208000004476 Acute Coronary Syndrome Diseases 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 239000005552 B01AC04 - Clopidogrel Substances 0.000 description 1
- BFXXQUCAVUDIPB-WVORFHHMSA-N CC(CC(C1)C2)(CC1C2C1)CCC1/C=C/C=C/C(NCc1ccc[n]1-c(cc1)ccc1N)=O Chemical compound CC(CC(C1)C2)(CC1C2C1)CCC1/C=C/C=C/C(NCc1ccc[n]1-c(cc1)ccc1N)=O BFXXQUCAVUDIPB-WVORFHHMSA-N 0.000 description 1
- PGOLTILJILJFLH-NNGXMHFZSA-N CCN(CC)c(cc1)ccc1-[n]1c(CNC(/C=C/C=C/C2(C3)C(C4)CC3(C)CC4C2)=O)ccc1 Chemical compound CCN(CC)c(cc1)ccc1-[n]1c(CNC(/C=C/C=C/C2(C3)C(C4)CC3(C)CC4C2)=O)ccc1 PGOLTILJILJFLH-NNGXMHFZSA-N 0.000 description 1
- 229940123900 Direct thrombin inhibitor Drugs 0.000 description 1
- 102000009123 Fibrin Human genes 0.000 description 1
- 108010073385 Fibrin Proteins 0.000 description 1
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 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
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 229940118340 Indirect thrombin inhibitor Drugs 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 102000032626 PAR-1 Receptor Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 206010050661 Platelet aggregation inhibition Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 102000007466 Purinergic P2 Receptors Human genes 0.000 description 1
- 108010085249 Purinergic P2 Receptors Proteins 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 229930003448 Vitamin K Natural products 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 238000004220 aggregation Methods 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
- 229960000711 alprostadil Drugs 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000010100 anticoagulation Effects 0.000 description 1
- 229940127218 antiplatelet drug Drugs 0.000 description 1
- 230000006502 antiplatelets effects Effects 0.000 description 1
- 229960004676 antithrombotic agent Drugs 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 230000037396 body weight Effects 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
- 239000006285 cell suspension Substances 0.000 description 1
- GKTWGGQPFAXNFI-HNNXBMFYSA-N clopidogrel Chemical compound C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl GKTWGGQPFAXNFI-HNNXBMFYSA-N 0.000 description 1
- 229960003009 clopidogrel Drugs 0.000 description 1
- 230000015271 coagulation Effects 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 239000003260 cyclooxygenase 1 inhibitor Substances 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 229950003499 fibrin Drugs 0.000 description 1
- 239000003527 fibrinolytic agent Substances 0.000 description 1
- 108700032141 ganirelix Proteins 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- CCZVEWRRAVASGL-UHFFFAOYSA-N lithium;2-methanidylpropane Chemical compound [Li+].CC(C)[CH2-] CCZVEWRRAVASGL-UHFFFAOYSA-N 0.000 description 1
- OVEHNNQXLPJPPL-UHFFFAOYSA-N lithium;n-propan-2-ylpropan-2-amine Chemical compound [Li].CC(C)NC(C)C OVEHNNQXLPJPPL-UHFFFAOYSA-N 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
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- SHUZOJHMOBOZST-UHFFFAOYSA-N phylloquinone Natural products CC(C)CCCCC(C)CCC(C)CCCC(=CCC1=C(C)C(=O)c2ccccc2C1=O)C SHUZOJHMOBOZST-UHFFFAOYSA-N 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- GMVPRGQOIOIIMI-DWKJAMRDSA-N prostaglandin E1 Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(O)=O GMVPRGQOIOIIMI-DWKJAMRDSA-N 0.000 description 1
- 235000019419 proteases Nutrition 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 238000000611 regression analysis Methods 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000003868 thrombin inhibitor Substances 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 235000019168 vitamin K Nutrition 0.000 description 1
- 239000011712 vitamin K Substances 0.000 description 1
- 150000003721 vitamin K derivatives Chemical class 0.000 description 1
- 229940046010 vitamin k Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/335—Radicals substituted by nitrogen atoms not forming part of a nitro radical
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to the drug world relevant to thrombotic disease.Specifically, the present invention relates to a class containing anilino-and PAR 1 antagonist of diene adamantane structure, Preparation Method And The Use.Wherein, R1、R2It is respectively selected from the alkyl of H, C1 C5.
Description
Technical field
The present invention relates to the drug world relevant to thrombus disease.Specifically, the present invention relates to thrombosis
Property the medicative class of disease containing anilino-and the PAR-1 antagonist of diene adamantane structure and preparation thereof
Method, containing they pharmaceutical composition and treatment thrombotic disease on purposes.
Background technology
Proteinase activated receptors 1 (Protease Activated Acceptor-1, PAR-1) is the anti-of discovery recently
The novel targets of platelet class antithrombotic reagent.Proteinase activated receptors 1 is again thrombin receptor, and thrombin is coagulated
In platelet thus activate platelet by PAR-1 receptor acting after the chain activation of blood, cause platelet aggregation from
And cause thrombosis and blood coagulation.Rich in platelet component in the thrombosis that PAR-1 causes, it is the main one-tenth of arterial thrombus
Cause.PAR-1 antagonist can block thrombin activation platelet, thus interruption artery thrombosis, may be used for
Treatment acute coronary artery disease (Acute Coronary Syndrome).Have at several PAR-1 inhibitor
In clinical research (Chackalamannil S., Thrombin Receptor (Protease Activated Receptor-1)
Antagonists as Potent Antithrombotic Agents with Strong Antiplatelet Effects,J.Med.
Chem.,2006,49(18),5389-5403)。
The medicine being traditionally used for preventing and treating thrombotic disease is divided three classes.The first kind is anticoagulation class, is divided into
Direct thrombin inhibitor and indirect thrombin inhibitor, such medicine is by acting on the different rings of coagulation cascade
Joint carrys out inhibition thrombosis, has the various thrombotic effects of suppression, as vitamin K antagon and Xa because of
Sub-inhibitor etc.；Equations of The Second Kind is antiplatelet class, such as COX-1 inhibitor and adp receptor antagonist etc., is somebody's turn to do
Class medicine is mainly used in preventing and treating arterial thrombus；3rd class is fibrinolytic agent, is mainly used in lysed blood
The fibrin formed.
Mostly antiplatelet drug is traditional arterial thrombus protective agents, such as clopidogrel and aspirin
Deng.The shortcoming of these medicines is that bleeding risk is bigger.And as newfound antiplatelet class antithrombotic reagent
PAR-1 antagonist, then there is less bleeding risk, therefore this compounds can be as treatment tremulous pulse
The most promising medicine of thrombosis.
The invention discloses a class and contain anilino-and the PAR-1 antagonist of diene adamantane structure, they can
For the medicine preparing anti-arterial thrombus disease.
Summary of the invention
It is an object of the present invention to provide a kind of there is good anti-thrombosis activity have formula I's
Compound and pharmaceutically acceptable salt.
It is a further object to provide preparation there is compounds of formula I and pharmaceutically can connect
The method of the salt being subject to.
It is also another object of the present invention to provide containing compounds of formula I and pharmaceutically acceptable thereof
Salt is as effective ingredient, and one or more pharmaceutically acceptable carriers, excipient or diluent is medicinal
Compositions, and the application in terms for the treatment of arterial thrombus.
In conjunction with the purpose of the present invention, present invention is specifically described.
The present invention has compounds of formula I and has a following structural formula:
Wherein, R1、R2It is respectively selected from the alkyl of H, C1-C5.
More preferably following have compounds of formula I,
The method of synthesis compound of Formula I:
Compound II synthesizes (US4001223) according to literature method.Compound II and PPh3Reaction obtains
Quaternary salt, then uses highly basic to process and obtains Wittig reagent, then react with III, and the diene obtained uses I2
Alltrans diene IV is obtained after process；IV hydrolysis obtains V；V Yu VI reacts in the presence of condensing agent, obtains
Product I.
Wherein, described highly basic selected from positive fourth lithium, isobutyl lithium, tertiary Ding Li, hexamethyl two silicon nitrilo sodium,
Hexamethyl two silicon nitrilo potassium, hexamethyl two silicon nitrilo lithium, lithium diisopropylamine；Described condensing agent is selected from
N, N'-dicyclohexyl carbodiimide, N-ethyl-N'-dimethylamino carbodiimides, carbonyl dimidazoles.
Wherein, R1、R2Defined as described above.
The pharmaceutically acceptable salt of compound of formula I of the present invention, includes, but are not limited to and various nothings
The salt that machine acid example hydrochloric acid, sulphuric acid, nitric acid, phosphoric acid, hydrobromic acid etc. are formed, also includes and various organic acid such as second
The salt that acid, succinic acid, maleic acid, malic acid and various aminoacid etc. are formed.
Compound of Formula I of the present invention has the antagonism of PAR-1, can use as effective ingredient
Medicine in terms of preparing antithrombotic.The activity of compound of Formula I of the present invention is by external mould
Type checking.
The compound of Formula I of the present invention is effective in comparatively wide dosage range.Such as every day takes
Dosage about in the range of 1mg-500mg/ people, be divided into once or be administered for several times.Actual take formula of the present invention
The dosage of I can be determined according to relevant situation by doctor.These situations include: the body of patient
Body state, route of administration, age, body weight, individual reaction to medicine, the order of severity etc. of symptom.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is further illustrated.It should be noted that following embodiment
It is only for explanation, and is not intended to limit the present invention.Those skilled in the art are done according to the teachings of the present invention
The various changes gone out all should be within the protection domain required by the application claim.
Embodiment 1
2.43g (10mmol) compound II and 2.62g (10mmol) PPh3It is dissolved in what 20mL was dried
In THF, reflux under nitrogen protection overnight.After reactant mixture is cooled to room temperature, obtain a white opacity
Solution.It is cooled to-78 DEG C under nitrogen protection, slowly drips 6.25mL (10mmol, 1.6M) n-BuLi's
Hexane solution.After dropping, continue stirring one hour, then drip compound 1.28g (10mmol) III
It is dissolved in the solution that 2mL THF makes.After dropping, reactant mixture is slowly ramped to room temperature, then returns
Flow 1 hour.Reactant mixture pours in frozen water, stirring, extracts with the dichloromethane of 50mL × 3, closes
And extraction phase brine It, anhydrous sodium sulfate is dried.Sucking filtration removes desiccant, adds 0.50g in filtrate
Iodine, is stirred overnight under room temperature.Reactant mixture 100mL 5% hypo solution washs, anhydrous sulfur
Acid sodium is dried.Sucking filtration removes desiccant, and filtrate is evaporated on a rotary evaporator, residue column chromatography purification,
Sterling to product IV；White solid, ESI-MS, m/z=275 ([M+H]+)。
1.37g (5mmol) compound IV is dissolved in 15mL methanol, adds the NaOH of 1mL 30%
Solution, then temperature rising reflux 10 minutes.After reactant mixture cooling, pour in 100mL frozen water, use
Concentrated hydrochloric acid regulation pH=2.Extract with the dichloromethane of 50mL × 3, merge extraction phase brine It,
Anhydrous sodium sulfate is dried.Sucking filtration removes desiccant, and filtrate is evaporated on a rotary evaporator, and residue column chromatography is pure
Change, obtain the sterling of product V；White solid, ESI-MS, m/z=245 ([M-H]-)。
0.74g (3mmol) compound V and 0.65g (3mmol) compound VI-1 is dissolved in 5mL and is dried
THF in, add 0.62g (3mmol) DCC, be stirred overnight under room temperature.TLC display reaction completes.
After reactant mixture cooling, pour in 100mL frozen water, extract with the dichloromethane of 50mL × 3, close
And extraction phase brine It, anhydrous sodium sulfate is dried.Sucking filtration removes desiccant, and filtrate is at Rotary Evaporators
On be evaporated, residue column chromatography purification, obtain the sterling of product I-1；White-yellowish solid, ESI-MS, m/z=
442([M-H]-)。
Embodiment 2-4
With reference to the method for embodiment 1, synthesize the following compounds with formula I.
The preparation of embodiment 5 reference compound D1
For absolutely proving the beneficial effect of the compounds of this invention, applicant describes discovery in experimentation
Following formula: compound D1 (is not disclosed), as drug effect reference compound.
Synthetic method is as follows:
2.43g (10mmol) compound II and 2.62g (10mmol) PPh3It is dissolved in what 20mL was dried
In THF, reflux under nitrogen protection overnight.After reactant mixture is cooled to room temperature, obtain a white opacity
Solution.It is cooled to-78 DEG C under nitrogen protection, slowly drips 6.25mL (10mmol, 1.6M) n-BuLi's
Hexane solution.After dropping, continue stirring one hour, then drip compound 1.28g (10mmol) III
It is dissolved in the solution that 2mL THF makes.After dropping, reactant mixture is slowly ramped to room temperature, then returns
Flow 1 hour.Reactant mixture pours in frozen water, stirring, extracts with the dichloromethane of 50mL × 3, closes
And extraction phase brine It, anhydrous sodium sulfate is dried.Sucking filtration removes desiccant, adds 0.50g in filtrate
Iodine, is stirred overnight under room temperature.Reactant mixture 100mL 5% hypo solution washs, anhydrous sulfur
Acid sodium is dried.Sucking filtration removes desiccant, and filtrate is evaporated on a rotary evaporator, residue column chromatography purification,
Sterling to product IV；White solid, ESI-MS, m/z=275 ([M+H]+)。
1.37g (5mmol) compound IV is dissolved in 15mL methanol, adds the NaOH of 1mL 30%
Solution, then temperature rising reflux 10 minutes.After reactant mixture cooling, pour in 100mL frozen water, use
Concentrated hydrochloric acid regulation pH=2.Extract with the dichloromethane of 50mL × 3, merge extraction phase brine It,
Anhydrous sodium sulfate is dried.Sucking filtration removes desiccant, and filtrate is evaporated on a rotary evaporator, and residue column chromatography is pure
Change, obtain the sterling of product V；White solid, ESI-MS, m/z=245 ([M-H]-)。
0.74g (3mmol) compound V and 0.52g (3mmol) compound VI-5 is dissolved in 5mL and is dried
THF in, add 0.62g (3mmol) DCC, be stirred overnight under room temperature.TLC display reaction completes.
After reactant mixture cooling, pour in 100mL frozen water, extract with the dichloromethane of 50mL × 3, close
And extraction phase brine It, anhydrous sodium sulfate is dried.Sucking filtration removes desiccant, and filtrate is at Rotary Evaporators
On be evaporated, residue column chromatography purification, obtain the sterling of product D1；White solid, ESI-MS, m/z=399
([M-H]-)。
Embodiment 6 extracorporeal platelet aggregation inhibition test
In 96 orifice plates, the platelet aggregation concentration induced at TRAP (Glycoprotein) carries out thing
The pharmacology test of matter.Being previously added the sodium citrate solution of 3.13% in syringe, then suction 20mL is good for
The blood of health volunteer, is centrifuged 20 minutes under 1500g, will be enriched in hematoblastic blood plasma (PRP) and isolate
Come and process with the amount of 1 μ L PGE1 solution (ethanol solution of 500 μ g/mL)/mL PRP.In room temperature
Under hatch 5 minutes after, by its under 1200g centrifugal 20 minutes to remove leukocyte.By without leukocyte
PRP transfers to 5mL/ part in the PP pipe of 15mL in batches, and centrifugal under 3600g makes pellet platelets.
Then, drain upper plasma, the pellet platelets deriving from 5mL PRP is suspended in 1mL Tyrode again
(120mM NaCl, 2.6mM KCl, 12mM NaHCO3, 0.39mM NaH2PO4, 10mM HEPES,
0.35%BSA, 5.5mM glucose, pH=7.4) in, and regulate the blood to 3 × 105/ μ L with Tyrode
Platelet number.By this for the 13mL cell suspension 10mM CaCl of 866 μ L2Solution processes, with often
The amount of hole 120 μ L is drawn in 96 orifice plates, adds 15 μ L the most in advance and treat in the hole of 96 orifice plates
Test substances.At room temperature dark is hatched 30 minutes, add 15 μ L TRAP solution (70-100 μM) and make
For agonist, vibrate 20 minutes at 37 DEG C in SpectraMax, under 650nm, note down kinetics,
Calculate negative control (tyrode/DMSO) and the area under curve of positive control (15 μ L agonist/DMSO), and
Difference is set to 100%.Compound to be tested is aspirated with the form of serial dilution thing, carries out in duplicate
Measure, the same AUC measuring each material concentration, calculate AUC compared with the control and suppress %.Pressed down by this
% processed calculates IC according to 4 parametric equations by nonlinear regression analysis50Value.Following table gives result.
| Compound | The suppression IC of platelet aggregation50(μM) |
| I-1 | 0.27 |
| I-2 | 0.92 |
| I-3 | 0.39 |
| I-4 | 0.61 |
| Reference compound D1 | 0.94 |
As can be seen from the above table, the compound of the present invention all shows preferably in platelet aggregation test
Inhibitory action.
Claims (4)
1. there is compound and the pharmaceutically acceptable salt thereof of general formula I,
Wherein, R1、R2It is respectively selected from the alkyl of H, C1-C5.
2. compound of Formula I defined in claim 1, is selected from:
3. the method for the arbitrary defined compounds of formula I of synthesis claim 1-2:
Compound II and PPh3Reaction obtains quaternary salt, then uses highly basic to process and obtains Wittig reagent, then
Reacting with III, the diene obtained uses I2Alltrans diene IV is obtained after process；IV hydrolysis obtains V；V
React in the presence of condensing agent with VI, obtain product I；Wherein said highly basic is selected from n-BuLi n-BuLi；
Described condensing agent is selected from N, N'-dicyclohexyl carbodiimide, N-ethyl-N'-dimethylamino carbodiimides, carbonyl
Base diimidazole；R1、R2Definition such as claim 1-2 arbitrary described.
4. compound of Formula I defined in any one of claim 1-2 and pharmaceutically acceptable salt are in system
Application in terms of standby treatment thrombotic medicine.
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