CN104837833A - Xia因子抑制剂的晶型 - Google Patents
Xia因子抑制剂的晶型 Download PDFInfo
- Publication number
- CN104837833A CN104837833A CN201380064797.5A CN201380064797A CN104837833A CN 104837833 A CN104837833 A CN 104837833A CN 201380064797 A CN201380064797 A CN 201380064797A CN 104837833 A CN104837833 A CN 104837833A
- Authority
- CN
- China
- Prior art keywords
- crystal formation
- base
- methyl
- tetrahydroisoquinoline
- fluoro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 229940122036 Factor XIa inhibitor Drugs 0.000 title 1
- 238000000034 method Methods 0.000 claims abstract description 31
- 230000009424 thromboembolic effect Effects 0.000 claims abstract description 13
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 12
- 239000013078 crystal Substances 0.000 claims description 132
- 230000015572 biosynthetic process Effects 0.000 claims description 96
- 150000001875 compounds Chemical class 0.000 claims description 87
- 239000002904 solvent Substances 0.000 claims description 43
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 29
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 28
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 23
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 23
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 22
- 238000011282 treatment Methods 0.000 claims description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 238000002425 crystallisation Methods 0.000 claims description 18
- 230000008025 crystallization Effects 0.000 claims description 17
- 201000010099 disease Diseases 0.000 claims description 11
- 208000035475 disorder Diseases 0.000 claims description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- 208000005189 Embolism Diseases 0.000 claims description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 7
- 210000004204 blood vessel Anatomy 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 7
- 125000006850 spacer group Chemical group 0.000 claims description 6
- 201000001320 Atherosclerosis Diseases 0.000 claims description 4
- 208000007536 Thrombosis Diseases 0.000 claims description 4
- 206010047249 Venous thrombosis Diseases 0.000 claims description 4
- 210000004369 blood Anatomy 0.000 claims description 4
- 239000008280 blood Substances 0.000 claims description 4
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N NMP Substances CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 3
- 238000001990 intravenous administration Methods 0.000 claims description 3
- 208000010125 myocardial infarction Diseases 0.000 claims description 3
- 206010003178 Arterial thrombosis Diseases 0.000 claims description 2
- 206010003658 Atrial Fibrillation Diseases 0.000 claims description 2
- 206010008088 Cerebral artery embolism Diseases 0.000 claims description 2
- 206010008092 Cerebral artery thrombosis Diseases 0.000 claims description 2
- 206010011091 Coronary artery thrombosis Diseases 0.000 claims description 2
- 206010033799 Paralysis Diseases 0.000 claims description 2
- 208000030831 Peripheral arterial occlusive disease Diseases 0.000 claims description 2
- 208000006193 Pulmonary infarction Diseases 0.000 claims description 2
- 206010038470 Renal infarct Diseases 0.000 claims description 2
- 206010042434 Sudden death Diseases 0.000 claims description 2
- 208000032109 Transient ischaemic attack Diseases 0.000 claims description 2
- 208000007814 Unstable Angina Diseases 0.000 claims description 2
- 230000001154 acute effect Effects 0.000 claims description 2
- 230000002612 cardiopulmonary effect Effects 0.000 claims description 2
- 208000002528 coronary thrombosis Diseases 0.000 claims description 2
- 210000004351 coronary vessel Anatomy 0.000 claims description 2
- 230000002526 effect on cardiovascular system Effects 0.000 claims description 2
- 238000001631 haemodialysis Methods 0.000 claims description 2
- 230000000322 hemodialysis Effects 0.000 claims description 2
- 201000010849 intracranial embolism Diseases 0.000 claims description 2
- 230000000302 ischemic effect Effects 0.000 claims description 2
- 208000021090 palsy Diseases 0.000 claims description 2
- 230000007575 pulmonary infarction Effects 0.000 claims description 2
- 208000011580 syndromic disease Diseases 0.000 claims description 2
- 201000005060 thrombophlebitis Diseases 0.000 claims description 2
- 230000001732 thrombotic effect Effects 0.000 claims description 2
- 201000010875 transient cerebral ischemia Diseases 0.000 claims description 2
- 235000019439 ethyl acetate Nutrition 0.000 claims 1
- 230000008569 process Effects 0.000 abstract description 8
- 239000012453 solvate Substances 0.000 abstract description 8
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- WYFCZWSWFGJODV-MIANJLSGSA-N 4-[[(1s)-2-[(e)-3-[3-chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]prop-2-enoyl]-5-(4-methyl-2-oxopiperazin-1-yl)-3,4-dihydro-1h-isoquinoline-1-carbonyl]amino]benzoic acid Chemical compound O=C1CN(C)CCN1C1=CC=CC2=C1CCN(C(=O)\C=C\C=1C(=CC=C(Cl)C=1F)N1N=NN=C1)[C@@H]2C(=O)NC1=CC=C(C(O)=O)C=C1 WYFCZWSWFGJODV-MIANJLSGSA-N 0.000 abstract 1
- 238000005755 formation reaction Methods 0.000 description 79
- 239000002585 base Substances 0.000 description 27
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 27
- 239000000203 mixture Substances 0.000 description 24
- 239000003795 chemical substances by application Substances 0.000 description 22
- 108010074864 Factor XI Proteins 0.000 description 21
- 238000002360 preparation method Methods 0.000 description 21
- 210000004027 cell Anatomy 0.000 description 20
- 239000000243 solution Substances 0.000 description 20
- 239000003814 drug Substances 0.000 description 18
- 239000007787 solid Substances 0.000 description 18
- 239000002775 capsule Substances 0.000 description 16
- 239000000463 material Substances 0.000 description 14
- 239000003826 tablet Substances 0.000 description 13
- 239000000523 sample Substances 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 11
- 238000002474 experimental method Methods 0.000 description 11
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 10
- 102100030563 Coagulation factor XI Human genes 0.000 description 10
- 238000002441 X-ray diffraction Methods 0.000 description 10
- -1 methane amide Chemical class 0.000 description 10
- 239000000126 substance Substances 0.000 description 10
- 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 9
- 229920002472 Starch Polymers 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- 239000000843 powder Substances 0.000 description 9
- 239000002002 slurry Substances 0.000 description 9
- 239000008107 starch Substances 0.000 description 9
- 229940032147 starch Drugs 0.000 description 9
- 235000019698 starch Nutrition 0.000 description 9
- 238000005516 engineering process Methods 0.000 description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- 238000000371 solid-state nuclear magnetic resonance spectroscopy Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 7
- 239000008101 lactose Substances 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 238000013459 approach Methods 0.000 description 6
- 230000023555 blood coagulation Effects 0.000 description 6
- 230000037396 body weight Effects 0.000 description 6
- 238000005384 cross polarization magic-angle spinning Methods 0.000 description 6
- 238000000113 differential scanning calorimetry Methods 0.000 description 6
- 239000002245 particle Substances 0.000 description 6
- 238000002411 thermogravimetry Methods 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 5
- 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 5
- 229930006000 Sucrose Natural products 0.000 description 5
- 229920002678 cellulose Polymers 0.000 description 5
- 239000001913 cellulose Substances 0.000 description 5
- 235000010980 cellulose Nutrition 0.000 description 5
- 239000007891 compressed tablet Substances 0.000 description 5
- 238000004821 distillation Methods 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 229960004756 ethanol Drugs 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 230000006870 function Effects 0.000 description 5
- 239000012535 impurity Substances 0.000 description 5
- 239000003112 inhibitor Substances 0.000 description 5
- 230000002969 morbid Effects 0.000 description 5
- 239000003880 polar aprotic solvent Substances 0.000 description 5
- 230000002265 prevention Effects 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 239000011877 solvent mixture Substances 0.000 description 5
- 239000005720 sucrose Substances 0.000 description 5
- 239000003981 vehicle Substances 0.000 description 5
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- 241000124008 Mammalia Species 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- 108010000499 Thromboplastin Proteins 0.000 description 4
- 102000002262 Thromboplastin Human genes 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 4
- 238000007906 compression Methods 0.000 description 4
- 230000006835 compression Effects 0.000 description 4
- 229960000935 dehydrated alcohol Drugs 0.000 description 4
- 230000003203 everyday effect Effects 0.000 description 4
- 239000000314 lubricant Substances 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 239000008213 purified water Substances 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 238000004088 simulation Methods 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- 230000001954 sterilising effect Effects 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 229920002785 Croscarmellose sodium Polymers 0.000 description 3
- 108010054265 Factor VIIa Proteins 0.000 description 3
- 108010074860 Factor Xa Proteins 0.000 description 3
- 238000005004 MAS NMR spectroscopy Methods 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 230000032683 aging Effects 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 239000007810 chemical reaction solvent Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000000084 colloidal system Substances 0.000 description 3
- 229920006037 cross link polymer Polymers 0.000 description 3
- 238000001938 differential scanning calorimetry curve Methods 0.000 description 3
- 238000006073 displacement reaction Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 229940012414 factor viia Drugs 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 239000007903 gelatin capsule Substances 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 230000006698 induction Effects 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- 239000003182 parenteral nutrition solution Substances 0.000 description 3
- 239000001253 polyvinylpolypyrrolidone Substances 0.000 description 3
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 3
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 3
- 230000005855 radiation Effects 0.000 description 3
- 239000000377 silicon dioxide Substances 0.000 description 3
- 229940080313 sodium starch Drugs 0.000 description 3
- 238000009987 spinning Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 238000001757 thermogravimetry curve Methods 0.000 description 3
- MEIRRNXMZYDVDW-MQQKCMAXSA-N (2E,4E)-2,4-hexadien-1-ol Chemical compound C\C=C\C=C\CO MEIRRNXMZYDVDW-MQQKCMAXSA-N 0.000 description 2
- QNRATNLHPGXHMA-XZHTYLCXSA-N (r)-(6-ethoxyquinolin-4-yl)-[(2s,4s,5r)-5-ethyl-1-azabicyclo[2.2.2]octan-2-yl]methanol;hydrochloride Chemical compound Cl.C([C@H]([C@H](C1)CC)C2)CN1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OCC)C=C21 QNRATNLHPGXHMA-XZHTYLCXSA-N 0.000 description 2
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 description 2
- XJMMNTGIMDZPMU-UHFFFAOYSA-N 3-methylglutaric acid Chemical compound OC(=O)CC(C)CC(O)=O XJMMNTGIMDZPMU-UHFFFAOYSA-N 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- 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 2
- 108010014172 Factor V Proteins 0.000 description 2
- 108010014173 Factor X Proteins 0.000 description 2
- 108010049003 Fibrinogen Proteins 0.000 description 2
- 102000008946 Fibrinogen Human genes 0.000 description 2
- 239000001828 Gelatine Substances 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- ATHHXGZTWNVVOU-UHFFFAOYSA-N N-methylformamide Chemical compound CNC=O ATHHXGZTWNVVOU-UHFFFAOYSA-N 0.000 description 2
- 229920000954 Polyglycolide Polymers 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 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
- 230000009471 action Effects 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 230000002785 anti-thrombosis Effects 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- 229960004676 antithrombotic agent Drugs 0.000 description 2
- 229940043232 butyl acetate Drugs 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 229940105329 carboxymethylcellulose Drugs 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 238000002648 combination therapy Methods 0.000 description 2
- 235000009508 confectionery Nutrition 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000002354 daily effect Effects 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 229940012952 fibrinogen Drugs 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 150000002334 glycols Chemical class 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 229940102223 injectable solution Drugs 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 2
- 229940011051 isopropyl acetate Drugs 0.000 description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 2
- YECIFGHRMFEPJK-UHFFFAOYSA-N lidocaine hydrochloride monohydrate Chemical compound O.[Cl-].CC[NH+](CC)CC(=O)NC1=C(C)C=CC=C1C YECIFGHRMFEPJK-UHFFFAOYSA-N 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 2
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 2
- 239000001923 methylcellulose Substances 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
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- KPSSIOMAKSHJJG-UHFFFAOYSA-N neopentyl alcohol Chemical compound CC(C)(C)CO KPSSIOMAKSHJJG-UHFFFAOYSA-N 0.000 description 2
- 239000012454 non-polar solvent Substances 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 229920000747 poly(lactic acid) Polymers 0.000 description 2
- 229920001610 polycaprolactone Polymers 0.000 description 2
- 239000004633 polyglycolic acid Substances 0.000 description 2
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229940068968 polysorbate 80 Drugs 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 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
- 238000007670 refining Methods 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 230000003595 spectral effect Effects 0.000 description 2
- 235000021092 sugar substitutes Nutrition 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- 238000001622 two pulse phase modulation pulse sequence Methods 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- XDIYNQZUNSSENW-UUBOPVPUSA-N (2R,3S,4R,5R)-2,3,4,5,6-pentahydroxyhexanal Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O XDIYNQZUNSSENW-UUBOPVPUSA-N 0.000 description 1
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- DDMOUSALMHHKOS-UHFFFAOYSA-N 1,2-dichloro-1,1,2,2-tetrafluoroethane Chemical compound FC(F)(Cl)C(F)(F)Cl DDMOUSALMHHKOS-UHFFFAOYSA-N 0.000 description 1
- CYSGHNMQYZDMIA-UHFFFAOYSA-N 1,3-Dimethyl-2-imidazolidinon Chemical compound CN1CCN(C)C1=O CYSGHNMQYZDMIA-UHFFFAOYSA-N 0.000 description 1
- SBASXUCJHJRPEV-UHFFFAOYSA-N 2-(2-methoxyethoxy)ethanol Chemical compound COCCOCCO SBASXUCJHJRPEV-UHFFFAOYSA-N 0.000 description 1
- GGDYAKVUZMZKRV-UHFFFAOYSA-N 2-fluoroethanol Chemical compound OCCF GGDYAKVUZMZKRV-UHFFFAOYSA-N 0.000 description 1
- BSYNRYMUTXBXSQ-FOQJRBATSA-N 59096-14-9 Chemical compound CC(=O)OC1=CC=CC=C1[14C](O)=O BSYNRYMUTXBXSQ-FOQJRBATSA-N 0.000 description 1
- 239000005541 ACE inhibitor Substances 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
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- 241000459479 Capsula Species 0.000 description 1
- 108091006146 Channels Proteins 0.000 description 1
- 206010070954 Congenital hypercoagulation Diseases 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
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 1
- 229940123900 Direct thrombin inhibitor Drugs 0.000 description 1
- 239000004278 EU approved seasoning Substances 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 108010054218 Factor VIII Proteins 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-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
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- DOJXGHGHTWFZHK-UHFFFAOYSA-N Hexachloroacetone Chemical compound ClC(Cl)(Cl)C(=O)C(Cl)(Cl)Cl DOJXGHGHTWFZHK-UHFFFAOYSA-N 0.000 description 1
- 102000004286 Hydroxymethylglutaryl CoA Reductases Human genes 0.000 description 1
- 108090000895 Hydroxymethylglutaryl CoA Reductases Proteins 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- OHLUUHNLEMFGTQ-UHFFFAOYSA-N N-methylacetamide Chemical compound CNC(C)=O OHLUUHNLEMFGTQ-UHFFFAOYSA-N 0.000 description 1
- 238000012565 NMR experiment Methods 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 108010051456 Plasminogen Proteins 0.000 description 1
- 102000013566 Plasminogen Human genes 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229920002730 Poly(butyl cyanoacrylate) Polymers 0.000 description 1
- 229930182556 Polyacetal Natural products 0.000 description 1
- 229920000331 Polyhydroxybutyrate Polymers 0.000 description 1
- 206010058046 Post procedural complication Diseases 0.000 description 1
- 208000035965 Postoperative Complications Diseases 0.000 description 1
- 208000002787 Pregnancy Complications Diseases 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 108010094028 Prothrombin Proteins 0.000 description 1
- 102100027378 Prothrombin Human genes 0.000 description 1
- 102000012479 Serine Proteases Human genes 0.000 description 1
- 108010022999 Serine Proteases Proteins 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical group [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 108010023197 Streptokinase Proteins 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- 108090000373 Tissue Plasminogen Activator Proteins 0.000 description 1
- 102000003978 Tissue Plasminogen Activator Human genes 0.000 description 1
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 description 1
- 238000006058 Ugi-reaction Methods 0.000 description 1
- 102000003990 Urokinase-type plasminogen activator Human genes 0.000 description 1
- 108090000435 Urokinase-type plasminogen activator Proteins 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 239000003741 agents affecting lipid metabolism Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 239000004411 aluminium Substances 0.000 description 1
- 229920000469 amphiphilic block copolymer Polymers 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000036783 anaphylactic response Effects 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 239000012296 anti-solvent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940127088 antihypertensive drug Drugs 0.000 description 1
- 229940127218 antiplatelet drug Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
- 229960003438 aspartame Drugs 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 229940097320 beta blocking agent 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
- 239000012472 biological sample Substances 0.000 description 1
- 210000001772 blood platelet Anatomy 0.000 description 1
- 239000012928 buffer substance Substances 0.000 description 1
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical class CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229960005069 calcium Drugs 0.000 description 1
- 235000001465 calcium Nutrition 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 150000001720 carbohydrates Chemical group 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 229940063834 carboxymethylcellulose sodium Drugs 0.000 description 1
- 206010061592 cardiac fibrillation Diseases 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 238000003889 chemical engineering Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 239000004927 clay Substances 0.000 description 1
- 230000015271 coagulation Effects 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 238000011284 combination treatment Methods 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 238000007887 coronary angioplasty Methods 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 239000011549 crystallization solution Substances 0.000 description 1
- 229940109275 cyclamate Drugs 0.000 description 1
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 1
- HCAJEUSONLESMK-UHFFFAOYSA-N cyclohexylsulfamic acid Chemical compound OS(=O)(=O)NC1CCCCC1 HCAJEUSONLESMK-UHFFFAOYSA-N 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 229940087091 dichlorotetrafluoroethane Drugs 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- GUVUOGQBMYCBQP-UHFFFAOYSA-N dmpu Chemical compound CN1CCCN(C)C1=O GUVUOGQBMYCBQP-UHFFFAOYSA-N 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- ANFZRGMDGDYNGA-UHFFFAOYSA-N ethyl acetate;propan-2-ol Chemical compound CC(C)O.CCOC(C)=O ANFZRGMDGDYNGA-UHFFFAOYSA-N 0.000 description 1
- 235000010228 ethyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004403 ethyl p-hydroxybenzoate Substances 0.000 description 1
- 229940043351 ethyl-p-hydroxybenzoate Drugs 0.000 description 1
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 description 1
- 229940125753 fibrate Drugs 0.000 description 1
- 230000002600 fibrillogenic effect Effects 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 235000011194 food seasoning agent Nutrition 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 238000013467 fragmentation Methods 0.000 description 1
- 238000006062 fragmentation reaction Methods 0.000 description 1
- 238000009432 framing Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 229940006607 hirudin Drugs 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 230000001631 hypertensive effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000003055 low molecular weight heparin Substances 0.000 description 1
- 229940127215 low-molecular weight heparin Drugs 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- MBHINSULENHCMF-UHFFFAOYSA-N n,n-dimethylpropanamide Chemical compound CCC(=O)N(C)C MBHINSULENHCMF-UHFFFAOYSA-N 0.000 description 1
- 230000003533 narcotic effect Effects 0.000 description 1
- 229940097496 nasal spray Drugs 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 229920001206 natural gum Polymers 0.000 description 1
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 235000019629 palatability Nutrition 0.000 description 1
- 125000001312 palmitoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000013618 particulate matter Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 230000010118 platelet activation Effects 0.000 description 1
- 239000000106 platelet aggregation inhibitor Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 239000005015 poly(hydroxybutyrate) Substances 0.000 description 1
- 229920000656 polylysine Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 229920006324 polyoxymethylene Polymers 0.000 description 1
- 239000004810 polytetrafluoroethylene Substances 0.000 description 1
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 238000001144 powder X-ray diffraction data Methods 0.000 description 1
- 208000012113 pregnancy disease Diseases 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 229940039716 prothrombin Drugs 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 208000037803 restenosis Diseases 0.000 description 1
- 239000000837 restrainer Substances 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 210000000582 semen Anatomy 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000007873 sieving Methods 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
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 238000007614 solvation Methods 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000011146 sterile filtration Methods 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000012414 sterilization procedure Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 229960005202 streptokinase Drugs 0.000 description 1
- 230000035882 stress Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000011885 synergistic combination Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 238000009492 tablet coating Methods 0.000 description 1
- 239000002700 tablet coating Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 description 1
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 1
- 239000003868 thrombin inhibitor Substances 0.000 description 1
- 230000002537 thrombolytic effect Effects 0.000 description 1
- 229940098465 tincture Drugs 0.000 description 1
- 229960000187 tissue plasminogen activator Drugs 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 229960005356 urokinase Drugs 0.000 description 1
- 238000009777 vacuum freeze-drying Methods 0.000 description 1
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 1
- FGQOOHJZONJGDT-UHFFFAOYSA-N vanillin Natural products COC1=CC(O)=CC(C=O)=C1 FGQOOHJZONJGDT-UHFFFAOYSA-N 0.000 description 1
- 235000012141 vanillin Nutrition 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
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
- C07D401/14—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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0043—Nose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4816—Wall or shell material
- A61K9/4825—Proteins, e.g. gelatin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Dermatology (AREA)
- Otolaryngology (AREA)
- Pulmonology (AREA)
- Urology & Nephrology (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Vascular Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Compounds Of Unknown Constitution (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本发明提供了(S,E)-4-(2-(3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酰基)-5-(4-甲基-2-氧代哌嗪-1-基)-1,2,3,4-四氢异喹啉-1-甲酰胺基)苯甲酸的晶型和其溶剂化物;生产该晶型的方法;包含该晶型的药物组合物;和使用该晶型或该药物组合物治疗血栓栓塞性病症的方法。
Description
发明领域
本发明涉及(S,E)-4-(2-(3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酰基)-5-(4-甲基-2-氧代哌嗪-1-基)-1,2,3,4-四氢异喹啉-1-甲酰胺基)苯甲酸的晶型和其溶剂化物,其生产方法,其药物组合物,以及使用其治疗血栓栓塞性病症的方法。
发明背景
因子XIa是参与调节血液凝固的血浆丝氨酸蛋白酶,其在体内通过使组织因子(TF)与因子VII(FVII)结合以产生因子VIIa(FVIIa)来起始。所得TF:FVIIa复合物活化因子IX(FIX)及因子X(FX)以产生因子Xa(FXa)。所生成的FXa催化凝血酶原转变成少量凝血酶,之后此途径被组织因子途径抑制剂(TFPI)关闭。然后凝血过程经由催化量的凝血酶对因子V、VIII及XI的反馈活化进一步扩散。(Gailani,D.et al,Arterioscler.Thromb.Vasc.Biol.,27:2507-2513(2007))所得凝血酶爆发物将纤维蛋白原转化成纤维蛋白(该纤维蛋白发生聚合以形成血块的结构框架),且活化作为凝血关键细胞组分的血小板(Hoffman,M.,Blood Reviews,17:S1-S5(2003))。因此,因子XIa在此扩增环的扩散中发挥关键作用且因此是抗血栓形成疗法的具有吸引力的靶标。
WO 2013/056060(其在此引入作为参考),公开了一种XIa抑制剂(S,E)-4-(2-(3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酰基)-5-(4-甲基-2-氧代哌嗪-1-基)-1,2,3,4-四氢异喹啉-1-甲酰胺基)苯甲酸(下文称为“化合物(I)”):
其用于预防或治疗血栓栓塞性病症。
上述病症的治疗或预防可通过向有此治疗或预防需要的人或动物受试者给予治疗有效量的化合物(I)来实现。使用化合物(I)的治疗可通过将其用作单一化合物,用作药物组合物成分,或与其它治疗剂组合来实现。化合物(I)可通过口服给药,连续静脉输注,快速静脉给药或任何其它适合的途径来给药,从而使其更好的实现所需的作用:预防自凝血酶原的因子XIa诱导的凝血酶形成。
此前并不知道化合物(I)晶型的存在。因此,存在可展现期望的且有益的化学和物理性质的晶型的需求。还存在可靠的且可重复的制备、纯化和配制化合物(I)的方法的需求以使其可商业化。本发明涉及这些方面以及其它重要方面。
发明概述
本发明提供化合物(I)的晶型,生产该形式的方法;包含该形式的药物组合物;和使用该晶型或该药物组合物治疗血栓栓塞性病症的方法。这些晶型的实施方案包括本文描述的晶型H.5-1、P13和HCl:SA-1。本文用于表征特定形式的名称,例如“P13”等,不应当被认为受限于具有类似或相同物理和化学特性的任何其它物质,而应当理解这些名称仅仅是标识,其应当根据本文呈现的表征信息来解释。
根据下文的详细说明,本发明的这些和其它方面将变得更为清楚。
附图简介
通过参照下文所述的附图解释本发明。
图1显示(S,E)-4-(2-(3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酰基)-5-(4-甲基-2-氧代哌嗪-1-基)-1,2,3,4-四氢异喹啉-1-甲酰胺基)苯甲酸的晶型HCl:SA-1的观测的和计算的(室温)粉末X-射线衍射图
图2显示(S,E)-4-(2-(3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酰基)-5-(4-甲基-2-氧代哌嗪-1-基)-1,2,3,4-四氢异喹啉-1-甲酰胺基)苯甲酸的晶型H.5-1的观测的和计算的(室温)粉末X-射线衍射图
图3显示(S,E)-4-(2-(3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酰基)-5-(4-甲基-2-氧代哌嗪-1-基)-1,2,3,4-四氢异喹啉-1-甲酰胺基)苯甲酸的晶型P13的观测的粉末X-射线衍射图
图4为(S,E)-4-(2-(3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酰基)-5-(4-甲基-2-氧代哌嗪-1-基)-1,2,3,4-四氢异喹啉-1-甲酰胺基)苯甲酸的晶型HCl:SA-1的差示扫描量热法热谱图。
图5为(S,E)-4-(2-(3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酰基)-5-(4-甲基-2-氧代哌嗪-1-基)-1,2,3,4-四氢异喹啉-1-甲酰胺基)苯甲酸的晶型P13的差示扫描量热法热谱图。
图6为(S,E)-4-(2-(3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酰基)-5-(4-甲基-2-氧代哌嗪-1-基)-1,2,3,4-四氢异喹啉-1-甲酰胺基)苯甲酸的晶型H.5-1的差示扫描量热法热谱图。
图7为(S,E)-4-(2-(3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酰基)-5-(4-甲基-2-氧代哌嗪-1-基)-1,2,3,4-四氢异喹啉-1-甲酰胺基)苯甲酸的晶型HCl:SA-1的热重分析热谱图。
图8为(S,E)-4-(2-(3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酰基)-5-(4-甲基-2-氧代哌嗪-1-基)-1,2,3,4-四氢异喹啉-1-甲酰胺基)苯甲酸的晶型P13的热重分析热谱图。
图9为(S,E)-4-(2-(3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酰基)-5-(4-甲基-2-氧代哌嗪-1-基)-1,2,3,4-四氢异喹啉-1-甲酰胺基)苯甲酸的晶型H.5-1的热重分析热谱图。
图10为(S,E)-4-(2-(3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酰基)-5-(4-甲基-2-氧代哌嗪-1-基)-1,2,3,4-四氢异喹啉-1-甲酰胺基)苯甲酸的晶型P13的C-13CPMASA谱图。旋转边带标记为“ssb”。
图11为(S,E)-4-(2-(3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酰基)-5-(4-甲基-2-氧代哌嗪-1-基)-1,2,3,4-四氢异喹啉-1-甲酰胺基)苯甲酸的晶型P13的F-19CPMAS谱图(质子去偶联)。旋转边带被标记并通过改变旋转速度确认。
发明详述
本发明(至少部分地)提供了化合物(I)的晶型作为新物质,尤其是其药学上可接受的形式。本文使用的术语“药学上可接受的”指的是在正确的医学判断范围内适于与人类和动物组织接触而无过度毒性、刺激、过敏反应或其它并发症、具有合理的受益/风险比的那些化合物、物质、组合物,和/或剂型。在一些优选实施方案中,化合物(I)为基本上纯的形式。本文使用的术语“基本上纯的”是指基于化合物的重量,具有纯度为大于约90%包括大于90、91、92、93、94、95、96、97、98和99重量%,也包括等于约100重量%化合物(I)的化合物。其它物质包括该化合物的其它形式,和/或反应杂质和/或其制备中出现的加工杂质。例如,根据本领域此时已知且通用的手段测量,若化合物(I)的晶型纯度大于90重量%,则其被视为基本上纯的,其中剩余的少于10%的物质包括化合物的(I)的其它形式和/或反应杂质和/或加工杂质。
本申请所使用的“多晶型物”是指具有相同化学组成但是形成晶体的分子和/或离子的空间排列不同的晶型。
本文所使用的“溶剂化物”是指进一步包含一种或多种溶剂分子掺入至结晶结构的分子和/或离子的晶型。溶剂化物中的溶剂分子可以规则的排列和/或无序排列存在。溶剂化物可包含化学计量量或非化学计量量的溶剂分子。例如,具有非化学计量量的溶剂分子的溶剂化物可自溶剂化物的溶剂部分丢失生成。
本文所使用的“无定形”是指非结晶的分子和/或离子的固体形式。无定形固体不会显示具有尖锐峰值的X射线衍射图。
可使用通常指定为美国专利申请61/547,292中教导的方法制备化合物(I),其公开内容整体引入本文作为参考。在下文的方案中,化合物(II)通过Ugi反应获得(Schuster,I.et al.(Letters in Organic Chemistry,4(2):102-108(2007))。化合物(II)脱保护得到化合物(I)。
可提供具有基本上纯的相均匀性的晶型的样品,表明存在支配量的单一晶型和任选少量的一种或多种其它晶型。样品中多于一种晶型的存在可通过技术如粉末X-射线衍射(PXRD)或固态核磁共振光谱(SSNMR)测定。例如,在实验测量的PXRD图与模拟的PXRD图的比较中,附加峰的存在可指示样品中有多于一种晶型。模拟的PXRD可自单一晶体X-射线数据计算得到。见Smith,D.K.,A FORTRAN Program for Calculating X-Ray Powder DiffractionPatterns,Lawrence Radiation Laboratory,Livermore,California,UCRL-7196(April 1963)。优选的晶型具有基本上纯的相均匀性,如在实验测量的PXRD图中的总峰面积中,模拟的PXRD图中不存在的附加峰的面积少于10%,优选少于5%,更优选少于2%所指示的。更优选的晶型具有基本上纯的相均匀性,在实验测量的PXRD图的总峰面积中,模拟的PXRD图中不存在的附加峰的面积少于1%。
晶型可通过多种方法制备,包括例如,自适宜的溶剂结晶或重结晶,升华,自熔体生长,自另一相的固态转变,自超临界流体的结晶,和喷射喷雾。晶型自溶剂混合物的结晶或重结晶的技术包括,例如,蒸发溶剂,降低溶剂的温度,晶体接种该分子和/或盐的过饱和溶剂混合物,冷冻干燥溶剂混合物,和向溶剂混合物中添加抗溶剂(反溶剂)。可采用高通量结晶技术制备晶型,包括多晶型物。
药物的晶体,包括多晶型物,制备方法和药物晶体的表征在Byrn,S.R.etal.,Solid-State Chemistry of Drugs,Second Edition,SSCI,West Lafayette,Indiana(1999)中有所讨论。
对于采用溶剂的结晶技术,溶剂的选择通常取决于一种或多种因素,如化合物的溶解度、结晶技术和溶剂的蒸汽压。可采用溶剂的组合,例如,可将化合物溶解于第一溶剂以形成溶液,然后添加抗溶剂以降低化合物在溶液中的溶解度并形成晶体。抗溶剂是一种化合物在其中具有低溶解度的溶剂。适宜的制备晶体的溶剂包括极性和非极性溶剂。
在一种制备晶体的方法中,将化合物(I)悬浮和/或搅拌于适宜的溶剂中以得到浆液,其可被加热以促进溶解。本文所用的术语“浆液”是指在给定温度下化合物(I)和溶剂的饱和溶液。在这点上,适宜的溶剂包括,例如极性非质子溶剂、极性质子溶剂、非极性溶剂和两种或多种这些溶剂的混合物。
适宜的极性非质子溶剂包括,例如,二氯甲烷(CH2Cl2或DCM)、四氢呋喃(THF)、丙酮、甲基乙基酮(MEK)、二甲基甲酰胺(DMF)、二甲基乙酰胺(DMAC)、1,3-二甲基-3,4,5,6-四氢-2(1H)-嘧啶酮(DMPU)、1,3-二甲基-2-咪唑烷酮(DMI)、N-甲基吡咯烷酮(NMP)、甲酰胺、N-甲基乙酰胺、N-甲基甲酰胺、乙腈(CAN或MeCN)、二甲亚砜(DMSO)、丙腈、甲酸乙酯、乙酸甲酯(MeOAc)、乙酸乙酯(EtOAc)、乙酸异丙酯(IpOAc)、乙酸丁酯(BuOAc)、乙酸叔丁酯、六氯丙酮、二噁烷、环丁砜、N,N-二甲基丙酰胺、硝基甲烷、硝基苯和六甲基磷酰胺。
适宜的极性质子溶剂包括,例如醇类和二醇类,如H2O、甲醇、乙醇、1-丙醇、2-丙醇、异丙醇(IPA)、1-丁醇(1-BuOH)、2-丁醇(2-BuOH)、异丁醇、叔丁醇、2-硝基乙醇、2-氟乙醇、2,2,2-三氟乙醇、乙二醇、2-甲氧基乙醇、2-乙氧基乙醇、二乙二醇、1-、2-或3-戊醇、新戊醇、叔戊醇、二乙二醇单甲基醚、二乙二醇单乙基醚、环己醇、苄醇、苯酚、甘油和甲基叔丁基醚(MTBE)。
优选的溶剂包括,例如丙酮、H2O、CH2Cl2、甲醇、乙醇、MEK、IPA和EtOAc。
除上述示例的溶剂外,基于本发明公开的内容,适于制备化合物(I)的浆液的其它溶剂对于本领域技术人员而言是清楚的。
种晶可被添加至任何结晶混合物中以促进结晶。技术人员清楚,接种被用作控制特定晶型生长的手段或控制结晶产物粒径分布的手段。因此,所需的晶种量的计算取决于可得到的晶种的大小和期望的平均产物颗粒的大小,例如"Programmed cooling of batch crystallizers",Mullin,J.W.et al.,ChemicalEngineering Science,26:369-377(1971)中所述。通常,需要小尺寸的晶种以有效地控制批次中晶体的生长。小尺寸的晶种可通过较大晶体的过筛,碾磨或微粉化形成,或通过溶液的微结晶生成。应当注意晶体的碾磨或微粉化不导致所需晶型结晶度的任何变化或形式转变(即,变成无定形或其它多晶型物)。
冷却的混合物可在真空下过滤,并且分离的固体可用适宜的溶剂如冷的重结晶溶剂洗涤,在氮气排气下干燥得到所需晶型。分离的固体可通过适宜的分光镜或分析型技术如SSNMR、DSC、PXRD等分析以确保产物优选晶型的形成。所得晶型通常以大于约70重量%分离收率,优选以大于90重量%的量生成,基于结晶操作中初始采用的化合物(I)的重量。如果需要,产物可被共研磨(comilled)或通过网筛将产物去块。
晶型可从制备化合物(I)的最终处理步骤的反应介质中直接制备。这可通过,例如在最终处理步骤中采用化合物(I)可从其中结晶的溶剂或溶剂混合物。或者,晶型可通过蒸馏或溶剂添加技术获得。适于此目的的溶剂包括任何本文所述的那些溶剂,包括极性质子溶剂如醇,和非质子极性溶剂如酮。
根据通用指导,可将反应混合物过滤以除去任何不期望的杂质,无机盐等,然后用反应或结晶溶剂洗涤。可将所得溶液浓缩以除去过量溶剂或气体成分。如果采用蒸馏,收集的最终蒸馏物的量是可变的,取决于处理因素,包括,例如容器大小,搅拌能力等,根据通用指导,反应溶液可被蒸馏至约初始体积的{分数(1/10)},然后进行溶剂置换。根据标准处理技术,可将反应取样并分析仪测定反应的程度和产物的重量%。如果需要,可添加额外的反应溶剂或除去额外的反应溶剂以最优化反应浓度。优选地,最终浓度调整至约50重量%,在此浓度通常形成浆液。
直接向反应容器中添加溶剂而不蒸馏反应混合物可能是优选的。用于该目的的优选溶剂为可最终参与晶格的那些,如上述关于溶剂交换所讨论的。尽管最终浓度根据所需纯度、回收等是可变的,但溶液中化合物(I)的最终浓度优选为约4%至约7%。可将反应混合物搅拌,然后添加溶剂并同时温热。通过解释,可将反应混合物搅拌约1h同时温热至约70℃。反应优选被热过滤并用反应溶剂、所添加的溶剂或其组合来洗涤。可向任何结晶溶液中添加种晶以启动结晶。
本文所述的各种形式可通过使用本领域普通技术人员已知的各种分析技术来彼此区别。此类技术包括,但不限于固态核磁共振(SSNMR)光谱、X-射线粉末衍射(PXRD)、差示扫描量热法(DSC)和/或热重分析(TGA)。
本领域技术人员应当理解可获得具有测量误差的X-射线衍射图,其取决于所采用的测量条件。具体地,众所周知X-射线衍射图的强度波动可取决于所采用的测量条件。应当进一步理解相对强度也可根据实验条件而变化,相应地,确切的强度等级不应考虑在内。此外,对于常规X-射线衍射图,衍射角的测量误差通常为约5%或更小,且由于与上文提及的衍射角有关,此程度的测量误差应当考虑在内。因此,应当理解本发明的晶型不限于提供与本文公开的附图中所述的X-射线衍射图完全相同的X-射线衍射图的晶型。任何提供与附图中公开的X-射线衍射图基本上相同的X-射线衍射图的晶型均落在本发明的范围内。确定X-射线衍射图基本上相同的能力在本领域普通技术人员的能力范围内。
在本发明的一方面,化合物(I)的晶型H.5-1可通过基本上与以下相同的晶胞参数表征:
晶胞参数:
α=90°
β=90°
γ=90°
空间群:I2(1)2(1)2(1)
分子/不对称单元:1
密度(计算值):1.401Mg/m3
其中晶型的测量温度为约23℃。
在一个不同方面,晶型H.5-1可通过基本上如表1所列的分数原子坐标来表征。
在一个不同的方面,晶型H.5-1可在室温通过包含以下2θ值 的粉末X-射线衍射图来表征:5.9、7.2、12.0、15.7、17.2、18.9、20.3、24.2和26.1。
在另一方面,化合物(I)的晶型HCI:SA-1可通过基本上与以下相同的晶胞参数来表征:
晶胞参数:
α=90°
β=90°
γ=90°
空间群:P2(1)2(1)2(1)
分子/不对称单元:1
密度(计算值):1.368Mg/m3
其中晶型的测量温度为约23℃。
在一个不同方面,晶型HCI:SA-1可通过基本上如表2所列的分数原子坐标来表征。
在一个不同方面,晶型HCI:SA-1可在室温通过包含以下2θ值 的粉末X-射线衍射图来表征:6.0、8.3、8.7、12.3、16.2、16.7、17.5、19.9和20.4。
在本发明的另一方面,化合物(I)的晶型P13可通过包含以下2θ值 的粉末X-射线衍射图来表征:8.4、8.9、12.7和17.9。
本文所述的化合物(I)的晶型可被调配成药物组合物和/或用于治疗性和/或预防性方法中。这些方法包括,但不限于,单独或与一种或多种其它药学活性剂组合给予结晶化合物(I),所述药学活性剂包括可用于治疗本文提及的病症的药剂。
“治疗有效量”意欲包括当单独或组合给药能有效抑制因子XIa的化合物(I)的晶型的量。如果化合物(I)与另一药物组合使用,本文所述的化合物的组合可生成协同组合。当组合给药时化合物的作用大于作为单一药剂单独给药时化合物的相加作用时,则发生例如Chou et al.,Adv.Enzyme Regul.,22:27-55(1984)中所述的协同作用。通常,协同作用在化合物的次最佳浓度被最清楚地证明。与单独的组分相比,协同作用可与更低的细胞毒性、增加抗血栓形成作用或该组合的一些其它的有益效果相关。
本文所用的“治疗”涵盖在哺乳动物中,尤其是在人中,治疗疾病状态,且包括:(a)预防疾病状态在哺乳动物中发生,尤其是当该哺乳动物易于罹患该疾病状态但尚未诊断患有该疾病状态时;(b)抑制该疾病状态,即阻碍其发展;和/或(c)缓解该疾病状态,即,引起该疾病状态消退。
化合物(I)的晶型和其药物组合物可用于抑制因子XIa。因此,本发明提供了在哺乳动物中治疗和/或预防血栓栓塞性病症(即,因子XIa相关的病症)的方法。通常,血栓栓塞性病症为由血块引起的循环疾病(即涉及纤维蛋白形成、血小板活化和/或血小板聚集的疾病)。本文所用的术语“血栓栓塞性病症”包括动脉心血管血管栓塞性病症、静脉心血管血管栓塞性病症和心腔的血管栓塞性病症。本文所用的术语“血管栓塞性病症”还包括选自但不限于不稳定性心绞痛或其它急性冠脉综合症、心房纤颤、心肌梗死的首次发作或复发、缺血性猝死、短暂性脑缺血发作、卒中、动脉粥样硬化、外周动脉闭塞性疾病、静脉血栓形成、深静脉血栓形成、血栓静脉炎、动脉栓塞、管状动脉血栓形成、脑动脉血栓形成、脑栓塞、肾栓塞、肺栓塞和由以下原因导致的血栓形成:(a)人工瓣膜或其它移植物,(b)留置导管,(c)支架,(d)心肺转流术,(e)血液透析,或(f)其中血液暴露于促进血栓形成的人工表面的其它操作。应当注意血栓形成包括闭塞(例如,在转流术后)和再闭塞(例如,在经皮腔内冠状动脉成形术过程中或之后)。血栓栓塞性病症可由以下病症导致,包括但不限于动脉粥样硬化,手术或手术并发症,长期不活动,动脉纤维化,先天性血栓形成倾向,癌症、糖尿病,药物或激素的作用,和妊娠并发症。据信本发明化合物的抗凝血作用是由于抑制因子XIa或凝血酶。
该方法优选地包括向患者给予药学有效量的本发明的新型晶体,优选与一种或多种药学上可接受的载体和/或赋形剂组合。活性成分与载体和/或赋形剂的相对比例可例如由该物质的溶解度和化学性质、所选的给药途径和标准制药规范来确定。
化合物(I)的晶型可以口服剂型如片剂、胶囊剂(每一胶囊包括缓释制剂或定时释放制剂)、丸剂、散剂、颗粒剂、酏剂、酊剂、混悬剂、糖浆剂和乳剂。它们也可以静脉(推注或输注)、腹膜内、皮下或肌肉内形式给药,所有给药方式均使用药学领域普通技术人员熟知的剂型。它们可单独给药,但通常与基于所选给药途径和标准制药规范而选择的药学载体一起给药。
当然,化合物(I)的晶型的剂量方案根据以下已知的因素而变化:如特定药剂的药代动力学特性和给药方式和途径;接受者的种类、年龄、性别、健康、医疗状况和体重;症状的性质和程度;共存治疗的种类;治疗频率;给药途径,患者的肾功和肝功,和所需的效果。医师或兽医可确定并开具预防、抗衡或阻碍血栓栓塞性病症进展所需的有效量的药物。显然,在约同一时间可给药数个单位剂型。最适于预防或治疗的化合物(I)的晶型的剂量可随给药形式、所选的化合物的特定晶型和在治疗下特定患者的生理学特性而变化。一般来说,可首次使用小剂量,如果需要小幅度增加直至达到在该情况下所需的效果。
根据通用指导,在成人中,适宜剂量的范围可在约0.001至约1000mg/Kg体重,和所有的范围和其中特定剂量的组合和亚组合。优选剂量可为约0.01至约100mg/kg体重,每天,吸入;优选0.1至70,更优选0.5至20mg/Kg体重,每天,口服给药;和约0.01至约50,优选0.01至10mg/Kg体重,每天,静脉给药。在各个特定案例中,剂量可根据因待治疗的受试者如年龄、体重、一般健康状况和其它可能影响药物产品疗效的特性而不同的因素来确定。化合物(I)的晶型可以单一日剂量给药,或者总日剂量可以分剂量每日2、3或4次给药。
对于以固体形式如片剂或胶囊剂口服给药,化合物(I)的晶型可与非毒性、药学上可接受的惰性载体组合,所述惰性载体如乳糖、淀粉、蔗糖、葡萄糖、甲基纤维素、硬脂酸镁、磷酸二钙、硫酸钙、甘露醇、山梨醇等。
优选地,除了活性成分之外,固体剂型可包含多种在本文称为“赋形剂”的其它成分。这些赋形剂中包括稀释剂,粘合剂,润滑剂,助流剂和崩解剂。还可引入着色剂。本文中使用的“稀释剂”是赋予制剂以体积从而制造具有用于压缩的实用大小的片剂。稀释剂的实例是乳糖和纤维素。本文中使用的“粘合剂”是用于赋予粉状材料以内聚性从而帮助确保片剂在压缩后仍完好无损,并改善粉末的自由流动性。典型的粘合剂的实例是乳糖,淀粉和多种糖。本文中使用的“润滑剂”具有数种功能,包括防止片剂粘着于压缩设备并改善颗粒在压缩或封装前的流动。润滑剂在大多数情况下是疏水性材料。然而,不希望过度使用润滑剂,因为其可导致制剂的药物物质的崩解下降和/或溶出延迟。本文中使用的“助流剂”是指可改善颗粒物质的流动特性的物质。助流剂的实例包括滑石和胶体二氧化硅。本文中使用的“崩解剂”是被添加到制剂中用于促进固体剂型在给药后的破碎或崩解的物质或物质的混合物。可用作崩解剂的材料包括淀粉,粘土,纤维素,藻酸,树胶和交联聚合物。在固体剂型中通常使用低浓度的,通常相对于剂量单位的总重量为1重量%至10重量%的被称为“超级崩解剂”的一组崩解剂。交联羧甲基纤维素,交联聚维酮和羟基乙酸淀粉钠分别代表交联纤维素,交联聚合物和交联淀粉的实例。羟基乙酸淀粉钠在不到30秒内膨胀7-12倍,有效地使包含其的颗粒崩解。
本发明中优选使用的崩解剂选自改性淀粉,交联羧甲基纤维素钠,羧甲基纤维素钙和交联聚维酮。本发明中更优选的崩解剂是改性淀粉如羟基乙酸淀粉钠。
优选的载体包括包含本文所述的固体药物剂型的胶囊或压缩片。优选的胶囊或压缩片形式通常包含治疗有效量的化合物(I)的晶型和一种或多种含量大于约10重量%(相对于胶囊内容物的总重量或片剂总重量)的崩解剂。
优选的胶囊制剂可包含每粒胶囊约5到约1000毫克的量的化合物(I)的晶型。优选的压缩片制剂可包含每个压缩片约5到约800毫克的量的化合物(I)的晶型。更优选的制剂包含每粒胶囊或压缩片约50到约200毫克。优选地,胶囊或压缩片药物剂型包括治疗有效量的化合物(I)的晶型;表面活性剂;崩解剂;粘合剂;润滑剂;和任选的另外的可药用赋形剂,诸如稀释剂,助流剂等;其中崩解剂选自改性淀粉;交联羧甲纤维素钠;羧甲基纤维素钙和交联聚维酮。
对于液体形式的口服给药,化合物(I)的晶型可与任何的口服无毒性的可药用惰性载体如乙醇、甘油、水等组合。液体组合物可包含使组合物更可口的甜味剂。甜味剂可选自糖,如蔗糖,甘露醇,山梨醇,木糖醇,乳糖等,或糖替代品,如环拉酸盐,糖精,阿斯巴甜等。如果糖替代品被选作甜味剂,则本发明组合物中的使用量将实质上低于如果使用的糖的量。考虑到这些,甜味剂的量可为约0.1到约50重量%,以及其中的范围和特定量的所有组合和亚组合。优选的量的范围为约0.5到约30重量%。
更优选的甜味剂是糖类,特别是蔗糖。已经发现所用的蔗糖粉末的粒径对最终组合物的物理性质及其最终可接受的味道有显著影响。当使用蔗糖组分时,其优选的粒径的范围为200目到低于325目美国标准筛,以及其中的范围和特定粒径的组合和亚组合。
无菌可注射溶液可通过将要求量的化合物(I)的晶型,如果需要还有本文列举的多种其它成分,合并到适当的溶剂中,然后进行过滤灭菌制备。通常,可将经灭菌的活性成分掺入到无菌的媒介物中制备分散剂,所述无菌媒介物含有分散介质和任何的其它所需组分。在用于制备无菌可注射溶液的无菌粉末的情况下,优选的制备方法可包括真空干燥和冻干技术,其可得到活性成分的粉末,加上得自先前经无菌过滤的溶液的任何另外的所需组分。
对于本领域普通技术人员显而易见的是,一旦获悉本公开的教导,当溶解时,化合物(I)丧失其晶体结构,并因此被认为是化合物(I)的溶液。然而,本发明的所有形式可用于制备化合物(I)在其中例如可被溶解或悬浮的液体制剂。另外,化合物(I)的晶型可被引入到固体制剂中。
液体组合物还可包含在配制药物组合物中常用的其它组分。这种组分的一个实例是卵磷脂。其在本发明组合物中用作乳化剂,含量为0.05到1重量%,和其中的范围和特定量的所有组合和再组合。更优选地,乳化剂可使用的量为约0.1到约0.5重量%。可用的组分的其它实例是抗菌性防腐剂,如苯甲酸或对羟基苯甲酸酯类;助悬剂,如胶体二氧化硅;抗氧化剂;局部口服麻醉剂;调味剂;和着色剂。
这些任选组分的选择以及它们在本发明组合物中的用量处在本领域技术人员水平的范围内,并且可从以下提供的工作实施例中得以更好的理解。
化合物(I)的晶型还可与作为可靶向于目标的药物载体的可溶性聚合物结合。这些聚合物可包括聚乙烯吡咯烷酮吡喃共聚物,聚羟基丙基甲基丙烯酰胺-苯酚,聚羟乙基-天冬酰胺苯酚或被棕榈酰基残基取代的聚氧乙烯-聚赖氨酸。此外,结晶化合物(I)可与用于实现药物控释的一类生物可降解的聚合物结合,所述聚合物例如,聚乳酸,聚乙醇酸,聚乳酸和聚乙醇酸的共聚物,聚ε-己内酯(polyepsilon caprolactone),聚羟基丁酸,聚原酸酯,聚缩醛,聚二氢吡喃,聚氰基丙烯酸酯和水凝胶的交联或两性嵌段共聚物。
化合物(I)的晶型的明胶胶囊可包含结晶化合物(I)和本文所述的液体或固体组合物。明胶胶囊还可包含粉状载体,如乳糖,淀粉,纤维素衍生物,硬脂酸镁,硬脂酸等。类似的稀释剂可用于制备压缩片。片剂和胶囊都可制备成为持续释放产品以在一定时段内提供药物的持续释放。片剂可被糖包衣或薄膜包衣,以掩蔽任何令人讨厌的味道,并用于保护片剂以免受到大气的破坏,或者片剂可被肠溶包衣,用于在胃肠道内选择性崩解。
通常,水、适当的油、盐水、含水右旋糖(葡萄糖)、和相关的糖溶液和二醇类例如丙二醇或聚乙二醇是用于胃肠外溶液的适当载体。用于胃肠外溶液的溶液可通过将结晶化合物(I)溶于载体,并且如有必要添加缓冲物质制备。抗氧化剂例如亚硫酸氢钠,亚硫酸钠或抗坏血酸,其单独或组合,是适当的稳定剂。还可使用柠檬酸及其盐和EDTA钠。胃肠外溶液还可包含防腐剂如苯扎氯铵,对羟基苯甲酸甲酯或对羟基苯甲酸乙酯,和三氯叔丁醇。
适当的药物载体描述在Remington’s Pharmaceutical Sciences,MackPublishing Co.中,该公开全文并入本文作为参考。用于本发明化合物给药的有用的药物剂型可解释如下:
胶囊
可通过将标准两片硬明胶胶囊填充100mg粉状活性成分(即,因子XIa抑制剂),150mg乳糖,50mg纤维素和6mg硬脂酸镁制备大量单位胶囊。
软明胶胶囊
可制备活性成分在可消化油如大豆油、棉籽油或橄榄油中的混合物并通过容积式泵注射至明胶中以形成含有100mg活性成分的软明胶胶囊。然后将胶囊洗涤并干燥。
片剂
可通过常规操作制备大量片剂从而使得剂量单位为100mg活性成分,0.2mg胶体二氧化硅,5mg硬脂酸镁,275mg微晶纤维素,11mg淀粉和98.8mg乳糖。可应用适当的包衣以增加适口性或延迟吸收。
混悬剂
可制备水性混悬剂用于口服给药从而使得每5ml含有25mg细分活性成分,200mg羧甲基纤维素钠,5mg苯甲酸钠,1.0g山梨醇溶液(U.S.P.)和0.025mg香草醛。
注射液
适于注射给药的胃肠外组合物可通过将1.5重量%的活性成分在10体积%的丙二醇和水中搅拌制备。该溶液通过常用技术灭菌。
鼻喷雾剂
制备水性溶液从而使得每1mL含有10mg活性成分,1.8mg对羟基苯甲酸甲酯,0.2mg对羟基苯甲酸丙酯和10mg甲基纤维素。将溶液分配至1mL小瓶中。
肺吸入剂
制备活性成分在聚山梨酯80中的均质混合物从而使得活性成分的终浓度为每容器10mg且聚山梨酯80的终浓度为1重量%。将混合物分配至各容器中,将阀门拧到容器上,并在压力下添加需要量的二氯四氟乙烷。
优选的化合物(I)的晶型可作为本发明的组分(a)且可独立地为任何剂型,如上文所述的那些,也可以多种组合给药,如上文所述。在以下说明中,应理解组分(b)代表一种或多种本文所述的适于组合疗法的药剂。
因此,化合物(I)的晶型可单独使用或与其它诊断剂、抗凝剂、抗血小板剂、溶纤维蛋白剂、抗血栓形成剂和/或纤溶酶原剂。例如,因子XIa抑制剂和标准肝素、低分子量肝素、直接凝血酶抑制剂(即,水蛭素)、阿司匹林、纤维蛋白原受体拮抗剂、链激酶、尿激酶和/或组织纤溶酶原激活剂的辅助给药可改善抗血栓形成或溶栓疗效或效率。可给药本文所述的晶体以治疗多种动物如灵长类(包括人,羊,马,牛,猪,狗,大鼠和小鼠)中的血栓并发症。因子XIa的抑制不仅可用于患有血栓病症的个体的抗凝疗法,而且可用于当需要抑制血液凝固的时候,从而预防所保存的全血的凝固并预防其它用于测试或保存的生物样品的凝固。因此,任何因子XIa抑制剂,包括本文所述的化合物(I)的晶型,可被添加至含有或疑似含有因子XIa和其中需要其抑制血液凝固的基质中,或将其与含有或疑似含有因子XIa和其中需要其抑制血液凝固的基质接触。
化合物(I)的晶型可与任何抗高血压药或胆固醇或脂质调节剂组合使用,或在治疗再狭窄、动脉粥样硬化或高血压中同时施用。可用于与本发明的化合物(I)的新形势组合治疗高血压的药剂的一些实例包括,例如,以下类型的化合物:β-阻滞剂,ACE抑制剂,钙通道拮抗剂和α-受体拮抗剂。可用于与本发明的化合物组合治疗升高的胆固醇水平或失调的脂质水平的药剂的一些实例包括已知的HMGCoA还原酶抑制剂化合物,或贝特类化合物。
因此,本发明的组分(a)和(b)可一起配制成单一剂量单位(即,在一个胶囊、片剂、散剂或液体制剂等中混合在一起),作为组合产品。当组分(a)和(b)不一起配制成单一剂量单位时,组分(a)可与组分(b)在同一时间给药或以任意顺序给药;例如,可首先给予本发明的组分(a),然后给予组分(b),或它们可以相反的顺序给药。如果组分(b)含有多于一种药剂,则这些药剂可一起给药或以任意顺序给药。当不在同一时间给药时,优选组分(a)和(b)的给药间隔小于约1小时。优选地,组分(a)和(b)的给药途径为口服。尽管,更优选组分(a)和组分(b)以相同的途径(即,例如,均为口服)或剂型给药,但是如果需要,它们可各自以不同途径(即,例如,组合产品的一种组分可口服给药,而另一组分可静脉给药)或剂型给药。
可用于治疗各种病症,且在一个或多个无菌容器中含有治疗有效量的包含化合物(I)的新形式的药物组合物,也在本发明的范围内。该试剂盒可进一步包含常规药物试剂盒组分,一旦获悉本发明的公开内容,其对于本领域技术人员而言是容易清楚的。容器的灭菌可使用本领域技术人员熟知的常规灭菌方法进行。
本发明在以下实施例中进一步描述。所有实施例均为实例。这些实施例不应解释为限制本发明权利要求的范围。
实施例
实施例1
单一晶型H.5-1和HCl:SA-1的制备
晶型H.5-1和HCl:SA-1的单一晶体X-射线测量
在具有MicroStarH generator的Bruker AXS APEX II衍射仪上使用Cu Kα辐射收集单一晶体X-射线数据。使用APEX2软件套组(BrukerAXS,Inc.,Madison,Wisconsin,USA)进行测量的X-射线强度数据的索引和处理。通过直接方法解析结构并使用SHELXTL crystallographic package(BrukerAXS,Inc.,Madison,Wisconsin,USA)基于所观测的反射精修。通过全矩阵最小二乘法精修衍生的原子参数(坐标和温度因子)。精修中最小化的函数为Σw(|Fo|-|Fc|)2。R定义为Σ||Fo|-|Fc||/Σ|Fo|,而Rw=[Σw(|Fo|-|Fc|)2/Σw|Fo|2]1/2,其中w为基于所观测的强度的误差的适当的权重函数。在精修的所有阶段检查差值傅立叶图。所有非氢原子用各向异性的热位移参数精修。氢原子自具有标准键长和角度的理想几何计算并使用骑士模型(riding model)精修。
单一晶型H.5-1的制备
通过将3mg化合物(I)添加至0.7mL乙酸乙酯和甲醇溶液(1:1)中来制备晶型H.5-1(半水合物)。在室温缓慢蒸发溶液一天后获得黄色棱柱形晶体。
晶体结构数据:
晶胞参数:
α=90°
β=90°
γ=90°
晶系:斜方晶系
空间群:I2(1)2(1)2(1)
分子/不对称单元:1
密度(计算值)=1.401Mg/m3
其中晶型的测量温度为约23℃。
表1
化合物(I)H.5-1的原子坐标(x 104)和等效各向同性位移参数
x | y | z | U(eq) * | |
Cl(1) | 1142(1) | 8638(1) | 1383(1) | 89(1) |
F(1) | 1133(2) | 7271(1) | 862(1) | 67(1) |
O(1) | 1102(2) | 5533(1) | -724(1) | 52(1) |
O(2) | -779(1) | 4373(1) | 15(1) | 48(1) |
O(3) | -4534(2) | 4606(1) | -1807(1) | 62(1) |
O(4) | -3952(2) | 3964(2) | -2477(1) | 109(1) |
O(5) | 3532(2) | 3748(1) | 1408(1) | 63(1) |
N(1) | 1127(2) | 8164(1) | -968(1) | 56(1) |
N(2) | 1654(2) | 7703(2) | -1270(1) | 73(1) |
N(3) | 1416(3) | 7825(2) | -1768(2) | 91(1) |
N(4) | 759(3) | 8363(2) | -1810(1) | 97(1) |
N(5) | 1100(2) | 5019(1) | 102(1) | 35(1) |
N(6) | -311(2) | 4095(1) | -837(1) | 46(1) |
N(7) | 2057(2) | 3304(1) | 1616(1) | 43(1) |
N(8) | 2218(2) | 3810(1) | 2664(1) | 57(1) |
C(1) | 1203(2) | 8493(2) | 699(1) | 57(1) |
C(2) | 1257(2) | 9049(2) | 342(2) | 59(1) |
x | y | z | U(eq) * | |
C(3) | 1267(2) | 8920(2) | -203(2) | 54(1) |
C(4) | 1218(2) | 8232(2) | -398(1) | 46(1) |
C(5) | 1210(2) | 7639(1) | -54(1) | 41(1) |
C(6) | 1193(2) | 7804(2) | 496(1) | 49(1) |
C(7) | 593(3) | 8565(2) | -1310(2) | 81(1) |
C(8) | 1150(2) | 6900(1) | -250(1) | 42(1) |
C(9) | 1279(2) | 6305(1) | 22(1) | 45(1) |
C(10) | 1151(2) | 5598(1) | -230(1) | 38(1) |
C(11) | 947(2) | 4321(1) | -154(1) | 33(1) |
C(12) | 1229(2) | 3707(1) | 214(1) | 36(1) |
C(13) | 1543(2) | 3812(1) | 746(1) | 35(1) |
C(14) | 1604(2) | 4554(1) | 977(1) | 38(1) |
C(15) | 912(2) | 5043(1) | 686(1) | 39(1) |
C(16) | 1171(2) | 3021(1) | 5(1) | 50(1) |
C(17) | 1412(2) | 2438(2) | 321(1) | 59(1) |
C(18) | 1711(2) | 2537(2) | 845(1) | 55(1) |
C(19) | 1785(2) | 3214(1) | 1053(1) | 41(1) |
C(20) | -134(2) | 4263(1) | -318(1) | 35(1) |
C(21) | -1221(2) | 4098(2) | -1108(1) | 42(1) |
C(22) | -1223(3) | 3919(2) | -1650(1) | 76(1) |
C(23) | -2072(3) | 3948(2) | -1947(1) | 78(1) |
C(24) | -2943(2) | 4163(2) | -1711(1) | 47(1) |
C(25) | -2940(2) | 4313(1) | -1170(1) | 40(1) |
C(26) | -2096(2) | 4271(1) | -864(1) | 42(1) |
C(27) | -3846(3) | 4228(2) | -2041(1) | 57(1) |
C(28) | 2912(2) | 3605(2) | 1747(1) | 45(1) |
C(29) | 3099(2) | 3770(2) | 2335(1) | 56(1) |
C(30) | 1304(2) | 3112(2) | 2016(1) | 59(1) |
C(31) | 1666(3) | 3151(2) | 2584(1) | 67(1) |
C(32) | 2477(4) | 3923(2) | 3236(1) | 90(1) |
O(1S) | 1006(2) | 5000 | 2500 | 50(1) |
*U(eq)定义为正交化Uij张量的迹(trace)的三分之一。
单一晶型HCl:SA-1的制备
晶型HCl:SA-1(溶剂化单-HCl盐)可通过将2mg化合物(I)添加至0.7mL甲醇、2-丁酮和乙酸丁酯溶液(2:1:1)中来制备。在室温缓慢蒸发溶液一天后获得黄色棱柱形晶体。
晶体结构数据:
晶胞参数:
α=90°
β=90°
γ=90°
晶系:斜方晶系
空间群:P2(1)2(1)2(1)
分子/不对称单元:1
密度(计算值)=1.368Mg/m3
其中晶型的测量温度为约23℃。
表2
化合物(I)HCl:SA-1的原子坐标(x 104)和等效各向同性位移参数
x | y | z | U(eq) * | |
Cl(2) | 4183(3) | 7590(1) | 7388(1) | 73(1) |
C(1) | 5350(8) | 5357(3) | -5(3) | 58(2) |
C(2) | 5189(9) | 5113(3) | 606(3) | 62(2) |
C(3) | 6122(9) | 4563(3) | 743(3) | 62(2) |
C(4) | 7131(8) | 4259(3) | 322(4) | 63(2) |
C(5) | 7186(9) | 4508(4) | -278(4) | 71(2) |
C(6) | 6312(9) | 5055(4) | -435(3) | 72(2) |
C(7) | 3624(12) | 6026(4) | -680(4) | 87(2) |
C(8) | 4120(11) | 5408(4) | 1083(3) | 76(2) |
C(9) | 3311(10) | 5137(4) | 1500(4) | 78(2) |
C(10) | 2308(8) | 5511(3) | 1938(3) | 57(2) |
C(11) | 481(11) | 4538(3) | 1991(4) | 79(2) |
C(12) | -331(9) | 4186(3) | 2541(4) | 71(2) |
C(13) | -1725(8) | 4599(3) | 2754(3) | 56(2) |
C(14) | -1568(8) | 5294(3) | 2755(3) | 51(2) |
C(15) | 41(8) | 5604(3) | 2612(3) | 50(2) |
C(16) | -3161(9) | 4326(3) | 2946(3) | 59(2) |
C(17) | -4444(9) | 4719(4) | 3106(3) | 69(2) |
C(18) | -4286(9) | 5400(4) | 3088(4) | 70(2) |
C(19) | -2842(8) | 5689(3) | 2911(3) | 60(2) |
C(20) | 938(8) | 5679(3) | 3244(3) | 54(2) |
x | y | z | U(eq) * | |
C(21) | 971(8) | 6440(3) | 4151(3) | 53(2) |
C(22) | 2064(8) | 6122(3) | 4526(3) | 61(2) |
C(23) | 2282(8) | 6336(4) | 5147(3) | 62(2) |
C(24) | 1416(8) | 6856(3) | 5378(3) | 54(2) |
C(25) | 315(9) | 7169(3) | 4999(3) | 64(2) |
C(26) | 103(9) | 6969(3) | 4387(3) | 62(2) |
C(27) | 1629(9) | 7122(4) | 6032(3) | 67(2) |
C(28) | -4232(14) | 3275(4) | 2493(4) | 101(3) |
C(29) | -3869(13) | 2532(4) | 2464(4) | 96(3) |
C(30) | -2699(9) | 2550(3) | 3483(3) | 66(2) |
C(31) | -2625(9) | 3285(3) | 3458(3) | 60(2) |
C(32) | -5588(10) | 2286(4) | 3384(5) | 102(3) |
Cl(1) | 8255(3) | 3595(1) | 563(1) | 95(1) |
F(1) | 6062(6) | 4310(2) | 1340(2) | 93(1) |
N(1) | 4510(8) | 5920(3) | -180(3) | 71(2) |
N(2) | 4579(11) | 6492(3) | 148(3) | 96(2) |
N(3) | 3701(14) | 6911(4) | -149(5) | 123(3) |
N(4) | 3089(12) | 6638(4) | -679(4) | 116(3) |
N(5) | 1037(7) | 5207(2) | 2179(2) | 58(1) |
N(6) | 645(7) | 6263(2) | 3524(2) | 58(1) |
N(7) | -3312(7) | 3606(2) | 2977(3) | 60(1) |
N(8) | -3972(7) | 2250(3) | 3097(3) | 68(2) |
O(1) | 2620(6) | 6081(2) | 2096(2) | 70(1) |
O(2) | 1744(6) | 5235(2) | 3465(2) | 63(1) |
O(3) | 971(7) | 7602(3) | 6233(2) | 91(2) |
O(4) | 2705(7) | 6777(2) | 6357(2) | 81(2) |
O(5) | -1867(7) | 3575(2) | 3864(3) | 80(2) |
O(1S) | 8222(7) | 5981(2) | 1227(2) | 70(1) |
O(2S) | 489(6) | 5435(3) | 69(3) | 103(2) |
O(3SB) | 9450(30) | 6486(13) | 631(17) | 126(8) |
O(3SA) | 9170(30) | 6463(11) | 1022(13) | 136(7) |
O(3SC) | 9560(30) | 6237(13) | 140(14) | 137(8) |
*U(eq)定义为正交化Uij张量的迹(trace)的三分之一。
实施例2
晶型HCl:SA-1的制备
在反应器中,将415g干燥的粗化合物(I)溶于9.0kg无水乙醇(200 Proofethanol)和纯化水(70:30)的溶液中。将该批次加热至66℃并精滤至另一反应器中。使用708g乙醇/水溶液淋洗第一反应器并通过该滤器转移至含有溶液混合物的容器中。将该批次的温度降低至50℃并一次性添加2.24化合物(I)。在30min后,历时4h将该批次冷却至0℃并在该温度老化60min。然后历时2h将该批次的温度升高至50℃并维持额外的30min。再次,然后历时4h将批次温度降低至0℃并向该批次中添加2.9L无水乙醇。在0℃过滤浆液并将湿滤饼用0.9L无水乙醇洗涤两次。将湿滤饼在40℃在真空烘箱中干燥最少12h,直至乙醇含量<6.6重量%。获得块状物质,其通过PXRD(GADDS-NB)、DSC和TGA分析表征且结果示于图1、4和7。
使用Bruker C2GADDS获得PXRD数据。辐射为Cu Kα(40KV,40mA)。样品-检测器距离为15cm。将粉末样品放置于密封的直径为1mm或更小的玻璃毛细管中;在数据收集过程中将毛细管转动。在约2≤2θ≤35°收集数据,样品暴露时间为至少1000秒。将所得的二维衍射弧积分得到在约2至35度2θ范围内的步长为0.05度2θ的传统的一维PXED图。
“混合(Hybrid)”模拟粉末X-射线图如文献(Yin.S.et al.,AmericanPharmaceutical Review,6(2):80(2003))中所述方法制得。室温晶胞参数通过采用CellRefine.xls程序进行晶胞精制获得。输入程序中的数据包括约10个反射的2-θ位置,其从实验室温粉末图获得;相应的米勒指数,hkl,基于收集的同构类似物的单晶数据赋值。感兴趣的分子的晶体结构通过两步方法获得:(1)通过用感兴趣的分子替换实验类似物晶体结构中的类似物分子。该步骤固定感兴趣的分子在类似物化合物的晶胞中的方向和位置;(2)将感兴趣的分子插入至自如上所述的感兴趣的实验PXRD获得的室温晶胞中。在该步骤中,分子以保留分子的大小和形状以及分子相对于晶胞原点的位置,但与晶胞的分子间距增大/缩小的方式插入。新的(混合)PXRD计算(通过软件程序,Alex或LatticeView之一)基于如上所述获得的晶体结构进行。
DSC(开放盘)
差式扫描量热法(DSC)实验采用TAQ2000、Q1000或2920型进行。将样本(约2-10mg)在铝盘中称重并准确记录至百分之一毫克,然后转移至DSC。将仪器用氮气以50mL/min吹扫。在室温至300℃之间,加热速率10℃/min,收集数据。作图,吸热峰指示向下。
TGA(开放盘)
热重分析(TGA)实验采用TAQ5000、Q500或2950型进行。将样本(约4-30mg)置于预先称重(previously tared)的铂盘内。准确测定样本重量,并通过仪器记录至千分之一毫克。将炉体用氮气以100mL/min吹扫。在室温至300℃之间,加热速率10℃/min,收集数据。
实施例3
晶型H.5-1的制备
在室温将60g干燥的粗化合物(I)溶于240mL无水乙醇(4mL/g)中。一次性添加13.25mL三乙胺(1.1equiv)并将反应混合物老化最少3h。将溶液冷却至0℃并维持在该温度最少30min。将浆液过滤并将固体用30mL无水乙醇(0.5mL/g)洗涤。将湿的滤饼溶于600mL纯化水(10mL/g)中并在室温搅拌最少30min。将浆液过滤并将固体用120mL纯化水(2mL/g)洗涤,然后用180mL纯化水(3mL/g)洗涤。将湿滤饼在真空下在45℃干燥最少12h。将获得的晶体进一步分析,结果示于图2、6和9。
实施例4
晶型P13的制备
将6.8g实施例1于33mL甲醇(4.9mL/g)和102mL二氯甲烷(15mL/g)中的浆液加热至40℃并变成均质溶液。在接下来的一小时,添加恒定体积的二氯甲烷(136mL)进行大气压蒸馏,批次温度维持在40℃。将批次冷却至15℃,并在减压下(150mmHg)在恒定体积下开始将溶剂从二氯甲烷/甲醇溶液交换成乙酸乙酯。将批次温度升高至37℃,使用400mL乙酸乙酯完成溶剂交换,剩余136mL乙酸乙酯在反应器中。将批次冷却至20℃并老化12h。将浆液过滤并将所得的湿滤饼在减压下在50℃干燥6h。将干燥的物质进行PXRD、固态核磁共振(SSNMR),结果示于图3、5、8、10和11。
在Bruker AV III仪器上在质子频率为400.1MHz操作进行碳交叉极化魔角旋转(CPMAS)固体NMR实验。固体样品在4mm ZrO2旋转器上以13KHz旋转。接触时间为3毫秒并在质子通道上从50%斜升至100%(Bennett,A.E.etal.,J.Chem.Phys.,103:6951(1995);Metz,G.et al.,J.Magn.Reson.A,110:219-227(1994))。将弛豫延迟维持在20秒。使用具有4微秒脉冲的TPPM序列(62.5KHz标称带宽)应用质子去偶联。光谱扫描宽度为300ppm,以100ppm为中心。获得4096个数据点并用0填充至8192个,然后用20Hz谱线宽化变迹(apodization with 20Hz line broadening)。通常共添加2096个自由感应衰减。使用3-甲基戊二酸将光谱间接参照TMS(Barich,D.et al.,Solid StateNuc.Mag.Res.,30:125-129(2006))。各实验使用约70mg样品。
在Bruker AV III仪器上在质子频率为400.1MHz进行氟魔角旋转(MAS)固态和交叉极化魔角旋转(CPMAS)固态NMR实验。将固体样品在4mm ZrO2旋转器中在11、12和13KHz旋转。报道在13KHz收集的数据。对于MAS,弛豫延迟维持在30秒,对于CPMAS实验维持在5秒。使用具有4微秒脉冲的TPPM序列(62.5KHz标称带宽)应用质子去偶至CPMAS实验。光谱扫描宽度为500ppm,以-100ppm为中心。获得4096个数据点并用0填充至8192个,然后用20Hz谱线宽化变迹。通常共添加2096个自由感应衰减。使用PTFE(在-122ppm)将光谱间接参照CCl3F(Barich,D.et al.,Solid State Nuc.Mag.Res.,30:125-129(2006))。各实验使用约70mg样品。
制备多种化合物(I)的晶型和其溶剂化物并且它们的特征峰位置如表3所列。这些实施例的晶胞数据和其它性质如表4-6所列。自单晶X-射线晶体学分析获得晶胞参数。晶胞的详细解释可在Stout et al.,X-Ray StructureDetermination:A Practical Guide,MacMillian(1968)第3章中找到。
表3
特征衍射峰位置(度数2θ±0.1)RT,基于使用旋转毛细管经2θ校准符合NIST其它适合的标准的衍射仪(CuKα)收集的高质量图谱
HCl:SA-1 | 游离碱H.5-1 | 游离碱P13 |
6.0 | 5.9 | 8.4 |
8.3 | 7.2 | 8.9 |
8.7 | 12.0 | 12.7 |
12.3 | 15.7 | 17.9 |
16.2 | 17.2 | |
16.7 | 18.9 | |
17.5 | 20.3 | |
19.9 | 24.2 | |
20.4 | 26.1 |
表4
晶型HCl:SA-1的单晶(输入)和混合(精制)的晶胞参数
表5
P13的碳化学位移(参照外部TMS)
编号 | (ppm) |
1 | 23.8 |
2 | 24.8 |
3 | 41.1 |
4 | 43.0 |
5 | 45.1 |
6 | 45.9 |
7 | 48.5 |
8 | 49.0 |
9 | 51.0 |
10 | 52.4 |
11 | 56.8 |
12 | 57.6 |
13 | 58.6 |
14 | 61.7 |
15 | 118.1 |
16 | 121.7 |
17 | 122.0 |
18 | 122.5 |
19 | 123.0 |
20 | 124.2 |
21 | 126.1 |
22 | 127.1 |
23 | 127.9 |
24 | 129.0 |
25 | 129.9 |
26 | 130.5 |
27 | 130.6 |
28 | 131.8 |
编号 | (ppm) |
29 | 132.6 |
30 | 133.3 |
31 | 135.0 |
32 | 139.9 |
33 | 140.4 |
34 | 143.6 |
35 | 146.1 |
36 | 147.3 |
37 | 156.6 |
38 | 157.9 |
39 | 159.2 |
40 | 160.4 |
41 | 165.7 |
42 | 166.3 |
43 | 168.7 |
44 | 169.7 |
45 | 171.4 |
表6
P13的F-19化学位移(参照外部CCl3F)
编号 | (ppm) |
1 | -109.8 |
2 | -106.3 |
鉴于上述教导,本发明为数众多的修饰和变型是可能的。因此,应当理解,在本发明权利要求的范围内,本发明可以除本文具体所述的方式实施。
Claims (20)
1.结晶(S,E)-4-(2-(3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酰基)-5-(4-甲基-2-氧代哌嗪-1-基)-1,2,3,4-四氢异喹啉-1-甲酰胺基)苯甲酸的晶型HCl:SA-1,其特征在于基本上与图1所示一致的粉末X-射线衍射图。
2.权利要求1的晶型HCl:SA-1,其具有包含四个或更多2θ值 6.0、8.3、8.7、12.3、16.2、16.7、17.5、19.9和20.4的粉末X-射线衍射图。
3.结晶(S,E)-4-(2-(3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酰基)-5-(4-甲基-2-氧代哌嗪-1-基)-1,2,3,4-四氢异喹啉-1-甲酰胺基)苯甲酸的晶型HCl:SA-1,其特征在于基本上与以下相同的晶胞参数:
晶胞参数:
α=90°
β=90°
γ=90°
空间群:P2(1)2(1)2(1)
分子/不对称单元:1
其中该晶型的测量温度为约23℃。
4.权利要求3的晶型HCl:SA-1,其特征在于基本上如表2所列的分数原子坐标。
5.结晶(S,E)-4-(2-(3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酰基)-5-(4-甲基-2-氧代哌嗪-1-基)-1,2,3,4-四氢异喹啉-1-甲酰胺基)苯甲酸的晶型HCl:SA-1,其特征在于基本上如表4所列的晶胞参数。
6.结晶(S,E)-4-(2-(3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酰基)-5-(4-甲基-2-氧代哌嗪-1-基)-1,2,3,4-四氢异喹啉-1-甲酰胺基)苯甲酸的晶型H.5-1,其特征在于基本上如图2所示一致的粉末X-射线衍射图。
7.权利要求6的晶型H.5-1,其具有包含四个或更多2θ值 5.9、7.2、12.0、15.7、17.2、18.9、20.3、24.2和26.1的粉末X-射线衍射图。
8.结晶(S,E)-4-(2-(3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酰基)-5-(4-甲基-2-氧代哌嗪-1-基)-1,2,3,4-四氢异喹啉-1-甲酰胺基)苯甲酸的晶型H.5-1,其特征在于基本上与以下相同的晶胞参数:
晶胞参数:
α=90°
β=90°
γ=90°
空间群:I2(1)2(1)2(1)
分子/不对称单元:1
密度(计算值):1.401Mg/m3
其中该晶型的测量温度为约23℃。
9.权利要求8的晶型H.5-1,其特征在于基本上如表1所列的分数原子坐标。
10.结晶(S,E)-4-(2-(3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酰基)-5-(4-甲基-2-氧代哌嗪-1-基)-1,2,3,4-四氢异喹啉-1-甲酰胺基)苯甲酸的晶型P13,其特征在于基本上与图3所示一致的粉末X-射线衍射图。
11.权利要求10的晶型P13,其具有包含四个或更多2θ值 8.4、8.9、12.7和17.9的粉末X-射线衍射图。
12.权利要求1、6和10任一项的晶型,其为基本上纯的形式。
13.权利要求12的晶型,其中基本上纯为大于90%纯。
14.药物组合物,其包含治疗有效量的(S,E)-4-(2-(3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酰基)-5-(4-甲基-2-氧代哌嗪-1-基)-1,2,3,4-四氢异喹啉-1-甲酰胺基)苯甲酸的晶型H.5-1和药学上可接受的载体。
15.药物组合物,其包含治疗有效量的(S,E)-4-(2-(3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酰基)-5-(4-甲基-2-氧代哌嗪-1-基)-1,2,3,4-四氢异喹啉-1-甲酰胺基)苯甲酸的晶型P13和药学上可接受的载体。
16.药物组合物,其包含治疗有效量的(S,E)-4-(2-(3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酰基)-5-(4-甲基-2-氧代哌嗪-1-基)-1,2,3,4-四氢异喹啉-1-甲酰胺基)苯甲酸的晶型HCl:SA-1和药学上可接受的载体。
17.治疗血栓栓塞性病症的方法,其包括:向有此需要的患者给予治疗有效量的权利要求14-16任一项的晶型。
18.权利要求17的方法,其中所述血栓栓塞性病症选自动脉心血管血管栓塞性病症、静脉心血管血管栓塞性病症和心腔的血管栓塞性病症。
19.权利要求17的方法,其中所述血栓栓塞性病症选自不稳定性心绞痛、急性冠脉综合症、心房纤颤、首次心肌梗死、复发心肌梗死、缺血性猝死、短暂性脑缺血发作、卒中、动脉粥样硬化、外周动脉闭塞性疾病、静脉血栓形成、深静脉血栓形成、血栓静脉炎、动脉栓塞、管状动脉血栓形成、脑动脉血栓形成、脑栓塞、肾栓塞、肺栓塞和由以下原因导致的血栓形成:(a)人工瓣膜或其它移植物,(b)留置导管,(c)支架,(d)心肺转流术,(e)血液透析,或(f)其中血液暴露于促进血栓形成的人工表面的其它操作。
20.制备化合物(I)的晶型的方法,其包括将化合物(I)在选自以下的溶剂中浆化的步骤:丙酮、甲醇、乙醇、CH2Cl2、DMF、NMP、MEK、2-BuOH、IPA、IpOAc、MTBE、EtOAc和BuOAc。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201261712850P | 2012-10-12 | 2012-10-12 | |
US61/712,850 | 2012-10-12 | ||
PCT/US2013/064423 WO2014059203A1 (en) | 2012-10-12 | 2013-10-11 | Crystalline forms of a factor xia inhibitor |
Publications (2)
Publication Number | Publication Date |
---|---|
CN104837833A true CN104837833A (zh) | 2015-08-12 |
CN104837833B CN104837833B (zh) | 2017-07-14 |
Family
ID=49474724
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201380064797.5A Active CN104837833B (zh) | 2012-10-12 | 2013-10-11 | Xia因子抑制剂的晶型 |
Country Status (34)
Country | Link |
---|---|
US (1) | US9920034B2 (zh) |
EP (1) | EP2906551B1 (zh) |
JP (1) | JP6154473B2 (zh) |
KR (1) | KR102143257B1 (zh) |
CN (1) | CN104837833B (zh) |
AU (1) | AU2013329125B2 (zh) |
BR (1) | BR112015007937A2 (zh) |
CA (1) | CA2888100A1 (zh) |
CL (1) | CL2015000916A1 (zh) |
CO (1) | CO7350621A2 (zh) |
CY (1) | CY1120238T1 (zh) |
DK (1) | DK2906551T3 (zh) |
EA (1) | EA032092B1 (zh) |
ES (1) | ES2668318T3 (zh) |
HK (1) | HK1212333A1 (zh) |
HR (1) | HRP20180465T1 (zh) |
HU (1) | HUE038272T2 (zh) |
IL (1) | IL238089B (zh) |
LT (1) | LT2906551T (zh) |
MA (1) | MA38071B1 (zh) |
MX (1) | MX351848B (zh) |
MY (1) | MY173058A (zh) |
NO (1) | NO2819265T3 (zh) |
NZ (1) | NZ707990A (zh) |
PE (1) | PE20150639A1 (zh) |
PH (1) | PH12015500678A1 (zh) |
PL (1) | PL2906551T3 (zh) |
PT (1) | PT2906551T (zh) |
RS (1) | RS57039B1 (zh) |
SG (1) | SG11201502605PA (zh) |
SI (1) | SI2906551T1 (zh) |
TR (1) | TR201807316T4 (zh) |
WO (1) | WO2014059203A1 (zh) |
ZA (1) | ZA201503238B (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106496249A (zh) * | 2015-09-07 | 2017-03-15 | 江苏恒瑞医药股份有限公司 | 噁唑并吲哚类衍生物、其制备方法及其在医药上的应用 |
CN109867660A (zh) * | 2017-12-01 | 2019-06-11 | 四川科伦博泰生物医药股份有限公司 | 含季铵离子的四氢异喹啉酰胺化合物及其药物用途 |
Families Citing this family (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TW201319068A (zh) | 2011-08-05 | 2013-05-16 | 必治妥美雅史谷比公司 | 作為xia因子抑制劑之環狀p1接合劑 |
TW201311689A (zh) | 2011-08-05 | 2013-03-16 | 必治妥美雅史谷比公司 | 作為因子xia抑制劑之新穎巨環化合物 |
PT2766346T (pt) | 2011-10-14 | 2017-05-26 | Bristol Myers Squibb Co | Compostos de tetrahidroisoquinolina substituídos como inibidores do fator xia |
WO2014059202A1 (en) | 2012-10-12 | 2014-04-17 | Bristol-Myers Squibb Company | Guanidine substituted tetrahydroisoquinoline compounds as factor xia inhibitors |
WO2014059214A1 (en) | 2012-10-12 | 2014-04-17 | Bristol-Myers Squibb Company | Guanidine and amine substituted tetrahydroisoquinoline compounds as factor xia inhibitors |
JP6479763B2 (ja) | 2013-03-25 | 2019-03-06 | ブリストル−マイヤーズ スクイブ カンパニーBristol−Myers Squibb Company | 第xia因子阻害剤としての置換アゾール含有のテトラヒドロイソキノリン |
NO2760821T3 (zh) | 2014-01-31 | 2018-03-10 | ||
IL298983B2 (en) | 2014-01-31 | 2024-03-01 | Bristol Myers Squibb Co | Macrocyclines with P2' heterocyclic groups as factor XIA inhibitors |
CN107074821B (zh) | 2014-09-04 | 2020-05-22 | 百时美施贵宝公司 | 为fxia抑制剂的二酰胺大环化合物 |
US9453018B2 (en) | 2014-10-01 | 2016-09-27 | Bristol-Myers Squibb Company | Pyrimidinones as factor XIa inhibitors |
EP3310777B1 (en) | 2015-06-19 | 2019-10-09 | Bristol-Myers Squibb Company | Diamide macrocycles as factor xia inhibitors |
EP3328851B1 (en) | 2015-07-29 | 2020-04-22 | Bristol-Myers Squibb Company | Factor xia macrocyclic inhibitors bearing alkyl or cycloalkyl p2' moieties |
EP3328852B1 (en) | 2015-07-29 | 2021-04-28 | Bristol-Myers Squibb Company | Factor xia macrocyclic inhibitors bearing a non-aromatic p2' group |
US10344039B2 (en) | 2015-10-29 | 2019-07-09 | Merck Sharp & Dohme Corp. | Macrocyclic spirocarbamate derivatives as factor XIa inhibitors, pharmaceutically acceptable compositions and their use |
TW201808908A (zh) | 2016-08-22 | 2018-03-16 | 美商默沙東藥廠 | 因子XIa抑制劑 |
CN111655686B (zh) | 2018-03-28 | 2024-02-09 | 四川科伦博泰生物医药股份有限公司 | 四氢异喹啉类衍生物及其制备方法和用途 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101304989A (zh) * | 2005-11-11 | 2008-11-12 | 弗·哈夫曼-拉罗切有限公司 | 作为凝血因子xa抑制剂的碳环稠合环胺 |
WO2009114677A1 (en) * | 2008-03-13 | 2009-09-17 | Bristol-Myers Squibb Company | Pyridazine derivatives as factor xia inhibitors |
WO2013056060A1 (en) * | 2011-10-14 | 2013-04-18 | Bristol-Myers Squibb Company | Substituted tetrahydroisoquinoline compounds as factor xia inhibitors |
Family Cites Families (62)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR7155E (fr) | 1906-03-16 | 1907-05-23 | Rene Gabriel Poncet | Séchoir rotatif |
FR1525186A (fr) | 1967-03-29 | 1968-05-17 | Roussel Uclaf | Nouvelles pénicillines et procédé de préparation |
ATA937274A (de) | 1973-12-17 | 1978-02-15 | Thomae Gmbh Dr K | Verfahren zur herstellung neuer araliphatischer ketone |
DE4034829A1 (de) | 1990-11-02 | 1992-05-07 | Merck Patent Gmbh | Cyclopeptide |
JP3190431B2 (ja) | 1991-07-01 | 2001-07-23 | 三菱化学株式会社 | ケトン誘導体 |
GB9206757D0 (en) | 1992-03-27 | 1992-05-13 | Ferring Bv | Novel peptide receptor ligands |
US5624936A (en) | 1995-03-29 | 1997-04-29 | Merck & Co., Inc. | Inhibitors of farnesyl-protein transferase |
WO1996034010A2 (en) | 1995-03-29 | 1996-10-31 | Merck & Co., Inc. | Inhibitors of farnesyl-protein transferase |
JP2000507597A (ja) | 1996-04-03 | 2000-06-20 | メルク エンド カンパニー インコーポレーテッド | ファルネシルタンパク質トランスフェラーゼ阻害剤 |
US5869682A (en) | 1996-04-03 | 1999-02-09 | Merck & Co., Inc. | Inhibitors of farnesyl-protein transferase |
TW557297B (en) | 1997-09-26 | 2003-10-11 | Abbott Lab | Rapamycin analogs having immunomodulatory activity, and pharmaceutical compositions containing same |
KR100928878B1 (ko) | 1998-03-19 | 2009-11-30 | 버텍스 파마슈티칼스 인코포레이티드 | 카스파제의 억제제 |
BR9911590A (pt) | 1998-05-26 | 2001-02-13 | Warner Lambert Co | Pirimidinas bicìclicas e 3,4-diidropirimidinas bicìclicas como inibidores da proliferação celular |
US6307049B1 (en) | 1998-09-30 | 2001-10-23 | The Procter & Gamble Co. | Heterocyclic 2-substituted ketoamides |
EP1016663A1 (en) | 1999-01-02 | 2000-07-05 | Aventis Pharma Deutschland GmbH | Novel malonic acid derivatives, processes for their preparation, their use and pharmaceutical compositions containing them (inhibition of factor Xa activity) |
TR200101903T2 (tr) | 1999-01-02 | 2001-11-21 | Aventis Pharma Deutschland Gmbh | Yeni malonik asit türevleri, bunların preparasyon işlemleri. |
MXPA01010114A (es) | 1999-04-09 | 2002-07-30 | Basf Ag | Inhibidores de peso molecular bajo de las proteasas complemento. |
EP1125925A1 (en) | 2000-02-15 | 2001-08-22 | Applied Research Systems ARS Holding N.V. | Amine derivatives for the treatment of apoptosis |
ES2252230T3 (es) | 2000-05-11 | 2006-05-16 | Bristol-Myers Squibb Company | Analogos de tetrahidroisoquinolina utiles como secretores de la hormona del crecimiento. |
SV2003000617A (es) | 2000-08-31 | 2003-01-13 | Lilly Co Eli | Inhibidores de la proteasa peptidomimetica ref. x-14912m |
WO2003011222A2 (en) | 2001-07-27 | 2003-02-13 | Merck & Co., Inc. | Thrombin inhibitors |
AU2002357692A1 (en) | 2001-11-09 | 2003-05-26 | Bristol-Myers Squibb Company | Tetrahydroisoquinoline analogs as modulators of chemokine receptor activity |
US7138412B2 (en) | 2003-03-11 | 2006-11-21 | Bristol-Myers Squibb Company | Tetrahydroquinoline derivatives useful as serine protease inhibitors |
US7129264B2 (en) | 2003-04-16 | 2006-10-31 | Bristol-Myers Squibb Company | Biarylmethyl indolines and indoles as antithromboembolic agents |
CA2531796A1 (en) | 2003-08-08 | 2005-02-17 | Transtech Pharma, Inc. | Aryl and heteroaryl compounds, compositions, and methods of use |
US7417063B2 (en) | 2004-04-13 | 2008-08-26 | Bristol-Myers Squibb Company | Bicyclic heterocycles useful as serine protease inhibitors |
US7453002B2 (en) | 2004-06-15 | 2008-11-18 | Bristol-Myers Squibb Company | Five-membered heterocycles useful as serine protease inhibitors |
US7429604B2 (en) | 2004-06-15 | 2008-09-30 | Bristol Myers Squibb Company | Six-membered heterocycles useful as serine protease inhibitors |
US20100190688A1 (en) | 2004-07-12 | 2010-07-29 | Bin Chao | Tetrapeptide analogs |
US7459564B2 (en) | 2005-01-13 | 2008-12-02 | Bristol-Myers Squibb Company | Substituted biaryl compounds as factor XIa inhibitors |
WO2006089005A2 (en) | 2005-02-17 | 2006-08-24 | Bristol-Myers Squibb Company | Combination of selective factor viia and/or xia and plasma kallikrein inhibitors |
US8466295B2 (en) | 2005-12-14 | 2013-06-18 | Bristol-Myers Squibb Company | Thiophene derivatives as factor XIa inhibitors |
EP1981854B1 (en) | 2005-12-14 | 2011-06-01 | Bristol-Myers Squibb Company | Arylpropionamide, arylacrylamide, arylpropynamide, or arylmethylurea analogs as factor xia inhibitors |
WO2007070818A1 (en) | 2005-12-14 | 2007-06-21 | Bristol-Myers Squibb Company | Six-membered heterocycles useful as serine protease inhibitors |
PE20071132A1 (es) | 2005-12-23 | 2007-12-14 | Bristol Myers Squibb Co | Compuestos macrociclicos como inhibidores del factor viia |
CN101605779B (zh) | 2006-12-15 | 2013-11-20 | 百时美施贵宝公司 | 作为凝血因子xia抑制剂的芳基丙酰胺、芳基丙烯酰胺、芳基丙炔酰胺或芳基甲基脲类似物 |
PE20081775A1 (es) | 2006-12-20 | 2008-12-18 | Bristol Myers Squibb Co | Compuestos macrociclicos como inhibidores del factor viia |
AU2008266228A1 (en) | 2007-06-13 | 2008-12-24 | Bristol-Myers Squibb Company | Dipeptide analogs as coagulation factor inhibitors |
US8624040B2 (en) | 2009-06-22 | 2014-01-07 | Millennium Pharmaceuticals, Inc. | Substituted hydroxamic acids and uses thereof |
US8513433B2 (en) | 2009-07-02 | 2013-08-20 | Angion Biomedica Corp. | Small molecule inhibitors of PARP activity |
TWI393716B (zh) | 2009-08-04 | 2013-04-21 | Merck Sharp & Dohme | 作為ixa因子抑制劑之雜環化合物 |
JP5841547B2 (ja) | 2010-02-11 | 2016-01-13 | ブリストル−マイヤーズ スクイブ カンパニーBristol−Myers Squibb Company | 第xia因子阻害剤としてのマクロ環 |
EP2729150B1 (en) | 2011-07-08 | 2016-09-14 | Merck Sharp & Dohme Corp. | Factor ixa inhibitors |
TW201319068A (zh) | 2011-08-05 | 2013-05-16 | 必治妥美雅史谷比公司 | 作為xia因子抑制劑之環狀p1接合劑 |
TW201311689A (zh) | 2011-08-05 | 2013-03-16 | 必治妥美雅史谷比公司 | 作為因子xia抑制劑之新穎巨環化合物 |
EP2766345B1 (en) | 2011-10-14 | 2016-03-16 | Bristol-Myers Squibb Company | Substituted tetrahydroisoquinoline compounds as factor xia inhibitors |
CN103987696B (zh) | 2011-10-14 | 2016-12-21 | 百时美施贵宝公司 | 作为因子xia抑制剂的取代的四氢异喹啉化合物 |
RU2630677C2 (ru) | 2011-12-21 | 2017-09-12 | Оно Фармасьютикал Ко., Лтд. | Соединения |
EP2807157A1 (en) | 2012-01-27 | 2014-12-03 | Novartis AG | 5-membered heteroarylcarboxamide derivatives as plasma kallikrein inhibitors |
US20140350034A1 (en) | 2012-01-27 | 2014-11-27 | Novartis Ag | Aminopyridine derivatives as plasma kallikrein inhibitors |
JP2015083542A (ja) | 2012-02-08 | 2015-04-30 | 大日本住友製薬株式会社 | 3位置換プロリン誘導体 |
AU2013258043B2 (en) | 2012-05-10 | 2017-11-30 | Bayer Pharma Aktiengesellschaft | Antibodies capable of binding to the coagulation factor XI and/or its activated form factor XIa and uses thereof |
GB201209138D0 (en) | 2012-05-24 | 2012-07-04 | Ono Pharmaceutical Co | Compounds |
WO2014014050A1 (ja) | 2012-07-19 | 2014-01-23 | 大日本住友製薬株式会社 | 1-(シクロアルキルカルボニル)プロリン誘導体 |
MX361370B (es) | 2012-08-03 | 2018-12-05 | Bristol Myers Squibb Co | Dihidropiridona p1 como inhibidores del factor xia. |
WO2014022767A1 (en) | 2012-08-03 | 2014-02-06 | Bristol-Myers Squibb Company | Dihydropyridone p1 as factor xia inhibitors |
WO2014059214A1 (en) | 2012-10-12 | 2014-04-17 | Bristol-Myers Squibb Company | Guanidine and amine substituted tetrahydroisoquinoline compounds as factor xia inhibitors |
WO2014059202A1 (en) | 2012-10-12 | 2014-04-17 | Bristol-Myers Squibb Company | Guanidine substituted tetrahydroisoquinoline compounds as factor xia inhibitors |
EP2934538B1 (en) | 2012-12-19 | 2021-03-31 | Merck Sharp & Dohme Corp. | Factor ixa inhibitors |
GB201300304D0 (en) | 2013-01-08 | 2013-02-20 | Kalvista Pharmaceuticals Ltd | Benzylamine derivatives |
GB2510407A (en) | 2013-02-04 | 2014-08-06 | Kalvista Pharmaceuticals Ltd | Aqueous suspensions of kallikrein inhibitors for parenteral administration |
JP6479763B2 (ja) | 2013-03-25 | 2019-03-06 | ブリストル−マイヤーズ スクイブ カンパニーBristol−Myers Squibb Company | 第xia因子阻害剤としての置換アゾール含有のテトラヒドロイソキノリン |
-
2013
- 2013-10-11 BR BR112015007937A patent/BR112015007937A2/pt not_active Application Discontinuation
- 2013-10-11 MY MYPI2015701150A patent/MY173058A/en unknown
- 2013-10-11 TR TR2018/07316T patent/TR201807316T4/tr unknown
- 2013-10-11 AU AU2013329125A patent/AU2013329125B2/en not_active Ceased
- 2013-10-11 PL PL13780287T patent/PL2906551T3/pl unknown
- 2013-10-11 DK DK13780287.2T patent/DK2906551T3/en active
- 2013-10-11 US US14/434,507 patent/US9920034B2/en active Active
- 2013-10-11 NZ NZ707990A patent/NZ707990A/en not_active IP Right Cessation
- 2013-10-11 PT PT137802872T patent/PT2906551T/pt unknown
- 2013-10-11 SI SI201330987T patent/SI2906551T1/en unknown
- 2013-10-11 LT LTEP13780287.2T patent/LT2906551T/lt unknown
- 2013-10-11 WO PCT/US2013/064423 patent/WO2014059203A1/en active Application Filing
- 2013-10-11 MX MX2015004328A patent/MX351848B/es active IP Right Grant
- 2013-10-11 JP JP2015536906A patent/JP6154473B2/ja active Active
- 2013-10-11 KR KR1020157011941A patent/KR102143257B1/ko active IP Right Grant
- 2013-10-11 EA EA201590548A patent/EA032092B1/ru not_active IP Right Cessation
- 2013-10-11 CA CA2888100A patent/CA2888100A1/en not_active Abandoned
- 2013-10-11 HU HUE13780287A patent/HUE038272T2/hu unknown
- 2013-10-11 SG SG11201502605PA patent/SG11201502605PA/en unknown
- 2013-10-11 RS RS20180328A patent/RS57039B1/sr unknown
- 2013-10-11 PE PE2015000477A patent/PE20150639A1/es not_active Application Discontinuation
- 2013-10-11 ES ES13780287.2T patent/ES2668318T3/es active Active
- 2013-10-11 EP EP13780287.2A patent/EP2906551B1/en active Active
- 2013-10-11 CN CN201380064797.5A patent/CN104837833B/zh active Active
-
2014
- 2014-05-21 NO NO14169333A patent/NO2819265T3/no unknown
-
2015
- 2015-03-26 PH PH12015500678A patent/PH12015500678A1/en unknown
- 2015-04-01 IL IL238089A patent/IL238089B/en active IP Right Grant
- 2015-04-10 CL CL2015000916A patent/CL2015000916A1/es unknown
- 2015-05-07 MA MA38071A patent/MA38071B1/fr unknown
- 2015-05-07 CO CO15104857A patent/CO7350621A2/es unknown
- 2015-05-11 ZA ZA2015/03238A patent/ZA201503238B/en unknown
-
2016
- 2016-01-07 HK HK16100130.3A patent/HK1212333A1/zh not_active IP Right Cessation
-
2018
- 2018-03-20 HR HRP20180465TT patent/HRP20180465T1/hr unknown
- 2018-05-18 CY CY20181100522T patent/CY1120238T1/el unknown
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101304989A (zh) * | 2005-11-11 | 2008-11-12 | 弗·哈夫曼-拉罗切有限公司 | 作为凝血因子xa抑制剂的碳环稠合环胺 |
WO2009114677A1 (en) * | 2008-03-13 | 2009-09-17 | Bristol-Myers Squibb Company | Pyridazine derivatives as factor xia inhibitors |
WO2013056060A1 (en) * | 2011-10-14 | 2013-04-18 | Bristol-Myers Squibb Company | Substituted tetrahydroisoquinoline compounds as factor xia inhibitors |
CN103974938A (zh) * | 2011-10-14 | 2014-08-06 | 百时美施贵宝公司 | 作为因子xia抑制剂的经取代的四氢异喹啉化合物 |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106496249A (zh) * | 2015-09-07 | 2017-03-15 | 江苏恒瑞医药股份有限公司 | 噁唑并吲哚类衍生物、其制备方法及其在医药上的应用 |
CN106496249B (zh) * | 2015-09-07 | 2019-12-13 | 江苏恒瑞医药股份有限公司 | 噁唑并吲哚类衍生物、其制备方法及其在医药上的应用 |
CN109867660A (zh) * | 2017-12-01 | 2019-06-11 | 四川科伦博泰生物医药股份有限公司 | 含季铵离子的四氢异喹啉酰胺化合物及其药物用途 |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN104837833A (zh) | Xia因子抑制剂的晶型 | |
JP4316794B2 (ja) | イソキノリン誘導体及び医薬 | |
JP5575979B2 (ja) | シアノ基を含有するチエノピリジンエステル誘導体、その調製方法、使用および組成物 | |
JP2022521491A (ja) | タンパク質アルギニンメチルトランスフェラーゼ5(prmt5)の選択的阻害剤 | |
BR112021008249A2 (pt) | sais cristalinos de um inibidor de calicreína plasmática | |
CN106916143B (zh) | 一种预防和治疗冠心病的药物及其应用 | |
WO2016206576A1 (zh) | 一种氘代噻吩并哌啶衍生物、制备方法及其应用 | |
JP2008514711A (ja) | ピラゾロ[3,4−c]ピリジンXA因子阻害剤の結晶フォーム | |
JP2008524228A (ja) | Xa因子阻害剤の結晶フォーム | |
JP5959617B2 (ja) | オタミキサバンの安息香酸塩 | |
US7410980B2 (en) | Crystals of taxane derivative and process for their production | |
JPH0211592A (ja) | 光学活性なジヒドロピリジンホスホン酸エステル | |
CN102260249B (zh) | (-)多沙唑嗪甲磺酸盐ⅱ型结晶、其制备方法及用途 | |
JP2013514981A (ja) | 第Xa因子阻害剤の結晶性塩 | |
JP2001114699A (ja) | キマーゼ阻害作用を有する化合物を有効成分とする血管新生阻害剤 | |
CN110655516A (zh) | 一种抗凝血药物的晶型 | |
JPH09512836A (ja) | 細胞付着抑制剤としての(−)−(3r)−3−メチル−4−{4−[4−(4−ピリジル)ピペラジン−1−イル]フェノキシ}酪酸 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |