ZA200006036B - Reduced partice size form of 1-(6-chloronaphth-2-ylsulphonyl)-4-[4-(4-pyridyl) benzoyl] piperazine. - Google Patents
Reduced partice size form of 1-(6-chloronaphth-2-ylsulphonyl)-4-[4-(4-pyridyl) benzoyl] piperazine. Download PDFInfo
- Publication number
- ZA200006036B ZA200006036B ZA200006036A ZA200006036A ZA200006036B ZA 200006036 B ZA200006036 B ZA 200006036B ZA 200006036 A ZA200006036 A ZA 200006036A ZA 200006036 A ZA200006036 A ZA 200006036A ZA 200006036 B ZA200006036 B ZA 200006036B
- Authority
- ZA
- South Africa
- Prior art keywords
- piperazine
- chloronaphth
- ylsulphonyl
- benzoyl
- pyridyl
- Prior art date
Links
- PSTBXECIKAJFMC-UHFFFAOYSA-N [4-(6-chloronaphthalen-2-yl)sulfonylpiperazin-1-yl]-(4-pyridin-4-ylphenyl)methanone Chemical compound C1=CC2=CC(Cl)=CC=C2C=C1S(=O)(=O)N(CC1)CCN1C(=O)C(C=C1)=CC=C1C1=CC=NC=C1 PSTBXECIKAJFMC-UHFFFAOYSA-N 0.000 title claims description 12
- 150000003839 salts Chemical class 0.000 claims description 25
- 239000000843 powder Substances 0.000 claims description 23
- 239000002245 particle Substances 0.000 claims description 22
- 238000000034 method Methods 0.000 claims description 14
- 108010074860 Factor Xa Proteins 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 12
- 239000012453 solvate Substances 0.000 claims description 11
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 8
- 201000010099 disease Diseases 0.000 claims description 5
- 230000001404 mediated effect Effects 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- GYMDDVRYIQMRMT-UHFFFAOYSA-N [4-(6-chloronaphthalen-2-yl)sulfonylpiperazin-1-yl]-(4-pyridin-4-ylphenyl)methanone;hydrochloride Chemical compound Cl.C1=CC2=CC(Cl)=CC=C2C=C1S(=O)(=O)N(CC1)CCN1C(=O)C(C=C1)=CC=C1C1=CC=NC=C1 GYMDDVRYIQMRMT-UHFFFAOYSA-N 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 238000013160 medical therapy Methods 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims 10
- MSQACBWWAIBWIC-UHFFFAOYSA-N hydron;piperazine;chloride Chemical compound Cl.C1CNCCN1 MSQACBWWAIBWIC-UHFFFAOYSA-N 0.000 claims 1
- 229940125904 compound 1 Drugs 0.000 description 22
- 150000001875 compounds Chemical class 0.000 description 18
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- -1 6-CHLORONAPHTH-2- YLSULPHONYL Chemical class 0.000 description 5
- 108091005804 Peptidases Proteins 0.000 description 5
- 239000004365 Protease Substances 0.000 description 5
- 230000002785 anti-thrombosis Effects 0.000 description 5
- ONCCWDRMOZMNSM-FBCQKBJTSA-N compound Z Chemical compound N1=C2C(=O)NC(N)=NC2=NC=C1C(=O)[C@H]1OP(O)(=O)OC[C@H]1O ONCCWDRMOZMNSM-FBCQKBJTSA-N 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 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 4
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 4
- 208000007536 Thrombosis Diseases 0.000 description 4
- 230000002429 anti-coagulating effect Effects 0.000 description 4
- 239000003146 anticoagulant agent Substances 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 230000015271 coagulation Effects 0.000 description 4
- 238000005345 coagulation Methods 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 3
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 3
- 229920002261 Corn starch Polymers 0.000 description 3
- 229920002785 Croscarmellose sodium Polymers 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 235000019759 Maize starch Nutrition 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 108090000190 Thrombin Proteins 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 239000002585 base Substances 0.000 description 3
- 230000023555 blood coagulation Effects 0.000 description 3
- 229960001681 croscarmellose sodium Drugs 0.000 description 3
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 239000012458 free base Substances 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 230000000704 physical effect Effects 0.000 description 3
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 208000026106 cerebrovascular disease Diseases 0.000 description 2
- 210000004351 coronary vessel Anatomy 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 230000000069 prophylactic effect Effects 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 239000007916 tablet composition Substances 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 229960004072 thrombin Drugs 0.000 description 2
- FMLPGZYYCBFFLU-UHFFFAOYSA-N 1-(6-chloronaphthalen-2-yl)sulfonylpiperazine Chemical compound C1=CC2=CC(Cl)=CC=C2C=C1S(=O)(=O)N1CCNCC1 FMLPGZYYCBFFLU-UHFFFAOYSA-N 0.000 description 1
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 1
- GZUBBCPCJHBRDY-UHFFFAOYSA-N 2-pyridin-4-ylbenzoic acid Chemical compound OC(=O)C1=CC=CC=C1C1=CC=NC=C1 GZUBBCPCJHBRDY-UHFFFAOYSA-N 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 206010002388 Angina unstable Diseases 0.000 description 1
- 206010003178 Arterial thrombosis Diseases 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 208000037260 Atherosclerotic Plaque Diseases 0.000 description 1
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical class C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 1
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 1
- 206010008088 Cerebral artery embolism Diseases 0.000 description 1
- 206010008132 Cerebral thrombosis Diseases 0.000 description 1
- 206010053567 Coagulopathies Diseases 0.000 description 1
- 101000783577 Dendroaspis angusticeps Thrombostatin Proteins 0.000 description 1
- 101000783578 Dendroaspis jamesoni kaimosae Dendroaspin Proteins 0.000 description 1
- 208000005189 Embolism Diseases 0.000 description 1
- 229940123583 Factor Xa inhibitor Drugs 0.000 description 1
- 201000001429 Intracranial Thrombosis Diseases 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108010094028 Prothrombin Proteins 0.000 description 1
- 102100027378 Prothrombin Human genes 0.000 description 1
- 208000010378 Pulmonary Embolism Diseases 0.000 description 1
- 206010038563 Reocclusion Diseases 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 108010023197 Streptokinase Proteins 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 229940111979 Thromboxane synthase inhibitor Drugs 0.000 description 1
- 108090000373 Tissue Plasminogen Activator Proteins 0.000 description 1
- 102000003978 Tissue Plasminogen Activator Human genes 0.000 description 1
- 208000007814 Unstable Angina Diseases 0.000 description 1
- 208000024248 Vascular System injury Diseases 0.000 description 1
- 208000012339 Vascular injury Diseases 0.000 description 1
- 206010047249 Venous thrombosis Diseases 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 238000002399 angioplasty Methods 0.000 description 1
- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 239000002506 anticoagulant protein Substances 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 229940127218 antiplatelet drug Drugs 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 239000012472 biological sample Substances 0.000 description 1
- 208000015294 blood coagulation disease Diseases 0.000 description 1
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- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000003841 chloride salts Chemical class 0.000 description 1
- 230000009852 coagulant defect Effects 0.000 description 1
- UTBIMNXEDGNJFE-UHFFFAOYSA-N collidine Natural products CC1=CC=C(C)C(C)=N1 UTBIMNXEDGNJFE-UHFFFAOYSA-N 0.000 description 1
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- 239000006071 cream Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
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- 229960001760 dimethyl sulfoxide Drugs 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
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- 230000002255 enzymatic effect Effects 0.000 description 1
- 239000003527 fibrinolytic agent Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
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- 239000000499 gel Substances 0.000 description 1
- 238000002682 general surgery Methods 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 210000003709 heart valve Anatomy 0.000 description 1
- 238000011540 hip replacement Methods 0.000 description 1
- QMEZUZOCLYUADC-UHFFFAOYSA-N hydrate;dihydrochloride Chemical compound O.Cl.Cl QMEZUZOCLYUADC-UHFFFAOYSA-N 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 230000000055 hyoplipidemic effect Effects 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 201000004332 intermediate coronary syndrome Diseases 0.000 description 1
- 201000010849 intracranial embolism Diseases 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 239000008263 liquid aerosol Substances 0.000 description 1
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000004452 microanalysis Methods 0.000 description 1
- 238000003801 milling Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 229940100662 nasal drops Drugs 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 229940097496 nasal spray Drugs 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000000106 platelet aggregation inhibitor Substances 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
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- CUQOHAYJWVTKDE-UHFFFAOYSA-N potassium;butan-1-olate Chemical compound [K+].CCCC[O-] CUQOHAYJWVTKDE-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 229940039716 prothrombin Drugs 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 208000037803 restenosis Diseases 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 229960005202 streptokinase Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 229960000103 thrombolytic agent Drugs 0.000 description 1
- 230000001732 thrombotic effect Effects 0.000 description 1
- 239000002396 thromboxane receptor blocking agent Substances 0.000 description 1
- 239000003768 thromboxane synthase inhibitor Substances 0.000 description 1
- 229960000187 tissue plasminogen activator Drugs 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
Description
~ »
REDUCED PARTICLE SIZE FORM OF 1~(6-CHLORONAPHTH-2- YLSULPHONYL) —4-[4-(4PYRIDYL) BENZOYL)
PIPERAZINE
The invention relates to pharmaceutically-acceptable salts of 1-(6-chloronaphth- 2-ylsulphonyl)-4-[4-(4-pyridyl)benzoyl]piperazine and reduced particle sized forms of either the compound or a pharmaceutically-acceptable salt thereof, which possess antithrombotic and anticoagulant properties and accordingly are useful in methods of treatment of humans or animals. The invention also relates to processes for the preparation of pharmaceutically- acceptable salts of the above compound and reduced particle size forms thereof, to pharmaceutical compositions containing them and to their use in the manufacture of medicaments for use in the production of an antithrombotic or anticoagulant effect in humans.
The antithrombotic and anticoagulant effect produced by the compounds of the invention is believed to be attributable to their strong inhibitory effect against the activated coagulation protease known as Factor Xa. Factor Xa is one of a cascade of proteases involved in the complex process of blood coagulation. The protease known as thrombin is the final protease in the cascade and Factor Xa is the preceding protease which cleaves prothrombin to generate thrombin.
Certain compounds are known to possess Factor Xa inhibitory properties and the field has been reviewed by R.B. Wallis, Current Opinion in Therapeutic Patents, 1993, 1173- 1179. Thus it is known that two proteins, one known as antistatin and the other known as tick anticoagulant protein (TAP), are specific Factor Xa inhibitors which possess antithrombotic properties in various animal models of thrombotic disease.
Itis also known that certain non-peptidic compounds possess Factor Xa inhibitory properties. Of the low molecular weight inhibitors mentioned in the review by R.B. Wallis, all possessed a strongly basic group such as an amidinophenyl or amidinonaphthyl group.
We have now found that 1-(6-chloronaphth-2-ylsulphonyl)-4- (4-(4-pyridyD)benzoyl]piperazine (hereinafter referred to as Compound 1) possesses Factor Xa inhibitory activity at concentrations which do not inhibit, or which inhibit to a lesser extent, the enzyme thrombin which is also a member of the blood coagulation enzymatic cascade.
The trifluoroacetic acid addition salt of Compound 1 is disclosed as Example 7 of
PCT Application No. GB97/03033.
Compound 1 possesses activity in the treatment or prevention of a variety of medical disorders where anticoagulant therapy is indicated, for example in the treatment or prevention of thrombotic conditions such as coronary artery and cerebro-vascular disease. Further examples of such medical disorders include various cardiovascular and cerebrovascular conditions such as myocardial infarction, the formation of atherosclerotic plaques, venous or arterial thrombosis, coagulation syndromes, vascular injury (including reocclusion and restenosis following angioplasty and coronary artery bypass surgery, thrombus formation after the application of blood vessel operative techniques or after general surgery such as hip replacement surgery, the introduction of artificial heart valves or on the recirculation of blood), cerebral infarction, cerebral thrombosis, stroke, cerebral embolism, pulmonary embolism, ischaemia and angina (including unstable angina). - Compound 1 is also useful as an inhibitor of blood coagulation in an ex-vivo .. .sitdation such as, for example, the storage of whole blood or other biological samples suspected to contain Factor Xa and in which coagulation is detrimental. = We have found that Compound 1, i.e. the free base, has limited aqueous solubility and limited bioavailabilty when dosed orally. We have investigated pharmaceutically- acceptable salts of Compound 1 and also solid forms of both Compound 1 and pharmaceutically-acceptable salts of Compound 1 with reduced particle size to try to improve upon the physical properties of Compound 1.
Our investigations have shown that pharmaceutically-acceptable salts of Compound 1 and reduced particle sized forms of Compound 1, and pharmaceutically-acceptable salts thereof, show improved physical properties. In particular the pharmaceutically-acceptable salts of Compound 1 showed improved physical properties such as aqueous solubility and oral bioavailabilty. In particular the reduced particle size form of a pharmaceutically-acceptable salt of Compound 1 showed an improved aqueous dissolution rate, oral bioavailabilty, and reduction in the variability in oral bioavailabilty when compared to Compound 1.
Accordingly provided in the present invention is: (a) areduced particle size form of a pharmaceutically-acceptable salt or a solvate thereof of Compound i; ®) a reduced particle size form of Compound 1 or a solvate thereof; and
Co WO 99/57112 PCT/GB99/01316 (c) a pharmaceutically-acceptable salt of Compound 1 or a solvate thereof.
As used hereinafter the term “a Compound of the invention” refers to either one of features (a), (b) or (c) described above.
By the use of the term “reduced particle size” we refer to solid Compound 1, or a pharmaceutically-acceptable salt thereof, or a solvate of either thereof, reduced by suitable processing techniques to a solid of smaller particle size and, consequently, greater surface area. Any number of processing techniques known in the pharmaceutical field may be used to reduce solid particle size, such as grinding, milling and micronising, reference should be made to Remington: The Science and Practise of Pharmacy, 19™ Ed., pages 1598-1602, for a more exhaustive review.
The range of particle sizes preferred in this invention start from, in increasing preference, moderately fine powder, fine powder, very fine powder, microfine powder to, most preferably, superfine powder.
The above references to particle sizes are taken from the British Pharmacopoeia 1993,
Volume II, Appendix XVII B, A193, and are reproduced below for reference.
Moderately fine powder
A powder all the particles of which pass through a sieve with a nominal mesh aperture of 355um and not more than 40.0% by weight pass through a sieve with a nominal mesh aperture of 250pum.
Fine powder
A powder all the particles of which pass through a sieve with a nominal mesh aperture of 180m and not more than 40.0% by weight pass through a sieve with a nominal mesh aperture of 125um.
Very fine powder
A powder all the particles of which pass through a sieve with a nominal mesh aperture of 125pm and not more than 40.0% by weight pass through a sieve with a nominal mesh aperture of 45um.
Microfine powder
A powder of which not less than 90% by weight of the particles pass through a sieve with a nominal mesh aperture of 45pm.
Sup erfine powder
A’powder of which not less than 90% by weight of the particles pass through a sieve with a ndiminal mesh aperture of 10pm.
The particular sieves to be used in determining the particle size are described in British
Pharmacopoeia 1993 Volume II, Appendix XVIIB, A193-A194, which part is incorporated héfein by reference.
Pharmaceutically-acceptable salts may be formed by reacting the basic moiety of
Compound 1 with any one of a number of pharmaceutically-acceptable organic or inorganic acids and precipitating the salt from solution. A preferred pharmaceutically-acceptable salt of
Compound 1 is the hydrochloride salt. In a more preferred from the chloride salt of
Compound 1 is solvated, preferably hydrated, and in particular the hemihydrate form is preferred.
A feature of the invention is.a Compound of the invention, as described above, for use in medical therapy.
According to a further feature of the invention there is provided a pharmaceutical composition which comprises a Compound of the invention, as described above, in association with a pharmaceutically-acceptable diluent or carrier.
The composition may be in a form suitable for oral use, for example a tablet, capsule, aqueous or oily solution, suspension or emulsion; for topical use, for example a cream, ointment, gel or aqueous or oily solution or suspension; for nasal use, for example a snuff, nasal spray or nasal drops; for vaginal or rectal use, for example a suppository; for administration by inhalation, for example as a finely divided powder such as a dry powder, a microcrystalline form or a liquid aerosol; for sub-lingual or buccal use, for example a tablet or capsule; or for parenteral use (including intravenous, subcutaneous, intramuscular, intravascular or infusion), for example a sterile aqueous or oily solution or suspension. In general the above compositions may be prepared in a conventional manner using conventional excipients.
The amount of a Compound of the invention, as described above that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 2 g of active agent compounded with an appropriate and convenient amount of excipient(s) which may vary from about 5 to about 98 percent by weight of the total composition. Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient.
The invention also includes the use of a Compound of the invention, as described above in the production of a medicament for use in:- (1) producing a Factor Xa inhibitory effect; (ii) producing an anticoagulant effect; (iii) producing an antithrombotic effect; (iv) treating a Factor Xa mediated disease or medical condition; (v) treating a thrombosis mediated disease or medical condition; (vi) treating coagulation disorders; and/or (vii) treating thrombosis or embolism involving Factor Xa mediated coagulation.
The invention also includes a method of producing an effect as defined hereinbefore or treating a disease or disorder as defined hereinbefore which comprises administering to a warm-blooded animal requiring such treatment an effective amount of form of a Compound of the invention, as described above.
The size of the dose for therapeutic or prophylactic purposes of a form of a
Compound of the invention, as described above, will naturally vary according to the nature and severity of the medical condition, the age and sex of the animal or patient being treated and the route of administration, according to well known principles of medicine. In using a
Compound of the invention it will generally be administered so that a daily oral dose in the range, for example, 0.1 to 50 mg/kg body weight/day is received, given if required in divided doses. In general lower doses will be administered when a parenteral route is employed, for example a dose for intravenous administration in the range, for example, 0.01 to 10 mg/kg body weight/day will generally be used. Preferred oral daily doses include, for example, 0.1 to 10 mg/kg body weight/day. In general a preferred dose range for either oral or parenteral administration would be 0.01 to 10 mg/kg body weight/day.
Compound 1 may conveniently be prepared by reacting (4-pyridyl)benzoic acid, or a reactive derivative thereof, for example the acylchloride derivative, with 1-(6-chloronaphth-2-ylsulphonyl)piperazine, or a salt thereof, for example, the hydrochloride salt. The reaction is conveniently carried out in the presence of a suitable base such as, for example, an alkali or alkaline earth metal carbonate, alkoxide, hydroxide or hydride, for example sodium carbonate, potassium carbonate, sodium ethoxide, potassium butoxide, sodium hydroxide, potassium hydroxide, sodium hydride or potassium hydride, or an organometallic base such as an alkyl-lithium, for example n-butyl-lithium, or a dialkylamino-lithium, for example lithium di-isopropylamide, or, for example, an organic . ... amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine or diazabicyclo[5.4.0Jundec-7-ene. The reaction is also preferably carried out in a suitable inert solvent or diluent, for example methylene chloride, chloroform, carbon tetrachloride, tetrahydrofuran, 1,2-dimethoxyethane, N,N-dimethylformamide, . N,N-dimethylacetamide, N-methylpyrrolidin-2-one, dimethylsulphoxide or acetone, and at a -temperature in the range, for example, -78° to 150°C, conveniently at or near ambient temperature.
Processes for the preparation of the two intermediates above, as well as for
Compound 1, may be found in PCT application number PCT/GB97/03033.
Compound 1 or a Compound of the invention may be administered as a sole therapy or they may be administered in conjunction with other pharmacologically active agents such as a thrombolytic agent, for example tissue plasminogen activator or derivatives thereof or streptokinase. The compounds of the invention may also be administered with, for example, a known platelet aggregation inhibitor (for example aspirin, a thromboxane antagonist or a thromboxane synthase inhibitor), a known hypolipidaemic agent or a known anti-hypertensive agent.
The dissolution rates of material were tested in analagous methods as described in the
Britsih Pharmacopoeia 1998 Appendix XIID A189-A191.
The invention will now be illustrated in the following Examples.
Example 1
Preparation of 1-(6-chloronaphth-2-ylsulphonyl)-4-[4-(4-pyridyl)benzoyl] piperazine hydrochloride from free base:
Free base 1-(6-chloronaphth-2-ylsulphonyl)-4-[4-(4-pyridyl)benzoyl]piperazine (54.8g) was dissolved in dichloromethane (800ml) and a solution of HCl in ethyl acetate ( 50 ml of 3.1 M, 1.1 eq.) was added with stirring; the mixture was stirred for 1hour, giving a copious precipitate. The solvent was removed in vacuo and the resulting colourless solid dried under a high vacuum. To the solid was added hot methanol (2.51), the suspension was brought to reflux (complete solution at this stage), filtered, and the volume then reduced on a steam bath until crystallisation started to occur; the solution was removed from the steam bath and allowed to crystallise to give 1-(6-chloronaphth-2-ylsulphonyl)-4-[4-(4- pyridyl)benzoyl]piperazine as the hydrochloride salt hemihydrate, 46.6g as a colourless - crystalline solid.
M.p. 250°C '"H NMR(d,-DMSO): 2.9 - 3.2 (broad s, 4H), 3.3 - 3.8 (broad s, 4H), 7.4 (d, 2H), 7.7 (m, 3H), 7.8 (m, 3H), 8.2 (d, 1H), 8.3 (m, 2H), 8.5 (s, 1H), 8.7 (d, 2H)
Microanalysis, found: C, 57.9; H, 4.5; N, 7.7; §, 6.2; CI, 13.0 %; CygHp3N303CIS. 1.0 HCI. 0.5 HpO requires: C, 58.0; H, 4.7; N, 7.8; S, 6.0; C1, 13.2 %
Mass spectrum (+ ive ESP) m/z 492/494 (M+H+).
Example 2
Preparation of Reduced Particle Size Form of Example 1
The hemihydrate hydrochloride salt of compound 1 (Example 1) was fed at a controlled rate into a fluid energy mill (microniser), in which the salt was subjected to self attrition caused by high energy streams of gas. The particles produced were continuously classified, with the fines collected via a filter.
The solid produced was measured as "Superfine Powder" (Reference: British Pharmacopoeia 1993 Vo.2 Appendix A193).
Example 3
Illustrative pharmaceutical dosage forms suitable for presenting a Compound of the invention for therapeutic or prophylactic use include the following tablet and capsule formulations, which may be obtained by conventional procedures well known in the art of pharmacy and are suitable for therapeutic use in humans: (a)* Tablet 1 mg/tablet
Compound Z* 1.0
Lactose Ph. Eur. 93.25
Croscarmellose sodium 4.0
Maize starch paste (5% w/v aqueous paste) 0.75
Magnesium Stearate 1.0 (b) Tablet IT mg/tablet
Compound Z* 50
Lactose Ph. Eur 223.75
Croscarmellose sodium 6.0
Maize starch 15.0
Polyvinylpyrrolidone (5% w/v aqueous paste) 2.25
Magnesium stearate 3.0 (c) Tablet III mg/tablet
Compound Z* 100
Lactose Ph. Eur. 182.75
Croscarmellose sodium 12.0
Maize starch paste (5% w/v aqueous paste) 2.25
Magnesium stearate 3.0
(d) Capsule mg/capsule
Compound Z* 10
Lactose Ph. Eur. 488.5
Magnesium stearate 1.5
Note - * The active ingredient Compound Z is a Compound of the invention, as described above.
The tablet compositions (a) - (c) may be enteric coated by conventional means, for example, with cellulose acetate phthalate.
Claims (16)
1. A reduced particle size form of either 1-(6-chloronaphth-2-ylsulphonyl)-4-[4-(4- - pyridyl)benzoyl]piperazine or a pharmaceutically-acceptable salt of 1-(6-chloronaphth-2- ylsulphonyl)-4-[4-(4-pyridyl)benzoyl]piperazine or a solvate of either thereof.
2. 1-(6-Chloronaphth-2-ylsulphonyl)-4-[4-(4-pyri dylbenzoyl]piperazine hydrochloride salt or a solvate thereof. :
3. 1-(6-Chloronaphth-2-ylsulphonyl)-4-[4-(4-pyridyl)benzoyl]piperazine hydrochloride hemi-hydrate salt.
4. A superfine powder of either 1-(6-chloronaphth-2-ylsulphonyl)-4-[4-(4- pyridyl)benzoyl]piperazine or a pharmaceutically-acceptable salt of 1-(6-chloronaphth-2- ylsulphonyl)-4-[4-(4-pyridyl)benzoyl]piperazine or a solvate of either thereof. :
5. A microfine powder of either 1-(6-chloronaphth-2-ylsulphonyl)-4-[4-(4- pyridyl)benzoyl]piperazine or a pharmaceutically-acceptable salt of 1-(6-chloronaphth-2- ylsulphonyl)-4-[4-(4-pyridyl)benzoyl]piperazine or a solvate of either thereof.
6. A very fine powder of either 1-(6-chloronaphth-2-ylsulphonyl)-4-[4-(4- pyridyl)benzoyl]piperazine or a pharmaceutically-acceptable salt of 1-(6-chloronaphth-2- ylsulphonyl)-4-[4-(4-pyridyl)benzoyl]piperazine or a solvate of either thereof.
7. Use of any substance defined in any one of claims 1 to 7 in medical therapy.
8. A pharmaceutical composition comprising a substance as defined in any claim from 1 to 7 in association with a pharmaceutically-acceptable diluent or carrier. 3009.
The use of a substance as defined in any claim from 1 to 7 in the production of a medicament for use in treating a Factor Xa mediated disease or medical condition.
10. A substance or composition for use in a method of treating a Factor Xa mediated disease or medical condition, said substance or composition comprising a substance as defined in any claim from 1 to 7, and said method comprising administering said substance or composition.
11. A piperazine, a salt or a solvate according to claim 1, substantially as herein described and illustrated.
12. A powder according to claim 4, claim 5 or claim 6, substantially as herein described and illustrated.
13. Use according to claim 7 or claim 9, substantially as herein described and illustrated.
14. A composition according to claim 8, substantially as herein described and illustrated.
15. A substance or composition for use in a method of treatment according to claim 10, substantially as herein described and illustrated.
16. A new piperazine, a new salt, a new solvate, a new powder, new use of a substance as defined in any claim from 1 to 7, a new composition, or a substance or composition for a new use in a method of treatment, substantially as herein described. AMENDED SHEET
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB9809350.3A GB9809350D0 (en) | 1998-05-02 | 1998-05-02 | Novel salt |
Publications (1)
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ZA200006036B true ZA200006036B (en) | 2002-01-25 |
Family
ID=10831311
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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ZA200006036A ZA200006036B (en) | 1998-05-02 | 2000-10-25 | Reduced partice size form of 1-(6-chloronaphth-2-ylsulphonyl)-4-[4-(4-pyridyl) benzoyl] piperazine. |
Country Status (16)
Country | Link |
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EP (1) | EP1084118A1 (en) |
JP (1) | JP2002513789A (en) |
KR (1) | KR20010043216A (en) |
CN (1) | CN1308629A (en) |
AU (1) | AU3719699A (en) |
BR (1) | BR9910176A (en) |
CA (1) | CA2331041A1 (en) |
EE (1) | EE200000638A (en) |
GB (1) | GB9809350D0 (en) |
HU (1) | HUP0102394A3 (en) |
IL (1) | IL139405A0 (en) |
NO (1) | NO20005498D0 (en) |
PL (1) | PL343705A1 (en) |
SK (1) | SK16522000A3 (en) |
WO (1) | WO1999057112A1 (en) |
ZA (1) | ZA200006036B (en) |
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DE69833036T2 (en) * | 1997-09-30 | 2006-06-22 | Daiichi Pharmaceutical Co., Ltd. | sulfonyl |
TWI290136B (en) | 2000-04-05 | 2007-11-21 | Daiichi Seiyaku Co | Ethylenediamine derivatives |
WO2003000657A1 (en) | 2001-06-20 | 2003-01-03 | Daiichi Pharmaceutical Co., Ltd. | Diamine derivatives |
DK1569912T3 (en) | 2002-12-03 | 2015-06-29 | Pharmacyclics Inc | 2- (2-hydroxybiphenyl-3-yl) -1h-benzoimidazole-5-carboxamidine derivatives as factor VIIa inhibitors. |
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UA56197C2 (en) * | 1996-11-08 | 2003-05-15 | Зенека Лімітед | Heterocyclic derivatives |
ATE334975T1 (en) * | 1997-05-30 | 2006-08-15 | Takeda Pharmaceutical | SULFONAMIDE DERIVATIVES, THEIR PRODUCTION AND USE |
DE69833036T2 (en) * | 1997-09-30 | 2006-06-22 | Daiichi Pharmaceutical Co., Ltd. | sulfonyl |
-
1998
- 1998-05-02 GB GBGB9809350.3A patent/GB9809350D0/en not_active Ceased
-
1999
- 1999-04-27 EE EEP200000638A patent/EE200000638A/en unknown
- 1999-04-27 PL PL99343705A patent/PL343705A1/en not_active Application Discontinuation
- 1999-04-27 WO PCT/GB1999/001316 patent/WO1999057112A1/en not_active Application Discontinuation
- 1999-04-27 KR KR1020007012149A patent/KR20010043216A/en not_active Application Discontinuation
- 1999-04-27 BR BR9910176-9A patent/BR9910176A/en not_active IP Right Cessation
- 1999-04-27 IL IL13940599A patent/IL139405A0/en unknown
- 1999-04-27 SK SK1652-2000A patent/SK16522000A3/en unknown
- 1999-04-27 CA CA002331041A patent/CA2331041A1/en not_active Abandoned
- 1999-04-27 EP EP99919395A patent/EP1084118A1/en not_active Withdrawn
- 1999-04-27 CN CN99808217A patent/CN1308629A/en active Pending
- 1999-04-27 JP JP2000547082A patent/JP2002513789A/en active Pending
- 1999-04-27 HU HU0102394A patent/HUP0102394A3/en unknown
- 1999-04-27 AU AU37196/99A patent/AU3719699A/en not_active Abandoned
-
2000
- 2000-10-25 ZA ZA200006036A patent/ZA200006036B/en unknown
- 2000-11-01 NO NO20005498A patent/NO20005498D0/en not_active Application Discontinuation
Also Published As
Publication number | Publication date |
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SK16522000A3 (en) | 2001-05-10 |
WO1999057112A1 (en) | 1999-11-11 |
EE200000638A (en) | 2002-04-15 |
HUP0102394A2 (en) | 2001-12-28 |
HUP0102394A3 (en) | 2003-01-28 |
IL139405A0 (en) | 2001-11-25 |
NO20005498L (en) | 2000-11-01 |
JP2002513789A (en) | 2002-05-14 |
BR9910176A (en) | 2001-01-09 |
GB9809350D0 (en) | 1998-07-01 |
NO20005498D0 (en) | 2000-11-01 |
CN1308629A (en) | 2001-08-15 |
CA2331041A1 (en) | 1999-11-11 |
EP1084118A1 (en) | 2001-03-21 |
KR20010043216A (en) | 2001-05-25 |
AU3719699A (en) | 1999-11-23 |
PL343705A1 (en) | 2001-08-27 |
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