EP0000254B1 - Antithrombotic 2-(gamma-(1-piperidinyl)propyl)1,2-benzisothiazol 3-one, its pharmaceutically acceptable acid addition salts, their preparation and their compositions - Google Patents
Antithrombotic 2-(gamma-(1-piperidinyl)propyl)1,2-benzisothiazol 3-one, its pharmaceutically acceptable acid addition salts, their preparation and their compositions Download PDFInfo
- Publication number
- EP0000254B1 EP0000254B1 EP78300050A EP78300050A EP0000254B1 EP 0000254 B1 EP0000254 B1 EP 0000254B1 EP 78300050 A EP78300050 A EP 78300050A EP 78300050 A EP78300050 A EP 78300050A EP 0000254 B1 EP0000254 B1 EP 0000254B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- compound
- formula
- acid addition
- pharmaceutically acceptable
- propyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 150000003839 salts Chemical class 0.000 title claims description 11
- 239000002253 acid Substances 0.000 title claims description 6
- 238000002360 preparation method Methods 0.000 title claims description 6
- LEHPTDUMTDRRKM-UHFFFAOYSA-N 2-(3-piperidin-1-ylpropyl)-1,2-benzothiazol-3-one Chemical compound S1C2=CC=CC=C2C(=O)N1CCCN1CCCCC1 LEHPTDUMTDRRKM-UHFFFAOYSA-N 0.000 title claims 2
- 239000000203 mixture Substances 0.000 title description 9
- 239000003146 anticoagulant agent Substances 0.000 title description 8
- 230000002785 anti-thrombosis Effects 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims description 44
- 239000000460 chlorine Substances 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 229940125782 compound 2 Drugs 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 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 claims 1
- 239000000243 solution Substances 0.000 description 8
- 241001465754 Metazoa Species 0.000 description 7
- 238000004220 aggregation Methods 0.000 description 7
- 230000002776 aggregation Effects 0.000 description 7
- 210000004623 platelet-rich plasma Anatomy 0.000 description 7
- 239000003981 vehicle Substances 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 6
- 239000008280 blood Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 208000007536 Thrombosis Diseases 0.000 description 5
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 239000002585 base Substances 0.000 description 4
- 210000001772 blood platelet Anatomy 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000006188 syrup Substances 0.000 description 4
- 235000020357 syrup Nutrition 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- 206010003178 Arterial thrombosis Diseases 0.000 description 3
- 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 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-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
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 230000002744 anti-aggregatory effect Effects 0.000 description 3
- -1 benzisothiazolone compound Chemical class 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 229920000609 methyl cellulose Polymers 0.000 description 3
- 239000001923 methylcellulose Substances 0.000 description 3
- 235000010981 methylcellulose Nutrition 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000000600 sorbitol Substances 0.000 description 3
- 235000010356 sorbitol Nutrition 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 238000011282 treatment Methods 0.000 description 3
- KANAPVJGZDNSCZ-UHFFFAOYSA-N 1,2-benzothiazole 1-oxide Chemical class C1=CC=C2S(=O)N=CC2=C1 KANAPVJGZDNSCZ-UHFFFAOYSA-N 0.000 description 2
- XTWYTFMLZFPYCI-KQYNXXCUSA-N 5'-adenylphosphoric acid Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O XTWYTFMLZFPYCI-KQYNXXCUSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 229940126062 Compound A Drugs 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 102000009123 Fibrin Human genes 0.000 description 2
- 108010073385 Fibrin Proteins 0.000 description 2
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 230000004931 aggregating effect Effects 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 229950003499 fibrin Drugs 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- WGTYBPLFGIVFAS-UHFFFAOYSA-M tetramethylammonium hydroxide Chemical compound [OH-].C[N+](C)(C)C WGTYBPLFGIVFAS-UHFFFAOYSA-M 0.000 description 2
- 239000008215 water for injection Substances 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- DSFZYLCRXIWFFW-UHFFFAOYSA-N 2-[(2-carbonochloridoylphenyl)disulfanyl]benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1SSC1=CC=CC=C1C(Cl)=O DSFZYLCRXIWFFW-UHFFFAOYSA-N 0.000 description 1
- JMUCXULQKPWSTJ-UHFFFAOYSA-N 3-piperidin-1-ylpropan-1-amine Chemical compound NCCCN1CCCCC1 JMUCXULQKPWSTJ-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 235000006491 Acacia senegal Nutrition 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 235000019489 Almond oil Nutrition 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- PAMIQIKDUOTOBW-UHFFFAOYSA-N CN1CCCCC1 Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 239000004150 EU approved colour Substances 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000019759 Maize starch Nutrition 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M Methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 206010050902 Postoperative thrombosis Diseases 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 239000004141 Sodium laurylsulphate Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 241001558496 Talpa caeca Species 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 206010047249 Venous thrombosis Diseases 0.000 description 1
- 0 [*+]*1Sc2ccccc2C1=O Chemical compound [*+]*1Sc2ccccc2C1=O 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 239000008168 almond oil Substances 0.000 description 1
- CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical compound [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 229940127090 anticoagulant agent Drugs 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- DMSMPAJRVJJAGA-UHFFFAOYSA-N benzo[d]isothiazol-3-one Chemical compound C1=CC=C2C(=O)NSC2=C1 DMSMPAJRVJJAGA-UHFFFAOYSA-N 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 235000015895 biscuits Nutrition 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 150000001733 carboxylic acid esters Chemical group 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000035602 clotting Effects 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 239000008157 edible vegetable oil Substances 0.000 description 1
- 230000000001 effect on platelet aggregation Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000003193 general anesthetic agent Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000002687 nonaqueous vehicle Substances 0.000 description 1
- 229940006093 opthalmologic coloring agent diagnostic Drugs 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000003182 parenteral nutrition solution Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000002278 tabletting lubricant Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 238000009827 uniform distribution Methods 0.000 description 1
- 210000001631 vena cava inferior Anatomy 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
- C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
Definitions
- This invention relates to antithrombotic compounds and in particular to a benzisothiazolone and its acid addition salts having particularly high activity.
- Arterial thrombosis develops initially from the aggregation of blood platelets within the artery. This aggregate may eventually lead to the formation of fibrin and the formation of a consolidated occlusive thrombus.
- the most widely used therapy for thrombosis is the use of anti-coagulant agents, which influence blood clotting.
- anti-coagulant therapy has no effect on platelet aggregation and has therefore limited effectiveness in arterial thrombosis. It is now accepted that anti-coagulant drugs have little to offer in the treatment of arterial thrombosis.
- U.S. Patent Specification 3,227,715 discloses a class of benzisothiazolones of the formula (I): wherein A represents a lower alkylene of 2 to 4 carbon atoms, R 1 and R 2 are hydrogen or halogen, R 3 and R 4 represent hydrogen, lower alkyl, cycloalkyl, hydroxyalkyl of 2 to 4 carbon atoms or alkoxyalkyl of 2 to 4 carbon atoms, and R 3 and R 4 together with the nitrogen atom on which they are substituted stand for an unsubstituted or lower alkyl substituted heterocyclic ring having from 5 to 6 atoms in the ring; as being useful for the therapy of inflammatory processes.
- A represents a lower alkylene of 2 to 4 carbon atoms
- R 1 and R 2 are hydrogen or halogen
- R 3 and R 4 represent hydrogen, lower alkyl, cycloalkyl, hydroxyalkyl of 2 to 4 carbon atoms or alkoxyalkyl of 2 to
- the present invention therefore provides the compound 2 - [y - (1 - piperidinyl)propyl] - 1,2 -benzisothiazol - 3 - one of formula (II), or a pharmaceutically acceptable acid addition salt thereof:-
- Suitable acid addition salts include inorganic salts such as sulphate, nitrate, phosphate, and borate, hydrohalides e.g. hydrochloride, hydrobromide, and hydroiodide, and organic acid addition salts such as acetate, oxalate, tartrate, maleate, citrate, succinate, benzoate, ascorbate, methanesulphonate, and p-toluenesulphonate.
- inorganic salts such as sulphate, nitrate, phosphate, and borate
- hydrohalides e.g. hydrochloride, hydrobromide, and hydroiodide
- organic acid addition salts such as acetate, oxalate, tartrate, maleate, citrate, succinate, benzoate, ascorbate, methanesulphonate, and p-toluenesulphonate.
- Preferred salts are the hydrochloride and hydrobromide.
- the compound of this invention may be prepared by reacting a compound of formula (III): wherein W and Z are the same or different and each is a halogen atom; with a compound of formula (lV):-
- W is chlorine and Z is chlorine or bromine.
- Suitable solvents for the reaction include carbon tetrachloride or other halogenated hydrocarbon solvents.
- a second method for the preparation of the compound of formula (II) comprises reaction of a compound of formula (V) or a salt thereof:- with a compound of formula (VI):- wherein Q is a readily displaceable group.
- Q is a halogen atom.
- the compound (VI) is used as its alkali metal salt, for example the sodium salt.
- a solvent such as dimethyl formamide or dimethylsulfoxide may be used, preferably at elevated temperatures.
- the corresponding 3-ether is also formed and the desired product may be separated by crystallisation, distillation and chromatographic techniques.
- Compound of formula (II) may also be prepared by treating a compound of formula (VII):_ with either a base or with chlorine or bromine.
- Suitable bases include 10% sodium hydroxide or other aqueous alkali and the reaction may be carried out at room temperature or elevated temperatures. If chlorine is employed in this reaction it may be bubbled into a solution of compound (VII) in an inert solvent such as carbon tetrachloride.
- the compound of formula (11) may also be prepared by treating a compound a formula (VIII) wherein CO Z R e is a carboxylic ester group; with a base.
- the group R a is an alkyl or aryl group.
- Suitable bases for the reaction include alkali metal alkoxides, alkali metal hydroxides and tetramethylammonium hydroxide in lower alcohols.
- the invention also provides a pharmaceutical composition which comprises a compound of formula (I) as defined above together with at least one pharmaceutically acceptable carrier.
- composition will usually be accompanied by or associated with written or printed directions for use in the medical treatment concerned, in this case as an agent for the inhibition of platelet aggregation or thrombus formation.
- compositions may be formulated for administration by any route, although an oral administration is preferred.
- the compositions may be in the form of tablets, capsules, powders, granules, lozenges, or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
- Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinyl-pyrollidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol, or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate.
- the tablets may be coated according to methods well known in normal pharmaceutical practice.
- Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
- Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or gum acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters, glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
- suspending agents for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monoo
- fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, water being preferred.
- the compound depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle.
- the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing.
- adjuvants such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.
- the composition can be frozen after filling into the vial and the water removed under vacuum. The dry lyophilized powder is then sealed in the vial and an accompanying vial of water for injection is supplied to reconstitute the liquid prior to use.
- Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration.
- the compound can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle.
- a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
- compositions may contain from 0.1 % to 99% by weight, preferably from 10-60% by weight, of the active material, depending on the method of administration. Where the compositions comprise dosage units, each unit will preferably contain from 1 - 500 mg., of the active ingredient.
- the dosage employed for adult treatment will of course depend on the dose-response characteristics of the particular active ingredient, and also on the blood volume and condition of the patient, but will normally be in the range 0.01 to 30 mg/kg/day depending on the route and frequency of administration.
- the preferred dose is 10 to 500 mg., orally 1 to 3 times a day for an adult human.
- compositions of the invention are useful for administration to humans and animals to prevent clot formation for example after surgery to prevent postoperative thrombosis; in geriatric patients to prevent transient cerebral ischemic attacks; and long-term prophylaxis following myocardial infarcts and strokes.
- the compounds of formula (II) may also have applications in the storage of whole blood in blood banks, and whole blood to be used in heart-lung machines, or to be circulated through organs, e.g. heart and kidneys, which have been removed from a cadaver and prior to transplant.
- reaction mixture was transferred to a separating funnel with dichloromethane and the suspension was washed with 10% aqueous sodium hydroxide solution, water and brine.
- the organic layer was dried (anhydrous MgS0 4 ), evaporated, and the residue was chromatographed on silica gel (150 g) using dichloromethane-methanol (90:10) as eluant.
- the compound of the Example was tested for their ability to inhibit platelet aggregation in the guinea pig ex vivo by the method given below, and was compared with two closely related compounds disclosed in U.S. Patent 3,337,715, and also with two compounds disclosed in French Patent Specification No, 2332019 as well as with three known anti-aggregant compounds.
- the dose ratio represents the ratio of the concentration of aggregating agent to cause aggregation in PRP from drug-treated animals to the concentration of aggregating agent to cause aggregation in PRP from control animals.
- Table 1 gives the results of this invention (compound A), two compounds disclosed in French Specification 2332019 (compounds B and C), two compounds disclosed in U.S. Patent 3,227,715 (compounds D and E) and three known anti-aggregant agents (compound F,G,H).
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
- This invention relates to antithrombotic compounds and in particular to a benzisothiazolone and its acid addition salts having particularly high activity.
- Arterial thrombosis develops initially from the aggregation of blood platelets within the artery. This aggregate may eventually lead to the formation of fibrin and the formation of a consolidated occlusive thrombus. The most widely used therapy for thrombosis is the use of anti-coagulant agents, which influence blood clotting. However, although effective in venous thrombosis, where the thrombus is formed mainly of fibrin, anti-coagulant therapy has no effect on platelet aggregation and has therefore limited effectiveness in arterial thrombosis. It is now accepted that anti-coagulant drugs have little to offer in the treatment of arterial thrombosis.
- With the increasing recognition of the primary role of platelets in thrombosis, attention had turned to drugs which are capable of inhibiting aggregation of platelets.
- U.S. Patent Specification 3,227,715 discloses a class of benzisothiazolones of the formula (I):
- U.S. Patent 3,227,715 does not suggest any anti-thrombotic activity for any of the compounds described therein.
- Our French Patent Specification No. 2332019 discloses a related class of benzisothiazolones as being effective in inhibiting platelet aggregation.
- We have now found that a benzisothiazolone compound which falls within the generic disclosure of U.S. Patent 3,227,715 but is not specifically described therein or in French Specification 2332019, has exceptionally high activity in inhibiting platelet aggregation which is not predictable from the prior art.
-
- Suitable acid addition salts include inorganic salts such as sulphate, nitrate, phosphate, and borate, hydrohalides e.g. hydrochloride, hydrobromide, and hydroiodide, and organic acid addition salts such as acetate, oxalate, tartrate, maleate, citrate, succinate, benzoate, ascorbate, methanesulphonate, and p-toluenesulphonate.
- Preferred salts are the hydrochloride and hydrobromide.
-
- Preferably W is chlorine and Z is chlorine or bromine. Suitable solvents for the reaction include carbon tetrachloride or other halogenated hydrocarbon solvents.
- A second method for the preparation of the compound of formula (II) comprises reaction of a compound of formula (V) or a salt thereof:-
- In this reaction a solvent such as dimethyl formamide or dimethylsulfoxide may be used, preferably at elevated temperatures. In general the corresponding 3-ether is also formed and the desired product may be separated by crystallisation, distillation and chromatographic techniques.
-
- Suitable bases include 10% sodium hydroxide or other aqueous alkali and the reaction may be carried out at room temperature or elevated temperatures. If chlorine is employed in this reaction it may be bubbled into a solution of compound (VII) in an inert solvent such as carbon tetrachloride.
-
- Suitably the group Ra is an alkyl or aryl group. Suitable bases for the reaction include alkali metal alkoxides, alkali metal hydroxides and tetramethylammonium hydroxide in lower alcohols.
- The invention also provides a pharmaceutical composition which comprises a compound of formula (I) as defined above together with at least one pharmaceutically acceptable carrier.
- As is common practice, such composition will usually be accompanied by or associated with written or printed directions for use in the medical treatment concerned, in this case as an agent for the inhibition of platelet aggregation or thrombus formation.
- The composition may be formulated for administration by any route, although an oral administration is preferred. The compositions may be in the form of tablets, capsules, powders, granules, lozenges, or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
- Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinyl-pyrollidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol, or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or gum acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters, glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents. The compound may also if desired by incorporated in a foodstuff, for example in the form of a biscuit.
- For parenteral administration, fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, water being preferred. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. The dry lyophilized powder is then sealed in the vial and an accompanying vial of water for injection is supplied to reconstitute the liquid prior to use. Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration. The compound can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
- The compositions may contain from 0.1 % to 99% by weight, preferably from 10-60% by weight, of the active material, depending on the method of administration. Where the compositions comprise dosage units, each unit will preferably contain from 1 - 500 mg., of the active ingredient.
- The dosage employed for adult treatment will of course depend on the dose-response characteristics of the particular active ingredient, and also on the blood volume and condition of the patient, but will normally be in the range 0.01 to 30 mg/kg/day depending on the route and frequency of administration. The preferred dose is 10 to 500 mg., orally 1 to 3 times a day for an adult human.
- The compositions of the invention are useful for administration to humans and animals to prevent clot formation for example after surgery to prevent postoperative thrombosis; in geriatric patients to prevent transient cerebral ischemic attacks; and long-term prophylaxis following myocardial infarcts and strokes.
- The compounds of formula (II) may also have applications in the storage of whole blood in blood banks, and whole blood to be used in heart-lung machines, or to be circulated through organs, e.g. heart and kidneys, which have been removed from a cadaver and prior to transplant.
- The following example illustrates the invention.
-
- Dry chlorine was passed into a suspension of 2,2'-dithiodibenzoyl chloride (2.41 g, 7.03 mmole) in dry CCI4 (50 ml) until solution was complete. Excess of chlorine was removed by passing nitrogen through the reaction mixture, the solution was filtered, and the filtrate was added dropwise with stirring to a solution of N - (3 - aminopropyl)piperidine (6.0 g, 42.25 m. mole) in dry CCI4 (100 ml) at room temperature.
- The reaction mixture was transferred to a separating funnel with dichloromethane and the suspension was washed with 10% aqueous sodium hydroxide solution, water and brine. The organic layer was dried (anhydrous MgS04), evaporated, and the residue was chromatographed on silica gel (150 g) using dichloromethane-methanol (90:10) as eluant.
- A solution of the product in diisopropyl ether was treated with animal charcoal, filtered, evaporated and the residue (c. 1.3g) was recrystallized from diisopropyl ether giving 2-Ly - piperidinyl) propyl] - 1,2 - benzisothiazol - 3 - one as colourless needles, 720 mg, (18.5%), m.p. 71.5 - 73°.
- The compound of the Example was tested for their ability to inhibit platelet aggregation in the guinea pig ex vivo by the method given below, and was compared with two closely related compounds disclosed in U.S. Patent 3,337,715, and also with two compounds disclosed in French Patent Specification No, 2332019 as well as with three known anti-aggregant compounds.
- Ten male guinea pigs weighing 250-300 g were orally dosed 1% methyl cellulose (5 ml/kg) in which the compound under test was suspended. Ten control animals were given methyl cellulose alone. Two hours later, each animal was killed and 4.5 ml blood drawn from the inferior vena cava into 0.5 ml trisodium citrate dihydrate. Platelet-rich-plasma (PRP) was prepared from each blood sample by centrifugation at 450 g for 5 min. The platelet concentration in each sample of PRP was adjusted with autologous platelet-poor plasma to give a count of 500.000 plateletsl,ul PRP. Aggregation was measured turbidometrically (G.V.R. Born, 1962 Nature, 194, 927-929) at 37° using a Bryston aggregometer coupled to a pen-recorder. The concentration of collagen producing approximately 50% maximal aggregation and the concentration of ADP (adenosive diphosphate) producing first-phase aggregation were compared in PRP samples from control and drug treated animals. Results are summarised in Table 1 together with some known anti-aggregant compounds for comparison.
- In Table 1 the dose ratio represents the ratio of the concentration of aggregating agent to cause aggregation in PRP from drug-treated animals to the concentration of aggregating agent to cause aggregation in PRP from control animals.
-
- It can be seen from Table 1 that compound A is substantially more active than any other compound in Table 1 as an inhibitor of platelet aggregation.
- The asterisk indicates that the results are statistically significant at p < 0.01.
Claims (4)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB2559977 | 1977-06-20 | ||
GB2559977 | 1977-06-20 |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0000254A1 EP0000254A1 (en) | 1979-01-10 |
EP0000254B1 true EP0000254B1 (en) | 1981-06-10 |
Family
ID=10230306
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP78300050A Expired EP0000254B1 (en) | 1977-06-20 | 1978-06-15 | Antithrombotic 2-(gamma-(1-piperidinyl)propyl)1,2-benzisothiazol 3-one, its pharmaceutically acceptable acid addition salts, their preparation and their compositions |
Country Status (16)
Country | Link |
---|---|
US (1) | US4186203A (en) |
EP (1) | EP0000254B1 (en) |
JP (1) | JPS549283A (en) |
AR (1) | AR216675A1 (en) |
AU (1) | AU516003B2 (en) |
CA (1) | CA1098447A (en) |
DE (1) | DE2860750D1 (en) |
DK (1) | DK275478A (en) |
ES (3) | ES470977A1 (en) |
FI (1) | FI781956A (en) |
IE (1) | IE46937B1 (en) |
IL (1) | IL54956A0 (en) |
IT (1) | IT7849941A0 (en) |
NO (1) | NO782129L (en) |
NZ (1) | NZ187628A (en) |
ZA (1) | ZA783508B (en) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS58177915A (en) * | 1982-04-12 | 1983-10-18 | Green Cross Corp:The | Antithrombotic agent |
FR2583046B1 (en) * | 1985-06-05 | 1987-07-17 | Cird | ALKYL OR ARALKYL THIO-2 CYCLOALKENE-1 CARBOXAMIDES-1 AND THEIR SULFOXIDES, THEIR PREPARATION PROCESSES AND THEIR APPLICATION TO THE SYNTHESIS OF SORTING AND TETRAMETHYLENE-4,5 ISOTHIAZOLINE-4, ONES-3 |
DE3617976A1 (en) * | 1986-05-28 | 1988-01-14 | Alter Sa | 1,4-DIHYDROPYRIDINE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE IN ANTITHROMBOTIC MEDICATIONS |
CA1335289C (en) * | 1987-10-26 | 1995-04-18 | Fujio Antoku | Piperidinyl benzisoxazole derivatives, their production and pharmaceutical use |
JP2581739Y2 (en) * | 1990-12-29 | 1998-09-24 | 箱竹 株式会社 | Multipurpose rack |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CH395094A (en) * | 1960-03-24 | 1965-07-15 | Wander Ag Dr A | Process for the preparation of 6-chloro-benzisothiazolone |
DE1147947B (en) * | 1961-07-25 | 1963-05-02 | Knoll Ag | Process for the preparation of new 1,2-benzisothiazolones |
US3661974A (en) * | 1970-04-27 | 1972-05-09 | Sherwin Williams Co | 2-carbalkoxy-phenyl sulfenamides |
NZ182325A (en) * | 1975-11-18 | 1979-03-16 | Beecham Group Ltd | 2-substituted-1,2-benzisothiazol-3-ones |
DE2602643C2 (en) * | 1976-01-24 | 1984-12-20 | Bayer Ag, 5090 Leverkusen | 1,2-Benzisothiazolinone-3, process for their preparation, as well as pharmaceuticals |
ZA776857B (en) * | 1976-12-04 | 1978-09-27 | Beecham Group Ltd | Heterocyclic compounds |
-
1978
- 1978-06-15 EP EP78300050A patent/EP0000254B1/en not_active Expired
- 1978-06-15 DE DE7878300050T patent/DE2860750D1/en not_active Expired
- 1978-06-19 FI FI781956A patent/FI781956A/en not_active Application Discontinuation
- 1978-06-19 ZA ZA00783508A patent/ZA783508B/en unknown
- 1978-06-19 DK DK275478A patent/DK275478A/en unknown
- 1978-06-19 US US05/917,069 patent/US4186203A/en not_active Expired - Lifetime
- 1978-06-19 IE IE1226/78A patent/IE46937B1/en unknown
- 1978-06-19 NO NO782129A patent/NO782129L/en unknown
- 1978-06-19 CA CA305,704A patent/CA1098447A/en not_active Expired
- 1978-06-19 AR AR272657A patent/AR216675A1/en active
- 1978-06-20 IT IT7849941A patent/IT7849941A0/en unknown
- 1978-06-20 JP JP7478278A patent/JPS549283A/en active Pending
- 1978-06-20 NZ NZ187628A patent/NZ187628A/en unknown
- 1978-06-20 ES ES470977A patent/ES470977A1/en not_active Expired
- 1978-06-20 IL IL7854956A patent/IL54956A0/en unknown
- 1978-06-20 AU AU37294/78A patent/AU516003B2/en not_active Expired
-
1979
- 1979-03-15 ES ES478686A patent/ES478686A1/en not_active Expired
- 1979-03-15 ES ES478685A patent/ES478685A1/en not_active Expired
Also Published As
Publication number | Publication date |
---|---|
IE781226L (en) | 1978-12-20 |
NZ187628A (en) | 1981-01-23 |
AU3729478A (en) | 1980-01-03 |
ZA783508B (en) | 1979-06-27 |
FI781956A (en) | 1978-12-21 |
IT7849941A0 (en) | 1978-06-20 |
CA1098447A (en) | 1981-03-31 |
AU516003B2 (en) | 1981-05-14 |
ES470977A1 (en) | 1979-10-01 |
JPS549283A (en) | 1979-01-24 |
IL54956A0 (en) | 1978-08-31 |
NO782129L (en) | 1978-12-21 |
US4186203A (en) | 1980-01-29 |
DK275478A (en) | 1978-12-21 |
EP0000254A1 (en) | 1979-01-10 |
ES478685A1 (en) | 1979-07-01 |
ES478686A1 (en) | 1979-07-01 |
IE46937B1 (en) | 1983-11-02 |
DE2860750D1 (en) | 1981-09-17 |
AR216675A1 (en) | 1980-01-15 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US4212872A (en) | 2-Substituted benzisothiazolones and use thereof | |
IE57326B1 (en) | Salts of omeprazole | |
EP0562599A1 (en) | Condensed thiadiazole derivative, method of its production, and use thereof | |
CH642955A5 (en) | THIAZOLE, USE OF THE SAME AND MEDICINAL PRODUCTS CONTAINING THEM. | |
EP0000254B1 (en) | Antithrombotic 2-(gamma-(1-piperidinyl)propyl)1,2-benzisothiazol 3-one, its pharmaceutically acceptable acid addition salts, their preparation and their compositions | |
JP2001002571A (en) | Medical composition | |
JP3408546B2 (en) | Anti-asthmatic | |
IE44873B1 (en) | Isothiazolo pyridines | |
EP0118036A1 (en) | Biologically active ketone derivative, preparation and use | |
EP0089634B1 (en) | Phenoxypropanolamine derivatives | |
JPS6258335B2 (en) | ||
EP0001503B1 (en) | Antithrombotic compositions containing benzisothiazolones | |
US4182768A (en) | Prophylaxis or treatment of thromboses and inhibition of platelet aggregation in human blood | |
WO1994005290A1 (en) | Platelet aggregation inhibitor | |
JPS632986A (en) | Novel piperazine derivative and antiulcer agent containing said compound as active ingredient | |
JP2962186B2 (en) | Piperidine derivative and serotonin antagonist containing the same | |
US3810991A (en) | A method of inducing fibrinolysis | |
DE2753391A1 (en) | BENZISOTHIAZOLONE, METHOD FOR THE PRODUCTION THEREOF AND MEDICAL PREPARATIONS CONTAINING THESE COMPOUNDS | |
JPS6241500B2 (en) | ||
JP2997892B2 (en) | Preventive and therapeutic agent for cardiovascular diseases containing hydantoin derivative as active ingredient | |
JPH09157236A (en) | Phenylenediamine derivative, radical scavenger, agent for suppressing cerebral infarction and agent for suppressing cerebral edema | |
DK152051B (en) | PROCEDURE FOR THE PREPARATION OF CRYSTALLINIC SODIUM CEOPERAZONE | |
JP2955768B2 (en) | New diazocin derivatives | |
SU1015824A3 (en) | Process for preparing derivatives of mercaptoimidazole or their acid addition salts | |
CA2012092A1 (en) | 5-ht3 receptor antagonist |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
AK | Designated contracting states |
Designated state(s): BE CH DE FR GB NL SE |
|
17P | Request for examination filed | ||
GRAA | (expected) grant |
Free format text: ORIGINAL CODE: 0009210 |
|
AK | Designated contracting states |
Designated state(s): BE CH DE FR GB NL SE |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: FR Payment date: 19810624 Year of fee payment: 4 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: NL Payment date: 19810630 Year of fee payment: 4 Ref country code: BE Payment date: 19810630 Year of fee payment: 4 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: SE Payment date: 19810731 Year of fee payment: 4 |
|
REF | Corresponds to: |
Ref document number: 2860750 Country of ref document: DE Date of ref document: 19810917 |
|
RAP2 | Party data changed (patent owner data changed or rights of a patent transferred) |
Owner name: BEECHAM GROUP PLC |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: BE Effective date: 19820615 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: SE Effective date: 19820616 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: CH Effective date: 19820630 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: NL Effective date: 19830101 |
|
NLV4 | Nl: lapsed or anulled due to non-payment of the annual fee | ||
REG | Reference to a national code |
Ref country code: CH Ref legal event code: PL |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: DE Effective date: 19830301 |
|
GBPC | Gb: european patent ceased through non-payment of renewal fee | ||
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: FR Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 19830331 |
|
REG | Reference to a national code |
Ref country code: FR Ref legal event code: ST |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: GB Effective date: 19881117 |
|
EUG | Se: european patent has lapsed |
Ref document number: 78300050.8 Effective date: 19850612 |
|
PLBE | No opposition filed within time limit |
Free format text: ORIGINAL CODE: 0009261 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT |