WO1982000585A1 - Sparteine derivative,method for its preparation,medicine containing such derivative and method for preparing such medicine - Google Patents
Sparteine derivative,method for its preparation,medicine containing such derivative and method for preparing such medicine Download PDFInfo
- Publication number
- WO1982000585A1 WO1982000585A1 PCT/EP1981/000127 EP8100127W WO8200585A1 WO 1982000585 A1 WO1982000585 A1 WO 1982000585A1 EP 8100127 W EP8100127 W EP 8100127W WO 8200585 A1 WO8200585 A1 WO 8200585A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- magnesium
- carries out
- acid
- bite
- proton donor
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 32
- SLRCCWJSBJZJBV-AJNGGQMLSA-N sparteine Chemical class C1N2CCCC[C@H]2[C@@H]2CN3CCCC[C@H]3[C@H]1C2 SLRCCWJSBJZJBV-AJNGGQMLSA-N 0.000 title claims description 12
- 239000003814 drug Substances 0.000 title claims description 10
- 238000002360 preparation method Methods 0.000 title claims description 5
- 150000003839 salts Chemical class 0.000 claims abstract description 10
- 239000011777 magnesium Substances 0.000 claims description 32
- 229910052749 magnesium Inorganic materials 0.000 claims description 32
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 31
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 22
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 20
- 239000000203 mixture Substances 0.000 claims description 18
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 11
- SLRCCWJSBJZJBV-UHFFFAOYSA-N alpha-isosparteine Natural products C1N2CCCCC2C2CN3CCCCC3C1C2 SLRCCWJSBJZJBV-UHFFFAOYSA-N 0.000 claims description 11
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 claims description 11
- 229960001945 sparteine Drugs 0.000 claims description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 11
- 229930008564 C01BA04 - Sparteine Natural products 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 8
- 229910052708 sodium Inorganic materials 0.000 claims description 8
- 239000011734 sodium Substances 0.000 claims description 8
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- 230000003288 anthiarrhythmic effect Effects 0.000 claims description 6
- 229910052700 potassium Inorganic materials 0.000 claims description 6
- 239000011591 potassium Substances 0.000 claims description 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 5
- 230000004913 activation Effects 0.000 claims description 5
- 229910052783 alkali metal Inorganic materials 0.000 claims description 5
- 150000001340 alkali metals Chemical class 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 3
- 150000007513 acids Chemical class 0.000 claims description 3
- 239000000010 aprotic solvent Substances 0.000 claims description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 3
- 238000005267 amalgamation Methods 0.000 claims description 2
- 239000000969 carrier Substances 0.000 claims description 2
- 150000002170 ethers Chemical class 0.000 claims description 2
- -1 magnesium halogen compound Chemical class 0.000 claims description 2
- LWJROJCJINYWOX-UHFFFAOYSA-L mercury dichloride Chemical compound Cl[Hg]Cl LWJROJCJINYWOX-UHFFFAOYSA-L 0.000 claims description 2
- 229910000510 noble metal Inorganic materials 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims description 2
- BWKNRAAXVUYXAH-TUVASFSCSA-N dehydrosparteine Chemical class C1N2C=CCC[C@@H]2[C@H]2CN3CCCC[C@H]3[C@@H]1C2 BWKNRAAXVUYXAH-TUVASFSCSA-N 0.000 claims 1
- 229910001629 magnesium chloride Inorganic materials 0.000 claims 1
- 229940100892 mercury compound Drugs 0.000 claims 1
- 150000002731 mercury compounds Chemical class 0.000 claims 1
- 231100000252 nontoxic Toxicity 0.000 claims 1
- 230000003000 nontoxic effect Effects 0.000 claims 1
- 150000002680 magnesium Chemical class 0.000 abstract 1
- 229910052751 metal Inorganic materials 0.000 abstract 1
- 239000002184 metal Substances 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 11
- 238000006471 dimerization reaction Methods 0.000 description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- 238000010992 reflux Methods 0.000 description 7
- 238000009835 boiling Methods 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- XFSBVAOIAHNAPC-UHFFFAOYSA-N Aconitin Natural products CCN1CC(C(CC2OC)O)(COC)C3C(OC)C(C(C45)(OC(C)=O)C(O)C6OC)C1C32C4CC6(O)C5OC(=O)C1=CC=CC=C1 XFSBVAOIAHNAPC-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000013543 active substance Substances 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- XFSBVAOIAHNAPC-XTHSEXKGSA-N 16-Ethyl-1alpha,6alpha,19beta-trimethoxy-4-(methoxymethyl)-aconitane-3alpha,8,10alpha,11,18alpha-pentol, 8-acetate 10-benzoate Chemical compound O([C@H]1[C@]2(O)C[C@H]3[C@@]45C6[C@@H]([C@@]([C@H]31)(OC(C)=O)[C@@H](O)[C@@H]2OC)[C@H](OC)[C@@H]4[C@]([C@@H](C[C@@H]5OC)O)(COC)CN6CC)C(=O)C1=CC=CC=C1 XFSBVAOIAHNAPC-XTHSEXKGSA-N 0.000 description 3
- 229910002016 Aerosil® 200 Inorganic materials 0.000 description 3
- 229920002261 Corn starch Polymers 0.000 description 3
- 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 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 229940039750 aconitine Drugs 0.000 description 3
- STDXGNLCJACLFY-UHFFFAOYSA-N aconitine Natural products CCN1CC2(COC)C(O)CC(O)C34C5CC6(O)C(OC)C(O)C(OC(=O)C)(C5C6OC(=O)c7ccccc7)C(C(OC)C23)C14 STDXGNLCJACLFY-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 206010003119 arrhythmia Diseases 0.000 description 3
- 230000006793 arrhythmia Effects 0.000 description 3
- 239000008120 corn starch Substances 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 230000036747 functional refractory period Effects 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000008188 pellet Substances 0.000 description 3
- 238000009419 refurbishment Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 102100030537 Spartin Human genes 0.000 description 2
- 101710015530 Spartin Proteins 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 229930013930 alkaloid Natural products 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 239000003416 antiarrhythmic agent Substances 0.000 description 2
- RCTYPNKXASFOBE-UHFFFAOYSA-M chloromercury Chemical compound [Hg]Cl RCTYPNKXASFOBE-UHFFFAOYSA-M 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000004140 cleaning Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 239000007862 dimeric product Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 229940126601 medicinal product Drugs 0.000 description 2
- 239000012188 paraffin wax Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- FCEHFCFHANDXMB-UMEYXWOPSA-N tocosimplex Chemical compound OS(O)(=O)=O.C1N2CCCC[C@@H]2[C@@H]2CN3CCCC[C@H]3[C@H]1C2 FCEHFCFHANDXMB-UMEYXWOPSA-N 0.000 description 2
- SLRCCWJSBJZJBV-LXTVHRRPSA-N (-)-Spartein Natural products C1N2CCCC[C@@H]2[C@H]2CN3CCCC[C@@H]3[C@H]1C2 SLRCCWJSBJZJBV-LXTVHRRPSA-N 0.000 description 1
- KPZGRMZPZLOPBS-UHFFFAOYSA-N 1,3-dichloro-2,2-bis(chloromethyl)propane Chemical compound ClCC(CCl)(CCl)CCl KPZGRMZPZLOPBS-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-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
- 206010015856 Extrasystoles Diseases 0.000 description 1
- 239000001358 L(+)-tartaric acid Substances 0.000 description 1
- 235000011002 L(+)-tartaric acid Nutrition 0.000 description 1
- FEWJPZIEWOKRBE-LWMBPPNESA-N L-(+)-Tartaric acid Natural products OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 238000011785 NMRI mouse Methods 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229920003080 Povidone K 25 Polymers 0.000 description 1
- 208000000418 Premature Cardiac Complexes Diseases 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 208000008131 Ventricular Flutter Diseases 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- XFSBVAOIAHNAPC-NPVHKAFCSA-N aconitin Chemical compound O([C@H]1[C@]2(O)C[C@H]3[C@@]45[C@H]6[C@@H]([C@@]([C@H]31)(OC(C)=O)[C@@H](O)[C@@H]2OC)[C@H](OC)[C@@H]4[C@]([C@@H](C[C@@H]5OC)O)(COC)CN6CC)C(=O)C1=CC=CC=C1 XFSBVAOIAHNAPC-NPVHKAFCSA-N 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 235000015278 beef Nutrition 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical class [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 239000012433 hydrogen halide Substances 0.000 description 1
- 229910000039 hydrogen halide Inorganic materials 0.000 description 1
- 210000005246 left atrium Anatomy 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 150000002730 mercury Chemical class 0.000 description 1
- YLGXILFCIXHCMC-JHGZEJCSSA-N methyl cellulose Chemical compound COC1C(OC)C(OC)C(COC)O[C@H]1O[C@H]1C(OC)C(OC)C(OC)OC1COC YLGXILFCIXHCMC-JHGZEJCSSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical class C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000010972 statistical evaluation Methods 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000816 toxic dose Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 206010047302 ventricular tachycardia Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Definitions
- New divisional derivative process for its preparation, medicinal product containing the derivative and process for producing the medicinal products
- the invention relates to 17S, 17'S bispartin, process for its preparation and medicament containing the derivative and process for the production of such medicaments.
- an antiarrhythmic has a wide therapeutic range, i.e. the ratio of toxic dose to active dose must be large. Furthermore, it is advantageous if an antiarrhythmic agent also acts after oral administration and over a longer period of time.
- the known division derivatives have the disadvantage that the antiarrhythmic effect after oral administration is only slight or the effect is short.
- the object of the present invention is to provide an active substance with a basic division structure with a more favorable activity profile than that of the known division derivatives and medicaments containing this derivative.
- -Diplospartyrins are division derivatives with chemical bonds between the carbon atoms 17 and 5 'or 12' or 14 ', but in no case compounds of the type 17S, 17' S bite part. This connection is new.
- the novel dimeric division derivative according to the invention can be prepared by reacting 17-hydroxysparteine or 17-dehydrosparteine salt, preferably the perchlorate salt, with an alkali metal or with active magnesium in a solvent.
- the compound thus obtained can be converted into its acid addition salts using physiologically tolerated acids.
- Aprotic solvents are preferably used as solvents.
- Ethers are preferably used, in particular tetrahydrofuran, diethyl ether, ethyl englycoldimethyl ether and / or mixtures thereof.
- the reaction is advantageously carried out at the boiling point of the solvent; in the case of higher-boiling solvents, the reaction can also be carried out below the boiling point.
- Magnesium with an active surface can be obtained using various methods:
- the magnesium is activated in the presence of the sparteine used as the starting compound, in particular the 17-hydroxysparteine.
- the dimerization to the bite spartin is also possible in a protic solvent in the presence of a proton donor - for example in the water / hydrogen halide system - it is advantageous to use a mixture of proton donor and aprotic as a solvent to use solvents.
- the proportion of the proton donor in the total volume of the liquid phase is 0.5 to 50% by volume, preferably 1 to 30% by volume. If an acid is used as the proton donor, an organic acid, in particular acetic acid or trifluoroacetic acid, is preferred.
- finely divided alkali metal in particular finely divided sodium, is preferably used.
- the basic 17S, 17 'S bite part is isolated from the reaction mixture and cleaned in a manner known per se. In particular, it can be extracted from an alkaline medium and the crude product can be purified by chromatography and / or crystallization.
- the acid addition salts obtainable according to the invention are obtained by reacting the basic 17S, 17 'S bite party with acids which form physiologically acceptable salts.
- acids which form physiologically acceptable salts.
- halides in particular chlorides, fumarates, naphthalene sulfonates, sulfates, phosphates, citrates, maleinates, tartrates.
- the salts produced by the process according to the invention are stable and stable both in aqueous solution and in solid form and can be processed into medicaments by mixing with pharmaceutically customary carriers and / or auxiliaries.
- the 17S, 17 'S-bite sparteine according to the invention has more favorable pharmacological, in particular antiarrhythmic properties than division in and the known 17-alkylsparteine.
- the new dimeric sparteine shows a comparable influence on the functional refractory period with a lower re or comparable toxicity even at a much lower dose.
- the compound according to the invention shows a good antiarrhythmic effect even after 3 hours of oral administration. On the other hand, no effect could be demonstrated for the known division derivatives under the same conditions.
- the table shows:
- the LD 50 is defined as the dose in ⁇ mol / kg at which the mortality rate on the 7th day after application is 50% of the test animals.
- the LD 50 was determined by probit analysis [L. Cavalli-Sforza, basic terms of biometry, in particular the statistical methods for the assessment of the value of biologically active substances, Gustav Fischer Verlag, Stuttgart (1964)].
- the influence of the active substance on male Wistar rats of the weight class 280 to 350 g infused with aconitin according to the Raschak method [M. Raschak, medic. - Research. (Drug Res.) 25 (4) (1975), 639-641].
- the effective dose is given in ⁇ mol / kg, at which the times until the occurrence of arrhythmias triggered by the aconitine were significantly delayed compared to a control group which had only received the vehicle.
- the time to the appearance of arrhythmias had to be extended significantly, and the substance had to be effective against at least two of the typical arrhythmia forms occurring after aconitine infusion (extrasystoles, ventricular tachycardia, ventricular flutter).
- the test substance suspended in 2 ⁇ iger Tylose MH 50 was administered orally to the animals 3 hours before the start of the aconitine infusion.
- the standard dose was 1/10 of the oral LD 50 value in the mouse. If a test substance was found to be effective at this dose, the. Dose reduced.
- the Student t-test after logarithmizing the effect values was used as the significance test (Lothar Sachs, Statistical Evaluation Methods, Springer Verlag, Berlin, Heidelberg, New York, 1969).
- the calculated molecular weight (MW) of the active substance is also given in the table.
- the 17-hydroxysparteine was obtained from sparteine according to DE-OS 23 25 117.4.
- the 17-dehydrosparteine perchlorate was prepared from 17-hydroxysparteine according to M. Rink and K. Grabowski, Arch. Pharm. 289 (1956) 695.
- Dimersization of 17-dehydrospartein perchlorate with freshly precipitated, finely divided magnesium using potassium 4 g of anhydrous magnesium chloride are heated under reflux together with 1.5 g of potassium for 3.5 hours in 100 ml of absolute tetrahydrofuran. The magnesium is deposited as a black dispersion. 12 g of 17-dehydrosparteine perchlorate are added to the suspension, which has cooled to room temperature, and the whole is heated to boiling with vigorous stirring for 2.5 hours. Then, while the reaction mixture is heated further, 10 ml of isopropanol are added, the suspension is then cooled and acidified with dilute hydrochloric acid.
- the excess magnesium After the excess magnesium has gone into solution, it is extracted twice with 100 ml of methylene chloride. After the addition of 20 g of ammonium chloride, the aqueous phase is made alkaline with 20% sodium hydroxide solution and then extracted twice with 100 ml of diethyl ether each time. The organic phase is evaporated in a water jet vacuum and the residue is taken up in methylene chloride. After drying over magnesium sulfate, the solvent is removed in vacuo.
- a crystalline ditartrate salt (mp: 186 ° C) is obtained by adding the calculated amount of L (+) tartaric acid to a hot solution of the bite party chamfer in isopropanol
- the amorphous tetrahydrochloride salt can be obtained by adding excess ethanolic hydrochloric acid to the bite party beef in isopropanol and evaporating the solution to dryness.
- Example 4 Under the conditions of Example 4, 10 g of dehydrospartein perchlorate are reacted with amalgamated magnesium (obtained from 1.45 g of magnesium chips and 3.25 g of mercury chloride) in 75 ml of tetrahydrofuran.
- the crude product obtained after the acid-base separation (see Example 1) is purified by crystallization without column chromatography.
- the crude product is dissolved in hot dichloromethane. After the addition of acetone, the 17 S, 17'S bite part precipitates.
- the 17S, 17'S bite sparteine crystallizes from a mixture of methylene chloride and acetone, as well as from ethanol.
- 17S, 17'S bite spartititartrate is premixed with lactose and corn starch in a Diosna mixer for 1 min. Moisten thoroughly with an aqueous solution of Kollidon 25 and pass the still moist granules through a 1.5 mm sieve. After drying, the mass is passed through a 1 mm sieve, mixed with Aerosil 200 and stearic acid, and the mixture obtained in this way is pressed into tablets on the rotary machine. The tablets weigh an average of 98.2 mg, so that 20 mg 17S, 17'S bite party and nitittrate are contained per tablet.
- Aerosil 200 0.5 mg
- 17S, 17'S bite-party intartrate is mixed together with lactose and corn starch in a cube mixer for 20 min. Aerosil 200 and magnesium stearate, after passing through a 0.2 mm sieve, are combined with the mixture and mixed within 5 min. The powder mixture is filled into size 4 capsules on an automatic capsule filling machine. Each capsule contains an average of 97 mg powder mix, corresponding to 20 mg 17S, 17'S bite party indittrate.
- 17S, 17 'S bite spartintetrachloride and sodium chloride are dissolved in bidistilled water.
- the solution is filtered, filled into ampoules and, after sealing, sterilized at 120 ° C. for 20 minutes.
- Each ampoule contains 1 ml of solution, corresponding to 5 mg of 17S, 17'S bite party tetrahedron.
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- Animal Behavior & Ethology (AREA)
- Heart & Thoracic Surgery (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)
- Medicinal Preparation (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NO821061A NO156866C (no) | 1980-08-27 | 1982-03-30 | Analogifremgangsmaate ved fremstilling av terapeutisk aktivt 17s, 17's-bisspartein og akseptable syreaddisjonssalter. |
| DK185182A DK151261C (da) | 1980-08-27 | 1982-04-26 | Fremgangsmaade til fremstilling af 17s,17's-bisspartein eller fysiologisk acceptable syreadditionssalte deraf |
| FI823260A FI66382C (fi) | 1980-08-27 | 1982-09-22 | Foerfarande foer framstaellning av farmaceutiskt anvaendbar 17 17's-bisspartein |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19803032219 DE3032219A1 (de) | 1980-08-27 | 1980-08-27 | Neues sparteinderivat, verfahren zu seiner herstellung, das derivat enthaltende arzneimittel und verfahren zur herstellung der arzneimittel |
| DE3032219800827 | 1980-08-27 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1982000585A1 true WO1982000585A1 (en) | 1982-03-04 |
Family
ID=6110471
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP1981/000127 WO1982000585A1 (en) | 1980-08-27 | 1981-08-18 | Sparteine derivative,method for its preparation,medicine containing such derivative and method for preparing such medicine |
Country Status (21)
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3522475A1 (de) * | 1985-06-22 | 1987-01-02 | Kali Chemie Pharma Gmbh | Neue aromatische verbindungen, ihre herstellung und verwendung |
| US5100647A (en) * | 1990-10-02 | 1992-03-31 | The Trustees Of The University Of Pennsylvania | Method and formulations for the therapy of cystic fibrosis, Bartter's syndrome and secretory diarrheas, and for diuretic treatment |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2360475C3 (de) | 1973-12-05 | 1980-11-20 | Kali-Chemie Pharma Gmbh, 3000 Hannover | arzneimittel zur Behandlung von Herzrhytmusstörungen |
-
1980
- 1980-08-27 DE DE19803032219 patent/DE3032219A1/de not_active Withdrawn
-
1981
- 1981-06-26 ZA ZA814355A patent/ZA814355B/xx unknown
- 1981-07-02 PT PT73304A patent/PT73304B/pt unknown
- 1981-08-05 IE IE1784/81A patent/IE51470B1/en unknown
- 1981-08-06 ES ES504588A patent/ES504588A0/es active Granted
- 1981-08-11 NZ NZ198007A patent/NZ198007A/xx unknown
- 1981-08-12 IL IL63561A patent/IL63561A/xx unknown
- 1981-08-18 WO PCT/EP1981/000127 patent/WO1982000585A1/en active IP Right Grant
- 1981-08-18 PH PH26062A patent/PH18399A/en unknown
- 1981-08-18 EP EP81106402A patent/EP0046565B1/de not_active Expired
- 1981-08-18 DD DD81232650A patent/DD201796A5/de unknown
- 1981-08-18 CA CA000384079A patent/CA1166638A/en not_active Expired
- 1981-08-18 DE DE8181106402T patent/DE3160183D1/de not_active Expired
- 1981-08-18 HU HU813208A patent/HU182760B/hu not_active IP Right Cessation
- 1981-08-18 JP JP56502804A patent/JPH0139435B2/ja not_active Expired
- 1981-08-18 AT AT81106402T patent/ATE2998T1/de active
- 1981-08-19 US US06/294,207 patent/US4415577A/en not_active Expired - Fee Related
- 1981-08-25 GR GR65863A patent/GR74997B/el unknown
- 1981-08-26 AU AU74633/81A patent/AU543477B2/en not_active Ceased
-
1982
- 1982-04-26 DK DK185182A patent/DK151261C/da not_active IP Right Cessation
- 1982-09-22 FI FI823260A patent/FI66382C/fi not_active IP Right Cessation
- 1982-09-24 SU SU823495101A patent/SU1149878A3/ru active
Non-Patent Citations (2)
| Title |
|---|
| Chemical Abstracts, vol. 77, published in 1972, (Columbus, Ohio, US), V.I. Vinogradova u.a.: "Dithermamine, a new biomolecular alkaloid from Thermopsis Lanceolata", page 238, abstract no. 58768n; & Khim. Prir. Soedin. 1972, 8 (1), 87-92 (Russ.) * |
| Tetrahedron, vol. 29, published, in 1973, Dublin (IE), D. Herlem u.a.: "Réactions photochimiques d'amines tertiaires et d'alcaloides III1,2", pages 2195-2202 * |
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