DK157489B - N-substituerede pyridiniumforbindelser og farmaceutiske praeparater indeholdende disse - Google Patents
N-substituerede pyridiniumforbindelser og farmaceutiske praeparater indeholdende disse Download PDFInfo
- Publication number
- DK157489B DK157489B DK067384A DK67384A DK157489B DK 157489 B DK157489 B DK 157489B DK 067384 A DK067384 A DK 067384A DK 67384 A DK67384 A DK 67384A DK 157489 B DK157489 B DK 157489B
- Authority
- DK
- Denmark
- Prior art keywords
- amino
- chloro
- sulfamoylbenzoyl
- inert
- general formula
- Prior art date
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- -1 N-SUBSTITUTED PYRIDINIUM COMPOUNDS Chemical class 0.000 title claims description 17
- 239000000825 pharmaceutical preparation Substances 0.000 title 1
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 7
- 239000001257 hydrogen Substances 0.000 claims abstract description 7
- 239000002253 acid Substances 0.000 claims abstract description 6
- 150000001450 anions Chemical class 0.000 claims abstract description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract 4
- 150000001875 compounds Chemical class 0.000 claims description 14
- SFAGGWFAHKODDV-UHFFFAOYSA-N 4-chloro-3-sulfamoyl-n-(2,4,6-trimethylpyridin-1-ium-1-yl)benzamide;hydroxide Chemical compound [OH-].CC1=CC(C)=CC(C)=[N+]1NC(=O)C1=CC=C(Cl)C(S(N)(=O)=O)=C1 SFAGGWFAHKODDV-UHFFFAOYSA-N 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- OBVZUOVKNYPMDO-UHFFFAOYSA-N 4-chloro-2-(furan-2-ylmethylamino)-5-sulfamoyl-n-(2,4,6-trimethylpyridin-1-ium-1-yl)benzamide;hydroxide Chemical compound [OH-].CC1=CC(C)=CC(C)=[N+]1NC(=O)C1=CC(S(N)(=O)=O)=C(Cl)C=C1NCC1=CC=CO1 OBVZUOVKNYPMDO-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 4
- IOSVEGFFXURGHD-UHFFFAOYSA-N 1-[(4-chloro-3-sulfamoylbenzoyl)amino]pyridin-1-ium-3-carboxamide;hydroxide Chemical compound [OH-].NC(=O)C1=CC=C[N+](NC(=O)C=2C=C(C(Cl)=CC=2)S(N)(=O)=O)=C1 IOSVEGFFXURGHD-UHFFFAOYSA-N 0.000 claims description 3
- ILWMJGNLIYWTHA-UHFFFAOYSA-N 4-chloro-3-sulfamoyl-n-(2,4,6-triphenylpyridin-1-ium-1-yl)benzamide;chloride Chemical compound [Cl-].C1=C(Cl)C(S(=O)(=O)N)=CC(C(=O)N[N+]=2C(=CC(=CC=2C=2C=CC=CC=2)C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 ILWMJGNLIYWTHA-UHFFFAOYSA-N 0.000 claims description 3
- CPIIWAIIVPFLNH-UHFFFAOYSA-N 4-chloro-n-(2,6-dimethylpyridin-1-ium-1-yl)-3-sulfamoylbenzamide;hydroxide Chemical compound [OH-].CC1=CC=CC(C)=[N+]1NC(=O)C1=CC=C(Cl)C(S(N)(=O)=O)=C1 CPIIWAIIVPFLNH-UHFFFAOYSA-N 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- VWVZFHRDLPHBEG-UHFFFAOYSA-N 1-(chloromethyl)-4-methylsulfanylbenzene Chemical group CSC1=CC=C(CCl)C=C1 VWVZFHRDLPHBEG-UHFFFAOYSA-N 0.000 claims 1
- ZQXACKUDEUQEGE-UHFFFAOYSA-M [Cl-].Cc1ccc[n+](C)c1C Chemical compound [Cl-].Cc1ccc[n+](C)c1C ZQXACKUDEUQEGE-UHFFFAOYSA-M 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 150000004679 hydroxides Chemical class 0.000 claims 1
- 150000003839 salts Chemical class 0.000 abstract description 16
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract description 3
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 abstract 1
- HLXPZPRPBBGADV-UHFFFAOYSA-M pyridin-1-ium-1-amine;hydroxide Chemical class [OH-].N[N+]1=CC=CC=C1 HLXPZPRPBBGADV-UHFFFAOYSA-M 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 39
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 27
- 239000000243 solution Substances 0.000 description 14
- 238000003756 stirring Methods 0.000 description 13
- 238000000034 method Methods 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 238000002329 infrared spectrum Methods 0.000 description 9
- 230000008018 melting Effects 0.000 description 9
- 238000002844 melting Methods 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 239000002244 precipitate Substances 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 210000002700 urine Anatomy 0.000 description 6
- 230000003204 osmotic effect Effects 0.000 description 5
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 229910006074 SO2NH2 Inorganic materials 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 230000001882 diuretic effect Effects 0.000 description 4
- KWIUHFFTVRNATP-UHFFFAOYSA-N glycine betaine Chemical compound C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- UYHMQTNGMUDVIY-UHFFFAOYSA-M 1-(2,4-dinitrophenyl)pyridin-1-ium;chloride Chemical class [Cl-].[O-][N+](=O)C1=CC([N+](=O)[O-])=CC=C1[N+]1=CC=CC=C1 UYHMQTNGMUDVIY-UHFFFAOYSA-M 0.000 description 3
- VYILDERYIAXWFS-UHFFFAOYSA-N 4-chloro-3-sulfamoyl-n-(2,4,6-triphenylpyridin-1-ium-1-yl)benzamide;hydroxide Chemical compound [OH-].C1=C(Cl)C(S(=O)(=O)N)=CC(C(=O)N[N+]=2C(=CC(=CC=2C=2C=CC=CC=2)C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 VYILDERYIAXWFS-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical class C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 125000000565 sulfonamide group Chemical group 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- CLSMFWMBUFOUGR-UHFFFAOYSA-N 4-chloro-3-sulfamoyl-n-(2,4,6-trimethylpyridin-1-ium-1-yl)benzamide;chloride Chemical compound [Cl-].CC1=CC(C)=CC(C)=[N+]1NC(=O)C1=CC=C(Cl)C(S(N)(=O)=O)=C1 CLSMFWMBUFOUGR-UHFFFAOYSA-N 0.000 description 2
- MWGBWYBJCXXYOU-UHFFFAOYSA-N 4-chloro-n-pyridin-1-ium-1-yl-3-sulfamoylbenzamide;hydroxide Chemical compound [OH-].C1=C(Cl)C(S(=O)(=O)N)=CC(C(=O)N[N+]=2C=CC=CC=2)=C1 MWGBWYBJCXXYOU-UHFFFAOYSA-N 0.000 description 2
- USSIQXCVUWKGNF-UHFFFAOYSA-N 6-(dimethylamino)-4,4-diphenylheptan-3-one Chemical compound C=1C=CC=CC=1C(CC(C)N(C)C)(C(=O)CC)C1=CC=CC=C1 USSIQXCVUWKGNF-UHFFFAOYSA-N 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 208000004880 Polyuria Diseases 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 230000001476 alcoholic effect Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 229960003237 betaine Drugs 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 229960001523 chlortalidone Drugs 0.000 description 2
- JIVPVXMEBJLZRO-UHFFFAOYSA-N chlorthalidone Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C2(O)C3=CC=CC=C3C(=O)N2)=C1 JIVPVXMEBJLZRO-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 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
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 150000003222 pyridines Chemical class 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 230000036325 urinary excretion Effects 0.000 description 2
- POPVUKGJWNLYGW-UHFFFAOYSA-N (hydroxyamino) hydrogen sulfate Chemical compound ONOS(O)(=O)=O POPVUKGJWNLYGW-UHFFFAOYSA-N 0.000 description 1
- RGQXHAWMLUYSTD-UHFFFAOYSA-N 1-(2,4-dinitrophenyl)pyridin-1-ium-3-carboxamide;chloride Chemical compound [Cl-].NC(=O)C1=CC=C[N+](C=2C(=CC(=CC=2)[N+]([O-])=O)[N+]([O-])=O)=C1 RGQXHAWMLUYSTD-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- JIVPVXMEBJLZRO-CQSZACIVSA-N 2-chloro-5-[(1r)-1-hydroxy-3-oxo-2h-isoindol-1-yl]benzenesulfonamide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC([C@@]2(O)C3=CC=CC=C3C(=O)N2)=C1 JIVPVXMEBJLZRO-CQSZACIVSA-N 0.000 description 1
- OSXMYKZLTJOZPP-UHFFFAOYSA-N 4-chloro-2-(furan-2-ylmethylamino)-5-sulfamoyl-n-(2,4,6-trimethylpyridin-1-ium-1-yl)benzamide;chloride Chemical compound [Cl-].CC1=CC(C)=CC(C)=[N+]1NC(=O)C1=CC(S(N)(=O)=O)=C(Cl)C=C1NCC1=CC=CO1 OSXMYKZLTJOZPP-UHFFFAOYSA-N 0.000 description 1
- SCYSJFKWFQZRJW-UHFFFAOYSA-N 4-chloro-3-sulfamoylbenzoyl chloride Chemical compound NS(=O)(=O)C1=CC(C(Cl)=O)=CC=C1Cl SCYSJFKWFQZRJW-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 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
- 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
- VYZAHLCBVHPDDF-UHFFFAOYSA-N Dinitrochlorobenzene Chemical compound [O-][N+](=O)C1=CC=C(Cl)C([N+]([O-])=O)=C1 VYZAHLCBVHPDDF-UHFFFAOYSA-N 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 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
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 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
- VEXQTVKQUUSBOD-UHFFFAOYSA-N ON=S(=O)=O Chemical compound ON=S(=O)=O VEXQTVKQUUSBOD-UHFFFAOYSA-N 0.000 description 1
- 206010030113 Oedema Diseases 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
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241000978776 Senegalia senegal Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 208000037849 arterial hypertension Diseases 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- HCAJEUSONLESMK-UHFFFAOYSA-N cyclohexylsulfamic acid Chemical compound OS(=O)(=O)NC1CCCCC1 HCAJEUSONLESMK-UHFFFAOYSA-N 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 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
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 238000000528 statistical test Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 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
- C07D213/60—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
-
- 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
- C07D213/89—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 with hetero atoms directly attached to the ring nitrogen atom
-
- 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
- A61P7/10—Antioedematous agents; Diuretics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Description
DK 157489 B
Den foreliggende opfindelse angår hidtil ukendte N-substituerede pyridiniumforbindelser og farmaceutiske præparater indeholdende disse.
Pyridiniumforbindelserne ifølge den foreliggende opfindelse er ejen-5 dommelige ved, at de har den almene formel henholdsvis I og II
?4 R-3 Rc I4
V/ 5 R A. R
jj R2 . /'x I® R2 R6 nq 1 a
HN
C = O ^
Rl r^vRl 1 i i H-NO-S s'* J .
2 2 Y H2N02S^y
Cl I
Cl i ii hvor
Rj_ betegner hydrogen eller 2-furylmethylamino; 10 R2, R3, R4, R5 og Rg har samme eller forskellig betydning og betegner hydrogen, alkyl, der er ligekædet eller forgrenet, aryl eller carbamoyl; og Θ X betegner anionen af en farmaceutisk acceptabel syre.
Blandt anionerne af farmaceutisk acceptable syrer kan som de vigtig-15 ste eksempler nævnes sådanne, som svarer til mineralsyrer såsom chlorid, bromid, iodid, nitrat, sulfat, phosphat, eller sådanne, som svarer til organiske syrer såsom acetat, citrat, oxalat, lactat, tartrat, methansulfonat, benzensulfonat, p-toluensulfonat og cyclo-hexylsulfamat.
2
DK i57489B
Forbindelserne ifølge opfindelsen med den almene formel I fås ved udøvelse af fremgangsmåder svarende til reaktions skemaerne A, B og C, og de tilsvarende salte med den almene formel II ved udøvelse af fremgangsmåden svarende til reaktions skema D.
5 Reaktionsskema A
NH, I 2
NH
p 1*0 », *1,Χ,Η I Ϊ * i Ϊ - Ti 0 r6 h2no2s^V^ *2^ n^r6
© di I
v© f
lv C = O
111 ,Α/'ι K2N02S-^X/
Cl
Ved reaktion af et pyriliumsalt med den almene formel III, som er syntetiseret i henhold til flere i og for sig kendte fremstillings-10 metoder, med en monosubstitueret hydrazin med den almene formel IV fås det tilsvarende salt, som, når det behandles med en base, giver anledning til dannelsen af betainen med den almene formel I.
I de ovenfor anførte almene formler III og IV har , R2, R3, R4, R5 og B-6 de ovenfor anførte betydninger, og Y® betegner anionerne 15 CIO4 og CF3SO3 .
DK 157489 B
3
Pyriliumsaltene med den almene formel III kan fx fås ved fremstillingsmetoder, som er beskrevet af A.T. Balaban og C.D. Nenitzescu, J. Chem. Soc., 1961, s. 3553-3566; P.F.G. Praill og A.L. Whitear, J. Chem. Soc., 1961, s. 3573-3579; 5 A.T. Balaban, Advanc. Heterocycl. Chem., 10, 1969, s. 241; A.T. Balaban et al., Org. Synt. Coll., bind V, s. 1106-1116; K. Dimroth et al., Org. Synt. Coll., bind V, s. 1135; A.G. Anderson og P.J. Stang, Org. Synt., 60, 1981, s. 34; E. Elshafie et al., Indian J. Chem. Sect. B, 20 B (5), 1981, s. 427; 10 J.A. Van Allan og G.A. Reynolds, J. Org. Chem., 33, 1968, s. 1102.
Detaljerne angående udøvelsen af fremgangsmåden ifølge reaktionsskema A er illustreret i eksemplerne.
Reaktions skema B
Cl
R4 c = o I
R3y^YR5 ^γκι_Ké>6 r2^Jn f C = 0 X»,
v vi I
h2no2s
Cl 15 N-aminopyridiniumsaltene med den almene formel V fås for eksempel ifølge metoden beskrevet af R. Gosi og A. Meuwsen, Org. Synt., 43, 1963, s. 1, ved at anvende vandige opløsninger af de tilsvarende pyridiner og hydroxylamino-O-sulfonsyre; eller ifølge metoden beskre
DK 157489B
4 vet af Y. Tamura, J. Minamikawa, M. Ikeda, Synthesis, 1977, s. 1 ved reaktion af de tilsvarende pyridiner med aminationsmidlet O-mesity-lensulfonylhydroxylamin.
Ved reaktion af N - aminopy r idiniums al tene med den almene formel V med 5 et syrechlorid med den almene formel VI under basiske betingelser fås de tilsvarende betainer med den almene formel I.
I de almene formler V og VI har Rj_, 1¾. R3, R4, R5 og Rg de ovenfor anførte betydninger, og Z® betegner anioneme _F* 3 01Θ,ΙΘ og H3C—^ ^-S030 \ch3 10
Detaljerne angående udøvelsen af fremgangsmåden ifølge reaktionsskema B er illustreret i eksemplerne.
DK 157489 B
5
Reaktionsskema C
NH- i 2
NH
C = O R
XX Ri R3s^\/R5 | + I — | N^P' Rg H2N02S^^j/ R2^ I ci© di p Χ^\χΝ02 NØ
I !» I
V X.
no, 1
f I
VII
Cl N-(2,4-dinitrophenyl)pyridiniumchlorideme ("Zincke- salte") med den 5 almene formel VII fås fx ved reaktion af 1-chlor-2,4-dinitrobenzen med den tilsvarende pyridin (jfr. T. Zincke, G. Henser og W. Moller,
Ann. 1904, 333, s. 296).
Ved reaktion af N-(2,4-dinitrophenyl)pyridiniumchloridet med den almene formel VII med en monosubstitueret hydrazin med den almene 10 formel IV og en tertiær amin som protoribinder fås de tilsvarende betainer med den almene formel I.
I de ovenfor anførte almene formler VII og IV har R^, R£, R3, R4, R5 og Rg de ovenfor anførte betydninger.
Detaljerne angående udøvelsen af fremgangsmåden ifølge reaktionsskema 15 C er illustreret i eksemplerne.
6 DK 157489B
Reaktionsskema D
f4 }R4 I® HN Qi X-—" X* h2n°2s Ay^1 h2no2s^\^ ci C1 i »
Ved omsætning af betainen med den almene formel I med en syre, H^xP, 5 i nærværelse af et hensigtsmæssigt opløsningsmiddel såsom en alkohol eller et keton fås de tilsvarende salte med den almene formel II.
I formlerne I og II har R^, R2, R3, R/,., R5 og Rg og xP de anførte betydninger.
Detaljerne angående udøvelsen af fremgangsmåden ifølge reaktionsskema 10 D er illustreret i eksemplerne.
På grund af deres gode diuretiske virkning og deres meget lave toxi-citet anvendes forbindelserne med de almene formler I og II som lægemidler, som kan administreres ved behandling af mennesker eller dyr.
Den foreliggende opfindelse angår således også de omhandlede for-15 bindeiser til anvendelse som lægemiddel samt farmaceutiske præparater indeholdende forbindelserne som aktiv bestanddel.
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7
Opfindelsen belyses nærmere ved nedenstående eksempler.
EKSEMPEL 1
Fremstilling af 1-[(4-chlor-3-sulfamoylbenzoyl)amino]pyridinium-hy-droxid, inert salt 5 En opløsning af 8,4 g N-(2,4-dinitrophenyl)pyridiniumchlorid (0,03 mol), 7,5 g 4-chlor-3-sulfamoylbenzoylhydrazid (0,03 mol) og 3,2 g triethylamin (0,032 mol) tilbagesvales i 2 timer i 250 ml ethanol.
Blandingen lades afkøle, og den filtreres og vaskes successivt med ethanol, vand, ethanol og til slut med ethylether. Det således vundne 10 bundfald tilbagesvales med 250 ml dioxan/vand (4:1) i 24 timer, og derefter afdampes dioxanen under reduceret tryk. Remanensen behandles med fortyndet saltsyre og filtreres. Den vandige opløsning neutraliseres med natriumhydroxid under omrøring i 2 timer. Blandingen lades afkøle, hvorved fås et bundfald, som efter omkrystallisation af van-15 dig ethanol giver 6,2 g (66%) af det inerte 1-[(4-chlor-3-sulfamoyl-benzoyl)amino]pyridiniumhydroxidsalt med formlen (=\v°AJr~\, Cl
\_J
so2nh2
Smeltepunkt 225-226°G.
20 IR-Spektrum (KBr): - 1625, 1600, 1550, 1355, 1335, 1160 cm'1.
^H-NMR-Spektrum (DMS0 (d6)); $ (ppm) - 7,25-8,30 (m, 7H); 8,60-8,95 (m, 3H).
DK 157489 B
s EKSEMPEL 2
Fremstilling af 1-[(4-chlor-3-sulfamoylbenzoyl) amino]-2,4,6-trimeth-ylpyridinium-hydroxid, inert salt
En frisk fremstillet opløsning af 3,87 g trimethylpyrilium-tetra-5 fluorborat (0,0184 mol) og 5,06 g 4-chlor-3-sulfamoylbenzoylhydrazid (0,0203 mol) tilbagesvales i 4 timer i 60'ml ethanol. Blandingen afkøles til omgivelsestemperatur under omrøring, og der tilsættes 1,22 g 85%'s kaliumhydroxid (0,0185 mol). Der omrøres i 1 time ved omgivelsestemperatur og opvarmes til kogning, det dannede kalium-10 tetrafluorborat filtreres varmt, og bundfaldet vaskes med ethanol ved 60°C. Ved krystallisation af den koncentrerede alkoholiske opløsning fås 4,93 g (76%) af det inerte 1-[(4-chlor-3-sulfamoylbenzoyl)araino]-2,4,6-trimethylpyridinium-hydroxidsalt med formlen g. ϊ ci ch3 so2nh2 15
Smeltepunkt: 264-265°G.
IR-Spektrum (KBr): = 1640, 1595, 1545, 1360, 1335, 1165 cnT^.
^H-NMR- Spektrum (DMSO (dg)): δ (ppm) =2,5 (s, 9H); 3,5 (bred, 2H); 7,55 (s, 2H); 7,60 (d, IH); 8,15 (q, IH); 8,65 (d, IH).
20 EKSEMPEL 3
Fremstilling af 1-[(4-chlor-3-sulfamoylbenzoyl)amino]-2,6-dimethylpy-ridinium-hydroxid, inert salt 2,5 g 1-amino-2,6-dime thy Xpyridinlun-iodid (0,01 mol) opløst i 20 ml vand og 10 ml acetone behandles med 2,8 g kaliumcarbonat (0,02 ml). I 25 løbet af 15 minutter tilsættes 2,54 g 4-chlør-3-sulfamoylbenzoylchlo-rid (0,01 mol) opløst i 10 ml acetone. Der omrares i 3 timer ved om-
DK 157489 B
9 givelsestemperatur, og blandingen koncentreres ved afdampning af acetone ved en temperatur under 40eC. Der ekstraheres med chloroform, tørres (Na2S04), filtreres, og opløsningsmidlet afdampes. Ved omkrystallisation af ethanol af den vundne remanens fås 2,1 g (62%) af 5 det inerte 1-[(4-chlor-3-sulfamoylbenzoyl)amino]-2,6-dimethylpyridi-nium-hydroxidsalt med formlen ch3 so2nh2
Smeltepunkt: 266-267°C.
10 IR-Spektrum (KBr): μ - 1632, 1590, 1540, 1360, 1330, 1165 cm'1.
1H-NHR-Spektrum (DMS0 (d6)): S (ppm) = 2,47 (s, 6H); 7,25-8,50 (m, 8H).
EKSEMPEL 4
Fremstilling af 1-[(4-chlor-3-sulfamoylbenzoyl)amino]-3-carbamoylpy-15 ridinium-hydroxid, inert salt
En opløsning af 6,5 g 3-carbamoyl-l-(2,4-dinitrophenyl)pyridinium-chlorid (0,02 mol), 5 g 4-chlor-3-sulfamoylbenzoylhydrazid (0,02 mol) og 2,15 g triethylamin (0,021 mol) omrøres i 6 timer ved omgivelsestemperatur i 50 ml methanol. Blandingen filtreres og vaskes med 20 methanol, vand, methanol og til slut med ethylether. Det vundne faste stof tilbagesvales i 15 timer i suspension i 100 ml dioxan/vand (4:1), og derefter afdampes dioxanet under reduceret tryk. Remanensen syrnes med fortyndet saltsyre, filtreres og vaskes med vand. Det vundne bundfald omrøres med kogende ethanol og filtreres varmt.
25 Bundfaldet omrøres med en fortyndet natriumhydroxidopløsning i 1 time, filtreres og vaskes med vand. Herved fås 4,1 g (57%) af det inerte 1-[(4-chlor-3-sulfamoylbenzoyl)amino]-3-carbamoylpyridinium-hydroxidsalt med formlen
DK 157489 B
10 ry-M^ya com2 S02NH2
Smeltepunkt 273-274°G.
IR-Spektrum (KBr): v — 1700, 1638, 1595, 1545, 1355, 1335 og
IE3X
5 1175 cm'1.
1H-HMR- Spektrum (DMSO): S (ppm) - 7,5-8,75 (m, 9H), 8,9 (d, IH), 9,13 (s, IH).
EKSEMPEL 5
Fremstilling af 1- {[4-chlor-2-(2-furylmethylamino)-5-sulfamoylben-10 zoyl]amino}-2,4,6-trimethylpyridinium-hydroxid, inert salt
En nyligt fremstillet opløsning af 3,87 g trimethylpyrilium-tetra-fluorborat (0,0184 mol) og 7,21 g 4-chlor-2-(2-furylmethylamino)-5-sulfamoylbenzoylhydrazid (0,02 mol) tilbagesvales i 6 timer i 70 ml ethanol. Blandingen afkøles til omgivelsestemperatur under omrøring, 15 der tilsættes 1,22 g 85%'s kaliumhydroxid (0,0185 mol), og omrøringen fortsættes i 1 time. Der filtreres og ekstraheres flere gange med ethanol. Den alkoholiske opløsning koncentreres, hvorved fås 4,7 g (55%) af det inerte 1-{[4-chlor-2-(2-f urylmethylamino)-5-sulfamoy1-benzoyl]amino)-2,4,6-trimethylpyridinium-hydroxidsalt med formlen
-- DK 157489 B
11
JU
w· · H3C—^N— tP- C _/V Cl CH^ SO2NH2
Smeltepunkt 274-275°C.
IR-Spektrum (KBr): * 1638, 1600, 1560, 1355, 1340, 1260, 5 1165 cm-^ 1H-NMR-Spektrum (DMSO (dg)): S (ppm) - 2,5 (s, 9H); 4,51 (s, 2H); 6,35 (d, 2H); 6,92 (s, IH); 7,18 (s, 2H); 7,62 (s, 3H); 8,63 (s, IH); 9,5 (bred, IH).
EKSEMPEL 6 10 Fremstilling af l-[(4-chlor-3-sulfamoylbenzoyl)amino]-2,4,6-triphe-nylpyridinium-hydroxid, inert salt
En opløsning af 3,96 g triphenylpyrilium-tetrafluorborat (0,01 mol) og 2,97 g 4-chlor-3-sulfamoylbenzoylhydrazid (0,011 mol) tilbagesvales i 15 timer i 50 ml ethanol. Blandingen afkøles under omrøring til 15 omgivelsestemperatur, og der tilsættes 0,68 g 85%'s kaliumhydroxid (0,0103 mol). Omrøringen fortsættes i 15 minutter, og der filtreres. Filtratet inddampes til tørhed og omkrystalliseres i bensen, hvorved fås 3,0 g (52%) af det inerte l-[(4-chlor-3-sulfamoylbenzoyl)amino|-2,4,6-triphenylpyridiniumhydroxidsalt med formlen
DK 157489 B
12 ,gh ~Q***-Q-
Ph S02NH2
Smeltepunkt 170-172°C.
IR-Spektrum (KBr): vmav - 1628, 1600, 1550, 1350, 1340, 1165 cm-1.
5 ^-NMR-Spektrum (DMSO (dg)): S (ppm) - 7,2-7,85 (m, 17H); 7,92-8,25 (m, 5H).
EKSEMPEL 7
Fremstilling af 1-[(4-chlor-3-sulfamoylbenzoyl)amino]-2,4,6-trimeth-ylpyridinium-chlorid 10 10 ml ethanol, der er mættet med saltsyre, sættes under omrøring til en opløsning af 3,5 g af det inerte salt af l-[(-4-chlor-3-sulfamoyl-benzoyl)amino]-2,4,6-trimethylpyridinium-hydroxid (0,01 mol) i 80 ml ethanol. Efter 1 times omrøring filtreres det dannede bundfald og vaskes med ethanol. Herved fås 3,6 g (92%) 1-[(4-chlor-3-sulfamoyl-15 benzoyl)amino]-2,4,6-trimethylpyridinium-chlorid med formlen
Oi3 S02NH2
Smeltepunkt 272-274°C.
IR-Spektrum (KBr): * 1705, 1642, 1348, 1165 cm ^·.
20 ^H-NMR-Spektrum (DMSO (dg)): S (ppm) - 2,6 (s, 3H); 2,7 (s, 6H); 4,85 (bred, 2H); 7,7-8,05 (m, 4H); 8,35-8,65 (m, 2H).
DK 157489B
13 EKSEMPEL 8
Fremstilling af 1 - {j 4 ~chlor-2-(2-furylmethylamino)-5-sulfamoylbenzo-yl]amino}-2,4,6-trimethylpyridinium-chlorid, chlorhydrat 20 ml ethanol, der er mættet med saltsyre, sættes under omrøring til 5 en suspension af 4,6 g af det inerte l-{[4-chlor-2-(2-furylmethyl-amino) - 5 - sulfamoylbenzoyl ] amino )-2,4,6- trime thylpyridinium-hydroxid-salt (0,01 mol) i 40 ml ethanol. Efter nogle sekunder fås en gennemsigtig opløsning, som øjeblikkeligt begynder at danne bundfald. Opløsningen filtreres og vaskes med ethanol, hvorved fås 4,9 g (98%) 10 af chlorhydratet af l-{[4-chlor-2-(2-furylmethylamino)-5-sulfamoyl-benzoyl]amino)-2,4,6-trimethylpyridinium-chlorid med formlen PS Θ /S02nh2
cjQ
Smeltepunkt 257-258eC.
15 IR.-Spektrum (KBr): y ^ =» 1668, 1635, 1565, 1355, 1165 cm”^·.
1H-NMR-Spektrum (DMSO (dg)): S (ppm) - 2,6 (s, 3H); 2,7 (s, 6H); 4,6 (s, 2H); 5-6 (bred, 5H); 6,4 (d, 2H); 7,1 (s, IH); 7,6 (s, IH); 7,95 (s, 2H); 8,73 (s, IH).
EKSEMPEL 9 20 Fremstilling af 1-[(4-chlor-3-sulfamoylbenzoyl)amino]-2,4,6-triphe-nylpyridinium-chlor id 10 ml ethanol, der er mættet med saltsyre, sættes under omrøring til en opløsning til 5,4 g af det inerte l-[(4-chlor-3-sulfamoylbenzoyl)-amino]-2,4,6-triphenylpyridinium-hydroxidsalt (0,01 mol) i 25 ml
DK 157489 B
14 ethanol. Efter en halv times omrøring filtreres det dannede bundfald, hvorved fås 5,2 g {90%) l-[(4-chlor-3-sulfamoylbenzoyl)amino]-2,4,6-triphenylpyridinium-chlorid med formlen
Ph Ω
Ph S02NH2 5
Smeltepunkt 290-292°G.
IR-Spektrum (KBr): - 1700, 1628, 1340, 1170 cm-*·.
*-H-NMR-Spektrum (DMSO (dg)): δ (ppm) — 4,5 (bred, 3H); 7,25-7,73 (m, 11H); 7,73-8,3 (m, 7H); 8,53 (s, 2H).
10 Diuretisk virkning
Metode beskrevet af R.M. Taylor, J.G. Topliss, J. Med. Pharm. Chem.
4, 1962, s. 312
Der anvendes Sprague-Dawley hanrotter (HC/CFY), der vejer mellem 150 og 200 g. Dyrene fratages føde og drikke i 16 timer før begyndelsen 15 af forsøget. Produkterne administreres suspenderet i en suspension af 0,5%'s carboxymethylcellulose i en 0,9%'s opløsning af natriumchlorid ved hjælp af en oesofagussonde med 50 ml/kg legemsvægt. Dyrene anbringes i enkeltbure til måling af metabolisme, og den totale mængde af den udskilte urin opsamles efter forløbet af følgende tidsrum: 1, 20 2, 3, 4, 5, 6 og 8 timer.
I urinen bestemmes følgende parametere: volumen (ml/kg); natrium og kalium (mEqV/kg/8 timer) (flammefotometer); chlorid (mEqV/kg/8 timer) (chlorimeter); pH-værdi/8 timer (pH-meter) og osmotisk tryk (mOsmol/kg/8 timer) (osmometer).
25 Kontroldyrene får 0,5%'s carboxymethylcellulosesuspension i en 0,9%'s natriumchloridopløsning med 50 ml/kg legemsvægt.
DK 157489B
15
Ved hjælp af den statistiske test betegnet "Student's t-test" for uafhængige værdier sammenlignes de ovenfor anførte parameterværdier for den gruppe, der var blevet behandlet med en dosis på 40 mg/kg og kontrolgruppen. Et produkt anses for at "have diuretisk virkning, når 5 forskellen mellem kontrolgruppen og den behandlede gruppe er signifikant (P<0,05) (C.I. Blin, "Statistics in Biology", bind II, McGraw-Hill, New York, 1970).
I den nedenfor anførte tabel 1 angives mængden af udskilt urin ved forskellige tidsintervaller efter administration af 40 mg/kg af de 10 forskellige forbindelser ifølge opfindelsen.
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16
Tabel 1
Urinudskillelse (ml/kg)
Produkt 1 time 2 timer 3 timer 4 timer 6 timer 8 timer 5 _
Kontrol 4,4 12,3 17,2 21,3 25,0 27,6
Eks. 2 10,4*** 22,3*** 30,2*** 36,0*** 41,5*** 45,6***
Eks. 1 7,3* 15,2 N.S 27,6*** 35,4*** 40,5*** 44,5***
Eks, 4 5,8 N.S 8,6 N.S 19,5 N.S 24,2 N.S 31,1 N.S 37,5* 10 Eks. 7 6,2 N.S 18,6** 28,4*** 36,1*** 47,3*** 52,4***
Eks. 5 1,1 N.S 3,4** 8,0* 12,5* 18,4 N.S 20,7 N.S
Eks. 8 0,0 N.S 11,9 N.S 19,6 N.S 28,5 N.S 34,4* 39,2**
Eks. 3 8,4 N.S 22,9** 31,9** 36,7*** 45,2*** 50,7***
Eks. 6 6,9 N.S 14,2 N.S 19,4 N.S 22,2 N.S 26,0 N.S 27,4 N.S
15 Eks. 9 5,2 N.S 12,6 N.S 16,8 N.S 19,0 N.S 21,5 N.S 25,3 N.S
Chlorta- lidon 8,7*** 21,0*** 30,9*** 37,6*** 45,6*** 49,8*** N.S. Ikke signifikant (P>0,05) 20 * signifikant (P<0,05) ** meget signifikant (P<0,01) *** i høj grad signifikant (P<0,001).
I den nedenstående tabel 2 anføres de forskellige parametere (Na, K,
Cl, pH-værdi, osmotisk tryk), der blev målt i den samlede mængde ud-25 skilt urin i løbet af 8 timer efter administration af 40 mg/kg af de forskellige forbindelser ifølge opfindelsen.
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17
Tabel 2
Urinudskillelse (8 timer)
Produkt Na K Cl pH-værdi Osmotisk tryk 5 ____
Kontrol 5,6 1,2 6,4 6,1 20,7
Eks. 2 9,1*** 1,7*** 11,8*** 6,0 N.S 29,7***
Eks. 1 8,3*** 1,5*** 9,2*** 6,6* 25,5***
Eks. 4 6,6 N.S 1,1 N.S 7,0 N.S 6,2 N.S. 20,8 N.S
10 Eks. 7 8,9*** 1,6** 9,3*** 6,3 N.S 31,0***
Eks. 5 3,0*** 1,3 N.S 6,2 N.S 6,1 N.S 16,6 N.S
Eks. 8 5,9 N.S 1,2 N.S 7,2 N.S 6,7** 23,4 N.S
Eks. 3 9,5*** 1,8*** 11,7*** 6,1 N.S 34,2***
Eks. 6 6,6* 1,1 N.S 8,1** 6,0 N.S 25,3** 15 Eks. 9 6,0 N.S 1,2 N.S 7,5* 6,2 N.S 25,1**
Chlor- talidon 9,3*** 1,9*** 10,8*** 6,6* 29,9***
Som ikke-begrænsende eksempel vises i tabel 3 de ED^q-værdier, der 20 svarer til mængderne af urin og til det osmotiske tryk af forbindelserne fra eksempel 1, 2 og 3 sammenlignet med chlortalidon.
Tabel 3 ED50 (mg/kg) Mængde urin Osmotisk tryk 25 Produkt (ml/kg/8 timer) (m osmol/kg/8 timer)
Eksempel 1 4,1 1,9
Eksempel 2 4,7 1,2
Eksempel 3 4,6 2,1 30 Chlortalidon 6,9 7,7
DK 157489 B
18 (1) ED,-q-værdien er beregnet på basis af en regressionslinje med 10-talslogaritmen for dosis i forhold til virkningen angivet i procent.
Akut toxicitet
Produktet administreres oralt suspenderet i 52's gummi arabicum til 5 albinomus CFLP-RE med en vægt på 20-25 g og til Sprague-Dawley-rotter CFY-RE med en vægt på 125-175 g. Den administrerede mængde er på 25 ml/kg til musene undtagen for maksimaldosen på 12.800 mg/kg, hvor der administreres en mængde på 50 ml/kg, og på 10 ml/kg til rotterne undtagen for maksimaldosen på 12.800 mg/kg, hvor der administreres en 10 mængde på 30 ml/kg.
Det var umuligt at bestemme LD^^-værdien på grund af, at der ikke forekom dødelighed.
De opnåede resultater for eksempel 2 er illustreret i eksempel 4.
Tabel 4 15 _
Dosis Mortalitet mg/kg Hanmus Hunmus Hanrotter Hunrotter 400 0/4 0/4 20 800 0/4 0/4 1.600 0/4 0/4 0/4 0/4 3.200 0/4 0/4 0/4 0/4 6.400 0/8 0/8 0/4 0/4 12.800 0/8 0/8 0/8 0/8 25 _
Til behandling af mennesker ligger den foreslåede dosis af forbindelserne ifølge den foreliggende opfindelse på mellem 20 og 60 mg/dag, fx administreret i form af tabletter.
I det følgende er som eksempel angivet en særlig galenisk form af 30 forbindelserne ifølge den foreliggende opfindelse.
- DK 157489 B
19
Eksempel på en tabletformulering 1-[(4-chlor-3-sulfamoyTbenzoyl)amino]-2,4,6-t r ime thylpyr idinium - hydroxid 0,020 g
Lactose 0,1015 g 5 Amidon 0,027 g
Mikrokrystallinsk cellulose 0,018 g
Prægelatiniseret amidon 0,0054 g
Polyvinylpyrrolidon 0,0054 g
Magnesiumstearat 0,0018 g 10 Kolloidt sillciumdioxid 0,0009 g 0,1800 g
De farmaceutiske præparater ifølge den foreliggende opfindelse kan på grund af deres saltdiuretiske egenskab anvendes effektivt til behand-15 ling af hjerte-, nyre- og leverødemer, til behandling af hjerteinsufficiens og arteriel hypertension og til sikring af blokering af mælkedannelsen.
Det er underforstået, at de farmaceutiske præparater ifølge den foreliggende opfindelse som aktiv bestanddel kan indeholde én eller 20 flere forbindelser ifølge opfindelsen i kombination med andre aktive bestanddele med forskellig eller komplementær aktivitet såsom fx et stof med /3-blokerende aktivitet, der er nyttigt til behandling af hypertension.
Claims (5)
1. C1 hvor Rj^ betegner hydrogen eller 2-furylmethylamino; R2, R3, R4, R5 og Rg har samme eller forskellig betydning 10 og betegner hydrogen, alkyl, der er ligekædet eller forgrenet, aryl eller carbamoyl; og yP betegner anionen af en farmaceutisk acceptabel syre.
1. N-substituerede pyridiniumforbindelser, kendetegnet ved, at de har den almene formel henholdsvis I og II 5 ?4 R, R5 I 4 jf R3 I® *2 f h! * C=0 1 Jyr^Y*' H NO S i. ^ 2 2 Ύ Η2Ν023^\γ Cl I
2. Forbindelse med den almene formel I ifølge krav 1, kendetegnet ved, at den er valgt blandt 15 det inerte l-[(4-chlor-3-sulfamoylbenzoyl)amino]pyridinlum-hydroxid-salt; det inerte 1-[(4-chlor-3-sulfamoylbenzoyl)amino]-2,4,6-trimethylpyri-dinium-hydroxidsalt; det inerte 1-[(4-chlor-3-sulfamoylbenzoyl)amino]-2,6-dimethylpyridi-20 nium-hydroxidsalt; det inerte 1-[(4-chlor-3-sulfamoylbenzoyl)amino]-3-carbamoylpyridini-um-hydroxidsalt; DK 157489 B det inerte l-{ [4-chlor-2-(2-furylmethylamino)-5-sulfamoylbenzoyl]ami-no}-2,4,6-trimethylpyridinium-hydroxidsalt og det inerte 1-[(4-chlor-3-sulfamoylbenzoyl)amino]-2,4.6-triphenylpyri-dinium-hydroxidsalt.
3. Forbindelse med den almene formel II ifølge krav 1, kendetegnet ved, at den er valgt blandt 1- [ [4-chlor-3-sulfamoylbenzoyl)amino] -2,4,6- trimethylpyridinium- chlo -rid; 1 - {[ 4 - chlor -2-(2- f urylme tbylamino ) - 5 - sulf amoylb enzoyl ] amino )-2,4,6-10 trimethylpyridinium-chlorid; og 1 - [ (4 - chlor - 3 - sulfamoylbenzoyl) amino ] -2,4,6-triphenylpyridinium-chlo -rid.
4. Forbindelse ifølge et hvilket som helst af kravene 1-3 til anvendelse som lægemiddel.
5. Farmaceutisk præparat, kendetegnet ved, at det ud over en farmaceutisk acceptabel bærer indeholder i det mindste én forbindelse med den almene formel I eller II ifølge et hvilket som helst af kravene 1-3.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8302380 | 1983-02-15 | ||
| FR8302380A FR2540870A1 (fr) | 1983-02-15 | 1983-02-15 | Nouveaux derives de betaines n-iminopyridinium, leur preparation et leur application en tant que medicaments |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| DK67384D0 DK67384D0 (da) | 1984-02-14 |
| DK67384A DK67384A (da) | 1984-08-16 |
| DK157489B true DK157489B (da) | 1990-01-15 |
| DK157489C DK157489C (da) | 1990-06-11 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK067384A DK157489C (da) | 1983-02-15 | 1984-02-14 | N-substituerede pyridiniumforbindelser og farmaceutiske praeparater indeholdende disse |
Country Status (23)
| Country | Link |
|---|---|
| US (1) | US4563467A (da) |
| EP (1) | EP0117196B1 (da) |
| JP (1) | JPS59155361A (da) |
| KR (1) | KR900001194B1 (da) |
| AT (1) | ATE21101T1 (da) |
| BR (1) | BR8400549A (da) |
| CA (1) | CA1221970A (da) |
| CS (1) | CS246074B2 (da) |
| DD (1) | DD216926A5 (da) |
| DE (1) | DE3460367D1 (da) |
| DK (1) | DK157489C (da) |
| ES (1) | ES8407477A1 (da) |
| FR (1) | FR2540870A1 (da) |
| GR (1) | GR79508B (da) |
| HU (1) | HU191126B (da) |
| MX (1) | MX162518A (da) |
| NO (1) | NO165144C (da) |
| PL (3) | PL141443B1 (da) |
| PT (1) | PT78062B (da) |
| RO (3) | RO90620A (da) |
| SU (1) | SU1376943A3 (da) |
| YU (1) | YU43838B (da) |
| ZA (1) | ZA84668B (da) |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5705585A (en) | 1993-06-30 | 1998-01-06 | Arqule, Inc. | Aminimide-containing molecules and materials as molecular recognition agents |
| EP0743857A4 (en) * | 1994-01-05 | 1998-07-15 | Arqule Inc | METHOD FOR PRODUCING POLYMERS WITH SPECIFIC PROPERTIES |
| US5734082A (en) * | 1994-10-20 | 1998-03-31 | Arqule Inc. | Hydroxyethyl aminimides |
| US5712171A (en) * | 1995-01-20 | 1998-01-27 | Arqule, Inc. | Method of generating a plurality of chemical compounds in a spatially arranged array |
| WO1996031263A1 (en) * | 1995-04-06 | 1996-10-10 | Arqule, Inc. | Method for rapid purification, analysis and characterization of collections of chemical compounds |
| US5962412A (en) * | 1996-06-10 | 1999-10-05 | Arqule, Inc. | Method of making polymers having specific properties |
| FI114538B (fi) * | 2001-01-12 | 2004-11-15 | Finnfeeds Finland Ltd | Glysiinibetaiinin käyttö verenpainetta alentavan tuotteen valmistukseen |
| US7307088B2 (en) * | 2002-07-09 | 2007-12-11 | Amgen Inc. | Substituted anthranilic amide derivatives and methods of use |
| JP4471572B2 (ja) * | 2003-01-31 | 2010-06-02 | 独立行政法人科学技術振興機構 | 光伝送方法 |
| LT6401B (lt) | 2015-07-28 | 2017-06-12 | Vilniaus Universitetas | Karboanhidrazės selektyvūs inhibitoriai |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE793606A (fr) * | 1972-01-05 | 1973-07-02 | Fisons Ltd | Acaricides |
| US4013669A (en) * | 1973-01-05 | 1977-03-22 | Fisons Limited | Ester-pyridinium compounds as acaricides |
-
1983
- 1983-02-15 FR FR8302380A patent/FR2540870A1/fr active Granted
-
1984
- 1984-01-21 ES ES529069A patent/ES8407477A1/es not_active Expired
- 1984-01-27 CA CA000446253A patent/CA1221970A/en not_active Expired
- 1984-01-30 ZA ZA84668A patent/ZA84668B/xx unknown
- 1984-02-06 PT PT78062A patent/PT78062B/pt not_active IP Right Cessation
- 1984-02-06 US US06/577,273 patent/US4563467A/en not_active Expired - Fee Related
- 1984-02-07 MX MX200257A patent/MX162518A/es unknown
- 1984-02-07 SU SU843697650A patent/SU1376943A3/ru active
- 1984-02-08 BR BR8400549A patent/BR8400549A/pt unknown
- 1984-02-13 RO RO84118152A patent/RO90620A/ro unknown
- 1984-02-13 DE DE8484400289T patent/DE3460367D1/de not_active Expired
- 1984-02-13 AT AT84400289T patent/ATE21101T1/de not_active IP Right Cessation
- 1984-02-13 NO NO840526A patent/NO165144C/no unknown
- 1984-02-13 DD DD84260051A patent/DD216926A5/de not_active IP Right Cessation
- 1984-02-13 RO RO118153A patent/RO91140B/ro unknown
- 1984-02-13 GR GR73791A patent/GR79508B/el unknown
- 1984-02-13 RO RO84113582A patent/RO87707A/ro unknown
- 1984-02-13 EP EP84400289A patent/EP0117196B1/fr not_active Expired
- 1984-02-14 PL PL1984251768A patent/PL141443B1/pl unknown
- 1984-02-14 PL PL1984246206A patent/PL141677B1/pl unknown
- 1984-02-14 DK DK067384A patent/DK157489C/da active
- 1984-02-14 YU YU256/84A patent/YU43838B/xx unknown
- 1984-02-14 PL PL1984251769A patent/PL141687B1/pl unknown
- 1984-02-14 HU HU84586A patent/HU191126B/hu not_active IP Right Cessation
- 1984-02-15 KR KR1019840000726A patent/KR900001194B1/ko not_active Expired
- 1984-02-15 JP JP59026909A patent/JPS59155361A/ja active Granted
- 1984-02-15 CS CS841071A patent/CS246074B2/cs unknown
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