NO833157L - SULFAMOYLBENZOFENON DERIVATIVES, PROCEDURE FOR THEIR PREPARATION, THEIR USE AND PHARMACEUTICAL PREPARATIONS BASED ON THESE COMPOUNDS - Google Patents
SULFAMOYLBENZOFENON DERIVATIVES, PROCEDURE FOR THEIR PREPARATION, THEIR USE AND PHARMACEUTICAL PREPARATIONS BASED ON THESE COMPOUNDSInfo
- Publication number
- NO833157L NO833157L NO833157A NO833157A NO833157L NO 833157 L NO833157 L NO 833157L NO 833157 A NO833157 A NO 833157A NO 833157 A NO833157 A NO 833157A NO 833157 L NO833157 L NO 833157L
- Authority
- NO
- Norway
- Prior art keywords
- formula
- hydrogen
- atoms
- compounds
- meaning
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims description 67
- 238000002360 preparation method Methods 0.000 title claims description 11
- 238000000034 method Methods 0.000 title claims description 5
- 239000000825 pharmaceutical preparation Substances 0.000 title 1
- 239000001257 hydrogen Substances 0.000 claims description 36
- 229910052739 hydrogen Inorganic materials 0.000 claims description 36
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 30
- 125000004432 carbon atom Chemical group C* 0.000 claims description 28
- 125000000217 alkyl group Chemical group 0.000 claims description 23
- -1 methylenedioxy Chemical group 0.000 claims description 22
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 15
- 125000006239 protecting group Chemical group 0.000 claims description 14
- 150000002989 phenols Chemical class 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 150000002431 hydrogen Chemical class 0.000 claims description 8
- 238000003776 cleavage reaction Methods 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- 230000007017 scission Effects 0.000 claims description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
- 239000000460 chlorine Substances 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 5
- 238000007127 saponification reaction Methods 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 125000000565 sulfonamide group Chemical group 0.000 claims description 4
- 150000001242 acetic acid derivatives Chemical class 0.000 claims description 3
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 3
- 238000005903 acid hydrolysis reaction Methods 0.000 claims description 2
- 238000005904 alkaline hydrolysis reaction Methods 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000002837 carbocyclic group Chemical group 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 230000032050 esterification Effects 0.000 claims description 2
- 238000005886 esterification reaction Methods 0.000 claims description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 2
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 2
- 238000005809 transesterification reaction Methods 0.000 claims description 2
- 101001053395 Arabidopsis thaliana Acid beta-fructofuranosidase 4, vacuolar Proteins 0.000 claims 1
- 239000002841 Lewis acid Substances 0.000 claims 1
- 150000007517 lewis acids Chemical class 0.000 claims 1
- 238000002844 melting Methods 0.000 description 40
- 230000008018 melting Effects 0.000 description 40
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- 239000000203 mixture Substances 0.000 description 17
- 239000013078 crystal Substances 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- REORSPZOQXYWIT-UHFFFAOYSA-N 2-[2,3-dichloro-4-(4-chloro-3-sulfamoylbenzoyl)phenoxy]acetic acid Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(=O)C=2C(=C(Cl)C(OCC(O)=O)=CC=2)Cl)=C1 REORSPZOQXYWIT-UHFFFAOYSA-N 0.000 description 10
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 239000007858 starting material Substances 0.000 description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 235000002639 sodium chloride Nutrition 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000002934 diuretic Substances 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- 230000003424 uricosuric effect Effects 0.000 description 5
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 description 4
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 229940030606 diuretics Drugs 0.000 description 4
- 239000013067 intermediate product Substances 0.000 description 4
- WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Inorganic materials [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 4
- YDCHPLOFQATIDS-UHFFFAOYSA-N methyl 2-bromoacetate Chemical compound COC(=O)CBr YDCHPLOFQATIDS-UHFFFAOYSA-N 0.000 description 4
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 4
- 230000000054 salidiuretic effect Effects 0.000 description 4
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 4
- 229940116269 uric acid Drugs 0.000 description 4
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 239000002168 alkylating agent Substances 0.000 description 3
- 229940100198 alkylating agent Drugs 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 230000001882 diuretic effect Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- LCPDWSOZIOUXRV-UHFFFAOYSA-N phenoxyacetic acid Chemical class OC(=O)COC1=CC=CC=C1 LCPDWSOZIOUXRV-UHFFFAOYSA-N 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- AVDBMBYECMTQJQ-UHFFFAOYSA-N 2-(2,3-dimethylphenoxy)acetic acid Chemical compound CC1=CC=CC(OCC(O)=O)=C1C AVDBMBYECMTQJQ-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- BXNIXDPWOQKNJK-UHFFFAOYSA-N 2-[3-chloro-4-(4-chloro-3-sulfamoylbenzoyl)-2-methylphenoxy]acetic acid Chemical compound C1=C(OCC(O)=O)C(C)=C(Cl)C(C(=O)C=2C=C(C(Cl)=CC=2)S(N)(=O)=O)=C1 BXNIXDPWOQKNJK-UHFFFAOYSA-N 0.000 description 2
- HVVKTEKBDCZCQY-UHFFFAOYSA-N 2-chloro-5-(2,3-dichloro-4-methoxybenzoyl)benzenesulfonamide Chemical compound ClC1=C(Cl)C(OC)=CC=C1C(=O)C1=CC=C(Cl)C(S(N)(=O)=O)=C1 HVVKTEKBDCZCQY-UHFFFAOYSA-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
- 201000004624 Dermatitis Diseases 0.000 description 2
- RPTUSVTUFVMDQK-UHFFFAOYSA-N Hidralazin Chemical compound C1=CC=C2C(NN)=NN=CC2=C1 RPTUSVTUFVMDQK-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- PQLVXDKIJBQVDF-UHFFFAOYSA-N acetic acid;hydrate Chemical compound O.CC(O)=O PQLVXDKIJBQVDF-UHFFFAOYSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 208000010668 atopic eczema Diseases 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 2
- 238000011097 chromatography purification Methods 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 230000007717 exclusion Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
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- 235000003599 food sweetener Nutrition 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 239000007788 liquid 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
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 2
- XOFKYSYTBXDTFY-UHFFFAOYSA-N n'-[2-chloro-5-(2,3-dichloro-4-hydroxybenzoyl)phenyl]sulfonyl-n,n-dimethylmethanimidamide Chemical compound C1=C(Cl)C(S(=O)(=O)N=CN(C)C)=CC(C(=O)C=2C(=C(Cl)C(O)=CC=2)Cl)=C1 XOFKYSYTBXDTFY-UHFFFAOYSA-N 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000000894 saliuretic effect Effects 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 238000010583 slow cooling Methods 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 235000009518 sodium iodide Nutrition 0.000 description 2
- 239000008174 sterile solution Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 229960004793 sucrose Drugs 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- MLBCURLNKYKBEQ-UHFFFAOYSA-N (2,6-dimethyl-phenoxy)-acetic acid Chemical compound CC1=CC=CC(C)=C1OCC(O)=O MLBCURLNKYKBEQ-UHFFFAOYSA-N 0.000 description 1
- DNXIKVLOVZVMQF-UHFFFAOYSA-N (3beta,16beta,17alpha,18beta,20alpha)-17-hydroxy-11-methoxy-18-[(3,4,5-trimethoxybenzoyl)oxy]-yohimban-16-carboxylic acid, methyl ester Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(C(=O)OC)C(O)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 DNXIKVLOVZVMQF-UHFFFAOYSA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- HFEASCCDHUVYKU-UHFFFAOYSA-N 1,2-dichloro-3-methoxybenzene Chemical compound COC1=CC=CC(Cl)=C1Cl HFEASCCDHUVYKU-UHFFFAOYSA-N 0.000 description 1
- LTVRGAWOEOKGJZ-UHFFFAOYSA-N 1-chloro-3-methoxy-2-methylbenzene Chemical compound COC1=CC=CC(Cl)=C1C LTVRGAWOEOKGJZ-UHFFFAOYSA-N 0.000 description 1
- OPQYFNRLWBWCST-UHFFFAOYSA-N 2-(2-chlorophenoxy)acetic acid Chemical compound OC(=O)COC1=CC=CC=C1Cl OPQYFNRLWBWCST-UHFFFAOYSA-N 0.000 description 1
- QJVXBRUGKLCUMY-UHFFFAOYSA-N 2-(2-methylphenoxy)acetic acid Chemical compound CC1=CC=CC=C1OCC(O)=O QJVXBRUGKLCUMY-UHFFFAOYSA-N 0.000 description 1
- VZECTCSEONQIPP-UHFFFAOYSA-N 2-(3-methylphenoxy)acetic acid Chemical compound CC1=CC=CC(OCC(O)=O)=C1 VZECTCSEONQIPP-UHFFFAOYSA-N 0.000 description 1
- SXERGJJQSKIUIC-UHFFFAOYSA-N 2-Phenoxypropionic acid Chemical compound OC(=O)C(C)OC1=CC=CC=C1 SXERGJJQSKIUIC-UHFFFAOYSA-N 0.000 description 1
- SCSHTTNMYXJZHH-UHFFFAOYSA-N 2-[2-chloro-4-(4-chloro-3-sulfamoylbenzoyl)-3-methylphenoxy]acetic acid Chemical compound CC1=C(Cl)C(OCC(O)=O)=CC=C1C(=O)C1=CC=C(Cl)C(S(N)(=O)=O)=C1 SCSHTTNMYXJZHH-UHFFFAOYSA-N 0.000 description 1
- IEWOSAWZJPLAHB-UHFFFAOYSA-N 2-[4-(4-chloro-3-sulfamoylbenzoyl)-2,3-dimethylphenoxy]acetic acid Chemical compound C1=C(OCC(O)=O)C(C)=C(C)C(C(=O)C=2C=C(C(Cl)=CC=2)S(N)(=O)=O)=C1 IEWOSAWZJPLAHB-UHFFFAOYSA-N 0.000 description 1
- RLYKEEYNFPONRT-UHFFFAOYSA-N 2-[4-(4-chloro-3-sulfamoylbenzoyl)-2-methylphenoxy]acetic acid Chemical compound C1=C(OCC(O)=O)C(C)=CC(C(=O)C=2C=C(C(Cl)=CC=2)S(N)(=O)=O)=C1 RLYKEEYNFPONRT-UHFFFAOYSA-N 0.000 description 1
- BZMDQYFRSNFPQB-UHFFFAOYSA-N 2-[5-chloro-4-(4-chloro-3-sulfamoylbenzoyl)-2-methylphenoxy]acetic acid Chemical compound C1=C(OCC(O)=O)C(C)=CC(C(=O)C=2C=C(C(Cl)=CC=2)S(N)(=O)=O)=C1Cl BZMDQYFRSNFPQB-UHFFFAOYSA-N 0.000 description 1
- YYGRRRBCAPNFRK-UHFFFAOYSA-N 2-chloro-1-methoxy-3-methylbenzene Chemical compound COC1=CC=CC(C)=C1Cl YYGRRRBCAPNFRK-UHFFFAOYSA-N 0.000 description 1
- DTONYCZJVVEOFA-UHFFFAOYSA-N 2-chloro-5-(2,3-dichloro-4-hydroxybenzoyl)benzenesulfonamide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(=O)C=2C(=C(Cl)C(O)=CC=2)Cl)=C1 DTONYCZJVVEOFA-UHFFFAOYSA-N 0.000 description 1
- KXAUHHRRZRXUCF-UHFFFAOYSA-N 2-chloro-5-(2-chloro-4-hydroxy-3-methylbenzoyl)benzenesulfonamide Chemical compound CC1=C(O)C=CC(C(=O)C=2C=C(C(Cl)=CC=2)S(N)(=O)=O)=C1Cl KXAUHHRRZRXUCF-UHFFFAOYSA-N 0.000 description 1
- ILPUOPPYSQEBNJ-UHFFFAOYSA-N 2-methyl-2-phenoxypropanoic acid Chemical compound OC(=O)C(C)(C)OC1=CC=CC=C1 ILPUOPPYSQEBNJ-UHFFFAOYSA-N 0.000 description 1
- RFZOGPABZLMDQW-UHFFFAOYSA-N 4-chloro-2-methoxy-1-methylbenzene Chemical compound COC1=CC(Cl)=CC=C1C RFZOGPABZLMDQW-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
- 241000416162 Astragalus gummifer Species 0.000 description 1
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- 229920002261 Corn starch Polymers 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
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- 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
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 1
- 229930064664 L-arginine Natural products 0.000 description 1
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- 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
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 244000246386 Mentha pulegium Species 0.000 description 1
- 235000016257 Mentha pulegium Nutrition 0.000 description 1
- 235000004357 Mentha x piperita Nutrition 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- ZTCLCSCHTACERP-AWEZNQCLSA-N N-[(1S)-1-[3-chloro-5-fluoro-2-[[2-methyl-4-(2-methyl-1,2,4-triazol-3-yl)quinolin-8-yl]oxymethyl]phenyl]ethyl]-2-(difluoromethoxy)acetamide Chemical compound C1=C(C=C(C(=C1Cl)COC1=CC=CC2=C(C=3N(N=CN=3)C)C=C(C)N=C12)[C@@H](NC(=O)COC(F)F)C)F ZTCLCSCHTACERP-AWEZNQCLSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 208000004880 Polyuria Diseases 0.000 description 1
- LCQMZZCPPSWADO-UHFFFAOYSA-N Reserpilin Natural products COC(=O)C1COCC2CN3CCc4c([nH]c5cc(OC)c(OC)cc45)C3CC12 LCQMZZCPPSWADO-UHFFFAOYSA-N 0.000 description 1
- QEVHRUUCFGRFIF-SFWBKIHZSA-N Reserpine Natural products O=C(OC)[C@@H]1[C@H](OC)[C@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)C[C@H]2[C@@H]1C[C@H]1N(C2)CCc2c3c([nH]c12)cc(OC)cc3 QEVHRUUCFGRFIF-SFWBKIHZSA-N 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 241001441724 Tetraodontidae Species 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 229940116731 Uricosuric agent Drugs 0.000 description 1
- GJEAMHAFPYZYDE-UHFFFAOYSA-N [C].[S] Chemical compound [C].[S] GJEAMHAFPYZYDE-UHFFFAOYSA-N 0.000 description 1
- ZCHPKWUIAASXPV-UHFFFAOYSA-N acetic acid;methanol Chemical compound OC.CC(O)=O ZCHPKWUIAASXPV-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- XSDQTOBWRPYKKA-UHFFFAOYSA-N amiloride Chemical compound NC(=N)NC(=O)C1=NC(Cl)=C(N)N=C1N XSDQTOBWRPYKKA-UHFFFAOYSA-N 0.000 description 1
- 229960002576 amiloride Drugs 0.000 description 1
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 125000003435 aroyl group Chemical group 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 1
- 229910001863 barium hydroxide Inorganic materials 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 229940045348 brown mixture Drugs 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940112822 chewing gum Drugs 0.000 description 1
- 235000015218 chewing gum Nutrition 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 229960002896 clonidine Drugs 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- IOLQWGVDEFWYNP-UHFFFAOYSA-N ethyl 2-bromo-2-methylpropanoate Chemical compound CCOC(=O)C(C)(C)Br IOLQWGVDEFWYNP-UHFFFAOYSA-N 0.000 description 1
- ARFLASKVLJTEJD-UHFFFAOYSA-N ethyl 2-bromopropanoate Chemical compound CCOC(=O)C(C)Br ARFLASKVLJTEJD-UHFFFAOYSA-N 0.000 description 1
- VEUUMBGHMNQHGO-UHFFFAOYSA-N ethyl chloroacetate Chemical compound CCOC(=O)CCl VEUUMBGHMNQHGO-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000003349 gelling agent Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 235000001050 hortel pimenta Nutrition 0.000 description 1
- 229960002474 hydralazine Drugs 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- NIQQIJXGUZVEBB-UHFFFAOYSA-N methanol;propan-2-one Chemical compound OC.CC(C)=O NIQQIJXGUZVEBB-UHFFFAOYSA-N 0.000 description 1
- STZCRXQWRGQSJD-GEEYTBSJSA-M methyl orange Chemical compound [Na+].C1=CC(N(C)C)=CC=C1\N=N\C1=CC=C(S([O-])(=O)=O)C=C1 STZCRXQWRGQSJD-GEEYTBSJSA-M 0.000 description 1
- 229940012189 methyl orange Drugs 0.000 description 1
- 229960001047 methyl salicylate Drugs 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- IUBSYMUCCVWXPE-UHFFFAOYSA-N metoprolol Chemical compound COCCC1=CC=C(OCC(O)CNC(C)C)C=C1 IUBSYMUCCVWXPE-UHFFFAOYSA-N 0.000 description 1
- 229960002237 metoprolol Drugs 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- WHQSYGRFZMUQGQ-UHFFFAOYSA-N n,n-dimethylformamide;hydrate Chemical compound O.CN(C)C=O WHQSYGRFZMUQGQ-UHFFFAOYSA-N 0.000 description 1
- BHGCNGDTJZDAEX-UHFFFAOYSA-N n,n-dimethylformamide;propan-2-ol Chemical compound CC(C)O.CN(C)C=O BHGCNGDTJZDAEX-UHFFFAOYSA-N 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000000346 nonvolatile oil Substances 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 235000010603 pastilles Nutrition 0.000 description 1
- KQXKVJAGOJTNJS-HNNXBMFYSA-N penbutolol Chemical compound CC(C)(C)NC[C@H](O)COC1=CC=CC=C1C1CCCC1 KQXKVJAGOJTNJS-HNNXBMFYSA-N 0.000 description 1
- 229960002035 penbutolol Drugs 0.000 description 1
- 150000008379 phenol ethers Chemical class 0.000 description 1
- NQUZAKPXCAFGRS-UHFFFAOYSA-N phenyl-(2,3,4-trichlorophenyl)methanone Chemical compound ClC1=C(Cl)C(Cl)=CC=C1C(=O)C1=CC=CC=C1 NQUZAKPXCAFGRS-UHFFFAOYSA-N 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- XTUSEBKMEQERQV-UHFFFAOYSA-N propan-2-ol;hydrate Chemical compound O.CC(C)O XTUSEBKMEQERQV-UHFFFAOYSA-N 0.000 description 1
- FZJCXIDLUFPGPP-UHFFFAOYSA-N propan-2-ol;toluene Chemical compound CC(C)O.CC1=CC=CC=C1 FZJCXIDLUFPGPP-UHFFFAOYSA-N 0.000 description 1
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- BJOIZNZVOZKDIG-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C([C]5C=CC(OC)=CC5=N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 BJOIZNZVOZKDIG-MDEJGZGSSA-N 0.000 description 1
- 229960003147 reserpine Drugs 0.000 description 1
- MDMGHDFNKNZPAU-UHFFFAOYSA-N roserpine Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(OC(C)=O)C(OC)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 MDMGHDFNKNZPAU-UHFFFAOYSA-N 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000004289 sodium hydrogen sulphite Substances 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 1
- LXMSZDCAJNLERA-ZHYRCANASA-N spironolactone Chemical compound C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)SC(=O)C)C[C@@]21CCC(=O)O1 LXMSZDCAJNLERA-ZHYRCANASA-N 0.000 description 1
- 229960002256 spironolactone Drugs 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 1
- 229940073455 tetraethylammonium hydroxide Drugs 0.000 description 1
- LRGJRHZIDJQFCL-UHFFFAOYSA-M tetraethylazanium;hydroxide Chemical compound [OH-].CC[N+](CC)(CC)CC LRGJRHZIDJQFCL-UHFFFAOYSA-M 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 235000012431 wafers Nutrition 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
- C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
- C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/06—One of the condensed rings being a six-membered aromatic ring the other ring being four-membered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
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- General Chemical & Material Sciences (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
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- Diabetes (AREA)
- Hematology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Physical Education & Sports Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
Oppfinnelsen vedrører forbindelse med formel V The invention relates to compounds of formula V
hvori in which
1 2 3 1 2 3
R , R og R er like eller forskjellige og betyr hydrogen, halogen, alkyl med 1 til 4 C-atomer eller alkoksy med 1 til 4 C-atomer, idet imidlertid R 1 og R 2 ikke samtidig kan bety hydrogen og idet R 1 og R 2 også sammen kan bety en bro av 2 til 5 metylengrupper eller metylendioksy, R , R and R are the same or different and mean hydrogen, halogen, alkyl with 1 to 4 C atoms or alkoxy with 1 to 4 C atoms, however, R 1 and R 2 cannot simultaneously mean hydrogen and since R 1 and R 2 also together can mean a bridge of 2 to 5 methylene groups or methylenedioxy,
1 0 1 0
R betyr alkyl med 1 til 4 C-atomer, en fenol-beskyttelsesgruppe, hydrogen eller en rest med formel VI, R means alkyl of 1 to 4 C atoms, a phenol protecting group, hydrogen or a residue of formula VI,
4 5 hvori R og R er like eller forskjellige og betyr hydrogen eller alkyl med 1 til 4 C-atomer eller er bestanddel en 3-til 7-leddet mettet karbocyklisk ring og Y betyr OR , hvori R betyr hydrogen, alkyl med 1 til 4 C-atomer som eventuelt kan være substituert med hydroksy eller alkoksy med 1 til 3 C-atomer eller betyr aralkyl med 7 til 9 C-atomer eller en overfor Lewissyre stabil beskyttelsesgruppe av karboksylfunksjonen og Z betyr to hydrogenatomer eller en beskyttelsesgruppe med formel III, 4 5 in which R and R are the same or different and means hydrogen or alkyl with 1 to 4 C atoms or is a component a 3- to 7-membered saturated carbocyclic ring and Y means OR , in which R means hydrogen, alkyl with 1 to 4 C atoms which may optionally be substituted with hydroxy or alkoxy with 1 to 3 C atoms or means aralkyl with 7 to 9 C atoms or a Lewis acid-stable protecting group of the carboxyl function and Z means two hydrogen atoms or a protecting group of formula III,
hvori R 7 betyr hydrogen eller alkyl med 1 til 4 C-atomer wherein R 7 means hydrogen or alkyl with 1 to 4 carbon atoms
8 9 8 9
og R og R betyr alkyl med 1 til 4 C-atomer,and R and R are alkyl having 1 to 4 carbon atoms,
samt deres fysiologisk tålbare salter.as well as their physiologically tolerable salts.
I litteraturen er det allerede omtalt flere i 4-stilling acylerte fenoksyeddiksyrederivater med salidiuretisk og/eller urikosurisk virkning (jfr. G.M. Shutske et. al., In the literature, several acylated phenoxyacetic acid derivatives with salidiuretic and/or uricosuric action in the 4-position have already been described (cf. G.M. Shutske et. al.,
J. Med. Chem. 2_5 , 36 - 44 (1 982) og den der siterte littera-tur) . Alle disse forbindelser har en lipofil aroyldel og virker knapt eller bare ved relativt høye doseringer salidiuretisk på rotter. Det var derfor meget overraskende at forbindelsene ifølge oppfinnelsen med formel I - som er såvel fenoksyeddiksyrederivater som også sulfonamider - såvel ut-øver en urikosurisk som også en salidiuretisk virkning og derved med hensyn til aktivitet og/eller virkningstid over-treffe ovennevnte forbindelser slik dette kan vises ved for-søk på rotter. J. Med. Chem. 2_5 , 36 - 44 (1 982) and the literature cited there). All these compounds have a lipophilic aroyl part and are hardly or only at relatively high doses salidiuretic in rats. It was therefore very surprising that the compounds according to the invention with formula I - which are both phenoxyacetic acid derivatives and also sulfonamides - both exert a uricosuric as well as a salidiuretic effect and thereby in terms of activity and/or duration of action surpass the above-mentioned compounds as this can appears when searching for rats.
Videre er det fra tysk patent 1 129 478 kjent benzo-fenonsulfonamid-derivater med diuretiskeog saluretiske egen-skaper som imidlertid ikke har noen urikosuriske eller hypo-urikemiske effekter. Furthermore, German patent 1,129,478 discloses benzo-phenonesulfonamide derivatives with diuretic and saluretic properties which, however, have no uricosuric or hypo-uricemic effects.
Foretrukket er slike forbindelser med formel V hvori Preferred are such compounds of formula V in which
Z betyr to hydrogenatomer og R 1 -R 6har ovennevnte betydning, spesielt slike forbindelser hvori Z betyr to hydrogenatomer, Z means two hydrogen atoms and R 1 -R 6 have the above meaning, especially such compounds in which Z means two hydrogen atoms,
R 1, R 2 og R 3 betyr hydrogen, halogen og/eller metyl, R betyr R 1 , R 2 and R 3 mean hydrogen, halogen and/or methyl, R means
4 5 6 R og R betyr hydrogen og/eller metyl, og R betyr hydrogen, alkyl med 1 til 4 C-atomer eller benzyl; idet forbindelsene er foretrukket, hvor 4 5 6 R and R mean hydrogen and/or methyl, and R means hydrogen, alkyl of 1 to 4 C atoms or benzyl; the compounds being preferred, where
Z betyr to hydrogenatomer,Z means two hydrogen atoms,
12 3 12 3
R , R og R betyr klor, metyl og/eller hydrogen, R , R and R mean chlorine, methyl and/or hydrogen,
R<10>betyr R<10>means
4 5 4 5
R og R betyr hydrogen og R and R mean hydrogen and
R betyr hydrogen eller alkyl med 1 til 4 C-atomer. R means hydrogen or alkyl with 1 to 4 carbon atoms.
Av alle forbindelser som omfattes av oppfinnelsen kommer som helt spesielt foretrukket slike i betraktning hvor Of all the compounds covered by the invention, particularly preferred are those in consideration where
Z betyr to hydrogenatomer,Z means two hydrogen atoms,
R betyr R stands for
1 2 1 2
R og R betyr klor eller metyl ogR and R mean chlorine or methyl and
3 6 3 6
R til R betyr hydrogen.R to R means hydrogen.
Oppfinnelsen vedrører videre fremgangsmåte til fremstilling av forbindelser med formel V, som erkarakterisertved at The invention further relates to a method for producing compounds of formula V, which is characterized by
et karboksylsyrederivat med formel II,a carboxylic acid derivative of formula II,
hvori Z betyr to hydrogenatomer eller en beskyttelsesgruppe med formel III wherein Z represents two hydrogen atoms or a protecting group of formula III
hvori R 7 betyr hydrogen eller alkyl med 1 til 4 C-atomer og wherein R 7 means hydrogen or alkyl with 1 to 4 carbon atoms and
8 9 8 9
R og R betyr alkyl med 1 til 4 C-atomer og hvori X betyr en Leaving-gruppe, spesiell imidlertid betyr klor, omsettes med et fenolderivat med den generelle formel IV R and R means alkyl of 1 to 4 C atoms and in which X means a Leaving group, in particular means chlorine, is reacted with a phenol derivative of the general formula IV
hvori in which
1 2 3 1 2 3
R , R og R har den ovennevnte betydning og R betyr a) alkyl med 1 til 4 C-atomer, en annen egnet fenol-beskyttelsesgru<p>pe eller hydrogen eller R , R and R have the above meaning and R means a) alkyl with 1 to 4 C atoms, another suitable phenol protecting group or hydrogen or
b) en rest med formel VI,b) a residue of formula VI,
4 5 6 hvori R og R har den ovennevnte betydning og Y betyr OR , R^ har den ovennevnte betydning eller betyr en overfor Lewis-syrer stabil beskyttelsesgruppe av karboksylfunksjonen, på i og for seg kjent måte ved Friedel-Crafts-acylering til forbindelser med den generelle formel V 1 2 3 10 hvori R , R , R , R og Z har ovennevnte betydning (idet forbindelser med formel V hvori Z er to hydrogenatomer og R 1 0 er en rest med formel VI, er identisk med forbindelser med formel I) og denne, hvis R 1 0 betyr alkyl med 1 til 4 C-atomer eller en annen egnet fenol-beskyttelsesgruppe, ved avspaltning av 10 10 resten R overfører til fenolene med formel V, hvori R betyr hydrogen og R 1 til R 3 og Z har ovennevnte betydning, idet forbindelser med formel V hvori Z har betydningen av en beskyttelsesgruppe med formel III på litteraturkjente måter (DOS 26 54 795; CA. 89 , 108 715 (1978)) lar seg oppnå fra forbindelser med ubeskyttede sulfonamidgruppe (Z = to hydrogenatomer) eller lar seg overføre i disse, fenolene fra ovennevnte formel V alkyleres med et eddiksyrederivat med formel VII 4 5 6 in which R and R have the above-mentioned meaning and Y means OR , R^ has the above-mentioned meaning or means a Lewis acid-stable protecting group of the carboxyl function, in a manner known per se by Friedel-Crafts acylation to compounds with the general formula V 1 2 3 10 in which R , R , R , R and Z have the above meaning (while compounds of formula V in which Z is two hydrogen atoms and R 10 is a residue of formula VI are identical to compounds of formula I ) and this, if R 1 0 means alkyl with 1 to 4 C atoms or another suitable phenolic protecting group, on cleavage of 10 10 the residue R transfers to the phenols of formula V, in which R means hydrogen and R 1 to R 3 and Z has the above meaning, since compounds of formula V in which Z has the meaning of a protecting group of formula III in ways known from the literature (DOS 26 54 795; CA. 89 , 108 715 (1978)) can be obtained from compounds with unprotected sulfonamide groups (Z = two hydrogen atoms) or can be transferred in these , the phenols of the above formula V are alkylated with an acetic acid derivative of formula VII
hvori R 4 , R 5 og Y har ovennevnte betydning og W har betydningen av en nukleofug gruppe som eksempelvis brom, klor, jod, p-toluensulfonyl eller metansulfonyl, til forbindelser med formel V hvori R 1 0 betyr en rest av ovennevnte formel VI og restene R 1 til R 5, Y og Z har ovennevnte betydning, disse, for det tilfelle at Z har betydningen av beskyttelsesgruppen med formel III, overføres ved alkalisk eller sur hydrolyse i forbindelsene med formel I og eventuelt omdannes disse forbindelser med formel I ved sur eller alkalisk forsåpning resp. sur katalysert forestring eller omforestrings-reaksjon vekselsidig i hverandre og eventuelt overføres forbindelser med formel I i deres fysiologisk tålbare salter. in which R 4 , R 5 and Y have the above meaning and W has the meaning of a nucleofuge group such as bromine, chlorine, iodine, p-toluenesulfonyl or methanesulfonyl, to compounds of formula V in which R 1 0 means a residue of the above formula VI and the residues R 1 to R 5 , Y and Z have the above meaning, these, in the event that Z has the meaning of the protecting group of formula III, are transferred by alkaline or acidic hydrolysis in the compounds of formula I and optionally these compounds of formula I are converted by acid or alkaline saponification or acid-catalyzed esterification or transesterification reaction alternately in each other and optionally transfer compounds of formula I in their physiologically tolerable salts.
Fremstilling av fenolderivatene med formel V (R 1 0 = hydrogen) foregår på i og for seg kjent måte ved at fenolderivatene med formel IV omsettes med karboksylsyrederivater med formel II etter typen av Friedel-Crafts-acylering (jfr. Houben-Weyl, bind VII/2a, side 15-62, Georg Thieme Verlag Stuttgart, 1973), idet det som Friedel-Crafts-katalysator fortrinnsvis finner anvendelse av aluminiumklorid. Alle for Friedel-Crafts-acylering vanlige oppløsningsmidler kan finne anvendelse, spesielt egnet er klorerte hydrokarboner som f.eks. metylenklorid eller 1,2-dikloretan, men også svovel-karbon kan være fordelaktig. Omsetningene foretas mellom -20 og 100°C med 1-4 ekvivalente katalysator, for unngåelse av biprodukter arbeider man fortrinnsvis ved temperaturer under 40°C og støkiometriske mengder katalysator. Preparation of the phenol derivatives of formula V (R 1 0 = hydrogen) takes place in a manner known per se by reacting the phenol derivatives of formula IV with carboxylic acid derivatives of formula II according to the type of Friedel-Crafts acylation (cf. Houben-Weyl, volume VII /2a, pages 15-62, Georg Thieme Verlag Stuttgart, 1973), with aluminum chloride preferably being used as a Friedel-Crafts catalyst. All solvents common to Friedel-Crafts acylation can be used, particularly suitable are chlorinated hydrocarbons such as e.g. methylene chloride or 1,2-dichloroethane, but also sulphur-carbon can be advantageous. The reactions are carried out between -20 and 100°C with 1-4 equivalents of catalyst, to avoid by-products, preferably work at temperatures below 40°C and stoichiometric amounts of catalyst.
Til overføring av fenoleterene med formel V i fenolene V (R<10>= hydrogen) egner det seg spesielt for R<10>For the transfer of the phenol ethers of formula V in the phenols V (R<10>= hydrogen) it is particularly suitable for R<10>
= metyl, alle vanlige spaltningsreagenser for aryl-alkyl-etere, spesielt foretrukket er bortribromid og aluminiumklorid, idet det som reaksjonsmedier spesielt anvendes klorerte hydrokarboner som metylenklorid og 1,2-dikloretan ved temperaturer mellom -20 og +80°C, fortrinnsvis imidlertid mellom +20 og +50°C. Men også i smelter av vannfri pyri-diniumhalogenider, spesielt pyridinhydroklorid, går spalt-ningen for seg ved temperaturer mellom 120 og 200°C, spesielt mellom 160 og 190°C. = methyl, all common cleavage reagents for aryl alkyl ethers, particularly preferred are boron tribromide and aluminum chloride, with chlorinated hydrocarbons such as methylene chloride and 1,2-dichloroethane being used as reaction media at temperatures between -20 and +80°C, preferably between +20 and +50°C. But also in melts of anhydrous pyridinium halides, especially pyridine hydrochloride, the cleavage takes place at temperatures between 120 and 200°C, especially between 160 and 190°C.
For unngåelse av bireksjoner anvendes i den etter-følgende alkyleringsreaksjon fortrinnsvis slike fenoler V (R 1 0 = hydrogen) hvis sulfonamidgruppe er beskyttet mot alkylering, dvs. hvori Z har betydningen av III. Det lykkes imidlertid også å alkylere fenoler med formel V (R<10>= hydrogen) med fri sulfamoylgruppe temmelig selektivt ved OH-gruppen, idet man omsetter med litt overskudd av alkyleringsmiddel med formel VII og en svak hjelpebase, fortrinnsvis natriumhydrogenkarbonat eller kaliumkarbonat i et polart aprotisk oppløsningsmiddel som spesielt aceton, metyletylketon, dimetylformamid. dimetylacetamid eller N-metylpyrro-lidon fortrinnsvis ved temperaturer mellom 0 og 50°C. For de tilfeller hvori de resulterende forbindelser med formel V (R 1 0 = gruppe med formel VI) dessuten må overføres i produktene I er f.eks. hydrolysen av estere (R c i betydningen av alkyl) til de frie fenoksyeddiksyrer (R c = H) er samtidig å foreta med en eventuell nødvendig avspaltning av sulfon-amidbeskyttelsesgruppen (Z i betydningen av formel III) såvel ved hjelp av en base som også en syre i nærvær av vann. Foregår avspaltningen under sure betingelser, så finner fortrinnsvis en sterk mineralsyre som saltsyre eller svovelsyre anvendelse. Forsåpes derimot alkalisk, så anvendes fortrinnsvis sterke uorganiske baser som alkali-•eller jordalkalibaser som f.eks. litium-, natrium- eller bariumhydroksyd, men også sterke organiske baser som kvartære ammoniumhydroksyder, f.eks. tetraetylammoniumhydroksyd kan benyttes. Som oppløs-ningsmiddel akn det finne anvendelse praktisk talt et hvilket som helst oppløsningsmiddel som er inert overfor reaksjons-deltagerne, som f.eks. alkoholer, fortrinnsvis metanol, eller, hvis det hydrolyseres surt, alkansyrer som f.eks. eddiksyre. Pr. forsåpbar gruppe må det minst tilsettes en ekvivalent vann til reaksjonsblandingen,for det meste anvendes imidlertid et større overskudd eller vann alene tjener som oppløs-ningsmiddel hvilket spesielt er fordelaktig for alkalisk forsåpning. Reaksjonstemperaturen kan ligge mellom 0 og 120°C, fortrinnsvis arbeides ved sure spaltninger ved oppløs-ningsmiddelets tilbakeløpstemperatur. Reaksjonsproduktenes isolering foregår mest hensiktsmessig ved at man i kokevarme tilsetter et ikke-oppløsningsmiddel som f.eks. vann til reak-sjonsblandingen, produktet faller da ut vanligvis ved av-kjøling krystallinsk. Ved alkalisk forsåpning arbeider man vanligvis ved temperaturer mellom 0 og 50°C, fortrinnsvis ved værelsetemperatur og feller etter nøytralisering over-skytende base ved tilsetning av ytterligere syre, eventuelt kokesalt, de frie syrer med formel I (R<6>hydrogen), fil-trerer eller ekstraherer med et egnet oppløsningsmiddel, fortrinnsvis eddiksyreetylester og omkrystalliserer eventuelt. To avoid bireactions, such phenols V (R 10 = hydrogen) are preferably used in the subsequent alkylation reaction whose sulfonamide group is protected against alkylation, i.e. in which Z has the meaning of III. However, it is also successful to alkylate phenols of formula V (R<10>= hydrogen) with a free sulfamoyl group rather selectively at the OH group, reacting with a slight excess of alkylating agent of formula VII and a weak auxiliary base, preferably sodium bicarbonate or potassium carbonate in a polar aprotic solvent such as in particular acetone, methyl ethyl ketone, dimethylformamide. dimethylacetamide or N-methylpyrrolidone preferably at temperatures between 0 and 50°C. For the cases in which the resulting compounds of formula V (R 1 0 = group of formula VI) must also be transferred in the products I are e.g. the hydrolysis of esters (R c in the sense of alkyl) to the free phenoxyacetic acids (R c = H) is to be carried out at the same time with any necessary cleavage of the sulfonamide protecting group (Z in the sense of formula III) both with the help of a base as well as a acid in the presence of water. If the cleavage takes place under acidic conditions, a strong mineral acid such as hydrochloric or sulfuric acid is preferably used. If, on the other hand, saponification is alkaline, strong inorganic bases such as alkali or alkaline earth bases are preferably used, such as lithium, sodium or barium hydroxide, but also strong organic bases such as quaternary ammonium hydroxides, e.g. tetraethylammonium hydroxide can be used. Practically any solvent which is inert towards the reaction participants can be used as a solvent, such as e.g. alcohols, preferably methanol, or, if acid hydrolysed, alkanoic acids such as acetic acid. Per saponifiable group, at least one equivalent of water must be added to the reaction mixture, in most cases, however, a larger excess is used or water alone serves as a solvent, which is particularly advantageous for alkaline saponification. The reaction temperature can be between 0 and 120°C, preferably working with acidic cleavages at the reflux temperature of the solvent. The isolation of the reaction products takes place most appropriately by adding a non-solvent such as e.g. water to the reaction mixture, the product usually precipitates out crystalline on cooling. In alkaline saponification, you usually work at temperatures between 0 and 50°C, preferably at room temperature, and after neutralization, excess base is trapped by the addition of further acid, possibly common salt, the free acids of formula I (R<6>hydrogen), file - triturate or extract with a suitable solvent, preferably acetic acid ethyl ester, and recrystallize if necessary.
I den følgende tekst betyr "værelsetemperatur" 20 - 25°C. In the following text, "room temperature" means 20 - 25°C.
De fysiologisk tålbare salter ifølge oppfinnelsen omfatter saltene av alkali- og jordalkalimetaller og av ikke-toksiske organiske baser, f.eks. av etanolamin, di-etanolamin, trishydroksymetylmetylamin, N-metylglukamin eller L-arginin. The physiologically tolerable salts according to the invention include the salts of alkali and alkaline earth metals and of non-toxic organic bases, e.g. of ethanolamine, diethanolamine, trishydroxymethylmethylamine, N-methylglucamine or L-arginine.
Ifølge oppfinnelsen kan det foruten de i utførelses-eksemplene omtalte forbindelser fås også de i følgende tabeller oppstilte forbindelser med den generelle formel I. According to the invention, in addition to the compounds mentioned in the embodiment examples, the compounds with the general formula I listed in the following tables can also be obtained.
Forbindelsene ifølge oppfinnelsen med formel I samt deres fysiologisk tålbare salter er diuretika og saluretika med ekstra urikosurisk komponent. De kan anvendes som farma-søytika i human- og veterinærmedisin. Dertil administreres de i doseringer på 1 - 50 mg/kg legemsvekt og dag oralt, parenteralt eller intravenøst. Alene eller i kombinasjon med andre blodtrykksenkende karutvidende eller diuretisk virksomme stoffer egner de seg såvel til behandling av hypertoni som også til behandling av kardialt, renalt eller hepatisk betingede ødemer og andre foreteelser som er å tilbakeføre på forstyrrelser av elektrolyttbalansen. Derved ligger den spesielle betydning av ovennevnte forbindelser i deres dob- belte virkning som diuretika og urikosurika. Det er kjent at under en diuretisk behandling med kjente diuretika øker i mange tilfeller urinsyrekonsentrasjonen i en pasients blod. En økning av urinsyrespeilet er et alvorlig problem ved gikt-pasienter. Dessuten anses et øket urinsyrespeil mer og mer som risikofaktor ved hjertesykdommer. Derfor kan den diuretiske virkning med samtidig utskillelse av urinsyre anses som en hovedfordel av forbindelsen ifølge oppfinnelsen. Forbindelsene kan anvendes alene eller i kombinasjon med andre salidiuretisk virksomme stoffer og andre virknings-typer. Spesielt er det å nevne: Spironolakton, triamtere, amilorid og andre K<+->retinerende forbindelser. Men også andre rent blodtrykksenkende forbindelser kommer på tale som muligekombinasjonspartnere, f.eks. hydralazin, klonidin, reserpin og spesielt også beta-blokkerende stoffer som f.eks. metoprolol eller penbutolol. The compounds according to the invention with formula I as well as their physiologically tolerable salts are diuretics and saluretics with an additional uricosuric component. They can be used as pharmaceuticals in human and veterinary medicine. In addition, they are administered in dosages of 1 - 50 mg/kg body weight per day orally, parenterally or intravenously. Alone or in combination with other blood pressure-lowering vasodilators or diuretics, they are suitable for the treatment of hypertension as well as for the treatment of cardiac, renal or hepatic edema and other phenomena that can be attributed to disturbances of the electrolyte balance. Thereby, the special importance of the above-mentioned compounds lies in their double effect as diuretics and uricosurics. It is known that during diuretic treatment with known diuretics the uric acid concentration in a patient's blood increases in many cases. An increase in the uric acid level is a serious problem in gout patients. In addition, an increased uric acid level is increasingly considered a risk factor for heart disease. Therefore, the diuretic effect with simultaneous excretion of uric acid can be considered a main advantage of the compound according to the invention. The compounds can be used alone or in combination with other salidiuretic active substances and other types of action. Special mention should be made of: Spironolactone, triamteres, amiloride and other K<+->retaining compounds. But other purely blood pressure-lowering compounds are also mentioned as possible combination partners, e.g. hydralazine, clonidine, reserpine and especially also beta-blocking substances such as e.g. metoprolol or penbutolol.
Virksomme mengder av forbindelsene ifølge oppfinnelsen kan administreres en pasient på forskjellig måte, f.eks. oralt i form av kapsler eller tabletter, parenteralt i form av sterile oppløsninger eller suspensjoner og i noen tilfeller også intravenøst som sterile oppløsninger. Effective amounts of the compounds according to the invention can be administered to a patient in different ways, e.g. orally in the form of capsules or tablets, parenterally in the form of sterile solutions or suspensions and in some cases also intravenously as sterile solutions.
De frie syrer som selv er virksomme kan formuleres og av grunner som stabilitet, bedre krystalliserbarhet, bedre oppløselighet etc. også administreres i form av deres farma-søytisk tålbare salter. The free acids which are themselves active can be formulated and, for reasons such as stability, better crystallisability, better solubility, etc., also administered in the form of their pharmaceutically acceptable salts.
For en oral administrering kan de virksomme forbindelser ifølge oppfinnelsen blandes med et fortynningsmiddel eller spisbar bærer, innesluttes i gelatinkapsler eller presses til tabletter. For en oral terapeutisk administrering kan de virksomme forbindelser innarbeides i bærere og anvendes i form av tabletter, pastiller, kapsler, eliksirer, suspensjoner, siruper, vafler, tyggegummi osv. Disse preparater skal inneholde minst 0,5% av virksomt stoff, i avhengig-het av deres spesielle form kan innholdet imidlertid svinge mellom 4 og 70% av enhetens vekt. Mengden av aktiv forbindelse i slike preparater er dimensjonert således at det kan oppnås en egnet dosering. Foretrukket i blandinger og prepa rater inneholder pr. oral enhetsdose mellom 10 og 300 mg av den virksomme forbindelse. For oral administration, the active compounds according to the invention can be mixed with a diluent or edible carrier, enclosed in gelatin capsules or pressed into tablets. For oral therapeutic administration, the active compounds can be incorporated into carriers and used in the form of tablets, pastilles, capsules, elixirs, suspensions, syrups, wafers, chewing gum, etc. These preparations must contain at least 0.5% of active substance, in dependent- however, due to their special shape, the content can fluctuate between 4 and 70% of the unit's weight. The amount of active compound in such preparations is sized so that a suitable dosage can be achieved. Preferred in mixtures and preparations containing pr. oral unit dose between 10 and 300 mg of the active compound.
Tabletter, piller, kapsler, pastiller osv. kan dessuten inneholde følgende bestanddeler: Bindemidler som mikro-krystallin cellulose, tragantgummi og gelatiner; bærere som stivelse eller laktose, sprengmidler som alginsyre, mais-stivelse osv., glidemidler som magnesiumstearat eller kollo-. idalt silisiumdioksyd, søtningsmidler som rørsukker eller sakkarin eller et aromastoff som peppermynte, metylsalicylat eller orangearoma. Tablets, pills, capsules, lozenges, etc. may also contain the following ingredients: Binders such as micro-crystalline cellulose, gum tragacanth and gelatins; carriers such as starch or lactose, disintegrants such as alginic acid, corn starch, etc., lubricants such as magnesium stearate or collo-. ideally silicon dioxide, sweeteners such as cane sugar or saccharin or an aroma such as peppermint, methyl salicylate or orange aroma.
I tilfelle en enhetsdosis i kapselform kan disse ved siden av de nevnte stoffer også inneholde en flytende bærer, f.eks. en olje. Tabletter eller dragéer kan f.eks. også In the case of a unit dose in capsule form, these can, in addition to the substances mentioned, also contain a liquid carrier, e.g. an oil. Tablets or dragées can e.g. also
være utstyrt med sukkere, skjellakk eller andre tarmopp-løselige overtrekk. En sirup kan ved siden av den virksomme forbindelse dessuten inneholde rørsukker som søtningsstoff, bestemte konserveringsmidler, fargestoffer og smaksstoffer. De til fremstilling av blandingene anvendte materialer bør være farmasøytisk rene og ugiftige i de mengder som tilsettes. be equipped with sugars, shellac or other enteric-soluble coatings. In addition to the active compound, a syrup can also contain cane sugar as a sweetener, certain preservatives, coloring agents and flavourings. The materials used for the preparation of the mixtures should be pharmaceutically pure and non-toxic in the quantities that are added.
For en parenteral terapeutisk administrering kan de virksomme forbindelser ifølge oppfinnelsen innarbeides i en oppløsning eller suspensjon. Slike preparater skal minst inneholde 0,1% av den aktive forbindelse, imidlertid kan innholdet variere mellom 0,5 og 30 vekt-%. Preparatene har et slikt innhold av virksom forbindelse at en egnet enhetsdose kan fås. Blandingene og preparatene ifølge oppfinnelsen inneholder fortrinnsvis mellom 10 og 500 mg aktivt stoff pr. parenteral doseringsenhet. For a parenteral therapeutic administration, the active compounds according to the invention can be incorporated into a solution or suspension. Such preparations must contain at least 0.1% of the active compound, however, the content can vary between 0.5 and 30% by weight. The preparations have such a content of active compound that a suitable unit dose can be obtained. The mixtures and preparations according to the invention preferably contain between 10 and 500 mg of active substance per parenteral dosage unit.
Oppløsningene og suspensjonene kan inneholde følg-ende komponenter: Et sterilt fortynningsmiddel som vann til injeksjon, saltoppløsning, ikke-flyktig olje, polyetylen-glykol, glyserol, propylenglykol eller andre syntetiske opp-løsningsmidler, antibakterielle midler som benzylalkohol; antioksydanter som askorbinsyre eller natriumbisulfitt; geleringsmidler som etylendiamintetraeddiksyre; puffere, The solutions and suspensions may contain the following components: A sterile diluent such as water for injection, saline solution, non-volatile oil, polyethylene glycol, glycerol, propylene glycol or other synthetic solvents, antibacterial agents such as benzyl alcohol; antioxidants such as ascorbic acid or sodium bisulphite; gelling agents such as ethylenediaminetetraacetic acid; puffers,
som acetater, sitrater eller fosfater, og midler til inn-stilling av toksisiteten som koksalt eller dekstrose._ De \ such as acetates, citrates or phosphates, and agents for adjusting the toxicity such as common salt or dextrose.
parenterale preparater kan fylles i ampuller, engangs-sprøyter eller fleregangers doseflasker av glass og plast. parenteral preparations can be filled in ampoules, disposable syringes or multiple dose bottles made of glass and plastic.
Oppfinnelsen skal forklares nærmere ved hjelp av noen eksempler. The invention will be explained in more detail with the help of some examples.
Eksemp_el_1_ Example_el_1_
2, 3- diklor- 4-( 4- klor- 3- sulfamoylbenzoyl)- fenoksyeddiksyre2, 3- dichloro- 4-( 4- chloro- 3- sulfamoylbenzoyl)- phenoxyacetic acid
a) 4- metoksy- 3'- sulfamoyl- 2, 3, 4'- triklorbenzofenona) 4- methoxy- 3'- sulfamoyl- 2, 3, 4'- trichlorobenzophenone
I en suspensjon av 610-g (4,6 mol) aluminiumklorid In a suspension of 610-g (4.6 mol) aluminum chloride
settes porsjonsvis under omrøring ved -10°C 635 g (2,5 mol) 4-klor-3-sulfamoyl-benzosyreklorid. Det omrøres ca. 30 min. ved -10 til -5°C og tildryppes deretter en oppløsning av 354 g (2,0 mol) 2,3-dikloranisol i 0,6 liter metylenklorid. add in portions while stirring at -10°C 635 g (2.5 mol) 4-chloro-3-sulfamoyl-benzoic acid chloride. It is stirred approx. 30 min. at -10 to -5°C and a solution of 354 g (2.0 mol) 2,3-dichloroanisole in 0.6 liters of methylene chloride is then added dropwise.
Den dannede blanding omrøres ved værelsetemperatur til HCl-utviklingen er avsluttet (2-5 dager), helles på en blanding av ca. 6 kg is og 1,5 liter konsentrert saltsyre, avsuges det utfelte faste stoff, vaskes godt med vann, natriumhydrogenkarbonat-oppløsning og igjen vann, tørkes og krystalliseres fra aceton, etanol eller dimetylformamid-vannblanding. Fargeløse krystaller av smeltepunkt 219-221°C. The resulting mixture is stirred at room temperature until the HCl evolution has ended (2-5 days), poured onto a mixture of approx. 6 kg of ice and 1.5 liters of concentrated hydrochloric acid, the precipitated solid is suctioned off, washed well with water, sodium bicarbonate solution and again water, dried and crystallized from acetone, ethanol or dimethylformamide-water mixture. Colorless crystals of melting point 219-221°C.
b) 4- hydroksy- 3'- sulfamoyl- 2, 3, 4'- triklorbenzofénonb) 4- hydroxy- 3'- sulfamoyl- 2, 3, 4'- trichlorobenzophenone
I en omrørt suspensjon av 21 g (0,053 mol) 4-metoksy-3'-sulfamoyl-2,3,4'-triklorbenzofenon i ca. 400 ml toluen dryppes ved -20°C 25 ml (0,26 mol) bortribromid. Etter 5 dager omrøring ved værelsetemperatur helles den rødbrune blanding under kraftig omrøring på ca. 0,7 liter iskold, mettet natriumhydrogenkarbonat-oppløsning, det beige-fargede, faste stoff adskilles ved frasugning, vaskes med fortynnet saltsyre og vann og tørkes i vakuumeksikkator over fosforpentoksyd. Kremfarget pulver av smeltepunkt 214-218°C (under spaltning). In a stirred suspension of 21 g (0.053 mol) of 4-methoxy-3'-sulfamoyl-2,3,4'-trichlorobenzophenone for approx. 400 ml of toluene are added dropwise at -20°C with 25 ml (0.26 mol) of boron tribromide. After 5 days of stirring at room temperature, the reddish-brown mixture is poured under vigorous stirring at approx. 0.7 liter of ice-cold, saturated sodium bicarbonate solution, the beige-coloured solid is separated by suction, washed with dilute hydrochloric acid and water and dried in a vacuum desiccator over phosphorus pentoxide. Cream-coloured powder of melting point 214-218°C (under decomposition).
Et omtrent likeverdig produkt får man også ved ca. 3-timers oppvarmning av en blanding av samme utgangsmateriale med 2,5 vektdeler vannfritt pyridinhydroklorid til 180°C under nitrogen og etterfølgende innføring av den ennå flytende smelte i en is-saltsyre-blanding, vasking og tørk- An approximately equivalent product is also obtained at approx. 3-hour heating of a mixture of the same starting material with 2.5 parts by weight of anhydrous pyridine hydrochloride to 180°C under nitrogen and subsequent introduction of the still liquid melt into an ice-hydrochloric acid mixture, washing and drying
ning av det dannede beige-fargede, faste stoff.ning of the beige-colored solid formed.
c) 2, 3- diklor- 4-( 4- klor- 3- sulfamoylbenzoyl)- fenoksyeddiksyre-metylester c) 2, 3- dichloro- 4-( 4- chloro- 3- sulfamoylbenzoyl)- phenoxyacetic acid methyl ester
En blanding av 58 g (0,152 mol) 4-hydroksy-3'-sulfa-moy1-2,3,4<1->triklorbenzofenon, 21 g (0,152 mol) malt kaliumkarbonat og 2,2 g (0,015 mol) natriumjodid oppløses respek-tivt suspenderes i ca. 1,2 liter avgasset metyletylketon. Man lar det meget langsomt ved værelsetemperatur tildryppe 29 g (0,195 mol) bromeddiksyremetylester, lar det etter-omrøre til fullstendig omsetning (tynnsjiktskromatografisk kontroll, 2-6 dager), filtrere, vasker filterkaken godt med varm aceton, inndamper filtratet på rotasjonsfordamper til tørrhet, digererer residuet inntil krystallisering med vann, adskiller det faste stoff, koker det med litt metanol, av-suger etter avkjøling og tørker i godt vakuum. Hvitt til kremfarget pulver av smeltepunkt 191-194°C. Etter omkrystallisering fra metanol-aceton: Fargeløse krystaller av smeltepunkt 203-206°C. d) 2, 3- diklor- 4-( 4- klor- 3- sulfamoylbenzoyl)- fenoksyeddiksyre 31,6 g (70 mmol) 2,3-diklor-4-(4-klor-3-sulfamoylbenzoyl) -f enoksyeddiksyremetylester (1c) suspenderes i ca.. 700 ml metanol. Ved 0°C tildryppes i løpet av 1 time 1 liter 0,15 N vandig litiumhydroksydoppløsning under omrøring. Man lar det omrøre natten over ved en temperatur mellom 0 og 10°C, blander deretter den klare oppløsning med 1,5 kg is og 0,5 liter mettet koksaltoppløsning, innstiller ved dråpevis tilsetning av 2 N saltsyre (ca. 70 ml) på pH 3, sentrifugerer det voluminøse lyse bunnfall, vasker sentrifugatet en gang med vann og omkrystalliserer fra en eddiksyre-vann-blanding under tilsetning av aktivkull og tørker ved 80°C og 150 torr over fosforpentoksyd. Fargeløse småblader av smeltepunkt 184-186°C. A mixture of 58 g (0.152 mol) 4-hydroxy-3'-sulfamoyl-2,3,4<1->trichlorobenzophenone, 21 g (0.152 mol) ground potassium carbonate and 2.2 g (0.015 mol) sodium iodide is dissolved respectively suspended for approx. 1.2 liters of degassed methyl ethyl ketone. 29 g (0.195 mol) bromoacetic acid methyl ester is allowed to be added dropwise very slowly at room temperature, it is then allowed to stir until complete reaction (thin-layer chromatographic control, 2-6 days), filtered, the filter cake is washed well with hot acetone, the filtrate is evaporated on a rotary evaporator to dryness, digest the residue until crystallization with water, separate the solid, boil it with a little methanol, filter off after cooling and dry in a good vacuum. White to cream colored powder of melting point 191-194°C. After recrystallization from methanol-acetone: Colorless crystals of melting point 203-206°C. d) 2,3-dichloro-4-(4-chloro-3-sulfamoylbenzoyl)-phenoxyacetic acid 31.6 g (70 mmol) 2,3-dichloro-4-(4-chloro-3-sulfamoylbenzoyl)-phenoxyacetic acid methyl ester ( 1c) is suspended in approx. 700 ml of methanol. At 0°C, 1 liter of 0.15 N aqueous lithium hydroxide solution is added dropwise over the course of 1 hour while stirring. It is left to stir overnight at a temperature between 0 and 10°C, then the clear solution is mixed with 1.5 kg of ice and 0.5 liters of saturated sodium chloride solution, adjusted by the dropwise addition of 2 N hydrochloric acid (approx. 70 ml) to pH 3, centrifuge the voluminous light precipitate, wash the centrifuged once with water and recrystallize from an acetic acid-water mixture with the addition of activated carbon and dry at 80°C and 150 torr over phosphorus pentoxide. Colorless small leaves of melting point 184-186°C.
Eksemgel_2 Eczema gel_2
5- klor- 2- mety1- 4-( 4- klor- 3- sulfamoylbenzoyl)- fenoksyeddiksyre 5- chloro- 2- methyl 1- 4-( 4- chloro- 3- sulfamoylbenzoyl)- phenoxyacetic acid
Forbindelsen fremstilles analogt den i eksempel 1 omtalte reaksjonsrekkefølge, imidlertid med 5-klor-2-metyl-anisol som utgangsmateriale. Mellomproduktene og slutt-produktene har følgende smeltepunkter: a) 2,4'-diklor-4-metoksy-5-metyl-3'-sulfamoylbenzofenon, smeltepunkt 172-173°C b) 2,4'-diklor-4-hydroksy-5-metyl-3'-sulfamoylbenzofenon, smeltepunkt 230-234°C c) 5-klor-2-metyl-4-(4-klor-3-sulfamoylbenzoyl)-fenoksy-eddiksyremetylester, smeltepunkt 165-169°C d) 5-klor-2-metyl-4-(4-klor-3-sulfamoylbenzoyl)-fenoksyeddiksyre, smeltepunkt 224-246°C The compound is prepared analogously to the reaction sequence mentioned in example 1, however with 5-chloro-2-methylanisole as starting material. The intermediates and final products have the following melting points: a) 2,4'-dichloro-4-methoxy-5-methyl-3'-sulfamoylbenzophenone, melting point 172-173°C b) 2,4'-dichloro-4-hydroxy- 5-methyl-3'-sulfamoylbenzophenone, melting point 230-234°C c) 5-chloro-2-methyl-4-(4-chloro-3-sulfamoylbenzoyl)-phenoxy-acetic acid methyl ester, melting point 165-169°C d) 5 -chloro-2-methyl-4-(4-chloro-3-sulfamoylbenzoyl)-phenoxyacetic acid, melting point 224-246°C
Eksemgel 3 Example 3
3- klor- 2- metyl- 4-( 4- klor- 3- sulfamoylbenzoyl)- fenoksyeddiksyre 3- chloro- 2- methyl- 4-( 4- chloro- 3- sulfamoylbenzoyl)- phenoxyacetic acid
Forbindelsen fremstilles analogt den i eksempel 1 omtalte reaksjonsrekkefølge, imidlertid.med 3-klor-2-metyl-anisol som utgangsmateriale. Mellomproduktene og slutt-produktene har følgende smeltepunkter: a) 2,4'-diklor-4-metoksy-3-metyl-3<1->sulfamoylbenzofenon, smeltepunkt 222-224°C b) 2,4'-diklor-4-hydroksy-3-metyl-3'-sulfamoylbenzofenon, smeltepunkt 220-224°C c) 3-klor-2-metyl-4-(4-klor-3-sulfamoylbenzoyl)-fenoksy-eddiksyremetylester, smeltepunkt 192-196°C d) 3-klor-2-metyl-4-(4-klor-3-sulfamoylbenzoyl)-fenoksyeddiksyre, smeltepunkt 182-184°C The compound is prepared analogously to the reaction order described in example 1, however, with 3-chloro-2-methylanisole as starting material. The intermediates and final products have the following melting points: a) 2,4'-dichloro-4-methoxy-3-methyl-3<1->sulfamoylbenzophenone, melting point 222-224°C b) 2,4'-dichloro-4- hydroxy-3-methyl-3'-sulfamoylbenzophenone, melting point 220-224°C c) 3-chloro-2-methyl-4-(4-chloro-3-sulfamoylbenzoyl)-phenoxy-acetic acid methyl ester, melting point 192-196°C d ) 3-chloro-2-methyl-4-(4-chloro-3-sulfamoylbenzoyl)-phenoxyacetic acid, melting point 182-184°C
Eksemp_el_4Example_el_4
Forbindelsen fremstilles analogt den i eksempel 1 omtalte reaksjonsrekkefølge, imidlertid med 2-klor-3-metyl-anisol som utgangsmateriale. Mellomproduktene og slutt-produktene har følgende smeltepunkter: The compound is prepared analogously to the reaction sequence mentioned in example 1, however with 2-chloro-3-methylanisole as starting material. The intermediate products and final products have the following melting points:
a) 3,4'-diklor-4-metoksy-2-metyl-3<1->sulfamoylbenzofenon, smeltepunkt 186-188°C b) 3,4'-diklor-4-hydroksy-2-metyl-3<1->sulfamoylbenzofenon, smeltepunkt 194-197°C c) 2-klor-3-metyl-4-(4-klor-3-sulfamoylbenzoyl)-fenoksy-eddiksyremetylester, smeltepunkt 152-154°C d) 2-klor-3-metyl-4-(4-klor-3-sulfamoylbenzoyl)-fenoksy eddiksyre, smeltepunkt 178-180°C Eksemp_el_5 2, 3- diklor- 4-( 4- klor- 3- sulfamoylbenzoyl)- fenoksyeddiksyre-etylester a) Forbindelsen fremstilles analogt den i eksempel 1 under 1c omtalte fremgangsmåte, imidlertid anvendes klor-eddiksyreetylester istedenfor bromeddiksyremetylester, og produktet renses ved søylekromatografi på kiselgel med Cl^C^-eddikester som elueringsmiddel og omkrystalliseres fra etanol-vann. Fargeløse krystaller av smeltepunkt 146-148°C. b) 4,4 g (10 mmol) 2,3-diklor-4-(4-klor-3-sulfamoylbenzoyl) -f enoksyeddiksyre (eksempel 1) blandes med 150 ml a) 3,4'-dichloro-4-methoxy-2-methyl-3<1->sulfamoylbenzophenone, melting point 186-188°C b) 3,4'-dichloro-4-hydroxy-2-methyl-3<1 ->sulfamoylbenzophenone, melting point 194-197°C c) 2-chloro-3-methyl-4-(4-chloro-3-sulfamoylbenzoyl)-phenoxy-acetic acid methyl ester, melting point 152-154°C d) 2-chloro-3- methyl-4-(4-chloro-3-sulfamoylbenzoyl)-phenoxy acetic acid, melting point 178-180°C Example_el_5 2,3-dichloro-4-(4-chloro-3-sulfamoylbenzoyl)-phenoxyacetic acid ethyl ester a) The compound is prepared analogously to the method described in example 1 under 1c, however, chloroacetic acid ethyl ester is used instead bromoacetic acid methyl ester, and the product is purified by column chromatography on silica gel with Cl^C^-acetic ester as eluent and recrystallized from ethanol-water. Colorless crystals of melting point 146-148°C. b) 4.4 g (10 mmol) of 2,3-dichloro-4-(4-chloro-3-sulfamoylbenzoyl)-phenoxyacetic acid (Example 1) are mixed with 150 ml
etanol, 0,2 g sterkt sur ioneutvekslerharpiks ("Dowex 50 W") og 50 ml toluen og omrøres under tilbakeløp (ca. 4 timer) til avslutning av vannutskilling i vannutskiller. Ione-utveksleren adskilles ved filtrering, filtratet inndampes i. vakuum og residuet omkrystalliseres fra en etanol/aceton/- vannblanding. Fargeløse krystaller av smeltepunkt 145-148°C. ethanol, 0.2 g of strongly acidic ion exchange resin ("Dowex 50 W") and 50 ml of toluene and stirred under reflux (about 4 hours) until the end of water separation in a water separator. The ion exchanger is separated by filtration, the filtrate is evaporated in vacuo and the residue is recrystallized from an ethanol/acetone/water mixture. Colorless crystals of melting point 145-148°C.
Eksempel_6 Example_6
2, 3- diklor- 4-( 4- klor- 3- sulfamoylbenzoyl)- fenoksyeddiksyre-tert- butylester 2, 3- dichloro- 4-( 4- chloro- 3- sulfamoylbenzoyl)- phenoxyacetic acid tert- butyl ester
Forbindelsen fremstilles analogt den i eksempel 1 under punkt 1c omtalte arbeidsmåte idet man imidlertid anvender bromeddiksyre-tert-butylester istedenfor bromeddiksyremetylester, og produktet omkrystalliseres etter søyle-kromatografisk rensning på kiselgel med Cr^C^-eddikester (20:1 til 3:1) som eluens fra isopropanol-vann og tørkes. The compound is prepared analogously to the working method mentioned in example 1 under point 1c, but bromoacetic acid tert-butyl ester is used instead of bromoacetic acid methyl ester, and the product is recrystallized after column chromatographic purification on silica gel with Cr^C^-acetic ester (20:1 to 3:1) as eluent from isopropanol-water and dried.
Blassgule krystaller av smeltepunkt 145-147°C.Pale yellow crystals of melting point 145-147°C.
Eksemp_el_7 Example_el_7
2, 3- diklor- 4-( 4- klor- 3- sulfamoylbenzoyl)- fenoksyeddiksyre-metylester 2, 3- dichloro- 4-( 4- chloro- 3- sulfamoylbenzoyl)- phenoxyacetic acid methyl ester
Forbindelsen er identisk med det i eksempel 1 under punkt 1c omtalte mellomprodukt og kan fremstilles som angitt der eller fås på følgende måte: 4,4 g (10 mmol) 2,3-diklor-4-(4-klor-3-sulfamoylbenzoyl)-fenoksyeddiksyre (dannet ifølge eksempel 1d) oppløses i 200 ml vannfri metanol og hensettes etter tilsetning av 1 ml konsentrert svovelsyre ca. 1 dag ved værelsetemperatur. Man frasuger det utfelte faste stoff, tørker i vakuum. Fargeløse krystaller av smeltepunkt 208-210°C. The compound is identical to the intermediate product mentioned in example 1 under point 1c and can be prepared as indicated there or obtained in the following way: 4.4 g (10 mmol) 2,3-dichloro-4-(4-chloro-3-sulfamoylbenzoyl) -phenoxyacetic acid (formed according to example 1d) is dissolved in 200 ml of anhydrous methanol and set aside after the addition of 1 ml of concentrated sulfuric acid approx. 1 day at room temperature. The precipitated solid is sucked off, dried in a vacuum. Colorless crystals of melting point 208-210°C.
Eksemp_el_8 Example_el_8
2, 3- dimetyl- 4-( 4- klor- 3- sulfamoylbenzoyl)- fenoksyeddiksyre2, 3- dimethyl- 4-( 4- chloro- 3- sulfamoylbenzoyl)- phenoxyacetic acid
40 g (0,3 mol) aluminiumklorid suspenderes i 300 ml metylenklorid og ved isbadtemperatur under fuktighetsutelukkelse innrøres 25,4 g (0,1 mol) 4-klpr-3-sulfamoyl-benzoylklorid. Man lar det etteromrøre i 45 minutter og tilsetter deretter ved 0°C under omrøring 18 g (0,1 mol) 2,3-dimetylfenoksyeddiksyre porsjonsvis. Man lar det videre-omrøre ved værelsetemperatur idet blandingen etter hvert blir viskøs. Etter flere dagers henstand spaltes med isvann-saltsyre-blanding, den vandige fase utrystes flere ganger med eddiksyreetylester, de organiske faser tørkes, inndampes på rotasjonsfordamper, og det harpiksaktige residuum omkrystalliseres først fra isopropanol og deretter fra vandig eddiksyre hver gang under tilsetning av aktivkull. Fargeløse krystaller av smeltepunkt 186-190°C. 40 g (0.3 mol) of aluminum chloride are suspended in 300 ml of methylene chloride and at ice bath temperature under exclusion of moisture 25.4 g (0.1 mol) of 4-klpr-3-sulfamoyl-benzoyl chloride are stirred in. It is left to stir for 45 minutes and then 18 g (0.1 mol) of 2,3-dimethylphenoxyacetic acid are added in portions at 0°C with stirring. It is allowed to stir further at room temperature as the mixture gradually becomes viscous. After standing for several days, the mixture is split with an ice-water-hydrochloric acid mixture, the aqueous phase is shaken several times with ethyl acetate, the organic phases are dried, evaporated on a rotary evaporator, and the resinous residue is recrystallized first from isopropanol and then from aqueous acetic acid each time while adding activated carbon. Colorless crystals of melting point 186-190°C.
Eksem<pe>l_9 Eczema<pe>l_9
2, 3- dimetyl- 4-( 4- klor- 3- sulfamoylbenzoyl)- fenoksyeddiksyre-metylester 2, 3- dimethyl- 4-( 4- chloro- 3- sulfamoylbenzoyl)- phenoxyacetic acid methyl ester
4,0 g (10 mmol) 2,3-dimetyl-4-(4-klor-3-sulfamoyl- 4.0 g (10 mmol) 2,3-dimethyl-4-(4-chloro-3-sulfamoyl-
benzoyl)-fenoksyeddiksyre (eksempel 9) oppløses i nøyaktig tilstrekkelig mengde kokende metanol og videreoppvarmes 15 minutter. De etter langsom avkjøling og utrivning dannede fargeløse krystaller samles og befris for oppløsningsmiddel i vakuum, smeltepunkt 157-162°C. benzoyl)-phenoxyacetic acid (Example 9) is dissolved in exactly sufficient boiling methanol and further heated for 15 minutes. The colorless crystals formed after slow cooling and extraction are collected and freed from solvent in vacuum, melting point 157-162°C.
Eksemp_el_1_0 Example_el_1_0
3- metyl- 4-( 4- klor- 3- sulfamoylbenzoyl) fenoksyeddiksyre 3- methyl- 4-( 4- chloro- 3- sulfamoylbenzoyl) phenoxyacetic acid
Forbindelsen fremstilles analogt eksempel 9, imidlertid med 3-metylfenoksyeddiksyre som utgangsmateriale.~Farge-løse krystaller av smeltepunkt 208-211°C. The compound is prepared analogously to example 9, however with 3-methylphenoxyacetic acid as starting material. ~ Colorless crystals of melting point 208-211°C.
2- metyl- 4-( 4- klor- 3- sulfamoylbenzoyl)- fenoksyeddiksyre 2- methyl- 4-( 4- chloro- 3- sulfamoylbenzoyl)- phenoxyacetic acid
Denne forbindelse fremstilles analogt den i eksempel 9 omtalte måte, imidlertid med 2-metylfenoksyeddiksyre som This compound is prepared analogously to the method mentioned in example 9, however with 2-methylphenoxyacetic acid as
utgangsmateriale. Fargeløse krystaller av smeltepunkt 198-200°C. starting material. Colorless crystals of melting point 198-200°C.
<Ek>sem<p>_<el>_2<2><Ek>sem<p>_<el>_2<2>
2, 6- dimetyl- 4-( 4- klor- 3- sulfamoylbenzoyl)- fenoksyeddiksyre 2, 6- dimethyl- 4-( 4- chloro- 3- sulfamoylbenzoyl)- phenoxyacetic acid
Forbindelsen fremstilles analogt eksempel 9, imidlertid med 2,6-dimetylfenoksyeddiksyre som utgangsmateriale. Fargeløse krystaller av smeltepunkt 237-240°C. The compound is prepared analogously to example 9, however with 2,6-dimethylphenoxyacetic acid as starting material. Colorless crystals of melting point 237-240°C.
Eksemp_el_1_3 Example_el_1_3
2- klor- 4-( 4- klor- 3- sulfamoylbenzoyl)- fenoksyeddiksyre 2- chloro- 4-( 4- chloro- 3- sulfamoylbenzoyl)- phenoxyacetic acid
Forbindelsen fremstilles analogt eksempel 9, idet det imidlertid anvendes 2-klorfenoksyeddiksyre istedenfor 2,3-dimetylfenoksyeddiksyre som utgangsmateriale, og kompo-nentene omrøres i 1,2-dikloretan ca. 3 dager ved ca. 50°C. Råproduktet renses flere på hverandre følgende omkrystalli-seringer fra vann-aceton og isopropanol-toluen. Hvite krystaller av smeltepunkt 163-167°C. The compound is prepared analogously to example 9, except that 2-chlorophenoxyacetic acid is used instead of 2,3-dimethylphenoxyacetic acid as starting material, and the components are stirred in 1,2-dichloroethane for approx. 3 days at approx. 50°C. The crude product is purified by several consecutive recrystallizations from water-acetone and isopropanol-toluene. White crystals of melting point 163-167°C.
Eksemgel 14 Example 14
2, 3- diklor- 4-( 4- klor- 3- sulfamoylbenzoyl)- fenoksyeddiksyre2, 3- dichloro- 4-( 4- chloro- 3- sulfamoylbenzoyl)- phenoxyacetic acid
a) 4- metoksy- 3'- dimetylaminometylenaminosulfonyl- 2, 3, 4'-triklorbenzofenon a) 4-Methoxy-3'-dimethylaminomethyleneaminosulfonyl-2,3,4'-trichlorobenzophenone
19,7 g (50 mmol) 4-metoksy-31-sulfamoyl-2,3,41 - triklorbenzofenon suspenderes i 200 ml metylenklorid og blandes ved værelsetemperatur under fuktighetsutelukkelse med 20 ml dimetylformamiddimetylacetal. Det inntrer under omrøring hurtig oppløsning som hensettes natten over. Inn-dampning til tørrhet og omkrystallisering av residuet fra isopropanol-dimetylformamid gir blassgule krystaller av smeltepunkt 200-202°C. 19.7 g (50 mmol) of 4-methoxy-31-sulfamoyl-2,3,41-trichlorobenzophenone are suspended in 200 ml of methylene chloride and mixed at room temperature under exclusion of moisture with 20 ml of dimethylformamide dimethyl acetal. Rapid dissolution occurs during stirring, which is left overnight. Evaporation to dryness and recrystallization of the residue from isopropanol-dimethylformamide gives pale yellow crystals of melting point 200-202°C.
b) 4- hydroksy- 3'- dimetylaminometylenaminosulfonyl- 2, 3, 4'-triklorbenzofenon 4 5 g (0,1 mol) 4-metoksy-3'-dimetylaminometylenamino-sulf onyl-2 , 3 , 4 ' -triklorbenzof enon (trinn a) suspenderes i 250 ml tørr 1,2-dikloretan og omrøres under nitrogenatmosfære. Porsjonsvis tilsettes 54,2 g (0,4 mol) aluminiumklorid idet temperaturen øker til ca. 35°C og blandingen blir omtrent homogen. Ved 40-50°C omrøres så lenge inntildet i tynnsjikts-kromatogram ikke mer er påvisbart utgangsmateriale (ca. 5 timer). Til den forbigående, harpiksaktige blanding settes under ytre avkjøling hurtig isvann og etteromrøres til utskillelse av et krystallinsk fast stoff. Dette frasuges, vaskes nøytralt med vann, tørkes og omkrystalliseres fra metanol under tilsetning av aktivkull.j Grågule krystaller av smeltepunkt 19 6-198°C. b) 4-hydroxy-3'-dimethylaminomethyleneaminosulfonyl-2,3,4'-trichlorobenzophenone 4 5 g (0.1 mol) 4-methoxy-3'-dimethylaminomethyleneamino-sulfonyl-2,3,4'-trichlorobenzophenone ( step a) is suspended in 250 ml of dry 1,2-dichloroethane and stirred under a nitrogen atmosphere. 54.2 g (0.4 mol) aluminum chloride is added in portions as the temperature increases to approx. 35°C and the mixture becomes approximately homogeneous. Stir at 40-50°C until starting material is no longer detectable in the thin-layer chromatogram (approx. 5 hours). Rapid ice water is added to the temporary, resinous mixture under external cooling and then stirred until a crystalline solid separates. This is filtered off, washed neutrally with water, dried and recrystallized from methanol with the addition of activated carbon. Grey-yellow crystals of melting point 19 6-198°C.
c) 2, 3- diklor- 4-( 4- klor- 3- dimetylaminometylenaminosulfonyl-benzyl)- fenoksyeddiksyremetylester c) 2, 3-dichloro-4-(4-chloro-3-dimethylaminomethyleneaminosulfonyl-benzyl)-phenoxyacetic acid methyl ester
4,3 g (10 mmol) 4-hydroksy-3'-dimetylaminometylen-aminosulf onyl-2 , 3 , 4 ' -triklorbenzof enon (trinn b), 1,7 g 4.3 g (10 mmol) 4-hydroxy-3'-dimethylaminomethylene-aminosulfonyl-2,3,4'-trichlorobenzophenone (step b), 1.7 g
(12 mmol) finmalt kaliumkarbonat, 0,75 g natriumjodid, 20 ml tørr dimetylformamid og 1,8 g (13 mmol) bromeddiksyremetylester has sammen i denne rekkefølge, omrøres heftig under tynnsjiktskromatografisk kontroll til fullstendig omsetning (ca. 4 timer) ved værelsetemperatur. Til opparbeidelse heller man på iskold, fortynnet saltsyre, frasuger det lysegule, (12 mmol) of finely ground potassium carbonate, 0.75 g of sodium iodide, 20 ml of dry dimethylformamide and 1.8 g (13 mmol) of bromoacetic acid methyl ester are combined in this order, stirred vigorously under thin-layer chromatographic control until complete reaction (approx. 4 hours) at room temperature. For processing, pour ice-cold, diluted hydrochloric acid, suck off the pale yellow,
faste stoff og omkrystalliserer det fra metanol-eddikester. Fargeløse krystaller av smeltepunkt 130-132°C. d) 2, 3- diklor- 4-( 4- klor- 3- sulfamoylbenzoyl)- fenoksyeddiksyre 44,5 g (0,09 mol) 2,3-diklor-4-(4-klor-3-dimetyl-aminometylenaminosulfonylbenzoyl)-fenoksyeddiksyremetylester (trinn c) omrøres under tilbakeløp i en blanding av 150 ml eddiksyre, 450 ml vann og 45 ml konsentrert saltsyre i 3 timer idet det oppstår en klar, fargeløs oppløsning. Ved langsom avkjøling oppstår en finkrystallinsk utfelling som frasuges, omkrystalliseres under eventuell tilsetning av aktivkull fra eddiksyre-vann. Fargeløse krystaller av smeltepunkt 186-188°C. solid and recrystallize it from methanol-acetic acid. Colorless crystals of melting point 130-132°C. d) 2,3-dichloro-4-(4-chloro-3-sulfamoylbenzoyl)-phenoxyacetic acid 44.5 g (0.09 mol) 2,3-dichloro-4-(4-chloro-3-dimethyl-aminomethyleneaminosulfonylbenzoyl) -phenoxyacetic acid methyl ester (step c) is stirred under reflux in a mixture of 150 ml of acetic acid, 450 ml of water and 45 ml of concentrated hydrochloric acid for 3 hours as a clear, colorless solution is formed. During slow cooling, a fine crystalline precipitate occurs which is sucked off, recrystallised during the possible addition of activated carbon from acetic acid water. Colorless crystals of melting point 186-188°C.
Eksemp_el_1_5 Example_el_1_5
2-/2, 3- diklor- 4-( 4- klor- 3- sulfamoylbenzoyl) 7~ fenoksypropion-syre 2-/2, 3- dichloro- 4-( 4- chloro- 3- sulfamoylbenzoyl) 7~ phenoxypropionic acid
Forbindelsen fremstilles analogt den i eksempel 15 angitte reaksjonsrekkefølge, imidlertid i trinn c) med 2-brom-propionsyreetylester som alkyleringsmiddel (ved 50°C). Mellomproduktet og sluttproduktet har følgende smeltepunkter: c) 2-/2,3-diklor-4-(4-klor-3-dimetylaminometylenamino-sulfonylbenzoyl) 7- fenoksypropionsyreetylester, smeltepunkt 141-143°C d) 2-/2 ,3-diklor-4- (4-klor-3-sulfamoylbenzoyl)_7l -fenoksy-propionsyre, smeltepunkt ca. 145°C (holder hårdnakket fast The compound is prepared analogously to the reaction order indicated in example 15, however in step c) with 2-bromopropionic acid ethyl ester as alkylating agent (at 50°C). The intermediate product and the final product have the following melting points: c) 2-/2,3-dichloro-4-(4-chloro-3-dimethylaminomethyleneamino-sulfonylbenzoyl) 7-phenoxypropionic acid ethyl ester, melting point 141-143°C d) 2-/2 ,3- dichloro-4-(4-chloro-3-sulfamoylbenzoyl)_7l-phenoxy-propionic acid, melting point approx. 145°C (holds the hard neck firmly
på oppløsningsmiddelrester).on solvent residues).
Eksempel _1_§ Example _1_§
2-/ 2, 3- diklor- 4-( 4- klor- 3- sulfamoylbenzoyl) 7~ fenoksy- 2-metylpropionsyre 2-/ 2, 3- dichloro- 4-( 4- chloro- 3- sulfamoylbenzoyl) 7~ phenoxy- 2-methylpropionic acid
Forbindelsen fremstilles analogt den i eksempel 15 omtalte reaksjonsrekkefølge, imidlertid i trinn c) med 2-brom-2-metylpropionsyreetylester som alkyleringsmiddel ved en reaksjonstemperatur på ca. 60°C og ca. 20 timers reak-sjonstid. Mellomproduktet (etter søylekromatografisk rensning) og sluttproduktet har følgende smeltepunkter: c) 2-/2,3-diklor-4-(4-klor-3-dimetylaminometylenamino-sulf ony lbenzoyl )_7f enoksy-2-metylpropionsyreety les ter, The compound is prepared analogously to the reaction order mentioned in example 15, however in step c) with 2-bromo-2-methylpropionic acid ethyl ester as alkylating agent at a reaction temperature of approx. 60°C and approx. 20 hour reaction time. The intermediate product (after column chromatographic purification) and the final product have the following melting points: c) 2-(2,3-dichloro-4-(4-chloro-3-dimethylaminomethyleneamino-sulfonylbenzoyl)_7f-enoxy-2-methylpropionic acid ethyl ester,
smeltepunkt 112-114°C.melting point 112-114°C.
d) 2-/2 , 3-diklor-4- (4-klor-3-sulf amoylbenzoyl)_7-f enoksy-2-metylpropionsyre, smeltepunkt 219-220°C. d) 2-(2,3-dichloro-4-(4-chloro-3-sulfamoylbenzoyl)-7-phenoxy-2-methylpropionic acid, melting point 219-220°C.
Claims (10)
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DE19823232922 DE3232922A1 (en) | 1982-09-04 | 1982-09-04 | SULFAMOYLBENZOPHENONE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, THEIR USE AND PHARMACEUTICAL PREPARATIONS BASED ON THESE COMPOUNDS |
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DE (1) | DE3232922A1 (en) |
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MA (1) | MA19893A1 (en) |
NO (1) | NO833157L (en) |
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AU2001268734A1 (en) | 2000-06-28 | 2002-01-08 | Merck & Co., Inc. | Use of agents capable of reducing uric acid levels for the treatment of cardiovascular disease |
EP1883405A4 (en) | 2005-05-09 | 2010-01-27 | Takeda Pharmaceuticals North A | Methods for treating nephrolithiasis |
WO2012033941A1 (en) | 2010-09-10 | 2012-03-15 | Takeda Pharmaceuticals North America, Inc. | Methods for concomitant treatment of theophylline and febuxostat |
JP5363636B2 (en) * | 2011-10-21 | 2013-12-11 | ファイザー・リミテッド | New salts and medical uses |
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PT77286A (en) | 1983-10-01 |
EP0104483A3 (en) | 1984-08-15 |
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PT77286B (en) | 1986-04-09 |
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FI833118A (en) | 1984-03-05 |
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