NO122651B - - Google Patents
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- Publication number
- NO122651B NO122651B NO4868A NO4868A NO122651B NO 122651 B NO122651 B NO 122651B NO 4868 A NO4868 A NO 4868A NO 4868 A NO4868 A NO 4868A NO 122651 B NO122651 B NO 122651B
- Authority
- NO
- Norway
- Prior art keywords
- group
- cyclopropyl
- general formula
- sulfanilamide
- methylthio
- Prior art date
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- 150000001875 compounds Chemical class 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 11
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 10
- 125000003277 amino group Chemical group 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 125000004414 alkyl thio group Chemical group 0.000 claims description 5
- 150000007529 inorganic bases Chemical class 0.000 claims description 5
- 150000007530 organic bases Chemical class 0.000 claims description 5
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical class NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 4
- 125000004442 acylamino group Chemical group 0.000 claims description 3
- 239000007795 chemical reaction product Substances 0.000 claims description 3
- 238000003776 cleavage reaction Methods 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 230000007017 scission Effects 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 229940124530 sulfonamide Drugs 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-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
- 239000000203 mixture Substances 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 6
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 5
- 239000007868 Raney catalyst Substances 0.000 description 5
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 5
- 229910000564 Raney nickel Inorganic materials 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- -1 methoxy, ethoxy, propoxy Chemical group 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 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 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000000155 melt Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- 235000011121 sodium hydroxide Nutrition 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 159000000000 sodium salts Chemical class 0.000 description 3
- KZTWONRVIPPDKH-UHFFFAOYSA-N 2-(piperidin-1-yl)ethanol Chemical compound OCCN1CCCCC1 KZTWONRVIPPDKH-UHFFFAOYSA-N 0.000 description 2
- JPJWDJDZHLOKFC-UHFFFAOYSA-N 4-cyclopropyl-5-methoxy-2-methylsulfanyl-1H-pyrimidin-6-one Chemical compound C1(CC1)C1=C(C(=NC(=N1)SC)O)OC JPJWDJDZHLOKFC-UHFFFAOYSA-N 0.000 description 2
- CHKKQVBMRAPQEH-UHFFFAOYSA-N COC1=C(Cl)N=C(SC)N=C1C1CC1 Chemical compound COC1=C(Cl)N=C(SC)N=C1C1CC1 CHKKQVBMRAPQEH-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 2
- 125000004705 ethylthio group Chemical group C(C)S* 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- VFGWJXCRWXZRHV-UHFFFAOYSA-N 2-cyclopropyl-4-hydroxy-1h-pyrimidin-6-one Chemical compound OC1=CC(O)=NC(C2CC2)=N1 VFGWJXCRWXZRHV-UHFFFAOYSA-N 0.000 description 1
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical compound CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 description 1
- XJPZKYIHCLDXST-UHFFFAOYSA-N 4,6-dichloropyrimidine Chemical compound ClC1=CC(Cl)=NC=N1 XJPZKYIHCLDXST-UHFFFAOYSA-N 0.000 description 1
- DUFGYCAXVIUXIP-UHFFFAOYSA-N 4,6-dihydroxypyrimidine Chemical compound OC1=CC(O)=NC=N1 DUFGYCAXVIUXIP-UHFFFAOYSA-N 0.000 description 1
- ROYOJXTZQSKWMF-UHFFFAOYSA-N 4-chloro-6-cyclopropyl-2-methylsulfanylpyrimidine Chemical compound CSC1=NC(Cl)=CC(C2CC2)=N1 ROYOJXTZQSKWMF-UHFFFAOYSA-N 0.000 description 1
- 150000005717 4-chloropyrimidines Chemical class 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- BWLUMTFWVZZZND-UHFFFAOYSA-N Dibenzylamine Chemical compound C=1C=CC=CC=1CNCC1=CC=CC=C1 BWLUMTFWVZZZND-UHFFFAOYSA-N 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 241000588747 Klebsiella pneumoniae Species 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- HTLZVHNRZJPSMI-UHFFFAOYSA-N N-ethylpiperidine Chemical compound CCN1CCCCC1 HTLZVHNRZJPSMI-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241000293871 Salmonella enterica subsp. enterica serovar Typhi Species 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 241000295644 Staphylococcaceae Species 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001409 amidines Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- BEPAFCGSDWSTEL-UHFFFAOYSA-N dimethyl malonate Chemical compound COC(=O)CC(=O)OC BEPAFCGSDWSTEL-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000000839 emulsion 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
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 235000013312 flour Nutrition 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- CGRKCGWEOIQFRD-UHFFFAOYSA-N sodium;(4-aminophenyl)sulfonylazanide Chemical compound [Na+].NC1=CC=C(S([NH-])(=O)=O)C=C1 CGRKCGWEOIQFRD-UHFFFAOYSA-N 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229950000329 thiouracil Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/56—One oxygen atom and one sulfur atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/60—Three or more oxygen or sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/69—Benzenesulfonamido-pyrimidines
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Analogifremgangsmåte for fremstilling av hittil ukjente, farmakodynamisk virksomme derivater av sulfanilamid. Analogy method for the production of hitherto unknown, pharmacodynamically active derivatives of sulfanilamide.
Oppfinnelsen vedrorer en fremgangsmåte for fremstilling av hittil ukjente derivater av sulfanilamid. The invention relates to a process for the production of hitherto unknown derivatives of sulfanilamide.
Det ble funnet at forbindelser med den generelle formel I, hvor R. og R 2 betyr hydrogen eller cyklopropylgruppen, idet en av restene eller R2 er cyklopropylgruppen, og It was found that compounds of the general formula I, where R. and R 2 mean hydrogen or the cyclopropyl group, one of the residues or R 2 being the cyclopropyl group, and
R^ betyr en lavere alkyl- eller alkoksygruppe, R 1 means a lower alkyl or alkoxy group,
såvel som deres salter med uorganiske eller organiske baser innehar en fremragende antibakteriell virkning. De egner seg derfor til behandling av infeksjonssykdommer. as well as their salts with inorganic or organic bases have an outstanding antibacterial effect. They are therefore suitable for the treatment of infectious diseases.
I forbindelsene med den generelle formel I er R^ som alkylgruppe f.eks. metyl-, etyl-, propyl- eller isopropylgruppen og som alkoksygruppe f.eks. metoksy-, etoksy-, propoksy- eller isoprop-oksygruppen. In the compounds of the general formula I, R 1 as an alkyl group is e.g. the methyl, ethyl, propyl or isopropyl group and as an alkoxy group e.g. the methoxy, ethoxy, propoxy or isopropoxy group.
For fremstilling av disse nye forbindelser reduserer man en forbindelse med den generelle formel II, For the production of these new compounds, a compound with the general formula II is reduced,
hvor R^<1> og R2' betyr cyklopropylgruppen eller en lavere alkyltiogruppe, idet en av restene R^' eller R2' er cyklopropylgruppen, where R^<1> and R2' mean the cyclopropyl group or a lower alkylthio group, one of the residues R^' or R2' being the cyclopropyl group,
R^ en lavere alkyl- eller alkoksygruppe, og R^ a lower alkyl or alkoxy group, and
X betyr aminogruppen eller en acylaminogruppe, X means the amino group or an acylamino group,
under avspaltning av en lavere alkyltiogruppe, omdanner, hvis during cleavage of a lower alkylthio group, converts, if
nbdvendig, gruppen X i det erholdte reaksjonsprodukt til den frie aminogruppe og overforer, hvis onsket, den erholdte forbindelse med den generelle formel I med en uorganisk eller organisk base til et salt. necessary, the group X in the obtained reaction product to the free amino group and, if desired, transfers the obtained compound of the general formula I with an inorganic or organic base to a salt.
R^' eller R2' er som lavere alkyltiogrupper fortrinnsvis metyltio- eller etyltiogruppen. Som reduksjonsmiddel for en forbindelse med den generelle formel II kommer f.eks. Raney-nikkel på tale, som kan anvendes i alkalisk opplbsning, f.eks. R 1' or R 2' are, as lower alkylthio groups, preferably the methylthio or ethylthio group. As a reducing agent for a compound with the general formula II, e.g. Raney nickel in speech, which can be used in alkaline solutions, e.g.
i natrium- eller kaliumkarbonatopplbsning eller i ammoniakalsk opplbsning. in sodium or potassium carbonate solution or in ammoniacal solution.
Den eventuelt etterfblgende overforing av gruppen X i reaksjons-produktet med den generelle formel II til den frie aminogruppe er alt etter arten av denne gruppe en hydrolyse eller en reduk-sjon . The possibly subsequent transfer of the group X in the reaction product with the general formula II to the free amino group is, depending on the nature of this group, a hydrolysis or a reduction.
Gjennom hydrolyse til aminogruppen overfbrbare rester X er f.eks. acylaminorester, som acetamidoresten. Denne hydrolyse for frisetning av aminogruppen kan f.eks. foretas i surt medium, som i konsentrert saltsyre eller ved oppvarming i.fortynnet metanolisk saltsyre. Den kan også finne sted under alkaliske betingelser, f.eks. ved hjelp av fortynnet natronlut ved tempe-raturer mellom 20 og lOO°. Residues X transferable through hydrolysis to the amino group are e.g. acylamino residues, such as the acetamido residue. This hydrolysis to release the amino group can e.g. carried out in an acidic medium, such as in concentrated hydrochloric acid or by heating in dilute methanolic hydrochloric acid. It can also take place under alkaline conditions, e.g. using diluted caustic soda at temperatures between 20 and 100°.
En forste gruppe av utgangsstoffer med den generelle formel II, hvis rest R2<1> betyr cyklopropylgruppen, fremstilles f.eks. som folger: Man går ut fra et lavere a-alkyl- eller oc-alkoksyderivat av (3-oxo-cyklopropanpropionsyreetylesteren, omsetter dette med tiourinstoff i etanol til et lavere 5-alkyl- henh. 5-alkoksyderivat av 6-cyklopropyl-2-mercapto-4-hydroksy-pyrimidinet, som med metyljodid i natriumhydroksydopplbsning gir et tilsvarende, i 5-stilling substituert 6-cyklopropyl-2-metyltio-4-hydroksy-pyrimidin; fosforoksyklorid i nærvær av N,N-dimetylanilin overforer denne forbindelse til et lavere 5-alkyl- henh. 5-alkoksy-av 6-cyklopropyl-2-metyltio-4-klor-pyrimidinet, som i nærvær av trimetylamin i dimetylsulfoksyd under avspaltning av klor- hydrogen kondenseres med natriumsaltet av en forbindelse med den generelle formel IV, A first group of starting materials with the general formula II, whose residue R2<1> means the cyclopropyl group, is prepared, e.g. as follows: One starts from a lower α-alkyl or α-alkyl derivative of the (3-oxo-cyclopropanepropionic acid ethyl ester, this is converted with thiourea in ethanol to a lower 5-alkyl or 5-alkyl derivative of 6-cyclopropyl-2- mercapto-4-hydroxy-pyrimidine, which with methyl iodide in sodium hydroxide solution gives a corresponding 5-substituted 6-cyclopropyl-2-methylthio-4-hydroxy-pyrimidine; phosphorus oxychloride in the presence of N,N-dimethylaniline converts this compound into a lower 5-alkyl- or 5-alkoxy-of the 6-cyclopropyl-2-methylthio-4-chloro-pyrimidine, which in the presence of trimethylamine in dimethylsulfoxide during elimination of chlorine- hydrogen is condensed with the sodium salt of a compound of the general formula IV,
i in
hvor X har den under formel II angitte betydning. where X has the meaning given under formula II.
En andre gruppe av utgangsstoffer med den generelle formel II, hvis rest R^<1> betyr cyklopropylgruppen, oppnås f.eks. ved å gå ut fra cyklopropylkarboksamidin. Dette amidin omdannes f.eks. med et lavere alkyl- eller alkoksyderivat av en malonsyredial-kylester, f.eks. malonsyredimetylesteren, i metanol i nærvær av natriummetylat til et tilsvarende lavere 5-alkyl- henh. 5-alkoksyderivat av 2-cyklopropyl-4,6-dihydroksypyrimidinet. Det erholdte dihydroksy-pyrimidin kan f.eks. overfores med fosforoksyklorid i nærvær av N-dimetylanilin til et tilsvarende 4,6-diklor-pyrimidin, hvilket med en molekvivalent natriumsalt av metantiolet i etanol gir et lavere 5-alkyl- henh. 5-alkoksyderivat av 2-cyklopropyl-4-klor-6-metyltio-pyrimidinet. Dette A second group of starting materials with the general formula II, whose residue R^<1> means the cyclopropyl group, is obtained, e.g. starting from cyclopropylcarboxamidine. This amidine is converted e.g. with a lower alkyl or alkoxy derivative of a malonic acid dialkyl ester, e.g. the malonic acid dimethyl ester, in methanol in the presence of sodium methylate to a correspondingly lower 5-alkyl acc. 5-Alkoxy derivative of the 2-cyclopropyl-4,6-dihydroxypyrimidine. The obtained dihydroxy-pyrimidine can e.g. is transferred with phosphorus oxychloride in the presence of N-dimethylaniline to a corresponding 4,6-dichloro-pyrimidine, which with a molar equivalent of the sodium salt of the methanethiol in ethanol gives a lower 5-alkyl henh. 5-Alkoxy derivative of the 2-cyclopropyl-4-chloro-6-methylthio-pyrimidine. This
4-klor-pyrimidin-derivat kondenseres analogt som det tilsvarende mellomprodukt, som forer til den forste gruppe av utgangsstoffer med natriumsaltet av en forbindelse med den generelle formel IV. 4-Chloro-pyrimidine derivative is condensed analogously to the corresponding intermediate, which leads to the first group of starting materials with the sodium salt of a compound of the general formula IV.
Analogt disse utgangsstoffer kan forbindelser med den generelle formel II fremstilles, hvis rest R^' eller R2' er en etyltio-gruppe. Analogously to these starting substances, compounds of the general formula II can be prepared, whose residue R 1' or R 2' is an ethylthio group.
De etter fremgangsmåten ifolge oppfinnelsen erholdte forbind-eiser med den generelle formel I overfores deretter, hvis onsket, med uorganiske eller organiske baser til deres salter. Fremstillingen av disse salter finner f.eks. sted ved omsetning av forbindelser med den generelle formel I med den ekvivalente mengde av en base i et egnet vandig-organisk eller organisk opplosningsmiddel, som f.eks. metanol, etanol, eter, kloroform eller metylenklorid. The compound ices of the general formula I obtained by the method according to the invention are then transferred, if desired, with inorganic or organic bases to their salts. The production of these salts can be found e.g. place by reacting compounds of the general formula I with the equivalent amount of a base in a suitable aqueous-organic or organic solvent, such as e.g. methanol, ethanol, ether, chloroform or methylene chloride.
For anvendelse som legemidler kan i stedet for de frie for- For use as pharmaceuticals, instead of the free pro-
bindelser med den generelle formal I deres salter med baser anvendes. Egnede salter er slike, hvis kationer ved de doser-inger «som kommer på tale ikke viser fysiologiske egenvirkninger. Videre er det av fordel, når de salter som anvendes som legemidler er godt krystalliserbare og ikke eller lite hygroskop-iske. Egnede salter er f.eks. natrium-, kalium-, magnesium-, bonds with the general formal In their salts with bases are used. Suitable salts are those whose cations at the dosages in question do not show physiological effects. Furthermore, it is advantageous when the salts used as pharmaceuticals are easily crystallizable and not or slightly hygroscopic. Suitable salts are e.g. sodium, potassium, magnesium,
kalsium- og ammoniumsalter såvel salter med etylamin, dimetyl- calcium and ammonium salts as well as salts with ethylamine, dimethyl-
amin, dietylamin, trietylamin, etylendiamin, cholin, benzylamin, dibenzylamin, pyridin, piperidin, morfolin, N-etylpiperidin, aminoetanol, dietylaminoetanol, dietanolamin, trietanolamin og 1-(2-hydroksyetyl)-piperidin. amine, diethylamine, triethylamine, ethylenediamine, choline, benzylamine, dibenzylamine, pyridine, piperidine, morpholine, N-ethylpiperidine, aminoethanol, diethylaminoethanol, diethanolamine, triethanolamine and 1-(2-hydroxyethyl)-piperidine.
De nye derivater av sulfanilamid tilsvarende den generelle for- The new derivatives of sulfanilamide corresponding to the general
mel I egner seg for tilberedelse av legemidler for innvortes eller utvortes anvendelse, f.eks. for behandling av infeksjoner gjennom grampositive bakterier, som Staphylokokker, streptokokker, Pneumokokker såvel som gjennom gramnegative bakterier, som flour I is suitable for the preparation of medicines for internal or external use, e.g. for the treatment of infections through gram-positive bacteria, such as staphylococci, streptococci, pneumococci, as well as through gram-negative bacteria, such as
Salmonella typhi, Escherichia coli og Klebsiella pneumoniae. Salmonella typhi, Escherichia coli and Klebsiella pneumoniae.
De etterfølgende eksempler redegjor nærmere for fremstillingen The following examples explain the preparation in more detail
av nye forbindelser med den generelle formel I og av hittil ikke beskrevne mellomprodukter. Temperaturene er angitt i Celsiusgrader. of new compounds of the general formula I and of previously undescribed intermediates. The temperatures are indicated in degrees Celsius.
EKSEMPEL 1 EXAMPLE 1
7,3 g N<1->(6-cyklopropyl-5-metoksy-2-metyltio-4-pyrimidinyl)-sulfanilamid tilsettes til en opplosning av 2,2 g natrium- 7.3 g of N<1->(6-cyclopropyl-5-methoxy-2-methylthio-4-pyrimidinyl)-sulfanilamide are added to a solution of 2.2 g of sodium
karbonat i 135 ml vann. Blandingen oppvarmes og går over ved ca. 60° i opplosning, hvorpå man tilsetter 35 g Raney-nikkel. carbonate in 135 ml of water. The mixture is heated and changes over at approx. 60° in solution, after which 35 g of Raney nickel is added.
Under roring koker man reaksjonsblandingen i 3 1/2 time ved en badtemperatur på 110°. Suspensjonen suges fra og filtratet innstilles på pH 5 - 6 med 6-n saltsyre. Derved utfelles råproduktet. Det omkrystalliseres fra vandig etanol, hvoretter det erholdte N^"-(6-cyklopropyl-5-metoksy-4-pyrimidinyl)-sulfanil- While stirring, the reaction mixture is boiled for 3 1/2 hours at a bath temperature of 110°. The suspension is sucked off and the filtrate is adjusted to pH 5 - 6 with 6-n hydrochloric acid. Thereby the raw product is precipitated. It is recrystallized from aqueous ethanol, after which N 2 -(6-cyclopropyl-5-methoxy-4-pyrimidinyl)-sulfanyl-
amid viser smeltepunktet 201 - 203°. amide shows melting point 201 - 203°.
Det som utgangsstof f nodvendige N^"- (6-cyklopropyl-5-metoksy-2-metyltio-4-pyrimidinyl)-sulfanilamid kan fremstilles på folgende måte: The starting material for the necessary N^"-(6-cyclopropyl-5-methoxy-2-methylthio-4-pyrimidinyl)-sulfanilamide can be prepared in the following way:
i in
i in
a) 7,15 g natrium omsettes i 145 ml torr etanol og tilsettes til den erholdte opplosning 39, 5 g oc-metoksy-(3-cyklopropan-propionsyreetylester og 28 g tiourinstoff. Blandingen kokes i 18 timer under tilbakelop, hvorved i begynnelsen og senere en suspensjon;foreligger. Man avdestillerer opplosningsmidlet under vakuum og opploser resten i 75 ml varmt vann. Den vandige opplosning rbres med 1 g aktivkull, filtreres og filtratet innstilles med 6-n saltsyre på pH 6. Man avkjbler det ansyrte filtrat i 1 time i isbad og suger av deretter rått 6-cyklopro-pyl-5-metok<i>sy-2-mercapto-4-pyrimidinolet. Det smelter ved 213 - 215° under spaltning. b) I en 70° varm opplbsning av 2,14 g natriumhydroksyd i 10 ml vann opplbses 10 g av det etter b) erholdte mercaptan, deretter tilsettes 20 ml etanol, og blandingen avkjbles til 30°. Under roring tildryppes 7,17 g metyljodid. Man oppvarmer reaksjonsopplbsningen i 20 minutter til 50° og ansyrer den så med 2-n saltsyre til pH 5. Derved utfelles et gulaktig bunn-fall, som man filtrerer fra etter 1 times avkjbling i isbad og tbrkes over fosforpentoksyd. Det rå 6-cyklopropyl-5-metoksy-2-metyltio-4-pyrimidinol smelter ved 155 - 166°. En omkrystal-lisasjon fra etanol og lite vann oker smeltepunktet til 165 - 167°. c) Man blander 79 ml fosforoksyklorid med 6,48 g N,N-di-metyl-anilin og drysser deretter inn 11,3 g rått 6-cyklopropyl-5- metoksy-2-metyltio-4-pyrimidinol. Blandingen oppvarmes ved en badtemperatur på 110° i 1 1/2 time, og den erholdte brune opplbsning inndampes under vakuum. Den oljelignende rest helles på is, og emulsjonen ekstraheres tre ganger med eter. Eteropp-lbsningeri vaskes i rekkefolge med iskald 5%' ig natriumbi-karbonatopplbsning og med mettet natriumkloridopplbsning. Deretter torkér man den over natriumsulfat, avdestillerer eteren og digererer den erholdte rest tre ganger med varm heksan... Etter avdestillering av heksanet blir det rå, oljelignende 6- cyklopropyl-5-metoksy-2-metyltio-4-klor-pyrimidin tilbake. d) En blanding av 7,4 g 6-cyklopropyl-5-metoksy-2-metyltio-4-klor-pyrimidin, 15,5 g sulfanilamid-natrium, 53 ml dimetylsulfoksyd og 0,78 g trimetylamin, opplost i 7 ml dimetylformamid, rores i 42 timer ved en badtemperatur på 60 - 70°. Den dannede morkebrune suspensjon inndampes ved et trykk på 0,1 Torr til torrhet. Resten opploses i vann, oppløsningen innstilles med karbondioksyd til pH 9 og rores i 2 timer under is-avkjoling. Deretter filtrerer man fra det ubrukte sulfanilamid og bringer filtratets pH på 5 med 5-n saltsyre. Etter 1 time filtrerer man fra det utfelte råprodukt og torker det over a) 7.15 g of sodium are reacted in 145 ml of dry ethanol and 39.5 g of oc-methoxy-(3-cyclopropane-propionic acid ethyl ester and 28 g of thiourea) are added to the resulting solution. The mixture is boiled for 18 hours under reflux, whereby at the beginning and later a suspension is present. The solvent is distilled off under vacuum and the residue is dissolved in 75 ml of hot water. The aqueous solution is stirred with 1 g of activated charcoal, filtered and the filtrate is adjusted to pH 6 with 6-N hydrochloric acid. The acidified filtrate is cooled for 1 hour in an ice bath and then suck off the crude 6-cyclopropyl-5-methoxy<i>sy-2-mercapto-4-pyrimidinol. It melts at 213 - 215° during cleavage. b) In a 70° hot solution of 2, 14 g of sodium hydroxide in 10 ml of water are dissolved in 10 g of the mercaptan obtained after b), then 20 ml of ethanol are added, and the mixture is cooled to 30°. While stirring, 7.17 g of methyl iodide are added dropwise. The reaction solution is heated for 20 minutes to 50° and then acidified with 2N hydrochloric acid to pH 5. This precipitates a yellowish precipitate, which is filtered off after cooling for 1 hour in an ice bath and dried over phosphorus pentoxide. The crude 6-cyclopropyl-5-methoxy-2-methylthio-4-pyrimidinol melts at 155 - 166°. A recrystallization from ethanol and a little water increases the melting point to 165 - 167°. c) Mix 79 ml of phosphorus oxychloride with 6.48 g of N,N-dimethylaniline and then sprinkle in 11.3 g of crude 6-cyclopropyl-5-methoxy-2-methylthio-4-pyrimidinol. The mixture is heated at a bath temperature of 110° for 1 1/2 hours, and the brown solution obtained is evaporated under vacuum. The oily residue is poured onto ice, and the emulsion is extracted three times with ether. Ether solutions are washed sequentially with ice-cold 5% sodium bicarbonate solution and with saturated sodium chloride solution. It is then dried over sodium sulphate, the ether is distilled off and the residue obtained is digested three times with hot hexane... After distilling off the hexane, crude, oil-like 6-cyclopropyl-5-methoxy-2-methylthio-4-chloro-pyrimidine is left. d) A mixture of 7.4 g of 6-cyclopropyl-5-methoxy-2-methylthio-4-chloro-pyrimidine, 15.5 g of sulfanilamide sodium, 53 ml of dimethyl sulfoxide and 0.78 g of trimethylamine, dissolved in 7 ml of dimethylformamide , stirred for 42 hours at a bath temperature of 60 - 70°. The dark brown suspension formed is evaporated at a pressure of 0.1 Torr to dryness. The residue is dissolved in water, the solution is adjusted with carbon dioxide to pH 9 and stirred for 2 hours under ice-cooling. The unused sulfanilamide is then filtered and the pH of the filtrate is brought to 5 with 5-n hydrochloric acid. After 1 hour, the precipitated crude product is filtered and dried
fosforpentoksyd. Man krystalliserer råproduktet fra etanol-vann og oppnår det rene N^-(6-cyklopropyl-5-metoksy-2-metyltio-4-pyrimidinyl)-sulfanilamid med smeltepunkt 205 - 207°. phosphorus pentoxide. The crude product is crystallized from ethanol-water and the pure N^-(6-cyclopropyl-5-methoxy-2-methylthio-4-pyrimidinyl)-sulfanilamide with melting point 205 - 207° is obtained.
EKSEMPEL 2 EXAMPLE 2
På analog måte, som er beskrevet i eksempel 1, oppnås fra 1 g N"*"- (2-cyklopropyl-5-metyl-6-metyltio-4-pyrimidinyl) -sulfanilamid i en opplosning av 0, 32 g natriumkarbonat i 20 ml vann og 5 g Raney-nikkel det rå N^"- (2-cyklopropyl-5-metyl-4-pyrimidinyl) - sulfanilamid. Det omkrystalliseres fra metyl-cellosolve-vann og smelter som rent produkt ved 272 - 273°. ;EKSEMPEL 3 ;Likeledes som beskrevet i eksempel 1, oppnås fra 2,5 g N"*"- (6-cyklopropyl-5-metyl-2-metyltio-4-pyrimidinyl)-sulfanilamid, 50 ml vann og 0,8 g natriumkarbonat ved hjelp av 12,5 g Raney-nikkel det rå N^"— (6—cyklopropyl-5—metyl—4-pyritnidinyl) — sulfanilamid. Etter en krystallisasjon fra dimetylformamid/ vandig alkohol smelter det rene produkt ved 237 - 239°. In an analogous manner, as described in example 1, is obtained from 1 g of N"*"-(2-cyclopropyl-5-methyl-6-methylthio-4-pyrimidinyl)-sulfanilamide in a solution of 0.32 g of sodium carbonate in 20 ml of water and 5 g of Raney nickel the crude N^"-(2-cyclopropyl-5-methyl-4-pyrimidinyl)-sulfanilamide. It is recrystallized from methyl-cellosolve-water and melts as a pure product at 272 - 273°. ; EXAMPLE 3 Similarly as described in example 1, 2.5 g of N"*"-(6-cyclopropyl-5-methyl-2-methylthio-4-pyrimidinyl)-sulfanilamide, 50 ml of water and 0.8 g of sodium carbonate are obtained using 12.5 g of Raney nickel the crude N^"-(6-cyclopropyl-5-methyl-4-pyritnidinyl)-sulfanilamide. After crystallization from dimethylformamide/aqueous alcohol, the pure product melts at 237 - 239°.
EKSEMPEL 4 EXAMPLE 4
Analogt som beskrevet i eksempel 1, avsvovles 3,7 g N 4-acetyl-N^-(6-cyklopropyl-5-metoksy-2-metyltio-4-pyrimidinyl)-sulfanilamid i en opplosning av 1,5 g natriumkarbonat i 100 ml vann med 18 g Raney-nikkel. Analogous to that described in example 1, 3.7 g of N 4-acetyl-N^-(6-cyclopropyl-5-methoxy-2-methylthio-4-pyrimidinyl)-sulfanilamide is desulfurized in a solution of 1.5 g of sodium carbonate in 100 ml of water with 18 g of Raney nickel.
Suspensjonen filtreres og i filtratet opploses 10 g natriumhydroksyd. Man koker derpå i 1 time under tilbakelop (bad- The suspension is filtered and 10 g of sodium hydroxide is dissolved in the filtrate. It is then boiled for 1 hour under reflux (bath
temperatur 100°) og utfeller deretter det rå N^-(6-cyklopropyl-5-metoksy-4-pyrimidinyl)-sulfanilamid ved tilsetning av 6-n saltsyre,1 inntil en pH-verdi på 5 - 6 er oppnådd. Råproduktet omkrystalliseres fra vandig alkohol. Det er identisk med det etter eksempel 1 erholdte produkt. temperature 100°) and then precipitates the crude N^-(6-cyclopropyl-5-methoxy-4-pyrimidinyl)-sulfanilamide by adding 6-n hydrochloric acid,1 until a pH value of 5 - 6 is obtained. The crude product is recrystallized from aqueous alcohol. It is identical to the product obtained according to example 1.
Claims (1)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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CH20167A CH476739A (en) | 1967-01-06 | 1967-01-06 | Process for the preparation of new derivatives of sulfanilamide |
Publications (1)
Publication Number | Publication Date |
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NO122651B true NO122651B (en) | 1971-07-26 |
Family
ID=4181546
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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NO4868A NO122651B (en) | 1967-01-06 | 1968-01-05 |
Country Status (12)
Country | Link |
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AT (1) | AT275529B (en) |
BE (1) | BE709034A (en) |
CH (1) | CH476739A (en) |
DE (1) | DE1695106A1 (en) |
DK (1) | DK116593B (en) |
ES (1) | ES348964A1 (en) |
FR (1) | FR1567151A (en) |
GB (1) | GB1206232A (en) |
NL (1) | NL6800191A (en) |
NO (1) | NO122651B (en) |
SE (1) | SE339472B (en) |
YU (1) | YU33108B (en) |
-
1967
- 1967-01-06 CH CH20167A patent/CH476739A/en not_active IP Right Cessation
- 1967-12-29 DK DK668167A patent/DK116593B/en unknown
-
1968
- 1968-01-04 FR FR1567151D patent/FR1567151A/fr not_active Expired
- 1968-01-04 SE SE9268A patent/SE339472B/xx unknown
- 1968-01-04 YU YU1868A patent/YU33108B/en unknown
- 1968-01-05 NO NO4868A patent/NO122651B/no unknown
- 1968-01-05 ES ES348964A patent/ES348964A1/en not_active Expired
- 1968-01-05 AT AT14968A patent/AT275529B/en active
- 1968-01-05 NL NL6800191A patent/NL6800191A/xx unknown
- 1968-01-05 BE BE709034D patent/BE709034A/xx unknown
- 1968-01-05 GB GB74568A patent/GB1206232A/en not_active Expired
- 1968-01-05 DE DE19681695106 patent/DE1695106A1/en active Pending
Also Published As
Publication number | Publication date |
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ES348964A1 (en) | 1969-03-16 |
YU33108B (en) | 1976-04-30 |
CH476739A (en) | 1969-08-15 |
SE339472B (en) | 1971-10-11 |
NL6800191A (en) | 1968-07-08 |
AT275529B (en) | 1969-10-27 |
BE709034A (en) | 1968-07-05 |
DK116593B (en) | 1970-01-26 |
FR1567151A (en) | 1969-05-16 |
YU1868A (en) | 1975-10-31 |
DE1695106A1 (en) | 1971-04-08 |
GB1206232A (en) | 1970-09-23 |
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