NO159158B - COVER WITH PIPE FOR A POWDER BOX WITH A FLEXIBLE WALL. - Google Patents
COVER WITH PIPE FOR A POWDER BOX WITH A FLEXIBLE WALL. Download PDFInfo
- Publication number
- NO159158B NO159158B NO832260A NO832260A NO159158B NO 159158 B NO159158 B NO 159158B NO 832260 A NO832260 A NO 832260A NO 832260 A NO832260 A NO 832260A NO 159158 B NO159158 B NO 159158B
- Authority
- NO
- Norway
- Prior art keywords
- general formula
- acid
- pyridyl
- residue
- group
- Prior art date
Links
- -1 mercapto, sulfo, sulfamoyl Chemical group 0.000 claims description 105
- 239000002253 acid Substances 0.000 claims description 39
- 150000001875 compounds Chemical class 0.000 claims description 39
- 150000001408 amides Chemical class 0.000 claims description 25
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 10
- 125000003277 amino group Chemical group 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 7
- 239000000194 fatty acid Substances 0.000 claims description 7
- 229930195729 fatty acid Natural products 0.000 claims description 7
- 150000004665 fatty acids Chemical class 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 239000004202 carbamide Substances 0.000 claims description 5
- 235000013877 carbamide Nutrition 0.000 claims description 5
- 125000005188 oxoalkyl group Chemical group 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical class [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 4
- 150000003927 aminopyridines Chemical class 0.000 claims description 4
- 125000005041 acyloxyalkyl group Chemical group 0.000 claims description 3
- 125000005236 alkanoylamino group Chemical group 0.000 claims description 3
- 125000003282 alkyl amino group Chemical group 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 150000007522 mineralic acids Chemical class 0.000 claims description 3
- 230000004048 modification Effects 0.000 claims description 3
- 238000012986 modification Methods 0.000 claims description 3
- 150000007524 organic acids Chemical class 0.000 claims description 3
- 238000012546 transfer Methods 0.000 claims description 3
- 235000021122 unsaturated fatty acids Nutrition 0.000 claims description 3
- 150000004670 unsaturated fatty acids Chemical class 0.000 claims description 3
- 150000003672 ureas Chemical class 0.000 claims description 3
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 235000005985 organic acids Nutrition 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 239000012279 sodium borohydride Substances 0.000 claims description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 2
- 125000003302 alkenyloxy group Chemical group 0.000 claims 1
- 125000005108 alkenylthio group Chemical group 0.000 claims 1
- 125000003545 alkoxy group Chemical group 0.000 claims 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims 1
- 125000004414 alkyl thio group Chemical group 0.000 claims 1
- 230000001186 cumulative effect Effects 0.000 claims 1
- 125000004093 cyano group Chemical group *C#N 0.000 claims 1
- 125000005117 dialkylcarbamoyl group Chemical group 0.000 claims 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 48
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 30
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
- 238000002844 melting Methods 0.000 description 25
- 230000008018 melting Effects 0.000 description 25
- 238000003756 stirring Methods 0.000 description 20
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 16
- 150000007513 acids Chemical class 0.000 description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- 238000001816 cooling Methods 0.000 description 15
- 239000000203 mixture Substances 0.000 description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 13
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- 239000003960 organic solvent Substances 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 11
- 238000004440 column chromatography Methods 0.000 description 11
- 239000005457 ice water Substances 0.000 description 11
- OZEIRGBZZHEBJJ-NQLNTKRDSA-N CCCCC/C=C\C/C=C\CCCCCCCC(=O)NC1=NC=C(C=C1)C Chemical compound CCCCC/C=C\C/C=C\CCCCCCCC(=O)NC1=NC=C(C=C1)C OZEIRGBZZHEBJJ-NQLNTKRDSA-N 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 239000007795 chemical reaction product Substances 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
- 235000020778 linoleic acid Nutrition 0.000 description 7
- OYHQOLUKZRVURQ-IXWMQOLASA-N linoleic acid Natural products CCCCC\C=C/C\C=C\CCCCCCCC(O)=O OYHQOLUKZRVURQ-IXWMQOLASA-N 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- CMBSSVKZOPZBKW-UHFFFAOYSA-N 5-methylpyridin-2-amine Chemical compound CC1=CC=C(N)N=C1 CMBSSVKZOPZBKW-UHFFFAOYSA-N 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 238000009835 boiling Methods 0.000 description 6
- 239000001569 carbon dioxide Substances 0.000 description 6
- 229910002092 carbon dioxide Inorganic materials 0.000 description 6
- 230000009467 reduction Effects 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- FBWMYSQUTZRHAT-HZJYTTRNSA-N (9z,12z)-octadeca-9,12-dienoyl chloride Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(Cl)=O FBWMYSQUTZRHAT-HZJYTTRNSA-N 0.000 description 5
- XJJSLPQZPMVOLM-HZJYTTRNSA-N CCCCC/C=C\C/C=C\CCCCCCCC(=O)NC1=NC=C(C=C1)Br Chemical compound CCCCC/C=C\C/C=C\CCCCCCCC(=O)NC1=NC=C(C=C1)Br XJJSLPQZPMVOLM-HZJYTTRNSA-N 0.000 description 5
- OYHQOLUKZRVURQ-HZJYTTRNSA-N Linoleic acid Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(O)=O OYHQOLUKZRVURQ-HZJYTTRNSA-N 0.000 description 5
- 206010028980 Neoplasm Diseases 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 150000004820 halides Chemical class 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- MRKXCQPDRPTZCG-IUQGRGSQSA-N (9e,12e,15e)-octadeca-9,12,15-trienoyl chloride Chemical compound CC\C=C\C\C=C\C\C=C\CCCCCCCC(Cl)=O MRKXCQPDRPTZCG-IUQGRGSQSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- RVGQFNRGHQLIOU-PDBXOOCHSA-N CC/C=C\C/C=C\C/C=C\CCCCCCCC(=O)NC1=NC=C(C=C1)[N+](=O)[O-] Chemical compound CC/C=C\C/C=C\C/C=C\CCCCCCCC(=O)NC1=NC=C(C=C1)[N+](=O)[O-] RVGQFNRGHQLIOU-PDBXOOCHSA-N 0.000 description 3
- CKHBAWVCVBFZIS-HZJYTTRNSA-N CCCCC/C=C\C/C=C\CCCCCCCC(=O)NC1=NC=C(C=C1)[N+](=O)[O-] Chemical compound CCCCC/C=C\C/C=C\CCCCCCCC(=O)NC1=NC=C(C=C1)[N+](=O)[O-] CKHBAWVCVBFZIS-HZJYTTRNSA-N 0.000 description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- DTOSIQBPPRVQHS-PDBXOOCHSA-N alpha-linolenic acid Chemical compound CC\C=C/C\C=C/C\C=C/CCCCCCCC(O)=O DTOSIQBPPRVQHS-PDBXOOCHSA-N 0.000 description 3
- 150000008064 anhydrides Chemical class 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000012948 isocyanate Substances 0.000 description 3
- 150000002513 isocyanates Chemical class 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Substances OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 3
- OYHQOLUKZRVURQ-NTGFUMLPSA-N (9Z,12Z)-9,10,12,13-tetratritiooctadeca-9,12-dienoic acid Chemical compound C(CCCCCCC\C(=C(/C\C(=C(/CCCCC)\[3H])\[3H])\[3H])\[3H])(=O)O OYHQOLUKZRVURQ-NTGFUMLPSA-N 0.000 description 2
- ORLGLBZRQYOWNA-UHFFFAOYSA-N 4-methylpyridin-2-amine Chemical compound CC1=CC=NC(N)=C1 ORLGLBZRQYOWNA-UHFFFAOYSA-N 0.000 description 2
- WGOLHUGPTDEKCF-UHFFFAOYSA-N 5-bromopyridin-2-amine Chemical compound NC1=CC=C(Br)C=N1 WGOLHUGPTDEKCF-UHFFFAOYSA-N 0.000 description 2
- MAXBVGJEFDMHNV-UHFFFAOYSA-N 5-chloropyridin-2-amine Chemical compound NC1=CC=C(Cl)C=N1 MAXBVGJEFDMHNV-UHFFFAOYSA-N 0.000 description 2
- UGSBCCAHDVCHGI-UHFFFAOYSA-N 5-nitropyridin-2-amine Chemical compound NC1=CC=C([N+]([O-])=O)C=N1 UGSBCCAHDVCHGI-UHFFFAOYSA-N 0.000 description 2
- KJOFVMXHMFQLDU-UHFFFAOYSA-N 9,10,12,13-tetrabromo-N-(5-methylpyridin-2-yl)octadecanamide Chemical compound CC=1C=CC(=NC1)NC(CCCCCCCC(C(CC(C(CCCCC)Br)Br)Br)Br)=O KJOFVMXHMFQLDU-UHFFFAOYSA-N 0.000 description 2
- MTNXGPGLYCYMBL-NQLNTKRDSA-N CCCCC/C=C\C/C=C\CCCCCCCC(=O)NC1=CN=C(C=C1)C Chemical compound CCCCC/C=C\C/C=C\CCCCCCCC(=O)NC1=CN=C(C=C1)C MTNXGPGLYCYMBL-NQLNTKRDSA-N 0.000 description 2
- OXOHUGQJXCYFCY-HZJYTTRNSA-N CCCCC/C=C\C/C=C\CCCCCCCC(=O)NC1=NC=C(C=C1)C(=O)N Chemical compound CCCCC/C=C\C/C=C\CCCCCCCC(=O)NC1=NC=C(C=C1)C(=O)N OXOHUGQJXCYFCY-HZJYTTRNSA-N 0.000 description 2
- WSAQXVJAVIFXOA-NQLNTKRDSA-N CCCCC/C=C\C/C=C\CCCCCCCC(NC(C=C1)=NC=C1C(C)=O)=O Chemical compound CCCCC/C=C\C/C=C\CCCCCCCC(NC(C=C1)=NC=C1C(C)=O)=O WSAQXVJAVIFXOA-NQLNTKRDSA-N 0.000 description 2
- 201000009030 Carcinoma Diseases 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-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
- 230000010933 acylation Effects 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 235000020661 alpha-linolenic acid Nutrition 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 238000010640 amide synthesis reaction Methods 0.000 description 2
- 229950011175 aminopicoline Drugs 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 150000001718 carbodiimides Chemical class 0.000 description 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000007256 debromination reaction Methods 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- MDKXBBPLEGPIRI-UHFFFAOYSA-N ethoxyethane;methanol Chemical compound OC.CCOCC MDKXBBPLEGPIRI-UHFFFAOYSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 150000002540 isothiocyanates Chemical class 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 229960004488 linolenic acid Drugs 0.000 description 2
- VULOVDMNTIQNCT-UHFFFAOYSA-N octadeca-7,9-dienoyl chloride Chemical compound C(CCCCCC=CC=CCCCCCCCC)(=O)Cl VULOVDMNTIQNCT-UHFFFAOYSA-N 0.000 description 2
- 150000007530 organic bases Chemical group 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- YEXPOXQUZXUXJW-UHFFFAOYSA-N oxolead Chemical compound [Pb]=O YEXPOXQUZXUXJW-UHFFFAOYSA-N 0.000 description 2
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 2
- 229940075930 picrate Drugs 0.000 description 2
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 2
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- MLQBTMWHIOYKKC-KTKRTIGZSA-N (z)-octadec-9-enoyl chloride Chemical compound CCCCCCCC\C=C/CCCCCCCC(Cl)=O MLQBTMWHIOYKKC-KTKRTIGZSA-N 0.000 description 1
- RAXXELZNTBOGNW-UHFFFAOYSA-N 1H-imidazole Chemical class C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 1
- BWZVCCNYKMEVEX-UHFFFAOYSA-N 2,4,6-Trimethylpyridine Chemical compound CC1=CC(C)=NC(C)=C1 BWZVCCNYKMEVEX-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- BTJIUGUIPKRLHP-UHFFFAOYSA-N 4-nitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1 BTJIUGUIPKRLHP-UHFFFAOYSA-N 0.000 description 1
- CJMIBVIERHDCHB-UHFFFAOYSA-N 5-methylpyridin-1-ium-2-amine;chloride Chemical compound Cl.CC1=CC=C(N)N=C1 CJMIBVIERHDCHB-UHFFFAOYSA-N 0.000 description 1
- ZLWYEPMDOUQDBW-UHFFFAOYSA-N 6-aminonicotinamide Chemical compound NC(=O)C1=CC=C(N)N=C1 ZLWYEPMDOUQDBW-UHFFFAOYSA-N 0.000 description 1
- YXFLGKSXYWHALA-UHFFFAOYSA-N 6-aminopyridine-3-sulfonic acid Chemical compound NC1=CC=C(S(O)(=O)=O)C=N1 YXFLGKSXYWHALA-UHFFFAOYSA-N 0.000 description 1
- QUXLCYFNVNNRBE-UHFFFAOYSA-N 6-methylpyridin-2-amine Chemical compound CC1=CC=CC(N)=N1 QUXLCYFNVNNRBE-UHFFFAOYSA-N 0.000 description 1
- HTORNZPNCYXGMR-UHFFFAOYSA-N 9,10,12,13-Tetrabromo-stearic acid Chemical compound CCCCCC(Br)C(Br)CC(Br)C(Br)CCCCCCCC(O)=O HTORNZPNCYXGMR-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- JCJFANDMUDRMBS-YSTUJMKBSA-N CC/C=C\C/C=C\C/C=C\CCCCCCCC(=O)NC1=CN=C(C=C1)C Chemical compound CC/C=C\C/C=C\C/C=C\CCCCCCCC(=O)NC1=CN=C(C=C1)C JCJFANDMUDRMBS-YSTUJMKBSA-N 0.000 description 1
- DPQURIDEMYWUOY-UHFFFAOYSA-N CC=1C=CC(=NC1)NC(CCCC=C/CC=C/CC=C/CC=C/CCCCC)=O Chemical compound CC=1C=CC(=NC1)NC(CCCC=C/CC=C/CC=C/CC=C/CCCCC)=O DPQURIDEMYWUOY-UHFFFAOYSA-N 0.000 description 1
- ZMUXBRAFQIDKHS-MURFETPASA-N CCCCC/C=C\C/C=C\CCCCCCCC(=O)NC1=CN=C(C=C1)OCC Chemical compound CCCCC/C=C\C/C=C\CCCCCCCC(=O)NC1=CN=C(C=C1)OCC ZMUXBRAFQIDKHS-MURFETPASA-N 0.000 description 1
- BVOZJHVWONESNL-MURFETPASA-N CCCCC/C=C\C/C=C\CCCCCCCC(=O)NC1=NC=C(C=C1)CC Chemical compound CCCCC/C=C\C/C=C\CCCCCCCC(=O)NC1=NC=C(C=C1)CC BVOZJHVWONESNL-MURFETPASA-N 0.000 description 1
- QXISHTBHYUYPPJ-XVTLYKPTSA-N CCCCC/C=C\C/C=C\CCCCCCCC(NC(C=C1)=NC=C1C(N(CC)CC)=O)=O Chemical compound CCCCC/C=C\C/C=C\CCCCCCCC(NC(C=C1)=NC=C1C(N(CC)CC)=O)=O QXISHTBHYUYPPJ-XVTLYKPTSA-N 0.000 description 1
- XUJYWGZKTIZZEC-HZJYTTRNSA-N CCCCC/C=C\C/C=C\CCCCCCCC(NC(C=C1)=NC=C1S(N)(=O)=O)=O Chemical compound CCCCC/C=C\C/C=C\CCCCCCCC(NC(C=C1)=NC=C1S(N)(=O)=O)=O XUJYWGZKTIZZEC-HZJYTTRNSA-N 0.000 description 1
- CTOSUCJLYZENSB-UTJQPWESSA-N CCCCC/C=C\C/C=C\CCCCCCCC(NC(C=N1)=CC=C1OCCCC)=O Chemical compound CCCCC/C=C\C/C=C\CCCCCCCC(NC(C=N1)=CC=C1OCCCC)=O CTOSUCJLYZENSB-UTJQPWESSA-N 0.000 description 1
- HXEPYHFNJKQADG-HZJYTTRNSA-N CCCCC/C=C\C/C=C\CCCCCCCC(NC(C=N1)=CC=C1S)=O Chemical compound CCCCC/C=C\C/C=C\CCCCCCCC(NC(C=N1)=CC=C1S)=O HXEPYHFNJKQADG-HZJYTTRNSA-N 0.000 description 1
- TUCQVVLQXRZFKX-MURFETPASA-N CCCCC/C=C\C/C=C\CCCCCCCC(NC1=CC=C(N(C)C)N=C1)=O Chemical compound CCCCC/C=C\C/C=C\CCCCCCCC(NC1=CC=C(N(C)C)N=C1)=O TUCQVVLQXRZFKX-MURFETPASA-N 0.000 description 1
- AVRHVMPWHUSFOU-HZJYTTRNSA-N CCCCC/C=C\C/C=C\CCCCCCCC(NC1=CC=CN=C1Cl)=O Chemical compound CCCCC/C=C\C/C=C\CCCCCCCC(NC1=CC=CN=C1Cl)=O AVRHVMPWHUSFOU-HZJYTTRNSA-N 0.000 description 1
- JYHPPPGBDVUWRC-XVTLYKPTSA-N CCCCCCOC(N=C1)=CC=C1NC(CCCCCCC/C=C\C/C=C\CCCCC)=O Chemical compound CCCCCCOC(N=C1)=CC=C1NC(CCCCCCC/C=C\C/C=C\CCCCC)=O JYHPPPGBDVUWRC-XVTLYKPTSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- RPWFJAMTCNSJKK-UHFFFAOYSA-N Dodecyl gallate Chemical compound CCCCCCCCCCCCOC(=O)C1=CC(O)=C(O)C(O)=C1 RPWFJAMTCNSJKK-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 241000712431 Influenza A virus Species 0.000 description 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 230000006181 N-acylation Effects 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 241000700584 Simplexvirus Species 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- IJCVBMSXIPFVLH-UHFFFAOYSA-N [C].S=O Chemical compound [C].S=O IJCVBMSXIPFVLH-UHFFFAOYSA-N 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 125000005336 allyloxy group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 150000007514 bases Chemical class 0.000 description 1
- WPUJEWVVTKLMQI-UHFFFAOYSA-N benzene;ethoxyethane Chemical compound CCOCC.C1=CC=CC=C1 WPUJEWVVTKLMQI-UHFFFAOYSA-N 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001589 carboacyl group Chemical group 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000007269 dehydrobromination reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- WASQWSOJHCZDFK-UHFFFAOYSA-N diketene Chemical compound C=C1CC(=O)O1 WASQWSOJHCZDFK-UHFFFAOYSA-N 0.000 description 1
- 239000000555 dodecyl gallate Substances 0.000 description 1
- 235000010386 dodecyl gallate Nutrition 0.000 description 1
- 229940080643 dodecyl gallate Drugs 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 1
- CCGKOQOJPYTBIH-UHFFFAOYSA-N ethenone Chemical compound C=C=O CCGKOQOJPYTBIH-UHFFFAOYSA-N 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- FMMOOAYVCKXGMF-MURFETPASA-N ethyl linoleate Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(=O)OCC FMMOOAYVCKXGMF-MURFETPASA-N 0.000 description 1
- 239000010685 fatty oil Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 229960002598 fumaric acid Drugs 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- KDCIHNCMPUBDKT-UHFFFAOYSA-N hexane;propan-2-one Chemical compound CC(C)=O.CCCCCC KDCIHNCMPUBDKT-UHFFFAOYSA-N 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229960000448 lactic acid Drugs 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- FMMOOAYVCKXGMF-UHFFFAOYSA-N linoleic acid ethyl ester Natural products CCCCCC=CCC=CCCCCCCCC(=O)OCC FMMOOAYVCKXGMF-UHFFFAOYSA-N 0.000 description 1
- KQQKGWQCNNTQJW-UHFFFAOYSA-N linolenic acid Natural products CC=CCCC=CCC=CCCCCCCCC(O)=O KQQKGWQCNNTQJW-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229940098895 maleic acid Drugs 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 238000000199 molecular distillation Methods 0.000 description 1
- ZCIDMOHPCZGVAV-UHFFFAOYSA-N n,n'-dipyridin-2-ylmethanediimine Chemical class N1=CC=CC=C1N=C=NC1=CC=CC=N1 ZCIDMOHPCZGVAV-UHFFFAOYSA-N 0.000 description 1
- JCXJVPUVTGWSNB-UHFFFAOYSA-N nitrogen dioxide Inorganic materials O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- HACBQSMIIGXKGA-UHFFFAOYSA-N octadeca-7,9-dienoic acid Chemical compound CCCCCCCCC=CC=CCCCCCC(O)=O HACBQSMIIGXKGA-UHFFFAOYSA-N 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 229940116315 oxalic acid Drugs 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 229960003424 phenylacetic acid Drugs 0.000 description 1
- 239000003279 phenylacetic acid Substances 0.000 description 1
- SIOXPEMLGUPBBT-UHFFFAOYSA-N picolinic acid Chemical class OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 229960001295 tocopherol Drugs 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- ZIBGPFATKBEMQZ-UHFFFAOYSA-N triethylene glycol Chemical compound OCCOCCOCCO ZIBGPFATKBEMQZ-UHFFFAOYSA-N 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
- B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
- B65D47/00—Closures with filling and discharging, or with discharging, devices
- B65D47/04—Closures with discharging devices other than pumps
- B65D47/046—Closures with swivelling dispensing devices
Landscapes
- Engineering & Computer Science (AREA)
- Mechanical Engineering (AREA)
- Closures For Containers (AREA)
- Cartons (AREA)
- Beverage Vending Machines With Cups, And Gas Or Electricity Vending Machines (AREA)
- Catching Or Destruction (AREA)
- Fertilizing (AREA)
- Tubes (AREA)
Description
Herpes simplex-Virus, influensa A-Virus og vak-sine-Virus, mens den tumorhemmende virkning lar seg påvise i dyreforsøk ved subcutan og oral administrasjon på transplanterte Ehrlich-Carcinom, på indusert methyl-kolanthren-Sarkom (MC-Sarkom) og på indusert dimethyl-ben-zarithracen-Hautcarcinom (DMBA-carcinom) Herpes simplex-Virus, influenza A-Virus and vak-sine-Virus, while the tumor-inhibiting effect can be demonstrated in animal experiments by subcutaneous and oral administration on transplanted Ehrlich-Carcinoma, on induced methyl-cholanthrene-Sarcoma (MC-Sarcoma) and on induced dimethyl-ben-zarithracen-Hautcarcinom (DMBA-carcinoma)
hos mus. For disse tumorforsøk ble serier på 5 in mice. For these tumor trials, series of 5
dyr pr. dose og dobbelt så store kontrollserier anvendt. Aktivstdffene ble administrert ved Ehr-lich-carcinom i 4 og ved induksjonstumorer i 8 animals per dose and twice as large control series used. The active drugs were administered in Ehrlich carcinoma in 4 and in induction tumors in 8
på hverandre følgende dager i doser som utgjorde høyst 1/4 henholdsvis 1/8 av dosen tolerata maxima (Dtm) og størrelsen av tumorene ble on consecutive days in doses that constituted no more than 1/4 and 1/8 of the dose tolerata maxima (Dtm) and the size of the tumors was
bestemt 6 henholdsvis 1 dag etter avslutning av forsøkene ved måling av tverrsnittet. Den av tumorveksthemningen fremtredende virkning W determined 6 and 1 day respectively after the end of the experiments by measuring the cross-section. The prominent effect of the tumor growth inhibition W
av en forbindelse b fastslått på grunn av dia-meterforminskelsen av tumorene i forsøksseriene overfor kontrollseriene. De nye ifølge oppfinnel- of a compound b established due to the diameter reduction of the tumors in the experimental series compared to the control series. The new according to invention
sen fremstilte forbindelser utmerker seg også late produced compounds also excel
ved sin overlegne virkning overfor den usubsti-tuerte grunnforbindelse, N-(2-pyridyl)-linolami- by its superior action compared to the unsubstituted base compound, N-(2-pyridyl)-linolami-
det [F. Zetzsche, Ber. 71 1516 - 1521 (1938)], it [F. Zetzsche, Ber. 71 1516 - 1521 (1938)],
som fremgår tydelig fra den i den etterfølgende tabell fremstilte sammenligning av denne grunnforbindelse med en karakteristisk representant av de nye amider med den generelle formel I. which is clear from the comparison of this basic compound with a characteristic representative of the new amides of the general formula I in the following table.
I forbindelsene med den generelle formel I In the compounds of the general formula I
er Rj-CO- f. eks. acylresten av linolsyre, a-linolensyre, 7,9-octadecadiensyre eller arachidon- is Rj-CO- e.g. the acyl residue of linoleic acid, α-linolenic acid, 7,9-octadecadienoic acid or arachidonic
syre. Substituenten R2 er f. eks. klor, fluor, brom, acid. The substituent R2 is e.g. chlorine, fluorine, bromine,
jod, en methyl-, ethyl-, n-propyl-, isopropyl-, n-butyl-, isobutyl-, tert.butyl-, methoxy-, ethoxy-, n-propoxy-, isopropoxy, n-butoxy-, iso-butoxy-, n-hexoxy-, allyloxy-, methallyloxy-, methyl-mercapto-, ethyl-mercapto-, isopropyl-mercapto-, n-butyl-mercapto-, allylmercapto-, hydroxymethyl-, a-hydroxy-ethyl-, a-hydroxy-propyl-, a-hydroxy-pentyl-, |3-hydroxy-ethyl-, acetoxymethyl-, a-acetoxy-ethyl-, formyl-, ace- iodine, a methyl-, ethyl-, n-propyl-, isopropyl-, n-butyl-, isobutyl-, tert.butyl-, methoxy-, ethoxy-, n-propoxy-, isopropoxy, n-butoxy-, iso- butoxy-, n-hexoxy-, allyloxy-, methallyloxy-, methyl-mercapto-, ethyl-mercapto-, isopropyl-mercapto-, n-butyl-mercapto-, allylmercapto-, hydroxymethyl-, a-hydroxy-ethyl-, a -hydroxy-propyl-, a-hydroxy-pentyl-, |3-hydroxy-ethyl-, acetoxymethyl-, a-acetoxy-ethyl-, formyl-, ace-
tyl-, propionyl-, butyryl-, valeryl-, acetonyl-, hydroxy-, mercapto-, sulfo-, sulfamoyl-, nitro-, cyano-, amino-, methylamino-, ethyl-amino-, isopropyl-amino-, n-butylamino-, dimethyl-amino-, diethylamino-, formamido-, acetami- tyl-, propionyl-, butyryl-, valeryl-, acetonyl-, hydroxy-, mercapto-, sulfo-, sulfamoyl-, nitro-, cyano-, amino-, methylamino-, ethyl-amino-, isopropyl-amino-, n -butylamino-, dimethyl-amino-, diethylamino-, formamido-, acetami-
do-, methoxycarbonyl-, ethoxycarbonyl-, car-båmoyl-, methylcarbamoyl-, ethylcarbamoyl-, dimethylcarbamoyl-, diethylcarbamoyl-, 4-klor-anilino-, 2,4-diklor-anilino-, eller 3,4-diklor-anilino-gruppen. do-, methoxycarbonyl-, ethoxycarbonyl-, carbamoyl-, methylcarbamoyl-, ethylcarbamoyl-, dimethylcarbamoyl-, diethylcarbamoyl-, 4-chloro-anilino-, 2,4-dichloro-anilino-, or 3,4-dichloro-anilino - the group.
R3 står f. eks. for hydrogen, et halogenatom R3 stands for e.g. for hydrogen, a halogen atom
eller en lavere alkylrest. Som slike kommer f. eks. or a lower alkyl residue. As such, e.g.
de under R2 oppregnede i betraktning. those under R2 enumerated in consideration.
Under den generelle formel I er å forstå også carbamidaddukter av forbindelser med den generelle formel I så vel som syreaddisjonssalter med uorganiske og organiske syrer av slike forbindelser med den generelle formel I, hvis pyridylrest som substituent R2 inneholder en saltdannende gruppe, som f. eks. en amino-, alkylamino- eller dialkylaminogruppe. Under the general formula I is meant also carbamide adducts of compounds with the general formula I as well as acid addition salts with inorganic and organic acids of such compounds with the general formula I, whose pyridyl residue as substituent R2 contains a salt-forming group, such as e.g. an amino, alkylamino or dialkylamino group.
For fremstilling av de nye amider med den generelle formel I omsetter man en syre med den generelle formel II, To produce the new amides with the general formula I, an acid with the general formula II is reacted,
hvor R]-CO- har den ovenfor angitte betydning, eller et reaksjonsdyktig funksjonelt derivat av en slik syre med et kjernesubstituert aminopyridin eller kjernesubstituert alkylaminopyridin med den generelle formel ni where R]-CO- has the meaning given above, or a reactive functional derivative of such an acid with a core-substituted aminopyridine or core-substituted alkylaminopyridine of the general formula nine
hvor R2, R8 og R4 har den ovenfor angitte betydning, eller med et reaksjonsdyktig funksjo- where R2, R8 and R4 have the above meaning, or with a reactive functional
nelt derivat av det samme. I utførelsen av denne fremgangsmåte omsettes f. eks. en syre med den generelle formel II med en forbindelse med den generelle formel III i nærvær av et carbodiimid, nel derivative of the same. In carrying out this method, e.g. an acid of the general formula II with a compound of the general formula III in the presence of a carbodiimide,
som f.eks. dicyclohexylcarbodiimid, i et inert oppløsningsmiddel, som f.eks. tetrahydrofuran. Lavere alkylestere som f. eks. methylesteren eller ethylesteren av syrer med den generelle formel II, videre også amidene gir ved oppvarmning like for example. dicyclohexylcarbodiimide, in an inert solvent, such as e.g. tetrahydrofuran. Lower alkyl esters such as the methyl ester or the ethyl ester of acids of the general formula II, furthermore also the amides give on heating
med forbindelser med den generelle formel III with compounds of the general formula III
de tilsvarende substituerte amider med den generelle formel I. the corresponding substituted amides of the general formula I.
Som ytterligere reaksjonsdyktige funksjonelle derivater av syrer med den generelle formel II egner halogenidene og anhydridene seg, i særdeleshet de blandede anhydridene med kar-bonsyrehalvesterne. Disse funksjonelle deriva-tene omsettes med en forbindelse med den generelle formel III fortrinnsvis i nærvær at et syrebindende middel, f. eks. en sterk tertiær organisk base som triethylamin, pyridin eller s-collidin, som i overskudd også kan tjene som reaksjonsmedium eller i nærvær av et overskudd av reaksjonskomponentene med den generelle formel III i nær- eller fravær av et inert organisk oppløsningsmiddel som f. eks. benzol, tetrahydrofuran eller dimethylformamid. As further reactive functional derivatives of acids with the general formula II, the halides and anhydrides are suitable, in particular the mixed anhydrides with the carboxylic acid half-esters. These functional derivatives are reacted with a compound of the general formula III preferably in the presence of an acid binding agent, e.g. a strong tertiary organic base such as triethylamine, pyridine or s-collidine, which in excess can also serve as reaction medium or in the presence of an excess of the reaction components with the general formula III in the presence or absence of an inert organic solvent such as e.g. benzene, tetrahydrofuran or dimethylformamide.
Som modifikasjon av omsetningen av syrehalogenider med forbindelser med den generelle formel III i nærvær av syrebindende middel skal nevnes omsetningen av syrehalogenider med egnede tertiære organiske baser, i særdeleshet triethylamin, i et inert organisk oppløsnings-middel, frafiltrering av det dannede hydroklorid og omsetning av det i oppløsningen foreliggende keten henholdsvis keten-dimer med den ønskede forbindelse med den generelle formel III. Reaksjonsdyktige estere av syrer med den generelle formel II er f. eks. deres p-nitro-fenylester og cyanmethylester, som omsettes med forbindelser med den generelle formel III i inerte organiske oppløsningsmidler, hvis nødvendig under oppvarmning. Under lignende betingelser omsettes 1-imidazolidene av de nevnte syrer med forbindelser med den generelle formel III. As a modification of the reaction of acid halides with compounds of the general formula III in the presence of an acid-binding agent, mention must be made of the reaction of acid halides with suitable tertiary organic bases, in particular triethylamine, in an inert organic solvent, filtering off the formed hydrochloride and reaction of the in the solution present ketene or ketene dimer with the desired compound with the general formula III. Reactive esters of acids with the general formula II are e.g. their p-nitro-phenyl ester and cyanomethyl ester, which are reacted with compounds of the general formula III in inert organic solvents, if necessary under heating. Under similar conditions, the 1-imidazolides of the aforementioned acids are reacted with compounds of the general formula III.
Som reaksjonsdyktige funksjonelle derivater av forbindelser med den generelle formel III, hvilke direkte kan omsettes med syrer med den generelle formel II, skal nevnes de fra forbindelser med den generelle formel III med et hy-drogenatom som R;i avledede isocyanater og isothiocyanater. Disse oppvarmes med syrene med den generelle formel II inntil den ekvimo-lare mengde karbondioxyd henholdsvis karbon-oxysulfid er frisatt. As reactive functional derivatives of compounds of the general formula III, which can be directly reacted with acids of the general formula II, are to be mentioned those from compounds of the general formula III with a hydrogen atom as R; in derived isocyanates and isothiocyanates. These are heated with the acids of the general formula II until the equimolar amount of carbon dioxide or carbon oxysulphide is released.
Reaksjonene med isocyanater og isothiocyanater kan gjennomføres i nær- eller fravær av et inert organisk oppløsningsmiddel med til-strekkelig høyt kokepunkt henholdsvis -område. I stedet for isocyanater kan også førstestadier av de samme anvendes, d.v.s. i særdeleshet omsettes azidene av tilsvarende definisjonen for R, og R., substituerte pyridincarboxylsyrer med syrer med den generelle formel II under oppvarmning i egnede inerte organiske oppløsningsmid-ler. Videre omsettes f. eks. N-klorcarbonyl-derivater av forbindelser med den generelle formel III, i særdeleshet av slike med en lavere alkylrest for R4, med salter, f. eks. alkalisalter av syrer med den generelle formel II i nær- eller fravær av inert organisk oppløsningsmiddel og re-aksjonsblandingene oppvarmes inntil den ekvi-molare mengde karbondioxyd er frisatt fra de primært dannede carboxylsyre-carbaminsyre-anhydrider. Likeledes fra forbindelser med den generelle formel III med en lavere alkylrest som R4 lar svovelsyrling-mono-alkylester-amider og fosforsyre-o-fenylendiester-amider seg avlede, som ved omsetning med syrer med den generelle formel II i organiske oppløsningsmidler som f. eks. pyridin, dioxan eller dimethylformamid henholdsvis benzol gir de ønskede amider med den generelle formel I. The reactions with isocyanates and isothiocyanates can be carried out in the presence or absence of an inert organic solvent with a sufficiently high boiling point or range. Instead of isocyanates, first stages of the same can also be used, i.e. in particular, the azides of the corresponding definition for R, and R, substituted pyridine carboxylic acids are reacted with acids of the general formula II under heating in suitable inert organic solvents. Furthermore, e.g. N-chlorocarbonyl derivatives of compounds of the general formula III, in particular of those with a lower alkyl residue for R4, with salts, e.g. alkali salts of acids with the general formula II in the presence or absence of an inert organic solvent and the reaction mixtures are heated until the equimolar amount of carbon dioxide is released from the primarily formed carboxylic acid-carbamic acid anhydrides. Similarly, from compounds of the general formula III with a lower alkyl residue as R4, sulfuric acid mono-alkyl ester amides and phosphoric acid o-phenylene diester amides can be derived, as by reaction with acids of the general formula II in organic solvents such as e.g. . pyridine, dioxane or dimethylformamide respectively benzene give the desired amides with the general formula I.
Ytterligere reaksjonsdyktige funksjonelle derivater av forbindelser med den generelle formel III er f. eks. de ved omsetning av disse ami-ner med trimethylsilylklorid i inerte, vannfrie organiske oppløsningsmidler oppnåelige N-tri!-methylsilylderivater, bl. a. f. eks. trimethylsilyl-aminopyridincarboxylsyreamider (R2 = CONH2), som omsetter seg med reaksjonsdyktige funksjonelle derivater av syrer med den generelle formel II, i inerte organiske oppløsningsmidler til N-trimethylsilylderivater av amider med den generelle formel I, fra hvilke ved spaltning med vann eller lavere alkanoler de ønskede amider dannes. Further reactive functional derivatives of compounds with the general formula III are e.g. the N-tri!-methylsilyl derivatives obtainable by reacting these amines with trimethylsilyl chloride in inert, anhydrous organic solvents, e.g. a. for example trimethylsilyl-aminopyridinecarboxylic acid amides (R2 = CONH2), which react with reactive functional derivatives of acids of the general formula II, in inert organic solvents to N-trimethylsilyl derivatives of amides of the general formula I, from which on cleavage with water or lower alkanols they desired amides are formed.
En ytterligere type av reaksjonsdyktige derivater av forbindelser med den generelle formel III er de i begge pyridinringene tilsvarende definisjonen for R2 og R.j substituerte N,N'-dipyri-dyl-carbodiimider, som på sin side f. eks. kan oppnås ved oppvarmning av de tilsvarende substituerte N,N'-dipyridyl-thiocarbamider med bly (Il)-oxyd i absolutt toluol under gradvis av-destillering av oppløsningsmiddelet. Ved oppvarmning av de nevnte carbodiimider med syrer med den generelle formel II i karbondioxydstrøm ved temperaturer omkring 200° dannes de ønskede amider med den generelle formel I. A further type of reactive derivatives of compounds with the general formula III are those in both pyridine rings corresponding to the definition for R2 and R.j substituted N,N'-dipyridyl-carbodiimides, which in turn e.g. can be obtained by heating the correspondingly substituted N,N'-dipyridyl-thiocarbamides with lead (II) oxide in absolute toluene while gradually distilling off the solvent. By heating the aforementioned carbodiimides with acids of the general formula II in a carbon dioxide stream at temperatures around 200°, the desired amides of the general formula I are formed.
I stedet for syrer med den generelle formel II eller deres reaksjonsdyktige funksjonelle derivater kan, hvis ønsket, de mettede bromaddi-sjonsprodukter av disse syrer eller reaksjonsdyktige funksjonelle derivater av de samme omsettes med kjernesubstituerte aminopyridiner eller kjernesubstituerte alkylaminopyridiner med den generelle formel III eller med reaksjonsdyktige funksjonelle derivater av de samme, og de umiddelbart erholdte amider av polybromfettsyrer med 18—20 karbonatomer debromeres på i og for seg kjent måte. Instead of acids of the general formula II or their reactive functional derivatives, the saturated bromine addition products of these acids or reactive functional derivatives thereof can, if desired, be reacted with core-substituted aminopyridines or core-substituted alkylaminopyridines of the general formula III or with reactive functional derivatives of the same, and the immediately obtained amides of polybromo fatty acids with 18-20 carbon atoms are debrominated in a manner known per se.
Som funksjonelle derivater av begge reaksjonskomponentene så vel som reaksjonsbetin-gelsene for amiddannelsen kommer i det vesent-lige de ovenfor for den direkte fremstilling av forbindelser med den generelle formel I nevnte på tale. Debromeringen finner sted f. eks. ved koking av mellomproduktene med sink i ethanol. Da bromaddisjonsproduktene av syrer med den generelle formel I ofte, f. eks. i tilfelle av linolsyre og linolensyre, i løpet av deres isolering fra naturlige fettsyreblandinger alikevel må fremstilles og etter at rensning har funnet sted igjen debromeres, bringer den foran nevnte frem-gangsmåtemodifikasjon ved å gå ut fra rå syre-blandinger ingen ytterligere reaksjonstrinn med seg, men er utelukkende en forandring av rekke-følgen. Functional derivatives of both reaction components as well as the reaction conditions for the amide formation are essentially those above for the direct preparation of compounds with the general formula I mentioned. The debromination takes place e.g. by boiling the intermediates with zinc in ethanol. Since the bromine addition products of acids with the general formula I often, e.g. in the case of linoleic acid and linolenic acid, in the course of their isolation from natural fatty acid mixtures must still be prepared and after purification has taken place again debrominated, the above-mentioned process modification by starting from crude acid mixtures brings with it no further reaction steps, but is exclusively a change of sequence.
Hvis ønsket, omvandles forbindelser med den generelle formel I, som fremstilles etter en av de foran nevnte fremgangsmåter, til andre forbindelser med denne generelle formel. I særdeleshet reduseres, hvis ønsket, forbindelser med den generelle formel I, som inneholder en nitrogruppe som rest R,, til tilsvarende forbindelser med en aminogruppe som rest R2. Det samme gjelder også for de tilsvarende substituerte polybromfettsyreamider, d.v.s. omvandlingen av nitrogruppen til aminogruppen kan ved krav nr. 2 nevnte fremgangsmåte også skytes inn mellom amiddannelsen og debromeringen. Reduksjonen av nitrogruppen til aminogruppen gjennomfø-res f.eks. ved hjelp av hydrogen i nærvær av en edelmetallkatalysator, som f. eks. palladium på kalsiumcarbonat, ved værelsestemperatur og normaltrykk i et organisk oppløsningsmiddel, som f. eks. ethanol, og avbrytes etter opptagelse av ca. den tredobbelte molare mengde hydrogen. If desired, compounds with the general formula I, which are prepared according to one of the methods mentioned above, are converted into other compounds with this general formula. In particular, if desired, compounds of the general formula I, which contain a nitro group as residue R 1 , are reduced to corresponding compounds with an amino group as residue R 2 . The same also applies to the correspondingly substituted polybromo fatty acid amides, i.e. the conversion of the nitro group to the amino group can also be inserted between the amide formation and the debromination in the method mentioned in claim no. 2. The reduction of the nitro group to the amino group is carried out, e.g. using hydrogen in the presence of a noble metal catalyst, such as palladium on calcium carbonate, at room temperature and normal pressure in an organic solvent, such as e.g. ethanol, and is discontinued after absorption of approx. the triple molar amount of hydrogen.
Videre reduseres, hvis ønsket, forbindelser med den generelle formel I eller de i krav nr. 2 nevnte fremgangsmåter som mellomprodukter opptredende polybromfettsyreamider, som inneholder som rest R2 en lavere oxoalkylrest, som f.eks. en lavere alkanoylrest (a-oxo-alkylrest), (3-oxo-alkylrest eller y-oxo-alkylrest som substituent, til tilsvarende forbindelser med en lavere hydroxyalkylrest som rest R2. Reduksjonen av forbindelser ifølge definisjonen med den generelle formel I finner f. eks. sted ved hjelp av na-trium- eller kaliumborhydrid i et organisk opp-løsningsmiddel som methanol, ethanol, dioxan eller tetrahydrofuran. Reduksjonen av de i py-ridinringen med en oxo-alkylrest substituerte polybromfettsyreamider kan f.eks. gjennomføres på katalytisk måte analogt reduksjonen av en nitrogruppe inntil opptagelsen av den ekvimo-lare mengde hydrogen. Furthermore, if desired, compounds with the general formula I or the methods mentioned in claim no. 2 are reduced as intermediate products polybromofatty acid amides, which contain as residue R2 a lower oxoalkyl residue, such as e.g. a lower alkanoyl residue (a-oxo-alkyl residue), (3-oxo-alkyl residue or y-oxo-alkyl residue as a substituent, to corresponding compounds with a lower hydroxyalkyl residue as residue R2. The reduction of compounds according to the definition with the general formula I finds e.g. e.g. using sodium or potassium borohydride in an organic solvent such as methanol, ethanol, dioxane or tetrahydrofuran. The reduction of the polybromofatty acid amides substituted in the pyridine ring with an oxo-alkyl residue can, for example, be carried out catalytically analogously to the reduction of a nitro group until the absorption of the equimolar amount of hydrogen.
Endelig lar, hvis ønsket, amider med den generelle formel I, som inneholder som rest R2 en lavere hydroxyalkylgruppe eller en aminogruppe eller de tilsvarende substituerte polybromfettsyreamider seg acylere til de tilsvarende amider med en lavere alkanoyloxyalkyl- eller alkanoylaminogruppe. Acyleringen finner sted f. eks. ved behandling med et lavere alkansyre-halogenid eller -anhydrid, hvis nødvendig, i nærvær av et syrebindende middel, som f. eks. pyridin eller et alkalicarbonat i et organisk opp-løsningsmiddel eller natronlut i et tofasig organisk-vandig system. Innføringen av acetylres-ten finner f. eks. sted enklest ved kokning av et primært reaksjonsprodukt med fri hydroxyl-eller aminogruppe i acetanhydrid i overskudd. Amidene som anvendes for acylering med den generelle formel I med aminogruppen eller en lavere hydroxyalkylgruppe som rest R2 ppnås på sin side f. eks. ved de i avsnittene foran om-talte reduksjoner av amider med den generelle formel I, som i tilsvarende stilling oppviser nitrogruppen henholdsvis en lavere oxoalkylgruppe som substituent. Det samme gjelder for de tilsvarende polybromfettsyreamider. Amider av umettede fettsyrer så vel som tilsvarende polybromfettsyrer, som oppviser som rest R2 hydro-xylgruppen, oppnår man f. eks. ved direkte N-acylering av tilsvarende pyridinderivater med den generelle formel III med syrer med den generelle formel II eller deres reaksjonsdyktige funksjonelle derivater henholdsvis med de tilsvarende polybromfettsyrer eller deres analoge derivater. Finally, if desired, amides of the general formula I, which contain as residue R2 a lower hydroxyalkyl group or an amino group or the corresponding substituted polybromofatty acid amides can be acylated to the corresponding amides with a lower alkanoyloxyalkyl or alkanoylamino group. The acylation takes place e.g. by treatment with a lower alkanoic acid halide or anhydride, if necessary, in the presence of an acid-binding agent, such as e.g. pyridine or an alkali carbonate in an organic solvent or caustic soda in a two-phase organic-aqueous system. The introduction of the acetyl residue can be found, e.g. place most simply by boiling a primary reaction product with a free hydroxyl or amino group in excess acetic anhydride. The amides which are used for acylation with the general formula I with the amino group or a lower hydroxyalkyl group as residue R2 are on their side e.g. in the reductions of amides with the general formula I mentioned in the paragraphs above, which in the corresponding position have the nitro group or a lower oxoalkyl group as a substituent. The same applies to the corresponding polybromo fatty acid amides. Amides of unsaturated fatty acids as well as corresponding polybromo fatty acids, which have the hydroxyl group as residue R2, are obtained, e.g. by direct N-acylation of corresponding pyridine derivatives of the general formula III with acids of the general formula II or their reactive functional derivatives respectively with the corresponding polybromo fatty acids or their analogous derivatives.
Omdannelsen av forbindelser med den generelle formel I til de allerede nevnte carbamidaddukter skjer f. eks. ved tilsetning av en forbindelse med den generelle formel I til en oppløsning av carbamid i methanol og adskil-ling av det utfelte addukt. The conversion of compounds with the general formula I into the already mentioned carbamide adducts takes place, e.g. by adding a compound of the general formula I to a solution of carbamide in methanol and separating the precipitated adduct.
Omdannelsen av hertil egnede forbindelser med den generelle formel I til de ovenfor allerede nevnte syreaddisjonssalter kan finne sted på vanlig måte. Til saltdannelse egnede syrer skal f. eks. nevnes: klorhydrogensyre, bromhy-drogensyre, svovelsyre, fosforsyre, methansul-fonsyre, ethandisulfonsyre, (3-hydroxyethansul-fonsyre, eddiksyre, melkesyre, oxalsyre, ravsyre, fumarsyre, maleinsyre, eplesyre, vinsyre, sitron-syre, benzoesyre, salicylsyre, fenyleddiksyre og mandelsyre. The conversion of suitable compounds of the general formula I into the acid addition salts already mentioned above can take place in the usual way. Acids suitable for salt formation shall e.g. mentioned: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanedisulfonic acid, (3-hydroxyethanesulfonic acid, acetic acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid, citric acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid.
Administrasjonen av de ifølge oppfinnelsen fremstillbare nye amider av umettede fettsyrer tilsvarende den generelle formel I kan finne sted i vanlige doseenhetsformer så vel oralt, rektalt som også parenteralt, i særdeleshet subcu-tant. Egnede administrasjonsf ormer for peroral administrasjon er f. eks. tabletter, dragéer og gelatinkapsler. Rektalt kan forbindelsene med den generelle formel I kombineres med vanlige suppositoriemasser, mange har selv et for denne administrasjonsmåte spesielt egnet smeltepunkt henholdsvis smelteområde. For subcutan injek-sjon kommer f. eks. oppløsninger i egnede fete oljer eller i blandinger av vann og oppløsnings-formidlere, som f. eks. triethylenglycol, i betraktning. Spesielt for behandling av virusin-feksjoner i luftveiene egner også sirupslignende administrasjonsf ormer seg. The administration of the new amides of unsaturated fatty acids which can be prepared according to the invention corresponding to the general formula I can take place in usual dosage unit forms as well orally, rectally as well as parenterally, in particular subcutaneously. Suitable forms of administration for oral administration are e.g. tablets, dragees and gelatin capsules. Rectally, the compounds of the general formula I can be combined with ordinary suppository masses, many of which even have a particularly suitable melting point or melting range for this method of administration. For subcutaneous injection, e.g. solutions in suitable fatty oils or in mixtures of water and solubilizers, such as e.g. triethylene glycol, in consideration. Especially for the treatment of viral infections in the respiratory tract, syrup-like administration forms are also suitable.
De etterfølgende eksempler redegjør for fremstillingen av de nye forbindelsene med den generelle formel I. Temperaturene er angitt i Celsiusgrader. The following examples explain the preparation of the new compounds with the general formula I. The temperatures are given in degrees Celsius.
EKSEMPEL 1 EXAMPLE 1
N- ( 5- klor- 2- pyridyl)- linolamiå N-(5-Chloro-2-pyridyl)-linoleic acid
2,57 g (0,02 mol) 2-amino-5-klor-pyridin og 2,22 g (0,022 mol, triethylamin oppløses i 100 ml benzol. Under røring og kjølning med isvann tildryppes 6 g (0,02 mol) linoleoylklorid, oppløst 1 30 ml benzol, i løpet av 10 minutter og blandingen røres ved værelsestemperatur ytterligere 2.57 g (0.02 mol) of 2-amino-5-chloro-pyridine and 2.22 g (0.022 mol, triethylamine are dissolved in 100 ml of benzene. While stirring and cooling with ice water, 6 g (0.02 mol) are added dropwise linoleoyl chloride, dissolved in 1 30 ml of benzene, during 10 minutes and the mixture is further stirred at room temperature
2 timer. Det utfelte triethylaminhydroklorid 2 hours. Triethylamine hydrochloride precipitated
nuts jes fra og vaskes med varm benzol. Filtratet inndampes etter tilsetning av en stabilisator [0,5 %0 dodecylgallat, 0,5 %n [D,L]-<x-tocofe-rol], og råproduktet (7,8 g) oppløses i lavtko-kende petrolether (40—60°) og kromatograferes Nuts are removed and washed with hot benzene. The filtrate is evaporated after addition of a stabilizer [0.5%0 dodecyl gallate, 0.5%n [D,L]-<x-tocopherol], and the crude product (7.8 g) is dissolved in low-boiling petroleum ether (40 —60°) and chromatographed
på 300 g aluminiumoxyd (trinn III, etter Brock-raann). De med petrolether (40—60°), petrolether- benzol og benzol eluerte fraksjoner prøves on 300 g of aluminum oxide (stage III, according to Brock-raann). The fractions eluted with petroleum ether (40-60°), petroleum ether-benzene and benzene are tested
tynnskikts-kromatografisk (etter Stahl, silciagel G, elueringsmiddel: aceton-hexan 1 : 4, fremkalling: fosformolybdensyre 20 % i alkohol, Rf-verdi av N-(5-klor-2-pyridyl)-Iinolamid: 0,7). thin-layer chromatographic (according to Stahl, silica gel G, eluent: acetone-hexane 1 : 4, development: phosphormolybdic acid 20% in alcohol, Rf value of N-(5-chloro-2-pyridyl)-inolamide: 0.7).
De rene N-(5-klor-2-pyridyl)-linolamid inneholdende fraksjoner renses og inndampes, smeltepunkt 28°. The pure N-(5-chloro-2-pyridyl)-linolamide containing fractions are purified and evaporated, melting point 28°.
Fraksjoner som inneholder forurenset produkt, renses, inndampes og kromatograferes ennå en gang (Alox III, 150 g). Som ovenfor be-skrevet identifiseres, renses og inndampes de rene N-(5-klor-2-pyridyl)-linolamid inneholdende fraksjoner. Fractions containing contaminated product are purified, evaporated and chromatographed once more (Alox III, 150 g). As described above, the pure N-(5-chloro-2-pyridyl)-linolamide containing fractions are identified, purified and evaporated.
På analog måte fremstilles f. eks. In an analogous way, e.g.
EKSEMPEL 2 EXAMPLE 2
N- ( 5- methyl- 2- pyridyl)- linolamid N-(5-methyl-2-pyridyl)-linolamide
4,32 g (0,04 mol) 2-amino-5-methyl-pyridin oppløses i 100 ml benzol. Under røring og kjølning (isvann) tildryppes 6,0 g (0,02 mol) linoleoylklorid i 30 ml benzol i løpet av 10 minutter, og blandingen røres ved værelsestemperatur ytterligere to timer. Det utfelte 2-amino-5-methyl-pyridin-hydroklorid nutsjes fra og vaskes med varm benzol. 4.32 g (0.04 mol) of 2-amino-5-methyl-pyridine are dissolved in 100 ml of benzene. While stirring and cooling (ice water), 6.0 g (0.02 mol) of linoleoyl chloride in 30 ml of benzene are added dropwise over the course of 10 minutes, and the mixture is stirred at room temperature for a further two hours. The precipitated 2-amino-5-methyl-pyridine hydrochloride is filtered off and washed with hot benzene.
Filtratet inndampes etter tilsetning av en stabilisator analogt eksempel 1, og råproduktet tilsettes 50 g carbamid, oppløst i 150 ml varm methanol, og den erholdte oppløsning står til henstand i 12 timer ved 10°. De utfelte krystaller av carbamidadduktet nutsjes fra, vaskes med 10 ml kald ether og omkrystalliseres fra methanol. De er sammensatt av 3 vektdeler carbamid og 1,1 vektdel N-(5-methyl-2-pyridyl)-linolamid. For spaltning av det erholdte kom-pleks helles 10 g av det samme på 100 ml vann, og den utskilte olje av N-(5-methyl-2-pyridyl)-linolamid utrystes med petrolether. Etter inndampning av oppløsningsmiddelet blir den rene, fargeløse substans tilbake, smeltepunkt 16°. The filtrate is evaporated after addition of a stabilizer analogously to example 1, and 50 g of carbamide, dissolved in 150 ml of hot methanol, is added to the crude product, and the resulting solution is allowed to stand for 12 hours at 10°. The precipitated crystals of the carbamide adduct are filtered off, washed with 10 ml of cold ether and recrystallized from methanol. They are composed of 3 parts by weight of carbamide and 1.1 parts by weight of N-(5-methyl-2-pyridyl)-linolamide. For cleavage of the complex obtained, 10 g of the same is poured into 100 ml of water, and the separated oil of N-(5-methyl-2-pyridyl)-linolamide is shaken with petroleum ether. After evaporation of the solvent, the pure, colorless substance remains, melting point 16°.
Råproduktet av N-(5-methyl-2-pyridyl)-linolamidet kan også renses ved sentrifugal-molekulardestillasj on. The crude product of N-(5-methyl-2-pyridyl)-linolamide can also be purified by centrifugal molecular distillation.
På analog måte fremstilles: N-(4,6-dimethyl-2-pyridyl)-linolamid Prepared in an analogous way: N-(4,6-dimethyl-2-pyridyl)-linolamide
n28" 1,5154, N- (6-methoxy-3-pyridyl) -linolamid n28" 1.5154, N-(6-methoxy-3-pyridyl)-linolamide
smeltepunkt 28°, melting point 28°,
N-(2-klor-3-pyridyl)-linolamid n <2>D<5>° 1,5222. N-(2-chloro-3-pyridyl)-linolamide n<2>D<5>° 1.5222.
EKSEMPEL 3 EXAMPLE 3
N- ( 5- sulfo- 2- pyridyl)- linolamid N-(5-sulfo-2-pyridyl)-linolamide
6,0 g (0,02 mol) llnoleoylklorid og 3,48 g (0,02 mol) 2-aminopyridin-5-sulfonsyre oppvarmes under røring i nitrogenstrøm i løpet av tre timer ved 160°. Etter avkjøling ekstraheres reaksjonsblandingen med kokende benzol, det tilbakeblivende reaksjonsprodukt vaskes med vann og omkrystalliseres fra methanolvann. Smeltepunkt 260° (spaltning). 6.0 g (0.02 mol) of oleoyl chloride and 3.48 g (0.02 mol) of 2-aminopyridine-5-sulfonic acid are heated with stirring in a stream of nitrogen during three hours at 160°. After cooling, the reaction mixture is extracted with boiling benzene, the remaining reaction product is washed with water and recrystallized from methanol water. Melting point 260° (decomposition).
EKSEMPEL 4 EXAMPLE 4
N- ( 6- methyl- 2- pyridyl) - linolamid N-(6-methyl-2-pyridyl)-linolamide
8,4 g (0,03 mol) linolsyre og 3,03 g (0,03 mol) triethylamin oppløses i 100 ml tetrahydrofuran, og oppløsningen avkjøles til —15°. Under røring tildryppes 3,23 g (0,03 mol) klormaursyreethy-lester, oppløst i 20 ml tetrahydrofuran, hvorved temperaturen ikke bør overstige —10°. Etter 15 minutters røring ved —10° tilsettes en oppløs- 8.4 g (0.03 mol) of linoleic acid and 3.03 g (0.03 mol) of triethylamine are dissolved in 100 ml of tetrahydrofuran, and the solution is cooled to -15°. While stirring, 3.23 g (0.03 mol) of chloroformic acid ethyl ester, dissolved in 20 ml of tetrahydrofuran, are added dropwise, whereby the temperature should not exceed -10°. After stirring for 15 minutes at -10°, a solvent is added
ning av 3,24 g 2-amino-6-methylpyridin i 20 ml tetrahydrofuran ved —8° til —12°. Blandingen røres 1 time ved —10° og, etter fjerningen av kjølingen, ytterligere 12 timer ved værelsestemperatur. Det utfelte triethylaminhydroklorid nutsjes fra og vaskes med varm benzol. Analogt eksempel 1 renses råproduktet ved søyle-kromatografi. ning of 3.24 g of 2-amino-6-methylpyridine in 20 ml of tetrahydrofuran at -8° to -12°. The mixture is stirred for 1 hour at -10° and, after removal of the cooling, for a further 12 hours at room temperature. The precipitated triethylamine hydrochloride is filtered off and washed with hot benzene. Analogous to example 1, the crude product is purified by column chromatography.
n<2>D<8>° : 1,5150. n<2>D<8>° : 1.5150.
EKSEMPEL 5 EXAMPLE 5
N- ( 4- methyl- 2- pyridyl)- linolamid N-(4-methyl-2-pyridyl)-linolamide
11,2 g (0,04 mol) linolsyre og 4,32 g (0,04 mol) 2-amino-4-methyl-pyridin oppløses i 100 ml tetrahydrofuran. Ved —10° tildryppes under røring en oppløsning av 8,24 g (0,04 mol) N,N'— dicyclohexyl-carbodlimid i 50 ml tetrahydrofuran. Etter 1 times røring ved —10° og 4 timer ved værelsestemperatur nutsjes det utfelte N,N'-dicyclohexylcarbamid fra, vaskes med tetrahydrofuran og filtratet inndampes. Aanalogt eksempel 1 renses råproduktet ved søylekroma-tografi. Smeltepunkt for pikratet: 85°. 11.2 g (0.04 mol) of linoleic acid and 4.32 g (0.04 mol) of 2-amino-4-methyl-pyridine are dissolved in 100 ml of tetrahydrofuran. At -10°, a solution of 8.24 g (0.04 mol) of N,N'-dicyclohexylcarbodlimide in 50 ml of tetrahydrofuran is added dropwise with stirring. After stirring for 1 hour at -10° and 4 hours at room temperature, the precipitated N,N'-dicyclohexylcarbamide is filtered off, washed with tetrahydrofuran and the filtrate is evaporated. Analogous to example 1, the crude product is purified by column chromatography. Melting point of the picrate: 85°.
EKSEMPEL 6 EXAMPLE 6
N- ( 5- nitro- 2- pyridyl) - linolamid N-(5-nitro-2-pyridyl)-linolamide
5,56 g (0,04 mol) 2-amino-5-nitro-pyridin oppløses i 200 ml pyridin. Under røring og kjøl-ning (isvann) tildryppes 12 g (0,04 mol) linoleoylklorid, og blandingen røres 6 timer ved værelsestemperatur. Det utfelte pyridinhydroklorid nutsjes fra, og pyridinet fjernes under vakuum (11 Torr) ved 45°. Resten renses analogt eksempel 1 ved søylekromatografi. Smeltepunkt 38°. 5.56 g (0.04 mol) of 2-amino-5-nitro-pyridine are dissolved in 200 ml of pyridine. While stirring and cooling (ice water), 12 g (0.04 mol) of linoleoyl chloride are added dropwise, and the mixture is stirred for 6 hours at room temperature. The precipitated pyridine hydrochloride is filtered off, and the pyridine is removed under vacuum (11 Torr) at 45°. The residue is purified analogously to example 1 by column chromatography. Melting point 38°.
På analog måte kan f. eks. følgende forbindelser fremstilles: N-(5-sulfamoyl-2-pyridyl)-linolamid, smp. 115°, N-(6-hydroxy-2-pyridyl)-linolamid, smp. 80°, N-(6-propoxy-3-pyridyl)-linolamid, smp. 41°, N-(6-hexoxy-3-pyridyl)-linolamid, smp. 34°, N-(5-cyano-2-pyridyl)-llnolamid, smp. 45°, N-(6-butoxy-3-pyridyl)-linolamid, smp. 31°, N-(6-mercapto-3-pyridyl)-linolamid, smp. 123°, N- (6-dimethylamino-3-pyridyl) -linolamid, In an analogous way, e.g. the following compounds are prepared: N-(5-sulfamoyl-2-pyridyl)-linolamide, m.p. 115°, N-(6-hydroxy-2-pyridyl)-linolamide, m.p. 80°, N-(6-propoxy-3-pyridyl)-linolamide, m.p. 41°, N-(6-hexoxy-3-pyridyl)-linolamide, m.p. 34°, N-(5-cyano-2-pyridyl)-IInolamide, m.p. 45°, N-(6-butoxy-3-pyridyl)-linolamide, m.p. 31°, N-(6-mercapto-3-pyridyl)-linolamide, m.p. 123°, N-(6-dimethylamino-3-pyridyl)-linolamide,
smp. 43°, xHcl 250°, N-(6-ethoxy-3-pyridyl)-linolamid, smp. 39°, N-(5-brom-2-pyridyl)-linolamid, smp. 45°, N-[6-(3',4'-diklor-fenylamino)-3-pyridyl]-linolamid, smp. 100°, N-(5-ethyl-2-pyridyl)-linolamid, n 2D8°: 1,5169, N-(6-methylmercapto-3-pyridyl) -linolamid, m.p. 43°, xHcl 250°, N-(6-ethoxy-3-pyridyl)-linolamide, m.p. 39°, N-(5-bromo-2-pyridyl)-linolamide, m.p. 45°, N-[6-(3',4'-dichloro-phenylamino)-3-pyridyl]-linolamide, m.p. 100°, N-(5-ethyl-2-pyridyl)-linolamide, n 2D8°: 1.5169, N-(6-methylmercapto-3-pyridyl)-linolamide,
smp. 48°, m.p. 48°,
N- (6-butylmercapto-3-pyridyl) -linolamid, N-(6-butylmercapto-3-pyridyl)-linolamide,
smp. 25°, m.p. 25°,
N- (6 - allylmer capto- 3 -pyridyl) -linolamid, N-(6-allymer capto-3-pyridyl)-linolamide,
smp. 30°, m.p. 30°,
N- (5-diethylcarbamoyl-2-pyridyl) -linolamid, N-(5-diethylcarbamoyl-2-pyridyl)-linolamide,
smp. 25°, m.p. 25°,
N- (5-methyl-2-pyridyl) -N-propyl-linolamid, N-(5-methyl-2-pyridyl)-N-propyl-linolamide,
n<2>D<8>°: 1,5234, N-(5-acetyl-2-pyridyl)-linolamid, smp. 60°, N-(5-carbethoxy-2-pyridyl)-linolamid, smp. 34°. n<2>D<8>°: 1.5234, N-(5-acetyl-2-pyridyl)-linolamide, m.p. 60°, N-(5-carbethoxy-2-pyridyl)-linolamide, m.p. 34°.
EKSEMPEL 7 EXAMPLE 7
N-( 5- klor- 2- pyridyl)- linolenamid N-(5-chloro-2-pyridyl)-linolenamide
2,57 g (0,02 mol) 2-amino-5-klor-pyridin og 2,22 g (0,22 mol) triethylamin oppløses i 100 ml benzol. Under røring og avkjølning (isvann) tildryppes i nitrogenatmosfære 6 g (0,02 mol) linolenoylklorid i 30 ml benzol i løpet av 10 minutter og blandingen røres 2 timer ved værelsestemperatur. Analogt eksempel 1 opparbeides og renses reaksjonsproduktet. n2D8°: 1,5251. 2.57 g (0.02 mol) of 2-amino-5-chloro-pyridine and 2.22 g (0.22 mol) of triethylamine are dissolved in 100 ml of benzene. While stirring and cooling (ice water), 6 g (0.02 mol) of linolenoyl chloride in 30 ml of benzene are added dropwise in a nitrogen atmosphere over 10 minutes and the mixture is stirred for 2 hours at room temperature. Analogous to example 1, the reaction product is worked up and purified. n2D8°: 1.5251.
På analog måte fremstilles: N-(6-klor-3-pyridyl) -linolenamid, smp. 39°, N-(5-brom-2-pyridyl)-linolenamid, smp. 42°, N-(5-jod-2-pyridyl)-linolenamid, smp. 52°, N-(6-methyl-2-pyridyl)-linolenamid, Prepared in an analogous way: N-(6-chloro-3-pyridyl)-linolenamide, m.p. 39°, N-(5-bromo-2-pyridyl)-linolenamide, m.p. 42°, N-(5-iodo-2-pyridyl)-linolenamide, m.p. 52°, N-(6-methyl-2-pyridyl)-linolenamide,
n2D8°: 1,5236, n2D8°: 1.5236,
N-(6-methyl-3-pyridyl)-linolenamid, smp. 28°, N,-(6-fluor-3-pyridyl)-linolenamid, smp. 28°, N- (5-methyl-2-pyridyl) -arachidonamid, N-(6-methyl-3-pyridyl)-linolenamide, m.p. 28°, N,-(6-fluoro-3-pyridyl)-linolenamide, m.p. 28°, N-(5-methyl-2-pyridyl)-arachidonamide,
n<2>D<80>: 1,5310. n<2>D<80>: 1.5310.
EKSEMPEL 8 EXAMPLE 8
N- ( 5- methyl- 2- pyridyl) - linolenamid N-(5-methyl-2-pyridyl)-linolenamide
4,32 g (0,04 mol) 2-amlno-5-methyl-pyridin oppløses i 100 ml benzol. Under røring og kjøl-ning (isvann) tildryppes i nitrogenstrøm 6 g (0,02 mol) linolenoylklorid, oppløst i 30 ml benzol. Etter 2 timers røring ved værelsestemperatur opparbeides og renses reaksjonsproduktet analogt eksempel 2. Smeltepunkt 31°. 4.32 g (0.04 mol) of 2-amino-5-methyl-pyridine are dissolved in 100 ml of benzene. While stirring and cooling (ice water), 6 g (0.02 mol) of linolenoyl chloride, dissolved in 30 ml of benzene, are added dropwise in a stream of nitrogen. After stirring for 2 hours at room temperature, the reaction product is worked up and purified analogously to example 2. Melting point 31°.
På analog måte oppnås f. eks.: N-(6-methoxy-3-pyridyl)-linolenamid, smp. 28°, N-(4,6-dimethyl-2-pyridyl) -linolenamid, In an analogous way, for example, N-(6-methoxy-3-pyridyl)-linolenamide is obtained, m.p. 28°, N-(4,6-dimethyl-2-pyridyl)-linolenamide,
n2D8°: 1,5240. n2D8°: 1.5240.
EKSEMPEL 9 EXAMPLE 9
N- ( 5- nitro- 2- pyridyl)- linolenamid N-(5-nitro-2-pyridyl)-linolenamide
5,56 g (0,04 mol) 2-amino-5-nitro-pyridin oppløses i 200 ml pyridin. Under røring og kjøl-ning (isvann) tildryppes 12 g (0,04 mol) linolenoylklorid i nitrogenstrøm, og reaksjonsblandingen røres 6 timer ved værelsestemperatur. Deretter opparbeides det analogt eksempel 6 og N- (5-nitro-2-pyridyl) -linolenamid isoleres. Smeltepunkt 42°. 5.56 g (0.04 mol) of 2-amino-5-nitro-pyridine are dissolved in 200 ml of pyridine. While stirring and cooling (ice water), 12 g (0.04 mol) of linolenoyl chloride are added dropwise in a stream of nitrogen, and the reaction mixture is stirred for 6 hours at room temperature. It is then worked up analogously to example 6 and N-(5-nitro-2-pyridyl)-linolenamide is isolated. Melting point 42°.
På analog måte oppnås f. eks.: N-(5-cyano-2-pyridyl)-linolenamid, smp. 40°, N-(6-ethoxy-3-pyridyl)-linolenamid, smp. 42°, N-[6-(3',4'-diklorf enylamino)-3-pyridyl]-linolenamid, smp. 108°, N-(6-allyloxy-3-pyridyl)-linolenamid, smp. 37°, N-(6-propoxy-3-pyridyl)-linolenamid, smp. 38°, N-(6-hexoxy-3-pyridyl)-linolenamid, smp. 30°, N-(butoxy-3-pyridyl)-linolenamid, smp. 36°, N- (5-ehyl-2-pyridyl) -linolenamid, In an analogous way, for example, N-(5-cyano-2-pyridyl)-linolenamide is obtained, m.p. 40°, N-(6-ethoxy-3-pyridyl)-linolenamide, m.p. 42°, N-[6-(3',4'-dichlorophenylamino)-3-pyridyl]-linolenamide, m.p. 108°, N-(6-allyloxy-3-pyridyl)-linolenamide, m.p. 37°, N-(6-propoxy-3-pyridyl)-linolenamide, m.p. 38°, N-(6-hexoxy-3-pyridyl)-linolenamide, m.p. 30°, N-(butoxy-3-pyridyl)-linolenamide, m.p. 36°, N-(5-ethyl-2-pyridyl)-linolenamide,
n<2>D<8>°: 1,5258. n<2>D<8>°: 1.5258.
EKSEMPEL 10 EXAMPLE 10
N- ( 4- methyl- 2- pyridyl)- linolamid N-(4-methyl-2-pyridyl)-linolamide
3,08 (0,01 mol) linolsyreethylester oppvarmes med 1,08 g (0,01 mol) 2-amino-4-methyl-pyridin under nitrogenstrøm og sterk røring i 2 timer ved 200°. Etter avkjølning renses råproduktet analogt eksempel 1 ved søylekromato- 3.08 (0.01 mol) linoleic acid ethyl ester is heated with 1.08 g (0.01 mol) 2-amino-4-methyl-pyridine under a stream of nitrogen and vigorous stirring for 2 hours at 200°. After cooling, the crude product is purified analogously to example 1 by column chromatography
grafi. Produktet er identisk med det ifølge eksempel 5 fremstilte N-(4-methyl-2-pyridyl)-linolamid. Smeltepunkt for pikratet 85°. graphics. The product is identical to the N-(4-methyl-2-pyridyl)-linolamide prepared according to example 5. Melting point for picrate 85°.
EKSEMPEL 11 EXAMPLE 11
N- ( 5- methyl- 2- pyridyl)- linolamid N-(5-methyl-2-pyridyl)-linolamide
a) Til en oppløsning av 11,2 g (0,04 mol) linolsyre og 5,6 g (0,04 mol) p-nitro-fenol i 100 a) To a solution of 11.2 g (0.04 mol) linoleic acid and 5.6 g (0.04 mol) p-nitro-phenol in 100
ml tetrahydrofuran tildryppes ved —10° under røring en oppløsning av 8,24 g (0,04 mol) N,N'-dicyclohexyl-carbodiimid i 50 ml tetrahydrofuran. Etter 1 times røring ved —10° og 4 timer ved værelsestemperatur nutsjes det utfelte N,N'-dicyclohexyl-carbamid fra, vaskes med tetrahydrofuran og inndampes. Det erholdte ut-gangsmateriale, linolsyre-p-nitrofenylester smel-ter ved 28°. b) 4,01 g (0,01 mol) linolsyre-p-nitrofenylester står til henstand med 10,8 g (0,1 mol) 2-amino-5-methyl-pyridin i 50 ml kloroform i 4 dager. Etter inndampning av oppløsningsmid-delet renses råproduktet analogt eksempel 1 ved søylekromatografi. Produktet er identisk med det ifølge eksempel 2 fremstilte N-(5-methyl-2-pyridyl)-linolamid. ml of tetrahydrofuran is added dropwise at -10° with stirring a solution of 8.24 g (0.04 mol) N,N'-dicyclohexylcarbodiimide in 50 ml of tetrahydrofuran. After stirring for 1 hour at -10° and 4 hours at room temperature, the precipitated N,N'-dicyclohexylcarbamide is filtered off, washed with tetrahydrofuran and evaporated. The starting material obtained, linoleic acid p-nitrophenyl ester, melts at 28°. b) 4.01 g (0.01 mol) of linoleic acid p-nitrophenyl ester is allowed to stand with 10.8 g (0.1 mol) of 2-amino-5-methyl-pyridine in 50 ml of chloroform for 4 days. After evaporation of the solvent, the crude product is purified analogously to example 1 by column chromatography. The product is identical to the N-(5-methyl-2-pyridyl)-linolamide prepared according to example 2.
EKSEMPEL 12 EXAMPLE 12
N- ( 5- methyl- 2- pyridyl)- 7, 9- octadeca-dien- amid N-( 5- methyl- 2- pyridyl)- 7, 9- octadeca-dien- amide
Analogt eksempel 2 omsettes 6,0 g (0,02 mol) octadeca-7,9-dienoylklorid med 4,32 g (0,04 mol) 2-amino-5-methyl-pyridin. Smeltepunkt 32°. Analogously to example 2, 6.0 g (0.02 mol) of octadeca-7,9-dienoyl chloride are reacted with 4.32 g (0.04 mol) of 2-amino-5-methyl-pyridine. Melting point 32°.
Det anvendte octadeca-7,9-dienoylklorid fremstilles ved bromering av oljesyren, dehydro-bromering av addisjonsproduktet og overføring til syrekloridet ved hjelp av oxalylklorid. The octadeca-7,9-dienoyl chloride used is produced by bromination of the oleic acid, dehydrobromination of the addition product and transfer to the acid chloride by means of oxalyl chloride.
På analog måte fremstilles f. eks.: In an analogous way, e.g.:
N- (5-klor-2-pyridyl) -7,9-octadeca-dien- N-(5-chloro-2-pyridyl)-7,9-octadeca-diene-
amid. Smeltepunkt 55°. amide. Melting point 55°.
EKSEMPEL 13 EXAMPLE 13
N- ( 5- amino- 2- pyridyl) - linolamid N-(5-amino-2-pyridyl)-linolamide
4,01 g (0,01 mol) N-(5-nitro-2-pyridyl)-linolamid (fremstilling se eksempel 6) oppløses i 150 ml destillert finsprit, tilsettes 1,5 g Pd-CACOs-katalysator og hydreres ved værelsestemperatur og normalt trykk inntil opptagelsen av 0,03 mol hydrogen (varighet ca. 30 timer). Den fra katalysatoren befridde oppløsning av reaksjonsproduktet inndampes og resten omkrystalliseres fra methanol. Smeltepunkt 42°, hydroklorid, smeltepunkt 87°. 4.01 g (0.01 mol) N-(5-nitro-2-pyridyl)-linolamide (preparation see example 6) is dissolved in 150 ml of distilled spirit, 1.5 g of Pd-CACOs catalyst is added and hydrated at room temperature and normal pressure until the absorption of 0.03 mol of hydrogen (duration approx. 30 hours). The solution of the reaction product freed from the catalyst is evaporated and the residue is recrystallized from methanol. Melting point 42°, hydrochloride, melting point 87°.
EKSEMPEL 14 EXAMPLE 14
N- ( 5- amino- 2- pyridyl) - linolenamid N-(5-amino-2-pyridyl)-linolenamide
4,01 g (0,01 mol) N-(5-nitro-2-pyridyl)-linolenamid (fremstilling se eksempel 9) oppløses i 150 ml destillert finsprit, tilsettes 1,5 g Pd-CaCOs-katalysator og hydreres ved værelsestemperatur og normaltrykk i 30 timer. Det fra katalysatoren befridde reaksjonsprodukt inndampes og omkrystalliseres fra methanol. Smeltepunkt 38°. 4.01 g (0.01 mol) N-(5-nitro-2-pyridyl)-linolenamide (preparation see example 9) is dissolved in 150 ml of distilled spirit, 1.5 g of Pd-CaCOs catalyst is added and hydrated at room temperature and normal pressure for 30 hours. The reaction product freed from the catalyst is evaporated and recrystallized from methanol. Melting point 38°.
EKSEMPEL 15 EXAMPLE 15
N- ( 5- brom- 2- pyridyl)- linolamid N-(5-bromo-2-pyridyl)-linolamide
2,22 g (0,022 mol) triethylamin oppløses i 50 ml absolutt ether. Under røring og kjølning 2.22 g (0.022 mol) of triethylamine are dissolved in 50 ml of absolute ether. While stirring and cooling
med isvann tildryppes 3 g (0,01 mol) linoleoylklorid, oppløst i 20 ml absolutt ether, i løpet av 5 minutter. Deretter tildryppes 1,73 g (0,01 mol) with ice water, 3 g (0.01 mol) of linoleoyl chloride, dissolved in 20 ml of absolute ether, are added dropwise over the course of 5 minutes. Then 1.73 g (0.01 mol) are added dropwise
2-amino-5-brom-pyridin, oppløst i 50 ml ethylacetat, i løpet av 10 minutter, og blandingen røres ytterligere i 2 timer. 2-amino-5-bromopyridine, dissolved in 50 ml of ethyl acetate, over 10 minutes, and the mixture is stirred for a further 2 hours.
, Det utfelte triethylaminhydroklorid nutsjes fra og vaskes med varm benzol. Fra filtratet oppnår man ved opparbeidelse og kromatografi på en aluminiumoxydsøyle analogt eksempel 1 N-(5-brom-2-pyridyl)-linolamidet, smeltepunkt 45°. , The precipitated triethylamine hydrochloride is filtered off and washed with hot benzene. From the filtrate, N-(5-bromo-2-pyridyl)-linolamide is obtained by work-up and chromatography on an aluminum oxide column analogous to example 1, melting point 45°.
EKSEMPEL 16 EXAMPLE 16
N- ( 5- brom- 2- pyridyl) - linolamid N-(5-bromo-2-pyridyl)-linolamide
2,79 g (0,01 mol) linolamid oppvarmes med 1,75 g (0,01 mol) 2-amino-5-brom-pyridin under røring og i nitrogenstrøm i 2 timer ved 220°. Etter avkjølning renses N-(5-brom-2-pyridyl)-linolamid analogt eksempel 1 ved søylekromato-grafi, smeltepunkt 45°. 2.79 g (0.01 mol) of linolamide are heated with 1.75 g (0.01 mol) of 2-amino-5-bromopyridine with stirring and in a stream of nitrogen for 2 hours at 220°. After cooling, N-(5-bromo-2-pyridyl)-linolamide is purified analogously to example 1 by column chromatography, melting point 45°.
EKSEMPEL 17 EXAMPLE 17
N- ( 5- carbamoyl- 2- pyridyl)- linolamid N-(5-carbamoyl-2-pyridyl)-linolamide
6,85 g (0,05 mol) 6-amino-nicotinamid opp-løses i 100 ml dimethylformamid og 5,05 g (0,05 mol) triethylamin. Under røring og kjølning med isvann tildryppes 5,43 g (0,05 mol) trime-thyl-silyl-klorid, oppløst i 30 ml dimethylformamid, i løpet av 10 minutter, og blandingen røres ved værelsestemperatur ytterligere 2 timer. Under røring og kjølning med isvann tildryppes 5,55 g (0,055 mol) triethylamin og deretter 15,0 g (0,05 mol) linoleoylklorid, oppløst i 30 ml dimethylformamid, og blandingen røres ytterligere 2 timer. Reaksjonsblandingen helles på 800 ml isvann, det utfelte produkt nutsjes fra og tørkes under høyvakuum (4 timer ved 40°). Oljen oppløses så i 100 ml kloroform og kromatograferes på 300 g aluminiumoxyd (aktivtrinn III, etter Brockmann). De med kloroform, klo-roformmethanol og methanol eluerte fraksjoner prøves ved hjelp av tynnskiktskromatografi (etter Stohl, silicagel G, elueringsmiddel: kloroform-methanol 20 : 1, fremkalling: fosformolybdensyre 20 pst. i ethanol). De rene N-(5-carbamoyl-2-pyridyl)-linolamid inneholdende fraksjoner forenes, inndampes og omkrystalliseres fra methanol-ether. Smeltepunkt 142°. 6.85 g (0.05 mol) of 6-amino-nicotinamide are dissolved in 100 ml of dimethylformamide and 5.05 g (0.05 mol) of triethylamine. While stirring and cooling with ice water, 5.43 g (0.05 mol) of trimethylsilyl chloride, dissolved in 30 ml of dimethylformamide, are added dropwise over the course of 10 minutes, and the mixture is stirred at room temperature for a further 2 hours. While stirring and cooling with ice water, 5.55 g (0.055 mol) of triethylamine and then 15.0 g (0.05 mol) of linoleoyl chloride, dissolved in 30 ml of dimethylformamide, are added dropwise, and the mixture is stirred for a further 2 hours. The reaction mixture is poured into 800 ml of ice water, the precipitated product is filtered off and dried under high vacuum (4 hours at 40°). The oil is then dissolved in 100 ml of chloroform and chromatographed on 300 g of aluminum oxide (active stage III, according to Brockmann). The fractions eluted with chloroform, chloroformmethanol and methanol are tested using thin-layer chromatography (according to Stohl, silica gel G, eluent: chloroform-methanol 20:1, developer: phosphormolybdic acid 20% in ethanol). The pure N-(5-carbamoyl-2-pyridyl)-linolamide containing fractions are combined, evaporated and recrystallized from methanol-ether. Melting point 142°.
EKSEMPEL 18 EXAMPLE 18
N- ( 5- methyl- 2- pyridyl- linolamid N- ( 5- methyl- 2- pyridyl- linolamide
2,80 g (0,01 mol) linolsyre, oppløst i 25 ml absolutt tetrahydrofuran, tilsettes ved værelsestemperatur 1,62 g l,l'-carbonyldiimidazol. 2.80 g (0.01 mol) of linoleic acid, dissolved in 25 ml of absolute tetrahydrofuran, are added at room temperature to 1.62 g of 1,1'-carbonyldiimidazole.
Etter avslutning av carbondioxydutviklingen tilsettes 1,06 g (0,01 mol) 2-amino-5-methyl-pyridin, hvilket er oppløst i 20 ml absolutt tetrahydrofuran, og reaksjonsblandingen oppvarmes ennå 10 minutter under tilbakeløp. Den etter ivdampning av tetrahydrofuranet erholdte rest apptas i 50 ml ether og ekstraheres tre ganger med 50 ml vann. Den etheriske oppløsning inndampes og N-(5-methyl-2-pyridyl)-linolamid renses analogt eksempel 1 ved søylekromato-grafi. Smeltepunkt 16°. After the evolution of carbon dioxide has ended, 1.06 g (0.01 mol) of 2-amino-5-methyl-pyridine is added, which is dissolved in 20 ml of absolute tetrahydrofuran, and the reaction mixture is heated for a further 10 minutes under reflux. The residue obtained after evaporation of the tetrahydrofuran is dissolved in 50 ml of ether and extracted three times with 50 ml of water. The ethereal solution is evaporated and N-(5-methyl-2-pyridyl)-linolamide is purified analogously to example 1 by column chromatography. Melting point 16°.
EKSEMPEL 19 EXAMPLE 19
N- ( 6- methyl- 3- pyridyl) - linolamid N-(6-methyl-3-pyridyl)-linolamide
1,48 g (0,01 mol) 6-methyl-nicotinazid og 2,8 g (0,01 mol) linolsyre oppløses i 10 ml xylol og oppvarmes inntil nitrogen- og karbondioxyd-utvikling. Varmekilden fjernes raskt og, såsnart den heftige karbondioxydutviklingen har av-tatt, oppvarmes reaksjonsblandingen til kokning under tilbakeløp. Etter avdampning av oppløs-ningsmiddelet renses N-(6-methyl-3-pyridyl)-linolamidet analogt eksempel 1 ved søylekroma-tografi. Smeltepunkt 23°. 1.48 g (0.01 mol) of 6-methyl-nicotinazide and 2.8 g (0.01 mol) of linoleic acid are dissolved in 10 ml of xylol and heated until nitrogen and carbon dioxide are evolved. The heat source is quickly removed and, as soon as the vigorous carbon dioxide evolution has subsided, the reaction mixture is heated to boiling under reflux. After evaporation of the solvent, the N-(6-methyl-3-pyridyl)-linolamide is purified analogously to example 1 by column chromatography. Melting point 23°.
EKSEMPEL 20 EXAMPLE 20
JV- ( 5- acetylamino- 2- pyridyl)- linolamid JV-(5-acetylamino-2-pyridyl)-linolamide
3,71 g (0,01 mol) N-(5-amino-2-pyridyl)-linolamid står til henstand i 10 ml pyridin og 10 ml acetanhydrid ved værelsestemperatur i 12 3.71 g (0.01 mol) N-(5-amino-2-pyridyl)-linolamide is allowed to stand in 10 ml of pyridine and 10 ml of acetic anhydride at room temperature for 12
timer. Reaksjonsproduktet helles på 150 g is og de utfelte krystaller av N-(5-acetylamino-2-pyridyl)-linolamidet nutsjes fra og omkrystalliseres fra methanol. Smeltepunkt 125°. hours. The reaction product is poured onto 150 g of ice and the precipitated crystals of N-(5-acetylamino-2-pyridyl)-linolamide are filtered off and recrystallized from methanol. Melting point 125°.
På analog mate kan fra N-[5-(l'-hydro-xyethyl) -2-pyridyl]-linolamid N-[5-(l'-acetoxy-ethyl) -2-pyridyl] -linolamidet fremstilles, In an analogous way, from N-[5-(1'-hydroxyethyl)-2-pyridyl]-linolamide N-[5-(1'-acetoxy-ethyl)-2-pyridyl]-linolamide can be prepared,
n<2>D80: 1,5110. n<2>D80: 1.5110.
EKSEMPEL 21 EXAMPLE 21
N-[ 5-( l'- hydroxyethyl)- 2- pyridyl]- linolamid N-[5-(1'-hydroxyethyl)-2-pyridyl]-linolamide
0,398 g (0,001 mol) N-(5-acetyl-2-pyridyl)-linolamid oppløses i 10 ml methanol, tilsettes ved værelsestemperatur 0,056 mg (0,0015 mol) natriumborhydrid og oppløsningen står til henstand i 2 timer. Reaksjonsoppløsningen konsen-treres ved forminsket trykk til 3 ml og helles på 30 g is. Den utfelte olje ekstraheres med 3 porsjoner hver på 50 ml ethylacetat, det organiske skikt vaskes med vann og inndampes etter tørking med natriumsulfat. N-[5-(l'-hydroxye-thyl)-2-pyridyl]-linolamid renses analogt eksempel 1 ved søylekromatografi, n <2>D<8>°: 1,5214. 0.398 g (0.001 mol) of N-(5-acetyl-2-pyridyl)-linolamide is dissolved in 10 ml of methanol, 0.056 mg (0.0015 mol) of sodium borohydride is added at room temperature and the solution is allowed to stand for 2 hours. The reaction solution is concentrated under reduced pressure to 3 ml and poured onto 30 g of ice. The precipitated oil is extracted with 3 portions of 50 ml each of ethyl acetate, the organic layer is washed with water and evaporated after drying with sodium sulphate. N-[5-(1'-hydroxyethyl)-2-pyridyl]-linolamide is purified analogously to example 1 by column chromatography, n<2>D<8>°: 1.5214.
EKSEMPEL 22 EXAMPLE 22
N- ( 5- methyl- 2- pyridyl)- linolamid N-(5-methyl-2-pyridyl)-linolamide
a) 1,06 g (0,01 mol) 2-amino-5-methylpy-ridin og 1,1 g (0,011 mol) triethylamin oppløses a) 1.06 g (0.01 mol) of 2-amino-5-methylpyridine and 1.1 g (0.011 mol) of triethylamine are dissolved
i 50 ml kloroform. Under røring og avkjølning med isvann tildryppes 6,18 g (0,01 mol) 9,10,12, 13-tetrabrom-stearinsyre, oppløst i 35 ml kloroform, i løpet av 10 minutter, og blandingen røres ved værelsestemperatur ytterligere 2 timer. Klo-roformoppløsningen vaskes tre ganger med vann og inndampes til tørrhet, og N-(5-methyl-2-pyridyl)- 9,10,12,13-tetrabrom-stearinamid omkrystalliseres fra ethermethanol. Smeltepunkt 102°. in 50 ml of chloroform. While stirring and cooling with ice water, 6.18 g (0.01 mol) of 9,10,12,13-tetrabromo-stearic acid, dissolved in 35 ml of chloroform, are added dropwise over the course of 10 minutes, and the mixture is stirred at room temperature for a further 2 hours. The chloroform solution is washed three times with water and evaporated to dryness, and N-(5-methyl-2-pyridyl)-9,10,12,13-tetrabromo-stearinamide is recrystallized from ethermethanol. Melting point 102°.
b) 0,690 g (0,001 mol) N-(5-methyl-2-pyridyl)-9,10,12,13-tetrabrom-stearinamid oppløses 1 b) 0.690 g (0.001 mol) N-(5-methyl-2-pyridyl)-9,10,12,13-tetrabromo-stearinamide is dissolved 1
5 ml absolutt ethanol, tilsettes under nltrogen-atmosfære 0,9 g aktivert zink-støv, og blandingen oppvarmes 1 time til kokning under tilbake-løp. Etter avkjølning skilles sinken fra ved fil-trering, oppløsningen inndampes til tørrhet og 5 ml of absolute ethanol, 0.9 g of activated zinc dust are added under a nitrogen atmosphere, and the mixture is heated to reflux for 1 hour. After cooling, the zinc is separated by filtration, the solution is evaporated to dryness and
N-(5-methyl-2-pyridyl) -linolamidet renses analogt eksempel 1 ved søylekromatografi. Smeltepunkt 16°. The N-(5-methyl-2-pyridyl)-linolamide is purified analogously to example 1 by column chromatography. Melting point 16°.
EKSEMPEL 23 EXAMPLE 23
N- ( 5- amino- 2- pyridyl)- linolamid N-(5-amino-2-pyridyl)-linolamide
4,02 g (0,01 mol) N-(5-nitro-2-pyridyl)-linolamid oppløses i en blanding av 30 ml vann, 4.02 g (0.01 mol) of N-(5-nitro-2-pyridyl)-linolamide is dissolved in a mixture of 30 ml of water,
6 ml dioxan og 6 ml methanol. 10 g jernpulver 6 ml of dioxane and 6 ml of methanol. 10 g iron powder
tilsettes og blandingen røres under nitrogenatmosfære i 30 minutter ved 90—93°. Reaksjonsblandingen filtreres varm, og filtratet inndampes til tørrhet. Analogt eksempel 1 renses N-(5-amino-2-pyridyl)-linolamidet ved søylekromato-grafi og omkrystalliseres fra hexan. Smeltepunkt 42°. is added and the mixture is stirred under a nitrogen atmosphere for 30 minutes at 90-93°. The reaction mixture is filtered hot, and the filtrate is evaporated to dryness. Analogous to example 1, the N-(5-amino-2-pyridyl)-linolamide is purified by column chromatography and recrystallized from hexane. Melting point 42°.
Claims (3)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR8210966A FR2529173B1 (en) | 1982-06-23 | 1982-06-23 | SPOUT LID FOR FLEXIBLE WALL POWDER BOX |
Publications (3)
Publication Number | Publication Date |
---|---|
NO832260L NO832260L (en) | 1983-12-27 |
NO159158B true NO159158B (en) | 1988-08-29 |
NO159158C NO159158C (en) | 1988-12-07 |
Family
ID=9275296
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO832260A NO159158C (en) | 1982-06-23 | 1983-06-22 | COVER WITH PIPE FOR A POWDER BOX WITH A FLEXIBLE WALL. |
Country Status (16)
Country | Link |
---|---|
AT (1) | AT392200B (en) |
BE (1) | BE897105A (en) |
CH (1) | CH660166A5 (en) |
DE (1) | DE3321524A1 (en) |
DK (1) | DK158889C (en) |
ES (1) | ES281242Y (en) |
FI (1) | FI78043C (en) |
FR (1) | FR2529173B1 (en) |
GB (1) | GB2125016B (en) |
GR (1) | GR77512B (en) |
IE (1) | IE54356B1 (en) |
IT (1) | IT1197666B (en) |
NL (1) | NL8302246A (en) |
NO (1) | NO159158C (en) |
PT (1) | PT76911B (en) |
SE (1) | SE454980B (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA1330780C (en) * | 1988-08-22 | 1994-07-19 | Robert J. Groya | Side dispensing closure |
DE102018117503A1 (en) * | 2018-07-19 | 2020-01-23 | Ketten-Wulf Betriebs-Gmbh | articulated chain |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3144180A (en) * | 1961-07-13 | 1964-08-11 | Owens Illinois Glass Co | Dispensing closure |
GB949139A (en) * | 1962-05-14 | 1964-02-12 | Korris Products Inc | Dispensing closure |
FR1395304A (en) * | 1964-05-15 | 1965-04-09 | Abbott Lab | Tamper-evident closure device for dispensing container |
US3529754A (en) * | 1968-10-11 | 1970-09-22 | Morton Int Inc | Apparatus for dispensing granular substances |
FR2157690B3 (en) * | 1971-10-25 | 1974-06-07 | Maestracci Charles | |
FR2467789A1 (en) * | 1979-10-19 | 1981-04-30 | Reckitt & Colmann Prod Ltd | Combined lid and pourer for powder - has integral lid with side stops over opening in lid |
-
1982
- 1982-06-23 FR FR8210966A patent/FR2529173B1/en not_active Expired
-
1983
- 1983-06-15 DE DE3321524A patent/DE3321524A1/en not_active Ceased
- 1983-06-15 GR GR71690A patent/GR77512B/el unknown
- 1983-06-20 IT IT48533/83A patent/IT1197666B/en active
- 1983-06-20 CH CH3371/83A patent/CH660166A5/en not_active IP Right Cessation
- 1983-06-20 SE SE8303508A patent/SE454980B/en not_active IP Right Cessation
- 1983-06-21 FI FI832271A patent/FI78043C/en not_active IP Right Cessation
- 1983-06-21 BE BE0/211044A patent/BE897105A/en not_active IP Right Cessation
- 1983-06-21 AT AT2273/83A patent/AT392200B/en not_active IP Right Cessation
- 1983-06-22 NO NO832260A patent/NO159158C/en unknown
- 1983-06-22 GB GB08316994A patent/GB2125016B/en not_active Expired
- 1983-06-22 ES ES1983281242U patent/ES281242Y/en not_active Expired
- 1983-06-22 PT PT76911A patent/PT76911B/en not_active IP Right Cessation
- 1983-06-22 IE IE1460/83A patent/IE54356B1/en not_active IP Right Cessation
- 1983-06-23 DK DK291383A patent/DK158889C/en active
- 1983-06-23 NL NL8302246A patent/NL8302246A/en not_active Application Discontinuation
Also Published As
Publication number | Publication date |
---|---|
PT76911A (en) | 1983-07-01 |
PT76911B (en) | 1986-01-27 |
GB2125016B (en) | 1985-12-18 |
DK158889C (en) | 1991-01-21 |
CH660166A5 (en) | 1987-03-31 |
AT392200B (en) | 1991-02-11 |
FR2529173B1 (en) | 1987-01-23 |
BE897105A (en) | 1983-12-21 |
IT8348533A0 (en) | 1983-06-20 |
ATA227383A (en) | 1990-08-15 |
FI832271A0 (en) | 1983-06-21 |
DE3321524A1 (en) | 1983-12-29 |
SE8303508D0 (en) | 1983-06-20 |
DK291383D0 (en) | 1983-06-23 |
ES281242Y (en) | 1985-10-01 |
IE54356B1 (en) | 1989-08-30 |
FI832271L (en) | 1983-12-24 |
DK158889B (en) | 1990-07-30 |
GR77512B (en) | 1984-09-24 |
IE831460L (en) | 1983-12-23 |
NO832260L (en) | 1983-12-27 |
SE8303508L (en) | 1983-12-24 |
FR2529173A1 (en) | 1983-12-30 |
FI78043B (en) | 1989-02-28 |
GB8316994D0 (en) | 1983-07-27 |
ES281242U (en) | 1985-02-16 |
SE454980B (en) | 1988-06-13 |
FI78043C (en) | 1989-06-12 |
NO159158C (en) | 1988-12-07 |
NL8302246A (en) | 1984-01-16 |
IT1197666B (en) | 1988-12-06 |
DK291383A (en) | 1983-12-24 |
GB2125016A (en) | 1984-02-29 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP0203435B1 (en) | Novel pyridine derivatives and process for preparing the same | |
Danishefsky et al. | Reactions of 3, 4-benzopyrrolidinones with. beta.-ketoesters | |
PL84190B1 (en) | 3-aroyl-alkenyleneimines[us3835149a] | |
US4988708A (en) | Analgesic and anti-inflammatory 4-OH quinoline carboxylic acid derivatives | |
Sacchi et al. | Research on heterocyclic compounds, XLI. 2-Phenylimidazo [1, 2-b] pyridazine-3-acetic derivatives: synthesis and anti-inflammatory activity | |
NO159158B (en) | COVER WITH PIPE FOR A POWDER BOX WITH A FLEXIBLE WALL. | |
US3555035A (en) | N-(substituted pyridyl) linolamides and -linolenamides | |
Basabe et al. | Synthesis of spongidines A and D: marine metabolites phospholipase A2 inhibitors | |
Di Braccio et al. | 1, 8-Naphthyridines VI. Synthesis and anti-inflammatory activity of 5-(alkylamino)-N, N-diethyl [1, 2, 4] triazolo [4, 3-a][1, 8] naphthyridine-6-carboxamides with a new substitution pattern on the triazole ring | |
NO128608B (en) | ||
US2266754A (en) | Synthesis of vitamin | |
US2850501A (en) | Basic esters of 9-pyrid (3, 4-b) indole alkanoic acid | |
US3528987A (en) | N-(substituted pyridyl)rinolamides and -linolenamides | |
US2985650A (en) | 6alpha-ammonio-derivatives of 11-keto cortical hormones | |
US3428639A (en) | Preparation of ergot alkaloids | |
US5583228A (en) | 17-halogeno-4-azaandrostene derivatives and process for the preparation thereof | |
US2986562A (en) | Reserpic and deserpidic acid lactone dienes | |
US5399576A (en) | Thiazoles | |
JPH03220194A (en) | Staurosporine carboxylic acid derivative | |
US4017490A (en) | Pyrido (3,4-d)pyridazines | |
Yamamoto et al. | Carbon Functionalizations on Pyridine Ring via Trimethylstannyl Derivatives--An Example of Fusaric Acid Synthesis | |
CH484133A (en) | Process for the production of new amides of unsaturated fatty acids | |
NO823213L (en) | PROCEDURE FOR THE PREPARATION OF ANTRANIC ACID ESTERS | |
NO784094L (en) | 3-DI-N-PROPYL-ACETOXY-BENZODIAZEPIN-2-ONES AND PROCEDURES FOR THEIR PREPARATION | |
JPH04330060A (en) | Di(nitroxyalkyl)amide of pyridine-2,4-and 2,5-dicarboxylic acid, and preparation and use thereof |