NO801876L - PROCEDURE FOR PREPARING ACYLAMINOBENZO ACID DERIVATIVES - Google Patents
PROCEDURE FOR PREPARING ACYLAMINOBENZO ACID DERIVATIVESInfo
- Publication number
- NO801876L NO801876L NO801876A NO801876A NO801876L NO 801876 L NO801876 L NO 801876L NO 801876 A NO801876 A NO 801876A NO 801876 A NO801876 A NO 801876A NO 801876 L NO801876 L NO 801876L
- Authority
- NO
- Norway
- Prior art keywords
- amino
- methyl
- bis
- benzoic acid
- benzoate
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 22
- 239000002253 acid Substances 0.000 title claims description 21
- 150000001875 compounds Chemical class 0.000 claims description 78
- 239000000203 mixture Substances 0.000 claims description 38
- 150000003839 salts Chemical class 0.000 claims description 30
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 28
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 26
- 125000004432 carbon atom Chemical group C* 0.000 claims description 24
- 238000002360 preparation method Methods 0.000 claims description 20
- 125000000217 alkyl group Chemical group 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- -1 methyl 3-amino-4-(n-hexadecanamido)-benzoate Chemical compound 0.000 claims description 12
- 125000001424 substituent group Chemical group 0.000 claims description 12
- 239000005711 Benzoic acid Substances 0.000 claims description 10
- 235000010233 benzoic acid Nutrition 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- ADQCGQPQICIRLP-UHFFFAOYSA-N methyl 3,4-bis(hexadecanoylamino)benzoate Chemical compound C(CCCCCCCCCCCCCCC)(=O)NC=1C=C(C(=O)OC)C=CC1NC(CCCCCCCCCCCCCCC)=O ADQCGQPQICIRLP-UHFFFAOYSA-N 0.000 claims description 8
- TVURZCDPXALPLA-UHFFFAOYSA-N 3,4-bis(dodecanoylamino)benzoic acid Chemical compound C(CCCCCCCCCCC)(=O)NC=1C=C(C(=O)O)C=CC1NC(CCCCCCCCCCC)=O TVURZCDPXALPLA-UHFFFAOYSA-N 0.000 claims description 7
- CZBKGPBHXLKFFY-UHFFFAOYSA-N methyl 4-amino-3-(octanoylamino)benzoate Chemical compound NC1=C(C=C(C(=O)OC)C=C1)NC(CCCCCCC)=O CZBKGPBHXLKFFY-UHFFFAOYSA-N 0.000 claims description 7
- 125000003342 alkenyl group Chemical group 0.000 claims description 6
- 125000004423 acyloxy group Chemical group 0.000 claims description 5
- ZRUIDXRFXLHRSM-UHFFFAOYSA-N 3,4-bis(hexadecanoylamino)benzoic acid Chemical compound C(CCCCCCCCCCCCCCC)(=O)NC=1C=C(C(=O)O)C=CC1NC(CCCCCCCCCCCCCCC)=O ZRUIDXRFXLHRSM-UHFFFAOYSA-N 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- CPEFAORKRPDVLS-UHFFFAOYSA-N methyl 4-amino-3-(hexadecanoylamino)benzoate Chemical compound NC1=C(C=C(C(=O)OC)C=C1)NC(CCCCCCCCCCCCCCC)=O CPEFAORKRPDVLS-UHFFFAOYSA-N 0.000 claims description 4
- USRUOUQUSROHCU-UHFFFAOYSA-N 3-amino-4-(octanoylamino)benzoic acid Chemical compound CCCCCCCC(=O)NC1=CC=C(C(O)=O)C=C1N USRUOUQUSROHCU-UHFFFAOYSA-N 0.000 claims description 3
- FXGGWISCHMSUBZ-UHFFFAOYSA-N 4-amino-3-(hexadecanoylamino)benzoic acid Chemical compound CCCCCCCCCCCCCCCC(=O)NC1=CC(C(O)=O)=CC=C1N FXGGWISCHMSUBZ-UHFFFAOYSA-N 0.000 claims description 3
- SSLPEZYAXOTFGH-UHFFFAOYSA-N methyl 3-amino-4-(dodecanoylamino)benzoate Chemical compound NC=1C=C(C(=O)OC)C=CC1NC(CCCCCCCCCCC)=O SSLPEZYAXOTFGH-UHFFFAOYSA-N 0.000 claims description 3
- MQILNHFIIYCJLX-UHFFFAOYSA-N methyl 4-amino-3-(dodecanoylamino)benzoate Chemical compound NC1=C(C=C(C(=O)OC)C=C1)NC(CCCCCCCCCCC)=O MQILNHFIIYCJLX-UHFFFAOYSA-N 0.000 claims description 3
- 230000009467 reduction Effects 0.000 claims description 3
- XPJMIIKQWALGDM-UHFFFAOYSA-N 2,3-bis(hexadecanoylamino)benzoic acid Chemical compound C(CCCCCCCCCCCCCCC)(=O)NC1=C(C(=O)O)C=CC=C1NC(CCCCCCCCCCCCCCC)=O XPJMIIKQWALGDM-UHFFFAOYSA-N 0.000 claims description 2
- FHSSLCMPKIIGAZ-UHFFFAOYSA-N 3,4-bis(2-methyltetradecanoylamino)benzoic acid Chemical compound CC(C(=O)NC=1C=C(C(=O)O)C=CC1NC(C(CCCCCCCCCCCC)C)=O)CCCCCCCCCCCC FHSSLCMPKIIGAZ-UHFFFAOYSA-N 0.000 claims description 2
- YJKBVLMUBNZHFC-UHFFFAOYSA-N 3,4-bis(heptadecanoylamino)benzoic acid Chemical compound C(CCCCCCCCCCCCCCCC)(=O)NC=1C=C(C(=O)O)C=CC1NC(CCCCCCCCCCCCCCCC)=O YJKBVLMUBNZHFC-UHFFFAOYSA-N 0.000 claims description 2
- MKRQDSWZGMWFCC-UHFFFAOYSA-N 3,4-bis(octanoylamino)benzoic acid Chemical compound C(CCCCCCC)(=O)NC=1C=C(C(=O)O)C=CC1NC(CCCCCCC)=O MKRQDSWZGMWFCC-UHFFFAOYSA-N 0.000 claims description 2
- ZUYZVYRKLUGCGQ-UHFFFAOYSA-N 3,4-bis(pentadecanoylamino)benzoic acid Chemical compound C(CCCCCCCCCCCCCC)(=O)NC=1C=C(C(=O)O)C=CC1NC(CCCCCCCCCCCCCC)=O ZUYZVYRKLUGCGQ-UHFFFAOYSA-N 0.000 claims description 2
- GNOVTWKUAZOMRO-UHFFFAOYSA-N 3,4-bis(tetradecanoylamino)benzoic acid Chemical compound C(CCCCCCCCCCCCC)(=O)NC=1C=C(C(=O)O)C=CC1NC(CCCCCCCCCCCCC)=O GNOVTWKUAZOMRO-UHFFFAOYSA-N 0.000 claims description 2
- JPGXSKJZQNPWKW-UHFFFAOYSA-N 3-amino-4-(dodecanoylamino)benzoic acid Chemical compound NC=1C=C(C(=O)O)C=CC1NC(CCCCCCCCCCC)=O JPGXSKJZQNPWKW-UHFFFAOYSA-N 0.000 claims description 2
- DJDWARKOQNKMDE-UHFFFAOYSA-N 4-amino-3-(2-butyldecanoylamino)benzoic acid Chemical compound NC1=C(C=C(C(=O)O)C=C1)NC(C(CCCCCCCC)CCCC)=O DJDWARKOQNKMDE-UHFFFAOYSA-N 0.000 claims description 2
- PTRSAFYCKWKOCG-UHFFFAOYSA-N 4-amino-3-(2-hexyloctanoylamino)benzoic acid Chemical compound NC1=C(C=C(C(=O)O)C=C1)NC(C(CCCCCC)CCCCCC)=O PTRSAFYCKWKOCG-UHFFFAOYSA-N 0.000 claims description 2
- RRUMRKDJQRDZLU-UHFFFAOYSA-N 4-amino-3-(octadecanoylamino)benzoic acid Chemical compound NC1=C(C=C(C(=O)O)C=C1)NC(CCCCCCCCCCCCCCCCC)=O RRUMRKDJQRDZLU-UHFFFAOYSA-N 0.000 claims description 2
- WAPNJCNNOJKVSC-UHFFFAOYSA-N 4-amino-3-(octanoylamino)benzoic acid Chemical compound NC1=C(C=C(C(=O)O)C=C1)NC(CCCCCCC)=O WAPNJCNNOJKVSC-UHFFFAOYSA-N 0.000 claims description 2
- 239000011248 coating agent Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- ODOFMBQBTBBYSC-UHFFFAOYSA-N methyl 3,4-bis(decanoylamino)benzoate Chemical compound C(CCCCCCCCC)(=O)NC=1C=C(C(=O)OC)C=CC1NC(CCCCCCCCC)=O ODOFMBQBTBBYSC-UHFFFAOYSA-N 0.000 claims description 2
- IFBYDKXBCOLHEB-UHFFFAOYSA-N methyl 3,4-bis(dodecanoylamino)benzoate Chemical compound C(CCCCCCCCCCC)(=O)NC=1C=C(C(=O)OC)C=CC1NC(CCCCCCCCCCC)=O IFBYDKXBCOLHEB-UHFFFAOYSA-N 0.000 claims description 2
- HNXDMCSUQRQHPU-UHFFFAOYSA-N methyl 3,4-bis(nonanoylamino)benzoate Chemical compound C(CCCCCCCC)(=O)NC=1C=C(C(=O)OC)C=CC1NC(CCCCCCCC)=O HNXDMCSUQRQHPU-UHFFFAOYSA-N 0.000 claims description 2
- XRGNTSBWCWKRHM-UHFFFAOYSA-N methyl 3,4-bis(octadecanoylamino)benzoate Chemical compound C(CCCCCCCCCCCCCCCCC)(=O)NC=1C=C(C(=O)OC)C=CC1NC(CCCCCCCCCCCCCCCCC)=O XRGNTSBWCWKRHM-UHFFFAOYSA-N 0.000 claims description 2
- PCXGEMVDECEVTI-UHFFFAOYSA-N methyl 3,4-bis(tetradecanoylamino)benzoate Chemical compound C(CCCCCCCCCCCCC)(=O)NC=1C=C(C(=O)OC)C=CC1NC(CCCCCCCCCCCCC)=O PCXGEMVDECEVTI-UHFFFAOYSA-N 0.000 claims description 2
- AYKBVSFZTBGFTQ-UHFFFAOYSA-N methyl 3,4-bis(tridecanoylamino)benzoate Chemical compound C(CCCCCCCCCCCC)(=O)NC=1C=C(C(=O)OC)C=CC1NC(CCCCCCCCCCCC)=O AYKBVSFZTBGFTQ-UHFFFAOYSA-N 0.000 claims description 2
- DJNKIZIEWZQCND-UHFFFAOYSA-N methyl 3,4-bis(undecanoylamino)benzoate Chemical compound C(CCCCCCCCCC)(=O)NC=1C=C(C(=O)OC)C=CC1NC(CCCCCCCCCC)=O DJNKIZIEWZQCND-UHFFFAOYSA-N 0.000 claims description 2
- IAYPFKNIRXZCKE-UHFFFAOYSA-N methyl 3-amino-4-(decanoylamino)benzoate Chemical compound NC=1C=C(C(=O)OC)C=CC1NC(CCCCCCCCC)=O IAYPFKNIRXZCKE-UHFFFAOYSA-N 0.000 claims description 2
- ZRRNYJOVBDYPJF-UHFFFAOYSA-N methyl 3-amino-4-(octanoylamino)benzoate Chemical compound NC=1C=C(C(=O)OC)C=CC1NC(CCCCCCC)=O ZRRNYJOVBDYPJF-UHFFFAOYSA-N 0.000 claims description 2
- IWVZDAOAOLHVSE-UHFFFAOYSA-N methyl 4-amino-3-(tetradecanoylamino)benzoate Chemical compound NC1=C(C=C(C(=O)OC)C=C1)NC(CCCCCCCCCCCCC)=O IWVZDAOAOLHVSE-UHFFFAOYSA-N 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 125000005605 benzo group Chemical group 0.000 claims 2
- 125000005843 halogen group Chemical group 0.000 claims 2
- BIKOFYYQYSBQKW-UHFFFAOYSA-N 3,4-bis(decanoylamino)benzoic acid Chemical compound C(CCCCCCCCC)(=O)NC=1C=C(C(=O)O)C=CC1NC(CCCCCCCCC)=O BIKOFYYQYSBQKW-UHFFFAOYSA-N 0.000 claims 1
- BEMHXKGOBDZVML-UHFFFAOYSA-N 3,4-bis(octadecanoylamino)benzoic acid Chemical compound C(CCCCCCCCCCCCCCCCC)(=O)NC=1C=C(C(=O)O)C=CC1NC(CCCCCCCCCCCCCCCCC)=O BEMHXKGOBDZVML-UHFFFAOYSA-N 0.000 claims 1
- ZSWRAMQXHDNWQW-UHFFFAOYSA-N 4-amino-3-(2-ethyldodecanoylamino)benzoic acid Chemical compound NC1=C(C=C(C(=O)O)C=C1)NC(C(CCCCCCCCCC)CC)=O ZSWRAMQXHDNWQW-UHFFFAOYSA-N 0.000 claims 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims 1
- SVOXRUJDYNKQRO-UHFFFAOYSA-N methyl 4-amino-3-(tridecanoylamino)benzoate Chemical compound NC1=C(C=C(C(=O)OC)C=C1)NC(CCCCCCCCCCCC)=O SVOXRUJDYNKQRO-UHFFFAOYSA-N 0.000 claims 1
- 239000007787 solid Substances 0.000 description 84
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 78
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 72
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 66
- 239000000243 solution Substances 0.000 description 53
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 51
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 36
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 34
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 32
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 26
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 19
- 238000001953 recrystallisation Methods 0.000 description 19
- ARBOVOVUTSQWSS-UHFFFAOYSA-N hexadecanoyl chloride Chemical compound CCCCCCCCCCCCCCCC(Cl)=O ARBOVOVUTSQWSS-UHFFFAOYSA-N 0.000 description 17
- 210000004027 cell Anatomy 0.000 description 16
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 14
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 14
- HEMGYNNCNNODNX-UHFFFAOYSA-N 3,4-diaminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1N HEMGYNNCNNODNX-UHFFFAOYSA-N 0.000 description 13
- 239000012894 fetal calf serum Substances 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 229960000583 acetic acid Drugs 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 12
- NQGIJDNPUZEBRU-UHFFFAOYSA-N dodecanoyl chloride Chemical compound CCCCCCCCCCCC(Cl)=O NQGIJDNPUZEBRU-UHFFFAOYSA-N 0.000 description 12
- 239000012362 glacial acetic acid Substances 0.000 description 11
- IOPLHGOSNCJOOO-UHFFFAOYSA-N methyl 3,4-diaminobenzoate Chemical compound COC(=O)C1=CC=C(N)C(N)=C1 IOPLHGOSNCJOOO-UHFFFAOYSA-N 0.000 description 11
- REEZZSHJLXOIHL-UHFFFAOYSA-N octanoyl chloride Chemical compound CCCCCCCC(Cl)=O REEZZSHJLXOIHL-UHFFFAOYSA-N 0.000 description 11
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- 238000004519 manufacturing process Methods 0.000 description 10
- 239000002904 solvent Substances 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- 239000003242 anti bacterial agent Substances 0.000 description 7
- 229940088710 antibiotic agent Drugs 0.000 description 7
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol group Chemical group [C@@H]1(CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C)[C@H](C)CCCC(C)C HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- 239000003960 organic solvent Substances 0.000 description 7
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 5
- 125000003785 benzimidazolyl group Chemical class N1=C(NC2=C1C=CC=C2)* 0.000 description 5
- 230000037396 body weight Effects 0.000 description 5
- IPIVAXLHTVNRBS-UHFFFAOYSA-N decanoyl chloride Chemical compound CCCCCCCCCC(Cl)=O IPIVAXLHTVNRBS-UHFFFAOYSA-N 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- XCDJRGBDKUNZSP-UHFFFAOYSA-N 4-amino-3-(nonadecanoylamino)benzoic acid Chemical compound NC1=C(C=C(C(=O)O)C=C1)NC(CCCCCCCCCCCCCCCCCC)=O XCDJRGBDKUNZSP-UHFFFAOYSA-N 0.000 description 4
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 4
- 239000003701 inert diluent Substances 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- VANIXZJNMJJWGE-UHFFFAOYSA-N methyl 4-(dodecanoylamino)-3-nitrobenzoate Chemical compound C(CCCCCCCCCCC)(=O)NC1=C(C=C(C(=O)OC)C=C1)[N+](=O)[O-] VANIXZJNMJJWGE-UHFFFAOYSA-N 0.000 description 4
- 239000003226 mitogen Substances 0.000 description 4
- BASNZTUXPUAQLZ-UHFFFAOYSA-N nonadecanoyl chloride Chemical compound CCCCCCCCCCCCCCCCCCC(Cl)=O BASNZTUXPUAQLZ-UHFFFAOYSA-N 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 238000007363 ring formation reaction Methods 0.000 description 4
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 4
- 239000008247 solid mixture Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- LPWCRLGKYWVLHQ-UHFFFAOYSA-N tetradecanoyl chloride Chemical compound CCCCCCCCCCCCCC(Cl)=O LPWCRLGKYWVLHQ-UHFFFAOYSA-N 0.000 description 4
- FJRPWCNFWGBGOF-UHFFFAOYSA-N tridecanoyl chloride Chemical compound CCCCCCCCCCCCC(Cl)=O FJRPWCNFWGBGOF-UHFFFAOYSA-N 0.000 description 4
- CYBJTIAYHLCKRR-UHFFFAOYSA-N 3-nitro-4-(octanoylamino)benzoic acid Chemical compound [N+](=O)([O-])C=1C=C(C(=O)O)C=CC1NC(CCCCCCC)=O CYBJTIAYHLCKRR-UHFFFAOYSA-N 0.000 description 3
- KHPJOVYNDNRHSO-UHFFFAOYSA-N 4-(hexadecanoylamino)-3-nitrobenzoic acid Chemical compound [N+](=O)([O-])C=1C=C(C(=O)O)C=CC1NC(CCCCCCCCCCCCCCC)=O KHPJOVYNDNRHSO-UHFFFAOYSA-N 0.000 description 3
- ZZNAYFWAXZJITH-UHFFFAOYSA-N 4-amino-3-nitrobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1[N+]([O-])=O ZZNAYFWAXZJITH-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 150000001266 acyl halides Chemical class 0.000 description 3
- 206010003246 arthritis Diseases 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 239000006071 cream Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- 230000003516 hyperlipidaemic effect Effects 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 238000002955 isolation Methods 0.000 description 3
- HNTLUEZVPLRQEV-UHFFFAOYSA-N methyl 4-amino-3-nitrobenzoate Chemical compound COC(=O)C1=CC=C(N)C([N+]([O-])=O)=C1 HNTLUEZVPLRQEV-UHFFFAOYSA-N 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- WTBAHSZERDXKKZ-UHFFFAOYSA-N octadecanoyl chloride Chemical compound CCCCCCCCCCCCCCCCCC(Cl)=O WTBAHSZERDXKKZ-UHFFFAOYSA-N 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000002002 slurry Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 230000007306 turnover Effects 0.000 description 3
- KKTUQAYCCLMNOA-UHFFFAOYSA-N 2,3-diaminobenzoic acid Chemical compound NC1=CC=CC(C(O)=O)=C1N KKTUQAYCCLMNOA-UHFFFAOYSA-N 0.000 description 2
- 206010002383 Angina Pectoris Diseases 0.000 description 2
- 208000037260 Atherosclerotic Plaque Diseases 0.000 description 2
- 241000700198 Cavia Species 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 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 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- RJECHNNFRHZQKU-UHFFFAOYSA-N Oelsaeurecholesterylester Natural products C12CCC3(C)C(C(C)CCCC(C)C)CCC3C2CC=C2C1(C)CCC(OC(=O)CCCCCCCC=CCCCCCCCC)C2 RJECHNNFRHZQKU-UHFFFAOYSA-N 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- 208000018262 Peripheral vascular disease Diseases 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 206010052779 Transplant rejections Diseases 0.000 description 2
- 206010053648 Vascular occlusion Diseases 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 150000001450 anions Chemical class 0.000 description 2
- 229940058303 antinematodal benzimidazole derivative Drugs 0.000 description 2
- 210000003433 aortic smooth muscle cell Anatomy 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 239000001569 carbon dioxide Substances 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 230000002490 cerebral effect Effects 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 235000012000 cholesterol Nutrition 0.000 description 2
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- 229910052749 magnesium Inorganic materials 0.000 description 1
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- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- OLISWDUPUFSSSV-UHFFFAOYSA-N methyl 4-(decanoylamino)-3-nitrobenzoate Chemical compound C(CCCCCCCCC)(=O)NC1=C(C=C(C(=O)OC)C=C1)[N+](=O)[O-] OLISWDUPUFSSSV-UHFFFAOYSA-N 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- NTQYXUJLILNTFH-UHFFFAOYSA-N nonanoyl chloride Chemical compound CCCCCCCCC(Cl)=O NTQYXUJLILNTFH-UHFFFAOYSA-N 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-M oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC([O-])=O ZQPPMHVWECSIRJ-KTKRTIGZSA-M 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
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- 238000007911 parenteral administration Methods 0.000 description 1
- 229940056360 penicillin g Drugs 0.000 description 1
- PQZWQGNQOVDTRF-UHFFFAOYSA-N pentadecanoyl chloride Chemical compound CCCCCCCCCCCCCCC(Cl)=O PQZWQGNQOVDTRF-UHFFFAOYSA-N 0.000 description 1
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- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
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- 239000003381 stabilizer Substances 0.000 description 1
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- 229960005322 streptomycin Drugs 0.000 description 1
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- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/08—Radicals containing only hydrogen and carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
Foreliggende oppfinnelse vedrorer nye terapeutisk anvendelige acylaminobenzosyrederivater, fremgangsmåte for fremstilling av disse og farmasøytiske .blandinger som innehol- The present invention relates to new therapeutically applicable acylaminobenzoic acid derivatives, methods for their production and pharmaceutical mixtures containing
der dem.there them.
Acylaminobenzosyrederivatene ifolge foreliggende oppfinnelse er forbindelser méd den generelle formel: The acylaminobenzoic acid derivatives according to the present invention are compounds with the general formula:
1 hvor R betyr et hydrogenatom eller en rettlinjet eller for- • grenet alkylgruppe inneholdende fra 1-6 karbonatomer. (hvilke kan være substituert ved en eller flere substituen-ter av samme type valgt fra hydroksygruppen, alkenylgrupper med 2-5 karbonatomer og alkanoyloksygrupper med 2-7 karbonatomer) , fortrinnsvis en metylgruppe, R° betyr et hydro-2 2 genatom eller en gruppe med formel -COR , og R betyr en rettlinjet eller forgrenet alkylgruppe, fortrinnsvis en rettlinjet alkylgruppe med 2-20 (fortrinnsvis.fra 7 - 16) karbona tomer, og farmasøytisk fordragelige salter .derav. 1 where R means a hydrogen atom or a straight or branched • alkyl group containing from 1-6 carbon atoms. (which may be substituted by one or more substituents of the same type selected from the hydroxy group, alkenyl groups with 2-5 carbon atoms and alkanoyloxy groups with 2-7 carbon atoms), preferably a methyl group, R° means a hydrogen atom or a group with formula -COR , and R means a linear or branched alkyl group, preferably a linear alkyl group with 2-20 (preferably from 7-16) carbon atoms, and pharmaceutically acceptable salts thereof.
Når R"<*>" er en substituert alkylgruppe kan den f.eks. være ■ When R"<*>" is a substituted alkyl group, it can e.g. be ■
en 2,3-dihydroksyprop-l-yl, allyl eller pivaloyloksymetyl-gruppe. a 2,3-dihydroxyprop-1-yl, allyl or pivaloyloxymethyl group.
For en fagmann er det klart at i visse tilfeller vil substi-12 For a person skilled in the art, it is clear that in certain cases substi-12
tuentene R og R g-i optisk isomeri. Alle sådanne former er omfattet av foreliggende oppfinnelse. tuents R and R g-i optical isomerism. All such forms are covered by the present invention.
Med uttrykket "farmasøytisk fordragelig salt" menes et salt som dannes når R° er et hydrogenatom ved omsetning med en syre eller, når R er et hydrogenatom, ved omsetning meden base, slik at.anionet (i tilfellet av et syreaddisjonssalt) eller kationst(i tilfellet av et salt dannet av en forbindelse med den generelle formel I, hvori. R"*" betyr et hydro genatom) er relativt harmløst overfor animalske organismer gitt i terapeutiske doser slik at de1 fordelaktige farmakologiske egenskaper til moderforbindelsen med den generelle formel I'ikke forstyrres av bivirkninger som må tilskrives dette anion eller kation. By the term "pharmaceutically acceptable salt" is meant a salt formed when R° is a hydrogen atom by reaction with an acid or, when R is a hydrogen atom, by reaction with base, such that the anion (in the case of an acid addition salt) or cation in the case of a salt formed from a compound of the general formula I wherein R"*" means a hydrogen atom) is relatively harmless to animal organisms given in therapeutic doses so that the beneficial pharmacological properties of the parent compound of the general formula I' not be disturbed by side effects that must be attributed to this anion or cation.
Egnede syreaddisjonssalter av sådanne forbindelser med den generelle formel I hvor R°betyr et hydrogenatom er salter med uorganiske syrer, f.eks. hydroklorider, hydrobromider, fosfater, sulfater og nitrater, og organiske syrer,, f.eks. metansulfonater, 2-hydroksyetansulfonatér, oksalater, lak-tater, tartrater, acetater, salicylater, citrater, propiona-ter, succinater, fumarater, maleater, metylen-bis-(3-hydrok-synaftoater, gentisater og di-p-toluoyltartrater0Suitable acid addition salts of such compounds with the general formula I where R° means a hydrogen atom are salts with inorganic acids, e.g. hydrochlorides, hydrobromides, phosphates, sulphates and nitrates, and organic acids, e.g. methanesulfonates, 2-hydroxyethanesulfonates, oxalates, lactates, tartrates, acetates, salicylates, citrates, propionates, succinates, fumarates, maleates, methylene-bis-(3-hydroxy-synaphtoates, gentisates and di-p-toluoyl tartrates0
Egnede salter som dannes av forbindelser med den generelle formel I hvori R"<*>" betyr et hydrogenatom omfatter alkalime-tallet (f.eks. natrium og kalium), jordalkalime.tall (f.eks. kalsium og magnesium) og ammoniumsalter, og salter .av ami-ner som er kjent på området som farmasøytisk.fordragelige, f.eks. etylendiamin, kolin, dietanolamin, triétanolamin, oktadecylamin, dietylamin, trietylamin, 2-amino-2-(hydroksy-metyl)propan-1,3-diol og 1-(3,4-dihydroksyfenyl)-2-isopropyl-aminoetanol. Suitable salts formed by compounds of the general formula I wherein R"<*>" represents a hydrogen atom include alkali metal (eg sodium and potassium), alkaline earth metal (eg calcium and magnesium) and ammonium salts, and salts .of amines which are known in the field as pharmaceutically acceptable, e.g. ethylenediamine, choline, diethanolamine, triethanolamine, octadecylamine, diethylamine, triethylamine, 2-amino-2-(hydroxymethyl)propane-1,3-diol and 1-(3,4-dihydroxyphenyl)-2-isopropylaminoethanol.
Det må være klart at hvor det i beskrivelsen er tale om forbindelser med den generelle formel I menes deres farmasøy-tisk fordragelige salter hvor forholdene tillater det. It must be clear that where the description refers to compounds of the general formula I, their pharmaceutically tolerable salts are meant where the conditions permit.
Forbindelsene med den generelle formel I har anvendelige farmasøytiske egenskaper. F.eks. reduserer de den vegetative formering av arteriske glatte muskelceller som er et hoved-trekk, ved ateromatiske plater. Videre, inhiberer de akkumu-' leringen av kolesterylester og innlemningen av kolesteryl- i oleat i total kolesterylester og andre komplekse lipider som er karakteristiske for enzymet 'fett acyl CoAtkolesterol acyl-transferase. Stimuleringen av dette enzymet i nærvær av hyperlipemisk plasma opptrer ved utvikling av ateromatiske lesjoner. Forbindelsene med den generelle- formel I undertrykker også lymfocyttransformasjon i likhet med anti-reumatiske medisiner. De er også anvendelige for forhind-ring eller behandling av atherosclerosis og av forbundne tilstander såsom angina, myoc.ardialt infarkt, .cerebral va sku-lær tilstopping, arteriell aneuri og periferale vaskulære sykdommer, samt artritt, immunologiske sykdommer, kreft og transplantasjonsavvisning. The compounds of the general formula I have useful pharmaceutical properties. E.g. they reduce the vegetative proliferation of arterial smooth muscle cells which is a main feature of atheromatous plaques. Furthermore, they inhibit the accumulation of cholesteryl esters and the incorporation of cholesteryl oleate into total cholesteryl esters and other complex lipids that are characteristic of the enzyme fatty acyl CoAtcholesterol acyl transferase. The stimulation of this enzyme in the presence of hyperlipemic plasma occurs in the development of atheromatous lesions. The compounds of the general formula I also suppress lymphocyte transformation like anti-rheumatic drugs. They are also useful for the prevention or treatment of atherosclerosis and associated conditions such as angina, myocardial infarction, cerebral vascular occlusion, arterial aneurysm and peripheral vascular diseases, as well as arthritis, immunological diseases, cancer and transplant rejection.
Forbindelser med den generelle formel I som er av-særlig interesse innbefatter de folgende forbindelser, og eventuelt deres optisk aktive former og salter: Compounds of the general formula I of particular interest include the following compounds, and optionally their optically active forms and salts:
Bokstavene A til SS er gitt forbindelsene for enkel henvis-ning senere i beskrivelsen, f.eks.; i tabellene. The letters A to SS are given to the compounds for easy reference later in the description, e.g.; in the tables.
Egenskapene til forbindelsene med den generelle formel I ble vist i de folgende forsok: I nhiberende aktivitet. i vegetativ formering av glatte aorta-muskelceller The properties of the compounds of the general formula I were shown in the following experiments: I inhibitory activity. in vegetative propagation of aortic smooth muscle cells
Glatte- muskelceller ble dyrket i en kultur fra eksplanta-sjoner av svinetoraks aorta ved bruk av Dulbecco's Modified Eagles (DME) Medium inneholdende 20% kalvefosterserum (FCS) og antibiotika. Cellene ble inkubert ved 37°C i en atmosfære av 95% luft og 5% karbondioksyd. Ved sam-menlop ble cellene rutinemessig dyrket ved trypsinisering og repletering ved omtrent 1/3 av sin sammenlopningsdensi-tet i DME Medium inneholdende 10% FCS og antibiotika. Smooth muscle cells were grown in culture from porcine thoracic aorta explants using Dulbecco's Modified Eagles (DME) Medium containing 20% fetal calf serum (FCS) and antibiotics. The cells were incubated at 37°C in an atmosphere of 95% air and 5% carbon dioxide. At confluence, the cells were routinely cultured by trypsinization and repletion at approximately 1/3 of their confluent density in DME Medium containing 10% FCS and antibiotics.
De glatte muskelceller ble plettert ut ved tettheter påThe smooth muscle cells were plated out at densities of
100 000 - 200 000 celler pr. 35 x 10 mm Falcon dish i 2 ml DME Medium inneholdende 10% FCS og antibiotika. Når cellene etter 2 4 timer hadde festet seg til skålene, ble mediet erstattet med 2 ml DME Medium inneholdende 1% FCS og antibiotika. Kulturene ble inkubert ytterligere 3 dager slik at cellene kom til stillstand (d.v.s. ikke lenger delte, seg) . Mediet ble så erstattet med 2 ml kontroll eller forsoksmedium. Forsoksmediet bestod av DME Medium (inneholdende 10% FCS og antibiotika) og forbindelsen som skulle proves ved en konsentrasjon på 5 ug/ml medium. Forbindelsene ble forut opplost i aceton slik at den ende-lige konsentrasjon av aceton i mediet var 0, 2% (v/v). Kontrollmediet bestod av DME Medium (inneholdende' 10% FCS 100,000 - 200,000 cells per 35 x 10 mm Falcon dish in 2 ml DME Medium containing 10% FCS and antibiotics. When the cells had attached to the dishes after 24 hours, the medium was replaced with 2 ml of DME Medium containing 1% FCS and antibiotics. The cultures were incubated for a further 3 days so that the cells became quiescent (i.e. no longer dividing). The medium was then replaced with 2 ml of control or trial medium. The trial medium consisted of DME Medium (containing 10% FCS and antibiotics) and the compound to be tested at a concentration of 5 ug/ml medium. The compounds were previously dissolved in acetone so that the final concentration of acetone in the medium was 0.2% (v/v). The control medium consisted of DME Medium (containing' 10% FCS
og antibiotika) og aceton i 0,2% (v/v) konsentrasjon. Etter 3 dagers inkubering i forsoks- eller kontrollmedium, ble and antibiotics) and acetone in 0.2% (v/v) concentration. After 3 days of incubation in test or control medium,
mediet erstattet med friskt forsoks- eller kontrollmedium og cellene inkubert i ytterligere 3 eller 4 dager. På slutten av 6 eller 7 dagers inkubasjonsperioden ble celle-tallene bestemt ved trypsinisering av cellene og telling av cellesuspensjonen i en Coulter-teller. the medium replaced with fresh experimental or control medium and the cells incubated for a further 3 or 4 days. At the end of the 6 or 7 day incubation period, cell numbers were determined by trypsinizing the cells and counting the cell suspension in a Coulter counter.
Alle resultatene i tabell I i det folgende betyr gjennomsnittsverdien for 4 skåler av celler0Andel inhibering av vegetativ formering ble beregnet ved bruk av folgende formel: All the results in Table I in the following mean the average value for 4 dishes of cells0 Percentage inhibition of vegetative propagation was calculated using the following formula:
Andel inhibering av vegetativ formeringProportion of inhibition of vegetative propagation
Hvor S. = Gjennomsnittlig, celleantall prQskål ved start av eksperiment (etter tilsetning av kontroll eller forsoksmedium). Where S. = Average cell number per dish at the start of the experiment (after addition of control or test medium).
T = Gjennomsnittlig celletall pr. skål i forsoks-kulturer■ved forsokets slutt. T = Average number of cells per bowl in experimental cultures■at the end of the experiment.
C = Gjennomsnittlig celletall pr. skål i kontrollkul-turer ved forsokets slutt. C = Average number of cells per bowl in control cultures at the end of the experiment.
TABELL ITABLE I
Forbindelse % inhiberingCompound % inhibition
Y 59,76,84,56,32,40,41,55 Y 59,76,84,56,32,40,41,55
B 51,52 B 51,52
D 61,61 D 61,61
C 54,48 C 54.48
A 71,76,47,40' A 71,76,47,40'
KK. 2 4,47 KK. 2 4.47
Inhibering av aktivitet på akkumulering av aortisk qlatt-muskeleelie- kolesterylester Inhibition of activity on the accumulation of aortic qlatt muscle cholesteryl ester
Aortiske glatte muskelceller som beskrevet i kultur nr. 8 ble dyrket til sammenlopning i Dulbecco's Modified Eagle's (DME) Medium inneholdende 10% kalvefosterserum (FCS) og antibiotika. Aortic smooth muscle cells as described in culture #8 were grown to confluence in Dulbecco's Modified Eagle's (DME) Medium containing 10% fetal calf serum (FCS) and antibiotics.
Fire replikatskåler med glatte muskelceller ble inkubert 24 timer i DME-medium inneholdende 10% v/v hyperlipemisk 3 Four replicate dishes of smooth muscle cells were incubated for 24 h in DME medium containing 10% v/v hyperlipemic 3
kaninserum, H-oleat kompleksert med avrettet bovinserum-albumin (molekylarforhold av fri fettsyre (FFA) : albumin 0,862; konsentrasjon av oleat i medietO,155 mM) , antibio-. tika (penicillin G 100 I.U./ml, streptomycin 100 ug/ml og kanamycin 100 ug/ml) og forsoksforbindelsen ved en konsentrasjon på 100 ug/ml medium. Kontrollskåler uten forsoks-forbindelse og kontrollskåler med 10% v/v FCS i stedet rabbit serum, H-oleate complexed with rectified bovine serum-albumin (molecular ratio of free fatty acid (FFA) : albumin 0.862; concentration of oleate in the medium 0.155 mM), antibio-. tika (penicillin G 100 I.U./ml, streptomycin 100 ug/ml and kanamycin 100 ug/ml) and the test compound at a concentration of 100 ug/ml medium. Control dishes without presox compound and control dishes with 10% v/v FCS instead
for hyperlipemisk'kaninserum ble også inkubertc.for hyperlipemic rabbit serum was also incubatedc.
Seraene ble varme - inaktivert for bruk og inneholdt 933 mg/dl eller 26 mg/dl av totalt kolesterol henholdsvis. Etter inkubering ble cellene vasket med Hanks losning, tryp-sinisert og sentrifugert, og proppen ble ultralydbehandlet ' i 0,27 mM EDTA. Cellulære konsentrasjoner av fritt og for.-. The sera were heat-inactivated for use and contained 933 mg/dl or 26 mg/dl of total cholesterol, respectively. After incubation, the cells were washed with Hank's solution, trypsinized and centrifuged, and the plug was sonicated in 0.27 mM EDTA. Cellular concentrations of free and for.-.
' estrert kolesterol og innbygning av ■<3>Hr-merket kolesteryl-oleat i totalt kolesterylester og andre komplekse lipider ble målt under sammenligning med. kontrollene. ' esterified cholesterol and incorporation of ■<3>Hr-labeled cholesteryl oleate into total cholesteryl esters and other complex lipids were measured in comparison with. the controls.
Alle resultater i tabellene II og III i det folgende betyr gjennomsnittsverdien for fire skåler med celler. All results in Tables II and III below mean the average value for four dishes of cells.
Mitogen- stimulert lymfeknutecelle- lymfocytt- transformerings-inhiberende aktivitet hos marsvin Mitogen-stimulated lymph node cell-lymphocyte-transformation-inhibitory activity in guinea pigs
Marsvin ble sensibilisert for Mycobacterium tuberculosum ved fotbladsinjeksjoner av Freund's Complete Adjuvant (FCA) Guinea pigs were sensitized to Mycobacterium tuberculosum by footpad injections of Freund's Complete Adjuvant (FCA)
(0,05. ml, 0,5 mg/ml av 50% v/v FCA-losning i sterilt fysio-logisk saltvann). (0.05 ml, 0.5 mg/ml of 50% v/v FCA solution in sterile physiological saline).
Etter 14 dager fikk man lymfeknuteceller og oppslemmet dem i Eagles Minimal Essential (EME) Medium, inneholdende 10% ' kalvefosterserum . (FCS) og bufret med Earle !s salter ved en konsentrasjon på 2,5 x 10^ celler/ml. After 14 days, lymph node cells were obtained and resuspended in Eagles Minimal Essential (EME) Medium, containing 10% fetal calf serum. (FCS) and buffered with Earle's salts at a concentration of 2.5 x 10^ cells/ml.
I 24 timer ble 0,1 ml cellesuspensjon inkubert ved 37°C i en atmosfære av 95% luft og 5% karbondioksyd i nærvær av 0,15 ml mitogen eller mitogen og forbindelsen som skal undersakes i EME Medium (inneholdende 10% FCS. og-bufret med Earle's salter). 18 timer for. hosting ble H-tymidin (1 ul■av 100 uCi/ml losning i 0,9% sterilt saltvann) tilsatt. For 24 hours, 0.1 ml of cell suspension was incubated at 37°C in an atmosphere of 95% air and 5% carbon dioxide in the presence of 0.15 ml of mitogen or mitogen and the compound to be investigated in EME Medium (containing 10% FCS. and -buffered with Earle's salts). 18 hours for. coughing, H-thymidine (1 µl of 100 uCi/ml solution in 0.9% sterile saline) was added.
Som en indeks for DNA syntese måles graden av - 3H-tymidin-innbygning av cellene sammenlignet med mitogenkontrollen. As an index for DNA synthesis, the degree of - 3H-thymidine incorporation by the cells is measured compared to the mitogen control.
Resultatene er gitt i den folgende tabell IV. The results are given in the following table IV.
Forbindelsenes anvendelighet okes ved at de bare er meget lite toksiske som vist i det folgende forsok: The compounds' applicability is increased by the fact that they are only very slightly toxic, as shown in the following experiment:
Oral toksisitet hos musOral toxicity in mice
Grupper av mus ble oralt gitt graderte doser av forsoksforbindelsen (i en 0,5% vekt/volum vandig losning av tragakant grot) og undersokt i 3 dager. Andelen av de som dode under perioden ved hvert doseringsnivå ble brukt for å konstruere en kurve, hvorfra LD^^, d.v.s. den dose i mg/kg dyrisk kroppsvekt som er nodvendig for å drepe 50% av musene, ble beregnet. Groups of mice were orally given graded doses of the test compound (in a 0.5% w/v aqueous solution of tragacanth root) and studied for 3 days. The proportion of those who died during the period at each dosage level was used to construct a curve, from which LD^^, i.e. the dose in mg/kg animal body weight required to kill 50% of the mice was calculated.
Forbindelsene med den generelle formel I som er angitt i listen ovenfor ble undersokt og LD5q for hver forbindelse' var storre enn 1000 mg/kg dyrisk kroppsvekt. The compounds of general formula I listed above were examined and the LD5q for each compound was greater than 1000 mg/kg animal body weight.
Foretrukne forbindelser ifolge oppfinnelsen er sådannePreferred compounds according to the invention are such
forut betegnet med bokstavene Y, A, B, D og C.previously denoted by the letters Y, A, B, D and C.
Forbindelsene med den generelle formel I kan fremstilles ved å anvende eller tilpasse kjente metoder (d.v.s. metoder som tidligere er brukteller beskrevet i den kjemiske litteratur), f.eks. som vist i det folgende. The compounds of the general formula I can be prepared by using or adapting known methods (i.e. methods previously used or described in the chemical literature), e.g. as shown in the following.
(A) Ifolge et trekk ved foreliggende oppfinnelse fremstilles forbindelsene med den generelle formel I, hvor R° (A) According to a feature of the present invention, the compounds of the general formula I are prepared, where R°
er et hydrogenatom ved reduksjon av en forbindelse med den generelle formel: is a hydrogen atom in the reduction of a compound with the general formula:
(hvor- R 1 og R 2er som forut angitt) ved kjente metoder for reduksjon av en nitrogruppe til en primær aminogruppe, f.eks. ved katalytisk hydrogenering, fortrinnsvis ved bruk av palladium på karbon som katalysator. (where R 1 and R 2 are as previously indicated) by known methods for the reduction of a nitro group to a primary amino group, e.g. by catalytic hydrogenation, preferably using palladium on carbon as catalyst.
(B) Ifolge et annet trekk'ved foreliggende oppfinnelse fremstilles forbindelsene med den generelle formel I, hvori (B) According to another feature of the present invention, the compounds of the general formula I are prepared, wherein
R betyr en gruppe med formel -COR (R 2er som forut angitt), eller substituentgruppen -NH-COR 2 (R 2er som forut angitt) er meta til substituentgruppen -COOR"'" (R"*" er som forut angitt) og R° betyr et hydrogenatom, ved omsetning .av en forbindelse med den generelle formel: (hvor er- som forut angitt) med et acyleringsmiddel med den generelle formel: R means a group of formula -COR (R 2 is as above), or the substituent group -NH-COR 2 (R 2 is as above) is meta to the substituent group -COOR"'" (R"*" is as above) and R° means a hydrogen atom, by reaction of a compound of the general formula: (where is- as indicated above) with an acylating agent of the general formula:
2 1 2 1
hvor R er som forut angitt, pg X betyr et halogen (fortrinnsvis klor) atom eller en hydroksygruppe. where R is as previously stated, pg X means a halogen (preferably chlorine) atom or a hydroxy group.
Særlig egnede betingelser er som folger:Particularly suitable conditions are as follows:
(i) Forbindelser med den generelle formel I, hvor R° betyr en gruppe med formelen -COR 2 (hvor R 2er som forut angitt). fremstilles ved omsetningen av en forbindelse med den generelle formel III (hvor R er som forut angitt) med et acylhalogenid med den generelle formel IV (hvor R 2 er som forut angitt, og X"^ betyr et halogen, fortrinnsvis' klor, atom) i et inert organisk løsningsmiddel, f.eks. diklormetan eller dimetylformamid, fortrinnsvis under vannfrie betingelser og fortrinnsvis i nærvær av et syrebindende mid-del, f.eks. et trialkylamin (f.eks. trietylamin), eller et alkalimetallkarbonat eller bikarbonat (f.eks. vannfritt natrium eller kaliumkarbonat), ved en temperatur som kan være hoyere enn omgivelsestemperaturen, f.eks. mellom 10 og 50°C. (ii) Forbindelser med den generelle formel I, hvori substituentgruppen -NH-COR 2 (R 2er som.forut angitt) er meta til substituentgruppen -COOR"^ (R"<*>" er som forut angitt) og R° betyr et hydrogenatom, fremstilles ved omsetning av en forbindelse med den generelle formel III (spesielt sådanne hvori R"*" betyr en rett- eller forgrenet alkylgruppe med 1-6 karbonatomer) med et.acylhalogenid med generell formel IV (hvor R<2>er som forut angitt og X<1>betyr et halogen, fortrinnsvis klor, atom), under lignende betingelser som beskrevet forut under (i), men ved bruk av en mindre mengde acylhalogenid og kontroll av temperaturen,, fortrinnsvis mellom 0°C og romtemperatur. (C) Ifolge et ytterligere trekk ved foreliggende oppfinnelse- fremstilles forbindelsene med den generelle formel I, (i) Compounds of the general formula I, where R° means a group of the formula -COR 2 (where R 2 is as previously indicated). is produced by the reaction of a compound of the general formula III (where R is as previously stated) with an acyl halide of the general formula IV (where R 2 is as previously stated, and X"^ means a halogen, preferably chlorine, atom) in an inert organic solvent, eg dichloromethane or dimethylformamide, preferably under anhydrous conditions and preferably in the presence of an acid-binding agent, eg a trialkylamine (eg triethylamine), or an alkali metal carbonate or bicarbonate (eg .eg anhydrous sodium or potassium carbonate), at a temperature which may be higher than the ambient temperature, eg between 10 and 50° C. (ii) Compounds of the general formula I, in which the substituent group -NH-COR 2 (R 2 as previously indicated) is meta to the substituent group -COOR"^ (R"<*>" is as previously indicated) and R° means a hydrogen atom, is prepared by reacting a compound of the general formula III (especially those in which R"* " means a straight or branched alkyl group with 1-6 carbons atoms) with an acyl halide of general formula IV (where R<2> is as previously indicated and X<1> is a halogen, preferably chlorine, atom), under similar conditions as described above under (i), but using a small amount of acyl halide and control of the temperature, preferably between 0°C and room temperature. (C) According to a further feature of the present invention, the compounds of the general formula I are prepared,
v '22 hvori R betyr en gruppe med formelen -COR (R er som forut angitt) fra en tilsvarende forbindelse med den generelle formel I (hvor R° betyr et hydrogenatom) ved omsetning med en forbindelse med den generelle formel IV ifolge kjente metoder. v '22 in which R means a group of the formula -COR (R is as previously indicated) from a corresponding compound of the general formula I (where R° means a hydrogen atom) by reaction with a compound of the general formula IV according to known methods.
Forbindelser med generell formel II kan fremstilles ved omsetning av en forbindelse med den generelle formel: Compounds of general formula II can be prepared by reacting a compound of the general formula:
(hvor R^ er som forut angitt) med. en forbindelse med generell formel IV på lignende måte som forut beskrevet under metode B (i). (where R^ is as previously indicated) with. a compound of general formula IV in a similar manner as previously described under method B (i).
Forbindelsene med generell formel V kan.fremstilles ved kjente metoder. The compounds of general formula V can be prepared by known methods.
(D) Ifolge et ytterligere trekk ved foreliggende oppfinnelse fremstilles- forbindelsene med generell formel I, hvori R"^ (D) According to a further feature of the present invention, the compounds of general formula I are prepared, in which R"^
betyr en rett- eller forgrenet alkylgruppe med 1- 6 karbonatomer (hvilke kan være substituert med en eller flere av den "samme type substituent valgt-fra hydroksygruppen, alkenylgrupper med 2-5 karbona tomer eller alkanoyloksygrupper med 2-7 karbona-tomer) , fremstilt ved forestring av en tilsvarende forbindelse med den generelle formel I, hvor R"^ betyr et hydrogenatom ved anvendelse eller tilpasning av kjente metoder, f.eks. ved omsetning med det til- means a straight or branched alkyl group with 1-6 carbon atoms (which may be substituted with one or more of the "same type of substituent selected from the hydroxy group, alkenyl groups with 2-5 carbon atoms or alkanoyloxy groups with 2-7 carbon atoms) , prepared by esterification of a corresponding compound of the general formula I, where R"^ means a hydrogen atom by using or adapting known methods, e.g. by turnover with the add-
svarende diazoalkan i nærvær av et inert organisk løsnings-middel. (E) Ifolge et ytterligere trekk ved foreliggende oppfinnelse fremstilles forbindelsene med den generelle formel I, corresponding diazoalkane in the presence of an inert organic solvent. (E) According to a further feature of the present invention, the compounds of the general formula I are prepared,
hvor R^" betyr et hydrogenatom ved alkalisk hydrolyse av en tilsvarende ester med generelle .formel I hvor R"<*>" betyr en rett eller forgrenet' alkylgruppe med 1-6 karbonatomer (som kan være substituert med en eller flere av samme typen substituent valgt fra hydroksygruppen, alkenylgrupper med 2-5 karbonatomer eller alkahoyloksygrupper med 2-7 karbonatomer), f.eks. ved behandling med et alkali-metallhydroksyd i et vandig organisk løsningsmiddelsystem og ved hoyere temperatur. where R^" means a hydrogen atom by alkaline hydrolysis of a corresponding ester of general formula I where R"<*>" means a straight or branched' alkyl group with 1-6 carbon atoms (which may be substituted with one or more of the same type substituent selected from the hydroxy group, alkenyl groups of 2-5 carbon atoms or alkahoyloxy groups of 2-7 carbon atoms), for example by treatment with an alkali metal hydroxide in an aqueous organic solvent system and at a higher temperature.
(F) Ifolge et ytterligere trekk ved foreliggende oppfinnelse overfores forbindelser med generell formel I, hvori (F) According to a further feature of the present invention, compounds of general formula I are provided, wherein
R betyr et hydrogenatom og/eller R° betyr et hydrogenatom til sine farmasøytisk fordragelige salter, og vice ver sa, ved anvendelse eller tilpasning av kjente metoder. R means a hydrogen atom and/or R° means a hydrogen atom to its pharmaceutically acceptable salts, and vice versa, using or adapting known methods.
■ Denne fremgangsmåten er både anvendelig i seg selv og for rensing av forbindelser med generell formel I og deres salter under utnyttelse av forskjellen i loselighet i vann og.forskjellige organiske løsningsmidler for forbindelsene og 'deres salter og for enhver tilstedeværende forurensning, ved hjelp av kjente. metoder såsom krystallisering. ■ This method is both applicable in itself and for the purification of compounds of general formula I and their salts using the difference in solubility in water and various organic solvents for the compounds and their salts and for any impurities present, by means of known methods . methods such as crystallization.
(i) Forbindelser med den generelle formel I hvor R1 betyr et hydrogenatom (R° og R<2>er som forut angitt) kan overfores til sine salter av farmasoytisk fordr.agelige baser, f.eks. ved omsetning med den riktige base, f.eks. det., riktige aminet eller en forbindelse med den generelle formel: (i) Compounds of the general formula I wherein R 1 is a hydrogen atom (R 0 and R< 2> are as previously indicated) may be converted into their salts of pharmaceutically acceptable bases, e.g. by turnover with the correct base, e.g. det., the appropriate amine or a compound of the general formula:
(hvor M1 betyr et alkalimetaIL, f.eks. natrium eller kalium, atom og R<3>betyr en alkylgruppe med opptil 4 karbon-, atomer, f.eks. metyl eller etyl, eller et hydrogenatom) i (where M1 means an alkali metal, e.g. sodium or potassium, atom and R<3> means an alkyl group of up to 4 carbon atoms, e.g. methyl or ethyl, or a hydrogen atom) in
et egnet løsningsmiddel, f.eks. metanol eller etanol, eller en blanding av vann og aceton, etterfulgt om nodvendig av fordampning av en del av eller alt losningsmidlet, og isolering av det faste saltet. a suitable solvent, e.g. methanol or ethanol, or a mixture of water and acetone, followed if necessary by evaporation of some or all of the solvent, and isolation of the solid salt.
Disse saltene kan igjen overfores til utgangsforbindelsene med den generelle'formel I, f.eks. ved omsetning med en passende syre, f.eks. iseddik i losning i et egnet løsnings-middel, f.eks. vann eller etanol, om nodvendig etterfulgt av inndampning av en del av eller alt losningsmidlet, og isolering av den faste forbindelse med generell formel I. (i) Forbindelser, med den generelle formel I, hvor R° betyr et hydrogenatom kan overfores til sine farmasoytisk fordragelige syreaddisjonssalter, f.eks. ved omsetning med den riktige syre i losning eller oppslemning i et egnet løs-ningsmiddel, f.eks. aceton, metanol eller etanol, om nodvendig etterfulgt av inndampning av en del av eller alt losningsmidlet, og isolering av det faste saltet. These salts can again be transferred to the starting compounds of the general formula I, e.g. by reaction with a suitable acid, e.g. glacial acetic acid in solution in a suitable solvent, e.g. water or ethanol, if necessary followed by evaporation of part or all of the solvent, and isolation of the solid compound of general formula I. (i) Compounds, of general formula I, where R° means a hydrogen atom can be transferred to their pharmaceutical tolerable acid addition salts, e.g. by reaction with the correct acid in solution or slurry in a suitable solvent, e.g. acetone, methanol or ethanol, if necessary followed by evaporation of some or all of the solvent, and isolation of the solid salt.
Syreaddisjonssaltene kan igjen overfores til- utgangsforbindelsene med den generelle formel I, f.eks. ved omsetning The acid addition salts can again be transferred to the starting compounds with the general formula I, e.g. by turnover
'med vandig ammoniakk' i nærvær av et passende losningsmiddel, 'with aqueous ammonia' in the presence of a suitable solvent,
f.eks. etanol, etterfulgt av behandling med en svak syre, f.eks. iseddik. e.g. ethanol, followed by treatment with a weak acid, e.g. glacial acetic acid.
Forbindelsene med den generelle formel I kan også brukes som utgangsmateriale for fremstilling av terapeutisk anvendelige benzimidazolderivater med den generelle formel: The compounds with the general formula I can also be used as starting material for the preparation of therapeutically useful benzimidazole derivatives with the general formula:
(hvor R 1 er som forut angitt, R<2>'betyr en rett eller forgrenet alkylgruppe med 7 - 20'karbonatomer), gruppen R<1>00C (where R 1 is as previously stated, R<2>' means a straight or branched alkyl group with 7 - 20' carbon atoms), the group R<1>00C
er knyttet til 4 eller 5-stillingen i benzimidazolringen,is attached to the 4 or 5 position of the benzimidazole ring,
som de kan overfores til ved anvendelse av.kjente metoder for cyklisering. to which they can be transferred using known methods of cyclization.
F.eks., For example,
v v
(i) når RQ i den generelle formel I er en gruppe med formel -COR 2 (R 2er som forut angitt), kan cyklisering under dannelse av et benzimidazolderivat med generell formel VII utfores ved hoydetemperatur, f.eks. mellom 60° og 100°C, (i) when RQ in general formula I is a group of formula -COR 2 (R 2 is as previously indicated), cyclization to form a benzimidazole derivative of general formula VII can be carried out at elevated temperature, e.g. between 60° and 100°C,
ved omsetning med en uorganisk syre, f.eks. saltsyre i nærvær av vann og i et organisk losningsmiddel, f.eks. en alkohol såsom metanol eller etanol, eller et keton såsom aceton eller metyletylketon, eller by reaction with an inorganic acid, e.g. hydrochloric acid in the presence of water and in an organic solvent, e.g. an alcohol such as methanol or ethanol, or a ketone such as acetone or methyl ethyl ketone, or
(ii) når R° i deri generelle formel I er et hydrogenatom,(ii) when R° in general formula I therein is a hydrogen atom,
kan cyklisering utfores enten under lignende betingelser som de' forut beskrevne under (i) eller, alternativt, ved omsetning med en organisk syre (f.eks. p-toluensulfonsyre) i vann eller et organisk løsningsmiddel (f.eks. toluen), fortrinnsvis ved en hoyere temperatur, f.eks. mellom 60° og 100°C, eller (iii) kan cyklisering utfores uten løsningsmiddel og ved hoyere. temperatur (f.eks. mellom 150° og 250°C, eller i nærvær av vann og en uorganisk syre (f.eks„ saltsyre) og i et egnet løsningsmiddel, f.eks. diglym. cyclization can be carried out either under similar conditions to those previously described under (i) or, alternatively, by reaction with an organic acid (e.g. p-toluenesulfonic acid) in water or an organic solvent (e.g. toluene), preferably at a higher temperature, e.g. between 60° and 100°C, or (iii) cyclization can be carried out without solvent and at higher temperature (e.g. between 150° and 250°C, or in the presence of water and an inorganic acid (e.g. hydrochloric acid) and in a suitable solvent, e.g. diglyme.
Det vil være klart for en fagmann at under.gjennomføringenIt will be clear to a person skilled in the art that during the implementation
av fremgangsmåten ovenfor og av foreliggende oppfinnelseof the above method and of the present invention
'kan det være ønskelig og innfore kjemiske beskyttelsesgrup-per i reaktantene for å unngå at bir.eaksjoner finner sted, f.eks. i fremgangsmåten for fremstilling av benzimidazoler som er bes]crevet forut kan hydroksygruppene i substituenten R<1>i den generelle formel I måtte beskyttes som. benzyloksy-grupper for den beskrevne omsetning med etterfølgende It may be desirable to introduce chemical protective groups in the reactants to avoid side reactions taking place, e.g. in the process for the preparation of benzimidazoles described above, the hydroxy groups in the substituent R<1> in the general formula I may have to be protected as benzyloxy groups for the described reaction with subsequent
fjerning av benzylgruppen.removal of the benzyl group.
Benzimidazolderivatene med. deri generelle formel VII er anvendelige, for å forebygge eller behandle, diabetes mellitus, hyperlipoproteinemiske tilstander, atherosale-rosisog- medfolgende tilstander såsom angina, myokardiale infarkt, cerebral vaskulær tilstopning, arteriell aneuri, perifere vaskulære sykdommer, gjentatte pankreåtitis og xanthomas, samt arthritis, immunologiske sykdommer, The benzimidazole derivatives with. wherein general formula VII are applicable, to prevent or treat, diabetes mellitus, hyperlipoproteinemic conditions, atherosale-rosis and accompanying conditions such as angina, myocardial infarction, cerebral vascular occlusion, arterial aneury, peripheral vascular diseases, recurrent pancreatitis and xanthomas, as well as arthritis, immunological diseases,
kreft og transplantasjonsavvisning.cancer and transplant rejection.
De folgende- eksempler illustrerer fremstillingen av forbindelsene ifolge foreliggende oppfinnelse. The following examples illustrate the preparation of the compounds according to the present invention.
EKSEMPEL 1EXAMPLE 1
F orbindelse AConnection A
Metyl 4-amino-3-(n-heksadekanamido)benzoat.ble fremstiltMethyl 4-amino-3-(n-hexadecanamido)benzoate was prepd
ve d en av de folgende metoder:by one of the following methods:
(i) En omrort losning av metyl 3,4-aminobenzoat (35 g) i tort dimetylformamid (1200 ml), inneholdende vannfritt natriumkarbonat (11,8 g) ble behandlet dråpevis med n-heksadekanoylklorid (58 g) i 1 time. Tilsetningshastigheten av n-heksadekanoylkloridet var slik at temperaturen i reaksjonsblandingen steg fra en begynnelsestemperatur på 10°C til romtemperatur. Blandingen ble så rort ved romtemperatur (i) A stirred solution of methyl 3,4-aminobenzoate (35 g) in dry dimethylformamide (1200 ml) containing anhydrous sodium carbonate (11.8 g) was treated dropwise with n-hexadecanoyl chloride (58 g) for 1 hour. The rate of addition of the n-hexadecanoyl chloride was such that the temperature of the reaction mixture rose from an initial temperature of 10°C to room temperature. The mixture was then stirred at room temperature
i en ytterligere periode på 3 timer og ble så helt . ifor a further period of 3 hours and then became completely . in
vann ( 5 1). Det.resulterende faste stoff ble oppsamlet og kokt i aceton (1000 ml) og den kokende blanding ble water ( 5 1). The resulting solid was collected and boiled in acetone (1000 mL) and the boiling mixture was
så filtrert. Filtratet ble kjolt til 0°C og det resulterende brungule fa ste stoff frafiltrert, hvilket ga 4-amino-3- (n-heksadekanamido)benzoat (48,2 g), smp. 112° - 114°C. then filtered. The filtrate was cooled to 0°C and the resulting tan solid filtered off to give 4-amino-3-(n-hexadecanamido)benzoate (48.2 g), m.p. 112° - 114°C.
(ii) En omrort losning av metyl 3,4-diaminobenzoat (16,6 g) i tort diklormetan (270 ml) inneholdende trietylamin (10,3 ,g) ble behandlet dråpevis med en losning av n-heksadekanoylklorid (27,5 g) i torr diklormetan (30 ml) i- 45 min.. Temperaturen under tilsetningen ble holdt mellom 16-og 20°C. Blandingen ble rort i ytterligere 2 timer. Det resulterende faste stoff ble oppsamlet og kokt i en blanding av.aceton (1000 ml) og metanol (150 ml) og det uloselige materialet ble fjernet ved filtrering. Filtratet ble avkjolt til 25°C og behandlet med vann (800 ml), hvilket ga metyl 4-amino-3-(n-heksadekanamido)benzoat i form av et brungult faststoff, smp. 112 - 114°C (ii) A stirred solution of methyl 3,4-diaminobenzoate (16.6 g) in dry dichloromethane (270 ml) containing triethylamine (10.3 g) was treated dropwise with a solution of n-hexadecanoyl chloride (27.5 g ) in dry dichloromethane (30 ml) for 45 min. The temperature during the addition was kept between 16 and 20°C. The mixture was stirred for an additional 2 hours. The resulting solid was collected and boiled in a mixture of acetone (1000 ml) and methanol (150 ml) and the insoluble material was removed by filtration. The filtrate was cooled to 25°C and treated with water (800 mL) to give methyl 4-amino-3-(n-hexadecanamido)benzoate as a tan solid, m.p. 112 - 114°C
EKSEMPEL 2EXAMPLE 2
Forbindelse BCompound B
En losning av metyl 3,4-diaminobenzoat (25,0 g) i tort di-metylf ormamid (1120 ml) inneholdende vannfritt natriumkarbonat (7,7 g) ble behandlet med n-dodekanoylklorid (30,5 g) på lignende måte som ovenfor beskrevet i eksempel 1 (i) hvilket ga rått metyl 4-amino-3-(n-dodekanamido)benzoat (41 g) i form av et brungult faststoff. A solution of methyl 3,4-diaminobenzoate (25.0 g) in dry dimethylformamide (1120 ml) containing anhydrous sodium carbonate (7.7 g) was treated with n-dodecanoyl chloride (30.5 g) in a manner similar to above described in Example 1 (i) which gave crude methyl 4-amino-3-(n-dodecanamido)benzoate (41 g) as a tan solid.
EKSEMPEL 3EXAMPLE 3
Forbindelse C Compound C
En omrort losning av metyl 3,4-diaminobenzoat (25,0 g) i . tort diklormetan (500 ml), inneholdende trietylamin (15,5 g) ble behandlet. dråpevis med en losning av n-tetradekanoyl-^klorid (37,12 g) i tort diklormetan (50 ml) på lignende måte som forut beskrevet i eksempel 1 (ii) hvilket ga rått metyl 4-amino-3-(n-tetradekanamido)benzoat (40 g) i form av et brungult faststoff. A stirred solution of methyl 3,4-diaminobenzoate (25.0 g) in . dry dichloromethane (500 ml), containing triethylamine (15.5 g) was treated. dropwise with a solution of n-tetradecanoyl chloride (37.12 g) in dry dichloromethane (50 ml) in a similar manner as previously described in Example 1 (ii) which gave crude methyl 4-amino-3-(n-tetradecananido) )benzoate (40 g) in the form of a brownish-yellow solid.
EKSEMPEL 4EXAMPLE 4
Forbindelse DCompound D
En losning av metyl 3,4-diaminobenzoat (17,8 g) i diklormetan (350 ml) inneholdende trietylamin (10,8 g) ble behandlet med n-tridekanoylklorid (25 g) på lignende måte som forut beskrevet i eksempel 1 (ii) hvilket ga rått metyl 4-r-amino-3-(n-tridekanamido) benzoat (40 g) . A solution of methyl 3,4-diaminobenzoate (17.8 g) in dichloromethane (350 ml) containing triethylamine (10.8 g) was treated with n-tridecanoyl chloride (25 g) in a similar manner as previously described in Example 1 (ii ) which gave crude methyl 4-r-amino-3-(n-tridecanamido)benzoate (40 g).
EKSEMPEL 5EXAMPLE 5
Forbindelse EConnection E
En losning av 3,4-diaminobenzosyre (7,5 g) i diklormetan (100 ml) inneholdende trietylamin (15 g) ble behandlet med n-heksadekanoylklorid (27,5 g) på lignende måte som forut beskrevet i eksempel 1 (ii) . Et fast stoff ble oppsamlet og omkrystallisert fra iseddik og deretter omkrystallisert fra metyl-etylketon (med filtrering av den varme losning) hvilket ga 3,4-bis(n-heksadekanamido)benzosyre (20 g) i form av et brungult faststoff, smp. 198 202°C.' A solution of 3,4-diaminobenzoic acid (7.5 g) in dichloromethane (100 ml) containing triethylamine (15 g) was treated with n-hexadecanoyl chloride (27.5 g) in a similar manner as previously described in Example 1 (ii) . A solid was collected and recrystallized from glacial acetic acid and then recrystallized from methyl ethyl ketone (with filtration of the hot solution) to give 3,4-bis(n-hexadecanamido)benzoic acid (20 g) as a tan solid, m.p. 198 202°C.'
EKSEMPEL 6EXAMPLE 6
Forbindelse FConnection F
En losning av metyl 3,4-diaminobenzoat (5,0 g) i diklormetan (50 ml) inneholdende trietylamin (6,2 g) ble behandlet med n-heksadekanoylklorid (16,5 g) på lignende måte som forut beskrevet i eksempel 1 (ii) (reaksjonsblandingens temperatur under tilsetningen fikk stige fra 20 - 30°C)„ Et faststoff ble oppsamlet og omkrystallisert fra kloroform og ga metyl 3,4-bis(n-heksadekanamido)benzoat (14,9 g) i form av et hvitt faststoff, smp. 129 - 132°C0A solution of methyl 3,4-diaminobenzoate (5.0 g) in dichloromethane (50 ml) containing triethylamine (6.2 g) was treated with n-hexadecanoyl chloride (16.5 g) in a similar manner as previously described in Example 1 (ii) (the temperature of the reaction mixture during the addition was allowed to rise from 20 - 30°C)„ A solid was collected and recrystallized from chloroform to give methyl 3,4-bis(n-hexadecanamido)benzoate (14.9 g) as a white solid, m.p. 129 - 132°C0
EKSEMPEL 7EXAMPLE 7
Forbindelse GConnection G
En losning av metyl 3,4-diaminobenzoat (17,9 g) i diklormetan (300 ml) inneholdende trietylamin (21,8 g) ble behandlet med n-undekanoylklorid (44,3 g) på lignende måte • som forut beskrevet i eksempel 6. Et faststoff ble oppsamlet og omkrystallisert to ganger fra etanol (med filtrering av den varme losning), hvilket ga metyl 3,4-bis(n-undekanamido)benzoat (40,2 g) i form av et hvitt faststoff, smp. 139 - 141°C. A solution of methyl 3,4-diaminobenzoate (17.9 g) in dichloromethane (300 ml) containing triethylamine (21.8 g) was treated with n-undecanoyl chloride (44.3 g) in a similar manner • as previously described in Example 6. A solid was collected and recrystallized twice from ethanol (with filtration of the hot solution) to give methyl 3,4-bis(n-undecanamido)benzoate (40.2 g) as a white solid, m.p. 139 - 141°C.
EKSEMPEL 8EXAMPLE 8
Forbindelse HConnection H
En omrort losning av metyl 3,4-diaminobenzoat (16,6 g) i tort dimetylformamid (600 ml) inneholdende vannfritt natriumkarbonat (5,3 g) ble behandlet dråpevis. med n-dekanoylklorid (19,1 g) på lignende måte som forut beskrevet i eksempel 1 (i), hvilket ga metyl 4-amino-3-(n-dekanamido)-benzoat (18,8 g) i form av et brungult faststoff, smp. 96 - 98°C. A stirred solution of methyl 3,4-diaminobenzoate (16.6 g) in dry dimethylformamide (600 ml) containing anhydrous sodium carbonate (5.3 g) was treated dropwise. with n-decanoyl chloride (19.1 g) in a similar manner as previously described in Example 1 (i), which gave methyl 4-amino-3-(n-decanamido)-benzoate (18.8 g) in the form of a tan solid, m.p. 96 - 98°C.
EKSEMPEL 9EXAMPLE 9
Forbindelse IConnection I
En losning av metyl 3,4-diaminobenzoat (41,2 g) i diklormetan (412 ml) inneholdende trietylamin (51,0 g) ble behandlet med en losning av n-oktanoylklorid (80,6 g) i diklormetan (330 ml) på lignende måte som forut beskrevet A solution of methyl 3,4-diaminobenzoate (41.2 g) in dichloromethane (412 ml) containing triethylamine (51.0 g) was treated with a solution of n-octanoyl chloride (80.6 g) in dichloromethane (330 ml) in a similar manner as previously described
i eksempel 6 under omkrysta11isering fra metanol (med behandling med aktivt karbon), hvilket ga metyl 3,4-bis(n-oktanamido)benzoat (81,8 g) i form av et hvitt faststoff, smp. 138 140°C„ in Example 6 during recrystallization from methanol (with activated carbon treatment), which gave methyl 3,4-bis(n-octanamido)benzoate (81.8 g) as a white solid, m.p. 138 140°C„
EKSEMPEL 10EXAMPLE 10
Forbindelse JConnection J
En losning av 3,4-diaminobenzosyre (13,85 g) i dimetylformamid (180 ml) inneholdende trietylamin (27,6 g) ble behandlet med n-pentadekanoylklorid (47,4.g) på lignende måte som forut beskrevet i eksempel 1 (i). Det resulterende faste stoff ble oppsamlet og omkrystallisert fra metyletylketon (ved behandling med aktivt karbon og med filtrering av den varme losning), hvilket ga 3,4-bis(n-pentadekanamido)benzosyre (49,3 g), smp. 178 - 180°C. A solution of 3,4-diaminobenzoic acid (13.85 g) in dimethylformamide (180 ml) containing triethylamine (27.6 g) was treated with n-pentadecanoyl chloride (47.4 g) in a similar manner as previously described in Example 1 (in). The resulting solid was collected and recrystallized from methyl ethyl ketone (by treatment with activated carbon and filtering the hot solution) to give 3,4-bis(n-pentadecanamido)benzoic acid (49.3 g), m.p. 178 - 180°C.
EKSEMPEL 11EXAMPLE 11
Forbindelse ÉConnection É
En omrort losning av 3,4-diaminobenzosyre (152 g) i dimetylformamid (1500 ml) inneholdende trietylamin (303 g) ble behandlet dråpevis med n-heksadekanoylklorid (549,0 g) i 1,5 time. Tilsetningshastigheteh av h-heksadekanoyl-.kloridet var slik at reaksjonsblandingens temperatur fikk stige fra romtemperatur til 35 - 40°Co Blandingen ble så rort ved romtemperatur i ytterligere 2 timer og ble deretter helt i varmt vann (10 1 ved 70°C), inneholdende konsentrert saltsyre (150 ml med styrke 36,5 % vekt/vol.). Det resulterende faste stoff ble oppsamlet og ga rått 3,4-bis(n-heksadekanamido)benzosyre (600 g) i form'av et brungult faststoff, smp.. 180 - 190°C. A stirred solution of 3,4-diaminobenzoic acid (152 g) in dimethylformamide (1500 ml) containing triethylamine (303 g) was treated dropwise with n-hexadecanoyl chloride (549.0 g) for 1.5 hours. The rate of addition of the h-hexadecanoyl chloride was such that the temperature of the reaction mixture was allowed to rise from room temperature to 35 - 40°C. The mixture was then stirred at room temperature for a further 2 hours and then poured into hot water (10 1 at 70°C), containing concentrated hydrochloric acid (150 ml with a strength of 36.5% w/v). The resulting solid was collected to give crude 3,4-bis(n-hexadecanamido)benzoic acid (600 g) as a tan solid, mp 180-190°C.
EKSEMPEL 12EXAMPLE 12
F orbindelse KConnection K
En omrort losning av metyl 3,4-diaminobenzoat (20 g) i tort diklormetan (250 ml) inneholdende trietylamin (24,2 g) ble behandlet dråpevis med en losning av nonanoylklorid (44,12 g) i tort diklormetan (50 ml) på lignende måte som forut beskrevet i eksempel 1 (ii), hvilket ga et lyserodt fast stoff som ble omkrystallisert fra metanol under be-' handling med aktivt karbon og ga metyl 3,4-bis(n-nonamido)-benzoat (30,3 g) i form av et hvitt fast stoff, smp„ 142 - 145°C. A stirred solution of methyl 3,4-diaminobenzoate (20 g) in dry dichloromethane (250 ml) containing triethylamine (24.2 g) was treated dropwise with a solution of nonanoyl chloride (44.12 g) in dry dichloromethane (50 ml) in a similar manner to that previously described in Example 1 (ii), yielding a pale red solid which was recrystallized from methanol under treatment with activated carbon to give methyl 3,4-bis(n-nonamido)-benzoate (30, 3 g) in the form of a white solid, m.p. 142 - 145°C.
EKSEMPEL 13EXAMPLE 13
Forbindelse LConnection L
En omrort losning av 3,4-diaminobenzosyre (45,6 g) i dimetylformamid (400 ml) inneholdende trietylamin (7 5,8 g) ble behandlet dråpevis med n-heptadekanoylklorid (130 g) på lignende måte som forut beskrevet i eksempel 11, hvilket ga rå 3,4-bis(n-heptadekanamido)benzosyre (140 g) i form av et lyserodt fast stoff. A stirred solution of 3,4-diaminobenzoic acid (45.6 g) in dimethylformamide (400 ml) containing triethylamine (75.8 g) was treated dropwise with n-heptadecanoyl chloride (130 g) in a manner similar to that previously described in Example 11 , which gave crude 3,4-bis(n-heptadecanamido)benzoic acid (140 g) as a pale red solid.
EKSEMPEL 14EXAMPLE 14
Forbindelse MConnection M
En omrort losning av 3,4-diaminobenzosyre (21,9 g) i dimetylformamid (175 ml) inneholdende trietylamin (43,6 g) A stirred solution of 3,4-diaminobenzoic acid (21.9 g) in dimethylformamide (175 ml) containing triethylamine (43.6 g)
ble behandlet dråpevis med n-heneisosanoylklorid (99,2 g)was treated dropwise with n-heneisosanoyl chloride (99.2 g)
på lignende måte som forut beskrevet i eksempel 11, hvilket ga rå 3,4-bis(n-heneicosanamido)benzosyre (126,5 g) in a similar manner to that previously described in Example 11, yielding crude 3,4-bis(n-heneicosanamido)benzoic acid (126.5 g)
i form av et lysebrunt fast stoff.in the form of a light brown solid.
EKSEMPEL 15EXAMPLE 15
Forbindelse NConnection N
En omrort losning av 3,4-diaminobenzosyre (18,3 g) i dimetylformamid (200 ml) inneholdende trietylamin (36,5 g) ble.behandlet dråpevis med n-eikosanoylklorid (79,4 g) på lignende måte- som1 forut beskrevet i eksempel' 11 og ga rå 3, 4-bis. (n-eicosanamido) benzosyre (93 g) i form av et lysebrunt'faststoff, smpo160 - 170°C. A stirred solution of 3,4-diaminobenzoic acid (18.3 g) in dimethylformamide (200 ml) containing triethylamine (36.5 g) was treated dropwise with n-eicosanoyl chloride (79.4 g) in a similar manner as previously described in example' 11 and gave crude 3, 4-bis. (n-eicosanamido)benzoic acid (93 g) as a light brown solid, mp 160 - 170°C.
EKSEMPEL 16 'EXAMPLE 16'
Forbindelse 0 Connection 0
En omrort losning av 3,4-diaminobenzosyre (38 g) i dimetylformamid (500 ml) inneholdende trietylamin (50,5 g) ble behandlet dråpevis med n-nonadekanoylklorid (79,1 g) på lignende måte som forut beskrevet i eksempel 11 og ga en orange-farget losning som ble helt i vann (3000 ml) inneholdende konsentrert saltsyre (100 ml med styrke 36,5 % vekt/volum). Det faste stoff ble oppsamlet, vasket med vann (2 x 100 ml) og så torket, hvilket ga rå 4-amino-3-(n-nonadekanamido)-benzosyre (107 g), smp. 103 - 113°C. A stirred solution of 3,4-diaminobenzoic acid (38 g) in dimethylformamide (500 ml) containing triethylamine (50.5 g) was treated dropwise with n-nonadecanoyl chloride (79.1 g) in a similar manner as previously described in Example 11 and gave an orange colored solution which was poured into water (3000 ml) containing concentrated hydrochloric acid (100 ml at strength 36.5% w/v). The solid was collected, washed with water (2 x 100 mL) and then dried to give crude 4-amino-3-(n-nonadecanamido)-benzoic acid (107 g), m.p. 103 - 113°C.
E KSEMPEL 17 Forbindelse P E XAMPLE 17 Connection P
En omrort losning av 3,4-diaminobenzosyre (17,5 g) i dimetylformamid (140 ml) inneholdende trietylamin (34,8 g) ble behandlet dråpevis med pentadekan-2-oylklorid (59,7. g) på lignende' måte ..som beskrevet forut i eksempel 11, hvilket A stirred solution of 3,4-diaminobenzoic acid (17.5 g) in dimethylformamide (140 ml) containing triethylamine (34.8 g) was treated dropwise with pentadecan-2-oyl chloride (59.7 g) in a similar manner. .as described previously in example 11, which
ga rå (RS)(RS)-3,4-bis(2-metyltetradekanamido)benzosyregave crude (RS)(RS)-3,4-bis(2-methyltetradecanamido)benzoic acid
(68 g). (68g).
EKSEMPEL 18 Forbindelse Q EXAMPLE 18 Compound Q
En omrort losning av 3,4-diaminobenzosyre (20,7 g) i dimetylformamid (165 ml) inneholdende trietylamin (56,5 ml) ble behandlet dråpevis med 2-heksyloktanoylklorid (67 g) på lignende måte som beskrevet i eksempel 11. Det'voksaktige faste stoff ble oppsamlet og opplost i dietyleter (500 ml)/og eterlosningen ble torket og inndampet og ga en rodbrun olje. Denne oljen ble ekstrahert med varm.metanol ved bruk av et kontinuerlig ekstraksjonsapparat i 5 timer. Den metanoliske losning ble inndampet på en rotasjonsfordamper og ga et brunt faststoff som ble omkrystallisert fra aceton og ga 4-amino-3-(2-heksyloktanamido)benzosyre (15,2 g) i form av et hvitt faststoff, smp0 219 - 221°C. A stirred solution of 3,4-diaminobenzoic acid (20.7 g) in dimethylformamide (165 ml) containing triethylamine (56.5 ml) was treated dropwise with 2-hexyloctanoyl chloride (67 g) in a similar manner to that described in Example 11. The waxy solid was collected and dissolved in diethyl ether (500 mL) and the ether solution was dried and evaporated to give a reddish brown oil. This oil was extracted with hot methanol using a continuous extraction apparatus for 5 hours. The methanolic solution was evaporated on a rotary evaporator to give a brown solid which was recrystallized from acetone to give 4-amino-3-(2-hexyloctanamido)benzoic acid (15.2 g) as a white solid, mp 0 219 - 221° C.
EKSEMPEL 19EXAMPLE 19
Forbindelse RCompound R
En omrort losning av 3,4-diaminobenzosyre (22,8 g) i dimetylformamid (200 ml) inneholdende trietylamin (22,7 g) A stirred solution of 3,4-diaminobenzoic acid (22.8 g) in dimethylformamide (200 ml) containing triethylamine (22.7 g)
ble behandlet dråpevis med 2-etyldodekanoylklorid (37 g) på lignende måte som forut beskrevet i eksempel 11. Etter opparbeiding av reaksjonsproduktet.som forut beskrevet i eksempel 18 fikk man et fast.stoff som ble omkrystallisert fra etylacetat under behandling med aktivt karbon ga (RS)-4-amino-3-(2-etyldodekanamido)benzosyre (22,2 g) i form av et hvitt faststoff, smp. 188 - 191°C. was treated dropwise with 2-ethyldodecanoyl chloride (37 g) in a similar manner as previously described in example 11. After working up the reaction product as previously described in example 18, a solid was obtained which was recrystallized from ethyl acetate during treatment with activated carbon to give ( RS)-4-amino-3-(2-ethyldodecanamido)benzoic acid (22.2 g) as a white solid, m.p. 188 - 191°C.
EKSEMPEL 20EXAMPLE 20
F orbindelse SConnection S
En omrort losning av 3,4-diaminobenzosyre (15,8 g) i dimetylformamid (130 ml) inneholdende trietylamin (43,4 g) ble behandlet dråpevis med 2-b.utyldekanoylklorid (51,4 g) på lignende måte som forut' beskrevet i eksempel 11. Etter, opparbeiding av reaksjonsproduktet som forut beskrevet i eksempel 18 fikk man (RS)-4-amino-3-(2-butyldekanamido)-benzosyre (9,8 g) i form av et hvitt faststoff, smp. A stirred solution of 3,4-diaminobenzoic acid (15.8 g) in dimethylformamide (130 ml) containing triethylamine (43.4 g) was treated dropwise with 2-b-butyldecanoyl chloride (51.4 g) in a similar manner as before. described in example 11. After working up the reaction product as previously described in example 18, (RS)-4-amino-3-(2-butyldecanamido)-benzoic acid (9.8 g) was obtained in the form of a white solid, m.p.
178 - 182°C. 178 - 182°C.
EKSEMPEL 21EXAMPLE 21
F orbindelse TConnection T
En losning av 2,3-diaminobenzosyre (20 g) i dimetylformamid (200 ml) inneholdende trietylamin (39,9 g) ble behandlet med n-tetradekanoylklorid (65,0 g). Tilsetningshastigheten av n-tetradekanoylklorid var slik at reaksjonstempera-turen steg fra romtemperatur til 45 - 50°C. Blandingen ble så rort ytterligere 2 timer og fikk stå ved romtemperatur natten over. Blandingen ble tilsatt 20 ml metanol og den resulterende blandingen ble rort 20 min. og deretter behandlet med konsentrert saltsyre (styrke 36,5% vekt/volum) inntil pH var 2. Den resulterende blanding ble helt i vann (1000 ml) og det svarte faste stoff oppsamlet, vasket.med vann (2 x 500 ml) og deretter med varm petroleter (kokepunkt 60 - 80°C, 500 ml) og ble til slutt omkrystallisert fra etanol under behandling med aktivt karbon, hvilket ga 2,3-bis (n-te.tradekanamido) benzosyre (17,7 g) i form av et brungult faststoff, smp. 150. - 158°C. A solution of 2,3-diaminobenzoic acid (20 g) in dimethylformamide (200 ml) containing triethylamine (39.9 g) was treated with n-tetradecanoyl chloride (65.0 g). The rate of addition of n-tetradecanoyl chloride was such that the reaction temperature rose from room temperature to 45 - 50°C. The mixture was then stirred for a further 2 hours and allowed to stand at room temperature overnight. To the mixture was added 20 ml of methanol and the resulting mixture was stirred for 20 min. and then treated with concentrated hydrochloric acid (strength 36.5% w/v) until the pH was 2. The resulting mixture was poured into water (1000 mL) and the black solid collected, washed with water (2 x 500 mL) and then with hot petroleum ether (b.p. 60 - 80°C, 500 ml) and was finally recrystallized from ethanol under treatment with activated carbon to give 2,3-bis(n-te.tradecanamido)benzoic acid (17.7 g) in form of a brownish-yellow solid, m.p. 150. - 158°C.
EKSEMPEL 22EXAMPLE 22
Forbindelse UConnection U
3-nitro-4-(n-heksadekanamido)benzosyre (22 g) opplost i.n-butanol (500 ml) ble hydrogenert under rysting i nærvær av 5 vekt-% palladium på karbon (2,5 g) ved 70°C og atmosfæretrykk i 6. timer. Blandingen ble filtrert varmtog filtratet avkjolt. Det resulterende faste stoff ble oppsamlet og vasket med etanol (100 ml), hvilket ga 3-amino-4-(heksade-kanamido)benzosyre (11,6 g) i form av et kremfarget faststoff ,.. smp. 160 - 162°C. 3-nitro-4-(n-hexadecanamido)benzoic acid (22 g) dissolved in n-butanol (500 ml) was hydrogenated with shaking in the presence of 5% by weight palladium on carbon (2.5 g) at 70°C and atmospheric pressure for 6 hours. The mixture was filtered hot and the filtrate cooled. The resulting solid was collected and washed with ethanol (100 mL) to give 3-amino-4-(hexadecanamido)benzoic acid (11.6 g) as a cream solid, m.p. 160 - 162°C.
3-nitro-4-(n-heksadekanamido)benzosyre som ble brukt som utgangsmateriale ble fremstilt som folger: En losning av 4-amino-3-nitrobenzosyre (18,2 g) og n-heksa-. dekanoylklorid (33,0 g) i tort dimetylformamid (100 ml) ble oppvarmet 90 min0ved 97°C. Losningen ble avkjolt og deretter helt på knust is (300 g). Det resulterende faste 3-nitro-4-(n-hexadecanamido)benzoic acid used as starting material was prepared as follows: A solution of 4-amino-3-nitrobenzoic acid (18.2 g) and n-hexa-. decanoyl chloride (33.0 g) in dry dimethylformamide (100 mL) was heated for 90 min at 97°C. The solution was cooled and then poured onto crushed ice (300 g). The resulting fast
stoff ble oppsamlet, vasket med vann (3 x 100 ml), torket og omkrystallisert fra en blanding av aceton og vann (5:1) .(under behandling med aktivt karbon), hvilket ga 3-nitro-4-(n-heksadekanamido)benzosyre (31,7 g) i form av et lysegult faststoff, smp. 153 - 154°C. material was collected, washed with water (3 x 100 mL), dried and recrystallized from a mixture of acetone and water (5:1) (under treatment with activated carbon) to give 3-nitro-4-(n-hexadecanamido )benzoic acid (31.7 g) in the form of a pale yellow solid, m.p. 153 - 154°C.
E KSEMPEL 23 Forbindelse V E XAMPLE 23 Compound V
Ved å gå frem på lignende måte som forut beskrevet i eksempel 16 for fremstilling av 4-amino-3-(n-nonadekanamido)-benzosyre, men erstatning av n-nonadekanoylklorid med n-oktanoylklorid fremstilte man 4-amino-3-(n-oktanamido)benzosyre i form av et gråhvitt faststoff, smp. 202 - 203°C etter omkrystallisering fra metanol, By proceeding in a similar manner to that previously described in example 16 for the production of 4-amino-3-(n-nonadecanamido)-benzoic acid, but replacing n-nonadecanoyl chloride with n-octanoyl chloride, 4-amino-3-(n -octanamido)benzoic acid in the form of a grey-white solid, m.p. 202 - 203°C after recrystallization from methanol,
EKSEMPEL 2 4 Forbindelse W EXAMPLE 2 4 Compound W
Ved å gå frem på lignende måte som forut beskrevet i eksempel 16 for fremstilling av 4-amino-3-(n-nonadekanamido)-benzosyre, men erstatte n-nonadekanoylklorid med n-dodekanoylklorid fremstilte man 4-amino-3-(n-dodekanamido)-benzosyre i form av et hvitt faststoff, smp. 183 - 185°C. By proceeding in a similar manner as previously described in example 16 for the production of 4-amino-3-(n-nonadecanamido)-benzoic acid, but replacing n-nonadecanoyl chloride with n-dodecanoyl chloride, 4-amino-3-(n- dodecanamido)-benzoic acid in the form of a white solid, m.p. 183 - 185°C.
EKSEMPEL 25 • EXAMPLE 25 •
Forbindelse X Compound X
Ved å gå frem på lignende måte som forut beskrevet i eksempel 16 for fremstilling av 4-amino-3-(n-nonadekanamido)-benzosyre, men erstatte n-nonadekanoylklorid med n-oktadekanoylklorid fremstilte man 4-amino-3-(n-oktadekanamido)-benzosyre i form av et lysebrunt faststoff, smp. 185 - 187°C etter omkrystallisering fra metyletylketon. By proceeding in a similar manner as previously described in example 16 for the preparation of 4-amino-3-(n-nonadecanamido)-benzoic acid, but replacing n-nonadecanoyl chloride with n-octadecanoyl chloride, 4-amino-3-(n- octadecanamido)-benzoic acid in the form of a light brown solid, m.p. 185 - 187°C after recrystallization from methyl ethyl ketone.
EKSEMPEL 26EXAMPLE 26
Forbindelse YCompound Y
. En losning av metyl 3,4-diaminobenzoat (83,1 g) i torr dimetylformamid (900 ml) inneholdende trietylamin (50,8 g) ble behandlet dråpevis med n-oktanoylklorid (81,3 g) i 30 min. ved en temperatur mellom 5 og 8°C. Blandingen . A solution of methyl 3,4-diaminobenzoate (83.1 g) in dry dimethylformamide (900 ml) containing triethylamine (50.8 g) was treated dropwise with n-octanoyl chloride (81.3 g) over 30 min. at a temperature between 5 and 8°C. The mixture
ble rort i ytterligere '2 timer. Det faste stoff ble fjer-was rowed for another '2 hours. The solid was removed
. net ved filtrering og. filtratet ble helt i vann (8000 ml). Det resulterende faste stoff ble oppsamlet og omkrystallisert 2 ganger fra metanol, hvilket ga metyl 4-amino-3-(n-oktanamido)benzoat (65,5 g) i form av et hvitt faststoff, smp. 120°C. . net by filtering and. the filtrate was poured into water (8000 ml). The resulting solid was collected and recrystallized twice from methanol to give methyl 4-amino-3-(n-octanamido)benzoate (65.5 g) as a white solid, m.p. 120°C.
EKSEMPEL 27'EXAMPLE 27'
Forbindelse BCompound B
Ved å gå frem på lignende måte som forut beskrevet i eksempel 26 for fremstilling av metyl 4-amino-3-(n-oktanamido)-benzoat, men erstatte n-oktanoylklorid med n-dodekanoylklorid, fremstilte man metyl 4-amino-3-(n-dodekanamido)-benzoat i form av et gråhvitt faststoff,smp. 102 - 105°C etter omkrystallisering fra metanol. By proceeding in a similar manner to that previously described in example 26 for the preparation of methyl 4-amino-3-(n-octanamido)-benzoate, but replacing n-octanoyl chloride with n-dodecanoyl chloride, methyl 4-amino-3- (n-dodecanamido)-benzoate in the form of an off-white solid, m.p. 102 - 105°C after recrystallization from methanol.
EKSEMPEL 28EXAMPLE 28
Forbindelse DCompound D
Ved å gå frem på lignende måte som forut beskrevet i eksempel 26 for fremstilling av metyl 4-amino-3-(n-oktan-amido) benzoat, men erstatte n-oktanoylklorid med n-tridekanoylklorid fremstilte man metyl 4-amino-3-(n-tridekanami-do)benzoat i form av et lysebrunt faststoff, smp. 101 - 104°C etter omkrystallisering fra metanol. By proceeding in a similar manner to that previously described in example 26 for the production of methyl 4-amino-3-(n-octane-amido) benzoate, but replacing n-octanoyl chloride with n-tridecanoyl chloride, methyl 4-amino-3- (n-tridecanami-do)benzoate in the form of a light brown solid, m.p. 101 - 104°C after recrystallization from methanol.
EKSEMPEL 29EXAMPLE 29
Forbindelse CCompound C
Ved å gå frem på lignende måte som forut beskrevet i eksempel 26 for fremstilling av metyl 4-amino-3-(n-oktanamido)-benzoat, men erstatte n-oktanoylklorid med n-tetradekanoyl- . klorid, fremstilte man metyl 4-amino-3-(n-tetradekanamido)-benzoat i form-av et lysebrunt faststoff, smp. 108 - 109°C etter.omkrystallisering fra metanol. By proceeding in a similar manner as previously described in example 26 for the preparation of methyl 4-amino-3-(n-octanamido)-benzoate, but replacing n-octanoyl chloride with n-tetradecanoyl-. chloride, methyl 4-amino-3-(n-tetradecanamido)-benzoate was prepared in the form of a light brown solid, m.p. 108 - 109°C after recrystallization from methanol.
EKSEMPEL 30EXAMPLE 30
Forbindelse ACompound A
Ved å gå frem på lignende måte som forut beskrevet i eksempel 26 for fremstilling av metyl 4-amino-3-(n-oktanamido)-benzoat,men erstatte n-oktanoylklorid med n-heksadekanoylklorid, fremstilte man metyl 4-amino-3-(n-heksadekanamido)-benzoat i form av et hvitt faststoff, smp. 109 - 110°C By proceeding in a similar manner as previously described in example 26 for the production of methyl 4-amino-3-(n-octanamido)-benzoate, but replacing n-octanoyl chloride with n-hexadecanoyl chloride, methyl 4-amino-3- (n-hexadecanamido)-benzoate in the form of a white solid, m.p. 109 - 110°C
etter omkrystallisering fra metanol.after recrystallization from methanol.
E KSEMPEL 31 Forbindelse F E XAMPLE 31 Compound F
: En omrort losning av metyl 3, 4-diaminobenzoat (5 g) i tort dime/tylformamid (50 ml) inneholdende trietylamin (6,1 g) : A stirred solution of methyl 3,4-diaminobenzoate (5 g) in dry dimethylformamide (50 ml) containing triethylamine (6.1 g)
ble behandlet dråpevis med en losning av n-heksadekanoylklorid (16,54 g) i tort dimetylformamid (40 ml) i 5 min.. Temperaturen fikk stige fra 20 - 50°C. Blandingen ble rort was treated dropwise with a solution of n-hexadecanoyl chloride (16.54 g) in dry dimethylformamide (40 ml) for 5 min. The temperature was allowed to rise from 20 - 50°C. The mixture was stirred
i ytterligere 3 timer. Den resulterende oppslemming ble helt i'vann (800 ml) inneholdende saltsyre (10 ml, 36,5% vekt/volum). Det resulterende faste stoff ble oppsamlet og omkrystallisert fra en blanding av kloroform og aceton (1:1), hvilket ga metyl 3,4-bis(n-heksadekanamido)benzoat (12,1 g). i form av et hvitt faststoff, smp. 129 - 132°C, hvilket er identisk med produktet fra eksempel 6. for another 3 hours. The resulting slurry was poured into water (800 mL) containing hydrochloric acid (10 mL, 36.5% w/v). The resulting solid was collected and recrystallized from a mixture of chloroform and acetone (1:1) to give methyl 3,4-bis(n-hexadecanamido)benzoate (12.1 g). in the form of a white solid, m.p. 129 - 132°C, which is identical to the product from example 6.
E KSEMPEL 32 Forbindelse 1" E XAMPLE 32 Connection 1"
Ved å gå frem på lignende måte som forut beskrevet i eksempel 31 for fremstilling av metyl 3,4-bis(n-heksadekanamido) - benzoat, men erstatte n-heksadekanoylklorid med n-oktanoyl- . klorid fikk man metyl 3,4-bis(n-oktanamido)benzoat i form By proceeding in a similar manner as previously described in example 31 for the production of methyl 3,4-bis(n-hexadecanamido)-benzoate, but replacing n-hexadecanoyl chloride with n-octanoyl-. chloride gave methyl 3,4-bis(n-octanamido)benzoate in the form
av et hvitt faststoff, smp. 145 - 147°C etter omkrystalli- ' sering fra aceton. of a white solid, m.p. 145 - 147°C after recrystallization from acetone.
EKSEMPEL 33EXAMPLE 33
Forbindelse ZCompound Z
Ved å gå frem på lignende måte som forut beskrevet i eksempel 31 for fremstilling av metyl 3,4-bis(n-heksadekanamido)-benzoat, men erstatte n-heksadekanoylklorid med n-dodekanoylklorid fikk man metyl 3,4-bis(n-dodekanamido)benzoat i form av et gråhvitt faststoff, smp. 129 - 131°C etter omkrystallisering fra aceton. By proceeding in a similar manner as previously described in example 31 for the production of methyl 3,4-bis(n-hexadecanamido)-benzoate, but replacing n-hexadecanoyl chloride with n-dodecanoyl chloride, methyl 3,4-bis(n- dodecanamido)benzoate in the form of an off-white solid, m.p. 129 - 131°C after recrystallization from acetone.
EKSEMPEL 34EXAMPLE 34
, Forbindelse AA, Connection AA
Ved å. gå frem på lignende måte som forut beskrevet i eksempel 31 for fremstilling av metyl 3,4-bis(n-heksadekanamido)-benzoat, men erstatte n-heksadekanoylklorid med n-tridekanoylklorid fikk man metyl 3,4-bis(n-tridekanamido)benzoat i form av et hvitt faststoff, smp. 132 - 134°C etter omkrystallisering fra aceton. By proceeding in a similar manner to that previously described in example 31 for the preparation of methyl 3,4-bis(n-hexadecanamido)-benzoate, but replacing n-hexadecanoyl chloride with n-tridecanoyl chloride, methyl 3,4-bis(n -tridecanamido)benzoate in the form of a white solid, m.p. 132 - 134°C after recrystallization from acetone.
EKSEMPEL 35EXAMPLE 35
Forbindelse BBConnection BB
Ved å gå frem på lignende måte som forut beskrevet i eksempel 31 for fremstilling av metyl 3, 4-bis (Yi-heksadekanamido)-benzoat, men erstatte n-heksadekanoylklorid med ri-tetradekanoylklorid fikk man metyl 3,4-bis(n-tetradekanamido)benzoat i form av et hvitt faststoff, smp. 132 - 133°C etter omkrystallisering fra aceton. By proceeding in a similar manner to that previously described in example 31 for the production of methyl 3,4-bis(Yi-hexadecanamido)-benzoate, but replacing n-hexadecanoyl chloride with ri-tetradecanoyl chloride, methyl 3,4-bis(n- tetradecanamido)benzoate in the form of a white solid, m.p. 132 - 133°C after recrystallization from acetone.
EKSEMPEL. 36EXAMPLE. 36
Forbindelse CCConnection CC
Ved å gå frem på lignende måte som forut beskrevet i eksempel 31 for fremstilling av metyl 3,4-bis(n-heksadekanamido)-benzoat, men erstatte n-heksadekanoylklorid med n-oktadekanoylklorid, fikk man metyl 3,4-bis(n-oktadekanamido)benzoat i form av et hvitt faststoff, sm<p>. 120°C etter omkrystallisering fra en blanding av aceton og metanol (1:1)c By proceeding in a similar manner as previously described in example 31 for the preparation of methyl 3,4-bis(n-hexadecanamido)-benzoate, but replacing n-hexadecanoyl chloride with n-octadecanoyl chloride, methyl 3,4-bis(n -octadecanamido)benzoate in the form of a white solid, sm<p>. 120°C after recrystallization from a mixture of acetone and methanol (1:1)c
EKSEMPEL 37 Forbindelse DD EXAMPLE 37 Compound DD
3-amino-4-(n-oktanamido)benzosyre (12,1 g) i metanol (200 ml) ble behandlet med eterisk diazometan inntil reaksjonen var fullstendig (som vist ved tynnsjiktskromatografi på kisel-gel ved bruk av metanol: kloroform: iseddik , 10:90:0,5). Eddiksyre (0,2 ml) ble så tilsatt og reaksjonsblandingen konsentrert under redusert trykk. Det resulterende faste stoff ble omkrystallisert fra etylacetat, hvilket ga metyl-3-amino-4-(n-oktanamido)benzoat (9,2 g) i form av et kremfarget faststoff, smp. 128 - 131°C. 3-Amino-4-(n-octanamido)benzoic acid (12.1 g) in methanol (200 mL) was treated with ethereal diazomethane until the reaction was complete (as shown by thin layer chromatography on silica gel using methanol:chloroform:glacial acetic acid , 10:90:0.5). Acetic acid (0.2 mL) was then added and the reaction mixture concentrated under reduced pressure. The resulting solid was recrystallized from ethyl acetate to give methyl 3-amino-4-(n-octanamido)benzoate (9.2 g) as a cream solid, m.p. 128 - 131°C.
EKSEMPEL 38 Forbindelse EE EXAMPLE 38 Compound EE
3- nitro-4-(n-oktanamido)benzosyre (25 g) opplost i etanol (500 ml) ved 50°C ble hydrogenert ved rysting i nærvær av 5% vekt/vekt palladium på karbon (2,5 g) ved 50°C og atmos-.færetrykk i 3 timer. Blandingen ble filtrert varmt og. filtratet ble inndampet i vakuum. Resten, ble omkrystallisert fra en blanding av etanol og vann (1:1) og ga 3-amino-4- (n-oktanamido)benzosyre (8 g) i fprm av et gult faststoff, smp. 155 - 156°C. 3-nitro-4-(n-octanamido)benzoic acid (25 g) dissolved in ethanol (500 mL) at 50°C was hydrogenated with shaking in the presence of 5% w/w palladium on carbon (2.5 g) at 50 °C and atmospheric pressure for 3 hours. The mixture was filtered hot and. the filtrate was evaporated in vacuo. The residue was recrystallized from a mixture of ethanol and water (1:1) to give 3-amino-4-(n-octanamido)benzoic acid (8 g) in fprm as a yellow solid, m.p. 155 - 156°C.
3-nitro-4-(n-oktanamido)benzosyre som ble brukt som utgangsmateriale ble fremstilt som folger: En losning av 4-amino-3~nitrobenzosyre (18,2 g) og n-oktanoylklorid (19,4 g) i tort dimetylformamid (100 ml) ble behandlet 90 min. ved 97°C. Losningen ble avkjolt og helt på is (300 g). Det resulterende faste stoff ble oppsamlet og vasket med vann (3 x 100 ml), torket og omkrystallisert fra en blanding av metanol og vann (8:1) (under behandling med aktivt karbon), hvilket ga 3-nitro-4-(n-oktanamido)-benzosyre (22 g) i form av et lysegult faststoff, smp„ 3-nitro-4-(n-octanamido)benzoic acid used as starting material was prepared as follows: A solution of 4-amino-3-nitrobenzoic acid (18.2 g) and n-octanoyl chloride (19.4 g) in tort dimethylformamide (100 ml) was treated for 90 min. at 97°C. The solution was cooled and poured onto ice (300 g). The resulting solid was collected and washed with water (3 x 100 mL), dried and recrystallized from a mixture of methanol and water (8:1) (under activated carbon treatment) to give 3-nitro-4-(n -octanamido)-benzoic acid (22 g) in the form of a pale yellow solid, m.p.
153-- 154°C. 153--154°C.
EKSEMPEL 39EXAMPLE 39
Forbindelse FFConnection FF
3-nitro-4-(n-dodekanamido)benzosyre (21 g) opplost i etylacetat (500 ml) ble hydrogenert ved rysting i nærvær av 5% vekt/vekt palladium på karbon (2,5 g) ved 50°C og atmosfæretrykk. Den resulterende blanding ble filtrert varmt og ga et kremfarget faststoff etter kjoling. Dette produktet ble omkrystallisert fra metanol og ga 3-amino-4-(n-dodekanamido)benzosyre (7,4 g) som beigefarget faststoff, 3-Nitro-4-(n-dodecanamido)benzoic acid (21 g) dissolved in ethyl acetate (500 ml) was hydrogenated with shaking in the presence of 5% w/w palladium on carbon (2.5 g) at 50°C and atmospheric pressure . The resulting mixture was filtered hot and gave a cream colored solid after cooling. This product was recrystallized from methanol to give 3-amino-4-(n-dodecanamido)benzoic acid (7.4 g) as a beige solid,
smp. 158 - 160°C. m.p. 158 - 160°C.
EKSEMPEL 40 F orbindelse H EXAMPLE 40 Compound H
Ved å gå frem på lignende måte som beskrevet i eksempel 26By proceeding in a similar manner as described in example 26
for fremstillingen av metyl 4-amino-3-(n-oktanamido)benzoat, men erstatte n-oktanoylklorid med n-dekanoylklorid fikk man metyl 4-amino-3-(n-dekanamido)benzoat i form av et hvitt fast stoff, smp. 96 - 100°C. for the preparation of methyl 4-amino-3-(n-octanamido)benzoate, but replacing n-octanoyl chloride with n-decanoyl chloride gave methyl 4-amino-3-(n-decanamido)benzoate in the form of a white solid, m.p. . 96 - 100°C.
EKSEMPEL 41 Forbindelse GG _ EXAMPLE 41 Compound GG _
Ved å gå frem på lignende måte som forut beskrevet i eksempel 31 for fremstilling av metyl 3,4-bis (n-heksadekanamido).-benzoat, men erstatte n-heksadekanoylklorid med n-dekanoylklorid fikk man metyl 3,4-bis(n-dekanamido)benzoat i form av et hvitt fast stoff, smp. 139 - 141°C etter omkrystalli- By proceeding in a similar manner as previously described in example 31 for the production of methyl 3,4-bis (n-hexadecanamido)-benzoate, but replacing n-hexadecanoyl chloride with n-decanoyl chloride, methyl 3,4-bis(n -decanamido)benzoate in the form of a white solid, m.p. 139 - 141°C after recrystallization
sering fra etanol.sering from ethanol.
EKSEMPEL 42EXAMPLE 42
Forbindelse HHConnection HH
En omrort losning av 3,4-diaminobenzosyre (10 g) i tort dimetylformamid (100 ml) inneholdende kaliumkarbonat (28 g) ble.behandlet dråpevis med en losning av n-dodekanoylklorid (33,1 g) i tort dimetylformamid (30 ml) i 5 min.. Temperaturen fikk stige fra 20 - 50°C. Blandingen ble rort ytterligere 3 timer. Den resulterende suspensjon ble filtrert og filtratet helt i vann (700 ml) inneholdende saltsyre (10 ml, 36,5 % vekt/volum)„ Det resulterende faste stoff ble oppsamlet og omkrystallisert fra iseddik, produktet ble så vasket med vann og omkrystallisert fra metyletylketon, hvilket ga 3,4-bis(n-dodekanamido)benzosyre (12,5 g) i form av et hvitt fast stoff, smp. 195 197°C. A stirred solution of 3,4-diaminobenzoic acid (10 g) in dry dimethylformamide (100 ml) containing potassium carbonate (28 g) was treated dropwise with a solution of n-dodecanoyl chloride (33.1 g) in dry dimethylformamide (30 ml) for 5 min. The temperature was allowed to rise from 20 - 50°C. The mixture was stirred for a further 3 hours. The resulting suspension was filtered and the filtrate poured into water (700 mL) containing hydrochloric acid (10 mL, 36.5% w/v)„ The resulting solid was collected and recrystallized from glacial acetic acid, the product was then washed with water and recrystallized from methyl ethyl ketone , which gave 3,4-bis(n-dodecanamido)benzoic acid (12.5 g) as a white solid, m.p. 195 197°C.
EKSEMPEL 43EXAMPLE 43
Forbindelse EConnection E
Ved å gå frem på lignende måte som forut beskrevet i eksempel 42 for fremstilling av 3,4-bis(n-dodekanamido)benzosyre, men erstatte n-dodekanoylklorid med n-heksadekanoylklorid og kaliumkarbonat med natriumkarbonat fikk man 3,4-bis(n-heksadekanamido)benzosyre i form av et hvitt fast stoff, smp.. 198 - 202°C etter påfolgende omkrystallisering fra iseddik og metyletylketon. By proceeding in a similar manner as previously described in example 42 for the preparation of 3,4-bis(n-dodecanamido)benzoic acid, but replacing n-dodecanoyl chloride with n-hexadecanoyl chloride and potassium carbonate with sodium carbonate, 3,4-bis(n -hexadecanamido)benzoic acid in the form of a white solid, m.p. 198 - 202°C after subsequent recrystallization from glacial acetic acid and methyl ethyl ketone.
EKSEMPEL 44EXAMPLE 44
Forbindelse IIConnection II
Ved å.gå frem på lignende måte som forut beskrevet i eksempel 42 for fremstilling av 3,4-bis(n-dodekanamido)benzosyre, men- erstatte n-dodekanoylklorid med n-oktanoylklorid fikk man 3,4-bis(n-oktanamido)benzosyre i form av et hvitt fast stoff, smp. 195 - 197°C etter påfolgende omkrystallisering fra iseddik og metyletylketon. • By proceeding in a similar manner as previously described in example 42 for the preparation of 3,4-bis(n-dodecanamido)benzoic acid, but replacing n-dodecanoyl chloride with n-octanoyl chloride, 3,4-bis(n-octanamido )benzoic acid in the form of a white solid, m.p. 195 - 197°C after subsequent recrystallization from glacial acetic acid and methyl ethyl ketone. •
EKSEMPEL 45EXAMPLE 45
. Forbindelse JJ. Connection JJ
Ved å gå frem på lignende måte som forut beskrevet i eksempel 42 for fremstilling av 3,4-bis(n-dodekanamido)benzosyre, men erstatte n-dodekanoylklorid med n-tetradekanoylklorid,. fikk man 3,4-bis(n-tetradekanamido)benzosyre i form av et hvitt fast stoff, smp. 201 - 206°C etter' påfolgende omkrystallisering fra iseddik og metyletylketon. By proceeding in a similar manner as previously described in example 42 for the production of 3,4-bis(n-dodecanamido)benzoic acid, but replacing n-dodecanoyl chloride with n-tetradecanoyl chloride. 3,4-bis(n-tetradecanamido)benzoic acid was obtained in the form of a white solid, m.p. 201 - 206°C after subsequent recrystallization from glacial acetic acid and methyl ethyl ketone.
E KSEMPEL 46 Forbindelse KK E XAMPLE 46 Connection KK
Metyl 4-(n-dodekanamido) — 3-nitrobenzoat (21 g) opplost iMethyl 4-(n-dodecanamido) — 3-nitrobenzoate (21 g) dissolved in
varm etylacetat (500 ml) (50 - 55°C) ble hydrogenert.ved rysting i nærvær av 5% vekt/vekt palladium på karbon (2,0 g) ved 60°C og atmosfæretrykk i 2 timer. Blandingen ble filtrert varmt og filtratet fikk kjolne. Det fast stoff ble oppsamlet og ga metyl 3-amino-4-(n-dodekanamido)benzoat (14,1 g) i form av et hvitt fast stoff, smp. 134 - 137°C0 hot ethyl acetate (500 ml) (50-55°C) was hydrogenated with shaking in the presence of 5% w/w palladium on carbon (2.0 g) at 60°C and atmospheric pressure for 2 hours. The mixture was filtered hot and the filtrate was allowed to settle. The solid was collected to give methyl 3-amino-4-(n-dodecanamido)benzoate (14.1 g) as a white solid, m.p. 134 - 137°C0
Metyl 4-(n-dodekanamido)-3-nitrobenzoatet som ble brukt som utgangsmateriale ble fremstilt som folger: Metyl 4-amino-3-nitrobenzoat (19,6 g) og n-dodekanoylklorid (23 g) i dimetylformamid (100 ml) ble oppvarmet 2 1/2 time ved 97°C under leilighetsvis rysting. Den restulerende losning ble helt på knust is (300 g) og det faste stoff oppsamlet og omkrystallisert fra én blanding av metanol og kloroform (5:1), hvilket ga metyl 4-(n-dodekanamido)-3-nitrobenzoat (31 g) i form av et gult fast stoff, smp. 78 - 80°C. The methyl 4-(n-dodecanamido)-3-nitrobenzoate used as starting material was prepared as follows: Methyl 4-amino-3-nitrobenzoate (19.6 g) and n-dodecanoyl chloride (23 g) in dimethylformamide (100 ml) was heated for 2 1/2 hours at 97°C with occasional shaking. The residual solution was poured onto crushed ice (300 g) and the solid collected and recrystallized from a mixture of methanol and chloroform (5:1) to give methyl 4-(n-dodecanamido)-3-nitrobenzoate (31 g) in the form of a yellow solid, m.p. 78 - 80°C.
Metyl 4-amino-3-nitrobenzoatet ble fremstilt som folger: 4-aminor3-nitrobenzosyre (70 g) ble satt til en losning av ' vannfritt hydrogenklorid i metanol [fremstilt fra acetyl-klorid (78 g) og torr metanol (300 ml)]. Den resulterende blanding ble tilbakelopskokt 10 timer, avkjolt i is og det faste stoff oppsamlet, hvilket ga metyl 4-amino-3-nitrobenzoat (62 g) i form av et gult fast stoff, smp. 193 - 195°C. " The methyl 4-amino-3-nitrobenzoate was prepared as follows: 4-amino-3-nitrobenzoic acid (70 g) was added to a solution of anhydrous hydrogen chloride in methanol [prepared from acetyl chloride (78 g) and dry methanol (300 ml) ]. The resulting mixture was refluxed 10 hours, cooled in ice and the solid collected to give methyl 4-amino-3-nitrobenzoate (62 g) as a yellow solid, m.p. 193 - 195°C. "
EKSEMPEL 47 Forbindelse LL EXAMPLE 47 Compound LL
Ved å gå frem på lignende måte som forut beskrevet i eksempel 46 for fremstillingen av metyl 3~amino-4-(n-do-:dekanamido)benzoat, men erstatte metyl 4-(n-dodekanamido)-3-nitrobenzoat med metyl 4-(n-heksadekanamido)-3-nitroben-. zoat fikk man metyl 3-amino-4-(n-heksadekanamido)benzoat i form av et hvitt fast stoff, smp. 135 - 137°C. By proceeding in a similar manner as previously described in example 46 for the preparation of methyl 3~amino-4-(n-do-:decanamido)benzoate, but replacing methyl 4-(n-dodecanamido)-3-nitrobenzoate with methyl 4 -(n-hexadecanamido)-3-nitrobene-. zoat gave methyl 3-amino-4-(n-hexadecanamido)benzoate in the form of a white solid, m.p. 135 - 137°C.
EKSEMPEL 48 EXAMPLE 48
Forbindelse MMConnection MM
Ved å gå frem på lignende måte som forut beskrevet.i eksempel 46 for fremstilling av metyl 3-amino-4-(n-dodekanamido)-benzoat, men erstatte metyl 4- (n-±x3ekanamido)-3-nitrobenzoat med metyl 4-(n-dekanamido)-3-nitrobenzoat, fikk man metyl 3-amino-4-(n-dekanamido)benzoat i form av et hvitt faststoff., smp. 131 - 133°C. By proceeding in a similar manner as previously described in Example 46 for the preparation of methyl 3-amino-4-(n-dodecanamido)-benzoate, but replacing methyl 4-(n-±x3ecanamido)-3-nitrobenzoate with methyl 4 -(n-decanamido)-3-nitrobenzoate, methyl 3-amino-4-(n-decanamido)benzoate was obtained in the form of a white solid, m.p. 131 - 133°C.
EKSEMPEL 49EXAMPLE 49
Forbindelse NNConnection NN
En omrort losning av 3,4-diaminobenzosyre (8,4 g) i tort dimetylformamid (100 imi) inneholdende kaliumkarbonat (15,-27- g) ble behandlet dråpevis med en losning av n-heksadekanoylklorid (15,17 g) i tort dimetylformamid (30 ml) i A stirred solution of 3,4-diaminobenzoic acid (8.4 g) in dry dimethylformamide (100 ml) containing potassium carbonate (15.27 g) was treated dropwise with a solution of n-hexadecanoyl chloride (15.17 g) in dry dimethylformamide (30 mL) i
30 min. ved O - 5°C. Blandingen ble rort ytterligere 2 30 min. at 0 - 5°C. The mixture was stirred a further 2
timer ved 0 - 5°C og fikk oppvarmes til romtemperatur ihours at 0 - 5°C and allowed to warm to room temperature i
30 min..30 min..
Losningen ble så helt i vann (700 ml) inneholdende saltsyre (10 ml, 36,5% vekt/volum). Det faste stoff ble oppsamlet, oppvarmet med aceton (300 ml) ved 5o°C og orakrystal- lisert fra metyletylketon, hvilket ga 4-amino-3-(n-heksade-kanamido) benzosyre (9,4 g) i form av et hvitt faststoff, smp. 197 - 199°C. The solution was then poured into water (700 ml) containing hydrochloric acid (10 ml, 36.5% w/v). The solid was collected, heated with acetone (300 mL) at 50°C and recrystallized from methyl ethyl ketone to give 4-amino-3-(n-hexadecanamido)benzoic acid (9.4 g) as a white solid, m.p. 197 - 199°C.
EKSEMPEL 50EXAMPLE 50
Forbindelse 00Connection 00
Ved å gå frem på lignende måte som forut beskrevet i eksempel 42 for fremstilling av 3,4-bis(n-dodekanamido)benzosyre, men erstatte n-dodekanoylklorid med n-dekanoylklorid, fremstilte man 3,4-bis(n-dekanamido)benzosyre i form av et hvitt faststoff, smp. 194 - 196°C etter påfolgende omkrystalli- ■ sering fra iseddik og metyletylketon. By proceeding in a similar manner as previously described in example 42 for the preparation of 3,4-bis(n-dodecanamido)benzoic acid, but replacing n-dodecanoyl chloride with n-decanoyl chloride, 3,4-bis(n-decanamido) was prepared benzoic acid in the form of a white solid, m.p. 194 - 196°C after subsequent recrystallization ■ from glacial acetic acid and methyl ethyl ketone.
EKSEMPEL 51EXAMPLE 51
Forbindelse PPConnection PP
Ved å gå frem på lignende måte som forut beskrevet i ekserru-pel 42 for fremstilling av 3,4-bis'(n-dodekanamido) benzosyre, men erstatte.n-dodekanoylklorid med n-tridekanoylklorid fikk man 3,4-bis(n-tridekanamido)benzosyre i form av et gråhvitt faststoff,'smp. 192 - 194°C etter påfolgende omkrystallisering fra iseddik og metyletylketon. By proceeding in a similar manner to that previously described in example 42 for the preparation of 3,4-bis'(n-dodecanamido)benzoic acid, but replacing n-dodecanoyl chloride with n-tridecanoyl chloride, 3,4-bis(n -tridecanamido)benzoic acid in the form of a grey-white solid, m.p. 192 - 194°C after subsequent recrystallization from glacial acetic acid and methyl ethyl ketone.
EKSEMPEL 52EXAMPLE 52
Forbindelse QQConnection QQ
Ved å gå frem på folgende måte som beskrevet i eksempel 42 for fremstilling av 3,4-bis(n-dodekanamido)benzosyre, men erstatte n-dodekanoylklorid med n-oktadekanoylklorid f ikk man 3,'4-bis (n-oktadekanamido) benzosyre i form av et hvitt faststoff, smp. 193 - 196°C etter påfolgende omkrystallisering fra iseddik og metyletylketon.. By proceeding in the following manner as described in example 42 for the preparation of 3,4-bis(n-dodecanamido)benzoic acid, but replacing n-dodecanoyl chloride with n-octadecanoyl chloride, 3,4-bis (n-octadecanamido) was obtained benzoic acid in the form of a white solid, m.p. 193 - 196°C after subsequent recrystallization from glacial acetic acid and methyl ethyl ketone..
EKSEMPEL 53EXAMPLE 53
Forbindelse RRConnection RR
En losning av 2,3-diaminobenzosyre (40 g) i dimetylformamid (600 ml) inneholdende trietylamin (79,7 g, ,109,5 ml), ble behandlet med n-heksadekanoylklorid (144,5 g). Tilsetningshastigheten var slik at temperaturen i reaksjonsblandingen steg- fra romtemperatur til 45 - 50°C. Blandingen ble så rort ytterligere 3 timer og fikk stå ved romtemperatur natten over. Den resulterende blanding ble satt til vann' A solution of 2,3-diaminobenzoic acid (40 g) in dimethylformamide (600 ml) containing triethylamine (79.7 g, 109.5 ml) was treated with n-hexadecanoyl chloride (144.5 g). The rate of addition was such that the temperature in the reaction mixture rose from room temperature to 45 - 50°C. The mixture was then stirred for a further 3 hours and allowed to stand at room temperature overnight. The resulting mixture was added to water'
(1200. ml) inneholdende konsentrert saltsyre (50 ml, med styrke 36,5% vekt/volum) og det resulterende faste stoff ble oppsamlet og vasket med vann (1200 ml). Det faste stoff ble rort med varmt vann (4000 ml, 65°C) i 30 min0. og ble oppsamlet og torket ved 70° C i vakuum, hvilket ga 2,3-bis(n-heksadekanamido)benzosyre. (1200 mL) containing concentrated hydrochloric acid (50 mL, strength 36.5% w/v) and the resulting solid was collected and washed with water (1200 mL). The solid was stirred with hot water (4000 ml, 65°C) for 30 min. and was collected and dried at 70° C. in vacuo to give 2,3-bis(n-hexadecanamido)benzoic acid.
EKSEMPEL 54EXAMPLE 54
F orbindelse SSConnection SS
Ved å.gå frem på lignende måte som forut beskrevet i eksempel 26 for fremstilling av metyl 4-amino-3-(n-oktanamido)-benzoat, men erstatte n-oktanoylklorid med n-heptanoylklo-rid fikk man metyl 4-amino-3-(n-heptariamido)benzoat i form By proceeding in a similar manner as previously described in example 26 for the preparation of methyl 4-amino-3-(n-octanamido)-benzoate, but replacing n-octanoyl chloride with n-heptanoyl chloride, methyl 4-amino- 3-(n-heptariamido)benzoate in form
o o
av et lysebrunt faststoff, smp. 103 - 106 C.of a light brown solid, m.p. 103 - 106 C.
Den foreliggende oppfinnelse omfatter også farmasøytiske blandinger som inneholder minst en av forbindelsene med den generelle formel I eller et farmasoytisk.fordragelig salt derav i forbindelse med et farmasoytisk fordragelig bære-eller overtrekksmiddel. I klinisk praksis kan forbindelsene The present invention also encompasses pharmaceutical mixtures containing at least one of the compounds of the general formula I or a pharmaceutically acceptable salt thereof in connection with a pharmaceutically acceptable carrier or coating agent. In clinical practice, the compounds can
ifolge foreliggende oppfinnelse gis parenteralt, men gis fortrinnsvis rektalt eller helst oralt. according to the present invention is given parenterally, but is preferably given rectally or preferably orally.
Faste blandinger for oral administrering innbefatter sammen-trykte tabletter, piller, pulvere og granulater. I slike faste blandinger blandes en eller flere av'de aktive forbindelser med minst et inert fortynningsmiddel såsom sti-velse,, sukker eller laktose. Blandingene, kan også omfatte, hvilket er normalt i praksis, ytterligere substanser bort-sett fra inerte fortynningsmidler, f.eks. smoremidler såsom magnesiumstearat. Solid compositions for oral administration include compressed tablets, pills, powders and granules. In such solid mixtures, one or more of the active compounds are mixed with at least one inert diluent such as starch, sugar or lactose. The mixtures can also include, which is normal in practice, further substances apart from inert diluents, e.g. lubricants such as magnesium stearate.
Flytende blandinger for oral administrering innbefatter far-masøytisk fordragelige emulsjoner, losninger, suspensjoner, . sirups og eliksirer som inneholder inerte fortynningsmidler som vanligvis brukes på området slik som vann og flytende parafin.. Ved siden av inerte fortynningsmidler kan slike blandinger inneholde hjelpestoffer såsom fukte- og suspen-sjonsmidler og søtningsstoffer, smaksstoffer, parfyme-rings- og preserveringsmidler. Blandingene ifolge oppfinnelsen for oral administrering innbefatter også kapsler av absorberbaré materialer såsom gelatin inneholdende en eller flere av de aktive substanser med eller uten tilsetning av fortynningsmidler eller eksipienter. Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, . syrups and elixirs that contain inert diluents that are usually used in the area such as water and liquid paraffin. In addition to inert diluents, such mixtures may contain auxiliaries such as wetting and suspending agents and sweeteners, flavourings, perfuming and preserving agents. The mixtures according to the invention for oral administration also include capsules of absorbable materials such as gelatin containing one or more of the active substances with or without the addition of diluents or excipients.
Preparatene ifolge oppfinnelsen for parenteral administrering omfatter sterile vandige, vandige-organiske og organiske losninger, suspensjoner og emulsjoner. Eksempler på organiske losningsmidler eller opp slemmingsmedia er propylen-glykol, polyetylenglykol, vegetabilske oljer såsom oliven-olje og injiserbare organiske estere såsom etyloleat. Disse blandingene kan også inneholde hjelpestoffer såsom stabili-serings-, preserverings-, fukte-, emulgerings- eller disper-sjonsmidler. De kan steriliseres, ved f .eks. filtrering gjennom et bakterie-stoppende filter, ved innforing av ste-rilisering smidler i blandingene, ved bestråling eller opp-varming. De kan også fremstilles i form av sterile faste blandinger som kan opploses i sterilt vann eller annet sterilt injiserbart medium umiddelbart for bruk. The preparations according to the invention for parenteral administration comprise sterile aqueous, aqueous-organic and organic solutions, suspensions and emulsions. Examples of organic solvents or slurry media are propylene glycol, polyethylene glycol, vegetable oils such as olive oil and injectable organic esters such as ethyl oleate. These mixtures may also contain auxiliaries such as stabilising, preserving, wetting, emulsifying or dispersing agents. They can be sterilized, by e.g. filtration through a bacteria-stopping filter, by introducing sterilizing agents into the mixtures, by irradiation or heating. They can also be produced in the form of sterile solid mixtures that can be dissolved in sterile water or other sterile injectable medium immediately for use.
Faste- blandinger for rektal administrering omfatter suppo-sitorier formulert i overensstemmelse med kjente metoder og som inneholder en eller flere av forbindelsene med formel. I eller et f arma soytisk f ordragelig salt derav.." Solid compositions for rectal administration include suppositories formulated in accordance with known methods and which contain one or more of the compounds of formula. In or a pharma soy tolerable salt thereof.."
Andelen av aktiv bestanddel i blandingene ifolge oppfin- neisen kan varieres, men det er nodvendig at den utgjor en slik andel at en riktig dosering oppnås. Det er åpenbart at flere enhetsdoseringsformer kan gis på omtrent samme tid. Den anvendte dose vil bli bestemt av legen.og avhenger av den onskede terapeutiske effekt, administreringsveien og varigheten av behandlingen og av pasientens tilstand. Hos voksne er dosene i alminnelighet mellom 0,1 og 50 mg/kg kroppsvekt pr. dag ved oral administrering, f.eks. som anti-atheroma-midler og i forbindelse kardiovaskulære sykdommer mellom 10 og 50 mg/kg kroppsvekt pr. dag ved oral administrering, og i behandling av arthritis og beslektede sykdommer mellom 0,1 og 10 mg/kg kroppsvekt pr. dag ved oral administrering. The proportion of active ingredient in the mixtures according to the invention can be varied, but it is necessary that it constitutes such a proportion that a correct dosage is achieved. It is obvious that several unit dosage forms can be given at about the same time. The dose used will be determined by the doctor and depends on the desired therapeutic effect, the route of administration and the duration of the treatment and on the patient's condition. In adults, the doses are generally between 0.1 and 50 mg/kg body weight per day by oral administration, e.g. as anti-atheroma agents and in connection with cardiovascular diseases between 10 and 50 mg/kg body weight per day by oral administration, and in the treatment of arthritis and related diseases between 0.1 and 10 mg/kg body weight per day by oral administration.
Det folgende eksempel illustrerer farmasoytiske blandinger, ifolge foreliggende oppfinnelse. The following example illustrates pharmaceutical mixtures according to the present invention.
EKSEMPEL 55EXAMPLE 55
Nr. 2 storrelse gelatinkapsler hver inneholdende:No. 2 size gelatin capsules each containing:
ble fremstilt ifolge den vanlige fremgangsmåte. was prepared according to the usual procedure.
Claims (7)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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GB7922011 | 1979-06-25 | ||
GB8013948 | 1980-04-28 |
Publications (1)
Publication Number | Publication Date |
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NO801876L true NO801876L (en) | 1980-12-29 |
Family
ID=26271953
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
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NO801876A NO801876L (en) | 1979-06-25 | 1980-06-23 | PROCEDURE FOR PREPARING ACYLAMINOBENZO ACID DERIVATIVES |
NO801875A NO801875L (en) | 1979-06-25 | 1980-06-23 | PROCEDURE FOR PREPARING BENZIMIDAZOLD DERIVATIVES |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO801875A NO801875L (en) | 1979-06-25 | 1980-06-23 | PROCEDURE FOR PREPARING BENZIMIDAZOLD DERIVATIVES |
Country Status (20)
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AT (1) | ATA328780A (en) |
AU (2) | AU5954680A (en) |
CA (1) | CA1141765A (en) |
DE (2) | DE3023432A1 (en) |
DK (2) | DK268080A (en) |
ES (2) | ES492693A0 (en) |
FI (2) | FI802008A (en) |
FR (2) | FR2459794A1 (en) |
GB (1) | GB2053912B (en) |
GR (2) | GR69291B (en) |
IL (2) | IL60378A0 (en) |
IT (2) | IT1131841B (en) |
LU (2) | LU82545A1 (en) |
NL (2) | NL8003628A (en) |
NO (2) | NO801876L (en) |
NZ (2) | NZ194123A (en) |
PH (1) | PH15713A (en) |
PT (2) | PT71445A (en) |
SE (2) | SE8004622L (en) |
YU (1) | YU163680A (en) |
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US5514676A (en) * | 1984-03-19 | 1996-05-07 | The Rockefeller University | Amino-benzoic acids and derivatives, and methods of use |
US5476849A (en) * | 1984-03-19 | 1995-12-19 | The Rockefeller University | Methods for glycosylation inhibition using amino-benzoic acids and derivatives |
US4716175A (en) * | 1987-02-24 | 1987-12-29 | Warner-Lambert Company | Saturated fatty acid amides as inhibitors of acyl-CoA:cholesterol acyltransferase |
GB2498922A (en) * | 2011-12-14 | 2013-08-07 | Madison Filter 981 Ltd | Antistatic link belt |
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Publication number | Priority date | Publication date | Assignee | Title |
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CH260770D (en) * | 1969-02-25 | |||
DE1948795A1 (en) * | 1969-09-26 | 1971-04-08 | Rhein Chemie Rheinau Gmbh | 4,5,6,7-Tetrahydrobenzimidazoles, process for their preparation and their use as corrosion inhibitors and anti-aging agents |
-
1980
- 1980-06-21 GR GR62276A patent/GR69291B/el unknown
- 1980-06-21 GR GR62277A patent/GR69292B/el unknown
- 1980-06-23 PH PH24182A patent/PH15713A/en unknown
- 1980-06-23 ES ES492693A patent/ES492693A0/en active Granted
- 1980-06-23 NZ NZ194123A patent/NZ194123A/en unknown
- 1980-06-23 SE SE8004622A patent/SE8004622L/en not_active Application Discontinuation
- 1980-06-23 GB GB8020548A patent/GB2053912B/en not_active Expired
- 1980-06-23 AU AU59546/80A patent/AU5954680A/en not_active Abandoned
- 1980-06-23 IL IL60378A patent/IL60378A0/en unknown
- 1980-06-23 PT PT71445A patent/PT71445A/en unknown
- 1980-06-23 AU AU59545/80A patent/AU5954580A/en not_active Abandoned
- 1980-06-23 FI FI802008A patent/FI802008A/en not_active Application Discontinuation
- 1980-06-23 IT IT22966/80A patent/IT1131841B/en active
- 1980-06-23 NO NO801876A patent/NO801876L/en unknown
- 1980-06-23 CA CA000354555A patent/CA1141765A/en not_active Expired
- 1980-06-23 DE DE19803023432 patent/DE3023432A1/en not_active Withdrawn
- 1980-06-23 NL NL8003628A patent/NL8003628A/en not_active Application Discontinuation
- 1980-06-23 SE SE8004621A patent/SE8004621L/en not_active Application Discontinuation
- 1980-06-23 FR FR8013846A patent/FR2459794A1/en not_active Withdrawn
- 1980-06-23 ES ES492692A patent/ES492692A0/en active Granted
- 1980-06-23 PT PT71444A patent/PT71444A/en unknown
- 1980-06-23 YU YU01636/80A patent/YU163680A/en unknown
- 1980-06-23 DK DK268080A patent/DK268080A/en not_active Application Discontinuation
- 1980-06-23 DK DK267880A patent/DK267880A/en not_active Application Discontinuation
- 1980-06-23 IL IL60379A patent/IL60379A0/en unknown
- 1980-06-23 NL NL8003627A patent/NL8003627A/en not_active Application Discontinuation
- 1980-06-23 FI FI802009A patent/FI802009A/en not_active Application Discontinuation
- 1980-06-23 FR FR8013845A patent/FR2459796A1/en not_active Withdrawn
- 1980-06-23 DE DE19803023433 patent/DE3023433A1/en not_active Withdrawn
- 1980-06-23 NO NO801875A patent/NO801875L/en unknown
- 1980-06-23 IT IT22965/80A patent/IT1197459B/en active
- 1980-06-23 NZ NZ194122A patent/NZ194122A/en unknown
- 1980-06-23 AT AT0328780A patent/ATA328780A/en not_active Application Discontinuation
- 1980-06-24 LU LU82545A patent/LU82545A1/en unknown
- 1980-06-24 LU LU82546A patent/LU82546A1/en unknown
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