NO801875L - PROCEDURE FOR PREPARING BENZIMIDAZOLD DERIVATIVES - Google Patents
PROCEDURE FOR PREPARING BENZIMIDAZOLD DERIVATIVESInfo
- Publication number
- NO801875L NO801875L NO801875A NO801875A NO801875L NO 801875 L NO801875 L NO 801875L NO 801875 A NO801875 A NO 801875A NO 801875 A NO801875 A NO 801875A NO 801875 L NO801875 L NO 801875L
- Authority
- NO
- Norway
- Prior art keywords
- benzimidazole
- methyl
- carboxylic acid
- carboxylate
- mixture
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 23
- 239000000203 mixture Substances 0.000 claims description 144
- 150000001875 compounds Chemical class 0.000 claims description 106
- -1 methyl 2-(n-heptyl)benzimidazole-5-carboxylate Chemical compound 0.000 claims description 41
- 150000003839 salts Chemical class 0.000 claims description 32
- 125000004432 carbon atom Chemical group C* 0.000 claims description 31
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 25
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 21
- 238000002360 preparation method Methods 0.000 claims description 21
- 238000010992 reflux Methods 0.000 claims description 18
- 125000000217 alkyl group Chemical group 0.000 claims description 16
- 239000002253 acid Substances 0.000 claims description 15
- 125000001424 substituent group Chemical group 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
- 239000003960 organic solvent Substances 0.000 claims description 11
- 239000011541 reaction mixture Substances 0.000 claims description 9
- 125000004423 acyloxy group Chemical group 0.000 claims description 8
- 125000003342 alkenyl group Chemical group 0.000 claims description 8
- 150000001556 benzimidazoles Chemical class 0.000 claims description 7
- COYPLDIXZODDDL-UHFFFAOYSA-N 3h-benzimidazole-5-carboxylic acid Chemical compound OC(=O)C1=CC=C2N=CNC2=C1 COYPLDIXZODDDL-UHFFFAOYSA-N 0.000 claims description 5
- 229940058303 antinematodal benzimidazole derivative Drugs 0.000 claims description 4
- SBQDVBVVATWUAF-UHFFFAOYSA-N 2-tridecan-7-yl-3H-benzimidazole-5-carboxylic acid Chemical compound CCCCCCC(CCCCCC)C=1NC2=C(N1)C=CC(=C2)C(=O)O SBQDVBVVATWUAF-UHFFFAOYSA-N 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 238000012546 transfer Methods 0.000 claims description 3
- SWSLUNUYJRKPMS-UHFFFAOYSA-N 2-pentadecyl-3h-benzimidazole-5-carboxylic acid Chemical compound C1=C(C(O)=O)C=C2NC(CCCCCCCCCCCCCCC)=NC2=C1 SWSLUNUYJRKPMS-UHFFFAOYSA-N 0.000 claims description 2
- ORVPLAVHXHCROP-UHFFFAOYSA-N 2-tridecan-3-yl-3H-benzimidazole-5-carboxylic acid Chemical compound CCC(CCCCCCCCCC)C=1NC2=C(N1)C=CC(=C2)C(=O)O ORVPLAVHXHCROP-UHFFFAOYSA-N 0.000 claims description 2
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical class [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 claims description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 2
- 239000011248 coating agent Substances 0.000 claims description 2
- 150000001879 copper Chemical class 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- QZTJWLFUDRRLCU-UHFFFAOYSA-N 2-tridecyl-3H-benzimidazole-5-carboxylic acid Chemical compound C(CCCCCCCCCCCC)C=1NC2=C(N1)C=CC(=C2)C(=O)O QZTJWLFUDRRLCU-UHFFFAOYSA-N 0.000 claims 2
- OQIQSTLJSLGHID-WNWIJWBNSA-N aflatoxin B1 Chemical compound C=1([C@@H]2C=CO[C@@H]2OC=1C=C(C1=2)OC)C=2OC(=O)C2=C1CCC2=O OQIQSTLJSLGHID-WNWIJWBNSA-N 0.000 claims 2
- VVQNAFBGAWCMLU-UHFFFAOYSA-N 1h-benzimidazole-4-carboxylic acid Chemical compound OC(=O)C1=CC=CC2=C1N=CN2 VVQNAFBGAWCMLU-UHFFFAOYSA-N 0.000 claims 1
- UUQJTYOJAAORQY-UHFFFAOYSA-N 2,2-dimethylpropanoyloxymethyl 2-pentadecyl-3H-benzimidazole-5-carboxylate Chemical compound C(CCCCCCCCCCCCCC)C=1NC2=C(N1)C=CC(=C2)C(=O)OCOC(C(C)(C)C)=O UUQJTYOJAAORQY-UHFFFAOYSA-N 0.000 claims 1
- NIHPGICHMPNPHW-UHFFFAOYSA-N 2,3-dihydroxypropyl 2-pentadecyl-3H-benzimidazole-5-carboxylate Chemical compound C(CCCCCCCCCCCCCC)C=1NC2=C(N1)C=CC(=C2)C(=O)OCC(CO)O NIHPGICHMPNPHW-UHFFFAOYSA-N 0.000 claims 1
- YETLXJLMQXGLHM-UHFFFAOYSA-N 2-decyl-3H-benzimidazole-5-carboxylic acid Chemical compound C(CCCCCCCCC)C=1NC2=C(N=1)C=CC(=C2)C(=O)O YETLXJLMQXGLHM-UHFFFAOYSA-N 0.000 claims 1
- QGFGLYOMJKJZIC-UHFFFAOYSA-N 2-dodecyl-1h-benzimidazole Chemical compound C1=CC=C2NC(CCCCCCCCCCCC)=NC2=C1 QGFGLYOMJKJZIC-UHFFFAOYSA-N 0.000 claims 1
- TVFUKKLDYCDOLF-UHFFFAOYSA-N 2-dodecyl-4-methyl-1h-benzimidazole Chemical compound C1=CC=C2NC(CCCCCCCCCCCC)=NC2=C1C TVFUKKLDYCDOLF-UHFFFAOYSA-N 0.000 claims 1
- ZIQWGKZMLONEBR-UHFFFAOYSA-N 2-heptadecyl-3H-benzimidazole-5-carboxylic acid Chemical compound C(CCCCCCCCCCCCCCCC)C=1NC2=C(N1)C=CC(=C2)C(=O)O ZIQWGKZMLONEBR-UHFFFAOYSA-N 0.000 claims 1
- NKZFTPGFPASHBV-UHFFFAOYSA-N 2-heptyl-3h-benzimidazole-5-carboxylic acid Chemical compound C1=C(C(O)=O)C=C2NC(CCCCCCC)=NC2=C1 NKZFTPGFPASHBV-UHFFFAOYSA-N 0.000 claims 1
- WFFOXZUCRUTSQP-UHFFFAOYSA-N 2-hexadecyl-3H-benzimidazole-5-carboxylic acid Chemical compound C(CCCCCCCCCCCCCCC)C=1NC2=C(N1)C=CC(=C2)C(=O)O WFFOXZUCRUTSQP-UHFFFAOYSA-N 0.000 claims 1
- HACWHGXFSQIXGG-UHFFFAOYSA-N 2-icosyl-3H-benzimidazole-5-carboxylic acid Chemical compound C(CCCCCCCCCCCCCCCCCCC)C=1NC2=C(N1)C=CC(=C2)C(=O)O HACWHGXFSQIXGG-UHFFFAOYSA-N 0.000 claims 1
- OFVZUKRCHSRBFN-UHFFFAOYSA-N 2-nonadecyl-3H-benzimidazole-5-carboxylic acid Chemical compound C(CCCCCCCCCCCCCCCCCC)C=1NC2=C(N1)C=CC(=C2)C(=O)O OFVZUKRCHSRBFN-UHFFFAOYSA-N 0.000 claims 1
- GMBJQUCFSAGJNO-UHFFFAOYSA-N 2-nonyl-3h-benzimidazole-5-carboxylic acid Chemical compound C1=C(C(O)=O)C=C2NC(CCCCCCCCC)=NC2=C1 GMBJQUCFSAGJNO-UHFFFAOYSA-N 0.000 claims 1
- YLIPWEOUPRQKRE-UHFFFAOYSA-N 2-octadecyl-3H-benzimidazole-5-carboxylic acid Chemical compound C(CCCCCCCCCCCCCCCCC)C=1NC2=C(N1)C=CC(=C2)C(=O)O YLIPWEOUPRQKRE-UHFFFAOYSA-N 0.000 claims 1
- IXXUVMLJTPMKJI-UHFFFAOYSA-N 2-tetradecyl-3H-benzimidazole-5-carboxylic acid Chemical compound C(CCCCCCCCCCCCC)C=1NC2=C(N=1)C=CC(=C2)C(=O)O IXXUVMLJTPMKJI-UHFFFAOYSA-N 0.000 claims 1
- PYLJZIFACMOPAS-UHFFFAOYSA-N 2-tridecan-5-yl-3H-benzimidazole-5-carboxylic acid Chemical compound CCCCC(CCCCCCCC)C=1NC2=C(N1)C=CC(=C2)C(=O)O PYLJZIFACMOPAS-UHFFFAOYSA-N 0.000 claims 1
- DQNUXNFKJKPDNQ-UHFFFAOYSA-N 2-tridecyl-1H-benzimidazole-4-carboxylic acid Chemical compound C(CCCCCCCCCCCC)C=1NC2=C(N=1)C=CC=C2C(=O)O DQNUXNFKJKPDNQ-UHFFFAOYSA-N 0.000 claims 1
- OPGUZRRLMQSMAQ-UHFFFAOYSA-N 5-(4-methoxyphenyl)-1-phenylbenzimidazole Chemical compound C1=CC(OC)=CC=C1C1=CC=C(N(C=N2)C=3C=CC=CC=3)C2=C1 OPGUZRRLMQSMAQ-UHFFFAOYSA-N 0.000 claims 1
- WKWALHSUNLUEBL-UHFFFAOYSA-N butyl 2-pentadecyl-3H-benzimidazole-5-carboxylate Chemical compound C(CCCCCCCCCCCCCC)C=1NC2=C(N1)C=CC(=C2)C(=O)OCCCC WKWALHSUNLUEBL-UHFFFAOYSA-N 0.000 claims 1
- PIVJIRIXQFUFJM-UHFFFAOYSA-N hexyl 2-pentadecyl-3H-benzimidazole-5-carboxylate Chemical compound C(CCCCCCCCCCCCCC)C=1NC2=C(N1)C=CC(=C2)C(=O)OCCCCCC PIVJIRIXQFUFJM-UHFFFAOYSA-N 0.000 claims 1
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Substances C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims 1
- BSTLQHQHZPKFTC-UHFFFAOYSA-N methyl 2-decyl-3H-benzimidazole-5-carboxylate Chemical compound C(CCCCCCCCC)C=1NC2=C(N1)C=CC(=C2)C(=O)OC BSTLQHQHZPKFTC-UHFFFAOYSA-N 0.000 claims 1
- AQZZCSCCSDQMBH-UHFFFAOYSA-N methyl 2-heptadecyl-3H-benzimidazole-5-carboxylate Chemical compound C(CCCCCCCCCCCCCCCC)C=1NC2=C(N1)C=CC(=C2)C(=O)OC AQZZCSCCSDQMBH-UHFFFAOYSA-N 0.000 claims 1
- ODKWIBBMDZIUPQ-UHFFFAOYSA-N methyl 2-hexadecyl-3H-benzimidazole-5-carboxylate Chemical compound C(CCCCCCCCCCCCCCC)C=1NC2=C(N1)C=CC(=C2)C(=O)OC ODKWIBBMDZIUPQ-UHFFFAOYSA-N 0.000 claims 1
- DDSTXKWPXFUFCW-UHFFFAOYSA-N methyl 2-nonadecyl-3H-benzimidazole-5-carboxylate Chemical compound C(CCCCCCCCCCCCCCCCCC)C=1NC2=C(N1)C=CC(=C2)C(=O)OC DDSTXKWPXFUFCW-UHFFFAOYSA-N 0.000 claims 1
- IPITWMFHXAFWJZ-UHFFFAOYSA-N methyl 2-octadecyl-3H-benzimidazole-5-carboxylate Chemical compound C(CCCCCCCCCCCCCCCCC)C=1NC2=C(N=1)C=CC(=C2)C(=O)OC IPITWMFHXAFWJZ-UHFFFAOYSA-N 0.000 claims 1
- MYUJJQIQDAILMF-UHFFFAOYSA-N propan-2-yl 2-pentadecyl-3H-benzimidazole-5-carboxylate Chemical compound C(CCCCCCCCCCCCCC)C=1NC2=C(N=1)C=CC(=C2)C(=O)OC(C)C MYUJJQIQDAILMF-UHFFFAOYSA-N 0.000 claims 1
- YNDLZNTYWDQTSR-UHFFFAOYSA-N tert-butyl 2-pentadecyl-3H-benzimidazole-5-carboxylate Chemical compound C(CCCCCCCCCCCCCC)C=1NC2=C(N1)C=CC(=C2)C(=O)OC(C)(C)C YNDLZNTYWDQTSR-UHFFFAOYSA-N 0.000 claims 1
- 239000007787 solid Substances 0.000 description 204
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 149
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 132
- 239000000243 solution Substances 0.000 description 120
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 101
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 86
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 85
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 75
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 72
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 72
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 66
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 45
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 39
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 38
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 35
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 34
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 26
- 238000000354 decomposition reaction Methods 0.000 description 25
- 239000007858 starting material Substances 0.000 description 25
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 20
- ARBOVOVUTSQWSS-UHFFFAOYSA-N hexadecanoyl chloride Chemical compound CCCCCCCCCCCCCCCC(Cl)=O ARBOVOVUTSQWSS-UHFFFAOYSA-N 0.000 description 19
- 239000003921 oil Substances 0.000 description 19
- 235000019198 oils Nutrition 0.000 description 19
- 238000001953 recrystallisation Methods 0.000 description 19
- 239000002904 solvent Substances 0.000 description 19
- 238000009835 boiling Methods 0.000 description 18
- IOPLHGOSNCJOOO-UHFFFAOYSA-N methyl 3,4-diaminobenzoate Chemical compound COC(=O)C1=CC=C(N)C(N)=C1 IOPLHGOSNCJOOO-UHFFFAOYSA-N 0.000 description 18
- 229960000583 acetic acid Drugs 0.000 description 17
- HEMGYNNCNNODNX-UHFFFAOYSA-N 3,4-diaminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1N HEMGYNNCNNODNX-UHFFFAOYSA-N 0.000 description 15
- 210000004027 cell Anatomy 0.000 description 15
- 239000012362 glacial acetic acid Substances 0.000 description 15
- 239000003208 petroleum Substances 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 14
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 14
- 239000000706 filtrate Substances 0.000 description 13
- NQGIJDNPUZEBRU-UHFFFAOYSA-N dodecanoyl chloride Chemical compound CCCCCCCCCCCC(Cl)=O NQGIJDNPUZEBRU-UHFFFAOYSA-N 0.000 description 12
- 239000005711 Benzoic acid Substances 0.000 description 11
- REEZZSHJLXOIHL-UHFFFAOYSA-N octanoyl chloride Chemical compound CCCCCCCC(Cl)=O REEZZSHJLXOIHL-UHFFFAOYSA-N 0.000 description 11
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 10
- GIWQIAFBONKYOM-UHFFFAOYSA-N Cl.C(CCCCCCCCCCCCCC)C=1NC2=C(N1)C=CC(=C2)C(=O)O Chemical compound Cl.C(CCCCCCCCCCCCCC)C=1NC2=C(N1)C=CC(=C2)C(=O)O GIWQIAFBONKYOM-UHFFFAOYSA-N 0.000 description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- 235000010233 benzoic acid Nutrition 0.000 description 10
- 241001465754 Metazoa Species 0.000 description 9
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- 238000004519 manufacturing process Methods 0.000 description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 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 description 7
- 238000003776 cleavage reaction Methods 0.000 description 7
- 235000005911 diet Nutrition 0.000 description 7
- 230000037213 diet Effects 0.000 description 7
- 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 description 7
- 230000007017 scission Effects 0.000 description 7
- 239000002002 slurry Substances 0.000 description 7
- 241000699670 Mus sp. Species 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 239000003242 anti bacterial agent Substances 0.000 description 6
- 229940088710 antibiotic agent Drugs 0.000 description 6
- 230000037396 body weight Effects 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 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 description 6
- 239000000047 product Substances 0.000 description 6
- 210000002966 serum Anatomy 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 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 description 5
- POIVSXODMPVBGX-UHFFFAOYSA-N Cl.C(CCCCCCCCCCCCCC)C=1NC2=C(N1)C=CC(=C2)C(=O)Cl Chemical compound Cl.C(CCCCCCCCCCCCCC)C=1NC2=C(N1)C=CC(=C2)C(=O)Cl POIVSXODMPVBGX-UHFFFAOYSA-N 0.000 description 5
- 229940126062 Compound A Drugs 0.000 description 5
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 5
- 239000001569 carbon dioxide Substances 0.000 description 5
- 229910002092 carbon dioxide Inorganic materials 0.000 description 5
- 235000012000 cholesterol Nutrition 0.000 description 5
- 206010012601 diabetes mellitus Diseases 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 5
- 230000008020 evaporation Effects 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 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 description 5
- LPWCRLGKYWVLHQ-UHFFFAOYSA-N tetradecanoyl chloride Chemical compound CCCCCCCCCCCCCC(Cl)=O LPWCRLGKYWVLHQ-UHFFFAOYSA-N 0.000 description 5
- 150000003626 triacylglycerols Chemical class 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
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 4
- DUNWQUZDSJMPJU-UHFFFAOYSA-N Cl.C(CCCCCCCCCCCCCC)C=1NC2=C(N1)C=CC(=C2)C(=O)OC Chemical compound Cl.C(CCCCCCCCCCCCCC)C=1NC2=C(N1)C=CC(=C2)C(=O)OC DUNWQUZDSJMPJU-UHFFFAOYSA-N 0.000 description 4
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- MQTMHAZBGNBILJ-UHFFFAOYSA-N O.C(CCCCCCCCCCCCCC)C=1NC2=C(N1)C=CC(=C2)C(=O)O Chemical compound O.C(CCCCCCCCCCCCCC)C=1NC2=C(N1)C=CC(=C2)C(=O)O MQTMHAZBGNBILJ-UHFFFAOYSA-N 0.000 description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
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- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 4
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- LENHLWVEJRGINP-UHFFFAOYSA-N methyl 4-(hexadecanoylamino)-3-nitrobenzoate Chemical compound C(CCCCCCCCCCCCCCC)(=O)NC1=C(C=C(C(=O)OC)C=C1)[N+](=O)[O-] LENHLWVEJRGINP-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- VIJMMQUAJQEELS-UHFFFAOYSA-N n,n-bis(ethenyl)ethenamine Chemical compound C=CN(C=C)C=C VIJMMQUAJQEELS-UHFFFAOYSA-N 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- NTQYXUJLILNTFH-UHFFFAOYSA-N nonanoyl chloride Chemical compound CCCCCCCCC(Cl)=O NTQYXUJLILNTFH-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000004533 oil dispersion Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 231100000418 oral toxicity Toxicity 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000002895 organic esters Chemical class 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- PQZWQGNQOVDTRF-UHFFFAOYSA-N pentadecanoyl chloride Chemical compound CCCCCCCCCCCCCCC(Cl)=O PQZWQGNQOVDTRF-UHFFFAOYSA-N 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 235000021395 porridge Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 150000003873 salicylate salts Chemical class 0.000 description 1
- 238000010517 secondary reaction Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 239000003206 sterilizing agent Substances 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 229940104230 thymidine Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- JUKPJGZUFHCZQI-UHFFFAOYSA-N undecanoyl chloride Chemical compound CCCCCCCCCCC(Cl)=O JUKPJGZUFHCZQI-UHFFFAOYSA-N 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 208000021331 vascular occlusion disease Diseases 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
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 vedrører nye terapeutisk virksomme benzimidazolderivater, fremgangsmåte for fremstilling av disse og farmasøytiske blandinger som inneholder dem. The present invention relates to new therapeutically effective benzimidazole derivatives, methods for their production and pharmaceutical mixtures containing them.
Benzimidazolderivatene ifølge foreliggende oppfinnelse er forbindelser med den generelle formel: The benzimidazole derivatives according to the present invention are compounds with the general formula:
hvori R betyr et hydrogenatom, en rett eller forgrenet alkylgruppe med 1 til 6 karbonatomer (som kan være substituert-med en eller flere av samme type substituenter valgt fra hydroksygruppen, alkenylgrupper med 2 til 5 karbonatomer og wherein R means a hydrogen atom, a straight or branched alkyl group of 1 to 6 carbon atoms (which may be substituted-with one or more substituents of the same type selected from the hydroxy group, alkenyl groups of 2 to 5 carbon atoms and
2 alkanoyloksygrupper med 2 til 7 karbonatomer), og R betyr en rett eller forgrenet alkylgruppe, fortrinnsvis en rett-kjedet alkylgruppe med 7 til 20 (fortrinnsvis 10 til 18) karbonatomer, og farmasøytisk fordragelige salter derav. Fortrinnsvis betyr R"*" et hydrogenatom eller en metylgruppe eller en n-butyl, 2,3-dihydroksyprop-l-yl, allyl eller pivaloyloksymetylgruppe. 2 alkanoyloxy groups of 2 to 7 carbon atoms), and R means a straight or branched alkyl group, preferably a straight-chain alkyl group of 7 to 20 (preferably 10 to 18) carbon atoms, and pharmaceutically acceptable salts thereof. Preferably, R"*" means a hydrogen atom or a methyl group or an n-butyl, 2,3-dihydroxyprop-1-yl, allyl or pivaloyloxymethyl group.
Gruppen R^OOC er knyttet til 4- eller fortrinnsvis 5-stillingen i benzimidazolringsystemet. The group R^OOC is linked to the 4- or preferably the 5-position in the benzimidazole ring system.
Det vil være klart for en fagmann at forbindelsen med den generelle formel I oppviser tautomeri slik at hydrogenatomet som er plassert på ett av nitrogenatomene kan sitte på det andre nitrogenatomet, og at begge formene som således er beskrevet kan foreligge i større eller mindre grad og befinn-er seg i en dynamisk likevektstilstand med hverandre. I tautomerene blir 4- og 5-stillingene hhv. 6- og 7-stilling-er. Videre bidrar i visse tilfeller substituentene R 1 og R<2>. til optisk isomeri. Alle slike former er omfattet av foreliggende oppfinnelse. It will be clear to a person skilled in the art that the compound of the general formula I exhibits tautomerism so that the hydrogen atom which is placed on one of the nitrogen atoms can sit on the other nitrogen atom, and that both forms thus described can exist to a greater or lesser degree and be - are in a dynamic state of equilibrium with each other. In the tautomers, the 4 and 5 positions are respectively 6 and 7 positions. Furthermore, in certain cases the substituents R 1 and R<2> contribute. to optical isomerism. All such forms are covered by the present invention.
Med uttrykket "farmasøytisk fordragelig salt" menes et salt som dannes ved omsetning med en syre eller , når R"^ betyr, et hydrogenatom, ved omsetning med en base, slik at anionene (i tilfelle av et syreaddisjonssalt) eller kationet (i til-; By the term "pharmaceutically acceptable salt" is meant a salt formed by reaction with an acid or, when R"^ means, a hydrogen atom, by reaction with a base, such that the anions (in the case of an acid addition salt) or the cation (in the case of ;
felle av"et salt dannet av en forbindelse med formel I hvor ' betyr et hydrogenatom) er relativt uskadelig for animalsk organisme ved bruk i terapeutiske doser slik at de fordel-aktige farmakologiske egenskapene til utgangsforbindelsen med den generelle formel I ikke ødelegges ved bivirkninger som tilskrives dette anionet eller kationet. • trap of a salt formed by a compound of formula I where ' means a hydrogen atom) is relatively harmless to the animal organism when used in therapeutic doses so that the beneficial pharmacological properties of the starting compound of the general formula I are not destroyed by side effects attributed to this anion or cation. •
Egnede syreaddisjonssalter innbefatter salter av uorganiske baser, f.eks hydroklorider, hydrobromider, fosfater, sulfat-er og nitrater, og organiske salter, f.eks. metansulfonater, Suitable acid addition salts include salts of inorganic bases, eg hydrochlorides, hydrobromides, phosphates, sulphates and nitrates, and organic salts, eg methanesulfonates,
2-hydroksyetansulfonater, oksalater, laktater, tartrater, 2-hydroxyethanesulfonates, oxalates, lactates, tartrates,
acetater, salicylater, sitrater, propionater, succinater, .fumarater, maleater, metylen-bis-|3-hydroksynaftoater, genti-sater og di-p-toluentartrater.. acetates, salicylates, citrates, propionates, succinates, fumarates, maleates, methylene-bis-|3-hydroxynaphthoates, gentisates and di-p-toluene tartrates..
Egnede salter som dannes med forbindelser med generell formel I hvori R"^ betyr et hydrogenatom innbefatter alkalimetall (f.eks. natrium og kalium), j ordalkalimetall, (f.eks.' kalsium og magnesium) og ammoniumsalter, og salter av aminer som er kjent for å være farmasøytisk f ordrage.].ige, f. eks. etylendiamin, cholin, dietanolamin, trietanolamin, oktade-cylamin, dietylamin, trietylamin, 2-amino-2-(hydroksymetyl)-propan-1,3-dien og 1-(3,4-dihydroksyfenyl)-2-isopropylamino-etanol. Suitable salts formed with compounds of general formula I wherein R"^ represents a hydrogen atom include alkali metal (e.g. sodium and potassium), alkaline metal (e.g. calcium and magnesium) and ammonium salts, and salts of amines which are known to be pharmaceutically acceptable, eg ethylenediamine, choline, diethanolamine, triethanolamine, octadecylamine, diethylamine, triethylamine, 2-amino-2-(hydroxymethyl)-propane-1,3-diene and 1-(3,4-dihydroxyphenyl)-2-isopropylaminoethanol.
Det må være klart at når det i denne beskrivelse henvises til forbindelser med den generelle formel I, menes også deres farmasøytisk fordragelige salter hvor sammenligning til-later dette. It must be clear that when in this description reference is made to compounds of the general formula I, their pharmaceutically tolerable salts are also meant where comparison allows this.
Forbindelsene med den generelle formel I har nyttige farmakologiske egenskaper, spesielt hypolipidemisk aktivitet. F.eks. reduserer de cholesterolkonsentrasjonene og konsentrasjonene av triglyserider i blodet. Videre hindrer de eller forebygger utvikling- av atheromatiske lesjoner, og dertil, reduserer de vegetativ formering av arterielle glatte muskel celler som er et hovedtrekk ved atheromatisk "plaques". Forbindelsene med den generelle formel I senker også blod-sukkernivået hos mus som lider av diabetes mellitus. For-bindelseiie med den generelle formel I nedsetter også lymfo-<:>cytt-transformasjonen i likehet med antireumatiske medisiner. De kan også anvendes for å forebygge eller behandle diabetes, mellitus, hyperlipoproteinemiske tilstander, atherosclerose<:>og medfølgende tilstander så som angina, myocardial infarkt,; cerebral vaskulær tilstopping, arterisk aneuri, perifere.; vaskulære sykdommer, inntatt pankreatitis og xanthomas samt arthrit, immunologiske sykdommer, kreft og transplantasjons-avvisning. The compounds of the general formula I have useful pharmacological properties, especially hypolipidemic activity. E.g. reduces the cholesterol concentrations and the concentrations of triglycerides in the blood. Furthermore, they prevent or prevent the development of atheromatous lesions, and in addition, they reduce the vegetative proliferation of arterial smooth muscle cells which is a main feature of atheromatous "plaques". The compounds of the general formula I also lower blood sugar levels in mice suffering from diabetes mellitus. Compounds of the general formula I also reduce lympho-<:>cyte transformation similarly to antirheumatic drugs. They can also be used to prevent or treat diabetes, mellitus, hyperlipoproteinemic conditions, atherosclerosis<:> and accompanying conditions such as angina, myocardial infarction,; cerebral vascular occlusion, arterial aneury, peripheral.; vascular diseases, including pancreatitis and xanthomas as well as arthritis, immunological diseases, cancer and transplant rejection.
Forbindelser' med den generelle formel I som er av særlig in-teresse er de følgende forbindelser, deres optisk aktive■ former og deres salter: Compounds of the general formula I of particular interest are the following compounds, their optically active forms and their salts:
Bokstavene A til PP betegner forbindelsene for å enklere kunne henvise til dem senere i beskrivelsen, f.eks. i ta-bellene. The letters A to PP denote the compounds to make it easier to refer to them later in the description, e.g. in the ta-bells.
Egenskapene til forbindelsene med den generelle formel I ble påvist 'gjennom de følgende forsøk: The properties of the compounds of the general formula I were demonstrated through the following experiments:
. Hypolipidemisk aktivitet hos rotter. Hypolipidemic activity in rats
Wistar. hannrotter som alle veide mellom 120 og 150 g ble buret i grupper på 8 og foret med en pulverdiett i 10 dager. Wistar. male rats all weighing between 120 and 150 g were caged in groups of 8 and fed a powdered diet for 10 days.
I de siste 7 dager av denne perioden ble forsøksforbindelse-ne gitt oralt ved å blande forbindelsene i dietten og la> dyrene fores normalt. FSrforbruket ble målt den 9. dag i hver gruppe. In the last 7 days of this period, the test compounds were given orally by mixing the compounds into the diet and the animals were fed normally. FSr consumption was measured on the 9th day in each group.
Midt på 10. dag ble dyrene avlivet ved inhalering av karbondioksyd fra fast karbondioksyd. En blodprøve ble fjernet vei d kardialpunktur og serum cholesterol og serum triglyseIr-idi! ier ble "■ analysert ved hjelp av en autoanalyser. In the middle of the 10th day, the animals were euthanized by inhalation of carbon dioxide from solid carbon dioxide. A blood sample was removed by cardiac puncture and serum cholesterol and serum triglycerides were taken. ier was "■ analyzed using an autoanalyser.
Kpntrollgrupper (som bare fikk normal, ikke medisintilsatt diett) inngikk i hvert forsøk. Control groups (which only received a normal, unmedicated diet) were included in each experiment.
i r in r
RéI d.uksjonsandelene i konsentrasjoner av serum cholesterolbg RéI d.uxition shares in concentrations of serum cholesterolbg
l i serum triglyserider ble beregnet ved sammenligning med sam-ti idige kontroller for hver konsentrasjon'av den anvendtej|for<->søksforbindelse. i | I serum triglycerides were calculated by comparison with simultaneous controls for each concentration of the test compound used. in |
i ■ - 1i ■ - 1
i in
De erholdte resultater er vist i den følgende tabell I. I The results obtained are shown in the following table I. I
Anti- atheroma- aktivitet hos kaniner.. Hvite New Zealand hannkaniher som alle veide 2,2-2,8 kg ble underkastet de-endotelialisering av hovedpulsåren og en lårarterie ved ballongkateter. Etter å.ha kommet seg fra bedøvelsen fikk de alle en diett som var tilsatt 1 vekt-' % cholesterol og en viss konsentrasjon ,av forsøksforbindels-. .en i 14 dager. På slutten av dette tidsrommet ble dyrene avlivet og konsentrasjonen av serum cholesterol ble bestemt. Aorta og lårarteriene ble fjernet, "intima-media" ble fjernet fra adventitia og cholesterolkonsentrasjonene ble bestemt. Deler av lårarteriene ble undersøkt histologisk. Anti-atheroma activity in rabbits.. New Zealand white male rabbits all weighing 2.2-2.8 kg were subjected to de-endothelialization of the main artery and a femoral artery by balloon catheter. After recovering from anaesthesia, they were all given a diet to which was added 1% by weight of cholesterol and a certain concentration of test compound. .one for 14 days. At the end of this period, the animals were sacrificed and the concentration of serum cholesterol was determined. The aorta and femoral arteries were removed, the "intima-media" was removed from the adventitia and the cholesterol concentrations were determined. Parts of the femoral arteries were examined histologically.
- En kontrollgruppe som ikke fikk forsøksforbindelsen inngikk- A control group that did not receive the experimental compound was included
i hvert forsøk. in each attempt.
Reduksjonsandelene i konsentrasjonene av serum cholesterol og arterisk cholesterol ble beregnet med sammenligning med samtidige kontroller. The percentages of reduction in the concentrations of serum cholesterol and arterial cholesterol were calculated with comparison with concurrent controls.
D.e erholdte resultater er vist i den følgende tabell II: The results obtained are shown in the following table II:
Hypoglykemiaktivitet hos diabetiske mus Hypoglycemic activity in diabetic mice
Diabetiske mus (stamme C 57, sorte, MRI-avledede Obese/Obese) av begge kjønn som alle veide mellom 45 og 70 g ble foret, med pulverisert diett i et tidsrom på en uke før forsøket. Behandlede dyr ble så gitt forsøksforbindelsen blandet, inn i dietten i en bestemt konsentrasjon i flere dager. Dyrene . ble veiet, bedøvet med karbondioksyd og årelatt ved kardialpunktur. Diabetic mice (strain C 57, black, MRI-derived Obese/Obese) of both sexes, all weighing between 45 and 70 g, were fed powdered diet for a period of one week prior to the experiment. Treated animals were then given the test compound mixed into the diet at a specific concentration for several days. The animals . were weighed, anesthetized with carbon dioxide and euthanized by cardiac puncture.
De følgende serumparametere ble målt:The following serum parameters were measured:
1. Glukose - ved glukose-oksidase-metoden til God-Perid1. Glucose - by the glucose-oxidase method of God-Perid
2. Cholesterol og triglyserider - disse ble målt med en auto-analyser etter å ha fjernet fosforlipider ved hjelp av aktiv-ert zeolitt og ekstraksjon med iso-. propanol. 2. Cholesterol and triglycerides - these were measured with an auto-analyser after removing phospholipids using activated zeolite and extraction with iso-. propanol.
Kontrollgrupper (som bare fikk normal, ikke medisintilsatt diett) inngikk i hvert forsøk. Control groups (which only received a normal, unmedicated diet) were included in each experiment.
Den prosentuelle reduksjonen av konsentrasjonene av serum-', glukose og serum-cholesterolog serum-triglyserider ble beregnet ved sammenligning med samtidige kontroller for hver , konsentrasjon av den anvendte forsøksforbindelse. The percentage reduction in the concentrations of serum, glucose and serum cholesterol and serum triglycerides was calculated by comparison with simultaneous controls for each concentration of the test compound used.
De erholdte resultater er vist i følgende tabell III. The results obtained are shown in the following table III.
Inhibierende virkning på vegetativ vekst av glatte aorta-muskelceller Glatte muskelceller ble dyrket i kultur fra eksplantasjoner Inhibitory effect on vegetative growth of aortic smooth muscle cells Smooth muscle cells were grown in culture from explants
av grise-thorax-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 • of pig thoracic aorta 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 •
av 95% luft og 5%'karbondioksyd. Ved sammenløpning ble cellene rutinemessig dyrket ved trypsinjisering og repletter-ing av omtrent 1/3 av deres sammenløpningsdensitet i DME Medium inneholdende 10% FCS og antibiotika. of 95% air and 5% carbon dioxide. At confluence, the cells were routinely cultured by trypsinization and repletting to approximately 1/3 of their confluent density in DME Medium containing 10% FCS and antibiotics.
De glatte muskelcellene ble plettert ut i densiteter påThe smooth muscle cells were plated at densities of
100 000 til 200 000 celler pr. 35 x 10 mm Falcon skål i 2 ml DME Medium som inneholdt 10% FCS og antibiotika. Etter 24 timer når cellen hadde festet seg til skålene ble mediet erstattet med 2 ml DME Medium inneholdende 1% FCS og antibiotika. Kulturene ble inkubert i ytterligere 3 dager for at cellene skulle bli statiske, d.v.s. ikke lenger.under-løpe_ celledeling). Mediet ble så erstattet med 2 ml kontroll -eller forsøksmedium. Forsøksmédiet besto av DME Medium (innholdende 10% FCS bg antibiotika) og forbindelsen som skulle undersøkes i en konsentrasjon på 5- ug/ml medium. Forbindelsene var forut oppløst i vann, aceton eller glyko-furol slik at sluttkonsentrasjonen til løsningsmidlet i mediet var 0,2% (v/v). Kontrollmediet besto av DME Medium (inneholdende 10%. FCS og antibiotika) og riktig løsnings-middel ved 0,2% (v/v) konsentrasjon. Etter tre dagers in-kubering i forsøks- eller kontrollmediet ble mediet erstattet med friskt forsøks- eller kontrollmedium og cellene inkubert 'i.ytterligere 3 eller 4 dager. På slutten av 6 eller 7 dagers inkuberingsperiodene ble celletallene bestemt ved • 100,000 to 200,000 cells per 35 x 10 mm Falcon dish in 2 ml DME Medium containing 10% FCS and antibiotics. After 24 hours, when the cells had attached to the dishes, the medium was replaced with 2 ml of DME Medium containing 1% FCS and antibiotics. The cultures were incubated for a further 3 days for the cells to become static, i.e. no longer.during-running_ cell division). The medium was then replaced with 2 ml of control or experimental medium. The test medium consisted of DME Medium (containing 10% FCS bg antibiotics) and the compound to be investigated in a concentration of 5 µg/ml medium. The compounds were previously dissolved in water, acetone or glycofurol so that the final concentration of the solvent in the medium was 0.2% (v/v). The control medium consisted of DME Medium (containing 10% FCS and antibiotics) and the correct solvent at 0.2% (v/v) concentration. After three days of incubation in the experimental or control medium, the medium was 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 periods, cell numbers were determined by •
trypsinjisering av celler og telling av cellesuspensjonen i en Coulter-teller. trypsinizing cells and counting the cell suspension in a Coulter counter.
Alle resultatene i tabell IV i det følgende gjengir gjennom-snittsverdien for 4 skåler med celler. Prosent inhibiering av vegetativ'vekst ble beregnet ved bruk av følgende formel: All the results in Table IV below represent the average value for 4 dishes of cells. Percent inhibition of vegetative growth was calculated using the following formula:
Prosentuell inhibiering av vegetativ vekstPercentage inhibition of vegetative growth
hvor S = gjennomsnittlig celletall pr. skål ved.start-en av eksperiment (etter tilsetning av kontroll- eller forsøksmedium). where S = average cell number per bowl at the start of the experiment (after addition of control or test medium).
T = Midlere celleantall pr. skål.i forsøkskulturer T = Average number of cells per bowl.in experimental cultures
ved eksperimentets avslutning.at the end of the experiment.
C = Gjennomsnittlig celletall pr. skål i kontroll-, C = Average number of cells per bowl in control,
kulturer ved eksperimentets avslutning. cultures at the end of the experiment.
Mitogen- stimulert lymfeknutecelle- lymfocytt- transformasjons-. inhibierende aktivitet hos marsvin Mitogen- stimulated lymph node cell- lymphocyte- transformation-. inhibitory activity in guinea pigs
Marsvin ble sensibilisert overfor Mycobacterium tuberculosum ved fotputeinjeksjoner 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; 0,05 mg/ml av 50% v/v FCA løsning i sterilt fysiologisk saltvann). (0.05 ml; 0.05 mg/ml of 50% v/v FCA solution in sterile physiological saline).
Etter 14 dager erholdtes lymfeknuteceller og ble suspendert i Eagles Minimal Essential (EME) Medium som inneholdt 10% kalvefosterserum'(FCS) og pufret med Earle's salter i en After 14 days, lymph node cells were obtained and suspended in Eagle's Minimal Essential (EME) Medium containing 10% fetal calf serum' (FCS) and buffered with Earle's salts in a
konsentrasjon på 2,5 x 10^ celler/ml.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 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 mitogen eller mitogen og forbindelsen som skulle under-søkes i EME medium (inneholdende 10% FCS og pufret med Earle's salter) ml mitogen or mitogen and the compound to be investigated in EME medium (containing 10% FCS and buffered with Earle's salts)
Atten timer før høsting ble 3H-thymidin (1 pl av 10 uCi/ml løsning i 0,9% sterilt saltvann) tilsatt. Eighteen hours before harvest, 3 H-thymidine (1 µl of 10 uCi/ml solution in 0.9% sterile saline) was added.
Som-en indeks på DNA-syntese ble graden av 3 H■-thymidin- . innebygning av cellene målt i sammenligning med mitogenkon-trollen. As an index of DNA synthesis, the degree of 3 H■-thymidine- . incorporation of the cells measured in comparison with the mitogen control.
Resultatene er angitt nedenfor i tabell V.The results are set out below in Table V.
Anvendeligheten av forbindelsene økes ved at de bare er meg-et lite toksiske som vist i det følgende forsøk: The applicability of the compounds is increased by the fact that they are only mildly toxic, as shown in the following experiment:
Oral toksisitet på musOral toxicity in mice
Grupper av mus ble oralt gitt graderte'doser av forsøksfor-'bindelsen (i en 0,5% w/v vandig suspensjon av tragant grøt) og observert i tre påfølgende dager. Prosentdelen av dyr som døde under denne perioden ved hvert doseringsnivå ble brukt til å konstruere en kurve hvorfra LD,-q, d.v.s. den dose i mg/kg animalsk kroppsvekt som var nødvendig 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 suspension of tragacanth porridge) and observed for three consecutive days. The percentage of animals that died during this period at each dose level was used to construct a curve from which LD,-q, i.e. the dose in mg/kg animal body weight that was necessary to kill. 50% of the mice, was calculated.
Forbindelser med formel I som er angitt, i listen ovenforCompounds of formula I as set forth in the above list
T T
ble undersøkt og LD^q for alle- forbindelser var større enn, 1000 mg/kg animalsk kroppsvekt was investigated and the LD^q for all compounds was greater than 1000 mg/kg animal body weight
Foretrukne forbindelser ifølge oppfinnelsen er de som i det følgende er angitt med bokstavene B, D, GG, KK, F, H, AA, U, Z , L og. 0. Preferred compounds according to the invention are those which are indicated in the following with the letters B, D, GG, KK, F, H, AA, U, Z, L and. 0.
Forbindelsene med den generelle formel I kan fremstillesThe compounds of the general formula I can be prepared
ved anvendelse .eller tilpasning av kjente metoder, f.eks.by applying or adapting known methods, e.g.
som angitt i det følgende. as indicated below.
1. Ifølge et trekk ved foreliggende oppfinnelse fremstilles forbindelser med den generelle formel I ved syklisering av en forbindelse med den generelle formel: 0 2 1 (hvor R betyr et hydrogenatom eller eh gruppe -COR , og R og R 2 er .som forut beskrevet), eventuelt fremstilt in situ, f,eks. ••som beskrevet i det følgende for sykliseringen av forbindelser med den generelle formel III eller IV. (i) Når således R 0 er en gruppe -COR 2, sykliseres en forbindelse med den generelle formel 12 ■ (hvori R og R er som forut angitt), fortrinnsvis ved høy-ere temperatur, f.eks. mellom 60° og .100°C, f.eks. ved eller nær 8 0°C, ved omsetning med en uorganisk syre, f.eks. saltsyre, i nærvær av vann og. i et organisk løsningsmiddel, f.eks. en alkohol så som metanol eller etanol, eller et ke-ton så som aceton eller, fortrinnsvis metyletylketon, eller . (ii) når R 0 er et hydrogvenatom (spesielt med hensyn til slike forbindelser hvor R"*" betyr en rettlinjet eller forgrenet alkylgruppe med 1 til 6 karbonatomer) sykliseres en forbind else med den generelle formel 1. According to a feature of the present invention, compounds of the general formula I are prepared by cyclization of a compound of the general formula: 0 2 1 (where R means a hydrogen atom or eh group -COR , and R and R 2 are as previously described ), possibly produced in situ, e.g. ••as described below for the cyclization of compounds of the general formula III or IV. (i) Thus, when R 0 is a group -COR 2, a compound of the general formula 12 is cyclized ■ (in which R and R are as previously indicated), preferably at a higher temperature, e.g. between 60° and .100°C, e.g. at or near 80°C, 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, preferably methyl ethyl ketone, or . (ii) when R 0 is a hydrogen atom (especially with respect to such compounds where R"*" means a linear or branched alkyl group of 1 to 6 carbon atoms) a compound is cyclized else with the general formula
■ 1 2 (hvori R og R er som forut angitt), enten under lignende betingelser som de som er forut beskrevet under (i), eller eventuelt ved omsetning med en organisk syre, f.eks. p-toluensulfonsyre i■vann eller et organisk løsningsmiddel, f.eks. toluen, fortrinnsvis ved høyere temperatur, f-, eks. mellom 60° og 100°C, f.eks. på eller nær 80°C,. eller (iii) (spesielt med hensyn til sådanne forbindelser hvor R"<*>" betyr en rettlinjet eller, forgrenet alkylgruppe med 1 til 6 karbonatomer) syklisering normalt uten isolering av et acylert mellomprodukt med formel III eller IV enten (a) uten et organisk 'løsningsmiddel og ved høyere temperatur, f.eks. mellom..150° og 250°C, eller (b) i nærvær av vann og "en uorganisk syre, f.eks. saltsyre, og i et egnet organisk løs-ningsmiddel, f.eks. diglym. 2. Ifølge et videre trekk ved foreliggende oppfinnelse- fremstilles forbindelser med den generelle formel I ved omsetning av en forbindelse med den generelle formel: ■ 1 2 (in which R and R are as previously indicated), either under similar conditions to those previously described under (i), or optionally 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, f-, e.g. between 60° and 100°C, e.g. at or near 80°C,. or (iii) (in particular with respect to such compounds where R"<*>" means a linear or branched alkyl group of 1 to 6 carbon atoms) cyclization normally without isolation of an acylated intermediate of formula III or IV either (a) without a organic solvent and at a higher temperature, e.g. between...150° and 250°C, or (b) in the presence of water and "an inorganic acid, e.g. hydrochloric acid, and in a suitable organic solvent, e.g. diglyme. 2. According to a further features of the present invention - compounds with the general formula I are prepared by reacting a compound with the general formula:
(hvori R er som. forut angitt) med en forbindelse, med den generelle formel: 2 (hvori R er som forut angitt) og et kopper(II)salt, for eksempel kppperacetat i nærvær av et- vandig inert organisk løsningsmedium, f.eks. en blanding av vann og metanol ved mellom romtemperatur og reaksjonsblandingens tilbakeløps-temperatur etterfulgt av overføring av det resulterende koppersalt i den tilsvarende forbindelse med formel I. 3. Ifølge et annet trekk ved foreliggende oppfinnelse fremstilles karboksylsyrer med den generelle formel I (hvor R<2>er som forut angitt og R"*" betyr et hydrogenatom) ved hydro- . lyse av en tilsvarende ester med den generelle formel I 2 1 hvor R er som forut angitt og R betyr en rettlinjet eller forgrenet alkylgruppe med 1 til 6 karbonatomer som kan sub-situeres med en eller flere av samme type substituenter valgt fra hydroksygruppen, alkenylgrupper med 2 til 5 karbon- . atomer eller alkanoyloksygrupper med 2 til 7 karbonatomer. Fortrinnsvis utføres hydrolysen under alkaliske betingelser, f.eks. med et alkalimetallhydroksyd i et vandig organisk løsning.smiddelsystem og ved høyere temperatur, f. eks. i nærvær av natriumhydroksyd i vandig etanol og ved tilbakeløps-temperatur.. 4. Ifølge et ytterligere trekk ved foreliggende oppfinnelse 2 fremstilles estere med den generelle formel I (hvor R er som forut angitt og R"'" betyr en rettlinjet eller forgrenet alkylgruppe med 1 til 6 karbonatomer, som kan være substitu-<:>ert med en eller flere av samme type substituenter valgt fra (in which R is as previously indicated) with a compound of the general formula: 2 (in which R is as previously indicated) and a copper(II) salt, for for example copper acetate in the presence of an aqueous inert organic solvent medium, e.g. a mixture of water and methanol at between room temperature and the reflux temperature of the reaction mixture followed by transfer of the resulting copper salt into the corresponding compound of formula I. 3. According to another feature of the present invention, carboxylic acids of the general formula I (where R<2 >is as previously indicated and R"*" means a hydrogen atom) by hydro- . lysis of a corresponding ester with the general formula I 2 1 where R is as previously indicated and R means a linear or branched alkyl group with 1 to 6 carbon atoms which can be substituted with one or more of the same type of substituents selected from the hydroxy group, alkenyl groups with 2 to 5 carbon atoms. atoms or alkanoyloxy groups of 2 to 7 carbon atoms. Preferably, the hydrolysis is carried out under alkaline conditions, e.g. with an alkali metal hydroxide in an aqueous organic solution.agent system and at a higher temperature, e.g. in the presence of sodium hydroxide in aqueous ethanol and at reflux temperature.. 4. According to a further feature of the present invention 2, esters of the general formula I are prepared (where R is as previously indicated and R"'" means a linear or branched alkyl group with 1 to 6 carbon atoms, which may be substituted with one or more substituents of the same type chosen from
hydroksygruppen, alkenylgrupper med 2 til 5 karbonatomer eller alkanoyloksygrupper med 2 til 7 karbonatomer) ved forestring av en tilsvarende karboksylsyre med generell formel the hydroxy group, alkenyl groups with 2 to 5 carbon atoms or alkanoyloxy groups with 2 to 7 carbon atoms) by esterification of a corresponding carboxylic acid with general formula
I hvor R er som forut angitt og R" betyr et hydrogenatom.Forestringén kan utføres ved anvendelsé eller tilpasning av kjente metoder,'.f.eks. ved omsetning av syren med et overskudd av den viktige alkoholen med den generelle formel: In where R is as previously indicated and R" means a hydrogen atom. The esterification can be carried out by using or adapting known methods, for example by reacting the acid with an excess of the important alcohol with the general formula:
T T
(hvori R 3 betyr en rettlinjet eller forgrenet alkylgruppe med 1 til 6 karbonatomer (som kan være substituert med en eller .flere av samme type substituenter valgt fra hydroksygruppen, alkenylgrupper med 2 til 5 karbonatomer eller alkanoyloksygrupper méd 2 til' 7 karbonatomer) eventuelt som løsningsmedium, og i nærvær av en uorganisk syre, f.eks. saltsyre, fortrinnsvis ved en høyere temperatur,. f.eks. mellom 60° og 100°C; eller ved omsetning med det tilsvarende alkylhalogenid. (where R 3 means a straight or branched alkyl group with 1 to 6 carbon atoms (which may be substituted with one or more of the same type of substituents selected from the hydroxy group, alkenyl groups with 2 to 5 carbon atoms or alkanoyloxy groups with 2 to 7 carbon atoms) optionally as solvent medium, and in the presence of an inorganic acid, eg hydrochloric acid, preferably at a higher temperature, eg between 60° and 100°C, or by reaction with the corresponding alkyl halide.
Syrekloridet som dannes ved omsetning med tionylklorid, eller salter av syrene kan brukes. The acid chloride formed by reaction with thionyl chloride, or salts of the acids can be used.
Med uttrykket "kjente metoder"' som brukes i foreliggende beskrivelse menes metoder som tidligere er brukt eller beskrevet i litteraturen. The term "known methods" used in the present description means methods that have previously been used or described in the literature.
5. Ifølge et ytterligere.trekk ved foreliggende oppfinnelse 5. According to a further feature of the present invention
kan forbindelser med den generelle formel I overføres i far-masøytisk fordragelige salter, og vice versa, ved anvendelse eller tilpasning av kjente metoder. Denne fremgangsmåten kan både være anvendelig i seg selv og kan brukes for rensning for forbindelser med den generelle formel I og deres salter ved å utnytte forskjeller i løselighet i vann og for-skjellige organiske løsningsmidler for forbindelsene og. deres salter og for hvilke, som helst tilstedeværende foru-rensninger ved hjelp,av kjente metoder slik som krystalli-sering. compounds of the general formula I can be converted into pharmaceutically acceptable salts, and vice versa, using or adapting known methods. This method can both be applicable in itself and can be used for purification of compounds of the general formula I and their salts by exploiting differences in solubility in water and different organic solvents for the compounds and. their salts and for any impurities present using known methods such as crystallization.
(i) Forbindelser med generell formel I kan overføres i sine farmasøytisk fordragelige syreaddisjonssalter, f.eks. ved omsetning med den riktige syre i løsning eller suspensjon i et passende løsningsmiddel, f.eks. aceton, metanol eller etanol, om nødvendig etterfulgt av inndampning av en del av eller alt løsningsmidlet og oppsamling av det faste salt. (ii) På den annen side kan syreaddisjonssaltene overføres til moderforbindelsene med den generelle formel I, f.eks. ved omsetning med vandig ammoniakk i nærvær av et egnet løs-ningsmiddel, f.eks. etanol, etterfulgt av behandling med en svak .syre, f. eks. iseddik.-(iii) Syrer med den generelle formel I hvor R betyr et . hydrogenatom (R 2 er som forut angitt) kan overføres til salter av farmasøytisk fordragelige baser, f.eks. ved omsetning med den riktige base, f.eks. ved riktig amin eller en forbindelse med den generelle formel: (i) Compounds of general formula I may be transferred in their pharmaceutically acceptable acid addition salts, e.g. by reaction with the appropriate acid in solution or suspension in a suitable solvent, e.g. acetone, methanol or ethanol, if necessary followed by evaporation of some or all of the solvent and collection of the solid salt. (ii) On the other hand, the acid addition salts can be transferred to the parent compounds of the general formula I, e.g. by reaction with aqueous ammonia in the presence of a suitable solvent, e.g. ethanol, followed by treatment with a weak acid, e.g. glacial acetic acid.-(iii) Acids with the general formula I where R means a . hydrogen atom (R 2 is as previously stated) can be transferred to salts of pharmaceutically acceptable bases, e.g. by turnover with the correct base, e.g. by the appropriate amine or a compound of the general formula:
(hvori M"*" betyr et alkalimetall, f. eks. natrium eller kalium, og. R 4betyr en alkylgruppe med opptil .4 karbonatomer, f .eks. metyl eller etyl, eller et hydrogenatom) i et egnet løsnings-middel, f.eks. metanol eller etanol, eller en blanding av vann og aceton, om nødvendig etterfulgt av inndampning av en del av eller alt løsningsmidlet, og oppsamling av. det faste salt. (where M"*" means an alkali metal, e.g. sodium or potassium, and R 4 means an alkyl group with up to .4 carbon atoms, e.g. methyl or ethyl, or a hydrogen atom) in a suitable solvent, e.g. .ex. methanol or ethanol, or a mixture of water and acetone, if necessary followed by evaporation of some or all of the solvent, and collection of. the solid salt.
(iv) Di.sse salter kan overføres til moderf orbindelsene med formel I f.eks. ved omsetning med en egnet syre, f.eks. iseddik, i løsning i et passende løsningmsiddel, f.eks. vann eller etanol, om nødvendig etterfulgt av inndampning av en del av eller alt løsningsmidlet, og oppsamling ay den faste forbindelse med formel I.- (iv) These salts can be transferred to the parent compounds of 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 collecting ay the solid compound of formula I.-
For en fagmann vil det være klart at under gjennomføringen av fremgangsmåten ifølge foreliggende oppfinnelse kan det være ønskelig å innføre kjemiske beskyttelsesgrupper i reak- It will be clear to a person skilled in the art that during the implementation of the method according to the present invention it may be desirable to introduce chemical protective groups into the reaction
tantene for å unngå sekundærreaksjoner, f.eks. i fremgangsmåte 1 forut beskrevet kan det ha vært nødvendig- å overføre hydroksygrupper i substituentén R"<*>" i den generelle formel II til benzyloksygrupper før den beskrevne omsetning med etter-følgende fjerning av benzylgruppen. Videre kan en fremstill-, ingsprosess velges fremfor andre som et middel til å frem-stille visse angitte forbindelser med generell formel I. the aunts to avoid secondary reactions, e.g. in method 1 previously described, it may have been necessary to transfer hydroxy groups in the substituent R"<*>" in the general formula II to benzyloxy groups before the described reaction with subsequent removal of the benzyl group. Furthermore, one manufacturing process may be chosen over others as a means of manufacturing certain indicated compounds of general formula I.
Forbindelser med generell- 'formel II hvor R^ betyr et hydro-.. genatom kan fremstilles fra forbindelser méd den generelle formel: Compounds of general formula II where R^ denotes a hydrogen atom can be prepared from compounds of the general formula:
12 12
(hvor R og R er som forut angitt) ved reduksjon, f, eks.-ved katalytisk.hydrogenering, ved bruk av f.eks. palladium-, på-karbon. (where R and R are as previously indicated) by reduction, e.g. by catalytic hydrogenation, by using e.g. palladium-on-carbon.
Forbindelser med den generelle formel II hvor R^ betyr en gruppe med formel -COR 2 (R 2 er som forut angitt) kan fremstilles fra forbindelser med den generelle formel II hvor R betyr et hydrogenatom ved.omsetning med forbindelser med den generelle formel XI som er angitt i det følgende. Compounds of the general formula II where R 2 means a group of the formula -COR 2 (R 2 is as previously indicated) can be prepared from compounds of the general formula II where R means a hydrogen atom by reaction with compounds of the general formula XI which is indicated in the following.
Forbindelser med generell formel IX kan fremstilles ved om-setningen av en forbindelse med. den generelle formel: Compounds of general formula IX can be prepared by the reaction of a compound with the general formula:
(hvor R"<*>" er som forut angitt) med en forbindelse med generell formel XI på lignende måte som beskrevet i metode A(i). Forbindelser med generell formel II hvori substituentgruppen 2 1 0 -NHCOR er meta til substituentgruppen -COOR' og hvori R betyr et hydrogenatom, kan fremstilles ved å omsette en forbindelse-med generell formel V med en forbindelse med generell formel XI som beskrevet i metode A(ii). (wherein R"<*>" is as previously indicated) with a compound of general formula XI in a similar manner as described in method A(i). Compounds of general formula II in which the substituent group 2 1 0 -NHCOR is meta to the substituent group -COOR' and in which R represents a hydrogen atom can be prepared by reacting a compound of general formula V with a compound of general formula XI as described in method A (ii).
Forbindelser med generell formel II hvor betyr'en gruppe med formel -COR 2 (R 2er'som forut beskrevet) kan også fremstilles ved omsetning av en forbindelse med generell formel V med en forbindelse med generell formel XI som beskrevet i metode A (i) . Compounds of general formula II where means a group of formula -COR 2 (R 2 is as previously described) can also be prepared by reacting a compound of general formula V with a compound of general formula XI as described in method A (i) .
Forbindelser med generell formel II hvori R betyr en rett-eller forgrenet alkylgruppe med 1 til 6 karbonatomer (som kan være substituert med en eller flere av samme type substituent valgt fra hydroksygruppen, alkenylgrupper med 2 til 5 karbonatomer. og alkanoyloksygrupper med 2 til 7 karbonatomer)' kan fremstilles ved forestring av de. tilsvarende forbindelser med generell formel II hvor R betyr et hydrogenatom ved anvendelse eller tilpasning av kjente metoder, f.eks. ved omsetning av det■tilsvarende diazoalkan i nærvær av et inert organisk løsningsmiddel. Compounds of general formula II in which R means a straight or branched alkyl group with 1 to 6 carbon atoms (which may be substituted by one or more of the same type of substituent selected from the hydroxy group, alkenyl groups with 2 to 5 carbon atoms. and alkanoyloxy groups with 2 to 7 carbon atoms )' can be produced by esterification of the. corresponding compounds of general formula II where R means a hydrogen atom by using or adapting known methods, e.g. by reacting the corresponding diazoalkane in the presence of an inert organic solvent.
Metode AMethod A
Forbindelsene med generell formel II kan fremstilles ved omsetning av en forbindelse med den generelle formel: The compounds of general formula II can be prepared by reacting a compound of the general formula:
(hvor R"*" er som forut angitt) med et' acyleringsmiddel med den generelle formel: ■ . hvori R 2 er som forut angitt og X 1' betyr et halogen, for- .trinnsvis klor, atom) eller en hydroksygruppe. (Ifølge en fremgangsmåte ved foreliggende oppfinnelse følger sykliseringen av det resulterende produkt eventuelt in situ). Spe sielt egnede betingelser er som følger: (i) Forbindelser med den generelle formel V (hvor R"<*>" er som forut angitt) kan omsettes med acylhalogenider med generell 2 t 1 formel XI (hvor R er som forut angitt og X betyr et halogen, fortrinnsvis klor, atom) i et inert organisk løsnings-middel, f.eks. diklormetan eller dimetylformamid, fortrinnsvis under vandige betingelser og fortrinnsvis i nærvær av et syrebindende middel, f.eks. et trialkylamin, f.eks. trietylamin, eller et alkalimetallkarbonat'eller -bikarbonat, f. eks. vannfritt natrium eller kaliumkarbonat. (ii) Forbindelser med generell formel V (spesielt sådanne hvor R"'" betyr en rettlinjet eller forgrenet alkylgruppe med 1. til 6 karbonatomer) kan omsettes med acylhalogenider med 1 generell formel XI (hvor R er som forut angitt og X betyr et halogen, fortrinnsvis klor, atom) under betingelser i lik-' het med sådanne som er beskrevet under, (i), men ved bruk av .en mindre mengde av acylhalogenidet og kontroll av temperaturen, fortrinnsvis ved mellom 0°C og. romtemperatur. (where R"*" is as previously indicated) with an acylating agent of the general formula: ■ . in which R 2 is as previously indicated and X 1' means a halogen, preferably chlorine, atom) or a hydroxy group. (According to a method of the present invention follows the cyclization of the resulting product possibly in situ). Spe particularly suitable conditions are as follows: (i) Compounds of the general formula V (wherein R"<*>" is as previously indicated) can be reacted with acyl halides of general formula XI (where R is as previously indicated and X means a halogen, preferably chlorine, atom) in an inert organic solvent, e.g. dichloromethane or dimethylformamide, preferably under aqueous conditions and preferably in the presence of an acid-binding agent, e.g. a trialkylamine, e.g. triethylamine, or an alkali metal carbonate or bicarbonate, e.g. anhydrous sodium or potassium carbonate. (ii) Compounds of general formula V (especially those where R"'" means a linear or branched alkyl group of 1 to 6 carbon atoms) can be reacted with acyl halides of 1 general formula XI (where R is as previously indicated and X means a halogen , preferably chlorine, atom) under conditions similar to those described under (i), but using a smaller amount of the acyl halide and controlling the temperature, preferably at between 0°C and room temperature.
■ Ved å bruke forsøksbetingelser mellom dem som forut er beskrevet under (i) og dem som forut er beskrevet under (ii) ville man få en blanding av mellomprodukter med generell formel III og IV, hvilke ville kunne .sykliseres under de betingelser som forut er beskrevet under l(i) og l(ii). ■ By using experimental conditions between those previously described under (i) and those previously described under (ii), a mixture of intermediates of general formula III and IV would be obtained, which could be cyclized under the conditions previously described described under l(i) and l(ii).
(iii). Forbindelser med generell formel V (spesielt sådanne . hvor R"*" betyr en rett eller forgrenet alkylgruppe med 1 til 6 karbonatomer) kan omsettes med forbindelser med generell (iii). Compounds of general formula V (especially those . where R"*" means a straight or branched alkyl group with 1 to 6 carbon atoms) can be reacted with compounds of general
formel XI (hvor R er som forut angitt og X betyr en hydroksygruppe eller et kloratom) for å danne forbindelser med generell formel I, normalt uten isolering av acylerté mellomprodukter, enten (a) uten løsningsmiddel og ved høyere temperatur, f.eks. ved mellom 150° og 250°C, eller (b) i nærvær av vann og en uorganisk syre, f.eks. saltsyre, og i et pass-' . formula XI (where R is as previously indicated and X means a hydroxy group or a chlorine atom) to form compounds of general formula I, normally without isolation of acylated intermediates, either (a) without solvent and at elevated temperature, e.g. at between 150° and 250°C, or (b) in the presence of water and an inorganic acid, e.g. hydrochloric acid, and in a pass-' .
ende løsningsmiddel, f.eks. diglym.end solvent, e.g. diglym.
De følgende eksempler og referanseeksempler illustrerer fremstillingen av forbindelsene ifølge foreliggende oppfinnelse. The following examples and reference examples illustrate the preparation of the compounds according to the present invention.
EKSEMPEL 1 EXAMPLE 1
Forbindelse ACompound A
En løsning av metyl 4-amino-3-(n-heksadekanamido)benzoat (46 A solution of methyl 4-amino-3-(n-hexadecanamido)benzoate (46
g) og p-toluensulfonsyre (15 g) i toluen (1000 ml) ble rørt og oppvarmet ved tilbakeløp i 2 timer mens vannet som ble g) and p-toluenesulfonic acid (15 g) in toluene (1000 ml) were stirred and heated at reflux for 2 hours while the water which became
dannet ble fjernet kontinuerlig ved hjelp av et Dean and Stark -apparat. Løsningen ble avkjølt til 60°C<p>g ble vasket med vandig natriumkarbonatløsning (2N; 2 x 200 ml). To- ■ luensjiktet .ble tørket over magnesiumsulfat og ble så konsentrert i vakuum og ga en olje. Oljen ble revet med petroleter (kokepunkt 40° til 60°C) og ga et.brungult fast stoff som, etter omkrystallisering fra petroleter (kokepunkt 40° formed was removed continuously using a Dean and Stark apparatus. The solution was cooled to 60°C<p>g was washed with aqueous sodium carbonate solution (2N; 2 x 200 ml). The toluene layer was dried over magnesium sulfate and then concentrated in vacuo to give an oil. The oil was triturated with petroleum ether (b.p. 40° to 60°C) and gave a tan solid which, after recrystallization from petroleum ether (b.p. 40°
til 60°C), ga metyl 2-(n-pentadecyl)benzimidazol-5-karboksylat (24,6 g) i form av et hvitt fast stoff, smp.. 96° til 98°C. to 60°C), gave methyl 2-(n-pentadecyl)benzimidazole-5-carboxylate (24.6 g) as a white solid, mp 96° to 98°C.
Metyl 4-amino-3-(n-heksadekanamido)benzoatet som brukes som utgangsmateriale ble fremstilt ved en av de følgende metoder: (i) En omrørt løsning av metyl 3,4-diaminobenzoat (35 g) i tørt dimetylformamid (1200 ml) som inneholdt vannfritt natriumkarbonat (11,8 g) ble behandlet dråpevis med n-heksadekanoylklorid (5-8 g) 1 time. Tilsetningshastigheten av n-heksadekanoylkloridet var slik at temperaturen i reaksjonsblandingen steg fra en begynnelsestemperatur på 10°C til romtemperatur. Blandingen ble så rørt ved romtemperatur i ytterligere 3 timer og deretter helt i vann (5 liter). Det resulterende faste stoff ble oppsamlet og kokt i aceton The methyl 4-amino-3-(n-hexadecanamido)benzoate used as starting material was prepared by one of the following methods: (i) A stirred solution of methyl 3,4-diaminobenzoate (35 g) in dry dimethylformamide (1200 ml) containing anhydrous sodium carbonate (11.8 g) was treated dropwise with n-hexadecanoyl chloride (5-8 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 for a further 3 hours and then poured into water (5 litres). The resulting solid was collected and boiled in acetone
(1000 ml) og den kokende blanding ble deretter filtrert. Filtratet ble avkjølt til 0°C og det resulterende brungule faste stoff frafiltrert, hvilket ga metyl 4-amino-3-(n-heksadekanamido)benzoat (48,2 g), smp. 112° til 114°C. (1000 mL) and the boiling mixture was then filtered. The filtrate was cooled to 0°C and the resulting tan solid filtered off to give methyl 4-amino-3-(n-hexadecanamido)benzoate (48.2 g), m.p. 112° to 114°C.
(ii) En omrørt løsning av metyl 3,4-diamino-benzoat (16,6 g)(ii) A stirred solution of methyl 3,4-diamino-benzoate (16.6 g)
i tørt diklormetan (270 ml) inneholdende trietylamin (10,3 g) ble behandlet dråpevis med en løsning av n-heksadekanoyl-klorid (27,5 g) i tørt diklormetan (30 ml) i 45 min.. Temperaturen under tilsetningen, ble holdt mellom 16° og 20°C. Blandingen ble rørt i ytterligere 2 timer. Det resulterende faste stoff ble så oppsamlet og kokt i en blanding av ace- 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 then collected and boiled in a mixture of ace-
ton (1000 ml) og metanol (150 ml)' og det uløselige materiale ble fjernet ved filtrering. Filtratet ble avkjølt til 25°C og behandlet med vann (800 ml) hvilket ga metyl 4-åmino-3-(n-heksadekanamido)benzoat i form av et brungult fast stoff, smp. 112° til 114°C. ton (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° to 114°C.
EKSEMPEL 2 EXAMPLE 2
Forbindelse ACompound A
En løsning av metyl 4-amino-3-(n-heksadekanamido)benzoatA solution of methyl 4-amino-3-(n-hexadecanamido)benzoate
(34 g; fremstilt som forut beskrevet i eksempel 1) i en blanding av etanol og vann (200 ml; 9:1 v/v) ble behandlet med et overskudd av en mettet løsning av hydrogenklorid i etanol. Blandingen ble oppvarmet ved tilbakeløp i.2 timer og ble så avkjølt. Det resulterende faste stoff ble oppsamlet og omkrystallisert fra en blanding av etanol og vann (9:1 v/v) hvilket ga metyl 2-(n-pentadecyl)benzimidazol-5-karboksylathydroklérid (24,2 g) i form av et hvitt fast stoff, smp. 230°-232°C (under spaltning). (34 g; prepared as previously described in Example 1) in a mixture of ethanol and water (200 ml; 9:1 v/v) was treated with an excess of a saturated solution of hydrogen chloride in ethanol. The mixture was heated at reflux for 2 hours and then cooled. The resulting solid was collected and recrystallized from a mixture of ethanol and water (9:1 v/v) to give methyl 2-(n-pentadecyl)benzimidazole-5-carboxylate hydrochloride (24.2 g) as a white solid substance, m.p. 230°-232°C (during decomposition).
EKSEMPEL 3EXAMPLE 3
Forbindelse ACompound A
Metyl 3,4-diaminobenzoat (8,8 g) og heksadekansyre (12,8,g) ble malt sammen til en grundig blanding. Blandingen ble oppvarmet ved. 200°C i 150 min. Blandingen ble så avkjølt til 60°C og ekstrahert med kokende petroleter (kokepunkt 60°-80°C; 200 ml). Ekstraktet ble konsentrert i vakuum dg ga en brun olje. Oljen ble oppløst i etanol (100 ml) og løs-ningen ble behandlet med en løsning av kaliumhydroksyd i. etanol (10 vekt-%) inntil blandingens pH var 7. Blandingen ble sa o • avkjølt til 0 oC og filtrert og filtratet ble konsentrert i vakuum og ga en brun olje (10,2 g). Oljen ble opp-løst i kloroform (15 ml) og kromatografert på kiselgel (275 Methyl 3,4-diaminobenzoate (8.8 g) and hexadecanoic acid (12.8 g) were ground together to a thorough mixture. The mixture was heated at 200°C for 150 min. The mixture was then cooled to 60°C and extracted with boiling petroleum ether (boiling point 60°-80°C; 200 ml). The extract was concentrated in vacuo to give a brown oil. The oil was dissolved in ethanol (100 ml) and the solution was treated with a solution of potassium hydroxide in ethanol (10% by weight) until the pH of the mixture was 7. The mixture was then cooled to 0 °C and filtered and the filtrate was concentrated in vacuo to give a brown oil (10.2 g). The oil was dissolved in chloroform (15 ml) and chromatographed on silica gel (275
g). Elueririg med kloroform ga et gråhvitt fast stoff (6,0 g) som ble omkrystallisert fra petroleter (kokepunkt 40°-60°C) g). Eluting with chloroform gave an off-white solid (6.0 g) which was recrystallized from petroleum ether (bp 40°-60°C)
og ga metyl 2-(n-pentadecyl)benzimidazol-5-karboksylat (5,3 and gave methyl 2-(n-pentadecyl)benzimidazole-5-carboxylate (5,3
g)' i form av et hvitt fast stoff, smp. 96°-98°C.g)' in the form of a white solid, m.p. 96°-98°C.
EKSEMPEL - 4 EXAMPLE - 4
Forbindelse B En omrørt løsning av metyl 2-(n-pentadecyl.) benzimidazol-5-karboksylat (3& g; fremstilt som forut beskrevet i eksempel 1 eller 3) i en blanding av etanol og vann (500 ml; 4:1-v/v) inneholdende natriumhydroksyd (8 g) ble oppvarmet under til-, bakeløp i 90 min. ■ Blandingen.ble avkjølt til Q°C og ble sur-gjort ved behandling med konsentrert saltsyre. Det resulterende gråhvite faste stoff ble oppsamlet og omkrystallisert , (under behandling med aktivt karbon) fra en blanding av etanol og vann (800 ml; 4:1 v/v) og ga 2-(n-pentadecyl)ben-zimidazol-5-karboksylsyre-hydroklorid (32 g) i form av et hvitt fast stoff, smp. 289°-291°C (under spaltning). Compound B A stirred solution of methyl 2-(n-pentadecyl.) benzimidazole-5-carboxylate (3&g; prepared as previously described in Example 1 or 3) in a mixture of ethanol and water (500 ml; 4:1-v /v) containing sodium hydroxide (8 g) was heated under reflux for 90 min. ■ The mixture was cooled to Q°C and acidified by treatment with concentrated hydrochloric acid. The resulting off-white solid was collected and recrystallized (under treatment with activated carbon) from a mixture of ethanol and water (800 mL; 4:1 v/v) to give 2-(n-pentadecyl)benzimidazol-5- carboxylic acid hydrochloride (32 g) as a white solid, m.p. 289°-291°C (under decomposition).
EKSEMPEL 5 .EXAMPLE 5.
Forbindelse BCompound B
En løsning av metyl 2-(n-pentadecyl)benzimidazol-5-karboksylat-hydroklorid (24,2 g;.fremstilt som forut beskrevet i eksempel 2) i en blanding av etanol og vann (2 50 ml; 4:1 v/v), inneholdende natriumhydroksyd (7 g) ble behandlet på lignende måte som forut beskrevet i eksempel 4 og ga 2-(n-pentadecyl) benzimidazol-5-karboksylsyre-hydroklorid (22,4 g) smp. 289<0>;-291<0>C (under spaltning) . A solution of methyl 2-(n-pentadecyl)benzimidazole-5-carboxylate hydrochloride (24.2 g; prepared as previously described in Example 2) in a mixture of ethanol and water (250 ml; 4:1 v/ v), containing sodium hydroxide (7 g) was treated in a similar manner as previously described in Example 4 and gave 2-(n-pentadecyl) benzimidazole-5-carboxylic acid hydrochloride (22.4 g) m.p. 289<0>;-291<0>C (under cleavage) .
EKSEMPEL 6 EXAMPLE 6
Forbindelse CCompound C
En løsning av metyl 4-.amino-3-(n-dodékanamido) benzoat (41,0 g) i toluen (1000 ml) inneholdende p-toluensulfonsyre (25 g) ble behandlet på. lignende måte som beskrevet'forut i eksempel. 1 og' ga metyl 2-(n-undecyl)-benzimidazol-5-karboksylat (27,0 g.) i form av et hvitt fast stoff, smp. 9-3°-95°C. A solution of methyl 4-amino-3-(n-dodecanamido)benzoate (41.0 g) in toluene (1000 ml) containing p-toluenesulfonic acid (25 g) was treated. similar way as described'before in example. 1 and' gave methyl 2-(n-undecyl)-benzimidazole-5-carboxylate (27.0 g.) in the form of a white solid, m.p. 9-3°-95°C.
Metyl 4-amino-3-(n-dodekanamido)benzoatet som brukes som utgangsmateriale ble fremstilt som følger: En løsning av metyl 3,4-diaminobenzoat (25,0 g) i tørt dimetylformamid (1120. ml) inneholdende vannfritt natriumkarbonat (7,7 g) ble behandlet med n-dodekanoylklorid (30,5 g) på;. lignende måte som forut beskrevet i eksempel l(i.) og ga. rått metyl 4-amino-3-(n-dodekånamido) benzoat (41 g) i form av et' brungult-fast stoff. The methyl 4-amino-3-(n-dodecanamido)benzoate used as starting material was prepared as follows: 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) on;. similar way as previously described in example l(i.) and ga. crude methyl 4-amino-3-(n-dodecaneamido)benzoate (41 g) as a tan solid.
' EKSEMPEL" 7 "EXAMPLE" 7
Forbindelse CCompound C
Metyl 3,4-diaminobenzoat (33 g) og dodekansyre (40 g).ble malt' sammen og ga en grundig blanding og blandingen ble oppvarmet ved 200°'C i 3 timer. Blandingen ble så behandlet på lignende måte som forut beskrevet i eksempel 3 og ga metyl 2-(n-undecyl)benzimidazol-5-karboksylat (19 g) i form av et hvitt fast stoff, smp. 92°-94°C. Methyl 3,4-diaminobenzoate (33 g) and dodecanoic acid (40 g) were ground together to give a thorough mixture and the mixture was heated at 200°C for 3 hours. The mixture was then treated in a similar manner as previously described in Example 3 and gave methyl 2-(n-undecyl)benzimidazole-5-carboxylate (19 g) as a white solid, m.p. 92°-94°C.
EKSEMPEL 8EXAMPLE 8
Forbindelse D En løsning av metyl 2-(n-undecyl)benzimidazol-5-karboksylat (28,6 g; fremstilt som forut beskrevet i eksempel 7) i en blanding 'av etanol og vann (350 ml; 4:1 v/v) inneholdende natriumhydroksyd (6,93 g) ble behandlet på lignende måte som forut beskrevet i eksempel 4 og ga 2-(n-undecyl)benzimidazol-5-karboksylsyrehydroklorid (22,3 g) i form av et.'hvitt fast stoff, smp. 289°-294°C (under spaltning). Compound D A solution of methyl 2-(n-undecyl)benzimidazole-5-carboxylate (28.6 g; prepared as previously described in Example 7) in a mixture of ethanol and water (350 ml; 4:1 v/v) ) containing sodium hydroxide (6.93 g) was treated in a similar manner as previously described in Example 4 and gave 2-(n-undecyl)benzimidazole-5-carboxylic acid hydrochloride (22.3 g) in the form of a white solid, m.p. 289°-294°C (under decomposition).
EKSEMPEL 9EXAMPLE 9
Forbindelse EConnection E
Metyl 3,4-diaminobenzoat (33,0 g) og n-tetradekansyre (45,6-g) ble malt sammen til en grundig blanding og blandingen ble oppvarmet ved 2 00°C i 6 timer. Blandingen ble avkjølt til Methyl 3,4-diaminobenzoate (33.0 g) and n-tetradecanoic acid (45.6 g) were ground together to a thorough mixture and the mixture was heated at 200°C for 6 hours. The mixture was cooled to
60°C og deretter ekstrahert med petroleter (kokepunkt 60°-80°C), og petroleterekstraktene ble konsentrert i vakuum og ga en brun olje. Oljen ble oppløst i etanol (500 ml) og løs-ningen ...ble behandlet med en løsning av kaliumhydroksyd i . etanol (10% w/v) inntil blandingens pH var 7. Blandingen ble.avkjølt til 0°C og filtrert og filtratet ble konsentrert"i vakuum og ga en brun olje. Oljen ble fordelt mellom en varm blanding av petroleter (kokepunkt 60°-80°C).og toluen (300 ml; .4:1 v/v) , og vann (300 ml). Det organiske sjiktet ble konsentrert i vakuum og ga en olje som deretter ble opp-løst i varm toluen (100 ml) og behandlet med et overskudd av en mettet løsning av hydrogenklorid i etanol. Det resul- 60°C and then extracted with petroleum ether (b.p. 60°-80°C), and the petroleum ether extracts were concentrated in vacuo to give a brown oil. The oil was dissolved in ethanol (500 ml) and the solution was treated with a solution of potassium hydroxide in . ethanol (10% w/v) until the pH of the mixture was 7. The mixture was cooled to 0°C and filtered and the filtrate was concentrated in vacuo to give a brown oil. The oil was partitioned between a hot mixture of petroleum ether (boiling point 60° -80°C). and toluene (300 ml; .4:1 v/v), and water (300 ml). The organic layer was concentrated in vacuo to give an oil which was then dissolved in hot toluene (100 ml) and treated with an excess of a saturated solution of hydrogen chloride in ethanol.
terende faste stoff ble oppsamlet og omkrystallisert fra etanol (under behandling med aktivt karbon) og ga metyl 2-(n-tridecyl)benzimidazol-5-karboksylathydroklorid (16 g) i form; av et hvitt fast stoff, smp; 228°-236°C (under spaltning). !• The precipitated solid was collected and recrystallized from ethanol (under treatment with activated carbon) to give methyl 2-(n-tridecyl)benzimidazole-5-carboxylate hydrochloride (16 g) in form; of a white solid, mp; 228°-236°C (under decomposition). !•
EKSEMPEL 10.. EXAMPLE 10..
■ Forbindelse E■ Connection E
Metyl 4-amino-3-(n-tetradekanamido)benzoat (40 g) ble behandlet på lignende måte som beskrevet forut i eksempel 2 og■ga metyl 2-(n-tridecyl)benzimidazol-5-karboksylathydroklorid (33 g) i form av et hvitt fast stoff, smp. 228°-234°C (under, spaltning). Methyl 4-amino-3-(n-tetradecanamido)benzoate (40 g) was treated in a similar manner as previously described in Example 2 to give methyl 2-(n-tridecyl)benzimidazole-5-carboxylate hydrochloride (33 g) in the form of a white solid, m.p. 228°-234°C (below, cleavage).
Metyl 4-amino-3-(n-tetradekanamido)benzoatet sorti brukes som utgangsmateriale ble fremstilt som følger: The methyl 4-amino-3-(n-tetradecanamido)benzoate variety used as starting material was prepared as follows:
En omrørt løsning av metyl 3,4-diaminobenzoat (25,0 g) iA stirred solution of methyl 3,4-diaminobenzoate (25.0 g) i
tørr diklormetan (500 ml) inneholdende trietylamin (15,5'g) , ble behandlet dråpevis med en løsning av n-tetradekanoylklorid (37,12 g) i tørr diklormetan (50 ml) på lignende måte som forut beskrevet i eksempel l(ii)og ga rått metyl 4-amino-3-(n-tetrådekanamido)benzoat (40 g) i form av et brungult fast stoff.. 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) ) and gave crude methyl 4-amino-3-(n-tetradecanamido)benzoate (40 g) as a tan solid.
EKSEMPEL 11EXAMPLE 11
Forbindelse FConnection F
En løsning av metyl 2-(n-tridecyl)benzimidazol-5-karboksylat (7,9 g) i en blanding av etanol og vann (200 ml; 4:1 v/v) inneholdende natriumhydroksyd (2,4 g) ble behandlet på lignende måte som forut beskrevet i eksempel 4 og ga 2-(n-tride-cyl ) bénzimidazol-5-karboksylsyrehydroklorid (5,7 g) i form av et hvitt fast stoff, smp. 299°- 306°C (under spaltning). A solution of methyl 2-(n-tridecyl)benzimidazole-5-carboxylate (7.9 g) in a mixture of ethanol and water (200 ml; 4:1 v/v) containing sodium hydroxide (2.4 g) was treated in a similar manner as previously described in Example 4 and gave 2-(n-tride-cyl)benzimidazole-5-carboxylic acid hydrochloride (5.7 g) in the form of a white solid, m.p. 299°- 306°C (under decomposition).
EKSEMPEL 12 Forbindelse B EXAMPLE 12 Compound B
2-(n-pentadecyl)benzimidazol-5-karboksylsyrehydroklorid2-(n-pentadecyl)benzimidazole-5-carboxylic acid hydrochloride
(15,0 g; fremstilt som forut beskrevet i eksempel 4) ble oppløst i en. varm blanding av etanol og vann (1000 ml;- 6:1 v/v). Den varme løsning ble behandlet med vandig ammoniakk-' (15.0 g; prepared as previously described in Example 4) was dissolved in a. hot mixture of ethanol and water (1000 ml; - 6:1 v/v). The hot solution was treated with aqueous ammonia-'
løsning (2N) inntil løsningen var alkalisk. Iseddik ble deretter satt til blandingen inntil løsningen var sur, og løs--' ningen ble avkjølt til 0 o C og ga et hvitt fast stoff (12,3 g.) .'r Dette faste stoff ble omkrystallisert fra en blanding av etanol og vann (4:1 v/v) og ga 2-(n-pentadecyl)benzimidazol-, 5-karboksylsyre (12,0 g) i form av et hvitt fast stoff, smp. 113°-115°C som ble antatt å være monohydratet. solution (2N) until the solution was alkaline. Glacial acetic acid was then added to the mixture until the solution was acidic, and the solution was cooled to 0°C to give a white solid (12.3 g.). This solid was recrystallized from a mixture of ethanol and water (4:1 v/v) to give 2-(n-pentadecyl)benzimidazol-,5-carboxylic acid (12.0 g) as a white solid, m.p. 113°-115°C which was assumed to be the monohydrate.
E KS: EMPEL 13 E KS: EMPEL 13
■ Forbindelse G■ Connection G
Metyl 4-amino-3-(n-tridekanamido)benzoat (fremstilt som iMethyl 4-amino-3-(n-tridecanamido)benzoate (prepared as in
det følgende beskrevet fra 17,8 g av metyl 3,4-diaminobenzoat og brukt uten ytterligere rensning) ble oppløst i varm etanol (500 ml) inneholdende et overskudd av saltsyre, og ble behandlet på lignende måte som beskrevet forut i eksempel 2 og ga 2-(n-dodecyl)benzimidazol-5-karboksylat-hydro-klorid (25,5 g) i form av et hvitt fast stoff, smp. 221°-225°C (under spaltning)'. (the following described from 17.8 g of methyl 3,4-diaminobenzoate and used without further purification) was dissolved in hot ethanol (500 ml) containing an excess of hydrochloric acid, and treated in a similar manner as previously described in Example 2 to give 2-(n-dodecyl)benzimidazole-5-carboxylate hydrochloride (25.5 g) as a white solid, m.p. 221°-225°C (under decomposition)'.
Metyl 4-amino-3-(n-tridekanamido)benzoatet som brukes som utgangsmateriale ble fremstilt som følger: "En løsning av metyl 3,4-diaminobenzoat (17,8 g) i diklor-. metan (350 ml)- inneholdende trietylenamin (10,8 g) ble behandlet med n-tridekanoylklorid (25 g) på lignende måte som forut beskrevet i eksempel l(ii) og ga rått metyl 4-amino-3-(n-tridekanamido)benzoat (40 g). The methyl 4-amino-3-(n-tridecanamido)benzoate used as starting material was prepared as follows: "A solution of methyl 3,4-diaminobenzoate (17.8 g) in dichloromethane (350 ml) containing triethyleneamine (10.8 g) was treated with n-tridecanoyl chloride (25 g) in a similar manner as previously described in Example 1(ii) to give crude methyl 4-amino-3-(n-tridecanamido)benzoate (40 g).
EKSEMPEL 14 Forbindelse H En løsning av metyl 2-(n-dodecyl)benzimidazol-5-karboksylat (15,5 g) i en blanding av etanol og vann (100 ml; 4:1 v/v), inneholdende natriumhydroksyd (50 g) ble behandlet på lignende måte som forut beskrevet i eksempel 4 oa ga 2-(n-dodecyl)-benzimidazol-5-karboksylsyréhydroklorid (11,7 g) i form av et hvitt fast. stoff, smp. 276°-290°C (under spaltning) . EKSEMPEL 15 Forbindelse B En løsning av 3,4-bis(n-heksadekanamido)benzosyre (20 g)'i metyletylketon (400 ml) ble behandlet med konsentrert salt- j syre (35 ml med styrke 36,5% w/v). Blandingen ble oppvarmet', ved tilbåkeløp i 5 timer og deretter avkjølt. Det resulter-, ende faste stoff ble oppsamlet og vasket med kokende petrol-; EXAMPLE 14 Compound H A solution of methyl 2-(n-dodecyl)benzimidazole-5-carboxylate (15.5 g) in a mixture of ethanol and water (100 ml; 4:1 v/v), containing sodium hydroxide (50 g ) was treated in a similar manner as previously described in example 4 oa to give 2-(n-dodecyl)-benzimidazole-5-carboxylic acid hydrochloride (11.7 g) in the form of a white solid. substance, m.p. 276°-290°C (under decomposition) . EXAMPLE 15 Compound B A solution of 3,4-bis(n-hexadecanamido)benzoic acid (20 g) in methyl ethyl ketone (400 ml) was treated with concentrated hydrochloric acid (35 ml at strength 36.5% w/v) . The mixture was heated at reflux for 5 hours and then cooled. The resulting solid was collected and washed with boiling petrol;
eter (kokepunkt 60°-80°C) og omkrystallisert fra etanol og ether (boiling point 60°-80°C) and recrystallized from ethanol and
ga 2-(n-pentadecyl)benzimidazol-5-karboksylsyrehydroklorid (15 g) i form av et hvitt fast stoff, smp. 298°-291°C (under1 spaltning). gave 2-(n-pentadecyl)benzimidazole-5-carboxylic acid hydrochloride (15 g) as a white solid, m.p. 298°-291°C (under 1 cleavage).
3,4-bis(n-heksadekanamido)benzosyren som brukes som. utgangsmateriale ble fremstilt som følger: The 3,4-bis(n-hexadecanamido)benzoic acid used as. starting material was prepared as follows:
En løsning av 3,4-diaminoben.z,osyre (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 l(ii). Et fast stoff ble oppsamlet og omkrystallisert fra iseddik og deretter omkrystallisert fra metyletylketon (under filtrering av den varme løsning) hvilket ga 3,4-bis(n-heksadekanamido)benzoat (20 g) i form av et brungult fast stoff, smp. 198-202°C. EKSEMPEL 16 Forbindelse A .En løsning av metyl 3,4-bis(n-heksadekanamido)benzoat (10,0 g) i metyletylketon (100 ml) ble behandlet på lignende måte som forut beskrevet i eksempel 15.. og ga metyl 2- (n-pentadecyl ) ben'zimidazol-5-karboksylathydroklorid (5,7 g) i form av et hvitt fast stoff, smp. 230°-232°C (under spaltning). 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 (filtering the hot solution) to give 3,4-bis(n-hexadecanamido)benzoate (20 g) as a tan solid, m.p. 198-202°C. EXAMPLE 16 Compound A .A solution of methyl 3,4-bis(n-hexadecanamido)benzoate (10.0 g) in methyl ethyl ketone (100 ml) was treated in a similar manner as previously described in Example 15... and gave methyl 2- (n-pentadecyl)benzimidazole-5-carboxylate hydrochloride (5.7 g) as a white solid, m.p. 230°-232°C (during decomposition).
Metyl 3,4-bis(n-heksadekanamido)benzoatet som ble brukt som The methyl 3,4-bis(n-hexadecanamido)benzoate which was used as
utgangsmateriale ble fremstilt som følger:starting material was prepared as follows:
En' løsning 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 l(ii) (reaksjonsblandingens tempera tur under tilsetningen fikk stige fra 20°C til 30°C). Et fast stoff ble-oppsamlet og omkrystallisert fra kloroform og ga metyl 3, 4-bis (n-heksadekanamido) benzoat (14,9 g) . i form av et hvitt fast stoff, smp. 129°-132°C. A 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°C to 30°C). A solid was collected and recrystallized from chloroform to give methyl 3,4-bis(n-hexadecanamido)benzoate (14.9 g). in the form of a white solid, m.p. 129°-132°C.
EKSEMPEL 17 Forbindelse I EXAMPLE 17 Compound I
En omrørt løsning av metyl 3,4-bis(n-undekanamido)benzoat (33,0 g) i metanol (400 ml) inneholdende konsentrert saltsyre (50 ml med styrke '3 6,5% v//v) ble oppvarmet ved tilbake-løp i 3 timfer. Blandingen ble deretter avkjølt til 0°C og filtrert, og det erholdt faste, stoff slått sammen med inn-dampningsresten fra filtratet i vakuum. De samlede faste stoffer ble vasket med varm petroleter (kokepunkt 60°-80°C; A stirred solution of methyl 3,4-bis(n-undecanamido)benzoate (33.0 g) in methanol (400 mL) containing concentrated hydrochloric acid (50 mL strength '3 6.5% v//v) was heated at back-run for 3 timfers. The mixture was then cooled to 0°C and filtered, and solid material was obtained combined with the evaporation residue from the filtrate in vacuo. The collected solids were washed with hot petroleum ether (boiling point 60°-80°C;
200 ml) og omkrystallisert fra etanol (under filtrering av den varme løsning) .og ga metyl 2-(n-decyl)benzimidazol-5-karboksylathydroklorid i form av et hvitt fast stoff (13,7 g), smp. 230°-240°C (under spaltning). 200 ml) and recrystallized from ethanol (while filtering the hot solution) to give methyl 2-(n-decyl)benzimidazole-5-carboxylate hydrochloride as a white solid (13.7 g), m.p. 230°-240°C (during decomposition).
Metyl 3,4-bis(n-undekanamido)benzoatet som brukes som utgangsmateriale ble fremstilt som følger: En løsning'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 16. Et fast stoff ble oppsamlet og omkrystallisert toganger fra etanol (under filtrering av den varme løsning) og ga metyl 3,4-bis(n-undekanamido)benzoat (40,2 g) i form av et hvitt fast stoff, smp. 139°-141°C.. The methyl 3,4-bis(n-undecanamido)benzoate used as starting material was prepared as follows: 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 to that previously described in Example 16. A solid was collected and recrystallized twice from ethanol (while filtering 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 18EXAMPLE 18
Forbindelse JConnection J
En løsning av metyl 2-(n-decyl)benzimidazol-5-karboksylat-hydroklorid (13,7 g; fremstilt som forut beskrevet i eksempel 17) i en blanding av etanol og vann (250 ml; 4:1 v/v) inneholdende natriumhydroksyd (4,6 g) ble behandlet på lignende måte som beskrevet i eksempel 4 og ga 2-(n-decyl)benzi-midazol-5-karboksylsyrehydroklorid (9,4 g) i form .av et hvitt fast stoff, smp. 270°-282°C (under spaltning). A solution of methyl 2-(n-decyl)benzimidazole-5-carboxylate hydrochloride (13.7 g; prepared as previously described in Example 17) in a mixture of ethanol and water (250 ml; 4:1 v/v) containing sodium hydroxide (4.6 g) was treated in a similar manner as described in Example 4 and gave 2-(n-decyl)benzimidazole-5-carboxylic acid hydrochloride (9.4 g) in the form of a white solid, m.p. . 270°-282°C (under decomposition).
EKSEMPEL 19EXAMPLE 19
Forbindelse BCompound B
En løsning -av 2-(n-pentadecyl) benzimidazol-5-karboksylsyre-monohydråt (11,16 g; fremstilt som forut beskrevet i eksempel 12) i metanol (150 ml) ble oppvarmet til 60°C og behand-•. A solution of 2-(n-pentadecyl) benzimidazole-5-carboxylic acid monohydrate (11.16 g; prepared as previously described in Example 12) in methanol (150 ml) was heated to 60°C and treated.
lét med en løsning av natriummetoksyd [fremstilt ved forsiktig oppløsning av natrium (0,69 g) i vannfri metanol (40 ml)] og blandingen ble deretter avkjølt. Løsningsmidlet ble inndampet i vakuum og resten ble omkrystallisert fra vann qg ga natrium 2-(n-pentadecyl)benzimidazol-5-karboksyl-atmonohydrat (9,7 g) i form av et hvitt fast stoff som mørkner ved 250°C og spaltes''ved over 300°C. was treated with a solution of sodium methoxide [prepared by carefully dissolving sodium (0.69 g) in anhydrous methanol (40 ml)] and the mixture was then cooled. The solvent was evaporated in vacuo and the residue was recrystallized from water to give sodium 2-(n-pentadecyl)benzimidazole-5-carboxylate monohydrate (9.7 g) as a white solid which darkens at 250°C and decomposes. 'at over 300°C.
. EKSEMPEL 2 0 Forbindelse B En omrørt suspensjon av 2-(n-pentadecyl)benzimidazol-5-kar-boksylsyremonohydrat (1,00 g; fremstilt som forut beskrevet i.eksempel 12) i aceton (30 ml) ble behandlet dråpevis med . EXAMPLE 20 Compound B A stirred suspension of 2-(n-pentadecyl)benzimidazole-5-carboxylic acid monohydrate (1.00 g; prepared as previously described in Example 12) in acetone (30 ml) was treated dropwise with
en løsning av metansulfonsyre (0,25 g) i metanol (15 ml)a solution of methanesulfonic acid (0.25 g) in methanol (15 ml)
ved romtemperatur. Blandingen ble oppvarmet i 4 0°C og ga •'. en løsning, og deretter ble løsningsmidlet fordampet i vakuum. Den hvite faste resten ble revet med aceton (30 ml) og det resulterende faste stoff ble oppsamlet og vasket med aceton (10 ml) og ga 2-(n-pentadecyl)benzimidazol-5-karboks-• ylsyremetansulfonat (1,19 g) i' form av et hvitt fast stoff, .. •smp. 115°-1170C. at room temperature. The mixture was heated to 40°C to give •'. a solution, and then the solvent was evaporated in vacuo. The white solid residue was triturated with acetone (30 mL) and the resulting solid was collected and washed with acetone (10 mL) to give 2-(n-pentadecyl)benzimidazol-5-carboxylic acid methanesulfonate (1.19 g) in' the form of a white solid, .. •m.p. 115°-1170C.
EKSEMPEL 21EXAMPLE 21
Forbindelse BCompound B
En omrørt suspensjon ay 2-(n-pentadecyl)benzimidazol-5-kar-boksylsyremonohydrat (1,00 g; fremstilt som forut beskrevet; A stirred suspension of 2-(n-pentadecyl)benzimidazole-5-carboxylic acid monohydrate (1.00 g; prepared as previously described;
i eksempel 12) i aceton (30 ml) ble behandlet med et overskudd av.en løsning av 2-hydroksyetylsulfonsyre (10% w/v) in Example 12) in acetone (30 ml) was treated with an excess of a solution of 2-hydroxyethylsulfonic acid (10% w/v)
i en blanding av metanol og vann (19:1 v/ v) .. Løsningen ble fordampet i vakuum og resten ble revet med aceton (30 ml). Det resulterende faste stoff ble oppsamlet og vasket med aceton (10 ml) og ga 2-(n-pentadecyl)benzimidazol-5-karboksylsyre 2-hydroksyetylsulfonat (1,24 g) i form av et hvitt fast stoff, smp. 93°- 95°C. in a mixture of methanol and water (19:1 v/v).. The solution was evaporated in vacuo and the residue was triturated with acetone (30 ml). The resulting solid was collected and washed with acetone (10 mL) to give 2-(n-pentadecyl)benzimidazole-5-carboxylic acid 2-hydroxyethyl sulfonate (1.24 g) as a white solid, m.p. 93°- 95°C.
EKSEMPEL 2, 2EXAMPLE 2, 2
Forbindelse A. 2-(n-pentadecyl)benzimidazol-5-karboksylsyrehydroklorid i (10,0 'g;"fremstilt som forut beskrevet i eksempel 4) ble oppløst i kokende metanol (250 ml) i en tilbakeløpsapparatur og deretter behandlet med konsentrert saltsyre (20 ml med styrke 36,5% w/v). Blandingen ble oppvarmet ved tilbakeløp Compound A. 2-(n-pentadecyl)benzimidazole-5-carboxylic acid hydrochloride i (10.0 g; prepared as previously described in Example 4) was dissolved in boiling methanol (250 mL) in a reflux apparatus and then treated with concentrated hydrochloric acid (20 ml at strength 36.5% w/v) The mixture was heated at reflux
i 3 timer og så avkjølt'til 0°C. Det resulterende hvite faste stoff ble oppsamlet, vasket med vann og omkrystallisert fra etanol og- ga metyl 2-(n-pentadecyl) benzimidaz.ol-5-karboksylathydroklorid ( 9, 2 g) ' i form av et hvitt fast stoff smp. 230°-232°C (under spaltning). for 3 hours and then cooled to 0°C. The resulting white solid was collected, washed with water and recrystallized from ethanol and methyl 2-(n-pentadecyl)benzimidazol-5-carboxylate hydrochloride (9.2 g) as a white solid m.p. 230°-232°C (during decomposition).
EKSEMPEL 23EXAMPLE 23
Forbindelse KConnection K
Metyl 3,4-diaminobenzoat (33,0 g) og n-oktadekansyre (56,8 g). ble malt sammen til en grundig blanding og blandingen ble oppvarmet ved 2 00°C i 210 min. Blandingen ble så behandlet på lignende måte som beskrevet forut i eksempel 9. Den erholdte brune olje ble etter fordeling mellom en varm blanding, av petroleter , toluen og vann, oppløst i kloroform (25 ml) og kromatografert på en kolonne av-kiselgel.. (750 g) . Eluering med en blanding.av kloroform og metanol (19:1 v/v)-ga et lysebrunt fast. stoff (40 g). Dette faste stoff ble oppløst i varm toluen (200 ml) og behandlet med et overskudd av en mettet oppløsning av hydrogenklorid i etanol. Det resulterende faste stoff ble oppsamlet og omkrystallisert .(.under behandling med aktivt karbon) fra en blanding av etanol og vann (9:1 v/v), og ga metyl 2-(n-heptadecyl)ben-zimidazol-5-karboksylathydroklorid (19,9 g) i form av et hvitt fast stoff, smp. 229°-234°C (under spaltning). Methyl 3,4-diaminobenzoate (33.0 g) and n-octadecanoic acid (56.8 g). was ground together to a thorough mixture and the mixture was heated at 200°C for 210 min. The mixture was then treated in a similar way as described previously in example 9. The brown oil obtained was, after distribution between a warm mixture of petroleum ether, toluene and water, dissolved in chloroform (25 ml) and chromatographed on a column of silica gel. (750g) . Elution with a mixture of chloroform and methanol (19:1 v/v) gave a light brown solid. fabric (40 g). This solid was dissolved in hot toluene (200 mL) and treated with an excess of a saturated solution of hydrogen chloride in ethanol. The resulting solid was collected and recrystallized (under treatment with activated carbon) from a mixture of ethanol and water (9:1 v/v) to give methyl 2-(n-heptadecyl)benzimidazole-5-carboxylate hydrochloride (19.9 g) as a white solid, m.p. 229°-234°C (under decomposition).
EKSEMPEL 2 4EXAMPLE 2 4
Forbindelse LConnection L
En løsning av metyl 2-(n-heptadecyl)benzimidazol-5-karboksy-lathydroklorid (11,5 g; fremstilt som forut beskrevet i eksempel 23) i en blanding av etanol og vann (2.00 ml; 1:1 v/v) inneholdende natriumhydroksyd (14,35 g) ble behandlet på lignende måte som forut beskrevet i eksempel 4 og ga A solution of methyl 2-(n-heptadecyl)benzimidazole-5-carboxylate hydrochloride (11.5 g; prepared as previously described in Example 23) in a mixture of ethanol and water (2.00 ml; 1:1 v/v) containing sodium hydroxide (14.35 g) was treated in a similar manner as previously described in Example 4 and gave
2- (-n-heptadecyl) benzimidazol-5-ka.rboksylsyrehydroklorid2-(-n-heptadecyl) benzimidazole-5-carboxylic acid hydrochloride
(8,8 g) i form'av et hvitt fast stoff, smp. 279°-284°C (8.8 g) as a white solid, m.p. 279°-284°C
(under spaltning). (under cleavage).
EKSEMPEL 2 5 Forbindelse M EXAMPLE 2 5 Compound M
En blanding av metyl 4-amino-3-(n-dekanamido)-benzoat (16 ,7 g) A mixture of methyl 4-amino-3-(n-decanamido)-benzoate (16.7 g)
r r
og toluen (600 ml) inneholdende p-toluensulfonsyre (5,0 g) ble behandlet på lignende måte som forut beskrevet i eksemp-, el 1 og ga metyl 2—(n-nonyl)benzimidazol-5-karboksylat (14,0 g) i form.av et hvitt fast stoff, smp. 101°-103°C.. and toluene (600 ml) containing p-toluenesulfonic acid (5.0 g) was treated in a similar manner as previously described in Example 1 to give methyl 2-(n-nonyl)benzimidazole-5-carboxylate (14.0 g ) in the form of a white solid, m.p. 101°-103°C..
Metyl 4-amino-3-(n-dekanamido)benzoatet som ble. brukt som utgangsmateriale ble fremstilt som følger:' The methyl 4-amino-3-(n-decanamido)benzoate which was used as starting material was prepared as follows:'
En omrørt løsning av metyl 3,4-diaminobenzoat (16,6 g) i tørr dimetylfprmamid (600 ml) inneholdende vannfritt natriumkarbonat (5,3 g) ble behandlet dråpevis med en dekanyl-klorid (19,1 g) på lignende måte søm forut beskrevet i eksempel l(i) og ga metyl 4-amino-3-(n-dekanamido)benzoat (18,8 g) i form av et brungult fast stoff, 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 a decanyl chloride (19.1 g) in a similar manner as previously described in Example 1(i) and gave methyl 4-amino-3-(n-decanamido)benzoate (18.8 g) as a tan solid, m.p. 96°-98°C.
EKSEMPEL 2 6EXAMPLE 2 6
Forbindelse NConnection N
En løsning av metyl 2-(n-nonyl)benzimidazol-5-karboksylat A solution of methyl 2-(n-nonyl)benzimidazole-5-carboxylate
(13,5 g; fremstilt som forut beskrevet i eksempel 25) i en blanding av etanol og vann (400 ml; 4:1 v/v) inneholdende natriumhydroksyd (3,6 g) ble behandlet på lignende måte som beskrevet forut i eksempel 4 og ga 2 —(n-nonyl)benzimidazol-5-karboksyisyrehydroklorid (8,6 g) i form av et hvitt fast stoff, -smp. 275°-280°C. (13.5 g; prepared as previously described in Example 25) in a mixture of ethanol and water (400 ml; 4:1 v/v) containing sodium hydroxide (3.6 g) was treated in a similar manner as described previously in Example 4 and gave 2-(n-nonyl)benzimidazole-5-carboxylic acid hydrochloride (8.6 g) as a white solid, m.p. 275°-280°C.
EKSEMPEL 27EXAMPLE 27
Forbindelse 0Connection 0
En omrørt løsning av metyl 3,4-bis(n-oktanamido)benzoat A stirred solution of methyl 3,4-bis(n-octanamido)benzoate
.(81,8 g) i metanol (800.ml) inneholdende konsentrert saltsyre (100 ml med styrke 36,5% w/v) ble oppvarmet ved til-bakeløp i 4 timer. Blandingen ble så avkjølt og behandlet på lignende måte som beskrevet forut i eksempel 17 og ga .(81.8 g) in methanol (800 ml) containing concentrated hydrochloric acid (100 ml with a strength of 36.5% w/v) was heated at reflux for 4 hours. The mixture was then cooled and treated in a similar manner as previously described in Example 17 and gave
metyl 2-(.n-heptyl) benzimidazol-5-karboksylathydroklorid (33,8 g) i form av et hvitt fast stoff, smp. 140°-142°C (under spaltning). methyl 2-(.n-heptyl) benzimidazole-5-carboxylate hydrochloride (33.8 g) as a white solid, m.p. 140°-142°C (during cleavage).
Metyl 3,4-bis(n-oktanamido)benzoatet som brukes som utgangs-; materiale ble fremstilt som følger: En.løsning av metyl 3,4-diaminobenzoat (41,2 g) i diklormetan (412 ml) inneholdende trietylamin (51,0 g) ble behandlet med en løsning av n-oktanoylklorid (80,6 g) i diklormetan (330 ml) på lignende måte som forut beskrevet i eksempel- 16 ved omkrystallisering fra metanol (under behandling med aktivt karbon) og ga metyl.3,4-bis(n-oktanamido)benzoat (81,8 g) i form av et hvitt fast stoff, smp. 138°-140°C. The methyl 3,4-bis(n-octanamido)benzoate used as starting; material was prepared as follows: 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 in example-16 by recrystallization from methanol (under treatment with activated carbon) and gave methyl 3,4-bis(n-octanamido)benzoate (81.8 g) in form of a white solid, m.p. 138°-140°C.
EKSEMPEL 2 8 Forbindelse P EXAMPLE 2 8 Compound P
En omrørt løsning av metyl 2-(n-heptyl)benzimidazol-5-kar-. boksylathydroklorid (23,0 g; fremstilt som forut beskrevet i eksempel 27) i en blanding av etanol og vann (200 ml; A stirred solution of methyl 2-(n-heptyl)benzimidazol-5-car-. boxylate hydrochloride (23.0 g; prepared as previously described in Example 27) in a mixture of ethanol and water (200 ml;
12:1 v/v) inneholdende natriumhydroksyd (8,9 g) ble oppvarmet ved tilbakeløp i 5 timer. Blandingen ble behandlet på lignende måte som beskrevet forut i eksempel 4 og ga.2-(n-heptyl) benzimidazol-5-karboksy'lsyrehydroklorid (14,4 g) i form av et hvitt fast stoff , smp. 310°-313°C . (under spaltning) . 12:1 v/v) containing sodium hydroxide (8.9 g) was heated at reflux for 5 hours. The mixture was treated in a similar manner as described previously in Example 4 and gave 2-(n-heptyl) benzimidazole-5-carboxylic acid hydrochloride (14.4 g) in the form of a white solid, m.p. 310°-313°C. (under cleavage) .
EKSEMPEL 2 9EXAMPLE 2 9
Forbindelse QConnection Q
En omrørt løsning av 3 , 4-bis(n-pentadekahamido)benzosyre (49,3 g) i en blanding av metyletylketon og konsentrert saltsyre (560 ml; 10.:.l v/v) ble oppvarmet ved tilbakeløp i 3 timer. Blandingen ble så avkjølt. Det resulterende faste stoff ble oppsamlet og tørket med metyletylketon (200 ml) og deretter vasket med kokende petroleter (-2 0 0 ml; kokepunkt 60°-80°C). Det ble omkrystallisert fra en blanding av etanol og vann (4:1 v/v) (under behandling med aktivt karbon og filtrering av den varme løsning) og -ga 2-(n-tetra-decyl)benzimidazol-5-karboksylsyrehydroklorid (15,7 g), smpJ A stirred solution of 3,4-bis(n-pentadecahamido)benzoic acid (49.3 g) in a mixture of methyl ethyl ketone and concentrated hydrochloric acid (560 ml; 10.:.1 v/v) was heated at reflux for 3 hours. The mixture was then cooled. The resulting solid was collected and dried with methyl ethyl ketone (200 mL) and then washed with boiling petroleum ether (-200 mL; b.p. 60°-80°C). It was recrystallized from a mixture of ethanol and water (4:1 v/v) (treating with activated carbon and filtering the hot solution) to give 2-(n-tetradecyl)benzimidazole-5-carboxylic acid hydrochloride (15 .7 g), m.p.J
• over 300°C (under spaltning) . 3,4-bis(n-pentadekanamido)benzosyre, som brukes som utgangsmateriale ble fremstilt som følger: En løsning av 3,4-diaminobenzosyre (13,85 g) i dimetylformamid (180 ml) inneholdende trietylamin (27,6 g) ble behandlet med pentadekanoylk-lorid (47,4 g) på lignende måte som forut beskrevet i eksempel l(i). Det resulterende faste stoff ble oppsamlet og omkrystallisert fra metyletylketon (under, behandling med. aktivt karbon og filtrering av den varme løsning) og ga 3,4-bis(n-pentadekanamido)benzosyre (49,3 g) smp. 178°-180°C. • above 300°C (during decomposition) . 3,4-bis(n-pentadecanamido)benzoic acid, which is used as starting material, was prepared as follows: A solution of 3,4-diaminobenzoic acid (13.85 g) in dimethylformamide (180 ml) containing triethylamine (27.6 g) was treated with pentadecanoyl chloride (47.4 g) in a similar manner as previously described in Example 1(i). The resulting solid was collected and recrystallized from methyl ethyl ketone (under, treatment with activated carbon and filtration of the hot solution) to give 3,4-bis(n-pentadecanamido)benzoic acid (49.3 g) m.p. 178°-180°C.
EKSEMPEL 3 0EXAMPLE 3 0
Forbindelse R Compound R
(a) En omrørt løsning av metyl 3,4-bis(n-nonatamido)benzoat (a) A stirred solution of methyl 3,4-bis(n-nonatamido)benzoate
(23,3 g) i metanol (300 ml) ble behandlet med konsentrert saltsyre (40 ml med styrke 36,5% v//v) . Blandingen ble oppvarmet ved tilbakeløp i 3 timer og løsningsmidlet fjernet i vakuum og'ga et hvitt fast stoff. Det faste stoff ble (23.3 g) in methanol (300 ml) was treated with concentrated hydrochloric acid (40 ml with strength 36.5% v//v). The mixture was heated at reflux for 3 hours and the solvent removed in vacuo to give a white solid. The solid became
vasket med varm petroleter (100 ml; kokepunkt 40°-60°C) og omkrystallisert fra vann (700 ml) under varm filtrering og ga metyl'2^n-oktylbenzimidazol-5-karboksylathydroklorid i form av et hvitt fast stoff, smp. 238°-243°C (12,Og). washed with hot petroleum ether (100 ml; b.p. 40°-60°C) and recrystallized from water (700 ml) under hot filtration to give methyl'2^n-octylbenzimidazole-5-carboxylate hydrochloride as a white solid, m.p. 238°-243°C (12.Og).
.(b) En. omrørt løsning av metyl 2-n-oktyl-benzimidazol-5-karboksylathydroklorid (11 g; fremstilt som ovenfor beskrevet) i en blanding av etanol og vann (240 ml; 12:1 v/v) inneholdende natriumhydroksyd (4,0 g) ble oppvarmet ved tilbake-løp i 4. timer. Blandingen ble behandlet på lignende måte .(b) One. stirred solution of methyl 2-n-octyl-benzimidazole-5-carboxylate hydrochloride (11 g; prepared as described above) in a mixture of ethanol and water (240 ml; 12:1 v/v) containing sodium hydroxide (4.0 g) was heated on return run for 4 hours. The mixture was treated in a similar manner
som beskrevet forut i eksempel 4 og ga 2-(n-oktyl)benzimida-zol-5-karboksylsyrehydroklorid (7,8 g) i form av et hvitt fast stoff, smp. 280°-300°C (under spaltning). as described above in Example 4 and gave 2-(n-octyl)benzimidazole-5-carboxylic acid hydrochloride (7.8 g) as a white solid, m.p. 280°-300°C (during decomposition).
Metyl 3,4-bis(n-nonanamido)benzoatet som brukes som utgangs-ma.teriale ble fremstilt som følger: (c) En omrørt løsning av metyl 3,4-diamino-benzoat (20 g) i The methyl 3,4-bis(n-nonanamido)benzoate used as starting material was prepared as follows: (c) A stirred solution of methyl 3,4-diamino-benzoate (20 g) in
tørt. diklormetan (250 ml), inneholdende trietylamin (24,2' g) ble behandlet dråpevis med en løsning av nonanoylklorid ' dry. dichloromethane (250 ml), containing triethylamine (24.2' g) was treated dropwise with a solution of nonanoyl chloride'
(44,12 g) i tørt diklormetan (50 ml) på lignende måte som forut beskrevet i eksempel l(ii). Det resulterende lyserøde'stoff ble omkrystallisert fra metanol under behandling med aktivt karbon og ga metyl 3,4-bis-(n-nonanamido)benzoat (44.12 g) in dry dichloromethane (50 ml) in a similar manner as previously described in example 1(ii). The resulting bright red substance was recrystallized from methanol under treatment with activated carbon to give methyl 3,4-bis-(n-nonanamido)benzoate
(30,3 g) i form av et hvitt fast stoff, smp. 142°-145°C. (30.3 g) as a white solid, m.p. 142°-145°C.
EKSEMPEL 31 Forbindelse S EXAMPLE 31 Compound S
2-(n-tetradecyl)benzimidazol-5-karboksylsyrehydroklorid2-(n-tetradecyl)benzimidazole-5-carboxylic acid hydrochloride
(8,5 g; fremstilt som forut beskrevet i eksempel.29) ble oppløst i kokende metanol (96 ml) i et tilbakeløpsapparat og ble så behandlet med konsentrert saltsyre (22 ml) med styrke 36,5% w/y). Blandingen ble tilbakeløpskokt 3 timer (8.5 g; prepared as previously described in example.29) was dissolved in boiling methanol (96 ml) in a reflux apparatus and was then treated with concentrated hydrochloric acid (22 ml) at a strength of 36.5% w/y). The mixture was refluxed for 3 hours
og deretter- behandlet på lignende måte som forut beskrevet i eksempel 22 og ga metyl 2-(n-tetradecyl)benzimidazol-5-karboksylathydroklorid (6,2 g) i form av et hvitt fast stoff, smp. 233°-235°C. and then treated in a similar manner as previously described in Example 22 to give methyl 2-(n-tetradecyl)benzimidazole-5-carboxylate hydrochloride (6.2 g) in the form of a white solid, m.p. 233°-235°C.
EKSEMPEL 3 2EXAMPLE 3 2
Forbindelse T Connection T
2-(n-heksadecyl)benzimidazol-5-karboksylsyrehydroklorid2-(n-hexadecyl)benzimidazole-5-carboxylic acid hydrochloride
(9,6 g; fremstilt som beskrevet i det følgende i eksempel(9.6 g; prepared as described below in Example
33) ble oppløst i kokende metanol (400 ml) i et tilbakeløps-apparat og så behandlet med konsentrert saltsyre (100 ml med styrke 36,5% w/v). Blandingen ble oppvarmet ved til-bakeløp i 8 timer, og deretter behandlet på lignende måte som forut beskrevet i eksempel 22 og ga metyl 2-(n-heksadecyl)-benzimidazol-5-karboksylathydroklorid (7,4 g) i form av et hvitt fast stoff, smp. 225°-230°C (under spaltning). 33) was dissolved in boiling methanol (400 ml) in a reflux apparatus and then treated with concentrated hydrochloric acid (100 ml at strength 36.5% w/v). The mixture was heated at reflux for 8 hours, and then treated in a similar manner as previously described in Example 22 to give methyl 2-(n-hexadecyl)-benzimidazole-5-carboxylate hydrochloride (7.4 g) as a white solid, m.p. 225°-230°C (during cleavage).
EKSEMPEL 33EXAMPLE 33
Forbindelse UConnection U
En løsning av 3,4-bis(n-heptadekanamido)benzosyre (250 g) i metyletylketon (1500 ml) ble behandlet med konsentrert salt-, syre (180 ml, styrke 36,5% w/v). Blandingen ble tilbake-løpskokt 8 timer og så behandlet på lignende måte som forut beskrevet i eksempel. 15 og ga 2-(n-heksadecyl)benzimidazol- 5-karboksylsyrehydroklorid. (44,9 g) i form av et gråhvitt fast stoff,' smp. 296°-306°C (under spaltning). A solution of 3,4-bis(n-heptadecanamido)benzoic acid (250 g) in methyl ethyl ketone (1500 ml) was treated with concentrated hydrochloric acid (180 ml, strength 36.5% w/v). The mixture was refluxed for 8 hours and then treated in a similar manner as previously described in the example. 15 and gave 2-(n-hexadecyl)benzimidazole-5-carboxylic acid hydrochloride. (44.9 g) in the form of an off-white solid, m.p. 296°-306°C (under decomposition).
3,4-bis(h-heptadekanamido)benzosyren som brukes som utgangs-! materiale ble fremstilt som følger: En omrørt løsning -av 3,4-diaminobenzosyre (45,6 g) i dimetylformamid (400 ml), inneholdende trietylamin (75,8 g) ble behandlet dråpevis med n-heptadekanoylklorid (130 g) i 1,5 timer. Tilsetningshastigheten av n-heptadekanoylkloridet var slik at reaksjonsblandingens temperatur fikk stige fra romtemperatur til 35°-40°C. Blandingen ble så rørt ved denne temperatur i ytterligere 2 timer og deretter helt i varmt vann (3500 ml ved 70°C) inneholdende konsentrert saltsyre (50 ml med styrke 36,5%) hvilket ga rått 3,4-bis-(n-heptadekanamido)benzosyre (140 g) i form av et lyserødt fast stoff. The 3,4-bis(h-heptadecanamido)benzoic acid used as starting! material was prepared as follows: 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 1 .5 hours. The rate of addition of the n-heptadecanoyl 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 this temperature for a further 2 hours and then poured into hot water (3500 ml at 70°C) containing concentrated hydrochloric acid (50 ml at strength 36.5%) which gave crude 3,4-bis-(n- heptadecanamido)benzoic acid (140 g) as a pink solid.
EKSEMPEL 3 4.EXAMPLE 3 4.
Forbindelse V Connection V
2-n-Eicosylbenzimidazol-5-karboksylsyrehydroklorid (12 g.; 2-n-Eicosylbenzimidazole-5-carboxylic acid hydrochloride (12 g.;
fremstilt som beskrevet i det følgende eksempel 35) i kloroform (300 ml) ble behandlet dråpevis under røring med tionylklorid (100 ml). Blandingen ble tilbakeløpskokt 4 timer og ble så avkjølt og overskuddet av tionylkloridet og løsnings-midlet ble fjernet i vakuum og ga et hvitt fast stoff. Det faste stoff ble oppslemmet i vannfri metanol (300 ml) og blandingen ble rørt og tilbakeløpskokt 8 timer og deretter avkjølt. Det faste stoff ble oppsamlet og vasket med metanol og ga metyl 2-(n-eicosyl)benzimidazol-5-karboksylat-hydroklorid (9,2 g) i form av et hvitt fast stoff, smp. 220°-226°C. prepared as described in the following example 35) in chloroform (300 ml) was treated dropwise with stirring with thionyl chloride (100 ml). The mixture was refluxed for 4 hours and then cooled and the excess thionyl chloride and solvent removed in vacuo to give a white solid. The solid was slurried in anhydrous methanol (300 mL) and the mixture was stirred and refluxed for 8 hours and then cooled. The solid was collected and washed with methanol to give methyl 2-(n-eicosyl)benzimidazole-5-carboxylate hydrochloride (9.2 g) as a white solid, m.p. 220°-226°C.
EKSEMPEL 3 5EXAMPLE 3 5
Forbindelse WConnection W
En løsning av 3,4-bis(n-heneicosanamido)-benzosyre (126,5 g) i metyletylketon (1000 ml) ble behandlet med konsentrert saltsyre (100 ml, 36,5% w/v). Blandingen ble tilbakeløps-kokt 10 timer og ble så behandlet på lignende måte som forut ■ beskrevet i eksempel 15, hvilket ga et hvitt fast stoff som .ble omkrystallisert fra n-butanol (1200 ml) og ga 2-(n-eico-syl)benzimidazol-5-karboksylsyrehydroklorid (45,1 g) i form av et hvitt fast stoff, smp. 294°-298°C (under spaltning). A solution of 3,4-bis(n-heneicosanamido)-benzoic acid (126.5 g) in methyl ethyl ketone (1000 mL) was treated with concentrated hydrochloric acid (100 mL, 36.5% w/v). The mixture was refluxed for 10 hours and then treated in a manner similar to that previously described in Example 15 to give a white solid which was recrystallized from n-butanol (1200 mL) to give 2-(n-eico-syl )benzimidazole-5-carboxylic acid hydrochloride (45.1 g) in the form of a white solid, m.p. 294°-298°C (under decomposition).
3,4-bis(n-heneicosanamido)benzosyren som ble brukt som ut-gangsmaterialé ble fremstilt som følger: . The 3,4-bis(n-heneicosanamido)benzoic acid used as starting material was prepared as follows: .
En omrørt løsning av 3,4-diaminobenzosyre (21,9.g) i dimetylformamid (175 ml), inneholdende tr i etylamin ,' (4 3 , 6 g) ble behandlet dråpevis med n-heneicosanoylklorid (99,2 g). på lignende måte som forut beskrevet i eksempel 33 hvilket ga rått 3,4-bis (n-hene.icosanamido) benzosyre (126,5 g) i form av et lysebrunt fast stoff. A stirred solution of 3,4-diaminobenzoic acid (21.9g) in dimethylformamide (175ml) containing triethylamine (43.6g) was treated dropwise with n-heneicosanoyl chloride (99.2g). in a similar manner to that previously described in Example 33 which gave crude 3,4-bis(n-hene.icosanamido)benzoic acid (126.5 g) in the form of a light brown solid.
EKSEMPEL 3 6 Forbindelse X EXAMPLE 3 6 Compound X
2-(n-nonadecyl)benzimidazol-5-karboksylsyrehydroklorid (14,6 g;. fremstilt som beskrevet i-det følgende eksempel 37) ble oppslemmet i tionylklorid (3 50 ml) og blandingen ble førtbg tilbakeløpskokt i 6 timer. Overskuddet av tionylkloridet ble fjernet i vakuum og ga et gulbrunt fast stoff. Det faste stoffet ble oppslemmet i vannfri metanol (500 ml) og blandingen ble rørt og tilbakeløpskokt i 3 timer. Blandingen ble så' behandlet på lignende måte som beskrevet i eksempel 34 og ga metyl 2-(n-nonadecyl)benzimidazol-5-karboksylat-hydroklorid (12,2 g) i form av et hvitt fast stoff, smp. 219°-227°C. 2-(n-nonadecyl)benzimidazole-5-carboxylic acid hydrochloride (14.6 g; prepared as described in the following Example 37) was slurried in thionyl chloride (350 ml) and the mixture was refluxed for 6 hours. The excess thionyl chloride was removed in vacuo to give a tan solid. The solid was slurried in anhydrous methanol (500 mL) and the mixture was stirred and refluxed for 3 hours. The mixture was then treated in a similar manner as described in Example 34 and gave methyl 2-(n-nonadecyl)benzimidazole-5-carboxylate hydrochloride (12.2 g) as a white solid, m.p. 219°-227°C.
EKSEMPEL<3>7EXAMPLE<3>7
Forbindelse Y En suspensjon av 3,4-bis(n-eicosanamido)benzosyre (89,1 g) i metyletylketon (1200 ml) ble oppvarmet med konsentrert salt- . syre (120 ml, 36,5%). Blandingen ble rørt og tilbakeløps-kokt i 8 timer og så behandlet på lignende måte som forut beskrevet i eksempel 15. og ga et hvitt fast stoff. Det'faste stoffet ble kokt med n-butanol (100 ml) og blandingen ble avkjølt å ga 2-(n-nonadecyl)benzimidazol-5-karboksylat-hydroklorid (36,5 g) i form av et hvitt fast stoff, smp. 290- 300°C (under spaltning). Compound Y A suspension of 3,4-bis(n-eicosanamido)benzoic acid (89.1 g) in methyl ethyl ketone (1200 ml) was heated with concentrated brine. acid (120 ml, 36.5%). The mixture was stirred and refluxed for 8 hours and then treated in a similar manner as previously described in Example 15 to give a white solid. The solid was boiled with n-butanol (100 mL) and the mixture was cooled to give 2-(n-nonadecyl)benzimidazole-5-carboxylate hydrochloride (36.5 g) as a white solid, m.p. 290- 300°C (during decomposition).
3,4-bis(n-eicosanamido)benzos<y>ren'som brukes som utgangsmateriale ble fremstilt som følger: 3,4-bis(n-eicosanamido)benzos<y>rene' used as starting material was prepared as follows:
En omrørt løsning av 3 ,4-diaminobenzosyre (1.8,3 g) i ■dimetyl-. formamid (200 ml) .inneholdende trietylamin (36,5 g) ble be- . handlet dråpevis med n-éicosanoylklorid (79,4 g) på lignende måte som forut beskrevet i eksempel 33 og ga rått 3,4-bis-(n-eicosanamido)benzosyre (93 g) i form av et lysebrunt fast stoff, smp. 160O-'170°C.' ' EKSEM PEL 3 8 Forbindelse Z En oppslemning av 4-amino-3-(n-nonadekanamido)benzosyre (107' g) i metyletylketon (1500 ml) ble behandlet med konsentrert saltsyre (100 ml, 36,5%). Blandingen ble rørt og tilbakeløpskokt 3 timer. Blandingen ble avkjølt til 10°C og det faste stoff oppsamlet, vasket med'metyletylketon (2 x 500 ml) og oppslemmet i vann (500 ml). Natriumhydrok-sydløsningen (50 g i vann (150 ml)) ble satt..til blandingen og blandingen ble rørt og oppvarmet til 60°C for oppløsning.' Iseddik ble tilsatt den omrørte blanding inntil blandingen hadde pH 5, og det resulterende faste stoff ble oppsamlet, vasket med vann (2 x 500 ml) og tørket. Det faste stoff ble omkrystallisert fra etanol under behandling med aktivt karbon og ga et hvitt.fast stoff som ble forsiktig tørket og deretter oppslemmet i metyletylketon (500 ml) inneholdende konsentrert saltsyre (100 ml, 36,5%). Blandingen ble rørt og tilbakeløpskokt en time og deretter avkjølt og ga 2-(n-oktadecyl)benzimidazol-5-karboksylsyrehydroklorid (33,8. g) i form av et hvitt fast stoff, smp. 292°-297°C (under spaltning) . 4-amino-3-(n-npnadekanamido)benzosyren som ble.brukt som utgangsmateriale ble fremstilt som følger: En omrørt løsning av 3,4-diaminobenzosyre (38 g) i dimetylformamid .'(500 ml) inneholdende trietylamin (50,5.g) ble be handlet dråpevis med n-nonadekanoylklorid (79,1 g) på lignende måte som forut beskrevet i eksempel 33 og ga en orange løsning som ble helt i vann (300.0 ml) inneholdende konsentrert saltsyre (100 ml, styrke 36,5%). Det faste stoff ble : oppsamlet, vasket med vann (2.x 100 ml) og så tørket og- ga rått 4-amino-3-(n-nonadekanamido)benzosyre (107 g), smp. 103°-113°C. A stirred solution of 3,4-diaminobenzoic acid (1.8.3 g) in ■dimethyl-. formamide (200 ml) containing triethylamine (36.5 g) was added. treated dropwise with n-eicosanoyl chloride (79.4 g) in a similar manner as previously described in Example 33 and gave crude 3,4-bis-(n-eicosanamido)benzoic acid (93 g) in the form of a light brown solid, m.p. 160O-'170°C.' EXAMPLE PEL 3 8 Compound Z A slurry of 4-amino-3-(n-nonadecanamido)benzoic acid (107g) in methyl ethyl ketone (1500ml) was treated with concentrated hydrochloric acid (100ml, 36.5%). The mixture was stirred and refluxed for 3 hours. The mixture was cooled to 10°C and the solid collected, washed with methyl ethyl ketone (2 x 500 mL) and slurried in water (500 mL). The sodium hydroxide solution (50 g in water (150 ml)) was added to the mixture and the mixture was stirred and heated to 60°C for dissolution. Glacial acetic acid was added to the stirred mixture until the mixture was pH 5, and the resulting solid was collected, washed with water (2 x 500 mL) and dried. The solid was recrystallized from ethanol under treatment with activated carbon to give a white solid which was carefully dried and then slurried in methyl ethyl ketone (500 mL) containing concentrated hydrochloric acid (100 mL, 36.5%). The mixture was stirred and refluxed for one hour and then cooled to give 2-(n-octadecyl)benzimidazole-5-carboxylic acid hydrochloride (33.8 g) as a white solid, m.p. 292°-297°C (under decomposition) . The 4-amino-3-(n-npnadecanamido)benzoic acid used as starting material was prepared as follows: 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 to that previously described in Example 33 and gave an orange solution which was poured into water (300.0 ml) containing concentrated hydrochloric acid (100 ml, strength 36, 5%). 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.
EKSEMPEL- 3 9 Forbindelse II 2-(n-oktadecyl)benzimidazol-5-karboksylsyrehydroklorid (12 EXAMPLE- 3 9 Compound II 2-(n-octadecyl)benzimidazole-5-carboxylic acid hydrochloride (12
g; fremstilt som forut beskrevet i eksempel 38) i tionylklorid (100 ml) ble rørt og tilbakeløpskokt i 3 timer og g; prepared as previously described in Example 38) in thionyl chloride (100 ml) was stirred and refluxed for 3 hours and
.deretter behandlet på lignende måte som forut beskrevet i eksempel 36, hvilket-ga metyl-2-(n-oktadecyl)benzimidazol-5-karboksylathydroklorid (11,6 g) i form av et hvitt fast stoff, smp. 224° - 230OC. EKSEMPEL 4 0 Forbindelse AA En oppslemning av 3,4-bis[2-metyltetradekanamido]benzosyre (53,1 g) i metyletylketon (250 ml) ble behandlet med konsentrert saltsyre (37,6 ml, styrke 36,5%). Blandingen ble rørt og tilbakeløpskokt 16 timer. Blandingen ble avkjølt til 0°C og det faste stoff oppsamlet (11,17 g) og vasket med metyletylketon (2 x 25 ml). Det faste stoff ble oppslemmet i vann (50 ml), og natriumhydroksydløsning [20 g i vann (50 ml)] ble satt til oppslemningen. Blandingen ble rørt og varmet til 60°C for oppløsning, og så ble iseddik satt til den omrørte blanding inntil blandingen hadde pH 5. Det resulterende faste stoff ble oppsamlet, vasket med vann og omkrystallisert fra etanol under, behandling med aktivt karbon,, og deretter behandlet på lignende måte som forut beskrevet i eksempel 3-8 og ga (RS)-2-(tetradek-2-yl)-benzimidazol-5-karboksylsyrehydroklorid (11 g) i form av et hvitt,fast stoff, smp. 214°-218°C. 3,4-bis[2-metyltetradekanamido]benzosyren som brukes som utgangsmatériale ble fremstilt som følger: En omrørt løsning 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 j lignende måte som forut bes<l>krevet i eksempel 33 og ga-rått 3,4-bis[2-metyltetradekanamido]benzosyre (68 g). .then treated in a similar manner as previously described in Example 36, which gave methyl 2-(n-octadecyl)benzimidazole-5-carboxylate hydrochloride (11.6 g) as a white solid, m.p. 224° - 230°C. EXAMPLE 40 Compound AA A slurry of 3,4-bis[2-methyltetradecanamido]benzoic acid (53.1 g) in methyl ethyl ketone (250 ml) was treated with concentrated hydrochloric acid (37.6 ml, strength 36.5%). The mixture was stirred and refluxed for 16 hours. The mixture was cooled to 0°C and the solid collected (11.17 g) and washed with methyl ethyl ketone (2 x 25 mL). The solid was slurried in water (50 mL) and sodium hydroxide solution [20 g in water (50 mL)] was added to the slurry. The mixture was stirred and heated to 60°C for dissolution, and then glacial acetic acid was added to the stirred mixture until the mixture reached pH 5. The resulting solid was collected, washed with water and recrystallized from ethanol under treatment with activated carbon, and then treated in a similar manner as previously described in examples 3-8 and gave (RS)-2-(tetradec-2-yl)-benzimidazole-5-carboxylic acid hydrochloride (11 g) in the form of a white solid, m.p. 214°-218°C. The 3,4-bis[2-methyltetradecanamido]benzoic acid used as starting material was prepared as follows: 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 previously described in Example 33 and gave crude 3,4-bis[2-methyltetradecanamido]benzoic acid (68 g).
EKSEMPEL' 41EXAMPLE' 41
Forbindelse CC En løsning av 4-amino-3-['2-heksyloktanamido] benzosyre (15,2 Compound CC A solution of 4-amino-3-['2-hexyloctanamido]benzoic acid (15.2
g) i metyletylketon (78 ml) ble behandlet med konsentrert saltsyre (18,2 ml, styrke 36,5%). Blandingen ble rørt og g) in methyl ethyl ketone (78 ml) was treated with concentrated hydrochloric acid (18.2 ml, strength 36.5%). The mixture was stirred and
tilbakeløpskokt 12 timer og metyletylketonet ble så fjernet i vakuum. Resten ble oppslemmet i vann (200 ml) og natrium-hydroksydløsning (50% i vann) ble satt til blandingen til refluxed 12 hours and the methyl ethyl ketone was then removed in vacuo. The residue was slurried in water (200 mL) and sodium hydroxide solution (50% in water) was added to the mixture until
pH var 11. Blandingen ble- oppvarmet til 9 0°C og deretter fortynnet med vann til et totalvolum på 1500 ml. Løsningen ble.behandlet med aktivt karbon og deretter behandlet med et overskudd av eddiksyre (2 5% i vann) hvilket ga et gråhvitt fast stoff. Det -faste stoff ble oppsamlet vasket med vann og omkrystallisert fra etyl-acetat hvilket ga 2-(tridek-7-yl)benzimidazol-5-karboksylsyre (8,89 g), smp. 157°-1580c. The pH was 11. The mixture was heated to 90°C and then diluted with water to a total volume of 1500 ml. The solution was treated with activated carbon and then treated with an excess of acetic acid (25% in water) which gave an off-white solid. The solid was collected, washed with water and recrystallized from ethyl acetate to give 2-(tridec-7-yl)benzimidazole-5-carboxylic acid (8.89 g), m.p. 157°-1580c.
Det faste stoff ble oppløst i aceton (350 ml) og. løsningen ble behandlet med konsentrert svovelsyre (1,55 ml, styrke 98%). ' Etter kjøling fikk man et hvitt fast stoff som ble omkrystallisert fra metyletylketon og ga 2-(tridek-7-yl)-benzimidazol-5-karboksylsyre-hemisulfat (6,8 g) i form av et hvitt fast stoff, smp,. 202°-205°C. The solid was dissolved in acetone (350 ml) and. the solution was treated with concentrated sulfuric acid (1.55 ml, strength 98%). After cooling, a white solid was obtained which was recrystallized from methyl ethyl ketone to give 2-(tridec-7-yl)-benzimidazol-5-carboxylic acid hemisulfate (6.8 g) as a white solid, m.p. 202°-205°C.
4-amxnd-3-[2-heksyloktanamido]benzosyre som brukes som utgangsmateriale ble fremstilt som følger: En omrørt løsning 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 lign-.ende måte som beskrevet i eksempel 33. Det voksaktige faste stoff ble oppsamlet og oppløst i dietyleter (500 ml), og 4-amxnd-3-[2-hexyloctanamido]benzoic acid used as starting material was prepared as follows: 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 33. The waxy solid was collected and dissolved in diethyl ether (500 ml), and
eterløsningen ble tørket og inndampet. -hvilket ga en rødbrun olje. Denne oljen ble ekstrahert med varm metanol ved bruk the ether solution was dried and evaporated. -which produced a reddish-brown oil. This oil was extracted with hot methanol in use
av et kontinuerlig ekstraksjoneapparat i 5 timer. Metanol-løsningen ble fordampet på en rotasjonsfordamper' og ga et brunt fast stoff som ble omkrystallisert fra aceton og ga 4-amino-3-[2-heksyloktanamido]benzosyre (15,2 g) i form av et hvitt fast stoff, smp. 219°-22°C. of a continuous extraction apparatus for 5 hours. The methanol 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, m.p. 219°-22°C.
EKSEMPEL 4 2 Forbindelse BB EXAMPLE 4 2 Compound BB
En løsning av 4-amino-3-(2-etyldodekanamido)benzosyre (24,7 1A solution of 4-amino-3-(2-ethyldodecanamido)benzoic acid (24.7 1
g) i metyletylketon (125 ml) ble behandlet med konsentrert saltsyre (29 ml, styrke 36,5%).. Blandingen ble rørt og til-bakeløpskokt i 12 timer og så behandlet på lignende måte som forut' beskrevet i eksempel; 41, hvilket ga et hvitt fast stoff som-ble omkrystallisert fra en blanding av aceton (200 ml) og vann (200 ml) og ga (RS)-2-(tridek-3-yl)benzimi-dazol-5-karboksylsyrehemis'ulfat (14,2 g) i form at ét hvitt fast stoff, smp. 185°-18'7°C. 4- amino-3-(2-etyldodekanamido)benzosyren som brukes som et utgangsmateriale.ble fremstilt som følger: En omrørt løsning av 3,4-diaminobenzosyre (22,8 g) i dimetylformamid (200 ml) inneholdende trietylamin (22,7 g) ble behandlet dråpevis med 2-etyldodekanoyIklorid (37 g) på lignende måte som forut beskrevet i eksempel 41 og ga et fast stoff .som ble omkrystallisert fra etylacetat under behandling med aktivt karbon, hvilket ga 4-amino-3-(2-etyldodekanamido)-benzosyre (22,2 g) i form av et hvitt fast stoff, smp. - 188°-191°C. g) in methyl ethyl ketone (125 ml) was treated with concentrated hydrochloric acid (29 ml, strength 36.5%). The mixture was stirred and refluxed for 12 hours and then treated in a similar manner as previously described in Example; 41, which gave a white solid which was recrystallized from a mixture of acetone (200 mL) and water (200 mL) to give (RS)-2-(tridec-3-yl)benzimidazole-5-carboxylic acid hemis' sulfate (14.2 g) in the form of a white solid, m.p. 185°-18'7°C. The 4-amino-3-(2-ethyldodecanamido)benzoic acid used as a starting material was prepared as follows: A stirred solution of 3,4-diaminobenzoic acid (22.8 g) in dimethylformamide (200 ml) containing triethylamine (22.7 g) was treated dropwise with 2-ethyldodecanoyl chloride (37 g) in a similar manner to that previously described in Example 41 and gave a solid which was recrystallized from ethyl acetate under treatment with activated carbon to give 4-amino-3-(2- ethyldodecanamido)-benzoic acid (22.2 g) as a white solid, m.p. - 188°-191°C.
EKSEMPEL 4 3EXAMPLE 4 3
Forbindelse DDConnection DD
En løsning av 4-amino-3-[ 2^-buty ldekanamido] benzosyre (9,8 g)A solution of 4-amino-3-[2^-butyl decanamido]benzoic acid (9.8 g)
i metyletylketon (50 ml) ble behandlet med konsentrert salt-; syre (11,5 ml, styrke 36,5%) på lignende måte som forut beskrevet i eksempel 41 og ga (RS)-2-(tri.dek-5-yl) benzimidazol-5- ka.rboksylsyrehem.isulfat (4,7 g) i form av et hvitt fast stoff, smp. 161°-164°C. in methyl ethyl ketone (50 ml) was treated with concentrated brine; acid (11.5 ml, strength 36.5%) in a similar manner as previously described in Example 41 to give (RS)-2-(tri.dec-5-yl) benzimidazole-5-carboxylic acid hemisulphate (4 .7 g) in the form of a white solid, m.p. 161°-164°C.
4-amino-3-[2-butyldekanamido]benzosyren som brukes som utgangsmateriale ble fremstilt som følger: En omrørt løsning av 3,4-diaminobenzosyre (15,8 g) i dimetylformamid (130 ml), inneholdende trietylamin (43,4 g) ble The 4-amino-3-[2-butyldecanamido]benzoic acid used as starting material was prepared as follows: A stirred solution of 3,4-diaminobenzoic acid (15.8 g) in dimethylformamide (130 ml), containing triethylamine (43.4 g ) became
behandlet .dråpevis med 2-b'utyldekanoylklo.rid (51,4 g) på lignende'måte som forut beskrevet i eksempel 41, hvilket ga 4-amino-3-'<[>2-but<y>ldekanamido] benzosyre (9,8 g) i form av et hvitt fast stoff, smp. 178°-182°C. treated dropwise with 2-b'butyldecanoyl chloride (51.4 g) in a similar manner as previously described in Example 41, which gave 4-amino-3-'<[>2-but<y>ldecanamido]benzoic acid ( 9.8 g) in the form of a white solid, m.p. 178°-182°C.
EKSEMPEL 44EXAMPLE 44
Forbindelse EE En blanding av 2-(n-pentadecyl)benzimidazol-5-karbonylklorid-hydroklorid (10 g) i etanol (25.0 ml) ble rørt og tilbakeløps-kokt i 2 timer.. Blandingen ble avkjølt til romtemperatur Compound EE A mixture of 2-(n-pentadecyl)benzimidazole-5-carbonyl chloride hydrochloride (10 g) in ethanol (25.0 mL) was stirred and refluxed for 2 h. The mixture was cooled to room temperature
og det faste stoff oppsamlet og vasket med etanol (50 ml)and the solid collected and washed with ethanol (50 mL)
og deretter med dietyleter (2 x 50 ml). Det faste stoff ble oppløst i.kokende etanol (25 ml) og løsningen behandlet med konsentrert saltsyre (0,5 ml med styrke 36,5%). Løsningen, ble avkjølt til 0°C og det resulterende faste stoff ble oppsamlet og ga etyl 2-(n-pentadecyl)benzimidazol-5-karboksylat-hydroklorid (7,8 g) i form av et hvitt fast stoff, smp. 207°-213°C. and then with diethyl ether (2 x 50 ml). The solid was dissolved in boiling ethanol (25 ml) and the solution treated with concentrated hydrochloric acid (0.5 ml at strength 36.5%). The solution was cooled to 0°C and the resulting solid was collected to give ethyl 2-(n-pentadecyl)benzimidazole-5-carboxylate hydrochloride (7.8 g) as a white solid, m.p. 207°-213°C.
2-(n-pentadecyl)benzimidazol-5-karbonylkloridet som brukes som utgangsmateriale ble fremstilt som følger: 2-(n-pentadecyl)benzimidåzol-5-karboksylsyremonohydrat (32 g) ble satt porsjonsvis til en omrørt løsning av tionylklorid The 2-(n-pentadecyl)benzimidazole-5-carbonyl chloride used as starting material was prepared as follows: 2-(n-pentadecyl)benzimidazole-5-carboxylic acid monohydrate (32 g) was added portionwise to a stirred solution of thionyl chloride
(250 ml) 'ved romtemperatur. Blandingen ble rørt og,tilbake-løpskokt 2 timer og deretter ble tionylkloridet fjernet i vakuum, hvilket ga 2-(n-pentadecyl)benzimidazol-5-karbonyl-klorid-hydroklorid (33 g) i form av et kremfarget fast stoff, smp. 286°-288°C (under spaltning).. (250 ml) 'at room temperature. The mixture was stirred and refluxed for 2 hours and then the thionyl chloride was removed in vacuo to give 2-(n-pentadecyl)benzimidazole-5-carbonyl chloride hydrochloride (33 g) as a cream solid, m.p. 286°-288°C (during decomposition)..
EKSEMPEL 4 5EXAMPLE 4 5
Forbindelse FFConnection FF
En blanding av 2-(n-pentadecyl)benzimidazol-5-karbonylklorid-hydroklorid (10 g; fremstilt som forut beskrevet i eksempel A mixture of 2-(n-pentadecyl)benzimidazole-5-carbonyl chloride hydrochloride (10 g; prepared as previously described in Example
44) i n-heksylalkohol (300 ml) ble behandlet på lignende 44) in n-hexyl alcohol (300 ml) was treated similarly
måte som forut beskrevet i eksempel 44 og ga heksyl 2-(n-pentadecyl)benzimidazol-5-karboksylathydroklorid (9,8 g) i ; manner as previously described in Example 44 and gave hexyl 2-(n-pentadecyl)benzimidazole-5-carboxylate hydrochloride (9.8 g) in ;
form av et hvitt fast stoff, smp. 166°- 170°C. form of a white solid, m.p. 166°- 170°C.
EKSEMPEL 4 6 Forbindelse GG En blanding av 2-(n-pentadecyl)benzimidazol-5-karbonylklorid-.hydroklqrid (10 g; fremstilt som forut beskrevet i eksempel ,44) i n-butylalkohol (300 ml) ble behandlet på lignende måte som forut beskrevet i eksempel 44 og ga butyl 2-(n-pentadecyl)benzimidazol-5-karboksylathydroklorid (8,9 g) i form av et hvitt fast stoff, smp. 170°-174°C. EXAMPLE 4 6 Compound GG A mixture of 2-(n-pentadecyl)benzimidazole-5-carbonyl chloride hydrochloride (10 g; prepared as previously described in Example 44) in n-butyl alcohol (300 ml) was treated in a manner similar to previously described in Example 44 and gave butyl 2-(n-pentadecyl)benzimidazole-5-carboxylate hydrochloride (8.9 g) as a white solid, m.p. 170°-174°C.
EKSEMPEL 4 7 Forbindelse HH En blanding av 2- (n-pentadecyl)benzimidazol-5-karbonylklorid-hydfoklorid (10 g; fremstilt som forut beskrevet i. eksempel 44) i isopropylalkohol (300 ml) ble behandlet- på lignende EXAMPLE 4 7 Compound HH A mixture of 2-(n-pentadecyl)benzimidazole-5-carbonyl chloride-hydrochloride (10 g; prepared as previously described in Example 44) in isopropyl alcohol (300 ml) was treated in a similar manner
måte som beskrevet forut i eksempel 44 og ga isopropyl 2-(n-pentadecyl)benzimidazol-5-karboksylathydroklorid (6,4 g) manner as described above in Example 44 and gave isopropyl 2-(n-pentadecyl)benzimidazole-5-carboxylate hydrochloride (6.4 g)
i form av et hvitt fast stoff, smp. 184°-186°C.in the form of a white solid, m.p. 184°-186°C.
EKSEMPEL 4 8 Forbindelse JJ EXAMPLE 4 8 Connection JJ
En omrørt blanding av natrium 2-(n-pentadecyl)behzimidazol-5-karboksylat (13,7 g; fremstilt som forut beskrevet i eks-.empel,19)' og klormetylpivalat (5 g) i heksametylfosforamid (35 ml) ble oppvarmet til 50°C i 3 timer. Etter kjøling ble blandingen helt i vann (250 ml) og ekstrahert med dietyl^. eter (3 x 75 ml). Det organiske sjiktet ble vasket med vann (3.x 100. ml) og tørket over magnesiumsulfat. Det organiske løsningsmiddel ble fjernet i vakuum og ga en brun olje, som ble kromatografert på kiselgel (4 00 g) ved bruk av kloroform som elueringsmiddel. Fraksjoner (100 ml) ble oppsamlet og fraksjonene 14 til 22 -ga etter fordampning av løsningsmidlet en fargeløs olje. Oljen ble oppløst i dietyleter og behandlet med en mettet løsning av saltsyre i etanol inntil blandingens pH var'1. Det hvite faste stoff ble oppsamlet og vasket med dietyleter (3 x 100 ml) og ga pivaloyloksymetyl 2-n-pentadecylbenzimidazol-5-karboksylathydroklorid (10 g) A stirred mixture of sodium 2-(n-pentadecyl)behzimidazole-5-carboxylate (13.7 g; prepared as previously described in Example 19)' and chloromethyl pivalate (5 g) in hexamethylphosphoramide (35 ml) was heated to 50°C for 3 hours. After cooling, the mixture was poured into water (250 mL) and extracted with diethyl ether. ether (3 x 75 ml). The organic layer was washed with water (3 x 100 ml) and dried over magnesium sulfate. The organic solvent was removed in vacuo to give a brown oil, which was chromatographed on silica gel (400 g) using chloroform as eluent. Fractions (100 ml) were collected and fractions 14 to 22 gave, after evaporation of the solvent, a colorless oil. The oil was dissolved in diethyl ether and treated with a saturated solution of hydrochloric acid in ethanol until the pH of the mixture was 1. The white solid was collected and washed with diethyl ether (3 x 100 mL) to give pivaloyloxymethyl 2-n-pentadecylbenzimidazole-5-carboxylate hydrochloride (10 g)
i form av et hvitt fast stoff, smp. 165°-175°C. in the form of a white solid, m.p. 165°-175°C.
EKSEMPEL 4 9 Forbindelse KK Natriumhydrid (12 g av en 50% oljedispersjon) ble'tilsatt EXAMPLE 4 9 Compound KK Sodium hydride (12 g of a 50% oil dispersion) was added
i løpet av 15 min. til en omrørt blanding av glyserol (100 g) og tørt tetrahydrofuran (10.0 ml). Etter ferdig. tilsetning ble blandingen rørt kraftig i ytterligere 30 min. og deretter ble 2-(n-pentadecyl)benzimidazol-5-karboksylsyrehydro-klorid (.20 g; fremstilt som forut beskrevet i eksempel 4) satt til blandingen i løpet av 5 min. Blandingen ble rørt .kraftig i 2' timer og fikk så stå natten over.Den brune blandingen ble helt i vann (800 ml) inneholdende iseddik (9,4 g) og det oljeaktige produkt ble ekstrahert over i kloroform (2 x 400 ml). De samlede ekstrakter.ble vasket med vann (2 x 500 ml> og tørket over natriumsulfat. Løs-ningsmidlet ble fordampet i vakuum, den resterende olje ble oppløst i toluen (300 ml) og løsningen ble filtrert og ga en brun gummi. Toluenet ble dekantert, dietyleter (100 ml) tilsatt og blandingen oppvarmet inntil gummien var oppløst. Etter rask kjøling til -30°Cutfeltes et hvitt fast stoff og ble oppsamlet og vasket'med dietyleter (2 x 100 ml), hvilket ga 2 ,'3-dihydroksyprop-l-yl 2-(n-pentadecyl) benzimi-dazol-5-karboksylat (6,6 g) i form av et hvitt fast stoff, smp. 10 9°-112OC. within 15 min. to a stirred mixture of glycerol (100 g) and dry tetrahydrofuran (10.0 ml). After finished. addition, the mixture was stirred vigorously for a further 30 min. and then 2-(n-pentadecyl)benzimidazole-5-carboxylic acid hydrochloride (.20 g; prepared as previously described in Example 4) was added to the mixture during 5 min. The mixture was stirred vigorously for 2 hours and then allowed to stand overnight. The brown mixture was poured into water (800 ml) containing glacial acetic acid (9.4 g) and the oily product was extracted into chloroform (2 x 400 ml). . The combined extracts were washed with water (2 x 500 ml) and dried over sodium sulfate. The solvent was evaporated in vacuo, the remaining oil was dissolved in toluene (300 ml) and the solution was filtered to give a brown gum. The toluene was decanted, diethyl ether (100 ml) added and the mixture heated until the gum was dissolved. After rapid cooling to -30°, a white solid was collected and washed with diethyl ether (2 x 100 ml) to give 2,'3- dihydroxyprop-1-yl 2-(n-pentadecyl) benzimidazole-5-carboxylate (6.6 g) as a white solid, mp 10 9°-112°C.
EKSEMPEL 5 0EXAMPLE 5 0
Forbindelse BCompound B
3,4-diaminobenzosyre (10 g) og palmitinsyre (168 g) i diglym• inneholdende konsentrert saltsyre (10 ml med styrke 3 6,5%) 3,4-diaminobenzoic acid (10 g) and palmitic acid (168 g) in diglym• containing concentrated hydrochloric acid (10 ml of strength 3 6.5%)
(100 ml) ble oppvarmet ved tilbakeløp i 10 timer. Den av-kjølte blanding ble helt i vann (300 ml) og det faste stoff oppsamlet. Det faste stoff ble vasket med"fortynnet saltsyre (2 x 100 ml med styrke 2N) og deretter kokende petroleter (4 x 100 ml, kokepunkt 40°-60°C). Det faste stoff ble omkrystallisert fra etanol under behandling med aktivt karbon hvilket ga 2-(n-pentadecyl)benzimidazol-5-karboksylsyre- (100 ml) was heated at reflux for 10 hrs. The cooled mixture was poured into water (300 mL) and the solid collected. The solid was washed with "dilute hydrochloric acid (2 x 100 ml of strength 2N) and then boiling petroleum ether (4 x 100 ml, boiling point 40°-60°C). The solid was recrystallized from ethanol under treatment with activated carbon which gave 2-(n-pentadecyl)benzimidazole-5-carboxylic acid-
hydroklorid (50 g) , smp., 295°-300°C (under'spaltning). hydrochloride (50 g), m.p., 295°-300°C (with decomposition).
EKSEMPEL 51 Forbindelse B 3,4-diaminobenzosyre-monohydroklorid (1,88 g) og n-heksadekanoylklorid (2,74 g) ble blandet godt sammen og blandingen.. ble oppvarmet ved 130 o G i 2 timer. Blandingen ble så av-kjølt til romtemperatur'og ble revet med vann (100 ml), hvilket ga 2-(n-pentadecyl)benzimidazol-5-karboksylsyrehydro- , klorid (0,1 g), smp. 298°-300°C (under spaltning). EXAMPLE 51 Compound B 3,4-diaminobenzoic acid monohydrochloride (1.88 g) and n-hexadecanoyl chloride (2.74 g) were mixed well and the mixture was heated at 130° G for 2 hours. The mixture was then cooled to room temperature and triturated with water (100 mL) to give 2-(n-pentadecyl)benzimidazole-5-carboxylic acid hydrochloride (0.1 g), m.p. 298°-300°C (under decomposition).
EKSEMPEL 52EXAMPLE 52
Forbindelse BCompound B
En omrørt løsning av 3,4-diaminobenzosyre (9 g) i dimetylformamid (190 ml) ble behandlet med n-heksadekanoylklorid (16,3 g) i 30 min. Blandingen ble så tilbakeløpskokt i 6 timer og helt i vann (100 ml). Det faste stoff ble oppsamlet og oppslemmet i fortynnet saltsyre (100 ml, styrke 2N)'. Det faste stoff ble igjen oppsamlet og vasket med vann og ga 2-(n-pentadecyl)benzimidazol-5-karboksylsyrehydroklorid (3 g), smp. 295°-300°C (under spaltning). A stirred solution of 3,4-diaminobenzoic acid (9 g) in dimethylformamide (190 ml) was treated with n-hexadecanoyl chloride (16.3 g) for 30 min. The mixture was then refluxed for 6 hours and poured into water (100 ml). The solid was collected and slurried in dilute hydrochloric acid (100 ml, strength 2N)'. The solid was again collected and washed with water to give 2-(n-pentadecyl)benzimidazole-5-carboxylic acid hydrochloride (3 g), m.p. 295°-300°C (under decomposition).
EKSEMPEL 5 3 Forbindelse B EXAMPLE 5 3 Compound B
En løsning av 2-(n-pentadecyl) benzimidazol-.5-karboksylsyre-mon<p>hydrat (390 g; fremstilt som forut beskrevet i eksempel 12) i en blanding av aceton (2000 ml) og vann (1000 ml) ble A solution of 2-(n-pentadecyl) benzimidazole-.5-carboxylic acid mono<p>hydrate (390 g; prepared as previously described in Example 12) in a mixture of acetone (2000 ml) and water (1000 ml) was
oppvarmet til 60°C og så behandlet med en vandig løsning av natriumhydroksyd (40 g i 50 ml vann). Blandingen .ble rørt i en time'under, tilbakeløp og ble så avkjølt til 0°C. Det faste stoff ble oppsamlet og omkrystallisert fra en blanding av aceton (1000 ml) og vann (500 ml) hvilket ga natrium 2-(n-pentadecyl)benzimidazol-5-karboksylatmonohydrat (345 g), smp. over 3 00°C under spaltning. heated to 60°C and then treated with an aqueous solution of sodium hydroxide (40 g in 50 ml of water). The mixture was stirred for one hour, refluxed and then cooled to 0°C. The solid was collected and recrystallized from a mixture of acetone (1000 mL) and water (500 mL) to give sodium 2-(n-pentadecyl)benzimidazole-5-carboxylate monohydrate (345 g), m.p. above 3 00°C during decomposition.
EKSEMPEL 5 4EXAMPLE 5 4
Forbindelse LLConnection LL
En løsning av 2,3-bis(n-tetradekanamido)benzosyre (17,6 g) i metyletylketon (250 ml) ble behandlet méd konsentrert salt syre (25 ml med styrke 36,5%). Blandingen ble tilbakeløps-kokt 5 timer, så avkjølt og behandlet på lignende måte som beskrevet forut i eksempel 15, hvilket ga 2-(n-tridecyl)-benzimidazol-4-karboksylsyrehydroklorid (6,5 g) i form av et brungult fast stoff, smp. 192°-200°C.. A solution of 2,3-bis(n-tetradecanamido)benzoic acid (17.6 g) in methyl ethyl ketone (250 ml) was treated with concentrated hydrochloric acid (25 ml at strength 36.5%). The mixture was refluxed for 5 hours, then cooled and treated in a manner similar to that previously described in Example 15 to give 2-(n-tridecyl)-benzimidazole-4-carboxylic acid hydrochloride (6.5 g) as a tan solid , m.p. 192°-200°C..
2,3-bis(n-tetradekanamido)benzosyren som brukes som utgangs-, materiale .ble.fremstilt * som følger: The 2,3-bis(n-tetradecanamido)benzoic acid used as starting material was prepared * as follows:
En løsning av 2,3-diaminobenzosyre (20 g) i dimetylformamid (200 ml), inneholdende trietylamin (39,9 g) ble behandlet med ri-tetradekanoylklorid' (65,0 g) . Tilsetningshastigheten til n-tetradekanoylkloridet var slik at reaksjonsblandingens temperatur fikk stige fra romtemperatur til 4 5°-50°C. , Blandingen ble så rørt i ytterligere 2 timer og fikk stå natten over ved romtemperatur. Metanol (20 ml) ble tilsatt blandingen,- og den resulterende blanding ble rørt 20 min. og deretter behandlet med konsentrert saltsyre (styrke 36,5%) 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 så 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-tetradekanamido) benzosyre (17,7 g) i form av et gulbrunt' fast stoff, smp. 150°-158°C. EKSEMPEL' 55 Forbindelse B En oppslemming av 3-amino-4-(heksadekanamido)benzosyre (2,0 g) 1 metyletylketon (60 ml) inneholdende saltsyre (1,5 ml. med styrke 3 6,5%) ble tilbakeløpskokt i 5 timer. Det resulterende faste stoff ble oppsamlet, vasket med kokende petroleter (kokepunkt 60°-80°C) og omkrystallisert fra etanol, hvilket ga 2-(n-pentadecyl)benzimidazol-5-karboksylsyre-hydroklorid (2,0 g) i form av et hvitt fast stoff med smp. 288°-290°C (under spaltning). 3-amino-4-(n-heksadekanamido)benzosyren som brukes, som ut-. gangsmateriale ble fremstilt som følger: En løsning av 3-nitr'o-4-(n-heksadekanamido) benzosyre (22 g) i n-butanol (500.ml) ble hydrogenert ved rysting i nærvær av 5% palladium-på-karbon' (2,5 g) ved 7 0°C og atmosfæretrykk i 6 timer. Blandingen ble filtrert varmt og .filtratet fikk, 'kjølne. Det resulterende faste stoff ble oppsamlet og vask--et med etanol (100 ml) hvilket ga 3-amino-4-(heksadekanamido)benzosyre (11,6 g) i form av et kremfarget fast.stoff med smp. 160 -162 C.. 3-nitro-4-(n-heksadekanamido) benzosyren som brukes som'utgangsmateriale ble fremstilt som følger: En løsning av 4-amino-3-nitrobenzosyre (18,2 g) og heksadekanoylklorid (33,0 g) i tørt dimetylformamid (100 ml) ble . oppvarmet 90 min. ved 97°C. Løsningen ble avkjølt og så helt på knust is (300 g). Det resulterende faste stoff ble oppsamlet, vasket med vann (3 x 10 0 ml) tørket 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 fast stoff, smp. 153°-154°C. A solution of 2,3-diaminobenzoic acid (20 g) in dimethylformamide (200 ml) containing triethylamine (39.9 g) was treated with tritetradecanoyl chloride (65.0 g). The rate of addition of the n-tetradecanoyl chloride was such that the temperature of the reaction mixture was allowed to rise from room temperature to 45°-50°C. , The mixture was then stirred for a further 2 hours and allowed to stand overnight at room temperature. Methanol (20 mL) was added to the mixture and the resulting mixture was stirred for 20 min. and then treated with concentrated hydrochloric acid (strength 36.5%) 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 (boiling point 60°-80°C;: 500 ml), and was finally recrystallized from ethanol under treatment with activated carbon, which gave 2,3-bis(n-tetradecanamido)benzoic acid (17.7 g) in the form of a yellowish-brown solid, m.p. 150°-158°C. EXAMPLE' 55 Compound B A slurry of 3-amino-4-(hexadecanamido)benzoic acid (2.0 g) 1 methyl ethyl ketone (60 ml) containing hydrochloric acid (1.5 ml. of strength 3 6.5%) was refluxed for 5 hours. The resulting solid was collected, washed with boiling petroleum ether (b.p. 60°-80°C) and recrystallized from ethanol to give 2-(n-pentadecyl)benzimidazole-5-carboxylic acid hydrochloride (2.0 g) as a white solid with m.p. 288°-290°C (under decomposition). The 3-amino-4-(n-hexadecanamido)benzoic acid used, as ut-. starting material was prepared as follows: A solution of 3-nitro-4-(n-hexadecanamido)benzoic acid (22 g) in n-butanol (500 ml) was hydrogenated by shaking in the presence of 5% palladium-on-carbon (2.5 g) at 70°C and atmospheric pressure for 6 hours. The mixture was filtered hot and the filtrate allowed to cool. 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.. The 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 hexadecanoyl chloride (33.0 g) in dry dimethylformamide (100 ml) was . heated 90 min. at 97°C. The solution was cooled and poured onto crushed ice (300 g). The resulting solid was collected, washed with water (3 x 10 0 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.
EKSEMPEL 5 6 Forbindelse MM EXAMPLE 5 6 Connection MM
En suspensjon av 2-(n-pentadecyl)benzimidazol-5-karboksyl-syrehydroklorid (9,6 g; fremstilt som forut beskrevet i A suspension of 2-(n-pentadecyl)benzimidazole-5-carboxylic acid hydrochloride (9.6 g; prepared as previously described in
eksempel 4) i tionylklorid (75 ml) ble tilbakeløpskokt 2 timer. Overskuddet av tionylklorid ble fjernet ved vakuum-'destillasjon, hvilket ga en brun fast rest. Det faste stoff, ble revet med toluen (200 ml) og toluenet fordampet i vakuum. Resten -ble satt til en løsning av trietylamin .(3,64 ml) 1 ' example 4) in thionyl chloride (75 ml) was refluxed for 2 hours. The excess thionyl chloride was removed by vacuum distillation, giving a brown solid residue. The solid was triturated with toluene (200 mL) and the toluene evaporated in vacuo. The residue -was added to a solution of triethylamine .(3.64 ml) 1 '
tert-butanol (250 ml) og blandingen ble tilbakeløpskokt 3 timer, Etter kjøling ble overskuddet av tert-butanol fordampet i vakuum og resten ble oppslemmet i etylacetat (150 ml). Oppslemmingen ble tilbakeløpskokt 10 min. og filtrert varmt. Filtratet ble avkjølt og det resulterende faste stoff ble oppsamlet. Det faste stoffet ble vasket med etanol (2 x 50 ml) og deretter med dietyleter (2 x 50 ml), og-■tørket hvilket ga tert-butyl 2-(n-pentadecyl)benzimidazol-5- tert-butanol (250 ml) and the mixture was refluxed for 3 hours. After cooling, the excess of tert-butanol was evaporated in vacuo and the residue was slurried in ethyl acetate (150 ml). The slurry was refluxed for 10 min. and filtered hot. The filtrate was cooled and the resulting solid was collected. The solid was washed with ethanol (2 x 50 mL) and then with diethyl ether (2 x 50 mL), and dried to give tert-butyl 2-(n-pentadecyl)benzimidazole-5-
karboksylathydroklorid (5,5 g) som gråhvitt fast stoff,carboxylate hydrochloride (5.5 g) as an off-white solid,
smp. 165°-168°G. m.p. 165°-168°G.
EKSEMPEL' 57 Forbindelse NN En blanding av 2-(n-pentadecyl) ben.zimidazo.l-5-karbonylklorid.. EXAMPLE' 57 Compound NN A mixture of 2-(n-pentadecyl)benzimidazo.1-5-carbonyl chloride..
( 15 g; fremstilt som forut beskrevet i eksempel 44) i allyl-alkohol (300 ml) ble behandlet på lignende måte som forut beskrevet' i eksempel 44 og ga 'ally 1 2-(n-pentadecyl) benzimi-dazol-5-karboksy.lathydroklorid (10,4 g) i form av et hvitt fast stoff, smp. 198°-200°C. (15 g; prepared as previously described in Example 44) in allyl alcohol (300 ml) was treated in a similar manner as previously described' in Example 44 to give 'ally 1 2-(n-pentadecyl) benzimidazole-5- carboxylate hydrochloride (10.4 g) as a white solid, m.p. 198°-200°C.
EKSEMPEL 58 Forbindelse M EXAMPLE 58 Compound M
En omrørt løsning av metyl 3,4-diaminobenzoat (9,8 g) i metanol (200 ml) ble tilsatt en løsning av kopper(II)acetat (23,6 g) i vann (300 ml) etterfulgt av en løsning av n-dekanal (10 g) i metanol (40 ml). Blandingen ble tilbake-løpskokt 1 time og fikk avkjøles, og det purpurfargede faste stoff ble oppsamlet. Det faste stoff ble oppløst.'i 75% v/v vandig metanol (600 ml) og hydrogensulfidgass ble ført gjennom løsningen inntil utfelling av koppersulfid opphørte. Koppersulfidet ble oppsamlet og filtratet ble konsentrert To a stirred solution of methyl 3,4-diaminobenzoate (9.8 g) in methanol (200 mL) was added a solution of copper(II) acetate (23.6 g) in water (300 mL) followed by a solution of n -decanal (10 g) in methanol (40 ml). The mixture was refluxed for 1 hour and allowed to cool, and the purple solid was collected. The solid was dissolved in 75% v/v aqueous methanol (600 ml) and hydrogen sulphide gas was passed through the solution until precipitation of copper sulphide ceased. The copper sulfide was collected and the filtrate was concentrated
og ga en rød olje. Oljen ble oppløst i metanol (100 ml) inneholdende konsentrert saltsyre (15 ml med styrke 36,5%) and yielded a red oil. The oil was dissolved in methanol (100 ml) containing concentrated hydrochloric acid (15 ml at strength 36.5%)
og løsningen ble tilbakeløpskokt i 4 timer. Etter avkjøl-ing ble det grågrønne faste stoff frafiltrert og oppløst i tetrahydrofuran (100 ml) inneholdende vandig ammoniakk (5 ml med styrke 33%),. Løsningen ble fortynnet med vann (400 ml) og det 'lyserød faste stoff frafiltrert... Det faste stoff ble kromato.grafert på kiselgel med en blanding av kloroform og and the solution was refluxed for 4 hours. After cooling, the grey-green solid was filtered off and dissolved in tetrahydrofuran (100 ml) containing aqueous ammonia (5 ml at strength 33%). The solution was diluted with water (400 ml) and the pink solid filtered off... The solid was chromatographed on silica gel with a mixture of chloroform and
metanol (25:1 v/v) som elueringsmiddel. Det isolerte mat-erialet ble oppløst i metyletylketon (25 ml) og konsentrert saltsyre (2,3 ml med styrke 36,5%) ble tilsatt under røring., Det resulterende faste stoff ble frafiltrert og vasket med dietyleter (2 x 50 ml) hvilket ga metyl 2-■ methanol (25:1 v/v) as eluent. The isolated material was dissolved in methyl ethyl ketone (25 mL) and concentrated hydrochloric acid (2.3 mL at strength 36.5%) was added with stirring. The resulting solid was filtered off and washed with diethyl ether (2 x 50 mL). which gave methyl 2-■
zol-5-karboksylathydroklorid (5,3 g) i form av et hvitt fast stoff,' smp. 234°-237°C (under spaltning) . zol-5-carboxylate hydrochloride (5.3 g) as a white solid, m.p. 234°-237°C (under decomposition) .
EKSEMPEL 5 9EXAMPLE 5 9
Forbindelse PP Konsentrert saltsyre (120 ml•med styrke 36,5%) ble tilsatt Compound PP Concentrated hydrochloric acid (120 ml•at strength 36.5%) was added
i løpet av 20 min. til en tilbakeløpskokende løsning av rått 2,3-bis(n-heksadekanamido)benzosyre (165,3 g) i metyletylketon (1200 ml), og blandingen ble tilbakeløpskokt i 6 timer_. Den resulterende løsning ble avkjølt og løsningsmidlet ble fjernet ved vakuumdestillasjon. Etter rivning av resten med vann (2000 ml) ble det granulær.e faste stoff oppsamlet og within 20 min. to a refluxing solution of crude 2,3-bis(n-hexadecanamido)benzoic acid (165.3 g) in methyl ethyl ketone (1200 ml), and the mixture was refluxed for 6 hours_. The resulting solution was cooled and the solvent was removed by vacuum distillation. After trituration of the residue with water (2000 ml), the granular solid was collected and
vasket med varm petroleter (kokepunkt 60°-80°C; 2 x 500 ml) . og så . med' dietyleter (500 ml). Det faste stoff ble oppløst washed with hot petroleum ether (boiling point 60°-80°C; 2 x 500 ml) . and then . with' diethyl ether (500 ml). The solid was dissolved
i kokende metyletylketon (2 50 ml) og løsningen ble behandlet med aktivt karbon' og filtrert varm. Filtratet ble. fordampet i vakuum hvilket ga et brungult fast stoff. Det faste stoff, ble kromatografert på kiselgel med en blanding av kloroform og metanol (9:1 v/v) som elueringsmiddel. Det resulterende produkt ble omkrystallisert fra etylacetat og ga 2-(n-pentadecyl ) benzimidazol-4-karboksylsyre (5,4 g) som et brungult fast stoff, smp-. 160°-166°C. in boiling methyl ethyl ketone (2 50 ml) and the solution was treated with activated carbon' and filtered hot. The filtrate was evaporated in vacuo to give a tan solid. The solid was chromatographed on silica gel with a mixture of chloroform and methanol (9:1 v/v) as eluent. The resulting product was recrystallized from ethyl acetate to give 2-(n-pentadecyl)benzimidazole-4-carboxylic acid (5.4 g) as a tan solid, m.p. 160°-166°C.
. 2,3-bis(n-heksadekanamido)benzosyren som brukes som utgangsmateriale ble fremstilt som følger: En løsning av .2,3-diaminobenzosyre (40 g) i dimetylformamid (600 ml) inneholdende trietylamin (79,7 g, 109,5 ml) ble behandlet med n-heksadekanoyl-klorid (144,5 g). Tilsetningshastigheten var slik at reaksjonsblandingens temperatur fikk stige fra romtemperatur til 4 5°-50°C. Blandingen ble så rørt i ytterligere 3 timer og fikk. stå ved romtemperatur, natten over. Blandingen ble satt til vann (1200 ml) inneholdende konsentrert saltsyre (50 ml, styrke 3 6,5%) og det resulterende .faste stoff oppsamlet og vasket med vann (1200 .. ml) . Det faste stoff ble rørt med varmt vann.. (4000 ml; 6 5°C) i .3 0 min. og ble oppsamlet og tørket ved 7 0°C i vakuum. . The 2,3-bis(n-hexadecanamido)benzoic acid used as starting material was prepared as follows: 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 of the reaction mixture was allowed to rise from room temperature to 45°-50°C. The mixture was then stirred for a further 3 hours and gave stand at room temperature, overnight. The mixture was added to water (1200 ml) containing concentrated hydrochloric acid (50 ml, strength 3 6.5%) and the resulting solid 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 vacuum.
Det resulterende produkt 2,3-bis(n-heksadekanamido)benzosyre ble brukt uten videre rensning i ovennevnte fremstilling. The resulting product 2,3-bis(n-hexadecanamido)benzoic acid was used without further purification in the above preparation.
REFERANSEEKSEMPEL 1REFERENCE EXAMPLE 1
En omrørt løsning av 3,4-diaminobenzosyre (152 g) i dimetyl-' A stirred solution of 3,4-diaminobenzoic acid (152 g) in dimethyl-'
formamid (1500 ml) inneholdende trietylamin (3 03 g) ble behandlet dråpevis med.n-heksadekanoylklorid (549,0 g) i 1,5 timer. Tilsetningshastigheten av n-heksadekanoylkloridet var slik at reaksjonsblandingens temperatur steg fra romtemperatur til 3 5°-4 0°C. Blandingen ble så rørt ved romtempera-i tur i ytterligere 2 timer og deretter helt i varm vann (10 -f holdt på 70°C) inneholdende konsentrert saltsyre (150 ml, formamide (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 n-hexadecanoyl chloride was such that the temperature of the reaction mixture rose 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 -f held at 70°C) containing concentrated hydrochloric acid (150 ml,
med styrke 36,5%). Det resulterende faste stoff ble oppsam-, let og ga rått 3,4-bis(n-heksadekanamido)benzosyre (600 g) with strength 36.5%). The resulting solid was collected to give crude 3,4-bis(n-hexadecanamido)benzoic acid (600 g)
i form av et gulbrunt fast stoff, smp. 180°-190°C, egnet for bruk- ved fremstillingen forut beskrevet i eksempel 15. in the form of a yellowish-brown solid, m.p. 180°-190°C, suitable for use in the preparation previously described in example 15.
REFERANSEEKSEMPEL 2REFERENCE EXAMPLE 2
Ved å gå frem på lignende måte som forut beskrevet i eksempel 38 for fremstillingen av 4-amino-3-(n-nonadekanamido)-benzosyre, men erstatte n-nonadekanoylkloridet med n-oktanoylklorid, fremstilte man 4^amino-3-(n-oktanamido)benzosyre i form av et gråhvitt fast stoff, smp. 202°-203°C etter orn-krystallisering fra metanol. By proceeding in a similar manner to that previously described in example 38 for the preparation of 4-amino-3-(n-nonadecanamido)-benzoic acid, but replacing the 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 orn crystallization from methanol.
REFERANSEEKSEMPEL 3REFERENCE EXAMPLE 3
Ved å gå frem på- lignende måte som forut beskrevet i eksempel, 38. for fremstillingen 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 fast-stoff, smp, 183°-185°C. By proceeding in a similar way to that previously described in example 38 for the preparation 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.
REFERANSEEKSEMPEL 4REFERENCE EXAMPLE 4
Ved å gå frem- på lignende måte som forut beskrevet i eksempel 38 for fremstillingen av -4-amino-3-(n-nonadekanamido)ben- . zosyre,- men erstatte n-nonadekanoylklorid med n-oktadekanoyl-klorid fremstilte man 4-amino-3-(n-oktadekanamido)benzosyre i form av et lysebrunt fast stoff, smp. 185°-187°C etter omkrystallisering fra metyletylketon. By proceeding in a similar manner to that previously described in example 38 for the preparation of -4-amino-3-(n-nonadecanamido)ben-. zosyre, - but replacing n-nonadecanoyl chloride with n-octadecanoyl chloride produced 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.
REFERANSEEKSEMPEL 5REFERENCE EXAMPLE 5
En løsning av metyl 3,4-diaminobenzoat (83,1 g) i tørt dimetylformamid (900 nil) 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 ble rørt ytterligere 2 timer. Det faste stoff ble fjernet ved filtrering og filtratet helt i vann (8000 ml). Det resulterende faste stoff ble oppsamlet og krystallisert to ganger fra metanol, hvilket ga metyl 4-amino-3-(n-oktanamido)benzoat (65,5 g) i form av et hvitt fast stoff, smp. l20°C....... A solution of methyl 3,4-diaminobenzoate (83.1 g) in dry dimethylformamide (900 nil) containing triethylamine (50.8 g) was treated dropwise with n-octanoyl chloride (81.3 g). for 30 min. at a temperature between 5° and 8°C. The mixture was stirred for an additional 2 hours. The solid was removed by filtration and the filtrate dissolved in water (8000 ml). The resulting solid was collected and crystallized twice from methanol to give methyl 4-amino-3-(n-octanamido)benzoate (65.5 g) as a white solid, m.p. l20°C.......
REFERANSEEKSEMPEL 6REFERENCE EXAMPLE 6
Ved å gå frem på lignende måte som forut beskrevet i referanseeksempel 5 for fremstilling av metyl 4-amiho-3-(n-oktan-amido) benzoat, men erstatter n-oktanoylklorid med n-dodekanoylklorid, fremstilte man metyl 4-amino-3-(n-dodékanamido)-benzoat i form av et gråhvitt fast stoff, smp. 102°-105°C etter omkrystallisering fra metanol. By proceeding in a similar manner as previously described in reference example 5 for the preparation of methyl 4-amiho-3-(n-octane-amido) 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.
REFERANSEEKSEMPEL 7REFERENCE EXAMPLE 7
. Ved å gå frem på lignende måte som forut beskrevet i ref-er-■anseeksempel 5 for fremstillingen av metyl 4-amino-3-(n-oktanamido)benzoat, men erstatte n-oktanoylklorid med n-tridekanoylklorid, fremstilte man metyl 4-amino-3-(n-tridekan-amido) benzoat i form av et lysebrunt fast s'toff, smp. 101°-104°C etter omkrystallisering fra metanol. . By proceeding in a similar manner as previously described in reference example 5 for the production of methyl 4-amino-3-(n-octanamido)benzoate, but replacing n-octanoyl chloride with n-tridecanoyl chloride, methyl 4- amino-3-(n-tridecane-amido) benzoate in the form of a light brown solid, m.p. 101°-104°C after recrystallization from methanol.
REFERANSEEKSEMPEL 8REFERENCE EXAMPLE 8
Ved å gå frem på en lignende måte som forut beskrevet i referanseeksempel 5 for fremstillingen av.metyl-4-amino-3-(n-oktanamido)benzoat, men erstatte n-oktanoylkloridet med n-tetradekanoylklorid, fremstilte man metyl 4-amino-3-(n-tetradekanamido)benzoatet i form av et lysebrunt fast stoff, smp. 108°-109OC etter omkrystallisering fra metanol. By proceeding in a similar way as previously described in reference example 5 for the preparation of methyl-4-amino-3-(n-octanamido)benzoate, but replacing the n-octanoyl chloride with n-tetradecanoyl chloride, methyl 4-amino- The 3-(n-tetradecanamido)benzoate as a light brown solid, m.p. 108°-109°C after recrystallization from methanol.
REFERANSEEKSEMPEL 9REFERENCE EXAMPLE 9
Ved å.gå frem på lignende måte som forut beskrevet i referanseeksempel 5 for fremstillingen av metyl 4-amino-3-(n-oktanamido)benzoat, men erstatte n-oktanoylkloridet med n-heksadekanoylklorid, fremstilte man metyl 4-amino-3-(n-heksadekanamido)benzoat i form av et hvitt fast stoff, smp. 109°-110°C etter omkrystallisering f r .7; metanol. By proceeding in a similar manner as previously described in reference example 5 for the preparation of methyl 4-amino-3-(n-octanamido)benzoate, but replacing the n-octanoyl chloride with n-hexadecanoyl chloride, methyl 4-amino-3- (n-hexadecanamido)benzoate as a white solid, m.p. 109°-110°C after recrystallization f r .7; methanol.
REFERANSEEKSEMPEL. IOREFERENCE EXAMPLE. IO
En omrørt løsning av metyl 3,4-diaminobenzoat (5 g) i tørt dimetylforraamid (50 ml) inneholdende trietylamin (6,1 g) ble. behandlet dråpevis med en'løsning av heksadekatroylklorid A stirred solution of methyl 3,4-diaminobenzoate (5 g) in dry dimethylformamide (50 ml) containing triethylamine (6.1 g) was treated dropwise with a solution of hexadecatroyl chloride
(16,54 g) i tørt dimetylformamid (40 ml) i 5 min. Temperaturen fikk stige fra 20°-50°C. Blandingen ble.rørt ytterligere 3. timer. Den resulterende oppslemming ble helt- i vann (800 ml) inneholdende saltsyre (10 ml, 36,5%) Det resulterende faste.stoff ble oppsamlet og omkrystallisert fra en blanding av kloroform og aceton (1:1) å ga metyl 3,4-bis-(n-heksadekanamido)benzoat (12,1 g) i form av et hvitt fast i stoff, smp. 129°-132°C, hvilket er identisk med utgangsmat-erialene som ble brukt i eksempel 16. (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 for a further 3 hours. The resulting slurry was poured into water (800 mL) containing hydrochloric acid (10 mL, 36.5%) 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) as a white solid, m.p. 129°-132°C, which is identical to the starting materials used in Example 16.
REFERANSEEKSEMPEL 11 REFERENCE EXAMPLE 11
Ved å gå frem på lignende måte som forut beskrevet i referanseeksempel 10 for fremstillingen av metyl 3,4-bis(n-heksadekanamido) benzoat , men erstatte n-heksadekanoylkloridet med n-oktanoylklorid, fremstilte man metyl 3,4-bis(n-oktanamido)-.benzoat i form av et hvitt fast stoff, smp. 145°-147°C etter omkrystallisering fra aceton. By proceeding in a similar manner as previously described in reference example 10 for the production of methyl 3,4-bis(n-hexadecanamido) benzoate, but replacing the n-hexadecanoyl chloride with n-octanoyl chloride, methyl 3,4-bis(n- octanamido)-.benzoate in the form of a white solid, m.p. 145°-147°C after recrystallization from acetone.
REFERANSEEKSEMPEL 12REFERENCE EXAMPLE 12
Ved å gå frem på lignende måte som forut beskrevet i referanseeksempel 10 for fremstillingen av metyl 3,4-bis(n-heksadekanamido) benzoat , men erstatte n-heksadekanoylkloridet med n-dodekanoylklorid, fremstilte man metyl 3,4-bis(n-dodekan-amido)benzoat i form av et gråhvitt fast stoff, smp. 129°-131°C etter omkrystallisering fra aceton. By proceeding in a similar manner as previously described in reference example 10 for the preparation of methyl 3,4-bis(n-hexadecanamido) benzoate, but replacing the n-hexadecanoyl chloride with n-dodecanoyl chloride, methyl 3,4-bis(n- dodecane-amido)benzoate in the form of an off-white solid, m.p. 129°-131°C after recrystallization from acetone.
REFERANSEEKSEMPEL 13REFERENCE EXAMPLE 13
Ved å gå frem på lignende måte som forut beskrevet i referanseeksempel 10 for fremstillingen av metyl 3,4-bis-(n-heksadekanamido )benzoat, men erstatte n-heksadekanoylkloridet med n-tridekanoylklorid, fremstilte man metyl 3,4-bis(n-tridekan-amino)benzoat.i form av et hvitt fast stoff, smp. 132°-134°C etter omkrystallisering fra.aceton. By proceeding in a similar manner as previously described in reference example 10 for the production of methyl 3,4-bis-(n-hexadecanamido)benzoate, but replacing the n-hexadecanoyl chloride with n-tridecanoyl chloride, methyl 3,4-bis(n -tridecane-amino)benzoate.in the form of a white solid, m.p. 132°-134°C after recrystallization from acetone.
REFERANSEEKSEMPEL 14REFERENCE EXAMPLE 14
Ved å gå frem på lignende måte som forut beskrevet i. eksempel 10 for fremstillingen av metyl 3,4-bis-(n-heksadekanamido)benzoat, men erstatte n-heksadekanoylkloridet med'n-tetradekanoylklorid, fremstilte man metyl 3,4-bis(n-tetra-' dekanamido)benzoat i form av et hvitt fast stoff, smp. 132°-. 133°C etter omkrystallisering fra aceton. By proceeding in a similar manner as previously described in example 10 for the preparation of methyl 3,4-bis-(n-hexadecanamido)benzoate, but replacing the n-hexadecanoyl chloride with n-tetradecanoyl chloride, methyl 3,4-bis was prepared (n-tetra-'decanamido)benzoate as a white solid, m.p. 132°-. 133°C after recrystallization from acetone.
REFERANSEEKSEMPEL 15REFERENCE EXAMPLE 15
Ved å gå frem på lignende måte som forut beskrevet i referanseeksempel 10 for fremstillingen av metyl 3,4-bis-(n-heksa-. dekanamido)benzoat, men erstatte n-heksadekanoylkloridet med n-oktadekanoyl.klorid, fremstilte man metyl 3 ,■ 4-bis- (n-oktadekanamido)benzoat. i form av et hvitt fast stoff, smp. 120°C. etter omkrystallisering fra en blanding av aceton og metanol, (1:1), By proceeding in a similar manner to that previously described in reference example 10 for the production of methyl 3,4-bis-(n-hexa-decanamido)benzoate, but replacing the n-hexadecanoyl chloride with n-octadecanoyl chloride, methyl 3 was produced, ■ 4-bis-(n-octadecanamido)benzoate. in the form of a white solid, m.p. 120°C. after recrystallization from a mixture of acetone and methanol, (1:1),
REFERANSEEKSEMPEL 16 REFERENCE EXAMPLE 16
3- amino-4-(n-oktanamido)benzosyre (12,1 g) i metanol (200 ml) ble behandlet med diazometanløsning i eter inntil reaksjonen var fullstendig (som vist ved tynnsjiktskromatografi på kiselgel 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 og ga metyl 3-amino-4- (n-oktanamido)benzoat (9,2 g) i form av et kremfarget fast stoff, smp. 128°-131°C. 3-Amino-4-(n-octanamido)benzoic acid (12.1 g) in methanol (200 mL) was treated with diazomethane solution in ether 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.
REFERANSEEKSEMPEL 17 REFERENCE EXAMPLE 17
3-nitro-4-(n-oktanamido)benzosyre (25 g) oppløst i etanol . (500.mi) ved 50°C ble hydrogenert under rysting i nærvær av 5% palladium-på-karbon (2,5 g) ved 50°C og atmosfæretfykk i 3 timer. Blandingen ble filtrert varm og filtratet ble inndampet i vakuum. Resten ble omkrystallisert fra en blanding av etanol og vann (1:1) hvilket .ga 3-amino-4-(n-oktanamido)-. 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% palladium-on-carbon (2.5 g) at 50°C and atmosphere 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)-.
benzosyre (8 g) i form av et gult fast stoff, smp. 155°-156°C. benzoic acid (8 g) in the form of a yellow solid, m.p. 155°-156°C.
3-nitro-4-(n-oktanamido)benzosyren som ble brukt som utgangs- The 3-nitro-4-(n-octanamido)benzoic acid used as starting
materiale', ble fremstilt som følger:material', was produced as follows:
En løsning av 4-amino-3-nitrobenzosyre (18,2 g) og n-oktanoylklorid (19,4 g) i tørt dimetylformamid (100 ml) ble behandlet i 90 min. ved 97°C. Løsningen- ble avkjølt og helt i is (300 g). Det resulterende faste stoff ble oppsamlet og. vasket med vann, (3 x 100 ml), tørket 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 fast stoff, smp. 153°-154°C. A solution of 4-amino-3-nitrobenzoic acid (18.2 g) and n-octanoyl chloride (19.4 g) in dry dimethylformamide (100 ml) was treated for 90 min. at 97°C. The solution was cooled and poured into 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 treatment with activated carbon) which gave 3-nitro-4-(n-octanamido)benzoic acid (22 g) as a pale yellow solid, m.p. 153°-154°C.
REFERANSEEKSEMPEL 18REFERENCE EXAMPLE 18
3-nitro-4-(n-dodekanamido)benzosyre (21 g) oppløst i etyl-acetat (500 ml) ble hydrogenert under rysting i nærvær av 5% w/w palladium på aktivt karbon (2,5 g) ved 50°C og atmosfæretrykk. Den resulterende blanding ble filtrert varm og ga et kremfarget fast stoff etter avkjøling. Dette produktet ble omkrystallisert fra metanol og ga 3-amino-4-(n-dodékan-amido)benzosyre (7,4 g) som et beigefarget fast stoff, smp. 158°-160°C. 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 activated 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-dodecane-amido)benzoic acid (7.4 g) as a beige solid, m.p. 158°-160°C.
' REFERANSEEKSEMPEL 19' REFERENCE EXAMPLE 19
Ved å gå frem på lignende måte som forut beskrevet i referanseeksempel 5 for fremstillingen av metyl 4-amino-3-(n-oktanamido)benzoat, men erstatte n-oktanoylkloridet med n-dekanoylklorid, fremstilte man metyl 4-amino-3-(n-dekahamido)-benzoat i form av et hvitt fast stoff, smp. 96°-100°C. By proceeding in a similar manner as previously described in reference example 5 for the preparation of methyl 4-amino-3-(n-octanamido)benzoate, but replacing the n-octanoyl chloride with n-decanoyl chloride, methyl 4-amino-3-( n-decahamido)-benzoate in the form of a white solid, m.p. 96°-100°C.
REFERANSEEKSEMPEL 2 0REFERENCE EXAMPLE 2 0
Ved å gå frem på lignende måte som forut beskrevet i referanseeksempel 10 ved.fremstillingen av metyl 3,4-bis(n-heksadekanamido)benzoat, men erstatte n-heksanoylkloridet med n-dekanoylklorid, fremstilte man metyl 3,4-bis-(n-dekan-amido ) benzoat i form av ét hvitt fast stoff, smp..139°-141°C'etter omkrystallisering fra etanol. By proceeding in a similar manner as previously described in reference example 10 in the production of methyl 3,4-bis(n-hexadecanamido)benzoate, but replacing the n-hexanoyl chloride with n-decanoyl chloride, methyl 3,4-bis-( n-decane-amido) benzoate in the form of a white solid, m.p. 139°-141°C' after recrystallization from ethanol.
REFERANSEEKSEMPEL 21REFERENCE EXAMPLE 21
En omrørt løsning av 3,4-diaminobenzosyre (10 g) i tørt dimetylf ormamid (100 ml) inneholdende kaliumkarbonat (28 g) ble behandlet dråpevis med en løsning av n-dodekanoylklorid ■ 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) i tørt dimetylformamid (30 ml) i 5 min.' Temperaturen fikk stige fra 20°-50°C. Blandingen ble rørt i ytter-' ligere 3"timer. Den resulterende oppslemming ble filtrert. (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 an additional 3 hours. The resulting slurry was filtered.
og filtratet helt i vann (700 ml) inneholdende saltsyre (10 ml, 36,5%). Det resulterende faste stoff ble oppsamlet og omkrystallisert fra iseddik, produktet ble deretter vask-' et 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. and the filtrate entirely in water (700 ml) containing hydrochloric acid (10 ml, 36.5%). The resulting solid was collected and recrystallized from glacial acetic acid, the product was then washed with water and recrystallized from methyl ethyl ketone to give 3,4-bis(n-dodecanamido)benzoic acid (12.5 g) as a white solid substance, m.p. 195°-197°C.
REFERANSEEKSEMPEL 2 2 REFERENCE EXAMPLE 2 2
Ved å gå frem på lignende måte som forut beskrevet i referanseeksempel 21 for fremstillingen av 3,4-bis(n-dodekanamido)-benzosyre, men erstatte n-dodekanoykloridet med n-heksadekanoylklorid og. kaliumkarbonatet med natriumkarbonat, fremstilte man 3,4-bis(n-heksadekanamido)benzosyre i form av et hvitt fast stoff, smp. 198°-202°C etter påfølgende■om-krystalliseringer fra iseddik og metyletylketon. By proceeding in a similar manner as previously described in reference example 21 for the preparation of 3,4-bis(n-dodecanamido)-benzoic acid, but replacing the n-dodecanoyl chloride with n-hexadecanoyl chloride and. the potassium carbonate with sodium carbonate, 3,4-bis(n-hexadecanamido)benzoic acid was prepared in the form of a white solid, m.p. 198°-202°C after successive ■recrystallizations from glacial acetic acid and methyl ethyl ketone.
REFERANSEEKSEMPEL 2 3REFERENCE EXAMPLE 2 3
Ved å gå- frem på lignende måte som forut beskrevet i referanseeksempel 21 for fremstillingen av 3,4-bis-(n-dodekan-amido) benzosyre, men erstatte n-dodekanoylkloridet med.n-oktanoylklorid, fremstilte man 3,4-bis(n-oktanamido)benzosyre i form av et hvitt fast stoff, smp. 195°-197°C etter påfølgende omkrystalliseringer. fra iseddik og metyletylketon. By proceeding in a similar manner as previously described in reference example 21 for the preparation of 3,4-bis-(n-dodecane-amido)benzoic acid, but replacing the n-dodecanoyl chloride with n-octanoyl chloride, 3,4-bis was prepared (n-octanamido)benzoic acid as a white solid, m.p. 195°-197°C after subsequent recrystallizations. from glacial acetic acid and methyl ethyl ketone.
REFERANSEEKSEMPEL 2 4REFERENCE EXAMPLE 2 4
Ved å gå frem på lignende måte som beskrevet i referanseeksempel 21 for fremstillingen av 3,4-bis(n-dodekanamido)-benzosyre, men' erstatte n-dodekanoylkloridet med n-tetradekanoylklorid, fremstilte man 3,4-bis(n-tetradekanamido)benzosyre i form av et hvitt fast stoff, smp. 201°-206°C etter påfølgende omkrystalliseringer fra iseddik og metyletylketon. By proceeding in a similar manner as described in reference example 21 for the preparation of 3,4-bis(n-dodecanamido)-benzoic acid, but replacing the n-dodecanoyl chloride with n-tetradecanoyl chloride, 3,4-bis(n-tetradecanamido )benzoic acid in the form of a white solid, m.p. 201°-206°C after subsequent recrystallizations from glacial acetic acid and methyl ethyl ketone.
REFERANSEEKSEMPEL 2 5REFERENCE EXAMPLE 2 5
Metyl 4-(n-dodekanamido)-3-nitr.obenzoat (21 g) oppløst i varmt etylacetat (500 ml) (50°-55°C) ble hydrogenert'ved rysting i nærvær av 5% w/w palladium-på-karbon (2,0 g) ved 60°C og atmosfæretrykk'i 2 timer. Blandingen ble filtrert varm og filtratet fikk avkjøles. Det faste stoffet ble oppsamlet og ga metyl 3-amino-4-(n-dodekanamido)benzoat (14,1 g) i Methyl 4-(n-dodecanamido)-3-nitrobenzoate (21 g) dissolved in 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 allowed to cool. The solid was collected to give methyl 3-amino-4-(n-dodecanamido)benzoate (14.1 g) in
form av et hvitt fast stoff, smp. 134°-137°C.form of a white solid, m.p. 134°-137°C.
Metyl 4-(n-dodekanamido]-3-nitrobenzoatet som ble brukt som : The methyl 4-(n-dodecanamido]-3-nitrobenzoate which was used as :
utgangsmateriale ble fremstilt som følger:starting material was prepared as follows:
Metyl 4-amino-3-nitrobenzoat (19,6 g) og n-dodekanoylklorid (23 g) i dimetylformamid (100 ml) ble oppvarmet i 2 1/2 time ved 97°C under leilighetsvis rysting. Den resulterende løs-ning ble helt på knust is (300 g) og det faste stoff oppsamlet og omkrystallisert fra en blanding av metanol og kloroform (5:1), hvilket ga 4-(n-dodekanamido)-3-nitrobenzo'at Methyl 4-amino-3-nitrobenzoate (19.6 g) and n-dodecanoyl chloride (23 g) in dimethylformamide (100 ml) were heated for 2 1/2 hours at 97°C with occasional shaking. The resulting 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 4-(n-dodecanamido)-3-nitrobenzoate
(31 g) i form av et gult fast stoff,, smp. 78°-80°C. (31 g) as a yellow solid, m.p. 78°-80°C.
Metyl 4-amino-3-nitrobenzoatet ble fremstilt som følger: 4-amino-3-nitrobenzosyre (70 g) ble satt til en løsning av vannfritt hydrogenklorid i metanol [fremstilt fra acetyl-klorid (78 g) og tørr metanol (300 ml)]. Den resulterende blanding ble tilbakeløpskokt 10 timer, avkjølt i is.og det faste stoff frafiltrert, hvilket ga metyl 4-amino-3-nitro-benzoat (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 filtered off, yielding methyl 4-amino-3-nitrobenzoate (62 g) as a yellow solid, m.p. 193°-195°C.
REFERANSEEKSEMPEL 2 6REFERENCE EXAMPLE 2 6
Ved å.ga frem på lignende måte som forut beskrevet i refer- , By presenting in a similar way as previously described in reference,
■ anseeksempel 25 for fremstillingen av metyl 3-amino-4-(n-dodekanamido)benzoat, men erstatter metyl 4-(n-dodekanamido)-3-nitrobenzoat méd metyl 4-(n-heksadekanamido)-3-nitroben-zoat, fremstilte man metyl 3-amino-4-(n-heksadekanamido)benzoat i form av et hvitt fast stoff, smp. 135°-137°C. ■ considered example 25 for the preparation of methyl 3-amino-4-(n-dodecanamido)benzoate, but replacing methyl 4-(n-dodecanamido)-3-nitrobenzoate with methyl 4-(n-hexadecanamido)-3-nitrobenzoate, methyl 3-amino-4-(n-hexadecanamido)benzoate was prepared in the form of a white solid, m.p. 135°-137°C.
REFERANSEEKSEMPEL 27REFERENCE EXAMPLE 27
Ved å gå frem på lignende måte som forut beskrevet i referanseeksempel 25 for fremstilling av metyl 3-amino-4-(n-dode- kanamido)benzoat, men erstatte metyl 4-(n-dodekanamido)-3-nitrobenzoat med metyl 4-(n-dekanamido)-3-nit.robenzoat, By proceeding in a similar manner as previously described in reference example 25 for the preparation of methyl 3-amino-4-(n-dodecanamido)benzoate, but replacing methyl 4-(n-dodecanamido)-3-nitrobenzoate with methyl 4- (n-decanamido)-3-nitrobenzoate,
•fxemstilte man metyl 3-amino-4-(n-dekanamido)benzoat i form• methyl 3-amino-4-(n-decanamido)benzoate was produced in the form
av et hvitt fast stoff, smp. 131°-133°C.. of a white solid, m.p. 131°-133°C..
REFERANSEEKSEMPEL 28 REFERENCE EXAMPLE 28
En omrørt løsning av 3,4-diaminobenzosyre (8,4 g) i tørt dimetylformamid (100 ml) inneholdende kaliumkarbonat (15,27 g) ble behandlet dråpevis med en løsning av n-heksadekanoyl-klorid (15,17 g) i tørt dimetylf ormamid' (30 ml) i 30 min. 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) for 30 min.
ved 0°-5°C. Blandingen ble rørt i ytterligere- 2 timer ved 0°-5°C og fikk oppvarmes til romtemperatur-over 3 0 min. at 0°-5°C. The mixture was stirred for an additional 2 hours at 0°-5°C and allowed to warm to room temperature over 30 min.
Løsningen ble så helt i vann (700 ml) inneholdende saltsyre (10 ml, -36,5%) . Det .faste stoff ble oppsamlet, oppvarmet med' aceton (300 ml) ved 50°C og omkrystallisert fra metyletylketon, hvilket ga 4-amino-3-(n-heksadékanamido)benzosyre (9,4 g) i form av et hvitt fast stoff,- smp. 197°-199°C. The solution was then poured into water (700 ml) containing hydrochloric acid (10 ml, -36.5%). 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 fabric, - m.p. 197°-199°C.
REFERANSEEKSEMPEL 2 9REFERENCE EXAMPLE 2 9
Ved å gå frem på lignende måte som forut- beskrevet i referanseeksempel 21 for fremstillingen av 3,4-bis(n-dodekanamido)-benzosyre, men erstatte n-dodekanoylklorid med n-dek'anoyl-klorid, fremstilte man 3,4-bis(n-dekanamido)benzosyre■i form av et hvitt fast stoff, smp. 194°-196°C etter påfølgende omkrystalliseringer fra iseddik og metyletylketon. By proceeding in a similar manner as previously described in reference example 21 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)benzoic acid■in the form of a white solid, m.p. 194°-196°C after subsequent recrystallizations from glacial acetic acid and methyl ethyl ketone.
REFERANSEEKSEMPEL 3 0REFERENCE EXAMPLE 3 0
Ved å gå frem på lignende måte som forut beskrevet i referanseeksempel 21.for fremstillingen av 3,4-bis(n-dodekanamido)-benzosyre, men erstatte n-dodekanoylkloridet med n-tridekanoylklorid, fremstilte man 3,4-bis(n-tridekanamido)benzosyre i. form av et gråhvitt fast stoff, smp. 192°-194°C etter på-følgende omkrystalliseringer fra iseddik og metyletylketon. By proceeding in a similar manner as previously described in reference example 21 for the production of 3,4-bis(n-dodecanamido)-benzoic acid, but replacing the 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 recrystallizations from glacial acetic acid and methyl ethyl ketone.
REFERANSEEKSEMPEL 31REFERENCE EXAMPLE 31
Ved å gå frem på lignende måte soti forut beskrevet i referanseeksempel 21 for fremstillingen av 3,4-bis(n-dodekan-amido) benzosyre , men erstatte n-dodekanoylkloridet med n- Proceeding in a similar manner to that previously described in Reference Example 21 for the preparation of 3,4-bis(n-dodecane-amido)benzoic acid, but replacing the n-dodecanoyl chloride with n-
oktadekanoylklorid, fremstilte man 3 , 4-bis (n-oktadekanamido,) - benzosyre i form av et hvitt fast stoff, smp. 193°-196°C octadecanoyl chloride, 3, 4-bis (n-octadecanamido,)-benzoic acid was prepared in the form of a white solid, m.p. 193°-196°C
etter påfølgende omkrystalliseringer fra iseddik og metyl-,;etylketon.. after subsequent recrystallizations from glacial acetic acid and methyl ethyl ketone..
Foreliggende oppfinnelse omfatter også farmasøytiske blandinger som inneholder minst en forbindelse:med den generelle formel I eller et farmasøytisk fordragelig salt derav i for-, bindelse med et farmasøytisk fordragelig bæremiddel eller overtrekksmiddel. I klinisk praksis kan forbindelsene ifølge foreliggende oppfinnelse gis parenteralt, men for-', trinnsvis gis de rektalt .eller helst oralt. The present invention also encompasses pharmaceutical mixtures containing at least one compound: with 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 according to the present invention can be given parenterally, but in stages they are given rectally or preferably orally.
Faste blandinger for oral administrering omfatter kompri-merte tabletter, piller, pulvere og granulater. I slike faste blandinger blandes en eller flere av de aktive forbindelser med minst et ineft fortyhningsmiddel så som stiv-else, sukrose eller laktose. Blandingene kan også omfatte, hvilket er normalt i praksis, ytterligere substanser .bort-sett fra inerte fortynningsmidler, f.eks. smøremidler så som 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 effective diluent such as starch, sucrose 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 omfatter farma-søytisk fordragelige emulsjoner, løsninger, suspensjoner, sirups og eliksirer som inneholder inerte fortynningsmidler som vanlig brukes på området så som vann og flytende parafin. Foruten inerte fortynningsmidler kan slike blandinger omfatte hjelpestoffer så som fukte- og suspensjonsmidler, og søtningsmidler, smaksstoffer, parfymerings- eller preserver-ingsmidlér. Blandingene ifølge oppfinnelsen for oral administrering omfatter også kapsler av absorberbare materialer så som gelatin, hvilke inneholder 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 containing inert diluents commonly used in the field such as water and liquid paraffin. In addition to inert diluents, such mixtures may include auxiliaries such as wetting and suspending agents, and sweeteners, flavourings, perfuming or preserving agents. The mixtures according to the invention for oral administration also comprise capsules of absorbable materials such as gelatin, which contain one or more of the active substances with or without the addition of diluents or excipients.
Preparater ifølge oppfinnelsen for parenteral administrering omfatter sterile, vandige, vandige-organiske. og organiske løsninger, suspensjoner og emulsjoner. Eksempler på organiske løsningsmidler eller suspensjonsmedia er propylenglykol, polyetylenglykol, vegetabilske oljer så som olivenolje, og Preparations according to the invention for parenteral administration include sterile, aqueous, aqueous-organic. and organic solutions, suspensions and emulsions. Examples of organic solvents or suspension media are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and
injiserbare organi.ske estere så som etyloleat. Disse bland--inger kan også inneholde hjelpestoffer så som stabiliserings-preserverings-, fukte- emulgerings- og dispergeringsmidler.... De kan steriliseres ved f.eks. filtrering gjennom et bakter--ietett filter, ved innføring av steriliseringsmidler i blandn-ingene, ved bestråling eller oppvarming. De kan også fremstilles i form av sterile faste blandinger som kan oppløses i sterilt vann eller annet sterilt injiserbart medium umid- . injectable organic esters such as ethyl oleate. These mixtures can also contain auxiliaries such as stabilising-preserving, wetting-emulsifying and dispersing agents.... They can be sterilized by e.g. filtration through a bacteria-proof 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.
delbart før. bruk.divisible before. use.
Faste blandinger for rektal administrering omfatter supposi-torier formulert i oversensstemmelse med kjente metoder og som inneholder en eller flere av forbindelsene med formel I eller et farmasøytisk fordragelig salt derav. Solid mixtures for rectal administration comprise suppositories formulated in accordance with known methods and which contain one or more of the compounds of formula I or a pharmaceutically acceptable salt thereof.
Andelen av aktiv bestanddel i blandingene ifølge oppfinnelsen kan varieres, men det er nødvendig at den utgjør en slik andel at en formålstjenlig dosering oppnås. Selvfølgelig kan flere enhetsdoseringsformer gis omtrent samtidig. Den anvendte dose vil bli bestemt av legen, og avhenger av den ønskede terapeutiske virkning, administreringsveg og behand-lingens varighet, og av pasientens tilstand. Hos voksne er dosene i alminnelighet mellom 0,1 og 50 mg/kg kroppsvekt pr. dag oral administrering, f-.eks. som hypolipidemiske og anti-ateromiske midler og ved beslektede kardiovaskulære sykdommer mellom 10 og 50 mg/kg kroppsvekt pr. dag ved oral administrering; i behandling av sukkersyke mellom 5 og 40 mg/kg kroppsvekt pr. dag oral administrering, og ved 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 an appropriate dosage is achieved. Of course, multiple unit dosage forms may be administered approximately simultaneously. The dose used will be determined by the doctor, and depends on the desired therapeutic effect, route of administration and duration of treatment, and on the patient's condition. In adults, the doses are generally between 0.1 and 50 mg/kg body weight per day oral administration, e.g. as hypolipidemic and anti-atheromic agents and in related cardiovascular diseases between 10 and 50 mg/kg body weight per day by oral administration; in the treatment of diabetes between 5 and 40 mg/kg body weight per day 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 følgende eksempel illustrerer farmasøytiske blandinger ifølge foreliggende oppfinnelse. The following example illustrates pharmaceutical compositions according to the present invention.
EKSEMPEL 6 0EXAMPLE 6 0
Gelatinkapsler størrelse nr. 2 som hver inneholdt: Gelatin capsules size No. 2 each containing:
ble fremstilt ifølge vanlig fremgangsmåte. was prepared according to the usual method.
Claims (8)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB7922011 | 1979-06-25 | ||
GB8013948 | 1980-04-28 |
Publications (1)
Publication Number | Publication Date |
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NO801875L true NO801875L (en) | 1980-12-29 |
Family
ID=26271953
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
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 Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO801876A NO801876L (en) | 1979-06-25 | 1980-06-23 | PROCEDURE FOR PREPARING ACYLAMINOBENZO ACID DERIVATIVES |
Country Status (20)
Country | Link |
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AT (1) | ATA328780A (en) |
AU (2) | AU5954580A (en) |
CA (1) | CA1141765A (en) |
DE (2) | DE3023432A1 (en) |
DK (2) | DK268080A (en) |
ES (2) | ES8105268A1 (en) |
FI (2) | FI802008A (en) |
FR (2) | FR2459794A1 (en) |
GB (1) | GB2053912B (en) |
GR (2) | GR69291B (en) |
IL (2) | IL60379A0 (en) |
IT (2) | IT1197459B (en) |
LU (2) | LU82546A1 (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 |
Family Cites Families (2)
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 DE DE19803023432 patent/DE3023432A1/en not_active Withdrawn
- 1980-06-23 AU AU59545/80A patent/AU5954580A/en not_active Abandoned
- 1980-06-23 SE SE8004622A patent/SE8004622L/en not_active Application Discontinuation
- 1980-06-23 FR FR8013846A patent/FR2459794A1/en not_active Withdrawn
- 1980-06-23 CA CA000354555A patent/CA1141765A/en not_active Expired
- 1980-06-23 IL IL60379A patent/IL60379A0/en unknown
- 1980-06-23 NO NO801876A patent/NO801876L/en unknown
- 1980-06-23 FI FI802008A patent/FI802008A/en not_active Application Discontinuation
- 1980-06-23 IL IL60378A patent/IL60378A0/en unknown
- 1980-06-23 IT IT22965/80A patent/IT1197459B/en active
- 1980-06-23 NZ NZ194123A patent/NZ194123A/en unknown
- 1980-06-23 ES ES492693A patent/ES8105268A1/en not_active Expired
- 1980-06-23 IT IT22966/80A patent/IT1131841B/en active
- 1980-06-23 NZ NZ194122A patent/NZ194122A/en unknown
- 1980-06-23 AU AU59546/80A patent/AU5954680A/en not_active Abandoned
- 1980-06-23 YU YU01636/80A patent/YU163680A/en unknown
- 1980-06-23 GB GB8020548A patent/GB2053912B/en not_active Expired
- 1980-06-23 PH PH24182A patent/PH15713A/en unknown
- 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 NO NO801875A patent/NO801875L/en unknown
- 1980-06-23 AT AT0328780A patent/ATA328780A/en not_active Application Discontinuation
- 1980-06-23 NL NL8003627A patent/NL8003627A/en not_active Application Discontinuation
- 1980-06-23 ES ES492692A patent/ES492692A0/en active Granted
- 1980-06-23 FI FI802009A patent/FI802009A/en not_active Application Discontinuation
- 1980-06-23 DE DE19803023433 patent/DE3023433A1/en not_active Withdrawn
- 1980-06-23 FR FR8013845A patent/FR2459796A1/en not_active Withdrawn
- 1980-06-23 DK DK268080A patent/DK268080A/en not_active Application Discontinuation
- 1980-06-23 PT PT71445A patent/PT71445A/en unknown
- 1980-06-23 DK DK267880A patent/DK267880A/en not_active Application Discontinuation
- 1980-06-23 PT PT71444A patent/PT71444A/en unknown
- 1980-06-24 LU LU82546A patent/LU82546A1/en unknown
- 1980-06-24 LU LU82545A patent/LU82545A1/en unknown
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