NO132094B - - Google Patents
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- Publication number
- NO132094B NO132094B NO2575/70A NO257570A NO132094B NO 132094 B NO132094 B NO 132094B NO 2575/70 A NO2575/70 A NO 2575/70A NO 257570 A NO257570 A NO 257570A NO 132094 B NO132094 B NO 132094B
- Authority
- NO
- Norway
- Prior art keywords
- tetrahydroisoquinoline
- sulfonyl
- propionyl
- cyclohexyl
- sulfonamide
- Prior art date
Links
- -1 α-naphthyl- Chemical group 0.000 claims description 57
- 150000001875 compounds Chemical class 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 11
- 125000004432 carbon atom Chemical group C* 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 229940100389 Sulfonylurea Drugs 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 7
- 239000007858 starting material Substances 0.000 claims description 7
- 239000003513 alkali Substances 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 125000003277 amino group Chemical group 0.000 claims description 6
- JOYRKODLDBILNP-UHFFFAOYSA-N urethane group Chemical group NC(=O)OCC JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 claims description 5
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical class [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- FOOQESAZHHBZBD-UHFFFAOYSA-N 1-cyclohexyl-3-[[2-(2-phenylpropanoyl)-3,4-dihydro-1H-isoquinolin-7-yl]sulfonyl]urea Chemical compound C1(=CC=CC=C1)C(C(=O)N1CC2=CC(=CC=C2CC1)S(=O)(=O)NC(=O)NC1CCCCC1)C FOOQESAZHHBZBD-UHFFFAOYSA-N 0.000 claims description 2
- ZPZBJMYPHWKXSS-UHFFFAOYSA-N CC1=CC=C(C=C1)C(C(=O)N1CC2=CC(=CC=C2CC1)S(=O)(=O)NC(=O)NC1CCCCC1)C Chemical compound CC1=CC=C(C=C1)C(C(=O)N1CC2=CC(=CC=C2CC1)S(=O)(=O)NC(=O)NC1CCCCC1)C ZPZBJMYPHWKXSS-UHFFFAOYSA-N 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000006267 biphenyl group Chemical group 0.000 claims description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- IQPQWNKOIGAROB-UHFFFAOYSA-N isocyanate group Chemical group [N-]=C=O IQPQWNKOIGAROB-UHFFFAOYSA-N 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- LEVJVKGPFAQPOI-UHFFFAOYSA-N phenylmethanone Chemical compound O=[C]C1=CC=CC=C1 LEVJVKGPFAQPOI-UHFFFAOYSA-N 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims 5
- 125000004343 1-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C([H])([H])[H] 0.000 claims 1
- RCIVSMPVTWFBIS-UHFFFAOYSA-N ClC1=CC=C(C=C1)C(C(=O)N1CC2=CC(=CC=C2CC1)S(=O)(=O)NC(=O)NC1CCCCC1)C Chemical compound ClC1=CC=C(C=C1)C(C(=O)N1CC2=CC(=CC=C2CC1)S(=O)(=O)NC(=O)NC1CCCCC1)C RCIVSMPVTWFBIS-UHFFFAOYSA-N 0.000 claims 1
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 79
- 159000000000 sodium salts Chemical class 0.000 description 78
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 50
- KQWGXHWJMSMDJJ-UHFFFAOYSA-N cyclohexyl isocyanate Chemical compound O=C=NC1CCCCC1 KQWGXHWJMSMDJJ-UHFFFAOYSA-N 0.000 description 44
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 42
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 38
- 239000000243 solution Substances 0.000 description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical class O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 36
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 33
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 30
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical class CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 29
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 20
- 238000001704 evaporation Methods 0.000 description 19
- 230000008020 evaporation Effects 0.000 description 19
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 229940124530 sulfonamide Drugs 0.000 description 17
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 16
- 150000003456 sulfonamides Chemical class 0.000 description 15
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 11
- 229960000583 acetic acid Drugs 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 11
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 10
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 238000001816 cooling Methods 0.000 description 8
- 235000019439 ethyl acetate Nutrition 0.000 description 8
- 239000002244 precipitate Substances 0.000 description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 8
- 238000001953 recrystallisation Methods 0.000 description 8
- 235000011121 sodium hydroxide Nutrition 0.000 description 8
- XTHPWXDJESJLNJ-UHFFFAOYSA-N sulfurochloridic acid Chemical compound OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 8
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 7
- 239000004202 carbamide Substances 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical compound OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000000284 extract Substances 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 239000000052 vinegar Substances 0.000 description 6
- 235000021419 vinegar Nutrition 0.000 description 6
- HFODCIWEQMGWCT-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;hydrochloride Chemical compound Cl.C1CNCC2=CC(S(=O)(=O)N)=CC=C21 HFODCIWEQMGWCT-UHFFFAOYSA-N 0.000 description 5
- IRUXSKJXJFMZPQ-UHFFFAOYSA-N 2,3,4,5-tetrahydro-1h-3-benzazepine-7-sulfonamide Chemical compound C1CNCCC2=CC(S(=O)(=O)N)=CC=C21 IRUXSKJXJFMZPQ-UHFFFAOYSA-N 0.000 description 5
- WSBZVFWAVDZIJU-UHFFFAOYSA-N C1(=CC=CC=C1)CCC(=O)N1CC2=CC(=CC=C2CC1)S(=O)(=O)N Chemical compound C1(=CC=CC=C1)CCC(=O)N1CC2=CC(=CC=C2CC1)S(=O)(=O)N WSBZVFWAVDZIJU-UHFFFAOYSA-N 0.000 description 5
- 239000012670 alkaline solution Substances 0.000 description 5
- 229910021529 ammonia Inorganic materials 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 239000012362 glacial acetic acid Substances 0.000 description 5
- UGLLZXSYRBMNOS-UHFFFAOYSA-N 1,2,3,4-tetrahydro-isoquinoline-7-sulfonic acid amide Chemical compound C1CNCC2=CC(S(=O)(=O)N)=CC=C21 UGLLZXSYRBMNOS-UHFFFAOYSA-N 0.000 description 4
- 238000003776 cleavage reaction Methods 0.000 description 4
- ALJDYAQEODFQCX-UHFFFAOYSA-N ethyl N-[[2-(3-phenylpropanoyl)-3,4-dihydro-1H-isoquinolin-7-yl]sulfonyl]carbamate Chemical compound CCOC(=O)NS(=O)(=O)C1=CC2=C(CCN(C2)C(=O)CCC2=CC=CC=C2)C=C1 ALJDYAQEODFQCX-UHFFFAOYSA-N 0.000 description 4
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 4
- 230000007017 scission Effects 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- AAFGZKYAEMJTLZ-UHFFFAOYSA-N 2-(2-phenylpropanoyl)-3,4-dihydro-1H-isoquinoline-7-sulfonamide Chemical compound C1(=CC=CC=C1)C(C(=O)N1CC2=CC(=CC=C2CC1)S(=O)(=O)N)C AAFGZKYAEMJTLZ-UHFFFAOYSA-N 0.000 description 3
- ILJBSAAGDQNOHZ-UHFFFAOYSA-N 2-[2-(4-chlorophenyl)propanoyl]-3,4-dihydro-1H-isoquinoline-7-sulfonamide Chemical compound ClC1=CC=C(C=C1)C(C(=O)N1CC2=CC(=CC=C2CC1)S(=O)(=O)N)C ILJBSAAGDQNOHZ-UHFFFAOYSA-N 0.000 description 3
- KSMVBYPXNKCPAJ-UHFFFAOYSA-N 4-Methylcyclohexylamine Chemical compound CC1CCC(N)CC1 KSMVBYPXNKCPAJ-UHFFFAOYSA-N 0.000 description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000002026 chloroform extract Substances 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- AOCYHPQXGJBAQQ-UHFFFAOYSA-N ethyl n-sulfonylcarbamate Chemical compound CCOC(=O)N=S(=O)=O AOCYHPQXGJBAQQ-UHFFFAOYSA-N 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000012948 isocyanate Substances 0.000 description 3
- 150000002513 isocyanates Chemical class 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 238000001665 trituration Methods 0.000 description 3
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- NABUFFLEHQEQPH-UHFFFAOYSA-N 1-(1,2,4,5-tetrahydro-3-benzazepin-3-yl)ethanone Chemical compound C1CN(C(=O)C)CCC2=CC=CC=C21 NABUFFLEHQEQPH-UHFFFAOYSA-N 0.000 description 2
- JBPPSLURCSFQDH-UHFFFAOYSA-N 1-(3,4-dihydro-1h-isoquinolin-2-yl)ethanone Chemical compound C1=CC=C2CN(C(=O)C)CCC2=C1 JBPPSLURCSFQDH-UHFFFAOYSA-N 0.000 description 2
- XWVFMJLNNGXNSG-UHFFFAOYSA-N 1-(7-amino-3,4-dihydro-1h-isoquinolin-2-yl)ethanone Chemical compound C1=C(N)C=C2CN(C(=O)C)CCC2=C1 XWVFMJLNNGXNSG-UHFFFAOYSA-N 0.000 description 2
- BIGSDRLRUNXANK-UHFFFAOYSA-N 2-(3-phenylbutanoyl)-3,4-dihydro-1H-isoquinoline-7-sulfonamide Chemical compound C1(=CC=CC=C1)C(CC(=O)N1CC2=CC(=CC=C2CC1)S(=O)(=O)N)C BIGSDRLRUNXANK-UHFFFAOYSA-N 0.000 description 2
- XYVQFXSDLNCVQQ-UHFFFAOYSA-N 2-acetyl-3,4-dihydro-1h-isoquinoline-7-sulfonamide Chemical compound C1=C(S(N)(=O)=O)C=C2CN(C(=O)C)CCC2=C1 XYVQFXSDLNCVQQ-UHFFFAOYSA-N 0.000 description 2
- WZYNHWTZPLQOAG-UHFFFAOYSA-N C1(=CC=CC=C1)C(C(=O)N1CC2=CC(=CC=C2CC1)S(=O)(=O)NC(OCC)=O)C Chemical compound C1(=CC=CC=C1)C(C(=O)N1CC2=CC(=CC=C2CC1)S(=O)(=O)NC(OCC)=O)C WZYNHWTZPLQOAG-UHFFFAOYSA-N 0.000 description 2
- DBESOTBONSCZLF-UHFFFAOYSA-N C1(=CC=CC=C1)C(CC(=O)N1CC2=CC(=CC=C2CC1)S(=O)(=O)NC(OCC)=O)C Chemical compound C1(=CC=CC=C1)C(CC(=O)N1CC2=CC(=CC=C2CC1)S(=O)(=O)NC(OCC)=O)C DBESOTBONSCZLF-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 238000000297 Sandmeyer reaction Methods 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 2
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000006260 foam Substances 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 150000007530 organic bases Chemical group 0.000 description 2
- 230000020477 pH reduction Effects 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 235000002639 sodium chloride Nutrition 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000012265 solid product Substances 0.000 description 2
- 239000012258 stirred mixture Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- WZHRJGWXUCLILI-UHFFFAOYSA-N sulfonylcarbamic acid Chemical class OC(=O)N=S(=O)=O WZHRJGWXUCLILI-UHFFFAOYSA-N 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 1
- VMEDBFRQSKKEEQ-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinolin-7-amine Chemical class C1CNCC2=CC(N)=CC=C21 VMEDBFRQSKKEEQ-UHFFFAOYSA-N 0.000 description 1
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical class C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 description 1
- FSYWMPRUEBTSIZ-UHFFFAOYSA-N 1-cyclohexyl-3-[[2-(4-methylbenzoyl)-3,4-dihydro-1H-isoquinolin-7-yl]sulfonyl]urea Chemical compound CC1=CC=C(C(=O)N2CC3=CC(=CC=C3CC2)S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 FSYWMPRUEBTSIZ-UHFFFAOYSA-N 0.000 description 1
- LOXPKSAIAHLVML-UHFFFAOYSA-N 2,3,4,5-tetrahydro-1h-3-benzazepin-7-amine Chemical class C1CNCCC2=CC(N)=CC=C21 LOXPKSAIAHLVML-UHFFFAOYSA-N 0.000 description 1
- MWVMYAWMFTVYED-UHFFFAOYSA-N 2,3,4,5-tetrahydro-1h-3-benzazepine Chemical class C1CNCCC2=CC=CC=C21 MWVMYAWMFTVYED-UHFFFAOYSA-N 0.000 description 1
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 1
- GSJVKPFXFCEEPQ-UHFFFAOYSA-N 2-(3-phenylpentanoyl)-3,4-dihydro-1H-isoquinoline-7-sulfonamide Chemical compound C1(=CC=CC=C1)C(CC(=O)N1CC2=CC(=CC=C2CC1)S(=O)(=O)N)CC GSJVKPFXFCEEPQ-UHFFFAOYSA-N 0.000 description 1
- PFDBEACWLCHWRZ-UHFFFAOYSA-N 2-(4-bromophenyl)propanoic acid Chemical compound OC(=O)C(C)C1=CC=C(Br)C=C1 PFDBEACWLCHWRZ-UHFFFAOYSA-N 0.000 description 1
- YOZILQVNIWNPFP-UHFFFAOYSA-N 2-(4-chlorophenyl)propanoic acid Chemical compound OC(=O)C(C)C1=CC=C(Cl)C=C1 YOZILQVNIWNPFP-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- APSGVUXOAHSBGR-UHFFFAOYSA-N 2-[2-(3,4-dichlorophenyl)propanoyl]-3,4-dihydro-1H-isoquinoline-7-sulfonamide Chemical compound ClC=1C=C(C=CC1Cl)C(C(=O)N1CC2=CC(=CC=C2CC1)S(=O)(=O)N)C APSGVUXOAHSBGR-UHFFFAOYSA-N 0.000 description 1
- UXSMEOLJRBKPKI-UHFFFAOYSA-N 2-[3-(3-chlorophenyl)propanoyl]-3,4-dihydro-1H-isoquinoline-7-sulfonamide Chemical compound ClC=1C=C(C=CC1)CCC(=O)N1CC2=CC(=CC=C2CC1)S(=O)(=O)N UXSMEOLJRBKPKI-UHFFFAOYSA-N 0.000 description 1
- MAUSSGMKFIPNAQ-UHFFFAOYSA-N 3-acetyl-1,2,4,5-tetrahydro-3-benzazepine-7-sulfonamide Chemical compound C(C)(=O)N1CCC2=C(CC1)C=CC(=C2)S(=O)(=O)N MAUSSGMKFIPNAQ-UHFFFAOYSA-N 0.000 description 1
- MFEILWXBDBCWKF-UHFFFAOYSA-N 3-phenylpropanoyl chloride Chemical compound ClC(=O)CCC1=CC=CC=C1 MFEILWXBDBCWKF-UHFFFAOYSA-N 0.000 description 1
- IKQCKANHUYSABG-UHFFFAOYSA-N 4-ethylcyclohexan-1-amine Chemical compound CCC1CCC(N)CC1 IKQCKANHUYSABG-UHFFFAOYSA-N 0.000 description 1
- 102100031126 6-phosphogluconolactonase Human genes 0.000 description 1
- 108010029731 6-phosphogluconolactonase Proteins 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 238000006418 Brown reaction Methods 0.000 description 1
- GUCLPCNETRTMIK-UHFFFAOYSA-N C(C)OC1=CC=C(C=C1)C(C(=O)N1CC2=CC(=CC=C2CC1)S(=O)(=O)N)C Chemical compound C(C)OC1=CC=C(C=C1)C(C(=O)N1CC2=CC(=CC=C2CC1)S(=O)(=O)N)C GUCLPCNETRTMIK-UHFFFAOYSA-N 0.000 description 1
- ATAAGXSCUHYATC-UHFFFAOYSA-N C(C1=CC=CC=C1)(=O)CC(=O)C1NCCC2=CC=C(C=C12)S(=O)(=O)N Chemical compound C(C1=CC=CC=C1)(=O)CC(=O)C1NCCC2=CC=C(C=C12)S(=O)(=O)N ATAAGXSCUHYATC-UHFFFAOYSA-N 0.000 description 1
- NASKLOJEFRXNCN-UHFFFAOYSA-N C(CC(C)C)(=O)N1CC2=CC(=CC=C2CC1)S(=O)(=O)N Chemical compound C(CC(C)C)(=O)N1CC2=CC(=CC=C2CC1)S(=O)(=O)N NASKLOJEFRXNCN-UHFFFAOYSA-N 0.000 description 1
- RSPVHMRCRNKTOA-UHFFFAOYSA-N C(CCC)(=O)N1CC2=CC(=CC=C2CC1)S(=O)(=O)N Chemical compound C(CCC)(=O)N1CC2=CC(=CC=C2CC1)S(=O)(=O)N RSPVHMRCRNKTOA-UHFFFAOYSA-N 0.000 description 1
- UIWGHTMEJUQOTF-UHFFFAOYSA-N C1(=CC=C(C=C1)CCC(=O)N1CC2=CC(=CC=C2CC1)S(=O)(=O)N)C Chemical compound C1(=CC=C(C=C1)CCC(=O)N1CC2=CC(=CC=C2CC1)S(=O)(=O)N)C UIWGHTMEJUQOTF-UHFFFAOYSA-N 0.000 description 1
- FSWUULHCNDYMGQ-UHFFFAOYSA-N CC(C(CC(=O)N1CC2=CC(=CC=C2CC1)S(=O)(=O)N)C1=CC=CC=C1)C Chemical compound CC(C(CC(=O)N1CC2=CC(=CC=C2CC1)S(=O)(=O)N)C1=CC=CC=C1)C FSWUULHCNDYMGQ-UHFFFAOYSA-N 0.000 description 1
- GRALOFCMPMMESQ-UHFFFAOYSA-N COC1=C(C=CC=C1)CCC(=O)N1CC2=CC(=CC=C2CC1)S(=O)(=O)N Chemical compound COC1=C(C=CC=C1)CCC(=O)N1CC2=CC(=CC=C2CC1)S(=O)(=O)N GRALOFCMPMMESQ-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- RKWGIWYCVPQPMF-UHFFFAOYSA-N Chloropropamide Chemical group CCCNC(=O)NS(=O)(=O)C1=CC=C(Cl)C=C1 RKWGIWYCVPQPMF-UHFFFAOYSA-N 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
- NBSCHQHZLSJFNQ-GASJEMHNSA-N D-Glucose 6-phosphate Chemical compound OC1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H](O)[C@H]1O NBSCHQHZLSJFNQ-GASJEMHNSA-N 0.000 description 1
- VFRROHXSMXFLSN-UHFFFAOYSA-N Glc6P Natural products OP(=O)(O)OCC(O)C(O)C(O)C(O)C=O VFRROHXSMXFLSN-UHFFFAOYSA-N 0.000 description 1
- 108010018962 Glucosephosphate Dehydrogenase Proteins 0.000 description 1
- 102000005548 Hexokinase Human genes 0.000 description 1
- 108700040460 Hexokinases Proteins 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- ACFIXJIJDZMPPO-NNYOXOHSSA-J NADPH(4-) Chemical compound C1=CCC(C(=O)N)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP([O-])(=O)OP([O-])(=O)OC[C@@H]2[C@H]([C@@H](OP([O-])([O-])=O)[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)O)O1 ACFIXJIJDZMPPO-NNYOXOHSSA-J 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- XJLXINKUBYWONI-DQQFMEOOSA-N [[(2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2s,3r,4s,5s)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@@H]2[C@H]([C@@H](O)[C@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-DQQFMEOOSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 150000001266 acyl halides Chemical class 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical group 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 230000004531 blood pressure lowering effect Effects 0.000 description 1
- 238000009395 breeding Methods 0.000 description 1
- 230000001488 breeding effect Effects 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000003245 coal Substances 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- VXVVUHQULXCUPF-UHFFFAOYSA-N cycloheptanamine Chemical compound NC1CCCCCC1 VXVVUHQULXCUPF-UHFFFAOYSA-N 0.000 description 1
- WUESWDIHTKHGQA-UHFFFAOYSA-N cyclohexylurea Chemical compound NC(=O)NC1CCCCC1 WUESWDIHTKHGQA-UHFFFAOYSA-N 0.000 description 1
- HSOHBWMXECKEKV-UHFFFAOYSA-N cyclooctanamine Chemical compound NC1CCCCCCC1 HSOHBWMXECKEKV-UHFFFAOYSA-N 0.000 description 1
- NISGSNTVMOOSJQ-UHFFFAOYSA-N cyclopentanamine Chemical compound NC1CCCC1 NISGSNTVMOOSJQ-UHFFFAOYSA-N 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000012954 diazonium Substances 0.000 description 1
- 150000001989 diazonium salts Chemical class 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- TXQDTCFYVNDVJK-UHFFFAOYSA-N ethyl N-ethoxycarbonyl-N-[[2-(3-phenylpropanoyl)-3,4-dihydro-1H-isoquinolin-7-yl]sulfonyl]carbamate Chemical compound C(=O)(OCC)N(S(=O)(=O)C1=CC=C2CCN(CC2=C1)C(CCC1=CC=CC=C1)=O)C(=O)OCC TXQDTCFYVNDVJK-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- YPGCWEMNNLXISK-UHFFFAOYSA-N hydratropic acid Chemical compound OC(=O)C(C)C1=CC=CC=C1 YPGCWEMNNLXISK-UHFFFAOYSA-N 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- HNHVTXYLRVGMHD-UHFFFAOYSA-N n-butyl isocyanate Chemical compound CCCCN=C=O HNHVTXYLRVGMHD-UHFFFAOYSA-N 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000004540 pour-on Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001256 steam distillation Methods 0.000 description 1
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/16—Benzazepines; Hydrogenated benzazepines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
- C07D217/06—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
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
Oppfinnelsens gjenstand er en analogifremgangsmåte til fremstilling av nye sulfonylurinstoffer av den generelle formel I, The object of the invention is an analogous process for the preparation of new sulfonylureas of the general formula I,
og deres fysiologisk tålbare alkali- og jordalkalisalter. and their physiologically tolerable alkali and alkaline earth salts.
I den ovenanførte formel I betyr In the above formula I means
en rettkjedet eller forgrenet mettet alkylrest med 1-4 karbonatomer, en eventuelt med en alkoksyrest med 1-3 karbonatomer, en metyl- eller trifluormetylgruppe, en eller to halogenatomer eller med en metoksygruppe i 2-stilling og et klor- a straight-chain or branched saturated alkyl residue with 1-4 carbon atoms, one optionally with an alkoxy acid residue with 1-3 carbon atoms, a methyl or trifluoromethyl group, one or two halogen atoms or with a methoxy group in the 2-position and a chlorine
atom i 5-stilling substituert fenylrest, en difenyl-, a-naftyl-, l,2,3,4-tetrahydronaftyl-(l)-, indanyl-(l)- eller benzoylrest, atom in the 5-position substituted phenyl radical, a diphenyl-, α-naphthyl-, 1,2,3,4-tetrahydronaphthyl-(l)-, indanyl-(l)- or benzoyl radical,
R2 n-butylresten, en eventuelt med en alkylrest med 1-2 karbonatomer substituert cykloalkylrest med 5-8 ring-karbonatomer eller en adamantyl-(1)-rest, R2 the n-butyl residue, a cycloalkyl residue with 5-8 ring carbon atoms optionally substituted by an alkyl residue with 1-2 carbon atoms or an adamantyl-(1) residue,
A en karbon-karbon-binding eller en eventuelt med en fenylrest substituert toverdig alifatisk hydrokarbonrest med 1-5 karbonatomer og A a carbon-carbon bond or a divalent aliphatic hydrocarbon residue with 1-5 carbon atoms optionally substituted with a phenyl residue and
n tallet 1 eller 2. n the number 1 or 2.
De nye forbindelser oppviser en meget god blodsukker-senkende virkning i lave doser og oppviser en meget liten toksisitet. The new compounds show a very good blood sugar-lowering effect in low doses and show very little toxicity.
Fremstillingen av de nye forbindelser finner sted ved omsetning av en acyl-7-sulfonyl-forbindelse av den generelle formel II The production of the new compounds takes place by reacting an acyl-7-sulfonyl compound of the general formula II
med en forbindelse av den generelle formel III, with a compound of the general formula III,
hvor where
R1, A, R 2 og n har den foran anførte betydning og X betyr enten en fri aminogruppe og Y en isocyanatgruppe, eller X betyr resten av en karbaminsyreester av formelen: R1, A, R2 and n have the meaning stated above and X means either a free amino group and Y an isocyanate group, or X means the residue of a carbamic acid ester of the formula:
hvor where
Alk betyr en lavere alkylrest, og Alk means a lower alkyl residue, and
Y betyr en fri aminogruppe. Y means a free amino group.
Omsetningen av et sulfonamid av formelen II med isocyanat av formelen III finner sted i et inert oppløsnings- eller fortynningsmiddel, fortrinnsvis i nærvær av en anorganisk eller tertiær organisk base og fortrinnsvis ved forhøyede temperaturer, særlig ved temperaturer mellom 50 og 150°C. Reaksjonen kan prinsipielt også gjennomføres ved romtemperatur, men reaksjons-varigheten er da betydelig lengere. Som anorganiske baser kommer alkalihydroksydet i betraktning, som tertiære organiske baser eksempelvis pyridin. Hensiktsmessig dannes først et alkalisalt av sulfonamidet av formelen II ved omsetning med en alkoholisk alkalihydroksyd-oppløsning og etterfølgende inndampning til tørrhet og dette omsettes med isocyanatet fra formelen III. The reaction of a sulfonamide of formula II with isocyanate of formula III takes place in an inert solvent or diluent, preferably in the presence of an inorganic or tertiary organic base and preferably at elevated temperatures, in particular at temperatures between 50 and 150°C. The reaction can in principle also be carried out at room temperature, but the reaction duration is then considerably longer. As inorganic bases, the alkali hydroxide comes into consideration, as tertiary organic bases, for example, pyridine. Appropriately, an alkali salt of the sulfonamide of formula II is first formed by reaction with an alcoholic alkali hydroxide solution and subsequent evaporation to dryness and this is reacted with the isocyanate from formula III.
Omsetningen av en sulfonylkarbaminsyreester av formelen II, i hvilken altså X betyr resten -NH-COO-Alk, med et amin av formelen III finner likeledes sted i et inert organisk oppløsnings-eller fortynningsmiddel, ved romtemperatur eller forhøyede temperaturer, fortrinnsvis ved temperaturer mellom 50 og 120°C. The reaction of a sulfonylcarbamic acid ester of the formula II, in which X means the radical -NH-COO-Alk, with an amine of the formula III likewise takes place in an inert organic solvent or diluent, at room temperature or elevated temperatures, preferably at temperatures between 50 and 120°C.
Som inerte oppløsnings- resp. fortynningsmidler kommer ved begge fremgangsmåte-varianter særlig i betraktning dimetylformamid, dimetylsulfoksyd og nitrobenzen, da disse oppviser de beste opp-løsningsegenskaper for de anvendte utgangsstoffer. As inert solution resp. diluents come into consideration in both process variants in particular dimethylformamide, dimethylsulfoxide and nitrobenzene, as these exhibit the best dissolution properties for the starting materials used.
De erholdte forbindelser av formel I kan om ønskes med alkali- eller jordalkalihydroksyder overføres til fysiologisk tålbare alkali- eller jordalkalisalter, foretrukket er natriumsaltene. The obtained compounds of formula I can, if desired, be transferred with alkali or alkaline earth hydroxides to physiologically tolerable alkali or alkaline earth salts, the sodium salts being preferred.
De som utgangsstoffer anvendte sulfonamider resp. sulfonylkarbaminsyreestere av formel II er likeledes nye, The sulfonamides used as starting substances resp. sulfonylcarbamic acid esters of formula II are also new,
Sulfonamidene av formel II kan fåes ved omsetning av 1,2,3,4-tetrahydro-isokinolin-7-sulfonamid resp. av 2,3,4,5-tetrahydro-lH-3-benzazepin-7-sulfonamid med et acylhalogenid av formel IV The sulfonamides of formula II can be obtained by reacting 1,2,3,4-tetrahydro-isoquinoline-7-sulfonamide resp. of 2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonamide with an acyl halide of formula IV
i hvilken in which
R^ og A har de innledningsvis nevnte betydninger og R^ and A have the initially mentioned meanings and
Hal betyr et halogenatom, hensiktsmessig i nærvær av et oppløsningsmiddel som pyridin eller med en karboksylsyre av formel V Hal means a halogen atom, conveniently in the presence of a solvent such as pyridine or with a carboxylic acid of formula V
i hvilken in which
R^ og A har de foran nevnte betydninger, under tilsetning av en aktivator som tionylklorid eller dicykloheksylkarbodiimid. De kan imidlertid også fåes ved omsetning av et sulfoklorid av formel VI R 1 and A have the aforementioned meanings, with the addition of an activator such as thionyl chloride or dicyclohexylcarbodiimide. However, they can also be obtained by reacting a sulfochloride of formula VI
i hvilken in which
, A og n har de innledningsvis nevnte betydninger med ammoniakk. , A and n have the initially mentioned meanings with ammonia.
Sulfonylkarbaminsyreestrene av formel II, i hvilken X betyr resten -NH-COO-Alk, fåes ved omsetning av de foran nevnte nye sulfonamider av formel II med en klormaursyrealkylester. The sulfonylcarbamic acid esters of formula II, in which X means the radical -NH-COO-Alk, are obtained by reacting the aforementioned new sulfonamides of formula II with a chloroformic acid alkyl ester.
l,2,3,4-tetrahydro-isokinolin-7-sulfonamid og 2,3,4,5-tetrahydro-lH-3-benzazepin-7-sulfonamid er likeledes hittil ikke beskrevet i litteraturen. De kan fåes fra 2-acetyl-l,2,3,4-tetrahydro-isokinolin resp. 3-acetyl-2,3,4,5-tetrahydro-lH-3-benzazepin ved klorsulfonering, omsetning med ammoniakk og til-sluttende avspaltning av acetylresten. 1,2,3,4-tetrahydroisokinolin-7-sulfonamid kan ennvidere fåes fra det litteratur-kjente 2-acetyl-7-amino-l,2,3,4-tetrahydro-isokinolin ved over-føring av aminogruppen til en klorsulfonylgruppe ved hjelp av en modifisert Sandmeyer-reaksjon (se H. Meerwein et. al. Chem. Ber. 90, 841 (1957), omsetning med ammoniakk og avspaltning av acetylresten i 2-stilling ved hjelp av fortynnede mineralsyrer. De likeledes nye sulfoklorider av formel VI kan sluttlig fåes fra de tilsvarende i 2-stilling acylerte 7-amino-l,2,3,4-tetrahydro-isokinoliner resp. av de tilsvarende i 3-stilling acylerte 7-amino-2,3,4,5-tetrahydro-lH-3-benzazepiner ved erstatning av aminogruppen med klorsulfonylgruppen ved hjelp av en modifisert Sandmeyer-reaksjon (se ovenfor) eller ved klorsulfonering av tilsvarende i 2-stilling acylerte 1,2,3,4-tetrahydro-isokinoliner resp. av tilsvarende i 3-stilling acylerte 2,3,4,5-tetrahydro-lH-3-benzazepiner. 1,2,3,4-tetrahydro-isoquinoline-7-sulfonamide and 2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonamide have likewise not been described in the literature so far. They can be obtained from 2-acetyl-1,2,3,4-tetrahydro-isoquinoline or 3-acetyl-2,3,4,5-tetrahydro-1H-3-benzazepine by chlorosulfonation, reaction with ammonia and subsequent cleavage of the acetyl residue. 1,2,3,4-tetrahydroisoquinoline-7-sulfonamide can also be obtained from the literature-known 2-acetyl-7-amino-1,2,3,4-tetrahydro-isoquinoline by transferring the amino group to a chlorosulfonyl group by by means of a modified Sandmeyer reaction (see H. Meerwein et. al. Chem. Ber. 90, 841 (1957), reaction with ammonia and cleavage of the acetyl residue in the 2-position by means of dilute mineral acids. The likewise new sulphochlorides of formula VI can finally be obtained from the corresponding 2-position acylated 7-amino-1,2,3,4-tetrahydro-isoquinolines or from the corresponding 3-position acylated 7-amino-2,3,4,5-tetrahydro -1H-3-benzazepines by replacing the amino group with the chlorosulfonyl group by means of a modified Sandmeyer reaction (see above) or by chlorosulfonation of corresponding in the 2-position acylated 1,2,3,4-tetrahydro-isoquinolines or of corresponding in 3-position acylated 2,3,4,5-tetrahydro-1H-3-benzazepines.
De etterfølgende eksempler A-M beskriver fremstillingen av de nye utgangsstoffer: The following examples A-M describe the production of the new starting materials:
A) 1, 2, 3, 4- tetrahydroisokinolin- 7- sulfonamid- hydroklorid A) 1, 2, 3, 4- tetrahydroisoquinoline- 7- sulfonamide hydrochloride
a) 175,2 g (IM) 2-acetyl-l,2,3,4-tetrahydroisokinolin, oppløst i 80 ml kloroform, dryppes under kjøling med is/koksalt a) 175.2 g (IM) 2-acetyl-1,2,3,4-tetrahydroisoquinoline, dissolved in 80 ml chloroform, added dropwise while cooling with ice/common salt
ved en indre temperatur av 8-15°C til 844 g (7,24 M) klorsulfonsyre. Etter henstand over natten ved 20°C dryppes reaksjons- at an internal temperature of 8-15°C to 844 g (7.24 M) chlorosulfonic acid. After standing overnight at 20°C, the reaction
blandingen på overskudd av is. Ved ekstraksjon med kloroform, tørking, filtrering og inndampning av kloroformfasen fåes 232 g rått sulfoklorid av en honningaktig konsistens. b) Det etter a) erholdte rå 2-acetyl-l,2,3,4-tetrahydroisokinolin-7-sulfoklorid (232 g) gjøres tyntflytende ved opp-varming og innrøres i 600 ml konsentrert vandig ammoniakk. Det røres i 1 time og knaes, derpå suger man fra den fargeløse utfeining, vasker denne flere ganger med vann og en gang med aceton og tørker den ved 80°C/0,1 Torr, man får 172 g sulfonamid av sm.p. 220-224°C. c) 172 g 2-acetyl-l,2,3,4-tetrahydroisokinolin-7-sulfonamid opphetes i 1,4 1 halvkonsentrert saltsyre i 3 timer under tilbakeløp. the mixture on excess ice. By extraction with chloroform, drying, filtration and evaporation of the chloroform phase, 232 g of crude sulphochloride of a honey-like consistency are obtained. b) The crude 2-acetyl-1,2,3,4-tetrahydroisoquinoline-7-sulfochloride (232 g) obtained according to a) is made thinner by heating and stirred into 600 ml of concentrated aqueous ammonia. It is stirred for 1 hour and kneaded, then the colorless liquid is sucked off, washed several times with water and once with acetone and dried at 80°C/0.1 Torr, 172 g of sulfonamide of m.p. 220-224°C. c) 172 g of 2-acetyl-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide are heated in 1.4 1 of semi-concentrated hydrochloric acid for 3 hours under reflux.
Til slutt tilsettes aktivt kull og det filtreres varmt gjennom Finally, activated charcoal is added and it is hot filtered through
et Celite-sjikt. Oppløsningen konsentreres i vakuum inntil be-gynnende krystallisering og derpå avkjøles. Etter avsugning og tørking fåes 105 g av hydrokloridet av den ønskede forbindelse av sm.p. 212-217°C (den frie base smelter ved 176-180°C). a Celite layer. The solution is concentrated in vacuo until crystallization begins and is then cooled. After suction and drying, 105 g of the hydrochloride of the desired compound of m.p. 212-217°C (the free base melts at 176-180°C).
B) 1, 2, 3, 4- tetrahydroisokinolin- 7- sulfonamid- hydroklorid B) 1, 2, 3, 4- tetrahydroisoquinoline- 7- sulfonamide hydrochloride
a) 7,61 g (0,040 M) 2-acetyl-7-amino-l,2,3,4-tetrahydroisokinolin av sm.p. 107-108°C (lit. sm.p. 109-111°C, E. Ochiai og a) 7.61 g (0.040 M) of 2-acetyl-7-amino-1,2,3,4-tetrahydroisoquinoline of m.p. 107-108°C (lit. m.p. 109-111°C, E. Ochiai and
T. Nakagome, Chem. Pharm. Bull. (Jap.) 6, 497 (1958)) oppløses i T. Nakagome, Chem. Pharm. Bull. (Jap.) 6, 497 (1958)) dissolves in
8,4 ml konsentrert saltsyre og ved en indre temperatur av maksimalt +5°C diazoteres med en oppløsning av 3,04 g (0,044 M) NaN02 i 6 ml vann. 8.4 ml of concentrated hydrochloric acid and at an internal temperature of maximum +5°C diazotized with a solution of 3.04 g (0.044 M) NaN02 in 6 ml of water.
Diazoniumsalt-oppløsningen tilsettes 3,04 g (0,032 M) vannfritt MgCl,,, oppvarmes til 30°C og innrøres hurtig ved 30°C The diazonium salt solution is added with 3.04 g (0.032 M) of anhydrous MgCl,,, heated to 30°C and stirred rapidly at 30°C
i 40 ml S0„ mettet iseddik som inneholder 2,2 g (0,0129 M) CuCl .2H„0. Ved ytre opphetning innstilles en indre temperatur av 48 oC og det omrøres i 25 minutter. Etter denne tid er utviklingen bare ganske liten. in 40 ml S0„ saturated glacial acetic acid containing 2.2 g (0.0129 M) CuCl .2H„0. During external heating, an internal temperature of 48 oC is set and it is stirred for 25 minutes. After this time, the development is only quite small.
Den mørkebrune reaksjonsoppløsning fortynnes med 60 ml The dark brown reaction solution is diluted with 60 ml
vann og ekstraheres koldt med eter. Den eteriske ekstrakt vaskes med fortynnet NaHC03, Na2C03-oppløsning av pH 8 - 9 og med vann, tørkes over Na2S04 og inndampes i vakuum til tørrhet. Det blir tilbake 7,0 g rå sulfoklorid av en honningaktig konsistens water and extracted cold with ether. The ethereal extract is washed with dilute NaHCO 3 , Na 2 CO 3 solution of pH 8 - 9 and with water, dried over Na 2 SO 4 and evaporated in vacuo to dryness. 7.0 g of crude sulfochloride of a honey-like consistency remains
b) 6,2 g (22,6 itiM) og det etter a) erholdte rå sulfoklorid overhelles med 30 ml konsentrert ammoniakk og det knaes under is-kjøling i 1 time. Krystallisatet avsuges, vaskes tre ganger med vann og to ganger med aceton. Det fåes 4,3 g sulfonamid av sm.p. 223-226°C. c) 4,0 g av det etter b) erholdte 2Tacetyl-l,2,3,4-tetrahydro-isokinolin-7-sulfonamid og 60 ml 10% HCl opphetes i 2,5 timer under tilbakeløp, tilsist koker man opp med noe aktivt kull. Den over Celite filtrerte oppløsning inndampes i vakuum til tørrhet. Etter omkrystallisering fra metanol fåes 3,3 g av hydrokloridet av den ønskede forbindelse av sm.p. 215-218°C. b) 6.2 g (22.6 itiM) and the crude sulfochloride obtained after a) are poured over with 30 ml of concentrated ammonia and kneaded under ice-cooling for 1 hour. The crystallisate is suctioned off, washed three times with water and twice with acetone. 4.3 g of sulfonamide are obtained from m.p. 223-226°C. c) 4.0 g of the 2Tacetyl-1,2,3,4-tetrahydro-isoquinoline-7-sulfonamide obtained according to b) and 60 ml of 10% HCl are heated for 2.5 hours under reflux, finally boiling with some activated charcoal. The solution filtered over Celite is evaporated in vacuo to dryness. After recrystallization from methanol, 3.3 g of the hydrochloride of the desired compound of m.p. 215-218°C.
C) 2-( 3- fenylpropionyl)- 1, 2, 3, 4- tetrahydroisokinolin- 7- sulfonamid C) 2-( 3- phenylpropionyl)- 1, 2, 3, 4- tetrahydroisoquinoline- 7- sulfonamide
Til en suspensjon av 548 g (2,2 M) 1,2,3,4-tetrahydroisokinolin-7-sulfonamid-hydroklorid av sm.p. 212-217°C i 4 1 pyridin (destillert over BaO) tildryppes 373 g (2,2 M) hydro-kanelsyreklorid under omrøring og kjøling på en slik måte at den indre temperatur ikke overstiger 15°C. Etter 4 timers omrøring ved 20°C avdestilleres pyridinet i vakuum. Det grøtaktige residuum utgnies med 3 1 vann, derpå avsuges, det utgnies enda en gang med 4 1 vann og det avsuges atter. Ved omkrystallisering av det tørkede faste produkt fra metanol/dimetylformamid (3 : 1) fåes 440 g av det ønskede sulfonamid av sm.p. 218-222°C. To a suspension of 548 g (2.2 M) of 1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hydrochloride of m.p. 212-217°C in 4 1 of pyridine (distilled over BaO) 373 g (2.2 M) of hydrocinnamic acid chloride are added dropwise while stirring and cooling in such a way that the internal temperature does not exceed 15°C. After 4 hours of stirring at 20°C, the pyridine is distilled off in a vacuum. The mushy residue is rubbed out with 3 1 of water, then aspirated, it is rubbed out once more with 4 1 of water and aspirated again. By recrystallization of the dried solid product from methanol/dimethylformamide (3:1), 440 g of the desired sulfonamide of m.p. 218-222°C.
D) 2-( 2- fenylpropionyl)- 1, 2, 3, 4- tetrahydroisokinolin- 7- sulfonamid D) 2-( 2- phenylpropionyl)- 1, 2, 3, 4- tetrahydroisoquinoline- 7- sulfonamide
Til 15,0 g (0,10 M) hydratropasyre og 24,9 g (0,10 M) 1,2,3,4-tetrahydroisokinolin-7-sulfonamid-hydroklorid av sm.p. 212-217°C i 250 ml pyridin (destillert over BaO) tildryppes lang-somt ved en indre temperatur av +5°C til +7°C 13,1 g (0,11 M) friskt destillert tionylklorid. Etter omrøring over natten ved 20°C avdestilleres pyridinet i vakuum. Ved utgniing av det smøraktige residuum med vann får man et fast produkt som kan avsuges og som man koker opp i eddikester. Etter avkjøling suger man fra utfeiningen, vasker den med eddikester og tørker den ved 80°C/20 mm Hg. Det fåes 19,2 g av det ønskede sulfonamid av sm.p. 199-201°C. To 15.0 g (0.10 M) hydratropic acid and 24.9 g (0.10 M) 1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hydrochloride of m.p. 212-217°C in 250 ml of pyridine (distilled over BaO) is slowly added dropwise at an internal temperature of +5°C to +7°C 13.1 g (0.11 M) of freshly distilled thionyl chloride. After stirring overnight at 20°C, the pyridine is distilled off in a vacuum. By rubbing the buttery residue with water, you get a solid product that can be sucked off and boiled in vinegar. After cooling, one sucks from the sweep, washes it with vinegar and dries it at 80°C/20 mm Hg. 19.2 g of the desired sulfonamide of m.p. 199-201°C.
E) N-[2-( 3- fenylpropionyl)- 1, 2, 3, 4- tetrahydroisokinolin- 7-sulfonyll- karbaminsyreetylester E) N-[2-(3-phenylpropionyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl-carbamic acid ethyl ester
20,2 g (0,06 M) 2-(3-fenylpropionyl)-1,2,3,4-tetrahydroisokinolin-7-sulfonamid av sm.p. 222-227°C, 33,2 g (0,24 M) K2C0320.2 g (0.06 M) of 2-(3-phenylpropionyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide of m.p. 222-227°C, 33.2 g (0.24 M) K2CO3
og 26,0 g (0,24 M) klormaursyreetylester opphetes sammen med 350 ml vannfritt aceton i 24 timer under tilbakeløp. Den filtrerte aceton-oppløsning inndampes i vakuum. and 26.0 g (0.24 M) ethyl chloroformate are heated together with 350 ml of anhydrous acetone for 24 hours under reflux. The filtered acetone solution is evaporated in vacuo.
Residuet (31 g) oppløses i kloroform. The residue (31 g) is dissolved in chloroform.
Kloroform-oppløsningen ryster man flere ganger med fortynnede alkalier (pH 8-9). Den vandig-alkaliske oppløsning innstilles derpå saltsur og ekstraheres med kloroform. Ved inndampning av den tørkede sure kloroformekstrakt blir det tilbake 12,9 g rått sulfonyluretan (stivnet skum, tynnsjiktkromatografisk enhetlig). The chloroform solution is shaken several times with diluted alkali (pH 8-9). The aqueous-alkaline solution is then adjusted to hydrochloric acid and extracted with chloroform. Evaporation of the dried acidic chloroform extract leaves 12.9 g of crude sulfonylurethane (solidified foam, thin-layer chromatographically uniform).
Den med vandige alkalier behandlede kloroformoppløsning etterlater etter tørkning og inndampning N,N-biskarbetoksy-2-(3-fenylpropionyl)-1,2,3,4-tetrahydroisokinolin-7-sulfonamid (18,2 g) av honningaktig konsistens. Dette tilsettes 3 ekvivalenter NaOH The aqueous alkali-treated chloroform solution leaves after drying and evaporation N,N-biscarbethoxy-2-(3-phenylpropionyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide (18.2 g) of a honey-like consistency. To this is added 3 equivalents of NaOH
i etanol under tilsetning av noe vann (eksoterm reaksjon) og etter inndampning i vakuum avdampes to ganger med etanol. Residuet oppløses i varmt vann. Den alkaliske oppløsning ekstraheres med kloroform, derpå ansyres med saltsyre og det utrystes atter med kloroform. Den sure kloroformekstrakt inneholder ytterligere 11,4 g av det tilsiktede sulfonyluretan. Ved omkrystallisering av råproduktet (11,4 g + 12,9 g) av eddikester/eter fåes 18,25 g fargeløst sulfonyluretan av sm.p. 138-141 C (spaltn.). in ethanol while adding some water (exothermic reaction) and after evaporation in a vacuum evaporate twice with ethanol. The residue is dissolved in warm water. The alkaline solution is extracted with chloroform, then acidified with hydrochloric acid and shaken again with chloroform. The acid chloroform extract contains an additional 11.4 g of the intended sulfonylurethane. By recrystallization of the crude product (11.4 g + 12.9 g) from acetic ester/ether, 18.25 g of colorless sulfonylurethane of m.p. 138-141 C (dec.).
F) N-[ 2-( 2- fenylpropionyl)- 1, 2, 3, 4- tetrahydroisokinolin- 7-sulfonyl]- karbaminsyreetylester F) N-[ 2-( 2- phenylpropionyl)- 1, 2, 3, 4- tetrahydroisoquinoline- 7-sulfonyl]- carbamic acid ethyl ester
8,4 g (0,0244 M) 2-(2-fenylpropionyl)-1,2,3,4-tetrahydroisokinolin-7-sulfonamid av sm.p. 199-201°C, 10,8 g (0,10 M) klormaursyreetylester og 14,0 g (0,10 M) K2C03 opphetes i 200 ml vannfri aceton i 32 timer under tilbakeløp. I tilslutning hertil avsuges fra faste stoffer og filtratet inndampes. Inndampningsresiduet opptas i fortynnet natronlut. Av den alkaliske opp- 8.4 g (0.0244 M) of 2-(2-phenylpropionyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide of m.p. 199-201°C, 10.8 g (0.10 M) ethyl chloroformate and 14.0 g (0.10 M) K 2 CO 3 are heated in 200 ml anhydrous acetone for 32 hours under reflux. In connection with this, solids are suctioned off and the filtrate is evaporated. The evaporation residue is taken up in dilute caustic soda. Of the alkaline up-
løsning kan ekstraheres med kloroform 3,5 g og etter ansyring med saltsyre 8,1 g. De fra den alkaliske oppløsning ekstraherte 3,5 g tilsettes natronlut og etanol. Etter inndampning ved 60°C med en rotasjonsfordamper tilsettes vann og først ekstraheres den alkaliske oppløsning, i tilslutning tilsettes saltsyre og den ansyrede oppløsning ekstraheres. De erholdte 2,7 g av den sure ekstrakt forenes med de tidligere erholdte 8,1 g og behandles i etanol med aktivt kull. Etter inndampning og skarp tørking fåes 9,2 g av det ensartede, skumaktige uretan. solution can be extracted with chloroform 3.5 g and after acidification with hydrochloric acid 8.1 g. The 3.5 g extracted from the alkaline solution are added with caustic soda and ethanol. After evaporation at 60°C with a rotary evaporator, water is added and first the alkaline solution is extracted, then hydrochloric acid is added and the acidified solution is extracted. The obtained 2.7 g of the acidic extract are combined with the previously obtained 8.1 g and treated in ethanol with activated charcoal. After evaporation and sharp drying, 9.2 g of the uniform, foamy urethane are obtained.
G) N-[ 2-( 3- fenyl- butvryl)- 1, 2, 3, 4- tetrahydroisokinolin- 7- sulfonyl]-karbaminsyreetylester G) N-[2-(3-phenyl-butvryl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl]-carbamic acid ethyl ester
21,5 g (0,06 M) 2-(3-fenylbutyryl)-1,2,3,4-tetrahydroisokinolin-7-sulfonamid av sm.p. 164-166°C, 26,1 g (0,24 M) klormaursyreetylester og 33,2 g (0,24 M) K2C03 opphetes i 600 ml vannfri aceton i 32 timer under tilbakeløp. Opparbeidelsen ut-føres som beskrevet i det foregående eksempel. Det fåes to sure kloroformekstrakter av 11,6 g og 10,2 g som sammen omkrystalliseres fra eddikester under tilsetning av eter, hvorunder det fåes 16,0 g enhetlig uretan av sm.p. 105-108°C. 21.5 g (0.06 M) of 2-(3-phenylbutyryl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide of m.p. 164-166°C, 26.1 g (0.24 M) ethyl chloroformate and 33.2 g (0.24 M) K 2 CO 3 are heated in 600 ml anhydrous acetone for 32 hours under reflux. Processing is carried out as described in the previous example. Two acidic chloroform extracts of 11.6 g and 10.2 g are obtained, which are recrystallized together from ethyl acetate with the addition of ether, during which 16.0 g of uniform urethane of m.p. 105-108°C.
H) N- l 2< - ( 2- p- klorf enylpropionyl) - 1, 2, 3, 4- tetrahydroisokinolin- 7-sulfonylI- karbaminsyreetylester H) N- l 2< - ( 2- p- chlorophenylpropionyl)- 1, 2, 3, 4- tetrahydroisoquinoline- 7-sulfonyl I- carbamic acid ethyl ester
10,35 g (27,4 mM) 2-(2-p-klorfenylpropionyl)-1,2,3,4-tetrahydroisokinolin-7-sulfonamid av sm.p. 147-150 C, 12,2 g (112 mM) klormaursyreetylester og 15,5 g (112 mM) K2C03 opphetes i 43 timer under tilbakeløp i 200 ml vannfri aceton. I tilslutning hertil avsuges fra faste stoffer og filtratet inndampes. Inndampningsresiduet oppløses i 2n-Na0H. Fra den alkaliske oppløsning kan ekstraheres 15,6 g og etter ansyring med saltsyre 0,1 g med kloroform. De alkalisk ekstraherte 15,6 g fordeles mellom kloroform og fortynnet saltsyre, fra kloroformfasen isoleres 12,7 g av et gulaktig skum. For videre rensing søylekromatograferes med kiselgel (cykloheksan: aceton: iseddik = 60 : 20 : 0,6). Man får, på denne måte 8,0 g av det enhetlige glassaktige uretan (iR-bånd ved 1760 cm"<1> for C = 0). 10.35 g (27.4 mM) of 2-(2-p-chlorophenylpropionyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide of m.p. 147-150 C, 12.2 g (112 mM) chloroformic acid ethyl ester and 15.5 g (112 mM) K 2 CO 3 are heated for 43 hours under reflux in 200 ml of anhydrous acetone. In connection with this, solids are suctioned off and the filtrate is evaporated. The evaporation residue is dissolved in 2n-NaOH. 15.6 g can be extracted from the alkaline solution and after acidification with hydrochloric acid 0.1 g with chloroform. The alkaline extracted 15.6 g is distributed between chloroform and dilute hydrochloric acid, 12.7 g of a yellowish foam is isolated from the chloroform phase. For further purification, column chromatography is performed with silica gel (cyclohexane: acetone: glacial acetic acid = 60 : 20 : 0.6). In this way, 8.0 g of the uniform glassy urethane is obtained (IR band at 1760 cm"<1> for C = 0).
I) 2-( 2- p- bromfenylpropionyl)- 1, 2, 3, 4- tetrahydroisokinolin- 7-sulfonamid I) 2-(2-p-bromophenylpropionyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide
En oppløsning av 7,80 g (31,4 mM) tetrahydroisokinolin-7-sulfonamid-hydroklorid, 7,20 g (31,4 mM) p-bromhydratropasyre, 3,18 g (31,4 mM) trietylamin og 7,22 g (62,8 mM) N-hydroksysuccin-imid i 500 ml vannfritt dimetylformamid tilsettes ved -22°C A solution of 7.80 g (31.4 mM) tetrahydroisoquinoline-7-sulfonamide hydrochloride, 7.20 g (31.4 mM) p-bromohydratropic acid, 3.18 g (31.4 mM) triethylamine and 7.22 g (62.8 mM) of N-hydroxysuccinimide in 500 ml of anhydrous dimethylformamide is added at -22°C
en oppløsning av 12,96 g (62,8 mM) dicykloheksylkarbodiimid i 83 ml dimetylformamid. Etter 2 timer ved -22°C og 20 timer ved 20°C avsuges fra utfeining og inndampes ved 12 mm Hg. Residuet oppløses i eddikester og rystes med NaHC03-oppløsning, 2n-HCl og vann. Fra. den tørkede og filtrerte eddikesteroppløsning får man 13 g råprodukt, som søylekromatograferes med kiselgel (cykloheksan: aceton =3:2) a solution of 12.96 g (62.8 mM) of dicyclohexylcarbodiimide in 83 ml of dimethylformamide. After 2 hours at -22°C and 20 hours at 20°C, aspirate from the sweep and evaporate at 12 mm Hg. The residue is dissolved in acetic acid and shaken with NaHCO 3 solution, 2n-HCl and water. From. the dried and filtered acetic ester solution gives 13 g of crude product, which is column chromatographed with silica gel (cyclohexane: acetone = 3:2)
Utbytte: 5,2 g av sm.p. 146-148°C (av eddikester) Yield: 5.2 g of m.p. 146-148°C (of vinegar)
K) 2-( 2- p- klorfenylpropionyl)- 1, 2, 3, 4- tetrahydroisokinolin- 7-sulfonamid K) 2-( 2- p- chlorophenylpropionyl)- 1, 2, 3, 4- tetrahydroisoquinoline- 7-sulfonamide
14,0 g (66 mM) 1,2,3,4-tetrahydroisokinolin-7-sulfonamid oppløser man varmt i 850 ml vannfri dioksan. Til den fremdeles varme oppløsning tilsetter man 12,2 g (66 mM) p-klorhydratropasyre. Etter avkjøling til 10°C lar man innen 10 minutter tilstrømme en oppløsning av 14,9 g (72 mM) dicykloheksylkarbodiimid i 70 ml dioksan. Etter 5 minutter blir oppløsningen allerede uklar og en fargeløs utfeining begynner å falle ut. Etter 16 timer ved 20°C avsuges og filtratet inndampes ved 12 mm Hg. Den erholdte lysegule viskøse olje (37 g) oppløses i meget kloroform og utrystes i så lang tid med 2n-Na0H til det kromatografisk ikke kan påvises noe sulfonamid i den organiske fase. De forenede NaOH-ekstrakter inn-røres i is/saltsyre. Ved fornyet ekstraksjon ved hjelp av kloroform fåes 17,4 g råprodukt, som renses søylekromatografisk med kiselgel (cykloheksan: aceton: iseddik = 60 : 40 : 0,4). 14.0 g (66 mM) of 1,2,3,4-tetrahydroisoquinoline-7-sulfonamide is dissolved hot in 850 ml of anhydrous dioxane. 12.2 g (66 mM) p-chlorohydratropic acid is added to the still warm solution. After cooling to 10°C, a solution of 14.9 g (72 mM) of dicyclohexylcarbodiimide in 70 ml of dioxane is allowed to flow within 10 minutes. After 5 minutes, the solution already becomes cloudy and a colorless smear begins to fall out. After 16 hours at 20°C, suction is applied and the filtrate is evaporated at 12 mm Hg. The pale yellow viscous oil obtained (37 g) is dissolved in a lot of chloroform and shaken for a long time with 2n-NaOH until no sulfonamide can be detected chromatographically in the organic phase. The combined NaOH extracts are stirred into ice/hydrochloric acid. Renewed extraction using chloroform yields 17.4 g of crude product, which is purified by column chromatography with silica gel (cyclohexane: acetone: glacial acetic acid = 60:40:0.4).
Ved omkrystallisering fra eddikester får man 10,3 g fargeløst sulfonamid av sm.p. 147-150 C. By recrystallization from acetic acid, 10.3 g of colorless sulphonamide of m.p. 147-150 C.
L) 3-( 2- p- bromfenylpropionyl)- 2, 3, 4, 5- tetrahydro- lH- 3- benzazepin-7- sulfonamid L) 3-( 2- p- bromophenylpropionyl)- 2, 3, 4, 5- tetrahydro- 1H- 3- benzazepine-7- sulfonamide
Oppløsningsmiddelfritt p-bromhydratropasyreklorid fremstilt av 8,0 g (35 mM) p-bromhydratropasyre med S0C12 i kloroform, tilsettes ved +5°C til 7,92 g (35 mM) 2,3,4,5-tetrahydro-lH-3-benzazepin-7-sulfonamid i 100 ml vannfritt pyridin. Etter henstand over natten ved 20°C avdestilleres pyridinet i vakuum. Residuet avsuges etter utgniing med vann/saltsyre, oppløses varmt i 2n-NaOH og ekstraheres med kloroform. Den alkalisk-vandige fase innrøres i is/saltsyre. Man ekstraherer med kloroform og ryster kloroformfasen grundig med NaHCO^-oppløsning og derpå med vann. Det fåes 7,9 g skumformet sulfonamid. Solvent-free p-bromohydrotropic acid chloride prepared from 8.0 g (35 mM) p-bromohydrotropic acid with SOCl 2 in chloroform is added at +5°C to 7.92 g (35 mM) 2,3,4,5-tetrahydro-lH-3 -benzazepine-7-sulfonamide in 100 ml of anhydrous pyridine. After standing overnight at 20°C, the pyridine is distilled off in a vacuum. The residue is suctioned off after rubbing with water/hydrochloric acid, dissolved hot in 2n-NaOH and extracted with chloroform. The alkaline-aqueous phase is stirred into ice/hydrochloric acid. Extract with chloroform and shake the chloroform phase thoroughly with NaHCO 3 solution and then with water. 7.9 g of foamy sulfonamide are obtained.
M) 2, 3, 4, 5- tetrahydro- l- H- 3- benzazepin- 7- sulfonamid M) 2, 3, 4, 5- tetrahydro- 1- H- 3- benzazepine- 7- sulfonamide
a) 130,6 g (0,688 M) 3-acetyl-2,3,4,5-tetrahydro-l-H-3-benzazepin av sm.p. 60-63°C innføres ved -5°C i løpet av 1 1/2 a) 130.6 g (0.688 M) of 3-acetyl-2,3,4,5-tetrahydro-1-H-3-benzazepine of m.p. 60-63°C is introduced at -5°C during 1 1/2
time porsjonsvis i 588 g (5,06 M) klorsulfonsyre. Etter 4 timers omrøring ved -5°C inntil 0°C helles på is og ekstraheres med benzen. Residuet fra den tørkede og inndampede benzenekstrakt: 164 g viskøs olje. hour portionwise in 588 g (5.06 M) chlorosulfonic acid. After stirring for 4 hours at -5°C until 0°C, pour on ice and extract with benzene. The residue from the dried and evaporated benzene extract: 164 g of viscous oil.
b) Det under a) erholdte rå sulfoklorid og 400 ml konsentrert ammoniakk oppvarmes lett på vannbad. Av den hurtig b) The crude sulphochloride and 400 ml of concentrated ammonia obtained under a) are heated lightly on a water bath. Off it fast
dannede klare oppløsning krystalliserer etter avkjøling 84,7 g fargeløst 3-acetyl-2,3,4,5-tetrahydro-l-H-3-benzazepin-7-sulfonamid av sm.p. 177-180°C. Ved ekstraksjon av moderluten med eddikester fåes ytterligere 7,6 g av sm.p. 176-178°C. formed clear solution crystallizes after cooling 84.7 g of colorless 3-acetyl-2,3,4,5-tetrahydro-1-H-3-benzazepine-7-sulfonamide of m.p. 177-180°C. By extracting the mother liquor with vinegar, a further 7.6 g of m.p. 176-178°C.
c) 92,3 g av det under b) erholdte sulfonamid opphetes i 1 1 halvkonsentrert saltsyre i 15 timer under tilbakeløp. Det ved inndampning til tørrhet og flere gangers avdampning med etanol erholdte residuum tilsettes med en ekvivalent ln-NaOH. Ved opp-varming, utgniing og avkjøling får man 72,8 g råkrystallisat av sm.p. 218-220°C. Omkrystallisering fra etanol/vann (2 1) gir 47,2 g fargeløst 2,3,4,5-tetrahydro-l-H-3-benzazepin-7-sulfonamid av sm.p. 225-228°C. c) 92.3 g of the sulfonamide obtained under b) is heated in 1 1 semi-concentrated hydrochloric acid for 15 hours under reflux. The residue obtained by evaporation to dryness and evaporation several times with ethanol is added with an equivalent of ln-NaOH. By heating, rubbing and cooling, 72.8 g of crude crystallisate of m.p. 218-220°C. Recrystallization from ethanol/water (2 1) gives 47.2 g of colorless 2,3,4,5-tetrahydro-1-H-3-benzazepine-7-sulfonamide of m.p. 225-228°C.
I henhold til de i eksemplene C, D, K, I og L beskrevne fremgangsmåter ble også fremstilt de i den etterfølgende tabell oppførte nye utgangsstoffer av formel II. According to the methods described in examples C, D, K, I and L, the new starting substances of formula II listed in the following table were also prepared.
De etterfølgende eksempler beskriver fremstillingen av The following examples describe the production of
de nye sulfonyl-urinstoffer: the new sulfonylureas:
Eksempel 1 Example 1
l- t 2-( 3- fenylpropionyl)- 1, 2, 3, 4- tetrahvdroisokinolin- 7- sulfonyl]-3- cykloheksyl- urinstoff 1- t 2-( 3- Phenylpropionyl)- 1, 2, 3, 4- Tetrahydroisoquinoline- 7- Sulfonyl]-3- Cyclohexyl- Urea
41,4 g (0,12 M) 2-(3-fenylpropionyl)-1,2,3,4-tetrahydroisokinolin-7-sulfonamid av sm.p. 222-227 C inndampes i vakuum med den ekvimolare mengde ln-NaOH (120 ml) og 200 ml etanol til tørrhet. Etter 30 minutters tørking ved 80°C/12 mm Hg suspenderes det på 41.4 g (0.12 M) of 2-(3-phenylpropionyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide of m.p. 222-227 C is evaporated in vacuo with the equimolar amount of ln-NaOH (120 ml) and 200 ml of ethanol to dryness. After 30 minutes of drying at 80°C/12 mm Hg, it is suspended on
denne måte tilberedte natriumsalt av sulfonamidet ill nitrobenzen og tilsettes dråpevis med 15,05 g (0,12 M) cykloheksylisocyanat. sodium salt of the sulfonamide ill nitrobenzene prepared in this way and is added dropwise with 15.05 g (0.12 M) of cyclohexyl isocyanate.
Etter 5 timers omrøring ved en indre temperatur av 95°C avkjøles. After 5 hours of stirring at an internal temperature of 95°C, cool.
Den frasentrifugerte utfeining oppløses i varmt vann, oppløsningen utetres etter at den er blitt kald og innrøres i overskudd av konsentrert HCl/is. Utfeiningen vaskes med meget vann, avsuges godt lufttørr og opptas i etanol. Etter inndampning i vakuum opptas residuet i varm eddikester. Den med Na2S0^ tørkede og filtrerte eddikesteroppløsning inndampes så meget at oppløsningen i kokevarme nettopp forblir klar. Ved avkjøling krystalliserte 31,5 g sulfonylurinstoff av sm.p. 135-140°C (DG 1 flekk). The de-centrifuged skimming is dissolved in warm water, the solution is filtered out after it has cooled and stirred in an excess of concentrated HCl/ice. The residue is washed with plenty of water, vacuumed well to air dry and absorbed in ethanol. After evaporation in a vacuum, the residue is taken up in hot vinegar. The Na2S0^-dried and filtered acetic ester solution is evaporated so much that the solution in boiling heat just remains clear. On cooling, 31.5 g of sulphonylurea of m.p. crystallized. 135-140°C (DG 1 spot).
På analog måte fremstilles: In an analogous way, the following is produced:
a) l- t 2-( 2- fenylpropionyl)- 1, 2, 3, 4- tetrahydroisokinolin- 7-sulfonyl]- 3- cykloheksylurinstoff av 10,3 g 2-(2-fenylpropionyl)-1,2,3,4-tetrahydroisokinolin-7-sulfonamid av sm.p. 199-201°C og 3,76 g cykloheksylisocyanat. Utbytte: 10,6 g av sm.p. 195-197°C (etanol). b) l-[ 2- acetyl- l, 2, 3, 4- tetrahydroisokinolin- 7- sulfonyl]- 3-cykloheksylurinstoff av 11,1 g 2-acetyl-l,2,3,4-tetrahydroisokinolin-7-sulfonamid av sm.p. 220-224°C og 5,46 g cykloheksylisocyanat. Utbytte: 8,4 g av sm.p. 100-110°C (syrefeining). c) l-[ 2- benzoyl- l, 2, 3, 4- tetrahydroisokinolin- 7- sulfonyl]- 3-cykloheksyl- urinstoff av 18,0 g 2-benzoyl-l,2,3,4-tetrahydroisokinolin-7-sulfonamid av sm.p. 222-224°C og 7,15 g cykloheksylisocyanat. Utbytte: 10,4 g av sm.p. 150-155°C (metyletylketon). d) l-[ 2-( 3- metylbenzoyl)- 1, 2, 3, 4- tetrahydroisokinolin- 7- sulfonyl]-3- cykloheksyl- urinstoff av 19,8 g 2-(3-metylbenzoyl)-1,2,3,4-tetrahydroisokinolin-7-sulfonamid av sm.p. 240-247°C og 7,5 g cykloheksylisocyanat. Utbytte: 5,2 g av sm.p. 154-158°C (ved utgniing med eter etter søylekromatografi). a) l- t 2-( 2- phenylpropionyl)- 1, 2, 3, 4- tetrahydroisoquinoline- 7-sulfonyl]- 3- cyclohexylurea of 10.3 g of 2-(2-phenylpropionyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide of m.p. 199-201°C and 3.76 g of cyclohexyl isocyanate. Yield: 10.6 g of m.p. 195-197°C (ethanol). b) 1-[2-acetyl-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl]-3-cyclohexylurea of 11.1 g of 2-acetyl-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide of m.p. 220-224°C and 5.46 g of cyclohexyl isocyanate. Yield: 8.4 g of m.p. 100-110°C (acid sweep). c) l-[2-benzoyl-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl]-3-cyclohexyl-urea of 18.0 g of 2-benzoyl-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide of m.p. 222-224°C and 7.15 g of cyclohexyl isocyanate. Yield: 10.4 g of m.p. 150-155°C (methyl ethyl ketone). d) 1-[2-(3-methylbenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl]-3-cyclohexyl-urea of 19.8 g of 2-(3-methylbenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide of m.p. 240-247°C and 7.5 g of cyclohexyl isocyanate. Yield: 5.2 g of m.p. 154-158°C (by trituration with ether after column chromatography).
e) l-[ 2-( 4- metylbenzoyl)- 1, 2, 3, 4- tetrahydroisokinolin- 7- sulfonyl]-3- cykloheksyl- urinstoff e) 1-[2-(4-methylbenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl]-3-cyclohexyl-urea
av 21,4 g 2-(4-metylbenzoyl)-1,2,3,4-tetrahydroisokinolin-7-sulfonamid av sm.p. 230-235°C og 8,14 g cykloheksylisocyanat. of 21.4 g of 2-(4-methylbenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide of m.p. 230-235°C and 8.14 g of cyclohexyl isocyanate.
Utbytte: 6,2 g av sm.p. 130-135°C (ved utgniing med eter etter søylekromatografi). Yield: 6.2 g of m.p. 130-135°C (by trituration with ether after column chromatography).
f) l-t 2-( 2- metyl- 3- fenyl- propionyl)- 1, 2, 3, 4- tetrahydroisokinolin-7- sulfonyl]- 3- cykloheksylurinstoff av 14,34 g 2-(2-metyl-3-fenyl-propionyl)-1,2,3,4-tetrahydroisokinolin-7-sulfonamid av sm.p. 214-215°C og 5,01 g cykloheksylisocyanat. Utbytte: 9,8 g av sm.p. 104-110°C (syrefeining). g) l-[ 2-( a- naftoyl)- 1, 2, 3, 4- tetrahydroisokinolin- 7- sulfonyl]-3- cykloheksylurinstoff av 18,3 g 2-(a-naftoyl)-1,2,3,4-tetrahydroisokinolin-7-sulfonamid av sm.p. 240-245°C og 6,3 g cykloheksylisocyanat. Utbytte: 4,5 g av sm.p. 170-175°C (etter søylekromatografi ved utgniing med aceton). h) l-[ 2-( 2- metoksybenzoyl)- 1, 2, 3, 4- tetrahydroisokinolin- 7-sulfonyl]- 3- cykloheksyl- urinstoff av 13,9 g 2-(2-metoksybenzoyl)-1,2,3,4-tetrahydroisokinolin-7-sulfonamid av sm.p. 232-238°C og 5,02 g cykloheksylisocyanat. Utbytte: 9,5 g av sm.p. 145-150°C (etanol). i) l-[ 2-( 4- metoksybenzoyl)- 1, 2, 3, 4- tetrahydroisokinolin- 7-sulfonyll- 3- cykloheksyl- urinstoff av 13,9 g 2-(4-metoksybenzoyl)-1,2,3,4-tetrahydroisokinolin-7-sulfonamid av sm.p. 220-225°C og 5,02 g cykloheksylisocyanat. Utbytte: 7,0 g av sm.p. 196-198°C (metyletylketon). f) l-t 2-(2-methyl-3-phenyl-propionyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl]-3-cyclohexylurea from 14.34 g of 2-(2-methyl-3-phenyl) -propionyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide of m.p. 214-215°C and 5.01 g of cyclohexyl isocyanate. Yield: 9.8 g of m.p. 104-110°C (acid sweep). g) 1-[2-(α-naphthoyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl]-3-cyclohexylurea from 18.3 g of 2-(α-naphthoyl)-1,2,3, 4-tetrahydroisoquinoline-7-sulfonamide of m.p. 240-245°C and 6.3 g of cyclohexyl isocyanate. Yield: 4.5 g of m.p. 170-175°C (after column chromatography by rubbing with acetone). h) 1-[2-(2-Methoxybenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl]-3-cyclohexyl-urea from 13.9 g of 2-(2-methoxybenzoyl)-1,2, 3,4-tetrahydroisoquinoline-7-sulfonamide of m.p. 232-238°C and 5.02 g of cyclohexyl isocyanate. Yield: 9.5 g of m.p. 145-150°C (ethanol). i) 1-[2-(4-methoxybenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl-3-cyclohexyl-urea from 13.9 g of 2-(4-methoxybenzoyl)-1,2,3 ,4-tetrahydroisoquinoline-7-sulfonamide of m.p. 220-225°C and 5.02 g of cyclohexyl isocyanate. Yield: 7.0 g of m.p. 196-198°C (methyl ethyl ketone).
j) l-[ 2- fenacetyl- l, 2, 3, 4- tetrahydroisokinolin- 7- sulfonyl]- 3-cykloheksyl- urinstoff j) 1-[2-phenacetyl-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl]-3-cyclohexyl-urea
av 5,57 g 2-fenacetyl-1,2,3,4-tetrahydroisokinolin-7-sulfonamid av sm.p. 182-187°C og 2,12 g cykloheksylisocyanat. of 5.57 g of 2-phenacetyl-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide of m.p. 182-187°C and 2.12 g of cyclohexyl isocyanate.
Utbytte: 5,0 g av sm.p. 140-145°C (utgniing med eddikester og eter). Yield: 5.0 g of m.p. 140-145°C (rubbing with acetic acid and ether).
k) 1-[ 2-( 3, 3- difenyl- propionyl)- 1, 2, 3, 4- tetrahydroisokinolin-7- sulfonyl]- 3- cykloheksyl- urinstoff av 12,6 g 2-(3 , 3-dif enyl-propionyl)-1, 2,, 3 , 4-tetrahydroisokinolin-7-sulfonamid av sm.p. 246-250°C og 3,80 g cykloheksylisocyanat. Utbytte: 9,55 g av sm.p. 171-174°C (aceton og vanntilsetning). 1) l-[ 2-( 4- fenylbutyryl)- 1, 2, 3, 4- tetrahydroisokinolin- 7- sulfonyl]-3- cykloheksyl- urinstoff av 7,17 g 2-(4-fenylbutyryl)-1,2,3,4-tetrahydroisokinolin-7-sulfonamid av sm.p. 140-146°C og 2,51 g cykloheksylisocyanat. Utbytte: 2,7 g av sm.p. 77-85°C (eter og petroletertilsetning). m) l-[ 2-( 3- benzoyl- propionyl)- 1, 2, 3, 4- tetrahydroisokinolin- 7-sulfonyl]- 3- cykloheksyl- urinstoff av 3,37 g 2-(3-benzoyl-propionyl)-1,2,3,4-tetrahydroisokinolin-7-sulfonamid av sm.p. 187-189°C og 1,14 g cykloheksylisocyanat. Utbytte: 3,7 g av sm.p. 183-184°C (aceton). n) l-[ 2-( 3- p- metylfenyl- propionyl)- 1, 2, 3, 4- tetrahydroisokinolin-7- sulfonyll- 3- cykloheksyl- urinstoff av 6,10 g 2-(3-p-metylfenyl-propionyl)-1, 2 , 3 ,.4-tetrahydroisokinolin-7-sulfonamid av sm.p. 154-160°C og 2,13 g cykloheksylisocyanat. Utbytte: 4,5 g av sm.p. 134-136°C (eddikester). o) l-[ 2-( 3- p- trifluormetylfenyl- propionyl)- 1, 2, 3, 4- tetrahydroisokinolin- 7- sulfonyl]- 3- cykloheksyl- urinstoff av 3,10 g 2-(3-p-trifluormetyl-fenyl-propionyl)-1,2,3,4-tetrahydroisokinolin-7-sulfonamid av sm.p. 184-186°C og 0,95 g cykloheksylisocyanat. Utbytte: 1,7 g av sm.p. 130-133°C (eddikester). k) 1-[ 2-( 3, 3- diphenyl- propionyl)- 1, 2, 3, 4- tetrahydroisoquinoline-7- sulfonyl]- 3- cyclohexyl- urea from 12.6 g of 2-(3 , 3-dif enyl-propionyl)-1,2,,3,4-tetrahydroisoquinoline-7-sulfonamide of m.p. 246-250°C and 3.80 g of cyclohexyl isocyanate. Yield: 9.55 g of m.p. 171-174°C (acetone and water addition). 1) 1-[2-(4-phenylbutyryl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl]-3-cyclohexyl-urea from 7.17 g of 2-(4-phenylbutyryl)-1,2, 3,4-tetrahydroisoquinoline-7-sulfonamide of m.p. 140-146°C and 2.51 g of cyclohexyl isocyanate. Yield: 2.7 g of m.p. 77-85°C (ether and petroleum ether addition). m) l-[ 2-( 3- benzoyl- propionyl)- 1, 2, 3, 4- tetrahydroisoquinoline- 7-sulfonyl]- 3- cyclohexyl- urea from 3.37 g of 2-(3- benzoyl-propionyl)- 1,2,3,4-tetrahydroisoquinoline-7-sulfonamide of m.p. 187-189°C and 1.14 g of cyclohexyl isocyanate. Yield: 3.7 g of m.p. 183-184°C (acetone). n) l-[ 2-( 3- p- methylphenyl- propionyl)- 1, 2, 3, 4- tetrahydroisoquinoline-7- sulfonyl- 3- cyclohexyl- urea from 6.10 g of 2-(3-p- methylphenyl- propionyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide of m.p. 154-160°C and 2.13 g of cyclohexyl isocyanate. Yield: 4.5 g of m.p. 134-136°C (acetic acid). o) l-[ 2-( 3-p-trifluoromethylphenyl- propionyl)- 1, 2, 3, 4- tetrahydroisoquinoline- 7- sulfonyl]- 3- cyclohexyl- urea from 3.10 g of 2-(3-p-trifluoromethyl -phenyl-propionyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide of m.p. 184-186°C and 0.95 g of cyclohexyl isocyanate. Yield: 1.7 g of m.p. 130-133°C (acetic acid).
p) 1-12-(3-( 2- metoksyfenyl)- propionyl)- 1, 2, 3, 4- tetrahydroisokinolin- 7- sulfonyl]- 3- cykloheksyl- urinstoff p) 1-12-(3-( 2- methoxyphenyl)- propionyl)- 1, 2, 3, 4- tetrahydroisoquinoline- 7- sulfonyl]- 3- cyclohexyl- urea
av 11,2 g 2-(3-(2-metoksyfenyl)-propionyl)-1,2,3,4-tetrahydroisokinolin-7-sulfonamid av sm.p. 232-238°C og 3,76 g cykloheksylisocyanat. Utbytte: 11,1 g av sm.p. 194-196°C (spaltn.) of 11.2 g of 2-(3-(2-methoxyphenyl)-propionyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide of m.p. 232-238°C and 3.76 g of cyclohexyl isocyanate. Yield: 11.1 g of m.p. 194-196°C (dec.)
(etanol). (ethanol).
q) l- t 2-( 2- fenylbutyryl)- 1, 2, 3, 4- tetrahydroisokinolin - 7- sulfonvl]-3- cykloheksyl- urinstoff av 6,9 g 2-(2-fenylbutyryl)-1,2,3,4-tetrahydroisokinolin-7-sulfonamid av sm.p. 158°C og 2,41 g cykloheksylisocyanat. Utbytte: 5,7 g av sm.p. 181-185°C (etanol). q) l- t 2-(2-phenylbutyryl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl]-3-cyclohexyl-urea from 6.9 g of 2-(2-phenylbutyryl)-1,2, 3,4-tetrahydroisoquinoline-7-sulfonamide of m.p. 158°C and 2.41 g of cyclohexyl isocyanate. Yield: 5.7 g of m.p. 181-185°C (ethanol).
Eksempel 2 Example 2
Natriumsaltet av l-[ 2-( 3- m- klorfenyl- propionyl)- 1, 2, 3, 4- tetrahydroisokinolin- 7- sulfonyl3- 3- cykloheksyl- urinstoff The sodium salt of l-[ 2-( 3- m- chlorophenyl- propionyl)- 1, 2, 3, 4- tetrahydroisoquinoline- 7- sulfonyl3- 3- cyclohexyl- urea
11,4 g (0,03 M) 2-(3-m-klorfenyl-propionyl)-1,2,3,4-tetrahydroisokinolin-7-sulfonamid av sm.p. 172-174°, en oppløsning av 1,68 g (0,03 M) KOH i 20 ml vann og 100 ml etanol inndampes sammen i vakuum tiltørrhet. Det tørre kaliumsalt av sulfonamidet innføres i 300 ml nitrobenzen. Etter tildrypping av 3,76 g (0,03 M) cykloheksylisocyanat omrøres i 5 timer ved 100°C. Nitrobenzenet fjernes ved vanndampdestillasjon. Det erholdte residuum oppløses i varmt vann. Den varme oppløsning innfiltreres gjennom en G 3-glassfritte i en omrørt blanding av is og overskudd av konsentrert saltsyre. Den avsugede utfeining behandles i varm etanolisk opp-løsning med A-kull. Den filtrerte etanoliske oppløsning tilsettes 1 ekvivalent NaOH, oppløst i en minimal mengde vann. Etterat den ble kold krystalliserte 6,5 g av det ønskede natriumsalt ved spaltningspunkt fra 280°C. 11.4 g (0.03 M) of 2-(3-m-chlorophenyl-propionyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide of m.p. 172-174°, a solution of 1.68 g (0.03 M) KOH in 20 ml of water and 100 ml of ethanol is evaporated together in vacuo to dryness. The dry potassium salt of the sulfonamide is introduced into 300 ml of nitrobenzene. After adding 3.76 g (0.03 M) of cyclohexyl isocyanate dropwise, the mixture is stirred for 5 hours at 100°C. The nitrobenzene is removed by steam distillation. The residue obtained is dissolved in hot water. The hot solution is filtered through a G 3 glass frit into a stirred mixture of ice and excess concentrated hydrochloric acid. The aspirated skimming is treated in hot ethanolic solution with A-carbon. To the filtered ethanolic solution is added 1 equivalent of NaOH, dissolved in a minimal amount of water. After it became cold, 6.5 g of the desired sodium salt crystallized at a cleavage point from 280°C.
Eksempel 3 Example 3
Natriumsaltet av 1-[ 2-( 3- fenyl- butyryl)- 1, 2, 3, 4- tetrahydroisokinolin- 7- sulfonylI- 3- cykloheksyl- urinstoff The sodium salt of 1-[ 2-( 3- phenyl- butyryl)- 1, 2, 3, 4- tetrahydroisoquinoline- 7- sulfonyl I- 3- cyclohexyl- urea
12,53 g (0,035 M) 2- (3-f enylbutyryl) -1, 2 , 3 , 4-tetrahydroisokinolin-7-sulfonamid av sm.p. 164-166°C, 35 ml ln-NaOH og 100 ml etanol inndampes i vakuum til tørrhet. Det tørre natriumsalt av sulfonamidet suspenderes i 300 ml nitrobenzen og tilsettes dråpevis 4,38 g (0,035 M) cykloheksylisocyanat. Etter 5 timers omrøring ved 100°C frasentrifugeres. Utfeiningen oppløses i varmt vann. Den avkjølte oppløsning ekstraheres med eter, derpå opphetes den vandige oppløsning atter og den filtreres gjennom en G 3-glassfritte i en omrørt blanding av is og overskudd av konsentrert saltsyre. Den frasugede utfelning oppløses i etanol og det tilsettes en opp-løsning av 0,035 M NaOH, oppløst i en minimal mengde vann. Det fåes 8,3 g fargeløst natriumsalt av sm.p. 280-285°C (spaltn.). 12.53 g (0.035 M) 2-(3-phenylbutyryl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide of m.p. 164-166°C, 35 ml of ln-NaOH and 100 ml of ethanol are evaporated in vacuo to dryness. The dry sodium salt of the sulfonamide is suspended in 300 ml of nitrobenzene and 4.38 g (0.035 M) cyclohexyl isocyanate is added dropwise. After 5 hours of stirring at 100°C, centrifuge. The solution is dissolved in warm water. The cooled solution is extracted with ether, then the aqueous solution is heated again and it is filtered through a G 3 glass frit in a stirred mixture of ice and excess concentrated hydrochloric acid. The aspirated precipitate is dissolved in ethanol and a solution of 0.035 M NaOH, dissolved in a minimal amount of water, is added. 8.3 g of colorless sodium salt of m.p. 280-285°C (dec.).
På den samme måte fremstilles følgende forbindelser: In the same way, the following compounds are produced:
a) Natriumsalt av l-[ 2- butyrvl- l, 2, 3, 4- tetrahydroisokinolin- 7-sulfonyl]- 3- cykloheksyl- urinstoff av 8,46 g 2-butyryl-l,2,3,4-tetrahydroisokinolin-7-sulfonamid av sm.p. 159-162°C og 3,76 g cykloheksylisocyanat. Utbytte: 10,0 g natriumsalt av sm.p. >300°C (etanol). b) Natriumsalt av l-[ 2-( 3- fenylpropionyl)- 1, 2, 3, 4- tetrahydroisokinolin- 7- sulfonyl]- 3- n- butyl- urinstoff av 10,3 g 2-(3-fenylpropionyl)-1,2,3,4-tetrahydroisokinolin-7-sulfonamid av sm.p. 222-227°C og 2,98 g butyl-isocyanat. Utbytte: 10,1 g natriumsalt av sm.p. 244-245°C (spaltn.) (etanol). c) Natriumsalt av l-[ 2-( 3- p- metoksyfenyl- propionyl)- 1, 2, 3, 4-tetrahydroisokinolin- 7- sulfonyl]- 3- cykloheksyl- urinstoff av 6,75 g 2-(3-p-metoksyfenyl-propionyl)-1,2,3,4-tetrahydroisokinolin-7-sulfonamid av sm.p. 166-167°C og 2,26 g cykloheksylisocyanat. Utbytte: 6,8 g natriumsalt av sm.p. fra 255°C (spaltn.) (etanol). a) Sodium salt of 1-[2-butyrvl-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl]-3-cyclohexyl-urea of 8.46 g of 2-butyryl-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide of m.p. 159-162°C and 3.76 g of cyclohexyl isocyanate. Yield: 10.0 g sodium salt of m.p. >300°C (ethanol). b) Sodium salt of l-[2-(3-phenylpropionyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl]-3-n-butyl-urea of 10.3 g of 2-(3-phenylpropionyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide of m.p. 222-227°C and 2.98 g of butyl isocyanate. Yield: 10.1 g sodium salt of m.p. 244-245°C (dec.) (ethanol). c) Sodium salt of 1-[2-(3-p-methoxyphenyl-propionyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl]-3-cyclohexyl-urea from 6.75 g of 2-(3-p -methoxyphenyl-propionyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide of m.p. 166-167°C and 2.26 g of cyclohexyl isocyanate. Yield: 6.8 g sodium salt of m.p. from 255°C (decomposition) (ethanol).
d) Natriumsalt av l-[ 2-( 3- fenyl- heksanoyl)- 1, 2, 3, 4- tetrahydroisokinolin- 7- sulfonylI- 3- cykloheksylurinstoff d) Sodium salt of l-[2-(3-phenyl-hexanoyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl I-3-cyclohexylurea
av 11,6 g 2-(3-fenyl-heksanoyl)-1,2,3,4-tetrahydroisokinolin-7-sulfonamid av sm.p. 130-134°C og 3,76 g cykloheksylisocyanat. Utbytte: 5,65 g natriumsalt av sm.p. 255-260°C of 11.6 g of 2-(3-phenyl-hexanoyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide of m.p. 130-134°C and 3.76 g of cyclohexyl isocyanate. Yield: 5.65 g sodium salt of m.p. 255-260°C
(metanol) (methanol)
e) Natriumsalt av l-[ 2-( 3- fenylpropionyl)- 1, 2, 3, 4- tetrahydroisokinolin- 7- sulfonyl]- 3- adamantyl( 1)- urinstoff av 6,22 g 2-(3-fenylpropionyl)-1,2,3,4-tetrahydroisokinolin-7-sulfonamid av sm.p. 222-227°C og 3,20 g adamantyl(1)-isocyanat. Utbytte: 1,08 g fargeløst natriumsalt av spaltning fra 260°C (aceton + vanntilsetning). f) Natriumsalt av l-[ 2-( 3- fenyl- valeryl)- 1, 2, 3, 4- tetrahydroisokinolin- 7- sulfonylI- 3- cykloheksyl- urinstoff av 13,6 g 2-(3-fenyl-valeryl)-1,2,3,4-tetrahydroisokinolin-7-sulfonamid og 5,0 g cykloheksylisocyanat. Utbytte: 7,65 g natriumsalt av sm.p. 272-280°C (spaltn.) (etanol). e) Sodium salt of 1-[2-(3-phenylpropionyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl]-3-adamantyl(1)-urea from 6.22 g of 2-(3-phenylpropionyl) -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide of m.p. 222-227°C and 3.20 g of adamantyl (1) isocyanate. Yield: 1.08 g colorless sodium salt from cleavage from 260°C (acetone + water addition). f) Sodium salt of 1-[2-(3-phenyl-valeryl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl1-3-cyclohexyl-urea from 13.6 g of 2-(3-phenyl-valeryl) -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide and 5.0 g of cyclohexyl isocyanate. Yield: 7.65 g sodium salt of m.p. 272-280°C (dec.) (ethanol).
g) Natriumsalt av 1-[ 2-( 3- p- klorfenyl- propionyl)- 1, 2, 3, 4- tetrahydroisokinolin- 7- sulfonylI- 3- cykloheksyl- urinstoff g) Sodium salt of 1-[ 2-( 3- p- chlorophenyl- propionyl)- 1, 2, 3, 4- tetrahydroisoquinoline- 7- sulfonyl I- 3- cyclohexyl- urea
av 4,55 g 2- (3-p-klorf enyl-propionyl^) -1,2,3, 4-tetrahydroisokinolin-7-sulfonamid av sm.p. 155-161 COg 1,5 g cykloheksylisocyanat. Utbytte: 3,5 g natriumsalt av sm.p. 260-263°C (spaltn.) of 4.55 g of 2-(3-p-chlorophenyl-propionyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide of m.p. 155-161 COg 1.5 g cyclohexyl isocyanate. Yield: 3.5 g sodium salt of m.p. 260-263°C (dec.)
(etanol). (ethanol).
h) Natriumsalt av 1-[ 2- isovaleryl- l, 2, 3, 4- tetrahydroisokinolin-7- sulfonyl]- 3- cykloheksyl- urinstoff av 10,4 g 2-isovaleryl-l,2,3,4-tetrahydroisokinolin-7-sulfonamid av sm.p. 142-145°C og 4,38 g cykloheksylisocyanat. Utbytte: 8,4 g natriumsalt av sm.p. 290°C (spaltn.) (etanol). h) Sodium salt of 1-[2-isovaleryl-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl]-3-cyclohexyl-urea from 10.4 g of 2-isovaleryl-1,2,3,4-tetrahydroisoquinoline- 7-sulfonamide of m.p. 142-145°C and 4.38 g of cyclohexyl isocyanate. Yield: 8.4 g sodium salt of m.p. 290°C (dec.) (ethanol).
i) Natriumsalt av l-[ 2-( 3- trifluormetyl- benzoyl)- 1, 2, 3, 4- tetrahydroisokinolin- 7- sulfonyl]- 3- cykloheksyl- urinstoff i) Sodium salt of 1-[2-(3-trifluoromethyl-benzoyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl]-3-cyclohexyl-urea
av 11,4 g 2-(3-trifluormetyl-benzoyl)-1,2,3,4-tetrahydroisokinolin-7-sulfonamid av sm.p. 250-255°C og 3,73 g cykloheksylisocyanat. Utbytte: 1,65 g natriumsalt av sm.p. 280-285°C (spaltn.) of 11.4 g of 2-(3-trifluoromethyl-benzoyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide of m.p. 250-255°C and 3.73 g of cyclohexyl isocyanate. Yield: 1.65 g sodium salt of m.p. 280-285°C (split.)
(etanol + eter). (ethanol + ether).
j) Natriumsalt av l-[ 2- benzoylacetyl- l, 2, 3, 4- tetrahydroisokinolin-7- sulfonyl]- 3- cykloheksyl- urinstoff av 1,88 g 2-benzoylacetyl-l,2,3,4-tetrahydroisokinolin-7-sulfonamid av sm.p. 151-153°C og 0,66 g cykloheksylisocyanat. Utbytte: 0,5 g natriumsalt av sm.p. 230-231°C (spaltn.) etter søylekromatografi og omkrystallisering fra metanol. k) Natriumsalt av l-[ 2-( 1, 2, 3, 4- tetrahydronaftyl( 1)- acetyl)-1, 2, 3, 4- tetrahydroisokinolin- 7- sulfonyl]- 3- cykloheksyl- urinstoff av 15,4 g 2-(1,2,3,4-tetrahydronaftyl(1)-acetyl)-1,2,3,4-tetrahydroisokinolin-7-sulfonamid og 5,0 g cykloheksylisocyanat. Utbytte: 10,0 g natriumsalt av sm.p. 268-270°C (spaltn.) (etanol). 1) . Natriumsalt av l-[ 2-( 3-( 5- klor- 2- metoksy- fenyl)- propionyl)-1, 2, 3, 4- tetrahydroisokinolin- 7- sulfonyl]- 3- cykloheksyl- urinstoff av 20,4 g 2-(3-(5-klor-2-metoksy-fenyl)-propionyl)-1,2,3,4-tetrahydroisokinolin-7-sulfonamid og 6,26 g cykloheksylisocyanat. Utbytte: 11,5 g natriumsalt som spaltes fra 270°C (etanol). m) Natriumsalt av l-[ 2-( indanvl( 1)- acetyl)- 1, 2, 3, 4- tetrahydroisokinolin- 7- sulfonyl]- 3- cykloheksyl- urinstoff av 11,1 g 2-(indanyl(l)-acetyl)-1,2,3,4-tetrahydroisokinolin-7-sulfonamid av sm.p. 160-165°C (spaltn.) og 3,76 g cykloheksylisocyanat. Utbytte: 6,4 g natriumsalt av sm.p. 273-276 C (spaltn.) (isopropanol/vann). n) Natriumsalt av l-[ 2-( 4- metyl- 3- fenyl- valeryl)- 1, 2, 3, 4- tetrahydroisokinolin- 7- sulfonyl]- 3- cykloheksyl- urinstoff av 11,6 g 2-(4-metyl-3-fenyl-valeryl)-l,2,3,4-tetrahydroisokinolin-7-sulfonamid av sm.p. 164-169°C og 3,7 g cykloheksylisocyanat. Utbytte: 4,9 g natriumsalt av sm.p. 253-259°C (etanol). j) Sodium salt of 1-[2-benzoylacetyl-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl]-3-cyclohexyl-urea from 1.88 g of 2-benzoylacetyl-1,2,3,4-tetrahydroisoquinoline- 7-sulfonamide of m.p. 151-153°C and 0.66 g of cyclohexyl isocyanate. Yield: 0.5 g sodium salt of m.p. 230-231°C (dec.) after column chromatography and recrystallization from methanol. k) Sodium salt of l-[ 2-( 1, 2, 3, 4- tetrahydronaphthyl( 1)- acetyl)-1, 2, 3, 4- tetrahydroisoquinoline- 7- sulfonyl]- 3- cyclohexyl- urea of 15.4 g of 2-(1,2,3,4-tetrahydronaphthyl(1)-acetyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide and 5.0 g of cyclohexyl isocyanate. Yield: 10.0 g sodium salt of m.p. 268-270°C (dec.) (ethanol). 1). Sodium salt of 1-[ 2-( 3-( 5- chloro- 2- methoxy- phenyl)- propionyl)-1, 2, 3, 4- tetrahydroisoquinoline- 7- sulfonyl]- 3- cyclohexyl- urea of 20.4 g 2-(3-(5-chloro-2-methoxy-phenyl)-propionyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide and 6.26 g of cyclohexyl isocyanate. Yield: 11.5 g of sodium salt which decomposes from 270°C (ethanol). m) Sodium salt of 1-[2-(indanyl(1)-acetyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl]-3-cyclohexyl- urea of 11.1 g of 2-(indanyl(1) -acetyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide of m.p. 160-165°C (dec.) and 3.76 g of cyclohexyl isocyanate. Yield: 6.4 g sodium salt of m.p. 273-276 C (dec.) (isopropanol/water). n) Sodium salt of 1-[ 2-( 4- methyl- 3- phenyl- valeryl)- 1, 2, 3, 4- tetrahydroisoquinoline- 7- sulfonyl]- 3- cyclohexyl- urea of 11.6 g of 2-(4 -methyl-3-phenyl-valeryl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide of m.p. 164-169°C and 3.7 g of cyclohexyl isocyanate. Yield: 4.9 g sodium salt of m.p. 253-259°C (ethanol).
o) Natriumsalt av 1- 12-( 2- p- fluorfenyl- propionyl)- 1, 2, 3, 4-tetrahydroisokinolin- 7- sulfonyl]- 3- cykloheksyl- urinstoff o) Sodium salt of 1- 12-( 2- p- fluorophenyl- propionyl)- 1, 2, 3, 4-tetrahydroisoquinoline- 7- sulfonyl]- 3- cyclohexyl- urea
av 3,99 g 2-(2-p-fluorfenyl-propionyl)-1,2,3,4-tetrahydroisokinolin-7-sulfonamid av sm.p. 165-169°C og 1,52 g cykloheksylisocyanat. Utbytte: 2,6 g natriumsalt av sm.p. 218-223°C (spaltn.) of 3.99 g of 2-(2-p-fluorophenyl-propionyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide of m.p. 165-169°C and 1.52 g of cyclohexyl isocyanate. Yield: 2.6 g sodium salt of m.p. 218-223°C (dec.)
(etanol). (ethanol).
p) Natriumsalt av l-[ 2-( 2-( 3, 4- diklorfenyl)- propionyl)- 1, 2, 3 , 4-tetrahydroisokinolin- 7- sulfonyl]- 3- cykloheksylurinstoff av 4,8 g 2-(2-(3,4-diklorfenyl)-propionyl)-1,2,3,4-tetrahydroisokinolin-7-sulfonamid av sm.p. 200-202°C og 1,59 g cykloheksylisocyanat. Utbytte: 2,47 g fargeløst natriumsalt av sm.p. 238-240°C (spaltn.) (metanol/benzen). q) Natriumsalt av l-[ 2-( 2- p- metylfenyl- propionyl)- 1, 2, 3, 4- tetrahydroisokinolin- 7- sulfonyl]- 3- cykloheksylurinstoff av 8,1 g 2-(2-p-metylfenyl-propionyl)-1,2,3,4-tetrahydroisokinolin-7-sulfonamid av sm.p. 165-168°C og 3,10 g cykloheksylisocyanat. Den som i eksempel 3 under tilsetning av cykloheksan frasentrifugerte utfelning omkrystalliseres straks fra etanol/ metanol. Man får 6,5 g fargeløst natriumsalt av sm.p. 233-235°C. p) Sodium salt of 1-[2-(2-(3,4-dichlorophenyl)-propionyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl]-3-cyclohexylurea of 4.8 g of 2-(2 -(3,4-dichlorophenyl)-propionyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide of m.p. 200-202°C and 1.59 g of cyclohexyl isocyanate. Yield: 2.47 g colorless sodium salt of m.p. 238-240°C (dec.) (methanol/benzene). q) Sodium salt of l-[ 2-( 2- p- methylphenyl- propionyl)- 1, 2, 3, 4- tetrahydroisoquinoline- 7- sulfonyl]- 3- cyclohexylurea from 8.1 g of 2-(2-p- methylphenyl) -propionyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide of m.p. 165-168°C and 3.10 g of cyclohexyl isocyanate. The precipitate that was centrifuged off in example 3 with the addition of cyclohexane is immediately recrystallized from ethanol/methanol. You get 6.5 g of colorless sodium salt of m.p. 233-235°C.
r) Natriumsalt av l-[ 2-( 2- p- trifluormetylfenyl- propionyl)- 1, 2, 3, 4-tetrahydroisokinolin- 7- sulfonyl]- 3- cykloheksyl- urinstoff r) Sodium salt of 1-[ 2-( 2- p- trifluoromethylphenyl- propionyl)- 1, 2, 3, 4-tetrahydroisoquinoline- 7- sulfonyl]- 3- cyclohexyl- urea
av 6,5 g viskøs 2-(2-p-trifluormetylfenyl-propionyl)-1,2,3,4-tetrahydroisokinolin-7-sulfonamid og 2,17 g cykloheksylisocyanat. Den frasentrifugerte utfelning rystes med 2n-HCl og kloroform. Kloroform-inndampningsresiduet renses ved søyle- of 6.5 g of viscous 2-(2-p-trifluoromethylphenyl-propionyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide and 2.17 g of cyclohexyl isocyanate. The centrifuged precipitate is shaken with 2n-HCl and chloroform. The chloroform evaporation residue is purified by column
kromatografi med kiselgel (cykloheksan: aceton: iseddik = 10: 5: 0,1). Man får 2,4 g skumaktig sulfonylurinstoff av hvilket man på vanlig måte fremstiller det fargeløse natriumsalt: sm.p. 224-227°C (spaltn.) (etanol og noe benzen). chromatography with silica gel (cyclohexane: acetone: glacial acetic acid = 10: 5: 0.1). 2.4 g of foamy sulphonylurea is obtained, from which the colorless sodium salt is prepared in the usual way: m.p. 224-227°C (dec.) (ethanol and some benzene).
s) Natriumsalt av l-[ 2-( 2- p- etoksyfenyl- propionyl)- 1, 2, 3, 4-tetrahydroisokinolin- 7- sulfonyl]- 3- cykloheksyl- urinstoff s) Sodium salt of l-[ 2-( 2- p- ethoxyphenyl- propionyl)- 1, 2, 3, 4-tetrahydroisoquinoline- 7- sulfonyl]- 3- cyclohexyl- urea
av 5,0 g skumaktig 2-(2-p-etoksyfenyl-propionyl)-1,2,3,4-tetrahydroisokinolin-7-sulfonamid og 1,77 g cykloheksylisocyanat. Etter reaksjonen tilsettes det 3- til 4-dobbelte volum absolutt eter og den lysegule utfelning avsuges. Ved omkrystallisering fra etanol/A-kull får man 6,0 g rått natriumsalt av sm.p. 220-224°c. of 5.0 g of foamy 2-(2-p-ethoxyphenyl-propionyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide and 1.77 g of cyclohexyl isocyanate. After the reaction, the 3- to 4-fold volume of absolute ether is added and the pale yellow precipitate is suctioned off. By recrystallization from ethanol/A-coal, 6.0 g of crude sodium salt of m.p. 220-224°c.
For rensing oppløser man i 2n-HCl og kloroform. Kloroform-inndampningsresiduet (5,7 g) kromatograferes som beskrevet i eksempel 3r og det erholdte skumaktige, fargeløse sulfonylurinstoff overføres i tilslutning hertil til natriumsalt. Utbytte: 1,18 g av sm.p. 224-226°C. For purification, dissolve in 2n-HCl and chloroform. The chloroform evaporation residue (5.7 g) is chromatographed as described in example 3r and the foamy, colorless sulphonylurea obtained is subsequently transferred to the sodium salt. Yield: 1.18 g of m.p. 224-226°C.
t) Natriumsalt av l-[ 2-( 2- p- n- propoksy- fenyl- propionyl)- 1, 2, 3, 4-tetrahydroiso' kinolin- 7- sulfonyl] - 3- cykloheksyl- urinstof f av 13,5 g skumaktig 2-(2-p-n-propoksy-fenyl-propionyl)-l,2,3,4-tetrahydroisokinolin-7-sulfonamid og 4,62 g cykloheksylisocyanat analogt med eksempel 3s. Man får det fargeløse sulfonylurinstoff med sm.p. 122-124°C (aceton/eter). og natriumsaltet med sm.p. 232-234°C u) Natriumsalt av l-[ 2-( 2- p- difenyl- propionyl)- 1, 2, 3, 4- tetrahydroisokinolin- 7- sulfonyl]- 3- cykloheksylurinstoff av 6,6 g 2-(2-p-difenyl-propionyl)-1,2,3,4-tetrahydroisokinolin-7-sulfonamid av sm.p. 188-192°C og 2,16 g cykloheksylisocyanat analogt med eksempel 3s. Man får 1,5 g fargeløst natriumsalt av sm.p. 245-250°C (spaltn.) v) Natriumsalt av l-[ 2-( 2-( a- naftyl)- propionyl)- 1, 2, 3, 4- tetra-hydroisoklnolin- 7- sulfonyl]- 3- cykloheksyl- urinstoff av 2,65 g 2-(2-(a-naftyl-propionyl)-1,2,3,4-tetrahydroisokinolin-7-sulfonamid av sm.p. 203-207°C og 0,93 g cykloheksylisocyanat analogt med eksempel 3q. Man omkrystalliserer den erholdte utfelning straks fra etanol/benzen flere ganger og man får 0,65 g fargeløst natriumsalt av sm.p. 263-265°C (spaltn.). w) 1-[ 3-( 2- p- bromfenyl- propionyl)- 2, 3, 4, 5- tetrahydro- lH- 3-benzazepin- 7- sulfonyl]- 3- cykloheksylurinstoff av 8,7 g skumaktig 3-(2-p-bromfenyl-propionyl)-2,3,4,5-tetrahydro-lH-3-benzazepin-7-sulfonamid og 2,74 g cykloheksylisocyanat. Etter reaksjonen tilsettes absolutt eter og den gul-aktige utfelning avsuges. Denne ryster man med 2n-HCl og kloroform Kloroform-inndampningsresiduet renses ved søylekromatografi med kiselgel (cykloheksan : aceton : iseddik = 30 : 10 : o,2) og bringer det fargeløse skumaktige sulfonylurinstoff til krystallisering ved utgniing med aceton/metyletylketon. Sm.p. 208-210°C (spaltn.). x) l-[ 3-( 2- p- klorfenyl- propionyl)- 2, 3, 4, 5- tetrahydro- lH- 3-benzazepin- 7- sulfonyl]- 3- cykloheksyl- urinstoff av 1,8 g skumaktig 3-(2-p-klorfenyl-propionyl)-2,3,4,5-tetrahydro-lH-3-benzazepin-7-sulfonamid og 0,63 g cykloheksylisocyanat analogt med eksempel 3w. Man får krystallinsk sulfonyl-urinstof f med sm.p. 205-207°C. t) Sodium salt of l-[2-(2-p-n-propoxy-phenyl-propionyl)-1,2,3,4-tetrahydroiso'quinoline-7-sulfonyl]-3-cyclohexyl-urea f of 13.5 g of foamy 2-(2-p-n-propoxy-phenyl-propionyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide and 4.62 g of cyclohexyl isocyanate analogous to example 3s. The colorless sulfonylurea is obtained with m.p. 122-124°C (acetone/ether). and the sodium salt with m.p. 232-234°C u) Sodium salt of l-[ 2-( 2- p- diphenyl- propionyl)- 1, 2, 3, 4- tetrahydroisoquinoline- 7- sulfonyl]- 3- cyclohexylurea of 6.6 g of 2-( 2-p-diphenyl-propionyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide of m.p. 188-192°C and 2.16 g of cyclohexyl isocyanate analogous to example 3s. You get 1.5 g of colorless sodium salt of m.p. 245-250°C (decomp.) v) Sodium salt of l-[ 2-( 2-( a-naphthyl)- propionyl)- 1, 2, 3, 4- tetra-hydroisoquinoline- 7- sulfonyl]- 3- cyclohexyl - urea of 2.65 g of 2-(2-(α-naphthyl-propionyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide of m.p. 203-207°C and 0.93 g of cyclohexyl isocyanate analogously with example 3q. The resulting precipitate is immediately recrystallized from ethanol/benzene several times and 0.65 g of colorless sodium salt is obtained, m.p. 263-265°C (dec.). w) 1-[ 3-( 2- p- bromophenyl- propionyl)- 2, 3, 4, 5- tetrahydro- 1H- 3-benzazepine- 7- sulfonyl]- 3- cyclohexylurea from 8.7 g of foamy 3-(2-p-bromophenyl- propionyl)-2 ,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonamide and 2.74 g of cyclohexyl isocyanate. After the reaction, absolute ether is added and the yellowish precipitate is filtered off. This is shaken with 2n-HCl and chloroform. The chloroform evaporation residue is purified by column chromatography with silica gel (cyclohexane : acetone : glacial acetic acid = 30 : 10 : o.2) and the colorless foamy sulfonylurea is brought to crystallization by trituration with acetone/methyl ethyl ketone. Sm.p. 208-210°C (dec.). x) l-[ 3-( 2- p- chlorophenyl- propionyl)- 2, 3, 4, 5- tetrahydro- 1H- 3-benzazepine- 7- sulfonyl]- 3- cyclohexyl- urea of 1.8 g foamy 3 -(2-p-chlorophenyl-propionyl)-2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonamide and 0.63 g of cyclohexyl isocyanate analogous to example 3w. Crystalline sulfonylurea f is obtained with m.p. 205-207°C.
Eksempel 4 Example 4
l-[ 2-( 3- fenylpropionyl)- 1, 2, 3, 4- tetrahydroisokinolin- 7- sulfonyl]-3-( 4- metylcykloheksyl)- urinstoff l-[ 2-( 3- phenylpropionyl)- 1, 2, 3, 4- tetrahydroisoquinoline- 7- sulfonyl]-3-( 4- methylcyclohexyl)- urea
4,0 g (9,6 mM) N-[2-(3-fenylpropionyl)-1,2,3,4-tetrahydroisokinolin-7-sulfonyl]-karbaminsyre-etylester av sm.p. 138-141°C og 1,02 g (10,2 mM) 4-metylcykloheksylamin (ca. 25% cis- og ca. 75% trans-isomer) opphetes i 5 ml dimetylformamid (destillert over P2 _05C) i 1 time til 100°C og 1/2 time til 120°C. Etter inndampning i vakuum opptas residuet i ln-saltsyre. Den uoppløselige del av- 4.0 g (9.6 mM) N-[2-(3-phenylpropionyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl]-carbamic acid ethyl ester of m.p. 138-141°C and 1.02 g (10.2 mM) 4-methylcyclohexylamine (approx. 25% cis- and approx. 75% trans-isomer) are heated in 5 ml of dimethylformamide (distilled over P2 _05C) for 1 hour to 100°C and 1/2 hour to 120°C. After evaporation in a vacuum, the residue is taken up in 1N hydrochloric acid. The insoluble part of the
suges, lufttørkes og omkrystalliseres fra eddikester. Utbytte: 1,5 g av sm.p. 155-158°C. is sucked, air-dried and recrystallized from acetic acid. Yield: 1.5 g of m.p. 155-158°C.
Eksempel 5 Example 5
Natriumsalt av l-[ 2-( 3- fenyl- propionyl)- 1, 2, 3, 4- tetrahydroisokinolin- 7- sulfonyl]- 3- cykloheptyl- urinstoff Sodium salt of 1-[2-(3-phenyl-propionyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl]-3-cycloheptyl-urea
4,17 g (10 mM) N-[2-(3-fenylpropionyl)-1,2,3,4-tetrahydroisokinolin-7-sulfonyl]-karbaminsyreetylester av sm.p. 138-141°C og 1,25 g (11 mM) cykloheptylamin opphetes i 5 ml vannfritt dimetylformamid i 1 time til 100°C og 1/2 time til 130°C. Etter inndampning i vakuum behandles residuet i varm etanol med A-kull. Til den filtrerte etanoliske oppløsning tilsettes 1 ekvivalent NaOH, oppløst i en minimal mengde vann, og det avkjøles. Man får 3,3 g natriumsalt av sm.p. 268-270°C (spaltn.). 4.17 g (10 mM) N-[2-(3-phenylpropionyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl]-carbamic acid ethyl ester of m.p. 138-141°C and 1.25 g (11 mM) of cycloheptylamine are heated in 5 ml of anhydrous dimethylformamide for 1 hour at 100°C and 1/2 hour at 130°C. After evaporation in a vacuum, the residue is treated in hot ethanol with A charcoal. To the filtered ethanolic solution is added 1 equivalent of NaOH, dissolved in a minimal amount of water, and it is cooled. You get 3.3 g of the sodium salt of m.p. 268-270°C (dec.).
På den samme måte fåes følgende forbindelser: In the same way, the following compounds are obtained:
a) Natriumsalt av l-[ 2-( 3- fenylpropionyl)- 1, 2, 3, 4- tetrahydroisokinolin- 7- sulfonyl]- 3- cyklooktyl- urinstoff av 4,17 g N-[2-(3-fenylpropionyl)-1,2,3,4-tetrahydroisokinolin-7-sulfonyl]-karbaminsyre-etylester av sm.p. 138-141°c og 1,40 g cyklooktylamin. Utbytte: 3,8 g natriumsalt av sm.p. 270-275°C (etanol). b) Natriumsalt av 1-[ 2-( 3- fenylpropionyl)- 1, 2, 3, 4- tetrahydroisokinolin- 7- sulfonyl]- 3- cyklopentyl- urinstoff av 4,17 g N-[2-(3-fenylpropionyl)-1,2,3,4-tetrahydroisokinolin-7-sulfonyl]-karbaminsyre-etylester av sm.p. 138-141°C og 1,40 g cyklopentylamin. Utbytte: 3,0 g natriumsalt av sm.p. 260-262°C (spaltn.) (etanol). a) Sodium salt of 1-[2-(3-phenylpropionyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl]-3- cyclooctyl-urea of 4.17 g of N-[2-(3-phenylpropionyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl]-carbamic acid ethyl ester of m.p. 138-141°c and 1.40 g of cyclooctylamine. Yield: 3.8 g sodium salt of m.p. 270-275°C (ethanol). b) Sodium salt of 1-[ 2-( 3-phenylpropionyl)- 1, 2, 3, 4- tetrahydroisoquinoline- 7- sulfonyl]- 3- cyclopentyl- urea of 4.17 g N-[2-(3-phenylpropionyl) -1,2,3,4-tetrahydroisoquinoline-7-sulfonyl]-carbamic acid ethyl ester of m.p. 138-141°C and 1.40 g of cyclopentylamine. Yield: 3.0 g sodium salt of m.p. 260-262°C (dec.) (ethanol).
c) Natriumsalt av l-[ 2-( 2- fenylpropionyl)- 1, 2, 3, 4- tetrahydroisokinolin- 7- sulfonyl]- 3-( 4- metylcykloheksyl)- urinstoff c) Sodium salt of 1-[2-(2-phenylpropionyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl]-3-(4-methylcyclohexyl)-urea
av 4,00 g N-[2-(2-fenylpropionyl)-1,2,3,4-tetrahydroisokinolin-7-sulfonyl]-karbaminsyre-etylester og 1,02 g 4-metylcykloheksylamin. Utbytte: 1,3 g natriumsalt av sm.p. 227- of 4.00 g of N-[2-(2-phenylpropionyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl]-carbamic acid ethyl ester and 1.02 g of 4-methylcyclohexylamine. Yield: 1.3 g sodium salt of m.p. 227-
228°C (etanol). 228°C (ethanol).
d) Natriumsalt av 1-[ 2-( 2- fenylpropionyl)- 1, 2, 3, 4- tetrahydroisokinolin- 7- sulfonylI- 3- adamantyl( 1)- urinstoff av 5,05 g N-[2-fenylpropionyl)-1,2,3,4-tetrahydroisokinolin-7-sulfonyl]-karbaminsyre-etylester, 2,50 g adamantyl-(1)-amin-hydroklorid og 1,35 g trietylamin. Utbytte: 0,8 g natriumsalt av sm.p. 225-229°C (etanol). e) Natriumsalt av l-[ 2-( 3- fenyl- butyryl)- 1, 2, 3, 4- tetrahydroisokinolin- 7- sulfonylI- 3-( 4- metyl- cykloheksyl)- urinstoff av 4,5 g N-[2-(3-fenyl-butyryl)-1,2,3,4-tetrahydroisokinoli: 7-sulfonyl]-karbaminsyre-etylester av sm.p. 105-108°c og 1,3 g 4-metylcykloheksylamin. Utbytte: 3,5 g natriumsalt av sm.p. 270-275°C (spaltn.) (etanol). f) Natriumsalt av l-[ 2-( 3- fenyl- butyryl)- 1, 2, 3, 4- tetrahydroisokinolin- 7- sulfonyl]- 3-( 4- etyl- cykloheksyl)- urinstoff av 4,5 g N-[2-(3-fenyl-butyryl)-1,2,3,4-tetrahydroisokinolin-7-sulfonyl]-karbaminsyre-etylester av sm.p. 105-108°C og 1,47 g 4-etylcykloheksylamin. Utbytte: 3,5 g natriumsalt av sm.p. 268-270°C (spaltn.) (etanol). g) Natriumsalt av 1-[ 2-( 3- fenyl- butyryl)- 1, 2, 3, 4- tetrahydroisokinolin- 7- sulfonyl]- 3- adamantyl( 1)- urinstoff av 4,5 g N-[2-(3-fenyl-butyryl)-1,2,3,4-tetrahydroisokinolin-7-sulfonyl]-karbaminsyre-etylester av sm.p. 105-108°c og 1,74 g adamantyl(1)-amin. Utbytte: 2,05 g natriumsalt av sm.p. 263-265°C (spaltn.) (etanol). d) Sodium salt of 1-[ 2-( 2- phenylpropionyl)- 1, 2, 3, 4- tetrahydroisoquinoline- 7- sulfonyl I- 3- adamantyl( 1)- urea of 5.05 g N-[2-phenylpropionyl)- 1,2,3,4-tetrahydroisoquinoline-7-sulfonyl]-carbamic acid ethyl ester, 2.50 g of adamantyl-(1)-amine hydrochloride and 1.35 g of triethylamine. Yield: 0.8 g sodium salt of m.p. 225-229°C (ethanol). e) Sodium salt of l-[2-(3-phenyl-butyryl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonylI-3-(4-methyl-cyclohexyl)-urea of 4.5 g N-[ 2-(3-phenyl-butyryl)-1,2,3,4-tetrahydroisoquinol: 7-sulfonyl]-carbamic acid ethyl ester of m.p. 105-108°c and 1.3 g of 4-methylcyclohexylamine. Yield: 3.5 g sodium salt of m.p. 270-275°C (dec.) (ethanol). f) Sodium salt of l-[2-(3-phenyl-butyryl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl]-3-(4-ethyl-cyclohexyl)-urea of 4.5 g N- [2-(3-phenyl-butyryl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl]-carbamic acid ethyl ester of m.p. 105-108°C and 1.47 g of 4-ethylcyclohexylamine. Yield: 3.5 g sodium salt of m.p. 268-270°C (dec.) (ethanol). g) Sodium salt of 1-[ 2-( 3- phenyl- butyryl)- 1, 2, 3, 4- tetrahydroisoquinoline- 7- sulfonyl]- 3- adamantyl( 1)- urea of 4.5 g N-[2- (3-phenyl-butyryl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl]-carbamic acid ethyl ester of m.p. 105-108°c and 1.74 g of adamantyl(1)-amine. Yield: 2.05 g sodium salt of m.p. 263-265°C (dec.) (ethanol).
h) Natriumsalt av l-[ 2-( 2- p- klorfenyl- propionyl)- 1, 2, 3, 4- tetrahydroisokinolin- 7- sulfonyl]- 3- cykloheksyl- urinstoff h) Sodium salt of l-[ 2-( 2- p- chlorophenyl- propionyl)- 1, 2, 3, 4- tetrahydroisoquinoline- 7- sulfonyl]- 3- cyclohexyl- urea
av 4,51 g glassaktig N-[2-(2-p-klorfenyl-propionyl)-1,2,3,4- of 4.51 g of glassy N-[2-(2-p-chlorophenyl-propionyl)-1,2,3,4-
tetrahydroisokinolin-7-sulfonyl]-karbaminsyre-etylester og 1,10 g cykloheksylamin. Utbytte: 0,8 g natriumsalt av sm.p. 228-230°C (spaltn.). tetrahydroisoquinoline-7-sulfonyl]-carbamic acid ethyl ester and 1.10 g of cyclohexylamine. Yield: 0.8 g sodium salt of m.p. 228-230°C (dec.).
Eksempel 6 Example 6
l-[ 2-( 2- p- klorfenyl- propionyl)- 1, 2, 3, 4- tetrahydroisokinolin- 7-sulfonylI- 3- cykloheksyl- urinstoff l-[ 2-( 2- p- chlorophenyl- propionyl)- 1, 2, 3, 4- tetrahydroisoquinoline- 7-sulfonyl I- 3- cyclohexyl- urea
En oppløsning av 4,23 g (11,2 mM) 2-(2-p-klorfenyl-propionyl) -1 , 2 , 3 , 4-tetrahydroisokinolin-7-sulfonamid av sm.p. 147-150°C og 1,26 g (11,2 mM) Kalium-tert.-butylat i 30 ml vannfritt dimetylformamid tilsettes ved 0° til +5°C dråpevis 1,50 g (11,2 mM) cykloheksylisocyanat. Det omrøres i 2 timer ved 0° til 5°C. Derpå filtreres og ansyres med 2n-HCl. Den utfelte smøraktige utfelning avsuges og oppløses i eddikester. Eddikesteroppløsninge.n vaskes med vann, tørkes over Na,,S04 og inndampningsresiduet kromatograferes med en kiselgelsøyle (cykloheksan : aceton : A solution of 4.23 g (11.2 mM) of 2-(2-p-chlorophenyl-propionyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide of m.p. 147-150°C and 1.26 g (11.2 mM) of potassium tert.-butylate in 30 ml of anhydrous dimethylformamide are added dropwise at 0° to +5°C 1.50 g (11.2 mM) of cyclohexyl isocyanate. It is stirred for 2 hours at 0° to 5°C. It is then filtered and acidified with 2n-HCl. The precipitated buttery precipitate is suctioned off and dissolved in vinegar. Acetic ester solutions are washed with water, dried over Na 2 SO 4 and the evaporation residue is chromatographed with a silica gel column (cyclohexane : acetone :
iseddik =40 : 20 : 0,4). Etter omkrystallisering fra eddikester/eter = 2/1 får man 3,4 g fargeløst urinstoff av sm.p. 110-115°C. glacial acetic acid =40 : 20 : 0.4). After recrystallization from ethyl acetate/ether = 2/1, 3.4 g of colorless urea of m.p. 110-115°C.
1,00 g (1,985 mM) av det ovenfor erholdte urinstoff av sm.p. 110-115°C oppløser man i 2 ml absolutt etanol under tilsetning av 1,985 ml ln-NaOH. Etter inndampning til tørrhet og tilsetning av benzen og aceton inntrer krystallisering. Man fra-suger den fargeløse utfelning, vasker med kald etanol, aceton og eter og tørker den ved 70°C/0,1 mm Hg. 1.00 g (1.985 mM) of the urea obtained above of m.p. 110-115°C dissolve in 2 ml of absolute ethanol while adding 1.985 ml of ln-NaOH. After evaporation to dryness and addition of benzene and acetone, crystallization occurs. The colorless precipitate is filtered off with suction, washed with cold ethanol, acetone and ether and dried at 70°C/0.1 mm Hg.
Utbytte: 1,0 g natriumsalt av sm.p. 227-231 C (spaltn.). Yield: 1.0 g sodium salt of m.p. 227-231 C (dec.).
På den samme måte fremstilles følgende forbindelse : In the same way, the following compound is produced:
a) Natriumsalt av l-[ 2-( 2- p- bromfenyl- propionyl)- 1, 2, 3, 4- tetrahydroisokinolin- 7- sulfonyl]- 3- cykloheksyl- urinstoff a) Sodium salt of l-[ 2-( 2- p- bromophenyl- propionyl)- 1, 2, 3, 4- tetrahydroisoquinoline- 7- sulfonyl]- 3- cyclohexyl- urea
av 5,20 g 2-(2-p-bromfenyl-propionyl)-1,2,3,4-tetrahydroisokinolin-7-sulfonamid av sm.p. 146-148°C og 3,70 g cykloheksylisocyanat . of 5.20 g of 2-(2-p-bromophenyl-propionyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide of m.p. 146-148°C and 3.70 g of cyclohexyl isocyanate.
Utbytte: 1,68 g fargeløst natriumsalt av sm.p. 222-225 C. Yield: 1.68 g colorless sodium salt of m.p. 222-225 C.
Sm.p. av det frie sulfonylurinstoff: 109-112 C Sm.p. of the free sulfonylurea: 109-112 C
FORSØKSRAPPORT TRIAL REPORT
Natriumsaltene av forbindelsene The sodium salts of the compounds
A = l-[2-(2-fenyl-propionyl)-1,2,3,4-tetrahydroisokinolin-7-sulfonyl]-3-cykloheksylurinstoff, A = 1-[2-(2-phenyl-propionyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl]-3-cyclohexylurea,
B = l-[2-; (2-p-klorf enyl— propionyl)-1, 2 , 3 ,4-tetrahydroisokinolin—7-sulfonyl]-3-cykloheksylurinstoff, B = 1-[2-; (2-p-chlorophenyl-propionyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl]-3-cyclohexylurea,
C = l-[2-(2-p-bromfenyl^propionyl)-1,2,3,4-tetrahydroisokinolin-7-sulfonyl]-3-cykloheksylurinstoff, C = 1-[2-(2-p-bromophenyl^propionyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl]-3-cyclohexylurea,
D = l-[2-(2-p-metylfenyl-propionyl)-1,2,3,4-tetrahydroisokinolin-7-sulfonyl]-3-cykloheksylurinstoff, D = 1-[2-(2-p-methylphenyl-propionyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl]-3-cyclohexylurea,
E = l-[2-(2-p-trifluormetylfenyl-propionyl)-1,2,3,4-tetrahydroisokinolin -7 -sulf onyl ] -3-cykloheksylurinstof f, E = 1-[2-(2-p-trifluoromethylphenyl-propionyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl]-3-cyclohexylurea f,
F = l-[2-(2-fenylpropionyl)-1,2 3,4-tetrahydroisokinolin-7-sulfonyl]-3-(4-metylcykloheksyl)-urinstoff, F = 1-[2-(2-phenylpropionyl)-1,2 3,4-tetrahydroisoquinoline-7-sulfonyl]-3-(4-methylcyclohexyl)-urea,
G = l-[2-(2-fenylpropionyl)-1,2,3,4-tetrahydroisokinolin-7-sulfonyl]-3-adamantyl-(1)-urinstoff, G = 1-[2-(2-phenylpropionyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl]-3-adamantyl-(1)-urea,
H = l-[2-(3-fenylpropionyl)-1,2,3,4-tetrahydroisokinolin-7-sulfonyl]-3-(4:-metylcykloheksyl) -urinstoff, H = 1-[2-(3-phenylpropionyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl]-3-(4:-methylcyclohexyl)-urea,
I = l-[2-(3-fenylbutyryl)-1,2,3,4-tetrahydroisokinolin-7-sulfonyl]-3-, cykloheksylurinstoff, I = 1-[2-(3-phenylbutyryl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl]-3-, cyclohexylurea,
J .ss l-[ 2-(3-fenylbutyryl) -1, 2 , 3 , 4-tetrahydroisokinolin-7-sulfonyl ]-3-(4-metylcykloheksyl)-urinstoff, J .ss 1-[2-(3-phenylbutyryl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl]-3-(4-methylcyclohexyl)-urea,
K = l-[2-(4-metyl-3-fenylvaleryl)-1,2,3,4-tetrahydroisokinolin-7-sulfonyl]-3-cykloheksylurinstoff, og K = 1-[2-(4-methyl-3-phenylvaleryl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl]-3-cyclohexylurea, and
L = l-[2-benzoylacetyl-l,2,3,4-tetrahydroisokinolin-7-sulfonyl]-3-cykloheksylurinstoff, L = 1-[2-benzoylacetyl-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl]-3-cyclohexylurea,
ble undersøkt med hensyn til sin blodtrykksenkende virkning sammen-lignet med natriumsaltet av was investigated with regard to its blood pressure-lowering effect compared to the sodium salt of
M = N-(4-klorbenzensulfonyl)-N'-n-propyl-urinstoff. M = N-(4-chlorobenzenesulfonyl)-N'-n-propylurea.
Efter oral administrering ble den maksimale blodtrykksenkning ( i pro-sent) bestemt på hanrotter (foret) med en gjennomsnittlig kroppsvekt på 180 g. Natriumsaltet av forbindelsene A-M ble suspendert i metyl-cellulose, administrert pr. oralt med spiserørsonde, og blodprøver ble tatt hver time fra halen (20 ^ul pr. prøve) for blodsukkerbestem-melse. After oral administration, the maximum blood pressure reduction (in percent) was determined in male rats (fed) with an average body weight of 180 g. The sodium salt of the compounds A-M was suspended in methyl cellulose, administered per orally with an oesophageal tube, and blood samples were taken every hour from the tail (20 µl per sample) for blood sugar determination.
Bestemmelsen av glukoseinnholdet ble foretatt automatisk på en så-kalt Technico-Autqanalyzer (se.U. Harding og G. Heinzel, Zeitschrift f. klin. Chem. u. klin. Biochem. 7, 640 til 643 [1969] ved heksokin-asemetoden (fosforylering av glukosen med ATP til glukose-6-fosfat, derefter reduksjon med glukose-6-fosfatdehydrogenase til glukonat-6-fosfat, og måling av det samtidig fra NADP dannede NADPH2 ble foretatt fotometrisk ved 334 mu). The determination of the glucose content was made automatically on a so-called Technico-Autqanalyzer (see U. Harding and G. Heinzel, Zeitschrift f. klin. Chem. u. klin. Biochem. 7, 640 to 643 [1969] by the hexokinase method (phosphorylation of the glucose with ATP to glucose-6-phosphate, then reduction with glucose-6-phosphate dehydrogenase to gluconate-6-phosphate, and measurement of the NADPH2 formed simultaneously from NADP was carried out photometrically at 334 mu).
Den akutte intravenøse toksisitet av natriumsaltene av forbindelsene A-M ble bestemt på grupper på hver 10 hvite, voksne mus av egen The acute intravenous toxicity of the sodium salts of the compounds A-M was determined on groups of 10 white adult mice each by separate
avl med en kroppsvekt på 18-25 g. Herunder ble forbindelsene administrert til dyr som hadde fastet i 16 timer. Hver forbindelse ble undersøkt i minst 4 doseringer med 10 dyr pr. dose. For dette for-mål ble natriumsaltene oppløst i 0,01 n-natronlut og injisert i halevenen. LD 50, den dose som førte til at 50% av dyrene døde innen 7 dager efter den intravenøse administrering, ble bestemt ved me-toden ifølge Lichtfield og Wilcoxon. breeding with a body weight of 18-25 g. Herein, the compounds were administered to animals that had fasted for 16 hours. Each compound was examined in at least 4 dosages with 10 animals per dose. For this purpose, the sodium salts were dissolved in 0.01 n sodium hydroxide solution and injected into the tail vein. The LD 50 , the dose which caused 50% of the animals to die within 7 days of the intravenous administration, was determined by the method of Lichtfield and Wilcoxon.
Den følgende tabell inneholder de fundne verdier: The following table contains the values found:
Claims (6)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19691933388 DE1933388A1 (en) | 1969-07-01 | 1969-07-01 | New sulfonylureas and processes for their preparation |
| DE19702027436 DE2027436A1 (en) | 1970-06-04 | 1970-06-04 | Sulphenylurea cpds, hypoglycaemics |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| NO132094B true NO132094B (en) | 1975-06-09 |
| NO132094C NO132094C (en) | 1975-09-17 |
Family
ID=25757577
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO2575/70A NO132094C (en) | 1969-07-01 | 1970-06-30 |
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| AT (1) | AT301568B (en) |
| BE (1) | BE752760A (en) |
| BG (1) | BG18181A1 (en) |
| CH (1) | CH536842A (en) |
| DK (1) | DK127928B (en) |
| ES (2) | ES381248A1 (en) |
| FI (1) | FI49828C (en) |
| FR (1) | FR2059465B1 (en) |
| GB (1) | GB1313539A (en) |
| IE (1) | IE34359B1 (en) |
| IL (1) | IL34820A (en) |
| NL (1) | NL7009704A (en) |
| NO (1) | NO132094C (en) |
| PL (1) | PL81112B1 (en) |
| RO (1) | RO56857A (en) |
| SE (1) | SE357745B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001087834A1 (en) * | 2000-05-16 | 2001-11-22 | Takeda Chemical Industries, Ltd. | Melanin-concentrating hormone antagonist |
-
1970
- 1970-06-17 FI FI701712A patent/FI49828C/en active
- 1970-06-24 SE SE08771/70A patent/SE357745B/xx unknown
- 1970-06-25 RO RO63739A patent/RO56857A/ro unknown
- 1970-06-26 BG BG16831A patent/BG18181A1/xx unknown
- 1970-06-27 ES ES381248A patent/ES381248A1/en not_active Expired
- 1970-06-29 CH CH982470A patent/CH536842A/en not_active IP Right Cessation
- 1970-06-30 GB GB3172270A patent/GB1313539A/en not_active Expired
- 1970-06-30 AT AT586870A patent/AT301568B/en not_active IP Right Cessation
- 1970-06-30 IE IE856/70A patent/IE34359B1/en unknown
- 1970-06-30 IL IL34820A patent/IL34820A/en unknown
- 1970-06-30 BE BE752760D patent/BE752760A/en unknown
- 1970-06-30 DK DK338970AA patent/DK127928B/en unknown
- 1970-06-30 PL PL1970141708A patent/PL81112B1/en unknown
- 1970-06-30 NO NO2575/70A patent/NO132094C/no unknown
- 1970-07-01 NL NL7009704A patent/NL7009704A/xx unknown
- 1970-07-01 FR FR7024368A patent/FR2059465B1/fr not_active Expired
-
1971
- 1971-07-19 ES ES393416A patent/ES393416A1/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| BG18181A1 (en) | 1974-09-02 |
| PL81112B1 (en) | 1975-08-30 |
| FR2059465B1 (en) | 1974-03-22 |
| IL34820A (en) | 1973-08-29 |
| GB1313539A (en) | 1973-04-11 |
| SE357745B (en) | 1973-07-09 |
| DK127928B (en) | 1974-02-04 |
| CH536842A (en) | 1973-05-15 |
| NL7009704A (en) | 1971-01-05 |
| FI49828B (en) | 1975-06-30 |
| RO56857A (en) | 1974-12-15 |
| BE752760A (en) | 1970-12-30 |
| NO132094C (en) | 1975-09-17 |
| IE34359B1 (en) | 1975-04-16 |
| ES381248A1 (en) | 1972-11-01 |
| IL34820A0 (en) | 1970-09-17 |
| FR2059465A1 (en) | 1971-06-04 |
| AT301568B (en) | 1972-09-11 |
| IE34359L (en) | 1971-01-01 |
| ES393416A1 (en) | 1974-06-01 |
| FI49828C (en) | 1975-10-10 |
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